The wide application of prostate-specific antigen (PSA)-based screening has led to a profound shift in the staging of prostate cancer (PCa).1 Although the vast majority of newly diagnosed PCa exhibit clinically localized disease, 15% of patients still present with high-risk tumors, and PCa remains a leading cause of cancer death.2,3 Men with high-risk disease are at the greatest risk for biochemical failure and prostate-cancer-related death; however, the effective management of high-risk PCa presents a significant clinical challenge to the physicians involved and remains controversial.4 The mainstay of treatment typically involves a combination of long-term androgen-deprivation therapy (ADT) with external beam radiation therapy (EBRT). Randomized trials have shown improved overall survival associated with this combination; however, even with this approach, more than half of patients experience disease recurrence.5,6

In 1998, D'Amico, et al.7 proposed a risk classification scheme for PCa, patients whose PSA level >20 ng/mL, Gleason score of 8-10, or clinical stage ≥T2c were included in high risk group. After validatation these risk classification via numerous studies, D'Amico risk classification is currently used in the litherature; however, the major shift among these risk groups over time suggests that the clinical relevance of this classification scheme may be diminishing. Moreover, this model is limited by the equal weight assigned to each factor and by the arbitrary selection of cutoffs for each risk factor.8 A relatively favorable prognosis was observed in high-risk PCa patients with low Gleason scores compared to those with high Gleason scores.9

Although prostate brachytherapy remains one of the first-line treatment options for men with clinically localized PCa, brachytherapy in high-risk PCa was reported only in higher volume centers.10,11 Therefore, we investigated the role of brachytherapy in high-risk PCa and analyzed its optimal indications.

With approval from the institutional review board, we reviewed the records of high-risk PCa patients who had undergone prostate ¹²⁵I low-dose rate (LDR) brachytherapy at our clinic since April 2007. The D'Amico risk group classification was used: clinical stage ≥T2c, PSA >20 ng/mL or biopsy Gleason score ≥8. We excluded those patients with a follow-up period <3 years. A total of 50 patients were included in our study. All the patients were assessed based on their clinical history, physical examination, transrectal ultrasound (TRUS) scan, uroflowmetry and pre-treatment International Prostate Symptom Score. Pelvic magnetic resonance imaging, abdominal and pelvic computed tomography (CT) and bone scans were performed if clinically indicated. Biochemical recurrence (BCR) followed the Phoenix definition (i.e., a post-treatment nadir plus 2.0 ng/mL).12

Of the 50 high-risk PCa patients who underwent ¹²⁵I LDR brachytherapy, the mean age was 68.8±6.1 years, the mean TRUS volume was 34.45±12.56 mL, and the initial mean PSA was 22.21±27.51 ng/mL. Twenty patients (40%) had biopsy Gleason score ≥9, whereas the other 30 patients (60%) had biopsy Gleason scores ≤8. Forty-eight patients (96%) received ADT, and 28 patients (56%) received adjuvant EBRT. Among the patients with biopsy Gleason scores ≤8, 28 (93.3%) had received ADT (oral anti-androgen) with median duration of 4 months, and 8 patients (26.7%) had received EBRT with median of 45 Gy. All patients with Gleason score ≥9 had received adjuvant ADT and EBRT both.

As can be seen in Table 1, patients with biopsy Gleason scores ≥9 had significantly higher PSA levels (p=0.001) and exhibited a higher rate of BCR (12; 60%) than those with a biopsy Gleason scores ≤8 (2; 6.7%) (p=0.007). Furthermore, a high proportion of these patients underwent adjuvant EBRT (p<0.001). Meanwhile, the two groups of patients showed no significant differences in age, prostate volume or clinical stage. The number of inserted seeds (94.3 vs. 89.6, p=0.556), mean D90 (Gy) (247.2 Gy vs. 240.0 Gy, p=0.716), mean D90 (%) (188.3% vs. 202.2%, p=0.407) and mean V100 (%) (99.9% vs. 99.8%, p=0.605) did not differ significantly between the groups.

At a median follow-up of 39.2 months, 14 patients (28%) had BCR. One cancer-specific mortality was observed. The BCR-free survival was significantly higher in patients with biopsy Gleason scores ≤8 compared to those with Gleason scores ≥9 (log-rank, p<0.001) (Fig. 1). The estimated 3-year BCR-free survival was 92% for the patients with biopsy Gleason scores ≤8, and 40% for those with Gleason scores ≥9.

Table 2 presents a multivariate Cox proportional hazard regression analysis, showing that only the Gleason score was a significant predictor for BCR (HR=6.601, 95% CI: 1.419-15.253, p=0.024). Other factors, such as age, PSA, clinical stage, and amount of D90 and EBRT, were not significant.

The comprehensive rates of toxicities are described in Table 3. Acute (<3 months) and late (>3 months) genitourinary (GU) toxicities were observed in 44 (88%) and 48 (96%) patients, respectively. Most of them were irritative voiding symptoms and were controlled by medication. RTOG grade 3 GU toxicities were observed in 10 patients during the acute period and in 16 patients during the late period. No significant difference was observed according to Gleason score. Acute and late gastrointestinal (GI) toxicities were observed in 38 (76%) and 32 (64%) patients, respectively. Most cases of acute GI toxicities were grade less than 3, which were rectal discomforts. One third of late GI toxicities were intermittent rectal bleeding, controlled by oral medications such as mesalamine. One recto-urethral fistula (grade 4) was developed in the group of Gleason score ≥9, and managed by surgical repair with gracilis muscle interposition in other institution. Another hemorrhagic ulceration (grade 4) requiring interventional procedure occurred in the group of Gleason score ≥9.

Prostate brachytherapy has been conducted at only a single institution in Korea since April 2007. In total, 250 patients with PCa received brachytherapy. This report is the first to present results from Korea, which can be used to interpret racial differences among patients treated with brachytherapy. In this study, a biopsy Gleason score ≥9 among patients with high-risk PCa was observed to be a significant predictor of BCR following ¹²⁵I LDR brachytherapy. Although several patients with biopsy Gleason scores <8 and PSA >20 ng/mL or clinical stage ≥T2c were classified as a high-risk group according to the D'Amico criteria, their estimated 3-year BCR rate was 92%, which is significantly better than those reported for Gleason scores ≥9.

Among patients with high-risk disease, biochemical control varies by treatment modality. Biochemical control at 5 years ranged from 32% to 60% for radical prostatectomy,7,17,18 12-47% for EBRT alone7,18,19 and 16-54% for brachytherapy alone.17-20 However, the patients with high-risk PCa generally had more favorable treatment outcomes following multimodal treatment. Stone, et al.21 suggested that high-risk PCa treated with a combination of EBRT and permanent seed implantation improved biochemical disease-free survival, metastasis-free survival, and overall survival. Furthermore, da Silva Franca, et al.22 demonstrated the benefits of a combined approach for cases with poor prognoses. Their analyses of the clinical parameters of the group treated with a combination of EBRT plus brachytherapy and the group treated by brachytherapy alone showed that 71% of patients in the combination therapy group were high-risk, and that 36% of the patients in the brachytherapy-only group were high-risk (p=0.003). The Seattle study, which combined EBRT+brachytherapy in high-risk PCa patients, also reported a BCR-free survival rate of 62.2% at both 5 and 10 years.11 In our preliminary study, the estimated 3-year BCR-free rate was observed to be 70.8%, which is similar to other results from large-scale studies.

Interestingly, the patients with biopsy Gleason scores ≥9 had significantly lower biochemical control rates despite the combination of EBRT and brachytherapy. Therefore, we concluded that high-risk PCa, as defined by the D'Amico classification, did not lead to the creation of a homogenous group; in particular, patients with higher Gleason scores represented a "very-high-risk" group within the "high-risk" group. Actually, as seen in the radical prostatectomy cohort, high-risk PCa patients showed nearly 50% disease-free survival rate at 5 years after surgery alone.23 Loeb, et al.24 reported that a high biopsy Gleason score was the strongest independent predictor of BCR, metastasis, and PCa death among high-risk patients.

The American Brachytherapy Society strongly recommends CT-based post-implant prostate dosimetry with quality cut-off points of V100 >80% and D90 >90%. Dosimetric implant quality is essential for the optimization of biochemical outcomes15: previous reports showed a statistically significant relationship between dosimetric parameters and biochemical controls because patients without BCR were those with better dosimetric values.21,22 Among several studies about prostate brachytherapy, the optimal dose had been widely investigated, D90 dose of 144 Gy was considered optimal prescription dose for ¹²⁵I implants.25 However, D90 doses of over 180 Gy with modified peripheral loading among prostate brachytherapy did not increase normal tissue toxicity. This suggests that a dose of 160 Gy may have a benefit to ensure a minimal D90 dose of 144 Gy.26 The concept that higher prostate doses can be achieved through the use of EBRT and brachytherapy has been studied using the biologically effective dose concept. In a recent study, biologically effective doses of over 150 Gy were found to be associated with a significantly higher rate of biochemical control.27 In our studies, the mean D90 value was 244.3 Gy (167.5-357.5 Gy) and the percent of D90 was 193.8% (136.2-252.2%) which is much higher than those in other studies. Although there is a concern regarding complications, high-energy transfer may result in effective tumor control: with high D90, BCR did not differ significantly between the groups treated with brachytherapy alone and brachytherapy with combined EBRT (p=0.094). For the same reason, EBRT was not a significant predictor of BCR in the current multivariate Cox proportional analysis (HR=1.032, p=0.059).

The toxicities in our series were higher than those in other series. Schafer, et al.28 showed that only 10.4% and 1% of men reported moderate and severe urinary symptoms, respectively, whereas Koontz, et al.29 reported that acute GU toxicity and GI toxicity occurred in approximately 80% and 24% of patients, respectively, and that late GU toxicity and GI toxicity occurred in 21% and 38% of patients, respectively. In our series, late GU toxicity was observed in nearly 96% of all patients, but 65% of them were classified as RTOG toxicity grade <3, which was controlled by medication. Late GI toxicity was observed in 64% of the patients in our series, which is higher than values reported by other studies. One patient experienced grade 4 GI toxicity, with recto-urethral fistula requiring surgical repair. Although there was higher incidence of complication rates because of the high D90 level, most patients managed to lead normal social lives. In more recent cases, we tried to avoid insertion of seed near the urethra and rectum. Thus, we inserted accurate seed amount to suspicious cancerous lesion near the urethra or rectum using calculation using real time planning system. Further advanced radiologic equipments to find accurate cancer lesion in prostate may be helpful for reducing these problems.

The main limitation of our study may be small number of patients included. However, this study represents the only report of high-risk PCa after brachytherapy in Korea. Another limitation of our study was that the D90 range was wide and the D90 level was high compared with other brachytherapy series. If the safety profile is stabilized over a longer follow-up period, the prospective data gathered here will further increase in value. Additional investigation is required.

In conclusion, our results showed that ¹²⁵I LDR prostate brachytherapy-based multimodal therapy in high-risk PCa produced encouraging long-term results among the Asian population, especially in patients with Gleason scores ≤8. The biopsy Gleason scores ≥9 was the only significant predictor of BCR among high risk PCa patients treated with brachytherapy after controlling other variables. Despite small number of subjects, the present results represent the only such report from Korea. Therefore, further efforts should be made to identify appropriate predictors for brachytherapy among high-risk PCa groups through studies with larger, prospective cohorts.