Feasibility of Switching Fluoropyrimidine Due to Cardiotoxicity Study (CardioSwitch)

• ClinicalTrials.gov Identifier: NCT04260269
• Recruitment Status: Enrolling by invitation
• First Posted: February 7, 2020
• Last Update Posted: February 7, 2020
• Sponsor: Helsinki University Central Hospital
• Collaborator: Tampere University Hospital
• Information provided by (Responsible Party): Pia Osterlund, Tampere University Hospital

Study Description

Brief Summary:

The purpose of the present study is to evaluate cardiotoxicity during re-challenge of a different modality of fluoropyrimidine (primary end-point S-1 and secondary any other fluoropyrimidine) after having perceived cardiotoxicity with a fluoropyrimidine based regimen previously. The patient population is being treated for solid tumors.

Condition or disease	Intervention/treatment
Solid Tumor	Drug: Fluoropyrimidine

Detailed Description:

Fluoropyrimidine chemotherapy agents, such as 5-fluorouracil and capecitabine, are occasionally associated with cardiotoxicity that may manifest as chest pain, ECG alterations, cardiac arrhythmia, and rarely myocardial infarction and sudden death. Clinical fluoropyrimidine cardiotoxicity is infrequent (1-8% of patients), but subclinical toxicity may be much more common (up to one third of patients). The underlying mechanisms are not well understood, but they may include abnormal coronary artery contractility or spasm, and myocardial toxicity. Cardiotoxicity may be less frequent with S-1 (a combination of tegafur, gimeracil and oteracil at a molar ratio of 1:0.4:1) as compared with 5-fluorouracil and capecitabine, but head-to-head comparisons are lacking.

Anecdotal evidence suggests that patients who have cardiotoxicity on other fluoropyrimidines may be successfully treated with S-1. The purpose of this retrospective study is to compare different 5-fluorouracil-based dosing modalities and S-1, and compare cardiotoxicity during these treatments.

The patient population was treated for solid tumors with a 5-fluorouracil based regimen and had a cardiac event grade 1-4. All patients were re-challenged with a different fluoropyrimidine or S-1 and assessed for cardiotoxicity during re-challenge.

Study Design

• Study Type: Observational
• Estimated Enrollment: 200 participants
• Observational Model: Cohort
• Time Perspective: Retrospective
• Official Title: Feasibility of Switching Fluoropyrimidine Due to Cardiotoxicity in Patients With Solid Tumors: A Retrospective, International and Non-interventional Study
• Actual Study Start Date: June 1, 2018
• Estimated Primary Completion Date: December 2020
• Estimated Study Completion Date: December 2025

Groups and Cohorts

Intervention Details:

• Drug: Fluoropyrimidine

  This is the assessment of a specific evaluation of cardiac safety for patients with solid tumors who have experienced cardiotoxicity grade 1-4 during treatment with a fluoropyrimidine based treatment and are re-challenged with a different fluoropyrimidine.

  This multicentre, retrospective database is built to assess the impact on the cardiac and global safety of two different fluoropyrimidine based treatment regimens, of which the first has caused cardiotoxicity grade 1-4.

  Cardiac data will be collected by medical record review from initiation of first fluoropyrimidine-based treatment and switch to second fluoropyrimidine-based treatment until death or last follow-up. Basic demographics, cancer and treatment information from the whole course of cancer until death or last follow-up.

  Other Names:

  • S-1 / Teysuno
  • capecitabine
  • 5-fluorouracil
  • tegafur
  • trifluridine-tipiracil / Lonsurf

Outcome Measures

Primary Outcome Measures :

1. Recurrence of fluoropyrimidine related cardiac toxicity after switch to S-1 based treatment [ Time Frame: After switch to and during one line of S-1 based chemotherapy (average 6 months) ]
   Cardiac tolerability according to NCI-CTCAE following cardiotoxicity initiated switch of fluoropyrimidine to S-1

Secondary Outcome Measures :

1. Recurrence of fluoropyrimidine related cardiac toxicity after switch to any fluoropyrimidine [ Time Frame: After switch to and during one line of another fluoropyrimidine regimen (average 6 months) ]
   Cardiac tolerability according to NCI-CTCAE following cardiotoxicity initiated switch of fluoropyrimidine to another fluoropyrimidine chemotherapy
2. Cardiac symptoms during fluoropyrimidine chemotherapy [ Time Frame: During one line of fluoropyrimidine based chemotherapy (average 6 months) ]
   Frequency and severity according to NCI-CTCAE of cardiac symptoms during different fluoropyrimidines and the correlation with other added cytotoxics or biologics
3. Diagnostic work-up [ Time Frame: During one line of fluoropyrimidine based chemotherapy (average 6 months) ]
   Diagnostic work-up for cardiotoxicity in real world data
4. Time-lines for cardiotoxicity [ Time Frame: During one line of fluoropyrimidine based chemotherapy (average 6 months) ]
   Time-lines for appearance of cardiotoxicity during fluoropyrimidine-based chemotherapy
5. Dose-intensity [ Time Frame: During one cycle (average 3 weeks) of fluoropyrimidine-based chemotherapy causing cardiac toxicity ]
   Dose-intensity of the therapy at the cycle causing cardiotoxicity
6. Alteration in cardiac functional parameters during fluoropyrimidine treatment induced cardiotoxicity [ Time Frame: During one cycle (average 3 weeks) of fluoropyrimidine-based chemotherapy causing cardiac toxicity ]

   The alterations of (if evaluated), graded as normal, non-significant abnormalities or significant abnormalities.:

   • ECG abnormalities
   • Ejection fraction in %
   • Coronary artery status on angiogram
   • Cardiac arrhythmias in ECG, Holter or cardiac monitor registration
   • Plasma troponin concentration and other cardiac enzymes and other laboratory tests as within reference range ro abnormal
   • Serum alpha-fluoro-beta-alanine (FBAL) concentration

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

All consecutive patients who fulfil the following inclusion criteria will be included in the database until the target number of patients has been included:

• Solid tumor
• Cardiotoxicity grade 1-4 during fluoropyrimidine-based treatment
• Re-challenge with a different fluoropyrimidine-based treatment. Primary endpoint is switch to S-1 and secondary any fluoropyrimidine population.

Criteria

Inclusion Criteria:

• Solid tumor
• Cardiotoxicity grade 1-4 during fluoropyrimidine-based treatment
• Re-challenge with a different fluoropyrimidine-based therapy

Exclusion Criteria:

• Participation in a trial with experimental drugs

Contacts and Locations

Locations

Denmark

Odense University Hospital

Odense, Denmark

Finland

Department of Oncology

Tampere, Pirkanmaa, Finland, 33520

Helsinki University Central Hospital

Helsinki, Uusimaa, Finland, 00290

Oulu university hospital

Oulu, Finland

Turku university hospital

Turku, Finland

Iceland

Landspitali

Reykjavík, Iceland

Ireland

St. Vincents University Hospital

Dublin, Ireland

Netherlands

Academic Medical Center

Amsterdam, Netherlands

Norway

Haukeland University Hospital

Bergen, Norway

Sweden

Skone university hospital

Lund, Sweden

Karolinska University Hospital

Stockholm, Sweden

Sundsvall hospital

Sundsvall, Sweden

Uppsala academic hospital

Uppsala, Sweden

Sponsors and Collaborators

Helsinki University Central Hospital

Tampere University Hospital

More Information

Publications:

Kwakman JJM, Baars A, van Zweeden AA, de Mol P, Koopman M, Kok WEM, Punt CJA. Case series of patients treated with the oral fluoropyrimidine S-1 after capecitabine-induced coronary artery vasospasm. Eur J Cancer. 2017 Aug;81:130-134. doi: 10.1016/j.ejca.2017.05.022. Epub 2017 Jun 15. No abstract available.

Kwakman JJ, Simkens LH, Mol L, Kok WE, Koopman M, Punt CJ. Incidence of capecitabine-related cardiotoxicity in different treatment schedules of metastatic colorectal cancer: A retrospective analysis of the CAIRO studies of the Dutch Colorectal Cancer Group. Eur J Cancer. 2017 May;76:93-99. doi: 10.1016/j.ejca.2017.02.009. Epub 2017 Mar 10.

Winther SB, Zubcevic K, Qvortrup C, Vestermark LW, Jensen HA, Krogh M, Sorbye H, Pfeiffer P; Academy of Geriatric Cancer Research (AgeCare). Experience with S-1 in older Caucasian patients with metastatic colorectal cancer (mCRC): Findings from an observational chart review. Acta Oncol. 2016 Jul;55(7):881-5. doi: 10.3109/0284186X.2016.1161825. Epub 2016 May 16.

Ye JX, Liu AQ, Ge LY, Zhou SZ, Liang ZG. Effectiveness and safety profile of S-1-based chemotherapy compared with capecitabine-based chemotherapy for advanced gastric and colorectal cancer: A meta-analysis. Exp Ther Med. 2014 May;7(5):1271-1278. doi: 10.3892/etm.2014.1576. Epub 2014 Feb 24.

Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 2009 Jun 16;53(24):2231-47. doi: 10.1016/j.jacc.2009.02.050.

Deboever G, Hiltrop N, Cool M, Lambrecht G. Alternative treatment options in colorectal cancer patients with 5-fluorouracil- or capecitabine-induced cardiotoxicity. Clin Colorectal Cancer. 2013 Mar;12(1):8-14. doi: 10.1016/j.clcc.2012.09.003. Epub 2012 Oct 26.

Polk A, Vaage-Nilsen M, Vistisen K, Nielsen DL. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: a systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev. 2013 Dec;39(8):974-84. doi: 10.1016/j.ctrv.2013.03.005. Epub 2013 Apr 10.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Osterlund P, Kinos S, Pfeiffer P, Salminen T, Kwakman JJM, Frodin JE, Shah CH, Sorbye H, Ristamaki R, Halonen P, Soveri LM, Heerva E, Algars A, Barlund M, Hagman H, McDermott R, O'Reilly M, Rockert R, Liposits G, Kallio R, Flygare P, Teske AJ, van Werkhoven E, Punt CJA, Glimelius B. Continuation of fluoropyrimidine treatment with S-1 after cardiotoxicity on capecitabine- or 5-fluorouracil-based therapy in patients with solid tumours: a multicentre retrospective observational cohort study. ESMO Open. 2022 Jun;7(3):100427. doi: 10.1016/j.esmoop.2022.100427. Epub 2022 Mar 30.

• Responsible Party: Pia Osterlund, Associate Professor Oncology, Tampere University Hospital
• ClinicalTrials.gov Identifier: NCT04260269
• Other Study ID Numbers: R18045
• First Posted: February 7, 2020
• Last Update Posted: February 7, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No

Additional relevant MeSH terms:

Cardiotoxicity; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Radiation Injuries; Wounds and Injuries; Trifluridine; Fluorouracil; Capecitabine; Tegafur; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antiviral Agents; Anti-Infective Agents