Japanese Journal of Clinical Oncology 31:93-99 (2001)
© 2001 Foundation for Promotion of Cancer Research
Phase I and Pharmacological Study of Paclitaxel Given Over 3 h with Cisplatin for Advanced Non-small Cell Lung Cancer
1Thoracic Oncology Division, National Cancer Center Hospital, Tokyo and 2Thoracic Oncology Division, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: To establish the toxicities and maximum tolerated dose of paclitaxel given over 3 h in combination with cisplatin, to determine the pharmacokinetic profiles of these two drugs and to observe their antitumor activity, we conducted a combination phase I study in non-small cell lung cancer.
Methods: Patients received paclitaxel doses of 150–210 mg/m2 given over 3 h and cisplatin doses of 60–80 mg/m2 as a 1 h infusion 2 h after the end of the paclitaxel infusion.
Results: A total of 25 patients with previously untreated non-small cell lung cancer were enrolled. Granulocytopenia was the most frequent hematological toxicity and the most prominent non-hematological toxicity was sensory dominant neuropathy. Two of six patients experienced dose limiting toxicities (leukopenia, infection and neuropathy) at a dose of paclitaxel 210 mg/m2 and cisplatin 60 mg/m2, which was considered the maximum tolerated dose. There were seven partial responses among 24 evaluable patients, for an overall response rate of 29%. The median survival time was 341 days and the 1 year survival rate was 45.8%. As the paclitaxel pharmacokinetic parameters in this study were consistent with those of our previous single agent study, we found no significant drug–drug interaction between the 3 h infusion paclitaxel and cisplatin.
Conclusion: The recommended doses for further study are determined to be paclitaxel 180 mg/m2 and cisplatin 80 mg/m2. This is a well-tolerated and active regimen for non-small cell lung cancer. In view of the promising survival outcome, further evaluation in prospective randomized trials versus other regimens is warranted.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Non-small cell lung cancer (NSCLC) is one of the main causes of cancer deaths in Japan. Of all primary malignant lung tumors, ~80% have non-small cell histology. Approximately 60% of NSCLC patients have locally advanced or metastatic disease at diagnosis. Although meta-analysis has shown that cisplatin (CDDP)-based combinations result in an improvement in survival (1), the role of chemotherapy for advanced disease is controversial because the survival benefit of chemotherapy is only modest. Therefore, many investigators have tried to identify new active agents.
Paclitaxel (Taxol) was the first new taxoid agent extracted from the bark of the Pacific yew (Taxus brevifolia) (2), and is now produced semi-synthetically. This agent induces excessive polymerization of tubulin and blocks cells in the G2/M phase. It has been demonstrated to have antitumor activity in several solid tumors. Early clinical trials using short infusion schedules showed unacceptable hypersensitivity reactions (3). As a consequence, longer infusion schedules were evaluated, as well as the use of premedication with corticosteroids, H-1 and H-2 histamine receptor antagonists (4). A randomized 2 x 2 factorial trial to 135 or 175 mg/m2 given over 3 or 24 h with premedication suggested that the incidence and severity of hypersensitivity reactions were low with 3 h infusion and this short infusion duration was safe. This trial also showed that the response rates for 3 and 24 h infusions were not significantly different (5). In addition, phase II studies of paclitaxel conducted with previously untreated NSCLC patients indicated that paclitaxel is one of the most active agents for NSCLC. Two phase II studies using 24 h infusion showed response rates of 21 and 25% with 1 year survivals of 41 and 38%, respectively (6,7). We performed a phase II study with paclitaxel given over 3 h in 60 previously untreated patients. The response rate in our study was 38% and the 1 year survival rate was 48% with a median survival time of 11.2 months (8). We observed no clinically significant hypersensitivity reaction. Based on this evidence, we decided to combine paclitaxel given over 3 h with CDDP. The purpose of this study was to establish the toxicities and maximum tolerated dose (MTD) of this combination, to determine the recommended dose of this combination for phase II study, to determine the pharmacokinetic profiles of these two drugs and to observe their antitumor activity.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patient Eligibility
Patients with histologically or cytologically proven stage IIIB or IV NSCLC were eligible. Eligibility criteria were as follows: (1) previously untreated; (2) measurable lesion; (3) age 20–74 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status 0–1; (5) life expectancy >3 months; (6) adequate organ function [a white blood cell count (WBC) 4000–10 000/µl, a neutrophil count
2000/µl, a platelet count 100 000/µl, a hemoglobin count 9.5 g/dl, serum total bilirubin 
1.5 mg/dl, serum transaminase 2.5 x upper normal limits, a serum creatinine <1.3 mg/dl, blood urea nitrogen (BUN) <25 mg/dl, creatinine clearance 60 ml/min]; and (7) normal electrocardiogram (ECG). Patients were treated as inpatients. Exclusion criteria included severe heart disease, cerebrovascular disease, uncontrollable diabetes mellitus, uncontrollable hypertension, severe infection, massive pleural effusion or ascites, pulmonary fibrosis, interstitial pneumonitis, active peptic ulcer, active concurrent malignancies, symptomatic brain metastases, pregnancy, lactation, acute inflammation and history of severe hypersensitivity reactions against drugs which include polyoxyethylated castor oil (Cremophor EL) such as cyclosporine, vitamin K, etc. This study was performed at the National Cancer Center Hospital and at the National Cancer Center Hospital East and was approved by the Institutional Review Board. Written informed consent was obtained from all patients. This study was conducted in accordance with Japanese good clinical practice (GCP). Central registration by fax to the Department of Health Science, Faculty of Medicine, University of Tokyo was employed.
Pretreatment and Follow-up Studies
Prior to entry, a complete history was taken and physical examination including height, weight, blood pressure, performance status and tumor stage, was performed. Pretreatment laboratory data included a complete blood cell count, differential WBC count, platelet count, serum electrolytes, total protein, albumin, total bilirubin, total cholesterol, alkaline phosphatase, transaminase, lactate dehydrogenase, BUN, creatinine, creatinine clearance and urinalysis. These laboratory studies were repeated weekly. The lesion measurements and ECGs were performed before and after each course. Toxicities were evaluated according to ECOG common toxicity criteria. Tumor response was assessed by the standard response criteria. A complete response (CR) required the complete disappearance of all clinical evidence of disease for at least 4 weeks. A partial response (PR) required a 50% decrease in the sum of the products of the perpendicular diameters of all measured lesions that persisted for at least 4 weeks. Progressive disease (PD) was defined as any increase of 25% in the products of the perpendicular diameters of any measured lesion or the appearance of a new lesion on any imaging study. The remaining patients were classified as no change (NC).
Drug Administration and Dose Escalation
Paclitaxel and CDDP were supplied by Bristol-Myers Squibb (Tokyo, Japan). Paclitaxel was provided as a solution containing 30 mg of this drug in 5 ml of 50% polyoxyethylated castor oil (Cremophor EL) and 50% ethanol and CDDP as a solution containing 10 or 50 mg. Patients received paclitaxel diluted in 500 ml of saline in a 3 h intravenous (iv) infusion and received CDDP in a 1 h iv infusion 2 h after the completion of paclitaxel infusion. Premedication consisted of 20 mg of dexamethasone given iv 12 and 6 h before paclitaxel, 50 mg of diphenhydramine orally and 50 mg of ranitidine iv, 30 min before paclitaxel. Granisetron 40 µg was given iv 30 min before CDDP for antiemetic prophylaxis and sufficient pre- and post-hydration was administered. Granulocyte colony-stimulating factor (G-CSF) prophylaxis was not administered. Subsequent treatment cycles could be repeated every 3 weeks until disease progression if patients fulfilled the eligibility criteria.
The starting dose of paclitaxel was 150 mg/m2 and CDDP 60 mg/m2. Dose escalations were performed as listed in Table 1. Intra-patient dose escalation was not allowed. If patients experienced dose limiting toxicity (DLT) in the initial course, the dosage of paclitaxel was reduced by 30 mg/m2 for the subsequent courses. At least three patients were treated at each dose level. Three additional patients were entered at the same dose level if DLT was observed in one of the first three patients. The MTD was defined as the dose level at which more than two patients out of three to six patients experienced DLT. The definition of DLT was as follows: (1) grade 4 granulocytopenia for more than 6 days, (2) grade 4 leukopenia and thrombocytopenia and (3) grade 3 non-hematological toxicity (except nausea, vomiting, fatigue).
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Pharmacokinetics and Pharmacodynamics
Sample Collection
Pharmacokinetic (PK) studies for both paclitaxel and CDDP were performed in all patients during their first course. Heparinized venous blood samples (3 ml) for paclitaxel PK were taken before administration, 1.5 h after the start of paclitaxel, at the end of the 3 h infusion and at 5, 15, 30 min and 1, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 24 and 48 h post-infusion. CDDP PK samples were taken in heparinized tubes before administration of CDDP, at the end of the 1 h infusion and at 0.5, 1, 1.5, 2, 3, 5, 7, 21 and 45 h post-infusion. Plasma samples were separated by centrifugation (2000 g for 5 min at 4°C) and stored below –20°C. Plasma ultrafiltrate (UF) samples were immediately prepared from the remaining plasma using four Amicon Centrifree Filters per sample (30 000 MW cut-off) (Amicon Division, W.R. Grace Company, Beverly, MA, USA). The filters were centrifuged (2000 g for 15 min at 4°C) and stored at –20°C until analysis.
HPLC Assay
Paclitaxel in plasma were determined by the validated high-performance liquid chromatographic (HPLC) procedure with minor modifications (9). Briefly, 0.5 ml of plasma sample was diluted with 2 ml of water and was applied to a Sep-Pak C18 cartridge. An internal standard (IS), n-hexyl p-hydroxybenzoate (2 ml, 1 µg/ml) was also added to the column. The column was washed with 2 ml of 30% acetonitrile. The eluate was evaporated to dryness under reduced pressure at 40°C and the residue was dissolved in 200 µl of 2 mM H3PO4–acetonitrile (55:45). HPLC analysis was performed on an Inertsil ODS column, 4.6 x 150 mm, particle size 5 µm (GL Science, Japan). The mobile phase was 0.01 M KH2PO4–acetonitrile (55:45). A linear standard response was obtained in the range of 0.015–2 µg/ml.
AAS Assay
Platinum concentration in plasma and UF was determined with a Hitachi polarized Zeeman spectrophotometer (Model Z-8200) according to Adnan and Iman (10). An aliquot of 100 µl of plasma was diluted with 1.9 ml of 0.5% Triton X-100 and 100 µl of UF were diluted with 100 µl of 1% Triton X-100. An aliquot of 20 µl of the sample solution was analyzed in duplicate. The sample was treated by drying at 75–120°C, ashing at 1400°C and atomization at 2600°C. The peak height of the absorption at 265.9 nm was measured and the concentration was calculated using linear regression analysis. The calibration curves were linear over the concentration range 200–5000 ng Pt/ml in plasma and UF.
Pharmacokinetic Analysis
From the concentration of paclitaxel and platinum in plasma and UF, the PK parameters, AUC, T and MRT, were calculated by a non-compartmental moment method (11). Cmax was the actually observed peak concentration. The terminal slope of the plasma log(concentration) vs time curve, elimination rate constant (ß), was determined by least-squares linear regression analysis using at least three points including the last assayed point. The apparent elimination half-life (T) was calculated by the equation T = ln2/ß. AUC was calculated by the trapezoidal rule plus the ratio of the plasma concentration at the last assayed point to the elimination rate constant. The total clearance (CLT) and the apparent volume of distribution at the steady state (Vss: Taxol) were calculated as follows: CLT = dose/AUC, Vss = dose x MRTiv/AUC, MRTiv = MRT – (infusion time/2).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Between January 1996 and March 1997, a total of 25 patients were enrolled into this phase I study. The total and the median number of courses were 61 and 2 (range 1–10), respectively. The patient characteristics are shown in Table 2. There were 17 males. The median age was 58 years (range 42–74 years). The majority of patients had a performance status of 1. Sixteen patients had adenocarcinoma and five squamous cell carcinoma. Twelve patients had stage IIIB and 13 had stage IV disease.
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Toxicities
All patients were assessable for toxicity. However, as one patient at dose level 3 received G-CSF because of grade 4 granulocytopenia without the confirmation of the period for granulocytopenia, she was excluded from the decision about dose escalation.
Hematological Toxicity
Granulocytopenia was the most frequent hematological toxicity, but was not considered to be dose related. Seven patients experienced grade 4 granulocytopenia, but none of the patients had granulocytopenia lasting more than 6 days during the first course. Absolute granulocyte and WBC nadirs for each dose level are listed in Table 3. The nadir for granulocytes occurred on day 12 (median, range 8–14), with median recovery time of 6 days (range 1–14 days). As for thrombocytopenia, all but one patient who experienced grade 4, had grade 0. No grade 3 or 4 anemia was observed.
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Non-hematological Toxicity
Sensory dominant neuropathy was frequent. There was one grade 3, one grade 2 and eight grade 1 neuropathy during the first course. At dose level 3, one patient developed grade 3 during the first course and another patient developed paresis of the lower limbs, grade 3 neuropathy, 42 days after the completion of two cycles. The neurologist diagnosed this paresis to be caused by the study chemotherapy. Among 20 patients who received more than two cycles, 13 experienced neuropathy during all their courses and only six of 13 cases showed symptomatic development/aggravation after course 2 or thereafter. One patient at dose level 3 experienced grade 4 infection, septic shock and grade 4 paralytic ileus with grade 4 leukopenia. This patient also developed grade 4 thrombocytopenia, grade 3 neuropathy and grade 3 elevation of total bilirubin and creatinine. The patient recovered 7 days after the initiation of symptoms. No treatment-related death was observed. As for diarrhea, one patient developed grade 3 at dose level 5. This occurred on days 3 and 7, with immediate recovery by treatment with loperamide. Grade 3 or 4 nausea/vomiting occurred in four patients at paclitaxel doses above 180 mg/m2; these episodes could be controlled by dexamethasone or granisetron. Alopecia was frequent but mild. Mild myalgia and arthritis were also frequent. There were four grade 3 elevations of total bilirubin; these were not considered DLTs as they were transient.
Overall toxicities during the first course are listed in Table 4. At dose level 3, two patients developed DLTs (one patient had grade 4 infection, leukopenia and neuropathy and the other patient grade 3 neuropathy after the second cycle). At dose level 5, only one patient developed a DLT (grade 3 diarrhea). Therefore, dose level 3, paclitaxel 210 mg/m2 with CDDP 60 mg/m2, was considered the MTD. The recommended dose level for further phase II study was determined to be paclitaxel 180 mg/m2 with CDDP 80 mg/m2 (dose level 5 in this study).
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Pharmacokinetics
PK studies were carried out in 25 patients during the first course. The PK parameters are listed in Table 5. As seen in other previous studies with paclitaxel given as a single agent, non-linearity was found between the dose of paclitaxel and the AUC and Cmax (Table 5). Typical concentration–time curves of paclitaxel are shown in Fig. 1. Table 6 shows the PK parameters of our previous study with single agent paclitaxel given over a 3 h infusion (12). The paclitaxel PK parameters we observed in the current combination study were consistent with those of our previous single-agent study. Hence we conclude that there was no significant drug–drug interaction. Interpatient variability on PK parameters was smaller than expected (data not shown).
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One patient who experienced infection (septic shock), leukopenia and neuropathy at dose level 3 had the highest paclitaxel AUC and Cmax (42.5 µg h/ml and 10.9 µg/ml, respectively). He was also a hepatitis C virus carrier. Two other patients who experienced DLTs had PK parameters similar to those of the other patients.
Response
Twenty-four of 25 patients were assessable for response; one patient at dose level 5 had breast cancer concurrently and was not assessable. There were seven partial responses, for an overall response rate of 29%. However, there was no clear dose–response relationship (Table 7). The median time to reach response was 29 days (range 14–49 days) and the median duration of response was 83 days (range 35–206 days). The median survival time was 341 days and the 1 year survival rate was 45.8%.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Previously, we reported a phase II study with paclitaxel using 3 h infusion in which the response rate was 38% and the median survival time was 11.2 months (8). Paclitaxel is a promising drug for use in combination with CDDP, as these drugs have different mechanisms of action and have non-overlapping toxicity profiles, aside from peripheral neuropathy.
In vitro studies have indicated that cell kill activity in several cell lines increased as the duration of paclitaxel exposure increased (13,14); however, the optimal administration schedule has not been determined. In our study we selected a 3 h infusion schedule for the patients’ convenience on the basis of its having been shown to be safe and efficacious (5). However, Georgiadis et al. (15) recently suggested that a longer duration of paclitaxel exposure (120 h in their studies) results in an increase in cytotoxicity in in vitro studies and consider both 3 and 24 h infusion schedules to be of relatively short duration. On this basis, we suggest that randomized clinical trials to compare short infusion schedules with longer ones, such as 96 or 120 h, are warranted.
Rowinsky et al. reported that the administration of CDDP followed by paclitaxel was more toxic than the reverse sequence (16). Moreover, sequence effects between paclitaxel and other anticancer drugs such as doxorubicin (17) and cyclophosphamide (18) have also been reported. Even though there is not much information regarding the optimal sequence schedule, we decided to administer paclitaxel before CDDP in this study, following Rowinsky et al.’s report.
In this phase I study, hematological toxicities, especially granulocytopenia, were frequent. Seventeen patients experienced grade 3 or 4 granulocytopenia; these were not dose related. However, none of these cases met the criteria for DLT. Severe thrombocytopenia and anemia were uncommon at all dose levels. As for non-hematological toxicities, sensory dominant neuropathy was frequent, but not severe. Although both paclitaxel and CDDP are known to induce neuropathy, only two patients experienced dose limiting grade 3 neuropathy, including one patient at dose level 3 who developed paresis of the lower limbs 42 days after the completion of two cycles. Recently, it has been reported that both cumulative paclitaxel dose and the magnitude of a single paclitaxel dose determined the severity of neuropathy (19). However, in our study, only six among 20 patients who had received more than two courses showed symptomatic development/aggravation after course 2 or thereafter. Therefore, we cannot establish whether neuropathy is related to cumulative doses of paclitaxel. The primary site of the peripheral neuropathy caused by paclitaxel is unclear; however, it is likely that paclitaxel induces both an axonopathy and a neuronopathy, with neuronopathy occurring with higher doses of paclitaxel and CDDP and an axonopathy pattern occurring at relatively low doses (19).
All neuropathies seen in our study were reversible. One patient at dose level 3 developed grade 4 septic shock, paralytic ileus and leukopenia. This patient was a hepatitis C virus carrier. His PK parameters (AUC, Cmax) were higher than the others, which could indicate that his clearance of paclitaxel might be lower as the main site of metabolism for paclitaxel is the liver. Dose finding and feasibility studies for patients who are hepatitis B or C virus carriers and yet fulfil the eligibility criteria for liver function may be important for future research.
Overall three patients experienced DLTs, two at dose level 3 (one infection, leukopenia and neuropathy and one grade 3 neuropathy after the second cycle) and one at dose level 5 (grade 3 diarrhea). Consequently, dose level 3, of paclitaxel 210 mg/m2 with CDDP 60 mg/m2, was considered to be the MTD. The recommended dose level for further phase II studies was determined to be paclitaxel 180 mg/m2 with CDDP 80 mg/m2.
There were seven partial responses, for an overall response rate of 29%. The median survival time was 341 days and the 1 year survival rate was 45.8%. Several studies have described the antitumor activity of a combination of 3 h infusion of paclitaxel and CDDP in advanced NSCLC, with an overall response rate ranging from 38 to 42% (20–22). In one study, reported by von Pawel et al., the median survival time (301 days) and 1 year survival rate (33%) are slightly lower than in the other studies, as the majority of patients had a performance status of 2 (20). In the other studies, the median survival time was 9.7 months and 328 days and the 1 year survival rate 43 and 40%, respectively (21–22). The overall response rate was relatively low in our study, but, in view of the survival outcome, it is comparable to these paclitaxel–CDDP studies and favorable with respect to the conventional platinum-based chemotherapy. Currently, the clinical value of the paclitaxel–CDDP combination is being studied in several randomized trials, which may clarify whether there are various differences between this regimen and others. Recently, other investigators have reported that there seemed to be a clear dose–response relationship with respect to response and survival. Huizing et al. indicated that the median survival duration and response rate were significantly better for paclitaxel doses 175 mg/m2 than for doses <175 mg/m2 in a dose-escalating study in combination with carboplatin (23).
Pharmacokinetic evaluations in this study showed non-linearity between the dose of paclitaxel and AUC and Cmax, as was seen previously in other studies with paclitaxel given as a single agent. Moreover, the inter-patient variability of pharmacokinetic parameters was smaller than expected. In this study we found no significant drug–drug interaction between the 3 h infusion of paclitaxel and CDDP and the PK parameters of paclitaxel were in good agreement with our previous study. However a rigorous comparison is not possible owing to the different patient population.
In conclusion, the combination of paclitaxel given over 3 h and cisplatin is well tolerated and active for non-small cell lung cancer. The recommended dose level for further studies is paclitaxel 180 mg/m2 with cisplatin 80 mg/m2. The pharmacokinetic study showed no significant drug–drug interaction.
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Acknowledgements |
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We thank the following participating investigators: Drs Kenji Eguchi, Nobuyuki Yamamoto, Seiji Nagashima, National Cancer Center Hospital, Tokyo and Drs Fumihiko Hojo, Koichi Goto, Seiji Niho, Toru Miyamoto, Jun Takafuji, Keiji Kodama, National Cancer Center Hospital East, Chiba. We are grateful to Dr Kazuo Ota (Nagoya Memorial Hospital), Dr Akira Wakui (Miyagi Cancer Center), Dr Yasuo Ohashi (University of Tokyo) and Dr Yutaka Ariyoshi (Aichi Prefectural Hospital) for their help as members of the monitoring committee for this study.
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FOOTNOTES |
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+ For reprints and all correspondence: Tomohide Tamura, Thoracic Oncology Division, National Cancer Center Hospital, 1–1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan
Abbreviations: NSCLC, non-small cell lung cancer; CDDP, cisplatin; MTD, maximum tolerated dose; ECOG, Eastern Cooperative Oncology Group; WBC, white blood cell count; BUN, blood urea nitrogen; ECG, electrocardiogram; GCP, good clinical practice; CR, complete response; PR, partial response; PD, progressive disease; NC, no change; iv, intravenous; G-CSF, granulocyte colony-stimulating factor; DLT, dose limiting toxicity; PK, pharmacokinetic; UF-Pt, ultrafiltered platinum; HPLC, high-performance liquid chromatography; IS, internal standard; AUC, area under the plasma concentration–time curve; T, half time; MRT, mean residence time; Cmax, peak plasma concentration; CL, clearance; Vss, volume of distribution at steady state; NE, not evaluable
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Received August 4, 2000; accepted December 15, 2000.
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