BackgroundPatients with advanced non-small-cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) gene are a heterogeneous population who often develop ...brain metastases (BM). The optimal management of patients with asymptomatic brain metastases is unclear given the activity of newer-generation targeted therapies in the central nervous system. We present a protocol for an individual patient data (IPD) prospective meta-analysis to evaluate whether the addition of stereotactic radiosurgery (SRS) before osimertinib treatment will lead to better control of intracranial metastatic disease. This is a clinically relevant question that will inform practice.MethodsRandomised controlled trials will be eligible if they include participants with BM arising from EGFR-mutant NSCLC and suitable to receive osimertinib both in the first-line and second-line settings (P); comparisons of SRS followed by osimertinib versus osimertinib alone (I, C) and intracranial disease control included as an endpoint (O). Systematic searches of Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), PsychInfo, ClinicalTrials.gov and the WHO’s International Clinical Trials Registry Platform’s Search Portal will be undertaken. An IPD meta-analysis will be performed using methodologies recommended by the Cochrane Collaboration. The primary outcome is intracranial progression-free survival, as determined by response assessment in neuro-oncology-BM criteria. Secondary outcomes include overall survival, time to whole brain radiotherapy, quality of life, and adverse events of special interest. Effect differences will be explored among prespecified subgroups.Ethics and disseminationApproved by each trial’s ethics committee. Results will be relevant to clinicians, researchers, policymakers and patients, and will be disseminated via publications, presentations and media releases.Prospero registrationCRD42022330532.
Pain is a common symptom in stage IV non-small cell lung cancer (NSCLC). The objective of the study was to examine the use of interventions and factors associated with interventions for pain. A ...population-based cohort study in Ontario, Canada was conducted with patients diagnosed with stage IV NSCLC from January 2007 to September 2018. An Edmonton Symptom Assessment System (ESAS) score of ≥4 defined moderate-to-severe pain following diagnosis. The study cohort included 13,159 patients, of which 68.5% reported at least one moderate-to-severe pain score. Most patients were assessed by a palliative care team (85.4%), and the majority received radiation therapy (73.2%). The use of nerve block was rare (0.8%). For patients ≥65 years of age who had drug coverage, 59.6% received an opiate prescription. Patients with moderate-to-severe pain were more likely to receive palliative assessment or radiation therapy compared to patients with none or mild pain. Patients aged ≥70 years and with a greater comorbidity burden were associated with less likelihood to receive radiation therapy. Patients from rural/non-major urban residence and with a greater comorbidity burden were also less likely to receive palliative care assessment. Factors associated with interventions for pain are described to inform future symptom management in this population.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
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Background: Drug price negotiation to lower cost to a cost-effectiveness threshold (λ) is a recognized approach to improve health care opportunities for the greater benefit of the ...population. Critics have raised concerns for this approach given the additional time required and speculated loss of quality-adjusted life-years (QALY) for patients. The current study aimed to quantify the incremental net health benefit (INHB) of publicly funded oncology drugs, if funding occurred at list prices without (w/o) negotiations. Methods: Pan-Canadian Oncology Drug Review submissions were reviewed to identify funded drugs with unique indications. For included drug indications economic guidance panel (EGP) reports were reviewed for incremental costs (ΔC) and ΔQALY from manufacturer’s base case cost-effectiveness analyses, EGP lower (LL) and upper limit (UL) re-analyzed estimates (based on list prices). Number of new cases in Ontario (most populous province in Canada) per indication (2017-18) was obtained from provincial databases. Annual QALY gain for each indication was determined by: (ΔQALY×cases). Provincial QALY gain/loss w/o price negotiations to reference λ was estimated by: (INHB= ΔQALY− (ΔC/λ) ×cases). Incremental net monetary benefit demonstrated annual monetary gain/loss w/o price negotiations to reference λ: (INMB= (ΔQALY×λ) −ΔC ×cases). Results: 34 drug indications including 4,629 new cases were identified. Annual QALY gain for funded indications using manufacturer, LL and UL estimates was 1,851, 1,617 and 1,301, respectively. At reference λ CAD$100,000/QALY, funding w/o negotiations resulted in loss of 2,176, 2,368, 2,451 QALY, representing budgetary diversions away from other health care interventions. This would result in a provincial net annual loss of 325, 751 and 1,150 QALY, respectively. INMB demonstrated provincial net monetary loss of CAD$32,472,389, $75,113,684 and $115,022,331, respectively. Conclusions: Despite an annual gain in QALY for funded drug indications, a net provincial loss in QALY w/o price negotiations was demonstrated. Thus, supportive evidence exists for drug price negotiations towards the promotion of health benefits for the population.
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Background: Activating mutations in the BRAF gene occur in 40-60% of melanomas with the majority of mutations resulting in V600E/K. Previous cohort studies have identified rates ...of non-V600E/K BRAF mutations to occur in 5-12% of patients. Despite this, there remains limited evidence characterizing the disease characteristics and outcomes of patients who harbor the non-classical BRAF mutation. Methods: Retrospective review of all melanoma patients treated at a tertiary cancer center that had BRAF mutation testing through targeted sequencing. Three groups of patients were identified and compared with respect to patient and disease characteristics: a) BRAF negative; b) BRAF V600E/K positive; c) BRAF non-V600E/K positive. Results: BRAF testing was performed in 168 melanoma patients of which 101 (60%) were BRAF negative; 55 (33%) were BRAF V600E/K positive; 12 (7%) were BRAF non-V600E/K positive (2 G466E, 1 of each G469E, K601N, K601E, L597Q, L597S, V741I, N594G, D594N, V600R and 1 with both K601N & V600E). Of these, 147 patients had baseline demographic and treatment data available for analysis. BRAF mutations were more common among males (45.6% of men vs. 22.7% of women, p = 0.03). No significant differences between other baseline patient demographics noted. Pathological characteristics revealed a non-significant trend toward poorer prognostic factors with BRAF non-V600E/K patients having increased Breslow depth (7.0 mm vs. 5.0 mm BRAF negative, 4.3 mm BRAF V600E/K) and higher rates of ulceration (71% vs. 44% BRAF negative, 30% BRAF V600E/K). BRAF non-V600E/K patients displayed a non-significant trend toward poorer overall survival (71 months vs. 215 months BRAF negative, 125 months BRAF V600E/K). Conclusions: Non-V600E/K BRAF positive patients appear to display less favorable disease characteristics and outcomes as compared to BRAF negative and BRAF V600E/K positive patients. Non-V600E/K melanoma show limited response to BRAF targeted therapy; however, evidence suggests the presence of non-classical mutations may confer susceptibility to MEK inhibition. Further characterization of non-V600E/K BRAF melanoma may allow for more refined prognostication and treatment decisions.
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Background: The therapeutic landscape for patients with mCSPC has evolved over the last decade given the growing body of evidence demonstrating efficacy for the earlier ...application of oral androgen receptor signaling inhibitors, such as with abiraterone and enzalutamide. Recently the success of the TITAN trial established the superior efficacy of apalutamide combined with androgen deprivation therapy (ADT), with a 33% reduction in mortality versus ADT alone, and a tolerable toxicity profile. However, with substantially higher costs than ADT alone, the cost-effectiveness of this combination is critical to evaluate. Methods: A cost-utility analysis of apalutamide+ADT versus ADT alone was conducted from the Canadian healthcare perspective. A state-transition model with probabilistic analysis was used to compare the two strategies over a lifetime horizon. Model inputs were informed by the TITAN trial (transition probabilities, adverse events AE, subsequent therapy), published literature (utilities) and Canadian costing resources (systemic therapy initial and subsequent, routine care physician visits, imaging, AE, end-of-life care costs). Primary outcomes included expected life-year gains (LYG), quality-adjusted life-years (QALY), lifetime cost (in 2018 Canadian dollars), and the incremental cost-effectiveness ratio (ICER). Multiple scenario analyses were conducted to assess parameter and model uncertainty. Cost and effectiveness were discounted at 1.5% as per Canadian guidelines. Results: From the base-case analysis expected LYG and QALY for ADT and apalutamide+ADT were 4.11, 5.57 and 3.50, 4.85, respectively. Expected cost over a lifetime horizon was $37,553 and $254,205, respectively. The ICER for apalutamide+ADT as compared to ADT alone was $160,483/QALY. Through scenario analysis, cost-effectiveness of apaluatmide+ADT was achieved with apalutamide price reductions of >50%, relative to a cost-effectiveness threshold (CET) of $100,000/QALY. Scenario analysis of alternative long-term survival expectations with apalutamide+ADT demonstrated cost-effectiveness (relative to CET $100,000/QALY) with expected improvements in the 5-year survival rate of 29% as compared to ADT (versus base-case expected improvement in 5-year survival of 15%). Conclusions: Apalutamide+ADT is unlikely to be cost-effective from the Canadian healthcare perspective at current list prices. Improvement in cost-effectiveness is most likely to be achieved through price reductions in apalutamide drug costs.
The introduction of oral vascular endothelial growth factor receptor tyrosine kinase inhibitors therapy has been associated with major improvements in outcome for patients with metastatic kidney ...cancer. Each drug has been licensed with rigid dosing criteria that are not optimal for all patients. This paper reviews the growing body of evidence suggesting that individualized dosing based on toxicity may be associated with optimal drug exposure for each patient and improved outcome both in the metastatic and adjuvant setting.
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Background: Patients with SCLC are at high risk for the development of IMD and, subsequently, rapid intracranial progression. SRS has supplanted WBRT as first-line treatment for IMD in most ...solid cancers, but WBRT remains first-line treatment for IMD in SCLC patients. Data on SRS in SCLC are limited to small retrospective studies. Methods: Studies reporting on SRS in SCLC patients with IMD were collected from EMBASE, MEDLINE, CENTRAL, and grey literature sources (n = 3,732 studies). Random-effects meta-analysis pooled hazard ratios (HR) for overall survival (OS) between SRS and WBRT ± SRS boost, as well as medians for OS in months (mo) and risk rates for intracranial local (LC) and intracranial distant control (DC) in single-arm SRS studies. Results: OS following SRS was non-inferior compared with WBRT ± SRS boost (HR 0.90; 95% confidence interval (95CI), 0.73-1.10; n = 7 studies; n = 18,130 patients), and superior compared with WBRT alone (HR 0.80; 95CI, 0.66-0.96; n = 7 studies; n = 16,961 patients). Pooled median OS from single-arm studies following SRS was 8.99 mo (95CI, 7.86-10.15; n = 14 studies; n = 1,682 patients). Pooled LC and DC estimates following SRS were 81% (95CI, 67%-99%) and 66% (95CI, 50%- 86%), respectively, at 6 mo, and 78% (95CI, 61%-98%) and 58% (95CI, 46%-75%), respectively, at 12 mo. Conclusions: This systematic review and meta-analysis provides evidence that SRS may achieve analogous survival outcomes compared with WBRT in patients with SCLC and IMD, indicating that a subset of SCLC patients may benefit from first-line SRS treatment. Prospective trials should investigate the impact of metastatic burden as well as LC and DC differences between WBRT- and SRS-treated SCLC patients.
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