P.S. Venkat

A genome-based model for adjusting radiotherapy dose (GARD): a retrospective, cohort-based study

BACKGROUND Despite its common use in cancer treatment, radiotherapy has not yet entered the era of precision medicine, and there have been no approaches to adjust dose based on biological differences between or within tumours. We aimed to assess whether a patient-specific molecular signature of radiation sensitivity could be used to identify the optimum radiotherapy dose. METHODS We used the gene-expression-based radiation-sensitivity index and the linear quadratic model to derive the genomic-adjusted radiation dose (GARD). A high GARD value predicts for high therapeutic effect for radiotherapy; which we postulate would relate to clinical outcome. Using data from the prospective, observational Total Cancer Care (TCC) protocol, we calculated GARD for primary tumours from 20 disease sites treated using standard radiotherapy doses for each disease type. We also used multivariable Cox modelling to assess whether GARD was independently associated with clinical outcome in five clinical cohorts: Erasmus Breast Cancer Cohort (n=263); Karolinska Breast Cancer Cohort (n=77); Moffitt Lung Cancer Cohort (n=60); Moffitt Pancreas Cancer Cohort (n=40); and The Cancer Genome Atlas Glioblastoma Patient Cohort (n=98). FINDINGS We calculated GARD for 8271 tissue samples from the TCC cohort. There was a wide range of GARD values (range 1·66-172·4) across the TCC cohort despite assignment of uniform radiotherapy doses within disease types. Median GARD values were lowest for gliomas and sarcomas and highest for cervical cancer and oropharyngeal head and neck cancer. There was a wide range of GARD values within tumour type groups. GARD independently predicted clinical outcome in breast cancer, lung cancer, glioblastoma, and pancreatic cancer. In the Erasmus Breast Cancer Cohort, 5-year distant-metastasis-free survival was longer in patients with high GARD values than in those with low GARD values (hazard ratio 2·11, 95% 1·13-3·94, p=0·018). INTERPRETATION A GARD-based clinical model could allow the individualisation of radiotherapy dose to tumour radiosensitivity and could provide a framework to design genomically-guided clinical trials in radiation oncology. FUNDING None.

Systematic review of case reports on the abscopal effect

Radiation therapy is a highly effective local treatment for cancer. However, sporadic events of tumor regression in unirradiated fields, known as abscopal effect, have been observed for decades. This abscopal effect has more recently been postulated to be a result of antitumor immune response induced by radiation therapy. With the advent of modern immunotherapy, the potential for immune activation by radiation therapy defines a novel role for radiation therapy in systemic disease. In this context, we have searched documented cases abscopal effect of radiation therapy in literature. A total of 46 reported cases have been identified from 1969 to 2014 with median radiation dose of 31 Gy, median follow-up of 17.5 months, and median documented time to notice the abscopal effect was 2 months. This review systematically summarizes all clinical case reports of abscopal effect to gain insight into this uncommon but important phenomenon.

Treatment delays, race, and outcomes in head and neck cancer

PURPOSE Patient race has been shown to predict for differences in outcomes and has been attributed to socioeconomic factors such as social support and access to healthcare. In head and neck cancer (HNC), a disease without recommended screening, we sought to investigate the association between race, treatment delays and outcome. METHODS Records of 1802 patients with non-metastatic squamous cell HNC treated between 1998 and 2013 were retrospectively assessed from an institutional database. Patient demographics, tumor and treatment characteristics, and patient outcomes were abstracted from the chart. Differences between groups were assessed via logistic regression multivariate analysis (MVA). Outcomes including locoregional control (LRC) and overall survival (OS) were then estimated via Kaplan-Meier and Cox-regression MVA. RESULTS Median follow up was 34 months. Patient races included white (n=1671, 93%), black (n=80, 4%), Asian (n=18, 1%), and other (n=33, 2%). On logistic regression MVA, Black patients were less likely to be married (39% vs. 63%; OR 0.5 95%CI 0.30-0.83, p=0.007) or be currently employed (43% vs. 61%; OR 0.44 95%CI 0.26-0.74, p=0.002) when compared to non-blacks. Black patients were also younger (54 vs. 59 years, p=0.001), more likely to present with advanced tumor stage (T4: 48% vs. 25%), and more often had >45days elapsed from diagnosis to treatment initiation (DTI) (61% vs. 49%, p=0.028). Delays in treatment, such as delayed diagnosis (advanced disease presentation) and delays in DTI>45days were also associated with marital and employment status. Black patients were associated with a lower 3-year LRC rate (65% vs. 81%, p<0.001) and OS rate (43% vs. 69%, p<0.001), compared to non-black patients. Patients with >45days DTI had a detriment in 3-year LRC (77% vs. 83%, p=0.002) and OS (66% vs. 69%, p=0.009). On Cox MVA, black race was independently prognostic for worse LRC (HR 1.62 95%CI 1.04-2.51, p=0.033) and OS (HR 1.55 95%CI 1.15-2.08, p=0.004) vs. non-blacks. CONCLUSION Black race is independently prognostic for LRC and OS. Delays in HNC treatment, such as more advanced tumor stage presentation and delays in treatment initiation, may be attributed to socioeconomic factors such as employment status and social support. Efforts to accommodate these factors may expedite treatment, in hopes of improving the race related outcome disparity in HNC.

Prognostic value of pre-treatment F-18-FDG PET-CT in patients with hepatocellular carcinoma undergoing radioembolization

AIM To evaluate the value of pre-treatment 18F-FDG PET/CT in patients with HCC following liver radioembolization. METHODS We identified 34 patients with HCC who underwent an FDG PET/CT scan prior to hepatic radioembolization at our institution between 2009 and 2013. Patients were seen in clinic one month after radioembolization and then at 2-3 mo intervals. We assessed the influence of FDG tumor uptake on outcomes including local liver control (LLC), distant liver control (DLC), time to distant metastases (DM), progression free survival (PFS) and overall survival (OS). RESULTS The majority of patients were males (n = 25, 74%), and had Child Pugh Class A (n = 31, 91%), with a median age of 68 years (46-84 years). FDG-avid disease was found in 19 (56%) patients with SUVmax ranging from 3 to 20. Female patients were more likely to have an FDG-avid HCC (P = 0.02). Median follow up of patients following radioembolization was 12 months (1.2-62.8 mo). FDG-avid disease was associated with a decreased 1 year LLC, DLC, DM and PFS (P < 0.05). Using multivariate analysis, FDG avidity predicted for LLC, DLC, and PFS (all P < 0.05). CONCLUSION In this retrospective study, pre-treatment HCC FDG-avidity was found to be associated with worse LLC, DLC, and PFS following radioembolization. Larger studies are needed to validate our initial findings to assess the role of F-18-FDG PET/CT scans as biomarker for patients with HCC following radioembolization.

Investigating multi-radiomic models for enhancing prediction power of cervical cancer treatment outcomes

Quantitative image features, also known as radiomic features, have shown potential for predicting treatment outcomes in several body sites. We quantitatively analyzed 18Fluorine-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET) uptake heterogeneity in the Metabolic Tumor Volume (MTV) of eighty cervical cancer patients to investigate the predictive performance of radiomic features for two treatment outcomes: the development of distant metastases (DM) and loco-regional recurrent disease (LRR). We aimed to fit the highest predictive features in multiple logistic regression models (MLRs). To generate such models, we applied backward feature selection method as part of Leave-One-Out Cross Validation (LOOCV) within a training set consisting of 70% of the original patient cohort. The trained MLRs were tested on an independent set consisted of 30% of the original cohort. We evaluated the performance of the final models using the Area under the Receiver Operator Characteristic Curve (AUC). Accordingly, six models demonstrated superior predictive performance for both outcomes (four for DM and two for LRR) when compared to both univariate-radiomic feature models and Standard Uptake Value (SUV) measurements. This demonstrated approach suggests that the ability of the pre-radiochemotherapy PET radiomics to stratify patient risk for DM and LRR could potentially guide management decisions such as adjuvant systemic therapy or radiation dose escalation.

Management of Oropharyngeal Cancer in the HPV Era.

BACKGROUND Historically, oropharyngeal cancer (OPC) has been attributed to risk factors such as smoking and alcohol use. The increased incidence of OPC has been driven by human papillomavirus (HPV) infection. METHODS A search of the literature involving HPV infection and OPC was performed, along with a search of ongoing clinical trials regarding HPV-positive OPC. RESULTS This review summarizes the differences in epidemiology and prognosis of HPV-positive OPC compared with non-HPV-related OPC. It will also discuss use of de-escalating treatment to minimize toxicity while maintaining excellent outcomes. Disease management is also addressed, including prevention and follow-up recommendations for this cohort of patients. CONCLUSIONS HPV-positive OPC is a distinct disease, and efforts should be made to personalize its management. Preventive measures and vaccinations, along with de-escalation of treatment, may help optimize outcomes in this population.

Recurrence patterns and associated factors of locoregional failure following neoadjuvant chemoradiation and surgery for esophageal cancer

Despite neoadjuvant chemoradiation (nCRT) followed by esophagectomy for locally advanced esophageal cancer, locoregional recurrence (LRR) is common and factors associated with LRR have not been clearly identified.

Fiducial markers coupled with 3D PET/CT offer more accurate radiation treatment delivery for locally advanced esophageal cancer

Background and aims  The role of three-dimensional positron emission tomography/computed tomography (3 D PET/CT) in esophageal tumors that move with respiration and have potential for significant mucosal inflammation is unclear. The aim of this study was to determine the correlation between gross tumor volumes derived from 3 D PET/CT and endoscopically placed fiducial markers. Methods  This was a retrospective, IRB approved analysis of 40 patients with esophageal cancer with fiducials implanted and PET/CT. The centroid of each fiducial was identified on PET/CT images. Distance between tumor volume and fiducials was measured using axial slices. Image features were extracted and tested for pathologic response predictability. Results  The median adaptively calculated threshold value of the standardized uptake value (SUV) to define the metabolic tumor volume (MTV) border was 2.50, which corresponded to a median 23 % of the maximum SUV. The median distance between the inferior fiducial centroid and MTV was – 0.60 cm (– 3.9 to 2.7 cm). The median distance between the superior fiducial centroid and MTV was 1.25 cm (– 4.2 to 6.9 cm). There was no correlation between MTV-to-fiducial distances greater than 2 cm and the gastroenterologist who performed the fiducial implantation. Eccentricity demonstrated statistically significant correlations with pathologic response. Conclusions  There was a stronger correlation between inferior fiducial location and MTV border compared to the superior extent. The etiology of the discordance superiorly is unclear, potentially representing benign secondary esophagitis, presence of malignant nodes, inflammation caused by technical aspects of the fiducial placement itself, or potential submucosal disease. Given the concordance inferiorly and the ability to more precisely set up the patient with daily image guidance matching to fiducials, it may be possible to minimize the planning tumor volume (PTV) margin in select patients, thereby, limiting dose to normal structures.

Effect of Edmonton Symptom Assessment Scale (ESAS) on symptom data collection in a radiation oncology department.

83 Background: ESAS has been used to examine quality of life and symptom burden of patients undergoing cancer treatment. The purpose of this study is to examine attitudes towards ESAS among patients in a Radiation Oncology clinic in conjunction with the perspective of cancer care professionals, to establish ideal implementation of this tool to improve patient care. METHODS Routine use of ESAS in a single Radiation Oncology Department was initiated in July 2015. Six months after implementation, an anonymous, electronic survey was administered to 50 healthcare providers within this department, including attending physicians, resident physicians, advanced practice nurses, physician assistants, and registered nurses. The survey collected information regarding the value of ESAS with regards to patient care, the numerical value at which an intervention is made, which clinical interventions had been implemented due to patient-reported scores on ESAS, which patient populations benefit from ESAS administration, and how frequently ESAS should be administered. Closed and open questions were included. RESULTS Out of 50 providers, 36 completed the survey. Of these, 31 reported finding ESAS useful. The most common intervention was questioning the patient further about symptoms (29/36.) ESAS data are being reviewed by clinical teams and stored as part of the patients medical record in order to compile longitudinal data. An anonymous paper survey is currently being administered to 50 patients at the end of their radiation treatment or at their first follow-up. The survey will collect information about how well symptoms are being communicated with the clinical team, if symptoms should be added to ESAS, how often ESAS should be administered, which specific clinical interventions were provided due to ESAS, and if ESAS improved the overall patient experience. CONCLUSIONS Our survey from the clinical team supports that ESAS is a useful modality to assess patient symptoms and to improve management for patient symptoms effectively. Our ongoing patient survey will validate these findings. These two surveys will be used to improve systematic collection of symptom data for radiation oncology patients.

Adjuvant radiation provides survival benefit for resected pancreatic adenocarcinomas of the tail

Background The appropriate adjuvant treatment for resected pancreatic cancer remains a controversy. We sought to determine the effect of adjuvant treatment on overall survival (OS) in patients with pancreatic tail adenocarcinoma. Methods Retrospective review of patients with upfront surgically resected pancreatic tail cancer treated at our institution between 2000-2012 was performed to determine outcomes of patients treated with and without adjuvant radiation therapy (RT). Survival curves were calculated according to the Kaplan-Meier method. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using the Cox proportional hazards model. Results Thirty-four patients met inclusion criteria. 79% received adjuvant chemotherapy, either concurrent with RT or alone. The groups were well matched, with the only significant difference being patient sex. On both UVA and MVA there was significantly worse survival in patients with a post-op CA19-9 >90 [hazard ratio (HR) 5.55; 95% confidence interval (CI): 1.20-25.7, P=0.03] and improved survival in patients treated with adjuvant RT (HR 0.15; 95% CI: 0.04-0.58, P=0.006). The median and 2-year OS were 21.6 months and 47% for patients treated with adjuvant RT compared with 11.3 months and 21% for those treated without RT. Conclusions Although few in patient numbers, this data suggests integration of adjuvant RT in resected pancreatic tail adenocarcinoma may improve OS.