Abstract: We included 42 studies addressing chemotherapy in 9463 patients with advanced pancreatic cancer. We did not identify any eligible studies on radiotherapy. We did not find any benefit for chemotherapy over best supportive care. However, two identified studies did not have sufficient data to be included in the analysis, and many of the chemotherapy regimens studied were outdated. Compared to gemcitabine alone, participants receiving 5FU had worse OS (HR 1.69, 95% CI 1.26 to 2.27, moderate-quality evidence), PFS (HR 1.47, 95% CI 1.12 to 1.92) and QoL. On the other hand, two studies showed FOLFIRINOX was better than gemcitabine for OS (HR 0.51 95% CI 0.43 to 0.60, moderate-quality evidence), PFS (HR 0.46, 95% CI 0.38 to 0.57) and response rates (RR 3.38, 95% CI 2.01 to 5.65), but it increased the rate of side effects. The studies evaluating CO-101, ZD9331 and exatecan did not show benefit or harm when compared with gemcitabine alone. Giving gemcitabine at a fixed dose rate improved OS (HR 0.79, 95% CI 0.66 to 0.94, high-quality evidence) but increased the rate of side effects when compared with bolus dosing. When comparing gemcitabine combinations to gemcitabine alone, gemcitabine plus platinum improved PFS (HR 0.80, 95% CI 0.68 to 0.95) and response rates (RR 1.48, 95% CI 1.11 to 1.98) but not OS (HR 0.94, 95% CI 0.81 to 1.08, low-quality evidence). The rate of side effects increased. Gemcitabine plus fluoropyrimidine improved OS (HR 0.88, 95% CI 0.81 to 0.95), PFS (HR 0.79, 95% CI 0.72 to 0.87) and response rates (RR 1.78, 95% CI 1.29 to 2.47, high-quality evidence), but it also increased side effects. Gemcitabine plus topoisomerase inhibitor did not improve survival outcomes but did increase toxicity. One study demonstrated that gemcitabine plus nab-paclitaxel improved OS (HR 0.72, 95% CI 0.62 to 0.84, high-quality evidence), PFS (HR 0.69, 95% CI 0.58 to 0.82) and response rates (RR 3.29, 95% CI 2.24 to 4.84) but increased side effects. Gemcitabine-containing multi-drug combinations (GEMOXEL or cisplatin/epirubicin/5FU/gemcitabine) improved OS (HR 0.55, 95% CI 0.39 to 0.79, low-quality evidence), PFS (HR 0.43, 95% CI 0.30 to 0.62) and QOL. We did not find any survival advantages when comparing 5FU combinations to 5FU alone. Combination chemotherapy has recently overtaken the long-standing gemcitabine as the standard of care. FOLFIRINOX and gemcitabine plus nab-paclitaxel are highly efficacious, but our analysis shows that other combination regimens also offer a benefit. Selection of the most appropriate chemotherapy for individual patients still remains difficult, with clinicopathological stratification remaining elusive. Biomarker development is essential to help rationalise treatment selection for patients.

Plain-language summary: We looked for all studies in people with pancreatic cancer that could not be operated on (locally advanced) or that had already spread beyond the pancreas (metastatic). We found 42 clinical studies involving 9463 participants who were receiving their first therapy for PC. Our search is current to June 2017. The studies compared one therapy against either best supportive care (symptom management only) or another type of therapy. Studies had to evaluate overall survival (or time to death). The study could be testing either chemotherapy (drugs that kill or slow the growth of cancer cells) or radiotherapy (X-ray treatment). We collected data on survival, tumour response rate, side effects and quality of life. The results of clinical studies addressing targeted/biological therapies, immunotherapies, second-line therapies and local treatments for locally advanced disease will be reported in a separate Cochrane Review. This review has shown that in advanced disease, combination chemotherapy with FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin combination); GEMOXEL (gemcitabine, oxaliplatin and capecitabine); cisplatin/epirubicin/5FU/gemcitabine; gemcitabine plus nab-paclitaxel; and gemcitabine plus a fluoropyrimidine agent, provide a survival advantage over gemcitabine alone. These combinations do increase side effects. Gemcitabine given slowly using a fixed rate of infusion may be more effective than giving it in the standard way, which is quickly over 30 minutes. The quality of the evidence varied greatly amongst comparisons. The highest quality evidence was for gemcitabine versus fixed dose rate gemcitabine and some of the gemcitabine combinations (fluoropyrimidine, topoisomerase, and taxane). We judged the studies for quality using factors like how well they were conducted, how well they reported results and whether they used a placebo.