An orthotopic prostate cancer model for new treatment development using syngeneic or patient-derived tumors.

BACKGROUND: There are limited preclinical orthotopic prostate cancer models due to the technical complexity of surgical engraftment and tracking the tumor growth in the mouse prostate gland. Orthotopic xenografts recapitulate the tumor microenvironment, tumor stromal interactions, and clinical behavior to a greater extent than xenografts grown at subcutaneous or intramuscular sites. METHODS: This study describes a novel micro-surgical technique for orthotopically implanting intact tumors pieces from cell line derived (transgenic adenocarcinoma mouse prostate [TRAMP]-C2) or patient derived (neuroendocrine prostate cancer [NEPC]) tumors in the mouse prostate gland and monitoring tumor growth using magnetic resonance (MR) imaging. RESULTS: The TRAMP-C2 tumors grew rapidly to a predetermined endpoint size of 10 mm within 3 weeks, whereas the NEPC tumors grew at a slower rate over 7 weeks. The tumors were readily detected by MR and confidently identified when they were approximately 2-3 mm in size. The tumors were less well-defined on CT. The TRAMP-C2 tumors were characterized by amorphous sheets of poorly differentiated cells similar to a high-grade prostatic adenocarcinoma and frequent macroscopic peritoneal and lymph node metastases. In contrast, the NEPC's displayed a neuroendocrine morphology with polygonal cells arranged in nests and solid sheets and high count. There was a local invasion of the bladder and other adjacent tissues but no identifiable metastases. The TRAMP-C2 tumors were more hypoxic than the NEPC tumors. CONCLUSIONS: This novel preclinical orthotopic prostate cancer mouse model is suitable for either syngeneic or patient derived tumors and will be effective in developing and advancing the current selection of treatments for patients with prostate cancer.

Utilization and Impact of a Radiation Nursing Clinic to Address Acute Care Needs for Patients with Gynecologic Cancers.

BACKGROUND: The risk factors for acute care utilization in gynecologic oncology patients are poorly understood. This study aimed to evaluate risk factors for the utilization of our centre's acute care radiation nursing clinic (RNC) by gynecologic oncology patients receiving radiotherapy (RT). METHODS: This was a retrospective cohort study of gynecological cancer patients treated with RT at an academic cancer centre between 1 August 2021 and 31 January 2022. Data on socio-demographics, clinical and treatment characteristics, and RNC visits were collected and summarized by descriptive statistics. The Wilcoxon rank sum test and chi-squared test/Fisher's exact test were used for comparisons of continuous and categorical variables, respectively. RESULTS: RT was delivered to 180 patients, of whom 42 (23%) received concurrent chemoradiation (CCR). Compared to those receiving RT alone, patients receiving CCR had higher rates of RNC utilization (55% vs. 19%, p < 0.001). Within the CCR cohort, patients who presented to the RNC were more likely to be unpartnered (43% vs. 11%, p = 0.04), receive a referral to Psychosocial Oncology (39% vs. 5.3%, p = 0.01), and experience treatment interruptions (52% vs. 16%, p = 0.02). There were no associations between RNC visits and age, disease site, or distance from the cancer centre. CONCLUSIONS: The receipt of CCR and specific psychosocial risk factors were associated with increased RNC utilization. Targeted strategies and early intervention to better meet the supportive care and psychosocial needs of this vulnerable population are needed.

Prospective evaluation of patient-reported anxiety and experiences with adaptive radiation therapy on an MR-linac.

Purpose: An integrated magnetic resonance scanner and linear accelerator (MR-linac) was implemented with daily online adaptive radiation therapy (ART). This study evaluated patient-reported experiences with their overall hospital care as well as treatment in the MR-linac environment. Methods: Patients pre-screened for MR eligibility and claustrophobia were referred to simulation on a 1.5 T MR-linac. Patient-reported experience measures were captured using two validated surveys. The 15-item MR-anxiety questionnaire (MR-AQ) was administered immediately after the first treatment to rate MR-related anxiety and relaxation. The 40-item satisfaction with cancer care questionnaire rating doctors, radiation therapists, the services and care organization and their outpatient experience was administered immediately after the last treatment using five-point Likert responses. Results were analyzed using descriptive statistics. Results: 205 patients were included in this analysis. Multiple sites were treated across the pelvis and abdomen with a median treatment time per fraction of 46 and 66 min respectively. Patients rated MR-related anxiety as "not at all" (87%), "somewhat" (11%), "moderately" (1%) and "very much so" (1%). Positive satisfaction responses ranged from 78 to 100% (median 93%) across all items. All radiation therapist-specific items were rated positively as 96-100%. The five lowest rated items (range 78-85%) were related to general provision of information, coordination, and communication. Overall hospital care was rated positively at 99%. Conclusion: In this large, single-institution prospective cohort, all patients had low MR-related anxiety and completed treatment as planned despite lengthy ART treatments with the MR-linac. Patients overall were highly satisfied with their cancer care involving ART using an MR-linac.

Targeting the CXCL12/CXCR4 pathway to reduce radiation treatment side effects.

High precision, image-guided radiotherapy (RT) has increased the therapeutic ratio, enabling higher tumor and lower normal tissue doses, leading to improved patient outcomes. Nevertheless, some patients remain at risk of developing serious side effects.In many clinical situations, the radiation tolerance of normal tissues close to the target volume limits the dose that can safely be delivered and thus the potential for tumor control and cure. This is particularly so in patients being re-treated for tumor progression or a second primary tumor within a previous irradiated volume, scenarios that are becoming more frequent in clinical practice.Various normal tissue 'radioprotective' drugs with the potential to reduce side effects have been studied previously. Unfortunately, most have failed to impact clinical practice because of lack of therapeutic efficacy, concern about concurrent tumor protection or excessive drug-related toxicity. This review highlights the evidence indicating that targeting the CXCL12/CXCR4 pathway can mitigate acute and late RT-induced injury and reduce treatment side effects in a manner that overcomes these previous translational challenges. Pre-clinical studies involving a broad range of normal tissues commonly affected in clinical practice, including skin, lung, the gastrointestinal tract and brain, have shown that CXCL12 signalling is upregulated by RT and attracts CXCR4-expressing inflammatory cells that exacerbate acute tissue injury and late fibrosis. These studies also provide convincing evidence that inhibition of CXCL12/CXCR4 signalling during or after RT can reduce or prevent RT side effects, warranting further evaluation in clinical studies. Greater dialogue with the pharmaceutical industry is needed to prioritize the development and availability of CXCL12/CXCR4 inhibitors for future RT studies.

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.

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

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.

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.

FBXW7-loss Sensitizes Cells to ATR Inhibition Through Induced Mitotic Catastrophe.

FBXW7 is a commonly mutated tumor suppressor gene that functions to regulate numerous oncogenes involved in cell-cycle regulation. Genome-wide CRISPR fitness screens identified a signature of DNA repair and DNA damage response genes as required for the growth of FBXW7-knockout cells. Guided by these findings, we show that FBXW7-mutant cells have high levels of replication stress, which results in a genotype-specific vulnerability to inhibition of the ATR signaling pathway, as these mutant cells become heavily reliant on a robust S-G2 checkpoint. ATR inhibition induces an accelerated S-phase, leading to mitotic catastrophe and cell death caused by the high replication stress present in FBXW7-/- cells. In addition, we provide evidence in cell and organoid studies, and mining of publicly available high-throughput drug screening efforts, that this genotype-specific vulnerability extends to multiple types of cancer, providing a rational means of identifying responsive patients for targeted therapy. SIGNIFICANCE: We have elucidated the synthetic lethal interactions between FBXW7 mutation and DNA damage response genes, and highlighted the potential of ATR inhibitors as targeted therapies for cancers harboring FBXW7 alterations.

Multi-institutional Prognostic Modeling in Head and Neck Cancer: Evaluating Impact and Generalizability of Deep Learning and Radiomics.

Artificial intelligence (AI) and machine learning (ML) are becoming critical in developing and deploying personalized medicine and targeted clinical trials. Recent advances in ML have enabled the integration of wider ranges of data including both medical records and imaging (radiomics). However, the development of prognostic models is complex as no modeling strategy is universally superior to others and validation of developed models requires large and diverse datasets to demonstrate that prognostic models developed (regardless of method) from one dataset are applicable to other datasets both internally and externally. Using a retrospective dataset of 2,552 patients from a single institution and a strict evaluation framework that included external validation on three external patient cohorts (873 patients), we crowdsourced the development of ML models to predict overall survival in head and neck cancer (HNC) using electronic medical records (EMR) and pretreatment radiological images. To assess the relative contributions of radiomics in predicting HNC prognosis, we compared 12 different models using imaging and/or EMR data. The model with the highest accuracy used multitask learning on clinical data and tumor volume, achieving high prognostic accuracy for 2-year and lifetime survival prediction, outperforming models relying on clinical data only, engineered radiomics, or complex deep neural network architecture. However, when we attempted to extend the best performing models from this large training dataset to other institutions, we observed significant reductions in the performance of the model in those datasets, highlighting the importance of detailed population-based reporting for AI/ML model utility and stronger validation frameworks. We have developed highly prognostic models for overall survival in HNC using EMRs and pretreatment radiological images based on a large, retrospective dataset of 2,552 patients from our institution.Diverse ML approaches were used by independent investigators. The model with the highest accuracy used multitask learning on clinical data and tumor volume.External validation of the top three performing models on three datasets (873 patients) with significant differences in the distributions of clinical and demographic variables demonstrated significant decreases in model performance. Significance: ML combined with simple prognostic factors outperformed multiple advanced CT radiomics and deep learning methods. ML models provided diverse solutions for prognosis of patients with HNC but their prognostic value is affected by differences in patient populations and require extensive validation.

A two-center experience: The impact of COVID-19 on two brachytherapy programs in Ontario - virtual care, service suspension and radiation therapy workflow.

INTRODUCTION: Most brachytherapy (BT) procedures require general anesthesia and are therefore considered aerosol generating medical procedures (AGMPs). The COVID-19 pandemic impacted BT as services were prioritized by balancing the harm associated with COVID-19 infection versus the effect of delay of potentially curative treatment. This article summarizes the impact of the pandemic on BT programs in two cancer centers in a Canadian province. METHODS: As part of a quality assurance project, a retrospective study was conducted for the first five months of the pandemic (March 1 to July 31, 2020). Chart review and COVID-19 related mitigation strategies were identified by BT Clinical Specialist Radiation Therapists (bCSRT) in each center using electronic medical records, departmental reports, policies and procedures. RESULTS: Impact included start of virtual care (VC), shortened fractionation, suspension of services and workflow changes.  Both centers implemented VC strategies to reduce clinic visits: "same-day size and treat" strategy for post-operative endometrial cancer patients and virtual patient education for all patients. BT services that were suspended were low-dose-rate and high-dose-rate (HDR) prostate treatments (Center 1), lung and esophagus HDR treatments (Center 2).  Workflow changes that affected staff and patients in both centers included COVID-19 screening and the use of personal protective equipment. The centers were marginally different in workflow adjustments for AGMP procedures.  Those considered high-risk AGMP and low-risk cancer were suspended temporarily with alternate treatment strategies sought for some patients. Others had temporizing treatment such as androgen deprivation therapy to facilitate oncological safe deferral of procedures. CONCLUSION: Both BT programs delivered treatment to most patients with minimal delays and cancellations, where feasible. Some of the pandemic workflow changes continued to the current state of the pandemic. Long-term follow-up is needed to assess the impact of COVID-19 and treatment interruptions on oncologic outcomes.

A phase I study of the Wee1 kinase inhibitor adavosertib (AZD1775) in combination with chemoradiation in cervical, upper vaginal, and uterine cancers.

OBJECTIVE: Wee1 kinase is a crucial regulator of the G2/M checkpoint which prevents entry of damaged DNA into mitosis. Adavosertib (AZD1775), a selective inhibitor of Wee1, induces G2 escape and increases cytotoxicity when combined with DNA damaging agents. We aimed to evaluate the safety and efficacy of adavosertib in combination with definitive pelvic radiotherapy and concurrent cisplatin in patients with gynecological cancers. METHODS: A multi-institutional, open-label phase I trial was designed to assess dose escalation (3+3 design) of adavosertib in combination with standard chemoradiation. Eligible patients with locally advanced cervical, endometrial or vaginal tumors were treated with a 5-week course of pelvic external beam radiation 45-50 Gy in 1.8-2 Gy daily fractions plus concurrent weekly cisplatin 40 mg/m2 and adavosertib 100 mg/m2 on days 1, 3 and 5 of each week during chemoradiation. The primary endpoint was to determine the recommended phase II dose of adavosertib. Secondary endpoints included toxicity profile and preliminary efficacy. RESULTS: Ten patients were enrolled (nine locally advanced cervical and one endometrial cancer). Two patients experienced a dose-limiting toxicity at dose level 1 (adavosertib 100 mg by mouth daily on days 1, 3 and 5), including one patient with grade 4 thrombocytopenia, and one with treatment hold >1 week due to grade 1 creatinine elevation and grade 1 thrombocytopenia. At dose level -1 (adavosertib 100 mg by mouth daily on days 3 and 5), one out of five patients enrolled had a dose-limiting toxicity in the form of persistent grade 3 diarrhea. The overall response rate at 4 months was 71.4%, including four complete responses. At 2 years follow-up, 86% of patients were alive and progression-free. CONCLUSION: The recommended phase II dose could not be determined due to clinical toxicity and early trial closure. Preliminary efficacy appears promising, yet selecting the adequate dose/schedule in combination chemoradiation warrants further investigation to limit overlapping toxicities.

Comparing dosimetry of locally advanced cervical cancer patients treated with 3 versus 4 fractions of MRI-guided brachytherapy.

PURPOSE: To demonstrate the feasibility of treating cervical cancer patients with MRI-guided brachytherapy (MRgBT) using 24 Gy in 3 fractions (F) versus a standard, more resource-intensive regimen of 28 Gy in 4F, and its ability to meet EMBRACE II planning aims. METHODS AND MATERIALS: A retrospective review of 224 patients with FIGO Stage IB-IVA cervical cancer treated with 28 Gy/4F (n = 91) and 24 Gy/3F (n = 133) MRgBT between 2016-2021 was conducted. Multivariable linear regression models were fitted to compare dosimetric parameters between the two groups, adjusting for CTVHR and T stage. RESULTS: Most patients had squamous cell carcinoma, T2b disease, and were treated with intracavitary applicator plus interstitial needles (96%). The 28 Gy/4F group had higher CTVHR (median 28 vs. 26 cm3, p = 0.04), CTVIR D98% (mean 65.5 vs. 64.5 Gy, p = 0.03), rectum D2cm3 (mean 61.7 vs. 59.2 Gy, p = 0.04) and bladder D2cm3 (81.3 vs. 77.9 Gy, p = 0.03). There were no significant differences in the proportion of patients meeting the EMBRACE II OAR dose constraints and planning aims, except fewer patients treated with 28 Gy/4F met rectum D2cm3 < 65 Gy (73 vs. 85%, p = 0.027) and ICRU rectovaginal point < 65 Gy (65 vs. 84%, p = 0.005). CONCLUSIONS: Cervical cancer patients treated with 24 Gy/3F MRgBT had comparable target doses and lower OAR doses compared to those treated with 28 Gy/4F. A less-resource intense fractionation schedule of 24 Gy/3F is an alternative to 28 Gy/4F in cervix MRgBT.

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

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 (Sinnoet al2021). 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 1.78-5.82µm.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 152-499µm2.s-1). CVXM resulted in generally smaller values for the extravasation parameterKext(mean 0.01-0.04 min-1) and extravascular extracellular volume fractionve(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' increasedvemeasurements were explained using Sinnoet 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.

Geographic Accessibility and Availability of Radiotherapy in Ghana.

Importance: Radiotherapy is critical for comprehensive cancer care, but there are large gaps in access. Within Ghana, data on radiotherapy availability and on the relationship between distance and access are unknown. Objectives: To estimate the gaps in radiotherapy machine availability in Ghana and to describe the association between distance and access to care. Design, Setting, and Participants: This is a cross-sectional, population-based study of radiotherapy delivery in Ghana in 2020 and model-based analysis of radiotherapy demand and the radiotherapy utilization rate (RUR) using the Global Task Force on Radiotherapy for Cancer Control investment framework. Exposures: Receipt of radiotherapy and the number of radiotherapy courses delivered. Main Outcomes and Measures: Geocoded location of patients receiving external beam radiotherapy (EBRT); median Euclidean distance from the district centroids to the nearest radiotherapy centers; proportion of population living within geographic buffer zones of 100, 150, and 200 km; additional capacity required for optimal utilization; and geographic accessibility after strategic location of a radiotherapy facility in an underserviced region. Results: A total of 2883 patients underwent EBRT courses in 2020, with an actual RUR of 11%. Based on an optimal RUR of 48%, 11 524 patients had an indication for radiotherapy, indicating that only 23% of patients received treatment. An investment of 23 additional EBRT machines would be required to meet demand. The median Euclidean distance from the district centroids to the nearest radiotherapy facility was 110.6 km (range, 0.62-513.2 km). The proportion of the total population living within a radius of 100, 150 and 200 km of a radiotherapy facility was 47%, 61% and 70%, respectively. A new radiotherapy facility in the northern regional capital would reduce the median of Euclidean distance by 10% to 99.4 km (range, 0.62-267.7 km) and increase proportion of the total population living within a radius of 100, 150 and 200 km to 53%, 69% and 84%, respectively. The greatest benefit was seen in regions in the northern half of Ghana. Conclusions and Relevance: In this cross-sectional study of geographic accessibility and availability of radiotherapy, Ghana had major national deficits of radiotherapy capacity, with significant geographic disparities among regions. Well-planned infrastructure scale-up that accounts for the population distribution could improve radiotherapy accessibility.

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

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.

Striving to Fill in Gaps between Clinical Practice and Standards: The Evolution of a Pan-Canadian Approach to Patient-Reported Outcomes Use.

Despite the known importance and necessity of the standardized collection and use of patient-reported outcomes (PROs), there remain challenges to successful clinical implementation. Facilitated through a quality improvement initiative spearheaded by the Canadian Partnership for Quality Radiotherapy (CPQR), and now guided by the Canadian Association of Radiation Oncology (CARO)'s Quality and Standards Committee, patient representatives and early-adopter radiation treatment programs continue to champion the expansion of PROs initiatives across the country. The current review discusses the evolution of a pan-Canadian approach to PROs use, striving to fill in gaps between clinical practice and guideline recommendations through multi-centre and multidisciplinary collaboration.

Provincial variations in radiotherapy utilization as a measure of access: A pan-Canadian study.

BACKGROUND AND PURPOSE: Access to radiotherapy (RT) is a key component of a cancer control strategy. However, radiotherapy utilization (RTU) rates fall short of desired benchmarks in certain Canadian provinces. We aimed to describe provincial variations in RTU across Canada. MATERIALS AND METHODS: We calculated radiotherapy utilization ratios (RTUR) for each Canadian province from 2016 (RT case counts divided by incidence counts), by cancer type (all cancers, lung, breast, rectal, prostate) and treatment intent (curative, palliative) where data were available. Data were extracted from each provincial RT data repository, cancer registry and/or RT department. We compared RTURs descriptively across provinces and to Ontario benchmarks, and calculated an estimated national RTUR. In provinces with capacity for data linkage, RTURs were compared to a linked (patient-specific) method of calculating utilization, by linking each incident case to whether RT was received within 1 year of diagnosis (RTU-1 yr). RESULTS: Excluding three provinces that included re-treatments, all-cancer RTURs ranged from 0.31 in Manitoba to 0.40 in Nova Scotia. The national all-cancer RTUR was 0.35, which was comparable to Ontario benchmarks (0.34). Larger variations were seen by cancer type, with an absolute difference in RTURs of 28% for lung cancers, 27% for breast cancers, 21% for rectal cancers, and 18% for prostate cancers. RTURs for nearly all provinces were below established Ontario benchmarks for each cancer type, except prostate cancer. RTURs over-estimated RTU-1 yr by at most 5%, except for prostate cancers where they over-estimated RTU-1 yr by up to 15%. CONCLUSIONS: RTU varies by province in Canada, and most notably by cancer subsite. More granular data at the regional level and by healthcare facility is required to further tailor strategies aimed at improving RT access. RTURs also serve as a reasonable surrogate for linked RTU, and both methods can contribute meaningfully to measure RTU depending on the context and data availability.

Impact of PET scanner non-linearity on the estimation of hypoxic fraction in cervical cancer patients.

BACKGROUND: Tumor hypoxia is defined as a low oxygen level in tissue and is associated with poor clinical outcome after chemo-/radiotherapy and surgery in many solid tumor types. Positron Emission Tomography (PET) imaging provides a non-invasive means of measuring local variations in the uptake of hypoxia-targeted agents (e.g. FAZA or FMISO). Accurate quantification of uptake is critically dependent on the PET scanner's linear count rate performance. In the context of cervix cancer, high PET agent accumulation in the bladder, low uptake in the tumor, and their relative proximity makes an accurate quantification of the tumor's hypoxic fraction challenging. The purpose of this study was to estimate the impact of PET scanner non-linearity on PET-based estimation of hypoxic fraction. MATERIAL AND METHODS: The impact of PET scanner non-linearity effect was assessed with a NEMA body phantom, using the cylinder as the "bladder-mimicking" compartment and the water filled background as a surrogate region for the tumor. A simple model of the non-linearity effect was then applied to a set of patient-derived FAZA-PET scans (N = 38) to estimate the impact of the non-linearity on the calculated hypoxic fraction (HF) for each patient. RESULTS: The NEMA body phantom measurements revealed a substantial overestimate of activity outside the injected "bladder mimicking" cylinder compartment. This uptake resulted in an overestimate in activity between 1.9 and 0.3 kBq/cc corresponding to distances from 1.0 - 7.0 cm from the cylinder. In the patient-derived PET images, the bladder-to-tumor distance ranged between 1.0 and 3.0 cm. For the 38 patients analyzed, the HF was demonstrated to decrease by 1.1-75.0 % [median 27.2 %] depending on distance and relative uptake levels. Additionally, the magnitude of the effect of the non-linearity was found to depend on the pre-scanning hydration protocol employed (p = 0.0065). CONCLUSION: Hypoxia imaging of tumors of the cervix is challenging due to patient specific activity accumulation in the bladder and the non-linear response of PET scanner performance. This can result in a substantial overestimate of the calculated hypoxic fraction in cervical tumors. Additional effort needs to be invested to improve the linearity of PET scanners in anatomical regions proximal to the bladder.

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

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 silicodatasets 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 ofKtransandvewhere 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've.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 ofKtransandvecompared to TM (lower by up to 63% and 76% respectively). It also allowed the detection of a diffusive flux (mean diffusivity 155µm2s-1) in the tumour tissue, as well as an increased convective flow at the periphery (mean velocity 2.3µm s-1detected). 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.

The Oral CXCR4 Inhibitor X4-136 Improves Tumor Control and Reduces Toxicity in Cervical Cancer Treated With Radiation Therapy and Concurrent Chemotherapy.

PURPOSE: Cervical cancer is a global health problem. Despite the growth of prevention programs, there is an important need to improve the effectiveness of treatment for patients with invasive, locally advanced disease. In this study we examined (1) the efficacy of radiation therapy (RT) with cisplatin (RTCT) and an orally administered CXCR4 inhibitor suitable for clinical use, X4-136; (2) biomarkers of response to RTCT and X4-136; and (3) intestinal toxicity from RTCT and X4-136. METHODS AND MATERIALS: Orthotopic cervical cancer xenografts derived from our patients were treated with RT (30 Gy; 2 Gy/d) and cisplatin (4 mg/kg/wk intraperitoneally) with or without concurrent X4-136 (100 mg/kg/d orally) for 3 weeks. Mice were euthanized immediately after treatment for biomarker assessment or followed to evaluate primary tumor growth delay and metastases. In separate experiments, acute and late intestinal injury were assessed histologically. RESULTS: RTCT alone increased CXCL12/CXCR4 signaling, intratumoral accumulation of myeloid cells, and PD-L1 expression. The addition of X4-136 during RTCT abrogated these effects, improved primary tumor response, and reduced metastases. Furthermore, X4-136 increased the proportion of surviving intestinal crypt cells after irradiation, in keeping with a reduction in acute RT toxicity, and reduced late histologic changes of late RT toxicity. CONCLUSIONS: The combination of RTCT and the CXCR4 inhibitor X4-136 improves cervical cancer primary tumor control and reduces lymph node metastases, while also reducing normal tissue injury associated with adverse intestinal effects. Few if any pharmacologic strategies have expanded the therapeutic window with RT, suggesting that this combination warrants testing in clinical trials. These benefits might apply to other tumors where RTCT plays a curative role.