Direct comparison of low-dose-rate brachytherapy versus radical prostatectomy using the surgical definition of biochemical recurrence for patients with intermediate-risk prostate cancer

Intermediate-risk prostate cancer affects patients with heterogeneous oncological outcomes and has various treatment options [1]. For patients who desire curative treatment, permanent seed brachytherapy (SEED-BT) and radical prostatectomy (RP) are widely accepted definitive therapeutic options [2‐5]. Clinicians should provide comparative information about these treatment modalities and their therapeutic effects to help their patients make informed decisions. Although conducting prospective randomized controlled studies comparing SEED-BT and RP is not feasible [6, 7], several retrospective studies have compared the oncological outcomes between these treatments [8, 9]. These studies experienced some difficulties in making these comparisons because they proposed different definitions of biochemical recurrence (BCR) for each treatment [10, 11]. Different patient characteristics at baseline and the impacts of surgical techniques on margin control during RP also made the comparison difficult [12].

In this study, we compared the oncological outcomes of intermediate-risk prostate cancer treatments between SEED-BT and RP using propensity score matching, which minimizes imbalances in patient characteristics between treatment modalities. Because the definitions of BCR differ between the two treatment modalities, we compared the BCR using the same definition, with the surgical definition of the prostate-specific antigen (PSA) cut-off value being 0.2 ng/mL for both SEED-BT and RP. We also compared the effectiveness of both treatment modalities by excluding patients with positive surgical margins for RP and their matched pairs for SEED-BT to eliminate the effect of surgical techniques on oncological outcomes.

Figure 1 shows the patient selection process. In total, 1267 patients with intermediate-risk prostate cancer were treated with either SEED-BT (n = 933) or RP (n = 334) at three institutions. Among them, 243 patients were excluded from the study; Fig. 1 provides the reasons for their exclusion. Finally, 1014 patients met the inclusion criteria. One-to-one propensity score matching was performed using the clinical data for the 1014 patients, which yielded 214 pairs. For further analysis, 63 patients with positive surgical margins for RP and 63 matched pairs who underwent SEED-BT were excluded to eliminate the effect of surgical technique on oncological outcomes.

Table 1 shows the patients’ characteristics after propensity score matching. The median follow-up was 96 months (range 1–158 months). Forty-three patients (20.0%) received salvage radiotherapy for the prostate bed after RP. Fifty-three patients (24.7%) received a combination of EBRT for SEED-BT. Sixty-three patients who underwent RP (29.4%) had positive surgical margins. Ninety-three patients who received RP (43.4%) underwent laparoscopic RP.

We used propensity score matching to evaluate and compare the oncological outcomes of patients with intermediate-risk prostate cancer who underwent SEED-BT with those who underwent RP. The BCR-free rates did not significantly differ between the two treatment modalities even when the BCR-free rates were evaluated using the same definition of a PSA cut-off value of 0.2 ng/mL for both treatments. When the analysis was performed with the assumption that no RP patients had positive surgical margins, the oncological outcomes still did not differ between the two treatment modalities. Additionally, the overall survival rate and prostate cancer-specific mortality rate did not significantly differ between the two treatments. Hence, SEED-BT and RP can be adequately compared for the oncological outcomes of intermediate-risk prostate cancer.

Grim et al. [2] performed a comparative analysis of PSA failure-free survival outcomes for patients with non-metastatic prostate cancer after radical therapy. For intermediate-risk patients, these authors reported a higher average BCR-free survival rate for SEED-BT than for RP. Goy et al. [9] compared the 10-year BCR-free rates between SEED-BT ± EBRT and RP for patients with intermediate-risk prostate cancer. When the BCR-free rates were calculated using the Phoenix definition for SEED-BT and the surgical definition for RP, SEED-BT yielded significantly higher 10-year BCR-free rates than did RP (80.2% vs 57.1%, P = 0.0003). Additionally, compared with SEED-BT, RP had a higher incidence of patients who received some form of salvage therapy. Our results were consistent with these reports. Compared with SEED-BT, RP may have a higher incidence of patients considered to have BCR and consequently need salvage therapies more frequently when the individual definition of PSA failure is used in daily clinical practice.

The surgical definition of a PSA cut-off value of 0.2 ng/mL is more sensitive than the Phoenix definition of PSA nadir plus 2 ng/mL is for detecting BCR [10, 11]. Different definitions of BCR make comparing the oncological outcomes between SEED-BT and RP difficult. To resolve this, we compared the BCR-free rate with the same definition of a PSA cut-off value of 0.2 ng/mL. Our results suggested that SEED-BT and RP had comparable BCR-free rates in this setting. Comparing the BCR-free rate between the two modalities using the surgical definition may be inadequate because PSA levels gradually decline after prostate SEED-BT and can take > 5 years to reach a nadir [18]. However, reaching a PSA value of < 0.2 ng/mL would be an important index for managing SEED-BT because patients who reach this PSA value are less likely to experience recurrence after SEED-BT [19, 20]. Morris et al. reported the reanalysis of androgen suppression combined with elective nodal and dose-escalated radiation therapy (the ASCENDE-RT trial) using the surgical definition of BCR in high- and intermediate-risk patients. Unlike dose-escalated EBRT, replacing the Phoenix definition with the surgical definition did not affect BCR after SEED-BT. These authors concluded that BCR after SEED-BT or RP can be directly compared using the surgical definition [21].

Differences in surgical techniques and the incidence of positive surgical margins also make comparing the oncological outcomes between SEED-BT and RP difficult [12]. Published data on positive surgical margins vary and depend on patient selection, the surgeons and the procedures [9, 22‐24]. In the present study, approximately 53% of patients had an unfavorable intermediate risk, and 29.4% of RP patients had positive surgical margins. The incidence of positive surgical margins in patients who underwent open RP was higher than that of patients who underwent laparoscopic RP (34.7% vs. 22.5%). The higher rate of positive surgical margins adversely influenced BCR after RP and independently predicted BCR. Our incidence of positive surgical margins yielded comparable or slightly higher rates than those of previous studies [9, 23‐25]. To eliminate the effects of surgical technique on clinical outcomes, we compared the effectiveness of the two treatments assuming that no RP patients had positive surgical margins. In this study, the BCR-free rates did not significantly differ. Advances in diagnostic imaging modalities and surgical techniques such as robot-assisted RP may decrease the positive-margin rates [12, 22, 25, 26]. However, obtaining no positive surgical margins in patients with intermediate-risk prostate cancer would be impossible because the incidence of pathological T3 exists to some extent by stage migration. The oncological outcomes after SEED-BT would be comparable even if the advanced procedure reduced the positive-margin rate to as close to zero as possible.

For RP, pathological findings from surgical specimens, including positive surgical margins, pathological T3–4, and Gleason grade groups, independently predict BCR or the use of salvage hormonal therapy. Predicting oncological outcomes from surgical specimens is considered as an advantage of RP over SEED-BT. However, for SEED-BT, we detected no risk factors for predicting BCR or the use of salvage hormonal therapy. The present study included SEED-BT alone and the combination of SEED-BT and EBRT. Although the 24.7% of patients who underwent combined therapy may have affected the analysis of these risk factors, the BCR-free rates did not significantly differ between SEED-BT alone and SEED-BT plus EBRT in our subgroup analysis. No consensus has been reached regarding the benefit of additional EBRT for patients with intermediate-risk prostate cancer [2, 27].

In addition to its retrospective nature, the present study had several limitations. First, our results lacked adequate power to generalize them with those of other institutions because this study represented the experiences of three tertiary centers. While overall survival rates did not significantly differ between the two treatments, our overall survival analysis was inadequate because we did not include factors related to life expectancy, such as co-morbidities and smoking history, in the propensity score matching. Survival data from multiple centers involving more patients with longer follow-up periods are needed. Second, no comparable applications for evaluating health-related quality of life were available in the present study. We did not evaluate patient-reported outcomes or erectile dysfunction between the two modalities. Third, pathological findings were not centrally reviewed. Additionally, we lacked information on prostate volume, nerve-sparing status, and individual surgeon volume. These variables were likely confounding factors influencing interpretation of the results. Finally, 30.3% of the SEED-BT patients received NHT for < 1 year. The short-term NHT may have affected the BCR rate.

Treatment with either SEED-BT or RP had comparable oncological outcomes for patients with intermediate-risk prostate cancer for our median 8-year follow-up even when the BCR rate was calculated using the same definition of a PSA cut-off value of 0.2 ng/mL for both treatments. We believe that our results may help patients decide which treatment best suits their medical needs. Further evaluation is needed regarding the role of definitive treatments for patients with intermediate-risk prostate cancer undergoing robot-assisted RP or stereotactic radiotherapy.