Quality-adjusted survival in women with gynecologic malignancies receiving IMRT after surgery: A Ppatient Rreported Ooutcome study of NRG oncology's RTOG 1203.

INTRODUCTION: NRG/RTOG 1203 compared 3-D conformal radiotherapy (3D CRT) to intensity-modulated radiotherapy (IMRT) in patients with endometrial or cervical cancer requiring post-operative radiotherapy after hysterectomy. The purpose of this study was to report the first quality-adjusted survival analysis comparing the two treatments. METHODS: NRG/RTOG 1203 randomized patients having undergone hysterectomy to either 3DCRT or IMRT. Stratification factors included RT dose, chemotherapy, and disease site. The EQ-5D, both index and visual analog scale (VAS), were obtained at baseline, 5 weeks after the start of RT, 4-6 weeks post RT and 1 and 3-years post RT. EQ-5D index and VAS scores along with quality-adjusted survival (QAS) were compared between treatment arms using the t-test at a two-sided significance level of 0.05. RESULTS: NRG/RTOG 1203 enrolled 289 patients of which 236 consented to participate in the patient reported outcome (PRO) assessments. QAS was higher in women treated with IMRT, 1374 vs 1333 days (p = 0.5) compared to patients treated with 3DCRT, but this difference was not statistically different. Patients treated with IMRT had less of a decline in VAS score 5 weeks post RT, -5.04, compared to patients treated with 3DCRT, -7.48, although not statistically significant (p = 0.38). CONCLUSION: This is the first report of the use of the EQ-5D comparing two radiotherapy techniques in the treatment of gynecologic malignancies after surgery. While there were no significant differences in QAS and VAS scores between patients who received IMRT vs. 3DCRT, RTOG 1203 was not powered to show statistical differences in these secondary endpoints.

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer.

BACKGROUND: Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear. METHODS: In this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort. RESULTS: In the 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy. CONCLUSIONS: In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.).

Intensity-Modulated Radiation Therapy Reduces Patient-Reported Chronic Toxicity Compared With Conventional Pelvic Radiation Therapy: Updated Results of a Phase III Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The purpose of this update was to determine differences in patient-reported chronic toxicity and disease outcomes with intensity-modulated radiation therapy (IMRT) compared with conventional pelvic radiation. Patients with cervical and endometrial cancers who received postoperative pelvic radiation were randomly assigned to conventional radiation therapy (CRT) or IMRT. Toxicity and quality of life were assessed using Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domains, and Functional Assessment of Cancer Therapy-General. Between 2012 and 2015, 279 eligible patients were enrolled to the study with a median follow-up of 37.8 months. There were no differences in overall survival (P = .53), disease-free survival (P = .21), or locoregional failure (P = .81). One year after RT, patients in the CRT arm experienced more high-level diarrhea frequency (5.8% IMRT v 15.1% CRT, P = .042) and a greater number had to take antidiarrheal medication two or more times a day (1.2% IMRT v 8.6% CRT, P = .036). At 3 years, women in the CRT arm reported a decline in urinary function, whereas the IMRT arm continued to improve (mean change in EPIC urinary score = 0.5, standard deviation = 13.0, IMRT v -6.0, standard deviation = 14.3, CRT, P = .005). In conclusion, IMRT reduces patient-reported chronic GI and urinary toxicity with no difference in treatment efficacy at 3 years.

Improvement in Patient-Reported Outcomes With Intensity-Modulated Radiotherapy (RT) Compared With Standard RT: A Report From the NRG Oncology RTOG 1203 Study.

PURPOSE: In oncology trials, the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) is the standard tool for reporting adverse events (AEs), but it may underreport symptoms experienced by patients. This analysis of the NRG Oncology RTOG 1203 compared symptom reporting by patients and clinicians during radiotherapy (RT). PATIENTS AND METHODS: Patients with cervical or endometrial cancer requiring postoperative RT were randomly assigned to standard 4-field RT or intensity-modulated RT (IMRT). Patients completed the 6-item patient-reported outcomes version of the CTCAE (PRO-CTCAE) for GI toxicity assessing abdominal pain, diarrhea, and fecal incontinence at various time points. Patients reported symptoms on a 5-point scale. Clinicians recorded these AEs as CTCAE grades 1 to 5. Clinician- and patient-reported AEs were compared using McNemar's test for rates > 0%. RESULTS: Of 278 eligible patients, 234 consented and completed the PRO-CTCAE. Patients reported high-grade abdominal pain 19.1% (P < .0001), high-grade diarrhea 38.5% (P < .0001), and fecal incontinence 6.8% more frequently than clinicians. Similar effects were seen between grade ≥ 1 CTCAE toxicity and any-grade patient-reported toxicity. Between-arm comparison of patient-reported high-grade AEs revealed that at 5 weeks of RT, patients who received IMRT experienced fewer GI AEs than patients who received 4-field pelvic RT with regard to frequency of diarrhea (18.2% difference; P = .01), frequency of fecal incontinence (8.2% difference; P = .01), and interference of fecal incontinence (8.5% difference; P = .04). CONCLUSION: Patient-reported AEs showed a reduction in symptoms with IMRT compared with standard RT, whereas clinician-reported AEs revealed no difference. Clinicians also underreported symptomatic GI AEs compared with patients. This suggests that patient-reported symptomatic AEs are important to assess in this disease setting.

Expanded validation of the EPIC bowel and urinary domains for use in women with gynecologic cancer undergoing postoperative radiotherapy.

OBJECTIVE: Women with endometrial or cervical cancer at risk for recurrence receive postoperative radiation therapy (RT). A patient reported outcomes (PRO) instrument to assess bowel and urinary toxicities is the Expanded Prostate Cancer Index Composite (EPIC), which has been validated in men with prostate cancer. As this instrument specifically measures bowel toxicity and the degree to which this is a problem, it was used in NRG Oncology/RTOG 1203 to compare intensity modulated RT (IMRT) to standard RT. This paper reports on the expanded validation of EPIC for use in women receiving pelvic RT. METHODS: In addition to the EPIC bowel domain, urinary toxicity (EPIC urinary domain), patient reported bowel toxicities (PRO-CTCAE) and quality of life (Functional Assessment of Cancer Therapy (FACT)) were completed before, during and after treatment. Sensitivity, reliability and concurrent validity were assessed. RESULTS: Mean bowel and urinary scores among 278 women enrolled were significantly worse during treatment and differed between groups. Acceptable to good reliability for bowel and urinary domain scores were obtained at all time points with the exception of one at baseline. Correlations between function and bother scores within the bowel and urinary domains were consistently stronger than those across domains. Correlations between bowel domain scores and PRO-CTCAE during treatment were stronger than those with the FACT. CONCLUSION: Correlations within and among the instruments indicate EPIC bowel and urinary domains are measuring conceptually discrete components of health. These EPIC domains are valid, reliable and sensitive instruments to measure PRO among women undergoing pelvic radiation.

Patient-Reported Toxicity During Pelvic Intensity-Modulated Radiation Therapy: NRG Oncology-RTOG 1203.

Purpose NRG Oncology/RTOG 1203 was designed to compare patient-reported acute toxicity and health-related quality of life during treatment with standard pelvic radiation or intensity-modulated radiation therapy (IMRT) in women with cervical and endometrial cancer. Methods Patients were randomly assigned to standard four-field radiation therapy (RT) or IMRT radiation treatment. The primary end point was change in patient-reported acute GI toxicity from baseline to the end of RT, measured with the bowel domain of the Expanded Prostate Cancer Index Composite (EPIC). Secondary end points included change in patient-reported urinary toxicity, change in GI toxicity measured with the Patient-Reported Outcome Common Terminology Criteria for Adverse Events, and quality of life measured with the Trial Outcome Index. Results From 2012 to 2015, 289 patients were enrolled, of whom 278 were eligible. Between baseline and end of RT, the mean EPIC bowel score declined 23.6 points in the standard RT group and 18.6 points in the IMRT group ( P = .048), the mean EPIC urinary score declined 10.4 points in the standard RT group and 5.6 points in the IMRT group ( P = .03), and the mean Trial Outcome Index score declined 12.8 points in the standard RT group and 8.8 points in the IMRT group ( P = .06). At the end of RT, 51.9% of women who received standard RT and 33.7% who received IMRT reported frequent or almost constant diarrhea ( P = .01), and more patients who received standard RT were taking antidiarrheal medications four or more times daily (20.4% v 7.8%; P = .04). Conclusion Pelvic IMRT was associated with significantly less GI and urinary toxicity than standard RT from the patient's perspective.

Preclinical Development of a Nontoxic Oral Formulation of Monoethanolamine, a Lipid Precursor, for Prostate Cancer Treatment.

Purpose: Most currently available chemotherapeutic agents target rampant cell division in cancer cells, thereby affecting rapidly dividing normal cells resulting in toxic side-effects. This nonspecificity necessitates identification of novel cellular pathways that are reprogrammed selectively in cancer cells and can be exploited to develop pharmacologically superior and less toxic therapeutics. Despite growing awareness on dysregulation of lipid metabolism in cancer cells, targeting lipid biosynthesis is still largely uncharted territory. Herein, we report development of a novel nontoxic orally deliverable anticancer formulation of monoethanolamine (Etn) for prostate cancer by targeting the Kennedy pathway of phosphatidylethanolamine (PE) lipid biosynthesis.Experimental Design: We first evaluated gastrointestinal tract stability, drug-drug interaction liability, pharmacokinetic, and toxicokinetic properties of Etn to evaluate its suitability as a nontoxic orally deliverable agent. We next performed in vitro and in vivo experiments to investigate efficacy and mechanism of action.Results: Our data demonstrate that Etn exhibits excellent bioavailability, gastrointestinal tract stability, and no drug-drug interaction liability. Remarkably, orally fed Etn inhibited tumor growth in four weeks by approximately 67% in mice bearing human prostate cancer PC-3 xenografts without any apparent toxicity. Mechanistically, Etn exploits selective overexpression of choline kinase in cancer cells, resulting in accumulation of phosphoethanolamine (PhosE), accompanied by downregulation of HIF-1α that induces metabolic stress culminating into cell death.Conclusions: Our study provides first evidence for the superior anticancer activity of Etn, a simple lipid precursor formulation, whose nontoxicity conforms to FDA-approved standards, compelling its clinical development for prostate cancer management. Clin Cancer Res; 23(14); 3781-93. ©2017 AACR.