Drug-Induced Colitis in a Patient With Metastatic Melanoma
Background:
Over the last decade, there has been an increasing incidence of drug-induced enterocolitis among cancer patients. This is largely due to the increasing use of immune checkpoint inhibitors (ICIs). However, a less well-known but equally important cause of drug-induced enterocolitis are Mitogen Activated Protein Kinase (MAPK) pathway inhibitors. Herein, we present a patient with metastatic melanoma developing severe inflammatory enterocolitis secondary to the use of inhibitors of BRAF and MEK, two proteins central to the MAPK pathway.
Methods:
A 32-year-old male with a history of metastatic melanoma with new onset inflammatory enterocolitis was referred by his oncologist to our IBD Center. His melanoma was diagnosed five years prior and was treated with excision of the lesion and local lymph nodes, followed by nivolumab for one year. He was eventually found to have liver metastases and was started on dabrafenib and trametinib, a combination BRAF and MEK inhibitor regimen. This resulted in radiologic remission. At the time of referral, he had been on these medications for three years. Upon starting this regimen, he experienced up to five watery, non-bloody stools per day. This was associated with abdominal pain, urgency and nighttime awakenings due to diarrhea. Despite this, he did not report his symptoms to his providers. Laboratory monitoring for medication toxicity revealed iron deficiency anemia prompting an esophagogastroduodenoscopy and colonoscopy.
Results:
The upper endoscopy showed duodenal ulcers, terminal ileitis, and deep continuous colonic ulcers. Pathology demonstrated duodenal villous blunting, chronic ileitis, and chronic active colitis with no architectural crypt abnormalities - findings not typically associated with IBD. No infectious etiologies were identified. Thus, he was referred to our IBD center for evaluation. During his visit, he denied any family history of IBD. He also denied any extraintestinal manifestations. Labs were significant for elevated CRP at 3.42 mg/dL (normal: < 0.50) and fecal calprotectin at >8000 μg/mg (normal: < 100 μg/mg). BRAF/MEK inhibitor-induced enterocolitis was suspected. Given his history of metastatic melanoma, there was hesitation with discontinuing these medications. A twelve week course of steroids was initially pursued; he however remained symptomatic and his fecal calprotectin remained markedly elevated. After a multidisciplinary discussion with the patient and his oncologist, a decision was made to stop his BRAF/MEK inhibitors. Within three months of cessation, he reported complete abatement of his symptoms.
Conclusions:
BRAF/MEK inhibitors have been implicated as a cause of inflammatory enterocolitis. Retrospective data have suggested a potentiating effect in patients who were previously treated with ICIs. However, the mechanisms by which BRAF/MEK inhibitors cause enterocolitis remain poorly understood. Commonly, patients present with abdominal pain and bloody diarrhea. Elevated inflammatory markers and anemia are also seen. Like ICI colitis, the clinical course is variable. Some patients experience only mild diarrhea, while others progress to GI bleeding and even perforation. If possible, drug discontinuation is preferred. Systemic glucocorticoids have also been used with varying results. Severe cases frequently require biologic therapy. With combination BRAF/MEK inhibitor use becoming more common, a high degree of clinical suspicion is needed to diagnose this under-recognized disease.
