Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix.
BACKGROUND
The National Cancer Institute (USA) alert in February 1999 stated that concomitant chemoradiotherapy should be considered for all patients with cervical cancer, based on evidence from five randomised controlled trials.


OBJECTIVE
To review all known randomised clinical controlled trials (RCTs) comparing concomitant chemotherapy and radiation therapy with radiotherapy for locally advanced cervical cancer.


METHODS
We searched electronic databases, trials registers and reference lists of published trial reports and review articles were also searched.


METHODS
This review includes RCTs in cervical cancer comparing concomitant chemotherapy and radiotherapy with radiotherapy. In the experimental arm, further adjuvant chemotherapy was allowable. Hydroxyurea was considered inactive and allowable. Trials using radiosensitisers or radioprotectors in the experimental arm were excluded.


METHODS
Two authors reviewed trials for inclusion and extracted data. For meta-analyses of time-to-event outcomes (survival, progression-free survival), a hazard ratio (HR) was extracted or estimated from trial reports, where possible. Only overall rates of local and distant recurrence were presented in many reports so only an odds ratios (OR) of recurrence rates could be calculated, which takes no account of time to recurrence or censoring. The HRs and ORs for individual trials were combined across all trials, using the fixed effect model. Few trials reported acute toxicity adequately. Data were therefore grouped and the number of toxic events was used to calculate a single OR for each site and grade. Late toxicity was rarely described so could only be reviewed qualitatively.


RESULTS
Nineteen trials (17 published, two unpublished) were identified including 4580 patients, although due to patient exclusion and differential reporting 62-78% were available for the various analyses. The review strongly suggests chemoradiation improves overall survival and progression free survival, whether platinum was used or not with absolute benefits of 12% and 16% respectively. There was, however, statistical heterogeneity for these outcomes There was some evidence that the effect was greater in trials including a high proportion of stage I and II patients. Chemoradiation also showed significant benefit for both local and distant recurrence. Haematological and gastrointestinal toxicity was significantly greater in the concomitant chemoradiation group. Details of late morbidity were sparse.


CONCLUSIONS
Concomitant chemotherapy and radiotherapy appears to improve overall survival and progression-free survival in locally advanced cervical cancer. It also reduces local and distant recurrence suggesting concomitant chemotherapy may afford cytotoxic and sensitisation effects. Some acute toxicity is increased, but data on long term side effects were sparse.
Green
J
J
Clatterbridge Centre for Oncology, Clatterbridge Hospital, Merseyside, UK, L63 4JY. J.A.Green@liverpool.ac.uk
Kirwan
J
J
Tierney
J
J
Symonds
P
P
Fresco
L
L
Williams
C
C
Collingwood
M
M
D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*