Long-term oncologic outcomes of radiotherapy combined with maximal androgen blockade for localized, high-risk prostate cancer

Prostate cancer (PCa) is a common malignancy characterized by both elevated morbidity and mortality. Most PCa patients, including those with high-risk disease, do not have metastatic tumors at diagnosis; therefore, local tumor resection could produce excellent long-term survival outcomes [1‐3]. In individuals with localized, high-risk disease, not suitable for radical prostatectomy (RP), combination therapies involving RT and androgen deprivation therapy (ADT) are preferred approaches.

As a new RT technique, modern brachytherapy was first applied for PCa in the 1980s when transrectal ultrasound became available to plan and guide radioactive seed placement within the prostate. Because of excellent 15-year PSA outcomes [4], brachytherapy is routinely performed either as monotherapy in individuals with low-risk or low-/intermediate-risk cancer or in combination with external beam radiation therapy (EBRT) in those with high-risk tumors [5]. A recent comprehensive literature review screening 18,000 articles with over 50,000 patients comparatively analyzed PSA-free survival outcomes in patients suffering from localized PCa treated with different radical therapies [1]. The results suggested that PSA outcomes are significantly favorable after brachytherapy in comparison with EBRT in low-risk cases, with the brachytherapy monotherapy achieving equivalent PSA outcomes compared to the EBRT and brachytherapy combination in individuals with intermediate-risk tumors. Here, we evaluated the clinical benefit of the MAB + EBRT + PPB combination by assessing long-term survival outcomes and PSA kinetics in subjects with localized high risk.

In the past 20 years, interstitial radiation therapy has been used as routine treatment for patients with clinically localized PCa, and most researchers believe that the 5-year PSA outcome of brachytherapy in low-risk patients is not statistically different from that of RP or EBRT. In addition, intermediate- and high-risk patients administered RP or EBRT may show a better response compared with those that undergo brachytherapy [8]. However, this view remains controversial. Polascik et al. reported that 7-year actuarial PSA progression-free survival following RP is remarkably higher than that of the I-125 brachytherapy group (97.8 vs 79%) [9, 10] in patients with localized PCa. Therefore, Polascik et al. proposed that brachytherapy should be cautiously recommended to patients with localized PCa. Sharkey and colleagues analyzed 1707 PCa patients with T1 or T2 stage disease treated by either brachytherapy or RP; they concluded that the time to PSA-indicated recurrence is better controlled by brachytherapy than RP in intermediate- (89 vs 58%, P < 0.05) and high-risk (88 vs 43%, P < 0.05) groups, but not in low-risk patients (89 vs 94%, P = 0.174) [11]. Moreover, Taira et al. evaluated 329 cases of high-risk PCa treated with brachytherapy + EBRT with a 10-year follow-up and found that cause-specific survival (CSS) in Gleason 5 patients is significantly lower than that of non-Gleason 5 patients (90.3 vs 98.1%, P = 0.011). However, no remarkable differences in BRFS and OS between these two groups of patients were observed [12]. In addition, Demanes et al. retrospectively assessed 209 cases treated with brachytherapy + EBRT with a 10-year follow-up and reported OS and CSS rates of 79 and 97%, respectively. Meanwhile, PSA progression-free survival rates were different for patients with low-, intermediate-, and high-risk disease (90, 87, and 69%, respectively) [13]. Another study reported that the combination strategy of brachytherapy + EBRT is significantly more advantageous than brachytherapy monotherapy in 5-year biochemical relapse-free survival (80 vs 59%, P < 0.01), although EBRT-treated cases showed more adverse disease factors [14]. Collectively, current clinical evidence supports brachytherapy + EBRT as a proven treatment regimen for all stages of localized PCa [15].

In the present analysis, EBRT + MAB + PPB showed a significant benefit for long-term OS and BRFS in localized high-risk patients compared to EBRT + MAB combination. In addition, the brachytherapy-based combination treatment also postponed several important clinical events: 3.3 years for PSA biochemical recurrence, 2.2 years for SRE, and 2.8 years for CCT. The recently open-published ASCENDE-RT trial [16] compared survival endpoints between the DE-EBRT and low-dose-rate brachytherapy (LDR-BT) arms in intermediate-/high-risk patients and showed that DE-EBRT is twice as likely to result in biochemical failure, while OS rates were similar between these two treatment arms (P = 0.62).

Recent studies reported that PSA kinetics is closely related to long-term survival outcomes in PCa patients [17, 18]. More importantly, PSA kinetics was confirmed to independently predict OS and BRFS by multivariate analysis in the current analysis. Specifically, PSA reduction over 90% was strongly associated with improved long-term survival as well as PSA biochemical progression in high-risk disease cases treated with RT + MAB. It is known that a short PSADT is associated with a promptly expanding tumor, a higher metastatic potential, and a somewhat elevated risk of cancer specific mortality [19‐21]. D’Amico et al. found that patients with a PSADT less than 3 months represent 10–15% of males showing biochemical recurrence, but a higher risk of systemic recurrence [20, 21] and cancer-specific mortality with a median survival of 6 years [22]. Similarly, in men post-RT, Crook et al. demonstrated systemic recurrence is correlated with elevated PSA nadir, as well as reduced PSADT; an average PSA nadir of 0.4 ng/mL in cases without disease recurrence was reached at 33 months, while 3.2, 7.7, and 1.4 ng/mL were obtained in individuals with local recurrence at 17 months, distant recurrence at 12 months, and biochemical recurrence at 24 months, respectively [23].

In recent years, high-dose-rate brachytherapy (HDR-BT) has attracted increasing attention and is used for more patients. Several clinical trials reported its excellent effects in high-risk patients. Ten-year actuarial biochemical control rates of 100, 91, 88, and 79% were found in subjects with low-, two intermediate-, only one high-, and 2–3 high-risk criteria, respectively (P = 0.004); hormone treatment did not affect these results [24]. A 5-year BRFS of 93.6% was reported in high-risk patients who underwent ADT + EBRT + HDR-BT, with 87.6% in the EBRT + HDR-BT group [25]. The overall 3-year OS and BRFS rates were 93.7 and 96.9% in high-risk cases administered ADT + EBRT + HDR-BT, respectively [26]. Satoshi et al. reported that both LDR-BT + EBRT and HDR-BT + EBRT are safe and suitable for individuals with localized prostate carcinoma, with some advantages of HDR-BT + EBRT over LDR-BT + EBRT in terms of recovery time [27]. Although no further long-term survival data were reported for these two radiation modalities in localized, high-risk patients, LDR-BT is generally administered as a monotherapy in early diagnosed cases, while HDR-BT is usually applied along with EBRT in cases of prostate cancer in unspecified stages [28]. In addition, some clinical trials found that a PSA nadir of less than 0.02 ng/mL within 12 months of radiotherapy is associated with significantly improved biochemical tumor control and cause-specific survival in cases of locally advanced and non-metastatic high-risk prostate cancer co-administered HDR-BT, EBRT, and long-term ADT [29]. Thorsten et al. reported a discrepant conclusion regarding the predictive value of PSA for the biochemical control rate in 79 cases with high-risk PCa administered HDR-BT following EBRT, with an average follow-up of 21 months; the authors described PSA as a negative predictive biomarker for local recurrence during follow-up, indicating that prolonged follow-up is required for reassessing long-term outcomes [30].

Overall, brachytherapy is a promising and effective radiation technique, with higher concentration of the radiation dose within the prostate, which decreases the risk of complications in other organs and reduces the frequency of urinary symptoms. PPB-based combined radiotherapy plays an extremely important role in improving OS and BRFS in high-risk PCa patients; time to the first SRE and CCT were also relatively prolonged. These clinical data further demonstrate that post-radiation PSA kinetics could significantly predict survival outcomes in cases with localized, high-risk disease; specifically, PSA nadir ≤ 1 ng/mL, time to PSA nadir ≤ 3 months, PSA doubling time > 12 months, and PSA reduction ≥ 90% were associated with improved tumor control. Therefore, more aggressive treatments should be considered for cases with non-favorable PSA kinetics.