levoleucovorin and Heart-Diseases

The syndrome of 5-fluorouracil (5-FU)-associated cardiotoxicity remains poorly defined.. We performed a literature review (1969 - 2007) and compiled data derived from 377 evaluable cases out of 448 reported cases.. Patient age ranged from 14 to 86 years. Of the patients 65% were 55 years old and the male:female ratio was 1.5:1. The most commonly treated tumors were gastrointestinal (60%), head and neck (22%) and breast (4%). Of the patients 14% had a history of heart disease whereas cardiac risk factors were found in 37%. Mode of administration included: continuous infusion (72%); bolus (22.5%); intermediate infusion (3%); oral (2%); and intraperitoneal (1 patient). The dosages of 5-FU used were < 750 mg/m(2)/day (36%), 751 - 999 (16%), 1,000 (26%), 1,001 - 1,499 (4%) and 1,500 (16%). Of the patients 54% received 5-FU in combination with other chemotherapeutic agents (cisplatin 44%) whereas 51% received 5-FU alone or with leucovorin. Only 4% patients had undergone previous or concomitant radiation therapy to the mediastinum. Of cardiac incidents that happened 69% were seen during or within 72 h of the first cycle of 5-FU. Angina occurred in 45% of patients whereas myocardial infarction was seen in 22%, arrhythmias in 23, acute pulmonary edema in 5, cardiac arrest and pericarditis in 1.4 and heart failure in 2. Electro-cardiographic evidence of ischemia or ST-T changes were recorded in 69% of patients, but abnormal cardiac enzymes were found in only 12%. The cardiac symptoms were reproducible in 47%, including in one patient subsequently treated with 5-FU p.o. Symptoms were also elicited when the same patients were treated with lower doses or different schedules. Of the patients 68% responded to conservative anti-anginal therapy, although prophylactic coronary vasodilators had limited efficacy. Overall, 8% of patients showing cardiotoxicity on 5-FU administration died. Furthermore, 13% reexposed to 5-FU died.. Our review suggests that 5-FU cardiotoxicity is an infrequent but real phenomenon that is independent of dose and may be related to a continuous infusion schedule. The presence of cardiac risk factors is not predictive. Patients should be observed closely and 5-FU administration discontinued if cardiac symptoms develop. A rechallenge with 5-FU should be reserved only for those patients in whom there is no reasonable alternative therapy and should be performed in the setting of aggressive prophylaxis and close monitoring.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Calcium Channel Blockers; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Fluorouracil; Heart Diseases; Humans; Leucovorin; Neoplasms; Risk Factors; Vasodilator Agents

Cardiotoxicity is a rare but serious complication of 5-fluorouracil therapy. Coronary vasospasm and, less frequently, acute myocarditis have been identified as underlying mechanisms. We report a case of severe toxicity in a relatively young and fit male patient being treated for metastatic colonic adenocarcinoma displaying characteristics that cannot be explained by either mechanism alone.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Arrhythmias, Cardiac; Cardiomyopathy, Dilated; Cardiovascular Agents; Colonic Neoplasms; Coronary Vasospasm; Fluorouracil; Heart Diseases; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Myocarditis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome; Ventricular Dysfunction, Left

To evaluate the changes in left ventricular myocardial function in patients with colorectal cancer undergoing chemotherapy with mFOLFOX6 (oxaliplatin + 5-fluorouracil + calcium folinate) using three-dimensional speckle-tracking echocardiography (3D-STE). Data were collected from 30 patients diagnosed with colorectal cancer in our hospital treated with mFOLFOX6. We used 3D-STE to measure the following parameters of left ventricle function: global longitudinal strain (GLS), global area strain (GAS), global circumferential strain (GCS), global radial strain (GRS), and left ventricular twist (LVtw). Myocardial composite index (MCI) was calculated from measured values (MCI = GLS × LVtw). The above listed parameters were compared before and after chemotherapy. Receiver operating curves (ROC) were prepared for each parameter and analyzed to identify correlations among MCI, LVEF, GLS, and cTnT. Compared with the pre-chemotherapy state, the absolute values of MCI, LVtw, GLS, GAS, GCS, and GRS decreased with increasing cumulative doses of chemotherapeutic drugs. The absolute values of GAS, GLS, MCI, and LVtw decreased after the first cycle of chemotherapy (P < 0.05). The areas under the ROC curves for MCI and GLS were 0.903 and 0.838, respectively. The correlation observed between MCI and cTnT (r = - 0.7228) was found to be stronger than that between GLS and cTnT (r = - 0.6008). In conclusion, 3D-STE may help detect early changes in left ventricular myocardial function caused by mFOLFOX6 treatment in patients with colorectal cancer. MCI is a relatively sensitive index among the various measurable parameters.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biomechanical Phenomena; Cardiotoxicity; Colorectal Neoplasms; Early Diagnosis; Echocardiography, Doppler; Echocardiography, Four-Dimensional; Female; Fluorouracil; Heart Diseases; Humans; Leucovorin; Male; Middle Aged; Oxaliplatin; Predictive Value of Tests; Time Factors; Ventricular Function, Left

Fluoropyrimidines are key agents for the treatment of gastrointestinal tract adenocarcinomas. The possible cardiotoxic effects in patients and occupationally exposed workers are multifactorial and remain a puzzle to solve for investigators. In the present study, we study what cell death pathways and what doses can determine direct cardiotoxic effects of 5-fluorouracil (5-FU) and doxorubicin (DOXO) on rat cardiocytes (H9c2) and a human colon adenocarcinoma (HT-29) cell line, already reported to be sensitive to 5-FU. We have found that 5-FU induced 50% growth inhibition (IC:50) at 72 h with concentrations of 400 μM and 4 μM on H9c2 and HT-29, respectively. Moreover, we have found that the addition of Levofolinic Acid (LF) to 5-FU potentiated the growth inhibition induced by 5-FU. The growth inhibition induced by 5-FU alone or in combination with LF in cardiocytes was paralleled by an increase of thiobarbituric acid-reactive species (Tbars) and end products of nitric oxide (NO) suggesting the increase of the oxidative stress status in cardiocytes. Interestingly, these effects were strongly potentiated by the addition of LF, a biochemical modulator of 5-FU activity. Our data suggest that agents such as 5-FU different from anthracyclines, conventionally related to the induction of cardiotoxic effects, can also induce cardiocyte damage paralleled by oxidative stress. The strategies based upon the use of scavengers could be used in order to prevent this effect.

Topics: Animals; Antimetabolites; Cell Death; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Fluorouracil; Free Radical Scavengers; Heart Diseases; Humans; Leucovorin; Myocytes, Cardiac; Nitric Oxide; Occupational Exposure; Oxidative Stress; Rats; Thiobarbituric Acid Reactive Substances

Topics: Adenocarcinoma; Aged; Anemia; Antifibrinolytic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Carcinoma, Squamous Cell; Cecal Neoplasms; Disseminated Intravascular Coagulation; Fatal Outcome; Female; Fibrinogen; Fibrinolysis; Fluorouracil; Heart Diseases; Hemorrhage; Humans; Leucovorin; Lung Neoplasms; Lymphatic Metastasis; Multiple Organ Failure; Neoplasms, Multiple Primary; Organoplatinum Compounds; Postoperative Complications; Thrombosis; Tranexamic Acid; Vulvar Neoplasms

The purpose of the study is evaluation and assessment of parameters of cardiac toxicity in patients subjected to 5-FU based chemotherapy. Cardiac morbidity is a reported outcome in different 5FU/LV regimens; however none of them are definite or proximate. The bimonthly regimen of high dose leucovorin is reported to be less toxic and more effective as compared to the monthly regimen of low dose leucovorin. We report the detailed assessment of few cardiac parameter of toxicity in patients of advanced colorectal carcinoma subjected to two Schedules of high and low dose Folinic Acid, 5-Fluorouracil, bolus and continuous infusion. The correlation of elevated cardiac biomarkers, angina and hypertension is comparatively assessed in patients with normal general status, hyperglycemia and known cardiac disorders subjected to two different 5FU based chemotherapeutic regimen.

Topics: Angina Pectoris; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Blood Pressure; Carcinoma; Chi-Square Distribution; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Heart Diseases; Humans; Hypertension; Leucovorin; Male; Middle Aged; Prospective Studies; Risk Factors; Time Factors; Treatment Outcome

Topics: Adenocarcinoma; Angina Pectoris; Electrocardiography; Female; Fluorouracil; Heart; Heart Diseases; Humans; Hypotension; Intestinal Neoplasms; Intestine, Small; Leucovorin; Middle Aged; Syndrome; Tachycardia; Ventricular Function, Left

Topics: Fluorouracil; Heart Diseases; Humans; Leucovorin

Cardiotoxicity related to the widely used cytotoxic compound 5-fluorouracil (5-FU) is rare compared with the frequency observed with the use of anthracyclines. More effective protocols incorporating active biomodulatory compounds like folinic acid (FA) or combination chemotherapy change type and severity of toxicity as well. The objective of the current study was to assess cardiotoxicity of the combination 5-FU and folinic acid.. The authors' multicenter experience with 390 patients treated for advanced gastrointestinal cancer with intermediate-dose folinic acid and 5-FU was reviewed.. The overall risk of cardiotoxicity was 3%, which is not significantly higher than that reported with 5-FU alone. Eight of 53 patients with a history of cardiac disease reported cardiac symptoms (15.1%), compared with 5 of 337 patients (1.5%) with a no history of cardiac disease. Median time to symptoms was 3 days (range, 2-6). Nine patients had symptoms resembling myocardial ischemia, one patient died due to assumed myocardial infarction related closely to fluorouracil treatment, four patients had supraventricular arrhythmia, and one patient had congestive heart failure. A history of cardiac disease was the only risk factor associated with cardiotoxicity. Relapses were frequent on reinstitution of therapy despite cardiac symptoms in the preceding cycle. Therapeutically or prophylactically administered nitrates had no significant effect.. Physicians should be aware of the cardiotoxic properties of active fluorouracil treatment. The combination of 5-FU and leucovorin does not differ from single-agent therapy in frequency or type of cardiotoxicity. Close monitoring of patients is mandatory, especially for those patients at high risk for cardiac side effects. Treatment should be discontinued if coronary symptoms develop, because neither effective treatment nor prophylaxis exists for such symptoms.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arrhythmias, Cardiac; Coronary Disease; Electrocardiography; Female; Fluorouracil; Gastrointestinal Neoplasms; Heart Diseases; Heart Failure; Humans; Leucovorin; Male; Middle Aged; Myocardial Infarction

Thirty-four consecutive patients with measurable advanced gastric cancer were treated in a disease oriented Phase II study with high-dose folinic acid (HDFA) 300 mg/m2 10 min. inf., followed immediately by etoposide 120 mg/m2 50 min. inf., followed immediately by 5-fluorouracil (5-FU) 500 mg/m2 10 min. inf., given on day 1,2,3 (ELF). Courses were repeated every 22-28 days. All patients who entered this study were older than 65 years or had underlying cardiac disease. Thirty-three patients were evaluable for response and toxicity (greater than or equal to 1 course). One patient was lost to follow up. The overall response rate was 48% (16/23) including 12% (4/33) complete remissions. Eight patients had minor responses or no change and 9 had progressive disease. Five of six patients with locally advanced and non-resectable disease had an objective response (1 CR, 4 PR's). The response rate in patients with metastatic disease was 41% (11/27). After a median observation time of 6.5 months, the median survival time was 10.5 months, with a median remission (CR + PR) duration of 8 months. Toxicity was manageable and included mild to moderate myelosuppression and gastrointestinal toxicities. One episode of life-threatening (Grade IV) leukopenia, and two episodes of severe diarrhea requiring hydration were noted. No treatment related death occurred. ELF is an effective combination in advanced gastric cancer and can be safely administered to elderly patients and patients with cardiac risk.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Etoposide; Female; Fluorouracil; Heart Diseases; Humans; Leucovorin; Male; Middle Aged; Remission Induction; Risk Factors; Stomach Neoplasms; Survival Rate

Response rates of metastatic soft part sarcomas to chemotherapy have varied from 27 and 44% for our ALOMAD and OMAD protocols to 46-55% reported for CYVADIC. The present combination, CYOMAD, consists of the induction part of ALOMAD (vincristine, high-dose methotrexate with citrovorum factor rescue, Adriamycin and DTIC) alternating with a condensed version of CYVADIC (cyclophosphamide, vincristine, adriamycin and DTIC). Forty-one patients with advanced soft-part sarcomas were entered on the CYOMAD program of whom 36 were considered evaluable. Complete responses (CR) were seen in four patients had partial (PR) in five patients for a major response rate of 25%. Responders had an overall longer survival than nonresponders (20 versus 13 months). Toxicity was substantial with both gastrointestinal side effects and myelosupression common. Possible Adriamycin cardiotoxicity was noted in four patients. Cyomad offered no therapeutic advantage over previous protocols and was even less well tolerated than some.

Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dacarbazine; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Female; Heart Diseases; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Nausea; Sarcoma; Vincristine; Vomiting