We psychiatrists encounter a wide variety of intense negative emotions in our patients on a daily basis, whether in the clinic or on an inpatient unit. These include rage, irritability, hostility, paranoia, loathing, and unadulterated hatred.

We evaluate, diagnose, and treat the underlying psychiatric brain disorders that generate such maladaptive emotions, and have our patients regain their baseline functioning by resolving the psychopathology that ignited their amygdala and their limbic circuitry.

But while we can manage the microcosm of one patient’s mental state, we are unable to intervene in the macrocosm of an entire society ravaged by extreme hyper-partisanship and naked bidirectional hatred. It is literally impossible for even the most skillful psychiatrists to repair a nation caught up in poisonous emotional turmoil, irreconcilable political differences, and a veritable war of belief systems that mimic religious fanaticism, which history tells us led to so many tragic wars over the centuries and millennia.

Ideally, politics is supposed to be an elegant cerebral process, a debate of ideas across disparate ideologies, the product of which is expected to be the advancement of the welfare of the nation and its citizens. But what we are currently witnessing is a distressing degeneration of politics into personal hatred and ad hominem attacks, with partisans frothing at the mouth as they describe the utter stupidity and dangerousness of their despised political opponents-cum-bitter enemies. They even declare each other “mentally ill,” which is an absurd explanation of why other people do not agree with their belief system. Neither side can find an iota of redeeming value in the political views of the “other side” and hurl insults and epithets verbally and in writing via dueling books that become instant best sellers among the partisan aficionados on both sides.

This disastrous political “climate change” may have ominous repercussions for the brains of the political combatants themselves, and even for those on the sidelines who are subjected to the relentless stress of witnessing a social train wreck in the making. As a neuropsychiatrist, I wonder if the collective national amygdala of the country is on fire, and the national prefrontal cortex is being corroded by the pervasive and ugly negativity that engulfs us all, with social media that incites its users night and day, adding gasoline to the fire. Chronic stress and its associated hypercortisolemia are known to be neurotoxic to the hippocampus and eventuate in clinical depression and its grave consequences.

Continued to: I think I sensed this odious scenario coming...

Henry A. Nasrallah, MD
Editor-in-Chief

We psychiatrists encounter a wide variety of intense negative emotions in our patients on a daily basis, whether in the clinic or on an inpatient unit. These include rage, irritability, hostility, paranoia, loathing, and unadulterated hatred.

We evaluate, diagnose, and treat the underlying psychiatric brain disorders that generate such maladaptive emotions, and have our patients regain their baseline functioning by resolving the psychopathology that ignited their amygdala and their limbic circuitry.

But while we can manage the microcosm of one patient’s mental state, we are unable to intervene in the macrocosm of an entire society ravaged by extreme hyper-partisanship and naked bidirectional hatred. It is literally impossible for even the most skillful psychiatrists to repair a nation caught up in poisonous emotional turmoil, irreconcilable political differences, and a veritable war of belief systems that mimic religious fanaticism, which history tells us led to so many tragic wars over the centuries and millennia.

Ideally, politics is supposed to be an elegant cerebral process, a debate of ideas across disparate ideologies, the product of which is expected to be the advancement of the welfare of the nation and its citizens. But what we are currently witnessing is a distressing degeneration of politics into personal hatred and ad hominem attacks, with partisans frothing at the mouth as they describe the utter stupidity and dangerousness of their despised political opponents-cum-bitter enemies. They even declare each other “mentally ill,” which is an absurd explanation of why other people do not agree with their belief system. Neither side can find an iota of redeeming value in the political views of the “other side” and hurl insults and epithets verbally and in writing via dueling books that become instant best sellers among the partisan aficionados on both sides.

This disastrous political “climate change” may have ominous repercussions for the brains of the political combatants themselves, and even for those on the sidelines who are subjected to the relentless stress of witnessing a social train wreck in the making. As a neuropsychiatrist, I wonder if the collective national amygdala of the country is on fire, and the national prefrontal cortex is being corroded by the pervasive and ugly negativity that engulfs us all, with social media that incites its users night and day, adding gasoline to the fire. Chronic stress and its associated hypercortisolemia are known to be neurotoxic to the hippocampus and eventuate in clinical depression and its grave consequences.

Continued to: I think I sensed this odious scenario coming...

Henry A. Nasrallah, MD
Editor-in-Chief

We psychiatrists encounter a wide variety of intense negative emotions in our patients on a daily basis, whether in the clinic or on an inpatient unit. These include rage, irritability, hostility, paranoia, loathing, and unadulterated hatred.

We evaluate, diagnose, and treat the underlying psychiatric brain disorders that generate such maladaptive emotions, and have our patients regain their baseline functioning by resolving the psychopathology that ignited their amygdala and their limbic circuitry.

But while we can manage the microcosm of one patient’s mental state, we are unable to intervene in the macrocosm of an entire society ravaged by extreme hyper-partisanship and naked bidirectional hatred. It is literally impossible for even the most skillful psychiatrists to repair a nation caught up in poisonous emotional turmoil, irreconcilable political differences, and a veritable war of belief systems that mimic religious fanaticism, which history tells us led to so many tragic wars over the centuries and millennia.

Ideally, politics is supposed to be an elegant cerebral process, a debate of ideas across disparate ideologies, the product of which is expected to be the advancement of the welfare of the nation and its citizens. But what we are currently witnessing is a distressing degeneration of politics into personal hatred and ad hominem attacks, with partisans frothing at the mouth as they describe the utter stupidity and dangerousness of their despised political opponents-cum-bitter enemies. They even declare each other “mentally ill,” which is an absurd explanation of why other people do not agree with their belief system. Neither side can find an iota of redeeming value in the political views of the “other side” and hurl insults and epithets verbally and in writing via dueling books that become instant best sellers among the partisan aficionados on both sides.

This disastrous political “climate change” may have ominous repercussions for the brains of the political combatants themselves, and even for those on the sidelines who are subjected to the relentless stress of witnessing a social train wreck in the making. As a neuropsychiatrist, I wonder if the collective national amygdala of the country is on fire, and the national prefrontal cortex is being corroded by the pervasive and ugly negativity that engulfs us all, with social media that incites its users night and day, adding gasoline to the fire. Chronic stress and its associated hypercortisolemia are known to be neurotoxic to the hippocampus and eventuate in clinical depression and its grave consequences.

Continued to: I think I sensed this odious scenario coming...

Henry A. Nasrallah, MD
Editor-in-Chief

I read with great interest Dr. Nasrallah’s editorial, “FAST and RAPID: Acronyms to prevent brain damage in stroke and psychosis” (From the Editor, Current Psychiatry, August 2018, p. 6-8). It makes me wonder about the ethics of allowing patients with active psychosis to participate in placebo-controlled studies. If a patient’s brain undergoes damage while psychotic, allowing the psychosis to continue without active treatment sounds possibly at odds with a physician’s oath. If a patient is in the placebo arm, then they are not receiving treatment for their psychotic symptoms. I wonder about his opinion on this.

Mitchell L. Glaser, MD
Board-Certified Child/Adolescent and General Psychiatrist
Assistant Professor of Psychiatry
Rush University Medical Center
Chairman
Department of Psychiatry
Medical Director of Child/Adolescent Psychiatry
St. Mary/Elizabeth Medical Center 
Clinical Assistant Professor of Psychiatry 
Rosalind Franklin University
Chicago, Illinois

Thank you, Dr. Nasrallah, for your incisive thinking and for bringing our attention as psychiatrists to the crucial issues of our clinical practice. I’d like to offer some nuance on the RAPID acronym. First, I’d like to counterpropose DASH: Delusions, Auditory hallucinations, Strange behavior, Hospital now. This is more in line with getting physicians to tune in to the symptoms that should alarm them and bring them to action. I agree that neurodegeneration and illness recurrence are the problems to address. One unsettled issue remains: With early intervention, can we eventually taper patients off antipsychotics to spare them the metabolic and immune morbidity associated with these medications? There is some evidence that this is possible, but it is difficult to collect data. One of the factors delaying treatment, other than lack of recognition, is the general public’s belief that the treatment is sometimes worse than the disease. If we can address this issue in a nuanced fashion, we may get more “early adopters” of these neuron-sparing treatments.

Michael S. Diamond, MD
Private psychiatric practice
Chevy Chase, Maryland

Dr. Nasrallah is right to focus on brain injury patterns, including inflammation and de-myelination, during psychotic episodes. He and Dr. Roque note that starting a patient on a long-acting injectable antipsychotic as soon as possible may prevent subsequent relapse and further brain damage. However, their editorial omits 2 treatments—minocycline and clemastine—that can help stop CNS inflammation, reduce brain damage, and promote remyelination.

Minocycline has been shown to reduce stroke infarct penumbra size and improve outcomes in functional recovery from stroke.^1,2 Minocycline’s effects as a potent CNS anti-inflammatory and antiapoptotic agent are well established.

Clemastine has been shown to improve function in multiple sclerosis by activating oligodendrocyte precursor cells into active agents of myelination and fiber bundle stabilization.³ Clemastine reverses acute leukoencephalopathy.⁴

If we are to treat acute psychosis as a neurologic emergency, we cannot rely on long-acting injectable antipsychotics as the sole treatment. Psychiatric medication alone is not sufficient across every neuropsychiatric condition in which inflammation and white matter damage are part of the etiology, destruction, and pattern of relapse.

The adverse effects risk of adjunctive minocycline and clemastine is low compared with the potential benefits of stopping inflammation, reducing apoptosis, and jump-starting white matter repair. Doses of oral minocycline in the 50- to 100-mg/d range and oral clemastine in the 1.34- to 2.68-mg/d range together can lead to reduced cranial heat, improved cranial suture mobility, and improved elasticity of white matter bundle tracts palpable on physical examination. Both medications show clinical results in improved emotional self-regulation, according to family reports and clinical observations in the outpatient setting. There is no reason to delay neurologic-based adjunctive treatment when our goal is to prevent and reverse brain damage.

Daniel Kerlinsky, MD
Child Psychiatrist
Clinical Assistant Professor
Burrell College of Osteopathic Medicine
Albuquerque, New Mexico

References

1. Hess DH, Fagan SC. Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline. Rev Neurol Dis. 2010;30(7 pt 2):55S-61S.
2. Vedantam S, Moller AR. Minocycline: a novel stroke therapy. J Neurol Stroke. 2015;2(6):00073. doi: 10.15406/jnsk.2015.02.00073.
3. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481-2489.
4. Cree BAC, Niu J, Hoi KK, et al. Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury. Brain. 2018;141(1):85-98.

Continue to: Dr. Nasrallah responds

 

 

Dr. Nasrallah responds

Thanks to my colleagues, Drs. Diamond, Glaser, and Kerlinsky, for their cogent letters about my editorial.

To Dr. Glaser: The “ethics” of conducting placebo-controlled studies when developing a new antipsychotic has been raging for some time. For decades, the FDA has insisted on using a placebo group because around 25% to 30% of research participants respond to placebo, and because participants receiving placebo also complain of many adverse effects. So a new drug has to demonstrate a statistically higher efficacy than a placebo, and the adverse effect profile of the placebo group will put the safety and tolerability profile of a new drug in proper perspective. However, in Europe, they do not conduct placebo-controlled studies; instead, they conduct what is called a “non-inferiority” trial of a new antipsychotic compared with a well-established antipsychotic.

Interestingly, even though the discovery of the neurodegenerative effects of untreated psychosis was only 20 years ago (in 1997 after serial MRI scans revealed progressive atrophy), in the 1960s, the first antipsychotic, chlorpromazine, was compared with placebo in a large national study for 6 months. This study showed without a doubt that chlorpromazine has a higher efficacy than placebo. After the study was done, Dr. Philip May at University of California, Los Angeles looked at what happened to the psychotic patients who received placebo for 6 months and found that they became less responsive to treatment, were re-hospitalized more often, and had more negative symptoms and a poorer overall outcome. That was a clue that untreated psychosis can be harmful, and it supports your point about the ethics of using placebo. In contemporary studies, a trial of oral antipsychotics is 6 weeks, not 6 months. In the year-long, placebo-controlled studies of injectable antipsychotics in stable patients, those who show the slightest increase in delusions, hallucinations, or suicidal/homicidal behavior were promptly taken out of the study and treated. This reduced the “harm,” although not completely. Perhaps the FDA will change its policies and adopt the non-inferiority model. That’s what is done with nonpsychiatric disorders such as pneumonia, stroke, or diabetes. But one last fact has to be stated: The placebo response in anxiety, depression, or psychosis is much higher (25% to 35%) than the 1% placebo response in pneumonia.

To Dr. Diamond: I really like DASH, and it is an acronym for quick symptomatic diagnosis. Speedy treatment then follows with the acronym RAPID to prevent brain damage that gets worse with delay.

As for the second issue of tapering off the antipsychotic medication, the evidence is overwhelming in favor of continuous pharmacotherapy. Just as hypertension and diabetes will return if medications are tapered or stopped, so will psychosis, and vengefully so because treatment resistance increases with each relapse.¹ This is also true for bipolar disorder recurrences.² A recent 20-year follow-up study showed that stopping antipsychotic treatment is associated with a much higher mortality rate than continuation therapy.³ Another 7-year study showed the same thing.⁴ It is literally deadly, and not just neurodegenerative, for persons with schizophrenia to stop their medications.

To Dr. Kerlinsky: I agree with you about using certain adjunctive pharmacotherapies for acute psychosis, which is associated with neuroinflammation, oxidative stress, and neuropil and myelin damage. I support using agents with anti-inflammatory effects (such as minocycline and omega-3 fatty acid), antioxidant effects (such as N-acetylcysteine), and neuroprotective effects (such as minocycline, clemastine, lithium, vitamin D, erythropoietin, etc.). I refer you to my past editorial, “Are you neuroprotecting your patients? 10 Adjunctive therapies to consider,”⁵ in which I mentioned all the above. I also pointed out the many neuro­protective effects of atypical antipsychotics in another editorial.⁶ Although off-label, those supplements can be useful interventions that can ameliorate the gray and white matter damage associated with acute psychotic relapses in patients with schizophrenia.

Henry A. Nasrallah, MD
Editor-in-Chief
The Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

References

1. Emsley R, Oosthuizen P, Koen L, et al. Comparison of treatment response in second-episode versus first-episode schizophrenia. J Clin Psychopharmacol. 2013;33(1):80-83.
2. Post RM. Preventing the malignant transformation of bipolar disorder. JAMA. 2018;E1-E2.
3. Tiihonen J, Tanskanen A, Taipale H. 20-year nationwide follow-up study on discontinuation of anti­psychotic treatment in first-episode schizophrenia. Am J Psychiatry. 2018;175(8):765-773.
4. Taipale H, Mittendorfer-Rutz E, Alexanderson K, et al. Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res. 2018;197:274-280.
5. Nasrallah HA. Are you neuroprotecting your patients? 10 Adjunctive therapies to consider. Current Psychiatry. 2016;15(12):12-14.
6. Nasrallah HA. A decade after the CATIE study, the focus has shifted from effectiveness to neuro­protection. Current Psychiatry. 2015;14(2):19-21.

I read with great interest Dr. Nasrallah’s editorial, “FAST and RAPID: Acronyms to prevent brain damage in stroke and psychosis” (From the Editor, Current Psychiatry, August 2018, p. 6-8). It makes me wonder about the ethics of allowing patients with active psychosis to participate in placebo-controlled studies. If a patient’s brain undergoes damage while psychotic, allowing the psychosis to continue without active treatment sounds possibly at odds with a physician’s oath. If a patient is in the placebo arm, then they are not receiving treatment for their psychotic symptoms. I wonder about his opinion on this.

Mitchell L. Glaser, MD
Board-Certified Child/Adolescent and General Psychiatrist
Assistant Professor of Psychiatry
Rush University Medical Center
Chairman
Department of Psychiatry
Medical Director of Child/Adolescent Psychiatry
St. Mary/Elizabeth Medical Center 
Clinical Assistant Professor of Psychiatry 
Rosalind Franklin University
Chicago, Illinois

Thank you, Dr. Nasrallah, for your incisive thinking and for bringing our attention as psychiatrists to the crucial issues of our clinical practice. I’d like to offer some nuance on the RAPID acronym. First, I’d like to counterpropose DASH: Delusions, Auditory hallucinations, Strange behavior, Hospital now. This is more in line with getting physicians to tune in to the symptoms that should alarm them and bring them to action. I agree that neurodegeneration and illness recurrence are the problems to address. One unsettled issue remains: With early intervention, can we eventually taper patients off antipsychotics to spare them the metabolic and immune morbidity associated with these medications? There is some evidence that this is possible, but it is difficult to collect data. One of the factors delaying treatment, other than lack of recognition, is the general public’s belief that the treatment is sometimes worse than the disease. If we can address this issue in a nuanced fashion, we may get more “early adopters” of these neuron-sparing treatments.

Michael S. Diamond, MD
Private psychiatric practice
Chevy Chase, Maryland

Dr. Nasrallah is right to focus on brain injury patterns, including inflammation and de-myelination, during psychotic episodes. He and Dr. Roque note that starting a patient on a long-acting injectable antipsychotic as soon as possible may prevent subsequent relapse and further brain damage. However, their editorial omits 2 treatments—minocycline and clemastine—that can help stop CNS inflammation, reduce brain damage, and promote remyelination.

Minocycline has been shown to reduce stroke infarct penumbra size and improve outcomes in functional recovery from stroke.^1,2 Minocycline’s effects as a potent CNS anti-inflammatory and antiapoptotic agent are well established.

Clemastine has been shown to improve function in multiple sclerosis by activating oligodendrocyte precursor cells into active agents of myelination and fiber bundle stabilization.³ Clemastine reverses acute leukoencephalopathy.⁴

If we are to treat acute psychosis as a neurologic emergency, we cannot rely on long-acting injectable antipsychotics as the sole treatment. Psychiatric medication alone is not sufficient across every neuropsychiatric condition in which inflammation and white matter damage are part of the etiology, destruction, and pattern of relapse.

The adverse effects risk of adjunctive minocycline and clemastine is low compared with the potential benefits of stopping inflammation, reducing apoptosis, and jump-starting white matter repair. Doses of oral minocycline in the 50- to 100-mg/d range and oral clemastine in the 1.34- to 2.68-mg/d range together can lead to reduced cranial heat, improved cranial suture mobility, and improved elasticity of white matter bundle tracts palpable on physical examination. Both medications show clinical results in improved emotional self-regulation, according to family reports and clinical observations in the outpatient setting. There is no reason to delay neurologic-based adjunctive treatment when our goal is to prevent and reverse brain damage.

Daniel Kerlinsky, MD
Child Psychiatrist
Clinical Assistant Professor
Burrell College of Osteopathic Medicine
Albuquerque, New Mexico

References

1. Hess DH, Fagan SC. Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline. Rev Neurol Dis. 2010;30(7 pt 2):55S-61S.
2. Vedantam S, Moller AR. Minocycline: a novel stroke therapy. J Neurol Stroke. 2015;2(6):00073. doi: 10.15406/jnsk.2015.02.00073.
3. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481-2489.
4. Cree BAC, Niu J, Hoi KK, et al. Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury. Brain. 2018;141(1):85-98.

Continue to: Dr. Nasrallah responds

 

 

Dr. Nasrallah responds

Thanks to my colleagues, Drs. Diamond, Glaser, and Kerlinsky, for their cogent letters about my editorial.

To Dr. Glaser: The “ethics” of conducting placebo-controlled studies when developing a new antipsychotic has been raging for some time. For decades, the FDA has insisted on using a placebo group because around 25% to 30% of research participants respond to placebo, and because participants receiving placebo also complain of many adverse effects. So a new drug has to demonstrate a statistically higher efficacy than a placebo, and the adverse effect profile of the placebo group will put the safety and tolerability profile of a new drug in proper perspective. However, in Europe, they do not conduct placebo-controlled studies; instead, they conduct what is called a “non-inferiority” trial of a new antipsychotic compared with a well-established antipsychotic.

Interestingly, even though the discovery of the neurodegenerative effects of untreated psychosis was only 20 years ago (in 1997 after serial MRI scans revealed progressive atrophy), in the 1960s, the first antipsychotic, chlorpromazine, was compared with placebo in a large national study for 6 months. This study showed without a doubt that chlorpromazine has a higher efficacy than placebo. After the study was done, Dr. Philip May at University of California, Los Angeles looked at what happened to the psychotic patients who received placebo for 6 months and found that they became less responsive to treatment, were re-hospitalized more often, and had more negative symptoms and a poorer overall outcome. That was a clue that untreated psychosis can be harmful, and it supports your point about the ethics of using placebo. In contemporary studies, a trial of oral antipsychotics is 6 weeks, not 6 months. In the year-long, placebo-controlled studies of injectable antipsychotics in stable patients, those who show the slightest increase in delusions, hallucinations, or suicidal/homicidal behavior were promptly taken out of the study and treated. This reduced the “harm,” although not completely. Perhaps the FDA will change its policies and adopt the non-inferiority model. That’s what is done with nonpsychiatric disorders such as pneumonia, stroke, or diabetes. But one last fact has to be stated: The placebo response in anxiety, depression, or psychosis is much higher (25% to 35%) than the 1% placebo response in pneumonia.

To Dr. Diamond: I really like DASH, and it is an acronym for quick symptomatic diagnosis. Speedy treatment then follows with the acronym RAPID to prevent brain damage that gets worse with delay.

As for the second issue of tapering off the antipsychotic medication, the evidence is overwhelming in favor of continuous pharmacotherapy. Just as hypertension and diabetes will return if medications are tapered or stopped, so will psychosis, and vengefully so because treatment resistance increases with each relapse.¹ This is also true for bipolar disorder recurrences.² A recent 20-year follow-up study showed that stopping antipsychotic treatment is associated with a much higher mortality rate than continuation therapy.³ Another 7-year study showed the same thing.⁴ It is literally deadly, and not just neurodegenerative, for persons with schizophrenia to stop their medications.

To Dr. Kerlinsky: I agree with you about using certain adjunctive pharmacotherapies for acute psychosis, which is associated with neuroinflammation, oxidative stress, and neuropil and myelin damage. I support using agents with anti-inflammatory effects (such as minocycline and omega-3 fatty acid), antioxidant effects (such as N-acetylcysteine), and neuroprotective effects (such as minocycline, clemastine, lithium, vitamin D, erythropoietin, etc.). I refer you to my past editorial, “Are you neuroprotecting your patients? 10 Adjunctive therapies to consider,”⁵ in which I mentioned all the above. I also pointed out the many neuro­protective effects of atypical antipsychotics in another editorial.⁶ Although off-label, those supplements can be useful interventions that can ameliorate the gray and white matter damage associated with acute psychotic relapses in patients with schizophrenia.

Henry A. Nasrallah, MD
Editor-in-Chief
The Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

References

1. Emsley R, Oosthuizen P, Koen L, et al. Comparison of treatment response in second-episode versus first-episode schizophrenia. J Clin Psychopharmacol. 2013;33(1):80-83.
2. Post RM. Preventing the malignant transformation of bipolar disorder. JAMA. 2018;E1-E2.
3. Tiihonen J, Tanskanen A, Taipale H. 20-year nationwide follow-up study on discontinuation of anti­psychotic treatment in first-episode schizophrenia. Am J Psychiatry. 2018;175(8):765-773.
4. Taipale H, Mittendorfer-Rutz E, Alexanderson K, et al. Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res. 2018;197:274-280.
5. Nasrallah HA. Are you neuroprotecting your patients? 10 Adjunctive therapies to consider. Current Psychiatry. 2016;15(12):12-14.
6. Nasrallah HA. A decade after the CATIE study, the focus has shifted from effectiveness to neuro­protection. Current Psychiatry. 2015;14(2):19-21.

I read with great interest Dr. Nasrallah’s editorial, “FAST and RAPID: Acronyms to prevent brain damage in stroke and psychosis” (From the Editor, Current Psychiatry, August 2018, p. 6-8). It makes me wonder about the ethics of allowing patients with active psychosis to participate in placebo-controlled studies. If a patient’s brain undergoes damage while psychotic, allowing the psychosis to continue without active treatment sounds possibly at odds with a physician’s oath. If a patient is in the placebo arm, then they are not receiving treatment for their psychotic symptoms. I wonder about his opinion on this.

Mitchell L. Glaser, MD
Board-Certified Child/Adolescent and General Psychiatrist
Assistant Professor of Psychiatry
Rush University Medical Center
Chairman
Department of Psychiatry
Medical Director of Child/Adolescent Psychiatry
St. Mary/Elizabeth Medical Center 
Clinical Assistant Professor of Psychiatry 
Rosalind Franklin University
Chicago, Illinois

Thank you, Dr. Nasrallah, for your incisive thinking and for bringing our attention as psychiatrists to the crucial issues of our clinical practice. I’d like to offer some nuance on the RAPID acronym. First, I’d like to counterpropose DASH: Delusions, Auditory hallucinations, Strange behavior, Hospital now. This is more in line with getting physicians to tune in to the symptoms that should alarm them and bring them to action. I agree that neurodegeneration and illness recurrence are the problems to address. One unsettled issue remains: With early intervention, can we eventually taper patients off antipsychotics to spare them the metabolic and immune morbidity associated with these medications? There is some evidence that this is possible, but it is difficult to collect data. One of the factors delaying treatment, other than lack of recognition, is the general public’s belief that the treatment is sometimes worse than the disease. If we can address this issue in a nuanced fashion, we may get more “early adopters” of these neuron-sparing treatments.

Michael S. Diamond, MD
Private psychiatric practice
Chevy Chase, Maryland

Dr. Nasrallah is right to focus on brain injury patterns, including inflammation and de-myelination, during psychotic episodes. He and Dr. Roque note that starting a patient on a long-acting injectable antipsychotic as soon as possible may prevent subsequent relapse and further brain damage. However, their editorial omits 2 treatments—minocycline and clemastine—that can help stop CNS inflammation, reduce brain damage, and promote remyelination.

Minocycline has been shown to reduce stroke infarct penumbra size and improve outcomes in functional recovery from stroke.^1,2 Minocycline’s effects as a potent CNS anti-inflammatory and antiapoptotic agent are well established.

Clemastine has been shown to improve function in multiple sclerosis by activating oligodendrocyte precursor cells into active agents of myelination and fiber bundle stabilization.³ Clemastine reverses acute leukoencephalopathy.⁴

If we are to treat acute psychosis as a neurologic emergency, we cannot rely on long-acting injectable antipsychotics as the sole treatment. Psychiatric medication alone is not sufficient across every neuropsychiatric condition in which inflammation and white matter damage are part of the etiology, destruction, and pattern of relapse.

The adverse effects risk of adjunctive minocycline and clemastine is low compared with the potential benefits of stopping inflammation, reducing apoptosis, and jump-starting white matter repair. Doses of oral minocycline in the 50- to 100-mg/d range and oral clemastine in the 1.34- to 2.68-mg/d range together can lead to reduced cranial heat, improved cranial suture mobility, and improved elasticity of white matter bundle tracts palpable on physical examination. Both medications show clinical results in improved emotional self-regulation, according to family reports and clinical observations in the outpatient setting. There is no reason to delay neurologic-based adjunctive treatment when our goal is to prevent and reverse brain damage.

Daniel Kerlinsky, MD
Child Psychiatrist
Clinical Assistant Professor
Burrell College of Osteopathic Medicine
Albuquerque, New Mexico

References

1. Hess DH, Fagan SC. Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline. Rev Neurol Dis. 2010;30(7 pt 2):55S-61S.
2. Vedantam S, Moller AR. Minocycline: a novel stroke therapy. J Neurol Stroke. 2015;2(6):00073. doi: 10.15406/jnsk.2015.02.00073.
3. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481-2489.
4. Cree BAC, Niu J, Hoi KK, et al. Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury. Brain. 2018;141(1):85-98.

Continue to: Dr. Nasrallah responds

 

 

Dr. Nasrallah responds

Thanks to my colleagues, Drs. Diamond, Glaser, and Kerlinsky, for their cogent letters about my editorial.

To Dr. Glaser: The “ethics” of conducting placebo-controlled studies when developing a new antipsychotic has been raging for some time. For decades, the FDA has insisted on using a placebo group because around 25% to 30% of research participants respond to placebo, and because participants receiving placebo also complain of many adverse effects. So a new drug has to demonstrate a statistically higher efficacy than a placebo, and the adverse effect profile of the placebo group will put the safety and tolerability profile of a new drug in proper perspective. However, in Europe, they do not conduct placebo-controlled studies; instead, they conduct what is called a “non-inferiority” trial of a new antipsychotic compared with a well-established antipsychotic.

Interestingly, even though the discovery of the neurodegenerative effects of untreated psychosis was only 20 years ago (in 1997 after serial MRI scans revealed progressive atrophy), in the 1960s, the first antipsychotic, chlorpromazine, was compared with placebo in a large national study for 6 months. This study showed without a doubt that chlorpromazine has a higher efficacy than placebo. After the study was done, Dr. Philip May at University of California, Los Angeles looked at what happened to the psychotic patients who received placebo for 6 months and found that they became less responsive to treatment, were re-hospitalized more often, and had more negative symptoms and a poorer overall outcome. That was a clue that untreated psychosis can be harmful, and it supports your point about the ethics of using placebo. In contemporary studies, a trial of oral antipsychotics is 6 weeks, not 6 months. In the year-long, placebo-controlled studies of injectable antipsychotics in stable patients, those who show the slightest increase in delusions, hallucinations, or suicidal/homicidal behavior were promptly taken out of the study and treated. This reduced the “harm,” although not completely. Perhaps the FDA will change its policies and adopt the non-inferiority model. That’s what is done with nonpsychiatric disorders such as pneumonia, stroke, or diabetes. But one last fact has to be stated: The placebo response in anxiety, depression, or psychosis is much higher (25% to 35%) than the 1% placebo response in pneumonia.

To Dr. Diamond: I really like DASH, and it is an acronym for quick symptomatic diagnosis. Speedy treatment then follows with the acronym RAPID to prevent brain damage that gets worse with delay.

As for the second issue of tapering off the antipsychotic medication, the evidence is overwhelming in favor of continuous pharmacotherapy. Just as hypertension and diabetes will return if medications are tapered or stopped, so will psychosis, and vengefully so because treatment resistance increases with each relapse.¹ This is also true for bipolar disorder recurrences.² A recent 20-year follow-up study showed that stopping antipsychotic treatment is associated with a much higher mortality rate than continuation therapy.³ Another 7-year study showed the same thing.⁴ It is literally deadly, and not just neurodegenerative, for persons with schizophrenia to stop their medications.

To Dr. Kerlinsky: I agree with you about using certain adjunctive pharmacotherapies for acute psychosis, which is associated with neuroinflammation, oxidative stress, and neuropil and myelin damage. I support using agents with anti-inflammatory effects (such as minocycline and omega-3 fatty acid), antioxidant effects (such as N-acetylcysteine), and neuroprotective effects (such as minocycline, clemastine, lithium, vitamin D, erythropoietin, etc.). I refer you to my past editorial, “Are you neuroprotecting your patients? 10 Adjunctive therapies to consider,”⁵ in which I mentioned all the above. I also pointed out the many neuro­protective effects of atypical antipsychotics in another editorial.⁶ Although off-label, those supplements can be useful interventions that can ameliorate the gray and white matter damage associated with acute psychotic relapses in patients with schizophrenia.

Henry A. Nasrallah, MD
Editor-in-Chief
The Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

References

1. Emsley R, Oosthuizen P, Koen L, et al. Comparison of treatment response in second-episode versus first-episode schizophrenia. J Clin Psychopharmacol. 2013;33(1):80-83.
2. Post RM. Preventing the malignant transformation of bipolar disorder. JAMA. 2018;E1-E2.
3. Tiihonen J, Tanskanen A, Taipale H. 20-year nationwide follow-up study on discontinuation of anti­psychotic treatment in first-episode schizophrenia. Am J Psychiatry. 2018;175(8):765-773.
4. Taipale H, Mittendorfer-Rutz E, Alexanderson K, et al. Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res. 2018;197:274-280.
5. Nasrallah HA. Are you neuroprotecting your patients? 10 Adjunctive therapies to consider. Current Psychiatry. 2016;15(12):12-14.
6. Nasrallah HA. A decade after the CATIE study, the focus has shifted from effectiveness to neuro­protection. Current Psychiatry. 2015;14(2):19-21.

Mr. S, age 47, weighs 209 lb and has a history of seizure disorder, bipolar disorder not otherwise specified, hypertension, and type 2 diabetes mellitus. He presents to the emergency department after not taking his medications for 2 days while on vacation. He has increased energy, decreased sleep, and pressured speech, and insists on walking for up to 10 hours per day “in preparation for a marathon,” even though he has a 4-cm foot ulcer. His family reports that he had been compliant with his medications until the present incident.

Mr. S has no known drug allergies. His medications include oral divalproex sodium delayed release (valproic acid [VPA]), 1,000 mg twice a day, oral lisinopril, 20 mg every morning, and insulin glargine, 22 units subcutaneously every evening.

A complete blood count, basic metabolic panel, creatine kinase level, VPA level, and urine drug screen are ordered. Relevant results include a serum creatinine level of 1.4 mg/dL (normal range: 0.6 to 1.2 mg/dL), a glucose serum level of 188 mg/dL (normal range: 70 to 100 mg/dL), and a VPA level of 23 mcg/mL (therapeutic range: 50 to 125 mcg/mL). A liver function panel is within normal limits: albumin level of 3.9 g/dL, aspartate aminotransferase level of 18 IU/L, and alanine aminotransferase level of 14 IU/L. In light of Mr. S’s seizure history, neurology is consulted and the decision is made to continue treating him with VPA because he has been seizure-free for 4.5 years and this medication has also helped with his bipolar disorder.

Mr. S is admitted to the hospital and his home medications are resumed at the current doses. On hospital Day 3, Mr. S’s VPA level is 62 mcg/mL, his obsession with a marathon has remitted, and his sleep pattern has normalized. Infectious disease and podiatry services are consulted for his diabetic foot infection, which has ulcerated down to the bone. IV ertapenem, 1,000 mg/d, is initiated with plans for debridement the following week. Two days later, Mr. S has a witnessed seizure; his VPA level is 9 mcg/mL.

A common question asked of pharmacists is, “Will protein binding changes affect drug dosages?” In this article, I describe how protein binding changes may occur, and the complexity of the dynamic. Being highly bound to a protein typically does not mean all medications will interact, but some interactions can be important. This article does not cover medications that bind to hormones.

Why is protein binding important? When a medication is bound to plasma protein, it is not free to act. There can be a delay in therapeutic effect (because no drug is available to react), delayed elimination, or possibly displacement of another protein-bound medication. Additionally, medications tend not to cross the blood-brain barrier or be eliminated when bound. For example, if a drug is 99% bound (leaving 1% free) and displacement now leaves 2% of the drug free, this event has doubled the amount of free drug. As the unbound medication is eliminated, the drug that is bound to the protein can act as a reservoir. A dynamic relationship exists between bound drug, unbound drug, and rate of elimination.

Which proteins do drugs commonly bind to? The proteins often associated with binding include albumin, alpha-1-acid glycoprotein (AAG), and lipoproteins. Albumin comprises 60% of total plasma protein in the plasma. Lipoproteins include very high-density lipoprotein (VHDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL).¹ Medications that bind to lipoproteins include cyclosporine, tacrolimus, and propofol.²

Continued to: What common disease states can cause hypoalbuminemia?

• free vs protein-bound drug in the plasma or tissue
• volume of distribution
• organs affected
• hepatic bioavailability
• drug clearance.

For example, VPA is 93% protein-bound and phenytoin is 91% protein-bound.¹ However, this interaction is affected by more than just protein binding. VPA not only displaces the protein-bound phenytoin, but also inhibits its metabolism, which together result in increased free phenytoin levels.

Continued to: Another area of concern is a critically ill patient...

What happened to Mr. S? Mr. S likely experienced a drug–drug interaction that resulted in a subtherapeutic VPA level and subsequent seizure. Case reports have shown evidence that the carbapenem class of antibiotics, which includes ertapenem, interacts with VPA.⁷ Proposed mechanisms include a lowering of VPA serum levels due to a redistribution of the VPA onto the RBCs due to carbapenem. Other theories include the possibility that carbapenems may limit oral VPA absorption, decrease VPA enterohepatic recirculation, and increase VPA metabolism.⁷ Using VPA and ertapenem together is discouraged because seizures have been reported among patients receiving this combination. If it is medically necessary to administer VPA and ertapenem, closely monitor VPA levels. In Mr. S’s case, another broad-spectrum antibiotic, such as piperacillin-tazobactam, could have been used, for his diabetic foot infection.

While many medications may have high protein binding, there are few clinically important known interactions. However, our understanding of the relationship between protein binding and drug interactions may improve with additional research.

CASE CONTINUED

Under neurology’s care, lacosamide is added for treatment of Mr. S’s seizures. No more seizures are noted during the remainder of his hospitalization. Infectious disease services change his antibiotic to piperacillin-tazobactam. Mr. S continues to progress well and is discharged to a rehabilitation center 2 days later.

Related Resource

• DrugBank. www.drugbank.ca. Canadian Institutes of Health Research.

Drug Brand Names
Amiodarone • Cordarone, Pacerone
Bumetanide • Bumex
Bupivacaine • Marcaine, Sensorcaine
Buprenorphine • Belbuca, Subutex
Ceftriaxone • Rocephin
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clozapine • Clozaril
Cyclosporine • Gengraf, Neoral
Diazepam • Valium
Doxycycline • Acticlate, Doryx
Duloxetine • Cymbalta
Ertapenem • Invanz
Fluoxetine • Prozac, Sarafem
Furosemide • Lasix
Glargine (Insulin) • Lantus, Toujeo
Glipizide • Glucotrol
Haloperidol • Haldol
Ibuprofen • Advil, Motrin
Imipramine • Tofranil
Lacosamide • Vimpat
Lisinopril • Prinivil, Zestril
Lorazepam • Ativan
Nicardipine • Cardene
Nortriptyline • Pamelor
Paclitaxel • Abraxane, Taxol
Phenytoin • Dilantin, Phenytek
Piperacillin-tazobactam • Zosyn
Propofol • Diprivan
Sertraline • Zoloft
Tacrolimus • Prograf
Tamoxifen • Soltamox
Valproic acid • Depakene, Depakote
Verapamil • Calan, Verelan
Warfarin • Coumadin, Jantoven

Mr. S, age 47, weighs 209 lb and has a history of seizure disorder, bipolar disorder not otherwise specified, hypertension, and type 2 diabetes mellitus. He presents to the emergency department after not taking his medications for 2 days while on vacation. He has increased energy, decreased sleep, and pressured speech, and insists on walking for up to 10 hours per day “in preparation for a marathon,” even though he has a 4-cm foot ulcer. His family reports that he had been compliant with his medications until the present incident.

Mr. S has no known drug allergies. His medications include oral divalproex sodium delayed release (valproic acid [VPA]), 1,000 mg twice a day, oral lisinopril, 20 mg every morning, and insulin glargine, 22 units subcutaneously every evening.

A complete blood count, basic metabolic panel, creatine kinase level, VPA level, and urine drug screen are ordered. Relevant results include a serum creatinine level of 1.4 mg/dL (normal range: 0.6 to 1.2 mg/dL), a glucose serum level of 188 mg/dL (normal range: 70 to 100 mg/dL), and a VPA level of 23 mcg/mL (therapeutic range: 50 to 125 mcg/mL). A liver function panel is within normal limits: albumin level of 3.9 g/dL, aspartate aminotransferase level of 18 IU/L, and alanine aminotransferase level of 14 IU/L. In light of Mr. S’s seizure history, neurology is consulted and the decision is made to continue treating him with VPA because he has been seizure-free for 4.5 years and this medication has also helped with his bipolar disorder.

Mr. S is admitted to the hospital and his home medications are resumed at the current doses. On hospital Day 3, Mr. S’s VPA level is 62 mcg/mL, his obsession with a marathon has remitted, and his sleep pattern has normalized. Infectious disease and podiatry services are consulted for his diabetic foot infection, which has ulcerated down to the bone. IV ertapenem, 1,000 mg/d, is initiated with plans for debridement the following week. Two days later, Mr. S has a witnessed seizure; his VPA level is 9 mcg/mL.

A common question asked of pharmacists is, “Will protein binding changes affect drug dosages?” In this article, I describe how protein binding changes may occur, and the complexity of the dynamic. Being highly bound to a protein typically does not mean all medications will interact, but some interactions can be important. This article does not cover medications that bind to hormones.

Why is protein binding important? When a medication is bound to plasma protein, it is not free to act. There can be a delay in therapeutic effect (because no drug is available to react), delayed elimination, or possibly displacement of another protein-bound medication. Additionally, medications tend not to cross the blood-brain barrier or be eliminated when bound. For example, if a drug is 99% bound (leaving 1% free) and displacement now leaves 2% of the drug free, this event has doubled the amount of free drug. As the unbound medication is eliminated, the drug that is bound to the protein can act as a reservoir. A dynamic relationship exists between bound drug, unbound drug, and rate of elimination.

Which proteins do drugs commonly bind to? The proteins often associated with binding include albumin, alpha-1-acid glycoprotein (AAG), and lipoproteins. Albumin comprises 60% of total plasma protein in the plasma. Lipoproteins include very high-density lipoprotein (VHDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL).¹ Medications that bind to lipoproteins include cyclosporine, tacrolimus, and propofol.²

Continued to: What common disease states can cause hypoalbuminemia?

• free vs protein-bound drug in the plasma or tissue
• volume of distribution
• organs affected
• hepatic bioavailability
• drug clearance.

For example, VPA is 93% protein-bound and phenytoin is 91% protein-bound.¹ However, this interaction is affected by more than just protein binding. VPA not only displaces the protein-bound phenytoin, but also inhibits its metabolism, which together result in increased free phenytoin levels.

Continued to: Another area of concern is a critically ill patient...

What happened to Mr. S? Mr. S likely experienced a drug–drug interaction that resulted in a subtherapeutic VPA level and subsequent seizure. Case reports have shown evidence that the carbapenem class of antibiotics, which includes ertapenem, interacts with VPA.⁷ Proposed mechanisms include a lowering of VPA serum levels due to a redistribution of the VPA onto the RBCs due to carbapenem. Other theories include the possibility that carbapenems may limit oral VPA absorption, decrease VPA enterohepatic recirculation, and increase VPA metabolism.⁷ Using VPA and ertapenem together is discouraged because seizures have been reported among patients receiving this combination. If it is medically necessary to administer VPA and ertapenem, closely monitor VPA levels. In Mr. S’s case, another broad-spectrum antibiotic, such as piperacillin-tazobactam, could have been used, for his diabetic foot infection.

While many medications may have high protein binding, there are few clinically important known interactions. However, our understanding of the relationship between protein binding and drug interactions may improve with additional research.

CASE CONTINUED

Under neurology’s care, lacosamide is added for treatment of Mr. S’s seizures. No more seizures are noted during the remainder of his hospitalization. Infectious disease services change his antibiotic to piperacillin-tazobactam. Mr. S continues to progress well and is discharged to a rehabilitation center 2 days later.

Related Resource

• DrugBank. www.drugbank.ca. Canadian Institutes of Health Research.

Drug Brand Names
Amiodarone • Cordarone, Pacerone
Bumetanide • Bumex
Bupivacaine • Marcaine, Sensorcaine
Buprenorphine • Belbuca, Subutex
Ceftriaxone • Rocephin
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clozapine • Clozaril
Cyclosporine • Gengraf, Neoral
Diazepam • Valium
Doxycycline • Acticlate, Doryx
Duloxetine • Cymbalta
Ertapenem • Invanz
Fluoxetine • Prozac, Sarafem
Furosemide • Lasix
Glargine (Insulin) • Lantus, Toujeo
Glipizide • Glucotrol
Haloperidol • Haldol
Ibuprofen • Advil, Motrin
Imipramine • Tofranil
Lacosamide • Vimpat
Lisinopril • Prinivil, Zestril
Lorazepam • Ativan
Nicardipine • Cardene
Nortriptyline • Pamelor
Paclitaxel • Abraxane, Taxol
Phenytoin • Dilantin, Phenytek
Piperacillin-tazobactam • Zosyn
Propofol • Diprivan
Sertraline • Zoloft
Tacrolimus • Prograf
Tamoxifen • Soltamox
Valproic acid • Depakene, Depakote
Verapamil • Calan, Verelan
Warfarin • Coumadin, Jantoven

Mr. S, age 47, weighs 209 lb and has a history of seizure disorder, bipolar disorder not otherwise specified, hypertension, and type 2 diabetes mellitus. He presents to the emergency department after not taking his medications for 2 days while on vacation. He has increased energy, decreased sleep, and pressured speech, and insists on walking for up to 10 hours per day “in preparation for a marathon,” even though he has a 4-cm foot ulcer. His family reports that he had been compliant with his medications until the present incident.

Mr. S has no known drug allergies. His medications include oral divalproex sodium delayed release (valproic acid [VPA]), 1,000 mg twice a day, oral lisinopril, 20 mg every morning, and insulin glargine, 22 units subcutaneously every evening.

A complete blood count, basic metabolic panel, creatine kinase level, VPA level, and urine drug screen are ordered. Relevant results include a serum creatinine level of 1.4 mg/dL (normal range: 0.6 to 1.2 mg/dL), a glucose serum level of 188 mg/dL (normal range: 70 to 100 mg/dL), and a VPA level of 23 mcg/mL (therapeutic range: 50 to 125 mcg/mL). A liver function panel is within normal limits: albumin level of 3.9 g/dL, aspartate aminotransferase level of 18 IU/L, and alanine aminotransferase level of 14 IU/L. In light of Mr. S’s seizure history, neurology is consulted and the decision is made to continue treating him with VPA because he has been seizure-free for 4.5 years and this medication has also helped with his bipolar disorder.

Mr. S is admitted to the hospital and his home medications are resumed at the current doses. On hospital Day 3, Mr. S’s VPA level is 62 mcg/mL, his obsession with a marathon has remitted, and his sleep pattern has normalized. Infectious disease and podiatry services are consulted for his diabetic foot infection, which has ulcerated down to the bone. IV ertapenem, 1,000 mg/d, is initiated with plans for debridement the following week. Two days later, Mr. S has a witnessed seizure; his VPA level is 9 mcg/mL.

A common question asked of pharmacists is, “Will protein binding changes affect drug dosages?” In this article, I describe how protein binding changes may occur, and the complexity of the dynamic. Being highly bound to a protein typically does not mean all medications will interact, but some interactions can be important. This article does not cover medications that bind to hormones.

Why is protein binding important? When a medication is bound to plasma protein, it is not free to act. There can be a delay in therapeutic effect (because no drug is available to react), delayed elimination, or possibly displacement of another protein-bound medication. Additionally, medications tend not to cross the blood-brain barrier or be eliminated when bound. For example, if a drug is 99% bound (leaving 1% free) and displacement now leaves 2% of the drug free, this event has doubled the amount of free drug. As the unbound medication is eliminated, the drug that is bound to the protein can act as a reservoir. A dynamic relationship exists between bound drug, unbound drug, and rate of elimination.

Which proteins do drugs commonly bind to? The proteins often associated with binding include albumin, alpha-1-acid glycoprotein (AAG), and lipoproteins. Albumin comprises 60% of total plasma protein in the plasma. Lipoproteins include very high-density lipoprotein (VHDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL).¹ Medications that bind to lipoproteins include cyclosporine, tacrolimus, and propofol.²

Continued to: What common disease states can cause hypoalbuminemia?

• free vs protein-bound drug in the plasma or tissue
• volume of distribution
• organs affected
• hepatic bioavailability
• drug clearance.

For example, VPA is 93% protein-bound and phenytoin is 91% protein-bound.¹ However, this interaction is affected by more than just protein binding. VPA not only displaces the protein-bound phenytoin, but also inhibits its metabolism, which together result in increased free phenytoin levels.

Continued to: Another area of concern is a critically ill patient...

What happened to Mr. S? Mr. S likely experienced a drug–drug interaction that resulted in a subtherapeutic VPA level and subsequent seizure. Case reports have shown evidence that the carbapenem class of antibiotics, which includes ertapenem, interacts with VPA.⁷ Proposed mechanisms include a lowering of VPA serum levels due to a redistribution of the VPA onto the RBCs due to carbapenem. Other theories include the possibility that carbapenems may limit oral VPA absorption, decrease VPA enterohepatic recirculation, and increase VPA metabolism.⁷ Using VPA and ertapenem together is discouraged because seizures have been reported among patients receiving this combination. If it is medically necessary to administer VPA and ertapenem, closely monitor VPA levels. In Mr. S’s case, another broad-spectrum antibiotic, such as piperacillin-tazobactam, could have been used, for his diabetic foot infection.

While many medications may have high protein binding, there are few clinically important known interactions. However, our understanding of the relationship between protein binding and drug interactions may improve with additional research.

CASE CONTINUED

Under neurology’s care, lacosamide is added for treatment of Mr. S’s seizures. No more seizures are noted during the remainder of his hospitalization. Infectious disease services change his antibiotic to piperacillin-tazobactam. Mr. S continues to progress well and is discharged to a rehabilitation center 2 days later.

Related Resource

• DrugBank. www.drugbank.ca. Canadian Institutes of Health Research.

Drug Brand Names
Amiodarone • Cordarone, Pacerone
Bumetanide • Bumex
Bupivacaine • Marcaine, Sensorcaine
Buprenorphine • Belbuca, Subutex
Ceftriaxone • Rocephin
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clozapine • Clozaril
Cyclosporine • Gengraf, Neoral
Diazepam • Valium
Doxycycline • Acticlate, Doryx
Duloxetine • Cymbalta
Ertapenem • Invanz
Fluoxetine • Prozac, Sarafem
Furosemide • Lasix
Glargine (Insulin) • Lantus, Toujeo
Glipizide • Glucotrol
Haloperidol • Haldol
Ibuprofen • Advil, Motrin
Imipramine • Tofranil
Lacosamide • Vimpat
Lisinopril • Prinivil, Zestril
Lorazepam • Ativan
Nicardipine • Cardene
Nortriptyline • Pamelor
Paclitaxel • Abraxane, Taxol
Phenytoin • Dilantin, Phenytek
Piperacillin-tazobactam • Zosyn
Propofol • Diprivan
Sertraline • Zoloft
Tacrolimus • Prograf
Tamoxifen • Soltamox
Valproic acid • Depakene, Depakote
Verapamil • Calan, Verelan
Warfarin • Coumadin, Jantoven

CASE Suicidal ideation, flare-up of ulcerative colitis

Mr. J, age 56, who has a history of major depressive disorder (MDD), generalized anxiety disorder (GAD), and ulcerative colitis (UC), presents to the emergency department (ED) with suicidal ideation and a plan to overdose on his medications. He reports no current emotional or financial stressors in his personal life. Home medications documented at the time of his arrival to the ED include sertraline, 100 mg/d, bupropion, 150 mg/d, buspirone, 10 mg 3 times daily, diazepam 10 mg 3 times daily, as needed, adalimumab, 40 mg IM every 2 weeks, and diphenhydramine, 50 mg every night.

A recent flare-up of UC resulted in Mr. J being placed on a 15-week prednisone taper, beginning at 80 mg/d and decreasing by 5 mg weekly, which was completed 2 weeks before he presented to the ED. After completing the prednisone taper, Mr. J went to his primary care physician (PCP) on 3 separate occasions due to episodes of severe depression. Although the PCP prescribed multiple medications to target Mr. J’s depressive symptoms, he continued to decline.

Subsequently, Mr. J came to the ED and is admitted to the psychiatric unit for safety and stabilization. Upon admission, Mr. J becomes bedridden, and reports that his current depressive episode is the most severe that he has ever experienced in his more than 30 years of having MDD. He says that neither bupropion nor buspirone are helping with his depression, anxiety, or any related symptom.

[polldaddy:10120537]

The authors’ observations

At admission, all of Mr. J’s home medications, except sertraline and adalimumab, which had been prescribed to treat UC (Box^1,2), were discontinued. His diazepam was discontinued because the clinician felt it may have been contributing to Mr. J’s inability to walk or get out of bed. Diazepam was not tapered because it was initiated 7 days prior to admission and was thought to be exacerbating his depression and suicidal ideation. Bupropion and buspirone, which were initiated 2 weeks prior, were discontinued because Mr. J reported that neither medication was helping with his depression, anxiety, or any related symptom.

EVALUATION Poor appetite, anxiety, and continued suicidality

During evaluation, vital signs, laboratory findings, and diagnostic testing are found to be unremarkable. Mr. J’s presentation and complaints are entirely subjective, and include poor appetite, fatigue, difficulty sleeping, sorrow, anxiety, and continued suicidality. Mr. J reports that he feels miserable, which is reflected by his poor eye contact, soft speech, and body language.

Continued to: The authors' observations

 

 

The authors’ observations

MDD is a mood disorder characterized by depressed mood and/or loss of interest or pleasure for more than 2 weeks.³ First-line pharmacotherapy for MDD includes monotherapy with a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion.⁴ Medication selection is typically based on patient-specific factors, adverse effect profile, drug–drug interactions, and cost. Other treatments include electroconvulsive therapy (ECT) or cognitive-behavioral therapy (CBT).^4,5 Augmentation agents, such as second-generation antipsychotics, lithium, thyroid hormone supplementation, buspirone, anticonvulsants, and combinations of antidepressants, may also be considered.⁴

TREATMENT Condition worsens

On Day 2 of hospitalization, Mr. J is started on aripiprazole, 5 mg/d, clonazepam, 1 mg twice daily, and melatonin, 5 mg, each night for sleep. Aripiprazole, 5 mg/d, is initiated as an adjunct to sertraline for MDD because Mr. J reports feeling much worse and continues to report that he would “rather die than feel this way.” Mr. J begins to believe that his current state is his new baseline, and that feeling better is no longer possible.

On Day 3 of hospitalization, records are obtained from a clinician at an outside facility who previously treated Mr. J; this clinician suspected Mr. J may have bipolar disorder. On Days 3 and 5 of hospitalization, aripiprazole is titrated to 10 mg/d, and then to 20 mg/d, respectively. On Day 6, sertraline is increased to 150 mg/d because Mr. J continues to report low mood and limited sleep and is less and less interactive during interviews. He remains suicidal, and because bipolar depression is suspected (although this is not a clear diagnosis in his records), a trial of divalproex sodium, 250 mg twice daily, is initiated on Day 6.

By Day 8 of hospitalization, there is no notable change in Mr. J’s depressive symptoms. On Day 9, sertraline is increased to 200 mg/d, with little improvement from Mr. J’s perspective. The multidisciplinary team evaluates him, and when directly asked, Mr. J cites his 4 greatest complaints to be poor sleep, fatigue, no appetite, and depressed mood. Once again, he states, “I would rather be dead than go on feeling this way.”

[polldaddy:10120587]

The authors’ observations

Due to Mr. J’s severe, unrelenting depressive episode, the treatment team obtained his informed consent to undergo ECT. On Day 9, before initiating ECT, the pharmacist recommended mirtazapine, even though the patient weighed almost 89 kg (196.21 lb) and had a body mass index of 27.8 kg/m². The treatment team thought that mirtazapine augmentation could potentially help the sertraline work more quickly while targeting Mr. J’s 4 greatest complaints.

Mirtazapine is a central alpha-2 antagonist or noradrenergic and specific serotonergic antidepressant (NaSSA) that works through antagonism of the presynaptic alpha-2 adrenergic receptors to indirectly regulate release of monoamines and increase the release of serotonin and norepinephrine.⁶ Additionally, mirtazapine has antagonist actions at 5HT2A, 5HT2C, 5HT3, and histamine-1 receptors.⁶ Potential adverse effects include drowsiness and increased appetite leading to weight gain.⁷ Mirtazapine’s therapeutic efficacy is similar to SSRIs for treating depression.⁴ Mirtazapine in combination with an SNRI has been referred to as “California rocket fuel” due to the theoretical pharmacologic synergy and resulting strong antidepressant action.⁶ It was hypothesized that similar effects could be seen by augmenting the SSRI sertraline with mirtazapine.

Continued to: The time to efficacy with mirtazapine...

OUTCOME Rapid improvement


On Day 9, Mr. J receives the first dose of mirtazapine, 7.5 mg at bedtime. On Day 10, when Mr. J wakes, his mood is notably improved. He is more interactive (sitting up in bed reading and making eye contact with the staff during an interview), and he reports improved sleep and eats most of his breakfast.

After receiving 3 doses of mirtazapine, Mr. J reports that he feels back to his normal self; he is interactive, alert, and eating well. Due to the rapid improvement in mood, ECT is discontinued, and he does not receive any ECT treatment during the remainder of his hospitalization.

On Day 11, divalproex is discontinued. Because Mr. J receives only 5 days of therapy with this agent, his divalproex level is not checked. At this point, the treatment team feels confident in ruling out bipolar disorder.

On Day 15, Mr. J is discharged with sertraline, 200 mg/d, mirtazapine, 7.5 mg/d at 7 pm, aripiprazole, 20 mg/d, clonazepam, 1 mg twice daily as needed for anxiety, melatonin 5 mg/d, and adalimumab, 40 mg IM every 2 weeks. Discharge instructions include a follow-up in 2 weeks to evaluate continuation strategies for the discharge medications.

Ten months after his depressive episode, Mr. J has had no further admissions at the hospital where he received the treatment described here.

Bottom Line

Evidence for the treatment of major depressive disorder induced by corticosteroid withdrawal is limited. Despite trials of agents from multiple medication classes, the depressive episode may not improve. Adding mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor may prove successful.

Related Resources

• Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528.
• Kenna HA, Poon AW, de los Angeles CP, et al. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65(6):549-560.

Drug Brand Names
Adalimumab • Humira
Aripiprazole • Abilify
Bupropion • Wellbutrin, Zyban
Buspirone • Buspar
Clonazepam • Klonopin
Diazepam • Valium
Diphenhydramine • Benadryl
Divalproex • Depakote, Depakote ER
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Prednisone • Deltasone
Sertraline • Zoloft

CASE Suicidal ideation, flare-up of ulcerative colitis

Mr. J, age 56, who has a history of major depressive disorder (MDD), generalized anxiety disorder (GAD), and ulcerative colitis (UC), presents to the emergency department (ED) with suicidal ideation and a plan to overdose on his medications. He reports no current emotional or financial stressors in his personal life. Home medications documented at the time of his arrival to the ED include sertraline, 100 mg/d, bupropion, 150 mg/d, buspirone, 10 mg 3 times daily, diazepam 10 mg 3 times daily, as needed, adalimumab, 40 mg IM every 2 weeks, and diphenhydramine, 50 mg every night.

A recent flare-up of UC resulted in Mr. J being placed on a 15-week prednisone taper, beginning at 80 mg/d and decreasing by 5 mg weekly, which was completed 2 weeks before he presented to the ED. After completing the prednisone taper, Mr. J went to his primary care physician (PCP) on 3 separate occasions due to episodes of severe depression. Although the PCP prescribed multiple medications to target Mr. J’s depressive symptoms, he continued to decline.

Subsequently, Mr. J came to the ED and is admitted to the psychiatric unit for safety and stabilization. Upon admission, Mr. J becomes bedridden, and reports that his current depressive episode is the most severe that he has ever experienced in his more than 30 years of having MDD. He says that neither bupropion nor buspirone are helping with his depression, anxiety, or any related symptom.

[polldaddy:10120537]

The authors’ observations

At admission, all of Mr. J’s home medications, except sertraline and adalimumab, which had been prescribed to treat UC (Box^1,2), were discontinued. His diazepam was discontinued because the clinician felt it may have been contributing to Mr. J’s inability to walk or get out of bed. Diazepam was not tapered because it was initiated 7 days prior to admission and was thought to be exacerbating his depression and suicidal ideation. Bupropion and buspirone, which were initiated 2 weeks prior, were discontinued because Mr. J reported that neither medication was helping with his depression, anxiety, or any related symptom.

EVALUATION Poor appetite, anxiety, and continued suicidality

During evaluation, vital signs, laboratory findings, and diagnostic testing are found to be unremarkable. Mr. J’s presentation and complaints are entirely subjective, and include poor appetite, fatigue, difficulty sleeping, sorrow, anxiety, and continued suicidality. Mr. J reports that he feels miserable, which is reflected by his poor eye contact, soft speech, and body language.

Continued to: The authors' observations

 

 

The authors’ observations

MDD is a mood disorder characterized by depressed mood and/or loss of interest or pleasure for more than 2 weeks.³ First-line pharmacotherapy for MDD includes monotherapy with a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion.⁴ Medication selection is typically based on patient-specific factors, adverse effect profile, drug–drug interactions, and cost. Other treatments include electroconvulsive therapy (ECT) or cognitive-behavioral therapy (CBT).^4,5 Augmentation agents, such as second-generation antipsychotics, lithium, thyroid hormone supplementation, buspirone, anticonvulsants, and combinations of antidepressants, may also be considered.⁴

TREATMENT Condition worsens

On Day 2 of hospitalization, Mr. J is started on aripiprazole, 5 mg/d, clonazepam, 1 mg twice daily, and melatonin, 5 mg, each night for sleep. Aripiprazole, 5 mg/d, is initiated as an adjunct to sertraline for MDD because Mr. J reports feeling much worse and continues to report that he would “rather die than feel this way.” Mr. J begins to believe that his current state is his new baseline, and that feeling better is no longer possible.

On Day 3 of hospitalization, records are obtained from a clinician at an outside facility who previously treated Mr. J; this clinician suspected Mr. J may have bipolar disorder. On Days 3 and 5 of hospitalization, aripiprazole is titrated to 10 mg/d, and then to 20 mg/d, respectively. On Day 6, sertraline is increased to 150 mg/d because Mr. J continues to report low mood and limited sleep and is less and less interactive during interviews. He remains suicidal, and because bipolar depression is suspected (although this is not a clear diagnosis in his records), a trial of divalproex sodium, 250 mg twice daily, is initiated on Day 6.

By Day 8 of hospitalization, there is no notable change in Mr. J’s depressive symptoms. On Day 9, sertraline is increased to 200 mg/d, with little improvement from Mr. J’s perspective. The multidisciplinary team evaluates him, and when directly asked, Mr. J cites his 4 greatest complaints to be poor sleep, fatigue, no appetite, and depressed mood. Once again, he states, “I would rather be dead than go on feeling this way.”

[polldaddy:10120587]

The authors’ observations

Due to Mr. J’s severe, unrelenting depressive episode, the treatment team obtained his informed consent to undergo ECT. On Day 9, before initiating ECT, the pharmacist recommended mirtazapine, even though the patient weighed almost 89 kg (196.21 lb) and had a body mass index of 27.8 kg/m². The treatment team thought that mirtazapine augmentation could potentially help the sertraline work more quickly while targeting Mr. J’s 4 greatest complaints.

Mirtazapine is a central alpha-2 antagonist or noradrenergic and specific serotonergic antidepressant (NaSSA) that works through antagonism of the presynaptic alpha-2 adrenergic receptors to indirectly regulate release of monoamines and increase the release of serotonin and norepinephrine.⁶ Additionally, mirtazapine has antagonist actions at 5HT2A, 5HT2C, 5HT3, and histamine-1 receptors.⁶ Potential adverse effects include drowsiness and increased appetite leading to weight gain.⁷ Mirtazapine’s therapeutic efficacy is similar to SSRIs for treating depression.⁴ Mirtazapine in combination with an SNRI has been referred to as “California rocket fuel” due to the theoretical pharmacologic synergy and resulting strong antidepressant action.⁶ It was hypothesized that similar effects could be seen by augmenting the SSRI sertraline with mirtazapine.

Continued to: The time to efficacy with mirtazapine...

OUTCOME Rapid improvement


On Day 9, Mr. J receives the first dose of mirtazapine, 7.5 mg at bedtime. On Day 10, when Mr. J wakes, his mood is notably improved. He is more interactive (sitting up in bed reading and making eye contact with the staff during an interview), and he reports improved sleep and eats most of his breakfast.

After receiving 3 doses of mirtazapine, Mr. J reports that he feels back to his normal self; he is interactive, alert, and eating well. Due to the rapid improvement in mood, ECT is discontinued, and he does not receive any ECT treatment during the remainder of his hospitalization.

On Day 11, divalproex is discontinued. Because Mr. J receives only 5 days of therapy with this agent, his divalproex level is not checked. At this point, the treatment team feels confident in ruling out bipolar disorder.

On Day 15, Mr. J is discharged with sertraline, 200 mg/d, mirtazapine, 7.5 mg/d at 7 pm, aripiprazole, 20 mg/d, clonazepam, 1 mg twice daily as needed for anxiety, melatonin 5 mg/d, and adalimumab, 40 mg IM every 2 weeks. Discharge instructions include a follow-up in 2 weeks to evaluate continuation strategies for the discharge medications.

Ten months after his depressive episode, Mr. J has had no further admissions at the hospital where he received the treatment described here.

Bottom Line

Evidence for the treatment of major depressive disorder induced by corticosteroid withdrawal is limited. Despite trials of agents from multiple medication classes, the depressive episode may not improve. Adding mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor may prove successful.

Related Resources

• Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528.
• Kenna HA, Poon AW, de los Angeles CP, et al. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65(6):549-560.

Drug Brand Names
Adalimumab • Humira
Aripiprazole • Abilify
Bupropion • Wellbutrin, Zyban
Buspirone • Buspar
Clonazepam • Klonopin
Diazepam • Valium
Diphenhydramine • Benadryl
Divalproex • Depakote, Depakote ER
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Prednisone • Deltasone
Sertraline • Zoloft

CASE Suicidal ideation, flare-up of ulcerative colitis

Mr. J, age 56, who has a history of major depressive disorder (MDD), generalized anxiety disorder (GAD), and ulcerative colitis (UC), presents to the emergency department (ED) with suicidal ideation and a plan to overdose on his medications. He reports no current emotional or financial stressors in his personal life. Home medications documented at the time of his arrival to the ED include sertraline, 100 mg/d, bupropion, 150 mg/d, buspirone, 10 mg 3 times daily, diazepam 10 mg 3 times daily, as needed, adalimumab, 40 mg IM every 2 weeks, and diphenhydramine, 50 mg every night.

A recent flare-up of UC resulted in Mr. J being placed on a 15-week prednisone taper, beginning at 80 mg/d and decreasing by 5 mg weekly, which was completed 2 weeks before he presented to the ED. After completing the prednisone taper, Mr. J went to his primary care physician (PCP) on 3 separate occasions due to episodes of severe depression. Although the PCP prescribed multiple medications to target Mr. J’s depressive symptoms, he continued to decline.

Subsequently, Mr. J came to the ED and is admitted to the psychiatric unit for safety and stabilization. Upon admission, Mr. J becomes bedridden, and reports that his current depressive episode is the most severe that he has ever experienced in his more than 30 years of having MDD. He says that neither bupropion nor buspirone are helping with his depression, anxiety, or any related symptom.

[polldaddy:10120537]

The authors’ observations

At admission, all of Mr. J’s home medications, except sertraline and adalimumab, which had been prescribed to treat UC (Box^1,2), were discontinued. His diazepam was discontinued because the clinician felt it may have been contributing to Mr. J’s inability to walk or get out of bed. Diazepam was not tapered because it was initiated 7 days prior to admission and was thought to be exacerbating his depression and suicidal ideation. Bupropion and buspirone, which were initiated 2 weeks prior, were discontinued because Mr. J reported that neither medication was helping with his depression, anxiety, or any related symptom.

EVALUATION Poor appetite, anxiety, and continued suicidality

During evaluation, vital signs, laboratory findings, and diagnostic testing are found to be unremarkable. Mr. J’s presentation and complaints are entirely subjective, and include poor appetite, fatigue, difficulty sleeping, sorrow, anxiety, and continued suicidality. Mr. J reports that he feels miserable, which is reflected by his poor eye contact, soft speech, and body language.

Continued to: The authors' observations

 

 

The authors’ observations

MDD is a mood disorder characterized by depressed mood and/or loss of interest or pleasure for more than 2 weeks.³ First-line pharmacotherapy for MDD includes monotherapy with a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion.⁴ Medication selection is typically based on patient-specific factors, adverse effect profile, drug–drug interactions, and cost. Other treatments include electroconvulsive therapy (ECT) or cognitive-behavioral therapy (CBT).^4,5 Augmentation agents, such as second-generation antipsychotics, lithium, thyroid hormone supplementation, buspirone, anticonvulsants, and combinations of antidepressants, may also be considered.⁴

TREATMENT Condition worsens

On Day 2 of hospitalization, Mr. J is started on aripiprazole, 5 mg/d, clonazepam, 1 mg twice daily, and melatonin, 5 mg, each night for sleep. Aripiprazole, 5 mg/d, is initiated as an adjunct to sertraline for MDD because Mr. J reports feeling much worse and continues to report that he would “rather die than feel this way.” Mr. J begins to believe that his current state is his new baseline, and that feeling better is no longer possible.

On Day 3 of hospitalization, records are obtained from a clinician at an outside facility who previously treated Mr. J; this clinician suspected Mr. J may have bipolar disorder. On Days 3 and 5 of hospitalization, aripiprazole is titrated to 10 mg/d, and then to 20 mg/d, respectively. On Day 6, sertraline is increased to 150 mg/d because Mr. J continues to report low mood and limited sleep and is less and less interactive during interviews. He remains suicidal, and because bipolar depression is suspected (although this is not a clear diagnosis in his records), a trial of divalproex sodium, 250 mg twice daily, is initiated on Day 6.

By Day 8 of hospitalization, there is no notable change in Mr. J’s depressive symptoms. On Day 9, sertraline is increased to 200 mg/d, with little improvement from Mr. J’s perspective. The multidisciplinary team evaluates him, and when directly asked, Mr. J cites his 4 greatest complaints to be poor sleep, fatigue, no appetite, and depressed mood. Once again, he states, “I would rather be dead than go on feeling this way.”

[polldaddy:10120587]

The authors’ observations

Due to Mr. J’s severe, unrelenting depressive episode, the treatment team obtained his informed consent to undergo ECT. On Day 9, before initiating ECT, the pharmacist recommended mirtazapine, even though the patient weighed almost 89 kg (196.21 lb) and had a body mass index of 27.8 kg/m². The treatment team thought that mirtazapine augmentation could potentially help the sertraline work more quickly while targeting Mr. J’s 4 greatest complaints.

Mirtazapine is a central alpha-2 antagonist or noradrenergic and specific serotonergic antidepressant (NaSSA) that works through antagonism of the presynaptic alpha-2 adrenergic receptors to indirectly regulate release of monoamines and increase the release of serotonin and norepinephrine.⁶ Additionally, mirtazapine has antagonist actions at 5HT2A, 5HT2C, 5HT3, and histamine-1 receptors.⁶ Potential adverse effects include drowsiness and increased appetite leading to weight gain.⁷ Mirtazapine’s therapeutic efficacy is similar to SSRIs for treating depression.⁴ Mirtazapine in combination with an SNRI has been referred to as “California rocket fuel” due to the theoretical pharmacologic synergy and resulting strong antidepressant action.⁶ It was hypothesized that similar effects could be seen by augmenting the SSRI sertraline with mirtazapine.

Continued to: The time to efficacy with mirtazapine...

OUTCOME Rapid improvement


On Day 9, Mr. J receives the first dose of mirtazapine, 7.5 mg at bedtime. On Day 10, when Mr. J wakes, his mood is notably improved. He is more interactive (sitting up in bed reading and making eye contact with the staff during an interview), and he reports improved sleep and eats most of his breakfast.

After receiving 3 doses of mirtazapine, Mr. J reports that he feels back to his normal self; he is interactive, alert, and eating well. Due to the rapid improvement in mood, ECT is discontinued, and he does not receive any ECT treatment during the remainder of his hospitalization.

On Day 11, divalproex is discontinued. Because Mr. J receives only 5 days of therapy with this agent, his divalproex level is not checked. At this point, the treatment team feels confident in ruling out bipolar disorder.

On Day 15, Mr. J is discharged with sertraline, 200 mg/d, mirtazapine, 7.5 mg/d at 7 pm, aripiprazole, 20 mg/d, clonazepam, 1 mg twice daily as needed for anxiety, melatonin 5 mg/d, and adalimumab, 40 mg IM every 2 weeks. Discharge instructions include a follow-up in 2 weeks to evaluate continuation strategies for the discharge medications.

Ten months after his depressive episode, Mr. J has had no further admissions at the hospital where he received the treatment described here.

Bottom Line

Evidence for the treatment of major depressive disorder induced by corticosteroid withdrawal is limited. Despite trials of agents from multiple medication classes, the depressive episode may not improve. Adding mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor may prove successful.

Related Resources

• Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528.
• Kenna HA, Poon AW, de los Angeles CP, et al. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65(6):549-560.

Drug Brand Names
Adalimumab • Humira
Aripiprazole • Abilify
Bupropion • Wellbutrin, Zyban
Buspirone • Buspar
Clonazepam • Klonopin
Diazepam • Valium
Diphenhydramine • Benadryl
Divalproex • Depakote, Depakote ER
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Prednisone • Deltasone
Sertraline • Zoloft

Although antipsychotics have revolutionized the treatment of severe mental illnesses, adverse effects often present a substantial obstacle to adherence. One of the most tenacious and difficult-to-treat adverse effects is tardive dyskinesia (TD), a neuromotor syndrome with characteristic involuntary repetitive movements, typically of the muscles of the jaw, lips, and tongue. In addition to spasms and grimacing, patients can have choreoathetoid movements of the neck. In more extreme presentations, some patients can have difficulty breathing. TD is a largely irreversible condition. It is often a disfiguring lifelong disability that can further stigmatize patients who already suffer scorn and derision. TD usually has a delayed onset after a patient is started on an antipsychotic.¹ The syndrome is more commonly associated with first-generation antipsychotics, but affects up to 20% of patients who are treated with second-generation antipsychotics.¹ In the United States, TD affects as many as 500,000 patients.¹

There are several palliative interventions for TD, but the evidence for a consistently reliable treatment is weak. Branched-chain amino acids, ginkgo biloba, melatonin, and vitamin E have been investigated as interventions. Other approaches include switching to an alternate antipsychotic such as clozapine, adjusting the antipsychotic dose, using anticholinergic medications, adjunctive amantadine, gamma aminobutyric acid agonists, or adding tetrabenazine.

The FDA recently approved two vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for addressing symptoms of TD. However, these medications can cost tens of thousands of dollars per year, and also carry the risk of adverse effects such as sedation, akathisia, urinary retention, constipation, and muscle pain.² When treating a patient who develops TD, one might consider other potentially effective therapies with low adverse effect profiles that may be more cost-effective than existing treatments. The bioactive form of vitamin B6 (pyridoxine), pyridoxal-5-phosphate, has been used to treat various antipsychotic-induced movement disorders. Preliminary evidence suggests that vitamin B6 may help reduce the symptoms of TD.

A recent Cochrane Database Review (2015)³ of pyridoxal-5-phosphate treatment for TD found a significant improvement in symptoms compared with placebo. Although the studies included in this review were limited by modest sample sizes and short follow-up periods, 2 of the investigations revealed improvements of >40% in extrapyramidal symptoms with vitamin B6 compared with placebo. Lerner et al (2001)⁴ conducted a randomized, double-blind, placebo-controlled crossover trial in which 15 inpatients with schizophrenia who met the criteria for TD were assigned to vitamin B6, 400 mg/d, or placebo for 4 weeks. After a 2-week washout period, the placebo group was given vitamin B6 and vice versa. Compared with placebo, mean scores on the parkinsonism and dyskinetic movement subscales of the Extrapyramidal Symptom Rating Scale were significantly better in the third week of treatment with vitamin B6.

Lerner et al (2007)⁵ later conducted a separate crossover study using the same design with a washout period. This trial included a larger sample size (50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD) and the dosage of vitamin B6 was increased to 1,200 mg/d over 26 weeks. Patients who received vitamin B6 experienced a significantly greater decrease in Extrapyramidal Symptom Rating Scale scores compared with those in the placebo group.

Continued to: A 29-year-old woman with treatment-resistant schizophrenia...

Vitamin B6 has been known to improve other psychotropic-induced movement disorders. In a study of lithium-induced tremors, treatment with pyridoxine, 900 to 1,200 mg/d, resulted in “impressive improvement until total disappearance of tremor.”⁸ Lerner et al (2004)⁹ also reported significant improvement for patients with neuroleptic-induced akathisia who were treated with vitamin B6.

Some proposed mechanisms of action

Pyridoxal-5-phosphate is a coenzyme in the synthesis of dopamine and other neuro­transmitters. This might explain in part the biochemical mechanism of vitamin B6 in attenuating motor symptoms following long-term dopamine blockade. Chronic neurotransmitter antagonism may result in an upregulation of dopamine receptors in response. This compensatory reaction might create a dopamine receptor super-sensitivity in the nigrostriatal pathways.¹⁰

Another potential mechanism of action might be vitamin B6’s potent antioxidant properties and its scavenging of free radicals. The neurotoxicity of oxidative stress has been implicated in various movement disorders and psychiatric conditions.

In all of the studies described here, patients continued to receive daily antipsychotic treatment. In these trials, the adverse effects of vitamin B6 were minimal or negligible. In one study, vitamin B6 was reported to have had a better adverse effect profile than placebo.⁴

Although antipsychotics have revolutionized the treatment of severe mental illnesses, adverse effects often present a substantial obstacle to adherence. One of the most tenacious and difficult-to-treat adverse effects is tardive dyskinesia (TD), a neuromotor syndrome with characteristic involuntary repetitive movements, typically of the muscles of the jaw, lips, and tongue. In addition to spasms and grimacing, patients can have choreoathetoid movements of the neck. In more extreme presentations, some patients can have difficulty breathing. TD is a largely irreversible condition. It is often a disfiguring lifelong disability that can further stigmatize patients who already suffer scorn and derision. TD usually has a delayed onset after a patient is started on an antipsychotic.¹ The syndrome is more commonly associated with first-generation antipsychotics, but affects up to 20% of patients who are treated with second-generation antipsychotics.¹ In the United States, TD affects as many as 500,000 patients.¹

There are several palliative interventions for TD, but the evidence for a consistently reliable treatment is weak. Branched-chain amino acids, ginkgo biloba, melatonin, and vitamin E have been investigated as interventions. Other approaches include switching to an alternate antipsychotic such as clozapine, adjusting the antipsychotic dose, using anticholinergic medications, adjunctive amantadine, gamma aminobutyric acid agonists, or adding tetrabenazine.

The FDA recently approved two vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for addressing symptoms of TD. However, these medications can cost tens of thousands of dollars per year, and also carry the risk of adverse effects such as sedation, akathisia, urinary retention, constipation, and muscle pain.² When treating a patient who develops TD, one might consider other potentially effective therapies with low adverse effect profiles that may be more cost-effective than existing treatments. The bioactive form of vitamin B6 (pyridoxine), pyridoxal-5-phosphate, has been used to treat various antipsychotic-induced movement disorders. Preliminary evidence suggests that vitamin B6 may help reduce the symptoms of TD.

A recent Cochrane Database Review (2015)³ of pyridoxal-5-phosphate treatment for TD found a significant improvement in symptoms compared with placebo. Although the studies included in this review were limited by modest sample sizes and short follow-up periods, 2 of the investigations revealed improvements of >40% in extrapyramidal symptoms with vitamin B6 compared with placebo. Lerner et al (2001)⁴ conducted a randomized, double-blind, placebo-controlled crossover trial in which 15 inpatients with schizophrenia who met the criteria for TD were assigned to vitamin B6, 400 mg/d, or placebo for 4 weeks. After a 2-week washout period, the placebo group was given vitamin B6 and vice versa. Compared with placebo, mean scores on the parkinsonism and dyskinetic movement subscales of the Extrapyramidal Symptom Rating Scale were significantly better in the third week of treatment with vitamin B6.

Lerner et al (2007)⁵ later conducted a separate crossover study using the same design with a washout period. This trial included a larger sample size (50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD) and the dosage of vitamin B6 was increased to 1,200 mg/d over 26 weeks. Patients who received vitamin B6 experienced a significantly greater decrease in Extrapyramidal Symptom Rating Scale scores compared with those in the placebo group.

Continued to: A 29-year-old woman with treatment-resistant schizophrenia...

Vitamin B6 has been known to improve other psychotropic-induced movement disorders. In a study of lithium-induced tremors, treatment with pyridoxine, 900 to 1,200 mg/d, resulted in “impressive improvement until total disappearance of tremor.”⁸ Lerner et al (2004)⁹ also reported significant improvement for patients with neuroleptic-induced akathisia who were treated with vitamin B6.

Some proposed mechanisms of action

Pyridoxal-5-phosphate is a coenzyme in the synthesis of dopamine and other neuro­transmitters. This might explain in part the biochemical mechanism of vitamin B6 in attenuating motor symptoms following long-term dopamine blockade. Chronic neurotransmitter antagonism may result in an upregulation of dopamine receptors in response. This compensatory reaction might create a dopamine receptor super-sensitivity in the nigrostriatal pathways.¹⁰

Another potential mechanism of action might be vitamin B6’s potent antioxidant properties and its scavenging of free radicals. The neurotoxicity of oxidative stress has been implicated in various movement disorders and psychiatric conditions.

In all of the studies described here, patients continued to receive daily antipsychotic treatment. In these trials, the adverse effects of vitamin B6 were minimal or negligible. In one study, vitamin B6 was reported to have had a better adverse effect profile than placebo.⁴

Although antipsychotics have revolutionized the treatment of severe mental illnesses, adverse effects often present a substantial obstacle to adherence. One of the most tenacious and difficult-to-treat adverse effects is tardive dyskinesia (TD), a neuromotor syndrome with characteristic involuntary repetitive movements, typically of the muscles of the jaw, lips, and tongue. In addition to spasms and grimacing, patients can have choreoathetoid movements of the neck. In more extreme presentations, some patients can have difficulty breathing. TD is a largely irreversible condition. It is often a disfiguring lifelong disability that can further stigmatize patients who already suffer scorn and derision. TD usually has a delayed onset after a patient is started on an antipsychotic.¹ The syndrome is more commonly associated with first-generation antipsychotics, but affects up to 20% of patients who are treated with second-generation antipsychotics.¹ In the United States, TD affects as many as 500,000 patients.¹

There are several palliative interventions for TD, but the evidence for a consistently reliable treatment is weak. Branched-chain amino acids, ginkgo biloba, melatonin, and vitamin E have been investigated as interventions. Other approaches include switching to an alternate antipsychotic such as clozapine, adjusting the antipsychotic dose, using anticholinergic medications, adjunctive amantadine, gamma aminobutyric acid agonists, or adding tetrabenazine.

The FDA recently approved two vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for addressing symptoms of TD. However, these medications can cost tens of thousands of dollars per year, and also carry the risk of adverse effects such as sedation, akathisia, urinary retention, constipation, and muscle pain.² When treating a patient who develops TD, one might consider other potentially effective therapies with low adverse effect profiles that may be more cost-effective than existing treatments. The bioactive form of vitamin B6 (pyridoxine), pyridoxal-5-phosphate, has been used to treat various antipsychotic-induced movement disorders. Preliminary evidence suggests that vitamin B6 may help reduce the symptoms of TD.

A recent Cochrane Database Review (2015)³ of pyridoxal-5-phosphate treatment for TD found a significant improvement in symptoms compared with placebo. Although the studies included in this review were limited by modest sample sizes and short follow-up periods, 2 of the investigations revealed improvements of >40% in extrapyramidal symptoms with vitamin B6 compared with placebo. Lerner et al (2001)⁴ conducted a randomized, double-blind, placebo-controlled crossover trial in which 15 inpatients with schizophrenia who met the criteria for TD were assigned to vitamin B6, 400 mg/d, or placebo for 4 weeks. After a 2-week washout period, the placebo group was given vitamin B6 and vice versa. Compared with placebo, mean scores on the parkinsonism and dyskinetic movement subscales of the Extrapyramidal Symptom Rating Scale were significantly better in the third week of treatment with vitamin B6.

Lerner et al (2007)⁵ later conducted a separate crossover study using the same design with a washout period. This trial included a larger sample size (50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD) and the dosage of vitamin B6 was increased to 1,200 mg/d over 26 weeks. Patients who received vitamin B6 experienced a significantly greater decrease in Extrapyramidal Symptom Rating Scale scores compared with those in the placebo group.

Continued to: A 29-year-old woman with treatment-resistant schizophrenia...

Vitamin B6 has been known to improve other psychotropic-induced movement disorders. In a study of lithium-induced tremors, treatment with pyridoxine, 900 to 1,200 mg/d, resulted in “impressive improvement until total disappearance of tremor.”⁸ Lerner et al (2004)⁹ also reported significant improvement for patients with neuroleptic-induced akathisia who were treated with vitamin B6.

Some proposed mechanisms of action

Pyridoxal-5-phosphate is a coenzyme in the synthesis of dopamine and other neuro­transmitters. This might explain in part the biochemical mechanism of vitamin B6 in attenuating motor symptoms following long-term dopamine blockade. Chronic neurotransmitter antagonism may result in an upregulation of dopamine receptors in response. This compensatory reaction might create a dopamine receptor super-sensitivity in the nigrostriatal pathways.¹⁰

Another potential mechanism of action might be vitamin B6’s potent antioxidant properties and its scavenging of free radicals. The neurotoxicity of oxidative stress has been implicated in various movement disorders and psychiatric conditions.

In all of the studies described here, patients continued to receive daily antipsychotic treatment. In these trials, the adverse effects of vitamin B6 were minimal or negligible. In one study, vitamin B6 was reported to have had a better adverse effect profile than placebo.⁴

During my residency training, I was trained in the standard “reactive” psychiatric consultation model. In this system, I would see consults placed by the primary team after they identified a behavioral issue in a patient. As a trainee, I experienced frequent frustrations working in this model: Consults that are discharge-dependent (“Can you see the patient before he is discharged this morning?”), consults for acute behavioral dysregulation (“The patient is near the elevator, can you come see him ASAP?”), or consults for consequences of poor management of alcohol/benzodiazepine withdrawal (“The patient is confused and trying to leave”).

As a fellow in consultation-liaison (C-L) psychiatry, I was introduced to the “proactive” consultation model, which avoids some of these issues. In this article, which is intended for residents who have not been exposed to this new approach, I explain how the proactive model changes our experience as C-L clinicians.

The Behavioral Intervention Team

At Yale New Haven Hospital, the Behavioral Intervention Team (BIT) is a proactive, multidisciplinary psychiatric consultation service that serves the internal medicine units at the hospital. The team consists of nurse practitioners, nurse liaison specialists, social workers, and psychiatrists. The team identifies and removes behavioral barriers in the care of hospitalized mentally ill patients.

The BIT collaborates closely with the medical team through formal and informal consultation; co-management of behavioral issues; education of medical, nursing, and social work staff; and direct care of complex patients with behavioral disorders. The BIT assists the medical team with transitions to appropriate outpatient and inpatient psychiatric care. The team also manages the relationship with the insurer when a patient requires a stay in a psychiatric unit.

This model has a critical financial benefit in reducing the length of stay, but it also has many other benefits. It focuses on early recognition and treatment, and helps mitigate the effects of mental or substance use disorders on patients’ recovery. BIT members educate their peers regarding management of a multitude of behavioral issues. This fosters extensive informal collaboration (“curbside consultation”), which helps patients who did not receive a formal consult. The model distributes work more rationally among different professional specialists. It yields a relationship with medical teams that is not only more effective, but also more enjoyable. In the BIT model, psychiatrists pick the cases where they feel they can have the most impact, and avoid the cases they feel they cannot have any.^1-3

CASE A better approach to alcohol withdrawal

Mr. X, age 56, has a history of alcohol use disorder, hypertension, and coronary artery disease. He’s had multiple past admissions for complicated alcohol withdrawal. He is transferred from a local community hospital, where he had presented with chest pain. His last drink was 2 days prior to admission, and his blood alcohol level is <10 mg/dL.

During Mr. X’s previous hospitalizations, psychiatric consults were performed in the standard reactive model. The primary team initially prescribed an ineffective dosage of benzodiazepines for his alcohol withdrawal. This escalated his withdrawal into delirium tremens, after which psychiatry was involved. Due to this early ineffective management, the patient had a prolonged medical ICU stay and overall stay, experienced increased medical complications, and required increased staff resources because he was extremely agitated.

Continued to: During this hospitalization...

During this hospitalization, Mr. X arrives with similar medical complaints. The nurse practitioner on the BIT service, who screened all admissions each day, examines the prior notes (she finds the team sign-outs to be particularly useful). She suggests a psychiatric consult on Day 1 of the admission, which the primary medical team orders. The BIT nurse practitioner gives apt recommendations of evidence-based management, including a benzodiazepine taper, high-dose thiamine, and psychopharmacologic approaches to severe agitation. The nurse liaison specialist on the service makes behavioral plans for managing agitation, which she communicates to the nurses caring for Mr. X.

Because his withdrawal is managed more promptly, Mr. X’s length of stay is shorter and he does not experience any medical complications. The BIT social worker helps find appropriate aftercare options, including residential treatment and Alcoholics Anonymous meetings, to which the patient agrees.

Participating in this case was highly educational for me as a trainee. This case is but one example among many where proactive consultation provided prompt care, lowered the rate of complications, reduced length of stay, and resulted in greater provider satisfaction. The Table⁴ contrasts the proactive and reactive consultation models. The following 5 factors are critical in the proactive consultation model^4,5:

1. Standardized and reliable procedure screening of all admissions, involving a mental health professional, through record review and staff contact. This screening should identify patients with issues who will benefit specifically from in-hospital services, rather than just patients with any psychiatric issue. An electronic medical record is essential to efficient screening, team communication, and progress monitoring. Truly integrated consultation would be impossible with a paper chart.

Research has shown the effectiveness of proactive, embedded, multidisciplinary approaches.^1-3,5 It was a gratifying experience to work in this model. I worked intimately with medical clinicians, and shared the burden of responsibilities leading to optimal patient outcomes. The proactive consultation model truly re-emphasizes the “liaison” component of C-L psychiatry, as it was originally envisioned.

During my residency training, I was trained in the standard “reactive” psychiatric consultation model. In this system, I would see consults placed by the primary team after they identified a behavioral issue in a patient. As a trainee, I experienced frequent frustrations working in this model: Consults that are discharge-dependent (“Can you see the patient before he is discharged this morning?”), consults for acute behavioral dysregulation (“The patient is near the elevator, can you come see him ASAP?”), or consults for consequences of poor management of alcohol/benzodiazepine withdrawal (“The patient is confused and trying to leave”).

As a fellow in consultation-liaison (C-L) psychiatry, I was introduced to the “proactive” consultation model, which avoids some of these issues. In this article, which is intended for residents who have not been exposed to this new approach, I explain how the proactive model changes our experience as C-L clinicians.

The Behavioral Intervention Team

At Yale New Haven Hospital, the Behavioral Intervention Team (BIT) is a proactive, multidisciplinary psychiatric consultation service that serves the internal medicine units at the hospital. The team consists of nurse practitioners, nurse liaison specialists, social workers, and psychiatrists. The team identifies and removes behavioral barriers in the care of hospitalized mentally ill patients.

The BIT collaborates closely with the medical team through formal and informal consultation; co-management of behavioral issues; education of medical, nursing, and social work staff; and direct care of complex patients with behavioral disorders. The BIT assists the medical team with transitions to appropriate outpatient and inpatient psychiatric care. The team also manages the relationship with the insurer when a patient requires a stay in a psychiatric unit.

This model has a critical financial benefit in reducing the length of stay, but it also has many other benefits. It focuses on early recognition and treatment, and helps mitigate the effects of mental or substance use disorders on patients’ recovery. BIT members educate their peers regarding management of a multitude of behavioral issues. This fosters extensive informal collaboration (“curbside consultation”), which helps patients who did not receive a formal consult. The model distributes work more rationally among different professional specialists. It yields a relationship with medical teams that is not only more effective, but also more enjoyable. In the BIT model, psychiatrists pick the cases where they feel they can have the most impact, and avoid the cases they feel they cannot have any.^1-3

CASE A better approach to alcohol withdrawal

Mr. X, age 56, has a history of alcohol use disorder, hypertension, and coronary artery disease. He’s had multiple past admissions for complicated alcohol withdrawal. He is transferred from a local community hospital, where he had presented with chest pain. His last drink was 2 days prior to admission, and his blood alcohol level is <10 mg/dL.

During Mr. X’s previous hospitalizations, psychiatric consults were performed in the standard reactive model. The primary team initially prescribed an ineffective dosage of benzodiazepines for his alcohol withdrawal. This escalated his withdrawal into delirium tremens, after which psychiatry was involved. Due to this early ineffective management, the patient had a prolonged medical ICU stay and overall stay, experienced increased medical complications, and required increased staff resources because he was extremely agitated.

Continued to: During this hospitalization...

During this hospitalization, Mr. X arrives with similar medical complaints. The nurse practitioner on the BIT service, who screened all admissions each day, examines the prior notes (she finds the team sign-outs to be particularly useful). She suggests a psychiatric consult on Day 1 of the admission, which the primary medical team orders. The BIT nurse practitioner gives apt recommendations of evidence-based management, including a benzodiazepine taper, high-dose thiamine, and psychopharmacologic approaches to severe agitation. The nurse liaison specialist on the service makes behavioral plans for managing agitation, which she communicates to the nurses caring for Mr. X.

Because his withdrawal is managed more promptly, Mr. X’s length of stay is shorter and he does not experience any medical complications. The BIT social worker helps find appropriate aftercare options, including residential treatment and Alcoholics Anonymous meetings, to which the patient agrees.

Participating in this case was highly educational for me as a trainee. This case is but one example among many where proactive consultation provided prompt care, lowered the rate of complications, reduced length of stay, and resulted in greater provider satisfaction. The Table⁴ contrasts the proactive and reactive consultation models. The following 5 factors are critical in the proactive consultation model^4,5:

1. Standardized and reliable procedure screening of all admissions, involving a mental health professional, through record review and staff contact. This screening should identify patients with issues who will benefit specifically from in-hospital services, rather than just patients with any psychiatric issue. An electronic medical record is essential to efficient screening, team communication, and progress monitoring. Truly integrated consultation would be impossible with a paper chart.

Research has shown the effectiveness of proactive, embedded, multidisciplinary approaches.^1-3,5 It was a gratifying experience to work in this model. I worked intimately with medical clinicians, and shared the burden of responsibilities leading to optimal patient outcomes. The proactive consultation model truly re-emphasizes the “liaison” component of C-L psychiatry, as it was originally envisioned.

During my residency training, I was trained in the standard “reactive” psychiatric consultation model. In this system, I would see consults placed by the primary team after they identified a behavioral issue in a patient. As a trainee, I experienced frequent frustrations working in this model: Consults that are discharge-dependent (“Can you see the patient before he is discharged this morning?”), consults for acute behavioral dysregulation (“The patient is near the elevator, can you come see him ASAP?”), or consults for consequences of poor management of alcohol/benzodiazepine withdrawal (“The patient is confused and trying to leave”).

As a fellow in consultation-liaison (C-L) psychiatry, I was introduced to the “proactive” consultation model, which avoids some of these issues. In this article, which is intended for residents who have not been exposed to this new approach, I explain how the proactive model changes our experience as C-L clinicians.

The Behavioral Intervention Team

At Yale New Haven Hospital, the Behavioral Intervention Team (BIT) is a proactive, multidisciplinary psychiatric consultation service that serves the internal medicine units at the hospital. The team consists of nurse practitioners, nurse liaison specialists, social workers, and psychiatrists. The team identifies and removes behavioral barriers in the care of hospitalized mentally ill patients.

The BIT collaborates closely with the medical team through formal and informal consultation; co-management of behavioral issues; education of medical, nursing, and social work staff; and direct care of complex patients with behavioral disorders. The BIT assists the medical team with transitions to appropriate outpatient and inpatient psychiatric care. The team also manages the relationship with the insurer when a patient requires a stay in a psychiatric unit.

This model has a critical financial benefit in reducing the length of stay, but it also has many other benefits. It focuses on early recognition and treatment, and helps mitigate the effects of mental or substance use disorders on patients’ recovery. BIT members educate their peers regarding management of a multitude of behavioral issues. This fosters extensive informal collaboration (“curbside consultation”), which helps patients who did not receive a formal consult. The model distributes work more rationally among different professional specialists. It yields a relationship with medical teams that is not only more effective, but also more enjoyable. In the BIT model, psychiatrists pick the cases where they feel they can have the most impact, and avoid the cases they feel they cannot have any.^1-3

CASE A better approach to alcohol withdrawal

Mr. X, age 56, has a history of alcohol use disorder, hypertension, and coronary artery disease. He’s had multiple past admissions for complicated alcohol withdrawal. He is transferred from a local community hospital, where he had presented with chest pain. His last drink was 2 days prior to admission, and his blood alcohol level is <10 mg/dL.

During Mr. X’s previous hospitalizations, psychiatric consults were performed in the standard reactive model. The primary team initially prescribed an ineffective dosage of benzodiazepines for his alcohol withdrawal. This escalated his withdrawal into delirium tremens, after which psychiatry was involved. Due to this early ineffective management, the patient had a prolonged medical ICU stay and overall stay, experienced increased medical complications, and required increased staff resources because he was extremely agitated.

Continued to: During this hospitalization...

During this hospitalization, Mr. X arrives with similar medical complaints. The nurse practitioner on the BIT service, who screened all admissions each day, examines the prior notes (she finds the team sign-outs to be particularly useful). She suggests a psychiatric consult on Day 1 of the admission, which the primary medical team orders. The BIT nurse practitioner gives apt recommendations of evidence-based management, including a benzodiazepine taper, high-dose thiamine, and psychopharmacologic approaches to severe agitation. The nurse liaison specialist on the service makes behavioral plans for managing agitation, which she communicates to the nurses caring for Mr. X.

Because his withdrawal is managed more promptly, Mr. X’s length of stay is shorter and he does not experience any medical complications. The BIT social worker helps find appropriate aftercare options, including residential treatment and Alcoholics Anonymous meetings, to which the patient agrees.

Participating in this case was highly educational for me as a trainee. This case is but one example among many where proactive consultation provided prompt care, lowered the rate of complications, reduced length of stay, and resulted in greater provider satisfaction. The Table⁴ contrasts the proactive and reactive consultation models. The following 5 factors are critical in the proactive consultation model^4,5:

1. Standardized and reliable procedure screening of all admissions, involving a mental health professional, through record review and staff contact. This screening should identify patients with issues who will benefit specifically from in-hospital services, rather than just patients with any psychiatric issue. An electronic medical record is essential to efficient screening, team communication, and progress monitoring. Truly integrated consultation would be impossible with a paper chart.

Research has shown the effectiveness of proactive, embedded, multidisciplinary approaches.^1-3,5 It was a gratifying experience to work in this model. I worked intimately with medical clinicians, and shared the burden of responsibilities leading to optimal patient outcomes. The proactive consultation model truly re-emphasizes the “liaison” component of C-L psychiatry, as it was originally envisioned.

Bone marrow aspirate showing MM

New York—Three novel treatment strategies that target B-cell maturation antigen (BCMA) are showing promise in recent multiple myeloma (MM) clinical trials, according to Shaji K. Kumar, MD, of Mayo Clinic Cancer Center in Rochester, Minnesota.

The strategies include B-cell maturation antigen (BCMA) antibody-drug conjugate, BCMA-specific chimeric antigen receptor (CAR) T-cell therapies, and bispecific T-cell engagers (BiTEs).

“Clearly, there are a lot of exciting drugs that are currently in clinical trials, but these 3 platforms appear to be much more advanced than the others, and hopefully we will see that in the clinic in the near future,” Dr. Kumar told attendees at the NCCN 13th Annual Congress: Hematologic Malignancies.

BCMA is required for plasma cell survival and is broadly expressed on malignant plasma cells.

BCMA antibody-drug conjugate

The antibody-drug conjugate, GSK2857916, is a humanized IgG1 anti-BCMA antibody conjugated to a microtubule-disrupting agent. It produced an overall response rate of 67% at the 2 highest dose levels in 9 MM patients who had previously received multiple standard-of-care agents.

“Some of the responses were quite durable, lasting several months,” he said.

Now, GSK2857916 is being evaluated in a variety of different combinations, he said, including in an upcoming phase 2 study of the antibody-drug conjugate in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone in patients with relapsed or refractory disease.

BCMA-specific CAR T-cell therapy

Some of the most “exciting” data with anti-BCMA CAR T-cell therapy in myeloma, according to Dr. Kumar, involves bb2121. bb2121 showed durable clinical responses in heavily pretreated patients, according to an ASH 2017 presentation.

“The overall response rate is quite significant,” Dr. Kumar said. He related a 94% rate of overall response that was even higher in patients treated with doses of 150 x 10⁶ CAR+ T cells or more. Many of the responses were lasting, he said, with 5 patients in ongoing response for more than a year.

“The results are exciting enough that this is actually moving forward with registration trials,” Dr. Kumar added.

Another novel CAR T-cell product, LCAR-B38M, has demonstrated promising results. LCAR-B38M principally targets BCMA and has led to a significant number of patients achieving stringent complete response that lasted beyond 1 year.

Multiple BCMA-targeting CAR T-cell products that use different vectors and different costimulatory molecules are currently in clinical trials, Dr. Kumar said.

BiTEs

In contrast to CAR T-cell products that must be customized to each patient in a process that takes weeks, BiTEs are a ready-made approach to allow T cells to engage with tumor cells.

“In patients with advanced disease, a lot can change in that short timeframe, so having an approach that is off-the-shelf, which is not patient specific, is quite attractive,” Dr. Kumar said.

BCMA-directed BiTE therapies to watch that are under investigation include AMG 420 and PF-06863135, he said. 

Bone marrow aspirate showing MM

New York—Three novel treatment strategies that target B-cell maturation antigen (BCMA) are showing promise in recent multiple myeloma (MM) clinical trials, according to Shaji K. Kumar, MD, of Mayo Clinic Cancer Center in Rochester, Minnesota.

The strategies include B-cell maturation antigen (BCMA) antibody-drug conjugate, BCMA-specific chimeric antigen receptor (CAR) T-cell therapies, and bispecific T-cell engagers (BiTEs).

“Clearly, there are a lot of exciting drugs that are currently in clinical trials, but these 3 platforms appear to be much more advanced than the others, and hopefully we will see that in the clinic in the near future,” Dr. Kumar told attendees at the NCCN 13th Annual Congress: Hematologic Malignancies.

BCMA is required for plasma cell survival and is broadly expressed on malignant plasma cells.

BCMA antibody-drug conjugate

The antibody-drug conjugate, GSK2857916, is a humanized IgG1 anti-BCMA antibody conjugated to a microtubule-disrupting agent. It produced an overall response rate of 67% at the 2 highest dose levels in 9 MM patients who had previously received multiple standard-of-care agents.

“Some of the responses were quite durable, lasting several months,” he said.

Now, GSK2857916 is being evaluated in a variety of different combinations, he said, including in an upcoming phase 2 study of the antibody-drug conjugate in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone in patients with relapsed or refractory disease.

BCMA-specific CAR T-cell therapy

Some of the most “exciting” data with anti-BCMA CAR T-cell therapy in myeloma, according to Dr. Kumar, involves bb2121. bb2121 showed durable clinical responses in heavily pretreated patients, according to an ASH 2017 presentation.

“The overall response rate is quite significant,” Dr. Kumar said. He related a 94% rate of overall response that was even higher in patients treated with doses of 150 x 10⁶ CAR+ T cells or more. Many of the responses were lasting, he said, with 5 patients in ongoing response for more than a year.

“The results are exciting enough that this is actually moving forward with registration trials,” Dr. Kumar added.

Another novel CAR T-cell product, LCAR-B38M, has demonstrated promising results. LCAR-B38M principally targets BCMA and has led to a significant number of patients achieving stringent complete response that lasted beyond 1 year.

Multiple BCMA-targeting CAR T-cell products that use different vectors and different costimulatory molecules are currently in clinical trials, Dr. Kumar said.

BiTEs

In contrast to CAR T-cell products that must be customized to each patient in a process that takes weeks, BiTEs are a ready-made approach to allow T cells to engage with tumor cells.

“In patients with advanced disease, a lot can change in that short timeframe, so having an approach that is off-the-shelf, which is not patient specific, is quite attractive,” Dr. Kumar said.

BCMA-directed BiTE therapies to watch that are under investigation include AMG 420 and PF-06863135, he said. 

Bone marrow aspirate showing MM

New York—Three novel treatment strategies that target B-cell maturation antigen (BCMA) are showing promise in recent multiple myeloma (MM) clinical trials, according to Shaji K. Kumar, MD, of Mayo Clinic Cancer Center in Rochester, Minnesota.

The strategies include B-cell maturation antigen (BCMA) antibody-drug conjugate, BCMA-specific chimeric antigen receptor (CAR) T-cell therapies, and bispecific T-cell engagers (BiTEs).

“Clearly, there are a lot of exciting drugs that are currently in clinical trials, but these 3 platforms appear to be much more advanced than the others, and hopefully we will see that in the clinic in the near future,” Dr. Kumar told attendees at the NCCN 13th Annual Congress: Hematologic Malignancies.

BCMA is required for plasma cell survival and is broadly expressed on malignant plasma cells.

BCMA antibody-drug conjugate

The antibody-drug conjugate, GSK2857916, is a humanized IgG1 anti-BCMA antibody conjugated to a microtubule-disrupting agent. It produced an overall response rate of 67% at the 2 highest dose levels in 9 MM patients who had previously received multiple standard-of-care agents.

“Some of the responses were quite durable, lasting several months,” he said.

Now, GSK2857916 is being evaluated in a variety of different combinations, he said, including in an upcoming phase 2 study of the antibody-drug conjugate in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone in patients with relapsed or refractory disease.

BCMA-specific CAR T-cell therapy

Some of the most “exciting” data with anti-BCMA CAR T-cell therapy in myeloma, according to Dr. Kumar, involves bb2121. bb2121 showed durable clinical responses in heavily pretreated patients, according to an ASH 2017 presentation.

“The overall response rate is quite significant,” Dr. Kumar said. He related a 94% rate of overall response that was even higher in patients treated with doses of 150 x 10⁶ CAR+ T cells or more. Many of the responses were lasting, he said, with 5 patients in ongoing response for more than a year.

“The results are exciting enough that this is actually moving forward with registration trials,” Dr. Kumar added.

Another novel CAR T-cell product, LCAR-B38M, has demonstrated promising results. LCAR-B38M principally targets BCMA and has led to a significant number of patients achieving stringent complete response that lasted beyond 1 year.

Multiple BCMA-targeting CAR T-cell products that use different vectors and different costimulatory molecules are currently in clinical trials, Dr. Kumar said.

BiTEs

In contrast to CAR T-cell products that must be customized to each patient in a process that takes weeks, BiTEs are a ready-made approach to allow T cells to engage with tumor cells.

“In patients with advanced disease, a lot can change in that short timeframe, so having an approach that is off-the-shelf, which is not patient specific, is quite attractive,” Dr. Kumar said.

BCMA-directed BiTE therapies to watch that are under investigation include AMG 420 and PF-06863135, he said. 

Photo courtesy of NIH

Older patients with untreated Hodgkin lymphoma (HL) can achieve significantly improved survival by adding brentuximab vedotin to their treatment before and after standard chemotherapy, a recent study found.

In patients with low comorbidity scores, responses were even more robust, reported lead author Andrew M. Evens, DO, of the Rutgers Cancer Institute of New Jersey, and colleagues.

“Causes of poor outcomes for older patients with HL are not fully understood but have been attributed to a combination of factors, including presence of comorbidities, poorer performance status, disease and biological differences, inability to tolerate chemotherapy at the full dose, and increased treatment-related toxicities,” the authors wrote in the Journal of Clinical Oncology.

The primary goal of the study was to improve outcomes for untreated, older patients, a group that’s historically been a difficult-to-treat patient population.

The phase 2 trial included 48 HL patients with a median age of 69 (range, 60 – 88).

All patients underwent geriatric assessment for comorbidities and loss of activities of daily living.

Treatment consisted of two doses of brentuximab followed by six cycles of doxorubicin, vinblastine, and dacarbazine (AVD), then four more doses of brentuximab (consolidation doses).

The primary endpoint was complete remission at completion of AVD.

Secondary outcomes included overall response rate, 2-year progression-free survival, 2-year overall survival, and safety.

Just over half the patients (52%) completed all cycles of therapy, and almost three quarters (73%) received at least one consolidation dose of brentuximab.

Among the first 23 evaluable patients, both the complete remission rate and overall response rate were 96%. Intention-to-treat survival rates for all 48 patients were 84% for 2-year progression-free survival and 93% for 2-year overall survival.

Historical 2-year progression-free survival rates in similar older patients is poor, at 50%, so the progression-free survival rate of 84% in this study represents a significant improvement.

Of note, patients with fewer comorbidities and without loss of instrumental activities of daily living showed more robust responses.

Patients with Cumulative Illness Rating Scale for Geriatrics (CIRS-G) comorbidity scores of less than 10 had a 2-year progression-free survival rate of 100% versus 45% for those with higher scores.

Similarly, patients without loss of instrumental activities achieved a progression-free survival rate of 94% versus 25% for those who had lost some instrumental activities.

Grade 3 or 4 adverse events occurred in 42% of patients, with neutropenia being the most common (44%).

“This study represents among the best-reported outcomes to date for untreated older patients with HL,” the investigators concluded.

Seattle Genetics supported the investigator-initiated trial. 

Photo courtesy of NIH

Older patients with untreated Hodgkin lymphoma (HL) can achieve significantly improved survival by adding brentuximab vedotin to their treatment before and after standard chemotherapy, a recent study found.

In patients with low comorbidity scores, responses were even more robust, reported lead author Andrew M. Evens, DO, of the Rutgers Cancer Institute of New Jersey, and colleagues.

“Causes of poor outcomes for older patients with HL are not fully understood but have been attributed to a combination of factors, including presence of comorbidities, poorer performance status, disease and biological differences, inability to tolerate chemotherapy at the full dose, and increased treatment-related toxicities,” the authors wrote in the Journal of Clinical Oncology.

The primary goal of the study was to improve outcomes for untreated, older patients, a group that’s historically been a difficult-to-treat patient population.

The phase 2 trial included 48 HL patients with a median age of 69 (range, 60 – 88).

All patients underwent geriatric assessment for comorbidities and loss of activities of daily living.

Treatment consisted of two doses of brentuximab followed by six cycles of doxorubicin, vinblastine, and dacarbazine (AVD), then four more doses of brentuximab (consolidation doses).

The primary endpoint was complete remission at completion of AVD.

Secondary outcomes included overall response rate, 2-year progression-free survival, 2-year overall survival, and safety.

Just over half the patients (52%) completed all cycles of therapy, and almost three quarters (73%) received at least one consolidation dose of brentuximab.

Among the first 23 evaluable patients, both the complete remission rate and overall response rate were 96%. Intention-to-treat survival rates for all 48 patients were 84% for 2-year progression-free survival and 93% for 2-year overall survival.

Historical 2-year progression-free survival rates in similar older patients is poor, at 50%, so the progression-free survival rate of 84% in this study represents a significant improvement.

Of note, patients with fewer comorbidities and without loss of instrumental activities of daily living showed more robust responses.

Patients with Cumulative Illness Rating Scale for Geriatrics (CIRS-G) comorbidity scores of less than 10 had a 2-year progression-free survival rate of 100% versus 45% for those with higher scores.

Similarly, patients without loss of instrumental activities achieved a progression-free survival rate of 94% versus 25% for those who had lost some instrumental activities.

Grade 3 or 4 adverse events occurred in 42% of patients, with neutropenia being the most common (44%).

“This study represents among the best-reported outcomes to date for untreated older patients with HL,” the investigators concluded.

Seattle Genetics supported the investigator-initiated trial. 

Photo courtesy of NIH

Older patients with untreated Hodgkin lymphoma (HL) can achieve significantly improved survival by adding brentuximab vedotin to their treatment before and after standard chemotherapy, a recent study found.

In patients with low comorbidity scores, responses were even more robust, reported lead author Andrew M. Evens, DO, of the Rutgers Cancer Institute of New Jersey, and colleagues.

“Causes of poor outcomes for older patients with HL are not fully understood but have been attributed to a combination of factors, including presence of comorbidities, poorer performance status, disease and biological differences, inability to tolerate chemotherapy at the full dose, and increased treatment-related toxicities,” the authors wrote in the Journal of Clinical Oncology.

The primary goal of the study was to improve outcomes for untreated, older patients, a group that’s historically been a difficult-to-treat patient population.

The phase 2 trial included 48 HL patients with a median age of 69 (range, 60 – 88).

All patients underwent geriatric assessment for comorbidities and loss of activities of daily living.

Treatment consisted of two doses of brentuximab followed by six cycles of doxorubicin, vinblastine, and dacarbazine (AVD), then four more doses of brentuximab (consolidation doses).

The primary endpoint was complete remission at completion of AVD.

Secondary outcomes included overall response rate, 2-year progression-free survival, 2-year overall survival, and safety.

Just over half the patients (52%) completed all cycles of therapy, and almost three quarters (73%) received at least one consolidation dose of brentuximab.

Among the first 23 evaluable patients, both the complete remission rate and overall response rate were 96%. Intention-to-treat survival rates for all 48 patients were 84% for 2-year progression-free survival and 93% for 2-year overall survival.

Historical 2-year progression-free survival rates in similar older patients is poor, at 50%, so the progression-free survival rate of 84% in this study represents a significant improvement.

Of note, patients with fewer comorbidities and without loss of instrumental activities of daily living showed more robust responses.

Patients with Cumulative Illness Rating Scale for Geriatrics (CIRS-G) comorbidity scores of less than 10 had a 2-year progression-free survival rate of 100% versus 45% for those with higher scores.

Similarly, patients without loss of instrumental activities achieved a progression-free survival rate of 94% versus 25% for those who had lost some instrumental activities.

Grade 3 or 4 adverse events occurred in 42% of patients, with neutropenia being the most common (44%).

“This study represents among the best-reported outcomes to date for untreated older patients with HL,” the investigators concluded.

Seattle Genetics supported the investigator-initiated trial. 

INTRODUCTION

Small cell lung cancer (SCLC) is an aggressive cancer of neuroendocrine origin that accounts for approximately 15% of all lung cancer cases, with approximately 33,000 patients diagnosed annually.¹ The incidence of SCLC in the United States has steadily declined over the past 30 years, presumably because of a decrease in the number of smokers and a change to low-tar filter cigarettes.² Although the overall incidence of SCLC has been decreasing, the incidence in women is increasing and the male-to-female incidence ratio is now 1:1.³ Nearly all cases of SCLC are associated with heavy tobacco exposure, making it a heterogeneous disease with a complex genomic landscape consisting of thousands of mutations.^4,5 Despite recent advances in the treatment of non-small cell lung cancer, the therapeutic options for SCLC remain limited, with a median overall survival (OS) of 9 months in patients with advanced disease.

DIAGNOSIS AND STAGING

CASE PRESENTATION

A 61-year-old man presents to the emergency department with progressive shortness of breath and cough over the past 6 weeks. He also reports a 20-lb weight loss over the same period. He is a current smoker and has been smoking 1 pack of cigarettes per day since the age of 18 years. A chest radiograph obtained in the emergency department shows a right hilar mass. Computed tomography (CT) scan confirms the presence of a 4.5-cm right hilar mass and enlarged mediastinal lymph nodes bilaterally.

• What are the next steps in diagnosis?

SCLC is characterized by rapid growth and early hematogenous metastasis. Consequently, only 25% of patients have limited-stage disease at the time of diagnosis. According to the Veterans Administration Lung Study Group (VALSG) staging system, limited-stage disease is defined as tumor that is confined to 1 hemithorax and can be encompassed within 1 radiation field. This typically includes mediastinal lymph nodes and ipsilateral supraclavicular lymph nodes. Approximately 75% of patients present with extensive-stage disease, which is defined as disease that cannot be classified as limited, including disease that extends beyond 1 hemithorax. Extensive-stage disease includes the presence of malignant pleural effusion and/or distant metastasis.⁶ The VALSG classification and staging system is more commonly used in clinical practice than the American Joint Committee on Cancer TNM staging system because it is less complex and directs treatment decisions, as most of the literature on SCLC classifies patients based on the VALSG system.⁷

Given SCLC’s propensity to metastasize quickly, none of the currently available screening methods have proven successful in early detection of SCLC. In the National Lung Cancer Screening Trial, 86% of the 125 patients who were diagnosed with SCLC while undergoing annual low-dose chest CT scans had advanced disease at diagnosis.^8,9 These results highlight the fact that most cases of SCLC develop in the interval between annual screening imaging.

SCLC frequently presents with a large hilar mass that is symptomatic. Common symptoms include shortness of breath and cough. In addition, patients with SCLC usually have bulky mediastinal adenopathy at presentation. SCLC is commonly located submucosally in the bronchus, and therefore hemoptysis is not a very common symptom at the time of presentation. Patients may present with superior vena cava syndrome from local compression by the tumor. Not infrequently, SCLC is associated with paraneoplastic syndromes that arise due to ectopic secretion of hormones or antibodies by the tumor cells. The paraneoplastic syndromes can be broadly categorized as endocrine or neurologic (Table 1). The presence of a paraneoplastic syndrome is often a clue to the potential diagnosis of SCLC in the presence of a hilar mass. Additionally, some paraneoplastic syndromes, more specifically endocrine paraneoplastic syndromes, follow the pattern of disease response and relapse, and therefore can sometimes serve as an early marker of disease relapse or progression.

The common sites of metastases include brain, liver, and bone. Therefore, the staging workup should include fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan. Contrast-enhanced CT scan of the chest and abdomen and bone scan can be obtained for staging in lieu of PET scan. Due to the physiologic FDG uptake, cerebral metastases cannot be assessed with sufficient certainty using PET-CT.¹⁰ Therefore, brain imaging with contrast-enhanced CT or magnetic resonance imaging (MRI) is also necessary. Although the incidence of metastasis to bone marrow is less than 10%, bone marrow aspiration and biopsy are warranted in patients with unexplained cytopenias, especially when the cytopenia is associated with teardrop-shaped red cells or nucleated red cells on peripheral blood smear, findings indicative of a marrow infiltrative process.⁷ The tissue diagnosis is established by obtaining a biopsy of the primary tumor or 1 of the metastatic sites. In localized disease, bronchoscopy (with endobronchial ultrasound, if necessary) with biopsy of the centrally located tumor and/or lymph node is required. Histologically, SCLC consists of monomorphic cells, a high nuclear-cytoplasmic ratio, and confluent necrosis. The tumor cells are positive for chromogranin, synaptophysin, and CD56 by immunohistochemistry, and very frequently are also positive for thyroid transcription factor 1.¹¹ Although serum tumor markers, including neuron-specific enolase and progastrin-releasing peptide, are frequently elevated in patients with SCLC, these markers are of limited value in clinical practice because they lack sensitivity and specificity.¹²

MANAGEMENT OF LIMITED-STAGE DISEASE

CASE CONTINUED

The patient undergoes FDG PET scan, which shows the presence of a hypermetabolic right hilar mass in addition to enlarged and hypermetabolic bilateral mediastinal lymph nodes. There are no other areas of FDG avidity. Brain MRI does not show any evidence of brain metastasis. Thus, the patient is confirmed to have limited-stage SCLC.

• What is the standard of care treatment for limited-stage SCLC?

SCLC is exquisitely sensitive to both chemotherapy and radiation, especially at the time of initial presentation. The standard of care treatment of limited-stage SCLC is 4 cycles of platinum-based chemotherapy in combination with thoracic radiation started within the first 2 cycles of chemotherapy (Figure 1).

CHOICE OF CHEMOTHERAPY

Etoposide and cisplatin is the most commonly used initial combination chemotherapy regimen in limited-stage SCLC.¹⁴ This combination has largely replaced anthracycline-based regimens given its favorable efficacy and toxicity profile.^15–17 Several small randomized trials have shown comparable efficacy of carboplatin and etoposide in extensive-stage SCLC.^18–20 A meta-analysis of 4 randomized trials comparing cisplatin-based versus carboplatin-based regimens in 663 patients with SCLC (32% had limited-stage disease and 68% had extensive-stage disease) showed no statistically significant difference in response rate, progression-free survival (PFS), or OS between the 2 regimens.²¹ Therefore, in clinical practice carboplatin is frequently used instead of cisplatin in patients with extensive-stage disease. In patients with limited-stage disease, cisplatin is still the drug of choice. However, the toxicity profile of the 2 regimens is different. Cisplatin-based regimens are more commonly associated with neuropathy, nephrotoxicity, and chemotherapy-induced nausea/vomiting,¹⁸ while carboplatin-based regimens are more myelosuppressive.²² In addition, the combination of thoracic radiation with either of these regimens is associated with a higher risk of esophagitis, pneumonitis, and myelosuppression.²³ The use of myeloid growth factors is not recommended in patients undergoing concurrent chemoradiation.²⁴ Of note, intravenous etoposide is always preferred over oral etoposide, especially in the curative setting given the unreliable absorption and bioavailability of oral formulations.

THORACIC RADIOTHERAPY

Adding thoracic radiotherapy to platinum-etoposide chemotherapy improves local control and OS. Two meta-analyses of 13 trials including more than 2000 patients have shown a 25% to 30% decrease in local failure and a 5% to 7% increase in 2-year OS with chemoradiation compared to chemotherapy alone in limited-stage SCLC.^25,26 Early (within the first 2 cycles) concurrent thoracic radiation is superior to delayed and/or sequential radiation in terms of local control and OS.^23,27,28 The dose and fractionation of thoracic radiation in limited-stage SCLC has remained a controversial issue. The Eastern Cooperative Oncology Group/Radiation Therapy Oncology Group randomized trial compared 45 Gy of radiotherapy delivered twice daily over a period of 3 weeks to 45 Gy once daily over 5 weeks concurrently with chemotherapy. The twice daily regimen led to a 10% improvement in 5-year OS (26% versus 16%), but a higher incidence of grade 3 and 4 adverse events.¹³ Despite the survival advantage demonstrated by hyperfractionated radiotherapy, the results need to be interpreted with caution because the radiation doses are not biologically equivalent. In addition, the difficult logistics of patients receiving radiation twice a day has limited the routine implementation of this strategy. Subsequently, another randomized phase 3 trial (CONVERT) compared 45 Gy radiotherapy twice daily with 66 Gy radiotherapy once daily in limited-stage SCLC.²⁹ This trial did not show any difference in OS. The patients in the twice daily arm had a higher incidence of grade 4 neutropenia. Considering the results of these trials, both strategies—45 Gy fractionated twice daily or 60 Gy fractionated once daily, delivered concurrently with chemotherapy—are acceptable in the setting of limited-stage SCLC. However, quite often a hyperfractionated regimen is not feasible for patients and many radiation oncology centers. Hopefully, the ongoing CALGB 30610 study will clarify the optimal radiation schedule for limited-stage disease.

PROPHYLACTIC CRANIAL IRRADIATION

Approximately 75% of patients with limited-stage disease experience disease recurrence, and brain is the site of recurrence in approximately half of these patients.³⁰ Prophylactic cranial irradiation (PCI) consisting of 25 Gy radiotherapy delivered in 10 fractions has been shown to be effective in decreasing the incidence of cerebral metastases.^30–32 Although individual small studies have not shown a survival benefit of PCI because of small sample size and limited power, a meta-analysis of these studies has shown a 25% decrease in the 3-year incidence of brain metastasis and 5.4% increase in 3-year OS.³⁰ Most patients included in these studies had limited-stage disease. Therefore, PCI is the standard of care for patients with limited-stage disease who attain a partial or complete response to chemoradiation.

ROLE OF SURGERY

Surgical resection may be an acceptable choice in a very limited subset of patients with peripherally located small (< 5 cm) tumors where mediastinal lymph nodes have been confirmed to be uninvolved with complete mediastinal staging.^33,34 Most of the data in this setting are derived from retrospective studies.^35,36 A 5-year OS between 40% and 60% has been reported with this strategy in patients with clinical stage I disease. In general, when surgery is considered, lobectomy with mediastinal lymph node dissection followed by chemotherapy (if there is no nodal involvement) or chemoradiation (if nodal involvement) is recommended.^37,38 Wedge or segmental resections are not considered to be optimal surgical options.

MANAGEMENT OF EXTENSIVE-STAGE DISEASE

CASE CONTINUED

The patient receives 4 cycles of cisplatin and etoposide along with 70 Gy radiotherapy concurrently with the first 2 cycles of chemotherapy. His post-treatment CT scans show a partial response. He undergoes PCI 6 weeks after completion of treatment. At routine follow-up 18 months later, he is doing generally well except for mildly decreased appetite and an unintentional weight loss of 5 lb. CT scans demonstrate multiple hypodense liver lesions ranging from 7 mm to 2 cm in size and a 2-cm left adrenal gland lesion highly concerning for metastasis. FDG PET scan confirms that the adrenal and liver lesions are hypermetabolic. In addition, the PET scan shows multiple FDG-avid bone lesions throughout the spine. Brain MRI is negative for brain metastasis.

• What is the standard of care for treatment of extensive-stage disease?

Chemotherapy is the mainstay of treatment for extensive-stage SCLC; the goals of treatment are prolongation of survival, prevention or alleviation of cancer-related symptoms, and improvement in quality of life. The combination of etoposide with a platinum agent (carboplatin or cisplatin) is the preferred first-line treatment option. Carboplatin is more commonly used in clinical practice in this setting because of its comparable efficacy and better tolerability compared to cisplatin (Figure 2).²¹ A Japanese phase 3 trial comparing cisplatin plus irinotecan with cisplatin plus etoposide in the first-line setting in extensive-stage SCLC showed improvement in median and 2-year OS with the cisplatin/irinotecan regimen; however, 2 subsequent phase 3 trials conducted in the United States comparing these 2 regimens did not show any difference in OS. In addition, the cisplatin/irinotecan regimen was more toxic than the etoposide-based regimen.^39,40 Therefore, 4 to 6 cycles of platinum/etoposide remains the standard of care first-line treatment for extensive-stage SCLC in the United States. The combination yields a 60% to 70% response rate, but the majority of patients invariably experience disease progression, with a median OS of 9 to 11 months.⁴¹ Maintenance chemotherapy beyond the initial 4 to 6 cycles does not improve survival and is associated with higher cumulative toxicity.⁴²

Multiple attempts at improving first-line chemotherapy in extensive-stage disease have failed to show any meaningful difference in OS. For example, the addition of ifosfamide, palifosfamide, cyclophosphamide, taxane, or anthracycline to platinum doublet failed to show improvement in OS and led to more toxicity.^43–46 Additionally, the use of alternating or cyclic chemotherapies in an attempt to curb drug resistance has also failed to show survival benefit.^47–49 The addition of the antiangiogenic agent bevacizumab to standard platinum-based doublet has not prolonged OS in SCLC and has led to an unacceptably higher rate of tracheoesophageal fistula when used in conjunction with chemoradiation in limited-stage disease.^50–55 Finally, the immune checkpoint inhibitor ipilimumab in combination with platinum plus etoposide failed to improve PFS or OS compared to platinum plus etoposide alone in a recent phase 3 trial, and maintenance pembrolizumab after completion of platinum-based chemotherapy did not improve PFS.^56,57

More recently, a phase 2 study of pembrolizumab in extensive-stage SCLC (KEYNOTE 158) reported an overall response rate of 35.7%, median PFS of 2.1 months, and median OS of 14.6 months in patients who tested positive for programmed death ligand-1 (PD-L1) expression (which was defined as a PD-L1 Combined Positive Score ≥ 1).⁵⁸ The median duration of response has not been reached in this study, indicating that pembrolizumab may be a promising approach in patients with extensive-stage SCLC, especially for those with PD-L1–positive tumors.

Patients with extensive-stage disease who have brain metastasis at the time of diagnosis can be treated with systemic chemotherapy first if the brain metastases are asymptomatic and there is significant extracranial disease burden. In that case, whole brain radiotherapy should be given after completion of systemic therapy.

SECOND-LINE CHEMOTHERAPY

Despite being exquisitely chemosensitive, SCLC is associated with a very poor prognosis largely because of invariable disease progression following first-line therapy and lack of effective second-line treatment options that can lead to appreciable disease control. The choice of second-line treatment is predominantly determined by the time of disease relapse after first-line platinum-based therapy. If this interval is 6 months or longer, re-treatment utilizing the same platinum doublet is appropriate. However, if the interval is 6 months or less, second-line systemic therapy options should be explored. Unfortunately, the response rate tends to be less than 10% with most of the second-line therapies in platinum-resistant disease (defined as disease progression within 3 months of receiving platinum-based therapy). If disease progression occurs between 3 and 6 months after completion of platinum-based therapy, the response rate with second-line chemotherapy is in the range of 25%.^59,60

A number of second-line chemotherapy options have been explored in small studies, including topotecan, irinotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, oral etoposide, gemcitabine, bendamustine, and CAV (cyclophosphamide, doxorubicin, vincristine) (Table 2).^61–77 Of these, topotecan (oral or intravenous) is the only second-line agent approved by the US Food and Drug Administration (FDA) for extensive-stage SCLC; this approval is based on a phase 3 trial showing a survival benefit with topotecan compared to best supportive care. The duration of second-line chemotherapy is not defined and is largely driven by duration of response and occurrence of side effects. Given the lack of effective treatment options, patients with platinum-resistant disease should be considered for clinical trials whenever possible. In patients with disease progression after second-line therapy, a third-line treatment can be considered if their Eastern Cooperative Oncology Group (ECOG) performance status is 0 to 2, but it is unclear whether further treatments would improve survival.

IMMUNOTHERAPY

The role of immune checkpoint inhibitors in the treatment of SCLC is evolving, and currently there are no FDA-approved immunotherapy agents for treating SCLC. A recently conducted phase 1/2 trial (CheckMate 032) studied the anti-programmed death(PD)-1 antibody nivolumab with or without the anti-cytotoxic T-lymphocyte–associated antigen (CTLA) -4 antibody ipilimumab in patients with relapsed SCLC. The authors reported response rates of 10% with nivolumab 3 mg/kg and 21% with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg.^78,79 The 2-year OS was 26% with the combination and 14% with single-agent nivolumab. Only 18% of patients had PD-L1 expression of ≥ 1%, and the response rate did not correlate with PD-L1 status. The rate of grade 3 or 4 adverse events was approximately 20%, and only 10% of patients discontinued treatment because of toxicity. Based on these data, nivolumab plus ipilimumab is now included in the National Comprehensive Cancer Network guidelines as an option for patients with SCLC who experience disease relapse within 6 months of receiving platinum-based therapy;⁷ however, it is questionable whether routine use of this combination is justified based on currently available data. The evidence for the combination of nivolumab and ipilimumab remains limited. The efficacy and toxicity data from both randomized and nonrandomized cohorts were presented together, making it hard to interpret the results.

Another phase 1b study (KEYNOTE-028) evaluated the anti-PD-1 antibody pembrolizumab (10 mg/kg intravenously every 2 weeks) in patients with relapsed SCLC who had received 1 or more prior lines of therapy and had PD-L1 expression of ≥ 1%. This study showed a response rate of 33%, with a median duration of response of 19 months and 1-year OS of 38%.⁸⁰ Although only 28% of screened patients had PD-L1 expression of ≥ 1%, these results indicated that at least a subset of SCLC patients are able to achieve durable responses with immune checkpoint inhibition. A number of clinical trials utilizing immune checkpoint inhibitors in various combinations and settings are currently underway.

ROLE OF PROPHYLACTIC CRANIAL IRRADIATION

The role of PCI in extensive-stage SCLC is not clearly defined. A randomized phase 3 trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) comparing PCI with no PCI in patients with extensive-stage SCLC who had a partial or complete response to initial platinum-based chemotherapy showed a decrease in the incidence of symptomatic brain metastasis and improvement in 1-year OS with PCI.⁸¹ However, this trial did not require mandatory brain imaging prior to PCI, and thus it is unclear if some patients in the PCI group had asymptomatic brain metastasis prior to enrollment and therefore received therapeutic benefit from brain radiation. Additionally, the dose and fractionation of PCI was not standardized across patient groups.

A more recent phase 3 study conducted in Japan that compared PCI (25 Gy in 10 fractions) with no PCI reported no difference in survival between the 2 groups.⁸² As opposed to the EORTC study, the Japanese study did require baseline brain imaging to confirm the absence of brain metastasis prior to enrollment. In addition, the control patients underwent periodic brain MRI to allow early detection of brain metastasis. Given the emergence of the new data, the impact of PCI on survival in patients with extensive-stage SCLC is unproven, and PCI likely has a role in a highly selected small group of patients with extensive-stage SCLC. PCI is not recommended for patients with poor performance status (ECOG performance score of 3 or 4) or underlying neurocognitive disorders.^34,83

The NMDA-receptor antagonist memantine can be used in patients undergoing PCI to delay the occurrence of cognitive dysfunction.⁶¹ Memantine 20 mg daily delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed compared to placebo in patients receiving whole brain radiotherapy.⁸⁴

ROLE OF RADIOTHERAPY

A subset of patients with extensive-stage SCLC may benefit from consolidative thoracic radiotherapy after completion of platinum-based chemotherapy. A randomized trial that enrolled patients who achieved complete or near complete response after 3 cycles of cisplatin plus etoposide compared thoracic radiotherapy in combination with continued chemotherapy versus chemotherapy alone.⁸⁵ The median OS was longer with the addition of thoracic radiotherapy compared to chemotherapy alone. Another phase 3 trial did not show improvement in 1-year OS with consolidative thoracic radiotherapy, but 2-year OS and 6-month PFS were longer.⁸⁶ In general, consolidative thoracic radiotherapy benefits patients who have residual thoracic disease and low-bulk extrathoracic disease that has responded to systemic therapy.⁸⁷ In addition, patients who initially presented with bulky symptomatic thoracic disease should also be considered for consolidative radiation.

Similar to other solid tumors, radiotherapy should be utilized for palliative purposes in patients with painful bone metastasis, spinal cord compression, or brain metastasis. Surgery is generally not recommended for spinal cord compression given the short life expectancy of patients with extensive-stage disease. Whole brain radiotherapy is preferred over stereotactic radiosurgery because micrometastasis is frequently present even in the setting of 1 or 2 radiographically evident brain metastasis.

NOVEL THERAPIES

The very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and high recurrence rate; however, at the same time this complexity can form the basis for effective targeted therapy for the disease. One of the major factors hindering the development of targeted therapies in SCLC is limited availability of tissue due to small tissue samples and the frequent presence of significant necrosis in the samples. In recent years, several different therapeutic strategies and targeted agents have been investigated for their potential role in SCLC. Several of them, including EGFR tyrosine kinase inhibitors (TKIs), BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors, have not been shown to provide a survival advantage in this disease. Several others, including PARP inhibitors, cellular developmental pathway inhibitors, and antibody-drug conjugates, are being tested. A phase 1 study of veliparib combined with cisplatin and etoposide in patients with previously untreated extensive-stage SCLC demonstrated a complete response in 14.3%, a partial response in 57.1%, and stable disease in 28.6% of patients with an acceptable safety profile.⁸⁸ So far, none of these agents are approved for use in SCLC, and the majority are in early- phase clinical trials.⁸⁹

One of the emerging targets in the treatment of SCLC is delta-like protein 3 (DLL3). DLL3 is expressed on more than 80% of SCLC tumor cells and cancer stem cells. Rovalpituzumab tesirine is an antibody-drug conjugate consisting of humanized anti-DLL3 monoclonal antibody linked to SC-DR002, a DNA-crosslinking agent. A phase 1 trial of rovalpituzumab in patients with relapsed SCLC after 1 or 2 prior lines of therapy reported a response rate of 31% in patients with DLL3 expression of ≥ 50%. The median duration of response and median PFS were both 4.6 months.⁹⁰ Rovalpituzumab is currently in later phases of clinical trials and has a potential to serve as an option for patients with extensive-stage disease after disease progression on platinum-based therapy.

SUMMARY

Four to 6 cycles of carboplatin and etoposide remain the standard of care first-line treatment for patients with extensive stage SCLC. The only FDA-approved second-line treatment option is topotecan. Re-treatment with the original platinum doublet is a reasonable option for patients who have disease progression 6 months or longer after completion of platinum-based therapy. The immune checkpoint inhibitors pembrolizumab and combination nivolumab and ipilimumab have shown promising results in the second-line setting and beyond. The role of PCI has become more controversial in recent years, and periodic brain MRI in lieu of PCI is now an acceptable approach.

 

 

RESPONSE ASSESSMENT/SURVEILLANCE

For patients undergoing treatment for limited-stage SCLC, response assessment with contrast-enhanced CT of the chest/abdomen should be performed after completion of 4 cycles of chemotherapy and thoracic radiation.⁷ The surveillance guidelines consist of history, physical exam, and imaging every 3 months during the first 2 years, every 6 months during the third year, and annually thereafter. If PCI is not performed, brain MRI or contrast-enhanced CT scan should be performed every 3 or 4 months during the first 2 years of follow up. For extensive-stage disease, response assessment should be performed after every 2 cycles of therapy. After completion of therapy, history, physical exam, and imaging should be done every 2 months during the first year, every 3 or 4 months during years 2 and 3, every 6 months during years 4 and 5, and annually thereafter. Routine use of PET scan for surveillance is not recommended. Any new pulmonary nodule should prompt evaluation for a second primary lung malignancy. Finally, smoking cessation counseling is an integral part of management of any patient with SCLC and should be included with every clinic visit.

CONCLUSION

SCLC is a heterogeneous and genetically complex disease with a very high mortality rate. The current standard of care includes concurrent chemoradiation with cisplatin and etoposide for limited-stage SCLC and the combination of platinum and etoposide for extensive SCLC. A number of novel treatment approaches, including immune checkpoint inhibitors and antibody-drug conjugates, have had promising results in early clinical trials. Given the limited treatment options and large unmet need for new treatment options, enrollment in clinical trials is strongly recommended for patients with SCLC.

INTRODUCTION

Small cell lung cancer (SCLC) is an aggressive cancer of neuroendocrine origin that accounts for approximately 15% of all lung cancer cases, with approximately 33,000 patients diagnosed annually.¹ The incidence of SCLC in the United States has steadily declined over the past 30 years, presumably because of a decrease in the number of smokers and a change to low-tar filter cigarettes.² Although the overall incidence of SCLC has been decreasing, the incidence in women is increasing and the male-to-female incidence ratio is now 1:1.³ Nearly all cases of SCLC are associated with heavy tobacco exposure, making it a heterogeneous disease with a complex genomic landscape consisting of thousands of mutations.^4,5 Despite recent advances in the treatment of non-small cell lung cancer, the therapeutic options for SCLC remain limited, with a median overall survival (OS) of 9 months in patients with advanced disease.

DIAGNOSIS AND STAGING

CASE PRESENTATION

A 61-year-old man presents to the emergency department with progressive shortness of breath and cough over the past 6 weeks. He also reports a 20-lb weight loss over the same period. He is a current smoker and has been smoking 1 pack of cigarettes per day since the age of 18 years. A chest radiograph obtained in the emergency department shows a right hilar mass. Computed tomography (CT) scan confirms the presence of a 4.5-cm right hilar mass and enlarged mediastinal lymph nodes bilaterally.

• What are the next steps in diagnosis?

SCLC is characterized by rapid growth and early hematogenous metastasis. Consequently, only 25% of patients have limited-stage disease at the time of diagnosis. According to the Veterans Administration Lung Study Group (VALSG) staging system, limited-stage disease is defined as tumor that is confined to 1 hemithorax and can be encompassed within 1 radiation field. This typically includes mediastinal lymph nodes and ipsilateral supraclavicular lymph nodes. Approximately 75% of patients present with extensive-stage disease, which is defined as disease that cannot be classified as limited, including disease that extends beyond 1 hemithorax. Extensive-stage disease includes the presence of malignant pleural effusion and/or distant metastasis.⁶ The VALSG classification and staging system is more commonly used in clinical practice than the American Joint Committee on Cancer TNM staging system because it is less complex and directs treatment decisions, as most of the literature on SCLC classifies patients based on the VALSG system.⁷

Given SCLC’s propensity to metastasize quickly, none of the currently available screening methods have proven successful in early detection of SCLC. In the National Lung Cancer Screening Trial, 86% of the 125 patients who were diagnosed with SCLC while undergoing annual low-dose chest CT scans had advanced disease at diagnosis.^8,9 These results highlight the fact that most cases of SCLC develop in the interval between annual screening imaging.

SCLC frequently presents with a large hilar mass that is symptomatic. Common symptoms include shortness of breath and cough. In addition, patients with SCLC usually have bulky mediastinal adenopathy at presentation. SCLC is commonly located submucosally in the bronchus, and therefore hemoptysis is not a very common symptom at the time of presentation. Patients may present with superior vena cava syndrome from local compression by the tumor. Not infrequently, SCLC is associated with paraneoplastic syndromes that arise due to ectopic secretion of hormones or antibodies by the tumor cells. The paraneoplastic syndromes can be broadly categorized as endocrine or neurologic (Table 1). The presence of a paraneoplastic syndrome is often a clue to the potential diagnosis of SCLC in the presence of a hilar mass. Additionally, some paraneoplastic syndromes, more specifically endocrine paraneoplastic syndromes, follow the pattern of disease response and relapse, and therefore can sometimes serve as an early marker of disease relapse or progression.

The common sites of metastases include brain, liver, and bone. Therefore, the staging workup should include fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan. Contrast-enhanced CT scan of the chest and abdomen and bone scan can be obtained for staging in lieu of PET scan. Due to the physiologic FDG uptake, cerebral metastases cannot be assessed with sufficient certainty using PET-CT.¹⁰ Therefore, brain imaging with contrast-enhanced CT or magnetic resonance imaging (MRI) is also necessary. Although the incidence of metastasis to bone marrow is less than 10%, bone marrow aspiration and biopsy are warranted in patients with unexplained cytopenias, especially when the cytopenia is associated with teardrop-shaped red cells or nucleated red cells on peripheral blood smear, findings indicative of a marrow infiltrative process.⁷ The tissue diagnosis is established by obtaining a biopsy of the primary tumor or 1 of the metastatic sites. In localized disease, bronchoscopy (with endobronchial ultrasound, if necessary) with biopsy of the centrally located tumor and/or lymph node is required. Histologically, SCLC consists of monomorphic cells, a high nuclear-cytoplasmic ratio, and confluent necrosis. The tumor cells are positive for chromogranin, synaptophysin, and CD56 by immunohistochemistry, and very frequently are also positive for thyroid transcription factor 1.¹¹ Although serum tumor markers, including neuron-specific enolase and progastrin-releasing peptide, are frequently elevated in patients with SCLC, these markers are of limited value in clinical practice because they lack sensitivity and specificity.¹²

MANAGEMENT OF LIMITED-STAGE DISEASE

CASE CONTINUED

The patient undergoes FDG PET scan, which shows the presence of a hypermetabolic right hilar mass in addition to enlarged and hypermetabolic bilateral mediastinal lymph nodes. There are no other areas of FDG avidity. Brain MRI does not show any evidence of brain metastasis. Thus, the patient is confirmed to have limited-stage SCLC.

• What is the standard of care treatment for limited-stage SCLC?

SCLC is exquisitely sensitive to both chemotherapy and radiation, especially at the time of initial presentation. The standard of care treatment of limited-stage SCLC is 4 cycles of platinum-based chemotherapy in combination with thoracic radiation started within the first 2 cycles of chemotherapy (Figure 1).

CHOICE OF CHEMOTHERAPY

Etoposide and cisplatin is the most commonly used initial combination chemotherapy regimen in limited-stage SCLC.¹⁴ This combination has largely replaced anthracycline-based regimens given its favorable efficacy and toxicity profile.^15–17 Several small randomized trials have shown comparable efficacy of carboplatin and etoposide in extensive-stage SCLC.^18–20 A meta-analysis of 4 randomized trials comparing cisplatin-based versus carboplatin-based regimens in 663 patients with SCLC (32% had limited-stage disease and 68% had extensive-stage disease) showed no statistically significant difference in response rate, progression-free survival (PFS), or OS between the 2 regimens.²¹ Therefore, in clinical practice carboplatin is frequently used instead of cisplatin in patients with extensive-stage disease. In patients with limited-stage disease, cisplatin is still the drug of choice. However, the toxicity profile of the 2 regimens is different. Cisplatin-based regimens are more commonly associated with neuropathy, nephrotoxicity, and chemotherapy-induced nausea/vomiting,¹⁸ while carboplatin-based regimens are more myelosuppressive.²² In addition, the combination of thoracic radiation with either of these regimens is associated with a higher risk of esophagitis, pneumonitis, and myelosuppression.²³ The use of myeloid growth factors is not recommended in patients undergoing concurrent chemoradiation.²⁴ Of note, intravenous etoposide is always preferred over oral etoposide, especially in the curative setting given the unreliable absorption and bioavailability of oral formulations.

THORACIC RADIOTHERAPY

Adding thoracic radiotherapy to platinum-etoposide chemotherapy improves local control and OS. Two meta-analyses of 13 trials including more than 2000 patients have shown a 25% to 30% decrease in local failure and a 5% to 7% increase in 2-year OS with chemoradiation compared to chemotherapy alone in limited-stage SCLC.^25,26 Early (within the first 2 cycles) concurrent thoracic radiation is superior to delayed and/or sequential radiation in terms of local control and OS.^23,27,28 The dose and fractionation of thoracic radiation in limited-stage SCLC has remained a controversial issue. The Eastern Cooperative Oncology Group/Radiation Therapy Oncology Group randomized trial compared 45 Gy of radiotherapy delivered twice daily over a period of 3 weeks to 45 Gy once daily over 5 weeks concurrently with chemotherapy. The twice daily regimen led to a 10% improvement in 5-year OS (26% versus 16%), but a higher incidence of grade 3 and 4 adverse events.¹³ Despite the survival advantage demonstrated by hyperfractionated radiotherapy, the results need to be interpreted with caution because the radiation doses are not biologically equivalent. In addition, the difficult logistics of patients receiving radiation twice a day has limited the routine implementation of this strategy. Subsequently, another randomized phase 3 trial (CONVERT) compared 45 Gy radiotherapy twice daily with 66 Gy radiotherapy once daily in limited-stage SCLC.²⁹ This trial did not show any difference in OS. The patients in the twice daily arm had a higher incidence of grade 4 neutropenia. Considering the results of these trials, both strategies—45 Gy fractionated twice daily or 60 Gy fractionated once daily, delivered concurrently with chemotherapy—are acceptable in the setting of limited-stage SCLC. However, quite often a hyperfractionated regimen is not feasible for patients and many radiation oncology centers. Hopefully, the ongoing CALGB 30610 study will clarify the optimal radiation schedule for limited-stage disease.

PROPHYLACTIC CRANIAL IRRADIATION

Approximately 75% of patients with limited-stage disease experience disease recurrence, and brain is the site of recurrence in approximately half of these patients.³⁰ Prophylactic cranial irradiation (PCI) consisting of 25 Gy radiotherapy delivered in 10 fractions has been shown to be effective in decreasing the incidence of cerebral metastases.^30–32 Although individual small studies have not shown a survival benefit of PCI because of small sample size and limited power, a meta-analysis of these studies has shown a 25% decrease in the 3-year incidence of brain metastasis and 5.4% increase in 3-year OS.³⁰ Most patients included in these studies had limited-stage disease. Therefore, PCI is the standard of care for patients with limited-stage disease who attain a partial or complete response to chemoradiation.

ROLE OF SURGERY

Surgical resection may be an acceptable choice in a very limited subset of patients with peripherally located small (< 5 cm) tumors where mediastinal lymph nodes have been confirmed to be uninvolved with complete mediastinal staging.^33,34 Most of the data in this setting are derived from retrospective studies.^35,36 A 5-year OS between 40% and 60% has been reported with this strategy in patients with clinical stage I disease. In general, when surgery is considered, lobectomy with mediastinal lymph node dissection followed by chemotherapy (if there is no nodal involvement) or chemoradiation (if nodal involvement) is recommended.^37,38 Wedge or segmental resections are not considered to be optimal surgical options.

MANAGEMENT OF EXTENSIVE-STAGE DISEASE

CASE CONTINUED

The patient receives 4 cycles of cisplatin and etoposide along with 70 Gy radiotherapy concurrently with the first 2 cycles of chemotherapy. His post-treatment CT scans show a partial response. He undergoes PCI 6 weeks after completion of treatment. At routine follow-up 18 months later, he is doing generally well except for mildly decreased appetite and an unintentional weight loss of 5 lb. CT scans demonstrate multiple hypodense liver lesions ranging from 7 mm to 2 cm in size and a 2-cm left adrenal gland lesion highly concerning for metastasis. FDG PET scan confirms that the adrenal and liver lesions are hypermetabolic. In addition, the PET scan shows multiple FDG-avid bone lesions throughout the spine. Brain MRI is negative for brain metastasis.

• What is the standard of care for treatment of extensive-stage disease?

Chemotherapy is the mainstay of treatment for extensive-stage SCLC; the goals of treatment are prolongation of survival, prevention or alleviation of cancer-related symptoms, and improvement in quality of life. The combination of etoposide with a platinum agent (carboplatin or cisplatin) is the preferred first-line treatment option. Carboplatin is more commonly used in clinical practice in this setting because of its comparable efficacy and better tolerability compared to cisplatin (Figure 2).²¹ A Japanese phase 3 trial comparing cisplatin plus irinotecan with cisplatin plus etoposide in the first-line setting in extensive-stage SCLC showed improvement in median and 2-year OS with the cisplatin/irinotecan regimen; however, 2 subsequent phase 3 trials conducted in the United States comparing these 2 regimens did not show any difference in OS. In addition, the cisplatin/irinotecan regimen was more toxic than the etoposide-based regimen.^39,40 Therefore, 4 to 6 cycles of platinum/etoposide remains the standard of care first-line treatment for extensive-stage SCLC in the United States. The combination yields a 60% to 70% response rate, but the majority of patients invariably experience disease progression, with a median OS of 9 to 11 months.⁴¹ Maintenance chemotherapy beyond the initial 4 to 6 cycles does not improve survival and is associated with higher cumulative toxicity.⁴²

Multiple attempts at improving first-line chemotherapy in extensive-stage disease have failed to show any meaningful difference in OS. For example, the addition of ifosfamide, palifosfamide, cyclophosphamide, taxane, or anthracycline to platinum doublet failed to show improvement in OS and led to more toxicity.^43–46 Additionally, the use of alternating or cyclic chemotherapies in an attempt to curb drug resistance has also failed to show survival benefit.^47–49 The addition of the antiangiogenic agent bevacizumab to standard platinum-based doublet has not prolonged OS in SCLC and has led to an unacceptably higher rate of tracheoesophageal fistula when used in conjunction with chemoradiation in limited-stage disease.^50–55 Finally, the immune checkpoint inhibitor ipilimumab in combination with platinum plus etoposide failed to improve PFS or OS compared to platinum plus etoposide alone in a recent phase 3 trial, and maintenance pembrolizumab after completion of platinum-based chemotherapy did not improve PFS.^56,57

More recently, a phase 2 study of pembrolizumab in extensive-stage SCLC (KEYNOTE 158) reported an overall response rate of 35.7%, median PFS of 2.1 months, and median OS of 14.6 months in patients who tested positive for programmed death ligand-1 (PD-L1) expression (which was defined as a PD-L1 Combined Positive Score ≥ 1).⁵⁸ The median duration of response has not been reached in this study, indicating that pembrolizumab may be a promising approach in patients with extensive-stage SCLC, especially for those with PD-L1–positive tumors.

Patients with extensive-stage disease who have brain metastasis at the time of diagnosis can be treated with systemic chemotherapy first if the brain metastases are asymptomatic and there is significant extracranial disease burden. In that case, whole brain radiotherapy should be given after completion of systemic therapy.

SECOND-LINE CHEMOTHERAPY

Despite being exquisitely chemosensitive, SCLC is associated with a very poor prognosis largely because of invariable disease progression following first-line therapy and lack of effective second-line treatment options that can lead to appreciable disease control. The choice of second-line treatment is predominantly determined by the time of disease relapse after first-line platinum-based therapy. If this interval is 6 months or longer, re-treatment utilizing the same platinum doublet is appropriate. However, if the interval is 6 months or less, second-line systemic therapy options should be explored. Unfortunately, the response rate tends to be less than 10% with most of the second-line therapies in platinum-resistant disease (defined as disease progression within 3 months of receiving platinum-based therapy). If disease progression occurs between 3 and 6 months after completion of platinum-based therapy, the response rate with second-line chemotherapy is in the range of 25%.^59,60

A number of second-line chemotherapy options have been explored in small studies, including topotecan, irinotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, oral etoposide, gemcitabine, bendamustine, and CAV (cyclophosphamide, doxorubicin, vincristine) (Table 2).^61–77 Of these, topotecan (oral or intravenous) is the only second-line agent approved by the US Food and Drug Administration (FDA) for extensive-stage SCLC; this approval is based on a phase 3 trial showing a survival benefit with topotecan compared to best supportive care. The duration of second-line chemotherapy is not defined and is largely driven by duration of response and occurrence of side effects. Given the lack of effective treatment options, patients with platinum-resistant disease should be considered for clinical trials whenever possible. In patients with disease progression after second-line therapy, a third-line treatment can be considered if their Eastern Cooperative Oncology Group (ECOG) performance status is 0 to 2, but it is unclear whether further treatments would improve survival.

IMMUNOTHERAPY

The role of immune checkpoint inhibitors in the treatment of SCLC is evolving, and currently there are no FDA-approved immunotherapy agents for treating SCLC. A recently conducted phase 1/2 trial (CheckMate 032) studied the anti-programmed death(PD)-1 antibody nivolumab with or without the anti-cytotoxic T-lymphocyte–associated antigen (CTLA) -4 antibody ipilimumab in patients with relapsed SCLC. The authors reported response rates of 10% with nivolumab 3 mg/kg and 21% with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg.^78,79 The 2-year OS was 26% with the combination and 14% with single-agent nivolumab. Only 18% of patients had PD-L1 expression of ≥ 1%, and the response rate did not correlate with PD-L1 status. The rate of grade 3 or 4 adverse events was approximately 20%, and only 10% of patients discontinued treatment because of toxicity. Based on these data, nivolumab plus ipilimumab is now included in the National Comprehensive Cancer Network guidelines as an option for patients with SCLC who experience disease relapse within 6 months of receiving platinum-based therapy;⁷ however, it is questionable whether routine use of this combination is justified based on currently available data. The evidence for the combination of nivolumab and ipilimumab remains limited. The efficacy and toxicity data from both randomized and nonrandomized cohorts were presented together, making it hard to interpret the results.

Another phase 1b study (KEYNOTE-028) evaluated the anti-PD-1 antibody pembrolizumab (10 mg/kg intravenously every 2 weeks) in patients with relapsed SCLC who had received 1 or more prior lines of therapy and had PD-L1 expression of ≥ 1%. This study showed a response rate of 33%, with a median duration of response of 19 months and 1-year OS of 38%.⁸⁰ Although only 28% of screened patients had PD-L1 expression of ≥ 1%, these results indicated that at least a subset of SCLC patients are able to achieve durable responses with immune checkpoint inhibition. A number of clinical trials utilizing immune checkpoint inhibitors in various combinations and settings are currently underway.

ROLE OF PROPHYLACTIC CRANIAL IRRADIATION

The role of PCI in extensive-stage SCLC is not clearly defined. A randomized phase 3 trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) comparing PCI with no PCI in patients with extensive-stage SCLC who had a partial or complete response to initial platinum-based chemotherapy showed a decrease in the incidence of symptomatic brain metastasis and improvement in 1-year OS with PCI.⁸¹ However, this trial did not require mandatory brain imaging prior to PCI, and thus it is unclear if some patients in the PCI group had asymptomatic brain metastasis prior to enrollment and therefore received therapeutic benefit from brain radiation. Additionally, the dose and fractionation of PCI was not standardized across patient groups.

A more recent phase 3 study conducted in Japan that compared PCI (25 Gy in 10 fractions) with no PCI reported no difference in survival between the 2 groups.⁸² As opposed to the EORTC study, the Japanese study did require baseline brain imaging to confirm the absence of brain metastasis prior to enrollment. In addition, the control patients underwent periodic brain MRI to allow early detection of brain metastasis. Given the emergence of the new data, the impact of PCI on survival in patients with extensive-stage SCLC is unproven, and PCI likely has a role in a highly selected small group of patients with extensive-stage SCLC. PCI is not recommended for patients with poor performance status (ECOG performance score of 3 or 4) or underlying neurocognitive disorders.^34,83

The NMDA-receptor antagonist memantine can be used in patients undergoing PCI to delay the occurrence of cognitive dysfunction.⁶¹ Memantine 20 mg daily delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed compared to placebo in patients receiving whole brain radiotherapy.⁸⁴

ROLE OF RADIOTHERAPY

A subset of patients with extensive-stage SCLC may benefit from consolidative thoracic radiotherapy after completion of platinum-based chemotherapy. A randomized trial that enrolled patients who achieved complete or near complete response after 3 cycles of cisplatin plus etoposide compared thoracic radiotherapy in combination with continued chemotherapy versus chemotherapy alone.⁸⁵ The median OS was longer with the addition of thoracic radiotherapy compared to chemotherapy alone. Another phase 3 trial did not show improvement in 1-year OS with consolidative thoracic radiotherapy, but 2-year OS and 6-month PFS were longer.⁸⁶ In general, consolidative thoracic radiotherapy benefits patients who have residual thoracic disease and low-bulk extrathoracic disease that has responded to systemic therapy.⁸⁷ In addition, patients who initially presented with bulky symptomatic thoracic disease should also be considered for consolidative radiation.

Similar to other solid tumors, radiotherapy should be utilized for palliative purposes in patients with painful bone metastasis, spinal cord compression, or brain metastasis. Surgery is generally not recommended for spinal cord compression given the short life expectancy of patients with extensive-stage disease. Whole brain radiotherapy is preferred over stereotactic radiosurgery because micrometastasis is frequently present even in the setting of 1 or 2 radiographically evident brain metastasis.

NOVEL THERAPIES

The very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and high recurrence rate; however, at the same time this complexity can form the basis for effective targeted therapy for the disease. One of the major factors hindering the development of targeted therapies in SCLC is limited availability of tissue due to small tissue samples and the frequent presence of significant necrosis in the samples. In recent years, several different therapeutic strategies and targeted agents have been investigated for their potential role in SCLC. Several of them, including EGFR tyrosine kinase inhibitors (TKIs), BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors, have not been shown to provide a survival advantage in this disease. Several others, including PARP inhibitors, cellular developmental pathway inhibitors, and antibody-drug conjugates, are being tested. A phase 1 study of veliparib combined with cisplatin and etoposide in patients with previously untreated extensive-stage SCLC demonstrated a complete response in 14.3%, a partial response in 57.1%, and stable disease in 28.6% of patients with an acceptable safety profile.⁸⁸ So far, none of these agents are approved for use in SCLC, and the majority are in early- phase clinical trials.⁸⁹

One of the emerging targets in the treatment of SCLC is delta-like protein 3 (DLL3). DLL3 is expressed on more than 80% of SCLC tumor cells and cancer stem cells. Rovalpituzumab tesirine is an antibody-drug conjugate consisting of humanized anti-DLL3 monoclonal antibody linked to SC-DR002, a DNA-crosslinking agent. A phase 1 trial of rovalpituzumab in patients with relapsed SCLC after 1 or 2 prior lines of therapy reported a response rate of 31% in patients with DLL3 expression of ≥ 50%. The median duration of response and median PFS were both 4.6 months.⁹⁰ Rovalpituzumab is currently in later phases of clinical trials and has a potential to serve as an option for patients with extensive-stage disease after disease progression on platinum-based therapy.

SUMMARY

Four to 6 cycles of carboplatin and etoposide remain the standard of care first-line treatment for patients with extensive stage SCLC. The only FDA-approved second-line treatment option is topotecan. Re-treatment with the original platinum doublet is a reasonable option for patients who have disease progression 6 months or longer after completion of platinum-based therapy. The immune checkpoint inhibitors pembrolizumab and combination nivolumab and ipilimumab have shown promising results in the second-line setting and beyond. The role of PCI has become more controversial in recent years, and periodic brain MRI in lieu of PCI is now an acceptable approach.

 

 

RESPONSE ASSESSMENT/SURVEILLANCE

For patients undergoing treatment for limited-stage SCLC, response assessment with contrast-enhanced CT of the chest/abdomen should be performed after completion of 4 cycles of chemotherapy and thoracic radiation.⁷ The surveillance guidelines consist of history, physical exam, and imaging every 3 months during the first 2 years, every 6 months during the third year, and annually thereafter. If PCI is not performed, brain MRI or contrast-enhanced CT scan should be performed every 3 or 4 months during the first 2 years of follow up. For extensive-stage disease, response assessment should be performed after every 2 cycles of therapy. After completion of therapy, history, physical exam, and imaging should be done every 2 months during the first year, every 3 or 4 months during years 2 and 3, every 6 months during years 4 and 5, and annually thereafter. Routine use of PET scan for surveillance is not recommended. Any new pulmonary nodule should prompt evaluation for a second primary lung malignancy. Finally, smoking cessation counseling is an integral part of management of any patient with SCLC and should be included with every clinic visit.

CONCLUSION

SCLC is a heterogeneous and genetically complex disease with a very high mortality rate. The current standard of care includes concurrent chemoradiation with cisplatin and etoposide for limited-stage SCLC and the combination of platinum and etoposide for extensive SCLC. A number of novel treatment approaches, including immune checkpoint inhibitors and antibody-drug conjugates, have had promising results in early clinical trials. Given the limited treatment options and large unmet need for new treatment options, enrollment in clinical trials is strongly recommended for patients with SCLC.

INTRODUCTION

Small cell lung cancer (SCLC) is an aggressive cancer of neuroendocrine origin that accounts for approximately 15% of all lung cancer cases, with approximately 33,000 patients diagnosed annually.¹ The incidence of SCLC in the United States has steadily declined over the past 30 years, presumably because of a decrease in the number of smokers and a change to low-tar filter cigarettes.² Although the overall incidence of SCLC has been decreasing, the incidence in women is increasing and the male-to-female incidence ratio is now 1:1.³ Nearly all cases of SCLC are associated with heavy tobacco exposure, making it a heterogeneous disease with a complex genomic landscape consisting of thousands of mutations.^4,5 Despite recent advances in the treatment of non-small cell lung cancer, the therapeutic options for SCLC remain limited, with a median overall survival (OS) of 9 months in patients with advanced disease.

DIAGNOSIS AND STAGING

CASE PRESENTATION

A 61-year-old man presents to the emergency department with progressive shortness of breath and cough over the past 6 weeks. He also reports a 20-lb weight loss over the same period. He is a current smoker and has been smoking 1 pack of cigarettes per day since the age of 18 years. A chest radiograph obtained in the emergency department shows a right hilar mass. Computed tomography (CT) scan confirms the presence of a 4.5-cm right hilar mass and enlarged mediastinal lymph nodes bilaterally.

• What are the next steps in diagnosis?

SCLC is characterized by rapid growth and early hematogenous metastasis. Consequently, only 25% of patients have limited-stage disease at the time of diagnosis. According to the Veterans Administration Lung Study Group (VALSG) staging system, limited-stage disease is defined as tumor that is confined to 1 hemithorax and can be encompassed within 1 radiation field. This typically includes mediastinal lymph nodes and ipsilateral supraclavicular lymph nodes. Approximately 75% of patients present with extensive-stage disease, which is defined as disease that cannot be classified as limited, including disease that extends beyond 1 hemithorax. Extensive-stage disease includes the presence of malignant pleural effusion and/or distant metastasis.⁶ The VALSG classification and staging system is more commonly used in clinical practice than the American Joint Committee on Cancer TNM staging system because it is less complex and directs treatment decisions, as most of the literature on SCLC classifies patients based on the VALSG system.⁷

Given SCLC’s propensity to metastasize quickly, none of the currently available screening methods have proven successful in early detection of SCLC. In the National Lung Cancer Screening Trial, 86% of the 125 patients who were diagnosed with SCLC while undergoing annual low-dose chest CT scans had advanced disease at diagnosis.^8,9 These results highlight the fact that most cases of SCLC develop in the interval between annual screening imaging.

SCLC frequently presents with a large hilar mass that is symptomatic. Common symptoms include shortness of breath and cough. In addition, patients with SCLC usually have bulky mediastinal adenopathy at presentation. SCLC is commonly located submucosally in the bronchus, and therefore hemoptysis is not a very common symptom at the time of presentation. Patients may present with superior vena cava syndrome from local compression by the tumor. Not infrequently, SCLC is associated with paraneoplastic syndromes that arise due to ectopic secretion of hormones or antibodies by the tumor cells. The paraneoplastic syndromes can be broadly categorized as endocrine or neurologic (Table 1). The presence of a paraneoplastic syndrome is often a clue to the potential diagnosis of SCLC in the presence of a hilar mass. Additionally, some paraneoplastic syndromes, more specifically endocrine paraneoplastic syndromes, follow the pattern of disease response and relapse, and therefore can sometimes serve as an early marker of disease relapse or progression.

The common sites of metastases include brain, liver, and bone. Therefore, the staging workup should include fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan. Contrast-enhanced CT scan of the chest and abdomen and bone scan can be obtained for staging in lieu of PET scan. Due to the physiologic FDG uptake, cerebral metastases cannot be assessed with sufficient certainty using PET-CT.¹⁰ Therefore, brain imaging with contrast-enhanced CT or magnetic resonance imaging (MRI) is also necessary. Although the incidence of metastasis to bone marrow is less than 10%, bone marrow aspiration and biopsy are warranted in patients with unexplained cytopenias, especially when the cytopenia is associated with teardrop-shaped red cells or nucleated red cells on peripheral blood smear, findings indicative of a marrow infiltrative process.⁷ The tissue diagnosis is established by obtaining a biopsy of the primary tumor or 1 of the metastatic sites. In localized disease, bronchoscopy (with endobronchial ultrasound, if necessary) with biopsy of the centrally located tumor and/or lymph node is required. Histologically, SCLC consists of monomorphic cells, a high nuclear-cytoplasmic ratio, and confluent necrosis. The tumor cells are positive for chromogranin, synaptophysin, and CD56 by immunohistochemistry, and very frequently are also positive for thyroid transcription factor 1.¹¹ Although serum tumor markers, including neuron-specific enolase and progastrin-releasing peptide, are frequently elevated in patients with SCLC, these markers are of limited value in clinical practice because they lack sensitivity and specificity.¹²

MANAGEMENT OF LIMITED-STAGE DISEASE

CASE CONTINUED

The patient undergoes FDG PET scan, which shows the presence of a hypermetabolic right hilar mass in addition to enlarged and hypermetabolic bilateral mediastinal lymph nodes. There are no other areas of FDG avidity. Brain MRI does not show any evidence of brain metastasis. Thus, the patient is confirmed to have limited-stage SCLC.

• What is the standard of care treatment for limited-stage SCLC?

SCLC is exquisitely sensitive to both chemotherapy and radiation, especially at the time of initial presentation. The standard of care treatment of limited-stage SCLC is 4 cycles of platinum-based chemotherapy in combination with thoracic radiation started within the first 2 cycles of chemotherapy (Figure 1).

CHOICE OF CHEMOTHERAPY

Etoposide and cisplatin is the most commonly used initial combination chemotherapy regimen in limited-stage SCLC.¹⁴ This combination has largely replaced anthracycline-based regimens given its favorable efficacy and toxicity profile.^15–17 Several small randomized trials have shown comparable efficacy of carboplatin and etoposide in extensive-stage SCLC.^18–20 A meta-analysis of 4 randomized trials comparing cisplatin-based versus carboplatin-based regimens in 663 patients with SCLC (32% had limited-stage disease and 68% had extensive-stage disease) showed no statistically significant difference in response rate, progression-free survival (PFS), or OS between the 2 regimens.²¹ Therefore, in clinical practice carboplatin is frequently used instead of cisplatin in patients with extensive-stage disease. In patients with limited-stage disease, cisplatin is still the drug of choice. However, the toxicity profile of the 2 regimens is different. Cisplatin-based regimens are more commonly associated with neuropathy, nephrotoxicity, and chemotherapy-induced nausea/vomiting,¹⁸ while carboplatin-based regimens are more myelosuppressive.²² In addition, the combination of thoracic radiation with either of these regimens is associated with a higher risk of esophagitis, pneumonitis, and myelosuppression.²³ The use of myeloid growth factors is not recommended in patients undergoing concurrent chemoradiation.²⁴ Of note, intravenous etoposide is always preferred over oral etoposide, especially in the curative setting given the unreliable absorption and bioavailability of oral formulations.

THORACIC RADIOTHERAPY

Adding thoracic radiotherapy to platinum-etoposide chemotherapy improves local control and OS. Two meta-analyses of 13 trials including more than 2000 patients have shown a 25% to 30% decrease in local failure and a 5% to 7% increase in 2-year OS with chemoradiation compared to chemotherapy alone in limited-stage SCLC.^25,26 Early (within the first 2 cycles) concurrent thoracic radiation is superior to delayed and/or sequential radiation in terms of local control and OS.^23,27,28 The dose and fractionation of thoracic radiation in limited-stage SCLC has remained a controversial issue. The Eastern Cooperative Oncology Group/Radiation Therapy Oncology Group randomized trial compared 45 Gy of radiotherapy delivered twice daily over a period of 3 weeks to 45 Gy once daily over 5 weeks concurrently with chemotherapy. The twice daily regimen led to a 10% improvement in 5-year OS (26% versus 16%), but a higher incidence of grade 3 and 4 adverse events.¹³ Despite the survival advantage demonstrated by hyperfractionated radiotherapy, the results need to be interpreted with caution because the radiation doses are not biologically equivalent. In addition, the difficult logistics of patients receiving radiation twice a day has limited the routine implementation of this strategy. Subsequently, another randomized phase 3 trial (CONVERT) compared 45 Gy radiotherapy twice daily with 66 Gy radiotherapy once daily in limited-stage SCLC.²⁹ This trial did not show any difference in OS. The patients in the twice daily arm had a higher incidence of grade 4 neutropenia. Considering the results of these trials, both strategies—45 Gy fractionated twice daily or 60 Gy fractionated once daily, delivered concurrently with chemotherapy—are acceptable in the setting of limited-stage SCLC. However, quite often a hyperfractionated regimen is not feasible for patients and many radiation oncology centers. Hopefully, the ongoing CALGB 30610 study will clarify the optimal radiation schedule for limited-stage disease.

PROPHYLACTIC CRANIAL IRRADIATION

Approximately 75% of patients with limited-stage disease experience disease recurrence, and brain is the site of recurrence in approximately half of these patients.³⁰ Prophylactic cranial irradiation (PCI) consisting of 25 Gy radiotherapy delivered in 10 fractions has been shown to be effective in decreasing the incidence of cerebral metastases.^30–32 Although individual small studies have not shown a survival benefit of PCI because of small sample size and limited power, a meta-analysis of these studies has shown a 25% decrease in the 3-year incidence of brain metastasis and 5.4% increase in 3-year OS.³⁰ Most patients included in these studies had limited-stage disease. Therefore, PCI is the standard of care for patients with limited-stage disease who attain a partial or complete response to chemoradiation.

ROLE OF SURGERY

Surgical resection may be an acceptable choice in a very limited subset of patients with peripherally located small (< 5 cm) tumors where mediastinal lymph nodes have been confirmed to be uninvolved with complete mediastinal staging.^33,34 Most of the data in this setting are derived from retrospective studies.^35,36 A 5-year OS between 40% and 60% has been reported with this strategy in patients with clinical stage I disease. In general, when surgery is considered, lobectomy with mediastinal lymph node dissection followed by chemotherapy (if there is no nodal involvement) or chemoradiation (if nodal involvement) is recommended.^37,38 Wedge or segmental resections are not considered to be optimal surgical options.

MANAGEMENT OF EXTENSIVE-STAGE DISEASE

CASE CONTINUED

The patient receives 4 cycles of cisplatin and etoposide along with 70 Gy radiotherapy concurrently with the first 2 cycles of chemotherapy. His post-treatment CT scans show a partial response. He undergoes PCI 6 weeks after completion of treatment. At routine follow-up 18 months later, he is doing generally well except for mildly decreased appetite and an unintentional weight loss of 5 lb. CT scans demonstrate multiple hypodense liver lesions ranging from 7 mm to 2 cm in size and a 2-cm left adrenal gland lesion highly concerning for metastasis. FDG PET scan confirms that the adrenal and liver lesions are hypermetabolic. In addition, the PET scan shows multiple FDG-avid bone lesions throughout the spine. Brain MRI is negative for brain metastasis.

• What is the standard of care for treatment of extensive-stage disease?

Chemotherapy is the mainstay of treatment for extensive-stage SCLC; the goals of treatment are prolongation of survival, prevention or alleviation of cancer-related symptoms, and improvement in quality of life. The combination of etoposide with a platinum agent (carboplatin or cisplatin) is the preferred first-line treatment option. Carboplatin is more commonly used in clinical practice in this setting because of its comparable efficacy and better tolerability compared to cisplatin (Figure 2).²¹ A Japanese phase 3 trial comparing cisplatin plus irinotecan with cisplatin plus etoposide in the first-line setting in extensive-stage SCLC showed improvement in median and 2-year OS with the cisplatin/irinotecan regimen; however, 2 subsequent phase 3 trials conducted in the United States comparing these 2 regimens did not show any difference in OS. In addition, the cisplatin/irinotecan regimen was more toxic than the etoposide-based regimen.^39,40 Therefore, 4 to 6 cycles of platinum/etoposide remains the standard of care first-line treatment for extensive-stage SCLC in the United States. The combination yields a 60% to 70% response rate, but the majority of patients invariably experience disease progression, with a median OS of 9 to 11 months.⁴¹ Maintenance chemotherapy beyond the initial 4 to 6 cycles does not improve survival and is associated with higher cumulative toxicity.⁴²

Multiple attempts at improving first-line chemotherapy in extensive-stage disease have failed to show any meaningful difference in OS. For example, the addition of ifosfamide, palifosfamide, cyclophosphamide, taxane, or anthracycline to platinum doublet failed to show improvement in OS and led to more toxicity.^43–46 Additionally, the use of alternating or cyclic chemotherapies in an attempt to curb drug resistance has also failed to show survival benefit.^47–49 The addition of the antiangiogenic agent bevacizumab to standard platinum-based doublet has not prolonged OS in SCLC and has led to an unacceptably higher rate of tracheoesophageal fistula when used in conjunction with chemoradiation in limited-stage disease.^50–55 Finally, the immune checkpoint inhibitor ipilimumab in combination with platinum plus etoposide failed to improve PFS or OS compared to platinum plus etoposide alone in a recent phase 3 trial, and maintenance pembrolizumab after completion of platinum-based chemotherapy did not improve PFS.^56,57

More recently, a phase 2 study of pembrolizumab in extensive-stage SCLC (KEYNOTE 158) reported an overall response rate of 35.7%, median PFS of 2.1 months, and median OS of 14.6 months in patients who tested positive for programmed death ligand-1 (PD-L1) expression (which was defined as a PD-L1 Combined Positive Score ≥ 1).⁵⁸ The median duration of response has not been reached in this study, indicating that pembrolizumab may be a promising approach in patients with extensive-stage SCLC, especially for those with PD-L1–positive tumors.

Patients with extensive-stage disease who have brain metastasis at the time of diagnosis can be treated with systemic chemotherapy first if the brain metastases are asymptomatic and there is significant extracranial disease burden. In that case, whole brain radiotherapy should be given after completion of systemic therapy.

SECOND-LINE CHEMOTHERAPY

Despite being exquisitely chemosensitive, SCLC is associated with a very poor prognosis largely because of invariable disease progression following first-line therapy and lack of effective second-line treatment options that can lead to appreciable disease control. The choice of second-line treatment is predominantly determined by the time of disease relapse after first-line platinum-based therapy. If this interval is 6 months or longer, re-treatment utilizing the same platinum doublet is appropriate. However, if the interval is 6 months or less, second-line systemic therapy options should be explored. Unfortunately, the response rate tends to be less than 10% with most of the second-line therapies in platinum-resistant disease (defined as disease progression within 3 months of receiving platinum-based therapy). If disease progression occurs between 3 and 6 months after completion of platinum-based therapy, the response rate with second-line chemotherapy is in the range of 25%.^59,60

A number of second-line chemotherapy options have been explored in small studies, including topotecan, irinotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, oral etoposide, gemcitabine, bendamustine, and CAV (cyclophosphamide, doxorubicin, vincristine) (Table 2).^61–77 Of these, topotecan (oral or intravenous) is the only second-line agent approved by the US Food and Drug Administration (FDA) for extensive-stage SCLC; this approval is based on a phase 3 trial showing a survival benefit with topotecan compared to best supportive care. The duration of second-line chemotherapy is not defined and is largely driven by duration of response and occurrence of side effects. Given the lack of effective treatment options, patients with platinum-resistant disease should be considered for clinical trials whenever possible. In patients with disease progression after second-line therapy, a third-line treatment can be considered if their Eastern Cooperative Oncology Group (ECOG) performance status is 0 to 2, but it is unclear whether further treatments would improve survival.

IMMUNOTHERAPY

The role of immune checkpoint inhibitors in the treatment of SCLC is evolving, and currently there are no FDA-approved immunotherapy agents for treating SCLC. A recently conducted phase 1/2 trial (CheckMate 032) studied the anti-programmed death(PD)-1 antibody nivolumab with or without the anti-cytotoxic T-lymphocyte–associated antigen (CTLA) -4 antibody ipilimumab in patients with relapsed SCLC. The authors reported response rates of 10% with nivolumab 3 mg/kg and 21% with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg.^78,79 The 2-year OS was 26% with the combination and 14% with single-agent nivolumab. Only 18% of patients had PD-L1 expression of ≥ 1%, and the response rate did not correlate with PD-L1 status. The rate of grade 3 or 4 adverse events was approximately 20%, and only 10% of patients discontinued treatment because of toxicity. Based on these data, nivolumab plus ipilimumab is now included in the National Comprehensive Cancer Network guidelines as an option for patients with SCLC who experience disease relapse within 6 months of receiving platinum-based therapy;⁷ however, it is questionable whether routine use of this combination is justified based on currently available data. The evidence for the combination of nivolumab and ipilimumab remains limited. The efficacy and toxicity data from both randomized and nonrandomized cohorts were presented together, making it hard to interpret the results.

Another phase 1b study (KEYNOTE-028) evaluated the anti-PD-1 antibody pembrolizumab (10 mg/kg intravenously every 2 weeks) in patients with relapsed SCLC who had received 1 or more prior lines of therapy and had PD-L1 expression of ≥ 1%. This study showed a response rate of 33%, with a median duration of response of 19 months and 1-year OS of 38%.⁸⁰ Although only 28% of screened patients had PD-L1 expression of ≥ 1%, these results indicated that at least a subset of SCLC patients are able to achieve durable responses with immune checkpoint inhibition. A number of clinical trials utilizing immune checkpoint inhibitors in various combinations and settings are currently underway.

ROLE OF PROPHYLACTIC CRANIAL IRRADIATION

The role of PCI in extensive-stage SCLC is not clearly defined. A randomized phase 3 trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) comparing PCI with no PCI in patients with extensive-stage SCLC who had a partial or complete response to initial platinum-based chemotherapy showed a decrease in the incidence of symptomatic brain metastasis and improvement in 1-year OS with PCI.⁸¹ However, this trial did not require mandatory brain imaging prior to PCI, and thus it is unclear if some patients in the PCI group had asymptomatic brain metastasis prior to enrollment and therefore received therapeutic benefit from brain radiation. Additionally, the dose and fractionation of PCI was not standardized across patient groups.

A more recent phase 3 study conducted in Japan that compared PCI (25 Gy in 10 fractions) with no PCI reported no difference in survival between the 2 groups.⁸² As opposed to the EORTC study, the Japanese study did require baseline brain imaging to confirm the absence of brain metastasis prior to enrollment. In addition, the control patients underwent periodic brain MRI to allow early detection of brain metastasis. Given the emergence of the new data, the impact of PCI on survival in patients with extensive-stage SCLC is unproven, and PCI likely has a role in a highly selected small group of patients with extensive-stage SCLC. PCI is not recommended for patients with poor performance status (ECOG performance score of 3 or 4) or underlying neurocognitive disorders.^34,83

The NMDA-receptor antagonist memantine can be used in patients undergoing PCI to delay the occurrence of cognitive dysfunction.⁶¹ Memantine 20 mg daily delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed compared to placebo in patients receiving whole brain radiotherapy.⁸⁴

ROLE OF RADIOTHERAPY

A subset of patients with extensive-stage SCLC may benefit from consolidative thoracic radiotherapy after completion of platinum-based chemotherapy. A randomized trial that enrolled patients who achieved complete or near complete response after 3 cycles of cisplatin plus etoposide compared thoracic radiotherapy in combination with continued chemotherapy versus chemotherapy alone.⁸⁵ The median OS was longer with the addition of thoracic radiotherapy compared to chemotherapy alone. Another phase 3 trial did not show improvement in 1-year OS with consolidative thoracic radiotherapy, but 2-year OS and 6-month PFS were longer.⁸⁶ In general, consolidative thoracic radiotherapy benefits patients who have residual thoracic disease and low-bulk extrathoracic disease that has responded to systemic therapy.⁸⁷ In addition, patients who initially presented with bulky symptomatic thoracic disease should also be considered for consolidative radiation.

Similar to other solid tumors, radiotherapy should be utilized for palliative purposes in patients with painful bone metastasis, spinal cord compression, or brain metastasis. Surgery is generally not recommended for spinal cord compression given the short life expectancy of patients with extensive-stage disease. Whole brain radiotherapy is preferred over stereotactic radiosurgery because micrometastasis is frequently present even in the setting of 1 or 2 radiographically evident brain metastasis.

NOVEL THERAPIES

The very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and high recurrence rate; however, at the same time this complexity can form the basis for effective targeted therapy for the disease. One of the major factors hindering the development of targeted therapies in SCLC is limited availability of tissue due to small tissue samples and the frequent presence of significant necrosis in the samples. In recent years, several different therapeutic strategies and targeted agents have been investigated for their potential role in SCLC. Several of them, including EGFR tyrosine kinase inhibitors (TKIs), BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors, have not been shown to provide a survival advantage in this disease. Several others, including PARP inhibitors, cellular developmental pathway inhibitors, and antibody-drug conjugates, are being tested. A phase 1 study of veliparib combined with cisplatin and etoposide in patients with previously untreated extensive-stage SCLC demonstrated a complete response in 14.3%, a partial response in 57.1%, and stable disease in 28.6% of patients with an acceptable safety profile.⁸⁸ So far, none of these agents are approved for use in SCLC, and the majority are in early- phase clinical trials.⁸⁹

One of the emerging targets in the treatment of SCLC is delta-like protein 3 (DLL3). DLL3 is expressed on more than 80% of SCLC tumor cells and cancer stem cells. Rovalpituzumab tesirine is an antibody-drug conjugate consisting of humanized anti-DLL3 monoclonal antibody linked to SC-DR002, a DNA-crosslinking agent. A phase 1 trial of rovalpituzumab in patients with relapsed SCLC after 1 or 2 prior lines of therapy reported a response rate of 31% in patients with DLL3 expression of ≥ 50%. The median duration of response and median PFS were both 4.6 months.⁹⁰ Rovalpituzumab is currently in later phases of clinical trials and has a potential to serve as an option for patients with extensive-stage disease after disease progression on platinum-based therapy.

SUMMARY

Four to 6 cycles of carboplatin and etoposide remain the standard of care first-line treatment for patients with extensive stage SCLC. The only FDA-approved second-line treatment option is topotecan. Re-treatment with the original platinum doublet is a reasonable option for patients who have disease progression 6 months or longer after completion of platinum-based therapy. The immune checkpoint inhibitors pembrolizumab and combination nivolumab and ipilimumab have shown promising results in the second-line setting and beyond. The role of PCI has become more controversial in recent years, and periodic brain MRI in lieu of PCI is now an acceptable approach.

 

 

RESPONSE ASSESSMENT/SURVEILLANCE

For patients undergoing treatment for limited-stage SCLC, response assessment with contrast-enhanced CT of the chest/abdomen should be performed after completion of 4 cycles of chemotherapy and thoracic radiation.⁷ The surveillance guidelines consist of history, physical exam, and imaging every 3 months during the first 2 years, every 6 months during the third year, and annually thereafter. If PCI is not performed, brain MRI or contrast-enhanced CT scan should be performed every 3 or 4 months during the first 2 years of follow up. For extensive-stage disease, response assessment should be performed after every 2 cycles of therapy. After completion of therapy, history, physical exam, and imaging should be done every 2 months during the first year, every 3 or 4 months during years 2 and 3, every 6 months during years 4 and 5, and annually thereafter. Routine use of PET scan for surveillance is not recommended. Any new pulmonary nodule should prompt evaluation for a second primary lung malignancy. Finally, smoking cessation counseling is an integral part of management of any patient with SCLC and should be included with every clinic visit.

CONCLUSION

SCLC is a heterogeneous and genetically complex disease with a very high mortality rate. The current standard of care includes concurrent chemoradiation with cisplatin and etoposide for limited-stage SCLC and the combination of platinum and etoposide for extensive SCLC. A number of novel treatment approaches, including immune checkpoint inhibitors and antibody-drug conjugates, have had promising results in early clinical trials. Given the limited treatment options and large unmet need for new treatment options, enrollment in clinical trials is strongly recommended for patients with SCLC.

INTRODUCTION

According to the Surveillance, Epidemiology and End Results database, in 2017 there were 28,000 new cases of gastric cancer, accounting for 1.8% of all malignancies in the United States, and an estimated 10,960 gastric cancer–related deaths.¹ Worldwide, gastric cancer is the fifth most common malignancy and the third most common cause of death from any cancer.² The incidence of gastric cancer varies significantly by geographic region, with countries in Eastern Asia (China, Japan), Eastern Europe, and Central and South America accounting for 50% of all new cases.³ Although the incidence of gastric cancer has declined in recent years, this decrease has not been observed consistently across all nations.² In particular, the incidence of gastric cancers arising from the cardia has been increasing, which is perhaps due to a higher prevalence of obesity in Western societies.⁴

In this article, we review key aspects of management of metastatic gastric cancer, including selection of first- and second-line therapy, and discuss targeted agents and upcoming clinical trials.

EPIDEMIOLOGY AND RISK FACTORS

Chronic infection with Helicobacter pylori, a gram-negative bacterium, is a strong etiological factor for the development of gastric cancer, contributing to up to 70% of cases.² The pathogen can colonize the gastric mucosa, leading to chronic inflammation. Although most patients remain asymptomatic, 1% to 3% develop gastric cancer and another 0.1% develop mucosa-associated lymphoid tissue lymphoma.⁵ H. pylori infection is more commonly associated with cancer of the gastric body than with cancer of the gastroesophageal junction (GEJ). The increased burden of gastric cancer in countries in Eastern Asia, Latin America, and Eastern Europe has been correlated to the prevalence of chronic H. pylori infection in these areas.

Carcinogenesis secondary to H. pylori infection may occur via several mechanisms. First, H. pylori can release virulence factors, such as cytotoxin-associated gene A, vacuolating cytotoxin, and outer membrane proteins, into the cytosol of host cells, leading to changes in patterns of cell proliferation and apoptosis.⁶ These virulence factors can modulate the host immune system, attenuating it to promote dysplasia. In addition, continued recognition of these factors by the immune system leads to a persistent inflammatory response, with the release of cytokines such as interleukin (IL) -1β, IL-6, and IL-8. This leads to chronic mucosal damage, further promoting dysplasia with eventual transformation into adenocarcinoma.⁷ In Japan and Korea, where screening for H. pylori infection is routinely performed, there have been improvements in overall survival (OS) rates for gastric cancer, with 5-year OS rates of 70%.⁸ The International Agency for Research on Cancer recommends further research into population-based screening and treatment programs for patients with chronic H. pylori infection. However, despite this recommendation, optimal screening strategies are not clearly defined.⁹

Other risk factors for the development of gastric cancer include chronic gastroesophageal reflux disease; smoking; alcohol use; exposure to radiation; diets high in fats, salt, and smoked items and low in fruits and vegetables; obesity; and exposure to chemotherapeutic agents such as procarbazine.¹⁰ Another pathogen suspected, but not proven, to be associated with increased risk for gastric cancer is the Epstein-Barr virus, a human herpesvirus found in 80% of all gastric carcinomas with lymphoid features.¹¹ In addition, whether the use of medications such as statins and nonsteroidal anti-inflammatory drugs confers a decreased risk of gastric cancers remains unclear.¹⁰

EVALUATION

CASE PRESENTATION

A 55-year-old Caucasian man with a history of type 2 diabetes mellitus presents to the gastrointestinal (GI) clinic with a 6-month history of dysphagia. The dysphagia is worsened with ingestion of solids, particularly towards the end of the day. He states that the food often gets “stuck in the middle of the chest.” The patient denies any nausea or emesis but notes that he has a poor appetite. He reports having worsening mid-epigastric abdominal pain that is non-radiating, dull in character, and 6/10 in intensity. He also reports a 10-lb weight loss over the past 2 months. He has no previous history of reflux, chest pain, dyspnea, or cough. Review of systems is otherwise benign. Physical exam is within normal limits.

• Which tests should be conducted when gastric cancer is suspected?

Persistent epigastric abdominal pain and weight loss are the most common early symptoms of gastric cancer. Nausea, early satiety, dysphagia, and occult GI bleeding can be other presenting signs. Patients presenting with alarm symptoms of nausea, emesis, early satiety, abdominal pain, or weight loss should be fully evaluated with upper GI endoscopy. Early diagnosis of gastric cancer is essential in obtaining a curative resection. However, at least 40% of patients present with de novo metastatic disease at the time of initial diagnosis.¹² Gastric cancer spreads by direct extension through the gastric wall, with the liver, peritoneum, and regional lymph nodes being the most common sites of metastatic deposits.¹³ Classically, Virchow’s node, the left supraclavicular lymph node, is involved with metastatic gastric cancer. Involvement of the left axillary lymph node (Irish node) or a periumbilical nodule (Sister Mary Joseph node) may also be observed. Other, less commonly noted sites of metastatic disease include the ovaries, central nervous system, bone, lung, and soft tissues.¹³

Upper GI endoscopy is the best method for determining tumor location and extent and obtaining a specimen for a definitive tissue diagnosis.¹⁴ It is essential to accurately identify the location of the tumor in the stomach and relative to the GEJ. The American Joint Committee on Cancer classification defines tumors involving the GEJ with an epicenter no more than 2 cm into the proximal stomach as esophageal cancers.¹⁵ Tumors of the GEJ with their epicenter more than 2 cm into the proximal stomach are defined as gastric cancers. If metastatic disease is suspected, computed tomography (CT) scan of the chest, abdomen, and pelvis with oral and intravenous contrast can be obtained to determine the extent of disease spread. In the absence of any metastatic disease, endoscopic ultrasound (EUS) should be conducted to determine the depth of tumor invasion (T staging) and lymph node status. In the era of targeted therapy, patients with metastatic disease should undergo testing for human epidermal growth factor-2 (HER-2) expression, microsatellite instability (MSI), and programmed death ligand 1 (PD-L1) expression. Patients should be staged according to the TNM staging system.

FIRST-LINE TREATMENT OPTIONS

CASE CONTINUED

The patient undergoes esophagoduodenoscopy (EGD) and is found to have a gastric cardia mass extending into the distal esophagus. EUS also demonstrates multiple abdominal and mediastinal lymph nodes. No gastric outlet obstruction is found. Biopsy shows poorly differentiated invasive adenocarcinoma. Warthin–Starry stain is negative for H. pylori organism. The tumor cells are positive for cytokeratin (CK7), CK19, and mucin-1 gene (MUC1); focally positive for CK20; and negative for MUC2. HER2 testing results are reported as immunohistochemistry (IHC) 3+, consistent with strongly positive HER2 protein expression. Further IHC testing for mismatch repair (MMR) proteins shows intact nuclear expression of MLH1, MSH2, MSH6, and PMS2 protein, consistent with a low probability of MSI-high tumor. The tumor is found to be PD-L1 positive. Imaging reveals abnormal mass-like nodular thickening of the gastric wall, with an infiltrative opacity within the pancreatico-duodenal groove, suspicious for tumor infiltration. Multiple metastatic deposits are noted in the liver, peritoneum, and bilateral lungs. There is extensive gastrohepatic ligament and periportal lymphadenopathy and mild enlargement of the pulmonary hilar lymph nodes. These findings are consistent with stage 4 (T4bN3aM1) gastric cancer. Given these findings, staging laparoscopy is deferred.

• What are the first-line treatment options for patients with metastatic gastric cancer?

Patients with metastatic gastric cancer have a poor prognosis, and management is stratified based on performance status (Figure). In patients with good performance status, systemic chemotherapy is the mainstay of treatment. The goal of therapy is not curative, but rather treatment focuses on palliation of symptoms arising from tumor spread. Given this treatment goal, there has been considerable interest in clarifying the utility of chemotherapy as opposed to best supportive care. In a recent Cochrane review of 64 randomized control trials involving 11,698 patients, chemotherapy was found to improve OS by 6.7 months as compared to best supportive care (hazard ratio [HR] 0.3 [95% confidence interval {CI} 0.24 to 0.55]).¹⁶ Five classes of cytotoxic chemotherapeutic agents have demonstrated activity in gastric cancer. These include fluoropyrimidine (either infusional fluorouracil or capecitabine), platinum agents (cisplatin or oxaliplatin), taxanes (docetaxel or paclitaxel), anthracyclines (epirubicin), and irinotecan.¹³ Treatment options are further divided based on whether the patient has HER2-overexpressing or non-expressing malignancy.

 

 

HER2-NEGATIVE DISEASE

For patients with HER2-negative disease, National Comprehensive Cancer Network (NCCN) guidelines recommend using 2-drug combination regimens rather than 3 drugs, given concern for increased toxicity with 3-drug regimens.¹⁷ For patients with a performance status of 0 to 1, utilization of a 3-drug regimen is a reasonable alternative. The combination of a fluoropyrimidine with a platinum agent is considered the standard of care, with regimens such as fluorouracil, leucovorin, and oxaliplatin (FOLFOX) being commonly used.

Epirubicin-containing regimens have also been extensively studied in advanced gastric cancer. In a study of 274 previously untreated patients with GEJ cancers, the combination of epirubicin, cisplatin, and fluorouracil (ECF) was compared to fluorouracil, doxorubicin, and methotrexate (FAMTX). There was an OS benefit favoring ECF (8.9 months versus 5.7 months) at 1 year (95% CI 27% to 45%, P = 0.0009). The ECF regimen was associated with an increased risk of nausea, emesis, and alopecia, while more hematologic toxicity and infections were noted with the FAMTX regimen.¹⁸ In addition, in a phase 3 trial, Van Cutsem and colleagues examined the role of docetaxel in combination with cisplatin and fluorouracil (DCF) compared to cisplatin and fluorouracil alone. Addition of docetaxel led to improved OS and time to progression (9.2 months versus 8.6 months for cisplatin and fluorouracil alone, P = 0.02) but with an increased risk of grade 3 and 4 toxicities (69% versus 59%). These adverse events included neutropenia (82% versus 57% of cisplatin and fluorouracil patients), diarrhea (19% versus 8%), stomatitis (21% versus 27%), and fatigue (19% versus 14%).¹⁹

The landmark phase 3 REAL-2 study compared 4 chemotherapy regimens in patients with untreated advanced esophagogastric cancer. This study was conducted to determine if the efficacy of cisplatin and oxaliplatin, a third-generation platinum agent, is equivalent to that of fluorouracil and capecitabine, an oral fluoropyrimidine. In this trial, a 2 × 2 design was used to compare 4 regimens: ECF versus epirubicin, cisplatin, and capecitabine (ECX) versus epirubicin, oxaliplatin, and fluorouracil (EOF) versus epirubicin, oxaliplatin, and capecitabine (EOX). The study found EOX to be noninferior to ECF, with a trend towards improved OS compared to other combination regimens (11.2 months versus 9.9 months, HR 0.80 [95% CI 0.66 to 0.97], P = 0.02).²⁰ Thus, the study demonstrated that an oxaliplatin and capecitabine-based regimen could replace cisplatin and fluorouracil. Given that fluorouracil administration requires long continuous infusions, the oral-based capecitabine regimen is an attractive option for patients.

Several trials have demonstrated the equivalency of oxaliplatin with cisplatin in combination regimens for the treatment of advanced gastric cancer. Oxaliplatin has the benefit of an improved toxicity profile as compared to cisplatin, with the major dose-limiting toxicity being peripheral neuropathy

Given previous evidence that DCF (docetaxel, cisplatin, fluorouracil) is superior to cisplatin and fluorouracil alone, there was interest in determining if the addition of docetaxel to a backbone of fluorouracil, oxaliplatin, and leucovorin (FLO) could elicit a higher response rate. This concept was investigated in a phase 2 trial that assigned 54 patients with metastatic gastric or GEJ adenocarcinoma to receive biweekly infusions of oxaliplatin, leucovorin, fluorouracil, and docetaxel.²¹ Median time to response was 1.54 months, and the overall response rate was 57.7%. Median progression-free survival (PFS) was 5.2 months, and OS was 11.1 months. The most common grade 3 or 4 toxicities included neutropenia (48%), leukopenia (27.8%), diarrhea (14.8%), and fatigue (11.1%).

Irinotecan-based regimens have also been extensively studied in the first-line treatment of metastatic gastric cancer, particularly as an alternative to platinum-based therapy, but superiority has not been established. The combination of fluorouracil, leucovorin, and irinotecan (FOLFIRI) was compared to ECX in a phase 3 trial.²² The study enrolled 416 patients with locally advanced or metastatic gastric or GEJ cancer. At a median follow up of 31 months, the time to progression was longer in the FOLFIRI arm as compared to the ECX arm (5.1 months versus 4.2 months, P = 0.008), but there was no difference in OS (9.5 months versus 9.7 months, P = 0.95), median PFS (5.3 months versus 5.8 months, P = 0.96), or response rate (39.2% versus 37.8%). However, the FOLFIRI regimen had an improved toxicity profile, with a lower overall rate of grade 3 or 4 toxicity (69% versus 84%, P < 0.001). Given these findings, the FOLFIRI regimen is an acceptable alternative to platinum-based therapy in suitable patients.²²

HER2-POSITIVE DISEASE

The HER2 proto-oncogene, initially described in breast cancer, has been implicated in several malignancies, including gastric and esophageal cancer. Overexpression or amplification of HER2 can be found in up to 30% of gastric cancers.²³ For these patients, adding trastuzumab to a standard regimen of platinum and fluoropyrimidine is the standard of care. The prospective phase 3 Trastuzumab for Gastric Cancer (ToGA) trial randomly assigned 594 patients with HER2-positive gastric cancer to receive either cisplatin and fluorouracil or capecitabine and cisplatin with trastuzumab (n = 294) or without (n = 290) trastuzumab every 3 weeks for a total of 6 cycles, followed by maintenance trastuzumab until disease progression was noted.²⁴ HER2 positivity was defined as HER2 protein overexpression by IHC (cutoff of 3+) or gene amplification by fluorescence in situ hybridization (FISH); tumors with IHC 2+ patterns were followed with FISH studies to confirm positivity. The study found a higher incidence of HER2-positive tumors in patients with GEJ tumors compared to patients with distal gastric cancers (33% versus 20%).²⁴ In this trial, the addition of trastuzumab was associated with an improvement in OS: 13.5 months in the trastuzumab cohort versus 11.1 months in those receiving chemotherapy alone (HR 0.74, P = 0.0048). There was not a significant difference in toxicities between the 2 cohorts, with nausea, emesis, and neutropenia being the most common adverse events. Rates of overall grade 3 or 4 events were similar as well (68% in each cohort). Further exploratory analysis was also conducted according to HER2 status by dividing patients into a “high-expressor” group (n = 446), defined as patients with IHC 3+ tumors or IHC 2+ and FISH positivity, and a “low-expressor” group (n = 131), which included patients with IHC 0 or 1+ tumors. Analysis of patients in the 2 subgroups demonstrated an improved OS with the addition of trastuzumab for the high-expressor cohort, with a median OS of 16 months (HR 0.65 [95% CI 0.51 to 0.83]) compared to 11.8 months in those receiving only chemotherapy.

Dual HER2 blockade has been investigated in metastatic gastric cancer. The phase 3 randomized JACOB trial assigned 780 patients to receive either trastuzumab with a cisplatin/fluoropyrimidine regimen with or without the addition of pertuzumab; the primary end point was OS.²⁵ A non-statistically significant trend towards improvement in OS was found in the pertuzumab arm (17.5 months) as compared with the standard of care arm (14.2 months, HR 0.84, P = 0.0565). The pertuzumab/trastuzumab/chemotherapy cohort experienced a higher incidence of diarrhea (61.6% versus 35.1% in control arm). Cardiac toxicity was comparable in the 2 cohorts.

The Table provides a summary of relevant clinical trials in metastatic gastric cancer.

SECOND-LINE THERAPY

CASE CONTINUED

The patient receives capecitabine, oxaliplatin, and trastuzumab therapy for 6 cycles, followed by trastuzumab for another 3 cycles. While on therapy, he develops a painful right clavicular lesion. He undergoes magnetic resonance imaging of the right clavicle, which shows a lesion in the distal two-thirds of the right clavicle measuring 9.7 × 3.7 × 3.8 cm. The patient is started on palliative radiation to the clavicle. However, repeat CT imaging shows progressive liver metastases.

• What is the approach to second-line therapy for metastatic gastric cancer?

Improvements in our understanding of the molecular pathways that lead to tumorigenesis have contributed to the development of several targeted agents whose efficacy in gastric cancer is being investigated. The NCCN guidelines recommend that for all patients who progress on frontline therapy, second-line therapy consists of a combination of ramucirumab and paclitaxel. Other options include single-agent docetaxel, paclitaxel, irinotecan, or ramucirumab. Combination therapy using irinotecan with either docetaxel, fluorouracil, or cisplatin may also be used.

Ramucirumab, a human IgG1 monoclonal antibody that targets the vascular endothelial growth factor receptor 2 (VEGFR2), was initially approved in 2014 as monotherapy for patients who had previously progressed on first-line chemotherapy. Its approval was based on the results of the phase 3 randomized, double-blind placebo-controlled REGARD study.²⁶ The trial randomly assigned 355 patients with advanced gastric or GEJ adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy to receive best supportive care plus either ramucirumab (n = 238) or placebo (n = 117). Monotherapy with ramucirumab significantly improved median OS compared with placebo (5.2 months versus. 3.8 months; HR 0.776 [95% CI 0.6 to 0.99], P = 0.047). There was also an improvement in PFS of 2.1 months in the ramucirumab cohort, as compared to 1.3 months in the placebo cohort (P < 0.0001). Patients in the ramucirumab arm experienced a higher incidence of hypertension (16% versus 8%), but all other adverse events occurred at comparable rates. Five deaths in the ramucirumab group were thought to be secondary to the study drug, as compared to 2 deaths in the placebo group.

In the subsequent phase 3 RAINBOW trial, the addition of ramucirumab to paclitaxel was investigated, with 330 patients assigned to the combination group and 335 to the paclitaxel-only group.²⁷ The trial again showed that combination therapy afforded patients a significant survival advantage compared to paclitaxel alone, with a median OS of 9.6 months versus 7.4 months for the monotherapy group (HR 0.807 [95% CI 0.678 to 0.962], P = 0.017). A PFS benefit of 4.4 months was observed in the combination therapy groups, as compared with 2.9 months in the monotherapy group (HR 0.635, P < 0.0001). The ramucirumab/paclitaxel group also had a higher overall response rate of 28% versus 16%. The combination cohort had an increased incidence of grade 3 or higher adverse hypertensive events (14% versus 2%) and neutropenia (41% versus 19%), while the incidence of grade 3 febrile neutropenic events was similar between the groups (3% versus 2%).

The addition of bevacizumab, another monoclonal antibody against VEGF, to standard chemotherapy regimens has been explored, but studies have failed to show a survival benefit with this agent in the first-line treatment of advanced gastric cancer. The phase 3 Avastin in Gastric Cancer (AVAGAST) trial was a multinational, randomized study where patients received either bevacizumab (n = 387) or placebo (n = 387) in addition to cisplatin and capecitabine.²⁸ The substitution of fluorouracil for capecitabine was permitted for patients who were unable to tolerate oral medications. Cisplatin was administered for a maximum of 6 cycles, while capecitabine and bevacizumab were administered until disease progression. The study failed to show an improvement in OS, with a median OS of 12.1 months noted in the bevacizumab cohort, as compared to 10.1 months in the placebo arm (HR 0.87 [95% CI 0.73 to 1.03], P = 0.1002). However, there was a modest improvement in median PFS (6.7 months versus 5.3 months; HR 0.80 [95% CI 0.68 to 0.93], P = 0.0037) and overall response rate (46% versus 37.4%, P = 0.0315). The most commonly reported grade 3 to 5 adverse events included neutropenia (35%), anemia (10%), and loss of appetite (8%). Interestingly, in a follow-up report, higher serum levels of VEGF-A were thought to correlate with an enhanced response to bevacizumab.²⁹ However, the routine use of biomarker analysis in selecting patients for treatment with bevacizumab in metastatic gastric cancer remains to be further clarified.

Use of other agents with anti-HER2 activity in the second-line treatment of patients who have experienced progression while on trastuzumab remains unclear. In the recent T-ACT trial, patients with disease refractory to frontline therapy with combination trastuzumab and fluoropyrimidine/platinum agents were randomly assigned to receive either weekly paclitaxel (n = 45) or weekly paclitaxel plus trastuzumab (n = 44).³⁰ Patients in the combination cohort received an initial dose of trastuzumab 8 mg/kg followed by 6 mg/kg every 3 weeks until progression. The study did not find a difference in either PFS (3.19 months versus 3.68 months; HR 0.91 [95% CI 0.67 to 1.22], P = 0.33) or OS (9.95 months versus 10.2 months; HR 1.23 [95% CI 0.75 to 1.99], P = 0.20). The study thus failed to show a benefit to continuing trastuzumab after progression in the first-line setting.

Lapatinib in combination with paclitaxel has been compared to paclitaxel alone for the treatment of advanced HER2-positive gastric cancer in an Asian population in the phase 3 TyTAN trial.³¹ With a primary end point of OS, the study randomly assigned 129 patients to receive paclitaxel alone and 132 patients to receive paclitaxel with lapatinib. There was a nonsignificant trend towards improvement in OS in the combination group (11 months) as compared to the paclitaxel-only group(8.9 months, P = 0.1044), with no significant difference in median PFS (5.4 months versus 4.4 months). However, it is important to note that only 15 patients in this trial had previously been exposed to trastuzumab. Another trial, the phase 3 GATSBY study, examined the efficacy of trastuzumab emtansine in the second-line setting compared to taxanes alone and failed to show any improvement in PFS or OS.³² Given these results, no alternative anti-HER2 therapy has been proven to be efficacious for patients who are trastuzumab refractory. Therefore, including anti-HER2 therapy in the second-line treatment of HER2-positive gastric cancer is not recommended.

IMMUNOTHERAPY AND OTHER TARGETED THERAPIES

Several other targeted therapies have been studied in advanced gastric cancer, without any demonstrable survival benefit. The PI3K/AKT/mTOR pathway is known to be involved in regulation of cell growth and angiogenesis, and the mTOR inhibitor everolimus is widely used to treat other malignancies, including breast cancer. The use of everolimus in the second-line setting was studied in the phase 3 GRANITE-1 trial, where it was compared to best supportive care and failed to provide any survival benefit.³³ Cetuximab, a recombinant human and mouse chimeric monoclonal antibody, and panitumumab, a recombinant human antibody against the epidermal growth factor receptor (EGFR), have also been examined in gastric and GEJ cancer patients. However, the large phase 3 EXPAND and REAL-3 trials did not show a survival benefit when these agents were added to standard chemotherapy.^34,35

Overexpression of MET, a proto-oncogene and tyrosine kinase receptor, has also been implicated in gastric cancer progression. The ligand for MET is the hepatocyte growth factor (HGF), and aberrant signaling of this pathway has been shown to correlate with an aggressive gastric cancer phenotype and poorer OS by promoting tumor growth and angiogenesis. However, no MET inhibitors thus far have been found to be clinically effective. RILOMET-1 and RILOMET-2 were phase 3 trials examining the efficacy of rilotumumab, a humanized anti-HGF antibody, in combination with chemotherapy (ECX and cisplatin with capecitabine, respectively) for the frontline treatment of MET-positive GEJ and gastric cancers. Both studies were discontinued due to a higher treatment-related mortality in patients receiving rilotumumab, with a higher incidence of adverse events due to disease progression being noted.³⁶ Similarly, onartuzumab, a monovalent monoclonal antibody against the MET receptor, was investigated in the phase 3 METGastric trial in combination with modified FOLFOX6 as first-line therapy for HER2-negative, MET-positive metastatic GEJ and gastric cancers. The study did not demonstrate any significant improvements in OS or PFS.³⁷

There has been significant interest in incorporating immunotherapy in the treatment of early and metastatic gastric cancer. Pembrolizumab is the first programmed death receptor (PD-1) inhibitor to be approved for treatment of patients with PD-L1−positive advanced gastric cancer who had previously received 2 or more lines of chemotherapy. Although earlier studies of pembrolizumab in lung cancer utilized the tumor proportion score (TPS) to determine PD-L1 positivity, this was not found to be applicable to gastric cancer. Instead, the combined positive score (CPS) is used in gastric cancer. The CPS evaluates the number of tumor cells and immune cells (macrophages and lymphocytes) that stain positive for PD-L1 relative to all viable tumor cells. Comparatively, the TPS only examines the percentage of viable tumor cells that show complete or partial positive staining for PD-L1. A CPS score of 1 or greater identifies patients who would be suitable candidates for pembrolizumab.

The approval of pembrolizumab was based on the positive findings from the recent KEYNOTE-059 trial.³⁸ The study included 259 patients who had previously received either fluoropyrimidine, cisplatin, or anti-HER2 therapy, with 148 patients (55%) of these patients having PD-L1−positive tumors. The PD-L1 status was determined using a pharmDx Kit, which is now approved by the US Food and Drug Administration to select patients who could benefit from pembrolizumab treatment. CPS was calculated as the number of PD-L1−staining cells divided by the total number of evaluated cells. The study included patients with microsatellite stable (MSI-S), undetermined, or deficient MMR status. The overall response rate to pembrolizumab across all patients was 11.6%, median PFS was 2 months, and the 12-month OS rate was 23.4%. In the subset of patients with MSI-H tumors, the overall response rate was 57.1%, with a complete response rate of 14.3%; in those with MSI-S tumors, the overall response rate was 9% and the complete response rate was 2.4%. Among patients with PD-L1–positive tumors, the overall response rate was 15.5% (95% CI 10.1% to 22.4). Common adverse events included fatigue, hypothyroidism, nausea, diarrhea, and arthralgia.³⁸

CASE CONCLUSION

This patient with metastatic gastric cancer receives second-line chemotherapy with ramucirumab and paclitaxel. Follow-up imaging shows persistent liver metastases and new lung metastasis. Because the tumor is PD-L1–positive, the patient receives 4 cycles of pembrolizumab, with no significant change noted in disease burden. He notes a significant decline in functional status with increased weight loss, nausea, emesis, and fatigue. The patient opts to forego any further therapy and instead chooses to pursue supportive care only.

SUMMARY

Gastric cancer is the third most common cause of cancer death worldwide. Common risk factors for developing gastric cancer include H. pylori infection, smoking, alcohol abuse, radiation exposure, high-fat diet, and obesity. Patients presenting with alarm symptoms of nausea, emesis, early satiety, abdominal pain, or weight loss should be fully evaluated with upper GI endoscopy. If there is suspicion for metastatic disease, CT evaluation of the chest, abdomen, and pelvis with oral and intravenous contrast should be obtained. Treatment of patients with metastatic gastric cancer is guided by their performance status at presentation. For patients with good performance status, a combination of platinum and fluoropyrimidine therapy, such as FOLFOX, can be considered. Doublet chemotherapy regimens are preferred over triplet chemotherapy regimens given their better tolerability. For patients with HER2-positive disease, the addition of trastuzumab to the platinum and fluoropyrimidine backbone is the standard of care in the first line.

Several targeted agents have been studied in patients progressing on initial therapy, with ramucirumab and paclitaxel being considered the regimen of choice in the second line. No anti-HER2 therapy has been approved for patients who are refractory to trastuzumab. Pembrolizumab is approved for use in patients who are PD-L1–positive and have previously progressed on at least 2 lines of chemotherapy. Pembrolizumab is also approved for the treatment of patients with unresectable or metastatic, MSI-H or MMR-deficient gastric cancers that have progressed after prior treatment and who have no satisfactory alternative treatment options.

INTRODUCTION

According to the Surveillance, Epidemiology and End Results database, in 2017 there were 28,000 new cases of gastric cancer, accounting for 1.8% of all malignancies in the United States, and an estimated 10,960 gastric cancer–related deaths.¹ Worldwide, gastric cancer is the fifth most common malignancy and the third most common cause of death from any cancer.² The incidence of gastric cancer varies significantly by geographic region, with countries in Eastern Asia (China, Japan), Eastern Europe, and Central and South America accounting for 50% of all new cases.³ Although the incidence of gastric cancer has declined in recent years, this decrease has not been observed consistently across all nations.² In particular, the incidence of gastric cancers arising from the cardia has been increasing, which is perhaps due to a higher prevalence of obesity in Western societies.⁴

In this article, we review key aspects of management of metastatic gastric cancer, including selection of first- and second-line therapy, and discuss targeted agents and upcoming clinical trials.

EPIDEMIOLOGY AND RISK FACTORS

Chronic infection with Helicobacter pylori, a gram-negative bacterium, is a strong etiological factor for the development of gastric cancer, contributing to up to 70% of cases.² The pathogen can colonize the gastric mucosa, leading to chronic inflammation. Although most patients remain asymptomatic, 1% to 3% develop gastric cancer and another 0.1% develop mucosa-associated lymphoid tissue lymphoma.⁵ H. pylori infection is more commonly associated with cancer of the gastric body than with cancer of the gastroesophageal junction (GEJ). The increased burden of gastric cancer in countries in Eastern Asia, Latin America, and Eastern Europe has been correlated to the prevalence of chronic H. pylori infection in these areas.

Carcinogenesis secondary to H. pylori infection may occur via several mechanisms. First, H. pylori can release virulence factors, such as cytotoxin-associated gene A, vacuolating cytotoxin, and outer membrane proteins, into the cytosol of host cells, leading to changes in patterns of cell proliferation and apoptosis.⁶ These virulence factors can modulate the host immune system, attenuating it to promote dysplasia. In addition, continued recognition of these factors by the immune system leads to a persistent inflammatory response, with the release of cytokines such as interleukin (IL) -1β, IL-6, and IL-8. This leads to chronic mucosal damage, further promoting dysplasia with eventual transformation into adenocarcinoma.⁷ In Japan and Korea, where screening for H. pylori infection is routinely performed, there have been improvements in overall survival (OS) rates for gastric cancer, with 5-year OS rates of 70%.⁸ The International Agency for Research on Cancer recommends further research into population-based screening and treatment programs for patients with chronic H. pylori infection. However, despite this recommendation, optimal screening strategies are not clearly defined.⁹

Other risk factors for the development of gastric cancer include chronic gastroesophageal reflux disease; smoking; alcohol use; exposure to radiation; diets high in fats, salt, and smoked items and low in fruits and vegetables; obesity; and exposure to chemotherapeutic agents such as procarbazine.¹⁰ Another pathogen suspected, but not proven, to be associated with increased risk for gastric cancer is the Epstein-Barr virus, a human herpesvirus found in 80% of all gastric carcinomas with lymphoid features.¹¹ In addition, whether the use of medications such as statins and nonsteroidal anti-inflammatory drugs confers a decreased risk of gastric cancers remains unclear.¹⁰

EVALUATION

CASE PRESENTATION

A 55-year-old Caucasian man with a history of type 2 diabetes mellitus presents to the gastrointestinal (GI) clinic with a 6-month history of dysphagia. The dysphagia is worsened with ingestion of solids, particularly towards the end of the day. He states that the food often gets “stuck in the middle of the chest.” The patient denies any nausea or emesis but notes that he has a poor appetite. He reports having worsening mid-epigastric abdominal pain that is non-radiating, dull in character, and 6/10 in intensity. He also reports a 10-lb weight loss over the past 2 months. He has no previous history of reflux, chest pain, dyspnea, or cough. Review of systems is otherwise benign. Physical exam is within normal limits.

• Which tests should be conducted when gastric cancer is suspected?

Persistent epigastric abdominal pain and weight loss are the most common early symptoms of gastric cancer. Nausea, early satiety, dysphagia, and occult GI bleeding can be other presenting signs. Patients presenting with alarm symptoms of nausea, emesis, early satiety, abdominal pain, or weight loss should be fully evaluated with upper GI endoscopy. Early diagnosis of gastric cancer is essential in obtaining a curative resection. However, at least 40% of patients present with de novo metastatic disease at the time of initial diagnosis.¹² Gastric cancer spreads by direct extension through the gastric wall, with the liver, peritoneum, and regional lymph nodes being the most common sites of metastatic deposits.¹³ Classically, Virchow’s node, the left supraclavicular lymph node, is involved with metastatic gastric cancer. Involvement of the left axillary lymph node (Irish node) or a periumbilical nodule (Sister Mary Joseph node) may also be observed. Other, less commonly noted sites of metastatic disease include the ovaries, central nervous system, bone, lung, and soft tissues.¹³

Upper GI endoscopy is the best method for determining tumor location and extent and obtaining a specimen for a definitive tissue diagnosis.¹⁴ It is essential to accurately identify the location of the tumor in the stomach and relative to the GEJ. The American Joint Committee on Cancer classification defines tumors involving the GEJ with an epicenter no more than 2 cm into the proximal stomach as esophageal cancers.¹⁵ Tumors of the GEJ with their epicenter more than 2 cm into the proximal stomach are defined as gastric cancers. If metastatic disease is suspected, computed tomography (CT) scan of the chest, abdomen, and pelvis with oral and intravenous contrast can be obtained to determine the extent of disease spread. In the absence of any metastatic disease, endoscopic ultrasound (EUS) should be conducted to determine the depth of tumor invasion (T staging) and lymph node status. In the era of targeted therapy, patients with metastatic disease should undergo testing for human epidermal growth factor-2 (HER-2) expression, microsatellite instability (MSI), and programmed death ligand 1 (PD-L1) expression. Patients should be staged according to the TNM staging system.

FIRST-LINE TREATMENT OPTIONS

CASE CONTINUED

The patient undergoes esophagoduodenoscopy (EGD) and is found to have a gastric cardia mass extending into the distal esophagus. EUS also demonstrates multiple abdominal and mediastinal lymph nodes. No gastric outlet obstruction is found. Biopsy shows poorly differentiated invasive adenocarcinoma. Warthin–Starry stain is negative for H. pylori organism. The tumor cells are positive for cytokeratin (CK7), CK19, and mucin-1 gene (MUC1); focally positive for CK20; and negative for MUC2. HER2 testing results are reported as immunohistochemistry (IHC) 3+, consistent with strongly positive HER2 protein expression. Further IHC testing for mismatch repair (MMR) proteins shows intact nuclear expression of MLH1, MSH2, MSH6, and PMS2 protein, consistent with a low probability of MSI-high tumor. The tumor is found to be PD-L1 positive. Imaging reveals abnormal mass-like nodular thickening of the gastric wall, with an infiltrative opacity within the pancreatico-duodenal groove, suspicious for tumor infiltration. Multiple metastatic deposits are noted in the liver, peritoneum, and bilateral lungs. There is extensive gastrohepatic ligament and periportal lymphadenopathy and mild enlargement of the pulmonary hilar lymph nodes. These findings are consistent with stage 4 (T4bN3aM1) gastric cancer. Given these findings, staging laparoscopy is deferred.

• What are the first-line treatment options for patients with metastatic gastric cancer?

Patients with metastatic gastric cancer have a poor prognosis, and management is stratified based on performance status (Figure). In patients with good performance status, systemic chemotherapy is the mainstay of treatment. The goal of therapy is not curative, but rather treatment focuses on palliation of symptoms arising from tumor spread. Given this treatment goal, there has been considerable interest in clarifying the utility of chemotherapy as opposed to best supportive care. In a recent Cochrane review of 64 randomized control trials involving 11,698 patients, chemotherapy was found to improve OS by 6.7 months as compared to best supportive care (hazard ratio [HR] 0.3 [95% confidence interval {CI} 0.24 to 0.55]).¹⁶ Five classes of cytotoxic chemotherapeutic agents have demonstrated activity in gastric cancer. These include fluoropyrimidine (either infusional fluorouracil or capecitabine), platinum agents (cisplatin or oxaliplatin), taxanes (docetaxel or paclitaxel), anthracyclines (epirubicin), and irinotecan.¹³ Treatment options are further divided based on whether the patient has HER2-overexpressing or non-expressing malignancy.

 

 

HER2-NEGATIVE DISEASE

For patients with HER2-negative disease, National Comprehensive Cancer Network (NCCN) guidelines recommend using 2-drug combination regimens rather than 3 drugs, given concern for increased toxicity with 3-drug regimens.¹⁷ For patients with a performance status of 0 to 1, utilization of a 3-drug regimen is a reasonable alternative. The combination of a fluoropyrimidine with a platinum agent is considered the standard of care, with regimens such as fluorouracil, leucovorin, and oxaliplatin (FOLFOX) being commonly used.

Epirubicin-containing regimens have also been extensively studied in advanced gastric cancer. In a study of 274 previously untreated patients with GEJ cancers, the combination of epirubicin, cisplatin, and fluorouracil (ECF) was compared to fluorouracil, doxorubicin, and methotrexate (FAMTX). There was an OS benefit favoring ECF (8.9 months versus 5.7 months) at 1 year (95% CI 27% to 45%, P = 0.0009). The ECF regimen was associated with an increased risk of nausea, emesis, and alopecia, while more hematologic toxicity and infections were noted with the FAMTX regimen.¹⁸ In addition, in a phase 3 trial, Van Cutsem and colleagues examined the role of docetaxel in combination with cisplatin and fluorouracil (DCF) compared to cisplatin and fluorouracil alone. Addition of docetaxel led to improved OS and time to progression (9.2 months versus 8.6 months for cisplatin and fluorouracil alone, P = 0.02) but with an increased risk of grade 3 and 4 toxicities (69% versus 59%). These adverse events included neutropenia (82% versus 57% of cisplatin and fluorouracil patients), diarrhea (19% versus 8%), stomatitis (21% versus 27%), and fatigue (19% versus 14%).¹⁹

The landmark phase 3 REAL-2 study compared 4 chemotherapy regimens in patients with untreated advanced esophagogastric cancer. This study was conducted to determine if the efficacy of cisplatin and oxaliplatin, a third-generation platinum agent, is equivalent to that of fluorouracil and capecitabine, an oral fluoropyrimidine. In this trial, a 2 × 2 design was used to compare 4 regimens: ECF versus epirubicin, cisplatin, and capecitabine (ECX) versus epirubicin, oxaliplatin, and fluorouracil (EOF) versus epirubicin, oxaliplatin, and capecitabine (EOX). The study found EOX to be noninferior to ECF, with a trend towards improved OS compared to other combination regimens (11.2 months versus 9.9 months, HR 0.80 [95% CI 0.66 to 0.97], P = 0.02).²⁰ Thus, the study demonstrated that an oxaliplatin and capecitabine-based regimen could replace cisplatin and fluorouracil. Given that fluorouracil administration requires long continuous infusions, the oral-based capecitabine regimen is an attractive option for patients.

Several trials have demonstrated the equivalency of oxaliplatin with cisplatin in combination regimens for the treatment of advanced gastric cancer. Oxaliplatin has the benefit of an improved toxicity profile as compared to cisplatin, with the major dose-limiting toxicity being peripheral neuropathy

Given previous evidence that DCF (docetaxel, cisplatin, fluorouracil) is superior to cisplatin and fluorouracil alone, there was interest in determining if the addition of docetaxel to a backbone of fluorouracil, oxaliplatin, and leucovorin (FLO) could elicit a higher response rate. This concept was investigated in a phase 2 trial that assigned 54 patients with metastatic gastric or GEJ adenocarcinoma to receive biweekly infusions of oxaliplatin, leucovorin, fluorouracil, and docetaxel.²¹ Median time to response was 1.54 months, and the overall response rate was 57.7%. Median progression-free survival (PFS) was 5.2 months, and OS was 11.1 months. The most common grade 3 or 4 toxicities included neutropenia (48%), leukopenia (27.8%), diarrhea (14.8%), and fatigue (11.1%).

Irinotecan-based regimens have also been extensively studied in the first-line treatment of metastatic gastric cancer, particularly as an alternative to platinum-based therapy, but superiority has not been established. The combination of fluorouracil, leucovorin, and irinotecan (FOLFIRI) was compared to ECX in a phase 3 trial.²² The study enrolled 416 patients with locally advanced or metastatic gastric or GEJ cancer. At a median follow up of 31 months, the time to progression was longer in the FOLFIRI arm as compared to the ECX arm (5.1 months versus 4.2 months, P = 0.008), but there was no difference in OS (9.5 months versus 9.7 months, P = 0.95), median PFS (5.3 months versus 5.8 months, P = 0.96), or response rate (39.2% versus 37.8%). However, the FOLFIRI regimen had an improved toxicity profile, with a lower overall rate of grade 3 or 4 toxicity (69% versus 84%, P < 0.001). Given these findings, the FOLFIRI regimen is an acceptable alternative to platinum-based therapy in suitable patients.²²

HER2-POSITIVE DISEASE

The HER2 proto-oncogene, initially described in breast cancer, has been implicated in several malignancies, including gastric and esophageal cancer. Overexpression or amplification of HER2 can be found in up to 30% of gastric cancers.²³ For these patients, adding trastuzumab to a standard regimen of platinum and fluoropyrimidine is the standard of care. The prospective phase 3 Trastuzumab for Gastric Cancer (ToGA) trial randomly assigned 594 patients with HER2-positive gastric cancer to receive either cisplatin and fluorouracil or capecitabine and cisplatin with trastuzumab (n = 294) or without (n = 290) trastuzumab every 3 weeks for a total of 6 cycles, followed by maintenance trastuzumab until disease progression was noted.²⁴ HER2 positivity was defined as HER2 protein overexpression by IHC (cutoff of 3+) or gene amplification by fluorescence in situ hybridization (FISH); tumors with IHC 2+ patterns were followed with FISH studies to confirm positivity. The study found a higher incidence of HER2-positive tumors in patients with GEJ tumors compared to patients with distal gastric cancers (33% versus 20%).²⁴ In this trial, the addition of trastuzumab was associated with an improvement in OS: 13.5 months in the trastuzumab cohort versus 11.1 months in those receiving chemotherapy alone (HR 0.74, P = 0.0048). There was not a significant difference in toxicities between the 2 cohorts, with nausea, emesis, and neutropenia being the most common adverse events. Rates of overall grade 3 or 4 events were similar as well (68% in each cohort). Further exploratory analysis was also conducted according to HER2 status by dividing patients into a “high-expressor” group (n = 446), defined as patients with IHC 3+ tumors or IHC 2+ and FISH positivity, and a “low-expressor” group (n = 131), which included patients with IHC 0 or 1+ tumors. Analysis of patients in the 2 subgroups demonstrated an improved OS with the addition of trastuzumab for the high-expressor cohort, with a median OS of 16 months (HR 0.65 [95% CI 0.51 to 0.83]) compared to 11.8 months in those receiving only chemotherapy.

Dual HER2 blockade has been investigated in metastatic gastric cancer. The phase 3 randomized JACOB trial assigned 780 patients to receive either trastuzumab with a cisplatin/fluoropyrimidine regimen with or without the addition of pertuzumab; the primary end point was OS.²⁵ A non-statistically significant trend towards improvement in OS was found in the pertuzumab arm (17.5 months) as compared with the standard of care arm (14.2 months, HR 0.84, P = 0.0565). The pertuzumab/trastuzumab/chemotherapy cohort experienced a higher incidence of diarrhea (61.6% versus 35.1% in control arm). Cardiac toxicity was comparable in the 2 cohorts.

The Table provides a summary of relevant clinical trials in metastatic gastric cancer.

SECOND-LINE THERAPY

CASE CONTINUED

The patient receives capecitabine, oxaliplatin, and trastuzumab therapy for 6 cycles, followed by trastuzumab for another 3 cycles. While on therapy, he develops a painful right clavicular lesion. He undergoes magnetic resonance imaging of the right clavicle, which shows a lesion in the distal two-thirds of the right clavicle measuring 9.7 × 3.7 × 3.8 cm. The patient is started on palliative radiation to the clavicle. However, repeat CT imaging shows progressive liver metastases.

• What is the approach to second-line therapy for metastatic gastric cancer?

Improvements in our understanding of the molecular pathways that lead to tumorigenesis have contributed to the development of several targeted agents whose efficacy in gastric cancer is being investigated. The NCCN guidelines recommend that for all patients who progress on frontline therapy, second-line therapy consists of a combination of ramucirumab and paclitaxel. Other options include single-agent docetaxel, paclitaxel, irinotecan, or ramucirumab. Combination therapy using irinotecan with either docetaxel, fluorouracil, or cisplatin may also be used.

Ramucirumab, a human IgG1 monoclonal antibody that targets the vascular endothelial growth factor receptor 2 (VEGFR2), was initially approved in 2014 as monotherapy for patients who had previously progressed on first-line chemotherapy. Its approval was based on the results of the phase 3 randomized, double-blind placebo-controlled REGARD study.²⁶ The trial randomly assigned 355 patients with advanced gastric or GEJ adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy to receive best supportive care plus either ramucirumab (n = 238) or placebo (n = 117). Monotherapy with ramucirumab significantly improved median OS compared with placebo (5.2 months versus. 3.8 months; HR 0.776 [95% CI 0.6 to 0.99], P = 0.047). There was also an improvement in PFS of 2.1 months in the ramucirumab cohort, as compared to 1.3 months in the placebo cohort (P < 0.0001). Patients in the ramucirumab arm experienced a higher incidence of hypertension (16% versus 8%), but all other adverse events occurred at comparable rates. Five deaths in the ramucirumab group were thought to be secondary to the study drug, as compared to 2 deaths in the placebo group.

In the subsequent phase 3 RAINBOW trial, the addition of ramucirumab to paclitaxel was investigated, with 330 patients assigned to the combination group and 335 to the paclitaxel-only group.²⁷ The trial again showed that combination therapy afforded patients a significant survival advantage compared to paclitaxel alone, with a median OS of 9.6 months versus 7.4 months for the monotherapy group (HR 0.807 [95% CI 0.678 to 0.962], P = 0.017). A PFS benefit of 4.4 months was observed in the combination therapy groups, as compared with 2.9 months in the monotherapy group (HR 0.635, P < 0.0001). The ramucirumab/paclitaxel group also had a higher overall response rate of 28% versus 16%. The combination cohort had an increased incidence of grade 3 or higher adverse hypertensive events (14% versus 2%) and neutropenia (41% versus 19%), while the incidence of grade 3 febrile neutropenic events was similar between the groups (3% versus 2%).

The addition of bevacizumab, another monoclonal antibody against VEGF, to standard chemotherapy regimens has been explored, but studies have failed to show a survival benefit with this agent in the first-line treatment of advanced gastric cancer. The phase 3 Avastin in Gastric Cancer (AVAGAST) trial was a multinational, randomized study where patients received either bevacizumab (n = 387) or placebo (n = 387) in addition to cisplatin and capecitabine.²⁸ The substitution of fluorouracil for capecitabine was permitted for patients who were unable to tolerate oral medications. Cisplatin was administered for a maximum of 6 cycles, while capecitabine and bevacizumab were administered until disease progression. The study failed to show an improvement in OS, with a median OS of 12.1 months noted in the bevacizumab cohort, as compared to 10.1 months in the placebo arm (HR 0.87 [95% CI 0.73 to 1.03], P = 0.1002). However, there was a modest improvement in median PFS (6.7 months versus 5.3 months; HR 0.80 [95% CI 0.68 to 0.93], P = 0.0037) and overall response rate (46% versus 37.4%, P = 0.0315). The most commonly reported grade 3 to 5 adverse events included neutropenia (35%), anemia (10%), and loss of appetite (8%). Interestingly, in a follow-up report, higher serum levels of VEGF-A were thought to correlate with an enhanced response to bevacizumab.²⁹ However, the routine use of biomarker analysis in selecting patients for treatment with bevacizumab in metastatic gastric cancer remains to be further clarified.

Use of other agents with anti-HER2 activity in the second-line treatment of patients who have experienced progression while on trastuzumab remains unclear. In the recent T-ACT trial, patients with disease refractory to frontline therapy with combination trastuzumab and fluoropyrimidine/platinum agents were randomly assigned to receive either weekly paclitaxel (n = 45) or weekly paclitaxel plus trastuzumab (n = 44).³⁰ Patients in the combination cohort received an initial dose of trastuzumab 8 mg/kg followed by 6 mg/kg every 3 weeks until progression. The study did not find a difference in either PFS (3.19 months versus 3.68 months; HR 0.91 [95% CI 0.67 to 1.22], P = 0.33) or OS (9.95 months versus 10.2 months; HR 1.23 [95% CI 0.75 to 1.99], P = 0.20). The study thus failed to show a benefit to continuing trastuzumab after progression in the first-line setting.

Lapatinib in combination with paclitaxel has been compared to paclitaxel alone for the treatment of advanced HER2-positive gastric cancer in an Asian population in the phase 3 TyTAN trial.³¹ With a primary end point of OS, the study randomly assigned 129 patients to receive paclitaxel alone and 132 patients to receive paclitaxel with lapatinib. There was a nonsignificant trend towards improvement in OS in the combination group (11 months) as compared to the paclitaxel-only group(8.9 months, P = 0.1044), with no significant difference in median PFS (5.4 months versus 4.4 months). However, it is important to note that only 15 patients in this trial had previously been exposed to trastuzumab. Another trial, the phase 3 GATSBY study, examined the efficacy of trastuzumab emtansine in the second-line setting compared to taxanes alone and failed to show any improvement in PFS or OS.³² Given these results, no alternative anti-HER2 therapy has been proven to be efficacious for patients who are trastuzumab refractory. Therefore, including anti-HER2 therapy in the second-line treatment of HER2-positive gastric cancer is not recommended.

IMMUNOTHERAPY AND OTHER TARGETED THERAPIES

Several other targeted therapies have been studied in advanced gastric cancer, without any demonstrable survival benefit. The PI3K/AKT/mTOR pathway is known to be involved in regulation of cell growth and angiogenesis, and the mTOR inhibitor everolimus is widely used to treat other malignancies, including breast cancer. The use of everolimus in the second-line setting was studied in the phase 3 GRANITE-1 trial, where it was compared to best supportive care and failed to provide any survival benefit.³³ Cetuximab, a recombinant human and mouse chimeric monoclonal antibody, and panitumumab, a recombinant human antibody against the epidermal growth factor receptor (EGFR), have also been examined in gastric and GEJ cancer patients. However, the large phase 3 EXPAND and REAL-3 trials did not show a survival benefit when these agents were added to standard chemotherapy.^34,35

Overexpression of MET, a proto-oncogene and tyrosine kinase receptor, has also been implicated in gastric cancer progression. The ligand for MET is the hepatocyte growth factor (HGF), and aberrant signaling of this pathway has been shown to correlate with an aggressive gastric cancer phenotype and poorer OS by promoting tumor growth and angiogenesis. However, no MET inhibitors thus far have been found to be clinically effective. RILOMET-1 and RILOMET-2 were phase 3 trials examining the efficacy of rilotumumab, a humanized anti-HGF antibody, in combination with chemotherapy (ECX and cisplatin with capecitabine, respectively) for the frontline treatment of MET-positive GEJ and gastric cancers. Both studies were discontinued due to a higher treatment-related mortality in patients receiving rilotumumab, with a higher incidence of adverse events due to disease progression being noted.³⁶ Similarly, onartuzumab, a monovalent monoclonal antibody against the MET receptor, was investigated in the phase 3 METGastric trial in combination with modified FOLFOX6 as first-line therapy for HER2-negative, MET-positive metastatic GEJ and gastric cancers. The study did not demonstrate any significant improvements in OS or PFS.³⁷

There has been significant interest in incorporating immunotherapy in the treatment of early and metastatic gastric cancer. Pembrolizumab is the first programmed death receptor (PD-1) inhibitor to be approved for treatment of patients with PD-L1−positive advanced gastric cancer who had previously received 2 or more lines of chemotherapy. Although earlier studies of pembrolizumab in lung cancer utilized the tumor proportion score (TPS) to determine PD-L1 positivity, this was not found to be applicable to gastric cancer. Instead, the combined positive score (CPS) is used in gastric cancer. The CPS evaluates the number of tumor cells and immune cells (macrophages and lymphocytes) that stain positive for PD-L1 relative to all viable tumor cells. Comparatively, the TPS only examines the percentage of viable tumor cells that show complete or partial positive staining for PD-L1. A CPS score of 1 or greater identifies patients who would be suitable candidates for pembrolizumab.

The approval of pembrolizumab was based on the positive findings from the recent KEYNOTE-059 trial.³⁸ The study included 259 patients who had previously received either fluoropyrimidine, cisplatin, or anti-HER2 therapy, with 148 patients (55%) of these patients having PD-L1−positive tumors. The PD-L1 status was determined using a pharmDx Kit, which is now approved by the US Food and Drug Administration to select patients who could benefit from pembrolizumab treatment. CPS was calculated as the number of PD-L1−staining cells divided by the total number of evaluated cells. The study included patients with microsatellite stable (MSI-S), undetermined, or deficient MMR status. The overall response rate to pembrolizumab across all patients was 11.6%, median PFS was 2 months, and the 12-month OS rate was 23.4%. In the subset of patients with MSI-H tumors, the overall response rate was 57.1%, with a complete response rate of 14.3%; in those with MSI-S tumors, the overall response rate was 9% and the complete response rate was 2.4%. Among patients with PD-L1–positive tumors, the overall response rate was 15.5% (95% CI 10.1% to 22.4). Common adverse events included fatigue, hypothyroidism, nausea, diarrhea, and arthralgia.³⁸

CASE CONCLUSION

This patient with metastatic gastric cancer receives second-line chemotherapy with ramucirumab and paclitaxel. Follow-up imaging shows persistent liver metastases and new lung metastasis. Because the tumor is PD-L1–positive, the patient receives 4 cycles of pembrolizumab, with no significant change noted in disease burden. He notes a significant decline in functional status with increased weight loss, nausea, emesis, and fatigue. The patient opts to forego any further therapy and instead chooses to pursue supportive care only.

SUMMARY

Gastric cancer is the third most common cause of cancer death worldwide. Common risk factors for developing gastric cancer include H. pylori infection, smoking, alcohol abuse, radiation exposure, high-fat diet, and obesity. Patients presenting with alarm symptoms of nausea, emesis, early satiety, abdominal pain, or weight loss should be fully evaluated with upper GI endoscopy. If there is suspicion for metastatic disease, CT evaluation of the chest, abdomen, and pelvis with oral and intravenous contrast should be obtained. Treatment of patients with metastatic gastric cancer is guided by their performance status at presentation. For patients with good performance status, a combination of platinum and fluoropyrimidine therapy, such as FOLFOX, can be considered. Doublet chemotherapy regimens are preferred over triplet chemotherapy regimens given their better tolerability. For patients with HER2-positive disease, the addition of trastuzumab to the platinum and fluoropyrimidine backbone is the standard of care in the first line.

Several targeted agents have been studied in patients progressing on initial therapy, with ramucirumab and paclitaxel being considered the regimen of choice in the second line. No anti-HER2 therapy has been approved for patients who are refractory to trastuzumab. Pembrolizumab is approved for use in patients who are PD-L1–positive and have previously progressed on at least 2 lines of chemotherapy. Pembrolizumab is also approved for the treatment of patients with unresectable or metastatic, MSI-H or MMR-deficient gastric cancers that have progressed after prior treatment and who have no satisfactory alternative treatment options.

INTRODUCTION

According to the Surveillance, Epidemiology and End Results database, in 2017 there were 28,000 new cases of gastric cancer, accounting for 1.8% of all malignancies in the United States, and an estimated 10,960 gastric cancer–related deaths.¹ Worldwide, gastric cancer is the fifth most common malignancy and the third most common cause of death from any cancer.² The incidence of gastric cancer varies significantly by geographic region, with countries in Eastern Asia (China, Japan), Eastern Europe, and Central and South America accounting for 50% of all new cases.³ Although the incidence of gastric cancer has declined in recent years, this decrease has not been observed consistently across all nations.² In particular, the incidence of gastric cancers arising from the cardia has been increasing, which is perhaps due to a higher prevalence of obesity in Western societies.⁴

In this article, we review key aspects of management of metastatic gastric cancer, including selection of first- and second-line therapy, and discuss targeted agents and upcoming clinical trials.

EPIDEMIOLOGY AND RISK FACTORS

Chronic infection with Helicobacter pylori, a gram-negative bacterium, is a strong etiological factor for the development of gastric cancer, contributing to up to 70% of cases.² The pathogen can colonize the gastric mucosa, leading to chronic inflammation. Although most patients remain asymptomatic, 1% to 3% develop gastric cancer and another 0.1% develop mucosa-associated lymphoid tissue lymphoma.⁵ H. pylori infection is more commonly associated with cancer of the gastric body than with cancer of the gastroesophageal junction (GEJ). The increased burden of gastric cancer in countries in Eastern Asia, Latin America, and Eastern Europe has been correlated to the prevalence of chronic H. pylori infection in these areas.

Carcinogenesis secondary to H. pylori infection may occur via several mechanisms. First, H. pylori can release virulence factors, such as cytotoxin-associated gene A, vacuolating cytotoxin, and outer membrane proteins, into the cytosol of host cells, leading to changes in patterns of cell proliferation and apoptosis.⁶ These virulence factors can modulate the host immune system, attenuating it to promote dysplasia. In addition, continued recognition of these factors by the immune system leads to a persistent inflammatory response, with the release of cytokines such as interleukin (IL) -1β, IL-6, and IL-8. This leads to chronic mucosal damage, further promoting dysplasia with eventual transformation into adenocarcinoma.⁷ In Japan and Korea, where screening for H. pylori infection is routinely performed, there have been improvements in overall survival (OS) rates for gastric cancer, with 5-year OS rates of 70%.⁸ The International Agency for Research on Cancer recommends further research into population-based screening and treatment programs for patients with chronic H. pylori infection. However, despite this recommendation, optimal screening strategies are not clearly defined.⁹

Other risk factors for the development of gastric cancer include chronic gastroesophageal reflux disease; smoking; alcohol use; exposure to radiation; diets high in fats, salt, and smoked items and low in fruits and vegetables; obesity; and exposure to chemotherapeutic agents such as procarbazine.¹⁰ Another pathogen suspected, but not proven, to be associated with increased risk for gastric cancer is the Epstein-Barr virus, a human herpesvirus found in 80% of all gastric carcinomas with lymphoid features.¹¹ In addition, whether the use of medications such as statins and nonsteroidal anti-inflammatory drugs confers a decreased risk of gastric cancers remains unclear.¹⁰

EVALUATION

CASE PRESENTATION

A 55-year-old Caucasian man with a history of type 2 diabetes mellitus presents to the gastrointestinal (GI) clinic with a 6-month history of dysphagia. The dysphagia is worsened with ingestion of solids, particularly towards the end of the day. He states that the food often gets “stuck in the middle of the chest.” The patient denies any nausea or emesis but notes that he has a poor appetite. He reports having worsening mid-epigastric abdominal pain that is non-radiating, dull in character, and 6/10 in intensity. He also reports a 10-lb weight loss over the past 2 months. He has no previous history of reflux, chest pain, dyspnea, or cough. Review of systems is otherwise benign. Physical exam is within normal limits.

• Which tests should be conducted when gastric cancer is suspected?

Persistent epigastric abdominal pain and weight loss are the most common early symptoms of gastric cancer. Nausea, early satiety, dysphagia, and occult GI bleeding can be other presenting signs. Patients presenting with alarm symptoms of nausea, emesis, early satiety, abdominal pain, or weight loss should be fully evaluated with upper GI endoscopy. Early diagnosis of gastric cancer is essential in obtaining a curative resection. However, at least 40% of patients present with de novo metastatic disease at the time of initial diagnosis.¹² Gastric cancer spreads by direct extension through the gastric wall, with the liver, peritoneum, and regional lymph nodes being the most common sites of metastatic deposits.¹³ Classically, Virchow’s node, the left supraclavicular lymph node, is involved with metastatic gastric cancer. Involvement of the left axillary lymph node (Irish node) or a periumbilical nodule (Sister Mary Joseph node) may also be observed. Other, less commonly noted sites of metastatic disease include the ovaries, central nervous system, bone, lung, and soft tissues.¹³

Upper GI endoscopy is the best method for determining tumor location and extent and obtaining a specimen for a definitive tissue diagnosis.¹⁴ It is essential to accurately identify the location of the tumor in the stomach and relative to the GEJ. The American Joint Committee on Cancer classification defines tumors involving the GEJ with an epicenter no more than 2 cm into the proximal stomach as esophageal cancers.¹⁵ Tumors of the GEJ with their epicenter more than 2 cm into the proximal stomach are defined as gastric cancers. If metastatic disease is suspected, computed tomography (CT) scan of the chest, abdomen, and pelvis with oral and intravenous contrast can be obtained to determine the extent of disease spread. In the absence of any metastatic disease, endoscopic ultrasound (EUS) should be conducted to determine the depth of tumor invasion (T staging) and lymph node status. In the era of targeted therapy, patients with metastatic disease should undergo testing for human epidermal growth factor-2 (HER-2) expression, microsatellite instability (MSI), and programmed death ligand 1 (PD-L1) expression. Patients should be staged according to the TNM staging system.

FIRST-LINE TREATMENT OPTIONS

CASE CONTINUED

The patient undergoes esophagoduodenoscopy (EGD) and is found to have a gastric cardia mass extending into the distal esophagus. EUS also demonstrates multiple abdominal and mediastinal lymph nodes. No gastric outlet obstruction is found. Biopsy shows poorly differentiated invasive adenocarcinoma. Warthin–Starry stain is negative for H. pylori organism. The tumor cells are positive for cytokeratin (CK7), CK19, and mucin-1 gene (MUC1); focally positive for CK20; and negative for MUC2. HER2 testing results are reported as immunohistochemistry (IHC) 3+, consistent with strongly positive HER2 protein expression. Further IHC testing for mismatch repair (MMR) proteins shows intact nuclear expression of MLH1, MSH2, MSH6, and PMS2 protein, consistent with a low probability of MSI-high tumor. The tumor is found to be PD-L1 positive. Imaging reveals abnormal mass-like nodular thickening of the gastric wall, with an infiltrative opacity within the pancreatico-duodenal groove, suspicious for tumor infiltration. Multiple metastatic deposits are noted in the liver, peritoneum, and bilateral lungs. There is extensive gastrohepatic ligament and periportal lymphadenopathy and mild enlargement of the pulmonary hilar lymph nodes. These findings are consistent with stage 4 (T4bN3aM1) gastric cancer. Given these findings, staging laparoscopy is deferred.

• What are the first-line treatment options for patients with metastatic gastric cancer?

Patients with metastatic gastric cancer have a poor prognosis, and management is stratified based on performance status (Figure). In patients with good performance status, systemic chemotherapy is the mainstay of treatment. The goal of therapy is not curative, but rather treatment focuses on palliation of symptoms arising from tumor spread. Given this treatment goal, there has been considerable interest in clarifying the utility of chemotherapy as opposed to best supportive care. In a recent Cochrane review of 64 randomized control trials involving 11,698 patients, chemotherapy was found to improve OS by 6.7 months as compared to best supportive care (hazard ratio [HR] 0.3 [95% confidence interval {CI} 0.24 to 0.55]).¹⁶ Five classes of cytotoxic chemotherapeutic agents have demonstrated activity in gastric cancer. These include fluoropyrimidine (either infusional fluorouracil or capecitabine), platinum agents (cisplatin or oxaliplatin), taxanes (docetaxel or paclitaxel), anthracyclines (epirubicin), and irinotecan.¹³ Treatment options are further divided based on whether the patient has HER2-overexpressing or non-expressing malignancy.

 

 

HER2-NEGATIVE DISEASE

For patients with HER2-negative disease, National Comprehensive Cancer Network (NCCN) guidelines recommend using 2-drug combination regimens rather than 3 drugs, given concern for increased toxicity with 3-drug regimens.¹⁷ For patients with a performance status of 0 to 1, utilization of a 3-drug regimen is a reasonable alternative. The combination of a fluoropyrimidine with a platinum agent is considered the standard of care, with regimens such as fluorouracil, leucovorin, and oxaliplatin (FOLFOX) being commonly used.

Epirubicin-containing regimens have also been extensively studied in advanced gastric cancer. In a study of 274 previously untreated patients with GEJ cancers, the combination of epirubicin, cisplatin, and fluorouracil (ECF) was compared to fluorouracil, doxorubicin, and methotrexate (FAMTX). There was an OS benefit favoring ECF (8.9 months versus 5.7 months) at 1 year (95% CI 27% to 45%, P = 0.0009). The ECF regimen was associated with an increased risk of nausea, emesis, and alopecia, while more hematologic toxicity and infections were noted with the FAMTX regimen.¹⁸ In addition, in a phase 3 trial, Van Cutsem and colleagues examined the role of docetaxel in combination with cisplatin and fluorouracil (DCF) compared to cisplatin and fluorouracil alone. Addition of docetaxel led to improved OS and time to progression (9.2 months versus 8.6 months for cisplatin and fluorouracil alone, P = 0.02) but with an increased risk of grade 3 and 4 toxicities (69% versus 59%). These adverse events included neutropenia (82% versus 57% of cisplatin and fluorouracil patients), diarrhea (19% versus 8%), stomatitis (21% versus 27%), and fatigue (19% versus 14%).¹⁹

The landmark phase 3 REAL-2 study compared 4 chemotherapy regimens in patients with untreated advanced esophagogastric cancer. This study was conducted to determine if the efficacy of cisplatin and oxaliplatin, a third-generation platinum agent, is equivalent to that of fluorouracil and capecitabine, an oral fluoropyrimidine. In this trial, a 2 × 2 design was used to compare 4 regimens: ECF versus epirubicin, cisplatin, and capecitabine (ECX) versus epirubicin, oxaliplatin, and fluorouracil (EOF) versus epirubicin, oxaliplatin, and capecitabine (EOX). The study found EOX to be noninferior to ECF, with a trend towards improved OS compared to other combination regimens (11.2 months versus 9.9 months, HR 0.80 [95% CI 0.66 to 0.97], P = 0.02).²⁰ Thus, the study demonstrated that an oxaliplatin and capecitabine-based regimen could replace cisplatin and fluorouracil. Given that fluorouracil administration requires long continuous infusions, the oral-based capecitabine regimen is an attractive option for patients.

Several trials have demonstrated the equivalency of oxaliplatin with cisplatin in combination regimens for the treatment of advanced gastric cancer. Oxaliplatin has the benefit of an improved toxicity profile as compared to cisplatin, with the major dose-limiting toxicity being peripheral neuropathy

Given previous evidence that DCF (docetaxel, cisplatin, fluorouracil) is superior to cisplatin and fluorouracil alone, there was interest in determining if the addition of docetaxel to a backbone of fluorouracil, oxaliplatin, and leucovorin (FLO) could elicit a higher response rate. This concept was investigated in a phase 2 trial that assigned 54 patients with metastatic gastric or GEJ adenocarcinoma to receive biweekly infusions of oxaliplatin, leucovorin, fluorouracil, and docetaxel.²¹ Median time to response was 1.54 months, and the overall response rate was 57.7%. Median progression-free survival (PFS) was 5.2 months, and OS was 11.1 months. The most common grade 3 or 4 toxicities included neutropenia (48%), leukopenia (27.8%), diarrhea (14.8%), and fatigue (11.1%).

Irinotecan-based regimens have also been extensively studied in the first-line treatment of metastatic gastric cancer, particularly as an alternative to platinum-based therapy, but superiority has not been established. The combination of fluorouracil, leucovorin, and irinotecan (FOLFIRI) was compared to ECX in a phase 3 trial.²² The study enrolled 416 patients with locally advanced or metastatic gastric or GEJ cancer. At a median follow up of 31 months, the time to progression was longer in the FOLFIRI arm as compared to the ECX arm (5.1 months versus 4.2 months, P = 0.008), but there was no difference in OS (9.5 months versus 9.7 months, P = 0.95), median PFS (5.3 months versus 5.8 months, P = 0.96), or response rate (39.2% versus 37.8%). However, the FOLFIRI regimen had an improved toxicity profile, with a lower overall rate of grade 3 or 4 toxicity (69% versus 84%, P < 0.001). Given these findings, the FOLFIRI regimen is an acceptable alternative to platinum-based therapy in suitable patients.²²

HER2-POSITIVE DISEASE

The HER2 proto-oncogene, initially described in breast cancer, has been implicated in several malignancies, including gastric and esophageal cancer. Overexpression or amplification of HER2 can be found in up to 30% of gastric cancers.²³ For these patients, adding trastuzumab to a standard regimen of platinum and fluoropyrimidine is the standard of care. The prospective phase 3 Trastuzumab for Gastric Cancer (ToGA) trial randomly assigned 594 patients with HER2-positive gastric cancer to receive either cisplatin and fluorouracil or capecitabine and cisplatin with trastuzumab (n = 294) or without (n = 290) trastuzumab every 3 weeks for a total of 6 cycles, followed by maintenance trastuzumab until disease progression was noted.²⁴ HER2 positivity was defined as HER2 protein overexpression by IHC (cutoff of 3+) or gene amplification by fluorescence in situ hybridization (FISH); tumors with IHC 2+ patterns were followed with FISH studies to confirm positivity. The study found a higher incidence of HER2-positive tumors in patients with GEJ tumors compared to patients with distal gastric cancers (33% versus 20%).²⁴ In this trial, the addition of trastuzumab was associated with an improvement in OS: 13.5 months in the trastuzumab cohort versus 11.1 months in those receiving chemotherapy alone (HR 0.74, P = 0.0048). There was not a significant difference in toxicities between the 2 cohorts, with nausea, emesis, and neutropenia being the most common adverse events. Rates of overall grade 3 or 4 events were similar as well (68% in each cohort). Further exploratory analysis was also conducted according to HER2 status by dividing patients into a “high-expressor” group (n = 446), defined as patients with IHC 3+ tumors or IHC 2+ and FISH positivity, and a “low-expressor” group (n = 131), which included patients with IHC 0 or 1+ tumors. Analysis of patients in the 2 subgroups demonstrated an improved OS with the addition of trastuzumab for the high-expressor cohort, with a median OS of 16 months (HR 0.65 [95% CI 0.51 to 0.83]) compared to 11.8 months in those receiving only chemotherapy.

Dual HER2 blockade has been investigated in metastatic gastric cancer. The phase 3 randomized JACOB trial assigned 780 patients to receive either trastuzumab with a cisplatin/fluoropyrimidine regimen with or without the addition of pertuzumab; the primary end point was OS.²⁵ A non-statistically significant trend towards improvement in OS was found in the pertuzumab arm (17.5 months) as compared with the standard of care arm (14.2 months, HR 0.84, P = 0.0565). The pertuzumab/trastuzumab/chemotherapy cohort experienced a higher incidence of diarrhea (61.6% versus 35.1% in control arm). Cardiac toxicity was comparable in the 2 cohorts.

The Table provides a summary of relevant clinical trials in metastatic gastric cancer.

SECOND-LINE THERAPY

CASE CONTINUED

The patient receives capecitabine, oxaliplatin, and trastuzumab therapy for 6 cycles, followed by trastuzumab for another 3 cycles. While on therapy, he develops a painful right clavicular lesion. He undergoes magnetic resonance imaging of the right clavicle, which shows a lesion in the distal two-thirds of the right clavicle measuring 9.7 × 3.7 × 3.8 cm. The patient is started on palliative radiation to the clavicle. However, repeat CT imaging shows progressive liver metastases.

• What is the approach to second-line therapy for metastatic gastric cancer?

Improvements in our understanding of the molecular pathways that lead to tumorigenesis have contributed to the development of several targeted agents whose efficacy in gastric cancer is being investigated. The NCCN guidelines recommend that for all patients who progress on frontline therapy, second-line therapy consists of a combination of ramucirumab and paclitaxel. Other options include single-agent docetaxel, paclitaxel, irinotecan, or ramucirumab. Combination therapy using irinotecan with either docetaxel, fluorouracil, or cisplatin may also be used.

Ramucirumab, a human IgG1 monoclonal antibody that targets the vascular endothelial growth factor receptor 2 (VEGFR2), was initially approved in 2014 as monotherapy for patients who had previously progressed on first-line chemotherapy. Its approval was based on the results of the phase 3 randomized, double-blind placebo-controlled REGARD study.²⁶ The trial randomly assigned 355 patients with advanced gastric or GEJ adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy to receive best supportive care plus either ramucirumab (n = 238) or placebo (n = 117). Monotherapy with ramucirumab significantly improved median OS compared with placebo (5.2 months versus. 3.8 months; HR 0.776 [95% CI 0.6 to 0.99], P = 0.047). There was also an improvement in PFS of 2.1 months in the ramucirumab cohort, as compared to 1.3 months in the placebo cohort (P < 0.0001). Patients in the ramucirumab arm experienced a higher incidence of hypertension (16% versus 8%), but all other adverse events occurred at comparable rates. Five deaths in the ramucirumab group were thought to be secondary to the study drug, as compared to 2 deaths in the placebo group.

In the subsequent phase 3 RAINBOW trial, the addition of ramucirumab to paclitaxel was investigated, with 330 patients assigned to the combination group and 335 to the paclitaxel-only group.²⁷ The trial again showed that combination therapy afforded patients a significant survival advantage compared to paclitaxel alone, with a median OS of 9.6 months versus 7.4 months for the monotherapy group (HR 0.807 [95% CI 0.678 to 0.962], P = 0.017). A PFS benefit of 4.4 months was observed in the combination therapy groups, as compared with 2.9 months in the monotherapy group (HR 0.635, P < 0.0001). The ramucirumab/paclitaxel group also had a higher overall response rate of 28% versus 16%. The combination cohort had an increased incidence of grade 3 or higher adverse hypertensive events (14% versus 2%) and neutropenia (41% versus 19%), while the incidence of grade 3 febrile neutropenic events was similar between the groups (3% versus 2%).

The addition of bevacizumab, another monoclonal antibody against VEGF, to standard chemotherapy regimens has been explored, but studies have failed to show a survival benefit with this agent in the first-line treatment of advanced gastric cancer. The phase 3 Avastin in Gastric Cancer (AVAGAST) trial was a multinational, randomized study where patients received either bevacizumab (n = 387) or placebo (n = 387) in addition to cisplatin and capecitabine.²⁸ The substitution of fluorouracil for capecitabine was permitted for patients who were unable to tolerate oral medications. Cisplatin was administered for a maximum of 6 cycles, while capecitabine and bevacizumab were administered until disease progression. The study failed to show an improvement in OS, with a median OS of 12.1 months noted in the bevacizumab cohort, as compared to 10.1 months in the placebo arm (HR 0.87 [95% CI 0.73 to 1.03], P = 0.1002). However, there was a modest improvement in median PFS (6.7 months versus 5.3 months; HR 0.80 [95% CI 0.68 to 0.93], P = 0.0037) and overall response rate (46% versus 37.4%, P = 0.0315). The most commonly reported grade 3 to 5 adverse events included neutropenia (35%), anemia (10%), and loss of appetite (8%). Interestingly, in a follow-up report, higher serum levels of VEGF-A were thought to correlate with an enhanced response to bevacizumab.²⁹ However, the routine use of biomarker analysis in selecting patients for treatment with bevacizumab in metastatic gastric cancer remains to be further clarified.

Use of other agents with anti-HER2 activity in the second-line treatment of patients who have experienced progression while on trastuzumab remains unclear. In the recent T-ACT trial, patients with disease refractory to frontline therapy with combination trastuzumab and fluoropyrimidine/platinum agents were randomly assigned to receive either weekly paclitaxel (n = 45) or weekly paclitaxel plus trastuzumab (n = 44).³⁰ Patients in the combination cohort received an initial dose of trastuzumab 8 mg/kg followed by 6 mg/kg every 3 weeks until progression. The study did not find a difference in either PFS (3.19 months versus 3.68 months; HR 0.91 [95% CI 0.67 to 1.22], P = 0.33) or OS (9.95 months versus 10.2 months; HR 1.23 [95% CI 0.75 to 1.99], P = 0.20). The study thus failed to show a benefit to continuing trastuzumab after progression in the first-line setting.

Lapatinib in combination with paclitaxel has been compared to paclitaxel alone for the treatment of advanced HER2-positive gastric cancer in an Asian population in the phase 3 TyTAN trial.³¹ With a primary end point of OS, the study randomly assigned 129 patients to receive paclitaxel alone and 132 patients to receive paclitaxel with lapatinib. There was a nonsignificant trend towards improvement in OS in the combination group (11 months) as compared to the paclitaxel-only group(8.9 months, P = 0.1044), with no significant difference in median PFS (5.4 months versus 4.4 months). However, it is important to note that only 15 patients in this trial had previously been exposed to trastuzumab. Another trial, the phase 3 GATSBY study, examined the efficacy of trastuzumab emtansine in the second-line setting compared to taxanes alone and failed to show any improvement in PFS or OS.³² Given these results, no alternative anti-HER2 therapy has been proven to be efficacious for patients who are trastuzumab refractory. Therefore, including anti-HER2 therapy in the second-line treatment of HER2-positive gastric cancer is not recommended.

IMMUNOTHERAPY AND OTHER TARGETED THERAPIES

Several other targeted therapies have been studied in advanced gastric cancer, without any demonstrable survival benefit. The PI3K/AKT/mTOR pathway is known to be involved in regulation of cell growth and angiogenesis, and the mTOR inhibitor everolimus is widely used to treat other malignancies, including breast cancer. The use of everolimus in the second-line setting was studied in the phase 3 GRANITE-1 trial, where it was compared to best supportive care and failed to provide any survival benefit.³³ Cetuximab, a recombinant human and mouse chimeric monoclonal antibody, and panitumumab, a recombinant human antibody against the epidermal growth factor receptor (EGFR), have also been examined in gastric and GEJ cancer patients. However, the large phase 3 EXPAND and REAL-3 trials did not show a survival benefit when these agents were added to standard chemotherapy.^34,35

Overexpression of MET, a proto-oncogene and tyrosine kinase receptor, has also been implicated in gastric cancer progression. The ligand for MET is the hepatocyte growth factor (HGF), and aberrant signaling of this pathway has been shown to correlate with an aggressive gastric cancer phenotype and poorer OS by promoting tumor growth and angiogenesis. However, no MET inhibitors thus far have been found to be clinically effective. RILOMET-1 and RILOMET-2 were phase 3 trials examining the efficacy of rilotumumab, a humanized anti-HGF antibody, in combination with chemotherapy (ECX and cisplatin with capecitabine, respectively) for the frontline treatment of MET-positive GEJ and gastric cancers. Both studies were discontinued due to a higher treatment-related mortality in patients receiving rilotumumab, with a higher incidence of adverse events due to disease progression being noted.³⁶ Similarly, onartuzumab, a monovalent monoclonal antibody against the MET receptor, was investigated in the phase 3 METGastric trial in combination with modified FOLFOX6 as first-line therapy for HER2-negative, MET-positive metastatic GEJ and gastric cancers. The study did not demonstrate any significant improvements in OS or PFS.³⁷

There has been significant interest in incorporating immunotherapy in the treatment of early and metastatic gastric cancer. Pembrolizumab is the first programmed death receptor (PD-1) inhibitor to be approved for treatment of patients with PD-L1−positive advanced gastric cancer who had previously received 2 or more lines of chemotherapy. Although earlier studies of pembrolizumab in lung cancer utilized the tumor proportion score (TPS) to determine PD-L1 positivity, this was not found to be applicable to gastric cancer. Instead, the combined positive score (CPS) is used in gastric cancer. The CPS evaluates the number of tumor cells and immune cells (macrophages and lymphocytes) that stain positive for PD-L1 relative to all viable tumor cells. Comparatively, the TPS only examines the percentage of viable tumor cells that show complete or partial positive staining for PD-L1. A CPS score of 1 or greater identifies patients who would be suitable candidates for pembrolizumab.

The approval of pembrolizumab was based on the positive findings from the recent KEYNOTE-059 trial.³⁸ The study included 259 patients who had previously received either fluoropyrimidine, cisplatin, or anti-HER2 therapy, with 148 patients (55%) of these patients having PD-L1−positive tumors. The PD-L1 status was determined using a pharmDx Kit, which is now approved by the US Food and Drug Administration to select patients who could benefit from pembrolizumab treatment. CPS was calculated as the number of PD-L1−staining cells divided by the total number of evaluated cells. The study included patients with microsatellite stable (MSI-S), undetermined, or deficient MMR status. The overall response rate to pembrolizumab across all patients was 11.6%, median PFS was 2 months, and the 12-month OS rate was 23.4%. In the subset of patients with MSI-H tumors, the overall response rate was 57.1%, with a complete response rate of 14.3%; in those with MSI-S tumors, the overall response rate was 9% and the complete response rate was 2.4%. Among patients with PD-L1–positive tumors, the overall response rate was 15.5% (95% CI 10.1% to 22.4). Common adverse events included fatigue, hypothyroidism, nausea, diarrhea, and arthralgia.³⁸

CASE CONCLUSION

This patient with metastatic gastric cancer receives second-line chemotherapy with ramucirumab and paclitaxel. Follow-up imaging shows persistent liver metastases and new lung metastasis. Because the tumor is PD-L1–positive, the patient receives 4 cycles of pembrolizumab, with no significant change noted in disease burden. He notes a significant decline in functional status with increased weight loss, nausea, emesis, and fatigue. The patient opts to forego any further therapy and instead chooses to pursue supportive care only.

SUMMARY

Gastric cancer is the third most common cause of cancer death worldwide. Common risk factors for developing gastric cancer include H. pylori infection, smoking, alcohol abuse, radiation exposure, high-fat diet, and obesity. Patients presenting with alarm symptoms of nausea, emesis, early satiety, abdominal pain, or weight loss should be fully evaluated with upper GI endoscopy. If there is suspicion for metastatic disease, CT evaluation of the chest, abdomen, and pelvis with oral and intravenous contrast should be obtained. Treatment of patients with metastatic gastric cancer is guided by their performance status at presentation. For patients with good performance status, a combination of platinum and fluoropyrimidine therapy, such as FOLFOX, can be considered. Doublet chemotherapy regimens are preferred over triplet chemotherapy regimens given their better tolerability. For patients with HER2-positive disease, the addition of trastuzumab to the platinum and fluoropyrimidine backbone is the standard of care in the first line.

Several targeted agents have been studied in patients progressing on initial therapy, with ramucirumab and paclitaxel being considered the regimen of choice in the second line. No anti-HER2 therapy has been approved for patients who are refractory to trastuzumab. Pembrolizumab is approved for use in patients who are PD-L1–positive and have previously progressed on at least 2 lines of chemotherapy. Pembrolizumab is also approved for the treatment of patients with unresectable or metastatic, MSI-H or MMR-deficient gastric cancers that have progressed after prior treatment and who have no satisfactory alternative treatment options.