summarizes trials involving radical prostatectomy (RP) with or without the addition of androgen deprivation therapy (ADT) or RP compared with “watchful waiting” (WW). Although some say that WW is not to be compared with AS, there is no clear consensus as to what constitutes WW and AS; thus, useful information may still be gleaned from their collective evaluation. The only major trial comparing WW with RP showed that with a median of 12.8 years, 166 men in the RP group and 201 in the WW group died of any cause (P
= .007) (3
). Of note, 55 and 81 of the deaths were attributed to prostate cancer to the RP and WW groups, respectively. The survival benefit observed appeared to be confined to men younger than age 65 years. The number needed to treat to avert one death was 15 overall and 7 for men younger than age 65 years. The remaining studies demonstrated that there is no advantage to adding ADT except as an adjuvant therapy in men with positive lymph nodes (11
Randomized trials using radical prostatectomy (RP) to “watchful waiting” or RP with or without androgen deprivation therapy (ADT) for clinically localized prostate cancer*
summarizes the three major trials addressing adjuvant postoperative radiotherapy (RT). The relevance of these studies to screening and AS may seem questionable because, for example, only 302 of the 431 patients on the Thompson trial had a preoperative prostate-specific antigen (PSA) and approximately 50% of these men had a PSA < 10ng/mL. However, despite screening, 25%–30% of men undergoing a radical prostatectomy will still have evidence of extracapsular extension or positive margins and thus will be candidates for adjuvant RT (15
). The data from the Thompson trial provide information regarding both the sample size and timeline required to document a survival benefit with adjuvant therapy. It took more than 10 years to show the benefits of postoperative RT; thus, it is likely that it would take an even longer follow-up period to demonstrate the impact of treatment in the remaining men with organ-confined disease. Furthermore, nonscreened men who are diagnosed with more advanced disease might be expected to have a prolonged survival due to early aggressive postoperative interventions further complicating the short-term analysis of men offered deferred management.
Postoperative external beam radiotherapy (EBRT) after radical prostatectomy (RP) for clinically localized prostate cancer*
addresses the role of primary external beam radiotherapy (EBRT) compared with other modalities (eg, radical prostatectomy or cryoablation with higher doses). Because of their small size and short follow-up at first review, it may appear that these studies would be of little relevance to the screening or AS controversies. However, their shortcomings tell us “what not to do” and explain why we have not resolved the uncertainty concerning the relative effectiveness of these treatment options. The point here is that we should avoid conducting underpowered studies when assessing interventions that are likely to have relatively small differences in effectiveness.
Radical prostatectomy (RP) vs external beam radiation therapy (EBRT) and EBRT vs Cryosurgery (CRYO)*
addresses the impact of different types and doses of radiation used in the treatment of prostate cancer. Several studies did not provide sufficient details to allow an accurate assessment of the number of low-risk patients included (23
). Some studies specifically excluded low-risk patients (26
). In several studies, approximately 20% of the patients could be considered low-risk patients (20
). In other studies, up to 40%–50% or more would generally be considered low-risk patients (25
). Ultimately, although the studies consistently show a reduction in the PSA detected recurrence rates with higher doses of radiation, there was no evidence that survival was improved. These findings should discourage investigators from expecting to detect improvements in survival between patients with early prostate cancer who were treated with relatively modest doses of radiation.
Radiation: dose escalation, protons, hypofractionation, neutrons, and brachytherapy*
summarizes phase III trials performed by the Radiation Therapy Oncology Group (RTOG) using radiation with or without ADT, and lists major non-RTOG phase III prostate cancer radiation trials with or without ADT. These studies when taken together provide a large body of level I evidence for the addition of ADT to EBRT in selected patients with intermediate- to high-risk prostate cancer. Their relevance to early-stage screening is that they provide data from which relative risk estimates, sample size estimates, and timelines can be made.
Phase III Radiation Therapy Oncology Group (RTOG) prostate cancer trials: radiation (RT) with or without andogen deprivation therapy (ADT), treatment volume effects*
Non-Radiation Therapy Oncology Group (RTOG) phase III prostate cancer trials radiation with or without androgen deprivation therapy (ADT)*
addresses the role of primary ADT with or without EBRT. Again, although the relevance of these data to AS or screening is not immediately obvious, there are lessons learned from these trials. The first two and the last two trials included only patients with locally advanced disease. The third trial listed included a subset of 1627 men with early-localized disease, who were randomized to placebo or 150mg of bicalutamide. When taken together, these studies demonstrated that treatment with ADT was beneficial in men with locally advanced disease, but such treatment resulted in a lower
survival in men on WW (54
). This study highlights that even though an intervention is beneficial to men with locally advanced disease, it does not necessarily mean that it will be beneficial in men with early disease. In addition, these data reinforce the notion that PSA alone is not an adequate endpoint and that it is important that studies be adequately powered.
Randomized prostate cancer trials: androgen deprivation therapy (ADT) vs deferred or radical prostatectomy (RP) and ADT with or without radiation therapy (RT)*
Based on these data, the following conclusions concerning the impact of various treatments on the survival of men with clinically localized disease can be drawn:
- RP prolongs survival compared with WW [Table 1, Bill-Axelson et al. (3)].
- Primary ADT appears to be more effective than observation in some subsets of patients, but there is no role for neoadjuvant ADT prior to RP. There may be a small impact on outcome in the adjuvant setting and a survival advantage with the use of early ADT in men with pathologically proven lymph node positive disease [Table 1, Studer et al. (4) and Messing et al. (11)].
- Postoperative EBRT delays the time to biochemical recurrences and may improve survival [Table 2, Thompson et al. (12), Wiegel et al. (13), and Bolla et al. (14)]. The addition of an oral antiandrogen therapy appears to further delay the time to clinical failure [Table 5, Shipley et al. (35)].
- The relative effectiveness of RP compared with EBRT and the effectiveness of cryoablation compared with EBRT also remain unresolved (). In general, all of these studies were underpowered for assessing a survival endpoint.
- Higher dose EBRT improves PSA control, but to date it provides no overall survival advantage (). Hypofractionation (large doses over a reduced number of days) has generated conflicting results and remains unproven as a strategy for improving outcomes ().
- Neutron-based EBRT may improve local control compared with low-dose photons but with a trend for increased complications. The effectiveness of mixed neutrons and photons on PSA control rates may be sequence dependent ().
- EBRT plus ADT is better than EBRT alone for intermediate- and high-risk patients ( and ). High-risk patients benefit from long-term ADT (2+ years), whereas those with intermediate-risk disease appear to require only 4–6 months ( and ).
- ADT plus EBRT is better than ADT alone for men with locally advanced disease. Adjuvant antiandrogen therapy may also improve survival in men with high-risk disease ().
- NNT is a common statistical tool (measured as the inverse of the absolute risk reduction), and with the ranges from the positive trials (shown in these tables) it supports the value of treatment for localized disease. For the RCTs that offer a survival advantage, NNT can be used as a tool to compare different treatment outcomes. With the assumption that relative risk reduction is constant for all levels of risk, NNT may be extrapolated to different patients with a baseline risk (1).
Remaining Questions and Important Gaps in Scientific or Medical Knowledge
Despite the considerable progress made due to the trials summarized above, there are still many unanswered questions. A partial list of completed, ongoing, or closed trials addressing some of the remaining questions among men treated for clinically localized disease is provided below:
- Which is the preferred treatment (RP vs EBRT or brachytherapy) for men who require treatment, with respect to quality of life and cancer outcomes (55)?
- Among men who experience local recurrences after EBRT, can “salvage” PPI be used safely and effectively (eg, RTOG 0526) (56)?
- Among men with adverse pathologic features noted after RP, should radiotherapy be administered immediately or held and administered at the time the PSA becomes detectable (eg, Radiotherapy and Androgen Deprivation in Combination After Local Surgery [RADICALS], GETUG-17, and Trans-Tasman Radiation Oncology Group Radiotherapy-Adjuvant Versus Early Salvage [TROG RAVES] trials).
- Can overall treatment time be reduced, by increasing EBRT dose fraction sizes improving outcomes and reducing cost without increasing morbidity (eg, RTOG 0415, 0938) (28)?
- Among men undergoing EBRT for recurrent disease after a RP, should ADT and or prophylactic whole pelvic lymph node radiotherapy (WPRT) be added to improve outcomes (eg, RTOG 0534) (57).
- Can prophylactic WPRT prolong overall survival in men with unfavorable intermediate- or favorable high-risk prostate cancer when combined with ADT without increasing morbidity (RTOG 0924) (58)?
- Can drugs active in the setting of castration-resistant prostate cancer be added earlier in the course of the disease and prolong survival longer compared with long-term ADT and EBRT (eg, RTOG 0521)?
- Can the prophylactic adjuvant use of pharmacologic agents reduce the risk of radiation-induced erectile dysfunction (eg, RTOG 0831)?