Combination chemotherapy with oral idarubicin and cyclophosphamide for metastatic breast cancer.

A group of 40 women with objectively measurable metastatic breast cancer was treated with idarubicin, 35 mg/m2 on day 1, and cyclophosphamide, 200 mg/m2 on days 2-5, both drugs being administered orally every 3 weeks. Of 37 evaluable patients, 4 (10.8%) achieved a complete response and 14 (37.8%) a partial response, for an overall response rate of 48.6% (95% confidence interval, 37.45%-59.75%). In previously untreated patients the response rate was 58.3%, whereas it was 44% in patients previously exposed to cytotoxic drugs. The median duration of response was 6.5 months, and the median survival of all patients was 10.5 months. Moderate nausea and vomiting were common. Diarrhoea, which occurred in 37% of the patients, was usually short-lived. Alopecia was generally mild, myelosuppression was the dose-limiting toxicity. Grade 3-4 leukopenia occurred only in pretreated patients. In previously untreated patients it was generally of grade 1-2. Laboratory evidence of cardiotoxicity (greater than or equal to 20% decrease in the left-ventricular ejection fraction from the baseline value) was observed in 3 out of 26 patients, who had at least two determinations of the left-ventricular ejection fraction, and was transient in nature. No cases of congestive heart failure were observed. These results indicate that the combination of idarubicin + cyclophosphamide represents a practical and effective regimen to be used in selected patients with advanced breast cancer.

A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia. A multicentric study from the Italian Co-operative Group GIMEMA.

255 patients with acute non-lymphoid leukaemia (ANLL), observed between October 1984 and June 1987, entered a chemotherapy regimen consisting of induction therapy with cytarabine in combination with idarubicin (IDA/ARA) or daunorubicin (DNR/ARA), followed by consolidation with four courses of IDA + ARA plus 6-thioguanine (6-TG) or DNR + ARA + 6-TG and a 6 month maintenance therapy with 6-TG and ARA. The median age was 62 years (range 55-78 years) and 33 were aged more than 70 years. The treatment groups were comparable for median age, FAB type, performance status and initial blood counts. 249 patients were randomised, 124 to the IDA/ARA arm and 125 to the DNR/ARA arm. Complete remission was achieved in 50 patients (40%) on the IDA/ARA treatment program and 49 patients (39%) on DNR/ARA. No definite differences were found between patients receiving IDA/ARA and those treated with DNR/ARA as far as complete response (CR), overall survival, failure free and relapse free survival are concerned. 74% of the complete responders in the IDA/ARA arm and 51% in the DNR/ARA arm achieved CR after a single course of treatment. Resistant leukaemia was observed in 13.7% of the patients in the IDA/ARA arm and in 31.2% in the DNR/ARA one, whereas hypoplastic death occurred in 29% and 14.4%, respectively. In conclusion, our data failed to show any advantage of idarubicin over daunorubicin even though there is some evidence that IDA, despite the higher toxicity, is more rapid in eradicating leukaemia as proved by the higher CR rate obtained after one course of induction.

Idarubicin in the treatment of acute leukemias. An overview of preclinical and clinical studies.

Idarubicin is a new derivative of Daunorubicin which was found to be more potent and more active than Daunorubicin and Doxorubicin in several experimental leukemias. Its antileukemic activity in preclinical models prompted the introduction of Idarubicin into clinical studies. As a single agent, Idarubicin produced complete remission in 20% and 30% of patients with heavily pretreated pediatric and adult acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) respectively. Idarubicin combined with Cytarabine and/or other antileukemic agents produced complete remissions in 46% of patients with refractory or relapsed AML and in 58% of patients with refractory or relapsed ALL (adult and pediatric). Subsequently, Idarubicin has been employed in untreated AML patients in combination with Cytarabine and/or Etoposide, producing complete remissions in more than 80% of patients. In ALL patients the drug has been used in combination with Vincristine, Cytarabine and Prednisone, producing complete remissions in 82% of patients. Recently, Idarubicin has been utilized in combination with intermediate doses of Cytarabine in refractory or relapsed ALL and AML, and 70% of patients achieved complete remission. Preliminary results of ongoing prospective randomized studies in untreated adult AML seem indicate that Idarubicin is at least equivalent, if not superior to Daunorubicin. The antileukemic activity of Idarubicin given orally as single agent, or in combination with other drugs, has been shown in AML and myelodysplastic syndromes. The toxicity of Idarubicin includes mild nausea and vomiting, alopecia and liver dysfunction. Ongoing randomized trials comparing Idarubicin to Daunorubicin should provide more information about the potential cardiotoxicity of this drug.

Idarubicin combined with intermediate-dose cytosine arabinoside in the treatment of refractory acute leukemia.

From December, 1985 to October, 1987, 16 patients aged from 14 to 62 (median 34) with acute leukemia in relapse (10 affected by ANLL and 6 by ALL) were treated with the following regimen: Idarubicin 12 mg/m2/day on days 1-2-3, Ara-C 600 mg/m2 twice a day from day 1 to 6. Twelve patients (75%) achieved complete remission (C.R.). Two (12%) died during the induction phase from alveolar pneumonitis. One patient was resistant. The median duration of C.R. and survival was respectively 12 (range 6 to 100 +) and 23 weeks (4 to 108 +). The median duration of granulocytopenia was 16 days (range 10 to 24 days). The most frequent non-hematological complications consisted of nausea, vomiting, diarrhea and mucositis. Four patients had hepatic and splenic microabscesses of suspected mycotic etiology, and one showed a transient cardiac arrhythmia. The C.R. rate obtained in this series may be considered satisfaying since all but 3 patients were on treatment at the time of relapse. Yet the short duration of C.R. suggests the opportunity of performing consolidation cycles or suprelethal therapy followed by bone marrow transplantation.

Phase II trial of oral idarubicin in advanced non-small cell lung cancer (NSCLC).

The antitumoral activity and toxicity of a new daunorubicin analog (4-demethoxydaunorubicin, IMI 30, Idarubicin) was tested in 20 consecutive patients with non-small cell lung cancer mostly pretreated with chemotherapy. The drug was administered orally at a dose of 15 mg/m2 for three days every 3-4 weeks. There were no clinical responses. Hematological and nonhematological toxicities were mild.

Idarubicin in sequential combination with cytosine arabinoside in the treatment of relapsed and refractory patients with acute non-lymphoblastic leukemia.

Sixteen adult patients with refractory acute non-lymphoblastic leukemia (ANLL) underwent reinduction therapy with idarubicin (12 mg/m2) i.v. on days 1-3) followed by cytosine arabinoside (120 mg/m2 every 12 h on days 4-10). Patients achieving complete remission (CR) received consolidation and early intensification courses which included idarubicin at lower dosage. CR was reached after a single course in 70% of the patients treated at first relapse, and two of the five subjects previously resistant to daunorubicin-containing regimens responded to the idarubicin protocol. The median duration of CR was 11 months. Gastrointestinal side-effects were not important; mild and reversible ECG changes were noted whereas delayed cardiac toxicity was not observed despite previous treatment with daunorubicin. These encouraging results confirm the efficacy of idarubicin in treating acute leukemia and suggest it may have a major role in the treatment of relapsed and refractory patients with ANLL.

Epirubicin in combination chemotherapy in the treatment of advanced stage non-Hodgkin's lymphomas.

From April 1981 to May 1984, 23 patients with advanced non-Hodgkin's lymphomas were treated with CEOP (cyclophosphamide, epirubicin, vincristine, and prednisone) or OEPP (vincristine, epirubicin, procarbazine, and prednisone) combination chemotherapy. CR was achieved in 58% and PR in 31% of the patients, giving an overall response rate of 89%. Nine of 15 (60%) previously untreated patients with unfavorable histology obtained a CR and 5 a PR. Median relapse-free survival was 33 months; median overall survival has not yet been reached, and the probability of survival for CRs was 91% after 54 months of follow-up. Acute toxicity was quite acceptable, and chronic cardiac toxicity was detected in 6 patients only. In conclusion, epirubicin used in combination chemotherapies induced durable remissions and prolonged survivals in advanced non-Hodgkin's lymphomas.

Idarubicin (4-demethoxydaunorubicin). A preliminary overview of preclinical and clinical studies.

4-Demethoxydaunorubicin (4-DMDR, IMI 30, Idarubicin, NSC 256439) is a new analog of daunorubicin (DNR) with antileukemic activity in experimental systems that is superior to that of daunorubicin (DNR) or doxorubicin (DX). The drug is more potent than DNR and DX and is active by both the intravenous and the oral routes of administration. After i.v. and oral administration in humans, Idarubicin is rapidly metabolized to its 13-dihydroderivative (Idarubicinol) and the plasma levels of this metabolite are consistently higher than those of the unchanged drug. Idarubicinol has been shown to be an active metabolite in experimental models, being as potent and as active as the parent compound. Phase II clinical trials of Idarubicin have indicated that: By I.V. route Idarubicin is a potent antileukemic agent active in relapsed or refractory, ANLL, ALL (adult and pediatric) either as single agent or in combination with Ara-C at doses of 8-12 mg/m2 by i.v. day 1, 2 and 3 or 7-8 mg/m2 i.v. daily X 5 days (adults). There is evidence of lack of cross-resistance with parent drugs and other antileukemic agents. Phase III studies in previously untreated acute leukemias have been initiated. By oral route Idarubicin has antitumor activity in breast cancer at the doses of 35-45 mg/m2 q 3-4 weeks or 15 mg/m2 daily X 3 days q 3-4 weeks. Idarubicin has activity as a single agent in adult leukemias at the doses of 20-30 mg/m2/day X 3 days. The safety of administration (no risk of extravasation), the good tolerability and the reduced potential for cardiac toxicity, make oral Idarubicin particular attractive for further clinical development. Whether Idarubicin proves to be more effective and/or less cardiotoxic in clinical therapy than DNR or DX remains to be seen through prospective randomized studies which have been already initiated both in leukemias and solid tumors.

Clinical studies with new anthracyclines: epirubicin, idarubicin, esorubicin.

Analogue development is one of the most intensively pursued anticancer drugs research projects. The rationale in anthracycline analogue development followed by Farmitalia Carlo Erba has been the selection of agents with improved therapeutic index with respect to the parent structures, different spectrum of activity, reduced toxicity to the myocardium and oral route of administration. The clinical development is based on Phase I, II and III studies. However, the best definition in terms of activity and toxicity of an anticancer agent is accomplished with Phase II clinical trials, especially if they are comparative in a randomized fashion with the parent compound. Esorubicin has just started Phase II clinical testing. Phase I studies have shown hints of activity in several malignant diseases. Idarubicin has already been shown to be an important antileukaemic agent in Phase II-III studies. Moreover this compound is the first oral anthracycline that has shown activity in breast cancer, lymphomas and leukaemias, together with potential for reduced cardiac toxicity. Epirubicin, which is now in Phase III clinical development, has been shown to possess a better therapeutic index than doxorubicin since it induces less acute toxicities (nausea and vomiting, mucositis, myelosuppression) and less cardiotoxicity than its parent compound, without loss of activity in responsive tumours.

Phase II trial with oral idarubicin in advanced breast cancer.

Idarubicin, a new analogue of daunorubicin, was administered to 27 patients with advanced breast cancer in a phase II trial. The drug was given orally at a dose of 30-35 mg/m2 every 3 weeks. Twenty-two patients were evaluable for response. All evaluable patients were previously treated with one or more chemotherapeutic regimens, including an anthracycline in more than 50% of the cases. Partial remissions were obtained in 5 patients, for a response rate of 23%. The median duration of response was 191 days. Mild nausea and vomiting were common. Diarrhea, which occurred in less than 50% of the patients, was usually short-lived. Alopecia was generally minimal. Myelosuppression was the dose-limiting toxic effect. Leukopenia was frequently seen, with full recovery by day 28 in 81% of the courses. Thrombocytopenia was less common than leukopenia. Four cases of grade 1 acute cardiac toxicity were recorded. This study suggests that idarubicin can induce regressions in advanced carcinoma of the breast, and justifies further studies in combination with other agents.

Clinical toxicity of 4'-epi-doxorubicin (epirubicin).

Epirubicin is a new derivative of doxorubicin characterized by an improved spectrum of activity and a better therapeutic index. At equimolar doses and in comparative studies, epirubicin proved to induce less acute toxicity than doxorubicin, in particular less vomiting, hair loss and myelotoxicity. While giving a comparable response rate in randomized breast cancer studies, epirubicin also proved to be less cardiotoxic than doxorubicin. The reduced potential for cardiac toxicity of epirubicin versus doxorubicin has been shown both by functional assessment (radionuclide cinecardioangiography) and by histopathologic evaluation (endomyocardial biopsies) at equally myelosuppressive doses or at equal doses (equimolar). The lessened cardiotoxicity of epirubicin versus doxorubicin can be explained by the different pharmacokinetic and metabolic properties of these two agents: epirubicin has been found to have a more rapid pharmacokinetic plasma clearance and an additional metabolic pathway (unique glucuronidation).

Epirubicin in non-Hodgkin's lymphomas.

Epirubicin (Epi-DX), a new analog of doxorubicin, was administered I.V. once q 3 weeks at the dose of 90 mg/m2 to 20 evaluable patients with non-Hodgkin's lymphomas (NHL). Eighty-two percent of patients with favorable histology and 67% with unfavorable histology achieved complete or partial remissions, with an overall response rate of 75%. Gastrointestinal and hematologic toxicity was generally mild to moderate. Reversible ST-T changes were observed only in two patients. Epi-DX has high activity in patients with NHL, and further studies in combination with other agents are recommended.

A phase II study of 4'-epi-doxorubicin plus cis-platinum in advanced solid tumors.

4'-Epi-doxorubicin (4'-epi-DX) is a new doxorubicin derivative that in phase II human studies has been demonstrated to be less toxic than doxorubicin. Sixty-four patients with advanced solid tumors were treated with the drug combination of 4'-epi-DX and cis-dichlorodiammineplatinum (CDDP) at the doses of 40-60 and 50 mg/m2, respectively, every 21-28 days. Out of 52 evaluable patients, complete remission (CR) was recorded in 5, partial remission (PR) in 12, minor remission (MR) in 7, no change (NC) in 16 and progression (P) in 12. The median duration of remission in patients who achieved a CR and PR was 9+ months. In particular, out of 19 patients with ovarian cancer, 2 CR (second look) and 7 PR have been documented. One CR and 3 PR also have been observed in 21 patients with lung carcinoma. Complete and partial responses also have been documented in breast cancer (1 CR/1), in bladder carcinoma (1 CR/2), in renal cancer (1 PR/5) and in testicular cancer (1 PR/1). Hematologic toxicity was generally mild to moderate (leukopenia less than or equal to 1500 cells/mm3 in 3% of the patients; thrombocytopenia less than or equal to 120,000 cells/mm3 in 2% of the patients). Vomiting was present in almost all patients while alopecia has been recorded in 63% of the patients. No case of cardiac toxicity had been observed up to now (median cumulative dose of 4'-epi-DX:240 mg/m2, range 40-650 mg/m2). The combination of 4'-epi-DX with CDDP appears to be an active and well-tolerated regimen in ovarian cancer and lung cancer.

Phase II study of epirubicin in advanced malignant melanoma.

Twenty patients with advanced malignant melanoma refractory to conventional chemotherapy, were entered into a Phase II study of epirubicin, one of the new doxorubicin analogues. The drug was given at a dose of 90 mg/m2 IV every 3 weeks. One partial response and three disease stabilizations were observed. Nausea and vomiting and alopecia were common. Mild to moderate leukopenia occurred in 6 patients. Three cases of reversible ST-T changes were recorded. The observed response rate of 5% with a 39.2% probability of a true response rate greater than or equal to 10%, does not suggest that epirubicin, in the dose and schedule chosen, is active in metastatic malignant melanoma.

Controlled study of DTIC versus DTIC plus epirubicin in metastatic malignant melanoma.

Forty-two previously untreated patients with metastatic malignant melanoma were randomized to receive DTIC at a dose of 250 mg/m2/day 4 IV on days 1-5 or the same drug plus epirubicin (Epi-DX) at a dose of 90 mg/m2 on day 1. Cycles were repeated every 3 weeks. Partial responses were observed in two out of 22 patients (9.1%) treated with DTIC, and in four out of 19 evaluable patients (21.1%) treated with Epi-DX + DTIC. Overall, Epi-DX + DTIC combination was well tolerated, thus permitting administration after a 3-week interval of the full drug dosages in all but two patients. No major cardiotoxicity was observed. Although patients in the Epi-DX + DTIC group had a better response rate than those in the DTIC group, the difference was not statistically significant, and the 21.1% response rate observed with the two-drug combination does not differ from that reported with DTIC used alone.

4'-epi-doxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data.

4'-epi-doxorubicin (4'-epi-DX) is a new anthracycline antibiotic. It differs from doxorubicin (DX) by the epimerization of the OH group in position 4' of the aminosugar moiety, and was synthesized in an effort to find agents with a superior therapeutic index to the parent compound doxorubicin (DX). 4'-epi-doxorubicin binds to DNA and inhibits nucleic acid synthesis and function. The antitumor activity of 4'-epi-DX in several experimental tumors (Leukemias L 1210, P 388, Gross Leukemia, Sarcoma 180 ascitic and solid, C3H/HE mammary carcinoma) is similar to that of DX. However, 4'-epi-doxorubicin has greater antitumor activity than doxorubicin in Lewis lung carcinoma, MS-2 sarcoma lung metastasis, and human melanoma in athymic mice. In chronic toxicity studies there were no qualitative differences between 4'-epi-DX and DX; quantitatively, however, 4'-epi-DX was less toxic. In different experimental models 4'-epi-DX has been shown to be less cardiotoxic than its parent compound. In chronic toxicity studies in the rabbit, histopathologic findings revealed the same pattern of cardiotoxicity for both drugs but less marked with 4'-epi-DX. Distribution studies in mice with tumors showed a lower concentration of 4'-epi-DX in the heart, spleen and kidneys; the hepatobiliary metabolism and excretion of 4'-epi-DX investigated in the rat, indicated that the new analogue was more extensively metabolized than the parent compound. Pharmacokinetics of 4'-epi-DX in humans showed a multiexponential decrease of plasma levels; the same pattern was observed for the metabolite 13-OH epidoxorubicinol but with lower concentrations than the unchanged drug. A high plasma clearance (0.9-1.41/min), a terminal half-life of about 30-40 hr and a large volume of distribution were the main pharmacokinetic characteristics of 4'-epi-DX. A reduction of the dose appears to be appropriate in patients with liver function impairment. Phase II studies with 4'-epi-DX have indicated that the drug produces a pattern of acute toxicity, including acute cardiac toxicity, qualitatively similar to that of DX at identical doses but quantitatively lower, with particular regard to leukopenia and gastrointestinal toxicity. The range of single active doses is between 60 and 90 mg/m2, the most frequently employed doses schedules being 75 or 90 mg/m2 i.v. every 3 weeks. 4'-epi-DX has shown activity in a variety of tumors such as breast carcinoma, soft tissues sarcomas, NH lymphomas, leukemias, ovarian cancer and gastric cancer. Preliminary evidence of activity has been found in melanoma, rectal cancer and pancreatic cancer suggesting a broad spectrum of activity. As to chronic cardiac toxicity up to now only 2 mild to moderate and reversible CHF have been observed at doses of 1120 and 1235 mg/m2 in about 700 treated patients. Specific and comparative studies are in progress: preliminary findings from a randomized comparison of 4'-epi-DX vs DX in breast cancer indicated that 4'-epi-DX may have a lower cumulative cardiotoxicity.

Clinical evaluation of 4'-epi-doxorubicin in advanced solid tumors.

A Phase II clinical evaluation of 4'-epi-doxorubicin has been carried out in 100 patients with various types of solid tumors. Hematopoietic toxicity was dose-limiting but reversible and of mild to moderate degree. Other acute toxic manifestations such as vomiting and alopecia were qualitatively similar to those usually reported for doxorubicin, but lower in frequency and less severe. A number of responding patients received cumulative doses of 4'-epi-doxorubicin in excess of 500 mg/m2. One patient manifested reversible clinical congestive heart failure at cumulative dose of 1,080 mg/m2. Therapeutic activity has been observed in breast carcinoma, in rectal carcinoma and in melanoma. In chemoresistant tumors as rectal cancer and melanoma 4'-epi-doxorubicin deserves further study.

Phase II study of 4'epi-doxorubicin.

Sixty-five patients with advanced solid tumors were treated with 4'epi-doxorubicin, a new analogue of doxorubicin (DXR). Forty-three of 61 evaluable patients had not received previous chemotherapy and/or hormonal treatment. 4'Epi-doxorubicin has been administered at the dose of 75 mg/m2 i.v. once every 21 days, for a minimum of 2 courses. The pattern of acute toxicity was similar to that of DXR. Transient electrocardiographic abnormalities were found in about 50% of patients. The ratio of pre-ejection period to the left ventricular ejection time (PEP/LVET) increased within 1 h after drug injection and returned to near basal values after 24 h. Three patients received a total dose of more than 550 mg/m2, still maintaining a baseline PEP/LVET ratio near to pretreatment values. Up to now, no patient has developed clinical signs of heart failure. Partial responses were seen in patients with tumors generally sensitive to DXR such as breast carcinoma (6 of 14) and soft tissue sarcomas (2 of 6), and in patients with tumors generally resistant to DXR such as melanoma (1 of 9), colorectal carcinoma (3 of 18) and pancreatic carcinoma (1 of 2). These data suggest that 4'epi-doxorubicin may have a broader spectrum of antitumor activity than DXR.

Pharmacokinetic approach to the selection of dose schedules for medroxyprogesterone acetate in clinical oncology.

The pharmacokinetic and bioavailability properties of medroxyprogesterone acetate (MPA) after single PO and IM doses in man were used as a basis to predict, on a theoretical pharmacokinetic basis, the blood level profile of the drug during repeated dose administration with various dosage schedules. Because of the unusually long-lasting depot effect of IM MPA, a different build-up process of blood levels is expected during repeated IM or PO administration, and this should be taken into account when dose schedules for use in clinical oncology are selected. As regards the IM route, dose schedules based on 4 weeks' treatment with daily injections of 500-1,000 mg followed by a maintenance therapy with 1,000 mg/week are suggested, since they permit rapid achievement and maintenance of relatively high plasma levels. A similar plasma level profile can be obtained with oral MPA provided that daily doses twice as large as the IM doses are given during the first month of treatment and continued during the maintenance period. The serum levels observed in 25 patients with advanced breast cancer treated with MPA given IM or PO according to various dose schedules and recent literature data are very close to the serum level profiles predicted on a theoretical pharmacokinetic basis.