Hemi-Gland Brachytherapy for Prostate Cancer: Reduced Toxicity at What Oncological Cost?

Can Focal Therapy Redefine Prostate Cancer Treatment?

Recent clinical trial data has raised important questions about the efficacy of hemi-gland brachytherapy (HGBT) for localized prostate cancer, with findings suggesting this focal approach may offer reduced toxicity but potentially at the cost of oncological control. The phase II trial conducted by the Spanish Radiation Oncology Research Group (GICOR) compared HGBT to whole-gland brachytherapy (WGBT) in patients with low-risk and favorable intermediate-risk prostate cancer, providing valuable insights into this treatment modality's benefits and limitations.

The study enrolled 38 patients with unilateral prostate cancer confirmed by multiparametric MRI. Participants received permanent implantation of Iodine-125 seeds to a dose of 145 Gy to the involved lobe only, with real-time ultrasound guidance under spinal anesthesia. With a mean follow-up period of 71.4 months, researchers were able to assess both short and long-term outcomes of this focal approach. The mean age of participants was 64.9 years, and nearly all patients (97.4%) had Gleason 3+3 disease, representing a typical low-risk prostate cancer population. The tumor was left-sided in 22 patients and right-sided in 16, with a mean baseline PSA of 6.12 ng/ml. Clinical staging was predominantly T1N0 (34 patients) with only four patients classified as T2N0.

Do Quality of Life and Toxicity Benefits Outweigh Oncological Risks?

The trial's primary endpoint focused on health-related quality of life using the 26-item Expanded Prostate Cancer Index Composite (EPIC) questionnaire. Results showed that while both HGBT and WGBT patients experienced some degree of quality of life impairment across urinary, bowel, and sexual domains, the HGBT group demonstrated significantly better urinary irritative-obstructive symptoms (p=0.002) compared to the historical WGBT cohort. This finding suggests that treating only half the prostate may indeed reduce some aspects of urinary morbidity, which represents an important potential benefit for patients concerned about treatment-related side effects. The participants' response rate to the EPIC questionnaire ranged from 63-95% in the HGBT study compared to 52-98% in the historical WGBT group, providing robust data for comparison.

The EPIC-26 results showed small-to-moderate deterioration of urinary incontinence, large worsening of urinary irritative-obstructive and bowel domains during the first three months after treatment (though these improved over time), and a sustained moderate-to-large sexual deterioration throughout the five-year follow-up period. Meanwhile, hormonal scores remained relatively stable. Sexual impairment notably increased over the entire follow-up period, representing an important consideration for patient counseling regarding the long-term effects of treatment.

Toxicity data further supported the safety profile of HGBT, with 57.9% of patients experiencing no urological symptoms according to CTCAE v5 criteria. Of those who did develop urological toxicity, the majority (36.8%) experienced only grade 1 events, with just one patient requiring transurethral resection (grade 3). Gastrointestinal toxicity was minimal, with only one patient developing minor (grade 1) rectal toxicity. These toxicity outcomes appear favorable when compared to the historical WGBT cohort, where 3.3% of patients experienced grade 3 genitourinary toxicity, including 17 patients requiring surgical intervention and one treatment-related death from urinary sepsis.

Is Unilateral Treatment Sufficient?

However, the oncological outcomes from this trial raise significant concerns about the efficacy of HGBT as a definitive treatment. The 5-year biochemical control rate was only 59.6%, meaning that over 40% of patients developed biochemical failure within five years. This contrasts sharply with the historical WGBT cohort's 95% biochemical control rate at the same timepoint. Among the 38 HGBT patients, 17 (44.7%) developed biochemical failure at a mean of 55.3 months, and 14 experienced local relapse. Notably, of those with local relapse, nine had contralateral disease (in the untreated lobe), four had both ipsilateral and contralateral recurrence, and one developed regional nodal disease.

The technical aspects of the treatment involved a mean treated volume (V100) of 17.34 cc (range 3.76-38.65), with a median of 12 needles (range 7-18) and 41.5 seeds (range 16-62) inserted per patient. Seed activity ranged from 0.34 to 0.56 mCi with a median of 0.504 mCi. These treatment parameters were consistent with established dosimetric guidelines, ensuring adequate coverage of the target volume while respecting dose constraints for organs at risk such as the urethra, bladder, and rectum. The dosimetric constraints followed included clinical target volume V100 ≥ 95%, D90 > 145 Gy, V150 ≤ 60%, rectum D2cc ≤ 145 Gy, D0.1cc < 200 Gy, urethra D10 < 150%, and D30 < 130%.

The high rate of contralateral disease suggests that unilateral treatment may be insufficient for many patients with apparently unilateral disease on initial imaging. This finding highlights potential limitations in current diagnostic approaches for determining candidacy for focal therapy. The investigators acknowledge that their patient selection process may have been suboptimal, as they did not universally employ the combination of mpMRI with systematic transperineal mapped biopsy that is now considered standard for focal therapy candidates. Additionally, the study did not include protocol-mandated follow-up biopsies at years 1 and 2, which might have detected recurrences earlier.

What Do PSA Trends and Salvage Therapies Reveal?

Interestingly, the PSA nadir was higher in the HGBT group (mean 1.4 ng/ml) compared to typical WGBT patients, likely reflecting the continued PSA production from the untreated contralateral lobe. This raises questions about the utility of PSA as a monitoring tool after focal therapy, though the investigators suggest it remains valuable despite these limitations. The mean time to PSA nadir was 27.55 months, highlighting the importance of long-term follow-up in these patients.

Fifteen patients in the HGBT group eventually required salvage therapy, including contralateral LDR-BT (n=7), HDR-BT (n=3), nodal radiotherapy with hormonal therapy (n=2), hormonal therapy alone (n=2), and prostatectomy (n=1). Encouragingly, all salvage-treated patients were alive and disease-free at last follow-up, suggesting that initial HGBT did not compromise subsequent treatment options. This "treatment sequencing" approach might represent a potential benefit of starting with focal therapy, as it preserves options for future interventions if needed. At the final follow-up point (median 71.4 months), 23 of the 38 patients were alive without biochemical failure, 12 were alive with biochemical failure, and three had died from causes unrelated to prostate cancer, while the mean PSA was 2.16 ng/ml.

Can Methodological Limitations Explain These Results?

The investigators attribute the inferior oncological outcomes partly to methodological limitations, noting that other studies of focal brachytherapy have reported better results. For example, the HAPpy trial reported treatment failure in only 6.7% of patients, compared to 44.7% in this study. Recent systematic reviews have also suggested more favorable outcomes for focal brachytherapy, with biochemical control rates of 79-91% at 5 years. The discrepancy might be explained by differences in patient selection, diagnostic workup, and technical aspects of the procedure.

A key limitation of this study was the slow recruitment rate, which prevented researchers from reaching their target sample size of 108 patients needed for adequate assessment of secondary outcomes. The recruitment challenges were attributed to the availability of multiple alternative treatment options for low-risk prostate cancer patients, including active surveillance and robotic prostatectomy. This limitation affects the statistical power of some findings, particularly regarding secondary endpoints, and underscores the difficulties in conducting randomized trials for localized prostate cancer treatments.

This study's findings align with the broader evidence base for focal therapies in prostate cancer, which remains limited and inconsistent. A recent systematic review by Bates et al. concluded there is insufficient high-certainty evidence to endorse focal treatment as an oncologically effective and durable approach compared with either active surveillance or radical treatment. Consequently, current guidelines recommend that focal therapies be performed only in the context of clinical trials or rigorously designed prospective studies.

How Might Future Research Shape Focal Therapy?

Could more sophisticated imaging and biopsy techniques improve patient selection for focal therapies like HGBT? The results of this trial suggest that careful selection of appropriate candidates through comprehensive diagnostic assessment is crucial. Future research should focus on standardized protocols combining advanced imaging with systematic biopsy to better identify patients with truly unilateral disease who might benefit from focal approaches. Additionally, what is the optimal surveillance strategy after focal therapy? This study's high rate of contralateral recurrence highlights the importance of monitoring the untreated portions of the prostate, potentially through protocol-mandated biopsies and regular imaging.

In conclusion, while HGBT appears to offer toxicity advantages over whole-gland treatment, the oncological outcomes in this trial were disappointing. The investigators acknowledge that hemi-gland brachytherapy remains a promising technique that warrants further investigation in well-designed prospective trials with appropriate patient selection. Until more definitive evidence emerges, patients considering focal therapy should be counseled about the potential tradeoff between reduced toxicity and the risk of earlier disease recurrence, and such treatments should ideally be offered within the context of clinical trials.

Summary

A phase II clinical trial by the Spanish Radiation Oncology Research Group (GICOR) evaluated hemi-gland brachytherapy (HGBT) as a focal treatment for localized prostate cancer, comparing it with whole-gland brachytherapy (WGBT). The study enrolled 38 patients with unilateral low-risk and favorable intermediate-risk prostate cancer confirmed by multiparametric MRI, treating only the affected lobe with permanent Iodine-125 seed implantation. After a mean follow-up of 71.4 months, HGBT demonstrated significantly better urinary irritative-obstructive symptoms and minimal toxicity compared to historical WGBT cohorts, with 57.9% of patients experiencing no urological symptoms and only one patient developing grade 3 toxicity. However, oncological outcomes were concerning, with only 59.6% biochemical control at five years compared to 95% in the WGBT group. Of the 38 HGBT patients, 17 developed biochemical failure and 14 experienced local relapse, with nine showing contralateral disease in the untreated lobe. The high rate of contralateral recurrence suggests limitations in current diagnostic approaches for identifying suitable focal therapy candidates and raises questions about the sufficiency of unilateral treatment. Fifteen patients required salvage therapy, though all remained alive and disease-free at last follow-up, suggesting that initial HGBT preserved subsequent treatment options. The investigators attributed inferior outcomes partly to methodological limitations, including suboptimal patient selection without universal use of systematic transperineal mapped biopsy and lack of protocol-mandated follow-up biopsies. These findings contrast with other focal brachytherapy studies reporting better results, such as the HAPpy trial with only 6.7% treatment failure. The study underscores the importance of careful patient selection through comprehensive diagnostic assessment and highlights the need for standardized protocols combining advanced imaging with systematic biopsy. Current evidence remains insufficient to endorse focal therapies outside clinical trials, and patients should be counseled about the potential tradeoff between reduced toxicity and increased risk of disease recurrence.