Abstract
Background/Aim: Intermediate-risk prostate cancer (PCa) is a highly heterogeneous disease. Although low-dose-rate brachytherapy (LDR-BT) is mainly used for low- to intermediate-risk PCa, limited reports have evaluated the detailed differences in outcomes, including differences between patients with ISUP grade group (GG) 2 and GG3 intermediate-risk PCa. This study aimed to investigate the differences in outcomes between intermediate-risk Japanese patients with GG2 and GG3 PCa who underwent LDR-BT. Patients and Methods: This single-center retrospective study included 342 consecutive patients with intermediate-risk PCa; 232 patients with GG2 and 110 with GG3 were treated with LDR-BT at Tokushima University Hospital between July 2004 and December 2019. Results: No significant difference in 5-year biochemical progression-free survival and cancer-specific survival was observed between patients with GG2 and those with GG3 (p=0.649 and p=0.633, respectively). Multivariate analysis showed that radiation doses up to 90% of the prostate volume (D90) and the percentage of positive cores were predictors of recurrence in all patients with intermediate-risk PCa. Group analyses showed that D90 was a predictor for recurrence in patients with GG2. In contrast, a high percentage of positive cores was a significant risk factor for recurrence in patients with GG3. Conclusion: Positive core ratios observed on prostate biopsy correlated with higher recurrence rates after LDR-BT. This indicates that the proportion of positive cores in the biopsy may be an important factor in predicting the likelihood of recurrence, especially for patients with GG3 PCa.
- Intermediate-risk prostate cancer
- low-dose-rate brachytherapy
- ISUP Grade group 2
- ISUP Grade group 3
- prostate biopsy
Intermediate-risk prostate cancer (PCa) is a highly heterogeneous disease defined by three factors: (i) prostate-specific antigen (PSA), (ii) clinical stage, and (iii) a Gleason score (GS) of 7 (GS 7) for histological malignancy. For example, Epstein et al. divided patients with GS 7 PCa, classified as intermediate based on histological evaluation, who underwent radical prostatectomy into International Society of Urological Pathology (ISUP) grade group (GG) 2 and GG3, demonstrating clearly different treatment outcomes (1). In addition, the histological evaluations of prostate biopsies are not always consistent with those of surgical specimens. Several reports have indicated that the prognosis is significantly worse for patients when the histological grade of the radical prostatectomy specimen is higher than that of the prostate biopsy (2).
Contrarily, in radiation therapy, including low-dose-rate brachytherapy (LDR-BT), histological evaluation primarily depends on prostate biopsy results. Furthermore, LDR-BT is mainly used for low- to intermediate-risk PCa. While there is evidence of different outcomes between patients with low- and intermediate-risk PCa, limited reports have evaluated detailed differences in outcomes, including differences between intermediate-risk patients with GG2 and GG3 PCa.
This study aimed to investigate the differences between intermediate-risk Japanese patients with GG2 and GG3 PCa who underwent LDR-BT.
Patients and Methods
Study design and patient selection. This was a single-center retrospective study of consecutive patients with intermediate-risk PCa treated with LDR-BT at Tokushima University Hospital in Japan between July 2004 and December 2019. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Tokushima University Hospital (ID:4140).
In accordance with the National Comprehensive Cancer Network criteria, patients were defined as having intermediate risk if they met at least one of the following criteria: (i) PSA, 10-20 ng/ml; and/or (ii) GS 7; and/or (iii) clinical stage, T2b or T2c. The clinical characteristics of the patients are summarized in Table I.
Clinicopathologic characteristics.
LDR-BT procedure and hormonal therapy. Neoadjuvant hormonal therapy (NHT) was used mainly for patients with a large prostatic volume, but no standard protocol was used for treatment. After LDR-BT completion, most patients were not treated with adjuvant hormonal therapy. Seed implantation plans were made based on the prostate volume (PV) analyzed in detail using transrectal ultrasound approximately 4 weeks before LDR-BT. LDR-BT was performed by ultrasound-guided transperineal prostate implantation using the Interplant software (CMS, St. Louis, MO, USA).
All patients underwent computed tomography and chest, kidney, ureter, and bladder radiography after seed implantation to assess the radiation doses up to 90% of the PV (D90) and seed migration.
Follow-up. Patients were followed up with PSA measurements every 3 months for the first 2 years, every 6 months for the next 5 years, and annually thereafter. Biochemical progression-free survival was determined according to the Phoenix definition (nadir PSA+2 ng/ml). Prostate biopsy and clinical information were collected from electronic medical records.
Statistical analysis. Fisher’s exact test was used to assess categorical variables, and the Mann-Whitney U-test was used to analyze continuous variables. Progression-free and overall survival were calculated using the Kaplan-Meier survival curve method and were compared using the log-rank test. Univariate and multivariate analyses using Cox proportional hazards regression models were used to identify the factors associated with survival. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), and statistical significance was set at p<0.05.
Results
Patient characteristics. The study included 342 patients who underwent LDR-BT for intermediate-risk PCa at Tokushima University Hospital; 232 and 110 patients were in the GG2 and GG3 groups, respectively. Only the presence or absence of NHT was significantly different between the GG2 and GG3 groups (p=0.015, Table I). The percentage of biopsy-positive cores >33% was 41.1% (92 patients) in the GG2 group and 40.9% (45 patients) in the GG3 group.
Biochemical recurrence and cancer-specific survival in patients with intermediate-risk PCa after LDR-BT. The overall 5-year biochemical recurrence-free survival for patients with intermediate-risk PCa, and for those in the GG2 and GG3 groups, were 92.4%, 91.7%, and 94.1%, respectively. There was no significant difference in the 5-year biochemical recurrence-free survival between the GG2 and GG3 groups (p=0.633, Figure 1). Similarly, there was no significant difference in cancer-specific survival between the GG2 and GG3 groups (p=0.649, Figure 2).
Biochemical progression-free survival of patients with GG2 and GG3 prostate cancer after low-dose-rate brachytherapy (p=0.633). LDR-BT: Low-dose-rate brachytherapy.
Cancer-specific survival of patients with GG2 and GG3 prostate cancer after low-dose-rate brachytherapy (p=0.649). LDR-BT: Low-dose-rate brachytherapy.
Factors predicting treatment failure in patients with intermediate-risk PCa after LDR-BT. The influence of clinical factors in each group was evaluated using the Kaplan-Meier method. Age, PSA levels, T stage, PV, and NHT did not affect biochemical recurrence-free survival in either group (Figure 3A-E). The risk of recurrence in the GG2 group was significantly higher when D90 was <160 Gy (p=0.002, Figure 3F). In contrast, in the GG3 group, the risk of recurrence increased when the percentage of positive cores was greater than 33% (p=0.002; Figure 3F). In the multivariate analysis, the GGs, number of positive cores, T stage, D90, and percentage of positive cores were predictors of recurrence in all patients with intermediate-risk PCa. Analysis of each group showed that D90 was a predictor of treatment failure for patients with GG2. In contrast, D90 was not a prognostic factor for patients with GG3, and a high percentage of positive cores was a significant risk factor for recurrence (Table II).
Kaplan-Meier curves for each factor in GG2 or GG3 groups. (A) Age, (B) initial prostate-specific antigen (iPSA), (C) clinical T stage, (D) prostate volume (P-vol), (E) positive biopsy core percent (PBCP), (F) neoadjuvant hormonal therapy (NHT), and (G) D90. LDR-BT: Low-dose-rate brachytherapy.
Univariate and multivariate analysis of biochemical progression-free survival after low-dose-rate brachytherapy.
Discussion
The GS at prostate biopsy is an important determinant of the treatment strategy for newly diagnosed localized PCa. In addition, the ISUP grade groups (1), based on the results of total prostatectomy, have become more prevalent as a classification that is strongly associated with treatment outcomes and is widely used as a predictor of treatment outcomes aside from surgery. For example, in GG4 and GG5 cases, combined hormonal therapy is recommended in addition to radiotherapy (3-5), and LDR-BT may be used to increase the treatment intensity by increasing the local dose.
In contrast, GG2 and GG3 have long been grouped as intermediates. However, this intermediate group has recently been shown to be heterogeneous, with wide variations in treatment outcomes (6). In the ISUP grade classification, patients with GS 7 PCa are divided into those with GG2 and GG3, and differences in outcomes after radical treatment have been observed (7). Similarly, studies on patients undergoing external beam radiation therapy have shown that primary Gleason pattern 4 predicts recurrence (8). As the difference in outcomes between GG2 and GG3 has become more clearly defined, active surveillance (AS) has become an option for patients with GG2 who meet the criteria (EAU guidelines) (9). The guidelines also indicate that AS may be an option for intermediate-risk patients if the histological evaluation of biopsies shows GG2 with a Gleason pattern 4 of <10%, PSA <10 ng/ml, less than three positive cores in patients with cT2a, and <50% tumor coverage. In addition, although a higher proportion of patients with GG3 underwent AS and subsequent definitive treatment, there was no significant difference between GG2 and GG1 in terms of adverse pathology or short-term outcomes after prostatectomy (10).
LDR-BT has been established as one of the standard treatments for D’Amico’s classification of low- and intermediate-risk localized PCa, with good results, either alone or in combination with hormonal therapy. LDR-BT for intermediate-risk PCa has demonstrated excellent local control, albeit not comparable to outcomes in low-risk PCa (11-13). However, few detailed studies have reported the differential treatment effects of LDR-BT within the heterogeneous group of Asians with intermediate-risk PCa. This study aimed to evaluate the outcomes of LDR-BT in patients with GG2 and GG3 PCa and analyze the factors that may influence the outcomes in each group.
In this study, the 5-year progression-free survival rate after LDR-BT for intermediate-risk PCa was 92.4%, which is consistent with previous studies (14-17). There was no significant difference in the 5-year progression-free survival between the GG2 and GG3 groups. This may be because patients with GG3 often receive 3–6 months of hormonal therapy.
To determine the factors that affect the outcomes of LDR-BT for intermediate-risk PCa, we performed a multivariate analysis of recurrence and overall survival in all patients, including the influence of GGs, PSA level, T stage, number of biopsies, PV, and hormonal therapy. The results showed that the GGs, PSA level, T stage, PV, and the presence of hormonal therapy were not predictors of recurrence. Conversely, the percentage of positive prostate biopsy cores was a prognostic factor. D90 was also a significant predictor of prognosis; however, this may be influenced by the results of the lower doses in early cases, both technologically and in the context of time.
Furthermore, we divided intermediate-risk patients into GG2 and GG3 groups and compared each group in detail. First, the effect of PSA levels, PV, hormonal therapy, and positive prostate biopsy rate was examined in patients with GG2 PCa. However, no difference in progression-free survival and overall survival was observed based on these factors. In contrast, although PSA levels, PV, and hormonal therapy did not significantly influence progression-free survival or overall survival, higher positive biopsy rates were associated with a worse prognosis in patients with GG3 PCa.
Several studies have shown discrepancies in grades between the results of prostate biopsies and those based on whole-mount specimens obtained from radical prostatectomies (18, 19). Furthermore, it has been demonstrated that in cases with GG3 on prostate biopsy, there is a higher likelihood of upgrade when the number of positive cores is greater (20). Thus, the findings of this study emphasize that histological evaluation, of Gleason score and other factors, such as the percentage of positive cores, should be carefully evaluated, as treatment decisions heavily depend on information from prostate biopsies in patients receiving radiation therapy.
Limitations. This study has several limitations. First, because the treatment occurred over a long period of time, some early cases with a low D90 were included because of technical problems. Second, prostate biopsies were performed at several institutions, biopsy protocols varied among institutions, and the number of biopsies changed significantly over time. Third, the percentage of cancer occupancy within each biopsy core was unavailable because of a lack of information. Fourth, prostate magnetic resonance imaging was not performed in many early cases, and the impact of tumor volume based on magnetic resonance imaging data had not been studied. In the future, examining the impact by obtaining more detailed information will be necessary before starting treatment.
Conclusion
For intermediate-risk patients, especially those with GG3, a positive core ratio on prostate biopsy correlates with the prognosis after LDR-BT and may be an important consideration in treatment selection.
Footnotes
Authors’ Contributions
Supervision: Tomoya Fukawa, Hitoshi Ikushima, and Masayuki Takahashi. Material preparation: Yoshito Kusuhara, Yoshiteru Ueno, and Tomoya Fukawa. Data collection: Yoshito Kusuhara, Tomoya Fukawa, Tomoharu Fukumori, Yoshiteru Ueno, Kei Daizumoto, Yutaro Sasaki, Ryotaro Tomida, Yasuyo Yamamoto, Kunihisa Yamaguchi, Chisato Tonoiso, Akiko Kubo, Takashi Kawanaka, and Shunsuke Furutani. Data analysis: Yoshito Kusuhara, Yoshiteru Ueno, and Tomoya Fukawa. The first draft of the manuscript was written by Yoshito Kusuhara and Tomoya Fukawa supervised the manuscript. All Authors commented on previous versions of the manuscript, read and approved of the final manuscript.
Conflicts of Interest
The Authors have no relevant financial or non-financial interests to disclose.
- Received July 11, 2023.
- Revision received August 7, 2023.
- Accepted August 8, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
