Annals for Hospitalists Inpatient Notes - Clinical PearlsA Young Man With Lung Cancer and Diarrhea

The patient is a 30-year-old man with metastatic nonsmall cell lung cancer who presents with diarrhea. The cancer was diagnosed 7 months prior to admission (PTA), with metastases to the brain, liver, and bone. He has been treated with radiation therapy to the brain and the right iliac wing. He also received 6 doses of pembrolizumab (last dose 6 weeks PTA). Reevaluation about 1 month PTA found disease progression, so the treatment regimen was switched to osimertinib. The patient has been receiving this treatment on a daily basis for the past 3 weeks. For the past 2 weeks, he has had diarrhea several times per day that intermittently contains dark blood. On the day of admission, he felt lightheaded, developed a new fever, and presented to the emergency department. He reported no exposure to people with gastrointestinal illness or new animals, travel, antibiotic use, or consumption of uncooked foods or unsafe water. On initial evaluation, the patient's heart rate was 122 beats per minute, blood pressure was 100/54 mm Hg, respiratory rate was 22 breaths per minute, and temperature was 38.3 C. Vital signs normalized with administration of fluids and broad-spectrum antibiotics, and he was admitted to the hospital for further care. Relevant laboratory studies included a leukocyte count of 5300/L and a hemoglobin level of 14.8 g/dL. Stool was negative for Clostridium difficile, and a gastrointestinal polymerase chain reaction panel (including studies for Shigella, Shiga-like toxin-producing Escherichia coli, and enteroinvasive E coli) was also negative. The diarrhea admixed with dark blood persisted over the next 48 hours, and the patient was referred for colonoscopy. Endoscopic evaluation found an area of severely altered, atrophic, congested, erythematous, friable, and hemorrhagic mucosa in the rectum, sigmoid colon, and descending colon. Biopsies were taken. The patient's oncologist suspected that these findings were related to the cancer therapy. How might this presentation be related to the patient's cancer treatment? Clinical Pearls 1. Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor, commonly causes diarrhea (1). However, diarrhea caused by this agent is almost always mild (grade 1 to 2) and only rarely treatment-limiting. In this case, the fever and blood suggested another cause of the symptoms. 2. Pembrolizumab is one of the drugs in a class of agents referred to as immune checkpoint inhibitors (ICPis) (2). These medications enhance antitumor immunity by blocking the effects of negative regulators (so-called checkpoints) on host T cells. Other ICPis include ipilimumab, nivolumab, atezolizumab, darvalumab, and avelumab. 3. ICPis are associated with a diverse side effect profile called immune-related adverse events (irAEs) (2). These side effects can involve almost any organ system and can present with symptoms ranging in severity from mild to life-threatening. Examples include rash, colitis, hepatitis, endocrinopathies (e.g., hypo- and hyperthyroidism, primary adrenal failure, and hypophysitis), pneumonitis, nephritis, inflammatory arthritis, myositis, myocarditis, pericarditis, and a range of neurologic and hematologic syndromes. 4. Immune-related colitis is one of the most common irAEs. In this case, the patient's colitis was believed to be caused by prior use of pembrolizumab, even though the medication had been discontinued weeks before the symptoms developed. Immune-related colitis can occur anywhere from 1 to 32 weeks after initiation of therapy, sometimes long after the ICPi has been discontinued (3). In this case, the diarrhea was intermittently bloody, but immune-related colitis can also present with nonbloody diarrhea. The pathology of immune-related colitis has not been well described. So far, there are no histologic features that seem to be pathognomonic for the condition (3). Overall, the histologic findings of immune-related colitis appear to be nonspecific, overlapping with other causes of colitis. In this case, the histology was indistinguishable from naturally occurring ulcerative colitis, emphasizing the importance of the clinical history in making an accurate diagnosis. 5. Treatment of irAEs includes discontinuation of the offending medications and judicious use of immunosuppressant medications, including corticosteroids (2, 4). Given the relative novelty of ICPis, there is little evidence to guide treatment of the side effects, and most contemporary recommendations are based on expert opinion. It is generally believed that mild symptoms can simply be monitored and may not require discontinuation of the drug; however, more severe symptoms usually do require discontinuation as well as corticosteroid therapy. Although the optimal corticosteroid regimen is not well established, 1 to 2 mg of prednisone/kg of body weight per day is typically recommended. More severe disease, or disease that is refractory to corticosteroids, has been treated with infliximab in some cases. It seems that irAEs usually resolve with treatment. 6. When patients receiving active cancer therapy are hospitalized, communication between the hospital team and the patient's oncologist is critical. This is especially true for patients being treated with novel medications or those that are associated with complex side effects. In this case, only the patient's oncologist suspected the diagnosis of pembrolizumab-associated immune-related colitis. As hospitalists continue to learn about these medications, it will be important to maintain open communication with the managing oncologists when these patients require hospital admission. Resolution The osimertinib therapy was withheld, and the patient was prescribed 1.5 mg/kg of body weight per day of intravenous methylprednisolone, which was later converted to oral prednisone. The patient improved rapidly, with only 1 to 2 nonbloody bowel movements per day at the time of discharge from the hospital. Summary When patients receiving cancer therapies are admitted to the hospital with acute illness, hospitalists should consider the possibility that the problem may be iatrogenic. Communication with the patient's oncologist can be very helpful in recognizing the admission problem as a side effect of treatment. As the use of ICPis expands, hospitalists will need to become familiar with the wide range of associated irAEs.