Modern Studies
The modern MH trials assume that the α/β for PCa is 1.5 Gy, and have complementary design, addressing different hypotheses. The superiority studies hypothesize a greater efficacy of hypofractionation with equivalent toxicity, while the non-inferiority studies aim to demonstrate equivalent efficacy with reduced or similar toxicity.
There are three large randomized non-inferiority trials (CHHiP [
18••,
19,
27], RTOG 0415 [
23•] and PROFIT [
24•]) evaluating the equivalence of MH and CF. The doses in the MH arms in these studies range from 57 to 70 Gy in 2.5–3.4 Gy per fraction. Overall, these studies demonstrate that the safety and efficacy of MH is similar to that of CF.
The largest non-inferiority randomized study of MH is the CHHiP study [
18••,
19,
27]. This study enrolled 3216 patients from 71 centres in the UK, Ireland, Switzerland and New Zealand. Patients were randomized to 74 Gy/37 fractions/7.4 weeks, 60 Gy/20 fractions/4 weeks, or 57 Gy/19 fractions/3.8 weeks, with treatment delivery using IMRT. The experimental fractionation schedule were designed to be isoeffective for α/β of 2.5 Gy (60-Gy schedule) and 1.5 Gy (57-Gy schedule). Twelve, 73, and 15% of patients in this study had low-, intermediate- or high-risk disease, respectively. Short-course hormonal therapy was mandated for patients with intermediate- or high-risk disease.
The primary end point in the CHHiP study was time to biochemical failure, with the critical hazard ratio for non-inferiority being 1.208.
After a median follow-up of 62.4 months, the 5-year biochemical or clinical failure-free survival was found to be 88.3% in the 74-Gy arm (95% CI 86.0–90.2), 90.6% in the 60-Gy arm (95% CI 88.5–92.3), and 85.9% in the 57-Gy arm (95% CI 83.4–88.0). The 60-Gy arm was non-inferior to the 74 Gy (HR 0.84, 90% CI 0.68–1.03; pNI = 0.0018). The 57-Gy arm was not non-inferior to the 74-Gy arm (HR 1.20, 90% CI 0.99–1.46). Overall mortality in each arm was similar; 8.6, 6.8 and 8.1% in the 74, 60 and 57-Gy arm, respectively. There were no statistically significant differences between the arms with respect to distant metastasis rate (3.0, 2.7 and 3.9% for the 74, 60 and 57Gy arms, respectively).
While acute RTOG GI/GU toxicity had become similar in each arm by 18 weeks, it peaked earlier in the hypofractionated arm (4–5 weeks) compared to the control arm (7–8 weeks). Early GI ≥grade 2 toxicity was significantly higher in the hypofractionated arms; it was 25% in the 74-Gy arm, 38% in the 60-Gy arm (p < 0.0001) and 38% in the 57-Gy arm (p < 0.0001).
5-year clinician and patient-reported side-effects were not significantly different. RTOG grade ≥2 GI toxicity was reported at 13.7, 11.9 and 11.5% in the 74-, 60- and 57-Gy arms respectively. Grade ≥2 GU toxicity was reported at 9.1, 11.7 and 6.6% in the 74-, 60- and 57-Gy arms, respectively.
Comparison of the 60- and 57-Gy arms revealed a slightly higher rate of cumulative LENT-SOM grade ≥2 GI toxicity (HR 1.39, 95% CI 1.14–1.70; p = 0.001) and GU toxicity (HR 1.58, 95% CI 1.13–2.20; p = 0.007).
The CHHiP [
18••,
19,
27] study provides compelling evidence for hypofractionation, with the authors recommending 60 Gy/20 fractions/4 weeks becoming the new standard of care for the management of localized PCa.
The PROFIT study (NCT00304759) has recently been presented [
24•]. The critical hazard ratio for non-inferiority in this study was set at 1.32. PROFIT [
24•] recruited 1206 men with intermediate-risk disease, randomizing them to 60 Gy/20 fractions/4 weeks or 78 Gy/39 fractions/7.8 weeks. All patients in PROFIT [
24•] had intermediate-risk disease, with none receiving hormonal therapy.
After a median follow-up of 6 years, no significant difference in 5-year biochemical failure (HR 0.96, 90% CI 0.80–1.15), acute ≥grade 3 GI/GU toxicity, or overall survival have been reported. Interestingly late toxicity was lower in the MH arm (3.5 vs 5.4%, difference = −1.9%, 95% CI −4.3 to 0.43).
The authors of PROFIT [
24•] conclude that, for patients with intermediate-risk disease, MH is non-inferior to CF, for both efficacy and acute/late toxicity.
The RTOG 0415 [
23•] study randomized 1092 patients, with low-risk disease, to 73.8 Gy/41 fractions/8.2 weeks or 70 Gy/28 fractions/5.6 weeks. The critical hazard ratios for non-inferiority were set at 1.52 for 5-year disease-free survival (primary end point), 1.67 for cumulative biochemical recurrence and 1.54 for overall survival.
After a median follow-up of 5.8 years, the MH arm was reported to be non-inferior to the CF arm with respect to 5-year disease-free survival (HR 0.85, 95% CI 0.64–1.14; p < 0.001), biochemical recurrence (HR 0.77, 95% CI 0.51–1.17; p < 0.001) and overall survival (HR 0.95, 95% CI 0.64–1.41; p = 0.008).
The acute side effects did not differ significantly in the two arms of the study. The MH arm had a significantly higher rate of grade 2–3 late GI toxicity (22.4 vs 14%; RR 1.55–1.59) and grade 2–3 late GU toxicity (29.7 vs 22.8%; RR 1.31–1.59).
The authors concluded that the efficacy of MH is not inferior to CF, though the late grade 2–3 GI/GU toxicity is higher.
CHHiP [
18••,
19,
27], RTOG 0415 [
23•] and PROFIT [
24•] include patients in different risk groups and differ in the use of hormonal therapy, but all studies give very similar hazard ratios (<1.0) for their primary end points, demonstrating that the efficacy of MH is not inferior to CF. They differ in their late toxicity outcomes.
In contrast to RTOG 0415 [
23•],CHHiP [
18••,
19,
27] has reported no difference in late toxicity, while PROFIT [
24•] reports a lower rate of late toxicity in the hypofractionated arm. These differences may partly be accounted for by the BED in the hypofractionated and control arms of each study. Assuming an α/β of 3.0 Gy for bladder/rectum, the BED in the hypofractionated arm is higher than the control arm in RTOG 0415 (128 Gy vs 118 Gy), similar to the control arm in CHHiP [
18••,
19,
27] (120 Gy vs 123 Gy), and lower than the control arm in PROFIT [
24•] (120 Gy vs 130 Gy).
Comparing PROFIT [
24•] and CHHiP [
18••,
19,
27], the use of hormonal therapy in some patients in CHHiP appears to improve biochemical control by 10%, although the impact of hypofractionation is similar with or without hormonal therapy.
Finally, the α/β estimated by CHHiP [
18••,
19,
27] (1.8 Gy) and PROFIT [
24•] (1.3 Gy) are both in keeping with the low range of 1.4–1.9 Gy estimated from meta-analyses and large series [
12‐
15], further re-enforcing the theoretical basis for MH.
In the four modern MH superiority randomized trials [
20,
21,
22•,
28‐
31], the dose in the MH arms ranges from 62 to 72 Gy in 2.4–3.4 Gy per fraction. Collectively, these studies have not demonstrated any differences in efficacy after 5 years. No differences in metastasis-free, cancer-specific survival or overall survival have been demonstrated.
Hoffman [
28,
29] and Pollack [
31] compared CF with MH and found no significant difference in 5-year biochemical recurrence-free survival.
Arcangeli [
30] recruited 168 patients with high-risk PCa, randomizing them to 80 Gy/40 fractions/8 weeks or 62 Gy/20 fractions/4 weeks, in conjunction with 9 months of hormonal therapy.
After a median follow-up of 70 months, a non-significant improvement in actuarial 5-year biochemical recurrence-free survival was demonstrated in the MH arm (85 vs 79%; p = 0.065). No significant difference in local or distant recurrence was demonstrated. However, subgroup analysis of patients with a PSA ≤20 ng/ml revealed a significant improvement in 5-year local and distant disease control, in addition to biochemical control.
The HYPRO study [
20,
21,
22•] is the largest of the MH superiority studies. HYPRO randomized 804 patients, with intermediate- or high-risk disease to 64.6 Gy/19 fractions/3 fractions per week/6.5 weeks or 78 Gy/39 fractions/5 fractions per week/7.8 weeks. The majority of patients in this study were high-risk (>70%), with 66% receiving concomitant hormonal therapy. The primary end point was 5-year relapse-free survival. An additional, non-inferiority, end point was the incidence of ≥grade 2 GI/GU toxicity, with a critical hazard ratio designated as 1.11/1.13, respectively.
After a median follow-up of 60 months, the 5-year relapse-free survival was not statistically different in the MH and CF arms (77.1 vs 80.5%; p = 0.36).
No differences in acute ≥grade 2 GU toxicity were reported between the MH (60.5%, 95% CI 55.8–65.3) and CF arms (57.8%, 95% CI 52.9–62.7%). However, the cumulative incidence for acute ≥grade 2 GI toxicity was significantly higher (OR 1.6; p = 0.0015) in the MH arm (42%, 95% CI 37.2–46.9%) compared to control (31.2%, 95% CI 26.6–35.8%). Furthermore, the cumulative incidence of late ≥grade 3 GU toxicity was significantly higher in the MH arm (19 vs 12%; p = 0.021). No statistically significant difference in cumulative ≥ grade 3 late gastrointestinal toxicity was found the two study arms (2.6 vs 3.3%).
In contrast to CHHiP [
18••,
19,
27] and PROFIT [
24•], HYPRO [
20,
21,
22•] concludes that hypofractionation is not non-inferior to CF, with respect to ≥grade 3 late GU toxicity.
For similar reasons to the higher toxicity seen in RTOG 0415 [
23•], the higher late toxicity in HYPRO [
20,
21,
22•] may relate to a higher BED delivered to organs at risk in the hypofractionated arm of HYPRO.
Additionally, compared to CHHiP [
18••,
19,
27], HYPRO [
20,
21,
22•] included a greater proportion of the seminal vesicles in the high-dose volume, which may account for the higher late toxicity. In HYPRO, patients with >10% risk of seminal vesicle involvement had their seminal vesicle included in the high-dose volume. Patients with a 10–25% probability of seminal vesicle involvement received a total dose of 70–72.15 Gy/1.85–2.0 Gy per fraction in the control arm or 54.4–57.76 Gy/3.04–3.4 Gy per fraction in the hypofractionated arm. For patients with a >25% risk of seminal vesicle involvement, the seminal vesicles were treated to the full dose of 78 Gy or 64.6 Gy in each respective arm. By contrast, in CHHiP [
18••,
19,
27], patients with >15% risk of seminal vesicle involvement received 96% of the prescribed dose to the base of the seminal vesicles, and 80% of the prescribed dose to the seminal vesicles, within each arm.
The outcome of HYPRO [
20,
21,
22•] is in keeping with other superiority hypofractionation trials, which did not demonstrate an improvement in efficacy outcomes with hypofractionation. Assuming α/β ratio of 1.5 Gy for PCa, the 2 Gy equivalent dose in the hypofractionated arm of HYPRO is 90.4 Gy. This dose escalation, over the control arm of 78 Gy/39 fractions, may have been expected to have resulted in a significant improvement in biochemical control. Its failure to do so may relate to the longer duration over which treatment was delivered (6.5 weeks), compared to other hypofractionation schedules.