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BACKGROUND: Adjuvant endocrine therapy is a gold standard in early-stage, hormone receptor positive breast cancer. In postmenopausal women, aromatase inhibitors (AIs) are associated with improved outcome compared to tamoxifen monotherapy. Differences in the toxicity profiles of these drugs are described; however, little is known about whether the risk of adverse events changes over time. METHODS: Sequential reports of large, randomized, adjuvant endocrine therapy trials comparing AIs to tamoxifen were reviewed. Data on pre-specified adverse events were extracted including cardiovascular events, bone fractures, cerebrovascular disease, endometrial cancer, secondary malignancies excluding breast cancer, venous thrombosis and death without recurrence. Odds ratios (ORs) were calculated for each adverse event at each time over the course of follow-up. The change in the ORs for adverse events over time was evaluated using weighted linear regression. RESULTS: Analysis included 21 reports of 7 trials comprising 30,039 patients and reporting outcomes between 28 and 128 months of follow-up. Compared to tamoxifen, AIs use was associated with a significant reduction in the magnitude of increased odds of bone fracture over time (ß = - 0.63, p = 0.013). There was a non-significant decrease in the magnitude of reduced odds of secondary malignancies over time (ß = 0.448, p = 0.094). The differences in other toxicity profiles between AIs and tamoxifen did not change significantly over time. CONCLUSIONS: The increased risk of bone fractures associated with adjuvant AIs falls over time and after discontinuation of treatment. Differences in other toxicities between AIs and tamoxifen do not change significantly over time including a persistently elevated risk of cardiovascular events.
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Antineoplásicos Hormonales/efectos adversos , Neoplasias de la Mama/terapia , Enfermedades Cardiovasculares/epidemiología , Fracturas Óseas/epidemiología , Inhibidores de la Aromatasa/efectos adversos , Neoplasias de la Mama/patología , Enfermedades Cardiovasculares/inducido químicamente , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Ensayos Clínicos Fase III como Asunto , Femenino , Fracturas Óseas/inducido químicamente , Humanos , Mastectomía , Estadificación de Neoplasias , Posmenopausia , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tamoxifeno/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Clinical practice guidelines (CPGs) are crucial to the practice of evidence-based medicine. Declared author financial conflicts of interest (FCOIs) are common in CPGs and have been associated with endorsement of treatment. Less is known about undeclared FCOIs. METHODS: The American Society of Clinical Oncology (ASCO) website was searched to identify all CPGs for systemic therapy published between August 2013 and June 2018. Data on self-reported author FCOIs and funding sources were extracted. The Open Payments database was then searched to identify compensation to CPG authors. Concordance between declared and undeclared but verified FCOIs was assessed with Cohen's κ. RESULTS: For 26 CPGs, 314 nonduplicate authors were identified; 184 of these authors (59%) disclosed FCOIs. Among the remaining 130 authors, data in Open Payments were unavailable for 71 authors (non-US residents or authors affiliated with a nonprofit organization). Among the 59 authors who declared no FCOIs and for whom Open Payments data were available, 55 (93%) had received payment from industry. The κ value for agreement between disclosed and verified FCOIs was 0.092. Among the 243 authors with FCOIs verifiable via Open Payments, 239 (98%) received payment from industry. Thirty-four authors (62%) received more than $1000 in nonresearch funding, and 19 (35%) received more than $5000. Among the 52 first and last authors, 44 (85%) received payment from industry; 14 of these payments (32%) were not declared. CONCLUSIONS: FCOIs among authors of ASCO CPGs are common and are not disclosed by a substantial proportion of authors with Open Payments data. Improved transparency of FCOIs should become standard practice among CPG authors. Professional societies and journal editors need to create a mechanism to verify self-reported FCOIs.
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Conflicto de Intereses , Revelación , Apoyo Financiero , Oncología Médica/normas , Guías de Práctica Clínica como Asunto , Humanos , Oncología Médica/economía , Estados UnidosRESUMEN
BACKGROUND: Hematometrocolpos caused by an imperforate hymen is a common form of vaginal outflow obstruction. This is a rare pediatric anomaly that can present with atypical or vague symptomatology, such as abdominal pain or constipation or urinary retention in the setting of amenorrhea. It is essential to obtain a gynecologic history and inquire about menstrual cycles to properly evaluate a young female with such a common complaint as abdominal pain. Failure to perform a gynecologic examination in the emergency department setting may delay diagnosis and appropriate care for this rare condition, which can lead to serious complications. CASE REPORT: This case describes a 12-year-old female who presented to the emergency department with a complaint of abdominal pain and urinary symptoms. Because of the severity of the patient's pain on abdominal examination, we obtained a computed tomography scan of her abdomen and pelvis, which showed findings consistent with hematometrocolpos. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Obstruction of the female genital outflow tract is a rare occurrence. Because abdominal pain is such a common complaint, not only in the pediatric emergency department but also in the outpatient setting, the diagnosis of hematometrocolpos may easily go undiagnosed for months or even years. Obtaining a complete gynecologic history is key when evaluating young females with abdominal pain or urinary retention. Early detection and timely management can prevent serious complications and long-term sequelae. This patient had a successful outcome and early surgical management of her hematometrocolpos which was caused by an imperforate hymen.
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Dolor Abdominal/etiología , Hematocolpos/complicaciones , Himen/anomalías , Trastornos de la Menstruación/complicaciones , Niño , Anomalías Congénitas , Servicio de Urgencia en Hospital/organización & administración , Femenino , Genitales/lesiones , Humanos , Imagen por Resonancia Magnética/métodos , Hemorragia Uterina/complicacionesRESUMEN
Approval of drugs is based on randomized trials observing statistically significant superiority of an experimental agent over a standard. Statistical significance results from a combination of effect size and sampling, with larger effect size more likely to translate to population effectiveness. We assess sample size justification in trials supporting cancer drug approvals. We identified US FDA anti-cancer drug approvals for solid tumors from 2015 to 2019. We extracted data on study characteristics, statistical plan, accrual, and outcomes. Observed power (Pobs) was calculated based on completed study characteristics and observed hazard ratio (HRobs). Studies were considered over-sampled if Pobs > expected with HRobs similar or worse than expected or if Pobs was similar to expected with HRobs worse than expected. We explored associations with over-sampling using logistic regression. Of 75 drug approvals (reporting 94 endpoints), 21% (20/94) were over-sampled. Over-sampling was associated with immunotherapy (OR: 5.5; p = 0.04) and associated quantitatively but not statistically with targeted therapy (OR: 3.0), open-label trials (OR: 2.5), and melanoma (OR: 4.6) and lung cancer (OR: 2.17) relative to breast cancer. Most cancer drug approvals are supported by trials with justified sample sizes. Approximately 1 in 5 endpoints are over-sampled; benefit observed may not translate to clinically meaningful real-world outcomes.
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Antineoplásicos , Neoplasias de la Mama , Estados Unidos , Humanos , Femenino , Aprobación de Drogas/métodos , Tamaño de la Muestra , United States Food and Drug Administration , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológicoRESUMEN
Locally advanced or metastatic urothelial carcinoma (aUC) presents a significant challenge with high mortality rates. Platinum-based chemotherapy remains the established frontline standard of care, and a switch-maintenance strategy with immunotherapy has now emerged as a new standard for aUC patients without disease progression, following initial platinum therapy. Examining the treatment patterns is imperative, given the evolving therapeutic landscape. In this study, we conducted a retrospective medical chart review of 17 Canadian oncologists treating patients with aUC to assess unmet needs in Canadian aUC patient care. Data from 146 patient charts were analyzed, revealing important clinical insights about the management of aUC. A substantial proportion of patients (53%) presented with de novo metastatic disease, which was possibly influenced by pandemic-related care disruptions. Variability was evident in the cisplatin eligibility criteria, with a majority (70%) of oncologists utilizing a 50 mL/min threshold. Most favored four cycles of platinum-based chemotherapy to spare the bone marrow for future therapies and prevent patient fatigue. Notably, some eligible patients were kept under surveillance rather than receiving maintenance therapy, suggesting a potential gap in awareness regarding evidence-based recommendations. Furthermore, managing treatment-related adverse events was found to be one of the biggest challenges in relation to maintenance immunotherapy. In conclusion, our findings provide the first comprehensive overview of aUC treatment patterns in Canada following the approval of maintenance immunotherapy, offering insights into the decision-making process and underscoring the importance of evidence-based guidelines in aUC patient management.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Neoplasias Urológicas , Humanos , Anticuerpos Monoclonales Humanizados/efectos adversos , Canadá , Carcinoma de Células Transicionales/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias Urológicas/tratamiento farmacológicoRESUMEN
PURPOSE: There is limited information about the clinical utility of targeted next-generation sequencing (NGS) panel testing to inform decision making for patients with advanced solid tumors. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) is a prospective study that enrolled more than 4,500 patients with solid tumor for NGS panel testing. We performed a retrospective survey of medical oncologists to evaluate the impact of NGS testing on treatment decisions. METHODS: Patients and treating oncologists were identified at the Princess Margaret Cancer Center between 2016 and 2021. Tumor-only sequencing was performed using a gene panel of either 555 or 161 cancer genes. Oncologists were asked to review testing results and complete a survey indicating whether NGS testing affected treatment decisions. The primary outcome of this study was rate of treatment change on the basis of mutation results. Patient, test, and physician factors were evaluated for association with treatment changes using univariate analyses and a mixed-effects model. RESULTS: Of the 582 surveys sent, 394 (67.7%) were completed. We found that 188 (47.7%) patients had testing results classified as actionable by the oncologist and 62 (15.7%) patients were matched to treatment, of whom 37 (60%) were enrolled in a clinical trial, 13 (21%) received an approved drug, four (6%) were prescribed off-label therapy, and eight (13%) avoided ineffective treatment. Patient, test, and physician characteristics were not significantly associated with treatment change. There was no difference in overall survival between patients who received matched treatment versus those who did not (P = .55, median survival not reached). CONCLUSION: OCTANE testing led to a change in drug treatment in 15.7% of patients, supporting the clinical utility of NGS panel testing for patients with advanced solid tumors.
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Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias , Centros de Atención Terciaria , Humanos , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Toma de Decisiones Clínicas , Adulto , Ontario , Estudios ProspectivosRESUMEN
Due to the increasing interest in the use of artificial intelligence (AI) algorithms in hepatocellular carcinoma detection, we performed a systematic review and meta-analysis to pool the data on diagnostic performance metrics of AI and to compare them with clinicians' performance. A search in PubMed and Scopus was performed in January 2024 to find studies that evaluated and/or validated an AI algorithm for the detection of HCC. We performed a meta-analysis to pool the data on the metrics of diagnostic performance. Subgroup analysis based on the modality of imaging and meta-regression based on multiple parameters were performed to find potential sources of heterogeneity. The risk of bias was assessed using Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) and Prediction Model Study Risk of Bias Assessment Tool (PROBAST) reporting guidelines. Out of 3177 studies screened, 44 eligible studies were included. The pooled sensitivity and specificity for internally validated AI algorithms were 84% (95% CI: 81,87) and 92% (95% CI: 90,94), respectively. Externally validated AI algorithms had a pooled sensitivity of 85% (95% CI: 78,89) and specificity of 84% (95% CI: 72,91). When clinicians were internally validated, their pooled sensitivity was 70% (95% CI: 60,78), while their pooled specificity was 85% (95% CI: 77,90). This study implies that AI can perform as a diagnostic supplement for clinicians and radiologists by screening images and highlighting regions of interest, thus improving workflow.
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Inteligencia Artificial , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/diagnóstico , Algoritmos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Sorafenib and pazopanib, two tyrosine kinase inhibitors (TKI), are widely used in patients with progressive symptomatic desmoid tumors (DT). Limited real-word data is available on long-term outcomes of patients who progressed on, stopped, or continued TKIs. METHODS: Patients diagnosed with DTs and treated with sorafenib or pazopanib between 2011 and 2022 at 11 institutions were reviewed. Patient history, response to therapy and toxicity were recorded. Statistical analyses utilized Kaplan-Meier and log-rank tests. RESULTS: 142 patients with DT treated with sorafenib (n = 126, 88.7 %) or pazopanib (n = 16, 11.3 %) were analyzed. The median treatment duration was 10.8 months (range: 0.07- 73.9). The overall response rate and the disease control rate were 26.0 % and 95.1 %, respectively. The median tumor shrinkage was - 8.5 % (range -100.0 %- +72.5 %). Among responders, the median time to an objective response was 15.2 months (range: 1.1 to 33.1). The 1-year and 2-year progression-free survival rates were 82 % and 80 %. Dose reductions were necessary in 34 (23.9 %) patients. Grade 3 or higher adverse events were reported in 36 (25.4 %) patients. On the last follow-up, 55 (38.7 %) patients continued treatment. Treatment discontinuation (n = 85, 59.9 %) was mainly for toxicity (n = 35, 45.9 %) or radiological or clinical progression (n = 30, 35.3 %). For the entire cohort, 36 (25.4 %) patients required subsequent treatment. In the 32 responders, only 1 (3.1 %) patient required a subsequent treatment. In patients who discontinued TKI, 25 (44.6 %) with stable disease received subsequent treatment compared to 0 (0.0 %) of responders. CONCLUSION: This retrospective study represents the largest cohort of DT patients treated with sorafenib or pazopanib to date. Discontinuation of treatment in responders is safe. The optimal treatment duration in patients with stable disease remains to be defined.
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Fibromatosis Agresiva , Indazoles , Pirimidinas , Sorafenib , Sulfonamidas , Humanos , Sorafenib/uso terapéutico , Sorafenib/efectos adversos , Sulfonamidas/uso terapéutico , Sulfonamidas/efectos adversos , Masculino , Femenino , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Persona de Mediana Edad , Adulto , Anciano , Adulto Joven , Fibromatosis Agresiva/tratamiento farmacológico , Fibromatosis Agresiva/patología , Adolescente , Estudios Retrospectivos , Anciano de 80 o más Años , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVE: Metastatic renal cell carcinoma (mRCC) patients have been reported to have better outcomes when treated with immunotherapies (IO) compared to targeted therapies (TT). This study aims to evaluate the impact of first-line systemic therapies on survival of mRCC patients with or without sarcomatoid features using real-world data. METHODS: Metastatic RCC patients of International mRCC Database Consortium (IMDC) intermediate or high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system. Patients were classified by initial treatment: (1) targeted therapy (TT) used alone or (2) immunotherapy (IO)-based systemic therapies used in combination of either IO-IO or IO-TT. The inverse probability of treatment weighting using propensity scores was used to balance for covariates. Cox proportional hazard models were used to assess the impact of initial treatment received on overall survival (OS). KEY FINDINGS AND LIMITATIONS: Of the 1202 eligible patients, 791 were treated with TT and 411 with IO combinations. Of the patients, 76% were male, and the majority (91%) had a nephrectomy before systemic therapy. In nonsarcomatoid patients (639 TT and 320 IO patients), treatment with IO was associated with improved OS compared with patients treated with TT (median of 72 vs 48 mo, hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.50-0.80, objective response rate [ORR] of 38.5% for IO and 23.5% for TT). In sarcomatoid patients (152 TT and 91 IO patients), treatment with IO was associated with improved OS (median of 48 vs 18 mo, HR 0.41, 95% CI 0.26-0.64, ORR of 49.5% for IO and 13.8% for TT). Similar results were observed in patients with synchronous metastatic disease only. CONCLUSIONS AND CLINICAL IMPLICATIONS: IO treatment was associated with improved survival in mRCC patients. The magnitude of benefit is increased in patients with sarcomatoid mRCC, consequently, identifying the sarcomatoid status early on could help healthcare providers make a better treatment decision. PATIENT SUMMARY: Metastatic renal cell carcinoma (mRCC) patients of International mRCC Database Consortium intermediate and high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system (CKCis). In this study, treatment with immunotherapy was associated to an improved survival and response rates for mRCC patients with and without sarcomatoid features. The magnitude of benefit is increased in patients with sarcomatoid mRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/terapia , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/patología , Masculino , Neoplasias Renales/patología , Neoplasias Renales/terapia , Neoplasias Renales/mortalidad , Neoplasias Renales/tratamiento farmacológico , Femenino , Persona de Mediana Edad , Anciano , Resultado del Tratamiento , Inmunoterapia , Estudios Retrospectivos , Tasa de Supervivencia , Terapia Molecular DirigidaRESUMEN
Background: To date, economic analyses of tissue-based next generation sequencing genomic profiling (NGS) for advanced solid tumors have typically required models with assumptions, with little real-world evidence on overall survival (OS), clinical trial enrollment or end-of-life quality of care. Methods: Cost consequence analysis of NGS testing (555 or 161-gene panels) for advanced solid tumors through the OCTANE clinical trial (NCT02906943). This is a longitudinal, propensity score-matched retrospective cohort study in Ontario, Canada using linked administrative data. Patients enrolled in OCTANE at Princess Margaret Cancer Centre from August 2016 until March 2019 were matched with contemporary patients without large gene panel testing from across Ontario not enrolled in OCTANE. Patients were matched according to 19 patient, disease and treatment variables. Full 2-year follow-up data was available. Sensitivity analyses considered alternative matched cohorts. Main Outcomes were mean per capita costs (2019 Canadian dollars) from a public payer's perspective, OS, clinical trial enrollment and end-of-life quality metrics. Findings: There were 782 OCTANE patients with 782 matched controls. Variables were balanced after matching (standardized difference <0.10). There were higher mean health-care costs with OCTANE ($79,702 vs. $59,550), mainly due to outpatient and specialist visits. Publicly funded drug costs were less with OCTANE ($20,015 vs. $24,465). OCTANE enrollment was not associated with improved OS (restricted mean survival time [standard error]: 1.50 (±0.03) vs. 1.44 (±0.03) years, log-rank p = 0.153), varying by tumor type. In five tumor types with ≥35 OCTANE patients, OS was similar in three (breast, colon, uterus, all p > 0.40), and greater in two (ovary, biliary, both p < 0.05). OCTANE was associated with greater clinical trial enrollment (25.4% vs. 9.5%, p < 0.001) and better end-of-life quality due to less death in hospital (10.2% vs. 16.4%, p = 0.003). Results were robust in sensitivity analysis. Interpretation: We found an increase in healthcare costs associated with multi-gene panel testing for advanced cancer treatment. The impact on OS was not significant, but varied across tumor types. OCTANE was associated with greater trial enrollment, lower publicly funded drug costs and fewer in-hospital deaths suggesting important considerations in determining the value of NGS panel testing for advanced cancers. Funding: T.P H holds a research grant provided by the Ontario Institute for Cancer Research through funding provided by the Government of Ontario (#IA-035 and P.HSR.158) and through funding of the Canadian Network for Learning Healthcare Systems and Cost-Effective 'Omics Innovation (CLEO) via Genome Canada (G05CHS).
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PURPOSE: Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor. PATIENTS AND METHODS: This first-in-human, multicenter, open-label, phase 1/2 study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase 2 dose (RP2D), and characterize the pharmacokinetics (PK); exploratory objectives included pharmacodynamics and efficacy. RESULTS: Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were grade 1/2. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The RP2D was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7 to 46.9), and the objective response rate as assessed by independent radiological review using Response Evaluation Criteria in Solid Tumors version 1.1 was 72%. CONCLUSIONS: Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT whose disease is not amenable to surgery.
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Antagonistas de Andrógenos/uso terapéutico , Neoplasias Encefálicas/secundario , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Neoplasias de las Glándulas Salivales/patología , Anciano , Antagonistas de Andrógenos/efectos adversos , Neoplasias Encefálicas/diagnóstico por imagen , Humanos , Masculino , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Patients presenting with multiple primary malignancies remain a growing challenge for physicians due to a lack of data for generalizable guidelines. Identification of driver mutations in carcinogenesis leads to the development of targeted treatment of many different cancer types, but its combination with other anti-cancer therapy is not well understood. We report a case of a 66-year-old woman who presented with triple-negative breast cancer, multifocal hormone receptor-positive breast cancer, primary epidermal growth factor receptor-mutated lung adenocarcinoma, possible primary lung adenocarcinoma of unspecified mutational status in the contralateral lung, and a solitary metastatic lesion in the brain from one of her primary cancers. She was treated with stereotactic radiosurgery and osimertinib in combination with carboplatin/nab-paclitaxel, doxorubicin/cyclophosphamide, and letrozole, with excellent clinical and radiographical response. We did not observe synergistic toxicity or unexpected adverse events from the treatment. To the best of our knowledge, this is the first report of concurrent osimertinib with these chemotherapy and hormonal therapy agents. As large-scale studies are difficult to conduct for these rare cases requiring exceptional treatment, it is important for physicians to build on the community's shared experience via case reports to better predict efficacy and safety of combining targeted agents with other conventional systemic treatments.
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Introduction: More complex research questions are being posed in early-phase oncology clinical trials, necessitating design strategies tailored to contemporary study objectives. This paper describes the proposed design of a Phase I trial concurrently evaluating the safety of a hematopoietic progenitor kinase-1 inhibitor (Agent A) as a single agent and in combination with an anti-PD-1 agent in patients with advanced malignancies. The study's primary objective was to concurrently determine the maximum tolerated dose (MTD) of Agent A with and without anti-PD-1 therapy among seven possible study dose levels. Methods: Our solution to this challenge was to apply a continual reassessment method shift model to meet the research objectives of the study. Results: The application of this method is described herein, and a simulation study of the design's operating characteristics is conducted. This work was developed through collaboration and mentoring between the authors at the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) annual AACR/ASCO Methods in Clinical Cancer Research Workshop. Conclusions: The aim of this manuscript is to highlight examples of novel design applications as a means of augmenting the implementation of innovative designs in the future and to demonstrate the flexibility of adaptive designs in satisfying modern design conditions. Although the design is presented using an investigation of Agent A with and without anti-PD-1 therapy as an illustrative example, the approach described is not specific to these agents and could be applied to other concurrent monotherapy and combination therapy studies with well-defined binary safety endpoints.
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PURPOSE: Standard-of-care therapies for metastatic renal cell carcinoma (mRCC) have greatly evolved. However, the availability of emerging options in global health care systems can vary. We sought to describe the integration and usage of systemic therapies for mRCC in Canada since 2011. METHODS: We included patients with mRCC enrolled in the Canadian Kidney Cancer Information System, a prospective cohort of patients from 14 Canadian academic centers, who received systemic therapy from January 1, 2011, to December 31, 2021. Patients were stratified by treatment era (cohort 1: 2011-2015, cohort 2: 2016-2021). Stacked bar charts were used to present treatment proportions; Sankey diagrams were used to show the evolution of treatment sequencing between the two cohorts. RESULTS: Four thousand one hundred seven patients were diagnosed with mRCC, of whom 2,752 (67%) received systemic therapy. Among these patients, mean age was 64 years, 74% were male, 75% had clear cell histology, and International Metastatic RCC Database Consortium risk classification was favorable, intermediate, and poor in 16%, 56%, and 28%, respectively. Utilization of immune checkpoint inhibition (ICI)-based treatments has increased in Canada and reflects global and local patterns of approval and adoption. The use of therapies after doublet ICI has mostly shifted toward vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs) that were previously used in first line with subsequent treatments reflecting approved and available agents after previous VEGF-TKI. Clinical trial participation among patients who received systemic therapy was 18% in first, 21% in second, and 24% in third line. CONCLUSION: In Canada's publicly funded health care system, availability of standard mRCC therapies broadly reflects access from government-funded clinical trials and compassionate access program sources. In an evolving therapeutic landscape, ongoing advocacy is required to continue to facilitate patient access to efficacious therapies.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Masculino , Persona de Mediana Edad , Femenino , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/uso terapéutico , Estudios Prospectivos , Canadá , Atención a la SaludRESUMEN
BACKGROUND: The introduction of novel hormonal agents (NHAs) such as abiraterone acetate (ABI) and enzalutamide (ENZ) for metastatic castration-resistant prostate cancer (mCRPC) was an important milestone given their survival benefits, tolerability, and ease of administration relative to taxane chemotherapies. This descriptive study sought to describe the utilization trends of ABI and ENZ in patients with mCRPC in the early years after their approval in the province of Quebec in Canada. METHODS: A retrospective population-based cohort was extracted from Quebec public healthcare administrative databases. The cohort included first-time users of NHAs (ABI or ENZ) from 2011 to 2016. The primary analyses aimed to describe the overall temporal trends (2011-2016) of NHA initiators by chemotherapy status (chemotherapy-naïve versus post-chemotherapy), and prescribing specialty (medical oncology versus urology versus others). RESULTS: The cohort comprised 2183 patients, with 1562 (72%) in the chemotherapy-naïve group and 621 (28%) in the post-chemotherapy group. While the majority of patients were post-chemotherapy NHA initiators in 2012, this proportion decreased over time and accounted for only 13% of NHA initiators by the end of 2016. Medical oncologists were the most frequent prescribers of NHAs (upwards of 60%) throughout 2012 but fell to 45% by the end of 2016. Conversely, the proportion of prescriptions by urologists increased from 22% in 2012 to 42% in 2016. CONCLUSION: Over time, there was an increasing proportion of (1) patients who initiated NHAs without prior chemotherapy treatment, (2) NHA prescribing by urologists, and (3) ENZ users. Taken together, this implies that the introduction of NHAs has altered the management of mCRPC and urologists quickly adopted NHAs into their practice.
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Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Estudios Retrospectivos , Quebec , Feniltiohidantoína/uso terapéuticoRESUMEN
BACKGROUND: The programmed cell death-1/programmed cell death ligand-1 (PD-L1) pathway, which plays a crucial role in cancer immune surveillance, is the target of several approved immunotherapeutic agents and is used as a predictive biomarker in some solid tumors. However, its use as a prognostic marker (i.e., regardless of therapy used) is not established clearly with available data demonstrating inconsistent prognostic impact of PD-L1 expression in solid tumors. METHODS: We conducted a systematic literature search of electronic databases and identified publications exploring the effect of PD-L1 expression on overall survival and/or disease-free survival. Hazard ratios were pooled in a meta-analysis using generic inverse-variance and random-effects modeling. We used the Deeks method to explore subgroup differences based on disease site, stage of disease, and method of PD-L1 quantification. RESULTS: One hundred and eighty-six studies met the inclusion criteria. Programmed cell death ligand-1 expression was associated with worse overall survival (hazard ratio 1.33, 95% confidence interval 1.26-1.39; p < 0.001). There was significant heterogeneity between disease sites (subgroup p = 0.002) with pancreatic, hepatocellular, and genitourinary cancers associated with the highest magnitude of adverse outcomes. Programmed cell death ligand-1 was also associated with worse overall disease-free survival (hazard ratio 1.19, 95% confidence interval 1.09-1.30; p < 0.001). Stage of disease did not significantly affect the results (subgroup p = 0.52), nor did the method of quantification via immunohistochemistry or messenger RNA (subgroup p = 0.70). CONCLUSIONS: High expression of PD-L1 is associated with worse survival in solid tumors albeit with significant heterogeneity among tumor types. The effect is consistent in early-stage and metastatic disease and is not sensitive to method of PD-L1 quantification. These data can provide additional information for the counseling of patients with cancer about prognosis.
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Antígeno B7-H1 , Neoplasias , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Humanos , Inmunoterapia/métodos , Ligandos , Neoplasias/genética , Neoplasias/terapia , PronósticoRESUMEN
BACKGROUND: The role of serum lymphocyte-based biomarkers, such as the neutrophil-to-lymphocyte (NLR), lymphocyte-to-monocyte (LMR), and platelet-to-lymphocyte (PLR) ratios, was previously studied in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy but remains underexplored in patients treated with trimodal therapy (TMT). OBJECTIVE: To analyze the impact of serum lymphocyte-based biomarkers on main oncological outcomes after TMT for MIBC. DESIGN SETTING AND PARTICIPANTS: A retrospective study, including 176 patients treated with TMT for nonmetastatic MIBC (cT2-4/cN0-2) between 2001 and 2017 at a tertiary academic center, was conducted. INTERVENTION: TMT, consisting of initial maximal transurethral resection of the bladder tumor, followed by radiotherapy with concurrent chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinicopathological characteristics, serum laboratory tests, and imaging reports were collected. NLR, LMR, and PLR were calculated before and at the end of TMT. Dynamic patterns of NLR, LMR, and PLR during TMT were studied. Multivariable regression models were performed to estimate the effect of these biomarkers on complete response (CR) to TMT and survival. RESULTS AND LIMITATIONS: The median age was 75 yr (interquartile range 66-82). Staging was cT2 in 156 (89%) and cN0 in 159 (90%) patients. A pretreatment NLR (pre-NLR) of ≥4.0 was independently associated with lower CR rates (odds ratio 0.32; p = 0.013). In addition, a pre-NLR of ≥4.0 was associated with worse cancer-specific survival (hazard ratio [HR] 1.88; p = 0.032) and overall survival (OS; HR 1.61; p = 0.033) together with other factors such as hydronephrosis, Eastern Cooperative Oncology Group performance status, and cT stage 3-4a. When both pre- and post-treatment variables were considered, an increase in NLR beyond 75% during TMT (HR 1.63; p = 0.035) was associated with worse OS. This study was limited by its retrospective design. CONCLUSIONS: A high pre-NLR value was independently associated with lower rates of CR and worse survival in MIBC patients undergoing TMT. Prospective validation is needed to implement NLR into clinical practice. PATIENT SUMMARY: In this study, we reported the oncological outcomes of patients with muscle-invasive bladder cancer treated with trimodal therapy. We found that the neutrophil-to-lymphocyte ratio, a cheap and available blood-derived biomarker, was associated with response to trimodal therapy and survival outcomes.
RESUMEN
BACKGROUND: Transthoracic echocardiography (TTE) is commonly used to assess cardiac morphology and function in cancer patients. The nature, distribution, and prevalence of significant echocardiographic abnormalities are unknown. We hypothesized that TTEs performed for cancer or cancer treatment indications, have a high prevalence of significant abnormalities (SA), including a large proportion of findings that may be overlooked by other imaging modalities. METHODS: All TTE studies performed in a tertiary cancer center over a six-month period, from January to June 2007, were reviewed. The TTEs were divided into studies performed for a cardiovascular indication (CV) and those done for a cancer-related indication (CA). Reports were classified as normal, mildly abnormal, and significantly abnormal (SA) based on findings. Abnormal findings' distributions were compared between indication groups. RESULTS: Three thousand nine hundred and twenty-four TTEs were performed and divided into either group CV (61.2%) or group CA (38.7%). The most common indication in the CV group was valvular diseases (29.9%). In the CA group, the majority of TTE were requested for evaluation during or after chemotherapy or radiation (94.7%). Around 41.9% of studies in group CV were classified as SA whereas 19.9% (P < 0.001) in the CA group were classified as such. The relative distributions of individual SA findings were compared between the indication groups and were not statistically different. CONCLUSIONS: One in five patients who had TTE studies for CA were found to have SA, and 81.5% of these may not have been found with other modalities. The TTE allows safe diagnosis of a wide range of abnormal findings that may be overlooked if alternative but less versatile modalities are used.