Switch to generic formulation of temozolomide results in statistically significant increase in grade 3 and 4 bone marrow toxicity in glioma patients in the province of Alberta.

Background: Temozolomide (TMZ) is an oral, systemic chemotherapy used chiefly for treating high-grade glioma. Due to the rising costs of systemic chemotherapy, many jurisdictions have replaced brand name with generic formulations. The aim of this study was to determine whether or not there was difference in the incidence of grade 3 or 4 bone marrow toxicity and median overall survival in patients treated with brand name versus generic TMZ in the province of Alberta, Canada. The province suspended the use of generic TMZ based on preliminary data pointing to excess toxicity. Methods: This multicenter, retrospective study included data from patients with newly diagnosed high-grade glioma that received treatment with TMZ in Alberta. Multivariate logistic regression analysis was performed to determine the association between grade 3 or 4 toxicity to generic versus brand name TMZ exposure, ECOG score, and age. Kaplan-Meier survival estimates and log-rank testing were used to determine differences in overall survival between the brand name and generic TMZ cohorts, as well as the cytopenic versus non-cytopenic patients. Furthermore, a screening analysis for grade 3 or 4 bone marrow toxicity was conducted on all de novo glioma patients treated with brand name TMZ after Alberta preemptively stopped generic TMZ. Results: Grade 3 or 4 neutropenia and thrombocytopenia were observed in 15% and 19% of patients treated with generic TMZ (n = 156) as compared to 3% and 5% of patients (n = 100) treated with brand name TMZ-treated patients; P= .003 and .001. A trend toward increased median overall survival in glioblastoma patients treated with generic TMZ (13.7 months) versus brand name (15.8 months, P = .178.) was also observed through meeting statistical significance. Based on these results, the province stopped the use of generic TMZ and reverted to the Merck TMZ. An initial review of all new glioma patients (n = 89) treated with Merck TMZ since the province stopped the generic drug demonstrated 3.4% and 10.1% grade 3 or 4 neutropenia, respectively. Conclusions: The statistically significant difference in toxicity profile has prompted the province of Alberta to replace generic TMZ with brand name TMZ in high-grade glioma patients pending more detailed analysis. Our study provides evidence supporting the importance of conducting prospective studies on long-term safety for generic chemotherapies.

Rationale and design of the Diet Restriction and Exercise-induced Adaptations in Metastatic breast cancer (DREAM) study: a 2-arm, parallel-group, phase II, randomized control trial of a short-term, calorie-restricted, and ketogenic diet plus exercise during intravenous chemotherapy versus usual care.

BACKGROUND: An underlying cause of solid tumor resistance to chemotherapy treatment is diminished tumor blood supply, which leads to a hypoxic microenvironment, dependence on anaerobic energy metabolism, and impaired delivery of intravenous treatments. Preclinical data suggest that dietary strategies of caloric restriction and low-carbohydrate intake can inhibit glycolysis, while acute exercise can transiently enhance blood flow to the tumor and reduce hypoxia. The Diet Restriction and Exercise-induced Adaptations in Metastatic Breast Cancer (DREAM) study will compare the effects of a short-term, 50% calorie-restricted and ketogenic diet combined with aerobic exercise performed during intravenous chemotherapy treatment to usual care on changes in tumor burden, treatment side effects, and quality of life. METHODS: Fifty patients with measurable metastases and primary breast cancer starting a new line of intravenous chemotherapy will be randomly assigned to usual care or the combined diet and exercise intervention. Participants assigned to the intervention group will be provided with food consisting of 50% of measured calorie needs with 80% of calories from fat and ≤ 10% from carbohydrates for 48-72 h prior to each chemotherapy treatment and will perform 30-60 min of moderate-intensity cycle ergometer exercise during each chemotherapy infusion, for up to six treatment cycles. The diet and exercise durations will be adapted for each chemotherapy protocol. Tumor burden will be assessed by change in target lesion size using axial computed tomography (primary outcome) and magnetic resonance imaging (MRI)-derived apparent diffusion coefficient (secondary outcome) after up to six treatments. Tertiary outcomes will include quantitative MRI markers of treatment toxicity to the heart, thigh skeletal muscle, and liver, and patient-reported symptoms and quality of life. Exploratory outcome measures include progression-free and overall survival. DISCUSSION: The DREAM study will test a novel, short-term diet and exercise intervention that is targeted to mechanisms of tumor resistance to chemotherapy. A reduction in lesion size is likely to translate to improved cancer outcomes including disease progression and overall survival. Furthermore, a lifestyle intervention may empower patients with metastatic breast cancer by actively engaging them to play a key role in their treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03795493 , registered 7 January, 2019.

Retrospective study of the incidence and outcomes from lung cancer in solid organ transplant recipients.

OBJECTIVE: Organ transplant recipients (OTR) have an increased risk of developing post-transplant malignancies with lung cancer being one of the most common. In this retrospective study, we investigated incidence, use of systemic therapy and outcomes from lung cancer in OTR. MATERIALS AND METHODS: Patients diagnosed with lung cancer following a solid organ transplant at the University Health Network, Toronto, ON, CA, from January 1, 1980 to June 30, 2016 were included. Data for the study population, patient characteristics, treatments and outcomes were abstracted from solid OTR databases, our cancer registry and patient charts. Univariate Kaplan-Meier curves estimated median overall survival (OS) by histology, stage and systemic therapy. RESULTS: Amongst 7944 OTR (heart [N = 765], lung [n = 1668], liver [n = 2238], kidney [n = 3273]), 101 (1.3 %) developed lung cancer which were included in our analyses. Of these, 81 % were non-small cell lung cancer (NSCLC), 11 % small cell lung cancer (SCLC) and 8% neuroendocrine tumor (NET). Median OS (months) was 25 in those that presented with Stage I/II NSCLC (44 %); 25 for Stage III NSCLC (7%); 3 for Stage IV NCLC (31 %); 10 for Limited stage SCLC (6%); 2 for Extensive stage (ES) SCLC (5%). NSCLC patients that received palliative chemotherapy had an OS of 8 months; ES-SCLC patients that received chemotherapy had an OS of 6 months. Of all patients who received platinum doublets (n = 16), 10 (62.5 %) required dose reductions at some point. Five patients experienced febrile neutropenia (31 %); two (12 %) had other toxicities leading to discontinuation. CONCLUSION: Patients with stage I/II NSCLC and NET had poorer survival compared to historical norms in non-transplant patients. Patients who had stage III NSCLC or received palliative systemic therapy had survivals at or slightly below historic norms, although numbers were small. Chemotherapy can be administered in selected OTR patients though dose reductions and febrile neutropenia were common.

Anaplastic lymphoma kinase 5A4 immunohistochemistry as a diagnostic assay in lung cancer: A Canadian reference testing center's results in population-based reflex testing.

BACKGROUND: The presence of anaplastic lymphoma kinase (ALK) rearrangement predicts response to ALK tyrosine kinase inhibitor (TKI) therapy. Fluorescence in situ hybridization (FISH) was the initial reference standard to detect ALK rearrangement, but immunohistochemistry (IHC) using D5F3 has gained acceptance as an alternative diagnostic method. ALK IHC assays using other ALK antibodies have also been used as screening methods, but data supporting their utility as diagnostic tests have not been widely reported. METHODS: Data from reflexive clinical ALK IHC test using the 5A4 clone concurrent with epidermal growth factor receptor (EGFR) mutation testing were analyzed. ALK IHC results were reported as negative (-), equivocal, or positive (+), with equivocal or positive staining validated by FISH break-apart probe testing. Treatment outcomes were reviewed for ALK IHC+ patients. RESULTS: Between 2012 and 2015, 146 (2.5%) cases were reported as ALK IHC+, 188 (3.2%) were reported as equivocal, and 5624 (94.4%) were reported as ALK IHC-. Of the ALK IHC+ cases, 131/143(91.6%) were ALK FISH+. Excluding 6 cases in which FISH was inconclusive or not performed, the positive predictive value was 95.6%, and the negative predictive value was 100%. Most specimens (n = 5352 [89.6%]) were also successfully tested for EGFR. Clinical responses to ALK TKIs were noted in 49 ALK IHC+ patients, with a median progression-free survival of 9.9 months. CONCLUSIONS: ALK 5A4 IHC can serve as a robust diagnostic test for ALK-rearranged lung cancer and is associated with treatment response and survival. Optimized tissue allocation resulted in high success rates of combined reflex EGFR and ALK testing.

Venous thromboembolism with EGFR monoclonal antibody necitumumab in stage IV non-small cell lung cancer: A retrospective cohort analysis.

INTRODUCTION: Metastatic non-small cell lung cancer (NSCLC) is a recognized risk factor for VTE. Some systemic treatments may increase this risk further. Here, we present the risk of VTE and its prognostic significance for patients treated with chemotherapy (chemo) and the EGFR monoclonal antibody necitumumab (neci) for metastatic NSCLC. METHODS: Four trials of 1st-line treatment for Stage IV NSCLC were analyzed: two randomized phase 3 studies of cisplatin/gemcitabine ±neci in squamous NSCLC (SQUIRE: N = 1079) and cisplatin/pemetrexed ±neci in non-squamous NSCLC (INSPIRE: N = 616); JFCL (N = 161), a randomized phase 2 trial of carboplatin/paclitaxel ±neci in squamous NSCLC; and JFCK (N = 61), a single arm phase 2 trial of cisplatin/gemcitabine +neci in squamous NSCLC. A Cox proportional hazards model with VTE as a time-dependent covariate was used for overall survival (OS) analyses. RESULTS: Neci + chemo was associated with an increased risk of VTE (Relative Risk [RR]: 1.579; 95% CI: 1.155-2.158). History of VTE (RR: 1.899; 95% CI: 1.142-3.156) and prior cardiac/cardiovascular events (RR: 1.514; 95% CI: 1.102-2.082) were associated with increased risk of VTE. Decreased VTE risk was seen with: male sex (RR: 0.696; 95% CI: 0.502-0.964), eastern European geographic region (RR: 0.387; 95% CI: 0.267-0.562) and squamous cell pathology (RR: 0.653; 95% CI: 0.483-0.883). VTE occurrence showed no association with OS (HR: 1.121; 95% CI: 0.930-1.351). CONCLUSION: Our data suggest that certain patient characteristics such as prior history of VTE and non-squamous histology might be associated with an increased risk of on-treatment VTE in NSCLC, although in this study, overall survival was not affected. Further studies to develop measures for identifying high-risk patients are needed to inform treatment decisions as well as VTE management and prophylaxis.

Monitoring and Management of Immune-Related Adverse Events Associated With Programmed Cell Death Protein-1 Axis Inhibitors in Lung Cancer.

Monoclonal antibodies targeting programmed cell death protein-1 (PD-1) represent a new treatment paradigm in non-small cell lung cancer. Three phase III trials have demonstrated a survival benefit and improved tolerability of nivolumab and pembrolizumab when compared with standard second-line chemotherapy. Nevertheless, the adverse events associated with PD-1 inhibitors are unique; early recognition and treatment are essential. This review summarizes the required monitoring and appropriate management of immune-related adverse events in lung cancer patients receiving these agents. THE ONCOLOGIST: 2017;22:70-80 IMPLICATIONS FOR PRACTICE: : The potential adverse events of immune checkpoint inhibitors differ from conventional chemotherapy and can require a multidisciplinary approach. Continued education is important for all physicians to ensure optimal care for patients.