Radiosensitization by the PARP inhibitor olaparib in BRCA1-proficient and deficient high-grade serous ovarian carcinomas.

OBJECTIVE: Approximately 15-25% of high-grade serous ovarian carcinomas (HGSOC) harbor BRCA1/2 mutations. Inhibition of Poly (ADP-ribose) polymerase (PARP) is synthetically lethal to cells and tumors with BRCA1/2 mutation. Our goal was to investigate the radiosensitizing effects of PARP inhibitor olaparib in HGSOC with different BRCA1 status. METHODS: The radiosensitizing effects of olaparib were tested on BRCA1-proficient and deficient HGSOC by clonogenic survival and tumor growth assays. The effects of olaparib and radiation on DNA damage, PARP activity, and apoptosis were determined. RESULTS: BRCA1-deficient HGSOC cells were more sensitive to RT alone and exhibited significantly higher levels of olaparib-mediated radiosensitization compared to BRCA1-proficient cells. Furthermore, when combined with RT, olaparib inhibited DNA damage repair and PARP1 activity, increased apoptosis, decreased growth of HGSOC xenografts and increased overall host survival. The growth-inhibitory effects of the combined olaparib and RT treatment were more pronounced in mice bearing BRCA1-deficient tumors compared to BRCA1-proficient tumors. CONCLUSIONS: These results provide a preclinical rationale for improved treatment modalities using olaparib as an effective radiosensitizer in HGSOC, particularly in tumors with BRCA1-deficiencies.

American Brachytherapy Task Group Report: Adjuvant vaginal brachytherapy for early-stage endometrial cancer: A comprehensive review.

This article aims to review the risk stratification of endometrial cancer, treatment rationale, outcomes, treatment planning, and treatment recommendations of vaginal brachytherapy (VBT) in the postoperative management of endometrial cancer patients. The authors performed a thorough review of the literature and reference pertinent articles pertaining to the aims of this review. Adjuvant VBT for early-stage endometrial cancer patients results in very low rates of vaginal recurrence (0-3.1%) with low rates of late toxicity which are primarily vaginal in nature. Post-Operative Radiation Therapy in Endometrial Cancer 2 (PORTEC-2) supports that VBT results in noninferior rates of vaginal recurrence compared to external beam radiotherapy for the treatment of high-intermediate risk patients. VBT as a boost after external beam radiotherapy, in combination with chemotherapy, and for high-risk histologies have shown excellent results as well though randomized data do not exist supporting VBT boost. There are many different applicators, dose-fractionation schedules, and treatment planning techniques which all result in favorable clinical outcomes and low rates of toxicity. Recommendations have been published by the American Brachytherapy Society and the American Society of Radiation Oncology to help guide practitioners in the use of VBT. Data support that patients and physicians prefer joint decision making regarding the use of VBT, and patients often desire additional treatment for a marginal benefit in risk of recurrence. Discussions regarding adjuvant therapy for endometrial cancer are best performed in a multidisciplinary setting, and patients should be counseled properly regarding the risks and benefits of adjuvant therapy.

A new short daily brachytherapy schedule in postoperative endometrial carcinoma. Preliminary results.

PURPOSE: To evaluate the preliminary results of vaginal-cuff relapses (VCR) and complications of a short brachytherapy (BT) schedule in postoperative endometrial carcinoma. METHODS AND MATERIALS: From September 2011 to December 2014, 102 patients were treated with postoperative BT for endometrial carcinoma. Seventy-four patients received a single 7 Gy dose after external beam irradiation (Group 1), and 28 intermediate-risk patients received three daily fractions of 6 Gy (Group 2). The dose was prescribed at 5 mm from the applicator surface. Toxicity was prospectively evaluated after the objective late effects of normal tissues-subjective, objective, management, analytic scores for vagina and RTOG scores for rectum and bladder. STATISTICS: χ2 and Student's t tests. RESULTS: The mean followup was 28.85 months (9.6-58.5) in Group 1 and 31.19 months (7.7-62.3) in Group 2. No VCR was found during followup. Late toxicity: vagina toxicity was developed in 24.32% of the patients in Group 1 (G1-G2) and in 21.4% in Group 2 (G1-G2 but 1 G3). Rectal toxicity appeared in only 2.7% of patients in Group 1 (G1). Neither Group 1 nor Group 2 presented late bladder toxicity. No differences were found in late toxicity between Groups 1 and 2. CONCLUSIONS: The present short BT schedule was safe in relation to VCR and late toxicity for the followup period studied. These results are similar to those of two larger previous schedules performed in our center in relation to the same point of followup.

Stage IVB endometrial cancer confined to the abdomen: is chemotherapy superior to radiotherapy?

PURPOSE: To determine the impact of clinical variables and adjuvant therapy on survival in patients with Stage IVB endometrial cancer (EC) confined to abdomen. METHODS AND METHODS: A total of 65 patients were included. Curative chemotherapy was defined as using only chemotherapy (platin based) or sandwich therapy. Patients receiving only radiotherapy had standard pelvic radiotherapy and extended-field radiotherapy when necessary. RESULTS: The optimal cytoreduction was achieved in 89.3% of patients. With a median follow-up of 18 months, two-year progression free survival (PFS) and overall survival (OS) were calculated as 33.4% and 42.2%, respectively. Optimal cytoreduction provided more longer PFS and OS compared to suboptimal cytoreduction. In univariate analysis, curative chemotherapy instead of radiotherapy improved the two-year PFS and two-year OS. Type of adjuvant therapy, tumor grade, and peritoneal cytology were found as the independent prognostic factors for PFS. Peritoneal cytology, adnexal involvement, and adjuvant therapy were independent prognostic factor for OS. CONCLUSION: Curative chemotherapy significantly improved both two-year PFS and OS in patients with Stage IVB endometrial disease confined to abdomen over only radiotherapy.

Adjuvant Pelvic Radiation Therapy±Vaginal Brachytherapy in Patients With High-risk Stage I or Stage II Uterine Papillary Serous, Clear Cell, and High-grade Endometrioid Carcinoma.

PURPOSE: Radiation therapy (RT) for stages I-II uterine papillary serous carcinoma (UPSC), clear cell (CC), and high-grade endometrioid (HGE) carcinoma present a treatment challenge. Regimens include external beam radiotherapy (EBRT) with or without brachytherapy. We examine the use of these radiation modalities in these endometrial cancers (EC) with respect to cause-specific survival (CSS). METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for patients with AJCC stages I-II UPSC, CC, or HGE cancer treated with hysterectomy and RT between 1998 and 2008. Patients who did not receive adjuvant RT or received brachytherapy alone were excluded. CSS was evaluated by the Kaplan-Meier survival analysis and the log-rank test was used to compare CSS. Multivariate analysis was performed using the Cox proportional hazards regression model. Adjusted hazard ratios (HR) were calculated for risk of EC death. RESULTS: There were 1653 patients included in this analysis. The overall 100-month CSS for the entire cohort was 81.0%. The 100-month CSS was 85.3% for EBRT alone and 86.5% for EBRT+brachytherapy (P=0.72). Stage IC/IIA/IIB patients had a greater risk of EC death compared with stage IA/IB patients (adjusted HR=2.39; P<0.0001). Patients with UPSC and CC had a slightly higher risk of EC death compared with HGE (adjusted HR=1.01 [P=0.97] and 1.42 [P=0.02], respectively). On subset analysis, there was no difference in CSS with the addition of brachytherapy for UPSC (P=0.37), CC (P=0.27), or HGE cancer patients (P=0.42). Patients treated with brachytherapy in addition to EBRT did not demonstrate a reduced adjusted risk of EC death compared with EBRT alone (P=0.38). CONCLUSIONS: The addition of brachytherapy to adjuvant EBRT in stages I-II UPSC, CC, and HGE cancer did not demonstrate superior CSS. Thus, patients may not benefit from the addition of brachytherapy to EBRT.