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Objectives: The development of novel cancer therapies, including immuno-oncology agents, has increased interest in reconstructed individual patient data (IPD) based restricted mean survival time (RMST) analyses. Additionally, reconstructed IPD-based RMST is recommended in cost-effectiveness analyses when original trial IPD are not available. Nevertheless, recently concerns regarding potential bias of reconstructed-IPD RMST have been presented, because reconstructed-IPD RMSTs have not been validated and previous validation endpoints may not capture the entire Kaplan-Meier (KM) curve, especially the "tail." Our study aims to validate the recommended method of IPD reconstruction by comparing reconstructed IPD- and original trial IPD-based RMST., Methods: Canadian Cancer Trials Group trials from 1990 to 2017 were included. Overall survival and progression-free survival IPD were reconstructed based on published KM curves using the Guyot method. Analysts were blinded to original trial IPD. RMST was calculated at 1 year and over the entire KM curve. Reconstructed-IPD and original trial-IPD (gold-standard) RMSTs were compared for accuracy and predictive error via mean deviation, mean absolute error (MAE), mean percentage bias, and Bland-Altman plots and across KM curve quality (vector traced or bitmapped)., Results: We identified 39 trials. The mean deviation, MAE, and mean percentage bias of RMST between the reconstructed IPD and original trial IPD were small. In particular, the mean deviation was -0.01 months and -0.04 months, MAE was 0.19 months and 0.24 months, and mean percentage bias was 0.82% and 0.84% in overall survival KM curves in control and experimental arms, respectively. Accuracy was generally not associated with KM curve quality., Conclusions: RMST derived from reconstructed IPD displayed excellent accuracy and predictive error compared with the gold standard. Reconstructed IPD could be used to calculate RMST in lieu of original trial IPD, to facilitate decision making for clinicians, researchers, and policy makers., (Copyright © 2022. Published by Elsevier Inc.)

Background: Use of value framework thresholds in the design of clinical trials may increase the proportion of randomized controlled trials that identify clinically meaningful advances for patients. Existing frameworks have not been applied to the research output of a cooperative cancer trials group. We apply value frameworks to the randomized controlled trial output of the Canadian Cancer Trials Group (CCTG)., Methods: Statistical design, study characteristics, and results of all published phase III trials of CCTG were abstracted. We applied the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) and American Society of Clinical Oncology Net Health Benefit to study results and the statistical power calculations to identify the proportion of all trials that were designed to detect a substantial clinical benefit., Results: During 1979 to 2017, CCTG published 113 phase III trials; 52.2% (59 of 113) of these trials were positive. One-half (50.4%, 57 of 113) of the trials were conducted in the palliative setting. In 37.2% (42 of 113) of trials, the primary endpoint was overall survival; disease-free survival or progression-free survival was used in 38.9% (44 of 113) of trials. The ESMO-MCBS could be applied to the power calculation for 69 trials; 73.9% (51 of 69) of these trials were designed to detect an effect size that could meet ESMO-MCBS thresholds for substantial benefit. Among the 51 positive trials for which the ESMO-MCBS could be applied, 41.1% (21 of 51) met thresholds for substantial benefit., Conclusions: Most CCTG phase III trials were designed to detect clinically meaningful differences in outcome, although less than one-half of positive trials met the threshold for substantial benefit. Application of value frameworks to the design of clinical trials is practical and may improve research efficiency and treatment options for patients., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In a prospective study, we sought to determine acceptability of linkage of administrative and clinical trial data among Canadian patients and Research Ethics Boards (REBs). The goal is to develop a more harmonized approach to data, with potential to improve clinical trial conduct through enhanced data quality collected at reduced cost and inconvenience for patients. On completion of the original LY.12 randomized clinical trial in lymphoma (NCT00078949), participants were invited to enrol in the Long-term Innovative Follow-up Extension (LIFE) component. Those consenting to do so provided comprehensive identifying information to facilitate linkage with their administrative data. We prospectively designed a global assessment of this innovative approach to clinical trial follow-up including rates of REB approval and patient consent. The pre-specified benchmark for patient acceptability was 80%. Of 16 REBs who reviewed the research protocol, 14 (89%) provided approval; two in Quebec declined due to small patient numbers. Of 140 patients invited to participate, 115 (82%, 95% CI 76 to 88%) from across 9 Canadian provinces provided consent and their full name, date of birth, health insurance number and postal code to facilitate linkage with their administrative data for long-term follow-up. Linkage of clinical trial and administrative data is feasible and acceptable. Further collaborative work including many stakeholders is required to develop an optimized secure approach to research. A more coordinated national approach to health data could facilitate more rapid testing and identification of new effective treatments across multiple jurisdictions and diseases from diabetes to COVID-19.

Thrombotic microangiopathy (TMA) is a life-threatening clinical syndrome characterized by hemolytic anemia, thrombocytopenia, and microvascular thrombosis, resulting in ischemia and organ damage. Multiple myeloma (MM) is a neoplasm arising from clonal plasma cells within the bone marrow. The treatment frequently includes multi-agent immunochemotherapy, often with the use of proteasome inhibitors (PIs) such as bortezomib, carfilzomib, or ixazomib. There are increasing reports of TMA in association with PI exposure. This review summarizes the epidemiology, pathogenesis, and diagnosis of PI-related drug-induced TMA. We will outline the definition and diagnosis of TMA and explore an important cause of hemolysis in patients with MM: drug-induced TMA after PI exposure, an increasingly recognized therapeutic complication. This will be emphasized through the description of 3 novel cases of TMA. These illustrative cases occurred after treatment with high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone as part of the MCRN003/MYX1 phase II clinical trial (NCT02597062) in relapsed MM., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Background: Economic evaluations are an integral component of many clinical trials. Costs used in those analyses are based on the prices of branded drugs when they first enter the market. The effect of genericization on the cost-effectiveness (ce) or cost-utility (cu) of an intervention is unknown because economic analyses are rarely updated using the costs of generic drugs., Methods: We re-examined the ce or cu of regimens previously evaluated in Canadian Cancer Trials Group (cctg) studies that included prospective economic evaluations and where genericization has occurred or is anticipated in Canada. We incorporated the new costs of generic drugs to characterize changes in ce or cu. We also determined acceptable cost levels of generic drugs that would make regimens reimbursable in a publicly funded health care system., Results: The four randomized controlled trials included (representing 1979 patients) were cctg br.10 (early lung cancer, adjuvant vinorelbine-cisplatin vs. observation, n = 172), cctg br.21 (metastatic lung cancer, erlotinib vs. placebo, n = 731), cctg co.17 (metastatic colon cancer, cetuximab vs. best supportive care, n = 557), and cctg ly.12 (relapsed or refractory lymphoma, gemcitabine-dexamethasone-cisplatin vs. cytarabine-dexamethasone-cisplatin, n = 619). Since the initial publication of those trials, the genericization of vinorelbine, erlotinib, cetuximab, and cisplatin has taken place or is expected in Canada. Costs of generics improved the ces and cus of treatment significantly. For example, genericization of erlotinib ($1460.25 per 30 days) resulted in an incremental cost-effectiveness ratio (icer) of $45,746 per life-year gained compared with $94,638 for branded erlotinib. Likewise, genericization of cetuximab ($275.80 per 100 mg) produced an icer of $261,126 per quality-adjusted life-year (qaly) gained compared with $299,613 for branded cetuximab. Decreases in the cost of generic cetuximab to $129.39 and $63.51 would further improve the icer to $150,000 and $100,000 per QALY respectively., Conclusions: Genericization of a costly oncology drug can modify the ce and cu of a regimen significantly. Failure to revisit economic analyses with the costs of generics could be a missed opportunity for funding bodies to optimize value-based allocation of health care resources. At current levels, the costs of generics might not be sufficiently low to sustain publicly funded health care systems., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

Background: Clinical trials are important but extremely costly. Utilization of routinely collected administrative data may simplify and enhance clinical trial data collection., Purpose: The aim of this study was to test the feasibility of use of administrative databases in Ontario, Canada, for long-term clinical trial follow-up, specifically (a) to determine whether limited patient identifiers held by the Canadian Cancer Trials Group can be used to probabilistically link with individuals in the Institute for Clinical Evaluative Sciences databases and if so, (b) the level of concordance between the two data sets., Methods: This retrospective study was conducted through collaboration of established health service (Institute for Clinical Evaluative Sciences) and clinical trial (Canadian Cancer Trials Group) research groups in the province of Ontario, Canada, where healthcare is predominantly funded by the government. Adults with pre-treated metastatic colorectal cancer previously enrolled in the Canadian Cancer Trials Group CO.17 and CO.20 randomized phase III trials were included, limited to those in Ontario. The main outcomes were rate of successful probabilistic linkage and concordance of survival data, stated a priori., Results: Probabilistic linkage was successful in 266/293 (90.8%) participants. In those patients for whom linkage was successful, the Canadian Cancer Trials Group (trial) and the Institute for Clinical Evaluative Sciences (administrative) data sets were concordant with regard to the occurrence of death during the period of clinical trial follow-up in 206/209 (98.6%). Death was recorded in the Institute for Clinical Evaluative Sciences, but not the Canadian Cancer Trials Group, for 57 cases, where the event occurred after the clinical trial cut-off dates. The recorded date of death matched closely between both databases. During the period of clinical trial conduct, administrative databases contained details of hospitalizations and emergency room visits not captured in the clinical trial electronic database., Conclusion: Prospective use of administrative data could enhance clinical trial data collection, both for long-term follow-up and resource utilization for economic analyses and do so less expensively than current primary data collection. Recording a unique identifier (e.g. health insurance number) in trial databases would allow deterministic linkage for all participants.

In 1962, Pete Seeger recorded "The Ballad of Doctor Dearjohn" about Canadian Medicare and the Saskatchewan doctors' strike of the same year. How had this New Yorker, recently relieved of a jail sentence, learned of Medicare in the distant prairie province? And why was his song never released? This paper traces the ballad's fortunes through the papers of composer Earl Robinson (University of Washington) and the archives of the American Medical Association. It is situated in the historiography of folk revival and the expatriate adventures of artistic Americans persecuted in the McCarthy era.

Background: Personal health information, including diagnoses and hospital admissions, is routinely collected in administrative databases. Patients enrolling on clinical trials consent to separate collection and storage of their personal health information. We evaluated patient preferences for linking long-term data from administrative databases with clinical trials., Methods: Adults with cancer attending outpatient clinics at 3 Ontario hospitals were surveyed about their willingness, when faced with the hypothetical scenario of participating in a clinical trial, to provide potentially identifying information such as initials and date of birth to facilitate long-term research access to normally deidentified publicly collected databases., Results: Of 569 patients surveyed, 335 (59%) were women, 452 (79%) were white, 385 (68%) had a post-secondary education, and 386 (68%) had never participated in a clinical trial. Median age in the group was 59 years. Most participants (93%, cohort 1) would allow long-term access to their information and allow personal information to be used to match clinical trial with administrative data. At the time of clinical trial closure, two thirds of participants (68%, cohort 2) preferred to make additional clinical information available through linkage with administrative databases, and 8 (9%) preferred to have no further information made available to researchers. No significant differences were found in the subset of patients who were part of a clinical trial and those who had never participated ( p = 0.65)., Interpretation: Almost all patients would allow a clinical trial research team to access their confidential information, providing a more comprehensive assessment of an intervention's long-term risks and benefits., Competing Interests: We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

Background: Cost avoidance occurs when, because of provision of a drug therapy [drug cost avoidance (dca)] or a pathology test [pathology cost avoidance (pca)] during trial participation, health care payers need not pay for standard treatments or testing. The aim of our study was to estimate the total dca and pca for Canadian patients enrolled in relevant phase iii trials conducted by the ncic Clinical Trials Group., Methods: Phase iii trials that had completed accrual and resulted in dca or pca were identified. The pca was calculated based on the number of patients screened and the test cost. The dca was estimated based on patients randomized, the protocol dosing regimen, drug cost, median dose intensity, and median duration of therapy. Costs are presented in Canadian dollars. No adjustment was made for inflation., Results: From 1999 to 2011, 4 trials (1479 patients) resulted in pca and 17 trials (3195 patients) resulted in dca. The total pca was estimated at $4,194,849, which included testing for KRAS ($141,058), microsatellite instability ($18,600), and 21-gene recurrence score ($4,035,191). The total dca was estimated at $27,952,512, of which targeted therapy constituted 43% (five trials). The combined pca and dca was $32,147,361., Conclusions: Over the study period, trials conducted by the ncic Clinical Trials Group resulted in total cost avoidance (pca and dca) of approximately $7,518 per patient. Although not all trials lead to cost avoidance, such savings should be taken account when the financial impact of conducting clinical research is being considered.

Background and Aim: The primary aim of this study was to determine whether randomised phase 2 (RP2) trials predict phase 3 trial outcome better than single arm phase 2 (SAP2) studies. Although theoretical superiority of RP2 trials has been postulated, no empiric studies have been conducted., Methods: Published phase 3 trials testing systemic cancer therapy were identified through a Medline search. Those of superiority design, which cited phase 2 trials supporting the experimental arm, were included. Trial design and outcome details were extracted. Statistical analysis was performed using the Generalized Estimating Equation method correlating phase 2 features with phase 3 outcome, accounting for any phase 3 duplication., Results: Of 189 eligible phase 3 trials, 18.5% were in haematological malignancies and 81.5% in solid tumors. The primary outcome was positive in 79 (41.8%). These were supported by 336 phase 2 trials (range 1-9 per phase 3 trial) including 66 RP2 trials. Positive phase 2 outcome, randomised or not, correlated with positive phase 3 outcome (p=0.03). RP2 studies were not superior to SAP2 studies at predicting phase 3 study success. Phase 2 trial features not predictive of phase 3 outcome included primary endpoint, sponsorship, sample size, similarity in patient population and therapy., Conclusions: RP2 studies were not superior to SAP2 trials at predicting phase 3 study success. Further research into phase 2 trial design is required given the added resources required to conduct RP2 studies and the lack of empiric evidence supporting superiority over single arm studies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Exemestane, a steroidal aromatase inhibitor, reduced invasive breast cancer incidence by 65% among 4,560 postmenopausal women randomly assigned to exemestane (25 mg per day) compared with placebo in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MAP.3 (Mammary Prevention 3) trial, but effects on quality of life (QOL) were not fully described., Patients and Methods: Menopause-specific and health-related QOL were assessed by using the four Menopause-Specific Quality of Life Questionnaire (MENQOL) domains and the eight Medical Outcomes Study Short Form Health Survey (SF-36) scales at baseline, 6 months, and yearly thereafter. MENQOL questionnaire completion was high (88% to 98%) in both groups at each follow-up visit. Change scores for each MENQOL and SF-36 scale, calculated at each assessment time relative to baseline, were compared by using the Wilcoxon rank-sum test. Clinically important worsened QOL was defined as a MENQOL change score increase of more than 0.5 (of 8) points and an SF-36 change score decrease of more than 5 (of 100) points from baseline., Results: Exemestane had small negative effects on women's self-reported vasomotor symptoms, sexual symptoms, and pain, which occurred mainly in the first 6 months to 2 years after random assignment. However, these changes represented only a small excess number of women being given exemestane with clinically important worsening of QOL at one time or another; specifically, 8% more in the vasomotor domain and 4% more each in the sexual domain and for pain. No other between-group differences were observed. Overall, slightly more women in the exemestane arm (32%) than in the placebo arm (28%) discontinued assigned treatment., Conclusion: Exemestane given for prevention has limited negative impact on menopause-specific and health-related QOL in healthy postmenopausal women at risk for breast cancer.

We hypothesized that exemestane (EXE) would reduce mammographic breast density and have unique effects on biomarkers of bone and lipid metabolism. Healthy postmenopausal women were randomized to EXE (25 mg daily) or placebo (PLAC) for 12 months and followed for a total of 24 months. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms and secondary endpoints were changes in serum lipid levels, bone biomarkers, and bone mineral density (BMD). Ninety-eight women were randomized (49 to EXE; 49 to PLAC) and 65 had PD data at baseline and 12 months. Among women treated with EXE, PD was not significantly changed from baseline at 6, 12, or 24 months and was not different from PLAC. EXE was associated with significant percentage increase from baseline in N-telopeptide at 12 months compared with PLAC. No differences in percent change from baseline in BMD (lumbar spine and femoral neck) were observed between EXE and PLAC at either 12 or 24 months. Patients on EXE had a significantly larger percent decrease in total cholesterol than in the PLAC arm at 6 months and in HDL cholesterol at 3, 6, and 12 months. No significant differences in percent change in LDL or triglycerides were noted at any time point between the two treatment arms. EXE administered for 1 year to healthy postmenopausal women did not result in significant changes in mammographic density. A reversible increase in the bone resorption marker N-telopeptide without significant change in bone specific alkaline phosphatase or BMD during the 12 months treatment period and 1 year later was noted. Changes in lipid parameters on this trial were modest and reversible.

Background: MA.17 evaluated letrozole or placebo after 5 years of tamoxifen and showed significant improvement in disease-free survival (DFS) for letrozole [hazard ratio (HR) 0.57, P = 0.00008]. The trial was unblinded and placebo patients were offered letrozole., Patients and Methods: An intent-to-treat analysis of all outcomes, before and after unblinding, on the basis of the original randomization was carried out., Results: In all, 5187 patients were randomly allocated to the study at baseline and, at unblinding, 1579 (66%) of 2383 placebo patients accepted letrozole. At median follow-up of 64 months (range 16-95), 399 recurrences or contralateral breast cancers (CLBCs) (164 letrozole and 235 placebo) occurred. Four-year DFS was 94.3% (letrozole) and 91.4% (placebo) [HR 0.68, 95% confidence interval (CI) 0.55-0.83, P = 0.0001] and showed superiority for letrozole in both node-positive and -negative patients. Corresponding 4-year distant DFS was 96.3% and 94.9% (HR 0.80, 95% CI 0.62-1.03, P = 0.082). Four-year overall survival was 95.1% for both groups. The annual rate of CLBC was 0.28% for letrozole and 0.46% for placebo patients (HR 0.61, 95% CI 0.39-0.97, P = 0.033)., Conclusions: Patients originally randomly assigned to receive letrozole within 3 months of stopping tamoxifen did better than placebo patients in DFS and CLBC, despite 66% of placebo patients taking letrozole after unblinding.

This multicenter trial examined the efficacy and safety of dextromethorphan (DM) as an enhancer of analgesia and modulator of opioid tolerance in cancer patients with pain. Eligible patients were randomized to slow-release morphine plus DM or slow-release morphine plus placebo. The initial DM dose was 60 mg four times daily for seven days, with an increase to 120 mg four times daily, if tolerated, for another seven days. During the study, patients recorded medications and scores for pain, nausea, drowsiness, and insomnia. Sixty-five patients were randomized. Although average pain scores (12.6 vs. 15.8), number of breakthrough doses (9 vs. 11.3), and change in total morphine consumption (550.9 mg vs. 597.1mg) were less in the DM group than placebo group, the differences were not statistically significant (P=0.31-0.33). Side-effect scores were not statistically significantly different. Dizziness was greater in the DM (58%) than placebo (36%) group. This study showed a statistically nonsignificant enhancement of analgesia or modulation of opioid tolerance in cancer patients with pain when DM was added to morphine. Participants receiving the DM also had more toxicity, particularly dizziness. This toxicity and the limited evidence of effect do not support the use of DM to enhance opioid analgesia or to modulate opioid tolerance in cancer patients.

Background: Aromatase inhibitors are widely employed in the adjuvant treatment of early stage breast cancer. The impact of aromatase inhibitors has not been established in ethnic minority women., Patients and Methods: The purpose of this study was to evaluate the impact of letrozole on minority women in MA.17, a placebo-controlled trial of letrozole following 5 years of tamoxifen in postmenopausal women with early stage breast cancer. Retrospective comparison of disease-free survival (DFS), side effects, and mean changes in quality of life (QOL) scores from baseline between Caucasian and minority women was performed., Results: Minority (n = 352) and Caucasian (n = 4708) women were analyzed. There was no difference between these groups in DFS (91.6% versus 92.4% respectively for 4 year DFS). Letrozole, compared with placebo, significantly improved DFS for Caucasians (HR = 0.55; P < 0.0001) but not for minorities (HR = 1.39; P = 0.53). Among women who received letrozole, minorities had a significantly lower incidence of hot flashes (49% versus 58%; P = 0.02), fatigue (29% versus 39%; P = 0.005), and arthritis (2% versus 7%; P = 0.006) compared with Caucasians. Mean change in QOL scores for minority women who received letrozole demonstrated improved mental health at the 6-month assessment (P = 0.02) and less bodily pain at the 12-month assessment (P = 0.046)., Conclusion: Letrozole improved DFS in Caucasians but a definite benefit in minority women has not yet been demonstrated. Minority women tolerated letrozole better than Caucasians in terms of toxicity. These results need confirmation in other trials of aromatase inhibitors.

Purpose: MA.17 was a double-blind placebo-controlled trial involving 5187 postmenopausal women that established letrozole to be of value in reducing recurrence of breast cancer when given in the extended adjuvant therapy setting after about 5 years of tamoxifen. Analyses were conducted to examine the relationships between duration of treatment on MA.17 and outcomes., Methods: The final MA.17 database that included all events up to the date of unblinding of the study was interrogated. A non-parametric kernel smoothing method was used to estimate the hazard rates for disease-free survival (DFS), distant DFS (DDFS) and overall survival (OS) at 6, 12, 24, 36 and 48 months of follow-up and the hazard ratios (HRs) of letrozole to placebo were determined. The trend in HRs over time was tested based on a Cox model with a time-dependent covariate., Results: Considering all patients, HRs for events in DFS and DDFS progressively decreased over time, favoring letrozole, with the trend being significant (p < 0.0001 and p = 0.0013, respectively) whereas the trend for OS was not significant. Considering the 2360 patients with node-positive status, the HRs for DFS, DDFS and OS all decreased over time with tests for trend all showing significance (p = 0.0004, 0.0005 and 0.038, respectively). Considering the 2568 patients with node-negative status, the HRs for DFS decreased over time with the test for trend being significant (p = 0.027) whereas the HRs for DDFS and OS showed no significant change over time., Conclusion: These analyses suggest that, at least out to about 48 months, longer duration of letrozole treatment is associated with greater benefit in the extended adjuvant therapy setting.

Cancer is one of the leading causes of mortality in the developed world, and prognostic assessment of cancer patients is indispensable in medical care. Medical researchers are accustomed to using regression models to predict patient outcomes. Neural networks have been proposed as an alternative with great potential. Nonetheless, empirical evidence remains lacking to support the application of this technique as the appropriate method to investigate cancer prognosis. Utilizing data on patients from two National Cancer Institute of Canada clinical trials, we compared predictive accuracy of neural network models and logistic regression models on risk of death of limited-stage small-cell lung cancer patients. Our results suggest that neural network and logistic regression models have similar predictive accuracy. The distributions of individual predicted probabilities are very similar. On occasion, however, the prediction pairs are quite different, suggesting that they do not always give the same interpretations of the same variables.

Purpose: To evaluate the impact of letrozole compared with placebo after adjuvant tamoxifen on quality of life (QOL) in the MA.17 trial., Methods: Patients completed the Short Form 36-item Health Survey (SF-36) and the Menopause Specific Quality of Life Questionnaire (MENQOL) at baseline, 6 months, and annually. Mean change scores from baseline were compared between groups for summary measures and domains. A response analysis compared the proportion of patients who demonstrated an important change in QOL., Results: Of 5,187 randomly assigned women in the trial, 3,612 (69.9%) participated in the QOL substudy: 1,799 were allocated to placebo and 1,813 were allocated to letrozole. No differences were seen between groups in mean change scores from baseline for the SF-36 physical and mental component summary scores at 6, 12, 24, and 36 months. Small (< 0.2 standard deviations) but statistically significant differences in mean change scores from baseline were seen for the SF-36 domains of physical functioning (12 months), bodily pain (6 months) and vitality (6 and 12 months), and the MENQOL vasomotor (6, 12, and 24 months) and sexual domains (12 and 24 months). On the response analysis, a significant difference was seen between groups for the bodily pain domain (percentage of patients reporting a worsening of QOL, 47% placebo v 51% letrozole; P = .009) and the vasomotor domain (22% placebo v 29% letrozole; P = .001)., Conclusion: Letrozole did not have an adverse impact on overall QOL. Small effects were seen in some domains consistent with a minority of patients experiencing changes in QOL compatible with a reduction in estrogen synthesis.

Background: Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial., Methods: Postmenopausal women completing 5 years of tamoxifen treatment were randomly assigned to a planned 5 years of letrozole (n = 2593) or placebo (n = 2594). The primary endpoint was disease-free survival (DFS); secondary endpoints included distant disease-free survival, overall survival, incidence of contralateral tumors, and toxic effects. Survival was examined using Kaplan-Meier analysis and log-rank tests. Planned subgroup analyses included those by axillary lymph node status. All statistical tests were two-sided., Results: After a median follow-up of 30 months (range = 1.5-61.4 months), women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm (DFS: hazard ratio [HR] for recurrence or contralateral breast cancer = 0.58, 95% confidence interval [CI] = 0.45 to 0.76; P < .001; distant DFS: HR = 0.60, 95% CI = 0.43 to 0.84; P = .002). Overall survival was the same in both arms (HR for death from any cause = 0.82, 95% CI = 0.57 to 1.19; P = .3). However, among lymph node-positive patients, overall survival was statistically significantly improved with letrozole (HR = 0.61, 95% CI = 0.38 to 0.98; P = .04). The incidence of contralateral breast cancer was lower in women receiving letrozole, but the difference was not statistically significant. Women receiving letrozole experienced more hormonally related side effects than those receiving placebo, but the incidences of bone fractures and cardiovascular events were the same., Conclusion: Letrozole after tamoxifen is well-tolerated and improves both disease-free and distant disease-free survival but not overall survival, except in node-positive patients.

Although there is abundant information about the independent effects of estrogen receptor (ER) and progesterone receptor (PR) on outcomes of breast cancer, comparatively little is known about the impact of joint (ER+PR+, ER+PR-, ER-PR+ and ER-PR-) ERPR expression. The purpose of this study was to evaluate the prognostic relevance of joint ERPR expression to progression free survival (PFS). Data from 710 patients with a median follow-up of 119 months has been analyzed retrospectively. Our results indicate that the effect of the ER+PR+ phenotype on PFS was significantly time-dependent (p<0.0001); favorable in the first 3 years of follow-up (HR=0.67, p=0.0175) compared to ER-PR- phenotype, but unfavorable during the later follow-up period (HR=2.89, p=0.0006). Similar patterns were also observed for ER+PR- and ER-PR+ phenotypes, but the effect did not reach statistical significance. In the tree-based analysis, we found that, among patients with more than 4 positive nodes and age greater than 40, those with ER-PR+ tumors had the worst PFS ( p=0.025), and among patients with 1--3 positive nodes and stage of T1 and T2, those with ER+PR- had the worst outcome ( p=0.006). Our results demonstrate that failure to recognize the time-varying effect of the steroid hormonal receptors can obscure their role in the prognosis of breast cancer. We also provide more evidence to support the concept that ER-PR+ is a real group representing a distinct clinical entity.

Purpose: We looked at the value of three preclinical cancer models, the in vitro human cell line, the human xenograft, and the murine allograft, to examine whether they are reliable in predicting clinical utility., Experimental Design: Thirty-one cytotoxic cancer drugs were selected. Literature was searched for drug activity in Phase II trials, human xenograft, and mouse allografts in breast, non-small cell lung, ovary, and colon cancers. Data from the National Cancer Institute Human Tumor Cell Line Screen were used to calculate drug in vitro preclinical activity for each cancer type. Phase II activity versus preclinical activity scatter plot and correlation analysis was conducted for each model, by tumor type (disease-oriented approach), using one tumor type as a predictor of overall activity in the other three tumor types combined (compound-oriented approach) and for all four tumor types together., Results: The in vitro cell line model was predictive for non-small cell lung cancer under the disease-oriented approach, for breast and ovarian cancers under the compound-oriented approach, and for all four tumor types together. The mouse allograft model was not predictive. The human xenograft model was not predictive for breast or colon cancers, but was predictive for non-small cell lung and ovarian cancers when panels of xenografts were used., Conclusions: These results suggest that under the right framework and when panels are used, the in vitro cell line and human xenograft models may be useful in predicting the Phase II clinical trial performance of cancer drugs. Murine allograft models, as used in this analysis, appear of limited utility.

Purpose: To evaluate the enrollment of older patients (>/= 65 years) in Canadian cancer treatment trials and compare accrual of older patients in Canada and the United States., Patients and Methods: A retrospective analysis of the number of older patients enrolled in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) treatment trials between 1993 and 1996 was performed. These rates were compared with the corresponding rates in the general population of patients who were >/= 65 years old and had cancer, obtained from Statistics Canada, and those published by the Southwest Oncology Group (SWOG) in the United States., Results: Between 1993 and 1996, 4,174 patients were enrolled onto 69 NCIC CTG trials of 16 tumor types. Older patients accounted for 22% of trial enrollees, compared with 58% of the Canadian population with cancer. This discrepancy existed in all cancer types except for multiple myeloma. The percentages of older patients enrolled were also analyzed by study type: 15% in adjuvant trials, 25% in metastatic trials, 29% in investigational new drug trials, 24% in phase I trials, and 21% in supportive care trials. The overall proportion of older patients enrolled onto Canadian trials (22%) was slightly lower than that in SWOG trials (25%)., Conclusion: Age remains a barrier for accrual onto cancer treatment trials, even when reimbursement is not an issue. Strategies to overcome this barrier, including the implementation of trials specifically tailored to patients aged >/= 65 years, are prudent in light of our aging population.

Purpose: This multi-institutional Phase III randomized study compared 10 Gy single-fraction radiotherapy (RT) with 20 Gy in five fractions in the palliation of thoracic symptoms from lung cancer., Methods and Materials: The primary end point was palliation of thoracic symptoms at 1 month after RT, evaluated by a patient-completed daily diary card. Secondary end points included quality of life, toxicity, and survival., Results: Most (69%) of 230 patients randomized had locally advanced disease unsuitable for curative treatment. The treatment arms were well balanced with respect to the known prognostic factors. At 1 month after RT, no difference was found in symptom control between the two arms, as judged by the daily diary scores. The changes in the scores on the Lung Cancer Symptom Scale indicated that the fractionated RT (five fractions) group had greater improvement in symptoms related to lung cancer (p = 0.009), pain (p = 0.0008), ability to carry out normal activities (p = 0.037), and better global quality of life (p = 0.039). The European Organization for Research and Treatment of Cancer QLQ-C30 scores showed that patients receiving five fractions had a greater improvement in scores with respect to pain (p = 0.04). No significant difference was found in treatment-related toxicity. Patients who received five fractions survived on average 2 months longer (p = 0.0305) than patients who received one fraction., Conclusion: Although the two treatment strategies provided a similar degree of palliation of thoracic symptoms, the difference in survival between the two study arms was of a clinically relevant magnitude.

Purpose: The previously described practice guidelines development cycle follows an iterative model in which recommendations are reached by a process that incorporates practitioners at all phases. A key feature is the separation of the evidence-based systematic review and the generation of recommendations from policy decisions surrounding implementation. This article describes how this implementation phase has evolved in Ontario and how implementation has affected the guidelines process., Methods: The development of the New Drug Funding Program in Ontario and the appointment of a policy advisory committee (PAC) to make funding recommendations were reviewed. The decision-making framework of the PAC is described in this article., Results: The PAC has had to address a number of issues in making funding recommendations. These issues have included dealing with evidence arising solely from phase II versus phase III trials, using economic information, and involving community representatives in its deliberations. Its activities have had a substantial impact on the practice guidelines initiative., Conclusion: It is possible to integrate an evidence-based, practitioner-driven approach to clinical guideline development with a funding program that takes policy considerations into account. However, even though these two roles are conceptually separate, the needs of the funding program have inevitably had an impact on the guidelines process.

Case reports and case series have identified putative risk factors for the development of bilateral massive adrenal hemorrhage (BMAH) in humans. The anatomy and physiology of the adrenal gland allow development of a model to fit the pathophysiology behind these risk factors. Until now, these risk factors were not systematically tested using analytical epidemiologic studies. A case-control study was undertaken using sources of cases and controls from multiple teaching hospitals in Ontario, Canada. The results of multivariate logistic regression indicated that thrombocytopenia (odds ratio [OR] = 14.6, 95% confidence intervals [CI] = 3.0-70.1, p < 0.001), heparin exposure of any route or type beyond 3 days (4-6 days: OR = 17.0, CI = 1.9-154.6; > 6 days: OR = 33.5, CI = 4.3-262.6; p < 0.001), and sepsis (OR = 6.3, CI = 1.2-32.2, p = 0.019) were most strongly and independently associated with development of BMAH. Another weaker positive association included invasive radiologic procedure (OR = 4.4, CI = 0.9-22.1, p = 0.055). Neither major surgery or duration of hospitalization were independent risk factors. Although coronary artery disease and possibly diabetes and hypertension appeared to be markers for lower risk of BMAH, this may be a result of bias introduced by using hospital controls ("Berkson bias"), as the effect was not explained by a protective effect of vasoactive medications. Thus, a picture of the high-risk patient should include a patient who has been treated with heparin (any route or type) beyond 3 days and has had thrombocytopenia (not necessarily induced by heparin) during the course of an illness. If the setting includes unexplained abdominal, chest, or back pain; fever; confusion; hypotension or shock; abrupt anemia; or electrolyte disorders, clinicians should not hesitate to cover empirically with lifesaving glucocorticoids while awaiting results of confirmatory tests.

Background: Ovarian cancer is the leading cause of death from gynecological malignancies and the fourth most frequent fatal malignancy in women. Despite improved surgical techniques as many as 20% of women with early stage disease will eventually relapse and die from their disease. The post-operative management of these women remains controversial. Here we present the long term follow-up data of our previously published study, as well as the incidence of second primary malignancies in these women., Patients and Methods: Two hundred fifty-seven eligible patients with stage I, IIA 'high risk' ovarian carcinoma and IIB, IIIO (disease confined to pelvis) were randomized to either whole abdominal radiotherapy 2.250 rads in ten fractions (107 patients), melphalan 8 mg/m2/d x 4 weeks x 18 courses (106 patients) or intraperitoneal chromic phosphate 10-20 mCi (44 patients). All patients were initially treated with pelvic radiotherapy., Results: Overall survival estimates at 10 years were: 45% in the whole abdominal radiotherapy arm; 49% in the melphalan arm and 50% in the intraperitoneal chromic phosphate arm (P = 0.30). Relapse-free survival estimates at 10 years were: 50% in the whole abdominal radiotherapy arm, 62% in the melphalan arm and 51% in the chromic phosphate arm (P = 0.147). Long term follow-up has not demonstrated a significant difference between treatment arms. Second primary malignancies developed in 29 women (11%) after 2,229 person years of follow-up. This compares to 18.7 second primary malignancies which would have been expected in this group of age-matched controls and was statistically significant (P = 0.018). There was no significant difference in the total number of second primary malignancies between treatment arms. Melphalan appeared to be associated with an increased risk of developing leukemia/myelodysplastic syndrome compared to the whole abdominal radiotherapy arm (P = 0.06)., Conclusions: Long-term follow-up has not demonstrated a significant difference in overall or disease free survival between treatment arms. An excess of second primary malignancies (35%) was observed suggesting that lifelong surveillance is required in this population. Further research with newer treatment programs are needed to improve the cure rates in this population.

Objective: To determine the value of visible retinal emboli as a diagnostic "test" for the detection of hemodynamically significant carotid artery stenosis in the setting of acute retinal artery occlusion., Methods: A cross-sectional diagnostic accuracy study was performed in a tertiary North American center, with the results of the dichotomous diagnostic test (the presence or absence of visible retinal emboli) being placed against the dichotomous outcome of the presence or absence of hemodynamically significant carotid artery stenosis (defined as > or = 60%, or < 60%, carotid artery stenosis on either side)., Results: Forty-eight (18.7%) of our 256 patients had hemodynamically significant carotid artery stenosis. The sensitivity and specificity of retinal emboli for the detection of hemodynamically significant carotid artery stenosis were 39% and 68%, respectively. The presence of a visible retinal embolus generated a likelihood ratio of 1.24 (95% confidence interval, 0.84-1.86). This value corresponds to a patient with a pretest probability of 50% having a posttest probability of 55.3%. The absence of a visible retinal embolus generated a likelihood ratio of 0.88 (95% confidence interval, 0.68-1.15)., Conclusions: The presence of a visible retinal embolus is a poor diagnostic test for the detection of hemodynamically significant carotid artery stenosis in the setting of acute retinal artery occlusion. Accordingly, the presence of an embolus should not influence the decision to perform carotid Doppler ultrasonography in patients with acute retinal arterial occlusion.