Somatization is the experience of psychological distress in the form of bodily symptoms. Somatic symptom and related disorders frequently prompt psychiatric consultation. Patients with suspected somatization disorders might resist psychiatric intervention, therefore modified approaches to the initial interview are helpful. Here I present an approach to such resistance.

Collecting a detailed history of physical symptoms can help the patient feel that you are listening to him (her) and that the chief concern is important. A detailed review of psychiatric symptoms (eg, hallucinations, paranoia, suicidality, etc.) should be deferred until later in the examination. Asking questions relating to psychiatric symptoms early could lead to further resistance by reinforcing negative preconceptions that the patient might have regarding mental illness.

Explicitly express empathy regarding physical symptoms throughout the interview to acknowledge any real suffering the patient is experiencing and to contradict any notion that psychiatric evaluation implies that the suffering could be imaginary.

Ask, “How has this illness affected your life?” This question helps make the connection between the patient’s physical state and social milieu. If somatization is confirmed, then the provider should assist the patient in reversing the arrow of causation. Although the ultimate goal is for the patient to understand how his (her) life has affected the symptoms, simply understanding that there are connections between the two is a start toward this goal.¹

Explore the response to the previous question. Expand upon it to elicit a detailed social history, listening for any social stressors.

Obtain family and personal histories of allergies, substance abuse, and medical or psychiatric illness.

Review psychiatric symptoms. Make questions less jarring² by adapting them to the patient’s situation, such as “Has your illness become so painful that at times you don’t even want to live?”

Perform cognitive and physical examinations. Conducting a physical examination could further reassure the patient that you are not ignoring physical complaints.

Educate the patient that the mind and body are connected and emotions affect how one feels physically. Use examples, such as “When I feel anxious, my heart beats faster” or “A headache might hurt more at work than at the beach.”

Elicit feedback and questions from the patient.

Discuss your treatment plan with the patient. Resistant patients with confirmed somatization disorders might accept psychiatric care as a means of dealing with the stress or pain of their physical symptoms.

Consider asking:

• What would you be doing if you weren’t in the hospital right now?
• Aside from your health, what’s the biggest challenge in your life?
• Everything has a good side and a bad side. Is there anything positive about dealing with your illness? Providing the patient with an example of negative aspects of a good thing (such as the calories in ice cream, the high cost of gold, etc.) can help make this point.
• What would your life look like if you didn’t have these symptoms?

Somatization is the experience of psychological distress in the form of bodily symptoms. Somatic symptom and related disorders frequently prompt psychiatric consultation. Patients with suspected somatization disorders might resist psychiatric intervention, therefore modified approaches to the initial interview are helpful. Here I present an approach to such resistance.

Collecting a detailed history of physical symptoms can help the patient feel that you are listening to him (her) and that the chief concern is important. A detailed review of psychiatric symptoms (eg, hallucinations, paranoia, suicidality, etc.) should be deferred until later in the examination. Asking questions relating to psychiatric symptoms early could lead to further resistance by reinforcing negative preconceptions that the patient might have regarding mental illness.

Explicitly express empathy regarding physical symptoms throughout the interview to acknowledge any real suffering the patient is experiencing and to contradict any notion that psychiatric evaluation implies that the suffering could be imaginary.

Ask, “How has this illness affected your life?” This question helps make the connection between the patient’s physical state and social milieu. If somatization is confirmed, then the provider should assist the patient in reversing the arrow of causation. Although the ultimate goal is for the patient to understand how his (her) life has affected the symptoms, simply understanding that there are connections between the two is a start toward this goal.¹

Explore the response to the previous question. Expand upon it to elicit a detailed social history, listening for any social stressors.

Obtain family and personal histories of allergies, substance abuse, and medical or psychiatric illness.

Review psychiatric symptoms. Make questions less jarring² by adapting them to the patient’s situation, such as “Has your illness become so painful that at times you don’t even want to live?”

Perform cognitive and physical examinations. Conducting a physical examination could further reassure the patient that you are not ignoring physical complaints.

Educate the patient that the mind and body are connected and emotions affect how one feels physically. Use examples, such as “When I feel anxious, my heart beats faster” or “A headache might hurt more at work than at the beach.”

Elicit feedback and questions from the patient.

Discuss your treatment plan with the patient. Resistant patients with confirmed somatization disorders might accept psychiatric care as a means of dealing with the stress or pain of their physical symptoms.

Consider asking:

• What would you be doing if you weren’t in the hospital right now?
• Aside from your health, what’s the biggest challenge in your life?
• Everything has a good side and a bad side. Is there anything positive about dealing with your illness? Providing the patient with an example of negative aspects of a good thing (such as the calories in ice cream, the high cost of gold, etc.) can help make this point.
• What would your life look like if you didn’t have these symptoms?

Somatization is the experience of psychological distress in the form of bodily symptoms. Somatic symptom and related disorders frequently prompt psychiatric consultation. Patients with suspected somatization disorders might resist psychiatric intervention, therefore modified approaches to the initial interview are helpful. Here I present an approach to such resistance.

Collecting a detailed history of physical symptoms can help the patient feel that you are listening to him (her) and that the chief concern is important. A detailed review of psychiatric symptoms (eg, hallucinations, paranoia, suicidality, etc.) should be deferred until later in the examination. Asking questions relating to psychiatric symptoms early could lead to further resistance by reinforcing negative preconceptions that the patient might have regarding mental illness.

Explicitly express empathy regarding physical symptoms throughout the interview to acknowledge any real suffering the patient is experiencing and to contradict any notion that psychiatric evaluation implies that the suffering could be imaginary.

Ask, “How has this illness affected your life?” This question helps make the connection between the patient’s physical state and social milieu. If somatization is confirmed, then the provider should assist the patient in reversing the arrow of causation. Although the ultimate goal is for the patient to understand how his (her) life has affected the symptoms, simply understanding that there are connections between the two is a start toward this goal.¹

Explore the response to the previous question. Expand upon it to elicit a detailed social history, listening for any social stressors.

Obtain family and personal histories of allergies, substance abuse, and medical or psychiatric illness.

Review psychiatric symptoms. Make questions less jarring² by adapting them to the patient’s situation, such as “Has your illness become so painful that at times you don’t even want to live?”

Perform cognitive and physical examinations. Conducting a physical examination could further reassure the patient that you are not ignoring physical complaints.

Educate the patient that the mind and body are connected and emotions affect how one feels physically. Use examples, such as “When I feel anxious, my heart beats faster” or “A headache might hurt more at work than at the beach.”

Elicit feedback and questions from the patient.

Discuss your treatment plan with the patient. Resistant patients with confirmed somatization disorders might accept psychiatric care as a means of dealing with the stress or pain of their physical symptoms.

Consider asking:

• What would you be doing if you weren’t in the hospital right now?
• Aside from your health, what’s the biggest challenge in your life?
• Everything has a good side and a bad side. Is there anything positive about dealing with your illness? Providing the patient with an example of negative aspects of a good thing (such as the calories in ice cream, the high cost of gold, etc.) can help make this point.
• What would your life look like if you didn’t have these symptoms?

Acupuncture is an ancient therapeutic tool known to be the core of traditional Chinese medicine. Two theories suggest positive outcomes in patients treated with acupuncture:

• The oxidative stress reduction theory states that a “large body of evidences demonstrated that acupuncture has [an] antioxidative effect in various diseases, but the exact mechanism remains unclear.”¹
• The neurophysiological theory states that “acupuncture stimulation can facilitate the release of certain neuropeptides in the CNS, eliciting profound physiological effects and even activating self-healing mechanisms.”²

For decades, acupuncture has been used for addiction management. Here we provide information on its utility for patients with substance use disorders.

Opioid use disorder. Multiple studies have looked at withdrawal, comorbid mood disorders, and its management with acupuncture alone or in combination with psychotherapy and/or opioid agonists. Studies from Asia reported good treatment outcomes but had low-method quality.³ Western studies had superior method quality but found that acupuncture was no better than placebo as monotherapy. When acupuncture is combined with psychotherapy and an opioid agonist, treatment results are promising, showing faster taper of medications (methadone and buprenorphine/naloxone) with fewer adverse effects.

Cocaine use disorder. Most studies had poor treatment outcomes of acupuncture over placebo and were of low quality. A number of small studies were promising and found that patients treated with acupuncture were most likely to have a negative urine drug screen.³ Although acupuncture is widely used in the United States to treat cocaine dependence, evidence does not confirm its efficacy.

Tobacco use disorder. A small group of studies favored acupuncture for smoking cessation.³ Other studies reported no benefit compared with placebo or neutral results. Some studies agreed that any intervention (acupuncture or sham acupuncture) with good results is better than no intervention at all.

Alcohol use disorder. Almost no advantage over placebo was found. Studies with significant findings were in small populations.³

Amphetamine, Cannabis, and other hallucinogen use disorders. Available data on stimulants were too limited to be relevant. No studies were found on Cannabis and hallucinogens.

Further studies are needed

There is a lack of conclusive, good quality studies supporting acupuncture’s benefits in treating substance abuse. Acupuncture has been known to lack adverse effects other than those related to needle manipulation, which is dependent on the methods (depth of needle insertion, accurate anatomical location, angle, etc.). Because this treatment option is virtually side-effect free, inexpensive, with positive synergistic results, more high-method quality studies are needed to consider it for our patients.

Acupuncture is an ancient therapeutic tool known to be the core of traditional Chinese medicine. Two theories suggest positive outcomes in patients treated with acupuncture:

• The oxidative stress reduction theory states that a “large body of evidences demonstrated that acupuncture has [an] antioxidative effect in various diseases, but the exact mechanism remains unclear.”¹
• The neurophysiological theory states that “acupuncture stimulation can facilitate the release of certain neuropeptides in the CNS, eliciting profound physiological effects and even activating self-healing mechanisms.”²

For decades, acupuncture has been used for addiction management. Here we provide information on its utility for patients with substance use disorders.

Opioid use disorder. Multiple studies have looked at withdrawal, comorbid mood disorders, and its management with acupuncture alone or in combination with psychotherapy and/or opioid agonists. Studies from Asia reported good treatment outcomes but had low-method quality.³ Western studies had superior method quality but found that acupuncture was no better than placebo as monotherapy. When acupuncture is combined with psychotherapy and an opioid agonist, treatment results are promising, showing faster taper of medications (methadone and buprenorphine/naloxone) with fewer adverse effects.

Cocaine use disorder. Most studies had poor treatment outcomes of acupuncture over placebo and were of low quality. A number of small studies were promising and found that patients treated with acupuncture were most likely to have a negative urine drug screen.³ Although acupuncture is widely used in the United States to treat cocaine dependence, evidence does not confirm its efficacy.

Tobacco use disorder. A small group of studies favored acupuncture for smoking cessation.³ Other studies reported no benefit compared with placebo or neutral results. Some studies agreed that any intervention (acupuncture or sham acupuncture) with good results is better than no intervention at all.

Alcohol use disorder. Almost no advantage over placebo was found. Studies with significant findings were in small populations.³

Amphetamine, Cannabis, and other hallucinogen use disorders. Available data on stimulants were too limited to be relevant. No studies were found on Cannabis and hallucinogens.

Further studies are needed

There is a lack of conclusive, good quality studies supporting acupuncture’s benefits in treating substance abuse. Acupuncture has been known to lack adverse effects other than those related to needle manipulation, which is dependent on the methods (depth of needle insertion, accurate anatomical location, angle, etc.). Because this treatment option is virtually side-effect free, inexpensive, with positive synergistic results, more high-method quality studies are needed to consider it for our patients.

Acupuncture is an ancient therapeutic tool known to be the core of traditional Chinese medicine. Two theories suggest positive outcomes in patients treated with acupuncture:

• The oxidative stress reduction theory states that a “large body of evidences demonstrated that acupuncture has [an] antioxidative effect in various diseases, but the exact mechanism remains unclear.”¹
• The neurophysiological theory states that “acupuncture stimulation can facilitate the release of certain neuropeptides in the CNS, eliciting profound physiological effects and even activating self-healing mechanisms.”²

For decades, acupuncture has been used for addiction management. Here we provide information on its utility for patients with substance use disorders.

Opioid use disorder. Multiple studies have looked at withdrawal, comorbid mood disorders, and its management with acupuncture alone or in combination with psychotherapy and/or opioid agonists. Studies from Asia reported good treatment outcomes but had low-method quality.³ Western studies had superior method quality but found that acupuncture was no better than placebo as monotherapy. When acupuncture is combined with psychotherapy and an opioid agonist, treatment results are promising, showing faster taper of medications (methadone and buprenorphine/naloxone) with fewer adverse effects.

Cocaine use disorder. Most studies had poor treatment outcomes of acupuncture over placebo and were of low quality. A number of small studies were promising and found that patients treated with acupuncture were most likely to have a negative urine drug screen.³ Although acupuncture is widely used in the United States to treat cocaine dependence, evidence does not confirm its efficacy.

Tobacco use disorder. A small group of studies favored acupuncture for smoking cessation.³ Other studies reported no benefit compared with placebo or neutral results. Some studies agreed that any intervention (acupuncture or sham acupuncture) with good results is better than no intervention at all.

Alcohol use disorder. Almost no advantage over placebo was found. Studies with significant findings were in small populations.³

Amphetamine, Cannabis, and other hallucinogen use disorders. Available data on stimulants were too limited to be relevant. No studies were found on Cannabis and hallucinogens.

Further studies are needed

There is a lack of conclusive, good quality studies supporting acupuncture’s benefits in treating substance abuse. Acupuncture has been known to lack adverse effects other than those related to needle manipulation, which is dependent on the methods (depth of needle insertion, accurate anatomical location, angle, etc.). Because this treatment option is virtually side-effect free, inexpensive, with positive synergistic results, more high-method quality studies are needed to consider it for our patients.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has unveiled a plan to eliminate the agency’s existing backlog of orphan designation requests and ensure timely responses to all new requests with firm deadlines.

The agency’s Orphan Drug Modernization Plan comes a week after FDA Commissioner Scott Gottlieb committed to eliminating the backlog within 90 days and responding to all new requests for designation within 90 days of receipt during his testimony before a Senate subcommittee.

As authorized under the Orphan Drug Act, the Orphan Drug Designation Program provides orphan status to drugs and biologics intended for the treatment, diagnosis, or prevention of rare diseases, which are generally defined as diseases that affect fewer than 200,000 people in the US.

Orphan designation qualifies a product’s developer for various development incentives, including tax credits for clinical trial costs, relief from prescription drug user fee if the indication is for a rare disease or condition, and eligibility for 7 years of marketing exclusivity if the product is approved.

A request for orphan designation is one step that can be taken in the development process and is different than the filing of a marketing application with the FDA.

Currently, the FDA has about 200 orphan drug designation requests that are pending review. The number of orphan drug designation requests has steadily increased over the past 5 years.

In 2016, the FDA’s Office of Orphan Products Development received 568 new requests for designation – more than double the number of requests received in 2012.

The FDA says this increased interest in the program is a positive development for patients with rare diseases, and, with the Orphan Drug Modernization Plan, the FDA is committing to advancing the program to ensure it can efficiently and adequately review these requests.

“People who suffer with rare diseases are too often faced with no or limited treatment options, and what treatment options they have may be quite expensive due, in part, to significant costs of developing therapies for smaller populations,” said FDA Commissioner Scott Gottlieb, MD.

“Congress gave us tools to incentivize the development of novel therapies for rare diseases, and we intend to use these resources to their fullest extent in order to ensure Americans get the safe and effective medicines they need, and that the process for developing these innovations is as modern and efficient as possible.”

Among the elements of the Orphan Drug Modernization Plan, the FDA will deploy a Backlog SWAT team comprised of senior, experienced reviewers with significant expertise in orphan drug designation. The team will focus solely on the backlogged applications, starting with the oldest requests.

The agency will also employ a streamlined Designation Review Template to increase consistency and efficiency of its reviews.

In addition, the Orphan Drug Designation Program will look to collaborate within the agency’s medical product centers to create greater efficiency, including conducting joint reviews with the Office of Pediatric Therapeutics to review rare pediatric disease designation requests.

To ensure all future requests receive a response within 90 days of receipt, the FDA will take a multifaceted approach.

These efforts include, among other new steps:

• Reorganizing the review staff to maximize expertise and improve workload efficiencies
• Better leveraging the expertise across the FDA’s medical product centers
• Establishing a new FDA Orphan Products Council that will help address scientific and regulatory issues to ensure the agency is applying a consistent approach to regulating orphan drug products and reviewing designation requests.

The FDA is planning for the backlog to be eliminated by mid-September.

The Orphan Drug Modernization Plan is the first element of several efforts the FDA plans to undertake under its new “Medical Innovation Development Plan,” which is aimed at ensuring the FDA’s regulatory tools and policies are modern, risk-based, and efficient.

The goal of the plan is to seek ways the FDA can help facilitate the development of safe, effective, and transformative medical innovations that have the potential to significantly impact disease and reduce overall healthcare costs.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has unveiled a plan to eliminate the agency’s existing backlog of orphan designation requests and ensure timely responses to all new requests with firm deadlines.

The agency’s Orphan Drug Modernization Plan comes a week after FDA Commissioner Scott Gottlieb committed to eliminating the backlog within 90 days and responding to all new requests for designation within 90 days of receipt during his testimony before a Senate subcommittee.

As authorized under the Orphan Drug Act, the Orphan Drug Designation Program provides orphan status to drugs and biologics intended for the treatment, diagnosis, or prevention of rare diseases, which are generally defined as diseases that affect fewer than 200,000 people in the US.

Orphan designation qualifies a product’s developer for various development incentives, including tax credits for clinical trial costs, relief from prescription drug user fee if the indication is for a rare disease or condition, and eligibility for 7 years of marketing exclusivity if the product is approved.

A request for orphan designation is one step that can be taken in the development process and is different than the filing of a marketing application with the FDA.

Currently, the FDA has about 200 orphan drug designation requests that are pending review. The number of orphan drug designation requests has steadily increased over the past 5 years.

In 2016, the FDA’s Office of Orphan Products Development received 568 new requests for designation – more than double the number of requests received in 2012.

The FDA says this increased interest in the program is a positive development for patients with rare diseases, and, with the Orphan Drug Modernization Plan, the FDA is committing to advancing the program to ensure it can efficiently and adequately review these requests.

“People who suffer with rare diseases are too often faced with no or limited treatment options, and what treatment options they have may be quite expensive due, in part, to significant costs of developing therapies for smaller populations,” said FDA Commissioner Scott Gottlieb, MD.

“Congress gave us tools to incentivize the development of novel therapies for rare diseases, and we intend to use these resources to their fullest extent in order to ensure Americans get the safe and effective medicines they need, and that the process for developing these innovations is as modern and efficient as possible.”

Among the elements of the Orphan Drug Modernization Plan, the FDA will deploy a Backlog SWAT team comprised of senior, experienced reviewers with significant expertise in orphan drug designation. The team will focus solely on the backlogged applications, starting with the oldest requests.

The agency will also employ a streamlined Designation Review Template to increase consistency and efficiency of its reviews.

In addition, the Orphan Drug Designation Program will look to collaborate within the agency’s medical product centers to create greater efficiency, including conducting joint reviews with the Office of Pediatric Therapeutics to review rare pediatric disease designation requests.

To ensure all future requests receive a response within 90 days of receipt, the FDA will take a multifaceted approach.

These efforts include, among other new steps:

• Reorganizing the review staff to maximize expertise and improve workload efficiencies
• Better leveraging the expertise across the FDA’s medical product centers
• Establishing a new FDA Orphan Products Council that will help address scientific and regulatory issues to ensure the agency is applying a consistent approach to regulating orphan drug products and reviewing designation requests.

The FDA is planning for the backlog to be eliminated by mid-September.

The Orphan Drug Modernization Plan is the first element of several efforts the FDA plans to undertake under its new “Medical Innovation Development Plan,” which is aimed at ensuring the FDA’s regulatory tools and policies are modern, risk-based, and efficient.

The goal of the plan is to seek ways the FDA can help facilitate the development of safe, effective, and transformative medical innovations that have the potential to significantly impact disease and reduce overall healthcare costs.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has unveiled a plan to eliminate the agency’s existing backlog of orphan designation requests and ensure timely responses to all new requests with firm deadlines.

The agency’s Orphan Drug Modernization Plan comes a week after FDA Commissioner Scott Gottlieb committed to eliminating the backlog within 90 days and responding to all new requests for designation within 90 days of receipt during his testimony before a Senate subcommittee.

As authorized under the Orphan Drug Act, the Orphan Drug Designation Program provides orphan status to drugs and biologics intended for the treatment, diagnosis, or prevention of rare diseases, which are generally defined as diseases that affect fewer than 200,000 people in the US.

Orphan designation qualifies a product’s developer for various development incentives, including tax credits for clinical trial costs, relief from prescription drug user fee if the indication is for a rare disease or condition, and eligibility for 7 years of marketing exclusivity if the product is approved.

A request for orphan designation is one step that can be taken in the development process and is different than the filing of a marketing application with the FDA.

Currently, the FDA has about 200 orphan drug designation requests that are pending review. The number of orphan drug designation requests has steadily increased over the past 5 years.

In 2016, the FDA’s Office of Orphan Products Development received 568 new requests for designation – more than double the number of requests received in 2012.

The FDA says this increased interest in the program is a positive development for patients with rare diseases, and, with the Orphan Drug Modernization Plan, the FDA is committing to advancing the program to ensure it can efficiently and adequately review these requests.

“People who suffer with rare diseases are too often faced with no or limited treatment options, and what treatment options they have may be quite expensive due, in part, to significant costs of developing therapies for smaller populations,” said FDA Commissioner Scott Gottlieb, MD.

“Congress gave us tools to incentivize the development of novel therapies for rare diseases, and we intend to use these resources to their fullest extent in order to ensure Americans get the safe and effective medicines they need, and that the process for developing these innovations is as modern and efficient as possible.”

Among the elements of the Orphan Drug Modernization Plan, the FDA will deploy a Backlog SWAT team comprised of senior, experienced reviewers with significant expertise in orphan drug designation. The team will focus solely on the backlogged applications, starting with the oldest requests.

The agency will also employ a streamlined Designation Review Template to increase consistency and efficiency of its reviews.

In addition, the Orphan Drug Designation Program will look to collaborate within the agency’s medical product centers to create greater efficiency, including conducting joint reviews with the Office of Pediatric Therapeutics to review rare pediatric disease designation requests.

To ensure all future requests receive a response within 90 days of receipt, the FDA will take a multifaceted approach.

These efforts include, among other new steps:

• Reorganizing the review staff to maximize expertise and improve workload efficiencies
• Better leveraging the expertise across the FDA’s medical product centers
• Establishing a new FDA Orphan Products Council that will help address scientific and regulatory issues to ensure the agency is applying a consistent approach to regulating orphan drug products and reviewing designation requests.

The FDA is planning for the backlog to be eliminated by mid-September.

The Orphan Drug Modernization Plan is the first element of several efforts the FDA plans to undertake under its new “Medical Innovation Development Plan,” which is aimed at ensuring the FDA’s regulatory tools and policies are modern, risk-based, and efficient.

The goal of the plan is to seek ways the FDA can help facilitate the development of safe, effective, and transformative medical innovations that have the potential to significantly impact disease and reduce overall healthcare costs.

A 34-year-old woman presents to your office for unbearable sweating on her hands, face, and axillary regions. It occurs nearly daily, causing social embarrassment. She has tried multiple antiperspirants to no avail. What can she can take to reduce the sweating?

Hyperhidrosis is a common, self-limiting problem that affects 2% to 3% of the United States population.² Patients may complain of localized sweating of the hands, feet, face, or underarms, or more systemic, generalized sweating in multiple locations. Either way, patients note a significant impact on their quality of life.

Treatment of hyperhidrosis has traditionally focused on topical therapies to the affected areas. Research by both subjective report and objective measurements has shown that antiperspirants containing aluminum salt are effective at reducing sweating, particularly in the axilla, hands, and feet.^3,4 Additionally, a systematic review of observational and experimental studies found topical glycopyrrolate to be efficacious for craniofacial hyperhidrosis, with minimal adverse effects.⁵ The availability of low-cost prescription and OTC aluminum-based antiperspirant agents makes topicals the firstline choice.

More invasive treatments are available for hyperhidrosis refractory to topicals. In a double-blind RCT, researchers injected either botulinum toxin type A (BTX-A) 50 U or placebo in patients with bilateral primary axillary hyperhidrosis.⁶ Of the 207 patients who received treatment injections, 96.1% had at least a 50% reduction of axillary sweating four weeks after initial injection, as measured by gravimetric assessment. The BTX-A injections also produced a prolonged effect; mean duration between injections was 30.6 weeks.

Other invasive treatments include iontophoresis, surgery, and laser therapy; however, these methods are not suitable for body-wide application and are thus not appropriate for patients with generalized hyperhidrosis.

Oxybutynin is the first oral agent to emerge as a treatment option for hyperhidrosis. This cholinergic antagonist has historically been used to treat overactive bladder. But oxybutynin not only reduces urinary frequency, it also decreases secretions in various locations and can therefore reduce perspiration and cause dry mouth.

In one prospective placebo-controlled trial, 50 patients with generalized hyperhidrosis were randomly assigned to either oxybutynin (titrated from 2.5 mg orally once daily to 5 mg orally twice daily) or placebo for six weeks.⁷ Seventeen patients (73.9%) receiving oxybutynin for palmar or axillary hyperhidrosis reported moderate to “great” resolution of their symptoms, compared with six patients (27.3%) in the placebo group. Dry mouth was reported in 34.8% of patients receiving oxybutynin versus 9.1% of those who received placebo; however, no patients dropped out of the study due to this adverse effect.⁷

STUDY SUMMARY

This multicenter RCT compared oxybutynin to placebo in 62 adults with localized or generalized hyperhidrosis from 12 outpatient dermatology practices in France. It is the first study to include patients with both localized and generalized forms of the condition.

Patients were included if they were older than 18, enrolled in the National Health Insurance system in France, and reported a Hyperhidrosis Disease Severity Scale (HDSS) score ≥ 2. The HDSS is a validated, one-question tool (“How would you rate the severity of your sweating?”). Patients provide a score of 1 (no perceptible sweating and no interference with everyday life) to 4 (intolerable sweating with constant interference with everyday life).⁸ Patients were excluded if they had any contraindications to the use of an anticholinergic medication.

Patients randomly assigned to oxybutynin took 2.5 mg/d by mouth initially and increased gradually over eight days until reaching an effective dose that was no more than 7.5 mg/d. They then continued at that dose for six weeks.

The primary outcome was improvement on the HDSS by one or more points, measured at the beginning of the trial and again at six weeks. Secondary outcomes included change in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and reported adverse effects. The DLQI is a dermatology-specific quality-of-life measure consisting of 10 questions. Scores range from 0 (where disease has no impact on quality of life) to 30 (maximum impact of disease on quality of life).⁹

Improved HDSS and DLQI scores. Most patients (83%) in the study had generalized hyperhidrosis. Patients were in their mid-30s. Sixty percent of patients in the oxybutynin group had an improvement of one point or more on the 4-point HDSS, compared to 27% in the placebo group. DLQI scores improved by 6.9 points in the oxybutynin group and 2.3 points in the placebo group.

The most common adverse effect was dry mouth, which occurred in 13 patients (43%) in the oxybutynin group and in three patients (11%) in the placebo group; it did not cause any patients to drop out of the study. The second most common adverse effect was blurred vision, which only occurred in the oxybutynin group (four patients; 13%).

WHAT’S NEW

This is the first RCT to demonstrate the efficacy of an oral agent for generalized primary hyperhidrosis. This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

CAVEATS

There are many situations for which anticholinergic medications are inappropriate, including use by geriatric patients and those with gastrointestinal disorders, urinary retention, or glaucoma.

CHALLENGES TO IMPLEMENTATION

Few, if any, challenges exist to the utilization of oxybutynin; inexpensive generic versions are widely available.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquires Network and The Journal of Family Practice (2017;66[6]:392-394).

A 34-year-old woman presents to your office for unbearable sweating on her hands, face, and axillary regions. It occurs nearly daily, causing social embarrassment. She has tried multiple antiperspirants to no avail. What can she can take to reduce the sweating?

Hyperhidrosis is a common, self-limiting problem that affects 2% to 3% of the United States population.² Patients may complain of localized sweating of the hands, feet, face, or underarms, or more systemic, generalized sweating in multiple locations. Either way, patients note a significant impact on their quality of life.

Treatment of hyperhidrosis has traditionally focused on topical therapies to the affected areas. Research by both subjective report and objective measurements has shown that antiperspirants containing aluminum salt are effective at reducing sweating, particularly in the axilla, hands, and feet.^3,4 Additionally, a systematic review of observational and experimental studies found topical glycopyrrolate to be efficacious for craniofacial hyperhidrosis, with minimal adverse effects.⁵ The availability of low-cost prescription and OTC aluminum-based antiperspirant agents makes topicals the firstline choice.

More invasive treatments are available for hyperhidrosis refractory to topicals. In a double-blind RCT, researchers injected either botulinum toxin type A (BTX-A) 50 U or placebo in patients with bilateral primary axillary hyperhidrosis.⁶ Of the 207 patients who received treatment injections, 96.1% had at least a 50% reduction of axillary sweating four weeks after initial injection, as measured by gravimetric assessment. The BTX-A injections also produced a prolonged effect; mean duration between injections was 30.6 weeks.

Other invasive treatments include iontophoresis, surgery, and laser therapy; however, these methods are not suitable for body-wide application and are thus not appropriate for patients with generalized hyperhidrosis.

Oxybutynin is the first oral agent to emerge as a treatment option for hyperhidrosis. This cholinergic antagonist has historically been used to treat overactive bladder. But oxybutynin not only reduces urinary frequency, it also decreases secretions in various locations and can therefore reduce perspiration and cause dry mouth.

In one prospective placebo-controlled trial, 50 patients with generalized hyperhidrosis were randomly assigned to either oxybutynin (titrated from 2.5 mg orally once daily to 5 mg orally twice daily) or placebo for six weeks.⁷ Seventeen patients (73.9%) receiving oxybutynin for palmar or axillary hyperhidrosis reported moderate to “great” resolution of their symptoms, compared with six patients (27.3%) in the placebo group. Dry mouth was reported in 34.8% of patients receiving oxybutynin versus 9.1% of those who received placebo; however, no patients dropped out of the study due to this adverse effect.⁷

STUDY SUMMARY

This multicenter RCT compared oxybutynin to placebo in 62 adults with localized or generalized hyperhidrosis from 12 outpatient dermatology practices in France. It is the first study to include patients with both localized and generalized forms of the condition.

Patients were included if they were older than 18, enrolled in the National Health Insurance system in France, and reported a Hyperhidrosis Disease Severity Scale (HDSS) score ≥ 2. The HDSS is a validated, one-question tool (“How would you rate the severity of your sweating?”). Patients provide a score of 1 (no perceptible sweating and no interference with everyday life) to 4 (intolerable sweating with constant interference with everyday life).⁸ Patients were excluded if they had any contraindications to the use of an anticholinergic medication.

Patients randomly assigned to oxybutynin took 2.5 mg/d by mouth initially and increased gradually over eight days until reaching an effective dose that was no more than 7.5 mg/d. They then continued at that dose for six weeks.

The primary outcome was improvement on the HDSS by one or more points, measured at the beginning of the trial and again at six weeks. Secondary outcomes included change in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and reported adverse effects. The DLQI is a dermatology-specific quality-of-life measure consisting of 10 questions. Scores range from 0 (where disease has no impact on quality of life) to 30 (maximum impact of disease on quality of life).⁹

Improved HDSS and DLQI scores. Most patients (83%) in the study had generalized hyperhidrosis. Patients were in their mid-30s. Sixty percent of patients in the oxybutynin group had an improvement of one point or more on the 4-point HDSS, compared to 27% in the placebo group. DLQI scores improved by 6.9 points in the oxybutynin group and 2.3 points in the placebo group.

The most common adverse effect was dry mouth, which occurred in 13 patients (43%) in the oxybutynin group and in three patients (11%) in the placebo group; it did not cause any patients to drop out of the study. The second most common adverse effect was blurred vision, which only occurred in the oxybutynin group (four patients; 13%).

WHAT’S NEW

This is the first RCT to demonstrate the efficacy of an oral agent for generalized primary hyperhidrosis. This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

CAVEATS

There are many situations for which anticholinergic medications are inappropriate, including use by geriatric patients and those with gastrointestinal disorders, urinary retention, or glaucoma.

CHALLENGES TO IMPLEMENTATION

Few, if any, challenges exist to the utilization of oxybutynin; inexpensive generic versions are widely available.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquires Network and The Journal of Family Practice (2017;66[6]:392-394).

A 34-year-old woman presents to your office for unbearable sweating on her hands, face, and axillary regions. It occurs nearly daily, causing social embarrassment. She has tried multiple antiperspirants to no avail. What can she can take to reduce the sweating?

Hyperhidrosis is a common, self-limiting problem that affects 2% to 3% of the United States population.² Patients may complain of localized sweating of the hands, feet, face, or underarms, or more systemic, generalized sweating in multiple locations. Either way, patients note a significant impact on their quality of life.

Treatment of hyperhidrosis has traditionally focused on topical therapies to the affected areas. Research by both subjective report and objective measurements has shown that antiperspirants containing aluminum salt are effective at reducing sweating, particularly in the axilla, hands, and feet.^3,4 Additionally, a systematic review of observational and experimental studies found topical glycopyrrolate to be efficacious for craniofacial hyperhidrosis, with minimal adverse effects.⁵ The availability of low-cost prescription and OTC aluminum-based antiperspirant agents makes topicals the firstline choice.

More invasive treatments are available for hyperhidrosis refractory to topicals. In a double-blind RCT, researchers injected either botulinum toxin type A (BTX-A) 50 U or placebo in patients with bilateral primary axillary hyperhidrosis.⁶ Of the 207 patients who received treatment injections, 96.1% had at least a 50% reduction of axillary sweating four weeks after initial injection, as measured by gravimetric assessment. The BTX-A injections also produced a prolonged effect; mean duration between injections was 30.6 weeks.

Other invasive treatments include iontophoresis, surgery, and laser therapy; however, these methods are not suitable for body-wide application and are thus not appropriate for patients with generalized hyperhidrosis.

Oxybutynin is the first oral agent to emerge as a treatment option for hyperhidrosis. This cholinergic antagonist has historically been used to treat overactive bladder. But oxybutynin not only reduces urinary frequency, it also decreases secretions in various locations and can therefore reduce perspiration and cause dry mouth.

In one prospective placebo-controlled trial, 50 patients with generalized hyperhidrosis were randomly assigned to either oxybutynin (titrated from 2.5 mg orally once daily to 5 mg orally twice daily) or placebo for six weeks.⁷ Seventeen patients (73.9%) receiving oxybutynin for palmar or axillary hyperhidrosis reported moderate to “great” resolution of their symptoms, compared with six patients (27.3%) in the placebo group. Dry mouth was reported in 34.8% of patients receiving oxybutynin versus 9.1% of those who received placebo; however, no patients dropped out of the study due to this adverse effect.⁷

STUDY SUMMARY

This multicenter RCT compared oxybutynin to placebo in 62 adults with localized or generalized hyperhidrosis from 12 outpatient dermatology practices in France. It is the first study to include patients with both localized and generalized forms of the condition.

Patients were included if they were older than 18, enrolled in the National Health Insurance system in France, and reported a Hyperhidrosis Disease Severity Scale (HDSS) score ≥ 2. The HDSS is a validated, one-question tool (“How would you rate the severity of your sweating?”). Patients provide a score of 1 (no perceptible sweating and no interference with everyday life) to 4 (intolerable sweating with constant interference with everyday life).⁸ Patients were excluded if they had any contraindications to the use of an anticholinergic medication.

Patients randomly assigned to oxybutynin took 2.5 mg/d by mouth initially and increased gradually over eight days until reaching an effective dose that was no more than 7.5 mg/d. They then continued at that dose for six weeks.

The primary outcome was improvement on the HDSS by one or more points, measured at the beginning of the trial and again at six weeks. Secondary outcomes included change in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and reported adverse effects. The DLQI is a dermatology-specific quality-of-life measure consisting of 10 questions. Scores range from 0 (where disease has no impact on quality of life) to 30 (maximum impact of disease on quality of life).⁹

Improved HDSS and DLQI scores. Most patients (83%) in the study had generalized hyperhidrosis. Patients were in their mid-30s. Sixty percent of patients in the oxybutynin group had an improvement of one point or more on the 4-point HDSS, compared to 27% in the placebo group. DLQI scores improved by 6.9 points in the oxybutynin group and 2.3 points in the placebo group.

The most common adverse effect was dry mouth, which occurred in 13 patients (43%) in the oxybutynin group and in three patients (11%) in the placebo group; it did not cause any patients to drop out of the study. The second most common adverse effect was blurred vision, which only occurred in the oxybutynin group (four patients; 13%).

WHAT’S NEW

This is the first RCT to demonstrate the efficacy of an oral agent for generalized primary hyperhidrosis. This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

CAVEATS

There are many situations for which anticholinergic medications are inappropriate, including use by geriatric patients and those with gastrointestinal disorders, urinary retention, or glaucoma.

CHALLENGES TO IMPLEMENTATION

Few, if any, challenges exist to the utilization of oxybutynin; inexpensive generic versions are widely available.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquires Network and The Journal of Family Practice (2017;66[6]:392-394).

INTRODUCTION

Lung cancer is the second most common type of cancer in the United States, with 222,500 estimated new cases in 2017, according to the American Cancer Society.¹ However, it is by far the number one cause of death due to cancer, with an estimated 155,870 lung cancer–related deaths occurring in 2017, which is higher than the number of deaths due to breast cancer, prostate cancer, and colorectal cancer combined.^1,2 Despite slightly decreasing incidence and mortality over the past decade, largely due to smoking cessation, the 5-year survival rate of lung cancer remains dismal at approximately 18%.^2–4

Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancer cases.⁴ Traditionally, it is further divided based on histology: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and not otherwise specified.⁵ Chemotherapy had been the cornerstone of treatment for stage IV NSCLC. It is not target-specific and is most effective against rapidly growing cells. Common adverse effects include alopecia, nausea/vomiting, myelosuppression, cardiotoxicity, neuropathy, and nephrotoxicity. However, this paradigm has shifted following the discovery of mutations of the epidermal growth factor receptor (EGFR) gene as an oncogenic driver that confers sensitivity to small molecule tyrosine kinase inhibitors (TKIs) targeting EGFR.⁶ The EGFR inhibitors are given orally and have a spectrum of toxicities (eg, such as rash, diarrhea, and elevated transaminases) different from that of systemic chemotherapy, which is often administered intravenously. Following the discovery of EGFR mutations, rearrangements of the anaplastic lymphoma kinase (ALK) gene⁷ and ROS1 gene⁸ were identified as targetable driver mutations in NSCLC. The frequency of both rearrangements is lower than that of EGFR mutations. Additionally, BRAF V600E mutation has been identified in NSCLC.^9–12 This activation mutation is commonly seen in melanoma. Agents that have already been approved for the treatment of melanoma with the BRAF V600E mutation are being tested in NSCLC patients with this mutation.^13–16

Given the effectiveness and tolerability of targeted therapy, identifying this distinct molecular subset of NSCLC patients is critical in treatment. Currently, molecular testing is mandatory in all stage IV patients with non-squamous cell carcinoma, as a preponderance of patients with driver mutations have this histology subtype.^5,17–19 For patients with squamous cell carcinoma, molecular testing should be considered if the biopsy specimen is small, there is mixed histology, or the patient is a nonsmoker.^5,20 Several techniques are commonly utilized in detecting these genetic alterations. EGFR mutation can be detected by polymerase chain reaction (PCR), ALK or ROS1 rearrangement can be detected by fluorescence in-situ hybridization (FISH), and immunohistochemistry (IHC) can also be used to detect ALK rearrangement. The current guideline is to use comprehensive genomic profiling to capture all the potential molecular targets simultaneously instead of running stepwise tests just for EGFR, ALK, and ROS1.⁵BRAF V600E mutation,^13–16 MET exon 14 skipping mutation,^21–24 RET rearrangements,^25–27 and HER2 mutations^28–30 are among the emergent genetic alterations with various responses to targeted therapy.³¹ Some of these targeted agents have been approved for other types of malignancy, and others are still in the development phase.

Several initiatives worldwide have reported better outcomes of patients with driver mutations treated with targeted therapy. For instance, the Lung Cancer Mutation Consortium in the United States demonstrated that the median survival of patients without driver mutations, with drivers mutations but not treated with targeted therapy, and with driver mutations and treated with targeted therapy was 2.08 years, 2.38 years, and 3.49 years, respectively.³² The French Cooperative Thoracic Intergroup-French National Cancer Institute demonstrated that the median survival for patients with driver mutations versus those without driver mutations was 16.5 months versus 11.8 months.³³ The Spanish Lung Cancer Group demonstrated that the overall survival (OS) for patients with EGFR mutations treated with erlotinib was 27 months.³⁴ The mutations in lung cancer, their frequencies, and the downstream signaling pathways are depicted in the Figure.³⁵

In this article, we discuss targeted therapy for patients with EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutation. We also discuss the management of patients with EGFR mutations who develop a secondary mutation after TKI therapy. Almost all of the targeted agents discussed herein have been approved by the US Food and Drug Administration (FDA), so they are considered standard of care. All available phase 3 trials pertinent to these targeted therapies are included in the discussion.

EGFR MUTATIONS

CASE PRESENTATION 1

A 54-year-old Caucasian man who is a former smoker with a 10 pack-year history and past medical history of hypertension and dyslipidemia presents with progressive dyspnea for several weeks. A chest x-ray shows moderate pleural effusion on the left side with possible mass-like opacity on the left upper lung field. An ultrasound-guided thoracentesis is performed and cytology is positive for adenocarcinoma of likely pulmonary origin. Staging workup including positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging of the brain with and without contrast is done. PET/CT shows a 5.5-cm mass in the left upper lobe of the lung with high fluorodeoxyglucose (FDG) uptake, several 1- to 2-cm mediastinal lymph nodes with moderate FDG uptake, and small pleural effusion on both sides with moderate FDG uptake. MRI-brain is negative for malignancy. The patient subsequently undergoes a CT-guided biopsy of the lung mass, which shows moderately differentiated adenocarcinoma. Comprehensive molecular profiling reveals EGFR L858R mutation only. The patient now presents for the initial consultation. Of note, his Eastern Cooperative Oncology Group performance status is 1.

• What is the next step in the management of this patient?

FIRST-LINE TKI FOR SENSITIZING EGFR MUTATIONS

The 2 most common EGFR mutations are deletions in exon 19 and substitution of arginine for leucine in exon 21 (L858R), found in approximately 45% and 40% of patients with EGFR mutations, respectively.³⁶ Both mutations are sensitive to EGFR TKIs. The benefit may be greater in patients with exon 19 deletions as compared to exon 21 L858R substitution,^37,38 but this has not been demonstrated consistently in clinical trials.^39-43 In the United States, EGFR mutations are found in approximately 10% of patients with NSCLC, while the incidence can be as high as 50% in Asia.⁴⁴ Even though the cobas EGFR mutation test is the companion diagnostic approved by the US FDA, a positive test result from any laboratory with the Clinical Laboratory Improvement Amendments (CLIA) certificate should prompt the use of an EGFR TKI as the initial treatment.

Three EGFR TKIs that have been approved as first-line therapy in the United States are available: erlotinib, afatinib, and gefitinib.⁵ Both erlotinib and gefitinib are considered first-generation TKIs. They have higher binding affinity for the 2 common EGFR mutations than wild-type EGFR. In addition, they reversibly bind to the intracellular tyrosine kinase domain, resulting in inhibition of autophosphorylation of the tyrosine residues. Afatinib, a second-generation and irreversible TKI, targets EGFR (HER1) as well as HER2 and HER4.⁴⁵

The superior efficacy of the EGFR TKIs over platinum doublet chemotherapy in treatment-naïve patients with EGFR mutations has been demonstrated in 7 randomized trials to date (Table).⁴⁶ Erlotinib was the TKI arm for the OPTIMAL,⁴¹ EURTAC,⁴² and ENSURE trials;³⁸ afatinib was the TKI arm for LUX-LUNG 3³⁷ and 6;⁴³ gefitinib was the TKI arm for NEJ002^39,47 and WJTOG3405.⁴⁰ A meta-analysis of these 7 trials by Lee et al showed that progression-free survival (PFS) was significantly prolonged by EGFR TKIs (hazard ratio [HR] 0.37 [95% confidence interval {CI} 0.32 to 0.42]).⁴⁶ For instance, in the EURTAC trial, median PFS was 9.7 months for patients treated with erlotinib as compared to 5.2 months for patients treated with platinum/gemcitabine or platinum/docetaxel.⁴² In this meta-analysis, prespecified subgroups included age, sex, ethnicity, smoking status, performance status, tumor histology, and EGFR mutation subtype. The superior outcome with TKIs was observed in all subgroups. Furthermore, patients with exon 19 deletions, nonsmokers, and women had even better outcomes.⁴⁶

Erlotinib is the most commonly used TKI in the United States largely because gefitinib was off the market for some time until it was re-approved by the FDA in 2015. Interestingly, this “re-approval” was not based on either 1 of the 2 prospective trials (NEJ002^39,47 and WJTOG3405⁴⁰), but rather was based on an exploratory analysis of the IPASS trial^48,49 as well as a prospective phase 4, single-arm trial in Europe (IFUM).⁵⁰ The superior efficacy of gefitinib over carboplatin/paclitaxel among patients with EGFR mutations in the IPASS trial was confirmed by blind independent central review, with longer PFS (HR 0.54 [95% CI 0.38 to 0.79] P = 0.0012) and higher objective response rate (ORR; odds ratio 3 [95% CI 1.63 to 5.54], P = 0.0004).⁴⁹

CASE 1 CONTINUED

Based on the EGFR L858R mutation status, the patient is started on erlotinib. He is quite happy that he does not need intravenous chemotherapy but wants to know what toxicities he might potentially have with erlotinib.

• What are the common adverse effects (AEs) of EGFR TKIs? How are AEs of TKIs managed?

Safety Profile

The important toxicities associated with EGFR TKIs are rash, gastrointestinal toxicity, hepatic toxicity, and pulmonary toxicity. Rash is an AE specific to all agents blocking the EGFR pathway, including small molecules and monoclonal antibodies such as cetuximab. The epidermis has a high level of expression of EGFR, which contributes to this toxicity.⁵¹ Rash usually presents as dry skin or acneiform eruption. Prophylactic treatment with oral tetracyclines and topical corticosteroids is generally recommended upon initiation of TKI therapy. Diarrhea is the most prevalent gastrointestinal toxicity. All patients starting treatment should be given prescriptions to manage diarrhea such as loperamide and be advised to call when it occurs. Hepatic toxicity is often manifested as elevated transaminases or bilirubin. Interstitial lung disease (ILD) is a rare but potentially fatal pulmonary toxicity.

Rash of any grade was reported in 49.2% of patients treated with erlotinib in clinical trials, while grade 3 rash occurred in 6% of patients and no grade 4 was reported. Diarrhea of any grade was reported in 20.3% of patients, grade 3 diarrhea occurred in 1.8%, and no grade 4 was reported. Grade 2 and 3 alanine aminotransferase (ALT) elevations were seen in 2% and 1% of patients, respectively. Grade 2 and 3 bilirubin elevations were seen in 4% and less than 1% of patients, respectively. The incidence of serious ILD-like events was less than 1%.⁵²

Afatinib is associated with higher incidences of rash and diarrhea. Specifically, diarrhea and rash of all grades were reported in 96% and 90% of patients treated with afatinib, respectively. Paronychia of all grades occurred in 58% of patients. Elevated ALT of all grades was seen in 11% of patients. Approximately 1.5% of patients treated with afatinib across clinical trials had ILD or ILD-like AEs.⁵³

Gefitinib, the most commonly used TKI outside United States, has a toxicity profile similar to erlotinib, except for hepatic toxicity. For instance, rash of all grades occurred in 47% of patients, diarrhea of all grades occurred in 29% of patients, and ILD or ILD-like AEs occurred in 1.3% of patients across clinical trials. In comparison, elevated ALT and aspartate aminotransferase (AST) of all grades was seen in 38% and 40% of patients, respectively.⁵⁴ Therefore, close monitoring of liver function is clinically warranted. In particular, patients need to be advised to avoid concomitant use of herbal supplements, a common practice in Asian countries.

CASE 1 CONTINUED

The patient does well while on erlotinib at 150 mg orally once daily for about 8 months, until he develops increasing abdominal pain. A CT scan of the abdomen and pelvis with contrast shows a new 8-cm right adrenal mass. Additionally, a repeat CT scan of the chest with contrast shows a stable lung mass but enlarging mediastinal lymphadenopathy.

• How would you manage the patient at this point?

MANAGEMENT OF T790M MUTATION AFTER PROGRESSION ON FIRST-LINE EGFR TKIS

As mentioned above, the median PFS of patients with EGFR mutations treated with 1 of the 3 TKIs is around 9 to 13 months.⁴⁶ Of the various resistance mechanisms that have been described, the T790M mutation is found in approximately 60% of patients who progress after treatment with first-line TKIs.^55,56 Other mechanisms, such as HER2 amplification, MET amplification, or rarely small cell transformation, have been reported.⁵⁶ The first- and second-generation EGFR TKIs function by binding to the ATP-binding domain of mutated EGFR, leading to inhibition of the downstream signaling pathways (Figure, part B) and ultimately cell death.³⁵ The T790M mutation hinders the interaction between the ATP-binding domain of EGFR kinase and TKIs, resulting in treatment resistance and disease progression.^57,58

Osimertinib is a third-generation irreversible EGFR TKI with activity against both sensitizing EGFR and resistant T790M mutations. It has low affinity for wide-type EGFR as well as insulin receptor and insulin-like growth factor receptor.⁵⁹ Osimertinib has been fully approved for NSCLC patients with EGFR mutations who have progressed on first-line EGFR TKIs with the development of T790M mutation. An international phase 3 trial (AURA3) randomly assigned 419 patients in a 2:1 ratio to either osimertinib or platinum/pemetrexed. Eligible patients all had the documented EGFR mutations and disease progression after first-line EGFR TKIs. Central confirmation of the T790M mutation was required. Median PFS by investigator assessment, the trial’s primary end point, was 10.1 months for osimertinib versus 4.4 months for chemotherapy (HR 0.3 [95% CI 0.23 to 0.41]; P < 0.001). ORR was 71% for osimertinib versus 31% for chemotherapy (HR 5.39 [95% CI 3.47 to 8.48], P < 0.001). A total of 144 patients with stable and asymptomatic brain metastases were also eligible. Median PFS for this subset of patients treated with osimertinib and chemotherapy was 8.5 months and 4.2 months, respectively (HR 0.32 [95% CI 0.21 to 0.49]). In the AURA3 trial, osimertinib was better tolerated than chemotherapy, with 23% of patients treated with osimertinib experiencing grade 3 or 4 AEs as compared to 47% of chemotherapy-treated patients. The most common AEs of any grade were diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%).⁶⁰

For the case patient, a reasonable approach would be to obtain a tissue biopsy of the adrenal mass and more importantly to check for the T790M mutation. Similar to the companion diagnostic for EGFR mutations, the cobas EGFR mutation test v2 is the FDA-approved test for T790M. However, if this resistance mutation is detected by any CLIA-certified laboratories, osimertinib should be the recommended treatment option. If tissue biopsy is not feasible, plasma-based testing should be considered. A blood-based companion diagnostic also is FDA approved.

ALK REARRANGEMENTS

CASE 2 PRESENTATION

A 42-year-old Korean woman who is a non-smoker with no significant past medical history presents with fatigue, unintentional weight loss of 20 lb in the past 4 months, and vague abdominal pain. A CT can of the abdomen and pelvis without contrast shows multiple foci in the liver and an indeterminate nodule in the right lung base. She subsequently undergoes PET/CT, which confirms multiple liver nodules/masses ranging from 1 to 3 cm with moderate FDG uptake. In addition, there is a 3.5-cm pleura-based lung mass on the right side with moderate FDG uptake. MRI-brain with and without contrast is negative for malignancy. A CT-guided biopsy of 1 of the liver masses is ordered and pathology returns positive for poorly differentiated adenocarcinoma consistent with lung primary. Molecular analysis reveals an echinoderm microtubule-associated protein-like 4 (EML4)-ALK rearrangement. She is placed on crizotinib by an outside oncologist and after about 3 weeks of therapy is doing well. She is now in your clinic for a second opinion. She says that some of her friends told her about another medication called ceritinib and was wondering if she would need to switch her cancer treatment.

• How would you respond to this patient’s inquiry?

FIRST-LINE TKIS FOR ALK REARRANGEMENTS

ALK rearrangements are found in 2% to 7% of NSCLC, with EML4-ALK being the most prevalent fusion variant.⁶¹ The inversion of chromosome 2p leads to the fusion of the EML4 gene and the ALK gene, which causes the constitutive activation of the fusion protein and ultimately increased transformation and tumorigenicity.^7,61 Patients harboring ALK rearrangements tend to be non-smokers. Adenocarcinoma, especially signet ring cell subtype, is the predominant histology. Compared to EGFR mutations, patients with ALK mutations are significantly younger and more likely to be men.⁶²ALK rearrangements can be detected by either FISH or IHC, and most next-generation sequencing (NGS) panels have the ability to identify this driver mutation.

Crizotinib is the first approved ALK inhibitor for the treatment of NSCLC in this molecular subset of patients.⁶³ PROFILE 1014 is a phase 3 randomized trial that compared crizotinib with chemotherapy containing platinum/pemetrexed for up to 6 cycles. Crossover to crizotinib was allowed for patients with disease progression on chemotherapy. The primary end point was PFS by independent radiologic review. The crizotinib arm demonstrated superior PFS (10.9 months versus 7 months; HR 0.45 [95% CI 0.35 to 0.6], P < 0.001) and ORR (74% versus 45%, P < 0.001). Median survival was not reached in either arm (HR 0.82 [95% CI 0.54 to 1.26], P = 0.36).⁶⁴ Based on this international trial, crizotinib is considered standard of care in the United States for treatment-naïve patients with advanced NSCLC harboring ALK rearrangements. The current recommended dose is 250 mg orally twice daily. Common treatment-related AEs of all grades include vision disorder (62%), nausea (53%), diarrhea (43%), vomiting (40%), edema (28%), and constipation (27%).⁶⁵ PROFILE 1007 compared crizotinib with pemetrexed or docetaxel in ALK-rearranged NSCLC patients with prior exposure to 1 platinum-based chemotherapy. The median PFS was 7.7 months for crizotinib as compared to 3 months for chemotherapy (HR 0.49 [95% CI 0.37 to 0.64], P < 0.001). The response rates were 65% and 20% for crizotinib and chemotherapy, respectively (P < 0.001).⁶⁶ In other countries, crizotinib following 1 prior platinum-based regimen may be considered standard of care based on this trial.

Ceritinib is an oral second-generation ALK inhibitor that is 20 times more potent than crizotinib based on enzymatic assays.⁶⁷ It also targets ROS1 and insulin-like growth factor 1 receptor but not c-MET. It was first approved by the FDA in April 2014 for metastatic ALK-rearranged NSCLC following crizotinib.⁶⁸ In May 2017, the FDA granted approval of ceritinib for treatment-naïve patients. This decision was based on the results of the ASCEND-4 trial, a randomized phase 3 trial assessing the efficacy and safety of ceritinib over chemotherapy in the first-line setting. The trial assigned 376 patients to either ceritinib at 750 mg once daily or platinum/pemetrexed for 4 cycles followed by maintenance pemetrexed. Median PFS was 16.6 months for ceritinib versus 8.1 months for chemotherapy (HR 0.55 [95% CI 0.42 to 0.73]; P < 0.00001).⁶⁹ Toxicities of ceritinib are not negligible, with gastrointestinal toxicity being the most prevalent. For instance, diarrhea, nausea, vomiting, abdominal pain, and constipation of all grades were seen in 86%, 80%, 60%, 54%, and 29% of patients, respectively. Furthermore, fatigue and decreased appetite occurred in 52% and 34% of patients, respectively. In terms of laboratory abnormalities, 84% of patients experienced decreased hemoglobin of all grades; 80% increased ALT; 75% increased AST; 58% increased creatinine; 49% increased glucose; 36% decreased phosphate; and 28% increased lipase. Due to these AEs, the incidence of dose reduction was about 58% and the median onset was around 7 weeks.⁷⁰

Alectinib is another oral second-generation ALK inhibitor that was approved by the FDA in December 2015 for the treatment of NSCLC patients with ALK rearrangements who have progressed on or are intolerant to crizotinib.⁷¹ Its indication will soon be broadened to the first-line setting based on the ALEX trial.⁷² Alectinib is a potent and highly selective TKI of ALK⁷³ with activity against known resistant mutations to crizotinib.^74,75 It also inhibits RET but not ROS1 or c-MET.⁷⁶ ALEX, a randomized phase 3 study, compared alectinib with crizotinib in treatment-naïve patients with NSCLC harboring ALK rearrangements. The trial enrolled 303 patients and the median follow-up was approximately 18 months. The alectinib arm (600 mg twice daily) demonstrated significantly higher PFS by investigator-assessment, the trial’s primary end point. The 12-month event-free survival was 68.4% (95% CI 61% to 75.9%) versus 48.7% (95% CI 40.4% to 56.9%) for alectinib and crizotinib, respectively (HR 0.47 [95% CI 0.34 to 0.65], P < 0.001). The median PFS was not reached in the alectinib arm (95% CI 17.7 months to not estimable) as compared to 11.1 months in the crizotinib arm (95% CI 9.1 to 13.1 months).⁷² Alectinib is generally well tolerated. Common AEs of all grades include fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). As alectinib can cause anemia, lymphopenia, hepatic toxicity, increased creatine phosphokinase, hyperglycemia, electrolyte abnormalities, and increased creatinine, periodic monitoring of these laboratory values is important, although most of these abnormalities are grade 1 or 2.⁷⁷

Brigatinib, another oral second-generation ALK inhibitor, was granted accelerated approval by the FDA in April 2017 for ALK-rearranged and crizotinib-resistant NSCLC based on the ALTA trial. This randomized phase 2 study of brigatinib showed an ORR by investigator assessment of 54% (97.5% CI 43% to 65%) in the 180 mg once daily arm with lead-in of 90 mg once daily for 7 days. Median PFS was 12.9 months (95% CI 11.1 months to not reached [NR]).⁷⁸ Currently, a phase 3 study of brigatinib versus crizotinib in ALK inhibitor–naïve patients is recruiting participants (ALTA-1L). It will be interesting to see if brigatinib can achieve a front-line indication.

Starting the case patient on crizotinib is well within the treatment guidelines. One may consider ceritinib or alectinib in the first-line setting, but both TKIs can be reserved upon disease progression. We would recommend a repeat biopsy at that point to look for resistant mechanisms, as certain secondary ALK mutations may be rescued by certain next-generation ALK inhibitors. For instance, the F1174V mutation has been reported to confer resistance to ceritinib but sensitivity to alectinib, while the opposite is true for I1171T. The G1202R mutation is resistant to ceritinib, alectinib, and brigatinib, but lorlatinib, a third-generation ALK inhibitor, has shown activity against this mutation.⁷⁹ Furthermore, brain metastasis represents a treatment challenge for patients with ALK rearrangements. It is also an efficacy measure of next-generation ALK inhibitors, all of which have demonstrated better central nervous system activity than crizotinib.^69,78,80 If the case patient were found to have brain metastasis at the initial diagnosis, either ceritinib or alectinib would be a reasonable choice since crizotinib has limited penetration of blood-brain barrier.⁸¹

ROS1 REARRANGEMENTS

CASE PRESENTATION 3

A 66-year-old Chinese woman who is a non-smoker with a past medical history of hypertension and hypothyroidism presents to the emergency department for worsening lower back pain. Initial workup includes x-ray of the lumbar spine followed by MRI with contrast, which shows a soft tissue mass at L3-4 without cord compression. CT of the chest, abdomen, and pelvis with contrast shows a 7-cm right hilar mass, bilateral small lung nodules, mediastinal lymphadenopathy, and multiple lytic lesions in ribs, lumbar spine, and pelvis. MRI-brain with and without contrast is negative for malignancy. She undergoes endo-bronchial ultrasound and biopsy of the right hilar mass, which shows poorly differentiated adenocarcinoma. While waiting for the result of the molecular analysis, the patient undergoes palliative radiation therapy to L2-5 with good pain relief. She is discharged from the hospital and presents to your clinic for follow up. Molecular analysis now reveals ROS1 rearrangement with CD74-ROS1 fusion.

• What treatment plan should be put in place for this patient?

FIRST-LINE THERAPY FOR ROS1 REARRANGEMENTS

Approximately 2.4% of lung adenocarcinomas harbor ROS1 rearrangements.⁸² This distinct genetic alteration occurs more frequently in NSCLC patients who are younger, female, and never-smokers, and who have adenocarcinomas.⁸ It has been shown that ROS1 rearrangements rarely overlap with other genetic alterations including KRAS mutations, EGFR mutations, and ALK rearrangements.⁸³ As a receptor tyrosine kinase, ROS1 is similar to ALK and insulin receptor family members.⁸⁴ Crizotinib, which targets ALK, ROS1, and c-MET, was approved by the FDA on March 11, 2016, for the treatment of metastatic ROS1-rearranged NSCLC.⁸⁵ The approval was based on a phase 2 expansion cohort of the original phase 1 study. Among 50 US patients enrolled in this expansion cohort, 3 had complete responses and 33 had partial responses with ORR of 72% (95% CI 58% to 84%). Median PFS was 19.2 months (95% CI 14.4 months to NR) and median duration of response (DOR) was 17.6 months (95% CI 14.5 months to NR).⁸⁶ During longer follow-up, independent radiology review confirmed high ORR of 66% and median DOR of 18.3 months.⁸⁵

Interestingly, no companion diagnostic assay has been approved for the detection of ROS1 rearrangements with the approval of crizotinib. In the United States, break apart FISH is the most common detection method. In fact, in the above mentioned phase 2 study, ROS1 rearrangements were detected in 49 out of 50 patients by this method.⁸⁶ FISH can be technically challenging when dealing with high volume and multiple targets. Reverse transcriptase-PCR is another detection method, but it requires knowledge of the fusion partners. To date, at least 14 ROS1 fusion partners have been reported, with CD74 being the most common.⁸⁷ NGS with appropriate design and validation can also be used to detect ROS1 rearrangements.

For the case patient, the recommendation would be to start her on crizotinib at 250 mg twice daily. Monitoring for vision disturbance, gastrointestinal complaints, and edema is warranted. Because the estimated onset of response is around 7.9 weeks,⁸⁶ plans should be made to repeat her scans in approximately 2 months.

BRAF V600E MUTATIONS

CASE PRESENTATION 4

A 71-year-old Caucasian man with a past medical history of hypertension, dyslipidemia, and ischemic cerebrovascular accident without residual deficits was diagnosed with stage IV adenocarcinoma of the lung about 8 months ago. He has a 40 pack-year smoking history and quit smoking when he was diagnosed with lung cancer. His disease burden involved a large mediastinal mass, scattered pleural nodules, multiple lymphadenopathy, and several soft tissue masses. His outside oncologist started him on chemotherapy containing carboplatin and pemetrexed for 6 cycles followed by maintenance pemetrexed. The most recent restaging scans show disease progression with enlarging soft tissue masses and several new lytic bone lesions. MRI-brain with and without contrast shows 2 subcentimeter enhancing lesions. He transferred care to you approximately 4 weeks ago. You ordered a repeat biopsy of 1 of the enlarging soft tissue masses. Molecular analysis revealed BRAF V600E mutation. In the interim, he underwent stereotactic radiosurgery for the 2 brain lesions without any complications. The patient is now in your clinic for follow up.

• What would be your recommended systemic treatment?

TARGETED THERAPIES FOR BRAF V600E MUTATION

BRAF mutations were first recognized as activating mutations in advanced melanomas, with BRAF V600E, resulting from the substitution of glutamic acid for valine at amino acid 600, being the most common. BRAF plays an important role in the mitogen-activated protein kinase (MAPK) signaling pathway. Briefly, the activation of MAPK pathway occurs upon ligand binding of receptor tyrosine kinases, which then involves RAS/BRAF/MEK/ERK in a stepwise manner, ultimately leading to cell survival. BRAF mutations have been increasingly recognized also as driver mutations in NSCLC.^9–12 They can be detected by PCR or NGS method. The characteristics of NSCLC patients harboring BRAF mutations have been described by various groups.^9–12 For instance, 1 case series showed that the incidence was 2.2% among patients with advanced lung adenocarcinoma; 50% of mutations were V600E, while G469A and D594G accounted for the remaining 39% and 11% of patients, respectively. All patients were either current or former smokers. The median OS of patients with BRAF mutations in this case series was NR, while it was 37 months for patients with EGFR mutations (P = 0.73) and NR for patients with ALK rearrangements (P = 0.64).⁹

For patients with BRAF V600E–mutant NSCLC who have progressed on platinum-based chemotherapy, the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) may represent a new treatment paradigm. This was illustrated in a phase 2, nonrandomized, open-label study. A total of 57 patients were enrolled and 36 patients (63.2% [95% CI 49.3% to 75.6%]) achieved an overall response by investigator assessment, the trial’s primary end point. Disease control rate was 78.9% (95% CI 66.1% to 88.6%), with 4% complete response, 60% partial response, and 16% stable disease. PFS was 9.7 months (95% CI [6.9 to 19.6 months]). The safety profile was comparable to what had been observed in patients with melanoma treated with this regimen. More specifically, 56% of patients on this trial reported serious AEs, including pyrexia (16%), anemia (5%), confusional state (4%), decreased appetite (4%), hemoptysis (4%), hypercalcemia (4%), nausea (4%), and cutaneous squamous cell carcinoma (4%). In addition, neutropenia (9%) and hyponatremia (7%) were the most common grade 3-4 AEs.¹⁶

The case patient has experienced disease progression after 1 line of platinum-based chemotherapy, so the combination of dabrafenib and trametinib would be a robust systemic treatment option. dabrafenib as a single agent has also been studied in BRAF V600E–mutant NSCLC in a phase 2 trial. The overall response by investigator assessment among 84 patients was 33% (95% CI 23% to 45%).¹⁴ Vemurafenib, another oral BRAF TKI, has demonstrated efficacy for NSCLC patients harboring BRAF V600E mutation. In the cohort of 20 patients with NSCLC, the response rate was 42% (95% CI 20% to 67%) and median PFS was 7.3 months (95% CI 3.5 to 10.8 months).¹³ Patients with non-V600E mutations have shown variable responses to targeted therapies. MEK TKIs may be considered in this setting; however, the details of this discussion are beyond the scope of this review.

CONCLUSION

The management of advanced NSCLC with driver mutations has seen revolutionary changes over the past decade. Tremendous research has been done in order to first understand the molecular pathogenesis of NSCLC and then discover driver mutations that would lead to development of targeted therapies with clinically significant efficacy as well as tolerability. More recently, increasing efforts have focused on how to conquer acquired resistance in patients with disease progression after first-line TKIs. The field of EGFR-mutant NSCLC has set a successful example, but the work is nowhere near finished. The goals are to search for more driver mutations and to design agents that could potentially block cell survival signals once and for all.

INTRODUCTION

Lung cancer is the second most common type of cancer in the United States, with 222,500 estimated new cases in 2017, according to the American Cancer Society.¹ However, it is by far the number one cause of death due to cancer, with an estimated 155,870 lung cancer–related deaths occurring in 2017, which is higher than the number of deaths due to breast cancer, prostate cancer, and colorectal cancer combined.^1,2 Despite slightly decreasing incidence and mortality over the past decade, largely due to smoking cessation, the 5-year survival rate of lung cancer remains dismal at approximately 18%.^2–4

Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancer cases.⁴ Traditionally, it is further divided based on histology: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and not otherwise specified.⁵ Chemotherapy had been the cornerstone of treatment for stage IV NSCLC. It is not target-specific and is most effective against rapidly growing cells. Common adverse effects include alopecia, nausea/vomiting, myelosuppression, cardiotoxicity, neuropathy, and nephrotoxicity. However, this paradigm has shifted following the discovery of mutations of the epidermal growth factor receptor (EGFR) gene as an oncogenic driver that confers sensitivity to small molecule tyrosine kinase inhibitors (TKIs) targeting EGFR.⁶ The EGFR inhibitors are given orally and have a spectrum of toxicities (eg, such as rash, diarrhea, and elevated transaminases) different from that of systemic chemotherapy, which is often administered intravenously. Following the discovery of EGFR mutations, rearrangements of the anaplastic lymphoma kinase (ALK) gene⁷ and ROS1 gene⁸ were identified as targetable driver mutations in NSCLC. The frequency of both rearrangements is lower than that of EGFR mutations. Additionally, BRAF V600E mutation has been identified in NSCLC.^9–12 This activation mutation is commonly seen in melanoma. Agents that have already been approved for the treatment of melanoma with the BRAF V600E mutation are being tested in NSCLC patients with this mutation.^13–16

Given the effectiveness and tolerability of targeted therapy, identifying this distinct molecular subset of NSCLC patients is critical in treatment. Currently, molecular testing is mandatory in all stage IV patients with non-squamous cell carcinoma, as a preponderance of patients with driver mutations have this histology subtype.^5,17–19 For patients with squamous cell carcinoma, molecular testing should be considered if the biopsy specimen is small, there is mixed histology, or the patient is a nonsmoker.^5,20 Several techniques are commonly utilized in detecting these genetic alterations. EGFR mutation can be detected by polymerase chain reaction (PCR), ALK or ROS1 rearrangement can be detected by fluorescence in-situ hybridization (FISH), and immunohistochemistry (IHC) can also be used to detect ALK rearrangement. The current guideline is to use comprehensive genomic profiling to capture all the potential molecular targets simultaneously instead of running stepwise tests just for EGFR, ALK, and ROS1.⁵BRAF V600E mutation,^13–16 MET exon 14 skipping mutation,^21–24 RET rearrangements,^25–27 and HER2 mutations^28–30 are among the emergent genetic alterations with various responses to targeted therapy.³¹ Some of these targeted agents have been approved for other types of malignancy, and others are still in the development phase.

Several initiatives worldwide have reported better outcomes of patients with driver mutations treated with targeted therapy. For instance, the Lung Cancer Mutation Consortium in the United States demonstrated that the median survival of patients without driver mutations, with drivers mutations but not treated with targeted therapy, and with driver mutations and treated with targeted therapy was 2.08 years, 2.38 years, and 3.49 years, respectively.³² The French Cooperative Thoracic Intergroup-French National Cancer Institute demonstrated that the median survival for patients with driver mutations versus those without driver mutations was 16.5 months versus 11.8 months.³³ The Spanish Lung Cancer Group demonstrated that the overall survival (OS) for patients with EGFR mutations treated with erlotinib was 27 months.³⁴ The mutations in lung cancer, their frequencies, and the downstream signaling pathways are depicted in the Figure.³⁵

In this article, we discuss targeted therapy for patients with EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutation. We also discuss the management of patients with EGFR mutations who develop a secondary mutation after TKI therapy. Almost all of the targeted agents discussed herein have been approved by the US Food and Drug Administration (FDA), so they are considered standard of care. All available phase 3 trials pertinent to these targeted therapies are included in the discussion.

EGFR MUTATIONS

CASE PRESENTATION 1

A 54-year-old Caucasian man who is a former smoker with a 10 pack-year history and past medical history of hypertension and dyslipidemia presents with progressive dyspnea for several weeks. A chest x-ray shows moderate pleural effusion on the left side with possible mass-like opacity on the left upper lung field. An ultrasound-guided thoracentesis is performed and cytology is positive for adenocarcinoma of likely pulmonary origin. Staging workup including positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging of the brain with and without contrast is done. PET/CT shows a 5.5-cm mass in the left upper lobe of the lung with high fluorodeoxyglucose (FDG) uptake, several 1- to 2-cm mediastinal lymph nodes with moderate FDG uptake, and small pleural effusion on both sides with moderate FDG uptake. MRI-brain is negative for malignancy. The patient subsequently undergoes a CT-guided biopsy of the lung mass, which shows moderately differentiated adenocarcinoma. Comprehensive molecular profiling reveals EGFR L858R mutation only. The patient now presents for the initial consultation. Of note, his Eastern Cooperative Oncology Group performance status is 1.

• What is the next step in the management of this patient?

FIRST-LINE TKI FOR SENSITIZING EGFR MUTATIONS

The 2 most common EGFR mutations are deletions in exon 19 and substitution of arginine for leucine in exon 21 (L858R), found in approximately 45% and 40% of patients with EGFR mutations, respectively.³⁶ Both mutations are sensitive to EGFR TKIs. The benefit may be greater in patients with exon 19 deletions as compared to exon 21 L858R substitution,^37,38 but this has not been demonstrated consistently in clinical trials.^39-43 In the United States, EGFR mutations are found in approximately 10% of patients with NSCLC, while the incidence can be as high as 50% in Asia.⁴⁴ Even though the cobas EGFR mutation test is the companion diagnostic approved by the US FDA, a positive test result from any laboratory with the Clinical Laboratory Improvement Amendments (CLIA) certificate should prompt the use of an EGFR TKI as the initial treatment.

Three EGFR TKIs that have been approved as first-line therapy in the United States are available: erlotinib, afatinib, and gefitinib.⁵ Both erlotinib and gefitinib are considered first-generation TKIs. They have higher binding affinity for the 2 common EGFR mutations than wild-type EGFR. In addition, they reversibly bind to the intracellular tyrosine kinase domain, resulting in inhibition of autophosphorylation of the tyrosine residues. Afatinib, a second-generation and irreversible TKI, targets EGFR (HER1) as well as HER2 and HER4.⁴⁵

The superior efficacy of the EGFR TKIs over platinum doublet chemotherapy in treatment-naïve patients with EGFR mutations has been demonstrated in 7 randomized trials to date (Table).⁴⁶ Erlotinib was the TKI arm for the OPTIMAL,⁴¹ EURTAC,⁴² and ENSURE trials;³⁸ afatinib was the TKI arm for LUX-LUNG 3³⁷ and 6;⁴³ gefitinib was the TKI arm for NEJ002^39,47 and WJTOG3405.⁴⁰ A meta-analysis of these 7 trials by Lee et al showed that progression-free survival (PFS) was significantly prolonged by EGFR TKIs (hazard ratio [HR] 0.37 [95% confidence interval {CI} 0.32 to 0.42]).⁴⁶ For instance, in the EURTAC trial, median PFS was 9.7 months for patients treated with erlotinib as compared to 5.2 months for patients treated with platinum/gemcitabine or platinum/docetaxel.⁴² In this meta-analysis, prespecified subgroups included age, sex, ethnicity, smoking status, performance status, tumor histology, and EGFR mutation subtype. The superior outcome with TKIs was observed in all subgroups. Furthermore, patients with exon 19 deletions, nonsmokers, and women had even better outcomes.⁴⁶

Erlotinib is the most commonly used TKI in the United States largely because gefitinib was off the market for some time until it was re-approved by the FDA in 2015. Interestingly, this “re-approval” was not based on either 1 of the 2 prospective trials (NEJ002^39,47 and WJTOG3405⁴⁰), but rather was based on an exploratory analysis of the IPASS trial^48,49 as well as a prospective phase 4, single-arm trial in Europe (IFUM).⁵⁰ The superior efficacy of gefitinib over carboplatin/paclitaxel among patients with EGFR mutations in the IPASS trial was confirmed by blind independent central review, with longer PFS (HR 0.54 [95% CI 0.38 to 0.79] P = 0.0012) and higher objective response rate (ORR; odds ratio 3 [95% CI 1.63 to 5.54], P = 0.0004).⁴⁹

CASE 1 CONTINUED

Based on the EGFR L858R mutation status, the patient is started on erlotinib. He is quite happy that he does not need intravenous chemotherapy but wants to know what toxicities he might potentially have with erlotinib.

• What are the common adverse effects (AEs) of EGFR TKIs? How are AEs of TKIs managed?

Safety Profile

The important toxicities associated with EGFR TKIs are rash, gastrointestinal toxicity, hepatic toxicity, and pulmonary toxicity. Rash is an AE specific to all agents blocking the EGFR pathway, including small molecules and monoclonal antibodies such as cetuximab. The epidermis has a high level of expression of EGFR, which contributes to this toxicity.⁵¹ Rash usually presents as dry skin or acneiform eruption. Prophylactic treatment with oral tetracyclines and topical corticosteroids is generally recommended upon initiation of TKI therapy. Diarrhea is the most prevalent gastrointestinal toxicity. All patients starting treatment should be given prescriptions to manage diarrhea such as loperamide and be advised to call when it occurs. Hepatic toxicity is often manifested as elevated transaminases or bilirubin. Interstitial lung disease (ILD) is a rare but potentially fatal pulmonary toxicity.

Rash of any grade was reported in 49.2% of patients treated with erlotinib in clinical trials, while grade 3 rash occurred in 6% of patients and no grade 4 was reported. Diarrhea of any grade was reported in 20.3% of patients, grade 3 diarrhea occurred in 1.8%, and no grade 4 was reported. Grade 2 and 3 alanine aminotransferase (ALT) elevations were seen in 2% and 1% of patients, respectively. Grade 2 and 3 bilirubin elevations were seen in 4% and less than 1% of patients, respectively. The incidence of serious ILD-like events was less than 1%.⁵²

Afatinib is associated with higher incidences of rash and diarrhea. Specifically, diarrhea and rash of all grades were reported in 96% and 90% of patients treated with afatinib, respectively. Paronychia of all grades occurred in 58% of patients. Elevated ALT of all grades was seen in 11% of patients. Approximately 1.5% of patients treated with afatinib across clinical trials had ILD or ILD-like AEs.⁵³

Gefitinib, the most commonly used TKI outside United States, has a toxicity profile similar to erlotinib, except for hepatic toxicity. For instance, rash of all grades occurred in 47% of patients, diarrhea of all grades occurred in 29% of patients, and ILD or ILD-like AEs occurred in 1.3% of patients across clinical trials. In comparison, elevated ALT and aspartate aminotransferase (AST) of all grades was seen in 38% and 40% of patients, respectively.⁵⁴ Therefore, close monitoring of liver function is clinically warranted. In particular, patients need to be advised to avoid concomitant use of herbal supplements, a common practice in Asian countries.

CASE 1 CONTINUED

The patient does well while on erlotinib at 150 mg orally once daily for about 8 months, until he develops increasing abdominal pain. A CT scan of the abdomen and pelvis with contrast shows a new 8-cm right adrenal mass. Additionally, a repeat CT scan of the chest with contrast shows a stable lung mass but enlarging mediastinal lymphadenopathy.

• How would you manage the patient at this point?

MANAGEMENT OF T790M MUTATION AFTER PROGRESSION ON FIRST-LINE EGFR TKIS

As mentioned above, the median PFS of patients with EGFR mutations treated with 1 of the 3 TKIs is around 9 to 13 months.⁴⁶ Of the various resistance mechanisms that have been described, the T790M mutation is found in approximately 60% of patients who progress after treatment with first-line TKIs.^55,56 Other mechanisms, such as HER2 amplification, MET amplification, or rarely small cell transformation, have been reported.⁵⁶ The first- and second-generation EGFR TKIs function by binding to the ATP-binding domain of mutated EGFR, leading to inhibition of the downstream signaling pathways (Figure, part B) and ultimately cell death.³⁵ The T790M mutation hinders the interaction between the ATP-binding domain of EGFR kinase and TKIs, resulting in treatment resistance and disease progression.^57,58

Osimertinib is a third-generation irreversible EGFR TKI with activity against both sensitizing EGFR and resistant T790M mutations. It has low affinity for wide-type EGFR as well as insulin receptor and insulin-like growth factor receptor.⁵⁹ Osimertinib has been fully approved for NSCLC patients with EGFR mutations who have progressed on first-line EGFR TKIs with the development of T790M mutation. An international phase 3 trial (AURA3) randomly assigned 419 patients in a 2:1 ratio to either osimertinib or platinum/pemetrexed. Eligible patients all had the documented EGFR mutations and disease progression after first-line EGFR TKIs. Central confirmation of the T790M mutation was required. Median PFS by investigator assessment, the trial’s primary end point, was 10.1 months for osimertinib versus 4.4 months for chemotherapy (HR 0.3 [95% CI 0.23 to 0.41]; P < 0.001). ORR was 71% for osimertinib versus 31% for chemotherapy (HR 5.39 [95% CI 3.47 to 8.48], P < 0.001). A total of 144 patients with stable and asymptomatic brain metastases were also eligible. Median PFS for this subset of patients treated with osimertinib and chemotherapy was 8.5 months and 4.2 months, respectively (HR 0.32 [95% CI 0.21 to 0.49]). In the AURA3 trial, osimertinib was better tolerated than chemotherapy, with 23% of patients treated with osimertinib experiencing grade 3 or 4 AEs as compared to 47% of chemotherapy-treated patients. The most common AEs of any grade were diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%).⁶⁰

For the case patient, a reasonable approach would be to obtain a tissue biopsy of the adrenal mass and more importantly to check for the T790M mutation. Similar to the companion diagnostic for EGFR mutations, the cobas EGFR mutation test v2 is the FDA-approved test for T790M. However, if this resistance mutation is detected by any CLIA-certified laboratories, osimertinib should be the recommended treatment option. If tissue biopsy is not feasible, plasma-based testing should be considered. A blood-based companion diagnostic also is FDA approved.

ALK REARRANGEMENTS

CASE 2 PRESENTATION

A 42-year-old Korean woman who is a non-smoker with no significant past medical history presents with fatigue, unintentional weight loss of 20 lb in the past 4 months, and vague abdominal pain. A CT can of the abdomen and pelvis without contrast shows multiple foci in the liver and an indeterminate nodule in the right lung base. She subsequently undergoes PET/CT, which confirms multiple liver nodules/masses ranging from 1 to 3 cm with moderate FDG uptake. In addition, there is a 3.5-cm pleura-based lung mass on the right side with moderate FDG uptake. MRI-brain with and without contrast is negative for malignancy. A CT-guided biopsy of 1 of the liver masses is ordered and pathology returns positive for poorly differentiated adenocarcinoma consistent with lung primary. Molecular analysis reveals an echinoderm microtubule-associated protein-like 4 (EML4)-ALK rearrangement. She is placed on crizotinib by an outside oncologist and after about 3 weeks of therapy is doing well. She is now in your clinic for a second opinion. She says that some of her friends told her about another medication called ceritinib and was wondering if she would need to switch her cancer treatment.

• How would you respond to this patient’s inquiry?

FIRST-LINE TKIS FOR ALK REARRANGEMENTS

ALK rearrangements are found in 2% to 7% of NSCLC, with EML4-ALK being the most prevalent fusion variant.⁶¹ The inversion of chromosome 2p leads to the fusion of the EML4 gene and the ALK gene, which causes the constitutive activation of the fusion protein and ultimately increased transformation and tumorigenicity.^7,61 Patients harboring ALK rearrangements tend to be non-smokers. Adenocarcinoma, especially signet ring cell subtype, is the predominant histology. Compared to EGFR mutations, patients with ALK mutations are significantly younger and more likely to be men.⁶²ALK rearrangements can be detected by either FISH or IHC, and most next-generation sequencing (NGS) panels have the ability to identify this driver mutation.

Crizotinib is the first approved ALK inhibitor for the treatment of NSCLC in this molecular subset of patients.⁶³ PROFILE 1014 is a phase 3 randomized trial that compared crizotinib with chemotherapy containing platinum/pemetrexed for up to 6 cycles. Crossover to crizotinib was allowed for patients with disease progression on chemotherapy. The primary end point was PFS by independent radiologic review. The crizotinib arm demonstrated superior PFS (10.9 months versus 7 months; HR 0.45 [95% CI 0.35 to 0.6], P < 0.001) and ORR (74% versus 45%, P < 0.001). Median survival was not reached in either arm (HR 0.82 [95% CI 0.54 to 1.26], P = 0.36).⁶⁴ Based on this international trial, crizotinib is considered standard of care in the United States for treatment-naïve patients with advanced NSCLC harboring ALK rearrangements. The current recommended dose is 250 mg orally twice daily. Common treatment-related AEs of all grades include vision disorder (62%), nausea (53%), diarrhea (43%), vomiting (40%), edema (28%), and constipation (27%).⁶⁵ PROFILE 1007 compared crizotinib with pemetrexed or docetaxel in ALK-rearranged NSCLC patients with prior exposure to 1 platinum-based chemotherapy. The median PFS was 7.7 months for crizotinib as compared to 3 months for chemotherapy (HR 0.49 [95% CI 0.37 to 0.64], P < 0.001). The response rates were 65% and 20% for crizotinib and chemotherapy, respectively (P < 0.001).⁶⁶ In other countries, crizotinib following 1 prior platinum-based regimen may be considered standard of care based on this trial.

Ceritinib is an oral second-generation ALK inhibitor that is 20 times more potent than crizotinib based on enzymatic assays.⁶⁷ It also targets ROS1 and insulin-like growth factor 1 receptor but not c-MET. It was first approved by the FDA in April 2014 for metastatic ALK-rearranged NSCLC following crizotinib.⁶⁸ In May 2017, the FDA granted approval of ceritinib for treatment-naïve patients. This decision was based on the results of the ASCEND-4 trial, a randomized phase 3 trial assessing the efficacy and safety of ceritinib over chemotherapy in the first-line setting. The trial assigned 376 patients to either ceritinib at 750 mg once daily or platinum/pemetrexed for 4 cycles followed by maintenance pemetrexed. Median PFS was 16.6 months for ceritinib versus 8.1 months for chemotherapy (HR 0.55 [95% CI 0.42 to 0.73]; P < 0.00001).⁶⁹ Toxicities of ceritinib are not negligible, with gastrointestinal toxicity being the most prevalent. For instance, diarrhea, nausea, vomiting, abdominal pain, and constipation of all grades were seen in 86%, 80%, 60%, 54%, and 29% of patients, respectively. Furthermore, fatigue and decreased appetite occurred in 52% and 34% of patients, respectively. In terms of laboratory abnormalities, 84% of patients experienced decreased hemoglobin of all grades; 80% increased ALT; 75% increased AST; 58% increased creatinine; 49% increased glucose; 36% decreased phosphate; and 28% increased lipase. Due to these AEs, the incidence of dose reduction was about 58% and the median onset was around 7 weeks.⁷⁰

Alectinib is another oral second-generation ALK inhibitor that was approved by the FDA in December 2015 for the treatment of NSCLC patients with ALK rearrangements who have progressed on or are intolerant to crizotinib.⁷¹ Its indication will soon be broadened to the first-line setting based on the ALEX trial.⁷² Alectinib is a potent and highly selective TKI of ALK⁷³ with activity against known resistant mutations to crizotinib.^74,75 It also inhibits RET but not ROS1 or c-MET.⁷⁶ ALEX, a randomized phase 3 study, compared alectinib with crizotinib in treatment-naïve patients with NSCLC harboring ALK rearrangements. The trial enrolled 303 patients and the median follow-up was approximately 18 months. The alectinib arm (600 mg twice daily) demonstrated significantly higher PFS by investigator-assessment, the trial’s primary end point. The 12-month event-free survival was 68.4% (95% CI 61% to 75.9%) versus 48.7% (95% CI 40.4% to 56.9%) for alectinib and crizotinib, respectively (HR 0.47 [95% CI 0.34 to 0.65], P < 0.001). The median PFS was not reached in the alectinib arm (95% CI 17.7 months to not estimable) as compared to 11.1 months in the crizotinib arm (95% CI 9.1 to 13.1 months).⁷² Alectinib is generally well tolerated. Common AEs of all grades include fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). As alectinib can cause anemia, lymphopenia, hepatic toxicity, increased creatine phosphokinase, hyperglycemia, electrolyte abnormalities, and increased creatinine, periodic monitoring of these laboratory values is important, although most of these abnormalities are grade 1 or 2.⁷⁷

Brigatinib, another oral second-generation ALK inhibitor, was granted accelerated approval by the FDA in April 2017 for ALK-rearranged and crizotinib-resistant NSCLC based on the ALTA trial. This randomized phase 2 study of brigatinib showed an ORR by investigator assessment of 54% (97.5% CI 43% to 65%) in the 180 mg once daily arm with lead-in of 90 mg once daily for 7 days. Median PFS was 12.9 months (95% CI 11.1 months to not reached [NR]).⁷⁸ Currently, a phase 3 study of brigatinib versus crizotinib in ALK inhibitor–naïve patients is recruiting participants (ALTA-1L). It will be interesting to see if brigatinib can achieve a front-line indication.

Starting the case patient on crizotinib is well within the treatment guidelines. One may consider ceritinib or alectinib in the first-line setting, but both TKIs can be reserved upon disease progression. We would recommend a repeat biopsy at that point to look for resistant mechanisms, as certain secondary ALK mutations may be rescued by certain next-generation ALK inhibitors. For instance, the F1174V mutation has been reported to confer resistance to ceritinib but sensitivity to alectinib, while the opposite is true for I1171T. The G1202R mutation is resistant to ceritinib, alectinib, and brigatinib, but lorlatinib, a third-generation ALK inhibitor, has shown activity against this mutation.⁷⁹ Furthermore, brain metastasis represents a treatment challenge for patients with ALK rearrangements. It is also an efficacy measure of next-generation ALK inhibitors, all of which have demonstrated better central nervous system activity than crizotinib.^69,78,80 If the case patient were found to have brain metastasis at the initial diagnosis, either ceritinib or alectinib would be a reasonable choice since crizotinib has limited penetration of blood-brain barrier.⁸¹

ROS1 REARRANGEMENTS

CASE PRESENTATION 3

A 66-year-old Chinese woman who is a non-smoker with a past medical history of hypertension and hypothyroidism presents to the emergency department for worsening lower back pain. Initial workup includes x-ray of the lumbar spine followed by MRI with contrast, which shows a soft tissue mass at L3-4 without cord compression. CT of the chest, abdomen, and pelvis with contrast shows a 7-cm right hilar mass, bilateral small lung nodules, mediastinal lymphadenopathy, and multiple lytic lesions in ribs, lumbar spine, and pelvis. MRI-brain with and without contrast is negative for malignancy. She undergoes endo-bronchial ultrasound and biopsy of the right hilar mass, which shows poorly differentiated adenocarcinoma. While waiting for the result of the molecular analysis, the patient undergoes palliative radiation therapy to L2-5 with good pain relief. She is discharged from the hospital and presents to your clinic for follow up. Molecular analysis now reveals ROS1 rearrangement with CD74-ROS1 fusion.

• What treatment plan should be put in place for this patient?

FIRST-LINE THERAPY FOR ROS1 REARRANGEMENTS

Approximately 2.4% of lung adenocarcinomas harbor ROS1 rearrangements.⁸² This distinct genetic alteration occurs more frequently in NSCLC patients who are younger, female, and never-smokers, and who have adenocarcinomas.⁸ It has been shown that ROS1 rearrangements rarely overlap with other genetic alterations including KRAS mutations, EGFR mutations, and ALK rearrangements.⁸³ As a receptor tyrosine kinase, ROS1 is similar to ALK and insulin receptor family members.⁸⁴ Crizotinib, which targets ALK, ROS1, and c-MET, was approved by the FDA on March 11, 2016, for the treatment of metastatic ROS1-rearranged NSCLC.⁸⁵ The approval was based on a phase 2 expansion cohort of the original phase 1 study. Among 50 US patients enrolled in this expansion cohort, 3 had complete responses and 33 had partial responses with ORR of 72% (95% CI 58% to 84%). Median PFS was 19.2 months (95% CI 14.4 months to NR) and median duration of response (DOR) was 17.6 months (95% CI 14.5 months to NR).⁸⁶ During longer follow-up, independent radiology review confirmed high ORR of 66% and median DOR of 18.3 months.⁸⁵

Interestingly, no companion diagnostic assay has been approved for the detection of ROS1 rearrangements with the approval of crizotinib. In the United States, break apart FISH is the most common detection method. In fact, in the above mentioned phase 2 study, ROS1 rearrangements were detected in 49 out of 50 patients by this method.⁸⁶ FISH can be technically challenging when dealing with high volume and multiple targets. Reverse transcriptase-PCR is another detection method, but it requires knowledge of the fusion partners. To date, at least 14 ROS1 fusion partners have been reported, with CD74 being the most common.⁸⁷ NGS with appropriate design and validation can also be used to detect ROS1 rearrangements.

For the case patient, the recommendation would be to start her on crizotinib at 250 mg twice daily. Monitoring for vision disturbance, gastrointestinal complaints, and edema is warranted. Because the estimated onset of response is around 7.9 weeks,⁸⁶ plans should be made to repeat her scans in approximately 2 months.

BRAF V600E MUTATIONS

CASE PRESENTATION 4

A 71-year-old Caucasian man with a past medical history of hypertension, dyslipidemia, and ischemic cerebrovascular accident without residual deficits was diagnosed with stage IV adenocarcinoma of the lung about 8 months ago. He has a 40 pack-year smoking history and quit smoking when he was diagnosed with lung cancer. His disease burden involved a large mediastinal mass, scattered pleural nodules, multiple lymphadenopathy, and several soft tissue masses. His outside oncologist started him on chemotherapy containing carboplatin and pemetrexed for 6 cycles followed by maintenance pemetrexed. The most recent restaging scans show disease progression with enlarging soft tissue masses and several new lytic bone lesions. MRI-brain with and without contrast shows 2 subcentimeter enhancing lesions. He transferred care to you approximately 4 weeks ago. You ordered a repeat biopsy of 1 of the enlarging soft tissue masses. Molecular analysis revealed BRAF V600E mutation. In the interim, he underwent stereotactic radiosurgery for the 2 brain lesions without any complications. The patient is now in your clinic for follow up.

• What would be your recommended systemic treatment?

TARGETED THERAPIES FOR BRAF V600E MUTATION

BRAF mutations were first recognized as activating mutations in advanced melanomas, with BRAF V600E, resulting from the substitution of glutamic acid for valine at amino acid 600, being the most common. BRAF plays an important role in the mitogen-activated protein kinase (MAPK) signaling pathway. Briefly, the activation of MAPK pathway occurs upon ligand binding of receptor tyrosine kinases, which then involves RAS/BRAF/MEK/ERK in a stepwise manner, ultimately leading to cell survival. BRAF mutations have been increasingly recognized also as driver mutations in NSCLC.^9–12 They can be detected by PCR or NGS method. The characteristics of NSCLC patients harboring BRAF mutations have been described by various groups.^9–12 For instance, 1 case series showed that the incidence was 2.2% among patients with advanced lung adenocarcinoma; 50% of mutations were V600E, while G469A and D594G accounted for the remaining 39% and 11% of patients, respectively. All patients were either current or former smokers. The median OS of patients with BRAF mutations in this case series was NR, while it was 37 months for patients with EGFR mutations (P = 0.73) and NR for patients with ALK rearrangements (P = 0.64).⁹

For patients with BRAF V600E–mutant NSCLC who have progressed on platinum-based chemotherapy, the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) may represent a new treatment paradigm. This was illustrated in a phase 2, nonrandomized, open-label study. A total of 57 patients were enrolled and 36 patients (63.2% [95% CI 49.3% to 75.6%]) achieved an overall response by investigator assessment, the trial’s primary end point. Disease control rate was 78.9% (95% CI 66.1% to 88.6%), with 4% complete response, 60% partial response, and 16% stable disease. PFS was 9.7 months (95% CI [6.9 to 19.6 months]). The safety profile was comparable to what had been observed in patients with melanoma treated with this regimen. More specifically, 56% of patients on this trial reported serious AEs, including pyrexia (16%), anemia (5%), confusional state (4%), decreased appetite (4%), hemoptysis (4%), hypercalcemia (4%), nausea (4%), and cutaneous squamous cell carcinoma (4%). In addition, neutropenia (9%) and hyponatremia (7%) were the most common grade 3-4 AEs.¹⁶

The case patient has experienced disease progression after 1 line of platinum-based chemotherapy, so the combination of dabrafenib and trametinib would be a robust systemic treatment option. dabrafenib as a single agent has also been studied in BRAF V600E–mutant NSCLC in a phase 2 trial. The overall response by investigator assessment among 84 patients was 33% (95% CI 23% to 45%).¹⁴ Vemurafenib, another oral BRAF TKI, has demonstrated efficacy for NSCLC patients harboring BRAF V600E mutation. In the cohort of 20 patients with NSCLC, the response rate was 42% (95% CI 20% to 67%) and median PFS was 7.3 months (95% CI 3.5 to 10.8 months).¹³ Patients with non-V600E mutations have shown variable responses to targeted therapies. MEK TKIs may be considered in this setting; however, the details of this discussion are beyond the scope of this review.

CONCLUSION

The management of advanced NSCLC with driver mutations has seen revolutionary changes over the past decade. Tremendous research has been done in order to first understand the molecular pathogenesis of NSCLC and then discover driver mutations that would lead to development of targeted therapies with clinically significant efficacy as well as tolerability. More recently, increasing efforts have focused on how to conquer acquired resistance in patients with disease progression after first-line TKIs. The field of EGFR-mutant NSCLC has set a successful example, but the work is nowhere near finished. The goals are to search for more driver mutations and to design agents that could potentially block cell survival signals once and for all.

INTRODUCTION

Lung cancer is the second most common type of cancer in the United States, with 222,500 estimated new cases in 2017, according to the American Cancer Society.¹ However, it is by far the number one cause of death due to cancer, with an estimated 155,870 lung cancer–related deaths occurring in 2017, which is higher than the number of deaths due to breast cancer, prostate cancer, and colorectal cancer combined.^1,2 Despite slightly decreasing incidence and mortality over the past decade, largely due to smoking cessation, the 5-year survival rate of lung cancer remains dismal at approximately 18%.^2–4

Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancer cases.⁴ Traditionally, it is further divided based on histology: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and not otherwise specified.⁵ Chemotherapy had been the cornerstone of treatment for stage IV NSCLC. It is not target-specific and is most effective against rapidly growing cells. Common adverse effects include alopecia, nausea/vomiting, myelosuppression, cardiotoxicity, neuropathy, and nephrotoxicity. However, this paradigm has shifted following the discovery of mutations of the epidermal growth factor receptor (EGFR) gene as an oncogenic driver that confers sensitivity to small molecule tyrosine kinase inhibitors (TKIs) targeting EGFR.⁶ The EGFR inhibitors are given orally and have a spectrum of toxicities (eg, such as rash, diarrhea, and elevated transaminases) different from that of systemic chemotherapy, which is often administered intravenously. Following the discovery of EGFR mutations, rearrangements of the anaplastic lymphoma kinase (ALK) gene⁷ and ROS1 gene⁸ were identified as targetable driver mutations in NSCLC. The frequency of both rearrangements is lower than that of EGFR mutations. Additionally, BRAF V600E mutation has been identified in NSCLC.^9–12 This activation mutation is commonly seen in melanoma. Agents that have already been approved for the treatment of melanoma with the BRAF V600E mutation are being tested in NSCLC patients with this mutation.^13–16

Given the effectiveness and tolerability of targeted therapy, identifying this distinct molecular subset of NSCLC patients is critical in treatment. Currently, molecular testing is mandatory in all stage IV patients with non-squamous cell carcinoma, as a preponderance of patients with driver mutations have this histology subtype.^5,17–19 For patients with squamous cell carcinoma, molecular testing should be considered if the biopsy specimen is small, there is mixed histology, or the patient is a nonsmoker.^5,20 Several techniques are commonly utilized in detecting these genetic alterations. EGFR mutation can be detected by polymerase chain reaction (PCR), ALK or ROS1 rearrangement can be detected by fluorescence in-situ hybridization (FISH), and immunohistochemistry (IHC) can also be used to detect ALK rearrangement. The current guideline is to use comprehensive genomic profiling to capture all the potential molecular targets simultaneously instead of running stepwise tests just for EGFR, ALK, and ROS1.⁵BRAF V600E mutation,^13–16 MET exon 14 skipping mutation,^21–24 RET rearrangements,^25–27 and HER2 mutations^28–30 are among the emergent genetic alterations with various responses to targeted therapy.³¹ Some of these targeted agents have been approved for other types of malignancy, and others are still in the development phase.

Several initiatives worldwide have reported better outcomes of patients with driver mutations treated with targeted therapy. For instance, the Lung Cancer Mutation Consortium in the United States demonstrated that the median survival of patients without driver mutations, with drivers mutations but not treated with targeted therapy, and with driver mutations and treated with targeted therapy was 2.08 years, 2.38 years, and 3.49 years, respectively.³² The French Cooperative Thoracic Intergroup-French National Cancer Institute demonstrated that the median survival for patients with driver mutations versus those without driver mutations was 16.5 months versus 11.8 months.³³ The Spanish Lung Cancer Group demonstrated that the overall survival (OS) for patients with EGFR mutations treated with erlotinib was 27 months.³⁴ The mutations in lung cancer, their frequencies, and the downstream signaling pathways are depicted in the Figure.³⁵

In this article, we discuss targeted therapy for patients with EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutation. We also discuss the management of patients with EGFR mutations who develop a secondary mutation after TKI therapy. Almost all of the targeted agents discussed herein have been approved by the US Food and Drug Administration (FDA), so they are considered standard of care. All available phase 3 trials pertinent to these targeted therapies are included in the discussion.

EGFR MUTATIONS

CASE PRESENTATION 1

A 54-year-old Caucasian man who is a former smoker with a 10 pack-year history and past medical history of hypertension and dyslipidemia presents with progressive dyspnea for several weeks. A chest x-ray shows moderate pleural effusion on the left side with possible mass-like opacity on the left upper lung field. An ultrasound-guided thoracentesis is performed and cytology is positive for adenocarcinoma of likely pulmonary origin. Staging workup including positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging of the brain with and without contrast is done. PET/CT shows a 5.5-cm mass in the left upper lobe of the lung with high fluorodeoxyglucose (FDG) uptake, several 1- to 2-cm mediastinal lymph nodes with moderate FDG uptake, and small pleural effusion on both sides with moderate FDG uptake. MRI-brain is negative for malignancy. The patient subsequently undergoes a CT-guided biopsy of the lung mass, which shows moderately differentiated adenocarcinoma. Comprehensive molecular profiling reveals EGFR L858R mutation only. The patient now presents for the initial consultation. Of note, his Eastern Cooperative Oncology Group performance status is 1.

• What is the next step in the management of this patient?

FIRST-LINE TKI FOR SENSITIZING EGFR MUTATIONS

The 2 most common EGFR mutations are deletions in exon 19 and substitution of arginine for leucine in exon 21 (L858R), found in approximately 45% and 40% of patients with EGFR mutations, respectively.³⁶ Both mutations are sensitive to EGFR TKIs. The benefit may be greater in patients with exon 19 deletions as compared to exon 21 L858R substitution,^37,38 but this has not been demonstrated consistently in clinical trials.^39-43 In the United States, EGFR mutations are found in approximately 10% of patients with NSCLC, while the incidence can be as high as 50% in Asia.⁴⁴ Even though the cobas EGFR mutation test is the companion diagnostic approved by the US FDA, a positive test result from any laboratory with the Clinical Laboratory Improvement Amendments (CLIA) certificate should prompt the use of an EGFR TKI as the initial treatment.

Three EGFR TKIs that have been approved as first-line therapy in the United States are available: erlotinib, afatinib, and gefitinib.⁵ Both erlotinib and gefitinib are considered first-generation TKIs. They have higher binding affinity for the 2 common EGFR mutations than wild-type EGFR. In addition, they reversibly bind to the intracellular tyrosine kinase domain, resulting in inhibition of autophosphorylation of the tyrosine residues. Afatinib, a second-generation and irreversible TKI, targets EGFR (HER1) as well as HER2 and HER4.⁴⁵

The superior efficacy of the EGFR TKIs over platinum doublet chemotherapy in treatment-naïve patients with EGFR mutations has been demonstrated in 7 randomized trials to date (Table).⁴⁶ Erlotinib was the TKI arm for the OPTIMAL,⁴¹ EURTAC,⁴² and ENSURE trials;³⁸ afatinib was the TKI arm for LUX-LUNG 3³⁷ and 6;⁴³ gefitinib was the TKI arm for NEJ002^39,47 and WJTOG3405.⁴⁰ A meta-analysis of these 7 trials by Lee et al showed that progression-free survival (PFS) was significantly prolonged by EGFR TKIs (hazard ratio [HR] 0.37 [95% confidence interval {CI} 0.32 to 0.42]).⁴⁶ For instance, in the EURTAC trial, median PFS was 9.7 months for patients treated with erlotinib as compared to 5.2 months for patients treated with platinum/gemcitabine or platinum/docetaxel.⁴² In this meta-analysis, prespecified subgroups included age, sex, ethnicity, smoking status, performance status, tumor histology, and EGFR mutation subtype. The superior outcome with TKIs was observed in all subgroups. Furthermore, patients with exon 19 deletions, nonsmokers, and women had even better outcomes.⁴⁶

Erlotinib is the most commonly used TKI in the United States largely because gefitinib was off the market for some time until it was re-approved by the FDA in 2015. Interestingly, this “re-approval” was not based on either 1 of the 2 prospective trials (NEJ002^39,47 and WJTOG3405⁴⁰), but rather was based on an exploratory analysis of the IPASS trial^48,49 as well as a prospective phase 4, single-arm trial in Europe (IFUM).⁵⁰ The superior efficacy of gefitinib over carboplatin/paclitaxel among patients with EGFR mutations in the IPASS trial was confirmed by blind independent central review, with longer PFS (HR 0.54 [95% CI 0.38 to 0.79] P = 0.0012) and higher objective response rate (ORR; odds ratio 3 [95% CI 1.63 to 5.54], P = 0.0004).⁴⁹

CASE 1 CONTINUED

Based on the EGFR L858R mutation status, the patient is started on erlotinib. He is quite happy that he does not need intravenous chemotherapy but wants to know what toxicities he might potentially have with erlotinib.

• What are the common adverse effects (AEs) of EGFR TKIs? How are AEs of TKIs managed?

Safety Profile

The important toxicities associated with EGFR TKIs are rash, gastrointestinal toxicity, hepatic toxicity, and pulmonary toxicity. Rash is an AE specific to all agents blocking the EGFR pathway, including small molecules and monoclonal antibodies such as cetuximab. The epidermis has a high level of expression of EGFR, which contributes to this toxicity.⁵¹ Rash usually presents as dry skin or acneiform eruption. Prophylactic treatment with oral tetracyclines and topical corticosteroids is generally recommended upon initiation of TKI therapy. Diarrhea is the most prevalent gastrointestinal toxicity. All patients starting treatment should be given prescriptions to manage diarrhea such as loperamide and be advised to call when it occurs. Hepatic toxicity is often manifested as elevated transaminases or bilirubin. Interstitial lung disease (ILD) is a rare but potentially fatal pulmonary toxicity.

Rash of any grade was reported in 49.2% of patients treated with erlotinib in clinical trials, while grade 3 rash occurred in 6% of patients and no grade 4 was reported. Diarrhea of any grade was reported in 20.3% of patients, grade 3 diarrhea occurred in 1.8%, and no grade 4 was reported. Grade 2 and 3 alanine aminotransferase (ALT) elevations were seen in 2% and 1% of patients, respectively. Grade 2 and 3 bilirubin elevations were seen in 4% and less than 1% of patients, respectively. The incidence of serious ILD-like events was less than 1%.⁵²

Afatinib is associated with higher incidences of rash and diarrhea. Specifically, diarrhea and rash of all grades were reported in 96% and 90% of patients treated with afatinib, respectively. Paronychia of all grades occurred in 58% of patients. Elevated ALT of all grades was seen in 11% of patients. Approximately 1.5% of patients treated with afatinib across clinical trials had ILD or ILD-like AEs.⁵³

Gefitinib, the most commonly used TKI outside United States, has a toxicity profile similar to erlotinib, except for hepatic toxicity. For instance, rash of all grades occurred in 47% of patients, diarrhea of all grades occurred in 29% of patients, and ILD or ILD-like AEs occurred in 1.3% of patients across clinical trials. In comparison, elevated ALT and aspartate aminotransferase (AST) of all grades was seen in 38% and 40% of patients, respectively.⁵⁴ Therefore, close monitoring of liver function is clinically warranted. In particular, patients need to be advised to avoid concomitant use of herbal supplements, a common practice in Asian countries.

CASE 1 CONTINUED

The patient does well while on erlotinib at 150 mg orally once daily for about 8 months, until he develops increasing abdominal pain. A CT scan of the abdomen and pelvis with contrast shows a new 8-cm right adrenal mass. Additionally, a repeat CT scan of the chest with contrast shows a stable lung mass but enlarging mediastinal lymphadenopathy.

• How would you manage the patient at this point?

MANAGEMENT OF T790M MUTATION AFTER PROGRESSION ON FIRST-LINE EGFR TKIS

As mentioned above, the median PFS of patients with EGFR mutations treated with 1 of the 3 TKIs is around 9 to 13 months.⁴⁶ Of the various resistance mechanisms that have been described, the T790M mutation is found in approximately 60% of patients who progress after treatment with first-line TKIs.^55,56 Other mechanisms, such as HER2 amplification, MET amplification, or rarely small cell transformation, have been reported.⁵⁶ The first- and second-generation EGFR TKIs function by binding to the ATP-binding domain of mutated EGFR, leading to inhibition of the downstream signaling pathways (Figure, part B) and ultimately cell death.³⁵ The T790M mutation hinders the interaction between the ATP-binding domain of EGFR kinase and TKIs, resulting in treatment resistance and disease progression.^57,58

Osimertinib is a third-generation irreversible EGFR TKI with activity against both sensitizing EGFR and resistant T790M mutations. It has low affinity for wide-type EGFR as well as insulin receptor and insulin-like growth factor receptor.⁵⁹ Osimertinib has been fully approved for NSCLC patients with EGFR mutations who have progressed on first-line EGFR TKIs with the development of T790M mutation. An international phase 3 trial (AURA3) randomly assigned 419 patients in a 2:1 ratio to either osimertinib or platinum/pemetrexed. Eligible patients all had the documented EGFR mutations and disease progression after first-line EGFR TKIs. Central confirmation of the T790M mutation was required. Median PFS by investigator assessment, the trial’s primary end point, was 10.1 months for osimertinib versus 4.4 months for chemotherapy (HR 0.3 [95% CI 0.23 to 0.41]; P < 0.001). ORR was 71% for osimertinib versus 31% for chemotherapy (HR 5.39 [95% CI 3.47 to 8.48], P < 0.001). A total of 144 patients with stable and asymptomatic brain metastases were also eligible. Median PFS for this subset of patients treated with osimertinib and chemotherapy was 8.5 months and 4.2 months, respectively (HR 0.32 [95% CI 0.21 to 0.49]). In the AURA3 trial, osimertinib was better tolerated than chemotherapy, with 23% of patients treated with osimertinib experiencing grade 3 or 4 AEs as compared to 47% of chemotherapy-treated patients. The most common AEs of any grade were diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%).⁶⁰

For the case patient, a reasonable approach would be to obtain a tissue biopsy of the adrenal mass and more importantly to check for the T790M mutation. Similar to the companion diagnostic for EGFR mutations, the cobas EGFR mutation test v2 is the FDA-approved test for T790M. However, if this resistance mutation is detected by any CLIA-certified laboratories, osimertinib should be the recommended treatment option. If tissue biopsy is not feasible, plasma-based testing should be considered. A blood-based companion diagnostic also is FDA approved.

ALK REARRANGEMENTS

CASE 2 PRESENTATION

A 42-year-old Korean woman who is a non-smoker with no significant past medical history presents with fatigue, unintentional weight loss of 20 lb in the past 4 months, and vague abdominal pain. A CT can of the abdomen and pelvis without contrast shows multiple foci in the liver and an indeterminate nodule in the right lung base. She subsequently undergoes PET/CT, which confirms multiple liver nodules/masses ranging from 1 to 3 cm with moderate FDG uptake. In addition, there is a 3.5-cm pleura-based lung mass on the right side with moderate FDG uptake. MRI-brain with and without contrast is negative for malignancy. A CT-guided biopsy of 1 of the liver masses is ordered and pathology returns positive for poorly differentiated adenocarcinoma consistent with lung primary. Molecular analysis reveals an echinoderm microtubule-associated protein-like 4 (EML4)-ALK rearrangement. She is placed on crizotinib by an outside oncologist and after about 3 weeks of therapy is doing well. She is now in your clinic for a second opinion. She says that some of her friends told her about another medication called ceritinib and was wondering if she would need to switch her cancer treatment.

• How would you respond to this patient’s inquiry?

FIRST-LINE TKIS FOR ALK REARRANGEMENTS

ALK rearrangements are found in 2% to 7% of NSCLC, with EML4-ALK being the most prevalent fusion variant.⁶¹ The inversion of chromosome 2p leads to the fusion of the EML4 gene and the ALK gene, which causes the constitutive activation of the fusion protein and ultimately increased transformation and tumorigenicity.^7,61 Patients harboring ALK rearrangements tend to be non-smokers. Adenocarcinoma, especially signet ring cell subtype, is the predominant histology. Compared to EGFR mutations, patients with ALK mutations are significantly younger and more likely to be men.⁶²ALK rearrangements can be detected by either FISH or IHC, and most next-generation sequencing (NGS) panels have the ability to identify this driver mutation.

Crizotinib is the first approved ALK inhibitor for the treatment of NSCLC in this molecular subset of patients.⁶³ PROFILE 1014 is a phase 3 randomized trial that compared crizotinib with chemotherapy containing platinum/pemetrexed for up to 6 cycles. Crossover to crizotinib was allowed for patients with disease progression on chemotherapy. The primary end point was PFS by independent radiologic review. The crizotinib arm demonstrated superior PFS (10.9 months versus 7 months; HR 0.45 [95% CI 0.35 to 0.6], P < 0.001) and ORR (74% versus 45%, P < 0.001). Median survival was not reached in either arm (HR 0.82 [95% CI 0.54 to 1.26], P = 0.36).⁶⁴ Based on this international trial, crizotinib is considered standard of care in the United States for treatment-naïve patients with advanced NSCLC harboring ALK rearrangements. The current recommended dose is 250 mg orally twice daily. Common treatment-related AEs of all grades include vision disorder (62%), nausea (53%), diarrhea (43%), vomiting (40%), edema (28%), and constipation (27%).⁶⁵ PROFILE 1007 compared crizotinib with pemetrexed or docetaxel in ALK-rearranged NSCLC patients with prior exposure to 1 platinum-based chemotherapy. The median PFS was 7.7 months for crizotinib as compared to 3 months for chemotherapy (HR 0.49 [95% CI 0.37 to 0.64], P < 0.001). The response rates were 65% and 20% for crizotinib and chemotherapy, respectively (P < 0.001).⁶⁶ In other countries, crizotinib following 1 prior platinum-based regimen may be considered standard of care based on this trial.

Ceritinib is an oral second-generation ALK inhibitor that is 20 times more potent than crizotinib based on enzymatic assays.⁶⁷ It also targets ROS1 and insulin-like growth factor 1 receptor but not c-MET. It was first approved by the FDA in April 2014 for metastatic ALK-rearranged NSCLC following crizotinib.⁶⁸ In May 2017, the FDA granted approval of ceritinib for treatment-naïve patients. This decision was based on the results of the ASCEND-4 trial, a randomized phase 3 trial assessing the efficacy and safety of ceritinib over chemotherapy in the first-line setting. The trial assigned 376 patients to either ceritinib at 750 mg once daily or platinum/pemetrexed for 4 cycles followed by maintenance pemetrexed. Median PFS was 16.6 months for ceritinib versus 8.1 months for chemotherapy (HR 0.55 [95% CI 0.42 to 0.73]; P < 0.00001).⁶⁹ Toxicities of ceritinib are not negligible, with gastrointestinal toxicity being the most prevalent. For instance, diarrhea, nausea, vomiting, abdominal pain, and constipation of all grades were seen in 86%, 80%, 60%, 54%, and 29% of patients, respectively. Furthermore, fatigue and decreased appetite occurred in 52% and 34% of patients, respectively. In terms of laboratory abnormalities, 84% of patients experienced decreased hemoglobin of all grades; 80% increased ALT; 75% increased AST; 58% increased creatinine; 49% increased glucose; 36% decreased phosphate; and 28% increased lipase. Due to these AEs, the incidence of dose reduction was about 58% and the median onset was around 7 weeks.⁷⁰

Alectinib is another oral second-generation ALK inhibitor that was approved by the FDA in December 2015 for the treatment of NSCLC patients with ALK rearrangements who have progressed on or are intolerant to crizotinib.⁷¹ Its indication will soon be broadened to the first-line setting based on the ALEX trial.⁷² Alectinib is a potent and highly selective TKI of ALK⁷³ with activity against known resistant mutations to crizotinib.^74,75 It also inhibits RET but not ROS1 or c-MET.⁷⁶ ALEX, a randomized phase 3 study, compared alectinib with crizotinib in treatment-naïve patients with NSCLC harboring ALK rearrangements. The trial enrolled 303 patients and the median follow-up was approximately 18 months. The alectinib arm (600 mg twice daily) demonstrated significantly higher PFS by investigator-assessment, the trial’s primary end point. The 12-month event-free survival was 68.4% (95% CI 61% to 75.9%) versus 48.7% (95% CI 40.4% to 56.9%) for alectinib and crizotinib, respectively (HR 0.47 [95% CI 0.34 to 0.65], P < 0.001). The median PFS was not reached in the alectinib arm (95% CI 17.7 months to not estimable) as compared to 11.1 months in the crizotinib arm (95% CI 9.1 to 13.1 months).⁷² Alectinib is generally well tolerated. Common AEs of all grades include fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). As alectinib can cause anemia, lymphopenia, hepatic toxicity, increased creatine phosphokinase, hyperglycemia, electrolyte abnormalities, and increased creatinine, periodic monitoring of these laboratory values is important, although most of these abnormalities are grade 1 or 2.⁷⁷

Brigatinib, another oral second-generation ALK inhibitor, was granted accelerated approval by the FDA in April 2017 for ALK-rearranged and crizotinib-resistant NSCLC based on the ALTA trial. This randomized phase 2 study of brigatinib showed an ORR by investigator assessment of 54% (97.5% CI 43% to 65%) in the 180 mg once daily arm with lead-in of 90 mg once daily for 7 days. Median PFS was 12.9 months (95% CI 11.1 months to not reached [NR]).⁷⁸ Currently, a phase 3 study of brigatinib versus crizotinib in ALK inhibitor–naïve patients is recruiting participants (ALTA-1L). It will be interesting to see if brigatinib can achieve a front-line indication.

Starting the case patient on crizotinib is well within the treatment guidelines. One may consider ceritinib or alectinib in the first-line setting, but both TKIs can be reserved upon disease progression. We would recommend a repeat biopsy at that point to look for resistant mechanisms, as certain secondary ALK mutations may be rescued by certain next-generation ALK inhibitors. For instance, the F1174V mutation has been reported to confer resistance to ceritinib but sensitivity to alectinib, while the opposite is true for I1171T. The G1202R mutation is resistant to ceritinib, alectinib, and brigatinib, but lorlatinib, a third-generation ALK inhibitor, has shown activity against this mutation.⁷⁹ Furthermore, brain metastasis represents a treatment challenge for patients with ALK rearrangements. It is also an efficacy measure of next-generation ALK inhibitors, all of which have demonstrated better central nervous system activity than crizotinib.^69,78,80 If the case patient were found to have brain metastasis at the initial diagnosis, either ceritinib or alectinib would be a reasonable choice since crizotinib has limited penetration of blood-brain barrier.⁸¹

ROS1 REARRANGEMENTS

CASE PRESENTATION 3

A 66-year-old Chinese woman who is a non-smoker with a past medical history of hypertension and hypothyroidism presents to the emergency department for worsening lower back pain. Initial workup includes x-ray of the lumbar spine followed by MRI with contrast, which shows a soft tissue mass at L3-4 without cord compression. CT of the chest, abdomen, and pelvis with contrast shows a 7-cm right hilar mass, bilateral small lung nodules, mediastinal lymphadenopathy, and multiple lytic lesions in ribs, lumbar spine, and pelvis. MRI-brain with and without contrast is negative for malignancy. She undergoes endo-bronchial ultrasound and biopsy of the right hilar mass, which shows poorly differentiated adenocarcinoma. While waiting for the result of the molecular analysis, the patient undergoes palliative radiation therapy to L2-5 with good pain relief. She is discharged from the hospital and presents to your clinic for follow up. Molecular analysis now reveals ROS1 rearrangement with CD74-ROS1 fusion.

• What treatment plan should be put in place for this patient?

FIRST-LINE THERAPY FOR ROS1 REARRANGEMENTS

Approximately 2.4% of lung adenocarcinomas harbor ROS1 rearrangements.⁸² This distinct genetic alteration occurs more frequently in NSCLC patients who are younger, female, and never-smokers, and who have adenocarcinomas.⁸ It has been shown that ROS1 rearrangements rarely overlap with other genetic alterations including KRAS mutations, EGFR mutations, and ALK rearrangements.⁸³ As a receptor tyrosine kinase, ROS1 is similar to ALK and insulin receptor family members.⁸⁴ Crizotinib, which targets ALK, ROS1, and c-MET, was approved by the FDA on March 11, 2016, for the treatment of metastatic ROS1-rearranged NSCLC.⁸⁵ The approval was based on a phase 2 expansion cohort of the original phase 1 study. Among 50 US patients enrolled in this expansion cohort, 3 had complete responses and 33 had partial responses with ORR of 72% (95% CI 58% to 84%). Median PFS was 19.2 months (95% CI 14.4 months to NR) and median duration of response (DOR) was 17.6 months (95% CI 14.5 months to NR).⁸⁶ During longer follow-up, independent radiology review confirmed high ORR of 66% and median DOR of 18.3 months.⁸⁵

Interestingly, no companion diagnostic assay has been approved for the detection of ROS1 rearrangements with the approval of crizotinib. In the United States, break apart FISH is the most common detection method. In fact, in the above mentioned phase 2 study, ROS1 rearrangements were detected in 49 out of 50 patients by this method.⁸⁶ FISH can be technically challenging when dealing with high volume and multiple targets. Reverse transcriptase-PCR is another detection method, but it requires knowledge of the fusion partners. To date, at least 14 ROS1 fusion partners have been reported, with CD74 being the most common.⁸⁷ NGS with appropriate design and validation can also be used to detect ROS1 rearrangements.

For the case patient, the recommendation would be to start her on crizotinib at 250 mg twice daily. Monitoring for vision disturbance, gastrointestinal complaints, and edema is warranted. Because the estimated onset of response is around 7.9 weeks,⁸⁶ plans should be made to repeat her scans in approximately 2 months.

BRAF V600E MUTATIONS

CASE PRESENTATION 4

A 71-year-old Caucasian man with a past medical history of hypertension, dyslipidemia, and ischemic cerebrovascular accident without residual deficits was diagnosed with stage IV adenocarcinoma of the lung about 8 months ago. He has a 40 pack-year smoking history and quit smoking when he was diagnosed with lung cancer. His disease burden involved a large mediastinal mass, scattered pleural nodules, multiple lymphadenopathy, and several soft tissue masses. His outside oncologist started him on chemotherapy containing carboplatin and pemetrexed for 6 cycles followed by maintenance pemetrexed. The most recent restaging scans show disease progression with enlarging soft tissue masses and several new lytic bone lesions. MRI-brain with and without contrast shows 2 subcentimeter enhancing lesions. He transferred care to you approximately 4 weeks ago. You ordered a repeat biopsy of 1 of the enlarging soft tissue masses. Molecular analysis revealed BRAF V600E mutation. In the interim, he underwent stereotactic radiosurgery for the 2 brain lesions without any complications. The patient is now in your clinic for follow up.

• What would be your recommended systemic treatment?

TARGETED THERAPIES FOR BRAF V600E MUTATION

BRAF mutations were first recognized as activating mutations in advanced melanomas, with BRAF V600E, resulting from the substitution of glutamic acid for valine at amino acid 600, being the most common. BRAF plays an important role in the mitogen-activated protein kinase (MAPK) signaling pathway. Briefly, the activation of MAPK pathway occurs upon ligand binding of receptor tyrosine kinases, which then involves RAS/BRAF/MEK/ERK in a stepwise manner, ultimately leading to cell survival. BRAF mutations have been increasingly recognized also as driver mutations in NSCLC.^9–12 They can be detected by PCR or NGS method. The characteristics of NSCLC patients harboring BRAF mutations have been described by various groups.^9–12 For instance, 1 case series showed that the incidence was 2.2% among patients with advanced lung adenocarcinoma; 50% of mutations were V600E, while G469A and D594G accounted for the remaining 39% and 11% of patients, respectively. All patients were either current or former smokers. The median OS of patients with BRAF mutations in this case series was NR, while it was 37 months for patients with EGFR mutations (P = 0.73) and NR for patients with ALK rearrangements (P = 0.64).⁹

For patients with BRAF V600E–mutant NSCLC who have progressed on platinum-based chemotherapy, the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) may represent a new treatment paradigm. This was illustrated in a phase 2, nonrandomized, open-label study. A total of 57 patients were enrolled and 36 patients (63.2% [95% CI 49.3% to 75.6%]) achieved an overall response by investigator assessment, the trial’s primary end point. Disease control rate was 78.9% (95% CI 66.1% to 88.6%), with 4% complete response, 60% partial response, and 16% stable disease. PFS was 9.7 months (95% CI [6.9 to 19.6 months]). The safety profile was comparable to what had been observed in patients with melanoma treated with this regimen. More specifically, 56% of patients on this trial reported serious AEs, including pyrexia (16%), anemia (5%), confusional state (4%), decreased appetite (4%), hemoptysis (4%), hypercalcemia (4%), nausea (4%), and cutaneous squamous cell carcinoma (4%). In addition, neutropenia (9%) and hyponatremia (7%) were the most common grade 3-4 AEs.¹⁶

The case patient has experienced disease progression after 1 line of platinum-based chemotherapy, so the combination of dabrafenib and trametinib would be a robust systemic treatment option. dabrafenib as a single agent has also been studied in BRAF V600E–mutant NSCLC in a phase 2 trial. The overall response by investigator assessment among 84 patients was 33% (95% CI 23% to 45%).¹⁴ Vemurafenib, another oral BRAF TKI, has demonstrated efficacy for NSCLC patients harboring BRAF V600E mutation. In the cohort of 20 patients with NSCLC, the response rate was 42% (95% CI 20% to 67%) and median PFS was 7.3 months (95% CI 3.5 to 10.8 months).¹³ Patients with non-V600E mutations have shown variable responses to targeted therapies. MEK TKIs may be considered in this setting; however, the details of this discussion are beyond the scope of this review.

CONCLUSION

The management of advanced NSCLC with driver mutations has seen revolutionary changes over the past decade. Tremendous research has been done in order to first understand the molecular pathogenesis of NSCLC and then discover driver mutations that would lead to development of targeted therapies with clinically significant efficacy as well as tolerability. More recently, increasing efforts have focused on how to conquer acquired resistance in patients with disease progression after first-line TKIs. The field of EGFR-mutant NSCLC has set a successful example, but the work is nowhere near finished. The goals are to search for more driver mutations and to design agents that could potentially block cell survival signals once and for all.

INTRODUCTION

The incidence of cutaneous melanoma has increased over the past 2 decades, with SEER estimates indicating that the number of new cases of melanoma diagnosed annually rose from 38,300 in 1996 to 76,000 in 2016.¹ Among persons younger than 50 years, the incidence is higher in females, and younger women (aged 15–39 years) are especially vulnerable.² Among persons older than 50, melanoma incidence in men is nearly twice that of women, in whom melanomas are often thicker and often associated with worse outcomes.^1,2 Approximately 85% of melanomas are diagnosed at early stages when surgery is curative, but the lifetime probability of developing invasive disease is 3% in men and 2% in women.

Prior to the advent of effective immunotherapies and targeted therapies, melanoma was often managed with chemotherapy, which had dismal response rates and commensurately poor outcomes. Advances in the understanding of the molecular etiopathogenesis and immune escape responses of cutaneous metastatic melanoma have transformed therapeutic approaches. Specifically, improved understanding of the genetic mutations driving melanoma tumorigenesis coupled with insights into mechanisms of tumor-mediated immune evasion resulted in development of inhibitors of mitogen-activated protein kinases (MAPK; BRAF and MEK) along with inhibitors of negative regulatory immune checkpoints (cytotoxic T lymphocyte–associated antigen 4 [CTLA-4] and programmed cell death-1 [PD-1]). In this review, we discuss the role of immune therapy, targeted therapy, and combinations of these in the treatment of metastatic cutaneous melanoma. We limit the immuno-therapy discussion to approved CTLA-4/PD-1 inhibitors and the targeted therapy discussion to approved BRAF/NRAS/MEK inhibitors and do not discuss non-checkpoint immunotherapies including cytokines (HD IL-2), vaccines, or adoptive T-cell approaches. Interested readers are directed to other excellent works covering these important topics.^26–29

DEVELOPMENT OF TARGETED AND NOVEL IMMUNE THERAPIES

For many years the degree of ultraviolet (UV) light exposure was considered the sole major risk factor for melanoma oncogenesis, even though its mechanism was largely unknown.³ However, clinical observations regarding the occurrence of melanoma on less exposed areas (trunk and limbs) in individuals with intermittent sun exposure led to the proposition that melanomas that arose in younger patients with intermittent sun exposure were distinct from melanomas that arose in older patients in association with markers of chronic sun exposure—the “divergent pathway” hypothesis.³ Critical to this understanding were whole-exome sequencing data from multiple groups, including The Cancer Genome Atlas, that identified patterns of mutations in oncogenic drivers that were distinct in patients with and without chronically sun-damaged (CSD) skin.^4–7 It is now clear that based on its association with CSD skin, melanoma can be subclassified into CSD or non-CSD melanoma. CSD and non-CSD melanoma have distinct clinico-pathological characteristics and are associated with different driver mutations. CSD melanomas typically arise in older patients on sun-exposed areas (head/neck, dorsal surfaces of distal extremities) and are associated with particular driver mutations (BRAF non-V600E, NRAS, NF1, or KIT) and genetic signatures of UV-induced DNA damage (G > T [UVA] or C > T [UVB]) transitions. Conversely, non-CSD melanomas typically arise in younger (< 55 years) patients on intermittently sun-exposed areas (trunk, proximal extremities) and are associated with BRAF V600E/K driver mutations and often lack genetic signatures of UV mutagenesis.

Identification of driver mutations in components of the MAPK pathway, including BRAF and NRAS, facilitated the development of targeted inhibitors. The BRAF inhibitors vemurafenib and dabrafenib have been shown in pivotal phase 3 studies to significantly improve overall and progression-free survival in patients with metastatic melanoma compared with chemotherapy and garnered regulatory approval (vemurafenib, BRIM-3;^8,9 dabrafenib, BREAK-3¹⁰). Concomitant MEK and BRAF inhibition extends the duration of benefit by preventing downstream kinase activation in the MAPK pathway. Notably, concomitant MEK inhibition alters the side-effect profile of BRAF inhibitors, with reduced incidence of keratoacanthomas and cutaneous squamous cell carcinomas that are attributable to on-target, off-tumor effects of BRAF inhibitors. Combined BRAF and MEK inhibition (vemurafenib/cobimetinib and dabrafenib/trametinib) further improved overall and progression-free survival compared to single-agent BRAF inhibition in phase 3 studies (COMBI-d,¹¹ COMBI-v,¹² and coBRIM¹³). Although often deep, the responses seen with the use of targeted kinase inhibitors are not often durable, with the vast majority of patients progressing after 12 to 15 months of therapy.In parallel, work primarily done in murine models of chronic viral infection uncovered the role played by co-inhibitory or co-excitatory immune checkpoints in mediating T-cell immune responses. These efforts clarified that tumor-mediated immune suppression primarily occurs through enhancement of inhibitory signals via the negative T-cell immune checkpoints CTLA-4 or PD-1.^14,15 Blockade of negative T-cell immune checkpoints resulted in activation of the adaptive immune system, resulting in durable anti-tumor responses as demonstrated in studies of the CTLA-4 inhibitor ipilimumab (CA184-020¹⁶ and CA184-024¹⁷) and the PD-1 inhibitors nivolumab (CA209-003,¹⁸ CheckMate 037,¹⁹ and CheckMate 066²⁰) and pembrolizumab (KEYNOTE-001²¹ and KEYNOTE-006²²). Compared to the deep but short-lived responses seen with targeted kinase inhibitors, patients treated with CTLA-4 or PD-1 immune checkpoint blockade often developed durable responses that persisted even after completion of therapy. Combined CTLA-4 and PD-1 blockade results in greater magnitude of response with proportionately increased toxicity.^23–25

IMMUNOTHERAPY

CTLA-4 AND PD-1 IMMUNE CHECKPOINT INHIBITORS

The novel success of immunotherapy in recent decades is largely attributable to improved understanding of adaptive immune physiology, specifically T-cell activation and regulation. T-cell activation requires 2 independent signaling events: it is initiated upon recognition of the antigen-MHC class II-receptor complex on antigen-presenting cells (APC), and requires a secondary co-stimulatory interaction of CD80/CD86 (B7.1/B7.2) on APCs and CD28 molecule on T-cells; without this second event, T-cells enter an anergic state.^30–32 Upon successful signaling and co-stimulation, newly activated T-cells upregulate CTLA-4, which can bind to B7 molecules with a nearly 100-fold greater affinity than CD28.^33,34 Unlike CD28, CTLA-4 engagement negatively regulates T-cell activation. The opposing signals produced by CD28 and CTLA-4 are integrated by the T-cell to determine eventual response to activation, and provide a means by which T-cell activation is homeostatically regulated to prevent exaggerated physiologic immune responses.³⁵ It was hypothesized that CTLA-4 blockade would permit T-cell activation, which is thwarted in the tumor microenvironment by tumor-mediated CTLA-4 engagement, thereby unleashing an anti-tumor immune response.³⁶

PD-1 is a member of the CD28 and CTLA-4 immunoglobulin super family and, similar to CTLA-4, binds activated T-cells. PD-1 has 2 ligands on activated T-cells: PD-L1 and PD-L2.³⁷ PD-L1 is constitutively expressed by a variety of immune and non-immune cells, particularly in inflammatory environments including tumor microenvironments, in response to the release of inflammatory cytokines such as interferon (IFN)-γ.^37,38 Conversely, PD-L2 is only minimally expressed constitutively, although its expression on immune and non-immune cells can be induced by similar cues from inflammatory microenvironments. PD-L1 and PD-L2 cross-compete for binding to PD-1, with PD-L2 exhibiting 2- to 6-fold greater relative affinity than PD-L1.³⁹ PD-L1/PD-1 binding results in phosphorylation of 2 tyrosinases in the intracellular portion of PD-1, which contains immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). PD-1 ITSM subsequently recruits either of 2 SH2-domain–containing protein tyrosine phosphatases: SHP-1 and SHP-2. SHP-2 signaling suppresses PI3K/Akt activation, down-regulates Bcl-xL, and suppresses expression of multiple transcription factors that mediate T-cell effector function including GATA-3, Eomes, and T-bet.^40–42 The net effect of PD-L1/PD-1 engagement is to suppress T-cell proliferation, cytokine production, cytolytic function, and survival. Unlike CTLA-4, which primarily affects the priming phase of naive T-cell activation, PD-1 chiefly regulates the effector phase of T-cell function. Furthermore, because PD-L1/PD-L2 expression is limited to inflammatory microenvironments, the effects of PD-1 are less generalized than those of CTLA-4.

SINGLE AGENT ACTIVITY OF CTLA-4 AND PD-1 INHIBITORS

Ipilimumab (MDX-010) is a human IgG1 monoclonal antibody shown to inhibit CTLA-4.⁴³ Early studies tested different formulations (transfectoma-derived and hybridoma-derived), doses, and schedules of ipilimumab primarily in patients with advanced refractory melanoma.^44–46 Although responses were infrequent, responding patients experienced durable remissions at 1- and 2-year time points. Notably, in a foreshadowing of changes to response criteria used to evaluate these agents, several treated patients who initially had radiographically stable disease upon completion of therapy subsequently experienced a gradual decline in tumor burden.

Ipilimumab was subsequently evaluated in 2 phase 3 trials. The first study (MDX010-020/CA184-020), which involved 676 HLA-A*0201–positive patients with advanced melanoma, compared ipilimumab 3 mg/kg every 3 weeks for 4 doses either singly or in combination with gp100 vaccine with a gp100-only control arm.¹⁶ Ipilimumab administration resulted in objective responses in 11% of patients and improved progression-free and overall survival compared to gp100 alone. Of note, ipilimumab monotherapy was superior to ipilimumab/gp100 combination, possibly related to timing of vaccine in relation to ipilimumab. A confirmatory study (CA184-024) compared a higher dose of ipilimumab (10 mg/kg) in combination with dacarbazine to dacarbazine monotherapy in previously untreated melanoma and was positive.¹⁷ Given the lack of augmented efficacy with the higher (10 mg/kg) dose, ipilimumab received regulatory approval in 2011 for the treatment of melanoma at the lower dose: 3 mg/kg administered every 3 weeks for 4 doses (Table 1). Survival data was strikingly similar to patterns observed in prior phase 2 studies, with survival curves plateauing after 2 years at 23.5% to 28.5% of treated patients. Pooled survival data from prospective and retrospective studies of ipilimumab corroborate the plateau of 22% (26% treated; 20% untreated) reached at year 3 regardless of prior therapy or ipilimumab dose, underscoring the durability of long-term survival in ipilimumab-treated patients.⁴⁷ Ipilimumab administration resulted in an unusual spectrum of toxicities including diarrhea, rash, hepatitis, and hypophysitis (termed immune-related adverse events, or irAEs) in up to a third of patients.

Pembrolizumab and nivolumab are humanized IgG4 monoclonal antibodies that target the PD-1 receptor found on activated T cells, B cells, and myeloid cells. Pembrolizumab and nivolumab are engineered similarly: by immunizing transgenic mice with recombinant human PD-1-Fc protein and subsequently screening murine splenic cells fused with myeloma cells for hybridomas producing antibodies reactive to PD-1-Fc.^48,49 Unlike IgG1, the IgG4 moiety neither engages Fc receptors nor activates complement, avoiding cytotoxic effects of the antibody upon binding to the T cells that it is intended to activate. Both pembrolizumab and nivolumab bind PD-1 with high affinity and specificity, effectively inhibiting the interaction between PD-1 and ligands PD-L1 and PD-L2.

Nivolumab was first studied in a phase 1 study (CA209-003) of 296 patients with advanced cancers who received 1, 3, or 10 mg/kg administered every 2 weeks.¹⁸ Histologies tested included melanoma, non–small-cell lung cancer (NSCLC), renal-cell cancer (RCC), castration-resistant prostate cancer (CRPC), and colorectal cancer (CRC). Responses were seen in melanoma and RCC and unusually in NSCLC, including in both squamous and non-squamous tumors. Objective responses were noted in 41% of the 107 melanoma patients treated at 3 mg/kg. Survival was improved, with 1- and 2-year survival rates of 62% and 43% at extended follow up.⁵⁰

Subsequently, nivolumab was compared to chemotherapy in a pair of phase 3 studies involving both previously untreated (Checkmate 066) and ipilimumab/BRAF inhibitor–refractory (CheckMate 037) patients.^19,20 In both studies, nivolumab produced durable responses in 32% to 34% of patients and improved survival over chemotherapy. Compared to ipilimumab, the incidence of irAEs was much lower with nivolumab. The depth and magnitude of responses observed led to regulatory approval for nivolumab in both indications (untreated and ipilimumab/BRAF inhibitor–treated melanoma) in 2014. Data from both studies are summarized in Table 1.

Pembrolizumab was first evaluated in a phase 1 study of 30 patients with a variety of solid organ malignancies in which no dose-limiting toxicities were observed and no defined maximal tolerated dose was reached.⁵¹ Per protocol, maximal administered dose was 10 mg/kg every 2 weeks. Following startling responses including 2 complete responses of long duration, pembrolizumab was evaluated in a large phase 1 study (KEYNOTE-001) of 1260 patients that evaluated 3 doses (10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, and 2 mg/kg every 3 weeks) in separate melanoma and NSCLC substudies.²¹ Both ipilimumab-naïve and ipilimumab-treated patients were enrolled in the melanoma substudy. Objective responses were seen in 38% ofpatients across all 3 dosing schedules and were similar in both ipilimumab-naïve and ipilimumab-treated patients. Similar to nivolumab, most responders experienced durable remissions.

Pembrolizumab was subsequently compared to ipilimumab in untreated patients (KEYNOTE-006) in which patients were randomly assigned to receive either ipilimumab or pembrolizumab at 1 of 2 doses: 10 mg/kg every 2 weeks and pembrolizumab 10 mg/kg every 3 weeks.²² Response rates were greater with pembrolizumab than ipilimumab, with commensurately greater 1-year survival rates. Rates of treatment-related adverse events requiring discontinuation of study drug were much lower with pembrolizumab than ipilimumab. This trial was instrumental in proving the superior profile of pembrolizumab over ipilimumab. The US Food and Drug Administration (FDA) granted pembrolizumab accelerated approval for second-line treatment of melanoma in 2014, and updated this to include a first-line indication in 2015 (Table 1).

EFFICACY OF COMBINED CTLA-4 AND PD-1 INHIBITION

Preclinical studies demonstrated that PD-1 blockade was more effective than CTLA-4 blockade and combination PD-1/CTLA-4 blockade was synergistic, with complete rejection of tumors in approximately half of the treated animals.¹⁴ This hypothesis was evaluated in a phase 1 study that explored both concurrent and sequential combinations of ipilimumab and nivolumab along with increasing doses of both agents in PD-1/CTLA-4–naïve advanced melanoma.²³ Responses were greater in the concurrent arm (40%) than in the sequential arm (20%) across dose-levels with a small fraction of patients treated in the concurrent arm experiencing a profound reduction (80%) in tumor burden.

The superiority of ipilimumab/nivolumab combination to ipilimumab monotherapy was demonstrated in a randomized blinded phase 2 study (CheckMate 069).²⁴ Of the 4 different ipilimumab/nivolumab doses explored in the phase 1 study (3 mg/kg and 0.3 mg/kg, 3 mg/kg and 1 mg/kg, 1 mg/kg and 3 mg/kg, 3 mg/kg and 3 mg/kg), ipilimumab 3 mg/kg and nivolumab 1 mg/kg (followed by nivolumab 3 mg/kg) was compared to ipilimumab and nivolumab-matched placebo. Responses were significantly greater with dual PD-1/CTLA-4 blockade compared to CTLA-4 blockade alone (59% versus 11%). Concurrently, a 3-arm randomized phase 3 study compared the same dose of ipilimumab/nivolumab to ipilimumab and nivolumab in previously untreated advanced melanoma (CheckMate 067).²⁵ Similar to CheckMate 069, CheckMate 067 demonstrated that ipilimumab/nivolumab combination resulted in more profound responses (58%) than either ipilimumab (19%) or nivolumab (44%) alone. Toxicity, primarily diarrhea, fatigue, pruritus, and rash, was considerable in the combination arm (55% grade 3/4 adverse events) and resulted in treatment discontinuation in 30% of patients. The profound and durable responses observed led to accelerated approval of ipilimumab/nivolumab combination in 2015 (Table 1).

Efforts to improve the toxicity/benefit ratio of ipilimumab/nivolumab combination have centered around studying lower doses and/or extended dosing schedules of ipilimumab, including ipilimumab 1 mg/kg every 6 or 12 weeks with nivolumab dosed at 3 mg/kg every 2 weeks or 480 mg every 4 weeks. Promising data from a first-line study in NSCLC (CheckMate 012) support the evaluation of nivolumab in combination with lower-dosed ipilimumab (1 mg/kg every 6 or 12 weeks).⁵² This approach is being tested against platinum doublet chemotherapy in a confirmatory phase 3 study in NSCLC (CheckMate 227).

TARGETED THERAPY

MAPK KINASE PATHWAY IN MELANOMA TUMORIGENESIS

The MAPK pathway mediates cellular responses to growth signals. RAF kinases are central mediators in the MAPK pathway and exert their effect primarily through MEK phosphorylation and activation following dimerization (hetero- or homo-) of RAF molecules. As a result, RAF is integral to multiple cellular processes, including transcriptional regulation, cellular differentiation, and cell proliferation. MAPK pathway activation is a common event in many cancers, primarily due to activating mutations in BRAF or RAS. Alternatively, MAPK pathway activation can occur in the absence of activating mutations in BRAF or NRAS through down-regulation of MAPK pathway inhibitory proteins (RAF-1 inhibitory protein or SPRY-2), C-MET overexpression, or activating mutations in non-BRAF/NRAS kinases including CRAF, HRAS, and NRAS.^53,54

Somatic point mutations in BRAF are frequently observed (37%–50%) in malignant melanomas and at lower frequency in a range of human cancers including NSCLC, colorectal cancer, papillary thyroid cancer, ovarian cancer, glioma, and gastrointestinal stromal tumor.^6,55,56BRAF mutations in melanoma typically occur within the activation segment of the kinase domain (exon 15). Between 80% and 90% of activating mutations result in an amino acid substitution of glutamate (E) for valine (V) at position 600: V600E.^57,58 V600E mutations are true oncogenic drivers, resulting in increased kinase activity with demonstrable transformational capacity in vitro. BRAF mutations are usually mutually exclusive, with tumors typically containing no other driver mutations in NRAS, KIT, NF1, or other genes.

NRAS mutations are less common than BRAF mutations, having a reported frequency of 13% to 25% in melanoma.⁴NRAS mutations generally occur within the P-loop region of the G domain (exon 2), or less commonly in the switch II region of the G domain (exon 3). Most NRAS exon 2 mutations comprise amino acid substitutions at position 61 from glutamine (Q) to arginine (R; 35%), lysine (K; 34%) and less often to glutamate (E), leucine (L), or proline (P). Preclinical data suggest that NRAS mutations paradoxically stimulate the MAPK pathway and thus enhance tumor growth in vitro.^59,60 Several important phenotypic differences distinguish NRAS- from BRAF-mutated melanoma. NRAS-mutated tumors are typically associated with increasing age and CSD skin, while BRAF-mutated tumors arise in younger patients in non-CSD skin. A large population-based study suggested that NRAS-mutated melanomas were associated with mitoses and lower tumor infiltrating lymphocytes (TIL) grade, and arose in anatomic sites other than the head/neck, while BRAF-mutated tumors were associated with mitoses and superficial spreading histology.⁶¹ Although the lower TIL grade seen with NRAS-mutated melanomas suggests a more immunosuppressed microenvironment and argues for poorer responses to immune therapies, clinical studies comparing responses to immunotherapies in various categories of driver mutations provide conflicting results for the prognostic role of NRAS mutations in relation to immune checkpoint blockade and other immune therapies.^62–64

NF1 represents the third known driver in cutaneous melanoma, with mutations reported in 12% of cases.^6,7NF1 encodes neurofibromin, which has GTPase activity and regulates RAS proteins; NF1 loss results in increased RAS.⁶⁵ Unlike BRAF or NRAS, which are usually mutually exclusive, NF1 mutations in melanoma can occur singly or in combination with either BRAF or NRAS mutations. In these settings, NF1 mutations are associated with RAS activation, MEK-dependence, and resistance to RAF inhibition.⁶⁶

MAPK PATHWAY INHIBITION SINGLY AND IN COMBINATION

Although multiple MEK 1/2 inhibitors (AS703026, AZD8330/ARRY-704, AZD6244, CH5126766, CI-1040, GSK1120212, PD0325901, RDEA119, and XL518) and RAF inhibitors (ARQ 680, GDC-0879, GSK2118436, PLX4032, RAF265, sorafenib, XL281/BMS-908662) were developed, the initial evaluation of MAPK pathway inhibitors in advanced human cancers began with CI-1040. Preclinical data suggested that CI-1040 potently and selectively inhibited both MEK1 and MEK2, but phase 1 and 2 human trial results were disappointing, likely because these trials were not selectively enriched for NRAS/BRAF–mutated tumors or cancers in which these oncogenic mutations were most commonly detected, such as melanoma.^67,68 The subsequent evaluation of selumetinib (AZD6244/ARRY-142886) in a phase 2 study was also negative. Although investigators enrolled a presumably enriched population (cutaneous melanoma), the incidence of NRAS/BRAF–mutated tumors was not ascertained to determine this, but rather assumed, which led to a discrepancy between the assumed (prestudy) and observed (on-study) proportions of BRAF/NRAS mutations that was not accounted for in power calculations.^69,70 Lessons learned from these earlier misadventures informed the current paradigm of targeted therapy development: (1) identification of a highly specific and potent inhibitor through high-throughput screening; (2) establishment of maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in unselected patients; (3) confirmation of RP2D in selected tumor types enriched for target of interest; and (4) confirmatory study against standard comparator to seek regulatory approval.

Vemurafenib and dabrafenib were evaluated in this tiered fashion in phase 1 dose-finding studies comprising unselected patients, followed by phase 2 studies in advanced BRAF V600E–mutated melanoma. Both were subsequently evaluated in randomized phase 3 trials (vemurafenib, BRIM-38; dabrafenib, BREAK-310) that compared them with dacarbazine (1000 mg/m² intravenously every 3 weeks) in the treatment of advanced BRAF V600E–mutated melanoma. Response kinetics for both agents were remarkably similar: single-agent BRAF inhibitors resulted in rapid (time to response 2–3 months), profound (approximately 50% objective responses) reductions in tumor burden that lasted 6 to 7 months. Adverse events common to both agents included rash, fatigue, and arthralgia, although clinically significant photosensitivity was more common with vemurafenib and clinically significant pyrexia was more common with dabrafenib. Class-specific adverse events included the development of cutaneous squamous-cell carcinomas and keratoacanthomas secondary to paradoxical activation of MAPK pathway signaling either through activating mutations in HRAS or mutations or amplifications in receptor tyrosine kinases upstream of BRAF, resulting in elevated levels of RAS–guanosine triphosphate complexes.⁷¹ Results of these studies resulted in regulatory approval of single-agent BRAF inhibitors for the treatment of BRAF V600E (and later V600K)–mutated melanoma (vemurafenib in 2011; dabrafenib in 2013). Details regarding trial populations, study interventions, efficacy, and adverse events are summarized in Table 2.

Responses to BRAF inhibitors are typically profound but temporary. Mechanisms of acquired resistance are diverse and include reactivation of MAPK pathway–dependent signaling (RAS activation or increased RAF expression), and development of MAPK pathway–independent signaling (COT overexpression; increased PI3K or AKT signaling) that permits bypass of inhibited BRAF signaling within the MAPK pathway.^72–76 These findings suggested that upfront inhibition of both MEK and mutant BRAF may produce more durable responses than BRAF inhibition alone. Three pivotal phase 3 studies established the superiority of combination BRAF and MEK inhibition over BRAF inhibition alone: COMBI-d11 (dabrafenib/trametinib versus dabrafenib/placebo), COMBI-v12 (dabrafenib/trametinib versus vemurafenib), and coBRIM13 (vemurafenib/cobimetinib versus vemurafenib/placebo). As expected, compared to BRAF inhibitor monotherapy, combination BRAF and MEK inhibition produced greater responses and improved progression-free and overall survival (Table 2). Interestingly, the rate of cutaneous squamous-cell carcinomas was much lower with combination therapy, reflecting the more profound degree of MAPK pathway inhibition achieved with combination BRAF and MEK inhibition. Based on these results, FDA approval was granted for both dabrafenib/trametinib and vemurafenib/cobimetinib combinations in 2015. Although the dabrafenib/trametinib combination was only approved in 2015, trametinib had independently gained FDA approval in 2013 for the treatment of BRAF V600E/K–mutated melanoma on the basis of the phase 3 METRIC study.⁷⁷

Encorafenib (LGX818) and binimetinib (MEK162, ARRY-162, ARRY-438162) are new BRAF and MEK inhibitors currently being evaluated in clinical trials. Encorafenib/binimetinib combination was first evaluated in a phase 3 study (COLUMBUS) that compared it with vemurafenib monotherapy in BRAF-mutant melanoma.⁷⁸ Unsurprisingly, encorafenib/binimetinib combination produced greater and more durable responses compared to vemurafenib monotherapy. The median progression-free survival of the encorafenib/binimetinib combination (14.9 months) was greater than vemurafenib monotherapy (7.3 months) in this study, and intriguingly greater than that seen with vemurafenib/cobimetinib (coBRIM 9.9 months) and dabrafenib/trametinib (COMBI-d 9.3 months; COMBI-v 11.4 months). Of note, although encorafenib has an IC50 midway between dabrafenib and vemurafenib in cell-free assays (0.8 nM dabrafenib, 4 nM encorafenib, and 31 nM vemurafenib), it has an extremely slower off-rate from BRAF V600E, which results in significantly greater target inhibition in cells following drug wash-out.⁷⁹ This may account for the significantly greater clinical benefit seen with encorafenib/binimetinib in clinical trials. Final study data are eagerly awaited. Regulatory approval has been sought, and is pending at this time.

Binimetinib has been compared to dacarbazine in a phase 3 study (NEMO) of patients with NRAS-mutant melanoma, most of whom had been previously treated with immunotherapy.⁸⁰ Response rates were low in both arms, although slightly greater with binimetinib than dacarbazine (15% versus 9%), commensurate with a modest improvement in progression-free survival. FDA approval has been sought and remains pending at this time.

KIT INHIBITION SINGLY AND IN COMBINATION

The KIT receptor protein tyrosine kinase is a transmembrane protein consisting of extracellular and intracellular domains. Activating KIT mutations occur in 2% to 8% of all melanoma patients and may be found in all melanoma subtypes but are commonest in acral melanomas (10%–20%) and mucosal melanomas (15%–20%). Activating KIT mutations primarily occur in exons 11 and 13, which code for the juxtamembrane and kinase domains, respectively.^5,81–83

Imatinib mesylate is a tyrosine kinase inhibitor of the 2-phenyl amino pyrimidine class that occupies the tyrosine kinase active site with resultant blocking of tyrosine kinase activity. Imatinib mesylate is known to block KIT and has been extensively studied in patients with gastrointestinal stromal tumors (GIST), 80% of whom harbor KIT mutations, in both the adjuvant and the metastatic settings. In melanoma, imatinib mesylate was studied in a Chinese open-label, phase 2 study of imatinib mesylate monotherapy in metastatic melanoma harboring KIT mutation or amplification; 25% of the study patients had mucosal disease and the rest had cutaneous disease, with acral involvement in 50% of all patients.⁸⁴ Overall response rate was 23%, while 51% of patients remained alive at 1 year with no differences in response rate and/or survival being noted between patients with either KIT mutations or amplifications. In a separate study of imatinib mesylate at 400 mg daily or 400 mg twice daily in Caucasian patients with KIT-mutated/amplified melanoma, similar response and survival rates were reported, although patients with KIT mutations did nonsignificantly better than those with KIT amplifications.⁸⁵

Other novel studies evaluating KIT inhibitors include KIT inhibition in combination with the VEGF inhibitor bevacizumab and a study of selective BCR-ABL kinase inhibitor nilotinib in imatinib-resistant melanoma. In the former phase 1/2 study, Flaherty and colleagues studied imatinib 800 mg daily and bevacizumab at 10 mg/kg every 2 weeks in 63 patients with advanced tumors, including 23 with metastatic melanoma. Although the combination was relatively nontoxic, no significant efficacy signal was seen and further accrual to the phase 2 portion was halted after the first stage was completed.⁸⁶ Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor intelligently designed based on the structure of the ABL-imatinib complex that is 10 to 30 times more potent than imatinib in inhibiting BCR-ABL1 tyrosine kinase activity. Nilotinib is approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML), with reported efficacy in patients with central nervous system (CNS) involvement.^87,88 Nilotinib has been studied in a single study of KIT-mutated/amplified melanoma that included patients with imatinib-resistance and those with treated CNS disease. Nilotinib appeared to be active in imatinib-resistant melanoma, although no responses were seen in the CNS disease cohort.⁸⁹ Overall, the response rates observed with KIT inhibition in melanoma are much lower than those observed in CML and GIST.

CONCLUSION AND FUTURE DIRECTIONS

Prior to 2011, the only approved agents for the treatment of advanced melanoma were dacarbazine and high-dose interleukin-2. Since 2011, drug approvals in melanoma have proceeded at a frenetic pace unmatched in any other disease. The primary events underlying this are advances in our understanding of the gene mutation landscape driving melanoma tumorigenesis, accompanied by insights into the means by which tumors circumvent the induction of effective anti-tumor T-cell responses. These insights have resulted in the development of inhibitors targeting MAPK pathway kinases BRAF, MEK, and NRAS), KIT, and regulatory immune checkpoints (CTLA-4 and PD-1). Although BRAF/MEK inhibition results in profound reductions and even occasional complete responses in patients, these responses are typically short lived, rarely lasting more than 9 to 11 months; the encorafenib/binimetinib combination may improve that duration marginally. However, the signature therapeutic advance in melanoma of the past decade is immunotherapy, particularly the development of inhibitors of CTLA-4 and PD-1 immune checkpoints. With these agents, significant proportions of treated patients remain free of progression off-therapy (ipilimumab 23%; nivolumab 34%; pembrolizumab 35%; ipilimumab/nivolumab 64%), and some patients can be successfully re-induced after delayed progression. Separately, the high response rates observed with the use of KIT inhibitors in CML and GIST have not been observed in KIT mutated/amplified melanoma and development of agents in this space has been limited. The challenges ahead center around identifying predictive biomarkers and circumventing primary or acquired resistance, with the eventual goal of producing durable remissions in the majority of treated patients.

Our improved understanding of the mechanisms of acquired resistance to BRAF/MEK inhibitors suggests that anti-tumor activity may be achieved by targeting multiple pathways, possibly with combination regimens comprising other inhibitors and/or immunotherapy. Preclinical data supports the use of combination strategies targeting both ERK and PI3K/mTOR to circumvent acquired resistance.⁹⁰ Ongoing studies are evaluating combinations with biguanides (metformin: NCT02143050 and NCT01638676; phenformin: NCT03026517), HSP90 inhibitors (XL888: NCT02721459; AT13387: NCT02097225), and decitabine (NCT01876641).

One complexity affecting management of resistance in the targeted therapy landscape remains tumor heterogeneity, particularly intra- and intertumoral heterogeneity, which may explain the apparent contradiction between continued efficacy of BRAF inhibitors in BRAF-resistant tumors and preclinical data predicting slower progression of resistant tumors on cessation of BRAF inhibitors.^91–94 These data provide a rationale to investigate intermittent dosing regimens with BRAF/MEK inhibitors; several studies exploring this approach are ongoing (NCT01894672 and NCT02583516).

Given the specificity, adaptability, and memory response associated with immunotherapy, it is likely that these agents will be used to treat the majority of patients regardless of mutational status. Hence, identifying predictive biomarkers of response to immune checkpoint inhibitors is vital. The presence of CD8+ T-cell infiltrate and IFN-γ gene signature, which indicate an “inflamed” tumor microenvironment, are highly predictive of clinical benefit from PD-1 inhibitors.^95,96 However, not all PD-1 responders have “inflamed” tumor microenvironments, and not all patients with an “inflamed” tumor microenvironment respond to immune checkpoint inhibitors. The complexity of the immune system is reflected in the multiple non-redundant immunologic pathways, both positive and negative, with checkpoints and ligands that emerge dynamically in response to treatment. Given the dynamic nature of the immune response, it is unlikely that any single immunologic biomarker identified pre-treatment will be completely predictive. Rather, the complexity of the biomarker approach must match the complexity of the immune response elicited, and will likely incorporate multifarious elements including CD8+ T-cell infiltrate, IFN-γ gene signature, and additional elements including microbiome, genetic polymorphisms, and tumor mutation load. The goal is to use multiple markers to guide development of combinations and then, depending on initial response, to examine tumors for alterations to guide decisions about additional treatment(s) to improve responses, with the eventual goal being durable clinical responses for all patients.

INTRODUCTION

The incidence of cutaneous melanoma has increased over the past 2 decades, with SEER estimates indicating that the number of new cases of melanoma diagnosed annually rose from 38,300 in 1996 to 76,000 in 2016.¹ Among persons younger than 50 years, the incidence is higher in females, and younger women (aged 15–39 years) are especially vulnerable.² Among persons older than 50, melanoma incidence in men is nearly twice that of women, in whom melanomas are often thicker and often associated with worse outcomes.^1,2 Approximately 85% of melanomas are diagnosed at early stages when surgery is curative, but the lifetime probability of developing invasive disease is 3% in men and 2% in women.

Prior to the advent of effective immunotherapies and targeted therapies, melanoma was often managed with chemotherapy, which had dismal response rates and commensurately poor outcomes. Advances in the understanding of the molecular etiopathogenesis and immune escape responses of cutaneous metastatic melanoma have transformed therapeutic approaches. Specifically, improved understanding of the genetic mutations driving melanoma tumorigenesis coupled with insights into mechanisms of tumor-mediated immune evasion resulted in development of inhibitors of mitogen-activated protein kinases (MAPK; BRAF and MEK) along with inhibitors of negative regulatory immune checkpoints (cytotoxic T lymphocyte–associated antigen 4 [CTLA-4] and programmed cell death-1 [PD-1]). In this review, we discuss the role of immune therapy, targeted therapy, and combinations of these in the treatment of metastatic cutaneous melanoma. We limit the immuno-therapy discussion to approved CTLA-4/PD-1 inhibitors and the targeted therapy discussion to approved BRAF/NRAS/MEK inhibitors and do not discuss non-checkpoint immunotherapies including cytokines (HD IL-2), vaccines, or adoptive T-cell approaches. Interested readers are directed to other excellent works covering these important topics.^26–29

DEVELOPMENT OF TARGETED AND NOVEL IMMUNE THERAPIES

For many years the degree of ultraviolet (UV) light exposure was considered the sole major risk factor for melanoma oncogenesis, even though its mechanism was largely unknown.³ However, clinical observations regarding the occurrence of melanoma on less exposed areas (trunk and limbs) in individuals with intermittent sun exposure led to the proposition that melanomas that arose in younger patients with intermittent sun exposure were distinct from melanomas that arose in older patients in association with markers of chronic sun exposure—the “divergent pathway” hypothesis.³ Critical to this understanding were whole-exome sequencing data from multiple groups, including The Cancer Genome Atlas, that identified patterns of mutations in oncogenic drivers that were distinct in patients with and without chronically sun-damaged (CSD) skin.^4–7 It is now clear that based on its association with CSD skin, melanoma can be subclassified into CSD or non-CSD melanoma. CSD and non-CSD melanoma have distinct clinico-pathological characteristics and are associated with different driver mutations. CSD melanomas typically arise in older patients on sun-exposed areas (head/neck, dorsal surfaces of distal extremities) and are associated with particular driver mutations (BRAF non-V600E, NRAS, NF1, or KIT) and genetic signatures of UV-induced DNA damage (G > T [UVA] or C > T [UVB]) transitions. Conversely, non-CSD melanomas typically arise in younger (< 55 years) patients on intermittently sun-exposed areas (trunk, proximal extremities) and are associated with BRAF V600E/K driver mutations and often lack genetic signatures of UV mutagenesis.

Identification of driver mutations in components of the MAPK pathway, including BRAF and NRAS, facilitated the development of targeted inhibitors. The BRAF inhibitors vemurafenib and dabrafenib have been shown in pivotal phase 3 studies to significantly improve overall and progression-free survival in patients with metastatic melanoma compared with chemotherapy and garnered regulatory approval (vemurafenib, BRIM-3;^8,9 dabrafenib, BREAK-3¹⁰). Concomitant MEK and BRAF inhibition extends the duration of benefit by preventing downstream kinase activation in the MAPK pathway. Notably, concomitant MEK inhibition alters the side-effect profile of BRAF inhibitors, with reduced incidence of keratoacanthomas and cutaneous squamous cell carcinomas that are attributable to on-target, off-tumor effects of BRAF inhibitors. Combined BRAF and MEK inhibition (vemurafenib/cobimetinib and dabrafenib/trametinib) further improved overall and progression-free survival compared to single-agent BRAF inhibition in phase 3 studies (COMBI-d,¹¹ COMBI-v,¹² and coBRIM¹³). Although often deep, the responses seen with the use of targeted kinase inhibitors are not often durable, with the vast majority of patients progressing after 12 to 15 months of therapy.In parallel, work primarily done in murine models of chronic viral infection uncovered the role played by co-inhibitory or co-excitatory immune checkpoints in mediating T-cell immune responses. These efforts clarified that tumor-mediated immune suppression primarily occurs through enhancement of inhibitory signals via the negative T-cell immune checkpoints CTLA-4 or PD-1.^14,15 Blockade of negative T-cell immune checkpoints resulted in activation of the adaptive immune system, resulting in durable anti-tumor responses as demonstrated in studies of the CTLA-4 inhibitor ipilimumab (CA184-020¹⁶ and CA184-024¹⁷) and the PD-1 inhibitors nivolumab (CA209-003,¹⁸ CheckMate 037,¹⁹ and CheckMate 066²⁰) and pembrolizumab (KEYNOTE-001²¹ and KEYNOTE-006²²). Compared to the deep but short-lived responses seen with targeted kinase inhibitors, patients treated with CTLA-4 or PD-1 immune checkpoint blockade often developed durable responses that persisted even after completion of therapy. Combined CTLA-4 and PD-1 blockade results in greater magnitude of response with proportionately increased toxicity.^23–25

IMMUNOTHERAPY

CTLA-4 AND PD-1 IMMUNE CHECKPOINT INHIBITORS

The novel success of immunotherapy in recent decades is largely attributable to improved understanding of adaptive immune physiology, specifically T-cell activation and regulation. T-cell activation requires 2 independent signaling events: it is initiated upon recognition of the antigen-MHC class II-receptor complex on antigen-presenting cells (APC), and requires a secondary co-stimulatory interaction of CD80/CD86 (B7.1/B7.2) on APCs and CD28 molecule on T-cells; without this second event, T-cells enter an anergic state.^30–32 Upon successful signaling and co-stimulation, newly activated T-cells upregulate CTLA-4, which can bind to B7 molecules with a nearly 100-fold greater affinity than CD28.^33,34 Unlike CD28, CTLA-4 engagement negatively regulates T-cell activation. The opposing signals produced by CD28 and CTLA-4 are integrated by the T-cell to determine eventual response to activation, and provide a means by which T-cell activation is homeostatically regulated to prevent exaggerated physiologic immune responses.³⁵ It was hypothesized that CTLA-4 blockade would permit T-cell activation, which is thwarted in the tumor microenvironment by tumor-mediated CTLA-4 engagement, thereby unleashing an anti-tumor immune response.³⁶

PD-1 is a member of the CD28 and CTLA-4 immunoglobulin super family and, similar to CTLA-4, binds activated T-cells. PD-1 has 2 ligands on activated T-cells: PD-L1 and PD-L2.³⁷ PD-L1 is constitutively expressed by a variety of immune and non-immune cells, particularly in inflammatory environments including tumor microenvironments, in response to the release of inflammatory cytokines such as interferon (IFN)-γ.^37,38 Conversely, PD-L2 is only minimally expressed constitutively, although its expression on immune and non-immune cells can be induced by similar cues from inflammatory microenvironments. PD-L1 and PD-L2 cross-compete for binding to PD-1, with PD-L2 exhibiting 2- to 6-fold greater relative affinity than PD-L1.³⁹ PD-L1/PD-1 binding results in phosphorylation of 2 tyrosinases in the intracellular portion of PD-1, which contains immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). PD-1 ITSM subsequently recruits either of 2 SH2-domain–containing protein tyrosine phosphatases: SHP-1 and SHP-2. SHP-2 signaling suppresses PI3K/Akt activation, down-regulates Bcl-xL, and suppresses expression of multiple transcription factors that mediate T-cell effector function including GATA-3, Eomes, and T-bet.^40–42 The net effect of PD-L1/PD-1 engagement is to suppress T-cell proliferation, cytokine production, cytolytic function, and survival. Unlike CTLA-4, which primarily affects the priming phase of naive T-cell activation, PD-1 chiefly regulates the effector phase of T-cell function. Furthermore, because PD-L1/PD-L2 expression is limited to inflammatory microenvironments, the effects of PD-1 are less generalized than those of CTLA-4.

SINGLE AGENT ACTIVITY OF CTLA-4 AND PD-1 INHIBITORS

Ipilimumab (MDX-010) is a human IgG1 monoclonal antibody shown to inhibit CTLA-4.⁴³ Early studies tested different formulations (transfectoma-derived and hybridoma-derived), doses, and schedules of ipilimumab primarily in patients with advanced refractory melanoma.^44–46 Although responses were infrequent, responding patients experienced durable remissions at 1- and 2-year time points. Notably, in a foreshadowing of changes to response criteria used to evaluate these agents, several treated patients who initially had radiographically stable disease upon completion of therapy subsequently experienced a gradual decline in tumor burden.

Ipilimumab was subsequently evaluated in 2 phase 3 trials. The first study (MDX010-020/CA184-020), which involved 676 HLA-A*0201–positive patients with advanced melanoma, compared ipilimumab 3 mg/kg every 3 weeks for 4 doses either singly or in combination with gp100 vaccine with a gp100-only control arm.¹⁶ Ipilimumab administration resulted in objective responses in 11% of patients and improved progression-free and overall survival compared to gp100 alone. Of note, ipilimumab monotherapy was superior to ipilimumab/gp100 combination, possibly related to timing of vaccine in relation to ipilimumab. A confirmatory study (CA184-024) compared a higher dose of ipilimumab (10 mg/kg) in combination with dacarbazine to dacarbazine monotherapy in previously untreated melanoma and was positive.¹⁷ Given the lack of augmented efficacy with the higher (10 mg/kg) dose, ipilimumab received regulatory approval in 2011 for the treatment of melanoma at the lower dose: 3 mg/kg administered every 3 weeks for 4 doses (Table 1). Survival data was strikingly similar to patterns observed in prior phase 2 studies, with survival curves plateauing after 2 years at 23.5% to 28.5% of treated patients. Pooled survival data from prospective and retrospective studies of ipilimumab corroborate the plateau of 22% (26% treated; 20% untreated) reached at year 3 regardless of prior therapy or ipilimumab dose, underscoring the durability of long-term survival in ipilimumab-treated patients.⁴⁷ Ipilimumab administration resulted in an unusual spectrum of toxicities including diarrhea, rash, hepatitis, and hypophysitis (termed immune-related adverse events, or irAEs) in up to a third of patients.

Pembrolizumab and nivolumab are humanized IgG4 monoclonal antibodies that target the PD-1 receptor found on activated T cells, B cells, and myeloid cells. Pembrolizumab and nivolumab are engineered similarly: by immunizing transgenic mice with recombinant human PD-1-Fc protein and subsequently screening murine splenic cells fused with myeloma cells for hybridomas producing antibodies reactive to PD-1-Fc.^48,49 Unlike IgG1, the IgG4 moiety neither engages Fc receptors nor activates complement, avoiding cytotoxic effects of the antibody upon binding to the T cells that it is intended to activate. Both pembrolizumab and nivolumab bind PD-1 with high affinity and specificity, effectively inhibiting the interaction between PD-1 and ligands PD-L1 and PD-L2.

Nivolumab was first studied in a phase 1 study (CA209-003) of 296 patients with advanced cancers who received 1, 3, or 10 mg/kg administered every 2 weeks.¹⁸ Histologies tested included melanoma, non–small-cell lung cancer (NSCLC), renal-cell cancer (RCC), castration-resistant prostate cancer (CRPC), and colorectal cancer (CRC). Responses were seen in melanoma and RCC and unusually in NSCLC, including in both squamous and non-squamous tumors. Objective responses were noted in 41% of the 107 melanoma patients treated at 3 mg/kg. Survival was improved, with 1- and 2-year survival rates of 62% and 43% at extended follow up.⁵⁰

Subsequently, nivolumab was compared to chemotherapy in a pair of phase 3 studies involving both previously untreated (Checkmate 066) and ipilimumab/BRAF inhibitor–refractory (CheckMate 037) patients.^19,20 In both studies, nivolumab produced durable responses in 32% to 34% of patients and improved survival over chemotherapy. Compared to ipilimumab, the incidence of irAEs was much lower with nivolumab. The depth and magnitude of responses observed led to regulatory approval for nivolumab in both indications (untreated and ipilimumab/BRAF inhibitor–treated melanoma) in 2014. Data from both studies are summarized in Table 1.

Pembrolizumab was first evaluated in a phase 1 study of 30 patients with a variety of solid organ malignancies in which no dose-limiting toxicities were observed and no defined maximal tolerated dose was reached.⁵¹ Per protocol, maximal administered dose was 10 mg/kg every 2 weeks. Following startling responses including 2 complete responses of long duration, pembrolizumab was evaluated in a large phase 1 study (KEYNOTE-001) of 1260 patients that evaluated 3 doses (10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, and 2 mg/kg every 3 weeks) in separate melanoma and NSCLC substudies.²¹ Both ipilimumab-naïve and ipilimumab-treated patients were enrolled in the melanoma substudy. Objective responses were seen in 38% ofpatients across all 3 dosing schedules and were similar in both ipilimumab-naïve and ipilimumab-treated patients. Similar to nivolumab, most responders experienced durable remissions.

Pembrolizumab was subsequently compared to ipilimumab in untreated patients (KEYNOTE-006) in which patients were randomly assigned to receive either ipilimumab or pembrolizumab at 1 of 2 doses: 10 mg/kg every 2 weeks and pembrolizumab 10 mg/kg every 3 weeks.²² Response rates were greater with pembrolizumab than ipilimumab, with commensurately greater 1-year survival rates. Rates of treatment-related adverse events requiring discontinuation of study drug were much lower with pembrolizumab than ipilimumab. This trial was instrumental in proving the superior profile of pembrolizumab over ipilimumab. The US Food and Drug Administration (FDA) granted pembrolizumab accelerated approval for second-line treatment of melanoma in 2014, and updated this to include a first-line indication in 2015 (Table 1).

EFFICACY OF COMBINED CTLA-4 AND PD-1 INHIBITION

Preclinical studies demonstrated that PD-1 blockade was more effective than CTLA-4 blockade and combination PD-1/CTLA-4 blockade was synergistic, with complete rejection of tumors in approximately half of the treated animals.¹⁴ This hypothesis was evaluated in a phase 1 study that explored both concurrent and sequential combinations of ipilimumab and nivolumab along with increasing doses of both agents in PD-1/CTLA-4–naïve advanced melanoma.²³ Responses were greater in the concurrent arm (40%) than in the sequential arm (20%) across dose-levels with a small fraction of patients treated in the concurrent arm experiencing a profound reduction (80%) in tumor burden.

The superiority of ipilimumab/nivolumab combination to ipilimumab monotherapy was demonstrated in a randomized blinded phase 2 study (CheckMate 069).²⁴ Of the 4 different ipilimumab/nivolumab doses explored in the phase 1 study (3 mg/kg and 0.3 mg/kg, 3 mg/kg and 1 mg/kg, 1 mg/kg and 3 mg/kg, 3 mg/kg and 3 mg/kg), ipilimumab 3 mg/kg and nivolumab 1 mg/kg (followed by nivolumab 3 mg/kg) was compared to ipilimumab and nivolumab-matched placebo. Responses were significantly greater with dual PD-1/CTLA-4 blockade compared to CTLA-4 blockade alone (59% versus 11%). Concurrently, a 3-arm randomized phase 3 study compared the same dose of ipilimumab/nivolumab to ipilimumab and nivolumab in previously untreated advanced melanoma (CheckMate 067).²⁵ Similar to CheckMate 069, CheckMate 067 demonstrated that ipilimumab/nivolumab combination resulted in more profound responses (58%) than either ipilimumab (19%) or nivolumab (44%) alone. Toxicity, primarily diarrhea, fatigue, pruritus, and rash, was considerable in the combination arm (55% grade 3/4 adverse events) and resulted in treatment discontinuation in 30% of patients. The profound and durable responses observed led to accelerated approval of ipilimumab/nivolumab combination in 2015 (Table 1).

Efforts to improve the toxicity/benefit ratio of ipilimumab/nivolumab combination have centered around studying lower doses and/or extended dosing schedules of ipilimumab, including ipilimumab 1 mg/kg every 6 or 12 weeks with nivolumab dosed at 3 mg/kg every 2 weeks or 480 mg every 4 weeks. Promising data from a first-line study in NSCLC (CheckMate 012) support the evaluation of nivolumab in combination with lower-dosed ipilimumab (1 mg/kg every 6 or 12 weeks).⁵² This approach is being tested against platinum doublet chemotherapy in a confirmatory phase 3 study in NSCLC (CheckMate 227).

TARGETED THERAPY

MAPK KINASE PATHWAY IN MELANOMA TUMORIGENESIS

The MAPK pathway mediates cellular responses to growth signals. RAF kinases are central mediators in the MAPK pathway and exert their effect primarily through MEK phosphorylation and activation following dimerization (hetero- or homo-) of RAF molecules. As a result, RAF is integral to multiple cellular processes, including transcriptional regulation, cellular differentiation, and cell proliferation. MAPK pathway activation is a common event in many cancers, primarily due to activating mutations in BRAF or RAS. Alternatively, MAPK pathway activation can occur in the absence of activating mutations in BRAF or NRAS through down-regulation of MAPK pathway inhibitory proteins (RAF-1 inhibitory protein or SPRY-2), C-MET overexpression, or activating mutations in non-BRAF/NRAS kinases including CRAF, HRAS, and NRAS.^53,54

Somatic point mutations in BRAF are frequently observed (37%–50%) in malignant melanomas and at lower frequency in a range of human cancers including NSCLC, colorectal cancer, papillary thyroid cancer, ovarian cancer, glioma, and gastrointestinal stromal tumor.^6,55,56BRAF mutations in melanoma typically occur within the activation segment of the kinase domain (exon 15). Between 80% and 90% of activating mutations result in an amino acid substitution of glutamate (E) for valine (V) at position 600: V600E.^57,58 V600E mutations are true oncogenic drivers, resulting in increased kinase activity with demonstrable transformational capacity in vitro. BRAF mutations are usually mutually exclusive, with tumors typically containing no other driver mutations in NRAS, KIT, NF1, or other genes.

NRAS mutations are less common than BRAF mutations, having a reported frequency of 13% to 25% in melanoma.⁴NRAS mutations generally occur within the P-loop region of the G domain (exon 2), or less commonly in the switch II region of the G domain (exon 3). Most NRAS exon 2 mutations comprise amino acid substitutions at position 61 from glutamine (Q) to arginine (R; 35%), lysine (K; 34%) and less often to glutamate (E), leucine (L), or proline (P). Preclinical data suggest that NRAS mutations paradoxically stimulate the MAPK pathway and thus enhance tumor growth in vitro.^59,60 Several important phenotypic differences distinguish NRAS- from BRAF-mutated melanoma. NRAS-mutated tumors are typically associated with increasing age and CSD skin, while BRAF-mutated tumors arise in younger patients in non-CSD skin. A large population-based study suggested that NRAS-mutated melanomas were associated with mitoses and lower tumor infiltrating lymphocytes (TIL) grade, and arose in anatomic sites other than the head/neck, while BRAF-mutated tumors were associated with mitoses and superficial spreading histology.⁶¹ Although the lower TIL grade seen with NRAS-mutated melanomas suggests a more immunosuppressed microenvironment and argues for poorer responses to immune therapies, clinical studies comparing responses to immunotherapies in various categories of driver mutations provide conflicting results for the prognostic role of NRAS mutations in relation to immune checkpoint blockade and other immune therapies.^62–64

NF1 represents the third known driver in cutaneous melanoma, with mutations reported in 12% of cases.^6,7NF1 encodes neurofibromin, which has GTPase activity and regulates RAS proteins; NF1 loss results in increased RAS.⁶⁵ Unlike BRAF or NRAS, which are usually mutually exclusive, NF1 mutations in melanoma can occur singly or in combination with either BRAF or NRAS mutations. In these settings, NF1 mutations are associated with RAS activation, MEK-dependence, and resistance to RAF inhibition.⁶⁶

MAPK PATHWAY INHIBITION SINGLY AND IN COMBINATION

Although multiple MEK 1/2 inhibitors (AS703026, AZD8330/ARRY-704, AZD6244, CH5126766, CI-1040, GSK1120212, PD0325901, RDEA119, and XL518) and RAF inhibitors (ARQ 680, GDC-0879, GSK2118436, PLX4032, RAF265, sorafenib, XL281/BMS-908662) were developed, the initial evaluation of MAPK pathway inhibitors in advanced human cancers began with CI-1040. Preclinical data suggested that CI-1040 potently and selectively inhibited both MEK1 and MEK2, but phase 1 and 2 human trial results were disappointing, likely because these trials were not selectively enriched for NRAS/BRAF–mutated tumors or cancers in which these oncogenic mutations were most commonly detected, such as melanoma.^67,68 The subsequent evaluation of selumetinib (AZD6244/ARRY-142886) in a phase 2 study was also negative. Although investigators enrolled a presumably enriched population (cutaneous melanoma), the incidence of NRAS/BRAF–mutated tumors was not ascertained to determine this, but rather assumed, which led to a discrepancy between the assumed (prestudy) and observed (on-study) proportions of BRAF/NRAS mutations that was not accounted for in power calculations.^69,70 Lessons learned from these earlier misadventures informed the current paradigm of targeted therapy development: (1) identification of a highly specific and potent inhibitor through high-throughput screening; (2) establishment of maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in unselected patients; (3) confirmation of RP2D in selected tumor types enriched for target of interest; and (4) confirmatory study against standard comparator to seek regulatory approval.

Vemurafenib and dabrafenib were evaluated in this tiered fashion in phase 1 dose-finding studies comprising unselected patients, followed by phase 2 studies in advanced BRAF V600E–mutated melanoma. Both were subsequently evaluated in randomized phase 3 trials (vemurafenib, BRIM-38; dabrafenib, BREAK-310) that compared them with dacarbazine (1000 mg/m² intravenously every 3 weeks) in the treatment of advanced BRAF V600E–mutated melanoma. Response kinetics for both agents were remarkably similar: single-agent BRAF inhibitors resulted in rapid (time to response 2–3 months), profound (approximately 50% objective responses) reductions in tumor burden that lasted 6 to 7 months. Adverse events common to both agents included rash, fatigue, and arthralgia, although clinically significant photosensitivity was more common with vemurafenib and clinically significant pyrexia was more common with dabrafenib. Class-specific adverse events included the development of cutaneous squamous-cell carcinomas and keratoacanthomas secondary to paradoxical activation of MAPK pathway signaling either through activating mutations in HRAS or mutations or amplifications in receptor tyrosine kinases upstream of BRAF, resulting in elevated levels of RAS–guanosine triphosphate complexes.⁷¹ Results of these studies resulted in regulatory approval of single-agent BRAF inhibitors for the treatment of BRAF V600E (and later V600K)–mutated melanoma (vemurafenib in 2011; dabrafenib in 2013). Details regarding trial populations, study interventions, efficacy, and adverse events are summarized in Table 2.

Responses to BRAF inhibitors are typically profound but temporary. Mechanisms of acquired resistance are diverse and include reactivation of MAPK pathway–dependent signaling (RAS activation or increased RAF expression), and development of MAPK pathway–independent signaling (COT overexpression; increased PI3K or AKT signaling) that permits bypass of inhibited BRAF signaling within the MAPK pathway.^72–76 These findings suggested that upfront inhibition of both MEK and mutant BRAF may produce more durable responses than BRAF inhibition alone. Three pivotal phase 3 studies established the superiority of combination BRAF and MEK inhibition over BRAF inhibition alone: COMBI-d11 (dabrafenib/trametinib versus dabrafenib/placebo), COMBI-v12 (dabrafenib/trametinib versus vemurafenib), and coBRIM13 (vemurafenib/cobimetinib versus vemurafenib/placebo). As expected, compared to BRAF inhibitor monotherapy, combination BRAF and MEK inhibition produced greater responses and improved progression-free and overall survival (Table 2). Interestingly, the rate of cutaneous squamous-cell carcinomas was much lower with combination therapy, reflecting the more profound degree of MAPK pathway inhibition achieved with combination BRAF and MEK inhibition. Based on these results, FDA approval was granted for both dabrafenib/trametinib and vemurafenib/cobimetinib combinations in 2015. Although the dabrafenib/trametinib combination was only approved in 2015, trametinib had independently gained FDA approval in 2013 for the treatment of BRAF V600E/K–mutated melanoma on the basis of the phase 3 METRIC study.⁷⁷

Encorafenib (LGX818) and binimetinib (MEK162, ARRY-162, ARRY-438162) are new BRAF and MEK inhibitors currently being evaluated in clinical trials. Encorafenib/binimetinib combination was first evaluated in a phase 3 study (COLUMBUS) that compared it with vemurafenib monotherapy in BRAF-mutant melanoma.⁷⁸ Unsurprisingly, encorafenib/binimetinib combination produced greater and more durable responses compared to vemurafenib monotherapy. The median progression-free survival of the encorafenib/binimetinib combination (14.9 months) was greater than vemurafenib monotherapy (7.3 months) in this study, and intriguingly greater than that seen with vemurafenib/cobimetinib (coBRIM 9.9 months) and dabrafenib/trametinib (COMBI-d 9.3 months; COMBI-v 11.4 months). Of note, although encorafenib has an IC50 midway between dabrafenib and vemurafenib in cell-free assays (0.8 nM dabrafenib, 4 nM encorafenib, and 31 nM vemurafenib), it has an extremely slower off-rate from BRAF V600E, which results in significantly greater target inhibition in cells following drug wash-out.⁷⁹ This may account for the significantly greater clinical benefit seen with encorafenib/binimetinib in clinical trials. Final study data are eagerly awaited. Regulatory approval has been sought, and is pending at this time.

Binimetinib has been compared to dacarbazine in a phase 3 study (NEMO) of patients with NRAS-mutant melanoma, most of whom had been previously treated with immunotherapy.⁸⁰ Response rates were low in both arms, although slightly greater with binimetinib than dacarbazine (15% versus 9%), commensurate with a modest improvement in progression-free survival. FDA approval has been sought and remains pending at this time.

KIT INHIBITION SINGLY AND IN COMBINATION

The KIT receptor protein tyrosine kinase is a transmembrane protein consisting of extracellular and intracellular domains. Activating KIT mutations occur in 2% to 8% of all melanoma patients and may be found in all melanoma subtypes but are commonest in acral melanomas (10%–20%) and mucosal melanomas (15%–20%). Activating KIT mutations primarily occur in exons 11 and 13, which code for the juxtamembrane and kinase domains, respectively.^5,81–83

Imatinib mesylate is a tyrosine kinase inhibitor of the 2-phenyl amino pyrimidine class that occupies the tyrosine kinase active site with resultant blocking of tyrosine kinase activity. Imatinib mesylate is known to block KIT and has been extensively studied in patients with gastrointestinal stromal tumors (GIST), 80% of whom harbor KIT mutations, in both the adjuvant and the metastatic settings. In melanoma, imatinib mesylate was studied in a Chinese open-label, phase 2 study of imatinib mesylate monotherapy in metastatic melanoma harboring KIT mutation or amplification; 25% of the study patients had mucosal disease and the rest had cutaneous disease, with acral involvement in 50% of all patients.⁸⁴ Overall response rate was 23%, while 51% of patients remained alive at 1 year with no differences in response rate and/or survival being noted between patients with either KIT mutations or amplifications. In a separate study of imatinib mesylate at 400 mg daily or 400 mg twice daily in Caucasian patients with KIT-mutated/amplified melanoma, similar response and survival rates were reported, although patients with KIT mutations did nonsignificantly better than those with KIT amplifications.⁸⁵

Other novel studies evaluating KIT inhibitors include KIT inhibition in combination with the VEGF inhibitor bevacizumab and a study of selective BCR-ABL kinase inhibitor nilotinib in imatinib-resistant melanoma. In the former phase 1/2 study, Flaherty and colleagues studied imatinib 800 mg daily and bevacizumab at 10 mg/kg every 2 weeks in 63 patients with advanced tumors, including 23 with metastatic melanoma. Although the combination was relatively nontoxic, no significant efficacy signal was seen and further accrual to the phase 2 portion was halted after the first stage was completed.⁸⁶ Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor intelligently designed based on the structure of the ABL-imatinib complex that is 10 to 30 times more potent than imatinib in inhibiting BCR-ABL1 tyrosine kinase activity. Nilotinib is approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML), with reported efficacy in patients with central nervous system (CNS) involvement.^87,88 Nilotinib has been studied in a single study of KIT-mutated/amplified melanoma that included patients with imatinib-resistance and those with treated CNS disease. Nilotinib appeared to be active in imatinib-resistant melanoma, although no responses were seen in the CNS disease cohort.⁸⁹ Overall, the response rates observed with KIT inhibition in melanoma are much lower than those observed in CML and GIST.

CONCLUSION AND FUTURE DIRECTIONS

Prior to 2011, the only approved agents for the treatment of advanced melanoma were dacarbazine and high-dose interleukin-2. Since 2011, drug approvals in melanoma have proceeded at a frenetic pace unmatched in any other disease. The primary events underlying this are advances in our understanding of the gene mutation landscape driving melanoma tumorigenesis, accompanied by insights into the means by which tumors circumvent the induction of effective anti-tumor T-cell responses. These insights have resulted in the development of inhibitors targeting MAPK pathway kinases BRAF, MEK, and NRAS), KIT, and regulatory immune checkpoints (CTLA-4 and PD-1). Although BRAF/MEK inhibition results in profound reductions and even occasional complete responses in patients, these responses are typically short lived, rarely lasting more than 9 to 11 months; the encorafenib/binimetinib combination may improve that duration marginally. However, the signature therapeutic advance in melanoma of the past decade is immunotherapy, particularly the development of inhibitors of CTLA-4 and PD-1 immune checkpoints. With these agents, significant proportions of treated patients remain free of progression off-therapy (ipilimumab 23%; nivolumab 34%; pembrolizumab 35%; ipilimumab/nivolumab 64%), and some patients can be successfully re-induced after delayed progression. Separately, the high response rates observed with the use of KIT inhibitors in CML and GIST have not been observed in KIT mutated/amplified melanoma and development of agents in this space has been limited. The challenges ahead center around identifying predictive biomarkers and circumventing primary or acquired resistance, with the eventual goal of producing durable remissions in the majority of treated patients.

Our improved understanding of the mechanisms of acquired resistance to BRAF/MEK inhibitors suggests that anti-tumor activity may be achieved by targeting multiple pathways, possibly with combination regimens comprising other inhibitors and/or immunotherapy. Preclinical data supports the use of combination strategies targeting both ERK and PI3K/mTOR to circumvent acquired resistance.⁹⁰ Ongoing studies are evaluating combinations with biguanides (metformin: NCT02143050 and NCT01638676; phenformin: NCT03026517), HSP90 inhibitors (XL888: NCT02721459; AT13387: NCT02097225), and decitabine (NCT01876641).

One complexity affecting management of resistance in the targeted therapy landscape remains tumor heterogeneity, particularly intra- and intertumoral heterogeneity, which may explain the apparent contradiction between continued efficacy of BRAF inhibitors in BRAF-resistant tumors and preclinical data predicting slower progression of resistant tumors on cessation of BRAF inhibitors.^91–94 These data provide a rationale to investigate intermittent dosing regimens with BRAF/MEK inhibitors; several studies exploring this approach are ongoing (NCT01894672 and NCT02583516).

Given the specificity, adaptability, and memory response associated with immunotherapy, it is likely that these agents will be used to treat the majority of patients regardless of mutational status. Hence, identifying predictive biomarkers of response to immune checkpoint inhibitors is vital. The presence of CD8+ T-cell infiltrate and IFN-γ gene signature, which indicate an “inflamed” tumor microenvironment, are highly predictive of clinical benefit from PD-1 inhibitors.^95,96 However, not all PD-1 responders have “inflamed” tumor microenvironments, and not all patients with an “inflamed” tumor microenvironment respond to immune checkpoint inhibitors. The complexity of the immune system is reflected in the multiple non-redundant immunologic pathways, both positive and negative, with checkpoints and ligands that emerge dynamically in response to treatment. Given the dynamic nature of the immune response, it is unlikely that any single immunologic biomarker identified pre-treatment will be completely predictive. Rather, the complexity of the biomarker approach must match the complexity of the immune response elicited, and will likely incorporate multifarious elements including CD8+ T-cell infiltrate, IFN-γ gene signature, and additional elements including microbiome, genetic polymorphisms, and tumor mutation load. The goal is to use multiple markers to guide development of combinations and then, depending on initial response, to examine tumors for alterations to guide decisions about additional treatment(s) to improve responses, with the eventual goal being durable clinical responses for all patients.

INTRODUCTION

The incidence of cutaneous melanoma has increased over the past 2 decades, with SEER estimates indicating that the number of new cases of melanoma diagnosed annually rose from 38,300 in 1996 to 76,000 in 2016.¹ Among persons younger than 50 years, the incidence is higher in females, and younger women (aged 15–39 years) are especially vulnerable.² Among persons older than 50, melanoma incidence in men is nearly twice that of women, in whom melanomas are often thicker and often associated with worse outcomes.^1,2 Approximately 85% of melanomas are diagnosed at early stages when surgery is curative, but the lifetime probability of developing invasive disease is 3% in men and 2% in women.

Prior to the advent of effective immunotherapies and targeted therapies, melanoma was often managed with chemotherapy, which had dismal response rates and commensurately poor outcomes. Advances in the understanding of the molecular etiopathogenesis and immune escape responses of cutaneous metastatic melanoma have transformed therapeutic approaches. Specifically, improved understanding of the genetic mutations driving melanoma tumorigenesis coupled with insights into mechanisms of tumor-mediated immune evasion resulted in development of inhibitors of mitogen-activated protein kinases (MAPK; BRAF and MEK) along with inhibitors of negative regulatory immune checkpoints (cytotoxic T lymphocyte–associated antigen 4 [CTLA-4] and programmed cell death-1 [PD-1]). In this review, we discuss the role of immune therapy, targeted therapy, and combinations of these in the treatment of metastatic cutaneous melanoma. We limit the immuno-therapy discussion to approved CTLA-4/PD-1 inhibitors and the targeted therapy discussion to approved BRAF/NRAS/MEK inhibitors and do not discuss non-checkpoint immunotherapies including cytokines (HD IL-2), vaccines, or adoptive T-cell approaches. Interested readers are directed to other excellent works covering these important topics.^26–29

DEVELOPMENT OF TARGETED AND NOVEL IMMUNE THERAPIES

For many years the degree of ultraviolet (UV) light exposure was considered the sole major risk factor for melanoma oncogenesis, even though its mechanism was largely unknown.³ However, clinical observations regarding the occurrence of melanoma on less exposed areas (trunk and limbs) in individuals with intermittent sun exposure led to the proposition that melanomas that arose in younger patients with intermittent sun exposure were distinct from melanomas that arose in older patients in association with markers of chronic sun exposure—the “divergent pathway” hypothesis.³ Critical to this understanding were whole-exome sequencing data from multiple groups, including The Cancer Genome Atlas, that identified patterns of mutations in oncogenic drivers that were distinct in patients with and without chronically sun-damaged (CSD) skin.^4–7 It is now clear that based on its association with CSD skin, melanoma can be subclassified into CSD or non-CSD melanoma. CSD and non-CSD melanoma have distinct clinico-pathological characteristics and are associated with different driver mutations. CSD melanomas typically arise in older patients on sun-exposed areas (head/neck, dorsal surfaces of distal extremities) and are associated with particular driver mutations (BRAF non-V600E, NRAS, NF1, or KIT) and genetic signatures of UV-induced DNA damage (G > T [UVA] or C > T [UVB]) transitions. Conversely, non-CSD melanomas typically arise in younger (< 55 years) patients on intermittently sun-exposed areas (trunk, proximal extremities) and are associated with BRAF V600E/K driver mutations and often lack genetic signatures of UV mutagenesis.

Identification of driver mutations in components of the MAPK pathway, including BRAF and NRAS, facilitated the development of targeted inhibitors. The BRAF inhibitors vemurafenib and dabrafenib have been shown in pivotal phase 3 studies to significantly improve overall and progression-free survival in patients with metastatic melanoma compared with chemotherapy and garnered regulatory approval (vemurafenib, BRIM-3;^8,9 dabrafenib, BREAK-3¹⁰). Concomitant MEK and BRAF inhibition extends the duration of benefit by preventing downstream kinase activation in the MAPK pathway. Notably, concomitant MEK inhibition alters the side-effect profile of BRAF inhibitors, with reduced incidence of keratoacanthomas and cutaneous squamous cell carcinomas that are attributable to on-target, off-tumor effects of BRAF inhibitors. Combined BRAF and MEK inhibition (vemurafenib/cobimetinib and dabrafenib/trametinib) further improved overall and progression-free survival compared to single-agent BRAF inhibition in phase 3 studies (COMBI-d,¹¹ COMBI-v,¹² and coBRIM¹³). Although often deep, the responses seen with the use of targeted kinase inhibitors are not often durable, with the vast majority of patients progressing after 12 to 15 months of therapy.In parallel, work primarily done in murine models of chronic viral infection uncovered the role played by co-inhibitory or co-excitatory immune checkpoints in mediating T-cell immune responses. These efforts clarified that tumor-mediated immune suppression primarily occurs through enhancement of inhibitory signals via the negative T-cell immune checkpoints CTLA-4 or PD-1.^14,15 Blockade of negative T-cell immune checkpoints resulted in activation of the adaptive immune system, resulting in durable anti-tumor responses as demonstrated in studies of the CTLA-4 inhibitor ipilimumab (CA184-020¹⁶ and CA184-024¹⁷) and the PD-1 inhibitors nivolumab (CA209-003,¹⁸ CheckMate 037,¹⁹ and CheckMate 066²⁰) and pembrolizumab (KEYNOTE-001²¹ and KEYNOTE-006²²). Compared to the deep but short-lived responses seen with targeted kinase inhibitors, patients treated with CTLA-4 or PD-1 immune checkpoint blockade often developed durable responses that persisted even after completion of therapy. Combined CTLA-4 and PD-1 blockade results in greater magnitude of response with proportionately increased toxicity.^23–25

IMMUNOTHERAPY

CTLA-4 AND PD-1 IMMUNE CHECKPOINT INHIBITORS

The novel success of immunotherapy in recent decades is largely attributable to improved understanding of adaptive immune physiology, specifically T-cell activation and regulation. T-cell activation requires 2 independent signaling events: it is initiated upon recognition of the antigen-MHC class II-receptor complex on antigen-presenting cells (APC), and requires a secondary co-stimulatory interaction of CD80/CD86 (B7.1/B7.2) on APCs and CD28 molecule on T-cells; without this second event, T-cells enter an anergic state.^30–32 Upon successful signaling and co-stimulation, newly activated T-cells upregulate CTLA-4, which can bind to B7 molecules with a nearly 100-fold greater affinity than CD28.^33,34 Unlike CD28, CTLA-4 engagement negatively regulates T-cell activation. The opposing signals produced by CD28 and CTLA-4 are integrated by the T-cell to determine eventual response to activation, and provide a means by which T-cell activation is homeostatically regulated to prevent exaggerated physiologic immune responses.³⁵ It was hypothesized that CTLA-4 blockade would permit T-cell activation, which is thwarted in the tumor microenvironment by tumor-mediated CTLA-4 engagement, thereby unleashing an anti-tumor immune response.³⁶

PD-1 is a member of the CD28 and CTLA-4 immunoglobulin super family and, similar to CTLA-4, binds activated T-cells. PD-1 has 2 ligands on activated T-cells: PD-L1 and PD-L2.³⁷ PD-L1 is constitutively expressed by a variety of immune and non-immune cells, particularly in inflammatory environments including tumor microenvironments, in response to the release of inflammatory cytokines such as interferon (IFN)-γ.^37,38 Conversely, PD-L2 is only minimally expressed constitutively, although its expression on immune and non-immune cells can be induced by similar cues from inflammatory microenvironments. PD-L1 and PD-L2 cross-compete for binding to PD-1, with PD-L2 exhibiting 2- to 6-fold greater relative affinity than PD-L1.³⁹ PD-L1/PD-1 binding results in phosphorylation of 2 tyrosinases in the intracellular portion of PD-1, which contains immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). PD-1 ITSM subsequently recruits either of 2 SH2-domain–containing protein tyrosine phosphatases: SHP-1 and SHP-2. SHP-2 signaling suppresses PI3K/Akt activation, down-regulates Bcl-xL, and suppresses expression of multiple transcription factors that mediate T-cell effector function including GATA-3, Eomes, and T-bet.^40–42 The net effect of PD-L1/PD-1 engagement is to suppress T-cell proliferation, cytokine production, cytolytic function, and survival. Unlike CTLA-4, which primarily affects the priming phase of naive T-cell activation, PD-1 chiefly regulates the effector phase of T-cell function. Furthermore, because PD-L1/PD-L2 expression is limited to inflammatory microenvironments, the effects of PD-1 are less generalized than those of CTLA-4.

SINGLE AGENT ACTIVITY OF CTLA-4 AND PD-1 INHIBITORS

Ipilimumab (MDX-010) is a human IgG1 monoclonal antibody shown to inhibit CTLA-4.⁴³ Early studies tested different formulations (transfectoma-derived and hybridoma-derived), doses, and schedules of ipilimumab primarily in patients with advanced refractory melanoma.^44–46 Although responses were infrequent, responding patients experienced durable remissions at 1- and 2-year time points. Notably, in a foreshadowing of changes to response criteria used to evaluate these agents, several treated patients who initially had radiographically stable disease upon completion of therapy subsequently experienced a gradual decline in tumor burden.

Ipilimumab was subsequently evaluated in 2 phase 3 trials. The first study (MDX010-020/CA184-020), which involved 676 HLA-A*0201–positive patients with advanced melanoma, compared ipilimumab 3 mg/kg every 3 weeks for 4 doses either singly or in combination with gp100 vaccine with a gp100-only control arm.¹⁶ Ipilimumab administration resulted in objective responses in 11% of patients and improved progression-free and overall survival compared to gp100 alone. Of note, ipilimumab monotherapy was superior to ipilimumab/gp100 combination, possibly related to timing of vaccine in relation to ipilimumab. A confirmatory study (CA184-024) compared a higher dose of ipilimumab (10 mg/kg) in combination with dacarbazine to dacarbazine monotherapy in previously untreated melanoma and was positive.¹⁷ Given the lack of augmented efficacy with the higher (10 mg/kg) dose, ipilimumab received regulatory approval in 2011 for the treatment of melanoma at the lower dose: 3 mg/kg administered every 3 weeks for 4 doses (Table 1). Survival data was strikingly similar to patterns observed in prior phase 2 studies, with survival curves plateauing after 2 years at 23.5% to 28.5% of treated patients. Pooled survival data from prospective and retrospective studies of ipilimumab corroborate the plateau of 22% (26% treated; 20% untreated) reached at year 3 regardless of prior therapy or ipilimumab dose, underscoring the durability of long-term survival in ipilimumab-treated patients.⁴⁷ Ipilimumab administration resulted in an unusual spectrum of toxicities including diarrhea, rash, hepatitis, and hypophysitis (termed immune-related adverse events, or irAEs) in up to a third of patients.

Pembrolizumab and nivolumab are humanized IgG4 monoclonal antibodies that target the PD-1 receptor found on activated T cells, B cells, and myeloid cells. Pembrolizumab and nivolumab are engineered similarly: by immunizing transgenic mice with recombinant human PD-1-Fc protein and subsequently screening murine splenic cells fused with myeloma cells for hybridomas producing antibodies reactive to PD-1-Fc.^48,49 Unlike IgG1, the IgG4 moiety neither engages Fc receptors nor activates complement, avoiding cytotoxic effects of the antibody upon binding to the T cells that it is intended to activate. Both pembrolizumab and nivolumab bind PD-1 with high affinity and specificity, effectively inhibiting the interaction between PD-1 and ligands PD-L1 and PD-L2.

Nivolumab was first studied in a phase 1 study (CA209-003) of 296 patients with advanced cancers who received 1, 3, or 10 mg/kg administered every 2 weeks.¹⁸ Histologies tested included melanoma, non–small-cell lung cancer (NSCLC), renal-cell cancer (RCC), castration-resistant prostate cancer (CRPC), and colorectal cancer (CRC). Responses were seen in melanoma and RCC and unusually in NSCLC, including in both squamous and non-squamous tumors. Objective responses were noted in 41% of the 107 melanoma patients treated at 3 mg/kg. Survival was improved, with 1- and 2-year survival rates of 62% and 43% at extended follow up.⁵⁰

Subsequently, nivolumab was compared to chemotherapy in a pair of phase 3 studies involving both previously untreated (Checkmate 066) and ipilimumab/BRAF inhibitor–refractory (CheckMate 037) patients.^19,20 In both studies, nivolumab produced durable responses in 32% to 34% of patients and improved survival over chemotherapy. Compared to ipilimumab, the incidence of irAEs was much lower with nivolumab. The depth and magnitude of responses observed led to regulatory approval for nivolumab in both indications (untreated and ipilimumab/BRAF inhibitor–treated melanoma) in 2014. Data from both studies are summarized in Table 1.

Pembrolizumab was first evaluated in a phase 1 study of 30 patients with a variety of solid organ malignancies in which no dose-limiting toxicities were observed and no defined maximal tolerated dose was reached.⁵¹ Per protocol, maximal administered dose was 10 mg/kg every 2 weeks. Following startling responses including 2 complete responses of long duration, pembrolizumab was evaluated in a large phase 1 study (KEYNOTE-001) of 1260 patients that evaluated 3 doses (10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, and 2 mg/kg every 3 weeks) in separate melanoma and NSCLC substudies.²¹ Both ipilimumab-naïve and ipilimumab-treated patients were enrolled in the melanoma substudy. Objective responses were seen in 38% ofpatients across all 3 dosing schedules and were similar in both ipilimumab-naïve and ipilimumab-treated patients. Similar to nivolumab, most responders experienced durable remissions.

Pembrolizumab was subsequently compared to ipilimumab in untreated patients (KEYNOTE-006) in which patients were randomly assigned to receive either ipilimumab or pembrolizumab at 1 of 2 doses: 10 mg/kg every 2 weeks and pembrolizumab 10 mg/kg every 3 weeks.²² Response rates were greater with pembrolizumab than ipilimumab, with commensurately greater 1-year survival rates. Rates of treatment-related adverse events requiring discontinuation of study drug were much lower with pembrolizumab than ipilimumab. This trial was instrumental in proving the superior profile of pembrolizumab over ipilimumab. The US Food and Drug Administration (FDA) granted pembrolizumab accelerated approval for second-line treatment of melanoma in 2014, and updated this to include a first-line indication in 2015 (Table 1).

EFFICACY OF COMBINED CTLA-4 AND PD-1 INHIBITION

Preclinical studies demonstrated that PD-1 blockade was more effective than CTLA-4 blockade and combination PD-1/CTLA-4 blockade was synergistic, with complete rejection of tumors in approximately half of the treated animals.¹⁴ This hypothesis was evaluated in a phase 1 study that explored both concurrent and sequential combinations of ipilimumab and nivolumab along with increasing doses of both agents in PD-1/CTLA-4–naïve advanced melanoma.²³ Responses were greater in the concurrent arm (40%) than in the sequential arm (20%) across dose-levels with a small fraction of patients treated in the concurrent arm experiencing a profound reduction (80%) in tumor burden.

The superiority of ipilimumab/nivolumab combination to ipilimumab monotherapy was demonstrated in a randomized blinded phase 2 study (CheckMate 069).²⁴ Of the 4 different ipilimumab/nivolumab doses explored in the phase 1 study (3 mg/kg and 0.3 mg/kg, 3 mg/kg and 1 mg/kg, 1 mg/kg and 3 mg/kg, 3 mg/kg and 3 mg/kg), ipilimumab 3 mg/kg and nivolumab 1 mg/kg (followed by nivolumab 3 mg/kg) was compared to ipilimumab and nivolumab-matched placebo. Responses were significantly greater with dual PD-1/CTLA-4 blockade compared to CTLA-4 blockade alone (59% versus 11%). Concurrently, a 3-arm randomized phase 3 study compared the same dose of ipilimumab/nivolumab to ipilimumab and nivolumab in previously untreated advanced melanoma (CheckMate 067).²⁵ Similar to CheckMate 069, CheckMate 067 demonstrated that ipilimumab/nivolumab combination resulted in more profound responses (58%) than either ipilimumab (19%) or nivolumab (44%) alone. Toxicity, primarily diarrhea, fatigue, pruritus, and rash, was considerable in the combination arm (55% grade 3/4 adverse events) and resulted in treatment discontinuation in 30% of patients. The profound and durable responses observed led to accelerated approval of ipilimumab/nivolumab combination in 2015 (Table 1).

Efforts to improve the toxicity/benefit ratio of ipilimumab/nivolumab combination have centered around studying lower doses and/or extended dosing schedules of ipilimumab, including ipilimumab 1 mg/kg every 6 or 12 weeks with nivolumab dosed at 3 mg/kg every 2 weeks or 480 mg every 4 weeks. Promising data from a first-line study in NSCLC (CheckMate 012) support the evaluation of nivolumab in combination with lower-dosed ipilimumab (1 mg/kg every 6 or 12 weeks).⁵² This approach is being tested against platinum doublet chemotherapy in a confirmatory phase 3 study in NSCLC (CheckMate 227).

TARGETED THERAPY

MAPK KINASE PATHWAY IN MELANOMA TUMORIGENESIS

The MAPK pathway mediates cellular responses to growth signals. RAF kinases are central mediators in the MAPK pathway and exert their effect primarily through MEK phosphorylation and activation following dimerization (hetero- or homo-) of RAF molecules. As a result, RAF is integral to multiple cellular processes, including transcriptional regulation, cellular differentiation, and cell proliferation. MAPK pathway activation is a common event in many cancers, primarily due to activating mutations in BRAF or RAS. Alternatively, MAPK pathway activation can occur in the absence of activating mutations in BRAF or NRAS through down-regulation of MAPK pathway inhibitory proteins (RAF-1 inhibitory protein or SPRY-2), C-MET overexpression, or activating mutations in non-BRAF/NRAS kinases including CRAF, HRAS, and NRAS.^53,54

Somatic point mutations in BRAF are frequently observed (37%–50%) in malignant melanomas and at lower frequency in a range of human cancers including NSCLC, colorectal cancer, papillary thyroid cancer, ovarian cancer, glioma, and gastrointestinal stromal tumor.^6,55,56BRAF mutations in melanoma typically occur within the activation segment of the kinase domain (exon 15). Between 80% and 90% of activating mutations result in an amino acid substitution of glutamate (E) for valine (V) at position 600: V600E.^57,58 V600E mutations are true oncogenic drivers, resulting in increased kinase activity with demonstrable transformational capacity in vitro. BRAF mutations are usually mutually exclusive, with tumors typically containing no other driver mutations in NRAS, KIT, NF1, or other genes.

NRAS mutations are less common than BRAF mutations, having a reported frequency of 13% to 25% in melanoma.⁴NRAS mutations generally occur within the P-loop region of the G domain (exon 2), or less commonly in the switch II region of the G domain (exon 3). Most NRAS exon 2 mutations comprise amino acid substitutions at position 61 from glutamine (Q) to arginine (R; 35%), lysine (K; 34%) and less often to glutamate (E), leucine (L), or proline (P). Preclinical data suggest that NRAS mutations paradoxically stimulate the MAPK pathway and thus enhance tumor growth in vitro.^59,60 Several important phenotypic differences distinguish NRAS- from BRAF-mutated melanoma. NRAS-mutated tumors are typically associated with increasing age and CSD skin, while BRAF-mutated tumors arise in younger patients in non-CSD skin. A large population-based study suggested that NRAS-mutated melanomas were associated with mitoses and lower tumor infiltrating lymphocytes (TIL) grade, and arose in anatomic sites other than the head/neck, while BRAF-mutated tumors were associated with mitoses and superficial spreading histology.⁶¹ Although the lower TIL grade seen with NRAS-mutated melanomas suggests a more immunosuppressed microenvironment and argues for poorer responses to immune therapies, clinical studies comparing responses to immunotherapies in various categories of driver mutations provide conflicting results for the prognostic role of NRAS mutations in relation to immune checkpoint blockade and other immune therapies.^62–64

NF1 represents the third known driver in cutaneous melanoma, with mutations reported in 12% of cases.^6,7NF1 encodes neurofibromin, which has GTPase activity and regulates RAS proteins; NF1 loss results in increased RAS.⁶⁵ Unlike BRAF or NRAS, which are usually mutually exclusive, NF1 mutations in melanoma can occur singly or in combination with either BRAF or NRAS mutations. In these settings, NF1 mutations are associated with RAS activation, MEK-dependence, and resistance to RAF inhibition.⁶⁶

MAPK PATHWAY INHIBITION SINGLY AND IN COMBINATION

Although multiple MEK 1/2 inhibitors (AS703026, AZD8330/ARRY-704, AZD6244, CH5126766, CI-1040, GSK1120212, PD0325901, RDEA119, and XL518) and RAF inhibitors (ARQ 680, GDC-0879, GSK2118436, PLX4032, RAF265, sorafenib, XL281/BMS-908662) were developed, the initial evaluation of MAPK pathway inhibitors in advanced human cancers began with CI-1040. Preclinical data suggested that CI-1040 potently and selectively inhibited both MEK1 and MEK2, but phase 1 and 2 human trial results were disappointing, likely because these trials were not selectively enriched for NRAS/BRAF–mutated tumors or cancers in which these oncogenic mutations were most commonly detected, such as melanoma.^67,68 The subsequent evaluation of selumetinib (AZD6244/ARRY-142886) in a phase 2 study was also negative. Although investigators enrolled a presumably enriched population (cutaneous melanoma), the incidence of NRAS/BRAF–mutated tumors was not ascertained to determine this, but rather assumed, which led to a discrepancy between the assumed (prestudy) and observed (on-study) proportions of BRAF/NRAS mutations that was not accounted for in power calculations.^69,70 Lessons learned from these earlier misadventures informed the current paradigm of targeted therapy development: (1) identification of a highly specific and potent inhibitor through high-throughput screening; (2) establishment of maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in unselected patients; (3) confirmation of RP2D in selected tumor types enriched for target of interest; and (4) confirmatory study against standard comparator to seek regulatory approval.

Vemurafenib and dabrafenib were evaluated in this tiered fashion in phase 1 dose-finding studies comprising unselected patients, followed by phase 2 studies in advanced BRAF V600E–mutated melanoma. Both were subsequently evaluated in randomized phase 3 trials (vemurafenib, BRIM-38; dabrafenib, BREAK-310) that compared them with dacarbazine (1000 mg/m² intravenously every 3 weeks) in the treatment of advanced BRAF V600E–mutated melanoma. Response kinetics for both agents were remarkably similar: single-agent BRAF inhibitors resulted in rapid (time to response 2–3 months), profound (approximately 50% objective responses) reductions in tumor burden that lasted 6 to 7 months. Adverse events common to both agents included rash, fatigue, and arthralgia, although clinically significant photosensitivity was more common with vemurafenib and clinically significant pyrexia was more common with dabrafenib. Class-specific adverse events included the development of cutaneous squamous-cell carcinomas and keratoacanthomas secondary to paradoxical activation of MAPK pathway signaling either through activating mutations in HRAS or mutations or amplifications in receptor tyrosine kinases upstream of BRAF, resulting in elevated levels of RAS–guanosine triphosphate complexes.⁷¹ Results of these studies resulted in regulatory approval of single-agent BRAF inhibitors for the treatment of BRAF V600E (and later V600K)–mutated melanoma (vemurafenib in 2011; dabrafenib in 2013). Details regarding trial populations, study interventions, efficacy, and adverse events are summarized in Table 2.

Responses to BRAF inhibitors are typically profound but temporary. Mechanisms of acquired resistance are diverse and include reactivation of MAPK pathway–dependent signaling (RAS activation or increased RAF expression), and development of MAPK pathway–independent signaling (COT overexpression; increased PI3K or AKT signaling) that permits bypass of inhibited BRAF signaling within the MAPK pathway.^72–76 These findings suggested that upfront inhibition of both MEK and mutant BRAF may produce more durable responses than BRAF inhibition alone. Three pivotal phase 3 studies established the superiority of combination BRAF and MEK inhibition over BRAF inhibition alone: COMBI-d11 (dabrafenib/trametinib versus dabrafenib/placebo), COMBI-v12 (dabrafenib/trametinib versus vemurafenib), and coBRIM13 (vemurafenib/cobimetinib versus vemurafenib/placebo). As expected, compared to BRAF inhibitor monotherapy, combination BRAF and MEK inhibition produced greater responses and improved progression-free and overall survival (Table 2). Interestingly, the rate of cutaneous squamous-cell carcinomas was much lower with combination therapy, reflecting the more profound degree of MAPK pathway inhibition achieved with combination BRAF and MEK inhibition. Based on these results, FDA approval was granted for both dabrafenib/trametinib and vemurafenib/cobimetinib combinations in 2015. Although the dabrafenib/trametinib combination was only approved in 2015, trametinib had independently gained FDA approval in 2013 for the treatment of BRAF V600E/K–mutated melanoma on the basis of the phase 3 METRIC study.⁷⁷

Encorafenib (LGX818) and binimetinib (MEK162, ARRY-162, ARRY-438162) are new BRAF and MEK inhibitors currently being evaluated in clinical trials. Encorafenib/binimetinib combination was first evaluated in a phase 3 study (COLUMBUS) that compared it with vemurafenib monotherapy in BRAF-mutant melanoma.⁷⁸ Unsurprisingly, encorafenib/binimetinib combination produced greater and more durable responses compared to vemurafenib monotherapy. The median progression-free survival of the encorafenib/binimetinib combination (14.9 months) was greater than vemurafenib monotherapy (7.3 months) in this study, and intriguingly greater than that seen with vemurafenib/cobimetinib (coBRIM 9.9 months) and dabrafenib/trametinib (COMBI-d 9.3 months; COMBI-v 11.4 months). Of note, although encorafenib has an IC50 midway between dabrafenib and vemurafenib in cell-free assays (0.8 nM dabrafenib, 4 nM encorafenib, and 31 nM vemurafenib), it has an extremely slower off-rate from BRAF V600E, which results in significantly greater target inhibition in cells following drug wash-out.⁷⁹ This may account for the significantly greater clinical benefit seen with encorafenib/binimetinib in clinical trials. Final study data are eagerly awaited. Regulatory approval has been sought, and is pending at this time.

Binimetinib has been compared to dacarbazine in a phase 3 study (NEMO) of patients with NRAS-mutant melanoma, most of whom had been previously treated with immunotherapy.⁸⁰ Response rates were low in both arms, although slightly greater with binimetinib than dacarbazine (15% versus 9%), commensurate with a modest improvement in progression-free survival. FDA approval has been sought and remains pending at this time.

KIT INHIBITION SINGLY AND IN COMBINATION

The KIT receptor protein tyrosine kinase is a transmembrane protein consisting of extracellular and intracellular domains. Activating KIT mutations occur in 2% to 8% of all melanoma patients and may be found in all melanoma subtypes but are commonest in acral melanomas (10%–20%) and mucosal melanomas (15%–20%). Activating KIT mutations primarily occur in exons 11 and 13, which code for the juxtamembrane and kinase domains, respectively.^5,81–83

Imatinib mesylate is a tyrosine kinase inhibitor of the 2-phenyl amino pyrimidine class that occupies the tyrosine kinase active site with resultant blocking of tyrosine kinase activity. Imatinib mesylate is known to block KIT and has been extensively studied in patients with gastrointestinal stromal tumors (GIST), 80% of whom harbor KIT mutations, in both the adjuvant and the metastatic settings. In melanoma, imatinib mesylate was studied in a Chinese open-label, phase 2 study of imatinib mesylate monotherapy in metastatic melanoma harboring KIT mutation or amplification; 25% of the study patients had mucosal disease and the rest had cutaneous disease, with acral involvement in 50% of all patients.⁸⁴ Overall response rate was 23%, while 51% of patients remained alive at 1 year with no differences in response rate and/or survival being noted between patients with either KIT mutations or amplifications. In a separate study of imatinib mesylate at 400 mg daily or 400 mg twice daily in Caucasian patients with KIT-mutated/amplified melanoma, similar response and survival rates were reported, although patients with KIT mutations did nonsignificantly better than those with KIT amplifications.⁸⁵

Other novel studies evaluating KIT inhibitors include KIT inhibition in combination with the VEGF inhibitor bevacizumab and a study of selective BCR-ABL kinase inhibitor nilotinib in imatinib-resistant melanoma. In the former phase 1/2 study, Flaherty and colleagues studied imatinib 800 mg daily and bevacizumab at 10 mg/kg every 2 weeks in 63 patients with advanced tumors, including 23 with metastatic melanoma. Although the combination was relatively nontoxic, no significant efficacy signal was seen and further accrual to the phase 2 portion was halted after the first stage was completed.⁸⁶ Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor intelligently designed based on the structure of the ABL-imatinib complex that is 10 to 30 times more potent than imatinib in inhibiting BCR-ABL1 tyrosine kinase activity. Nilotinib is approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML), with reported efficacy in patients with central nervous system (CNS) involvement.^87,88 Nilotinib has been studied in a single study of KIT-mutated/amplified melanoma that included patients with imatinib-resistance and those with treated CNS disease. Nilotinib appeared to be active in imatinib-resistant melanoma, although no responses were seen in the CNS disease cohort.⁸⁹ Overall, the response rates observed with KIT inhibition in melanoma are much lower than those observed in CML and GIST.

CONCLUSION AND FUTURE DIRECTIONS

Prior to 2011, the only approved agents for the treatment of advanced melanoma were dacarbazine and high-dose interleukin-2. Since 2011, drug approvals in melanoma have proceeded at a frenetic pace unmatched in any other disease. The primary events underlying this are advances in our understanding of the gene mutation landscape driving melanoma tumorigenesis, accompanied by insights into the means by which tumors circumvent the induction of effective anti-tumor T-cell responses. These insights have resulted in the development of inhibitors targeting MAPK pathway kinases BRAF, MEK, and NRAS), KIT, and regulatory immune checkpoints (CTLA-4 and PD-1). Although BRAF/MEK inhibition results in profound reductions and even occasional complete responses in patients, these responses are typically short lived, rarely lasting more than 9 to 11 months; the encorafenib/binimetinib combination may improve that duration marginally. However, the signature therapeutic advance in melanoma of the past decade is immunotherapy, particularly the development of inhibitors of CTLA-4 and PD-1 immune checkpoints. With these agents, significant proportions of treated patients remain free of progression off-therapy (ipilimumab 23%; nivolumab 34%; pembrolizumab 35%; ipilimumab/nivolumab 64%), and some patients can be successfully re-induced after delayed progression. Separately, the high response rates observed with the use of KIT inhibitors in CML and GIST have not been observed in KIT mutated/amplified melanoma and development of agents in this space has been limited. The challenges ahead center around identifying predictive biomarkers and circumventing primary or acquired resistance, with the eventual goal of producing durable remissions in the majority of treated patients.

Our improved understanding of the mechanisms of acquired resistance to BRAF/MEK inhibitors suggests that anti-tumor activity may be achieved by targeting multiple pathways, possibly with combination regimens comprising other inhibitors and/or immunotherapy. Preclinical data supports the use of combination strategies targeting both ERK and PI3K/mTOR to circumvent acquired resistance.⁹⁰ Ongoing studies are evaluating combinations with biguanides (metformin: NCT02143050 and NCT01638676; phenformin: NCT03026517), HSP90 inhibitors (XL888: NCT02721459; AT13387: NCT02097225), and decitabine (NCT01876641).

One complexity affecting management of resistance in the targeted therapy landscape remains tumor heterogeneity, particularly intra- and intertumoral heterogeneity, which may explain the apparent contradiction between continued efficacy of BRAF inhibitors in BRAF-resistant tumors and preclinical data predicting slower progression of resistant tumors on cessation of BRAF inhibitors.^91–94 These data provide a rationale to investigate intermittent dosing regimens with BRAF/MEK inhibitors; several studies exploring this approach are ongoing (NCT01894672 and NCT02583516).

Given the specificity, adaptability, and memory response associated with immunotherapy, it is likely that these agents will be used to treat the majority of patients regardless of mutational status. Hence, identifying predictive biomarkers of response to immune checkpoint inhibitors is vital. The presence of CD8+ T-cell infiltrate and IFN-γ gene signature, which indicate an “inflamed” tumor microenvironment, are highly predictive of clinical benefit from PD-1 inhibitors.^95,96 However, not all PD-1 responders have “inflamed” tumor microenvironments, and not all patients with an “inflamed” tumor microenvironment respond to immune checkpoint inhibitors. The complexity of the immune system is reflected in the multiple non-redundant immunologic pathways, both positive and negative, with checkpoints and ligands that emerge dynamically in response to treatment. Given the dynamic nature of the immune response, it is unlikely that any single immunologic biomarker identified pre-treatment will be completely predictive. Rather, the complexity of the biomarker approach must match the complexity of the immune response elicited, and will likely incorporate multifarious elements including CD8+ T-cell infiltrate, IFN-γ gene signature, and additional elements including microbiome, genetic polymorphisms, and tumor mutation load. The goal is to use multiple markers to guide development of combinations and then, depending on initial response, to examine tumors for alterations to guide decisions about additional treatment(s) to improve responses, with the eventual goal being durable clinical responses for all patients.

INTRODUCTION

Colorectal cancer (CRC) is one of the most prevalent malignancies and is the fourth most common cancer in the United States, with an estimated 133,490 new cases diagnosed in 2016. Of these, approximately 95,520 are located in the colon and 39,970 are in the rectum.¹ CRC is the third leading cause of cancer death in women and the second leading cause of cancer death in men, with an estimated 49,190 total deaths in 2016.² The incidence appears to be increasing,³ especially in patients younger than 55 years of age;⁴ the reason for this increase remains uncertain.

A number of risk factors for the development of CRC have been identified. Numerous hered-itary CRC syndromes have been described, including familial adenomatous polyposis,⁵ hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome,⁶ and MUTYH-associated polyposis.^7,8 A family history of CRC doubles the risk of developing CRC,⁹ and current guidelines support lowering the age of screening in individuals with a family history of CRC to 10 years younger than the age of diagnosis of the family member or 40 years of age, whichever is lower.¹⁰ Patients with a personal history of adenomatous polyps are at increased risk for developing CRC, as are patients with a personal history of CRC, with a relative risk ranging from 3 to 6.¹¹ Ulcerative colitis and Crohn’s disease are associated with the development of CRC and also influence screening, though evidence suggests good control of these diseases may mitigate risk.¹² Finally, modifiable risk factors for the development of CRC include high red meat consumption,¹³ diets low in fiber,¹⁴ obesity,¹³ smoking, alcohol use,¹⁵ and physical inactivity¹⁶; lifestyle modification targeting these factors has been shown to decrease rates of CRC.¹⁷ The majority of colon cancers present with clinical symptoms, often with rectal bleeding, abdominal pain, change in bowel habits, or obstructive symptoms. More rarely, these tumors are detected during screening colonoscopy, in which case they tend to be at an early stage.

SURGICAL MANAGEMENT

A critical goal in the resection of early-stage colon cancer is attaining R0 resection. Patients who achieve R0 resection as compared to R1 (microscopic residual tumor) and R2 (macroscopic residual tumor)¹⁸ have significantly improved long-term overall survival.¹⁹ Traditionally, open resection of the involved colonic segment was employed, with end-end anastomosis of the uninvolved free margins. Laparoscopic resection for early-stage disease has been utilized in attempts to decrease morbidity of open procedures, with similar outcomes and node sampling.²⁰ Laparoscopic resection appears to provide similar outcomes even in locally advanced disease.²¹ Right-sided lesions are treated with right colectomy and primary ileocolic anastomosis.²² For patients presenting with obstructing masses, the Hartmann procedure is the most commonly performed operation. This involves creation of an ostomy with subtotal colectomy and subsequent ostomy reversal in a 2- or 3-stage protocol.²³ Patients with locally advanced disease and invasion into surrounding structures require multivisceral resection, which involves resection en bloc with secondarily involved organs.²⁴ Intestinal perforation presents a unique challenge and is associated with surgical complications, infection, and lower overall survival (OS) and 5-year disease-free survival (DFS). Complete mesocolic excision is a newer technique that has been performed with reports of better oncologic outcome at some centers; however, this approach is not currently considered standard of care.²⁵

STAGING

According to a report by the National Cancer Institute, the estimated 5-year relative survival rates for localized colon cancer (lymph node negative), regional (lymph node positive) disease, and distant (metastatic) disease are 89.9%, 71.3%, and 13.9%, respectively.¹ However, efforts have been made to further classify patients into distinct categories to allow fine-tuning of prognostication. In the current system, staging of colon cancer utilizes the American Joint Committee on Cancer tumor/node/metastasis (TNM) system.²⁰ Clinical and pathologic features include depth of invasion, local invasion of other organs, nodal involvement, and presence of distant metastasis (Table 1). Studies completed prior to the adoption of the TNM system used the Dukes criteria, which divided colon cancer into A, B, and C, corresponding to TNM stage I, stage IIA–IIC, and stage IIIA-IIIC. This classification is rarely used in more contemporary studies.

Adjuvant chemotherapy seeks to eliminate micrometastatic disease present following curative surgical resection. When stage 0 cancer is discovered incidentally during colonoscopy, endoscopic resection alone is the management of choice, as presence of micrometastatic disease is exceedingly unlikely.²⁶ Stage I–III CRCs are treated with surgical resection withcurative intent. The 5-year survival rate for stage I and early-stage II CRC is estimated at 97% with surgery alone.^27,28 The survival rate drops to about 60% for high-risk stage II tumors (T4aN0), and down to 50% or less for stage II-T4N0 or stage III cancers. Adjuvant chemotherapy is generally recommended to further decrease the rates of distant recurrence in certain cases of stage II and in all stage III tumors.

DETERMINATION OF BENEFIT FROM CHEMOTHERAPY: PROGNOSTIC MARKERS

Prior to administration of adjuvant chemotherapy, a clinical evaluation by the medical oncologist to determine appropriateness and safety of treatment is paramount. Poor performance status and comorbid conditions may indicate risk for excessive toxicity and minimal benefit from chemotherapy. CRC commonly presents in older individuals, with the median age at diagnosis of 69 years for men and 73 years for women.²⁹ In this patient population, comorbidities such as cardiovascular disease, diabetes, and renal dysfunction are more prevalent.³⁰ Decisions regarding adjuvant chemotherapy in this patient population have to take into consideration the fact that older patients may experience higher rates of toxicity with chemotherapy, including gastrointestinal toxicities and marrow suppression.³¹ Though some reports indicate patients older than 70 years derive similar benefit from adjuvant chemotherapy,^32,33 a large pooled analysis of the ACCENT database, which included 7 adjuvant therapy trials and 14,528 patients, suggested limited benefit from the addition of oxaliplatin to fluorouracil in elderly patients.³² Other factors that weigh on the decision include stage, pathology, and presence of high-risk features. A common concern in the postoperative setting is delaying initiation of chemotherapy to allow adequate wound healing; however, evidence suggests that delays longer than 8 weeks leads to worse overall survival, with hazard ratios (HR) ranging from 1.4 to 1.7.^34,35 Thus, the start of adjuvant therapy should ideally be within this time frame.

HIGH-RISK FEATURES

Multiple factors have been found to predict worse outcome and are classified as high-risk features (Table 2). Histologically, high-grade or poorly differentiated tumors are associated with higher recurrence rate and worse outcome.³⁶ Certain histological subtypes, including mucinous and signet-ring, both appear to have more aggressive biology.³⁷ Presence of microscopic invasion into surrounding blood vessels (vascular invasion) and nerves (perineural invasion) is associated with lower survival.³⁸ Penetration of the cancer through the visceral peritoneum (T4a) or into surrounding structures (T4b) is associated with lower survival.³⁶ During surgical resection, multiple lymph nodes are removed along with the primary tumor to evaluate for metastasis to the regional nodes. Multiple analyses have demonstrated that removal and pathologic assessment of fewer than 12 lymph nodes is associated with high risk of missing a positive node, and is thus equated with high risk.^39–41 In addition, extension of tumor beyond the capsules of any single lymph node, termed extracapsular extension, is associated with an increased risk of all-cause mortality.⁴² Tumor deposits, or focal aggregates of adenocarcinoma in the pericolic fat that are not contiguous with the primary tumor and are not associated with lymph nodes, are currently classified as lymph nodes as N1c in the current TNM staging system. Presence of these deposits has been found to predict poor outcome stage for stage.⁴³ Obstruction and/or perforation secondary to the tumor are also considered high-risk features that predict poor outcome.

SIDEDNESS

As reported at the 2016 American Society of Clinical Oncology annual meeting, tumor location predicts outcome in the metastatic setting. A report by Venook and colleagues based on a post-hoc analysis found that in the metastatic setting, location of the tumor primary in the left side is associated with longer OS (33.3 months) when compared to the right side of the colon (19.4 months).⁴⁴ A retrospective analysis of multiple databases presented by Schrag and colleagues similarly reported inferior outcomes in patients with stage III and IV disease who had right-sided primary tumors.⁴⁵ However, the prognostic implications for stage II disease remain uncertain.

BIOMARKERS

Given the controversy regarding adjuvant therapy of patients with stage II colon cancer, multiple biomarkers have been evaluated as possible predictive markers that can assist in this decision. The mismatch repair (MMR) system is a complex cellular enzymatic mechanism that identifies and corrects DNA errors during cell division and prevents mutagenesis.⁴⁶ The familial cancer syndrome HNPCC is linked to alteration in a variety of MMR genes, leading to deficient mismatch repair (dMMR), also termed microsatellite instability-high (MSI-high).^47,48 Epigenetic modification can also lead to silencing of the same implicated genes and accounts for 15% to 20% of sporadic colorectal cancer.⁴⁹ These epigenetic modifications lead to hypermethylation of the promotor region of MLH1 in 70% of cases.⁵⁰ The 4 MMR genes most commonly tested are MLH-1, MSH2, MSH6, and PMS2. Testing can be performed by immunohistochemistry or polymerase chain reaction.⁵¹ Across tumor histology and stage, MSI status is prognostic. Patients with MSI-high tumors have been shown to have improved prognosis and longer OS both in stage II and III disease^52–54 and in the metastatic setting.⁵⁵ However, despite this survival benefit, there is conflicting data as to whether patients with stage II, MSI-high colon cancer may benefit less from adjuvant chemotherapy. One early retrospective study compared outcomes of 70 patients with stage II and III disease and dMMR to those of 387 patients with stage II and III disease and proficient mismatch repair (pMMR). Adjuvant fluorouracil with leucovorin improved DFS for patients with pMMR (HR 0.67) but not for those with dMMR (HR 1.10). In addition, for patients with stage II disease and dMMR, the HR for OS was inferior at 2.95.⁵⁶ Data collected from randomized clinical trials using fluorouracil-based adjuvant chemotherapy were analyzed in an attempt to predict benefit based on MSI status. Benefit was only seen in pMMR patients, with a HR of 0.72; this was not seen in the dMMR patients.⁵⁷ Subsequent studies have had different findings and did not demonstrate a detrimental effect of fluorouracil in dMMR.^58,59 For stage III patients, MSI status does not appear to affect benefit from chemotherapy, as analysis of data from the NSABP C-07 trial (Table 3) demonstrated benefit of FOLFOX (leucovorin, fluorouracil, oxaliplatin) in patients with dMMR status and stage III disease.⁵⁹

Another genetic abnormality identified in colon cancers is chromosome 18q loss of heterozygosity (LOH). The presence of 18q LOH appears to be inversely associated with MSI-high status. Some reports have linked presence of 18q with worse outcome,⁶⁰ but others question this, arguing the finding may simply be related to MSI status.^61,62 This biomarker has not been established as a clear prognostic marker that can aid clinical decisions.

Most recently, expression of caudal-type homeobox transcription factor 2 (CDX2) has been reported as a novel prognostic and predictive tool. A 2015 report linked lack of expression of CDX2 to worse outcome; in this study, 5-year DFS was 41% in patients with CDX2-negative tumors versus 74% in the CDX2-positive tumors, with a HR of disease recurrence of 2.73 for CDX2-negative tumors.⁶³ Similar numbers were observed in patients with stage II disease, with 5-year OS of 40% in patients with CDX2-negative tumors versus 70% in those with CDX2-positive tumors. Treatment of CDX2-negative patients with adjuvant chemotherapy improved outcomes: 5-year DFS in the stage II subgroup was 91% with chemotherapy versus 56% without, and in the stage III subgroup, 74% with chemotherapy versus 37% without. The authors concluded that patients with stage II and III colon cancer that is CDX2-negative may benefit from adjuvant chemotherapy. Importantly, CDX2-negativity is a rare event, occurring in only 6.9% of evaluable tumors.

RISK ASSESSMENT TOOLS

Several risk assessment tools have been developed in an attempt to aid clinical decision making regarding adjuvant chemotherapy for patients with stage II colon cancer. The Oncotype DX Colon Assay analyses a 12-gene signature in the pathologic sample and was developed with the goal to improve prognostication and aid in treatment decision making. The test utilizes reverse transcription-PCR on RNA extracted from the tumor.⁶⁴ After evaluating 12 genes, a recurrence score is generated that predicts the risk of disease recurrence. This score was validated using data from 3 large clinical trials.^65–67 Unlike the Oncotype Dx score used in breast cancer, the test in colon cancer has not been found to predict the benefit from chemotherapy and has not been incorporated widely into clinical practice.

Adjuvant! Online (available at www.adjuvantonline.com) is a web-based tool that combines clinical and histological features to estimate outcome. Calculations are based on US SEER tumor registry-reported outcomes.⁶⁸ A second web-based tool, Numeracy (available at www.mayoclinic.com/calcs), was developed by the Mayo Clinic using pooled data from 7 randomized clinical trials including 3341 patients.⁶⁸ Both tools seek to predict absolute benefit for patients treated with fluorouracil, though data suggests Adjuvant! Online may be more reliable in its predictive ability.⁶⁹ Adjuvant! Online has also been validated in an Asian population70 and patients older than 70 years.⁷¹

MUTATIONAL ANALYSIS

Multiple mutations in proto-oncogenes have been found in colon cancer cells. One such proto-oncogene is BRAF, which encodes a serine-threonine kinase in the rapidly accelerated fibrosarcoma (RAF). Mutations in BRAF have been found in 5% to 10% of colon cancers and are associated with right-sided tumors.⁷² As a prognostic marker, some studies have associated BRAF mutations with worse prognosis, including shorter time to relapse and shorter OS.^73,74 Two other proto-oncogenes are Kristen rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma rat sarcoma viral oncogene homolog (NRAS), both of which encode proteins downstream of epidermal growth factor receptor (EGFR). KRAS and NRAS mutations have been shown to be predictive in the metastatic setting where they predict resistance to the EGFR inhibitors cetuximab and panitumumab.^75,76 The effect of KRAS and NRAS mutations on outcome in stage II and III colon cancer is uncertain. Some studies suggest worse outcome in KRAS-mutated cancers,⁷⁷ while others failed to demonstrate this finding.⁷³

CASE PRESENTATION 1

A 53-year-old man with no past medical history presents to the emergency department with early satiety and generalized abdominal pain. Laboratory evaluation shows a microcytic anemia with normal white blood cell count, platelet count, renal function, and liver function tests. Computed tomography (CT) scan of the abdomen and pelvis show a 4-cm mass in the transverse colon without obstruction and without abnormality in the liver. CT scan of the chest does not demonstrate pathologic lymphadenopathy or other findings. He undergoes robotic laparoscopic transverse colon resection and appendectomy. Pathology confirms a 3.5-cm focus of adenocarcinoma of the colon with invasion through the muscularis propria and 5 of 27 regional lymph nodes positive for adenocarcinoma and uninvolved proximal, distal, and radial margins. He is given a stage of IIIB pT3 pN2a M0 and referred to medical oncology for further management, where 6 months of adjuvant FOLFOX chemotherapy is recommended.

ADJUVANT CHEMOTHERAPY IN STAGE III COLON CANCER

Postoperative adjuvant chemotherapy is the standard of care for patients with stage III disease. In the 1960s, infusional fluorouracil was first used to treat inoperable colon cancer.^78,79 After encouraging results, the agent was used both intraluminally and intravenously as an adjuvant therapy for patients undergoing resection with curative intent; however, only modest benefits were described.^80,81 The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-01 trial (Table 3) was the first study to demonstrate a benefit from adjuvant chemotherapy in colon cancer. This study randomly assigned patients with stage II and III colon cancer to surgery alone, postoperative chemotherapy with fluorouracil, semustine, and vincristine (MOF), or postoperative bacillus Calmette-Guérin (BCG). DFS and OS were significantly improved with MOF chemotherapy.⁸² In 1990, a landmark study reported on outcomes after treatment of 1296 patients with stage III colon cancer with adjuvant fluorouracil and levamisole for 12 months. The combination was associated with a 41% reduction in risk of cancer recurrence and a 33% reduction in risk of death.⁸³ The NSABP C-03 trial (Table 3) compared MOF to the combination of fluorouracil and leucovorin and demonstrated improved 3-year DFS (69% versus 73%) and 3-year OS (77% versus 84%) in patients with stage III disease.⁸⁴ Building on these outcomes, the QUASAR study (Table 3) compared fluorouracil in combination with one of levamisole, low-dose leucovorin, or high-dose leucovorin. The study enrolled 4927 patients and found worse outcomes with fluorouracil plus levamisole and no difference in low-doseversus high-dose leucovorin.⁸⁵ Levamisole fell out of use after associations with development of multifocal leukoencephalopathy,⁸⁶ and was later shown to have inferior outcomes versus leucovorin when combined with fluorouracil.^87,88 Intravenous fluorouracil has shown similar benefit when administered by bolus or infusion,⁸⁹ although continuous infusion has been associated with lower incidence of severe toxicity.⁹⁰ The efficacy of the oral fluoropyrimidine capecitabine has been shown to be equivalent to that of fluorouracil.⁹¹

Fluorouracil-based treatment remained the standard of care until the introduction of oxaliplatin in the mid-1990s. After encouraging results in the metastatic setting,^92,93 the agent was moved to the adjuvant setting. The MOSAIC trial (Table 3) randomly assigned patients with stage II and III colon cancer to fluorouracil with leucovorin (FULV) versus FOLFOX given once every 2 weeks for 12 cycles. Analysis with respect to stage III patients showed a clear survival benefit, with a 10-year OS of 67.1% with FOLFOX chemotherapy versus 59% with fluorouracil and leucovorin.^94,95 The NSABP C-07 (Table 3) trial used a similar trial design but employed bolus fluorouracil. More than 2400 patients with stage II and III colon cancer were randomly assigned to bolus FULV or bolus fluorouracil, leucovorin, and oxaliplatin (FLOX). The addition of oxaliplatin significantly improved outcomes, with 4-year DFS of 67% versus 71.8% for FULV and FLOX, respectively, and a HR of death of 0.80 with FLOX.^59,96 The multicenter N016968 trial (Table 3) randomly assigned 1886 patients with stage III colon cancer to adjuvant capecitabine plus oxaliplatin (XELOX) or bolus fluorouracil plus leucovorin (FU/FA). The 3-year DFS was 70.9% versus 66.5% with XELOX and FU/FA, respectively, and 5-year OS was 77.6% versus 74.2%, respectively.^97,98

In the metastatic setting, additional agents have shown efficacy, including irinotecan,^99,100 bevacizumab,^101,102 cetuximab,^103,104 and regorafenib.¹⁰⁵ This observation led to testing of these agents in earlier stage disease. The CALGB 89803 trial compared fluorouracil, leucovorin, and irinotecan to fluorouracil with leucovorin alone. No benefit in 5-year DFS or OS was seen.¹⁰⁶ Similarly, infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) was not found to improve 5-year DFS as compared to fluorouracil with leucovorin alone in the PETACC-3 trial.¹⁰⁷ The NSABP C-08 trial considered the addition of bevacizumab to FOLFOX. When compared to FOLFOX alone, the combination of bevacizumab to FOLFOX had similar 3-year DFS (77.9% versus 75.1%) and 5-year OS (82.5% versus 80.7%).¹⁰⁸ This finding was confirmed in the Avant trial.¹⁰⁹ The addition of cetuximab to FOLFOX was equally disappointing, as shown in the N0147 trial110 and PETACC-8 trial.¹¹¹ Data on regorafenib in the adjuvant setting for stage III colon cancer is lacking; however, 2 ongoing clinical trials, NCT02425683 and NCT02664077, are each studying the use of regorafenib following completion of FOLFOX for patients with stage III disease.

Thus, after multiple trials comparing various regimens and despite attempts to improve outcomes by the addition of a third agent, the standard of care per National Comprehensive Cancer Network (NCCN) guidelines for management of stage III colon cancer remains 12 cycles of FOLFOX chemotherapy. Therapy should be initiated within 8 weeks of surgery. Data are emerging to support a short duration of therapy for patients with low-risk stage III tumors, as shown in an abstract presented at the 2017 American Society of Clinical Oncology annual meeting. The IDEA trial was a pooled analysis of 6 randomized clinical trials across multiple countries, all of which evaluated 3 versus 6 months of FOLFOX or capecitabine and oxaliplatin in the treatment of stage III colon cancer. The analysis was designed to test non-inferiority of 3 months of therapy as compared to 6 months. The analysis included 6088 patients across 244 centers in 6 countries. The overall analysis failed to establish noninferiority. The 3-year DFS rate was 74.6% for 3 months and 75.5% for 6 months, with a DFS HR of 1.07 and a confidence interval that did not meet the prespecified endpoint. Subgroup analysis suggested noninferiority for lower stage disease (T1–3 or N1) but not for higher stage disease (T4 or N2). Given the high rates of neuropathy with 6 months of oxaliplatin, these results suggest that 3 months of adjuvant therapy can be considered for patients with T1–3 or N1 disease in an attempt to limit toxicity.¹¹²

CASE PRESENTATION 2

A 57-year-old woman presents to the emergency department with fever and abdominal pain. CT of the abdomen and pelvis demonstrates a left-sided colonic mass with surrounding fat stranding and pelvic abscess. She is taken emergently for left hemicolectomy, cholecystectomy, and evacuation of pelvic abscess. Pathology reveals a 5-cm adenocarcinoma with invasion through the visceral peritoneum; 0/22 lymph nodes are involved. She is given a diagnosis of stage IIC and referred to medical oncology for further management. Due to her young age and presence of high-risk features, she is recommended adjuvant therapy with FOLFOX for 6 months.

ADJUVANT CHEMOTHERAPY IN STAGE II COLON CANCER

Because of excellent outcomes with surgical resection alone for stage II cancers, the use of adjuvant chemotherapy for patients with stage II disease is controversial. Limited prospective data is available to guide adjuvant treatment decisions for stage II patients. The QUASAR trial, which compared observation to adjuvant fluorouracil and leucovorin in patients with early-stage colon cancer, included 2963 patients with stage II disease and found a relative risk (RR) of death or recurrence of 0.82 and 0.78, respectively. Importantly, the absolute benefit of therapy was less than 5%.¹¹³ The IMPACT-B2 trial (Table 3) combined data from 5 separate trials and analyzed 1016 patients with stage II colon cancer who received fluorouracil with leucovorin or observation. Event-free survival was 0.86 versus 0.83 and 5-year OS was 82% versus 80%, suggesting no benefit.¹¹⁴ The benefit of addition of oxaliplatin to fluorouracil in stage II disease appears to be less than the benefit of adding this agent in the treatment of stage III CRC. As noted above, the MOSAIC trial randomly assigned patients with stage II and III colon cancer to receive adjuvant fluorouracil and leucovorin with or without oxaliplatin for 12 cycles. After a median follow-up of 9.5 years, 10-year OS rates for patients with stage II disease were 78.4% versus 79.5%. For patients with high-risk stage II disease (defined as T4, bowel perforation, or fewer than 10 lymph nodes examined), 10-year OS was 71.7% and 75.4% respectively, but these differences were not statistically significant.⁹⁴

Because of conflicting data as to the benefit of adding oxaliplatin in stage II disease, oxaliplatin is not recommended for standard-risk stage II patients. The use of oxaliplatin in high-risk stage II tumors should be weighed carefully given the toxicity risk. Oxaliplatin is recognized to cause sensory neuropathy in many patients, which can become painful and debilitating.¹¹⁵ Two types of neuropathy are associated with oxaliplatin: acute and chronic. Acute neuropathy manifests most often as cold-induced paresthesias in the fingers and toes and is quite common, affecting up to 90% of patients. These symptoms are self-limited and resolve usually within 1 week of each treatment.¹¹⁶ Some patients, with reports ranging from 10% to 79%, develop chronic neuropathy that persists for 1 year or more and causes significant decrements in quality of life.¹¹⁷ Patients older than age 70 may be at greater risk for oxaliplatin-induced neuropathy, which would increase risk of falls in this population.¹¹⁸ In addition to neuropathy, oxaliplatin is associated with hypersensitivity reactions that can be severe and even fatal.¹¹⁹ In a single institution series, the incidence of severe reactions was 2%.¹²⁰ Desensitization following hypersensitivity reactions is possible but requires a time-intensive protocol.¹²¹

Based on the inconclusive efficacy findings and due to concerns over toxicity, each decision must be individualized to fit patient characteristics and preferences. In general, for patients with stage II disease without high-risk features, an individualized discussion should be held as to the risks and benefits of single-agent fluorouracil, and this treatment should be offered in cases where the patient or provider would like to be aggressive. Patients with stage II cancer who have 1 or more high-risk features are often recommended adjuvant chemotherapy. Whether treatment with fluorouracil plus leucovorin or FOLFOX is preferred remains uncertain, and thus the risks and the potential gains of oxaliplatin must be discussed with the individual patient. MMR status can also influence the treatment recommendation for patients with stage II disease. In general, patients with standard-risk stage II tumors that are pMMR are offered MMR with leucovorin or oral capecitabine for 12 cycles. FOLFOX is considered for patients with MSI-high disease and those with multiple high-risk features.

MONITORING AFTER THERAPY

After completion of adjuvant chemotherapy, patients enter a period of survivorship. Patients are seen in clinic for symptom and laboratory monitoring of the complete blood count, liver function tests, and carcinoembryonic antigen (CEA). NCCN guidelines support history and physical examination with CEA testing every 3 to 6 months for the first 2 years, then every 6 months for the next 3 years, after which many patients continue to be seen annually. CT imaging of the chest, abdomen, and pelvis for monitoring of disease recurrence is recommended every 6 to 12 months for a total of 5 years. New elevations in CEA or liver function tests should prompt early imaging. Colonoscopy should be performed 1 year after completion of therapy; however, if no preoperative colonoscopy was performed, this should be done 3 to 6 months after completion. Colonoscopy is then repeated in 3 years and then every 5 years unless advanced adenomas are present.¹²²

SUMMARY

The addition of chemotherapy to surgical management of colon cancer has lowered the rate of disease recurrence and improved long-term survival. Adjuvant FOLFOX for 12 cycles is the standard of care for patients with stage III colon cancer and for patients with stage II disease with certain high-risk features. Use of adjuvant chemotherapy in stage II disease without high-risk features is controversial, and treatment decisions should be individualized. Biologic markers such as MSI and CDX2 status as well as patient-related factors including age, overall health, and personal preferences can inform treatment decisions. If chemotherapy is recommended in this setting, it would be with single-agent fluorouracil in an infusional or oral formulation, unless the tumor has the MSI-high feature. Following completion of adjuvant therapy, patients should be followed with clinical evaluation, laboratory testing, and imaging for a total of 5 years as per recommended guidelines.

INTRODUCTION

Colorectal cancer (CRC) is one of the most prevalent malignancies and is the fourth most common cancer in the United States, with an estimated 133,490 new cases diagnosed in 2016. Of these, approximately 95,520 are located in the colon and 39,970 are in the rectum.¹ CRC is the third leading cause of cancer death in women and the second leading cause of cancer death in men, with an estimated 49,190 total deaths in 2016.² The incidence appears to be increasing,³ especially in patients younger than 55 years of age;⁴ the reason for this increase remains uncertain.

A number of risk factors for the development of CRC have been identified. Numerous hered-itary CRC syndromes have been described, including familial adenomatous polyposis,⁵ hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome,⁶ and MUTYH-associated polyposis.^7,8 A family history of CRC doubles the risk of developing CRC,⁹ and current guidelines support lowering the age of screening in individuals with a family history of CRC to 10 years younger than the age of diagnosis of the family member or 40 years of age, whichever is lower.¹⁰ Patients with a personal history of adenomatous polyps are at increased risk for developing CRC, as are patients with a personal history of CRC, with a relative risk ranging from 3 to 6.¹¹ Ulcerative colitis and Crohn’s disease are associated with the development of CRC and also influence screening, though evidence suggests good control of these diseases may mitigate risk.¹² Finally, modifiable risk factors for the development of CRC include high red meat consumption,¹³ diets low in fiber,¹⁴ obesity,¹³ smoking, alcohol use,¹⁵ and physical inactivity¹⁶; lifestyle modification targeting these factors has been shown to decrease rates of CRC.¹⁷ The majority of colon cancers present with clinical symptoms, often with rectal bleeding, abdominal pain, change in bowel habits, or obstructive symptoms. More rarely, these tumors are detected during screening colonoscopy, in which case they tend to be at an early stage.

SURGICAL MANAGEMENT

A critical goal in the resection of early-stage colon cancer is attaining R0 resection. Patients who achieve R0 resection as compared to R1 (microscopic residual tumor) and R2 (macroscopic residual tumor)¹⁸ have significantly improved long-term overall survival.¹⁹ Traditionally, open resection of the involved colonic segment was employed, with end-end anastomosis of the uninvolved free margins. Laparoscopic resection for early-stage disease has been utilized in attempts to decrease morbidity of open procedures, with similar outcomes and node sampling.²⁰ Laparoscopic resection appears to provide similar outcomes even in locally advanced disease.²¹ Right-sided lesions are treated with right colectomy and primary ileocolic anastomosis.²² For patients presenting with obstructing masses, the Hartmann procedure is the most commonly performed operation. This involves creation of an ostomy with subtotal colectomy and subsequent ostomy reversal in a 2- or 3-stage protocol.²³ Patients with locally advanced disease and invasion into surrounding structures require multivisceral resection, which involves resection en bloc with secondarily involved organs.²⁴ Intestinal perforation presents a unique challenge and is associated with surgical complications, infection, and lower overall survival (OS) and 5-year disease-free survival (DFS). Complete mesocolic excision is a newer technique that has been performed with reports of better oncologic outcome at some centers; however, this approach is not currently considered standard of care.²⁵

STAGING

According to a report by the National Cancer Institute, the estimated 5-year relative survival rates for localized colon cancer (lymph node negative), regional (lymph node positive) disease, and distant (metastatic) disease are 89.9%, 71.3%, and 13.9%, respectively.¹ However, efforts have been made to further classify patients into distinct categories to allow fine-tuning of prognostication. In the current system, staging of colon cancer utilizes the American Joint Committee on Cancer tumor/node/metastasis (TNM) system.²⁰ Clinical and pathologic features include depth of invasion, local invasion of other organs, nodal involvement, and presence of distant metastasis (Table 1). Studies completed prior to the adoption of the TNM system used the Dukes criteria, which divided colon cancer into A, B, and C, corresponding to TNM stage I, stage IIA–IIC, and stage IIIA-IIIC. This classification is rarely used in more contemporary studies.

Adjuvant chemotherapy seeks to eliminate micrometastatic disease present following curative surgical resection. When stage 0 cancer is discovered incidentally during colonoscopy, endoscopic resection alone is the management of choice, as presence of micrometastatic disease is exceedingly unlikely.²⁶ Stage I–III CRCs are treated with surgical resection withcurative intent. The 5-year survival rate for stage I and early-stage II CRC is estimated at 97% with surgery alone.^27,28 The survival rate drops to about 60% for high-risk stage II tumors (T4aN0), and down to 50% or less for stage II-T4N0 or stage III cancers. Adjuvant chemotherapy is generally recommended to further decrease the rates of distant recurrence in certain cases of stage II and in all stage III tumors.

DETERMINATION OF BENEFIT FROM CHEMOTHERAPY: PROGNOSTIC MARKERS

Prior to administration of adjuvant chemotherapy, a clinical evaluation by the medical oncologist to determine appropriateness and safety of treatment is paramount. Poor performance status and comorbid conditions may indicate risk for excessive toxicity and minimal benefit from chemotherapy. CRC commonly presents in older individuals, with the median age at diagnosis of 69 years for men and 73 years for women.²⁹ In this patient population, comorbidities such as cardiovascular disease, diabetes, and renal dysfunction are more prevalent.³⁰ Decisions regarding adjuvant chemotherapy in this patient population have to take into consideration the fact that older patients may experience higher rates of toxicity with chemotherapy, including gastrointestinal toxicities and marrow suppression.³¹ Though some reports indicate patients older than 70 years derive similar benefit from adjuvant chemotherapy,^32,33 a large pooled analysis of the ACCENT database, which included 7 adjuvant therapy trials and 14,528 patients, suggested limited benefit from the addition of oxaliplatin to fluorouracil in elderly patients.³² Other factors that weigh on the decision include stage, pathology, and presence of high-risk features. A common concern in the postoperative setting is delaying initiation of chemotherapy to allow adequate wound healing; however, evidence suggests that delays longer than 8 weeks leads to worse overall survival, with hazard ratios (HR) ranging from 1.4 to 1.7.^34,35 Thus, the start of adjuvant therapy should ideally be within this time frame.

HIGH-RISK FEATURES

Multiple factors have been found to predict worse outcome and are classified as high-risk features (Table 2). Histologically, high-grade or poorly differentiated tumors are associated with higher recurrence rate and worse outcome.³⁶ Certain histological subtypes, including mucinous and signet-ring, both appear to have more aggressive biology.³⁷ Presence of microscopic invasion into surrounding blood vessels (vascular invasion) and nerves (perineural invasion) is associated with lower survival.³⁸ Penetration of the cancer through the visceral peritoneum (T4a) or into surrounding structures (T4b) is associated with lower survival.³⁶ During surgical resection, multiple lymph nodes are removed along with the primary tumor to evaluate for metastasis to the regional nodes. Multiple analyses have demonstrated that removal and pathologic assessment of fewer than 12 lymph nodes is associated with high risk of missing a positive node, and is thus equated with high risk.^39–41 In addition, extension of tumor beyond the capsules of any single lymph node, termed extracapsular extension, is associated with an increased risk of all-cause mortality.⁴² Tumor deposits, or focal aggregates of adenocarcinoma in the pericolic fat that are not contiguous with the primary tumor and are not associated with lymph nodes, are currently classified as lymph nodes as N1c in the current TNM staging system. Presence of these deposits has been found to predict poor outcome stage for stage.⁴³ Obstruction and/or perforation secondary to the tumor are also considered high-risk features that predict poor outcome.

SIDEDNESS

As reported at the 2016 American Society of Clinical Oncology annual meeting, tumor location predicts outcome in the metastatic setting. A report by Venook and colleagues based on a post-hoc analysis found that in the metastatic setting, location of the tumor primary in the left side is associated with longer OS (33.3 months) when compared to the right side of the colon (19.4 months).⁴⁴ A retrospective analysis of multiple databases presented by Schrag and colleagues similarly reported inferior outcomes in patients with stage III and IV disease who had right-sided primary tumors.⁴⁵ However, the prognostic implications for stage II disease remain uncertain.

BIOMARKERS

Given the controversy regarding adjuvant therapy of patients with stage II colon cancer, multiple biomarkers have been evaluated as possible predictive markers that can assist in this decision. The mismatch repair (MMR) system is a complex cellular enzymatic mechanism that identifies and corrects DNA errors during cell division and prevents mutagenesis.⁴⁶ The familial cancer syndrome HNPCC is linked to alteration in a variety of MMR genes, leading to deficient mismatch repair (dMMR), also termed microsatellite instability-high (MSI-high).^47,48 Epigenetic modification can also lead to silencing of the same implicated genes and accounts for 15% to 20% of sporadic colorectal cancer.⁴⁹ These epigenetic modifications lead to hypermethylation of the promotor region of MLH1 in 70% of cases.⁵⁰ The 4 MMR genes most commonly tested are MLH-1, MSH2, MSH6, and PMS2. Testing can be performed by immunohistochemistry or polymerase chain reaction.⁵¹ Across tumor histology and stage, MSI status is prognostic. Patients with MSI-high tumors have been shown to have improved prognosis and longer OS both in stage II and III disease^52–54 and in the metastatic setting.⁵⁵ However, despite this survival benefit, there is conflicting data as to whether patients with stage II, MSI-high colon cancer may benefit less from adjuvant chemotherapy. One early retrospective study compared outcomes of 70 patients with stage II and III disease and dMMR to those of 387 patients with stage II and III disease and proficient mismatch repair (pMMR). Adjuvant fluorouracil with leucovorin improved DFS for patients with pMMR (HR 0.67) but not for those with dMMR (HR 1.10). In addition, for patients with stage II disease and dMMR, the HR for OS was inferior at 2.95.⁵⁶ Data collected from randomized clinical trials using fluorouracil-based adjuvant chemotherapy were analyzed in an attempt to predict benefit based on MSI status. Benefit was only seen in pMMR patients, with a HR of 0.72; this was not seen in the dMMR patients.⁵⁷ Subsequent studies have had different findings and did not demonstrate a detrimental effect of fluorouracil in dMMR.^58,59 For stage III patients, MSI status does not appear to affect benefit from chemotherapy, as analysis of data from the NSABP C-07 trial (Table 3) demonstrated benefit of FOLFOX (leucovorin, fluorouracil, oxaliplatin) in patients with dMMR status and stage III disease.⁵⁹

Another genetic abnormality identified in colon cancers is chromosome 18q loss of heterozygosity (LOH). The presence of 18q LOH appears to be inversely associated with MSI-high status. Some reports have linked presence of 18q with worse outcome,⁶⁰ but others question this, arguing the finding may simply be related to MSI status.^61,62 This biomarker has not been established as a clear prognostic marker that can aid clinical decisions.

Most recently, expression of caudal-type homeobox transcription factor 2 (CDX2) has been reported as a novel prognostic and predictive tool. A 2015 report linked lack of expression of CDX2 to worse outcome; in this study, 5-year DFS was 41% in patients with CDX2-negative tumors versus 74% in the CDX2-positive tumors, with a HR of disease recurrence of 2.73 for CDX2-negative tumors.⁶³ Similar numbers were observed in patients with stage II disease, with 5-year OS of 40% in patients with CDX2-negative tumors versus 70% in those with CDX2-positive tumors. Treatment of CDX2-negative patients with adjuvant chemotherapy improved outcomes: 5-year DFS in the stage II subgroup was 91% with chemotherapy versus 56% without, and in the stage III subgroup, 74% with chemotherapy versus 37% without. The authors concluded that patients with stage II and III colon cancer that is CDX2-negative may benefit from adjuvant chemotherapy. Importantly, CDX2-negativity is a rare event, occurring in only 6.9% of evaluable tumors.

RISK ASSESSMENT TOOLS

Several risk assessment tools have been developed in an attempt to aid clinical decision making regarding adjuvant chemotherapy for patients with stage II colon cancer. The Oncotype DX Colon Assay analyses a 12-gene signature in the pathologic sample and was developed with the goal to improve prognostication and aid in treatment decision making. The test utilizes reverse transcription-PCR on RNA extracted from the tumor.⁶⁴ After evaluating 12 genes, a recurrence score is generated that predicts the risk of disease recurrence. This score was validated using data from 3 large clinical trials.^65–67 Unlike the Oncotype Dx score used in breast cancer, the test in colon cancer has not been found to predict the benefit from chemotherapy and has not been incorporated widely into clinical practice.

Adjuvant! Online (available at www.adjuvantonline.com) is a web-based tool that combines clinical and histological features to estimate outcome. Calculations are based on US SEER tumor registry-reported outcomes.⁶⁸ A second web-based tool, Numeracy (available at www.mayoclinic.com/calcs), was developed by the Mayo Clinic using pooled data from 7 randomized clinical trials including 3341 patients.⁶⁸ Both tools seek to predict absolute benefit for patients treated with fluorouracil, though data suggests Adjuvant! Online may be more reliable in its predictive ability.⁶⁹ Adjuvant! Online has also been validated in an Asian population70 and patients older than 70 years.⁷¹

MUTATIONAL ANALYSIS

Multiple mutations in proto-oncogenes have been found in colon cancer cells. One such proto-oncogene is BRAF, which encodes a serine-threonine kinase in the rapidly accelerated fibrosarcoma (RAF). Mutations in BRAF have been found in 5% to 10% of colon cancers and are associated with right-sided tumors.⁷² As a prognostic marker, some studies have associated BRAF mutations with worse prognosis, including shorter time to relapse and shorter OS.^73,74 Two other proto-oncogenes are Kristen rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma rat sarcoma viral oncogene homolog (NRAS), both of which encode proteins downstream of epidermal growth factor receptor (EGFR). KRAS and NRAS mutations have been shown to be predictive in the metastatic setting where they predict resistance to the EGFR inhibitors cetuximab and panitumumab.^75,76 The effect of KRAS and NRAS mutations on outcome in stage II and III colon cancer is uncertain. Some studies suggest worse outcome in KRAS-mutated cancers,⁷⁷ while others failed to demonstrate this finding.⁷³

CASE PRESENTATION 1

A 53-year-old man with no past medical history presents to the emergency department with early satiety and generalized abdominal pain. Laboratory evaluation shows a microcytic anemia with normal white blood cell count, platelet count, renal function, and liver function tests. Computed tomography (CT) scan of the abdomen and pelvis show a 4-cm mass in the transverse colon without obstruction and without abnormality in the liver. CT scan of the chest does not demonstrate pathologic lymphadenopathy or other findings. He undergoes robotic laparoscopic transverse colon resection and appendectomy. Pathology confirms a 3.5-cm focus of adenocarcinoma of the colon with invasion through the muscularis propria and 5 of 27 regional lymph nodes positive for adenocarcinoma and uninvolved proximal, distal, and radial margins. He is given a stage of IIIB pT3 pN2a M0 and referred to medical oncology for further management, where 6 months of adjuvant FOLFOX chemotherapy is recommended.

ADJUVANT CHEMOTHERAPY IN STAGE III COLON CANCER

Postoperative adjuvant chemotherapy is the standard of care for patients with stage III disease. In the 1960s, infusional fluorouracil was first used to treat inoperable colon cancer.^78,79 After encouraging results, the agent was used both intraluminally and intravenously as an adjuvant therapy for patients undergoing resection with curative intent; however, only modest benefits were described.^80,81 The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-01 trial (Table 3) was the first study to demonstrate a benefit from adjuvant chemotherapy in colon cancer. This study randomly assigned patients with stage II and III colon cancer to surgery alone, postoperative chemotherapy with fluorouracil, semustine, and vincristine (MOF), or postoperative bacillus Calmette-Guérin (BCG). DFS and OS were significantly improved with MOF chemotherapy.⁸² In 1990, a landmark study reported on outcomes after treatment of 1296 patients with stage III colon cancer with adjuvant fluorouracil and levamisole for 12 months. The combination was associated with a 41% reduction in risk of cancer recurrence and a 33% reduction in risk of death.⁸³ The NSABP C-03 trial (Table 3) compared MOF to the combination of fluorouracil and leucovorin and demonstrated improved 3-year DFS (69% versus 73%) and 3-year OS (77% versus 84%) in patients with stage III disease.⁸⁴ Building on these outcomes, the QUASAR study (Table 3) compared fluorouracil in combination with one of levamisole, low-dose leucovorin, or high-dose leucovorin. The study enrolled 4927 patients and found worse outcomes with fluorouracil plus levamisole and no difference in low-doseversus high-dose leucovorin.⁸⁵ Levamisole fell out of use after associations with development of multifocal leukoencephalopathy,⁸⁶ and was later shown to have inferior outcomes versus leucovorin when combined with fluorouracil.^87,88 Intravenous fluorouracil has shown similar benefit when administered by bolus or infusion,⁸⁹ although continuous infusion has been associated with lower incidence of severe toxicity.⁹⁰ The efficacy of the oral fluoropyrimidine capecitabine has been shown to be equivalent to that of fluorouracil.⁹¹

Fluorouracil-based treatment remained the standard of care until the introduction of oxaliplatin in the mid-1990s. After encouraging results in the metastatic setting,^92,93 the agent was moved to the adjuvant setting. The MOSAIC trial (Table 3) randomly assigned patients with stage II and III colon cancer to fluorouracil with leucovorin (FULV) versus FOLFOX given once every 2 weeks for 12 cycles. Analysis with respect to stage III patients showed a clear survival benefit, with a 10-year OS of 67.1% with FOLFOX chemotherapy versus 59% with fluorouracil and leucovorin.^94,95 The NSABP C-07 (Table 3) trial used a similar trial design but employed bolus fluorouracil. More than 2400 patients with stage II and III colon cancer were randomly assigned to bolus FULV or bolus fluorouracil, leucovorin, and oxaliplatin (FLOX). The addition of oxaliplatin significantly improved outcomes, with 4-year DFS of 67% versus 71.8% for FULV and FLOX, respectively, and a HR of death of 0.80 with FLOX.^59,96 The multicenter N016968 trial (Table 3) randomly assigned 1886 patients with stage III colon cancer to adjuvant capecitabine plus oxaliplatin (XELOX) or bolus fluorouracil plus leucovorin (FU/FA). The 3-year DFS was 70.9% versus 66.5% with XELOX and FU/FA, respectively, and 5-year OS was 77.6% versus 74.2%, respectively.^97,98

In the metastatic setting, additional agents have shown efficacy, including irinotecan,^99,100 bevacizumab,^101,102 cetuximab,^103,104 and regorafenib.¹⁰⁵ This observation led to testing of these agents in earlier stage disease. The CALGB 89803 trial compared fluorouracil, leucovorin, and irinotecan to fluorouracil with leucovorin alone. No benefit in 5-year DFS or OS was seen.¹⁰⁶ Similarly, infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) was not found to improve 5-year DFS as compared to fluorouracil with leucovorin alone in the PETACC-3 trial.¹⁰⁷ The NSABP C-08 trial considered the addition of bevacizumab to FOLFOX. When compared to FOLFOX alone, the combination of bevacizumab to FOLFOX had similar 3-year DFS (77.9% versus 75.1%) and 5-year OS (82.5% versus 80.7%).¹⁰⁸ This finding was confirmed in the Avant trial.¹⁰⁹ The addition of cetuximab to FOLFOX was equally disappointing, as shown in the N0147 trial110 and PETACC-8 trial.¹¹¹ Data on regorafenib in the adjuvant setting for stage III colon cancer is lacking; however, 2 ongoing clinical trials, NCT02425683 and NCT02664077, are each studying the use of regorafenib following completion of FOLFOX for patients with stage III disease.

Thus, after multiple trials comparing various regimens and despite attempts to improve outcomes by the addition of a third agent, the standard of care per National Comprehensive Cancer Network (NCCN) guidelines for management of stage III colon cancer remains 12 cycles of FOLFOX chemotherapy. Therapy should be initiated within 8 weeks of surgery. Data are emerging to support a short duration of therapy for patients with low-risk stage III tumors, as shown in an abstract presented at the 2017 American Society of Clinical Oncology annual meeting. The IDEA trial was a pooled analysis of 6 randomized clinical trials across multiple countries, all of which evaluated 3 versus 6 months of FOLFOX or capecitabine and oxaliplatin in the treatment of stage III colon cancer. The analysis was designed to test non-inferiority of 3 months of therapy as compared to 6 months. The analysis included 6088 patients across 244 centers in 6 countries. The overall analysis failed to establish noninferiority. The 3-year DFS rate was 74.6% for 3 months and 75.5% for 6 months, with a DFS HR of 1.07 and a confidence interval that did not meet the prespecified endpoint. Subgroup analysis suggested noninferiority for lower stage disease (T1–3 or N1) but not for higher stage disease (T4 or N2). Given the high rates of neuropathy with 6 months of oxaliplatin, these results suggest that 3 months of adjuvant therapy can be considered for patients with T1–3 or N1 disease in an attempt to limit toxicity.¹¹²

CASE PRESENTATION 2

A 57-year-old woman presents to the emergency department with fever and abdominal pain. CT of the abdomen and pelvis demonstrates a left-sided colonic mass with surrounding fat stranding and pelvic abscess. She is taken emergently for left hemicolectomy, cholecystectomy, and evacuation of pelvic abscess. Pathology reveals a 5-cm adenocarcinoma with invasion through the visceral peritoneum; 0/22 lymph nodes are involved. She is given a diagnosis of stage IIC and referred to medical oncology for further management. Due to her young age and presence of high-risk features, she is recommended adjuvant therapy with FOLFOX for 6 months.

ADJUVANT CHEMOTHERAPY IN STAGE II COLON CANCER

Because of excellent outcomes with surgical resection alone for stage II cancers, the use of adjuvant chemotherapy for patients with stage II disease is controversial. Limited prospective data is available to guide adjuvant treatment decisions for stage II patients. The QUASAR trial, which compared observation to adjuvant fluorouracil and leucovorin in patients with early-stage colon cancer, included 2963 patients with stage II disease and found a relative risk (RR) of death or recurrence of 0.82 and 0.78, respectively. Importantly, the absolute benefit of therapy was less than 5%.¹¹³ The IMPACT-B2 trial (Table 3) combined data from 5 separate trials and analyzed 1016 patients with stage II colon cancer who received fluorouracil with leucovorin or observation. Event-free survival was 0.86 versus 0.83 and 5-year OS was 82% versus 80%, suggesting no benefit.¹¹⁴ The benefit of addition of oxaliplatin to fluorouracil in stage II disease appears to be less than the benefit of adding this agent in the treatment of stage III CRC. As noted above, the MOSAIC trial randomly assigned patients with stage II and III colon cancer to receive adjuvant fluorouracil and leucovorin with or without oxaliplatin for 12 cycles. After a median follow-up of 9.5 years, 10-year OS rates for patients with stage II disease were 78.4% versus 79.5%. For patients with high-risk stage II disease (defined as T4, bowel perforation, or fewer than 10 lymph nodes examined), 10-year OS was 71.7% and 75.4% respectively, but these differences were not statistically significant.⁹⁴

Because of conflicting data as to the benefit of adding oxaliplatin in stage II disease, oxaliplatin is not recommended for standard-risk stage II patients. The use of oxaliplatin in high-risk stage II tumors should be weighed carefully given the toxicity risk. Oxaliplatin is recognized to cause sensory neuropathy in many patients, which can become painful and debilitating.¹¹⁵ Two types of neuropathy are associated with oxaliplatin: acute and chronic. Acute neuropathy manifests most often as cold-induced paresthesias in the fingers and toes and is quite common, affecting up to 90% of patients. These symptoms are self-limited and resolve usually within 1 week of each treatment.¹¹⁶ Some patients, with reports ranging from 10% to 79%, develop chronic neuropathy that persists for 1 year or more and causes significant decrements in quality of life.¹¹⁷ Patients older than age 70 may be at greater risk for oxaliplatin-induced neuropathy, which would increase risk of falls in this population.¹¹⁸ In addition to neuropathy, oxaliplatin is associated with hypersensitivity reactions that can be severe and even fatal.¹¹⁹ In a single institution series, the incidence of severe reactions was 2%.¹²⁰ Desensitization following hypersensitivity reactions is possible but requires a time-intensive protocol.¹²¹

Based on the inconclusive efficacy findings and due to concerns over toxicity, each decision must be individualized to fit patient characteristics and preferences. In general, for patients with stage II disease without high-risk features, an individualized discussion should be held as to the risks and benefits of single-agent fluorouracil, and this treatment should be offered in cases where the patient or provider would like to be aggressive. Patients with stage II cancer who have 1 or more high-risk features are often recommended adjuvant chemotherapy. Whether treatment with fluorouracil plus leucovorin or FOLFOX is preferred remains uncertain, and thus the risks and the potential gains of oxaliplatin must be discussed with the individual patient. MMR status can also influence the treatment recommendation for patients with stage II disease. In general, patients with standard-risk stage II tumors that are pMMR are offered MMR with leucovorin or oral capecitabine for 12 cycles. FOLFOX is considered for patients with MSI-high disease and those with multiple high-risk features.

MONITORING AFTER THERAPY

After completion of adjuvant chemotherapy, patients enter a period of survivorship. Patients are seen in clinic for symptom and laboratory monitoring of the complete blood count, liver function tests, and carcinoembryonic antigen (CEA). NCCN guidelines support history and physical examination with CEA testing every 3 to 6 months for the first 2 years, then every 6 months for the next 3 years, after which many patients continue to be seen annually. CT imaging of the chest, abdomen, and pelvis for monitoring of disease recurrence is recommended every 6 to 12 months for a total of 5 years. New elevations in CEA or liver function tests should prompt early imaging. Colonoscopy should be performed 1 year after completion of therapy; however, if no preoperative colonoscopy was performed, this should be done 3 to 6 months after completion. Colonoscopy is then repeated in 3 years and then every 5 years unless advanced adenomas are present.¹²²

SUMMARY

The addition of chemotherapy to surgical management of colon cancer has lowered the rate of disease recurrence and improved long-term survival. Adjuvant FOLFOX for 12 cycles is the standard of care for patients with stage III colon cancer and for patients with stage II disease with certain high-risk features. Use of adjuvant chemotherapy in stage II disease without high-risk features is controversial, and treatment decisions should be individualized. Biologic markers such as MSI and CDX2 status as well as patient-related factors including age, overall health, and personal preferences can inform treatment decisions. If chemotherapy is recommended in this setting, it would be with single-agent fluorouracil in an infusional or oral formulation, unless the tumor has the MSI-high feature. Following completion of adjuvant therapy, patients should be followed with clinical evaluation, laboratory testing, and imaging for a total of 5 years as per recommended guidelines.

INTRODUCTION

Colorectal cancer (CRC) is one of the most prevalent malignancies and is the fourth most common cancer in the United States, with an estimated 133,490 new cases diagnosed in 2016. Of these, approximately 95,520 are located in the colon and 39,970 are in the rectum.¹ CRC is the third leading cause of cancer death in women and the second leading cause of cancer death in men, with an estimated 49,190 total deaths in 2016.² The incidence appears to be increasing,³ especially in patients younger than 55 years of age;⁴ the reason for this increase remains uncertain.

A number of risk factors for the development of CRC have been identified. Numerous hered-itary CRC syndromes have been described, including familial adenomatous polyposis,⁵ hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome,⁶ and MUTYH-associated polyposis.^7,8 A family history of CRC doubles the risk of developing CRC,⁹ and current guidelines support lowering the age of screening in individuals with a family history of CRC to 10 years younger than the age of diagnosis of the family member or 40 years of age, whichever is lower.¹⁰ Patients with a personal history of adenomatous polyps are at increased risk for developing CRC, as are patients with a personal history of CRC, with a relative risk ranging from 3 to 6.¹¹ Ulcerative colitis and Crohn’s disease are associated with the development of CRC and also influence screening, though evidence suggests good control of these diseases may mitigate risk.¹² Finally, modifiable risk factors for the development of CRC include high red meat consumption,¹³ diets low in fiber,¹⁴ obesity,¹³ smoking, alcohol use,¹⁵ and physical inactivity¹⁶; lifestyle modification targeting these factors has been shown to decrease rates of CRC.¹⁷ The majority of colon cancers present with clinical symptoms, often with rectal bleeding, abdominal pain, change in bowel habits, or obstructive symptoms. More rarely, these tumors are detected during screening colonoscopy, in which case they tend to be at an early stage.

SURGICAL MANAGEMENT

A critical goal in the resection of early-stage colon cancer is attaining R0 resection. Patients who achieve R0 resection as compared to R1 (microscopic residual tumor) and R2 (macroscopic residual tumor)¹⁸ have significantly improved long-term overall survival.¹⁹ Traditionally, open resection of the involved colonic segment was employed, with end-end anastomosis of the uninvolved free margins. Laparoscopic resection for early-stage disease has been utilized in attempts to decrease morbidity of open procedures, with similar outcomes and node sampling.²⁰ Laparoscopic resection appears to provide similar outcomes even in locally advanced disease.²¹ Right-sided lesions are treated with right colectomy and primary ileocolic anastomosis.²² For patients presenting with obstructing masses, the Hartmann procedure is the most commonly performed operation. This involves creation of an ostomy with subtotal colectomy and subsequent ostomy reversal in a 2- or 3-stage protocol.²³ Patients with locally advanced disease and invasion into surrounding structures require multivisceral resection, which involves resection en bloc with secondarily involved organs.²⁴ Intestinal perforation presents a unique challenge and is associated with surgical complications, infection, and lower overall survival (OS) and 5-year disease-free survival (DFS). Complete mesocolic excision is a newer technique that has been performed with reports of better oncologic outcome at some centers; however, this approach is not currently considered standard of care.²⁵

STAGING

According to a report by the National Cancer Institute, the estimated 5-year relative survival rates for localized colon cancer (lymph node negative), regional (lymph node positive) disease, and distant (metastatic) disease are 89.9%, 71.3%, and 13.9%, respectively.¹ However, efforts have been made to further classify patients into distinct categories to allow fine-tuning of prognostication. In the current system, staging of colon cancer utilizes the American Joint Committee on Cancer tumor/node/metastasis (TNM) system.²⁰ Clinical and pathologic features include depth of invasion, local invasion of other organs, nodal involvement, and presence of distant metastasis (Table 1). Studies completed prior to the adoption of the TNM system used the Dukes criteria, which divided colon cancer into A, B, and C, corresponding to TNM stage I, stage IIA–IIC, and stage IIIA-IIIC. This classification is rarely used in more contemporary studies.

Adjuvant chemotherapy seeks to eliminate micrometastatic disease present following curative surgical resection. When stage 0 cancer is discovered incidentally during colonoscopy, endoscopic resection alone is the management of choice, as presence of micrometastatic disease is exceedingly unlikely.²⁶ Stage I–III CRCs are treated with surgical resection withcurative intent. The 5-year survival rate for stage I and early-stage II CRC is estimated at 97% with surgery alone.^27,28 The survival rate drops to about 60% for high-risk stage II tumors (T4aN0), and down to 50% or less for stage II-T4N0 or stage III cancers. Adjuvant chemotherapy is generally recommended to further decrease the rates of distant recurrence in certain cases of stage II and in all stage III tumors.

DETERMINATION OF BENEFIT FROM CHEMOTHERAPY: PROGNOSTIC MARKERS

Prior to administration of adjuvant chemotherapy, a clinical evaluation by the medical oncologist to determine appropriateness and safety of treatment is paramount. Poor performance status and comorbid conditions may indicate risk for excessive toxicity and minimal benefit from chemotherapy. CRC commonly presents in older individuals, with the median age at diagnosis of 69 years for men and 73 years for women.²⁹ In this patient population, comorbidities such as cardiovascular disease, diabetes, and renal dysfunction are more prevalent.³⁰ Decisions regarding adjuvant chemotherapy in this patient population have to take into consideration the fact that older patients may experience higher rates of toxicity with chemotherapy, including gastrointestinal toxicities and marrow suppression.³¹ Though some reports indicate patients older than 70 years derive similar benefit from adjuvant chemotherapy,^32,33 a large pooled analysis of the ACCENT database, which included 7 adjuvant therapy trials and 14,528 patients, suggested limited benefit from the addition of oxaliplatin to fluorouracil in elderly patients.³² Other factors that weigh on the decision include stage, pathology, and presence of high-risk features. A common concern in the postoperative setting is delaying initiation of chemotherapy to allow adequate wound healing; however, evidence suggests that delays longer than 8 weeks leads to worse overall survival, with hazard ratios (HR) ranging from 1.4 to 1.7.^34,35 Thus, the start of adjuvant therapy should ideally be within this time frame.

HIGH-RISK FEATURES

Multiple factors have been found to predict worse outcome and are classified as high-risk features (Table 2). Histologically, high-grade or poorly differentiated tumors are associated with higher recurrence rate and worse outcome.³⁶ Certain histological subtypes, including mucinous and signet-ring, both appear to have more aggressive biology.³⁷ Presence of microscopic invasion into surrounding blood vessels (vascular invasion) and nerves (perineural invasion) is associated with lower survival.³⁸ Penetration of the cancer through the visceral peritoneum (T4a) or into surrounding structures (T4b) is associated with lower survival.³⁶ During surgical resection, multiple lymph nodes are removed along with the primary tumor to evaluate for metastasis to the regional nodes. Multiple analyses have demonstrated that removal and pathologic assessment of fewer than 12 lymph nodes is associated with high risk of missing a positive node, and is thus equated with high risk.^39–41 In addition, extension of tumor beyond the capsules of any single lymph node, termed extracapsular extension, is associated with an increased risk of all-cause mortality.⁴² Tumor deposits, or focal aggregates of adenocarcinoma in the pericolic fat that are not contiguous with the primary tumor and are not associated with lymph nodes, are currently classified as lymph nodes as N1c in the current TNM staging system. Presence of these deposits has been found to predict poor outcome stage for stage.⁴³ Obstruction and/or perforation secondary to the tumor are also considered high-risk features that predict poor outcome.

SIDEDNESS

As reported at the 2016 American Society of Clinical Oncology annual meeting, tumor location predicts outcome in the metastatic setting. A report by Venook and colleagues based on a post-hoc analysis found that in the metastatic setting, location of the tumor primary in the left side is associated with longer OS (33.3 months) when compared to the right side of the colon (19.4 months).⁴⁴ A retrospective analysis of multiple databases presented by Schrag and colleagues similarly reported inferior outcomes in patients with stage III and IV disease who had right-sided primary tumors.⁴⁵ However, the prognostic implications for stage II disease remain uncertain.

BIOMARKERS

Given the controversy regarding adjuvant therapy of patients with stage II colon cancer, multiple biomarkers have been evaluated as possible predictive markers that can assist in this decision. The mismatch repair (MMR) system is a complex cellular enzymatic mechanism that identifies and corrects DNA errors during cell division and prevents mutagenesis.⁴⁶ The familial cancer syndrome HNPCC is linked to alteration in a variety of MMR genes, leading to deficient mismatch repair (dMMR), also termed microsatellite instability-high (MSI-high).^47,48 Epigenetic modification can also lead to silencing of the same implicated genes and accounts for 15% to 20% of sporadic colorectal cancer.⁴⁹ These epigenetic modifications lead to hypermethylation of the promotor region of MLH1 in 70% of cases.⁵⁰ The 4 MMR genes most commonly tested are MLH-1, MSH2, MSH6, and PMS2. Testing can be performed by immunohistochemistry or polymerase chain reaction.⁵¹ Across tumor histology and stage, MSI status is prognostic. Patients with MSI-high tumors have been shown to have improved prognosis and longer OS both in stage II and III disease^52–54 and in the metastatic setting.⁵⁵ However, despite this survival benefit, there is conflicting data as to whether patients with stage II, MSI-high colon cancer may benefit less from adjuvant chemotherapy. One early retrospective study compared outcomes of 70 patients with stage II and III disease and dMMR to those of 387 patients with stage II and III disease and proficient mismatch repair (pMMR). Adjuvant fluorouracil with leucovorin improved DFS for patients with pMMR (HR 0.67) but not for those with dMMR (HR 1.10). In addition, for patients with stage II disease and dMMR, the HR for OS was inferior at 2.95.⁵⁶ Data collected from randomized clinical trials using fluorouracil-based adjuvant chemotherapy were analyzed in an attempt to predict benefit based on MSI status. Benefit was only seen in pMMR patients, with a HR of 0.72; this was not seen in the dMMR patients.⁵⁷ Subsequent studies have had different findings and did not demonstrate a detrimental effect of fluorouracil in dMMR.^58,59 For stage III patients, MSI status does not appear to affect benefit from chemotherapy, as analysis of data from the NSABP C-07 trial (Table 3) demonstrated benefit of FOLFOX (leucovorin, fluorouracil, oxaliplatin) in patients with dMMR status and stage III disease.⁵⁹

Another genetic abnormality identified in colon cancers is chromosome 18q loss of heterozygosity (LOH). The presence of 18q LOH appears to be inversely associated with MSI-high status. Some reports have linked presence of 18q with worse outcome,⁶⁰ but others question this, arguing the finding may simply be related to MSI status.^61,62 This biomarker has not been established as a clear prognostic marker that can aid clinical decisions.

Most recently, expression of caudal-type homeobox transcription factor 2 (CDX2) has been reported as a novel prognostic and predictive tool. A 2015 report linked lack of expression of CDX2 to worse outcome; in this study, 5-year DFS was 41% in patients with CDX2-negative tumors versus 74% in the CDX2-positive tumors, with a HR of disease recurrence of 2.73 for CDX2-negative tumors.⁶³ Similar numbers were observed in patients with stage II disease, with 5-year OS of 40% in patients with CDX2-negative tumors versus 70% in those with CDX2-positive tumors. Treatment of CDX2-negative patients with adjuvant chemotherapy improved outcomes: 5-year DFS in the stage II subgroup was 91% with chemotherapy versus 56% without, and in the stage III subgroup, 74% with chemotherapy versus 37% without. The authors concluded that patients with stage II and III colon cancer that is CDX2-negative may benefit from adjuvant chemotherapy. Importantly, CDX2-negativity is a rare event, occurring in only 6.9% of evaluable tumors.

RISK ASSESSMENT TOOLS

Several risk assessment tools have been developed in an attempt to aid clinical decision making regarding adjuvant chemotherapy for patients with stage II colon cancer. The Oncotype DX Colon Assay analyses a 12-gene signature in the pathologic sample and was developed with the goal to improve prognostication and aid in treatment decision making. The test utilizes reverse transcription-PCR on RNA extracted from the tumor.⁶⁴ After evaluating 12 genes, a recurrence score is generated that predicts the risk of disease recurrence. This score was validated using data from 3 large clinical trials.^65–67 Unlike the Oncotype Dx score used in breast cancer, the test in colon cancer has not been found to predict the benefit from chemotherapy and has not been incorporated widely into clinical practice.

Adjuvant! Online (available at www.adjuvantonline.com) is a web-based tool that combines clinical and histological features to estimate outcome. Calculations are based on US SEER tumor registry-reported outcomes.⁶⁸ A second web-based tool, Numeracy (available at www.mayoclinic.com/calcs), was developed by the Mayo Clinic using pooled data from 7 randomized clinical trials including 3341 patients.⁶⁸ Both tools seek to predict absolute benefit for patients treated with fluorouracil, though data suggests Adjuvant! Online may be more reliable in its predictive ability.⁶⁹ Adjuvant! Online has also been validated in an Asian population70 and patients older than 70 years.⁷¹

MUTATIONAL ANALYSIS

Multiple mutations in proto-oncogenes have been found in colon cancer cells. One such proto-oncogene is BRAF, which encodes a serine-threonine kinase in the rapidly accelerated fibrosarcoma (RAF). Mutations in BRAF have been found in 5% to 10% of colon cancers and are associated with right-sided tumors.⁷² As a prognostic marker, some studies have associated BRAF mutations with worse prognosis, including shorter time to relapse and shorter OS.^73,74 Two other proto-oncogenes are Kristen rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma rat sarcoma viral oncogene homolog (NRAS), both of which encode proteins downstream of epidermal growth factor receptor (EGFR). KRAS and NRAS mutations have been shown to be predictive in the metastatic setting where they predict resistance to the EGFR inhibitors cetuximab and panitumumab.^75,76 The effect of KRAS and NRAS mutations on outcome in stage II and III colon cancer is uncertain. Some studies suggest worse outcome in KRAS-mutated cancers,⁷⁷ while others failed to demonstrate this finding.⁷³

CASE PRESENTATION 1

A 53-year-old man with no past medical history presents to the emergency department with early satiety and generalized abdominal pain. Laboratory evaluation shows a microcytic anemia with normal white blood cell count, platelet count, renal function, and liver function tests. Computed tomography (CT) scan of the abdomen and pelvis show a 4-cm mass in the transverse colon without obstruction and without abnormality in the liver. CT scan of the chest does not demonstrate pathologic lymphadenopathy or other findings. He undergoes robotic laparoscopic transverse colon resection and appendectomy. Pathology confirms a 3.5-cm focus of adenocarcinoma of the colon with invasion through the muscularis propria and 5 of 27 regional lymph nodes positive for adenocarcinoma and uninvolved proximal, distal, and radial margins. He is given a stage of IIIB pT3 pN2a M0 and referred to medical oncology for further management, where 6 months of adjuvant FOLFOX chemotherapy is recommended.

ADJUVANT CHEMOTHERAPY IN STAGE III COLON CANCER

Postoperative adjuvant chemotherapy is the standard of care for patients with stage III disease. In the 1960s, infusional fluorouracil was first used to treat inoperable colon cancer.^78,79 After encouraging results, the agent was used both intraluminally and intravenously as an adjuvant therapy for patients undergoing resection with curative intent; however, only modest benefits were described.^80,81 The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-01 trial (Table 3) was the first study to demonstrate a benefit from adjuvant chemotherapy in colon cancer. This study randomly assigned patients with stage II and III colon cancer to surgery alone, postoperative chemotherapy with fluorouracil, semustine, and vincristine (MOF), or postoperative bacillus Calmette-Guérin (BCG). DFS and OS were significantly improved with MOF chemotherapy.⁸² In 1990, a landmark study reported on outcomes after treatment of 1296 patients with stage III colon cancer with adjuvant fluorouracil and levamisole for 12 months. The combination was associated with a 41% reduction in risk of cancer recurrence and a 33% reduction in risk of death.⁸³ The NSABP C-03 trial (Table 3) compared MOF to the combination of fluorouracil and leucovorin and demonstrated improved 3-year DFS (69% versus 73%) and 3-year OS (77% versus 84%) in patients with stage III disease.⁸⁴ Building on these outcomes, the QUASAR study (Table 3) compared fluorouracil in combination with one of levamisole, low-dose leucovorin, or high-dose leucovorin. The study enrolled 4927 patients and found worse outcomes with fluorouracil plus levamisole and no difference in low-doseversus high-dose leucovorin.⁸⁵ Levamisole fell out of use after associations with development of multifocal leukoencephalopathy,⁸⁶ and was later shown to have inferior outcomes versus leucovorin when combined with fluorouracil.^87,88 Intravenous fluorouracil has shown similar benefit when administered by bolus or infusion,⁸⁹ although continuous infusion has been associated with lower incidence of severe toxicity.⁹⁰ The efficacy of the oral fluoropyrimidine capecitabine has been shown to be equivalent to that of fluorouracil.⁹¹

Fluorouracil-based treatment remained the standard of care until the introduction of oxaliplatin in the mid-1990s. After encouraging results in the metastatic setting,^92,93 the agent was moved to the adjuvant setting. The MOSAIC trial (Table 3) randomly assigned patients with stage II and III colon cancer to fluorouracil with leucovorin (FULV) versus FOLFOX given once every 2 weeks for 12 cycles. Analysis with respect to stage III patients showed a clear survival benefit, with a 10-year OS of 67.1% with FOLFOX chemotherapy versus 59% with fluorouracil and leucovorin.^94,95 The NSABP C-07 (Table 3) trial used a similar trial design but employed bolus fluorouracil. More than 2400 patients with stage II and III colon cancer were randomly assigned to bolus FULV or bolus fluorouracil, leucovorin, and oxaliplatin (FLOX). The addition of oxaliplatin significantly improved outcomes, with 4-year DFS of 67% versus 71.8% for FULV and FLOX, respectively, and a HR of death of 0.80 with FLOX.^59,96 The multicenter N016968 trial (Table 3) randomly assigned 1886 patients with stage III colon cancer to adjuvant capecitabine plus oxaliplatin (XELOX) or bolus fluorouracil plus leucovorin (FU/FA). The 3-year DFS was 70.9% versus 66.5% with XELOX and FU/FA, respectively, and 5-year OS was 77.6% versus 74.2%, respectively.^97,98

In the metastatic setting, additional agents have shown efficacy, including irinotecan,^99,100 bevacizumab,^101,102 cetuximab,^103,104 and regorafenib.¹⁰⁵ This observation led to testing of these agents in earlier stage disease. The CALGB 89803 trial compared fluorouracil, leucovorin, and irinotecan to fluorouracil with leucovorin alone. No benefit in 5-year DFS or OS was seen.¹⁰⁶ Similarly, infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) was not found to improve 5-year DFS as compared to fluorouracil with leucovorin alone in the PETACC-3 trial.¹⁰⁷ The NSABP C-08 trial considered the addition of bevacizumab to FOLFOX. When compared to FOLFOX alone, the combination of bevacizumab to FOLFOX had similar 3-year DFS (77.9% versus 75.1%) and 5-year OS (82.5% versus 80.7%).¹⁰⁸ This finding was confirmed in the Avant trial.¹⁰⁹ The addition of cetuximab to FOLFOX was equally disappointing, as shown in the N0147 trial110 and PETACC-8 trial.¹¹¹ Data on regorafenib in the adjuvant setting for stage III colon cancer is lacking; however, 2 ongoing clinical trials, NCT02425683 and NCT02664077, are each studying the use of regorafenib following completion of FOLFOX for patients with stage III disease.

Thus, after multiple trials comparing various regimens and despite attempts to improve outcomes by the addition of a third agent, the standard of care per National Comprehensive Cancer Network (NCCN) guidelines for management of stage III colon cancer remains 12 cycles of FOLFOX chemotherapy. Therapy should be initiated within 8 weeks of surgery. Data are emerging to support a short duration of therapy for patients with low-risk stage III tumors, as shown in an abstract presented at the 2017 American Society of Clinical Oncology annual meeting. The IDEA trial was a pooled analysis of 6 randomized clinical trials across multiple countries, all of which evaluated 3 versus 6 months of FOLFOX or capecitabine and oxaliplatin in the treatment of stage III colon cancer. The analysis was designed to test non-inferiority of 3 months of therapy as compared to 6 months. The analysis included 6088 patients across 244 centers in 6 countries. The overall analysis failed to establish noninferiority. The 3-year DFS rate was 74.6% for 3 months and 75.5% for 6 months, with a DFS HR of 1.07 and a confidence interval that did not meet the prespecified endpoint. Subgroup analysis suggested noninferiority for lower stage disease (T1–3 or N1) but not for higher stage disease (T4 or N2). Given the high rates of neuropathy with 6 months of oxaliplatin, these results suggest that 3 months of adjuvant therapy can be considered for patients with T1–3 or N1 disease in an attempt to limit toxicity.¹¹²

CASE PRESENTATION 2

A 57-year-old woman presents to the emergency department with fever and abdominal pain. CT of the abdomen and pelvis demonstrates a left-sided colonic mass with surrounding fat stranding and pelvic abscess. She is taken emergently for left hemicolectomy, cholecystectomy, and evacuation of pelvic abscess. Pathology reveals a 5-cm adenocarcinoma with invasion through the visceral peritoneum; 0/22 lymph nodes are involved. She is given a diagnosis of stage IIC and referred to medical oncology for further management. Due to her young age and presence of high-risk features, she is recommended adjuvant therapy with FOLFOX for 6 months.

ADJUVANT CHEMOTHERAPY IN STAGE II COLON CANCER

Because of excellent outcomes with surgical resection alone for stage II cancers, the use of adjuvant chemotherapy for patients with stage II disease is controversial. Limited prospective data is available to guide adjuvant treatment decisions for stage II patients. The QUASAR trial, which compared observation to adjuvant fluorouracil and leucovorin in patients with early-stage colon cancer, included 2963 patients with stage II disease and found a relative risk (RR) of death or recurrence of 0.82 and 0.78, respectively. Importantly, the absolute benefit of therapy was less than 5%.¹¹³ The IMPACT-B2 trial (Table 3) combined data from 5 separate trials and analyzed 1016 patients with stage II colon cancer who received fluorouracil with leucovorin or observation. Event-free survival was 0.86 versus 0.83 and 5-year OS was 82% versus 80%, suggesting no benefit.¹¹⁴ The benefit of addition of oxaliplatin to fluorouracil in stage II disease appears to be less than the benefit of adding this agent in the treatment of stage III CRC. As noted above, the MOSAIC trial randomly assigned patients with stage II and III colon cancer to receive adjuvant fluorouracil and leucovorin with or without oxaliplatin for 12 cycles. After a median follow-up of 9.5 years, 10-year OS rates for patients with stage II disease were 78.4% versus 79.5%. For patients with high-risk stage II disease (defined as T4, bowel perforation, or fewer than 10 lymph nodes examined), 10-year OS was 71.7% and 75.4% respectively, but these differences were not statistically significant.⁹⁴

Because of conflicting data as to the benefit of adding oxaliplatin in stage II disease, oxaliplatin is not recommended for standard-risk stage II patients. The use of oxaliplatin in high-risk stage II tumors should be weighed carefully given the toxicity risk. Oxaliplatin is recognized to cause sensory neuropathy in many patients, which can become painful and debilitating.¹¹⁵ Two types of neuropathy are associated with oxaliplatin: acute and chronic. Acute neuropathy manifests most often as cold-induced paresthesias in the fingers and toes and is quite common, affecting up to 90% of patients. These symptoms are self-limited and resolve usually within 1 week of each treatment.¹¹⁶ Some patients, with reports ranging from 10% to 79%, develop chronic neuropathy that persists for 1 year or more and causes significant decrements in quality of life.¹¹⁷ Patients older than age 70 may be at greater risk for oxaliplatin-induced neuropathy, which would increase risk of falls in this population.¹¹⁸ In addition to neuropathy, oxaliplatin is associated with hypersensitivity reactions that can be severe and even fatal.¹¹⁹ In a single institution series, the incidence of severe reactions was 2%.¹²⁰ Desensitization following hypersensitivity reactions is possible but requires a time-intensive protocol.¹²¹

Based on the inconclusive efficacy findings and due to concerns over toxicity, each decision must be individualized to fit patient characteristics and preferences. In general, for patients with stage II disease without high-risk features, an individualized discussion should be held as to the risks and benefits of single-agent fluorouracil, and this treatment should be offered in cases where the patient or provider would like to be aggressive. Patients with stage II cancer who have 1 or more high-risk features are often recommended adjuvant chemotherapy. Whether treatment with fluorouracil plus leucovorin or FOLFOX is preferred remains uncertain, and thus the risks and the potential gains of oxaliplatin must be discussed with the individual patient. MMR status can also influence the treatment recommendation for patients with stage II disease. In general, patients with standard-risk stage II tumors that are pMMR are offered MMR with leucovorin or oral capecitabine for 12 cycles. FOLFOX is considered for patients with MSI-high disease and those with multiple high-risk features.

MONITORING AFTER THERAPY

After completion of adjuvant chemotherapy, patients enter a period of survivorship. Patients are seen in clinic for symptom and laboratory monitoring of the complete blood count, liver function tests, and carcinoembryonic antigen (CEA). NCCN guidelines support history and physical examination with CEA testing every 3 to 6 months for the first 2 years, then every 6 months for the next 3 years, after which many patients continue to be seen annually. CT imaging of the chest, abdomen, and pelvis for monitoring of disease recurrence is recommended every 6 to 12 months for a total of 5 years. New elevations in CEA or liver function tests should prompt early imaging. Colonoscopy should be performed 1 year after completion of therapy; however, if no preoperative colonoscopy was performed, this should be done 3 to 6 months after completion. Colonoscopy is then repeated in 3 years and then every 5 years unless advanced adenomas are present.¹²²

SUMMARY

The addition of chemotherapy to surgical management of colon cancer has lowered the rate of disease recurrence and improved long-term survival. Adjuvant FOLFOX for 12 cycles is the standard of care for patients with stage III colon cancer and for patients with stage II disease with certain high-risk features. Use of adjuvant chemotherapy in stage II disease without high-risk features is controversial, and treatment decisions should be individualized. Biologic markers such as MSI and CDX2 status as well as patient-related factors including age, overall health, and personal preferences can inform treatment decisions. If chemotherapy is recommended in this setting, it would be with single-agent fluorouracil in an infusional or oral formulation, unless the tumor has the MSI-high feature. Following completion of adjuvant therapy, patients should be followed with clinical evaluation, laboratory testing, and imaging for a total of 5 years as per recommended guidelines.

Whether patients are having a biopsy, surgical excision, or Mohs surgery, the outcome will be improved when the proper skin care is used before and after the procedure. This is a guide that you can use to educate your patients about pre- and postprocedure skin care needs.

Presurgery skin care and supplements

The goal is to speed healing and minimize infection, scarring, and hyperpigmentation. For 2 weeks prior to surgery, recommend products that have been shown to speed wound healing by increasing keratinization and/or collagen production. Ingredients that should be used prior to wounding include retinoids such as tretinoin and retinol. Several studies have convincingly shown that pretreatment with tretinoin speeds wound healing.^1,2,3 Kligman and associates evaluated healing after punch biopsy and found the wounds on arms pretreated with tretinoin cream 0.05% to 0.1% were significantly smaller – by 35% to 37% – on days 1 and 4, and were 47% to 50% smaller on days 6, 8, and 11, compared with the untreated arms.⁴ Most studies suggest a 2- to 4-week tretinoin pretreatment regimen⁵ because peak epidermal hypertrophy occurs after 7 days of tretinoin application and normalizes after 14 days of continued treatment.⁶ This approach allows the skin to recover from any retinoid dermatitis prior to surgery. Adapalene should be started 5-6 weeks prior to procedures because it has a longer half-life and requires an earlier initiation period.⁷

Although wound healing studies have not been conducted in this area, pretreating skin with topical ascorbic acid⁸ and hydroxyacids⁹ might help speed wound healing by increasing collagen synthesis.
 

Ingredients and activities to avoid presurgery

Patients should avoid using ingredients that could promote skin tumor growth. Although there are no studies evaluating the effects of growth factors on promoting the growth of skin cancer, caution is prudent. To reduce bruising, patients should avoid aspirin, ibuprofen, naproxen, St. John’s Wort, vitamin E, omega-3 fatty acids supplements, flax seed oil, ginseng, salmon, and alcohol. Most physicians agree that these should be avoided for 10 days prior to the procedure. Smoking should be avoided 4 weeks prior to the procedure.

Postsurgery skin care and supplements

Oral vitamin C and zinc supplements have been shown to speed wound healing in rats when taken immediately after a procedure.¹⁰ Oral Arnica tablets and tinctures are often used prior to and after surgery to reduce bruising and inflammation. There is much anecdotal support for the use of Arnica, but clinical trial evidence substantiating its efficacy to prevent bruising and reduce swelling is scant.

Ingredients to avoid post surgery

Topical retinoids should not be used post skin cancer surgery until epithelialization is complete. A study by Hung et al.¹⁶ in a porcine model used 0.05% tretinoin cream daily for 10 days prior to partial-thickness skin wounding demonstrated that use of tretinoin 10 days prior to wounding sped reepithelialization while use after the procedure slowed wound healing.

Acidic products will sting wounded skin. For this reason, benzoic acid, hydroxy acids, and ascorbic acid should be avoided until the skin has completely reepithelialized. Products with preservatives and fragrance should be avoided if possible.

Vitamin E derived from oral supplement capsules slowed healing after skin cancer surgery and had a high rate of contact dermatitis.¹⁷ Chemical sunscreens are more likely to cause an allergic contact dermatitis and should be avoided for 4 weeks after skin surgery. Organic products with essential oils and botanical ingredients may present a higher risk of contact dermatitis due to allergen exposure.
 

Conclusion

To ensure the best outcome from surgical treatments, patient education is a must! The more that patients know and understand about the ways in which they can prepare for their procedure and treat their skin after the procedure, the better the outcomes will be. Providers should give this type of information in an easy-to-follow printed instruction sheet because studies show that patients cannot remember most of the oral instructions offered by practitioners.

Encourage your patients to ask questions during their consultation and procedure and to get in touch with your office should they have any concerns when they leave. These steps help improve patient compliance and satisfaction, which will help you maintain a trusting relationship with established patients and attract new ones through word-of-mouth referrals.

Please email me at [email protected] if you have any other pre- and postprocedure skin care advice.
 

Dr. Leslie S. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.

References

1. Aesthetic Plast Surg. 1995 May-Jun;19(3):243-6.

2. Plast Reconstr Surg. 2011 Mar;127(3):1343-5.

3. J Am Acad Dermatol. 1998 Aug;39(2 Pt 3):S79-81.

4. Br J Dermatol. 1995 Jan;132(1):46-53.

5. J Am Acad Dermatol. 2004 Dec;51(6):940-6.

6. J Korean Med Sci. 1996 Aug;11(4):335-41.

7. Eur J Dermatol. 2002 Mar-Apr;12(2):145-8.

8. Proc Natl Acad Sci U S A. 1981 May;78(5):2879-82.

9. Exp Dermatol. 2003;12 Suppl 2:57-63.

10. Surg Today. 2004;34(9):747-51.

11. Ophthal Plast Reconstr Surg. 2017 Jan/Feb;33(1):47-52.

12. Wound Repair Regen. 1998 Mar-Apr;6(2):167-77.

13. Dermatol Surg. 1998 Jun;24(6):661-4.

14. Plast Reconstr Surg. 2013 Nov;132(5):1159-71.

15. ACS Nano. 2016 Feb 23;10(2):1810-9.

16. Arch Dermatol. 1989 Jan;125(1):65-9.

17. Dermatol Surg. 1999 Apr;25(4):311-5.

Whether patients are having a biopsy, surgical excision, or Mohs surgery, the outcome will be improved when the proper skin care is used before and after the procedure. This is a guide that you can use to educate your patients about pre- and postprocedure skin care needs.

Presurgery skin care and supplements

The goal is to speed healing and minimize infection, scarring, and hyperpigmentation. For 2 weeks prior to surgery, recommend products that have been shown to speed wound healing by increasing keratinization and/or collagen production. Ingredients that should be used prior to wounding include retinoids such as tretinoin and retinol. Several studies have convincingly shown that pretreatment with tretinoin speeds wound healing.^1,2,3 Kligman and associates evaluated healing after punch biopsy and found the wounds on arms pretreated with tretinoin cream 0.05% to 0.1% were significantly smaller – by 35% to 37% – on days 1 and 4, and were 47% to 50% smaller on days 6, 8, and 11, compared with the untreated arms.⁴ Most studies suggest a 2- to 4-week tretinoin pretreatment regimen⁵ because peak epidermal hypertrophy occurs after 7 days of tretinoin application and normalizes after 14 days of continued treatment.⁶ This approach allows the skin to recover from any retinoid dermatitis prior to surgery. Adapalene should be started 5-6 weeks prior to procedures because it has a longer half-life and requires an earlier initiation period.⁷

Although wound healing studies have not been conducted in this area, pretreating skin with topical ascorbic acid⁸ and hydroxyacids⁹ might help speed wound healing by increasing collagen synthesis.
 

Ingredients and activities to avoid presurgery

Patients should avoid using ingredients that could promote skin tumor growth. Although there are no studies evaluating the effects of growth factors on promoting the growth of skin cancer, caution is prudent. To reduce bruising, patients should avoid aspirin, ibuprofen, naproxen, St. John’s Wort, vitamin E, omega-3 fatty acids supplements, flax seed oil, ginseng, salmon, and alcohol. Most physicians agree that these should be avoided for 10 days prior to the procedure. Smoking should be avoided 4 weeks prior to the procedure.

Postsurgery skin care and supplements

Oral vitamin C and zinc supplements have been shown to speed wound healing in rats when taken immediately after a procedure.¹⁰ Oral Arnica tablets and tinctures are often used prior to and after surgery to reduce bruising and inflammation. There is much anecdotal support for the use of Arnica, but clinical trial evidence substantiating its efficacy to prevent bruising and reduce swelling is scant.

Ingredients to avoid post surgery

Topical retinoids should not be used post skin cancer surgery until epithelialization is complete. A study by Hung et al.¹⁶ in a porcine model used 0.05% tretinoin cream daily for 10 days prior to partial-thickness skin wounding demonstrated that use of tretinoin 10 days prior to wounding sped reepithelialization while use after the procedure slowed wound healing.

Acidic products will sting wounded skin. For this reason, benzoic acid, hydroxy acids, and ascorbic acid should be avoided until the skin has completely reepithelialized. Products with preservatives and fragrance should be avoided if possible.

Vitamin E derived from oral supplement capsules slowed healing after skin cancer surgery and had a high rate of contact dermatitis.¹⁷ Chemical sunscreens are more likely to cause an allergic contact dermatitis and should be avoided for 4 weeks after skin surgery. Organic products with essential oils and botanical ingredients may present a higher risk of contact dermatitis due to allergen exposure.
 

Conclusion

To ensure the best outcome from surgical treatments, patient education is a must! The more that patients know and understand about the ways in which they can prepare for their procedure and treat their skin after the procedure, the better the outcomes will be. Providers should give this type of information in an easy-to-follow printed instruction sheet because studies show that patients cannot remember most of the oral instructions offered by practitioners.

Encourage your patients to ask questions during their consultation and procedure and to get in touch with your office should they have any concerns when they leave. These steps help improve patient compliance and satisfaction, which will help you maintain a trusting relationship with established patients and attract new ones through word-of-mouth referrals.

Please email me at [email protected] if you have any other pre- and postprocedure skin care advice.
 

Dr. Leslie S. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.

References

1. Aesthetic Plast Surg. 1995 May-Jun;19(3):243-6.

2. Plast Reconstr Surg. 2011 Mar;127(3):1343-5.

3. J Am Acad Dermatol. 1998 Aug;39(2 Pt 3):S79-81.

4. Br J Dermatol. 1995 Jan;132(1):46-53.

5. J Am Acad Dermatol. 2004 Dec;51(6):940-6.

6. J Korean Med Sci. 1996 Aug;11(4):335-41.

7. Eur J Dermatol. 2002 Mar-Apr;12(2):145-8.

8. Proc Natl Acad Sci U S A. 1981 May;78(5):2879-82.

9. Exp Dermatol. 2003;12 Suppl 2:57-63.

10. Surg Today. 2004;34(9):747-51.

11. Ophthal Plast Reconstr Surg. 2017 Jan/Feb;33(1):47-52.

12. Wound Repair Regen. 1998 Mar-Apr;6(2):167-77.

13. Dermatol Surg. 1998 Jun;24(6):661-4.

14. Plast Reconstr Surg. 2013 Nov;132(5):1159-71.

15. ACS Nano. 2016 Feb 23;10(2):1810-9.

16. Arch Dermatol. 1989 Jan;125(1):65-9.

17. Dermatol Surg. 1999 Apr;25(4):311-5.

Whether patients are having a biopsy, surgical excision, or Mohs surgery, the outcome will be improved when the proper skin care is used before and after the procedure. This is a guide that you can use to educate your patients about pre- and postprocedure skin care needs.

Presurgery skin care and supplements

The goal is to speed healing and minimize infection, scarring, and hyperpigmentation. For 2 weeks prior to surgery, recommend products that have been shown to speed wound healing by increasing keratinization and/or collagen production. Ingredients that should be used prior to wounding include retinoids such as tretinoin and retinol. Several studies have convincingly shown that pretreatment with tretinoin speeds wound healing.^1,2,3 Kligman and associates evaluated healing after punch biopsy and found the wounds on arms pretreated with tretinoin cream 0.05% to 0.1% were significantly smaller – by 35% to 37% – on days 1 and 4, and were 47% to 50% smaller on days 6, 8, and 11, compared with the untreated arms.⁴ Most studies suggest a 2- to 4-week tretinoin pretreatment regimen⁵ because peak epidermal hypertrophy occurs after 7 days of tretinoin application and normalizes after 14 days of continued treatment.⁶ This approach allows the skin to recover from any retinoid dermatitis prior to surgery. Adapalene should be started 5-6 weeks prior to procedures because it has a longer half-life and requires an earlier initiation period.⁷

Although wound healing studies have not been conducted in this area, pretreating skin with topical ascorbic acid⁸ and hydroxyacids⁹ might help speed wound healing by increasing collagen synthesis.
 

Ingredients and activities to avoid presurgery

Patients should avoid using ingredients that could promote skin tumor growth. Although there are no studies evaluating the effects of growth factors on promoting the growth of skin cancer, caution is prudent. To reduce bruising, patients should avoid aspirin, ibuprofen, naproxen, St. John’s Wort, vitamin E, omega-3 fatty acids supplements, flax seed oil, ginseng, salmon, and alcohol. Most physicians agree that these should be avoided for 10 days prior to the procedure. Smoking should be avoided 4 weeks prior to the procedure.

Postsurgery skin care and supplements

Oral vitamin C and zinc supplements have been shown to speed wound healing in rats when taken immediately after a procedure.¹⁰ Oral Arnica tablets and tinctures are often used prior to and after surgery to reduce bruising and inflammation. There is much anecdotal support for the use of Arnica, but clinical trial evidence substantiating its efficacy to prevent bruising and reduce swelling is scant.

Ingredients to avoid post surgery

Topical retinoids should not be used post skin cancer surgery until epithelialization is complete. A study by Hung et al.¹⁶ in a porcine model used 0.05% tretinoin cream daily for 10 days prior to partial-thickness skin wounding demonstrated that use of tretinoin 10 days prior to wounding sped reepithelialization while use after the procedure slowed wound healing.

Acidic products will sting wounded skin. For this reason, benzoic acid, hydroxy acids, and ascorbic acid should be avoided until the skin has completely reepithelialized. Products with preservatives and fragrance should be avoided if possible.

Vitamin E derived from oral supplement capsules slowed healing after skin cancer surgery and had a high rate of contact dermatitis.¹⁷ Chemical sunscreens are more likely to cause an allergic contact dermatitis and should be avoided for 4 weeks after skin surgery. Organic products with essential oils and botanical ingredients may present a higher risk of contact dermatitis due to allergen exposure.
 

Conclusion

To ensure the best outcome from surgical treatments, patient education is a must! The more that patients know and understand about the ways in which they can prepare for their procedure and treat their skin after the procedure, the better the outcomes will be. Providers should give this type of information in an easy-to-follow printed instruction sheet because studies show that patients cannot remember most of the oral instructions offered by practitioners.

Encourage your patients to ask questions during their consultation and procedure and to get in touch with your office should they have any concerns when they leave. These steps help improve patient compliance and satisfaction, which will help you maintain a trusting relationship with established patients and attract new ones through word-of-mouth referrals.

Please email me at [email protected] if you have any other pre- and postprocedure skin care advice.
 

Dr. Leslie S. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.

References

1. Aesthetic Plast Surg. 1995 May-Jun;19(3):243-6.

2. Plast Reconstr Surg. 2011 Mar;127(3):1343-5.

3. J Am Acad Dermatol. 1998 Aug;39(2 Pt 3):S79-81.

4. Br J Dermatol. 1995 Jan;132(1):46-53.

5. J Am Acad Dermatol. 2004 Dec;51(6):940-6.

6. J Korean Med Sci. 1996 Aug;11(4):335-41.

7. Eur J Dermatol. 2002 Mar-Apr;12(2):145-8.

8. Proc Natl Acad Sci U S A. 1981 May;78(5):2879-82.

9. Exp Dermatol. 2003;12 Suppl 2:57-63.

10. Surg Today. 2004;34(9):747-51.

11. Ophthal Plast Reconstr Surg. 2017 Jan/Feb;33(1):47-52.

12. Wound Repair Regen. 1998 Mar-Apr;6(2):167-77.

13. Dermatol Surg. 1998 Jun;24(6):661-4.

14. Plast Reconstr Surg. 2013 Nov;132(5):1159-71.

15. ACS Nano. 2016 Feb 23;10(2):1810-9.

16. Arch Dermatol. 1989 Jan;125(1):65-9.

17. Dermatol Surg. 1999 Apr;25(4):311-5.

Return visit (RV) rate is a quality measure commonly used in the emergency department (ED) setting. This metric may represent suboptimal care at the index ED visit.^1-5 Although patient- and visit-level factors affecting ED RVs have been evaluated,^1,3,4,6-9 hospital-level factors and factors of a hospital’s patient population that may play roles in ED RV rates have not been examined. Identifying the factors associated with increased RVs may allow resources to be designated to areas that improve emergent care for children.¹⁰

Hospital readmission rates are a closely followed quality measure and are linked to reimbursement by the federal government, but a recent study found the influence a hospital can have on this marker may be mitigated by the impact of the social determinates of health (SDHs) of the hospital’s patient population.¹¹ That study and others have prompted an ongoing debate about adjusting quality measures for SDHs.^12,13 A clearer understanding of these interactions may permit us to focus on factors that can truly lead to improvement in care instead of penalizing practitioners or hospitals that provide care to those most in need.

Prior work has identified several SDHs associated with higher ED RV rates in patient- or visit-level analyses.^3,11,14 We conducted a study of hospital-level characteristics and characteristics of a hospital’s patient population to identify potentially mutable factors associated with increased ED RV rates that, once recognized, may allow for improvement in this quality measure.

This study was not considered human subjects research in accordance with Common Rule 45 CFR§46.104(f) and was evaluated by the Ann and Robert H. Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine Institutional Review Boards and deemed exempt from review.

Study Population and Protocol

Our study had 2 data sources (to be described in detail): the Pediatric Health Information System (PHIS) and a survey of ED medical directors of the hospitals represented within PHIS. Hospitals were eligible for inclusion in the study if their data (1) met PHIS quality control standards for ED patient visits as determined by internal data assurance processes incorporated in PHIS,^3,14,15 (2) included data only from an identifiable single main ED, and (3) completed the ED medical director’s survey.

PHIS Database

PHIS, an administrative database managed by Truven Health Analytics, includes data from ED, ambulatory surgery, observation, and inpatient encounters across Children’s Hospital Association member children’s hospitals in North America. Data are subjected to validity checks before being included in the database.¹⁶ PHIS assigns unique patient identifiers to track individual patient visits within participating institutions over time.

Hospitals were described by percentages of ED patients in several groups: age (<1, 1-4, 5-9, 10-14, and 15-18 years)¹⁷; sex; race/ethnicity; insurance type (commercial, government, other); ED International Classification of Diseases, Ninth Edition (ICD-9) diagnosis code–based severity classification system score (1-2, low severity; 3-5, high severity)¹⁸; complex chronic condition presence at ED visits in prior year^14,19-21; home postal (Zip) code median household income from 2010 US Census data compared with Federal Poverty Level (<1.5, 1.5-2, 2-3, and >3 × FPL)¹⁷; and primary care physician (PCP) density in Federal Health Service Area of patient’s home address as reported by Dartmouth Atlas of Health Care modeled by quartiles.²² Density of PCPs—general pediatricians, family practitioners, general practitioners, and general internists—is calculated as number of PCPs per 100,000 residents. We used PCP density to account for potential care provided by any of the PCPs mentioned. We also assessed, at hospital level, index visit arrival time (8:01 am to 4:00 pm; 4:01 pm to 12:00 am; 12:01 am to 8:00 am) and index visit season.²³

ED Medical Director Survey

A web-based survey was constructed in an iterative process based on literature review and expert opinion to assess hospital-level factors that may impact ED RV rates.^3,7,24-26 The survey was piloted at 3 institutions to refine its structure and content.

The survey included 15 close-ended or multiple-choice questions on ED environment and operations and 2 open-ended questions, “What is the largest barrier to reducing the number of return visits within 72 hours of discharge from a previous ED visit?” and “In your opinion, what is the best way of reducing the number of the return visits within 72 hours of previous ED visit ?” (questionnaire in Supplemental material). Hospital characteristics from the survey included total clinical time allotment, or full-time equivalent (FTE), among all physicians, pediatric emergency medicine (PEM) fellowship-trained physicians, and all other (non-PEM) physicians. The data were standardized across sites by calculating FTE-per-10,000-visits values for each hospital; median duration of ED visit for admitted and discharged patients; median time from arrival to ED physician evaluation; rate of leaving without being seen; discharge educational material authorship and age specificity; follow-up visit scheduling procedure; and percentage of ED patients for whom English was a second language.

Responses to the 2 open-ended questions were independently categorized by Drs. Pittsenbarger and Alpern. Responses could be placed in more than 1 category if multiple answers to the question were included in the response. Categorizations were compared for consistency, and any inconsistencies were resolved by the consensus of the study investigators.

Outcome Measures From PHIS Database

All ED visits within a 12-month period (July 1, 2013–June 30, 2014) by patients younger than 18 years at time of index ED visit were eligible for inclusion in the study. An index visit was defined as any ED visit without another ED visit within the preceding 72 hours. The 72-hour time frame was used because it is the most widely studied time frame for ED RVs.⁵ Index ED visits that led to admission, observation status, death, or transfer were excluded.

The 2 primary outcomes of interest were (1) RVs within 72 hours of index ED visit discharge and (2) RVs within 72 hours that resulted in hospital admission or observation status at the next ED visit (RVA).^7,9,27-30 For patients with multiple ED revisits within 72 hours, only the first was assessed. There was a 72-hour minimum between index visits for the same patient.

Statistical Analyses

To determine hospital groups based on RV and RVA rates, we adjusted RV and RVA rates using generalized linear mixed-effects models, controlling for clustering and allowing for correlated data (within hospitals), nonconstant variability (across hospitals), and non-normally distributed data, as we did in a study of patient-level factors associated with ED RV and RVA.³ For each calculated rate (RV, RVA), the hospitals were then classified into 3 groups based on whether the hospital’s adjusted RV and RVA rates were outside 2 SDs from the mean, below the 5th or above the 95th percentile, or within that range. These groups were labeled lowest outliers, highest outliers, and average-performing hospitals.

After the groups of hospitals were determined, we returned to using unadjusted data to statistically analyze them. We summarized continuous variables using minimum and maximum values, medians, and interquartile ranges (IQRs). We present categorical variables using counts and percentages. To identify hospital characteristics with the most potential to gain from improvement, we also analyzed associations using 2 collapsed groups: hospitals with RV (or RVA) rates included in the average-performing and lowest outlier groups and hospitals within the highest outlier group. Hospital characteristics and hospital’s patient population characteristics from the surveys are summarized based on RV and RVA rate groups. Differences in distributions among continuous variables were assessed by Kruskal-Wallis 1-way analysis of variance. Chi-square tests were used to evaluate differences in proportions among categorical variables. All statistical analyses were performed with SAS Version 9.4 (SAS Institute); 2-sided P < 0.05 was considered statistically significant.

Return Visit Rates and Hospital ED Site Population Characteristics

Twenty-four of 35 (68%) eligible hospitals that met PHIS quality control standards for ED patient visits responded to the ED medical director survey. The included hospitals that both met quality control standards and completed the survey had a total of 1,456,377 patient visits during the study period. Individual sites had annual volumes ranging from 26,627 to 96,637 ED encounters. The mean RV rate across the institutions was 3.7% (range, 3.0%-4.8%), and the mean RVA rate across the hospitals was 0.7% (range, 0.5%-1.1%) (Figure).

There were 5 hospitals with RV rates less than 2 SDs of the mean rate, placing them in the lowest outlier group for RV; 13 hospitals with RV rates within 2 SDs of the mean RV rate, placing them in the average-performing group; and 6 hospitals with RV rates above 2 SDs of the mean, placing them in the highest outlier group. Table 1 lists the hospital ED site population characteristics among the 3 RV rate groups. Hospitals in the highest outlier group served populations with higher proportions of patients with insurance from a government payer, lower proportions of patients covered by a commercial insurance plan, and higher proportion of patients with lower median household incomes.

RV Rates and Hospital-Level Factors Survey Characteristics

Table 2 lists the ED medical director survey hospital-level data among the 3 RV rate groups. There were fewer FTEs by PEM fellowship-trained physicians per 10,000 patient visits at sites with higher RV rates (Table 2). Hospital-level characteristics assessed by the survey were not associated with RVA rates (Supplemental Table 2).

Evaluating characteristics of hospitals with the most potential to gain from improvement, hospitals with the highest RV rates (highest outlier group), compared with hospitals in the lowest outlier and average-performing groups collapsed together, persisted in having fewer PEM fellowship-trained physician FTEs per patient visit (Table 3). A similar collapsed analysis of RVA rates demonstrated that hospitals in the highest outlier group had longer-wait-to-physician time (81 minutes; IQR, 51-105 minutes) compared with hospitals in the other 2 groups (30 minutes; IQR, 19-42.5 minutes) (Table 3).

Other studies have identified patient- and visit-level characteristics associated with higher ED RV and RVA rates.^3,8,9,31 However, as our goal was to identify possible modifiable institutional features, our study examined factors at hospital and population-served levels (instead of patient or visit level) that may impact ED RV and RVA rates. Interestingly, our sample of tertiary-care pediatric center EDs provided evidence of variability in RV and RVA rates. We identified factors associated with RV rates related to the SDHs of the populations served by the ED, which suggests these factors are not modifiable at an institution level. In addition, we found that the increased availability of PEM providers per patient visit correlated with fewer ED RVs.

Hospitals serving ED populations with more government-insured and fewer commercially insured patients had higher rates of return to the ED. Similarly, hospitals with larger proportions of patients from areas with lower median household incomes had higher RV rates. These factors may indicate that patients with limited resources may have more frequent ED RVs,^3,6,32,33 and hospitals that serve them have higher ED RV rates. Our findings complement those of a recent study by Sills et al.,¹¹ who evaluated hospital readmissions and proposed risk adjustment for performance reimbursement. This study found that hospital population-level race, ethnicity, insurance status, and household income were predictors of hospital readmission after discharge.

Of note, our data did not identify similar site-level attributes related to the population served that correlated with RVA rates. We postulate that the need for admission on RV may indicate an inherent clinical urgency or medical need associated with the return to the ED, whereas RV without admission may be related more to patient- or population-level sociodemographic factors than to quality of care and clinical course, which influence ED utilization.^1,3,30 EDs treating higher proportions of patients of minority race or ethnicity, those with fewer financial resources, and those in more need of government health insurance are at higher risk for ED revisits.

We observed that increased PEM fellowship-trained physician staffing was associated with decreased RV rates. The availability of specialty-trained physicians in PEM may allow a larger proportion of patients treated by physicians with honed clinical skills for the patient population. Data from a single pediatric center showed PEM fellowship-trained physicians had admission rates lower than those of their counterparts without subspecialty fellowship training.³⁴ The lower RV rate for this group in our study is especially interesting in light of previously reported lower admission rates at index visit in PEM trained physicians. With lower index admission rates, it may have been assumed that visits associated with PEM trained physician care would have an increased (rather than decreased) chance of RV. In addition, we noted the increased RVA rates were associated with longer waits to see a physician. These measures may indicate the effect of institutional access to robust resources (the ability to hire and support more specialty-trained physicians). These novel findings warrant further evaluation, particularly as our sample included only pediatric centers.

Our survey data demonstrated the impact that access to care has on ED RV rates. The ED medical directors indicated that limited access to outpatient appointments with PCPs and specialists was an important factor increasing ED RVs and a potential avenue for interventions. As the 2 open-ended questions addressed barriers and potential solutions, it is interesting that the respondents cited access to care and discharge instructions as the largest barriers and identified innovations in access to care and discharge education as important potential remedies.

This study demonstrated that, at the hospital level, ED RV quality measures are influenced by complex and varied SDHs that primarily reflect the characteristics of the patient populations served. Prior work has similarly highlighted the importance of gaining a rigorous understanding of other quality measures before widespread use, reporting, and dissemination of results.^11,35-38 With this in mind, as quality measures are developed and implemented, care should be taken to ensure they accurately and appropriately reflect the quality of care provided to the patient and are not more representative of other factors not directly within institutional control. These findings call into question the usefulness of ED RVs as a quality measure for comparing institutions.

Study Limitations

This study had several limitations. The PHIS dataset tracks only patients within each institution and does not include RVs to other EDs, which may account for a proportion of RVs.³⁹ Our survey response rate was 68% among medical directors, excluding 11 hospitals from analysis, which decreased the study’s power to detect differences that may be present between groups. In addition, the generalizability of our findings may be limited to tertiary-care children’s hospitals, as the PHIS dataset included only these types of healthcare facilities. We also included data only from the sites’ main EDs, and therefore cannot know if our results are applicable to satellite EDs. ED staffing of PEM physicians was analyzed using FTEs. However, number of clinical hours in 1 FTE may vary among sites, leading to imprecision in this hospital characteristic.

Hospitals with the highest RV rates served populations with a larger proportion of patients with government insurance and lower household income, and these hospitals had fewer PEM trained physicians. Variation in RV rates among hospitals may be indicative of the SDHs of their unique patient populations. ED revisit rates should be used cautiously in determining the quality of care of hospitals providing care to differing populations.

Disclosure

Nothing to report.

Return visit (RV) rate is a quality measure commonly used in the emergency department (ED) setting. This metric may represent suboptimal care at the index ED visit.^1-5 Although patient- and visit-level factors affecting ED RVs have been evaluated,^1,3,4,6-9 hospital-level factors and factors of a hospital’s patient population that may play roles in ED RV rates have not been examined. Identifying the factors associated with increased RVs may allow resources to be designated to areas that improve emergent care for children.¹⁰

Hospital readmission rates are a closely followed quality measure and are linked to reimbursement by the federal government, but a recent study found the influence a hospital can have on this marker may be mitigated by the impact of the social determinates of health (SDHs) of the hospital’s patient population.¹¹ That study and others have prompted an ongoing debate about adjusting quality measures for SDHs.^12,13 A clearer understanding of these interactions may permit us to focus on factors that can truly lead to improvement in care instead of penalizing practitioners or hospitals that provide care to those most in need.

Prior work has identified several SDHs associated with higher ED RV rates in patient- or visit-level analyses.^3,11,14 We conducted a study of hospital-level characteristics and characteristics of a hospital’s patient population to identify potentially mutable factors associated with increased ED RV rates that, once recognized, may allow for improvement in this quality measure.

This study was not considered human subjects research in accordance with Common Rule 45 CFR§46.104(f) and was evaluated by the Ann and Robert H. Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine Institutional Review Boards and deemed exempt from review.

Study Population and Protocol

Our study had 2 data sources (to be described in detail): the Pediatric Health Information System (PHIS) and a survey of ED medical directors of the hospitals represented within PHIS. Hospitals were eligible for inclusion in the study if their data (1) met PHIS quality control standards for ED patient visits as determined by internal data assurance processes incorporated in PHIS,^3,14,15 (2) included data only from an identifiable single main ED, and (3) completed the ED medical director’s survey.

PHIS Database

PHIS, an administrative database managed by Truven Health Analytics, includes data from ED, ambulatory surgery, observation, and inpatient encounters across Children’s Hospital Association member children’s hospitals in North America. Data are subjected to validity checks before being included in the database.¹⁶ PHIS assigns unique patient identifiers to track individual patient visits within participating institutions over time.

Hospitals were described by percentages of ED patients in several groups: age (<1, 1-4, 5-9, 10-14, and 15-18 years)¹⁷; sex; race/ethnicity; insurance type (commercial, government, other); ED International Classification of Diseases, Ninth Edition (ICD-9) diagnosis code–based severity classification system score (1-2, low severity; 3-5, high severity)¹⁸; complex chronic condition presence at ED visits in prior year^14,19-21; home postal (Zip) code median household income from 2010 US Census data compared with Federal Poverty Level (<1.5, 1.5-2, 2-3, and >3 × FPL)¹⁷; and primary care physician (PCP) density in Federal Health Service Area of patient’s home address as reported by Dartmouth Atlas of Health Care modeled by quartiles.²² Density of PCPs—general pediatricians, family practitioners, general practitioners, and general internists—is calculated as number of PCPs per 100,000 residents. We used PCP density to account for potential care provided by any of the PCPs mentioned. We also assessed, at hospital level, index visit arrival time (8:01 am to 4:00 pm; 4:01 pm to 12:00 am; 12:01 am to 8:00 am) and index visit season.²³

ED Medical Director Survey

A web-based survey was constructed in an iterative process based on literature review and expert opinion to assess hospital-level factors that may impact ED RV rates.^3,7,24-26 The survey was piloted at 3 institutions to refine its structure and content.

The survey included 15 close-ended or multiple-choice questions on ED environment and operations and 2 open-ended questions, “What is the largest barrier to reducing the number of return visits within 72 hours of discharge from a previous ED visit?” and “In your opinion, what is the best way of reducing the number of the return visits within 72 hours of previous ED visit ?” (questionnaire in Supplemental material). Hospital characteristics from the survey included total clinical time allotment, or full-time equivalent (FTE), among all physicians, pediatric emergency medicine (PEM) fellowship-trained physicians, and all other (non-PEM) physicians. The data were standardized across sites by calculating FTE-per-10,000-visits values for each hospital; median duration of ED visit for admitted and discharged patients; median time from arrival to ED physician evaluation; rate of leaving without being seen; discharge educational material authorship and age specificity; follow-up visit scheduling procedure; and percentage of ED patients for whom English was a second language.

Responses to the 2 open-ended questions were independently categorized by Drs. Pittsenbarger and Alpern. Responses could be placed in more than 1 category if multiple answers to the question were included in the response. Categorizations were compared for consistency, and any inconsistencies were resolved by the consensus of the study investigators.

Outcome Measures From PHIS Database

All ED visits within a 12-month period (July 1, 2013–June 30, 2014) by patients younger than 18 years at time of index ED visit were eligible for inclusion in the study. An index visit was defined as any ED visit without another ED visit within the preceding 72 hours. The 72-hour time frame was used because it is the most widely studied time frame for ED RVs.⁵ Index ED visits that led to admission, observation status, death, or transfer were excluded.

The 2 primary outcomes of interest were (1) RVs within 72 hours of index ED visit discharge and (2) RVs within 72 hours that resulted in hospital admission or observation status at the next ED visit (RVA).^7,9,27-30 For patients with multiple ED revisits within 72 hours, only the first was assessed. There was a 72-hour minimum between index visits for the same patient.

Statistical Analyses

To determine hospital groups based on RV and RVA rates, we adjusted RV and RVA rates using generalized linear mixed-effects models, controlling for clustering and allowing for correlated data (within hospitals), nonconstant variability (across hospitals), and non-normally distributed data, as we did in a study of patient-level factors associated with ED RV and RVA.³ For each calculated rate (RV, RVA), the hospitals were then classified into 3 groups based on whether the hospital’s adjusted RV and RVA rates were outside 2 SDs from the mean, below the 5th or above the 95th percentile, or within that range. These groups were labeled lowest outliers, highest outliers, and average-performing hospitals.

After the groups of hospitals were determined, we returned to using unadjusted data to statistically analyze them. We summarized continuous variables using minimum and maximum values, medians, and interquartile ranges (IQRs). We present categorical variables using counts and percentages. To identify hospital characteristics with the most potential to gain from improvement, we also analyzed associations using 2 collapsed groups: hospitals with RV (or RVA) rates included in the average-performing and lowest outlier groups and hospitals within the highest outlier group. Hospital characteristics and hospital’s patient population characteristics from the surveys are summarized based on RV and RVA rate groups. Differences in distributions among continuous variables were assessed by Kruskal-Wallis 1-way analysis of variance. Chi-square tests were used to evaluate differences in proportions among categorical variables. All statistical analyses were performed with SAS Version 9.4 (SAS Institute); 2-sided P < 0.05 was considered statistically significant.

Return Visit Rates and Hospital ED Site Population Characteristics

Twenty-four of 35 (68%) eligible hospitals that met PHIS quality control standards for ED patient visits responded to the ED medical director survey. The included hospitals that both met quality control standards and completed the survey had a total of 1,456,377 patient visits during the study period. Individual sites had annual volumes ranging from 26,627 to 96,637 ED encounters. The mean RV rate across the institutions was 3.7% (range, 3.0%-4.8%), and the mean RVA rate across the hospitals was 0.7% (range, 0.5%-1.1%) (Figure).

There were 5 hospitals with RV rates less than 2 SDs of the mean rate, placing them in the lowest outlier group for RV; 13 hospitals with RV rates within 2 SDs of the mean RV rate, placing them in the average-performing group; and 6 hospitals with RV rates above 2 SDs of the mean, placing them in the highest outlier group. Table 1 lists the hospital ED site population characteristics among the 3 RV rate groups. Hospitals in the highest outlier group served populations with higher proportions of patients with insurance from a government payer, lower proportions of patients covered by a commercial insurance plan, and higher proportion of patients with lower median household incomes.

RV Rates and Hospital-Level Factors Survey Characteristics

Table 2 lists the ED medical director survey hospital-level data among the 3 RV rate groups. There were fewer FTEs by PEM fellowship-trained physicians per 10,000 patient visits at sites with higher RV rates (Table 2). Hospital-level characteristics assessed by the survey were not associated with RVA rates (Supplemental Table 2).

Evaluating characteristics of hospitals with the most potential to gain from improvement, hospitals with the highest RV rates (highest outlier group), compared with hospitals in the lowest outlier and average-performing groups collapsed together, persisted in having fewer PEM fellowship-trained physician FTEs per patient visit (Table 3). A similar collapsed analysis of RVA rates demonstrated that hospitals in the highest outlier group had longer-wait-to-physician time (81 minutes; IQR, 51-105 minutes) compared with hospitals in the other 2 groups (30 minutes; IQR, 19-42.5 minutes) (Table 3).

Other studies have identified patient- and visit-level characteristics associated with higher ED RV and RVA rates.^3,8,9,31 However, as our goal was to identify possible modifiable institutional features, our study examined factors at hospital and population-served levels (instead of patient or visit level) that may impact ED RV and RVA rates. Interestingly, our sample of tertiary-care pediatric center EDs provided evidence of variability in RV and RVA rates. We identified factors associated with RV rates related to the SDHs of the populations served by the ED, which suggests these factors are not modifiable at an institution level. In addition, we found that the increased availability of PEM providers per patient visit correlated with fewer ED RVs.

Hospitals serving ED populations with more government-insured and fewer commercially insured patients had higher rates of return to the ED. Similarly, hospitals with larger proportions of patients from areas with lower median household incomes had higher RV rates. These factors may indicate that patients with limited resources may have more frequent ED RVs,^3,6,32,33 and hospitals that serve them have higher ED RV rates. Our findings complement those of a recent study by Sills et al.,¹¹ who evaluated hospital readmissions and proposed risk adjustment for performance reimbursement. This study found that hospital population-level race, ethnicity, insurance status, and household income were predictors of hospital readmission after discharge.

Of note, our data did not identify similar site-level attributes related to the population served that correlated with RVA rates. We postulate that the need for admission on RV may indicate an inherent clinical urgency or medical need associated with the return to the ED, whereas RV without admission may be related more to patient- or population-level sociodemographic factors than to quality of care and clinical course, which influence ED utilization.^1,3,30 EDs treating higher proportions of patients of minority race or ethnicity, those with fewer financial resources, and those in more need of government health insurance are at higher risk for ED revisits.

We observed that increased PEM fellowship-trained physician staffing was associated with decreased RV rates. The availability of specialty-trained physicians in PEM may allow a larger proportion of patients treated by physicians with honed clinical skills for the patient population. Data from a single pediatric center showed PEM fellowship-trained physicians had admission rates lower than those of their counterparts without subspecialty fellowship training.³⁴ The lower RV rate for this group in our study is especially interesting in light of previously reported lower admission rates at index visit in PEM trained physicians. With lower index admission rates, it may have been assumed that visits associated with PEM trained physician care would have an increased (rather than decreased) chance of RV. In addition, we noted the increased RVA rates were associated with longer waits to see a physician. These measures may indicate the effect of institutional access to robust resources (the ability to hire and support more specialty-trained physicians). These novel findings warrant further evaluation, particularly as our sample included only pediatric centers.

Our survey data demonstrated the impact that access to care has on ED RV rates. The ED medical directors indicated that limited access to outpatient appointments with PCPs and specialists was an important factor increasing ED RVs and a potential avenue for interventions. As the 2 open-ended questions addressed barriers and potential solutions, it is interesting that the respondents cited access to care and discharge instructions as the largest barriers and identified innovations in access to care and discharge education as important potential remedies.

This study demonstrated that, at the hospital level, ED RV quality measures are influenced by complex and varied SDHs that primarily reflect the characteristics of the patient populations served. Prior work has similarly highlighted the importance of gaining a rigorous understanding of other quality measures before widespread use, reporting, and dissemination of results.^11,35-38 With this in mind, as quality measures are developed and implemented, care should be taken to ensure they accurately and appropriately reflect the quality of care provided to the patient and are not more representative of other factors not directly within institutional control. These findings call into question the usefulness of ED RVs as a quality measure for comparing institutions.

Study Limitations

This study had several limitations. The PHIS dataset tracks only patients within each institution and does not include RVs to other EDs, which may account for a proportion of RVs.³⁹ Our survey response rate was 68% among medical directors, excluding 11 hospitals from analysis, which decreased the study’s power to detect differences that may be present between groups. In addition, the generalizability of our findings may be limited to tertiary-care children’s hospitals, as the PHIS dataset included only these types of healthcare facilities. We also included data only from the sites’ main EDs, and therefore cannot know if our results are applicable to satellite EDs. ED staffing of PEM physicians was analyzed using FTEs. However, number of clinical hours in 1 FTE may vary among sites, leading to imprecision in this hospital characteristic.

Hospitals with the highest RV rates served populations with a larger proportion of patients with government insurance and lower household income, and these hospitals had fewer PEM trained physicians. Variation in RV rates among hospitals may be indicative of the SDHs of their unique patient populations. ED revisit rates should be used cautiously in determining the quality of care of hospitals providing care to differing populations.

Disclosure

Nothing to report.

Return visit (RV) rate is a quality measure commonly used in the emergency department (ED) setting. This metric may represent suboptimal care at the index ED visit.^1-5 Although patient- and visit-level factors affecting ED RVs have been evaluated,^1,3,4,6-9 hospital-level factors and factors of a hospital’s patient population that may play roles in ED RV rates have not been examined. Identifying the factors associated with increased RVs may allow resources to be designated to areas that improve emergent care for children.¹⁰

Hospital readmission rates are a closely followed quality measure and are linked to reimbursement by the federal government, but a recent study found the influence a hospital can have on this marker may be mitigated by the impact of the social determinates of health (SDHs) of the hospital’s patient population.¹¹ That study and others have prompted an ongoing debate about adjusting quality measures for SDHs.^12,13 A clearer understanding of these interactions may permit us to focus on factors that can truly lead to improvement in care instead of penalizing practitioners or hospitals that provide care to those most in need.

Prior work has identified several SDHs associated with higher ED RV rates in patient- or visit-level analyses.^3,11,14 We conducted a study of hospital-level characteristics and characteristics of a hospital’s patient population to identify potentially mutable factors associated with increased ED RV rates that, once recognized, may allow for improvement in this quality measure.

This study was not considered human subjects research in accordance with Common Rule 45 CFR§46.104(f) and was evaluated by the Ann and Robert H. Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine Institutional Review Boards and deemed exempt from review.

Study Population and Protocol

Our study had 2 data sources (to be described in detail): the Pediatric Health Information System (PHIS) and a survey of ED medical directors of the hospitals represented within PHIS. Hospitals were eligible for inclusion in the study if their data (1) met PHIS quality control standards for ED patient visits as determined by internal data assurance processes incorporated in PHIS,^3,14,15 (2) included data only from an identifiable single main ED, and (3) completed the ED medical director’s survey.

PHIS Database

PHIS, an administrative database managed by Truven Health Analytics, includes data from ED, ambulatory surgery, observation, and inpatient encounters across Children’s Hospital Association member children’s hospitals in North America. Data are subjected to validity checks before being included in the database.¹⁶ PHIS assigns unique patient identifiers to track individual patient visits within participating institutions over time.

Hospitals were described by percentages of ED patients in several groups: age (<1, 1-4, 5-9, 10-14, and 15-18 years)¹⁷; sex; race/ethnicity; insurance type (commercial, government, other); ED International Classification of Diseases, Ninth Edition (ICD-9) diagnosis code–based severity classification system score (1-2, low severity; 3-5, high severity)¹⁸; complex chronic condition presence at ED visits in prior year^14,19-21; home postal (Zip) code median household income from 2010 US Census data compared with Federal Poverty Level (<1.5, 1.5-2, 2-3, and >3 × FPL)¹⁷; and primary care physician (PCP) density in Federal Health Service Area of patient’s home address as reported by Dartmouth Atlas of Health Care modeled by quartiles.²² Density of PCPs—general pediatricians, family practitioners, general practitioners, and general internists—is calculated as number of PCPs per 100,000 residents. We used PCP density to account for potential care provided by any of the PCPs mentioned. We also assessed, at hospital level, index visit arrival time (8:01 am to 4:00 pm; 4:01 pm to 12:00 am; 12:01 am to 8:00 am) and index visit season.²³

ED Medical Director Survey

A web-based survey was constructed in an iterative process based on literature review and expert opinion to assess hospital-level factors that may impact ED RV rates.^3,7,24-26 The survey was piloted at 3 institutions to refine its structure and content.

The survey included 15 close-ended or multiple-choice questions on ED environment and operations and 2 open-ended questions, “What is the largest barrier to reducing the number of return visits within 72 hours of discharge from a previous ED visit?” and “In your opinion, what is the best way of reducing the number of the return visits within 72 hours of previous ED visit ?” (questionnaire in Supplemental material). Hospital characteristics from the survey included total clinical time allotment, or full-time equivalent (FTE), among all physicians, pediatric emergency medicine (PEM) fellowship-trained physicians, and all other (non-PEM) physicians. The data were standardized across sites by calculating FTE-per-10,000-visits values for each hospital; median duration of ED visit for admitted and discharged patients; median time from arrival to ED physician evaluation; rate of leaving without being seen; discharge educational material authorship and age specificity; follow-up visit scheduling procedure; and percentage of ED patients for whom English was a second language.

Responses to the 2 open-ended questions were independently categorized by Drs. Pittsenbarger and Alpern. Responses could be placed in more than 1 category if multiple answers to the question were included in the response. Categorizations were compared for consistency, and any inconsistencies were resolved by the consensus of the study investigators.

Outcome Measures From PHIS Database

All ED visits within a 12-month period (July 1, 2013–June 30, 2014) by patients younger than 18 years at time of index ED visit were eligible for inclusion in the study. An index visit was defined as any ED visit without another ED visit within the preceding 72 hours. The 72-hour time frame was used because it is the most widely studied time frame for ED RVs.⁵ Index ED visits that led to admission, observation status, death, or transfer were excluded.

The 2 primary outcomes of interest were (1) RVs within 72 hours of index ED visit discharge and (2) RVs within 72 hours that resulted in hospital admission or observation status at the next ED visit (RVA).^7,9,27-30 For patients with multiple ED revisits within 72 hours, only the first was assessed. There was a 72-hour minimum between index visits for the same patient.

Statistical Analyses

To determine hospital groups based on RV and RVA rates, we adjusted RV and RVA rates using generalized linear mixed-effects models, controlling for clustering and allowing for correlated data (within hospitals), nonconstant variability (across hospitals), and non-normally distributed data, as we did in a study of patient-level factors associated with ED RV and RVA.³ For each calculated rate (RV, RVA), the hospitals were then classified into 3 groups based on whether the hospital’s adjusted RV and RVA rates were outside 2 SDs from the mean, below the 5th or above the 95th percentile, or within that range. These groups were labeled lowest outliers, highest outliers, and average-performing hospitals.

After the groups of hospitals were determined, we returned to using unadjusted data to statistically analyze them. We summarized continuous variables using minimum and maximum values, medians, and interquartile ranges (IQRs). We present categorical variables using counts and percentages. To identify hospital characteristics with the most potential to gain from improvement, we also analyzed associations using 2 collapsed groups: hospitals with RV (or RVA) rates included in the average-performing and lowest outlier groups and hospitals within the highest outlier group. Hospital characteristics and hospital’s patient population characteristics from the surveys are summarized based on RV and RVA rate groups. Differences in distributions among continuous variables were assessed by Kruskal-Wallis 1-way analysis of variance. Chi-square tests were used to evaluate differences in proportions among categorical variables. All statistical analyses were performed with SAS Version 9.4 (SAS Institute); 2-sided P < 0.05 was considered statistically significant.

Return Visit Rates and Hospital ED Site Population Characteristics

Twenty-four of 35 (68%) eligible hospitals that met PHIS quality control standards for ED patient visits responded to the ED medical director survey. The included hospitals that both met quality control standards and completed the survey had a total of 1,456,377 patient visits during the study period. Individual sites had annual volumes ranging from 26,627 to 96,637 ED encounters. The mean RV rate across the institutions was 3.7% (range, 3.0%-4.8%), and the mean RVA rate across the hospitals was 0.7% (range, 0.5%-1.1%) (Figure).

There were 5 hospitals with RV rates less than 2 SDs of the mean rate, placing them in the lowest outlier group for RV; 13 hospitals with RV rates within 2 SDs of the mean RV rate, placing them in the average-performing group; and 6 hospitals with RV rates above 2 SDs of the mean, placing them in the highest outlier group. Table 1 lists the hospital ED site population characteristics among the 3 RV rate groups. Hospitals in the highest outlier group served populations with higher proportions of patients with insurance from a government payer, lower proportions of patients covered by a commercial insurance plan, and higher proportion of patients with lower median household incomes.

RV Rates and Hospital-Level Factors Survey Characteristics

Table 2 lists the ED medical director survey hospital-level data among the 3 RV rate groups. There were fewer FTEs by PEM fellowship-trained physicians per 10,000 patient visits at sites with higher RV rates (Table 2). Hospital-level characteristics assessed by the survey were not associated with RVA rates (Supplemental Table 2).

Evaluating characteristics of hospitals with the most potential to gain from improvement, hospitals with the highest RV rates (highest outlier group), compared with hospitals in the lowest outlier and average-performing groups collapsed together, persisted in having fewer PEM fellowship-trained physician FTEs per patient visit (Table 3). A similar collapsed analysis of RVA rates demonstrated that hospitals in the highest outlier group had longer-wait-to-physician time (81 minutes; IQR, 51-105 minutes) compared with hospitals in the other 2 groups (30 minutes; IQR, 19-42.5 minutes) (Table 3).

Other studies have identified patient- and visit-level characteristics associated with higher ED RV and RVA rates.^3,8,9,31 However, as our goal was to identify possible modifiable institutional features, our study examined factors at hospital and population-served levels (instead of patient or visit level) that may impact ED RV and RVA rates. Interestingly, our sample of tertiary-care pediatric center EDs provided evidence of variability in RV and RVA rates. We identified factors associated with RV rates related to the SDHs of the populations served by the ED, which suggests these factors are not modifiable at an institution level. In addition, we found that the increased availability of PEM providers per patient visit correlated with fewer ED RVs.

Hospitals serving ED populations with more government-insured and fewer commercially insured patients had higher rates of return to the ED. Similarly, hospitals with larger proportions of patients from areas with lower median household incomes had higher RV rates. These factors may indicate that patients with limited resources may have more frequent ED RVs,^3,6,32,33 and hospitals that serve them have higher ED RV rates. Our findings complement those of a recent study by Sills et al.,¹¹ who evaluated hospital readmissions and proposed risk adjustment for performance reimbursement. This study found that hospital population-level race, ethnicity, insurance status, and household income were predictors of hospital readmission after discharge.

Of note, our data did not identify similar site-level attributes related to the population served that correlated with RVA rates. We postulate that the need for admission on RV may indicate an inherent clinical urgency or medical need associated with the return to the ED, whereas RV without admission may be related more to patient- or population-level sociodemographic factors than to quality of care and clinical course, which influence ED utilization.^1,3,30 EDs treating higher proportions of patients of minority race or ethnicity, those with fewer financial resources, and those in more need of government health insurance are at higher risk for ED revisits.

We observed that increased PEM fellowship-trained physician staffing was associated with decreased RV rates. The availability of specialty-trained physicians in PEM may allow a larger proportion of patients treated by physicians with honed clinical skills for the patient population. Data from a single pediatric center showed PEM fellowship-trained physicians had admission rates lower than those of their counterparts without subspecialty fellowship training.³⁴ The lower RV rate for this group in our study is especially interesting in light of previously reported lower admission rates at index visit in PEM trained physicians. With lower index admission rates, it may have been assumed that visits associated with PEM trained physician care would have an increased (rather than decreased) chance of RV. In addition, we noted the increased RVA rates were associated with longer waits to see a physician. These measures may indicate the effect of institutional access to robust resources (the ability to hire and support more specialty-trained physicians). These novel findings warrant further evaluation, particularly as our sample included only pediatric centers.

Our survey data demonstrated the impact that access to care has on ED RV rates. The ED medical directors indicated that limited access to outpatient appointments with PCPs and specialists was an important factor increasing ED RVs and a potential avenue for interventions. As the 2 open-ended questions addressed barriers and potential solutions, it is interesting that the respondents cited access to care and discharge instructions as the largest barriers and identified innovations in access to care and discharge education as important potential remedies.

This study demonstrated that, at the hospital level, ED RV quality measures are influenced by complex and varied SDHs that primarily reflect the characteristics of the patient populations served. Prior work has similarly highlighted the importance of gaining a rigorous understanding of other quality measures before widespread use, reporting, and dissemination of results.^11,35-38 With this in mind, as quality measures are developed and implemented, care should be taken to ensure they accurately and appropriately reflect the quality of care provided to the patient and are not more representative of other factors not directly within institutional control. These findings call into question the usefulness of ED RVs as a quality measure for comparing institutions.

Study Limitations

This study had several limitations. The PHIS dataset tracks only patients within each institution and does not include RVs to other EDs, which may account for a proportion of RVs.³⁹ Our survey response rate was 68% among medical directors, excluding 11 hospitals from analysis, which decreased the study’s power to detect differences that may be present between groups. In addition, the generalizability of our findings may be limited to tertiary-care children’s hospitals, as the PHIS dataset included only these types of healthcare facilities. We also included data only from the sites’ main EDs, and therefore cannot know if our results are applicable to satellite EDs. ED staffing of PEM physicians was analyzed using FTEs. However, number of clinical hours in 1 FTE may vary among sites, leading to imprecision in this hospital characteristic.

Hospitals with the highest RV rates served populations with a larger proportion of patients with government insurance and lower household income, and these hospitals had fewer PEM trained physicians. Variation in RV rates among hospitals may be indicative of the SDHs of their unique patient populations. ED revisit rates should be used cautiously in determining the quality of care of hospitals providing care to differing populations.

Disclosure

Nothing to report.

It has been theorized that the physiologic stress that hospitalized patients experience accounts for their transient vulnerability after discharge, or posthospital syndrome.¹ Their acute illness and life-habit changes during hospitalization result in continued impairment of physiologic systems after discharge, and this impairment might leave them more susceptible to new health threats.¹ However, the theory that the stress experienced after a hospitalization might be associated with readmission has never been investigated.

Four biomarkers of the hypothalamic-pituitary-adrenal (HPA) axis may help quantify posthospitalization stress: (1) midregional pro-adrenomedullin (ADM), a precursor reflecting adrenomedullin activity²; (2) copeptin (the C-terminal part of prepro-vasopressin, produced by the hypothalamus in response to stress^3,4), the level of which closely correlates to the vasopressin level but is more stable and lacks circadian rhythm fluctuations^5-7; (3) cortisol, released by the adrenal cortex in response to stress; and (4) prolactin, an indicator of HPA axis activity. These 4 stress biomarkers have been related to the severity, complications, or mortality of several diseases.^3,5,8-17 Besides explaining the hypothetical association between posthospitalization stress and readmission and death, these biomarkers might be valuable in predicting which patients are at higher risk for readmission. Indeed, many prediction models have been developed to identify those patients, but most of these models underperform, target only very specific populations, or have not been externally validated.¹⁸

We hypothesized that the hospitalization stress measured by biomarkers is associated with readmission or death after discharge. In a prospective cohort study, we evaluated the association between 4 stress biomarkers (ADM, copeptin, cortisol, prolactin) and 30-day unplanned readmissions and deaths after an acute-care medical hospitalization, and assessed their additive value to validated readmission prediction scores.

Study Design and Population

Our prospective cohort study included all consecutive patients aged ≥50 years and admitted to the department of general internal medicine at Fribourg Cantonal Hospital in Switzerland between April 8, 2013 and September 23, 2013. Exclusion criteria were discharge on day of admission; death before discharge; discharge to another division, another acute-care hospital, a rehabilitation clinic, or a palliative-care clinic; and refusal or inability to give informed consent. In this hypothesis-generating observational study, we collected data on a convenience sample of patients and did not calculate sample size before data collection. The study was approved by the local ethics committee, and all patients gave informed consent.

Outcomes

The primary outcome was the composite of first unplanned readmission (to any division of any acute-care hospital) or death within 30 days after discharge from index admission. We also included deaths that occurred after discharge, hypothesizing that patients who died may have been readmitted had they lived. The secondary outcome was the same as the primary, but the period was 90 days. Planned readmission was defined as scheduled hospitalization for nonemergent treatment (eg, chemotherapy) or investigation (eg, elective coronarography). All patients were called 6 months after discharge, and readmissions and deaths recorded. If a patient could not be reached directly, we called his or her next of kin, primary care physician, or nursing home, depending on availability. Furthermore, we checked electronic health records for any readmission or death recorded within the Fribourg hospital network, which includes all 3 acute-care hospitals (Fribourg, Riaz, Tavel) in the same canton (state).

Independent Variables

Stress biomarkers. We measured serum levels of 4 stress biomarkers (ADM, copeptin, cortisol, prolactin) at 8 am on an empty stomach on both day of admission and day of discharge. For a patient whose discharge decision was made after 8 hours for the same day, a blood sample was collected as soon as discharge was planned.

Clinical data. Collected data included demographics, history of hospitalization within 6 months before index admission, hospitalization diagnosis, and Charlson Comorbidity Index (CCI), which includes a list of medical conditions that are assigned a number of 1, 2, 3, or 6 points, according to their severity, and which has been associated with mortality.¹⁹

Causes of Admission, Unplanned Readmission, and Death

Causes of index admission, unplanned readmission, and death were obtained from medical records. We used our consensus opinion and a previous analysis²⁰ to classify these causes by body system, and added 2 categories, cancer and infection (both associated with readmission²⁰). The resulting 9 categories were (1) cancer, (2) respiratory disorder, (3) infectious disorder, (4) neurologic disorder (including dementia, psychiatric disorder, alcohol disorder, and intoxication), (5) gastrointestinal disorder, (6) osteoarticular disorder, (7) renal disorder, (8) cardiovascular disorder (including ischemic disease and heart failure), and (9) other.

Additional Performance With Existing Predictive Models

To better define the explanatory power of biomarkers to predict our outcome, we assessed the performance improvement of 2 validated readmission prediction scores by adding the stress biomarkers. As large effect sizes from additional predictors are needed to increase the power discrimination of a model, a significant performance improvement would further support the biomarkers’ important explanatory power. The 2 prediction scores tested were the LACE index (Length of stay, Admission Acuity, CCI, number of Emergency department visits within preceding 6 months²¹) and the HOSPITAL score (Hemoglobin level at discharge, discharge from Oncology service, Sodium level at discharge, any Procedure performed during index hospitalization, Index admission Type, number of Admissions within preceding 12 months, Length of stay). As we did not have an oncology service, we replaced “discharge from oncology service” with “active diagnosis of cancer.” “Length of stay” was tailored to the median in Switzerland (8 days instead of 5 days; Supplement Table 1).^22,23

Data Analysis

Continuous variables were presented as medians with interquartile ranges (IQRs) because of their non-normal distribution, and categorical variables were presented as frequencies and percentages. We compared medians using the nonparametric K-sample test on the equality of medians, and compared frequencies using the Pearson χ² test. The discriminatory power of each biomarker in predicting readmission and death was calculated with the area under the receiver operating characteristic (ROC) curve (AUROC), using serum levels at discharge to better reflect the postdischarge period. Cutoff levels were selected by taking the best compromise between sensitivity and specificity according to the ROC curves (point nearest top left corner).²⁴

Univariate logistic regression analysis was used to test the prediction of 30-day and 90-day unplanned readmission or death by each biomarker. We built 2 different multivariate models: one adjusting for age and LACE index points²¹ and the other adjusting for age and HOSPITAL score.^22,23

To explore any association between reduction of stress during hospitalization and postdischarge outcome, we additionally calculated for each biomarker the difference between admission and discharge serum levels and assessed its association with readmission or death by logistic regression analysis. Because of the modification of cortisol serum levels during corticosteroid therapy, we excluded patients who underwent systemic corticosteroid therapy before or during hospitalization for the cortisol analysis (n = 105/346). Patients with a missing biomarker level were excluded from the respective analyses: discharge (ADM, 28 patients; copeptin, 27; cortisol, 24; prolactin, 24) and admission (ADM, 12 patients; copeptin, 15; cortisol, 8; prolactin, 8).

To assess an additional value of the biomarkers to prediction scores, we assessed the accuracy of the HOSPITAL score and LACE index in their original versions^21,22 and after adding each biomarker. We used AUROC to assess the discriminatory power and used the method of DeLong et al.²⁵ to compare results with and without adding each biomarker. Calibration was evaluated by comparing Hosmer-Lemeshow goodness-of-fit tests (P > 0.05 indicates good fit). Risk reclassification was assessed by Net Reclassification Improvement (NRI),²⁶ quantifying how appropriately a new model reclassifies patients, compared with an old model. Basically, patients without outcome are assigned +1 if correctly reclassified to a lower risk category or –1 if incorrectly reclassified to a higher risk category. NRI_nonevent is the sum of all points/numbers of patients. Conversely, patients with outcome are assigned +1 if correctly reclassified to a higher risk category or –1 if incorrectly reclassified to a lower risk category. NRI_event is the sum of all points/numbers of patients. NRI_overall is the sum of NRI_event and NRI_nonevent ranging from –2 to 2, with a positive value indicating better classification with the new model.

Two-sided P < 0.05 was used for statistical significance. All statistical analyses were performed with Stata Release 13.0 (StataCorp).

Among the 530 patients admitted to the ward, 184 were excluded (120 meeting exclusion criteria, 64 unable to give consent, Figure). Among the 346 patients included, 11.6% (n = 40) had a 30-day unplanned readmission or death (37 were readmitted, 2 died during readmission, 3 died without readmission). Within 90 days, 26.6% (n = 92) had a readmission or death (84 were readmitted, 10 died during or after readmission, 8 died without readmission).

Clinical Characteristics

Table 1 lists the patients’ baseline characteristics. Median age was 73 years (IQR, 64-82 years). Of the 346 patients included, 172 (49.7%) were men. Median CCI was 7 (IQR, 5-9); according to this index, 310 patients (89.6%) had at least 2 comorbidities. Median length of stay was 7 days (IQR, 4-12 days).

Primary Diagnoses of Admission, Unplanned Readmission, and Death

The 3 main causes of index admission were cardiovascular disorder (n = 92), infectious disorder (n = 70), and neurologic disorder (n = 66). Table 2 lists the causes of readmissions and deaths. A same-diagnosis category between index admission and readmission was found in 17 (45.9%) of the 37 readmitted patients and in 3 (60%) of the 5 patients who died.

Biomarkers and 30-Day Unplanned Readmission or Death

AUROC was 0.53 (95% confidence interval [CI], 0.43-0.63) for ADM, 0.60 (95% CI, 0.50-0.70) for copeptin, 0.59 (95% CI, 0.44-0.73) for cortisol, and 0.56 (95% CI, 0.45-0.66) for prolactin. The difference between admission and discharge levels was not associated with unplanned readmission or death for any of the biomarkers (Supplemental Table 2).

ADM and readmission or death. Median ADM level was not different between patients with and without readmission or death (1.0 nmol/L in each case; P = 1.00). The best cutoff level for ADM was 2 nmol/L (sensitivity, 16.7%; specificity, 91.8%). At this level, ADM was associated with a nonstatistically significant 130% increased odds of 30-day readmission or death (P = 0.09; Table 3, Supplemental Table 3). Conversely, the association with the 90-day outcome was significant (P = 0.02; Table 3, Supplemental Table 4).

Copeptin and readmission or death. Patients with 30-day readmission or death had a higher median copeptin level at discharge than patients without (10.4 pmol/L vs 7.3 pmol/L; P = 0.03). At a copeptin level higher than 9 pmol/L (to convert to pg/mL, divide by 0.249; sensitivity, 66.7%; specificity, 59.7%), both 30-day readmission or death (adjusted odds ratio [OR], 2.69; 95% CI, 1.29-5.64; P = 0.009) and 90-day readmission or death (adjusted OR, 2.76; 95% CI, 1.56-4.88; P < 0.001) were nearly 3 times as likely (Table 3, Supplemental Tables 3 and 4).

Cortisol and readmission or death. Median cortisol was not statistically different between patients with and without the primary outcome (431 nmol/L vs 465 nmol/L; P = 0.72). At a cortisol level higher than 590 nmol/L (to convert to μg/dL, divide by 27.59; sensitivity, 54.6%; specificity, 76.4%), 30-day outcome was more than 3 times as likely (adjusted OR, 3.43; 95% CI, 1.36-8.65; P = 0.009; Table 3, Supplemental Table 3). At 90 days, only the model that adjusted for age and LACE index points remained statistically significant (P = 0.02; Table 3, Supplemental Table 4).

Prolactin and readmission or death. Median prolactin was not statistically different between patients with and without the primary outcome (15.1 μg/L vs 14.1 μg/L; P = 0.24). The best cutoff level for prolactin was 23 μg/L (to convert to mIU/L, divide by 0.05; sensitivity, 27.8%; specificity, 82.9%). Prolactin was associated with a nonstatistically significant increased odds of 30-day (P = 0.16) and 90-day (P = 0.24) readmission or death (Table 3, Supplemental Tables 3 and 4).

Additive Value of Biomarkers to HOSPITAL Score and LACE Index

The AUROC for the original HOSPITAL score, 0.70 (95% CI, 0.60-0.80), nonsignificantly increased to 0.76 after adding the biomarkers (P > 0.14). For the LACE index, AUROC was 0.59 (95% CI, 0.49-0.68), with a significant 0.10 increase with cortisol (P = 0.04) and a near significant increase with copeptin (P = 0.08). Calibration remained almost unchanged after adding the biomarkers to both models (Supplemental Table 5). NRI_overall was positive for all biomarkers, with statistical significance for copeptin added to the HOSPITAL score (0.47; 95% CI, 0.13-0.79) and for cortisol added to the LACE index (0.62; 95% CI, 0.15-1.06).

In this prospective cohort study, 30-day and 90-day unplanned readmission or death was nearly 3 times as likely for patients with high copeptin levels on discharge from an acute-care medical hospitalization, and 30-day readmission or death was more than 3 times as likely for patients with high cortisol levels. High ADM and prolactin levels were not consistently associated with readmission or death. Adding such biomarkers to readmission prediction models improved their performance.

These findings support the theory of posthospital syndrome,¹ which describes a period of vulnerability with increased stress after discharge from an acute-care hospitalization, and which may be associated with adverse outcome. The hormones cortisol and copeptin are strongly related to the stress response in humans.^4,5 As copeptin level has been associated with adverse prognosis for several disorders affecting a wide range of physiologic systems,^3,5,15,27 it may be a valuable biomarker of a stressful condition, even independent of the system affected by the acute illness, and its use may be widely generalizable, in contrast to predictive factors identified in other studies.^18,28,29

Although cortisol was independently associated with 30-day readmission or death, and may be an interesting biomarker and less expensive than copeptin, its measurement is limited in patients treated with systemic corticosteroids. Compared with cortisol, copeptin does not undergo diurnal variation, is less affected by corticosteroid therapy, and mirrors stress levels better.^5,7,30,31 Our results showed that, contrary to cortisol, copeptin was also associated with longer term outcome. High ADM level was associated with readmission or death at 90 days only; lack of a significant association at 30 days might be attributable to a lack of power (fewer outcomes at 30 days). Conversely, prolactin level was consistently not associated with outcome. Prolactin may be affected by many drugs that act on the dopaminergic system (eg, domperidone), and therefore its levels may be more difficult to interpret.

Levels of biomarkers were similar to those measured in patients without previously studied conditions (eg, myocardial infarction).^{5,8,10,13,14,16,17} In most previous analyses, levels were measured during a stressful event, whereas we measured them at discharge. Therefore, these biomarkers may constitute sensitive markers of remaining stress at discharge.

Our finding that copeptin level was independently associated with readmission or death supports its relevance as a possible simple measure of the risk of adverse postdischarge outcome, independently of disease type and independently of known predictors. Stress biomarkers may therefore be valuable predictors of which patients are at high risk. All these biomarkers can be measured within 30 minutes, extending their use beyond everyday practice, except for the possible need of an extra blood draw.

The most accurate and validated models are the HOSPITAL score (AUROC range, 0.68-0.77^23,32-36) and the LACE index (AUROC range, 0.56-0.68^23,34,35,37). Adding biomarkers to these models improved overall performance (up to 0.10 increase in AUROC), which is remarkable given that, once a particular level of discriminatory power is reached, extremely large effect sizes from additional markers are needed to increase AUROC.²⁶ Incremental improvement is objectively supported by positive NRI. Our results suggest biomarkers added to prediction models may improve identification of high-risk patients.

We found that less than 50% of the primary diagnoses belonged to the same diagnosis category at readmission and at index admission. This result is in line with previous findings that readmissions were related to the primary diagnosis at index admission in only 22% to 46% of cases,^20,38 and supports our study hypothesis that readmission is related to underlying stress factors often independent of the underlying illness.¹

Study Limitations and Strengths

Our study had some limitations. First, it was a single-center study with a limited sample size. However, we found significant results within the sample. Second, we could not adjust for drugs that were acting on the dopaminergic system and might have affected prolactin levels. However, such interactions would limit the use of this biomarker in clinical practice anyway. Third, we used specific cutoffs, which might decrease analytical power, in comparison with continuous analyses. However, we followed a recognized method²⁴ and found a significant association even with categorized levels. Furthermore, the distribution of biomarkers could not be normalized by logarithmic transformation, and cutoff values have the advantage of being integrable into score point systems (eg, HOSPITAL score, LACE index). Fourth, although in 2 models we found consistent associations with several potential confounders, we could not exclude residual confounding. Fifth, this study was not powered to assess the biomarkers’ predictive value for readmission and death, which might explain the lack of significant differences between AUROC with and without the biomarkers. For all these reasons, this study should be considered hypothesis-generating.

Our study also had its strengths. First, to our knowledge, this is the first study of the association between stress biomarkers at discharge and unplanned readmission or death. Second, the quality of our data was high, with a low percentage of missing biomarker levels. Third, we excluded planned readmissions. Fourth, we used an unselected medical patient population, which had the noteworthy advantage of widening the generalizability of results.

In this prospective cohort study, high copeptin and cortisol levels at discharge were significantly associated with increased odds, ranging from 2-fold to more than 3-fold, of unplanned readmission or death within 30 days after discharge from an internal medicine ward. This finding supports the theory that a physiologic stress that patients experience during hospitalization makes them more susceptible to new health threats (posthospital syndrome). These biomarkers, copeptin in particular, may help us better identify patients at high risk of early unplanned readmission or death.

Acknowledgment

Biomarker measurement was funded by the research fund of the Department of General Internal Medicine, Fribourg Cantonal Hospital, Fribourg, Switzerland.

Disclosure

Nothing to report.

It has been theorized that the physiologic stress that hospitalized patients experience accounts for their transient vulnerability after discharge, or posthospital syndrome.¹ Their acute illness and life-habit changes during hospitalization result in continued impairment of physiologic systems after discharge, and this impairment might leave them more susceptible to new health threats.¹ However, the theory that the stress experienced after a hospitalization might be associated with readmission has never been investigated.

Four biomarkers of the hypothalamic-pituitary-adrenal (HPA) axis may help quantify posthospitalization stress: (1) midregional pro-adrenomedullin (ADM), a precursor reflecting adrenomedullin activity²; (2) copeptin (the C-terminal part of prepro-vasopressin, produced by the hypothalamus in response to stress^3,4), the level of which closely correlates to the vasopressin level but is more stable and lacks circadian rhythm fluctuations^5-7; (3) cortisol, released by the adrenal cortex in response to stress; and (4) prolactin, an indicator of HPA axis activity. These 4 stress biomarkers have been related to the severity, complications, or mortality of several diseases.^3,5,8-17 Besides explaining the hypothetical association between posthospitalization stress and readmission and death, these biomarkers might be valuable in predicting which patients are at higher risk for readmission. Indeed, many prediction models have been developed to identify those patients, but most of these models underperform, target only very specific populations, or have not been externally validated.¹⁸

We hypothesized that the hospitalization stress measured by biomarkers is associated with readmission or death after discharge. In a prospective cohort study, we evaluated the association between 4 stress biomarkers (ADM, copeptin, cortisol, prolactin) and 30-day unplanned readmissions and deaths after an acute-care medical hospitalization, and assessed their additive value to validated readmission prediction scores.

Study Design and Population

Our prospective cohort study included all consecutive patients aged ≥50 years and admitted to the department of general internal medicine at Fribourg Cantonal Hospital in Switzerland between April 8, 2013 and September 23, 2013. Exclusion criteria were discharge on day of admission; death before discharge; discharge to another division, another acute-care hospital, a rehabilitation clinic, or a palliative-care clinic; and refusal or inability to give informed consent. In this hypothesis-generating observational study, we collected data on a convenience sample of patients and did not calculate sample size before data collection. The study was approved by the local ethics committee, and all patients gave informed consent.

Outcomes

The primary outcome was the composite of first unplanned readmission (to any division of any acute-care hospital) or death within 30 days after discharge from index admission. We also included deaths that occurred after discharge, hypothesizing that patients who died may have been readmitted had they lived. The secondary outcome was the same as the primary, but the period was 90 days. Planned readmission was defined as scheduled hospitalization for nonemergent treatment (eg, chemotherapy) or investigation (eg, elective coronarography). All patients were called 6 months after discharge, and readmissions and deaths recorded. If a patient could not be reached directly, we called his or her next of kin, primary care physician, or nursing home, depending on availability. Furthermore, we checked electronic health records for any readmission or death recorded within the Fribourg hospital network, which includes all 3 acute-care hospitals (Fribourg, Riaz, Tavel) in the same canton (state).

Independent Variables

Stress biomarkers. We measured serum levels of 4 stress biomarkers (ADM, copeptin, cortisol, prolactin) at 8 am on an empty stomach on both day of admission and day of discharge. For a patient whose discharge decision was made after 8 hours for the same day, a blood sample was collected as soon as discharge was planned.

Clinical data. Collected data included demographics, history of hospitalization within 6 months before index admission, hospitalization diagnosis, and Charlson Comorbidity Index (CCI), which includes a list of medical conditions that are assigned a number of 1, 2, 3, or 6 points, according to their severity, and which has been associated with mortality.¹⁹

Causes of Admission, Unplanned Readmission, and Death

Causes of index admission, unplanned readmission, and death were obtained from medical records. We used our consensus opinion and a previous analysis²⁰ to classify these causes by body system, and added 2 categories, cancer and infection (both associated with readmission²⁰). The resulting 9 categories were (1) cancer, (2) respiratory disorder, (3) infectious disorder, (4) neurologic disorder (including dementia, psychiatric disorder, alcohol disorder, and intoxication), (5) gastrointestinal disorder, (6) osteoarticular disorder, (7) renal disorder, (8) cardiovascular disorder (including ischemic disease and heart failure), and (9) other.

Additional Performance With Existing Predictive Models

To better define the explanatory power of biomarkers to predict our outcome, we assessed the performance improvement of 2 validated readmission prediction scores by adding the stress biomarkers. As large effect sizes from additional predictors are needed to increase the power discrimination of a model, a significant performance improvement would further support the biomarkers’ important explanatory power. The 2 prediction scores tested were the LACE index (Length of stay, Admission Acuity, CCI, number of Emergency department visits within preceding 6 months²¹) and the HOSPITAL score (Hemoglobin level at discharge, discharge from Oncology service, Sodium level at discharge, any Procedure performed during index hospitalization, Index admission Type, number of Admissions within preceding 12 months, Length of stay). As we did not have an oncology service, we replaced “discharge from oncology service” with “active diagnosis of cancer.” “Length of stay” was tailored to the median in Switzerland (8 days instead of 5 days; Supplement Table 1).^22,23

Data Analysis

Continuous variables were presented as medians with interquartile ranges (IQRs) because of their non-normal distribution, and categorical variables were presented as frequencies and percentages. We compared medians using the nonparametric K-sample test on the equality of medians, and compared frequencies using the Pearson χ² test. The discriminatory power of each biomarker in predicting readmission and death was calculated with the area under the receiver operating characteristic (ROC) curve (AUROC), using serum levels at discharge to better reflect the postdischarge period. Cutoff levels were selected by taking the best compromise between sensitivity and specificity according to the ROC curves (point nearest top left corner).²⁴

Univariate logistic regression analysis was used to test the prediction of 30-day and 90-day unplanned readmission or death by each biomarker. We built 2 different multivariate models: one adjusting for age and LACE index points²¹ and the other adjusting for age and HOSPITAL score.^22,23

To explore any association between reduction of stress during hospitalization and postdischarge outcome, we additionally calculated for each biomarker the difference between admission and discharge serum levels and assessed its association with readmission or death by logistic regression analysis. Because of the modification of cortisol serum levels during corticosteroid therapy, we excluded patients who underwent systemic corticosteroid therapy before or during hospitalization for the cortisol analysis (n = 105/346). Patients with a missing biomarker level were excluded from the respective analyses: discharge (ADM, 28 patients; copeptin, 27; cortisol, 24; prolactin, 24) and admission (ADM, 12 patients; copeptin, 15; cortisol, 8; prolactin, 8).

To assess an additional value of the biomarkers to prediction scores, we assessed the accuracy of the HOSPITAL score and LACE index in their original versions^21,22 and after adding each biomarker. We used AUROC to assess the discriminatory power and used the method of DeLong et al.²⁵ to compare results with and without adding each biomarker. Calibration was evaluated by comparing Hosmer-Lemeshow goodness-of-fit tests (P > 0.05 indicates good fit). Risk reclassification was assessed by Net Reclassification Improvement (NRI),²⁶ quantifying how appropriately a new model reclassifies patients, compared with an old model. Basically, patients without outcome are assigned +1 if correctly reclassified to a lower risk category or –1 if incorrectly reclassified to a higher risk category. NRI_nonevent is the sum of all points/numbers of patients. Conversely, patients with outcome are assigned +1 if correctly reclassified to a higher risk category or –1 if incorrectly reclassified to a lower risk category. NRI_event is the sum of all points/numbers of patients. NRI_overall is the sum of NRI_event and NRI_nonevent ranging from –2 to 2, with a positive value indicating better classification with the new model.

Two-sided P < 0.05 was used for statistical significance. All statistical analyses were performed with Stata Release 13.0 (StataCorp).

Among the 530 patients admitted to the ward, 184 were excluded (120 meeting exclusion criteria, 64 unable to give consent, Figure). Among the 346 patients included, 11.6% (n = 40) had a 30-day unplanned readmission or death (37 were readmitted, 2 died during readmission, 3 died without readmission). Within 90 days, 26.6% (n = 92) had a readmission or death (84 were readmitted, 10 died during or after readmission, 8 died without readmission).

Clinical Characteristics

Table 1 lists the patients’ baseline characteristics. Median age was 73 years (IQR, 64-82 years). Of the 346 patients included, 172 (49.7%) were men. Median CCI was 7 (IQR, 5-9); according to this index, 310 patients (89.6%) had at least 2 comorbidities. Median length of stay was 7 days (IQR, 4-12 days).

Primary Diagnoses of Admission, Unplanned Readmission, and Death

The 3 main causes of index admission were cardiovascular disorder (n = 92), infectious disorder (n = 70), and neurologic disorder (n = 66). Table 2 lists the causes of readmissions and deaths. A same-diagnosis category between index admission and readmission was found in 17 (45.9%) of the 37 readmitted patients and in 3 (60%) of the 5 patients who died.

Biomarkers and 30-Day Unplanned Readmission or Death

AUROC was 0.53 (95% confidence interval [CI], 0.43-0.63) for ADM, 0.60 (95% CI, 0.50-0.70) for copeptin, 0.59 (95% CI, 0.44-0.73) for cortisol, and 0.56 (95% CI, 0.45-0.66) for prolactin. The difference between admission and discharge levels was not associated with unplanned readmission or death for any of the biomarkers (Supplemental Table 2).

ADM and readmission or death. Median ADM level was not different between patients with and without readmission or death (1.0 nmol/L in each case; P = 1.00). The best cutoff level for ADM was 2 nmol/L (sensitivity, 16.7%; specificity, 91.8%). At this level, ADM was associated with a nonstatistically significant 130% increased odds of 30-day readmission or death (P = 0.09; Table 3, Supplemental Table 3). Conversely, the association with the 90-day outcome was significant (P = 0.02; Table 3, Supplemental Table 4).

Copeptin and readmission or death. Patients with 30-day readmission or death had a higher median copeptin level at discharge than patients without (10.4 pmol/L vs 7.3 pmol/L; P = 0.03). At a copeptin level higher than 9 pmol/L (to convert to pg/mL, divide by 0.249; sensitivity, 66.7%; specificity, 59.7%), both 30-day readmission or death (adjusted odds ratio [OR], 2.69; 95% CI, 1.29-5.64; P = 0.009) and 90-day readmission or death (adjusted OR, 2.76; 95% CI, 1.56-4.88; P < 0.001) were nearly 3 times as likely (Table 3, Supplemental Tables 3 and 4).

Cortisol and readmission or death. Median cortisol was not statistically different between patients with and without the primary outcome (431 nmol/L vs 465 nmol/L; P = 0.72). At a cortisol level higher than 590 nmol/L (to convert to μg/dL, divide by 27.59; sensitivity, 54.6%; specificity, 76.4%), 30-day outcome was more than 3 times as likely (adjusted OR, 3.43; 95% CI, 1.36-8.65; P = 0.009; Table 3, Supplemental Table 3). At 90 days, only the model that adjusted for age and LACE index points remained statistically significant (P = 0.02; Table 3, Supplemental Table 4).

Prolactin and readmission or death. Median prolactin was not statistically different between patients with and without the primary outcome (15.1 μg/L vs 14.1 μg/L; P = 0.24). The best cutoff level for prolactin was 23 μg/L (to convert to mIU/L, divide by 0.05; sensitivity, 27.8%; specificity, 82.9%). Prolactin was associated with a nonstatistically significant increased odds of 30-day (P = 0.16) and 90-day (P = 0.24) readmission or death (Table 3, Supplemental Tables 3 and 4).

Additive Value of Biomarkers to HOSPITAL Score and LACE Index

The AUROC for the original HOSPITAL score, 0.70 (95% CI, 0.60-0.80), nonsignificantly increased to 0.76 after adding the biomarkers (P > 0.14). For the LACE index, AUROC was 0.59 (95% CI, 0.49-0.68), with a significant 0.10 increase with cortisol (P = 0.04) and a near significant increase with copeptin (P = 0.08). Calibration remained almost unchanged after adding the biomarkers to both models (Supplemental Table 5). NRI_overall was positive for all biomarkers, with statistical significance for copeptin added to the HOSPITAL score (0.47; 95% CI, 0.13-0.79) and for cortisol added to the LACE index (0.62; 95% CI, 0.15-1.06).

In this prospective cohort study, 30-day and 90-day unplanned readmission or death was nearly 3 times as likely for patients with high copeptin levels on discharge from an acute-care medical hospitalization, and 30-day readmission or death was more than 3 times as likely for patients with high cortisol levels. High ADM and prolactin levels were not consistently associated with readmission or death. Adding such biomarkers to readmission prediction models improved their performance.

These findings support the theory of posthospital syndrome,¹ which describes a period of vulnerability with increased stress after discharge from an acute-care hospitalization, and which may be associated with adverse outcome. The hormones cortisol and copeptin are strongly related to the stress response in humans.^4,5 As copeptin level has been associated with adverse prognosis for several disorders affecting a wide range of physiologic systems,^3,5,15,27 it may be a valuable biomarker of a stressful condition, even independent of the system affected by the acute illness, and its use may be widely generalizable, in contrast to predictive factors identified in other studies.^18,28,29

Although cortisol was independently associated with 30-day readmission or death, and may be an interesting biomarker and less expensive than copeptin, its measurement is limited in patients treated with systemic corticosteroids. Compared with cortisol, copeptin does not undergo diurnal variation, is less affected by corticosteroid therapy, and mirrors stress levels better.^5,7,30,31 Our results showed that, contrary to cortisol, copeptin was also associated with longer term outcome. High ADM level was associated with readmission or death at 90 days only; lack of a significant association at 30 days might be attributable to a lack of power (fewer outcomes at 30 days). Conversely, prolactin level was consistently not associated with outcome. Prolactin may be affected by many drugs that act on the dopaminergic system (eg, domperidone), and therefore its levels may be more difficult to interpret.

Levels of biomarkers were similar to those measured in patients without previously studied conditions (eg, myocardial infarction).^{5,8,10,13,14,16,17} In most previous analyses, levels were measured during a stressful event, whereas we measured them at discharge. Therefore, these biomarkers may constitute sensitive markers of remaining stress at discharge.

Our finding that copeptin level was independently associated with readmission or death supports its relevance as a possible simple measure of the risk of adverse postdischarge outcome, independently of disease type and independently of known predictors. Stress biomarkers may therefore be valuable predictors of which patients are at high risk. All these biomarkers can be measured within 30 minutes, extending their use beyond everyday practice, except for the possible need of an extra blood draw.

The most accurate and validated models are the HOSPITAL score (AUROC range, 0.68-0.77^23,32-36) and the LACE index (AUROC range, 0.56-0.68^23,34,35,37). Adding biomarkers to these models improved overall performance (up to 0.10 increase in AUROC), which is remarkable given that, once a particular level of discriminatory power is reached, extremely large effect sizes from additional markers are needed to increase AUROC.²⁶ Incremental improvement is objectively supported by positive NRI. Our results suggest biomarkers added to prediction models may improve identification of high-risk patients.

We found that less than 50% of the primary diagnoses belonged to the same diagnosis category at readmission and at index admission. This result is in line with previous findings that readmissions were related to the primary diagnosis at index admission in only 22% to 46% of cases,^20,38 and supports our study hypothesis that readmission is related to underlying stress factors often independent of the underlying illness.¹

Study Limitations and Strengths

Our study had some limitations. First, it was a single-center study with a limited sample size. However, we found significant results within the sample. Second, we could not adjust for drugs that were acting on the dopaminergic system and might have affected prolactin levels. However, such interactions would limit the use of this biomarker in clinical practice anyway. Third, we used specific cutoffs, which might decrease analytical power, in comparison with continuous analyses. However, we followed a recognized method²⁴ and found a significant association even with categorized levels. Furthermore, the distribution of biomarkers could not be normalized by logarithmic transformation, and cutoff values have the advantage of being integrable into score point systems (eg, HOSPITAL score, LACE index). Fourth, although in 2 models we found consistent associations with several potential confounders, we could not exclude residual confounding. Fifth, this study was not powered to assess the biomarkers’ predictive value for readmission and death, which might explain the lack of significant differences between AUROC with and without the biomarkers. For all these reasons, this study should be considered hypothesis-generating.

Our study also had its strengths. First, to our knowledge, this is the first study of the association between stress biomarkers at discharge and unplanned readmission or death. Second, the quality of our data was high, with a low percentage of missing biomarker levels. Third, we excluded planned readmissions. Fourth, we used an unselected medical patient population, which had the noteworthy advantage of widening the generalizability of results.

In this prospective cohort study, high copeptin and cortisol levels at discharge were significantly associated with increased odds, ranging from 2-fold to more than 3-fold, of unplanned readmission or death within 30 days after discharge from an internal medicine ward. This finding supports the theory that a physiologic stress that patients experience during hospitalization makes them more susceptible to new health threats (posthospital syndrome). These biomarkers, copeptin in particular, may help us better identify patients at high risk of early unplanned readmission or death.

Acknowledgment

Biomarker measurement was funded by the research fund of the Department of General Internal Medicine, Fribourg Cantonal Hospital, Fribourg, Switzerland.

Disclosure

Nothing to report.

It has been theorized that the physiologic stress that hospitalized patients experience accounts for their transient vulnerability after discharge, or posthospital syndrome.¹ Their acute illness and life-habit changes during hospitalization result in continued impairment of physiologic systems after discharge, and this impairment might leave them more susceptible to new health threats.¹ However, the theory that the stress experienced after a hospitalization might be associated with readmission has never been investigated.

Four biomarkers of the hypothalamic-pituitary-adrenal (HPA) axis may help quantify posthospitalization stress: (1) midregional pro-adrenomedullin (ADM), a precursor reflecting adrenomedullin activity²; (2) copeptin (the C-terminal part of prepro-vasopressin, produced by the hypothalamus in response to stress^3,4), the level of which closely correlates to the vasopressin level but is more stable and lacks circadian rhythm fluctuations^5-7; (3) cortisol, released by the adrenal cortex in response to stress; and (4) prolactin, an indicator of HPA axis activity. These 4 stress biomarkers have been related to the severity, complications, or mortality of several diseases.^3,5,8-17 Besides explaining the hypothetical association between posthospitalization stress and readmission and death, these biomarkers might be valuable in predicting which patients are at higher risk for readmission. Indeed, many prediction models have been developed to identify those patients, but most of these models underperform, target only very specific populations, or have not been externally validated.¹⁸

We hypothesized that the hospitalization stress measured by biomarkers is associated with readmission or death after discharge. In a prospective cohort study, we evaluated the association between 4 stress biomarkers (ADM, copeptin, cortisol, prolactin) and 30-day unplanned readmissions and deaths after an acute-care medical hospitalization, and assessed their additive value to validated readmission prediction scores.

Study Design and Population

Our prospective cohort study included all consecutive patients aged ≥50 years and admitted to the department of general internal medicine at Fribourg Cantonal Hospital in Switzerland between April 8, 2013 and September 23, 2013. Exclusion criteria were discharge on day of admission; death before discharge; discharge to another division, another acute-care hospital, a rehabilitation clinic, or a palliative-care clinic; and refusal or inability to give informed consent. In this hypothesis-generating observational study, we collected data on a convenience sample of patients and did not calculate sample size before data collection. The study was approved by the local ethics committee, and all patients gave informed consent.

Outcomes

The primary outcome was the composite of first unplanned readmission (to any division of any acute-care hospital) or death within 30 days after discharge from index admission. We also included deaths that occurred after discharge, hypothesizing that patients who died may have been readmitted had they lived. The secondary outcome was the same as the primary, but the period was 90 days. Planned readmission was defined as scheduled hospitalization for nonemergent treatment (eg, chemotherapy) or investigation (eg, elective coronarography). All patients were called 6 months after discharge, and readmissions and deaths recorded. If a patient could not be reached directly, we called his or her next of kin, primary care physician, or nursing home, depending on availability. Furthermore, we checked electronic health records for any readmission or death recorded within the Fribourg hospital network, which includes all 3 acute-care hospitals (Fribourg, Riaz, Tavel) in the same canton (state).

Independent Variables

Stress biomarkers. We measured serum levels of 4 stress biomarkers (ADM, copeptin, cortisol, prolactin) at 8 am on an empty stomach on both day of admission and day of discharge. For a patient whose discharge decision was made after 8 hours for the same day, a blood sample was collected as soon as discharge was planned.

Clinical data. Collected data included demographics, history of hospitalization within 6 months before index admission, hospitalization diagnosis, and Charlson Comorbidity Index (CCI), which includes a list of medical conditions that are assigned a number of 1, 2, 3, or 6 points, according to their severity, and which has been associated with mortality.¹⁹

Causes of Admission, Unplanned Readmission, and Death

Causes of index admission, unplanned readmission, and death were obtained from medical records. We used our consensus opinion and a previous analysis²⁰ to classify these causes by body system, and added 2 categories, cancer and infection (both associated with readmission²⁰). The resulting 9 categories were (1) cancer, (2) respiratory disorder, (3) infectious disorder, (4) neurologic disorder (including dementia, psychiatric disorder, alcohol disorder, and intoxication), (5) gastrointestinal disorder, (6) osteoarticular disorder, (7) renal disorder, (8) cardiovascular disorder (including ischemic disease and heart failure), and (9) other.

Additional Performance With Existing Predictive Models

To better define the explanatory power of biomarkers to predict our outcome, we assessed the performance improvement of 2 validated readmission prediction scores by adding the stress biomarkers. As large effect sizes from additional predictors are needed to increase the power discrimination of a model, a significant performance improvement would further support the biomarkers’ important explanatory power. The 2 prediction scores tested were the LACE index (Length of stay, Admission Acuity, CCI, number of Emergency department visits within preceding 6 months²¹) and the HOSPITAL score (Hemoglobin level at discharge, discharge from Oncology service, Sodium level at discharge, any Procedure performed during index hospitalization, Index admission Type, number of Admissions within preceding 12 months, Length of stay). As we did not have an oncology service, we replaced “discharge from oncology service” with “active diagnosis of cancer.” “Length of stay” was tailored to the median in Switzerland (8 days instead of 5 days; Supplement Table 1).^22,23

Data Analysis

Continuous variables were presented as medians with interquartile ranges (IQRs) because of their non-normal distribution, and categorical variables were presented as frequencies and percentages. We compared medians using the nonparametric K-sample test on the equality of medians, and compared frequencies using the Pearson χ² test. The discriminatory power of each biomarker in predicting readmission and death was calculated with the area under the receiver operating characteristic (ROC) curve (AUROC), using serum levels at discharge to better reflect the postdischarge period. Cutoff levels were selected by taking the best compromise between sensitivity and specificity according to the ROC curves (point nearest top left corner).²⁴

Univariate logistic regression analysis was used to test the prediction of 30-day and 90-day unplanned readmission or death by each biomarker. We built 2 different multivariate models: one adjusting for age and LACE index points²¹ and the other adjusting for age and HOSPITAL score.^22,23

To explore any association between reduction of stress during hospitalization and postdischarge outcome, we additionally calculated for each biomarker the difference between admission and discharge serum levels and assessed its association with readmission or death by logistic regression analysis. Because of the modification of cortisol serum levels during corticosteroid therapy, we excluded patients who underwent systemic corticosteroid therapy before or during hospitalization for the cortisol analysis (n = 105/346). Patients with a missing biomarker level were excluded from the respective analyses: discharge (ADM, 28 patients; copeptin, 27; cortisol, 24; prolactin, 24) and admission (ADM, 12 patients; copeptin, 15; cortisol, 8; prolactin, 8).

To assess an additional value of the biomarkers to prediction scores, we assessed the accuracy of the HOSPITAL score and LACE index in their original versions^21,22 and after adding each biomarker. We used AUROC to assess the discriminatory power and used the method of DeLong et al.²⁵ to compare results with and without adding each biomarker. Calibration was evaluated by comparing Hosmer-Lemeshow goodness-of-fit tests (P > 0.05 indicates good fit). Risk reclassification was assessed by Net Reclassification Improvement (NRI),²⁶ quantifying how appropriately a new model reclassifies patients, compared with an old model. Basically, patients without outcome are assigned +1 if correctly reclassified to a lower risk category or –1 if incorrectly reclassified to a higher risk category. NRI_nonevent is the sum of all points/numbers of patients. Conversely, patients with outcome are assigned +1 if correctly reclassified to a higher risk category or –1 if incorrectly reclassified to a lower risk category. NRI_event is the sum of all points/numbers of patients. NRI_overall is the sum of NRI_event and NRI_nonevent ranging from –2 to 2, with a positive value indicating better classification with the new model.

Two-sided P < 0.05 was used for statistical significance. All statistical analyses were performed with Stata Release 13.0 (StataCorp).

Among the 530 patients admitted to the ward, 184 were excluded (120 meeting exclusion criteria, 64 unable to give consent, Figure). Among the 346 patients included, 11.6% (n = 40) had a 30-day unplanned readmission or death (37 were readmitted, 2 died during readmission, 3 died without readmission). Within 90 days, 26.6% (n = 92) had a readmission or death (84 were readmitted, 10 died during or after readmission, 8 died without readmission).

Clinical Characteristics

Table 1 lists the patients’ baseline characteristics. Median age was 73 years (IQR, 64-82 years). Of the 346 patients included, 172 (49.7%) were men. Median CCI was 7 (IQR, 5-9); according to this index, 310 patients (89.6%) had at least 2 comorbidities. Median length of stay was 7 days (IQR, 4-12 days).

Primary Diagnoses of Admission, Unplanned Readmission, and Death

The 3 main causes of index admission were cardiovascular disorder (n = 92), infectious disorder (n = 70), and neurologic disorder (n = 66). Table 2 lists the causes of readmissions and deaths. A same-diagnosis category between index admission and readmission was found in 17 (45.9%) of the 37 readmitted patients and in 3 (60%) of the 5 patients who died.

Biomarkers and 30-Day Unplanned Readmission or Death

AUROC was 0.53 (95% confidence interval [CI], 0.43-0.63) for ADM, 0.60 (95% CI, 0.50-0.70) for copeptin, 0.59 (95% CI, 0.44-0.73) for cortisol, and 0.56 (95% CI, 0.45-0.66) for prolactin. The difference between admission and discharge levels was not associated with unplanned readmission or death for any of the biomarkers (Supplemental Table 2).

ADM and readmission or death. Median ADM level was not different between patients with and without readmission or death (1.0 nmol/L in each case; P = 1.00). The best cutoff level for ADM was 2 nmol/L (sensitivity, 16.7%; specificity, 91.8%). At this level, ADM was associated with a nonstatistically significant 130% increased odds of 30-day readmission or death (P = 0.09; Table 3, Supplemental Table 3). Conversely, the association with the 90-day outcome was significant (P = 0.02; Table 3, Supplemental Table 4).

Copeptin and readmission or death. Patients with 30-day readmission or death had a higher median copeptin level at discharge than patients without (10.4 pmol/L vs 7.3 pmol/L; P = 0.03). At a copeptin level higher than 9 pmol/L (to convert to pg/mL, divide by 0.249; sensitivity, 66.7%; specificity, 59.7%), both 30-day readmission or death (adjusted odds ratio [OR], 2.69; 95% CI, 1.29-5.64; P = 0.009) and 90-day readmission or death (adjusted OR, 2.76; 95% CI, 1.56-4.88; P < 0.001) were nearly 3 times as likely (Table 3, Supplemental Tables 3 and 4).

Cortisol and readmission or death. Median cortisol was not statistically different between patients with and without the primary outcome (431 nmol/L vs 465 nmol/L; P = 0.72). At a cortisol level higher than 590 nmol/L (to convert to μg/dL, divide by 27.59; sensitivity, 54.6%; specificity, 76.4%), 30-day outcome was more than 3 times as likely (adjusted OR, 3.43; 95% CI, 1.36-8.65; P = 0.009; Table 3, Supplemental Table 3). At 90 days, only the model that adjusted for age and LACE index points remained statistically significant (P = 0.02; Table 3, Supplemental Table 4).

Prolactin and readmission or death. Median prolactin was not statistically different between patients with and without the primary outcome (15.1 μg/L vs 14.1 μg/L; P = 0.24). The best cutoff level for prolactin was 23 μg/L (to convert to mIU/L, divide by 0.05; sensitivity, 27.8%; specificity, 82.9%). Prolactin was associated with a nonstatistically significant increased odds of 30-day (P = 0.16) and 90-day (P = 0.24) readmission or death (Table 3, Supplemental Tables 3 and 4).

Additive Value of Biomarkers to HOSPITAL Score and LACE Index

The AUROC for the original HOSPITAL score, 0.70 (95% CI, 0.60-0.80), nonsignificantly increased to 0.76 after adding the biomarkers (P > 0.14). For the LACE index, AUROC was 0.59 (95% CI, 0.49-0.68), with a significant 0.10 increase with cortisol (P = 0.04) and a near significant increase with copeptin (P = 0.08). Calibration remained almost unchanged after adding the biomarkers to both models (Supplemental Table 5). NRI_overall was positive for all biomarkers, with statistical significance for copeptin added to the HOSPITAL score (0.47; 95% CI, 0.13-0.79) and for cortisol added to the LACE index (0.62; 95% CI, 0.15-1.06).

In this prospective cohort study, 30-day and 90-day unplanned readmission or death was nearly 3 times as likely for patients with high copeptin levels on discharge from an acute-care medical hospitalization, and 30-day readmission or death was more than 3 times as likely for patients with high cortisol levels. High ADM and prolactin levels were not consistently associated with readmission or death. Adding such biomarkers to readmission prediction models improved their performance.

These findings support the theory of posthospital syndrome,¹ which describes a period of vulnerability with increased stress after discharge from an acute-care hospitalization, and which may be associated with adverse outcome. The hormones cortisol and copeptin are strongly related to the stress response in humans.^4,5 As copeptin level has been associated with adverse prognosis for several disorders affecting a wide range of physiologic systems,^3,5,15,27 it may be a valuable biomarker of a stressful condition, even independent of the system affected by the acute illness, and its use may be widely generalizable, in contrast to predictive factors identified in other studies.^18,28,29

Although cortisol was independently associated with 30-day readmission or death, and may be an interesting biomarker and less expensive than copeptin, its measurement is limited in patients treated with systemic corticosteroids. Compared with cortisol, copeptin does not undergo diurnal variation, is less affected by corticosteroid therapy, and mirrors stress levels better.^5,7,30,31 Our results showed that, contrary to cortisol, copeptin was also associated with longer term outcome. High ADM level was associated with readmission or death at 90 days only; lack of a significant association at 30 days might be attributable to a lack of power (fewer outcomes at 30 days). Conversely, prolactin level was consistently not associated with outcome. Prolactin may be affected by many drugs that act on the dopaminergic system (eg, domperidone), and therefore its levels may be more difficult to interpret.

Levels of biomarkers were similar to those measured in patients without previously studied conditions (eg, myocardial infarction).^{5,8,10,13,14,16,17} In most previous analyses, levels were measured during a stressful event, whereas we measured them at discharge. Therefore, these biomarkers may constitute sensitive markers of remaining stress at discharge.

Our finding that copeptin level was independently associated with readmission or death supports its relevance as a possible simple measure of the risk of adverse postdischarge outcome, independently of disease type and independently of known predictors. Stress biomarkers may therefore be valuable predictors of which patients are at high risk. All these biomarkers can be measured within 30 minutes, extending their use beyond everyday practice, except for the possible need of an extra blood draw.

The most accurate and validated models are the HOSPITAL score (AUROC range, 0.68-0.77^23,32-36) and the LACE index (AUROC range, 0.56-0.68^23,34,35,37). Adding biomarkers to these models improved overall performance (up to 0.10 increase in AUROC), which is remarkable given that, once a particular level of discriminatory power is reached, extremely large effect sizes from additional markers are needed to increase AUROC.²⁶ Incremental improvement is objectively supported by positive NRI. Our results suggest biomarkers added to prediction models may improve identification of high-risk patients.

We found that less than 50% of the primary diagnoses belonged to the same diagnosis category at readmission and at index admission. This result is in line with previous findings that readmissions were related to the primary diagnosis at index admission in only 22% to 46% of cases,^20,38 and supports our study hypothesis that readmission is related to underlying stress factors often independent of the underlying illness.¹

Study Limitations and Strengths

Our study had some limitations. First, it was a single-center study with a limited sample size. However, we found significant results within the sample. Second, we could not adjust for drugs that were acting on the dopaminergic system and might have affected prolactin levels. However, such interactions would limit the use of this biomarker in clinical practice anyway. Third, we used specific cutoffs, which might decrease analytical power, in comparison with continuous analyses. However, we followed a recognized method²⁴ and found a significant association even with categorized levels. Furthermore, the distribution of biomarkers could not be normalized by logarithmic transformation, and cutoff values have the advantage of being integrable into score point systems (eg, HOSPITAL score, LACE index). Fourth, although in 2 models we found consistent associations with several potential confounders, we could not exclude residual confounding. Fifth, this study was not powered to assess the biomarkers’ predictive value for readmission and death, which might explain the lack of significant differences between AUROC with and without the biomarkers. For all these reasons, this study should be considered hypothesis-generating.

Our study also had its strengths. First, to our knowledge, this is the first study of the association between stress biomarkers at discharge and unplanned readmission or death. Second, the quality of our data was high, with a low percentage of missing biomarker levels. Third, we excluded planned readmissions. Fourth, we used an unselected medical patient population, which had the noteworthy advantage of widening the generalizability of results.

In this prospective cohort study, high copeptin and cortisol levels at discharge were significantly associated with increased odds, ranging from 2-fold to more than 3-fold, of unplanned readmission or death within 30 days after discharge from an internal medicine ward. This finding supports the theory that a physiologic stress that patients experience during hospitalization makes them more susceptible to new health threats (posthospital syndrome). These biomarkers, copeptin in particular, may help us better identify patients at high risk of early unplanned readmission or death.

Acknowledgment

Biomarker measurement was funded by the research fund of the Department of General Internal Medicine, Fribourg Cantonal Hospital, Fribourg, Switzerland.

Disclosure

Nothing to report.