Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer

Abstract

Purpose: To determine if escalated radiation dose using hypofractionation significantly reduces biochemical and/or clinical disease failure (BCDF) in men treated primarily for prostate cancer.

Patients and methods: Between June 2002 and May 2006, men with favorable- to high-risk prostate cancer were randomly allocated to receive 76 Gy in 38 fractions at 2.0 Gy per fraction (conventional fractionation intensity-modulated radiation therapy [CIMRT]) versus 70.2 Gy in 26 fractions at 2.7 Gy per fraction (hypofractionated IMRT [HIMRT]); the latter was estimated to be equivalent to 84.4 Gy in 2.0 Gy fractions. High-risk patients received long-term androgen deprivation therapy (ADT), and some intermediate-risk patients received short-term ADT. The primary end point was the cumulative incidence of BCDF. Secondarily, toxicity was assessed.

Results: There were 303 assessable patients with a median follow-up of 68.4 months. No significant differences were seen between the treatment arms in terms of the distribution of patients by clinicopathologic or treatment-related (ADT use and length) factors. The 5-year rates of BCDF were 21.4% (95% CI, 14.8% to 28.7%) for CIMRT and 23.3% (95% CI, 16.4% to 31.0%) for HIMRT (P = .745). There were no statistically significant differences in late toxicity between the arms; however, in subgroup analysis, patients with compromised urinary function before enrollment had significantly worse urinary function after HIMRT.

Conclusion: The hypofractionation regimen did not result in a significant reduction in BCDF; however, it is delivered in 2.5 fewer weeks. Men with compromised urinary function before treatment may not be ideal candidates for this approach.

Trial registration: ClinicalTrials.gov NCT00062309.

Fig 1.

CONSORT diagram. Ca, cancer; CIMRT, conventional fractionated intensity-modulated radiotherapy; Dx, diagnosis; HIMRT, hypofractionated intensity-modulated radiotherapy.

Fig 2.

Incidence of biochemical or clinical disease failure (BCDF) using (A) protocol-adjusted ASTRO (American Society for Radiation Oncology) and (B) nadir plus 2 criteria for biochemical failure and (C) overall survival (OS) and incidence of prostate cancer death (PRCA) and death resulting from other causes. P values compare treatment arms using Gray's test for cumulative incidence of BCDF and PRCA; log-rank test was used for OS. The 5-year rates for BCDF using the protocol-adjusted ASTRO definition of biochemical failure were 21.4 (95% CI, 14.8 to 28.7) and 23.3 (95% CI, 16.4 to 31.0) for conventional fractionated intensity-modulated radiotherapy (CIMRT) and hypofractionated intensity-modulated radiotherapy (HIMRT), respectively. The 5-year rates for BCDF using the nadir plus 2 definition of biochemical failure were 14.8 (95% CI, 9.3 to 21.4) and 19.0 (95% CI, 12.6 to 26.5) for CIMRT and HIMRT, respectively. Vertical bars depict 95% CIs.

Fig 3.

(A, B) Prevalence and (C, D, E) incidence of (A, C) GI and (B, D, E) genitourinary (GU) adverse effects. (A, B) Prevalence plots display baseline, acute (3 months), and late reactions (≥ 6 months). (C, D, E) Cumulative incidence plots display first grade ≥ 2 toxicity occurring ≥ 3 months after completing irradiation using (C, D) original GI and GU definitions and (E) amended GU criteria. P values compare adverse reactions by treatment arm using Gray's test. Vertical bars depict 95% CIs. CIMRT, conventional fractionated intensity-modulated radiotherapy; HIMRT, hypofractionated intensity-modulated radiotherapy.

Fig 4.

Cumulative incidence of late grade ≥ 2 genitourinary (GU) toxicity subdivided by treatment arm (conventional fractionated intensity-modulated radiotherapy [CIMRT] v hypofractionated intensity-modulated radiotherapy [HIMRT]) and International Prostate Symptom Score (IPSS) at a cut point of 12. Results using (A) original protocol definition of GU toxicity and (B) amended criteria are shown. P value determined using Gray's test.