Long-term results of a study using individualized planning target volumes for hypofractionated intensity-modulated radiotherapy boost for prostate cancer

We previously showed that the magnitude of intrafraction prostate motion was small (AP 0.72 ± 1.80 mm, SI 0.45 ± 1.27 mm and ML 0.14 ± 0.92 mm), and derived average PTV margins of 4 mm (range 2–8 mm) AP, 3 mm (range 2–7 mm) SI and 3 mm (range 2-5 mm) ML [21]. Since our initial report, additional analyses of prostate fiducial markers with electronic portal images corroborate our findings [28-30]. Kotte et al. [28] showed that margins of at least 2 mm account for intrafraction prostate motion, and Middleton et al. [29] derived PTV margins (AP 3.9 mm, SI 3.2 mm and ML 4.3 mm) that were comparable to ours.

The goal of utilizing a daily-image guidance strategy and reducing the PTV margin is to realize a clinically meaningful difference in treatment toxicity. In the randomized trials of dose escalation the PTV margins used across the studies were heterogeneous, ranging from 5-15 mm. While these studies demonstrated a benefit in biochemical control, there was an increase in late grade 2 or greater GI toxicity (odds ratio of 1.58; 99% CI 1.24–2; p < 0.0001) [31]. In Tables 2 and 3, the PTV margins utilized and the reported late toxicities in the randomized trials of dose escalation [1-9], and contemporary mild hypofractionation [32-36], are summarized alongside the results of the current study for illustrative purposes. Our study was limited by a small sample size and only two years of toxicity follow-up. The variability in the reported toxicities across studies is likely due to differences in the PTV margins, treatment techniques, and dose and fractionation schedules.

Since Brenner and Hall first reported that prostate cancer may have a low α/β ratio [14], there has been growing interest to use hypofractionated treatment regimens to capitalize on the therapeutic ratio that may exist between the sensitivity of prostate cancer to higher doses of radiation per treatment fraction and reduced normal tissue toxicity. The promise of hypofractionation lies in the potential for improved tumour control and increased patient convenience with a shorter overall treatment time and lower costs compared to a standard course of dose-escalated treatment. To date, data from four contemporary randomized trials comparing hypofractionated to dose-escalated radiotherapy do not demonstrate increased biochemical control with higher biologic equivalent doses to the prostate and equivalent late toxicities [34,36]; or the same biochemical control and less late toxicity with isoeffective doses delivered to the prostate as hypothesized [32,33,37-39] (Table 3).

Based on a α/β ratio of 1.4 [13], we delivered an equivalent dose of 81 Gy in 2 Gy fractions. Our pilot study was small, however, it was reassuring to observe that our BC rate was similar to the MD Anderson (8-year Phoenix 78%) [1]; and higher than the UK (5-year ASTRO 71%) [7,8], French (5-year Phoenix 76%) [9] and Dutch (7-year Phoenix 56%) [3,4] dose-escalation trials. In comparison to the hypofractionated treatment arms of the mild hypofractionation trials (Table 3), our BC rate was also similar to the rates reported by Pollack et al. [36] (5-year Phoenix 86%) and Arcangeli et al. [32,37,38] (5-year Phoenix 85%), and lower than the rate reported by Kuban et al. [34] (5-year Phoenix 96%). While these comparisons look favourable, we recognize the wide confidence intervals in our BC rate due to the small sample size. Furthermore, we have not reached a plateau in our biochemical control curve like those seen with brachytherapy where higher biological doses are given [40,41]. This suggests that further biological dose-escalation is warranted. Our group and others have explored more extreme hypofractionation protocols [42-46]. Recent reports of 135 low- and intermediate-risk patients treated with stereotactic body radiotherapy (SBRT; median follow-up 60 months) showed a 5-year bDFS of 99% for low-risk patients and 93% for intermediate-risk patients. Grade 3 or higher toxicities are reported in approximately 1% of patients with 35–40 Gy delivered with 5-fraction SBRT [43,47]. Thus, the benefits of hypofractionation are being realized with doses of 7–8 Gy per fraction.