Understanding Immunotherapy Late Adverse Effects in Cancer Survivors
Because of the novel mechanisms of action of immunotherapies, extended treatment period, and unique toxicities, cancer treatment with immunotherapy warrants special consideration from a survivorship standpoint, suggested Katy K. Tsai, MD, Clinical Instructor, Division of Hematology/Oncology, University of California, San Francisco (UCSF), at the 2018 Cancer Survivorship Symposium.
“As immunotherapy continues to expand, we really need to be equipped to take better care of these patients,” Dr Tsai said.
Many immunotherapies have been approved in the past 6 to 7 years, and some patients have seen unprecedented results. But with the increase in cancer survival, attention is now being paid to the question of when to stop therapy with these drugs.
“In the past, we either continued therapy until it was too toxic, or until patients had progressive disease,” she said. “So I feel this is a very luxurious question to be asking.”
According to Dr Tsai, the length of optimal treatment can vary from patient to patient, but treatment discontinuation studies and longer follow-up periods are needed before definitive recommendations can be incorporated into survivorship care plans.
“On the one hand, it’s comforting to know that certain patients do achieve durable and complete response, but on the flipside, it raises the question of whether we’re treating for too long and increasing the risk of toxicity,” she said.
Management of Immune-Related Adverse Events
Treatment with checkpoint inhibitors can cause mild to severe immune-related adverse events. Possible mechanisms of toxicity include increased levels of inflammatory cytokines, cross-reactivity between antigens in tumors and healthy normal tissue, and increased levels of preexisting autoantibodies. The target organ can vary, from the more common gastrointestinal and dermatologic, to the slightly less common endocrine and pulmonary, to the rare cardiac and renal toxicities.
“As time has gone on, we really have become quite aware that any organ in the body is at risk of inflammatory side effects,” Dr Tsai said. “We’re past the days of thinking patients only get colitis.”
In terms of first-line defense, glucocorticoids are usually indicated, and the route of administration (eg, topical, oral, or intravenous) and dosage (eg, 0.5 mg/kg; 1-2 mg/kg daily) will depend on the severity of the side effects. “Something to emphasize is that a long taper of 4 to 6 weeks is required,” she cautioned. “With too short a taper, patients will flare up, and then we’re back to square one.”
However, a long period of tapering a steroid comes with side effects of its own, including the possibility for Cushing syndrome, osteoporosis, leg edema, and opportunistic infections; therefore, it is vital that oncologists understand the fundamentals of immunology to knowledgeably deal with these issues.
Patients with side effects that are refractory to glucocorticoids can be carefully considered for additional immunosuppression with treatments such as infliximab (Remicade) or mycophenolate mofetil (CellCept), she added.
Education Is Crucial
All patients and providers on the care team should receive immunotherapy education before, during, and after treatment, either on their own or through educational workshops, Dr Tsai advised. This knowledge can help patients with early reporting of adverse events by recognizing their side effects and preventing long-term morbidity and late or permanent immune-related adverse events. “Identify resources to address those gaps in education,” she suggested.
If left untreated, immune-related adverse events can flare up and result in lasting morbidity, emphasizing the need for cancer survivors who have received immunotherapy to have a point person with access to multidisciplinary care so that referrals can be made in a timely manner.
Dr Tsai and colleagues at UCSF have begun collecting data on new-onset diabetes in patients who received immunotherapy. They found that the time from therapy initiation to the onset of side effects varied from 42 to 252 days.
“So now patients not only have to deal with being on chronic therapies, but also with the very real risk of late-onset immune-related adverse events,” she said.
With a growing number of younger patients receiving immunotherapy, discussion around fertility and family-planning issues is becoming increasingly important.
The National Comprehensive Cancer Network guidelines advise that patients of reproductive age use effective birth control during and for at least 5 months after immunotherapy.
“But I’ve demonstrated how long that course of therapy can be, so as a group we need to get better about talking about these issues,” Dr Tsai said.
To answer the question of whether immunotherapy affects fertility, Dr Tsai and colleagues are launching several prospective studies at UCSF. They are currently collecting semen analyses in men starting immunotherapy and are hoping to add a female cohort once the infrastructure is in place.
To bring attention to the unique needs of cancer survivors who have received immunotherapy, Dr Tsai suggested expanding the collective vernacular to better define this unique cohort of survivors, perhaps calling them “on-treatment responders.”
“These are, for all intents and purposes, survivors, but maybe we need to find a better phrase to capture exactly what they’re going through,” she said.
“People tend to think of survivorship care as something that happens after the discontinuation of therapy,” she observed. “But I think we’re really missing an opportunity to make a big difference in patients on chronic therapy who also need a toolkit to deal with things like fear of recurrence and anxiety, even while continuing their infusions,” she added.