Michael Milosevic

Expanding Access to Computed Tomographic Staging and Three-Dimensional Intensity Modulated Radiotherapy for Cervical Cancer in Ghana

PURPOSE To build capacity for improved treatment of locally advanced cervical cancer in Ghana, including computed tomography (CT) staging and intensity modulated radiotherapy (IMRT). MATERIALS AND METHODS Patients with histologically confirmed cervical cancer were prospectively staged with abdominopelvic CT and ultrasound and offered the opportunity to have IMRT instead of conventional two-dimensional radiotherapy. The development of an efficient, high-quality, and safe IMRT program was facilitated by investment in new technology and comprehensive training of the interdisciplinary radiotherapy team in collaboration with a North American center of excellence. RESULTS Of 215 patients with cervical cancer referred in 2022, 66% were able to afford CT scans and 26% were able to afford IMRT. Lymph node metastases were identified in 52% of patients by CT but in only 2% of patients by ultrasound. The use of CT resulted in 63% of patients being upstaged and changed treatment intent or radiation treatment volumes in 67% of patients. Patients who had IMRT experienced fewer acute side effects and were more likely to complete treatment as planned. CONCLUSION It is feasible to provide state-of the-art cancer treatment with CT staging and IMRT to patients with cervical cancer in low-resource settings and achieve meaningful improvements in outcomes. It requires a broad commitment by program leadership to invest in technology and staff training. Major challenges include balancing improved clinical care with reduced patient throughput when radiation treatment capacity is constrained, and with the additional cost in the absence of universal health coverage.

Incorporating cross-voxel exchange into the analysis of dynamic contrast-enhanced imaging data: theory, simulations and experimental results

Abstract Predictions of tumour perfusion are key determinants of drug delivery and responsiveness to therapy. Pharmacokinetic models allow for the estimation of perfusion properties of tumour tissues but many assume no dispersion associated with tracer transport away from the capillaries and through the tissue. At the level of a voxel, this translates to assuming no cross-voxel tracer exchange, often leading to the misinterpretation of derived perfusion parameters. Tofts model (TM), a compartmental model widely used in oncology, also makes this assumption. A more realistic description is required to quantify kinetic properties of tracers, such as convection and diffusion. We propose a Cross-Voxel Exchange Model (CVXM) for analysing cross-voxel tracer kinetics. In silico datasets quantifying the roles of convection and diffusion in tracer transport (which TM ignores) were employed to investigate the interpretation of Tofts’ perfusion parameters compared to CVXM. TM returned inaccurate values of K t r a n s and v e where diffusive and convective mechanisms are pronounced (up to 20% and 300% error respectively). A mathematical equation, developed in this work, predicts and gives the correct physiological interpretation of Tofts’ v e . Finally, transport parameters were derived from dynamic contrast enhanced-magnetic resonance imaging of a TS-415 human cervical carcinoma xenograft by using TM and CVXM. The latter deduced lower values of K t r a n s and v e compared to TM (lower by up to 63% and 76% respectively). It also allowed the detection of a diffusive flux (mean diffusivity 155 μ m 2 s −1 ) in the tumour tissue, as well as an increased convective flow at the periphery (mean velocity 2.3 μ m s −1 detected). The results serve as a proof of concept establishing the feasibility of using CVXM for accurately determining transport metrics that characterize the exchange of tracer between voxels. CVXM needs to be investigated further as its parameters can be linked to the tumour microenvironment properties (permeability, pressure…), potentially leading to enhanced personalized treatment planning.

Incorporating cross-voxel exchange for the analysis of dynamic contrast-enhanced imaging data: pre-clinical results

Abstract Tumours exhibit abnormal interstitial structures and vasculature function often leading to impaired and heterogeneous drug delivery. The disproportionate spatial accumulation of a drug in the interstitium is determined by several microenvironmental properties (blood vessel distribution and permeability, gradients in the interstitial fluid pressure). Predictions of tumour perfusion are key determinants of drug delivery and responsiveness to therapy. Pharmacokinetic models allow for the quantification of tracer perfusion based on contrast enhancement measured with non-invasive imaging techniques. An advanced cross-voxel exchange model (CVXM) was recently developed to provide a comprehensive description of tracer extravasation as well as advection and diffusion based on cross-voxel tracer kinetics (Sinno et al 2021). Transport parameters were derived from DCE-MRI of twenty TS-415 human cervical carcinoma xenografts by using CVXM. Tracer velocity flows were measured at the tumour periphery (mean 1.78–5.82 μm.s−1) pushing the contrast outward towards normal tissue. These elevated velocity measures and extravasation rates explain the heterogeneous distribution of tracer across the tumour and its accumulation at the periphery. Significant values for diffusivity were deduced across the tumours (mean 152–499 μm2.s−1). CVXM resulted in generally smaller values for the extravasation parameter K e x t (mean 0.01–0.04 min−1) and extravascular extracellular volume fraction v e (mean 0.05–0.17) compared to the standard Tofts parameters, suggesting that Toft model underestimates the effects of inter-voxel exchange. The ratio of Tofts’ extravasation parameters over CVXM’s was significantly positively correlated to the cross-voxel diffusivity (P < 0.0001) and velocity (P = 0.0005). Tofts’ increased v e measurements were explained using Sinno et al (2021)’s theoretical work. Finally, a scan time of 15 min renders informative estimations of the transport parameters. However, a duration as low as 7.5 min is acceptable to recognize the spatial variation of transport parameters. The results demonstrate the potential of utilizing CVXM for determining metrics characterizing the exchange of tracer between the vasculature and the tumour tissue. Like for many earlier models, additional work is strongly recommended, in terms of validation, to develop more confidence in the results, motivating future laboratory work in this regard.

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 < .001; and 82% v 24%, P < .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.

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 < 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 < 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 < 0.001). Higher risk scores were associated with lower expression (all P < 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.

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.

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.