Role of Brachytherapy Boost in Clinically Localized Intermediate and High-Risk Prostate Cancer: Lack of Benefit in Patients with Very High-Risk Factors T3b–4 and/or Gleason 9–10

Simple Summary In general, brachytherapy (BT) improves biochemical control in intermediate-to high-risk prostate cancer. We previously reported that importance of very high-risk factors (VHR: T3b–4 or Gleason score 9–10) and patients with double VHR (VHR-2) showed the worst prognosis among high-risk groups. We explored the role of BT-boost in patients with VHR and compared it to intermediate- and other high-risk groups. We confirmed that BT-boost improved prostate-specific antigen (PSA) control but resulted in equivalent overall survival rates for the intermediate- and high-risk groups, except for the patients with VHR. In the VHR-1 group (single VHR), BT-boost showed superior PSA control to conventional-dose RT (EQD2 ≤ 72 Gy) but not to the dose-escalated radiotherapy group (EQD2 ≥ 74 Gy). In the VHR-2 group, BT-boost did not improve the biochemical control rate of either Conv RT or DeRT. BT-boost showed no benefit over modern DeRT in the patients with VHR. Abstract This study examined the role of brachytherapy boost (BT-boost) and external beam radiotherapy (EBRT) in intermediate- to high-risk prostate cancer, especially in patients with very high-risk factors (VHR: T3b–4 or Gleason score 9–10) as patients with double very high-risk factors (VHR-2: T3b–4 and Gleason score 9–10) previously showed worst prognosis in localized prostate cancer. We retrospectively reviewed multi-institutional data of 1961 patients that were administered radiotherapy (1091 BT-boost and 872 EBRT: 593 conventional-dose RT (Conv RT: equivalent to doses of 2 Gy per fraction = EQD2 ≤ 72 Gy) and 216 dose-escalating RT (DeRT = EQD2 ≥ 74 Gy). We found that BT-boost improved PSA control and provided an equivalent overall survival rate in the intermediate- and high-risk groups, except for patients within the VHR factor group. In the VHR-1 group (single VHR), BT-boost showed a superior biochemical control rate to the Conv RT group but not to the DeRT group. In the VHR-2 group, BT-boost did not improve outcomes of either Conv RT or DeRT groups. In conclusion, BT-boost showed no benefit to modern DeRT in the patients with VHR; therefore, they are not good candidates for BT-boost to improve outcome and may be amenable to clinical trials using multimodal intensified systemic treatments.


Introduction
Dose escalation in radiotherapy is an established strategy to improve the biochemical control rate in clinically localized through intermediate-and high-risk localized prostate cancer [1][2][3][4]. Brachytherapy boost (BT-boost) combined with external beam radiotherapy (EBRT) is a good option to elevate the prescribed dose of radiotherapy without increasing the toxicity due to the superior character of the BT; the rapid falloff of the dose gradient enables us to treat tumors at high doses while maintaining low doses to the surrounding organs at risk. Retrospective [4][5][6][7][8] and prospective analyses, including three randomized controlled trials [9][10][11][12], as well as meta-analysis, confirmed the benefit of biochemical control for BT-boost [13].
Recent exploration of risk stratification has introduced a new concept of very high-risk factors (VHR). The most widely used risk classification system in clinics is the National Comprehensive Cancer Network (NCCN) [14], in which the VHR includes a >4 biopsy cores with a Gleason score of 8-10, clinical stage T3b-T4 or primary Gleason score of 5, [14]. For risk stratification including VHR, summation of the number of VHRs (T3b-4 and Gleason score 9-10) was a useful system to identify the worst oncological population [15]. As data were scarce regarding the merits of dose escalation in patients with VHR, the present study examined the role of dose escalation with BT-boost in patients with intermediateto high-risk cancer as well as VHR. In addition, the NCCN Clinical Practice Guidelines in Oncology stated that doses of ≤70 Gy in conventional fractions are not sufficient for the treatment of intermediate-or high-risk prostate cancer [14,15]. Therefore, we divided the control group into conventional dose (Conv RT, doses ≤ 72 Gy) and dose-escalated radiotherapy (DeRT, prescribed dose of ≥74 Gy, equivalent to doses of 2 Gy per fraction [EQD2]) groups.
Therefore, this study examined the role of BT-boost in patients with VHR for the prognostication of clinically localized high-risk prostate cancer.

Patients
We used freely available public data to analyze a large cohort of 1961 patients; among these, 1145 BT-boost (1091 patients administered high-dose BT (HDR-BT) boost from open data for public use [16] and 63 patients treated with low-dose BT (LDR-BT) boost at the Kyoto Prefectural Medical School) [17]. This study included a total of 809 patients administered EBRT (388 administered Conv RT as identified from open data) and 421 patients [16] administered DeRT using intensity-modulated radiotherapy [IMRT] from open data [16] at Uji Takeda Hospital [18] (Table 1). Patients eligible for this study were treated with EBRT with BT-boost or EBRT alone; had histology-proven adenocarcinoma with clinical TNM stage T1-T4N0M0 disease; and had accessible and available data on T classification, Gleason score sum, and initial PSA [iPSA] level. The patients categorized as intermediate or high risks were eligible according to the NCCN risk classification [14]. A simple VHR index was calculated and applied by summing the number of VHR factors in the high-risk group: VHR-0, no VHR; VHR-1, Gleason score 9-10 or T3b-T4; VHR-2, Gleason score = 9-10 and T3b-T4 [19].
We defined PSA failure according to the Phoenix definitions (nadir, +2 ng/mL). Prostate cancer-specific mortality (PCSM) was defined when prostate cancer was the primary cause of death. Biochemical disease-free survival (bDFS), PCSM, overall survival (OS), and metastasis-free survival (MFS) rates were defined as the intervals from the start of RT to bDFS, distant metastasis, PCSM, and death, respectively. Patients included in the public data provided informed consent during the process of building the database and all patients from Uji Takeda Hospital and Kyoto Prefectural Medical School provided written informed consent [19]. This study was approved by the Institutional Review Board of the Kyoto Prefectural University of Medicine (ERB-C-1403) and conducted by the principles of the Declaration of Helsinki.

BT-Boost
The BT-boost groups included HDR-BT and LDR-BT. A multi-institution data of HDR-BT was provided from an open data source [16], and details of treatment have been described elsewhere [20,21]. In brief, the median dose of HDR-BT was 31.5 Gy (range, 10.5-31.5 Gy) in median fraction size 6.3 Gy (range, 5-11 Gy) combined with EBRT in various dose and fractions (median 3 Gy; range, 1.9-3.1 Gy) (Supplemental Table S1). The detailed treatment schedule for LDR-BT (Iodine-125 implantation) was described previously [17]. We included patients with T3a disease or Gleason score sum ≤ 8 or a summed Gleason score of 7 (4 + 3), but not for those with a summed Gleason score of 7 (3 + 4) [17] using prescription dose 110 Gy (LDR-BT) with EBRT by three-dimensional conformal radiotherapy (3D-CRT) 40 Gy/20 fractions (Supplemental Table S1). Whole pelvic RT were used in several institutions as a part of EBRT (Supplemental Table S1).

External Beam Radiotherapy (EBRT)
The EBRT group consisted of conventional two-dimensional treatment, 3D-CRT, and IMRT. Supplemental Table S1 depicted the details of patient backgrounds. A freely accessible dataset (n = 417) was used to draw some of EBRT data [16]; 141 image-guided IMRTs using helical TomoTherapy were performed at the Department of Radiology, Uji Takeda Hospital, and detailed technique has been described elsewhere [18]. In brief, the prescribed dose was 74 Gy/37 fractions (2 Gy/fraction, n = 79) or 74.8 Gy/34 fractions (2.2 Gy/fraction, n = 62) for the intermediate-risk and high-risk and groups [18]. We divided a control group into conventional dose group (Conv RT) using does up to 72 Gy and dose-escalated radiotherapy (DeRT) using dose 74 Gy or more in equivalent to doses of 2 Gy per fraction (EQD2). Detail of treatment schedules was depicted in Supplemental  Table S1.

Statistical Analysis
EZR stat package [22] and StatView 5.0 (SAS Institute, Inc., Cary, NC, USA) were used to perform the statistical analyses. Percentages were analyzed using Fisher's exact tests for two groups and chi-square tests for three or more groups. To compare means or medians, Student t-tests were used for normally distributed data, and Mann-Whitney Uand Kruskal-Wallis tests for skewed data (i.e., PSA values) [22]. To analyze the biochemical disease-free survival rate (bDFS), distant metastasis-free survival (DMSF), overall survival (OS), and prostate cancer-specific survival rate (PCS), the Kaplan-Meier method was used. Log-rank tests and Bonferroni correction comparisons were performed in analysis of statistically significance. Cox's proportional hazard model for bDFS was used for univariate and multivariate analyses. Statistical significance was set at p < 0.05. The propensity score was the probability of being assigned to each group and was calculated using a logistic regression model constructed with the baseline covariates shown in Table 2 (age, T classification, GS, pretreatment PSA, and hormonal therapy history). We used propensity score matching to reduce the selection bias for BT-boost or EBBT (a 1:1 matched cohort was made for comparison of BT-boost and EBRT in the total population and BT-boost versus DeRT).

Patient and Disease Characteristics
All 1961 patients with intermediate-to-high-risk prostate cancer were treated with either BT-boost (n = 1152) or EBRT (n = 809). The median patient age was 71 years (range, 49-89 years). The median initial PSA value was 14.0 ng/mL (range, 2.682-1454 ng/mL). The clinical characteristics of the patients are summarized in Table 1. The median follow-up duration was 69.0 (range: 2-177) months.
As shown in Table 3, the predictors of biochemical control on multivariate analysis included age, treatment modality (BT-boost vs. EBRT or DeRT or Conv RT), iPSA, T classification, and Gleason score sum.

Discussion
The present study explored the role of BT-boost in intermediate-to high-risk prostate

Discussion
The present study explored the role of BT-boost in intermediate-to high-risk prostate cancer. The results demonstrated that BT-boost showed superior bDFS compared to that in the EBRT group except for the VHR-2 group. To our knowledge, this is the first report to show the merits and limitations of BT-boost in patients with intermediate-to highrisk prostate cancer, with a focus on the VHR-2 group. In their meta-analysis of three randomized control trials (RCTs), Kee et al. reported a significant benefit in 5-year bDFS in favor of BT-boost versus EBRT but not in OS and grade ≥ 3 late toxicities [12]. However, two of the RCTs [9-11] had a major bias in their methodologies, as the EBRT arm was not the standard care of treatment (too few doses were delivered in the EBRT arm) and their findings could not be translated into modern clinical situations. However, the recent Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT) trial showed that even with escalated EBRT, BT-boost provided better benefits in terms of biochemical control [9]. Our data were also consistent with their data demonstrating superior bDFS for BT-boost compared to both Conv RT and DeRT in patients without VHR. The use of androgen deprivation therapy (ADT) and its optimal duration was another confounding factor for bDFS analysis. The bDFS was significantly better regardless of the BT technique used (low or high dose rates) in these three RCTs, independent of the ADT duration. Higher BED delivered by BT (12-38%) with the better dose distribution due to the steep dose gradient, which delivered a non-homogeneous dose escalation [12,13], was an important factor to improve the outcomes. Furthermore, several studies have reported the superior efficacy of BT-boost not only in terms of bDFS but also in PCS and OS [7,8]. Therefore, BT-boost for intermediate-and high-risk prostate cancer was an attractive technique in numerous retrospective and prospective studies.
The concept of VHR was recently introduced. High-risk prostate cancer has been subdivided according to VHR in several ways. The NCCN used clinical stage T3b-T4 lesions, primary Gleason score = 5, or > 4 biopsy cores with Gleason scores of 8-10 [14]. After the initial estimation [23], a confirmation study was conducted, despite different definitions of VHR [14,24,25]. We also confirmed the importance of VHR factors, in which VHR-2 showed a higher hazard risk for DMSF, PCS, and OS than VHR-0 (hazard ratio = 8.81, 11.99, and 4.644, respectively) and VHR-1 (hazard ratio = 5.268, 2.359, and 2.896, respectively), and was a potentially better stratification system than the previous ones [15]. Our results add additional evidence of VHR-2 in a population at very high risk for recurrence outside the prostate (i.e., distant metastasis), even with the highest intensification of local radiotherapy with BT-boost. Our data could provoke a controversy regarding the indication for BT-boost in the patients with VHR, who may not be good candidates for BT-boost. These VHR criteria may be beneficial for better treatment choice for individual patients according to prognosis of the high-risk disease predisposing a risk of aggressive oncological outcomes, which may require intensive follow-up for metastasis using modern technologies; prostate-specific membrane antigen positron emission tomography scan [26] and earlier and/or adjuvant systemic therapy; or longer periods of ADT use in addition to abiraterone, docetaxel, and enzalutamide [27][28][29][30], which could be in a multimodal treatment clinical trial setting.
The present study has several limitations. First, the role of the biopsy core in the VHR system could not be analyzed because the public database did not contain these data. In addition, recent image-guided biopsy techniques made it impossible to assess older data as it was not compatible with recent systems. Second, the retrospective nature, limited follow-up time, and small sample size (especially in the VHR-2 group) in this study may limit the application of its findings. Thus, studies with longer follow-up and larger samples are needed to obtain concrete conclusions; although it could be difficult to perform, an RCT is anticipated.

Conclusions
BT-boost improved bDFS in intermediate-and higher risk groups, except for the patients with very high-risk factors (VHR-2: T3b-4 and Gleason 9-10). In the VHR-1 group (single VHR), BT-boost showed a superior biochemical control rate to the Conv RT group but not the DeRT group. In the VHR-2 group (double VHR), BT-boost did not improve outcomes of either the Conv RT or DeRT group. BT-boost showed no benefit to modern DeRT in the patients with VHR; therefore, they are not good candidates for BT-boost to improve outcome and may be amenable to clinical trials using multimodal intensified systemic treatments.  Table S1: Detailed treatment schedule, Table  S2: Comparison of background of Patient characteristics after propensity score matching, Table S3: Background Comparison between BT-boost and DeRT after propensity score matching.  Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Data Availability Statement:
The data of HDR-BT and part of EBRT for this manuscript can be obtained from the public database [19] and another part of EBRT and LDR-BT can be obtained from the author upon reasonable request.