- In a retrospective study of 60 melanoma patients who developed severe gastroenterocolitis during checkpoint inhibitor therapy, hospital admission was necessary at a median of 10 weeks after the first dose
- Common symptoms were diarrhea, abdominal pain and nausea and vomiting; a smaller proportion of patients also presented with melena or hematochezia
- 50% of patients required second-line immunosuppression, but it had no detrimental effect on survival
- If patients were not readmitted for symptom recurrence, their colitis was likely to improve substantially within three months after discharge
Immunotherapy with checkpoint inhibitors (CPIs) has revolutionized cancer therapy. Their benefits can be offset, however, by immune-related adverse events that increase the risk of morbidity and mortality. Gastroenterocolitis is one of the most frequent of these, yet severe CPI-related colitis has not been well described.
Melanoma was the first indication for CPI approval in the U.S. Kerry L. Reynolds, MD, director of the Severe Immunotherapy Complications Service at the Massachusetts General Hospital Cancer Center, Michael Dougan, MD, PhD, physician in the Division of Gastroenterology at Mass General, and colleagues recently characterized the typical disease course of severe CPI-related colitis in patients with melanoma. Their findings appear in Cancer Medicine.
The researchers studied 60 adults (88 admissions) with stage III/IV melanoma who were hospitalized at Mass General for CPI-related colitis between February 5, 2011 and December 13, 2016. Patients were followed for further admissions until December 31, 2017.
Admissions occurred a median of 74 days (range, 18–1,075) after the first CPI dose. Presenting symptoms included diarrhea (94% of admissions), nausea/vomiting (36%), abdominal pain (42%), melena/hematochezia (20%) and fecal incontinence (6%).
Diagnostic endoscopy was substantially superior to radiography in revealing inflammation. Endoscopy was performed during 79 admissions, and mucosal inflammation was found in 72%. By comparison, cross-sectional imaging was performed during 38 admissions and was abnormal in only 53%.
Need for Second-Line Treatment
The first-line treatment for CPI-related colitis is immunosuppression with a high-dose corticosteroid (1–2 mg/kg daily of prednisone or the equivalent). Thirty of the 60 patients had persistent symptoms despite steroid treatment or symptom recurrence after attempted steroid taper and went on to receive a tumor necrosis factor-alpha inhibitor, usually infliximab.
Predictors of the need for second-line immunosuppression were:
- Ipilimumab monotherapy
- Stage III disease post-resection
- Absence of gastrointestinal metastases
- Lower serum albumin (average 3.5 g/dL)
- Lower lactate dehydrogenase (average 190 U/L)
- Lower relative lymphocyte count (average 12.9%)
The need for second-line immunosuppression was not associated with the severity of colitis, the CPI(s) given, the patient's performance status, corticosteroid use prior to admission or the presence/absence of radiographic or endoscopic abnormalities.
The average progression-free survival (PFS) and overall survival (OS) were 24 and 36 months, respectively. There were no significant differences in survival between the groups that did or did not require second-line immunosuppression.
Other Outcomes After Discharge
Following the first admission, the rate of colitis resolution (to grade 1 or the baseline level) was 87.5% at one-month post-discharge and 98% at three months. The same pattern was observed regardless of second-line immunosuppression.
One-third of the patients required at least one readmission for symptom recurrence. The need for second-line immunosuppression did not influence the readmission rate.
The Effect of Steroid Exposure Timing
In a subgroup analysis, the researchers included patients with stage IV melanoma who received at least two cycles of ipilimumab. They examined survival with respect to the timing of colitis and subsequent corticosteroid exposure: early exposure (<64 days after the first dose of CPI) or late exposure (≥64 days after).
- Early exposure to corticosteroid was significantly associated with decreased PFS (HR, 2.26; 95% CI, 1.00–5.11, P = .05)
- Early exposure had no significant effect on OS
One explanation for the finding about PFS is that patients who were admitted later for CPI-related colitis, and thus received corticosteroids later, may have benefited from receiving more immunotherapy. Another possibility, however, is that corticosteroid therapy limited the antitumor response.
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