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AIMS: Uncertainty remains regarding the optimal therapy for patients with stage II or III rectal cancer. Systematic reviews and practice guidelines on preoperative and postoperative therapy for rectal cancer were published by the Gastrointestinal Cancer Disease Site Group in 2003 and 2000, respectively. The systematic reviews were updated and revised and new recommendations for preoperative and postoperative therapy were developed based on the updated body of evidence. The following research questions were addressed: After appropriate preoperative staging tests, should patients with resectable clinical stage II or III rectal cancer be offered preoperative radiotherapy (with or without chemotherapy)? What is the role of postoperative radiotherapy and/or chemotherapy for patients with resected stage II or III rectal cancer who have not received preoperative radiotherapy, in terms of improving survival and delaying local recurrence? MATERIALS AND METHODS: The MEDLINE, EMBASE and Cochrane Library databases, as well as meeting proceedings from the American Society of Clinical Oncology, were searched for reports of randomised controlled trials and meta-analyses comparing preoperative or postoperative therapy with surgery alone or other preoperative or postoperative therapy for stage II or III rectal cancer. The draft practice guideline and systematic reviews were distributed through a mailed survey to 129 health care providers in Ontario for review. RESULTS: Systematic reviews on preoperative and postoperative therapy for rectal cancer were developed. On the basis of the evidence contained in these reviews, the Gastrointestinal Cancer Disease Site Group drafted recommendations. Of the 33 practitioners who responded to the mailed survey, 97% agreed with the draft recommendations as stated, 88% agreed that the report should be approved as a practice guideline and 94% indicated that they were likely to use the guideline in their own practice. CONCLUSIONS: Preoperative chemoradiotherapy is preferred, compared with standard fractionation preoperative radiotherapy alone, to decrease local recurrence. Preoperative chemoradiotherapy is also preferred, compared with a postoperative approach, to decrease local recurrence and adverse effects. For patients with relative contraindications to chemotherapy in the preoperative period, an acceptable alternative is preoperative radiotherapy alone followed by surgery. Patients with resected stage II or III rectal cancer who have not received preoperative radiotherapy should be offered postoperative therapy with concurrent chemoradiotherapy plus fluoropyrimidine-based chemotherapy. [ABSTRACT FROM AUTHOR]

AIMS: Oesophageal cancer is an aggressive disease and the optimal therapy for patients with resectable tumours remains unclear. A systematic review and companion practice guideline were published in 2004; however, new evidence has become available since the publication of the original report. An update of the literature search and a revision of the recommendations were undertaken to incorporate the new data. The following research question was addressed: should patients with resectable oesophageal cancer receive preoperative or postoperative therapy together with surgery? The outcomes of interest were survival, adverse effects and quality of life. MATERIALS AND METHODS: The literature search of the original systematic review was updated to April 2007. MEDLINE, EMBASE, Cochrane Library and abstracts from the American Society of Clinical Oncology and the American Society for Therapeutic Radiology and Oncology were searched for reports of randomised controlled trials and meta-analyses comparing preoperative or postoperative therapy with surgery alone or other preoperative or postoperative therapy. After the completion of the draft systematic review and practice guideline, the report was distributed through a mailed survey to 133 health care providers in Ontario for review and feedback. RESULTS: The updated literature search yielded eight new randomised controlled trial reports and seven new meta-analysis reports for consideration, together with the evidence reviewed in the original review publication. Of the 31 practitioners who responded to the mailed survey, 80% agreed with the draft recommendations as stated, 83% agreed that the report should be approved as a practice guideline and 86% indicated that they would probably use the guideline in their own practice. CONCLUSIONS: Preoperative cisplatin-based chemotherapy plus radiotherapy is recommended as the preferred modality for the management of surgically resectable patients with oesophageal cancer. Preoperative cisplatin-based chemotherapy alone is an alternative choice for the management of these patients. [ABSTRACT FROM AUTHOR]

Background: Palliative treatment options for painful hepatic cancer can be restricted due to patients eventually becoming refractory to standard treatment. The aim of this study was to determine whether radiotherapy improves hepatic pain from cancer., Methods: In this open-label, randomised, controlled, phase 3 trial (CCTG HE1) done in nine cancer centres across Canada, we included patients aged 18 years or older with hepatocellular carcinoma or liver metastases, who were refractory to standard treatment, with an Eastern Cooperative Oncology Group performance status of 0-3, with life expectancy of more than 3 months, and pain or discomfort at its worst in the past 24 hours on the Brief Pain Inventory (BPI) of at least 4 out of 10, which was stable for up to 7 days before randomisation. Patients were randomly assigned (1:1), via a minimisation method after stratification by centre and type of cancer (hepatocellular carcinoma vs liver metastases), to single-fraction radiotherapy (8 Gy) to the liver with 8 mg ondansetron (or equivalent) orally and 4 mg dexamethasone orally given 1-2 h before radiotherapy plus best supportive care (including non-opioid or opioid analgesia, or dexamethasone, or a combination of these) or best supportive care alone. The primary endpoint was improvement in patient-reported liver cancer pain or discomfort of at least 2 points on worst pain intensity on the BPI at 1 month after randomisation. All patients with both baseline and 1-month assessments were included in the primary endpoint analysis. Safety was assessed in all patients randomly assigned to treatment. This trial is registered with ClinicalTrials.gov, NCT02511522, and is complete., Findings: Between July 25, 2015, and June 2, 2022, 66 patients were screened and randomly assigned to radiotherapy plus best supportive care (n=33) or best supportive care (n=33). Median age was 65 years (IQR 57-72), 37 (56%) of 66 patients were male, 29 (44%) were female, 43 (65%) had liver metastases, and 23 (35%) had hepatocellular carcinoma (data on race and ethnicity were not collected). As of data cutoff (Sept 8, 2022), median follow-up was 3·2 months (95% CI 3·0-3·4). 24 (73%) of 33 in the radiotherapy plus best supportive care group and 18 (55%) of 33 in the best supportive care only group completed baseline and 1-month assessments. An improvement in hepatic pain of at least 2 points in worst pain intensity on the BPI at 1 month was seen in 16 (67%) of 24 patients in the radiotherapy plus best supportive care group versus four (22%) of 18 patients in the best supportive care group (p=0·0042). The most common grade 3-4 adverse events within 1 month after randomisation were abdominal pain (three [9%] of 33 in the radiotherapy group vs one [3%] of 33 in best supportive care group) and ascites (two [6%] vs one [3%]). No serious adverse events or treatment-related deaths were observed., Interpretation: Single-fraction radiotherapy plus best supportive care improved pain compared with best supportive care alone in patients with liver cancer, and could be considered a standard palliative treatment., Funding: Canadian Cancer Society., Competing Interests: Declaration of interests LAD had a licensing agreement with Raysearch Oncology and has received a grant from Merck and an honorarium from AstraZeneca. DR is the current president of the Canadian Association of Radiation Oncology (CARO) and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Accuray and Varian Medical Systems. PW has received a grant from AstraZeneca. JJK has received grants from Ibsen, Roche, and Merck and consulting fees from AstraZeneca, Ibsen, Incyte, Roche, and Eisai. ASB has received an honorarium from Eisai. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Tumor hypoxia is a negative prognostic factor in many tumors and is predictive of metastatic spread and poor responsiveness to both chemotherapy and radiotherapy. Purpose: To assess the feasibility of using 18 F-Fluoroazomycin arabinoside (FAZA) PET/MR to image tumor hypoxia in patients with locally advanced rectal cancer (LARC) prior to and following neoadjuvant chemoradiotherapy (nCRT). The secondary objective was to compare different reference tissues and thresholds for tumor hypoxia quantification. Patients and Methods: Eight patients with histologically proven LARC were included. All patients underwent 18 F-FAZA PET/MR prior to initiation of nCRT, four of whom also had a second scan following completion of nCRT and prior to surgery. Tumors were segmented using T 2 -weighted MR. Each voxel within the segmented tumor was defined as hypoxic or oxic using thresholds derived from various references: ×1.0 or ×1.2 SUVmean of blood pool [BP] or left ventricle [LV] and SUVmean +3SD for gluteus maximus. Correlation coefficient (CoC) between HF and tumor SUVmax/reference SUVmean TRR for the various thresholds was calculated. Hypoxic fraction (HF), defined as the % hypoxic voxels within the tumor volume was calculated for each reference/threshold. Results: For all cases, baseline and follow-up, the CoCs for gluteus maximus and for BP and LV (×1.0) were 0.241, 0.344, and 0.499, respectively, and HFs were (median; range) 16.6% (2.4-33.8), 36.8% (0.3-72.9), and 30.7% (0.8-55.5), respectively. For a threshold of ×1.2, the CoCs for BP and LV as references were 0.611 and 0.838, respectively, and HFs were (median; range) 10.4% (0-47.6), and 4.3% (0-20.1%), respectively. The change in HF following nCRT ranged from (-18.9%) to (+54%). Conclusions: Imaging of hypoxia in LARC with 18 F-FAZA PET/MR is feasible. Blood pool as measured in the LV appears to be the most reliable reference for calculating the HF. There is a wide range of HF and variable change in HF before and after nCRT.

We aimed to determine if clinical parameters and radiomics combined with sarcopenia status derived from baseline 18 F-FDG-PET/CT could predict developing metastatic disease and overall survival (OS) in gastroesophageal cancer (GEC). Patients referred for primary staging who underwent 18 F-FDG-PET/CT from 2008 to 2019 were evaluated retrospectively. Overall, 243 GEC patients (mean age = 64) were enrolled. Clinical, histopathology, and sarcopenia data were obtained, and primary tumor radiomics features were extracted. For classification (early-stage vs. advanced disease), the association of the studied parameters was evaluated. Various clinical and radiomics models were developed and assessed. Accuracy and area under the curve (AUC) were calculated. For OS prediction, univariable and multivariable Cox analyses were performed. The best model included PET/CT radiomics features, clinical data, and sarcopenia score (accuracy = 80%; AUC = 88%). For OS prediction, various clinical, CT, and PET features entered the multivariable analysis. Three clinical factors (advanced disease, age ≥ 70 and ECOG ≥ 2), along with one CT-derived and one PET-derived radiomics feature, retained their significance. Overall, 18 F-FDG PET/CT radiomics seems to have a potential added value in identifying GEC patients with advanced disease and may enhance the performance of baseline clinical parameters. These features may also have a prognostic value for OS, improving the decision-making for GEC patients.

Background: Patient-reported outcomes measures (PROM) are self-reflections of an individual's physical functioning and emotional well-being. The Edmonton Symptom Assessment Scale (ESAS) is a simple and validated PRO tool of 10 common symptoms and a patient-reported functional status (PRFS) measure. The prognostic value of this tool is unknown in patients with gastroesophageal cancer (GEC). In this study, we examined the association between the ESAS score and overall survival (OS) in patients with GEC, the prognostication difference between ESAS and Eastern Cooperative Oncology Group (ECOG), and assessed the correlation between PRFS and the physician-reported ECOG performance status (PS)., Methods: The study was a retrospective cohort study of 211 patients with GEC with localized (stages I-III) and metastatic disease who completed at least one baseline ESAS prior to treatment. Patients were grouped into 3 cohorts based on ESAS score. OS was assessed using the Kaplan-Meier method, and the concordance index (c-index) was calculated for ESAS and physician-reported ECOG. The agreement between PRFS and physician-ECOG was also assessed., Results: In total, 211 patients were included. The median age was 60.8 years; 90% of patients were ECOG PS 0-1; 38% of patients were stages I-III, while 62% were de novo metastatic patients. Median OS in low, moderate, high symptom burden (SB) patients' cohorts was 19.17 m, 16.39 mm, and 12.68 m, respectively (P < .04). The ability to predict death was similar between physician-ECOG and ESAS (c-index 0.56 and 0.5753, respectively) and PRFS and physician-ECOG (c-index of 0.5615 and 0.5545, respectively). The PS agreement between patients and physicians was 50% with a weighted Kappa of 0.27 (95% CI: 0.17-0.38)., Conclusion: Patient's SB seems to carry a prognostic significance. ESAS and physician-reported ECOG exhibit comparable prognostic values. Physicians and patients can frequently have divergent opinions on PS. ESAS takes a patient-centered approach and should be encouraged in practice among patients with GEC as an additional tool for prognostication., (© The Author(s) 2024. Published by Oxford University Press.)

Radioligand therapy (RLT) is a targeted approach to treating cancer that has been shown to be safe and effective in a variety of disease states, including gastroenteropancreatic neuroendocrine tumors, lymphoma, and most recently, advanced prostate cancer. In the United States, patient access to this therapy is currently variable. Implementation of new RLT programs and expansion of existing programs are needed to broaden patient access to and standardize the delivery of RLT, especially as new therapies are introduced into clinical practice. Drawing from experience in establishing RLT programs in different settings, we have developed practical recommendations for building and implementing a robust RLT program. In this review, we present our recommendations for minimal requirements and optimal requirements, as well as system considerations, and special issues associated with implementing an RLT program in North American centers., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To confirm and investigate why pathological high-frequency oscillations (pHFOs), including ripples (80-200 Hz) and fast ripples (200-600 Hz), are generated during the UP-DOWN transition of the slow wave and if information transmission mediated by ripple temporal coupling is disrupted in the seizure-onset zone (SOZ)., Methods: We isolated 217 total units from 175.95 intracranial electroencephalography (iEEG) contact-hours of synchronized macro- and microelectrode recordings from 6 patients. Sleep slow oscillation (.1-2 Hz) epochs were identified in the iEEG recording. iEEG HFOs that occurred superimposed on the slow wave were transformed to phasors and adjusted by the phase of maximum firing in nearby units (i.e., maximum UP). We tested whether, in the SOZ, HFOs and associated action potentials (APs) occur more often at the UP-DOWN transition. We also examined ripple temporal correlations using cross-correlograms., Results: At the group level in the SOZ, HFO and HFO-associated AP probability was highest during the UP-DOWN transition of slow wave excitability (p < < .001). In the non-SOZ, HFO and HFO-associated AP was highest during the DOWN-UP transition (p < < .001). At the unit level in the SOZ, 15.6% and 20% of units exhibited more robust firing during ripples (Cohen's d = .11-.83) and fast ripples (d = .36-.90) at the UP-DOWN transition (p < .05 f.d.r. corrected), respectively. By comparison, also in the SOZ, 6.6% (d = .14-.30) and 8.5% (d = .33-.41) of units had significantly less firing during ripples and fast ripples at the UP-DOWN transition, respectively. Additional data shows that ripple and fast ripple temporal correlations, involving global slow waves, between the hippocampus, entorhinal cortex, and parahippocampal gyrus were reduced by >50% in the SOZ compared to the non-SOZ (N = 3)., Significance: The UP-DOWN transition of slow wave excitability facilitates the activation of pathological neurons to generate pHFOs. Ripple temporal correlations across brain regions may be important in memory consolidation and are disrupted in the SOZ, perhaps by pHFO generation., (© 2023 International League Against Epilepsy.)

Purpose: The TOPGEAR phase 3 trial hypothesized that adding preoperative chemoradiation therapy (CRT) to perioperative chemotherapy will improve survival in patients with gastric cancer. Owing to the complexity of gastric irradiation, a comprehensive radiation therapy quality assurance (RTQA) program was implemented. Our objective is to describe the RTQA methods and outcomes., Methods and Materials: RTQA was undertaken in real time before treatment for the first 5 patients randomized to CRT from each center. Once acceptable quality was achieved, RTQA was completed for one-third of subsequent cases. RTQA consisted of evaluating (1) clinical target volume and organ-at-risk contouring and (2) radiation therapy planning parameters. Protocol violations between high- (20+ patients enrolled) and low-volume centers were compared using the Fisher exact test., Results: TOPGEAR enrolled 574 patients, of whom 286 were randomized to receive preoperative CRT and 203 (71%) were included for RTQA. Of these, 67 (33%) and 136 (67%) patients were from high- and low-volume centers, respectively. The initial RTQA pass rate was 72%. In total, 28% of cases required resubmission. In total, 200 of 203 cases (99%) passed RTQA before treatment. Cases from low-volume centers required resubmission more often (44/136 [33%] vs 13/67 [18%]; P = .078). There was no change in the proportion of cases requiring resubmission over time. Most cases requiring resubmission had multiple protocol violations. At least 1 aspect of the clinical target volume had to be adjusted in all cases. Inadequate coverage of the duodenum was most common (53% major violation, 25% minor violation). For the remaining cases, the resubmission process was triggered secondary to poor contour/plan quality., Conclusions: In a large multicenter trial, RTQA is feasible and effective in achieving high-quality treatment plans. Ongoing education should be performed to ensure consistent quality during the entire study period., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The paradigm of oligometastatic disease (OMD), characterized by a limited number of metastases potentially amenable to local therapies, presents unique opportunities and challenges in clinical trial design and implementation. Although local ablative therapies, such as stereotactic body radiation therapy, have shown promise in improving outcomes for patients with OMD, there is a lack of large-scale randomized phase III trials supporting their widespread use. This paper outlines the key challenges in trial design and implementation in the oligometastatic setting, including appropriate patient selection, the definition of the oligometastatic state, trial design considerations, endpoint selection, and logistical considerations related to enrollment and follow-up. We suggest potential strategies to address these challenges, emphasizing the importance of a comprehensive, patient-centric approach, and the integration of multidisciplinary teams in trial design and implementation. The aim is to encourage the design of well-structured clinical trials, ultimately refining best practices and enhancing patient outcomes in the management of OMD., (Copyright © 2023. Published by Elsevier Inc.)

The neuronal circuit disturbances that drive inter-ictal and ictal epileptiform discharges remain elusive. Using a combination of extra-operative macro-electrode and micro-electrode inter-ictal recordings in six pre-surgical patients during non-rapid eye movement sleep, we found that, exclusively in the seizure onset zone, fast ripples (200-600 Hz), but not ripples (80-200 Hz), frequently occur <300 ms before an inter-ictal intra-cranial EEG spike with a probability exceeding chance (bootstrapping, P < 1e-5). Such fast ripple events are associated with higher spectral power ( P < 1e-10) and correlated with more vigorous neuronal firing than solitary fast ripple (generalized linear mixed-effects model, P < 1e-9). During the intra-cranial EEG spike that follows a fast ripple, action potential firing is lower than during an intra-cranial EEG spike alone (generalized linear mixed-effects model, P < 0.05), reflecting an inhibitory restraint of intra-cranial EEG spike initiation. In contrast, ripples do not appear to prime epileptiform spikes. We next investigated the clinical significance of pre-spike fast ripple in a separate cohort of 23 patients implanted with stereo EEG electrodes, who underwent resections. In non-rapid eye movement sleep recordings, sites containing a high proportion of fast ripple preceding intra-cranial EEG spikes correlate with brain areas where seizures begin more than solitary fast ripple ( P < 1e-5). Despite this correlation, removal of these sites does not guarantee seizure freedom. These results are consistent with the hypothesis that fast ripple preceding EEG spikes reflect an increase in local excitability that primes EEG spike discharges preferentially in the seizure onset zone and that epileptogenic brain regions are necessary, but not sufficient, for initiating inter-ictal epileptiform discharges., Competing Interests: M.R.S. has received compensation for speaking at continuing medical education (CME) programmes from Medscape, Projects for Knowledge, International Medical Press and Eisai. He has consulted for Medtronic, Neurelis and Johnson & Johnson. He has received research support from Eisai, Medtronic, Neurelis, SK Life Science, Takeda, Xenon, Cerevel, UCB Pharma, Janssen and Engage Pharmaceuticals. He has received royalties from Oxford University Press and Cambridge University Press. The remainder of the authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: To retrospectively review the clinical outcomes of patients with metastatic breast cancer (MBCa) following liver directed ablative intent radiotherapy (RT)., Methods: Demographics, disease and treatment characteristics of patients with MBCa who received liver metastasis (LM) directed ablative RT between 2004-2020 were analysed. The primary outcome was local control (LC), secondary outcomes included overall survival (OS) and progression-free survival (PFS) analyzed by univariate (UVA) and multi-variable analysis (MVA)., Results: Thirty MBCa patients with 50 LM treated with 5-10 fraction RT were identified. Median follow-up was 14.6 (range 0.9-156.2) months. Class of metastatic disease was described as induced (12 patients, 40%), repeat (15 patients, 50%) and de novo (three patients, 10%). Median size of treated LM was 3.1 cm (range 1-8.8 cm) and median biologically effective dose delivered was 122 (Q1-Q3; 98-174) Gy 3 . One-year LC rate was 100%. One year and two-year survival was 89% and 63%, respectively, with size of treated LM predictive of OS (HR 1.35, p = 0.023) on UVA. Patients with induced OMD had a significantly higher rate of progression (HR 4.77, p = 0.01) on UVA, trending to significance on MVA (HR 3.23, p = 0.051)., Conclusions: Hypo-fractionated ablative liver RT in patients with MBCa provides safe, tolerable treatment with excellent LC.

We investigated the prognostic value of sarcopenia measurements and metabolic parameters of primary tumors derived from 18 F-FDG-PET/CT among patients with primary, metastatic esophageal and gastroesophageal cancer. A total of 128 patients (26 females; 102 males; mean age 63.5 ± 11.7 years; age range: 29-91 years) with advanced metastatic gastroesophageal cancer who underwent 18 F-FDG-PET/CT as part of their initial staging between November 2008 and December 2019 were included. Mean and maximum standardized uptake value (SUV) and SUV normalized by lean body mass (SUL) were measured. Skeletal muscle index (SMI) was measured at the level of L3 on the CT component of the 18 F-FDG-PET/CT. Sarcopenia was defined as SMI < 34.4 cm 2 /m 2 in women and <45.4 cm 2 /m 2 in men. A total of 60/128 patients (47%) had sarcopenia on baseline 18 F-FDG-PET/CT. Mean SMI in patients with sarcopenia was 29.7 cm 2 /m 2 in females and 37.5 cm 2 /m 2 in males. In a univariable analysis, ECOG (<0.001), bone metastases ( p = 0.028), SMI ( p = 0.0075) and dichotomized sarcopenia score ( p = 0.033) were significant prognostic factors for overall survival (OS) and progression-free survival (PFS). Age was a poor prognostic factor for OS ( p = 0.017). Standard metabolic parameters were not statistically significant in the univariable analysis and thus were not evaluated further. In a multivariable analysis, ECOG ( p < 0.001) and bone metastases ( p = 0.019) remained significant poor prognostic factors for OS and PFS. The final model demonstrated improved OS and PFS prognostication when combining clinical parameters with imaging-derived sarcopenia measurements but not metabolic tumor parameters. In summary, the combination of clinical parameters and sarcopenia status, but not standard metabolic values from 18 F-FDG-PET/CT, may improve survival prognostication in patients with advanced, metastatic gastroesophageal cancer.

Purpose: To describe the long-term outcomes of a 5-fraction normal tissue tolerance adapted strategy for the management of oligometastases (OM)., Methods and Materials: Patients with histologically confirmed solid tumors, ≤5 extracranial metastases, suitable for a definitive approach for all metastatic lesions, at least one lesion suitable for Stereotactic Body Radiotherapy (SBRT), Eastern Coooperative Oncology Group Performance Status ≤2 were eligible. Treatment intervention was a 5-fraction (25-55 Gy) normal tissue adapted dosing strategy. The primary outcome was cumulative local progression rate at 12 months., Results: Between March 2013 and January 2018, 137 patients started SBRT. Median follow-up was 35.7 months. In addition, 107 (78%) patients had a solitary OM. The mean planning target volume D 95 was 39.6 (standard deviation, 8.8; biological effective dose using an alpha/beta ratio of 10, 70.8) Gy. Mean planning target volume D 95 was highest for lung lesions (48.7 [standard deviation, 4.7]; biological effective dose using an alpha/beta ratio of 10, 96.1) Gy but was <40 Gy for all other anatomic sites. Two grade 3 toxicities (gastrointestinal bleed) were observed with stomach D 0.05 30.3 Gy and 30.4 Gy. The cumulative local progression rate at 12 of 36 months was 16.1% (95% CI, 10-22) and 38.3% (95% CI 30-46.7); overall survival was 90% and 37%, and progression free survival was 58% and 19%, respectively. Mean symptom burden (Edmonton Symptom Assessment Total Score) worsened in patients with progressive disease (+8.8) at 12 months and was paralleled by changes in mean European Organization for Research and Treatment Quality of Life Core Questionnaire Summary Score and Global Health Quality of Life Score. Systemic therapy was initiated in 55% of patients at an average of 12.7 (standard deviation 12.4) months., Conclusions: If long-term progression free survival is the primary goal of therapy, SBRT for OM achieved this in <20% of patients attributable to a high risk of distant failure. Favorable local progression free survival is accompanied by preservation of quality of life, avoidance of symptom progression and reduced need of antineoplastic therapies at 12 months. Information on symptom burden, quality of life, as well as pattern of antineoplastic therapy use after progressive disease is useful to support conversations between patients, families, and health care providers. Strategies to improve patient selection and reduce distant progression rate remain a priority for further study., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

We investigated, whether 18[18F]-FDG PET/CT-derived radiomics combined with sarcopenia measurements improves survival prognostication among patients with advanced, metastatic gastroesophageal cancer. In our study, 128 consecutive patients with advanced, metastatic esophageal and gastroesophageal cancer (n = 128; 26 females; 102 males; mean age 63.5 ± 11.7 years; age range: 29−91 years) undergoing 18[18F]-FDG PET/CT for staging between November 2008 and December 2019 were included. Segmentation of the primary tumor and radiomics analysis derived from PET and CT images was performed semi-automatically with a commonly used open-source software platform (LIFEX, Version 6.30, lifexsoft.org). Patients’ nutritional status was determined by measuring the skeletal muscle index (SMI) at the level of L3 on the CT component. Univariable and multivariable analyses were performed to establish a survival prediction model including radiomics, clinical data, and SMI score. Univariable Cox proportional hazards model revealed ECOG (<0.001) and bone metastasis (p = 0.028) to be significant clinical parameters for overall survival (OS) and progression free survival (PFS). Age (p = 0.017) was an additional prognostic factor for OS. Multivariable analysis showed improved prognostication for overall and progression free survival when adding sarcopenic status, PET and CT radiomics to the model with clinical parameters only. PET and CT radiomics derived from hybrid 18[18F]-FDG PET/CT combined with sarcopenia measurements and clinical parameters may improve survival prediction among patients with advanced, metastatic gastroesophageal cancer.

Background: Rapid ethical access to personal health information (PHI) to support research is extremely important during pandemics, yet little is known regarding patient preferences for consent during such crises. This follow-up study sought to ascertain whether there were differences in consent preferences between pre-pandemic times compared to during Wave 1 of the COVID-19 global pandemic, and to better understand the reasons behind these preferences., Methods: A total of 183 patients in the pandemic cohort completed the survey via email, and responses were compared to the distinct pre-pandemic cohort (n = 222); all were patients of a large Canadian cancer center. The survey covered (a) broad versus study-specific consent; (b) opt-in versus opt-out contact approach; (c) levels of comfort sharing with different recipients; (d) perceptions of commercialization; and (e) options to track use of information and be notified of results. Four focus groups (n = 12) were subsequently conducted to elucidate reasons motivating dominant preferences., Results: Patients in the pandemic cohort were significantly more comfortable with sharing all information and biological samples (90% vs. 79%, p = 0.009), sharing information with the health care institution (97% vs. 83%, p < 0.001), sharing information with researchers at other hospitals (85% vs. 70%, p < 0.001), sharing PHI provincially (69% vs. 53%, p < 0.002), nationally (65% vs. 53%, p = 0.022) and internationally (48% vs. 39%, p = 0.024) compared to the pre-pandemic cohort. Discomfort with sharing information with commercial companies remained unchanged between the two cohorts (50% vs. 51% uncomfortable, p = 0.58). Significantly more pandemic cohort patients expressed a wish to track use of PHI (75% vs. 61%, p = 0.007), and to be notified of results (83% vs. 70%, p = 0.012). Thematic analysis uncovered that transparency was strongly desired on outside PHI use, particularly when commercialization was involved., Conclusions: In pandemic times, patients were more comfortable sharing information with all parties, except with commercial entities, where levels of discomfort (~ 50%) remained unchanged. Focus groups identified that the ability to track and receive results of studies using one's PHI is an important way to reduce discomfort and increase trust. These findings meaningfully inform wider discussions on the use of personal health information for research during global crises., (© 2022. The Author(s).)

Background: Maintaining and improving quality of life (QOL) are important goals of anal cancer management. This disease is generally curable, with many long-term survivors., Objective: Long-term QOL after chemoradiation for patients with anal cancer was evaluated., Design: This was a prospective cohort study., Settings: This study used data from a prospective study of patients with anal cancer who were treated with chemoradiation between 2008 and 2013., Patients: Patients with anal cancer who were treated with image-guided intensity-modulated radiation therapy were included., Interventions: English-speaking patients completed European Organization for Research and Treatment of Cancer cancer-specific (C30) and site-specific (CR29) QOL questionnaires at baseline, at end of radiation, at 3 and 6 months, and then annually., Main Outcomes Measures: Long-term QOL was evaluated clinically (a change in score of ≥10 points was considered clinically significant) and statistically (using repeated-measurement analysis) by comparing the subscale scores at 1, 2, and 3 years with baseline scores. Subanalysis compared patients who received a radiation dose of 45 to 54 Gy versus 63 Gy., Results: Ninety-six patients were included (median follow-up of 56.5 months). The symptom and functional scales showed a clinically significant decline at the end of treatment with improvement by 3 months after treatment. There was a long-term statistically significant decline in dyspnea, body image, bowel embarrassment, fecal incontinence, and hair loss, and there was long-term statistically and clinically significant worsening of impotence. Higher radiation dose (63 Gy) was not associated with significantly worse QOL., Limitations: Limitations included single-institution, single-arm study design, and lack of dose reconstruction (ie, analyses were based on prescribed, rather than delivered, dose)., Conclusions: Patients with anal cancer treated with chemoradiation reported recovery of overall QOL to baseline levels. Specific symptoms remained bothersome, emphasizing the need to address and manage the chemoradiation-induced symptoms, during treatment and in the long term. See Video Abstract at http://links.lww.com/DCR/B905., Impacto De La Quimiorradiacin Definitiva En Cambios En La Calidad De Vida De Los Pacientes Con Cncer Anal Resultados a Largo Plazo De Un Estudio Prospective: ANTECEDENTES:Mantener y mejorar la calidad de vida son objetivos importantes del tratamiento del cáncer anal, ya que esta enfermedad generalmente es curable, con muchos sobrevivientes a largo plazo.OBJETIVO:Se evaluó la calidad de vida a largo plazo después de la quimiorradiación en pacientes con cáncer anal.DISEÑO:Este fue un estudio de cohorte prospectivo.ENTORNO CLINICO:Utilizamos datos de un estudio prospectivo en pacientes con cáncer anal tratados con quimiorradiación entre 2008-2013.PACIENTES:Los pacientes con cáncer anal fueron tratados con radioterapia de intensidad modulada guiada por imágenes.INTERVENCIONES:Los pacientes de habla inglesa completaron los cuestionarios de calidad de vida específicos de cáncer (C30) y específicos del sitio (CR29) de la Organización Europea para la Investigación y el Tratamiento del Cáncer al inicio, al final de la radiación, 3 y 6 meses, y luego anualmente.PRINCIPALES MEDIDAS DE RESULTADOS:Se evaluó a largo plazo la calidad de vida clínicamente (un cambio en la puntuación de ≥10 puntos se consideraron clínicamente significativo) y estadísticamente (usando análisis de medición repetida) comparando las subescalas de puntuación al 1, 2, y 3 años. Con puntuaciones de referencia. El subanálisis comparó pacientes que recibieron 45-54 Gy versus 63 Gy.RESULTADOS:Se incluyeron un total de 96 pacientes (mediana de seguimiento: 56,5 meses). La mayoría de las escalas funcionales y de síntomas mostraron una disminución clínicamente significativa al final del tratamiento con una mejoría a los 3 meses posteriores al tratamiento. Hubo una disminución estadísticamente significativa a largo plazo en disnea, imagen corporal, vergüenza intestinal, incontinencia fecal y pérdida de cabello; y hubo un empeoramiento a largo plazo estadística y clínicamente significativo en impotencia. La dosis de radiación más alta (63 Gy) no se asoció con una calidad de vida significativamente peor.LIMITACIONES:Institución única, diseño de estudio de un solo brazo y falta de recomposición de la dosis (es decir, los análisis se basan en la dosis prescrita, en lugar de la administrada).CONCLUSIÓNES:Los pacientes con cáncer anal tratados con quimiorradiación reportaron una recuperación de la QOL en general a los niveles de base. Síntomas específicos siguieron siendo molestos, lo que enfatiza la necesidad de resolver y tartar los síntomas inducidos por la quimiorradiación no solo durante el tratamiento, sino a largo plazo. Consulte Video Resumen en http://links.lww.com/DCR/B905. (Traducción- Dr. Francisco M. Abarca-Rendon)., (Copyright © The ASCRS 2022.)

Background: Anal adenocarcinoma is a rare clinical entity for which the optimal management is not defined., Objective: This study aimed to describe the multidisciplinary management and outcomes of patients with anal adenocarcinoma., Design: This is a retrospective cohort study., Setting: This study was conducted at a quaternary cancer center., Patients: Men and women with anal adenocarcinoma treated between 1995 and 2016 were selected., Interventions: Fifty-two patients were treated with either chemoradiotherapy or trimodality therapy including radiation therapy, chemotherapy, and surgical resection., Main Outcome Measures: Local failure, regional failure, and distant metastasis rates were estimated using the cumulative incidence method. The Kaplan-Meier method was used to estimate progression-free survival and overall survival. The multivariable Cox proportional hazards model was used to evaluate the clinical predictors of outcome., Results: There was a higher 5-year rate of local failure in patients treated with chemoradiotherapy compared with trimodality therapy (53% vs 10%; p < 0.01). The 5-year incidence of distant metastases was 29% (trimodality therapy) versus 30% (chemoradiotherapy; p = 0.9); adjuvant chemotherapy did not reduce the incidence of distant metastases (p = 0.8). Five-year overall survival was 73% (trimodality therapy) versus 49.4% (chemoradiotherapy; p = 0.1). On multivariable analysis, factors associated with worse overall survival were treatment with chemoradiotherapy, cT3-4 category disease, and node-positive disease., Limitations: This study is limited by its small sample size and retrospective nature., Conclusions: Although treatment may continue to be tailored to individual patients, better outcomes with a trimodality therapy approach were observed. See Video Abstract at http://links.lww.com/DCR/B708.ADENOCARCINOMA ANAL: UNA ENTIDAD POCO FRECUENTE EN NECESIDAD DE UN MANEJO MULTIDISCIPLINARIO., Antecedentes: El adenocarcinoma anal es una entidad clínica poco frecuente por lo que aún no se define el manejo óptimo., Objetivo: Describir el manejo multidisciplinario y los resultados de los pacientes con adenocarcinoma anal., Diseo: Estudio de cohorte retrospectivo., Entorno Clinico: Centro de cáncer cuaternario., Pacientes: Hombres y mujeres con adenocarcinoma anal tratados entre 1995 y 2016., Intervenciones: Cincuenta y dos pacientes fueron tratados con quimiorradioterapia o terapia trimodal que incluyó: radioterapia, quimioterapia y resección quirúrgica., Principales Medidas De Valoracion: Se estimaron las tasas de falla local, falla regional y metástasis a distancia mediante el método de incidencia acumulada. Se utilizó el método de Kaplan-Meier para estimar la supervivencia libre de progresión y la supervivencia global. Los riesgos proporcionales de multivariable Cox se utilizaron para evaluar los predictores clínicos de los resultados., Resultados: Hubo una mayor tasa de falla local a cinco años en pacientes tratados con quimiorradioterapia en comparación con terapia trimodal (53% vs 10%; p < 0,01). La incidencia a cinco años de metástasis a distancia fue del 29% (terapia trimodal) versus 30% (quimiorradioterapia) (p = 0,9); la quimioterapia adyuvante no redujo la incidencia de metástasis a distancia (p = 0,8). La supervivencia global a cinco años fue del 73% (terapia trimodal) versus 49,4% (quimiorradioterapia); p = 0,1. En el análisis multivariable, los factores asociados con una peor supervivencia general fueron el tratamiento con quimiorradioterapia, enfermedad de categoría cT3-4 y enfermedad con ganglios positivos., Limitaciones: Este estudio está limitado por su pequeño tamaño de muestra y su naturaleza retrospectiva., Conclusiones: Aunque el tratamiento puede seguir adaptándose a pacientes individuales, se observaron mejores resultados con un enfoque TTM. Conslute Video Resumen en http://links.lww.com/DCR/B708. (Traducción- Dr. Francisco M. Abarca-Rendon)., (Copyright © The ASCRS 2021.)

Introduction: Metastatic gastroesophageal adenocarcinoma (GEA) is a heterogeneous disease with an overall poor prognosis. The impact of sites of metastatic dissemination on survival is not well characterized. This study aimed to evaluate whether certain sites of metastatic disease impacts survival., Methods: A retrospective analysis of 375 patients with metastatic GEA treated at the Princess Margaret Cancer Centre from 2006 to 2016 was performed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to assess the association between sites of metastases and OS adjusting for baseline patient characteristics., Results: Median duration of follow-up was 47.8 months. Median OS in this cohort was 11.8 months (95% CI: 10.2-12.9 months). Patients with lymph node only disease, compared to those with other sites of metastases, had the longest median OS (20.4 vs. 10.6 months; p < 0.001) and PFS (11.4 vs. 6.3 months; p < 0.001). On multivariable analysis adjusting for relevant clinical factors including age, sex, and Eastern Cooperative Oncology Group performance status, the presence of lung (HR 1.67, 95% CI: 1.23-2.26; p < 0.001) or bone metastases (HR 1.84, 95% CI: 1.31-2.59; p < 0.001) were independently associated with shorter OS. The majority of patients (68%) were treated with palliative intent first-line platinum-based chemotherapy., Discussion/conclusion: Patients with metastatic GEA have an overall poor prognosis. The presence of lung or bone metastases is an independent risk factor for decreased survival. Prognostic models incorporating sites of metastasis should be considered in the clinical evaluation of metastatic GEA., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

The University of Toronto - Department of Radiation Oncology (UTDRO) has had a well-established Fellowship Program for over 20 years. An assessment of its graduates was conducted to evaluate training experience and perceived impact on professional development. Graduates of the UTDRO Fellowship Program between 1991 and 2015 were the focus of our review. Current employment status was collected using online tools. A study-specific web-based questionnaire was distributed to 263/293 graduates for whom active e-mails were identified; questions focused on training experience, and impact on career progression and academic productivity. As a surrogate measure for the impact of UTDRO Fellowship training, a comparison of current employment and scholarly activities of individuals who obtained their Fellow of the Royal College of Physicians of Canada (FRCPC) designation in Radiation Oncology between 2000 and 2012, with (n = 57) or without (n = 230) UTDRO Fellowship training, was conducted. Almost all UTDRO Fellowship graduates were employed as staff radiation oncologists (291/293), and most of those employed were associated with additional academic (130/293), research (53/293), or leadership (68/293) appointments. Thirty-eight percent (101/263) of alumni responded to the online survey. The top two reasons for completing the Fellowship were to gain specific clinical expertise and exposure to research opportunities. Respondents were very satisfied with their training experience, and the vast majority (99%) would recommend the program to others. Most (96%) felt that completing the Fellowship was beneficial to their career development. University of Toronto, Department of Radiation Oncology Fellowship alumni were more likely to hold university, research, and leadership appointments, and author significantly more publications than those with FRCPC designation without fellowship training from UTDRO. The UTDRO Fellowship Program has been successful since its inception, with the majority of graduates reporting positive training experiences, benefits to scholarly output, and professional development for their post-fellowship careers. Key features that would optimize the fellowship experience and its long-term impact on trainees were also identified., (© 2020. The Author(s).)

Background: Despite the paucity of prospective evidence, stereotactic radiotherapy (SRT) is increasingly being considered in the setting of oligoprogression to delay the need to change systemic therapy., Objective: To determine the local control (LC), progression-free survival (PFS), cumulative incidence of changing systemic therapy, and overall survival (OS) after SRT to oligoprogressive metastatic renal cell carcinoma (mRCC) lesions in patients who are on tyrosine kinase inhibitor (TKI) therapy., Design, Setting, and Participants: A prospective multicenter study was performed to evaluate the use of SRT in oligoprogressive mRCC patients. Patients with mRCC who had previous stability or response after ≥3 mo of TKI therapy were eligible if they developed progression of five of fewer metastases. Thirty-seven patients with 57 oligoprogressive tumors were enrolled., Intervention: Oligoprogressive tumors were treated with SRT, and the same TKI therapy was continued afterward., Outcome Measurements and Statistical Analysis: Competing risk analyses and the Kaplan-Meir methodology were used to report the outcomes of interest., Results and Limitations: The median duration of TKI therapy prior to study entry was 18.6 mo; 1-yr LC of the irradiated tumors was 93% (95% confidence interval [CI] 71-98%). The median PFS after SRT was 9.3 mo (95% CI 7.5-15.7 mo). The cumulative incidence of changing systemic therapy was 47% (95% CI 32-68%) at 1 yr, with a median time to change in systemic therapy of 12.6 mo (95% CI 9.6-17.4 mo). One-year OS was 92% (95% CI 82-100%). There were no grade 3-5 SRT-related toxicities., Conclusions: LC of irradiated oligoprogressive mRCC tumors was high, and the need to change systemic therapy was delayed for a median of >1 yr., Patient Summary: The use of stereotactic radiotherapy in metastatic kidney cancer patients, who develop growth of a few tumors while on oral targeted therapy, can significantly delay the need to change to the next line of drug therapy., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort ( n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = -8.4, 95% CI -11.4--5.4, p = 3.9 × 10 -8 ) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3-6.7, p = 7.4 × 10 -7 ) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = -1.5, 95% CI -5.3-2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8-3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

The aim of this study was to determine whether quantitative PET parameters on baseline 68 Ga-DOTATATE PET/CT and interim PET (iPET) performed before the second cycle of therapy are predictive of the therapy response and progression-free survival (PFS). Methods: Ninety-one patients with well-differentiated neuroendocrine tumors (mean Ki-67 index, 8.3%) underwent 68 Ga-DOTATATE PET/CT to determine suitability for peptide receptor radionuclide therapy as part of a prospective multicenter study. The mean follow-up was 12.2 mo. Of the 91 patients, 36 had iPET. The tumor metrics evaluated were marker lesion-based measures (mean SUV max and ratio of the mean lesion SUV max to the SUV max in the liver or the SUV max in the spleen), segmented 68 Ga-DOTATATE tumor volumes (DTTVs), SUV max and SUV mean obtained with the liver and spleen as thresholds, and heterogeneity parameters (coefficient of variation, kurtosis, and skewness). The Wilcoxon rank sum test was used for the association between continuous variables and the therapy response, as determined by the clinical response. Univariable and multivariable Cox proportional hazards models were used for the association with PFS. Results: There were 71 responders and 20 nonresponders. When marker lesions were used, higher mean SUV max and ratio of the mean lesion SUV max to the SUV max in the liver were predictors of the therapy response ( P  = 0.018 and 0.024, respectively). For DTTV parameters, higher SUV max and SUV mean obtained with the liver as a threshold and lower kurtosis were predictors of a favorable response ( P  = 0.025, 0.0055, and 0.031, respectively). The latter also correlated with a longer PFS. The iPET DTTV SUV mean obtained with the liver as a threshold and the ratio of mean SUV max obtained from target lesions at iPET to baseline PET correlated with the therapy response ( P  = 0.024 and 0.048, respectively) but not PFS. From the multivariable analysis with adjustment for age, primary site, and Ki-67 index, the mean SUV max ( P  = 0.019), ratio of the mean lesion SUV max to the SUV max in the liver ( P  = 0.018), ratio of the mean lesion SUV max to the SUV max in the spleen ( P  = 0.041), DTTV SUV mean obtained with the liver ( P  = 0.0052), and skewness ( P  = 0.048) remained significant predictors of PFS. Conclusion: The degree of somatostatin receptor expression and tumor heterogeneity, as represented by several metrics in our analysis, were predictive of the therapy response or PFS. Changes in these parameters after the first cycle of peptide receptor radionuclide therapy did not correlate with clinical outcomes., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The legal criteria for medical assistance in dying (MAiD) for adults with a grievous and irremediable medical condition were established in Canada in 2016. There has been concern that potentially reversible states of depression or demoralization may contribute to the desire for death (DD) and requests for MAiD. However, little is known about the emergence of the DD in patients, its impact on caregivers, and to what extent supportive care interventions affect the DD and requests for MAiD. The present observational study is designed to determine the prevalence, predictors, and experience of the DD, requests for MAiD and MAiD completion in patients with advanced or metastatic cancer and the impact of these outcomes on their primary caregivers., Methods: A cohort of patients with advanced or metastatic solid tumour cancers and their primary caregivers will be recruited from a large tertiary cancer centre in Toronto, Ontario, Canada, to a longitudinal, mixed methods study. Participants will be assessed at baseline for diagnostic information, sociodemographic characteristics, medical history, quality of life, physical and psychological distress, attitudes about the DD and MAiD, communication with physicians, advance care planning, and use of psychosocial and palliative care interventions. Measures will subsequently be completed every six months and at the time of MAiD requests. Quantitative assessments will be supplemented by qualitative interviews in a subset of participants, selected using quota sampling methods., Discussion: This study has the potential to add importantly to our understanding of the prevalence and determinants of the DD, MAiD requests and completions in patients with advanced or metastatic cancer and of the experience of both patients and caregivers in this circumstance. The findings from this study may also assist healthcare providers in their conversations about MAiD and the DD with patients and caregivers, inform healthcare providers to ensure appropriate access to MAiD, and guide modifications being considered to broaden MAiD legislation and policy., (© 2021. The Author(s).)

This article summarizes the role of PET imaging for detection, characterization, and theranostic/therapy planning for neuroendocrine tumors. Topics in this article span overall imaging accuracy with mostly 68 Ga-DOTA-peptide imaging as well as basic principles of individualized dosimetry. There is also some discussion around further specialized approaches in dosimetry in theranostics. In addition, an overview of the literature on functional imaging in neuroendocrine tumors and the current understanding of imaging-derived clinical outcome prediction are presented., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the most frequent neurodegenerative disorder that commonly causes dementia in the elderly. Recent evidence indicates that network abnormalities, including hypersynchrony, altered oscillatory rhythmic activity, interneuron dysfunction, and synaptic depression, may be key mediators of cognitive decline in AD. In this review, we discuss characteristics of neuronal network excitability in AD, and the role of Aβ and tau in the induction of network hyperexcitability. Many patients harboring genetic mutations that lead to increased Aβ production suffer from seizures and epilepsy before the development of plaques. Similarly, pathologic accumulation of hyperphosphorylated tau has been associated with hyperexcitability in the hippocampus. We present common and divergent roles of tau and Aβ on neuronal hyperexcitability in AD, and hypotheses that could serve as a template for future experiments., (Copyright © 2021 Kazim et al.)

Background: Immense volumes of personal health information (PHI) are required to realize the anticipated benefits of artificial intelligence in clinical medicine. To maintain public trust in medical research, consent policies must evolve to reflect contemporary patient preferences., Methods: Patients were invited to complete a 27-item survey focusing on: (a) broad versus specific consent; (b) opt-in versus opt-out approaches; (c) comfort level sharing with different recipients; (d) attitudes towards commercialization; and (e) options to track PHI use and study results., Results: 222 participants were included in the analysis; 83% were comfortable sharing PHI with researchers at their own hospital, although younger patients (≤ 49 years) were more uncomfortable than older patients (50 + years; 13% versus 2% uncomfortable, p < 0.05). While 56% of patients preferred broad consent, 38% preferred specific consent; 6% preferred not sharing at all. The majority of patients (63%) preferred to be asked for permission before entry into a contact pool. Again, this trend was more pronounced for younger patients (≤ 49 years: 76%). Approximately half of patients were uncomfortable sharing PHI with commercial enterprises (51% uncomfortable, 27% comfortable, 22% neutral). Most patients preferred to track PHI usage (61%), with the highest proportion once again reported by the youngest patients (≤ 49 years: 71%). A majority of patients also wished to be notified regarding study results (70%)., Conclusions: While most patients were willing to share their PHI with researchers within their own institution, many preferred a transparent and reciprocal consent process. These data also suggest a generational shift, wherein younger patients preferred more specific consent options. Modernizing consent policies to reflect increased autonomy is crucial in fostering sustained public engagement with medical research.

Background: In patients with hepatocellular carcinoma (HCC), macrovascular invasion (MVI) is associated with a poor prognosis. The purpose of this study is to describe long-term outcomes of patients with HCC and MVI treated with stereotactic body radiation therapy (SBRT)., Methods: Patients with HCC and MVI who were treated with SBRT from January 2003 to December 2016 were analyzed. Patients who had extrahepatic disease or previous liver transplant were excluded. Demographical, clinical, and treatment variables were analyzed., Results: 128 eligible patients with HCC and MVI were treated with SBRT. Median age was 60.5 years (39 to 90 years). Baseline Child-Pugh (CP) score was A5 in 67%, A6 in 20%. Median SBRT dose was 33.3 Gy (range: 27 to 54 Gy) in 5 fractions. Local control at 1 year was 87.4% (95% CI 78.6 to 96.1%). Median overall survival (OS) was 18.3 months (95% CI 11.2 to 21.4 months); ECOG performance status > 1 (HR:1.85, p = 0.0138) and earlier treatment era (HR: 2.20, p = 0.0015) were associated with worsening OS. In 43 patients who received sorafenib following SBRT, median OS was 37.9 months (95% CI 19.5 to 54.4 months). Four patients developed GI bleeding possibly related to SBRT at 2 to 8 months, and 27% (31/112 evaluable patients) had worsening of CP class at three months after SBRT., Conclusions: SBRT was associated with encouraging outcomes for patients with HCC and MVI, especially in those patients who received sorafenib after SBRT. Randomized phase III trials of SBRT with systemic and/or regional therapy are warranted and ongoing., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laura. A. Dawson reports patent/License Fees/Copyright: Raysearch., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: The coronavirus disease 2019 (COVID-19) pandemic has propelled health care workers to the front lines against the pandemic. In addition to anxiety related to infection risks, trainees have the additional burden of learning and career planning while providing care in an uncertain and rapidly changing environment. We conducted a survey to evaluate the practical and psychosocial impact on radiation oncology fellows during the first month of the pandemic., Methods and Materials: A 4-part survey was designed and distributed to the fellows in our program. The survey was designed to evaluate the impact of the pandemic on scope of activity and well-being ("Impact on You") and to identify key lessons learned and social factors ("About You") using Likert scales and open-ended response options. The survey included items from the Oldenburg Burnout questionnaire., Results: A total of 17 participants (71%) responded to the survey. Although there was a significant reduction in the mean time spent on in-person clinics (13.5 h/wk [pre-COVID] vs 9.3 h/wk [3 weeks into the COVID emergency response]; P = .002), this was replaced by virtual consults and other COVID-related activities. The proportion of respondents demonstrating features of burnout in the domains of "disengagement" and "exhaustion" was 71% and 64%, respectively. However, there was also evidence of resilience, with 47% respondents "feeling energized." Top "concerns" and "negative changes" identified related to learning, infection risk and safety, patient care, coping, and concerns about their home country. Top "positive changes" highlighted include work culture, appreciation for leadership caring for the team, the insistence on evidence to guide change, and the implementation of virtual health care., Conclusions: Negative impact needs to be anticipated, acknowledged, and managed. We anticipate understanding the positives that have emerged under these extraordinary circumstances is the "silver lining" of the pandemic, giving us tools and the best leverage to plan for the future., (© 2020 The Author(s).)

Background: MEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors., Patients and Methods: Eligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005-0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response., Results: From November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks., Conclusion: IT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations., Trial Registration Number: NCT02556463., Competing Interests: Competing interests: LS reports consultant fees for Merck, Pfizer, Celgene, AstraZeneca, MorphoSys, Roche, GeneSeeq, Loxo, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi; grant/research funding (for institution) from Novartis, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, Bayer, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks, and Avid. Her spouse reports stocks in Agios. JB reports grant/research funding (for institution) from Merck, Bristol-Myers Squibb, Acerta Pharma, Genentech, Kite/Gilead, Celldex Therapeutics, Celgene. SG reports grant/research funding (for institution) from Bristol-Myers Squibb; personal fees from Bristol-Myers Squibb, Exelixis, Merck, AstraZeneca, and Janssen. AM is the principal investigator of clinical trials for Roche/Genentech, Bristol-Myers Squibb, Merck, MSD, Pfizer, Lytix Pharma, Eisai, AstraZeneca, Chugai, and Tesaro; reports scientific/advisory board fees from GlaxoSmithKline, AstraZeneca, Merck Serono, eTheRNA, Lytix Biopharma, Kyowa, Novartis, Bristol-Myers Squibb, Symphogen, Genmab, Amgen, Biothera, Nektar, Tesaro, OncoSec, Pfizer, Seattle Genetics, AstraZeneca, Servier, Gritstone Oncology, Molecular Partners, Bayer, Partner Therapeutics, Sanofi, Pierre Fabre, Redx Pharma, OSE Immunotherapeutics, Medicxi; speakers’ bureau fees from Roche/Genentech, Bristol-Myers Squibb, Merck, MSD, Merck Serono, AstraZeneca, Amgen, Sanofi, Servier; consultant fees from Roche, Pierre Fabre, Onxeo, Eisai, Bayer, Genticel, Rigontec, Daiichi Sankyo, IMAXIO, Sanofi, BioNTech, Molecular Partners, Pillar Partners, and BPI; patent holder: anti-CD81 (Stanford University); research support from Merus; and research grants (for institution) from Bristol-Myers Squibb, Boehringer Ingelheim, MSD Avenir, and PRTK INCa. AJ reports grant/research funding (for institution) from Bristol-Myers Squibb, Merck Serono, Pfizer, AstraZeneca, Holy Stone Healthcare, Moderna, Iovance, Roche, and Squeeze Therapeutics. PM reports consultant fees from HUYA Bioscience International; leadership roles with Alessa Therapeutics; a patent/royalty/IP with Alessa Therapeutics; honoraria from AtlasMedX, CStone Pharmaceuticals, Xynomic Pharmaceuticals (to institution) McVeigh, Epigene, and Celgene; research funding (to institution) from: Merck, Pfizer, Novartis, GlaxoSmithKline, OncoMed, Celgene, Intellikine, Onconova Therapeutics, Nektar, Sanofi, Merrimack, Roche/Genentech, OncoSec, Bristol-Myers Squibb, Plexxikon, Piramal Life Science, Andes Biotechnologies, Immune Design, and BioMarin. AH reports consultant fees from Amgen, AstraZeneca (to institution), Gritstone Oncology, Incyte (to institution), Lilly, Spectrum Pharmaceuticals (to institution), and Debiopharm Group (to institution); travel/accommodation/expenses from Amgen, Servier, Lilly, AstraZeneca, Roche, and Incyte; other from AbbVie, Agios, Amgen, argenx, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, AVEO, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai, Clovis Oncology, Daiichi Sankyo, Debiopharm Group, Eisai, Exelixis, FORMA Therapeutics, GamaMabs Pharma, Genentech, GlaxoSmithKline, H3 Biomedicine, Innate Pharma, Janssen-Cilag, Kyowa, Loxo, Lytix Biopharma, Menarini, Merck, Merrimack, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar, Octimet, OncoEthix, Onyx, Orion Pharma GmbH, Oryzon Genomics, Pfizer, Pierre Fabre, Roche/Genentech, Sanofi/Aventis, Taiho Pharmaceutical, Tesaro, Xencor, Roche, Servier, Lilly; and honoraria from Merck Serono. JW reports grant/research funding (for institution) from Bristol-Myers Squibb, Merck, Nanobiotix, Mavupharma, and Checkmate Pharmaceuticals; scientific/advisory board fees from Alpine Immune Sciences, Mavupharma, Merck, OncoResponse, and Reflection; consultant fees from AstraZeneca, MolecularMatch, and Nanobiotix; stocks/shares in Checkmate Pharmaceuticals and Reflection; and business ownership of Healios. DSH reports grant/research funding (for institution) from AbbVie, Adaptimmune, Aldi-Norte, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, Loxo, Merck, Mirati, Mirna, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, Turning Point Therapeutics; travel/accommodations/expenses from Loxo, Mirna, Genmab, AACR, ASCO, and SITC; consultant/advisory fees from Alpha Insights, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD; and other ownership interests with MolecularMatch (Advisor), OncoResponse (Founder), Presagia Inc (Advisor). YW, CM, OH, FW, ZC, RK, and CF are current or former employees of and stockholders in AstraZeneca., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: For many oncology training programs in low- and middle-income countries, dedicated time for research education and mentorship of trainees is limited. Here, we report a 1-year-long collaboration between a cancer center in Canada and one in Ghana with the aim of imparting clinical research skills and mentoring the research of radiation oncology residents., Methods: On the basis of a needs assessment conducted in Ghana, we designed a curriculum consisting of 13 weekly seminars delivered via videoconference, followed by a 1-year-long mentorship program to support research projects. The primary outcome was the feasibility of the program from seminars to manuscript preparation. We used multiple secondary outcomes to capture the learning experience with study-specific questionnaires. We evaluated critical thinking ability using the Berlin questionnaire. Funding was made available for research and travel to international conferences., Results: Five Ghanaian trainees submitted research proposals. Nine Canadian faculty members delivered the seminars and two served as methodology mentors, and two Ghanaian faculty acted as local supervisors. Feedback questionnaires from all participants showed that they agreed strongly that they would recommend the sessions to another resident (75%), that the objectives were clear (71%), and that the topics were useful for their training (73%). At the end of the program, two Ghanaian trainees finalized their manuscripts and one was published., Conclusion: Here, we report on the implementation of a mentorship program focused on research methods and evidence-based medicine in sub-Saharan Africa. The program was successful in the drafting and publication of abstracts and manuscripts by local trainees.

The relative survival benefits and postoperative mortality among the different types of neoadjuvant treatments (such as chemotherapy only, radiotherapy only or chemoradiotherapy) for esophageal cancer patients are not well established. To evaluate the relative efficacy and safety of neoadjuvant therapies in resectable esophageal cancer, a Bayesian network meta-analysis was performed. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched for publications up to May 2016. ASCO and ASTRO annual meeting abstracts were also searched up to the 2015 conferences. Randomized controlled trials that compared at least two of the following treatments for resectable esophageal cancer were included: surgery alone, surgery preceded by neoadjuvant chemotherapy, neoadjuvant radiotherapy or neoadjuvant chemoradiotherapy. The primary outcome assessed from the trials was overall survival. Thirty-one randomized controlled trials involving 5496 patients were included in the quantitative analysis. The network meta-analysis showed that neoadjuvant chemoradiotherapy improved overall survival when compared to all other treatments including surgery alone (HR 0.75, 95% CR 0.67-0.85), neoadjuvant chemotherapy (HR 0.83. 95% CR 0.70-0.96) and neoadjuvant radiotherapy (HR 0.82, 95% CR 0.67-0.99). However, the risk of postoperative mortality increased when comparing neoadjuvant chemoradiotherapy to either surgery alone (RR 1.46, 95% CR 1.00-2.14) or to neoadjuvant chemotherapy (RR 1.58, 95% CR 1.00-2.49). In conclusion, neoadjuvant chemoradiotherapy improves overall survival but may also increase the risk of postoperative mortality in patients locally advanced resectable esophageal carcinoma., (© 2018 UICC.)

Purpose: To assess the baseline albumin-bilirubin (ALBI) score as a predictor of toxicity and survival in a prospective cohort of Western patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT) in 2 prospective trials., Methods and Materials: The study included 102 patients with Child-Pugh class A liver disease who received 6-fraction SBRT for HCC. Univariate and multivariable logistic regression investigated factors associated with toxicity, defined as an increase in Child-Pugh score ≥ 2 within 3 months of SBRT. Univariate and multivariable Cox regression analyses investigated factors predictive of overall survival (OS). The ALBI score was analyzed as a continuous and binary variable in separate analyses., Results: On multivariable analysis of toxicity, including the ALBI score as a continuous variable, the ALBI score (odds ratio [OR] per 0.1-unit increase, 1.51; 95% confidence interval [CI] 1.23-1.85; P = .00074), mean liver dose (OR, 1.31; 95% CI 1.02-1.68; P = .036), and dose received by 800 cm 3 of normal liver (OR, 1.10; 95% CI 1.01-1.20; P = .028) were significant. When the ALBI score was included as a dichotomous variable, the ALBI grade remained a significant predictor of toxicity (OR, 7.44; 95% CI 2.34-23.70; P = .00069). On multivariable analysis of OS, including the ALBI score as a continuous variable, the ALBI score (hazard ratio [HR] per 0.1-unit increase, 1.09; 95% CI 1.03-1.17; P = .004), tumor thrombus (HR, 1.94; 95% CI 1.23-3.07; P = .004), and treatment in trial 1 versus trial 2 (HR, 1.92; 95% CI 1.23-3.03; P = .004) were significant. Similarly, when the ALBI score was included as a binary variable, the ALBI grade, tumor thrombus, and trial were significant predictors of OS. When the ALBI score was considered, the Child-Pugh score (A6 vs A5) was not significant in multivariable models analyzing toxicity or survival. Concordance statistics indicated models containing the ALBI score were superior to those containing the Child-Pugh score., Conclusions: The baseline ALBI score was more discriminating than the Child-Pugh score in predicting OS and toxicity in patients with Child-Pugh class A liver disease. The ALBI score should be used as a factor for stratification in future HCC SBRT trials., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The practice of radiation oncology is primarily based on precise technical delivery of highly conformal, image-guided external beam radiotherapy or brachytherapy. However, systematic research efforts are being made to facilitate individualised radiation dose prescriptions on the basis of gene-expressssion profiles that reflect the radiosensitivity of tumour and normal tissue. This advance in precision radiotherapy should complement those benefits made in precision cancer medicine that use molecularly targeted agents and immunotherapies. The personalisation of cancer therapy, predicated largely on genomic interrogation, is facilitating the selection of therapies that are directed against driver mutations, aberrant cell signalling, tumour microenvironments, and genetic susceptibilities. With the increasing technical power of radiotherapy to safely increase local tumour control for many solid tumours, it is an opportune time to rigorously explore the potential benefits of combining radiotherapy with molecular targeted agents and immunotherapies to increase cancer survival outcomes. This theme provides the basis and foundation for this American Society for Radiation Oncology guideline on combining radiotherapy with molecular targeting and immunotherapy agents., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Fragile X premutation disorder is caused by CGG triplet repeat expansions in the 5' untranslated region of FMR1 mRNA. The question of how expanded CGG repeats cause disease is a subject of continuing debate. Our work indicates that CGG-repeat structures compete with regulatory BC1 RNA for access to RNA transport factor hnRNP A2. As a result, BC1 RNA is mislocalized in vivo, as its synapto-dendritic presence is severely diminished in brains of CGG-repeat knock-in animals (a premutation mouse model). Lack of BC1 RNA is known to cause seizure activity and cognitive dysfunction. Our working hypothesis thus predicted that absence, or significantly reduced presence, of BC1 RNA in synapto-dendritic domains of premutation animal neurons would engender cognate phenotypic alterations. Testing this prediction, we established epileptogenic susceptibility and cognitive impairments as major phenotypic abnormalities of CGG premutation mice. In CA3 hippocampal neurons of such animals, synaptic release of glutamate elicits neuronal hyperexcitability in the form of group I metabotropic glutamate receptor-dependent prolonged epileptiform discharges. CGG-repeat knock-in animals are susceptible to sound-induced seizures and are cognitively impaired as revealed in the Attentional Set Shift Task. These phenotypic disturbances occur in young-adult premutation animals, indicating that a neurodevelopmental deficit is an early-initial manifestation of the disorder. The data are consistent with the notion that RNA mislocalization can contribute to pathogenesis.

Purpose: The EORTC QLQ-C30 and the Brief Pain Inventory (BPI) are validated tools for measuring quality of life (QOL) and the impact of pain in patients with advanced cancer. Interpretation of these instrument scores can be challenging and it is difficult to know what numerical changes translate to clinically significant impact in patients' lives. To address this issue, our study sought to establish the minimal clinically important differences (MCID) for these two instruments in a prospective cohort of patients with advanced cancer and painful bone metastases., Methods: Both anchor-based and distribution-based methods were used to estimate the MCID scores from patients enrolled in a randomized phase III trial evaluating two different re-irradiation treatment schedules. For the anchor-based method, the global QOL item from the QLQ-C30 was chosen as the anchor. Spearman correlation coefficients were calculated for all items and only those items with moderate or better correlation (|r| ≥ 0.30) with the anchor were used for subsequent analysis. A 10-point difference in the global QOL score was used to classify improvement and deterioration, and the MCID scores were calculated for each of these categories. These results were compared with scores obtained by the distribution-method, which estimates the MCID purely from the statistical characteristics of the sample population., Results: A total of 375 patients were included in this study with documented pain responses and completed QOL questionnaires at 2 months. 9/14 items in the QLQ-C30 and 6/10 items in the BPI were found to have moderate or better correlation with the anchor. For deterioration, statistically significant MCID scores were found in all items of the QLQ-C30 and BPI. For improvement, statistically significant MCID scores were found in 7/9 items of the QLQ-C30 and 2/6 items of the BPI. The MCID scores for deterioration were uniformly higher than the MCIDs for improvement. Using the distribution-based method, there was good agreement between the 0.5 standard deviation (SD) values and anchor-based scores for deterioration. For improvement, there was less agreement and the anchor-based scores were lower than the 0.5 SD values obtained from the distribution-based method., Conclusion: We present MCID scores for the QLQ-C30 and BPI instruments obtained from a large cohort of patients with advanced cancer undergoing re-irradiation for painful bone metastases. The results from this study were compared to other similar studies which showed larger MCID scores for improvement compared to deterioration. We hypothesize that disease trajectory and patient expectations are important factors in understanding the contrasting results. The results of this study can guide clinicians and researchers in the interpretation of these instruments.

Purpose: To explore the age difference in response and patient-reported outcomes in patients with cancer having bone metastases undergoing palliative radiotherapy., Methods: Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life (QOL) Bone Metastases module (QLQ-BM22), EORTC QOL Core-15-Palliative (QLQ-C15-PAL), and Dexamethasone Symptom Questionnaire (DSQ) before a single 8-Gy radiation treatment, on days 10 and 42 after treatment. Patient demographics, performance status, analgesic consumption, BM22, C15, and DSQ were compared with multivariant analysis between patients under 75 years and 75 years and older. Multiple linear regression models were used to assess the differences between age-groups, adjusting for baseline demographics and primary disease sites., Results: There were 298 patients (170 male) with 209 (70%) less than 75 years of age. Most common primary cancer sites include lung, prostate, and breast. At baseline, younger patients had better performance status, consumed more analgesic, and reported worse scores in nausea, insomnia, and functional interference, while older patients more commonly had prostate cancer. There were no significant differences in the incidence of radiation-induced pain flare; response to radiation; changes from baseline for BM22, C15-PAL; and DSQ, nor overall survival at day 42 between the 2 groups. Responders to radiation in the elderly group reported better improvement in physical and emotional domains when compared with nonresponders., Conclusions: In patients with cancer having bone metastases undergoing palliative radiotherapy, there was no significant difference in general with age in response to radiation and patient-reported outcomes. Palliative radiotherapy should be offered to elderly patients when needed.

Background and Purpose: Patient's gender and age may influence physicians in prescribing palliative radiotherapy. The purpose of this secondary analysis of the National Cancer Institute of Canada Clinical Trials Group Symptom Control Trial SC.20 was to explore the gender and age differences in pain and patient reported outcomes in cancer patients with bone metastases undergoing re-irradiation., Materials and Methods: Response to radiation was evaluated using the International Bone Metastases Consensus Endpoint Definitions. Patients completed the Brief Pain Inventory (BPI) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (C30) before and 2 months after re-irradiation., Results: A total of 847 patients were analyzed. At baseline, men had more dyspnea, and mild pain. Older patients consumed less analgesic. More women reported clinically significant improvement in mood and enjoyment of life in the BPI after radiation. Similarly, younger patients reported better improvement in enjoyment of life. There were no significant gender or age differences in overall survival, response to radiation, or in C30 scores at 2 months., Conclusion: Similar benefit in terms of pain relief was observed across all patient groups. Cancer patients with bone metastases should be offered palliative re-irradiation irrespective of gender or age., Trial Registration: NCT00080912; https://clinicaltrials.gov/ct2/show/NCT00080912., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Gender differences may contribute to variations in disease presentations and health outcomes. To explore the gender difference in pain and patient reported outcomes in cancer patients with bone metastases undergoing palliative radiotherapy on the National Cancer Institute of Canada (NCIC) SC.23 randomized trial., Methods: Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) bone metastases module (QLQ-BM22) and EORTC QOL Core-15-Palliative (QLQ-C15-PAL) before treatment and at days 10 and 42 after a single 8 Gy radiation treatment. Patient demographics, performance status, analgesic consumption, BM22 and C15 were compared between males and females using the 2-sample t-test for continuous variables or the Chi-squared test for categorical variables. Multiple linear regression models were used to check the difference between gender groups adjusting for the baseline demographics and primary disease sites., Results: There were 298 patients (170 male, 128 female) with median age of 69 years. The most common primary cancer sites were lung, prostate and breast. At baseline, there were no differences in BM22 and C15 scores, except a worse nausea and vomiting score (P=0.03) in females on the C15. In patients with moderate baseline worst pain scores (WPS), females reported worse scores in painful sites of BM22. At day 42, there was no significant difference in response to radiotherapy. Among the responders, females reported better improvement in emotional aspect., Conclusions: In cancer patients with bone metastases undergoing palliative radiotherapy, the majority of symptom presentations, patient reported outcomes, and response to radiation was not significantly different between genders., Trial Registration: NCT01248585.

Importance: Many studies that found improved quality of life (QOL) after radiotherapy of bone metastases have small sample sizes and do not use specific questionnaires. How soon after radiotherapy one can expect an improvement in QOL is unknown., Objective: To investigate QOL at days 10 and 42 after radiotherapy with a bone metastases-specific QOL tool., Design, Setting, and Participants: In this secondary analysis of the NCIC Clinical Trials Group Symptom Control Trial SC.23, a double-blind randomized clinical trial that investigated dexamethasone for the prophylaxis of pain flare after radiotherapy, patients were accrued from 23 Canadian centers from May 30, 2011, to December 11, 2014, and were followed up for 42 days after treatment. Participants referred for radiotherapy for bone metastases were required to have a pain score at the site(s) of treatment of at least 2 (range, 0-10)., Interventions: Patients were treated with a single 8-Gy radiotherapy dose for 1 or 2 bone metastases., Main Outcomes and Measures: Patients reported their worst pain score and analgesic intake at baseline and days 10 and 42 after treatment. Pain response was assessed with International Bone Metastases Consensus Endpoint Definitions. Self-reported QOL was completed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Bone Metastases Module (QLQ-BM22) and the European Organisation for Research and Treatment of Cancer Quality of Life Core 15 Palliative (QLQ-C15-PAL) at the same time points., Results: A total of 298 patients were accrued (median age, 68.8 [range, 32-94] years at day 10 and 68.0 [range, 34-90] years at day 42). A total of 122 patients (40.9%) responded to radiotherapy at day 10 and 116 patients (38.9%) at day 42. At day 10, compared with nonresponders, patients with a pain response had a greater reduction in pain (mean reduction, 17.0 vs 1.8; P = .002) and pain characteristics (mean reduction, 12.8 vs 1.1; P = .002), as well as greater improvements in functional interference (mean increase, 11.6 vs 3.6; P = .01) and psychosocial aspects (mean increase, 1.2 points in responders vs mean decrease of 2.2 points in nonresponders, P = .04). Comparing changes in QOL from baseline to day 42, responders had significantly greater improvements in the physical (mean increase, 6.2 vs -9.0; P < .001), emotional (mean increase, 12.3 vs -5.5; P < .001), and global domains (mean increase, 10.3 vs -4.5; P < .001) of the QLQ-C15-PAL compared with nonresponders., Conclusions and Relevance: Forty percent of patients experienced pain reduction and better QOL at day 10 after radiotherapy with further improvements in QOL at day 42 in responders. A single 8-Gy radiotherapy dose for bone metastases should be offered to all patients, even those with poor survival., Trial Registration: clinicaltrials.gov Identifier: NCT01248585.

Background and Purpose: To determine maximum tolerated dose (MTD) and toxicities of sorafenib combined with stereotactic radiotherapy (SBRT) or whole liver radiotherapy (WLRT) in patients with liver metastases., Material and Methods: Eligible patients had unresectable liver metastases. Sorafenib dose was escalated in 2 strata: I - SBRT: effective liver volume irradiated (V eff )<80% (30-60Gy in 6 fractions); II - WLRT: V eff >80% (21.6Gy in 6 fractions). Four weeks of sorafenib, with radiotherapy during weeks 2-3, was delivered at 3 escalating dose levels (200-400mg twice daily). Dose limiting toxicity was defined as any grade 3+ liver toxicity, or grade 4+ treatment-related toxicity., Results: Thirty-three patients were treated: 18 in stratum I (median dose 42Gy), 15 in stratum II. The MTD was not reached. Grade 3+ toxicity was seen in 33% of patients, at a median of 10days. Two deaths from non-classic liver toxicity occurred post WLRT in stratum II. The median overall survival was 22.3 and 5.7months for strata I and II respectively., Conclusions: Sorafenib and 21.6Gy in 6 fraction WLRT resulted in unacceptably high rates of liver toxicity. Although sorafenib combined with SBRT was tolerable, the observed efficacy does not merit further clinical evaluation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: We evaluated the effect of consecutive protocols on overall survival (OS) for cervical esophageal carcinoma (CEC)., Methods and Materials: All CEC cases that received definitive radiation therapy (RT) with or without chemotherapy from 1997 to 2013 in 3 consecutive protocols were reviewed. Protocol 1 (P1) consisted of 2-dimensional RT of 54 Gy in 20 fractions with 5-fluorouracil plus either mitomycin C or cisplatin. Protocol 2 (P2) consisted of 3-dimensional conformal RT (3DRT) of ≥60 Gy in 30 fractions plus elective nodal irradiation plus cisplatin. Protocol 3 (P3) consisted of intensity modulated RT (IMRT) of ≥60 Gy in 30 fractions plus elective nodal irradiation plus cisplatin. Multivariable analyses were used to assess the effect of the treatment protocol, RT technique, and RT dose on OS, separately., Results: Of 81 cases (P1, 21; P2, 23; and P3, 37), 34 local (P1, 11 [52%]; P2, 12 [52%]; and P3, 11 [30%]), 16 regional (P1, 6 [29%]); P2, 3 [13%]; and P3, 7 [19%]), and 34 distant (P1, 10 [48%]; P2, 9 [39%]; and P3, 15 [41%]) failures were identified. After adjusting for age (P=.49) and chemotherapy (any vs none; hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.3-0.9; P=.023), multivariable analysis showed P3 had improved OS compared with P1 (HR 0.4, 95% CI 0.2-0.8; P=.005), with a trend shown for benefit compared with P2 (HR 0.6, 95% CI 0.3-1.0; P=.061). OS between P1 and P2 did not differ (P=.29). Analyzed as a continuous variable, higher RT doses were associated with a borderline improved OS (HR 0.97, 95% CI 0.95-1.0; P=.075). IMRT showed improved OS compared with non-IMRT (HR 0.57, 95% CI 0.3-0.8; P=.008)., Conclusions: The present retrospective consecutive cohort study showed improved OS with our current protocol (P3; high-dose IMRT with concurrent high-dose cisplatin) compared with historical protocols. The outcomes for patients with CEC remain poor, and novel approaches to improve the therapeutic ratio are warranted., (Copyright © 2017 Elsevier Inc. All rights reserved.)