Elsevier

The Lancet Oncology

Volume 8, Issue 6, June 2007, Pages 475-487
The Lancet Oncology

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Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial

https://doi.org/10.1016/S1470-2045(07)70143-2Get rights and content

Summary

Background

In men with localised prostate cancer, conformal radiotherapy (CFRT) could deliver higher doses of radiation than does standard-dose conventional radical external-beam radiotherapy, and could improve long-term efficacy, potentially at the cost of increased toxicity. We aimed to present the first analyses of effectiveness from the MRC RT01 randomised controlled trial.

Methods

The MRC RT01 trial included 843 men with localised prostate cancer who were randomly assigned to standard-dose CFRT or escalated-dose CFRT, both administered with neoadjuvant androgen suppression. Primary endpoints were biochemical-progression-free survival (bPFS), freedom from local progression, metastases-free survival, overall survival, and late toxicity scores. The toxicity scores were measured with questionnaires for physicians and patients that included the Radiation Therapy Oncology Group (RTOG), the Late Effects on Normal Tissue: Subjective/Objective/Management (LENT/SOM) scales, and the University of California, Los Angeles Prostate Cancer Index (UCLA PCI) scales. Analysis was done by intention to treat. This trial is registered at the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN47772397.

Findings

Between January, 1998, and December, 2002, 843 men were randomly assigned to escalated-dose CFRT (n=422) or standard-dose CFRT (n=421). In the escalated group, the hazard ratio (HR) for bPFS was 0·67 (95% CI 0·53–0·85, p=0·0007). We noted 71% bPFS (108 cumulative events) and 60% bPFS (149 cumulative events) by 5 years in the escalated and standard groups, respectively. HR for clinical progression-free survival was 0·69 (0·47–1·02; p=0·064); local control was 0·65 (0·36–1·18; p=0·16); freedom from salvage androgen suppression was 0·78 (0·57–1·07; p=0·12); and metastases-free survival was 0·74 (0·47–1·18; p=0·21). HR for late bowel toxicity in the escalated group was 1·47 (1·12–1·92) according to the RTOG (grade ≥2) scale; 1·44 (1·16–1·80) according to the LENT/SOM (grade ≥2) scales; and 1·28 (1·03–1·60) according to the UCLA PCI (score ≥30) scale. 33% of the escalated and 24% of the standard group reported late bowel toxicity within 5 years of starting treatment. HR for late bladder toxicity according to the RTOG (grade ≥2) scale was 1·36 (0·90–2·06), but this finding was not supported by the LENT/SOM (grade ≥2) scales (HR 1·07 [0·90–1·29]), nor the UCLA PCI (score ≥30) scale (HR 1·05 [0·81–1·36]).

Interpretation

Escalated-dose CFRT with neoadjuvant androgen suppression seems clinically worthwhile in terms of bPFS, progression-free survival, and decreased use of salvage androgen suppression. This additional efficacy is offset by an increased incidence of longer term adverse events.

Introduction

Prostate cancer is now the most commonly diagnosed cancer in men in the UK, USA, and western Europe; in 2000, the global estimate of deaths per year was 263 000.1 The introduction of PSA testing has led to an increasing proportion of patients presenting with localised disease. Management options are controversial and include radical prostatectomy, external-beam radiotherapy, brachytherapy, and active surveillance or monitoring of men with favourable prognostic factors2 or, alternatively, watchful waiting for those who are unsuitable for a radical curative treatment approach. External-beam radiotherapy might be most appropriate for men with intermediate-risk or high-risk features,3, 4, 5 and is associated with long-term disease control in most men with prostate cancer.6 Advances in radiation technology have enabled more precise and accurate treatment that allows the delivery of higher radiation doses and improved disease control while maintaining an acceptable frequency of side-effects.

Conventional radical external-beam radiotherapy is limited to doses of 64–70 Gy in 1·8–2·0 Gy fractions because of the risk of long-term toxic effects to the bladder and rectum. Within 5 years of being treated with this type of radiotherapy, up to 33% of patients will have relapsed (either clinically or biochemically, ie, increasing prostate serum antigen [PSA] concentrations) or died.7 Conformal radiotherapy (CFRT) techniques use linear accelerators with multileaf collimators or customised shaped blocks to shape the radiotherapy beam. Due to improved imaging and radiotherapy planning techniques, CFRT allows radiotherapy to be delivered more accurately to the tumour. As a result, the volume of normal tissue irradiated and the number of expected local adverse effects can be decreased.8 CFRT techniques also raise the possibility that the dose of radiotherapy could be increased and, therefore, long-term outcomes could be improved.9

The Medical Research Council (MRC) RT01 trial was a large, multicentre, randomised controlled trial of patients with localised prostate cancer who were randomised to either a standard dose of 64 Gy or an escalated dose of 74 Gy, both delivered by CFRT with neoadjuvant androgen suppression. The current trial followed a single-centre pilot study.10 The MRC RT01 trial lent support to the implementation of CFRT techniques in the UK by developing and standardising quality-assurance processes for CFRT delivery. The design, objectives, eligibility criteria, patients, treatment, and early toxicity data have been presented in detail.11, 12 Here, we present the first analyses of effectiveness and set these in the context of long-term toxicity data.

Section snippets

Patients and procedures

The MRC RT01 trial recruited men with histologically confirmed T1b-T3a, N0, M0 prostate cancer,13 who had PSA concentrations of under 50 ng/mL; WHO performance status of 0 or 1; normal blood count; and no previous: pelvic radiotherapy or radical prostatectomy, androgen deprivation, substantial past medical history which precluded radical radiotherapy, hip prostheses, or conditions which precluded standard radiotherapy. After written informed consent was obtained, we registered the patients,

Results

Between January, 1998, and December, 2002, 843 men were randomly assigned to receive escalated-dose CFRT (74 Gy/37f; n=422) or standard-dose CFRT (64 Gy/32f; n=421), as shown in figure 1. Baseline characteristics for age, disease, and risk factors for participants were evenly distributed according to allocated treatment (table 1). The median age of participants was 67 years (IQR 63–71); median pre-androgen suppression PSA concentration was 12·8 ng/mL and mean pre-androgen suppression PSA

Discussion

The MRC RT01 trial is the largest randomised controlled trial to report outcomes with the use of dose-escalated CFRT, and—to our knowledge—is the only trial other than its pilot study10 to use a uniform policy of neoadjuvant androgen suppression. The associated quality-assurance programmes have helped the implementation of CFRT in the UK, which was in its infancy at the start of the MRC RT01 trial. The current trial has shown that using CFRT to increase radiotherapy dose from 64 Gy to 74 Gy,

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