Conventional versus hypofractionated EBRT

In a small randomized trial, primarily from one treatment center, conventional hypofractionation was not found to be superior to conventional fractionation.[72] In the trial, 303 assessable men were randomly assigned to receive IMRT for a total of 76 Gy in 38 fractions at 2.0 Gy per fraction (conventional IMRT [CIMRT]) versus IMRT for a total of 70.2 Gy in 26 fractions at 2.7 per fraction (hypofractionated IMRT [HIMRT]).

In a small randomized trial, primarily from one treatment center, conventional hypofractionation was not found to be superior to conventional fractionation.[72] In the trial, 303 assessable men were randomly assigned to receive IMRT for a total of 76 Gy in 38 fractions at 2.0 Gy per fraction (conventional IMRT [CIMRT]) versus IMRT for a total of 70.2 Gy in 26 fractions at 2.7 per fraction (hypofractionated IMRT [HIMRT]).

The primary end point was biochemical or clinical disease failure (BCDF). The 5-year BCDF rates in the two arms were 21.4% for the CIMRT arm (95% CI, 14.8%–28.7%) and 23.3% for the HIMRT arm (95% CI, 16.4%–31.0%; P = .75).

In a small randomized trial, primarily from one treatment center, conventional hypofractionation was not found to be superior to conventional fractionation.[72] In the trial, 303 assessable men were randomly assigned to receive IMRT for a total of 76 Gy in 38 fractions at 2.0 Gy per fraction (conventional IMRT [CIMRT]) versus IMRT for a total of 70.2 Gy in 26 fractions at 2.7 per fraction (hypofractionated IMRT [HIMRT]).

Likewise, there were no statistically significant differences in the secondary end points of overall mortality, prostate–cancer-specific mortality, prostate local failure, or distant failure, despite low mortality rates, and the trial was underpowered for mortality end points.[72][Level of evidence B1]

The much larger, multicenter CHHiP trial (NCT00392535) evaluated conventional or hypofractionated high-dose intensity-modulated radiotherapy in 3,216 men with prostate cancer. The men had stages T1b–T3a, N0, M0 cancer and an estimated risk of seminal vesicle involvement of less than 30% and were randomly assigned in a 1:1:1 ratio to receive either 74 Gy in 37 fractions (the conventional-fraction arm), 60 Gy in 20 fractions, or 57 Gy in 19 fractions.[73,74] The trial was designed as a noninferiority study.

The much larger, multicenter CHHiP trial (NCT00392535) evaluated conventional or hypofractionated high-dose intensity-modulated radiotherapy in 3,216 men with prostate cancer. The men had stages T1b–T3a, N0, M0 cancer and an estimated risk of seminal vesicle involvement of less than 30% and were randomly assigned in a 1:1:1 ratio to receive either 74 Gy in 37 fractions (the conventional-fraction arm), 60 Gy in 20 fractions, or 57 Gy in 19 fractions.[73,74] The trial was designed as a noninferiority study.

The primary end point of biochemical or clinical treatment failure was reported after a median follow-up of 62.4 months. The 5-year failure-free survival rates were 88.3% (conventional, 74 Gy group), 90.6% (60 Gy group), and 85.9% (57 Gy group). The 60 Gy hypofractionated group fulfilled noninferiority criteria compared with conventional 74 Gy fractionation, but the 57 Gy group did not.[74][Level of evidence B1]

The much larger, multicenter CHHiP trial (NCT00392535) evaluated conventional or hypofractionated high-dose intensity-modulated radiotherapy in 3,216 men with prostate cancer. The men had stages T1b–T3a, N0, M0 cancer and an estimated risk of seminal vesicle involvement of less than 30% and were randomly assigned in a 1:1:1 ratio to receive either 74 Gy in 37 fractions (the conventional-fraction arm), 60 Gy in 20 fractions, or 57 Gy in 19 fractions.[73,74] The trial was designed as a noninferiority study.

Overall mortality rates were very similar in the three groups: 9%, 7%, and 8%.[74][Level of evidence A1]

The much larger, multicenter CHHiP trial (NCT00392535) evaluated conventional or hypofractionated high-dose intensity-modulated radiotherapy in 3,216 men with prostate cancer. The men had stages T1b–T3a, N0, M0 cancer and an estimated risk of seminal vesicle involvement of less than 30% and were randomly assigned in a 1:1:1 ratio to receive either 74 Gy in 37 fractions (the conventional-fraction arm), 60 Gy in 20 fractions, or 57 Gy in 19 fractions.[73,74] The trial was designed as a noninferiority study.

A QOL substudy was conducted with 2,100 participants and showed nearly identical patient-reported outcomes in each of the three arms at 2 years after study entry (median follow-up, 50 months).[73][Level of evidence A3]

The much larger, multicenter CHHiP trial (NCT00392535) evaluated conventional or hypofractionated high-dose intensity-modulated radiotherapy in 3,216 men with prostate cancer. The men had stages T1b–T3a, N0, M0 cancer and an estimated risk of seminal vesicle involvement of less than 30% and were randomly assigned in a 1:1:1 ratio to receive either 74 Gy in 37 fractions (the conventional-fraction arm), 60 Gy in 20 fractions, or 57 Gy in 19 fractions.[73,74] The trial was designed as a noninferiority study.

The primary patient-reported outcome was bowel bother. Frequency of moderate bother was 5%, 6%, and 5% in the three study groups. Severe bother was reported in less than 1% of men in each study group.

The much larger, multicenter CHHiP trial (NCT00392535) evaluated conventional or hypofractionated high-dose intensity-modulated radiotherapy in 3,216 men with prostate cancer. The men had stages T1b–T3a, N0, M0 cancer and an estimated risk of seminal vesicle involvement of less than 30% and were randomly assigned in a 1:1:1 ratio to receive either 74 Gy in 37 fractions (the conventional-fraction arm), 60 Gy in 20 fractions, or 57 Gy in 19 fractions.[73,74] The trial was designed as a noninferiority study.

Likewise, there were no differences in any of the secondary outcomes, which included overall QOL, overall urinary bother, or overall sexual bother.

The multicenter, randomized, phase III HYPRO trial (ISRCTN85138529) enrolled 820 men with intermediate- or high-risk prostate cancer (stages T1b–T4, NX–0, MX–0). The men were randomly assigned to receive either conventional radiation therapy (78 Gy in 39 fractions over 8 weeks) or hypofractionated radiation therapy (64.6 Gy in 19 fractions over 6.5 weeks) in a noninferiority design for hypofractionation.[75,76] Median follow-up was 60 months.

The multicenter, randomized, phase III HYPRO trial (ISRCTN85138529) enrolled 820 men with intermediate- or high-risk prostate cancer (stages T1b–T4, NX–0, MX–0). The men were randomly assigned to receive either conventional radiation therapy (78 Gy in 39 fractions over 8 weeks) or hypofractionated radiation therapy (64.6 Gy in 19 fractions over 6.5 weeks) in a noninferiority design for hypofractionation.[75,76] Median follow-up was 60 months.

The primary end point, 5-year relapse-free survival, was similar in the two study arms: 80.5% (95% CI, 75.7%–84.4%) with hypofractionation versus 77.1% (95% CI, 71.9%–81.5%), with conventional fractionation (HR, 0.86; 95% CI, 0.63–1.16; P = .36).[76][Level of evidence B1] The overall 5-year survival rate in the two arms was also similar: 86.2% (95% CI, 82.3%–89.4%) with hypofractionation versus 85.9% (95% CI, 81.8%–89.2%) with conventional fractionation (HR, 1.02; 95% CI, 0.71–1.46; P = .92).[76][Level of evidence A1]

The multicenter, randomized, phase III HYPRO trial (ISRCTN85138529) enrolled 820 men with intermediate- or high-risk prostate cancer (stages T1b–T4, NX–0, MX–0). The men were randomly assigned to receive either conventional radiation therapy (78 Gy in 39 fractions over 8 weeks) or hypofractionated radiation therapy (64.6 Gy in 19 fractions over 6.5 weeks) in a noninferiority design for hypofractionation.[75,76] Median follow-up was 60 months.

With respect to toxicity (key end points of genitourinary [GU] or gastrointestinal [GI] grade 2 or higher toxicities at 3 years), noninferiority for hypofractionated radiation therapy could not be established after a median follow-up of 5 years: cumulative GU toxicity of 41.3% with hypofractionated radiation therapy versus 39% with conventional radiation therapy doses (HR, 1.16; 90% CI, 0.98–1.38); GI toxicity of 21.9% versus 17.7% (HR, 1.19; 90% CI, 0.93–1.52).

The multicenter, randomized, phase III HYPRO trial (ISRCTN85138529) enrolled 820 men with intermediate- or high-risk prostate cancer (stages T1b–T4, NX–0, MX–0). The men were randomly assigned to receive either conventional radiation therapy (78 Gy in 39 fractions over 8 weeks) or hypofractionated radiation therapy (64.6 Gy in 19 fractions over 6.5 weeks) in a noninferiority design for hypofractionation.[75,76] Median follow-up was 60 months.

Cumulative GU grade 3 or higher toxicity was more common in the hypofractionation group: 19.0% versus 12.9% (P = .02).

The multicenter, randomized, phase III HYPRO trial (ISRCTN85138529) enrolled 820 men with intermediate- or high-risk prostate cancer (stages T1b–T4, NX–0, MX–0). The men were randomly assigned to receive either conventional radiation therapy (78 Gy in 39 fractions over 8 weeks) or hypofractionated radiation therapy (64.6 Gy in 19 fractions over 6.5 weeks) in a noninferiority design for hypofractionation.[75,76] Median follow-up was 60 months.

Stool frequency (≥6 qd) was higher in the hypofractionation group: 7% versus 3% (P = .034).

The multicenter, randomized, phase III HYPRO trial (ISRCTN85138529) enrolled 820 men with intermediate- or high-risk prostate cancer (stages T1b–T4, NX–0, MX–0). The men were randomly assigned to receive either conventional radiation therapy (78 Gy in 39 fractions over 8 weeks) or hypofractionated radiation therapy (64.6 Gy in 19 fractions over 6.5 weeks) in a noninferiority design for hypofractionation.[75,76] Median follow-up was 60 months.

In a substudy of 322 men who had a baseline assessment and at least one follow-up assessment, and either no or short-term androgen therapy, erectile dysfunction was similar between the two study arms during 3 years of follow-up.[77]

The RTOG reported a noninferiority trial of 1,115 men with low-risk prostate cancer (T1b–T2c) who were randomly assigned to receive hypofractionated radiation therapy (70 Gy in 28 fractions over 5.6 weeks) versus conventional radiation therapy doses (73.8 Gy in 41 fractions over 8.2 weeks).[78]

The RTOG reported a noninferiority trial of 1,115 men with low-risk prostate cancer (T1b–T2c) who were randomly assigned to receive hypofractionated radiation therapy (70 Gy in 28 fractions over 5.6 weeks) versus conventional radiation therapy doses (73.8 Gy in 41 fractions over 8.2 weeks).[78]

After a median follow-up of 5.8 years, the hypofractionated radiation therapy arm met the prospective noninferiority criterion with respect to DFS: 86.3% with hypofractionated radiation therapy versus 85.3% with conventional radiation therapy doses (consistent with HR, <1.52; P < .001 for the hypothesis of noninferiority).[78][Level of evidence B1]

The RTOG reported a noninferiority trial of 1,115 men with low-risk prostate cancer (T1b–T2c) who were randomly assigned to receive hypofractionated radiation therapy (70 Gy in 28 fractions over 5.6 weeks) versus conventional radiation therapy doses (73.8 Gy in 41 fractions over 8.2 weeks).[78]

There were 49 deaths in the hypofractionated radiation therapy arm and 51 deaths in the conventional radiation therapy doses arm (HR for OS, 0.95; conventional radiation therapy doses vs. hypofractionated radiation therapy; 95% CI, 0.64–1.41).

The RTOG reported a noninferiority trial of 1,115 men with low-risk prostate cancer (T1b–T2c) who were randomly assigned to receive hypofractionated radiation therapy (70 Gy in 28 fractions over 5.6 weeks) versus conventional radiation therapy doses (73.8 Gy in 41 fractions over 8.2 weeks).[78]

However, late GI grade 2 or higher toxicity was worse in the hypofractionated radiation therapy arm: 22.4% versus 14.0% (P = .002); there was also a trend toward worse late GU grade 2 or higher toxicity: 29.7% versus 22.8% (P = .06).

In a multicenter trial (NCT00304759), 1,206 men with intermediate-risk prostate cancer (T1–2a Gleason score ≤6, PSA 10.1–20 ng/mL; T2b–2c Gleason ≤6, PSA ≤20 ng/mL; or T1–2 Gleason = 7, PSA ≤20 ng/mL) were randomly assigned in a noninferiority trial design to receive conventional radiation therapy (78 Gy in 39 fractions) versus hypofractionated radiation therapy (60 Gy over 20 fractions).[79]

In a multicenter trial (NCT00304759), 1,206 men with intermediate-risk prostate cancer (T1–2a Gleason score ≤6, PSA 10.1–20 ng/mL; T2b–2c Gleason ≤6, PSA ≤20 ng/mL; or T1–2 Gleason = 7, PSA ≤20 ng/mL) were randomly assigned in a noninferiority trial design to receive conventional radiation therapy (78 Gy in 39 fractions) versus hypofractionated radiation therapy (60 Gy over 20 fractions).[79]

After a median follow-up of 6 years (maximum 10 years), the primary end point of biochemical clinical failure (87%, PSA failure) was nearly identical with each radiation therapy schedule (85% in both arms; [DFS, 95% CI, 82%–88%]; HR, 0.96; 90% CI, 0.77–1.20).[79][Level of evidence B1]

In a multicenter trial (NCT00304759), 1,206 men with intermediate-risk prostate cancer (T1–2a Gleason score ≤6, PSA 10.1–20 ng/mL; T2b–2c Gleason ≤6, PSA ≤20 ng/mL; or T1–2 Gleason = 7, PSA ≤20 ng/mL) were randomly assigned in a noninferiority trial design to receive conventional radiation therapy (78 Gy in 39 fractions) versus hypofractionated radiation therapy (60 Gy over 20 fractions).[79]

The trial was severely underpowered to detect any differences in overall or prostate-specific mortality. Only 12 deaths in the conventional radiation therapy arm and 10 deaths in the hypofractionated radiation therapy arm were from prostate cancer. Only 14% of all deaths were attributed to prostate cancer.

In a multicenter trial (NCT00304759), 1,206 men with intermediate-risk prostate cancer (T1–2a Gleason score ≤6, PSA 10.1–20 ng/mL; T2b–2c Gleason ≤6, PSA ≤20 ng/mL; or T1–2 Gleason = 7, PSA ≤20 ng/mL) were randomly assigned in a noninferiority trial design to receive conventional radiation therapy (78 Gy in 39 fractions) versus hypofractionated radiation therapy (60 Gy over 20 fractions).[79]

Short- and long-term genitourinary and gastrointestinal toxicities were similar in both study groups.