Patient Education Key in Managing Immune-Related Adverse Events

Because immunotherapy activates the immune system instead of suppressing it, immune-related adverse events (irAEs) are completely different than AEs typically associated with chemotherapy, explained Lisa A. Kottschade, MSN, APRN, CNP.¹

Kottschade, nurse practitioner-associate professor of oncology, Mayo Clinic-Rochester, recently presented at the ONS Bridge about irAE management. Her presentation, “The Long and the Short of it: Monitoring Immune Related Toxicity Across the Cancer Continuum” highlighted the 4 most common categories of irAEs, as well as some of the life-threatening irAEs oncology nurses should be aware of.

“I tell people to think of it as kind of like putting the pedal to the metal in the car,” described Kottschade in reference to irAEs. “They can attack any tissue organ or body system. They can be severe and there have been fatalities reported.”

“It's really important to remember that these are not the same mechanisms of action for side effect management, thereby treatments being very different. So how do we deal with this? Education, education, education. You know, we need to know and educate our patients. We need to educate other care providers outside of oncology. We need to recognize these immune-related adverse events very early because we know that if we delay that, we're going to have worsening adverse events.”

Dermatologic Events

Dermatologic irAEs are most commonly associated with anti-CTLA4 and anti-PD1 blockades, shared Kottschade, noting that these events are seen about 40% of the time with single agent therapies and around 60% with combination therapies. Most patients will experience diffuse maculopapular rash and/or pruritus, as well as vitiligo. It is possible for patients to develop Stevens-Johnson syndrome or toxic epidermal necrolysis and between 10% to 30% of patients experience pruritus despite the absence of rash.

She advised that nurses take into consideration the percentage of body surface area covered by rash. Patients should be taught to report any skin peeling, fever, or lesions in their oral, anal, or genital area.

Immunotherapy will generally continue if the dermatologic irAE (rash, bullous pemphigoid, lichenoid reaction, pruritus) is a mild grade 1. Treatment for this grade irAE includes oral antihistamines and high dose topical steroids. Oral steroids are considered necessary if the rash progresses to grade 2, as well as treatment with moderate potency topical steroids and/or prednisone at a dosage of 0.5-1 mg/kg/day. It may be appropriate to consider holding immunotherapy.

When a patient experiences a rash that is grade 3 or higher, it becomes necessary to discuss the risk-benefit ratio with patients. Prednisone should be administered at 0.5-1 mg/kg/day and dosage increased to 2 mg/kg/day if the condition does not improve. At grade 3 or 4, it may become appropriate to admit the patient to inpatient care and to consult urgent dermatology.

Nurse management of rash or pruritus involves contacting the patient 1 to 2 times between treatments, assessing medication compliance with both topical and oral prescriptions, and instructing the patient to avoid hot showers, excessive drying, and anything that might further irritate the skin.

Gastrointestinal

Diarrhea and colitis, the 2 common gastrointestinal irAEs, are more commonly associated with anti-CTLA-4 inhibitors (30%) than with PD1/PD-L1 inhibitors (15%) but are most common with combination therapy (50%). Colitis shares histologic features with Crohn’s disease and fatal bowel perforation is reported in 1% of patients treated with ipilimumab (Yervoy).

To manage GI irAEs, nurses should determine the number of stools over baseline, assess abdominal pain, if there is any blood or mucus present in the stool, fever, and promptly rule out any infectious etiology, taking care to not hold steroids while awaiting results. If any of the previously noted irAEs present themselves, bowel perforation should be ruled out immediately.

The CTCAE grading of diarrhea defines an increase of 4 stools over baseline per day as grade 1 severity. An increase of 4 to 6 stools is considered grade 2. An increase of 7 stools is considered grade 3 and is considered cause for hospitalization. An increase greater than 7 stools is considered life threatening.

Kottschade also presented an algorithm to manage diarrhea/colitis related to immune checkpoint inhibition. For all grade irAEs, other causes should first be ruled out through stool studies including C. difficile and enteric pathogens. Grade 1 irAEs should be managed with the BRAT diet. If the condition progresses but is still grade 1, then entocort 12 mg or uceris 9mg daily should be administered. Grade 2 irAEs should be treated with entocort 12 mg or uceris 9mg daily and, upon progression, prednisone should be added to treatment at 0.5-2.0 mg/kg daily.

Grade 3 gastrointestinal irAEs should be treated with entocort 12 mg or uceris 9mg daily plus, prednisone at 1.0-2.0 mg/kg daily. If the AE progresses, a gastroenterologist should be consulted and solumedrol should be given at 1 gm IV daily. If the severity becomes grade 4, not only should a gastroenterologist should be consulted and solumedrol should be given at 1 gm IV daily, but infliximab should be given at 5 mg/kg and colectomy should be considered if condition worsens.

Patient education should focus on increasing fluid intake and instructing them to report an increase in stool frequency, bloody stools, or abdominal pain. Patients should be contacted weekly between treatments and bi-weekly if they begin to present with higher grade irAEs.

Kottschade emphasized that with the diarrhea colitis, “many patients can have really good responses to steroids within 1 to 2 days. But they also can have rebound diarrhea. So patients we see in the hospital that we're giving high-dose steroids to intravenously and we switch them over to oral, a lot of times we will hang on to them another 24 to 48 hours because they have a lot of rebound diarrhea where they're back, having as many stools as they were at baseline. We generally don't start taper until the patients at grade 0 or 1. And if they have been started on both budesonide and systemic steroids are going to start tapering the systemic steroids first. We caution against giving antidiarrheals to patients with greater than grade 2 diarrhea because it can get toxic megacolon and are at higher risk for perforation.”

Hepatic irAEs

Hepatotoxicity, or asymptomatic transaminitis and/or hyperbilirubinemia is seen in 30% of patients treated with combination therapy (15% of which present with grade 3 or 4 severity) and less than 10% of patients treated with monotherapy, Kottschade explained.

Around 0.2% of patients experience hepatic failure. Nurses should rule out new or progressive hepatic involvement by malignancy. She also advised utilizing the algorithm-based treatment chart from the National Comprehensive Cancer Network (NCCN).

Nursing specific management of hepatitis involves assessing compliance with steroids and other immunosuppressants, instructing patients to avoid acetaminophen and alcohol, and emphasizing the need for patients to get their laboratory blood draws as instructed.

Endocrine

The 2 main classifications of endocrinopathies include thyroid dysfunction, which is most common with PD-L1 endocrinopathies, and pituitary dysfunction, which is most common with anti-CTLA-4 inhibitors.

Thyroid dysfunction accounts for between 0% and 15% of cases but is more associated with combination therapy (40%) than with single agent regimens.

Nurses should assess patients who experience thyroid disorders for fatigue, hair loss, weight fluctuations, palpitations, sweating, nervousness, cold intolerance, and tightness of clothing around neck.

“Again, assessing for kind of the normal side of side effects that we expect from hypo/hyperthyroidism, we're going to see fatigue in both, [as well as] hair loss, and weight gain. For hyperthyroidism, we're also going to see palpitations and sweating, it's going to be important to know if they're tachycardic because we do treat with that they may be cold and tolerant and both may experience feeling that tightness around their neck if they have cold in there.”

Nursing responsibilities in monitoring patients with thyroid disorders include monitoring patient compliance with medication, persistently reassessing symptoms, educating patients in proper method for thyroid replacement medications.

“This is really important,” Kottschade emphasized. “I find a lot of patients don't take this correctly. You know when our first thing upon rising and an hour prior to food or other medications and nothing but water, avoiding iron and acids and calcium supplements when they can.”

Nurses should also monitor for hypophysitis, sometimes known as the “run over by a truck” phenomenon.” “[These] patients are going to come in and say oh, you know, Lisa, I just feel like I got hit by a truck. I'm sleeping 18 hours a day. I can't do anything. I can barely get out of bed. I've got this horrible headache and I feel kind of sick to my stomach. These patients are going to have undetectable ACTH & AM cortisol levels,” advised Kottschade. In addition, 75% of these patients will show an enlarged pituitary gland on an MRI.

“We always want to make sure that we don't have new involvement of central nervous system (CNS), either cancer or worsening of their CNS disease if already present,” she reminded the audience. “Assess for the following things again, fatigue, nausea, vomiting, and the unrelenting headache. Patients may just tell you they feel weak. In patients who have primary adrenal insufficiency we may see abnormal sodium so low sodium and high potassium and low sugars.”

Because primary adrenal insufficiency (AI) is a medical emergency, these patients will need to immediately go to the ICU. Marked by volume depletion electrolyte abnormality and low or undetectable cortisol and high SCTH, these patients will require fluid replacement, electrolyte replenishment, and high dose steroids (1-2 mg/kg) once they are hospitalized.

In comparison, patients with secondary AI will have low or undetectable am cortisol and low ACTH. This can come from hypophysitis or long-term steroids use.

Education for patients with adrenal insufficiency includes taking their steroids as directed and ensuring that patients understand that they will likely be needing their steroids lifelong. “We do this in conjunction with our endocrine colleagues, but it's great for oncology nurses to be able to reinforce that and know what that teaching is” she said.

Patients will need to understand “sick day” steroids, stress dose steroids, and will need to wear a medical alert bracelet since most pituitary and adrenal abnormalities do not resolve.

Life Threatening irAEs

Pneumonitis may present asymptomatically, but symptoms include shortness of breath at rest, orthopnea, and dyspnea on exertion, and can also include dry nagging cough, chest pain and fever. Pneumonitis can be seen radiographically.

Although neurotoxicity is not a common irAE, when it occurs, it can be life-threatening.

The incidence rate for this irAE e is 3.8 % with CTLA-4 inhibitors, 6% with PD-1 inhibitors, 12% with combination therapy, Kottschade explained, and presentation can vary due to

nonspecific symptoms and a wide range of differentials.

Typical onset is anywhere between 3 days to 17 months, but the median is 6 weeks. Some of the conditions associated with neurotoxicity include Guillan Barre syndrome, myasthenia gravis, central or peripheral neuropathy, encephalitis, aseptic meningitis, and transverse myelitis.

Conditions associated with cardiac toxicity are myocarditis/pericarditis/cardiomyopathy. While exact incidence rates vary, once patients develop a cardiac toxicity, the fatality rate is about 50%.

Opportunities for Growth

“In summary, we know that immune checkpoint inhibitors are really great cancer therapies. And these target our host immune system, we need to carefully assess our patients prior to each ICI therapy,” concluded Kottschade. She reminded nurses that prior to immunotherapy initiation, patients should be assessed for their prior autoimmune conditions, transplant history, as well as vaccination or antibiotic status, because these factors can impact whether immunotherapy is appropriate for the individual.

Moving forward, Kottschade hopes to see better monitoring and early recognition of some of the life threatening irAEs. She also anticipates treatment optimization across tumor types that affect various organs.

The final point that Kottschade discussed was conversations surrounding survivorship issues. “It's hard to have a discussion with a 30-year-old patient who is going to get adjuvant nivolumab for her resected high-risk melanoma and look her in the eye and say, ‘Hey, if I happen to blow your pituitary or something else, you may not be able to get pregnant.’ [But] that's a big discussion that we should be having with our patients.”

“We don't know all the long-term side effects, especially in the adjuvant population, but it's something that I think in the [interest] of full disclosure, we should be talking with our patients with,” she concluded.

Reference

Kottschade LA. The long and the short of it: monitoring immune related toxicity across the cancer continuum. Present