Addition of Platinum Derivatives to Fluoropyrimidine-Based Neoadjuvant Chemoradiotherapy for Stage II/III Rectal Cancer: Systematic Review and Meta-Analysis

Abstract

Background: Current guidelines recommend neoadjuvant therapy for patients with stage II or III rectal cancer. The addition of platinum derivatives to fluoropyrimidine-based chemoradiotherapy has been frequently investigated, but their role in this setting remains controversial.

Methods: PubMed, Cochrane Library, and Web of Science were systematically searched for randomized trials comparing chemoradiotherapy with or without platinum agents in stage II or III rectal cancer. Main outcome parameters were overall and disease-free survival, additional outcomes included pathological complete response, isolated local recurrence, distant recurrence, toxicity, and perioperative morbidity. Time-to-event data were pooled as hazard ratios (HRs) by the inverse variance method and binary outcomes as odds ratios (ORs) by the Peto method with their respective 95% confidence interval (CI). All statistical tests were two-sided.

Results: Ten randomized controlled trials with data on 5599 patients were included in the meta-analysis. Platinum derivatives did not statistically significantly improve overall survival (HR = 0.93, 95% CI = 0.82 to 1.05, P = .23), disease-free survival (HR = 0.91, 95% CI = 0.83 to 1.01, P = .07), or local recurrence (OR = 0.83, 95% CI = 0.66 to 1.05, P = .12). However, it led to a statistically significant increase of pathological complete response (OR = 1.31, 95% CI = 1.10 to 1.55, P = .002) and a statistically significant reduction of distant recurrence (OR = 0.78, 95% CI = 0.66 to 0.92, P = .004). Benefits were accompanied by higher rates of grade 3 or 4 toxicities.

Conclusions: Intensified neoadjuvant chemoradiotherapy with the addition of platinum derivatives cannot be recommended routinely because it did not improve overall or disease-free survival and was associated with increased toxicity. It needs to be elucidated whether the benefits in distant recurrence and pathological complete response may be advantageous for selected high-risk patients.

© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Preferred reporting items for systematic reviews and meta-analyses flowchart. RTCs = randomized controlled trials.

Figure 2.

Forest plots for survival endpoints. Analyses for (A) overall survival (OS) and (B) disease-free survival (DFS) are shown. Hazard ratios (HRs) were pooled in meta-analyses by the generic inverse variance method, and P values for the overall effects were calculated based on a two-sided Z-test for independent samples for effect measures on the log scale. 5-FU = 5-fluorouracil; CI = confidence interval; CRT = chemoradiotherapy.

Figure 3.

Forest plot for pathological complete response. Odds ratios (ORs) were pooled in meta-analyses by the Peto method, and P values for the overall effects were calculated based on a two-sided Z-test for independent samples for effect measures on the log scale. 5-FU = 5-fluorouracil; CI = confidence interval; CRT = chemoradiotherapy.

Figure 4.

Forest plots for recurrence endpoints. Analyses for (A) local recurrence and (B) distant recurrence are shown. Odds ratios (ORs) were pooled in meta-analyses by the Peto method, and P values for the overall effects were calculated based on a two-sided Z-test for independent samples for effect measures on the log scale. 5-FU = 5-fluorouracil; CI = confidence interval; CRT = chemoradiotherapy.