The cardioprotector ADR-529 and high-dose epirubicin given in combination with cyclophosphamide, 5-fluorouracil,and tamoxifen: a phase I study in metastatic breast cancer

The purpose of this study was to determine the maximal tolerble dose (MTD) of epirubicin and ADR-529 given in combination with cyclophophamide, 5-fluorouracil, and tamoxifen. A total of 64 breast cancer patients with locally advanced disease or a first metastatic event were included. Using fixed doses of cyclophosphamide, 5-fluorouracil, and tamoxifen, cohorts of ten patients were treated with escalating doses of epirubicin and ADR-529. With the use of protocol criteria specifying evaluation after the first course, the MTD was not reached. Dose reductions carried out due to hematologic toxicity during the first four courses made it impossible to escalate doses of epirubicin beyond 80 mg/m² given together with ADR-529 600 mg/m². The vascular toxicity of ADR-529 necessitated central venous access in a number of patients. For phase III evaluation of ADR-529 given together with cyclophosphamide, epirubicin, 5-fluorouracil, and tamoxifen (CEF/TAM) we recommend using epirubicin/ADR-529 at 60/600 mg/m². Together with evaluation of the cardioprotective properties of ADR-529, we recommend evaluating the impact of ADR-529 on the efficacy of cytotoxic therapy and investigating further the toxicity of ADR-529.     

Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin.

BACKGROUND: Although doxorubicin is an anticancer agent with a wide spectrum of activity, therapy with this anthracycline must often be discontinued at a time of benefit to the patient because of the drug's cumulative cardiotoxicity. ICRF-187 (ADR-529, dexrazoxane) is a bisdioxopiperazine compound that protects against cardiac toxicity induced by doxorubicin. PURPOSE: Our objectives in this study were to determine the maximum tolerated dose of ADR-529 (which uses a different vehicle than ICRF-187) when given with a fixed doxorubicin dose and to determine whether ADR-529 alters doxorubicin pharmacokinetics. METHODS: Twenty-five patients were treated with doxorubicin (60 mg/m2) preceded by administration of ADR-529 in escalating dosages (i.e., 60, 300, 600, 750, and 900 mg/m2) to groups of three to nine patients. ADR-529 was administered over a 15-minute period beginning 30 minutes before doxorubicin treatment; the protocol was repeated every 3 weeks. Blood was sampled frequently for drug levels, which were determined by high-pressure liquid chromatography with fluorescence (doxorubicin) and electrochemical detection (ADR-529). RESULTS: Dose-limiting neutropenia occurred in four of six previously treated patients at an ADR-529 dose of 600 mg/m2; the dose ratio of ADR-529 to doxorubicin was 10:1. For three additional patients with better Eastern Cooperative Oncology Group performance status and a maximum of one prior chemotherapy regimen, 600 mg/m2 was tolerated, but grade 3 or 4 neutropenia occurred in four of six patients who received an ADR-529 dose of 900 mg/m2 and in three of four patients at a dose of 750 mg/m2. Doxorubicin's estimated terminal half-life was 39.5 +/- 18.3 (mean +/- SD) hours; the area under the curve for plasma concentration of drug x time (AUC) was 1.74 +/- 0.40 (micrograms/microL) x hour. Total-body clearance was 598 +/- 142 microL/m2 per minute (N = 20), and it did not vary with ADR-529 dose. Estimated distribution and elimination phase half-lives for plasma ADR-529 were 0.46 +/- 0.30 hours and 4.16 +/- 2.94 hours, respectively. Total-body clearance was 111 +/- 87 microL/m2 per minute (N = 18); AUC was linear (r2 = .92), and the clearance rate was constant (r2 = .18) from 60 to 900 mg/m2. CONCLUSIONS: Myelotoxicity was dose limiting for ADR-529 at 600-750 mg/m2 when given with a fixed dose of doxorubicin at 60 mg/m2 (dose ratios of ADR-529 to doxorubicin ranged from 10:1 to 12.5:1). When used in combination, ADR-529 did not perturb doxorubicin's distribution, metabolism, or excretion; therefore, other mechanisms of cardioprotection must be involved. IMPLICATIONS: We recommend that an ADR-529 dose of 600 mg/m2 be given with single-agent doxorubicin at a dose of 60 mg/m2 in future studies.     

Reducing doxorubicin cardiotoxicity in the rat using deferred treatment with ADR-529

Summary The purpose of this study was to evaluate the optimal timing of ADR-529 administration to protect rats treated with doxorubicin (DXR) against drug-induced cardiotoxicity. Complete electrocardiographic monitoring (QRS complex, ST segment and T wave) and the histopathological analysis of cardiac tissue were used to assess the degree of heart damage produced in female rats treated with ten i.v. doses of 1 mg/kg DXR over a period of 15 weeks; body-weight increase and survival were also analyzed to evaluate the toxicity of treatments. Cardiac alterations induced by DXR were compared with those occurring in animals receiving 20 mg/kg i.v. ADR-529 at 30 min prior to DXR administration, starting at the first, third, or sixth DXR dose and given until the end of the study (15th week). Rats treated with DXR were severely cardiomyopathic, showing progressive and irreversible ECG alterations (QRS-complex and ST-segment widening and T-wave flattening) and marked degeneration of the myocardium (myocyte vacuolation, myofibrillar loss, and endomyocardial fibrosis). The most effective cardiac protection was provided by the administration of ADR-529 beginning with the first or third DXR dose. Delaying treatment with ADR-529 until the sixth DXR dose resulted in a significant reduction in its therapeutic action on heart damage. A significant difference in body-weight increase and survival was observed between the treatment groups: ADR-529 injected prior to the first DXR dose significantly protected animals from DXR toxicity, but this schedule was significantly more toxic than the administration of ADR-529 beginning with the third or sixth DXR dose. Taking into account the degree of cardiac protection and the toxicity of combination treatments, the results of the present study demonstrate the superiority of ADR-529 given prior to the third DXR dose over the other schedules tested. This finding suggests that significant protection against DXR-induced chronic cardiotoxicity in the rat can be obtained using deferred treatment with ADR-529.Presented in part at the 81st Annual Meeting of the American Association for Cancer Research, Washington, D. C., May 23–26, 1990ADR-529 is the proprietary name (Farmitalia Carlo-Erba, Milano, Italy) for ICRF-187     

A functional assessment of the relative cardiotoxicity of adriamycin and epirubicin in the rat

The cardiotoxicity of the two anthracyclines, adriamycin and epirubicin, were studied in 14-week-old Sprague-Dawley rats after the intravenous administration of single doses of 1-4 mg/kg of adriamycin and 2-6 mg/kg of epirubicin. These doses of the two drugs were well tolerated with little acute toxicity. Acute toxicity was characterised by a transient reduction in body weight with recovery within 14 days. The cardiac output of the rats was measured at 4-weekly intervals, for up to 20 weeks, using an external counting technique with the radioactive tracer, 99mTc. The time-related changes in cardiac function in the rat after adriamycin and epirubicin were similar. The time course of the changes in cardiac output were biphasic. There was an initial phase of rapid decline in cardiac output in the first 12 weeks (phase I) and a second phase of persistent depression in cardiac function (phase II) after 12 weeks. The late progression of anthracycline-induced cardiotoxicity could be predicted from the measurements of cardiac output at 12 weeks. The relative cardiotoxicity of adriamycin and epirubicin was evaluated from the reductions in cardiac output and from the incidence of deaths related to cardiotoxicity. Both methods of evaluation showed that adriamycin was approximately twice as cardiotoxic as epirubicin. This relationship was independent both of the dose level of drugs used and of the damage level used for the evaluation. Dose-response curves were steeper for adriamycin than for epirubicin. The present findings agree with the somewhat limited clinical data suggesting that the present rat model is highly predictive and clinically relevant.     

The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi's sarcoma patients treated with pegylated liposomal doxorubicin

Background: Pegylated liposomal doxorubicin (PL-DOX) has been shown in preclinical models to induce less cardiotoxicity than non-liposomal doxorubicin. Endomyocardial biopsy is a highly sensitive and specific method for detecting anthracycline-induced cardiac damage.Patients and methods: Myocardial tissue from ten KS patients who had received cumulative PL-DOX (20 mg/m²/biweekly) of 440–840 mg/m² was evaluated for evidence of anthracycline-induced cardiac damage. Controls were assembled from patients who had received cumulative doxorubicin doses of 174–671 mg/m² in two earlier cardiac biopsy protocols. Two control groups were selected on the basis of both cumulative (±10 mg/m²) and peak doxorubicin dose (60 or 20 mg/m², control group 1), or peak dose alone (20 mg/m², control group 2).Results: PL-DOX patients had significantly lower biopsy scores compared with those of doxorubicin controls despite higher cumulative doses of anthracycline. The median biopsy scores for the PL-DOX and doxorubicin groups, respectively, were 0.3 vs. 3.0 (P = 0.002, Cochran–Mantel–Haenszel row mean difference test) for group 1 and 1.25 for group 2 (P < 0.001, Wilcoxon rank-sum test).Conclusions: Less severe cardiac changes were seen in patients given PL-DOX relative to historical control patients given comparable cumulative doses of doxorubicin.     

Activity of high-dose epirubicin in advanced non-small cell lung cancer

24 patients with unresectable non-small cell lung cancer (NSCLC) (14 stage IIIB and 10 stage IV) with a performance status of 70% or higher and without liver metastases received 120–165 mg/m² epirubicin as an intravenous bolus every 21–28 days up to the maximum cumulative dose of 900 mg/m². 6 patients (25%) (95% confidence limits 9.8–46.7%) achieved partial remission for a median duration of 7.5 months (range: 3–13+). The median dose actually administered per course was 120 mg/m² in responsive and non-responsive patients. The dose-limiting side-effect was neutropenia. 1 patient receiving the higher dose died of drug-related infection. Other non-dose-related grade 3 side-effects were alopecia (100%) and vomiting (17%). In 4 patients, the treatment was interrupted because of a >10% reduction in the left ventricular ejection fraction as calculated by radionuclide angiocardiography. None of these patients suffered from cardiac symptoms. The median survival was 10 months (range 1–16). These data suggest that epirubicin at 120–135 mg/m² may have higher antitumour activity than standard doses in patients with NSCLC. Further studies are needed to clarify whether or not high-dose epirubicin increases, the risk of cardiotoxicity compared to standard doses.     

Identification of the highest dose of docetaxel associable with active doses of epirubicin. Results from a dose-finding study in advanced breast cancer patients

Purpose:To determine the maximum tolerated dose (MTD) and thedose limiting toxicity (DLT) of docetaxel in combination with fixed doses ofepirubicin. Patients and methods:Women with locally advanced or metastaticbreast cancer were given docetaxel, 60 mg/m² in escalated doses bysteps of 10 mg/m², in association with two fixed doses ofepirubicin (90 mg/m², and 75 mg/m²). Since neutropeniawas foreseen to be the most likely DLT, a third group with prophylactic G-CSFsupport was planned to define the MTD of docetaxel with 90 mg/m²of epirubicin. Selected patients underwent pharmacokinetic evaluation ofdocetaxel. Results:Fifty-eight patients entered the study. At the first step(90 mg/m² of epirubicin) the MTD was obtained at 60mg/m² of docetaxel. At the second step (75 mg/m² ofepirubicin) the MTD of docetaxel was 80 mg/m². At the third step(epirubicin 90 mg/m²) G-CSF allowed a safe escalation of docetaxelup to 90 mg/m². Neutropenia was the most common hematologicaladverse event. Without G-CSF, grade 4 neutropenia occurred in 69% ofcycles, of which 11% was complicated by fever. In G-CSF group, grade4 neutropenia and neutropenic fever occurred in 31% and 3%,respectively. Most frequent non-hematological adverse effects were asthenia(45%), nausea (39%) and mucositis (36%). No patientdeveloped congestive heart failure. Two toxic deaths occurred. Overallresponse rate was 73% in 42 out of 58 patients, with no apparentepirubicin dose-related effect. No statistically significant effect of the twodoses of epirubicin was observed in docetaxel pharmacokinetics. Conclusions:On the basis of the toxicity profile, the docetaxelpharmacokinetics and the response rate observed, epirubicin 75mg/m² combined with docetaxel 80 mg/m² can berecommended for further studies.     

A randomized trial of two regimens of cyclophosphamide,methotrexate, 5-fluorouracil,and prednisone in advanced breast cancer

Summary One-hundred evaluable patients with progressive advanced breast carcinoma untreated by cytotoxic chemotherapy but resistant to hormone therapy and irradiation were randomly allocated to receive either a combination of cyclophosphamide (600 mg/m²), methotrexate (40 mg/m²), 5-fluorouracil (600 mg/m²) IV every 3 weeks and prednisone 20 mg/m² PO daily, with diminishing doses (intermittent group), or a combination of cyclophosphamide (100 mg/m² PO on days 1–15, alternating with a 15-day rest period), methotrexate 20 mg/m² IV, 5-fluorouracil 500 mg/m² IV weekly for 20 weeks and prednisone 20 mg/m² PO daily, with diminishing doses in the remission induction period, followed by a maintenance regimen of cyclophosphamide 100 mg/m² PO on days 1–15, methotrexate 20 mg/m² IV on days 1, 8, and 15, 5-fluorouracil 500 mg/m² IV on days 1, 8, and 15, and prednisone 20 mg/m² PO on days 1–15, with a 3-week rest period between the courses (intensive group). Entry was from 1 December 1982 to 30 November 1983. Objective responses were seen in 20/49 (41%) patients in the intermittent group and 34/51 (67%) in the intensive group (²=6.72; P<0.01). The estimated median duration of response was 11 months in the intermittent group and 14 months in the intensive group. The estimated median survival was greater in the intensive group, but the difference was not statistically significant, although this parameter can be influenced with alternative additional chemotherapy. Toxicity was similar in both groups. These data suggest there are no therapeutic and survival advantages to the 3-weekly IV protocol compared with our previous regimen CMFP.     

The relative toxicity of intravenous and intraperitoneal doses of epirubicin

Summary The toxicity of single doses of the anthracycline epirubicin was compared in the rat after either the intravenous (i.v.: 2–6 mg/kg) or intraperitoneal (i.p.; 4–8 mg/kg) administration of the drug. These doses produced comparable acute toxicity that was characterised by a dose-dependent, transient reduction in body weight (<15%) in the first 2 weeks after drug administration. Sequential measurements of cardiac output in animals that received i.v. doses of epirubicin showed that the time-related changes in cardiac function were biphasic. There was an initial decline in cardiac output in the first 12 weeks, which was followed by a phase of persistent depression in cardiac output between 12 weeks and 20 weeks. The time-related changes in cardiac function after i.p. doses of the drug were more variable, although the trend of changes, as after i.v. administration, appeared to be dose-dependent. Recovery of cardiac function occurred at 20 weeks after an i.p. dose of 4 mg/kg; however, after 6 mg/kg, cardiac function was significantly depressed after 16 weeks. For both routes of administration, the likelihood of late cardiac complications was dependent on the level of the reduction in cardiac output at 12 weeks. A study of the impairment of cardiac output and the incidence of cardiac-related mortality demonstrated that epirubicin was more cardiotoxic after i.v. administration. Equivalent cardiotoxic doses of epirubicin after i.v. and i.p. administration were highly linearly correlated (r=0.998), although there appeared to be a threshold dose of 3.33 mg/kg after i.p. administration of the drug. Thus, the relative cardiotoxicity between the two routes of administration was found to be dependent on the drug dose and, hence, the level of effect. The difference in the effect was less for high drug doses. The LD₅₀ for deaths due to cardiotoxicity at 20 weeks was 4.42±0.42 mg/kg after i.v. administration, which was significantly lower than the value of 6.28±0.41 mg/kg obtained after i.p. administration of the drug (P<0.01). There was no qualitative difference in the histological lesions induced in the myocardium after the i.v. vs i.p. administration of epirubicin.     

A phase I study of ixabepilone in combination with epirubicin in patients with metastatic breast cancer

PurposeThe objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLT), pharmacokinetics, and the recommended phase II dose for ixabepilone in combination with epirubicin in women with metastatic breast cancer.Patients and MethodsPatients ≥18 years old with an histologically or cytologically confirmed diagnosis of invasive breast cancer and clinical evidence of locally recurrent or metastatic disease were enrolled and treated with a fixed dose of epirubicin (75 mg/m²) and escalating doses of ixabepilone (25, 30, and 35 mg/m²).ResultsForty-two women were treated at 3 different dose levels of ixabepilone: 25 (n = 6), 30 (n = 30), and 35 mg/m² (n = 6) in combination with 75 mg/m² epirubicin. The MTD of ixabepilone in combination with epirubicin 75 mg/m² was 30 mg/m², and the DLT dose was 35 mg/m² with grade 4 neutropenia. Grade 3/4 neutropenia was the most frequent moderate-to-severe adverse event and was manageable and reversible. No deaths were reported. Objective responses were achieved in 18 of 32 patients with measurable disease (56% [90% CI, 40%-71%]) and in 9 of 22 evaluable patients treated at the MTD (41% [90% CI, 23%-61%]). Ixabepilone clearance and the epirubicin pharmacokinetic profile were similar across ixabepilone dose levels.ConclusionsThe combination of ixabepilone and epirubicin was clinically active. The recommended dose for evaluation in phase II is epirubicin 75 mg/m², followed by ixabepilone 30 mg/m² every 3 weeks.     

Doxorubicin: Effect of different schedules on toxicity and anti-tumor efficacy

The risk of congestive heart failure restricts the clinical use of doxorubicin to cumulative doses of 450–550 mg/m², when it is given using high-dose rapid intravenous application. As the high peak serum levels which follow rapid administration seem to be correlated with cardiotoxicity, application schedules leading to lower peak serum concentrations have been developed. This paper reviews the influence of those schedules on cardiotoxicity, non-cardiac toxicities, pharmacokinetic data and antineoplastic efficacy. While the reduction of cardiotoxicity by long-term application schedules is well documented, much less can be said about the antitumor effect of those schedules. Controlled studies dealing with this problem are needed. This review provides a base for that purpose.     

Dexrazoxane-afforded protection against chronic anthracycline cardiotoxicity in vivo: effective rescue of cardiomyocytes from apoptotic cell death

Background:

Dexrazoxane (DEX, ICRF-187) is the only clinically approved cardioprotectant against anthracycline cardiotoxicity. It has been traditionally postulated to undergo hydrolysis to iron-chelating agent ADR-925 and to prevent anthracycline-induced oxidative stress, progressive cardiomyocyte degeneration and subsequent non-programmed cell death. However, the additional capability of DEX to protect cardiomyocytes from apoptosis has remained unsubstantiated under clinically relevant in vivo conditions.

Methods:

Chronic anthracycline cardiotoxicity was induced in rabbits by repeated daunorubicin (DAU) administrations (3 mg kg⁻¹ weekly for 10 weeks). Cardiomyocyte apoptosis was evaluated using TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling) assay and activities of caspases 3/7, 8, 9 and 12. Lipoperoxidation was assayed using HPLC determination of myocardial malondialdehyde and 4-hydroxynonenal immunodetection.

Results:

Dexrazoxane (60 mg kg⁻¹) co-treatment was capable of overcoming DAU-induced mortality, left ventricular dysfunction, profound structural damage of the myocardium and release of cardiac troponin T and I to circulation. Moreover, for the first time, it has been shown that DEX affords significant and nearly complete cardioprotection against anthracycline-induced apoptosis in vivo and effectively suppresses the complex apoptotic signalling triggered by DAU. In individual animals, the severity of apoptotic parameters significantly correlated with cardiac function. However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation.

Conclusion:

This study identifies inhibition of apoptosis as an important target for effective cardioprotection against chronic anthracycline cardiotoxicity and suggests that lipoperoxidation-independent mechanisms are involved in the cardioprotective action of DEX.     

Influence of trastuzumab on epirubicin pharmacokinetics in metastatic breast cancer patients.

BACKGROUND: Anthracycline cardiotoxicity is increased by the contemporaneous administration of trastuzumab. The mechanism by which it occurs is as yet unknown. The aim of this study was to evaluate whether trastuzumab modifies the pharmacokinetics of epirubicin and its metabolites. PATIENTS AND METHODS: Women with HER2-positive metastatic breast cancer were treated with epirubicin 75 mg/m(2) i.v. bolus followed by docetaxel 75 mg/m(2) in a 1-h infusion, every 3 weeks for six cycles, and trastuzumab (once at 4 mg/m(2), then 2 mg/m(2) weekly thereafter) in a 30-min infusion. Epirubicin pharmacokinetic data of seven patients were evaluated at the first cycle of therapy (baseline, with trastuzumab administered 24 h after epirubicin), and at the sixth cycle (i.e. 15 weeks after baseline, with trastuzumab administered immediately before epirubicin). RESULTS: No pharmacokinetic change in the parent compound epirubicin was detected. The area under the plasma concentration-time curve (AUC(0-24 h)) was 1230 +/- 318 [mean +/- standard deviation (SD)] at the first cycle and 1287 +/- 385 h. micro g/l at the sixth. The mean (+/-SD) maximum plasma concentration (C(max)) and the terminal elimination half-life at the first cycle (1303 +/- 490 micro g/l and 12.5 +/- 3.1 h, respectively) were similar to those obtained at the sixth cycle (1229 +/- 580 micro g/l and 11.5 +/- 2.9 h, respectively). Pharmacokinetic data of epirubicin metabolites evaluated at the first and sixth cycle of chemotherapy were superimposable without any statistical difference. CONCLUSION: Enhanced anthracycline cardiotoxicity related to trastuzumab administration was not linked to pharmacokinetic interferences with epirubicin and its metabolites.     

Pharmacokinetic study of gemcitabine, given as prolonged infusion at fixed dose rate, in combination with cisplatin in patients with advanced non-small-cell lung cancer

Introduction

Although some studies have suggested that gemcitabine delivered as a fixed dose rate (FDR) infusion of 10 mg/m²/min could be more effective than when administered as the standard 30-min infusion, the available pharmacokinetic data are still too limited to draw definitive conclusions. This study is aimed to investigate the plasmatic and intracellular pharmacokinetics of gemcitabine given as FDR at doses of 600 and 1,200 mg/m² in combination with 75 mg/m² of cisplatin in advanced non-small-cell lung cancer (NSCLC) patients.

Patients and method

The patients were divided into two groups receiving different initial doses of the drug: 4 patients received 600 mg/m² gemcitabine 60-min i.v. infusion and 4 patients 1,200 mg/m² gemcitabine 120-min i.v. infusion both as a FDR of 10 mg/m²/min on days 1 and 8 of a 21-day cycle (at first cycle). At the second cycle, all patients were treated with gemcitabine at 1,200 mg/m² 120-min i.v. infusion (FDR of 10 mg/m²/min) on days 1 and 8 of a 21-day cycle. At each cycle, gemcitabine was administered alone on day one, and in combination with 75 mg/m² of cisplatin on day 8. Plasmatic and intracellular pharmacokinetic analyses were performed on blood samples collected at defined time points before, during and after gemcitabine infusion.

Results

The plasmatic pharmacokinetic parameters were clearly different when the patients received a higher gemcitabine dose in the second cycle compared to the lower dose of the first course; in the same time, the intracellular drug levels were not modified. Comparing the pharmacokinetic parameters of different patients treated at different dose levels, the results appeared to be quite similar.

Conclusions

A substantially higher accumulation of metabolites in peripheral blood mononuclear cells was observed when the longer infusion time was employed, suggesting a pharmacological advantage for this treatment schedule.     

Phase I, pharmacokinetic, and biological studies of TSU-68, a novel multiple receptor tyrosine kinase inhibitor, administered after meals with solid tumors

Purpose

TSU-68 is a low molecular weight inhibitor of the tyrosine kinases for vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor ??, and fibroblast growth factors receptor 1. In this study, we assessed the recommended dose with TSU-68 administration of twice-daily (b.i.d.) or thrice-daily (t.i.d.) after meals for 4?weeks in Japanese patients with solid tumors based on the safety and tolerability and investigated the relationship between angiogenesis biomarker and clinical outcomes.

Methods

The study design was a dose-escalation method with alternating enrollment of b.i.d. administration and t.i.d. administration after meal by traditional three-patient cohort.

Results

We enrolled 24 patients at doses of 200, 400, and 500?mg/m² b.i.d. or 200 and 400?mg/m² t.i.d. No dose-limiting toxicity (DLT) occurred in the 200?mg/m² b.i.d. or t.i.d., and 3 patients experienced DLTs at 400?mg/m² b.i.d. or 400?mg/m² t.i.d. As main toxicity, blood albumin decreased, malaise, diarrhea, alkaline phosphatase increased, anorexia, abdominal pain, nausea, and vomiting were observed as almost all grade 1?C2. There were no apparent differences in pharmacokinetic parameters between days 2 and 28 after the repeated b.i.d. and t.i.d. doses. Although tumor shrinkage was not observed, the disease control rate was 41.7%. As an angiogenesis-related factor of stratified analysis, plasma vascular endothelial growth factor and plasminogen activator inhibitor-1 were detected as a significant increase with progressive disease patients.

Conclusions

A recommended dosage of TSU-68 for this administration schedules was estimated to be 400?mg/m² or less b.i.d.     

Persistence,Up to 18 Months of Follow‐Up,of Epirubicin‐Induced Myocardial Dysfunction Detected Early by Serial Tissue Doppler Echocardiography: Correlation with Inflammatory and Oxidative Stress Markers

A phase II, open, nonrandomized trial was carried out in a group of epirubicin‐treated cancer patients with the aim of detecting early preclinical changes that are predictive of the risk for heart failure. Thirty‐one patients (male/female ratio, 8/23; mean age ± standard deviation, 59 ± 14 years) with tumors at different sites and scheduled to be treated with an epirubicin‐based chemotherapy regimen, were enrolled. We prospectively evaluated the acute (1 week after) and late (3, 6, 12, and 18 months of follow‐up) effects of epirubicin administration. A significant impairment in systolic left ventricular (LV) function was observed at a cumulative epirubicin dose of 200 mg/m². This was shown by a reduction in the strain rate (SR) peak in comparison with baseline and persisted throughout the treatment and follow‐up, up to 18 months; strain (Σ) remained unchanged. The Sm wave showed a progressive reduction that became significant only at the 18‐month follow‐up. On TDI the E_m/A_m ratio declined at the 200‐mg/m² cumulative epirubicin dose versus baseline and persisted throughout the treatment and up to the 18‐month follow‐up. On conventional echocardiography the E/A ratio declined significantly only at the 300‐mg/m² cumulative epirubicin dose. Interleukin (IL)‐6, soluble IL‐6 receptor, and reactive oxygen species (ROS) increased significantly at the 200‐mg/m² dose, and IL‐6 was persistently high at the 300‐ and 400‐mg/m² doses, returning to within baseline values during follow‐up. ROS, after the peak reached at the 200‐mg/m² dose, returned to within baseline values. A significant inverse correlation between ΔSR and the increase in both IL‐6 and ROS was observed. A multiple regression analysis showed that both the IL‐6 and ROS variables were independent and strongly predictive of ΔSR. The clinical meaningfulness of our findings warrants further investigations on a larger number of patients for a longer period of follow‐up.     

A dose escalation and pharmacokinetic study of the biweekly administration of paclitaxel, gemcitabine and oxaliplatin in patients with advanced solid tumors

Purpose

To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) of the paclitaxel, gemcitabine, oxaliplatin combination administered biweekly in patients with advanced solid tumors.

Patients and methods

Patients received escalated doses of paclitaxel (starting dose: 100 mg/m²), gemcitabine (starting dose: 800 mg/m²) and oxaliplatin (starting dose: 50 mg/m²) on days 1 and 15 in cycles of every 4 weeks. DLTs were evaluated during the first cycle.

Results

Twenty-seven patients (median age 65 years) with performance status 0–1 were treated on six dose escalation levels. Eleven patients (40.7%) were chemotherapy naïve, six (22.2%) had received 1 prior chemotherapy regimen and ten (37.1%) 2 or more. The DLT level was reached at the doses of paclitaxel 110 mg/m², gemcitabine 1,150 mg/m² and LOHP 70 mg/m². The dose-limiting events were grade 4 neutropenia and grade 3 febrile neutropenia. Neutropenia was the most common adverse event. A median of 3 cycles per patient was administered. One complete and five partial responses were observed in patients with ovarian carcinoma, NSCLC, urothelial cancer, mesothelioma and cancer of unknown primary. No pharmacokinetic drug interactions were detected.

Conclusions

The recommended doses for future phase II studies of this combination are paclitaxel 110 mg/m², gemcitabine 1,000 mg/m² and oxaliplatin 70 mg/m² every 2 weeks. The regimen is generally well tolerated and merits further evaluation.     

5-Fluorouracil,Epirubicin and Cyclophosphamide (FEC Combination) in Advanced Breast Cancer

Summary

Thirty patients with advanced breast cancer, not pretreated with chemotherapy for advanced disease, received a polychemotherapy regimen containing 5-fluorouracil (500 mg/m² iv), epirubicin (50 mg/m² iv) and cyclophosphamide (500 mg/m² iv) every four weeks.

All patients were evaluable for response and for toxicity. No complete remissions were observed, while 13 patients (43.5%) achieved a partial remission for a median duration of 46 weeks. The main side-effects were alopecia (grade 2-3 in 57%), leukopenia (grade 3-4 in 33%) and nausea/vomiting (grade 3-4 in 27%). In three cases we observed laboratory signs of cardiotoxicity without clinical symptoms.     

Phase I study of 3-weekly combination chemotherapy using epirubicin, oxaliplatin, and S-1 (EOS) in patients with previously untreated advanced gastric cancer

Purpose

This study was performed to determine the recommended dose (RD) and dose-limiting toxicity (DLT) associated with epirubicin, oxaliplatin, and S-1 (EOS) combination therapy in patients with previously untreated advanced gastric cancer (AGC).

Materials and methods

Previously untreated patients with histologically proven metastatic AGC, with an ECOG performance status of 0?C2, were enrolled in this study. A fixed dose of epirubicin (50?mg/m²) and oxaliplatin (130?mg/m²) was intravenously administered on day 1 of treatment, followed by oral S-1 administration twice daily on days 1?C14. The S-1 dose was escalated according to the following schedule: level I, 35?mg/m²; level II, 40?mg/m²; level III, 45?mg/m²; Level IV, 50?mg/m². Each cycle was repeated every 21?days. DLTs were evaluated during the first two cycles of treatment.

Results

Nineteen patients with a median age of 53?years (range, 40?C71?years) were enrolled in this study. One case of DLT (grade 4 neutropenia lasting more than 5?days) developed from among the six dose level II patients, while 2 DLTs (grade 3 diarrhea and nausea) were observed among the 4 dose level III patients. Based on these results, dose level II was determined as the RD. Of the 13 patients with measurable lesions, eight achieved partial response, three showed stable disease, and the objective response rate was 61.5?% (95?% confidence interval (CI), 13.3?C66.6?%). The median progression-free survival and overall survival of all patients was 6.8?months (95?% CI, 1.4?C9.5?months) and 13.3?months (95?% CI, 1.9?C24.6?months), respectively.

Conclusion

The RD of the EOS regimen in patients with previously untreated AGC was 50?mg/m² of epirubicin and 130?mg/m² of oxaliplatin on day 1, with administration of 40?mg/m² of S-1 twice a day on days 1?C14 for each 21-day cycle. The EOS regimen described produced promising results.     

A phase I trial of 5-fluorouracil,leucovorin, and dipyridamole given by concurrent 120-h continuous infusions

Summary A phase I trial of 5-fluorouracil (FUra) and leucovorin (LV) given with and without dipyridamole (DP) by concurrent 120-h continuous infusion was performed in 27 patients with advanced solid malignancies, 8 of whom had previously received FUra. The LV and DP doses were fixed at 500 mg/m² daily and 7.7 mg/kg daily, respectively, whereas the FUra dose was escalated. Level 3 (450 mg/m² FUra daily) represented the maximum tolerated dose for both FUra/LV+DP and FUra/LV. Dose-limiting stomatitis (grade 3 or grade 2 occurring during the infusion) was encountered in 75% of the first courses given at level 4 (600 mg/m² daily). Stomatitis was observed in 44/78 (56%) courses.Diarrhea was infrequent and mild. DP infusions were complicated by mild to moderate headache, which was controlled with narcotic analgesics, and mild to moderate nausea/vomiting. FUra-related toxicity was not enhanced by DP administration. Limited pharmacokinetic sampling at levels 3 and 4 revealed mean steady-state FUra concentrations of around 1.0 M with infusions of FUra/LV+DP. Among three paired courses given with and without DP, no statistically significant difference was found in the total body clearance of FUra (P=0.44). One partial response was seen in a patient with metastatic gastric carcinoma. For phase II trials, we recommend that concurrent 120-h continuous infusions of FUra (450mg/m² daily) and LV (500 mg/m² daily) be given with and without DP (7.7 mg/kg daily) every 21 days.This study was supported by NIH contracts NO1-CM-57735 and NO1-CM-07306 and was partially supported by NIH grant MO1 RR03186. The senior author(H. B.) was partially supported by grant TA32-CA09614.