The optimal management of high-risk prostate cancer remains a topic of ongoing investigation. The quest for therapy that maximizes cancer control while minimizing toxicity is constant.
Over the past decade, there has been mounting evidence that the addition of a brachytherapy boost to external-beam radiation therapy (EBRT) results in a significantly superior outcome than EBRT alone for men with high-risk prostate cancer. These men are typically also receiving long-term androgen-deprivation therapy, usually for 2 years, which can be severely toxic for these men and often considered the most difficult part of this multimodality treatment. A recent study published in the International Journal of Radiation Oncology • Biology • Physics offers the potential to decrease the duration of androgen-deprivation therapy with radiotherapy.
Different Trials, Similar Findings
TRIP/TRIGU0907 was a phase III multi-institutional randomized control trial in Japan, comprising 332 men across 37 centers.1 A total of 90.4% of men had National Comprehensive Cancer Network (NCCN)-defined high-risk disease, and 9.6% had NCCN-defined unfavorable intermediate-risk disease and were staged using conventional imaging. All men received 110 Gy of iodine-125 low-dose–rate prostate brachytherapy, followed by 45 Gy in 25 fractions of EBRT to the prostate and proximal seminal vesicles. Additionally, all participants received 6 months of neoadjuvant and concurrent (during radiotherapy) androgen-deprivation therapies and were randomly assigned to receive an additional 24 months of androgen deprivation therapies, for a total of 30 months, or placebo. At a median follow-up of 9.2 years, there was no difference in the 7-year and 9-year rates of biochemical disease progression of 9% and 10%, respectively.
Manuj Agarwal, MD
These findings are in line with the outcomes seen in ASCENDE-RT, which demonstrated a 9-year biochemical control rate of 84% with the use of low-dose–rate prostate brachytherapy plus EBRT and 12 months of androgen-deprivation therapy, compared with 62.4% for EBRT and 12 months of androgen-deprivation therapy without low-dose-rate prostate brachytherapy.2 The improved outcomes are likely the result of a higher biologic effective dose (BED2).
Compelling data have demonstrated that achieving a BED2 of ≥ 200 Gy results in improved biochemical relapse–free survival, overall survival, and distant metastasis–free survival compared with ≤ 200 Gy.3 Achieving a BED2 of ≥ 200 Gy surpasses other predictive factors, including Gleason grade, and the use of androgen-deprivation therapy. The median BED2 in the TRIP/TRIGU0907 trial was 217 Gy, and EBRT is estimated to provide a BED2 of 156 Gy. In the current trial, the biochemical failure curves merged at the 4-year mark, suggesting the high radiation dose’s ablative effect is a primary contributor to the biochemical control. Similarly, there was no difference in distant metastases. These findings emphasize the potency of low-dose–rate prostate brachytherapy in eradicating local disease, particularly when paired with short-term androgen-deprivation therapy.
Androgen-Deprivation Therapy: Long Term vs Short Term
The use of low-dose–rate prostate brachytherapy may offset the potential benefit of long-term androgen-deprivation therapy that has previously shown to be beneficial in the context of EBRT alone. Several trials have demonstrated improved outcomes with the use of long-term vs short-term androgen-deprivation therapy combined with EBRT, including modern trials using dose-escalated EBRT. Indeed, the cohort analysis study from Kishan et al suggested a minimum duration of 26.3 months is required for EBRT, whereas there appears to be no benefit of extending androgen-deprivation therapy beyond 12 months for patients receiving a brachytherapy boost.4
The potential for men with high-risk prostate cancer to receive short-term androgen-deprivation therapy alone compared with long-term therapy is crucial, as long-term androgen-deprivation therapy is associated with several unwanted and potentially severe side effects that can considerably affect patients’ quality of life. In this experience, men were able to recover testosterone after 7.2 months, compared with 15.6 months, and a higher percentage achieved baseline levels after 6 years compared with those on the longer regimen. This is despite a high level of compliance with long-term androgen-deprivation therapy (86%), surpassing the 53% and 72% compliance rates in the 36-month arms of the PCS IV trial and EORTC 22961, respectively.5,6 Regardless, there was no difference in overall survival. The authors noted the low rates of major cardiovascular events may be influenced by exclusive composition of Japanese men. When compared with an American cohort, Japanese patients seemed to have significant differences in the prevalence of heart disease.
In contrast to the initial ASCENDE-RT publication, there were low rates of acute and late genitourinary toxicities, with just 1.2% grade 3 radiation-related toxicity. This is in line with the AFTER-ASCENDE experience, whereby the same group of brachytherapists in the ASCENDE-RT trial revised their technique and quality-assurance process, reporting similar biochemical outcomes and lower rates of toxicity.7
The study outcomes are strengthened by its multi-institutional randomized controlled trial design, high compliance rate with androgen-deprivation therapy, extensive brachytherapy training, and brachytherapy standardization. Moreover, the option of tailoring the EBRT dose based on D90 (90% of the total particles are smaller than this size) results stands out as a robust methodology to optimize treatment efficacy. Despite its strengths, the study is not designed as a noninferiority trial; thus, it cannot definitively conclude that 6 months of androgen-deprivation therapy is not inferior to 30 months. Its exclusive inclusion of Japanese men suggests the need for caution when generalizing the findings across diverse populations.
‘A Significant Leap Forward’
This study’s insights into the duration of androgen-deprivation therapy and the role of a brachytherapy boost in prostate cancer treatment represent a significant leap forward in managing the disease. The ability to reduce the duration of androgen-deprivation therapy without compromising treatment efficacy offers a promising avenue for improving patients’ quality of life by mitigating the side effects associated with long-term androgen-deprivation therapy.
The 9-year, 90% biochemical control rate of high-risk prostate cancer is the highest reported in a phase III randomized controlled trial. The combination of high cure rates, low radiation-related toxicity, and the potential ability to decrease the duration of androgen-deprivation therapy highlights the critical role of low-dose–rate prostate brachytherapy in the management of advanced prostate cancer. This potent combination maximizes treatment efficacy while minimizing adverse effects, broadening the therapeutic ratio. This approach underscores the importance of personalized, evidence-based cancer care. The study not only contributes valuable data to this endeavor, but also sets the stage for future research aimed at refining and enhancing treatment protocols for prostate cancer, ensuring patients receive the most effective, least burdensome care possible.
DISCLOSURE: Dr. Agarwal reported no conflicts of interest.
REFERENCES
1. Yorozu A, Namiki M, Saito S, et al: Trimodality therapy with iodine-125 brachytherapy, external beam radiation therapy, and short- or long-term androgen deprivation therapy for high-risk localized prostate cancer: Results of a multicenter, randomized phase 3 trial (TRIP/TRIGU0907). Int J Radiat Oncol Biol Phys 118:390-401, 2024.
2. Oh J, Tyldesley S, Pai H, et al: An updated analysis of the survival endpoints of ASCENDE-RT. Int J Radiat Oncol Biol Phys 115:1061-1070, 2023.
3. Stock RG, Buckstein M, Liu JT, et al: The relative importance of hormonal therapy and biological effective dose in optimizing prostate brachytherapy treatment outcomes. BJU Int 112:E44-E50, 2013.
4. Kishan AU, Steigler A, Denham JW, et al: Interplay between duration of androgen deprivation therapy and external beam radiotherapy with or without a brachytherapy boost for optimal treatment of high-risk prostate cancer: A patient-level data analysis of 3 cohorts. JAMA Oncol 8:e216871, 2022.
5. Nabid A, Carrier N, Martin AG, et al: Duration of androgen deprivation therapy in high-risk prostate cancer: A randomized phase III trial. Eur Urol 74:432-441, 2018.
6. Bolla M, de Reijke TM, Van Tienhoven G, et al: Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 360:2516-2527, 2009.
7. Oh J, Morris WJ, Spadinger I, et al: After ASCENDE-RT: Biochemical and survival outcomes following combined external beam radiotherapy and low-dose-rate brachytherapy for high-risk and unfavourable intermediate-risk prostate cancer, a population-based analysis. Brachytherapy 21:605-616, 2022.
Dr. Agarwal is a radiation oncologist practicing in Wayne, Pennsylvania, and is a cofounder of the Prostate Cancer Institute of Pennsylvania.
