Phase III randomised trial
A phase III study of accelerated versus conventional hypofractionated whole brain irradiation in patients of good performance status with brain metastases not suitable for surgical excision

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Abstract

Background and purpose

An accelerated prescription for whole brain irradiation (WBI) in the treatment of brain metastases has been reported to provide favourable survival in good performance status patients. Because it was not known whether this outcome represented patient selection or a radiobiologically advantageous regimen, a phase III study to compare overall survival following accelerated and conventional hypofractionated daily WBI was proposed.

Materials and methods

Ninety patients were randomized between 1996 and 2003 at two centres. The investigational arm received 40 Gy in 20 fractions of 2 Gy twice daily. The control arm received 20 Gy in 5 daily fractions. The study was designed to detect an increase in median survival of 1.75×. Outcome measures included acute side effects (WHO epilation score), neurological function (modified Barthel Index) and late toxicity (LENT/SOMA score for the CNS).

Results

Both arms of the study were balanced by RPA class. The median survival was 19 weeks in both arms. Subset analysis showed time to retreatment for intracranial relapse was 14 weeks in the control arm and 32 weeks in the accelerated arm (p = 0.03). Trends for more severe epilation and improved neurological function in the accelerated arm did not reach statistical significance. Overall survival was associated with RPA class and colorectal pathology.

Conclusions

Although accelerated WBI may improve local control this did not translate into improved overall survival in the patients studied.

Section snippets

Patients and methods

The main purpose of this trial was to determine whether a course of accelerated WBI resulted in an increased overall survival time for patients. A secondary endpoint was to determine the duration of the control of the growth of intracranial metastases by measuring the time from initial treatment to the time salvage therapy was delivered for intracranial tumour progression. The acute side effects of treatment were studied by applying the WHO epilation score. This scale was selected in order to

Results

Ninety patients were entered into this study between 2nd October 1996 and 5th November 2003; 76 at Centre A and 14 at Centre B. There were 45 patients in each arm. There were 4 protocol violations comprising 1 patient who was ineligible (ECOG 3) and 1 patient who withdrew from the study before treatment. In addition, radiotherapy was discontinued in 2 patients: 1 in the control arm and 1 in the investigational arm. All 90 randomized patients are included in the results for overall survival. The

Conclusions

This is a randomized study that failed to demonstrate an overall survival advantage for accelerated WBI over conventional hypofractionated treatment. The dataset did validate RTOG RPA classes of features prognostic for survival as well as the adverse survival outcome in patients with colorectal cancer. Retrospective subset analysis did raise the possibility that accelerated WBI improves local control using time to retreatment as a surrogate endpoint. (It would seem unlikely that patients in the

Acknowledgements

The original statistician for this study was Dr. Gerrit DeBoer who passed away in 2005. The authors are grateful to the following physicians who entered patients on this study: Dr. E. Chow (1), Dr. C. Danjoux (3), Dr. M. Doherty (6), Dr. C. Hayter (3), Dr. J. Kamra (3), and Dr. M. Tsao (2). Funding for this study was provided by the CNS Site Group at the Odette Cancer Centre.

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