Medical Hypotheses 83 (2014) 116–118
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Is there any effect of bolus and/or infusion 5-fluorouracil treatment on microalbuminuria in immediate or long term? Ozgur Tanriverdi ⇑ Mugla Sitki Kocman University Faculty of Medicine, Department of Medical Oncology, Mugla, Turkey
a r t i c l e
i n f o
Article history: Received 9 November 2013 Accepted 27 March 2014
a b s t r a c t 5-Fluorouracil is a widely used cytotoxic chemotherapeutic agent in the treatment settings particularly in patients with gastrointestinal cancer. Various studies on the cardiac adverse effects of 5-fluorouracil, reported the likelihood of altered myocardial contractility and vascular endothelial damage caused by this agent. However, the mechanism underlying 5-fluorouracil-related cardiotoxicity is not clear. In certain experimental studies, thrombotic processes occurring in microvascular field were supposed to play a role in this condition. In the light of this knowledge, the administration of 5-fluorouracil may be considered to cause renal vascular endothelial damage that may result in the altered endothelial permeability. As a result of endothelial dysfunction, increased urinary albumin excretion may be in question and no study investigating this potential direct relationship has been available in medical literature. Based on this evidence, the hypothesis of that 5-fluorouracil might cause renal vascular dysfunction and microalbuminuria, was discussed in this article along with the basic knowledge. Ó 2014 Elsevier Ltd. All rights reserved.
Background 5-Fluorouracil (5-FU), is a member of fluoropyrimidine family. Its chemotherapeutic effect is specific to the S phase process of the cell cycle and it is an anti-metabolite. The active metabolite of 5-FU is 5-fluorodeoxyuridylate (5-FdUMP) and it inhibits thymidylate synthetase and leads to cell death by preventing DNA synthesis [1–4]. 5-FU has been widely used in treatment settings in oncology practice, particularly in various stages of gastrointestinal system malignancies [1]. 5-Fluorouracil-related toxicity is connected with the concurrent administration of the other drugs, chemotherapy scheme and drug administration schedules and it is associated with nausea, vomiting, diarrhea, stomatitis, alopecia and leucopenia [5]. Cardiac and vascular endothelial toxicities are rare and their mechanism is not clear [1–4]. Numerous studies have reported that angina pectoris, elevated levels of cardiac enzymes and electrocardiogram (ECG) alterations may be associated with 5-FU therapy [1,2]. Furthermore there are many studies in the medical literature demonstrating the potential responsibility of vascular damage and endothelial dysfunction for cardiac adverse effects. Experimental studies have demonstrated
that this situation is related to the thrombogenic effect and direct toxicity to vascular endothelium of 5-FU [1,5–8]. When the knowledge in medical literature is considered, most of these 5-FU studies are on the alterations in the cardiac contractility and structural characteristics [10,10]. While cardiotoxicity of bolus 5-FU was reported as 1.6–3% in previous studies, cardiac adverse effects of 5-FU, particularly when administered as 4–5 days continuous infusions, was reported as about 7.6–18% [1,2,4,11–13]. After all, as stated in a number of studies, a cyclic contractility alteration without any clinical or electrocardiographic sign was found to be associated with 5-FU infusions [15]. When asymptomatic patients or patients who do not have any ECG alteration are considered, the actual incidence of 5-fluorouracil-related cardiotoxicity in clinical practice is not clear. In addition, there are certain preclinical and clinical trial on cardiac vascular endothelial damage caused by 5-FU. However no information was available about the renal vascular damage caused by 5-FU in medical literature. Based on this evidence, the hypothesis of that 5-fluorouracil might cause renal vascular dysfunction and microalbuminuria, was discussed in this article along with the basic knowledge. Hypothesis
⇑ Address: Mugla Universitesi Eg˘itim ve Arastirma Hastanesi, Onkoloji Bolumu, 48000 Mugla, Turkey. Tel.: +90 252 214 13 26; fax: +90 252 212 68 04. E-mail address: [email protected] http://dx.doi.org/10.1016/j.mehy.2014.03.030 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
Experimental and clinical studies have demonstrated that 5-FU may cause adverse effects on cardiac vascular endothelium and myocardial contractility at varying degree. No definite opinion
O. Tanriverdi / Medical Hypotheses 83 (2014) 116–118
has been found on the impact of 5-FU on renal functions and renal vascular endothelium in previous studies. However, due to the altered cardiac contractility associated with 5-FU administration and its thrombogenic and vasoconstructive effects in vascular field and vascular endothelial damage demonstrated in the experimental studies, microalbuminuria is an expectable condition. In this article one will focus on the hypothesis of whether 5-FU leads to microalbuminuria. . Preliminary results of a pilot study The preliminary results of a pilot study on this hypothesis were presented as a poster paper, in the Symposium on Current Therapies in Clinical Oncology (8th Aydin Oncology Days) held by the Medical Oncology Department of the Medical School of Aydin Adnan Menderes University in Kusßadası, Turkey. 4 patients with early stage gastric cancer and 8 patients with colorectal cancer that we had full access to all patient’s file information retrospectively, a total of 12 patients who underwent adjuvant chemotherapy consisting of 5-FU-folinic acid (FA) (de Gramont regimen) or 5-FU, FA, and oxaliplatin (FOLFOX4 or mFOLFOX6 regimens), were included in this study. The exclusion criteria were determined as diabetes mellitus, hypertensive nephropathy, chronic renal insufficiency, hematological malignancies and recent cerebrovascular disease. During the measurements of urinary protein excretion, the absence of increased body temperature, urinary infection or acute renal failure was demonstrated. The measurements of microalbuminuria in 24-h urine were carried out by nephelometry before the first course of chemotherapy and following the completion of adjuvant chemotherapy (a total of 12 courses given at 2week intervals in colorectal cancer and a total of 6 courses given at 2-week intervals within the period of time before radiotherapy, in gastric cancer). The mean age of the patients was 54 ± 16 years and the mean body mass index was 26.4 ± 4.8 kg/m2. The optimal treatment duration could not be achieved in three patients due to intolerance. A total of 128 chemotherapy courses were administered and the mean treatment duration including all adjuvant chemotherapy courses was 156 ± 9 days. In the comparison between the measurements performed before chemotherapy and after the completion of chemotherapy: the mean relative increase in urinary protein excretion was determined as 41 ± 12 mg/24 h. 9 patients (75%) developed microalbuminuria at the completion of adjuvant therapy. Evaluation 5-FU is a widely used chemotherapeutic agent in oncological practice, particularly in patients with gastrointestinal cancer [1]. Taking into consideration possible adverse effects of this drug is crucial for the management of the co-morbidities of the patients and for the maintenance of their quality of life. One may suggest that this hypothetic approach based on the literature knowledge may provide some benefits in the clinical practice. First of all, this hypothetic approach based on the studies demonstrating cardiac adverse effects may lead to closer observation of the patients in terms of renal co-morbidities and hypoalbuminemia resulting from the hypothetical 5-fluorouracil-related renal vascular damage. The significant increase in the urinary albumin excretion following 5-FU administration was emphasized in the unique study investigating the relationship between 5-FU and cardiac events. Secondly, this approach may provide a closer observation of the urinary albumin excretion that may be resulted from the administration of 5-FU, in hypertensive patients and/or patients with diabetic nephropathy or patients with renal disorder presenting with microalbuminuria. In spite of the studies indicating a wide interval
117
of safety in 5-FU in patients with renal dysfunction, or cancer patients with chronic renal failure requiring hemodialysis, there is no a definite suggestion for the patients revealing microalbuminuria or overt nephropathy [16]. This hypothetical approach may constitute a small step to develop an algorithm in these patients. Thirdly, since 5-FU exhibits a moderate binding affinity to serum albumin to reach its target tissue; the determination of the tissue concentration of this agent and its efficacy in patients with microalbuminuria may be another subject of study [1]. In conclusion; in order to demonstrate the accuracy of this hypothesis, certain criteria and variables should be taken into consideration. Primarily, designing prospective studies with a large patient population and exclusion criteria intended for main purpose is important. In these studies the detection of acute changes both in the renal vascular field and in urinary protein excretionwhich can be determined by the urinary albumin/creatinine ratioresulting from bolus 5-FU treatment or infusion 5-FU treatment should be the main purpose. Renal arterial and venous Doppler ultrasonography performed appropriately by experienced professionals may partially reveal the microvascular thrombotic process and vascular blood flow disorders. Additionally, the effect of this hypothesis on the demonstration of 5-fluorouracil-related acute and chronic renal vascular endothelial dysfunction and consequently microalbuminuria may be clarified by prospective studies. Discussion Although its cardiotoxicity effects are not definite, numerous studies reported that 5-FU may cause certain dysfunctions in the vascular endothelial field and alteration in myocardial contractility. In the light of this knowledge, microalbuminuria and renal vascular endothelial dysfunction and thrombotic processes in the renal vascular field as one of the major causes of microalbuminuria demonstrated by clinical and experimental studies, will be significant in clinical practice. The demonstration of the hypothesis of that 5-FU and its derivatives, that take place in the treatment settings of metastatic diseases apart from the early stage cancer patients, may lead to the increased urinary albumin excretion; will facilitate to perform close observation for the assessment of the efficacy of the treatment particularly in patients with already impaired renal function or hypertensive/diabetic microalbuminuria; or overt proteinuria; the revision the adverse effect profile; and maintenance of quality of life. Therefore, even this approach is hypothetical, keeping this probable adverse effect in mind may be significant in clinical oncology practice. Conflict of interest I certify that all of my affiliations with or without financial involvement, within the past 5 years and foreseeable future and, any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript are completely disclosed (e.g., employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, and royalties). References [1] Sorrentino MF, Kim J, Foderaro AE, Truesdell AG. 5-Fluorouracil induced cardiotoxicity: review of the literature. Cardiol J 2012;19(5):453–8. [2] Kosmas C, Kallistratos M, Kopterides P, Syrios J, Skopelitis H, Mylonakis N, et al. Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol 2008;134(1):75–82. [3] Stewart T, Pavlakis N, Ward M. Cardiotoxicity with 5-fluorouracil and capecitabine: more than just vasospastic angina. Intern Med J 2010;40(4):303–7.
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O. Tanriverdi / Medical Hypotheses 83 (2014) 116–118
[4] Labianca R, Beretta G, Clerici M, Frascini P, Luporini G. Cardiac toxicity of 5fluorouracil: a study of 1083 patients. Tumori 1982;68(6):505–10. [5] Cwikiel M, Eskilsson J, Albertsson M, Stavenow L. The influence of 5fluorouracil and methotrexate on vascular endothelium. An experimental study using endothelial cells in the culture. Ann Oncol 1996;7(7):731–7. [6] Porta C, Moroni M, Ferrari S, Nastasi G. Endothelin-1 and 5-fluorouracilinduced cardiotoxicity. Neoplasma 1998;45(2):81–2. [7] Kuo L, Thengchaisri N, Hein WH. Regulation of coronary vasomotor function by reactive oxygen species. Mol Med Ther 2012;1(1):1–4. [8] Kinhult S, Albertsson M, Eskilsson J, Cwikiel M. Effects of probucol on endothelial damage by 5-fluorouracil. Acta Oncol 2003;42(4):304–8. [9] Connolly S, Scott P, Cochrane D, Harte R. A case report of 5-fluorouracilinduced coronary artery vasospasm. Ulster Med J 2010;5779(3):135–6. [10] Jensen SA, Sorensen JB. 5-Fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity. Cancer Chemother Pharmacol 2012;69(1):57–64.
[11] de Forni M, Malet-Martino MC, Jaillais P, Shubinski RE, Bachaud JM, Lemaire L, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol 1992;10(11):1795–801. [12] Meydan N, Kundak I, Yavuzsen T, Oztop I, Barutca S, Yilmaz U, et al. Cardiotoxicity of de Gramont’s regimen: incidence, clinical characteristics and long-term follow-up. Jpn J Clin Oncol 2005;35(5):265–70. [13] Meyer CC, Calis KA, Burke LB, Walawander CA, Grasela TH. Symptomatic cardiotoxicity associated with 5-fluorouracil. Pharmacotherapy 1997;17(4):729–36. [14] Ceyhan C, Meydan N, Barutca S, Tekten T, Onbasili A, Ozturk B, et al. Ultrasound tissue characterization by integrated backscatter for analyzing fluorouracil induced myocardial damage. Echocardiography 2005;22(3):233–8. [15] Janus N, Thariat J, Boulanger H, Deray G, Launay-Vacher V. Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients. Ann Oncol 2010;21(7):1395–403.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Is there any effect of bolus and/or infusion 5-fluorouracil treatment on microalbuminuria in immediate or long term? Ozgur Tanriverdi ⇑ Mugla Sitki Kocman University Faculty of Medicine, Department of Medical Oncology, Mugla, Turkey
a r t i c l e
i n f o
Article history: Received 9 November 2013 Accepted 27 March 2014
a b s t r a c t 5-Fluorouracil is a widely used cytotoxic chemotherapeutic agent in the treatment settings particularly in patients with gastrointestinal cancer. Various studies on the cardiac adverse effects of 5-fluorouracil, reported the likelihood of altered myocardial contractility and vascular endothelial damage caused by this agent. However, the mechanism underlying 5-fluorouracil-related cardiotoxicity is not clear. In certain experimental studies, thrombotic processes occurring in microvascular field were supposed to play a role in this condition. In the light of this knowledge, the administration of 5-fluorouracil may be considered to cause renal vascular endothelial damage that may result in the altered endothelial permeability. As a result of endothelial dysfunction, increased urinary albumin excretion may be in question and no study investigating this potential direct relationship has been available in medical literature. Based on this evidence, the hypothesis of that 5-fluorouracil might cause renal vascular dysfunction and microalbuminuria, was discussed in this article along with the basic knowledge. Ó 2014 Elsevier Ltd. All rights reserved.
Background 5-Fluorouracil (5-FU), is a member of fluoropyrimidine family. Its chemotherapeutic effect is specific to the S phase process of the cell cycle and it is an anti-metabolite. The active metabolite of 5-FU is 5-fluorodeoxyuridylate (5-FdUMP) and it inhibits thymidylate synthetase and leads to cell death by preventing DNA synthesis [1–4]. 5-FU has been widely used in treatment settings in oncology practice, particularly in various stages of gastrointestinal system malignancies [1]. 5-Fluorouracil-related toxicity is connected with the concurrent administration of the other drugs, chemotherapy scheme and drug administration schedules and it is associated with nausea, vomiting, diarrhea, stomatitis, alopecia and leucopenia [5]. Cardiac and vascular endothelial toxicities are rare and their mechanism is not clear [1–4]. Numerous studies have reported that angina pectoris, elevated levels of cardiac enzymes and electrocardiogram (ECG) alterations may be associated with 5-FU therapy [1,2]. Furthermore there are many studies in the medical literature demonstrating the potential responsibility of vascular damage and endothelial dysfunction for cardiac adverse effects. Experimental studies have demonstrated
that this situation is related to the thrombogenic effect and direct toxicity to vascular endothelium of 5-FU [1,5–8]. When the knowledge in medical literature is considered, most of these 5-FU studies are on the alterations in the cardiac contractility and structural characteristics [10,10]. While cardiotoxicity of bolus 5-FU was reported as 1.6–3% in previous studies, cardiac adverse effects of 5-FU, particularly when administered as 4–5 days continuous infusions, was reported as about 7.6–18% [1,2,4,11–13]. After all, as stated in a number of studies, a cyclic contractility alteration without any clinical or electrocardiographic sign was found to be associated with 5-FU infusions [15]. When asymptomatic patients or patients who do not have any ECG alteration are considered, the actual incidence of 5-fluorouracil-related cardiotoxicity in clinical practice is not clear. In addition, there are certain preclinical and clinical trial on cardiac vascular endothelial damage caused by 5-FU. However no information was available about the renal vascular damage caused by 5-FU in medical literature. Based on this evidence, the hypothesis of that 5-fluorouracil might cause renal vascular dysfunction and microalbuminuria, was discussed in this article along with the basic knowledge. Hypothesis
⇑ Address: Mugla Universitesi Eg˘itim ve Arastirma Hastanesi, Onkoloji Bolumu, 48000 Mugla, Turkey. Tel.: +90 252 214 13 26; fax: +90 252 212 68 04. E-mail address: [email protected] http://dx.doi.org/10.1016/j.mehy.2014.03.030 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
Experimental and clinical studies have demonstrated that 5-FU may cause adverse effects on cardiac vascular endothelium and myocardial contractility at varying degree. No definite opinion
O. Tanriverdi / Medical Hypotheses 83 (2014) 116–118
has been found on the impact of 5-FU on renal functions and renal vascular endothelium in previous studies. However, due to the altered cardiac contractility associated with 5-FU administration and its thrombogenic and vasoconstructive effects in vascular field and vascular endothelial damage demonstrated in the experimental studies, microalbuminuria is an expectable condition. In this article one will focus on the hypothesis of whether 5-FU leads to microalbuminuria. . Preliminary results of a pilot study The preliminary results of a pilot study on this hypothesis were presented as a poster paper, in the Symposium on Current Therapies in Clinical Oncology (8th Aydin Oncology Days) held by the Medical Oncology Department of the Medical School of Aydin Adnan Menderes University in Kusßadası, Turkey. 4 patients with early stage gastric cancer and 8 patients with colorectal cancer that we had full access to all patient’s file information retrospectively, a total of 12 patients who underwent adjuvant chemotherapy consisting of 5-FU-folinic acid (FA) (de Gramont regimen) or 5-FU, FA, and oxaliplatin (FOLFOX4 or mFOLFOX6 regimens), were included in this study. The exclusion criteria were determined as diabetes mellitus, hypertensive nephropathy, chronic renal insufficiency, hematological malignancies and recent cerebrovascular disease. During the measurements of urinary protein excretion, the absence of increased body temperature, urinary infection or acute renal failure was demonstrated. The measurements of microalbuminuria in 24-h urine were carried out by nephelometry before the first course of chemotherapy and following the completion of adjuvant chemotherapy (a total of 12 courses given at 2week intervals in colorectal cancer and a total of 6 courses given at 2-week intervals within the period of time before radiotherapy, in gastric cancer). The mean age of the patients was 54 ± 16 years and the mean body mass index was 26.4 ± 4.8 kg/m2. The optimal treatment duration could not be achieved in three patients due to intolerance. A total of 128 chemotherapy courses were administered and the mean treatment duration including all adjuvant chemotherapy courses was 156 ± 9 days. In the comparison between the measurements performed before chemotherapy and after the completion of chemotherapy: the mean relative increase in urinary protein excretion was determined as 41 ± 12 mg/24 h. 9 patients (75%) developed microalbuminuria at the completion of adjuvant therapy. Evaluation 5-FU is a widely used chemotherapeutic agent in oncological practice, particularly in patients with gastrointestinal cancer [1]. Taking into consideration possible adverse effects of this drug is crucial for the management of the co-morbidities of the patients and for the maintenance of their quality of life. One may suggest that this hypothetic approach based on the literature knowledge may provide some benefits in the clinical practice. First of all, this hypothetic approach based on the studies demonstrating cardiac adverse effects may lead to closer observation of the patients in terms of renal co-morbidities and hypoalbuminemia resulting from the hypothetical 5-fluorouracil-related renal vascular damage. The significant increase in the urinary albumin excretion following 5-FU administration was emphasized in the unique study investigating the relationship between 5-FU and cardiac events. Secondly, this approach may provide a closer observation of the urinary albumin excretion that may be resulted from the administration of 5-FU, in hypertensive patients and/or patients with diabetic nephropathy or patients with renal disorder presenting with microalbuminuria. In spite of the studies indicating a wide interval
117
of safety in 5-FU in patients with renal dysfunction, or cancer patients with chronic renal failure requiring hemodialysis, there is no a definite suggestion for the patients revealing microalbuminuria or overt nephropathy [16]. This hypothetical approach may constitute a small step to develop an algorithm in these patients. Thirdly, since 5-FU exhibits a moderate binding affinity to serum albumin to reach its target tissue; the determination of the tissue concentration of this agent and its efficacy in patients with microalbuminuria may be another subject of study [1]. In conclusion; in order to demonstrate the accuracy of this hypothesis, certain criteria and variables should be taken into consideration. Primarily, designing prospective studies with a large patient population and exclusion criteria intended for main purpose is important. In these studies the detection of acute changes both in the renal vascular field and in urinary protein excretionwhich can be determined by the urinary albumin/creatinine ratioresulting from bolus 5-FU treatment or infusion 5-FU treatment should be the main purpose. Renal arterial and venous Doppler ultrasonography performed appropriately by experienced professionals may partially reveal the microvascular thrombotic process and vascular blood flow disorders. Additionally, the effect of this hypothesis on the demonstration of 5-fluorouracil-related acute and chronic renal vascular endothelial dysfunction and consequently microalbuminuria may be clarified by prospective studies. Discussion Although its cardiotoxicity effects are not definite, numerous studies reported that 5-FU may cause certain dysfunctions in the vascular endothelial field and alteration in myocardial contractility. In the light of this knowledge, microalbuminuria and renal vascular endothelial dysfunction and thrombotic processes in the renal vascular field as one of the major causes of microalbuminuria demonstrated by clinical and experimental studies, will be significant in clinical practice. The demonstration of the hypothesis of that 5-FU and its derivatives, that take place in the treatment settings of metastatic diseases apart from the early stage cancer patients, may lead to the increased urinary albumin excretion; will facilitate to perform close observation for the assessment of the efficacy of the treatment particularly in patients with already impaired renal function or hypertensive/diabetic microalbuminuria; or overt proteinuria; the revision the adverse effect profile; and maintenance of quality of life. Therefore, even this approach is hypothetical, keeping this probable adverse effect in mind may be significant in clinical oncology practice. Conflict of interest I certify that all of my affiliations with or without financial involvement, within the past 5 years and foreseeable future and, any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript are completely disclosed (e.g., employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, and royalties). References [1] Sorrentino MF, Kim J, Foderaro AE, Truesdell AG. 5-Fluorouracil induced cardiotoxicity: review of the literature. Cardiol J 2012;19(5):453–8. [2] Kosmas C, Kallistratos M, Kopterides P, Syrios J, Skopelitis H, Mylonakis N, et al. Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol 2008;134(1):75–82. [3] Stewart T, Pavlakis N, Ward M. Cardiotoxicity with 5-fluorouracil and capecitabine: more than just vasospastic angina. Intern Med J 2010;40(4):303–7.
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O. Tanriverdi / Medical Hypotheses 83 (2014) 116–118
[4] Labianca R, Beretta G, Clerici M, Frascini P, Luporini G. Cardiac toxicity of 5fluorouracil: a study of 1083 patients. Tumori 1982;68(6):505–10. [5] Cwikiel M, Eskilsson J, Albertsson M, Stavenow L. The influence of 5fluorouracil and methotrexate on vascular endothelium. An experimental study using endothelial cells in the culture. Ann Oncol 1996;7(7):731–7. [6] Porta C, Moroni M, Ferrari S, Nastasi G. Endothelin-1 and 5-fluorouracilinduced cardiotoxicity. Neoplasma 1998;45(2):81–2. [7] Kuo L, Thengchaisri N, Hein WH. Regulation of coronary vasomotor function by reactive oxygen species. Mol Med Ther 2012;1(1):1–4. [8] Kinhult S, Albertsson M, Eskilsson J, Cwikiel M. Effects of probucol on endothelial damage by 5-fluorouracil. Acta Oncol 2003;42(4):304–8. [9] Connolly S, Scott P, Cochrane D, Harte R. A case report of 5-fluorouracilinduced coronary artery vasospasm. Ulster Med J 2010;5779(3):135–6. [10] Jensen SA, Sorensen JB. 5-Fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity. Cancer Chemother Pharmacol 2012;69(1):57–64.
[11] de Forni M, Malet-Martino MC, Jaillais P, Shubinski RE, Bachaud JM, Lemaire L, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol 1992;10(11):1795–801. [12] Meydan N, Kundak I, Yavuzsen T, Oztop I, Barutca S, Yilmaz U, et al. Cardiotoxicity of de Gramont’s regimen: incidence, clinical characteristics and long-term follow-up. Jpn J Clin Oncol 2005;35(5):265–70. [13] Meyer CC, Calis KA, Burke LB, Walawander CA, Grasela TH. Symptomatic cardiotoxicity associated with 5-fluorouracil. Pharmacotherapy 1997;17(4):729–36. [14] Ceyhan C, Meydan N, Barutca S, Tekten T, Onbasili A, Ozturk B, et al. Ultrasound tissue characterization by integrated backscatter for analyzing fluorouracil induced myocardial damage. Echocardiography 2005;22(3):233–8. [15] Janus N, Thariat J, Boulanger H, Deray G, Launay-Vacher V. Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients. Ann Oncol 2010;21(7):1395–403.
