Marianne Davies, DNP, MSN,
CNS, ACNP, AOCNP
Though once merely an intriguing research question, harnessing a patient’s own immune system to kill tumor cells is now a reality in cancer treatment, offering fresh hope to many patients who may have run out of options.
Three immunotherapy drugs are currently FDA-approved in the melanoma setting (ipilimumab, pembrolizumab [Keytruda], and nivolumab [Opdivo]). Nivolumab is also approved for the treatment of squamous non–small cell lung cancer (NSCLC).
The FDA recently assigned a priority review designation to pembrolizumab as a treatment for patients with advanced NSCLC across all histologies. With more positive findings for nivolumab reported at the recent American Society of Clinical Oncology (ASCO) annual meeting, the drug’s manufacturer, Bristol-Myers Squibb, announced that it will seek FDA approval for the agent to treat the more common, non-squamous NSCLC subtype.
For Marianne Davies, DNP, MSN, CNS, ACNP, AOCNP, an oncology nurse practitioner at the Smilow Cancer Hospital at Yale-New Haven and an assistant professor at the Yale School of Nursing, immunotherapy really has changed the face of lung cancer treatment:
“We are seeing phenomenal responses in patients that have non–small cell lung cancer,” Davies said during an interview with Oncology Nursing News at the recent Oncology Nursing Society (ONS) Annual Congress where she presented on the topic. “We are actually seeing long durable responses for these patients. They are living several years after therapy.”
“The field of targeted immunotherapy gets more exciting every year,” concurred Lynn M. Schuchter, MD, as part of a press briefing on immunotherapies for multiple hard-to-treat cancers she moderated at the 2015 ASCO Annual Meeting. Schuchter is division chief, Hematology/Oncology at Penn Medicine, and melanoma program leader at the Abramson Cancer Center at the University of Pennsylvania.
“We’re rapidly moving past the era in which immunotherapies are seen as breakthroughs for melanoma alone,” Schuchter continued. “Remarkably, these drugs are proving effective in other cancers where practically no other treatments work. Just as important, it’s possible that we’ll be able to pinpoint, in advance, which patients are the best candidates for these therapies.”
As immunotherapy expands into the treatment for many cancer types, how will this impact oncology nursing practice? Which patients are most likely to respond to immunotherapies? What are the most important considerations when caring for these patients?
Patient Assessment and Screening
For the oncology nurse, immunotherapy represents an exciting new way of treating patients with cancer, but also a challenging one, as this treatment approach varies from cytotoxic and targeted therapies in many important ways, noted Davies. Immunotherapy drugs differ, not only by their mechanism of action, but especially their adverse event profiles, which require careful monitoring by clinicians and an understanding of how these drugs work by patients so they know what to report back to their nurse before a side effect becomes a crisis.
And, importantly, these drugs are not for everyone.
Because immunotherapy works by activating T-cells to attack the cancer, they can also inflame healthy tissues, meaning that patients with autoimmune conditions, such as lupus, rheumatoid arthritis, and Crohn’s disease, who already have a hyperactive immune system, are not appropriate for the therapy. “It has the potential to have a significant increase in morbidity, perhaps even mortality for those patients,” Davies cautioned. Similarly, patients with a prior organ transplant or history of liver damage would not be good candidates for the therapy.
Steroid use is another important consideration when doing a baseline medical history, unless the patient can be tapered off them, Davies said. In addition to steroids, patients should be monitored for all prescription and nonprescription medications, including vitamins and herbal supplements.
Lynn M. Schuchter, MD
Patients with more aggressive tumors may need chemotherapy which works faster, Davies added: “Immunotherapy really doesn’t work that way. It takes time for your body’s immune system to be restored to recognize the tumor and have effect. The times of responses or reduction in tumor burden may be variable and may not be appreciated until 12 weeks or even after discontinuation of therapy.”
Educating Patients—and Their Caregivers
The most common side effects reported by patients are fatigue, musculoskeletal pain, and nausea. These are typically mild. However, there is a unique side effect profile that nurses, practitioners, and patients need to be aware of: immune-related adverse events (IRAEs).
Although serious IRAEs are infrequent, treatable, and respond well to steroids, “patient education is incredibly important,” said Davies. Teaching should begin prior to the decision to initiate immunotherapy and include both patients and their caregivers, because early recognition of any IRAEs is essential to effective treatment. And, unlike chemotherapy, these events tend to be delayed.
“Oftentimes the onset might be 8, 10, even 12 weeks after the start of therapy. We might see a few of the minor side effects a little earlier on, but we need to tell patients, ‘yes, you’ve done well for a few months, but now we may begin to see some side effects. Sometimes the side effects can occur after you’ve discontinued the therapy.’”
Patients can be reassured that clinicians will be monitoring their blood counts, potential side effects, and doing a full review of their systems. IRAEs tend to involve anything that becomes inflamed—anything that can have an “itis” or an “opathy,” Davies explained. “Any organ system can be affected, and a patient can have many organ systems affected.” (Table)
And, the onset of IRAEs of different organs may not occur at the same time.
Table: Immune-Related Adverse Events1-3
Select Adverse Events
Diarrhea, colitis, perforation
Thyroiditis, hypophysitis, hypopituitarism, adrenal insufficiency
Acute interstitial nephritis
Central and peripheral; aseptic meningitis, Guillain-Barré syndrome, myasthenia gravis
Lichenoid/spongiotic dermatitis, rash, vitiligo
Uveitis, iritis, episcleritis, conjunctivitis
Some of these may be very subtle laboratory changes, Davies continued, for example, a patient who experiences inflammation in the liver, may have elevated liver function tests. When patients are asymptomatic for a period of time, they may not even realize they are experiencing inflammation in these areas, which makes patient education paramount:
“Teaching patients to report every symptom, no matter how subtle, is very important,” said Davies. “Even things like diarrhea. We are used to chemotherapy-induced diarrhea in which we instruct patients to take antidiarrheals. However, in patients on immunotherapy, that approach could be toxic, as it could mask an immune-mediated colitis.
“Patients need to make sure they are monitoring for any side effect and report them to us immediately. Nurses and providers need to evaluate if a symptom is related or unrelated to the immunotherapy, so that appropriate treatment can be initiated.”
Effective Management of IRAEs
Thus, optimal patient management depends on early recognition of IRAEs. Pneumonitis provides a case-in-point, and it can be particularly difficult to manage in patients with lung cancer, explained Davies, because these patients often have an underlying pulmonary issue, such as COPD or emphysema, and because of the tumor burden, they might already be out of breath.
To manage pneumonitis, Davies said it’s really important to obtain the patients’ baseline walking oxygenation status, so that when they come in for their rechecks, it will be easier to determine if there is any change. In addition to monitoring oxygenation status, patients may require additional diagnostic tests, such as chest x-ray, CT scan, and many will require a lung tissue biopsy to find out what’s behind the event (eg, infectious pneumonia vs tumor growth vs pneumonitis). If pneumonitis is confirmed, the immunotherapy will be discontinued and high-dose steroids administered.
Overall, if a patient receiving immunotherapy is experiencing any grade 3/4 toxicity, permanent discontinuation of the immunotherapy is likely; patients will be started on intravenous methylprednisolone and when stable, transition to oral prednisone. This should be tapered over at least 1 month until their symptoms are under control, and then they will be tapered off slowly to avoid a flare of the inflammatory response, Davies explained.
Grade 1 toxicities require close monitoring and follow-up tailored to the specific abnormality, and for patients experiencing grade 2 IRAEs, their immunotherapy is usually discontinued temporarily, with treatment restarted if their toxicity improves to grade 1. Persistent grade 2 IRAEs are treated with oral prednisone, and patients will have laboratory monitoring every 2 to 3 days.
Another important aspect of immunotherapy that patients need to be aware of is that their disease may show initial signs of progression, but their treatment can continue through this “pseudo-progression.” Signs of this include a sudden and painful increase in tumor size, rash, a low-grade fever, bone pain, and an increase in new lesions seen in initial imaging studies.
Davies added that although patients are for the most part very diligent about side effect reporting, she would like to see guidelines tailored to immunotherapy like those ONS has developed for symptom management.
Immunotherapy was a topic of intense interest at the recent ASCO meeting, where encouraging clinical trial findings were presented for a variety of solid tumors beyond the melanoma and lung cancer setting.
Immunotherapy agents are gaining ground in renal cell carcinoma, liver cancer, glioblastoma, and in the head and neck setting, among others. And, importantly, research reported at ASCO and elsewhere is beginning to illuminate how mutations, biomarkers, and an individual’s cancer cell DNA can help predict which tumors are most likely to respond to immunotherapy.
“We don’t know how broad this approach is going to be—we’ve certainly seen activity in hematologic malignancies,” said Schuchter. “The scope of cancers keeps expanding, and then the concept of combining immunotherapies will also begin to expand how we use these drugs.
“This is a really good example of where the investment in basic science has led to these very important new discoveries and new approaches to treatment, and now the key is really robust clinical trials to further expand the activity of these agents and know who best responds to these treatments.”
Davies M. New modalities of cancer treatment for NSCLC: focus on immunotherapy. Cancer Manag Res. 2014;6:63-75.
Fecher LA, Agarwala SS, Hodi FS, Weber JS. Ipilimumab and its toxicities: a multidisciplinary approach. Oncologist. 18(6):733-743.
Perazella MA, Izzedine H. New drug toxicities in the onco-nephrology world. Kidney Int. 2015;87(5):909-917.