PMID- 29557103 OWN - NLM STAT- MEDLINE DCOM- 20180427 LR - 20231011 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 3 IP - 3 DP - 2018 Mar 20 TI - Chemotherapy and radiotherapy for advanced pancreatic cancer. PG - CD011044 LID - 10.1002/14651858.CD011044.pub2 [doi] LID - CD011044 AB - BACKGROUND: Pancreatic cancer (PC) is a highly lethal disease with few effective treatment options. Over the past few decades, many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review attempts to synthesise all the randomised data available to help better inform patient and clinician decision-making when dealing with this difficult disease. OBJECTIVES: To assess the effect of chemotherapy, radiotherapy or both for first-line treatment of advanced pancreatic cancer. Our primary outcome was overall survival, while secondary outcomes include progression-free survival, grade 3/4 adverse events, therapy response and quality of life. SEARCH METHODS: We searched for published and unpublished studies in CENTRAL (searched 14 June 2017), Embase (1980 to 14 June 2017), MEDLINE (1946 to 14 June 2017) and CANCERLIT (1999 to 2002) databases. We also handsearched all relevant conference abstracts published up until 14 June 2017. SELECTION CRITERIA: All randomised studies assessing overall survival outcomes in patients with advanced pancreatic ductal adenocarcinoma. Chemotherapy and radiotherapy, alone or in combination, were the eligible treatments. DATA COLLECTION AND ANALYSIS: Two review authors independently analysed studies, and a third settled any disputes. We extracted data on overall survival (OS), progression-free survival (PFS), response rates, adverse events (AEs) and quality of life (QoL), and we assessed risk of bias for each study. MAIN RESULTS: 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studies did not have sufficient data to be included in the analysis, and many of the chemotherapy regimens studied were outdated.Compared to gemcitabine alone, participants receiving 5FU had worse OS (HR 1.69, 95% CI 1.26 to 2.27, moderate-quality evidence), PFS (HR 1.47, 95% CI 1.12 to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. AUTHORS' CONCLUSIONS: 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. FAU - Chin, Venessa AU - Chin V AD - The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria Street Darlinghurst, Sydney, NSW, Australia, 2010. FAU - Nagrial, Adnan AU - Nagrial A FAU - Sjoquist, Katrin AU - Sjoquist K FAU - O'Connor, Chelsie A AU - O'Connor CA FAU - Chantrill, Lorraine AU - Chantrill L FAU - Biankin, Andrew V AU - Biankin AV FAU - Scholten, Rob Jpm AU - Scholten RJ FAU - Yip, Desmond AU - Yip D LA - eng PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Review PT - Systematic Review DEP - 20180320 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 RN - 0 (130-nm albumin-bound paclitaxel) RN - 0 (Albumins) RN - 0 (Pyrimidines) RN - 0W860991D6 (Deoxycytidine) RN - 3Z8479ZZ5X (Epirubicin) RN - K8CXK5Q32L (pyrimidine) RN - P88XT4IS4D (Paclitaxel) RN - Q20Q21Q62J (Cisplatin) RN - U3P01618RT (Fluorouracil) RN - 0 (Gemcitabine) SB - IM UOF - doi: 10.1002/14651858.CD011044 MH - Albumins/administration & dosage MH - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use MH - Cisplatin/administration & dosage MH - Deoxycytidine/administration & dosage/adverse effects/analogs & derivatives MH - Epirubicin/administration & dosage MH - Fluorouracil/administration & dosage MH - Humans MH - Paclitaxel/administration & dosage MH - Pancreatic Neoplasms/*drug therapy/mortality/pathology/radiotherapy MH - Pyrimidines/administration & dosage MH - Randomized Controlled Trials as Topic MH - Treatment Outcome MH - Gemcitabine PMC - PMC6494171 COIS- VC: Venessa Chin received scholarship funding from the Research and Education Foundation of the Royal Australasian College of Physicians, Pancare Australia, Sydney Catalyst, National Health and Medical Research Council, and the Garvan Institute of Medical Research for work related to this review. AN: none known. KS: Katrin Sjoquist received programme grant funding from the National Health and Medical Research Council for work related to this review. She has received consultancy fees, fees for expert testimony and travel support for work unrelated to this review. CO: none known. LC: Lorraine Chantrill is employed (part-time) by NSW Health as a staff specialist in medical oncology and enrolled full-time in PhD studies supported by the Australian Federal Government. She has been paid as an advisory board member in relation to chemotherapy for pancreas cancer and has been paid for formulating educational materials and presentations. She has received grants for the practice of clinical trials in pancreas and other cancers. AB: Andew Biankin received grant funding from the Cancer Institute NSW for work related to this review. He also received consultancy fees from Celegene and Clovis Oncology for work unrelated to this review. His institution received consultancy fees from Roche for work unrelated to this review. RS: Rob Scholten's institution has received grant funding from the Belgian Health Care Knowledge Centre for work related to this review. His institution has also received funding from the WHO and World Federation of Haemophilia for travel and consultancy unrelated to this review. DY: Advisory Board Member, Specialised Therapeutics. EDAT- 2018/03/21 06:00 MHDA- 2018/04/28 06:00 PMCR- 2019/03/20 CRDT- 2018/03/21 06:00 PHST- 2018/03/21 06:00 [pubmed] PHST- 2018/04/28 06:00 [medline] PHST- 2018/03/21 06:00 [entrez] PHST- 2019/03/20 00:00 [pmc-release] AID - CD011044.pub2 [pii] AID - 10.1002/14651858.CD011044.pub2 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2018 Mar 20;3(3):CD011044. doi: 10.1002/14651858.CD011044.pub2.