Long-term results of a phase II study of hypofractionated proton therapy for prostate cancer: moderate versus extreme hypofractionation

The α/β ratio for prostate cancer is known to be very low (range, 0.9–2.2 Gy) [1‐5]. A lower α/β ratio than that of the surrounding normal tissue has suggested that hypofractionated schedules might increase the therapeutic ratio. We have previously reported the interim results of phase II trial comparing five different hypofractionation dose schedules using proton beam therapy (PBT) [6]. Because of its unique dose-distribution, PBT is better for delivering highly conformal radiation to the prostate while sparing the adjacent rectum and bladder [7], and is considered an effective method to deliver high doses per fraction, although there is no clear evidence that PBT offers a clinical advantage over any other form of definitive radiotherapy. As comparative studies on the efficacy of different hypofractionation dose schedules are lacking, we conducted an exploratory analysis of the phase II trial comparing outcomes between moderate hypofractionation (MHF; fractional dose < 5 Gy) and extreme hypofractionation (EHF; fractional dose ≥5 Gy).

To our knowledge, this is the first prospective study to compare the efficacy of EHF and MHF in patients with prostate cancer. In our exploratory analyses, the 7-year BCFFS rates of the MHF and EHF groups were 76 and 46%, respectively, for all patients (p = 0.005). The effect of the fractionation schedule was statistically significant for the intermediate risk group (84 vs. 43%, respectively; p = 0.018), but not for the low or high risk group. For the low risk group, the difference in the 7-year BCFFS was substantial (91 vs. 57%, p = 0.154), but did not reach significance because of the small sample size (n = 28 patients). For the high risk group, the 7-year BCFFS was suboptimal regardless of the fractionation scheme in which the ADT should have been added to the radiotherapy as standard care. The BCF tended to be a late event with a median time to occurrence of 60.0 months. As shown in Fig. 1, there was a steep decline in the BCFFS in the EHF group between the 4th and 5th years, which further suggested that a long-term follow-up was needed.

There are several possible explanations why the BCFFS of EHF was inferior to that of MHF. The two assumptions in this study were that the α/β ratio was 1.5 Gy and that repopulation was negligible during treatment. Assuming an α/β ratio of 1.5 Gy, the EQD2 for the EHF group was 85 Gy, which was greater than the 77.1–83.3 Gy of the MHF group (Table 1), but the actual outcomes were worse in the EHF group, which was contrary to our expectation. Although most of the evidence supports a very low α/β value for prostate cancer involving < 2.0 Gy [1‐4], there have been a few studies supporting higher values. Miralbell et al. [5] reported that the α/β ratio could be increased from 1.5 Gy to 4 Gy when the overall treatment time is longer than the lag period for accelerated repopulation. Williams et al. [11] examined the effects of fraction size and total dose of radiotherapy in 3756 patients treated with radiation alone at three institutions, and estimated an α/β ratio of 3.7 Gy. Nahum et al. [12] reported α/β ratios of 8.5 Gy and 15.5 Gy, when considering the heterogeneity of prostate cancer and hypoxia.

In a review of comparative randomized trials, Pollack et al. [13] reported the results of a trial comparing hypofractionation (HF) (70.2 Gy/26 fractions) with conventional fractionation (CF) (76 Gy/36 fractions). Assuming an α/β ratio of 1.5 Gy, the EQD2 for HF of 84.4 Gy would significantly reduce the biochemical/clinical disease failure (BCDF), but there was no significant difference in the BCDF between the treatment arms (23.3 vs. 21.4% at 5 years, respectively; p = 0.268). In the RTOG 0415 trial [14], 1092 men with low risk prostate cancer were randomly assigned to CF (73.8 Gy/41 fractions/8.2 weeks) or HF (70 Gy/28 fractions/5.6 weeks). The 5-year disease-free survival was 85.3 vs. 86.3%, respectively, so it was concluded that the efficacy of the 70 Gy/28 fractions was not inferior to the 73.8 Gy/41 fractions. Incrocci et al. [15] reported the results of a randomized trial (HYPRO) comparing a HF of 64.6 Gy/19 fractions with a CF of 78.0 Gy/39 fractions in patients with intermediate and high risk prostate cancers. Based on an α/β ratio of 1.5 Gy, the EQD2 was 90.4 Gy for the HF compared with 78.0 Gy for the CF. Two-thirds of the patients also received concomitant ADT for 32 months. With a median follow-up of 60 months, the 5-year relapse-free survival was 80.5 vs. 77.1%, respectively (p = 0.36). The CHHiP trial [16] was a phase III non-inferiority trial involving patients with localized prostate cancer who were randomly assigned (1:1:1) to the CF arm (74 Gy/37 fractions/7.4 weeks) or to one of two HF arms (60 Gy/20 fractions/4 weeks or 57 Gy/19 fractions/3.8 weeks). Most patients were treated with radiotherapy with 3–6 months of neoadjuvant and concurrent ADT. With a median follow-up of 62.4 months, the BCDF at 5 years was 88.3% in the 74 Gy group, 90.6% in the 60 Gy group, and 85.9% in the 57 Gy group. The 60 Gy group was non-inferior to the 74 Gy group but there was no non-inferiority for the 57 Gy group compared with the 74 Gy group. In the PROFIT trial [17], more than 1200 intermediate risk patients were randomly allocated to a CF of 78 Gy/39 fractions/8 weeks or to a HF of 60 Gy/20 fractions/4 weeks. ADT was not permitted. With a median follow-up of 6.0 years, the 5-year BCFFS was 85% in both arms. All of these studies reported that the α/β ratio of prostate cancer was low, but there was considerable uncertainty concerning the estimated value. Table 4 summarizes the treatment outcomes of the MHF and EHF trials with an estimated EQD2. We showed EQD2 assuming an α/β ratio of 1.5 Gy, as well as 3–4 Gy for comparison. Interestingly, the outcomes between the CF and HF in these trials could be better explained with a higher α/β ratio of 3 or 4 Gy for the first four trials [13‐16] except for the PROFIT trial [17]. Likewise, for the present study, assuming an α/β ratio of 3–4 Gy better fitted for the outcomes which were worse among the EHF group. The EQD2s for the EHF group were greater than those for the MHF group when an α/β ratio of 1.5 Gy was assumed (85 Gy vs. 77.1–83.3 Gy). Assuming an α/β ratio of 4 Gy, the EQD2s for each schedule were 70.0, 68.4, 68.2, 64.2, and 64.2 Gy, respectively (Table 4).

Several single-arm EHF trials using stereotactic body radiotherapy (SBRT) for prostate cancer [18‐22] have been conducted to date. The largest series with the longest follow-up [22] involved 515 patients treated with 35–36.25 Gy/5 fractions using SBRT. At a median follow-up of 72 months, the 7-year BCFFSs were 95.8, 89.3, and 68.5% for the low-, intermediate-, and high-risk groups, respectively. In a pooled analysis of 1100 patients from eight centers, King et al. [19] reported 5-year BCFFSs of 95.8, 89.3, and 68.5%, respectively, with a median follow-up of 36 months. The corresponding values determined in our study were 57.1, 42.9, and 40.0% at 7 years, despite a very similar dose fractionation scheme (35 Gy/5 fractions). The superior outcome of the former studies could be attributed to the administration of ADT; 8, 16.3, and 55.3% for the low, intermediate, and high risk groups, respectively, in one study [22], and 8, 15, and 38%, respectively, in the other [19]. In our study, ADT was not administered unless there was BCF during follow-up. Additionally, our study had the longest follow-up with a median of 90 months, which could be attributed to the lower BCFFS rates, because BCF is a late event with a median time to failure of 60 months, which could have been even longer when ADT was administered in the former studies.

Time/dose/fractionation schemes might also have been responsible for the discrepancies in the outcomes. The only noticeable difference in the time/dose/fractionation was the frequency of treatment. In previous studies, treatments were administered daily or every other day with an overall treatment time (OTT) per 1.0–1.5 weeks. In our study, patients were treated twice a week (Arm 4) or weekly (Arm 5) with an OTT of 2–4 weeks. Tumor cell repopulation in prostate cancer has been considered negligible when the OTT is no longer than 9–10 weeks [8]. A recent study [23] estimated the tumor repopulation rate and its onset time from previous reports of prostate cancer [8, 24, 25] based on a linear quadratic model and suggested an onset time of 34 days and not longer than 58 days. A few studies [26‐28] have reported a detrimental effect of prolonged OTT in a CF scheme. In a study of 1796 patients with low risk prostate cancer treated with radiotherapy alone, D’Ambrosio et al. [28] reported that prolonged OTT due to treatment breaks was an adverse factor for the BCF. In another study by Thames et al. [26], a multi-institutional retrospective analysis of 4839 patients with low and intermediate risk disease, the OTT and dose were significant predictors of BCFFS, in which OTT was significant in patients treated with ≥70 Gy. However, there was no evidence that an OTT of 2.0–4.0 weeks (< 35 days) negatively affected outcomes when compared with an ultra-short OTT of 1.0–1.5 weeks. An ongoing phase II trial of prostate SBRT called PATRIOT (NCT01423474) which compared 40 Gy/ 5 fractions delivered every other day over 11 days vs. once per week over 29 days is expected to clarify this issue.

Acute GU toxicities were more common in the MHF than the EHF group (85% vs. 57%, p = 0.009), but late GI and GU toxicities were not different between the groups. These findings were consistent with EQD2 estimates for acute response (α/β = 10 Gy) and late response (α/β = 3 Gy) in the normal tissue (Table 1).

The strength of the present study includes a long-term median follow-up of 90 months, which showed a split of the survival curve after 4 years. A shorter follow-up would not have detected this discrepancy. Additionally, strict eligibility criteria of the ADT-naive patients revealed the sole effect of the fractionation scheme excluding confounding effects due to ADT.

A limitation of this study is that it was an exploratory analysis with a small sample size, which was originally intended to compare acute toxicity among five different dose schedules. The criteria for dividing these five groups into MHF and EHF groups were therefore somewhat arbitrary, although the same subdivision was recently described as “moderate hypofractionation” and “ultrahypofractionation” [29]. In addition, the risk groups were not evenly distributed between the MHF and EHF groups. There were more intermediate-risk patients in the EHF group and more low- and high-risk patients in the MHF group. To overcome this limitation, we compared BCFFS between the two groups according to the risk groups (Fig. 2) and found a statistically significant difference in the intermediate-risk group despite a small sample size (p = 0.018). Although our data showed a substantial difference in the efficacy of different hypofractionation schemes in favor of MHF, the result should be interpreted with caution because it is based on an exploratory analysis with a small sample size; our findings should therefore be confirmed in a larger scaled prospective trial. Treating patients with high-risk disease with PBT alone was suboptimal for the current standard of care, with a 7-year BCFFS of approximately 40% in both the MHF and EHF groups. We did not treat seminal vesicles or regional lymph nodes electively due to toxicity concerns when using hypofractionation. However, we recommend androgen deprivation therapy immediately after the occurrence of biochemical failure. Overall survival at 7 years was 97.5% for all patients with a very low disease-specific mortality of 1.2% at 7 years. Only one among the three deaths was related to the progression of bone metastases from prostate cancer.

Although we are not able to draw a definitive conclusion from the current exploratory analysis, the efficacy of EHF is potentially inferior to MHF; further studies are therefore warranted to confirm these findings. This study is hypothesis-generating; therefore, radiobiological models must be better understood to design a dose/fractionation study. The comparative efficacy of MFH vs. EHF can only be determined by well-designed phase 3 randomized trials comparing “apples with apples”.