Fabrizio Villani

Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study.

PURPOSE To define the maximum-tolerated dose (MTD) and better tolerated sequence of paclitaxel by 3-hour infusion plus bolus doxorubicin (DOX) and to evaluate antitumor efficacy. PATIENTS AND METHODS Thirty-five women with metastatic breast cancer (dominant visceral metastases in 56%, and involvement of > or = three sites in 67%) who never received chemotherapy of any type were studied. Paclitaxel every 3 weeks (125 mg/m2 starting dose) was increased by 25-mg/m2 steps in subsequent cohorts of patients. DOX (60 mg/m2 fixed dose) was administered 15 minutes before the start of or after the end of paclitaxel for a maximum of eight cycles. Subsequently, patients in continuous response could receive single-agent paclitaxel (175 to 200 mg/m2 every 3 weeks). The drug sequence was alternated in consecutive patients and in the first two cycles. RESULTS Severe neutropenia that lasted greater than 7 days (n = 4), febrile neutropenia (n = 7) and grade III oral mucositis (n = 6) defined the MTD of paclitaxel at 200 mg/m2 in 34 assessable patients. Grade II peripheral neuropathy occurred in 33% of patients. Six women (18%) developed clinically reversible congestive heart failure (CHF) after a median of 480 mg/m2 total DOX. Drug sequence had no effect on toxicities. High efficacy on all metastatic sites in 32 assessable patients accounted for a 41% complete response (CR) rate (95% confidence interval [CI], 24% to 59%) and 94% overall-response rate (95% CI, 79% to 99%). After a median follow-up of 12 months (range 3 to 18), the median response duration is 8 months (range, 2+ to 18+) for complete responders and 11 months (range 1+ to 15+) for partial responders. CONCLUSION The rate of CR and incidence of CHF may be an expression of therapeutic and toxic enhancement due to the schedule used in this trial. Until clarification of this possibility, this promising combination should be used in investigational trials.

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 Hodgkins 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.

ABVD Plus Subtotal Nodal Versus Involved-Field Radiotherapy in Early-Stage Hodgkin's Disease: Long-Term Results

PURPOSE Radiation therapy (RT) alone can cure more than 80% of all patients with pathologic stage IA, IB, and IIA Hodgkins disease, but some prognostic factors unfavorably affect treatment outcome. Combined-modality approaches improved results compared with RT, but the optimal extent of RT fields when combined with chemotherapy warranted additional evaluation. PATIENTS AND METHODS In February 1990, we activated a prospective trial in patients with early, clinically staged Hodgkins disease to assess efficacy and tolerability of four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by either subtotal nodal plus spleen irradiation (STNI) or involved-field radiotherapy (IFRT). RESULTS Main patient characteristics were fairly well balanced between the two arms. Complete remission was achieved in 100% and in 97% of patients, respectively. The 12-year freedom from progression rates were 93% (95% CI, 83% to 100%) after ABVD and STNI, and 94% (95% CI, 88% to 100%) after ABVD and IFRT, whereas the figures for overall survival were 96% (95% CI, 91% to 100%) and 94% (95% CI, 89% to 100%), respectively. Apart from three patients who developed second malignancies in the STNI arm, treatment-related morbidities were mild. CONCLUSION Present long-term findings suggest that, after four cycles of ABVD, IFRT can achieve a worthwhile outcome. The limited size of our patient sample, however, had no adequate statistical power to test for noninferiority of IFRT versus STNI. Despite this, ABVD followed by IFRT can be considered an effective and safe modality in early Hodgkins disease with both favorable and unfavorable presentation.

Effect of Dietary Supplementation with Polyunsaturated Fatty Acids on Bronchial Hyperreactivity in Subjects with Seasonal Asthma

Dietary supplementation with omega-3 essential fatty acids results in the production of uniqe 5-lipoxygenase and cyclooxygenase products which are biologically less active and may inhibit the production, or actions, of the eicosanoids produced when arachidonic acid is the substrate for 5-lipoxygenase and cyclooxygenase, rather than omega-3 essential fatty acids. Since airway inflammation may play a central role in the pathophysiology of asthma, we studied the effect of omega-3 essential fatty acids on bronchial responsiveness in 7 atopic patients suffering from seasonal asthma due to airborne allergens, and positive to intracutaneous skin reaction to two or more allergens. Bronchial responsiveness to ultrasonically nebulized distilled water (UNDW) was determined 30 days from the initial ingestion of 3 g/day of omega-3 essential fatty acids and 30 days after stopping dietary supplementation. Flow volume curves and Raw were recorded before the provocation test, at the end of inhalation, and at 10-, 20-, 30- and 60-min intervals. The maximum fall in forced expiratory volume in 1 s (FEV1) and the maximum increase in airway resistance (Raw) were chosen as the main outcome parameters. After 30 days of dietary supplementation, bronchial responsiveness to UNDW was significantly improved (in fact maximum fall in FEV1 was –11% vs. –28% before treatment, and maximum increase in Raw was +37% vs. +265% before treatment). The challenge test repeated 30 days after stopping dietary supplementation was the same as that recorded before treatment. The present data strongly suggest the hypothesis that dietary supplementation with omega-3 essential fatty acids could decrease bronchial hyperreactivity in atopic patients.

Influence of adriamycin on calcium exchangeability in cardiac muscle and its modification by ouabain

Abstract Ten μg/ml of adriamycin produces a significant decrease in peak tension of isolated guinea pig atria without modification of cellular Ca content. The analysis of the curve of Ca exchanges shows that adriamycin significantly reduces the calcium exchangeable fraction, whereby the Ca fast exchanging compartment is suppressed and the slow exchanging one is slightly increased. Ouabain prevents the negative inotropic effect of adriamycin and restores the rapid Ca compartment without significantly modifying either the cellular Ca content or the amount of calcium exchangeable fraction. These results demonstrate that calcium plays a role in the negative inotropic effect of adriamycin in cardiac muscle and confirm the importance of the fast exchanging fraction in regulating the contractile force of the heart.

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.

Effect of ICRF-187 pretreatment against doxorubicin-induced delayed cardiotoxicity in the rat

Doxorubicin (DXR), administered iv in rats at the weekly dose of 3 mg/kg for 5 weeks, significantly impaired body weight gain and induced irreversible ECG alterations, mainly consisting of a progressive prolongation of ST and QT intervals. Five weeks after the last DXR administration, the contractile performance of atria isolated from treated animals was significantly reduced. At the same time, relevant morphologic lesions, consisting of myocyte vacuolization and myofibrillar loss, were also present in the myocardium of the same rats. The study showed that ICRF-187, administered ip at a dose of 125 mg/kg, significantly prevented body weight loss. QT and ST prolongation, and the decreased contractile force induced by DXR. In addition, ICRF-187 caused a significant reduction in incidence and severity of myocardial lesions. The cardioprotective effect of ICRF-187 is not mediated by a modification in DXR pharmacokinetics in heart, since the drug was actually found to increase DXR uptake in myocardial cells.

EFFECT OF GLUTATHIONE AND N- ACETYLCYSTEINE ON IN VITRO AND IN VIVO CARDIAC TOXICITY OF DOXORUBICIN

The effects of two sulfhydryl compounds, glutathione (GSH) and N-acetylcysteine (NAC), on the cardiotoxicity of doxorubicin (DXR) were tested on in vitro and in vivo models. DXR was administered to rats as 4 weekly i.v. doses of 3 mg/kg. GSH (1.5 mmoles/kg), given i.v. 10 min before and 1 hr after DXR, was found to prevent the development of the delayed cardiotoxic effects of DXR, as assessed by electrocardiographic and mechanical parameters, as well as by histological examination of left ventricular preparations. In contrast, equimolar oral doses of NAC (1 hr before and 2 hrs after DXR) were found to be ineffective. Both GSH and NAC prevented the negative inotropic effect produced by DXR on isolated rat atria. A good correlation exists between the cardioprotective effects of the two agents and their ability to enhance the non-protein sulfhydryl group content of the myocardium. Differences observed in vivo between GSH and NAC might be accounted for by pharmacokinetic factors.

Evaluation of cardiac toxicity of idarubicin (4-demethoxydaunorubicin)

Cardiac toxicity of idarubicin (4-demethoxydaunorubicin), a new daunorubicin derivative, was tested in 49 phase II patients with advanced malignancies. In 26 patients the drug was given intravenously at a dose of 13 mg/m2 and in 23 orally at a dose of 45 mg/m2. Cardiac toxicity was evaluated by means of electrocardiography, left ventricular systolic time intervals, echocardiography and radionuclide cineangiography. The type and incidence of ECG abnormalities were comparable to those observed with other anthracycline analogs. Other functional parameters, serially measured to evaluate delayed cardiotoxicity in patients who received more than 65 mg/m2 intravenously or 225 mg/m2 orally, were not significantly different from pretreatment values. No patient developed clinical congestive heart failure. Only one patient exhibited a drop in the left ventricular ejection fraction of more than 15% from pretreatment values. These data indicate that idarubicin given orally or intravenously at the tested doses has no significant cardiotoxic activity in the range of the cumulative doses attained.

Myocardial contractility and heart pharmacokinetics of adriamycin following a single administration in rat

SummaryA single administration of adriamycin (DXR) 6.0 mg/kg i. v. to rats brings about a biphasic impairment of the maximal myocardial contractile performance, measured as dF/dt of ex vivo isolated atria incubated in the presence of calcium concentrations varying up to 12 mM. The initial impairment of the contractile performance peaks 1 week after DXR administration and recovers within 3 weeks (acute phase of cardiotoxicity). After this time and up to the end of the observation period (8 weeks after treatment), delayed cardiotoxicity occurs, showing a progressive and irreversible impairment of the contractile performance of the atria. This behaviour parallels the previously shown ECG and morphological abnormalities. Tissue determinations of DXR showed that the drug is present in myocardium during the acute phase of cardiotoxicity, while the metabolite adriamycinol is not detectable 1 week after DXR administration. These data show that the presence of DXR and/or metabolites in heart muscle is not necessary for the delayed form of cardiotoxicity to become apparent and suggest that this form of cardiotoxicity is related to a mechanism different from that involved in acute cardiotoxicity.