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)

David Dearnaley,Clare L Griffin,Rebecca Lewis,Philip Mayles,Helen Mayles,Olivia F Naismith,Victoria Harris,Christopher D Scrase,John Staffurth,Isabel Syndikus,Anjali Zarkar,Daniel R Ford,Yvonne L Rimmer,Gail Horan,Vincent Khoo,John Frew,Ramachandran Venkitaraman,Emma Hall

doi:10.1016/j.ijrobp.2018.10.003

Abstract

PurposeTo 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 MaterialsIn 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.ResultsOne 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.ConclusionsPIVOTAL 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.

Highlights

Prostate cancer is the most common cancer among men in the United Kingdom.1 the majority of patients with newly diagnosed cancer have localized disease, a significant proportion have locally advanced disease, carrying a high risk of pelvic lymph node (LN) involvement
To establish the toxicity profile of high-dose pelvic lymph node intensitymodulated radiation therapy (IMRT) and to assess whether it is safely deliverable at multiple centers
In this phase 2 noncomparative multicenter trial, 124 patients with locally advanced, high-risk prostate cancer were randomized between prostateonly intensity-modulated radiation therapy (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)

Summary

Introduction

Prostate cancer is the most common cancer among men in the United Kingdom. the majority of patients with newly diagnosed cancer have localized disease, a significant proportion have locally advanced disease, carrying a high risk of pelvic lymph node (LN) involvement. The majority of patients with newly diagnosed cancer have localized disease, a significant proportion have locally advanced disease, carrying a high risk of pelvic lymph node (LN) involvement. Current treatment for such patients is long-term androgen suppression and radiation therapy, which confers an improvement in overall survival.. Regional nodal irradiation provides a survival advantage to patients with localized high-risk breast cancer; it is uncertain whether the same effect is seen in prostate cancer.. Intensity-modulated radiation therapy (IMRT) was used in some cases, the pelvic radiation dose was generally conservative, and median follow-up was 81 months; there might not have been sufficient time to observe an effect on overall survival. The radiation therapy techniques used in these studies have since been superseded by IMRT, enabling better shaping of dose distributions to target volume, reducing bowel irradiation, and allowing dose escalation to the LN.

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