Overall Severe Morbidity After Chemo-Radiation Therapy and Magnetic Resonance Imaging-Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.

PURPOSE: To evaluate overall severe late morbidity (grade ≥3) in patients with locally advanced cervical cancer treated with chemo-radiation therapy and magnetic resonance image guided adaptive brachytherapy within the prospective EMBRACE-I study, and to compare the results with published literature after standard radiograph based brachytherapy (BT). METHODS AND MATERIALS: From 2008 to 2015 the EMBRACE-I study enrolled 1416 patients. Morbidity was assessed (Common Terminology Criteria for Adverse Events version 3.0) every 3 months the 1st year, every 6 months the second and third year, and yearly thereafter and 1251 patients had available follow-up on late morbidity. Morbidity events (grade 3-5) were summarized as the maximum grade during follow-up (crude incidence rates) and actuarial estimates at 3 and 5 years. To compare with the published literature on standard radiograph based BT, Common Terminology Criteria for Adverse Events scores from the EMBRACE-I study were retrospectively converted into a corresponding score in the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer system. RESULTS: In total, 534 severe events occurred in 270 patients; 429 events were grade 3 and 105 were grade 4 events. Actuarial estimates for grade ≥3 gastrointestinal (GI), genitourinary (GU), vaginal and fistula events at 5 years were 8.5% (95% confidence interval [CI], 6.9%-10.6%), 6.8% (95% CI, 5.4%-8.6%), 5.7% (95% CI, 4.3%-7.6%), and 3.2% (95% CI, 2.2%-4.5%), respectively. The 5-year actuarial estimate for organ-related events (GI, GU, vaginal, or fistula) was 18.4% (95% CI, 16.0%-21.2%). The 5-year actuarial estimate when aggregating all G≥3 endpoints (GI, GU, vaginal, fistulas, and non-GI/GU/vaginal) was 26.6% (95% CI, 23.8%-29.6%). Thirteen patients had a treatment-related death, 8 of which were associated with GI morbidity. CONCLUSIONS: This report assesses severe morbidity from the largest prospective study on chemo-radiation therapy and image guided adaptive brachytherapy for locally advanced cervical cancer to date. Severe late morbidity was limited per endpoint and organ category, but considerable when aggregated across organs and all endpoints. The late morbidity results in the EMBRACE-I study compare favorably with published literature on standard radiograph based BT for GI morbidity, vaginal morbidity, and fistulas.

Evidence-Based Dose Planning Aims and Dose Prescription in Image-Guided Brachytherapy Combined With Radiochemotherapy in Locally Advanced Cervical Cancer.

The last 2 decades have witnessed the development and broad adoption of image-guided adaptive brachytherapy (IGABT) combined with radiochemotherapy in patients with locally advanced cervical cancer. A variety of brachytherapy techniques and dose/fractionation schedules have been applied, and until recently, there was no strong evidence available for preferring one approach to another. However, large volumes of data have now provided high level clinical evidence for dose-effect relations for both disease and morbidity endpoints. It is therefore now possible to apply evidence based dose planning aims and dose prescription protocols in IGABT for locally advanced cervical cancer. This review gives an overview of targets/organs-at-risk and disease/morbidity endpoints which are relevant in the context of treatment planning and dose prescription in IGABT. The dosimetric and clinical evidence is summarized to support the implementation of dose prescription protocols which include hard and soft constraints for targets and organs at risk.

Cone beam computed tomography-based monitoring and management of target and organ motion during external beam radiotherapy in cervical cancer.

BACKGROUND AND PURPOSE: Organ motion is a challenge during high-precision external beam radiotherapy in cervical cancer, and improved strategies for treatment adaptation and monitoring of target dose coverage are needed. This study evaluates a cone beam computed tomography (CBCT)-based approach. MATERIALS AND METHODS: In twenty-three patients, individualized internal target volumes (ITVs) were generated from pre-treatment MRI and CT scans with full and empty bladders. The target volumes encompassed high-risk clinical target volume (CTV-T HR) (gross tumor volume + remaining cervix) and low risk (LR) CTV-T (CTV-T HR + uterus + parametriae + upper vagina). Volumetric Modulated Arc Therapy (VMAT) was used to deliver a dose of 45 Gy in 25 fractions. CBCTs were used for setup and for radiation therapists (RTTs) to evaluate the target coverage (inside/outside the planning target volume). CBCTs were reviewed offline. Estimates of the dose delivered with minimum (point) doses across all fractions to CTV-T HR (aim 42.75 Gy) and CTV-T LR (aim 40 Gy) were assessed. In patients with insufficient dose coverage, re-plans were generated based on previous imaging. RESULTS: Median (range) of the ITV-margins (mean of anterior-posterior margins) related to uterus and cervix was 1.2 (0.5-2.2 and 1.0-2.1) cm. RTTs were able to assess the target coverage in 90% of all CBCTs (505/563). With re-planning, one patient had considerable benefit (12.7 Gy increase of minimum dose) to CTV-T LR_vagina, four patients had improved dose to the CTV-T LR_uterus (1.2-1.8 Gy), and 3 patients did not benefit from re-planning. CONCLUSIONS: Daily CBCT-based monitoring of target coverage by the RTTs has proven safe with limited workload. It allows for reduction in the treated volumes without compromising the target dose coverage.

Bowel morbidity following radiochemotherapy and image-guided adaptive brachytherapy for cervical cancer: Physician- and patient reported outcome from the EMBRACE study.

BACKGROUND/PURPOSE: This study describes late bowel morbidity prospectively assessed in the multi-institutional EMBRACE study on MRI-guided adaptive brachytherapy in locally advanced cervical cancer (LACC). MATERIALS/METHODS: A total of 1176 patients were analyzed. Physician reported morbidity (CTCAE v.3.0) and patient reported outcome (PRO) (EORTC QLQ C30/CX24) were assessed at baseline and at regular follow-up. RESULTS: At 3/5 years the actuarial incidence of bowel morbidity grade 3-4 was 5.0%/5.9%, including incidence of stenosis/stricture/fistula of 2.0%/2.6%. Grade 1-2 morbidity was pronounced with prevalence rates of 28-33% during follow-up. Diarrhea and flatulence were most frequently reported, significantly increased after 3 months and remained elevated during follow-up. Incontinence gradually worsened with time. PRO revealed high prevalence rates. Diarrhea ≥"a little" increased from 26% to 37% at baseline to 3 months and remained elevated, difficulty in controlling bowel increased from 11% to 26% at baseline to 3 months gradually worsening with time. Constipation and abdominal cramps improved after treatment. CONCLUSION: Bowel morbidity reported in this large cohort of LACC patients was limited regarding severe/life-threatening events. Mild-moderate diarrhea, flatulence and incontinence were prevalent after treatment with PROs indicating a considerable and clinically relevant burden. Critical knowledge based on the extent and manifestation pattern of treatment-related morbidity will serve future patient management.

Physician assessed and patient reported urinary morbidity after radio-chemotherapy and image guided adaptive brachytherapy for locally advanced cervical cancer.

BACKGROUND AND PURPOSE: The EMBRACE study is a prospective multi-institutional study on MRI guided adaptive brachytherapy (IGABT) in locally advanced cervix cancer (LACC). This analysis describes early to late urinary morbidity assessed by physicians and patients (PRO). MATERIAL AND METHODS: A total of 1176 patients were analysed. Median follow up (FU) was 27 (1-83) months. Morbidity (CTCAE v.3) and PRO (EORTC QLQ-C30&CX24) was prospectively assessed at baseline (BL), and during FU. RESULTS: The most frequent symptoms were frequency/urgency, incontinence, and cystitis with grade 2-4 prevalence rates of 4.3%, 5.0% and 1.7% and grade 1-4 prevalence rates of 24.5%, 16.1% and 5.8% at 3-years. The most frequent PRO endpoints were "urinary frequency" and "leaking of urine". Prevalence of "Quite a bit" or "very much" bother fluctuated from 14.0% to 21.5% for "frequency", while "leaking of urine" increased from 4.6% at BL to 9.3% at 3-years. Actuarial 3-year incidence of grade 3-4 urinary morbidity was 5.3% with most events being urinary frequency, incontinence and ureteral strictures. Grade 3-4 fistula, bleeding, spasm and cystitis were all <1.0% at 3/5-years. No grade 5 toxicity occurred. CONCLUSION: Urinary grade 3-4 morbidity with IGABT was limited. Urinary morbidity grade 2-4 comprises mainly frequency/urgency, incontinence and cystitis and has considerable prevalence in PRO. Various urinary morbidity endpoints have different patterns of manifestation and time course.

The EMBRACE II study: The outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies.

The publication of the GEC-ESTRO recommendations one decade ago was a significant step forward for reaching international consensus on adaptive target definition and dose reporting in image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer. Since then, IGABT has been spreading, particularly in Europe, North America and Asia, and the guidelines have proved their broad acceptance and applicability in clinical practice. However, a unified approach to volume contouring and reporting does not imply a unified administration of treatment, and currently both external beam radiotherapy (EBRT) and IGABT are delivered using a large variety of techniques and prescription/fractionation schedules. With IGABT, local control is excellent in limited and well-responding tumours. The major challenges are currently loco-regional control in advanced tumours, treatment-related morbidity, and distant metastatic disease. Emerging evidence from the RetroEMBRACE and EMBRACE I studies has demonstrated that clinical outcome is related to dose prescription and technique. The next logical step is to demonstrate excellent clinical outcome with the most advanced EBRT and brachytherapy techniques based on an evidence-based prospective dose and volume prescription protocol. The EMBRACE II study is an interventional and observational multicentre study which aims to benchmark a high level of local, nodal and systemic control while limiting morbidity, using state of the art treatment including an advanced target volume selection and contouring protocol for EBRT and brachytherapy, a multi-parametric brachytherapy dose prescription protocol (clinical validation of dose constraints), and use of advanced EBRT (IMRT and IGRT) and brachytherapy (IC/IS) techniques (clinical validation). The study also incorporates translational research including imaging and tissue biomarkers.