Separate phase III trials presented at the 2016 Genitourinary Cancers Symposium demonstrated that modest hypofractionated radiotherapy is noninferior to conventional radiotherapy for men with intermediate- and low-risk prostate cancer and should be considered a new standard of care.^1,2 However, it is not clear how widely adopted hypofractionation schedules will be.

NRG Oncology RTOG 0415

NRG Oncology RTOG 0415 was a randomized, phase III, noninferiority study comparing two fractionation schedules in men with low-risk prostate cancer: conventional radiotherapy (73 Gy in 41 fractions over 8.3 weeks) vs hypofractionation (70 Gy in 28 fractions over 5.6 weeks).¹

The study enrolled 1,115 patients with low-risk prostate cancer. No androgen suppression was given. Patients were stratified according to Gleason score 2–4 and Gleason score 5–6.

The primary endpoint was disease-free survival, defined as local disease progression, distant disease progression, biochemical recurrence, or death from any cause. There were three planned interim analyses.

Both arms were well balanced for demographic and disease characteristics; more than 50% were younger than age 70; 17% were African American; 80% had a prostate-specific antigen (PSA) level of between 4 and 10 ng/mL; more than 75% had nonpalpable disease.

At the third planned interim analysis, the data monitoring committee recommended that trial results be reported early, at a median follow-up of 5.9 years. The most common outcome was death without recurrence, followed by biochemical recurrence. No prostate cancer–specific deaths were reported.

W. Robert Lee, MD, of Duke University Medical Center, Durham, North Carolina, reported updated results of this trial at the 2016 Genitourinary Cancers Symposium. Five-year disease-free survival was 86% for the conventional arm vs 85% for the hypofractionation arm, which met the predefined criteria for noninferiority. The rate of biochemical recurrence at 5 years was 8% in the conventional arm vs 6% in the hypofractionation arm— which also met the predefined criteria for noninferiority.

Acute adverse genitourinary and gastrointestinal events were not significantly different statistically for both treatment assignments. Physician-reported late adverse events showed significantly greater grade 2 toxicity in the 70-Gy arm, but there were no differences observed in severe late effects between the two arms.

CHHiP Trial

In the CHHiP trial, following treatment with 3 to 6 months of androgen-deprivation therapy, 3,216 men from 71 centers with predominantly intermediate-risk prostate cancer (stage T1b to T3a) were randomized to receive conventional fractionation (74 Gy in 37 fractions) or one of two experimental arms: 60 Gy in 20 fractions or 57 Gy in 19 fractions.² The primary endpoint was biochemical failure or prostate cancer recurrence.

The primary results of the CHHiP trial were presented at the 2016 European Cancer Congress. At the 2016 Genitourinary Cancers Symposium, David Dearnaley, MD, of the Institute of Cancer Research and Royal Marsden Hospital, London, United Kingdom, updated these results comparing the two experimental arms.

The median age was 69 years; the majority of men had T2 disease; the median PSA level was 10 ng/mL; 98% received radiotherapy as planned. Nearly three-quarters of the patients had intermediate-risk disease, 15% had low-risk disease, and 12% had high-risk prostate cancer. Sixty-two percent had a Gleason score of 7, and 35% had a Gleason score of less than 7.

Five-year progression-free survival was 88.3% in the 74-Gy arm, 90.6% in the 60-Gy arm, and 85.9% in the 57-Gy arm. The 60-Gy arm met the noninferiority criterion compared with the 74-Gy schedule, but the 57-Gy arm did not. The all-cause mortality rate was 8.6%, 6.8%, and 8.1%, respectively, with only 1.2% of men dying from prostate cancer.

“We can say that the 60-Gy arm is at least as good and is noninferior to 74 Gy. But we cannot claim noninferiority for the 57-Gy arm,” Dr. Dearnaley told the audience. “Comparing the two experimental arms, 57 Gy is statistically inferior.”

Acute bowel toxicity was significantly worse for both hypofractionated arms compared with standard fractionation (P < .001 for each comparison), but these differences had resolved 18 weeks after the start of radiotherapy, and no patients had a grade 3 side effect. Treatment with 60 Gy in 20 fractions was associated with a small increase in late bowel toxicity compared with 57 Gy. There was no significant difference in acute bowel or bladder toxicity between the two hypofractionation arms. There was no difference in sexual dysfunction between the three treatment arms.

“We believe that modified hypofractionation, using 60 Gy in 20 fractions, delivered with high-quality radiotherapy, can now be recommended as a new standard of care in patients with this type of localized prostate cancer,” he said. “The low side-effect profile, in general, probably reflects the technique of radiotherapy and the strict use of dose constraint and quality assurance,” concluded Dr. Dearnaley. ■

Disclosure: Dr. Lee has received honoraria from Ferring. Dr. Dearnaley has received honoraria and travel expenses from Takeda; is a consultant or advisor for FirstWord, AstraZeneca, Janssen, Astellas and Ipsen, Janssen Research and Development, Sandoz, and Takeda.

References

1. Lee WR, Dignam JJ, Amin M, et al: NRG Oncology RTOG 0415. 2016 Genitourinary Cancers Symposium. Abstract 1. Presented January 7, 2016.

2. Dearnaley DP, Syndikus I, Mossop H, et al: Comparison of hypofractionated high-dose intensity-modulated radiotherapy schedules for prostate cancer. 2016 Genitourinary Cancers Symposium. Abstract 2. Presented January 7, 2016.