Biochemical control in intermediate- and high-risk prostate cancer after EBRT with and without brachytherapy boost.

PURPOSE: External beam radiotherapy (EBRT) with or without brachytherapy boost (BTB) has not been compared in prospective studies using guideline-recommended radiation dose and recommended androgen-deprivation therapy (ADT). In this multicenter retrospective analysis, we compared modern-day EBRT with BTB in terms of biochemical control (BC) for intermediate-risk (IR) and high-risk (HR) prostate cancer. METHODS: Patients were treated for primary IR or HR prostate cancer during 1999-2019 at three high-volume centers. Inclusion criteria were prescribed ≥ 76 Gy EQD2 (α/ß = 1.5 Gy) for IR and ≥ 78 Gy EQD2 (α/ß = 1.5 Gy) for HR as EBRT alone or with BTB. All HR patients received ADT and pelvic irradiation, which were optional in IR cases. BC between therapies was compared in survival analyses. RESULTS: Of 2769 initial patients, 1176 met inclusion criteria: 468 HR (260 EBRT, 208 BTB) and 708 IR (539 EBRT, 169 BTB). Median follow-up was 49 and 51 months for HR and IR, respectively. BTB patients with ≥ 113 Gy EQD2Gy experienced a stable, good BC outcome compared with BTB at lower doses. Patients treated with ≥ 113 Gy EQD2Gy also experienced significantly improved BC compared with EBRT (10-year BC failure rates after ≥ 113 Gy BTB and EBRT: respectively 20.4 and 41.8% for HR and 7.5 and 20.8% for IR). CONCLUSIONS: In patients with IR and HR prostate cancer, BTB with ≥ 113 Gy EQD2Gy offered a BC advantage compared with dose-escalated EBRT and lower BTB doses.

AAPM Task Group Report 267: A joint AAPM GEC-ESTRO report on biophysical models and tools for the planning and evaluation of brachytherapy.

Brachytherapy utilizes a multitude of radioactive sources and treatment techniques that often exhibit widely different spatial and temporal dose delivery patterns. Biophysical models, capable of modeling the key interacting effects of dose delivery patterns with the underlying cellular processes of the irradiated tissues, can be a potentially useful tool for elucidating the radiobiological effects of complex brachytherapy dose delivery patterns and for comparing their relative clinical effectiveness. While the biophysical models have been used largely in research settings by experts, it has also been used increasingly by clinical medical physicists over the last two decades. A good understanding of the potentials and limitations of the biophysical models and their intended use is critically important in the widespread use of these models. To facilitate meaningful and consistent use of biophysical models in brachytherapy, Task Group 267 (TG-267) was formed jointly with the American Association of Physics in Medicine (AAPM) and The Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology (GEC-ESTRO) to review the existing biophysical models, model parameters, and their use in selected brachytherapy modalities and to develop practice guidelines for clinical medical physicists regarding the selection, use, and interpretation of biophysical models. The report provides an overview of the clinical background and the rationale for the development of biophysical models in radiation oncology and, particularly, in brachytherapy; a summary of the results of literature review of the existing biophysical models that have been used in brachytherapy; a focused discussion of the applications of relevant biophysical models for five selected brachytherapy modalities; and the task group recommendations on the use, reporting, and implementation of biophysical models for brachytherapy treatment planning and evaluation. The report concludes with discussions on the challenges and opportunities in using biophysical models for brachytherapy and with an outlook for future developments.

Radiotherapy in localized prostate cancer: a multicenter analysis evaluating tumor control and late toxicity after brachytherapy and external beam radiotherapy in 1293 patients.

BACKGROUND AND PURPOSE: Comparing oncological outcomes and toxicity after primary treatment of localized prostate cancer using HDR- or LDR-mono-brachytherapy (BT), or conventionally (CF) or moderately hypofractionated (HF) external beam radiotherapy. MATERIALS AND METHODS: Retrospectively, patients with low- (LR) or favorable intermediate-risk (IR) prostate cancer treated between 03/2000 and 09/2022 in two centers were included. Treatment was performed using either CF with total doses between 74 and 78 Gy, HF with 2.4-2.6 Gy per fraction in 30 fractions, or LDR- or HDR-BT. Biochemical control (BC) according to the Phoenix criteria, and late gastrointestinal (GI), and genitourinary (GU) toxicity according to RTOG/EORTC criteria were assessed. RESULTS: We identified 1293 patients, 697 with LR and 596 with IR prostate cancer. Of these, 470, 182, 480, and 161 were treated with CF, HF, LDR-BT, and HDR-BT, respectively. For BC, we did not find a significant difference between treatments in LR and IR (p = 0.31 and 0.72). The 5­year BC for LR was between 93 and 95% for all treatment types. For IR, BC was between 88% in the CF and 94% in the HF group. For CF and HF, maximum GI and GU toxicity grade ≥ 2 was between 22 and 27%. For LDR-BT, we observed 67% grade ≥ 2 GU toxicity. Maximum GI grade ≥ 2 toxicity was 9%. For HDR-BT, we observed 1% GI grade ≥ 2 toxicity and 19% GU grade ≥ 2 toxicity. CONCLUSION: All types of therapy were effective and well received. HDR-BT caused the least late toxicities, especially GI.

EviGUIDE - a tool for evidence-based decision making in image-guided adaptive brachytherapy for cervical cancer.

PURPOSE: To develop a novel decision-support system for radiation oncology that incorporates clinical, treatment and outcome data, as well as outcome models from a large clinical trial on magnetic resonance image-guided adaptive brachytherapy (MR-IGABT) for locally advanced cervical cancer (LACC). METHODS: A system, called EviGUIDE, was developed that combines dosimetric information from the treatment planning system, patient and treatment characteristics, and established tumor control probability (TCP), and normal tissue complication probability (NTCP) models, to predict clinical outcome of radiotherapy treatment of LACC. Six Cox Proportional Hazards models based on data from 1341 patients of the EMBRACE-I study have been integrated. One TCP model for local tumor control, and five NTCP models for OAR morbidities. RESULTS: EviGUIDE incorporates TCP-NTCP graphs to help users visualize the clinical impact of different treatment plans and provides feedback on achievable doses based on a large reference population. It enables holistic assessment of the interplay between multiple clinical endpoints and tumour and treatment variables. Retrospective analysis of 45 patients treated with MR-IGABT showed that there exists a sub-cohort of patients (20%) with increased risk factors, that could greatly benefit from the quantitative and visual feedback. CONCLUSION: A novel digital concept was developed that can enhance clinical decision- making and facilitate personalized treatment. It serves as a proof of concept for a new generation of decision support systems in radiation oncology, which incorporate outcome models and high-quality reference data, and aids the dissemination of evidence-based knowledge about optimal treatment and serve as a blueprint for other sites in radiation oncology.

Implementation of online workshops on image-guided adaptive brachytherapy (interventional radiotherapy) in locally advanced cervical cancer: Experience of BrachyAcademy.

PURPOSE: To provide educational support to brachytherapy users during the COVID-19 pandemic, online workshops were developed and implemented by BrachyAcademy, non-profit peer-to-peer educational initiative in Elekta. METHODS AND MATERIALS: In 2021-2022 two online workshops were organized. Participating teams had to send a clinical case of locally advanced cervical cancer (LACC) including brachytherapy Digital Imaging and Communications in Medicine (DICOM) files and questions to the faculty. During the workshop, feedback was given to each clinical case by five faculty members (two Radiation Oncologists, one Radiologist, two Medical Physicists). Participants competed a post-workshop questionnaire which included combination of qualitative and quantitative questions via yes/no responses, Likert scale, and 1 to 10 scale. RESULTS: Twenty-one teams from eight countries (Europe, Asia, Latin America) participated in two online workshops. The total number of participants was 49. The clinical cases represented LACC with The International Federation of Gynecology and Obstetrics (FIGO) stages from IB3 to IVA. During both, Workshop1 (W1) and Workshop 2 (W2) the following areas of improvement were identified: familiarity with the GEC ESTRO and The International Commission on Radiation Units & Measurements, Report 89 (ICRU 89) recommendations for contouring and planning based on clinical drawings and MRI sequencing choice; appropriate applicator selection; experience with interstitial needles; appropriate applicator reconstruction; dose optimization. The participants rated both workshops with overall scores 8,3 for W1, and 8,5 for W2. In 82% participants the training course fully met expectations for W1, and in 76% in W2. CONCLUSIONS: We successfully implemented the online workshops on image-guided adaptive brachytherapy (IGABT) in LACC. Main performance issues and areas for improvement were identified based on multidisciplinary discussion of participant's clinical cases through all steps of the brachytherapy procedure. We encourage teams to consider online workshops in addition to hands-on training.

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.

Tools for large-scale data analytics of an international multi-center study in radiation oncology for cervical cancer.

PURPOSE: To develop and implement a software that enables centers, treating patients with state-of-the-art radiation oncology, to compare their patient, treatment, and outcome data to a reference cohort, and to assess the quality of their treatment approach. MATERIALS AND METHODS: A comprehensive data dashboard was designed, which al- lowed holistic assessment of institutional treatment approaches. The software was tested in the ongoing EMBRACE-II study for locally advanced cervical cancer. The tool created individualized dashboards and automatic analysis scripts, verified pro- tocol compliance and checked data for inconsistencies. Identified quality assurance (QA) events were analysed. A survey among users was conducted to assess usability. RESULTS: The survey indicated favourable feedback to the prototype and highlighted its value for internal monitoring. Overall, 2302 QA events were identified (0.4% of all collected data). 54% were due to missing or incomplete data, and 46% originated from other causes. At least one QA event was found in 519/1001 (52%) of patients. QA events related to primary study endpoints were found in 16% of patients. Sta- tistical methods demonstrated good performance in detecting anomalies, with precisions ranging from 71% to 100%. Most frequent QA event categories were Treatment Technique (27%), Patient Characteristics (22%), Dose Reporting (17%), Outcome 156 (15%), Outliers (12%), and RT Structures (8%). CONCLUSION: A software tool was developed and tested within a clinical trial in radia- tion oncology. It enabled the quantitative and qualitative comparison of institutional patient and treatment parameters with a large multi-center reference cohort. We demonstrated the value of using statistical methods to automatically detect implau- sible data points and highlighted common pitfalls and uncertainties in radiotherapy for cervical cancer.

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.

Risk Factors for Local Failure Following Chemoradiation and Magnetic Resonance Image-Guided Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.

PURPOSE: To report clinical and treatment characteristics, remission and failure patterns, and risk factors for local failure (LF) from the EMBRACE-I study. MATERIALS AND METHODS: EMBRACE-I was a prospective, observational, multicenter cohort study on magnetic resonance imaging-based image-guided adaptive brachytherapy (MR-IGABT) in locally advanced cervical cancer. Treatment consisted of external beam radiotherapy, concurrent chemotherapy, and MR-IGABT. LF was defined as progressive or recurrent disease in the cervix, uterus, parametria, pelvic wall, or vagina. Competing risk analysis was used to estimate local tumor control (LC) and Cox proportional regression models for multivariable analysis and dose-response analysis. RESULTS: One thousand three hundred eighteen patients with a median follow-up of 52 months were available for this analysis. Eighty-one patients had persistent disease 3 months after end of treatment. Of those, 60 patients achieved LC at 6-9 months without further treatment, whereas 21 patients had progressive disease. In addition, 77 patients developed a local recurrence after complete remission comprising a total number of 98 LFs. LFs were located inside the MR-IGABT target volumes in 90% of patients with LF. In multivariable analysis, histology, minimal dose to 90% of high-risk clinical target volume (CTVHR), maximum tumor dimension, CTVHR > 45 cm3, overall treatment time, tumor necrosis on magnetic resonance imaging at diagnosis, uterine corpus infiltration at diagnosis and at MR-IGABT, and mesorectal infiltration at MR-IGABT had significant impact on LF. Dose-response analysis showed that a minimal dose to 90% of 85 Gy to the CTVHR led to 95% (95% CI, 94 to 97) LC 3 years postintervention for squamous cell in comparison to 86% (95% CI, 81 to 90) for adeno/adenosquamous carcinoma histology. CONCLUSION: The present study demonstrates the safety and validity of the GYN GEC-ESTRO/ICRU-89 target concept and provides large-scale evidence for dose prescription and new risk factors for LF in MR-IGABT in locally advanced cervical cancer.

The Effect of Land-Use Categories on Traffic Noise Annoyance.

Land-use categories are often used to define the exposure limits of national environmental noise policies. Often different guideline values for noise are applied for purely residential areas versus residential areas with mixed-use. Mixed-use includes living plus limited activities through crafts, commerce, trade, agriculture, and forestry activities. This differentiation especially when rating noise from road, railway, and air traffic might be argued by different expectations and therefore noise annoyance in those two categories while scientific evidence is missing. It should be tested on empirically derived data. Surveys from two studies in the state of Tyrol in urban and rural areas were retrospectively matched with spatial data to analyze the potential different influences on noise effects. Using non-parametric tests, the correlation between land-use category on self-reported noise sensitivity and noise annoyance was investigated. Exposure-response for the two analyzed land-use categories showed no significant impact on noise sensitivity and exposure-response relationships for the three traffic noise sources. Including only noise annoyance, there is not sufficient evidence to define different noise policies for those two land-use categories.

AAPM task group report 303 endorsed by the ABS: MRI implementation in HDR brachytherapy-Considerations from simulation to treatment.

The task group (TG) on magnetic resonance imaging (MRI) implementation in high-dose-rate (HDR) brachytherapy (BT)-Considerations from simulation to treatment, TG 303, was constituted by the American Association of Physicists in Medicine's (AAPM's) Science Council under the direction of the Therapy Physics Committee, the Brachytherapy Subcommittee, and the Working Group on Brachytherapy Clinical Applications. The TG was charged with developing recommendations for commissioning, clinical implementation, and on-going quality assurance (QA). Additionally, the TG was charged with describing HDR BT workflows and evaluating practical consideration that arise when implementing MR imaging. For brevity, the report is focused on the treatment of gynecologic and prostate cancer. The TG report provides an introduction and rationale for MRI implementation in BT, a review of previous publications on topics including available applicators, clinical trials, previously published BT-related TG reports, and new image-guided recommendations beyond CT-based practices. The report describes MRI protocols and methodologies, including recommendations for the clinical implementation and logical considerations for MR imaging for HDR BT. Given the evolution from prescriptive to risk-based QA, an example of a risk-based analysis using MRI-based, prostate HDR BT is presented. In summary, the TG report is intended to provide clear and comprehensive guidelines and recommendations for commissioning, clinical implementation, and QA for MRI-based HDR BT that may be utilized by the medical physics community to streamline this process. This report is endorsed by the American Brachytherapy Society.

Neural network-assisted automated image registration for MRI-guided adaptive brachytherapy in cervical cancer.

PURPOSE: In image-guided adaptive brachytherapy (IGABT) a quantitative evaluation of the dosimetric changes between fractions due to anatomical variations, can be implemented via rigid registration of images from subsequent fractions based on the applicator as a reference structure. With available treatment planning systems (TPS), this is a manual and time-consuming process. The aim of this retrospective study was to automate this process. A neural network (NN) was trained to predict the applicator structure from MR images. The resulting segmentation was used to automatically register MR-volumes. MATERIAL AND METHODS: DICOM images and plans of 56 patients treated for cervical cancer with high dose-rate (HDR) brachytherapy were used in the study. A 2D and a 3D NN were trained to segment applicator structures on clinical T2-weighted MRI datasets. Different rigid registration algorithms were investigated and compared. To evaluate a fully automatic registration workflow, the NN-predicted applicator segmentations (AS) were used for rigid image registration with the best performing algorithm. The DICE coefficient and mean distance error between dwell positions (MDE) were used to evaluate segmentation and registration performance. RESULTS: The mean DICE coefficient for the predicted AS was 0.70 ±â€¯0.07 and 0.58 ±â€¯0.04 for the 3D NN and 2D NN, respectively. Registration algorithms achieved MDE errors from 8.1 ±â€¯3.7 mm (worst) to 0.7 ±â€¯0.5 mm (best), using ground-truth AS. Using the predicted AS from the 3D NN together with the best registration algorithm, an MDE of 2.7 ±â€¯1.4 mm was achieved. CONCLUSION: Using a combination of deep learning models and state of the art image registration techniques has been demonstrated to be a promising solution for automatic image registration in IGABT. In combination with auto-contouring of organs at risk, the auto-registration workflow from this study could become part of an online-dosimetric interfraction evaluation workflow in the future.

Dosimetric impact of target definition in brachytherapy for cervical cancer - Computed tomography and trans rectal ultrasound versus magnetic resonance imaging.

Background and Purpose: Magnetic Resonance Imaging (MRI) based target definition in cervix brachytherapy is limited by its availability, logistics and financial implications, therefore, use of computed tomography (CT) and Trans Rectal UltraSonography (TRUS) has been explored. The current study evaluated the dosimetric impact of CT + TRUS based target volumes as compared to gold standard MRI. Methods and Materials: Images of patients (n = 21) who underwent TRUS followed by MRI and CT, were delineated with High-Risk Clinical Target Volume in CT (CTVHR-CT) and in MRI (CTVHR-MR). CTVHR-CT was drawn on CT images with TRUS assistance. For each patient, two treatment plans were made, on MRI and CT, followed by fusion and transfer of CTVHR-MR to the CT images, referred as CTVHR-MRonCT. The agreement between CTVHR-MRonCT and CTVHR-CT was evaluated for dosimetric parameters (D90, D98 and D50; Dose received by 90%, 98% and 50% of the volumes) using Bland-Altman plots, linear regression, and Pearson correlation. Results: No statistically significant systematic difference was found between MRI and CT. Mean difference (±1.96 SD) of D90, D98 and D50 between CTVHR-MRonCT and CTVHR-CT was 2.0, 1.2 and 5.6 Gy respectively. The number of patients who have met the dose constraints of D90 > 85 Gy were 90% and 80% in MR and in CT respectively, others were in the borderline, with a minimum dose of 80 Gy. The mean ± SD dose-difference between MR and CT plans for bladder was significant (5 ± 13 Gy; p = 0.12) for D0.1cm3, while others were statistically insignificant. Conclusion: CT + TRUS based delineation of CTVHR appear promising, provide useful information to optimally utilize for brachytherapy planning, however, MRI remains the gold standard.

Prognostic Implications of Uterine Cervical Cancer Regression During Chemoradiation Evaluated by the T-Score in the Multicenter EMBRACE I Study.

PURPOSE: A simple scoring system (T-score, TS) for integrating findings from clinical examination and magnetic resonance imaging (MRI) of the primary tumor at diagnosis has shown strong prognostic capability for predicting local control and survival in locally advanced cervical cancer treated with chemoradiation and MRI-guided brachytherapy (BT). The aim was to validate the performance of TS using the multicenter EMBRACE I study and to evaluate the prognostic implications of TS regression obtained during initial chemoradiation. METHODS AND MATERIALS: EMBRACE I recruited 1416 patients, of whom 1318 were available for TS. Patients were treated with chemoradiation followed by MRI-guided BT. A ranked ordinal scale of 0 to 3 points was used to assess 8 anatomic locations typical for local invasion of cervical cancer. TS was calculated separately at diagnosis (TSD) and at BT (TSBT) by the sum of points obtained from the 8 locations at the 2 occasions. RESULTS: Median TSD and TSBT was 5 and 4, respectively. TS regression was observed in 71% and was an explanatory variable for BT technique (intracavitary vs intracavitary/interstitial) and major dose-volume histogram parameters for BT, such as high-risk clinical target (CTVHR), CTVHR D90 (minimal dose to 90% of the target volume), D2cm3 bladder (minimal dose to the most exposed 2 cm3 of the bladder), and D2cm3 rectum. TS regression (TSBT≤5) was associated with improved local control and survival and with less morbidity compared with patients with TSBT remaining high (>5) despite initial chemoradiation. TS regression was significant in multivariate analysis for both local control and survival when analyzed in consort with already established prognostic parameters related to the patient, disease, and treatment. CONCLUSIONS: TS was validated in a multicenter setting and proven to be a strong multidisciplinary platform for integration of clinical findings and imaging with the ability to quantitate local tumor regression and its prognostic implications regarding BT technique, dose-volume histogram parameters, local control, survival, and morbidity.

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.

Severity and Persistency of Late Gastrointestinal Morbidity in Locally Advanced Cervical Cancer: Lessons Learned From EMBRACE-I and Implications for the Future.

PURPOSE: The purpose was to evaluate patient- and treatment-related risk factors for physician-assessed and patient-reported gastrointestinal (GI) symptoms after radio(chemo)therapy and image guided adaptive brachytherapy in locally advanced cervical cancer. METHODS AND MATERIALS: Of 1416 patients from the EMBRACE-I study, 1199 and 1002 were prospectively evaluated using physician-assessed (Common Terminology Criteria for Adverse Events [CTCAE]) and patient-reported (European Organization for Research and Treatment of Cancer [EORTC]) GI symptoms, respectively. CTCAE severe grade (grade [G] ≥3) events were pooled according to the location in the GI tract (anus/rectum, sigmoid, and colon/small bowel). CTCAE G ≥2 and EORTC "very much" and "quite a bit" plus "very much" scores (≥ "quite a bit") were analyzed for individual symptoms with Cox regression. Logistic regression was used for persistent G ≥1 and EORTC ≥ "quite a bit" symptoms, defined if present in at least half of follow-ups. RESULTS: The incidence of G ≥3 events was 2.8%, 1.8%, and 2.3% for G ≥3 anus/rectum, sigmoid, and colon/small bowel events, respectively. Among G ≥2 symptoms, diarrhea and flatulence were the most prevalent (8.5% and 9.9%, respectively). Among patient-related factors, baseline morbidity, increasing age, smoking status, and low body mass index were associated with GI symptoms to varying degrees. Among treatment-related factors, rectum D2cm3 and the International Commission on Radiation Units and Measurements recto-vaginal reference point (ICRU RV-RP) correlated with G ≥3 anus/rectum events and moderate/persistent diarrhea, proctitis, bleeding, abdominal cramps, and difficulty in bowel control. Bowel D2cm3 correlated with G ≥3 sigmoid and colon/small bowel events and moderate/persistent diarrhea and flatulence. For external beam radiation therapy (EBRT), prescription dose correlated with G ≥3 anus/rectum, diarrhea, and difficulty in bowel control. Patients with large lymph-node boost (V57Gy) were at higher risk for G ≥3 sigmoid events, moderate/persistent diarrhea, proctitis, and cramps. CONCLUSIONS: The analysis showed that both EBRT and image guided adaptive brachytherapy contribute to GI symptoms after locally advanced cervical cancer treatment. Rectum D2cm3, ICRU RV-RP , and bowel D2cm3 are risk factors for GI morbidity. The risk for various symptoms was lower with an EBRT prescription of 45 Gy than 50 Gy and increased with larger V57Gy.

Toward 3D-TRUS image-guided interstitial brachytherapy for cervical cancer.

PURPOSE: To qualitatively and quantitatively analyze needle visibility in combined intracavitary and interstitial cervical cancer brachytherapy on 3D transrectal ultrasound (TRUS) in comparison to gold standard MRI. METHODS AND MATERIALS: Image acquisition was done with a customized TRUS stepper unit and software (Medcom, Germany; Elekta, Sweden; ACMIT, Austria) followed by an MRI on the same day with the applicator in place. Qualitative assessment was done with following scoring system: 0 = no visibility 1 (= poor), 2 (= fair), 3 (= excellent) discrimination, quantitative assessment was done by measuring the distance between each needle and the tandem two centimeters (cm) above the ring and comparing to the respective measurement on MRI. RESULTS: Twenty-nine implants and a total of 188 needles (132 straight, 35 oblique, 21 free-hand) were available. Overall, 79% were visible (87% straight, 51% oblique, 76% free-hand). Mean visibility score was 1.4 ± 0.5 for all visible needles. Distance of the visible needles to tandem was mean ± standard deviation (SD) 21.3 millimeters (mm) ± 6.5 mm on MRI and 21.0 mm ± 6.4 mm on TRUS, respectively. Difference between MRI and TRUS was max 14 mm, mean ± SD -0.3 mm ± 2.6 mm. 11% differed more than 3 mm. CONCLUSIONS: Straight needles were better detectable than oblique needles (87% vs. 51%). Detectability was impaired by insufficient rotation of the TRUS probe, poor image quality or anatomic variation. As needles show a rather indistinct signal on TRUS, online detection with a standardized imaging protocol in combination with tracking should be investigated, aiming at the development of real time image guidance and online treatment planning.

Quantitative and qualitative application of clinical drawings for image-guided brachytherapy in cervical cancer patients.

PURPOSE: Clinical drawings are integral part of image-guided adaptive brachytherapy (IGABT) of cervical cancer. It was used in EMBRACE study protocol as a useful tool. In our study clinical drawings from EMBRACE study were modified to include scales in all the dimensions for more accurate representation of various tumor related volumes. The aim of the present study was to understand patterns of tumor regression and relationship between gross tumor at diagnosis (GTVD) and high-risk clinical target volume (CTV-THR)/intermediate-risk clinical target volume (CTV-TIR) in brachytherapy (BRT), using modified clinical drawings. MATERIAL AND METHODS: 42 cervical cancer patients, staged as FIGO IIB-IIIB according to EMBRACE study, were enrolled. Advanced schematic 3D mapping diagram (3D-MD) in axial, coronal, and sagittal orientations, with a measurement scale (grid with 10 mm distance) for precise assessment and documentation was applied (through MRI at diagnosis and during brachytherapy). Dimensions, including height, width, and thickness as well as volumes (GTVD, CTV-THR and CTV-TIR) were compared both qualitatively and quantitatively. RESULTS AND CONCLUSIONS: We found qualitative and quantitative correlation of the dimensions of final CTV-THR with initial GTVD. Meticulous mapping of tumor volumes can provide useful insights to CTV-THR volume during brachytherapy.

Low-Dose-Rate versus High-Dose-Rate intracavitary brachytherapy in cervical cancer - Final Results of a Phase III randomized trial.

PURPOSE: Intracavitary brachytherapy using High-Dose-Rate (HDR) and Low-dose-rate (LDR) in cervical cancer has been utilized. We report the long-term final results of a large randomized trial in terms of toxicities and efficacy. METHODS AND MATERIALS: Between 1996 to 2005, 816 patients were randomized to LDR (n = 441 patients) or HDR brachytherapy (n = 369 patients) stratified by FIGO Stage grouping. Patients with Stage I-II received external irradiation of 40 Gy in 20 fractions (with midline block (MLB)) followed by either 2 LDR Intracavitary applications of 30 Gy to point A (2-3 weeks apart) or 5 HDR Intracavitary applications of 7 Gy to point A once weekly. Patients with Stage III received 50 Gy in 25 fractions (with MLB after 40 Gy) followed by either one application of LDR 30 Gy to point A or three applications of HDR 7 Gy to point A once weekly. RESULTS: With a median follow-up was 64 months (interquartile range [IQR]: 21 - 111), moderate to severe rectal and bladder complications were higher in LDR arm as compared to HDR arm (9.7% vs. 3.6%; p = 0.02) and (10.5% vs. 5.5%; p = 0.06) for Stage I-II. No difference in rectal or bladder complications for Stage III patients. Disease free and overall survivals were similar in both the arms for all stages. CONCLUSIONS: HDR intracavitary brachytherapy with 7 Gy per fraction weekly is superior to LDR in terms of late rectal and bladder complications. Local control rates and survivals are similar irrespective of stages.