A randomised assessment of image guided radiotherapy within a phase 3 trial of conventional or hypofractionated high dose intensity modulated radiotherapy for prostate cancer

Abstract

Background and purpose: Image-guided radiotherapy (IGRT) improves treatment set-up accuracy and provides the opportunity to reduce target volume margins. We introduced IGRT methods using standard (IGRT-S) or reduced (IGRT-R) margins in a randomised phase 2 substudy within CHHiP trial. We present a pre-planned analysis of the impact of IGRT on dosimetry and acute/late pelvic side effects using gastrointestinal and genitourinary clinician and patient-reported outcomes (PRO) and evaluate efficacy.

Materials and methods: CHHiP is a randomised phase 3, non-inferiority trial for men with localised prostate cancer. 3216 patients were randomly assigned to conventional (74 Gy in 2 Gy/fraction (f) daily) or moderate hypofractionation (60 or 57 Gy in 3 Gy/f daily) between October 2002 and June 2011. The IGRT substudy included a second randomisation assigning to no-IGRT, IGRT-S (standard CTV-PTV margins), or IGRT-R (reduced CTV-PTV margins). Primary substudy endpoint was late RTOG bowel and urinary toxicity at 2 years post-radiotherapy.

Results: Between June 2010 to July 2011, 293 men were recruited from 16 centres. Median follow-up is 56.9(IQR 54.3-60.9) months. Rectal and bladder dose-volume and surface percentages were significantly lower in IGRT-R compared to IGRT-S group; (p < 0.0001). Cumulative proportion with RTOG grade ≥ 2 toxicity reported to 2 years for bowel was 8.3(95% CI 3.2-20.7)%, 8.3(4.7-14.6)% and 5.8(2.6-12.4)% and for urinary 8.4(3.2-20.8)%, 4.6(2.1-9.9)% and 3.9(1.5-9.9)% in no IGRT, IGRT-S and IGRT-R groups respectively. In an exploratory analysis, treatment efficacy appeared similar in all three groups.

Conclusion: Introduction of IGRT was feasible in a national randomised trial and IGRT-R produced dosimetric benefits. Overall side effect profiles were acceptable in all groups but lowest with IGRT and reduced margins.

Isrctn: 97182923.

Keywords: Dosimetry; Image-guided radiotherapy; Prostate; Toxicity.

Fig. 1

CONSORT diagram.

Fig. 2

Boxplots illustrating dose volume and dose surface histograms, the calculated volume and surface percentages for rectum (A) and bladder (B) normal tissues by IGRT group and dose KEY: All doses are equivalent dose in 2 Gy fractions. Red boxplots represent patients treated with no IGRT, green boxplots are those patients treated with IGRT standard margins and blue boxplots are those patients treated with IGRT reduced margins.

Fig. 2

Boxplots illustrating dose volume and dose surface histograms, the calculated volume and surface percentages for rectum (A) and bladder (B) normal tissues by IGRT group and dose KEY: All doses are equivalent dose in 2 Gy fractions. Red boxplots represent patients treated with no IGRT, green boxplots are those patients treated with IGRT standard margins and blue boxplots are those patients treated with IGRT reduced margins.

Fig. 3

Acute RTOG bowel (A) and bladder (B) toxicity by timepoint and IGRT group. Distribution of grade and prevalence.

Fig. 4

Bowel (A) and bladder (B) toxicity assessed using RTOG, RMH and LENTSOM by timepoint and IGRT group. Distribution and cumulative proportion with grade ≥1 and grade ≥2 radiation induced late toxicity. KEY: For cumulative proportion plots: red = No IGRT, Green = IGRT-S, Blue = IGRT-R. Solid lines indicated grade ≥1 events and dashed lines indicate grade ≥2 events NB. Late toxicity data have been included in stacked bar charts if they were reported within 6 weeks of the 6 month visit, within 3 months of the 12–24 month visits and within 6 months of the 36 and 48 month visits.

Fig. 4

Bowel (A) and bladder (B) toxicity assessed using RTOG, RMH and LENTSOM by timepoint and IGRT group. Distribution and cumulative proportion with grade ≥1 and grade ≥2 radiation induced late toxicity. KEY: For cumulative proportion plots: red = No IGRT, Green = IGRT-S, Blue = IGRT-R. Solid lines indicated grade ≥1 events and dashed lines indicate grade ≥2 events NB. Late toxicity data have been included in stacked bar charts if they were reported within 6 weeks of the 6 month visit, within 3 months of the 12–24 month visits and within 6 months of the 36 and 48 month visits.