Idarubicin A Review of its Pharmacodynamic and Pharmacokinetic Properties,and Therapeutic Potential in the Chemotherapy of Cancer
Lisa M.Hollingshead and Diana Faulds
Adis International Limited,Auckland,New Zealand
Various sections of the manuscript reviewed by: G.Avvisati,Hematology Department of Human Biopathology, University of Rome La Sapienza,Rome, Italy; L. Bastholt, Department of Oncology,Head and Neck Cancer Section,Odense University Hospital,Odense,Denmark;M.Broggini,Istituto di Richerche Farmacologiche,Mario Negri,Milan,Italy;A.M.Carella,Department of Haematology,Osped San Martino,Genoa,Italy;A.M.Casazza, Division of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; E.J. Freireich,MD Anderson Cancer Center,University of Texas,Houston Texas,USA;K.Kolaric,Medical Oncology Department,Središnji Institut Za Tumore I Sliče Bolesti,Zagreb,Yugoslavia;G.Lambertenghi-Deliliers,Clinica Medica I,Università di Milano, Istituto di Scienze Mediche,Padiglione Granelli,Milan,Italy;R.M.Lowenthal, Clinical Haematology and Medical Oncology Unit,Royal Hobart Hospital,Hobart,Tasmania,Australia;J.M.Reid, Division of Developmental Oncology Research, Department of Oncology,Mayo Clinic and Foundation, Rochester,Minnesota,USA;D.B. Smith,Department of Medical Oncology,CRC Laboratories,Charing Cross Hospital,London,England;N.S.A. Stuart,ICRF Clinical Oncology Unit,Churchill Hospital,University of Ox-ford,Headington,Oxford,England.
Contents
Idarubicin in Cancer:A Review

691

5.Dosage and Administration
6.Place of Idarubicin in Therapy
Summary
Synopsis
Idarubicin is a 4-demethoxy-anthracycline analogue ofdaunorubicin which, when administered intravenously in combination with cytarabine,has therapeutic efficacy superior to that of standard induction and salvage treatment regimens in acute myelogenous leukaemia. Idarubicin alone or in combination regimens has also been effective in limited studies in patients with other acute leukaemias, advanced breast cancer, multiple myeloma and non-Hodgkin’s lymphoma. Idarubicin is more lipophilic than its parent drug daunorubicin. It intercalates DNA, induces DNA strand breaks and delays cell cycle progression.
Leucopenia is often dose-limiting in patients with solid tumours treated with idarubicin, and most other adverse effects are similar in incidence and severity to those experienced with other anthracycline cytotoxic agents, except for alopecia which appears to occur with a reduced incidence and severity. Cardiotoxic effects have been reported with idarubicin as with other anthracyclines, but animal data and preliminary clinical findings suggest the possibility of reduced cardiotoxicity with idarubicin-a potentially important advantage ifconfirmed on further study. A maximum cumulative dose of idarubicin beyond which the incidence of cardiotoxicity rapidly increases has not been determined.
Thus, intravenous idarubicin is a useful alternative to other anthracyclines (particularly in combination with cytarabine) in the treatment ofacute myelogenous leukaemia, and there is some evidence that it is less cardiotoxic than other anthracycline drugs. Further studies are required to establish the use ofintravenous idarubicin as a replacement for other intravenous anthracyclines, especially its effect on response duration and survival, and toconfirm the evidence of reduced cardiotoxic effects.The role of idarubicin as consolidation and maintenance therapy for various malignancies requires further investigation, as does the potential use oforal idarubicin which is currently under development.
Pharmacodynamic Properties
The absence of a methoxyl group at position 4 of idarubicin’s anthracycline structure results in an increased lipophilicity and rate of cellular uptake compared with the related compound daunorubicin. Idarubicin is 10-fold more cytotoxic than daunorubicin, with greater activity than daunorubicin or doxorubicin (adriamycin) against cultured human cancer cells. The primary me-tabolite, idarubicinol (4-demethoxy-daunorubicinol),demonstrated similar activity to idarubicin in vitro. Both idarubicin and the metabolite showed antitumour activity superior to that of dox-orubicin and at least equivalent to that of daunorubicin in experimental leukaemia models in vivo when administered intravenously or orally. Importantly, the ratio of cardiotoxic to antitu-mour dose for idarubicin exceeded that for daunorubicin and doxorubicin.
Idarubicin intercalates DNA,disrupting nucleic acid synthesis. It induces DNA strand breaks by inhibiting DNA topoisomerase II and generating free radicals,arresting cells in the G2 phase of the cell cycle.
Animal toxicity tests demonstrated decreased cardiotoxicity of idarubicin compared with dau-norubicin and doxorubicin;haematolymphopoietic and gastrointestinal symptoms were consist-ent with those observed with other cytotoxic agents.
Pharmacokinetic Properties
The pharmacokinetic properties of idarubicin following oral or intravenous administration have been studied in patients with solid tumours or acute leukaemias. Bioavailability of orally administered idarubicin varied widely between patients and studies, although a mean of about 30% was generally observed.Idarubicin is rapidly converted by the liver to its only detected
metabolite, idarubicinol, and higher concentrations of idarubicinol are produced following oral rather than intravenous dosing, probably due to first pass metabolism in the liver.
Biphasic and triphasic plasma clearance of idarubicin have been observed.Following intra-venous administration,initial phase half-life was 9 to 30 minutes, intermediate phase 3.2 to 27 hours and elimination phase 6 to 35 hours. Plasma concentrations of idarubicinol exceeded those of idarubicin, and the metabolite accumulated over 3 consecutive days of idarubicin 10 mg/m2 4-hour infusions.Idarubicin has a large volume of distribution (up to 1889 L/m2),and concen-tration independent mean plasma protein binding of idarubicin and idarubicinol were 97 and 94%,respectively.
Idarubicin was undetectable in plasma (less than 2 μg/L) 24 hours after oral administration of idarubicin 30 to 70 mg/㎡2,and 72 hours following intravenous administration of idarubicin 12.5 to 15 mg/㎡.The metabolite was still detectable in plasma for at least 72 hours following intravenous idarubicin 15 mg/m2 and up to 7 days following oral administration of idarubicin 15 mg/㎡2.Total body clearance rates for idarubicin of 30 to 122 L/㎡2/h were reported,and less than 5% of the delivered idarubicin dose was recovered as idarubicin or its metabolite in urine over 24 or 96 hours.Dosage reduction should not be necessary in patients with impaired renal function but may be required in patients with hepatic impairment.
Therapeutic Efficacy
Intravenous idarubicin, in combination with cytarabine,has demonstrated therapeutic efficacy in patients with relapsed or refractory acute myelogenous leukaemia (complete response rates of 24 to 70%). Response duration was short although 1 patient remained in complete remission for longer than 14 months with idarubicin plus cytarabine consolidation therapy.As induction treat-ment for patients with acute myelogenous leukaemia, intravenous idarubicin plus cytarabine was at least as effective as daunorubicin plus cytarabine, with complete response rates being signifi-cantly higher with the idarubicin regimen in several studies. Mean duration of response tended to be longer in idarubicin plus cytarabine recipients,the difference between groups reaching sta-tistical significance in 2 studies (for example 30 vs 13 months, p =0.012). Mean duration of survival was also significantly longer in idarubicin plus cytarabine recipients compared with dau-norubicin plus cytarabine recipients in 2 of 3 large US comparative studies in previously untreated acute myelogenous leukaemia patients (probability of survival at 18 months 48 vs 28% and 35 vs 23%, p < 0.05). Intravenous idarubicin plus cytarabine plus etoposide as induction therapy in acute myelogenous leukaemia produced a complete response rate of 81% (25/31 patients) in 1 trial.While these early results are clearly encouraging,further data are required regarding duration of remission and survival, and the role of idarubicin in consolidation and maintenance regimens in patients with acute myelogenous leukaemia.
Intravenous idarubicin plus cytarabine also appears effective in acute lymphoblastic leukaemia (complete response rates of 56 to 77% in pretreated patients). Oral idarubicin alone or in com-bination therapy has shown some efficacy in patients with advanced breast cancer,although comparisons with standard treatment regimens are lacking and results are equivocal.There is also evidence of an antitumour effect of oral idarubicin monotherapy in limited studies of patients with multiple myeloma,and of both intravenous and oral idarubicin in non-Hodgkin's lym-phoma.Further study is warranted in these indications.
Tolerability
When administered as mono-or combination therapy, the tolerability profile of intravenous idarubicin is generally similar to that of the anthracyclines daunorubicin and doxorubicin with regard to incidence and severity of nausea and vomiting, diarrhoea, mucositis, myelosuppression and infection, although infection and mucositis were more frequent and severe in idarubicin plus cytarabine recipients than in daunorubicin plus cytarabine recipients during consolidation therapy.
Leucopenia was dose-limiting in patients with solid tumours receiving idarubicin 18 mg/m2 intravenously.Importantly, as suggested by animal studies, in clinical trials there was some evi-dence for a reduction of cardiotoxicity compared with doxorubicin; however, a maximum cu-mulative noncardiotoxic dose of idarubicin has not yet been determined.The incidence and
Idarubicin in Cancer:A Review

693
severity of other adverse effects were similar in intravenous idarubicin-and daunorubicin-treated patients.
Leucopenia was dose-limiting in patients with solid tumours receiving oral idarubicin 50 to 60 mg/㎡ and the incidence of alopecia appeared to be reduced in patients receiving oral ida-rubicin.Further comparative studies are required to verify these findings.
Dosage and Administration
For patients with acute myelogenous leukaemia, the recommended intravenous dose of ida-rubicin for induction therapy is 12 mg/㎡2 daily for 3 days by slow (10 to 15 minutes) infusion, in combination with cytarabine 100 mg/㎡2 daily by continuous infusion for 7 days or cytarabine 25mg/m2 intravenous bolus followed by 200 mg/㎡ daily for 5 days continuous infusion.A dose reduction should be considered in patients with hepatic impairment but may not be required in patients with compromised renal function. Dosage recommendations for children are not cur-rently available and intravenous idarubicin 8 mg/㎡2 for 5 days has been successfully used with cytarabine in the elderly. Idarubicin should not be administered to patients with pre-existing bone marrow suppression,heart disease or those who have received high cumulative doses of other anthracyclines or potentially cardiotoxic drugs. Cardiac monitoring is recommended in all patients and regular blood counts and hepatic and renal function tests should be performed. Oral admin-istration remains experimental and dosage guidelines are not currently available.
1.Pharmacodynamic Properties
Idarubicin (4-demethoxy-daunorubicin),an an-thracycline antitumour agent, is a daunorubicin analogue in which the C-4 methoxyl group in the D ring of the aglycone is replaced with a hydrogen atom (fig. 1). It is more lipophilic than daunorub-icin, with improved absorption across the gastroin-testinal mucosa (section 2.1) and enhanced uptake into tumour cells in vitro. Idarubicin is 5 to 6 times more potent (ratio between optimal antitumour doses), and less cardiotoxic than daunorubicin (Ar-camone et al. 1976;Banning et al.1987;Casazza et al.1980;Di Marco et al. 1977;Penco et al.1983). Idarubicin is most commonly administered intra-venously,although an oral formulation is under development.
1.1 In Vitro Activity Against Cultured Cancer Cells
A number of in vitro studies with animal and human tumour cell lines have demonstrated the increased cytotoxicity of idarubicin compared with daunorubicin. Idarubicin was 27 to 100 times more potent than its parent compound in inhibiting the cloning efficiency of HeLa cells (Ganzina et al.

1986; Supino et al. 1977), and at a concentration of 0.1 μmol/L idarubicin and daunorubicin inhib-ited proliferation of the H-35 rat hepatoma by 83 and less than 30%,respectively(Woods et al.1989).
Idarubicin demonstrated greater cytotoxicity than daunorubicin or doxorubicin (adriamycin) against a range of human adenocarcinomas (Salmon et al. 1981), and showed dose-proportional anti-proliferative effects against human ovary, cervix, breast and melanoma tumour cell lines (Berens et al. 1987).Furthermore,a 2-to 20-fold lower con-centration of idarubicin was required to inhibit 70% of tumour colony formation compared with dox-orubicin (Berens et al. 1987). In a similar study, idarubicin was active against 2 of 6 ovarian car-cinomas(1 from a patient having received no prior chemotherapy,the other previously exposed to a multiagent regimen), 1 of 3 breast carcinomas and 1 of 4 adenocarcinomas of unknown origin from patients (Dodion et al. 1987).
The major metabolite of idarubicin in humans is idarubicinol (4-demethoxy-daunorubicinol) [sec-tion 2]. In vitro antitumour activity of this metab-olite is similar to that of idarubicin (Barbieri et al. 1983). Idarubicinol 0.1 mg/L was active against 2 of 6 ovarian samples (as was idarubicin), suggest-ing it may play a role in the biological activity of

Daunorubicin Idarubicin

Doxorubicin
Fig.1.Structural formulae of daunorubicin,idarubicin and doxorubicin.
idarubicin (Dodion et al. 1987), but was inactive against the 3 breast cancer and 4 adenocarcinoma samples.
A goal of development of new antineoplastic drugs is to obtain molecules lacking cross resist-ance with classical agents. However, in vitro models of drug resistance should be extrapolated to the clinical situation with caution (Schott &Robert 1989). When tested in vitro on a human small cell lung cancer (SCLC) line (GLC4) and a subclone resistant to daunorubicin (GLC4/ADR), idarubicin was active and demonstrated a low degree of cross-resistance (degree of resistance for doxorubicin, daunorubicin and idarubicin 43.1,5.9 and 4.8,re-spectively) [Zijlstra et al. 1987]. This was also ob-served in doxorubicin-resistant rat glioblastoma cells and multi-drug-resistant (including dauno-rubicin) Friend leukaemia cells(Arcamone et al. 1976;Schott&Robert 1989;Tolomeo et al. 1991).

1.2 In Vivo Antitumour Activity
In murine tumour models, idarubicin has shown 4- to 8-fold greater potency than doxorubicin and/ or daunorubicin against L1210,Gross and P388 leukaemias,and several experimental T cell lym-phomas(Arcamone et al.1976;Broggini et al.1984; Casazza et al.1980).
Published data regarding the activity of idarub-icin against solid tumours in animals is limited, but an antitumour effect has been demonstrated in murine solid tumour models, including early mammary carcinoma,sarcoma 180 and MS-2 sar-coma (Arcamone et al. 1978;Casazza et al.1980; Di Marco et al. 1977; Formelli et al. 1979). In tests against several solid murine tumours, intravenous idarubicin was active at doses 4-to 10-fold lower than daunorubicin or doxorubicin (data on file, Adria Laboratories).
Idarubicin in Cancer:A Review
Idarubicin was active when administered orally as well as intravenously, the same antitumour ac-tivity being achieved with an oral dose 4 times higher than the optimal intravenous dose (Di Marco et al. 1977). Sarcoma 180 tumour growth in mice was reduced dose-proportionally following a 3-day course of oral idarubicin 0.5, 1.0 or 2.0 mg/kg/day. Oral idarubicin 2 mg/kg/day caused a 50% reduc-tion in tumour growth and an increase in mean survival time from 17 (untreated control) to 38 days (table I).
Idarubicin and daunorubicin had similar activ-ity against breast, lung, melanoma, ovarian and sarcoma human tumour xenografts in nude mice (Giuliani & Kaplan 1984). Idarubicinol demon-strated antitumour activity equivalent to that of idarubicin in similar experimental murine systems (Barbieri et al. 1983; Casazza et al. 1983).
1.3 Mechanism of Action
The mechanism of action of anthracyclines is poorly understood and a number of mechanisms have been proposed. Cytotoxicity has been attri-buted to intercalation of the drug into DNA and/ or inhibition of DNA topoisomerase II activity(Di Marco 1975;Glisson & Ross 1987;Tewey et al. 1984).The formation of intracellular free radicals by cyclic redox reactions involving activation of the drugs' quinone group may damage DNA and/ or induce oxidative injury to cell membrane lipids, mitochondria or endoplasmic reticulum (Bachur et al.1977,1978;Lazzarino et al.1987).The B,C,D ring portion of the anthracycline molecule is re-

695
sponsible for the redox reactions and intercalation with DNA (fig. 1;Lown et al. 1979) and the drug arrests actively proliferating cells in the G2 phase of the cell cycle (Barlogie et al. 1981).
Idarubicin appears to have a similar mechanism of action to other anthracyclines. The binding af-finity of idarubicin for DNA, and its ability to in-tercalate DNA and inhibit topoisomerase II activ-ity were similar to or slightly better than that of daunorubicin and/or doxorubicin (Arlandini et al. 1977;Di Marco 1975,1978;Neidle 1977;Plum-bridge & Brown 1978;Rose 1988;Zunino et al. 1976). Idarubicin induced a higher number of double and single strand DNA breaks than dau-norubicin or doxorubicin in intact tumour cells (Capranico et al.1987).The increased in vitro cyto-toxicity and in vivo antitumour activity of idarub-icin compared with daunorubicin (sections 1.1 and 1.2) may be due in part to the increased lipophil-icity and DNA binding capacity of idarubicin (Di Marco et al.1978;Plumbridge &Brown 1978;Zu-nino et al.1979).
Idarubicin also differs from other anthracy-clines in its reactions with iron, which affects the mechanism for generating free radicals (Grankvist et al. 1989). It reduces in vitro human polymor-phonuclear leucocyte superoxide radical formation compared with daunorubicin (Cairo et al. 1990).
1.4 Effects on Healthy Cells and Tissues
Acute and chronic toxicity tests in animals demonstrate that idarubicin has reduced cardio-toxicity when given intravenously compared with
Table I.Effect of oral idarubicin treatment on the growth of sarcoma S180 in mice (n =10 in each treatment group)[after Di Marco et al.1977]
Idarubicin Tumour growtha Median survival
(mg/kg/day) day 8 day 11 (days)
0(control) 100 100 17
0.5 98 85 17
1.0 95 63 21
2.0 48 55 38
a Tumour volume index(treatment/control%).

daunorubicin and doxorubicin, with therapeutic indices (ratio of cardiotoxic to therapeutic dose) of 3.1,1.1 and 0.7,respectively, in mice.Oral admin-istration further reduced idarubicin's cardiotoxic effects (Arcamone et al. 1978;Casazza 1979;Di Marco et al.1977,1978;Penco et al.1983).
No myocardial lesions were found in dogs treated intravenously for 3 consecutive days each week for 13 weeks at an idarubicin dosage 100% lethal to the animals (Di Marco et al. 1978). Sim-ilar data were obtained in rabbits (data on file;Far-mitalia Carlo Erba). A correlation between dimin-ished superoxide generation (section 1.3) and reduced idarubicin-associated cardiotoxicity has been suggested (Cairo et al.1990;Lown et al. 1979).
Acute toxicity studies showed the haematolym-phopoietic system and gastrointestinal tract are most profoundly affected by idarubicin, indicating a greater effect of the drug on actively proliferating tissue.Subacute toxicity tests agree with these find-ings and,on a 3-day repeated dosing schedule ida-rubicin appears to be twice as myelotoxic as dox-orubicin. Idarubicin should therefore be tolerated in patientsto at least the same extent as doxo-rubicin when the recommended clinical doses are taken into account (i.e. 12 mg/㎡2 per 3-day cycle for idarubicin and 60 to 75 mg/㎡2 per 3-day cycle for doxorubicin), since idarubicin is clinically 5- to 6-fold more potent than doxorubicin (data on file, Adria Laboratories).
Organogenesis studies in rats showed idarubicin was embryotoxic and teratogenic at a dose not toxic to the mother.However,no teratogenic effects were seen in similar studies in rabbits (data on file,Ad-ria Laboratories). Similar results having been ob-tained for doxorubicin and daunorubicin (Thomp-son et al. 1978).Furthermore,idarubicin tended to produce fewer adverse effects on the immune sys-tem of mice compared with doxorubicin (Massa et al.1982).
In in vitro assays against healthy human mye-loid progenitor stem cells, idarubicin was signifi-cantly more cytotoxic than daunorubicin and about 2.5 times more cytotoxic than idarubicinol(Do-dion et al.1987).

2.Pharmacokinetic Properties
The pharmacokinetic properties of idarubicin after oral and intravenous administration have been studied in patients with solid tumours or acute leu-kaemia.Idarubicin and its only detected metabo-lite,idarubicinol (4-demethoxy-daunorubicinol), were measured quantitatively in biological fluids using high performance liquid chromatography with a lower detection limit of 0.25 μg/L (Eksborg et al. 1990; Smith et al.1987). Other methods for ida-rubicin analysis, based on modifications of meth-ods for analysis of doxorubicin and daunorubicin, have been published in the bioanalytical literature (Cummings et al.1987; Moro et al.1983;Pizzorno et al 1985;Speth et al.1986).
Despite variability in pharmacokinetic para-meters between patients and studies, particularly for bioavailability, the majority of studies pro-vided similar overall findings, and there appeared to be no major differences in idarubicin and ida-rubicinol pharmacokinetics in children compared with adults (Reid et al. 1990;Smith et al.1987; Speth et al. 1986;Tan et al. 1987)[table II].
2.1 Absorption
Idarubicin is absorbed rapidly following oral administration with a lag time of only 0.5 hours before concentrations can be detected in plasma (Gillies et al. 1987; Speth et al. 1989). In contrast, daunorubicin and doxorubicin are not absorbed to any appreciable degree following oral administra-tion (Di Marco et al. 1977). Peak plasma concen-trations of 2.2 to 11 μg/L were attained 1 to 4 hours after ingestion of idarubicin 10 to 60 mg/㎡2.Bio-availability varied widely between patients with a mean value of approximately 30% (table II).
2.2 Plasma Concentrations and Distribution
Although a biphasic pattern of plasma idarub-icin clearance was observed in some studies (Gil-lies et al. 1987; Lu et al. 1986; Speth et al. 1989), triphasic plasma clearance has also been reported, with a rapid initial (α) distribution phase, an inter-
Idarubicin in Cancer:A Review

697
Table II. Mean pharmacokinetic parameters in patients with various types of cancer receiving intravenous or oral doses of idarubicin
Reference

No.of

Dosage

tyaa

tyzs

tyzr

Cmaxa

tmax

Vda

CL

Bioavail-
(%)
Intravenous idar ubicin
Berman et al. 3 12.5 10.5
(1983)
Daghestani et 5 10-12.5 9.4 3.8 24.8
al.(1985)
Eksborg et al. 10 10 1.3 1.3 24 189
(1990)
Gillies et al. 20 15 29.4 12.7 1533 98.7
(1987)
Kaplan et al. 4 5-18 30 6
(1982)
Lu et al.(1986) 9 10-12.5 12.8 27 63.9 L/kg 71.4
Reid et al. 21 10-15 13 2.1 17.6 562 41
(1990)b
Robert et al. 8 7-9 14.2 19.3 1700 77
(1987)
Smith et al. 28 15 9.6 3.2 34.7 89.2
(1987)
Speth et al. 7 10 20 15.4 49 2250L
(1986)
Tan et al. 7 5-13.3 2.4 0.6 11.3 18-33
(1987)
Oral idarubicin
Berman et al. 1 50 9.8 32-35
(1983)
Eksborg et al. 10 35 8;4 4:3
(1990)°
Elbaek et al. 14 22.5 19 5.7 3
(1989)
Gillies et al. 11 30-70 13.9 12.65 2.7 1718 107.9 29
(1987)
Kaplan et al. 5 40-60 8.2 3.2 30
(1984)
Lu et al.(1986) 10 10 34.8 1 39
Pannuti et al. 12 10-15 23.7 4-10
(1986)
Smith et al. 5 15 20.4 24
(1987)
Speth etal. 7 30 39 12 11 2-4 30
(1986)
Stewart et al. 9 15-25 5.6-11.6 2.2-5.4 3.5 1214-1889 99-122 30
(1991)
a Unless otherwise stated.
b Children.
c Values given for nonfasting and fasting(no food 9h before and 3h after treatment) conditions
Abbreviations: tyz = plasma half-life; α = initial phase; β=intermediate phase; y = terminal phase; Cmax = maximum plasma concentration;tmax=time to maximum plasma concentration; Vd = volume of distribution; CL = plasma clearance.
Concentration(ug/L)
Fig.2. Plasma concentration decay curves of idarubicin and idarubicinol following bolus intravenous administration of idarubicin 15 mg/㎡2 in 5 patients with advanced breast can-cer (after Smith et al.1987).
mediate (β) distribution phase and then a much slower elimination (γ) phase (fig.2;table II;Dag-hestani et al. 1985;Smith et al. 1987; Reid et al. 1990; Tan et al. 1987). Following intravenous administration,the half-life of the initial phase ap-pears to be 9 to 30 minutes and estimates for the intermediate phase half-life range from 2.1 to 27 hours.Estimates of values for these parameters fol-lowing oral administration generally fall within the same ranges (table II), and the mean elimination half-life for idarubicinol has been reported to range between 36 and 73 hours following oral or intra-venous administration of idarubicin (Lu et al. 1986).
The shape of the plasma concentration vs time curve after 4-hour intravenous infusions of idarub-icin 10 mg/㎡2 on 3 consecutive days was similar to that for orally administered idarubicin (fig. 3). Plasma concentrations of idarubicinol exceeded those of idarubicin, and the metabolite accumu-lated over the 3 days of treatment (Gillies et al. 1987;Kaplan et al. 1982; Lu et al. 1986; Smith et al. 1987). Rapid infusion of idarubicin on consec-utive days produced large daily. fluctuations in

plasma idarubicin concentrations,with minor day to day differences but no drug accumulation.In contrast,plasma idarubicinol concentrations in-creased with repeated injections,with negligible daily fluctuation (fig.4;Daghestani et al.1985;Reid et al. 1990; Robert et al.1987).
Idarubicin 10 mg/m2 administered as a contin-uous 24-hour infusion over 3 consecutive days re-sulted in peak plasma concentrations of about 6 ug/L,10-fold lower than those achieved following bolus injection (fig. 4). Maximal idarubicinol con-centrations were similar to those obtained follow-ing rapid infusion.
Idarubicin has a very large volume of distri-bution,suggesting that much of the drug is bound to tissue. Values of 1214 to 1889 L/㎡2,2250L and 63.9 L/kg have been reported in adults (table II).
Mean plasma protein binding of 97 and 94% for idarubicin and its metabolite, respectively,were found;the binding was concentration independent (data on file, Adria Laboratories). In patients with leukaemia,peak nucleated blood and bone marrow cell concentrations of idarubicin were attained a few minutes after idarubicin injection, and idarub-icin and idarubicinol were present in these cells at concentrations more than 100-fold higher than those in plasma (data on file, Adria Laboratories). The high concentrations of idarubicin and its me-tabolite found in whole blood suggest extensive up-

Time(days)
Fig. 3.Concentration vs time curve of idarubicin and ida-rubicinol in plasma following 4-hour intravenous infusions of idarubicin 10 mg/m on 3 consecutive days(→→)in a patient with acute leukaemia (after Speth et al. 1986).
Rapid injection
Concentration(ug/L)
Time(days)
Concentration(ug/L)
Time(days)
Fig.4.Concentration vs time curve of idarubicin and ida-rubicinol in plasma following rapid injections (t) or contin-uous 24-hour infusion (→→) of idarubicin 10 mg/㎡2 for 3 con-secutive days in a patient with acute leukaemia (after Speth et al.1986).
take by erythrocytes,and these may serve as a drug pool, releasing drug slowly intothe plasma(Pan-nuti et al. 1986; Stewart et al.1991).
Interestingly,idarubicin (0.14and 1.57 μg/L)was detected in 2 of 21 CSF samples taken 18 to 30 hours following intravenous idarubicin 12.5 mg/ ㎡ administered on the third day of a once-daily regimen,and idarubicinol (up to 1.05 μg/L)was detected in 20 of the 21 CSF samples following ida-rubicin 10,12.5 or 13.5 mg/m2 on a once-weekly for 3 weeks or once-daily for 3 days schedule (Reid et al.1990).
2.3 Metabolism and Elimination
Idarubicin was no longer detectable in plasma (less than 2 μg/L)72 hours after oral administra-tion of 22.5 to 70 mg/㎡2 and 72 hours following

intravenous administration of idarubicin 12.5 to 15 mg/㎡ (Berman et al. 1983; Elbaek et al.1989; Gillies et al. 1987; Kaplan et al. 1984), due to bio-transformation of idarubicin to idarubicinol in the liver (fig. 5; Broggini et al. 1984). The plasma con-centration of idarubicinol exceeded that of idarub-icin 2 hours after ingestion. Peak plasma concen-trations of the metabolite (4.1 to 40 μg/L)were achieved 3 to 8 hours after idarubicin 10 to 70mg/ ㎡2(Elbaek et al.1989;Gillies et al.1987;Kaplan et al.1984;Pannuti et al. 1986;Stewart et al. 1991). About 2-fold more metabolite is produced follow-ing oral compared with intravenous administra-tion, probably as a result of 'first-pass' metabolism (Smith et al. 1987; Speth et al. 1986).Idarubicinol was detectable in plasma for at least 72 hours after intravenous idarubicin 10 mg/㎡2 or 15mg/㎡2,and for up to 7 days following idarubicin 15 mg/m orally (Reid et al. 1990; Smith et al. 1987).
The enzyme aldoketoreductase, which converts idarubicin to idarubicinol, is extensively distrib-uted in extravascular tissues, possibly explaining the plasma clearance of idarubicin being twice the expected hepatic plasma flow. It follows that the mean elimination half-life for idarubicinol (8 to 73 hours)is considerably longer than that for idarub-icin (6 to 35 hours) following doses of idarubicin 5 to 60 mg/㎡2 orally or 10 to 12.5 mg/m2 intra-venously (Eksborg et al. 1990; Lu et al.1986;Reid et al.1990; Smith et al. 1987;Stewart et al. 1991). It has also been reported that the mean elimination half-life of idarubicin is not altered by its coad-ministration with cytarabine (data on file,Adria Laboratories).The rate of disappearance of ida-rubicin and idarubicinol from tissue (elimination half-lives 15 and 72 hours,respectively) was com-parable with that from plasma (data on file,Adria Laboratories).
Total body clearance rates for idarubicin of 30 to 122 L/㎡2/h have been noted in adults (table II). Less than 5% of the delivered dose of idarubicin was recovered as idarubicin or its metabolite in the urine over 24 or 96 hours,and the mean ratios of idarubicinol to idarubicin in urine were 3:1 and 6: 1 after administration ofidarubicin by the intra-venous and oral routes, respectively (Elbaek et al.
Aldoketoreductase
Idarubicin

Idarubicinol
Fig.5. Metabolism of idarubicin to the active metabolite idarubicinol.
1989; Kaplan et al. 1984; Smith et al. 1987).No conclusive data is available regarding the extent of biliary excretion(Pannuti et al. 1986; Tamassia et al.1987).
2.4 Effects of Disease States
The pharmacokinetic properties of idarubicin have not been evaluated specifically in patients with hepatic impairment, but it is expected that in patients with moderate or severe dysfunction ida-rubicin metabolism may be affected,leading to higher than normal systemic drug concentrations (data on file, Adria Laboratories).
Renal dysfunction would not be expected to al-ter the pharmacokinetics of idarubicin since urin-ary excretion is a minor route of elimination(sec-tion 2.3).
3.Therapeutic Efficacy
The chemotherapeutic efficacy of idarubicin has been investigated in a number of different malig-nancies.At present, the intravenous formulation is marketed in a number of countries and is the form-ulation which has been used to treat acute and chronic myelogenous leukaemia, and acute lym-phoblastic leukaemia.
Intravenous idarubicin in combination with cy-tarabine has shown high activity in patients with

acute myelogenous leukaemia(AML), and mod-erate to good activity in preliminary studies of patients with acute lymphoblastic leukaemia(ALL). The oral formulation of idarubicin, which is not commercially available, has been used mainly in advanced breast cancer, where preliminary results have been equivocal. Encouraging results were seen in patients with previously untreated AML,mul-tiple myeloma or non-Hodgkin's lymphoma taking oral idarubicin, but these results again require con-firmation.
The assessment of objective response has been largely standardised. In the majority of studies in patients with solid tumours or lymphomas, com-plete response was defined as the complete disap-pearance of all identifiable tumours, with no new lesions or calcification of lytic bone metastases; partial response was defined as a greater than 50% reduction in the sum of the products of the longest perpendicular axes of measurable lesions(UICC or WHO criteria;Hayward et al.1977;WHO 1979).
In patients with acute leukaemia, complete re-sponse was usually defined as a normocellular bone marrow with less than 5% leukaemic blasts and normal maturation of haematopoietic cell lineages. However, in patients with chronic myelogenous leukaemia in blast crisis, a return to the chronic disease phase was usually considered a complete response.
Clinical studies have predominantly been non-
Idarubicin in Cancer:A Review
comparative, although a few large,well designed randomised comparative studies of idarubicin alone or in combination with other antineoplastic drugs have been performed. Follow-up duration in all studies has generally been less than 2 years,pre-cluding assessment of long term patient survival. Many studies demonstrated the uséfulness of ida-rubicin as palliative therapy based on remission rate or duration, but quality of life was not assessed. Many trials included poor risk patients (advanced disease and/or heavy pretreatment), so treatment tolerability was an important outcome measure.
In the following discussion, induction of remis-sion refers to the use of idarubicin in patients not previously treated with chemotherapy;intensifi-cation or consolidation therapy refers to maintain-ing remission and improving partial remission achieved with induction chemotherapy; mainten-ance chemotherapy refers to usually low-dose treatment to prolong remission,and salvage chemotherapy refers to the treatment of cancers re-fractory to or relapsed from previous chemother-apy.
Comparison of results between studies in re-lapsed and/or refractory patients is difficult, since differences in patient age, disease status (refractory or not), median length of first complete response and nature of prior treatment are very likely to af-fect outcome(Champlin&Gale 1987).
3.1 Acute Myelogenous Leukaemia
Acute myelogenous leukaemias include the fol-lowing 7 subtypes: acute myelocytic leukaemia without differentiation (MI), acute myelocytic leu-kaemia with differentiation (M2), acute promye-locytic leukaemia (M3),acute myelomonocytic leukaemia (M4), acute monocytic leukaemia (M5), erythroleukaemia (M6) and megakaryoblastic leu-kaemia(M7). With aggressive induction chemo-therapy (usually cytarabine and daunorubicin) a complete response may be achieved in 50 to 80% of patients; however, over 70% of patients relapse within 2 years.The remission rate is less than 30% with the first salvage regimen and less than 10% with subsequent treatments, and longterm sur-

701
vival is less than 5% (Walters et al. 1988). Mye-lodysplastic syndromes which may progress to acute leukaemia also occur, particularly in older patients. Comprehensive overviews of idarubicin in the treatment of acute leukaemias are given by Carella et al. (1990a) and Fields and Koeller(1991).
3.1.1 Intravenous Idarubicin
In preliminary studies of idarubicin monother-apy for adult AML, 15 to 72 mg/m2 administered intravenously over 2 to 6 days has been used (Av-visati et al. 1990; Carella et al. 1985;Daghestani et al. 1985; Harousseau et al. 1987, Hayat et al. 1984;Lambertenghi-Deliliers et al. 1983;Sessa et al. 1985; Young et al. 1985). In patients with pre-viously treated AML refractory to,or relapsed after standard chemotherapy, complete remission rates ranged from 13 to 22%, only 1 small study having no complete responders (Carella et al. 1985; Dag-hestani et al. 1985; Harousseau et al.1987;Hayat et al. 1984; Lambertenghi-Deliliers et al.1983;Sessa et al. 1985; Young et al. 1985).
Idarubicin (6 to 12 mg/㎡/day) monotherapy generally produced a complete response rate sim-ilar to that seen with therapeutic doses of doxo-rubicin, daunorubicin or amsacrine monotherapy (about 18%) [Arlin et al. 1980;Muggia &Carter 1987]. Importantly, 2 of 8 patients with AML re-fractory to cytarabine,anthracyclines and amsa-crine therapy achieved complete remission after idarubicin 8 mg/m2 for 3 days, indicating a pos-sible lack of cross-resistance between these agents and idarubicin (Carella et al. 1985). This observ-ation requires confirmation in larger randomised studies.
Induction therapy with idarubicin 10 to 12 mg/ m2 for 6 days as a rapid intravenous infusion re-sulted in complete remission in 22of 27 patients (81%) with previously untreated acute promyelo-cytic leukaemia (Avvisati et al. 1990).The median time to complete response from the end of induc-tion chemotherapy was 23 days,and only 1 patient was resistant to idarubicin (Avvisati et al. 1990). Median durations of complete response were re-ported rarely but 12 of 22 complete responders in this study were alive and still in first remission after
a minimal follow up of 30 months from onset of complete response.Six of the 12 patients received continuous maintenance treatment for 2 years with mitoxantrone and mercaptopurine, 5 received transplants (4 autologous,1 allogenic) and 1 re-ceived no further therapy after a consolidation course with high dose doxorubicin plus cyclophos-phamide (personal communication C. Avvisati).
These results prompted investigation of idarub-icin in combination regimens. Idarubicin in com-bination with cytarabine has been used successfully to treat patients with relapsed or refractory AML (table III). Complete response rates of 24 to 70% were achieved in studies including more than 6 patients. The best complete response rates (57 to 70%) occurred with idarubicin and intermediate dose cytarabine(1200 to 2000 mg/㎡2)for 3 to 6 days (Carella et al. 1989;Harousseau et al. 1989a; Leone et al. 1989),and were similar to those achieved with high dose cytarabine regimens(Leone et al. 1989). Complete response occurred in several patients who had previously been refractory to an-thracyclines(Lambertenghi-Deliliers et al. 1987). Response duration was relatively short (as for the daunorubicin plus cytarabine regimen), although 1

patient has remained in complete remission for over 14 months after receiving idarubicin plus cytara-bine consolidation therapy (Lambertenghi-Deli-liers et al. 1987). Further study is required to de-termine whether inclusion of idarubicin in consolidation and intensification regimens will prolong the duration of response. Deaths occurring during aplasia or during early treatment were mainly due to sepsis (table III).
The use of idarubicin plus cytarabine has also been evaluated as induction therapy for AML(table IV). In prospective randomised studies, idarubicin plus cytarabine had an efficacy and tolerability su-perior to that of daunorubicin plus cytarabine (table IV; section 4),with complete response rates being significantly higher in patients receiving idarubicin plus cytarabine in 2 of the 3 US pivotal studies (Berman et al. 1991; Vogler 1991) and in a large Italian multicentre study (Mandelli et al. 1991). Idarubicin plus cytarabine induced a significantly higher number of complete responses in the first cycle of treatment than did daunorubicin plus cy-tarabine(74 vs 51%),and fewer cases of resistant disease were observed (14 vs 31%) [Mandelli et al. 1991].Younger patients (less than 60 years of age)
Table Ill.Summary of noncomparative studies evaluating intravenous idarubicin (I) plus intravenous cytarabine (Cy) in patients with relapsed or refractory acute myelogenous leukaemia
relapsed or refractory acute myelogenous leukaemia
Reference Dosage regimen Complete responsea Median response Early/aplastic
(mg/㎡2/day) (%) duration deathsb
(months)
Berman et al.(1989a) 1 10x3 or 4d+Cy 200x5d 8/34(24) 2
Berman et al.(1989b) 112x3d+Cy 6000x3d 12/24 (50)
Carella et al.(1989) 112x3d+Cy 2000x3d 4/7(57) 4-≥6℃ 2
Cavanna et al.(1990) 112x3d+Cy 3000x3d 1/1(100) ≥12
Fülle &Hellriegel(1986) 110x3d+Cy 240x5d 1/5(20) 'Short'
Harousseau et al.(1989a) 18x5d+Cy 2000x3d 21/35(60) 4
Lambertenghi-Deliliers et al. 18x3d+Cy 240x5d (0)9/0 2
(1983)
Lambertenghi-Deliliers et al. 112x3d+Cy 240x7d 9/16(56) 11 3
(1987)
Leone et al.(1989) 112x3d+Cy 1200x6d 7/10(70) 3 2
a As defined in the introduction to section 3.
b Deaths occurring during the first few days of treatment or during aplasia.
C Range.
Abbreviation:d=days.
Idarubicin in Cancer:A Review

703
Table IV. Summary of studies evaluating idarubicin (1) plus intravenous cytarabine (Cy) as induction therapy in patients with acute myelogenous leukaemia
myelogenous leukaemia
Reference Dosage regimen Complete Median response Early/aplastic
(mg/m/day) responsea duration deathsb
(%) (months)
Noncomparative studies
Lambertenghi-Deliliers 18x3d+Cy 240x5d 1/4(25) 3
et al.(1983)
Lambertenghi-Deliliers 112x3d+Cy 240x7d 45/56 (80) 19 8
et al.(1989)
Comparative studies
Berman et al.(1991) 112x3d+Cy 200x5d° 48/60(80)d 9.5° 4
D 50x3d+Cy 200x5d 35/60(58) 8.5
Reiffers et al.(1991)h 18x5d+Cy 100x7dc 68/98(70) 19
D 50x3d+Cy 100x7d 61/99 (61) 13.5
Wiernik etal.(1989) 113x3d+Cy 100x7d° 68/97(70) 1 11/519
Wiernik(1991) D 45x3d+Cy 100x7d 65/111(59) 15/51
Mandelli et al.(1991)h 112x3d+Cy 100x7d° 50/124(40) 47
D 45x3d+Cy 100x7d 49/125(39) 27
Vogler(1991) 112x3d+Cy 100x7d° 75/105(71) 14k 18
D 45x3d+Cy 100x7d 65/113(58) 11 25
a As defined in the introduction to section 3.
b Deaths occurring during the first few days of treatment or during bone marrow aplasia.
C Consolidation and/or maintenance therapy given.
d Significant difference between I+Cy and D+Cy(p=0.005).
Median duration of survival 19.5 vs 13.5 months for l+Cy and D +Cy groups,respectively (p=0.025).
f Median duration of response and survival significantly longer for I + Cy than D+Cy groups (p <0.05).
6 Preliminary results with 102 evaluable patients in Wiernik et al. (1989).
h Elderly patients.
Number of complete responses after 1 course of therapy significantly higher in I+Cy group(p=0.02).No significant difference in duration of remission and survival.
Significant difference between I+Cy and D+Cy(p=0.03).
k No significant difference in duration of survival.
Abbreviations:d=days;D=daunorubicin.
were more likely to achieve a complete response than older patients, particularly those receiving idarubicin plus cytarabine (Vogler 1991;Wiernik 1991). However, 1 study reported similar complete response rates in patients aged 55 to 65 years(65%) and those aged 65 to 75 years (64%),although the median duration of remission was significantly longer in the younger group (Reiffers et al. 1991). Wiernik(1991)reported complete response rates of 88 vs 70% in young patients (≤ 50 years) receiving idarubicin vs daunorubicin in combination with cytarabine (p =0.035).However,the complete re-sponse rate in those over 60 years was 49 vs 44%,

respectively, for the 2 groups, andthe death rate was increased in elderly patients receiving idarub-icin vs daunorubicin (47 vs 27 patients) in 1 study (Mandelli et al.1991).
The median duration of response was signifi-cantly longer in patients receiving idarubicin vs daunorubicin plus cytarabine in 2 of the 4 major comparative trials (Berman et al. 1991;Wiernik 1991).
In 2 of 3 large US comparative studies in patients with AML, the duration of survival was significantly longer in patients receiving idarubicin plus cytarabine than in those receiving daunorub-
icin plus cytarabine (probability of survival at 18 months 48 vs 28% and 35 vs 23%, p < 0.05)[Ber-man et al. 1991; data on file, Adria Laboratories; Wiernik 1991]. However, in the third study,which unlike the previous 2 included 3 courses of inten-sive maintenance therapy, survival duration was not significantly different between the 2 groups of patients(Vogler 1991).
The combination of idarubicin (8 mg/m2 for 3 days),cytarabine(150 or 200 mg/㎡2 for 5 days) and etoposide (150 mg/m2 for 3 days) produced partial response in 1 of 5 heavily pretreated patients with AML(Fülle & Hellriegel 1986) and a com-plete response rate of 83.5% (56 of 67 patients) in previously untreated patients, including 92.5% of those aged 15 to 48 years,and 70% of those aged 49 to 76 years (Carella et al. 1990b). In this study, 71% of all complete responses were observed after the first course of treatment and 23% of these patients were still disease-free a median of 32 months later. There were 7 deaths during induc-tion, 6 in patients over 40 years of age.
3.1.2 Oral Idarubicin
A few studies using oral idarubicin monother-apy 60 to 90 mg/m2 administered over 3 days have been performed in adults with AML (Davis et al. 1991;Harousseau et al. 1989b; Lowenthal et al. 1987; Malik et al. 1989). Previously untreated patients generally responded well to oral idarubicin with 2 of 9 (22%) poor risk, and 8 of 20(40%) elderly patients achieving complete remission with idarubicin 20 to 30 mg/m2 for 3 days (Harousseau et al. 1989b; Lowenthal et al. 1987). However,there were no complete responses in a study of previ-ously treated AML patients (Malik et al. 1989).
Oral idarubicin 30 mg/㎡2 for 3 days in com-bination with low dose subcutaneous cytarabine(20 mg/m2 for 10 days) produced a complete response in 14 of 26 poor risk patients (54%) and there were 5 early deaths or deaths due to aplastic anaemia (Helg et al. 1990).Furthermore,when used as in-duction therapy, idarubicin 20 mg/m2 for 3 days plus cytarabine (25 mg/㎡2 then 100 mg/㎡ con-tinuous infusion for 7 days) resulted in a 67% (35/ 52)complete response rate,compared with 58%(28/

48) for patients receiving doxorubicin 30 mg/m for 3 days plus the same regimen of cytarabine (Bezwoda &Dansey 1990).
3.2 Acute Lymphoblastic Leukaemia(ALL)
Standard intensive chemotherapy regimens in-duce complete response rates of more than 60% in children and 20 to 35% of adults with acute lym-phoblastic leukaemia. However,relapses are com-mon and the duration of second remission is usu-ally short with a low probability of cure (Giona et al. 1990).
Idarubicin monotherapyproduced complete re-sponse rates of 30 to 33% in pretreated adults(Car-ella et al.1985;Daghestani et al. 1985) and 25 to 40% in pretreated children (Madon et al.1987;Tan et al. 1987) with ALL. Intravenous idarubicin in combination with cytarabine produced complete response rates of 56 to 77% in studies including more than 10 pretreated patients with ALL, a num-ber of whom had refractory disease (table V).Re-sponses were of limited duration, the longest being in 8 patients who received bone marrow trans-plantation after achieving complete remission;these patients were still alive and in remission at a me-dian of 36 months later (Carella et al.1989;Giona et al. 1990). Best response rates appear to occur with idarubicin 12 mg/㎡2 for 2 to 3 days or 5 mg/ ㎡2 for 6 days in combination with intermediate or high dose cytarabine (table V).
Children responded particularly well, with com-plete response rates of 63% (20/32) and 68% (21/ 31) being achieved with idarubicin 12 mg/m2 for 2 to 3 days plus cytarabine 6000 mg/m2 for 3 days. This compares with a 50 to 54% remission rate in adults (Giona et al. 1990; Petti & Mandelli 1989). Of the 20 complete responders in the study by Petti and Mandelli (1989),3 had had previous CNS re-lapse,as had a further 2 patients over 15 years of age.These results suggest the possibility that ida-rubicinol may cross the blood-brain barrier (see also section 2.2).
Complete response rates were significantly af-fected by white blood cell count at the start of treatment (being significantly lower for patients
Idarubicin in Cancer:A Review

705
Table V. Noncomparative studies of intravenous idarubicin (1) as a component of combination regimens in patients with relapsed or refractory acute lymphoblastic leukaemia
or refractory acute lymphoblasticleukaemia
Reference Dosage regimen Complete responsea Median response Early/aplastic
(mg/㎡/day) (%) duration deathsb
(months)
Idarubicin plus cytarabine (Cy)
Berman et al.(1989a) 110x3-4d+Cy 200x5d 0/10(0)
Berman et al.(1989b) 112x3+Cy 6000x3d 2/7 (29)
Carella et al.(1989) 112x3d+Cy 2000x3d 10/13(77) 1
Cavanna et al.(1990) 112x3d+Cy 3000x3d 2/2(100) WAV6 0
Fülle &Hellriegel(1986) 110x3d+Cy 240x5d 0/1(0)
Giona et al.(1990)° 112x2d+Cy 6000x3d 52/88(59)d 36 13
Leone et al.(1989) 112x3d+Cy 1200x6d 5/6 (83) 1.5-≥6 1
Petti & Mandelli(1989)° 112x3d+Cy 6000x3d 36/64(56) 10
P9x00010+9x 21/31(68) 2
Idarubicin,Vincristine (V),Prednisone (PI)+Asparginase(A)
Mandelli et al.(1986)° I 10 weeklyx3-4 weeks+V2+11/19(58)9 2
PI 40+A 6000 U/㎡2
(+Mf+Cy 30 in patients
(+Mf+Cy 30 in patients
without CNS involvement)
a As defined in the introduction to section 3.
b Deaths occurring during the first few days of treatment or during aplasia.
0 Study includes children.
d Projected disease free survival for all responding patients 19% at 46 months.
e Range.
f Dose according to age.
g Median survival 7 months (range 3-13.5).
Abbreviations:d =days;M=methotrexate.
with a count > 20 x109/L),and duration of first remission (with more patients achieving complete remission following a first remission of 18 months or more) [Giona et al. 1990].
Idarubicin 10 mg/㎡2 weekly plus vincristine, prednisone and asparaginase achieved complete re-sponse rates comparable to those of idarubicin plus cytarabine (table V), with children again respond-ing particularly well (complete response rates 75 to 81%).
3.3 Chronic Myelogenous Leukaemia
When blast crisis occurs in chronic myelogen-ous leukaemia(CML),early progenitor haemo-poietic cells undergo acute leukaemic transforma-tion.There are a range of possible morphologies and it is considered the most malignant of the acute

leukaemias. Intensive chemotherapy to induce marrow aplasia and permit normal stem cell re-generation produces remission rates of less than 30% with a median survival of 3 to 6 months.
Only 1 of 67 patients with chronic myelogenous leukaemia in blast crisis or accelerated phase achieved a complete response with idarubicin with or without cytarabine in 9 studies (Bandini et al. 1985; Battista et a1.1986; Berman et al. 1989a, 1989b; Carella et al. 1985; Daghestani et al.1985; Harousseau et al.1987;Lambertenghi-Deliliers et al. 1983; Malik et al. 1989).However,blastic cell counts decreased by up to 91.2×109/L(38 days after intravenous idarubicin 15 mg/㎡2) in previ-ously untreated patients and by up to 71.7 x109/ L(10 days after 2 doses of intravenous idarubicin 8 mg/m2 10 days apart) in patients previously treated with anthracyclines,suggesting idarubicin
may be useful as palliative treatment in these patients (Bandini et al. 1985; Malik et al. 1989).
The annual rate of transformation from CML to acute phase CML (AP-CML) is approximately 25%,with remission rates of AP-CML of 25 to 30% and a median survival of about 6 months.Eight patients with AP-CML treated with intravenous idarubicin, intermediate dose cytarabine and eto-poside underwent a median of 3 consecutive leu-cophoresis. In 5 of 8 patients the peripheral cells were Philadelphia chromosome negative, suggest-ing that this treatment regimen may induce a high degree of suppression of the Philadelphia positive clones (Carella et al. 1991).
3.4 Advanced Breast Cancer
A regimen including an anthracycline is the most frequently used first-line therapy for treatment of metastatic breast cancer,with response rates of ap-proximately 56% (Madsen et al. 1991). In the ad-juvant or palliative treatment of breast cancer,reg-imens containing cyclophosphamide,methotrexate and fluorouracil (CMF), and CMF plus vincristine and prednisone (CMFVP), are among the most commonly used,with an objective response rate of approximately 50%(Brodie & Elefanty 1988;Hen-ney&DeVita 1987;Muggia&Carter 1987).Doxo-rubicin, usually with vincristine, is frequently given after CMF in an attempt to improve response rates (Coates 1984;Marcellino &Bizzarri 1988).Dox-orubicin monotherapy produces an objective re-sponse in approximately 43% of previously un-treated patients and 26% of previously treated patients(Muggia & Carter 1987).
3.4.1 Intravenous Idarubicin
In 2 studies of intravenous idarubicin 15 mg/ ㎡ compared with esorubicin 30 or 40 mg/m,only 1 patient experienced a completeresponse(whilst taking idarubicin). Of 27 patients who went on to receive doxorubicin following unsuccessful therapy with the initial drug, 1 achieved a complete re-sponse and 6 a partial response(3 from each study) suggesting a possible lack of cross-resistance be-tween idarubicin and doxorubicin (ten Bokkel

Huinink et al. 1986,1987).Idarubicin appeared to produce a slightly higher overall response rate than esorubicin, but patient numbers were too small for any conclusion to be made (table VI).
3.4.2 Oral Idarubicin
In noncomparative studies,oral idarubicin monotherapy in 3 different dosage schedules pro-duced overall (complete plus partial) response rates of 11 to 36% in patients with advanced breast can-cer(idarubicin over 3 days every 3 to 4 weeks: De Lena et al. 1988; Chevallier et al. 1990;Kolarić et al.1987;Lionetto et al. 1986; Martoni et al. 1985; Wander et al. 1986; idarubicin once every 3 weeks: Bastholt & Dalmark 1987;Hurteloup et al.1989; Lopez et al. 1986b; Stuart et al. 1988; Bonfante et al. 1986; idarubicin weekly:Bastholt et al.1990; Smith&Howell 1989).The best complete response rate achieved was only 11%(Chevallier et al.1990), and 1 study of 22 patients achieved no responses at all (Casper et al. 1987).
In comparative studies of anthracycline mono-therapy,the overall response rate in 1 study was significantly higher in patients administered doxo-rubicin intravenously [currently considered the most active single agent used in the chemotherapy of advanced breast cancer (Henderson et al. 1989; Neidhart et al. 1986)] than in those administered idarubicin orally (p =0.02), although in another trial overall response rates were similar for the 2 drugs (table VI). Most patients had received prior chemotherapy but not anthracyclines, and previ-ously untreated patients had a higher overall re-sponse rate (Lopez et al.1989).However,differ-ences in response rates in these studies may be due to the small sample sizes.
The median time to response (about 2 months), the duration of response, time to disease progres-sion (about 3.5 months) and patient survival were similar for patients receiving doxorubicin or ida-rubicin (table VI). Responses were observed in all disease sites involved, although responses in soft tissue lesions were more frequent with both drugs (Lopez et al. 1989; Martoni et al.1990).
None of 10 patients who crossed over following unsuccessful therapy with the first drug in 1 study
Idarubicin in Cancer:A Review

707
Table VI. Summary of randomised studies comparing monotherapy with idarubicin (I) and other anthracycline agents in patients with advanced breast cancer
advanced breast cancer
Reference Dosage regimena No.of evaluable Complete Complete+ Median response
(mg/m2/day) patients responseb partial responseb duration
(%) (%) (months)
Lopez et al.(1989)c 145 PO 34 6 21d a9
Dx 75 IV 37 11 46 6
Martoni et al.(1990) 145 PO 37 3 30 8.59
Dx 75 IV 19 0 32 7
ten Bokkel Huinink etal. 115 IV 29 3 14
(1986)h E 30 IV 29 0 7
Dx 60 IV 18 6 22
ten Bokkel Huinink et al. 115 IV 22 0 14
(1987)h E 40 IV 18 0 11
Dx 60 IV 9 0 33
a Regimens were single doses administered every 3 weeks.
b As defined in the introduction to section 3.
C Parallel study design.All other studies had a crossover design.
d Statistically significant difference between response rates for idarubicin and doxorubicin(p =0.02).
e Median survival 14 vs 20 months for idarubicin and doxorubicin patients,respectively.
f Idarubicin administered over 3 consecutive days every 4 weeks.
g Survival rates for idarubicin and doxorubicin not significantly different.
h Patients crossed over to doxorubicin treatment if there was ‘no change’ or disease progression.
i 12 patients after idarubicin,6 after esorubicin.
j3 patients after idarubicin,6 after esorubicin.
Abbreviations: PO = oral, IV = intravenous; E = esorubicin; Dx =doxorubicin.
responded to alternative treatment (idarubicin or doxorubicin), suggesting the existence of cross-resistance(Martoni et al. 1990).
Studies evaluating the use of idarubicin in com-bination regimens in patients with advanced breast cancer are few,and comparisons with standard combination regimens do not appear to have been published. Oral idarubicin in combination with cy-clophosphamide produced an overall response rate of 25 to 49%(Kolarić & Mechl 1991;Lopez et al. 1991; Papaldo et al. 1986), with best results in-cluding 2 complete remissions in previously un-treated,post-menopausal patients. The median duration of remission was 7 months and median survival was greater than 14 months (Kolarić & Mechl 1991). Similarly, an overall response rate of 58% (1 complete, 6 partial responders) was seen in patients previously untreated with chemotherapy, whereas in those previously treated,a response rate of 44% was seen (3 complete, 8 partial responders).

The median duration of response was 6.5 months and median survival 10.5 months(Lopez et al. 1991). Reduction of the idarubicin dose (to 20 to 40mg/㎡2) may have resulted in a reduced overall response rate (25%) [Papaldo et al. 1986]. How-ever,comparisons between studies,even those with similar doses and regimens, may be inappropriate due to differences in patients’ prognostic features and risk factors (Kolarić & Mechl 1991).
Idarubicin in combination with dibromodulci-tol produced response rates no different from those reported for idarubicin alone (26 to 30%) and the median duration of remission was 6 months (Mechl et al. 1989; Smith & Howell 1989).A combination of idarubicin, cyclophosphamide and fluorouracil elicited an overall response rate of 55%(compar-able to that reported for doxorubicin,cyclophos-phamide plus fluorouracil) with a complete re-sponse rate of 12%, which is comparable to that reported for other anthracycline-containing regi-
mens (10 to 20%) [Kolarić et al. 1988].Interest-ingly,a very good response rate(61%) was achieved for visceral metastatic disease; this is especially notable as idarubicin monotherapy did not show particularly high activity at these sites (up to 20%; Kolarić et al. 1987). Responses were also signifi-cant in soft tissue lesions (55%) and the median duration of remission was 8 months (Kolarić et al. 1988).Large randomised studies comparing this regimen with standard therapy are required to con-solidate these findings.
3.5 Other Malignancies
3.5.1 Intravenous Idarubicin
Of 13 patients with relapsing non-Hodgkin’s lymphoma treated with a combination of idarub-icin plus cytarabine, 62% responded (5 complete, 3 partial) [Dufour et al. 1988]. Intravenous ida-rubicin monotherapy in previously treated or untreated patients has shown very little or no ac-tivity in clinical evaluations of a number of solid tumours including:
·non-small cell lung cancer (Joss et al. 1984).
·ovarian cancer (Hakes et al. 1985).
·malignant melanoma (Stanton et al. 1985).
·gastric cancer (Einzig et al.1984;MacCormick et al.1991).
·colorectal cancer (Harper et al. 1984).
·endometrial cancer(Hakes &Raymond 1987).
·lymphoma(various types)[Coonley et al.1983; Gillies et al.1988].
·renal cell carcinoma (Scher et al.1985).
·cervical cancer (Hakes et al. 1986).
·pancreatic cancer (Mittelman et al. 1987).
3.5.2 Oral Idarubicin
A response rate of about 50% was seen in 14 pretreated patients with multiple myeloma receiv-ing oral idarubicin monotherapy (Chisesi et al. 1988).Further trials are needed to substantiate this result. No response was obtained with etoposide, idarubicin and prednisone in combination in these patients(Capnist &Chisesi 1988),although there was a partial response in 3 of 4 patients receiving idarubicin plus cyclophosphamide,and predniso-

lone or vincristine and cyclophosphamide (Eridani et al.1985).
In patients with non-Hodgkin’s lymphoma, oral idarubicin monotherapy produced response rates of 58%(10 complete, 16 partial responders),31% (1 complete,4 partial responders) and 65%(2 com-plete, 11 partial responders) in 3 studies of 45,16 (all untreated) and 20 patients, respectively,the majority of whom had received prior chemother-apy and/or radiotherapy (Case et al.1990;Errante et al.1991;Lopez et al. 1986a).The response rate was higher in previously untreated patients (85%) than in those with prior exposure to chemotherapy (29%) [Lopez et al. 1986a].Further study is re-quired in this indication.
As with intravenous therapy, oral idarubicin monotherapy in previously treated or untreated patients has not been demonstrated to be of sig-nificant benefit in myelodysplasia (Johnson &Par-apia 1987;Lowenthal & Lambertenghi-Deliliers 1990,1991) and the following solid tumours:
·non-small cell lung cancer (Ardizzoni et al. 1988;Ettinger et al. 1989;Hochster et al.1986; Kris et al. 1985;Presgrave et al. 1988b;Umsa-wasdi et al. 1989,1990).
·small cell lung cancer (Ardizzoni et al.1989; Milroy et al. 1987; Smith et al. 1988).
·ovarian cancer (Bruzzone et al. 1987; Kavan-agh et al.1986;Williams 1990).
·malignant melanoma (Lopez et al. 1986c; Martoni et al. 1986).
·gastric cancer (Abad-Esteve et al.1989;Rosso et al.1986).
·colorectal cancer (Presgrave et al. 1988a).
·AIDS-associated Kaposi’s sarcoma(Chachoua et al.1987).
4.Tolerability
In clinical trials the toxicity profile of idarubicin has been qualitatively similar to that of the an-thracyclines daunorubicin and doxorubicin.In 3 large US studies in previously untreated patients with AML, intravenous idarubicin plus cytarabine or daunorubicin plus cytarabine combination in-duction regimens had a similar incidence and se-
Idarubicin in Cancer:A Review
verity of the adverse effects usually seenwith cyto-toxic therapy. Table VII gives details of the induction regimens. In particular these adverse events include nausea and vomiting, mucositis and infection (figure 6 shows the incidence of adverse effects during induction therapy in 1 US study rep-resentative of other similar studies).However,in-fection and mucositis were more frequent and sev-ere in the idarubicin group during consolidation therapy(table VII gives details of the consolidation regimens in the 3 pivotal US studies). Incidences of other spontaneously reported adverse effects did not differ significantly between the 2 groups of patients. However, it is difficult to compare the toxicity of different dosage schedules since plasma pharmacokinetics will differ, and it is known that there is a correlation between plasma kinetics and severity of toxicity (personal communication,L. Bastholt).
4.1 Haematological Toxicity
4.1.1 Intravenous Idarubicin
Myelosuppression,predominantly neutropenia, was the most frequently reported toxicity associ-

709
ated with idarubicin therapy, used alone or in combination with other agents. In the setting of acute leukaemia, this is an expected and desired effect.
The median duration of myelosuppression (white blood cell count<1x109/L and platelet count <50x109/L) was investigated in 3 large US comparative studies in patients with AML (fig. 7). Results show that aplasia was of comparable duration for the 2 combination regimens in 2 of the studies, but in the other the duration of neu-tropenia and thrombocytopenia was longer in patients receiving the daunorubicin combination (Memorial Sloan-Kettering Cancer Center Study, data on file,Adria Laboratories).
The incidence of infections was seen in the US studies:92 vs 95% incidence of overall infection and 60 vs 64% incidence of severe infection in the idarubicin and daunorubicin groups, respectively, during induction therapy. During consolidation therapy,however, the duration of aplasia was sig-nificantly longer in patients receiving idarubicin compared with daunorubicin-treated patients in each of the 3 US studies, with a concomitant in-
Table VIl. Induction and consolidation regimens used in 3 US parallel studies of patients with AML
Reference No.of Induction regimen Consolidation regimen
evaluable (mg/㎡2/day)
patients
MSKCC study: 130 1 12x3d IV plus 2 courses | 12x2d IV plus
data on file, Cy 25 IV bol then Cy 200x5d CI Cy 25 IV bol then Cy 200x4d CI
Adria Laboratories D 50x3d IV plus 2 courses D 50x2d IV plus
Cy 25 IV bol then Cy 200x5d Cl Cy 25 IV bol then Cy 200x4d CI
US multicentre trial; 214 13x3d IV plus Cy 100x7d CI 2 courses | 13 x2d IV plus Cy 100x5d CI
data on file,Adria D 45x3d IV plus Cy 100x7d CI 2 courses D 45 x 2d IV plus Cy 100x5d Cl
Laboratories
SEG study: 230 1 12x3d IV plus Cy 100x7d CI 3 courses I 15 x1d IV plus
data on file, Cy 100 q12hx10 Cl plus
Adria Laboratories 6-TG 100 q12h x 10 PO
D 45x3d IV plus Cy 100x7d Cl 3 courses D 50x1d IV plus
Cy 100 q12h x10 Cl plus
6-TG 100 q12hx10 PO
Abbreviations:I = idarubicin; Cy = cytarabine;D =daunorubicin; IV = intravenous; IV bol = intravenous bolus; CI = continuous infusion; PO = oral; q = every; d = days; h = hours; 6-TG =6-thioguanine;MSKCC=Memorial Sloan-Kettering Cancer Center; SEG=Southeastern Cancer Study Group.
Percentage of patients
Fig.6. Incidence of adverse effects during the induction phase of a US study of patients with untreated AML receiving intravenous idarubicin 12 mg/m2 plus cytarabine 100 mg/m2 continuous infusion for 7 days (n =110) or intravenous daunorubicin 45 mg/m plus cytarabine 100 mg/m continuous infusion for 7 days (n =118) [data on file,Adria Labora-tories].
crease in the incidence and mean severity of in-fection; patients receiving idarubicin plus cytara-bine experiencing a higher rate of infection than daunorubicin plus cytarabine recipients(74 vs 55% incidence overall; 44 vs 29% grade 3 or 4 severity) [data on file, Adria Laboratories].
In the trials reviewed, deaths during induction of remission were almost all the result of sepsis. Bleeding secondary to bone marrow suppression had a similar incidence (64 vs 63%) and severity ('severe' in 15 vs 14%) in patients receiving ida-rubicin plus cytarabine versus daunorubicin plus cytarabine in the US studies (data on file,Adria Laboratories). The bone marrow suppression as-sociated withidarubicin was dose-proportional and did not appear to be cumulative, although the de-gree of suppression could be profound,especially at the higher doses (20 to 45 mg/㎡) used in patients with acute leukaemias (Salva-Martin & Wiernik 1990; Tan et al.1987).

Leucopenia was dose-limiting at a single intra-venous dose of 18 mg/m2 (Cavalli et al. 1982).
4.1.2 Oral Idarubicin
Leucopenia was also the main haematological toxicity in patients receiving oral idarubicin mono-therapy for solid tumours and was dose-limiting at a single dose of 50 to 60 mg/㎡2 (Cavalli et al.1982).
4.2 Gastrointestinal Effects
4.2.1 Intravenous Idarubicin
Nausea and vomiting occurred with equivalent frequency (85%) in patients with AML receiving idarubicin plus cytarabine or daunorubicin plus cy-tarabine in 3 US studies and was severe in 4 and 8% of patients, respectively. The incidence of mu-cositis in these studies was similar in patients re-ceiving both regimens (58 vs 56%),but there was a trend towards more severe episodes in patients
Idarubicin in Cancer:A Review
receiving idarubicin (13 vs 9%). During the con-solidation phase, both the incidence and severity of mucositis was higher in idarubicin recipients(32 vs 22% overall incidence, 3 vs 1% grade 3 or 4 se-verity).The incidence of diarrhoea was 63 and 61% in patients receiving idarubicin plus cytarabine or daunorubicin plus cytarabine, respectively, with a similar incidence of severe episodes (12 vs 14%) [data on file, Adria Laboratories].Patients receiv-ing intravenous idarubicin plus cytarabine experi-enced less extrahaematological toxicity than those taking zorubicine plus cytarabine (the best avail-able combination used against AML in France) and significantly more mucositis and nausea or vom-iting occurred in the latter group. The high com-plete response rate in patients over 50 years old receiving idarubicin in this study (77.3 vs 66.7% for idarubicin and zorubicine groups,respectively) could be related to the good tolerance of idarubicin in this age group (Harrouseau 1990).
Bonfante et al.(1986) reported a decreased in-cidence of vomiting in patients with breast cancer receiving intravenous rather than oral idarubicin monotherapy (26 vs 72%). Other gastrointestinal
ldarubicin +cytarabine
Daunorubicin+cytarabine

Fig. 7. Duration of neutropenia [white blood cells (WBC)< 1x109/L] and thrombocytopenia(platelets<50x109/L) in patients with acute myelogenous leukaemia following in-duction therapy(table VII) in 3 US studies:A=Memorial Sloan-Kettering Cancer Center Trial;B=US Multicenter Trial;C=Southwestern Cancer Study Group (data on file, Adria Laboratories).

711
effects were infrequent and there did not appear to be any significant difference in the incidence of these events between idarubicin plus cytarabine versus daunorubicin plus cytarabine recipients(data on file,Adria Laboratories).
4.2.2 Oral Idarubicin
Oral idarubicin appeared to be associated with a high incidence of severe diarrhoea in a study by Lowenthal et al. (1987), with 4 of 8 (50%) of patients receiving idarubicin 90 mg/m2 and 1 of 10(10%) of those receiving lower dose idarubicin (60 to 75 mg/㎡) experiencing this major adverse effect.A significantly lower incidenceof nausea and vom-iting was experienced by patients with breast can-cer receiving oral idarubicin compared with intra-venous doxorubicin monotherapy (86 vs 100%; Lopez et al. 1989).There was a significantly lower incidence of stomatitis in a group of breast cancer patients administered oral idarubicin monotherapy compared with a group receiving intravenous doxorubicin monotherapy (6 vs 53%,Lopez et al. 1989). Oral idarubicin induced a higher incidence of mucositis than intravenous idarubicin in a com-parative study (21 vs 11%; Bonfante et al. 1986).
4.3 Cardiac Effects
4.3.1 Intravenous Idarubicin
The use of anthracyclines is accompanied by the risk of acute and chronic cardiotoxicity,and patients should not receive cumulative doses of daunorubicin or doxorubicin exceeding 500 to 600 mg/㎡(Zbinden et al.1978).
Patients undergoing chemotherapy for malig-nancies may have received extensive prior expos-ure to anthracyclines, and are at high risk of sec-ondary complications such as sepsis and anaemia. The fluid overload that often occurs in these patients as a result of multiple transfusions, anti-biotic infusion and continuous infusion of chem-otherapeutic agents frequently results in symptoms of congestive heart failure. Thus, while it is ex-pected that idarubicin may display some cardio-toxicity, its frequency is difficult to assess.
There were no statistically significant differ-
ences in the incidence of cardiotoxicity between treatments during the induction phase of 3 large US studies of previously untreated patients with AML who received combination chemotherapy with idarubicin plus cytarabine or daunorubicin plus cytarabine. The incidence of death during in-duction was also similar in the 2 groups (data on file,Adria Laboratories).Mean changes from base-line in left ventricular ejection fraction(LVEF)and the number of patients experiencing a moderate to severe decrease in LVEF were not significantly dif-ferent between the 2 groups,although idarubicin-treated patients tended to have a lower incidence of clinically important changes in LVEF(11 vs 18% and 1 vs 3% of patients experienced a moderate or severe decrease in LVEF at cumulative doses of idarubicin up to greater than 150 mg/㎡2 and dau-norubicin up to greater than 600 mg/m2,respec-tively). A cumulative dose of idarubicin beyond which the incidence of cardiotoxicity rapidly in-creases has not been determined.Myocardial in-sufficiency and arrhythmias were usually reversible and occurred in the setțing of sepsis,anaemia and aggressive fluid accumulation.These events were reported more frequently in patients over 60 years of age and in those with pre-existing cardiac dis-ease (data on file,Adria Laboratories).
4.3.2 Oral Idarubicin
The reviewed studies of patients administered oral idarubicin as monotherapy or in combination regimens for breast cancer reported no episodes of clinical congestive heart failure, and decreases in LVEF and ECG changes were generally mild and reversible. In a comparative study of idarubicin versus doxorubicin in patients with pretreated (ex-cluding anthracyclines) advanced breast cancer,16% (2 severe cases) vs 0% of patients in the doxorub-icin and idarubicin groups, respectively,experi-enced clinical cardiotoxicity (Martoni et al. 1990). Further,congestive heart failure occurred in 11% in a similar patient population treated with doxo-rubicin versus none on idarubicin (Lopez et al. 1989).
Clinical data regarding cardiotoxicity in leu-kaemic and breast cancer patients are inconclusive.

Further long term studies are required to delineate the risk in such patients.
4.4 Other Effects
4.4.1 Intravenous Idarubicin
The incidenceof alopecia reported in the US studies of previously untreated patients with AML was similar in patients receiving idarubicin plus cytarabine or daunorubicin plus cytarabine (70% in each group;severe in 40 and 37%,respectively) [data on file,Adria Laboratories].
The incidence of grade 3 or 4(WHO equivalent grading criteria) changes in laboratory test vari-ables was not significantly different in patients re-ceiving idarubicin plus cytarabine or daunorubicin plus cytarabine in 3 US studies of patients with AML(severe changes in hepatic and renal function occurred in about 1 and 5% of patients receiving the idarubicin and daunorubicin combinations,re-spectively) [data on file, Adria Laboratories].
The incidence and severity of other adverse ef-fects expected with anthracycline plus cytarabine therapy (such as fever, neurotoxicity, anorexia, local skin reactions and other dermatological re-actions) were also similar for the idarubicin plus cytarabine and daunorubicin plus cytarabine com-binations in these studies (data on file,Adria La-boratories). There were no significant differences in the incidences of spontaneously reported ad-verse effects between the groups in 1 US study rep-resentative of other similar trials. However, it is difficult to ascertain whether the effects reported were caused by the therapy itself.
Rare toxicities seen in patients receiving ida-rubicin plus cytarabine included development of bullous erythrodermatous skin rash on the hands and feet of 2 patients (this was apparently similar to an effect seen with high dose cytarabine therapy). The rash healed without sequelae and did not recur with further administration of idarubicin. Intes-tinal perforation (in some cases related to instru-mentation) was also reported (data on file, Adria Laboratories).
4.4.2 Oral Idarubicin
In patients with breast cancer,alopecia occurred in up to 86% of patients administered oral idarub-icin monotherapy every 3 weeks compared with 54% receiving a weekly schedule (Bastholt&Dal-mark 1987; Bastholt et al. 1990). Oral idarubicin monotherapy induced a significantly lower inci-dence of alopecia than intravenous doxorubicin monotherapy in 2 comparative studies (31 vs 91%, Lopez et al. 1989;and 66 vs 95%, Martoni et al. 1990).
5. Dosage and Administration
Various treatment schedules for idarubicin alone and in combination with other cytotoxic drugs have been used in clinical trials (tables II to VII). How-ever,the only currently recommended regimen is that employed in the US,consisting of idarubicin 12 mg/m2 daily for 3 days by slow (10- to 15-min-ute) intravenous injection, in combination with cy-tarabine 100 mg/㎡2 daily by continuous infusion for 7 days or cytarabine 25 mg/m2 intravenous bolus followed by 200 mg/m2 daily for 5 days con-tinuous infusion, as induction therapy for adults with AML.[Idarubicin 8 mg/m2 for 5 days has been used successfully in combination with cytarabine 100 mg/m2 for 7 days in elderly patients(Reiffers et al. 1991)]. A second course may be administered in patients with definite evidence of leukaemia after the first course. A 25% dose reduction of idarubicin is recommended for the second course if the patient has experienced severe mucositis. Dose reduction should be considered in patients with hepatic im-pairment, but possibly not in those with renal impairment. Recommended schedules are unavail-able for the use of idarubicin in consolidation reg-imens but 2 different consolidation regimens have been administered in US studies of patients with AML (see table VII for dosages used) [data on file, Adria Laboratories]. The safety and effectiveness of idarubicin in children has not been established, although some studies have included children who were administered the same idarubicin regimen as adults (Giona et al. 1990; Petti & Mandelli 1989).

Cardiac function should be monitored during treatment, and regular blood counts and hepatic and renal function tests should be performed.Dose reduction of idarubicin should be considered if the bilirubin level is above the normal range and per-haps if creatinine is markedly raised.
Idarubicin should not be administered to patients with pre-existing bone marrow suppres-sion,heart disease or those who have received high cumulative doses of anthracycline or other poten-tially cardiotoxic drugs, unless the benefit warrants the risk of idarubicin therapy in these patients(data on file, Adria Laboratories).
Idarubicin has been administered as an oral preparation predominantly in patients with breast cancer(see section 3),but results are limited and dosage guidelines are presently unavailable.
6. Place of Idarubicin in Therapy
Anthracycline research has been directed to-wards development of analogues which have greater antitumour efficacy,especially against tumours re sistant to the parent drug (i.e. non-cross-resistant), cause less cardiotoxicity and can be administered orally.
Overall,the high intravenous efficacy of the daunorubicin analogue, idarubicin, has been dem-onstrated when administered as a component of induction and salvage regimens for patients with acute myelogenous leukaemia. The combination of idarubicin plus cytarabine appears to be superior to similar regimens containing daunorubicin. However,long term comparative, prospective trials are required to continue investigations into the oc-currence of cardiotoxicity, implications for im-proved quality of life, survival, and the role of ida-rubicin as a component of consolidation and maintenance regimens.
There is also a need to compare standard regi-mens with those including idarubicin as first or second line therapy for patients with advanced breast cancer. Idarubicin may also be useful in patients with acute lymphocytic leukaemia,mul-tiple myeloma or non-Hodgkin's lymphoma if
wider clinical experience substantiates preliminary findings.
The tolerability profile of intravenous idarubi-cin appears similar to that of daunorubicin at an equiactive dose,and some studies of oral idarub-icin monotherapy in patients have reported a sig-nificantly lower incidence of alopecia compared with intravenous doxorubicin. In animal studies, idarubicin was less cardiotoxic than daunorubicin or doxorubicin. While clinical studies have not clearly demonstrated such an advantage, prelimi-nary indications point to a similar conclusion.
Of particular interest is the oral activity of ida-rubicin, unlike daunorubicin and doxorubicin. Ida-rubicin may prove to have an advantage over these other agents in selected cases such as patients un-able to tolerate parenteral administration, and for long term therapy. However,this route of admin-istration is still under development and,because of unpredictable bioavailability,patients receiving oral idarubicin must be carefully monitored.
Thus, intravenous idarubicin has established a role in the treatment of patients with acute mye-logenous leukaemia (particularly in combination with cytarabine),where it provides an effective al-ternative to other anthracyclines. It may also have potential in patients with other acute leukaemias or advanced breast cancer. Importantly, if prelim-inary indications are confirmed, idarubicin may also be associated with reduced cardiotoxicity, a potentially important advantage. Further long term, well controlled studies are required to establish the role of idarubicin as a cytotoxic chemotherapeutic agent in these indications.
References
Abad-Esteve A,Diaz-Rubio E,Jimeno JM,Rosell R,Villar A,et al. Oral idarubicin in measurable gastric cancer.American Journal of Clinical Oncology 12:14-16,1989
Arcamone F,Bernardi L,Giardino P,Patelli B,Di Marco A,et al.Synthesis and antitumor activity of 4-demethoxydaunorub-icin,4-demethoxy-7,9-diepidaunorubicin, and their β anom-ers.Cancer Treatment Reports 60:829-834,1976
Arcamone F,Bernardi L,Patelli B,Giardino P,Di Marco A,et al.Synthesis and antitumour activity of new daunorubicin and adriamycin analogues. Experientia 34:1255-1257,1978
Ardizzoni A,Pennucci C,Fusco V,Gulisano M,Bonavia M,et al.Oral chemotherapy for poor risk small-cell lung cancer patients with combined idarubicin and etoposide.Anticancer Research 9:937-940,1989

Ardizzoni A,Pronzato P,Repetto L,De Palma M,Canobbio L, et al.Phase II trial of oral idarubicin in advanced non-small cell lung cancer(NSCLC).Cancer Investigation 6:409-411,1988 Arlandini E,Vigevani A,Arcamone F.Interaction of new deriv-atives of daunorubicin and adriamycin with DNA.Farmaco-Edizione Scientifica 32:315-323,1977
Arlin ZA,Sklaroff RB,Gee TS,Kempin SJ,Howard J,et al. Phase I and II trial of4'-(9-acridinylamino)methanesulfon-m-anisidide in patients with acute leukaemia.Cancer Research 40:3304-3306,1980
Avvisati G,Mandelli F,Petti MC,Vegna ML,Spadea A, et al. Idarubicin(4-demethoxydaunorubicin) as single agent for re-mission induction of previously untreated acute promyelocytic leukemia: a pilot study of the Italian Cooperative Group GIMEMA.European Journal of Haematology 44:257-260,1990 Bachur NR,Gordon SL,Gee MV.Anthracycline antibiotic aug-mentation of microsomal electran transport and free radical formation.Molecular Pharmacology 13:901-910,1977
Bachur NR,Gordon SL,Gee MV.A general mechanism for mi-crosomal activation of quinone anticancer agents to free rad-icals.Cancer Research 38:1745-1750,1978
Bandini G,Comotti B,Scapoli G,Leoni F,Di Prisco U,et al. Effect of 4-demethoxydaunorubicin (4-DMDR) in chronic myeloid leukemia in blastic transformation and relapsed acute leukemias.Haematologica 70:155-159,1985
Banning JW,Abramson HN,Wormser HC,Wu J,Corbett TH. Relative cardiotoxicity and cytotoxicity of anthraquinonyl glu-cosaminosides.Cancer Chemotherapy and Pharmacology 19: 207-212,1987
Barbieri B,Casazza AM,Penco S,Cassinelli G,Podestà A. Biol-ogic activity of 13-OH anthracyclines in K.H.Spitzy and K. Karrer (Eds) 13th International Congress on Chemotherapy, Vienna,August 28 to September 2,1983.Proceedings.Ab-stract PS 12.4 8-6 in part 285,p.22
Barlogie B,Drewinko B,Johnston DA,Freireich EJ.The effect of adriamycin on the cell cycle traverse of a human lymphoid cell line.Cancer Research 36:1975,1981
Bastholt L,Dalmark M.Phase II study of idarubicin given orally in the treatment of anthracycline-naive advanced breast cancer patients.Cancer Treatment Reports 71:451-454,1987
Bastholt L,Dalmark M,Jakobsen A,Gadeberg CC,Sandberg E, et al.Weekly oral idarubicin in postmenopausal women with advanced breast cancer.A phase II study.Acta Oncologica 29: 143-146,1990
Battista R,D'Emilio A,Vespignani M,Pacciarini MA,Dini E. Preliminary observations on intravenous idarubicin(4-deme-thoxydaunorubicin) in the chronic and accelerated phase of chronic myelogenous leukemia.Tumori 72:389-393,1986
Berens ME,Saito T,Welander CE,Modest EJ.Antitumour ac-tivity of new anthracycline analogues in combination with in-terferon alfa.Cancer Chemotherapy and Pharmacology 19:301-306,1987
Berman E,Heller G,Santorsa JA,McKenzie S,Gee T,et al.Re-sults of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubucin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leu-kemia.Blood 77:1666-1674,1991
Berman E,Raymond V,Daghestani A,Arlin ZA,Gee TS,et al. 4-Demethoxydaunorubicin (idarubicin) in combination with 1-β-D-arabinofuranosylcytosine in the treatment of relapsed or refractory acute leukemia.Cancer Research 49:477-481,1989a Berman E,Raymond V,Gee T,Kempin SJ,Gulati S,et al.Ida-
rubicin in acute leukemia: results of studies at Memorial Sloan-
Kettering Cancer Center.Seminars in Oncology 16:30-34,1989b
Berman E,Wittes RE,Leyland-Jones B,Casper ES,Gralla RJ,et al.Phase I and clinical pharmacology studies of intravenous and oral administration of 4-demethoxydaunorubicin in patients with advanced cancer.Cancer Research 43:6096-6101,1983 Bezwoda WR, Dansey RD. Idarubicin plus cytarabine versus
Idarubicin in Cancer:A Review
doxorubicin plus cytarabine in induction therapy for acute non-lymphoid leukaemia:a randomized trial.Leukemia and Lym-phoma 1:221-225,190
Bonfante V,Ferrari L,Brambilla C,Rossi A,Villani F,et al.New anthracycline analogs in advanced breast cancer.European
Journal of Cancer and Clinical Oncology 22:1379-1385,1986 Brodie GN,Elefanty A.Breast cancer.Advances in management. Drugs 35:584-595,1988
Broggini M,Italia C,Colombo T,Marmonti L,Donelli MG.Ac-tivity and distribution of IV and oral 4-demethoxydaunorub-icin in murine experimental tumors.Cancer Treatment Re-ports 68:739-747,1984
Bruzzone M,Chiara S,Falcone A,Graziani G,Conte PF,et al. 4-Demethoxydaunorubicin(IMI-30) in refractory epithelial ovarian cancer: a pilot study.Chemioterapia 6:137-139,1987 Cairo MS,Toy C,Sender L,van de Ven C. Effect of idarubicin
and epirubicin on in vitro polymorphonuclear function:di-minished superoxide radical formation compared to their par-ent compounds daunorubicin and doxorubicin.Journal of Leukocyte Biology 47:224-233,1990
Capnist G,Chisesi T. Etoposide plus idarubicin and prednisone in refractory or relapsed multiple myeloma. A phase II study. Correspondence.Haematologica 73:431-432,1988
Capranico G,Riva A,Tinelli S,Dasdia T,Zunino F.Markedly reduced levels of anthracycline-induced DNA strand breaks in resistant P388 leukemia cells and isolated nuclei.Cancer Re-search 47:3752-3756,1987
Carella AM,Berman E,MIaraone MP,Ganzina F.Idarubicin in the treatment of acute leukemias. An overview of preclinical and clinical studies.Haematologica 75:1-11,1990a
Carella AM,Gaozza E,Piatti G,Nati S,et al.A new combination of idarubicin,etoposide and cytarabine in untreated acute non lymphoblastic leukemia.Leukemia and Lymphoma 2:317-322, 1990b
Carella AM,Gaozza E,Raffo MR,Carlier P,Frassoni F,et al. Therapy of acute phase chronic myelogenous leukemia with intensive chemotherapy,blood cell autotransplant and cyclo-sporine A.Leukemia 5:517-521,1991
Carella AM,Pungolino E,Piatti G,Gaozza E,Nati S, et al.Ida-rubicin in combination with intermediate-dose cytarabine in the treatment of refractory or relapsed acute leukemias.Euro-pean Journal of Haematology 43:309-313,1989
Carella AM,Santini G,Martinengo M,Giordano D,Nati S,et al.4-Demethoxydaunorubicin(idarubicin) in refractory or re-lapsed acute leukemias.A pilot study.Cancer 55:1452-1454, 1985
Casazza AM.Experimental evaluation of anthracycline analogs. Cancer Treatment Reports 63:835-844,1979.
Casazza AM,Barbieri B,Fumagalli A,Geroni MC.Biologic ac-tivity of 4-demethoxy-13-dihydrodaunorubicin (4-dm-13-OH-DNR).Abstract 991.Proceedings American Association for Cancer Research 24:251,1983
Casazza AM,Di Marco A,Bonadonna G,Bonfante V,Bertazzoli C,et al. Effects of modifications in position 4 of the chromo-phore or in position 4' of the aminosugar, on the antitumor activity and toxicity of daunorubicin and doxorubicin.In Crook ST,Reich SD(Eds) Anthracyclines-current status and new developments pp.403-430,Academic Press,New York,1980 Case Jr DC,Hayes DM,Gerber M,Gams R,Ervin TJ,et al.
Phase II study of oral idarubicin in favorable histology non-Hodgkin's lymphoma.Cancer Research 50:6833-6835,1990
Casper ES,Raymond V,Hakes TB,Currie VE,Kaufman RJ. Phase II evaluation of orally administered idarubicin in patients with advanced breast cancer.Cancer Treatment Reports 71: 1289-1290,1987
Cavalli F,Kaplan S,Varini M,Togni P,Martini A.Phase-I trial with 4-demethoxydaunorubicin.In Muggia F, et al. (Eds) An-thracycline antibiotics in cancer therapy,pp.495-503,Mar-tinus Nijihoff,The Hague,1982

715
Cavanna L,DiStasi M,Fornari F,Civardi G,Sbolli G,et al. Idarubicin plus attenuated high-dose cytosine arabinoside in the treatment of relapsed and refractory acute leukemia.Cor-respondence.European Journal of Haematology 45:180-187, 1990
Chachoua A,Green M,Laubenstein L,Wernz J,Muggia FM. Phase II study of oral idarubicin in patients with AIDS-asso-ciated Kaposi's sarcoma.Cancer Treatment Reports 71:775-776,1987
Champlin R,Gale RP.Acute myelogenous leukemia:recent ad-vances in therapy.Blood 69:1551-1562,1987
Chevallier B,Monnier A,Metz R,Namer M,Marty M,et al. Phase II study of oral idarubicin in elderly patients with ad-vanced breast cancer.American Journal of Clinical Oncology 13:436-439,1990
Chisesi T,Capnist G,De Dominicis E,Dini E.A phase II study of idarubicin (4-demethoxydaunorubicin) in advanced mye-loma.European Journal of Cancer and Clinical Oncology 24: 681-684,1988
Coates A.Current status of chemotherapy of breast cancer.Drugs 28:93-98,1984
Coonley CJ,Warrell Jr RP,Straus DJ,Young CW.Clinical eval-uation of 4-demethoxydaunorubicin in patients with advanced malignant lymphoma.Cancer Treatment Reports 67:949-950, 1983
Cummings J,Milroy R,Banham SW,Kaye SB.Method for the determination of 4-demethoxydaunorubicin, its quinone and hydroquinone metabolites in human plasma and urine by high-performance liquid chromatography.Cancer Chemotherapy and Pharmacology 19:296-300,1987
Daghestani AN,Arlin ZA,Leyland-Jones B,Gee TS,Kempin SJ, et al.Phase I and II clinical and pharmacological study of 4-demethoxydaunorubicin(idarubicin) in adult patients with acute leukemia.Cancer Research 45:1408-1412,1985
Davis CL,Rohatiner AZS,Amess JAL,Lister TA.Oral idarub-icin as a palliative agent in leukemia.Hematological Oncology 9:59-62,1991
De Lena M,Brandi M,Bozzi D,Calabrese P,Romito S.4-De-methoxydaunorubicin administered orally in advanced breast cancer.A phase II study.Tumori 74:65-70,1988
Di Marco A.Adriamycin (NSC-123127): mode and mechanism of action.Cancer Chemotherapy Reports 6:91-106,1975
Di Marco A,Casazza AM,Pratesi G. Antitumor activity of 4-demethoxydaunorubicin administered orally.Cancer Treat-ment Reports 61:893-894,1977
Di Marco A,Zunino F,Casazza AM.Comparison of biochemical and biological methods in the evaluation of new anthracycline drugs.Antibiotic Chemotherapy 23:12-20,1978
Dodion P,Sanders C,Rombaut W,Mattelaer MA,Rozencweig M,et al.Effect of daunorubicin,carminomycin,idarubicin and 4-demethoxydaunorubicinol against human normal myeloid stem cells and human malignant cells in vitro.European Jour-nal of Cancer and Clinical Oncology 23:1909-1914,1987
Dufour P,Herbrecht B,Hurteloup P,Maloisel F,Duclos t al.Idarubicin (Ida) and high dose cytosine arabinoside(Ara C) as salvage therapy for non Hodgkin lymphoma(NHL):fea-sibility study and preliminary results. Abstract P-0392.Euro-pean Conference on Clinical Oncology,London,3-7 Septem-ber 1988
Einzig A,Kelsen D,Cheng E,Sordillo P,Raymond V,et al.Phase II study of 4-demethoxydaunorubicin in patients with adeno-carcinoma of the upper gastrointestinal tract.Cancer Treat-ment Reports 68:1415-1416,1984
Eksborg S,Soderberg M,Nilsson B,Antila K.Plasma phar-macokinetics of idarubicin and its 13-hydroxymetabolite after intravenous and oral administration under fasting and non-fasting conditions.Acta Oncologica 29:921-925,1990
Elbaek K,Ebbehøj E,Jakobsen A,Juul P,Rasmussen SN,et al. Pharmacokinetics of oral idarubicin in breast cancer patients
with reference to antitumor activity and side effects.Clinical Pharmacology and Therapeutics 45:627-634,1989
Eridani S,Slater NGP,Singh AK,Pearson TC.Intravenous and oral demethoxydaunorubicin (NSC 256-439) in the treatment of acute leukemia and lymphoma:a pilot study. Blut 50:369-372,1985
Errante D,Sorio R,Zagonel V,Carbone A,Monfardini S,et al. A phase II study of oral idarubicin(4-demethoxidaunorubicin) in previously untreated elderly patients with non-Hodgkin's lymphoma.American Journal of Clinical Oncology-Cancer Clinical Trials 14:243-245,1991
Ettinger DS,Finkelstein DM,Donehower RC,Chang AYC,Green M,et al.Phase II study of N-methylformamide,spirogerman-ium, and 4-demethoxydaunorubicin in the treatment of non-small cell lung cancer (EST 3583): an Eastern Cooperative On-cology Group study.Medical and Pediatric Oncology 17:197-201,1989
Fields SM,Koeller JM.Idarubicin:a second-generation anthra-
cycline.DICP:Annals of Pharmacotherapy 25:505-517,1991 Formelli F,Casazza AM,Di Marco A,Mariani A,Pollini C.Fluo-rescence assay of tissue distribution of 4-demethoxydaunorub-icin and 4-demethoxydoxorubicin in mice bearing solid tu-mors.Cancer Chemotherapy and Pharmacology 3:261-269, 1979
Fülle HH,Hellriegel KP.Idarubicin in refractory acute leukemia. Onkologie 9:152-153,1986
Ganzina F,Pacciarini MA,Di Pietro N.Idarubicin(4-deme-thoxydaunorubicin):a preliminary overview of preclinical and clinical studies. Investigational New Drugs 4:85-105,1986
Gillies HC,Herriott D,Liang R,Ohashi K,Rogers HJ,et al. Pharmacokinetics of idarubicin(4-demethoxydaunorubicin; IMI-30;NSC 256439)following intravenous and oral admin-istration in patients with advanced cancer. British Journal of Clinical Pharmacology 23:303-310,1987
Gillies H,Liang R,Rogers H,Harper P,Parapia L,et al.Phase II trial of idarubicin in patients with advanced lymphoma. Cancer Chemotherapy and Pharmacology 21:261-264,1988 Giona F,Testi AM,Amadori S,Meloni G,Carotenuto M,et al.
Idarubicin and high-dose cytarabine in the treatment of re-fractory and relapsed acute lymphoblastic leukemia.Annals of Oncology 1:51-55,1990
Giuliani FC,Kaplan NO.The use of athymic mice in the screen-ing of new anthracycline derivatives. In Sordat B.(Ed.)Im-mune-deficient animals,pp.374-378,Karger,Basel,Switzer-land,1984
Glisson BS,Ross WE.DNA topoisomerase II: a primer on the enzyme and its unique role as a multidrug target in cancer chemotherapy.Pharmacology and Therapeutics 32:69-106, 1987
Grankvist K, Stendahl U,Henriksson R. Comparative study of demethoxydaunorubicin with other anthracyclines on gener-ation of oxygen radicals and clonogenic survival of fibroblasts. Pharmacology and Toxicology 65:40-44,1989
Hakes TB,Dahgestani AN,Dougherty JB,Weiselberg L,Ray-mond V.Phase II study of 4-demethoxydaunorubicin in ad-vanced ovarian carcinoma.Cancer Treatment Reports 69:559-560,1985
Hakes TB,Dougherty JB,Raymond V.Phase II study of ida-rubicin in advanced cervical carcinoma.American Journal of Clinical Oncology 9:262-263,1986
Hakes TB,Raymond V.Phase II study of idarubicin in advanced endometrial carcinoma.Cancer Treatment Reports 71:535-536,1987
Harousseau JL.The French experience,Goelam Data.Abstract. Present and future in treatment of AML.Satellite Symposium in conjunction with the ISH-ASH Meeting,November 28-De-cember 4,1990
Harousseau JL,Hurteloup P,Reiffers J,Rigal-Huguet F,Hayat M.Idarubicin in the treatment of relapsed or refractory acute

myeloid leukemia.Correspondence.Cancer Treatment Re-ports 71:991-992,1987
Harousseau JL,Reiffers J,Hurteloup P,Milpied N,Guy H,et al.Treatment of relapsed acute myeloid leukemia with ida-rubicin and intermediate-dose cytarabine.Journal of Clinical Oncology 7:45-49,1989a
Harousseau JL,Rigal-Huguet F,Hurteloup P,Guy H,Milipied N,et al.Treatment of acute myeloid leukemia in elderly patients with oral idarubicin as a single agent. European Journal of Haematology 42:182-185,1989b
Harper HD,Kemeny NE,Ahmed T,Cheng E,Arena F,et al. Phase II trial of 4-demethoxydaunorubicin in advanced colo-rectal carcinoma.Cancer Treatment Reports 68:689-690,1984 Hayat M,Hurteloup P,Parmentier C,Carde P,Pico JO,et al. Phase I trial of idarubicin(4-demethoxydaunorubicin) in adult
acute leukemia.Investigational New Drugs 2:375-379,1984 Hayward JL,Carbone PP,Heuson J-C,Kumaoka S,Segaloff A, et al. Assessment of response to therapy in advanced breast cancer.European Journal of Cancer 18:89-94,1977
Helg C,Chapuis B,Grob J-Ph,Pugin P.Leucémies myéloides aigues de mauvais pronostic:traitement par 4-démethoxydau-norubicine (idarubicine) per os et cytarabine à doses réduites par voie sous-cutanée.Schweizerische Medizinische Wochen-schrift 120:548-552,1990
Henderson IC,Allegra JC,Woodcock T,Wolff S,Bryan S,et al. Randomized clinical trial comparing mitoxantrone with dox-orubicin in previously treated patients with metastatic cancer. Journal of Clinical Oncology 7:560-571,1989
Henney JE,DeVita VT.Breast cancer. In Braunwald et al.(Eds) Harrison's principles of internal medicine,11th ed.,Vol.2,pp. 1567-1574,McGraw-Hill,New York,1987
Hochster HS,Green MD,Blum RH,Wernz JC,Speyer JL,et al. Oral 4-demethoxydaunorubicin (idarubicin) in bronchogenic lung cancer:phase II trial.Investigational New Drugs 4:275-278,1986
Hurteloup P,Armand JP,Schneider M,Bastit P,Chevallier B, et al. Phase II trial of idarubicin(4-demethoxydaunorubicin) in advanced breast cancer.European Journal of Cancer and Clinical Oncology 25:423-428,1989
Johnson E,Parapia LA.Successful oral chemotherapy with ida-rubicin in refractory anaemia with excess blasts.European Journal of Haematology 39:278-281,1987
Joss RA,Obrecht J-P,Alberto P,Siegenthaler P,VanHelvoirt A, et al.Phase II trial of 4-demethoxydaunorubicin in patients with non-small cell lung cancer.Cancer Treatment Reports 68: 563-564,1984
Kaplan S,Martini A,Varini M,Togni P,Cavalli F.Phase I trial of 4-demethoxydaunorubicin with single i.v.doses.European Journal of Cancer and Clinical Oncology 18:1303-1306,1982 Kaplan S,Sessa C,Willems Y,Pacciarini MA,Tamassia V,et al.
Phase I trial of 4-demethoxydaunorubicin(idarubicin)with single oral doses.Investigational New Drugs 2:281-286,1984 Kavanagh JJ,Copeland LJ,Gershenson DM,Saul PB,Edwards CL.A phase II trial of 4-demethoxydaunorubicin in refractory
epithelial ovarian cancer.Gynecologic Oncology 24:23-26,1986 Kolarić K,Mechl Z, Potrebica V,Šopkova B. Phase II study of
oral 4-demethoxydaunorubicin in previously treated (except anthracyclines) metastatic breast cancer patients.Oncology 44: 82-86,1987
Kolaric K,Mechl Z. Combination of idarubicin and cyclophos-phamide administered orally in untreated postmenopausal breast cancer patients.A phase II study. Oncology 48:93-96, 1991
Kolaric K,Potrebica V,Vukas D,Mechl Z,Sopkova B.Com-bination chemotherapy with 5-flourouracil,oral idarubicin,and cyclophosphamide(FIC) in metastatic breast cancer: an open phase II study.Journal of Cancer Research and Clinical On-cology 114:301-305,1988
Krarup-Hansen A,Andersen E,Elbaek K,Rasmussen SN,Dal-
Idarubicin in Cancer:A Review
mark M. Phase I study of 4-demethoxydaunorubicin by oral route in patients with advanced cancer. Acta Oncologica 27: 521-525,1988
Kris MG,Gralla RJ,Kelsen DP,Casper ES,Burke MT,et al. Phase II trial of oral 4-demethoxydaunorubicin in patients with non-small cell lunger cancer.American Journal of Clinical Oncology-Cancer Clinical Trials 8:377-379,1985
Lambertenghi-Deliliers G,Maiolo AT,Annaloro C,Cortelezzi A, Pogliani E,et al. Idarubicin in sequential combination with cytosine arabinoside in the treatment of relapsed and refrac-tory patients with acute non-lymphoblastic leukemia.Euro-pean Journal of Cancer and Clinical Oncology 23:1041-1045, 1987
Lambertenghi-Deliliers G,Pogliani E,Maiolo AT,Pacciarini MA,
Polli EE.Therapeutic activity of 4-demethoxydaunorubicin (idarubicin) in adult acute leukemia. Tumori 69: 515-519,1983 Lambertenghi-Deliliers G,Annaloro C,Cortelezzi A,Cortellaro
M,Della Volpe A, et al. Idarubicin plus cytarabine as first-line treatment of acute nonlymphoblastic leukemia.Seminars in Oncology 16(Suppl.2):16-20,1989
Lazzarino G,Viola AR,Mulieri L,Rotilio G,Mayelli I.Preven-tion by fructose-1,6-biphosphate of cardiac oxidative damage induced in mice by subchronic doxorubicin treatment.Cancer Research 47:6511-6516,1987
Leone G,Pagano L,Marra R,Di Pietro N,Storti S,et al.lda rubicin combined with intermediate-dose cytose arabinoside in the treatment of refractory acute leukemia.Haematologica 74:57-61,1989
Lionetto R,Pronzato P,Conte PF,Sertoli MR,Amoroso D,et al.Idarubicin in advanced breast cancer.a phase II study.Can-cer Treatment Reports 70:1439-1440,1986
Lopez M,Contegiacomo A,Vivi P,Dello Ioio C,Di Lauro L,et al.A prospective randomized trial of doxorubicin versus ida-rubicin in the treatment of advanced breast cancer.Cancer 64: 2431-2436,1989
Lopez M,Di Lauro L,Papaldo P.Oral idarubicin in non-Hodg-kin's lymphomas.Investigational New Drugs 4:263-267,1 Lopez M,Di Lauro L,Papaldo P,Ganzina F,Di Pietro N,et al.
Phase II evaluation of oral idarubicin(4-demethoxydaunorub-icin) in patients with disseminated malignant melanoma.Can-cer Treatment Reports 70:911-912,1986c
Lopez M,Di Lauro L,Papaldo P,Lazzaro B,Ganzina F,et al. Phase II trial with oral idarubicin in advanced breast cancer. Investigational New Drugs 4:39-42,1986b
Lopez M,Vici P,Carpano S,Natali M,Ganzina F, et al.Com-bination chemotherapy with oral idarubicin and cyclophos-phamide for metastatic breast cancer.Journal of Cancer e search and Clinical Oncology 117:61-64,1991
Lowenthal RM,Chesterman CN,Griffiths JD,Manoharan A, Harris MG,et al Oral idarubicin as single-agent treatment of acute nonlymphocytic leukemia in poor-risk patients.Cancer Treatment Reports 71:1279-1281,1987
Lowenthal RM,Lambertenghi-Deliliers G.Oral idarubicin as treatment for advanced myelodysplastic syndrome.Abstract. Australian and New Zealand Journal of Medicine 20(Suppl): 420,1990
Lowenthal RM,Lambertenghi-Deliliers G. Oral idarubicin as treatment for advanced myelodysplastic syndrome.Haema-tologica,in press,1991
Lown JW,Chen H-H,Plambeck JA. Diminished superoxide an-ion generation by reduced 5-iminodaunorubicin relative to daunorubicin and the relationship to cardiotoxicity of the an-thracycline antitumor agents.Biochemical Pharmacology 28: 2563-2568,1979
Lu K,Savaraj N,Kavanagh J,Feun LG,Burgess M,et al.Clinial pharmacologyof 4-demethoxydaunorubicin(DMDR).Cancer Chemotherapy and Pharmacology17:143-148,1986
MacCormick R.Hirsch G,Gupta S,Shannon P,Rotstein L.A

717
phase II study of idarubicin in the treatment of measurable gastric cancer.Cancer 67:2988-2989,1991
Madon E,Grazia G,De Bernardi B,Comelli A,Carli M,et al. Phase II study of idarubicin administered IV to pediatric patients with acute lymphoblastic leukemia.Cancer Treatment Reports 71:855-856,1987
Madsen EL,Andersson M,Mouridsen HT,Pedersen D,Over gaard M,et al.A randomized study of CAF+TAM(tamoxifen) versus CMF+TAM in disseminated breast cancer.Abstract. 5th Breast Cancer Working Conference,Leuven,Sept 3-6,1991
Malik STA,Tucker J,Rohatiner AZS,Brace W,Lister TA.Oral idarubicin in the treatment of acute myelogenous leukaemia and the blast phase of chronic myeloid leukaemia.Hemato-logical Oncology 7:423-427,1989
Mandelli F,Petti MC,Ardia A,Di Pietro N,Di Raimondo F.A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia.European Journal of Cancer 27:750-755, 1991
Mandelli F,Testi AM,Spiriti MAA,Giona F,Meloni G,et al. Evaluation of a polychemotherapeutic regimen including ida-rubicin(4-demethoxydaunorubicin)in relapsed acute lympho-cytic leukemia.Haematologica 71:34-38,1986
Marcellino LR,Bizzarri M.Mitoxantrone in advanced breast cancer refractory to previous chemotherapeutic treatment.Ab-stract.6th Mediterranean Congress of Chemotherapy,Italy,p. 26,1988
Martoni A,Pacciarini MA,Pannuti F.Activity of 4-demethoxy-daunorubicin by the oral route in advanced breast cancer. European Journal of Cancer and Clinical Oncology 21:803-806,1985
Martoni A,Pacciarini MA,Piana E,Pannuti F.A pilot study of oral idarubicin in metastatic melanoma.Chemioterapia 5:414-415,1986
Martoni A,Piana E,Guaraldi M,Cilenti G,Farris A,et al.Com-parative phase II study of idarubicin versus doxorubicin in advanced breast cancer.Oncology 47:427-432,1990
Massa G,Bogliolo G,D'Amore F,Muzzulini C,Ghio R,Pan-nacciulli I.Hematopoietic precursor cells in mice treated with 4-demethoxydaunorubicin and doxorubicin.Journal of the National Cancer Institute 68:971-976,1982
Mechl Z,Šopkova B,Nemec J,Toth S, Nekulova M.Idarubicin and dibromodulcitol in the therapy of advanced breast cancer. International Journal of Experimental and Clinical Chemo-therapy 2:47-50,1989
Milroy R,Cummings J,Kaye SB,Banham SW.Phase II clinical and pharmacological study of oral 4-demethoxydaunorubicin in advanced non-pretreated small cell lung cancer.Cancer Chemotherapy and Pharmacology 20:75-77,1987
Mittelman A,Magill GB,Raymond V,Sternberg CN,Cheng EW, et al. Phase II trial of idarubicin in patients with pancreatic cancer.Cancer Treatment Reports 71:657-658,1987
Moro E,Bellotti V,Jannuzzo MG,Stegnjaich S,Valzelli G.High-performance liquid chromatographic method for pharmco-kinetic studies on the new anthracycline 4-demethoxydauno-rubicin and its 13-dihydro derivative.Journal of Chromato-graphy 274:281-287,1983
Muggia FM,Carter SK.Malignant diseases.In Speight TM(Ed.) Avery's drug treatment: principles and practice of clinical pharmacology and therapeutics, 3rd ed., pp.1023-1077,Adis Press,New Zealand,1987
Neidhart JA,Gochnour D,Roach R,Hoth D,Young D.A com-parison of mitoxantrone and doxorubicin in breast cancer. Journal of Clinical Oncology 4:672-677,1986
Neidle S. A hypothesis concerning possible new derivatives of a daunorubicin and adriamycin with enhanced DNA-binding properties.Cancer Treatment Reports 61:928-929,1977
Pannuti F,Camaggi CM,Strocchi E,Comparsi R,Angelelli B,et
al.Low dose oral administration of 4-demethoxydaunorubicin
(idarubicin) in advanced cancer patients.Cancer Chemother-apy and Pharmacology 16:295-299,1986
Papaldo P,Di Lauro L,Carpano S,Vici P,Balice A,et al.Oral idarubicin plus cyclophosphamide in metastatic breast cancer. Abstract 218.Cancer Immunology and Immunotherapy 23 (Suppl.):A55,1986
Penco S,Casazza AM,Franchi G,Barbieri B,Bellini O,et al. Synthesis,antitumor activity,and cardiac toxicity of new 4-demethoxyanthracyclines.Cancer Treatment Reports 67:665-673,1983
Petti MC,Mandelli F.Idarubicin in acute leukemias:experience of the Italian Cooperative Group GIMEMA.Seminars in On-cology 16(Suppl.2):10-15,1989
Pizzorno G,Trave F,Mazzoni A,Russello O,Nicolin A.Con-temporary detection of 4-demethoxydaunorubicin and its me-tabolites 13-dihydro-4-demethoxydaunorubicin and 4-deme-thoxydaunorubicinone by reverse phase high-performance liquid chromatography.Journal of Liquid Chromatography 8:2557-2566,1985
Plumbridge TW,Brown JR.Studies on the mode of interaction of 4'-epi-adriamycin and 4-demethoxy-daunomycin with DNA. Biochemical Pharmacology 27:1881-1882,1978
Presgrave P,Woods R,Dalley D,Bell D,Levi J.A phase II trial of oral 4'demethoxydaunorubicin in advanced colorectal car-cinoma.American Journal of Clinical Oncology 11:564-565, 1988a
Presgrave P.Woods P,Kefford R,Bell D,Raghavan D,et al.A phase II trial of oral 4'demethoxydaunorubicin(DMDR)in inoperable non small cell lung cancer.Investigational New Drugs 6:219-221,1988b
Reid JM,Pendergrass TW,Krailo MD,Hammond GD,Ames MM.Plasma pharmacokinetics and cerebrospinal fluid con-centrations of idarubicin and idarubicinol in pediatric leuke-mia patients: a childrens cancer study group report.Cancer Research 50:6525-6528,1990
Reiffers J,Stoppa AM,Rigal-Huguet F,Michallet M,Marit G, et al. Age as an adverse prognostic factor for acute myeloid leukemia:the experience of the BGMT group.Abstract.20th Annual Meeting of the International Society for Experimental Hematology(ISEH),Parma,Jul 21-25,1991
Robert J,Rigal-Huguet F,Harousseau JL,Pris J,Huet S, et al. Pharmacokinetics of idarubicin after daily intravenous admin-istration in leukemic patients. Leukemia Research 11:961-964, 1987
Rose KM.DNA topoisomerases as targets for chemotherapy. FASEB Journal 2:2474-2478,1988
Rosso R,Ardizzoni A,Bruzzone M,Chiara S,Conte PF,et al. Phase IItrials of idarubicin, a new anthracycline.Abstract 244.
Cancer Chemotherapy and Pharmacology 18(Suppl.):A61,1986 Salmon SE,Liu RM,Casazza AM.Evaluation of new anthra-cycline analogs with the human tumor stem cell assay.Cancer
Chemotherapy and Pharmacology 6:103-110,1981
Salva-Martin KM,Wiernik PH.Focus on idarubicin:an anthra-cycline analogue with significant activity against acute leuke-mia.Hospital Formulary 25:1143-1156,1990
Scher HI,Yagoda A,Ahmed T,Budman D,Sordillo P,et al. Phase II trial of 4-demethoxydaunorubicin(DMDR) for ad-vanced hypernephroma.Cancer Chemotherapy and Pharma-cology 14:79-80,1985
Schott B,Robert J.Comparative cytotoxicity,DNA synthesis in-hibition and drug incorporation of eight anthracyclines in a model of doxorubicin-sensitive and-resistant rat glioblastoma cells.Biochemical Pharmacology 38:167-172,1989
Sessa C,Tschopp L,Fopp M,Cavalli F. Phase I trial of 4-de-methoxydaunorubicin in acute leukaemias.Investigational New Drugs 3:357-359,1985
Smith DB,Howell A. A phase II study of oral weekly 4-deme-thoxydaunorubicin in advanced breast cancer.European Jour-nal of Cancer and Clinical Oncology 23:391-394,1987

Smith DB, Howell A. A phase II trial of oral idarubicin plus di-bromodulcitol in advanced breast cancer.European Journal of Cancer and Clinical Oncology 25:141-143,1989
Smith DB,Margison JM,Lucas SB,Wilkinson PM,Howell A. Clinical pharmacology of oral and intravenous 4-demethoxy-daunorubicin.Cancer Chemotherapy and Pharmacology 19: 138-142,1987
Smith SR,Cullen MH,Benfield GFA,Woodroffe CM.Testing new drugs in untreated small cell cancer may prejudice the efficacy of standard treatment: a phase II study of oral ida-rubicinin extensive disease.Abstract. Thorax 43:245P,1988 Speth PAJ,Linssen PCM,Boezeman JBM,Wessels JMC,Haanen
C.Rapid quantitative determination of four anthracyclines and their main metabolites in human nucleated haematopoietic cells. Journal of Chromatography 377:415-422,1986
Speth PAJ,Minderman H,Haanen C.Idarubicin v daunorubicin: preclinical and clinical pharmacokinetic studies.Seminars in Oncology 16:2-9,1989
Speth PAJ,van de Loo FAJ,Linssen PCM,Wessels HMC,Haa-nen C.Plasma and human leukemic cell pharmacokinetics of oral and intravenous 4-demethoxydaunomycin.Clinical Pharmacology and Therapeutics 40:643-649,1986
Stanton G,Casper ES,Friedman B.Phase II trial of 4-deme-thoxydaunorubicin in patients with advanced malignant mel-anoma.Cancer Treatment Reports 69:915-916,1985
Stewart DJ,Grewaal D,Green RM,Verma S,Maroun JA,et al. Bioavailability and pharmacology of oral idarubicin.Cancer Chemotherapy and Pharmacology 27:308-314,1991
Stuart NSA,Cullen MH,Priestman TJ,Blackledge GRP,Tyrrell CJ. A phase II study of oral idarubicin (4-demethoxydauno-rubicin)in advanced breast cancer.Cancer Chemotherapy and Pharmacology 21:351-354,1988
Supino R,Necco A,Dasdia T,Casazza AM,Di Marco A.Re-lationship between effects on nucleic acid synthesis in cell cul-tures and cytotoxicity of 4-demethoxy derivatives of dauno-rubicin and adriamycin.Cancer Research 37:4523-4528,1977 Tamassia V,Pacciarini MA,Moro E,Piazza E,Vago G,et al.
Pharmacokinetic study of intravenous and oral idarubicin in cancer patients.International Journal of Clinical Pharmacol-ogy Research 7:419-426,1987
Tan CTC,Hancock C,Steinherz P,Bacha DM,Steinherz L,et al.Phase I and clinical pharmacological study of 4-demethoxy-daunorubicin(idarubicin) in children with advanced cancer. Cancer Research 47:2990-2995,1987
ten Bokkel Huinink WW,Clavel M,Cavalli F,Renard J.Eso-rubicin v idarubicin in advanced breast cancer.A randomized phase II study of the Early Clinical Trials Group of EORTC. Clinical Trials Journal 24(Suppl.1):143-149,1987
ten Bokkel Huinink WW,Clavel M,Howell T,Renard J,Pinedo HM.Esorubicin (E) versus idarubicin (I),a randomized phase II study in advanced breast cancer with a cross over to dox-orubicin (D). A study of the Early Clinical Trials Group of EORTC.Abstract 268.Cancer Immunology and Immuno-therapy 23(Suppl.):A67,1986
Tewey KM,Rowe TC,Yang L,Halligan BD,Liu LF.Adria-mycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 226:466-468,1984
Thompson DJ,Molello JA,Strebing RJ,Dyke IL.Teratogenicity of adriamycin and daunomycin in the rat and rabbit. Tera-tology 17:151-158,1978
Tolomeo M,Luparello M,Caravello E,Perricone R,Abbadessa V,et al. Effects of epirubicin and idarubicin in multi-drug re-sistant(MDR)Friend leukemia cells.Abstract 222.XIth Met-ing of the International Society of Haematology-European and African Division, Basel, Aug 31-Sep 6 1991 Switzerland. Schweizerische Wochenschrift 121(Suppl.43):137,1991
Umsawasdi T,Felder TB,Jeffries D,Newman RA.Phase II study of 4-demethoxydaunorubicin in previously untreated exten-
Idarubicin in Cancer:A Review
sive disease non-small cell lung cancer.Investigational New Drugs 8:S73-S78,1990
Umsawasdi T,Holoye PY,Jeffries D,Carr DT.Phase II study of idarubicin in extensive-disease non-small-cell lung cancer. American Journal of Clinical Oncology12:519-520,1989
Vogler WR.The role of idarubicin in remission induction and survival in acute myelogenous leukemia(AML).Abstract.20th Annual Meting of the International Society for Experimental Hematology(ISEH),Parma,Jul 21-25,1991
Walters RS,Kantarjian HM,Keating MJ,Plunkett WK,Estey EH,et al.Mitoxantrone and high-dose cytosine arabinoside in refractory acute myelogenous leukemia.Cancer 62:677-682, 1988
Wander H-E,Meyer D,Schuff-Werner P,Nagel GA.Phase II trial of oral idarubicin (4-demethoxydaunorubicin) in advanced breast cancer.Onkologie 9:236-238,1986
WHO handbook for reporting results of cancer treatment.Ge-neva,WHO Offset Publication no.48,1979
Wiernik PH. New agents in the treatment of acute myeloid leu-kemia. Seminars in Hematology 28(Suppl. 4):95-98,1991
Wiernik PH,Case Jr DC,Periman PO,Arlin ZA,Weitberg AB, et al. A multicenter trial of cytarabine plus idarubicin or dau-norubicin as induction therapy for adult nonlymphocytic leu-kemia.Seminars in Oncology 16(Suppl.2):25-29,1989
Williams CJ. A phase II study of oral idarubicin in advanced recurrent or refractory ovarian carcinoma.Cancer Chemo-therapy and Pharmacology 25:304-305,1990
Woods KE,Ellis AL,Randolph JK,Gewirtz DA.Enhanced sen-

719
sitivity of the rat hepatoma cell to the daunorubicin analogue 4-demethoxydaunorubicin associated with induction of DNA damage.Cancer Research 49:4846-4851,1989
Young CW,Berman E,Raymond V,Cassidy C,Hancock C,et al.Idarubicin in leukemia:American experience.Abstract WS-4-15.International Congress of Chemotherapy,p.40,Kyoto, Japan,23-28 June,1985
Zbinden G,Bachmann E,Holderegger C.Model systems for car-diotoxic effects of anthracyclines. Fundamentals in Cancer Chemotherapy 23:255-270,1978
Zijlstra JG,Meijer C,Timmer-Bosscha H,Le TKP,de Vries EGE, et al. Activity of(7)anthracycline related compounds in an doxorubicin sensitive human small cell lung cancer line and its doxorubicin resistant descendant.European Journal of Res-piratory Disease(Suppl.149):53-55,1987
Zunino F,Gambetta R,Di Marco A.Effecs of the stereochemical configuration on interaction of some daunomycin derivatives with DNA.Biochemical and Biophysical Research Commu-nication 69:744-750,1976
Zunino F,Di Marco A,Zaccara A.Molecular structural effects involved in the interaction of anthracyclines with DNA. Chemico-Biological Interactions 24:217-225,1979
Correspondence:Lisa M.Hollingshead,Adis International Lim-ited,41 Centorian Drive,Private Bag,Mairangi Bay,Auckland 10,New Zealand.