Epirubicin

nalogue development is an intensively pursued goal. e rationale behind this is the selection of agents with cn "^proved therapeutic index with respect to the parent ^Pound but with an enhanced spectrum of activity, reduced toxicity. Sj P'^ubicin is a new anthracycline antibiotic, syntheed in an effort to find a cytotoxic agent with a better Cjr0raPeutic index than that of Adriamycin the parent ^9 with which all clinical oncologists are familiar. Pirubicin differs from Adriamycin in the configuration


Hpirubicin in Childhood Cancer
Cornish, A. Oakhill, M. G. Mott. Br'stol Children's Hospital nalogue development is an intensively pursued goal. e rationale behind this is the selection of agents with cn "^proved therapeutic index with respect to the parent ^Pound but with an enhanced spectrum of activity, reduced toxicity. Sj P'^ubicin is a new anthracycline antibiotic, syntheed in an effort to find a cytotoxic agent with a better Cjr0raPeutic index than that of Adriamycin the parent ^9 with which all clinical oncologists are familiar. rripth0 ctnern'ca' name is:? (75:95) -9-hydroxyacetyl-4- (2 ^ fiOxy~7'8,9,10,7,9, '""trideoxy-3-amino-x-L-arabino-Hexopyranosyl)-5, naPhthacenedione, hydrochloride. Epirubicin has increased lipid solubility compared with Adriamycin, which results in a higher influx rate and cellular accumulation of this analogue. It also undergoes more extensive metabolism to inactive or more rapidly excreted metabolites.
Tumour cells exhibit a lower Ph value (because of their higher lactate content) thus allowing for more dissociated drug to act upon the cellular mechanisms. This may account for the reduced toxicity of Epirubicin without loss of cytotoxicity. Epirubicin also interferes with the integrity and activity of cell-membranes, and maximal cell kill occurs during the S phase of the cell cycle.

Pharmacokinetics and Metabolism
The pharmacokinetics of Epirubicin have been studied in cancer patients after rapid intravenous administration, and the highest uptake appears to be in the tumour, surrounding areas, and gall bladder, the lowest being in adipose tissues, muscles, spleen and serous membranes. The distribution does not differ substantially from that of Adriamycin, although, as suggested by animal data, the tissue concentrations of Epirubicin are lower, and it is less retained in the heart. Following intravenous administration, there is a rapid distribution phase and prolonged elimination phase consistent with extensive drug retention within the peripheral tissues and gradual release thereafter.
Epirubicin, like Adriamycin, is primarily eliminated by the hepatobiliary system (40% of the administered dose in 4 days). The terminal half-life of Epirubrcin is 30-40 hours in contrast with a 40-70 hour elimination half-life for Adriamycin; it therefore has a shorter terminal halflife and higher plasma clearance.
Epirubicin is characterised not only by a faster elimination than Adriamycin, but also an additional metabolic pathway. Whereas Adriamycin has only one metabolite, several metabolites can be detected in plasma and urine after Epirubicin administration. In particular, a unique formation of glucuronides have been detected which have not been demonstrated for Adriamycin and may account for the faster elimination of Epirubicin.

Phase I and Phase II Studies
Phase I Studies are designed to define the toxicological pattern of a drug and to determine the maximum tolerated dose in men.
Phase I Studies carried out in two major centres, the National Tumour Institute in Milan, and the Memorial Sloan-Kettering Cancer Centre, New York, have shown a reduced incidence of acute toxicities such as vomiting, mucositis and neutropenia for Epirubicin. In the U.S., studies demonstrated a remarkable range for dose-limiting myelosuppression of Epirubicin, with doses escalating to 135mgs/m2, without major myelotoxocity (our study raised this level even higher). A similar earlier study carried out by the same investigators in the same institution had demonstrated that only a few patients receiving Adriamycin could tolerate doses of 90mg/m2. Similarly, statistical analysis indicated that there was a linear dose-dependant relationship for acute cardiotoxicity of Epirubicin, as with Adriamycin, but Epirubicin has a lower toxic effect on myocardial contractility than Adriamycin.
The Phase II Studies were disease-orientated and numerous, and designed principally to evaluate the spectrum of anticancer activity while further investigating toxicity. Broadly speaking, it was found that Epirubicin had equivalent efficacy to its parent compound, Adriamycin with reduced toxicity.
Our own study using Epirubicin started in February 1986. The general principles of cancer chemotherapy apply in the treatment of paediatric malignancy, although the effectiveness of these agents depends even more on achieving the maximum tolerated dosage without prohibitive toxicity. Most children are able to tolerate higher doses of chemotherapeutic agents than adults.
From February 1986 to January 1987, 14 patients received 37 courses of Epirubicin, 33 of them at a dose of 150mg/m2. The dose was modified in 4 courses, the reasons being:?

Previous radiation (2 courses).
3. Medical reluctance (first dose given at the Children's Hospital in February 1986, with previous published data suggesting a maximum of 90 mgs/m2 as a single dose).
The Epirubicin was administered intravenously in N Saline over one hour, usually following a single IV dose of Vincristine, and was part of a regime, the Bristol Children's Hospital Resistant Tumour Protocol. In this protocol, the Epirubicin and Vincristine are given as part of a 9-week cycle that includes Ifosfamide and VP16, and Carboplatinum, alternating at 3 weekly intervals, usually for 5 complete cycles or a total of 1 year. The patients characteristics are tabulated above and cover the typical range of paediatric resistant tumours.
We found that the degree of myelosuppression with Epirubicin was acceptable. rophils and platelets occurred between the 8th and 15th day after administration, usually at day 10, and neutropenia was observed more often than thrombocytopenia. There was, however, complete bone marroW recovery by the third week after administration, and there were no delays in giving the next drug in the cycle. Neutropenia of <1x109/L occurred in 22 of the 37 courses, although there was only one admission to hospital for treatment of a neutropenic fever. 7 of the 37 courses resulted in a thrombocytopenia of <100x109/l_, but no patient needed support with platelet transfusions, and there were no bleeding manifestations.
There was a low incidence of anaemia, and we did not consider this a significant problem. Gastrointestinal effects were frequently reported, the most common being nausea and vomiting. All our pa' tients were treated, and some pre-treated, with antiemetics, and vomiting on this regime was nil to moderate. Alopecia was universal, but other drugs were als? contributory to this.
Thrombophlebitis was seen in all patients who did not have central venous catheters.
Cardiotoxicity was noted in only one patient, a youn9 man undergoing re-treatment for a relapse of his Ewings tumour, who had previously been treated with AdriamY* cin. He developed an abnormal echocardiogram at 300mgs/m2 of Epirubicin,and we stopped at this dose-All patients had an echo performed before each dose of Epirubicin, and so far we have reached a total cumulate dose of 750 mgs/m2 in one young patient, with no signS of cardiotoxicity. CONCLUSION We have shown that Epirubicin is tolerated by children at doses substantially higher than those given as standard therapy with the parent compound, Adriamycin. The schedule and administration is easily manageable, most' ly on an Out-Patient basis, and it induces less acute toxicity and is less myelosuppressive than Adriamycin-Further studies are required to develop optimal dules, and to define further its spectrum of efficacy an range of activity and to evaluate its potential when conn' bined with other cytotoxic agents.