Managing treatment-related toxicities in cancer patients is an important aspect of oncology care. Historically, chemotherapy has been the foundation of therapy for the majority of cancers, and over time oncologists have become adept at identifying and treating these treatment-related adverse events. More recently, targeted therapies directed at inhibition of the MAPK pathway in melanoma have emerged with their own set of toxicities that require a different approach to management.
In the past 5 years, immunotherapies using immune checkpoint inhibitors have become another mainstay of therapy for patients with melanoma, and are becoming important tools in treatment of other solid and hematological malignancies. The challenge of administering immunotherapies safely has been in identifying and learning how to treat immune-mediated toxicities.
Early identification and treatment of toxicities leads to decreased patient morbidity. Studies describing the practice of experienced oncologists in the management of immune-mediated toxicities provide details about the approaches employed to date and their outcomes. What is encouraging is that immune-related toxicities and their treatment do not seem to affect the efficacy of the treatment. Continued evaluation of these patient cohorts will be necessary to determine if the approach to symptom management of immune-mediated toxicities affects long-term survival.
The immune-modulatory therapies are here to stay, and new combination treatments will be introduced -- with increased efficacy, but also with an increased risk of toxicities. Continued education on recognizing and treating these toxicities is needed in order to best serve our patients. Although initially it was feared that treating immune-related toxicities aggressively might lead to disease progression, that does not seem to be the case according to pooled analyses from multiple clinical trials of anti-PD1 therapy with nivolumab or pembrolizumab as well as the institutional experience of patients treated with ipilimumab at Memorial Sloan Kettering Cancer Center. These data are encouraging but require close monitoring for long-term outcomes.
When using immunotherapies and targeted therapies to treat melanoma, oncologists should educate their patients about the potential of adverse events, both specifically what they might be and when they are likely to occur.
"Adverse events are more likely than not to happen. Oncologists should expect adverse events and be prepared to treat them early on so patients can receive the maximum benefit from therapy," said Mario LaCouture, MD, of Memorial Sloan-Kettering Cancer Center (MSKCC), in an interview.
Both targeted therapies with BRAF and MEK inhibitors and immunotherapies with checkpoint inhibitors can have an adverse impact on quality of life, although the impact will be lower than that observed with cytotoxic chemotherapy or older immunotherapies in melanoma, he said.
"The psychosocial impact is not considered significant since patients don't typically lose their hair or develop a rash on the face," although trametinib as a single agent does induce skin rashes. "It's more the functional impact. Targeted therapies, for example, can cause severe fatigue, and oncologists should use fatigue-reducing measures during treatment."
Management of adverse events due to targeted therapies should be tailored to the symptom. Patients taking BRAF inhibitors may develop dry, thick skin that needs frequent application of moisturizers containing an exfoliant, such as salicylic acid. "For diarrhea, use anti-motility agents and also provide counseling from a nutritionist or dietitian," LaCouture said.
For fatigue, exercise is important as well as a referral to a physical medicine or rehabilitation specialist. Oral corticosteroids and psychostimulants, such as methylphenidate, may also help.
With immunotherapies, the most common adverse events are cutaneous (rash, itching) and gastrointestinal (diarrhea, nausea, vomiting, and liver enzyme elevations), as well as inflammation of the lungs and fatigue, and arthralgia.
Fatigue from immunotherapy may be treated with exercise, psychostimulants, or corticosteroids. For rash and pruritus, prescribe oral and topic corticosteroids and antihistamines. Patients with diarrhea or colitis first need an imaging study. "If a patient has abdominal pain or blood in the stool, rule out infections by doing a stool panel. Treat with oral steroids or tumor necrosis factor alpha (TNFα) inhibitors, such as infliximab, for two cycles," LaCouture said, noting that prophylactic budesonide shows no benefit.
Patients with hepatitis should stop therapy and have an imaging study. "Give oral corticosteroids for more than three weeks, and mycophenolate mofetil if that doesn't work. Do not use infliximab for autoimmune hepatitis, because it also causes liver toxicity."
Pneumonitis may develop in melanoma patients at a higher incidence if they have lung cancer and take combination immunotherapies, he said. Perform imaging to exclude infections, and then provide oral corticosteroids, mycophenolate mofetil, infliximab, or cyclophosphamide. "These patients have a low threshold for hospitalization. They can decompensate quickly if their breathing is impaired," he said.
"Immunotherapy should be held for moderate to severe pneumonitis, or hepatitis, diarrhea, or colitis. These drugs have a long half-life. You need to control these events before re-administering the drugs."
Practitioners should be prepared to treat immune-related adverse events, LaCouture continued. A recent study of melanoma patients treated with ipilimumab at MSKCC found that about one-third needed systemic corticosteroids, and almost one-third of those required further immune suppression with anti-TNFα therapy.
The good news is that "new immunotherapies do not affect clinical outcome," he said. A pooled analysis of four ongoing trials of nivolumab in advanced melanoma found that nearly all drug-related grade 3-4 select adverse events (i.e., those of immune-related etiology) resolved with the use of immune-modulating agents, which did not appear to have an impact on tumor response.
Some adverse events correlate with outcome, he noted: Melanoma patients treated with nivolumab who develop rash and vitiligo may have increased survival. "Knowing that adverse events correlate with survival helps patients cope. Treating adverse events will not negatively affect outcome."
Adverse events will likely increase in the future with more use of combination immunotherapies. The silver lining is that two-thirds of patients who stop combination immunotherapy appear to respond to the drugs.
LaCouture emphasized that patients should know the timeline of adverse events. Typically, dermatologic adverse events occur after 5 weeks of therapy, gastrointestinal events at weeks 7 to 8, and pulmonary and endocrine events at week 10. "Tell patients honestly that these treatments are effective, but that they should expect to experience some adverse events. Knowing what to expect will make it easier to cope."
To not overwhelm patients, though, he suggests rationing information about when adverse events are likely to occur, near the timeline of an event rather than mentioning all the possible problems at once.
In conclusion, LaCouture said: "The earlier we treat adverse events, the better. Patients should be evaluated thoroughly at every visit. Both practitioners and patients should know when to expect events so they can be ready for them."
LaCouture disclosed relationships with Quintiles, Boehringer Ingelheim, AstraZeneca Pharmaceuticals, Dignitana, Genentech, Foamix, Janssen R&D, Michael's Mission, Novartis, Oncology Training International (OTI), RP Pharmaceuticals, Berg, Roche, and Bristol-Myers Squibb.