Epirubicin toxicity

Epirubicin-monitor cumulative dose for cardiac toxicity (not to exceed 1000 mg/M2) vesicant—avoid extravasation... 

Unfortunately, none of the seven randomized trials that have compared radiation therapy alone vs neoadjuvant cisplatin-containing chemotherapy plus radiation therapy demonstrated an improvement in overall or disease-free survival with combined-modality therapy (Table 2). Two studies actually demonstrated poorer survival with neoadjuvant chemotherapy. Souhami et al. (15) reported a significantly poorer survival rate with neoadjuvant chemotherapy in a small trial of patients with stage IIIB disease. This outcome was partly due to increased toxicity and poor compliance in patients who received chemotherapy. Another trial of neoadjuvant epirubicin and cisplatin was closed early when interim analysis revealed a significantly higher recurrence rate in the chemotherapy arm (16). These trials fail to provide any evidence that sequential cisplatin-containing chemotherapy and radiation therapy are of benefit. Possible explanations for the disappointing results include the effects of chemotoxicity, altered compliance, and possible accelerated repopulation of resistant clones after neoadjuvant chemotherapy. 

EPIRUBICIN H2 RECEPTOR BLOCKERS -CIMETIDINE t epirubicin levels, with risk of toxicity Attributed to inhibition of hepatic metabolism of epirubicin by cimetidine Avoid concurrent treatment and consider using an alternative H2 receptor blocker, e.g. ranitidine, famotidine... 

Epirubicin is considered to cause substantially less cardiotoxicity than doxorubicin on a molar basis (4,21). This has been attributed to its more rapid clearance rather than a different action (22). In a randomized, double-blind comparison of epirubicin and doxorubicin, there was a significant reduction in left ventricle ejection fraction with doxorubicin but not with epirubicin (23). However, data from large clinical series and from morphological examination of endomyocardial biopsies in smaller series of patients suggest that the incidence and severity of cumulative cardiac toxicity associated with epirubicin 900 mg/m is similar to that associated with doxorubicin 450-550 mg/raf (24). In 29 patients treated with epirubicin in cumulative doses ranging... 

Mucositis is a well-documented toxic effect of anthracyclines it has been reported in 8% of combination chemotherapeutic courses including epirubicin in a dose of 180 mg/m (68). 

Valrubicin (a novel A-trifluoroacetyl, 14-valerate derivative of doxorubicin) is currently licensed in the USA for intravesical use in prophylaxis in patients with BCG-refractory carcinoma in situ after transurethral resection. It has a similar toxicity profile to that of epirubicin and doxorubicin (113). 

Launchbury AP, Habboubi N. Epirubicin and doxorubicin a comparison of their characteristics, therapeutic activity and toxicity. Cancer Treat Rev 1993 19(3) 197-228. 

Toxic megacolon occurred after five cycles of epirubicin 70 mg/m, 5-fluorouracil 500 mg/m, and oral cyclophosphamide 75 mg/m for 14 days (18). The clinical presentation included a raised erythrocyte sedimentation rate and a colonic diameter of greater than 9 cm the outcome can be fatal. 

Simonsen LE, Wahlby U, Sandstrom M, et al. Haematological toxicity following different dosing schedules of 5-fluorouracil and epirubicin in rats. Anticancer Res. 2000 20(3A) 1519-1525. 

The major toxicities of these four groups are bone marrow depression, nausea and vomiting, mucositis, and diarrhea. Daunorubicin, doxorubicin, epirubicin, idarubicin, and to a lesser extent, mitoxantrone, cause cardiac toxicity. Mitomycin and bleomycin cause... 

Cardiomyopathy is the most common chemotherapy-associated cardiac toxicity. Myocardial ischemia, pericarditis, arrhythmias, miscellaneous electrocardiogram (ECG) changes, and angina occur much less frequently. The anthracyclines (da-unorubicin, doxorubicin, epirubicin, and idarubicin) have the highest consistent risk for cardiomyopathy, which is cumulative dose related. There is evidence that high-dose cyclophosphamide, mitoxantrone, and fluorouracil also pose an increased risk of cardiac damage. The concurrent use of traztuzu-mab with an anthracycline and cyclophosphamide is associated with a risk of cardiac dysfunction, but the consequences of sequential use are not yet known. 

Kramar et al. (70) showed that the maximum likelihood CRM previously described in this chapter may be useful in a two-drug combination Phase 1 study. As for a single agent, the method requires a priori dose-toxicity profiles. Isobolograms can be obtained using these profiles available from the monotherapy Phase 1 studies of each drug separately, as well as from previous monotherapy Phase 2/3 studies. The method has been used by Morita et al. (71) for designing a Phase 1 clinical trial of capecitabine in combination with cyclophosphamide and epirubicin. 

Gurney HP, Ackland S, Gebski V, Farrell G. Factors affecting epirubicin pharmacokinetics and toxicity evidence against using body-surface area for dose calculation. J Clin Oncol 1998 16 2299-2304. 

Toxicity associated with combinations of paclitaxel with doxorubicin or epirubicin depends on the order of administration. Some modest pharmacokinetic changes may occur when paclitaxel and epirubicin are given together. The combination of doxorubicin and pacUtaxel is more cardiotoxic than doxorubicin alone paclitaxel increases doxorubicin levels but doxorubicin does not alter pacUtaxel levels. Docetaxel may modestly affect the pharmacokinetics of epirubicin and doxorubicin. 

Conversely, a study of the combination of docetaxel and epirubicin did not find that the sequence of drug administration affected the pharmacokinetics of epirubicin, nor was there any difference in toxicity. In another study, 16 patients with breast cancer had a transient but significant increase in epirubicin plasma levels during the subsequent infusion (after an interval of 1 hour) of docetaxel 75 mg/m, which was not seen if the docetaxel was given within 10 minutes of epiruhicin. ... 

Studies in mice have found that the taxanes docetaxel and paclitaxel, and the vehicle used for paclitaxel Cremophor, may all modify the distribution and metabolism of doxorubicin increasing its levels in the heart, liver and kidneys. This may contribute to the cardiac toxicity seen during use with paclitaxel. Similarly, m vitro studies in human myocardium showed that paclitaxel and docetaxel increased the conversion of doxorubicin to doxorubicinol, the metabolite that is thought to be responsible for cardiotoxicity. An in vitro study on the effect of paclitaxel and Cremophor on epirubicin metabolism in human blood found that paclitaxel slightly decreased production of epirubicinol. A marked inhibition of epirubicinol production occurred in the presence of Cremophor, hut because of the low... 

Venturini M, Lunardi G, Del Mastro L, Vannozzi MO, Tolino G, Numico G, Viale M, Pas-trone I, Angiolini C, BertelU G, Straneo M, Rosso R, Eposito M. Sequence effect of epirubicin and pacUtocel treatment on pharmacokinetics and toxicity. J Clin Oncol (2000) 18, 2116-25. 

In a study in 8 patients, cimetidine 400 mg twice daily increased the AUC of epirubicin by 50%. At the same time the AUCs of two metabolites of epirubicin, epirubicinol and 7-deoxydoxorubicinol aglycone, increased by 41% and 357%, respectively. Liver blood flow also increased by 17%. The mechanism is unknown. More study of this interaction is needed but be aware of the possibility of cimetidine inereasing the exposure to epirubicin monitor the patient closely and adjust epirubicin dosage if needed. Cimetidine is available without a preseription in some countries so that patients may unwittingly increase the toxicity of epirubicin. Cimetidine has also increased the levels or toxicity of some other antineoplastics, see Nitrosoureas + Cimetidine , p.655, Cyclophosphamide + H2-receptor antagonists , p.626 and Fluorouracil + H2-reeeptor antagonists , p.633. 

It is worth noting that PEG-poly (aspartate) block copolymers containing a epirubicin-hydrazone conjugate also showed higher tumor accumulation over free drug and decreased cardiac toxicity are in a Phase I clinical trial, suggesting the potential of prodrug incorporation in micelles for cancer therapy [60]. 

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