|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2001 American Society for Clinical Oncology Clinical and Pharmacologic Study of the Epirubicin and Paclitaxel Combination in Women With Metastatic Breast CancerFrom the Division of Medical Oncology A, Division of Radiodiagnostic, Service of Cardiology, and Operation Office, Istituto Nazionale dei Tumori, Milan, Italy. Address reprint requests to Luca Gianni, MD, Division of Medical Oncology A, Istituto Nazionale dei Tumori di Milano, Via Venezian, 1, 20133 Milan, Italy; email: gianni{at}istitutotumori.mi.it
PURPOSE: A pharmacokinetic interaction may cause increased cardiotoxicity of paclitaxel (PTX) and high cumulative dose of doxorubicin. We tested antitumor activity, tolerability, and pharmacokinetics of the lesser cardiotoxic epirubicin (EPI) and PTX (ET combination).
PATIENTS AND METHODS: Twenty-seven women with untreated metastatic breast cancer, median age of 56 years, and prominent visceral involvement (74%) were studied. Three-weekly EPI (90 mg/m2) and PTX (200 mg/m2 over 3 hours) were given for a maximum nine cycles. EPI was administered 24 hours before PTX (E
RESULTS: Patients received 205 cycles of ET and a median EPI dose of 720 mg/m2. Grade 4 neutropenia (49% of cycles) was the most frequent toxicity. Cardiac contractility was decreased in five patients. Mild congestive heart failure occurred in two (7.4%). Response rate was 76% (28% complete). Median overall survival was 29 months. On the basis of intrapatient comparison in the first 24 hours of E CONCLUSION: ET is feasible, devoid of excessive cardiac toxicity, and active. A reciprocal pharmacokinetic interference between the two drugs has pharmacodynamic consequences, and suggests a direct effect of PTX on EPI metabolism requiring ad hoc investigation.
THE HIGH antitumor activity of anthracyclines1 and paclitaxel (PTX)2 in women with breast cancer has prompted the conduct of a number of recent trials testing the combination of doxorubicin (DOX) and the taxane.3-5 PTX has unique pharmacologic features that are directly relevant to its use in combination with anthracyclines. It follows nonlinear pharmacokinetics.6 It is formulated in Cremophor EL, a vehicle involved in the nonlinear disposition of PTX,7 and responsible for an altered pharmacokinetic behavior of DOX leading to increased plasma and tissue exposure to the anthracycline.8 Finally, the sequence of drug administration has different pharmacokinetic and pharmacodynamic effects when PTX is infused over 24 hours in combination with DOX.9,10 In the past, we reported the clinical results of the combination of PTX infused over 3 hours with bolus DOX.5 The treatment showed high antitumor activity, lack of measurable effect of the order of drug administration when an interval of 15 minutes between drugs was adopted, and a high incidence of cardiac toxicity (20%) at a median cumulative dose of 480 mg/m2 of DOX.5 In the pharmacokinetic portion of that study, PTX was shown to cause nonlinear disposition of DOX and its metabolite doxorubicinol (DOXOL),11 leading to persistence of elevated plasma concentrations of the anthracyclines that contribute to explaining the therapeutic and cardiotoxic effects of the combination.5,12 Epirubicin (EPI) is an anthracycline differing from DOX only in the epimerization of the hydroxyl group in position 4 of the aminosugar moiety (reviewed in Bonadonna et al13). The drug has been widely used in Europe for many years, and has recently been approved in the United States. The widespread use of EPI instead of DOX in Europe is largely because of the lower cardiotoxic potential of the analog.14 A formal comparison of the antitumor activity of DOX and EPI is missing, but the analog is credited with therapeutic effects similar to those of the parent compound.13 Indeed, the doses of EPI equimyelotoxic and equicardiotoxic to 1 mg of DOX are 1.5 and 2 mg, respectively.13 Such a difference allows for administration of more cycles of EPI than DOX before reaching a limiting cumulative cardiotoxic dose.13 In attempts to overcome the problem of cardiotoxic sequelae with the combination of PTX and DOX, EPI has been used with the taxane in studies that also explored the possible pharmacokinetic interaction between the two drugs.15-17 The pharmacology of the combination again indicated a complex interaction characterized by the taxane influencing the plasma profile of the anthracycline’s metabolites,15,16 and by differing effects of the order of drug administration on the concentrations of EPI.17 The role of the reported interactions on the clinical effects of the combination is unclear. We here present the results of a clinical and pharmacologic study evaluating the antitumor activity and safety profile of the combination of EPI and PTX in previously untreated metastatic breast cancer patients. In this study, we also explored the pharmacokinetic and pharmacodynamic interaction between the two drugs by measuring the plasma and urine concentrations of either drug and metabolites in a subset of patients who received the combination according to different schedules.
Patients From April to December 1996, 27 patients were enrolled onto the study. All patients had metastatic breast cancer and had never been treated with chemotherapy for metastatic disease. Patients could have received prior radiotherapy, immunotherapy, hormonal therapy, or surgery. Adjuvant chemotherapy was allowed, provided that no anthracyclines were given. Inclusion criteria were histologic proof of breast cancer, age 18 to 70 years, performance status 0 to 2 (Eastern Cooperative Oncology Group [ECOG] scale), absolute neutrophil count (ANC) greater than or equal to 2,000/µL and platelet count greater than or equal to 100,000/µL, normal function tests for liver (bilirubin level < 1.25 times the upper limits of normal [ULN]) and kidneys (creatinine level < 1.25 times the ULN), left ventricular ejection fraction (LVEF) greater than or equal to the normal limit of 50% by echocardiography, and presence of at least one neoplastic lesion bidimensionally measurable by physical examination or instrumental studies. Patients with CNS metastases or with bone metastases as the only site of disease were excluded. The trial was approved by the ethical committee of the Istituto Nazionale Tumori. All patients provided informed consent.
Treatment Plan and Dose Modifications EPI dose was reduced to 75 mg/m2 and PTX dose to 175 mg/m2 (dose level -1) in the following cases: ANC less than 500/µL for more than 7 days, ANC less than 100/µL for more than 3 days, febrile neutropenia (ANC < 500/µL and fever > 38°C), World Health Organization (WHO) grade 4 thrombocytopenia requiring platelet transfusions, grade 3 stomatitis or mucositis, grade 3 neurologic toxicity, or other major organ toxicity (excluding alopecia, nausea, vomiting) of grade 3 or greater. If ANC was less than 1,500/µL or stomatitis grade was more than 1 on day 21, treatment was delayed 1 week and full dose was delivered if patients fully recovered from toxicity. If similar toxicities were observed after the first dose reduction, patients were treated with EPI at 50 mg/m2 and PTX at 150 mg/m2 (dose level -2). Patients were taken off study in the following cases: heart function toxicity grade greater than or equal to 2, symptomatic arrhythmia or atrioventricular block (except first degree), no complete hematologic recovery by day 42, or no improvement after two cycles at reduced dose for grade 3 neurotoxicity.
Patient Monitoring and Response Assessment All patients were monitored with weekly CBC (twice weekly from days 7 to 21 in patients enrolled onto the pharmacologic study, see below) and evaluated every 3 weeks by physical examination and renal and liver function tests. Toxicities were recorded according to WHO criteria at each visit. Cardiac monitoring consisted of ECG recording every cycle and of echocardiographic assessment of LVEF at study entry; before cycles 4, 7, and 9; and every 6 weeks during follow-up. The definition of response adhered to the criteria defined by Miller et al,18 and response of evaluable site of disease was assessed according to WHO criteria every two cycles. All responses required the same type of assessment by two different radiologic techniques.
Pharmacokinetic Study Design
High-Pressure Liquid Chromatography Methods
Frozen plasma samples were thawed at room temperature, centrifuged at 1,100 x g for 10 minutes at 4°C, and 0.6 mL was transferred in 2-mL amber vials (Hewlett Packard, Palo Alto, CA). Six microliters of internal standard, DNR for anthracyclines and CEP for PTX, was added to final concentrations of 0.1 and 0.65 µmol/L, respectively. Samples were analyzed by injecting 0.5 mL into the HPLC system. Taxanes and anthracyclines were separated by two different HPLC methods with on-line extraction according to the method previously described for DOX.11 Chromatographic elution followed the already reported conditions.6 Buffers and eluants were prepared and filtered daily. For detection of anthracyclines, an HP1046A fluorimeter (Hewlett Packard) was used with excitation and emission wavelength set at 227 and 552 nm, respectively. Taxanes were detected by an HP1050 UV detector (Hewlett Packard) at 230 nm. The retention times for EOL-glu, EPI-glu, EOL, EPI, and DNR were 8.2, 8.9, 9.6, 10.6, and 11.7 minutes, respectively. Retention times for 6 For EPI-glu and EOL-glu quantitation, the standard curves of EPI and EOL were used as reference, assuming that the same fluorescence of the glucuronated metabolites (evaluated as peak area) corresponded to identical nonglucuronated concentrations. All standard curves were best fitted to a two-phase linear equation, and the r2 of the fit was always better than .99. Urinary excretion of EPI and metabolites was evaluated in eight patients in cycles 1 and 2. Thawed urine samples were sonicated for 10 minutes and thoroughly mixed. An aliquot of 200 µL was treated with 150 µL of 1 M Tris buffer (hydroxymethyl-aminomethane) at pH 7. After internal standard addition (DNR, 0.2 µmol/L final concentration), 25 µL of urine was injected and analyzed by the previously described HPLC method. Standard curves for EPI and EOL were prepared in 10 mmol/L ammonium acetate buffer, pH 3.9, from 0.5 to 50 µmol/L.
Pharmacokinetic data analysis was performed by noncompartment models. For PTX, total-body clearance (CLTB), area under the time x concentration curve from time 0 to infinity (AUC0-
Clinical Study A total of 27 patients were enrolled onto the study. All patients were evaluable for toxicity, whereas two were not evaluable for antitumor activity. They went off study after two cycles of chemotherapy because of toxicity without further assessment of tumor response. Patients’ characteristics are listed in Table 1. The median age was 56 years and the median ECOG performance status was 0. All patients had measurable disease, and none had received any type of chemotherapy for metastatic disease or any anthracycline-containing chemotherapy as adjuvant treatment. Only five patients (19%) had received adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil. Seventeen patients (63%) had three or more involved sites and 20 (74%) had dominant visceral disease. In four patients there was concomitant involvement of liver and lung. A total of 205 cycles of the combination were administered; the median number of cycles per patient was nine (range, two to nine).
Six patients required dose reduction by one level, and five patients reduced the dose twice. The median interval between cycles was 21 days, and treatment was recycled after 30 days in seven courses only. The reasons for dose reduction and treatment delay were mainly neutropenia (see below) and stomatitis. One patient only required dose reduction because of neurotoxicity grade 3 after seven cycles of combined chemotherapy. After discontinuation of the anthracycline, 12 patients received 52 cycles of PTX as single-agent therapy (median, 3.5 cycles; range, one to nine). The median cumulative dose of EPI was 720 mg/m2 (range, 165 to 810 mg/m2). The dose of single-agent PTX was maintained equal to that delivered during the last cycle of the combination and corresponded to a median of 175 mg/m 2, with three patients who had the dose adjusted to 150 mg/m2 because of neurotoxicity.
The most frequent toxicity observed in the study was severe neutropenia (grade 3 or 4 in 84% of evaluable cycles) ( Table 2) that was of short duration and not cumulative. Grade 4 neutropenia was reported in 49% of all evaluable cycles and had a median duration of 5 days. Febrile neutropenia occurred in seven patients (eight cycles), and one of them had serious infectious complications requiring hospitalization. Neutropenia was rarely associated with thrombocytopenia and anemia, and these never required ad hoc intervention. Interestingly, we observed significant differences in the severity of neutropenia between E
Extrahematologic toxicities of the combination were nausea and vomiting, stomatitis, peripheral neuropathy, pruritus, myalgia, visual symptoms (subjective reduction of visual acuity and scotomata), and skin and nail toxicity (Table 2). Mild to moderate neurotoxicity was reported in 76% of all cycles (47% grade 1, and 29% grade 2); grade 3 neurotoxicity was observed in only one patient for two cycles (1%). Cardiac toxicity was not common. Five patients had a relevant decline of LVEF, three by less then 20% of baseline value (grade 1 of National Cancer Institute common toxicity criteria), and two by greater then 20% of baseline (grade 2). The latter two patients had an absolute decrease of LVEF to less then 50% EF units after a cumulative EPI dose of 810 mg/m2. One developed a mild congestive heart failure (CHF) (New York Heart Association class II) and was successfully treated on an outpatient basis with angiotensin-converting enzyme (ACE) inhibitors and diuretics. The second patient required hospitalization for progressive dyspnea and received digoxin, diuretics, and ACE inhibitors, with prompt relief of symptoms. Maintenance therapy with PTX alone was well tolerated, and toxicity data do not differ significantly from those observed and described in previous studies19 (data not shown). As expected, neurotoxicity worsened with the increasing cumulative dose of PTX, and almost all patients experienced paresthesias (grade 1 in 23% of cycles, grade 2 in 58%, and grade 3 in 13%). The combination of EPI and PTX showed good antitumor activity. Seven patients (28%) obtained a CR and 12 (48%) a PR, for an overall response rate of 76%. Three patients (12%) had stable disease and three progressed on therapy. The median duration of response was 5 months for CR and 10 months for PR. After a median observation time of 35 months (range, 8 to 40), the median freedom from progression time was 10 months (12 months for patients who obtained an objective response). At the time of this analysis, only one patient was still free of relapse. After the beginning of chemotherapy with ET, 22 patients (81%) at 12 months and 15 patients (55%) at 24 months were still alive. The median overall survival time was 29 months. For patients who obtained a PR, the median survival time was 21.5 months, whereas for patients who had a CR it is estimated in excess of 30 months (the median value has not yet been reached).
Pharmacokinetic Study
The urinary excretion of EPI in the first 24 hours was about 5% of the total dose on either cycle, but elimination of glucuronides was 2.5 times higher with ET than with E  T, accounting for an overall increase of the total anthracycline urinary excretion from 8.2% to 11.8% of the administered dose. As in plasma, EPI-glu accounted for the largest fraction of the total increment of excretion also in urine (Fig 2B).
Of note, the pharmacokinetics of PTX also was different in the two cycles. Cmax and AUC0-
Finally, bone marrow toxicity of E
PTX is one of the most active therapies in women with breast cancer, with improved results in terms of response and efficacy with respect to standard chemotherapy in the metastatic and adjuvant setting, respectively.20,21 The obvious choice of combining the taxane with DOX has been explored in several studies, showing that the combination is very active in the treatment of metastatic breast cancer, but is also associated with a high risk of cardiac toxicity when the cumulative dose of the anthracycline exceeds 360 to 380 mg/m2,5,12,22 possibly because of the complex pharmacokinetic interaction occurring between the two drugs.11 In view of the better therapeutic index of EPI, the purpose of the present study was to evaluate the antitumor activity and toxicity of EPI and PTX in combination while exploring the features of potential pharmacokinetic interaction between the drugs. On the basis of our prior experience using 60 mg/m2 of DOX in combination,5 and on the myelotoxic equivalence of 1 mg of DOX to 1.5 mg of EPI,13 we selected a dose of 90 mg/m2 of the latter for the present trial without performing a formal dose-finding study. The dose of PTX was maintained at 200 mg/m2 because this is the maximum-tolerated dose (MTD) of the taxane in combination with 60 mg/m2 of DOX.5 After we started the trial, a dose-finding study by Conte et al15 demonstrated that the selected doses of EPI and PTX are the MTD of the combination. Identical doses have also been used by Venturini et al17 in a feasibility and pharmacokinetic study of EPI and PTX in women with operable breast cancer. With the exception of a somewhat higher incidence of stomatitis, the toxicity profile of the combination we reported here is similar to the one that we had observed with DOX,5 and to the one reported by Conte et al15 with the EPI combination. The main problem was neutropenia, which was severe in many patients but of short duration and almost never of clinical concern. Peripheral neuropathy was also frequent, but in one patient only it was of grade 3 severity. Of note, cardiac toxicity was rare, with only two patients requiring treatment for a CHF that was promptly controlled with appropriate medication, and only three additional patients who had a nonsymptomatic drop of LVEF of less than 20 units. The data are in agreement with a recent analysis of cardiac toxicity after EPI plus PTX reported by Gennari et al.23 According to that experience, the risk of CHF is 7.7% at 720 mg/m2 of EPI, and it is higher in women with the cardiac risk factors of prior radiotherapy to the left chest, advanced age, hypertension, and diabetes mellitus.23 The median cumulative dose of EPI delivered to our patients was 720 mg/m2, corresponding to an equicardiotoxic dose of 360 mg/m2 of DOX. At this cumulative dose, the combination of DOX with PTX can also be given without exposing patients to excessive cardiac risk.22 For this reason, our data cannot confirm or refute the hypothesis that substituting EPI for DOX was really effective for significantly decreasing the risk of cardiac toxicity. The overall response rate in the present study was 76%, with a complete response rate of 28%. With only one patient still free of relapse, the median survival was 29 months. Again, the data are consistent with those described by Conte et al,15 who reported an objective response rate of 84% and a CR rate of 18%. Of note, 15 of the 49 patients in the latter series had failed to respond to an anthracycline-based adjuvant chemotherapy,15 whereas patients in the present study were all anthracycline-naive. The response rate in the present study is lower than the one of 94% overall response and 41% CR that we previously observed for the combination of PTX and DOX.5 Although comparison of results between small series of patients treated in uncontrolled studies is often misleading, the present and our prior report5 relate to patients treated in the same institution by the same group of doctors following identical criteria of selection and follow-up. The criteria for selecting patients as candidates for these trials deserve a brief comment. In both studies, the adopted principle was that of administering the two drugs to patients without any prior exposure to chemotherapy in view of using the treatment in women with operable breast cancer and similarly never exposed to any kind of chemotherapy. This type of selection obviously introduces a bias in favor of observing a high rate of responses, and may be not informative of the true potential of the combination in women with metastatic disease, who are mostly represented by patients relapsing after adjuvant systemic therapy and possibly less tolerant to the toxic effects and/or sensitive to the antitumor activity of another chemotherapy. However, the same bias well serves the purpose of defining the optimal pattern of activity and tolerability that can be exploited in women who are candidates for adjuvant treatment. In our hands, the combination with DOX afforded an antitumor activity better than that with EPI, although both combinations are clearly very active and worth exploring in operable breast cancer at a cumulative dose of the anthracyclines devoid of excessive cardiac risk.
The pharmacologic analysis we conducted in 14 patients contributes some important information about the known pharmacokinetic interference between PTX and EPI, and about possible pharmacodynamic consequence of such interference. The design of our pharmacokinetic study allowed for comparing the disposition of EPI without PTX during the first 24 hours of E These observations deserve some in-depth discussion within the context of what is already known about the interaction of PTX with EPI, and our own report on the interaction with DOX.11 In the case of DOX, the taxane causes a significant increase of the AUC by about 30%, a prolongation of the terminal half-life, and doubling of the plasma exposure to DOXOL.11 These effects are most likely because of the taxane, or the Cremophor EL present in its clinical formulation, competing with the anthracyclines for biliary excretion.24,25 Because of the unique glucuronidation metabolism in humans, the overall disposition of EPI is different from that of DOX.26 Figure 4 illustrates EPI disposition and the sites of possible interference by PTX. The fate of EPI and metabolites in tissue is mainly dictated by active and passive mechanisms of transport. EPI can be excreted into bile, and tends to equilibrium with plasma concentrations, similar to the metabolite EOL. However, EOL is too polar a compound for partitioning back to tissue very efficiently. The water-soluble EPI-glu and EOL-glu are efficiently excreted into bile, where EOL-glu is more abundant than EPI-glu,27 and are either transported or diffused to plasma, from where they are cleared with urine. Analogous to the mechanism of competition for biliary excretion proposed for DOX,11 the effect of the taxane on EPI liver elimination would drive toward higher tissue concentrations that should result in increased plasma concentrations. However, our data and those of others16 rule out an increase of EPI in plasma when the two drugs are almost concomitantly administered in ET cycles. This observation cannot be solely accounted for by an effect of PTX on biliary elimination of the anthracyclines. Other authors have described the increase of plasma exposure to EOL, EPI-glu, and EOL-glu in patients, and attributed the effect to induction of liver metabolism.26 The effect of PTX on plasma and urine concentrations of the anthracyclines could be explained by a taxane-dependent induction or a more efficient turnover of EPI metabolism to EPI-glu and EOL and EOL-glu (Fig 4) compensating for the lack of increase of EPI plasma concentration that would be expected from impairment of its biliary excretion. Interestingly, the possibility of a metabolic induction is also in keeping with the findings of Esposito et al.16 They compared the anthracyclines’ pharmacokinetics in plasma after administration of single-agent EPI, ET, or EPI with docetaxel (that is not formulated with Cremophor EL), and found that docetaxel also caused an increase of EOL AUC, although to a lesser extent than the one caused by PTX.16 Along the same lines is also the report of Colombo et al,28 indicating an increased tissue concentration of DOXOL after docetaxel coadministration in an animal model. Together, these observations lend support to the hypothesis that the taxane structure per se may be interacting with the metabolism of the anthracyclines. In addition, in a sequence study comparing ET with the opposite sequence of PTX given immediately before EPI (TE), Venturini et al17 reported that TE led to higher plasma concentrations of the anthracycline than observed with ET as given in the present study, and to a significant reduction of the plasma AUC of EPI-glu and EOL.17 On the basis of our observation and on those reported by Venturini et al17 and Esposito et al,16 the observed pattern of plasma concentrations of EPI in ET cycles could be because of a combined effect of the taxane characterized by competition with biliary excretion of all anthacyclines, and induction of metabolism to EOL and glucuronides, where both mechanisms would be sensitive to the concentrations of PTX and/or its vehicle Cremophor EL.
In addition to the complex alterations caused by PTX on the disposition of EPI and metabolites, we also observed that the taxane’s Cmax and AUC were about 30% higher, and the ClTB 30% slower in ET than in E T cycles. A similar trend toward increment was also clearly visible for the plasma disposition of 6 -OH-PTX, the major metabolite of PTX, and for the time above the critical PTX concentration level of 0.05 µmol/L, but in both cases the difference was not statistically significant. This is the first report of such an effect, and can again be explained on the basis of a competition between anthracyclines and PTX for biliary elimination.
The obvious immediate question raised by observing the described complex pharmacology is whether the interaction between PTX and EPI has any clinically relevant consequence. The design of our study allows for only limited pharmacodynamic observations comparing E In conclusion, our study shows that the combination of EPI and PTX is active and feasible in women with metastatic breast cancer, the majority of whom were also chemotherapy-naive. The clinical results support the ongoing investigation of the combination as adjuvant systemic therapy in operable breast cancer.17 Our companion pharmacologic study contributes to a more comprehensive understanding of the complex interaction between EPI and PTX, and shows for the first time that it may cause pharmacodynamic consequences. The study also shows the novel aspect that the interaction is involving a reciprocal interference, possibly at the level of biliary excretion, and suggests a direct effect of PTX on EPI metabolism. The latter point calls into focus an as yet unexplored relationship between taxanes and anthracyclines that will require ad hoc studies to clarify the nature and extent of the metabolic interference between two classes of drugs that are increasingly used in combination.
Supported in part by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), Bristol-Myers Squibb Pharmaceutical Research Institute, and Pharmacia & Upjohn.
1. Honig S: Treatment of metastatic breast cancer: Hormonal therapy and chemotherapy, in Harris JR, Lippman ME, Morrow M, et al (eds): Disease of the Breast. Philadelphia, PA, Lippincott-Raven, 1996, pp 669-734
2.
Holmes FA, Walters RS, Theriault RL, et al: Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83: 1797-1805, 1991 3. Sledge GW, Neuberg D, Ingle J, et al: Phase III trial of doxorubicin vs. paclitaxel vs. doxorubicin plus paclitaxel as first-line therapy for metastatic breast cancer: An intergroup trial. Proc Am Soc Clin Oncol 16: 1a, 1997 (abstr 2)
4.
Holmes FA, Madden T, Newman RA, et al: Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer. J Clin Oncol 14: 2713-2721, 1996 5. Gianni L, Munzone E, Capri G, et al: 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. J Clin Oncol 13: 2688-2699, 1995[Abstract]
6.
Gianni L, Kearns CM, Giani A, et al: Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 13: 180-190, 1995 7. Sparreboom A, Verweij J, van der Burg MEL, et al: Disposition of Cremophor EL in humans limits the potential for modulation of multidrug resistance phenotype in vivo. Clin Cancer Res 4: 1937-1942, 1998[Abstract] 8. Millward LK, Cosson EJ, Stokes KH, et al: Cremophor EL changes the pharmacokinetics of doxorubicin. Proc Am Assoc Cancer Res 36: 373, 1995 (abstr 2221)
9.
Holmes FA, Valero V, Walters RS, et al: Paclitaxel by 24-hour infusion with doxorubicin by 48-hour infusion as initial therapy for metastatic breast cancer: Phase I results. Ann Oncol 10: 403-411, 1999
10.
Berg SL, Cowan KH, Balis FM, et al: Pharmacokinetics of taxol and doxorubicin administered alone and in combination by continuous 72-hour infusion. J Natl Cancer Inst 86: 143-145, 1994
11.
Gianni L, ViganòL, Locatelli A, et al: Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol 15: 1906-1915, 1997
12.
Gehl J, Boesgaard M, Paaske T, et al: Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic. Ann Oncol 7: 687-693, 1996
13.
Bonadonna G, Gianni L, Santoro A, et al: Drugs ten years later: Epirubicin. Ann Oncol 4: 359-369, 1993 14. Nielsen D, Jensen JB, Dombernowsky P, et al: Epirubicin cardiotoxicity: A study of 135 patients with advanced breast cancer. J Clin Oncol 8: 1806-1810, 1990[Abstract]
15.
Conte PF, Baldini E, Gennari A, et al: Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: A regimen with high activity and low cardiotoxicity in advanced breast cancer. J Clin Oncol 15: 2510-2517, 1997
16.
Esposito M, Venturini M, Vannozzi MO, et al: Comparative effects of paclitaxel and docetaxel on the metabolism and pharmacokinetics of epirubicin in breast cancer patients. J Clin Oncol 17: 1132-1140, 1999
17.
Venturini M, Lunardi G, Del Mastro L, et al: Sequence effect of epirubicin and paclitaxel treatment on pharmacokinetics and toxicity. J Clin Oncol 18: 2116-2125, 2000 18. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 207-214, 1981[Medline]
19.
Gianni L, Munzone E, Capri G, et al: Paclitaxel in metastatic breast cancer: A trial of two doses by 3-hour infusion in patients with disease recurrence after prior therapy with anthracyclines. J Natl Cancer Inst 87: 1169-1175, 1995
20.
Bishop JF, Dewar J, Toner GC, et al: Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncol 17: 2355-2364, 1999 21. Henderson IC, Berry D, Demetri G, et al: Improved disease-free and overall survival from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose-level in the adjuvant chemotherapy of patients with node-positive primary breast cancer. Proc Am Soc Clin Oncol 17: 101a, 1998 (abstr 390) 22. Gianni L, Dombernowsky P, Sledge G, et al: Cardiac function following combination therapy with taxol and doxorubicin for advanced breast cancer. Proc Am Soc Clin Oncol 17: 115a, 1998 (abstr 444)
23.
Gennari A, Salvadori B, Donati S, et al: Cardiotoxicity of epirubicin/paclitaxel-containing regimens: Role of cardiac risk factors. J Clin Oncol 17: 3596-3602, 1999
24.
Colombo T, Parisi I, Zucchetti M, et al: Pharmacokinetic interactions of paclitaxel, docetaxel and their vehicles with doxorubicin. Ann Oncol 10: 391-395, 1999
25.
Sparreboom A, van Tellingen O, Nooijen WJ, et al: Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Res 56: 2112-2115, 1996 26. Mross K, Maessen P, Van der Vijgh WJF, et al: Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans. J Clin Oncol 6: 517-526, 1988[Abstract] 27. Camaggi CM, Comparsi R, Strocchi E, et al: Epirubicin and doxorubicin comparative metabolism and pharmacokinetics: A cross-over study. Cancer Chemother Pharmacol 21: 221-228, 1988[Medline] 28. Colombo T, Parisi I, Zucchetti M, et al: Pharmacokinetic interactions of paclitaxel, docetaxel and their vehicles with doxorubicin. Ann Oncol 10: 391-395, 1999 Submitted September 18, 2000; accepted December 27, 2000.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
), and terminal half-life (t1/2) were estimated using the Lagrange function as previously described.
