What is the efficacy of radiation post radical prostatectomy in patients with extra capsular extension, seminal vesicle involvement or positive surgical margins for locally advanced disease?

Adjuvant external beam radiotherapy

The role of post-prostatectomy radiotherapy was not well defined until recently. Historically, post-prostatectomy radiotherapy was not widely adopted primarily due to concerns about toxicity associated with radiotherapy. In addition, there were limited data on the efficacy of radiotherapy post prostatectomy. The recent publication of three randomised controlled trials examining the efficacy of adjuvant radiotherapy post radical prostatectomy in patients with extracapsular extension, seminal vesicle involvement and/or positive surgical resection margins has provided us with a clearer understanding of the benefits of post-prostatectomy radiotherapy.

The European Organisation for Research and Treatment of Cancer (EORTC) 22911 trial randomised 1005 patients and reported their outcomes with a median follow-up of five years.^[1] The South Western Oncology Group (SWOG) 8749 trial that randomised 425 men initially presented its results with a median follow-up of 9.7 years^[2], but has since updated these results in publications with median follow-up of 10.6 years^[3] and 12.7 years^[4] respectively. The ARO 96-02 trial randomised 385 men, however only a subgroup of 307 men with an undetectable PSA after surgery was analysed, with a median follow-up of 54 months.^[5]^[6]^[7]

These trials were similar in respect to entry criteria, radiation dose and techniques. It should be noted that a small percentage of patients in each of the trials received neoadjuvant androgen deprivation therapy (SWOG 8–9%, EORTC 9%, ARO unknown %). The primary endpoint in two of the trials (EORTC and ARO) was biochemical relapse-free survival, however different definitions were used. In the third trial (SWOG) the primary endpoint was metastasis-free survival. Biochemical relapse-free survival was a secondary endpoint. Local control as a secondary endpoint was reported for two of the trials (EORTC and SWOG appendices). These trials were not blinded, however, an intention-to-treat analysis was performed in two of the trials (EORTC and SWOG).

All three trials demonstrated improved biochemical progression-free survival in patients receiving adjuvant radiotherapy (EORTC: hazard ratio=0.48, 98% CI=0.37to0.62, p<0.0001; SWOG: hazard ratio=0.43, 95% CI=0.31to0.58. p<0.001; ARO: hazard ratio=0.49; 95% CI=0.32to0.75, p=0.001). The two trials examining local control also report a statistically significant improvement with adjuvant radiotherapy. While a non-significant trend towards improved metastasis-free survival was initially reported in the SWOG trial, with longer follow-up this has become statistically significant (hazard ratio=0.71, 95% CI=0.54to0.94, p=0.016). In addition, a statistically significant improvement in overall survival has now been demonstrated in those patients receiving adjuvant radiotherapy (hazard ratio=0.72, 95% CI=0.55to0.96, p=0.023).^[4]

It is important to note that these trials did not have planned salvage therapy for patients in the observation arm and only 25–50% of patients received salvage radiotherapy. There is some retrospective evidence, such as that by Stephenson et al,^[8] that suggests salvage radiotherapy when given early (first sign of PSA failure) may be as effective as adjuvant radiotherapy. This is the subject of continuing randomised controlled trials such as that by the Trans Tasman Radiation Oncology Group (TROG) with the RAVES trial (radiotherapy–adjuvant versus early salvage).

While adjuvant radiotherapy is associated with increased acute radiotherapy toxicity and increased late toxicity,^[1]^[2] rates of serious toxicity are low. In the EORTC trial five-year cumulative incidence rates of grade 3 late toxicities were 4.2% for radiotherapy and 2.6% for the control group (p=0.07); in the SWOG trial^[3] 3.3% of radiotherapy patients experienced rectal complications as opposed to none in the control arm (p=0.02), and 18% of radiotherapy patients experienced urethral stricture compared with 10% of control patients (p=0.02). In a small trial (n=107), urinary continence was not significantly affected by post-surgery radiotherapy,^[9] however in the larger SWOG trial there was a non-significant increase in urinary incontinence with radiotherapy.^[3] While quality of life data from the SWOG study^[10] collected up to five years after treatment indicated significantly worse bowel function and urinary frequency post treatment, both appeared to improve with time and global health related quality-of-life, while initially worse, was better at five years in those patients receiving adjuvant radiotherapy.

Adjuvant systemic chemotherapy

See Emerging therapies

Adjuvant androgen deprivation therapy

See Radiotherapy and androgen deprivation therapy

Comments

Back to top

Evidence summary and recommendations

Evidence summary	Level	References
There is good evidence to support adjuvant radiotherapy post radical prostatectomy in patients with extra capsular extension, seminal vesicle involvement or positive surgical margins. It is important to note that these trials did not have planned salvage therapy for patients in the observation arm. The role of early salvage radiotherapy is the subject of a recently activated Australian and New Zealand (TROG) randomised controlled trials.	II	^[1], ^[2], ^[5], ^[6], ^[9]

Evidence-based recommendation	Grade
It is recommended that patients with extracapsular extension, seminal vesicle involvement or positive surgical margins receive post-operative EBRT within four months of surgery. The role of active surveillance and early salvage radiotherapy has not been defined.	B