Abstract
Background/Aim: A recent clinical trial indicated the usefulness of local radiation therapy of the prostate in patients with low-volume metastatic prostate cancer. High-dose-rate brachytherapy (HDR-BT) is used mainly for high-risk, localized, and locally advanced cases. However, few studies exist on the efficacy of HDR-BT and external beam radiation therapy (EBRT) for metastatic prostate cancer. Patients and Methods: We conducted a retrospective analysis of 39 patients diagnosed with regional lymph node metastasis and/or a limited number of metastases who underwent HDR-BT and EBRT with long-term androgen deprivation therapy. We utilized Cox’s proportional hazards models to identify predictors of oncological outcomes. Treatment outcomes, including biochemical recurrence-free survival (BCRFS), clinical progression-free survival (CPFS), and castration-resistant prostate cancer-free survival (CRPCFS), were compared according to the clinical stage. Results: The median follow-up duration was 49 months (range=23-136 months). The 5-year BCRFS, CPFS, CRPCFS, and cancer-specific survival rates were 62.2%, 67.2%, 83.2%, and 93.4%, respectively. Based on Kaplan–Meier analysis, N1M0 and N0-1M1b showed favorable outcomes compared with N1M1a. Multivariate analysis revealed that N1M1a prostate cancer was an independent risk factor for poor BCRFS, CPFS, and CRPCFS. Conclusion: HDR-BT and EBRT with androgen deprivation therapy is a feasible approach for patients with newly diagnosed regional and low-metastatic-burden prostate cancer. However, in our cohort M1a prostate cancer had significantly inferior outcomes. A well-controlled prospective study is imperative to confirm our results.
The number of patients diagnosed with localized prostate cancer has increased due to the introduction of community prostate cancer screening. According to the Centers for Disease Control and Prevention, approximately 15% of prostate cancer cases in the United States are regional or metastatic, and the rate of metastatic cases is increasing (1). Historically, metastatic prostate cancer was considered an incurable disease, and systemic therapy was the initial treatment for such patients. However, emerging evidence has shown the potential benefits of radiation therapy of the prostate in patients with regional lymph node metastasis and/or a limited number of metastases, called oligo-metastases. The National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer recommend androgen deprivation therapy (ADT) with or without radiation therapy or radical prostatectomy for regional disease (2). Additionally, based on the STAMPEDE trial results (3), the NCCN guidelines recommend radiation therapy of the prostate in patients with low-volume metastatic disease (2).
High-dose-rate brachytherapy (HDR-BT) has been applied mainly to high-risk, localized, and locally advanced cases. In contrast, only one study evaluated the use of HDR-BT and external beam radiation therapy (EBRT) for metastatic prostate cancer (4). Here, we investigated the oncological outcomes of patients with metastatic prostate cancer who underwent HDR-BT and EBRT combined with ADT.
Patients and Methods
Patient demographics. This study included patients with metastatic prostate cancer who received HDR-BT with EBRT between July 2013 and December 2020 at The Jikei University Hospital, Tokyo, Japan. Patients were categorized as having metastatic prostate cancer if they were clinically diagnosed with regional or distant metastases (cN1 or cM1) at the time of diagnosis. M1b patients had three or fewer metastatic lesions. The clinical stage was based on findings from digital rectal examinations, computed tomography (CT), magnetic resonance imaging (MRI), and bone scintigraphy. The diagnosis of extracapsular and seminal vesicle invasion was made using either MRI or digital rectal examinations. Clinically positive lymph nodes were defined as having a short axis >10 mm on CT or MRI, associated with subsequent size shrinkage after neoadjuvant ADT on follow-up imaging. Biopsy slides were reviewed by two genitourinary pathologists (SS and HT). The eighth edition of the American Joint Committee on Cancer Staging manual was used to classify the anatomical extent of the tumor, lymph node, and metastasis, as well as the prognostic groups. Follow-up was initiated from the start of HDR-BT. This study was approved by The Jikei University Institutional Review Board [33-077(10689)].
Radiation therapy. The HDR-BT treatment protocol has been described previously (5, 6). According to our HDR-BT protocol, patients usually receive neoadjuvant ADT for 6 months, followed by HDR-BT, after which additional EBRT is continued with adjuvant ADT for at least 2 years after HDR-BT. ADT includes a gonadotropin-releasing hormone agonist either alone (22.5 mg leuprorelin acetate or 10.8 mg goserelin acetate) or, in some cases, combined with 80 mg/day bicalutamide. After HDR-BT, a 2-week break is usually stipulated before initiating EBRT, and timing was generally followed in this study. All patients were treated with two HDR-BT and EBRT protocols. Briefly, through July 2013, HDR-BT was administered at a once-daily dose of 9 Gy for 2 days (9 Gy × 2 fractions, totaling 18 Gy), followed approximately 2 weeks later by EBRT at 40 Gy (2.0 Gy/fraction) to the prostate, seminal vesicles, and pelvic lymph nodes (Protocol 1). In June 2016, IMRT replaced EBRT (Protocol 2).
Follow-up. Biochemical recurrence-free survival (BCRFS) was defined using the American Society of Therapeutic Radiology and Oncology–Phoenix definition of biochemical failure of PSA nadir plus 2 ng/ml (7). Local progression was defined as the reappearance of a biopsy-proven local tumor at the primary site and/or local tumor recurrence detected using MRI. If the biopsy and MRI indicated local progression, the prostate biopsy date took precedence over the MRI date. Various imaging studies, including chest radiography, CT, bone scintigraphy, and MRI, were utilized to determine failure in patients with biochemical recurrence (BCR). Clinical progression (CP) included local and distant failure. This study defined castrate-resistant prostate cancer (CRPC) based on recommendations from the prostate cancer clinical trial working group (8). Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events, version 5.0. Acute toxicity was defined as toxicity occurring no longer than 90 days from the day of brachytherapy. All subsequent follow-ups were included in the late toxicity evaluation.
Statistical analysis. The Kaplan–Meier method, with log-rank comparison when indicated, was employed to compute BCRFS, CP-free survival (CPFS), and CRPC-free survival (CRPCFS) from the end of brachytherapy. CPFS was defined as survival without detection of CP, including local progression and distant failure. Univariate and multivariate Cox proportional hazards regression models were utilized to analyze the time to BCR, CP, and CRPC. A p-value <0.05 was considered to indicate statistical significance. All statistical analyses were conducted using Stata version 13.1 (StataCorp, College Station, TX, USA).
Results
We analyzed data from 39 consecutive patients with cT1-4N1M0 or cT1-4N1-0M1 prostate cancer treated with HDR-BT and EBRT combined with long-term ADT. The patients’ demographic data are listed in Table I. The median patient age was 68 years (range=52-80 years), and the median initial PSA level was 38.4 ng/ml (range=3.95-1,860 ng/ml). The median follow-up duration from the start of HDR-BT was 49 months (range=23-136 months), and the median duration of neoadjuvant hormonal therapy was six months (range=3-17 months). Of the 39 patients, 24 were diagnosed as N1M0, six as N1M1a, four as N0M1b, and five as N1M1b. During the follow-up period, 12 patients (30.8%) developed BCR, and 10 (25.6%) developed CP. The CP site was local in two patients, in the lymph nodes in two, and in the bone in eight (with some patients experiencing multiple types). Seven patients (17.9%) developed CRPC, and three (7.7%) died of prostate cancer.
Patient characteristics (n=39).
The 3-year BCRFS, CPFS, CRPCFS, and overall survival (OS) rates were 82.7%, 88.1%, 88.1%, and 97.6%, respectively, as depicted in Figure 1. The 5-year rates were 62.2%, 67.2%, 83.2%, and 93.4%, respectively (Figure 1). Kaplan–Meier curves indicated significantly inferior BCRFS, CPFS, CRPCFS, and OS in stage IVB prostate cancer patients compared with stage IVA patients (Figure 2). We stratified stage IVB patients into N1M1a and N0-1M1b and generated new Kaplan–Meier curves. As shown in Figure 3, we observed significantly different BCRFS, CPFS, CRPCFS, and cancer-specific survival (CSS) rates between the N1M1a and N0-1M1b patients. Visual inspection suggested more unfavorable survival in patients with N1M1a prostate cancer (Figure 3). Indeed, the 3-year BCRFS rate was 91.7% in N1M0, 88.9% in N0-1M1b, and 25.0% in N1M1a patients (p=0.018). The 3-year CPFS rate was 95.8% in N1M0, 77.8% in N0-1M1b, and 66.7% in N1M1a patients (p=0.015). The 3-year CRPCFS rate was 91.7% in N1M0, 88.9% in N0-1M1b, and 66.7% in N1M1a patients (p=0.017). The 3-year CSS rate was 100% in N1M0, 88.9% in N0-1M1b, and 100% in N1M1a patients (p=0.048). Interestingly, multivariate Cox regression analysis identified N1M1a as an independent predictor of BCR (HR=9.50, p=0.009), CP (HR=19.27, p=0.005), and CRPC (HR=30.55, p=0.026) (Table II, Table III, and Table IV).
Kaplan–Meier curves for biochemical recurrence-free survival (BCRFS), clinical progression-free survival (CPFS), castration-resistant prostate cancer-free survival (CRPCFS), and cancer specific-free survival (CSS) in all patients with clinically advanced prostate cancer.
Kaplan–Meier curves for (A) biochemical recurrence-free survival (BCRFS), (B) clinical progression-free survival (CPFS), (C) castration-resistant prostate cancer-free survival (CRPCFS), and (D) cancer specific-free survival (CSS) of stage IVA and IVB patients.
Kaplan–Meier curves for (A) biochemical recurrence-free survival (BCRFS), (B) clinical progression-free survival (CPFS), (C) castration-resistant prostate cancer-free survival (CRPCFS), and (D) cancer specific-free survival (CSS) of N1M0, N1M1a, and N0-1M1b patients.
Predictive factors for biochemical recurrence after high-dose-rate brachytherapy.
Predictive factors for clinical progression after high-dose-rate brachytherapy.
Predictive factors for castration resistant prostate cancer after high-dose-rate brachytherapy.
Grade 2 acute genitourinary (GU) complications were experienced by seven patients (17.9%), while none experienced acute grade 3 GU complications. No patients experienced acute grade 2 or 3 gastrointestinal (GI) complications. Eight (20.5%) patients developed grade 2 GU events, and one patient developed three late GU events (radiation cystitis) (Table V). The incident rates of adverse events were comparable with those in our previous study (2).
Toxicities after high-dose-rate brachytherapy with external beam radiation therapy.
Discussion
We investigated oncological outcomes in patients with metastatic prostate cancer who received HDR-BT and EBRT combined with long-term ADT. This is the first study to compare the oncological outcomes of patients with N1M0, N1M1a, and N0-1M1b prostate cancer treated with HDR-BT and EBRT combined with long-term ADT. Based on the Kaplan–Meier analysis, patients with N1M0 and N0-1M1b showed more favorable outcomes than those with N1M1a. Furthermore, multivariate analysis demonstrated that N1M1a significantly predicted oncological outcomes.
The NCCN guidelines recommend long-term ADT with or without radiation therapy or radical prostatectomy for N1M0 prostate cancer patients (2). However, as ADT alone is the most common treatment for N1M0 prostate cancer patients in the United States (9), many N1M0 prostate cancer patients receive lifelong ADT, which is not considered a curative treatment. The main reasons for this are the rarity of N1M0 prostate cancer and a lack of prospective studies comparing ADT alone and ADT with EBRT. However, multiple retrospective studies and database analyses have shown the efficacy of local radiation therapy for N1M0 prostate cancer patients (10-12). Notably, Nakamura et al. recently reported the oncological outcomes of prostate cancer with regional lymph node metastases after whole-pelvic intensity-modulated radiation therapy (12). The median follow-up was 81.6 months, and the 10-year BCRFS, OS, and CSS rates were 59.8%, 79.6%, and 86.3%, respectively (12). In our study, metastatic patients underwent HDR-BT and EBRT of the prostate, seminal vesicles, and pelvic lymph nodes, and the 5-year BCRFS, CSS, and OS rates were 75.2%, 100%, and 100%, respectively. While the follow-up duration differed from that in the study by Nakamura et al. (12), the oncological outcomes are comparable between the two studies. Additionally, we previously assessed the outcomes of HDR and EBRT combined with long-term ADT in high- and very high-risk localized prostate cancer and reported 5-year BCRFS, OS, and CSS rates of 82.2%, 95.7%, and 99.6%, respectively (6), which are comparable with those in this study. Therefore, HDR-BT and EBRT combined with long-term ADT could be a viable treatment option for N1M0 prostate cancer patients.
Recent evidence suggests that patients with stage IVB prostate cancer with a low metastatic burden may benefit from local radiation therapy combined with ADT compared with ADT alone (3). Our study did not directly compare clinical outcomes with those treated with ADT alone; however, as shown in Figure 3, the oncological outcomes were comparable between N0-1M1b and N1M0 stages, which supports the use of local radiation therapy for low-burden M1b patients. In a previous study, we identified Grade Group and clinical T stage as prognostic factors for oncological outcomes in locally advanced prostate cancer patients treated with HDR-BT and EBRT combined with long-term ADT (13). However, as this study focused solely on metastatic prostate cancer, which is more aggressive, these characteristics did not result in significant differences in oncological outcomes. Surprisingly, N1M1a cancer was a significant predictor of worse oncological outcomes. A recent multi-institutional study investigated clinical outcomes in patients with de novo metastatic hormone-sensitive prostate cancer with a low or high metastatic burden in Japan; among those with a low metastatic burden, PFS was worse for M1a than M1b disease, suggesting that M1a disease may be more aggressive than oligo-metastatic bone disease (14). In contrast, as with previous clinical trials (1, 15-21), the diagnosis of metastatic disease in our study was determined by conventional imaging (CT and bone scans). A recent consensus meeting concluded that 68Ga-labelled prostate-specific membrane antigen-11 positron emission tomography (PSMA-PET) is considered most appropriate for diagnosing primary and recurrent M1a disease (22). Newer and more sensitive next-generation imaging modalities, such as PSMA-PET and whole-body MRI, may enable restaging of M1a prostate cancer patients and selection of better candidates for local radiation therapy of the prostate.
Our study has certain limitations that should be considered. First, as with any retrospective observational study, unmeasured confounders may have been present. Second, traditional imaging modalities such as CT and bone scintigraphy may lack sufficient sensitivity to accurately identify metastatic spread, whereas the use of PSMA-PET improves disease staging accuracy. Third, we did not compare the clinical significance of irradiation of the prostate with ADT alone. Fourth, the number of patients included in our study was small, warranting further evaluation or validation. Therefore, high-quality clinical trials are needed to investigate the appropriate management of metastatic prostate cancer and confirm the clinical significance of using HDR-BT and EBRT of the prostate combined with long-term ADT in metastatic prostate cancer patients.
In conclusion, although significant inferior outcomes were observed in our cohort for M1a prostate cancer, HDR-BT and EBRT combined with ADT could be a viable strategy for patients with newly diagnosed regional and low-metastatic-burden prostate cancer. A well-designed prospective study is needed to validate the findings of our investigation.
Acknowledgements
The Authors thank Textcheck for the English language editing.
Footnotes
Authors’ Contributions
Conception and design: Hirotaka Suzuki, Fumihiko Urabe, Takahiro Kimura; Administrative support: Hirotaka Suzuki, Fumihiko Urabe, Kosuke Iwatani; Provision of study materials or patients: Hirotaka Suzuki, Fumihiko Urabe; Collection and assembly of data: All Authors; Data analysis and interpretation: Hirotaka Suzuki, Fumihiko Urabe, Kosuke Iwatani, Takahiro Kimura; Manuscript writing: All Authors; Final approval of manuscript: All Authors.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received April 20, 2023.
- Revision received May 19, 2023.
- Accepted May 24, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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