Enthusiasm for immunotherapy in the treatment of cancer must be balanced with a healthy consideration of the power of T-cell activation, which can cause the immune system to overact and create new problems.
Although the side effects of immunotherapy drugs are usually mild, they occasionally can be fatal and, therefore, should be treated without delay, according to Stephanie Andrews, MS, ANP-BC, a hospitalist specializing in medical oncology at Moffitt Cancer Center in Tampa, FL.
Ms. Andrews discussed this topic at the 2017 conference of the National Comprehensive Cancer Network (NCCN).
“Most immune-related adverse events occur within the first 6 to 12 months of therapy, though many may occur days, weeks, or months, or even after discontinuation of therapy,” said Ms. Andrews.
However, some “immune related toxicities may be fatal, and delaying adequate care could lead to poor prognosis,” she said.
Therefore, patients who are receiving immunotherapy drugs should consult with their doctor immediately if any side effect occurs.
Common Side Effects of Immunotherapy
The most common side effects associated with immunotherapy are inflammatory conditions that can affect different parts of the body.
Skin conditions are the most common side effects associated with immunotherapy drugs, which include checkpoint inhibitors or monoclonal antibodies, and can occur early in the treatment course.
Many of these side effects are skin conditions, but they can also affect any organ systems, not just the skin. The side effects include:
- Dermatitis (skin rash)
- Enterocolitis (inflammation of the digestive system)
- Hepatitis (inflammation of the liver)
- Endocrinopathies (disorders of the endocrine glands)
- Nephritis (inflammation of the kidneys)
- Pneumonitis (chest pain, shortness of breath)
Side effects such as colitis (inflammation of the colon), endocrinopathies, and liver-, lung-, or kidney-related side effects can occur later in the treatment course, and are less frequent than skin reactions.
Who Is at Risk?
Patients with cancer who also have other medical conditions (for example, diabetes or heart disease) are at a greater risk of having side effects with immunotherapy than patients who don’t have other medical conditions.
In addition, patients who are older than age 60 are at a greater risk than younger patients for side effects of immunotherapies.
Immunotherapy-Related Endocrinopathies and Colitis
Most side effects can be easily treated and resolved, according to Ms. Andrews. “However, endocrinopathies may or may not be permanent,” she said; this particular side effect can be difficult to treat.
The symptoms of immunotherapy-related endocrinopathies are vague and difficult to diagnose, in part because they can occur with many other conditions.
These symptoms include:
- Changes in weight
- Changes in mood or behavior
- Deeper voice
- Feeling warmer or colder than usual
- Hair loss
- Increased hunger or thirst
- Persistent or unusual headache
Management of Skin-Related Side Effects
The management of adverse reactions associated with immunotherapy (checkpoint inhibitors) depends on the grade of symptoms.
In the case of skin-related side effects, doctors should follow the most recent NCCN melanoma guideline.
For example, Yervoy (ipilimumab) can be continued to be used for grade 1 skin adverse reactions, while treating the symptoms; stopping Yervoy use is recommended for grade 2 skin adverse reactions; and discontinuing the drug and using steroids is recommended for grade 3 to 4 skin-related side effects.
The checkpoint inhibitor Opdivo (nivolumab) should be withheld for grade 3 skin side effects, with resumption when the reaction returns to grade 0 or 1. Permanently stopping Opdivo is recommended for grade 4 skin rash. In addition, using prednisone 1 mg/kg to 2 mg/kg daily is also recommended.
Keytruda (pembrolizumab) is another checkpoint inhibitor and has similar recommendations for treating skin side effects. Other immunotherapy drugs can be considered if grade 3 or 4 skin toxicity is not controlled with corticosteroids.
This strategy is advisable for steroid-refractory side effects that are responding to steroids with any of the checkpoint inhibitors.
Dose reductions of immunotherapy are not recommended. Instead, Keytruda should be withheld or discontinued and another immunotherapy used. Overall, a slow reduction of the steroid (for a minimum of 4 weeks) is advised.
Tecentriq (atezolizumab) is another immunotherapy that can also have immune-related side effects similar to the other immunotherapy drugs.
Opdivo should be stopped when grade 2 adrenal insufficiency occurs, and permanently discontinued for grade 3 or 4 adrenal insufficiency, whereas Keytruda and Tecentriq can continue to be used with grade 2 adrenal insufficiency, but should be stopped when grade 3 or 4 side effects occur.
Another symptom with immunotherapy is hypothyroidism; if this occurs, thyroid therapy is needed, but without changing the dose of the checkpoint inhibitor (immunotherapy), unless the hypothyroidism is grade 3 or 4, in which case skipping a dose of the immunotherapy is recommended.
Using Steroids for Immune-Related Side Effects
“Because immune checkpoint inhibitors are being used for cancer treatment more and more, healthcare professionals should be familiar with the distinct side-effect profile of each of these drugs,” said Myint A. Win, MD, Department of Emergency Medicine, M.D. Anderson Cancer Center in Texas, at the 2017 NCCN meeting.
We need to remember that steroids are not without side effects of their own, so gastrointestinal prophylaxis, as well as opportunistic infection is necessary.
— Stephanie Andrews, MS, ANP-BC
“Management of these adverse events depends on grade and severity. We take it on a case-by-case basis. If the adverse event is severe, we stop the immune checkpoint inhibitor and start steroids. If it is mild, we observe the patient,” Dr. Win added.
Discussing the use of steroids to treat these side effects, Ms. Andrews said, “We need to remember that steroids are not without side effects of their own, so gastrointestinal prophylaxis, as well as opportunistic infection prophylaxis is necessary.”
Steroid use for treating immune-related side effects does not affect the treatment outcomes. Blood sugar levels should also be checked in patients who receive steroids while using immunotherapy.
The NCCN guidelines suggests the use of Remicade (infliximab) as the preferred drug for treating colitis associated with immunotherapy that does not respond promptly to high-dose steroids.
The treatment of other immune-related inflammatory adverse events also relies on the use of systemic steroids.
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 getting immunotherapy. The tool is available at www.NCCN.org.
Separate sections of the tool have been constructed for patients and for healthcare professionals, listing specific adverse events and their symptoms.
- The side effects associated with immunotherapies are generally easy to treat
- However, occasionally these side effects can be fatal; therefore, patients should contact their doctor without delay if side effects occur
- Treating immune-related inflammatory side effects often involves the use of steroids
- The NCCN has a tool for patients and doctors and other providers that can help to educate people and those who treat or monitor patients who are getting immunotherapy
NCCN Immunotherapy Teaching/Monitoring Tool
American Cancer Society
National Cancer Institute