Kathy Han

Retained Surgical Sponge in the Pelvis From Magnetic Resonance Imaging–Guided Cervix Brachytherapy

Magnetic resonance imaging-guided brachytherapy is an essential component of curative treatment in locally advanced cervical cancer. The use of interstitial needles improves local control rate for locally advanced cervical cancer compared to intracavitary brachytherapy alone. Bleeding is one of the most common complications from cervix interstitial brachytherapy, typically managed by pressure with surgical sponge/packing with or without a hemostatic agent. Herein, we present a case of stage IVA cervical cancer with retained surgical sponge in the pelvis from magnetic resonance imaging-guided intracavitary/interstitial brachytherapy, and recommendations for future brachytherapy procedures.

Pain control and opioid use as a function of workflow in MRI-guided interstitial cervix brachytherapy

/Objective(s): Pain management during brachytherapy for cervix cancer is challenging. Institutional practice for brachytherapy delivery and pain management varies. Here we retrospectively assessed pain control and opioid use requirements during different MRI-guided interstitial cervix brachytherapy workflows. /Methods: In this retrospective study, data was collected on ninety-one patients receiving MR-guided interstitial brachytherapy for cervix cancer between June 2022 and June 2024. Abstracted data included: demographics, disease characteristics, pain scores, opioid use, and brachytherapy workflow. Patients were either treated as in-patients or out-patients. In-patients remained overnight to receive a second fraction the following day. Out-patients received a single fraction and were discharged the same day. Out-patients were further divided into intra-operative versus post-operative treatment. For intra-operative treatment the entire procedure was performed under general anesthesia (GA). For post-operative treatment only applicator insertion was under GA. Multivariable linear regression modelling was used for analysis of opioid dose and pain scores. Ninety-one patients were eligible for inclusion, corresponding to 201 separate insertions. Median age was 51. Majority (69 %) had cT2b disease. Mean CTV In-patient treatment was associated with worse pain control, despite increased opioid use. Within those treated as out-patients, intra-operative treatment further improved pain management.

Clinical Outcomes of 3 Versus 4 Fractions of Magnetic Resonance Image-Guided Brachytherapy in Cervical Cancer

Magnetic resonance image-guided brachytherapy is essential in the management of locally advanced cervical cancer. This study compares disease and toxicity outcomes in cervical cancer patients treated with 24 Gy/3 fractions (Fr) versus the conventional 28 Gy/4 Fr. This retrospective study included 241 consecutive patients with International Federation of Gynecology and Obstetrics 2018 stage IB to IVA cervical cancer treated with definitive chemoradiation between April 2014 and March 2021. Disease-free survival (DFS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Cumulative incidence of local failure (LF), distant failure (DF), and G2+ gastrointestinal (GI), urinary and vaginal toxicity were estimated using the cumulative incidence function with death as a competing risk and compared using Gray's test. Of the 241 patients, 42% received 24 Gy/3 Fr and 58% received 28 Gy/4 Fr. With a median follow-up of 3.2 (range, 0.2-9.2) years, there were 14 local, 41 regional nodal, and 51 distant failures in 63 (26%) patients. No significant differences were found between the 24 Gy/3 Fr and 28 Gy/4 Fr groups in 3-year DFS (77% vs 68%, P = .21), the 3-year cumulative incidence of LF (5% vs 7%, P = .57), DF (22% vs 25%, P = .86), G2+ GI toxicity (11% vs 20%, P = .13), or G2+ vaginal toxicity (14% vs 17%, P = .48), respectively. The 3-year cumulative G2+ urinary toxicity rate was lower in the 24 Gy/3 Fr group (9% vs 23%, P = .03). Patients with cervical cancer treated with 24 Gy/3 Fr had similar DFS, LF, DF, GI, and vaginal toxicity rates and a trend toward a lower G2+ urinary toxicity rate compared with those treated with 28 Gy/4 Fr. A less resource-intensive brachytherapy fractionation schedule of 24 Gy/3 Fr is a safe alternative to 28 Gy/4 Fr for definitive treatment of cervical cancer.

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.

Sensitivity of radiomic features to inter-observer variability and image pre-processing in Apparent Diffusion Coefficient (ADC) maps of cervix cancer patients

The aims of this study are to evaluate the stability of radiomic features from Apparent Diffusion Coefficient (ADC) maps of cervical cancer with respect to: (1) reproducibility in inter-observer delineation, and (2) image pre-processing (normalization/quantization) prior to feature extraction. Two observers manually delineated the tumor on ADC maps derived from pre-treatment diffusion-weighted Magnetic Resonance imaging of 81 patients with FIGO stage IB-IVA cervical cancer. First-order, shape, and texture features were extracted from the original and filtered images considering 5 different normalizations (four taken from the available literature, and one based on urine ADC) and two different quantization techniques (fixed-bin widths from 0.05 to 25, and fixed-bin count). Stability of radiomic features was assessed using intraclass correlation coefficient (ICC): poor (ICC < 0.75); good (0.75 ≤ ICC ≤ 0.89), and excellent (ICC ≥ 0.90). Dependencies of the features with tumor volume were assessed using Spearman's correlation coefficient (ρ). The approach using urine-normalized values together with a smaller bin width (0.05) was the most reproducible (428/552, 78% features with ICC ≥ 0.75); the fixed-bin count approach was the least (215/552, 39% with ICC ≥ 0.75). Without normalization, using a fixed bin width of 25, 348/552 (63%) of features had an ICC ≥ 0.75. Overall, 26% (range 25-30%) of the features were volume-dependent (ρ ≥ 0.6). None of the volume-independent shape features were found to be reproducible. Applying normalization prior to features extraction increases the reproducibility of ADC-based radiomics features. When normalization is applied, a fixed-bin width approach with smaller widths is suggested.

A Phase II Randomized Trial of Chemoradiation with or without Metformin in Locally Advanced Cervical Cancer

Abstract Purpose: Tumor hypoxia is associated with poor response to radiation (RT). We previously discovered a novel mechanism of metformin: enhancing tumor RT response by decreasing tumor hypoxia. We hypothesized that metformin would decrease tumor hypoxia and improve cervical cancer response to RT. Patients and Methods: A window-of-opportunity, phase II randomized trial was performed in stage IB–IVA cervical cancer. Patients underwent screening positron emission tomography (PET) imaging with hypoxia tracer fluoroazomycin arabinoside (FAZA). Only patients with FAZA uptake (hypoxic tumor) were included and randomized 2:1 to receive metformin in combination with chemoRT or chemoRT alone. A second FAZA-PET/CT scan was performed after 1 week of metformin or no intervention (control). The primary endpoint was a change in fractional hypoxic volume (FHV) between FAZA-PET scans, compared using the Wilcoxon signed-rank test. The study was closed early due to FAZA availability and the COVID-19 pandemic. Results: Of the 20 consented patients, 6 were excluded due to no FAZA uptake and 1 withdrew. FHV of 10 patients in the metformin arm decreased by an average of 10.2% (44.4%–34.2%) ± SD 16.9% after 1 week of metformin, compared with an average increase of 4.7% (29.1%–33.8%) ± 11.5% for the 3 controls (P = 0.027). Those with FHV reduction after metformin had significantly lower MATE2 expression. With a median follow-up of 2.8 years, the 2-year disease-free survival was 67% for the metformin arm versus 33% for controls (P = 0.09). Conclusions: Metformin decreased cervical tumor hypoxia in this trial that selected for patients with hypoxic tumor. See related commentary by Lyng et al., p. 5233

Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer

PURPOSE Most cervical cancers are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our pilot study using digital polymerase chain reaction (dPCR) showed that detectable HPV ctDNA at the end of chemoradiation (CRT) is associated with inferior progression-free survival (PFS) and that a next-generation sequencing approach (HPV-seq) may outperform dPCR. We aimed to prospectively validate HPV ctDNA as a tool for early detection of residual disease. METHODS This prospective, multicenter validation study accrued patients with stage IB-IVA cervical cancer treated with CRT between 2017 and 2022. Participants underwent phlebotomy at baseline, end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT for HPV ctDNA levels. Plasma HPV genotype–specific DNA levels were quantified using both dPCR and HPV-seq. The primary end point was 2-year PFS. RESULTS With a median follow-up of 2.2 (range, 0.5-5.5) years, there were 24 PFS events among the 70 patients with HPV+ cervical cancer. Patients with detectable HPV ctDNA on dPCR at the end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT had significantly worse 2-year PFS compared with those with undetectable HPV ctDNA (77% v 51%, P = .03; 82% v 15%, P &lt; .001; and 82% v 24%, P &lt; .001, respectively); the median lead time to recurrence was 5.9 months. HPV-seq showed similar results as dPCR. On multivariable analyses, detectable HPV ctDNA on dPCR and HPV-seq remained independently associated with inferior PFS. CONCLUSION Persistent HPV ctDNA after CRT is independently associated with inferior PFS. HPV ctDNA testing can identify, as early as at the end of CRT, patients at high risk of recurrence for future treatment intensification trials.

Updated Trends in the Utilization of Brachytherapy in Cervical Cancer in the United States: A Surveillance, Epidemiology, and End-Results Study

Our previous Surveillance, Epidemiology, and End Results (SEER) study revealed a concerning decline in brachytherapy utilization in the United States between 1988 and 2009. This study evaluates recent trends in brachytherapy utilization in cervical cancer and identifies factors and survival benefit associated with the use of brachytherapy treatment. Using SEER data, 8500 patients with International Federation of Gynecologists and Obstetricians 2009 stage IB2-IVA cervical cancer treated with external beam radiation therapy (EBRT) between 2000 and 2020 were identified. Logistic regression analysis was performed on potential factors associated with brachytherapy use: age, marital status, race, ethnicity, income, metropolitan status, year of diagnosis, SEER region, histology, grade, and stage. To adjust for differences between patients who received brachytherapy and those who did not, propensity-score matching was used. Multivariable Cox regression analysis assessed the association of brachytherapy use with cervical cancer-specific mortality (CSM) and all-cause mortality (ACM) in the matched cohort. Sixty-four percent of the 8500 women received brachytherapy in combination with EBRT; 36% received EBRT alone. The brachytherapy utilization rate declined sharply in 2003/2004 (lowest rate 44% in 2003) and then gradually improved especially in 2018 to 2020 (76%). Factors associated with higher odds of brachytherapy use included younger age, married (vs single), later years of diagnosis, certain SEER regions, and earlier stage. In the propensity-score matched cohort, brachytherapy treatment was associated with lower 4-year cumulative incidence of cancer death (32.1% vs 43.4%; P < .001) and better overall survival (64.0% vs 51.4%; P < .001). Brachytherapy treatment was independently associated with lower CSM (hazard ratio, 0.70; 95% CI, 0.64-0.76; P < .001) and ACM (hazard ratio, 0.72; 95% CI, 0.67-0.78; P < .001). Brachytherapy utilization among SEER regions has improved since 2004 in patients with stage IB2-IVA cervical cancer. Brachytherapy use remains independently associated with significantly lower CSM and ACM and is an essential component of treatment for patients with locally advanced cervical cancer.

An Immune Gene Expression Risk Score for Distant Metastases after Radiotherapy for Cervical Cancer

Abstract Purpose: To develop an immune-based gene expression risk score to identify patients with cervical cancer at increased risk of distant metastases (DM). Experimental Design: Tumor biopsies were obtained from 81 patients prior to chemoradiotherapy. Whole-transcriptome RNA sequencing was performed (Illumina NextSeq500). Beginning with 4,723 immune-related genes, a 55-gene risk score for DM was derived using Cox modeling and principal component analysis. It was validated in independent cohorts of 274 patients treated at the Norwegian Radium Hospital (NRH) and 206 patients from The Cancer Genome Atlas (TCGA). Results: The risk score was predictive of DM (HR, 2.7; P &amp;lt; 0.0001) and lower cause-specific survival (CSS) by univariate analysis (HR, 2.0; P = 0.0003) and multivariate analysis adjusted for clinical factors (DM HR, 3.0; P &amp;lt; 0.0001; CSS HR, 2.2; P = 0.0004). The risk score predicted DM (HR, 1.4; P = 0.05) and CSS (HR, 1.48; P = 0.013) in the NRH cohort and CSS (HR, 1.4; P = 0.03) in TCGA cohort. Higher risk scores were associated with lower CIBERSORT estimates of tumor-infiltrating immune cells, including CD8 T cells and M1 and M2 macrophages (all P &amp;lt; 0.001). Higher risk scores were associated with lower expression (all P &amp;lt; 0.001) of important chemokines (CXCL12, CXCR4), IFN-regulated genes (IRF1, STAT1, IDO1), and immune checkpoint regulators (PD-1, PD-L1, CTLA-4). Conclusions: The immune metastatic risk score addresses important challenges in the treatment of cervical cancer—identifying patients at high risk of DM after radiotherapy. The findings of this study indicate that high tumor mutational burden and a “cold,” immune-excluded tumor microenvironment influence distant metastatic recurrence. Further validation of the risk score is needed.

MRI-guided brachytherapy for vaginal recurrence of endometrial cancer

Vaginal recurrence of endometrial cancer can be salvaged by external beam radiotherapy and vaginal brachytherapy, but data on MRI-guided brachytherapy is limited. This study evaluated disease and toxicity outcomes of patients treated with MRI-guided brachytherapy for vaginal recurrence of endometrial cancer. Patients who received salvage MRI-guided interstitial/intracavitary brachytherapy for vaginal recurrence of endometrial cancer between 2015 and 2023 were retrospectively reviewed. Local failure (LF) was estimated using the cumulative incidence function. Disease-free (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Toxicities were assessed using the Common Terminology Criteria for Adverse Events (version 5). Of the 56 patients, 17 (30%) and 39 (70%) were treated with intracavitary (multichannel vaginal applicator) and interstitial (Syed-Neblett template) brachytherapy, respectively. Fifty-three (94%) had endometroid adenocarcinoma histology. The median high-risk clinical target volume D Patients with vaginal recurrence of endometrial cancer treated with MRI-guided interstitial/intracavitary brachytherapy had favorable local control, DFS, OS and toxicity rates.

Intra-operative process efficiency for in-room MRI-guided combined intracavitary/interstitial brachytherapy for cervical cancer.

Magnetic resonance image-guided brachytherapy (MRgBT) is the gold-standard treatment for cervical cancer. This study examined workflow times in an integrated MRgBT suite and conventional operating room (OR), and factors contributing to intraoperative efficiency. Consecutive patients with FIGO stage IB-IVA cervical cancer who underwent MRgBT procedures between 2019-2022 were retrospectively reviewed. Workflow times were collected: applicator insertion, MR-imaging, contouring, treatment planning, treatment execution and total procedure time. Procedure durations between applicators and over time were compared. The 161 patients included in this study underwent 267 procedures in the MRgBT suite, and 56 procedures in the OR using ovoid and tandem applicator (O&T, 46%), ring and tandem (R&T, 28%), or Syed-Neblett template (Template, 27%). The median duration (minutes) of each step was: general anesthesia induction (18), applicator insertion (31), MR-imaging (28), parallel contouring (48) and applicator/needle registration & treatment plan optimization (83), and treatment execution (19). Total procedure time was much longer in the OR (488 minutes) than MRgBT suite (205 minutes). Template cases were significantly longer in insertion, MR-imaging, contouring, planning and total procedure time (by 52 minutes) compared with those using the R&T/O&T applicators (p<0.001). Total procedure time for Template cases reduced by 10 minutes/year since 2019 (p<0.001). Regardless of applicator type, total procedure time for subsequent insertions was 21 minutes less than the first (p<0.001). MRgBT procedure time was longer for Syed-Neblett template cases, but shorter in subsequent insertions. The overall procedure time was much shorter in the integrated MRgBT suite than conventional OR.

A T2-weighted MRI-based radiomic signature for disease-free survival in locally advanced cervical cancer following chemoradiation: An international, multicentre study

To develop and validate a T2-weighted magnetic resonance imaging (MRI)-based radiomic signature associated with disease-free survival (DFS) in locally advanced cervical cancer. The study comprised a training dataset of 132 patients (93 Norwegian; 39 The Cancer Imaging Archive (TCIA) and an independent validation Canadian dataset of 199 patients with FIGO stage IB-IVA cervical cancer treated with chemoradiation. Radiomic features were extracted using PyRadiomics. A radiomic signature was developed based on a multivariable radiomic prognostic model for DFS built using the training dataset, with minimal redundancy maximum relevancy feature selection method. Univariate and multivariable Cox regression analyses were then conducted to examine the association of the derived radiomic signature with DFS. A radiomic signature was prognostic for DFS in the training cohort (Norwegian hazard ratio [HR] 5.54, p = 0.002; TCIA HR 3.59, p = 0.04). The radiomic signature remained independently associated with DFS (HR 3.70, p = 0.004) when adjusted for stage and tumor volume. The radiomic signature was also prognostic for DFS in the validation cohort, both on univariate analysis (HR 2.22, p = 0.003), and multivariable analysis adjusted for stage and tumor volume (HR 1.84, p = 0.04). The 4-year DFS rates of patients with radiomic signature score > 0 vs ≤ 0 were 48.2 % vs 87.9 %, and 56.4 % vs 80.8 % for training and validation cohorts respectively. An MRI-based radiomic signature can be used as a prognostic biomarker for DFS in patients with locally advanced cervical cancer undergoing chemoradiation.

Generalizability of deep learning in organ-at-risk segmentation: A transfer learning study in cervical brachytherapy.

Deep learning can automate delineation in radiation therapy, reducing time and variability. Yet, its efficacy varies across different institutions, scanners, or settings, emphasizing the need for adaptable and robust models in clinical environments. Our study demonstrates the effectiveness of the transfer learning (TL) approach in enhancing the generalizability of deep learning models for auto-segmentation of organs-at-risk (OARs) in cervical brachytherapy. A pre-trained model was developed using 120 scans with ring and tandem applicator on a 3T magnetic resonance (MR) scanner (RT3). Four OARs were segmented and evaluated. Segmentation performance was evaluated by Volumetric Dice Similarity Coefficient (vDSC), 95 % Hausdorff Distance (HD95), surface DSC, and Added Path Length (APL). The model was fine-tuned on three out-of-distribution target groups. Pre- and post-TL outcomes, and influence of number of fine-tuning scans, were compared. A model trained with one group (Single) and a model trained with all four groups (Mixed) were evaluated on both seen and unseen data distributions. TL enhanced segmentation accuracy across target groups, matching the pre-trained model's performance. The first five fine-tuning scans led to the most noticeable improvements, with performance plateauing with more data. TL outperformed training-from-scratch given the same training data. The Mixed model performed similarly to the Single model on RT3 scans but demonstrated superior performance on unseen data. TL can improve a model's generalizability for OAR segmentation in MR-guided cervical brachytherapy, requiring less fine-tuning data and reduced training time. These results provide a foundation for developing adaptable models to accommodate clinical settings.

FDG-PET and Circulating HPV in Patients With Cervical Cancer Treated With Definitive Chemoradiation (II)

Nearly all cervical cancers are caused by the human papilloma virus (HPV), which can be detected in cancer tissue by laboratory tests. There is evidence that the virus can also be detected from a blood sample to monitor the effects of treatment. Previous studies have shown that a special test called 18F-Fluorodeoxyglucose (FDG) Positron Emission Tomography/Computed Tomography (PET-CT) at 3 months after treatment may predict survival in cervical cancer. The purpose of this study is to see how well the FDG-PET Scan and blood tests for HPV can detect leftover cervical cancer cells after treatment. This study is not a particular form of treatment and patients will receive standard of care treatment.

Liquid Biopsy Evaluation and Repository Development at Princess Margaret

The objective of this protocol is to develop an institution-wide liquid biopsy protocol that will establish a common process for collecting blood and corresponding archived tumor specimens for future research studies at the University Health Network's Princess Margaret Cancer Centre. Circulating cell-free nucleic acids (cfNA), including cell-free DNA (cfDNA) and cell-free RNA (cfRNA), are non-invasive, real-time biomarkers that can provide diagnostic and prognostic information before cancer diagnosis, during cancer treatment, and at disease progression. Cancer research scientists and clinicians at the Princess Margaret are interested in incorporating the collection of peripheral blood samples ("liquid biopsies") into research protocols as a means of non-invasively assessing tumor progression and response to treatment at multiple time points during a patient's course of disease.