A Prospective Multi-Institutional Phase I/II Trial of Step-Wise Dose-per-Fraction Escalation in Low and Intermediate Risk Prostate Cancer

Abstract

Purpose:

This phase I/II, multi-institutional trial explored the tolerance and efficacy of stepwise increasing hypofractionation (HPFX) radiation therapy regimens for fraction sizes up to 4.3 Gy in localized prostate cancer.

Methods and Materials:

Three escalating dose-per-fraction schedules were designed to yield similar predicted tumor control while maintaining equivalent predicted late toxicity. HPFX levels I, II, and III were carried out sequentially and delivered schedules of 64.7 Gy/22 fx/2.94 Gy, 58.08 Gy/16 fx/3.63 Gy, and 51.6 Gy/12 fx/4.3 Gy, respectively with next level escalations contingent upon acceptable gastrointestinal (GI) toxicity. The primary endpoints were biochemical control and toxicity.

Results:

A total of 347 patients were recruited by 5 institutions with 101, 111, and 135 patients treated on HPFX levels I, II, and III with median follow-ups of 100, 85.5, and 61.7 months, respectively (83.2 months combined). The National Comprehensive Cancer Network low- or intermediate-risk group distribution was 46% and 54%, respectively. Sixteen percent of patients, primarily intermediate risk, received 6 months of androgen deprivation therapy. The 8-year nadir + 2 actuarial biochemical control rates for HPFX levels I, II, and III were 91.1% ± 3.0%, 92.7% ± 2.7%, and 88.5% ± 4.6%, respectively (Kaplan-Meier log rank, 0.903). Among clinical covariates, only Gleason score reached near significance in multivariate analysis (P = .054). Twenty-six patients failed biochemically (crude incidence of 7.5%), and there were 5 cause-specific deaths. GI and genitourinary toxicities were acceptable and similar across the 3 HPFX levels. The combined actuarial cumulative incidence of grade 2+ GI and genitourinary toxicities at 7 years were 16.3% ± 2.1% and 22.1% ± 2.4%, respectively.

Conclusions:

HPFX employing fraction sizes extending into the 3.6 to 4.3 Gy/fraction range can be delivered with excellent oncologic outcomes. Such schedules, positioned between moderate and ultra-HPFX, may provide additional options for patients wishing to avoid prolonged treatment schedules associated with conventionally fractionated radiation therapy for prostate cancer.

Introduction

Hypofractionation (HPFX) for prostate cancer was originally used for its resource utilization efficiency and its convenience. However, emerging evidence that prostate cancers may have a greater sensitivity to increasing fraction sizes than do late-responding adjacent organs^1–3 has provided an additional rationale for its use, leading to increased recent interest. To date, a significant number of prospective moderate HPFX trials have generally supported this hypothesis.^4–8 They have shown rates of tumor control that seem consistent with linear quadratic modeling and α-to-β ratios for tumor control of about 1.5, although with some remaining question about applicability to more advanced, higher grade tumors.^9,10 Long-term follow-up data remain more limited, however. Furthermore, the majority of moderate HPFX investigations have studied fraction sizes of 2.5 to 3 Gy, with less information available on the interval between these and doses per fraction of ≥6 Gy, which are typically employed in so-called extreme or ultra-HPFX. Here, we report on long-term biochemical control and toxicity outcomes of a prospective phase I/II multi-institutional trial that explored step-wise dose-per-fraction escalation with 3 successive regimens, 2 of which fall between moderate and extreme HPFX.

Methods and Materials

Protocol design and toxicity scoring

The design of this trial (registration number NCT00214097) included a step-wise, sequentially more hypofractionated treatment regimen. The 3 HPFX levels tested were 64.7 Gy in 22 fractions of 2.94 Gy, 58.08 Gy in 16 fractions of 3.63 Gy, and 51.6 Gy in 12 fractions of 4.3 Gy, respectively. These fractionation schedules were predicted to yield near equivalent tumor control and late toxicities, with equivalent dose at 2 Gy (EQD2) doses of 82 to 85 Gy for tumor control (α/β = 1.5) and 75 to 77 Gy for late effects (α/β = 3) (Table E1, available online at https://doi.org/10.1016/j.prro.2020.02.013). The late effects equivalent doses were chosen to be similar to those from numerous dose-escalated, conventionally fractionated trials and to the one large moderate HPFX study available at that time that reported acceptable toxicities.⁷ Yet, because of HPFX’s potential improvement in therapeutic ratio, the predicted tumor-specific equivalent doses were somewhat higher than in any of those prior studies.

This study contained 2 nested escalations, 1 for dose-per-fraction escalation conditioned upon late gastrointestinal (GI) tolerance and a second within it for fractions-per-week that was conditioned upon acute GI or genitourinary (GU) tolerance. The maximum tolerated dose-per-fraction was defined as that fractionation regimen that yields at most a 20% rate of late grade 2 rectal toxicity at 2 years. A modified Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer grading system was used.¹¹ Although rectal tolerance was chosen for its clinical relevance, the extended follow-up it required would have made a standard sequential design impractically long (accrual plus 2 years of follow-up before escalation). Therefore, a modified class of prorated designs was used instead.¹² Proration implies, for example, that 2 patients observed for 1 year each, constituting 2 patient-years of follow-up, is equivalent to 1 patient followed for 2 years. This implicitly used the results of Teshima et al,¹³ in which the cumulative incidence of late grade 2 rectal complications reached about 50% of the final value within 12 months of treatment and was approximately linear with time over that first 2 years.

The prorated design required the following conditions for continuing accrual at an HPFX level and eventually escalating to the next: at least 20 patient-years of observation; a minimum of 5 patients followed for 1 year; and at most a 20% toxicity rate per 2 years (ie, at most 1 toxicity per 10 patient-years observed). In addition, the nested fractions-per-week escalation (or de-escalation) for each level allowed adjustment for any unacceptable levels of acute toxicities during treatment. Each new HPFX level was initiated at 4 fractions per week, increasing to 5 if there was no greater than a 20% rate of acute grade 3 GI or GU toxicity in the first 15 patients at each level with 3 months of follow-up. This condition was met for all 3 HPFX levels. The overall escalation design is illustrated in Figure E1 (available online at https://doi.org/10.1016/j.prro.2020.02.013).

Radiation therapy planning

Treatments at the 5 participating centers were delivered with LINAC- or Tomo therapy–based intensity modulated radiation therapy (RT) with daily image guidance. The clinical target volume was defined as the prostate plus the base of the seminal vesicles as visualized on computed tomography. The planning target volume then equaled the clinical target volume plus a 0.3 to 0.4 cm margin posteriorly and up to 0.7 cm elsewhere. The planning target volume was required to receive ≥92% of the prescription dose. RT planning constraint details are listed in Table E1 (available online at https://doi.Org/10.1016/j.prro.2020.02.013).

Follow-up

Patients were seen for posttreatment follow-up at 4 weeks, then every 3 months during the first year, every 4 months during years 2 to 3, every 6 months years 4 to 5, and then annually. At each visit a prostate specific antigen (PSA), examination, and physician assessment of toxicities were performed. In addition, patient-reported quality of life outcome (PRO) assessments were completed pretreatment and at 12, 24, and 36 months posttreatment, with outcomes previously reported.¹⁴

Statistical analyses

The primary objective of the study was assessment of the safety of increasingly larger radiation fraction sizes, and biochemical control was the secondary objective. Accrual to each of the HPFX levels was targeted at 100 patients, stopping rules permitting. Accrual to the second and third levels was later expanded with evidence of patient tolerance and to permit improved final assessments of toxicity and biochemical control.

Biochemical failure was defined for this analysis according to the nadir plus 2 ng/mL standard.¹⁵ Biochemically failure-free patients were censored at the date of last PSA, at last follow-up if a PSA was available in the preceding 4 months, or at death. A death associated with a pre-existing biochemical failure was scored as a cause-specific death. Log rank testing was used to compare Kaplan-Meier biochemically failure-free survival curves for HPFX levels and for low versus intermediate risk patients. Regression models for the risk of biochemical failure included T stage, initial PSA, Gleason score, National Comprehensive Cancer Network risk, use of androgen deprivation therapy, and HPFX level and were analyzed using the Cox proportional hazards model. Covariates in the multivariate analysis were selected based on significance in univariate analysis. GI and GU toxicities were examined for prevalence from the initiation of RT and for cumulative incidence starting 3 months after RT completion. The prevalences and cumulative incidence toxicities were compared versus HPFX level using Fisher exact test and Gray’s test, respectively. Statistical analyses were carried out using Statistical Package for the Social Sciences (SPSS) version 25 (IBM, Armonk, New York).

Results

Patient characteristics

Institutional review board approvals were obtained at the 5 treatment sites and all patients were appropriately consented before enrollment. A total of 347 patients were enrolled across 5 institutions between 2004 and 2012. Eligibility required histologically proven adenocarcinoma of the prostate, stage ≤ T2b disease, Gleason score ≤ 7, PSA ≤ 20 ng/mL, and no evidence of distant metastasis. Patient characteristics are summarized in Table 1. In total, 101, 111, and 135 patients were enrolled in HPFX levels I, II, and III, with median follow-ups of 105, 87, and 63 months, respectively. The median follow-up for the entire group was 83 months. Risk factor frequencies were similar across the 3 HPFX levels with the exception of a lower frequency of Gleason 7 patients in HPFX level I (P = .02). Sixteen percent of patients, primarily with intermediate risk, received 6 months of androgen deprivation beginning before radiation and at similar rates across the 3 HPFX levels (P = .57). Further details are shown in Table 1.

Table 1.

Clinical characteristics of recruited patients

Parameter	Level I (22 fx)	Level II (16 fx)	Level III (12 fx)	P value*	Levels combined
No. of patients	101	111	135	N/A	347
Age
Median	67 (47-83)	67 (45-81)	68 (52-85)	.28	67
Follow-up (months)
Median	104.8 (12-146)	87.0 (1-128)	63.1 (3-110)	N/A	83.1 (1-146)
Baseline IPSS (range)
Median	8 (0-23)	7 (0-30)	7 (0-24)	.40	7 (0 – 24)
Baseline PSA (mg/mL): no. of pts (%)
≤10	82(81.2%)	90 (81.1%)	109 (80.7%)	.86	281 (81.0%)
>10-20	19 (18.8%)	21 (18.9%)	26 (19.3%)	—	66 (19.0%)
Gleason score: no. of pts (%)
<7	68 (67.3%)	57 (51.4%)	71 (52.6%)	.02	196 (56.5%)
7	33 (32.7%)	54 (48.6%)	64 (47.4%)	—	151 (43.5%)
T stage: no. of pts (%)
T1c	72 (71.3%)	86 (77.5%)	108 (80%)	.24	266 (76.7%)
T2†	24 (28.7%)	25 (22.5%)	27 (20%)	—	81 (23.3%)
Androgen deprivation (6 mo.): no. of pts (%)
Yes	19 (18.8%)	16 (14.4%)	22 (16.3%)	.57	57 (16.4%)
No	82 (81.2%)	95 (85.6%)	113 (83.7%)	—	290 (83.6%)
NCCN risk group: no. of pts (%)
Low	54 (53.5%)	45 (40.5%)	57 (42.2%)	.03	156 (45%)
Intermediate	47 (46.5%)‡	66 (59.5%)	78 (57.8%)§	—	191 (55%)

Abbreviations: fx = fraction; IPSS = International Prostate Symptom Scores; NCCN = National Comprehensive Cancer Network; PSA = prostate specific antigen; pts = patients.

^*Pearson χ².

^†The majority were T2a tumors. Only 3, 6, and 6 patients had T2b tumors in levels I, II, and III, respectively, and there was 1 level I T2c tumor.

^‡Includes 2 high-risk patients.

^§Includes 4 high-risk patients.

Biochemical relapse free survival and cause-specific survival

There were 26 biochemical failures out of 347 enrolled patients, for a crude overall failure rate of 7.5%, with 8, 9, and 9 failures each in HPFX levels I, II, and III, respectively. The 8-year nadir + 2 actuarial biochemical control rates for HPFX levels I, II, and III were 91.1 ± 3.0%, 92.7 ± 2.7%, and 88.5 ± 4.6%, respectively (Fig 1a and Table 2), and their associated Kaplan-Meier freedom from biochemical failure curves were statistically not different (P = .90). Posttreatment PSA kinetics for the 3 HPFX levels were essentially superimposable (Fig E1, available online at https://doi.org/10.1016/j.prro.2020.02.013). Biochemical control rates at additional time points and for risk groups are tabulated in Table 2.

Figure 1.

Biochemical control versus (a) fractionation level or (b) risk group. Cause-specific survival (c) and overall survival (d) are shown for combined hypofractionation (HPFX) levels.

Table 2.

Biochemical control versus treatment level and risk group

			% Biochemical control
Fractionation level	No. of pts	Median follow-up (months)	5 years	7 years	8 years	10 years
I	101	102	92.5 ± 2.7	91.1 ± 3.0	91.1 ± 3.0	91.1 ± 3.0
II	111	85.6	92.7 ± 2.7	92.7 ± 2.7	92.7 ± 2.7	— — — —
III	135	61.8	94.1 ± 2.2	92.3 ± 2.8	88.5 ± 4.6	— — — —
Combined I, II, & III	347	83.1	93.5 ± 1.4	92.1 ± 1.6	91.4 ± 1.7
Risk group
Low	156	85.9	95.7 ± 1.7	94.7 ± 2.0	93.2 ± 2.5	— — — —
Intermediate/high	191	70.0	91.6 ± 2.2	89.9 ± 2.4	89.9 ± 2.4	— — — —

Abbreviation: pts = patients.

National Comprehensive Cancer Network intermediate versus low-risk patients trended nonsignificantly toward a higher biochemical failure rate (Fig 1b), with a hazard ratio of 1.65 (95% confidence interval, 0.73, 3.70; P = .23) (Table 3). Overall, 60 deaths were recorded during the follow-up period, with 22, 18, and 20 in HPFX levels I, II, and III, respectively. Of the 60 deaths, 5 were associated with a biochemical recurrence and as per protocol definition were scored conservatively as prostate cancer–specific deaths (Fig 1c).

Table 3.

Hazard ratios for biochemical control versus clinical characteristics

Factor	Univariate		Multivariate
	Hazard ratio (95% CI)	P value	Hazard ratio (95% CI)	P value
HPFX levels I vs II vs III	— — — — — —	.903	— — — —	— — — —
PSA > vs ≤ 10	1.68 (0.71-3.99)	.242	1.84 (0.77-4.39)	.172
Gleason (7 vs ≤ 6)	2.39 (1.08-5.29)	.032	2.20 (0.99-4.91)	.054
T2 vs T1	2.17 (0.99-4.79)	.054	2.05 (.92-4.58)	.079
Intermediate vs low risk	1.65 (0.73-3.70)	.228	— — — —	— — — —
ADT vs no ADT	1.38 (0.52-3.68)	.514	— — — —	— — — —

Abbreviations: ADT = androgen deprivation therapy; CI = confidence interval; HPFX = hypofractionation.

Clinical covariates potentially predictive of biochemical failure were analyzed and univariate and multivariate hazard ratios were calculated (Table 3). Initial PSA (>10 vs ≤ 10 ng/mL) did not significantly correlate with biochemical control in univariate analysis (P = .24), whereas Gleason score (P = .03) and T2 versus T1 stage (P = .054) showed or strongly trended toward significance, respectively. Both higher Gleason score (P = .054) and higher T stage (P = .079) continued to strongly trend toward significance on multivariate analysis.

Toxicities

The treatments at all HPFX levels were generally well tolerated and, in all cases, the observed acute toxicity levels allowed escalation from 4 to 5 fractions per week and sequential transitions to the next HPFX levels.

Prevalence and cumulative incidence outcomes for grade 2+ GI toxicity are shown in Figures 2a and 2b, respectively. The prevalence trends were not statistically different for the 3 HPFX levels (P = .85, .67, and .33 at 3, 24, and 60 months, respectively), all displaying a brief initial increase in grade 2+ symptoms that substantially diminished by 3 months posttreatment. Treatment-level-averaged 5- and 7-year prevalences were only 0.9% and 0.7%, respectively. Cumulative incidences were also similar across HPFX levels (P = .78) and with 5- and 7-year averaged incidences of 15.3% ± 2.0% and 16.3% ± 2.1%, respectively. Grade 2+ toxicities included 5 grade-3 events (crude incidence of 1.4%) with 2, 2, and 1 each in HPFX levels I, II, and III, respectively. No grade 4 or higher events were recorded.

Figure 2.

Prevalence (a, b) and cumulative incidence (c, d) of grade 2+ gastrointestinal (GI) (a,c) and genitourinary (GU) (b, d) toxicity versus time and fractionation level. The GU cumulative toxicity is shown with or without including alpha blocker initiation as a grade 2 toxicity.

Similarly, grade 2+ GU prevalence and cumulative incidence trends are shown in Figure 2c and 2d, respectively. Prevalence trends that include new alpha blocker use as a grade 2+ event were not statistically different across the 3 HPFX levels (P = .33, .54, and .52, at 3, 24, and 60 months, respectively), with an initial increase in symptoms for all treatment levels during and shortly after treatment, followed by a recovery. This was then followed by a slow rise in the 4- to 6-year time frame followed by another apparent decline. The averaged 5- and 7-year GU grade 2+ prevalences were 18.1 and 15.5%, respectively. The associated cumulative incidences are shown in Figure 2d, but now with and without the effect of scoring treatment-related alpha blocker initiation as a grade 2 event. When alpha blocker use was not scored, all HPFX grade 2+ GU cumulative incidences were substantially lower. However, HPFX level I appeared to trend even lower than levels II or III and, although these 3 cumulative toxicities were as a group statistically nondifferent (P = .13), the lower value for level I did reach significance when compared with combined levels II and III (P = .04). Although the reason for the difference for level I is unclear, it was noted that a significantly greater number of level I versus level II or III patients did receive alpha blockers, lending some uncertainty to the interpretation and significance of this observed difference.

Notably, however, no such differences among HPFX levels were observed in these patients’ International Prostate Symptom Scores¹⁶ (Fig 3) (P = .87, .96, and .73 at 3, 24, and 60 months, respectively), nor in the GU-related portions of our previously reported, more detailed PRO report.¹⁴ Thus, against a background of variable symptom management by treating physicians, the GU quality-of-life measures for the 3 HPFX levels were very similar. Of note, within the GU grade 2+ category, there were a total of 12 grade 3 events for a crude incidence of 3.5%, distributed as 3, 5, and 4 each across the 3 HPFX levels I through III. There were no grade 4 or higher events observed.

Figure 3.

International Prostate Symptom Scores (IPSS) versus time and hypofractionation (HPFX) level.

Discussion

Interest in moderate HPFX for prostate cancer relates to the potential radiobiological advantage (a greater therapeutic ratio) of treating prostate cancer with larger fraction sizes.^2,17 The improved utilization of resources and convenience are attractive features as well.

A large single-arm trial⁷ followed by at least 7 large, contemporary randomized trials^{4–6,8,9,18,19} have found moderate HPFX to be safe and to achieve biochemical control rates that are either noninferior,^4,5,8 nonsuperior,^18,20 or marginally superior⁶ to what each study defined as its conventional fractionation standard. All employed fraction sizes of ≤3 Gy, except for the HYPOfractionated Irradiation for PROstate Cancer (HYPRO) trial, which delivered 19 fractions of 3.4 Gy each.¹⁸ Although several studies noted marginal increases in late GI or GU toxicity,^8,9,18 the majority found that HPFX produced low toxicity rates similar to those seen in their respective conventional fractionation arms. Based on these clinical outcomes data, 2 evidence-based practice guidelines^21,22 have concluded that moderate HPFX is an acceptable treatment approach in localized low, intermediate, and high-risk prostate cancer.

When this current study was designed, little long-term safety or efficacy data existed for HPFX regimens other than at 2.5 Gy/fraction.^7,23 Although this is no longer the case, there currently have been no mature clinical biochemical relapse free survival (BRFS) data for fraction sizes between 3.5 Gy and ultra-HPFX schedules using 6 Gy per fraction or greater. Thus, by exploring several schedules in this intermediate range between moderate and ultra-HPFX, this current trial provides information of interest both for its potential clinical utility and its radiobiology.

The 3 sequentially delivered, increasingly HPFX regimens investigated here were designed using linear quadratic estimates yielding similar EQD2s (Table E1, available online at https://doi.org/10.1016/j.prro.2020.02.013) and thus, similar predicted tumor control and toxicity outcomes. Based on the observed outcomes, these predictions appear to have been reasonably well met for the schedules and fraction sizes tested. Favorable, similar toxicity and biochemical control outcomes were found across the trial’s 3 HPFX levels, suggesting the applicability of linear quadratic modeling within this fraction size range up to 4.3 Gy. However, any α/β ratio estimates for tumor response from these data would be subject to very wide error estimates owing to the sparsity of failure events, given 8 year BRFS’s in excess of 88% for each of the 3 arms.

Comparison of tumor control outcomes from other trials is challenged by potential or known differences in the risk profiles of their patients, the proportion of patients receiving hormonal therapy, and differing predicted EQD2s of the HPFX regimens used. However, the randomized MD Anderson HPFX trial,⁶ which used a HPFX schedule of 2.4 Gy × 30 fractions, had a similar low- or intermediate-risk distribution, low use of hormonal therapy, and similar predicted tumor EQD2 of 80.3 Gy versus 82 to 85.6 Gy for the present trial. It found an 8-year BRFS of 89.3% versus 88.5% to 91.1% in our study’s 3 arms. The Prostate Fractionated Irradiation Trial (PROFIT)⁴ and Conventional versus Hypofractionated High dose Intensity-modulated radiotherapy for Prostate cancer (CHHIP)⁵ trials, on the other hand, predominantly treated intermediate-risk patients and both delivered HPFX tumor EQD2s of 77.2 Gy with their 60 Gy in 20 fraction HPFX arms. They reported 5-year BRFS’s of 85% and 90.6%, respectively, which is comparable to the combined biochemical control of 91.6% ± 2.2% for the present study’s intermediate risk patient subgroup. RTOG-0415,⁸ which treated only low-risk patients and delivered a tumor HPFX EQD2 of 80 Gy using a 2.5 Gy × 28 fraction schedule, reported a 5-year BRFS of 86.3%, compared with the present study’s 5-year BRFS for low-risk patients of 95.7%. Thus, the present study, employing more strongly hypofractionated regimens, found biochemical control outcomes equivalent to or potentially slightly better than those from published moderate HPFX studies.

Toxicity comparisons with published trials also face challenges given differences in treatment planning constraints and delivery, rectal and bladder doses, estimated biologically effective doses, and scoring systems used. However, several comparisons can be made by focusing on those moderate HPFX arms of randomized trials with similar estimated EQD2s for late effects. The present study, for reference, found cumulative incidences of ≥grade 2 late GI toxicities of 15.3% ± 2.0% and 16.3% ± 2.1% at 5 and 7 years, respectively. This compares with 5-year cumulative incidence rates of 12.5% and 11.9% in the HPFX arms of the MD Anderson⁶ and CHHIP⁵ trials and with crude incidence rates of 8.9% and 22.9% over 5 years for the PROFIT⁴ and RTOG-0415⁸ trials, respectively. Thus, late GI toxicity rates in the current study appear similar to those observed in other HPFX trials delivering similar^6,8 or somewhat lower^4,5 late effect EQD2s.

For ≥grade 2 late GU toxicities, this present study found combined 5- and 7-year cumulative incidences of 19.9% ± 2.2% and 22.1% ± 2.4% respectively, excluding alpha blocker use as a grade 2 event. This compares with 5-year cumulative incidences of 14.5% and 11.7% for the HPFX arms of the MD Anderson⁶ and CHHIP⁵ trials, respectively and with crude incidence rates of 22.2% and 29.8% over 5 years for PROFIT⁴ and RTOG-0415,⁸ respectively. Thus, GU toxicities found here also appear similar to those from other HPFX trials that delivered equivalent^6,8 or somewhat lower^4,5 late effect EQD2s.

This present study previously reported its 1-, 2-, and 3-year PRO outcomes¹⁴ and found all 3 HPFX levels to be well tolerated and largely equivalent in their effects on quality of life. Bowel quality of life trends paralleled the physician-scored grade 2+ prevalences shown in Figure 2a, with an initial increase in symptoms for all HPFX levels followed by recovery to or near to pretreatment levels by 3 years. Bladder PRO trends, however, unlike the physician-scored grade 2+ prevalences shown in Figure 2b, did not demonstrate a significant persisting increase in symptoms at 3 years for any of the HPFX levels. This discordance likely reflects the inclusion of alpha blocker use as a grade 2 event, as shown in Figure 2b, highlighting the effectiveness of these drugs in attenuating bladder-related symptoms. The Spitzer Quality of Life Index was also statistically unchanged at 3 years relative to baseline for all of the treatment levels.¹⁴

Subsequently, RTOG 0938 reported 1- and 2-year PRO outcomes from a randomized phase II trial that, adopting from preliminary data from our present study,²⁴ compared this same 4.3 Gy × 12 regimen against a 7.25 Gy × 5 ultra-HPFX regimen.²⁵ As in the present study, changes in quality-of-life scores for the 4.3 Gy per fraction arm were modest and acceptable. The reporting of long-term BRFS outcomes from RTOG 0938 awaits further follow-up.

Even more extreme HPFX with ≥ 6 Gy fractions delivered in 4 to 7 fractions has more recently been gaining much prominence. Termed ultra-HPFX (or SBRT or Stereotactic ablative radiotherapy), these treatment schedules may rely relatively more on treatment conformality²⁶ and image guidance than on the radiobiological advantage thought more operative with the smaller fraction sizes associated with moderate HPFX.²⁷ Two large meta-analyses of individual single arm prospective trials,^28,29 as well as the recently published, randomized ultra-hypofractionated versus conventionally fractionated HYPO-RT-PC trial,³⁰ have reported promising long-term efficacy and safety profiles. Ultra-HPFX has also been conditionally accepted in one evidence-based practice guideline,²² and is also supported by a second.²¹ It has also been increasingly adopted by a number of practices as a de facto standard form of care.³¹ However, with results from only the single randomized HYPO-RT-PC trial available to date, the completion or reporting of other pending randomized ultra-HPFX trials, including PACE-B,³² RTOG 0938,²⁵ and NRG GU005 (NCT03367702), may help further solidify the evidence supporting the approach. Together with moderate HPFX and the intermediate HPFX schedules reported on in this present study, patients could benefit from a wide range of standard of care HPFX options.

Although the purpose of this study’s sequential design was to safely test for treatment tolerance, it did, however, also introduce 2 potential limitations. The first is the resulting shorter follow-up for those patients accrued to HPFX levels later in the sequence, potentially compromising comparisons of outcomes for the 3 levels. However, the median and maximum follow-ups for the final HPFX level accrued to were still substantial at 63 and 110 months, respectively, thus still allowing for robust comparisons. Second, some imbalances in risk groups occurred among the 3 levels, a shortcoming that any sequential trial design is susceptible to. However, multivariable analysis, at least, did not reveal any significant differences in outcome between low- and intermediate-risk patients.

Conclusions

This prospective, multi-institutional study found that hypofractionation employing fraction sizes extending into the 3.6 to 4.3 Gy/fraction range can be delivered with excellent oncologic outcomes. Such schedules, positioned between moderate- and ultra-hypofractionation, may provide additional options for patients wishing to avoid prolonged treatment schedules associated with conventionally fractionated radiation therapy for prostate cancer.