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).

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.

Evaluation of margining algorithms in commercial treatment planning systems.

INTRODUCTION: During commissioning of the Pinnacle (Philips) treatment planning system (TPS) the margining algorithm was investigated and was found to produce larger PTVs than Plato (Nucletron) for identical GTVs. Subsequent comparison of PTV volumes resulting from the QA outlining exercise for the CHHIP (Conventional or Hypofractionated High Dose IMRT for Prostate Ca.) trial confirmed that there were differences in TPS's margining algorithms. Margining and the clinical impact of the different PTVs in seven different planning and virtual simulation systems (Pinnacle, Plato, Prosoma (MedCom), Eclipse (7.3 and 7.5) (Varian), MasterPlan (Nucletron), Xio (CMS) and Advantage Windows (AW) (GE)) is investigated, and a simple test for 3D margining consistency is proposed. METHODS: Using each TPS, two different sets of prostate GTVs on 2.5mm and 5mm slices were margined according to the CHHIP protocol to produce PTV3 (prostate+5 mm/0 mm post), PTV2 (PTV3+5 mm) and PTV1 (prostate and seminal vesicles+10 mm). GTVs and PTVs were imported into Pinnacle for volume calculation. DVHs for 5mm slice plans, created using the smallest PTVs, were recalculated on the largest PTV dataset and vice versa. Since adding a margin of 50 mm to a structure should give the same result as adding five margins of 10 mm, this was tested for each TPS (consistency test) using an octahedron as the GTV and CT datasets with 2.5 mm and 5 mm slices. RESULTS: The CHHIP PTV3 and PTV1 volumes had a standard deviation, across the seven systems, of 5% and PTV2 (margined twice) 9%, on the 5 mm slices. For 2.5 mm slices the standard deviations were 4% and 6%. The ratio of the Pinnacle and the Eclipse 7.3 PTV2 volumes was 1.25. Rectal doses were significantly increased when encompassing Pinnacle PTVs (V(50)=42.8%), compared to Eclipse 7.3 PTVs (V(50)=36.4%). Conversely, fields that adequately treated an Eclipse 7.3 PTV2 were inadequate for a Pinnacle PTV2. AW and Plato PTV volumes were the most consistent (0.3%) and (-0.4%). However, the 1x50mm margin in Pinnacle produced a 15.9% larger volume than 5 x 10 mm margins, while for Eclipse 7.3 the single margined volume was 14.3% smaller. These inconsistencies were reduced to approximately 5% by adjusting the superior/inferior margins. CONCLUSIONS: Accurate margin algorithms are necessary to ensure that volume expansion does not add extra uncertainty to the radiotherapy planning process. We have found significant differences in the 3D margining algorithms of TPSs, devised a simple test to predict inconsistency and suggested corrective action to minimise the variation.