Patient & Survivor Care

 

Patients with cancer perceived physicians who did not use a computer as more compassionate, more professional, and better at communication, according to results of a randomized, video-based study presented at the Palliative and Supportive Care in Oncology Symposium.

In addition, the majority of patients said they would prefer having a doctor who communicated face to face (in other words, without aid of a computer) to be their provider, said Ali Haider, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Brian Jackson/iStockphoto

“This study gives us a message that patients would prefer their doctors to give them undivided attention,” Dr. Haider said in a press conference. “Better communication can enhance patient trust and satisfaction.”

This is one of the few, if not only, studies to evaluate how the presence of a computer affects exam room interactions between physicians and patients, Dr. Haider said in a press conference held during the meeting.

To test the impact of the computer in the exam room, Dr. Haider and his colleagues created four different 3-minute video vignettes featuring two different actors playing physicians in an encounter with a patient. Each actor created one video in which he used a computer and one in which he did not. To minimize potential bias, the videos had identical scripts, and actors were careful to use the same gestures, expressions, and nonverbal communication in each video.

A total of 120 cancer patients were randomized to view two of the videos and fill out validated questionnaires rating their perception of the physician’s compassion, communication skills, and professionalism.

The face-to-face clinical encounter videos were associated with a median compassion score of 9 on a scale of 0-50 where 0 is best and 50 is worst; by comparison, the encounters with computers scored worse, at a median of 20 out of 50 (P = .0003). Likewise, the patients rated the face-to-face encounter videos significantly higher on communication skills (P = .0001) and professionalism (P = .013).

After watching both videos, the patients were asked which encounter they would personally prefer, and 86 (72%) said they liked the face-to-face communication video better.

Actors and patients were all blinded to the purpose of the study, according to the researchers.

Further research is required to confirm these findings in other clinical settings and populations, according to Dr. Haider.

“We believe these results may be different if we choose a younger population, or patients with high computer literacy,” he explained.

While more research may be needed, “face-to-face communication seems quite possibly the preferred route, despite the pressures clinicians have to search and document in the medical record,” said medical oncologist Andrew S. Epstein, MD, of Memorial Sloan Kettering Cancer Center, New York, who was not involved with the study.

“In an age of ubiquitous technology, this study is an important reminder of the need to address the potential for technology to interfere with the patient-physician interface,” said Dr. Epstein, who moderated the press conference from the palliative care symposium, which was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

 

Patients with cancer perceived physicians who did not use a computer as more compassionate, more professional, and better at communication, according to results of a randomized, video-based study presented at the Palliative and Supportive Care in Oncology Symposium.

In addition, the majority of patients said they would prefer having a doctor who communicated face to face (in other words, without aid of a computer) to be their provider, said Ali Haider, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Brian Jackson/iStockphoto

“This study gives us a message that patients would prefer their doctors to give them undivided attention,” Dr. Haider said in a press conference. “Better communication can enhance patient trust and satisfaction.”

This is one of the few, if not only, studies to evaluate how the presence of a computer affects exam room interactions between physicians and patients, Dr. Haider said in a press conference held during the meeting.

To test the impact of the computer in the exam room, Dr. Haider and his colleagues created four different 3-minute video vignettes featuring two different actors playing physicians in an encounter with a patient. Each actor created one video in which he used a computer and one in which he did not. To minimize potential bias, the videos had identical scripts, and actors were careful to use the same gestures, expressions, and nonverbal communication in each video.

A total of 120 cancer patients were randomized to view two of the videos and fill out validated questionnaires rating their perception of the physician’s compassion, communication skills, and professionalism.

The face-to-face clinical encounter videos were associated with a median compassion score of 9 on a scale of 0-50 where 0 is best and 50 is worst; by comparison, the encounters with computers scored worse, at a median of 20 out of 50 (P = .0003). Likewise, the patients rated the face-to-face encounter videos significantly higher on communication skills (P = .0001) and professionalism (P = .013).

After watching both videos, the patients were asked which encounter they would personally prefer, and 86 (72%) said they liked the face-to-face communication video better.

Actors and patients were all blinded to the purpose of the study, according to the researchers.

Further research is required to confirm these findings in other clinical settings and populations, according to Dr. Haider.

“We believe these results may be different if we choose a younger population, or patients with high computer literacy,” he explained.

While more research may be needed, “face-to-face communication seems quite possibly the preferred route, despite the pressures clinicians have to search and document in the medical record,” said medical oncologist Andrew S. Epstein, MD, of Memorial Sloan Kettering Cancer Center, New York, who was not involved with the study.

“In an age of ubiquitous technology, this study is an important reminder of the need to address the potential for technology to interfere with the patient-physician interface,” said Dr. Epstein, who moderated the press conference from the palliative care symposium, which was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

 

Patients with cancer perceived physicians who did not use a computer as more compassionate, more professional, and better at communication, according to results of a randomized, video-based study presented at the Palliative and Supportive Care in Oncology Symposium.

In addition, the majority of patients said they would prefer having a doctor who communicated face to face (in other words, without aid of a computer) to be their provider, said Ali Haider, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Brian Jackson/iStockphoto

“This study gives us a message that patients would prefer their doctors to give them undivided attention,” Dr. Haider said in a press conference. “Better communication can enhance patient trust and satisfaction.”

This is one of the few, if not only, studies to evaluate how the presence of a computer affects exam room interactions between physicians and patients, Dr. Haider said in a press conference held during the meeting.

To test the impact of the computer in the exam room, Dr. Haider and his colleagues created four different 3-minute video vignettes featuring two different actors playing physicians in an encounter with a patient. Each actor created one video in which he used a computer and one in which he did not. To minimize potential bias, the videos had identical scripts, and actors were careful to use the same gestures, expressions, and nonverbal communication in each video.

A total of 120 cancer patients were randomized to view two of the videos and fill out validated questionnaires rating their perception of the physician’s compassion, communication skills, and professionalism.

The face-to-face clinical encounter videos were associated with a median compassion score of 9 on a scale of 0-50 where 0 is best and 50 is worst; by comparison, the encounters with computers scored worse, at a median of 20 out of 50 (P = .0003). Likewise, the patients rated the face-to-face encounter videos significantly higher on communication skills (P = .0001) and professionalism (P = .013).

After watching both videos, the patients were asked which encounter they would personally prefer, and 86 (72%) said they liked the face-to-face communication video better.

Actors and patients were all blinded to the purpose of the study, according to the researchers.

Further research is required to confirm these findings in other clinical settings and populations, according to Dr. Haider.

“We believe these results may be different if we choose a younger population, or patients with high computer literacy,” he explained.

While more research may be needed, “face-to-face communication seems quite possibly the preferred route, despite the pressures clinicians have to search and document in the medical record,” said medical oncologist Andrew S. Epstein, MD, of Memorial Sloan Kettering Cancer Center, New York, who was not involved with the study.

“In an age of ubiquitous technology, this study is an important reminder of the need to address the potential for technology to interfere with the patient-physician interface,” said Dr. Epstein, who moderated the press conference from the palliative care symposium, which was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

Cardio-oncology is expanding, fed by a steadily increasing population of cancer survivors at elevated risk for a range of cardiovascular diseases and complications because of the anticancer treatments they received. Cardio-oncology’s quick growth has also been driven by the rapidly expanding universe of cancer treatments with direct or indirect adverse effects on a diverse range of cardiovascular functions.

During the past year, the field’s rapid evolution has featured the first formal diagnostic and care standards in two iterations: A position paper on the cardiovascular toxicities of cancer treatment from the European Society of Cardiology (ESC), released in August 2016 (Eur Heart J. 2016 Sept 21;37[36]:2766-801); and a guideline for preventing and monitoring cardiac dysfunction in adult cancer survivors, issued last December by the American Society of Clinical Oncology (ASCO) and endorsed by the American Heart Association (J Clin Oncol. 2017 March 10;35[8]:893-913), but notably not endorsed by the American College of Cardiology, despite having an ACC representative on the guideline panel. In 2015, the ACC started a Cardio-Oncology Section, one of 20 special-interest sections it maintains, and by mid-2017 the section had some 500 members.

Despite these milestones and spread of the cardio-oncology concept, the cardiovascular consequences of cancer treatment remain underappreciated and incompletely understood by many cardiologists and primary care physicians, experts say. Other current limitations include the absence of a well defined cardio-oncology subspecialty and training infrastructure and significant gaps in the field’s evidence base, including no direct proof of the clinical value of screening for the earliest signs of cardiovascular adverse effects in cancer patients.

“I’ve had recent conversations with cardiologists who said ‘I’m not sure what cardio-oncology is,’ ” said Tomas G. Neilan, MD, director of the cardio-oncology program at Massachusetts General Hospital in Boston.

“The number one priority for cardio-oncology is to raise awareness about it at every level: patients, their support people, oncologists, cardiologists, and primary care physicians,” said Daniel J. Lenihan, MD, until recently professor of medicine and a cardio-oncologist at Vanderbilt University in Nashville, Tenn., who in September moved to Washington University in St. Louis to start a cardio-oncology program there.

More than just heart failure

A few decades ago, in the primordial days of cardio-oncology, the concept of cardiovascular damage during cancer therapy focused entirely on myocardial damage caused by anthracyclines and chest radiation, a concern that eventually expanded to include trastuzumab (Herceptin) and other agents that target the human epidermal growth factor receptor 2 (HER2). These treatments cause significantly reduced left ventricular ejection fractions and heart failure in a significant minority of treated patients. Patients who receive combined treatment with an anthracycline and trastuzumab are at the highest risk for developing heart failure with reduced ejection fraction, but even among patients treated with this combination, fewer than 5% develop outright heart failure.

While this parochial view of cardio-oncology has recently shifted, it remains true that myocardial damage from a relatively large cumulative anthracycline dose, or from radiation, causes some of the most extreme cases of cardiovascular adverse effects and remains an ongoing problem as these treatments stay front line for selected cancer patients.

But some of the recent burgeoning of cardio-oncology has followed the recognition that many other drugs and drug classes can cause a spectrum of adverse cardiovascular effects.

“Cardio-oncology has become more complicated, with hundreds of new cancer treatments, each one with an adverse effect profile. Many of the new drugs cause vascular or metabolic issues,” said Javid J. Moslehi, MD, director of cardio-oncology at Vanderbilt University. Heart failure and ejection fraction were the “easiest things to tackle” in the recent ASCO guidelines, but there are many other manifestations of cardiovascular toxicity from cancer treatments.

“There has been a significant focus on heart failure and cardiomyopathy due to anthracyclines and HER2-targeted therapies. I think the field will continue to evolve over the next 5 years to focus on other cardiovascular complications, including arrhythmias and vascular disease,” observed Michael Fradley, MD, director of cardio-oncology at Moffitt Cancer Center in Tampa. “In addition, there will be an increased focus on targeted drugs and immunotherapies,” agents that Dr. Fradley said “have many unique cardiovascular complications. We need additional guidelines regarding the management of a variety of cardiotoxicities as well as long-term monitoring strategies.”

In a review article Dr. Moslehi published toward the end of 2016, he fleshed out the wider scope of adverse cardiovascular effects from cancer therapies, noting that the vascular endothelial growth factor (VEGF) signaling pathway inhibitors, drugs such as bevacizumab (Avastin) and aflibercept (Zaltrap), have been documented to cause hypertension, arterial thromboembolic events, and cardiomyopathy; and that tyrosine kinase inhibitors have been shown to cause vascular events, QT interval prolongation, and cerebral and peripheral vascular events (N Engl J Med. 2016 Oct 13;375[15]:1457-67).

In his own recent review, Dr. Fradley highlighted adverse cardiovascular effects from additional anticancer drug classes, including proteasome inhibitors, which can trigger hypertension and cardiomyopathy; immunomodulators, implicated in causing both venous and arterial thromboembolism; and the immune checkpoint inhibitors, linked with myocarditis, arrhythmias, hypotension, and myocardial ischemia (Eur Heart J. 2016 Sept 21;37[36]:2740-2). A similarly broad spectrum of adverse cardiovascular effects linked with a wide range of anticancer treatments also appeared in the ESC 2016 position paper on cancer treatments.

But while the range of cancer treatments that can have some impact on the cardiovascular system is strikingly large, experts uniformly caution that far from every patient treated for cancer needs an immediate cardiology consult and work-up, especially when the cancers appear in young adults.

“We’re not quite at the point where every cancer patient needs to be seen by a cardiologist or cardio-oncologist,” Dr. Fradley noted in an interview.

The most common cardiology referrals made by Sandra M. Swain, MD, are for patients with either breast cancer or lymphoma who undergo treatment with an anthracycline. “If a patient receiving this treatment has a history of any cardiovascular disease, I’ll refer them. But if a patient is just undergoing adjuvant chemotherapy with another drug, and if everything looks fine and an echocardiogram shows everything is normal, then I don’t refer. I refer [to a cardiologist] any patient with a cardiac history just in case they experience toxicity, but that’s not every patient. It’s not feasible to refer every patient,” said Dr. Swain, a medical oncologist who is professor of medicine and associate dean for research development at Georgetown University in Washington.

“If a patient develops hypertension while on treatment I refer them to a PCP or cardiologist. I don’t treat hypertension myself. But if a patient is ‘normal’ they don’t need a cardiology assessment up front. It’s impossible to refer all patients, especially younger patients, with current resources. There are too many patients who receive cardiotoxic therapies to refer everyone. I involve the cardiologist once there is evidence of damage,”she explained.
 

 

Cardio-oncology centers or community practice?

The rise of cardio-oncology, especially over the last decade or so, has given rise to a new academic niche, the cardio-oncology clinic. Starting from almost no programs a few years ago, by 2016 one tally put the total number of U.S. self-designated cardio-oncology centers at about 40 (Heart Fail Clin. 2017 April;13[2]:347-55), and that number undoubtedly grew even more during the year since. While these programs promote and advance the nascent subspecialty of cardio-oncology, and provide a foundation for development of formalized training programs, many experts see a clear hierarchy of risk that distinguishes the patients who should ideally be managed at these focused, multidisciplinary programs from the lower-risk patients who probably do fine under the care of just their oncologist or their oncologist in collaboration with a community cardiologist or primary care physician.

“The cardio-oncology community recognizes that it is nice to have programs at academic centers but it’s more important to deliver this care in the community,” said Dr. Lenihan. “Many cancer patients have no prior history of cardiovascular disease. These low-risk patients don’t necessarily need a cardio-oncologist. They may need to have their blood pressure managed more effectively or receive other preventive care, but that can certainly be done locally. There are low-risk patients who don’t need to go to a major center.” Dr. Lenihan and other cardio-oncologists see the majority of cancer patients as low risk when it comes to cardiovascular complications.

But it’s different when patients receive an anthracycline or an anthracycline plus trastuzumab. “This high-risk population is best seen at a cardio-oncology center.” Dr. Lenihan also included in this high-risk subgroup patients treated with mediastinal radiation, an option often used during the 1980s-2000s.

“Any time a patient receives treatment with the potential to cause a cardiovascular effect, which is pretty much any drug that now comes out, you need an accurate baseline assessment. But that doesn’t mean you need do anything different; you still treat the patient’s cancer. A thorough baseline assessment is a necessity, but it does not need to be done at a cardio-oncology center,” Dr. Lenihan said in an interview.

“For the vast majority of patients, care can be at community hospitals, similar to the delivery of the vast majority of oncology care. Some patients need referral to tertiary cardiology centers for advanced heart failure or to undergo advanced procedures, but that is a very small percentage of patients,” said Ana Barac, MD, director of the cardio-oncology program at the MedStar Heart Institute in Washington, and chair of the ACC’s Cardio-Oncology Section.

“Patients receiving more novel or unusual therapies, and those participating in trials” are appropriate for centers, while community care by a cardiologist and oncologist should suffice for more routine patients, said Dr. Fradley.

“Cardio-oncology centers are good for patients with type I damage from anthracycline treatment, especially patients who already had underlying heart disease,” said Michael S. Ewer, MD, a cardiologist and professor of medicine at MD Anderson Cancer Center in Houston. Specialist centers are also for patients with cardiovascular risk factors: older age, diabetes, preexisting coronary artery disease, and patients who receive cardiotoxic type I therapy (J Clin Oncol. 2005 May;23[13]:2900-2). Also, patients with a significant, immediate cardiac reaction to treatment, and those with an unexpected cardiac reaction, Dr. Ewer said.

A somewhat more expansive view of the typical cardio-oncology patient came from Dr. Neilan, based on the patients he sees at his program in Boston. Dr. Neilan estimated that roughly 60%-70% of his patients first present while they undergo active cancer treatment, with another 20% coming to the program as cancer survivors, and a small percentage of patients showing up for cardiology assessments and treatments without a cancer history. Among those with a cancer history, he guessed that perhaps 10%-20% were treated with an anthracycline, at least 10% received trastuzumab, and about 10% received radiation treatment. “I also see a lot of patients with complications from treatment” with tyrosine kinase inhibitors, VEGF inhibitors, and immunotherapies. “I don’t see a lot of patients for cardiovascular disease assessment before they start cancer therapy,” Dr. Neilan added.
 

Cardio-oncology heads toward a new cardiology subspecialty

These views of how cardio-oncology is practiced in the real world raise a question about the role of the growing roster of U.S. cardio-oncology programs. If most cancer patients can have their cardiology needs taken care of in the community, how do all the academic programs fit in? The answer seems to be that they model successful oncology and cardiology collaborations, provide a training ground for physicians from both specialties to learn how to collaborate, and serve as the home for research that broadens the field’s evidence base and moves knowledge forward.

 

“Education and partnerships with oncology teams is the key,” said Dr. Barac. “Our traditional subspecialty training focused on ‘treating cancer’ and ‘treating cardiovascular disease.’ Learning about and seeing effective partnerships during training” is the best model to foster cardiology and oncology partnerships among early-career physicians, she suggested.

“What is the spectrum of knowledge required to be proficient in cardio-oncology, and how do we enhance training at the resident or fellowship level? How do we get [all cardiology] trainees exposed to this knowledge?” wondered Dr. Lenihan, who viewed cardio-oncology programs as a way to meet these needs. “Cardio-oncology is not an established subspecialty. A goal is to establish training requirements and expand training opportunities. And the whole field needs to contribute to clinical research. We need cardio-oncologists to share their experience and improve our level of research.”

ASCO’s cardiac dysfunction practice guideline, first released last December and formally published in March, is likely helping to further entrench cardio-oncology as a new subspecialty. The guideline was “a remarkable step forward,” said Dr. Barac. In addition to establishing a U.S. standard of care for preventing and monitoring cardiac dysfunction in cancer patients, “I use it as a guide for creation of referral pathways with my oncology colleagues, as well as in education of cardiovascular and oncology trainees,” she said in an interview.

Though produced primarily through ASCO’s leadership, the target audience for the guideline seems to be as much cardiologists as it is oncologists. Dissemination of the guideline to cardiologists snagged when it failed to appear in the cardiology literature. That wasn’t the original plan, said guideline participants.

“Before we started, it was agreed that both ASCO and the ACC would publish it. We had a [letter] signed by the president of the ACC saying the ACC would publish it,” recalled Dr. Lenihan, a guideline coauthor. “After all the details were settled, the ACC bailed. They said that they had changed their organizational structure and that they wouldn’t publish the guideline even though they had agreed to.” Not having the guideline appear simultaneously in the cardiology literature “hinders getting the message to the cardiology community,” he said, a sentiment echoed by other cardio-oncologists.

“I served as the ACC representative on the guideline, and the lack of ACC endorsement was the unfortunate consequence of approval and publication timing that coincided with restructuring of the ACC committees,” said Dr. Barac. “It absolutely does not reflect a lack of interest from the ACC.” As an example of the College’s commitment example, she cited an ACC 1.5-day educational course on cardiovascular care of oncology patients held for the first time in February 2017 and scheduled for a second edition next February.

Publication of the guideline in a cardiology journal “would indeed help dissemination among U.S. cardiologists,” agreed Pamela S. Douglas, MD, professor of medicine at Duke University in Durham, N.C., and another of the several cardiologists who served on the ASCO guideline’s panel.

“It will be important to publish more cardio-oncology articles, recommendations, and guidelines in the major cardiology journals in order to further increase awareness and attention,” said Dr. Fradley.

Further advancing awareness of patients with cardio-oncology issues, what Dr. Moslehi has called “an emerging epidemic,” seems the most fundamental of the goals currently advanced by many active in this field.

One step to grow the subspecialty that he and his associates at Vanderbilt have taken is to start this year a formally recognized fellowship program in cardio-oncology; an initial class of three cardiologists started in the program this summer. The Vanderbilt group also plans to launch a website before the end of 2017 that will include an oncology-drug database that compiles all available information on each agent’s cardiovascular effects. The planned website will aggregate links to all existing cardio-oncology programs.

“We will absolutely see the field grow,” said Dr. Swain. “It has only sprung up in the past 10 or so years. It is now getting recognition, people are being trained in cardio-oncology, and it will grow as a subspecialty. It’s very exciting, and it’s better for patients.”

“A cardiologist with no cancer patients or survivors in their practice is unheard of; many cardiologists just don’t realize that,” Dr. Lenihan said. At least 10%-15% of the U.S. population in their 60s or older has a cancer history, he noted. The common mindset among cardiologists has been that cancer patients and survivors are not among their patients.

“It’s unlikely that a busy cardiology practice has no cancer survivors or active cancer patients,” Dr. Douglas suggested. When this happens, a likely explanations is that the cardiologist simply failed to elicit a completely comprehensive history from the practice’s patient roster. And even a cardiology practice today that includes no cancer patients or survivors will likely see some turning up soon, she predicted, because so many are receiving cardiovascular-toxic therapies and then surviving longer than ever before.

“What oncologists and cardiologists want to do is to optimize oncologic outcomes but with an acceptable adverse event profile. The cardio-oncologist helps push that envelope. The goal is not to eliminate cardiac events at the expense of oncologic outcomes, but to shift the balance to fewer and less severe cardiac events without unduly compromising oncologic outcomes,” explained Dr. Ewer. Cardio-oncology grapples with one of the core challenges of medicine, how to balance the potential risks from treatment against its potential benefits, he observed.

Dr. Neilan has been a consultant to Ariad and Takeda. Dr. Lenihan has been a consultant to Janssen and Roche and has received research funding from Takeda. Dr. Moslehi has been a consultant to Acceleron, Ariad, Bristol-Myers Squibb, Incyte, Pfizer, Takeda/Millennium, Verastem and Vertex. Dr. Ewer, Dr. Fradley, and Dr. Barac had no relevant disclosures. Dr. Swain has been a consultant to Genentech and Roche. Dr. Douglas has been a consultant to CardioDx, Interleukin Genetics, and Omicia, and has an ownership interest in CardioDx.

 

[email protected]

On Twitter @mitchelzoler

Cardio-oncology is expanding, fed by a steadily increasing population of cancer survivors at elevated risk for a range of cardiovascular diseases and complications because of the anticancer treatments they received. Cardio-oncology’s quick growth has also been driven by the rapidly expanding universe of cancer treatments with direct or indirect adverse effects on a diverse range of cardiovascular functions.

During the past year, the field’s rapid evolution has featured the first formal diagnostic and care standards in two iterations: A position paper on the cardiovascular toxicities of cancer treatment from the European Society of Cardiology (ESC), released in August 2016 (Eur Heart J. 2016 Sept 21;37[36]:2766-801); and a guideline for preventing and monitoring cardiac dysfunction in adult cancer survivors, issued last December by the American Society of Clinical Oncology (ASCO) and endorsed by the American Heart Association (J Clin Oncol. 2017 March 10;35[8]:893-913), but notably not endorsed by the American College of Cardiology, despite having an ACC representative on the guideline panel. In 2015, the ACC started a Cardio-Oncology Section, one of 20 special-interest sections it maintains, and by mid-2017 the section had some 500 members.

Despite these milestones and spread of the cardio-oncology concept, the cardiovascular consequences of cancer treatment remain underappreciated and incompletely understood by many cardiologists and primary care physicians, experts say. Other current limitations include the absence of a well defined cardio-oncology subspecialty and training infrastructure and significant gaps in the field’s evidence base, including no direct proof of the clinical value of screening for the earliest signs of cardiovascular adverse effects in cancer patients.

“I’ve had recent conversations with cardiologists who said ‘I’m not sure what cardio-oncology is,’ ” said Tomas G. Neilan, MD, director of the cardio-oncology program at Massachusetts General Hospital in Boston.

“The number one priority for cardio-oncology is to raise awareness about it at every level: patients, their support people, oncologists, cardiologists, and primary care physicians,” said Daniel J. Lenihan, MD, until recently professor of medicine and a cardio-oncologist at Vanderbilt University in Nashville, Tenn., who in September moved to Washington University in St. Louis to start a cardio-oncology program there.

More than just heart failure

A few decades ago, in the primordial days of cardio-oncology, the concept of cardiovascular damage during cancer therapy focused entirely on myocardial damage caused by anthracyclines and chest radiation, a concern that eventually expanded to include trastuzumab (Herceptin) and other agents that target the human epidermal growth factor receptor 2 (HER2). These treatments cause significantly reduced left ventricular ejection fractions and heart failure in a significant minority of treated patients. Patients who receive combined treatment with an anthracycline and trastuzumab are at the highest risk for developing heart failure with reduced ejection fraction, but even among patients treated with this combination, fewer than 5% develop outright heart failure.

While this parochial view of cardio-oncology has recently shifted, it remains true that myocardial damage from a relatively large cumulative anthracycline dose, or from radiation, causes some of the most extreme cases of cardiovascular adverse effects and remains an ongoing problem as these treatments stay front line for selected cancer patients.

But some of the recent burgeoning of cardio-oncology has followed the recognition that many other drugs and drug classes can cause a spectrum of adverse cardiovascular effects.

“Cardio-oncology has become more complicated, with hundreds of new cancer treatments, each one with an adverse effect profile. Many of the new drugs cause vascular or metabolic issues,” said Javid J. Moslehi, MD, director of cardio-oncology at Vanderbilt University. Heart failure and ejection fraction were the “easiest things to tackle” in the recent ASCO guidelines, but there are many other manifestations of cardiovascular toxicity from cancer treatments.

“There has been a significant focus on heart failure and cardiomyopathy due to anthracyclines and HER2-targeted therapies. I think the field will continue to evolve over the next 5 years to focus on other cardiovascular complications, including arrhythmias and vascular disease,” observed Michael Fradley, MD, director of cardio-oncology at Moffitt Cancer Center in Tampa. “In addition, there will be an increased focus on targeted drugs and immunotherapies,” agents that Dr. Fradley said “have many unique cardiovascular complications. We need additional guidelines regarding the management of a variety of cardiotoxicities as well as long-term monitoring strategies.”

In a review article Dr. Moslehi published toward the end of 2016, he fleshed out the wider scope of adverse cardiovascular effects from cancer therapies, noting that the vascular endothelial growth factor (VEGF) signaling pathway inhibitors, drugs such as bevacizumab (Avastin) and aflibercept (Zaltrap), have been documented to cause hypertension, arterial thromboembolic events, and cardiomyopathy; and that tyrosine kinase inhibitors have been shown to cause vascular events, QT interval prolongation, and cerebral and peripheral vascular events (N Engl J Med. 2016 Oct 13;375[15]:1457-67).

In his own recent review, Dr. Fradley highlighted adverse cardiovascular effects from additional anticancer drug classes, including proteasome inhibitors, which can trigger hypertension and cardiomyopathy; immunomodulators, implicated in causing both venous and arterial thromboembolism; and the immune checkpoint inhibitors, linked with myocarditis, arrhythmias, hypotension, and myocardial ischemia (Eur Heart J. 2016 Sept 21;37[36]:2740-2). A similarly broad spectrum of adverse cardiovascular effects linked with a wide range of anticancer treatments also appeared in the ESC 2016 position paper on cancer treatments.

But while the range of cancer treatments that can have some impact on the cardiovascular system is strikingly large, experts uniformly caution that far from every patient treated for cancer needs an immediate cardiology consult and work-up, especially when the cancers appear in young adults.

“We’re not quite at the point where every cancer patient needs to be seen by a cardiologist or cardio-oncologist,” Dr. Fradley noted in an interview.

The most common cardiology referrals made by Sandra M. Swain, MD, are for patients with either breast cancer or lymphoma who undergo treatment with an anthracycline. “If a patient receiving this treatment has a history of any cardiovascular disease, I’ll refer them. But if a patient is just undergoing adjuvant chemotherapy with another drug, and if everything looks fine and an echocardiogram shows everything is normal, then I don’t refer. I refer [to a cardiologist] any patient with a cardiac history just in case they experience toxicity, but that’s not every patient. It’s not feasible to refer every patient,” said Dr. Swain, a medical oncologist who is professor of medicine and associate dean for research development at Georgetown University in Washington.

“If a patient develops hypertension while on treatment I refer them to a PCP or cardiologist. I don’t treat hypertension myself. But if a patient is ‘normal’ they don’t need a cardiology assessment up front. It’s impossible to refer all patients, especially younger patients, with current resources. There are too many patients who receive cardiotoxic therapies to refer everyone. I involve the cardiologist once there is evidence of damage,”she explained.
 

 

Cardio-oncology centers or community practice?

The rise of cardio-oncology, especially over the last decade or so, has given rise to a new academic niche, the cardio-oncology clinic. Starting from almost no programs a few years ago, by 2016 one tally put the total number of U.S. self-designated cardio-oncology centers at about 40 (Heart Fail Clin. 2017 April;13[2]:347-55), and that number undoubtedly grew even more during the year since. While these programs promote and advance the nascent subspecialty of cardio-oncology, and provide a foundation for development of formalized training programs, many experts see a clear hierarchy of risk that distinguishes the patients who should ideally be managed at these focused, multidisciplinary programs from the lower-risk patients who probably do fine under the care of just their oncologist or their oncologist in collaboration with a community cardiologist or primary care physician.

“The cardio-oncology community recognizes that it is nice to have programs at academic centers but it’s more important to deliver this care in the community,” said Dr. Lenihan. “Many cancer patients have no prior history of cardiovascular disease. These low-risk patients don’t necessarily need a cardio-oncologist. They may need to have their blood pressure managed more effectively or receive other preventive care, but that can certainly be done locally. There are low-risk patients who don’t need to go to a major center.” Dr. Lenihan and other cardio-oncologists see the majority of cancer patients as low risk when it comes to cardiovascular complications.

But it’s different when patients receive an anthracycline or an anthracycline plus trastuzumab. “This high-risk population is best seen at a cardio-oncology center.” Dr. Lenihan also included in this high-risk subgroup patients treated with mediastinal radiation, an option often used during the 1980s-2000s.

“Any time a patient receives treatment with the potential to cause a cardiovascular effect, which is pretty much any drug that now comes out, you need an accurate baseline assessment. But that doesn’t mean you need do anything different; you still treat the patient’s cancer. A thorough baseline assessment is a necessity, but it does not need to be done at a cardio-oncology center,” Dr. Lenihan said in an interview.

“For the vast majority of patients, care can be at community hospitals, similar to the delivery of the vast majority of oncology care. Some patients need referral to tertiary cardiology centers for advanced heart failure or to undergo advanced procedures, but that is a very small percentage of patients,” said Ana Barac, MD, director of the cardio-oncology program at the MedStar Heart Institute in Washington, and chair of the ACC’s Cardio-Oncology Section.

“Patients receiving more novel or unusual therapies, and those participating in trials” are appropriate for centers, while community care by a cardiologist and oncologist should suffice for more routine patients, said Dr. Fradley.

“Cardio-oncology centers are good for patients with type I damage from anthracycline treatment, especially patients who already had underlying heart disease,” said Michael S. Ewer, MD, a cardiologist and professor of medicine at MD Anderson Cancer Center in Houston. Specialist centers are also for patients with cardiovascular risk factors: older age, diabetes, preexisting coronary artery disease, and patients who receive cardiotoxic type I therapy (J Clin Oncol. 2005 May;23[13]:2900-2). Also, patients with a significant, immediate cardiac reaction to treatment, and those with an unexpected cardiac reaction, Dr. Ewer said.

A somewhat more expansive view of the typical cardio-oncology patient came from Dr. Neilan, based on the patients he sees at his program in Boston. Dr. Neilan estimated that roughly 60%-70% of his patients first present while they undergo active cancer treatment, with another 20% coming to the program as cancer survivors, and a small percentage of patients showing up for cardiology assessments and treatments without a cancer history. Among those with a cancer history, he guessed that perhaps 10%-20% were treated with an anthracycline, at least 10% received trastuzumab, and about 10% received radiation treatment. “I also see a lot of patients with complications from treatment” with tyrosine kinase inhibitors, VEGF inhibitors, and immunotherapies. “I don’t see a lot of patients for cardiovascular disease assessment before they start cancer therapy,” Dr. Neilan added.
 

Cardio-oncology heads toward a new cardiology subspecialty

These views of how cardio-oncology is practiced in the real world raise a question about the role of the growing roster of U.S. cardio-oncology programs. If most cancer patients can have their cardiology needs taken care of in the community, how do all the academic programs fit in? The answer seems to be that they model successful oncology and cardiology collaborations, provide a training ground for physicians from both specialties to learn how to collaborate, and serve as the home for research that broadens the field’s evidence base and moves knowledge forward.

 

“Education and partnerships with oncology teams is the key,” said Dr. Barac. “Our traditional subspecialty training focused on ‘treating cancer’ and ‘treating cardiovascular disease.’ Learning about and seeing effective partnerships during training” is the best model to foster cardiology and oncology partnerships among early-career physicians, she suggested.

“What is the spectrum of knowledge required to be proficient in cardio-oncology, and how do we enhance training at the resident or fellowship level? How do we get [all cardiology] trainees exposed to this knowledge?” wondered Dr. Lenihan, who viewed cardio-oncology programs as a way to meet these needs. “Cardio-oncology is not an established subspecialty. A goal is to establish training requirements and expand training opportunities. And the whole field needs to contribute to clinical research. We need cardio-oncologists to share their experience and improve our level of research.”

ASCO’s cardiac dysfunction practice guideline, first released last December and formally published in March, is likely helping to further entrench cardio-oncology as a new subspecialty. The guideline was “a remarkable step forward,” said Dr. Barac. In addition to establishing a U.S. standard of care for preventing and monitoring cardiac dysfunction in cancer patients, “I use it as a guide for creation of referral pathways with my oncology colleagues, as well as in education of cardiovascular and oncology trainees,” she said in an interview.

Though produced primarily through ASCO’s leadership, the target audience for the guideline seems to be as much cardiologists as it is oncologists. Dissemination of the guideline to cardiologists snagged when it failed to appear in the cardiology literature. That wasn’t the original plan, said guideline participants.

“Before we started, it was agreed that both ASCO and the ACC would publish it. We had a [letter] signed by the president of the ACC saying the ACC would publish it,” recalled Dr. Lenihan, a guideline coauthor. “After all the details were settled, the ACC bailed. They said that they had changed their organizational structure and that they wouldn’t publish the guideline even though they had agreed to.” Not having the guideline appear simultaneously in the cardiology literature “hinders getting the message to the cardiology community,” he said, a sentiment echoed by other cardio-oncologists.

“I served as the ACC representative on the guideline, and the lack of ACC endorsement was the unfortunate consequence of approval and publication timing that coincided with restructuring of the ACC committees,” said Dr. Barac. “It absolutely does not reflect a lack of interest from the ACC.” As an example of the College’s commitment example, she cited an ACC 1.5-day educational course on cardiovascular care of oncology patients held for the first time in February 2017 and scheduled for a second edition next February.

Publication of the guideline in a cardiology journal “would indeed help dissemination among U.S. cardiologists,” agreed Pamela S. Douglas, MD, professor of medicine at Duke University in Durham, N.C., and another of the several cardiologists who served on the ASCO guideline’s panel.

“It will be important to publish more cardio-oncology articles, recommendations, and guidelines in the major cardiology journals in order to further increase awareness and attention,” said Dr. Fradley.

Further advancing awareness of patients with cardio-oncology issues, what Dr. Moslehi has called “an emerging epidemic,” seems the most fundamental of the goals currently advanced by many active in this field.

One step to grow the subspecialty that he and his associates at Vanderbilt have taken is to start this year a formally recognized fellowship program in cardio-oncology; an initial class of three cardiologists started in the program this summer. The Vanderbilt group also plans to launch a website before the end of 2017 that will include an oncology-drug database that compiles all available information on each agent’s cardiovascular effects. The planned website will aggregate links to all existing cardio-oncology programs.

“We will absolutely see the field grow,” said Dr. Swain. “It has only sprung up in the past 10 or so years. It is now getting recognition, people are being trained in cardio-oncology, and it will grow as a subspecialty. It’s very exciting, and it’s better for patients.”

“A cardiologist with no cancer patients or survivors in their practice is unheard of; many cardiologists just don’t realize that,” Dr. Lenihan said. At least 10%-15% of the U.S. population in their 60s or older has a cancer history, he noted. The common mindset among cardiologists has been that cancer patients and survivors are not among their patients.

“It’s unlikely that a busy cardiology practice has no cancer survivors or active cancer patients,” Dr. Douglas suggested. When this happens, a likely explanations is that the cardiologist simply failed to elicit a completely comprehensive history from the practice’s patient roster. And even a cardiology practice today that includes no cancer patients or survivors will likely see some turning up soon, she predicted, because so many are receiving cardiovascular-toxic therapies and then surviving longer than ever before.

“What oncologists and cardiologists want to do is to optimize oncologic outcomes but with an acceptable adverse event profile. The cardio-oncologist helps push that envelope. The goal is not to eliminate cardiac events at the expense of oncologic outcomes, but to shift the balance to fewer and less severe cardiac events without unduly compromising oncologic outcomes,” explained Dr. Ewer. Cardio-oncology grapples with one of the core challenges of medicine, how to balance the potential risks from treatment against its potential benefits, he observed.

Dr. Neilan has been a consultant to Ariad and Takeda. Dr. Lenihan has been a consultant to Janssen and Roche and has received research funding from Takeda. Dr. Moslehi has been a consultant to Acceleron, Ariad, Bristol-Myers Squibb, Incyte, Pfizer, Takeda/Millennium, Verastem and Vertex. Dr. Ewer, Dr. Fradley, and Dr. Barac had no relevant disclosures. Dr. Swain has been a consultant to Genentech and Roche. Dr. Douglas has been a consultant to CardioDx, Interleukin Genetics, and Omicia, and has an ownership interest in CardioDx.

 

[email protected]

On Twitter @mitchelzoler

Cardio-oncology is expanding, fed by a steadily increasing population of cancer survivors at elevated risk for a range of cardiovascular diseases and complications because of the anticancer treatments they received. Cardio-oncology’s quick growth has also been driven by the rapidly expanding universe of cancer treatments with direct or indirect adverse effects on a diverse range of cardiovascular functions.

During the past year, the field’s rapid evolution has featured the first formal diagnostic and care standards in two iterations: A position paper on the cardiovascular toxicities of cancer treatment from the European Society of Cardiology (ESC), released in August 2016 (Eur Heart J. 2016 Sept 21;37[36]:2766-801); and a guideline for preventing and monitoring cardiac dysfunction in adult cancer survivors, issued last December by the American Society of Clinical Oncology (ASCO) and endorsed by the American Heart Association (J Clin Oncol. 2017 March 10;35[8]:893-913), but notably not endorsed by the American College of Cardiology, despite having an ACC representative on the guideline panel. In 2015, the ACC started a Cardio-Oncology Section, one of 20 special-interest sections it maintains, and by mid-2017 the section had some 500 members.

Despite these milestones and spread of the cardio-oncology concept, the cardiovascular consequences of cancer treatment remain underappreciated and incompletely understood by many cardiologists and primary care physicians, experts say. Other current limitations include the absence of a well defined cardio-oncology subspecialty and training infrastructure and significant gaps in the field’s evidence base, including no direct proof of the clinical value of screening for the earliest signs of cardiovascular adverse effects in cancer patients.

“I’ve had recent conversations with cardiologists who said ‘I’m not sure what cardio-oncology is,’ ” said Tomas G. Neilan, MD, director of the cardio-oncology program at Massachusetts General Hospital in Boston.

“The number one priority for cardio-oncology is to raise awareness about it at every level: patients, their support people, oncologists, cardiologists, and primary care physicians,” said Daniel J. Lenihan, MD, until recently professor of medicine and a cardio-oncologist at Vanderbilt University in Nashville, Tenn., who in September moved to Washington University in St. Louis to start a cardio-oncology program there.

More than just heart failure

A few decades ago, in the primordial days of cardio-oncology, the concept of cardiovascular damage during cancer therapy focused entirely on myocardial damage caused by anthracyclines and chest radiation, a concern that eventually expanded to include trastuzumab (Herceptin) and other agents that target the human epidermal growth factor receptor 2 (HER2). These treatments cause significantly reduced left ventricular ejection fractions and heart failure in a significant minority of treated patients. Patients who receive combined treatment with an anthracycline and trastuzumab are at the highest risk for developing heart failure with reduced ejection fraction, but even among patients treated with this combination, fewer than 5% develop outright heart failure.

While this parochial view of cardio-oncology has recently shifted, it remains true that myocardial damage from a relatively large cumulative anthracycline dose, or from radiation, causes some of the most extreme cases of cardiovascular adverse effects and remains an ongoing problem as these treatments stay front line for selected cancer patients.

But some of the recent burgeoning of cardio-oncology has followed the recognition that many other drugs and drug classes can cause a spectrum of adverse cardiovascular effects.

“Cardio-oncology has become more complicated, with hundreds of new cancer treatments, each one with an adverse effect profile. Many of the new drugs cause vascular or metabolic issues,” said Javid J. Moslehi, MD, director of cardio-oncology at Vanderbilt University. Heart failure and ejection fraction were the “easiest things to tackle” in the recent ASCO guidelines, but there are many other manifestations of cardiovascular toxicity from cancer treatments.

“There has been a significant focus on heart failure and cardiomyopathy due to anthracyclines and HER2-targeted therapies. I think the field will continue to evolve over the next 5 years to focus on other cardiovascular complications, including arrhythmias and vascular disease,” observed Michael Fradley, MD, director of cardio-oncology at Moffitt Cancer Center in Tampa. “In addition, there will be an increased focus on targeted drugs and immunotherapies,” agents that Dr. Fradley said “have many unique cardiovascular complications. We need additional guidelines regarding the management of a variety of cardiotoxicities as well as long-term monitoring strategies.”

In a review article Dr. Moslehi published toward the end of 2016, he fleshed out the wider scope of adverse cardiovascular effects from cancer therapies, noting that the vascular endothelial growth factor (VEGF) signaling pathway inhibitors, drugs such as bevacizumab (Avastin) and aflibercept (Zaltrap), have been documented to cause hypertension, arterial thromboembolic events, and cardiomyopathy; and that tyrosine kinase inhibitors have been shown to cause vascular events, QT interval prolongation, and cerebral and peripheral vascular events (N Engl J Med. 2016 Oct 13;375[15]:1457-67).

In his own recent review, Dr. Fradley highlighted adverse cardiovascular effects from additional anticancer drug classes, including proteasome inhibitors, which can trigger hypertension and cardiomyopathy; immunomodulators, implicated in causing both venous and arterial thromboembolism; and the immune checkpoint inhibitors, linked with myocarditis, arrhythmias, hypotension, and myocardial ischemia (Eur Heart J. 2016 Sept 21;37[36]:2740-2). A similarly broad spectrum of adverse cardiovascular effects linked with a wide range of anticancer treatments also appeared in the ESC 2016 position paper on cancer treatments.

But while the range of cancer treatments that can have some impact on the cardiovascular system is strikingly large, experts uniformly caution that far from every patient treated for cancer needs an immediate cardiology consult and work-up, especially when the cancers appear in young adults.

“We’re not quite at the point where every cancer patient needs to be seen by a cardiologist or cardio-oncologist,” Dr. Fradley noted in an interview.

The most common cardiology referrals made by Sandra M. Swain, MD, are for patients with either breast cancer or lymphoma who undergo treatment with an anthracycline. “If a patient receiving this treatment has a history of any cardiovascular disease, I’ll refer them. But if a patient is just undergoing adjuvant chemotherapy with another drug, and if everything looks fine and an echocardiogram shows everything is normal, then I don’t refer. I refer [to a cardiologist] any patient with a cardiac history just in case they experience toxicity, but that’s not every patient. It’s not feasible to refer every patient,” said Dr. Swain, a medical oncologist who is professor of medicine and associate dean for research development at Georgetown University in Washington.

“If a patient develops hypertension while on treatment I refer them to a PCP or cardiologist. I don’t treat hypertension myself. But if a patient is ‘normal’ they don’t need a cardiology assessment up front. It’s impossible to refer all patients, especially younger patients, with current resources. There are too many patients who receive cardiotoxic therapies to refer everyone. I involve the cardiologist once there is evidence of damage,”she explained.
 

 

Cardio-oncology centers or community practice?

The rise of cardio-oncology, especially over the last decade or so, has given rise to a new academic niche, the cardio-oncology clinic. Starting from almost no programs a few years ago, by 2016 one tally put the total number of U.S. self-designated cardio-oncology centers at about 40 (Heart Fail Clin. 2017 April;13[2]:347-55), and that number undoubtedly grew even more during the year since. While these programs promote and advance the nascent subspecialty of cardio-oncology, and provide a foundation for development of formalized training programs, many experts see a clear hierarchy of risk that distinguishes the patients who should ideally be managed at these focused, multidisciplinary programs from the lower-risk patients who probably do fine under the care of just their oncologist or their oncologist in collaboration with a community cardiologist or primary care physician.

“The cardio-oncology community recognizes that it is nice to have programs at academic centers but it’s more important to deliver this care in the community,” said Dr. Lenihan. “Many cancer patients have no prior history of cardiovascular disease. These low-risk patients don’t necessarily need a cardio-oncologist. They may need to have their blood pressure managed more effectively or receive other preventive care, but that can certainly be done locally. There are low-risk patients who don’t need to go to a major center.” Dr. Lenihan and other cardio-oncologists see the majority of cancer patients as low risk when it comes to cardiovascular complications.

But it’s different when patients receive an anthracycline or an anthracycline plus trastuzumab. “This high-risk population is best seen at a cardio-oncology center.” Dr. Lenihan also included in this high-risk subgroup patients treated with mediastinal radiation, an option often used during the 1980s-2000s.

“Any time a patient receives treatment with the potential to cause a cardiovascular effect, which is pretty much any drug that now comes out, you need an accurate baseline assessment. But that doesn’t mean you need do anything different; you still treat the patient’s cancer. A thorough baseline assessment is a necessity, but it does not need to be done at a cardio-oncology center,” Dr. Lenihan said in an interview.

“For the vast majority of patients, care can be at community hospitals, similar to the delivery of the vast majority of oncology care. Some patients need referral to tertiary cardiology centers for advanced heart failure or to undergo advanced procedures, but that is a very small percentage of patients,” said Ana Barac, MD, director of the cardio-oncology program at the MedStar Heart Institute in Washington, and chair of the ACC’s Cardio-Oncology Section.

“Patients receiving more novel or unusual therapies, and those participating in trials” are appropriate for centers, while community care by a cardiologist and oncologist should suffice for more routine patients, said Dr. Fradley.

“Cardio-oncology centers are good for patients with type I damage from anthracycline treatment, especially patients who already had underlying heart disease,” said Michael S. Ewer, MD, a cardiologist and professor of medicine at MD Anderson Cancer Center in Houston. Specialist centers are also for patients with cardiovascular risk factors: older age, diabetes, preexisting coronary artery disease, and patients who receive cardiotoxic type I therapy (J Clin Oncol. 2005 May;23[13]:2900-2). Also, patients with a significant, immediate cardiac reaction to treatment, and those with an unexpected cardiac reaction, Dr. Ewer said.

A somewhat more expansive view of the typical cardio-oncology patient came from Dr. Neilan, based on the patients he sees at his program in Boston. Dr. Neilan estimated that roughly 60%-70% of his patients first present while they undergo active cancer treatment, with another 20% coming to the program as cancer survivors, and a small percentage of patients showing up for cardiology assessments and treatments without a cancer history. Among those with a cancer history, he guessed that perhaps 10%-20% were treated with an anthracycline, at least 10% received trastuzumab, and about 10% received radiation treatment. “I also see a lot of patients with complications from treatment” with tyrosine kinase inhibitors, VEGF inhibitors, and immunotherapies. “I don’t see a lot of patients for cardiovascular disease assessment before they start cancer therapy,” Dr. Neilan added.
 

Cardio-oncology heads toward a new cardiology subspecialty

These views of how cardio-oncology is practiced in the real world raise a question about the role of the growing roster of U.S. cardio-oncology programs. If most cancer patients can have their cardiology needs taken care of in the community, how do all the academic programs fit in? The answer seems to be that they model successful oncology and cardiology collaborations, provide a training ground for physicians from both specialties to learn how to collaborate, and serve as the home for research that broadens the field’s evidence base and moves knowledge forward.

 

“Education and partnerships with oncology teams is the key,” said Dr. Barac. “Our traditional subspecialty training focused on ‘treating cancer’ and ‘treating cardiovascular disease.’ Learning about and seeing effective partnerships during training” is the best model to foster cardiology and oncology partnerships among early-career physicians, she suggested.

“What is the spectrum of knowledge required to be proficient in cardio-oncology, and how do we enhance training at the resident or fellowship level? How do we get [all cardiology] trainees exposed to this knowledge?” wondered Dr. Lenihan, who viewed cardio-oncology programs as a way to meet these needs. “Cardio-oncology is not an established subspecialty. A goal is to establish training requirements and expand training opportunities. And the whole field needs to contribute to clinical research. We need cardio-oncologists to share their experience and improve our level of research.”

ASCO’s cardiac dysfunction practice guideline, first released last December and formally published in March, is likely helping to further entrench cardio-oncology as a new subspecialty. The guideline was “a remarkable step forward,” said Dr. Barac. In addition to establishing a U.S. standard of care for preventing and monitoring cardiac dysfunction in cancer patients, “I use it as a guide for creation of referral pathways with my oncology colleagues, as well as in education of cardiovascular and oncology trainees,” she said in an interview.

Though produced primarily through ASCO’s leadership, the target audience for the guideline seems to be as much cardiologists as it is oncologists. Dissemination of the guideline to cardiologists snagged when it failed to appear in the cardiology literature. That wasn’t the original plan, said guideline participants.

“Before we started, it was agreed that both ASCO and the ACC would publish it. We had a [letter] signed by the president of the ACC saying the ACC would publish it,” recalled Dr. Lenihan, a guideline coauthor. “After all the details were settled, the ACC bailed. They said that they had changed their organizational structure and that they wouldn’t publish the guideline even though they had agreed to.” Not having the guideline appear simultaneously in the cardiology literature “hinders getting the message to the cardiology community,” he said, a sentiment echoed by other cardio-oncologists.

“I served as the ACC representative on the guideline, and the lack of ACC endorsement was the unfortunate consequence of approval and publication timing that coincided with restructuring of the ACC committees,” said Dr. Barac. “It absolutely does not reflect a lack of interest from the ACC.” As an example of the College’s commitment example, she cited an ACC 1.5-day educational course on cardiovascular care of oncology patients held for the first time in February 2017 and scheduled for a second edition next February.

Publication of the guideline in a cardiology journal “would indeed help dissemination among U.S. cardiologists,” agreed Pamela S. Douglas, MD, professor of medicine at Duke University in Durham, N.C., and another of the several cardiologists who served on the ASCO guideline’s panel.

“It will be important to publish more cardio-oncology articles, recommendations, and guidelines in the major cardiology journals in order to further increase awareness and attention,” said Dr. Fradley.

Further advancing awareness of patients with cardio-oncology issues, what Dr. Moslehi has called “an emerging epidemic,” seems the most fundamental of the goals currently advanced by many active in this field.

One step to grow the subspecialty that he and his associates at Vanderbilt have taken is to start this year a formally recognized fellowship program in cardio-oncology; an initial class of three cardiologists started in the program this summer. The Vanderbilt group also plans to launch a website before the end of 2017 that will include an oncology-drug database that compiles all available information on each agent’s cardiovascular effects. The planned website will aggregate links to all existing cardio-oncology programs.

“We will absolutely see the field grow,” said Dr. Swain. “It has only sprung up in the past 10 or so years. It is now getting recognition, people are being trained in cardio-oncology, and it will grow as a subspecialty. It’s very exciting, and it’s better for patients.”

“A cardiologist with no cancer patients or survivors in their practice is unheard of; many cardiologists just don’t realize that,” Dr. Lenihan said. At least 10%-15% of the U.S. population in their 60s or older has a cancer history, he noted. The common mindset among cardiologists has been that cancer patients and survivors are not among their patients.

“It’s unlikely that a busy cardiology practice has no cancer survivors or active cancer patients,” Dr. Douglas suggested. When this happens, a likely explanations is that the cardiologist simply failed to elicit a completely comprehensive history from the practice’s patient roster. And even a cardiology practice today that includes no cancer patients or survivors will likely see some turning up soon, she predicted, because so many are receiving cardiovascular-toxic therapies and then surviving longer than ever before.

“What oncologists and cardiologists want to do is to optimize oncologic outcomes but with an acceptable adverse event profile. The cardio-oncologist helps push that envelope. The goal is not to eliminate cardiac events at the expense of oncologic outcomes, but to shift the balance to fewer and less severe cardiac events without unduly compromising oncologic outcomes,” explained Dr. Ewer. Cardio-oncology grapples with one of the core challenges of medicine, how to balance the potential risks from treatment against its potential benefits, he observed.

Dr. Neilan has been a consultant to Ariad and Takeda. Dr. Lenihan has been a consultant to Janssen and Roche and has received research funding from Takeda. Dr. Moslehi has been a consultant to Acceleron, Ariad, Bristol-Myers Squibb, Incyte, Pfizer, Takeda/Millennium, Verastem and Vertex. Dr. Ewer, Dr. Fradley, and Dr. Barac had no relevant disclosures. Dr. Swain has been a consultant to Genentech and Roche. Dr. Douglas has been a consultant to CardioDx, Interleukin Genetics, and Omicia, and has an ownership interest in CardioDx.

 

[email protected]

On Twitter @mitchelzoler

 

SAN DIEGO – The intravenous echinocandin anidulafungin effectively treated invasive candidiasis in a single-arm, multicenter, open-label trial of 47 children aged 2-17 years.

The overall global response rate of 72% resembled that from the prior adult registry study (76%), Emmanuel Roilides, MD, PhD, and his associates reported in a poster presented at an annual scientific meeting on infectious diseases.

At 6-week follow-up, two patients (4%) had relapsed, both with Candida parapsilosis, which was more resistant to treatment with anidulafungin (Eraxis) than other Candida species, the researchers reported. Treating the children with 3.0 mg/kg anidulafungin on day 1, followed by 1.5 mg/kg every 24 hours, yielded similar pharmacokinetics as the 200/100 mg regimen used in adults. The most common treatment-emergent adverse effects included diarrhea (23%), vomiting (23%), and fever (19%), which also reflected findings in adults, the investigators said. Five patients (10%) developed at least one severe treatment-emergent adverse event, including neutropenia, gastrointestinal hemorrhage, increased hepatic transaminases, hyponatremia, and myalgia. The study (NCT00761267) is ongoing and continues to recruit patients in 11 states in the United States and nine other countries, with final top-line results expected in 2019.

CDC/Dr. William Kaplan

Historically, invasive candidiasis has caused significant morbidity and mortality in children. Infection risk is highest in those who are immunocompromised by hematologic malignancies, primary or secondary immunodeficiencies, solid organ or hematopoietic stem cell transplantation, or prematurity (J Pediatric Infect Di Soc. 2017 Sep 1;6[suppl_1]:S3-S11).

Although rates of invasive candidiasis appear to be decreasing in children overall, the population at risk is expanding, experts have noted. Relevant guidelines from the Infectious Disease Society of America and the European Society of Clinical Microbiology and Infectious Diseases list amphotericin B, echinocandins, and azoles as treatment options, but these recommendations are extrapolated mainly from adult studies, noted Dr. Roilides, who is a pediatric infectious disease specialist at Aristotle University School of Health Sciences and Hippokration General Hospital in Thessaloniki, Greece.

To better characterize the safety and efficacy of anidulafungin in children, the researchers enrolled patients up to 17 years of age who had signs and symptoms of invasive candidiasis and Candida cultured from a normally sterile site. Patients received intravenous anidulafungin (3 mg/kg on day 1, followed by 1.5 mg/kg every 24 hours) for at least 10 days, after which they could switch to oral fluconazole. Treatment continued for at least 14 days after blood cultures were negative and signs and symptoms resolved.

At interim data cutoff in October 2016, patients were exposed to anidulafungin for a median of 11.5 days (range, 1-28 days). Among 47 patients who received at least one dose of anidulafungin, about two-thirds were male, about 70% were white, and the average age was 8 years (standard deviation, 4.7 years). Rates of global success – a combination of clinical and microbiological response – were 82% in patients up to 5 years old and 67% in older children. Children whose baseline neutrophil count was at least 500 per mm³ had a 78% global response rate versus 50% among those with more severe neutropenia. C. parapsilosis had higher minimum inhibitory concentrations than other Candida species, and in vitro susceptibility rates of 85% for C. parapsilosis versus 100% for other species.

All patients experienced at least one treatment-emergent adverse effect. In addition to diarrhea, vomiting, and pyrexia, adverse events affecting more than 10% of patients included epistaxis (17%), headache (15%), and abdominal pain (13%). Half of patients switched to oral fluconazole. Four patients stopped treatment because of vomiting, generalized pruritus, or increased transaminases. A total of 15% of patients died, although no deaths were considered treatment related. The patient who stopped treatment because of pruritus later died of septic shock secondary to invasive candidiasis, despite having started treatment with fluconazole and micafungin, the investigators reported at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

Nearly all patients had bloodstream infections, and catheters also cultured positive in more than two-thirds of cases, the researchers said. Many patients had multiple risk factors for infection such as central venous catheters, broad-spectrum antibiotic therapy, total parenteral nutrition, and chemotherapy. Cultures were most often positive for Candida albicans (38%), followed by C. parapsilosis (26%) and C. tropicalis (13%).

Pfizer makes anidulafungin and sponsored the study. Dr. Roilides disclosed research grants and advisory relationships with Pfizer, Astellas, Gilead, and Merck.

 

SAN DIEGO – The intravenous echinocandin anidulafungin effectively treated invasive candidiasis in a single-arm, multicenter, open-label trial of 47 children aged 2-17 years.

The overall global response rate of 72% resembled that from the prior adult registry study (76%), Emmanuel Roilides, MD, PhD, and his associates reported in a poster presented at an annual scientific meeting on infectious diseases.

At 6-week follow-up, two patients (4%) had relapsed, both with Candida parapsilosis, which was more resistant to treatment with anidulafungin (Eraxis) than other Candida species, the researchers reported. Treating the children with 3.0 mg/kg anidulafungin on day 1, followed by 1.5 mg/kg every 24 hours, yielded similar pharmacokinetics as the 200/100 mg regimen used in adults. The most common treatment-emergent adverse effects included diarrhea (23%), vomiting (23%), and fever (19%), which also reflected findings in adults, the investigators said. Five patients (10%) developed at least one severe treatment-emergent adverse event, including neutropenia, gastrointestinal hemorrhage, increased hepatic transaminases, hyponatremia, and myalgia. The study (NCT00761267) is ongoing and continues to recruit patients in 11 states in the United States and nine other countries, with final top-line results expected in 2019.

CDC/Dr. William Kaplan

Historically, invasive candidiasis has caused significant morbidity and mortality in children. Infection risk is highest in those who are immunocompromised by hematologic malignancies, primary or secondary immunodeficiencies, solid organ or hematopoietic stem cell transplantation, or prematurity (J Pediatric Infect Di Soc. 2017 Sep 1;6[suppl_1]:S3-S11).

Although rates of invasive candidiasis appear to be decreasing in children overall, the population at risk is expanding, experts have noted. Relevant guidelines from the Infectious Disease Society of America and the European Society of Clinical Microbiology and Infectious Diseases list amphotericin B, echinocandins, and azoles as treatment options, but these recommendations are extrapolated mainly from adult studies, noted Dr. Roilides, who is a pediatric infectious disease specialist at Aristotle University School of Health Sciences and Hippokration General Hospital in Thessaloniki, Greece.

To better characterize the safety and efficacy of anidulafungin in children, the researchers enrolled patients up to 17 years of age who had signs and symptoms of invasive candidiasis and Candida cultured from a normally sterile site. Patients received intravenous anidulafungin (3 mg/kg on day 1, followed by 1.5 mg/kg every 24 hours) for at least 10 days, after which they could switch to oral fluconazole. Treatment continued for at least 14 days after blood cultures were negative and signs and symptoms resolved.

At interim data cutoff in October 2016, patients were exposed to anidulafungin for a median of 11.5 days (range, 1-28 days). Among 47 patients who received at least one dose of anidulafungin, about two-thirds were male, about 70% were white, and the average age was 8 years (standard deviation, 4.7 years). Rates of global success – a combination of clinical and microbiological response – were 82% in patients up to 5 years old and 67% in older children. Children whose baseline neutrophil count was at least 500 per mm³ had a 78% global response rate versus 50% among those with more severe neutropenia. C. parapsilosis had higher minimum inhibitory concentrations than other Candida species, and in vitro susceptibility rates of 85% for C. parapsilosis versus 100% for other species.

All patients experienced at least one treatment-emergent adverse effect. In addition to diarrhea, vomiting, and pyrexia, adverse events affecting more than 10% of patients included epistaxis (17%), headache (15%), and abdominal pain (13%). Half of patients switched to oral fluconazole. Four patients stopped treatment because of vomiting, generalized pruritus, or increased transaminases. A total of 15% of patients died, although no deaths were considered treatment related. The patient who stopped treatment because of pruritus later died of septic shock secondary to invasive candidiasis, despite having started treatment with fluconazole and micafungin, the investigators reported at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

Nearly all patients had bloodstream infections, and catheters also cultured positive in more than two-thirds of cases, the researchers said. Many patients had multiple risk factors for infection such as central venous catheters, broad-spectrum antibiotic therapy, total parenteral nutrition, and chemotherapy. Cultures were most often positive for Candida albicans (38%), followed by C. parapsilosis (26%) and C. tropicalis (13%).

Pfizer makes anidulafungin and sponsored the study. Dr. Roilides disclosed research grants and advisory relationships with Pfizer, Astellas, Gilead, and Merck.

 

SAN DIEGO – The intravenous echinocandin anidulafungin effectively treated invasive candidiasis in a single-arm, multicenter, open-label trial of 47 children aged 2-17 years.

The overall global response rate of 72% resembled that from the prior adult registry study (76%), Emmanuel Roilides, MD, PhD, and his associates reported in a poster presented at an annual scientific meeting on infectious diseases.

At 6-week follow-up, two patients (4%) had relapsed, both with Candida parapsilosis, which was more resistant to treatment with anidulafungin (Eraxis) than other Candida species, the researchers reported. Treating the children with 3.0 mg/kg anidulafungin on day 1, followed by 1.5 mg/kg every 24 hours, yielded similar pharmacokinetics as the 200/100 mg regimen used in adults. The most common treatment-emergent adverse effects included diarrhea (23%), vomiting (23%), and fever (19%), which also reflected findings in adults, the investigators said. Five patients (10%) developed at least one severe treatment-emergent adverse event, including neutropenia, gastrointestinal hemorrhage, increased hepatic transaminases, hyponatremia, and myalgia. The study (NCT00761267) is ongoing and continues to recruit patients in 11 states in the United States and nine other countries, with final top-line results expected in 2019.

CDC/Dr. William Kaplan

Historically, invasive candidiasis has caused significant morbidity and mortality in children. Infection risk is highest in those who are immunocompromised by hematologic malignancies, primary or secondary immunodeficiencies, solid organ or hematopoietic stem cell transplantation, or prematurity (J Pediatric Infect Di Soc. 2017 Sep 1;6[suppl_1]:S3-S11).

Although rates of invasive candidiasis appear to be decreasing in children overall, the population at risk is expanding, experts have noted. Relevant guidelines from the Infectious Disease Society of America and the European Society of Clinical Microbiology and Infectious Diseases list amphotericin B, echinocandins, and azoles as treatment options, but these recommendations are extrapolated mainly from adult studies, noted Dr. Roilides, who is a pediatric infectious disease specialist at Aristotle University School of Health Sciences and Hippokration General Hospital in Thessaloniki, Greece.

To better characterize the safety and efficacy of anidulafungin in children, the researchers enrolled patients up to 17 years of age who had signs and symptoms of invasive candidiasis and Candida cultured from a normally sterile site. Patients received intravenous anidulafungin (3 mg/kg on day 1, followed by 1.5 mg/kg every 24 hours) for at least 10 days, after which they could switch to oral fluconazole. Treatment continued for at least 14 days after blood cultures were negative and signs and symptoms resolved.

At interim data cutoff in October 2016, patients were exposed to anidulafungin for a median of 11.5 days (range, 1-28 days). Among 47 patients who received at least one dose of anidulafungin, about two-thirds were male, about 70% were white, and the average age was 8 years (standard deviation, 4.7 years). Rates of global success – a combination of clinical and microbiological response – were 82% in patients up to 5 years old and 67% in older children. Children whose baseline neutrophil count was at least 500 per mm³ had a 78% global response rate versus 50% among those with more severe neutropenia. C. parapsilosis had higher minimum inhibitory concentrations than other Candida species, and in vitro susceptibility rates of 85% for C. parapsilosis versus 100% for other species.

All patients experienced at least one treatment-emergent adverse effect. In addition to diarrhea, vomiting, and pyrexia, adverse events affecting more than 10% of patients included epistaxis (17%), headache (15%), and abdominal pain (13%). Half of patients switched to oral fluconazole. Four patients stopped treatment because of vomiting, generalized pruritus, or increased transaminases. A total of 15% of patients died, although no deaths were considered treatment related. The patient who stopped treatment because of pruritus later died of septic shock secondary to invasive candidiasis, despite having started treatment with fluconazole and micafungin, the investigators reported at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

Nearly all patients had bloodstream infections, and catheters also cultured positive in more than two-thirds of cases, the researchers said. Many patients had multiple risk factors for infection such as central venous catheters, broad-spectrum antibiotic therapy, total parenteral nutrition, and chemotherapy. Cultures were most often positive for Candida albicans (38%), followed by C. parapsilosis (26%) and C. tropicalis (13%).

Pfizer makes anidulafungin and sponsored the study. Dr. Roilides disclosed research grants and advisory relationships with Pfizer, Astellas, Gilead, and Merck.

Wound complications after pre- or post-operative radiation for soft tissue sarcomas are well established.¹ The ability to predict who will have a wound complication remains difficult. Some studies have looked at risk factors such as smoking, and the preoperative nutritional status of patients has been identified as a risk factor for wound complication in patients with elective orthopedic surgical procedures.² One validated method of measuring preoperative nutritional status in patients with gastrointestinal malignant tumors has been with Onodera’s Prognostic Nutritional Index (OPNI). It uses the patient’s preoperative albumin (g/dL) and absolute lymphocyte values (per mm³). The prognostic value of the OPNI has been demonstrated in patients with colorectal, esophageal, and gastric cancers, and has been shown to be prognostic for postoperative wound healing and overall prognosis.^3-5 In this study, we investigate the significance of preoperative nutritional status, measured by OPNI, as a predictor of wound complications in patients treated with pre- or postoperative radiation for soft tissue sarcoma.

Methods

After receiving Institutional Review Board approval for the study, we conducted a retrospective review of consecutive patients treated during July 2012-April 2016 for a soft tissue sarcoma by the orthopedic oncology division at Cooper University Hospital in Camden, New Jersey. Inclusion criteria were patients with biopsy-proven soft tissue sarcoma, who were older than 18 years, had received pre- or postoperative radiation, and who had a recorded preoperative albumin and total lymphocyte count. A minimum follow-up of 3 months was required to assess for postoperative wound complications. Exclusion criteria included patients who had a bone sarcoma, had not received radiation therapy, or had a missing preoperative albumin or total lymphocyte count.

All of the surgeries were performed by 2 fellowshiptrained orthopedic oncologists. Patients received either pre- or postoperative radiation therapy by multiple radiation oncologists.

The OPNI was calculated based on the published formula OPNI = (10*albumin level [g/dL]) + (0.005*total lymphocyte count [per mm³]). The albumin level and total lymphocyte counts closest to the index operation were chosen.

Demographic information including gender, age at diagnosis, height, and weight were recorded. Data related to the patients’ pathologic diagnosis, stage at presentation, radiation therapy, and surgical resection were collected. A minor wound complication was defined as a wound problem that did not require operative intervention. Major wound complication was defined as a complication requiring operative intervention with or without flap reconstruction. Wound complications occurring within the 3-month postoperative period were considered.

Univariate and multiple variable analysis was performed. A P value <.05 was considered significant. A receiver operating curve as well as recursive partitioning was performed for OPNI and age to determine the best cut-off point to use in the analysis. The Sobel test was used to evaluate mediation. All statistical analysis was performed using SAS v9.4 and JMP10. (SAS Institute, Cary, NC).

Results

In all, 44 patients (28 men, 16 women) were included in the study. Their mean age was 61.2 years (range, 19-94). The average size of the tumors was 8.5 cm in greatest dimension (range, 1.2-27.4 cm), and all of the patients had nonmetastatic disease at the time of surgical resection; 37 patients had R0 resections, and 7 patients had a positive margin from an outside hospital, but obtained R0 resections on a subsequent resection (Table 1 and Table 2).

In all, 30 patients received preoperative radiation, 14 patients received postoperative radiation, 32 patients received external beam radiation, 8 received Cyberknife treatment, and information for 4 patients was not unavailable. Mean preoperative external beam radiation and Cyberknife dose was 4,931 Gy and 3,750 Gy, respectively. Mean postoperative external beam and Cyberknife radiation dose was 6,077 Gy and 4,000 Gy, respectively. When evaluating radiation dose delivered between those who had wound complications and those who did not, there was no significant difference (Table 3).

Of the total, 13 patients had a wound complication (30%). Ten patients had preoperative radiation, and 3 had postoperative radiation. Ten patients had major wound complications requiring a combined 27 surgeries. Three patients had minor wound complications, which resolved with conservative management. One patient had a major wound complication in the group that had an initial R1 resection.

The OPNI was calculated based on the aforementioned formula. When the univariate analysis was performed, only age and OPNI were statistically significant. Patients older than 72.6 years had a 6.8 times higher risk of a wound complication (P = .01; 95% confidence interval [CI], 1.6-28.7). When the OPNI value of 45.4 was used as the threshold, a patient with a preoperative OPNI value of <45.4 had a 7.5 times increased risk of developing a wound complication (P = .005; 95% CI, 1.8-31.0).

When the receiver operating curve and recursive partitioning was performed, an OPNI value of 45.4 showed a sensitivity of 62% and specificity of 82% in predicting wound complications (Figure 1).

When a multiple variable analysis was performed, OPNI and age were not statistically significant (P = .06 and P = .11, respectively). A test for mediation was performed, and the OPNI seemed to mediate the effect age has on wound complications, accounting for 36% of the total effect (Sobel test statistic, 1.79; P = .07).

 

Discussion

Wound complications after pre- and postoperative radiation for soft tissue sarcomas are well known. The best study to date to demonstrate that relationship was a randomized controlled trial performed in Canada, which showed that preoperative radiation resulted in 37% wound complications, compared with 17% for postoperative radiation.⁶ In that study, of the wound complications in both radiation types, more than 50%-60% required a secondary surgical procedure, designating it as a major wound complication. Other variables that have been shown to contribute to wound complications include being older than 40 years and/or having large tumors, diabetes, peripheral vascular disease, and begin a smoker.^7-10

In our study, we applied OPNI to orthopedic oncology and showed that the patient’s age and preoperative nutritional status were significant predictors of developing a wound complication. An OPNI of <45.4 increased the chance of a wound complication by 7.5 times. Being older than 73 years increased the risk of a wound complication by 6.8 times. Most of these wound complications were major and required surgical intervention.

In general surgical oncology, the evaluation of nutritional status has had a significant impact on the care of patients, especially for those patients undergoing gastrointestinal surgery. The OPNI was initially designed to assess the nutritional and immunological statuses of patients undergoing gastrointestinal surgery.¹¹ Preoperative OPNI has been shown to be a good predictor of postoperative complications and survival in patients with colorectal cancer, malignant mesothelioma, hepatocellular carcinoma and in patients who undergo total gastrectomy.^12-15 Chen and colleagues evaluated the significance of OPNI in patients with colorectal cancer. They found an optimal cut-off value of 45. An OPNI value <45 has a sensitivity and specificity of 85% and 69%, respectively, in predicting 5-year overall survival.¹⁶ Hong and colleagues noted that an OPNI cut-off value of 52.6 as a predictor of overall survival.¹⁷

Poor preoperative nutritional status has been shown to have a negative impact on wound healing. In patients who underwent emergency laparotomy, a low OPNI had significantly higher rates of wound dehiscence and infection.¹⁸ This happens because protein deficiency leads to decreased wound tensile strength, decreased T-cell function, decreased phagocytic activity, which ultimately diminish the patient’s ability to heal and defend against wound infections.^19-21

In soft tissue sarcoma patients, poor preoperative nutritional status is further compromised by radiation therapy to the wound. Gu and colleagues showed that radiation to wounds in mice showed early inhibition of the inflammatory phase, injury and inhibition of fibroblasts, and collagen formation, and then prolonged re-epithelialization.²² This “double hit” with radiation onto host tissue that is already nutritionally compromised could be an important cause of why wound complications occur at such high rates in our soft tissue sarcoma patients.

There are several limitations to this study. First, the study has a small sample size, which was a direct result of the number of patients who were excluded because an OPNI value could not be calculated for them. Second, we could not determine if the OPNI was more valuable in patients who underwent pre- or postoperative radiation. This study did not look at other nutritional indices such as prealbumin and vitamin levels. Third, the radiation was provided by different providers, so technique was variable, but the patients received nearly equivalent doses and variability in technique is likely limited. Fourth, we were not able to meaningfully analyze the role of chemotherapy in this patient population because there was a significant heterogeneity of patients receiving pre- and postoperative chemotherapy.

Our findings strongly suggest that a preoperative OPNI of <45.4 and being older than 73 years are strong predictors of patients who will experience a wound complication after radiation therapy for soft tissue sarcomas. This study has led us to start measuring preoperative albumin levels and assess complete metabolic panels. Our goal is to identify patients who are at high risk of wound complication and perform interventions to improve nutrition, then to study whether the interventions help lower the rates of wound complications.

Wound complications after pre- or post-operative radiation for soft tissue sarcomas are well established.¹ The ability to predict who will have a wound complication remains difficult. Some studies have looked at risk factors such as smoking, and the preoperative nutritional status of patients has been identified as a risk factor for wound complication in patients with elective orthopedic surgical procedures.² One validated method of measuring preoperative nutritional status in patients with gastrointestinal malignant tumors has been with Onodera’s Prognostic Nutritional Index (OPNI). It uses the patient’s preoperative albumin (g/dL) and absolute lymphocyte values (per mm³). The prognostic value of the OPNI has been demonstrated in patients with colorectal, esophageal, and gastric cancers, and has been shown to be prognostic for postoperative wound healing and overall prognosis.^3-5 In this study, we investigate the significance of preoperative nutritional status, measured by OPNI, as a predictor of wound complications in patients treated with pre- or postoperative radiation for soft tissue sarcoma.

Methods

After receiving Institutional Review Board approval for the study, we conducted a retrospective review of consecutive patients treated during July 2012-April 2016 for a soft tissue sarcoma by the orthopedic oncology division at Cooper University Hospital in Camden, New Jersey. Inclusion criteria were patients with biopsy-proven soft tissue sarcoma, who were older than 18 years, had received pre- or postoperative radiation, and who had a recorded preoperative albumin and total lymphocyte count. A minimum follow-up of 3 months was required to assess for postoperative wound complications. Exclusion criteria included patients who had a bone sarcoma, had not received radiation therapy, or had a missing preoperative albumin or total lymphocyte count.

All of the surgeries were performed by 2 fellowshiptrained orthopedic oncologists. Patients received either pre- or postoperative radiation therapy by multiple radiation oncologists.

The OPNI was calculated based on the published formula OPNI = (10*albumin level [g/dL]) + (0.005*total lymphocyte count [per mm³]). The albumin level and total lymphocyte counts closest to the index operation were chosen.

Demographic information including gender, age at diagnosis, height, and weight were recorded. Data related to the patients’ pathologic diagnosis, stage at presentation, radiation therapy, and surgical resection were collected. A minor wound complication was defined as a wound problem that did not require operative intervention. Major wound complication was defined as a complication requiring operative intervention with or without flap reconstruction. Wound complications occurring within the 3-month postoperative period were considered.

Univariate and multiple variable analysis was performed. A P value <.05 was considered significant. A receiver operating curve as well as recursive partitioning was performed for OPNI and age to determine the best cut-off point to use in the analysis. The Sobel test was used to evaluate mediation. All statistical analysis was performed using SAS v9.4 and JMP10. (SAS Institute, Cary, NC).

Results

In all, 44 patients (28 men, 16 women) were included in the study. Their mean age was 61.2 years (range, 19-94). The average size of the tumors was 8.5 cm in greatest dimension (range, 1.2-27.4 cm), and all of the patients had nonmetastatic disease at the time of surgical resection; 37 patients had R0 resections, and 7 patients had a positive margin from an outside hospital, but obtained R0 resections on a subsequent resection (Table 1 and Table 2).

In all, 30 patients received preoperative radiation, 14 patients received postoperative radiation, 32 patients received external beam radiation, 8 received Cyberknife treatment, and information for 4 patients was not unavailable. Mean preoperative external beam radiation and Cyberknife dose was 4,931 Gy and 3,750 Gy, respectively. Mean postoperative external beam and Cyberknife radiation dose was 6,077 Gy and 4,000 Gy, respectively. When evaluating radiation dose delivered between those who had wound complications and those who did not, there was no significant difference (Table 3).

Of the total, 13 patients had a wound complication (30%). Ten patients had preoperative radiation, and 3 had postoperative radiation. Ten patients had major wound complications requiring a combined 27 surgeries. Three patients had minor wound complications, which resolved with conservative management. One patient had a major wound complication in the group that had an initial R1 resection.

The OPNI was calculated based on the aforementioned formula. When the univariate analysis was performed, only age and OPNI were statistically significant. Patients older than 72.6 years had a 6.8 times higher risk of a wound complication (P = .01; 95% confidence interval [CI], 1.6-28.7). When the OPNI value of 45.4 was used as the threshold, a patient with a preoperative OPNI value of <45.4 had a 7.5 times increased risk of developing a wound complication (P = .005; 95% CI, 1.8-31.0).

When the receiver operating curve and recursive partitioning was performed, an OPNI value of 45.4 showed a sensitivity of 62% and specificity of 82% in predicting wound complications (Figure 1).

When a multiple variable analysis was performed, OPNI and age were not statistically significant (P = .06 and P = .11, respectively). A test for mediation was performed, and the OPNI seemed to mediate the effect age has on wound complications, accounting for 36% of the total effect (Sobel test statistic, 1.79; P = .07).

 

Discussion

Wound complications after pre- and postoperative radiation for soft tissue sarcomas are well known. The best study to date to demonstrate that relationship was a randomized controlled trial performed in Canada, which showed that preoperative radiation resulted in 37% wound complications, compared with 17% for postoperative radiation.⁶ In that study, of the wound complications in both radiation types, more than 50%-60% required a secondary surgical procedure, designating it as a major wound complication. Other variables that have been shown to contribute to wound complications include being older than 40 years and/or having large tumors, diabetes, peripheral vascular disease, and begin a smoker.^7-10

In our study, we applied OPNI to orthopedic oncology and showed that the patient’s age and preoperative nutritional status were significant predictors of developing a wound complication. An OPNI of <45.4 increased the chance of a wound complication by 7.5 times. Being older than 73 years increased the risk of a wound complication by 6.8 times. Most of these wound complications were major and required surgical intervention.

In general surgical oncology, the evaluation of nutritional status has had a significant impact on the care of patients, especially for those patients undergoing gastrointestinal surgery. The OPNI was initially designed to assess the nutritional and immunological statuses of patients undergoing gastrointestinal surgery.¹¹ Preoperative OPNI has been shown to be a good predictor of postoperative complications and survival in patients with colorectal cancer, malignant mesothelioma, hepatocellular carcinoma and in patients who undergo total gastrectomy.^12-15 Chen and colleagues evaluated the significance of OPNI in patients with colorectal cancer. They found an optimal cut-off value of 45. An OPNI value <45 has a sensitivity and specificity of 85% and 69%, respectively, in predicting 5-year overall survival.¹⁶ Hong and colleagues noted that an OPNI cut-off value of 52.6 as a predictor of overall survival.¹⁷

Poor preoperative nutritional status has been shown to have a negative impact on wound healing. In patients who underwent emergency laparotomy, a low OPNI had significantly higher rates of wound dehiscence and infection.¹⁸ This happens because protein deficiency leads to decreased wound tensile strength, decreased T-cell function, decreased phagocytic activity, which ultimately diminish the patient’s ability to heal and defend against wound infections.^19-21

In soft tissue sarcoma patients, poor preoperative nutritional status is further compromised by radiation therapy to the wound. Gu and colleagues showed that radiation to wounds in mice showed early inhibition of the inflammatory phase, injury and inhibition of fibroblasts, and collagen formation, and then prolonged re-epithelialization.²² This “double hit” with radiation onto host tissue that is already nutritionally compromised could be an important cause of why wound complications occur at such high rates in our soft tissue sarcoma patients.

There are several limitations to this study. First, the study has a small sample size, which was a direct result of the number of patients who were excluded because an OPNI value could not be calculated for them. Second, we could not determine if the OPNI was more valuable in patients who underwent pre- or postoperative radiation. This study did not look at other nutritional indices such as prealbumin and vitamin levels. Third, the radiation was provided by different providers, so technique was variable, but the patients received nearly equivalent doses and variability in technique is likely limited. Fourth, we were not able to meaningfully analyze the role of chemotherapy in this patient population because there was a significant heterogeneity of patients receiving pre- and postoperative chemotherapy.

Our findings strongly suggest that a preoperative OPNI of <45.4 and being older than 73 years are strong predictors of patients who will experience a wound complication after radiation therapy for soft tissue sarcomas. This study has led us to start measuring preoperative albumin levels and assess complete metabolic panels. Our goal is to identify patients who are at high risk of wound complication and perform interventions to improve nutrition, then to study whether the interventions help lower the rates of wound complications.

Wound complications after pre- or post-operative radiation for soft tissue sarcomas are well established.¹ The ability to predict who will have a wound complication remains difficult. Some studies have looked at risk factors such as smoking, and the preoperative nutritional status of patients has been identified as a risk factor for wound complication in patients with elective orthopedic surgical procedures.² One validated method of measuring preoperative nutritional status in patients with gastrointestinal malignant tumors has been with Onodera’s Prognostic Nutritional Index (OPNI). It uses the patient’s preoperative albumin (g/dL) and absolute lymphocyte values (per mm³). The prognostic value of the OPNI has been demonstrated in patients with colorectal, esophageal, and gastric cancers, and has been shown to be prognostic for postoperative wound healing and overall prognosis.^3-5 In this study, we investigate the significance of preoperative nutritional status, measured by OPNI, as a predictor of wound complications in patients treated with pre- or postoperative radiation for soft tissue sarcoma.

Methods

After receiving Institutional Review Board approval for the study, we conducted a retrospective review of consecutive patients treated during July 2012-April 2016 for a soft tissue sarcoma by the orthopedic oncology division at Cooper University Hospital in Camden, New Jersey. Inclusion criteria were patients with biopsy-proven soft tissue sarcoma, who were older than 18 years, had received pre- or postoperative radiation, and who had a recorded preoperative albumin and total lymphocyte count. A minimum follow-up of 3 months was required to assess for postoperative wound complications. Exclusion criteria included patients who had a bone sarcoma, had not received radiation therapy, or had a missing preoperative albumin or total lymphocyte count.

All of the surgeries were performed by 2 fellowshiptrained orthopedic oncologists. Patients received either pre- or postoperative radiation therapy by multiple radiation oncologists.

The OPNI was calculated based on the published formula OPNI = (10*albumin level [g/dL]) + (0.005*total lymphocyte count [per mm³]). The albumin level and total lymphocyte counts closest to the index operation were chosen.

Demographic information including gender, age at diagnosis, height, and weight were recorded. Data related to the patients’ pathologic diagnosis, stage at presentation, radiation therapy, and surgical resection were collected. A minor wound complication was defined as a wound problem that did not require operative intervention. Major wound complication was defined as a complication requiring operative intervention with or without flap reconstruction. Wound complications occurring within the 3-month postoperative period were considered.

Univariate and multiple variable analysis was performed. A P value <.05 was considered significant. A receiver operating curve as well as recursive partitioning was performed for OPNI and age to determine the best cut-off point to use in the analysis. The Sobel test was used to evaluate mediation. All statistical analysis was performed using SAS v9.4 and JMP10. (SAS Institute, Cary, NC).

Results

In all, 44 patients (28 men, 16 women) were included in the study. Their mean age was 61.2 years (range, 19-94). The average size of the tumors was 8.5 cm in greatest dimension (range, 1.2-27.4 cm), and all of the patients had nonmetastatic disease at the time of surgical resection; 37 patients had R0 resections, and 7 patients had a positive margin from an outside hospital, but obtained R0 resections on a subsequent resection (Table 1 and Table 2).

In all, 30 patients received preoperative radiation, 14 patients received postoperative radiation, 32 patients received external beam radiation, 8 received Cyberknife treatment, and information for 4 patients was not unavailable. Mean preoperative external beam radiation and Cyberknife dose was 4,931 Gy and 3,750 Gy, respectively. Mean postoperative external beam and Cyberknife radiation dose was 6,077 Gy and 4,000 Gy, respectively. When evaluating radiation dose delivered between those who had wound complications and those who did not, there was no significant difference (Table 3).

Of the total, 13 patients had a wound complication (30%). Ten patients had preoperative radiation, and 3 had postoperative radiation. Ten patients had major wound complications requiring a combined 27 surgeries. Three patients had minor wound complications, which resolved with conservative management. One patient had a major wound complication in the group that had an initial R1 resection.

The OPNI was calculated based on the aforementioned formula. When the univariate analysis was performed, only age and OPNI were statistically significant. Patients older than 72.6 years had a 6.8 times higher risk of a wound complication (P = .01; 95% confidence interval [CI], 1.6-28.7). When the OPNI value of 45.4 was used as the threshold, a patient with a preoperative OPNI value of <45.4 had a 7.5 times increased risk of developing a wound complication (P = .005; 95% CI, 1.8-31.0).

When the receiver operating curve and recursive partitioning was performed, an OPNI value of 45.4 showed a sensitivity of 62% and specificity of 82% in predicting wound complications (Figure 1).

When a multiple variable analysis was performed, OPNI and age were not statistically significant (P = .06 and P = .11, respectively). A test for mediation was performed, and the OPNI seemed to mediate the effect age has on wound complications, accounting for 36% of the total effect (Sobel test statistic, 1.79; P = .07).

 

Discussion

Wound complications after pre- and postoperative radiation for soft tissue sarcomas are well known. The best study to date to demonstrate that relationship was a randomized controlled trial performed in Canada, which showed that preoperative radiation resulted in 37% wound complications, compared with 17% for postoperative radiation.⁶ In that study, of the wound complications in both radiation types, more than 50%-60% required a secondary surgical procedure, designating it as a major wound complication. Other variables that have been shown to contribute to wound complications include being older than 40 years and/or having large tumors, diabetes, peripheral vascular disease, and begin a smoker.^7-10

In our study, we applied OPNI to orthopedic oncology and showed that the patient’s age and preoperative nutritional status were significant predictors of developing a wound complication. An OPNI of <45.4 increased the chance of a wound complication by 7.5 times. Being older than 73 years increased the risk of a wound complication by 6.8 times. Most of these wound complications were major and required surgical intervention.

In general surgical oncology, the evaluation of nutritional status has had a significant impact on the care of patients, especially for those patients undergoing gastrointestinal surgery. The OPNI was initially designed to assess the nutritional and immunological statuses of patients undergoing gastrointestinal surgery.¹¹ Preoperative OPNI has been shown to be a good predictor of postoperative complications and survival in patients with colorectal cancer, malignant mesothelioma, hepatocellular carcinoma and in patients who undergo total gastrectomy.^12-15 Chen and colleagues evaluated the significance of OPNI in patients with colorectal cancer. They found an optimal cut-off value of 45. An OPNI value <45 has a sensitivity and specificity of 85% and 69%, respectively, in predicting 5-year overall survival.¹⁶ Hong and colleagues noted that an OPNI cut-off value of 52.6 as a predictor of overall survival.¹⁷

Poor preoperative nutritional status has been shown to have a negative impact on wound healing. In patients who underwent emergency laparotomy, a low OPNI had significantly higher rates of wound dehiscence and infection.¹⁸ This happens because protein deficiency leads to decreased wound tensile strength, decreased T-cell function, decreased phagocytic activity, which ultimately diminish the patient’s ability to heal and defend against wound infections.^19-21

In soft tissue sarcoma patients, poor preoperative nutritional status is further compromised by radiation therapy to the wound. Gu and colleagues showed that radiation to wounds in mice showed early inhibition of the inflammatory phase, injury and inhibition of fibroblasts, and collagen formation, and then prolonged re-epithelialization.²² This “double hit” with radiation onto host tissue that is already nutritionally compromised could be an important cause of why wound complications occur at such high rates in our soft tissue sarcoma patients.

There are several limitations to this study. First, the study has a small sample size, which was a direct result of the number of patients who were excluded because an OPNI value could not be calculated for them. Second, we could not determine if the OPNI was more valuable in patients who underwent pre- or postoperative radiation. This study did not look at other nutritional indices such as prealbumin and vitamin levels. Third, the radiation was provided by different providers, so technique was variable, but the patients received nearly equivalent doses and variability in technique is likely limited. Fourth, we were not able to meaningfully analyze the role of chemotherapy in this patient population because there was a significant heterogeneity of patients receiving pre- and postoperative chemotherapy.

Our findings strongly suggest that a preoperative OPNI of <45.4 and being older than 73 years are strong predictors of patients who will experience a wound complication after radiation therapy for soft tissue sarcomas. This study has led us to start measuring preoperative albumin levels and assess complete metabolic panels. Our goal is to identify patients who are at high risk of wound complication and perform interventions to improve nutrition, then to study whether the interventions help lower the rates of wound complications.

A survey has found that 24% of cancer patients at an ambulatory cancer center in Seattle report being active cannabis users.

Respondents said that the legalization of both medical and recreational marijuana increased the likelihood that they’d use the drug, and with most having a strong interest in learning about cannabis during treatment, according to findings published online Sept. 25 in Cancer (doi: 10.1002/cncr.30879).

Doug Menuez/thinkstockphotos

“Cannabis was used commonly for the relief of physical symptoms, but use for neuropsychiatric symptoms was nearly as frequent,” said Steven Pergam, MD, lead author and medical director of infection prevention at the Seattle Cancer Care Alliance, where the study was carried out. “Even among never users, the respondents indicated substantial interest in learning more about the role of cannabis in cancer care.”

A total of 926 of 2,737 possible patients – or 34% – filled out the survey.

Twenty-four percent had used cannabis in the last year, and 21% in the last month, with about half smoking cannabis and half consuming edibles.

About half of the respondents reported using cannabis for pain, the top physical symptom for use, with nausea a close second. About 30 to 50% of patients reported using cannabis for nonphysical symptoms such as depression and mood problems. But the researchers noted that the evidence of benefit is mixed at best for all of these symptoms.

“There is a need to better understand methods of cannabis use,” Dr. Pergam said, “to maximize benefit and limit risk because patients are already using a wide variety of products.”

Researchers reported receiving consulting fees from Merck Sharp & Dohme, Optimer/Cubist Pharmaceuticals, Gilead Sciences, and Quartet Health.

A survey has found that 24% of cancer patients at an ambulatory cancer center in Seattle report being active cannabis users.

Respondents said that the legalization of both medical and recreational marijuana increased the likelihood that they’d use the drug, and with most having a strong interest in learning about cannabis during treatment, according to findings published online Sept. 25 in Cancer (doi: 10.1002/cncr.30879).

Doug Menuez/thinkstockphotos

“Cannabis was used commonly for the relief of physical symptoms, but use for neuropsychiatric symptoms was nearly as frequent,” said Steven Pergam, MD, lead author and medical director of infection prevention at the Seattle Cancer Care Alliance, where the study was carried out. “Even among never users, the respondents indicated substantial interest in learning more about the role of cannabis in cancer care.”

A total of 926 of 2,737 possible patients – or 34% – filled out the survey.

Twenty-four percent had used cannabis in the last year, and 21% in the last month, with about half smoking cannabis and half consuming edibles.

About half of the respondents reported using cannabis for pain, the top physical symptom for use, with nausea a close second. About 30 to 50% of patients reported using cannabis for nonphysical symptoms such as depression and mood problems. But the researchers noted that the evidence of benefit is mixed at best for all of these symptoms.

“There is a need to better understand methods of cannabis use,” Dr. Pergam said, “to maximize benefit and limit risk because patients are already using a wide variety of products.”

Researchers reported receiving consulting fees from Merck Sharp & Dohme, Optimer/Cubist Pharmaceuticals, Gilead Sciences, and Quartet Health.

A survey has found that 24% of cancer patients at an ambulatory cancer center in Seattle report being active cannabis users.

Respondents said that the legalization of both medical and recreational marijuana increased the likelihood that they’d use the drug, and with most having a strong interest in learning about cannabis during treatment, according to findings published online Sept. 25 in Cancer (doi: 10.1002/cncr.30879).

Doug Menuez/thinkstockphotos

“Cannabis was used commonly for the relief of physical symptoms, but use for neuropsychiatric symptoms was nearly as frequent,” said Steven Pergam, MD, lead author and medical director of infection prevention at the Seattle Cancer Care Alliance, where the study was carried out. “Even among never users, the respondents indicated substantial interest in learning more about the role of cannabis in cancer care.”

A total of 926 of 2,737 possible patients – or 34% – filled out the survey.

Twenty-four percent had used cannabis in the last year, and 21% in the last month, with about half smoking cannabis and half consuming edibles.

About half of the respondents reported using cannabis for pain, the top physical symptom for use, with nausea a close second. About 30 to 50% of patients reported using cannabis for nonphysical symptoms such as depression and mood problems. But the researchers noted that the evidence of benefit is mixed at best for all of these symptoms.

“There is a need to better understand methods of cannabis use,” Dr. Pergam said, “to maximize benefit and limit risk because patients are already using a wide variety of products.”

Researchers reported receiving consulting fees from Merck Sharp & Dohme, Optimer/Cubist Pharmaceuticals, Gilead Sciences, and Quartet Health.

Even advanced primary care practices are not providing comprehensive cancer survivorship care, with deficiencies in how cancer survivors are categorized, how they’re transitioned to primary care, and in the information systems used in their care, according to a new study published online September 25 in JAMA Internal Medicine.

The analysis came from data gathered by investigators at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., who performed case studies on 12 advanced primary care centers across a variety of practice types and geographic settings. The centers were chosen using a national registry of “workforce innovators” compiled by the Robert Wood Johnson Foundation in 2011 and 2012. All but three of the centers were designated patient-centered medical homes (JAMA Intern Med. 2017. doi: 10.1001/jamainternmed.2017.4747).

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“None of these practices had any comprehensive cancer survivorship services,” said lead author Ellen Rubinstein, PhD, who was at Rutgers at the time and is now at the department of family medicine at the University of Michigan, Ann Arbor. “Instead, survivors received care equivalent to that of nonsurvivors [patients who never had cancer].”

Researchers noted the tremendous importance of primary care to cancer survivors. Only about a third of cancer survivors continue to be seen by a cancer specialist 5 years after their diagnosis, but 75% are seen in primary care. The importance of preventive screening, surveillance for recurrence, interventions for long-term effects, and care coordination between specialty and primary care were noted in an Institute of Medicine report in 2006.

Researchers found that the primary care clinicians don’t treat cancer survivors as a distinct population; they get limited information or follow-up guidance on cancer care; and information systems aren’t good at supporting survivorship care.

“Codifying survivorship as a distinct clinical category that belongs on problem lists with payment-linked – fee, value-based, or capitated – care services is a critical first step toward bringing comprehensive cancer survivorship services to primary care,” Dr. Rubinstein said.

Researchers described what they called “cancer exceptionalism,” in which a cancer diagnosis follows a different clinical norm and patients are referred to oncology and then become disengaged with primary care.

On transition of care, one primary care physician told an interviewer that it seems that patients’ cancer treatment “kind of happens in a black box” and that they feel “a little intimidated” in providing the needed follow-up care.

Another said that while a patient’s cancer history could be seen “at a glance” in old paper charts, their electronic health record requires searching multiple screens and “sometimes it’s a needle in a haystack.”

“Despite the push from national organizations to enhance cancer survivorship care capacity in primary care,” Dr. Rubinstein said, “findings from this study suggest that cancer survivorship care does not integrate easily into advanced primary care.”

The researchers reported no conflicts of interest.

Even advanced primary care practices are not providing comprehensive cancer survivorship care, with deficiencies in how cancer survivors are categorized, how they’re transitioned to primary care, and in the information systems used in their care, according to a new study published online September 25 in JAMA Internal Medicine.

The analysis came from data gathered by investigators at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., who performed case studies on 12 advanced primary care centers across a variety of practice types and geographic settings. The centers were chosen using a national registry of “workforce innovators” compiled by the Robert Wood Johnson Foundation in 2011 and 2012. All but three of the centers were designated patient-centered medical homes (JAMA Intern Med. 2017. doi: 10.1001/jamainternmed.2017.4747).

Thinkstock

“None of these practices had any comprehensive cancer survivorship services,” said lead author Ellen Rubinstein, PhD, who was at Rutgers at the time and is now at the department of family medicine at the University of Michigan, Ann Arbor. “Instead, survivors received care equivalent to that of nonsurvivors [patients who never had cancer].”

Researchers noted the tremendous importance of primary care to cancer survivors. Only about a third of cancer survivors continue to be seen by a cancer specialist 5 years after their diagnosis, but 75% are seen in primary care. The importance of preventive screening, surveillance for recurrence, interventions for long-term effects, and care coordination between specialty and primary care were noted in an Institute of Medicine report in 2006.

Researchers found that the primary care clinicians don’t treat cancer survivors as a distinct population; they get limited information or follow-up guidance on cancer care; and information systems aren’t good at supporting survivorship care.

“Codifying survivorship as a distinct clinical category that belongs on problem lists with payment-linked – fee, value-based, or capitated – care services is a critical first step toward bringing comprehensive cancer survivorship services to primary care,” Dr. Rubinstein said.

Researchers described what they called “cancer exceptionalism,” in which a cancer diagnosis follows a different clinical norm and patients are referred to oncology and then become disengaged with primary care.

On transition of care, one primary care physician told an interviewer that it seems that patients’ cancer treatment “kind of happens in a black box” and that they feel “a little intimidated” in providing the needed follow-up care.

Another said that while a patient’s cancer history could be seen “at a glance” in old paper charts, their electronic health record requires searching multiple screens and “sometimes it’s a needle in a haystack.”

“Despite the push from national organizations to enhance cancer survivorship care capacity in primary care,” Dr. Rubinstein said, “findings from this study suggest that cancer survivorship care does not integrate easily into advanced primary care.”

The researchers reported no conflicts of interest.

Even advanced primary care practices are not providing comprehensive cancer survivorship care, with deficiencies in how cancer survivors are categorized, how they’re transitioned to primary care, and in the information systems used in their care, according to a new study published online September 25 in JAMA Internal Medicine.

The analysis came from data gathered by investigators at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., who performed case studies on 12 advanced primary care centers across a variety of practice types and geographic settings. The centers were chosen using a national registry of “workforce innovators” compiled by the Robert Wood Johnson Foundation in 2011 and 2012. All but three of the centers were designated patient-centered medical homes (JAMA Intern Med. 2017. doi: 10.1001/jamainternmed.2017.4747).

Thinkstock

“None of these practices had any comprehensive cancer survivorship services,” said lead author Ellen Rubinstein, PhD, who was at Rutgers at the time and is now at the department of family medicine at the University of Michigan, Ann Arbor. “Instead, survivors received care equivalent to that of nonsurvivors [patients who never had cancer].”

Researchers noted the tremendous importance of primary care to cancer survivors. Only about a third of cancer survivors continue to be seen by a cancer specialist 5 years after their diagnosis, but 75% are seen in primary care. The importance of preventive screening, surveillance for recurrence, interventions for long-term effects, and care coordination between specialty and primary care were noted in an Institute of Medicine report in 2006.

Researchers found that the primary care clinicians don’t treat cancer survivors as a distinct population; they get limited information or follow-up guidance on cancer care; and information systems aren’t good at supporting survivorship care.

“Codifying survivorship as a distinct clinical category that belongs on problem lists with payment-linked – fee, value-based, or capitated – care services is a critical first step toward bringing comprehensive cancer survivorship services to primary care,” Dr. Rubinstein said.

Researchers described what they called “cancer exceptionalism,” in which a cancer diagnosis follows a different clinical norm and patients are referred to oncology and then become disengaged with primary care.

On transition of care, one primary care physician told an interviewer that it seems that patients’ cancer treatment “kind of happens in a black box” and that they feel “a little intimidated” in providing the needed follow-up care.

Another said that while a patient’s cancer history could be seen “at a glance” in old paper charts, their electronic health record requires searching multiple screens and “sometimes it’s a needle in a haystack.”

“Despite the push from national organizations to enhance cancer survivorship care capacity in primary care,” Dr. Rubinstein said, “findings from this study suggest that cancer survivorship care does not integrate easily into advanced primary care.”

The researchers reported no conflicts of interest.

INTRODUCTION

Fatigue is a common distressing effect of cancer.¹ It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors alike. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”² CRF differs from fatigue reported by individuals without cancer in that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, with estimates ranging between 25% and 99%.^2,3 The methods used for screening patients for fatigue and the characteristics of the patient groups may account for this variability. In this article, we review evaluation of CRF and approaches to its management.

PATHOPHYSIOLOGY

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of multiple mechanisms contributing to fatigue in an individual patient.

CENTRAL NERVOUS SYSTEM DISTURBANCES

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores.⁴ Increased levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF.⁵ However, there is not enough evidence at this time to support central nervous system disturbance as the main factor contributing to fatigue in cancer patients.

CIRCADIAN RHYTHM DYSREGULATION

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways.² Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors.⁶ These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

INHIBITION OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis.⁶ Inhibition of the HPA axis may occur with higher levels of serotonin as well.⁷ The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue.⁸ Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue.²

SKELETAL MUSCLE EFFECT

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction.⁹ ATP infusion improved muscle strength in 1 trial, but this was not confirmed in another trial.^10,11 Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls.¹² This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles.^13,14

PRO-INFLAMMATORY CYTOKINES

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom of fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Levels of interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma.¹⁵ IL-6 was also associated with increased fatigue in breast cancer survivors.¹⁶ Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy.¹⁷ Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients.^18,19 Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients.²⁰ Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF.²¹

 

OTHER HYPOTHESES

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support,²² genetic alterations in the immune pathway,²³ epigenetic changes,²⁴ accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation,²⁵ elevated vascular endothelial growth factor levels,²⁶ and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction¹³ all have been postulated to cause CRF.

EVALUATION AND TREATMENT

Fours steps are involved in the evaluation and treatment of CRF (Figure).

Patients are screened for fatigue as the first step, and those who have fatigue undergo a primary evaluation to assess for potential precipitating causes. The third step is implementation of pharmacologic and nonpharmacologic interventions aimed at alleviating or mitigating fatigue. The fourth step involves reevaluating patients periodically to recognize and manage changes in fatigue levels. A multidisciplinary approach involving nursing, physical therapy, social work, and nutrition is critical in managing fatigue in these patients. Education and counselling of patients and involvement of the family are essential for effective management as well.

SCREENING

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to under-recognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue.² Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials.²⁷ A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF.² This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors.²⁸ The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue.^29,30 The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day.³¹ The 9-item BFI is often used in clinical trials.²⁹ It measures the severity of fatigue over the previous 24 hours and has been validated in patients who do not speak English.³²

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which assesses 5 dimensions of fatigue—general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue—and compares the patient’s results with those of individuals without cancer.^33,34 The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments.³⁵

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales.³⁶ Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic reevaluation, and moderate and severe fatigue need further evaluation and management.³⁷

PRIMARY EVALUATION

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living.³⁷ Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse, which may cause poor sleep and fatigue.

 

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below. 

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels.³⁸ Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or auto-immune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes.³⁹ Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond.⁴⁰ Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL.⁴¹

Sleep disturbance. Poor sleep is common in fatigued cancer survivors.⁴² Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuro­endocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue.⁴³ Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep.⁴⁴ Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep.⁴⁵ Melatonin agonists are approved for insomnia in the United States, but not in Europe.⁴⁶

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men.⁴⁷

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster.⁴⁸ A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating one of these symptoms without addressing other symptoms is not effective.⁴⁹ Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy— such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue.⁵⁰

MANAGEMENT

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time.^51,52 When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients.⁵³

 

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy.⁵⁴ CBT interventions that optimize sleep quality may improve fatigue.⁵⁵ More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF.⁵⁶

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations.⁵⁷ Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship.⁵⁸ Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve their cardiorespiratory fitness, muscle strength, and body composition.⁵⁷ Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended for younger patients as well as for the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors.⁵⁹ In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone.⁶⁰ This effect was also shown in a randomized controlled trial of 160 patients with stage 0 to III breast cancer undergoing radiation therapy.⁶¹ The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits only in the physical fatigue components, but not in the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week.⁶² An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes.⁶³ Patients with comorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy.³⁷ Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life.^64,65 We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training.⁶⁶ Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life.⁶⁷

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors.⁶⁸ In breast cancer patients undergoing chemotherapy, yoga was shown to benefit both physical and cognitive fatigue.⁶⁹ DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF.⁷⁰ More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months.⁷¹ Additional research is needed in this area.

Acupuncture. A randomized controlled trial in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue.⁷² However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue.⁷³ Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done; of the studies that have been done, the results are mixed, and additional research is needed.⁷⁴ Currently, there are not sufficient data to recommend any of these modalities.

 

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF,^75–77 but randomized controlled trials have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of nonpharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment.³⁷

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. Randomized controlled trials of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF.⁷⁸ Likewise, in an analysis of 5 randomized controlled trials, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo.⁷⁹ However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease.⁸⁰ Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically.⁸¹ In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner.⁸² However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment.⁸³ Also, other randomized controlled trials in patients undergoing adjuvant chemotherapy for breast cancer⁸⁴ and patients receiving radiation therapy for brain tumors⁸⁵ failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm.⁸⁶ Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation.⁸⁷ A placebo effect was also noted in patients with multiple myeloma⁸⁸ and patients with primary brain tumors.⁸⁹ In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue.⁹⁰ In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7).⁹¹ This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional randomized controlled trials are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF.³⁷

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines.⁹² In a randomized controlled trial evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo.⁹³ A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo.⁹⁴ Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis.³⁷

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups.⁹⁵

Antidepressants have failed to demonstrate benefit in CRF without depression.⁸ However, if a patient has both fatigue and depression, antidepressants may help.⁹⁶ A selective serotonin receptor inhibitor is recommended as a first-line antidepressant.⁹⁷ Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

 

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF.⁷⁴ The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF.⁹⁸

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo.⁹⁹ Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects.¹⁰⁰ Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

The seed extract of the guarana plant (Paullinia cupana) traditionally has been used as a stimulant. An improvement in fatigue scores was seen with the use of oral guarana (100 mg daily) at the end of 21 days in breast cancer patients receiving chemotherapy.¹⁰¹ Further studies are needed for these results to be generalized and to understand the adverse effects and interaction profile of guarana.

Reevaluation

Patients who have completed cancer treatment must be monitored for fatigue over the long term, as fatigue may exist beyond the period of active treatment. Many studies have shown fatigue in breast cancer survivors, and fatigue has been demonstrated in survivors of colorectal, lung, and prostate cancers as well as myeloproliferative neoplasms.²⁸ Therefore, it is important to screen patients for fatigue during follow-up visits. There are currently no studies evaluating the long-term treatment of fatigue. In our experience, the timing of follow-up depends on the level of fatigue and interventions prescribed. Once fatigue is stabilized to a level with which the patient is able to cope, the time interval for follow-up may be lengthened. Annual visits may suffice in patients with mild fatigue. Follow-up of patients with moderate to severe fatigue depends on the level of fatigue, the ability to cope, choice of treatment, and presence of contributing factors.

CONCLUSION

CRF is a complex condition that places a significant burden on patients and caregivers, resulting in emotional distress, poor functioning, and suffering. Fatigue can occur before, during, and long after cancer treatment. The approach to CRF begins with screening for and educating patients and their caregivers about the symptoms. Many screening scales are available that may be used to follow patients’ progress over time. The evaluation and management of contributing conditions may help improve fatigue. If the fatigue persists, an individualized approach with a combination of nonpharmacologic and pharmacologic approaches should be considered. More research is needed to understand brain signaling pathways, cytokine changes, and genomic changes in cancer patients with fatigue. Though many hypotheses have been proposed, to date there is no biological marker to assess this condition. Biomarker research needs to be advanced to help to identify patients at risk for fatigue. As cytokines have a major role in CRF, targeted therapy to block cytokine pathways may also be explored in the future.

Acknowledgment: The authors thank Bryan Tutt for providing editorial assistance during the writing of this article.

INTRODUCTION

Fatigue is a common distressing effect of cancer.¹ It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors alike. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”² CRF differs from fatigue reported by individuals without cancer in that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, with estimates ranging between 25% and 99%.^2,3 The methods used for screening patients for fatigue and the characteristics of the patient groups may account for this variability. In this article, we review evaluation of CRF and approaches to its management.

PATHOPHYSIOLOGY

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of multiple mechanisms contributing to fatigue in an individual patient.

CENTRAL NERVOUS SYSTEM DISTURBANCES

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores.⁴ Increased levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF.⁵ However, there is not enough evidence at this time to support central nervous system disturbance as the main factor contributing to fatigue in cancer patients.

CIRCADIAN RHYTHM DYSREGULATION

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways.² Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors.⁶ These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

INHIBITION OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis.⁶ Inhibition of the HPA axis may occur with higher levels of serotonin as well.⁷ The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue.⁸ Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue.²

SKELETAL MUSCLE EFFECT

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction.⁹ ATP infusion improved muscle strength in 1 trial, but this was not confirmed in another trial.^10,11 Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls.¹² This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles.^13,14

PRO-INFLAMMATORY CYTOKINES

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom of fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Levels of interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma.¹⁵ IL-6 was also associated with increased fatigue in breast cancer survivors.¹⁶ Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy.¹⁷ Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients.^18,19 Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients.²⁰ Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF.²¹

 

OTHER HYPOTHESES

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support,²² genetic alterations in the immune pathway,²³ epigenetic changes,²⁴ accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation,²⁵ elevated vascular endothelial growth factor levels,²⁶ and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction¹³ all have been postulated to cause CRF.

EVALUATION AND TREATMENT

Fours steps are involved in the evaluation and treatment of CRF (Figure).

Patients are screened for fatigue as the first step, and those who have fatigue undergo a primary evaluation to assess for potential precipitating causes. The third step is implementation of pharmacologic and nonpharmacologic interventions aimed at alleviating or mitigating fatigue. The fourth step involves reevaluating patients periodically to recognize and manage changes in fatigue levels. A multidisciplinary approach involving nursing, physical therapy, social work, and nutrition is critical in managing fatigue in these patients. Education and counselling of patients and involvement of the family are essential for effective management as well.

SCREENING

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to under-recognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue.² Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials.²⁷ A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF.² This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors.²⁸ The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue.^29,30 The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day.³¹ The 9-item BFI is often used in clinical trials.²⁹ It measures the severity of fatigue over the previous 24 hours and has been validated in patients who do not speak English.³²

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which assesses 5 dimensions of fatigue—general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue—and compares the patient’s results with those of individuals without cancer.^33,34 The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments.³⁵

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales.³⁶ Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic reevaluation, and moderate and severe fatigue need further evaluation and management.³⁷

PRIMARY EVALUATION

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living.³⁷ Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse, which may cause poor sleep and fatigue.

 

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below. 

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels.³⁸ Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or auto-immune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes.³⁹ Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond.⁴⁰ Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL.⁴¹

Sleep disturbance. Poor sleep is common in fatigued cancer survivors.⁴² Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuro­endocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue.⁴³ Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep.⁴⁴ Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep.⁴⁵ Melatonin agonists are approved for insomnia in the United States, but not in Europe.⁴⁶

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men.⁴⁷

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster.⁴⁸ A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating one of these symptoms without addressing other symptoms is not effective.⁴⁹ Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy— such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue.⁵⁰

MANAGEMENT

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time.^51,52 When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients.⁵³

 

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy.⁵⁴ CBT interventions that optimize sleep quality may improve fatigue.⁵⁵ More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF.⁵⁶

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations.⁵⁷ Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship.⁵⁸ Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve their cardiorespiratory fitness, muscle strength, and body composition.⁵⁷ Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended for younger patients as well as for the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors.⁵⁹ In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone.⁶⁰ This effect was also shown in a randomized controlled trial of 160 patients with stage 0 to III breast cancer undergoing radiation therapy.⁶¹ The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits only in the physical fatigue components, but not in the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week.⁶² An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes.⁶³ Patients with comorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy.³⁷ Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life.^64,65 We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training.⁶⁶ Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life.⁶⁷

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors.⁶⁸ In breast cancer patients undergoing chemotherapy, yoga was shown to benefit both physical and cognitive fatigue.⁶⁹ DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF.⁷⁰ More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months.⁷¹ Additional research is needed in this area.

Acupuncture. A randomized controlled trial in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue.⁷² However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue.⁷³ Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done; of the studies that have been done, the results are mixed, and additional research is needed.⁷⁴ Currently, there are not sufficient data to recommend any of these modalities.

 

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF,^75–77 but randomized controlled trials have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of nonpharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment.³⁷

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. Randomized controlled trials of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF.⁷⁸ Likewise, in an analysis of 5 randomized controlled trials, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo.⁷⁹ However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease.⁸⁰ Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically.⁸¹ In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner.⁸² However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment.⁸³ Also, other randomized controlled trials in patients undergoing adjuvant chemotherapy for breast cancer⁸⁴ and patients receiving radiation therapy for brain tumors⁸⁵ failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm.⁸⁶ Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation.⁸⁷ A placebo effect was also noted in patients with multiple myeloma⁸⁸ and patients with primary brain tumors.⁸⁹ In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue.⁹⁰ In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7).⁹¹ This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional randomized controlled trials are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF.³⁷

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines.⁹² In a randomized controlled trial evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo.⁹³ A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo.⁹⁴ Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis.³⁷

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups.⁹⁵

Antidepressants have failed to demonstrate benefit in CRF without depression.⁸ However, if a patient has both fatigue and depression, antidepressants may help.⁹⁶ A selective serotonin receptor inhibitor is recommended as a first-line antidepressant.⁹⁷ Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

 

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF.⁷⁴ The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF.⁹⁸

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo.⁹⁹ Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects.¹⁰⁰ Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

The seed extract of the guarana plant (Paullinia cupana) traditionally has been used as a stimulant. An improvement in fatigue scores was seen with the use of oral guarana (100 mg daily) at the end of 21 days in breast cancer patients receiving chemotherapy.¹⁰¹ Further studies are needed for these results to be generalized and to understand the adverse effects and interaction profile of guarana.

Reevaluation

Patients who have completed cancer treatment must be monitored for fatigue over the long term, as fatigue may exist beyond the period of active treatment. Many studies have shown fatigue in breast cancer survivors, and fatigue has been demonstrated in survivors of colorectal, lung, and prostate cancers as well as myeloproliferative neoplasms.²⁸ Therefore, it is important to screen patients for fatigue during follow-up visits. There are currently no studies evaluating the long-term treatment of fatigue. In our experience, the timing of follow-up depends on the level of fatigue and interventions prescribed. Once fatigue is stabilized to a level with which the patient is able to cope, the time interval for follow-up may be lengthened. Annual visits may suffice in patients with mild fatigue. Follow-up of patients with moderate to severe fatigue depends on the level of fatigue, the ability to cope, choice of treatment, and presence of contributing factors.

CONCLUSION

CRF is a complex condition that places a significant burden on patients and caregivers, resulting in emotional distress, poor functioning, and suffering. Fatigue can occur before, during, and long after cancer treatment. The approach to CRF begins with screening for and educating patients and their caregivers about the symptoms. Many screening scales are available that may be used to follow patients’ progress over time. The evaluation and management of contributing conditions may help improve fatigue. If the fatigue persists, an individualized approach with a combination of nonpharmacologic and pharmacologic approaches should be considered. More research is needed to understand brain signaling pathways, cytokine changes, and genomic changes in cancer patients with fatigue. Though many hypotheses have been proposed, to date there is no biological marker to assess this condition. Biomarker research needs to be advanced to help to identify patients at risk for fatigue. As cytokines have a major role in CRF, targeted therapy to block cytokine pathways may also be explored in the future.

Acknowledgment: The authors thank Bryan Tutt for providing editorial assistance during the writing of this article.

INTRODUCTION

Fatigue is a common distressing effect of cancer.¹ It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors alike. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”² CRF differs from fatigue reported by individuals without cancer in that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, with estimates ranging between 25% and 99%.^2,3 The methods used for screening patients for fatigue and the characteristics of the patient groups may account for this variability. In this article, we review evaluation of CRF and approaches to its management.

PATHOPHYSIOLOGY

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of multiple mechanisms contributing to fatigue in an individual patient.

CENTRAL NERVOUS SYSTEM DISTURBANCES

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores.⁴ Increased levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF.⁵ However, there is not enough evidence at this time to support central nervous system disturbance as the main factor contributing to fatigue in cancer patients.

CIRCADIAN RHYTHM DYSREGULATION

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways.² Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors.⁶ These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

INHIBITION OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis.⁶ Inhibition of the HPA axis may occur with higher levels of serotonin as well.⁷ The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue.⁸ Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue.²

SKELETAL MUSCLE EFFECT

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction.⁹ ATP infusion improved muscle strength in 1 trial, but this was not confirmed in another trial.^10,11 Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls.¹² This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles.^13,14

PRO-INFLAMMATORY CYTOKINES

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom of fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Levels of interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma.¹⁵ IL-6 was also associated with increased fatigue in breast cancer survivors.¹⁶ Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy.¹⁷ Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients.^18,19 Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients.²⁰ Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF.²¹

 

OTHER HYPOTHESES

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support,²² genetic alterations in the immune pathway,²³ epigenetic changes,²⁴ accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation,²⁵ elevated vascular endothelial growth factor levels,²⁶ and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction¹³ all have been postulated to cause CRF.

EVALUATION AND TREATMENT

Fours steps are involved in the evaluation and treatment of CRF (Figure).

Patients are screened for fatigue as the first step, and those who have fatigue undergo a primary evaluation to assess for potential precipitating causes. The third step is implementation of pharmacologic and nonpharmacologic interventions aimed at alleviating or mitigating fatigue. The fourth step involves reevaluating patients periodically to recognize and manage changes in fatigue levels. A multidisciplinary approach involving nursing, physical therapy, social work, and nutrition is critical in managing fatigue in these patients. Education and counselling of patients and involvement of the family are essential for effective management as well.

SCREENING

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to under-recognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue.² Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials.²⁷ A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF.² This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors.²⁸ The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue.^29,30 The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day.³¹ The 9-item BFI is often used in clinical trials.²⁹ It measures the severity of fatigue over the previous 24 hours and has been validated in patients who do not speak English.³²

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which assesses 5 dimensions of fatigue—general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue—and compares the patient’s results with those of individuals without cancer.^33,34 The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments.³⁵

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales.³⁶ Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic reevaluation, and moderate and severe fatigue need further evaluation and management.³⁷

PRIMARY EVALUATION

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living.³⁷ Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse, which may cause poor sleep and fatigue.

 

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below. 

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels.³⁸ Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or auto-immune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes.³⁹ Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond.⁴⁰ Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL.⁴¹

Sleep disturbance. Poor sleep is common in fatigued cancer survivors.⁴² Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuro­endocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue.⁴³ Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep.⁴⁴ Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep.⁴⁵ Melatonin agonists are approved for insomnia in the United States, but not in Europe.⁴⁶

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men.⁴⁷

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster.⁴⁸ A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating one of these symptoms without addressing other symptoms is not effective.⁴⁹ Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy— such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue.⁵⁰

MANAGEMENT

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time.^51,52 When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients.⁵³

 

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy.⁵⁴ CBT interventions that optimize sleep quality may improve fatigue.⁵⁵ More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF.⁵⁶

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations.⁵⁷ Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship.⁵⁸ Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve their cardiorespiratory fitness, muscle strength, and body composition.⁵⁷ Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended for younger patients as well as for the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors.⁵⁹ In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone.⁶⁰ This effect was also shown in a randomized controlled trial of 160 patients with stage 0 to III breast cancer undergoing radiation therapy.⁶¹ The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits only in the physical fatigue components, but not in the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week.⁶² An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes.⁶³ Patients with comorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy.³⁷ Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life.^64,65 We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training.⁶⁶ Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life.⁶⁷

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors.⁶⁸ In breast cancer patients undergoing chemotherapy, yoga was shown to benefit both physical and cognitive fatigue.⁶⁹ DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF.⁷⁰ More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months.⁷¹ Additional research is needed in this area.

Acupuncture. A randomized controlled trial in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue.⁷² However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue.⁷³ Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done; of the studies that have been done, the results are mixed, and additional research is needed.⁷⁴ Currently, there are not sufficient data to recommend any of these modalities.

 

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF,^75–77 but randomized controlled trials have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of nonpharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment.³⁷

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. Randomized controlled trials of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF.⁷⁸ Likewise, in an analysis of 5 randomized controlled trials, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo.⁷⁹ However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease.⁸⁰ Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically.⁸¹ In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner.⁸² However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment.⁸³ Also, other randomized controlled trials in patients undergoing adjuvant chemotherapy for breast cancer⁸⁴ and patients receiving radiation therapy for brain tumors⁸⁵ failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm.⁸⁶ Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation.⁸⁷ A placebo effect was also noted in patients with multiple myeloma⁸⁸ and patients with primary brain tumors.⁸⁹ In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue.⁹⁰ In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7).⁹¹ This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional randomized controlled trials are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF.³⁷

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines.⁹² In a randomized controlled trial evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo.⁹³ A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo.⁹⁴ Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis.³⁷

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups.⁹⁵

Antidepressants have failed to demonstrate benefit in CRF without depression.⁸ However, if a patient has both fatigue and depression, antidepressants may help.⁹⁶ A selective serotonin receptor inhibitor is recommended as a first-line antidepressant.⁹⁷ Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

 

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF.⁷⁴ The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF.⁹⁸

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo.⁹⁹ Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects.¹⁰⁰ Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

The seed extract of the guarana plant (Paullinia cupana) traditionally has been used as a stimulant. An improvement in fatigue scores was seen with the use of oral guarana (100 mg daily) at the end of 21 days in breast cancer patients receiving chemotherapy.¹⁰¹ Further studies are needed for these results to be generalized and to understand the adverse effects and interaction profile of guarana.

Reevaluation

Patients who have completed cancer treatment must be monitored for fatigue over the long term, as fatigue may exist beyond the period of active treatment. Many studies have shown fatigue in breast cancer survivors, and fatigue has been demonstrated in survivors of colorectal, lung, and prostate cancers as well as myeloproliferative neoplasms.²⁸ Therefore, it is important to screen patients for fatigue during follow-up visits. There are currently no studies evaluating the long-term treatment of fatigue. In our experience, the timing of follow-up depends on the level of fatigue and interventions prescribed. Once fatigue is stabilized to a level with which the patient is able to cope, the time interval for follow-up may be lengthened. Annual visits may suffice in patients with mild fatigue. Follow-up of patients with moderate to severe fatigue depends on the level of fatigue, the ability to cope, choice of treatment, and presence of contributing factors.

CONCLUSION

CRF is a complex condition that places a significant burden on patients and caregivers, resulting in emotional distress, poor functioning, and suffering. Fatigue can occur before, during, and long after cancer treatment. The approach to CRF begins with screening for and educating patients and their caregivers about the symptoms. Many screening scales are available that may be used to follow patients’ progress over time. The evaluation and management of contributing conditions may help improve fatigue. If the fatigue persists, an individualized approach with a combination of nonpharmacologic and pharmacologic approaches should be considered. More research is needed to understand brain signaling pathways, cytokine changes, and genomic changes in cancer patients with fatigue. Though many hypotheses have been proposed, to date there is no biological marker to assess this condition. Biomarker research needs to be advanced to help to identify patients at risk for fatigue. As cytokines have a major role in CRF, targeted therapy to block cytokine pathways may also be explored in the future.

Acknowledgment: The authors thank Bryan Tutt for providing editorial assistance during the writing of this article.

 

Recommendations for improved communication between oncologists and their patients are the focus of a new guideline issued by a panel convened by the American Society of Clinical Oncology (ASCO).

The guideline recommends that oncologists establish care goals with each patient, address the costs of care, and initiate discussion of end-of-life preferences early in the course of incurable disease.

Susan London/Frontline Medical News

Training programs that emphasize role playing to develop skills, as well as observation and critique of actual patient interactions need to be available to oncologists at every level. Also, patients should be encouraged to discuss their concerns and to participate in deciding what is discussed during each visit, Timothy D. Gilligan, MD, panel cochair, and other panel members recommend in the guideline (J Clin Oncol. 2017 Sep 11. doi: 10.1200/JCO.2017.75.2311).

Patients also should be made aware of all treatment options, which may include clinical trials and, for certain patients, palliative care alone, the panel recommended.

The ASCO Expert Panel included medical oncologists, psychiatrists, nurses, and experts in hospice and palliative medicine, communication skills, health disparities, and advocacy. Their consensus-based, patient-clinician communication guideline drew on the panel’s systematic evaluation of guidelines, reviews and meta-analyses, and randomized, controlled trials published from 2006 through Oct. 1, 2016.

More specifics on the guideline are available here and feedback can be provided at asco.org/guidelineswiki.

Dr. Gilligan of the Taussig Cancer Institute and the Center for Excellence in Healthcare Communication, Cleveland Clinic, disclosed support from WellPoint; other panel members disclosed various consultancy roles or funding from pharmaceutical companies and CVS Health.

[email protected]

On Twitter @NikolaidesLaura

 

Recommendations for improved communication between oncologists and their patients are the focus of a new guideline issued by a panel convened by the American Society of Clinical Oncology (ASCO).

The guideline recommends that oncologists establish care goals with each patient, address the costs of care, and initiate discussion of end-of-life preferences early in the course of incurable disease.

Susan London/Frontline Medical News

Training programs that emphasize role playing to develop skills, as well as observation and critique of actual patient interactions need to be available to oncologists at every level. Also, patients should be encouraged to discuss their concerns and to participate in deciding what is discussed during each visit, Timothy D. Gilligan, MD, panel cochair, and other panel members recommend in the guideline (J Clin Oncol. 2017 Sep 11. doi: 10.1200/JCO.2017.75.2311).

Patients also should be made aware of all treatment options, which may include clinical trials and, for certain patients, palliative care alone, the panel recommended.

The ASCO Expert Panel included medical oncologists, psychiatrists, nurses, and experts in hospice and palliative medicine, communication skills, health disparities, and advocacy. Their consensus-based, patient-clinician communication guideline drew on the panel’s systematic evaluation of guidelines, reviews and meta-analyses, and randomized, controlled trials published from 2006 through Oct. 1, 2016.

More specifics on the guideline are available here and feedback can be provided at asco.org/guidelineswiki.

Dr. Gilligan of the Taussig Cancer Institute and the Center for Excellence in Healthcare Communication, Cleveland Clinic, disclosed support from WellPoint; other panel members disclosed various consultancy roles or funding from pharmaceutical companies and CVS Health.

[email protected]

On Twitter @NikolaidesLaura

 

Recommendations for improved communication between oncologists and their patients are the focus of a new guideline issued by a panel convened by the American Society of Clinical Oncology (ASCO).

The guideline recommends that oncologists establish care goals with each patient, address the costs of care, and initiate discussion of end-of-life preferences early in the course of incurable disease.

Susan London/Frontline Medical News

Training programs that emphasize role playing to develop skills, as well as observation and critique of actual patient interactions need to be available to oncologists at every level. Also, patients should be encouraged to discuss their concerns and to participate in deciding what is discussed during each visit, Timothy D. Gilligan, MD, panel cochair, and other panel members recommend in the guideline (J Clin Oncol. 2017 Sep 11. doi: 10.1200/JCO.2017.75.2311).

Patients also should be made aware of all treatment options, which may include clinical trials and, for certain patients, palliative care alone, the panel recommended.

The ASCO Expert Panel included medical oncologists, psychiatrists, nurses, and experts in hospice and palliative medicine, communication skills, health disparities, and advocacy. Their consensus-based, patient-clinician communication guideline drew on the panel’s systematic evaluation of guidelines, reviews and meta-analyses, and randomized, controlled trials published from 2006 through Oct. 1, 2016.

More specifics on the guideline are available here and feedback can be provided at asco.org/guidelineswiki.

Dr. Gilligan of the Taussig Cancer Institute and the Center for Excellence in Healthcare Communication, Cleveland Clinic, disclosed support from WellPoint; other panel members disclosed various consultancy roles or funding from pharmaceutical companies and CVS Health.

[email protected]

On Twitter @NikolaidesLaura