February 2018 VOL 9, NO 2
Immunotherapy: Managing Severe Treatment-Related Toxicities
Immunotherapy has changed the landscape of oncology, particularly in advanced metastatic disease, where the chance of prolonged remission is now measured in years or even into the early decades in some cancers. However, significant improvements in outcome have brought new challenges concerning toxicities that increasingly require multidisciplinary teams to manage. At the 2017 Palliative and Supportive Care in Oncology Symposium, Sandip P. Patel, MD, addressed the more severe toxicities associated with checkpoint inhibitors.
“Immunotherapy can be effective at achieving durable remissions, but immune-related toxicities require vigilance,” said Dr Patel, Assistant Professor of Medicine at UC San Diego Moores Cancer Center and Deputy Director of the San Diego Center for Precision Immunotherapy. “As these agents get wider utilization, management of toxicities will become more and more appreciated, and palliative and supportive care will be essential to taking care of the needs of our patients.”
For patients on immunotherapy, a cough with fever may be a sign of pneumonia, or it may be autoimmune pneumonitis, a rare but potentially fatal side effect.
“Unfortunately, there is no gold standard diagnostic criteria aside from biopsy,” said Dr Patel. “The symptoms are hard to distinguish from upper respiratory infection, pneumonia, or chronic obstructive pulmonary disease.”
As Dr Patel reported, onset of pneumonitis can occur at any time between weeks 6 and 24 after treatment initiation. Common characteristics include involvement of several or all lung fields, diffuse ground-glass opacities, diffuse reticular opacities, multifocal consolidations, and traction bronchiectasis. Dr Patel recommended a CT scan of the chest with contrast to rule out pulmonary embolism, pneumonia, and pneumonitis.
Treatment entails admission to the intensive care unit, IV steroids, and IV antibiotics, and may require infliximab, mycophenolate, cyclophosphamide, or IV immunoglobulin. Steroids do not affect survival with immune checkpoint blockade, said Dr Patel, particularly if treating immune-related adverse events.
According to Dr Patel, endocrine toxicities are notoriously difficult to ascertain in this population, so treatment plans for immunotherapy infusion should include monitoring for these side effects.
“Many patients come into the clinic with generalized fatigue and other symptoms that are hard to discern from endocrine cause versus their cancer,” said Dr Patel, who noted that thyroid dysfunction is the most common endocrine toxicity.
Regarding thyroid dysfunction, hyperthyroidism due to autoimmune side effects is much less common than hypothyroidism, which is seen in 80% to 90% of the time in the clinic. Thyroid function is routinely checked prior to each dose of immunotherapy, said Dr Patel, so it’s generally found on pretreatment screening labs. Fatigue is the most common symptom of thyroid dysfunction, which occurs in approximately 2% of patients treated with ipilimumab.
Acute thyroiditis is treated with steroids (prednisone 1 mg/kg daily for 2 weeks). For hypothyroidism, levothyroxine is prescribed. And for hyperthyroidism, Dr Patel advised endocrine consultation as well as a beta-blocker.
Another endocrine toxicity that’s difficult to distinguish from other treatment-related side effects, autoimmune adrenalitis can be found on laboratory evaluation (indicated by high potassium and low sodium levels), and is associated with hypotension and dehydration. Dr Patel recommended ordering a basic metabolic panel, testing for aldosterone, adrenocorticotropic hormone, and renin, as well as endocrine consultation.
Autoimmune adrenalitis is treated similarly to sepsis, with IV fluids and steroids (dexamethasone initially and prednisone or hydrocortisone as maintenance). Patients may also require fludrocortisone for mineralocorticoid replacement, and if end-organ destruction has occurred, patients will need lifelong hydrocortisone supplementation, said Dr Patel.
Hypophysitis or inflammation of the pituitary gland typically presents with nonspecific symptoms like fatigue, headache, nausea, or vision change. The condition occurs in approximately 1.8% of patients receiving ipilimumab and 0.5% receiving pembrolizumab. Hypophysitis is managed with steroids (prednisone 1 mg/kg daily). Depending on when this is detected, however, patients may need lifelong hormonal supplementation.
Dr Patel highlighted only the more severe immunotherapy-related toxicities, but any organ in the body could develop a rare autoimmune condition.
“Treating with immunotherapy requires a very different skillset in terms of interviewing patients and discussing side effects than is typically seen with cytotoxic therapy, which has a more predictable side effect profile,” said Dr Patel. “With immune-related adverse events, there is a more delayed time onset, so clinicians have to remain vigilant for a longer time.”