The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have released new guidelines designed to help clinicians manage the unique and sometimes severe side effects associated with cancer immunotherapy agents.

These guidelines meet a growing need to help practicing clinicians identify and best manage immune-related adverse events, according to Bryan J. Schneider, MD, of the University of Michigan Comprehensive Cancer Center, and vice chair of the NCCN Panel on Management of Immunotherapy-Related Toxicities.

“The mechanism of action of these anticancer therapies is so much different from anything that we’re used to,” Dr. Schneider said in an interview.

“We’re experienced with chemotherapy, and we are very comfortable with the side effects,” he said. “The immunotherapy story is just an entirely different world because, as I tell patients, the therapies aren’t directly damaging cancer cells like chemotherapy. Instead, they are helping the immune system to identify the cancer cells as abnormal and mount an assault. Proteins on cancer cells may suppress the immune response and these therapies effectively ‘release these brakes’ so the immune system can attack.”

Critical need for guidance

The ASCO and NCCN guidelines are “critically important” to ensure uniform management of common immune-related adverse events, according to Stephen M. Ansell, MD, PhD, professor of medicine and chair of the Lymphoma Group at Mayo Clinic, Rochester, Minn.

“I think it also specifically highlights a few side effects that many people may not necessarily think about, from eye toxicities to thyroid effects, or the type of things that the average oncologist who is now using this in their practice quite regularly may not necessarily think about,” Dr. Ansell said. “Those kind of effects are now clearly outlined with clear guidance about what should be done, and I think that allows oncologists a resource to go and look at this carefully so that they do the right thing.”

The spectrum of adverse effects associated with checkpoint inhibitors is markedly different from what is seen with cytotoxic chemotherapy, the guidelines note. Most often, the side effects are seen in the skin, GI tract, and lungs, as well as the endocrine, adrenal, nervous, thyroid, pituitary, musculoskeletal, cardiovascular, ocular, and hematologic systems.

Stepwise approach

Side effects of checkpoint inhibitors are typically mild, but they can be severe and sometimes life-threatening, according to ASCO and NCCN.

If immune-related adverse events are mild (i.e., grade 1), treatment can continue with close monitoring, according to the guidelines. By contrast, moderate to severe immune-related adverse events can lead to severe declines in organ function and quality of life, or even fatal outcomes, so early detection and proper management are needed.

Grade 2 toxicities warrant suspending immune checkpoint inhibitor treatment, and resuming it once symptoms subside to grade 1 or less, according to the guidelines. Grade 3 toxicities should also prompt suspension of treatment, plus initiation of high-dose corticosteroids tapered over at least 4-6 weeks.

For most toxicities that reach grade 4, permanent discontinuation of checkpoint inhibitors is recommended.

A thoughtful discussion of potential risks and benefits is needed before using immune checkpoint inhibitors in patients who have autoimmune disease or prior organ transplant, according to the guidelines.

Vigilance required

Checkpoint inhibitors have been approved by the Food and Drug Administration to treat a variety of cancers, including melanoma, lung cancer, and Hodgkin lymphoma, as well as lung, liver, kidney, and bladder cancers.

Clinicians managing patients on checkpoint inhibitors should always be vigilant because immune-related adverse event symptoms can be subtle, according to Julie Brahmer, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore.

“Everyone has to work as a team, which includes being educated on possible side effects to immunotherapy prior to prescribing it,” said Dr. Brahmer, chair of the ASCO panel and vice chair of the NCCN panel that developed the guidelines.

The guidelines were published Feb. 14 in two documents that are similar in content, but different in format. The ASCO guideline was published in the Journal of Clinical Oncology (doi: 10.1200/JCO.2017.77.6385) and the NCCN Clinical Practice Guidelines in Oncology were posted on the NCCN website.

While the first edition of the guidelines focuses specifically on immune checkpoint inhibitors, an update anticipated for 2019 will include guidance on chimeric antigen receptor (CAR) T-cell therapy, which is associated with several important side effects, notably cytokine release syndrome.

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Cancer groups offer guidance on immune-related adverse events