Prospective randomised study of split-course radiotherapy versus cisplatin plus split-course radiotherapy in inoperable squamous cell carcinoma of the oesophagus

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Abstract

Between 1983 and 1989, 211 patients with inoperable squamous cell carcinoma of the oesophagus were randomised in a study comparing split-course irradiation (two courses of 20 Gy in five fractions of 4 Gy, separated by a rest of 2 weeks) (arm A) and the same split-course irradiation in combination with cisplatin (CDDP) (3–4 days before each of the two courses of radiotherapy, repeated every 3–4 weeks, for a total of six cycles) (arm B). The Cox's regression model with retrospective stratification was used to compare the two arms to correct for the imbalance at randomisation of the T classification. The median overall survival was 7.9 (95% confidence interval (CI) 7.3–9.4) months in arm A and 9.6 (95% CI 8–13.5) months in arm B. The difference in overall survival was only borderline significant (P=0.048) with a reduction of the instantaneous rate of death of 24%. The 1 and 2 year overall survival rate were respectively 29% (95% CI 21–37%) and 15% (95% CI 8–22%) in arm A and 45% (95% CI 36–54%) and 20% (95% CI 13–27%) in arm B; thereafter, the survival curves became similar. The median progression free survival (PFS) was 5.0 (95% CI 4.6–5.7) versus 6.9 (95% CI 5.3–8.7) months (P=0.028) and the median time to local progression was 6.2 (95% CI 5.1–7.6) months versus 10.9 (95% CI 8.1–15.5) months (P=0.018), respectively, in arms A and B. Haematological toxicities were slightly more commonly observed in the combined group (1% versus 6%). This study shows that split-course irradiation in combination with CDDP is very well tolerated and should be preferred to radiotherapy alone.

Introduction

The prognosis of patients with oesophageal cancer is poor, even after a curative resection. Most of the patients die from distant metastases which indicates that from the first clinical symptoms of the disease it is systemic in most of the patients. This fact ensures strong support for combined treatment modalities that expect to have a maximal local effect and to eradicate distant micrometastases in order to improve survival. The Gastro Intestinal Tract Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC) initiated in 1983 a phase III controlled clinical trial of irradiation versus irradiation and cisplatin (CDDP) in patients with irresectable squamous cell carcinoma of the oesophagus (EORTC 40831). In the early eighties, results from phase II trials showed that CDDP and bleomycin were among the most active drugs against oesophageal carcinomas. The group chose to test CDDP as a single agent in combination with irradiation because of the risk of pulmonary toxicity associated with the use of bleomycin which might be aggravated with concomitant mediastinal irradiation and because there was no clear demonstration of a benefit with polychemotherapy. At that time, the total dose of irradiation was given on an inpatient basis due to the poor tolerance by the majority of the patients. An admission of more than 5 weeks was considered to be too long for patients with an expected short survival. To prevent a long hospital stay, it was therefore decided to introduce a split-course scheme, a method which was described for patients with bronchogenic carcinoma [1], head and neck cancer [2] and in the early seventies for oesophagus carcinoma [3].

Section snippets

Patients

All patients were required to have squamous cell carcinoma, be aged under 70 years, have had no prior chemotherapy, a performance status of World Health Organization (WHO) 0–2; any T1–3 lesion according to the 1979 International Union Against Cancer (UICC) classification (T1: tumour ⩽5 cm, T2: tumour >5 cm, T3: extra oesophageal spread), but without superficial (cervical) lymph node metastases or distant metastases (infradiaphragmatic lymph node involvement was not a reason for exclusion

Results

From December 1983 to February 1989, 221 patients from 11 institutions were randomised (Fig. 1). Then it was decided to close the trial because of the low accrual rate. There were 111 patients in the radiotherapy arm (A) and 110 in the radiotherapy+CDDP arm (B). All patients were evaluated and 18 (8%) were considered ineligible (10 in A and 8 in B). The reasons for ineligibility were inadequate staging (15), poor physical condition (2) and prior treatment (1).

Except for clinical stage at entry,

Discussion

CDDP is a common component of combination chemotherapy for squamous cell carcinoma of the oesophagus, although it is not known whether CDDP is really an essential component of combination chemotherapy for oesophageal cancer 7, 8. CDDP-containing combinations may, however, give a response rate of almost 50%. In these combinations toxic effects are considerable, and although tolerable, these effects may have a very negative effect on the remaining months of the patient's life. CDDP as a single

Acknowledgements

This publication was supported by grant number 2U10 CA11488-13 through 5U CA1488-29 from the National Cancer Institute (Bethesda, MD, USA) Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the National Cancer Institute.

References (16)

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