Rechallenge of 5-Fluorouracil in a Patient With Coronary Vasospasm Unable to Receive Oral Medications

Abstract

Background

Fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are vital in gastrointestinal cancer treatment but can cause coronary vasospasm (CV). Although calcium channel blockers and nitrates enable rechallenge, the optimal management of patients who cannot tolerate oral medications remains uncertain.

Case Presentation

A 38-year-old man with metastatic gastric adenocarcinoma developed 5-FU-induced CV during 5-FU, leucovorin, oxaliplatin, and docetaxel chemotherapy. Rechallenge with extended-release nifedipine and isosorbide mononitrate was initially successful, but worsening dysphagia precluded oral prophylaxis. Transdermal nitroglycerin was attempted but failed, necessitating 5-FU interruption and sublingual nitroglycerin. Because of inadequate oncologic response and human epidermal growth factor receptor 2 positivity, treatment transitioned to trastuzumab.

Conclusions

This case highlights the challenge of 5-FU rechallenge in patients unable to take oral prophylaxis. Transdermal nitroglycerin monotherapy proved insufficient, suggesting that intravenous prophylaxis may be required. Future studies should determine optimal strategies for preventing CV in patients with a similar presentation.

Graphical Abstract

Fluoropyrimidines, including 5-fluorouracil (5-FU) and its oral prodrug capecitabine, are commonly used chemotherapy agents for treating gastrointestinal tract malignancies. Among conventional cytotoxic chemotherapies, 5-FU is the second most common drug associated with cardiotoxicity after anthracyclines, with cardiac effects ranging from chest pain (CP) to sudden cardiac death. Coronary vasospasm (CV) is thought to be the predominant mechanism of CP.¹ First described in the early 1960s, studies have typically demonstrated that those who experienced CV were younger and had a lower incidence of pre-existing cardiovascular risk factors than those who did not develop CV. Most of the patients had vasospasm during the first cycle, commonly presenting with CP and ST/T-wave changes.²

Take-Home Messages

• •This case highlights a rare instance of 5-FU rechallenge in a patient with gastrointestinal cancer who could not tolerate oral medications. Initially, rechallenge with oral nitrate and CCB prophylaxis prevented the recurrence of chest pain. However, when oral administration was not feasible, transdermal nitroglycerin alone failed to prevent coronary spasm, underscoring the limitations of transdermal nitroglycerin monotherapy.
• •Our experience suggests that for patients unable to take oral prophylaxis, a more aggressive approach using intravenous nitrates and IV CCBs may be required before rechallenging with 5-FU.

Managing these patients is challenging, as recurrent vasospasm can occur in up to 90% of patients re-exposed to 5-FU.³ Most of the clinicians consider rechallenge as a last resort given the relative lack of data supporting the effectiveness of preventive regimens. Nonetheless, if fluoropyrimidine-based treatment is deemed the best option for cancer therapy, a rechallenge can be considered.

Pharmacologic interventions that aim to prevent cardiac symptoms mainly target vasospasm.⁴ Based on data from limited case series, if rechallenge is considered, 5-FU should be administered as a bolus, rather than continuous infusion. One published protocol involves pretreatment with nifedipine extended release (ER) and isosorbide mononitrate 3 to 4 hours before the 5-FU infusion; administration of short-acting diltiazem and sublingual nitroglycerin as needed during the infusion; post-treatment with nifedipine and isosorbide mononitrate 12 hours after the first dose of pretreatment nitrate or calcium channel blocker (CCB); and administration of nifedipine 24 hours after the first dose.⁵

Although this regimen was generally effective in preventing the recurrence of cardiovascular symptoms during 5-FU rechallenge, all patients were able to tolerate oral medications. We describe a unique case of a patient with gastric cancer who developed CV after the first cycle of 5-FU and was successfully rechallenged. However, because of progression of cancer and subsequent worsening dysphagia, oral medications were suspended, leading to a clinical dilemma.

Case Presentation

A 38-year-old Caucasian man presented in 2023 with recurrent epigastric discomfort after treatment for Helicobacter pylori infection. On physical examination, he exhibited tenderness in the epigastric region that worsened with palpation. He has a medical history notable for hepatitis B virus infection and a 13-year history of smoking. Esophagogastroduodenoscopy revealed a cratered ulcer with irregular tissue in the antrum/incisura. Biopsy findings confirmed poorly differentiated adenocarcinoma (AC) with signet ring cell features, and endoscopic ultrasound staged the tumor as T3N1.

The patient began neoadjuvant chemotherapy with 5-FU, leucovorin, oxaliplatin, and docetaxel in June 2023. Twenty-four hours after starting the 5-FU, leucovorin, oxaliplatin, and docetaxel infusion, the patient developed substernal chest discomfort. When these symptoms persisted for an additional 2 hours, he presented to the emergency department. An initial electrocardiogram (ECG) showed no ischemic changes compared with the baseline ECG. However, 3 hours later, the patient developed ST-segment elevation in the inferoposterior and anterolateral leads (Figure 1A). He underwent coronary angiography shortly after, which revealed no evidence of epicardial coronary disease (Figure 1B). During this time, the patient maintained normal blood pressure, oxygen saturation, and a normal cardiopulmonary examination result. After aspirin administration and cardiac catheterization, his pain subsided, and a reduction in ST-segment elevation was observed. Amlodipine 5 mg daily was initiated for vasospasm prevention. An echocardiogram showed mildly depressed global longitudinal strain (−17%, normal <−18%) and a normal left ventricular ejection fraction of 55%. Troponin T levels were mildly elevated (peak 0.05 ng/mL; normal limit 0.01 ng/mL).

Figure 1.

Case Illustration

(A) Electrocardiogram (ECG) during the first episode of coronary vasospasm. (B) Coronary angiography demonstrating no evidence of coronary artery disease. (C) ECG during the second chest pain episode suggestive of hyperacute T waves, which reverted to baseline (D). 5-FU = 5-fluorouracil; CCB = calcium channel blocker; ER = extended release.

One month later, the patient switched to neoadjuvant chemoradiation therapy with weekly carboplatin/paclitaxel and underwent laparoscopic subtotal gastrectomy with Roux-en-Y reconstruction. Pathology confirmed poorly differentiated AC with signet ring carcinoma features, staged as endoscopic ultrasound T4N2. In March 2024, the patient was readmitted with severe malnutrition due to gastric outlet obstruction, inflammation, and stricture at the gastrojejunostomy, which was not amenable to endoscopic intervention at that time. Diagnostic laparoscopy revealed extensive peritoneal carcinomatosis, and biopsy confirmed metastatic gastric AC. The patient was subsequently started on carboplatin area under the curve and paclitaxel. There was evidence of peritoneal disease progression after the fifth cycle. A subsequent gastric biopsy showed the same poorly differentiated invasive AC, now with human epidermal growth factor receptor 2/neu 3+ expression. After discussions with the patient, a decision was made to rechallenge with folinic acid, 5-FU, and oxaliplatin (FOLFOX).

The cardio-oncology team evaluated the patient and initiated nifedipine ER 30 mg daily and isosorbide mononitrate ER 30 mg daily before hospitalization. 5-FU was administered during hospitalization with telemetry monitoring and observation for 24 hours after the infusion before discharge. The doses of the medications could not be increased further because of borderline low blood pressure and headache. With this regimen, the patient did not experience CV events after the first, second, and third rechallenges in August, September, and October 2024, respectively. However, after the last cycle of 5-FU, the patient was completely unable to tolerate enteral medication and was placed on total parenteral nutrition. At that point, trastuzumab was initiated, and the fourth cycle of FOLFOX was scheduled. Because of the inability to take oral medications, a Nitro-Dur nitroglycerin transdermal (TD NTG) patch (0.1 mg/h applied for 12 hours/d) was started 12 hours before 5-FU administration in place of oral vasodilators due to the inability to administer enteral medication.

The patient was initially asymptomatic after initiation of the 5-FU infusion. However, 33 hours into treatment, the patient experienced oppressive CP, initially rated 6/10 in intensity. The TD NTG patch was not in place at this time. The 5-FU infusion was interrupted, and sublingual NTG was administered, resulting in rapid resolution of the pain. There was no increase in troponin (high-sensitivity troponin T: 9 and 11 ng/L; normal ≤19 ng/L), but the ECG during the CP episode showed a pattern suggestive of hyperacute T waves (Figure 1C), which returned to baseline shortly after (Figure 1D).

After the recurrence of vasospasm, it was determined that if another rechallenge was necessary, the patient would be initiated on intravenous (IV) NTG and continuous IV CCB therapy before rechallenge, with close monitoring in the intensive care unit. Ultimately, as the tumor was human epidermal growth factor receptor 2 positive and his response to FOLFOX was inadequate, 5-FU rechallenge was deferred and fam-trastuzumab deruxtecan-nxki (Enhertu) was started. The timeline of key events in the patient’s clinical course is summarized in Figure 2.

Figure 2.

Timeline Summarizing the Key Events in the Patient's Clinical Course

5-FU = 5-fluorouracil; CCB = calcium channel blocker; ER = extended release; FLOT = 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel; FOLFOX = folinic acid, 5-fluorouracil, and oxaliplatin.

Discussion

This case was notable for 2 reasons. First, we describe a successful rechallenge of 5-FU after CV, using prophylaxis with extended-release nitrate and CCB. Second, the inability to administer oral medication compromised the optimal treatment for preventing cardiovascular events. The attempt to administer TD NTG was ineffective, leading to a recurrence of vasospasm, which was aborted early after the administration of 5-FU in a hospital setting with the rapid initiation of appropriate measures.

Initially, this patient was successfully managed according to the protocol outlined by Clasen et al.⁵ They described a series of 11 consecutive patients who were treated with 5-FU bolus infusion, CCBs, and extended-release nitrates, all of whom underwent a successful rechallenge.⁵ Using this protocol, our patient initially remained asymptomatic for 3 cycles of FOLFOX. Preventing the recurrence of cardiac symptoms is of significant concern, as previous reports have indicated that without preventive treatment, 13% of patients rechallenged after initial 5-FU-related cardiac events died of recurrent toxicity, compared with an 8% mortality rate for initial events.⁶

Despite initial success with 5-FU rechallenge, the patient's oncologic disease progressed, and his dysphagia limited our ability to administer the oral medications. Because the patient required treatment with 5-FU, we attempted to manage vasospasm empirically with TD NTG monotherapy during rechallenge. Another option that could have been considered instead of TD NTG was nitropaste; however, it was not available at our hospital at the time. Although IV NTG and continuous IV diltiazem infusion were considered, we opted for this less aggressive approach, believing that it would be sufficient to prevent cardiovascular side effects and avoid the need for and risks inherent to recurrent admissions to the intensive care unit for administration with each subsequent infusion.

The TD NTG patches are marked as once-daily use with a 12-hour drug-free interval to avoid tolerance.⁷ TD formulations of NTG have proven effective antianginal therapy for use up to 4-week duration, with the most consistent results seen in patches delivering at least 0.4 mg of NTG per hour. NTG has a short half-life of around 3 minutes and so is cleared quickly after patch removal. Some trials have demonstrated increased frequency of angina in some patients during the nitrate-free interval.⁸ The dose effectiveness of sublingual NTG and effects of a nitrate-free interval on 5-FU CV are not well studied.

To our knowledge, few cases of 5-FU rechallenge with TD NTG monotherapy have been reported in the literature. Cianci et al⁹ described 3 cases of 5-FU-associated CV. After developing CP with 5-FU, 2 of the 3 patients were rechallenged with a reduced dose of 5-FU and TD NTG with no recurrence of cardiac symptoms.⁹ The dosing regimen of TD NTG was not described. With regard to nitrate monotherapy in prevention of recurrent cardiac symptoms, one retrospective study identified 115 patients with 5-FU-induced CV between 2001 and 2020. Of 115 patients, 84 continued with 5-FU therapy, with 78 receiving cardiac pretreatment before rechallenge. Pretreatment either consisted of nitrates only, CCBs only, or both. In this cohort, 19 patients received long-acting nitrate therapy alone. No patient on nitrate monotherapy sustained a myocardial infarction after rechallenge, and there were no significant differences in occurrence of CP between the nitrate-only group and the other 2 pretreatment groups.¹⁰

We hypothesize that a more aggressive strategy might have been effective in preventing the vasospasm episode and will likely be the preferred approach in similar cases in the future. However, because of the lack of data for managing such situations, we initially opted for a less aggressive strategy.

Conclusions

We present a unique case of a patient with metastatic gastric cancer who was successfully rechallenged with 5-FU after an episode of CV. Because of progressive oncologic disease, the patient required total parenteral nutrition and was unable to take oral medications for vasospasm prevention. Treatment with a transdermal nitroglycerin patch and 5-FU bolus infusion was attempted but failed. Although more aggressive preventive therapy was considered, changing the oncologic treatment was ultimately deemed the most appropriate course of action. Given the high risk of recurrence, preventive strategies with both CCBs and nitrates should be prioritized to prevent CV in similar cases. Future studies are needed to evaluate how to successfully prevent cardiac toxicity in patients with cancer treated with fluoropyrimidines who are physically unable to take oral medications.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.