Disposition of total and unbound etoposide following high-dose therapy

Total and unbound etoposide pharmacokinetics were studied in 16 adult patients (median age, 34 years; range, 18–61 years) undergoing autologous bone marrow transplantation for advanced lymphoma after receiving high-dose etoposide (35–60 mg/kg) as a single intravenous infusion. Pretreatment values for mean serum albumin and total bilirubin were 3.0±0.4 g/dl and 0.5±0.4 mg/dl, respectively. Etoposide plasma concentrations and protein binding (% unbound) were determined by high-performance liquid chromatography (HPLC) and equilibrium dialysis, respectively. Pharmacokinetic parameters for unbound and total etoposide were calculated by nonlinear regression analysis using a two-compartment model. Te mean (±SD) parameters for total etoposide included: clearance (CL), 31.8±17.7 ml min^–1 m^–2; volume of distribution (V_ss), 11.5±5.9 l/m², and terminal half-life (t _1/2 ), 7.2±3.7 h. Mean unbound CL was 209.6±62.7 ml min^–1 m^–2 and %unbound was 16%±5%. The mean etoposide %unbound was inversely related to serum albumin (r ²=0.45,P=0.0043). The mean %unbound at the end of the etoposide infusion was higher than that at the lowest measured concentration (21% vs 13%, respectively;P=0.017), suggesting that concentration-dependent binding may occur after high etoposide doses. The median total CL was higher in patients with serum albumin concentrations of 3.0 g/dl than in those with levels of >3.0 g/dl (34.6 vs 23.5 ml min^–1 m^–2,P=0.05). Total CL was directly related to %unbound (r ²=0.61,P=0.0004). Unbound CL was unrelated to either serum albumin or %unbound. These results demonstrate that hypoalbuminemia is independently associated with an increased etoposide %unbound and rapid total CL after the administration of high-dose etoposide. Unbound CL in hypoalbuminemic patients is unchanged in the presence of normal total bilirubin values.This study was supported in part by Bristol-Myers. Oncology Division     

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.     

Effect of the nonimmunosuppressive cyclosporin analog SDZ PSC-833 on colchicine and doxorubicin biliary secretion by the rat in vivo

Colchicine and doxorubicin are secreted into bile as a major pathway of their elimination. Colchicine and doxorubicin are also substrates for P-glycoprotein, and P-glycoprotein has been demonstrated to be present at the liver canalicular membrane. Cyclosporin (CsA) inhibits colchicine biliary secretion in vivo. In the present study, the effects of SDZ PSC-833, a nonimmunosuppressive cyclosporin D analog, on the biliary secretion of colchicine and doxorubicin were investigated. SDZ PSC-833 given at a bolus dose of 2 mg/kg promptly decreased colchicine biliary clearance from 9.05±0.2 to 2.41±0.43 ml min^–1 kg^–1 (P<0.001) and the colchicine bile/plasma ratio from 146±8 to 35±5 (P<0.001). SDZ PSC-833 also inhibited doxorubicin biliary clearance (basal: 10.5±3 vs post-SDZ PSC-833: 2.48±0.94 ml min^–1 kg^–1;P=0.06) and the doxorubicin bile/plasma ratio (basal: 228±64 vs post-SDZ PSC-833: 48±22;P<0.01). Colchicine renal secretion was completely inhibited by SDZ PSC-833. Thus, SDZ PSC-833 inhibits the constitutive transport of the multidrug-resistance substrates colchicine and doxorubicin and is more potent than cyclosporin in this regard. The possibility of increased toxicity to normal tissues because of impaired elimination of cytotoxic agents will need to be considered if SDZ PSC-833 is used to chemosensitize cancer cells.This work was supported in part by the Research Service, Department of Veterans Affairs     

The effect of food on oral melphalan absorption

Summary Fifteen patients receiving oral melphalan (4.2–5.3 mg/m²) for a variety of neoplastic disorders were studied. Ten patients received the drug on separate occasions, with and without a standardized breakfast. Eight of these patients also received an IV bolus dose (5 mg/m²) to determine bioavailability. Serial melphalan plasma samples were taken over 5 h after administration and assayed by high-performance liquid chromatography. The median area under the curve (AUC) when taken fasting was 179 (range 95–336) ng · h · ml^-1, and when taken with food, 122 (47–227) ng · h · ml^-1, the median reduction being 39% (P0.01). In one patient, who died before completing the study, the drug was not detectable at all after being taken with food. In the eight patients who were also given IV melphalan, the median terminal melphalan half-life (57 min, range 38–71) was no different from its oral half-life [55 (27–104) min fasting; 55 (30–72) min with food] (P>0.1). In these patients bioavailability was 85% (26–96)% when the drug was taken fasting and 58% (7–99)% when taken with food (P0.025). Median clearance following IV administration was 362 ml/min/m² (range 104–694). It was found that the melphalan level in a single plasma sample drawn 1.5 h after administration was highly predictive of oral melphalan AUC (r_s=0.915, P0.1). This study suggests that to ensure optimum absorption of the drug, melphalan should not be taken with food.     

A pharmacokinetic and pharmacodynamic study of the new anthracycline pirarubicin in breast cancer patients

Summary We evaluated the pharmacokinetics of pirarubicin during 16 courses of therapy in 4 patients suffering from breast cancer who were treated with an association of pirarubicin (30–60 mg/m² according to the hematologic tolerance to the previous course, the first course being given at a dose of 40 mg/m²) and continuous infusions of 5-fluorouracil (750 mg/m² daily for 5 days). Pirarubicin's pharmacokinetics and metabolism were linear within this dose range; the metabolites identified were pirarubicinol, doxorubicin and doxorubicinol (AUC ratios of metabolite/pirarubicin were 0.6, 0.64 and 0.57 respectively). Pirarubicin's decay from plasma followed a twocompartmental pattern, showing half-lives of 15.6 min and 16.6 h: the total plasma clearance of the drug was 140 l/h^–1/m^–2, and the total volume of distribution was 2,830 l/m². A relationship was observed between some pharmacokinetic parameters and the toxic effects of the drug: the percentage of survival of granulocytes was significantly correlated with the AUC values for doxorubicin and doxorubicinol, whereas that of platelets was significantly correlated with the AUC values for pirarubicin and pirarubicinol. This is the first study to demonstrate a pharmacokinetic/pharmacodynamic relationship for pirarubicin.     

Eight-hour infusion versus bolus injection of doxorubicin in the EAP regimen in patients with advanced gastric cancer: A prospective randomised trial

Background:Doxorubicin (40 mg/m²/cycle), etoposide(360 mg/m²/cycle) and cisplatin (80 mg/m²/cycle)comprise an efficient regimen in patients with advanced gastric cancer (AGC).However, its excessive hematological toxicity led doctors to avoid using thecombination. Doxorubicin is the main cause of myelotoxicity in the EAPregimen. The aim of this study was to compare an eight-hour infusion ofdoxorubicin (arm A) with intravenous injection of doxorubicin (arm B) in theEAP regimen with respect to toxicity, objective responses, time to progression(TTP) and survival in patients with AGC. Patients and methods:One-hundred twenty chemotherapy-naïvepatients with measurable AGC were randomised between September 1994 and August1998. Sixty patients in arm A and sixty patients in arm B were considered asfully evaluable. The arms were well balanced for age, sex distribution,previous therapy, histological grade and performance status. One-hundredeighty cycles were applied in arm A (median 2) and 201 in arm B (median 4). Results:No difference was detected (P = 0.28) in theresponse rate of arm A 20% (CR 3; PR 9; 95% CI: 10–30) andB 28% (CR 3; PR 14; 95% CI: 17–40). But there was asignificant difference in PD (P = 0.005) between arm A (51%)and arm B (36%). TTP (P = 0.01) and survival (P =0.02) analyses detected an advantage for arm B vs. arm A. Grades 3–4toxicity were as follows (arms A%/B%): anemia 8/10, leukopenia24/26, thrombocytopenia 6/16 (significance, P = 0.05),nausea/vomiting 5/8, diarrhea 6/2, mucositis 8/5. Apart from thetrombocytopenia, there was no significant difference in toxicity grades3–4 between the two arms. Four treatment-related deaths occurred, twoin each arm. Conclusions:Bolus injection of doxorubicin is superior toeight-hour doxorubicin infusion in the EAP regimen in terms of survival, TTPand PD without being significantly more toxic.     

A comparative study of bisantrene given by two dose schedules in patients with metastatic breast cancer

Summary Schedule dependency of bisantrene was evaluated in refractory metastatic breast cancer. Patients were randomly assigned to receive either a single (S) bolus injection of 300 mg/m² (37 patients) or an injection of 80 mg/m² daily for 5 days (Dx5) (35 patients) every 3–4 weeks after stratification by performance status, dominant disease site, and response to prior doxorubicin therapy. All but one patient had received prior doxorubicin. Partial remission (PR) was achieved by 5 of 35 patients (14%) in the S arm and 7 of 35 patients (20%) in the Dx5 arm (P=NS). There were 4 patients who had primary refractoriness to doxorubicin but responded to bisantrene. The median number of courses was two for both arms. The median time to progression was 5 months for the responders in each arm and 3 and 4 months, respectively, for patients who showed no change in the S and Dx5 arms. Myelosuppression was dose-limiting and greater for the Dx5 arm. Drug fever (34% versus 21% of courses; P=0.02) and myalgia (22% versus 10% of courses; P=0.02) were reported more often in the Dx5 arm; malaise was greater in the S arm. Grade 2–3 nausea and vomiting occurred more often in the S arm (40% versus 10% of courses; P<0.01). Significant hypotension that was not symptomatic occurred in 1 patient in the Dx5 arm. Phlebitis occurred in 3 patients without a central line. One patient who had previously received doxorubicin and mitomycin C developed heart failure, which was controlled with medication. Bisantrene is an effective drug for metastatic breast cancer that has incomplete cross resistance to doxorubicin, and there was no schedule dependency in this study.Presented, in part, at the 8th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas, November 7–8, 1985This study was supported by a grant from American Cyanamid Company, Medical Research Division, Lederle Laboratories     

Effect of a low-protein diet on doxorubicin pharmacokinetics in the rabbit

Summary Malnutrition involving protein deficiency, which commonly occurs in cancer patients receiving anthracycline treatment, is considered to be a risk factor for the development of cardiotoxicity. Protein deficiency has been shown to impair the metabolism of drugs such as theophylline and acetaminophen. If protein deficiency also impairs anthracycline metabolism, it could explain at least in part the enchanced anthracycline toxicity associated with malnutrition. We tested this idea by determining the effect of a low- protein, isocaloric diet on doxorubicin pharmacokinetics in rabbits. The animals were randomized into two groups for 8–12 weeks. Rabbits in group 1 received a low-protein (5%), isocaloric diet, whereas those in group 2 received a normal-protein (15%) diet. Both groups (group 1,n=15; group 2,n=14) were given 5 mg/kg doxorubicin by i.v. bolus. After doxorubicin injection, blood samples were obtained over the next 52 h for the measurement of doxorubicin and doxorubicinol plasma concentrations by high-performance liquid chromatography (HPLC) with fluorometric detection. The low-protein diet significantly decreased doxorubicin clearance (48±3 vs 59±4 ml min^–1 kg^–1;P<0.05), prolonged the terminal climination half-life (28±2 vs 22±2 h;P<0.05), and increased the area under the plasma concentration/time curve extrapolated to infinity (1722±122 vs 1405±71 ng h ml^–1;P<0.05) as compared with the values determined for rabbits fed the standard rabbit chow (15% protein). The volume of distribution for doxorubicin was not altered by the low-protein diet. In addition, in rabbits fed the the low-portein diet, the terminal elimination half-life of the alcohol metabolite, doxorubicinol was prolonged (52±5 vs 40±2 h;P<0.05). Thus, a low-protein diet causes a reduction in the ability of rabbits to eliminate doxorubicin and possibly its alcohol metabolite doxorubicinol. If a similar alteration in anthracycline pharmacokinetics occurs in malnourished cancer patients, this phenomenon may contribute to their increased risk of developing cardiotoxicity associated with anthracycline therapy.Supported by the Department of Veterans Affairs and the American Heart Foundation     

The kinetics of the auto-induction of ifosfamide metabolism during continuous infusion

It has often been reported that the oxazaphosphorines ifosfamide and cyclophosphamide induce their own metabolism. This phenomenon was studied in 21 paediatric patients over 35 courses of therapy. All patients received 9 g m^–2 of ifosfamide as a continuous infusion over 72 h. Plasma concentrations of parent drug and of the major metabolite in plasma, 3-dechloroethylifosfamide (3DC) were determined using a quantitative thin-layer chromatography (TLC) technique: A one-compartment model was fitted simultaneously to both ifosfamide and 3DC data. The model included a time-dependent clearance term, increasing asymptotically from an initial value to a final induced clearance and characterised by a first-order rate constant. A time lag, before induction of clearance began, was determined empirically. Metabolite kinetics were characterised by an elimination rate constant for the metabolite and a composite parameter comprising a formation clearance, proportional to the time-dependent clearance of parent drug, divided by the volume of distribution of the metabolite. Thus, the parameters to estimate were the volume of distribution of parent drug (V), initial clearance (Cli), final clearance (Cls), the rate constant for changing clearance (Kc), the elimination rate constant for the metabolite (Km) and Vm/fm, the metabolite volume of distribution divided by the fractional clearance to 3DC. The model of drug and metabolite kinetics produced a good fit to the data in 22 of 31 courses. In a further 4 courses an auto-inductive model for parent drug alone could be used. In the remaining courses, auto-induction could be demonstrated, but there were insufficient data to fit the model. For some patients this was due to a long time lag (up to 54 h) relative to the infusion time. The time lag varied from 6 to 54 (median, 12) h and values for the other parameters were Cli, 3.27±2.52 l h^–1m^–2, Cls, 7.50±3.03 l h^–1m^–2, V, 22.0±11.0 l m^–2,Kc, 0.086±0.074 h^–1;Km, 0.159±0.077 h^–1 and Vm/fm, 104±82 l m^–2. The values ofKc correspond to a halflife of change in clearance ranging from 2 to 157 h, although for the majority of the patients the half-life was less than 7 h and a new steady-state level was achieved during the 72 h infusion period. This model provides insight into the time course of enzyme induction during ifosfamide administration, which may continue for up to 10 days in some protocols. Since other drugs, including common anti-neoplastic agents, are metabolised by the same P450 enzyme as is ifosfamide, auto-induction may have implications for the scheduling of combined chemotherapy.     

Prediction of response to repeat utilization of anthracycline in recurrent breast cancer patients previously administered anthracycline-containing chemotherapeutic regimens as neoadjuvant or adjuvant chemotherapy

Summary Purpose: The aim of this study was to identify the predictors of the response to doxorubicin plus cyclophosphamide in patients with recurrent breast cancer (RBC) previously treated with anthracycline-containing regimens in a neoadjuvant or adjuvant setting. Method: Between December 1993 and October 2005, 664 patients had received combined doxorubicin plus cyclophosphamide chemotherapy (doxorubicin, 40 mg/m², iv on day 1; cyclophosphamide, 500 mg/m², iv on day 1, every 21 days) for RBC at our institution. In this study, we retrospectively analyzed the efficacy of doxorubicin plus cyclophosphamide in 99 of these 664 RBC patients who had also previously been administered an anthracycline-based chemotherapy in a neoadjuvant or adjuvant setting. Results: The median cumulative dose of the previously administered anthracycline was 156 mg/m². The median disease-free interval (DFI) and median anthracycline-free interval were 33.8 and 43.7 months, respectively. The overall response rate to doxorubicin plus cyclophosphamide therapy was 38.4% (95% CI; range, 28.8–48.0%). The median time to progression and overall survival were 6.2 and 17.5 months, respectively. The results of a multivariate logistic regression analysis revealed a significant association of the response to doxorubicin plus cyclophosphamide therapy with the DFI (P = 0.02); human epidermal receptor type 2 (HER2) status also tended to affect the response rate, however the association was not statistically significant (P = 0.06). Conclusion: DFI and HER2 status may be associated with the response to repeat utilization of anthracycline-containing regimens in RBC patients also treated previously with anthracycline-containing chemotherapeutic regimens in a neoadjuvant or adjuvant setting.     

Sequential doxorubicin and docetaxel as first-line treatment in metastatic breast cancer: a GEICAM-9801 phase II study

Purpose. To evaluate the efficacy and the toxicity profile of the sequential administration of doxorubicin and docetaxel as first-line chemotherapy in metastatic breast cancer (MBC). Patients and methods. Eighty-one patients received a total of 436 cycles of chemotherapy: 236 of doxorubicin (75 mg/m²) and 200 of docetaxel (100 mg/m² every 21 days). The first 35 patients received doxorubicin every 14 days with G-CSF support, and in the other 46 cases doxorubicin was administered every 21 days without G-CSF. Results. After entire treatment the overall response rate was 65% (18 complete responses). With a median follow-up of 19 months (range, 1–48 months), the median time to progression was 11.3 months and the median survival time was 31 months. As expected, febrile neutropenia was the most important toxicity and it appeared in 26 cycles (6%) and 19 patients (23%). In the patients that received doxorubicin every 14 days, the febrile neutropenia incidence was higher during docetaxel treatment, especially after its first administration. Conclusions. The dose and schedule of doxorubicin and docetaxel used in this trial seems to be active in first-line treatment of patients with MBC. The toxicity profile appears to be better than observed with concomitant schedules.     

Clinical pharmacokinetics of carboplatin in children

The present study was undertaken to evaluate in children the plasma pharmacokinetics of free carboplatin given at different doses and schedules and to evaluate the inter- and intrapatient variability and the possible influence of schedule on drug exposure. A total of 35 children (age range, 1–17 years) with malignant tumors were studied. All patients had normal renal function (creatinine clearance corrected for surface body area, above 70 ml min^–1 m^–2; range, 71–151 ml min^–1 m^–2) and none had renal involvement by malignancy. Carboplatin was given at the following doses and schedules: 175, 400, 500, and 600 mg/m² given as a 1-h infusion; 1,200 mg/m² divided into equal doses and infused over 1 h on 2 consecutive days; and 875 and 1,200 mg/m² given as a 5-day continuous infusion. A total of 57 courses were studied. Carboplatin levels in plasma ultrafiltrate (UF) samples were measured both by high-performance liquid chromatography and by atomic absorption spectrophotometry. Following a 1-h infusion, carboplatin free plasma levels decayed biphasically; the disappearance half-lives, total body clearance, and apparent volume of distribution were similar for different doses. In children with normal renal function as defined by creatinemia and blood urea nitrogen (BUN) and creatinine clearance, we found at each dose studied a limited interpatient variability of the peak plasma concentration (C_max) and the area under the concentration-time curve (AUC) and a linear correlation between the dose and both C_max (r=0.95) and AUC (r=0.97). The mean value ± SD for the dose-normalized AUC was 13±2 min m² l^–1 (n=57). The administration schedule does not seem to influence drug exposure, since prolonged i.v. infusion or bolus administration of 1,200 mg/m² achieved a similar AUC (13.78±2.90 and 15.05±1.44 mg ml^–1 min, respectively). In the nine children studied during subsequent courses a limited interpatient variability was observed and no correlation (r=0.035) was found between AUC and subsequent courses by a multivariate analysis of dose, AUC, and course number. The pharmacokinetic parameters were similar to those previously reported in adults; however, a weak correlation (r=0.52,P=0.03) between carboplatin total body clearance and creatinine clearance varying within the normal range was observed. A dosing formula appears unnecessary in children with normal renal function since a generally well-predictable free carboplatin AUC is achieved following a given dose.Supported by the Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.)     

A dose-finding study of liposomal daunorubicin with CVP (COP-X) in advanced NHL

Background:Standard therapy for lymphoma consists of acyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P) (CHOP)combination regimen. Liposomal daunorubicin (DaunoXome®) is an alternativeto doxorubicin for patients with lymphoma because of its more favorable safetyprofile and potentially more selective uptake in lymphoma. The objectives ofthis study were to determine the maximum tolerated dose (MTD) of liposomaldaunorubucin with CVP (COP-X) and the tolerability of the regimen in patientswith indolent lymphoma. Patients and methods:Patients with low-grade andintermediate-grade lymphoma having adequate cardiac, hepatic, and renalfunction were enrolled. Patients received C 750 mg/m², V 1.4mg/m² (maximum 2.0 mg), and liposomal daunorubicin 50–100mg/m² i.v. on day 1 and P 100 mg p.o. on days 1–5. MTD wasthe liposomal daunorubicin dose associated with 20% dose-limitingtoxicity (ANC <500/mm³ for >5 days or febrile neutropenia). Results:Twenty patients, median age 59 years, were treated. Theliposomal daunorubicin MTD combined with CVP was 70–80 mg/m²,depending on patient population. No significant non-hematologic toxicityoccurred. Response rate was 44% (2 complete and 5 partial responses). Conclusions:A liposomal daunorubicin dose of 80 mg/m²in the COP-X regimen was well tolerated with little non-hematologic toxicity.     

Compensatory renal response after unilateral partial and whole volume high-dose irradiation of the human kidney

Renal function was prospectively analysed in 26 patients treated with radiotherapy for various types of malignancies. In patients with gastric non-Hodgkin's lymphoma stage I–II (gNHL, n = 5), the ^99mTc-diethylenetriamine-penta-acetic acid (^99mTc-DTPA) renal uptake and the relative ^99mTc-dimercapto-succinyl acid (^99mTc-DMSA) accumulation decreased gradually and concomitantly in the high-dose, whole-volume irradiated left kidney (40 Gy/5, 5 weeks), down to 25 ± 10% (mean ± 1 S.E.M.) and 31 ± 11%, respectively, after 6–9 years. The absolute ^99mTc-DMSA uptake in the left kidney declined down to 33 ± 12% whereas in the low-dose, whole-volume irradiated right kidney (12–13 Gy/3 weeks) it increased up to 187 ± 11%. When considering renal volume changes with single photon emission computed tomography, the left kidney in the gNHL patients was reduced to 30 ± 13%, with,surprisingly, a contralateral enlargement up to only 119 ± 7% (P < 0.05). The overall renal function in this group of patients, as assessed by creatinine clearance and by [¹²⁵I]iothalamate/¹³¹I]hippuran clearance was reduced to 48–68%. In the Hodgkin's disease patients (HD, n = 7) given 40 Gy in 4 weeks to 30–50% of the left kidney, the ^99mTc-DTPA filtration and the relative ^99mTc-DMSA uptake in the left kidney was reduced to 75 ± 4% and 81 ± 3%, respectively. The absolute ^99mTc-DMSA changes were 78 ± 10% and 135 ± 13%, respectively. No significant renal functional alterations were observed in patients with either ovarian carcinoma (n = 7) or seminoma (n = 7). These data suggest a significant, compensatory response of the non-irradiated or low-dose irradiated kidney which, however, appears to be incomplete after contralateral, whole-volume, high-dose irradiation. Such compensatory response might be overestimated when considering only relative or absolute changes in radioactivity uptake.     

Treatment of acute leukemia with idarubicin,etoposide and cytarabine (IDEA). A randomized study of etoposide schedule

Background The differences in toxicity of etoposide following continuous or bolus infusion are unknown.Methods We studied the schedule-dependent toxicity of high-dose etoposide when combined with high-dose cytarabine and idarubicin (IDEA) in 138 patients with acute leukemia. Four groups of patients were studied: group I, relapse; group II, secondary acute myeloid leukemia (AML); group III, de novo AML, age >60 years; and group IV, induction failure or blast crisis of myeloproliferative syndrome. Treatment for groups I–III was idarubicin 8 mg/m² per day days 1–3, cytarabine 2000 mg/m² once a day days 1–6, and etoposide 1600 mg/m² total dose. Group IV treatment differed by cytarabine given twice daily days 1–6. Patients were randomized to etoposide as a continuous infusion days 1–6 or as a bolus infusion over 10 h on day 7.Results Continuous infusion etoposide produced significantly more oral mucositis than bolus etoposide. In groups I–III, comparing continuous and bolus etoposide, there was a median of 3 vs 0 days of grade 2 or more oral mucositis (P<0.0001) and 13.5 vs 0 days of total parenteral nutrition (TPN) (P=0.0003). Group IV patients had a median 7 vs 0 days of grade 2 or more oral mucositis (P<0.01) and 21 vs 7 days of TPN (P<0.003), respectively. There were no differences in hematologic recovery, length of hospital stay, complete remission rate or overall survival between the two etoposide schedules. Of groups I–III patients, 51% achieved complete remission, and 11% died from treatment-related complications.Conclusion The toxicity profile of high-dose etoposide is schedule-dependent with prolonged exposure producing significantly more non-hematologic toxicity.This work was supported in part by research funds from Adria Laboratories and Kabi Pharmacia Inc.     

Pharmacokinetics of continuous-infusion amsacrine and teniposide for the treatment of relapsed childhood acute nonlymphocytic leukemia

Summary The systemic disposition of both amsacrine and teniposide was determined in children receiving treatment for resistant acute nonlymphocytic leukemia. As part of a phase I–II study, amsacrine and teniposide were given as continuous 72-h i.v. infusions at doses of 75–150 and 150–250 mg m^–2 day^–1, respectively. Plasma samples obtained during steady state were analyzed for drug concentrations by high-performance liquid chromatography assays specific for each compound. Clearance and systemic exposure values for both amsacrine and teniposide were calculated for 14 patients, and data were available for teniposide alone in an additional 14 subjects. Interpatient variability in clearance was substantial for each drug, producing overlapping systemic exposure across dose levels. No evidence of dose-dependent drug clearance was evident. Clearance values for teniposide given in combination with amsacrine were similar to previous values obtained when teniposide was given in an identical manner but as a single agent. In all, 80% of patients experienced some degree of mucositis after chemotherapy administration. Severe mucositis (Pediatric Oncology Group grades 3–4) occurred in 18% of cases, all of whom showed teniposide steady-state plasma concentrations above the median population value (11.9 g/ml;P<0.0001). A comparison of the results of the present study on teniposide combined with amsacrine with those previously obtained for single-agent teniposide suggest that amsacrine produced little additive gastrointestinal toxicity. The evaluation of anticancer drug pharmacokinetics in individual patients during combination chemotherapy regimens helps to determine the relative importance of each agent when toxicity patterns are similar.Supported in part by Leukemia Program Project CA20180, by Cancer Center CORE grant CA21765, by a Center of Excellence grant from the State of Tennessee, and by ALSAC     

A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer.

Background:Previous phase I–II studies have shown that the combination of paclitaxel–cisplatin–etoposide (TEP) is very active and well tolerated in patients with small-cell lung cancer (SCLC). In order to compare the TEP combination to cisplatin–etoposide (EP) regimen as front-line treatment in patients with SCLC, we conducted a randomised multicenter study. Patients and methods:One hundred thirty-three chemotherapy-naïve patients with histologically proven limited or extensive stage SCLC were randomised to receive either paclitaxel 175 mg/m² i.v. three-hour infusion on day 1 and cisplatin 80 mg/m² i.v. on day 2 and etoposide 80 mg/m² i.v. on days 2–4 with G-CSF support (5 mcg/kg s.c. days 5–15) or cisplatin 80 mg/m² i.v. on day 1 and etoposide 120 mg/m² i.v. on days 1–3 in cycles every twenty-eight days. Results:Due to excessive toxicity and mortality observed in the TEP arm, an early interim analysis was performed and the study was closed. Sixty-two patients received two hundred sixty-one cycles of TEP and seventy-one patients three hundred twenty-three cycles of EP. The two patient groups were well balanced for age, sex, performance status, stage of disease and the presence of abnormal LDH at diagnosis. In an intention-to-treat overall analysis both regimens were equally active with a complete and partial response rate of 50% (95% confidence interval (CI): 37.5%–62.4%) for TEP and 48% (95% CI: 36.2%–59.5%) for EP (P = 0.8). The median time to disease progression was 11 months for TEP and 9 months for EP (P = 0.02). The duration of response, one-year survival and overall survival were similar in the two arms. Similarly, in an intention-to-treat subgroup analysis of patients with limited or extensive stage disease, there was no difference in the activity between the two regimens except of a longer median time to disease progression in the extensive stage in favour of the TEP regimen, eight versussix months (P = 0.04). However, there were eight toxic deaths in the TEP arm versusnone in the EP arm (P = 0.001). Moreover, the TEP regimen was associated with more severe toxicity than the EP regimen in terms of grade 4 neutropenia (P = 0.04), grade 3–4 thrombocytopenia (P = 0.02), febrile neutropenia (P = 0.08), grade 3–4 diarrhea (P = 0.01), grade 3–4 asthenia (P = 0.05) and grade 3 neurotoxicity (P = 0.06). Conclusions:In this early terminated study, the TEP regimen was significantly more toxic than the EP regimen. The TEP regimen is associated with significant toxicity and mortality, and should not be used outside of a protocol setting. For future investigations, dose and schedule modifications are necessary to reduce toxicity.     

Four-step high-dose sequential chemotherapy with hematopoietic progenitor-cell support as induction treatment for patients with solid tumors

Background: Despite recent progress in modern chemotherapy, metastatic solid tumors still have a poor outcome. The delivery of increased dose intensities of cytotoxic agents could improve response rates. We assessed the feasibility and safety of a high-dose sequential chemotherapy program in chemotherapy-naive patients with solid tumors.Patients and methods: Thirty patients (14 with carcinoma of unknown primary site, seven with metastatic breast cancer, six with small-cell lung cancer, and three with other diseases) were treated by an induction therapy regimen consisting of four cycles of high-dose chemotherapy with hematopoietic progenitor cell and growth factor support. Peripheral blood progenitor cells were collected by apheresis as the leukocyte counts recovered from the nadir induced by the first cycle of chemotherapy (doxorubicin 75 mg/m², cyclophosphamide 6000 mg/m²). Patients then received two cycles of etoposide (800 mg/m²) and carboplatin (900 mg/m²) separated by one cycle of doxorubicin (75 mg/m²) and cyclophosphamide (3000 mg/m²). G-CSF (5 µg/kg/d) was given until engraftment. Cycles were scheduled to be delivered every three weeks.Results: A total of 108 cycles of chemotherapy were administered. Six patients went off study before the end of the program (three because of progressive disease, three because of toxicity). After the first cycle, a median number of 10 × 10⁶/kg CD34+ cells (range 8–30) were collected. The median number of apheresis procedures was 1 (range 1–3). From cycle 2 to cycle 4, the median number of days when there was an absolute neutrophil count of less than 500/µl increased from three to five, and the median number of days when the platelet count was less than 25,000/µl increased from three to six. Episodes of febrile neutropenia occurred in 36%, 50% and 46% of cycles during cycles 2, 3 and 4, respectively. The median numbers of days between cycle 1 and cycle 2, cycle 2 and cycle 3, cycle 3 and cycle 4 were 24 (range 20–30), 22 (range 20–36) and 22 (range 18–35), respectively. There were no treatment-related deaths. Non-hematologic toxicity included severe (WHO grades 3 or 4) nausea/vomiting in 19 (18%) cycles, mucositis in 8 (7%) cycles and diarrhea in 7 (6%) cycles.Conclusion: Support with hematopoietic progenitor cells and growth factors allows the timely administration of repetitive cycles of high-dose chemotherapy in chemotherapy-naive patients, resulting in a significant increase in dose intensity. Toxicity is noteworthy but manageable and does not compromise further therapy.     

A phase II study of pegylated liposomal doxorubicin for treatment of advanced hepatocellular carcinoma

Background:Pegylated liposomal doxorubicin has an enhancedefficacy and reduced toxicity compared with free doxorubicin. The efficacy andtoxicity of pegylated liposomal doxorubicin was investigated in patients withhepatocellular carcinoma. Patients and methods:Patients with histologically confirmed,locally advanced or metastatic hepatocellular carcinoma and a Karnofsky index>60% were included in this prospective single-arm study. Exclusioncriteria were liver cirrhosis stage Child–Pugh C, previous chemotherapy,or chemoembolization. Pegylated liposomal doxorubicin was given in a dose of30 mg/m² every three weeks until progression of disease. Afterinclusion of five patients the dose could be escalated to 40 mg/m²in absence of toxicity grade 3 and 4. Results:Sixteen patients were evaluable for response. Noobjective response was achieved. The median survival time was 140 days(95% confidence interval: 126–154 days). Treatment toxicitiesgrade 3 comprised increased liver enzymes in patients with preexistinggrade 1 or 2 elevation (n = 6), hematologic toxicity (n =5), and hypersensitivity (n = 2). Conclusions:Pegylated liposomal doxorubicin is not effective fortreatment of advanced hepatocellular carcinoma. The favorable toxicity profilewas confirmed even in patients with underlying liver disease.     

Comparative in vitro cytotoxicity of taxol and Taxotere against cisplatin-sensitive and-resistant human ovarian carcinoma cell lines

Summary Using the sulforhodamine B assay, we compared the cytotoxic properties of the novel microtubule agent taxol and the semi-synthetic related compound Taxotere in nine human ovarian-carcinoma cell lines, including three pairs of cell lines rendered resistant to cisplatin or carboplatin. In addition, the cytotoxicity of the commonly used anticancer drugs cisplatin and adriamycin and the topoisomerase II inhibitor etoposide was determined. The results of continuous drug exposure showed that taxol [mean concentration producing 50% growth inhibition (IC₅₀), 1.1×10^–9 m; range, 2.8×10^–9–5×10^–10 m and Taxotere (mean IC₅₀, 5.1×10^–10 m; range, 7.2–3.3×10^–10 m) were >1,000 times more cytotoxic than either cisplatin (mean IC₅₀, 3.1×10^–6 m;P<0.05) or etoposide (mean IC₅₀, 2.3×10^–6 m;P<0.05) and >100 times more cytotoxic than Adriamycin (mean IC₅₀, 6.9×10^–8 m;P<0.05). Taxotere was more cytotoxic than taxol; following continuous exposure, the mean difference across the cell lines was 2 orders of magnitude (range, 1.1–3.9 orders of magnitude for individual lines). Although this difference did not reach statistical significance for any individual cell line (P values ranged from 0.17 for HX/62 to 0.9 for OVCAR-3), when all IC₅₀ values for the 96-h experiments were pooled, Taxotere was found to be significantly more potent than taxol (P=0.05). Following 2 h exposure, the mean cytotoxicity of Taxotere was 3.9-fold > that of taxol across the nine lines (range, 0.75- to 10-fold;P<0.05 for the CH1 cell line; overall pooled IC₅₀ data,P=0.05). Although a 71-fold range of sensitivity to cisplatin was observed across the six parent cell lines (IC₅₀ most resistant line/IC₅₀ most sensitive line), this was largely abolished by treatment with taxol (5.6-fold range) and Taxotere (2.2-fold rante). Following continuous exposure of the three pairs of lines exhibiting acquired resistance to platinum, no cross-resistance with either Taxotere or taxol was found (resistance factors, <1.5). In the 41M and 41McisR pair of lines, in which previous studies have shown resistance to be due to reduced platinum accumulation, taxol and Taxotere exhibited some collateral sensitivity (resistance factors, 0.69 and 0.66, respectively). Taxotere and, particularly, taxol showed a pronounced concentration times exposure duration (CxT) dependence as compared with cisplatin (P<0.05). The mean loss in potency across the nine lines for 2 vs 96 h exposure was 97 for taxol, 35 for Taxotere, 30 for Adriamycin and only 9.9 for cisplatin. However, these differences in potency loss observed between taxol and Taxotere did not reach statistical significance (P=0.18). These data indicate that Taxotere is approximately 2 times more cytotoxic than taxol and shows an encouraging lack of cross-resistance in three cell lines exhibiting acquired resistance to cisplatin and carboplatin.This study was supported by grants to the Institute of Cancer Research, Royal Cancer Hospital, from the Cancer Research Campaign and, through the European Organisation for Research and Treatment of Cancer (EORTC) Clonogenic Assay Screening Group, by grant 90031 from Rhone-Poulenc Rorer.