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Expert Commentary
Long-term results following RP are suboptimal when used as monotherapy for high-risk prostate cancer. There is no accepted multimodal strategy for high-risk disease and recurrence following current treatment approaches remains high. With the publication of updated results from SWOG 8794, level I evidence now exists to support the use of adjuvant RT following RP in patients that are found at RP to have one or more of ECE, SVI or SM+. The improvement in median survival (2 years) is statistically and clinically significant. Mature survival data from the similarly-designed EORTC 22911 and ARO 96-02 trials are awaited. Several questions regarding postoperative RT remain. Should it be applied in other high-risk scenarios (e.g., high-grade, organ-confined disease)? Can it be delayed until early biochemical failure without loss of efficacy? Will the addition of ADT to RT further improve outcomes? The answers to these questions will hinge on the findings of trials in progress.

The evidence for systemic therapies given prior to or following RP remains much more tenuous. Multiple trials of neoadjuvant ADT as well as the EPC trial of adjuvant bicalutamide have all failed to show an advantage in survival. Trials of docetaxel-based neoadjuvant and adjuvant chemotherapy are underway. Lengthy follow-up will probably be required before conclusions regarding treatment efficacy can be made. The finding in SWOG 8794 that local, rather than distant, relapse is the predominant mode of failure among those observed after surgery[31] strongly suggests, however, that adjuvant strategies relying solely on systemic therapies are misguided.

Whereas low-risk prostate cancer is all too frequently overtreated, it may be argued that high-risk disease, in view of the poor results of contemporary approaches, is significantly undertreated. Improving survival in these patients will require the rational integration of local and novel systemic therapies. Widespread support of the trials described above is required from the urological and oncological communities.

Five-year View
In the coming years, models employed to predict recurrence after primary treatment of localized prostate cancer and to predict cancer-specific mortality will continue to be refined. As in other solid tumors, these models will increasingly take account of tissue and molecular markers to complement the established clinicopathologic factors. Already, a systems pathology approach has demonstrated promise in this regard.[19] Ultimately, these models will enable greater individualization of treatment.

In light of the findings of SWOG 8794 confirming a significant survival advantage for adjuvant RT in pathologic T3 or margin-positive disease, the coming years will probably see a broader uptake of postoperative RT in this setting by the urological community. New trials of adjuvant systemic therapy will need to make provisions for postoperative RT, while existing protocols that do not allow for RT will require amendment.

Publication of early results from the trials of neoadjuvant and adjuvant chemotherapy in high-risk localized prostate cancer is also anticipated within the next 5 years. While prostate cancer lags behind other solid tumors in the evaluation of adjuvant systemic therapy, the role for docetaxel-based chemotherapy and ADT in this setting should soon become better defined.

Multiple new classes of agents are at present the subject of intensive investigation in castration-resistant prostate cancer. These include bone-targeted agents, such as bisphosphonates, endothelin-A receptor antagonists and RANK ligand inhibitors; anti-angiogenic agents, such as bevacizumab and thalidomide; abiraterone, a potent inhibitor of adrenal androgen synthesis; and vaccine therapies. Those which prove to be effective in this context will probably be moved forward for evaluation in the adjuvant setting.

Table 1. Active Randomized Controlled Trials Comparing Adjuvant and Salvage Approaches for the Timing of Radiotherapy Following Radical Prostatectomy

Trial Key eligibility criteria Randomization Post-RP PSA failure definition RT dose ADT use Primary end point Planned accrual (n)
GETUG 17 NCT00667069 pT3 or pT4 (bladder neck invasion only), R1, pN0/NX If pT3b, Gleason < 8 Post-RP PSA < 0.1 Immediate RT plus ADT x 6 months vs RT plus ADT x 6 months at PSA failure PSA > 0.2 66 Gy in 33 fractions LHRH-a bPFS 718
RAVES (TROG) NCT00860652 pT3 R0-1 or pT2 R1 Post-RP PSA = 0.1 Immediate RT versus RT at PSA failure PSA = 0.2 64 Gy in 32 fractions Reserved for PSA failure after RT bPFS 470
RADICALS (MRC/ NCIC) NCT00541047 Uncertainty principle (see text) Post-RP PSA < 0.4 Immediate RT versus RT at PSA failure Two consecutive rises in PSA and PSA > 0.1 or three consecutive rises in PSA 66 Gy in 33 fractions or 52.5 Gy in 20 fractions Randomized (see Table 2) PCSS 3800 (overall)

All PSA values are quoted in ng/ml.
ADT: Androgen-deprivation therapy; bPFS: Biochemical progression-free survival; GETUG: Groupe d'Étude des Tumeurs Uro-Génitales; LHRH-a: Luteinizing hormone-releasing hormone agonist; MRC: Medical Research Council; NCIC: National Cancer Insitute of Canada; PCSS: Prostate cancer-specific survival; PSA: Prostate-specific antigen; RADICALS: Radiotherapy and Androgen Deprivation in Combination After Local Surgery; RAVES: Radiotherapy Adjuvant Versus Early Salvage; RP: Radical prostatectomy; RT: Radiotherapy; TROG: Trans-Tasman Radiation Oncology Group.

Table 2. Active Randomized Controlled Trials Investigating the Use of ADT in Addition to RT Following Radical Prostatectomy

Trial Key eligibility criteria Randomization ADT RT timing and dose Primary end point Planned accrual (n)
GETUG 16 NCT00423475 pT2-4, pN0/Nx Post-RP PSA < 0.1 PSA = 0.2 and = 2.0 at study entry RT plus ADT x 6 months versus RT alone Goserelin Salvage; 66 Gy in 33 fractions bPFS 466
RADICALS (MRC/ NCIC) NCT00541047 Uncertainty principle (see text) Post-RP PSA < 0.4 RT alone versus RT plus 6 months ADT versus RT plus 24 months ADT LHRH-a or bicalutamide 150 mg daily Randomized; see Table 1 PCSS 3800
RTOG 96-01 NCT00023829 pT3 N0 or pT2 R1 N0 Post-RP PSA = 0.2 and = 4.0 RT plus ADT x 2 years versus RT plus placebo Bicalutamide 150 mg daily Salvage; 64.8 Gy in 36 fractions OS 810 (accrual complete)
RTOG 05-34 NCT00567580 pT3 N0/NX or pT2 R0-1 N0/NX Post-RP PSA = 0.2 and = 2.0 Gleason = 8 Prostate bed RT alone versus prostate bed RT plus ADT x 4-6 months versus prostate bed and pelvic lymph node RT plus ADT x 4-6 months LHRH-a and oral antiandrogen Salvage; 64.8-70.2 Gy in 36-39 fractions to prostate bed, 45 Gy in 25 fractions to pelvic nodes bPFS 1764

All PSA values are quoted in ng/ml.
ADT: Androgen-deprivation therapy; bPFS: Biochemical progression-free survival; GETUG: Groupe d'Étude des Tumeurs Uro-Génitales; LHRH-a: Luteinizing hormone-releasing hormone agonist; MRC: Medical Research Council; NCIC: National Cancer Insitute of Canada; OS: Overall survival; PCSS: Prostate cancer-specific survival; PSA: Prostate-specific antigen; RADICALS: Radiotherapy and Androgen Deprivation in Combination After Local Surgery; RP: Radical prostatectomy; RT: Radiotherapy; RTOG: Radiation Therapy Oncology Group.

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