Review

The QT interval prolongation potential of anticancer and

supportive drugs: a comprehensive overview
Eline L Giraud*, Kaylee R M Ferrier*, Nienke A G Lankheet, Ingrid M E Desar, Neeltje Steeghs, Rypko J Beukema, Nielka P van Erp, Elise J Smolders

Patients with cancer are prone to prolongation of the corrected QT interval (QTc) due to the use of anticancer drugs Lancet Oncol 2022; 23: e406–15
with QTc-prolonging potential in combination with electrolyte imbalances caused by, for example, gastrointestinal *Joint first authors
side-effects. However, most anticancer drugs were approved with little information on their QTc-prolonging potential Department of Clinical
and the added risk of torsade de pointes. The absence of this information on the drug label poses a considerable Pharmacy, Radboud Institute
challenge to clinicians regarding the measures that need to be taken to safely start anticancer treatment. In this for Health Sciences
(E L Giraud PharmD,
Review, we provide a comprehensive overview of the evidence for the QTc-prolonging properties of 205 anticancer Prof N P van Erp PhD,
drugs and 14 antiemetic drugs available from drug labels, assessment reports, and published studies. We classify the E J Smolders PhD), Department
drugs as low-risk, moderate-risk, or high-risk for QTc prolongation. We also discuss the clinical relevance of these of Medical Oncology
(I M E Desar MD), and
findings and include practical recommendations to guide clinicians to select the drugs with the least QTc-prolonging
Department of Cardiology
properties and to adequately monitor susceptible patients. (R J Beukema PhD), Radboud
University Medical Center,
Introduction torsade de pointes, a history of cardiovascular diseases, Nijmegen, Netherlands;
Department of Clinical
Cancer is one of the leading causes of death, accounting older age (>65 years), female sex, a family history of (or
Pharmacy, Medisch Spectrum
for around 10 million deaths worldwide in 2020.1 In genetic predisposition to) congenital long QT syndrome, Twente, Enschede, Netherlands
the same year, 19·3 million new cases of cancer were a high baseline QTc, hypothyroidism, the use of other (K R M Ferrier PharmD,
reported, and this number is expected to increase in the drugs that can prolong the QT interval, and reduced N A G Lankheet PhD);
Department of Medical
coming years.1 Many anticancer drugs are therefore kidney or liver function.9,10
Oncology, Netherlands Cancer
in clinical use, with even more being approved as drug Patients with cancer are susceptible to QTc prolongation Institute, Amsterdam,
development continues. because they often take many drugs at the same time, Netherlands (N Steeghs MD);
Each anticancer drug has its own risk–benefit profile. including anticancer and supportive drugs alongside any Department of Clinical
Pharmacy, Isala Hospital,
One important and potentially harmful property is the drugs used for comorbidities. Furthermore, patients with
Zwolle, Netherlands
ability to prolong cardiac repolarisation, which is reflected cancer frequently have electrolyte imbalances due to (E J Smolders)
in the electrocardiogram (ECG) by a prolonged QT interval. malignancies and common gastrointestinal side effects Correspondence to:
The QT interval is the interval between the beginning of such as nausea, vomiting, and diarrhoea, which increase Dr Elise J Smolders, Department
the QRS complex and the end of the T wave on the ECG, the risk of QTc prolongation. Health-care professionals of Clinical Pharmacy, Radboud
University Medical Center,
and can be corrected by the heart rate to give the corrected should therefore be aware of the risks of drug-induced
Nijmegen 6500, Netherlands
QT interval (QTc).2 One of the most severe consequences QTc prolongation and possible subsequent life- elise.smolders@radboudumc.nl
of a prolonged QT interval is a ventricular arrythmia threatening arrhythmias.11
known as torsade de pointes, which can lead to sudden In the early stages of drug development, all new chemical
death.3 Although uncertain, several studies have estimated entities first undergo preclinical assessments in which in-
the incidence of drug-induced QTc prolongation and vitro hERG assays and in-vivo QT assays are done to study
subsequent torsade de pointes, with results ranging the potential risk of delayed ventricular depolarisation and
from 0·8 to 4·0 per million person-years.4 Unfortunately, QTc-interval prolongation in humans.12,13 On the basis of
data on the incidence of torsade de pointes in patients with these assays, drugs can either be rejected for clinical
cancer is currently absent. A proposed mechanism by testing or go into phase 1 of clinical drug development. For
which drugs can prolong the QT interval is by blocking most drugs, thorough QT/QTc studies are usually done in
the cardiac human ether-a-go-go-related gene (hERG) healthy volunteers to evaluate whether a drug is likely to
potassium channel. This channel blockage disturbs the prolong the QTc interval.14,15 However, for anticancer drugs,
balance of influx (through calcium and sodium channels) these studies are usually conducted in the target patient
and efflux (through potassium channels) of electrolytes population owing to safety concerns, in which patients
leading to delayed repolarisation of the heart, which is with baseline normal QTc and electrolyte values are
characterised by a prolonged QT interval.5 The hERG selected. Reference values for the QTc interval are 450 ms
channel is one of multiple ion channels that QTc- or less for men and 470 ms or less for women, according to
prolonging drugs block, but other channels and guidelines from the European Society of Cardiology16 and
mechanisms have also been described.6 For example, on the American Heart Association.17 A QTc interval of at least
the basis of an in vitro study, Roden and colleagues 500 ms or prolongation of at least 60 ms from the baseline
suggested that tyrosine kinase inhibitors can prolong the are usually used as thresholds for the discon­ tinuation
QT interval either by directly inhibiting phosphoinositide of treatment. Guidelines from the European Medicines
3-kinases or by inhibiting upstream kinases.7,8 Agency (EMA)14 and the US Food and Drug Administration
The most important risk factors for developing a (FDA)15 state that drugs that prolong the mean QTc interval
prolonged QT interval include a history of drug-induced by less than 5 ms, with the upper bound of the 95% CI less

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 Review
369 drugs identified from search of ATC code L01
(excluding L01XD), L02B, and L04
79 excluded (no EMA, US FDA, or MHRA
registration)
85 excluded (drugs that are diagnostic, are not
used for a malignant disease, are registered
as a combination of two drugs, are not used
systemically, or have a double ATC code)
205 anticancer drugs included for evaluation
Figure 1: Selection of anticancer drugs
ATC=Anatomical Therapeutic Chemical. EMA=European Medicines Agency.
US FDA=United States Food and Drug Administration. MHRA=Medicines and
Healthcare products Regulatory Agency.
than 10 ms, do not seem to cause torsade de pointes and
can therefore be classified as low-risk drugs. Drugs that
cause a QTc interval prolongation of at least 5 ms but less
than 20 ms, with an upper bound of the 95% CI of at least
10 ms, are classified as moderate-risk drugs. Drugs that
prolong the mean QTc interval by 20 ms or more are
classified as high-risk drugs, as they have a substantially
increased risk of being proarrhythmic. For moderate-risk
and high-risk drugs, additional research in subsequent
phases of drug development to evaluate the risk of QTc
prolongation is mandatory.
Although thorough QT/QTc studies can give an
indication of the extent of QTc prolongation, these
phase 1 studies are done under controlled circumstances
See Online for appendix in patients with cancer who still have a good performance
status. Therefore, the extrapolation of these results to the
real-world population with cancer, who are more prone
to QTc prolongation, should be done with caution. The
prediction of whether patients are at risk of QTc
prolongation is complicated by limitations in the clinical
decision support systems in hospitals. These systems
generate QT alerts solely on the basis of drug–drug
interactions and lack, for example, the ability to account
for patients’ individual risk factors. This Review provides
a comprehensive overview of the available information,
through which we aim to help health-care professionals
to make a balanced decision in the treatment of patients
with cancer, select the drugs with the least QTc-
prolonging properties, and provide close monitoring for
susceptible patients.
Data collection
Drug selection
For this Review, we identified anticancer drugs using
the WHO Collaborating Centre for Drug Statistics
Methodology index, searching for drugs with anatomical
and therapeutic chemical (ATC) codes L01 (antineoplastic
agents; excluding L01XD [sensitisers used in photo­
dynamic or radiotherapy]), L02B (endocrine therapy),
e407 www.thelancet.com/oncology Vol 23 September 2022
and L04 (immunosuppressants). Only anti­cancer drugs
with EMA or FDA approval or that were registered with
the UK Medicines and Healthcare products Regulatory
Agency (MHRA) up to Feb 4, 2022 were included. The
following drugs were excluded from selection: diagnostic
anticancer drugs, drugs not used for a malignant disease,
drugs that are not used systemically (eg, those for dermal
or intravitreal use), or drugs with a double ATC code
(figure 1).
Because many anticancer drugs are prescribed in
combination with antiemetics, we expanded this Review
to include the 14 recommended antiemetics listed in the
American Society of Clinical Oncology18 and European
Society for Medical Oncology19 guidelines. Furthermore,
we provide general considerations regarding the use of
analgesics, antidepressants, antibiotics, and antifungals.
Search strategy and selection criteria
We searched PubMed and official drug registration
documentation as published by the FDA, EMA or MHRA
between Dec 15, 2021, and Feb 4, 2022. We used the most
recently published official US prescribing information
and clinical pharmacology and medical reviews from the
FDA website. We retrieved the latest Summary of Product
Characteristics from the MHRA website or from the
European Public Assessment Report on the EMA website.
If different generic versions were available, we used the
label or Summary of Product Characteristics for the
originally registered product. For PubMed searches, we
used a search strategy combining synonyms and available
medical subject headings for QTc prolongation (“torsades
de pointes”, “long qt syndrome”, “qt prolongation”, and
“qt”) and the specific drug name (appendix, p 2). Only
articles published in English were included.
Evidence synthesis
For all included anticancer drugs, we searched FDA labels,
Summary of Product Characteristics, clinical pharma­
cology, and medical and other reviews from the FDA, and
European Public Assessment Reports and scientific
discussions from the EMA, for information concerning
QTc prolongation. From the PubMed searches, articles and
case reports were included if they contained relevant
information on QTc prolongation. Only studies performed
in humans were included. Two independent reviewers
(KRMF and ELG) searched the literature and summarised
the data in the appendix (pp 3–36). The summary was
independently reviewed by an expert (EJS).
For each drug, we summarise the following information
in the appendix (pp 3–36): the maintenance dose as listed
in the EMA, FDA, or MHRA label; the doses tested in the
thorough QT/QTc study; the corresponding observed
change in mean QTc; whether QTc-interval prolongation
is concentration-dependent; the time taken to reach peak
plasma concentration (Tmax), because this is when the most
pronounced QTc prolongation is expected; and the quality
(described by the level of evidence) of the available

information on the QTc-prolonging properties of the drug.
The risk classification (low, medium, or high) was then
given on the basis of collected data and on the ranges
specified in the QT/QTc guidelines.14,15 If descriptive
information on QTc prolongation was provided in one of
the data sources, it was added to the comments section of
the appendix. For all studies, the levels of evidence were
added on the basis of the International Conference on
Harmonization (ICH) E14 guidance (clinical evaluation of
QT/QTc interval prolongation and proarrhythmic potential
for non-antiarrhythmic drugs) and explained in the
panel.14,15 For levels of evidence 2 and 3, we stated whether
the value for mean QTc change was placebo-corrected.
When QT studies are not placebo-corrected, the risk
classification can be falsely high, which should be
considered when interpreting the data.
To predict the extent of QTc prolongation, the half-
maximal inhibitory concentration (IC50) for the hERG
channel of a drug at its maximum plasma concentration
(Cmax) has been used in previous studies.20 However,
because the predictive effect of the in-vitro ability of a
drug to block the hERG channel on the risk of QTc
prolongation is inconclusive and can sometimes
contradict the results of the thorough QT/QTc study, this
value was not included in the appendix.6 Moreover,
because QTc prolongation was not concentration-
dependent (or was not known to be concentration-
dependent) for many drugs, use of the hERG IC50 and the
Cmax was not considered to be clinically relevant.
Results
We identified 205 eligible anticancer drugs and
14 antiemetic drugs from a search done between
Dec 15, 2021, and Feb 4, 2022. All anticancer drugs are
listed in alphabetical order, with their expected risk
classification, in the appendix (pp 3–33). A thorough QT/
QTc study according to guidelines had been conducted
for only 22 of these anticancer drugs. For 133 (65%) of
the 205 drugs, we added an expected risk classification
on the basis of the collected data (level of evidence 2 or 3).
Considering all of the expected risk classifications, we
identified eight high-risk drugs, 40 moderate-risk drugs,
and 107 low-risk drugs; for 50 drugs, no data on QTc
prolongation were available. All antiemetic drugs, with
their expected risk classification, are listed in the
appendix (pp 34–36). These include two moderate-risk
drugs and nine low-risk drugs; for three antiemetics, no
data on QTc prolongation were available. We summarise
all included drugs and their risk classifi­cation in figure 2.
To help health-care professionals to make a balanced
decision on the use of drugs with QTc-prolonging
potential in daily clinical practice, we developed a
flowchart (figure 3) on the basis of evidence from the
literature and expert opinion. We used the classifications
of low-risk, moderate-risk, or high-risk drugs as stated
in the appendix (pp 3–36). Before the start of anticancer
or supportive therapy, additional measures can be
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Review
Panel: Levels of evidence
• Level 0: no thorough QT/QTc study is required for large,
targeted proteins and monoclonal antibodies according
to the ICH E14 guidelines
• Level 1a: a thorough QT/QTc study according to ICH E14
guidelines (eg, in healthy volunteers, placebo-corrected
and with a positive control)
• Level 1b: level of evidence 1a, but in the desired patient
population
• Level 2: prospective clinical trial, not following the ICH
E14 guidelines
• Level 3: small observational study, case reports, or both
• Level 4: no evidence
ICH=International Conference on Harmonization.
taken to reduce the risk of QTc-prolongation-related
arrhythmias, such as pausing or discontinuing treatment
(if possible) with concomitant drugs that could cause or
enhance QTc prolongation, using the lowest dose for the
shortest duration possible, and correcting electrolyte
abnormalities (if applicable). When a patient is known to
have long QT syndrome, which is an absolute contra­
indication for starting QTc-prolonging drugs, consul­
tation with a cardiologist is recommended to discuss the
possible risks of fatal arrhythmias and the benefits of
anticancer treatment. Consulting a cardiologist is also
recommended if a patient develops a QTc interval of
500 ms or more; some of these patients could have an
unknown congenital long QT syndrome or could be
genetically predisposed to develop drug-induced QTc
prolongation,10 which could also have consequences for
their family members. However, other patients with a
normal QTc interval but a predisposed risk of QT
prolongation cannot be identified upfront on the basis of
their baseline ECGs. Furthermore, if the QTc-prolonging
drug has a concentration-dependent QTc-prolongation
effect, the QTc interval is not expected to be prolonged
after reaching the Cmax.21 Therefore, in cases for which an
ECG is recommended, it should be recorded at the time
of Cmax (Tmax), preferably at steady-state concentrations
(after 3–5 elimination half-lives). For drugs with a long
half-life, recording an ECG both at the first Tmax and at Tmax
at steady state should be considered. The ECG should be
repeated after dose changes or changes in any risk factors,
such as electrolyte imbalances. When patients are at risk,
they should be informed to immediately warn a physician
when having palpitations, lightheadedness, or dizziness.
Several risk models have been designed to help to
identify patients at high risk of developing QTc-interval
prolongation when using two or more QTc-prolonging
drugs.22,23 However, predicting the effect on QTc pro­
longation when two or more drugs with QTc-prolonging
properties are used simultaneously is difficult. In clinical
practice, if the QTc interval is less than 500 ms or there is
 Review

Anticancer drugs Antiemetics

High risk of QTc prolongation

Arsenic trioxide Ivosidenib Ribociclib Toremifene*

Imatinib Nilotinib Thiotepa Vandetanib

Moderate risk of QTc prolongation

Abirateron Capecitabine Encorafenib Ixazomib Pralatrexate Talazoparib Dolasetron*

Aflibercept Ceritinib Eribulin Lapatinib* Romidepsin Tegafur Domperidone*
Apalutamide Cladribine Enzalutamide Melphalan Rucaparib Tivozanib Ondansetron*
Axitinib Crizotinib 5-Fluorouracil Nilutamide Selpercatinib* Trifluridine
Avapritinib Darolutamide Flutamide Osimertinib Sorafenib Vemurafenib
Bicalutamide Dasatinib Gilteritinib Panobinostat Sotorasib
Cabozantinib* Duvelisib Glasdegib* Pazopanib Sunitinib*

Low risk of QTc prolongation†

Abemaciclib Bosutinib* Dostarlimab Isatuximab Olaparib Sacituzumab govitecan Aprepitant*

Acalabrutinib* Brentuximab vedotin Durvalumab Ixabepilone Olaratumab Selinexor Fosaprepitant*
Afatinib Brigatinib Elotuzumab Larotrectinib* Omacetaxine mepesuccinate Sonidegib Fosnetupitant*
Alectinib Cabazitaxel Enasidenib Lenalidomide* Palbociclib Tazemetostat Granisetron
Alemtuzumab Calaspargase-pegol Enfortumab vedotin Lenvatinib* Panitumumab Temsirolimus Netupitant*
Alpelisib Capmatinib Entrectinib Lurbinectedin Pembrolizumab Tepotinib Olanzapine
Amivantamab Carfilzomib Erdafitinib Midostaurin* Pemigatinib Trabectedin Palonosetron*
Asciminib Cemiplimab Erlotinib Mitotane Pertuzumab Trametinib Rolapitant
Asparaginase Cetuximab Everolimus* Mogamulizumab Pexidartinib* Trastuzumab
Atezolizumab Clofarabine Fedratinib Moxetumomab psudotox Polatuzumab vedotin Trastuzumab deruxtecan
Avelumab Cobimetinib Fludarabine Necitumumab Pomalidomide* Trastuzumab duocarmazine
Belantamab mafodotin Copanlisib Gefitinib Nelarabine Ponatinib Trastuzumab-emtasine
Belinostat Dabrafenib Gemtuzumab ozogamicin Neratinib* Pralsetinib Tucatinib*
Bendamustine Dacomitinib Ibrutinib* Nintedanib Ramucirumab Venetoclax
Bevacizumab Daratumumab Idelalisib* Niraparib Regorafenib Vismodegib*
Binimetinib Decitabine Infigratinib Nivolumab Ripretinib Vorinostat
Blinatumomab Dinutuximab Inotuzumab ozogamicin Obinutuzumab Rituximab Zanubrutinib*
Bortezomib Docetaxel Ipilimumab Ofatumumab Ruxolitinib*

No available evidence

Amsacrine Cyclophosphamide Fulvestrant Mercaptopurine Procarbazine Treosulfan Dexamethasone

Anastrozole Cytarabine Gemcitabine Methotrexate Raltitrexed Vinblastine Prochlorperazine
Azacitidine Dacarbazine Hydroxycarbamide Mitomycin Streptozocin Vincristine Metoclopramide
Bleomycin Dactinomycin Idarubicin Mitoxantrone Tamoxifen Vinflunine
Busulfan Daunorubicin Ifosfamide Oxaliplatin Temozolomide Vinorelbine
Carboplatin Doxorubicin Irinotecan Paclitaxel Teniposide
Carmustine Epirubicin Letrozole Pemetrexed Thalidomide
Chlorambucil Etoposide Lomustine Pentostatin Thioguanine
Cisplatin Exemestane Lorlatinib Pixanrone Topotecan

Figure 2: Risk classification of anticancer and antiemetic drugs

*A thorough QT/QTc study according to the ICH E14 guidelines has been conducted. For all other drugs, the risk classification is the authors’ expectation, as no thorough QT/QTc study according to the
ICH E14 guidelines has been done or no evidence is available. †No thorough QT/QTc study is required for large, targeted proteins and monoclonal antibodies. A low risk of QTc prolongation is expected.

For CredibleMeds see
https://crediblemeds.org/
an increase of less than 60 ms from the baseline value, a
third drug can carefully be added. The sum of the average
QTc interval prolongations (appendix, pp 3–36) per drug
could also give an indication of the total expected QTc
prolongation.21 Although it seems rational to expect an
additive risk of QTc prolongation when using two or
more QTc-prolonging drugs, clinical evidence for this is
inconclusive and this strategy is therefore conservative.
Potential risk of QTc prolongation with
supportive drugs
Other drug classes that are frequently used by patients
with cancer include analgesics, antidepressants, anti­
biotics, and antifungals. The potential for these drugs
to prolong the QTc interval can be searched on
CredibleMeds, which is a database that categorises drugs
into the following groups: drugs with a known risk of
torsade de pointes, drugs with a possible risk of torsade de
pointes, drugs with a conditional risk of torsade de pointes,
drugs to avoid in congenital long QT syndrome, and drugs
that are not classified. Combinations of drugs can increase
the risk of QTc prolongation owing to pharmacodynamic
and pharmacokinetic drug inter­actions. Pharmacodynamic
interactions occur when two or more drugs that indivi­
dually prolong the QTc interval are used simultaneously
(figure 2). Pharmaco­kinetic interactions are caused by, for
example, the inhibition of drug-metabolising enzymes or
drug transporters, resulting in higher concentrations of
(and therefore higher exposure to) the drug that has a risk
of QTc prolongation.11
Analgesics
Opioids such as morphine, oxycodone, fentanyl,
buprenorphine, and methadone are frequently used by

e409 www.thelancet.com/oncology Vol 23 September 2022

 Review

Patient with malignancy starting anticancer treatment

Risk factors for QTc prolongation?

Female sex, age ≥65 years, electrolyte imbalances (drug-induced or otherwise), history of cardiovascular diseases,
reduced kidney or liver function, use of ≥1 QTc-prolonging drug, congenital LQTS or a family history (absolute
contraindication), baseline QT interval ≥450 ms (male) or ≥470 ms (female), and hypothyroidism

Yes No

Absolute contraindication Congenital LQTS?

• Consult cardiologist to discuss risk–benefit Yes
assessment and possible treatment options

No

• Correct electrolyte imbalances

• Discontinue or find low-risk alternative to
QTc-prolonging comedication
QTc interval
below threshold
Record baseline ECG

Prolonged QTc interval

Patient at risk of QTc prolongation Patient not at risk of QTc prolongation

Determine risk classification of anticancer drug and supportive drug

Anticancer drug and supportive drug Anticancer drug

High Moderate Low Low

plus plus plus or
moderate or high moderate low or moderate moderate
or high or
high

Moderate or high risk comedication or Recommendation based on highest

supportive drug in use? risk factor

Yes

Look for alternative comedications and No Patient at risk of QTc prolongation Patient not at risk of QTc prolongation
supportive drugs to safely start Low: start drug Low or moderate: start drug
Alternatives anticancer treatment Moderate or high: record baseline ECG High: record baseline ECG and ECG at
possible and ECG at Tmax Tmax

No alternatives

Record baseline ECG and ECG at Tmax

Interpretation of ECG results

• QTc interval <500 ms or <60 ms increase from baseline: continue drug
• QTc interval ≥500 ms or ≥60 ms increase from baseline: discontinue QTc prolonging drug until QTc interval <500 ms or <60 ms from baseline.
If discontinuation is not desirable, discuss potential risks with patient or family. Consider consulting cardiologist.

Figure 3: Decision support flowchart when prescribing QTc-prolonging anticancer drugs and supportive drugs
LQTS=Long-QT syndrome. QT interval=interval between the Q wave and the T wave in the heart’s electrical cycle. QTc=corrected QT interval (corrected by heart rate). ECG=electrocardiogram. Tmax=time
to peak plasma concentration.

patients with cancer to control pain. The product label during treatment, especially at high daily doses
for methadone warns that several cases of QTc (>200 mg/day).24–26 CredibleMeds also states that
prolongation and torsade de pointes have been observed methadone has an increased risk of QTc prolongation; as

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 Review
such, changing to or starting with a low-risk opioid,
such as fentanyl, is recommended. The tricyclic anti­
depressants nortriptyline and amitriptyline, which are
used to treat neuropathic pain, can also prolong the QTc
interval according to CredibleMeds. Although no risk
classification for amitriptyline could be made owing to
the absence of a thorough QT/QTc study, its drug label
recommends that an ECG is recorded before the start of
treatment, and that the drug should be used with caution
in patients with electrolyte imbalances, as this increases
the risk of arrhythmias. Pregabalin (or other anti­
convulsive agents) could be used as a safer alternative to
amitriptyline as little effect on the QTc interval is expected
from drugs of this class, although no thorough QT/QTc
study has been conducted.27
Antidepressants
Patients with cancer often develop depression and
therefore frequently use antidepressants.28 As discussed,
amitriptyline and nortriptyline are known to prolong the
QTc interval; other antidepressants known for their
QTc-prolonging properties are the selective serotonin
reuptake inhibitors (SSRI) citalopram and escitalopram.
A placebo-controlled clinical trial showed a dose-
dependent QTc prolongation of 7·5 ms (90% upper CI
9·1 ms) for a dose of 20 mg/day citalopram and 16·7 ms
(18·4 ms) for a dose of 60 mg/day citalopram, suggesting
that citalopram is a low-risk or moderate-risk drug,
depending on the dose.29 For both citalopram and
escitalopram, which showed similar values, several cases
of QTc-prolongation—including torsade de pointes—
have been reported, mainly in women and in patients
with hypokalaemia, a history of cardiac diseases, or
both.29–31 The use of these drugs could therefore be
undesirable when given to patients at high risk of QTc
prolongation or together with other QTc-prolonging
anticancer drugs.32 Safer alternatives—such as the SSRIs
fluoxetine, fluvoxamine, sertraline, and paroxetine—
should be considered.33 Another alternative could be the
serotonin–norepinephrine reuptake inhibitor venlafaxine,
which was suggested to be a low-risk drug with a
QTc-prolonging potential of 3·7 ms (90% upper CI
5·8 ms).34 Health-care professionals should be aware of
possible pharmacokinetic interactions, as most SSRIs are
potent inhibitors of cytochrome P450 isoenzyme 2D6
(CYP2D6) and therefore inhibit the conversion of drugs
metabolised by CYP2D6, which could increase the
concentration of any such drugs showing concentration-
dependent QTc-prolongation.
Antifungals and antibiotics
In general, macrolide and fluoroquinolone antibiotics
and triazole antifungals have a risk of QTc prolongation.35
Notably, among fluoroquinolones and macrolides there
seems to be some intraclass variability. Ciprofloxacin (a
fluoroquinolone) and azithromycin (a macrolide) seemed
to be the safest drugs in their classes with respect to
e411 www.thelancet.com/oncology Vol 23 September 2022
cardiac toxicity profile, as indicated by very few cases of
torsade de pointes. The risk of QTc prolongation is
modest at low doses in particular, with increasing risk at
higher doses.36 A retrospective analysis of adverse drug
reactions reported in the FDA’s Adverse Event Reporting
System confirmed that macrolides (eg, azithromycin,
clarithromycin, and erythromycin) had the greatest
proportion of reports of torsades de pointes (2·7%)
among antibiotics.37
Although such studies are scarce, some triazoles have
been associated with an increased risk of QTc
prolongation and subsequent torsade de pointes.35 The
drug label for voriconazole describes a study in which the
effect on the QTc interval of oral voriconazole
(800–1600 mg) and oral ketoconazole (800 mg) was
studied.38 For both drugs, the mean maximum placebo-
corrected increase in QTc interval seemed to be less than
10 ms. Nevertheless, the drug label states that cases of
arrhythmias and torsade de pointes have been reported
during clinical development and post-marketing surveil­
lance, especially in patients with risk factors such as a
history of cardiac diseases and hypokalaemia, and those
who use other QTc-prolonging drugs. Caution should
therefore be exercised when giving voriconazole to
patients with risk factors for QTc prolongation. Caution
is also advised on the drug label for fluconazole.39 In
addition, the drug labels of both fluconazole and
voriconazole warn of their concomitant use with other
drugs that have concentration-dependent QTc-prolonging
properties and which are substrates for CYP3A4, because
both drugs are known CYP3A4 inhibitors.39
An even greater risk can arise when antibiotics and
antifungals are used simultaneously, which is not
uncommon in the treatment of patients with cancer. An
example is the use of ciprofloxacin and fluconazole,
which are commonly used as prophylaxis for and
treatment of infections in patients with haematological
malignancies.40–42 Although monotherapy with these
drugs only slightly prolonged the QTc interval, their
simultaneous use increased the QTc interval towards
10·7 ms (90% CI 7·2–14·1 ms), which suggests that
interactions between these drugs result in a moderate
risk of QTc prolongation.36
QT-interval measurements
When treatment with a QTc-prolonging anticancer drug
is started, both a baseline ECG and an ECG at the Tmax of
the QTc-prolonging drug is recommended. Although
seemingly straightforward, the proper measurement and
interpretation of the QTc interval is challenging.43,44
Lead II is used for QT measurements because the vector
axis is predominantly directed inferolateral and therefore
in the direction of lead II.45 The tangent method is
suggested for the correct measurement of the QT interval
(figure 4). In this method, a tangent is drawn to the
steepest descending slope of the assumed T wave. The
intersection of this drawn line with the baseline is

defined as the end of the T wave. The QT interval is
measured from the beginning of the QRS complex to
this intersection point. However, one problem that
clinicians can encounter when measuring the QTc
interval is discriminating between the T wave and the
U wave, which sometimes merge. In a study by Viskin
and colleagues,46 it seemed that fewer than 25% of
cardiologists and other clinicians were able to correctly
measure the QTc interval on a total of four ECGs.46
After measuring the QT interval, it is corrected for
heart rate (RR) with Fridericia’s correction method
³
QTcF = QT/√RR
using the preceding RR interval.47 Many other correction
methods have also been developed; however, all have
shortcomings and none is perfect, but Fridericia’s
correction is considered to be the most accurate and we
would recommend its use.48
Other difficulties in the interpretation of the QTc
interval can arise when the heart rate is irregular or in
the case of a pre-existing bundle branch block or
pacemaker rhythm.49,50 Furthermore, both the intra­
individual and interindividual variability in ECG
recordings can lead to inaccurate results. The ICH E14
guidelines discuss how interindividual variability can
arise from differences in activity level, circadian patterns,
and food ingestion.14,15 The guidelines suggest that this
problem could be reduced by collecting multiple baseline
ECGs during the day from each individual during the
thorough QT/QTc study to obtain an average reading.
The challenging nature of measurement and inter­
pretation of the QTc interval—in addition to inter-reader
and intrareader variability—could potentially lead to
inaccurate results, eventually leading to unnecessary
additional ECG measurements or under­estimation of the
risk of QTc prolongation.
Discussion
We assessed the QTc-prolongation risk of 205 anticancer
drugs and 14 antiemetic drugs by conducting a thorough
review of literature, drug labels, and assessment reports.
We developed a flowchart with recommendations for
prescribing QTc-prolonging drugs to patients with
cancer, which could be particularly useful in helping
clinicians to make a balanced decision because the
available data on QTc prolongation is usually obtained
under controlled settings and is therefore not always
directly transferable to patients with cancer in the clinic.
Although this flowchart could be a helpful support tool,
patients with cancer are a very heterogeneous group in
terms of, for example, fitness and presence of
comorbidities, and the extent of QTc prolongation of
each drug could therefore vary greatly between and
within individuals. Several factors can have a role in the
decision to start treatment with a QTc-prolonging drug,
in which not only are the extent of QTc prolongation and
www.thelancet.com/oncology Vol 23 September 2022 e412
Review
RR interval
R
T
P
U
Q S
QT interval
Figure 4: QT interval measurements
RR interval=interval between successive heartbeats. QT interval=interval between the Q wave and the T wave in
the heart’s electrical cycle.
existing risk factors important to consider, but also the
therapeutic urgency of starting treatment with anticancer
drugs. Balancing the risks introduced by QTc-prolonging
drugs against the risks from cancer itself and the
prognosis of the patient is therefore extremely important.
As such, the flowchart should be interpreted only by a
patient’s own clinician, who is well aware of the condition
of the patient.
The extent of QTc prolongation is an imperfect
biomarker for the risk of developing torsade de
pointes.14,15 Patients with risk factors could be more
prone to developing QTc prolongation and subsequently
torsade de pointes. However, electrolyte imbalances
(eg, hypokalaemia) are also directly related to an
increased risk of developing torsade de pointes, which
does not always lead to a prolonged QTc interval.51
Electrolyte imbalances together with the use of a
QTc-prolonging drug therefore amplify the risks of both
QTc prolongation and subsequent torsade de pointes,
and extra caution is recommended in patients who are
taking drugs that cause electrolyte imbalances, as such
drugs could already be the cause of QTc prolongation or
torsade de pointes. Electrolyte imbalances should always
be corrected in patients at risk of QTc prolongation and
torsade de pointes.
A thorough QT/QTc study following the ICH E14
guidelines had been conducted for only 22 of the
205 anticancer drugs in this Review. For the remaining
drugs, either the guidelines had not been properly
followed or little or no evidence was available. The fact
that so few thorough QT/QTc studies have been
conducted even for the newer anticancer drugs is
remarkable, because a thorough evaluation according to
the ICH E14 guideline has been obligatory since 2005.
However, following the recommended design of such a
study—randomised, double-blind, placebo-controlled,
and positive-controlled in healthy volunteers—is not
suitable for many anticancer drugs mainly because of
ethical concerns.52 One problem is the recommendation
to include at least one supratherapeutic dose, which is
usually undesirable for anticancer drugs owing to their
 Review
toxicity. Furthermore, some researchers suggest that
placebo-controlled clinical trials in patients with cancer
are unethical, and giving anticancer drugs to healthy
volunteers is often considered unethical. Owing to the
absence of a control group, the described mean QTc
change from baseline could be an over­estimation of the
true value, which should be considered when interpreting
the results. To overcome such problems, Cantet and
colleagues53 used a simulation-estimation approach to
evaluate concentration–QT modelling in the oncology
setting. Patel and colleagues54 developed a quantitative
system toxicology and safety model that used in-vitro
cardiac safety data to eventually simulate thorough QT/
QTc studies. Although not yet fully optimised, modelling
strategies could potentially replace thorough QT/QTc
studies for new anticancer drugs in the future.
An important aspect of the clinical evaluation of the QTc
prolongation of drugs is the analysis of the concentration–
response relationship.14,15,55 Surprisingly, this parameter has
been studied for only 86 drugs, of which 36 showed
concentration-dependent QTc prolongation. Because
pharmacological principles suggest that greater effects will
be seen at higher concentrations, recording ECGs at Tmax
and carefully considering drug interactions that can lead to
higher concentrations of drugs with QTc-prolongation
potential are recommended.56 The FDA guidelines also
recommend assessment of the QTc-prolongation at Cmax,
although the maximum effect on the QTc interval might
not always occur at this concentration.14,15 Additionally,
although some drugs might seem to have a low risk of QTc
prolongation according to thorough QT/QTc studies, a
prolonged QTc interval can sometimes occur only after
long-term treatment.6
One limitation of this Review is that it provides a static
overview that includes available information on QTc
prolongation summarised up to Feb 4, 2022. However,
most publications on QTc prolongation are case reports
and incidences on QTc prolongation in real-world
populations. Very few post-marketing thorough QT/QTc
studies are being done, and these are the only studies
that could potentially change the risk classifications,
based on the EMA or FDA guidelines, that we provide in
this Review. In addition to this Review, the CredibleMeds
database could also be consulted for more up-to-date
knowledge on whether a drug has a known risk for
torsade de pointes or QTc prolongation, or for
information on newly licensed drugs.57
Conclusion
In this Review we discuss the QTc-prolonging properties
of anticancer drugs and antiemetics, including practical
recommendations to help clinicians to make a balanced
decision when prescribing QTc-prolonging drugs. We
provide a comprehensive overview of the evidence
available from drug labels, assessment reports, and
published literature for 205 anticancer drugs and
14 antiemetics. Since the ICH E14 guidelines were
e413 www.thelancet.com/oncology Vol 23 September 2022
implemented in 2005, more information on the QTc-
prolonging properties of anticancer drugs has been
generated. Although imple­mentation of the guidelines is
a step forward in assessing the risk of QTc prolongation,
issues remain when conducting proper thorough QT/
QTc studies for anticancer drugs. In addition, correctly
measuring and interpreting the QTc interval is a daunting
task, especially in patients who have risk factors for QTc
prolongation. With this Review we aim to guide health-
care professionals to select the drugs with the least
QTc-prolonging properties and to monitor susceptible
patients more closely.
Contributors
NPvE and NAGL developed the concept and design of the Review.
ELG and KRMF collected the data. ELG, KRMF, NAGL, and EJS
interpreted the data. ELG, KRMF, and EJS prepared the manuscript.
EJS, NPvE, IMED, NS, NAGL, and RJB were responsible for critical
revision of the manuscript, interpretation of the literature, and
interpretation of the risk classification. All authors gave final approval of
the version to be submitted.
Declaration of interests
NS has received research grants for the Antoni van Leeuwenhoek
Ziekenhuis from AB Science, AbbVie, Actuate Therapeutics, ADC
Therapeutics, Amgen, Array, Ascendis Pharma, Astex Pharmaceuticals,
AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim,
BridgeBio, Bristol-Myers Squibb, Cantargia, Celgene, CellCentric,
Crescendo Biologics, Cytovation, Deciphera, Eli Lilly, Exelixis, Genentech,
Genmab, Gilead Sciences, GlaxoSmithKline, Incyte, InteRNA
Technologies, Janssen/Johnson & Johnson, Kinnate Biopharma, Merck,
Merck Sharp & Dohme, Merus, Molecular Partners, Novartis, Numab,
Pfizer, Laboratoires Pierre Fabre, Regeneron, Roche, Sanofi, Seattle
Genetics, Servier, Taiho Pharmaceutical, and Takeda, outside of the
submitted work. NS also attended advisory boards for Boehringer
Ingelheim and Ellipses Pharma. NPvE has received research grants for
Radboudumc from Astellas Pharma, Janssen-Cilag, Ipsen, KWF, and
ZonMW, and has received payments for Radboudumc from Sanofi,
Bayer, and Pfizer. IMED has received a research grant for Radboudumc
from EORTC-QLG and has received honoraria for the institute from
Zorginstituut Nederland. NAGL has received honoraria from Roche
Nederland. KRMF, ELG, EJS, and RJB declare no competing interests.
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