Alternative Treatment Options in Patients with Colorectal Cancer Who Encounter Fluoropyrimidine-Induced Cardiotoxicity

Figures & data

Table 1 The Most Frequent Cardiac Complications Related to 5-FU Administration²

Cardiac Manifestations of 5-FU/Capecitabine Toxicities
Cardiac Event	%
Angina	45%
Myocardial infarction	22%
Arrhythmias (notably atrial fibrillation, VT, and VF)	23%
Acute pulmonary edema	5%
Cardiac arrest	1.4%
Pericarditis	1.4%
Congestive heart failure	2%

Table 2 Potential Mechanisms Underlying 5-FU Cardiotoxicity^2,5

Mechanism	Results
Autoimmune	A delayed immune reaction has been proposed to explain 5-FU cardiotoxicity. These investigators also reported a beneficial effect of steroids, further supporting the above possible explanation.
Direct myocardial damage	Edema of myocardial fibers and loss of striations were found within 12 hours of exposure to 5-FU in a rat model. Injected radiolabeled ^14C-labeled-5-FU into a mouse model showed localization within the myocardium which was retained for 96 hours (longer than most organ systems). In another preclinical study, repeated infusions of 5-FU induced left ventricular hypertrophy, foci of myocardial necrosis, thickening of intra-myocardial arterioles, and disseminated apoptosis in myocardial cells of the epicardium, as well as endothelial cells of the distal coronary arteries.
Impurities in 5-FU formulation	Commercial vials of 5-FU over time develop 5-FU degradation products, ie, fluoroacetaldehyde (FACET) and fluoromalon-aldehydic acid (Fmald) which are cardiotoxic in animal models. Also, 5-FU gets metabolized into two compounds, alpha-fluoro-beta-hydroxypropionic acid (FHPA) and fluoroacetate, which are again cardiotoxic.
Interference with TCA cycle	Analysis of TCA cycle intermediates in animal studies revealed an accumulation of citrate within the myocardium, possibly resulting from an inhibition of aconitase by fluorocitrate, as a cause of depletion of the high-energy phosphates. 5-FU depletes high-energy phosphate compounds in the myocardium resulting in metabolic dysfunction.
Vasospasm	Administration of 5-FU caused vasospasm of the aortic rings of rabbits which was dose dependent. 5-FU may have a direct endothelial-independent vasoconstriction secondary to activation of PKC, probably via activation of PKC receptors. An elevated level of endothelin-1 (ET-1), a potent natural vasoconstrictor, was found in two patients with cardiac toxicity from 5-FU.
Hypercoagulability	Increase in fibrinopeptide A (FPA) levels and decrease in Protein C activity as compared to Protein C antigen levels was observed in a study during the continuous infusion of 5-FU, which returned to the baseline at the end of 5 days of CIV.
Increased iron content	Increased iron content might be associated with increased oxygen consumption. Animal studies showed iron was 20% higher compared to time zero when measured by a Flame Atomic absorption spectrophotometer, hence supporting the cardiac ischemia related to 5-FU.
Cytotoxic effect	The inhibition of mature cytoplasmic rRNA production may be an important common mechanism of RNA-directed cytotoxicity for all the fluoropyrimidines
Effect on erythrocytes	Exposure of the erythrocytes to 5-FU irreversibly affects their energetic metabolism as well as their functioning. Using ^31P NMR spectroscopy, a rapid increase in O2 consumption in 5-FU treated erythrocytes was observed which lead to severe changes in the metabolism of phosphate compounds in erythrocytes. Erythrocytes produced more 2.3-BPG in order to maintain the metabolism of oxygen within the physiological range, which led to deoxygenation of oxy-Hb. This made oxygen transport and/or delivery more difficult, resulting in ischemic damage.

Figure 1 Mechanisms of cardiac toxicities associated with 5-FU/capecitabine Adapted from Shiga, T, Hiraide, M Cardiotoxicities of 5-Fluorouracil and Other Fluoropyrimidines. Curr. Treat. Options in Oncol. 2020;21(27). This article is licensed under a Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0/ .⁶

Table 3 Switch to a Different Fluoropyrimidine

Drug	Composition	Cardiac Safety	Mechanism of Potential Decreased Cardiac Toxicity	Comparison or Challenge After 5-FU and Capecitabine	Availability
TAS-102 (Lonsurf)	TAS-102 consists of nucleoside analog (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil).^Citation13	We performed a meta-analysis of 869 publications including 1877 patients. Compared with placebo, TAS-102 did not increase the risk of myocardial infarction (OR=1.97; 95% CI=0.22–17.89), hypertension (OR=0.73; 95% CI=0.37–1.44), palpitations (OR=1.51; 95% CI=0.30–7.56), cardio-pulmonary arrest (OR=0.83; 95% CI=0.11–6.32), or syncope (OR=1.50; 95% CI=0.06–37.14).^Citation14	1.TAS 102 has a different oncological target (tri-fluorothymidine monophosphate [TF-TMP] and tri-fluorothymidine triphosphate [TF-TTP]) vs 5-FU or capecitabine (FdUMP fluorodeoxyuridine monophosphate [FdUMP] and fluorodeoxyuridine triphosphate [FdUTP]). 2.Possibly higher tumoral incorporation of FTD into DNA than its incorporation into normal tissues DNA, thereby, decreasing cardiac damage. 3.Finally, TAS 102 is not catabolized by DPD, hence cardiotoxic catabolites of 5-FU, such as FBAL, F-citrate are significantly lower quantitatively resulting in less cardiotoxicity.	In the registration Phase III study that led to its FDA approval, only one patient treated with TAS-102 was reported to have an episode of cardiac ischemia among 800 treated patients who have been exposed to 5-FU previously.^Citation15	Approved only for refractory colon and gastric cancer at present in the US.
S-1	S-1 contains tegafur (FF) and two types of enzyme inhibitor, gimeracil/5-chloro-2,4-dihydroxypyridine (CDHP) a potent inhibitor of DPD and potassium oxonate (Oxo) which inhibits phosphorylation of intestinal 5-FU in a molar ratio of 1:0.4:1.^Citation16	In the published Phase II or III studies of S-1, no grade III or IV cardiovascular events were reported.^Citation16	1.S-1 is an oral DPD inhibitory fluoropyrimidine (DIF) based on a biochemical modulation of 5-FU. Gimeracil is a highly active reversible DPD inhibitor, 180-fold more active than uracil (the DPD inhibitor in UFT). Because of the significant DPD inhibition by gimeracil, levels of cardiotoxic catabolites of 5-FU levels are significantly lower than after capecitabine or I.V. 5-FU administration, and hence less cardiotoxicity can be expected.^Citation17	Experience with S-1 in CRC patients with previous 5–FU- or capecitabine-induced cardiotoxicity is limited to anecdotal reports.^Citation18	S-1 is approved in Japan, China, Taiwan, Korea, Singapore, and European countries but not available in the US.
UFT	Combination of ftorafur with uracil, which UFT. Uracil competitively inhibits the enzyme DPD, leading to higher intratumoral concentrations of 5-FU.^Citation19	In animal experiments, adding uracil to tegafur reduced cardiotoxicity as compared with tegafur alone.^Citation15 Cardiotoxicity, such as angina pectoris, arrhythmia, congestive heart failure, myocardial infarction, and cardiac arrest have been reported in only 1% with UFT than with 5-FU or capecitabine.^Citation19	Uracil is a natural substrate for DPD, and competes with 5-FU for this enzyme, reducing the degradation of 5-FU to its toxic metabolites FBAL and F-citrate.	The experience with this strategy is limited to isolated case reports. However, report of death of one patient following rechallenge with UFT who had prior cardiotoxicity associated with I.V. 5-FU (De Gramont’s schedule) has been published.^Citation20	UFT has been in widespread use in many areas worldwide, including Japan, Asia, South America, and Spainfor over 20 years. UFT is not available in the US.
Raltitrexed	Raltitrexed is chemically similar to folic acid and is in the class of chemotherapy drugs called folate antimetabolites, which inhibit one or more of three enzymes that use folate and derivatives as substrates: DHFR, GARFT and thymidylate synthase. Raltitrexed is fully active after polyglutamylation, which allows cellular retention of the drug. By inhibiting Thymidylate synthase (TS), thus formation of precursor pyrimidine nucleotides, raltitrexed prevents the formation of DNA and RNA, which are required for the growth and survival of both normal cells and cancer cells.^Citation21	Raltitrexed alone as well as in combination with oxaliplatin or irinotecan provides a safe option in terms of cardiac toxicity for such patients based on previous studies.^Citation22	The metabolism of raltitrexed is independent of DPD. Other than its intracellular polyglutamation, raltitrexed is not metabolized and is excreted largely unchanged in the urine.	Ransom et al have published a successful rechallenge with raltitrexed in 42 patients with mCRC who had to stop 5-FU or capecitabine due to cardiotoxicity. No patient suffered any subsequent cardiac problems.^Citation23	Overall, raltitrexed is considered inferior to 5-FU because of higher treatment-related mortality and is therefore not widely available. Currently, available in Canada, Europe, Singapore, and Middle East only.

Table 4 Summary of Few Cases Rechallenged with Bolus5-FU

Pt. No	Age, Years	Sex	Regimen	Re-Challenge with Bolus 5-FU	Outcome
1	35	M	FOLFOX	FLOX	Tolerated without cardiac symptoms and signs
2	34	M	5-FU CIV with concurrent XRT	Bolus 5-FU with LCV on Mon/Wed/Fri per week	Tolerated without cardiac symptoms and signs
3	54	M	FOLFOX	FLOX	Tolerated without cardiac symptoms and signs
4	39	M	5-FU CIV with concurrent XRT	Bolus 5-FU with LCV on Mon/Wed/Fri per week	Tolerated without cardiac symptoms and signs
5	56	M	5-FU CIV with concurrent XRT	Bolus 5-FU with LCV on Mon/Wed/Fri per week	Tolerated without cardiac symptoms and signs
6	61	M	ECF	Weekly bolus 5-FU and LCV	Tolerated without cardiac symptoms and signs

Abbreviations: FOLFOX: oxaliplatin, 5-FU and leucovorin; ECF: Epirubicin, cisplatin and 5-FU, NA: not available; LCV: leucovorin, CIV: continuous infusion of 5-FU, XRT: radiotherapy

Table 5 Non-Fluoropyrimidine Containing Chemotherapy Regimen

Agent	Line of Therapy	Any Potential Cardiac Toxicity
Irinotecan as a single agent	Second-line irinotecan alone for advanced CRC^Citation26	Not reported.
Irinotecan in combination with Cetuximab	Cetuximab plus irinotecan with irinotecan alone after fluoropyrimidine and oxaliplatin failure in mCRC patients with KRAS wild type.^Citation27	Not reported.
Irinotecan in combination with aflibercept (zaltrap)	Velour study showed superiority of FOLFIRI plus aflibercept compared to FOLFIRI in patients who have failed oxaliplatin-based regimen with or without bevacizumab.^Citation28	Like other anti-VEGF agents are known to cause arterial thromboembolism.
Oxaliplatin as a single agent	Oxaliplatin as monotherapy was initially approved in the second-line setting in Europe.^Citation29 However, later studies showed inferiority of oxaliplatin over its combination with 5-FU. Monotherapy use of oxaliplatin is generally not recommended, especially in the US, based on ECOG E3200 study.	No known cardiotoxicity.
Combining irinotecan with oxaliplatin (IROX)	IROX regimen has documented activity in phase III studies in first and second-line treatment of metastatic CRC.^Citation30 But it is important to remember that the efficacy of IROX was significantly inferior to FOLFOX in first-line treatment. In second-line treatment after 5-FU failure, IROX was found to be superior to irinotecan monotherapy.^Citation31	Not reported.
Cetuximab or panitumumab monotherapy	Cetuximab and panitumumab are active as a single agent in chemo-refractory mCRC patients with K-RAS wild type tumors.^Citation32,Citation33	Not reported.
Regorafenib	Regorafenib has been approved to treat mCRC that has progressed after all standard therapies (fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy).^Citation34	Like other anti-VEGF agents are known to cause arterial thromboembolism.
TAS-102	TAS-102 has been approved to treat mCRC that has progressed after all standard therapies (fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy).^Citation15	In the registration RECOURSE phase III study that led to its FDA approval, only one patient treated with TAS-102 was reported to have an episode of cardiac ischemia among 800 treated patients who have been exposed to 5-FU previously.
Immunotherapy (for MSI-high)	In May 2017, the FDA granted approval for using pembrolizumab, a programmed cell death protein 1 (PD-1) antibody, in patients with microsatellite unstable mCRC.^Citation35	Cases of cardiotoxicity, such as myocarditis, Tako-Tsubo cardiomyopathy, cardiac arrest, myocardial infarction, have been reported, that usually occur immediately after the infusion or during the first year of therapy.
Mitomycin (MMC)	Data does not support use of single agent based on a multicenter, multinational analysis of mitomycin C in refractory metastatic colorectal cancer.^Citation36 MIXE regimen (mitomycin plus capecitabine) has shown activity as salvage therapy but cannot be recommended due to capecitabine’s cardiotoxicity previously discussed.^Citation37	MMC has been implicated as a possible cardiotoxic agent (CHF).
Mitomycin (MMC) + Oxaliplatin (MOX)	One possible alternative regimen is MOX (mitomycin with oxaliplatin) which has shown some activity in salvage setting of mCRC.^Citation38 We recently published the first case series that reports the safety and feasibility of s-MOX in patients with mCRC who developed cardiac toxicity to 5-FU or capecitabine^Citation4,Citation8,Citation9,Citation39	Overall, the s-MOX regimen was well tolerated. The most common toxicities included < grade 2 peripheral neuropathy, nausea, vomiting, thrombocytopenia, and anemia.^Citation38
Mitomycin (MMC) + Irinotecan (MIRI)	MIRI regimen (mitomycin with irinotecan) has also shown some activity in salvage setting of mCRC.^Citation39,Citation40 We have developed a modified regimen (s-MIRI – unpublished) administering mitomycin 7mg/m^2 on day 1 and irinotecan 150 mg/m^2 on day 1 and day 15 every 28 days (unpublished) which was found to be safer without any recurrent cardiac toxicities in five patients who had previously encountered cardiotoxicity to 5-FU and/or capecitabine (unpublished).	s-MIRI did not result in recurrent cardiac toxicities in five patients who had previously encountered cardiotoxicity to 5-FU and/or capecitabine (unpublished).
TAS-102	TAS-102 shares similarities with fluoropyrimidines, but its mechanism of action is distinct. In some investigators’ opinion, switching to TAS-102 should be considered as switching to a non-fluoropyrimidine.^Citation13,Citation14	There is ample data suggesting that TAS-102 is the first “cardio-gentle” fluoropyrimidine in the colorectal cancer landscape.^Citation41
Combination of other oral fluoropyrimidines (S-1 and UFT) with irinotecan (TEGAFIRI), oxaliplatin (TEGAFOX, UFOX) are also viable options outside the US.

Table 6 Suggested Recommendations

Pre-treatment
History: Cardiac disease, risk factors, cardiotoxic medications Family History Exam: Cardiac, weight Tests: Baseline EKG
During treatment
Monitor for cardiovascular symptoms Weight and Fluid balance Electrolyte monitoring (especially when used in combination with cisplatin) Be careful when administering 5-FU with other cardiotoxic drugs, including anti-VEGF agents Immediately stop infusion or capecitabine if cardiovascular symptom develops (including hypotension) Treat with conventional therapy for such cardiac event Complete cardiac work-up
Re-challenge
Only perform in selected patients if clinically important and no alternate therapy available Close monitoring Consider continuous electrocardiographic monitoring Consult a cardiologist Otherwise consider alternative treatment options

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