ART implies that the patient achieved an undetectable post-RP PSA level (depending on the detection system that has to be documented) and, despite this apparent success, is irradiated. Evidently, a dilemma results from the unavoidable overtreatment by ART, which must be justified by clinical advantage. Overtreatment is estimated to involve 40–50% of the patients, which is the percentage of stable remissions 5 years after RP alone.[34,46] Furthermore, in patients whose tumors already spread beyond the pelvis, ART is useless and 30% of ART patients are expected to develop progression or die despite treatment.[34,47] Such concern probably causes low ART application rates.[48–50] However, ART might be superior to (delayed) SRT for those patients who ultimately develop post-RP recurrence and who could profit from early initiation of RT.
Three randomized clinical trials have dealt with the significance of ART in patients with locally advanced PC, namely:
The SWOG 8794 trial:[51,52,204] the primary end point in this study was metastasis-free survival. bNED was a secondary end point (PSA cut-off 0.4 ng/ml). A total of 425 men with pT3 N0 M0 PC were randomized after RP. At least one of the following criteria for extraprostatic disease had to be fulfilled: extracapsular tumor; positive surgical margins; or seminal vesicle invasion. An undetectable post-RP PSA was not required (a third of the tests were >0.2 ng/ml). A total of 211 men were assigned to observation and 214 to ART with 60–64 Gy. With the recruiting period from 1988 to 1997, therapy was based on 2D plans;
The EORTC trial 22911:[33,53] PSA progression was the 'revised primary end point' (initially it was metastasis-free survival), defined as PSA 0.2 ng/ml above the post-RP minimum. After RP, 503 patients were randomly assigned to the wait-and-see arm and 502 to ART. Patients with T2–3 N0 M0 PC and at least one of these criteria were eligible: capsule perforation; positive surgical margins; or invasion of seminal vesicles. ART (no 3D planning) patients received 50 Gy to the prostate bed plus a 10 Gy boost (five fractions) to a reduced volume, starting irradiation within 16 weeks after surgery;
The ARO trial 96-02: the primary end point was bNED (PSA threshold <0.1 ng/ml). This study focused on patients with pT3 N0 tumors with positive or negative surgical margins and an undetectable PSA. A total of 192 men were eligible for active surveillance and 193 for ART with 60 Gy, planned in 3D and beginning 6–12 weeks post-RP. Ultimately, 114 patients underwent RT (starting within 12 week post-RP) and 154 patients had a wait-and-see policy.
For these three studies, with their different inclusion criteria and treatment conditions, systematic reviews are already available.[2,55–59] It is agreed in unison that up to the reporting date, ART improved bNED; the overall hazard ratio ranges from 0.4 to 0.6 in favor of ART. In the early trial reports, reliable information was not available for all long-term effects. Meanwhile, the SWOG trial was updated with a median follow-up of over 12 years, now stating a significantly improved metastasis-free and overall survival with a hazard ratio of 0.7 for both end points; the authors calculated that, on average, 12.2 patients had to be treated with ART to prevent one case of metastatic disease and 9.1 patients to prevent one death at 12.6 years of median follow-up. However, it has been argued that the survival benefit after ART was largely due to a lower rate of competing-cause deaths without evidence of distant metastasis, and that the impact of ART on metastatic disease and cancer-specific death was still uncertain. In contrast to SWOG, no significant difference for these end points was achieved in the EORTC trial after 10.6 years median follow-up. The ARO-96 trial reported on 53 months of overall median follow-up and, therefore, there were too few events to report on survival with any statistical significance. In all three trials, ART increased the risk of (mostly mild) normal tissue complications, involving bowel and bladder function. Erectile dysfunction, which was assessed only in the SWOG trial, occurred independent of the treatment arms. Technical advancements should help reduce side effects even after higher doses, as shown for first-line RT.
In a retrospective analysis, ART within a half-year post-RP has been reported. Such a delay may occur due to healing complications. A strict definition of ART would rather refer to an undetectable PSA than to the onset of radiation. However, for patients with intermediate- or high-risk profile, ART with 60–64 Gy 3–4 months post-PR has been recommended,[23,35] while one retrospective analysis of 334 ART patients (including 37% non-3D) found an advantage for bNED and disease-free survival after 70.2 versus 66.6 Gy (median dose given in 1.8 Gy fractions). A total of 64 Gy is the intended dose in the ongoing RAVES study by the Trans-Tasman Radiation Oncology Group. Patients with adverse prognostic factors are randomized either to ART, initiating within 4 months post-RP or to early SRT triggered by PSA rising to ≥0.2 ng/ml. The primary end point in this study is biochemical failure, defined as PSA >0.4 ng/ml and rising. In the international RADICALS trial, 66 Gy in 33 fractions or alternatively 55 Gy in 20 fractions are planned. With its large patient number, RADICALS should help to answer the question under which conditions ART is superior to SRT. In Germany, a multicenter study is about to start in 2013 under the acronym ART-2. A total of 298 RP patients with R0/R1, pN1 (≤2 lymph nodes involved) will be randomized to wait-and-see or to ART with 50.4 Gy (R0 patients) or 64.8 Gy (R1 patients). ART can be applied conventionally (3D) or by intensity-modulated RT (IMRT), and also fast application (arc technique) is possible. Driven by steadily developing radiation techniques, dose modifications, including hypofractionation, will certainly remain matters of debate,[62–64] and even intraoperative RT has been discussed.
Future Oncol. 2013;9(5):669-679. © 2013 Future Medicine Ltd.