ecancermedicalscience

Review

QTc prolongation assessment in anticancer drug development: clinical and methodological issues

12 Jan 2009
G Curigliano, G Spitaleri, F De Braud, D Cardinale, C Cipolla, M Civelli, N Colombo, A Colombo, M Locatelli, A Goldhirsch

Cardiac safety assessments are commonly employed in the clinical development of investigational oncology medications. In anti-cancer drug development there has been increasing consideration for the potential of a compound to cause adverse electrocardiographic changes, especially QT interval prolongation, which can be associated with risk of torsades de pointes and sudden death. Irrespective of overt clinical toxicities, QTc assessment can potentially influence decision making at many levels during the conduct of clinical studies, including eligibility for protocol therapy, dose delivery or discontinuation, and analyses of optimal dose for subsequent development. Given the potential for serious and irreversible morbidity from cardiac adverse events, it is understandable that cardiac safety results can have broad impact on study conduct and patient management. The methodologies for risk management of QTc prolongation for non cardiac drugs have been developed out of experiences primarily from drugs used to treat non life-threatening illnesses in a chronic setting such as antibiotics or antihistamines. Extrapolating these approaches to drugs for treating cancer over an acute period may not be appropriate. Few specific guidelines are available for risk management of cardiac safety in the development and use of oncology drugs. In this manuscript, clinical and methodological issues related to QTc prolongation assessment will be reviewed. Discussions about limitations in phase-I design and oncology drug development will be highlighted. Efforts are needed to refine strategies for risk management, avoiding unintended consequences that negatively affect patient access and clinical development of promising new cancer treatments. A thoughtful risk management plan generated by an organized collaboration between oncologists, cardiologists, and regulatory agencies to support a development programme essential for oncology agents with cardiac safety concerns.

Related Articles

Tasneem Dawood, Yasmin Abdul Rashid, Saqib Raza Khan, Adnan Abdul Jabbar, Muhammad Nauman Zahir, Munira Shabbir Moosajee
Jad Najdi, Mariana El Hawa, Adnan El-Achkar, Nour Naji, Talar Telvizian, Maya Romani, Albert El Hajj, Deborah Mukherji
Sergio Luis Ramos Rodriguez, David Francisco Stein Montoro, Gabriel De la Cruz Ku, Consuelo del Rocio Luna Munoz, Cesar Ramon Razuri Bustamante
Fernanda J Martin, Isabel M Saffie, Mabel A Hurtado, Diana Avila-Jaque, Rodrigo A Lagos, Carolina A Selman, Jonathan Z Huserman, Valentina A Castillo, Badir J Chahuán