Ivan Buzurovic

Definitive radiotherapy for vaginal recurrence of early-stage endometrial cancer: survival outcomes and effect of mismatch repair status

To evaluate clinical outcomes, prognostic factors, and toxicity in patients with vaginal recurrence of early-stage endometrial cancer treated with definitive radiotherapy. Retrospective review identified 62 patients with stage I-II endometrial cancer and vaginal recurrence treated with external beam radiotherapy and image-guided brachytherapy with definitive intent from November 2004 to July 2017. All patients had prior hysterectomy without adjuvant radiotherapy and >3 months follow-up. Mismatch repair (MMR) status was determined by immunohistochemical staining of the four mismatch repair proteins (MLH1, MSH2, PMS2, and MSH6) when available in the pathology record. Rates of vaginal control, recurrence-free survival, and overall survival were calculated by Kaplan-Meier. Univariate and multivariate analyses were performed by Cox proportional hazards. Most patients had endometrioid histology (55, 89%), grade 1 or 2 tumor (53, 85%), and vaginal-only recurrence (55, 89%). With a median follow-up of 39 months (range, 3-167), 3- and 5-year rates of vaginal control, recurrence-free survival, and overall survival were 86% and 82%, 69% and 55%, and 80% and 61%, respectively. On multivariate analysis, non-endometrioid histology (HR 12.5, P<0.01) was associated with relapse when adjusted for chemotherapy use. Patients with non-endometrioid histology also had a 4.5-fold higher risk of death when adjusted for age (P=0.02). Twenty patients had known MMR status, all with grade 1-2 endometrioid tumors and 10 (50%) with MMR deficiency. The 3-year recurrence-free survival was 100% for MMR-proficient tumors and 52% for MMR-deficient (P=0.03). Late grade 2 and 3 gastrointestinal, genitourinary and vaginal toxicity was reported in 27% and 3%, 15% and 2%, and 16% and 2% of patients, respectively. Definitive radiotherapy with image-guided brachytherapy resulted in 5-year local control rates exceeding 80% and late severe toxicity rates were under 3%. Distant recurrence was common and highest for those with grade 3 or non-endometrioid tumors and MMR deficient grade 1-2 disease.

Low-dose adjuvant vaginal cylinder brachytherapy for early-stage non-endometrioid endometrial cancer: recurrence risk and survival outcomes

The aim of this study was to evaluate recurrence patterns and survival outcomes for patients with early-stage non-endometrioid endometrial adenocarcinoma treated with adjuvant high-dose rate vaginal brachytherapy with a low-dose scheme. A retrospective review was performed of patients with International Federation of Gynecology and Obstetrics (FIGO) stage I-II non-endometrioid endometrial cancer who received adjuvant vaginal brachytherapy with a low-dose regimen of 24 Gy in six fractions from November 2005 to May 2017. All patients had >6 months of follow-up. Rates of recurrence-free survival, overall survival, vaginal, pelvic, and distant recurrence were calculated by the Kaplan-Meier method. Prognostic factors for recurrence and survival were evaluated by Cox proportional hazards modeling. A total of 106 patients were analyzed. Median follow-up was 49 months (range 9-119). Histologic subtypes were serous (47%, n=50), clear cell (10%, n=11), mixed (27%, n=29), and carcinosarcoma (15%, n=16). Most patients (79%) had stage IA disease, 94% had surgical nodal assessment, and 13% had lymphovascular invasion. Adjuvant chemotherapy was delivered to 75%. The 5-year recurrence-free and overall survival rates were 74% and 83%, respectively. By histology, 5-year recurrence-free/overall survival rates were: serous 73%/78%, clear cell 68%/88%, mixed 88%/100%, and carcinosarcoma 56%/60% (p=0.046 and p<0.01). On multivariate analysis, lymphovascular invasion was significantly associated with recurrence (HR 3.3, p<0.01). The 5-year vaginal, pelvic, and distant recurrence rates were 7%, 8%, and 21%, respectively. Vaginal and pelvic recurrence rates were highest for patients with carcinosarcoma, lymphovascular invasion and/or FIGO stage IB/II disease. At 5 years, vaginal and pelvic recurrence rates for patients with lymphovascular invasion were 33% and 40%, respectively. Patients with stage IA disease or no lymphovascular invasion had 5-year vaginal recurrence rates of 4% and pelvic recurrence rates of 6% and 3%, respectively. Adjuvant high-dose rate brachytherapy with a low-dose scheme is effective for most patients with early-stage non-endometrioid endometrial cancer, particularly stage IA disease and no lymphovascular invasion. Pelvic radiation therapy should be considered for those with carcinosarcoma, lymphovascular invasion and/or stage IB/II disease.

Low-Dose Adjuvant Cylinder Brachytherapy for Endometrioid Endometrial Cancer

Our purpose was to evaluate outcomes and sites of failure for women with early stage endometrial adenocarcinoma treated with adjuvant high-dose-rate (HDR) vaginal brachytherapy (VB) with a low dose scheme. Retrospective review identified 318 patients with International Federation of Gynecology and Obstetrics (FIGO) stage I-II endometrioid endometrial cancer who received adjuvant HDR VB to a dose of 24 Gray (Gy) in 6 fractions from 2005 to 2017. Patients with <6 months follow-up were excluded. Dose was prescribed to cylinder surface and computerized tomography (CT) imaging was performed before each fraction to assess cylinder placement. Rates of vaginal relapse (VR), pelvic nodal relapse, distant metastasis, recurrence-free survival, and overall survival were calculated by Kaplan-Meier method. Univariate analysis was performed by log rank test or Cox proportional hazards. Pretreatment CT images were analyzed for patients with VR. Median follow-up was 42 months for 243 patients. The 3-year rates of VR, pelvic nodal relapse, distant metastasis, recurrence-free survival, and overall survival were 1.9%, 1.5%, 4.3%, 94.1%, and 98.9%, respectively. The 3-year VR rates by Gynecologic Oncology (GOG)-99 risk groups were 0%, 1.4%, and 3.2% for low risk, low-intermediate risk, and high-intermediate risk (HIR) disease (P = .5). By Post-operative Radiation Therapy in Endometrial Carcinoma (PORTEC) risk stratification, 3-year VR rate was 1.3% for HIR disease. On review of pretreatment CT images of the 6 patients with VR, 3 patients had relapse at the introitus outside of the treated vaginal length, and 3 had in-field recurrence at the vaginal apex. Higher body mass index (BMI) was associated with VR, with a 14% increase in risk per BMI unit (kg/m Adjuvant HDR VB with a low-dose regimen results in excellent clinical outcomes for patients with early stage endometrioid endometrial cancer. Patients with higher BMI may be at increased risk of VR, and additional study is needed to optimize brachytherapy treatment parameters.

Interfraction dose deviation and catheter position in cervical interstitial and intracavitary image guided HDR brachytherapy

Interstitial and intracavitary gynecological HDR brachytherapy involve precise, localized delivery to targets with high dose gradients, sparing adjacent organs at risk (OAR). Due to the proximity of the rectum, bowel and bladder to the target, deviations in the applicator or catheter with respect to patient anatomy can significantly increase dose to OAR. The magnitude and direction of applicator and catheter migration at each fraction was assessed for template interstitial and tandem and ring (T&R) cohorts. The cohort included twelve gynecological patients with intact cervical lesions treated with external beam and brachytherapy. Pre-treatment CT images were registered to the simulation CT with respect to the target. Treatment catheter positions transformed into the planning CT coordinate system to evaluate localized catheter displacement and dose distributions calculated at each fraction. Dose was evaluated on the planning CT with planning contours and dwell locations at treatment position. Absolute deviation, depth and deflection angle for all patients were 4.6 ± 4.2 mm, -1.4 ± 4.0 mm, and 3.1 ± 2.3° respectively (n = 516 catheter positions for all treatment fractions and patients, mean ± SD). Absolute catheter deviation and deflection magnitude for interstitial treatments increased overall with each subsequent fraction with an overall increase of catheter retraction at each fraction (p < 0.005, n = 492 catheters, Kruskal-Wallis). A target EQD2 D90 reduction of 10 ± 10% and 7.7 ± 8.7% of the planned dose for interstitial and T&R cohorts respectively. There was an overall increase in bladder and rectal doses at each fraction. Catheter tracking in interstitial and intracavitary gynecological treatments with CT imaging revealed significant changes in catheter positioning with respect to the target volume. Overall deviations increased in magnitude with each subsequent fraction in the interstitial treatments. This caused patient dosimetry deviations, including target dose reduction and adjacent OAR doses changes.