Publications by authors named "Michelle B Nadler"

9 Publications

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Fragility index of trials supporting approval of anti-cancer drugs in common solid tumours.

Cancer Treat Rev 2021 Mar 16;94:102167. Epub 2021 Feb 16.

Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Electronic address:

Background: The Fragility Indexquantifies the reliability of positive trials by estimating the number of events, which would change statistically significant results to non-significant results.

Methods: We identified randomized trials supporting drug approvals by the US FDA between 2009 and 2019 in lung, breast, prostate, and colon cancers and in melanoma. We reconstructed survival tablesand calculated the number of events, which would result in a non-significant result for the primary endpoint. The FI was then compared to the number of patients in each trial who withdrew consent or were lost to follow-up. Regression analyses were used to explore associations between RCT characteristics and FI and trials in which FI was lower or equal to number of participants who withdrew consent or were lost to follow-up.

Results: Among 81 RCTs, the median FI was 28. The median number of patients who withdrew consent or were lost to follow up was 27. FI was equal or lower than the number of patients who withdrew consent or were lost to follow-up in 47 trials (58%). There was a modest increase in FI over time (p = 0.02). Trials with overall survival as the primary endpoint (p = 0.006) and those in the palliative setting (p < 0.001) had lower FI. There was no association with trial sample size or duration of follow-up.

Findings: Statistical significance of RCTs in common solid tumours can be reversed often with a small number of additional events. Post-approval RCTs or real-world data analyses should be performed to ensure results of registration trials are robust.
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http://dx.doi.org/10.1016/j.ctrv.2021.102167DOI Listing
March 2021

Development of an evidence-informed recommendation guide to facilitate physical activity counseling between oncology care providers and patients in Canada.

Transl Behav Med 2021 Feb 16. Epub 2021 Feb 16.

School of Kinesiology and Health Studies, Queen's University, Kingston, ON, Canada.

Decision support aids help reduce decision conflict and are reported as acceptable by patients. Currently, an aid from the American College of Sports Medicine exists to help oncology care providers advise, assess, and refer patients to physical activity (PA). However, some limitations include the lack of specific resources and programs for referral, detailed PA, and physical function assessments and not being designed following an international gold standard (Appraisal of Guidelines for Research and Evaluation [AGREE] II). This study aimed to develop a recommendation guide to facilitate PA counseling by assessing the risk for PA-related adverse events and offering a referral to an appropriate recommendation. Recommendation guide development followed AGREE II, and an AGREE methodologist was consulted. Specifically, a stakeholder group of oncology care providers and cancer survivors were engaged to develop the assessment criteria for comorbidities, PA levels, and physical function. Assessment criteria were developed from published PA interventions, consultations with content experts, and targeted web-based searches for cancer-specific PA programs. Feedback on the recommendation guide was solicited from stakeholders and external reviewers with relevant knowledge and clinical experience. Independent AGREE methodologists appraised the development process. The recommendation guide is a five-page document, including a preamble, assessment criteria for absolute contraindications to PA, comorbidities, and PA/functional capacity with a list of appropriate resources. Independent AGREE methodologists rated the development process as strong and recommended the guide for use. The recommendation guide has the potential to facilitate PA counseling between oncology care providers and cancer survivors, thus, potentially impacting PA behavior.
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http://dx.doi.org/10.1093/tbm/ibaa127DOI Listing
February 2021

Increasing Referrals of Patients With Gastrointestinal Cancer to a Cancer Rehabilitation Program: A Quality Improvement Initiative.

JCO Oncol Pract 2021 Apr 8;17(4):e593-e602. Epub 2020 Dec 8.

University of Toronto, ON, Canada.

Background: People with cancer are at risk for initial, late, and long-term effects of cancer and its treatments. Cancer rehabilitation (CR) focuses on prevention/treatment of these sequelae and optimization of physical, social, and vocational functioning. Our center has a multidisciplinary impairment-driven outpatient CR program, but referrals of patients with GI cancer were low.

Aims: We aimed (for 2019, relative to 2018) (1) to increase CR referrals of patients with GI cancer by 50% and (2) to increase the proportion of referrals coming from oncologists. Balancing measures included inappropriate referrals and cancellations.

Methods: A rapid cycle improvement approach was used to optimize GI referrals to the CR program. Barriers to CR referral were identified through a literature review and informal interviews of GI clinicians. Barriers included (a) knowledge of CR program existence, (b) awareness of the referral process, (c) time, and (d) lack of CR program exposure. The team used Plan-Do-Study-Act (PDSA) cycles every 2 months from January to December 2019 to address barriers. A p-chart was used to analyze the results.

Results: PDSA cycles included CR program advertisement, a presentation to GI staff, nurse-led patient identification, patient-facing posters, and clinician thank-you emails. The p-chart showed a 100% relative increase in referral numbers and an improvement in the percentage of patients referred by oncologists from 51% to 75%. There was no significant change in inappropriate referrals or cancellations.

Conclusion: Through PDSA cycles, we improved the total number of patients with GI cancer and percentage referred by an oncologist to a CR program. Future work will assess sustainability.
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http://dx.doi.org/10.1200/OP.20.00432DOI Listing
April 2021

Comparison of treatment-related adverse events of different Cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer: A network meta-analysis.

Cancer Treat Rev 2020 Nov 17;90:102086. Epub 2020 Aug 17.

Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Palbociclib, ribociclib and abemaciclib have all been approved in combination with endocrine therapy in hormone-receptor positive, HER2 negative metastatic breast cancer. While the efficacy of these drugs appears similar, differences in safety and tolerability are apparent.

Methods: We searched PubMed and ASCO, ESMO and SABCS proceedings to identify randomized trials of palbociclib, ribociclib and abemaciclib. Data on common and serious adverse events (AE) were extracted for each approved drug. The odds ratio for each AE and the hazard ratio for progression-free survival were calculated relative to endocrine therapy alone. A network meta-analysis was then performed for each endocrine therapy backbone (aromatase inhibitor (AI) or fulvestrant) to compare ribociclib and abemaciclib to palbociclib.

Results: 8 trials were included in the analysis and comprised 2799 patients receiving cyclin-dependent kinase 4/6 inhibitors palbociclib: 873 patients; ribociclib: 1153 patients; abemaciclib: 773 patients. In 5 trials (1524 patients), the endocrine therapy backbone was an AI and in 3 trials (1275 patients) it was fulvestrant. Compared to palbociclib, ribociclib and abemaciclib showed significantly lower grade 3-4 neutropenia, but significantly higher GI toxicity. Treatment discontinuation was higher with abemaciclib than other drugs. Efficacy of the 3 drugs was similar. Compared to palbociclib, for AI backbone, the HR for PFS for ribociclib was 0.98 and for abemaciclib 1.02. For fulvestrant backbone, the HR were 0.88 and 0.93 respectively.

Conclusions: Palbociclib, ribociclib and abemaciclib have comparable efficacy, but differences in safety and tolerability. Abemaciclib has worse tolerability with significantly higher treatment discontinuation likely due to GI toxicity.
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http://dx.doi.org/10.1016/j.ctrv.2020.102086DOI Listing
November 2020

Strategies to support health care providers during the COVID-19 pandemic.

CMAJ 2020 05;192(19):E522

Psychiatrist, Department of Supportive Care, Princess Margaret Cancer Centre, Toronto, Canada and University of Toronto, Toronto, Ont.

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http://dx.doi.org/10.1503/cmaj.75499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234263PMC
May 2020

Influence of Competing Risks on Estimates of Recurrence Risk and Breast Cancer-specific Mortality in Analyses of the Early Breast Cancer Trialists Collaborative Group.

Sci Rep 2020 03 5;10(1):4091. Epub 2020 Mar 5.

Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, Ontario, Canada.

Early-stage breast cancer (BC) is a curable disease with many patients dying of causes other than BC. The influence of non-BC death and other competing risks on the interpretation of Kaplan-Meier (KM)-based analyses for BC-specific outcomes are unknown. We searched the Oxford University website to identify all meta-analyses published by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) between 2005 and 2018. The potential influence of competing risks was estimated using a validated multivariable linear model that predicts the difference between KM and cumulative incidence function (CIF) on estimates of BC-specific outcomes. The initial search identified 14 EBCTCG papers, 10 (71%) reported data on BC and competing events. Eight (80%) had a relative difference between KM and the competing risk adjusted estimates exceeding 10%. The median relative difference was 28.4% for local-recurrence; 16.8% for distant-recurrence, and 6.7% for BC-specific mortality. There was a 18.9% relative difference between KM and CIF adjusted analyses beyond 10 years. The use of KM-based methods when competing risks are present biases risk estimates in studies of early BC especially for uncommon outcomes such as local recurrence. The use of CIF to calculate BC-specific outcomes may be preferable in this setting.
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http://dx.doi.org/10.1038/s41598-020-61093-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058037PMC
March 2020

A critique of the fragility index.

Lancet Oncol 2019 10 30;20(10):e552. Epub 2019 Sep 30.

Division of Medical Oncology, Princess Margaret Cancer Centre and the University of Toronto, Toronto ON, M5G 2M9, Canada. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(19)30583-2DOI Listing
October 2019

The Effect of Exercise on Quality of Life, Fatigue, Physical Function, and Safety in Advanced Solid Tumor Cancers: A Meta-analysis of Randomized Control Trials.

J Pain Symptom Manage 2019 11 15;58(5):899-908.e7. Epub 2019 Jul 15.

Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, Ontario, Canada.

Background: People with metastatic cancers experience poor quality of life (QoL), fatigue, and decreased physical function. Exercise improves these symptoms in the curative setting, but the efficacy and safety of exercise in the metastatic setting is uncertain.

Methods: Prospective, randomized trials of moderate/high-intensity aerobic exercise or resistance training vs. control in patients with advanced/metastatic solid cancers were identified from prior reviews and updated using a search of PubMed. The mean and SD for validated outcome measures (QoL, physical function, and fatigue) were extracted for intervention and control groups at baseline and postintervention. The Mann-Whitney test was used to evaluate the effect of exercise on the pooled change between baseline and postintervention. Safety was evaluated qualitatively.

Results: Sixteen trials were analyzed. Among patients with scores at the mean or 2SD above, exercise was not associated with significant or clinical difference in QoL or fatigue. In patients with baseline scores 2SD below mean, exercise was associated with nonsignificant difference meeting minimal clinical important difference in QoL (-2.8 vs. 4.6, P = 0.28). For function, patients at the mean had nonstatistically significant, but clinically meaningful difference in the six-minute walk test (6-MWT) (14.7 vs. 29.0 m, P = 0.44). In patients 2 SD below the mean, there was a clinically meaningful difference in two patient-reported functional subscales (0.1 vs. 5.3, P = 0.076 and 0.44 vs. 8.5, P = 0.465) and a clinically meaningful improvement in the 6-MWT (-7.5 vs. 27.0 m, P = 0.34), although none of these associations met statistical significance. There were no differences in falls, fractures, or pain.

Discussion: Exercise is associated with clinically meaningful improvements in QoL, function, and 6-MWT in some patients with metastatic cancer. Despite poor reporting of safety, there was no signal of increased harm from exercise in this setting.
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http://dx.doi.org/10.1016/j.jpainsymman.2019.07.005DOI Listing
November 2019

Moving Cancer Care Ontario's Exercise for People with Cancer guidelines into oncology practice: using the Theoretical Domains Framework to validate a questionnaire.

Support Care Cancer 2019 Jun 14;27(6):1965-1968. Epub 2019 Feb 14.

McMaster University, Hamilton, ON, Canada.

Evidence supporting the benefits of exercise surrounding cancer treatment has led to internationally published guidelines, with minimal uptake by oncology care providers (OCPs). There is a need to understand how to implement research evidence into practice. Our team developed a questionnaire to assess OCPs' knowledge of exercise guidelines and barriers/facilitators to exercise counseling and program referral. We validated the questionnaire using the Theoretical Domains Framework, a knowledge translation (KT) framework used to implement evidence-based guidelines into practice. In this commentary, we describe this process and the rationale for integrating a KT framework into intervention development and implementation in oncology practice. The revised questionnaire, entitled Clinicians Perspectives on Exercise in Patients with Cancer (CliPEC), is shared to facilitate the implementation process and allow for comparison across oncology practices.
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http://dx.doi.org/10.1007/s00520-019-04689-1DOI Listing
June 2019