Neoadjuvant chemotherapy for locally advanced cervix cancer.
BACKGROUND
Despite the enrollment of more than 3000 women in randomised trials, the benefits and risks of neoadjuvant chemotherapy in the treatment of locally advanced cervical cancer remained uncertain.


OBJECTIVE
This systematic review and individual patient data (IPD) meta-analysis aimed to assess the effect of neoadjuvant chemotherapy in two comparisons: (1) neoadjuvant chemotherapy followed by radical radiotherapy compared to the same radiotherapy alone; and (2) neoadjuvant chemotherapy followed by surgery compared to radical radiotherapy alone.


METHODS
Medline and CancerLit searches were supplemented with information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists and organisations. These searches have been updated regularly until December 2002.


METHODS
To be included, trials had to be properly randomised and had to include patients with locally advanced cervical cancer who had received neoadjuvant cytotoxic chemotherapy before radiotherapy or surgery or both treatments. Concurrent chemoradiotherapy trials were not included. The comparisons had to be unconfounded by use of additional agents or interventions. Patient enrollment should have started after 1 January 1975 and be completed by September 2000.


METHODS
We collected, validated and re-analysed updated trial data on all randomised patients from all relevant trials. Any queries were resolved and the final database entries verified by the responsible trial investigator, data manager or statistician. Two separate sets of analyses (by intention-to-treat) were carried out according to the treatment comparisons (1 and 2) already described. For all outcomes, we obtained overall pooled hazard ratios using the fixed effect model. To explore the potential impact of trial design, we pre-planned analyses that grouped trials by important aspects of their design that might influence the treatment effect. To investigate the effects of neoadjuvant chemotherapy within pre-specified subgroups of patients stratified logrank analyses were done on the primary endpoint of survival.


RESULTS
In the first comparison, we obtained data from 18 trials and 2074 patients. When all trials were considered together, a high level of statistical heterogeneity suggested that the results could not be combined indiscriminately. A substantial amount of heterogeneity was explained by separate analyses of groups of trials. Trials using chemotherapy cycle lengths shorter than 14 days (HR = 0.83, 95% CI = 0.69 to 1.00, p = 0.046) or cisplatin dose intensities greater than 25 mg/m2 per week (HR = 0.91, 95% CI = 0.78 to 1.05, p = 0.20) tended to show an advantage for neoadjuvant chemotherapy on survival. In contrast, trials using cycle lengths longer than 14 days (HR = 1.25, 95% CI = 1.07 to 1.46, p = 0.005) or cisplatin dose intensities lower than 25 mg/m2 per week (HR = 1.35, 95% CI = 1.11 to 1.14, p = 0.002) tended to show a detrimental effect of neoadjuvant chemotherapy on survival. In the second comparison, data from 5 trials and 872 patients were obtained. The combined results from all trials (HR = 0.65, 95% CI = 0.53 to 0.80, p = 0.0004) indicated a highly significant reduction in the risk of death with neoadjuvant chemotherapy, but there were some differences between trials in their design and results.


CONCLUSIONS
Despite some unexplained heterogeneity, the timing and dose intensity of cisplatin-based neoadjuvant chemotherapy appears to have an important impact on whether or not it benefits women with locally advanced cervical cancer and warrants further exploration.
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000627:therapeutic use; D005260:Female; D006801:Humans; D020360:Neoadjuvant Therapy; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D002945:Cisplatin