Abstract
Various first-line chemotherapy treatment regimens for patients with metastatic pancreatic cancer have been approved in Japan, including gemcitabine (GEM); fluorouracil, leucovorin, irinotecan, and oxaliplatin combination (FOLFIRINOX); GEM plus albumin-bound paclitaxel (GEM+NPTX), and S-1 (tegafur + gimeracil + oteracil). However, direct comparisons of these chemotherapy regimens are limited. To assess the short-term and long-term outcomes associated with first-line chemotherapy regimens for metastatic pancreatic cancer compared with chemotherapy regimens recommended in Japanese guidelines. In this systematic review and network meta-analysis, the bibliographic databases PubMed, Cochrane Library, and Web of Science, as well as medical journals published between January 1, 2002, and December 31, 2018, were searched for clinical trials comparing chemotherapy regimens. Randomized 2-arm clinical trials evaluating first-line chemotherapy for advanced or metastatic pancreatic cancer were included. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions was followed for data abstractions. Data were pooled using a random-effects model. The SIGN 50 Quality Assessment Instrument was used to assess the risk of bias and overall study quality of the selected trials. The primary end point was overall survival (OS), and the secondary end point was progression-free survival (PFS) compared with GEM for first-line chemotherapy for metastatic pancreatic cancer. The Kaplan-Meier curve of GEM from the literature and the estimated hazard ratios (HRs) were used to model the long-term associations to calculate the area under the curve (AUC) (person-months) for OS and PFS of each chemotherapy. Sensitivity analyses with multiple functional models were conducted to confirm the long-term estimations. A total of 22 regimens (25 studies) for OS and a total of 18 regimens (21 studies) for PFS were identified from literature. The total number of participants was 10 186, with 5856 male (57.5%) and 4330 female (42.5%). The FOLFIRINOX and GEM+NPTX regimens were associated with reduction in the risk of death, with an HR of 0.57 (95% CI, 0.41-0.79) and 0.72 (95% CI, 0.55-0.95) compared with GEM, respectively. The curve estimation also showed that FOLFIRINOX had the largest AUC for survival at 15.49 person-months (range, 13.84-15.51 person-months), followed by GEM+NPTX with 12.36 person-months (range, 10.98-12.59 person-months), GEM+ERLO with 10.84 person-months (range, 9.66-11.23 person-months), S-1 with 8.44 person-months (range, 8.26-9.74 person-months), and GEM with 8.10 person-months (range, 7.93-9.38 person-months). The results of this network meta-analysis support the relative short-term and long-term outcomes associated with first-line chemotherapy for metastatic pancreatic cancer used clinically in Japan.
Highlights
Pancreatic cancer, a leading cause of cancer deaths in high-income countries, is one of the deadliest carcinomas worldwide.[1,2] It has the fourth highest site-specific cancer mortality rate in Japan,[3,4,5] and it is asymptomatic in the early stages and difficult to detect.[6]
The FOLFIRINOX and GEM+albumin-bound paclitaxel (NPTX) regimens were associated with reduction in the risk of death, with an hazard ratios (HRs) of 0.57 and 0.72 compared with GEM, respectively
The Japan Pancreas Society Clinical Practice Guidelines for Pancreatic Cancer 2019 described FOLFIRINOX as “a therapy that should be administered to patients up to 75 years old with a good performance status and organ function, such as bone marrow function.”[7]. GEM plus albumin-bound paclitaxel (GEM+NPTX) statistically significantly improved the overall survival (OS) and progression-free survival (PFS) in patients with metastatic pancreatic cancer in 2013.10 the median OS and PFS durations in GEM+NPTX were slightly inferior to those of the FOLFIRINOX phase 3 trial, the results showed a good balance between comparative efficacy and safety in terms of mild hematologic toxic effects
Summary
Pancreatic cancer, a leading cause of cancer deaths in high-income countries, is one of the deadliest carcinomas worldwide.[1,2] It has the fourth highest site-specific cancer mortality rate in Japan,[3,4,5] and it is asymptomatic in the early stages and difficult to detect.[6]. FOLFIRINOX has a potential to cause some serious adverse events.[9] The Japan Pancreas Society Clinical Practice Guidelines for Pancreatic Cancer 2019 described FOLFIRINOX as “a therapy that should be administered to patients up to 75 years old with a good performance status and organ function, such as bone marrow function.”[7] GEM plus albumin-bound paclitaxel (GEM+NPTX) statistically significantly improved the OS and PFS in patients with metastatic pancreatic cancer in 2013.10 the median OS and PFS durations in GEM+NPTX were slightly inferior to those of the FOLFIRINOX phase 3 trial, the results showed a good balance between comparative efficacy and safety in terms of mild hematologic toxic effects. Tegafur + gimeracil + oteracil (S-1), an approved chemotherapy regimen for pancreatic cancer in Japan and Korea, is recommended by the Japan Pancreas Society Clinical Practice Guidelines for Pancreatic Cancer 2019.7 several clinical trials have shown that S-1 is comparable to GEM, it is better tolerated than the FOLFIRINOX and GEM+NPTX therapies owing to its minor adverse events.[11,12,13,14] since S-1 can be administered orally, it is thought to be beneficial as an alternative therapy in terms of reducing the treatment burden on patients
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