The Promise of Cancer Immunotherapy: Why Patient Education Is Critical, Part II

In Part I of this article, Ms Madden discussed the enthusiasm concerning new immunotherapies, the need for caution in interpreting results while the data is still young, and the necessity for more mature data on a much larger number of patients. Here in Part II, she continues her discussion on why it is critical to educate patients and their families concerning what to expect from immunotherapy, with a particular focus on the unique spectrum of adverse effects that may be associated with these agents.

In the popular media and elsewhere, when reporting the potential benefits of immunotherapy, some have stated that when compared with traditional cancer treatments, there are “few to no side effects.” Though immunotherapies are typically not associated with the same side effects that result with chemotherapeutic agents the statement “few to no side effects” does not tell the entire story and may be misleading for patients. In fact, it’s the very promise of cancer immunotherapies—ie, the mechanisms of action that harness and enhance the immune system’s abilities to recognize and fight cancer cells—that may also lead to serious harms in some patients. In addition to enabling a continued attack against cancerous cells, increased inflammatory reactions and enhanced immunologic responses with immunotherapies such as the checkpoint inhibitors may impact normal body cells and tissues, resulting in adverse effects. Autoimmune in nature, such effects are collectively known as “immune-related adverse events (irAEs),” and are thought to occur due to general immunologic enhancement. ^4,12

• Serious irAEs are infrequent and treatable, but patient education is crucial, since early recognition of such effects is critical in ensuring effective treatment. Patients and caregivers must be made aware of irAEs before initiating treatment. Healthcare providers should also discuss the concept of pseudo-progression with patients and caregivers, and that associated symptoms may include low-grade fever, a painful and sudden increase in tumor size, rash, and bone pain.

• In contrast to adverse effects with standard cancer therapies, irAEs may tend to be delayed, with onset of some symptoms potentially developing weeks or months following treatment initiation. Patients must therefore recognize that they may experience such side effects after having previously done well clinically and that some irAEs may develop after completion of treatment.

• irAEs may involve inflammation of any organ system, may affect more than one organ system, and may impact different organs at different times.

• The signs of some irAEs may present solely as lab value changes, eg, elevated values of liver function tests due to hepatic inflammation.

• The medical care team should urge their patients to monitor for any side effects during and in the months following their immunotherapy and to report all symptoms, no matter how subtle they may seem. Patients and their caregivers need to understand the importance of prompt evaluation for such signs and symptoms to determine whether they are due to an immune-mediated toxicity and to ensure that appropriate treatment is promptly initiated.

• Because no prospective clinical trials have yet been conducted to inform the management of irAEs, treatment is currently based on clinical experience. In addition, general guidelines for irAE treatment due to checkpoint inhibitor therapy are included in the FDA’s REMS for the checkpoint inhibitor ipilimumab. In general, treatment of moderate or severe irAEs includes corticosteroid immunosuppression, symptomatic management based on the specific toxicity and severity, and discontinuation or interruption of checkpoint inhibition.

The chart below outlines specific irAEs reported in association with immunotherapy for some patients:^4,12

System

Symptoms

Dermatologic

Dermatologic toxicities may result in serious skin reactions, where symptoms may include:

• Rash with or without itching
• Skin blistering or peeling
• Dry mouth
• Mouth sores (oral mucositis)
• Loss of skin pigmentation in blotches (vitiligo)
• In rare cases, severe rashes, such as Stevens-Johnson syndrome

Gastrointestinal

Inflammation of the intestinal lining (colitis) may lead to holes or tears (perforation) in the intestines. Associated symptoms may include:

• Abdominal pain
• Diarrhea
• Increased frequency of bowel movements
• Dark, tarry stools
• Blood in the stools

Hepatic

Inflammation of the liver (hepatitis) can lead to liver failure. Symptoms and findings associated with hepatitis may include:

• Elevated liver enzyme levels (AST and ALT)
• Fever
• Yellowing of the skin or the whites of the eyes (jaundice)
• Nausea or vomiting
• Dark urine
• Increased bruising
• Pain on the right side of the stomach

Neurologic

Nerve damage (neuropathy) may develop, with symptoms that may include:

• Tingling or numbness in the hands and feet
• Abnormal weakness of the arms, legs, or face
• Various neurologic syndromes have also been reported in association with checkpoint inhibitors, including: Guillain-Barre syndrome, where the immune system attacks part of the peripheral nervous system Myasthenia gravis, an autoimmune neuromuscular disease characterized by fluctuating weakness and fatigue of voluntary muscles Inflammation of layers of the brain (aseptic meningitis)

Endocrine

Endocrine toxicities may primarily affect the pituitary gland (hypophysitis), the thyroid gland (hypothyroidism), and adrenal glands (adrenal insufficiency). Associated symptoms may include:

• Persistent headaches
• Fatigue
• Nausea
• Vision changes
• Weight gain
• Dizziness
• Fainting
• Changes in mood and behavior

Adrenal insufficiency, a serious endocrine toxicity potentially associated with the checkpoint inhibitors, is considered an emergency and may cause hypotension, dehydration, and electrolyte imbalances.

Renal

Symptoms and signs may include:

• Decreased amount of urine
• Blood in the urine
• Swelling of the ankles
• Loss of appetite

Ocular

Symptoms associated with eye inflammation may include:

• Blurry vision
• Double vision
• Eye redness
• Eye pain
• Dryness of the eyes
• Sensitivity of the eyes

Pulmonary

Symptoms associated with lung inflammation (pneumonitis) may include:

• New or worsening cough
• Shortness of breath
• Chest pain

It is said that Hippocrates wrote, “Natural forces within us are the true healers of disease.” Our hope is that many of the long-sought answers to curing cancer will indeed lie within our own immune systems—and that our next step on this lengthy path will be to find the keys to expanding immunotherapy’s promise to many more of us. In the interim, however, as we strive toward this goal, it’s crucial for our healthcare providers to appropriately inform patients and help to manage expectations.

References

1. Dizon DS, Krilov L, Cohen E, et al. Clinical cancer advances 2016: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol. 2016;34(9):987-1011. doi:10.1200/JCO.2015.65.8427.

2. Feltman R. Why it’s too early to get excited about this “unprecedented” new cancer treatment. The Washington Post website. https://www.washingtonpost.com/news/speaking-of-science/wp/2016/02/16/why-its-too-early-to-get-excited-about-this-unprecedented-new-cancer-treatment/. Published February 16, 2016. Accessed March 21, 2016.

3. Yuhas A. Cancer researchers claim “extraordinary results” using T-cell therapy. The Guardian website. https://www.theguardian.com/science/2016/feb/15/cancer-extraordinary-results-t-cell-therapy-research-clinical-trials. Published February 15, 2016. Accessed March 21, 2016.

4. Green LM. Immunotherapy in cancer care: educating patients about what to expect. Oncology Nursing News website. http://nursing.onclive.com/publications/oncology-nurse/2015/june-2015/immunotherapy-in-cancer-care-educating-patients-about-what-to-expect#sthash.FeNfHPaO.dpuf. Published June 30, 2015. Accessed March 21, 2016.

5. McGranahan N, Furness AJS, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockage [published online March 3, 2016]. Science. doi:10.1126/science.aaf1490.

6. Begley S. The newest cancer therapies don’t work on everyone. Now, doctors have a clue why. StatNews website. https://www.statnews.com/2016/03/03/cancer-immunotherapy-neoantigens/. Published March 3, 3016. Accessed March 21, 2016.

7. Garron E. Time to response to immunotherapy and the concept of pseudoprogression (video transcript). Global Resource for Advancing Cancer Education website. Published December 15, 2015. Accessed March 22, 2016. http://cancergrace.org/lung/2015/12/15/gcvl_lu_immunotherapy_response_time_pseudoprogression_concept/

8. Assessing immunotherapy response—why irRC matters: clinical optimization. Institute for Clinical Immuno-Oncology website. http://accc-iclio.org/resources/assessing-immunotherapy-response-why-irrc-matters/. Published June 25, 2015. Accessed March 22, 2016.

9. West H. 5 key points on immune checkpoint inhibitors for lung cancer: game changer or just leveling up? Global Resource for Advancing Cancer Education website. Published January 5, 2014. Accessed March 21, 2016. http://cancergrace.org/lung/2014/01/05/5-key-points-on-immunotherapy-for-lc/

10. Kim T, Amaria RN, Spencer C, Reuben A, Cooper ZA, Wargo JA. Combining targeted therapy and immune checkpoint inhibitors in the treatment of metastatic melanoma. Cancer Biol Med. 2014;11(4):237-246. doi:10.7497/j.issn.2095-3941.2014.04.002.

11. Pilones KA, Vanpouille-Box C, Demaria S. Combination of radiotherapy and immune checkpoint inhibitors. Semin Radiat Oncol. 2015;25(1):28-33. doi:10.1016/j.semradonc.2014.07.004.

12. Postow M, Wolchok J. Toxicities associated with checkpoint inhibitor immunotherapy. UpToDate website. http://www.uptodate.com/contents/toxicities-associated-with-checkpoint-inhibitor-immunotherapy. Literature review current through: Feb 2016. Updated Jan 6, 2016. Accessed March 22, 2016.