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TAS-102, the first “cardio-gentle” fluoropyrimidine in the colorectal cancer landscape?
© The Author(s). 2016
- Received: 16 January 2016
- Accepted: 15 June 2016
- Published: 4 July 2016
Cardiotoxicity in the form of cardiac arrhythmia, myocardial infarction, and angina-like symptoms are not rare complications of fluoropyrimidines as 5-Fluorouracil (5FU) and capecitabine.
Tas-102, a novel oral fluoropyrimidine, was recently approved by FDA for the treatment of advanced and refractory colorectal cancer. Its unique mechanism of action doesn’t seem linked with cardiotoxicity in clinical trials reported so far.
TAS 102 may represent one of the drugs of choice for patients with advanced colorectal cancer with cardiac disease. This intriguing and clinically relevant issue is briefly examined.
Cardiotoxicity of capecitabine, 5-Fluorouracil, TAS 102 and S1
Unstable angina pectoris, angina pectoris, myocardial ischemia, atrial fibrillation, cardiac arrhythmia, tachycardia, Palpitation
Ventricular fibrillation, QT prolongation, torsade de pointes, bradycardia, vasospasm
Myocardial infarction, myocardial ischemia, cardiac arrhythmia, myocarditis, heart failure, dilated cardiomyopathy
Cardiac arrest, sudden cardiac death
Myocardial infarction, myocardial ischemia, chest pain, bradycardia, tachycardia
Cardiac failure, acute myocardial infarction, pericardial effusion, atrial fibrillation, angina pectoris, cardiac fibrillation, tachycardia, palpitations
We searched for phase I, phase II and randomized phase III trials to evaluate if cardiovascular events were reported and if any, which type of toxicity was observed [7, 9–13]. Only studies reporting the current, labeled scheduled of TAS 102 were considered. Among 4 phase I studies, no cardiotoxic events were reported, including 3 single agent TAS 102 trials and a phase I study of a combination of TAS 102 with a fixed dose of irinotecan (121 patients overall). In the phase II trials comparing TAS 102 (at the labeled dose) with placebo, 112 patients were randomized but no cardiotoxic events were reported yet. Finally in the pivotal phase III study by Mayer et al. n = 3 and n = 2 cardiac events (cardiac ischemia) were recorded in the experimental and control arms respectively, with no rate of cardiac arrhythmia observed. The rate of cardiotoxicity in this trial is 0.5 % that represents from 2 to 40-fold numerically less frequent of that reported with 5FU in literature. A potential limitation of our observation is that the patients who had cardiotoxicity during previous treatments might have been excluded from TAS102 trials, which enrolled patients heavely pretreated with many previous lines of therapies. Nevertheless, we think that the different mechanism of action of TAS 102 compared with others fluoropyrimydines might still explain the lack of cardiotoxicity reported so far with this novel drug.
A different autophagic induction of TAS 102 compared to 5FU. In Focaccetti et al. paper cited above, autophagic features at the ultrastructural and molecular levels, in particular in 5-FU exposed cardiomyocytes and endothelial cells can be observed. Conversely, TFT was more potent than 5FU, because it induces higher levels of cell death and does not elicit an autophagic survival response in the cancer cell lines .
A different oncological target (DNA damage and synthesis) for TAS 102 itself compared to 5FU or capecitabine: TF-TMP (tri-fluorothymidine monophosphate) and TF-TTP (tri-fluorothymidine triphosphate) vs FdUMP (fluorodeoxyuridine monophosphate) and FdUTP (fluorodeoxyuridine triphosphate).
The incorporation of FTD into DNA in tumor tissues is significantly higher than its incorporation into DNA in normal tissues, thus sparing cardiovascular tissues .
TAS 102 is not catabolized by dihydropyridine dehydrogenase (DPD), that is predominantly expressed in the liver and inactivates more than 80 % of administered 5FU, with consequently reduced the formation of FBAL . This is somewhat similar to that happen with S-1 that is a combination of tegafur, gimeracil, and OXO. Because of the significant DPD inhibition by gimeracil, FBAL and other cardiotoxic 5FU catabolites (F-citrate) levels are significantly lower than after capecitabine or I.V. 5-FU administration, and less cardiotoxicity can be expected . F-citrate inhibits the Krebs cycle by inhibition of aconitase, limiting the cellular production of adenosine triphosphate (ATP). Fluoroacetate is known to be highly cardiotoxic and neurotoxic .
We can reasonably affirm that the new oral agent TAS 102, represent one of the true drugs of choice for patients with advanced colorectal cancer with known (pre-existing) cardiac disease or for those which manifest cardiac complications during 5FU or capecitabine treatment. It has several potential advantages over raltitrexed (oral route and less renal toxicity) and S-1 that is not still labeled for colorectal cancer in western countries. Another possible benefit of TAS 102 is the possibility of administering the drug to those subjects with known DPD deficiency, so reducing the expected risk of severe gastrointestinal toxicity. Combination studies with other cytotoxics are in fiery, including biological agents. Hematological toxicities represent the limiting event, but with very low rate of febrile neutropenia. In the meanwhile TAS 102 appear as one the most cardio-gentle nucleoside analog available in clinical practice and may represent the agent of choice when 5FU is indicated but relevant comorbidities increase the cardiovascular risk.
5FU, 5-Fluorouracil; ATP, adenosine triphosphate; ci, continuous infusion; DPD, dihydropyridine dehydrogenase; FBAL, alpha-fluoro-beta-alanine; FdUMP, fluorodeoxyuridine monophosphate; FdUTP, fluorodeoxyuridine triphosphate; ROS, reactive oxygen species; TFT, tri-fluorothymidine; TF-TMP, tri-fluorothymidine monophosphate; TF-TTP, tri-fluorothymidine triphosphate; TPI, thymidine phosphorylase; TS, thymidylate synthase
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FP draft the manuscript and performed the bibliographic research. SB draft the manuscript and performed the bibliographic research. PB draft and revised the manuscript. AZ draft and revised the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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