Overall, approximately 35% of men undergoing RRP will have a recurrence of their prostate cancer within 5 to 10 years (342-346). The following preoperative findings are associated with a high risk of surgical failure: cT3 lesions, cT1 or cT2 tumors with >Gleason grade 4 number on prostate biopsy, and serum PSA >10 ng/ml. Additional risk factors for recurrence after attempted definitive therapy include such additional pathologic determinants as tumor volume, vascular invasion, seminal vesicle or lymph node involvement, and positive surgical margins. The location of the positive margin can influence the likelihood of tumor recurrence and must be taken into consideration (292).
The use of post-operative radiotherapy has been the focus of extensive investigation in recent years, including both retrospective and randomised prospective studies. The use of radiotherapy post-RRP can be with either adjuvant or salvage intent. Adjuvant radiotherapy is that used immediately post-operatively, in the aim of eliminating potential but as yet unidentifiable residual disease. Salvage therapy is conducted when recurrence is suspected - typically when a PSA rise is seen - although the immediate use of radiotherapy when an undetectable post-RRP PSA is not returned may also be regarded in this category.
A number of retrospective comparative series have examined the potential benefit to adjuvant radiotherapy. Unselected series have suggested biochemical control rates in the combined surgery plus adjuvant radiotherapy cases of 52-93% compared to surgery only rates of 25-74% (488-492). More concordant results were seen in two published matched pair analyses which showed surgery only freedom from biochemical failure (FFbF) of 55-59% which was increased to 88-89% with the addition of radiotherapy (493, 494).
Three randomised studies of adjuvant therapy have now been announced in abstract or publication form. These trials have focused on a subset of men at high risk of having residual disease with inclusion requiring either pathologically involved surgical margins or pathological stage T3 disease. The EORTC 22911 trial (495) randomised 1005 such patients to observation or post-RRP radiotherapy (60Gy) from 1992-2001. 30% of these had a detectable post-operative PSA. At a median follow-up of 5 years, biochemical progression-free survival was significantly improved in the irradiated arm (74.0% versus 52.6%; hazard ratio 0.48 [95% CI 0.37-0.62]). Clinical progression and loco-regional failure were also significantly improved. Too few death events have been recorded as yet to show a difference, although approximately twice as many deaths from prostate cancer had occurred in the observation arm compared with the irradiated. Grade 3 toxicity was uncommon, and not significantly different between the treatment arms (4.2% and 2.6% cumulative incidence rate at 5 years for the radiotherapy and observed arms respectively). In a detailed companion study, urinary incontinence (as defined by patient reported questionnaires and pad weight measurements) was found to not be increased by the addition of radiotherapy (496).
Two additional similar randomised studies have been presented in abstract form to date. The German Cancer Society trial (ARO 96-02 / AUO AP 0995) was designed to asses to impact of adjuvant radiotherapy in those with pT3 disease or positive margins who achieved an undetectable PSA post-RRP (497). With a median follow-up of over 3 years, the results from 261 patients showed a better than 20% absolute improvement in the biochemical failure rate in the radiotherapy arm (hazard ratio 0.40 for the addition of radiotherapy when analysed by treatment received, p<0.0001). Grade 3 rectal toxicity was not observed in either group. Similarly, the Southwest Oncology Group study (SWOG 8794) randomised 419 pT3 and margin positive men to have either observation or radiotherapy (498). 55% had a detectable post-RRP PSA. The risk of biochemical recurrence was reduced by 56% by adding adjuvant radiotherapy, and prospective quality of life assessment suggested no significant differences in the gastrointestinal, urinary and sexual domains at 5 years. The risk of needing future salvage androgen suppression therapy was reduced by 56% also and clinically apparent relapse by 38% (both statistically significant). Distant metastasis and survival events were too infrequent in both studies to make meaningful assessment.
This combination of randomised trial data (amounting to level 1 evidence) suggest that there is an unequivocal capacity for post-RRP adjuvant radiotherapy to approximately halve the chance of having a future PSA-detectable tumour recurrence in pT3 / margin positive patients, while maintaining a low level of toxicity. More maturity to the data is awaited to determine the overall impact this has on distant metastases or survival.
The role of salvage radiotherapy is far less clearly defined, with no prospective studies of efficacy or toxicity to guide decisions. Retrospective analyses suggest that the PSA level prior to initiating the salvage radiotherapy is strongly predictive of outcome (499-501), with some series suggesting that treatment at PSA levels below 1 ng/mL do substantially better than those above this level (502). This PSA effect has been shown to be independent of the PSA doubling time (503), potentially indicating that these patients benefit from early referral for treatment regardless of PSA dynamics. Indeed, one series demonstrated an independent benefit to the use of immediate adjuvant therapy rather than waiting until requiring salvage (504). Other prognostic factors which have described, although not consistently, have included seminal vesicle invasion, margin positivity, post-operative PSA nadir level, high gleason grade, and radiation dose (501-503). Larger series typically show a 5 year biochemical control rate in the order of 50% typically (501, 505), and over 70% for those with a pre-treatment PSA of less than 1 ng/mL and an operative Gleason score of 7 or lower (502). Despite the apparent ability to provide a substantial chance for long-term control in relapsed men, there is concerning data that post-RRP radiotherapy may be under-utilised. Only 55% and the 38% of the biochemical failures in the observation arms of the EORTC and SWOG randomised trials respectively underwent potentially curative salvage radiotherapy, with the remaining being treated palliatively with observation or androgen suppression therapy. Prospective efficacy and toxicity data will be required to fully appreciate the therapeutic ratio of radiotherapy in this group of men.