Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial

doi:10.1016/S1470-2045(16)30070-5

The Lancet Oncology

Volume 17, Issue 8, August 2016, Pages 1061-1069

https://doi.org/10.1016/S1470-2045(16)30070-5 Get rights and content

Summary

Background

Studies have reported a low α/β ratio for prostate cancer, suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity. In the multicentre phase 3, HYpofractionated irradiation for PROstate cancer (HYPRO) trial, hypofractionated radiotherapy was compared with conventionally fractionated radiotherapy for treatment of prostate cancer. We have previously reported acute and late incidence of genitourinary and gastrointestinal toxicity; here we report protocol-defined 5-year relapse-free survival outcomes.

Methods

We did an open-label, randomised, phase 3 trial at seven Dutch radiotherapy centres. We enrolled patients with intermediate-risk to high-risk T1b–T4NX–N0MX–M0 localised prostate cancer, a prostate-specific antigen concentration of 60 μg/L or less, and a WHO performance status of 0–2. We used a web-based application to randomly assign (1:1) patients to either hypofractionated radiotherapy of 64·6 Gy (19 fractions of 3·4 Gy, three fractions per week) or conventionally fractionated radiotherapy of 78·0 Gy (39 fractions of 2·0 Gy, five fractions per week). Based on an estimated α/β ratio for prostate cancer of 1·5 Gy, the equivalent total dose in fractions of 2·0 Gy was 90·4 Gy for hypofractionation compared with 78·0 Gy for conventional fractionation. The primary endpoint was relapse-free survival. All analyses were done on an intention-to-treat basis in all eligible patients. The HYPRO trial completed recruitment in 2010 and follow-up is ongoing. This trial is registered with ISRCTN, number ISRCTN85138529.

Findings

Between March 19, 2007, and Dec 3, 2010, 820 patients were enrolled, of whom 804 were eligible and assessable for intention-to-treat analyses. Of these, 407 were assigned hypofractionated radiotherapy and 397 were allocated conventionally fractionated radiotherapy. 537 (67%) of 804 patients received concomitant androgen deprivation therapy for a median duration of 32 months (IQR 10–44). Median follow-up was 60 months (IQR 51–69). Treatment failure was reported in 169 (21%) of 804 patients, 80 (20%) in the hypofractionation group and 89 (22%) in the conventional fractionation group. 5-year relapse-free survival was 80·5% (95% CI 75·7–84·4) for patients assigned hypofractionation and 77·1% (71·9–81·5) for those allocated conventional fractionation (adjusted hazard radio 0·86, 95% CI 0·63–1·16; log-rank p=0·36). There were no treatment-related deaths.

Interpretation

Hypofractionated radiotherapy was not superior to conventional radiotherapy with respect to 5-year relapse-free survival. Our hypofractionated radiotherapy regimen cannot be regarded as the new standard of care for patients with intermediate-risk or high-risk prostate cancer.

Funding

Dutch Cancer Society.

Introduction

Dose-escalated external beam radiotherapy significantly improves relapse-free survival compared with treatment doses of 72·0 Gy and lower in patients with localised prostate cancer.1, 2, 3 Treatment up to 78·0 Gy in 39 fractions of 2·0 Gy has been introduced widely in the Netherlands after findings of a dose-escalation trial¹ showed superior results with that schedule compared with 34 fractions of 2·0 Gy. The associated increase in radiation-induced toxic effects, however, restricts options for further dose escalation using conventional fractionation.2, 3, 4 Radiobiological models suggesting a low α/β ratio for prostate cancer have sparked interest in hypofractionation as a means to increase the radiobiological tumour dose without increasing treatment-induced toxic effects.5, 6, 7, 8 Moreover, hypofractionated radiotherapy is delivered in fewer fractions, improving patients' convenience, hospital logistics, and possibly reducing health-care costs.

Between 2007 and 2010, the HYpofractionated irradiation for PROstate cancer (HYPRO) trial—a randomised, phase 3, multicentre trial for intermediate-risk and high-risk localised prostate cancer—was conducted in the Netherlands to investigate whether hypofractionated external beam radiotherapy (19 fractions of 3·4 Gy) improves relapse-free survival without increasing toxic effects, compared with conventionally fractionated radiotherapy (39 fractions of 2·0 Gy). The hypofractionated regimen was chosen based on the assumption of an α/β ratio for prostate cancer of 1·5 Gy,7, 8 achieving dose escalation in 2·0 Gy fractions of 12·4 Gy up to an equivalent total dose of 90·4 Gy in 2·0 Gy fractions for hypofractionated treatment. We have previously reported the acute and late toxicity results from this trial; the postulated non-inferiority of hypofractionation compared with conventional fractionation was not shown.9, 10 Here, we present prespecified relapse-free survival outcomes after 5 years.

Research in context

Evidence before this study

We searched PubMed between Jan 1, 2000, and Dec 31, 2006, when the HYPRO trial design was completed, with the terms “prostate” AND (“randomized trial” OR “randomised trial”) AND (“hypofractionated” OR “hypofractionation”). We retrieved published reports of three randomised phase 3 trials, mostly of low radiotherapy treatment doses by current standards. The suggested low α/β ratio for prostate cancer clearly showed a need for additional, large, randomised hypofractionation trials to test the predicted increase in radiobiological tumour dose using hypofractionated radiotherapy. The aim of the HYPRO trial was to show superiority of hypofractionation compared with conventional fractionation in terms of relapse-free survival.

Added value of this study

The hypofractionated treatment regimen used in this trial (19 fractions of 3·4 Gy) was not superior to conventional treatment (39 fractions of 2·0 Gy) with respect to relapse-free survival. The postulated superiority of hypofractionation was based on calculations with the linear quadratic model, assuming an α/β ratio for prostate cancer of 1·5 Gy. Results of the HYPRO trial accord with those of other studies and, therefore, raise questions about the actual α/β ratio for prostate cancer, which might be higher than originally predicted. However, frequent use of long-term (>12 months) androgen deprivation therapy could have obscured potential differences between both treatment regimens.

Implications of all available evidence

Hypofractionated treatment with 19 fractions of 3·4 Gy cannot be regarded as the standard of care for patients with intermediate-risk and high-risk prostate cancer. Hypofractionation could be offered to selected patients with few genitourinary and gastrointestinal baseline complaints based on our previously published acute and late toxicity results. Prolonged follow-up of the HYPRO trial results and those of other large randomised trials is needed to define further the role of hypofractionation for prostate cancer in clinical practice.

Section snippets

Study design and participants

We did an open-label, randomised, phase 3 trial at seven radiotherapy centres in the Netherlands (appendix p 1). We recruited patients aged 44–85 years with histologically confirmed stage T1b–T4NX–N0MX–M0 localised prostate cancer,¹¹ an initial prostate-specific antigen (PSA) concentration of 60 μg/L or lower, and a WHO performance status of 0–2.⁹ Patients with low-risk disease (stage T1b–T2a, Gleason score ≤6, or PSA <10 μg/L), according to the single-factor definition proposed by Chism and

Results

Between March 19, 2007, and Dec 3, 2010, 820 patients were randomised to radiotherapy with hypofractionation (n=410) or conventional fractionation (n=410). The median time from randomisation to start of treatment was 34 days (IQR 22–49). Among the 820 registered patients, 16 (2%) were not eligible for the study (three allocated hypofractionation and 13 assigned conventional fractionation) and, therefore, they were excluded from the intention-to-treat analysis of relapse-free survival (figure 1

Discussion

The findings of our phase 3 trial provide no evidence for the postulated superiority of hypofractionated radiotherapy over conventional fractionation in terms of relapse-free survival in patients with intermediate-risk and high-risk localised prostate cancer. Assuming an α/β ratio for prostate cancer of 1·5 Gy,7, 8 we calculated that hypofractionated radiotherapy would result in a dose escalation to the equivalent of 12·4 Gy in 2·0 Gy fractions. We postulated that this dose escalation would

References (25)

DP Dearnaley et al.
Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial
Lancet Oncol
(2007)
A Pollack et al.
Prostate cancer radiation dose response: results of the M D Anderson phase III randomized trial
Int J Radiat Oncol Biol Phys
(2002)
ST Peeters et al.
Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy
Int J Radiat Oncol Biol Phys
(2005)
R Miralbell et al.
Dose-fractionation sensitivity of prostate cancer deduced from radiotherapy outcomes of 5 969 patients in seven international institutional datasets: alpha/beta=1·4 (0·9–2·2) Gy
Int J Radiat Oncol Biol Phys
(2012)
DJ Brenner et al.
Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue
Int J Radiat Oncol Biol Phys
(2002)
S Aluwini et al.
Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): acute toxicity results from a randomised non-inferiority phase 3 trial
Lancet Oncol
(2015)
S Aluwini et al.
Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial
Lancet Oncol
(2016)
DB Chism et al.
A comparison of the single and double factor high-risk models for risk assignment of prostate cancer treated with 3D conformal radiotherapy
Int J Radiat Oncol Biol Phys
(2004)
AW Partin et al.
Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium
Urology
(2001)
M Roach et al.
Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference
Int J Radiat Oncol Biol Phys
(2006)

G Arcangeli et al.

A prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer

Int J Radiat Oncol Biol Phys

(2010)

S Arcangeli et al.

Updated results and patterns of failure in a randomized hypofractionation trial for high-risk prostate cancer

Int J Radiat Oncol Biol Phys

(2012)

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^†: Contributed equally

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ArticlesHypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Lancet Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Lancet Oncol

Lancet Oncol

Int J Radiat Oncol Biol Phys

Urology

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Articles
Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial