In men with localized prostate cancer (PCa), radical prostatectomy (RP) is often the treatment of choice and has shown exceptional long-term outcomes (1,2). In patients with adverse pathological features at surgery (positive margins, extracapsular extension, and/or seminal vesicle invasion), randomized trials recommend adjuvant radiotherapy (aRT) to achieve optimal disease control (3-5). In clinical practice, the decision to treat patients with aRT is dependent on several variables, the primary factors including: disease characteristics, degree of added benefit, and risk of unnecessary radiation-related complications. While the role of aRT in patients with adverse pathology at surgery has been extensively explored, the exact benefit in those patients who have some adverse features, but still localized disease, such as a pT2 disease with a positive margin, or pT3a disease with a negative margin remains to be fully elucidated. In view of this void in recent literature, Hackman et al. reported on the Finnish randomized trial (6).
This report adds to three prior trials within this clinical milieu (3,5,7), in that it is the first to examine the benefit of aRT in patients with pT2 disease and positive margins or pT3a disease (pN0M0). Hackman et al. found that the 10-year biochemical recurrence-free (BCR-free) survival was 82% in the adjuvant group and 61% in the observation group [HR 0.26 (95% CI, 0.14–0.48), P<0.001]. However, this improvement in BCR is not without a cost as these patients displayed higher rates of toxicity. In the aRT arm, there was a higher rate of grade 3 adverse events (56% versus 40% in the observation group, P=0.016), which primarily consisted of erectile dysfunction and urinary incontinence. Furthermore, although patients treated with aRT displayed significant benefit in terms of BCR-free survival, these men did not experience improved overall survival (OS) outcomes at 10 years [HR 0.69 (95% CI, 0.29–1.60), P=0.4]. Such findings that aRT does not provide survival benefit in the subset of patients studied by the current report, and at the same time exposes them to radiation-related complications, should be weighed against the significant risk of BCR in patients treated with RP alone.
When appraising the findings of this randomized trial, it is important to view the primary endpoint, BCR-free survival, through an informed lens. BCR-free survival is commonly used as a proxy for OS; however, it has been shown that the two may not indicate interchangeable outcomes. For instance, in 1999, Pound et al. showed that only 34% of patients with BCR developed metastases suggesting that elevated PSA following RP does not necessarily demonstrate aggressive oncologic progression (8). These findings are further complemented by various studies indicating that in patients with BCR, only certain individuals with poor tumor differentiation and PSA kinetics are at a high risk of disease progression (9-11). Recently, a systematic review of 77 studies analyzed the impact BCR may have on survival, and concluded that in patients who underwent RP and subsequently developed BRC, the main prognostic factor for distant metastases, PCa specific mortality, and overall mortality was a short PSA doubling time (PSA-DT), a high pathologic Gleason Stage (>8), and a short interval to biochemical failure (12). Such findings suggest that the mere presence of BCR following RP is a relatively insignificant indicator of aggressive disease and survival when compared to PSA-DT, Gleason stage >8, and short interval to BCR. The BCR-free survival estimates presented in the present study should be interpreted with this in mind.
While Hackman et al. did not address PSA-DT, or interval to biochemical failure, 94.4% of patients that were included in the adjuvant arm, and 93.5% in the observation arm had PCa disease that was Gleason 7 or lower, suggesting that these patients were at low risk of developing distant metastases, PCa specific mortality, and overall mortality. For this subset of patients, BCR may not be quite as sinister as was once thought, especially in the presence of additional disease characteristics such as a lower Gleason score and/or disease ≤ pT2. As such, while statistically significant, the 21% reduction in BCR between the observation and adjuvant arms, may in fact exaggerate the clinical benefit patients receive from aRT and rushing to treat men with less adverse disease may expose patients to unwarranted toxicity.
As stated previously, Hackman et al. found that 61% of patients in the observation group were BCR-free at 10 years versus 82% in the aRT group. Thus, if aRT is widely adopted for these patients, roughly 61% will incur overtreatment and are at increased risk for radiation-related complications. For the subset of patients analyzed by Hackman et al., utilization of salvage radiotherapy (sRT) may be more appropriate. Current AUA guidelines recommend sRT administration in men with “PSA or local recurrence after RP in whom there is no evidence of distant metastatic disease” (4). In the present study, 43 patients with protocol-define BCR received sRT, and of these patients, 28 achieved PSA remission and nine required systemic therapy. As stated by the authors, recent data supports the utilization of early sRT (PSA <0.5 mg/L) (13), and in the present study, sRT was given at a cutoff PSA of 0.7 mg/L, which is considered late sRT. It is likely that the implementation of early sRT in the select patients in this study would provide adequate disease management, and at the same time prevent overtreatment in many patients.
Hackman et al. conducted a novel investigation with various strengths. Of particular importance, the present study examined randomized groups representative of contemporary patients (2004 to 2012) and had relatively long median follow-up periods. The median follow-up was 9.3 years in the adjuvant group and 8.6 years in the observation group, indicating that the study relied upon minimal extrapolation for its 10-year BCR-free, overall and metastasis-free survival estimates. Additionally, Hackman et al. collected objective (physician-reported toxicity) and subjective (patient reported quality of life) data to assess the degree of toxicity in these lower risk patients. Despite these strengths, the present study is not devoid of limitations, as stated by the authors. Namely, the study only included a total sample of 250 patients; thus, the small sample size may have impeded its power to fully detect differences in metastases and/or OS, which were secondary endpoints analyzed in this study. To combat this limitation and improve risk stratification in patients whom benefit most from aRT, additional tools may be necessary, a propitious option being genetic classification. Recent literature has shown genetic classification modalities (Prolaris, Oncotype Dx, and Decipher) in conjunction with clinicopathologic variables to be promising in predicting metastasis in RP patients and helpful in decision making of aRT versus sRT (14-16). Hackman et al. found that in these lower-risk patients, there were 2 PCa-related deaths (one in each arm), six patients (two in the aRT arm and four in the observation arm) developed metastasis, and nine were castration resistant (three in aRT group and six in the observation group). Genetic classification methods could certainly be advantageous in risk stratifying this population of men studied by Hackman et al., to further aid in the proactive selection of patients with unfavorable outcomes who would benefit from aRT, further preventing overtreatment in patients with less aggressive disease.
In all, the report by Hackman et al. is an important contribution to recent literature as it answers questions about the role of aRT in a subset of PCa patients for which the benefit of aRT still needs to be conclusively defined. In view of the present study findings, treatment of all patients with surgical margins and extracapsular extension with aRT poses a considerable risk of unnecessary treatment, and at the same time does not provide a survival and metastatic benefit. Although Hackman et al. displayed that aRT improves BCR-free survival when compared to initial observation, the significance of this discovery should be kept in perspective and considered in juxtaposition with other endpoints like OS, PCa-specific survival and metastasis-free survival. In addressing this conflict of overtreatment versus disease control, genomic classification and sRT prove to be promising options in optimally selecting patients that benefit from aRT and reducing unnecessary radiation toxicity, respectively. We look forward to future explorations that complement the conclusions presented by Hackman et al. and continue to optimize clinical management in PCa patients.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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