Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localized prostate cancer.

— David Dearnaley, FRCR, and colleagues

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Two recent European phase III trials with different study designs focused on hypofractionated vs conventional radiotherapy in localized prostate cancer. Investigators in the CHHiP trial¹ showed that the hypofractionated approach is noninferior to standard fractionation, with no increase in side effects, and suggested it should become a new standard of care. Investigators in the HYPRO trial² cautioned against dose escalation to much higher levels without adjusting the volume of tissues to be treated to high dose, as a result of higher toxicity without a statistically significant gain in disease control. Side effects assessed with several other physician- and patient-completed instruments/scores also showed no differences between the standard and hypofractionated schedules. The CHHiP findings were reported by David Dearnaley, FRCR, of The Institute of Cancer Research, London, and the HYPRO findings were reported by Luca Incrocci, MD, of Erasmus MC Cancer Institute, both in The Lancet Oncology.

CHHiP Trial

In the open-label noninferiority CHHiP trial, 3,216 men with localized prostate cancer (T1b–T3aN0M0) from 71 sites in the UK, Republic of Ireland, Switzerland, and New Zealand were randomized between October 2002 and June 2011 to receive conventional radiotherapy at 74 Gy in 37 fractions over 7.4 weeks (n = 1,065) or hypofractionated radiotherapy at 60 Gy in 20 fractions over 4 weeks (n = 1,074) or 57 Gy in 19 fractions over 3.8 weeks (n = 1,077) given by intensity-modulated techniques. Most patients received radiotherapy with 3 to 6 months of neoadjuvant and concurrent androgen suppression. The primary endpoint was time to biochemical or clinical failure in the intent-to-treat population, with a hazard ratio (HR) for noninferiority of 1.208. The current analysis reports 5-year outcomes; long-term follow-up is ongoing.

Median follow-up was 62.4 months. At 5 years, biochemical or clinical failure–free rates were 88.3% (95% confidence interval [CI] = 86.0%–90.2%) in the conventional 74-Gy group, 90.6% (95% CI = 88.5%–92.3%) in the hypofractionated 60-Gy group (noninferior to conventional radiotherapy; HR = 0.84, 90% CI = 0.68–1.03, P = .0018 for noninferiority), and 85.9% (95% CI = 83.4%–88.0%) in the hypofractionated 57-Gy group (noninferiority not shown vs conventional radiotherapy; HR = 1.20, 90% CI = 0.99–1.46, P = .48 for noninferiority).

Hypofractionated radiotherapy was not superior to conventional radiotherapy with respect to 5-year relapse-free survival. Our hypofractionated radiotherapy regimen cannot be regarded as the new standard of care for patients with intermediate-risk or high-risk prostate cancer.

— Luca Incrocci, MD, and colleagues

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Acute Radiation Therapy Oncology Group (RTOG) bowel and bladder symptoms peaked sooner in the hypofractionated groups (4–5 vs 7–8 weeks). RTOG grade ≥ 2 bowel and bladder toxicity occurred in 25% and 46% of the conventional group, 38% and 49% of the 60-Gy group, and 38% and 46% of the 57-Gy group, respectively. By 18 weeks, rates were similar among the groups. Long-term adverse effects were similar among groups. Estimated cumulative 5-year rates of RTOG grade ≥ 2 bowel and bladder adverse events were 13.7% and 9.1%, 11.9% and 11.7%, and 11.3% and 6.6%, respectively. There were no treatment-related deaths.

The investigators concluded: “Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localized prostate cancer.”

HYPRO Trial

In the Dutch open-label HYPRO trial, 804 evaluable patients from 7 sites in the Netherlands with intermediate- to high-risk T1b–T4NX–N0MX–M0 localized disease were randomized between March 2007 and December 2010 to receive conventional radiotherapy at 78.0 Gy in 39 fractions of 2.0 Gy in 5 fractions per week (n = 397) or hypofractionated radiotherapy at 64.6 Gy in 19 fractions of 3.4 Gy in 3 fractions per week (n = 407). Intensity-modulated radiotherapy was used in 95% of patients. Androgen-deprivation therapy was received by 67% of patients for a median of 32 months. The primary endpoint was relapse-free survival in the intent-to-treat population, with the current (final) analysis reporting results at 5 years. Follow-up is ongoing.

Median follow-up was 60 months. Treatment failure occurred in 22% of the conventional group and 20% of the hypofractionated group. Relapse-free survival at 5 years was 77.1% (95% CI = 71.9%–81.5%) in the conventional group vs 80.5% (95% CI = 75.7%–84.4%) in the hypofractionation group (adjusted HR = 0.86, P = .36).

Acute and late toxicities were reported in earlier publications.^3,4 Differences between the groups in grade ≥ 2 acute toxicities were no longer apparent at 3 months after treatment, and no significant differences in grade ≥ 2 late toxic effects were observed. There were no treatment-related deaths.

The investigators concluded: “Hypofractionated radiotherapy was not superior to conventional radiotherapy with respect to 5-year relapse-free survival. Our hypofractionated radiotherapy regimen cannot be regarded as the new standard of care for patients with intermediate-risk or high-risk prostate cancer.” ■

Disclosure: The CHHiP trial was funded by Cancer Research UK, the Department of Health, and the National Institute for Health Research Cancer Research Network. The HYPRO trial was funded by the Dutch Cancer Society. For full disclosures of the study authors, visit www.thelancet.com.

References

1. Dearnaley D, Syndikus I, Mossop H, et al: Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol 17:1047-1060, 2016.

2. Incrocci L, Wortel RC, Alemayehu WG, et al: Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): Final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 17:1061-1069, 2016.

3. Aluwini S, Pos F, Schimmel E, et al: Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): Acute toxicity results from a randomised non-inferiority phase 3 trial. Lancet Oncol 16:274-283, 2015.

4. Aluwini S, Pos F, Schimmel E, et al: Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): Late toxicity results from a randomised, non-inferiority, phase 3 trial. Lancet Oncol 17:464-474, 2016.