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Clinical Trials |
The Institute for Drug Development, Cancer Therapy and Research Center, San Antonio Texas and The University of Texas Health Science Center, San Antonio, Texas 78229 [E. K. R., S. D. B.]; Dana Farber Cancer Institute, Boston, Massachusetts 02115 [M. J.]; Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois 60612 [P. B.]; and Vanderbilt University Medical Center, Nashville, Tennessee 37232 [D. J.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The identification of pharmacological determinants of drug effect may enhance the therapeutic index of any anticancer agent. For example, the clearance rates of methotrexate, teniposide, and cytarabine appear to be principal determinants of therapeutic outcome in childhood acute lymphocytic leukemia (2) . Furthermore, the results of prospective evaluation suggests that therapeutic monitoring of the plasma concentrations of these agents and "real time" adaptive dosing may lead to improved outcome (2) . For carboplatin, retrospective analyses of therapeutic and toxicological results in both untreated and previously treated women with ovarian cancer have indicated that plasma AUC3 may be an accurate determinant of both therapeutic outcome and toxicity (3 , 4) . Accordingly, the use of this determinant for carboplatin dosing has been incorporated into general clinical practice. Identifying pharmacokinetic determinants of drug effect may also lead to a greater understanding of the influence of dose and schedule on both disease outcome and toxicity in the clinic.
For paclitaxel, treatment duration appears to be the most important pharmacological determinant of drug effect in vitro (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) . Prolonging the duration of drug exposure in vitro generally produces much greater cytotoxicity than increasing drug concentration, although paclitaxel concentration is also an important variable until a threshold level is exceeded (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) . In clinical practice, the principal pharmacokinetic determinants of paclitaxel effect have not been determined prospectively; however, the influences of paclitaxel dose and schedule on clinical efficacy are being addressed in Phase III evaluations in many disease settings (16, 17, 18, 19, 20, 21, 22) . In early clinical trials, the principal toxicities of the taxanes have been related to several pharmacokinetic parameters, including peak plasma concentration, plasma Css, AUC, and the duration that plasma concentrations exceed relevant threshold levels (23, 24, 25, 26, 27, 28, 29, 30) . For example, the results of several studies of paclitaxel on 3- and 24-h schedules have indicated that the severity of myelosuppression is related to the duration that plasma concentrations exceed 0.05–0.1 µmol/liter (23, 24, 25, 26, 27) . In other studies, the severity of neuromuscular effects and mucositis has been demonstrated to correlate with AUC or Css (24 , 25 , 29, 30, 31) .
Encouraged by the 1-year survival rates observed in single-agent trials of paclitaxel in patients with stage IIIb–IV NSCLC, ECOG designed a Phase III study (E5592) to evaluate the effect of paclitaxel on survival (19 , 31) . Chemotherapy-naive stage IIIb–IV NSCLC patients were randomized to treatment with 75 mg/m2 cisplatin i.v. on day 1 and 100 mg/m2 etoposide i.v. on days 1–3 (EC arm), which was selected as the reference arm because it had produced the highest 1-year survival in previous ECOG trials, or 75 mg/m2 i.v. cisplatin combined with either a low dose of paclitaxel (135 mg/m2, 24-h i.v. infusion; PC arm) or a higher dose of paclitaxel (250 mg/m2 i.v.) with G-CSF (PCG arm). The primary objective of this trial was to compare survival in patients treated with paclitaxel-cisplatin versus etoposide-cisplatin. Secondary clinical objectives included comparisons of serial quality of life measurements, response rates, and toxicity profiles as well as comparisons of the same parameters for two dose levels of paclitaxel (135 versus 250 mg/m2). Patients randomized to the paclitaxel-containing regimens experienced superior response rates and improved survival compared to patients randomized to treatment with EC (median survival, 9.9 versus 7.6 months; 1-year survival, 39.9 versus 31.8%, P = 0.048; Ref. 19 ). However, there were no differences in response or survival relative to paclitaxel dose (19) . With the exception of increased myalgia with paclitaxel and increased neurotoxicity with high-dose paclitaxel, toxicity and quality of life in the three treatment arms were similar.
E5592 provided a unique opportunity to prospectively perform population pharmacodynamic studies in patients receiving paclitaxel to determine whether disease outcome or toxicity or both are related to the plasma paclitaxel Css. The study also provided an opportunity to gauge the importance of paclitaxel pharmacokinetics relative to other treatment, demographic, and stratification variables, such as the paclitaxel treatment arm (paclitaxel dose), age, sex, performance status, weight loss in the previous 6 months, and disease stage. The results of these studies are detailed here.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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5% weight loss during the previous 6 months; (c) stage IIIb versus stage IV disease; and (d) bidimensional measurable disease versus evaluable disease. Medical or interval histories, physical examinations, tumor measurements, and routine chemistry and electrolyte studies were performed before each course of treatment. Complete blood counts and differential WBC counts were performed at least weekly. Grading and tumor response were according to ECOG criteria (32)
. Patient demographic, toxicity, response, and survival data were obtained from the ECOG statistical office using the central study database used for the principal analysis of the clinical study results (19) .
Paclitaxel Plasma Sampling and Analytical Assay.
Blood samples (7–10 ml) were collected in heparinized tubes from patients who were treated with paclitaxel during the last hour of the 24-h i.v. infusion of paclitaxel during the first and second courses of treatment. Treating physicians and their staff were instructed to centrifuge the samples immediately, store the plasma at -20°C, and ship the sample on dry ice to the central analytical pharmacology laboratory. Paclitaxel concentrations were measured by a high-performance liquid chromatography assay, as described previously (25)
. Using the mean kinetic parameters for paclitaxel disposition on the 24-h schedule, end-of-infusion paclitaxel concentrations have been demonstrated to be nearly equal, on average, to Csss, using the formula derived by Weiss (33
, 34)
. Paclitaxel Csss exceeding 5 µmol/liter (five patients) were excluded from the analyses because they were mostly due to plasma sampling proximal to the drug infusion and represented more than three SDs above the mean Csss in this and other studies that used identical paclitaxel dose schedules (23
, 25
, 27)
. In all of these subjects, paclitaxel Csss were at least 8–596-fold higher than the paired sample.
Demographic and Outcome Comparisons: Univariate Analysis.
Both nonparametric and parametric statistical tests were used to assess whether there were differences in relevant demographic characteristics or indices of outcome between patients in the low- and high-dose paclitaxel treatment arms (PC versus PCG arm). Descriptive statistics were used to describe relevant demographic characteristics, stratification variables, paclitaxel Csss, and disease outcome parameters (mean, median, SD, and range). The paired t test was used to compare Csss between courses 1 and 2 in those patients whom had matched pairs. The Fisher’s exact test was used to compare each of the following categorical parameters between the treatment arms: ECOG performance status (0 or 1), sex (male or female), weight loss (<5% or 5%) in the previous 6 months, disease stage (IIIb or IV), disease measurability (bidimensional or evaluable), response (STD/PD or CR/PR), and survival status (alive or dead). The Wilcoxon rank sums test was used to compare median values for the following data between the PC and PCG treatment arms: Css during course 1, Css during course 2, average Css for courses 1 and 2 (Css,avg), age, TTF [time from study arm randomization to the first evidence of treatment failure, death, or last follow-up evaluation (censored)], and survival (time from study arm randomization to the time of death or last follow-up, which was censored).
The Kruskal-Wallis Rank Sums test was used evaluate differences in paclitaxel Css during course 1, Css during course 2, and Css,avgs in patients who achieved the following as their best responses to treatment with PC or PCG: CR, PR, STD, or PD. Similarly, the Kruskal-Wallis Rank Sums test was used to evaluate differences in paclitaxel Css among patients who experienced a range of ECOG toxicity grades (leukopenia, neurosensory toxicity, or neuromotor toxicity) as their worst toxicity during treatment with PC or PCG. There were insufficient data available in the database to assess neutropenia. The Wilcoxon rank sums test was used to assess differences in paclitaxel Csss between responders (CR/PR as their best response) and nonresponders (STD/PD as their best response) and as a function of survival status. Associations between paclitaxel Css and TTF were evaluated using linear regression analysis. The Tukey-Kramer honestly significant difference method was used to test for type I error when multiple pairs of means were compared.
Multivariate Analysis.
The influence of the paclitaxel Css,avg and other potentially relevant patient characteristics on response, TTF, and survival were evaluated in multiple logistic regression analyses. The logistic and phreg procedures in SAS (SAS Institute, Cary, NC) were used to assess the degree of association of paclitaxel treatment arm (PC versus PCG), Css,avg, age, ECOG performance status (0 versus 1), sex (male versus female), weight loss (<5% versus 5%), and stage (IIIb versus IV) with response, TTF, and survival (35
, 36)
.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patient Demographics and Paclitaxel Css.
Demographic characteristics and relevant parameters of disease outcome in patients who were treated with PC and PCG and had plasma sampling during both courses are depicted in Table 1
. There were no significant differences between the PC and PCG arms with regard to age, ECOG performance status, disease stage, or weight loss. However, paclitaxel Csss in courses 1 and 2 as well as Css,avg differed significantly between patients treated with the low- and high-dose paclitaxel regimens, as shown in Tables 1
and 2
. The median (range) paclitaxel Csss in course 1 were 0.32 µmol/liter (0.10–4.63 µmol/liter) and 0.85 µmol/liter (0.15–4.53 µmol/liter) in patients in the PC and PCG treatment arms, respectively (P < 0.0001), and corresponding values in course 2 were 0.25 µmol/liter (0.04–3.64 µmol/liter) and 0.75 µmol/liter (0.07–4.97 µmol/liter), respectively (P < 0.0001). Similarly, median (range) paclitaxel Css,avgs in patients with plasma sampling performed during both courses 1 and 2 differed significantly between patients in the PC and PCG treatment arms [0.32 µmol/liter (0.12–3.70 µmol/liter) versus 0.81 µmol/liter (0.11–3.60 µmol/liter), P < 0.0001].
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Relationship between Paclitaxel Css and Disease Outcome.
Relationships between paclitaxel Css and disease outcome were evaluated using univariate methods. There was no difference between responders (i.e., patients who had either CR or PR as their best response) and nonresponders (i.e., patients who had either STD or PD as their best response) in the magnitude of paclitaxel Css,avg [median, 0.40 µmol/liter (range, 0.16–1.6 µmol/liter) versus 0.55 µmol/liter (range, 0.11–3.6 µmol/liter), P = 0.15]. Median paclitaxel Css,avgs were also similar in patients segregated according to whether they experienced CR, PR, STD, or PD as their best response (0.47, 0.39, 0.66, and 0.48 µmol/liter, respectively). Scatterplots depicting individual paclitaxel Css,avgs according to categorical response are depicted in Fig. 1
. The relationship between paclitaxel Css,avg and TTF was also evaluated. As shown in Fig. 2
, this relationship was weak (r2 = 0.00003, P = 0.94). The results are nearly identical if categorical response and TTF are related to paclitaxel Css achieved during either course 1 or course 2 (results not shown).
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. The overall combined effect of all covariates in the model did not predict significantly for either response (P = 0.1544) or TTF (P = 0.2574), whereas the combined effect of all covariates predicted significantly for survival (P = 0.0249). Analysis of individual variables demonstrated that a lower disease stage (stage IIIb) was the only significant positive determinant of response (P = 0.0173), female sex was the only significant favorable predictor of TTF (P = 0.0195), and a lower ECOG performance status (= 0) was the only significant positive determinant of survival (P = 0.0121). Several of the covariates predicted marginally, albeit not significantly, for response [Css,avg (P = 0.0971)], longer TTF [stage IIIb (P = 0.0544)], and longer survival [female sex (P = 0.0798)].
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. The magnitude of the paclitaxel Css,avg was not related to the propensity to experience neuromotor or neurosensory toxicities nor to the toxicity grade (P = 0.2033 and 0.5000, respectively). Although the relationship between paclitaxel Css,avg and grade of leukopenia approached a level of marginal statistical significance (P = 0.0796), further analysis using the Tukey-Kramer honestly significant difference test revealed a very low likelihood that any single one of the multiple paired comparisons was significant. Similar results were achieved when analyses were performed using paclitaxel Css achieved during either course 1 or course 2 (results not shown).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although the 146 patients in whom paclitaxel Css,avgs were calculated represent a subset of the 398 patients entered on both paclitaxel arms, this subset was representative of the entire group of patients. There sole requirement for including patients in the pharmacodynamic component of the study was plasma sampling at the end of both courses 1 and 2, which should not be influenced by either demographic or disease-related factors. In fact, comparisons of the distribution of demographic and disease-related variables (age, sex, weight loss, stage, and performance status) and principal study end points (response rate, TTF, and survival) revealed no differences between the 398 total patients entered on the PC and PCG arms and the subset of patients participating in the pharmacodynamic component of the study.4
The questions of whether plasma Css is an appropriate parameter to use for the pharmacodynamic analyses performed in this study and whether alternate pharmacokinetic parameters would yield disparate results must also be considered. Because the paclitaxel plasma concentration at the end of infusion has been demonstrated to be nearly equivalent to Css when paclitaxel is administered over 24 h, relationships between it and other pharmacokinetic parameters, such as AUC and duration of exposure to drugs at concentrations of >0.05–0.1 µmol/liter, become stronger with more prolonged infusions (25, 26, 27, 28, 29, 30 , 33 , 34) . Another consideration in using paclitaxel Css for these studies was the feasibility of obtaining plasma samples during both courses 1 and 2 in a sufficiently large number of patients in a Phase III multicenter study. However, one potential pitfall in using Css,avg is that it is derived from the first two courses only, whereas disease outcome and toxicity represent summations of effects overall courses. This concern is perhaps most applicable to neurotoxicity, which, in contrast to myelosuppression, is clearly a cumulative effect of paclitaxel and cisplatin (30 , 34 , 37) . In this study, neither the total number of courses nor the cumulative dose of paclitaxel was considered in the pharmacodynamic analyses relating Css to toxicity. However, minimal intrasubject course-to-course variability in pharmacokinetics has been reported in previous studies of paclitaxel. In addition, there was good concordance in paclitaxel Css between courses 1 and 2 in this study, suggesting that the pharmacokinetic behavior of paclitaxel during the first two courses is a satisfactory representation of paclitaxel pharmacokinetics during subsequent courses (23 , 24 , 29 , 38) .
Even in situations in which there are true dose-, concentration-, or duration of exposure-response relationships, small, albeit significant, differences between patients treated at various dose levels may not be appreciated if there is large interindividual pharmacokinetic variability and an insufficient sample size. Because these factors may have, in part, accounted for the apparent lack of a significant differences in disease outcome between patients receiving low- and high-dose paclitaxel in combination with cisplatin in this study, population pharmacokinetic and pharmacodynamic assessments across both dose levels were undertaken to better identify relationships between paclitaxel Css and disease outcome. Indeed, there was substantial interindividual variability in paclitaxel Css in patients treated with paclitaxel doses of 135 mg/m2 (PC arm) and 250 mg/m2 (PCG arm), but there was a clear difference between patients in the PC and PCG treatment arms [median Css,avgs, 0.32 and 0.81 µmol/liter, respectively (P < 0.0001)]. However, no relationships between paclitaxel Css,avg and either response, TTF, survival, or worst grade of leukopenia, neurosensory toxicity, or neuromotor toxicity were apparent. In the multivariate models that included potential determinants of outcome, paclitaxel Css,avg was not a determinant of response, TTF, or survival. In fact, a lower disease stage (stage IIIb) was the only significant positive determinant of response (P = 0.0173), female sex was the only significant predictor of time to progression (P = 0.0195), and a lower ECOG performance status (= 0) was the only significant positive determinant of survival (P = 0.0121) in the models.
The results of these pharmacodynamic studies support the initial clinical results indicating no differences between the PC and PCG arms in disease outcome despite 
2-fold differences in paclitaxel dose and median Css,avgs. At first glance, these results may not appear to be congruent with those of in vitro studies (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
. Although the duration of paclitaxel treatment appears to be a more important determinant of drug effect than drug concentration in vitro, the magnitude of most biological effects of paclitaxel (i.e., cytotoxicity, formation of microtubule bundles and mitotic asters, increase in tubulin polymer mass, stabilization of microtubules against depolymerization, apoptosis, radiosensitization, antiangiogenesis, and inhibition of chemotaxis and motility) are also related to drug concentration (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
. However, a plateauing of dose response or a situation of diminishing returns is typically noted as paclitaxel concentrations increase, and the drug concentration at which the plateauing of effect occurs varies from cell line to cell line (5, 6, 7
, 18)
. The broad clinical implications of these results is that there may be a critical "plateau" paclitaxel concentration or dose above which toxicity but not efficacy increases, but there also appears to be a critical concentration, below which drug effects do not usually occur. The cumulative results of in vitro studies suggest that the precise concentration at which plateauing occurs depends upon the specific treatment schedule, and the "threshold" concentration is inversely related to the duration of treatment.
In essence, clinical observations to date resemble those of in vitro studies. On the basis of the results of both nonrandomized and randomized clinical trials that have evaluated relationships between paclitaxel dose and disease outcome, the flat or plateau portion of the dose- or concentration-response curve in vitro is noted in the clinic with paclitaxel at doses of >135 mg/m2 on a 24-h schedule (18, 19, 20) . For example, a pooled analysis of 191 ovarian cancer patients treated with paclitaxel doses ranging from 110 to 300 mg/m2 as a 24-h infusion in the first five disease-directed studies used for registration in the United States that controlled for the effects of individual study, performance status, number of prior regimens, platinum sensitivity, and age, demonstrated that the probability of responding and longer progression-free and overall survival were not related to paclitaxel dose in the range of 110–300 mg/m2 (24-h infusion; Ref. 39 ). In addition, a Phase III intergroup study in which patients with recurrent and refractory ovarian cancer were treated with 24-h infusions of paclitaxel at 175 or 250 mg/m2 plus G-CSF demonstrated only modest a difference in overall response rates, 36 versus 28%, respectively (18) . This modest difference was even nullified by a higher response rate in platinum-sensitive patients treated with the lower dose and no differences in both progression-free and overall survival between the high- and low-dose groups. The dose-response issue has also been evaluated in ECOG study E1393 in which patients with metastatic or locally advanced head and neck cancer who had not previously received chemotherapy for recurrent disease were randomized to treatment with 75 mg/m2 cisplatin following either low-dose paclitaxel (135 mg/m2, 24-h schedule) or high-dose 200 mg/m2 paclitaxel (24-h schedule) plus G-CSF. Response rates were identical (35%) with both treatments, and there was no difference in survival (20) . Although the results of these studies indicate that paclitaxel doses of >135 mg/m2 on a 24-h schedule produces either no or little, if any, further benefit, this generalization is applicable to the 24-h paclitaxel schedule only, and the precise dose with other schedules at which plateauing of the dose- or concentration-response curve occurs must be determined prospectively. However, the results of randomized trials in ovarian, breast, and lung cancer to date suggest that plateauing occurs at paclitaxel doses of at least 175 mg/m2 on shorter (3-h) schedules (16 , 17 , 22) .
The lack of relationships between disease outcome and both paclitaxel dose and Css may be explained by saturation of paclitaxel receptors on ß-tubulin at Csss achieved with paclitaxel doses at or above 135 mg/m2 on a 24-h schedule. In addition, plasma paclitaxel Csss may not reflect drug effects in peripheral tissues. The pharmacokinetic behavior of a drug in plasma cannot always be generalized to actions at the cellular level, particularly when drug concentrations in plasma and peripheral tissues are disparate. For the taxanes, plasma concentrations achieved with almost any dose schedule are capable of inducing relevant biological effects in vitro, but the degree of tissue distribution for the taxanes is very large, most likely due to avid drug binding to tubulin, plasma proteins, and high tissue:plasma concentration ratios, have been noted in virtually all tissues except testes and brain in animal studies (23 , 24 , 40) . Not only are high paclitaxel concentrations achieved in almost all peripheral tissues, but biologically relevant drug concentrations are sequestered in peripheral tissues and tumors for relatively long periods, which may not be accurately estimated from plasma concentration data (40 , 41) . Therefore, paclitaxel Css, which is seemingly a relevant parameter based on the results of in vitro studies, may correlate poorly with drug actions in peripheral tissues. In addition, Css,avg achieved following a 24-h infusion may not reflect the duration that paclitaxel concentrations are above the threshold levels of 0.05–0.1 µmol/liter, which have been determined to be both biologically and clinically relevant (8, 9, 10, 11, 12, 13 , 25, 26, 27) .
These results indicate that the plasma paclitaxel Css alone is not a determinant of disease outcome or principal toxicities in patients with advanced NSCLC receiving treatment with paclitaxel as a 24-h infusion combined with cisplatin. On the basis of both the clinical and pharmacodynamic results of E5592, there is also no compelling reason to administer paclitaxel on a 24-h treatment schedule at doses of >135 mg/m2 in combination with cisplatin in patients with advanced NSCLC, although higher doses are associated with higher paclitaxel Csss, on average. Although it is likely that similar dose and concentration effects occur with other paclitaxel schedules and in other disease settings, the generalizability of these results is not known, and the precise paclitaxel dose range or concentrations at which the plateauing of drug effects occurs should be based on the results of randomized prospective trials similar to the study described here.
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FOOTNOTES |
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1 This study was conducted by the Eastern Cooperative Oncology Group (Dr. Robert L. Comis, Chair) and was supported in part by USPHS Grants CA25988, CA23318, CA49957, CA66636, and CA2115 from the National Cancer Institute, NIH, and Department of Health and Human Services. Its contents are solely the responsibilities of the authors and do not necessarily represent the official views of the National Cancer Institute. 
2 To whom requests for reprints should be addressed, at The Institute for Drug Development, Cancer Therapy and Research Center, 8122 Datapoint Drive, Suite 700, San Antonio, TX 78229. Phone: (210) 616-5945; Fax: (210) 616-5865; E-mail: erowinsk{at}saci.org
3 The abbreviations used are: AUC, area under the time versus concentration curve; NSCLC, non-small cell lung cancer; ECOG, Eastern Cooperative Oncology Group; G-CSF, granulocyte colony-stimulating factor; TTF, time to treatment failure; STD, stable disease; PD, progressive disease; CR, complete response; PR, partial response.
4 P. Bonomi, unpublished results.
Received 11/17/98; accepted 1/22/99.
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, medians.
