Dose Rate Brachytherapy Research Articles

PO0239: A Phase II Feasibility Study of a Single Dose of HDR Interstitial Brachytherapy Following Pelvic Chemo/Radiotherapy for Patients with Locally Advanced Cervix Cancer. Effectiveness and Toxicity Report

PO0239: A Phase II Feasibility Study of a Single Dose of HDR Interstitial Brachytherapy Following Pelvic Chemo/Radiotherapy for Patients with Locally Advanced Cervix Cancer. Effectiveness and Toxicity Report

Three-dimensional source position verification in image-guided high-dose-rate brachytherapy using an XCT-based gel dosimeter.

Comprehensive quality assurance (QA) for a seamless workflow of high-dose-rate brachytherapy, from imaging to planning and irradiation, is uncommon, and QA of the source dwell position is performed in one- or two-dimensions. Gel dosimetry using magnetic resonance imaging (MRI) is effective in verifying the three-dimensional distribution of doses for image-guided brachytherapy (IGBT). However, MRI scanners are not readily accessible, and MRI scanning is time-consuming. Nevertheless, X-ray computed tomography (XCT) is available for IGBT planning. In this study, we designed and developed an efficient method for QA for a seamless workflow of IGBT with a new commercially available XCT-based polymer gel dosimeter. To enable direct insertion of brachytherapy applicators, the gelatinizing agent of the dosimeter was modified. A cylindrical polyvinyl chloride jar was filled with the modified gel dosimeter, which was subsequently used to determine the reproducibility of source dwell positions, detectability of source positional errors from intentionally introduced catheter length offsets, effect of looped source transfer tubes on the average displacement, extent of inter-observer variation, and gel robustness following multiple needle-insertions. Three ProGuide sharp needles were inserted into the jar. The dwell time at each point was determined to identify the irradiated volume with a diameter of approximately 10mm on XCT images. All the times were the same. The plan was delivered using an afterloader with an Ir-192 radioactive source, and the irradiated gel dosimeter was scanned using an XCT scanner. The subtracted images were generated from pre- and post-irradiated images. Volumes with incremented Hounsfield units were manually identified and contoured. The centroid of the volume was defined as the measured source dwell position. Subsequently, planned source dwell positions were extracted from the DICOM file of the plan. Finally, the source dwell positions in plan and irradiated gel were compared in three axes. The hardness of the dosimeter was 1250% greater than that of the previously reported gel dosimeter. Source dwell positions were visually identified in the XCT image. Testing of CT acquisition, planning, irradiation, and analysis was completed in approximately 1h. In the reproducibility test of source dwell positions, created by inserting three needles (each with three source dwell positions), the average displacements of the source positions from the first source dwell position were within 0.5mm in all three directions. In the detectability test, displacements were less than 1mm in the x-y plane but greater than 1mm in the z-axis, which was the source path direction. When errors of 1-3mm were intentionally introduced, the measured displacement was within 0.7mm of the median (range: 0.21-1.65mm) of intentional errors. When the transfer tube was looped, the source dwell position displaced by approximately 1mm. After 20 needle-insertions, the source dwell position displacement was within 1mm. The maximum inter-observer variation of contouring was 0.57mm. The XCT-based gel dosimeter enabled verification of three-dimensional source dwell positions for a seamless workflow of IGBT with high precision and efficiency.

Retrospective assessment of HDR brachytherapy dose calculation methods in locally advanced cervical cancer patients: AcurosBV vs. AAPM TG43 formalism.

This retrospective analysis was completed to investigate the use of a model-based dose calculation algorithm (MBDCA) AcurosBV, for use in HDR BT treatments for locally advanced cervical cancer treated with tandem and ovoid applicators with interstitial needles. A cohort of 32 patients receiving post-EBRT HDR brachytherapy boost with a prescription dose of 5.5Gy × 5 fractions to the high-risk clinical target volume (CTVHR) were selected for this study. For standard TG43 dose calculation, applicators were manually digitized on the planning images, while for AcurosBV calculations, solid renderings of Titanium Fletcher Suite Delclos (FSD) applicators included in BrachyVision were matched to those used clinically and Ti needles were manually digitized. The dose was recalculated using Varian's AcurosBV 13.5 and dose-to-medium-in-medium (Dm,m) was reported. EQD2 values for targets and organs at risk were compared between dose calculation formalisms. D90% and D98% values were reported for the high and intermediate-risk CTVs, and values were reported for OARs including bladder, rectum, sigmoid, bowel, and vagina. Due to variability within the patient cohort, the dosimetric impact of AcurosBV was investigated corresponding to planning image modality (CT vs. CBCT), presence of Ti needles, and contrast within vaginal balloons used to stabilize implants. AcurosBV showed lower dosimetric values for all plans compared to TG43. The average±standard deviation of dosimetric reduction in D90% was 4.33±0.09% for CTVHR and 4.12±0.09% for CTVIR. The reduction to OARs was: 4.99±0.15% for bladder, 7.87±0.16% for rectum, 5.79±0.17% for sigmoid, 6.91±0.14% for bowel, and 4.55±0.14% for vagina. AcurosBV should be utilized for HDR BT GYN cases, treated with tandem and ovoid applicators, with high degrees of heterogeneity and calculated in tandem with TG43.

Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial

At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, the addition of pembrolizumab to chemoradiotherapy provided a statistically significant and clinically meaningful improvement in progression-free survival in patients with locally advanced cervical cancer. We report the overall survival results from the second interim analysis of this study. Eligible patients with newly diagnosed, high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered intravenously. Patients were stratified at randomisation by planned external beam radiotherapy type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cervical cancer stage at screening (FIGO 2014 stage IB2-IIB node positive vs III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy [equivalent dose of 2 Gy]). Primary endpoints were progression-free survival per RECIST 1.1 by investigator or by histopathological confirmation of suspected disease progression and overall survival defined as the time from randomisation to death due to any cause. Safety was a secondary endpoint. Between June 9, 2020, and Dec 15, 2022, 1060 patients at 176 sites in 30 countries across Asia, Australia, Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the pembrolizumab-chemoradiotherapy group and 531 patients in the placebo-chemoradiotherapy group. At the protocol-specified second interim analysis (data cutoff Jan 8, 2024), median follow-up was 29·9 months (IQR 23·3-34·3). Median overall survival was not reached in either group; 36-month overall survival was 82·6% (95% CI 78·4-86·1) in the pembrolizumab-chemoradiotherapy group and 74·8% (70·1-78·8) in the placebo-chemoradiotherapy group. The hazard ratio for death was 0·67 (95% CI 0·50-0·90; p=0·0040), meeting the protocol-specified primary objective. 413 (78%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 371 (70%) of 530 in the placebo-chemoradiotherapy group had a grade 3 or higher adverse event, with anaemia, white blood cell count decreased, and neutrophil count decreased being the most common adverse events. Potentially immune-mediated adverse events occurred in 206 (39%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 90 (17%) of 530 patients in the placebo-chemoradiotherapy group. This study is registered with ClinicalTrials.gov, NCT04221945. Pembrolizumab plus chemoradiotherapy significantly improved overall survival in patients with locally advanced cervical cancer These data, together with results from the first interim analysis, support this immuno-chemoradiotherapy strategy as a new standard of care for this population. Merck Sharp & Dohme, a subsidiary of Merck & Co.

Image-guided brachytherapy for pediatric bladder and/or prostate rhabdomyosarcoma: toward an increased personalization of treatment.: Brachytherapy in uro-pediatric rhabdomyosarcoma

IntroductionRhabdomyosarcoma (RMS) is the most common soft tissue cancer in children. Around 15% of RMS involve the bladder and/or prostate (BP). Overall survival is around 85%. After chemotherapy, patients receive local treatment based on surgery and/or radiotherapy. In recent decades, image guidance and pulsed dose-rate (PDR) brachytherapy have made it possible to personalize treatment, reduce radiation-related toxicity, while maintaining a good tumor control. We report one of the largest series of image-guided brachytherapy for pediatric RMS BP. Material and methodsThe clinical and dosimetric parameters of children treated with brachytherapy for BP RMS between July 2014 and September 2020 were retrospectively reviewed. Patients were treated with a multimodal conservative approach, combining partial conservative surgery (preservation of the bladder neck and urethra), followed by an interstitial brachytherapy procedure. Iridium-192 PDR treatment was administered on the basis of CT and MRI planning. Toxicities were reported according to version 4.0 of the Common Terminology Criteria for Adverse Events. ResultsA total of 75 patients were identified, with a median age of 29 months (range 2–84) at diagnosis. The median brachytherapy dose was 60.06 Gy (143 pulses, 0.42 Gy/pulse). With a median follow-up of 44.1 months (range 0.7–90), the 5-year OS and PFS rates were 97.3% and 92% respectively. Median D50% for the bladder and D1cc for the rectum were 38.6 Gy and 49 Gy respectively. The 5-year probability of survival without severe late urinary toxicity (grade 3 or higher) was estimated at 78.8% (CI95%: 68.1–91.1). A total of 9.3% of children experienced grade 2 or 3 late rectal toxicity. ConclusionsImage-guided PDR brachytherapy offers a personalized treatment for pediatric BP RMS, with a favorable therapeutic index. No prognostic factors for urinary toxicity have been identified. Multicenter studies with larger numbers of patients are needed to clarify these data.

3535: The role of brachytherapy (interventional radiotherapy) dose escalation for organ preservation in head & neck cancer

3535: The role of brachytherapy (interventional radiotherapy) dose escalation for organ preservation in head & neck cancer

Advancing Cancer Care Infrastructure in Cambodia: Summary of the First 100 Patients with Cervical Cancer Treated at the National Cancer Centre

Background: Cervical cancer is Cambodia’s leading cause of female malignancy in both incidence and mortality. Cambodia’s first dedicated multidisciplinary cancer center, the National Cancer Centre (NCC), opened in January 2018 in Phnom Penh, and serves as the main public referral center for the region. Methods: This cross-sectional study retrospectively reviewed the care experience of the first 100 patients with cervical cancer treated at the NCC to collect demographic, diagnostic, and treatment characteristics. Results: The most common FIGO Stage was IIB (T2bN0M0) (n = 17). Squamous cell carcinoma represented 85% of cases. Definitive-intent therapy was recommended for 65 patients; neoadjuvant chemotherapy followed by external beam radiotherapy (EBRT) &amp; tandem and ovoid (T&amp;O) brachytherapy +/- concurrent cisplatin was the most common treatment regimen (n=23). Thirty-five patients presented with recurrent (n=22) or metastatic (n=13) disease and were treated with salvage/palliative intent; neoadjuvant chemotherapy followed by EBRT +/- concurrent cisplatin was the most common treatment regimen (n=10). Of the patients treated with definitive-intent treatment, 92% were prescribed an EBRT dose of 45 Gy in 25 fractions, and the median prescribed T&amp;O brachytherapy dose was 28 Gy in 4 fractions. Mean cumulative EQD2 HR-CTV D90 dose was 91.8 Gy, or ~69-70 Gy to Point A, depending on planning technique. Follow-up data was limited to 27 patients; of the 14 patients whose follow-up period exceeded 1 year, 13 (93%) were alive and disease-free at their last assessment. Conclusion: With multidisciplinary partnership, the NCC has demonstrated that high quality complex cancer care can be delivered in a resource-constrained setting. This early sample of patients treated for cervical cancer is an initial step towards a better understanding of Cambodia’s patient population and an early snapshot of their cancer care delivery capacity.

Improvement of accumulated dose distribution in combined cervical cancer radiotherapy with deep learning-based dose prediction.

Difficulties remain in dose optimization and evaluation of cervical cancer radiotherapy that combines external beam radiotherapy (EBRT) and brachytherapy (BT). This study estimates and improves the accumulated dose distribution of EBRT and BT with deep learning-based dose prediction. A total of 30 patients treated with combined cervical cancer radiotherapy were enrolled in this study. The dose distributions of EBRT and BT plans were accumulated using commercial deformable image registration. A ResNet-101-based deep learning model was trained to predict pixel-wise dose distributions. To test the role of the predicted accumulated dose in clinic, each EBRT plan was designed using conventional method and then redesigned referencing the predicted accumulated dose distribution. Bladder and rectum dosimetric parameters and normal tissue complication probability (NTCP) values were calculated and compared between the conventional and redesigned accumulated doses. The redesigned accumulated doses showed a decrease in mean values of V50, V60, and D2cc for the bladder (-3.02%, -1.71%, and -1.19 Gy, respectively) and rectum (-4.82%, -1.97%, and -4.13 Gy, respectively). The mean NTCP values for the bladder and rectum were also decreased by 0.02‰ and 0.98%, respectively. All values had statistically significant differences (p < 0.01), except for the bladder D2cc (p = 0.112). This study realized accumulated dose prediction for combined cervical cancer radiotherapy without knowing the BT dose. The predicted dose served as a reference for EBRT treatment planning, leading to a superior accumulated dose distribution and lower NTCP values.

Pattern of care and clinical outcome of patients with carcinoma endometrium and the impact of central histopathological review on management: A tertiary cancer centre experience.

Endometrial carcinoma (EC) is the third most common gynecological malignancy in India. Recent PORTEC-3 analysis emphasized the role of central histopathological review. We aimed to retrospectively analyze the demographic and histopathological characteristics of EC patients treated at our institute and assess the impact of the central histopathological review on management and also analyze clinical outcomes in this cohort of patients. Data of 75 EC patients treated at our center between 2013 and 2022 were retrieved from our departmental archives. Patients were analyzed for demographic details, histopathological findings, details of surgery and histopathology (HPE), results of a review of HPE, adjuvant treatment details, and clinical outcomes. All patients with HPE outside of our institute were reviewed at our center prior to initiation of treatment. In cases of discordance, patients were discussed in the multidisciplinary tumor board for the final treatment decisions. Patients were staged as per International Federation of Gynaecology and Obstetrics 2018. The median age was 57 years (range: 37-74 years). Twenty-seven patients with HPE reported from the outside center were reviewed at our institute and changes were observed in 26 patients (96.3%). HPE review changes were observed in terms of histological grade, histological type, myometrial invasion, and lymph node involvement in five (18.5%), three (11.1%), seven (25.9%), and three (42.8%), respectively. HPE review leads to changes in the management of 19/26 patients. Stage distribution was I: II: III in 48 (64%): 9 (13.3%): 18 (24%) patients, respectively. The median external beam radiotherapy dose was 50 Gray (range: 45-50.4 Gray at 1.8-2 Gray per fraction). The median brachytherapy dose for patients treated with brachytherapy alone was 7 Gray each for three sessions and in combination with EBRT was 6 Gray each in two sessions. At a median follow-up of 51 months (range: 6-116 months), seven (9.3%) patients developed distant metastasis, two (2.7%) patients had local plus distant metastasis, and two (2.7%) patients had local recurrence. The overall survival and disease-free survival rates at 3 years were 93.5% and 86.7%, respectively. EC patients treated at our center have excellent local control rates with a combination of external beam radiotherapy and brachytherapy. The central histopathological review may result in changes impacting patient management and should be routinely done prior to initiation of treatment in EC.

Neural network dose prediction for cervical brachytherapy: Overcoming data scarcity for applicator-specific models.

3D neural network dose predictions are useful for automating brachytherapy (BT) treatment planning for cervical cancer. Cervical BT can be delivered with numerous applicators, which necessitates developing models that generalize to multiple applicator types. The variability and scarcity of data for any given applicator type poses challenges for deep learning. The goal of this work was to compare three methods of neural network training-a single model trained on all applicator data, fine-tuning the combined model to each applicator, and individual (IDV) applicator models-to determine the optimal method for dose prediction. Models were produced for four applicator types-tandem-and-ovoid (T&O), T&O with 1-7 needles (T&ON), tandem-and-ring (T&R) and T&R with 1-4 needles (T&RN). First, the combined model was trained on 859 treatment plans from 266 cervical cancer patients treated from 2010 onwards. The train/validation/test split was 70%/16%/14%, with approximately 49%/10%/19%/22% T&O/T&ON/T&R/T&RN in each dataset. Inputs included four channels for anatomical masks (high-risk clinical target volume [HRCTV], bladder, rectum, and sigmoid), a mask indicating dwell position locations, and applicator channels for each applicator component. Applicator channels were created by mapping the 3D dose for a single dwell position to each dwell position and summing over each applicator component with uniform dwell time weighting. A 3D Cascade U-Net, which consists of two U-Nets in sequence, and mean squared error loss function were used. The combined model was then fine-tuned to produce four applicator-specific models by freezing the first U-Net and encoding layers of the second and resuming training on applicator-specific data. Finally, four IDV models were trained using only data from each applicator type. Performance of these three model types was compared using the following metrics for the test set: mean error (ME, representing model bias) and mean absolute error (MAE) over all dose voxels and ME of clinical metrics (HRCTV D90% and D2cc of bladder, rectum, and sigmoid), averaged over all patients. A positive ME indicates the clinical dose was higher than predicted. 3D global gamma analysis with the prescription dose as reference value was performed. Dice similarity coefficients (DSC) were computed for each isodose volume. Fine-tuned and combined models showed better performance than IDV applicator training. Fine-tuning resulted in modest improvements in about half the metrics, compared to the combined model, while the remainder were mostly unchanged. Fine-tuned MAE=3.98%/2.69%/5.36%/3.80% for T&O/T&R/T&ON/T&RN, and ME over all voxels=-0.08%/-0.89%/-0.59%/1.42%. ME D2cc were bladder=-0.77%/1.00%/-0.66%/-1.53%, rectum=1.11%/-0.22%/-0.29%/-3.37%, sigmoid=-0.47%/-0.06%/-2.37%/-1.40%, and ME D90=2.6%/-4.4%/4.8%/0.0%. Gamma pass rates (3%/3mm) were 86%/91%/83%/89%. Mean DSCs were 0.92%/0.92%/0.88%/0.91% for isodoses ≤150% of prescription. 3D BT dose was accurately predicted for all applicator types, as indicated by the low MAE and MEs, high gamma scores and high DSCs. Training on all treatment data overcomes challenges with data scarcity in each applicator type, resulting in superior performance than can be achieved by training on IDV applicators alone. This could presumably be explained by the fact that the larger, more diverse dataset allows the neural network to learn underlying trends and characteristics in dose that are common to all treatment applicators. Accurate, applicator-specific dose predictions could enable automated, knowledge-based planning for any cervical brachytherapy treatment.

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.

Development of learning-based online C-arm CT imaging technique for image-guided adaptive brachytherapy

Existing protocols for image-guided adaptive brachytherapy (BT) pose distinct limitations, which include: (1) the possible misalignment of the application position as a consequence of patient translocation between the treatment room and the computed tomography (CT)/magnetic resonance imaging (MRI) suite, (2) an inherent inability to continually monitor physiological and anatomical changes during the course of 3–10 fraction treatment regimens, and (3) insufficient tracing of the radioactive source movement within the patient's body. In response to these challenges, this study proposes an innovative deep-learning-based C-arm CT/SPECT imaging system tailored specifically for image-guided adaptive BT. This technological advancement aims to enable the execution of high-precision online adaptive BT, thereby amplifying the adaptability and effectiveness of oncological care. An image dataset of 66 non-contrast pelvic CT studies was acquired and limited-angle cone-beam CT (CBCT) images were generated by mathematically calculating sinograms for voxel phantoms based on these CT images. Using a Generative Adversarial Network (GAN), low-quality CBCT images obtained using a 110° limited-angle rotating C-arm system were transformed into high-quality diagnostic CT images. The performances of these networks were evaluated by comparing them with CBCT images reconstructed using an iterative reconstruction method and ground-truth images. Synthetic CT images were successfully transformed from low-quality CBCT images, considerably reducing streaking artifacts and preserving the anatomical structures. Our deep-learning-based image reconstruction technique could successfully improve the image quality of limited-angle CBCT, similar to the ground-truth image quality, with a faster speed than the latest iterative reconstruction algorithm. We expect that this will be effectively implemented in online image-guided adaptive BT and patient dose verification.

Survey of current practices in the management of cervical cancer by Moroccan radiotherapists

ObjectiveTo assess the applicability degree of the international guidelines by Moroccan radiotherapists, in order to improve the management of cervical cancer (CC), since CC is the second most common cancer for women in Morocco. MethodsThis cross-sectional study was carried out using a questionnaire sent online to Moroccan radiotherapists. The questionnaire covered participants' characteristics, initial assessment and treatment preparation, techniques and indications for radiotherapy and brachytherapy, dose and indications, as well as on the protocol adopted in the intermediate stages and the location of adjuvant treatments and assessments' follow-up. Results74 radiotherapists out of 300 have responded to the survey. Only 27.0% of practitioners reported discussing patient records systematically in a multidisciplinary consultation meeting (MCM). For the initial assessment, 77.0% requested pelvic magnetic resonance imaging (MRI). It is significantly less requested in regional oncology centers (ROCs) than in university hospital centers (UHCs) or the private sector (P ​< ​0.001). Furthermore, Clinicians in ROCs do not have access to new techniques of radiotherapy. In 83.8% of cases, the most prescribed radiotherapy protocols were 45–46 ​Gy in 1.8–2 ​Gy per fraction. Three-dimensional gynaecological brachytherapy high-throughput dose guided by dosimetric scanner was available in 75.5% of structures while interstitial gynaecological brachytherapy was only available in 23% of centers. The two most prescribed dose protocols were 4 ​× ​7 ​Gy and 3 ​× ​7 ​Gy in 74.4% and 21.6% of cases, respectively. Finally, monitoring during the first two years was based mainly on pelvic MRI (82.2%) while PET/CT was recommended by only less than 10%. ConclusionsThe findings obtained show that our radiotherapists generally comply with international guidelines for the cervical cancer management. However, they should still enhance their practices for the first staging evaluation, the use of systematic MCMs, the doses and treatment techniques used, and the follow-up evaluation.

Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial

Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer. In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB node positive vs stage III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1-by investigator or by histopathologic confirmation of suspected disease progression-and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants. Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab-chemoradiotherapy group and 531 to the placebo-chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3-22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab-chemoradiotherapy group versus 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55-0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49-1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group. Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD).

Equivalent uniform RBE-weighted dose in eye plaque brachytherapy.

Brachytherapy for ocular melanoma is based on the application of eye plaques with different spatial dose nonuniformity, time-dependent dose rates and relative biological effectiveness (RBE). We propose a parameter called the equivalent uniform RBE-weighted dose (EUDRBE) that can be used for quantitative characterization of integrated cell survival in radiotherapy modalities with the variable RBE, dose nonuniformity and dose rate. The EUDRBE is applied to brachytherapy with 125I eye plaques designed by the Collaborative Ocular Melanoma Study (COMS). The EUDRBE is defined as the uniform dose distribution with RBE=1 that causes equal cell survival for a given nonuniform dose distribution with the variable RBE>1. The EUDRBE can be used for comparison of cell survival for nonuniform dose distributions with different RBE, because they are compared to the reference dose with RBE=1. The EUDRBE is applied to brachytherapy with 125I COMS eye plaques that are characterized by a steep dose gradient in tumor base-apex direction, protracted irradiation during time intervals of 3-8 days, and variable dose-rate dependent RBE with a maximum of about 1.4. The simulations are based on dose of 85Gy prescribed to the farthest intraocular extent of the tumor (tumor apex). To compute the EUDRBE in eye plaque brachytherapy and correct for protracted irradiation, the distributions of physical dose have been converted to non-uniform distributions of biologically effective dose (BED) to include the biological effects of sublethal cellular repair, Our radiobiological analysis considers the combined effects of different time-dependent dose rates, spatial dose non-uniformity, dose fractionation and different RBE and can be used to derive optimized dose regimens brachytherapy. Our simulations show that the EUDRBE increases with the prescription depths and the maximum increase may achieve 6% for the tumor height of 12mm. This effect stems from a steep dose gradient within the tumor that increases with the prescription depth. The simulations also show that the EUDRBE increase may achieve 12% with increasing the dose rate when implant duration decreases. The combined effect of dose nonuniformity and dose rate may change the EUDRBE up to 18% for the same dose prescription of 85Gy to tumor apex. The absolute dose range of 48-61Gy (RBE) for the EUDRBE computed using 4 or 5 fractions is comparable to the dose prescriptions used in stereotactic body radiation therapy (SBRT) with megavoltage X-rays (RBE=1) for different cancers. The tumor control probabilities in SBRT and eye plaque brachytherapy are very similar at the level of 80% or higher that support the hypothesis that the selected approximations for the EUDRBE are valid. The computed range of the EUDRBE in 125I COMS eye plaque brachytherapy suggests that the selected models and hypotheses are acceptable. The EUDRBE can be useful for analysis of treatment outcomes and comparison of different dose regimens in eye plaque brachytherapy.

Dosimetric Comparison of Isodose Surface Volume and Total Reference Air Kerma (TRAK) based Volume in Cervical Cancer Brachytherapy.

We aim to compare TRAK & TPS based isodose volumes in cervical cancer brachytherapy and assess the feasibility, accuracy and potential future implications of TRAK in this regard and as a newer emerging tool to assess treatment intensity in cervical cancer brachytherapy. one hundred patients with histologically proven squamous cell carcinoma of cervix uteri were assessed for brachytherapy (after completion of external radiation) and prospectively enrolled for the study. 60 Gy, 75 Gy, and 85 Gy isodose volumes were obtained from the TPS (VTPS) for 50, 25 & 25 patients with Manchester, Fletcher & interstitial implant respectively, receiving various fractionation schedules by Ir192 HDR remote after-loading system. Using the formula Vpred=4965(TRAK/dref)3/2+170(TRAK/dref)-1.5 the TRAK based isodose surface volumes (Vpred) were derived. Reference doses (dref) were calculated based on accumulated EBRT and brachytherapy doses. The two sets of volume were compared with respect to applicator type, standard, and optimised plan. Surrogate point A dose was also correlated. VTPS - Vpred were 5.24 ± 2.7%, all volumes being predicted within 10%. Correlation of TRAK vs VTPS60/ VTPS75/ VTPS85 showed R2 of 0.994, 0.987 and 0.971 respectively. There was no significant difference in predicted volumes with respect to applicator type. The surrogate point A showed mean volume and standard deviation of 7.44 ± 13.4%, 17.63 ± 16.38 and 3.5 ± 0.95 for Manchester optimised, Fletcher optimised and standard plans respectively. TRAK with point A (R2=0.5632), bladder (R2=0.2015) and rectal doses (R2=0.121) yielded no correlation. Volumes calculated by TRAK correlate with TPS obtained volumes significantly and the formula predicting isodose surface volumes within 10% accuracy for ICBT applications and not for pure interstitial implants. However, TRAK fails to correlate with surrogate point A, bladder and rectal doses hence has questionable utility as a marker for biological response & treatment intensity.

Therapeutic pathomorphosis of stage IB–IIA cervical cancer cells after various regimens of preoperative HDR brachytherapy

Background. Despite of the constant improvement of existing treatment methods, involving the latest technologies into the treatment programs, the results of the treatment remain unsatisfactory. It is impossible to prevent the dissemination of tumor cells during surgery, which cause the tumor recurrence. Even in case of early stage cervical cancer, after only adequate conducted surgery, the relapse-rate is 20–30%, and the five-year survival rate is 40–60%. The aim of the work is to evaluate the effectiveness of different doses of preoperative HDR-brachytherapy in cervical cancer patients stage IB–IIA, based on the data of therapeutic pathomorphosis of the tumor. Materials and methods. There was investigated the structural and functional status of cells of squamous cell cervical cancer stage IB–IIA in two treatment schemes. According to the first scheme, there was conducted two sessions of brachytherapy with a single dose of 5 Gy with an interval of 7 days, up to the common dose of 10 Gy (5+5 Gy). According to another scheme, the single dose at the first session was 7 Gy, at the second session – 5 Gy, total dose was 12 Gy. The comparison group included primary patients with squamous cell cervical cancer and patients, who received fractional EBRT and EBRT + LDR-brachytherapy, total dose of 20 Gy and 40 Gy respectively. The morphofunctional status of cancer cells was investigated using standard electron microscopy methods. In all studied groups, there was detected the frequency of tumors samples, which contain large cells, the frequency of tumors with the presence of mitoses, and frequency of cases with significant therapeutic pathomorphosis. The obtained data was processed by the application of non-parametric statistical methods, using the «Biostat» software, and non-parametric criterion of the most plausible reliability assessment for small selections. Results. It is established that 26.9% of primary patients with cervical cancer had tumors with large cancer cells. After fractional irradiation with total doses of 20 and 40 Gy, an increase in the frequency of cases of tumors with such cells to 37.5 and 50.0%, respectively, was observed although these changes were unreliable in comparison with the control group of primary patients. However, after the first session of HDR-brachytherapy in a single dose of 5 or 7 Gy, in contrast to the indicators in the group of primary patients, there was a sharp and reliable increase in the frequency of tumors cases with large cancer cells up to 83.3% and 90%, respectively. At the same time, pronounced therapeutic pathomorphosis did not exceed 10.0–16.7% of cases. The second session of HDR brachytherapy at a dose of 5 Gy (total doses of 10 and 12 Gy) led both to a decrease in the frequency of tumors with large cancer cells to the level of control values (20 and 27.3%), and to a dose-dependent increase in the indicators of pronounced therapeutic pathomorphosis ( 40 and 70% respectively). Conclusions. There has been established that HDR-brachytherapy with the initial single dose of 5 or 7 Gy initiate a significant reaction, when the primary population of cancer cells is replaced by others, where prevail their large forms, which may be giant polyploid cancer cells. After the second session of brachytherapy of 5 Gy, the proportion of tumors, which are composed of large cells, significantly decreases simultaneously with the increase of significant therapeutic pathomorphosis in the cellpopulation of cervical cancer. The application of HDR-brachytherapy of 7 Gy at the first session will lead to the higher efficacy of the proposed scheme of the preoperative irradiation in cervical cancer patients stages IB–IIA, when the therapeutic pathomorphosis reaches 70%, when at the same time with a total dose of brachytherapy of 10 Gy, therapeutic pathomorphosis is only 40%.

Comparison of Local Disease Control and Toxicities in Two High Dose Rate Intracavitatory Brachytherapy Dose Fractionation Regimens (7Gy/3# v/s 9Gy/2#) in the Radical Treatment of Carcinoma Cervix: a Prospective Randomized Trial in Sub-Himalayan Region

Comparison of Local Disease Control and Toxicities in Two High Dose Rate Intracavitatory Brachytherapy Dose Fractionation Regimens (7Gy/3# v/s 9Gy/2#) in the Radical Treatment of Carcinoma Cervix: a Prospective Randomized Trial in Sub-Himalayan Region

Dose and fractionation regimen for brachytherapy boost in cervical cancer in the US

PurposeCurative-intent radiotherapy for locally advanced and select early stage cervical cancer in the US includes external beam radiotherapy (EBRT) with brachytherapy. Although there are guidelines for brachytherapy dose and fractionation regimens, there are limited data on practice patterns. This study aims to evaluate the contemporary utilization of cervical cancer brachytherapy in the US and its association with patient demographics and facility characteristics. MethodsWe retrospectively analyzed clinical covariates of cervical cancer patients diagnosed and treated in 2018–2020 with curative-intent radiotherapy from the 2020 National Cancer Database. Associations between patient and institutional factors with the number of brachytherapy fractions were identified with logistic regression. Factors with association (p < 0.10) were then included in a multivariable logistic regression model. All tests were two-sided with significance <0.05 unless specified otherwise. ResultsAmong the eligible 2517 patients, 97.3% received HDR or LDR and is further analyzed. More patients received HDR than LDR brachytherapy (98.9% vs 1.1%) and intracavitary than interstitial brachytherapy (86.4% vs 13.6%). The most common number of HDR fractions prescribed were 5 (51.0%), 4 (32.9%), and 3 (8.6%). After adjusting for the other variables in the model, ethnicity, private insurance status, overall insurance status, and facility type were the only factors that were significantly associated with the number of brachytherapy factions (p < 0.0001, p = 0.028, p = 0.001, and p < 0.0001, respectively, n = 2184). ConclusionsIn the US, various HDR brachytherapy regimens are utilized depending on patient and institutional factors. Future research may optimize cervical cancer brachytherapy by correlating specific dose and fractionation regimens with patient outcomes.

Disease mapping: Geographic differences in population rates of interventional treatment for prostate cancer in Australia.

Treatment decisions for men diagnosed with prostate cancer depend on a range of clinical and patient characteristics such as disease stage, age, general health, risk of side effects and access. Associations between treatment patterns and area-level factors such as remoteness and socioeconomic disadvantage have been observed in many countries. To model spatial differences in interventional treatment rates for prostate cancer at high spatial resolution to inform policy and decision-making. Hospital separations data for interventional treatments for prostate cancer (radical prostatectomy, low dose rate and high dose rate brachytherapy) for men aged 40 years and over were modelled using spatial models, generalised linear mixed models, maximised excess events tests and k-means statistical clustering. Geographic differences in population rates of interventional treatments were found (p<0.001). Separation rates for radical prostatectomy were lower in remote areas (12.2 per 10 000 person-years compared with 15.0-15.9 in regional and major city areas). Rates for all treatments decreased with increasing socioeconomic disadvantage (radical prostatectomy 19.1 /10 000 person-years in the most advantaged areas compared with 12.9 in the most disadvantaged areas). Three groups of similar areas were identified: those with higher rates of radical prostatectomy, those with higher rates of low dose brachytherapy, and those with low interventional treatment rates but higher rates of excess deaths. The most disadvantaged areas and remote areas tended to be in the latter group. The geographic differences in treatment rates may partly reflect differences in patients' physical and financial access to treatments. Treatment rates also depend on diagnosis rates and thus reflect variation in investigation rates for prostate cancer and presentation of disease. Spatial variation in interventional treatments may aid identification of areas of under-treatment or over-treatment.