Long-term outcome of early stage prostate cancer treated with brachytherapy analysis after a mean follow-up of 7 years

Brachytherapy is a radical treatment that can achieve the same effect as radical prostatectomy and external beam radiotherapy (EBRT) (Nag et al. 1999; Davis et al. 2012; Park et al. 2013). However, studies of the long-term clinical outcome in large cohorts of prostate cancer patients treated with brachytherapy from mainland China are lacking. A total of 564 patients with localized prostate cancer were treated with brachytherapy from December 2003 to August 2013 in Peking Union Medical College Hospital. Among the 138 patients who underwent brachytherapy before December 2007, 117 patients were followed.

With a mean follow-up of 84 months and a median follow-up of 86 months (19–114 months), the nadir PSA level ranged from 0 to 1.27 ng/ml (median 0.01 ng/ml). Thirty-three patients had biochemical recurrence, producing a bNED rate of 72% (Figure 1). Twelve patients died, 4 of them from prostate cancer, for an overall survival rate of 90% (Figure 2) and a disease-specific survival rate of 97%.

Among the 22 cases of low-risk prostate cancer, 3 experienced biochemical recurrence at 11 months, 48 months and 73 months after brachytherapy; the bNED rate was 86%. No patient died, and the overall survival rate was 100% for low-risk patients. Six of the 29 patients with intermediate-risk disease had biochemical recurrence at 7 months, 19 months, 30 months, 34 months, 37 months and 60 months after the procedure; the bNED rate was 79%. Three deaths occurred because of lung cancer, myocardial infarction and pancreatic cancer at 53 months, 95 months and 109 months after the procedure, producing an overall survival rate of 90% among the intermediate-risk patients. When combined, the low- and intermediate-risk patients had a bNED rate of 82% and an overall survival rate of 94%. Of the 66 high-risk patients, 24 biochemical recurrences were observed between 7 and 70 months after brachytherapy (16 occurred within a year). The bNED rate of this group was 64%. Nine deaths occurred, 4 of which were due to prostate cancer, at 41 months, 41 months, 86 months and 89 months after the procedure. The other 5 cases died from pancreatic cancer, lung cancer, cerebral hemorrhage, pneumonia and renal failure at 19 months, 35 months, 56 months, 81 months and 101 months after the procedure. The overall survival rate of the combined group was 86%. EBRT and ADT were prescribed for patients who biochemically relapsed during the follow-up period. The biochemical control results of the three subgroups were significantly different (P = 0.040) (Figure 3); however, the overall survival rate of the three groups demonstrated no significant difference (P = 0.189).

bNED was also examined among the different subgroups (Table 3). Patients whose PPC was lower than 50% had a lower biochemical recurrence likelihood than those whose PPC was higher than 50% (P = 0.006) (Figure 4). Patients who received a D90 higher than 140 Gy had better biochemical control than those who received a D90 lower than 140 Gy (P = 0.009) (Figure 5). Patients with a PSA level lower than 20 ng/ml had a lower biochemical recurrence rate than those with a PSA level higher than 20 ng/ml (P = 0.028). The bNED rate did not significantly differ between clinical stage T1b-T2b and T2c (P = 0.094). Additionally, no significant differences in biochemical relapse were observed in the subgroups with a Gleason score higher or lower than 7 or the subgroups with a prostate volume larger or smaller than 30 ml (P = 0.137, 0.104).

Factors	N (bNED rate, %)
PSA
0-20.0 ng/ml	79 (59/76)
>20.0 ng/ml	60 (25/42)
p-value	0.028
Gleason score
<7	77 (53/69)
≥7	65 (31/48)
p-value	0.137
Clinical stage
T1b-T2b	78 (52/67)
T2c	64 (32/50)
p-value	0.094
Prostate volume
≥30 ml	74 (40/54)
<30 ml	70 (44/63)
p-value	0.740
PPC
<50%	81 (56/69)
≥50%	58 (28/48)
p-value	0.006
D 90
≥140 Gy	81 (63/78)
<140 Gy	52 (17/33)
p-value	0.009

The radical effect of brachytherapy for localized prostate cancer has been confirmed worldwide. Since the first introduction of ¹²⁵I brachytherapy from western countries to China occurred more than a decade ago, few centers have reported long-term outcomes. To our knowledge, this is one of the largest cohort of prostate cancer patients treated with brachytherapy with the longest follow-up from mainland China reported to date, though the results represent our early experience.

The indication for brachytherapy suggested by the American Brachytherapy Society (ABS) is localized prostate cancer (Nag et al. 1999; Davis et al. 2012). Brachytherapy monotherapy can achieve radical effects for localized low-risk prostate cancer. However, for intermediate- and high-risk patients, EBRT or ADT should be added. Although patients may benefit from the combined therapy in terms of overall survival rate, they also experience increased economic burden, additional complications, and greater inconvenience to their daily lives. For these reasons, the latest ABS guidelines suggest that brachytherapy monotherapy can also be applied in intermediate-risk localized prostate cancer (Davis et al. 2012). Although there is solid evidence indicating that brachytherapy monotherapy achieves the same curative effect as brachytherapy combined with EBRT (Blasko et al. 2000), many clinical centers have added ADT or EBRT routinely for intermediate-risk localized prostate cancer patients (Davis et al. 2012). In our study population, we prescribed 6 months of ADT in intermediate-risk patients. We initially planned to add EBRT for high-risk patients before or after brachytherapy. However, due to the serious urinary track irritation and rectal irritation symptoms associated with the first 6 patients and the relatively optimistic outcomes from other clinics with high-risk patients treated with brachytherapy monotherapy (Merrick et al. 2003; Marshall et al. 2014), we did not perform EBRT in the high-risk patients and opted for brachytherapy monotherapy instead.

Regarding the combination with ADT, we refer to the experience of EBRT combined with ADT: long-term (2–3 years) ADT can improve the biochemical relapse-free survival rate and the overall survival rate of high-risk prostate cancer (Bolla et al. 2009; Hanks et al. 2003). In our study, all of the high-risk patients received ADT, 39 of whom underwent ADT for more than 2 years; ADT in the other 27 cases was administered for less than 2 years for a variety of reasons. Marshall et al.’s study reported that ADT had a benefit in reducing the biochemical recurrence rate after brachytherapy (Marshall et al. 2014). However, Stock has stated that ADT improves FBF only in the setting of lower doses, i.e., a biological effective dose <220 Gy (Stock et al. 2013). The benefit of ADT may primarily be as an enhancer of local control, explaining why high radiation doses can compensate for its absence. Therefore, we prescribed ADT for all high-risk and intermediate-risk patients. Regarding the low-risk patients, the neoadjuvant endocrine therapy was aimed at reducing the volume of the prostate to reduce the interference of the pubic arch.

For early stage prostate cancer, a radical effect can be achieved with brachytherapy, EBRT, brachytherapy combined with EBRT and radical prostatectomy (Davis et al. 2012; Aizer et al. 2009; Kupelian et al. 2004), with similar 5-year biochemical recurrence-free survival rates (Kupelian et al. 2004). Patients can obtain a satisfactory curative effect despite the risk category they fall in (Marshall et al. 2014). Marshall et al.’s analyzed 2495 patients with localized prostate cancer. The 12-year biochemical recurrence-free survival rate was 83% (90% for the low-risk group, 84% for the intermediate-risk group and 64% for the high-risk group). The cancer-specific survival rate was 95%, and the overall survival rate was 70%. A meta-analysis performed by Merrick et al. (2003) showed different clinical outcomes among different centers. The biochemical recurrence-free survival rate for low-, intermediate- and high-risk patients 3 to 7 years after brachytherapy ranged from 85%-96%, 74%-97% and 38%-82%, respectively. With a 7-year follow-up, our study population had an overall biochemical recurrence-free survival rate of 72% (86%, 79% and 64% for the low-, intermediate- and high-risk patients, respectively). The cancer-specific survival rate was 97%, and the overall survival rate was 90%. Compared with previous studies, we obtained similar results in the intermediate-risk patients and relatively poor outcomes in the low-risk patients. We believe the reasons for these findings are as follows. 1. The study enrolled a relatively small study cohort. 2. The study administered a low therapeutic radiation dose. Of the 111 patients in our cohort treated with brachytherapy alone, 33 cases had a D90 < 140 Gy, among which 17 patients had biochemical relapse. The biochemical relapse rate was higher in patients with a D90 < 140 Gy than in those with a D90 ≥ 140 Gy, indicating that the therapeutic radiation dose is related to the cure effect (Stone et al. 2005). 3. In our center, the ¹²⁵I seeds were implanted with a Mick applicator, rather than using a seed strand, thus resulting in a relatively reduction of therapeutic radiation due to seed migration (Lin et al. 2007). However, the seed strand method has not yet been introduced to mainland China.

In general, the factors affecting the effect of brachytherapy can be divided into preoperative, operative and postoperative. The preoperative factors are the PSA level (Potters et al. 2008), Gleason score (Sylvester et al. 2011), risk stratification (Taira et al. 2010), PPC (Taira et al. 2011) and prostate volume (Le et al. 2013). The operative factors are therapeutic radiation dose (Stone et al. 2005) and the proficiency of implantation (Zelefsky et al. 2007), and the postoperative factor is combination with ADT (Marshall et al. 2014) or EBRT (Davis et al. 2012). The results indicated that biochemical recurrence rates differ significantly among groups of patients with different risk factors, showing compliance with results from other centers. However, the overall survival rates among the three groups were of not significantly different, most likely due to our relatively small sample. Based on the analysis of the risk factors, PSA ≥20 ng/ml, PPC ≥50%, and a D90 < 140 Gy were associated with a high biochemical recurrence rate, as suggested by previous studies (Stone et al. 2005; Potters et al. 2008; Taira et al. 2011). Interestingly, we discovered that PPC had a more obvious relationship with the biochemical relapse rate than other factors such as clinical stage or risk stratification. Researchers have also suggested that PPC, being an independent predictive factor, plays a significant role in predicting the biochemical relapse-free survival rate and the overall survival rate in patients undergoing radical prostatectomy (Briganti et al. 2007), EBRT (Spalding et al. 2007) and brachytherapy (Urani et al. 2007).

Urinary retention is the commonly observed complication after brachytherapy for prostate cancer. However, the majority of cases can be improved by urinary catheterization combined with alpha blockers; only a few require TURP intervention. TURP should be delayed 6 months after brachytherapy to avoid urinary incontinence. One of the patients in our study population who had repeated recurrence of urinary retention underwent TURP, with subsequent symptom improvement. Prostate rectal fistula has a relatively low incidence, lower than 1%; however, with a difficult intervention, these cases often require fecal and urinary diversion (Elebrezze & Medich 2003). No prostate rectal fistula was observed in our patients because we were conservative about the radiation dose delivered to the prostate area adjacent to the rectum. The reduced local radiation dose might inevitably have led to relatively poorer treatment effect.

In conclusion, we believe that ¹²⁵I brachytherapy for prostate cancer is an effective, less traumatic method with fewer complications than radical methods of prostate cancer treatment. Further randomized controlled studies with larger samples from multiple centers are needed to verify the efficacy and complications of this method in mainland China.