Hypofractionated Radiotherapy May Be New Standard of Care in Prostate Cancer

David P. Dearnaley, MD

Hypofractionated radiotherapy demonstrated similar toxicity and was noninferior to standard radiation therapy for preventing PSA increases or disease recurrences for men with intermediate-risk prostate cancer, according to data from the phase III randomized CHHiP trial reported at the 2016 GU Cancers Symposium.

After 62 months of follow-up, hypofractionated radiotherapy at 60 Gy over 20 fractions reduced the risk of biochemical failure or recurrence by 16% versus standard 74 Gy radiotherapy (HR, 0.84; 90% CI, 0.68-1.03; P = .004). Moreover, a significant difference was not observed between each schedule for acute bladder or bowel toxicity.

“The treatments are all pretty good,” said lead investigator David P. Dearnaley, MD, Academic Unit of Radiotherapy at The Royal Marsden and The Institute of Cancer Research. “We believe that modest hypofractionation at 60 Gy in 20 fractions delivered with high quality radiotherapy techniques can now be recommended as a new standard of care in patients with this type of intermediate and low/high-risk cancer.”

In the 3-arm study, 3163 patients were randomized to receive standard 74 Gy in 37 fractions over 7.4 weeks (n = 1065), 60 Gy in 20 fractions over 4 weeks (n = 1074), or 57 Gy in 19 fractions over 3.8 weeks (n = 1077). Patients received hormonal therapy for a median of 3.8 months prior to starting radiotherapy. Overall, the total duration of hormonal therapy was a median 5.6 months.

The median age of patients across all groups was 69 years, and the median PSA was 10 ng/ml. Patients primarily were at intermediate risk (73%), with 15% in the low- and 12% in the high-risk groups. The Gleason score was ≤6 for 35% of patients, 62% had a Gleason of 7 and 3% had an 8.

The primary endpoint of the study assessed non-inferiority between each dose for biochemical failure or prostate cancer recurrence. For this measurement, the therapy was considered non-inferior if the hazard ratio was below 1.208 or within a 5% margin. Secondary outcome measures included toxicity, quality of life, and overall survival.

The 5-year biochemical control rate was 88.3% in the standard 74 Gy arm. The event-free rate with the 60 Gy dose was 90.6%, representing non-inferiority compared with the standard dose.

The 5-year event-free rate in the 57 Gy arm was 85.9%. The 60 Gy dose was superior 57 Gy (HR, 1.44; 95% CI, 1.13-1.82; P = .003). The hazard ratio for the 57 Gy dose versus standard 74 Gy radiotherapy was 1.20 (90% CI, 0.99-1.46; P = .96).

“We can conclusively say that 60 Gy is noninferior to 74 Gy, which is the main endpoint of the study," said Dearnaley. “We cannot claim noninferiority for the 57 Gy group, because that straddles the 1.20 critical hazard ratio.”

The data for overall survival remained immature at the 5-year analysis, with 1.2% of patients having died from prostate cancer and 7.8% dying from all causes. The hazard ratio for the 60 Gy dose versus the 74 Gy dose was 0.78 (95% CI, 0.57-1.05).

“We've only got 1.2% prostate cancer deaths. Total deaths are 7.8%. We'll have to wait and see,” said Dearnaley.

Grade 3/4 bladder-specific symptoms were experience by 9.2% of those in the 60 Gy arm and for 9.3% of patients in the 57 Gy arm. For the standard therapy arm, 8.1% of patients had grade 3/4 bladder toxicity.

Grade ≥2 bowel toxicity was significantly worse with hypofractionated radiotherapy (P <.001). Overall, 38.5% and 37.8% of patients in the 60 Gy and 57 Gy arms experienced a grade ≥2 event, respectively.

“Overall, there is no difference in acute bladder reactions but you get different timing in the wave of reactions,” said Dearnaley. “For bowel, its a bit different. You get the same difference in the timing but you do get a significant increase in grade 1, 2, and 3 side effects.”

At 24 months, 5.4% of those in the 60 Gy and 4.4% of those in the 57 Gy arm had late grade ≥2 GI toxicity. At 60 months, 5.2% and 3.9% of patients had a grade ≥2 late event in the 60 Gy and 57 Gy groups, respectively. At 24 and 60 months, bowel-related toxicity resulted in a small change in quality of life patients in the 60 Gy and 57 Gy groups; however, these changes were not deemed statistically significant.

Overall, the cumulative incidence of bowel events was higher in the 60 Gy arm compared with the 57 Gy group. At 60 months, the cumulative rate of grade ≥2 bowel toxicity was 25.9% in the 60 Gy arm versus 18.5% in the 57 Gy group. Grade ≥1 bowel events were 17% higher (P = .002) and grade ≥2 events were 28% more common (P = .001) in the 60 Gy group versus the 57 Gy arm.

Neither group demonstrated a statistically significant difference compared with standard therapy, noted Dearnaley.

Overall, bladder symptoms were less common at the 2- and 5-year analyses compared with pretreatment measurements. The cumulative incidence of grade ≥2 bladder toxicity at 60 months was 50% in the 60 Gy group versus 41.4% in the 57 Gy arm (HR, 0.84; P = .02).

“Actually, the bladder gets a bit better when you treat the prostate. You can see a small difference post-treatment between the 57 and the 60 Gy, which is of borderline significance,” said Dearnaley. “There's also really no difference between the 3 groups for sexual dysfunction.”

The overall low incidence of adverse events seen in the study may have been attributed to the technique utilized for delivering radiation therapy, Dearnaley theorized. In the study, forward or inverse planned intensity-modulated radiotherapy was administered simultaneously with an integrated boost technique with normal tissue dose constraints.

Building on the findings from the study, Dearnaley noted that image-guided radiotherapy could help to further perfect the 57 Gy dose using a boost dose for dominant intraprostatic lesions. This could have advantages, since this lower dose was associated with fewer adverse events.

Dearnaley DP, Syndikus I, Mossop H, et al. Comparison of hypofractionated high-dose intensity-modulated radiotherapy schedules for prostate cancer: Results from the phase III randomized CHHiP trial (CRUK/06/016). J Clin Oncol. 2016;34 (suppl 2S; abstr 2).

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