Postprostatectomy Radiation Therapy

An Evidence-based Review

Mark V Mishra; Colin E Champ; Robert B Den; Eli D Scher; Xinglei Shen; Edouard J Trabulsi; Costas D Lallas; Karen E Knudsen; Adam P Dicker; Timothy N Showalter

Disclosures

Future Oncol. 2011;7(12):1429-1440. 

In This Article

Randomized Clinical Trials of ART

Southwest Oncology Group 8794

This was a randomized multi-institutional prospective trial of ART versus observation for locally advanced PC following a RP.[5] The study enrolled 425 patients between 1988 and 1997 with pathological stage T3 (pT3) tumors who had one or more of the following pathological criteria: ECE, positive SM(s) or SVI. All patients in this study were required to undergo a pelvic lymph node dissection at the time of RP. An undetectable PSA level at time of enrollment was not required for this study. Among patients for whom PSA level data were available, only 66.2% of patients had a PSA that was undetectable at the time of randomization. A total 8% of patients received pre-RP androgen deprivation therapy (ADT).

Patients randomized to the immediate ART arm began RT within 18 weeks of surgery (16 weeks to time of randomization). RT details are not described in the publication, but it is presumed that treatment delivery was done utilizing 2D-based planning aimed at the prostatic fossa and paraprostatic tissues. The RT prescription dose was 60–64 Gy.

The primary end point of the study was distant metastasis-free survival. A biochemical failure was defined as PSA level greater than 0.4 ng/ml. At the time initial publication of the study (median follow-up 10.6 years),[5] there was a significant benefit for patients treated with immediate ART in terms of PSA relapse-free survival (>0.4 ng/ml) (median time to PSA relapse 10.3 vs 3.3 years; p < 0.001) and recurrence-free survival (median time 13.8 vs 9.9 years; p = 0.001). By 5 years, twice as many men in the observation arm had received hormonal therapy versus men in the ART arm (21 vs 10%; p<0.001). The initial report did not reveal a metastasis-free survival or overall survival advantage for ART. However, after longer follow-up (median follow-up of 12.5 years), a subsequent publication demonstrated a significant improvement in metastasis-free survival (12.9 years for the observation arm vs 14.7 years for the ART arm; p = 0.016) as well as an overall survival benefit in favor of ART (59% for the ART arm vs 48%, observation arm; p = 0.023).[6]

European Organization for Research & Treatment of Cancer 22911

The European Organization for Research and Treatment of Cancer (EORTC) 22911[4,5] was a Phase III clinical trial of postoperative external-beam RT versus no immediate further treatment for patients with an APFs. A total of 1005 patients were accrued to the trial between 1992 and 2001. All patients were status-post RP as well as ilio-obturator lymphadenectomy. Enrollment criteria for the trial included age <75 years and having at least one of the following pathological features: ECE, SVI or a positive SM(s) (microscopic or gross). Unlike the Southwest Oncology Group (SWOG) and German Study Group trial (discussed below), patients with pT2 tumors with positive margins were also included in this study. An undetectable PSA following prostatectomy was not a requirement for enrollment in the study. In total, 69.5% of patients had an undetectable PSA following their RP. A total of 10% of patients received pre-RP ADT.

Patients were randomized to ART or observation. For patients randomized to the ART arm, RT was initiated within 16 weeks following surgery, after recovery of urinary function. RT was delivered using 2D-based treatment planning to a dose of 60 Gy over a period of 6 weeks.

The primary end point of the study was bPFS. Biochemical progression was defined as an increase of more than 0.2 ng/ml over the lowest postoperative value measured on three occasions at least 2 weeks apart. After a median follow-up of 5 years, bPFS was significantly improved in the ART group (74 vs 56%; p < 0.0001). Clinical progression-free survival and the cumulative rate of local regional failures were also significantly improved in the ART group. In total, 22.5% of men in the observation arm subsequently underwent pelvic RT and 9% eventually required hormonal treatment. Although there were twice as many PC-related deaths in the observation arm, this did not reach statistical significance with a median follow-up of 5 years. Updated results with 10 years of follow-up data showed a continued bPFS advantage in favor or ART (61 vs 41%; p < 0.001) and a nonsignificant trend towards improved overall survival in the ART group (81 vs 77%; p > 0.1).[11]

German Study Group (ARO-96–02/AUO AP 09/95)

The third Phase III trial of ART versus observation for patients with APFs (ECE, SVI and SM[s])[7] enrolled a total of 385 patients between 1994 and 2004. Unlike the SWOG and EORTC trials, patients were required to have an undetectable PSA following RP. All patients were required to have undergone a pelvic lymph node dissection. Approximately 11% of patients received pre-RP ADT.

Unlike the prior two studies, patients in this trial were treated with more modern 3D conformal RT. RT was prescribed to a dose of 60 Gy and initiated within 6–12 weeks following RP.

The primary end point of the study was PSA relapse-free survival. A biochemical failure was defined as a PSA increase out of the undetectable range with a consecutive confirmation. With a median follow-up of 5 years, a significant improvement in bPFS was noted for the ART arm (72 vs 54%; p = 0.0015). There was no benefit for metastasis-free survival or overall survival, although longer follow-up will be needed before this can be formally assessed.

In summary, all three randomized trials of ART versus observation demonstrated improved in outcomes in PC patients with APFs in the RP specimen who received ART. The implementation of these clinical trial results has been limited; however, since the control arms (i.e., observation) do not accurately represent the currently-used strategy of close surveillance with selective use of early SRT.

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