Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials

Abstract

Background: After a 1999 National Cancer Institute (NCI) clinical alert was issued, chemoradiotherapy has become widely used in treating women with cervical cancer. Two subsequent systematic reviews found that interpretation of the benefits was complicated, and some important clinical questions were unanswered.

Patients and methods: We initiated a meta-analysis seeking updated individual patient data from all randomized trials to assess the effect of chemoradiotherapy on all outcomes. We prespecified analyses to investigate whether the effect of chemoradiotherapy differed by trial or patient characteristics.

Results: On the basis of 13 trials that compared chemoradiotherapy versus the same radiotherapy, there was a 6% improvement in 5-year survival with chemoradiotherapy (hazard ratio [HR] = 0.81, P < .001). A larger survival benefit was seen for the two trials in which chemotherapy was administered after chemoradiotherapy. There was a significant survival benefit for both the group of trials that used platinum-based (HR = 0.83, P = .017) and non-platinum-based (HR = 0.77, P = .009) chemoradiotherapy, but no evidence of a difference in the size of the benefit by radiotherapy or chemotherapy dose or scheduling was seen. Chemoradiotherapy also reduced local and distant recurrence and progression and improved disease-free survival. There was a suggestion of a difference in the size of the survival benefit with tumor stage, but not across other patient subgroups. Acute hematologic and GI toxicity was increased with chemoradiotherapy, but data were too sparse for an analysis of late toxicity.

Conclusion: These results endorse the recommendations of the NCI alert, but also demonstrate their applicability to all women and a benefit of non-platinum-based chemoradiotherapy. Furthermore, although these results suggest an additional benefit from adjuvant chemotherapy, this requires testing in randomized trials.

Fig A1.

Event flow diagram (main analysis group of 13 trials only).

Fig 1.

(A) Hazard ratio (HR) plot for survival. Each trial is represented by a square, the center of which gives the hazard ratio for that trial. Size of square is proportional to the information in that trial. Ends of horizontal bars denote 99% CI and inner bars mark 95% CI. Trials are ordered chronologically by date of start of trials (oldest first). The shaded diamonds give the overall hazard ratio for the combined results of all trials; the center denotes the hazard ratio, and the extremities, the 95% CI. Trials of chemoradiation versus radiotherapy: HR = 0.81 (95% CI, 0.71 to 0.91), P = .0006; heterogeneity χ² = 12.43, P = .646; I² = 0.00. Trials of chemoradiotherapy + adjuvant chemotherapy versus radiotherapy: HR = 0.46 (95% CI, 0.32 to 0.66), P = .00002; heterogeneity χ² = 0.00, P = .945; I² = 0.00. Interaction test: χ² = 8.39, df = 1, P = .004. (B) Kaplan-Meier curves for survival. GOG, Gynecologic Oncology Group; SWOG, Southwest Oncology Group; FU, fluorouracil; MMC, mitomycin; CDDP, cisplatin; CDBCA, carboplatin; VCR, vincristine; BLM, bleomycin; CTRT, chemoradiotherapy; O-E, observed minus expected events.

Fig 2.

(A) Survival and (B) disease-free survival by tumor stage (main group of 13 trials only). CTRT, chemoradiotherapy.

Fig 3.

(A) Hazard ratio (HR) plot for survival (sensitivity analysis). Main group of trials: HR = 0.81 (95% CI, 0.71 to 0.91), P = .0006; heterogeneity χ² = 12.43, I² = 0.00. Trials using HU on control arms: HR = 0.63 (95% CI, 0.54 to 0.74), P = .00000002; heterogeneity χ² = 1.39, I² = 0.00. Trials using additional radiotherapy (RT) on control: HR = 0.50 (95% CI, 0.37 to 0.67), P = .000006. (B) Kaplan-Meier curves for survival (sensitivity analysis). GOG, Gynecologic Oncology Group; RTOG, Radiation Therapy Oncology Group; FU, fluorouracil; MMC, mitomycin; CDDP, cisplatin; CDBCA, carboplatin; VCR, vincristine; BLM, bleomycin; HU, hydroxyurea; CTRT, chemoradiotherapy; O-E, observed minus expected events.