Postprostatectomy Radiation Therapy

Determining the Optimal Timing of Postprostatectomy Radiotherapy

In spite of the of level I evidence unequivocally showing a bPFS advantage in favor of ART for patients with APFs, practice patterns for its use have not changed within the USA.^[8] There are currently two treatment approaches for the management of patients with APFs following a RP, largely based upon differences in physician beliefs and practices of ART between treating to before radiation oncologists and urologists.^[18] One approach is to treat all patients with APFs with ART, based upon the aforementioned level I evidence. An alternative approach is to closely follow patients with serial PSA readings and initiate early SRT once a PSA failure is detected.

Proponents of SRT have noted that the previously mentioned randomized clinical trials were initiated at a time when PSA kinetics was not well understood. Up to 30% of patients in the SWOG and EORTC trials had a detectable PSA following RP,^[4,5] which is now known to be a negative prognostic factor. Treatment considered for these patients would now be SRT rather than ART. Others have argued that RT may be safely delayed in PC treatment given the slow-growing, indolent course of many low-grade PCs and the encouraging SRT data. However, it is known that delaying postoperative RT for a matter of weeks in other cancers, such as breast and head and neck cancers, decreases local control; an effect that is stronger in faster-growing tumors.^[19] Although no significant time-delay threshold has been identified for postoperative RT for PC, it is possible that one may exist; such a threshold delay would be expected to be protracted, perhaps by months or years, owing to the indolent nature of PC and may vary based on tumor grade or GS. This is a worthwhile concern in PC, where local control is associated with risk of metastasis and PC-related death after definitive^[20] and adjuvant^[6] RT.

Do All Patients With Adverse Pathological Features Benefit From ART?

Several studies have been performed to identify which APFs are most predictive of a benefit from immediate ART. In a post hoc analysis of the EORTC trial, prostatectomy specimens of nearly half of the patients who participated in the trial (n = 552 of 1005) were subjected to central pathology review in an effort to identify which pathological feature(s) were most predictive for increased benefit from ART.^[21] Margin status was found to be the strongest predictor of improved biochemical disease-free survival for patients treated with ART (hazard ratio [HR]: 0.38; 95% CI: 0.26–0.54; p < 0.0001). The benefit was present even for the subset of patients with pT2R1 patients (a group excluded from the SWOG and German study group trial). There was no benefit for patients with ECE or SVI without a positive SM. However, it should be noted that these findings are in contrast to a previous analysis of all prostatectomy specimens from this trial for which local pathology review was available (n = 972).^[22] This study had shown a bPFS benefit for all subgroups of patients treated with ART, including those with negative margins. Furthermore, patients excluded from this post hoc analysis were found to have a significantly poorer prognosis than those included in the study. Thus, while hypothesis-generating, these data require validation in an independent data set prior to the drawing of any conclusions from these findings.

SVI is a known poor prognostic factor for patients irrespective of receipt of postprostatectomy RT.^[23] Many have argued that SVI is a harbinger of micrometastatic disease, and thus local therapy with ART is unlikely to provide a benefit to these patients. However, a post hoc analysis of patients with SVI enrolled on the SWOG 8794 study demonstrated a significant 10-year biochemical freedom from failure survival advantage, and trend towards an improved metastasis-free survival and overall survival for patients treated with ART.^[23] Thus, there is no clear subset of patients with APFs who do not appear to benefit from ART.

Which Patients Can be Safely Treated With SRT?

Several studies have been performed to determine which subset of patients may be safely treated with SRT.^[24] In a multicenter analysis of 501 patients undergoing SRT, patients with a PSA <0.6 ng/ml were found to have an improved outcome following SRT compared with men with a PSA ≥0.61 ng/ml.^[25] A preradiotherapy level of >2.0 ng/ml was found to be an independent predictor of disease progression following SRT. Based on the results of this study, many physicians have concluded that a PSA level of <0.6 ng/ml is the 'threshold' at which RT can be safely delayed.

In another study, a large retrospective analysis of 1638 men status post-RP carried out at Duke University with unfavorable PC (preoperative PSA >20, GS 7–10, or pT3 disease) was performed. Findings from this study demonstrated that receipt of SRT for men with a PSA doubling time of ≤10 months was an independent predictor of higher all-cause mortality (adjusted HR: 3.42; 95% CI: 1.27–9.20; p = 0.016), after adjusting for age, T stage, APFs, preoperative PSA, comorbidity and hormonal use. There was, however, no difference in all-cause mortality for patients treated with immediate ART versus SRT for those men with a PSA doubling time of ≥10 months. Another study found that SRT initiated within 2 years of biochemical recurrence resulted in a decreased PC-specific mortality compared with men treated with no SRT if the PSA doubling time was less than 6 months, independent of pathological stage or GS.^[26] These findings indicate that even patients with aggressive disease, traditionally thought to be at high risk for distant metastatic disease, derive a benefit from local RT.

Can SRT be Equivalent to ART?

Although there is no level I evidence to answer the question of whether early SRT can be equivalent to ART, there have been several retrospective comparative studies that have been designed to address this issue. A matched-pair analysis of 149 patients with a pT3N0 PC treated with ART or SRT at Thomas Jefferson University demonstrated a 88% reduction in the risk of PSA relapse for patients treated with ART compared with SRT.^[27] In a similar multi-institutional matched-pair analysis of 192 patients with APFs, the 5-year freedom from biochemical failure following completion of RT for patients treated with ART was found to be 73% compared with 50% for patients treated with SRT (HR: 2.3; p = 0.0007).^[28] Factors found to be independent predictors of decreased freedom from biochemical failure were receipt of SRT and GS ≥8. Similar findings have also been noted in other retrospective comparative studies.^[29] However, there have also been other studies which have revealed that close observation with early SRT is a safe and effective treatment regimen.^[25,30,31]

For the subset of patients who do receive SRT, it is known that those patients who achieve an undetectable PSA following SRT appear to do significantly better than those with a detectable PSA following treatment. In a single-institution analysis of patients treated with SRT in Germany, an undetectable post-RT PSA was found to be the most significant prognostic factor correlated with freedom from biochemical failure.^[32] Patients with an undetectable post-SRT PSA had a calculated biochemical relapse-free survival at 3.5 years of 75% compared with only 18% for those patients detectable PSA after SRT.

There are currently two cooperative groups with Phase III trials open that will hopefully help to determine the optimal timing for RT in the postoperative setting. The Trans-Tasman Radiation Oncology Group currently has a Phase III trial for patients with APFs in which patients are randomized to ART, initiated within 4 months following a RP or early SRT initiated once the PSA levels are ≥0.2 ng/ml. The primary end point of this study will be PSA failure. The second study, the RADICALS trial run by the Medical Research Council in England, is randomizing patients with APFs to ART or early SRT (initiated following two consecutive PSA rises >0.1 ng/ml or three consecutive PSA rises). Although these trials will provide important information about the efficacy of SRT versus ART, data from these trials are not expected to become available for another decade. In the meantime, there is no consensus on whether patients should be treated with ART or SRT and treatment decisions are largely based upon individual beliefs of treating physicians.

Table 1. Randomized trials of adjuvant radiation versus observation following radical prostatectomy for men with adverse pathologic features.
Study	Number	Randomization	RT technique	bPFS (%)	p-value	OS (%)	p-value	Ref.
Total	Randomized
SWOG 8794	425	211	Observation	2D	36 (10 years)	<0.001	48 (12.5 years)	0.023	[6]
		214	60–64 Gy		65 (10 years)		59 (12.5 years)
EORTC 22911	1005	503	Observation	2D	41 (10 years)	<0.001	77 (10 years)	>0.1	[11]
		502	60 Gy		61 (10 years)		81 (10 years)
ARO 96–02	307^†	159	Observation	3D	54 (5 years)	0.0015	NR		[7]
		148	60 Gy		72 (5 years)		NR

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