High-risk PCa features are associated with poor pathological outcomes after RP [
3,
21]. Increasing Gleason score, high PSA level, and advanced clinical stage have all been shown to be correlated with EPE, SV invasion, and positive surgical margins. Both Partin's tables and Naito's Japanese nomograms have demonstrated the increased incidence of the above-mentioned pathological findings with higher risk features [
22,
23]. These pathological findings have also been shown to be associated with higher rates of biochemical failure [
21,
24]. Explanations for these outcomes have focused on the presence of microscopic dissemination of cancer cells at initial diagnosis. For this reason, little attention has been focused on optimizing local control and more on developing new systemic approaches. The patterns of failure following standard treatment for high-risk PCa reveal a large component of local recurrence in addition to distant spread of disease [
25,
26].
In patients at greater risk for EPE, a BT boost combined with additional EBRT can ensure adequate margin of coverage of surrounding tissues even in the case of minimal spread of disease. As there is mounting evidence that dose escalation leads to a decrease in the rate of treatment failure [
27-
29], this combined BT and supplemental EBRT is now commonly used to provide a very conformal high-dose-boost to the prostate. Indeed, this synergistic effect of the combination strategy of two types of RT can induce a greater biologically effective dose (BED), the values of which are strongly correlated with treatment outcomes in biochemical control of disease [
6,
30]. Stone
et al. have shown that local control improves from 78% to 98% (as determined by biopsy) when the BED is increased from ≤ 150 Gy to > 200 Gy [
31]. Our protocol with combination of BT boost and EBRT should deliver similar high doses, thus greatly decreasing the likelihood that local failure will be responsible for future PSA increase. The protocol also allows centers to adjust their EBRT component based on the delivered D90 so the final BED will be between 200 and 220 Gy. This RCT will be the first to test the hypothesis of whether longer use of HT can prevent relapse and death that results from coexistent micrometastases when high-risk PCa is treated with high radiation doses. Zelefsky
et al. have shown that even 81 Gy of IMRT is associated with a much higher local failure (12%) and that I-125 monotherapy is superior to 81 Gy in both biochemical control and achieving a lower PSA nadir [
29].
The combination of HT has an independent cytotoxic effect on prostate cancer cells, and the rationale for combining HT with radiation is to act as a "sensitizer" for radiation to enhance the cytotoxic effect on cancer cells, and to eradicate micrometastatic disease beyond the radiation volume. Several RCTs have documented a prolongation in DSS and/or OS when HT is added to EBRT in comparison to EBRT alone in the treatment of men with localized high-risk and locally advanced PCa [
10-
12]. Recently, Widmark
et al. reported that DSS and OS at 10 years were significantly higher with HT plus EBRT than with HT alone [
32]. However, as mentioned above these studies were performed with insufficient radiation dose and whether the benefit from the prolonged HT was from a local or distant effect, or a combination of both is unknown. The majority of these prior RCTs were performed with conventional doses of EBRT (65-70 Gy) and it remains to be seen how the studies would turn out if higher IMRT doses were used. However, even 81 Gy of IMRT might prove insufficient to control the local disease in high-risk PCa.
There are several aspects of our study that are similar to the RCTs done with HT for breast cancer. In several trials that directly compared approximately 5 years of tamoxifen with 1 to 2 years involving more than 18,000 women, with a mean length of follow-up of 5 person-years, the estimated risk reductions were 15% (P < 0.001) for recurrence and 8% (P = 0.01) for breast cancer mortality [
33]. An important feature for the breast cancer RCTs was the success of the combined modality therapy in treating the primary lesion, lumpectomy and whole breast irradiation. The risk of local recurrence after the primary treatment is less than 5%. Thus the breast cancer RCTs were testing the hypothesis that long term HT would reduce the chance of a breast cancer related death.
Adequate local control has been the challenge when treating locally advanced and high grade PCa. Often patients are offered radical prostatectomy, especially if they are young. However, three recent RCTs involving adjuvant EBRT following RP demonstrated markedly decreased local recurrence and improved survival in the EBRT arm [
34-
36]. As discussed above, achieving an adequate dose of IMRT to eradicate all local disease is not currently possible. The need for very high local dose was recently shown in a multicenter report in Gleason score 8-10 PCa where patients receiving a BED of > 220 Gy (I-125 implant D90 of 130 Gy combined with 45 Gy EBRT) had a 25% improvement in biochemical control, decreased bone metastases and improved survival when compared to men who received lower dose of irradiation [
6].
Relatively few data are available, mostly from single institutions, on the morbidity of this combined modality treatment, despite the increased use of this treatment strategy during the 1990s [
37-
40]. Since the 1990s, ultrasound-guided transperineal interstitial permanent BT has been a commonly used treatment strategy for patients with PCa [
17,
41]. In Japan,
125I-BT was added to the Japanese armamentarium for treatment of localized PCa in 2003 [
15]. Since then, more than 10,000 patients have undergone this procedure. Although there are many benefits of combined use of HT with EBRT, the potential adverse events significantly caused by this treatment should be taken into consideration [
13,
42]. The PROST-QA study prospectively measured patient-reported QOL outcomes before and after PCa treatment [
14]. Sexual function was persistently poorer among radiation patients who received HT than among those who did not. Vitality and other outcomes related to HT (
e.g., fatigue, weight change, gynecomastia, depression, and hot flashes) were also poorer in the HT patients. In contrast, a meta-analysis of randomized trials suggested that HT plus RT decreases recurrence and mortality rates of patients with high-risk PCa, without affecting toxicity [
43].
The optimal duration of concomitant HT for high-risk PCa when combined with dose-escalated RT is not yet known. The period of 3 years of adjuvant HT was chosen empirically; shortening of this period would reduce costs and side effects due to longer HT and may be possible, as patients with locally advanced prostate cancer in the late 1990s had less tumor burden and were younger than those of the mid-1980s. The RTOG study 92-02 demonstrated that the additional 2.5 years of HT to EBRT group showed significant improvement over EBRT alone for all endpoints except OS in comparison to 4 months of HT with EBRT [
11]. The EORTC study 22961 also showed that the combination of EBRT plus short-term HT provides inferior survival to EBRT plus long-term HT for 3 years in the treatment of locally advanced PCa [
12].
On the other hand, the role of HT in conjunction with BT for high-risk PCa patients is not as clearly defined. Moreover, the ABS also provides no clear indication for adjuvant HT when combination of BT and EBRT are performed for intermediate- to high-risk PCa, except in the aim of downsizing the prostate gland when the initial size surpasses 60 cc [
7]. Although some authors have certainly reported clinical advantages to addition of HT to BT [
20,
44,
45], a large retrospective matched-pair analysis failed to show a benefit of HT in conjunction with BT for any risk group, Gleason score, pretreatment PSA level, or clinical stage [
46]. Taken together, the lack of evidence from randomized trials has resulted in a variety of treatment approaches performed in both clinical community and academic settings, so that variations in sequence of EBRT and BT, choice of isotope, use of HT, and the experience of reporting institutions have all led to uncertainties in extrapolating reported results. Furthermore, there is still uncertainty regarding not only the adequate duration of HT but also both the optimal timing and contents of HT, with regard to adding HT to EBRT and/or BT in high-risk PCa.
Accordingly, we have designed this TRIP study of trimodality treatment consisting of
125I-BT, EBRT, and either short- or long- term HT for high-risk PCa. To our knowledge, there have been no previous reports of prospective studies documenting the efficacy and safety of trimodality therapy for high-risk PCa patients. Initially, we assess the tumor control outcomes of patients treated with this modality (BT and supplemental EBRT with neoadjuvant and concurrent HT) with or without adjuvant HT for 2 years. In this setting, the present multi-institutional TRIP study was designed to determine the efficacy of the combination of EBRT with
125I-BT boost in all patients treated with uniform widely accepted guidelines for RT in addition to use of HT. Although Lee
et al. reported a significant advantage of adding HT to BT in patients with high-risk PCa, improvements in biochemical outcome were restricted to those patients with "low-dose" implants [
44]. In addition, the ability to adequately irradiate the periprostatic region using extracapsular seeds may also improve biochemical outcome. Taking into account the potential learning curve for
125I-BT, participating institutions in our study were required to have performed at least 50 previous
125I-BT procedures, thus mitigating the impact of inexperience with this procedure while being inclusive of the majority of facilities at which
125I-BT is performed. In addition a dosimetry assessment committee will review the BT outcomes of all participants. Given the variable nature of delivered implant dose, all centers will be encouraged to irradiate their patients to a dose of 200-220 Gy, in the event the implant dose is too low or high. The uniformity of dose delivery will more closely mimic a much higher, more homogeneous dose of EBRT. Finally, this RCT also provided additional insight regarding the efficacy and limitations of the addition of 2 years of adjuvant HT to this trimodality therapy (dose escalated RT plus HT before and during RT), with evaluation of the primary endpoint of bPFS at 7 years. Insight should be gained as to whether extended HT would benefit the patients who harbor micrometastases when adequate local therapy has been delivered.
1 Shin Egawa,2 Shiro Saito,3 Atsunori Yorozu,4 Hiroyuki Takahashi,5 Keiko Miyakoda,6 Masanori Fukushima,6 Takushi Dokiya,7 Hidetoshi Yamanaka,8 Nelson N Stone,9 and Mikio Namiki1
publication history