Oncol Rev (2010) 4:223–232 DOI 10.1007/s12156-010-0058-8

REVIEW

Drug-induced QT interval prolongation in cancer patients Torben K. Becker • Sai-Ching J. Yeung

Received: 9 April 2010 / Accepted: 28 June 2010 / Published online: 9 July 2010  Springer-Verlag 2010

Abstract Cancer patients are at an increased risk for QT interval prolongation and subsequent potentially fatal Torsade de pointes tachycardia due to the multiple drugs used for treatment of malignancies and the associated symptoms and complications. Based on a systematic review of the literature, this article analyzes the risk for prolongation of the QT interval with antineoplastic agents and commonly used concomitant drugs. This includes anthracyclines, fluorouracil, alkylating agents, and new molecularly targeted therapeutics, such as vascular disruption agents. Medications used in the supportive care can also prolong QT intervals, such as methadone, 5-HT3-antagonists and antihistamines, some antibiotics, antifungals, and antivirals. We describe the presumed mechanism of QT interval prolongation, drug-specific considerations, as well as important clinical interactions. Multiple risk factors and drug–drug interactions increase this risk for dangerous arrhythmias. We propose a systematic approach to evaluate cancer patients for the risk of QT interval prolongation and how to prevent adverse effects. Keywords QT prolongation
Long QT syndrome
Chemotherapy
Supportive care
Risk assessment

T. K. Becker
S.-C. J. Yeung (&) Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, The University of Texas MD Anderson Cancer Center, Unit 1465, P.O. Box 301402, Houston, TX 77230-1402, USA e-mail: [email protected]

Introduction Case scenario A 25-year-old man presents to the emergency room at a comprehensive cancer center with a chief complaint of loss of consciousness earlier that day. His medical history includes T-cell acute lymphoblastic leukemia for which he recently received chemotherapy. The patient is accompanied by his mother who reports that her son experienced a sudden loss of consciousness that morning as well as three prior episodes in the past week. An EKG shows prolongation of the QT interval to 490 ms (ms). The patient is admitted to telemetry for further medical evaluation. Syncope is a common presentation seen in the emergency room. It often challenges the clinician due to its extensive differential diagnosis and the difficulty to obtain a detailed and conclusive history from the patient [1]. The above case scenario showcased a Long QT Syndrome (LQTS) as the initial working diagnosis for the patient’s recurrent syncopal episodes. This diagnosis of LQTS demands a comprehensive diagnostic process to identify the root cause, which may be inherited or acquired. Additionally, certain treatment-related conditions need to be taken into consideration in cancer patients. LQTS is among multiple cardiac problems faced by cancer patients, but it puts these patients at an additional risk for sudden cardiac death and morbidities due to injuries sustained from syncopal falls. Cancer patients are often at an even higher risk for an adverse outcome because of general deconditioning, frequently coexisting electrolyte abnormalities, long-term sequelae of radiation to the chest, chemotherapy-induced cardiotoxicities and tissue changes, such as cardiomyopathy or pulmonary hypertension. This review describes the pharmaceutical agents commonly used in cancer patients which can cause LQTS and outlines the necessary clinical considerations.

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Search and selection strategy The authors conjointly searched the PubMed database for the keywords, ‘‘QT interval’’, ‘‘QT interval prolongation’’, ‘‘prolonged QT interval’’ and ‘‘long QT syndrome’’ in combination with any of the keywords ‘‘cancer’’, ‘‘antineoplastic’’, ‘‘chemotherapy’’, ‘‘targeted therapy’’, ‘‘antibiotics’’, ‘‘antimicrobials’’, ‘‘analgesics’’, ‘‘antiemetic’’, ‘‘supportive care’’, ‘‘alternative medicine’’, ‘‘therapy’’, ‘‘genetics’’. Articles in the English, German, Spanish, and French languages were reviewed. Evaluation and subsequent selection for inclusion in this article were based on the following criteria: describes general genetics and pathophysiology of QT interval prolongation, describes therapeutic considerations for QT interval prolongation, describes relevance of QT interval prolongation in cancer patients, describes anti-cancer drugs which influence the QT interval, describes antimicrobials or analgesics or antiemetics which influence the QT interval, describes remedies used as alternative medicine in cancer patients which influence the QT interval.

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leading to LQTS. Four congenital forms of the LQTS (Romano-Ward syndrome, Lange-Nielsen syndrome, Andersen-Tawil syndrome and Timothy syndrome) have been recognized to date. The Romano-Ward syndrome can remain unrecognized until adulthood; it is caused by mutated genes which code for a specific Na? channel or for the Ankyrin-2 protein. The Lange-Nielsen syndrome is accompanied by deafness and less common than the Romano-Ward syndrome which has an incidence of about 1:7,000. The Lange-Nielsen syndrome is usually detected while investigating deafness in a child. It is caused by inherited mutations in genes coding for K? channels. The severity of symptoms varies between clinically normal and sudden cardiac death. The Andersen-Tawil and Timothy syndromes represent extremely rare forms of congenital LQTS [7–9]. More than 700 mutations in 12 genes leading to LQTS are currently known [9]. Some data suggest that drug-induced LQTS variants can be regarded as a subclinical form of the inherited variants [10].

Drugs causing QT interval prolongation Definition and pathophysiology

Antineoplastic agents

The estimated overall incidence of the LQTS is ranging between 1:2,500 and 1:5,000 [2, 3]. As cancer is one of the leading causes of morbidity worldwide, these data need to be taken in consideration by oncologists as well. Even though the exact incidence among cancer patients remains unknown, the rate of EKG changes in cancer patients has been reported as high as 36% [4]. LQTS is characterized by a Bazett-corrected QT interval time (QTc) greater or equal 450 ms and T wave alterations and can lead to a potentially fatal polymorphic ventricular tachycardia known as Torsade de pointes (Tdp). Persons with a QTc greater or equal 500 ms are regarded at high risk for Tdp, but no threshold has been established as definitively ‘‘safe’’ [5, 6]. The QT interval in the EKG represents the sum of the action potential duration of the ventricular cardiomyocytes. The cardiac action potential during depolarization is characterized by inward sodium (Na?) and calcium (Ca??) currents. During repolarization, the inward Ca?? current decreases and the outward-rectifier potassium current via human ether-a-go-go-related potassium (hERG K?) channels increases. Therefore, drugs can induce LQTS either by hindering the repolarizing K? influx or by prolonging the depolarizing Ca?? or Na? currents. Indirect effects leading to QT interval prolongation include electrolyte disorders, especially hypokalemia, caused by pharmaceuticals and drug–drug interactions at the cytochrome P450 isoenzyme CYP3A4. The inhibition of this enzyme can increase the plasma levels of other direct ion channel modifiers, thereby

Many commonly used antineoplastic agents can prolong the QT interval (Table 1). Direct hERG K? channel inhibition is a common mechanism of the undesired QT interval prolongation, but direct damage of the cardiomyocytes and CYP450 enzyme interactions play important roles as well. From a drug development standpoint, hERG K? channels are regarded as ‘‘antitargets’’ (i.e., as unwanted targets because of the risk of LQTS associated with their blockade), but hERG K? channels are present in many other tissues than solely the heart, specifically also in cancer cells, where they may serve as a possible target for future anti-cancer drugs [11, 12]. Cumulative or daily dose, prior treatment, drug formulation, as well as concurrent electrolyte abnormalities also influence the likelihood and severity of QT interval prolongation.

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5-Fluorouracil (5-FU) 5-FU is a pyrimidine antimetabolite used as standard chemotherapy for many solid tumors, such as breast, colon, pancreatic or ovarian cancer. Multiple EKG changes, which are usually rather nonspecific, but may include prolonged QT intervals, have been described in patients receiving 5-FU. These are dose-dependent (single application and/or total treatment course) and also correlate with the infusion rate. In addition, the potential for cardiotoxicity and especially arrhythmias is increased by its ability to cause coronary vasospasm [13–15].

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Table 1 Antineoplastic agents which can cause a QT interval prolongation Pharmaceutical agent

Clinical aspects

5-Fluorouracil

Dose-dependency

Amsacrine (topoisomerase II inhibitor)

Causes concurrent hypomagnesemia

Anti-estrogens

Tamoxifen, but not clomiphene

Arsenic trioxide

High rate of Tdp if QT interval prolongation occurs

Anthracyclines

Magnitude of QT interval prolongation may predict development of acute heart failure, dose-dependency

Cyclophosphamide

Magnitude of QT interval prolongation may predict development of acute heart failure, dose-dependency, irradiation is a common risk factor

Histone deacetylase inhibitors

Dose-dependency not likely

Platinum compounds

Clinical relevance questionable

Trastuzumab

Increases toxicity of anthracyclines

Tyrosine kinase inhibitors and angiogenesis inhibitors (bevacizumab, dasatinib, vandetanib etc.)

QT interval prolongation occurs frequently

Amsacrine Amsacrine, a topoisomerase II inhibitor, is used to treat acute leukemia. It can cause QT interval prolongation directly and indirectly by hERG K? channel inhibition and concurrent hypomagnesemia, although only a few cases of LQTS have been described in the literature to date [16, 17]. Anti-estrogens Anti-estrogens compete with estrogen for binding sites in target tissues and are used for the treatment of estrogenreceptor positive breast cancer. A QT interval prolongation has been described for tamoxifen, but not for clomiphene. This has been attributed to tamoxifen’s ability to inhibit hERG K? channels [18, 19]. Arsenic trioxide Arsenic trioxide is used in refractory or relapsed acute promyelocytic leukemia and induces apoptosis by DNA fragmentation and protein degradation. QT interval prolongation is relatively in patients receiving arsenic trioxide. Case reports suggest a high rate of arsenic trioxide-induced LQTS which will precipitate episodes of Tdp [20, 21]. Anthracyclines Anthracyclines (doxorubicin, daunorubicin, and epirubicin) are antibiotics. Their cytostatic effect is due to DNA intercalation. They are frequently used in the treatment of hematologic (e.g., acute leukemia) and solid (e.g., breast cancer) malignancies. A prolonged QT interval is a well known side effect of treatment with anthracyclines and is thought to reflect cardiomyocyte damage. This is consistent with findings that the QT interval dispersion may predict the development of

acute heart failure. Cardiotoxicity and subsequent LQTS exhibit a cumulative dose-dependency. Application of liposomal anthracycline preparations and dexrazoxane is associated with less cardiotoxic effects [22–28]. Cyclophosphamide Cyclophosphamide, a nitrogen mustard alkylating agent, cross-links tumor cell DNA, and thus damages DNA and inhibits DNA replication. It is widely used for treatment of hematologic malignancies and solid tumors. QT interval prolongation is also commonly observed in patients treated with cyclophosphamide. Cardiomyocyte damage is usually considered to be the origin of this, even though it may not be the initial site of injury and direct ion channel interactions may exist. Previous irradiation to the chest is a common risk factor, likely due to cellular damage. The magnitude of the QT interval prolongation is also predictive for the future development of acute heart failure [14, 29–31]. Histone deacetylase inhibitors Histone deacetylase inhibitors (e.g., vorinostat), aim to reverse aberrant epigenetic changes associated with cancer, and are licensed in the United States for treatment of cutaneous T-cell lymphoma. They lead to hyperacetylation of histones and transcription factors, and thereby affect gene expression. LQTS cases have been observed with histone deacetylase inhibitors and data suggest that the occurrence of the QT interval prolongation is dose-independent [13, 32]. Platinum compounds Platinum compounds (cisplatin and carboplatin), commonly used for treatment of lung, ovarian and many other

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types of cancer, form platinum–DNA coordination complexes or adducts in tumor cells, leading not only to inhibition of DNA replication and transcription, but also DNA damage response-associated apoptosis. Except in the context of severe hypomagnesemia associated with platinum compounds, QT interval prolongation has been reported rarely for platinum compounds. In addition, the clinical relevance is questionable, as the prolongation does not seem to lead to Tdp [13, 33, 34].

tract). Due to the relatively high risk of Tdp, close EKG monitoring during therapy is warranted [13, 36–38]. In spite of this, patients who develop a prolonged QT interval during therapy with these agents may as well remain asymptomatic. Therefore, attention should be paid towards the identification of additional risk factors, which can help to identify patients at higher risk for life-threatening arrhythmias. Synergistic effects

Trastuzumab Trastuzumab is a monoclonal antibody, which binds to the human epidermal growth factor receptor 2 (HER2) in breast cancer patients, thereby inhibiting HER2-driven tumor cell proliferation and survival. It increases the toxicity of anthracyclines and thereby indirectly the risk for LQTS and Tdp. These effects are at least partially reversible [12, 22, 23, 35]. Tyrosine kinase inhibitors and angiogenesis inhibitors QT interval prolongation is commonly observed during treatment with tyrosine kinase inhibitors (e.g., dasatinib, imatinib, erlotinib, used as treatment for hematologic malignancies) and angiogenesis inhibitors, such as bevacizumab and vandetanib (typically used to treat non-small cell lung cancer and malignancies of the gastrointestinal

Even though anthracyclines are rather old drugs, the physician needs to be well aware of their potential for adverse effects. New targeted therapy agents, such as monoclonal antibodies and receptor blockers can increase the effect of QT prolongation of these older drugs or lead to cardiac toxicity by themselves [39]. As mentioned above, this has been described in particular for anthracyclines or paclitaxel in combination with trastuzumab [22, 23, 35, 40]. In fact, almost one third of post-marketing withdrawals of the new targeted therapy agents have been due to QT interval prolongation or Tdp [37]. Concomitant medication Other drugs commonly used in cancer patients for comorbid conditions and treatment-related complications may also cause LQTS (Table 2).

Table 2 Pharmaceutical agents often used concomitantly in cancer patients which can cause QT interval prolongation

Analgesics

Antiemetics

Antimicrobials

Alternative medicine

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Pharmaceutical agent

Clinical aspects

Methadone

Most common QT interval prolonging drug within group of analgesics (5–30%), QT interval shortens rapidly after discontinuation

Buprenorphine

Less pronounced than methadone

Oxycodone

Dose-dependency

5-HT3-antagonists

QT interval shortens rapidly after discontinuation

Haloperidol

Hypokalemia and hypomagnesemia are strongest risk factors for Tdp, LQTS can occur even with low doses

Promethazine

Very low arrhythmogenic potential

Fluoroquinolones

Delayed onset of QT prolongation, patients who experience LQTS usually have multiple risk factors

Macrolides

Patients who experience LQTS usually have multiple risk factors

Telavancin

Clinical significance yet to be determined

Trimethoprim-sulfamethoxazole

LQTS very rare

Azoles

LQTS can occur even with low doses

Foscarnet

Can lead to severe hypocalcemia causing QT interval prolongation

Amantadine

High doses only

Pentamidine

Chemical similarity to procainamide

Cesium

Treatment consists of Prussian blue and electrolyte replacement

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Analgesics Pain is a symptom faced by almost every cancer patient during the course of the disease. In accordance with the World Health Organization (WHO) analgesic ladder, it often requires multiple and very potent analgesic drugs to control pain and its associated symptoms. QT interval prolongation generally occurs most often (5–30%) with methadone due to CYP3A4 interactions and direct hERG K? channel inhibition. Therefore, a close EKG monitoring throughout the therapy is warranted. The QT interval shortens rapidly after discontinuation of methadone [33, 41– 46]. Buprenorphine is regarded as a safer alternative even in patients who developed Tdp while receiving methadone, as its QT interval prolonging effect is less pronounced [33, 46– 48]. Oxycodone dose-dependently inhibits hERG K? channel and can thus cause LQTS as well [33, 49]. Antiemetics Chemotherapy, pain, antibiotics and the tumor itself or its complications, among other substances and causes, can provoke nausea and emesis, which substantially decreases the perceived sense of wellbeing. Unfortunately, 5-HT3antagonists and promethazine, as some of the most commonly used antiemetics, are known to cause QT interval prolongation and may subsequently lead to cardiac arrhythmias. If LQTS is observed during therapy with 5-HT3-antagonists, a close monitoring for 8 h after discontinuation of the drug is sufficient, as the QT interval prolongation subsides quickly [33, 50, 51]. Promethazine can cause LQTS via direct hERG K? channel inhibition and CYP450 interactions, but clinical data suggest that its arrhythmogenic potential is very low [52, 53]. Haloperidol, often used in an antiemetic intention, causes QT interval prolongation as most antipsychotics. Accompanying hypokalemia and hypomagnesemia are the strongest risk factors for LQTS and subsequent Tdp. There are several reports of Tdp even in patients who only received a low dose of haloperidol [54–57]. Antimicrobials

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consequences such as Tdp and ventricular fibrilation are relatively rare. The onset of the QT interval prolongation may be delayed [58–62]. Macrolides interact with hERG K? channels as well [58–60, 63]. The new antibiotic televancin also prolongs the QT interval, but no significant clinical adverse effects have been reported to date [64, 65]. LQTS seems to be a very rare complication of treatment with trimethoprim-sulfamethoxazole [60]. Special attention needs to be paid while using Azole antifungals, as a potential QT interval prolongation may happen independently of the dose. Direct hERG K? channel inhibition versus CYP3A4 interaction are debated as mechanism of actions, but the current findings are contradictory [66–70]. Foscarnet binds calcium; this can lead to a severe hypocalcemia, thus indirectly prolonging the QT interval. Cases of indirect QT interval prolongation have been reported with very high doses or overdosing of amantadine, as this agent causes hypokalemia [71]. The mechanisms of the QT interval prolonging effects of pentamidine are unknown, but its chemical similarity to the antiarrhythymic procainamide suggests interactions with cardiac ion channels [58, 60, 61, 72]. Alternative medicine Some cancer patients also use nutritional supplements or seek help from alternative medicine practitioners who may advise them to use specific ‘‘natural’’ remedies [73, 74]. Several cases of a cesium-induced life-threatening Tdp have been reported, the treatment in such situations consists of Prussian blue and electrolyte replacement [75, 76].

Considerations for risk assessment To evaluate an individual patient’s risk of developing a clinically relevant LQTS, several additional factors need to be taken into consideration (Table 3). A higher incidence Table 3 Risk factors for life-threatening events in patients with LQTS Risk factors for life-threatening events in patients with LQTS Female sex

Many cancer patients acquire infections during the course of their treatment, often because of a chemotherapyinduced neutropenia. In patients with hematologic malignancies, a prophylactic use of antimicrobials is therefore commonly indicated. Fluoroquinolones and macrolides are infamous for the potential QT interval prolongation due to the vast experience with these drugs, but this adverse reaction almost exclusively happens in patients with multiple risk factors for LQTS [58]. Fluoroquinolones cause a direct hERG K? channel inhibition, but severe

Older age ([40 years) Adolescent male History of symptoms Positive family history QT interval prolonging drugs Subtype of genetic mutations in LQT1–LQT12 genes Bradycardia Coronary artery disease Structural heart disease

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of prolonged QT interval and Tdp has been shown repeatedly in women [77–81]. This is true for congenital variants of LQTS as well as for a drug-induced prolongation of the QT interval [77]. Data suggests that estrogens predispose to LQTS, while androgens reduce drug effects on cardiac repolarization. Gender-related differences in cardiac ion channels have been discussed as well [80]. However, these findings are not sufficient enough to completely account for the significant sex-related differences in the risk of arrhythmia. Older patients ([40 years) and male adolescents are at an increased risk for LQTS [82, 83]. Close genetic kinship to a population with certain founder mutations is consistent with an increased chance to suffer from LQTS [84, 85]. Ethnicity is debated as an additional factor, but the results remain inconclusive [86– 89]. Cancer patients commonly face several symptoms which require pharmacologic interventions at once; therefore, it is important to evaluate the patient’s medication profile to identify all drugs that may prolong the QT interval. Also, as many of the QT interval prolonging drugs are metabolized by the cytochrome P450 isoenzyme CYP3A4, interaction of these or inhibition of CYP3A4 increases the risk for a life-threatening Tdp [90]. A preexisting structural or vascular heart disease is another risk factor for a clinically relevant prolongation of the QT interval [61, 86, 90–92]. Certain chemotherapeutic agents, such as anthracyclines, alkylating agents, fluorouracil, bevacizumab or trastuzumab, and mediastinal radiation treatment can lead to structural heart damage. Therefore, a continuous monitoring of cardiac function may be necessary even for patients without any past cardiovascular history [14, 23, 31, 40]. Electrolyte disorders, more specifically hypokalemia as well as hypomagnesemia and hypocalcemia, are very common in cancer patients due to malnutrition, polypharmacy, or infusion therapy and increase the risk of Tdp [67, 90, 93].

Clinical consequences LQTS may have serious or even fatal consequences for a cancer patient. The risk for LQTS is considerable in this patient population due to the high potential for multiple drug interactions, cancer-related pathologies and treatmentassociated long-term sequelae. Therefore, we propose a multi-step screening approach to select cancer patients for further testing and prevention of LQTS and its potential complications (Fig. 1). Additional diagnostic and preventive steps should be based on these findings, thus avoiding unnecessary and costly measures, while ensuring a high-level of patient safety. Initially, all cancer patients should be screened for a family history and a past medical history positive for a

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Fig. 1 Risk assessment for LQTS in cancer patients: A systematic analysis of risk factors determines the appropriate diagnostic and preventive measures and influences the therapeutic regimen

diagnosis of LQTS and genetic syndromes associated with QT interval prolongation, unexplained cases of sudden death or syncopes. Past cardiovascular problems or cardiac risk factors including again the family history as well as previous cardiotoxic treatments complete this step. An EKG should be obtained for all cancer patients to have a baseline measurement of the QT interval length. Depending on the information obtained from the medical history, further workup may be necessary, such as Holter EKGs for unexplained syncopes, molecular testing for patients with a suspicion for an inherited LQTS or echocardiographic imaging, and stress testing in patients with a presumed or confirmed structural heart disease. In cases of chemotherapy-induced cardiomyopathy, brain natriuretic peptide and other biomarker testing may be helpful in assessing the risk, too [22, 94]. Careful evaluation of the patient for presyncopal events, syncopes, and palpitations is a cornerstone to early diagnosis and intervention. Caregivers, such as nurses and family members, need to be aware of these signs and should report them immediately to the physician. For drugs which dose-dependently increase the QT interval, patients need to be monitored with daily EKGs and, if additional risk factors are present (Table 3), may require telemetry monitoring during dose-increased phases. In patients with a confirmed LQTS, the following preventive measures are considered standard of care [95–98]: • • • • •

avoidance of strenuous physical activity avoidance of vagal stimulation avoidance of emotional stress use of beta-blockers in patients with a genetic form of LQTS avoidance/cautious use of beta-blockers in patients with acquired LQTS

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The use of beta-blockers in patients with long QT syndrome aims at blunting the adrenergic surge associated with emotional or physical stress by reducing the QT hysteresis (the adaptation delay of the QT interval to heart rate changes) [98]. However, beta-blockers also reduce the heart rate and thus prolong the QT interval. Therefore, we recommend a selective use of this drug in high-risk patients, i.e., individuals with a confirmed genetic form of LQTS (LQT1 genotype, in particular [99]). For patients who remain symptomatic and refractory to standard initial therapy, the necessity to perform a left cardiac sympathetic denervation and to implant an implantable cardioverter-defibrillator needs to be considered [8, 95, 96, 100]. If a cancer patient develops QT interval prolongation during his treatment course, the triggering drugs should be identified and discontinued, if possible. Otherwise, close clinical monitoring is necessary. Potassium levels should be kept in a high-normal range and magnesium levels need to be kept above 2.0 mg/dl to reduce the risk of hypokalemia- or hypomagnesemia-associated Tdp. If necessary, electrolyte replacement needs to be adjusted to other existing conditions, such as renal insufficiency. Also, genetic testing for LQTS mutations should be considered, as drug-induced LQTS may reflect a subclinical form of the inherited variants [10].

Conclusion LQTS, although not an ‘‘everyday practice problem’’, is a potentially fatal, but preventable side effect of medications typically used in cancer patients. As with every medication, physicians need to be aware of the potential side effects, common and rare ones, to weigh the risks and benefits for an individual patient. QT interval prolongation and subsequent Tdp are relevant adverse effects that may occur with typical treatment regimens used in a curative intention. Even though many patients remain asymptomatic, some suffer from potentially fatal Tdp. In patients with a non-curable condition, the focus of care shifts towards quality of life. The prevention of LQTS and its deadly sequelae should be within the focus of this care, as the simple selection of a different antibiotic or analgesic is often the only necessary measure. Therefore physicians working with cancer patients in a palliative situation should be aware when supportive care measures may pose additional risks, how to prevent them as well as how to recognize and treat them. Risk assessment and stratification are complex tasks, as multiple factors need to be taken into consideration, such as genetics, drug–drug interactions and preexisting cardiac conditions. In addition, fluctuating parameters, e.g., drug

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dosages and electrolyte abnormalities, may influence the severity of symptoms and the response to therapeutic interventions. Multiple other drugs used in conditions not directly caused by or related to the malignancy and its treatment may lead to a prolonged QT interval, either directly or via enzyme inhibition. Therefore, the evaluation for a possible or worsening QT interval prolongation still varies from case to case. We propose an approach to facilitate and structure such a complex task. Early recognition, treatment and monitoring of patients at risk is a complex but manageable task in the medical care of cancer patients.

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