Hypofractionation for prostate cancer and PROs
Authors: Michel Bolla
Journal: The Lancet Oncology (2015)

In the non-inferiority CHHiP trial, 3216 patients underwent intensity-modulated radiotherapy for localised prostate cancer. The study compared conventional fractionation at a dose of 74 Gy in 37 fractions, previously assessed in the RT01 trial,1Dearnaley DP Sydes MR Graham JD et al.Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer; first results from MRC RT01 randomized controlled trial.Lancet Oncol. 2007; 20: 475-487Summary Full Text Full Text PDF Scopus (765) Google Scholar with two moderately hypofractionated schedules: 60 Gy in 20 fractions and 57 Gy in 19 fractions, with fractions of 3 Gy per day. The quality-of-life (QoL) substudy by Anna Wilkins and colleagues2Wilkins A Mossop H Syndikus I et al.Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer assessed with patient-reported outcomes: 2-year follow up of the randomised, non-inferiority, phase 3 CHHiP trial.Lancet Oncol. 2015; (published online Oct 28.)http://dx.doi.org/10.1016/S1470-2045(15)00280-6PubMed Google Scholar describes the patient-reported outcomes (PROs) of 2100 patients, which were assessed with several QoL instruments. The incidence of bowel and urinary symptoms were low and similar in the control and hypofractionated groups up to 24 months of follow-up, with no differences with respect to time-to-event analysis of small or worse overall bowel, urinary, and sexual bother. Intensity-modulated radiotherapy is a high-precision external beam radiotherapy approach that is regarded as the gold standard for the treatment of localised prostate cancer.3European Association of UrologyGuidelines on prostate cancer. European Association of Urology, Arnhem2015Google Scholar Intensity modulation has offered the opportunity to launch phase 3 randomised trials to investigate whether overall treatment times can be reduced by increasing the dose per fraction, without increasing acute and late toxic effects, and while maintaining quality of life for patients. Prostate cancer has a low cell renewal rate;4Khoo V Pollack A Cowen D et al.Relationship of Ki-67 labeling index to DNA-ploidy, S-phase fraction, and outcome in prostate cancer treated with radiotherapy.Prostate. 1999; 41: 166-172Crossref PubMed Scopus (42) Google Scholar its low α/β ratio, about 1·4,5Miralbell R Roberts SA Zubizarreta E Hendry JH Dose-fractionation sensitivity of prostate cancer deduced from radiotherapy outcomes of 5,969 patients in seven international institutional datasets: α/β = 1.4 (0.9-2.2) Gy.Int J Radiat Oncol Biol Phys. 2012; 82: e17-e24Summary Full Text Full Text PDF PubMed Scopus (382) Google Scholar describes the association between the delivered dose and the clinical response. Such a ratio enables radiation oncologists to choose a hypofractionation regimen that is biologically equivalent to a conventional fractionation treatment with 2 Gy per fraction. Hence, prostate cancer is expected to have a greater sensitivity to the higher dose per fraction (2·5–4·0 Gy) offered by moderate hypofractionation. An interim analysis of the CHHiP trial6Dearnaley D Syndicus I Sumo G et al.Conventional versus hypofractionated high dose intensity-modulated radiotherapy for prostate cancer: preliminary safety results from the CHHiP randomised controlled trial.Lancet Oncol. 2012; 13: 43-54Summary Full Text Full Text PDF PubMed Scopus (242) Google Scholar that included 457 patients reported no difference between treatment groups in the proportion of patients with grade 2 or higher gastrointestinal or bladder toxic effects. The trial had a comprehensive methodology and strict radiotherapy quality assurance with appropriate dose constraints, and is the first to report quality of life with PROs in such a large population. However, a few points should be raised. The inclusion of high-risk prostate cancer is controversial because pelvic lymph node irradiation is needed for such cases, which might be harmful if delivered by hypofractionation because of the radiosensitivity of the small bowel. The dose used in the control group (74 Gy) would usually be regarded as an intermediate dose: a high dose would typically fall in the range of 78–80 Gy. High-risk prostate cancer requires a longer duration of androgen deprivation therapy compared with lower risk forms: 2–3 years rather than 3–6 months.7Bolla M de Reijke TM Van Tienhoven G et al.Duration of androgen suppression in the treatment of prostate cancer.N Engl J Med. 2009; 360: 2516-2527Crossref PubMed Scopus (753) Google Scholar As mentioned by the authors,2Wilkins A Mossop H Syndikus I et al.Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer assessed with patient-reported outcomes: 2-year follow up of the randomised, non-inferiority, phase 3 CHHiP trial.Lancet Oncol. 2015; (published online Oct 28.)http://dx.doi.org/10.1016/S1470-2045(15)00280-6PubMed Google Scholar radiotherapy-related toxic effects, particularly faecal incontinence, rectal bleeding, and use of urinary pads, were likely to be underestimated because of the use of different QoL instruments. The results of the QoL substudy support the superiority of intensity-modulated radiotherapy compared with conformal external beam radiotherapy. In both the CHHiP and RT01 trials, the intensity-modulated schedules show significantly fewer adverse gastrointestinal events compared with the 74 Gy schedules.8Syndikus I Morgan RC Sydes MR et al.Late gastrointestinal toxicity after dose-escalated conformal radiotherapy for early prostate cancer: results from the UK Medical Research Council RT01 trial (ISRCTN47772397).Int J Radiat Oncol Phys. 2010; 77: 773-783Summary Full Text Full Text PDF PubMed Scopus (69) Google Scholar Other phase 3 randomised trials have investigated moderate hypofractionation for localised prostate cancer, but these were done with different techniques and sometimes had no comprehensive health-related QoL assessments: a systematic review9Koontz BF Bossi A Cozzarini C Wiegel T D'Amico A Systematic review of hypofractionation for primary management of prostate cancer.Eur Urol. 2015; 68: 683-691Summary Full Text Full Text PDF PubMed Scopus (81) Google Scholar of these studies supports the safety of moderate hypofractionation but also emphasises the scarcity of data about long-term efficacy. In oncology, treatment choices are based on efficacy, toxic effects, patient quality of life, and finally treatment costs (once the other parameters have been met). Before moderate hypofractionation can be recommended in daily practice for low-risk and intermediate-risk prostate cancer,10D'Amico AV Whittington R Malkowicz SB et al.Biochemical outcome after radical prostatectomy external beam radiation therapy or interstitial radiation therapy for clinically localized prostate cancer.JAMA. 1998; 280: 969-974Crossref PubMed Scopus (3674) Google Scholar mature data from the CHHiP trial are needed (showing the non-inferiority of hypofractionated regimens and 5-year urinary, bowel, and sexual adverse event data), as are results from trials such as the Radiation Therapy Oncology Group 0415 trial and the PROFIT trial from the Ontario Clinical Oncology Group. If moderate hypofractionation is non-inferior to fractionated intensity-modulated radiotherapy, this approach could be more convenient for patients, improve access to treatment, and might reduce treatments costs. In the near future, the use of hypofractionation will face other challenges, including whether moderate hypofractionation can be combined with brachytherapy, and the advent of extreme hypofractionation (5–10 Gy in four to seven fractions). Such approaches will have to be managed within the framework of clinical research, with careful estimation of each patient's comorbidities and their gastrointestinal and genitourinary function, as assessed with the International Prostate Symptom Score and uroflowmetry recordings. Treatment delivery can be improved with image-guided radiotherapy, with strict quality assurance to avoid compromising a potential salvage treatment in case of local relapse. I declare no competing interests. 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 trialThe incidence of patient-reported bowel symptoms was low and similar between patients in the 74 Gy control group and the hypofractionated groups up to 24 months after radiotherapy. If efficacy outcomes from CHHiP show non-inferiority for hypofractionated treatments, these findings will add to the growing evidence for moderately hypofractionated radiotherapy schedules becoming the standard treatment for localised prostate cancer. Full-Text PDF Open Access