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.

National Trends and Dynamic Responses in the Canadian Radiation Oncology Workforce From 1990 to 2018.

PURPOSE: To report radiation oncology (RO) workforce and cancer incidence trends in Canada and explore the relationship between the two. METHODS AND MATERIALS: Canadian radiation oncologist, trainee, and cancer incidence data from 1990 to 2018 were collected from the following publicly accessible administrative and health information databases: Canadian Post-MD Education Registry (1990-2018), Canadian Medical Association Physician Data Centre (1994-2018), Canadian Institute for Health Information/Scott's Medical Database (1990-2017), Canadian Cancer Registry (1990-2017), and Statistics Canada (1990-2017). Descriptive statistics were used to summarize the data. RESULTS: The Canadian RO workforce grew from 240 radiation oncologists in 1990 to 567 in 2018, with the largest growth period from 2005 to 2015 adding 207 radiation oncologists. Regional analyses revealed steady or stepwise growth in all Canadian regions, except in Québec, where the number of radiation oncologists decreased from 86 in 1990 to 57 in 2003 before rising to 139 by 2018. Trainee totals were between 54 and 173 per year with 2 periods of growth (1990-1996 and 2001-2008) and regression (1996-2001 and 2008-2018), signifying trainee supply variability. Female proportions of the workforce and trainees, respectively, rose steadily from 18% to 38% and 28% to 50%, while the workforce proportion with non-Canadian medical degrees decreased from 40% to 26%. Radiation oncologists younger than 40 years increased from 70 to 171, whereas those age 60 years and older decreased from 85 in 1990 to 31 in 2002 and then increased to 108 in 2017. Annual cancer incidence rose steadily from 103,780 to 206,290 cases/year. The annual cancer incidence-to-provider ratio fluctuated (364-475:1) and trended lower with time, and proportional cancer incidence-to-provider ratios varied between 0.7:1 and 1.6:1 in Canada's regions before approaching 1:1. CONCLUSIONS: Our study demonstrates the challenges and successes of managing the Canadian radiation oncologist workforce. These data will inform policy makers and other stakeholders to ensure that the profession meets the current and future needs of Canadian cancer patients.

Vulnerabilities of radiomic signature development: The need for safeguards.

PURPOSE: Refinement of radiomic results and methodologies is required to ensure progression of the field. In this work, we establish a set of safeguards designed to improve and support current radiomic methodologies through detailed analysis of a radiomic signature. METHODS: A radiomic model (MW2018) was fitted and externally validated using features extracted from previously reported lung and head and neck (H&N) cancer datasets using gross-tumour-volume contours, as well as from images with randomly permuted voxel index values; i.e. images without meaningful texture. To determine MW2018's added benefit, the prognostic accuracy of tumour volume alone was calculated as a baseline. RESULTS: MW2018 had an external validation concordance index (c-index) of 0.64. However, a similar performance was achieved using features extracted from images with randomized signal intensities (c-index = 0.64 and 0.60 for H&N and lung, respectively). Tumour volume had a c-index = 0.64 and correlated strongly with three of the four model features. It was determined that the signature was a surrogate for tumour volume and that intensity and texture values were not pertinent for prognostication. CONCLUSION: Our experiments reveal vulnerabilities in radiomic signature development processes and suggest safeguards that can be used to refine methodologies, and ensure productive radiomic development using objective and independent features.

The Utility of Serum CA9 for Prognostication in Prostate Cancer.

BACKGROUND/AIM: Carbonic anhydrase IX (CA9) catalyses the interconversion of carbon dioxide to carbonic acid and bicarbonate and is considered a putative biomarker of tumour hypoxia. We set out to evaluate the prognostic significance of CA9 in prostate cancer. PATIENTS AND METHODS: Plasma samples were assessed from 68 men with high-risk localised prostate cancer treated with radical prostatectomy (RP) or radiotherapy (RT), and 20 men with castration-resistant prostate cancer (CRPC) treated with docetaxel chemotherapy between 2010 and 2012 at the Princess Margaret Cancer Centre, Canada. RESULTS: Of the 68 patients with high-risk localised prostate cancer, 57 underwent RP and 11 underwent RT. Baseline CA9 was not associated with recurrence or prostate-specific antigen in either group (p=0.98 and 0.20, respectively). CA9 levels before chemotherapy correlated with overall survival (r=-0.37; two-sided p=0.11). CONCLUSION: Baseline CA9 in men with CRPC may portend a more aggressive prostate cancer phenotype with poorer survival.

A prospective study of DWI, DCE-MRI and FDG PET imaging for target delineation in brachytherapy for cervical cancer.

BACKGROUND AND PURPOSE: We examined the utility of dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted MRI (DWI), and FDG-PET imaging for brachytherapy target delineation in patients with locally advanced cervical cancer. MATERIALS AND METHODS: Twenty-two patients had DWI, DCE-MRI, and FDG-PET/CT scans after brachytherapy applicator insertion, in addition to standard T2-weighted (T2w) 3T MRI. Gross tumor volume (GTVB) and high-risk clinical target volume (HRCTV) were contoured first on T2w images, and then modified if indicated upon review of DWI/DCE-MRI/FDG-PET images by two observers. The primary endpoint was utility, determined by the number of patients whose volumes were modified, and interobserver variability. RESULTS: Eleven patients' T2w-GTVB were modified based on DWI/DCE-MRI/FDG-PET by observer 1, due to clearer demarcation (7) and residual disease not well visualized on T2w MRI (4). GTVB was modified in 17 patients by observer 2 (11 and 6, respectively). Incorporation of functional imaging improved the conformity index (CI) for GTVB from 0.54 (T2w alone) to 0.65 (P=0.003). HRCTV was modified in 3 and 8 patients by observers 1 and 2, respectively, with a trend toward higher CI using functional imaging (0.71 to 0.76, P=0.06). CONCLUSIONS: DWI/DCE-MRI/FDG-PET imaging as a supplement to T2w MRI decreased interobserver variability in GTVB delineation.

Association between Metformin Use and Mortality after Cervical Cancer in Older Women with Diabetes.

BACKGROUND: To examine the association between metformin use and mortality in patients with diabetes and cervical cancer. METHODS: Using Ontario health databases, a retrospective, population-based cohort study was conducted in women with diabetes ≥ age 66 years diagnosed with cervical cancer between 1997 and 2010. The association between metformin exposure and cervical cancer-specific mortality was examined using Fine-Gray regression models, with noncancer death as a competing risk and cumulative metformin use as a time-varying exposure. The association with overall mortality was examined using Cox regression models. RESULTS: Among the 181 women with diabetes and cervical cancer, there were 129 deaths, including 61 cervical cancer-specific deaths. The median follow-up was 5.8 years (interquartile range 4.2-9.6 years) for surviving patients. Cumulative dose of metformin after cervical cancer diagnosis was independently associated with a decreased risk of cervical cancer-specific mortality and overall mortality in a dose-dependent fashion [HR 0.79; 95% confidence interval (CI), 0.63-0.98; and HR 0.95; 95% CI, 0.90-0.996 per each additional 365 g of metformin use, respectively]. There was no significant association between cumulative use of other antidiabetic drugs and cervical cancer-specific mortality. CONCLUSION: This study suggests an association between cumulative metformin use after cervical cancer diagnosis and lower cervical cancer-specific and overall mortality among older women with diabetes. IMPACT: Cumulative dose of metformin use after cervical cancer diagnosis among older women with diabetes may be associated with a significant decrease in mortality. This finding has important implications if validated prospectively, as metformin is inexpensive and can be easily combined with standard treatment for cervical cancer.

Sorafenib Increases Tumor Hypoxia in Cervical Cancer Patients Treated With Radiation Therapy: Results of a Phase 1 Clinical Study.

PURPOSE: Preclinical studies have shown that angiogenesis inhibition can improve response to radiation therapy (RT). The purpose of this phase 1 study was to examine the angiogenesis inhibitor sorafenib in patients with cervical cancer receiving radical RT and concurrent cisplatin (RTCT). METHODS AND MATERIALS: Thirteen patients with stage IB to IIIB cervical cancer participated. Sorafenib was administered daily for 7 days before the start of standard RTCT in patients with early-stage, low-risk disease and also during RTCT in patients with high-risk disease. Biomarkers of tumor vascularity, perfusion, and hypoxia were measured at baseline and again after 7 days of sorafenib alone before the start of RTCT. The median follow-up time was 4.5 years. RESULTS: Initial complete response was seen in 12 patients. One patient died without achieving disease control, and 4 experienced recurrent disease. One patient with an extensive, infiltrative tumor experienced pelvic fistulas during treatment. The 4-year actuarial survival was 85%. Late grade 3 gastrointestinal toxicity developed in 4 patients. Sorafenib alone produced a reduction in tumor perfusion/permeability and an increase in hypoxia, which resulted in early closure of the study. CONCLUSIONS: Sorafenib increased tumor hypoxia, raising concern that it might impair rather than improve disease control when added to RTCT.

A facility for magnetic resonance-guided radiation therapy.

Magnetic resonance (MR) imaging is routinely employed in the design of radiotherapy (RT) treatment plans for many disease sites. It is evident that tighter integration of MR imaging into the RT process would increase confidence in dose placement and facilitate the integration of new MR imaging information (including anatomical and functional imaging) into the therapy process. To this end, a dedicated MR-guided RT (MRgRT) facility has been created that integrates a state-of-the-art linear accelerator delivery system, high-dose rate brachytherapy afterloader, and superconducting MR scanner to allow MR-based online treatment guidance, adaptive replanning, and response monitoring while maintaining the clinical functionality of the existing delivery systems. This system is housed within a dedicated MRgRT suite and operates in a coordinated fashion to assure safe and efficient MRgRT treatments.

High tumor interstitial fluid pressure identifies cervical cancer patients with improved survival from radiotherapy plus cisplatin versus radiotherapy alone.

Radiotherapy (RT) with concurrent cisplatin (CRT) is standard treatment for locally advanced cervical cancer. However, not all patients benefit from the addition of cisplatin to RT alone. This study explored the value of pretreatment tumor interstitial fluid pressure (IFP) and hypoxia measurements as predictors of cisplatin response in 291 patients who were treated with RT (1994-1998) or RT plus concurrent cisplatin (1999-2009). Clinical characteristics were similar between the two groups, apart from a greater proportion of patients with pelvic lymph node metastases and hypoxic tumors in the CRT cohort. Patients were followed for a median duration of 5.6 years. Information about recurrence and survival was recorded prospectively. The addition of cisplatin to RT improved survival compared to treatment with RT alone (HR 0.61, p = 0.0097). This improvement was confined to patients with high-IFP tumors at diagnosis (HR 0.40, p = 0.00091). There was no benefit of adding cisplatin in those with low-IFP tumors (HR 1.05, p = 0.87). There was no difference in the effectiveness of cisplatin in patients with more or less hypoxic tumors. In conclusion, patients with locally advanced cervical cancer and high tumor IFP at diagnosis have greater benefit from the addition of cisplatin to RT than those with low IFP. This may reflect high tumor cell proliferation, which is known to influence IFP, local tumor control and patient survival.

Simultaneous nonrigid registration, segmentation, and tumor detection in MRI guided cervical cancer radiation therapy.

External beam radiation therapy (EBRT) for the treatment of cancer enables accurate placement of radiation dose on the cancerous region. However, the deformation of soft tissue during the course of treatment, such as in cervical cancer, presents significant challenges for the delineation of the target volume and other structures of interest. Furthermore, the presence and regression of pathologies such as tumors may violate registration constraints and cause registration errors. In this paper, automatic segmentation, nonrigid registration and tumor detection in cervical magnetic resonance (MR) data are addressed simultaneously using a unified Bayesian framework. The proposed novel method can generate a tumor probability map while progressively identifying the boundary of an organ of interest based on the achieved nonrigid transformation. The method is able to handle the challenges of significant tumor regression and its effect on surrounding tissues. The new method was compared to various currently existing algorithms on a set of 36 MR data from six patients, each patient has six T2-weighted MR cervical images. The results show that the proposed approach achieves an accuracy comparable to manual segmentation and it significantly outperforms the existing registration algorithms. In addition, the tumor detection result generated by the proposed method has a high agreement with manual delineation by a qualified clinician.

An integrated approach to segmentation and nonrigid registration for application in image-guided pelvic radiotherapy.

External beam radiotherapy (EBRT) has become the preferred options for nonsurgical treatment of prostate cancer and cervix cancer. In order to deliver higher doses to cancerous regions within these pelvic structures (i.e. prostate or cervix) while maintaining or lowering the doses to surrounding non-cancerous regions, it is critical to account for setup variation, organ motion, anatomical changes due to treatment and intra-fraction motion. In previous work, manual segmentation of the soft tissues is performed and then images are registered based on the manual segmentation. In this paper, we present an integrated automatic approach to multiple organ segmentation and nonrigid constrained registration, which can achieve these two aims simultaneously. The segmentation and registration steps are both formulated using a Bayesian framework, and they constrain each other using an iterative conditional model strategy. We also propose a new strategy to assess cumulative actual dose for this novel integrated algorithm, in order to both determine whether the intended treatment is being delivered and, potentially, whether or not a plan should be adjusted for future treatment fractions. Quantitative results show that the automatic segmentation produced results that have an accuracy comparable to manual segmentation, while the registration part significantly outperforms both rigid and nonrigid registration. Clinical application and evaluation of dose delivery show the superiority of proposed method to the procedure currently used in clinical practice, i.e. manual segmentation followed by rigid registration.

Comparing oxygen-sensitive MRI (BOLD R2*) with oxygen electrode measurements: a pilot study in men with prostate cancer.

PURPOSE: To explore the relationship between oxygen-sensitive Magnetic Resonance Imaging (MRI) and oxygen measurements in prostate cancer. METHODS: Nine men underwent MRI examinations followed by needle oxygen measurements of tumor bearing region within prostate gland and five men further consented to biopsy. Median pO2 and hypoxic fraction < 5 mm Hg (HP5) were derived. Biopsies were immunostained for Carbonic Anhydrase IX (CA IX), Hypoxia Inducible Factor-1 (HIF 1) and Glucose Transporter-1 (GLUT 1). Corresponding Regions-of-Interest (ROI) were delineated on T2-weighted (T2w) MRI by two observers. Median R2* was calculated for each ROI. Spearman correlation was calculated between R2* and HP5/pO2. RESULTS: MRI quality evaluation resulted in exclusion of 4/18 ROI due to motion (n = 2) and rectal air susceptibility artifact (n = 2). Quality of remaining data was validated by concordance of R2* with T2w, indices and with secondary observer R2* (r = 0.94, p = 0.005). Correlation was observed between R2* and HP5 (r = 0.76, p = 0.02) and a trend was noted between R2* and pO2 (r = -0.66, p = 0.07). GLUT 1 and HIF 1 were expressed in all patients, and CA IX was expressed in one patient with high HP5 (77%) and low pO2 (1.4 mm Hg). CONCLUSIONS: MRI using R2* quantification is a promising tool for non-invasive imaging of prostate cancer hypoxia.

Development of multiorgan finite element-based prostate deformation model enabling registration of endorectal coil magnetic resonance imaging for radiotherapy planning.

PURPOSE: Endorectal coil (ERC) magnetic resonance imaging (MRI) provides superior visualization of the prostate compared with computed tomography at the expense of deformation. This study aimed to develop a multiorgan finite element deformable method, Morfeus, to accurately co-register these images for radiotherapy planning. METHODS: Patients with prostate cancer underwent fiducial marker implantation and computed tomography simulation for radiotherapy planning. A series of axial MRI scans were acquired with and without an ERC. The prostate, bladder, rectum, and pubic bones were manually segmented and assigned linear elastic material properties. Morfeus mapped the surface of the bladder and rectum between two imaged states, calculating the deformation of the prostate through biomechanical properties. The accuracy of deformation was measured as fiducial marker error and residual surface deformation between the inferred and actual prostate. The deformation map was inverted to deform from 100 cm(3) to no coil. RESULTS: The data from 19 patients were analyzed. Significant prostate deformation occurred with the ERC (mean intrapatient range, 0.88 +/- 0.25 cm). The mean vector error in fiducial marker position (n = 57) was 0.22 +/- 0.09 cm, and the mean vector residual surface deformation (n = 19) was 0.15 +/- 0.06 cm for deformation from no coil to 100-cm(3) ERC, with an image vector resolution of 0.22 cm. Accurately deformed MRI scans improved soft-tissue resolution of the anatomy for radiotherapy planning. CONCLUSIONS: This method of multiorgan deformable registration enabled accurate co-registration of ERC-MRI scans with computed tomography treatment planning images. Superior structural detail was visible on ERC-MRI, which has potential for improving target delineation.

Long-term outcome of radiation-based conservation therapy for invasive bladder cancer.

PURPOSE: To report the long-term results and examine factors associated with bladder preservation, risk of relapse, and survival in patients treated with radical radiotherapy for invasive bladder cancer. MATERIALS AND METHODS: Between 1986 and 1997, 340 patients with T1-T4 bladder cancer were treated at Princess Margaret Hospital and received radiotherapy alone, radiotherapy and concurrent cisplatin chemotherapy, or neoadjuvant chemotherapy followed by radiotherapy. Patients having complete response were followed with regular cystoscopy. Cystectomy was undertaken in suitable patients with persistent or locally recurrent disease. RESULTS: The median age of patients was 71 years, 13% had evidence of regional lymph node involvement, and 27% were medically unfit for radical cystectomy. A total of 247 patients received radiotherapy alone, 36 radiotherapy and concurrent cisplatin chemotherapy, and 57 neoadjuvant chemotherapy followed by radiotherapy. Complete response was obtained in 63.5% of patients overall, and median follow-up was 7.9 years. The 10-year overall survival, cause-specific survival, and local relapse-free rates were 19%, 35%, and 32%, respectively. In 131 patients with muscle-invasive disease confined to the bladder wall (T2N0M0), 10-year cause-specific survival (P = 0.02) and local relapse-free rates (P = 0.03) were 68% and 60% when carcinoma in situ was absent, and 47% and 28%, respectively, when present. In multivariable analysis, younger age, lower T category, and absence of carcinoma in situ were associated with a statistically significant improvement in survival and local control (P

Time response of interstitial fluid pressure measurements in cervix cancer.

Increased interstitial fluid pressure (IFP) is a common finding in malignant tumors as a result of the abnormal tumor vasculature and a lack of functional lymphatics. A recent clinical study by Milosevic et al. [Cancer Res. 61 (2001) 6400] reported a link between elevated IFP and survival in patients with cancer of the cervix. Patients with high IFP were more likely to have recurrence of tumors even after radiotherapy and were also more likely to die of progressive disease, independent of other prognostic factors. In this complementary study, using human data, we analyze 152 cervical tumor pressure IFP measurements from 42 patients with clinically diagnosed cancer of the cervix, randomly selected from the sample of 102 patients involved in the original study. We propose a simple biophysical model, based on flow through porous media, to explain the time response of the measured pressure curves in human cervical tumors. The response of IFP was governed by a time-constant tau(IFP) = 14 +/- 1 s averaged over multiple tumor sites. Interstitial hydraulic conductivity was computed to be approximately equal to 4.3 x 10(-6) cm(2)/mm Hgs.

Stage II testicular seminoma: patterns of recurrence and outcome of treatment.

OBJECTIVES: To review treatment outcome and patterns of failure for patients with stage II testicular seminoma and to identify prognostic factors for relapse. METHODS: From 1981 to 1999, 126 men with stage II seminoma were treated at Princess Margaret Hospital. Of these, 95 were treated with radiotherapy (RT) and 31 with chemotherapy (ChT). Patient and tumour characteristics were analyzed for prognostic significance for subsequent relapse. RESULTS: At median follow-up of 8.5 years, the 5- and 10-year overall survival were both 93%, the 5- and 10-year cause-specific survival were both 94% and the 5- and 10-year relapse-free rates were both 85%. Patients with stage IIA and IIB disease treated with RT and stage IIB treated with chemotherapy had 5-year relapse-free rates of 91.7%, 89.7% and 83.3%, respectively. Seventeen percent of patients treated with radiotherapy and 6% of those treated with chemotherapy have relapsed. Of the RT patients the commonest sites of relapse were left supraclavicular fossa, lung/mediastinum, bone, para-aortics and liver; nine patients had a solitary site of relapse. Two patients treated with chemotherapy had recurrence in the para-aortic and iliac nodes. For RT patients, larger primary tumour size was associated with a reduction in relapse rate. Age, rete testis invasion and lymphovascular invasion were found not to be of prognostic significance. CONCLUSIONS: In stage IIA/B seminoma, radiotherapy continues to provide excellent results, as the majority of patients will be cured with this treatment alone. Chemotherapy is the treatment of choice for stage IIC seminoma.

Functional CT imaging of prostate cancer.

The purpose of this paper is to investigate the distribution of blood flow (F), mean capillary transit time (Tc), capillary permeability (PS) and blood volume (vb) in prostate cancer using contrast-enhanced CT. Nine stage T2-T3 prostate cancer patients were enrolled in the study. Following bolus injection of a contrast agent, a time series of CT images of the prostate was acquired. Functional maps showing the distribution of F, Tc, PS and vb within the prostate were generated using a distributed parameter tracer kinetic model, the adiabatic approximation to the tissue homogeneity model. The precision of the maps was assessed using covariance matrix analysis. Finally, maps were compared to the findings of standard clinical investigations. Eight of the functional maps demonstrated regions of increased F, PS and vb, the locations of which were consistent with the results of standard clinical investigations. However, model parameters other than F could only be measured precisely within regions of high F. In conclusion functional CT images of cancer-containing prostate glands demonstrate regions of elevated F, PS and Vb. However, caution should be used when applying a complex tracer kinetic model to the study of prostate cancer since not all parameters can be measured precisely in all areas.

Appropriate radiation volume for stage IIA/B testicular seminoma.

PURPOSE: Prophylactic left supraclavicular fossa irradiation has been suggested to reduce relapse rates in patients treated for Stage IIA/B testicular seminoma. To address this issue, we reviewed patterns of failure and treatment outcome in patients treated with radiation therapy at our institution. METHODS AND MATERIALS: Between 1981 and 1999, 79 men with Stage II seminoma (IIA, 49; IIB, 30) were treated with radiation therapy (RT) to the para-aortic and ipsilateral (+/- contralateral) pelvic lymph nodes (dose: 25-35 Gy). RESULTS: With a median follow-up of 8.5 years, the 5-year relapse-free rate was 91% (standard error: 3%), and 2 patients have died of seminoma, giving a 5-year cause-specific survival of 97%. A total of 7 patients have relapsed with 2 isolated to the left supraclavicular fossa. Five of 7 patients have been successfully salvaged. CONCLUSIONS: Prophylactic left supraclavicular fossa irradiation might have prevented relapse in 2 of 79 patients in Stage IIA/B seminoma. However, 97% of patients would have received unnecessary left neck RT, so we continue to recommend, as standard treatment, infradiaphragmatic RT only.