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

Therefore, this new Cochrane review was initiated, based on IPD.  The researchers found 25 eligible trials that had compared concomitant chemoradiotherapy (with or without surgery) with the same radiotherapy (with or without surgery), as well as three further trials that used additional treatments for the control groups, but had contributed to the NCI guidance.  They could not obtain data from 10 trials (including 1,113 patients) either because they were unable to make contact with the investigators, or because the original investigators were unable to locate the data.  Data were obtained for 18 trials including 4,818 women. The main analyses were based on the 15 trials which had an unconfounded comparison of chemoradiotherapy versus radiotherapy.  The three additional trials that had used different or additional treatment on the control arm but contributed to the 1999 NCI guidance were not eligible for the main analyses, but were included in a separate sensitivity analysis.

Eleven trials used cisplatin based chemoradiotherapy, three used non-cisplatin based regimens and one three-arm trial compared both a cisplatin and a non-cisplatin based treatment arm with a single control group.  All used similar radiotherapy schedules, although one trial had not given brachytherapy because chemoradiotherapy was given in addition to upfront radical surgery.  Two of the eleven trials of cisplatin-based chemoradiotherapy gave additional chemotherapy after chemoradiotherapy.

For overall survival, the IPD review found a benefit of chemoradiotherapy. There was a significant difference in the size of the benefit according to whether all the chemotherapy was given entirely with radiotherapy (HR=0.81, 95% CI 0.71 – 0.91, p=0.0006) or whether additional chemotherapy was given after chemoradiotherapy (HR=0.46, 95% CI 0.32 – 0.66, p=0.00002).  The subsequent analyses were restricted to the group of trials that gave chemotherapy entirely with radiotherapy (13 trials in total).   These found no evidence that the size of the benefit of chemoradiotherapy varied according to the choice of chemotherapy agent used, planned radiotherapy dose or duration, or the chemotherapy dose or cycle length, but the power of these analyses was more limited and the radiotherapy used in all trials was broadly similar.

This same group of 13 trials showed benefits of chemoradiotherapy for disease-free survival, local and distant recurrence-free survival and time to local or distant recurrence, although there was a smaller and less convincing improvement in the time to distant recurrence.

The effect was consistent in patient subgroups defined by age, tumour histology, grade and whether or not pelvic nodes were involved.  However, there was the suggestion of variation in the size of the benefit by tumour stage, with smaller benefits for patients with more advanced tumour stage.  Unfortunately, there were too few data available on late complications of treatment to support formal analysis.

All data were obtained for the three trials in the sensitivity analysis trials (1,366 women) and this showed a large increase in heterogeneity when these trials were included alongside the 13 trials of the main analysis, such that there was a significant difference in the size of the treatment effect, both for the group of trials using additional hydroxyurea for the control group (test for interaction p=0.029) and for the single trial that used extended field radiotherapy for the control group only (test for interaction p=0.004).  The reviewers also noted that survival of women in the control group for these 3 trials was lower than that of the main group of 13 trials.

The findings of this review, including data from 18 trials from 11 countries, provide an unconfounded estimate of the effect of chemoradiotherapy compared with radiotherapy for women with cervical cancer.  The results endorse the recommendations made by the NCI in 1999 but with far greater reliability and precision regarding the benefits of chemoradiotherapy.  The effect of chemoradiotherapy seems to be consistent whether cisplatin-based or non-cisplatin-based chemotherapy is used, and, as such, non-cisplatin-based regimens may be an option for women who are not able to tolerate cisplatin.  The benefit of chemoradiotherapy on all outcomes seems consistent for all radiotherapy doses and schedules, and by the cycle length or dose intensity of the chemotherapy employed, such that there is insufficient evidence to suggest any one treatment schedule over another.  Furthermore, the benefit is consistent for women of all ages, histology, grade, or pelvic nodal involvement; although this benefit may be less for women with the higher stages of disease.

Finally, these results suggest additional benefit from giving further chemotherapy after chemoradiotherapy, which requires further testing in the context of randomised trials.

^{1. Green JA, Kirwan JJ, Tierney J, Vale CL, Symonds PR, Fresco LL, Williams C, Collingwood M. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD002225. DOI: 10.1002/14651858.CD002225.pub2}