This study did not demonstrate an association between PPI use and median OS in patients with CRC. This is the second retrospective analysis conducted to examine this association, but unlike that conducted by Graham et al., our study featured considerably more patients (117 vs 192) who were using PPI [19]. While Graham et al. only reported about 9% of their patients were using a PPI, our study showed over 25% were exposed to a PPI, 37% of which used the PPI for over a year. This likely more closely represents the general population given the increased use of PPI [2]. In addition, fewer patients in our study had an advanced CRC stage, with around 47% having stage 3 or 4 as compared to 62% of patients in the Graham et al. study. This difference is relevant, as more advanced disease would significantly impact OS and may explain the observed association between PPI use and OS in Graham et al. study.
Our study showed no difference in demographic characteristics among patients who used PPI compared to non-users. Although there was a higher incidence of HTN, HLD, DM, and CKD among patients with a history of PPI use, there were no differences in histologic grade, stage, or location between the two groups. The absence of an association between PPI use and known negative prognostic factors supports our conclusion that PPI use does not impact OS among CRC patients.
Graham et al. did not describe the racial make-up of their study population, but it is likely that our study had a higher proportion of Asian patients given that they comprised 60% of the study population [19]. It has been widely noted that incidence and mortality rates of CRC are lowest in Asians and Pacific Islanders in the United States, though more recent studies suggest that both the incidence and mortality of CRC is rising in Asia [20,21]. However, even after adjusting for race, there was no PPI impact on OS in our study. Our unique study population is racially diverse which enhances the generalizability of the results.
Our study has several limitations, in particular due to the retrospective nature of the analysis. Due to this research method, all data was extracted from patient charts, though every effort was made to limit errors at each step. Due to the nature of chart review data, it is also not certain that the patients listed as taking PPIs were compliant with the medications or were using the medication intermittently. Moreover, it is extremely hard to determine the intake duration accurately. In addition, the measured outcome in our study is overall survival rather than cancer specific survival. Cancer specific survival would be an important endpoint to study given the purported physiologic interaction between PPI use and CRC progression. Furthermore, all the patients in the study, after data refinement, underwent surgery, and this explains the relatively low percentage of patients with advanced stage (Stage III & IV). On the other hand, our study has a large sample size, as well as a multi-racial population which is unique and helps in generalizing the results on the general population.
In a large retrospective study of a racially diverse CRC patients, our study did not demonstrate an association between PPI use and CRC overall survival. Future studies would ideally be prospective, collect data about PPI history prior to and after diagnosis of CRC, and include a measure of cancer specific survival in the outcomes analysis. We would suggest that, until high quality prospective data are available, oncologists and other physicians not stop PPIs that are otherwise clinically indicated.