ABSTRACT
PURPOSE: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects women of African ancestry (WAA) and is often associated with poor survival. Although there is a high prevalence of TNBC across West Africa and in women of the African diaspora, there has been no comprehensive genomics study to investigate the mutational profile of ancestrally related women across the Caribbean and West Africa. METHODS: This multisite cross-sectional study used 31 formalin-fixed paraffin-embedded (FFPE) samples from Barbadian and Nigerian TNBC participants. High-resolution whole exome sequencing (WES) was performed on the Barbadian and Nigerian TNBC samples to identify their mutational profiles and comparisons were made to African American, European American and Asian American sequencing data obtained from The Cancer Genome Atlas (TCGA). Whole exome sequencing was conducted on tumors with an average of 382 × coverage and 4335 × coverage for pooled germline non-tumor samples. RESULTS: Variants detected at high frequency in our WAA cohorts were found in the following genes NBPF12, PLIN4, TP53 and BRCA1. In the TCGA TNBC cases, these genes had a lower mutation rate, except for TP53 (32% in our cohort; 63% in TCGA-African American; 67% in TCGA-European American; 63% in TCGA-Asian). For all altered genes, there were no differences in frequency of mutations between WAA TNBC groups including the TCGA-African American cohort. For copy number variants, high frequency alterations were observed in PIK3CA, TP53, FGFR2 and HIF1AN genes. CONCLUSION: This study provides novel insights into the underlying genomic alterations in WAA TNBC samples and shines light on the importance of inclusion of under-represented populations in cancer genomics and biomarker studies.
Subject(s)
Triple Negative Breast Neoplasms , Barbados , Cross-Sectional Studies , Female , Genomics , Humans , Mutation , Nigeria/epidemiology , Triple Negative Breast Neoplasms/epidemiology , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathologyABSTRACT
PURPOSE: Vasomotor symptoms (VMS) such as hot flashes and night sweats are common in breast cancer patients and can affect both quality of life and treatment adherence. However, there is limited practical data to guide clinicians in the optimal selection of therapeutic strategies. A survey of health care providers was performed to better understand perspectives and prescribing practices for managing this problem. METHODS: Canadian health care providers who treat patients with early stage breast cancer (EBC) participated in an anonymous electronic survey. Participants provided their perspectives on the prevalence and severity of VMS among patients with EBC, outlined their management strategies, and provided feedback on the perceived efficacy of interventions for VMS. RESULTS: Responses were received from 65 providers including breast oncologists (36/65, 55%) and nurses with oncology expertise (29/65, 45%). Seventy-seven percent of participants reported regularly asking patients about VMS, and most indicated that bothersome VMS occurred in the majority of patients. Health care providers cited hot flash severity and sleep disruption as the most important issues for patients. The most common first- and second-line interventions recommended were lifestyle modifications (n = 32/65, 49.2%) and pharmacologic strategies (n = 27/65, 41.5%), respectively. Most respondents felt that interventions, including pharmacologic, over-the-counter, and complementary therapies, were only "somewhat effective". Overall, half of respondents (n = 35/65, 54%) reported being "confident" in managing VMS. CONCLUSION: Given the variability of treatment recommendations, and health care provider uncertainty around the benefits of therapies for VMS, more 'real-world' trials are needed to optimize patient care.
Subject(s)
Breast Neoplasms , Menopause , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Canada , Female , Health Personnel , Hot Flashes/epidemiology , Hot Flashes/etiology , Hot Flashes/therapy , Humans , Quality of Life , Surveys and Questionnaires , SweatingABSTRACT
PURPOSE: Prior to docetaxel chemotherapy, incomplete dosing of steroid premedication is common. The lack of standardized steroid replacement strategies can lead to variability in care and delays in starting docetaxel. METHODS: This randomized trial compared physician-directed with fixed-dose dexamethasone. Patients who had missed at least one dose of steroid premedication were randomized to physician-directed replacement (any choice of steroid, dose or route) or to dexamethasone 8 mg oral before starting docetaxel. The primary outcome was time from randomization to starting docetaxel. Secondary outcomes included rates of acute and delayed hypersensitivity reactions, fluid retention and skin toxicity. RESULTS: Of 60 eligible patients, 30 (50%) and 30 (50%) were randomized to physician-directed and fixed-dose arms, respectively. Overall tumour types: breast (42 [70%]), gastrointestinal (7 [12%]), prostate (7 [12%]) and lung (3 [7%]). Dexamethasone was most commonly incompletely taken with cycles 1 (28 [48%]) and 2 (13 [22%]) of docetaxel. Seven different replacement strategies were used in the physician-choice arm. Patients in the fixed-dose arm received docetaxel a mean of 21.2 (95% CI for the difference is 2.1 to 44.6) minutes earlier than the physician-choice arm (p = 0.033 Wilcoxon rank sum test or p = 0.073 two-sample t test). Median time to docetaxel was 47.5 vs 61 min (mean 62.2 vs 83.4 min) by arm, respectively. No significant difference in toxicity rates was observed. CONCLUSION: While not meeting our predefined criteria of improving the time from randomization to starting docetaxel by 30 min, the fixed-dose replacement strategy reduced both the time to starting docetaxel and treatment variability. Fixed dosing with oral dexamethasone 8 mg should be the preferred standard of care. REGISTRATION: www.clinicaltrials.gov NCT02815319 REGISTRATION DATE: June 28, 2016.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Dexamethasone/therapeutic use , Docetaxel/therapeutic use , Drug Administration Schedule , Glucocorticoids/therapeutic use , Premedication/methods , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Dexamethasone/pharmacology , Docetaxel/pharmacology , Female , Glucocorticoids/pharmacology , Humans , Male , Middle AgedABSTRACT
OBJECTIVE: Delay in diagnosis of endometrial cancer may be associated with disease progression and impact management and outcomes. Social and cultural barriers influence recognition of symptoms and self-advocacy in seeking care. Associations between social determinants of health (SDH) and disease presentation have been shown in some settings. Our objective was to investigate these in Ontario's universal access system. METHODS: Endometrial cancer patients in Ontario diagnosed 2009-2017 were identified, and clinical, social and demographic information extracted from administrative databases using ICES (Institute of Evaluative Sciences) algorithms. SDH were quantified using previously validated marginalization indices for material deprivation, residential instability and ethnic concentration. Associations between SDH and disease stage were explored using logistic regression. RESULTS: 20,228 patients were identified. 73% of cancers were confined to the uterus. Stage distribution differed across marginalization quintiles (p < 0.001) with advanced disease found more frequently in highly marginalized patients: 29% vs. 25% (p < 0.001) for material deprivation, OR = 1.06/quintile (CI, 1.03-1.09); 29% vs. 24% (p < 0.001) for ethnic concentration, OR = 1.05/quintile (CI, 1.03-1.08); 30% vs. 27% (p < 0.001) for residential instability, OR = 1.02/quintile (CI, 1.0-1.05). Marginalization was persistently associated with advanced disease on multivariable analysis adjusted for age, comorbidity score, obesity and disease histology (OR = 1.05/quintile, CI 1.01-1.10, p = 0.03). CONCLUSIONS: Socioeconomic marginalization is associated with advanced disease at presentation among endometrial cancer patients in Ontario. Mediators of this association are likely multifactorial, and need to be further investigated in order to create opportunities for improved patient education and advocacy, redistribution of resources and the promotion of health equity.
Subject(s)
Delayed Diagnosis/statistics & numerical data , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/epidemiology , Social Determinants of Health/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Health Services Accessibility/statistics & numerical data , Humans , Middle Aged , National Health Programs/statistics & numerical data , Ontario , Retrospective Studies , Social Class , Young AdultABSTRACT
BACKGROUND: Previous studies assessing breast cancer risk in families with Lynch syndrome (LS) have yielded conflicting results. Furthermore, conclusions are limited by small sample size and few breast cancer outcomes. This study assesses breast cancer risk in a large prospectively followed LS cohort. METHODS: Pedigrees of 325 unrelated families with LS within the Familial Gastrointestinal Cancer Registry in Canada were examined for breast cancer diagnoses. Standardised incidence ratios (SIR) and lifetime cumulative incidence calculations were used to compare the incidence of breast cancer in mutation carriers with the general population. RESULTS: Forty-one mutation carriers diagnosed with breast cancer belonging to 34 unrelated families were identified. Mean age at diagnosis was 54 years. The mutation distribution among the LS patients with breast cancer was statistically different from those without breast cancer (p=0.015), reflecting the predominance of MSH2 mutations among affected patients (74%). Eighty-eight per cent of LS families with breast cancer met Amsterdam criteria, compared with 49% of LS families without breast cancer (p=0.03). Lifetime cumulative incidence of breast cancer in female MSH2 mutation carriers in our cohort was 22% (p<0.001). The SIR for breast cancer of female MSH2 mutation carriers in our cohort was 3.11 (95% CI 1.95 to 4.71). CONCLUSIONS: An increased risk of breast cancer in MSH2 mutation carriers was demonstrated in a Canadian familial cancer registry. Women with breast cancer often had a personal and family history of multiple LS-related malignancies. These results suggest a potential role for intensified breast cancer surveillance among women with LS.
Subject(s)
Breast Neoplasms/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , MutS Homolog 2 Protein/genetics , Canada/epidemiology , Female , Genetic Association Studies , Genetic Predisposition to Disease , Heterozygote , Humans , Incidence , Pedigree , RegistriesSubject(s)
Critical Care/statistics & numerical data , Emergency Service, Hospital/statistics & numerical data , Home Care Services/statistics & numerical data , Hospitalization/statistics & numerical data , Palliative Care/statistics & numerical data , Terminal Care/statistics & numerical data , Time Factors , Adolescent , Adult , Aged , Aged, 80 and over , Canada , Cohort Studies , Female , Humans , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
INTRODUCTION: Although virtual care (VC) has become an integral part of oncology care and healthcare delivery, clinicians' perspectives on and satisfaction with this modality are not well understood. METHODS: Using a National Network Forum framework and expert panel review, we developed a questionnaire to measure oncologists' satisfaction with VC. The questionnaire was distributed to Canadian oncologists through medical society email lists (n = 1541). We used a 5-point Likert scale to capture their responses, which included strongly disagree (1), disagree (2), undecided (3), agree (4), and strongly agree (5). RESULTS: A total of 61 oncologists and/or oncology trainees, of 768 (7.9%) who opened their email, completed questionnaires between October 2022 and January 2023. Every questionnaire item had a response rate greater than 98%. Seventy-two percent of the respondents were satisfied with VC. Oncologists who were less comfortable with technology were more likely to report lower levels of satisfaction (p < 0.001, Wilcoxon rank-sum). The questionnaire items that received the highest levels of agreement were related to VC reducing costs and improving access for patients and concerns about missing a diagnosis and assessing patients' functional status. The questionnaire items that received the greatest disagreement were related to VC improving access for patients with language barriers, VC being associated with time-savings for clinicians, improvements in clinical efficacy, and more readily available lab tests. CONCLUSIONS: Most of the oncologists surveyed are satisfied with VC; however, there are some concerns with VC that need to be addressed. Future research on optimizing VC should address clinicians' concerns, in addition to addressing the patient experience.
Subject(s)
Oncologists , Humans , Surveys and Questionnaires , Oncologists/psychology , Telemedicine , Female , Male , Canada , Medical Oncology/methods , Attitude of Health Personnel , Personal Satisfaction , Middle AgedABSTRACT
BACKGROUND: The prospective randomized PRECISE trial demonstrated that magnetic resonance imaging (MRI) with only targeted biopsy (TBx) was noninferior to systematic transrectal ultrasound biopsy (SBx) in the detection of International Society of Urological Pathology grade group (GG) ≥2 prostate cancer (PC). An unanswered question is the outcome for patients who avoided a biopsy because of negative MRI findings. OBJECTIVE: To explore the rate of PC diagnosis based on 2-yr MRI for PRECISE participants who had no biopsy and for patients who had a negative result or GG 1 on TBx in comparison to those with a negative result or GG 1 on SBx. DESIGN, SETTING, AND PARTICIPANTS: The PRECISE prospective trial was conducted at five Canadian academic centers. The present analysis was for trial participants who were not diagnosed with clinically significant PC (csPC) at baseline. Of 453 randomized patients, 146 were diagnosed with GG ≥2 at baseline and were excluded. Eligible patients for this study included 83 men from the MRI arm who had negative MRI findings and no biopsy, 120 from the overall cohort who had a negative SBx or TBx, and 72 from the overall cohort who were diagnosed with GG 1 disease. INTERVENTION: MRI at 2 yr in all men in the MRI and SBx arms and TBx for lesions with a Prostate Imaging-Reporting and Data System score of ≥3 or on the basis of clinical suspicion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the proportion of men diagnosed with GG ≥2 cancer. Secondary outcomes included the MRI outcome and the proportion of men diagnosed with GG 1 PC. RESULTS AND LIMITATIONS: Evaluable 2-yr MRI scans were available for 75 (56%) eligible patients in the MRI arm and 69 (49%) in the SBx arm. Of these patients, 55 (73%) in the MRI arm and 51 (67%) SBx arm had negative 2-yr MRI. Of the 76 patients in the SBx arm with 2-yr MRI, 16 (21%) had a biopsy, for which the result was negative in eight (10%), GG1 in two (2.6%), and GG ≥2 in six (7.9%) cases. Of the 75 men in the MRI arm with 2-yr MRI, eight (11%) were biopsied, for which the result was negative in four cases (5%) and GG ≥2 in the other four (5%). At 2 yr, including baseline biopsy results, 116/221 (52.5%) in the MRI arm and 113/204 (55%) in the SBx arm were free of GG ≥2 disease, treatment, death from any cause, or progression (OR 1.08; p = 0.66). CONCLUSIONS: After 2-yr follow-up including MRI for patients in both arms of PRECISE, there was no difference in the rate of csPC diagnosis between the MRI and SBx groups, even though 38% of men in the MRI group avoided an initial biopsy. PATIENT SUMMARY: The PRECISE trial compared systematic biopsy of the prostate to a strategy of magnetic resonance imaging (MRI) with targeted biopsy of any lesions suspicious for cancer on the scan. After 2 years of follow-up that included 2-year MRI with or without biopsy in both groups, there was no difference in the rate of diagnosis of significant cancer, even though 38% of men in the initial MRI arm avoided an initial biopsy, and 30% avoided biopsy altogether. The PRECISE trial is registered on ClinicalTrials.gov as NCT02936258.
ABSTRACT
BACKGROUND: Randomized controlled trials (RCTs) are a critical component of evidence-based medicine and the evolution of patient care. However, the costs of conducting a RCT can be prohibitive. A promising approach toward reduction of costs and lessening of the burden of intensive and lengthy patient follow-up is the use of routinely collected healthcare data (RCHD), commonly called real-world data. We propose a scoping review to identify existing RCHD case definitions of breast cancer progression and survival and their diagnostic performance. METHODS: We will search MEDLINE, EMBASE, and CINAHL to identify primary studies of women with either early-stage or metastatic breast cancer, managed with established therapies, that evaluated the diagnostic accuracy of one or more RCHD-based case definitions or algorithms of disease progression (i.e., recurrence, progression-free survival, disease-free survival, or invasive disease-free survival) or survival (i.e., breast-cancer-free survival or overall survival) compared with a reference standard measure (e.g., chart review or a clinical trial dataset). Study characteristics and descriptions of algorithms will be extracted along with measures of the diagnostic accuracy of each algorithm (e.g., sensitivity, specificity, positive predictive value, negative predictive value), which will be summarized both descriptively and in structured figures/tables. DISCUSSION: Findings from this scoping review will be clinically meaningful for breast cancer researchers globally. Identification of feasible and accurate strategies to measure patient-important outcomes will potentially reduce RCT budgets as well as lessen the burden of intensive trial follow-up on patients. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework ( https://doi.org/10.17605/OSF.IO/6D9RS ).
Subject(s)
Breast Neoplasms , Female , Humans , Breast Neoplasms/therapy , Breast Neoplasms/drug therapy , Disease-Free Survival , Review Literature as Topic , Systematic Reviews as TopicABSTRACT
PURPOSE: This study documents the creation of automated, longitudinal, and prospective data and analytics platform for breast cancer at a regional cancer center. This platform combines principles of data warehousing with natural language processing (NLP) to provide the integrated, timely, meaningful, high-quality, and actionable data required to establish a learning health system. METHODS: Data from six hospital information systems and one external data source were integrated on a nightly basis by automated extract/transform/load jobs. Free-text clinical documentation was processed using a commercial NLP engine. RESULTS: The platform contains 141 data elements of 7,019 patients with newly diagnosed breast cancer who received care at our regional cancer center from January 1, 2014, to June 3, 2022. Daily updating of the database takes an average of 56 minutes. Evaluation of the tuning of NLP jobs found overall high performance, with an F1 of 1.0 for 19 variables, with a further 16 variables with an F1 of > 0.95. CONCLUSION: This study describes how data warehousing combined with NLP can be used to create a prospective data and analytics platform to enable a learning health system. Although upfront time investment required to create the platform was considerable, now that it has been developed, daily data processing is completed automatically in less than an hour.
Subject(s)
Breast Neoplasms , Learning Health System , Humans , Female , Breast Neoplasms/diagnosis , Breast Neoplasms/epidemiology , Breast Neoplasms/therapy , Prospective Studies , Natural Language Processing , Data WarehousingABSTRACT
PURPOSE: There is strong interest from patients, researchers, the pharmaceutical industry, medical journal editors, funders of research, and regulators in sharing clinical trial data for secondary analysis. However, data access remains a challenge because of concerns about patient privacy. It has been argued that synthetic data generation (SDG) is an effective way to address these privacy concerns. There is a dearth of evidence supporting this on oncology clinical trial data sets, and on the utility of privacy-preserving synthetic data. The objective of the proposed study is to validate the utility and privacy risks of synthetic clinical trial data sets across multiple SDG techniques. METHODS: We synthesized data sets from eight breast cancer clinical trial data sets using three types of generative models: sequential synthesis, conditional generative adversarial network, and variational autoencoder. Synthetic data utility was evaluated by replicating the published analyses on the synthetic data and assessing concordance of effect estimates and CIs between real and synthetic data. Privacy was evaluated by measuring attribution disclosure risk and membership disclosure risk. RESULTS: Utility was highest using the sequential synthesis method where all results were replicable and the CI overlap most similar or higher for seven of eight data sets. Both types of privacy risks were low across all three types of generative models. DISCUSSION: Synthetic data using sequential synthesis methods can act as a proxy for real clinical trial data sets, and simultaneously have low privacy risks. This type of generative model can be one way to enable broader sharing of clinical trial data.
Subject(s)
Breast Neoplasms , Privacy , Humans , Female , Breast Neoplasms/diagnosis , Breast Neoplasms/therapy , Medical Oncology , Research PersonnelABSTRACT
OBJECTIVE: The aggressive triple-negative breast cancer (TNBC) subtype disproportionately affects women of African ancestry across the diaspora, but its frequency across Africa has not been widely studied. This study seeks to estimate the frequency of TNBC among African populations. DESIGN: Systematic review and meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. DATA SOURCES: PubMed, EMBASE, African Journals Online and Web of Science were searched on 25 April 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included studies that use breast cancer tissue samples from indigenous African women with sample size of eligible participants ≥40 and full receptor status for all three receptors (oestrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2)) reported. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias using the modified assessment tool by Hoy et al. (2012) for prevalence studies. A random-effects meta-analysis was performed, and data were pooled using the inverse-variance method and logit transformation. Pooled frequencies were reported with 95% CIs calculated with the Clopper-Pearson method and heterogeneity quantified with I2 statistic. GRADE assessed the certainty of the evidence. RESULTS: 1808 potentially eligible studies were identified of which 67 were included in the systematic review and 60 were included in the meta- analysis. Pooled TNBC frequency across African countries represented was estimated to be 27.0%; 95% CI: 24.0% to 30.2%, I2=94%. Pooled TNBC frequency was highest across West Africa, 45.7% (n=15, 95% CI: 38.8% to 52.8%, I2=91%) and lowest in Central Africa, 14.9% (n=1, 95% CI: 8.9 % to 24.1%). Estimates for TNBC were higher for studies that used Allred guidelines for ER/PR status compared with American Society of Clinical Oncology(ASCO)/College of American Pathologists(CAP) guidelines, and for studies that used older versions of ASCO/CAP guidelines for assessing HER2 status. Certainty of evidence was assessed to be very low using GRADE approach. CONCLUSION: TNBC frequency was variable with the highest frequency reported in West Africa. Greater emphasis should be placed on establishing protocols for assessing receptor status due to the variability among studies.
Subject(s)
Triple Negative Breast Neoplasms , Africa/epidemiology , Female , Humans , Population Groups , Prevalence , Receptors, Estrogen/metabolism , Triple Negative Breast Neoplasms/epidemiology , Triple Negative Breast Neoplasms/metabolismABSTRACT
BACKGROUND: Response rate (RR) alone may be insensitive to drug activity in phase II trials. Early progressive disease (EPD) could improve sensitivity as well as increase stage I stopping rates. This study compares the previously developed dual endpoint stopping rule (DESR), which incorporates both RR and EPD into a two-stage, phase II trial, with rules using only RR. METHODS: Stopping rules according to the DESR were compared with studies conducted under the Fleming (16 trials) or Gehan (23 trials) designs. The RR hypothesis for the DESR was consistent with the comparison studies (ralt = 0.2, rnul = 0.05). Two parameter sets were used for EPD rates of interest and disinterest respectively (epdalt, epdnul): (0.4, 0.6) and (0.3, 0.5). RESULTS: Compared with Fleming, the DESR was more likely to allow stage two of accrual and to reject the null hypothesis (Hnul) after stage two, with rejection being more common with EPD parameters (0.4, 0.6) than (0.3, 0.5). Compared with Gehan, both DESR parameter sets accepted Hnul in 15 trials after stage I compared with 8 trials by Gehan, with consistent conclusions in all 23 trials after stage II. CONCLUSIONS: The DESR may reject Hnul when EPD rates alone are low, and thereby may improve phase II trial sensitivity to active, cytostatic drugs having limited response rates. Conversely, the DESR may invoke early stopping when response rates are low and EPD rates are high, thus shortening trials when drug activity is unlikely. EPD parameters should be chosen specific to each trial.
Subject(s)
Clinical Trials, Phase II as Topic , Endpoint Determination/methods , Neoplasms/drug therapy , Humans , Pharmaceutical Preparations , Research Design , Sample Size , Treatment OutcomeABSTRACT
BACKGROUND: Response rate (RR), the most common early means of assessing oncology drugs, is not suitable as the sole endpoint for phase II trials of drugs which induce disease stability but not regression. Time to progression (TTP) may be more sensitive to such agents, but induces recruitment delays in multistage studies. Early progressive disease (EPD) is the earliest signal of time to progression, but is less intuitive to investigators, To study drugs with unknown anti-tumour effect, we designed the Combination Stopping Rule (CSR), which allows investigators to establish a hypothesis using RR and TTP, while the program also employs early progressive disease (EPD) to assess for drug inactivity during the first stage of study accrual. METHODS: A computer program was created to generate stopping rules based on specified error rates, trial size, and RR and median TTP of interest and disinterest for a two-stage phase II trial. Rules were generated for stage II such that the null hypothesis (H(nul)) was rejected if either RR or TTP met desired thresholds, and accepted if both did not. Assuming an exponential distribution for progression, EPD thresholds were determined based on specified TTP values. Stopping rules were generated for stage I such that Hnul was accepted and the study stopped if both RR and EPD were unacceptable. RESULTS: Patient thresholds were generated for RR, median TTP, and EPD which achieved specified error rates and which allowed early stopping based on RR and EPD. For smaller proportional differences between interesting and disinteresting values of RR or TTP, larger trials are required to maintain alpha error, and early stopping is more common with a larger first stage. CONCLUSION: Stopping rules are provided for phase II trials for drugs which have either a desirable RR or TTP. In addition, early stopping can be achieved using RR and EPD.
Subject(s)
Antineoplastic Agents/therapeutic use , Clinical Trials, Phase II as Topic/methods , Medical Oncology/methods , Neoplasms/drug therapy , Clinical Trials, Phase II as Topic/standards , Disease Progression , Endpoint Determination/methods , Endpoint Determination/standards , Humans , Medical Oncology/standards , Neoplasms/pathology , Research Design/standards , Software , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Adjuvant zoledronate is widely used in patients with early stage breast cancer (EBC), but its optimal duration and dosing interval is still unknown. While a single-dose of zoledronate can improve bone density for many years, a proper evaluation of its effects on breast cancer-related outcomes would require a large trial. In this pilot study we evaluated the feasibility of performing such a trial. METHODS: Eligible patients with EBC were randomised to receive either one dose of zoledronate or 7 doses (6-monthly dosing for 3 years). Feasibility was assessed by a combination of primary outcomes including: activation of at least 6 Ontario sites within a year, active participation (i.e. approaching eligible patients for study participation) of at least half of the medical oncologists, and enrolment of at least 100 patients across all sites within 9 months of the sixth site being activated. RESULTS: All 6 sites were activated within 1 year and of 47 medical oncologists, 27 (57%) approached patients. Between November 2018 and April 2020, 211 eligible patients were randomised, 106 (50.2%) to a single dose of zoledronate and 105 (49.8%) to 6-monthly dosing. Baseline characteristics of randomised patients included; median age 59 (range 36-88), ER and/or PR positive (85%), Her2 positive (23%), menopausal status (premenopausal [19%], perimenopausal [6.7%] and postmenopausal [74%]) and 74% received neo/adjuvant chemotherapy. CONCLUSIONS: All study feasibility endpoints were met in this trial comparing alternative schedules for adjuvant zoledronate. We will now seek funding for performing a larger efficacy trial.Trial registration: NCT03664687.
ABSTRACT
Multiparametric assays for risk stratification are widely used in the management of both node negative and node positive hormone receptor positive invasive breast cancer. Recent data from multiple sources suggests that different tests may provide different risk estimates at the individual patient level. The TEAM pathology study consists of 3284 postmenopausal ER+ve breast cancers treated with endocrine therapy Using genes comprising the following multi-parametric tests OncotypeDx®, Prosigna™ and MammaPrint® signatures were trained to recapitulate true assay results. Patients were then classified into risk groups and survival assessed. Whilst likelihood χ2 ratios suggested limited value for combining tests, Kaplan-Meier and LogRank tests within risk groups suggested combinations of tests provided statistically significant stratification of potential clinical value. Paradoxically whilst Prosigna-trained results stratified Oncotype-trained subgroups across low and intermediate risk categories, only intermediate risk Prosigna-trained cases were further stratified by Oncotype-trained results. Both Oncotype-trained and Prosigna-trained results further stratified MammaPrint-trained low risk cases, and MammaPrint-trained results also stratified Oncotype-trained low and intermediate risk groups but not Prosigna-trained results. Comparisons between existing multiparametric tests are challenging, and evidence on discordance between tests in risk stratification presents further dilemmas. Detailed analysis of the TEAM pathology study suggests a complex inter-relationship between test results in the same patient cohorts which requires careful evaluation regarding test utility. Further prognostic improvement appears both desirable and achievable.
ABSTRACT
Importance: Magnetic resonance imaging (MRI) with targeted biopsy is an appealing alternative to systematic 12-core transrectal ultrasonography (TRUS) biopsy for prostate cancer diagnosis, but has yet to be widely adopted. Objective: To determine whether MRI with only targeted biopsy was noninferior to systematic TRUS biopsies in the detection of International Society of Urological Pathology grade group (GG) 2 or greater prostate cancer. Design, Setting, and Participants: This multicenter, prospective randomized clinical trial was conducted in 5 Canadian academic health sciences centers between January 2017 and November 2019, and data were analyzed between January and March 2020. Participants included biopsy-naive men with a clinical suspicion of prostate cancer who were advised to undergo a prostate biopsy. Clinical suspicion was defined as a 5% or greater chance of GG2 or greater prostate cancer using the Prostate Cancer Prevention Trial Risk Calculator, version 2. Additional criteria were serum prostate-specific antigen levels of 20 ng/mL or less (to convert to micrograms per liter, multiply by 1) and no contraindication to MRI. Interventions: Magnetic resonance imaging-targeted biopsy (MRI-TB) only if a lesion with a Prostate Imaging Reporting and Data System (PI-RADS), v 2.0, score of 3 or greater was identified vs 12-core systematic TRUS biopsy. Main Outcome and Measures: The proportion of men with a diagnosis of GG2 or greater cancer. Secondary outcomes included the proportion who received a diagnosis of GG1 prostate cancer; GG3 or greater cancer; no significant cancer but subsequent positive MRI results and/or GG2 or greater cancer detected on a repeated biopsy by 2 years; and adverse events. Results: The intention-to-treat population comprised 453 patients (367 [81.0%] White, 19 [4.2%] African Canadian, 32 [7.1%] Asian, and 10 [2.2%] Hispanic) who were randomized to undergo TRUS biopsy (226 [49.9%]) or MRI-TB (227 [51.1%]), of which 421 (93.0%) were evaluable per protocol. A lesion with a PI-RADS score of 3 or greater was detected in 138 of 221 men (62.4%) who underwent MRI, with 26 (12.1%), 82 (38.1%), and 30 (14.0%) having maximum PI-RADS scores of 3, 4, and 5, respectively. Eighty-three of 221 men who underwent MRI-TB (37%) had a negative MRI result and avoided biopsy. Cancers GG2 and greater were identified in 67 of 225 men (30%) who underwent TRUS biopsy vs 79 of 227 (35%) allocated to MRI-TB (absolute difference, 5%, 97.5% 1-sided CI, -3.4% to ∞; noninferiority margin, -5%). Adverse events were less common in the MRI-TB arm. Grade group 1 cancer detection was reduced by more than half in the MRI arm (from 22% to 10%; risk difference, -11.6%; 95% CI, -18.2% to -4.9%). Conclusions and Relevance: Magnetic resonance imaging followed by selected targeted biopsy is noninferior to initial systematic biopsy in men at risk for prostate cancer in detecting GG2 or greater cancers. Trial Registration: ClinicalTrials.gov Identifier: NCT02936258.
Subject(s)
Magnetic Resonance Imaging, Interventional , Multiparametric Magnetic Resonance Imaging , Prostatic Neoplasms , Biopsy , Canada , Humans , Image-Guided Biopsy/methods , Magnetic Resonance Imaging , Male , Prospective Studies , Prostate/diagnostic imaging , Prostate/pathology , Prostatic Neoplasms/pathology , UltrasonographyABSTRACT
PURPOSE: The standard of care in management of patients with good performance status and unresectable stage III non-small cell lung cancer (NSCLC) therapy is concurrent chemoradiation. Newer techniques such as intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) are replacing 3-dimensional conformal radiation (3DCRT) despite low-quality evidence of improved outcomes. We used population-based data to examine survival outcomes by radiation technique. METHODS AND MATERIALS: A population-based retrospective cohort of patients with stage III NSCLC treated with concurrent chemoradiation from 2009 to 2017 in Ontario were identified. The primary outcome was a comparison of overall survival among 3DCRT, IMRT, and VMAT, calculated using the Kaplan-Meier method and compared using log-rank test. Cox regression was used to investigate effect of radiation type on overall survival adjusted for other covariates. RESULTS: A total of 3872 patients were treated with 3DCRT (n = 1178), IMRT (n = 1847), or VMAT (n = 847). A decline in 3DCRT and increase in VMAT use were observed over time. Median survival in months was 21.2 (95% confidence interval [CI], 20.0-22.8) for 3DCRT, 23.9 (95% CI, 22.3-25.6) for IMRT, and 24.9 (95% CI, 22.5-27.4) for VMAT, but these differences were not statistically significant (P = .06). CONCLUSIONS: Our study demonstrates that survival is not compromised in patients receiving IMRT or VMAT (compared with 3DCRT). Thus, given the potential dosimetric advantages associated with these techniques, VMAT and IMRT are recommended for the management of patients with stage III NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/radiotherapy , Chemoradiotherapy/methods , Lung Neoplasms/pathology , Lung Neoplasms/radiotherapy , Adolescent , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Staging , Radiotherapy Dosage , Radiotherapy, Intensity-Modulated , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: The initial report from the ASIST trial showed little benefit from targeted biopsy for men on active surveillance (AS) for prostate cancer. Data after 2-yr follow-up are now available for analysis. OBJECTIVE: To determine if there was a difference in the AS failure rate in a 2-yr follow-up period among men undergoing magnetic resonance imaging (MRI) before initial confirmatory biopsy (CBx) compared to those who did not. DESIGN, SETTING, AND PARTICIPANTS: This is the 2-yr post-CBx follow-up for the ASIST trial, a prospective, randomized, multicenter, open-label study for men with Gleason grade group (GG) 1 cancer eligible for AS. Patients were randomized to CBx with 12-core systematic sampling or MRI with systematic and targeted sampling. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients with GGâ¯≤â¯1 on CBx were followed for 2â¯yr and had MRI and biopsy at that time point. Patients failed AS if they were no longer under AS because of grade progression, clinical progression, subject choice, clinical judgment, treatment, or lost to follow-up. Clinically significant cancer (CSC) was defined as GGâ¯≥â¯2. RESULTS AND LIMITATIONS: In total, 259 men underwent CBx, 132 in the non-MRI and 127 in the MRI arm. After biopsy, 101 men in the non-MRI arm (76%) and 98 in the MRI arm (77%) continued AS. There were fewer men with AS failures in the MRI (19/98, 19%) compared to the non-MRI group (35/101, 35%; pâ¯=⯠0.017). At 2-yr biopsy there were fewer men with CSC in the MRI arm (9.9%, 8/81) than in the non-MRI arm (23%, 17/75; pâ¯=⯠0.048). Significant differences in AS failure rates were detected across the three centers in the MRI arm only (4.2% [2/48] vs 17% [4/24] vs 27% [7/26]; pâ¯=⯠0.019). CONCLUSIONS: Baseline MRI before CBx during AS results in 50% fewer AS failures and less grade progression over 2â¯yr. The center where MRI and targeted biopsy is performed may influence AS failure rates. PATIENT SUMMARY: The ASIST trial randomized 273 men on active surveillance with low-grade prostate cancer diagnosed within the last year to systematic biopsy or magnetic resonance imaging (MRI) with systematic and targeted biopsy. The initial report showed little benefit from targeted biopsy. However, after 2â¯yr of follow-up we found that baseline MRI before confirmatory biopsy resulted in 50% fewer failures of surveillance and less progression to higher-grade cancer. This confirms the value of MRI in men on surveillance. This study is registered at ClinicalTrials.gov (NCT01354171).
Subject(s)
Magnetic Resonance Imaging , Prostate/diagnostic imaging , Prostate/pathology , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Aged , Biopsy/methods , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , Prostatic Neoplasms/therapy , Time Factors , Watchful WaitingABSTRACT
INTRODUCTION: Indiscriminate ordering of Oncotype DX (ODX) is expensive and of poor value to patients, physicians, and health care providers. The 3 Magee equations, Gage Algorithm, and University of Tennessee predictive algorithm all use standard clinicopathologic data to provide surrogate ODX scores. In this hypothesis-generating study, we evaluated whether these prognostic scores could be used to identify patients unlikely to benefit from additional ODX testing. PATIENTS AND METHODS: Retrospective data was collected from 302 patients with invasive ductal breast cancer and available ODX scores. Additional data was available for: Magee equations 1 (212 patients), 2 (299 patients), 3 (212 patients), Gage Algorithm (299 patients), and University of Tennessee predictive algorithm (286 patients). ODX scores were banded according to the TAILORx results. RESULTS: Correlation with ODX scores was between 0.7 and 0.8 (Gage), 0.8 and 0.9 (Magee 2, University of Tennessee predictive algorithm), and > 0.9 (Magee 1 and 3). Magee 3 was the most robust and is proposed as a screening tool: for patients aged ≤ 50 years, ODX testing would be not required if the Magee 3 score was < 14 or ≥ 20; for those aged > 50 years, ODX would not be required if the Magee 3 score was < 18 or ≥ 26. Using these cut-offs, 110 (51.9%) of 212 patients would be deemed as not requiring ODX testing, and 109 (99.1%) of110 patients would be appropriately managed. CONCLUSIONS: Use of all formulae, and the Magee 3 equation in particular, are proposed as possible screening tools for ODX testing, resulting in significantly reduced frequency of ODX testing. This requires validation in other populations.