Elsevier

Progress in Cardiovascular Diseases

Volume 53, Issue 2, September–October 2010, Pages 164-172
Progress in Cardiovascular Diseases

Prolonged QTc Interval in Cancer Therapeutic Drug Development: Defining Arrhythmic Risk in Malignancy

https://doi.org/10.1016/j.pcad.2010.05.005Get rights and content

Abstract

Anticancer therapy drug development is an arduous task, taking 10 to 15 years to complete, requiring approximately 1 billion dollars, and rarely leads to Food and Drug Administration approval. Methods to predict unacceptable drug-induced toxicity, such as a prolonged QTc interval/risk of torsade de pointes, should be highly informative to quickly and accurately determine if further resources should be allocated in the continued development of an agent. Expert consensus has established guidelines to ascertain the ability of a new drug to prolong the QTc interval. Although QTc measurement is the best way to assess arrhythmic risk, it is imprecise for a variety of reasons. In addition, oncology patients have multiple risk factors for QTc prolongation at baseline. Competing interests involved in assessing arrhythmic risk of a new oncology agent include inability to precisely follow published guidelines for QTc assessment, patients' concomitant medical problems interfering with drug assessment and therefore clinical trial enrollment, patient safety concerns, general public safety concerns regarding toxicity assessment, need for discovery of more curative drug therapies, and individual patient perception of therapeutic risk vs benefit. Oncology patients are concerned about access to experimental agents, as well as early abandonment of a potentially beneficial agent because of a low estimated risk of toxicity, even if the event is catastrophic. We review the issues involved in evaluating the QTc interval–prolonging risk in new anticancer agents.

Section snippets

What is the incidence of drug-induced TdP?

Defining the risk of TdP is challenging. In one study of consecutive patients on continuous monitoring receiving any proarrhythmic drug in Sweden, the incidence of TdP was estimated at approximately 4 cases per 100,000 patients.3 Other estimates, especially for noncardiac medications, have ranged from <1 in 10,000 to 1 in 100,000 cases.4, 5 When adjusted for TdP risk factors, the range could be as frequent as 1 in 2000 to >20,000.6 It is necessary to know that the risk of TdP for cisapride was

The importance of the Qt interval and measurement problems

The QTc interval is monitored meticulously by drug regulatory agencies, and its prolongation is the most common reason for FDA withdrawal, nonapprovals, or delayed approval for all categories of noncardiology drugs.8 The QTc interval is at this time the best, although very imprecise, way to measure cardiac repolarization. It is considered a marker for the risk of TdP,4, 9 even though the actual clinical relationship between drug-induced QTc interval prolongation and TdP is likely only with very

Oncology patients present a high risk for pQTc interval

Appraising QTc intervals in oncology patients is confounded by several factors, including preexisting cardiac perturbations. In a compilation of 4 early-phase cancer trials, 36% of patients displayed some type of ECG abnormality at screening.19 A prolonged or borderline pQTc interval was seen in 14% to 15%.19, 20 Cancer patients possess many of the risk factors for cardiac disease and pQTc interval, such as older age, underlying coronary disease, or previous myocardial infarction. Even without

Current international recommendations for general QTc interval testing

Even with the limitations of QTc measurement, monitoring QT is an essential component of the drug development process. Essentially, every drug is initially considered to be proarrhythmic. To form consensus on best practices and improve communication as industry moves drugs forward, the ICHTR published guidelines in 2005 on the “Clinical Evaluation of QT/QTc Prolongation and Proarrhythmic Potential.”2, 25 A preclinical document, ICH S7B, focuses on repolarization capacities of new drugs before

Issues in testing the QTc interval in oncology patients

Anticancer agents form a large category of drugs whose testing must deviate from the regular ICH E14 guidelines.2 Most importantly, complex advanced cancer patients must be used as the subjects in anticancer drug trials assessing pQTc interval; administering more than limited dosing of an anticancer agent in subjects without malignancy would expose these healthy volunteers to unnecessary genetic and other adverse effects. Traditionally, phase 1 clinical trials are designed to find the maximally

Proceeding with a pQTc interval

QTc prolongation approximately >500 milliseconds or a change from baseline of >60 milliseconds are of clinical concern2 and are common criteria to indicate potential cardiotoxicity and impede further development. If the QTc interval is discovered to be prolonged from baseline to just below those values, further drug development does not have to be necessarily discontinued, with the caveat that these numbers are biomarkers that do not always correspond with clinical outcomes. More credence can

Summary

There are several key points regarding the investigation of the QTc interval in anticancer drug development:

  • QTc interval is imprecisely measured because of wide diurnal variations; the incidence of drug-induced pQTc leading to TdP is estimated as small, but would be unacceptable for a healthy population.

  • Oncology patients have multiple risk factors for pQTc at presentation, so the incidence of TdP is theoretically higher, but may not be attributable to drug alone, confounding assessment new

Current state

The FDA has convened a “QT interdisciplinary review team” with the expertise to assess QT interval studies and discuss plans for modified TQTSs.27 Published lists of medications associated with pQTc interval steer healthcare providers from possible additive risks of pQTc interval, especially after drug approval.32 In this way, much-needed cancer therapeutics such as romidepsin (ISTODAX; Gloucester Pharmaceuticals Inc., Cambridge, MA)33 for cutaneous T-cell lymphoma are being approved (November

Future directions

The development of new powerful cancer drugs that do not cause TdP will proceed on many fronts:

  • expanding knowledge of multiple ion channels and pathways involved with repolarization, aiming for improved preclinical models, such that only a small fraction of QTc prolonging drugs progress to human studies;

  • discovering genetic changes such as polymorphisms involved in drug-induced QT prolongation, such that future testing, can be tailored to a patient's unique susceptibility,36 avoiding drug

Statement of Conflict of Interest

The author declares that there are no conflicts of interest.

References (36)

  • VitolaJ. et al.

    Cisapride-induced torsades de pointes

    J Cardiovasc Electrophysiol

    (1998)
  • StrevelE.L. et al.

    Molecularly targeted oncology therapeutics and prolongation of the QT interval

    J Clin Oncol

    (2007)
  • FingertH. et al.

    Safety biomarkers and the clinical development of oncology therapeutics: considerations for cardiovascular risk and safety management

    AAPS J

    (2006)
  • ZehenderM. et al.

    QT-interval prolonging drugs: mechanisms and clinical relevance of their arrhythmic hazards

    Cardiovasc Drugs Ther

    (1991)
  • AginM.A. et al.

    Assessing QT variability in normal volunteers

    Proc Am Coll Clin Pathol

    (2003)
  • PrioriS.G. et al.

    Risk stratification in the long-QT syndrome

    N Engl J Med

    (2003)
  • AndersomM.E. et al.

    Cardiac repolarization: current knowledge, critical gaps, and new approaches to drug development and patient management

    Am Heart J

    (2002)
  • RedfernW.S. et al.

    Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsades de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development

    Cardiovasc Res

    (2003)
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    Statement of Conflict of Interest: see page 171.

    Address reprint requests to Joanna Brell, MD, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, 6130 Executive Blvd. EPN 2017, Bethesda, MD 20892.

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