QT interval prolongation and torsades de pointes with oxaliplatin

Oxaliplatin is a platinum-containing antineoplastic agent that is used in the treatment of gastrointestinal cancers [Stein and Arnold, 2012; Alcindor and Beauger, 2011]. It is one of the most important treatments for colorectal cancer, and is commonly used in combination therapy with other cytotoxic drugs [Stein and Arnold, 2012; Alcindor and Beauger, 2011]. It may have survival benefits and better tolerability than cisplatin for advanced unresectable gastric cancer [Montagnani et al. 2011]. Oxaliplatin may also be an alternative treatment for patients with ovarian cancer, who have shown hypersensitivity to carboplatin [Bogliolo et al. 2015].

In December 2015, oxaliplatin was added to the CredibleMeds® database (https://www.crediblemeds.org/) lists of drugs with a known risk of torsades de pointes (TdP) cardiac arrhythmia and of drugs to avoid in patients with congenital long QT syndrome (LQTS). As TdP is potentially fatal, an off-target association between a drug and TdP is notable. Drugs in the CredibleMeds® ‘known risk of TdP’ category are those for which there is deemed to be convincing causal evidence for TdP when used according to recommended guidelines [Schwartz and Woosley, 2016]. A PubMed search for ‘oxaliplatin AND (torsad* or long QT)’ executed on 18 June 2016 found three reports of TdP/QT interval prolongation with oxaliplatin [Chang et al. 2013; Kim et al. 2013; Woei Chung et al. 2009]. As of the same date, publically accessible information at the European Medicines Agency database of suspected drug reaction reports showed five individual cases of TdP reported by medical professionals, with no fatalities [European Medicines Agency, 2016]. The first published case report of oxaliplatin-linked acquired LQTS (aLQTS) concerned a 44-year-old woman treated for appendiceal adenocarcinoma [Woei Chung et al. 2009]. Under treatment with oxaliplatin together with folinic acid and 5-fluorouracil, during her 11th treatment cycle she developed palpitations, dizziness and syncope after ~30 mins following oxaliplatin infusion, with hypotension and bradycardia [Woei Chung et al. 2009]. Her electrocardiogram (ECG) showed a rate-corrected QT (QT_c) interval of 516 ms, without concurrent electrolyte abnormalities. Symptoms ceased within ~1 hour, with no further evidence of QT_c prolongation. A previous ECG had shown a QT_c interval of 426 ms and the patient had not received other QT_c interval prolonging drugs [Woei Chung et al. 2009]. The proximity of onset of symptoms to oxaliplatin infusion, without other obvious risk factors for aLQTS, made oxaliplatin the likely causative agent. In 2013, a 72-year-old man with gastric cancer was reported to develop recurrent episodes of syncope after two cycles of oxaliplatin combination therapy [Kim et al. 2013]. About 7 days after discharge following treatment he visited the outpatient clinic reporting 2–3 episodes of syncope per day. On admission for evaluation, his ECG exhibited 2:1 atrioventricular block and a prolonged QT_c interval of 680 ms [Kim et al. 2013]. An earlier ECG before chemotherapy showed a slightly prolonged QT_c interval of 467 ms. During inpatient monitoring self-terminating TdP was observed, with the R on T phenomenon preceding TdP [Kim et al. 2013]. There was no evidence of ischaemic heart disease or electrolyte abnormalities. After oxaliplatin discontinuation, the QT_c interval shortened to pretreatment levels [Kim et al. 2013]. A second case report in 2013 described QT interval prolongation in a 67-year-old woman treated for metastatic lower rectal cancer [Chang et al. 2013]. She also had dilated cardiomyopathy and congestive heart failure [Chang et al. 2013]. On admission for a third round of oxaliplatin combination therapy, her pretreatment ECG showed atrial fibrillation but a normal QT_c interval of 370 ms. Soon after commencement of oxaliplatin infusion, she experienced chest tightness and hypotension, showing ST segment depression and a prolonged QT_c interval of 628 ms. She lost consciousness concurrently with appearance of TdP on her ECG; this was successfully treated with defibrillation and cardiopulmonary resuscitation (CPR), supplemented with adrenaline and dopamine infusion [Chang et al. 2013]. A 12-lead ECG recording after resuscitation showed a QT_c interval of 459 ms and ST segment elevation in leads III and aVF, with ST depression in V4–6. No abnormalities in electrolytes or cardiac enzymes were found. The QT_c interval had normalized to 397 ms 4 days following this episode. Coronary angiography was normal. The proposed mechanism in this case was anaphylactic coronary vasospasm together with oxaliplatin-induced QT interval prolongation [Chang et al. 2013].

Most drugs associated with aLQTS and TdP produce pharmacological inhibition of human ether-à-go-go Related Gene (hERG)-encoded potassium channels that underpin the cardiac ventricular rapid delayed rectifier current (I_Kr) [Hancox et al. 2008]. Although oxaliplatin can inhibit voltage-gated potassium channels in peripheral nerve fibres [Kagiava et al. 2008], there is no published evidence of hERG channel or cardiac I_Kr inhibition by the drug. The related compound cisplatin increases hERG channel expression in gastric cancer cells [Zhang et al. 2012], which argues against hERG channel trafficking inhibition by this class of drugs. An alternative mechanism for reported QT_c interval prolongation and TdP susceptibility with oxaliplatin may be altered sodium channel function [Wu et al. 2009]. Oxaliplatin has been shown to produce a concentration-dependent slowing of inactivation of sodium currents from the NG108-15 neuronal cell line [Wu et al. 2009] and to increase fast and persistent sodium (Na) current (I_Na) amplitudes from cooled large diameter dorsal root ganglion cells [Sittl et al. 2012]. Limited experiments on recombinant channels encoded by SCN5A, which is responsible for cardiac Nav1.5 channels, showed a modest reduction in peak I_Na by oxaliplatin together with a slowing of I_Na inactivation [Wu et al. 2009]. It is possible that slowed ventricular I_Na inactivation induced by oxaliplatin could prolong action potentials and predispose towards TdP, akin to the LQT3 form of congenital LQTS. Experiments on native cardiac tissue and cell preparations are required to verify this. Notably, ranolazine, which is currently under extensive investigation for antiarrhythmic applications, was reported to reverse oxaliplatin-induced slowing of neuronal I_Na inactivation [Wu et al. 2009]. If similar effects of oxaliplatin and ranolazine can be demonstrated in cardiac preparations, ranolazine may have value in prevention or treatment of oxaliplatin-induced aLQTS and TdP.