Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient data meta-analysis.
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.


OBJECTIVE
We initiated a meta-analysis seeking updated individual patient data (IPD) from all randomised controlled trials (RCTs) to assess the effect of chemoradiotherapy on all outcomes. We pre-specified analyses to investigate whether the effect of chemoradiotherapy differed by trial or patient characteristics.


METHODS
We supplemented MEDLINE, LILACS and CANCERLIT searches with information from trial registers, by handsearching relevant meeting proceedings and by discussion with relevant trialists and organisations. Searches were updated until October 2009.


METHODS
Both published and unpublished trials were eligible for inclusion provided the patients had been randomised between radiotherapy (with or without surgery) versus concomitant chemoradiotherapy (with or without surgery); that the method of randomisation precluded prior knowledge of the treatment to be assigned; and that the trial had completed patient recruitment before the date of the final analyses.


METHODS
We carried out a quantitative meta-analysis using updated information from individual patients from all available RCTs. We sought data from all patients randomised in all eligible trials. We obtained updated information on survival, recurrence and date of last follow up. To avoid potential bias, we requested information for all randomised patients, including those who had been excluded from the investigators' original analyses.


RESULTS
Eighteen trials were identified and 15 of these were eligible for inclusion in the main analysis. 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 < 0.001). A larger survival benefit was seen for the two further 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 = 0.017) and non-platinum based (HR = 0.77, P = 0.009) 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 (DFS). There was a suggestion of a difference in the size of the survival benefit with tumour stage, but not across other patient subgroups. Acute haematological and gastro-intestinal toxicity were increased with chemoradiotherapy, but data were too sparse for an analysis of late toxicity.


CONCLUSIONS
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 RCTs.
See list of members in acknowledgements section, UK.
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy / Q000379:methods; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D016685:Mitomycin / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*
D016685:Mitomycin; D002945:Cisplatin; D005472:Fluorouracil