The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy

Robben, Norbertus C.; Pippas, Andrew W.; Moore, Joseph O.

doi:10.1002/1097-0142(19930115)71:2<493::aid-cncr2820710235>3.0.co;2-c

Cited by 166 publications

(116 citation statements)

References 78 publications

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“…Vascular toxicity is a known side-effect of 5-FU/Leucovorin, most often presenting like coronary vasospasms, but solitary bowel ischaemia has also been described (Fata et al, 1999). The precise mechanisms behind these circulatory changes are unknown (Robben et al, 1993). Overall, in this study the toxicity seen after chemotherapy was not different from the toxicity of previous studies using 5-FU/Leucovorin, and thus appears not to be influenced by the immunotherapy given in our clinical trial.…”

Section: -Fu+asi For Stage III Colon Cancer a Baars Et Alcontrasting

confidence: 55%

A phase II study of active specific immunotherapy and5-FU/Leucovorin as adjuvant therapy for stage III colon carcinoma

et al. 2002

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Active specific immunotherapy, using vaccines with autologous tumour cells and BCG, significantly reduces the rate of tumour recurrence in stage II colon cancer patients, while no clinical benefit has yet been observed in stage III patients. Adjuvant treatment with 5-Fluorouracil/Leucovorin is now considered standard therapy for stage III colon carcinoma and results in an absolute survival benefit of approximately 10%. Yet, the 5-year overall survival rate of stage III colon cancer patients is only 40 -50%. Combining chemotherapy and immunotherapy might improve prognosis for stage III patients, especially when considering that active specific immunotherapy and chemotherapy have shown synergistic effects in pre-clinical tumour models. We performed a phase II study with 56 patients, using the combination of active specific immunotherapy and chemotherapy as an adjuvant therapy in stage III colon cancer patients to assess the influence of 5-Fluorouracil/Leucovorin on anti-tumour immunity induced by autologous tumour cell vaccinations. Anti-tumour immunity was measured before and after chemotherapy by means of delayed type hypersensitivity reactions, taken 48 h after the third and the fourth vaccination. We also investigated the toxicity of this combined immuno-chemotherapy treatment. Delayed type hypersensitivity reactions before chemotherapy had a median size of 20.3 mm, while after chemotherapy delayed type hypersensitivity size was 18.4 mm (P=0.01), indicating that chemotherapy hardly affected anti-tumour immunity. The severity of ulcers at the BCG vaccination sites was comparable to previous studies. In 30% of the patients grade III or grade IV chemotherapy related toxicity was seen; this is comparable to what is normally observed after adjuvant chemotherapy alone. This study shows that the active specific immunotherapy-induced anti-tumour immune response is only minimally impaired by consecutive chemotherapy and that the combined treatment of stage III colon cancer patients with active specific immunotherapy and 5-Fluorouracil/Leucovorin does not cause unexpected toxicity. Colon cancer is one of the most prevalent malignancies in the industrialised world, with approximately 240 000 new cases diagnosed each year in the USA and Western Europe. When colon cancer is detected early, in stages I or II (Dukes A or B), the 5 year survival rate with surgery alone is 60 -90%, depending on the depth of invasion of the tumour into the bowel wall. When the cancer has spread to the regional lymph nodes, or stage III (Dukes C), the 5 year survival rate is 25 -60%. Important prognostic factors in stage III colon carcinoma include the number of positive nodes, extra-nodal growth, invasion of adjacent organs, grade of histologic differentiation and post-operative CEA level. When distant metastases are diagnosed, stage IV (Dukes D), the 5 year survival rate is less than 5% (Cohen et al, 1997).Currently most patients with stage III colon carcinoma receive an adjuvant treatment with 5-Fluorouracil (5-FU) and Leucovorin. Several lar...

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Section: -Fu+asi For Stage III Colon Cancer a Baars Et Alcontrasting

confidence: 55%

A phase II study of active specific immunotherapy and5-FU/Leucovorin as adjuvant therapy for stage III colon carcinoma

et al. 2002

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“…This DNA-directed antimetabolite mechanism is therefore a very unlikely cause of 5-FU cardiotoxicity. As the recurrence rate of cardiotoxicity after exposure to 5-FU is thought to be 90% (Robben et al, 1993), cardiotoxic side-effects after a total of seven exposures to raltitrexed would have been expected, assuming that the direct cytotoxic effect on DNA synthesis is responsible for cardiotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Raltitrexed (Tomudex): an alternative drug for patients with colorectal cancer and 5-fluorouracil associated cardiotoxicity

Köhne

Thuss-Patience²,

Friedrich³

et al. 1998

Br J Cancer

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Summary Two patients with proven 5-fluorouracil (5-FU)-associated cardiotoxicity were treated with the specific thymidylate synthase inhibitor raltitrexed safely, without evidence of cardiotoxicity. Raltitrexed might be an alternative for patients with advanced colorectal cancer and 5-FU-associated cardiotoxicity. 5-FU cardiotoxicity is not due to the antineoplastic mechanisms via thymidilate synthase.Keywords: 5-fluorouracil; cardiotoxicity; raltitrexed; colorectal neoplasms 5-Fluorouracil (5-FU)-associated cardiotoxicity was recognized 18 years after its first clinical use, after symptoms of chest pain typical of angina pectoris, in patients treated with 5-FU (Dent and McColl, 1965). Estimates of its incidence have been given with a range of 1.6% in larger series (Labianca et al, 1982) and up to 10% in smaller cohorts (Collins and Weiden, 1987). 5-FU should be discontinued in the case of cardiotoxicity to avoid the development of serious or fatal cardiac damage (Anand, 1994). However, the arsenal of effective antineoplastic compounds for the treatment of colorectal cancer is limited, and the identification of a drug that may be safely given to patients with cardiac toxicity after 5-FU administration is important. Here, we report the successful administration of raltitrexed (Zeneca, Macclesfield, Cheshire, UK), a new specific thymidylate synthase inhibitor, in two patients with 5-FU-induced cardiotoxicity. PATIENTS AND METHODS Case 1A 58-year-old female without any history of cardiovascular disease presented at our institution with lung and liver metastases of a sigmoid adenocarcinoma. She had received three cycles of weekly folinic acid 500 mg m-2 as a 2-h infusion and 5-FU 500 mg m-2 as an i.v. bolus in the middle of the folinic acid infusion repeated for 6 weeks followed by a 2-week rest period. This therapy was tolerated well without any cardiac toxicity. When the tumour progressed, treatment with high-dose 5-FU 2600 mg m-2 given as a weekly 24-h infusion plus folinic acid 500 mg m-2 as a 2-h infusion before 5-FU was initiated. Approximately 22 h after the start of the 5-FU infusion the patient complained of dyspnoea and retrosternal pain and the 5-FU infusion was stopped. The blood pressure was 80/60 mmHg and the heart rate was regular with 100 beats per min. The ECG obtained after onset of symptoms revealed non-specific ST segment elevation in the anterior and posterior leads with a normalization after 24 h (Figures 1 and 2). Serial measurements of serum cardiac enzymes were normal. One week later, the patient was given the same 5-FU/folinic acid regimen and also received isosorbide dinitrate, molsidomine and acetylsalicylic acid. Approximately 10 h after the start of the 5-FU infusion, the patient complained of dyspnoea and retrosternal chest pain. The ECG revealed temporary changes similar to those observed a week earlier. Again, serial determination of serum cardiac enzyme levels remained unchanged. An echocardiogram was normal except for a localized apical hypokinesia. The global ejection fraction w...

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“…Trombogenicity of intravenous infusion of 5-FU has been suggested as a causative factor (1). Previous studies have shown that rheological changes are involved in a variety of cardiovascular diseases (20)(21).…”

Section: Discussionmentioning

confidence: 99%

Changes of Blood Viscosity in Patients Treated with 5-Fluorouracil—A Link to Cardiotoxicity?

et al. 1995

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The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy

Cited by 166 publications

References 78 publications

A phase II study of active specific immunotherapy and5-FU/Leucovorin as adjuvant therapy for stage III colon carcinoma

A phase II study of active specific immunotherapy and5-FU/Leucovorin as adjuvant therapy for stage III colon carcinoma

Raltitrexed (Tomudex): an alternative drug for patients with colorectal cancer and 5-fluorouracil associated cardiotoxicity

Changes of Blood Viscosity in Patients Treated with 5-Fluorouracil—A Link to Cardiotoxicity?

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