Comparative Outcomes of First-Line Chemotherapy for Metastatic Pancreatic Cancer Among the Regimens Used in Japan: A Systematic Review and Network Meta-analysis

Abstract

Importance: 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.

Objective: 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.

Data sources: 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.

Study selection: Randomized 2-arm clinical trials evaluating first-line chemotherapy for advanced or metastatic pancreatic cancer were included.

Data extraction and synthesis: 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.

Main outcomes and measures: 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.

Results: 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).

Conclusions and relevance: 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.

Figure 1.. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram of Study Selection Process

Figure 2.. Pooled Estimates of the Network Meta-analysis of Recommended Chemotherapy Regimens in Japan

ERLO indicates erlotinib; FFX, fluorouracil + leucovorin + irinotecan + oxaliplatin; GEM, gemcitabine; HR, hazard ratio; NPTX, albumin-bound paclitaxel; OS, overall survival; PFS, progression-free survival; S-1, tegafur + gimeracil + oteracil.

Figure 3.. Comparison With Estimated Survival Curves

ERLO indicates erlotinib; FFX, fluorouracil + leucovorin + irinotecan + oxaliplatin; GEM, gemcitabine; KM, Kaplan-Meier; NPTX, albumin-bound ‎paclitaxel; OS, overall survival; PFS, progression-free survival; S-1, tegafur + gimeracil + oteracil.