F. Huang

Evaluation of brachytherapy applicators and their association with morbidity and local control in cervix cancer: An EMBRACE I analysis

To investigate the effects of brachytherapy (BT) applicator and implant type on morbidity and local control (LC) in locally advanced cervix cancer patients. 1071 patients treated with radiochemotherapy including MRI-guided BT using tandem&ring (T&R) or tandem&ovoids (T&O) from 19 EMBRACE-I centers were analyzed. Intracavitary (IC) or intracavitary/interstitial (IC/IS) implants were used. Centers came from different brachytherapy traditions and followed their institutional dose aims and planning strategies. LC and physician-assessed morbidity (median follow-up 48 months) was compared between applicator/implant types using Cox proportional hazard model adjusting for patient characteristics and treatment-related potential confounders. Moderate-to-severe (G ≥ 2) genito-urinary (cystitis/frequency/incontinence), gastro-intestinal (proctitis/bleeding/diarrhea) and vaginal (stenosis/mucositis) symptoms were analysed individually. Severe events (G ≥ 3) were pooled per organ. The T&O (n = 346) compared to T&R (n = 725) had a higher risk of morbidity, with HRs > 1.3 in 14/16 individual G ≥ 2 symptoms and in 3/4 G ≥ 3 pooled organ symptoms. Patients treated with IC/IS (n = 512) compared to IC (n = 559) were not at higher risk of G ≥ 2 symptoms, with HRs < 1 in 6/8 MVAs. Crude incidence of local failure was 7.3 % (25/343) for T&O and 6.6 % (47/712) for T&R. In this patient cohort, treated between 2008-2015, T&R and T&O demonstrated comparable LC. However, a higher risk of morbidity is reported for T&O. This increased risk was partly explained by hotspot doses, with factors such as irradiated volumes and organ irradiation length also contributing. Additionally, implant quality, dose planning aims and strategies, and morbidity reporting may have impacted the observed differences in morbidity. IC/IS applicators did not increase morbidity risk compared to IC applicators.

Management of oligo-metastatic and oligo-recurrent cervical cancer: A pattern of care survey within the EMBRACE research network

In the metastatic or recurrent cervical cancer, systemic chemotherapy constitutes the main treatment. Though there is an increasing use of high dose external radiation and brachytherapy in the metastatic setting, no consensus exists. A 17-item survey was designed with additional case-based questions to explore present management of oligo-metastatic and oligo-recurrent cervix cancer within EMBRACE research group participating sites. The questions were designed to elicit prevailing practices in the management of de-novo oligo-metastasis and oligo-recurrent setting after completing the primary treatment of cervix cancer. The survey was sent electronically with two rounds of email reminders to respond over a 2-week survey period. The online survey was designed such that it was mandatory to complete all questions. The responses were recorded and results were summarized as proportions and summary statistics were generated. Twenty-two centers responded to this survey. A majority (90%) of respondents reported a low incidence of de-novo oligo-metastatic cervical cancer in their practice (<5%), with a higher proportion of patients with oligo-recurrence after completing primary treatment (5-10%). All responding sites preferred to treat pelvic disease in the de-novo oligo-metastatic setting albeit with different fractionation regimens. While 68.2% of respondents recommended chemo-radiation and brachytherapy, 31.8% considered additional systemic therapy. Overall 77.3% centers recommended the use of stereotactic ablative radiation therapy to oligo-metastasis. For out-of-field nodal recurrences, 63.7% of respondents considered treating with curative intent, while 59% preferred treating in-field recurrence with palliative intent. A vast majority of the participating centers (90%) have stereotactic radiation therapy capacity and would consider a clinical trial addressing oligo-metastatic and oligo-recurrent cervical cancer. Although contemporary practice is variable, a substantial proportion of EMBRACE centers consider high dose radiation in de-novo metastatic and oligo-recurrence settings. However, there is clear need for a joint clinical protocol and prospective studies to address the role of high dose radiation within oligo-recurrent and oligo-metastatic scenarios.

Importance of the ICRU bladder point dose on incidence and persistence of urinary frequency and incontinence in locally advanced cervical cancer: An EMBRACE analysis

To identify patient- and treatment-related risk factors and dose-effects for urinary frequency and incontinence in locally advanced cervical cancer (LACC) treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). Physician-assessed (CTCAE) and patient-reported (EORTC) frequency and incontinence recorded in the EMBRACE-I study were analysed. Risk factors analysis was performed in patients without bladder infiltration and with baseline morbidity available. Cox regression was used for CTCAE grade (G) ≥ 3 and G ≥ 2 and for EORTC "very much" and "quite a bit" or worse. Logistic regression was used for late persistent morbidity defined when CTCAE G ≥ 1 or EORTC ≥ "quite a bit" were scored in at least half of follow-ups. Longitudinal data on 1153 and 884 patients were available for CTCAE and EORTC analysis, respectively. Median follow-up was 48[3-120] months. Crude incidence rates of G≥2 were 13% and 11% for frequency and incontinence, respectively. Baseline morbidity and overweight-obesity were risk factors for both symptoms. Elderly patients were at higher risk for incontinence. Patients receiving conformal-radiotherapy were at higher risk for frequency. ICRU bladder point (ICRU-BP) dose was a stronger predictor for incontinence than bladder D ICRU-BP dose, in addition to clinical parameters, is a risk factor for urinary incontinence and shows a dose-effect after radio(chemo)therapy and IGABT. ICRU-BP dose should be monitored during treatment planning alongside volumetric parameters. Frequency seems associated with larger irradiated volumes.

Response to Yuce Sari et al.

Risk factors and dose-effects for bladder fistula, bleeding and cystitis after radiotherapy with imaged-guided adaptive brachytherapy for cervical cancer: An EMBRACE analysis

To identify patient- and treatment-related risk factors for fistula, bleeding, cystitis, pain and difficulty in voiding in locally advanced cervical cancer patients treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). Morbidity within the EMBRACE-I study was prospectively reported for physician-assessed (CTCAE) fistula, bleeding and cystitis and patient-reported (EORTC) pain and difficulty in voiding. Analysis of risk factors was performed in patients without bladder infiltration. Risk factors were tested with Cox regression for grade (G) ≥ 3 cystitis, for G ≥ 2 fistula, bleeding and cystitis, and for EORTC "very much" and "quite a bit" or worse. Of 1416 patients enrolled, 1153 and 884 patients without bladder infiltration were evaluable for the analysis of CTCAE and EORTC items, respectively. Median follow-up was 48[3-120] months. Crude incidence rates for G ≥ 2 fistula, bleeding and cystitis were 0.7%, 2.7% and 8.8%, respectively, and 16% and 14% for "quite a bit" or worse pain and difficulty in voiding, respectively. Baseline urinary morbidity and overweight/obesity were significant risk factors for most endpoints. Bladder D Clinical and treatment-related risk factors for bladder fistula, bleeding and cystitis were identified within a prospective and multi-institutional setting. A dose-effect was established with bladder D

BAIRDA: a novel in vitro setup to quantify radiobiological parameters for cervical cancer brachytherapy dose estimations

AbstractObjective. Brachytherapy (BT) dose prescriptions for locally advanced cervical cancer are made with account for the radiobiological parameters,α/βratio and halftime of repair (T1/2). However, a wide range of parameter values has been reported which can challenge commonly held equivalencies between dose prescriptions. This is the first reported study that aims to develop anin vitroexperimental technique using clinical high-dose-rate (HDR) and pulsed-dose-rate (PDR) Ir-192 brachytherapy afterloaders to quantify these parametersin vitroand to contextualize findings within contemporary practice.Approach. To efficiently quantifyα/βandT1/2,in vitroexperiments more reflective of clinical BT practice than traditional clonogenic survival assays were developed and applied to four squamous cell carcinoma cell lines (CaSki, C-33A, SiHa, and SW756). Radiation was delivered using single acute and fractionated dose treatments with a conventional irradiator and clinical HDR and PDR BT afterloaders. For the latter, a novelbrachytherapyafterloaderin vitroradiationdeliveryapparatus (BAIRDA) was developed.Main Results. Theα/βandT1/2values determined using BAIRDA and the conventional irradiator showed close agreement, validating the novel apparatus and technique. For CaSki, C-33A, SiHa, and SW756, the BAIRDA-measuredα/βratios (5.2 [4.6–5.8], 5.6 [4.5–6.6], 6.3 [4.9–7.7], and 5.3 [4.7–6.0] Gy, respectively) were consistently smaller, while theT1/2(3.3 [2.7–3.9], 2.7 [2.0–3.3], 2.8 (2.4–3.1], and 4.8 [4.1–5.4] hours) larger, than the widely accepted values in clinical practice (α/β= 10 Gy;T1/2 = 1.5 h).Significance.In vitroexperiments using BAIRDA provided evidence for differences between the conventionally selected and experimentally determinedα/βratio andT1/2. Treatment regimens using HDR-BT and PDR-BT, designed to deliver equivalent radiobiological doses based on conventional values, were shown to differ by up to 27 Gy EQD2 – an effect that could impact treatment outcomes in cervical cancer. Furthermore, with BAIRDA, we have developed a novel method for radiobiological research in BT.

Towards robust deep learning-based autosegmentation in MRI-planned gynecological brachytherapy: Importance of scalable development and comprehensive evaluation

To present comprehensive development and evaluation methodologies for a generalizable deep learning (DL)-driven autocontouring model of standard pelvic organs-at-risk (OARs) in MRI-planned cervical brachytherapy. A curated dataset of 200 3D-MRIs (85% training/validation, 15% testing) including multiple applicator types, varying treated anatomies, and manual contours of OARs (bladder, rectum, sigmoid, small bowel) by 3 physicians was utilized to develop an nnU-Net-based autocontouring model. Iterative tuning was conducted to determine the optimal hyperparameters and enhance evaluation metrics. Model performance was assessed using quantitative metrics, like geometric (e.g., Dice Coefficient (DC) and Hausdorff Distance 95th Percentile (HD95)) and dosimetric (dose-volume histograms (DVHs), dose differences (ΔD2cc)), and then correlated with qualitative physician-review (modified Turing and Likert tests). Geometric metrics were best for bladder (e.g., mean ± SD DC|HD95(mm) 0.93 ± 0.02|2.26 ± 1.07) with greater variability exhibited for small bowel (0.62 ± 0.16|24.90 ± 14.36). Dosimetric comparisons of manual vs predicted contours showed high agreement in DVHs, with mean ΔD2cc <0.60 Gy EQD2 The DL-based autocontouring model, trained on a heterogeneous in-house dataset, demonstrates clinical acceptability for OARs as determined by comprehensive evaluation. It also shows promise for translatability to target contouring, and adaptability to other gynecological (noncervix) brachytherapy applications. Differences in qualitative and quantitative results exist; directionality and magnitude should be considered in clinical usability assessments of brachytherapy autocontouring models.

A Clinical Trial to Assess the Effectiveness of NRF2 Activator (Oral Sodium-copper- Chlophyllin ) in Locally Advanced Cervical Cancer to Reduce Late Radiotherapy Toxicity.

Cervical cancer is the second most common cancer in Indian women, and most patients are diagnosed at advanced stages. The standard treatment for these stages is concurrent chemoradiotherapy, but this can cause long-term side effects such as bladder inflammation, strictures, ulcers, and tissue damage, which negatively impact patients' quality of life. Previous studies have shown that oral sodium-copper-chlorophyllin can help reduce radiation-related side effects in rectal, prostate, and cervical cancer patients. However, no study has compared side effects between patients receiving standard follow-up care and those taking sodium-copper-chlorophyllin during follow-up. We hypothesize that the use of sodium-copper-chlorophyllin as a short-duration adjuvant is associated with reduced incidence of late grade 2 or higher gastrointestinal and genitourinary toxicities compared to patients receiving standard-of-care follow-up.