Julie Lemieux

Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents

Metformin, an inexpensive oral agent commonly used to treat type 2 diabetes, has been garnering increasing attention as a potential anti-cancer agent. Preclinical, epidemiologic, and clinical evidences suggest that metformin may reduce overall cancer risk and mortality, with specific effects in breast cancer. The extensive clinical experience with metformin, coupled with its known (and modest) toxicity, has allowed the traditional process of drug evaluation to be shortened. We review the rationale for a modified approach to evaluation and outline the key steps that will optimize development of this agent in breast cancer, including discussion of a Phase III adjuvant trial (NCIC MA.32) that has recently been initiated.

Quality-of-Life Measurement in Randomized Clinical Trials in Breast Cancer: An Updated Systematic Review (2001–2009)

BACKGROUND Quality-of-life (QOL) measurement is often incorporated into randomized clinical trials in breast cancer. The objectives of this systematic review were to assess the incremental effect of QOL measurement in addition to traditional endpoints (such as disease-free survival or toxic effects) on clinical decision making and to describe the extent of QOL reporting in randomized clinical trials of breast cancer. METHODS We conducted a search of MEDLINE for English-language articles published between May-June 2001 and October 2009 that reported: 1) a randomized clinical trial of breast cancer treatment (excluding prevention trials), including surgery, chemotherapy, hormone therapy, symptom control, follow-up, and psychosocial intervention; 2) the use of a patient self-report measure that examined general QOL, cancer-specific or breast cancer-specific QOL or psychosocial variables; and 3) documentation of QOL outcomes. All selected trials were evaluated by two reviewers, and data were extracted using a standardized form for each variable. Data are presented in descriptive table formats. RESULTS A total of 190 randomized clinical trials were included in this review. The two most commonly used questionnaires were the European Organization for Research and Treatment of Cancer QOL Questionnaire and the Functional Assessment of Cancer Therapy/Functional Assessment of Chronic Illness Therapy. More than 80% of the included trials reported the name(s) of the instrument(s), trial and QOL sample sizes, the timing of QOL assessment, and the statistical method. Statistical power for QOL was reported in 19.4% of the biomedical intervention trials and in 29.9% of the nonbiomedical intervention trials. The percentage of trials in which QOL findings influenced clinical decision making increased from 15.2% in the previous review to 30.1% in this updated review for trials of biomedical interventions but decreased from 95.0% to 63.2% for trials of nonbiomedical interventions. Discordance between reviewers ranged from 1.1% for description of the statistical method (yes vs no) to 19.9% for the sample size for QOL. CONCLUSION Reporting of QOL methodology could be improved.

Canadian Cardiovascular Society Guidelines for Evaluation and Management of Cardiovascular Complications of Cancer Therapy

Modern treatment strategies have led to improvements in cancer survival, however, these gains might be offset by the potential negative effect of cancer therapy on cardiovascular health. Cardiotoxicity is now recognized as a leading cause of long-term morbidity and mortality among cancer survivors. This guideline, authored by a pan-Canadian expert group of health care providers and commissioned by the Canadian Cardiovascular Society, is intended to guide the care of cancer patients with established cardiovascular disease or those at risk of experiencing toxicities related to cancer treatment. It includes recommendations and important management considerations with a focus on 4 main areas: identification of the high-risk population for cardiotoxicity, detection and prevention of cardiotoxicity, treatment of cardiotoxicity, and a multidisciplinary approach to cardio-oncology. All recommendations align with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Key recommendations for which the panel provides a strong level of evidence include: (1) that routine evaluation of traditional cardiovascular risk factors and optimal treatment of preexisting cardiovascular disease be performed in all patients before, during, and after receiving cancer therapy; (2) that initiation, maintenance, and/or augmentation of antihypertensive therapy be instituted per the Canadian Hypertension Educational Program guidelines for patients with preexisting hypertension or for those who experience hypertension related to cancer therapy; and (3) that investigation and management follow current Canadian Cardiovascular Society heart failure guidelines for cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction during or after cancer treatment. This guideline provides guidance to clinicians on contemporary best practices for the cardiovascular care of cancer patients.

Effect of Metformin vs Placebo on Weight and Metabolic Factors in NCIC CTG MA.32

BACKGROUND Metformin may improve metabolic factors (insulin, glucose, leptin, highly sensitive C-reactive protein [hs-CRP]) associated with poor breast cancer outcomes. The NCIC Clinical Trials Group (NCIC CTG) MA.32 investigates effects of metformin vs placebo on invasive disease-free survival and other outcomes in early breast cancer. Maintaining blinding of investigators to outcomes, we conducted a planned, Data Safety Monitoring Committee-approved, analysis of the effect of metformin vs placebo on weight and metabolic factors at six months, including examination of interactions with baseline body mass index (BMI) and insulin, in the first 492 patients with paired blood samples. METHODS Eligible nondiabetic subjects with T1-3, N0-3, M0 breast cancer who had completed surgery and (neo)adjuvant chemotherapy (if given) provided fasting plasma samples at random assignment and at six months. Glucose was measured locally; blood was aliquoted, frozen, and stored at -80°C. Paired plasma aliquots were analyzed for insulin, hs-CRP, and leptin. Spearman correlation coefficients were calculated and comparisons analyzed using Wilcoxon signed rank test. All statistical tests were two-sided. RESULTS Mean age was 52.1±9.5 years in the metformin group and 52.6 ± 9.8 years in the placebo group. Arms were balanced for estrogen/progesterone receptor, BMI, prior (neo)adjuvant chemotherapy, and stage. At six months, decreases in weight and blood variables were statistically significantly greater in the metformin arm (vs placebo) in univariate analyses: weight -3.0%, glucose -3.8%, insulin -11.1%, homeostasis model assessment -17.1%, leptin -20.2%, hs-CRP -6.7%; all P values were less than or equal to .03. There was no statistically significant interaction of change in these variables with baseline BMI or insulin. CONCLUSIONS Metformin statistically significantly improved weight, insulin, glucose, leptin, and CRP at six months. Effects did not vary by baseline BMI or fasting insulin.

Identification of Cancer Care and Protocol Characteristics Associated With Recruitment in Breast Cancer Clinical Trials

PURPOSE It is estimated that only 5% of patients with cancer participate in a clinical trial. Barriers to participation may relate to available protocols, physicians, and patients, but few data exist on barriers related to cancer care environments and protocol characteristics. METHODS The primary objective was to identify characteristics of cancer care environments and clinical trial protocols associated with a low recruitment into breast cancer clinical trials. Secondary objectives were to determine yearly recruitment fraction onto clinical trials from 1997 to 2002 in Ontario, Canada, and to compare recruitment fraction among years. Questionnaires were sent to hospitals requesting characteristics of cancer care environments and to cooperative groups/pharmaceutical companies for information on protocols and the number of patients recruited per hospital/year. Poisson regression was used to estimate the recruitment fraction. RESULTS Questionnaire completion rate varied between 69% and 100%. Recruitment fraction varied between 5.4% and 8.5% according to year. More than 30% of patients were diagnosed in hospitals with no available trials. In multivariate analysis, the following characteristics were associated with recruitment: use of placebo versus not (relative risk [RR] = 0.80; P = .05), nonmetastatic versus metastatic trial (RR = 2.80; P < .01), and for nonmetastatic trials, protocol allowing an interval of 12 weeks or longer versus less than 12 weeks (from diagnosis, surgery, or end of therapy) before enrollment (RR = 1.36; P < .01). CONCLUSION Allowable interval of 12 weeks or longer to randomly assign patients in clinical trials could help recruitment. In our study, absence of an available clinical trial represented the largest barrier to recruitment.

Autologous Hematopoietic Stem Cell Transplantation for Refractory Lymphomatoid Granulomatosis

Abstract Lymphomatoid granulomatosis (LG) is a rare lymphoproliferative disorder. There is no standard therapy for refractory patient. Here we present the case of a patient with LG of the lung and the brain who was refractory to polychemotherapy. An autologous hematopoietic stem cell transplantation was done and the patient achieved a complete remission. This represents the first case of high-dose chemotherapy with hematopoietic stem cell support in this disease.

Eligibility criteria in randomized phase II and III adjuvant and neoadjuvant breast cancer trials: Not a significant barrier to enrollment

Background Clinical trial recruitment can be impeded by eligibility criteria being too numerous or too restrictive. Purpose This study’s principal objective was to determine whether a specific category of eligibility criteria could be identified as a major barrier to patient enrollment. Methods Nine phase II or III clinical trials, opened between June 2004 and July 2008, were selected. A retrospective cohort of women diagnosed with invasive, nonmetastatic breast cancer and potentially eligible for these clinical trials was used. All eligibility criteria were sorted into the following categories: definition of disease, precision, safety, ethical and legal, or administrative. A total of 985 patient-trials were evaluated, defined as the experimental unit since one patient could be eligible to more than one trial. Proportions of cases with ‘not met’ eligibility criteria were assessed for each category in each trial. Results Two clinical trials had a ‘not met’ subcategory criterion of over 20%. ‘Pathology’ and ‘consent’ subcategory criteria were ‘not met’ in 24.2% and 92.7% of cases for the NEOCAN and NCIC CTG MA.27 trials, respectively. NCIC CTG MA.27 had the highest proportion of ‘not met’ subcategory due to an inclusion criterion requiring participation to two companion studies. National Surgical Adjuvant Breast and Bowel Project (NSABP) B-38 had a proportion of 18.8% of cases ‘not meeting’ the receptor status subcategory criterion. All other subcategories of eligibility criteria assessed were ‘not met’ by less than 15% of patients. Overall, few subcategories had over 10% of ineligible patients. Limitations Many eligibility criteria were considered ‘nonevaluable’ because the information evaluated would have required additional procedures not performed as part of the general practice. Conclusion The subjects from the study population are not precluded from entry in a trial because of stringent eligibility criteria. Eligibility criteria should reflect as much as possible the whole population to whom the treatment will be offered, with the exception of drugs targeting a specific receptor or pathway where only a subpopulation is hypothesized to benefit from the therapy. In the breast cancer clinical trials evaluated for the present study, no criterion precluding recruitment was shared by many or all trials and no specific eligibility criterion was consistently the reason for patients’ ineligibility.

Responsiveness to change to change due to supportive-expressive group therapy, improvement in mood and disease progression in women with metastatic breast cancer

ObjectiveTo compare the responsiveness of six questionnaires using three hypotheses of change: (i) change due to supportive-expressive group therapy (SEGT), (ii) improved mood defined as a small effect size (.2) on Profile of Mood States (POMS) Total Mood Disturbance score and (iii) progression of disease.MethodData from the “Breast Expressive-Supportive Therapy” study, a multicentre randomized controlled trial of change due to SEGT versus standard of care in women with metastatic breast cancer were used. Questionnaires studied were: POMS, Impact of Event Scale, Psychosocial Adjustment to Illness Scale (PAIS), EORTC QLQ-C30, Mental Adjustment to Cancer and a Pain visual analog scale (VAS). Responsiveness to change was evaluated using the standardized response mean. POMS was used as the standard.ResultsPOMS was the most responsive questionnaire to change due to SEGT. Questionnaires measuring psychosocial attributes were responsive to improvement in mood. EORTC QLQ-C30, PAIS, PAIN VAS and MAC were the most responsive to disease progression. More responsive questionnaires were associated with the smallest sample size required to detect an effect.ConclusionsResponsiveness to change is context specific. The POMS was the most responsive questionnaire to psychosocial therapy.

Paraneoplastic encephalomyelitis, stiff person syndrome and breast carcinoma.

Paraneoplastic Encephalomyelitis, Stiff Person Syndrome and Breast Carcinoma Paraneoplastic syndromes (PNS) are the rarest non-metastatic neurological complications of cancers in which no specific etiology can be identified. Among PNS, stiff person syndrome is characterized by “rock-hard” rigidity and painful spasms in distal limbs, most frequently legs, and abnormal foot and/or hand posture. General posture is rigid; ambulation is difficult and may result in falls. Paraneoplastic syndromes are postulated to be autoimmune diseases. Stiff person syndrome associated to cancer display high antibody titers directed against neuronal proteins1,2. We present the case of a woman first diagnosed with stiff person syndrome, which led to the diagnosis of an invasive ductal carcinoma of the breast. Paraneoplastic antibodies titers previously reported in literature were all negative.

Characteristics and long-term survival of patients diagnosed with pure tubular carcinoma of the breast

Pure tubular carcinomas (TC) of the breast are generally considered to have an excellent prognosis. This study aimed to analyze the characteristics and survival of patients with TC.