Delayed Coronary in a Patient with Metastatic Gastric Cancer Receiving FOLFOX Therapy

Christopher James Little, MD; Bao Sean Nguyen, MD; and Pamela J. Tsing, MD A 40-year-old man with stage IV gastric adenocarcinoma was found to have coronary artery vasospasm in the setting of recent 5- administration.

Christopher Little is a oronary artery vasospasm is a rare to demonstrate this.4,5 The pathophysiology of Resident Physician in Anesthesiology and Bao but well-known adverse effect of 5- 5-FU-induced cardiotoxicity is unknown, but Nguyen is a Resident Phy- Cfluorouracil (5-FU) that can be life threat- adverse effects on cardiac microvasculature, sician in Internal Medicine, ening if unrecognized. Patients typically pres- myocyte metabolism, platelet aggregation, both at UCLA Medical Center in Los Angeles, ent with anginal and ST elevations and coronary vasoconstriction have all been California. Pamela Tsing on electrocardiogram (ECG) without athero- proposed.3,6 is a Hospitalist Physician at the VA Greater Los An- sclerotic disease on coronary angiography. In the current case, we present a patient geles Healthcare System This phenomenon typically occurs during or with stage IV gastric adenocarcinoma who in California, and Assistant Clinical Professor at the shortly after infusion and resolves within hours complained of chest pain during hospitalization David Geffen School of to days after cessation of 5-FU. and was found to have coronary artery vaso- Medicine at UCLA. In this report, we present an unusual case of spasm in the setting of recent 5-FU adminis- Correspondence: Pamela Tsing coronary artery vasospasm that intermittently re- tration. Following coronary angiography that ([email protected]) curred for 25 days following 5-FU treatment in a showed a lack of atherosclerotic disease, the Fed Pract. 2021;38 (suppl 2). 40-year-old male with stage IV gastric adenocar- patient continued to experience episodes of Published online May 13. cinoma. We also review the literature on typical chest pain with ST elevations on ECG that re- doi:10.12788/fp.0123 presentation and risk factors for 5-FU-induced curred despite cessation of 5-FU and repeated coronary vasospasm, findings on coronary angi- administration of vasodilatory medications. ography, and management options. 5-FU is an IV administered antimetabolite CASE PRESENTATION chemotherapy commonly used to treat solid A male aged 40 years was admitted to the tumors, including gastrointestinal, pancreatic, hospital for abdominal pain, with initial imag- breast, and head and neck tumors. 5-FU in- ing concerning for partial small bowel obstruc- hibits thymidylate synthase, which reduces tion. His history included recently diagnosed levels of thymidine, a key pyrimidine nucleo- stage IV gastric adenocarcinoma complicated side required for DNA replication within tumor by peritoneal carcinomatosis status post initi- cells.1 For several decades, 5-FU has re- ation of infusional FOLFOX-4 (5-FU, leucovo- mained one of the first-line drugs for colorec- rin, and oxaliplatin) 11 days prior. The patient tal cancer because it may be curative. It is the was treated for small bowel obstruction. How- third most commonly used chemotherapy in ever, several days after admission, he de- the world and is included on the World Health veloped nonpleuritic, substernal chest pain Organization’s list of essential medicines.2 unrelated to exertion and unrelieved by rest. Cardiotoxicity occurs in 1.2 to 18% of pa- The patient reported no known risk factors, tients who receive 5-FU therapy.3 Although family history, or personal history of coronary there is variability in presentation for acute artery disease. Baseline echocardiography cardiotoxicity from 5-FU, including sudden and ECG performed several months prior death, pectoris, , showed normal left ventricular function with- and ventricular , the mechanism out ischemic findings. most commonly implicated is coronary artery Physical examination at the time of chest vasospasm.3 The direct observation of active pain revealed a heart rate of 140 beats/min. coronary artery vasospasm during left heart The remainder of his vital signs were within catheterization is rare due its transient nature; normal range. There were no murmurs, rubs, however, several case studies have managed gallops, or additional heart sounds heard on

S76 • FEDERAL PRACTITIONER SPECIAL ISSUE • MAY 2021 FIGURE 1 Electrocardiogram Obtained During Patient’s Initial Chest Pain Episode

ST elevations can be seen in leads II, III, aVF, V4, V5, and V6, and reciprocal depressions in leads I and aVL. cardiac auscultation. Chest pain was not re- Treatment producible to palpation or positional in nature. Following catheterization, the patient returned An ECG demonstrated dynamic inferolateral to the medical intensive care unit, where he ST elevations with reciprocal changes in leads continued to report intermittent episodes of I and aVL (Figure 1). A bedside echocardio- chest pain with ST elevations. In the following gram showed hypokinesis of the septal wall. days, he was started on isosorbide mononi- -I returned below the detectable level. trate 150 mg daily and amlodipine 10 mg daily. The patient was taken for emergent coronary Although these vasodilatory agents reduced the catheterization, which demonstrated patent epi- frequency of his chest pain episodes, intermit- cardial coronary arteries without atherosclerosis, tent chest pain associated with ST elevations on a left ventricular ejection fraction of 60%, and a ECG continued even with maximal doses of iso- right dominant heart (Figures 2 and 3). Ventricu- sorbide mononitrate and amlodipine. Adminis- logram showed normal wall motion. Repeat tro- tration of sublingual nitroglycerin during chest ponin-I several hours after catheterization was pain episodes effectively relieved his chest pain. again below detectable levels. Given the severity and frequency of the patient’s Given the patient’s acute onset of chest pain chest pain, the oncology consult team recom- and inferolateral ST elevations seen on ECG, mended foregoing further chemotherapeutic the working diagnosis prior to coronary cath- treatment with 5-FU. erization was . The differential diagnosis included other causes of Outcome life-threatening chest pain, including pulmo- Despite holding 5-FU throughout the patient’s nary embolism, pneumonia, aortic dissection, hospitalization and treating the patient with an- , , cardiac tianginal mediations, frequent chest pain epi- tamponade, or coronary artery vasospasm. sodes associated with ST elevations continued Computed tomography (CT) angiography of to recur until 25 days after his last treatment with the chest was not consistent with pulmonary 5-FU (Figure 4). The patient eventually expired embolism or other acute cardiopulmonary pro- during this hospital stay due to cancer-related cess. Based on findings from coronary angiog- complications. raphy and recent exposure to 5-FU, as well as resolution followed by recurrence of chest pain DISCUSSION and ECG changes over weeks, the most likely Coronary artery vasospasm is a well-known diagnosis after coronary catheterization was complication of 5-FU that can be life threatening coronary artery vasospasm. if unrecognized.6-8 As seen in our case, patients

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FIGURE 2 Left Coronary Artery System fusional administration of 5-FU is thought to be associated with a higher rate of cardiotoxicity and a higher tumor response rate.9 Most cases of coronary vasospasm occur either during infusion of 5-FU or within hours to days after completion. The median time of presentation for 5-FU-induced coronary ar- tery vasospasm is about 12 hours postinfusion, while the most delayed presentation reported in the literature is 72 hours postinfusion.6,8 De- layed presentation of vasospasm may result from the release of potent vasoactive metabo- lites of 5-FU that accumulate over time; there- fore, infusional administration may accentuate this effect.6,9 Remarkably, our patient’s chest pain episodes persisted for 25 days despite treatment with anti-anginal medications, high- Patent left anterior descending and left cir- lighting the extent to which infusional 5-FU can cumflex arteries. produce a delay in adverse cardiotoxic effects FIGURE 3 Right Coronary Artery System and the importance of ongoing clinical vigilance after 5-FU exposure. Vasospasm alone does not completely ex- plain the spectrum of cardiac toxicity attributed to 5-FU administration. As in our case, coronary angiography during symptomatic episodes often fails to demonstrate coronary vasospasm.8 Ad- ditionally, ergonovine, an alkaloid agent used to assess coronary vasomotor function, failed to induce coronary vasospasm in some patients with suspected 5-FU-induced cardiac toxicity.10 The lack of vasospasm in some patients with 5-FU-induced cardiac toxicity suggests multiple independent effects of 5-FU on cardiac tissue that are poorly understood. In the absence of obvious macrovascular ef- fects, there also may be a deleterious effect of 5-FU on the coronary microvasculature that may Patent right coronary artery, posterior descend- result in coronary artery vasospasm. Though cor- ing artery, and posterolateral extension. onary microvasculature cannot be directly visu- alized, observation of slowed coronary blood typically present with anginal chest pain relieved velocity indicates a reduction in microvascular with nitrates and ST elevations on ECG in the flow.8 Thus, the failure to observe epicardial coro- absence of occlusive macrovascular disease on nary vasospasm in our patient does not preclude coronary angiography. a vasospastic pathology. A unique aspect of 5-FU is its variability in The heterogeneous presentation of coronary dose and frequency of administration across artery vasospasm demands consideration of chemotherapeutic regimens. Particularly, 5-FU other disease processes such as atherosclerotic can be administered in daily intravenous bolus , , myopericar- doses or as a continuous infusion for a pro- ditis, primary arrythmias, and stress-induced car- tracted length of time. The spectrum of toxicity diomyopathy, all of which have been described from 5-FU differs depending on the dose and fre- in association with 5-FU administration.8 A quency of administration. Bolus administration of 12-lead ECG should be performed during a sus- 5-FU, for example, is thought to be associated pected attack. An ECG will typically demonstrate with a higher rate of myelosuppression, while in- ST elevations corresponding to spasm of the

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FIGURE 4 Electrocardiogram Obtained During Chest Pain Episode 25 days After Last Administration of 5-Flurouracil

ST elevations in leads II, III, aVF, V4, V5, and V6, and reciprocal depressions in lead aVL demonstrated. involved vessel. Reciprocal ST depressions in benefits are deemed to outweigh risks, infusions the contralateral leads also may be seen. ECG should be given in an inpatient setting with con- may be useful in the acute setting to identify re- tinuous cardiac monitoring.16 gional wall motion abnormalities or to rule out Calcium channel blockers and oral nitrates pericardial effusion as a cause. Cardiac bio- have been found to produce benefit in patients markers such as troponin-I, -C, and creatine ki- in acute settings; however, there is little evi- nase typically are less useful because they are dence to attest to their effectiveness as pro- often normal, even in known coronary artery phylactic agents in those receiving 5-FU. Some vasospasm.11 reports demonstrate episodes where both cal- Coronary angiography during an episode cium channel blockers and oral nitrates failed may show a localized region of vasospasm in to prevent subsequent .17 Although an epicardial artery. Diffuse multivessel vaso- this was the case for our patient, short-acting spasm does occur, and the location of vaso- sublingual nitroglycerin seemed to be effective spasm may change, but these events are rare. in reducing the frequency of anginal symptoms. Under normal circumstances, provocative test- Long-term outcomes have not been well ing involving angiography with administration of investigated for patients with 5-FU-induced acetylcholine, ergot agents, or hyperventilation coronary vasospasm. However, many case re- can be performed. However, this type of inves- ports show improvements in left ventricular tigation should be limited to specialized centers function between 8 and 15 days after discon- and should not be performed in the acute phase tinuation of 5-FU.7,10 Although this would be a of the disease.12 valuable topic for further research, the rarity of Treatment of suspected coronary vaso- this phenomenon creates limitations. spasm in patients receiving 5-FU involves stop- ping the infusion and administering calcium CONCLUSIONS channel blockers or oral nitrates to relieve an- 5-FU is a first-line chemotherapy for gastro- ginal symptoms.13 5-FU-induced coronary ar- intestinal cancers that is generally well toler- tery vasospasm has a 90% rate of recurrence ated but may be associated with potentially with subsequent infusions.8 If possible, alter- life-threatening cardiotoxic effects, of which nate chemotherapy regimens should be consid- coronary artery vasospasm is the most com- ered once coronary artery vasospasm has been mon. Coronary artery vasospasm presents identified.14,15 If further 5-FU use is required, or if with anginal chest pain and ST elevations on

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ECG that can be indistinguishable from acute 2004;11(1):46-49. doi:10.1177/107327480401100207 5. Luwaert RJ, Descamps O, Majois F, Chaudron JM, coronary syndrome. Diagnosis requires car- Beauduin M. Coronary artery spasm induced by diac catheterization, which will reveal patent 5-fluorouracil. Eur Heart J. 1991;12(3):468-470. coronary arteries. Infusional administration of doi:10.1093/oxfordjournals.eurheartj.a059919 6. Saif MW, Shah MM, Shah AR. Fluoropyrimidine- 5-FU may be more likely to produce late car- associated cardiotoxicity: revisited. Expert Opin Drug Saf. diotoxic effects and a longer period of per- 2009;8(2):191-202. doi:10.1517/14740330902733961 7. Patel B, Kloner RA, Ensley J, Al-Sarraf M, Kish J, sistent symptoms, necessitating close Wynne J. 5-Fluorouracil cardiotoxicity: left ven- monitoring for days or even weeks from last tricular dysfunction and effect of coronary va- administration of 5-FU. Coronary artery va- sodilators. Am J Med Sci. 1987;294(4):238-243. doi:10.1097/00000441-198710000-00004 sospasm should be treated with anti-anginal 8. Sara JD, Kaur J, Khodadadi R, et al. 5-fluoroura- medications, though varying degrees of effec- cil and cardiotoxicity: a review. Ther Adv Med Oncol. 2018;10:1758835918780140. Published 2018 Jun 18. tiveness can be seen; clinicians should remain doi:10.1177/1758835918780140 vigilant for recurrent episodes of chest pain 9. Hansen RM, Ryan L, Anderson T, et al. Phase III study despite treatment. of bolus versus infusion fluorouracil with or without cis- platin in advanced colorectal cancer. J Natl Cancer Inst. 1996;88(10):668-674. doi:10.1093/jnci/88.10.668 Author disclosures 10. Kim SM, Kwak CH, Lee B, et al. A case of severe cor- The authors report no actual or potential conflicts of interest onary spasm associated with 5-fluorouracil chemo- with regard to this article. therapy. Korean J Intern Med. 2012;27(3):342-345. doi:10.3904/kjim.2012.27.3.342 11. Swarup S, Patibandla S, Grossman SA. Coronary Artery Disclaimer Vasospasm. StatPearls. Treasure Island (FL): StatPearls The opinions expressed herein are those of the authors and do Publishing LLC.; 2021. not necessarily reflect those of Federal Practitioner, Frontline 12. Beijk MA, Vlastra WV, Delewi R, et al. Myocardial infarc- Medical Communications Inc., the US Government, or any tion with non-obstructive coronary arteries: a focus on of its agencies. This article may discuss unlabeled or inves- vasospastic angina. Neth Heart J. 2019;27(5):237-245. tigational use of certain drugs. Please review the complete doi:10.1007/s12471-019-1232-7 prescribing information for specific drugs or drug combina- 13. Giza DE, Boccalandro F, Lopez-Mattei J, et al. Isch- tions—including indications, contraindications, warnings, and emic heart disease: special considerations in cardio adverse effects—before administering pharmacologic therapy -oncology. Curr Treat Options Cardiovasc Med. to patients. 2017;19(5):37. doi:10.1007/s11936-017-0535-5 14. Meydan N, Kundak I, Yavuzsen T, et al. Cardiotoxicity of de References Gramont’s regimen: incidence, clinical characteristics and 1. Wacker A, Lersch C, Scherpinski U, Reindl L, Sey- long-term follow-up. Jpn J Clin Oncol. 2005;35(5):265-270. farth M. High incidence of angina pectoris in patients doi:10.1093/jjco/hyi071 treated with 5-fluorouracil. A planned surveillance 15. Senkus E, Jassem J. Cardiovascular effects of systemic study with 102 patients. Oncology. 2003;65(2):108-112. cancer treatment. Cancer Treat Rev. 2011;37(4):300-311. doi:10.1159/000072334 doi:10.1016/j.ctrv.2010.11.001 2. World Health Organization Model List of Essential Medi- 16. Rezkalla S, Kloner RA, Ensley J, et al. Continuous am- cines, 21st List, 2019. Accessed April 14, 2021. https:// bulatory ECG monitoring during fluorouracil therapy: a apps.who.int/iris/rest/bitstreams/1237479/retrieve prospective study. J Clin Oncol. 1989;7(4):509-514. 3. Jensen SA, Sørensen JB. Risk factors and prevention of doi:10.1200/JCO.1989.7.4.509 cardiotoxicity induced by 5-fluorouracil or capecitabine. 17. Akpek G, Hartshorn KL. Failure of oral nitrate and cal- Cancer Chemother Pharmacol. 2006;58(4):487-493. cium channel blocker therapy to prevent 5-fluoro- doi:10.1007/s00280-005-0178-1 uracil-related myocardial : a case report. 4. Shoemaker LK, Arora U, Rocha Lima CM. 5-fluoroura- Cancer Chemother Pharmacol. 1999;43(2):157-161. cil-induced coronary vasospasm. Cancer Control. doi:10.1007/s002800050877

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