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Sequence Effect of Epirubicin and Paclitaxel Treatment on Pharmacokinetics and Toxicity

From the Department of Medical Oncology I and Pharmacotoxicology Laboratory, Istituto Nazionale per la Ricerca sul Cancro, Genova; and Department of Medical Oncology, Ospedale S. Croce e Carle, Cuneo, Italy.

Address reprint requests to Marco Venturini, MD, Divisione di Oncologia Medica, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132, Genova, Italy; email mventur{at}hp380 .ist.unige.it.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Sequence-dependent clinical and pharmacokinetic interactions between paclitaxel and doxorubicin have been reported. Some data have shown an influence of paclitaxel on epirubicin metabolism, but no data are available about the effect of diverse sequences of these drugs. We investigated whether reversing the sequence of epirubicin and paclitaxel affects the pattern or degree of toxicity and pharmacokinetics.

PATIENTS AND METHODS: Patients receiving epirubicin 90 mg/m² by intravenous bolus followed by paclitaxel 175 mg/m² over 3-hour infusion or the opposite sequence every 3 weeks for four cycles were eligible. Toxicity was recorded at nadir. Pharmacokinetic data were evaluated at the first and the second cycle and were correlated with toxicity parameters.

RESULTS: Thirty-nine consecutive stage II breast cancer patients were treated. Twenty-one patients received epirubicin followed by paclitaxel (ET group), and 18 received the opposite sequence (TE group). No significant difference in nonhematologic toxicity was seen. A lower neutrophil and platelet nadir and a statistically significant slower neutrophil recovery was observed in the TE group. Area under the concentration-time curve (AUC) of epirubicin was higher in the TE group (2,346 ng/mL · h v 1,717 ng/mL · h; P = .002). An inverse linear correlation between epirubicin AUC and neutrophil recovery was also observed (P = .012). No difference was detected in paclitaxel pharmacokinetics.

CONCLUSION: Our results support a sequence-dependent effect of paclitaxel over epirubicin pharmacokinetics that is associated with increased myelotoxicity. Because schedule modifications of anthracyclines and paclitaxel can have clinical consequences, the classical way of administration (ie, anthracyclines followed by paclitaxel) should be maintained in clinical practice.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PACLITAXEL IS A microtubule-stabilizing agent with remarkable antineoplastic activity in human cancer. Because of its high activity as a single agent in metastatic breast cancer, the search for active combinations containing paclitaxel has been the focus of recent clinical trials. Anthracyclines are among the most effective drugs in the treatment of breast cancer, and the combination of paclitaxel with doxorubicin has been reported as an active regimen in the treatment of advanced breast cancer.¹ However, major issues remain unresolved, including the optimal schedule of administration and sequence-dependent toxicity. Effects of drug sequence on toxicity have been reported in studies of the paclitaxel-doxorubicin combination. Holmes et al^2,3 administered doxorubicin as a continuous infusion over 48 hours and paclitaxel over 24 hours in different sequences. When paclitaxel was given as the first drug, the clearance of doxorubicin was reduced by approximately 30%, and toxicity was greater than that observed in the opposite sequence. Gianni et al⁴ reported no sequence-dependent effect on toxicity when paclitaxel was given by a shorter infusion (over 3 hours) along with doxorubicin infused over 15 minutes. However, the same authors noted that paclitaxel given over a 3-hour period before doxorubicin increased the doxorubicin peak level and both the peak level and the area under the concentration-time curve (AUC) of doxorubicinol, its main metabolite.⁵

These pharmacokinetic interactions are regarded as the main cause of enhanced cardiotoxicity observed with the combination of doxorubicin and paclitaxel. In attempts to overcome this problem, epirubicin was used in place of its parent compound in some clinical trials. Actually, some phase II studies indicated that the combination of epirubicin and paclitaxel was quite active and less cardiotoxic than the combination of doxorubicin and paclitaxel.⁶ Attention has also been given to the possible pharmacokinetic interactions between epirubicin and paclitaxel. Paclitaxel administered over 3 hours immediately after epirubicin did not seem to modify the pharmacokinetic behavior of the anthracycline. However, the taxane treatment resulted in a clear increase in all of the epirubicin metabolites.^7,8 The clinical meaning of these interactions and the impact of different sequencing of paclitaxel and epirubicin on their pharmacokinetics and pharmacodynamics is not yet fully clear. Therefore, the main objective of this study was to investigate possible sequence-dependent interactions of paclitaxel with epirubicin and their clinical counterparts.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The study was monocentric and was conducted at the Department of Medical Oncology of the Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. All clinical and pharmacokinetic protocols were approved by the protocol review and the ethics committees of the same institute. Informed consent was obtained from all patients before study entry.

Patient Selection and Drug Administration
Consecutive stage II and III breast cancer patients who received a combination of epirubicin and paclitaxel as adjuvant therapy after radical mastectomy or breast-conserving surgery were eligible for this study. Other main eligibility criteria were age younger than 70 years, Eastern Cooperative Oncology Group performance status of 0 to 1, no prior chemotherapy, no clinical or imaging evidence of distant metastases, and no other serious medical or psychiatric illness that would preclude intensive treatment and/or informed consent. All patients had to have normal bone marrow, liver, and kidney functions.

Chemotherapy consisted of either epirubicin 90 mg/m² administered via intravenous (IV) bolus followed immediately by paclitaxel 175 mg/m² over 3-hour infusion (ET group) or the opposite sequence, ie, paclitaxel 175 mg/m² over 3-hour infusion followed by epirubicin 90 mg/m² via IV bolus (TE group). Cycles were repeated every 3 weeks, provided that the WBC count was more than 3,000/µL and/or the absolute neutrophil count (ANC) was more than 2,000/µL and the platelet (PLT) count was more than 100,000/µL. Otherwise, chemotherapy was delayed by 1 week or until hematologic recovery. Four cycles of chemotherapy were given. Epirubicin, paclitaxel, and premedication therapy were given as previously described.⁷

We planned to perform toxicity evaluation of ET and TE sequences administered at the first cycle in 40 patients (20 patients in each group). At the second cycle, eight patients in each group received the opposite sequence for pharmacokinetics (see Pharmacokinetics), whereas 12 patients received the same sequence during the four cycles of chemotherapy.

Specimen Collection and Sample Analyses
In each group, pharmacokinetic evaluations were planned in the first eight consecutive patients who agreed to undergo blood sample collection. Heparinized venous blood samples were obtained before and at various times after epirubicin treatment and before, during, and after paclitaxel infusion. Epirubicin levels were measured at 5, 15, 30, and 60 minutes and 2, 3, 4, 6, and 24 hours after bolus end. Paclitaxel levels were measured at 15 and 60 minutes and 2, 3, 4, 6, and 24 hours after the beginning of the infusion. Blood samples were immediately centrifuged at room temperature, and the plasma was separated and stored in aliquots at -20°C until analysis. Epirubicin and its metabolites were measured by high-performance liquid chromatography as previously described.⁷ Paclitaxel was measured by high-performance liquid chromatography using the method described by Huizing et al.⁹ Paclitaxel was identified by means of chromatographic comparison with standard solution, and its minimal detectable concentration was 10 ng/mL.

Data were collected and analyzed using HP3365 Series II ChemStation software (Hewlett-Packard, Palo Alto, CA).

Pharmacokinetics
The elimination of epirubicin and its metabolites (epirubicinol [EOL], 7-deoxydoxorubicinone [7d-Aone], and the two more polar metabolites sensitive to glucuronidase treatment,⁷ ie, metabolite 1, hereafter called EOL-glucuronide, and metabolite 2, hereafter called epirubicin-glucuronide) from plasma was investigated at the first cycle of chemotherapy consisting of epirubicin administered before or after paclitaxel infusion. All patients underwent a second evaluation at the successive cycle of chemotherapy, in which the sequence was inverted, so that each patient served as her own control in the pharmacokinetic data analysis.

Plasma epirubicin concentrations against time curves were fitted to the following multiexponential equation:

where C_p is the drug concentration at time t; A, B, and C are constants; and , ß, and are the apparent first-order elimination rate constants. The pharmacokinetic data were analyzed by an integrated computer system (Siphar program; Simed, Utrecht, the Netherlands) on an IBM/IC computer (IBM, White Plains, NY).

The AUC extrapolated to infinity was calculated from the sum of A/, B/ß, and C/. The central volume of distribution (V_c) was calculated by D/(A + B + C), where D is the dose given. The total clearance was equal to D divided by the AUC, the terminal half-life (t1/2_elim) was 0.693 divided by , and the tissue volume of distribution (V_d(area)) was D divided by (AUC · ). The linear trapezoidal rule was used to calculate the AUCs of epirubicin metabolites and of paclitaxel during the first 24 hours.

Toxicity and Statistics
At the beginning of the therapy, all patients underwent clinical evaluation, cardiac assessment with ECG, and physical examination (including measurement of blood pressure, heart rate, evaluation of edemas, and presence of dyspnea), hematologic evaluation (hemoglobin, WBC, ANC, and PLT counts), and blood chemistries (blood urea nitrogen, creatinine, bilirubin, alkaline phosphatase, lactate dehydrogenase, total protein, albumin, glucose, AST, ALT, and serum electrolytes). Hematology was performed twice a week and daily whenever ANC was less than 500/µL. At each cycle of chemotherapy, clinical examination, biochemical profile, and toxicity evaluation were performed. Cardiac imaging was performed only if clinically indicated. Toxicity was recorded and graded according to World Health Organization criteria.¹⁰ Follow-up consisted of clinical examination every 3 months and mammography every 12 months.

The mean counts of neutrophils and platelets were plotted against time for all four cycles of chemotherapy. The percentage of recovery on day 21, at the first cycle, was estimated as follows:

Linear regression analyses were performed using nadir and percentage recovery on day 21 of PLT and ANC as dependent variables and maximum peak plasma concentration (C_max), AUC, total clearance of epirubicin, and C_max and AUC of paclitaxel as independent variables. Paired pharmacokinetic data were compared using the nonparametric Wilcoxon matched-pairs signed-ranks test. Differences between pharmacodynamic parameters for different individuals within a group were compared using the Mann-Whitney U test. The nonparametric Spearman’s correlation was used for the linear regression analyses. A probability of P < .05 was considered significant.

	RESULTS

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Forty patients entered the study. One patient who was assigned to the TE sequence refused the treatment and was excluded from the analysis. Another patient who was scheduled to receive the TE sequence actually received the ET sequence and was evaluated in this latter group. Therefore, thirty-nine women were assessable and actually received either epirubicin followed by paclitaxel (21 patients) or paclitaxel followed by epirubicin (18 patients) at the first cycle. Main patient characteristics were comparable between the two groups (Table 1). All patients had stage II disease and received chemotherapy as an adjuvant treatment. Performance status was always 0. Twenty-nine patients received breast radiotherapy at the end of the chemotherapy program.

No grade 4 nonhematologic toxicity was observed. Grade 3 alopecia was universal. Only one episode of grade 3 asthenia was recorded in both groups. One episode of grade 3 vomiting was reported in the ET group, and one patient had grade 3 myalgia in the TE group. All other nonhematologic toxicity was mild or moderate (Table 2). The seriousness and the occurrence of this toxicity were similar in both groups. During treatment as well as during follow-up (median, 18 months; range, 7 to 37 months), no episode of clinical cardiotoxicity was observed, and no patient developed symptoms requiring cardiac imaging.

View larger version (19K): [in this window] [in a new window]   Fig 1. Mean neutrophil count–time curve in patients who received the TE () or ET regimen ().

View larger version (14K): [in this window] [in a new window]   Fig 2. Mean platelet count–time curve in patients who received the TE () or ET regimen ().

Pharmacokinetics
One patient in the TE group underwent pharmacokinetics analysis at the first cycle of chemotherapy but refused blood sample collection at the second cycle. Therefore, pharmacokinetic data obtained from 15 patients were available. The TE sequence was associated with an increase in the epirubicin plasma concentrations compared with the reverse sequence (Fig 3). Mean epirubicin pharmacokinetic parameters are listed in Table 3. In all of the patients, epirubicin C_max was always higher when paclitaxel by 3-hour infusion preceded epirubicin than when the taxane followed the anthracycline (TE sequence, 2,551 ± 1,047 ng/mL [mean ± SD] versus ET sequence, 1,544 ± 794 ng/mL; P = .004). On average, patients who received paclitaxel as the first drug experienced a 37% increase in epirubicin AUC (2,346 ± 1,162 ng/mL · h v 1,717 ± 542 ng/mL · h; P = .002). This enhancement was associated with a 25% reduction in the total clearance (P = .002) and 46% and 18% decreases in V_c (P = .013) and V_d(area) (P = .016) of epirubicin, respectively. The t1/2_elim of epirubicin was not significantly influenced by the sequence of drug administration (Table 3).

View larger version (8K): [in this window] [in a new window]   Fig 3. Semilogarithmic plot of mean plasma epirubicin concentrations versus time in 15 patients, acting as their own controls, who received the TE () or ET regimen ().

View larger version (15K): [in this window] [in a new window]   Fig 4. Plot of mean plasma epirubicin-glucuronide concentrations versus time in 15 patients, acting as their own controls, who received the TE () or ET regimen (). Upper panel, AUC0-24 hours values (mean ± SD) of epirubicin-glucuronide for each sequence of drug administration.

Correlation Between Pharmacokinetics and Toxicity
At the first cycle, correlations between the primary pharmacokinetic parameters and hematologic toxicity were explored. A higher total plasma exposure to epirubicin, as measured by AUC, was correlated with a lower percentage of ANC recovery on day 21 (P = .012; Fig 5). Analyzing this finding within the two sequences left it unchanged (TE, P = .010; ET, P = .036). Furthermore, total clearance of epirubicin was correlated directly with the percentage of ANC recovery (P = .011), whereas C_max of epirubicin did not (P = .101). We found no statistically significant correlation between epirubicin pharmacokinetics and neutrophil nadir.

View larger version (7K): [in this window] [in a new window]   Fig 5. Relationship of the AUC of plasma epirubicin and the percentage of neutrophil recovery on day 21 in patients who received the TE () or ET regimen () at the first cycle (Spearman’s correlation coefficient = -0.629; P = .012).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Paclitaxel and its vehicle, cremophor, are able to influence the metabolic and pharmacokinetic property of various antineoplastic agents. Among these, anthracyclines seem to be particularly affected not only by the use of paclitaxel itself,^7,8 but also by the timing and the sequence of the administration of these drugs. Conflicting results have been reported about the association of paclitaxel and doxorubicin. When paclitaxel was given as a 24-hour infusion and doxorubicin as a 48-hour infusion, a sequence-dependent effect was observed, because the paclitaxel-doxorubicin sequence was more toxic than the reverse one.^2,3,12 Although prior infusion of paclitaxel could interfere with the anthracycline pharmacokinetics, Gianni et al⁴ did not find clinical evidence of sequence-dependent effect on toxicity after 3-hour infusion of paclitaxel and bolus doxorubicin.

The main objective of our study was to investigate the presence of a possible sequence-dependent effect with the combination of paclitaxel and epirubicin. The design of our trial allowed us to study the pharmacokinetic behavior of epirubicin during its administration either before or after a 3-hour infusion of paclitaxel in the same patient, thus decreasing the interpatient variability. We found that the magnitude of effect on total epirubicin behavior was sequence-dependent. When paclitaxel preceded epirubicin, the AUC of epirubicin was increased by 37% and the C_max by 65%. This was associated with an average decrease of 25% in total clearance. Plasma sample collection stopped 24 hours after epirubicin infusion, which limited the ability to determine accurately the terminal half-lives for epirubicin, but no apparent impact of drug sequencing on the t1/2_elim of the anthracycline was suggested.

The sequence of drug administration did not seem to cause significant quantitative modifications in plasma exposure to EOL and 7d-Aone. However, in the TE sequence, the plasma profiles of EOL were qualitatively different from those observed in the ET sequence. This suggests that the EOL disposition could be influenced by the paclitaxel concentration reached in the plasma at the time of epirubicin injection. Interestingly, the administration of paclitaxel as first drug was associated with a statistically significant decrease in AUC of epirubicin-glucuronide. The glucuronide of epirubicin represents the major metabolite of this anthracycline in plasma and urine.^13,14 The AUC reduction of epirubicin-glucuronide may lead to a less efficient and a lower elimination of the unchanged drug. We also found a 46% decrease of V_c of epirubicin in the TE sequence. These findings suggest an altered distribution of epirubicin in plasma that contributes to the large increase of epirubicin AUC and the lower clearance resulted in the TE sequence. A contributing effect of cremophor, the vehicle of paclitaxel formulation, in the observed pharmacokinetic changes could be hypothesized. Inhibition by cremophor of the P-glycoprotein transporter in normal tissues may result in decreased elimination of epirubicin. Cremophor effects on P-glycoprotein reach maximal inhibition at a concentration of 1 µL/mL, which was observed at the end of a 3-hour infusion of paclitaxel.^15,16 Therefore, it cannot be dismissed that the differences in epirubicin pharmacokinetics between the two sequences of drug administration may, at least in part, depend on differences in cremophor plasma concentration at the time of epirubicin injection.

From a clinical point of view, no substantial difference in nonhematologic toxicity was observed between the two sequences. Conversely, we were able to detect a sequence-dependent effect on the myelotoxicity profile. Patients treated with the TE sequence experienced a lower nadir of both the WBC and the ANC as well as the PLT. The prominent myelotoxic effect of the TE group was also confirmed by the observation of a different behavior of the neutrophils at the time of chemotherapy administration. As previously observed,¹¹ the use of epirubicin given before paclitaxel resulted in a clear and statistically significant increase of ANC on the day of the recycle of each chemotherapy cycle in comparison with baseline. This rebound phenomenon was virtually absent in the TE treated patients. This could be due to a stronger effect on the early hematopoietic precursor cells induced by the higher plasma AUC of epirubicin in the TE sequence. Anthracyclines, as well as some alkylating agents, have an exponential dose effect on early hematopoietic progenitor cells.¹⁷ An increase in the anthracycline dose leads to increased myelotoxicity on early progenitor cells. A lower nadir and a slower recovery¹⁸ are the clinical manifestations of this toxicity. In our series of patients, a severe neutropenia was predictable regardless of the sequence used, and actually all of the patients had grade 4 neutropenia at nadir. Therefore, it was quite difficult to see any statistically significant difference in ANC nadir between sequences. On the contrary, we were able to see a difference in recovery. Throughout the planned four cycles of chemotherapy, ANC on the 21st day was significantly lower in the TE group than in the ET group (Fig 1).

Jakobsen et al¹⁹ performed a detailed pharmacokinetic analysis and a subsequent evaluation of myelotoxicity in 55 patients who had been treated with four different doses of single-agent epirubicin (40, 60, 90, or 135 mg/m² given as a 10-minute IV infusion). A significantly positive correlation was demonstrated between the AUC and the myelotoxicity of epirubicin. In the present study, we identified a relationship in individual patients between the AUC of epirubicin and the reduction in the percentage of neutrophil recovery on cycle 1, regardless of the sequence of drug administration used (Fig 5). However, it is important to note that higher epirubicin AUC and slower ANC recovery were found in the TE group than in the ET group. Our results, along with the observations of Jakobsen et al¹⁹ suggest that the plasma exposure to epirubicin is clinically important in terms of hematologic toxicity. A further explanation of the increased myelotoxicity of TE sequence comes from in vitro experiments on MCF-7 human breast cancer cells.²⁰ A greater cytotoxicity was observed when paclitaxel preceded doxorubicin compared with the reverse sequence. It has been suggested that this effect may be due to an increase of both topoisomerase II and cell accumulation in G₂-M, a phase in which DNA-damaging topoisomerase II blockers, like anthracyclines, are likely to induce significant cytotoxicity. Overall, these findings suggest that at least two different mechanisms may influence the clinical toxicity of the combined treatment of epirubicin and paclitaxel: an increase in plasma exposure to the anthracycline and a taxane effect on the cell cycle progression.

The importance of the degree of myelotoxicity has been highlighted by some authors both in advanced-stage²¹ and early-stage²² breast cancer patients. These studies indicated a statistically significant correlation between WBC nadir and overall survival, because patients with lower WBC nadir had better chances of a longer life. Myelotoxicity could be considered a marker of higher cytotoxicity and, consequently, of better chemotherapy efficacy. In reference to our results, whether the higher myelotoxicity observed in the TE group was a marker of higher activity is a matter for future studies. Despite the fact that patients in the TE group experienced more myelotoxicity at nadir, this did not compromise the administration of chemotherapy at the dose and the schedule planned. This occurred because thrombocytopenia was moderate, and neutropenia lasted a short while and was easily reversible within the 21 days of a chemotherapy cycle. Moreover, the other nonhematologic toxicity remained quite similar in the two groups of patients. However, our results should be cautiously viewed because of the suggestion that a further increase in the dose of epirubicin greater than 90 mg/m² was not associated with a parallel increase of activity, at least not in advanced disease.²³ Furthermore, our findings were obtained in early-stage breast cancer patients who received only four cycles of adjuvant chemotherapy. When more than four cycles of chemotherapy are planned, as generally occurs for metastatic patients, toxicity may worsen with the increase in the number of cycles, and myelotoxicity, particularly anemia, may be cumulative.

In summary, our data confirmed a clear and complex pharmacokinetic interaction between paclitaxel and epirubicin. Further studies should be conducted to indicate whether this interaction may be exploited to obtain increased efficacy. In the meantime, because schedule modifications of anthracyclines and paclitaxel may have clinical consequences, the classical way of administration (ie, anthracyclines followed by paclitaxel) should be maintained in clinical practice.

	ACKNOWLEDGMENTS

 
Supported in part by Associazione Italiana per la Ricerca sul Cancro, Milano; Consiglio Nazionale delle Ricerche, Roma; Pharmacia & Upjohn, Milano; and Lions Club of Genova-Sampierdarena, Genova, Italy.

We appreciate the English language support of Nadia Accettulli-Bottero in the preparation of the manuscript.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted September 27, 1999; accepted January 25, 2000.

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