Understanding Side Effects of Cancer Immunotherapy

What is Immunotherapy?

Immunotherapy is a type of cancer treatment that harnesses the body’s immune system to fight cancer cells. Unlike traditional treatments such as chemotherapy and radiation, which directly target and kill cancer cells, immunotherapy works by stimulating or enhancing the immune system’s natural ability to recognize and destroy cancer cells. There are several types of immunotherapy, including checkpoint inhibitors, CAR T-cell therapy, monoclonal antibodies, and cancer vaccines. Each type works differently but shares the common goal of boosting the immune system’s response to cancer.

In this video, the mechanism of action of PD-L1 (an immune checkpoint inhibitor) is presented.

Why Does Immunotherapy Cause Side Effects?

Immunotherapy can cause side effects because it activates the immune system, which can lead to inflammation and autoimmune reactions. When the immune system is stimulated, it can sometimes attack not only cancer cells but also healthy cells and tissues. This can result in a range of side effects, known as immune-related adverse events (irAEs). These side effects can affect various organs and systems in the body, including the skin, gastrointestinal tract, liver, endocrine system, and lungs. The severity and type of side effects depend on the specific immunotherapy used and the individual patient’s response.

When to Expect Side Effects?

The timing of side effects from immunotherapy can vary widely. Some side effects may appear within days of starting treatment, while others may not occur until several weeks or months later. In some cases, new side effects can even emerge months after treatment has ended. Several factors influence the timing of immunotherapy side effects. The type of immunotherapy plays a significant role, as different drugs have varying timelines for side effect onset.

For instance, immune checkpoint inhibitors can cause both early and delayed side effects, whereas CAR T-cell therapy often leads to rapid onset of cytokine release syndrome. Dosage and combination therapy also impact side effect timing, with higher doses and combination treatments, such as anti-CTLA-4 and anti-PD-1 drugs, leading to more severe and earlier side effects.

How Long Do Side Effects of Immunotherapy Last?

The duration of immunotherapy side effects can also vary. Some side effects are short-term and resolve quickly after treatment ends, while others can be long-lasting or even permanent. Understanding these timelines is crucial for effective management.

• Short-Term Side Effects: Immunotherapy can cause side effects within days or weeks of starting treatment, usually resolving within a few weeks after stopping or with proper management. Common early side effects include flu-like symptoms (fever, chills, fatigue, muscle aches) and skin reactions (rashes, itching), which often improve with topical treatments or corticosteroids. Gastrointestinal issues like diarrhea and colitis may require medication for inflammation. Thyroid dysfunctions (hypothyroidism or hyperthyroidism) can develop in the first few months, often needing temporary or long-term hormone replacement therapy.
• Long-Term Side Effects: Some side effects persist for months or years after treatment ends, needing ongoing management. Endocrine disorders (hypothyroidism, hyperthyroidism, adrenal insufficiency) often require long-term hormone replacement therapy. Chronic conditions like pneumonitis, arthritis, and neuropathy may need prolonged treatment with immunosuppressive drugs or other therapies. These side effects can significantly impact the patient’s quality of life, requiring multidisciplinary care.
• Permanent Side Effects: Rarely, immunotherapy can cause irreversible side effects with permanent damage. Severe endocrine disorders like type 1 diabetes or inflammation of the pituitary gland may need lifelong hormone replacement therapy. Severe organ damage (myocarditis, pneumonitis, nephritis) can lead to permanent impairment or organ failure if not promptly treated. Early detection and intervention are crucial to prevent long-term complications.

Early detection and prompt management are crucial for minimizing the duration and severity of side effects. Patients should be educated about potential side effects and encouraged to report new or worsening symptoms immediately. Regular monitoring and individualized management plans are essential to address both acute and chronic side effects effectively, helping to maintain patient quality of life.

What Are the Side Effects of Cancer Immunotherapy?

Immunotherapy can cause a wide range of side effects, which can be categorized based on the affected organ systems:

Common Side Effects

• Fatigue: The most common side effect, often mild but can be severe in some cases.
• Skin Reactions: Rashes, itching, and redness are frequent, with some patients experiencing more severe conditions like blistering or sensitivity to sunlight.
• Gastrointestinal Issues: Diarrhea, colitis, nausea, and vomiting are common, with colitis being a potentially severe condition requiring prompt treatment.
• Endocrine Disorders: Hypothyroidism, hyperthyroidism, adrenal insufficiency, and other hormone-related issues can occur, often requiring long-term hormone replacement therapy.
• Respiratory Issues: Pneumonitis, characterized by inflammation of the lungs, can cause symptoms like cough and shortness of breath and may be severe.

Rare but Severe Side Effects

• Neurological Issues: Encephalitis, neuropathy, and other neurological conditions can occur, sometimes leading to severe complications.
• Cardiovascular Issues: Myocarditis and other heart-related conditions, though rare, can be life-threatening.
• Hepatitis: Inflammation of the liver can lead to symptoms like jaundice and elevated liver enzymes.
• Kidney Issues: Nephritis and other renal impairments can occur, requiring careful monitoring and management.

The image is taken from the American Association for Cancer Research website.

Do Side Effects Mean That Treatment is Working?

The relationship between immunotherapy side effects and treatment effectiveness is complex. Some studies suggest a correlation between irAEs and better outcomes, but this is not a definitive indicator. Research shows that patients with irAEs, like skin reactions, endocrine disorders, or gastrointestinal issues, often have better survival rates in cancers such as melanoma, non-small cell lung cancer, and renal cell carcinoma treated with immune checkpoint inhibitors.

This may be due to a heightened immune response that attacks both cancer cells and healthy tissues. Clinical observations also support this, with conditions like pneumonitis and thyroid dysfunction during treatment linked to improved survival. However, side effects do not guarantee treatment success, as some patients with significant side effects may not see benefits, while others with minimal side effects may still respond well. This variability makes side effects an unreliable marker of treatment efficacy. Regular monitoring and a personalized approach to treatment are essential for optimizing patient outcomes.

Immunotherapy vs. Chemotherapy Side Effects

Both immunotherapy and chemotherapy can cause a range of side effects, including fatigue, nausea, vomiting, and diarrhea. However, the underlying mechanisms of these side effects differ. Chemotherapy targets rapidly dividing cells, affecting both cancerous and healthy cells, which leads to a broad spectrum of side effects. Immunotherapy, on the other hand, activates the immune system, which can result in immune-related adverse events.

Chemotherapy side effects typically occur shortly after treatment and subside once the treatment ends. Immunotherapy side effects can appear later and may persist long after treatment has concluded. Additionally, chemotherapy affects a wide range of rapidly dividing cells, leading to side effects like hair loss and bone marrow suppression. Immunotherapy side effects are more specific to immune system activation and can include autoimmune reactions affecting various organs.

Managing Side Effects of Immunotherapy

Effective management of immunotherapy side effects involves early detection, prompt treatment, and ongoing monitoring. Here are some general strategies:

Early Detection and Reporting

Early detection and prompt reporting of side effects are essential for effective management. Patients should be educated about the potential side effects of immunotherapy and encouraged to report any new or worsening symptoms immediately, even if they seem minor. This proactive approach allows healthcare providers to address side effects before they become severe or life-threatening.

Common Side Effects and Management Strategies

• Fatigue: To manage fatigue, patients should balance rest and activity, ensuring adequate sleep and engaging in light exercise or physical activity as permitted by their healthcare provider. Maintaining a healthy diet and staying hydrated are also important. Patients may benefit from speaking with a mental health expert to manage stress and cope with the emotional impact of fatigue.
• Skin Reactions: Immunotherapy can cause various skin reactions, including rashes, itching, dryness, and blistering. To manage these reactions, patients should keep their skin clean and moisturized, avoid exposure to extreme temperatures and irritants, and wear loose-fitting, breathable clothing. Using mild, unscented soap and lukewarm water for bathing can help prevent further irritation. In more severe cases, a dermatologist may prescribe topical corticosteroids or other medications to alleviate symptoms.
• Gastrointestinal Issues: Gastrointestinal side effects, such as nausea, vomiting, diarrhea, and colitis, are common with immunotherapy. To manage nausea and vomiting, patients should follow a simple diet of bland foods and clear liquids, and consider relaxation techniques or acupuncture. For diarrhea, staying hydrated is crucial, and patients should eat low-fiber, non-spicy foods to reduce irritation. Healthcare providers may prescribe antidiarrheals or corticosteroids to manage severe gastrointestinal symptoms.
• Respiratory Issues: Respiratory side effects, such as coughing, shortness of breath, and lung inflammation (pneumonitis), can occur with immunotherapy. Patients should avoid exposure to respiratory irritants, such as smoke or pollution, and notify their healthcare team immediately if they experience any respiratory symptoms. Medications like corticosteroids may be prescribed to manage lung inflammation.

Severe side effects, such as high fever, severe abdominal pain, chest pain, or difficulty breathing, require immediate medical attention. Patients should seek emergency care if they experience any of these symptoms. In some cases, severe side effects may necessitate the discontinuation of immunotherapy. However, the immune system may continue to recognize and attack cancer cells even after treatment has stopped, providing ongoing benefits.

Because some side effects of immunotherapy can appear months or even years after treatment has ended, long-term monitoring is essential. Patients should have regular follow-up appointments with their healthcare team to monitor for late-onset side effects and adjust treatment plans as necessary. This ongoing care is crucial for early detection and management of any new or worsening symptoms.

Educating patients about the potential side effects of immunotherapy and how to manage them is a key component of care. Patients should be provided with detailed information about their treatment, including a card with information about their immunotherapy drugs and potential side effects. This card can be shown to other healthcare providers to ensure coordinated care. Additionally, patients should be advised not to start any new medications, including over-the-counter drugs and herbal supplements, without consulting their cancer specialist.

Common immune-related adverse events associated with immune checkpoint blockade. The image is taken from a paper by Morgado et al. (2020).

When to See a Doctor

Patients undergoing immunotherapy should contact their healthcare provider if they experience any new or worsening symptoms, even if they seem minor. Immediate medical attention is required for severe symptoms such as difficulty breathing, chest pain, severe abdominal pain, high fever, or signs of an allergic reaction. Regular follow-up appointments are essential to monitor for late-onset side effects and adjust treatment plans as necessary.

In conclusion, while immunotherapy offers promising benefits for cancer treatment, it also comes with a range of potential side effects that require careful management. By understanding these side effects and working closely with their healthcare team, patients can better navigate their treatment journey and improve their overall outcomes.

This video prepared by ASCO provides patients with an easy-to-follow overview of potential side effects during immunotherapy treatment for cancer, how to recognize symptoms, and the importance of communicating with their healthcare team.

Sources

1. Immunotherapy and its side effects – Cancer Research UK
2. Side Effects of Immunotherapy – American Society of Clinical Oncology
3. Systemic adverse effects and toxicities associated with immunotherapy: A review – World Journal of Clinical Oncology
4. Immunotherapy’s Skin Side Effects: Are Microbes to Blame? – National Cancer Institute
5. Timeline of Adverse Events during Immune Checkpoint Inhibitors for Advanced Melanoma and Their Impacts on Survival – Cancers
6. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance – Nature Reviews Clinical Oncology 
7. Cancer immunotherapy and the management of side effects – Clinical Medicine
8. Immunotherapy toxicity: identification and management – Breast Cancer Research and Treatment
9. Immunotherapy vs. Chemotherapy: What’s the Difference? – Cancer Research Institute