|Adjuvant radiotherapy following radical prostatectomy for pathologic T3 or margin-positive prostate cancer: guideline recommendations
|Morgan S C, Waldron T, Eapen L, Mayhew L A, Winquist E, Lukka H, Genitourinary Cancer Disease Site Group
This review concluded that adjuvant radiotherapy has not been shown to improve overall survival compared to observation following radical prostatectomy in patients with pathologic T3 or margin-positive prostate cancer. However, longer follow-up is required, and adjuvant radiotherapy did improve biochemical progression-free survival without excess severe late toxicity. These conclusions appear reliable given the evidence presented, but additional evidence may exist.
To compare adjuvant radiotherapy with observation and delayed salvage therapy following radical prostatectomy in patients with pathologic T3 or margin-positive prostate cancer.
MEDLINE, EMBASE and the Cochrane Library were searched for English language studies from inception to early 2008. Search terms were reported. The National Cancer Institute Trials Registry was searched in December 2007. In addition, experts were contacted, reference lists were screened and conference proceedings of the American Society of Clinical Oncology, American Society for Therapeutic Radiology and Oncology and American Urological Association were searched from 2000 to 2007.
Randomised controlled trials (RCTs) comparing adjuvant external beam radiotherapy to the prostatic bed against observation with therapies held in reserve for salvage were eligible for inclusion in the review. To be included, these trials had to include patients with prostate cancer and either tumour extension beyond the prostatic capsule (pT3a), seminal vesicle invasions (pT3b), positive resection margins, or more than one of these features.
Among included trials, radiotherapy was delivered at a dose of 60 to 64 Grays in 30 to 32 fractions. Treatments received by the observational arms of these trials included pelvic radiotherapy, hormonal treatment, and surgical castration. Reported outcomes included overall survival, metastasis-free survival, biochemical progression-free survival, time to initiation of androgen deprivation therapy, and toxicity. Median age, where reported, was 64.9 and 65 years. Trials appear to have been conducted at centres in the USA and Europe.
Two reviewers independently selected studies for inclusion, with disagreements resolved by consensus.
Assessment of study quality
Validity of included trials was assessed according to the following criteria: randomisation; concealment of allocation; reporting of patient withdrawals and dropouts; and use of intention-to-treat analysis. Each criterion was rated as 'met', 'unmet' or 'unclear'. Where it was unclear whether any of these criteria were met, study authors were contacted.
Two reviewers independently assessed study validity.
Where reported, hazard ratios (HRs) were extracted from included trials, with their associated variances calculated from reported confidence intervals (CIs) or p values.
Data was extracted by one reviewer and checked by a second.
Methods of synthesis
Where possible, pooled hazard ratios with 95% confidence intervals were calculated using a random-effects model. Heterogeneity was evaluated by examining forest plots and calculating both χ2 and I2 values.
Results of the review
Three RCTs were included in the review (n=1,743 patients). Median follow-up for each of the three trials was 4.5 years, 5 years and 10.6 years. Two of the RCTs met all validity criteria, the third did not provide sufficient details to allow a full assessment of validity.
Adjuvant radiotherapy appeared to increase biochemical progression-free survival (HR 0.47, 95% CI: 0.40 to 0.56; three RCTs) but not overall survival (two trials, p=0.52) or metastasis-free survival (one trial, p=0.06). Excluding one trial that did not report intention-to-treat data did not change the the findings of the biochemical progression-free survival meta-analysis.
Time to initiation of androgen deprivation therapy was reported by a single trial, finding a significant reduction in androgen deprivation therapy use in those randomised to adjuvant radiotherapy at five years of follow-up (HR 0.45; 95% CI: 0.29 to 0.68).
One RCT reported a significantly greater cumulative incidence of any-grade toxicity associated with adjuvant radiotherapy when compared with observation (64.9% versus 54.3%, p=0.005), but not for grade 3 toxicities alone. Another RCT reported higher rates of complications potentially related to treatment in the adjuvant radiotherapy arm (23.8% versus 11.9%, p=0.002).
Where reported, outcomes related to prostate cancer-specific survival, loco-regional recurrence-free survival, clinical progression-free survival and quality of life were also summarised.
Adjuvant radiotherapy has not been shown to improve overall survival compared to active surveillance, though longer follow-up is required to accurately assess this outcome. However, adjuvant radiotherapy did significantly improve biochemical progression-free survival and was not associated with excess severe late toxicity.
The review question was clearly defined in terms of the participants, interventions, comparators and study designs of interest. Attempts were made throughout the review process to minimise the potential for bias and errors. Appropriate methods were used to quality assess and synthesise the identified trials. Although a range of sources were searched to identify relevant studies, only those published in English were considered eligible for inclusion, raising the possibility of language bias. The potential for publication bias was not investigated in the review. The authors' conclusions appear to be reliable given the evidence presented in the review, but the existence of additional relevant evidence outside the review cannot be discounted.
Implications of the review for practice and research
Practice: The authors stated that early referral following radical prostatectomy to a radiation oncologist for a discussion around the pros and cons of adjuvant radiotherapy is advisable.
Research: The authors stated that an individual patient data meta-analysis of the existing trials would permit a more accurate estimation of the effects of adjuvant radiotherapy and allow the examination of various pathologic subgroups
Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario.
Morgan S C, Waldron T, Eapen L, Mayhew L A, Winquist E, Lukka H, Genitourinary Cancer Disease Site Group. Adjuvant radiotherapy following radical prostatectomy for pathologic T3 or margin-positive prostate cancer: guideline recommendations. Cancer Care Ontario. 2008. Evidence-based Series 3-17. Available at: http://www.cancercare.on.ca/pdf/pebc3-17s.pdf
[Accessed October 2009]
This paper is produced by Cancer Care Ontario Practice Guidelines Initiative. The series is published on the Internet and regularly updated. To ensure that you are viewing the most up to date version, go to the Cancer Care Ontario website at: https://www.cancercare.on.ca/toolbox/qualityguidelines/
Other publications of related interest
Morgan SC, Waldron TS, Eapen L, et al. Adjuvant radiotherapy following radical prostatectomy for pathologic T3 or margin-positive prostate cancer: a systematic review and meta-analysis. Radiother Oncol 2008;88:1-9.
Subject indexing assigned by CRD
Combined Modality Therapy; Humans; Male; Prostatectomy; Prostatic Neoplasms; Quality of Life; Radiotherapy Dosage; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Survival Analysis
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.