The improvement in biochemical relapse free and overall survival of patients with prostate cancer were found to be dose-dependent (Kalbasi et al. 2015; Kuban et al. 2008). Several studies have shown the great potential of CIRT in the management of prostate cancer (Akakura er al. 2004; Ishikawa et al. 2006; Nomiya et al. 2016; Okada et al. 2012; Takakusagi et al. 2020), most of these studies were from Japanese institutes. However, the biological model used in European and our center (LEM model) were different from Japanese institutes (MKM model) (Molinelli et al. 2016). And our previous studies shown that the RBE-weighted doses at our center is too conservative compare with Japanese institutes, and the RBE-weighted doses using MKM for targets and OARs should be converted to LEM doses using conversion curves for prostate cancer treated with CIRT (Wang et al.2020). The clinical study also found that the 5-year local control (71%) of skull base chordoma treated with CIRT at CANO is inferior to the results reported by Japanese centers (76–92%) using the same prescription dose, and they found that 92% of the local recurrences were attributable to suboptimal target dose in regions close to the brainstem or optic pathways (Iannalfi et al. 2020; Koto et al. 2020; Takagi et al. 2018). These studies indicated that we cannot replicate the prescription dose from Japanese experiences for prostate cancer CIRT. Until now, the optimal dose for CIRT with LEM model in localized prostate cancer remain unknown.
The first dose escalation clinical trial of CIRT for prostate cancer was started in Japan. The 5-year bRFS of the 57.6 GyE/16 fractions regimen was 88.5% (Okada et al. 2012). In a multi-institutional study, which collected and re-analyzed data from prospective clinical trials conducted in 3 institutions in Japan, the 5-year bRFS in low-risk, intermediate-risk, and high-risk patients was 92%, 89%, and 92%, respectively (Nomiya et al.2016). At first, 63/66 GyE in 23/24 fractions was applied to treat the prostate cancer patients in our institute. The dose regimens were well tolerated and without any ≥ grade 2 late GI and GU toxicity. To determine the optimal radiation dose, we prospectively evaluated the safety and feasibility of dose escalated CIRT for patients with localized prostate cancer (NCT02739659). A total of 118 patients treated by CIRT in our institute achieved satisfactory short-term biochemical control without developing serious adverse events. As we known, this is the first dose escalated clinical trial in prostate cancer received CIRT with LEM model.
In the current study, five dose levels were used in this study. 118 patients were treated by 59.2 GyE (n = 43), 60.8 GyE (n = 10), 62.4 GyE (n = 9), 64.0 GyE (n = 25) and 65.6 GyE (n = 31). Five patients developed biochemical relapse, all of them were in the 59.2GyE group. None of the patients developed biochemical relapse in the ≥ 60.8 GyE groups within the follow-up period. The comparative analysis for efficacy between low dose and high dose group was not performed maybe due to the relatively short follow-up. The prescribed dose was 57.60 Gy (RBE) in 16 fractions in NIRS. Our previous study shown that 3.60 Gy (RBE) per fraction for 16 fractions in MKM, could be converted to 4.21 Gy (RBE) per fraction for 16 fractions in LEM (Wang et al.2020). Hence it is expected that a better tumor control of the patients treated by high dose groups will be achieved. And we have enrolled 43 patients into the phase 2 clinical trial with the fixed dose at 65.6GyE in 16 fractions. The primary endpoint of the phase 2 study is to evaluate the efficacy of the dose regimen in LEM model system.
In terms of acute toxicity, according to the results from Radiation Therapy Oncology Group (RTOG) 0126 clinical trial (Michalski et al. 2018), 751 patients treated with 79.2Gy photon therapy, the incidence of grade 1, 2 and 3 acute GU toxicity was 19%, 16% and 1%, respectively, and the incidence of grade 1, 2 and 3 acute GI toxicity was 7%, 7% and < 1%, respectively. Ion Prostate Irradiation (IPI) study from Heidelberg Ion-Beam Therapy Center (HIT) (Habl et al. 2016), 91 patients treated with 66GyE in 20 fractions carbon ion or proton, which shown that the incidence of grade 1, 2 and 3 acute GU toxicity was 34.1%, 17.6% and 0%, respectively, and the incidence of grade 1, 2 and 3 acute GI toxicity was 60.4%, 7.7% and 2.2%, respectively. In our study, there were no significant differences between groups for acute GU and GI toxicities (Table 2). Patients in the high dose group seems experienced higher rates of acute grade 2 GU toxicities than those in the low dose group (26.2% vs.9.4%). No ≥ grade 3 GU toxicity was observed. The incidence of acute GU toxicities in our study is consistent with 79.2Gy arms in RTOG 0126 study, but is lower than the IPI study. The incidence of acute GI toxicity in our study is very rare, and is significantly lower than IPI study. Possible explanation for differences may lie in half patients received proton therapy in IPI, and daily in room CT was applied in our center since 2020. The association between the candidate prognostic factors and the acute toxicities has been investigated in the current study. We found CTV volume was associated with acute GU toxicities, Previous studies also indicated that patients with a large prostate volume have a great risk of irritative/obstructive symptoms (particularly dysuria) in the acute radiotherapy phase (Pinkawa et al. 2008). This may be due to more bladder volume were irradiated and lower urinary bother score before CIRT for patient with large prostate. So, for patients with large prostate, neoadjuvant hormone therapy is often recommended to reduce prostate volume.
Late toxicities tend to be more problematic than acute toxicities in radiotherapy for prostate cancer. The incidence of late grade 2 and 3 GU toxicity after radiotherapy has been reported as 11% and 3% in RTOG 0126 trial (79.2Gy arm) (Michalski et al. 2018). According to the results from a multi institutional study from Japan Carbon Ion Radiation Oncology Study Group (J-CROS) analyzing 2157 patients treated with CIRT, the incidence of late grade 2 and 3 GU toxicity was 4.2% and 0% (Nomiya et al.2016). In the present study, the incidence of late grade 2 and 3 GU toxicity was 1.7% and 0%, respectively. The incidence of late grade 2 and 3 GI toxicity was 16% and 5% in RTOG 0126 trial (79.2Gy arm). The incidence of late grade 2 and 3 GU toxicity was 0.5% and 0% in J-CROS trial, which was more favorable than photon therapy. And in our study, there was no patient suffer from GI toxicity within the follow-up period, that may be due to the short follow-up time. Ishikawa’s study shown that 81% late toxicities occurred within 2 years after CIRT. the median follow-up time of patients in low dose and high dose group was 49 and 17 months, respectively (Ishikawa et al.2006). Therefore, toxicities were evaluated for a sufficient period in low dose group, but were not sufficient in high dose group.
The limitations in this study include short follow up time, low sample size and single institution study. With 30.2 months follow up, we were only able to assess acute and early late toxicity, were too short to evaluate the long time outcome for prostate cancer.