Elsevier

European Journal of Cancer

Volume 39, Issue 17, November 2003, Pages 2470-2486
European Journal of Cancer

Neoadjuvant chemotherapy for locally advanced cervical cancer: a systematic review and meta-analysis of individual patient data from 21 randomised trials

https://doi.org/10.1016/S0959-8049(03)00425-8Get rights and content

Abstract

Despite the enrolment of more than 3000 women in randomised trials, the benefits and risks of neoadjuvant chemotherapy in the treatment of locally advanced cervical cancer remain uncertain. We carried out a systematic review and meta-analysis of individual patient data to assess the effect of neoadjuvant chemotherapy in two comparisons. In the first comparison, of neoadjuvant chemotherapy followed by radical radiotherapy compared with the same radiotherapy alone, 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 of 14 days and shorter (Hazard Ratio (HR))=0.83, 95% Confidence Interval (CI)=0.69–1.00, P=0.046) or cisplatin dose intensities greater than or equal to 25 mg/m2per week (HR=0.91, 95% CI=0.78-1.05, 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=1.07–1.46, P=0.005) or cisplatin dose intensities lower than 25mg/m2 per week (HR=1.35, 95% CI=1.11-1.14, P=0.002) tended to show a detrimental effect of neoadjuvant chemotherapy on survival. In the second comparison, of neoadjuvant chemotherapy followed by surgery compared with radical radiotherapy alone, data from 5 trials and 872 patients were obtained. The combined results from all trials (HR=0.65, 95% CI=0.53–0.80, P=0.0004) indicated a highly significant reduction in the risk of death with neoadjuvant chemotherapy, but there were some differences between the trials in their design and results. 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.

Introduction

The incidence of cervical cancer has declined in both North America and Europe. However, on a global scale, it is the second most common cancer in women, and is the most prevalent female malignancy in many developing countries [1]. Most patients (in the developed world) present with early disease, either confined to the cervix or with limited extension beyond it (International Federation of Gynecology and Obstetrics (FIGO) stages IB1–IIA). In the past, standard treatment was usually radical radiotherapy or radical hysterectomy, with node dissection, each giving 5-year survival rates of around 80–90% [2]. Radical radiotherapy, comprising external beam and intracavitary treatment, tended to be the treatment of choice for locally advanced disease (FIGO stages IIB, III and IVA) and offered an alternative to radical surgery for patients with tumours larger than 4 cm confined to the cervix (FIGO stage IB bulky) [3]. Pelvic radiotherapy offered a good chance of cure, but the maximum radiation dose that was given to patients was limited by normal tissue tolerance, particularly of the small bowel, rectum and bladder, and 5-year survival using radiotherapy ranged from approximately 60% for patients with stage IIB disease to only approximately 20% for patients with stage IV disease [2]. In 1999, a National Cancer Institute Alert, based on the results of five randomised trials recommended that concomitant chemoradiation should be considered instead of radiotherapy alone in women with cervical cancer. A subsequent systematic review and meta-analysis of data presented in publications suggested a large benefit of concomitant chemoradiotherapy on survival, progression-free survival and local and distant control rates [4]. Thus, for many, concomitant chemoradiotherapy has become the new ‘standard of care’ for locally advanced disease.

There are, however, still potential therapeutic advantages to giving chemotherapy alongside local treatments that were standard for locally advanced disease, prior to the widespread use of concomitant chemoradiotherapy. Neoadjuvant chemotherapy given before radiotherapy may reduce the tumour size and control micrometastatic disease. In addition, by giving chemotherapy prior to radiotherapy, rather than concomitantly, increased radiotherapy toxicity may be less likely. Chemotherapy given prior to surgery may render inoperable tumours (FIGO stages IIB–IIIB) operable and treat metastases. A number of randomised trials have explored the use of neoadjuvant chemotherapy as an adjunct to either radiotherapy or surgery in comparison with radiotherapy alone and cisplatin-based regimens have been favoured, because of the impressive response rates [3]. Most of these randomised trials have been relatively small and their results range from a significant increase in survival [5] to a significant reduction in survival with neoadjuvant chemotherapy [6]. Most trials, however, have shown inconclusive results. Nevertheless, the combination of the results of all relevant trials in a meta-analysis (within each treatment setting) might give sufficient statistical power to determine whether neoadjuvant chemotherapy is useful. A prior systematic review and meta-analysis based on published summary data extracted from trial reports was of limited value, because only a subset of the trials were published at the time of the analysis and, of those, some did not report sufficient survival data to allow an appropriate analysis to be performed [7]. As noted in the publication, the only analysis that could be carried out might be unrepresentative and potentially biased and no firm conclusions could be drawn.

We therefore initiated a systematic review and individual patient data (IPD) meta-analysis to collect, validate and re-analyse trial data on all randomised patients from all relevant trials. The advantages of collecting IPD over published summary data for a meta-analysis are many [8]. In particular, it allows us to summarise the effect of neoadjuvant chemotherapy from all, not just the published trials; it permits more sensitive time-to-event analysis and enables us to examine whether any effect of treatment differs between subgroups of patients. Furthermore, by seeking updated follow-up, it provides a unique opportunity to look at long-term survival and adverse effects in a relatively young group of women. This IPD meta-analysis was initiated and coordinated by the Medical Research Council (UK) Clinical Trials Unit and carried out by the Neoadjuvant Chemotherapy for Cervical Cancer Meta-analysis Collaboration.

Section snippets

Patients and methods

This systematic review and meta-analysis followed a detailed, pre-specified protocol (March 1999), which set out the objectives, inclusion criteria for trials, data to be collected, and analyses to be done. These are summarised here, but a full protocol is available on request.

Treatment comparison 1

Searches identified 24 potentially eligible trials. Three were subsequently found to be ineligible, two because chemotherapy was given concurrently with radiotherapy 14, 15 and one because it was ongoing at time of the original analysis (Gynecological Oncology Group Protocol 141). Twenty-one trials were therefore eligible for inclusion. Two unpublished trials could not be included, one because the patient data could not be located (44 patients, Protocol C1, Western General Hospital, Edinburgh,

Discussion

At the outset of this project, despite the enrolment of more than 3000 women in randomised trials, it was not clear whether neoadjuvant chemotherapy was effective in the treatment of locally advanced cervical cancer. In the interim, concomitant chemotherapy and radiotherapy has probably become a ‘standard of care’ for women with locally advanced disease. This was in response to a National Cancer Institute Alert based on the results of five randomised trials stating “strong consideration should

NACCCMA Collaboration

Collaboration participants: P. Benedetti-Panici (Libera Università “Campus Bio-Medico” di Roma, Rome, Italy), A. Bermudez (Buenos Aires University, Buenos Aires, Argentina), P. Blake (Royal Marsden Hospital, London, UK), J. Cárdenas (Centro Estatal de Cancerologia, Colima, Mexico), T.-C. Chang (Chang Gung Memorial Hospital, Linkou, Taiwan), S. Chiara (Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy), G. Di Paola (Buenos Aires University, Buenos Aires, Argentina), A. Floquet (Institut

Acknowledgements

The British Medical Research Council funded the coordination of the meta-analysis and the collaborators’ meeting. We would like to thank all those women who took part in the trials and contributed to this research. The meta-analysis would not have been possible without them or without the help of the collaborating institutions that kindly collated and supplied their trial data. We are particularly grateful to Paul Symonds for his very helpful advice and input into the early stages of the

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    1

    All aspects of this systematic review and meta-analysis were carried out under the auspices of the NACCCMA Collaboration. See Section 5 for Collaboration participants.

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    [email protected]

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