Ultrahypofractionation Should be a Standard of Care Option for Intermediate-Risk Prostate Cancer

Abstract

The American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO) and American Urological Association (AUA) hypofractionation guideline defines moderate hypofractionation as 2.4–3.4 Gy/day and ultrahypofractionated (UHF) radiotherapy as doses per treatment of 5.0 Gy/day or higher [[1]Morgan S.C. Hoffman K. Loblaw D.A. Buyyounouski M.K. Patton C. Barocas D. et al.Hypofractionated radiation therapy for localized prostate cancer: an ASTRO, ASCO, and AUA evidence-based guideline.J Clin Oncol. 2018; 36: 3411-3430Crossref Scopus (91) Google Scholar]. According to that guideline, in men with low-risk prostate cancer who decline active surveillance and choose active treatment with external beam radiotherapy (EBRT), UHF may be offered as an alternative to conventional fractionation (Key Question 3A) [[1]Morgan S.C. Hoffman K. Loblaw D.A. Buyyounouski M.K. Patton C. Barocas D. et al.Hypofractionated radiation therapy for localized prostate cancer: an ASTRO, ASCO, and AUA evidence-based guideline.J Clin Oncol. 2018; 36: 3411-3430Crossref Scopus (91) Google Scholar]. In men with intermediate-risk prostate cancer receiving EBRT, UHF may be offered as an alternative to conventional fractionation (Key Question 3B). However, the joint society task force strongly encouraged that these patients be treated as part of a clinical trial or multi-institutional registry. Since the literature search cut-off date for the guideline of January 2017, important prospective datasets (including three randomised studies) have been presented and/or published. In this special issue of Clinical Oncology, experts in hypofractionation debate whether UHF should be a standard of care option for intermediate-risk prostate cancer. According to the ASCO/Cancer Care Ontario guidelines, brachytherapy should be offered to all eligible men with intermediate-risk prostate cancer [[2]Chin J. Rumble R.B. Kollmeier M. Heath E. Efstathiou J. Dorff T. et al.Brachytherapy for patients with prostate cancer: American Society of Clinical Oncology/Cancer Care Ontario joint guideline update.J Clin Oncol. 2017; 35: 1737-1743Crossref PubMed Scopus (106) Google Scholar]. This recommendation was on the basis of three published randomised controlled trials (RCTs) showing that brachytherapy + EBRT ± androgen deprivation therapy (ADT) had superior biochemical disease-free survival (bDFS) [3Hoskin P.J. Rojas A.M. Bownes P.J. Lowe G.J. Ostler P.J. Bryant L. Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer.Radiother Oncol. 2012; 103: 217-222Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar, 4Morris W.J. Tyldesley S. Rodda S. Halperin R. Pai H. McKenzie M. et al.ASCENDE-RT: an analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high- and intermediate-risk prostate cancer.Int J Radiat Oncol Biol Phys. 2017; 98: 275-285Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar, 5Sathya J.R. Davis I.R. Julian J.A. Guo Q. Daya D. Dayes I.S. et al.Randomized trial comparing iridium implant plus external-beam radiation therapy with external-beam radiation therapy alone in node-negative locally advanced cancer of the prostate.J Clin Oncol. 2005; 23: 1192-1199Crossref PubMed Scopus (336) Google Scholar]. However, brachytherapy (either as monotherapy or as a boost) has been recognised as a standard of care option since the mid–1990s, based mainly on retrospective single-institutional reviews showing excellent medium-to long-term bDFS [[6]Crook J. Long-term oncologic outcomes of radical prostatectomy compared with brachytherapy-based approaches for intermediate- and high-risk prostate cancer.Brachytherapy. 2015; 14: 142-147Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar]. One of the early studies suggesting that prostate cancer had a low α:β ratio was based on a high dose rate (HDR) boost series (either two or three HDR implants + 23–25 fractions of EBRT) [[7]Brenner D.J. Martinez A.A. Edmundson G.K. Mitchell C. Thames H.D. Armour E.P. 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; 52: 6-13Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar]. Their estimate of the α:β ratio based on this dataset was 1.2. Many publications have sought to refine the α:β ratio for prostate cancer since. One of the largest, published by Miralbell et al. [[8]Miralbell R. Roberts S.A. Zubizarreta E. Hendry J.H. 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-e24Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar], included 5969 patients with dose/fraction ranging from 1.8 to 6.7 Gy given in five to 39 fractions [[8]Miralbell R. Roberts S.A. Zubizarreta E. Hendry J.H. 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-e24Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar]. The Miralbell estimate of the α:β ratio was 1.4, supporting the validity of the linear quadratic model for treatments with as few as five fractions (i.e. UHF). It is, however, necessary, but not sufficient, that the linear quadratic model supports UHF to accept UHF as a standard of care. The first prospective study of UHF EBRT (33.25 Gy in five fractions over 1 week) was activated in 2000 and published in 2007 with a median follow-up of 41 months. All of these patients (n = 40) had low-risk prostate cancer [[9]Madsen B.L. Hsi R.A. Pham H.T. Fowler J.F. Esagui L. Corman J. Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five fractions for localized disease: first clinical trial results.Int J Radiat Oncol Biol Phys. 2007; 67: 1099-1105Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar]. The ASTRO/ASCO/AUA guideline identified six prospective studies with a median follow-up of at least 48 months [[1]Morgan S.C. Hoffman K. Loblaw D.A. Buyyounouski M.K. Patton C. Barocas D. et al.Hypofractionated radiation therapy for localized prostate cancer: an ASTRO, ASCO, and AUA evidence-based guideline.J Clin Oncol. 2018; 36: 3411-3430Crossref Scopus (91) Google Scholar]. There were 532 patients in total, but 80% of those had low-risk disease. The treatment was well tolerated, with a weighted average of 0.6% and 1.2% acute grade 3 + gastrointestinal and genitourinary toxicities and 2.6% and 3.0% late grade 3 + gastrointestinal and genitourinary toxicities, respectively. Ninety-eight per cent of patients were biochemically controlled at 5 years, similar to the low dose rate (LDR) brachytherapy series [[10]Morris W.J. Keyes M. Spadinger I. Kwan W. Liu M. McKenzie M. et al.Population-based 10-year oncologic outcomes after low-dose-rate brachytherapy for low-risk and intermediate-risk prostate cancer.Cancer. 2013; 119: 1537-1546Crossref PubMed Scopus (95) Google Scholar]. Loblaw et al. [[11]Loblaw A. Pickles T. Crook J. Martin A.-G. Vigneault E. Souhami L. et al.Stereotactic ablative radiotherapy versus low dose rate brachytherapy or external beam radiotherapy: propensity score matched analyses of Canadian data.Clin Oncol. 2017; 29: 161-170Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] combined their initial stereotactic ablative body radiotherapy (SABR) experience with the Genitourinary Radiation Oncologists of Canada PROCARS EBRT and brachytherapy database. Six hundred and two patients with low-risk prostate cancer from five high volume Canadian centres were identified. Patients were treated with UHF using SABR 35 Gy in five fractions over 29 days (n = 80), LDR brachytherapy 144–145 Gy (n = 458) or EBRT (74–79.8 Gy in 37–42 fractions over 7.5–8.5 weeks). The median follow-up was >60 months for all patients. There were no significant differences in bDFS before or after matching for SABR versus LDR. For SABR versus EBRT, SABR had a bDFS trend before matching (P = 0.08), which became significant after matching (P < 0.001). It was notable that the prostate-specific antigen (PSA) nadir was lower after LDR versus SABR (0.05 versus 0.47 ng/ml, P < 0.001) but our group subsequently showed that 40 Gy in five fractions (equivalent biological dose to 2 Gy per day or EQD2 = 110 Gy) yielded PSA nadirs of 0.1 ng/ml, more comparable with brachytherapy nadirs [[12]Alayed Y. Cheung P. Pang G. Mamedov A. D'Alimonte L. Deabreu A. et al.Dose escalation for prostate stereotactic ablative radiotherapy (SABR): late outcomes from two prospective clinical trials.Radiother Oncol. 2018; 127: 213-218Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar]. Although one can be reassured of the low toxicity rates in low-risk patients receiving UHF, active surveillance is the current standard for low-risk prostate cancer according to ASCO and Cancer Care Ontario [[13]Chen R.C. Rumble R.B. Loblaw D.A. Finelli A. Ehdaie B. Cooperberg M.R. et al.Active surveillance for the management of localized prostate cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline endorsement.J Clin Oncol. 2016; 34: 2182-2190Crossref PubMed Scopus (230) Google Scholar,[14]Morash C. Tey R. Agbassi C. Klotz L. McGowan T. Srigley J. et al.Active surveillance for the management of localized prostate cancer: guideline recommendations.Can Urol Assoc J. 2015; 9: 171Crossref PubMed Scopus (143) Google Scholar]. Therefore, UHF would be considered overtreatment for most of these patients. It is reasonable to ask what the oncological outcomes are for intermediate-risk patients. Published after the ASTRO/ASCO/AUA guidelines, Kishan et al. [[15]Kishan A.U. Dang A. Katz A.J. Mantz C.A. Collins S.P. Aghdam N. et al.Long-term outcomes of stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer.JAMA Netw Open. 2019; 2e188006Crossref PubMed Scopus (152) Google Scholar] summarised the medium-term outcomes of 2142 patients treated with SABR (69% robotic arm-mounted and 31% gantry-mounted linear accelerator) from 10 single-institutional phase II prospective studies and two multi-institutional prospective studies [[15]Kishan A.U. Dang A. Katz A.J. Mantz C.A. Collins S.P. Aghdam N. et al.Long-term outcomes of stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer.JAMA Netw Open. 2019; 2e188006Crossref PubMed Scopus (152) Google Scholar]. The median follow-up in this series was 83 months, with 297 patients having over 9 years of follow-up. The 7-year biochemical failure rate was 10.2% for intermediate-risk patients (only 5.4% received short-term ADT). In the Martell et al. [[35]Martell K. Mendez L.C. Chung H.T. Tseng C.L. Alayed Y. Cheung P. et al.Results of 15 Gy HDR-BT boost plus EBRT in intermediate-risk prostate cancer: Analysis of over 500 patients.Int J Rad Onc Biol Phys. 2019; https://doi.org/10.1016/j.radonc.2019.08.017Abstract Full Text Full Text PDF Scopus (26) Google Scholar] HDR boost series of intermediate-risk patients (no ADT), the 7-year bDFS was 90.8% [[16]Helou J. D'Alimonte L.D. Loblaw A. Chung H. Cheung P. Szumacher E. et al.High dose-rate brachytherapy boost for intermediate risk prostate cancer: long-term outcomes of two different treatment schedules and early biochemical predictors of success.Radioth Oncol. 2015; 115: 84-89Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar]. In the Japanese HDR monotherapy series (between two and nine fractions of HDR), the 5-year bDFS was 94% for intermediate-risk patients (it is noted that 70% of patients also received ADT). The Kishan et al. [[15]Kishan A.U. Dang A. Katz A.J. Mantz C.A. Collins S.P. Aghdam N. et al.Long-term outcomes of stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer.JAMA Netw Open. 2019; 2e188006Crossref PubMed Scopus (152) Google Scholar] series reported even lower rates of grade 3 + gastrointestinal and genitourinary toxicities than the ASCO series: 0.1% and 0.6% acutely, 0.4% and 2.4% in late term, respectively. In sum, UHF EBRT (SABR) seemed to have similar biochemical control and toxicities compared with brachytherapy boost or brachytherapy monotherapy for intermediate-risk patients. There are no RCTs of UHF versus brachytherapy (monotherapy or boost); the only propensity matched study is mentioned above. However, it is well recognised in the guideline methodology literature that medical evidence is hierarchical and that RCTs provide more certainty about ‘the truth’ than prospective studies, even propensity matched studies. There are three RCTs (n = 4939) [17Catton C.N. Lukka H. Gu C.-S. Martin J.M. Supiot S. Chung P.W.M. et al.Randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer.J Clin Oncol. 2007; 35: 1884-1890Crossref Scopus (402) Google Scholar, 18Dearnaley D. Syndikus I. Mossop H. Khoo V. Birtle A. Bloomfield D. et al.Conventional 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; 17: 1047-1060Abstract Full Text Full Text PDF PubMed Scopus (740) Google Scholar, 19Lee W.R. Dignam J.J. Amin M.B. Bruner D.W. Low D. Swanson G.P. et al.Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer.J Clin Oncol. 2016; 34: 2325-2332Crossref PubMed Scopus (387) Google Scholar] testing the hypothesis that moderately hypofractionated EBRT is non-inferior to conventionally fractionated EBRT (1.8–2.0 Gy/fraction) and four RCTs (n = 1497) [20Aluwini S. Pos F. Schimmel E. van Lin E. Krol S. van der Toorn P.P. 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: 274-283Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 21Pollack A. Walker G. Horwitz E.M. Price R. Feigenberg S. Konski A.A. et al.Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer.J Clin Oncol. 2013; 31: 3860-3868Crossref PubMed Scopus (370) Google Scholar, 22Hoffman K.E. Voong K.R. Levy L.B. Allen P.K. Choi S. Schlembach P.J. et al.Randomized trial of hypofractionated, dose-escalated, intensity-modulated radiation therapy (IMRT) versus conventionally fractionated IMRT for localized prostate cancer.J Clin Oncol. 2018; 36: 2943-2949Crossref PubMed Scopus (32) Google Scholar, 23Arcangeli G. Saracino B. Arcangeli S. Gomellini S. Petrongari M.G. Sanguineti G. et al.Moderate hypofractionation in high-risk, organ confined prostate cancer: final results of a phase III randomized trial.J Clin Oncol. 2017; 35: 1891-1897Crossref PubMed Scopus (114) Google Scholar] testing the hypothesis that moderate hypofractionation is superior to conventional fractionation. All studies had median follow-ups > 5 years. For the outcome of bDFS, the three former studies were non-inferior and the four latter studies were negative [[1]Morgan S.C. Hoffman K. Loblaw D.A. Buyyounouski M.K. Patton C. Barocas D. et al.Hypofractionated radiation therapy for localized prostate cancer: an ASTRO, ASCO, and AUA evidence-based guideline.J Clin Oncol. 2018; 36: 3411-3430Crossref Scopus (91) Google Scholar]. These seven RCTs, and others, are consistent with the hypothesis that the α:β ratio for prostate cancer is low [[24]Vogelius I.R. Bentzen S.M. Dose response and fractionation sensitivity of prostate cancer after external beam radiation therapy: a meta-analysis of randomized trials.Int J Radiat Oncol Biol Phys. 2018; 100: 858-865Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. There are two RCTs that have been published or presented examining whether UHF is non-inferior to conventional or moderately hypofractionated (CMHRT) EBRT. The HYPO-RT-PC study randomised 1200 patients to 78 Gy in 39 fractions over 8 weeks or an UHF regimen of 42.7 in seven fractions over 2.5 weeks (EQD21.4 = 94 Gy). Eighty-nine per cent of patients were intermediate risk (11% were high risk) and 80% of the treatments were delivered using three-dimensional conformal radiation [[25]Widmark A. Gunnlaugsson A. Beckman L. Thellenberg-Karlsson C. Hoyer M. Lagerlund M. et al.Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial.Lancet. 2019; 394: 385-395Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar]. With a median follow-up of 5 years, there was no difference in failure-free survival between the two arms (hazard ratio 1.002, 95% confidence interval 0.76–1.33; the lower bound confidence interval did not cross the pre-specified hazard ratio limit of 1.338, so was non-inferior). Although there were no significant differences in acute or late grade 2 + gastrointestinal or genitourinary toxicities, there were worse patient-reported outcomes (PROs) in the acute gastrointestinal and genitourinary domains, which settled after 3 months. There may be two reasons why acute patient reported outcomes were worse than conventional fractionation in HYPO-RT-PC. As 80% of patients in the HYPO-RT-PC trial received 3-dimensional conformal radiotherapy (3D-CRT) with 7 mm clinical target volume–planning target volume (CTV–PTV) margins for patients with gold seed fiducials, it may be that more modern radiotherapy would have better acute tolerability. In the Prostate Advances in Comparative Evidence (PACE-B; NCT01584258) study, 874 low- or intermediate-risk patients were randomised to UHF (SABR 36.25 Gy in five fractions over 11 days) or CMHRT EBRT (78 Gy in 39 fractions over 8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively). Note that doses in this trial were prescribed to the PTV and all patients were treated with modern image-guided intensity modulated radiotherapy (CTV–PTV margins were 5–9 mm/3–7 mm posteriorly for conventional radiotherapy and 4–5 mm/3–5 mm posteriorly for SABR). Eight hundred and forty-nine patients (415 SABR; 432 CMHRT received at least one fraction). The worst acute Radiation Therapy Oncology Group (RTOG) grade 2 + gastrointestinal toxicity rates were 10.4% (43/415) for SABR versus 12.3% (53/432) for CMHRT (P = 0.38). The worst acute RTOG grade 2 + genitourinary toxicity rates were 23.1% (96/415) SABR versus 27.3% (118/432) for CMHRT (P = 0.16). So, even though the SABR arm in PACE-B had an equivalent EQD21.4 of 94.8 Gy and a shorter overall treatment time (OTT; 1.5 weeks for PACE-B versus 2.5 weeks for HYPO-RT-PC), there was less toxicity seen in PACE-B. Much of that difference can probably be attributed to image guidance and tighter margins. So, let us assume that all UHF in the future will be delivered using image-guided radiotherapy machines (i.e. SABR). This was also recommended in the ASTRO/ASCO/AUA hypofractionation guideline (Key Question 8A) [[1]Morgan S.C. Hoffman K. Loblaw D.A. Buyyounouski M.K. Patton C. Barocas D. et al.Hypofractionated radiation therapy for localized prostate cancer: an ASTRO, ASCO, and AUA evidence-based guideline.J Clin Oncol. 2018; 36: 3411-3430Crossref Scopus (91) Google Scholar]. However, OTT is known to affect acute toxicity. In the PATRIOT study (NCT01423474), 152 men (13%, 58%, 29% with low-, favourable intermediate- and unfavourable intermediate-risk prostate cancer) from three Canadian centres received 40 Gy in five fractions to the CTV (38 Gy to PTV) and were randomised to once weekly (OTT 29 days) versus every other day treatment (EOD; OTT 11 days). The median follow-up for the first report was 47 months [[26]Quon H.C. Ong A. Cheung P. Chu W. Chung H.T. Vesprini D. et al.Once-weekly versus every-other-day stereotactic body radiotherapy in patients with prostate cancer (PATRIOT): a phase 2 randomized trial.Radiother Oncol. 2018; 127: 206-212Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. Patients treated once weekly had superior acute bowel quality of life (QOL) with 47/69 (68%) reporting a minimally clinically important difference compared with 63/70 (90%) treated EOD (P = 0.002). Fewer patients treated once weekly reported moderate–severe problems with bowel QOL during the acute period compared with EOD (14/70 [20%] versus 40/70 [57%], P < 0.001). Acute urinary QOL was also better in the once weekly arm, with 52/67 (78%) versus 65/69 (94%) experiencing a minimally clinically important difference (P = 0.006). There were no significant differences in late urinary or bowel QOL at 2 years or last follow-up. Updated results with a median follow-up of 63 months presented at ASTRO 2019 showed no difference in late gastrointestinal or genitourinary toxicities, nadir PSA, biochemical failure or metastases rate [[27]Loblaw D.A. Quon H.C. Ong A.T. Alayed Y. Cheung P. Chu W. et al.Accelerating prostate stereotactic ablative body radiotherapy (SABR): efficacy and toxicity of a randomized phase II study of 11 versus 29 days overall treatment time (PATRIOT Study; ClinicalTrials.gov NCT01423474).Int J Radiat Oncol Biol Phys. 2019; 105: S56Abstract Full Text Full Text PDF Google Scholar]. Therefore, by offering SABR every week (versus EOD), acute toxicity and QOL may well be improved over CMHRT without compromising medium-term oncological outcomes. There are two other RCTs evaluating UHF that continue to accrue patients: HEAT (n = 456; 36.25/5 versus 70.2/28; NCT01794403) and NRG-GU005 (n = 606; 36.25/5 versus 70/28; NCT03367702). For us to conclude that UHF was inferior to CMHRT, these two studies and PACE-B would have to have dramatically worse biochemical failure rates than have been documented in any of the 2000 + prospective trials to date. Although possible, it is highly unlikely. SABR is the clear winner over CMHRT even in Canada, where the government pays for the cancer building and radiotherapy machinery in terms of cost, patient convenience/out of pocket expenses and treatment capacity. In a microcosting analysis at Sunnybrook Health Sciences Centre, five-fraction SABR cost the radiotherapy department Canadian $1716 (£1064), whereas 60 Gy in 20 fractions cost $2985 (£1852) and 78 Gy in 39 fractions cost $5254 (£3260). There are about 72 000 men diagnosed with prostate cancer in Canada and the UK each year. Even if 25% of men receive SABR instead of 60 Gy in 20 fractions, it would save radiotherapy departments Canadian $22.8 million in the two countries. If one extends these savings to the 1.3 million men diagnosed each year worldwide [[28]GLOBOCAN Prostate cancer: estimated incidence, mortality and prevalence worldwide in 2012.http://globocan.iarc.fr/old/FactSheets/cancers/prostate-new.aspDate: 2012Google Scholar], the figure becomes astronomical. One can easily see that SABR allows a department to treat four to eight times as many patients with the same radiotherapy resources; in many radiotherapy centres around the world increasing treatment capacity reduced overtime wages and wait times for patients, both critical issues for the oncological healthcare system. Using the above example, 270,000 fractions of radiotherapy could be freed up for other patients to use in Canada and the UK. Finally, we must not forget the time and cost burden that patients must endure travelling to/from cancer centres. We calculated that the cost savings of travel and parking for a five-fraction versus a 39-fraction treatment was Canadian $1930 [[29]Sethukavalan P. Cheung P. Tang C.I. Quon H. Morton G. Nam R. et al.Out-of pocket patient costs associated with external beam radiotherapy for localized prostate cancer: the benefits of hypofractionated over conventionally fractionated RT.Can J Urol. 2012; 19: 5343-5347Google Scholar]. For many patients that is a significant financial burden not to mention the hours of driving and waiting incurred. UHF using older technology has been shown in one large RCT to be non-inferior to conventionally fractionated EBRT for failure-free survival and equal in terms of late toxicity. Although acute toxicity/PROs were slightly worse in the UHF arm, PACE-B results (with modern image-guided radiotherapy) shows that acute toxicity/QOL change is the same for SABR over 1.5 weeks versus conventional or moderately hypofractionated EBRT. PATRIOT showed us that protracting SABR over 4 weeks reduces toxicity/improves QOL versus an 11-day regimen and, if logic prevails, weekly SABR should be better tolerated than moderate hypofractionation or conventional fractionation.