Saskatchewan Cancer Agency

S0221 investigated weekly vs every 2 weeks dosing of doxorubicin (A) and cyclophosphamide (C) followed by paclitaxel in patients with high-risk early breast cancer. After an interim analysis, random assignment to the 2 AC arms was stopped for futility, and the trial was modified to study only the paclitaxel schedules. Between December 2003 and November 2010, a total of 2716 patients were randomly assigned in a 2 × 2 factorial design to 15 weeks of weekly A and daily C vs 6 cycles of every 2 weeks AC; and weekly paclitaxel for 12 weeks vs 6 cycles of every 2 weeks paclitaxel. Between January 2011 and January 2012, an additional 578 patients were assigned to 4 cycles of every 2 weeks AC and randomly assigned to weekly vs every 2 weeks paclitaxel. Updated survival was assessed using log-rank tests and Cox regression models. We compared outcomes by breast cancer subtype as well. At a median follow-up of 12.1 years, there were no statistically significant differences among the 4 treatment arms in disease-free survival (DFS) (P = .91) or overall survival (P = .34) in the original protocol. Among the 578 patients assigned AC for 4 cycles and randomly assigned to paclitaxel weekly vs every 2 weeks paclitaxel, there were no overall differences in DFS (P = .32) or overall survival (P = .42). As there were no statistically significant outcome differences in DFS or overall survival between the studied schedules of AC and paclitaxel with extended follow-up in the original or revised protocol, either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference.

BackgroundHereditary angioedema (HAE) therapies have demonstrated improvements in clinical symptoms and health-related quality of life (HR-QoL) in patients with HAE. Specific causes for improvement in HR-QoL have not been sufficiently explored in Canada.ObjectiveTo understand patient perspectives on the burden of HAE and their experiences taking subcutaneous plasma-derived C1 inhibitor concentrate (SC-pdC1INH), and to investigate changes in HR-QoL domains which include physical, mental, emotional, functional, social, and medical well-being.MethodsA qualitative research design was employed using telephone interviews from May to July 2023 and a quantitative self-administered Angioedema QoL questionnaire (AE-QoL), which has a recall period of 4 weeks. A conceptual map was generated from the interviews that illustrated HR-QoL domains most important to patients.ResultsThis study included 20 patients (50% female; mean age of 51 years; 85% HAE Type 1/2). Patients reported more controlled HAE since starting SC-pdC1INH, with fewer attacks (85%) and even no/nearly no attacks (60%) in the past year. Patients reported emotional benefits (reduced stress/anxiety regarding potential attacks [75%], and increased confidence in managing HAE [95%]). Positive impacts also included increased productivity/less missed days from work/school (40%) and improved physical ability/well-being (50%). The total mean AE-QoL Score was 34 (range 0–87; SD 24.9), indicating a small effect of HAE on HR-QoL in the 4-week pre-interview period.ConclusionOverall, patients on long-term prophylaxis with SC-pdC1INH reported improvements in many HR-QoL domains, but most significantly relief of stress and anxiety associated with HAE, and improvement in social and physical well-being.

Abstract Background Childhood obesity can result in adverse health outcomes. Objectives Objectives were to describe the prevalence of obesity and determine the association between obesity at cancer diagnosis and event-free survival (EFS) and overall survival (OS) in children diagnosed with cancer in Canada. Design/Methods We conducted a retrospective cohort study using the Cancer in Young People in Canada database, a population-based surveillance program collecting data from all paediatric cancer patients. This study included all children with newly diagnosed cancer aged 2 to 18 years across Canada from 2001 to 2020. Obesity was defined as age and sex-adjusted body mass index ≥ 95th percentile. EFS was defined as the time from diagnosis to first event (relapse, progression, secondary malignancies, or death). Univariate and multivariable Cox proportional hazards models compared EFS and OS between patients with and without obesity. Results A total of 11,291 patients were included (37.1% leukemias, 14.5% lymphomas, 21.8% central nervous system (CNS) tumors, 26.6% non-CNS solid tumors). At diagnosis, 10.5% were obese and the prevalence of obesity was significantly higher at 1 year (15.7%, p<0.001) and 2 years (20.1%, p<0.001) after diagnosis. The prevalence of obesity was higher in the leukemia and lymphoma cohort compared to other cancer categories (11.4% vs. 9.5%, p=0.001). In multivariable models controlling for age at diagnosis, sex, ethnicity, neighborhood income quintile, treatment era and cancer categories, obesity at diagnosis remained significantly associated with inferior EFS [adjusted HR (aHR) 1.16, 95% CI 1.02–1.32] and OS [aHR 1.29, 95% CI 1.11–1.49]. In children with acute lymphoblastic leukemia (ALL) (n=3458, 82.5% of all leukemias), after adjusting for high-risk features such as age, white blood cell count and CNS status, obesity at diagnosis remained significantly associated with inferior EFS [aHR 1.55, 95% CI 1.17–2.04] and OS [aHR 1.75, 95% CI 1.23–2.49]. In patients with CNS tumors, obesity at diagnosis was also independently associated with inferior EFS [aHR 1.38, 95% CI 1.09–1.76] and OS [aHR 1.47, 95% CI 1.13–1.91]. Conclusion In this population-based study of children with cancer, the prevalence of obesity was 11% at diagnosis and continued to increase in the following 2 years. Obesity at cancer diagnosis was independently associated with inferior survival across the entire cohort, especially in children with ALL and CNS tumors. Prevention of childhood obesity should be emphasized as it can lead to several adverse health outcomes in children with cancer.

SummarySteroid‐refractory acute graft‐versus‐host disease (SR‐aGvHD) remains a significant challenge after haematopoietic cell transplantation (HCT). While ruxolitinib (RUX) has shown efficacy for SR‐aGvHD, failure predictors are poorly defined. We assessed 78 patients from six Canadian centres who received RUX for SR‐aGvHD. Failure‐free survival (FFS) was the primary end‐point. Endothelial activation and stress index (EASIX) scores were calculated at defined time points, dichotomized using recursive partitioning. A risk score for RUX failure was developed based on key variables. At RUX initiation, 76% of patients had grade 3–4 aGvHD. The best overall response rate was 75%; 58% experienced RUX failure, while the 6‐month FFS was 25.7%. EASIX gradually increased over time even after RUX (p < 0.001). Patients with high EASIX at RUX ≥1.11 had a lower FFS at 6 months (17%) than the patients with low EASIX (54%) (hazard ratio [HR] 2.75 [95%CI 1.23–6.15], p = 0.014). A three‐factor RUX failure risk score—gut aGvHD, grade 4 aGvHD and high EASIX at RUX start—stratified patients by 6‐month FFS rates: 85.7%, 28.0% and 11.0% for score 0 (n = 28), 1 (n = 25) and ≥2 (n = 34) (HR 2.25[1.42–3.55], p < 0.001). High EASIX can predict the risk of RUX failure in addition to gut aGvHD and grade 4 aGvHD. We propose to add other therapeutic interventions to RUX therapy pre‐emptively to high EASIX patients.

Purpose: This report seeks to validate some of the findings in animal models of cancer chemotherapy with observations in the real-world management of endemic Burkitt lymphoma in Nigerian children between 1979 and 1986. Materials and Methods: Between 1979 and 1981, a period of relative affluence in Nigeria, children with Burkitt lymphoma were treated with an induction course of four 14-day cycles of combination regimens: vincristine 1.4 mg/m2 on day 1, cyclophosphamide 1000 mg/m2 on day 1, methotrexate 12.5 mg/m2 on day 2, 3 and 4, and intrathecal treatment with methotrexate 12.5/m2 or cytosine arabinoside 50mg/m2 on day 1 and day 5 of 4 cycles, followed by 4-6 28-day cycles as maintenance. By 1981-1983, socioeconomic challenges led to loss of treatment quality, including variability in dose intensity and duration. Between 1984 and 1986, the children were managed on a randomized phase II clinical trial, in which donated cytosine arabinoside at high doses, e.g., 1000mg/m2 IV q12 hours x 4 doses – was given, with the aim of overcoming physiological barrier for better control of central nervous system involvement. Results: Chi-square test showed strong correlation between remission rate and dose intensity of single agents and mean relative dose intensity of combination chemotherapy (p&lt; 0.0001), while Cox proportion hazard model revealed association between progression free survival and mean relative dose intensity (p = 0.0001) regardless of central nervous system involvement (p = 0.0003). Evaluation by log-rank test revealed highly significant association between less than 42, and more than 43 to 95 treatment days and progression free survival (p&lt;0.0001), but, counterintuitively, not with more than 95 days (p=0.809). The clinical trial regimens led to complete plus partial response rates of 100% vs 45% and progression free survival rate of 64% vs 19.7% (p=0.205), and mean relative dose intensities of 592.2 vs 102.6 (p&lt;0.0001) in the experimental and control arms, respectively. Conclusion: The clinical manifestations of the disease as well as the treatment outcomes in correlation with treatment qualities reflect predictable observations in animal models, thus, confirming the relevance of adherence to the principles of chemotherapy in clinical practice.

Loss of function screens using shRNA (short hairpin RNA) and CRISPR (clustered regularly interspaced short palindromic repeats) are routinely used to identify genes that modulate responses of tumor cells to anti-cancer drugs. Here, by integrating GSEA (Gene Set Enrichment Analysis) and CMAP (Connectivity Map) analyses of multiple published shRNA screens, we identified a core set of pathways that affect responses to multiple drugs with diverse mechanisms of action. This suggests that these pathways represent “weak points” or “Achilles heels”, whose mild disturbance should make cancer cells vulnerable to a variety of treatments. These “weak points” include proteasome, protein synthesis, RNA splicing, RNA synthesis, cell cycle, Akt-mTOR, and tight junction-related pathways. Therefore, inhibitors of these pathways are expected to sensitize cancer cells to a variety of drugs. This hypothesis was tested by analyzing the diversity of drugs that synergize with FDA-approved inhibitors of the proteasome, RNA synthesis, and Akt-mTOR pathways. Indeed, the quantitative evaluation indicates that inhibitors of any of these signaling pathways can synergize with a more diverse set of pharmaceuticals, compared to compounds inhibiting targets distinct from the “weak points” pathways. Our findings described here imply that inhibitors of the “weak points” pathways should be considered as primary candidates in a search for synergistic drug combinations.