We defined a subset of CPI associated colitis that we term “CPI microscopic colitis” that can be identified endoscopically and responds to colonic formulated budesonide, enabling treatment of this toxicity without the use of systemic glucocorticoids and while continuing immunotherapy for the underlying malignancy. The definition of CPI microscopic colitis that we use is based on mucosal assessment by endoscopy paired with biopsies; these patients have no mucosal evidence of inflammation (Mayo Endoscopic Score 0) but have lymphocytic/collagenous-pattern colitis on histopathology. We excluded patients with concurrent enteritis from this definition, as small intestinal inflammation is difficult to treat with currently available budesonide formulations, and thus such patients behave differently in the setting of available treatments. Whether this cohort definition identifies a distinct pathologic entity, or a milder subtype of CPI enterocolitis with a distinct treatment response, is unclear [6, 23]. In this retrospective analysis, we offer an estimate of CPI microscopic colitis incidence with approximately a third of our patients with mucosal inflammation falling into this group. We further describe key features of the typical disease course, and compare them to non-microscopic colitis. In our cohort, budesonide was effective as first-line treatment for CPI microscopic colitis, as it is in patients who develop spontaneous microscopic colitis [24, 25]. Importantly, many of our patients were able to remain on immunotherapy after initiation of budesonide. Although immunotherapy was ultimately discontinued in most patients, often for the development of another irAE, several patients in the cohort were able to complete their immunotherapy treatment course while on budesonide.
Most of the patients in our cohort were identified by flexible sigmoidoscopy paired with a negative upper endoscopy. Although CPI colitis can often have regional variability, approximately 95% of patients have disease on the left side, which would be observable by flexible sigmoidoscopy . For most of our cohort, we cannot exclude the possibility that right-sided mucosal injury would have been apparent had a full colonoscopy been performed; however, our data suggest that colitis occurring in the absence of left-sided mucosal injury can be treated with budesonide, regardless of whether information about the right colon is available. Determining whether isolated right-sided colitis is a rare cause of failure to respond to budesonide in otherwise apparent CPI microscopic colitis will require evaluation of larger cohorts. Upper gastrointestinal inflammation occurred in 39.5% (15/38) of our cohort, either in isolation or paired with colitis, indicating that gastric and duodenal inflammation is common in patients with gastrointestinal toxicities from CPIs and may be an important cause of diarrhea in patients on CPIs who do not have colitis on lower endoscopy .
From the range of cancers represented in our cohort, we suggest that CPI microscopic colitis occurs across cancer types, indicating a relationship to the immunotherapeutic agent rather than to cancer-specific factors. The relatively large proportion of melanoma and non-small cell lung cancer in our cohorts likely reflects the prevalence of those cancers among patients on CPIs more generally. We did not find a female preponderance in our study, and in our analysis of the prevalence of selected known risk factors for spontaneous microscopic colitis, we found no predictors of disease . Proton pump inhibitor use and hormonal exposure in particular were more common in the microscopic colitis cohort, though this finding did not reach statistical significance. Larger analyses will be necessary in order to definitively determine whether such an association exists, as has been reported for spontaneous microscopic colitis [24, 25].
We identified few clinical distinctions between CPI microscopic colitis and enterocolitis presenting with mucosal signs of inflammation, aside from the endoscopic features used to define these cohorts. CPI microscopic colitis and non-microscopic colitis were indistinguishable by CTCAE grade on presentation, as well as by routine laboratory testing. The frequency of microscopic colitis was numerically higher in patients treated with single agent PD-(L)1 blockade, though this association did not reach statistical significance in this cohort. Nevertheless, the finding is suggestive that combination immunotherapy, which induces more frequent colitis, may also lead to more significant mucosal injury. We did find that the time interval between CPI exposure and symptom onset was longer for CPI microscopic colitis (median 150.0 days) than for non-microscopic colitis (median 68.0 days), though the intervals between the two cohorts overlapped enough to preclude an accurate diagnosis of microscopic colitis using time of onset alone. The absence of other clear indicators of CPI microscopic colitis, and the availability of a specific management strategy (i.e. local glucocorticoids) underscores the potential value of early endoscopic evaluation in patients with suspected CPI enterocolitis. This subset of CPI enterocolitis appears to be common (approximately 1/3 of our total CPI enterocolitis cohort), and the use of budesonide for treatment could not only prevent the use of systemic glucocorticoids, but also enable some patients to received further immunotherapy.
Most patients who develop enterocolitis from CPIs, regardless of the severity of mucosal inflammation, will eventually discontinue CPI treatment due to toxicity; these findings are in line with prior literature [10, 11, 15]. Absence of recrudescence after initial symptom control was achieved in over 80% of the microscopic colitis cohort. As the patients with microscopic colitis generally continued to receive immunotherapy for longer than those patients with severe CPI enterocolitis, we would expect a higher incidence of dose or time dependent adverse events. The incidence of novel irAE development in our cohort (23.7%) is consistent with prior studies on overall CPI enterocolitis rechallenged with immunotherapy, and was statistically identical between the two groups .
Our survival analyses of TTTF and PFS are intriguing, though confounded by multiple variables in our heterogeneous cohort, including different underlying stage and type of malignancy, the specific therapies used, and duration of therapy prior to onset of toxicity. Budesonide use was statistically significantly associated with decreased risk of treatment failure (HR 0.28). The heterogeneous mixture of treatments and malignancies in our cohort coupled with its small size reduce our ability to determine the clinical importance of this finding. Although consistent with a beneficial effect of local glucocorticoid delivery on antitumor immunity, the reduction in the risk of treatment failure could also reflect the longer duration of CPI use prior to symptom onset, or, less likely, differences in underlying biology between microscopic and non-microscopic colitis induced by CPIs. Ultimately, prospective analyses with more uniform cohorts will be necessary to determine whether these preliminary cancer outcome findings are clinically meaningful.
Our study’s retrospective nature precluded causal inference and introduced inherent survival bias, and our small sample size precluded multivariate regression; we performed univariate Cox regression modeling to ensure that we did not overfit our data. The relatively short time frame of the study precluded a long-term survival analysis. Several of our variables were highly correlated, limiting our ability to parse out their individual effects and introducing potential codependence into our findings. Most patients in the cohort received PD-1 or PD-L1 inhibitors, reflecting current practice but also potentially reflecting differences in the risk for this syndrome according to immunotherapeutic agent. Our sample size also precluded stratification by tumor type or stage.