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Reply to G.B. Holt.

In his letter, Holt expressed concern that the survival difference we observed in our study between intraperitoneal (IP)/intravenous (IV) chemotherapy and IV chemotherapy may be a result of residual confounding between the two groups (eg, differences between institutional practices) rather than because of the treatment itself. The main finding of our study was that IP/IV chemotherapy was associated with a significantly improved survival compared with IV chemotherapy, with a hazard ratio (HR) of 0.68 obtained from a univariable Cox proportional hazards regression model within the propensity score–matched sample. We acknowledge that the standardized differences between groups after propensity score matching exceeded the standard threshold of 10% for some covariates (ie, age, Charlson score, primary tumor site, and histology); however, examination of the raw frequencies of these variables within the propensity score–matched sample demonstrates that they are reasonably well balanced between groups. In addition, when we conducted a multivariable Cox proportional hazards regression model that included these variables within the propensity score–matched sample—a doubly robust analysis—we obtained a similar HR of 0.71. We were concerned that our results might be a result of differences between institutions, rather than treatment, and performed a sensitivity analysis to examine this. Specifically, we excluded each institution, one by one, to ensure that the survival benefit observed was not driven by outcomes at a single institution. As reported in our article, the adjusted HRs ranged from 0.61 to 0.76 upon excluding each institution one by one, indicating that the survival benefit observed was not driven by outcomes at a single institution. We were further reassured that this was unlikely because institution was not significantly associated with overall survival in the full cohort (P5 .16) or within treatment subgroups within the propensity score–matched sample (P5 .77 for IP/IV and P 5 .11 for IV). Nevertheless, we performed additional analyses to address the potential for Simpson’s paradox. In brief, Simpson’s paradox occurs when an association does not appear within subgroups but does appear when data are combined, or vice versa. In the context of our study, Simpson’s paradox with the lurking variable of institution would be problematic if a survival benefit for IP/IV chemotherapy was not observed within institutions. As shown in Table 1, the overall survival was similar between institutions, and the central estimates were in favor of IP/IV for each institution, which is consistent with the aggregate results. In addition, we have included in Table 2 the raw percentages by institution that were omitted from Appendix Table A1 in our original article. Together, these results suggest that the survival benefit we observed was unlikely to be driven by differences in practices at any individual institution, particularly because the HR that we observed was similar to results from several prior randomized controlled trials.