External beam radiotherapy, along with radical prostatectomy, has been a mainstay treatment option for prostate cancer and is currently recommended by numerous guidelines for the treatment of intermediate- and high-risk disease.1-3 While external beam radiotherapy has been foundational in prostate cancer treatment for decades, there have been significant changes in the delivery of radiotherapy, corresponding to technical advances.
These advances have manifest in two major, co-related, developments: more targeted delivery of radiotherapy and dose escalation. More targeted radiotherapy delivery, using approaches beginning with conformal radiotherapy (CRT) and evolving to intensity modulated radiotherapy (IMRT) and image guided radiotherapy (IGRT), allows the sparing of adjacent organs (reducing toxicity) while facilitating increase dose delivery to the prostate.
In addition to facilitating dose escalation, advances in radiotherapy technology have allowed for hypofractionation in which fewer, larger doses of radiotherapy are administered. Classically, external beam radiotherapy has been administered in a non-fractionated schedule of 1.8 – 2.0 Gy per day, five days per week for 6 to 8 weeks. However, prostate cancer cells are known to have a higher sensitivity to fractional radiation doses and thus, theoretically, should benefit from hypofractionated schedules. This characteristic is reflected by a low alpha/beta (α/β) value, which is a measure of fractionation sensitivity and is related to the inherent ability of tumor cells to repair sublethal DNA damage inflicted by ionizing radiation.4 This low α/β ratio characteristic of prostate cancer is further accentuated by the high (α/β) ratios of the surrounding tissues, with ratios of 5.6 Gy and 3 Gy estimated for late toxicity effects on the bladder and rectum.5-8
In addition to its potential therapeutic ratio benefits, hypofractionation schedules mandate less frequent patient visits which can have major implications on reduction of treatment-related costs and improved patient quality of life. Two schedules of hypofractionation have gained popularity over the last decade: moderate hypofractionation, defined as 2.4 – 3.4 Gy/fraction, and ultrahypofractionation, defined as 5.0 Gy/fraction or higher.1
Several trials have recently focused on defining the optimal radiotherapy fractionation schedule for the primary treatment of prostate cancer, comparing the efficacy and safety of hypofractionated and conventional schedules. In this Center of Excellence article, we review the available evidence for hypo- and ultra-fractionated external beam radiotherapy for treatment of localized prostate cancer.
Moderate Hypofractionation
Hypofractionation schedules were initially evaluated in patients with low-risk prostate cancer. The NRG Oncology RTOG 0415 trial was a multicenter, non-inferiority phase III trial that randomized 1,115 men with low-risk prostate cancer in a 1:1 fashion to either conventional radiotherapy (73.8 Gy in 41 fractions over 8.2 weeks) or moderate hypofractionation (70 Gy in 28 fractions over 5.6 weeks). Given the low-risk disease status of these patients, androgen deprivation therapy was not allowed, other than as salvage therapy in the case of prostate cancer recurrence. The primary outcome was 5-year disease-free survival, with a non-inferiority margin set at 7.65% (hazard ratio <1.52). At a median follow-up of 5.8 years, there were no significant differences in the 5-year disease free survival rates between patients treated in the conventional fractionation arm (85.3% (95% CI: 8.19 – 88.1%) and the hypofractionated arm (86.3% (95% CI: 83.1 – 89.0%). The disease-free survival hazard ratio was 0.85 (95% CI: 0.64 – 1.14), meeting the pre-defined non-inferiority criterion (p < 0.001):
There were no significant differences in early gastrointestinal or genitourinary toxicities. However, late grade 2 and 3 gastrointestinal adverse events were higher in men in the hypofractionated arm (22.2% vs 13.9% in the conventional arm, p = 0.002), as well as late grade 2 and 3 genitourinary adverse events (29.5% vs 22.4% in the conventional arm, p = 0.06).9
In 2016, efficacy results of the multicenter phase III Dutch HYPRO trial were published in Lancet Oncology, comparing moderate hypofractionation to conventionally fractionated radiotherapy among patients with intermediate-risk to high-risk T1b-T4Nx-N0Mx-M0 localized prostate cancer. This patient cohort more accurately represents those who receive radiotherapy today. Patients were randomized 1:1 to either moderately hypofractionated radiotherapy with a total dose of 64.6 Gy (19 fractions of 3.4 Gy, three fractions per week) or conventionally fractionated radiotherapy for a total dose of 78.0 Gy (39 fractions of 2.0 Gy, five fractions per week). The primary endpoint was relapse-free survival. There were 804 patients assessed in the intention-to-treat analysis, of which 407 were assigned moderately hypofractionated radiotherapy and 397 were allocated to conventionally fractionated radiotherapy. Notably, 67% of patients received concomitant androgen deprivation therapy for a median duration of 32 months (IQR: 10 – 44). Over a median follow-up of 60 months (IQR: 51 - 69), treatment failure was reported in 21% of patients: 20% in the hypofractionation arm and 22% in the conventional fractionation arm. The 5-year relapse-free survival was 80.5% (95% CI: 75.7 – 84.4%) for patients assigned to hypofractionation and 77.1% (71.9 – 81.5%) for those allocated to a conventional fractionation schedule (HR: 0.86, 95% CI: 0.63 – 1.16, log-rank p = 0.36). Additionally, there was no difference in overall survival between these two arms (HR: 1.02, 95% CI: 0.71 – 1.46, log-rank p = 0.92):
Based on these results, the authors noted that this current regimen of hypofractionated radiotherapy was not superior to conventional radiotherapy.10
In 2017, Catton et al. published results of the PROFIT trial, a randomized, non-inferiority, multicenter trial of moderate hypofractionation versus conventional fractionation in 1,206 patients with intermediate-risk prostate cancer only. Patients were randomized 1:1 either to conventional radiotherapy at 78 Gy (39 fractions over 8 weeks) or moderate hypofractionation at 60 Gy (20 fractions over 4 weeks). Importantly, use of androgen deprivation therapy was not permitted, per study protocol. The primary study outcome was biochemical or clinical failure, defined as PSA nadir + 2 (Phoenix Criteria), hormonal intervention, clinical local or distant failure, or prostate cancer death. The noninferiority margin was set at 7.5% (i.e., HR <1.32). After a median follow up of 6.0 years, no significant differences were noted in 5-year biochemical-failure disease-free survival: 85% in both arms (95% CI: 82 – 88%). The adjusted hazard ratio was significantly lower than the pre-defined hazard ratio for non-inferiority: 0.96 (90% CI: 0.77 – 1.20). There were no differences in the rates of grade 3 or worse genitourinary toxicities in the acute period (4% in both arms), whereas the rates were slightly lower in the hypofractionated arm in the late period (2.1% versus 3.0%). Grade 3 or worse gastrointestinal toxicities were non-significantly different in both the acute (0.5 - 0.7%) and late settings (1.5 - 2.7%). Based on these results, the authors concluded that moderate hypofractionation was non-inferior to conventional fractionation schedules.11 These results are further supported by those seen in the CHIRP trial, a phase II trial which randomized 111 men with high-risk prostate cancer to conventional fractionation (78 Gy in 39 fractions) or moderate hypofractionation (68 Gy in 25 fractions) along with 18 months of androgen suppression. After a median follow up of 38.0 months, there were no differences in 3-year biochemical recurrence-free survival (hypofractionated: 97.3% versus conventional: 91.0%; HR: 0.96, 90% CI: 0.77 – 1.20), overall survival (94.8% versus 100.0%, p=0.116), and 24-month physician or patient-reported genitourinary and gastrointestinal symtpoms.12
Published in Lancet Oncology in 2019, the CHHiP trial was a multi-center, randomized, phase III trial, designed as a non-inferiority clinical trial, randomizing men with pT1b-T3aN0M0 prostate cancer 1:1:1 to conventional (74 Gy delivered in 37 fractions over 7.4 weeks) or one of two moderate hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3.8 weeks) all delivered with intensity-modulated techniques. Randomization was stratified by NCCN risk group, with low-, intermediate-, and high-risk patients included. Most patients (97%) were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. The primary endpoint was time to biochemical or clinical failure, and the critical hazard ratio for non-inferiority was 1.208. In this large trial, 3,216 men were enrolled from 71 centers and randomly assigned, as follows: 1,065 patients to the 74 Gy group, 1,074 patients to the 60 Gy group, and 1,077 patients to the 57 Gy group. The median follow-up was 62.4 months (IQR: 53.9 – 77.0) over which the proportion of patients who were biochemical or clinical failure-free at five years was 88.3% (95% CI 86.0-90.2) in the 74 Gy group, 90.6% (95% CI 88.5-92.3) in the 60 Gy group, and 85.9% (95% CI 83.4-88.0) in the 57 Gy group. The 60 Gy hypofractionated schedule was non-inferior to the conventional 74 Gy schedule (HR: 0.84, 90% CI: 0.68-1.03, p-value for noninferiority = 0.0018), but non-inferiority was not possible for 57 Gy hypofractionation compared with 74 Gy (HR: 1.20, 90% CI: 0.99 – 1.46, p-value for noninferiority = 0.48).13
Ultrahypofractionation
Given the demonstrated non-inferior efficacy of moderate hypofractionated schedules, along with its favorable adverse event profile, there has been increased interest in evaluating ultrahypofractionated schedules. The term ultrahypofractionation is commonly used interchangeably with stereotactic body radiation therapy (SBRT) or stereotactic ablative body radiation (SABR). However, it must be clarified that ultrahypofractionation strictly refers to the fraction size/dose, whereas the latter two terms refer additionally to the platform of beam delivery and radiation technique.
The Scandinavian HYPO-RT-PC randomized controlled phase III trial was initially presented at ESTRO 2018, and subsequently published in The Lancet in 2019.14 This was a randomized, non-inferiority trial across 12 centers in Sweden and Denmark that randomized 1,200 men with intermediate (89%) and high-risk (11%) prostate cancer to either conventional fractionation (n= 602; 78.0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultrahypofractionation (n=598; 42.7 Gy in seven fractions, three days per week for 2.5 weeks). No androgen deprivation therapy was allowed. The primary endpoint was time to biochemical or clinical failure in the per-protocol population. The prespecified non-inferiority margin was 4% at 5 years, corresponding to a critical hazard ratio limit of 1.338. Median follow-up was 5.0 years (IQR: 3.1 – 7.0). The estimated failure-free survival at five years was 84% (95% CI: 80 – 87%) in both treatment groups, with an adjusted hazard ratio of 1.002 (95% CI: 0.758 – 1.325; log-rank p=0.99):
There was weak evidence of an increased frequency of acute physician reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy (158 [28%] of 569 patients vs 132 [23%] of 578 patients; p = 0.057). There were no significant differences between groups in the frequency of RTOG grade 2 or worse urinary toxicity (5% in both arms, p = 1.0) or bowel toxicity (1% versus 4%; p = 0.14) at 5 years. Patient-reported outcomes revealed significantly higher levels of acute urinary and bowel symptoms in the ultra-hypofractionation group compared with the conventional fractionation group but no significant increases in late symptoms were found, except for increased urinary symptoms at 1-year follow-up, consistent with physician-evaluated toxicity.
While the HYPO-RT-PC trial demonstrated that ultrahypofractionation is non-inferior to conventional fractionation for the treatment of intermediate and high-risk prostate cancer patients, there are important limitations to this trial. No androgen deprivation therapy was given to patients in this trial, which is in contrast to current guideline recommendations supporting use of concurrent hormone therapy with external beam radiotherapy for patients with intermediate and high-risk prostate cancer.1 Importantly, recent work has shown that the provision of concurrent ADT contributes more to outcomes for patients with localized prostate cancer treated with radiotherapy than does dose escalation.15 Further, in the HYPO-RT-PC trial, the seminal vesicles were not included in the clinical target volume, which is inconsistent with current EORTC guidelines recommending inclusion of the proximal 1-2 cm for intermediate and high-risk patients. This trial also used seven fractions, instead of the commonly reported five seen in ultrahypofractionation reports, and 80% of patients were only treated with conventional 3D planning.4,14
Following the publication of the HYPO-RT-PC trial, the acute toxicity findings from the PACE-B trial, an international multicenter, phase III, open-label, randomized, non-inferiority trial, were published. This trial randomized men with low- or intermediate-risk prostate cancer (Grade Group 3 excluded) in a 1:1 fashion to either conventionally (78 Gy in 39 fractions over 7.8 weeks) or moderately hypofractionated radiotherapy (62 Gy in 20 fractions over 4 weeks) versus stereotactic body radiotherapy (36.25 Gy in five fractions over one to two weeks). Similar to the HYPO-RT-PC trial, androgen deprivation therapy was not allowed. The primary endpoint of the PACE-B trial is freedom from biochemical or clinical failure. However, for the initial toxicity report published in Lancet Oncology, the co-primary outcomes were grade 2 or worse RTOG gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. There were 874 men randomized to conventional/moderate hypofractionation (n=441) or stereotactic body radiotherapy (n=433):
Worst acute RTOG gastrointestinal toxic effects were as follows: grade 2 or more severe toxic effects in 12% of patients in the conventional/moderate hypofractionation arm versus 10% in the stereotactic body radiotherapy group (difference −1.9 percentage points, 95% CI: −6.2 to 2.4; p = 0.38). There were similarly no significant differences in worst acute RTOG genitourinary toxicity effects with grade 2 or worse toxicity noted in 27% and 23% of patients, respectively (difference −4.2 percentage points, 95% CI: −10.0 to 1.7; p = 0.16). There were no treatment-related deaths.16 These results are in contrast to those seen in the HYPO-RT-PC trial which suggested higher patient-reported toxicity with ultrahypofractionation, compared to increased acute toxicity with conventional/moderate hypofractionation seen in the PACE-B trial.
Conclusions
Integrating these data, there has been a clear migration towards hypofractionation for patients opting for external beam radiotherapy in the treatment of localized prostate cancer. Moderate hypofractionation is the "preferred” approach for patients across nearly all risk groups according to the recent NCCN clinical practice guidelines in oncology while ultra-hypofractionation (SBRT) is considered an appropriate regime in most settings apart from regional N1 disease. Hypofractionation offers considerable logistic benefits to the patient, decreased health system costs, and equivalent or improved clinical outcomes.
Published Date: December 2022