“Immunotherapy has a completely different side-effect profile than chemotherapy, and that has caught physicians off guard,” noted Drew Pardoll, MD, PhD, in an article published earlier this year in The Washington Post.1 Since then, efforts have moved forward on several fronts to bring physicians, as well as patients, up to speed on immunotherapy and particularly immune checkpoint inhibitors.
On the national front, there is the recent release of guidelines jointly developed by ASCO and the National Comprehensive Cancer Network® (NCCN®) to assist clinicians in assessing and managing the side effects of checkpoint inhibitors.2,3 At the institutional level, Dr. Pardoll, who is Director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University and Co-Director of the Cancer Immunology Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, reported continued progress in the development of a multidisciplinary approach to understanding and managing immunotherapy toxicities.
The bottom line is that the physicians and the patients have to partner.— Drew Pardoll, MD, PhD
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On the all-important physician-patient level, “The bottom line is that the physicians and the patients have to partner,” Dr. Pardoll said, and that is happening, too. While the side effects of checkpoint inhibitors are usually mild, they are sometimes severe and can be life-threatening if not identified, reported, and managed promptly.
“If you have the right relationship between the physician and the patient, and the patient feels engaged, the patient leaves the office knowing what to look for and knowing when to immediately go to the emergency room,” Dr. Pardoll said in an interview with The ASCO Post. Patients being treated with immunotherapy at Johns Hopkins receive wallet-sized cards they can use to inform ER staff they are receiving immunotherapy and asking them to contact their oncologist.
Most Common Side Effects
“Immunotherapy-related side effects can occur at any time and can affect any organ,” according to the ASCO announcement of the guidelines for managing adverse events associated with checkpoint inhibitors.2 “The most common side effects are rash, diarrhea, low thyroid hormone levels, and fatigue, but they can also include inflammation of the lung, intestines, or liver; hormonal abnormalities; and kidney, heart, or neurologic problems.”
“Pneumonitis is the one we worry about the most because of its potential lethality,” Dr. Pardoll said. Another relatively common adverse event, affecting about 5% of patients receiving checkpoint inhibitor therapy, is temporary endocrine involvement, he noted. The thyroid is the most commonly involved organ, “but it can involve other endocrine organs as well. Those effects are all manageable by the appropriate hormone replacement, particularly if you taper down. As long as you are aware of these adverse events and are testing, for example, thyroid function, then they are pretty easily managed by hormone manipulation.”
Clinicians and researchers are still trying to understand why particular side effects occur and how to predict which systems are going to be affected, because those effects “are amazingly diverse among different patients,” Dr. Pardoll stated. “We are all responsible—physician, patient, family members—to make sure the consequences of side effects are minimized as much as possible, so the benefits can be maximized.”
Rapid Communication Is Essential
Stefanie Joho, a health advocate and consultant based in Philadelphia, corroborates Dr. Pardoll’s emphasis on the importance of the physician-patient relationship in managing the side effects of immunotherapy. Now 27 years old, Ms. Joho was diagnosed with metastatic colon cancer at age 22. Despite treatment with two surgeries, FOLFOX (leucovorin, fluorouracil [5-FU], and oxaliplatin), and FOLFIRI (leucovorin, 5-FU, and irinotecan), the cancer progressed, and she was then told it was inoperable.
Patients should understand that doctors need our feedback constantly, and that science and medicine do not advance without us.— Stefanie Joho
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She enrolled in a clinical trial (see sidebar, “The Clinical Significance of ClinicalTrials.gov”) and, Dr. Pardoll said, “was basically cured of her metastatic colon cancer by pembrolizumab (Keytruda) in the very first Johns Hopkins trial of the agent.” The trial was evaluating pembrolizumab for patients with unresectable or metastatic, microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors that had progressed despite prior treatment, and Ms. Joho had MSI-H colon cancer.
Ms. Joho was quick to report any side effects and would receive a response back by e-mail, text, or phone within 5 minutes, she said. “I don’t think many patients appreciate that some of these side effects need to be identified and mitigated within 24 hours. Your life could suddenly be at risk because these toxicities can be a little quiet in the beginning. It’s critical that patients, and their care partners, report any changes—even ones they don’t believe to be of significance. That was made crystal clear before I even started immunotherapy,” she noted.
‘I Knew Something Was Happening’
While on the trial, Ms. Joho received treatment every 2 weeks at Johns Hopkins. “Within 3 days after my first infusion, I started feeling relief from my back pain, which had been relentless,” despite treatment with painkillers for over a year. “I knew something was happening,” she said. She developed hypothyroidism and also had to be hospitalized for what turned out, at the time, to be unrecognized opiate withdrawal as a result of her needing less pain medication as her cancer responded to the immunotherapy. “I really couldn’t get out of bed. So I was thinking the thing that was going to save my life is going to kill me,” Ms. Joho said.
“After things calmed down, I was able to resume the treatment,” Ms. Joho said, and was assured she would start feeling better. “Sure enough, I did. Within 3 months, my tumor had shrunk by 65%, and within about a year, there was no evidence of disease in my body.” Her latest scan, performed last month, was clear.
Even when immunotherapy is stopped, the side effects don’t necessarily vanish. “I have a wonderful life. I feel incredible, but I would be lying if I said that it comes at zero cost,” Ms. Joho acknowledged. “There are things I deal with on a daily basis, just because my body is constantly under surveillance by my immune system.” She reported that she has chronic joint pain in her knees and chronic fatigue but is “totally fine” with the tradeoff of minor side effects in exchange for being alive and overall leads “a very normal life.”
Dr. Pardoll noted that in clinical trials with checkpoint inhibitors, patients “are on the drug for only about 2 years, because once you retrain the immune system, then the patient is doing all the work.”
Impediments to Reporting
Dr. Pardoll said the main reason patients sometimes fail to report immunotherapy side effects is the feeling that they don’t want to bother their doctor.
“It is definitely something we encounter in clinical practice,” agreed Jarushka Naidoo, MBBCh, Assistant Professor of Oncology at Sidney Kimmel Comprehensive Cancer Center. “There is a general perception that immunotherapy is safe, tolerable, and in some ways, natural, because we all have an immune system. However, these treatments do have side effects that are distinct from the side effects that occur with chemotherapy, radiation therapy, and other standard anticancer agents.”
Ms. Joho stressed that reporting side effects to physicians is not a bother to them. “That is a notion that needs to be corrected, because your life could depend on it,” Ms. Joho said. “Of course physicians want to know.” Oncologists need the help of patients to figure out how best to use immunotherapy and identify and manage the side effects, Ms. Joho added. “Collaboration is critical.”
Another concern is that patients may be downplaying the side effects or complications of immunotherapy because they fear being removed from a clinical trial. To help allay those fears, Dr. Pardoll said, “physicians can explain upfront that in many cases, the drug may be stopped for a period of time, to let patients get over their side effects, and resumed later.”
He continued: “The [beneficial] effects of the antibodies don’t wear off until 2 to 3 months after the antibody is stopped. So, you can stop the antibodies to manage the side effects, but the immune-enhancing effects of the antibodies will continue. Patients should be made to feel comfortable that they are not harming themselves in being ‘thrown off a trial’ by reporting side effects early on. The more that physicians learn about side effects, the more they can tailor their conversations with patients so these sorts of misperceptions don’t occur.”
Overcoming the Impediments
Overcoming impediments to the effective management of immunotherapy side effects is “a work in progress,” Dr. Pardoll said. “Physicians absolutely have to keep up to date on these issues because the frequency and number of patients using checkpoint inhibitors are going up astronomically. Certainly, we want to see as steep a learning curve as possible.”
Laura Cappelli, MD
Dr. Naidoo is leading the effort at the Bloomberg~Kimmel Institute for Cancer Immunotherapy to improve our understanding of the mechanisms and management of immune-related side effects, as well as educate physicians and other health professionals about the side effects of immunotherapy to optimize toxicity management algorithms and policies. The Johns Hopkins Immune-Related Toxicity Team is a novel multidisciplinary group of oncology providers and medicine subspecialists that functions as a central service “to assist providers in diagnosingand managing complex immune-related toxicities, which can be challenging to identify and then treat,” Dr. Naidoo said.
“To our knowledge, we are the first formal, cross-disciplinary team that has been established focused on this issue,” she said. The team consists of 8 medical oncologists, 4 oncology nursing specialists, and more than 20 medicine specialists and is chaired by Dr. Naidoo and Laura Cappelli, MD, a rheumatologist and Assistant Professor of Medicine at Johns Hopkins.
The side effects of immunotherapy are often “well-known conditions that medicine subspecialists diagnose and manage, occurring outside of the context of immunotherapy,” Dr. Naidoo explained. “Autoimmune conditions are a well-established group of conditions, and rheumatologists and other related specialists are important in guiding their diagnosis and management. In the cae of autoimmunity that occurs from immunotherapy, this ideally would occur alongside oncologic management.”
During the pilot phase and continuing development of the Immune-Related Toxicity Team program, several immunotherapy toxicities emerged as the most common or troubling. “Before we started collaborating, the phenomenon of inflammatory arthritis as a side effect of immunotherapy was not fully appreciated,” Dr. Naidoo said. “We were one of the first groups to describe this phenomenon, delineate relevant subtypes, and propose an algorithm for diagnosis and management,” she said.
Go-to Person for Each Discipline
“It is not just rheumatologists who need to be involved,” Dr. Naidoo explained. Other immune-related toxicities, such as pneumonitis or encephalitis, can affect other organ systems in the body. It is essential to have a go-to person within each medical discipline who has seen a critical mass of patients with these side effects and has experience and knowledge about how to diagnose and manage these side effects, with the goal of providing subspecialist input when required, alongside the treating oncologist.”
The team holds regular meetings, “to discuss complex cases, summarize the educational pearls, identify growing and nuanced service needs, and discuss emerging data regarding optimal diagnostic evaluation and management of these cases,” Dr. Naidoo said. “This kind of forum allows us to identify patients who may be developing multiple immune side effects.”
Team members are also developing content for a health professional section on immunotherapy toxicities that will be available on the Bloomberg~Kimmel Institute for Cancer Immunotherapy website. In addition, the team will be strengthened by the addition of Ms. Joho as a patient advocate, to provide a patient’s perspective to educational materials, and other relevant resources.
Ms. Joho, who said she “took the opportunity of being a patient to educate myself,” is now sharing what she has learned with other patients by developing the section of the website “geared toward patients, their partners, and their families—people who really want to understand what is going on with immunotherapy, how the side effects differ from those of other cancer treatments, and how to navigate this world. This is a unique thing that I believe I can contribute,” she said, having been through numerous treatments and procedures at several different institutions.
“I feel a sense of mission to educate and empower patients,” Ms. Joho said. “It is about patients understanding that they are at the helm and leading the ship with their oncologist. It is about that teamwork. That message is so important in the side-effects conversation, because it can be life-saving,” she said. “Patients should understand that doctors need our feedback constantly, and that science and medicine do not advance without us.”
Major components of the website, expected to be up and running later this year, will include videos. “It is important to show patients and doctors in conversation with one another,” Ms. Joho said. “One of the wonderful experiences I had as a patient at Hopkins was really feeling like a partner and being able to bounce ideas off my doctor. I know that is not a situation unique to me, but I think highlighting how it can happen is important,” she said.
“The videos could show patients discussing options or coming to their physician and talking about side effects they have experienced or questions they have,” Ms. Joho said. The goal is to enable patients to approach dialogues with their physicians “in as productive a way as possible, arming patients with information and education so they can walk into that appointment and make it a productive 15, 20, or 30 minutes.”
In addition to the videos, there will be printable or downloadable information. “One of the downloadable PDFs is going to be a glossary of immunology or immunotherapy terms, so we are all speaking the same language,” Ms. Joho commented. ■
DISCLOSURE: Dr. Naidoo and Ms. Joho reported no conflicts of interest.
3. Brahmer JR, Lacchetti C, Schneider BJ, et al: The management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline and NCCN Guidelines for Management of Immunotherapy-Related Toxicities. J Clin Oncol. February 14, 2018 (early release online).
Jarushka Naidoo, MBBCh
Clifford A. Hudis, MD, FACP, FASCO
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