Toxicity and Patient-Reported Outcomes of a Phase 2 Randomized Trial of Prostate and Pelvic Lymph Node Versus Prostate only Radiotherapy in Advanced Localised Prostate Cancer (PIVOTAL)

Abstract

Purpose: To establish the toxicity profile of high-dose pelvic lymph node intensity-modulated radiation therapy (IMRT) and to assess whether it is safely deliverable at multiple centers.

Methods and materials: In this phase 2 noncomparative multicenter trial, 124 patients with locally advanced, high-risk prostate cancer were randomized between prostate-only IMRT (PO) (74 Gy/37 fractions) and prostate and pelvic lymph node IMRT (P&P; 74 Gy/37 fractions to prostate, 60 Gy/37 fractions to pelvis). The primary endpoint was acute lower gastrointestinal (GI) Radiation Therapy Oncology Group (RTOG) toxicity at week 18, aiming to exclude a grade 2 or greater (G2+) toxicity-free rate of 80% in the P&P group. Key secondary endpoints included patient-reported outcomes and late toxicity.

Results: One hundred twenty-four participants were randomized (62 PO, 62 P&P) from May 2011 to March 2013. Median follow-up was 37.6 months (interquartile range [IQR], 35.4-38.9 months). Participants had a median age of 69 years (IQR, 64-74 years) and median diagnostic prostate-specific androgen level of 21.6 ng/mL (IQR, 11.8-35.1 ng/mL). At week 18, G2+ lower GI toxicity-free rates were 59 of 61 (96.7%; 90% confidence interval [CI], 90.0-99.4) for the PO group and 59 of 62 (95.2%; 90% CI, 88.0-98.7) for the P&P group. Patients in both groups reported similarly low Inflammatory Bowel Disease Questionnaire symptoms and Vaizey incontinence scores. The largest difference occurred at week 6 with 4 of 61 (7%) and 16 of 61 (26%) PO and P&P patients, respectively, experiencing G2+ toxicity. At 2 years, the cumulative proportion of RTOG G2+ GI toxicity was 16.9% (95% CI, 8.9%-30.9%) for the PO group and 24.0% (95% CI, 8.4%-57.9%) for the P&P group; in addition, RTOG G2+ bladder toxicity was 5.1% (95% CI, 1.7%-14.9%) for the PO group and 5.6% (95% CI, 1.8%-16.7%) for the P&P group.

Conclusions: PIVOTAL demonstrated that high-dose pelvic lymph node IMRT can be delivered at multiple centers with a modest side effect profile. Although safety data from the present study are encouraging, the impact of P&P IMRT on disease control remains to be established.

Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1

PIVOTAL Consolidated Standards of Reporting Trials flowchart.

Fig. 2

Distribution of acute Radiation Therapy Oncology Group (RTOG) toxicity and prevalence of grade 1+, grade 2+, and grade 3+ toxicity at weeks 2, 4, 6, 8, 10, and 18 from the start of radiation therapy. (A) Lower gastrointestinal symptoms. (B) Bladder symptoms.

Fig. 3

Distribution of late (A) Common Terminology Criteria for Adverse Events (CTCAE) and (B) Radiation Therapy Oncology Group (RTOG) lower gastrointestinal and bladder toxicity and time to first reported G1+ and G2+ toxicity.

Fig. 3

Distribution of late (A) Common Terminology Criteria for Adverse Events (CTCAE) and (B) Radiation Therapy Oncology Group (RTOG) lower gastrointestinal and bladder toxicity and time to first reported G1+ and G2+ toxicity.

Fig. 4

The percentage of patients with clinically significant changes in patient-reported outcomes from pre–radiation therapy to each assessment time for the (A) Inflammatory Bowel Disease Questionnaire (IBDQ) score, (B) Vaizey score, and (C) International Prostate Symptom Score (IPSS) score. An improvement from pre–radiation therapy is indicated as a positive percentage score and a deterioration from pre–radiation therapy is indicated as a negative percentage score.