Oxaliplatin, a platinum derivative, has demonstrated significant activity against colorectal cancer in combination with 5-fluorouracil (5-FU) and folinic acid (FA), both in the adjuvant as well as the metastatic setting.2
In our institution oxaliplatin is used to treat metastatic colorectal cancer in combination with capecitabine.3
Side-effects most commonly include diarrhoea, neutropenic sepsis, anorexia, acute (laryngopharyngeal dysaesthesia) and chronic (peripheral sensory neuropathy) neurotoxicity, dyspnoea, cough, nausea and vomiting, stomatitis/mucositis, abdominal pain, constipation, fatigue, and injection site reaction.4
Our patient suffered an acute and transient episode of laryngopharyngeal dysaesthesia followed by continuous chest pain. The acute, transient oxaliplatin-induced neuropathy is thought to be due to involvement of dysfunctional voltage-gated Na+
channels causing hyperexcitablility.5
Polymorphisms of Na+
channels, in particular SCN2A R19K polymorphism associated with further voltage-gated Na+ channel alterations, appear to be responsible for channel dysfunction.6
Many mutations within sodium channels are known and some, such as mutations in the SCN5A voltage-gated Na+
channel, are associated with cardiac disorders.7
To our knowledge, none of the known mutations of voltage-gated Na+
channels implicated in oxaliplatin-induced Na+
channelopathies have been found to be involved in cardiac disorders. This case report, however, raises the possibility of an interaction between such voltage-gated Na+
channels. This appears to be the first report of oxaliplatin-induced acute coronary spasms, also known as Princemetal angina8
or atypical angina.9
Osler introduced the concept of coronary spasms in 191010
and nowadays it is well recognised that although ST-segment elevation is a common finding during spasm, ST-segment depression and T-wave changes may also be observed during ischaemic episodes.9
T-wave inversions were the predominant feature in our patient (). Patients with coronary artery spasms are at risk of arrhythmias such as ventricular fibrillation/tachycardia, complete heart block and sudden death.9
It is not known why these spasms occur but coronary spasms are a sudden and temporary narrowing or tightening of a small part or parts of a coronary artery ().
Distribution of coronary arteries and boxed picture showing narrowing of coronary arteries leading to coronary artery spasm.
However, there is considerable evidence to suggest that endothelium-derived vasoactive substances play an important part in regulating not only the vasomotion of the large epicardial coronary arteries but also coronary blood flow.11
Experimental studies investigating the cardiotoxicity of 5-FU have revealed potential mechanisms of cardiotoxicity ranging from direct toxic effects on vascular endothelium involving endothelial nitric oxide synthase leading to coronary spasms and endothelium independent vasoconstriction via protein kinase C.12
Cisplatin, another platinum derivate, can cause serious vascular complications such as myocardial infarction and several factors appear to be responsible, including increased thrombogenicity and vascular spasm due to hypomagnesaemia.13
Oxaliplatin is not known to cause any cardiotoxicity. However, the time frame within which the acute oxaliplatin-induced laryngopharyngeal dysaesthesia and the coronary artery spasm leading to a NSTMI occurred in our patient, makes the patient’s coronary artery spasm likely to be a drug-related incidence. It is possible that oxaliplatin-induced Na+
channelopathy led to coronary artery spasm through hyperexcitable voltage-gated Na+
channels. Further research may help to elucidate such a possible mechanism and may subsequently lead to increased investigation of drugs such as xaliproden14
that can reduce oxaliplatin-induced neurotoxicity. In the light of recent studies advocating the substitution of cisplatin by oxaliplatin in patients with upper gastrointestinal cancer,15
it is crucial to be aware of unusual but potentially dangerous side-effects of oxaliplatin. It is unlikely that either the patient’s medical conditions or the incidentally diagnosed Hürthle cell carcinoma of the thyroid are implicated in the coronary artery spasm.
This is the first report of oxaliplatin-induced cardiotoxicity manifesting itself as coronary artery spasm. The possible mechanism(s) remains elusive but involvement of voltage-gated Na+ channels appears more than plausible and future research may help to clarify this issue.
- It is important to be vigilant regarding unknown and unexpected drug side-effects as new mechanism of action or insight into pathophysiology may be gained.