Background: We performed a critical overview of published systematic reviews (SRs) of chemotherapy for advanced and locally advanced pancreatic cancer, and evaluated their quality using AMSTAR2 and ROBIS tools. Materials and Methods: PubMed and Cochrane Central Library were searched for SRs on 13th June 2020. SRs with metaanalysis which included only randomized controlled trials and that had assessed chemotherapy as one of the treatment arms were included. The outcome measures, which were looked into, were progression-free survival (PFS), overall survival (OS), and adverse events (AEs) of grade 3 or above. Two reviewers independently assessed all the SRs with both ROBIS and AMSTAR2. Results: Out of the 1,879 identified records, 26 SRs were included for the overview. Most SRs had concluded that gemcitabine-based combination regimes, prolonged OS and PFS, but increased the incidence of grade 3-4 toxicities, when compared to gemcitabine monotherapy, but survival benefits were not consistent when gemcitabine was combined with molecular targeted agents. As per ROBIS, 24/26 SRs had high risk of bias, with only 1/26 SR having low risk of bias. As per AMSTAR2, 25/26 SRs had critically low, and 1/26 SR had low, confidence in the results. The study which scored ‘low’ risk of bias in ROBIS scored ‘low confidence in results’ in AMSTAR2. The inter-rater reliability for scoring the overall confidence in the SRs with AMSTAR2 and the overall domain in ROBIS was substantial; ROBIS: kappa=0.785, SEM=0.207, p<0.001; AMSTAR2: kappa=0.649, SEM=0.323, p<0.001. Conclusion: Gemcitabine-based combination regimens can prolong OS and PFS but also worsen AEs when compared to gemcitabine monotherapy. The included SRs have an overall low methodological quality and high risk of bias as per AMSTAR2 and ROBIS respectively.

The risk of composite outcome was significantly lower among SGLT2 inhibitor therapy users compared to IBT users (Hazard ratio (HR):0.778, p=0.001, 95% confidence interval (CI):0.671-0.904). When individual outcomes were considered SGLT2 inhibitor users had a lower risk of stroke (HR:0.831, p=0.028, 95%CI:0.704-0.981) and MI (HR:0.704, p=0.024, 95%CI:0.519-0.955) compared to IBT users. However, the difference in the risk of all-cause mortality was non-significant between two groups (HR:1.605, p=0.433, 95%CI:0.492-5.238). Among patients with co-morbid HF, the risk of HF-related ER visits was significantly lower for SGLT2 inhibitor therapy users (HR:0.629, p,0.001, 95% CI:0.507-0.779) compared to IBT users, but the association was not significant for HF-related hospitalizations (HR:0.770, p=0.109, 95%CI:0.560-1.060). Conclusions: SGLT2 inhibitor therapy use was associated with a lower risk of stroke, MI, and HF-related ER visits compared to IBT use.

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