Drugs ten years later: epirubicin.
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Cardiomyopathies↗
Biomedical subjects
V Bonfante
Publications and source records attributed to V Bonfante.
Early stage Hodgkin's disease: ten-year results of a non-randomised study with radiotherapy alone or combined with MOPP.
From September 1976 to June 1982, 201 consecutive patients with stage I (A and B)-IIA Hodgkin's disease were stratified in two groups according to prognostic factors. The F group included 116 patients with favourable presentation: they were staged with laparotomy and treated with subtotal or total nodal radiotherapy alone. The U group included 85 cases with unfavourable presentation who were staged by laparoscopy and treated with 3MOPP (mechlorethamine, vincristine, procarbazine, prednisone)-radiotherapy-3MOPP. At 10 years the F group showed a freedom from progression (FFP) of 71% with significant difference between stage I and II (85% vs. 59%; P = 0.003) and an overall survival of 84%. The results of the U group were: FFP 83%, overall survival 74%, and the findings were not influenced by stage. FFP in patients with bulky vs. not bulky lymphoma was 70% vs. 87% (P = 0.04). No secondary acute non-lymphocytic leukaemia developed among patients treated with radiotherapy and in continuous complete remission, while acute leukaemia occurred in the F group patients who received salvage chemotherapy (4 of 31 cases) and in the U group (3 of 85 cases). Present results confirm the usefulness of radiotherapy alone in favourable pathological stage IA. All other disease stages will require a different strategy that should consist of radiotherapy combined with short-term effective regimens, such as ABVD (doxorubicin, bleomycin, vinblastine and decarbazine) or VBM (vinblastine, bleomycin and methotrexate) to reduce the incidence of MOPP-associated gonadal dysfunction and leukaemogenesis.
Adolescent↗
ABVD in the treatment of Hodgkin's disease.
This paper summarizes the clinical results achieved at the Milan Cancer Institute in advanced Hodgkin's disease through successive randomized studies performed during the last two decades. Long-term results confirm the therapeutic activity of a regimen containing bleomycin and doxorubicin, such as ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine), as salvage treatment and as primary chemotherapy, either when combined with radiation or cyclically alternated with MOPP (mechlorethamine/vincristine/procarbazine/prednisone). Delayed iatrogenic morbidity (namely, sterility and leukemogenesis) was less frequently documented in ABVD-treated patients compared with MOPP-treated patients. Nevertheless, bleomycin- and anthracycline-containing regimens can be refined in the attempt to further decrease iatrogenic toxicity.
Adult↗
Primary and salvage chemotherapy in advanced Hodgkin's disease: the Milan Cancer Institute experience.
This paper reviews the most relevant therapeutic results achieved by the Milan Cancer Institute through successive randomized studies in advanced Hodgkin's disease. The experience achieved confirms the therapeutic importance of an anthracycline-containing regimen such as ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) as salvage treatment and as primary chemotherapy, either when combined with irradiation or cyclically alternated with MOPP (mechlorethamine/vincristine/procarbazine/prednisone). Anthracycline-based combinations can be further refined to decrease toxicity. The biologic aspects of drug-sensitive v drug-resistant tumor cells and the accurate definition of prognostic categories at the time of first treatment failure are also discussed.
Antineoplastic Combined Chemotherapy Protocols↗
Salvage chemotherapy in Hodgkin's disease. Results in patients relapsing more than twelve months after first complete remission.
Forty-nine patients with Hodgkin's disease who relapsed after a first complete remission of more than 12 months following primary chemotherapy were treated with salvage therapy regimens. A total of 41 patients (84%) achieved complete remission. In particular, complete response was documented in 17 of 19 patients re-treated with the same initial drug combination. The five-year freedom from progression, relapse-free and overall survivals were 51%, 57% and 65%, respectively. In our experience, consolidation radiotherapy following drug-induced remission failed to improve the five-year relapse-free survival. Present findings indicate that about half of patients relapsing after a disease-free interval exceeding 12 months can remain alive and disease-free 5 years after starting salvage chemotherapy.
Adult↗
Hodgkin's disease: the Milan Cancer Institute experience with MOPP and ABVD.
The report includes the essential therapeutic and toxic results following MOPP vs. MOPP/ABVD and MOPP vs. ABVD within a combined modality setting. The findings indicate that in stage IV the alternating regimen is superior to MOPP while in stage IIB-III ABVD plus radiotherapy yielded superior results associated with no treatment-induced sterility and leukemia compared with MOPP plus radiotherapy.
Antineoplastic Combined Chemotherapy Protocols↗
Phase II study with ifosfamide in advanced malignant melanoma.
Ifosfamide was tested in a phase II study in 12 evaluable patients with advanced malignant melanoma. The drug was administered at the dose of 3 g/m2 on days one and two every 3-weeks. Seven patients were not previously treated and 5 received only minimal prior chemotherapy. Visceral involvement was present in 9 patients, and the remaining 3 had only soft tissue lesions. No patient showed objective tumor response. Mild vomiting was observed in 75% of patients; alopecia occurred in all of them. No other major side effects were observed, in particular, myelotoxicity and urotoxicity. Lack of response advised us to discontinue patient accrual. Our data do not support a therapeutic role of ifosfamide at the given dose schedule in the treatment of metastatic malignant melanoma.
Adult↗
Clinical evaluation of the cardiac toxicity of 4'-deoxy-doxorubicin.
4'-deoxy-doxorubicin, a new doxorubicin analog, was tested in 65 phase II patients with advanced malignancies. Cardiac toxicity evaluation was performed by means of electrocardiography (ECG), left ventricular systolic time intervals, echocardiography and radionuclide left ventricular ejection fraction. ECG abnormalities were observed in a lower percentage of patients (23%) compared to that described for doxorubicin and other anthracycline analogs such as 4'-epi-doxorubicin and 4-demethoxy-daunorubicin. Other functional parameters serially measured to evaluate chronic cardiotoxicity in 23 patients, who received more than 200 mg/m2 were not significantly different from mean pretreatment values. No patient developed congestive heart failure but some of them exhibited a fall of left ventricular function parameters more than 15% from pretreatment values. These data suggest that this new analogue is probably less cardiotoxic than the parent compound doxorubicin but not completely devoid of cardiotoxicity.
Adolescent↗
Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy.
In an attempt to reduce some of the delayed sequelae associated with combined modality therapy in Hodgkin's disease, we randomly tested stages IIB, IIIA, and IIIB MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) v ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine). In 232 previously untreated patients, three cycles of either combination preceded and followed extensive irradiation. The complete remission rate was 80.7% following MOPP and 92.4% following ABVD (P less than .02). The 7-year results indicated that ABVD was superior to MOPP in terms of freedom from progression (80.8% v 62.8%; P less than .002), relapse-free survival (87.7% v 77.2%; P = .06), and overall survival (77.4% v 67.9%; P = .03). Moreover, the comparative iatrogenic morbidity showed that irreversible gonadal dysfunction as well as acute leukemia occurred only in patients subjected to MOPP, while cardiopulmonary studies failed to document significant laboratory differences between the two treatment groups. Present findings indicate that ABVD followed by extensive irradiation represents a valid therapeutic alternative to the widely used alkylating agent-containing regimens plus radiotherapy.
Adult↗
New anthracycline analogs in advanced breast cancer.
To test the activity and toxicity of new anthracycline analogs, a series of Phase II disease-oriented studies were performed in women with advanced breast cancer previously untreated with doxorubicin. All drugs were administered every 3 weeks, and the doses in mg/m2 were as follows: doxorubicin and epirubicin 75 i.v., esorubicin 35 i.v., idarubicin 13 i.v. and 45 p.o. When epirubicin was tested vs doxorubicin, both response rate (13 of 21 or 62% vs 11 of 21 or 52%) and median response duration (11 months vs 13 months) were comparable. In 24 patients, esorubicin yielded complete plus partial response in 21% with a median duration of 15 months. In 27 patients given idarubicin intravenously the response rate was 11% for 4 months and the corresponding findings when the drug was administered orally to 25 women were 24% for 8 months. Acute toxic manifestations were lower following treatment with all three analogs compared to doxorubicin. Cardiac toxicity, as documented by echocardiography, systolic time interval and left ventricular ejection fraction was virtually absent following therapy with epirubicin and idarubicin. After a median cumulative dose of 600 mg/m2 for doxorubicin-treated women there was a significant fall in LVEF compared to basal values. Similar findings were observed after a median cumulative dose of 210 mg/m2 for esorubicin. We conclude that epirubicin is as effective as doxorubicin but comparatively less toxic when administered at the same dose schedule. At the doses and schedules utilized in this study, esorubicin and idarubicin resulted less active in breast cancer.
Adult↗
CCNU, etoposide, and prednimustine (CEP) in refractory Hodgkin's disease.
Starting in February 1980, 58 patients with Hodgkin's disease refractory to both MOPP and ABVD received as third-line chemotherapy a combination of CCNU or lomustine, etoposide, and prednimustine (CEP). Complete response (CR) was achieved in 40% of cases and partial response (PR) in 14%. The median duration of CR was greater than 15 months, and the median survival of complete responders was longer than 24 months. In addition, CEP alternating with ABVD was given to 21 patients refractory to MOPP chemotherapy. In this series, CR was documented in 67% of patients with a median duration of 24+ months and a median survival of 36+ months. Treatment was generally well tolerated, and all acute side effects were reversible. Present findings indicate that CEP is an effective regimen in patients refractory to MOPP and ABVD.
Antineoplastic Combined Chemotherapy Protocols↗
Salvage chemotherapy in Hodgkin's disease irradiation failures: superiority of doxorubicin-containing regimens over MOPP.
One hundred and twenty-two consecutive patients with Hodgkin's disease who relapsed after primary curative irradiation were treated with either MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) or a doxorubicin-containing regimen (ADM-Reg). The main pretreatment characteristics were comparable in the two groups. Complete remission was achieved in 74.6% of patients treated with MOPP (44 of 59) and in 90.5% of those given ADM-Reg (57 of 63). No difference was observed in the incidence of complete remission with regard to the type of ADM-Reg utilized [MABOP (mechlorethamine, doxorubicin, bleomycin, vincristine, and prednisone), 92.9%; ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), 95.6%; and MOPP alternated with ABVD, 84.6%]. The superiority of ADM-Reg versus MOPP was also confirmed in the 7-year analysis of freedom from disease progression (73.2% vs 42.2%), relapse-free survival (81.2% vs 54.3%), and overall survival (80.5% vs 44.4%). Thrombocytopenia was less frequently observed with ADM-Reg (30%), particularly following ABVD (13%), compared to MOPP (73%). The lowest incidence of alopecia occurred in patients given MOPP (15%) or MOPP/ABVD (19%). Acute nonlymphoblastic leukemia was observed in patients treated with MOPP (five of 59) and MABOP (one of 14). The observed findings indicate that in patients failing to respond to primary radiotherapy, salvage regimens containing doxorubicin are more effective than MOPP. Furthermore, combinations devoid of procarbazine and alkylating agents (ABVD) or with less intensive administration of these drugs (MOPP/ABVD) were not associated with secondary leukemia.
Adolescent↗
Phase II study of doxorubicin versus epirubicin in advanced breast cancer.
Doxorubicin and its epimerized analog epirubicin were tested at a dose of 75 mg/m2 given iv every 3 weeks to 42 patients with advanced breast cancer, 23 of whom were in relapse from prior cyclophosphamide, methotrexate, and 5-FU (CMF) chemotherapy. The median cumulative dose was 540 mg/m2 (range, 225-650) for doxorubicin and 565 mg/m2 (range, 150-600) for epirubicin. Complete plus partial response was documented in 11 of 21 patients (52%) following doxorubicin and in 13 of 21 patients (62%) following epirubicin. The median observation period was 22 months (range, 14-30); the median duration of response and the median survival were superimposable. Doxorubicin and epirubicin exhibited a superior response rate in previously untreated patients [six of eight (75%) vs eight of 11 (73%)] compared to those previously given CMF with or without endocrine therapy [five of 13 (38%) vs five of ten (50%)]. Vomiting, mucositis, and leukopenia were documented less frequently following administration of epirubicin as compared to doxorubicin. Regarding cardiac evaluation, no significant differences were evident between the two drugs. However, a significant fall in the left ventricular ejection fraction was documented in women who received doxorubicin following a cumulative dose greater than 550 mg/m2. Following completion of doxorubicin therapy at cumulative doses of 580 and 562 mg/m2, two women developed left ventricular failure at 6 and 14 months, respectively. Epirubicin appears to be an effective drug for the treatment of breast cancer and, given at equal doses, is less toxic than doxorubicin.
Adult↗
Cytarabine and cisplatin in advanced malignant melanoma.
Twenty-seven consecutive patients with advanced malignant melanoma were treated with cytarabine (Ara-C) and cisplatin. Of 25 evaluable patients, four achieved partial response, for a median duration of 3 months. Three of four responders belonged to the group of seven patients given Ara-C at a dose of 3 g/m2. The predominant toxic effect was hematologic and related to the dose of Ara-C. The cost-benefit ratio of this combination is inferior to that of dacarbazine or carmustine alone.
Aged↗
Gonadal toxicity after combination chemotherapy for Hodgkin's disease. Comparative results of MOPP vs ABVD.
The comparative gonadal toxicity following two equally effective and non-cross-resistant regimens (MOPP and ABVD) was prospectively evaluated in 53 males with Hodgkin's disease. The median age was 29 yr (range 16-45). MOPP produced azoospermia in 28/29 patients (97%) while ABVD induced oligoazoospermia in 13/24 patients (54%). Follicle-stimulating hormone levels were consistently and significantly increased after MOPP while their median value remained within normal range after ABVD. Sperm count was repeated in 34 patients. Recovery of spermatogenesis occurred in 3/21 cases treated with MOPP and in all 13 cases given ABVD. Present findings confirm that the two alkylating agents, mechlorethamine and procarbazine, included in the MOPP regimen cause sterility in most patients while the drugs included in ABVD are not associated with permanent gonadal dysfunction.
Adolescent↗
Third-line salvage chemotherapy in Hodgkin's disease.
CEP (CCNU, etoposide, and prednimustine) was tested as third-line chemotherapy in 40 patients resistant to both MOPP and ABVD. The observed response rate (complete remission, 35%, and partial remission, 25%) is encouraging. Treatment was generally well tolerated and all acute side effects were reversible.
Adolescent↗
Phase I study with 4'-deoxydoxorubicin.
4'-Deoxydoxorubicin (dxDx), a new doxorubicin analogue, was administered intravenously on a 3-week schedule to 73 patients affected by advanced malignant neoplasms. Sixty-five patients, treated with eight dose levels ranging from 10 to 45 mg/m2, were evaluable. The dose-limiting toxicity was myelosuppression, mainly leukopenia. About one third of the patients complained of vomiting which was almost always mild. Minimal hair loss was also documented in about 40% of patients. No hepatic or renal toxicity was observed. Transient and aspecific electrocardiographic changes were recorded in 6% of patients after 1 h and in 3% after 24 h from drug injection. Left ventricular ejection fraction was decreased in two patients after a cumulative dose of 90 mg/m2. One patient died with cardiorespiratory insufficiency and his initial cardiovascular disease might have been aggravated by dxDx. No changes in myocardial function parameters were documented in 18 patients who reached higher cumulative doses, i.e. greater than or equal to 100 mg/m2 and greater than or equal to 200 mg/m2. The highest total dose administered in this study was 340 mg/m2. Therapeutic activity was observed with doses ranging from 25 to 45 mg/m2. Partial response was documented in pancreatic, colon, anal and breast carcinomas as well as in non-Hodgkin's lymphoma. Minor response was observed in prostatic, thyroid, and renal carcinomas as well as in chronic lymphocytic leukemia. The maximum tolerated dose was assessed to be between 40 and 45 mg/m2. A Phase II trial is ongoing utilizing the dose of 35 mg/m2 every 3 weeks.
Adolescent↗
Phase I study of 4-demethoxydaunorubicin.
4-demethoxydaunorubicin (4-dm DNR), a new analog of daunorubicin, was tested at an every 3-week dose schedule in 63 evaluable patients with various forms of disseminated malignancy. Utilizing the intravenous (i.v.) route of administration, the maximum tolerated dose (MTD) was 15-18 mg/m2; with the oral route the MTD was 60 mg/m2. Myelosuppression represented the dose-limiting factor, and leukopenia was more often observed than thrombocytopenia. However, leukopenia was more frequently detected following i.v. administration while vomiting represented the most frequent toxic sign after oral administration. Loss of hair was moderate with either route of administration and comparatively less frequent and pronounced than that observed after doxorubicin (DX) and its analog 4'-epi-doxorubicin (4'-epi-DX). Aside from transient aspecific electrocardiographic changes recorded in 30% of patients, no cardiac toxicity was documented. Tumor response was documented in seven patients with malignant lymphomas, breast cancer, melanoma and carcinoma of uterine cervix. Two out of the seven responders achieved prolonged complete remission and four were resistant to doxorubicin. 4-dm DNR appears to be an analog worth further clinical trials.
Administration, Oral↗