Chronic, late effects of cancer treatment: The consequences of a cure
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Substantial improvements in cancer treatment during the past several decades are an unequivocal victory for oncology — making long-term survival a reality for many patients.
As more cancer survivors look forward to full life spans, they face the increased possibility of chronic comorbidities and long-term treatment effects. Because these effects may not emerge until years after completion of treatment, the responsibility for detecting and managing them ultimately may lie with primary care physicians or other specialists.
Additionally, as the number of long-term survivors continues to increase, the oncology workforce may not be sufficient to keep up with the needs of this population.
“Oncology is a bit of a diminishing profession — we’ve got a whole group of excellent oncologists who are near retirement age, and not many new physicians are moving into the oncological realm,” Balazs Bodai, MD, director of the breast cancer survivorship institute at Kaiser Permanente Health, said in an interview with Healio. “Oncologists who used to follow their patients forever can’t follow them anymore because there are just too many people. So, the burden is going to fall on the primary care doctors to pick up the slack in the long-term management of these patients.”
Chronic effects vs. late effects
In some cases, adverse events associated with various cancer treatments become apparent immediately and persist throughout treatment. Other effects may last beyond treatment, and some may not emerge until months or years later.
“Chronic effects of cancer therapy are those problems that were present during primary cancer treatment and continue in the posttreatment period,” Catherine M. Alfano, PhD, vice president of survivorship at the American Cancer Society, told Healio. “A late effect is something that was not present while treatment was going on, like during chemotherapy or radiation, but pops up seemingly out of nowhere a few years, even 10 years later.”
Alfano cited fatigue as a common chronic effect, as well as the psychosocial implications of battling and surviving cancer.
“There is a lot of what we call fear of recurrence, which is a certain kind of anxiety,” she said. “A lot of patients call it ‘scanxiety,’ because it involves excess anxiety around the time of their scans or their diagnosis anniversary.”
Other chronic effects may include pain symptoms, lymphedema and cognitive issues such as memory problems, Alfano said.
“Chemotherapy can also cause neuropathy in the hands and feet, which can lead to numbness and tingling,” she said. “Usually, this is present during treatment and continues, so it can be a chronic effect. Sometimes it is a late effect.”
Survivors also may experience late effects such as cardiotoxicities (damage to the cardiovascular system), bone loss and reproductive issues, such as infertility, according to Alfano. She said the type of late effect often is dependent on the cancer treatment modality.
“There are effects common to chemotherapy agents, certain kinds of radiation or, in some cases, certain kinds of immunotherapy or targeted hormonal agents,” Alfano said.
Who should manage cases?
When it comes to who should be responsible for identifying and treating chronic and/or late effects of cancer treatments, Alfano said there is no simple answer. She noted that due to the current shortage of oncologists, PCPs frequently find themselves faced with the prospect of handling these cases. However, she said they generally are not trained to diagnose and manage late effects of cancer treatments.
She said special clinics have been developed specifically for cancer survivors.
“We’re now seeing these hybrid clinics popping up in some areas of the United States,” Alfano said. “They might be called survivorship care clinics or cancer follow-up clinics. Sometimes, they’re staffed by an advanced practice provider, like a physician’s assistant or nurse practitioner. Sometimes, it’s a special kind of internal medicine doctor or an oncologist. It depends on the model. We don’t have any good statistics on this, but most patients probably don’t have access to these clinics yet.”
Although survivorship may not be part of standard training for PCPs, some have extensive knowledge of how to manage cancer survivors.
Larissa Nekhlyudov, MD, MPH, associate professor in the department of medicine at Harvard Medical School and a practicing internist at Brigham and Women’s Hospital, also serves as clinical director of internal medicine in the David B. Perini Jr. Quality of Life Clinic at Dana-Farber Cancer Institute. There, she provides consultative clinical care for long-term survivors of childhood and adolescent cancers.
In an interview with Healio, Nekhlyudov discussed some basic steps clinicians can take to heighten their awareness of potential cancer treatment effects.
“A primary care provider has to be aware of the patient’s cancer history; that needs to be front and center,” Nekhlyudov said. “It has to be in the chart, on the problem list: history of breast cancer, history of Hodgkin lymphoma, history of testicular cancer. Often, a long-term survivor may not bring up their history, or they will assume it’s in the chart.”
Nekhlyudov discussed the ways in which PCPs should make a differential diagnosis based on knowledge of a patient’s cancer and treatment background. She pointed out that the treatment modality provides important clues as to whether the patient’s symptom may be associated with the treatment.
For example, in the case of a woman 40 years old who presents with chest pain, the clinician should consider whether the woman previously underwent cardiotoxic chemotherapy or radiation for a cancer such as Hodgkin lymphoma.
“In that case, we would need to consider potential heart disease including blood vessel occlusion or cardiomyopathy,” she said. “However, we also have to think about the treatment exposures: if the radiation field was to the hip, then cardiovascular disease is not going to be at the top of your list.”
She said there are several ways PCPs can increase their knowledge and diagnostic skills related to late effects of cancer treatments.
“There are resources out there, including CME programs,” Nekhlyudov said. “There are definitely ways that a primary care provider can gain some basic understanding of the potential late effects.”
Cardiovascular effects: Common and dangerous
Of the various late effects that cancer survivors may experience, cardiovascular effects are among the most common and most serious. According to Javid J. Moslehi, MD, associate professor of medicine in the division of cardiovascular medicine at Vanderbilt University Medical Center, cardiovascular late effects may include heart failure, arrhythmia, pulmonary hypertension, claudication, myocardial infarction, stroke and more.
“There is a broad range of cardiovascular diseases, and one symptom could mean many things,” Moslehi said in an interview with Healio. “This issue is further complicated by the various traditional and novel therapies that lead to diverse pathophysiological processes.”
Traditional chemotherapies such as anthracyclines have been associated with cardiomyopathy, whereas new kinase inhibitors, such as nilotinib (Tasigna, Novartis) — used for certain leukemias — are associated with long-term vascular disease.
In 2016, Moslehi and colleagues described fulminant myocarditis (severe inflammation of the heart) after treatment with immune checkpoint inhibitors — arguably the most revolutionary class of novel cancer therapies — in certain patients. Although these cases often were deadly, they were fortunately infrequent.
“To better understand what was essentially a new clinical syndrome, we started a web-based platform, www.cardioonc.org, to collect cases from around the world,” Moslehi said. Soon, his group showed more cases of myocarditis that was less severe. “What happens long-term to these smoldering cases of myocarditis is incompletely unclear,” he said.
Moslehi’s group has applied for an NIH grant to better characterize long-term cardiovascular effects of cancer immunotherapies.
Cardiotoxicities can depend upon how the patient was treated, whether with certain types of chemotherapy or radiation, or certain kinds of immunotherapy or targeted hormonal agents, according to Alfano. “The classic example we’ve been studying is anthracyclines and trastuzumab. That combination can really do a double whammy on the cardiac system,” she said.
According to Bodai, who regularly treats patients with breast cancer, doxorubicin also is known to have profound cardiotoxic effects. This chemotherapy has been associated with sinus tachycardia, tachyarrhythmia, ventricular tachycardia, bradycardia, bundle branch occlusion and congestive heart failure.
Bodai noted that radiation also can have cardiotoxic effects; even radiation targeted to the right breast could reach the left side, which in turn could reach the heart.
“We have to keep in mind that heart disease is actually the No. 1 killer of women in the United States, not breast cancer,” Bodai said. “Heart disease kills three to five times as many women every year. We’re doing a very, very good job curing breast cancer, but it comes at a little bit of a cost.”
The breadth of cardiovascular issues that a cancer survivor may experience presents a challenge for the treating clinician, whether it is the patient’s oncologist or the PCP, according to Moslehi. At Vanderbilt, Moslehi and his group developed an “ABCDE” algorithm for the prevention and early detection of cardiovascular disease among cancer survivors.
“This checklist will simplify and standardize established preventive guidelines for all cancer survivors,” he said.
The guidelines, released by the National Comprehensive Cancer Network at the end of March, specify that cancer survivors should be counseled on and assessed for cardiovascular risks; be treated with aspirin if appropriate; have their blood pressure and cholesterol assessed and monitored; participate in a discussion of smoking cessation, diet and weight management, diabetes prevention and management, and exercise; and be evaluated with an echocardiogram or EKG.
“This will be relevant to all physicians, including primary care doctors, across the country, not just cardio-oncologists,” Moslehi said.
Effects of immunotherapy: Mild to life-threatening
Although chemotherapy, radiation and bone marrow transplantation are the modalities most frequently linked to cancer treatment toxicities, researchers are learning more about the effects of newer treatments, such as immunotherapies. These drugs, which have transformed the treatment of various types of cancer, have been associated with a variety of adverse events that can occur in most organs in the body.
“Checkpoints in the immune system, in their normal state, attenuate T-cell responses and turn off T-cell activation,” Cassandra Calabrese, DO, a rheumatologist affiliated with Cleveland Clinic, told Healio. “These are being blocked by these drugs, so that the immune response remains activated and revs up to target the tumor. Unfortunately, the revved-up immune system can target healthy tissue, as well, and cause untoward off-target autoimmune and inflammatory side effects.”
These effects, known as immune-related adverse events (IRAEs), can emerge at any point from the first cancer treatment infusion to years later. Calabrese said rheumatologic IRAEs often include joint and muscle pain, joint swelling and inflammation. However, some IRAEs are almost indistinguishable from other common autoimmune conditions.
“For example, we see patients develop something that looks like rheumatoid arthritis, although usually without the traditional autoantibodies that we see in de novo rheumatoid arthritis,” Calabrese said.
Other IRAEs Calabrese sees include myositis, polymyalgia rheumatica and vasculitis. “As a rheumatologist, I most commonly see patients who develop joint inflammation, but IRAEs have been described to affect essentially every organ and range from mild and self-limiting to severe and life-threatening,” she said.
In terms of making a differential diagnosis, Calabrese said knowledge of a patient’s immunotherapy treatment often makes this distinction clear.
“The vast majority of these patients come to me from oncology,” she said. “If these patients are taking these drugs, they’re seeing their oncologist very frequently, and it will usually be the oncologist who reaches out to me.”
Calabrese said she typically manages these patients with mild to moderate doses of prednisone upfront, but that many will require a steroid-sparing agent. She said there has been a shift from higher doses of prednisone over longer durations to more targeted treatment regimens.
“My goal is to enable the patient to continue their cancer treatment,” Calabrese said. “If their side effects are severe or life-threatening, then they might have to stop their cancer treatment. So, I see patients whose treatment is on hold or I comanage patients who are still getting their cancer treatments.”
Pediatric endocrine late effects
Children undergoing cancer treatment are among the most vulnerable patients, and they have the longest duration of survivorship ahead of them. For this reason, it is especially important to consider the long-term impact of cancer treatments in this unique population.
“Every pediatric patient should be considered a survivor, even as early as the time of cancer diagnosis; hence, it is essential to consider the many years of late effects that they will have to face,” Sogol Mostoufi-Moab, MD, MSCE, a dual-certified pediatric oncologist and endocrinologist who serves as director of the Endocrine Late Effects after Childhood Cancer Therapy Program at Children’s Hospital of Philadelphia, said in an interview with Healio. “That’s the essential part of how we approach treating a pediatric patient and an important lesson to consider.”
Mostoufi-Moab noted that cranial radiation, once a common treatment for the majority of children with acute lymphoblastic leukemia, results in numerous cognitive, endocrine and metabolic late effects that compromise survivors’ quality of life.
“Given the marked learning disabilities as well as pituitary deficits as a result of cranial radiation, even with low doses in young patients, we have come to understand the importance of a risk stratification treatment approach in pediatric oncology, as not every patient with acute lymphoblastic leukemia requires cranial radiation to achieve successful cure,” Mostoufi-Moab said.
Mostoufi-Moab considers the specific circumstances of a patient’s treatment regimen when deciding how to manage a case. She said she factors in the patient’s age at diagnosis and at the time of treatment, the type of treatment modality (ie, chemotherapy or radiation), and treatment factors such as tumor location, radiation dose, radiation modality or type of chemotherapy (ie, alkylating chemotherapy).
“Understanding these factors is critical to recognize and anticipate the spectrum of late effects that can present over years,” Mostoufi-Moab said. “For example, if a patient received high-dose alkylating chemotherapy, this may cause gonadal dysfunction.”
A child aged 4 years with relapsed acute leukemia who requires a bone marrow transplantation and receives total-body irradiation as part of the transplant conditioning regimen “can experience suboptimal growth due to growth hormone deficiency,” she said. Similarly, the chemotherapy for the transplant may result in ovarian damage impacting pubertal development.
On the other hand, a post-pubertal patient aged 16 years undergoing a similar regimen “would be at significant risk for acute ovarian failure and cessation of menses,” Mostoufi-Moab said. “This adolescent should receive ovarian hormone replacement promptly to prevent long-term consequences of gonadal hormone deficiency such as reduced bone accrual resulting in lifetime skeletal fragility, as well as cardiovascular implications of long-term estrogen deficiency.”
Mostoufi-Moab said she feels a responsibility for her patients as she helps shepherd them through diagnosis, treatment and survivorship. She emphasized the importance of health care benefits to protect this vulnerable population.
“We must ensure that health care benefits continue for all childhood survivors of cancer as they reach adulthood,” she said. “I worry about what might happen to these children once they age out of their parents’ insurance. What happens if the health care system changes and these patients are denied coverage due to preexisting condition? That worry is enough to keep me up at night.” – by Jennifer Byrne
- Reference:
- Salem JE, et al. J Am Coll Cardiol. 2019;doi:10.1016/j.jacc.2019.07.056.
- For more information:
- Catherine M. Alfano, PhD, can be reached at: catherine.alfano@cancer.org.
- Balazs Bodai, MD, can be reached at: balazs.bodai@kp.org.
- Cassandra Calabrese, DO, can be reached at: calabrc@ccf.org.
- Javid J. Moslehi, MD, can be reached at javid.moslehi@vanderbilt.edu.
- Sogol Mostoufi-Moab, MD, MSCE, can be reached at: moab@email.chop.edu.
- Larissa Nekhlyudov, MD, MPH, can be reached at: larissa_nekhlyudov@dfci.harvard.edu.
Disclosures: Nekhlyudov reports serving as an editor for UpToDate. Alfano, Bodai, Mostoufi-Moab and Nekhlyudov report no relevant financial disclosures. Moslehi reports serving on advisory boards for Novartis, BMS, Pfizer, Takeda, AstraZeneca, Nektar, Glaxo-Smith Kline and Regeneron.
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