Results of the MINDACT Trial Quality Assurance Questionnaire

MINDACT (Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy) is a large and complex trial expecting to recruit 6,000 patients in over 90 centers in 9 countries. MINDACT was designed to evaluate the added value of the 70-gene signature to traditional prognostic factors and determine whether the 70-gene signature could be used to predict response to prescribed adjuvant treatments for early breast cancer patients. The trial also aims to compare the docetaxel-capecitabine regimen, possibly associated with increased efficacy and reduced long-term toxicities, to commonly used anthracycline-based chemotherapy regimens. The last primary objective will be to determine the best endocrine treatment strategy, i.e., single agent up-front letrozole for 7 years compared to sequential endocrine strategy of 2 years of tamoxifen followed by 5 years of letrozole. It is a ground breaking clinical trial with a central question that requires significant translational research. The logistics required to conduct this trial are a challenge, and good interaction between the different departments involved in the conduct of the trial, e.g. medical oncology, surgery, and pathology, as well as a trained research nurse/fellow are essential.

In order to ensure a high and homogenous level of quality in the MINDACT trial, a Quality Assurance Program is in place, and in July 2009, as part of this program, a questionnaire was sent to the Principal Investigators (PI) in the 76 centers participating at that time. The questionnaire was designed to gather information concerning several aspects of the trial including screening and recruitment, clinical versus genomic risk randomization, chemotherapy and endocrine therapy randomization, and communication with the EORTC or the National Coordinating Centers (NCCs).

Result Highlights

Responses to the QA Questionnaire were received from 60 of the 76 centers (79% response rate).

Screening, recruitment, and enrollment

In 97% of the centers the decision to invite a patient to participate in the MINDACT trial was made by specialists, i.e., a surgeon, a medical oncologist, or by means of a multidisciplinary meeting. Similarly, in 88% of the reporting centers the protocol was explained to the patients by a specialist(i.e., the PI, senior oncologists), or by a research nurse.

The logistics for this study are complex and involve handling and shipping on a real-time basis of frozen samples to a central laboratory for testing to determine patient genomic risk.  In this regard, the study timelines and overall logistics were well perceived by the majority of the respondents: 97% of the reporting centers found the protocol timelines for enrollment and randomization suitable, and the majority of the reporting centers reported no problems with obtaining and storing frozen samples (95%), frozen sample preparation by pathologists (84%), sample shipment (91%), receiving genomic test results in a reasonable timeframe (73%), or with the web platform (86%).

The questionnaire also indicated that 90% of the responding centers found the procedures for registration and enrollment in the study to be practical and clear, and the majority of the respondents were comfortable enrolling high clinical risk and node positive patients, in the study.

The accrual curve for this trial up to 25 January 2010 is shown above.

Treatment arms

Concerning the chemotherapy treatment arms, the majority of respondents trusted the effectiveness of the treatments and did not have concerns regarding toxicity; any preconceived notions that the docetaxel/capecitabine experimental treatment arm might be perceived as being more toxic than the anthracycline control treatment arm were not substantiated. Also, within the anthracycline control treatment arm, effectiveness was not a concern for 87% of the respondents in the case of node negative disease and 75% of the respondents in the case of node positive disease.

Similarly for the endocrine therapy arms, treatment effectiveness was well accepted, and almost all of the respondents reported having no concerns regarding toxicity in either the tamoxifen-letrozole or letrozole treatment arms. The longer duration of treatment in the endocrine therapy arms, a total of 7 years, was not a concern for 71% of the respondents.

General Issues

In general, 98% of the respondents reported that patients were satisfied with their participation in the trial, and the majority of the respondents reported that the communication between the PIs and the MINDACT team were satisfactory.

Overall, questionnaire responses indicated satisfaction with study procedures and logistics and support the feasibility of conducting such a large and complex trial.

Dr. Gustavo Werutsky: TRANSBIG traineeship

Since December 2008, Dr. Gustavo Werutsky has been working on the MINDACT trial. The MINDACT trial is an avant-garde trial with a central translational research component/question. The logistics in this trial are challenging for the sites and require coherent interaction between the various departments (medical oncology, surgery, pathology, etc.) to ensure that the trial runs smoothly. Upon his arrival at the EORTC, Dr Werutsky, under the supervision of Dr. Denis Lacombe and Dr. Jocelyne Flament of the EORTC and in collaboration with Dr. Fatima Cardoso from the Institut Jules Bordet, began working on a project, Quality Assurance (QA) in the MINDACT Trial, whose main objective was to ensure a high and homogeneous level of quality in the MINDACT trial as well as to evaluate and provide input on all of the trial’s logistical processes.

Gustavo developed and implemented the QA Project in the MINDACT trial which was presented in March 2009 at the MINDACT-TRANSBIG Steering Committee Meeting. This project is based on three components: frequently asked questions (FAQs), questionnaires, and QA metrics.

FAQs is a system in which all medical questions originating from the sites are centralized. The goal of FAQs is to provide uniform and standardized replies to the sites. FAQs also helps to identify possible shortcomings of the protocol that can be ascertained for future clarifications and/or amendments.

A QA questionnaire was developed for principal investigators and their research teams with the aim of gathering feedback related to the understanding of trial procedures as well as trial concepts such as patient risk assessment by genomic testing and the randomized chemotherapy and endocrine therapy arms. Those results were circulated to the principal investigators and are discussed above.

QA metrics is a tool that establishes data measurements to ensure quality. A report comparing our current trial data with several quality parameters described in breast cancer treatment guidelines and in quality control recommendations for clinical trials is generated. This report analyses a range of topics concerning the trial such as recruitment/screen failures, logistical aspects, treatment (surgery, radiotherapy, chemotherapy and endocrine therapy), documentation, and site information.

Overall, the QA project ensures a high level of quality in the trial management and foresees confident results generated by this innovative and complex trial. In parallel with this effort, Dr. Werutsky participated as a member of the MINDACT-TRANSBIG Executive Committee and in the TRANSBIG Ethical-Legal Committee which gave him broad exposure to the many facets of a multinational clinical trial. He has also been involved in the International Male Breast Cancer Registry, a joint effort between the Breast International Group (BIG) and the North American Breast Cancer Groups (NABCG) coordinated by the EORTC, and has been participating in the study design, development, and writing of the protocol for the retrospective EORTC trial 10085 and prospective EORTC trial 10092. The results of the International Male Breast Cancer Registry will be a milestone in the understanding of breast cancer in males, and it will allow us to assess the feasibility of launching an international clinical trial for this patient population.

Dr. Werutsky received his medical degree from the Pontifical Catholic University of Rio Grande do Sul (PUCRS) in Porto Alegre, Brazil. He completed his residency in Internal Medicine and Medical Oncology and was junior staff member and clinical investigator at São Lucas Hospital (PUCRS) in Porto Alegre before coming to the EORTC.

Gustavo plans to continue managing the QA for the MINDACT trial and will be involved in the development and writing of the protocol for the EORTC 40091 trial. He will also set up a new project entitled QA levels in chemotherapy in collaboration with the QA Committee of the EORTC. Publications related to these projects are expected later this year.

Gustavo gratefully acknowledges the excellent opportunity afforded to him by his stay at the EORTC. Support for his fellowship was provided initially by a TRANSBIG traineeship through support by the EORTC Charitable Trust and for the second year, by Fonds Cancer (FOCA).  He appreciates the knowledge he has gained concerning the conduct of cancer clinical trials and translational research and in particular the importance of designing trials where the refinement of therapy should be linked to biomarker-defined subgroups. He considers this an experience that will be of great value in his future career as a medical oncologist and clinical investigator. We at the EORTC are pleased to have been able to support him in this important endeavor.

Gustavo Werutsky, Valéry Daubie, Fatima Cardoso, Laura Vanhemelryck,
Miet Celis, Lissandra Dal Lago, Kristal Engelen, and John Bean