Efficacy of a nurse-led sexual rehabilitation intervention for women with gynaecological cancers receiving radiotherapy: results of a randomised trial.

BACKGROUND: The multicentre randomised SPARC trial evaluated the efficacy of a nurse-led sexual rehabilitation intervention on sexual functioning, distress, dilator use, and vaginal symptoms after radiotherapy for gynaecological cancers. METHODS: Eligible women were randomised to the rehabilitation intervention or care-as-usual. Four intervention sessions were scheduled over 12 months, with concurrent validated questionnaires and clinical assessments. Primary outcome was the Female Sexual Function Index (FSFI). A generalised-mixed-effects model compared groups over time. RESULTS: In total, 229 women were included (n = 112 intervention; n = 117 care-as-usual). No differences in FSFI total scores were found between groups at any timepoint (P = 0.37), with 12-month scores of 22.57 (intervention) versus 21.76 (care-as-usual). The intervention did not significantly improve dilator use, reduce sexual distress or vaginal symptoms compared to care-as-usual. At 12 months, both groups had minimal physician-reported vaginal stenosis; 70% of women were sexually active and reported no or mild vaginal symptoms. After radiotherapy and brachytherapy, 85% (intervention) versus 75% (care-as-usual) of participants reported dilation twice weekly. DISCUSSION: Sexual rehabilitation for women treated with combined (chemo)radiotherapy and brachytherapy improved before and during the SPARC trial, which likely contributed to comparable study groups. Best practice involves a sexual rehabilitation appointment 1 month post-radiotherapy, including patient information, with dilator guidance, preferably by a trained nurse, and follow-up during the first year after treatment. CLINICAL TRIAL REGISTRATION: NCT03611517.

Malnutrition is associated with poor survival in women receiving radiotherapy for cervical cancer.

OBJECTIVE: Cancer patients are at risk of malnutrition, which is associated with poor oncological outcomes. The aim of this study was to assess the incidence of malnutrition before, during, and after radiotherapy in locally advanced cervical cancer patients. In addition, we evaluated the impact of malnutrition on survival, and whether and when malnourished patients were referred to a dietitian. METHODS: This retrospective cohort study included cervical cancer patients who received primary or adjuvant radiotherapy with curative intent between January 2013 and January 2021. Patient and treatment characteristics, including longitudinal data on weight and dietary care, were retrieved from the electronic patient files. Malnutrition was defined by body mass index and weight loss according to the Global Leadership Initiative on Malnutrition (GLIM). Overall survival was estimated using the Kaplan-Meier method. Cox proportional hazard regression analysis was used to estimate hazard ratios for key prognostic factors. RESULTS: A total of 294 patients were included. Median follow-up was 40 months (range 7-101 months). Malnutrition occurred in 44 patients (15%) at baseline, in 132 (45%) during radiotherapy, and in 63 (21%) during follow-up. Referral to a dietician occurred in 45% of the 138 patients who were malnourished before or during radiotherapy. Malnutrition was significantly associated with worse survival after adjusting for age, performance score, diabetes, histology, International Federation of Gynecology and Obstetrics (FIGO) stage, and nodal stage. The 3 year overall survival in patients with malnutrition was 77% (95% confidence interval (CI) 70% to 85%) and without malnutrition 89% (95% CI 83% to 95%); p=0.001). Independent significant risk factors for worse overall survival were: malnutrition, age ˃52 years, adenocarcinoma, FIGO stage III/IV, and N1 disease. CONCLUSION: Malnutrition was common in cervical cancer patients treated with radiotherapy and was associated with a shorter overall survival. Further studies are needed to evaluate the effectiveness of better monitoring of malnutrition and faster and better dietary intervention on survival and quality of life.

The role of hyperthermia in the treatment of locally advanced cervical cancer: a comprehensive review.

Radiotherapy with cisplatin (chemoradiation) is the standard treatment for women with locally advanced cervical cancer. Radiotherapy with deep hyperthermia (thermoradiation) is a well established alternative, but is rarely offered as an alternative to chemoradiation, particularly for patients in whom cisplatin is contraindicated. The scope of this review is to provide an overview of the biological rationale of hyperthermia treatment delivery, including patient workflow, and the clinical effectiveness of hyperthermia as a radiosensitizer in the treatment of cervical cancer. Hyperthermia is especially effective in hypoxic and nutrient deprived areas of the tumor where radiotherapy is less effective. Its radiosensitizing effectiveness depends on the temperature level, duration of treatment, and the time interval between radiotherapy and hyperthermia. High quality hyperthermia treatment requires an experienced team, adequate online adaptive treatment planning, and is preferably performed using a phased array radiative locoregional hyperthermia device to achieve the optimal thermal dose effect. Hyperthermia is well tolerated and generally leads to only mild toxicity, such as patient discomfort. Patients in whom cisplatin is contraindicated should therefore be referred to a hyperthermia center for thermoradiation.

Phase II study of definitive chemoradiation for locally advanced squamous cell cancer of the vulva: An efficacy study.

OBJECTIVE: To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival. METHODS: In a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated. RESULTS: 52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute ≥ grade 3 toxicities were regarding skin/mucosa and pain (54% and 37%). Late ≥grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years. CONCLUSIONS: Definitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity.

Definitive radiotherapy with image-guided adaptive brachytherapy for primary vaginal cancer.

Primary vaginal cancer is a rare cancer and clinical evidence to support recommendations on its optimal management is insufficient. Because primary vaginal cancer resembles cervical cancer in many aspects, treatment strategies are mainly adopted from evidence in locally advanced cervical cancer. To date, the organ-sparing treatment of choice is definitive radiotherapy, consisting of external beam radiotherapy and brachytherapy, combined with concurrent chemotherapy. Brachytherapy is an important component of the treatment and its steep dose gradient enables the delivery of high doses of radiation to the primary tumour, while simultaneously sparing the surrounding organs at risk. The introduction of volumetric CT or MRI image-guided adaptive brachytherapy in cervical cancer has led to better pelvic control and survival, with decreased morbidity, than brachytherapy based on x-ray radiographs. MRI-based image-guided adaptive brachytherapy with superior soft-tissue contrast has also been adopted sporadically for primary vaginal cancer. This therapy has had promising results and is considered to be the state-of-the-art treatment for primary vaginal cancer in standard practice.

Analysis of isolated loco-regional recurrence rate in intermediate risk early cervical cancer after a type C2 radical hysterectomy without adjuvant radiotherapy.

BACKGROUND: The efficacy of adjuvant radiotherapy in patients with intermediate risk early cervical cancer after radical hysterectomy is still under debate. Most guidelines recommend adjuvant radiotherapy, whereas others consider observation a viable option. OBJECTIVE: To investigate if patients with intermediate risk factors for cervical cancer who underwent radical hysterectomy may benefit from adjuvant radiotherapy. METHODS: Consecutive patients with tumor confined to the cervix and intermediate risk factors (according to Sedlis), treated between January 1982 and December 2014 who were observed after a type C2 radical hysterectomy formed the basis for this study. The frequency of recurrences, specifically isolated loco-regional recurrences, and the risk of death from recurrences, were analyzed. Data were analyzed using SPSS, version 23.0 for Windows RESULTS: A total of 161 patients were included in the analysis. Median age was 40 (range 20-76). Stages IB1 and IB2 were seen in 87 (54%) and 74 patients (46%), respectively. Squamous cell and non-squamous histology was seen in 114 (70.8%) and 47 patients (29.2%), respectively. Of the 161 patients, 25 (15.5%) had recurrent disease, of whom nine had an isolated loco-regional recurrence (5.6%). Median time to recurrence for isolated loco-regional recurrences was 28 months (range 9-151). Treatment for an isolated loco-regional recurrence was radiotherapy (n = 4) and chemoradiotherapy (n = 5). Four patients (2.5%) died from disease as a result of an isolated loco-regional recurrence. Actuarial disease- specific survival was 93.0% for the total group. No variables were found that predicted an isolated loco-regional recurrence. DISCUSSION: The mortality from isolated loco-regional recurrence in patients with intermediate risk factors for cervical cancer who underwent only radical hysterectomy type C2 was 2.5%. Further studies should compare outcomes between patients who undergo a type C2 radical hysterectomy without adjuvant radiotherapy with those undergoing a less radical hysterectomy but with adjuvant radiotherapy.

Target tailoring and proton beam therapy to reduce small bowel dose in cervical cancer radiotherapy : A comparison of benefits.

PURPOSE: The aim of the study was to investigate the potential clinical benefit from both target tailoring by excluding the tumour-free proximal part of the uterus during image-guided adaptive radiotherapy (IGART) and improved dose conformity based on intensity-modulated proton therapy (IMPT). METHODS: The study included planning CTs from 11 previously treated patients with cervical cancer with a >4-cm tumour-free part of the proximal uterus on diagnostic magnetic resonance imaging (MRI). IGART and robustly optimised IMPT plans were generated for both conventional target volumes and for MRI-based target tailoring (where the non-invaded proximal part of the uterus was excluded), yielding four treatment plans per patient. For each plan, the V15Gy, V30Gy, V45Gy and Dmean for bladder, sigmoid, rectum and bowel bag were compared, and the normal tissue complication probability (NTCP) for ≥grade 2 acute small bowel toxicity was calculated. RESULTS: Both IMPT and MRI-based target tailoring resulted in significant reductions in V15Gy, V30Gy, V45Gy and Dmean for bladder and small bowel. IMPT reduced the NTCP for small bowel toxicity from 25% to 18%; this was further reduced to 9% when combined with MRI-based target tailoring. In four of the 11 patients (36%), NTCP reductions of >10% were estimated by IMPT, and in six of the 11 patients (55%) when combined with MRI-based target tailoring. This >10% NTCP reduction was expected if the V45Gy for bowel bag was >275 cm3 and >200 cm3, respectively, during standard IGART alone. CONCLUSIONS: In patients with cervical cancer, both proton therapy and MRI-based target tailoring lead to a significant reduction in the dose to surrounding organs at risk and small bowel toxicity.

Completing or Abandoning Radical Hysterectomy in Early-Stage Lymph Node-Positive Cervical Cancer: Impact on Disease-Free Survival and Treatment-Related Toxicity.

INTRODUCTION: Management regarding completing hysterectomy in case of intraoperative finding of positive lymph nodes in early-stage cervical cancer differs between institutions. The aim of this study was to compare survival and toxicity after completed hysterectomy followed by adjuvant (chemo-)radiotherapy versus abandoned hysterectomy and primary treatment with chemoradiotherapy (CRT). METHODS: A retrospective multicenter cohort study was performed. All patients were scheduled for radical hysterectomy with pelvic lymphadenectomy (RHL). In the RHL group, hysterectomy was completed followed by adjuvant (chemo-)radiotherapy. In the second group, hysterectomy was abandoned, and CRT was conducted. Primary outcomes were disease-free survival (DFS) and overall survival. A multivariable analysis on DFS was performed. Toxicity was scored according to the National Cancer Institute CTCAE (Common Terminology Criteria for Adverse Events) v4.03. RESULTS: A total of 121 patients were included (RHL, n = 89; CRT, n = 32). There was no difference in overall survival (84% vs 77%). Five-year DFS was in favor of completing RHL (81% vs 67%). Multivariable analysis showed that, corrected for lymph node variables, treatment regimen was not associated with DFS. After RHL, pelvic recurrence rate was significantly lower compared with CRT (2% vs 16%). CTCAE grade 3-4 toxicity rates were higher in the CRT compared with the RHL group (59% vs 30%), mainly because of differences in chemotherapy-related hematologic toxicity. CONCLUSIONS: In patients with clinically N0 early-stage cervical cancer with intraoperative detection of positive nodes, completing RHL followed by adjuvant (chemo-)radiotherapy may result in a better pelvic control compared with abandoning hysterectomy and treatment with chemoradiotherapy. However, if corrected for lymph node variables, treatment (RHL or CRT) was not associated with DFS.

Long-Term Morbidity and Quality of Life in Cervical Cancer Survivors: A Multicenter Comparison Between Surgery and Radiotherapy as Primary Treatment.

OBJECTIVE: To compare long-term morbidity and quality of life after primary surgery or primary radiotherapy for stage IB/II cervical cancer. METHODS: A cross-sectional study was performed. Patients treated for stage IB/II cervical cancer between 2000 and 2010 were approached to participate. Primary treatment consisted of radical hysterectomy with pelvic lymphadenectomy (RHL), for selected cases followed by adjuvant (chemo-)radiotherapy, or primary (chemo)radiotherapy (PRT). European Organization for Research and Treatment of Cancer-C30 and European Organization for Research and Treatment of Cancer-CX24 questionnaires were administered. A multivariable analysis was performed to identify factors associated with morbidity/quality of life. In a subgroup analysis, we compared patients with RHL + adjuvant radiotherapy with those after PRT. RESULTS: Three hundred twenty-three cervical cancer survivors were included (263 RHL/60 PRT). In the PRT group, International Federation of Gynecology and Obstetrics stage was higher and women were older. In the RHL group, more women had a partner. Women treated with PRT reported lower physical (ß, -6.01) and social functioning (ß, -15.2), more financial problems (ß, 10.9), diarrhea (ß, 9.98), symptom experience (ß, 6.13), sexual worry (ß, 11.3), and worse sexual/vaginal functioning (ß, 11.4). Women treated with RHL reported significantly more lymphedema (ß, -16.1). No differences in global health were found. In the subgroup analysis, women after PRT (n = 60) reported poorer social functioning, less sexual enjoyment, and higher symptoms experience than women after RHL and adjuvant radiotherapy (n = 60). The latter reported more lymphedema. CONCLUSIONS: Although global health scores are not significantly different, women after PRT report more physical, social, and sexual symptoms. These results can be well used by physicians to inform their patients about treatment-related morbidity.

Hyperthermia treatment planning for cervical cancer patients based on electrical conductivity tissue properties acquired in vivo with EPT at 3 T MRI.

Introduction The reliability of hyperthermia treatment planning (HTP) is strongly dependent on the accuracy of the electric properties of each tissue. The values currently used are mostly based on ex vivo measurements. In this study, in vivo conductivity of human muscle, bladder content and cervical tumours, acquired with magnetic resonance-based electric properties tomography (MR-EPT), are exploited to investigate the effect on HTP for cervical cancer patients. Methods Temperature-based optimisation of five different patients was performed using literature-based conductivity values yielding certain antenna settings, which are then used to compute the temperature distribution of the patient models with EPT-based conductivity values. Furthermore, the effects of altered bladder and muscle conductivity were studied separately. Finally, the temperature-based optimisation was performed with patient models based on EPT conductivity values. Results The tumour temperatures for all EPT-based dielectric patient models were lower compared to the optimal tumour temperatures based on literature values. The largest deviation was observed for patient 1 with ΔT90 = -1.37 °C. A negative impact was also observed when the treatment was optimised based on the EPT values. For four patients ΔT90 was less than 0.6 °C; for one patient it was 1.5 °C. Conclusions Electric conductivity values acquired by EPT are higher than commonly used from literature. This difference has a substantial impact on cervical tumour temperatures achieved during hyperthermia. A higher conductivity in the bladder and in the muscle tissue surrounding the tumour leads to higher power dissipation in the bladder and muscle, and therefore to lower tumour temperatures.

Improving referral rates for smoking cessation: A multifaceted intervention aimed at radiation oncologists.

Objective: Continuation of smoking after a cancer diagnosis increases the burdensome side effects from cancer treatment, and decreases the chances of cure. Smoking cessation may improve oncological outcomes in cancer patients. This study aims to evaluate if radiation oncologists can be motivated by a smoking cessation awareness intervention to discuss smoking status more frequently and increase the referral rate for smoking cessation-support.Study design and Setting:A multifaceted approach was used to improve awareness: First, current practice was evaluated by a retrospective chart review of 282 patients referred for radiotherapy to ascertain smoking status, discussion of smoking cessation support and referral rates. Secondly, radiation oncologists were interviewed about their motives and barriers to discuss smoking status and smoking cessation support. The results were fed back in a teaching lecture to the doctors involved. Finally, the effect of this smoking cessation awareness intervention was prospectively evaluated in 100 patients. Results: After the smoking cessation awareness intervention, smoking cessation was more frequently discussed compared to baseline (77% (10/13)) and 39.5% (17/43) respectively. The referral rate for smoking cessation increased from 2.3% (1/43) to 69.2% (9/13). Conclusion: Without an active smoking prevention awareness policy, referral for smoking cessation support for cancer patients by radiation oncologists is low. A relatively short and simple smoking awareness intervention for radiation oncologist may result in a more frequent discussion with patients about smoking cessation and an even larger increase in referrals for smoking cessation support.

The effectiveness of smoking cessation interventions after cancer diagnosis: A systematic review and meta-analysis.

OBJECTIVES: patients with cancer who smoke have more side effects during and after treatment, and a lower survival rate than patients with cancer who quit smoking. Supporting patients with cancer to quit smoking should be standard care. The aim of this systematic review was to determine the most effective smoking cessation method for patients diagnosed with cancer. METHODS: PubMed, Embase, Web of Science and Google Scholar were systematically searched. Included were randomized controlled trials and observational studies published after January 2000 with any smoking cessation intervention in patients with any type of cancer. Result of these studies were evaluated in a meta-analysis. RESULTS: A total of 18,780 papers were retrieved. After duplicate removal and exclusion based on title and abstract, 72 publications were left. After full text screening, 19 (randomized) controlled trials and 20 observational studies were included. The overall methodological quality of the included studies, rated by GRADE criteria, was very low. Two out of 21 combined intervention trials showed a statistical significant effect. Meta-analysis of 18 RCTs and 3 observational studies showed a significant benefit of combined modality interventions (OR 1.67, 95% C.I.: 1.24-2.26, p = 0.0008) and behavioural interventions (OR 1.33, 95% C.I.: 1.02 - 1.74, p = 0.03), but not for single modality pharmacological interventions (OR 1.11; 95% C.I.: 0.69-1.78, p = 0.66). CONCLUSION: A combination of pharmacological and behavioural interventions may be the most effective intervention for smoking cessation in patients with cancer.

Automatic landmark correspondence detection in medical images with an application to deformable image registration.

Purpose: Deformable image registration (DIR) can benefit from additional guidance using corresponding landmarks in the images. However, the benefits thereof are largely understudied, especially due to the lack of automatic landmark detection methods for three-dimensional (3D) medical images. Approach: We present a deep convolutional neural network (DCNN), called DCNN-Match, that learns to predict landmark correspondences in 3D images in a self-supervised manner. We trained DCNN-Match on pairs of computed tomography (CT) scans containing simulated deformations. We explored five variants of DCNN-Match that use different loss functions and assessed their effect on the spatial density of predicted landmarks and the associated matching errors. We also tested DCNN-Match variants in combination with the open-source registration software Elastix to assess the impact of predicted landmarks in providing additional guidance to DIR. Results: We tested our approach on lower abdominal CT scans from cervical cancer patients: 121 pairs containing simulated deformations and 11 pairs demonstrating clinical deformations. The results showed significant improvement in DIR performance when landmark correspondences predicted by DCNN-Match were used in the case of simulated ( p = 0 e 0 ) as well as clinical deformations ( p = 0.030 ). We also observed that the spatial density of the automatic landmarks with respect to the underlying deformation affect the extent of improvement in DIR. Finally, DCNN-Match was found to generalize to magnetic resonance imaging scans without requiring retraining, indicating easy applicability to other datasets. Conclusions: DCNN-match learns to predict landmark correspondences in 3D medical images in a self-supervised manner, which can improve DIR performance.

Brachytherapy boost in anal canal cancer - A GEC ESTRO PDR task force meta-analysis.

Purpose: A meta-analysis is presented comparing clinical outcomes and toxicities between high dose rate (HDR) and pulsed dose rate (PDR) brachytherapy (BT) for anal cancer. Methods and material: Retrospective or prospective clinical trials were identified on electronical databases. Data were collected per Preferred Reporting Items for Systematic Reviews and meta-Analyses guidelines. Pooled effect size for HDR and PDR BT were compared using subgroup analyses. Results: Nine retrospective studies with a total of 481 patients treated were included of which 219 with HDR and 262 with PDR. Significant differences were observed between the two groups for baseline characteristics and treatment. The cumulative proportion of stage T3-T4 was lower in the HDR group, 0.15 [95 % confidence interval (CI) 0.07-0.29] vs 0.27 [95 %CI 0.09-0.57] in the LDR group, p < 0.001. Lower BT doses (in equivalent 2-Gy fraction dose) were given for patients in the HDR group, 11.9 Gy [95 %CI 8.2-15.5] vs 19.5 Gy [95 %CI 15.0-24.0] in the PDR group, p < 0.001. No significant differences were found for clinical outcomes or toxicities. The pooled effect size of the overall survival at 5 years for HDR and PDR was respectively 0.82 [95 %CI 0.70-0.94] and 0.82 [95 %CI 0.73-0.91], p > 0.99. The 5 years local control was 0.86 [95 % confidence interval (CI) 0.81-0.91] and 0.83 [95 %CI 0.77-0.89], p = 0.62. Cumulative toxicity-related colostomy proportion was 0.04 [95 %CI 0.02-0.09] and 0.03 [95 %CI 0.02-0.07], p = 0.85. Conclusion: Both modalities provided a good profile of tolerance and are effective organ conservative strategies for patients with anal canal cancer. In parallel with ongoing developments to better determine the optimal fractionation and dose for HDR-BT treatments, especially in large tumors, PDR BT still has a crucial role for dose escalation strategy in advanced cases.

Towards artificial intelligence-based automated treatment planning in clinical practice: A prospective study of the first clinical experiences in high-dose-rate prostate brachytherapy.

PURPOSE: This prospective study evaluates our first clinical experiences with the novel ``BRachytherapy via artificial Intelligent GOMEA-Heuristic based Treatment planning'' (BRIGHT) applied to high-dose-rate prostate brachytherapy. METHODS AND MATERIALS: Between March 2020 and October 2021, 14 prostate cancer patients were treated in our center with a 15Gy HDR-brachytherapy boost. BRIGHT was used for bi-objective treatment plan optimization and selection of the most desirable plans from a coverage-sparing trade-off curve. Selected BRIGHT plans were imported into the commercial treatment planning system Oncentra Brachy . In Oncentra Brachy a dose distribution comparison was performed for clinical plan choice, followed by manual fine-tuning of the preferred BRIGHT plan when deemed necessary. The reasons for plan selection, clinical plan choice, and fine-tuning, as well as process speed were monitored. For each patient, the dose-volume parameters of the (fine-tuned) clinical plan were evaluated. RESULTS: In all patients, BRIGHT provided solutions satisfying all protocol values for coverage and sparing. In four patients not all dose-volume criteria of the clinical plan were satisfied after manual fine-tuning. Detailed information on tumour coverage, dose-distribution, dwell time pattern, and insight provided by the patient-specific trade-off curve, were used for clinical plan choice. Median time spent on treatment planning was 42 min, consisting of 16 min plan optimization and selection, and 26 min undesirable process steps. CONCLUSIONS: BRIGHT is implemented in our clinic and provides automated prostate high-dose-rate brachytherapy planning with trade-off based plan selection. Based on our experience, additional optimization aims need to be implemented to further improve direct clinical applicability of treatment plans and process efficiency.

The Effect of Contemporary Brachytherapy Practices on Prognosis in Women with Locally Advanced Cervical Cancer.

(1) Background: Over the past two decades use of new imaging modalities and the adaptation of applicators have allowed for advances in volumetric (3D) imaging-based brachytherapy practices for patients with locally advanced cervical cancer. The aim of this study was to compare the oncological outcome and toxicity for three consecutively introduced brachytherapy practices in a large single-center cohort; (2) Methods: Patients treated for cervical cancer with primary radiotherapy and curative intent were consecutively included in this retrospective, single-center cohort study from 2006 to 2019. This cohort was divided into three groups (CT, MRI, and MRI+needles) based on the timing of the introduction of a novel brachytherapy practice; 3D brachytherapy planning using CT- and MRI-guided adaptive brachytherapy and the use of parametrial interstitial needles, respectively. Actuarial estimates were compared between groups. Multivariable Cox regression analyses were performed to correct for other risk factors. Crude rates of severe (≥grade 3) late toxicity were reported; (3) Results: A total of 397 patients were included in this cohort. At a median follow-up of 40 months (interquartile range (IQR) 22-62), actuarial 3-year local control, pelvic control, disease-free survival, and overall survival for the entire cohort were 91% (95% (Confidence Interval (CI)) 88-94), 88% (95% CI 84-91), 69% (95% CI 64-74), and 75% (95% CI 70-79), respectively). Local control, disease-free survival, and overall survival were significantly improved in the MRI+needles group compared to the CT group (p = 0.040, p = 0.004, and p < 0.001, respectively). Independent risk factors for overall survival were treatment in either the CT or MRI group (vs. MRI+needles), older age at diagnosis, adeno (squamous) carcinoma, FIGO stage III/IV, and lymph node metastases. The crude rate of severe late toxicity was 27% in the CT, 26% in the MRI, and 20% in the MRI+needles group; (4) Conclusions: Prognosis in women with locally advanced cervical cancer treated with state-of-the-art MRI-guided adaptive brachytherapy combined with parametrial interstitial needles compares favorably to patients treated with more traditional CT only based brachytherapy.

GEC-ESTRO (ACROP)-ABS-CBG Consensus Brachytherapy Target Definition Guidelines for Recurrent Endometrial and Cervical Tumors in the Vagina.

PURPOSE: Representatives from the Gynecologic Groupe European de Curietherapie-European Society for Radiation Therapy and Oncology (GYN GEC-ESTRO), the American Brachytherapy Society (ABS), and the Canadian Brachytherapy Group (CBG) met to develop international consensus recommendations for target definitions for image-guided adaptive brachytherapy for vaginal recurrences of endometrial or cervical cancer. METHODS AND MATERIALS: Seventeen radiation oncologists and 2 medical physicists participated. Before an in-person meeting each participant anonymously contoured 3 recurrent endometrial/cervical cancer cases. Participants contoured the residual gross primary tumor volume (GTV-Tres), a high-risk clinical target volume (CTV-THR), and an intermediate-risk clinical target volume (CTV-TIR), on T2-weighted magnetic resonance images (MRIs). All contours were drawn using Falcon EduCase. Contours were reviewed at an in-person meeting during which a consensus document was created defining agreed-upon target definitions (Trial 1). After establishing these definitions, the group was sent one of the cases again (recurrent cervical cancer vaginal recurrence) and asked to contour the targets again (Trial 2). The Computerized Environment for Radiation Research (CERR) software (The Mathworks, Natwick, MA) was used to analyze the contours. Kappa statistics were generated to assess level of agreement between contours. A conformity index (CI), defined as the ratio between the intersection and union volume of a given pair of contours, was calculated. A simultaneous truth and performance level estimation (STAPLE) contour was created for the CTV-THR and CTV-TIR for the postmeeting case. RESULTS: Consensus definitions for GTV-Tres, CTV-THR, and CTV-TIR were established. Kappa statistics (Trial 1/Trial 2) for GTV-Tres, CTV-THR, and CTV-TIR were 0.536/0.583, 0.575/0.743 and 0.522/0.707. Kappa statistics for Trial 2 for the CTV-THR and CTV-TIR showed "substantial" agreement while the GTV-Tres remained at moderate agreement. CONCLUSIONS: This consensus provides recommendations to facilitate future collaborations for MRI-guided adaptive brachytherapy target definitions in endometrial/cervical vaginal recurrences.

Transarterial Chemoembolization With Drug-Eluting Beads Versus Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Outcomes From a Multicenter, Randomized, Phase 2 Trial (the TRENDY Trial).

PURPOSE: To compare transarterial chemoembolization delivered with drug eluting beads (TACE-DEB) with stereotactioc body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC) in a multicenter randomized trial. METHODS AND MATERIALS: Patients were included if they were eligible for TACE. They could also be recruited if they required treatment prior to liver transplantation. A maximum of four TACE-DEB procedures and ablation after incomplete TACE-DEB were both allowed. SBRT was delivered in six fractions of 8-9Gy. Primary end point was time to progression (TTP). Secondary endpoints were local control (LC), overall survival (OS), response rate (RR), toxicity, and quality of life (QoL). The calculated sample size was 100 patients. RESULTS: Between May 2015 and April 2020, 30 patients were randomized to the study. Due to slow accrual the trial was closed prematurely. Two patients in the SBRT arm were considered ineligible leaving 16 patients in the TACE-DEB arm and 12 in the SBRT arm. Median follow-up was 28.1 months. Median TTP was 12 months for TACEDEB and 19 months for SBRT (p=0.15). Median LC was 12 months for TACE-DEB and >40 months (not reached) for SBRT (p=0.075). Median OS was 36.8 months for TACEDEB and 44.1 months for SBRT (p=0.36). A post-hoc analysis showed 100% for SBRT 1- and 2-year LC, and 54.4% and 43.6% for TACE-DEB (p=0.019). Both treatments resulted in RR>80%. Three episodes of possibly related toxicity grade ≥3 were observed after TACE-DEB. No episodes were observed after SBRT. QoL remained stable after both treatment arms. CONCLUSIONS: In this trial, TTP after TACE-DEB was not significantly improved by SBRT, while SBRT showed higher local antitumoral activity than TACE-DEB, without detrimental effects on OS, toxicity and QoL. To overcome poor accrual in randomized trials that include SBRT, and to generate evidence for including SBRT in treatment guidelines, international cooperation is needed.

Dose-effect relationship between vaginal dose points and vaginal stenosis in cervical cancer: An EMBRACE-I sub-study.

BACKGROUND AND PURPOSE: To evaluate dose-effect relationships between vaginal dose points and vaginal stenosis in patients treated for locally advanced cervical cancer with radio(chemo)therapy and image-guided adaptive brachytherapy. MATERIAL AND METHODS: Patients from six centres participating in the EMBRACE-I study were included. Information on doses to different vaginal dose points, including the Posterior-Inferior Border of Symphysis (PIBS) points and recto-vaginal reference (RV-RP) point, were retrieved from the treatment planning system. In addition, the vaginal reference length (VRL) was evaluated. Vaginal stenosis was prospectively assessed according to the CTCAEv3.0 system at baseline and follow-up. Primary endpoint was grade 2 or higher (G ≥ 2) vaginal stenosis. Impact of dose to the vaginal dose points, and impact of VRL, age, vaginal involvement and applicator on vaginal stenosis G ≥ 2 was evaluated with a Cox proportional-hazard regression model. RESULTS: 301 patients were included. Median follow-up was 49 months. During follow-up, the incidence of G0, G1, G2, and G3 vaginal stenosis was 25% (76), 52% (158), 20% (59) and 3% (8), respectively. Median total doses to PIBS+2 cm, PIBS, PIBS-2 cm and the RV-RP were 52.9 (IQR 49.3-64.7), 41.0 (IQR 15.4-49.0), 4.1 (IQR 2.9-7.0) and 64.6 (IQR 60.0-70.6) Gy EQD23, respectively. Higher doses to the PIBS, PIBS + 2 cm and RV-RP points were significantly associated with increased risk for vaginal stenosis G ≥ 2. Other risk factors for vaginal stenosis were: vaginal involvement at diagnosis, higher age, shorter VRL and use of a tandem-ovoid applicator. CONCLUSION: Higher doses to the PIBS+2 cm, PIBS and RV-RP dose points are associated with vaginal stenosis G ≥ 2.

Patterns of Hearing Loss in Irradiated Survivors of Head and Neck Rhabdomyosarcoma.

PURPOSE: The frequency and patterns of HL in a HNRMS survivor cohort were investigated. A dose-effect relationship between the dose to the cochlea and HL was explored. METHODS: Dutch survivors treated for HNRMS between 1993 and 2017 with no relapse and at least two years after the end of treatment were eligible for inclusion. The survivors were evaluated for HL with pure-tone audiometry. HL was graded according to the Muenster, Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and International Society for Paediatric Oncology (SIOP) classification. We defined deleterious HL as Muenster ≥ 2b, CTCAE ≥ 2, and SIOP ≥ 2. Mixed-effects logistic regression was used to search for the dose-effect relationship between the irradiation dose to the cochlea and the occurrence of HL. RESULTS: Forty-two HNRMS survivors underwent pure-tone audiometry. The Muenster, CTCAE and SIOP classification showed that 19.0% (n = 8), 14.2% (n = 6) and 11.9% (n = 5) of survivors suffered from HL, respectively. A low-frequency HL pattern with normal hearing or milder hearing loss in the higher frequencies was seen in four survivors. The maximum cochlear irradiation dose was significantly associated with HL (≥Muenster 2b) (p = 0.047). In our series, HL (≥Muenster 2b) was especially observed when the maximum dose to the cochlea exceeded 19 Gy. CONCLUSION: HL occurred in up to 19% of survivors of HNRMS. More research is needed on HL patterns in HNRMS survivors and on radiotherapy dose-effect relationships.