Citations

SummaryBackgroundThe goal of hepatorenal syndrome type 1 (HRS‐1) treatment is to improve renal function. Terlipressin, a synthetic vasopressin analogue, is a systemic vasoconstrictor used for the treatment of HRS‐1, where it is available.AimTo compare the efficacy of terlipressin plus albumin vs. placebo plus albumin in patients with HRS‐1.MethodsPooled patient‐level data from two large phase 3, randomised, placebo‐controlled studies were analysed for HRS reversal [serum creatinine (SCr) value ≤133 μmol/L], 90‐day survival, need for renal replacement therapy and predictors of HRS reversal. Patients received intravenous terlipressin 1–2 mg every 6 hours plus albumin or placebo plus albumin up to 14 days.ResultsThe pooled analysis comprised 308 patients (terlipressin: n = 153; placebo: n = 155). HRS reversal was significantly more frequent with terlipressin vs. placebo (27% vs. 14%; P = 0.004). Terlipressin was associated with a more significant improvement in renal function from baseline until end of treatment, with a mean between‐group difference in SCr concentration of −53.0 μmol/L (P < 0.0001). Lower SCr, lower mean arterial pressure and lower total bilirubin and absence of known precipitating factors for HRS were independent predictors of HRS reversal and longer survival in terlipressin‐treated patients.ConclusionsTerlipressin plus albumin resulted in a significantly higher rate of HRS reversal vs. albumin alone in patients with HRS‐1. Terlipressin treatment is associated with improved renal function. (ClinicalTrials.gov identifier: OT‐0401, NCT00089570; REVERSE, NCT01143246).

48 Background: The purpose of this study is to identify differences in toxicity, quality of life (QOL), and dosimetric endpoints among patients with low-risk prostate adenocarcinoma treated with either standard fractionation or hypofractionation proton-beam therapy. Methods: We analyzed the results of the first 75 patients treated in our phase III trial comparing 38Gy relative biological effectiveness (RBE) in 5 fractions (fx) (n = 46) vs. 79.2Gy (RBE) in 44 fx. (n = 29). All patients had low-risk prostate cancer and were treated with proton radiation using fiducial markers and daily image guidance. We evaluated American Urological Association (AUA) Symptom Index, adverse events (AEs), and Expanded Prostate Index Composite (EPIC) domains at pretreatment and 3, 6, 12, 18, 24, 36 and 48 months. Doses to the prostate were selected based on similar long term effects to normal tissue based on an α/β = 3.5 for an EQD2 of 76Gy. Results: The median follow-up was 36 months for both groups; 23 (30%) patients reached a follow-up of 48 months. We observed a small difference in AUA score (3.2 vs. 8.6, p = 0.002) at 1-year favoring the 79.2Gy arm. AUA scores were not statistically different at 18 months and after. Similarly, EPIC Urinary symptoms favored the 79.2Gy arm at 1 year (92.3 vs. 84.5, p = 0.009) and 18 months (92.3 vs. 85.3, p = 0.03); bother scores were not significantly different at any other time points. G2 or higher GU toxicity was similar between arms (p = 0.8). No differences in EPIC Bowel symptoms, EPIC Sexual symptoms, or bowel G2 or higher toxicities were seen. One death was observed in the 38Gy arm due to an unrelated case of multiple myeloma. The bladder V80 (79.2Gy arm, p = 0.04) and V39 (38Gy arm, p = 0.05) were predictive for G2 or higher GU AE. There was no association observed between rectal dose and G2 or higher rectal toxicity. Conclusions: Patients treated in the hypofractionated and standard arms tolerated treatment well. A small and temporary difference in the GU domain was seen favoring the standard arm. As predicted long term effects on the GU domain and bowel were similar for both arms, suggesting that the α/β is similar to 3.5 for long term effects. Clinical trial information: 01230866.

389 Background: The liver is one of the most radiosensitive organs, making radiation therapy (RT) for liver tumors extremely challenging. RT is appropriate only for a minority of liver patients with limited tumor burden; a reduction in the prescribed radiation dose may be needed to lower the probability of radiation-induced liver disease especially in the presence of cirrhosis. Proton beam therapy (PBT) delivers less dose to the liver than photon therapy and is expected to reduce toxicity while also permitting safe dose escalation for some patients with liver tumors. Methods: The Proton Collaborative Group REG001-09 trial (NCT01255748) prospectively collects data for PBT patients with a variety of cancer types. To better understand treatment details and outcomes associated with liver PBT, patients enrolled on the PCG registry trial from 5 institutions who received liver PBT for any cancer between 2012 and 2016 were analyzed. Results: A total of 43 liver cancer patients were included, most with hepatocellular carcinoma (48.8%) or cholangiocarcinoma (25.6%). The vast majority did not have surgery at any time (86%). Most were treatment naive prior to PBT; 2 previously had RT and 8 had prior chemotherapy (mostly cholangiocarcinoma patients). The median total prescribed PBT dose was 58.05 Gy(RBE) (range 21.7-67.5). The median number of prescribed fractions was 15 (range 12-37). PBT was delivered to only the liver in 90.7% of patients; inclusion of lymph nodes was rare. Uniform scanning was used in 26 (72.1%) and pencil beam scanning in 2 patients (4.7%); the delivery technique used for the remaining patients was unknown (23.2%). With median follow up of 4.4 months (range 1.3-17.9), 3 patients (7%) had an intrahepatic recurrence, 2 patients (4.6%) developed distant metastasis, and 10 patients (23.3%) died. No grade 3 or higher toxicity was reported although 17 patients (39.5%) had grade 2 toxicity predominantly fatigue, anorexia, nausea, or vomiting. Conclusions: Although longer follow up is needed to assess late toxicities as well as disease control, early outcomes from the PCG registry trial for liver cancer patients shows that predominantly hypofractionated PBT has a very favorable acute toxicity profile.

Abstract Background: Post-mastectomy radiotherapy improves survival in women with node-positive breast cancer. Pencil beam scanning proton therapy is attractive due to potential to reduce the dose to the heart and lungs compared with traditional photon techniques while improving conformality and limiting skin dose compared with passively scanned proton therapy. The optimal dose and fractionation for pencil-beam scanning proton therapy remains unknown. Trial Design: This is a multi-center open label phase II randomized controlled trial to determine the safety of 15 fraction vs 25 fraction pencil beam scanning proton radiotherapy after mastectomy in patients requiring regional nodal irradiation. Eligibility Criteria: Patients ≥ 18 years with primary, non-inflammatory invasive breast cancer who have undergone mastectomy with or without immediate reconstruction and chest wall and regional nodal irradiation planned. Aims: To determine whether the 24 month complication rate (defined as grade 3 or greater late adverse events, and unplanned surgical intervention in patients who undergo mastectomy with reconstruction) of 15 fraction chest wall and regional node pencil beam scanning proton radiotherapy is acceptable relative to 25 fraction chest wall and regional nodal pencil beam scanning proton radiotherapy and worthy of further investigation. Statistical methods: The study is designed as a non-inferiority/superiority “hybrid” design using the approach of Freidlin et al. It is Using a one-sided type I error rate of 0.05 (corresponding equivalently to constructing a 1-sided 95% confidence limit), 72 evaluable patients will have 80% power to reject the null hypothesis that the 24-month complication rate in the experimental arm is higher than that of the control arm by more than 10% (i.e. rule out inferiority) under the alternative hypothesis that the complication rate in the experimental arm is 5% less than that of the control arm (i.e. superiority). However, the design will have only 41% power when the two treatment arms are equivalent (i.e. the complication rate is 10% for both arms). Accrual: The study opened in June 2016. Five of a planned eighty-two patients have been accrued to date. Citation Format: Mutter RW, Park SS, Hieken TJ, Vargas CE, Mei-Yin PC, Kathryn RJ, Hector VR, Kimberly CS, Elizabeth YS, Daniel VW. A randomized trial of 15 fraction vs 25 fraction pencil beam scanning proton radiotherapy after mastectomy in patients requiring regional nodal irradiation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-03-03.

PURPOSE: The toxicity profile of fluorouracil (5-FU)–based chemotherapy given on 5 consecutive days at doses of 370 to 450 mg/m2 has been well documented. A meta-analysis of six North Central Cancer Treatment Group (NCCTG) cancer control trials involving 786 patients indicated that women treated with this type of regimen experienced more severe stomatitis and leukopenia than men. After these findings, an additional meta-analysis of the toxicity profiles on five NCCTG colorectal cancer treatment trials was undertaken. METHODS: Data for 1,093 women and 1,355 men from 12 different treatment arms were included. The primary end points were the incidence of stomatitis, leukopenia, alopecia, diarrhea, nausea, and vomiting, recorded with standard National Cancer Institute common toxicity criteria. Fisher’s exact test was used to compare incidence and severity across sexes, supplemented by Forrest meta-analysis plots and logistic regression. RESULTS: The incidence of four out of six toxicities studied was significantly greater for women than men; the exceptions were severe nausea and vomiting. Overall, almost half of the women compared with a third of the men experienced severe toxicity (P < .0001). Logistic regression confirmed the univariate findings while adjusting for the effects of study, dose, body mass index, and age. The differences were consistent across treatment cycles. Response rates and survival distributions were the same for both sexes. CONCLUSION: This study confirms an earlier finding that women receiving 5-FU–based chemotherapy in a 5-day bolus schedule experience toxicity more frequently and with more severity than men. These data raise the question of whether the recommended initial dose of 5-FU–based chemotherapy for women should be lower than that for men.

PURPOSE: This article summarizes the third step of a research program to identify variables that supplement the predictive power of the the Eastern Cooperative Oncology Group (ECOG) performance status (PS) for survival. The objective was to produce a simple, practical, stratification factor for phase III oncology clinical trials involving patients with advanced malignant disease. PATIENTS AND METHODS: A questionnaire was administered to 729 patients with metastatic colorectal or lung cancers. Patients provided a Karnofsky index and appetite rating while physicians provided a survival estimate and the ECOG-PS. Scores for each item were categorized as having a positive, neutral, or negative indication for survival. A patient was classified as having a relatively good prognosis if three or more of the four items showed a positive indication, a bad prognosis if three or more items were negative, and an uncertain prognosis otherwise (Good/Bad/Uncertain [GBU] index). RESULTS: The GBU index improved on the prognostic power of a Cox model quartile index and PS alone and increased the accuracy of survival classification estimates by 5% to 10% more than ECOG-PS alone. For patients with PS of 0 or 1, significant survival patterns exist between GBU groups (P= .002 and .0001, respectively). CONCLUSION: The GBU index may be recommended as a supplementary stratification factor for certain future phase III trials in metastatic lung or colorectal cancer where patient heterogeneity is a particular concern. The GBU represents a relatively modest increase to the cost and patient burden of a clinical trial given the additional control that is achieved over the potentially confounding concomitant to the treatment variable.