The Scottish and Manchester randomised trial of neo-adjuvant chemotherapy for advanced cervical cancer

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Abstract

204 eligible patients were entered into a multicentre randomised trial of neo-adjuvant chemotherapy prior to radical radiotherapy. The aim of this study was to assess whether there was any survival advantage in patients undergoing chemotherapy and radiotherapy compared with those given radiotherapy alone. Patients were aged up to 70 years, performance status 0–1/2, with bulky stage IIb, stage III or stage IVa squamous or adenosquamous carcinoma. Three cycles of methotrexate 100 mg/m2 and cisplatin 50 mg/m2 were given at 2-weekly intervals before radical radiotherapy. 104 eligible patients received the combination treatment and 100 radiotherapy only. The two arms of the study were well balanced for tumour and patient characteristics. The response rate to chemotherapy was 49%. 33% of patients in the radiotherapy (XRT) alone arm and 45% of the combination arm were clinically free of tumour at the end of treatment. The median follow-up for surviving patients is 5.4 years (range: 11 months–8 years) and 84% have been followed-up for more than 4 years. 134 patients have died (68 XRT only, 66 combined arm). The median survival RT alone was 111 weeks (95% confidence interval (CI) 72–151 weeks), combination arm 125 weeks (95% CI 79–170 weeks). The estimated death ratio is 0.79 (P=0.19, 95% CI 0.56–1.12). The estimated 3-year survival is 40% (95% CI 30–50%) RT only compared with 47% (95% CI 37–57%) in the combination arm. Acute and late toxicity of radiotherapy was not increased by the addition of chemotherapy.

Introduction

There are potential advantages in giving chemotherapy before radiotherapy in the treatment of locally advanced cervical cancer [1]. Both clinical studies and animal experiments have shown that radiation doses which will consistently eradicate small tumours will be effective in only a minority of larger lesions. However the maximum radiation dose that can be given to patients with carcinoma of the cervix is limited by the tolerance of surrounding organs such as the bladder or bowel. Even employing what we currently regarded as optimal external beam fractionation policies in combination with intracavity treatment, local control is seen in only approximately half of patients with advanced tumours. Attempts to increase pelvic radiation dosage have resulted in increased morbidity outweighing any increase in local control [2]. However, local control using conventional radiotherapy schedules could be increased if the tumour size were to be reduced by chemotherapy given before radiotherapy.

In a pilot study [1] the response rate following two pulses of cisplatin, vincristine and bleomycin combination chemotherapy was 53%. Patients then received full dose radical radiotherapy. The survival of chemotherapy responders was markedly superior to non-responders.

The actuarial survival at 24 months of responders to chemotherapy was 71% against 37% for non-responders. The responding patients had an estimated reduction in mortality of 36% (P=0.014, 95% confidence interval (CI) 15–81%).

These results demonstrated the feasibility of this approach and a multicentre randomised trial was designed. A 2-weekly schedule of methotrexate and cisplatin was chosen. Both agents are active against cervical cancer and are relatively non-myelosuppressive allowing chemotherapy to be given every 2 weeks [3]. Three cycles of chemotherapy were given over 28 days and radiotherapy was only delayed by 6 weeks. This short period of chemotherapy may have two advantages. The first is pragmatic, as the delay in beginning potentially curative radiotherapy is short. The second is more theoretical and speculative as the scheduling and dose intensity of cisplatin may be important in obtaining tumour shrinkage.

Section snippets

Patients and methods

Patients in the trial had bulky stage IIb (tumour size >5 cm), stage III or stage IVa squamous or adenosquamous carcinoma of cervix. Performance status was normal or near normal (WHO performance status 0–2) and all were aged up to and including 70 years. Patients had to be fit for both chemotherapy and radiotherapy with adequate marrow reserves (white blood cell count (WBC)>3×109/l and platelets>100×109/l) and good renal function (glomerular filtration rates (GFR)>50 ml/min). The trial was

Results

215 patients were randomised into the study. 11 patients were judged to be ineligible when patient details were checked prior to analysis. The reasons for exclusion are listed in Table 1. Only entered eligible patients were considered for subsequent analysis. Although all but one of the excluded patients were in the radiotherapy only arm there was no suggestion of problems with the randomisation or that their exclusion led to a bias in the comparisons. The clinical and pathological

Discussion

Trials of neo-adjuvant chemotherapy have so far produced conflicting results. Survival was better in the radiotherapy control arm in two studies but the majority showed no significant differences between each arm. In contrast, three cycles of vincristine, bleomycin and cisplatin given at 10-day intervals has improved survival in patients with bulky stage Ib and stage IIIb tumours (see Table 8).

The most striking negative finding was seen in patients treated in the countries of the Pacific rim

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