Immunotherapy has changed the face of cancer care, especially for patients with advanced or metastatic (spreading) cancer by using the patient’s immune system. The immune system produces antibodies as a way of attacking anything that is threatening to the body. Drugs called monoclonal antibodies have been designed to flag the cancer cells to the immune system to attack them. Many such drugs are now available for the treatment of different cancers.
Immune Checkpoint Inhibitors
The PD-1/PD-L1 and CTLA-4 pathways are immune checkpoints that help cancer cells evade an attack from the immune system. In the past decade, new drugs known as immune checkpoint inhibitors have been approved for the treatment of patients with cancers expressing high levels of PD-1/PD-L1.
These drugs have greatly improved survival, but the enthusiasm for the power of these drugs must be balanced with the realization that the power of immunotherapy, especially the immune checkpoint inhibitors, to activate T-cells to attack the cancer can also cause the immune system to overact and lead to new side effects.
Although the side effects associated with immunotherapy are generally easy to manage, occasionally they can be fatal. Therefore, they should be treated without delay, according to Stephanie Andrews, MS, ANP-BC, a hospitalist specializing in medical oncology at the Moffitt Cancer Center in Tampa, Florida.
“Most immune-related adverse events occur within the first 6 to 12 months of therapy, though many may occur days, weeks, months, or even after discontinuation of therapy,” advises Ms. Andrews. However, in some cases, she says, “immune-related toxicities may be fatal, and delaying adequate care could lead to poor prognosis.”
Therefore, patients who are receiving immunotherapy should consult with their doctor immediately if and when any side effects occur.
Several immune checkpoint inhibitors have been approved by the FDA in the past few years for different types of cancer, including bladder cancer, lung cancer, melanoma, Merkel-cell carcinoma, and classical Hodgkin lymphoma.
Some of these drugs have been approved for more than one type of cancer, including the PD-1/PD-L1 checkpoint inhibitors Bavencio (avelumab), Imfinzi (durvalumab), Keytruda (pembrolizumab), Opdivo (nivolumab), Tecentriq (atezolizumab), and the CTLA-4 antibody Yervoy (ipilimumab).
“Immunotherapy can be effective at achieving durable remissions, but immune-related toxicities require vigilance,” says Sandip P. Patel, MD, Deputy Director, San Diego Center for Precision Immunotherapy, University of California, La Jolla, California.
“As these agents get wider utilization, management of toxicities will become more and more appreciated,” Dr. Patel suggests.
Who Is at Risk?
Patients with cancer who have other medical conditions on top of cancer, especially chronic conditions (such as diabetes or heart disease), and autoimmune conditions (such as rheumatoid arthritis or inflammatory skin conditions), are at a greater risk of having side effects with immunotherapy than patients who don’t have other medical conditions.
“The presence of autoimmune diseases, such as rheumatoid arthritis or lupus, makes patients more susceptible to immune-related toxicities,” according to David Ettinger, MD, Alex Grass Professor of Oncology at Johns Hopkins Medicine, in Baltimore, Maryland.
Although having one of these conditions does not mean the patient cannot use immunotherapy, some conditions do increase the risk for using immunotherapy, because of the great risk for serious side effects.
Ms. Andrews agrees that having some of these conditions does not exclude the use of
immunotherapy. However, she says, according to information from clinical trials data and the prescribing information for these medications, “persons with autoimmune disorders are not candidates, at least outside of a clinical trial.”
In a clinical trial, patients are monitored carefully for any potential side effects and have expert supervision on an ongoing basis, which reduces the risk for serious complications.
In addition, patients above age 60 are at a greater risk than younger patients.
Inflammatory Side Effects
The most common side effects of immunotherapy are inflammatory disorders that can affect different body systems or organs, including the skin. Skin conditions can occur early in the treatment course.
Other body systems include the digestive system, the liver, the endocrine glands, the kidneys, and the lungs.
The most common adverse reactions include dermatitis (skin rash), enterocolitis (affecting the digestive system), hepatitis (liver infection), endocrinopathies (disorders of the endocrine glands), nephritis (inflammation of the kidneys), and pneumonitis (inflammation of the lungs).
With the exception of skin effects, the other side effects can occur later in the treatment.
Endocrine Disorders & Immunotherapy
Most of the side effects can be easily treated and resolved, according to Ms. Andrews, but some of these effects may remain for a long time. “Endocrinopathies may or may not be permanent,” she says, noting that this can be particularly difficult to treat. The symptoms of immunotherapy-related endocrine disorders are vague and difficult to diagnose, because they can occur with many other conditions. These symptoms include:
- Deeper voice
- Feeling warmer or colder than usual
- Hair loss
- Increased hunger or thirst
- Mood or behavior changes
- Persistent or unusual headache
- Weight changes
Dr. Patel agrees that endocrine toxicities are notoriously difficult to confirm in patients receiving immunotherapy.
“Many patients come into the clinic with generalized fatigue and other symptoms that are hard to discern from endocrine cause versus their cancer,” Dr. Patel says, noting that thyroid dysfunction is the most common endocrine toxicity associated with immunotherapy.
Fatigue is the most common symptom of thyroid dysfunction, which occurs in approximately 2% of patients who receive treatment with Yervoy, according to Dr. Patel.
For patients receiving immunotherapy, a cough with fever may be a sign of pneumonia, or it may be autoimmune pneumonitis, a rare but potentially fatal side effect. Recognizing pneumonitis can be challenging, according to Dr. Patel. “The symptoms are hard to distinguish from upper respiratory infection, pneumonia, or chronic obstructive pulmonary disease,” he says.
Pneumonitis can begin any time between 6 weeks and 24 weeks after the start of treatment with an immune checkpoint inhibitor.
Treatment of pneumonitis requires admission to the intensive care unit, use of intravenous steroids and/or antibiotics, and other treatments.
Steroids Used for Immunotherapy Side Effects
The National Comprehensive Cancer Network (NCCN), a major organization that develops many guidelines for cancer treatment that are used by cancer doctors in the United States, has recently developed the first guidelines for the management of side effects related to immunotherapy.
The management of adverse reactions depends on the severity (or grade) of the symptoms. In most cases, steroids are used to treat these side effects.
“We need to remember that steroids are not without side effects of their own,” Ms. Andrews says. However, according to Dr. Patel, the use of steroids for treating immunotherapy side ffects does not affect survival in the United States.
Helpful Tool for Patients
The NCCN has developed a tool for patients and for doctors and other providers that can help to educate people and those who treat or monitor patients who are receiving immunotherapy. The tool is available at www.NCCN.org. Separate sections of the tool have been developed for patients and for healthcare professionals, listing specific side effects and their symptoms.
- Although many side effects of immunotherapy may be well-managed, occasionally they can be fatal
- Patients should contact their doctor immediately if side effects occur
- Side effects from immunotherapy can occur weeks or months after starting treatment, or even after treatment if over
- Several immune checkpoint inhibitors were recently approved by the FDA for different cancers
- Steroids are often used for the treatment of side effects associated with immunotherapy