Raltitrexed as a substitute for 5-fluorouracil in combination with pembrolizumab and platinum in a patient with metastatic esophageal squamous cell carcinoma and coronary artery disease: a case report

Introduction

Esophageal cancer is the 7^th leading cause of cancer deaths globally, with incidence rates continuing to rise (1). The vast majority of cases worldwide are squamous cell carcinoma (SCC); however, adenocarcinoma is now the predominant histology in Western Europe and North America (2). Prognosis remains poor, with a 5-year survival rate of less than 25% for all stages, and less than 5% in those presenting with distant disease (3). For patients with advanced/metastatic esophageal SCC (ESCC), the standard of care is chemoimmunotherapy.

5-fluorouracil (5-FU) is an antimetabolite drug that is commonly used in the management of gastrointestinal cancers, including esophageal cancer, often in combination with platinum-based chemotherapy (4). The active metabolite of 5-FU works by inhibiting thymidylate synthase, an enzyme critical for deoxyribonucleic acid (DNA) synthesis (5). Importantly, 5-FU and its oral prodrug, capecitabine, collectively referred to as “fluoropyrimidines”, have a mean cardiotoxicity risk of approximately 5% (4). Raltitrexed, a folate analogue which directly inhibits thymidylate synthase without the use of an active metabolite, has been shown to be favourable when compared to 5-FU when used in cancer patients with a previous history of fluoropyrimidine-induced cardiotoxicity or other cardiac history. In a highly skewed, at-risk population, incidence of cardiotoxicity with raltitrexed was 4.5%, compared to up to 19% (mean 5.0%) overall cardiotoxicity incidence with 5-FU (4). For this reason, raltitrexed has often been used as an alternative to 5-FU in patients with a history of cardiotoxicity secondary to fluoropyrimidines or significant coronary artery disease (CAD) (4,6-8).

Recent randomized trials have also investigated the role of immunotherapy in the treatment of advanced ESCC. The KEYNOTE-590 and CheckMate 648 studies showed significantly longer overall survival for patients treated with immunotherapy (pembrolizumab or nivolumab, respectively) plus chemotherapy (5-FU and cisplatin) compared with chemotherapy alone (9,10).

Given that many of the strongest risk factors for the development of ESCC, namely alcohol consumption and smoking, are the same as those for cardiovascular disease, patients with esophageal cancer also face considerable risk of death from other causes including ischemic heart disease and cerebrovascular disease (1,11). Therefore, patient comorbidities must be taken into great consideration during the selection of chemotherapeutic agents for the management of esophageal cancer.

We report the first case, to our knowledge, of the use of raltitrexed in place of 5-FU in combination with pembrolizumab and platinum-based chemotherapy for the treatment of metastatic esophageal cancer in a patient with CAD. We present this case in accordance with the CARE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-25-38/rc).

Case presentation

A 75-year-old gentleman presented to the emergency department in September 2022 with a 2-month history of worsening chest pain, on the background of preexisting CAD. His Eastern Cooperative Oncology Group (ECOG) performance status scale score was 2. He also reported an insidious onset of dysphagia that gradually worsened over the course of one year and was associated with intermittent regurgitation, early satiety, and weight loss. His past medical history was significant for multivessel CAD requiring percutaneous coronary intervention (PCI) in 2002, hypertension, type 2 diabetes mellitus, remote seizure disorder, prostate cancer (pT3b N0, Gleason 4+3=7, treated with prostatectomy and bilateral pelvic lymphadenectomy with adjuvant radiotherapy; undetectable prostate-specific antigen for over 5 years), dyslipidemia, and resected basal cell carcinoma of the left ear. His most recent cardiac catheterization prior to presentation, in August 2022, showed a 40% stenosis in the proximal left anterior descending artery and an 85% stenosis in the mid left anterior descending artery, as well as a 75% restenosis in the proximal circumflex artery stent, an 80% stenosis in the first obtuse marginal artery, and a 100% restenosis in the mid right coronary artery stent. As a result, he was referred to cardiac surgery for consideration of a coronary artery bypass graft, but was not seen prior to this presentation to the emergency department.

In parallel to a cardiac assessment, the patient underwent an esophagogastroduodenoscopy (EGD) which demonstrated a large esophageal mass ulcerating deep into the mucosa at the level of the gastroesophageal junction (GEJ). Pathology from biopsy of the ulcerative mass at the GEJ revealed poorly differentiated carcinoma with squamous differentiation [p63 positive, p40 positive, and cytokeratin 7 (CK7) negative on immunohistochemistry (IHC)]. Next-generation sequencing did not show alterations or fusions. Programmed death-ligand 1 (PD-L1) IHC revealed a combined positive score ≥10%. Imaging with computed tomography (CT) of the thorax, abdomen, and pelvis demonstrated moderate to severe thickening of the wall of the GEJ, mild stranding of the adjacent fat concerning for extension beyond the wall, right para-aortic lymph nodes at the level of the mass, multiple peri-celiac and gastrohepatic lymph nodes, liver heterogeneity, and a query cystic lesion measuring 0.5 cm in the tail of the pancreas (Figure 1A). Magnetic resonance cholangiopancreatography showed seven hepatic lesions scattered throughout the liver with features consistent with metastatic disease. ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT revealed an intensely hypermetabolic lesion at the distal esophagus and GEJ involving an approximately 6.6 cm segment in craniocaudal dimension, a hypermetabolic right thoracic inlet lymph node, several minimally prominent peri-gastric and celiac lymph nodes with low-grade FDG uptake, and several bi-lobar hypermetabolic focal hepatic lesions.

Figure 1 Serial axial CT images of gastrohepatic lymphadenopathy. The yellow circles indicate the location of the gastrohepatic lymph nodes. (A) Baseline diagnostic imaging in September 2022 demonstrated multiple gastrohepatic lymph nodes. (B) Significant interval reduction in the size of numerous gastrohepatic lymph nodes with almost complete disappearance of the left gastrohepatic node conglomerate in February 2023 after 1 month of chemoimmunotherapy. (C) Mixed response with a small interval increases in the size of a right gastrohepatic lymph node seen in May 2023. (D) Near complete response in the gastrohepatic lymphadenopathy in September 2023 after 8 months of chemoimmunotherapy with the exception of a single slowly growing right gastrohepatic lymph node since February 2023. CT, computed tomography.

Considering a new diagnosis of metastatic GEJ carcinoma, cardiac surgery recommended medical management of his triple-vessel CAD with a plan for reassessment for surgical intervention after initiating systemic treatment for his malignancy. In December 2022, the patient received palliative locoregional radiotherapy to a dose of 40 Gy in 15 fractions to the lower mediastinum, GEJ, and upper abdomen with the intent of achieving local control, managing symptoms, and improving quality of life. Given an improvement in the patient’s dysphagia and performance status to ECOG 1 following radiation therapy, the decision was made to proceed with palliative systemic therapy with a platinum-based chemotherapy and pembrolizumab. Taking into account his significant cardiac history and therefore an unacceptably high risk of precipitating serious cardiotoxicity with 5-FU, raltitrexed was combined with carboplatin and pembrolizumab every three weeks. The patient received his first treatment in January 2023 with raltitrexed at a 15% dose reduction (standard dosing 3 mg/m²) and carboplatin at a 50% dose reduction [standard dosing at area under the curve (AUC) 5] to account for his age and performance status. After funding approval, pembrolizumab (2 mg/kg) was added with the second cycle of chemotherapy and raltitrexed and carboplatin were further dose reduced by a total of 25% and 60%, respectively, due to grade 1 myelosuppression after cycle 1. Repeat cross-sectional imaging in February 2023 demonstrated treatment response with improvement in mucosal thickening at the distal esophagus as well as diminishment of gastrohepatic lymphadenopathy, and only a small increase in the prominence of a right upper paraesophageal lymph node (Figure 1B). Following four cycles of this regimen, the decision was made to omit carboplatin in further cycles due to concerns regarding worsening myelosuppression and fatigue affecting quality of life.

Radiographic reassessment with a CT scan in May 2023 showed a mixed response with stability of the mild circumferential thickening of the distal esophagus, significant decrease in the size of a right upper paraesophageal lymph node, mild increase in the size of small gastrohepatic and retroperitoneal lymph nodes, and interval progression of several liver metastases (Figure 1C). In view of a clinical response and improvement in most lesions on imaging, the patient was continued on raltitrexed and pembrolizumab maintenance. Repeat response assessment in August 2023 and then again in September 2023 demonstrated stable disease (SD) with mild circumferential wall thickening of the distal esophagus, significant further reduction in the size of a right upper paraesophageal node, decrease in the size and conspicuity of the hepatic metastases, decrease in the size of the gastrohepatic ligament lymph node, and stability of an aortocaval lymph node (Figure 1D, Figure 2). When evaluated using RECIST 1.1 criteria, the objective response was SD.

Figure 2 Interval decrease in the size and conspicuity of a hepatic metastasis in segment IV on axial CT images in May 2023 (A) and August 2023 (B). The yellow circles indicate the location of the hepatic metastasis. CT, computed tomography.

In September 2023, the patient presented to the emergency department with severe epigastric pain that had been progressively worsening over a 1-week period. Upon admission to hospital, he was diagnosed with a non-ST-elevation myocardial infarction (NSTEMI) with evidence of a new left bundle branch block on electrocardiogram and high sensitivity troponin T elevations up to 1,036 ng/L from baseline of 30 ng/L. The patient subsequently underwent heart catheterization, which again showed severe multi-vessel CAD with some progression at the ostium of the circumflex artery. Given that he was deemed not to be a candidate for either coronary artery bypass grafting or PCI due to high risk of morbidity and mortality with these procedures, medical management with optimization of therapy to stabilize the coronary vasculature was pursued and he was ultimately discharged once his pain was well controlled.

The patient continued to receive raltitrexed and pembrolizumab until he presented to the emergency department in November 2023 with recurrent chest pain. He was diagnosed with an NSTEMI and admitted to the coronary care unit where he was started on medical management. Despite stability of his malignancy on systemic therapy, he was once again not considered to be a candidate for any form of cardiac intervention. Due to progressive deterioration of his chest pain and resultant quality of life, the patient was transitioned to a comfort-focused care approach and transferred to the palliative care unit where he passed away shortly thereafter with the cause of death being acute coronary syndrome. The timeline of the present case is shown in Figure 3.

Figure 3 Timeline depicting the events surrounding the patient’s diagnosis and management. CT, computed tomography; EGD, esophagogastroduodenoscopy; GEJ, gastroesophageal junction; NSTEMI, non-ST-elevation myocardial infarction; PD-L1+, programmed death-ligand 1 positive; SCC, squamous cell carcinoma.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of the case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Fluoropyrimidine plus platinum-based chemotherapy has been a mainstay of treatment for metastatic ESCC for many decades until more recent data in the last few years showed overall and progression-free survival (PFS) benefits with the use of immunotherapy, an anti-programmed cell death protein 1 (PD-1) monoclonal antibody, in combination with standard chemotherapy (9,10).

While it is known that there is an approximately 5% risk of cardiotoxicity associated with fluoropyrimidines; the specific pathophysiology remains elusive (4,12). Coronary vasospasm and direct myocardial toxicity have been proposed as potential mechanisms (13,14). In order to mitigate this risk, raltitrexed has previously been used as an alternative to 5-FU in patients with a history of cardiotoxicity from fluoropyrimidines or significant CAD, including in some cases of gastric cancer (4,6,15).

To our knowledge, the case we present is the first report of raltitrexed being used as a substitute for 5-FU in combination with pembrolizumab and platinum-based chemotherapy for the treatment of advanced esophageal cancer. Although the patient unfortunately passed away prematurely due to pre-existing CAD, there was no evidence of disease progression in the 10 months that he received this regimen. This is comparable to the median PFS in the experimental groups of both the KEYNOTE-590 (6.3 months) and CheckMate 648 (5.8 months) studies, suggesting that there may not be a loss of efficacy when using raltitrexed as a substitute for 5-FU with platinum and immunotherapy. In addition to an encouraging PFS, the patient reported an overall improvement in quality of life while on therapy with no signals of toxicity from raltitrexed itself or any immunotherapy.

Although the patient did pass away from acute coronary syndrome, his cancer treatment remained effective. Had the patient not been treated, we believe he would have had a shorter overall survival due to cancer progression, potentially causing symptoms such as esophageal obstruction or dysphagia. The therapy provided reduced his disease burden and was tolerated well, despite being medically not fit for more aggressive therapy. His treatment also significantly improved his quality of life during this time.

In addition, while the carboplatin dose reduction/discontinuation could have influenced treatment efficacy, this decision was made with the treatment goal of improving the patient’s quality of life. In the end, the patient passed away from a cardiovascular cause without his cancer causing him symptoms. Therefore, these dose reductions contributed to improved treatment efficacy by reducing side effects from chemotherapy while still achieving symptom relief.

The outcomes from this case report are of particular relevance due to the many overlapping characteristics of patients with cardiac pathology and ESCC. Two of the strongest risk factors for the development of ESCC are alcohol consumption and smoking (16,17), which are also major risk factors for cardiovascular disease (18,19). Therefore, it is likely that patients presenting with metastatic ESCC may also have cardiac comorbidities that contraindicate treatment with 5-FU or capecitabine, meaning that the effectiveness of raltitrexed combined with immunotherapy and platinum-based chemotherapy is of great interest to this patient population.

Conclusions

In conclusion, chemotherapy in combination with immunotherapy for the treatment of advanced esophageal cancer appears to be safe and effective when raltitrexed is substituted for 5-FU in the setting of preexisting CAD. Going forward, further data and longer follow-up is needed to confirm the efficacy and toxicity of chemo-immunotherapy involving raltitrexed.

Acknowledgments

We would like to thank Mr. Gabriel Boldt, clinical research librarian at London Health Sciences Centre (London, ON, Canada), for his assistance in performing the initial literature search. We are also deeply grateful to the patient and his family for granting permission to publish this case report.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-25-38/rc

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-25-38/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-25-38/coif). S.V. participated on an advisory board for Bristol Myers Squibb and received travel support to a meeting from Daiichi Sankyo. D.B. has received honoraria for consultancies from AstraZeneca, Janssen, BeiGene, Boehringer Ingelheim, Bayer, and Amgen; speaking fees from Merck, AstraZeneca, and Roche; and received travel support to a meeting from Daiichi Sankyo. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
2. Edgren G, Adami HO, Weiderpass E, et al. A global assessment of the oesophageal adenocarcinoma epidemic. Gut 2013;62:1406-14. [Crossref] [PubMed]
3. SEER*Explorer Application [cited 2024 Oct 1]. Available online: https://seer.cancer.gov/statistics-network/explorer/application.html?site=17&data_type=4&graph_type=2&compareBy=sex&chk_sex_1=1&relative_survival_interval=5&race=1&age_range=1&stage=106&advopt_precision=1&advopt_show_ci=on&hdn_view=1&advopt_show_apc=on&advopt_display=1#resultsRegion1
4. Kelly C, Bhuva N, Harrison M, et al. Use of raltitrexed as an alternative to 5-fluorouracil and capecitabine in cancer patients with cardiac history. Eur J Cancer 2013;49:2303-10. [Crossref] [PubMed]
5. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003;3:330-8. [Crossref] [PubMed]
6. Ransom D, Wilson K, Fournier M, et al. Final results of Australasian Gastrointestinal Trials Group ARCTIC study: an audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines. Ann Oncol 2014;25:117-21. [Crossref] [PubMed]
7. Ladak I, Preti B, Dias B, et al. Raltitrexed as a substitute for capecitabine in metastatic gastric cancer: a case report and literature review. Ann Transl Med 2022;10:1285. [Crossref] [PubMed]
8. Li S, Li X, Zhu Q, et al. Raltitrexed Chemotherapy Regimen Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer: A Prospective Multicenter Phase II Trial. Cancer Control 2024;31:10732748241275012. [Crossref] [PubMed]
9. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet 2021;398:759-71. [Crossref] [PubMed]
10. Doki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med 2022;386:449-62. [Crossref] [PubMed]
11. Xie SH, Wahlin K, Lagergren J. Cause of death in patients diagnosed with esophageal cancer in Sweden: a population-based study. Oncotarget 2017;8:51800-9. [Crossref] [PubMed]
12. Saif MW, Shah MM, Shah AR. Fluoropyrimidine-associated cardiotoxicity: revisited. Expert Opin Drug Saf 2009;8:191-202. [Crossref] [PubMed]
13. Kanduri J, More LA, Godishala A, et al. Fluoropyrimidine-Associated Cardiotoxicity. Cardiol Clin 2019;37:399-405. [Crossref] [PubMed]
14. Raber I, Warack S, Kanduri J, et al. Fluoropyrimidine-Associated Cardiotoxicity: A Retrospective Case-Control Study. Oncologist 2020;25:e606-e609. [Crossref] [PubMed]
15. Kerr DJ. Clinical efficacy of 'Tomudex' (raltitrexed) in advanced colorectal cancer. Anticancer Drugs 1997;8:S11-S15. [Crossref] [PubMed]
16. Weidenbaum C, Gibson MK. Approach to Localized Squamous Cell Cancer of the Esophagus. Curr Treat Options Oncol 2022;23:1370-87. [Crossref] [PubMed]
17. Liang H, Fan JH, Qiao YL. Epidemiology, etiology, and prevention of esophageal squamous cell carcinoma in China. Cancer Biol Med 2017;14:33-41. [Crossref] [PubMed]
18. Mukamal KJ. The effects of smoking and drinking on cardiovascular disease and risk factors. Alcohol Res Health 2006;29:199-202.
19. Shin J, Paik HY, Joung H, et al. Smoking and alcohol consumption influence the risk of cardiovascular diseases in Korean adults with elevated blood pressure. Nutr Metab Cardiovasc Dis 2022;32:2187-94. [Crossref] [PubMed]