Hypofractionation for prostate cancer: tested and proven
Authors: W Robert Lee
Journal: The Lancet Oncology (2016)

In The Lancet Oncology, results of two randomised phase 3 trials of hypofractionation—ie, fewer, larger, daily fractions of radiotherapeutic treatment—for prostate cancer are reported.1Dearnaley D Syndikus I Mossop H et al.on behalf of the CHHiP InvestigatorsConventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial.Lancet Oncol. 2016; (published online June 20.)http://dx.doi.org/http://dx.doi.org/10.1016/S1470-2045(16)30102-4Google Scholar, 2Incrocci L Wortel RC Alemayehu WG et al.Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial.Lancet Oncol. 2016; (published online June 20.)http://dx.doi.org/http://dx.doi.org/10.1016/S1470-2045(16)30070-5Google Scholar In the final results from the Conventional or Hypofractionated High-dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial, David Dearnaley and colleagues advocate for hypofractionation,1Dearnaley D Syndikus I Mossop H et al.on behalf of the CHHiP InvestigatorsConventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial.Lancet Oncol. 2016; (published online June 20.)http://dx.doi.org/http://dx.doi.org/10.1016/S1470-2045(16)30102-4Google Scholar whereas in the final results from the Hypofractionated Irradiation for Prostate cancer (HYPRO) trial, Luca Incrocci and colleagues recommend that hypofractionation not be adopted.2Incrocci L Wortel RC Alemayehu WG et al.Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial.Lancet Oncol. 2016; (published online June 20.)http://dx.doi.org/http://dx.doi.org/10.1016/S1470-2045(16)30070-5Google Scholar How can we explain this apparent discordance? The short explanation is that the two trials have different hypotheses. What is the rationale for hypofractionation in prostate cancer? In 1999, Brenner and Hall claimed that the fractionation sensitivity of prostate cancer was such that “appropriately designed hypofractionation schemes would be expected to maintain current levels of tumor control and late sequelae…with the logistical and financial advantages of fewer numbers of fractions”.3Brenner DJ Hall EJ Fractionation and protraction for radiotherapy of prostate carcinoma.Int J Radiat Oncol Biol Phys. 1999; 43: 1095-1101Summary Full Text Full Text PDF PubMed Scopus (799) Google Scholar As a result, investigators across the globe designed prospective trials to test the hypofractionation hypothesis in prostate cancer. Trials took two forms depending on the nature of the hypothesis: a superiority design or a non-inferiority design. Some investigators postulated that hypofractionation would increase efficacy compared with conventional fractionation, which in retrospect was an overinterpretation of Brenner and Hall's paper. Hypofractionation has not been proven superior to conventional fractionation in any superiority trial to date.4Arcangeli S Strigari L Gomellini S 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; 84: 1172-1178Summary Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 5Pollack A Walker G Horwitz EM et al.Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer.J Clin Oncol. 2013; 31: 3860-3868Crossref PubMed Scopus (372) Google Scholar HYPRO is the largest of the published superiority trials (n=804).2Incrocci L Wortel RC Alemayehu WG et al.Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial.Lancet Oncol. 2016; (published online June 20.)http://dx.doi.org/http://dx.doi.org/10.1016/S1470-2045(16)30070-5Google Scholar The primary hypothesis was that hypofractionation (19 fractions of 3·4 Gy, three fractions per week) would increase 5-year relapse-free survival by 10%, from 70% to 80%, compared with conventional fractionation (39 fractions of 2·0 Gy, five fractions per week). HYPRO enrolled men with intermediate-risk and high-risk disease, although most patients were high risk (>70%). After a median follow-up of 60 months (IQR 51–69), Incrocci and colleagues reported 5-year relapse-free survival of 80·5% (95% CI 75·7–84·4) in patients allocated hypofractionation and 77·1% (71·9–81·5) in individuals assigned conventional fractionation (adjusted hazard ratio [HR] 0·86, 95% CI 0·63–1·16; plogrank=0·36).2Incrocci L Wortel RC Alemayehu WG et al.Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial.Lancet Oncol. 2016; (published online June 20.)http://dx.doi.org/http://dx.doi.org/10.1016/S1470-2045(16)30070-5Google Scholar Their conclusion is in keeping with all previous superiority trials; simply put, the evidence to date does not support the notion that moderately hypofractionated radiotherapy results in improved efficacy. The increase in acute6Aluwini S Pos F Schimmel E 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; 16: 274-283Summary Full Text Full Text PDF PubMed Scopus (126) Google Scholar and late7Aluwini S Pos F Schimmel E 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; 17: 464-474Summary Full Text Full Text PDF PubMed Scopus (182) Google Scholar gastrointestinal and genitourinary toxic effects recorded with the hypofractionation regimen used in HYPRO should temper enthusiasm for this fractionation schedule. Other, perhaps more cautious, investigators designed trials with a non-inferiority hypothesis. Specifically, these trials investigated whether moderately hypofractionated radiotherapy was not worse than conventionally fractionated radiotherapy regarding relapse-free survival. CHHiP is a large (n=3216), three-arm, non-inferiority trial comparing two hypofractionation regimens (60·0 Gy delivered as 20 fractions of 3·0 Gy, five fractions per week; and 57·0 Gy delivered as 19 fractions of 3·0 Gy, five fractions per week) with a conventionally fractionated regimen (74·0 Gy as 37 fractions of 2·0 Gy, five fractions per week).1Dearnaley D Syndikus I Mossop H et al.on behalf of the CHHiP InvestigatorsConventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial.Lancet Oncol. 2016; (published online June 20.)http://dx.doi.org/http://dx.doi.org/10.1016/S1470-2045(16)30102-4Google Scholar Most patients enrolled in CHHiP had low-risk or intermediate-risk disease, although 12% had high-risk disease. After a median follow-up of 62·4 months (IQR 53·9–77·0), 5-year biochemical or clinical failure-free rates were 90·6% (95% CI 88·5–92·3) in patients allocated the 60·0 Gy hypofractionation schedule compared with 85·9% (83·4–88·0) in those assigned the 57·0 Gy hypofractionation schedule and 88·3% (86·0–90·2) in those allocated conventional fractionation. The critical HR for non-inferiority was 1·208. The 60·0 Gy hypofractionation schedule was judged non-inferior to the conventional regimen of 74·0 Gy (HR 0·84, 90% CI 0·68–1·03; pNI=0·0018); however, non-inferiority of the 57·0 Gy hypofractionation schedule could not be claimed (1·20, 0·99–1·46; pNI=0·48). Results of the non-inferiority NRG Oncology 0415 trial have also been reported.8Lee WR Dignam JJ Amin MB et al.Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer.J Clin Oncol. 2016; (published online April 4.)https://doi.org/10.1200/JCO.2016.67.0448Crossref Scopus (396) Google Scholar After a median follow-up of 5·8 years, researchers concluded that hypofractionation (28 fractions of 2·5 Gy, five fractions per week) was non-inferior to conventional fractionation (41 fractions of 1·8 Gy, five fractions per week) in men with low-risk prostate cancer (HR for the primary endpoint of 5-year disease-free survival 0·85, 95% CI 0·64–1·14), which met the predefined non-inferiority criterion (critical HR <1·52). Findings of a large non-inferiority trial of 1200 patients (PROFIT; NCT003046759), comparing 60·0 Gy hypofractionation (the same regimen as in the CHHiP trial) with 78·0 Gy conventional fractionation are awaiting publication (Catton C, Princess Margaret Cancer Centre, personal communication). It is noteworthy that the HRs for the primary endpoint in the NRG Oncology (0·85) and CHHiP (0·84) trials are similar. This consistency is noted despite the inclusion of patients with different risk groupings, varying durations of androgen suppression (ranging from none to 6 months), and diverse radiotherapy regimens. The fact that both studies report a HR below 1·0 should mitigate any concerns that hypofractionation is less effective than conventional fractionation. These findings together should reassure skeptical practitioners that hypofractionation can be introduced without a decrease in efficacy. On the other hand, the findings of the non-inferiority studies are somewhat inconsistent with respect to toxic effects. The CHHiP trial has reported extensive information relating to clinician-reported toxic effects and patient-reported outcomes. Acute toxic effects peaked sooner with hypofractionation compared with conventional fractionation, but no differences in long-term toxic effects or patient-reported outcomes9Wilkins A Mossop H Syndikus I et al.Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial.Lancet Oncol. 2015; 16: 1605-1616Summary Full Text Full Text PDF PubMed Scopus (111) Google Scholar were reported. Researchers on the NRG Oncology trial also noted a slight increase in late grade 2 gastrointestinal and genitourinary toxic effects, but no differences in severe toxic effects were recorded.8Lee WR Dignam JJ Amin MB et al.Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer.J Clin Oncol. 2016; (published online April 4.)https://doi.org/10.1200/JCO.2016.67.0448Crossref Scopus (396) Google Scholar The observation of increased late toxic effects is perhaps not surprising, because the biological effective dose of the hypofractionated regimen in NRG Oncology 0415 (128·0 Gy) is slightly greater than that of the hypofractionated regimen in CHHiP (120·0 Gy), assuming the α/β ratio of rectum and bladder to be 3·0 Gy. To put these results into context, it is important to acknowledge that there are several other radiotherapeutic approaches currently in use for men with low-risk and intermediate-risk prostate cancer, including brachytherapy (low-dose rate and high-dose rate), and active surveillance in selected patients. More germane is the use of extreme hypofractionation schedules or stereotactic body radiotherapy. Preliminary results of extreme hypofractionation schedules (four or five fractions of 7·0–10·0 Gy) have been reported,10King CR Freeman D Kaplan I et al.Stereotactic body radiotherapy for localized prostate cancer: pooled analysis from a multi-institutional consortium of prospective phase II trials.Radiother Oncol. 2013; 109: 217-221Summary Full Text Full Text PDF PubMed Scopus (345) Google Scholar but no data from randomised trials of stereotactic body radiotherapy have been published up to now. In one randomised trial (ISRCTN45905321), 39 fractions of 2·0 Gy were compared with seven fractions of 6·1 Gy. Although not technically stereotactic body radiotherapy, this trial is probably the closest comparison of extreme hypofractionation with conventional fractionation that we will have in the short term. Evidence to support stereotactic body radiotherapy is growing but remains weak (in quality and quantity) compared with more moderate hypofractionation schedules. In view of these reports, should radiation oncologists routinely abandon conventional fractionation and move to hypofractionation? I do not think so; I agree with the HYPRO investigators that the hypofractionation regimen used in their study (19 fractions of 3·4 Gy) should not be adopted. On the other hand, the results from NRG Oncology 04158Lee WR Dignam JJ Amin MB et al.Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer.J Clin Oncol. 2016; (published online April 4.)https://doi.org/10.1200/JCO.2016.67.0448Crossref Scopus (396) Google Scholar and CHHiP1Dearnaley D Syndikus I Mossop H et al.on behalf of the CHHiP InvestigatorsConventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial.Lancet Oncol. 2016; (published online June 20.)http://dx.doi.org/http://dx.doi.org/10.1016/S1470-2045(16)30102-4Google Scholar suggest that hypofractionation will not result in any loss of efficacy and could make treatment less expensive and more convenient for patients when compared with conventionally fractionated radiotherapy. The NRG Oncology trial investigators did note a slight increase in clinician-reported grade 2 gastrointestinal and genitourinary toxic effects, and practitioners might use this finding as justification not to adopt this particular hypofractionation schedule, particularly in patients with large prostates or clinically significant pre-existing urinary dysfunction. I expect that future ancillary analyses of the NRG Oncology study will define the appropriate dose constraints to keep grade 2 gastrointestinal and genitourinary toxic effects low, as we learned with dose-escalation studies of conventional fractionation. Excess toxic effects, however, were not recorded with 60·0 Gy in 20 fractions in the CHHiP trial;1Dearnaley D Syndikus I Mossop H et al.on behalf of the CHHiP InvestigatorsConventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial.Lancet Oncol. 2016; (published online June 20.)http://dx.doi.org/http://dx.doi.org/10.1016/S1470-2045(16)30102-4Google Scholar the results of the PROFIT trial will provide more information on the 4-week schedule. For practitioners interested in judicious use of resources and patients' convenience, this regimen can be presented confidently and discussed with patients as an alternative to conventional fractionation. I declare no competing interests. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trialHypofractionated 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. Full-Text PDF Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trialHypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer. Full-Text PDF Open Access