Is There a Place for Brachytherapy in Vulvar Cancer? A Narrative Review.

Vulvar cancer is a relatively rare neoplasm. The essential treatment is surgery for the primary tumour. However, postoperative recurrence rates are high, even in early-stage disease when tumour-free surgical margins are achieved or in the absence of associated risk factors (lymph node metastases, deep stromal invasion or invasion of the lymphatic vascular space). Radiotherapy plays an important role in the treatment of vulvar cancer. Adjuvant treatment after surgery as well as primary treatment of locally advanced vulvar cancer (LAVC) is composed of two key radiotherapy treatment scenarios, external beam radiation therapy (EBRT) either combined or not combined with brachytherapy (BT). In a recurrence setting, where surgery is not an option, BT alone or in combination with EBRT can be used. Compared to EBRT, BT has the radiobiological potential to improve dose to the target volume, minimise the dose to organs at risk, and facilitate hypofractionated-accelerated treatment. This narrative review presents recent data on the role of BT in the treatment of primary and/or recurrent vulvar cancer, including radiobiological, clinical, and therapeutic aspects.

Stages I-III Inoperable Endometrial Carcinoma: A Retrospective Analysis by the Gynaecological Cancer GEC-ESTRO Working Group of Patients Treated with External Beam Irradiation and 3D-Image Guided Brachytherapy.

BACKGROUND/PURPOSE: Analyse the outcomes of stages I-III inoperable endometrial cancer (IEC) patients treated with external-beam-irradiation (EBRT) and 3D-image-guided-brachytherapy (IGBT). MATERIAL AND METHODS: Medical records of IEC patients receiving EBRT + IGBT in eight European and one Canadian centres (2004-2019) were examined, including: pelvic ± para-aortic EBRT and lymph node boost; anaesthetic procedure, applicators, BT-planning imaging, clinical target volume (CTV), brachytherapy schedule, and EQD2 to the CTV(α/ß=4.5Gy) and D2 cm3(α/ß=3Gy) for organs at risk. Complications are evaluated using CTCAEv4 scores. The 2- and 5-year survival probability according to stages was estimated (cancer-specific survival (CSS), disease-free survival (DFS), local relapse-free survival (LRFS), loco-regional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS)). STATISTICS: descriptive analysis and the Kaplan-Meier method. RESULTS: 103 patients (stages: I-44, II-14, III-44) were included. Median follow-up: 28 months (7-170). All patients received pelvic ± para-aortic EBRT. Median D90-EQD2(α/ß=4.5) to the CTV:73.3 Gy (44.6-132.7), 69.9 Gy (44.7-87.9 and 75.2 Gy (55.1-97) in stages I, II, and III, respectively. Thirty patients presented relapse (stages: 10-I, 3-II, 17-III): 24 uterine (stages: 7-I, 3-II, 14-III), 15 nodal (stages: 4-I, 1-II, 10-III), and 23 distant (stages: 6-I, 2-II, 15-III). Five year CSS was 71.2% (stages: 82%-I-II and 56%-III) and DFS, LRFS, LRRFS, and DMFS were 55.5%, 59%, 72%, and 67.2%, respectively. Late G3-G4 complications (crude): 1.3% small bowel, 2.5% rectum, and 5% bladder. CONCLUSION: In stages I-III of the IEC, EBRT + IGBT offer good 2- and 5-year CSS of 88.7% and 71.2%, respectively, with the best outcomes in stages I-II. Prospective studies are needed to determine how better outcomes can be achieved.

Radiation therapy for vulvar cancer: consensus guidelines of the GINECOR working group of the Spanish Society of Radiation Oncology. Part 1: clinical recommendations

Purpose The present consensus statement was developed by the GINECOR working group on behalf of the Spanish Society of Radiation Oncology (SEOR). Given the lack of prospective data on the management of vulvar carcinoma, this document provides an up-to-date review of radiotherapy treatment in vulvar cancer and a series of consensus-based recommendations from a group of experts. Methods A two-round, online modified Delphi study was conducted to reach consensus treatment recommendations in three clinical settings: 1) adjuvant treatment, 2) locally-advanced vulvar cancer (LAVC), and 3) recurrent disease. After the first round, we comprehensively reviewed the available medical literature from peer-reviewed journals to assess and define the evidence-based treatment options. In the second round, participants were asked to indicate their level of agreement with the preliminary recommendations according to the GRADE (Grade of Recommendation, Assessment, Development, and Evaluation) criteria, as follows: strongly agree; agree; neither agree nor disagree; disagree; strongly disagree. Results The main recommendations were as follows: 1) following surgical resection, adjuvant radiotherapy is recommended with the presence of adverse risk factors (primarily positive margins and lymph node involvement); 2) radiotherapy (with or without chemotherapy) should be considered in LAVC; and 3) in recurrent disease, radiotherapy should be individualised on a case-by-case basis. A high level of agreement over 80% was reached. Conclusions In the absence of robust clinical data, these final recommendations may help to select the optimal radiotherapy approach for this relatively rare cancer (AU)

Radiation therapy for vulvar cancer: consensus guidelines of the GINECOR working group of the Spanish Society of Radiation Oncology. Part 1: clinical recommendations.

PURPOSE: The present consensus statement was developed by the GINECOR working group on behalf of the Spanish Society of Radiation Oncology (SEOR). Given the lack of prospective data on the management of vulvar carcinoma, this document provides an up-to-date review of radiotherapy treatment in vulvar cancer and a series of consensus-based recommendations from a group of experts. METHODS: A two-round, online modified Delphi study was conducted to reach consensus treatment recommendations in three clinical settings: 1) adjuvant treatment, 2) locally-advanced vulvar cancer (LAVC), and 3) recurrent disease. After the first round, we comprehensively reviewed the available medical literature from peer-reviewed journals to assess and define the evidence-based treatment options. In the second round, participants were asked to indicate their level of agreement with the preliminary recommendations according to the GRADE (Grade of Recommendation, Assessment, Development, and Evaluation) criteria, as follows: strongly agree; agree; neither agree nor disagree; disagree; strongly disagree. RESULTS: The main recommendations were as follows: 1) following surgical resection, adjuvant radiotherapy is recommended with the presence of adverse risk factors (primarily positive margins and lymph node involvement); 2) radiotherapy (with or without chemotherapy) should be considered in LAVC; and 3) in recurrent disease, radiotherapy should be individualised on a case-by-case basis. A high level of agreement over 80% was reached. CONCLUSIONS: In the absence of robust clinical data, these final recommendations may help to select the optimal radiotherapy approach for this relatively rare cancer.

Radiation therapy for vulvar cancer: consensus technical guidelines of the GINECOR working group of the Spanish Society of Radiation Oncology. Part 2: radiotherapy recommendations.

PURPOSE: The present consensus statement was developed by the GINECOR working group on behalf of the Spanish Society of Radiation Oncology (SEOR). This document provides an up-to-date review of the technical aspects in radiation treatment of vulvar cancer. METHODS: A two-round modified Delphi study was conducted to reach consensus on the appropriateness of technical aspects of external beam radiotherapy and brachytherapy. Three clinical scenarios were proposed: adjuvant treatment of vulvar cancer, radiation treatment of locally advanced vulvar carcinoma and locoregional recurrences. After the first round, an extensive analysis of current medical literature from peer-reviewed journal was performed to define evidence-based treatment options. In the second round, participants were asked to indicate their level of agreement with the preliminary recommendations according to the GRADE (Grade of Recommendation, Assessment, Development, and Evaluation) criteria, as follows: strongly agree; agree; neither agree nor disagree; disagree and strongly disagree. RESULTS: The main recommendations on external beam radiotherapy and brachytherapy, both in adjuvant setting and local advanced disease are summarized. Recommendations include treatment technique, treatment volume, and doses in target and organs at-risk. Taking into consideration the different clinical scenarios of recurrent disease, the radiation treatment should be individualized. CONCLUSIONS: In the absence of robust clinical data, these recommendations may help to select the optimal radiotherapy approach for this relatively rare cancer.

Recommendations of the Spanish brachytherapy group of the Spanish Society of Radiation Oncology and the Spanish Society of Medical Physics for interstitial high-dose-rate brachytherapy for gynaecologic malignancies.

The present document includes consensus-based recommendations from the Brachytherapy Group (GEB) of the Spanish Society of Radiation Oncology (SEOR) and the Spanish Society of Medical Physics (SEFM) for interstitial high-dose-rate (HDR) brachytherapy (BT) for gynaecologic malignancies. A nine-item survey-which included questions on experience with interstitial BT; indications and technique; applicator type; magnetic resonance imaging (MRI)-based planning; dose; fractionation schedule; and treatment planning-was sent to all radiation oncology departments (n = 174) in Spain in 2021. Responses were received from 36 centres (50% of all centres [n = 72] with a BT unit). The consensus-based recommendations presented here are based on a review of the available literature, professional experience among the group of experts, and in-person discussions held during the annual meeting of these two societies. We describe the results of the survey and the following: indications; contraindications; patient selection; description of applicators; role of imaging in planning; contouring; dose prescription; dosimetric reconstruction; optimisation; and dose indications for cancers of the cervix, vagina, and vulva. The various clinical scenarios in which interstitial BT is used in the treatment of gynaecological tumours are described in detail, including cervix intracavitary/interstitial hybrid HDR-BT; cervix perineal templates/freehand implants; primary vaginal malignancies/vaginal recurrences; and vulvar interstitial implants.

Very accelerated partial breast irradiation Phase I-II multicenter trial (VAPBI): Feasibility and early results.

PURPOSE: This is a multicenter Phase I-II trial endorsed by the GEC-ESTRO Breast Working Group, to analyze if very accelerated partial breast irradiation (VAPBI) with multicatheter interstitial brachytherapy is feasible and safe compared with the standard APBI treatment in 4-5 days for early stage breast carcinomas. METHODS AND MATERIALS: We have included 81 patients with pT1-2 pN0 invasive carcinomas after breast-conserving surgery. Between August 2017 and July 2019, 33 women received high-dose-rate brachytherapy, four fractions of 6.25 Gy in 2-3 days, and 48 patients received three fractions of 7.45 Gy in 2 days. Thirty-six patients were implanted perioperatively and 45 postoperatively. Mean age was 68 (51-90). Free surgical margins were of 2 mm or greater. RESULTS: Acute effects were 11% dermatitis, 18.5% hematoma, 3.7% infection, and 14.8% pain. At a median followup of 20 months (range 8-35), no relapse has occurred. Pigmentation changes in the entrance and exit of tubes were visible in 16%, but 1 year later, few cases remained. Patients developed G1-2 induration or fibrosis in 18.5% and 2.5%, respectively. No patient developed telangiectasia. The cosmetic outcome was good/excellent in 97.5% and fair in 2.5%. CONCLUSIONS: VAPBI with multicatheter interstitial brachytherapy using four fractions of 6.25 Gy or three fractions of 7.45 Gy in two or 3 days is feasible. No excess has been observed in acute effects. At a mean followup of 20 months, late side effects seem to be similar to standard fractionation. VAPBI in two to 3 days is beneficial for the patients and reduces the workload of the brachytherapy units.

Initiatives for education, training, and dissemination of morbidity assessment and reporting in a multiinstitutional international context: Insights from the EMBRACE studies on cervical cancer.

In 2008, the GEC ESTRO Gyn network launched the first multiinstitutional, observational, and prospective international study on MRI-guided brachytherapy in locally advanced cervical cancer patients (EMBRACE-I). EMBRACE-I was followed by EMBRACE-II from 2016 and ongoing. Among the aims of the EMBRACE studies are to benchmark morbidity outcomes and develop dose-volume effects and predictive models for morbidity. The EMBRACE studies collect both physician (CTCAE v.3) and patient (EORTC QLQ-C30/CX24) reported outcomes, including baseline information, in a regular follow-up schedule. The EMBRACE studies feature high numbers of patients (EMBRACE-I N = 1416, EMBRACE-II N = 1500 expected) enrolled from many institutions worldwide (EMBRACE-I n = 23, EMBRACE-II n = 45). This large-scale multiinstitutional approach offers a unique opportunity to investigate and develop new strategies for improving the quality of assessment and reporting of morbidity. This report presents an overview of the challenges and pitfalls regarding the assessment and reporting of morbidity encountered during more than a decade of development and research activities within the EMBRACE consortium. This includes the recognition and evaluation of inconsistencies in the morbidity assessment, and consequently, the provision of assistance and training in the scoring procedure to reduce systematic assessment bias. In parallel, a variety of methodological approaches were tested to comprehensively summarize morbidity outcomes, and a novel approach was developed to refine dose-effect models and risk factor analyses. The purpose of this report is to present an overview of these findings, describe the learning process, and the strategies that have consequently been implemented regarding educational activities, training, and dissemination.

Hybrid TRUS/CT with optical tracking for target delineation in image-guided adaptive brachytherapy for cervical cancer.

OBJECTIVE: To prospectively compare the interobserver variability of combined transrectal ultrasound (TRUS)/computed tomography (CT)- vs. CT only- vs. magnetic resonance imaging (MRI) only-based contouring of the high-risk clinical target volume (CTVHR) in image-guided adaptive brachytherapy (IGABT) for locally advanced cervical cancer (LACC). METHODS: Five patients with LACC (FIGO stages IIb-IVa) treated with radiochemotherapy and IGABT were included. CT, TRUS, and T2-weighted MRI images were performed after brachytherapy applicator insertion. 3D-TRUS image acquisition was performed with a customized ultrasound stepper device and software. Automatic applicator reconstruction using optical tracking was performed in the TRUS dataset and TRUS and CT images were fused with rigid image registration with the applicator as reference structure. The CTVHR (based on the GEC-ESTRO recommendations) was contoured by five investigators on the three modalities (CTVHR_CT, CTVHR_TRUS-CT, and CTVHR_MRI). A consensus reference CTVHR_MRI (MRIref) was defined for each patient. Descriptive statistics and overlap measures were calculated using RTslicer (SlicerRT Community and Percutaneous Surgery Laboratory, Queen's University, Canada), comparing contours of every observer with one another and with the MRIref. RESULTS: The interobserver coefficient of variation was 0.18 ± 0.05 for CT, 0.10 ± 0.04 for TRUS-CT, and 0.07 ± 0.03 for MRI. Interobserver concordance in relation to the MRIref expressed by the generalized conformity index was 0.75 ± 0.04 for MRI, 0.51 ± 0.10 for TRUS-CT, and 0.48 ± 0.06 for CT. The mean CTVHR_CT volume of all observers was 71% larger than the MRIref volume, whereas the mean CTVHR_TRUS-CT volume was 15% larger. CONCLUSION: Hybrid TRUS-CT as an imaging modality for contouring the CTVHR in IGABT for LACC is feasible and reproducible among multiple observers. TRUS-CT substantially reduces overestimation of the CTVHR volume of CT alone while maintaining similar interobserver variability.

Physician assessed and patient reported lower limb edema after definitive radio(chemo)therapy and image-guided adaptive brachytherapy for locally advanced cervical cancer: A report from the EMBRACE study.

BACKGROUND/PURPOSE: To evaluate the pattern of manifestation and risk factors for lower limb edema (LLE) within the prospective, observational, multi-center EMBRACE study on radiochemotherapy and MRI-guided brachytherapy in locally advanced cervical cancer (LACC). MATERIAL/METHODS: LLE was prospectively assessed according to the physician-reported CTCAE v.3 and patient-reported EORTC QLQ-CX24 questionnaire at baseline and regular follow-up. RESULTS: In total, 1176 patients were evaluated with a median follow-up of 27 months. Actuarial analyses revealed 3/5-year estimates of 27%/31% of CTCAE G ≥ 1, 6.1%/6.6% of G ≥ 2 and 0.5%/0.5% for G ≥ 3. Prevalence rates for G ≥ 1 LLE at 3 months, 1, 3 and 5 years after end of treatment were 7%, 12%, 12%, 15% for physician-assessed and 25%, 30%, 30%, 34% for any patient-reported symptoms and showed a steady increase over time. Invasive lymph node staging and obesity at diagnosis are independent significant risk factors for G ≥ 1 LLE, whereas nodal boost has no impact. Extended radiation fields including para-aortic and/or inguinal nodes show a tendency to increase the risk. CONCLUSION: Severe LLE after definitive radiochemotherapy in LACC is rare. However, the risk for mild LLE is considerable, and related to patient-, diagnostic- and treatment characteristics. Less invasive diagnostic surgical procedures or non-invasive assessment, less invasive radiotherapy management and active rehabilitation are important pathways for future developments.