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180 pacli y filtro

  1. 1. Nonlinear Pharmacokinetics and Metabolism of Paclitaxel and Its Pharmacokinetic/Pharmacodynamic Relationships in Humans By Luca Gianni, Christine M. Kearns, Antonio Giani, Giuseppe Capri, Lucia Vigan6, Alberta Locatelli, Gianni Bonadonna, and Merrill J. Egorin Purpose: To characterize and model the disposition pie nonlinear processes. Neutropenia was not related to of paclitaxel in humans and define a pharmacodynamic the areas under the curves (AUCs) of paclitaxel or 6a- relationships between paclitaxel disposition and its tox- hydroxylpaclitaxel, or to palitaxel peak concentrations icity and efficacy. (C.,ax). Neutropenia was related to the duration that Patients and Methods: Paclitaxel pharmacokinetics plasma concentrations were : 0.05 /mol/L, a relation- were studied in 55 courses of therapy in 30 patients. ship that is well described by a sigmoid maximum re- Paclitaxel was administered at 135 mg/M 2 or 175 mg/ sponse (Ema,) model. m 2 by either a 3- or a 24-hour infusion schedule to pa- Conclusion: The disposition of paclitaxel in humans tients with advanced ovarian cancer (n = 15), or at 225 is nonlinear. Paclitaxel metabolism to 6a-hydroxylpacli- mg/m2 by 3-hour infusion to patients with advanced taxel is likely an important detoxification pathway. My- breast cancer (n = 15). Paclitaxel and 6a-hydroxylpacli- elosuppression is related to the duration that plasma taxel were quantified by high-performance liquid chro- paclitaxel concentrations are : 0.05 jtmol/L. Trials of matography (HPLC). Pharmacokinetics were assessed new doses and schedules of paclitaxel should take into by noncompartmental and model-dependent methods. account its nonlinear disposition to rule out adverse clini- Pharmacodynamic correlations were evaluated statisti- cal consequences, especially if the drug is administered cally and by regression models. by short infusion. Our pharmacokinetic model should Results: Paclitaxel disposition is nonlinear in humans prove to be a powerful tool in predicting paclitaxel dis- an nthe 3-hour schedule, 6a-hydroxylpaclitaxel was position, regardless of dose and schedule, and should identified in the plasma of all patients treated. The facilitate further pharmacodynamic investigations. plasma disposition of paclitaxel and 6a-hydroxylpacli- J Clin Oncol 13:180-190. C 1995 by American So- taxel was well described by a model that featured multi- ciety of Clinical Oncology. RECENTLY, several studies have evaluated the ad- The comparative safety of short (3-hour) versus longer ministration of paclitaxel by 3-hour infusion. These (24-hour) infusions of paclitaxel with premedication was trials have generated unexpected clinical observations that recently addressed by a multicenter European-Canadian are at variance with those in earlier studies that used 24- study.' This study also explored the dose-response rela- hour infusions. The most intriguing finding is that identi- tionship of paclitaxel in patients with ovarian cancer who cal doses of paclitaxel were markedly less myelosuppres- had relapsed after prior therapy with platinum-containing sive when delivered by 3-hour than by 24-hour infusion.1 regimens. In the bifactorial design of the study, patients Also, the description and model of the pharmacokinetics were randomized to receive either 135 or 175 mg/m2 of of paclitaxel derived from a large number of early clinical paclitaxel by either 3- or 24-hour intravenous (IV) infu- investigations 2 7 did not adequately describe the disposi- sion. This bifactorial design provided the unique opportu- tion of the drug when administered over 3 hours. nity to evaluate the pharmacokinetics of paclitaxel admin- istered at two different dosages and by two different schedules to a group of homogeneously pretreated pa- From the Division of Medical Oncology, Laboratory of Clinical tients. Accordingly, we studied the pharmacokinetics of Pharmacology,Istituto Nazionaleperlo Studio e la Cura dei Tumori, Milano, Italy; and Division of Developmental Therapeutics, Univer- paclitaxel in 15 patients accrued to the trial at the Istituto sity of Maryland Cancer Center, Baltimore, MD. Nazionale Tumori in Milan. Submitted March 7, 1994; accepted August 31, 1994. The Istituto Nazionale Tumori was also concurrently Supported in part by grants no. CNR 92.02330.PF39, CNR engaged in a phase II trial of paclitaxel in women with 93.02309.PF39 from the Italian Research Council, and breast cancer who had relapsed after receiving anthracy- UIO.CA44691 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD, and by grants from cline-containing chemotherapy regimens.8 In this study, Associazione Italiana Ricerca sul Canero, Italy, and Bristol-Myers 225 mg/m 2 of paclitaxel was administered as a 3-hour IV Squibb, Princeton, NJ. infusion. We studied the pharmacokinetics of paclitaxel Address reprint requests to Luca Gianni, MD, Division of Medical in 15 women enrolled onto this study. Oncology, Laboratory of Clinical Pharmacology,Istituto Nazionale From our analysis of these studies, we now describe per lo Studio e la Cura dei Tumori, Via Venezian, 1 20133-Milano, Italy. the nonlinear disposition of paclitaxel in these patients; © 1995 by American Society of Clinical Oncology. describe a metabolite of paclitaxel, ostensibly 6a- 0732 -183X/95/1301-0025$3.00/0 hydroxylpaclitaxel, that is measurable in plasma; and de- 180 Journal of Clinical Oncology, Vol 13, No 1 (January), 1995: pp 180-190 Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on October 11, 2010 from 186.136.221.124 Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
  2. 2. PACLITAXEL PHARMACOKINETICS AND METABOLISM 181 Table 1. Noncompartmental Analysis of Paclitaxel Pharmacokinetics Dose Infusion No. of No. of Cax AUC Apparent CIT Apparent tl/2 Urinary Excretion 2 mg/m2 (hours) Patients Cycles (pmol/L) (pM-h) (L/h/m ) (hours) (%) 135 3 4 12 3.3 - 0.4 10.9 ± 1.1 14.8 - 1.4 9.2 - 4.2 3.5 ± 1.4 175 3 3 8 5.9 - 0.9 18.5 3.0 11.4 - 1.8 6.5 - 3.4 2.1 0.5 225 3 15 15 7.6 + 1.9 24.3 - 6.8 11.6 + 3.10 7.4 - 2.0 - 135 24 4 9 0.3 + 0.1 12.4 - 2.2 13.9 ± 3.5 16.2 - 6.8 2.2 + 1.3 175 24 4 11 0.5 + 0.1 16.0 - 4.4 13.9 ± 4.2 14.6 ± 8.9 4.4 - 1.6 Total 30 55 scribe relationships between the pharmacokinetics of administration for preparation of individual standard curves and evaluation of possible interfering peaks in the high-performance paclitaxel and the dose-limiting neutropenia associated liquid chromatographs (HPLC). Blood samples for analysis of pacli- with its use. taxel in patients who received 24-hour infusions were obtained at the following times: before infusion, 1 hour, 22 hours, 23 hours, PATIENTS AND METHODS and 23 hours 55 minutes during infusion; and 5 minutes, 15 minutes, The pharmacokinetics of paclitaxel were studied in 55 cycles of 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, and 21 therapy administered to 30 patients (Table 1). Fifteen patients had hours postinfusion. For patients who received paclitaxel by 3-hour a diagnosis of relapsed or refractory ovarian cancer, and 15 patients infusion, blood samples were collected at the following times: before had a diagnosis of relapsed or refractory breast cancer. Both groups infusion; 1 hour, 2 hours, and 2 hours 55 minutes during infusion; of patients were of comparable age and performance status. The and 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 6 median age of all patients was 54 years (range, 45 to 69), and the hours, 12 hours, and 21 hours postinfusion. Seven patients from the median Eastern Cooperative Oncology Group performance status breast cancer study group had additional samples obtained at 10 was 0 (range, 0 to 2). No patient had evidence of major alterations minutes and 1.5 hours during the infusion. All blood samples were of hepatic, renal, or cardiac function at the time of study. All patients drawn from a vein in the arm opposite to that used for paclitaxel with ovarian cancer had received at least one and a maximum of infusion. Samples were collected in tubes that contained potassium two prior chemotherapy regimens that contained cisplatin and/or edetic acid. Plasma was immediately separated by centrifugation at carboplatin. All breast cancer patients had received at least one 1,000 x g for 15 minutes at 4°C and stored in polypropylene vials and no more than two prior chemotherapy regimens that contained at -20 0 C until analysis. doxorubicin or an equivalent anthracycline. For patients with ovarian cancer, urine was collected from the start Ampules that contained 30 mg of paclitaxel formulated in Cremo- of the infusion through 21 hours postinfusion. Whenever possible, phor EL:ethanol (1:1 vol/vol) were provided by Bristol-Myers samples of the infusate were collected before and after passage Squibb (Wallingford, CT). For patient administration, paclitaxel was through the IVEX II filter so that actual drug delivery could be diluted in 5% dextrose solution to a final concentration 5 0.6 mg/ assessed. mL. The drug was infused via a Life Care Model 4 volumetric pump (Abbott Laboratories, N Chicago, IL) into a large peripheral HPLC Determination of Paclitaxel and or central vein. For women who had undergone mastectomy, pacli- 6a-Hydroxylpaclitaxel taxel was not infused in the arm on the mastectomy side. Because Paclitaxel (NSC 125973) and cephalomannine were provided by a small number of fibers (within acceptable limits of the United the Pharmaceutical Resources Branch of the National Cancer Insti- States Pharmacopeia particulate matter test for large-volume paren- tute, Bethesda, MD. Pure 6a-hydroxylpaclitaxel was a gift of James teral solutions) have been observed in paclitaxel solutions, in-line Harris of the Division of Clinical Pharmacology, Food and Drug filtration was mandated. All solutions were administered through 9 Administration, Rockville, MD. 0.22-pm pore-size cellulose acetate filters (IVEX II; Millipore, Mols- Paclitaxel in plasma and urine was measured by a previously heim, France). 0 described HPLC method o with modification as described later. For Premedication was uniform for all patients and consisted of the simultaneous quantitation of both paclitaxel and 6a-hydroxylpacli- following: (1) prednisone (25 mg orally) 12 hours before infusion, taxel, the HPLC methodology was further modified as described. (2) chlorphenamine (10 mg intramuscularly [IM]) 1 hour before A stock solution of paclitaxel 1.2 mmol/L was prepared in ethanol infusion, (3) hydrocortisone (250 mg IV) 30 minutes before the start and stored at -80'C. Standard curves for the quantitation of pacli- of the paclitaxel infusion, and (4) cimetidine (300 mg IV) 30 minutes taxel were prepared for each patient using that patient's pretreatment before the start of the paclitaxel infusion. plasma. Standard curves for paclitaxel initially spanned concentra- tions from 0.0625 to 4.0 gmol/L, but were subsequently expanded Pharmacokinetic Study Design to encompass concentrations between 0.005 and 14 pmol/L. A 500- Evaluation of paclitaxel pharmacokinetics was planned for the gL aliquot of standard or sample was mixed with 10 pL of 0.065- first three cycles of therapy for ovarian cancer patients and for only mmol/L cephalomannine internal standard and applied to a 100-mg the first cycle of therapy for breast cancer patients. Because patients Bond Elut LRC C18 cartridge (Varian, Harbor City, CA) that had in the ovarian cancer study were randomized by each participating been preconditioned with sequential washings of 2 mL of acetonitrile center, patients were evenly distributed among the four arms of that and 2 mL of distilled water. After the plasma sample had been applied, study (Table 1). the cartridges were washed with 3 mL of distilled water, and paclitaxel In each patient, sufficient plasma was obtained before paclitaxel and internal standard were then eluted from the cartridge with 2 Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on October 11, 2010 from 186.136.221.124 Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
  3. 3. 182 GIANNI ET AL mL of acetonitrile. The eluant was vacuum-dried on a Speed-Vac concentration versus time curve from time zero to infinity (AUC), concentrator (Savant Instruments, Inc, Farmingdale, NY). The dried and terminal half-life (t1 /2) were estimated using the LaGrange func- residues were reconstituted with 150 pL of acetonitrile:distilled water tion as implemented by the computer program LAGRAN." The (50:50 vol/vol), and 70 pL of the reconstituted solution was injected extrapolated areas accounted for 3.5% + 2.8% for 3-hour infusions into the HPLC system. The HPLC system used a Superspher CIs 4- and for 9.3% _ 8.1% of the total AUC for 24-hour infusions. The pm, 125- x 4-mm column (Hewlett-Packard, Palo Alto, CA) protected apparent clearance was calculated using the following formula: CITB with a Lichrosphere RP-18 5-,um, 4- x 4-mm guard column (Merck, = (Dose/AUC). Darmstadt, Germany). Samples were isocratically eluted with acetoni- For compartmental analysis, pharmacokinetic models were fit to trile:distilled water (50:50 vol/vol) at a rate of 1 mL/min, and column individual patient's concentration-versus-time data using the ID eluate was monitored at 230 nm with a Hewlett-Packard model 1050 module in the ADAPT II pharmacokinetic software package.' 2 Mod- diode array detector. The detector signal was processed with Hewlett- els were designed to fit paclitaxel and 6a-hydroxylpaclitaxel concen- Packard HPLC Chemstation software implemented on a personal com- tration-time data simultaneously. Data on both parent compound and puter running under Microsoft Windows 3.0 (Microsoft Corp, Red- metabolite were available from the 15 patients with breast cancer. mond, WA). Concentrations of paclitaxel were calculated by determin- In the 15 ovarian cancer patients, for whom data were available for ing the ratio of paclitaxel signal to the internal standard signal in that paclitaxel only, parameters concerned with metabolism of the parent sample and comparison of that ratio with a concomitantly performed compound to 6a-hydroxylpaclitaxel were held constant at the mean standard curve. The retention times for cephalomannine and paclitaxel values calculated from breast cancer patients. were 5.3 and 6.1 minutes, respectively. There were no materials in Initially, all data were fit by weighted least-squares regression. pretreatment plasma samples that interfered with the peaks of interest Because the total number of concentration-time observations per in the HPLC. Recovery of paclitaxel was 95% + 1.9% at 0.1 ymol/ individual was relatively small compared with the number of param- L, and recovery of cephalomannine was 90% + 3.7% at 1.3 Aimol/ eters estimated, refinement of the parameter estimates was sought L. Standard curves were fitted by a linear equation with proportional through an iterative two-stage approach." 3 The mean values and weighting. Paclitaxel standard curves were linear between 0.005 and variances for each parameter were calculated and entered as the prior 14 Mmol/L, with an RZ value greater than .99 in all instances. The information for subsequent Bayesian estimation. For individuals in intraassay coefficient of variation (CV%) was 10.6 at 0.0625 ysmol/ whom information was available from multiple courses, pharmacoki- L and 2.8 at 8 pmol/L (n = 6). The interassay CV% values were netic estimations from each course were weighted by the reciprocal 10.2 and 9.7 at 0.0625 and 8 pmol/L, respectively. of the total number of courses studied, so that all patients were For samples in which both paclitaxel and 6a-hydroxylpaclitaxel equally represented in the final calculations. This iterative two-stage were quantitated, the analytic procedure was identical to that de- approach was repeated, in each cycle updating the Bayesian priors, scribed, except that the mobile phase was adjusted to acetonitrile/ until the mean estimates of all parameters differed by less than distilled water (48:52 vol/vol). Separate standard curves for pacli- 10% from the previous mean estimate, which was our arbitrarily taxel and 6a-hydroxylpaclitaxel were prepared for each patient's predefined stopping point. pretreatment plasma level. Paclitaxel standard curves were generated The goodness of fit of constructed models was assessed by mini- as described earlier. Standard curves for 6ac-hydroxylpaclitaxel mization of the sums of squares, examination of the residuals for ranged between 0.005 and 4.0 uimol/L. Again, concentrations of lack of heteroscedasticity,' 4 and dose independence of the estimated paclitaxel and 6a-hydroxylpaclitaxel in samples were determined by parameters. As the complexity of the model increased, previous calculating the ratio of the paclitaxel or 6a-hydroxylpaclitaxel signal assignments of nonlinear processes and additional compartments to that of the internal standard and then comparing that ratio to the were reassessed as to their necessity. appropriate standard curve. The retention times of 6a-hydroxylpacli- Relationships were sought between a variety of paclitaxel pharma- taxel, cephalomannine, and paclitaxel were 4.8, 6.6, and 7.6 minutes, cokinetic parameters and the dose-limiting neutropenia associated respectively. Recovery of 6a-hydroxylpaclitaxel was 104% + 2.6% with paclitaxel administration. Pharmacokinetic parameters explored at 1.0 ftmol/L. The 6a-hydroxylpaclitaxel standard curve was linear included plasma peak concentration (C,,,x), AUC, mean residence between 0.0125 to 3.5 Mmol/L, with an intraassay CV% of 2.5 at 1 time, and durations spent above several arbitrarily selected plasma ymol/L. The interassay CV% values for 6a-hydroxylpaclitaxel were concentrations. Because plasma paclitaxel concentrations were mea- 14.8 and 11.5 at 0.025 and 2 ymol/L, respectively. Recovery and sured at intervals too widely spaced to allow precise definition of assay CV% values for cephalomannine and paclitaxel were essen- duration at or above given thresholds, the time spent at or above tially unchanged from those stated. various plasma paclitaxel concentrations was determined from con- A slightly modified procedure was used to determine the concen- centration-versus-time profiles generated for each patient by using tration of paclitaxel in urine and in the infusate. Briefly, samples that patient's unique pharmacokinetic parameter estimates and the were diluted 1:10 (vol:vol) with mobile phase. External standard SIM module in ADAPT II.12 These simulations were designed to curves that encompassed paclitaxel concentrations between 0.5 and report plasma paclitaxel concentrations in 30-minute increments 8.0 ymol/L for urine, and between 8.0 and 64.0 pmol/L for infusate from time 0 to 50 or 60 hours postinfusion. Neutropenia was evalu- measurement, were prepared in mobile phase without internal stan- ated in two ways. Within individual patients, myelosuppression was dard, and were consistently linear with an R2 value greater than .98. described as the continuous variable, percentage reduction in abso- Identical volumes (70 pL for urine and 10 yL for infusate) of samples lute neutrophil count (ANC). The pretherapy ANC (ANCpre) was and standards were injected directly into the HPLC system. determined on the day of therapy or on the day before therapy. Following treatment with paclitaxel, patient ANCs were obtained Pharmacokinetic and PharmacodynamicAnalysis on a weekly or twice-per-week basis. The nadir of patients who The pharmacokinetics of paclitaxel and 6a-hydroxylpaclitaxel were sampled twice per week was not different from the one that were evaluated by both noncompartmental and model-dependent would have been measured with a weekly complete blood cell sam- methods. For the noncompartmental analysis, total-body clearance pling. The lowest measured ANC value was used in the equation as (ClB), steady-state volume of distribution (Vdss), area under the the ANCadir,. Relative neutropenia was calculated as follows: ANC Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on October 11, 2010 from 186.136.221.124 Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
  4. 4. PACLITAXEL PHARMACOKINETICS AND METABOLISM 183 % change = ([ANCp, - ANCnadi]/[ANCp]) x 100. To avoid poten- paclitaxel were identical (4.8 minutes). Furthermore, the tially confounding information due to cumulative toxicity, neutro- ultraviolet spectra of 6a-hydroxylpaclitaxel and the sus- penia data from only course 1 of paclitaxel therapy in each patient was used. pected metabolite collected during the chromatographic A sigmoid maximum response (EMAX) model was used to describe procedure had 99.5% concordance in the region from 210 the relationship between relative neutropenia and duration at or to 300 nm. In the absence of sufficient plasma for defini- above a number of defined threshold plasma concentrations of pacli- tive mass spectrographic analysis and nuclear magnetic taxel (0.1, 0.05, and 0.03 pmol/L). A modified form of the Hill resonance spectroscopy, these observations were taken as 15 equation, 16 as follows was used: E = EMIN ([EMAx - DH]/[DH% + DH]). Again, the ID module of ADAPT II was used to fit the presumptive evidence of identity between the unknown model to the data. In this equation, E represents effect, defined as peak in plasma and 6a-hydroxylpaclitaxel. Although a the percentage reduction in ANC. EMIN is the minimum reduction suspected metabolite peak was present in the HPLCs of possible, which was fixed at a value of 0. The maximum response, all patients who received paclitaxel by 3-hour infusion, or EMAX, was fixed at value of 100, which represented a theoretic insufficient pretreatment plasma and posttreatment sam- maximum 100% reduction from baseline ANC. D is the duration of time at or above evaluated threshold plasma concentrations of ples remained to reanalyze for 6a-hydroxylpaclitaxel the paclitaxel, and D50, is the duration of time predicted to result in samples from ovarian cancer patients treated at paclitaxel 50% of the maximum response. The Hill constant, H, is a term that doses of 135 and 175 mg/m2. Therefore, as stated earlier, describes the sigmoidicity of the curve. Model fits were evaluated quantitation of 6a-hydroxylpaclitaxel in plasma was lim- for goodness of fit by minimization of sums of the squared residuals ited to patients with breast cancer who received 3-hour and by reduction of the estimated CV% for fitted parameters. The best fit was that to the data generated with the 0.05-gLmol/L threshold. infusions of paclitaxel at 225 mg/m2 . In addition, occurrence of grade 3 or 4 neutropenia, assessed as a discontinuous variable, was evaluated with respect to dose, schedule, Pharmacokineticsof Paclitaxeland peak concentration, AUC, and duration of time at or above specified threshold concentrations. Significance of these relationships was as- 6a-Hydroxylpaclitaxel sessed by construction of contingency tables with subsequent X2 Mean pharmacokinetic parameters for paclitaxel, as analysis. calculated by noncompartmental methods, are listed in RESULTS Table 1. It was planned that the patients enrolled onto the ovarian cancer study would have pharmacokinetic Because preparation of paclitaxel for infusion is often studies performed for cycles 1 through 3 of therapy. All associated with fiber formation, in-line filtration was man- 15 patients were studied during cycle 1. Data from cycles datory for all patients described in this study. To rule out 1 and 2 were available in 14 patients, and data from the possibility that filtration caused a significant loss of cycles 1, 2, and 3 were available in 11 patients. In these the planned dose, samples of infusate distal and proximal to the filter were analyzed in 32 cycles of therapy adminis- patients, the ratios of cycle 2 AUC to cycle 1 AUC and tered at 135 or 175 mg/m 2 by either 3- or 24-hour infusion. cycle 3 AUC to cycle 1 AUC were 114% + 33% (mean + SD) and 129% ± 36%, respectively. For patients who At all doses and schedules, the mean postfilter concentra- tions of paclitaxel were 97% ± 10% of the respective received paclitaxel by 3-hour infusion, examination of prefilter concentration. This was within the range of vari- the relationship between dose administered and both the ance of the assay procedure. measured plasma paclitaxel CMAX and the AUC indicated a nonlinear relationship (Fig IB; Table 1). For example, Identification of 6a-Hydroxylpaclitaxel 3-hour paclitaxel infusions at 135 mg/m 2 resulted in a Samples from patients who had received paclitaxel on mean CMAX of 3.3 pm and a mean AUC of 10.4 pmol/ the multicenter ovarian cancer study were analyzed by L-h, while 3-hour infusions at 175 mg/m 2 resulted in a the initial HPLC procedure described. Chromatographs mean CMAX of 5.9 ymol/L and a mean AUC of 18.0 /mol/ from all patients on this study treated with 3-hour IV L h. Thus, a 30% increase in dose resulted in an 80% infusions contained a peak with a retention time of ap- increase in CMAX and a 75% increase in AUC (Table 1). proximately 3.5 minutes. This peak reached maximum For patients who received 24-hour infusions, the rela- height immediately after the end of the infusion and de- tionships between dose and the mean end of infusion clined rapidly thereafter. The assay procedure was subse- paclitaxel concentrations (CMAx) and calculated AUCs quently modified, as described, so that baseline resolution were also disproportionate. However, these nonlinear re- of this peak could be achieved. This modified HPLC lationships were less pronounced than those observed procedure was used to quantify both paclitaxel and the with 3-hour infusion schedules. Representative patient presumed metabolite, in plasma, from all patients in the plasma paclitaxel concentration-versus-time profiles from breast cancer study. The retention times of the suspected both 3- and 24-hour infusions appear in Fig 2. plasma metabolite and of a pure standard of 6a-hydroxyl- In patients who received 3-hour paclitaxel infusions, Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on October 11, 2010 from 186.136.221.124 Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
  5. 5. 184 GIANNI ET AL 4A :L A B 0 o o :3 X J1 I- 0 P o o. O 4 < W a- W o 0 i0 o o 2 a. < IL 4 uJ ,) . ul DOSE (mg/m2 ) DOSE (mg/m 2) Fig 1. Relationships between paclitaxel dose and (A) measured plasma paclitaxel C..., or (B) paclitaxel AUC in patients who received 3- hour paclitaxel infusions. Lines indicate linear relationships expected if either C..x or AUC increased proportionally with dose. plasma paclitaxel concentrations decreased rapidly imme- were described by first-order rate constants." From the diately after cessation of the infusion. This was followed noncompartmental analysis, it appeared likely that central by a more prolonged terminal phase. The concentration- elimination also included a nonlinear component, as AUC time course of the metabolite followed the same general increased disproportionately to administered dose (Table pattern as the parent, but metabolite concentrations in 1; Fig IB). Central elimination of paclitaxel and the ap- plasma were always well below corresponding concentra- tions of parent compound (Fig 3). The plasma CMAX Of 6a-hydroxylpaclitaxel ranged from 0.48 to 3.00 pmol/L and occurred between 5 and 15 minutes after completion of the 3-hour paclitaxel infusion (Table 2). Noncompart- mental pharmacokinetic parameters for 6a-hydroxyl- paclitaxel are listed in Table 2. In that measured concen- trations of 6a-hydroxylpaclitaxel were always much lower than corresponding parent drug concentrations, the 4 relative AUC of paclitaxel was 4.5 to 18 times greater I -j than that of the metabolite. In contrast to the nonlinearity observed in plasma, dose and schedule did not have measurable effect on the rela- tively small amount of paclitaxel excreted in the urine a. during the first 24 hours after initiation of the infusion. Urinary elimination accounted for only 2% to 4% of the total dose administered (Table 1). We sought to define a pharmacokinetic model that 0. would explain the observed nonlinearity in paclitaxel dis- 0 position. Initially, the data were fit to a two-compartment TIME (h) model with a single, nonlinear Michaelis-Menten process that described distribution from the central to the periph- Fig 2. Plasma paclitaxel concentration-v-time profiles of represen- tative patients who received the drug at various indicated doses and eral compartment. In this model, both return from the infusion durations. Symbols represent actual measured plasma pacli- peripheral to central compartment and central elimination taxel concentrations and lines represent model fit curves. Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on October 11, 2010 from 186.136.221.124 Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
  6. 6. PACLITAXEL PHARMACOKINETICS AND METABOLISM 185 pearance of the metabolite in plasma were both best de- Table 2. Summary of Noncompartmental Pharmacokinetic Parameters scribed by Michaelis-Menten processes. The final model of 6-a-Hydroxypaclitaxel After Administration of 225 mg/m2 by 3-Hour Infusion and the mean + SD for all model-derived processes and Paclitoxel-to-6a- volumes appear in Fig 4. Comparison of the parameters C•x TMA AUC Hydroxypoclitaxel Variable (pmol/L) (hours) (pmol/L-h) AUC Ratio for central elimination (oVm, oKm) and appearance of 6a- Mean + SD 1.27 - 0.62 3.19 - 0.09 3.22 - 1.7 9.28 + 4.47 hydroxylpaclitaxel in plasma (mVm, mKm) shows that the Minimum 0.48 3.08 0.94 4.47 central elimination pathway is, by far, the predominant Maximum 3.00 3.25 7.15 18.69 CV% 49 2.7 53 48 route of elimination. The pathway that describes the ap- pearance of 6a-hydroxylpaclitaxel accounts for only me- Abbreviation: TMx, time to CAx. tabolite identified in plasma, which is likely only a frac- tion of the total 6a-hydroxylpaclitaxel formed. Because ther 3 hours or 24 hours, there was an increase in neutro- 6a-hydroxylpaclitaxel pharmacokinetics could not be penia, both in terms of incidence and severity, as dose evaluated independently of parent compound, our esti- and AUC increased. However, the most striking observa- mates for volume and elimination of the metabolite are tion was that for any dose, the 24-hour infusion schedule simply descriptive of the observed data. However, this was associated with significantly more neutropenia than model does describe well the measured plasma concentra- the identical dose administered as a 3-hour infusion (Ta- tions of both paclitaxel and 6a-hydroxylpaclitaxel (when ble 3). As a result, total plasma exposure to paclitaxel, available) at all doses and schedules studied. as measured by AUC, and plasma CMAX of paclitaxel were not predictive of toxicity. In an attempt to explain Pharmacokinetic/Pharmacodynamic Relationships of the relationships between neutropenia, schedule, and Paclitaxel dose, we reasoned that neutropenia could be related to Neutropenia was the most common and relevant toxic- the time that plasma paclitaxel concentrations were at ity that could be investigated in our patients. We were or above a threshold concentration. This duration would able to evaluate neutropenia in 29 of 30 patients who therefore be a function of dose, infusion schedule, and received the first course of paclitaxel. Table 3 lists the the disposition of paclitaxel in any individual patient. absolute, relative, and World Health Organization- We initially investigated a threshold value of 0.1 gmol/ graded neutropenia observed with respect to dose and L, as this has been reported by some investigators to be schedule of paclitaxel. Within an individual schedule, ei- the lowest cytotoxic concentration of paclitaxel that was clinically relevant. 5',"8 9 However, other investigators have observed that paclitaxel concentrations as low as 0.05 pmol/L cause microtubular abnormalities and cyto- toxicity in vitro.20 Moreover, in a study of patients who received prolonged infusions of paclitaxel, in which plasma concentrations remained less than 0.1 pmol/L, z significant toxicity and grade 4 neutropenia were ob- i 2 served.21 It was evident, therefore, that a threshold pacli- taxel concentration of 0.1 pmol/L would not be an appro- z priate predictor of neutropenia. Thus, we evaluated 0 z threshold concentrations less than 0.1 pmol/L. For indi- 0 vidual patients, the duration that plasma paclitaxel con- centrations remained > 0.05 pmol/L is depicted in Fig I 5; only data from course 1 of therapy are included. As expected, the mean duration of time that plasma paclitaxel concentrations were > 0.05 Mmol/L increased with in- creasing dose and length of infusion. However, there was 0.1 considerable overlap among the doses and schedules, pre- 0 sumably reflective of interpatient pharmacokinetic vari- TIME (h) ability. We found that by using a threshold paclitaxel concen- Fig 3. Plasma concentrations of paclitaxel (0-) and 6a-hydroxyl- tration of 0.05 pmol/L, our sigmoid EMAX model described 2 paclitaxel (0) in plasma of a patient treated with 225 mg/m of paclitaxel as a 3-hour infusion. Symbols represent actual measured well the observed relative neutropenia versus duration at plasma paclitaxel concentrations and lines represent model fit curves. or above the threshold (Fig 6). For this model, the EMAX Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on October 11, 2010 from 186.136.221.124 Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
  7. 7. 186 GIANNI ET AL infusion Vm = 17.7 ± 7.2 PM/h Km = 0.23 + 0.12 jCM k21 = 1.4 + 0.2 h-1 k4l Vm/Km k1 4 = 2.6 ± 1.3 h-1 4 kk4l 1, k4 1 = 0.60 + 0.30 h-1 k14 k21 oVm = 29.9 + 1.5 /pM/h oVm mVm oKm = 7.0 + 1.6 pM Km mK Vi = 3.8 + 0.3 L/m 2 mVm = 1.61 + 0.01 ipM/h 3 mKm = 60.4 ± 16.8 pM I eVm = 1.9 + 0.7 pM/h eVm eKm eKm = 0.43 ± 0.21 pM 2 V3 = 0.37 ± 0.01 L/m Fig 4. Structure of the pharmacokinetic model developed for paclitaxel and 6a-hydroxylpaclitaxel. 1, Paclitaxel central compartment; 2, first paclitaxel peripheral compartment; 3, 6a-hydroxylpaclitaxel compartment; 4, second peripheral compartment of paclitaxel. Solid lines refer to the parent compound, dotted lines to the metabolite. V, and K. are Michaelis-Menten constant estimates for the saturable distribution of paclitaxel from 1 to 2. k21 is the first-order constant for return from 2 to 1. k 14 and k4 1 are the first-order rate constants for movement out of 1 to 4 and return from 4 to 1. mV. and mK, are Michaelis-Menten constants for formation of 6a-hydroxylpaclitaxel in plasma, and eV. and eK, are Michaelis-Menten constants for its elimination from plasma. V1 is the estimated volume of the central compartment of paclitaxel. V 3 is the estimated volume of the compartment of the metabolite. Mean + SD values for each parameter in the model are indicated. was fixed at 100% and the EMIN at 0%; the D50% was neutropenia. The duration of exposure to paclitaxel con- estimated to be 17.4 hours and the Hill constant was 2.3. centrations ý- 0.05 ymol/L was significantly related to Of particular importance is that duration at or above the the incidence of grade 3 or 4 neutropenia: 12 of 16 pa- threshold, irrespective of the actual dose or schedule ad- tients with exposure durations more than 24 hours experi- ministered, was the defining parameter predictive of neu- enced grade 3 or 4 neutropenia, as opposed to only two tropenia. of 13 patients with durations < 24 hours (P < .005, X2). For completeness, we evaluated threshold paclitaxel Administration schedule, per se, was not an independent concentrations both greater than and less than 0.05 ymol/ predictor of toxicity. Although six of seven patients who L. A threshold concentration of 0.1 bpmol/L produced a received 24-hour infusions experienced grade 3 or 4 neu- step function, in which profound neutropenia would be tropenia versus eight of 22 patients who received 3-hour manifest as an all-or-none event. This was inconsistent infusions, the patients who received 24-hour infusions with our clinical observations. As the threshold was de- were actually a subset of all patients who experienced > creased to 0.03 pbmol/L, the entire curve was shifted to 0.05 ymol/L paclitaxel exposures for more than 24 hours. the right, with no improvement in our measures of good- ness of fit. DISCUSSION With respect to incidence of grade 3 or 4 toxicity, there The data we have generated in the present study com- was no correlation between measured plasma paclitaxel plement and expand previous knowledge of the clinical C,,,, AUC, or dose, and occurrence of grade 3 or 4 pharmacology of paclitaxel and have important practical Table 3. Paclitaxel-Associated Neutropenia by Dose and Schedule Time Dose AUC Mean ANC at Nadir ANCNADIR Cycles With Grade 3-4 (hours) (mg/m2) (pmol/L h - SD) (c/pL ± SEM) (% + SEM) ANC (%) 3 135 10.9 1.1 1,841 ± 335* 49- 9 25 3 175 18.9 - 3.0 1,374+ 331 71 ± 6 37 3 225 24.3 - 6.8 1,075 + 207 77 - 6 50 24 135 12.4 - 2.2 846 ± 110* 80 ± 8 78 24 175 16.0 - 4.4 634 - 79* 80 - 4 89 *Statistically significant difference (P -5 .05, two-tailed t test) between samples. Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on October 11, 2010 from 186.136.221.124 Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
  8. 8. PACLITAXEL PHARMACOKINETICS AND METABOLISM 187 A• 40 - taxel accumulates in plasma of patients with biliary ob- co struction, and that large amounts of hydroxylated pacli- - 40- taxel metabolites, 22 and especially 6a-hydroxylpaclitaxel, 8 can be measured in bile. We therefore speculated that the o 35- 0 majority of 6a-hydroxylpaclitaxel formed is eliminated 0 _j 30- directly into the bile, and that metabolite measurable in C 0 plasma represents overflow at times of relative saturation 25- or blockade of biliary elimination. With respect to our o pharmacokinetic model, metabolic conversion to 6a-hy- 4 20- 0 .0 droxylpaclitaxel is embedded within both the central 4 0 elimination (oVm, oKm) and metabolite in plasma (mVm, 15- 0 mKm) parameters. In many cases, the metabolite in 0. 10- plasma component was relatively insignificant, with re- LU spect to the central elimination pathway. However, in S5- patients with liver abnormalities by neoplastic or nonneo- U_ - plastic disease that caused intrahepatic or extrahepatic 135/3 175/3 225/3 135/24 175/24 cholestasis, this may not be the case. 2 DOSE (mg/m )/INFUSION SCHEDULE (h) Another important point of this investigation is the demonstration that in-line filtration in paclitaxel infusion Fig 5. Values for duration spent at a plasma paclitaxel concentra- systems does not sequester the drug. Thus, the actual tion - 0.05 pmol/L with respect to various doses and schedules of delivered dose is equivalent to the intended dose, and administration. Circles represent individual patients. Bars depict mean values for each group. the different clearances of paclitaxel observed at various doses and schedules were not an artifact of the delivery system. For the purposes of the present study, the clarifi- implications for its optimal clinical use. The discovery cation of this practical point ruled out that the administra- and identification of 6a-hydroxylpaclitaxel as the major paclitaxel metabolite in human plasma was an important finding. Biliary excretion of paclitaxel and hydroxylated 100- metabolites can account for approximately 25% of the 90- S administered dose. 22 Recently, it was shown that 6a-hy- 13 droxylation is the prevalent biotransformation of pacli- 80- 0 0 taxel in isolated human liver microsomes, where it is 1 11q catalyzed by cytochrome P450-3A9' 23 24 or -2C according o 70- z o to other investigators.2 5 Since the metabolite is approxi- z 60- o mately 30 times less toxic than paclitaxel, 9 our data indi- uJ - cate that 6a-hydroxylation could be an important detoxi- O 50- LU fication pathway. As a consequence, induction or A inhibition of paclitaxel 6a-hydroxylation by other drugs o o 40- metabolized by cyt P450 3A 23,24 or -2C 25 will eventually * 30- A 2 175mg/m -3h 2 require paclitaxel dose adjustments to avoid under- or o- o 225 mg/m - 3h 2 over-dosage. In our patients, we observed that the total 20- * 135mg/m -24h amount of 6a-hydroxylpaclitaxel in plasma accounted for A 175 mg/m2-24h 10- I only approximately one fifth to one twentieth of the total paclitaxel dose. Also, the metabolite was only detectable n- f • . ,' . ... in plasma during times of relatively high concomitant U 5 10 15 20 25 30 35 40 45 50 parent compound concentrations, like those produced by TIME PLASMA [PACLITAXEL] a 0.05 pM (h) the shorter 3-hour infusion schedule. From the in vitro Fig 6. Pharmacokinetic/pharmacodynamic relationship between data on microsomal metabolism, one would expect a large duration spent at a plasma paclitaxel concentration > 0.05 pmol/L fraction of paclitaxel to be metabolized to 6a-hydroxyl- and percentage reduction in ANC in the first course of therapy. Sym- paclitaxel. In an effort to reconcile this apparent discrep- bols represent individuals treated at different doses and schedules (see Legend). Curve depicts the sigmoid Em_, model fit to the data. ancy, we recalled the observations by one of us (M.J. The broken portion of the curve represents that region for which data Egorin, unpublished observations) that 6a-hydroxylpacli- were not available. Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on October 11, 2010 from 186.136.221.124 Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
  9. 9. 188 GIANNI ET AL tion system could be a source of the observed nonlinearity sented model is necessary for the accurate estimation of of paclitaxel disposition. complete paclitaxel and 6a-hydroxylpaclitaxel concentra- In our study, the disposition of paclitaxel was clearly tion-time profiles. nonlinear and complex. When analyzing paclitaxel con- The mean parameter estimates provided for the model centration-versus-time data from patients treated with 3- are the result of the combined estimates from 55 courses hour infusions, the measured CMAX and the calculated of paclitaxel administered to 30 patients. While we recog- AUCs were not proportional to the doses administered. nize that this is a relatively small sample size from which The same trends were evident when the data from the to estimate population characteristics, these estimates 24-h schedule were evaluated, although the nonlinearity have thus far proven durable. was less evident at the relatively low plasma concentra- Our development of the pharmacokinetic model pre- tions of paclitaxel associated with the longer infusion. sented for paclitaxel disposition has allowed us to define The data were consistent with a saturable elimination a relationship between paclitaxel pharmacokinetics and system according to which low plasma concentrations neutropenia. Neutropenia can be related to the time at would appear to be cleared at a relatively faster rate than which plasma paclitaxel concentrations are - 0.05 pmol/ high concentrations. Thus, when concentrations declined, L. Total dose and AUC did not correspond with the inci- particularly below the saturation point of the elimination dence or severity of neutropenia. The relationship be- system, clearance would approach a linear or proportional tween time > 0.05 Ipmol/L and neutropenia is well de- relationship with respect to concentration. Therefore, dif- scribed by a sigmoid EMAX model. ferences in clearance rates would be more evident at rela- Other investigators have suggested that a paclitaxel tively high concentrations as opposed to low concentra- threshold of 0.1 jimol/L was informative with respect to tions. This may explain why previous investigators failed neutropenia.7' However, a study of 96-hour infusions of to identify the nonlinear disposition of paclitaxel at low paclitaxel in 34 patients at doses of 120, 140, and 160 mg/ doses infused over 1 or 6 hours. 2'6 Still, as other investiga- m 2 resulted in mean steady-state concentrations of 0.05, tors have shown, if the pharmacokinetics of paclitaxel 0.07, and 0.08 pmol/L, respectively. 21 Grade 4 neutropenia are assessed over a sufficiently wide range of doses, the was observed in 14 of these patients. A threshold concentra- deviation from linearity of the drug plasma kinetics is tion of 0.1 ymol/L would have predicted no toxicity in these evident even during prolonged infusions.26 patients. Furthermore, examination of the data presented to The nonlinear disposition of paclitaxel may have con- support the 0.1-jimol/L threshold shows that the relationship siderable ramifications with respect to the clinical use of between percentage reduction in ANC and time at or above the drug. Increases or decreases in dose, with no concur- the threshold is a step function.7 This implies that profound rent adjustment of time of infusion, will result in nonpro- neutropenia is an all-or-none phenomenon, which is incon- portionally higher or lower CMAX values and total plasma sistent with clinical observations. exposures or AUCs. Longer or shorter infusion schedules Our chosen threshold of 0.05 Aimol/L paclitaxel correlates could also result in nonproportionally lower or higher well with the neutropenia observed in our patients, and was predicted plasma concentrations and total AUCs for the selected between three different and arbitrary values (0.1, same delivered dose of paclitaxel. The demonstration of 0.05, and 0.03 /mol/L) on the basis of measures of goodness nonlinearity suggests the opportunity that new doses and of fit to the pharmacodynamic model. However, additional schedules of paclitaxel should be tried with suitable phar- data concerning neutropenia from relatively short durations macokinetic studies that would help the interpretation of at > 0.05 pmol/L is necessary to confirm the lower end of possible unexpected clinical effects. our model. More information on the lower portion of the The pharmacokinetic model presented here accurately curve is also important, because it may change the threshold describes the plasma concentration-time profiles of pacli- value. We are currently engaged in such an effort. taxel in patients at all doses and schedules studied, and In addition to neutropenia, hypersensitivity reactions could be used to predict paclitaxel disposition at as yet and peripheral neurosensory symptoms have been de- untested doses and schedules. Until now, simpler linear scribed as the most common dose-limiting toxicities asso- biexponential2-6 27 or triexponential models7 have been ' 5 ciated with paclitaxel administration. 1,3-,28-30 The defini- used to describe paclitaxel disposition. At first, these tion of pharmacodynamic relationships for these and other models appear to fit postinfusion plasma disappearance of paclitaxel toxicities is of great interest. In our study, we paclitaxel, even in the case of 3-hour infusions.7 However, could not assess whether a pharmacodynamic relationship they consistently underestimate plasma concentrations existed between paclitaxel pharmacokinetics and periph- during the infusion and fail to yield dose-independent eral neurosensory symptoms. Half of the patients we stud- parameter estimates. Thus, the complexity of the pre- ied had been previously treated with platinum-based che- Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on October 11, 2010 from 186.136.221.124 Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
  10. 10. PACUTAXEL PHARMACOKINETICS AND METABOLISM 189 motherapy regimens and had preexisting neurotoxicity. toxicity of paclitaxel is different for bone marrow pro- In these patients, the overall incidence of discomfort from genitors of neutrophils and for ovarian cancer cells. 1 paclitaxel was much greater than in the 15 patients with Thus, in the case of paclitaxel, toxic and therapeutic breast cancer who had never received neurotoxic drugs. pharmacodynamic relationships will most likely be As far as hypersensitivity is concerned, the clinical find- based on different pharmacokinetic parameters. More- ings of the European-Canadian trial, which contributed over, relationships between pharmacokinetics and ther- some of the patients investigated in the present study, apeutic response may well vary depending on tumor ruled out that the infusion schedule is related to the inci- type. Therefore, the relationship between paclitaxel dence and severity of hypersensitivity reactions in pa- pharmacokinetics and antineoplastic response will need tients who received adequate premedication. 1 to be defined for each tumor type against which pacli- The characterization of the therapeutic range of con- taxel demonstrates activity. The pharmacokinetic centrations of a drug requires not only the definition of model presented here should prove to be a powerful pharmacodynamic relationships to predict or produce an tool in investigating each of these issues and relation- acceptable level of toxicity, but also the definition of ships. Furthermore, should a range of plasma paclitaxel pharmacodynamic relationships to produce the maximum concentrations be associated with optimal therapeutic likelihood of response. The observation that the probabil- index, in light of demonstrated interpatient variability, ity of response in previously treated patients with ovarian the model will provide the basis for using adaptive cancer was not related to the duration of infusion seems control with feedback dosing strategies to achieve those to indicate that the biochemical/biologic target(s) of concentrations in individual patients. REFERENCES 1. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et lation and parameter estimation in pharmacokinetic systems. Comput al: European-Canadian randomized trial of paclitaxel in relapsed Prog Biomed 9:115-134, 1979 ovarian cancer: High-versus low-dose and long versus short infusion. 13. Steimer JL, Mallet A, Golmard JL, et al: Alternative ap- J Clin Oncol 12:2654-2666, 1994 proaches to estimation of population pharmacokinetic parameters: 2. Grem JL, Tutsch KD, Simon KJ, et al: Phase I study of Taxol Comparison with the nonlinear mixed-effect model. 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  11. 11. 190 GIANNI ET AL major metabolite of Taxol in human liver microsomes. Drug Metab codynamic study of Taxol in refractory acute leukemias. Cancer Res Disp 22:177-179, 1994 49:4640-4647, 1989 25. Cresteil T, Monsarrat B, Alvinerie P, et al: Taxol metabolism 28. Sarosy G, Kohn E, Stone DA, et al: Phase I study of Taxol by human liver microsomes: Identification of cytochrome P450 iso- and granulocyte colony-stimulating factor in patients with refractory zymes involved in its biotransformation. Cancer Res 54:386-392, ovarian cancer. J Clin Oncol 10:1165-1170, 1992 29. Kohn EC, Sarosy G, Bicher A, et al: Dose-intense Taxol: 1994 High response rate in patients with platinum-resistant recurrent ovar- 26. Sonnichsen D, Hurwitz CA, Pratt CB, et al: Saturable pharma- ian cancer. J Natl Cancer Inst 86:18-24, 1994 cokinetics and paclitaxel pharmacodynamics in children with solid 30. Holmes FA, Walters RS, Theriault RL, et al: Phase II trial tumors. J Clin Oncol 12:532-538, 1994 of Taxol, an active drug in the treatment of metastatic breast cancer. 27. Rowinsky EK, Burke PJ, Karp JE, et al: Phase I and pharma- J Natl Cancer Inst 83:1797-1805, 1991 Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on October 11, 2010 from 186.136.221.124 Copyright © 1995 American Society of Clinical Oncology. All rights reserved.

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