Japanese Journal of Clinical Oncology 33:626-630 (2003)
© 2003 Foundation for Promotion of Cancer Research
Study of Paclitaxel and Dose Escalation of Cisplatin in Patients with Advanced Non-small Cell Lung Cancer
Division of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: We conducted a dose-finding and feasibility study in which we administered a fixed dose 3-h infusion of paclitaxel and an escalating dose of cisplatin in Japanese patients with advanced non-small cell lung cancer.
Methods: Chemotherapy consisted of fixed dose (210 mg/m2) paclitaxel given over 3 h on day 1 and an escalating dose of cisplatin on day 2, every 3–4 weeks. The dose of cisplatin was 40 mg/m2 at level 1, 60 mg/m2 at level 2 and 80 mg/m2 at level 3.
Results: Between October 1999 and February 2001, 24 patients were enrolled and 58 cycles were administered. The major hematological toxicities were leukopenia and neutropenia. Grade 4 neutropenia developed in 83.3%, 66.7% and 83.3% of patients at the dose levels of 1, 2 and 3, respectively. The major non-hematological toxicities consisted of alanine aminotransferase (ALT) elevation and peripheral neuropathy. Grade 3 ALT elevation was observed in two of the 12 patients at level 3, but both recovered within 3 days. The peripheral neuropathy was sensory-dominant and frequent, and it was almost tolerable. The maximum tolerated dose was not identified even at the highest dose of paclitaxel (210 mg/m2) and cisplatin (80 mg/m2) administered in the study. The recommended dose was determined to be paclitaxel 210 mg/m2 on day 1 and cisplatin 80 mg/m2 on day 2, every 3–4 weeks. Seven partial responses were observed in the 24 patients.
Conclusions: The combination of paclitaxel 210 mg/m2 and cisplatin 80 mg/m2 was found to be a well-tolerated active regimen in Japanese patients with advanced non-small cell lung cancer.
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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 most common causes of cancer death in many countries, including Japan, and only about 30% of patients present with surgically resectable disease. Although meta-analysis of 9387 patients from 52 randomized clinical trials has shown that cisplatin (CDDP)-based chemotherapy improves survival over the best supportive care alone, the survival benefit of chemotherapy has been only modest (1).
Paclitaxel is derived from the western yew (Taxus brevifolia) and is a new class of antitumor agent. It induces tubulin polymerization with the formation of extremely stable nonfunctional microtubules (2,3). Paclitaxel, both alone and in combination with other chemotherapeutic agents, has shown promising clinical activity in a wide variety of malignancies, including ovarian, breast, head and neck and lung cancer. In Japan, a phase I study of paclitaxel infused over 3 h revealed the maximum tolerated dose (MTD) to be 240 mg/m2, and the recommended dose for the phase II study was determined to be 210 mg/m2 (4). A subsequent phase II study of paclitaxel given over 3 h in 60 previously untreated patients yielded a response rate of 38% and a median survival time (MST) of 11.2 months (5).
In our previous phase I study of combination CDDP therapy, escalating doses of paclitaxel were given over 3 h with 60 or 80 mg/m2 of CDDP in 25 patients with untreated NSCLC (6). At the dose levels of paclitaxel 210 mg/m2 and CDDP 60 mg/m2, two of the six patients experienced dose-limiting toxicity (DLT), this level was therefore considered to be the MTD; paclitaxel 180 mg/m2 and CDDP 80 mg/m2 (one dose level below) was concluded to be the recommended dosage for the phase II study. However, the two patients who experienced DLT at the MTD level had special characteristics. The patient who experienced grade 4 septic shock, paralytic ileus and leukopenia was a hepatitis C virus carrier. The area under the patient’s plasma concentration–time curve (AUC) of paclitaxel was about three-fold greater than in other patients at the same dose level, and paclitaxel metabolism may have been influenced by the hepatic dysfunction. The other patient experienced grade 3 peripheral neuropathy on day 42 of the second treatment cycle, but it was reversible. The peripheral neuropathy in the other remaining patients was also reversible and acceptable (6). It appeared to be possible to increase the dose of paclitaxel in the majority of patients. Published data suggest that higher paclitaxel dose regimens (
200 mg/m2) yield a better response than lower dose regimens (<200 mg/m2) (7–9).
Based on the results of the previous phase I study of combination therapy and the suggestion of a dose–response relationship for paclitaxel, we conducted a dose-finding and feasibility study for a fixed-dose paclitaxel and escalating-dose CDDP regimen. The objectives of this study were to evaluate toxicities, determine the MTD and the recommended dose and assess the antitumor activity of the combination.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility
Patients with histologically or cytologically confirmed stage IIIB (with malignant effusion)/IV or post-operative-recurrent NSCLC were eligible for this study. Patients who had received prior chemotherapy and/or radiotherapy were excluded. Other eligibility criteria included: (i) age 20–74 years; (ii) Eastern Cooperative Oncology Group (ECOG) performance status 0–1; (iii) measurable lesion; (iv) adequate bone marrow function [white blood cell (WBC) count, 4000–12 000/µl; absolute neutrophil count (ANC)
2000/µl; hemoglobin >9.5 g/dl; platelets >10 x 104/µl]; adequate renal function (serum creatinine 
1.5 mg/dl, blood urea nitrogen 25 mg/dl, creatinine clearance 60 ml/min) and liver function [aspartate aminotransaminase (AST) and/or alanine aminotransaminase (ALT) levels 2x upper limit of normal; serum total bilirubin 1.5 mg/dl]; (v) stable sinus rhythm with no clinical heart disease; and (vi) absence of moderate or severe peripheral neuropathy. Patients with brain metastasis were eligible if they were asymptomatic and did not require steroids or radiotherapy. Written informed consent was obtained from all patients before enrolment in the study. Exclusion criteria included (i) hepatitis B or C virus carrier; (ii) severe heart disease; (iii) cerebrovascular disease; (iv) uncontrollable diabetes mellitus; (v) uncontrollable hypertension; (vi) severe infection; (vii) massive pleural effusion or ascites; (viii) pulmonary fibrosis or interstitial pneumonia; (ix) active peptic ulcer; (x) active concurrent malignancy; (xi) symptomatic brain metastasis; (xii) pregnancy or lactation; (xiii) acute inflammation and history of severe hypersensitivity reactions against pharmaceutical preparations containing polyoxyethylated castor oil (Cremophor EL), such as cyclosporine, vitamin K, etc. Patients with a past history of other malignancy were also excluded. This study was approved by the Institutional Review Board of the National Cancer Center.
Pre-treatment Assessment and Follow-up Studies
Prior to study entry, a detailed medical history was taken and all patients underwent a physical examination that included determination of height, weight, blood pressure and performance status. Pre-treatment laboratory data were obtained for complete blood cell count (CBC), electrolytes, renal and liver function and urinalysis. An electrocardiogram (ECG) was mandatory. Required radiographs included a baseline chest radiograph, computed tomography (CT) scan of the chest, and CT and/or ultrasound examination of the abdomen. A CT scan and/or magnetic resonance imaging (MRI) scan of the brain and a radionuclide bone scan were also required. A physical examination was performed daily after the start of chemotherapy. CBCs and routine serum chemistry studies were repeated weekly. A chest radiograph was required weekly and CT scans and an ECG were performed before and after each cycle of treatment.
Drug Administration and Dose Escalation
Paclitaxel was diluted in 500 ml of normal saline and administered as a 3-h intravenous infusion on day 1; CDDP was administered as a 1-h infusion on day 2. Polyethylene-lined nitroglycerine tubing and in-line filtration with a 0.22 µm filter were used for all infusions. Continuous electrocardiographic telemetry and blood pressure estimations at 30-min intervals were performed during the paclitaxel infusion. To prevent hypersensitivity reactions to paclitaxel, all patients were premedicated with: (i) dexamethasone (20 mg, intravenously) 1 h before paclitaxel, (ii) ranitidine (50 mg, intravenously) 1 h before paclitaxel, and (iii) diphenhydramine (50 mg, orally) 30 min before paclitaxel, as previously reported (10,11). Granisetron (40 mg) was routinely given 30 min before CDDP for antiemetic prophylaxis and sufficient pre- and post-hydration was provided intravenously. Granulocyte colony stimulating factor (G-CSF) was administered to patients who developed grade 4 leukopenia and/or neutropenia. Prophylactic use of G-CSF was not permitted.
Two of the six patients in the previous phase I study experienced DLT at the 210 mg/m2 dose of paclitaxel and the 60 mg/m2 dose of CDDP, and these dose levels were determined to be the MTD. Based on these findings, the starting doses of the combination used in the present study were paclitaxel 210 mg/m2 and CDDP 40 mg/m2.
Dose escalations of CDDP in three increments and fixed-dose paclitaxel (210 mg/m2) were administered as stated in Table 1. Six patients were entered at each dose level. The dose level was escalated if no more than two of the six patients experienced DLT in the first cycle. The intrapatient dose escalation was not allowed. Subsequent treatment cycles were repeated every 3–4 weeks in the absence of disease progression or intolerable toxicity. The definition of DLT was: (i) grade 4 neutropenia exceeding 5 days during G-CSF support, (ii) febrile neutropenia, (iii) platelet count 2 x 104/µl or (iv) grade 3 or 4 non-hematological toxicity.
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Evaluation of Toxicity and Antitumor Activity
All toxicities were graded according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) version 2.0. MTD was defined as the dose level at which three or more of six patients experienced DLT in the first cycle. One dose level below the MTD was adopted as the recommended dose.
Tumor response was assessed based on the WHO criteria (12). Patients with measurable lesions were evaluated for response to therapy. Tumors were measured as the sum of the products of tumor diameters in two dimensions on CT scans, MRI scans or chest radiographs. A complete response (CR) was defined as the disappearance of all measurable and evaluable disease without evidence of new lesions for a minimum of 4 weeks. A partial response (PR) required a 50% decrease without progression of evaluable disease or evidence of new disease for a minimum of 4 weeks. Stable disease (SD) was defined as <50% regression or <25% increase without evidence of new lesions for a minimum of 4 weeks. Progressive disease (PD) was reported if there was a 25% increase over the smallest sum observed or if there was clear worsening of evaluable disease, the appearance of any lesion, or failure to return for evaluation because of deterioration. Patients considered not evaluable (NE) for response included those who discontinued treatment before tumor re-evaluation in the absence of PD.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patient Characteristics
A total of 24 patients were enrolled in this phase I study between September 1999 and February 2001. Six patients each at levels 1 and 2, and 12 patients at level 3 were entered. The total number and the median number of chemotherapy cycles delivered were 59 and 2 (range, 1–4), respectively. Three-week cycle treatment could be achieved safely at 55.9% (33 cycles out of 59). All patients were eligible and received chemotherapy. The pre-treatment characteristics of the 24 patients are shown in Table 1. The patients had a median age of 60 years (range, 22–73 years) and a median performance status of 1 (range, 0–1). There were 16 men (66.7%) and eight women (33.3%). Nineteen patients had adenocarcinoma, three had squamous cell carcinoma, one had large cell carcinoma and one had unclassified non-small cell carcinoma. Nine patients had stage IIIB disease and 13 had stage IV disease. Two patients had post-operative recurrent disease.
Toxicity
All patients could be evaluated for toxicity. Hematological and non-hematological toxicities in the first cycle and in all cycles are summarized in Tables 2 and 3, respectively. The major hematological toxicities were leukopenia and neutropenia. Grade 3 leukopenia was observed in 21% of patients. There was no grade 4 leukopenia. Grade 3 or 4 neutropenia was observed in 80% of patients in the first cycle. The neutropenia resolved in a few days, and no serious hematological events occurred. No severe thrombocytopenia or anemia was observed at any dose level. Febrile neutropenia was observed in four (16.7%) of the 24 patients in the first cycle and in four (6.9%) of the 58 cycles. The major non-hematological toxicities were peripheral neuropathy and hepatic enzyme elevation. Grade 1 neuropathy was observed in 10 patients and grade 2 neuropathy in one patient in the first cycle. The neuropathy was sensory dominant. In the first cycle, three patients developed peripheral neuropathy at dose level 1, two at dose level 2 and six at dose level 3. One patient developed grade 3 neuropathy during the second cycle of treatment at dose level 1. Two patients developed grade 3 ALT elevation in the first cycle at dose level 3. One patient had grade 3 diarrhea at dose level 3 in the first cycle, but administration of loperamide resulted in immediate recovery. No serious myalgia or arthralgia was observed.
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DLT and MTD
At level 1, two of the six patients developed DLT. One patient developed grade 3 lower-limb-dominant neuropathy during the second cycle of treatment. Because it did not respond sufficiently to supportive treatment, it was identified as a DLT in this combination. The other patient had febrile neutropenia. At level 2, one of the six patients developed febrile neutropenia. At level 3, one patient experienced grade 3 diarrhea with febrile neutropenia, and two other patients had a grade 3 ALT elevation. Three of the six patients developed DLT at this level which was regarded as the MTD in the study protocol. However, since the ALT elevations resolved within 3 days without any medication, we concluded that these hepatic toxicities were temporary events and required further evaluation, and the monitoring committee reached the same conclusion. Accordingly, we decided to accrue an additional six patients at level 3 and continue the study. These hepatic toxicities were observed in two of the 12 patients at level 3 and were considered to be acceptable. In one patient, diarrhea was observed as a DLT at level 3 simultaneously with febrile neutropenia. Based on the toxicities, including DLT, even the highest dose level was not determined to be the MTD. Based on these findings, the recommended dose was determined to be paclitaxel 210 mg/m2 on day 1 with CDDP 80 mg/m2 on day 2 (i.e. level 3).
Antitumor Activity
All patients could be evaluated for response. The results of the tumor response evaluations are shown in Table 4. The results were: partial response (PR), no change (NC) and progressive disease (PD) in 7, 13 and 4 patients, respectively. The response rate was 29.2%. The MST was 17.9 months and the 1-year-survival rate was 58.3%.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We conducted a dose-finding and feasibility study for a fixed dose 3-h infusion of paclitaxel (210 mg/m2) and escalating dose of CDDP in Japanese patients with advanced NSCLC in order to determine the recommended doses and the MTD of this combination. Based on an assessment of all of the toxicities, including DLT, the MTD was not reached even at the highest dose level. The recommended dose was determined to be paclitaxel 210 mg/m2 on day 1 and CDDP 80 mg/m2 on day 2.
Neutropenia was the major hematological toxicity. It was determined as a DLT and was similar to previous studies, however, no serious complications occurred by G-CSF support (6,7,13). Non-hematological toxicities considered to be dose-limiting were peripheral neuropathy, liver dysfunction and diarrhea. One patient developed peripheral neuropathy as DLT during the second cycle of treatment, but the peripheral neuropathy in the other patients was acceptable. Liver dysfunction was observed in two patients at level 3, but it resolved immediately without any symptoms or medication. Diarrhea followed by febrile neutropenia occurred in one patient, but it appeared to be secondary to febrile neutropenia and antibiotic therapy, not a toxicity related to the drug combination. In view of all of these toxicity profiles, dose level 3 was considered to be acceptable. We therefore determined dose level 3 to be the recommended dose in the present study.
Several investigators have demonstrated that the interactions between paclitaxel and CDDP are highly schedule-dependent. An isobologram analysis in vitro demonstrated that paclitaxel and CDDP had an additive or even synergistic effect when CDDP was given 24 h after paclitaxel (14). When the two drugs were given simultaneously or when CDDP was given prior to paclitaxel, however, a strong antagonistic interaction was observed. Moreover, the sequence of CDDP before paclitaxel, which has less antitumor activity in vitro, has been reported to induce more profound neutropenia than the reverse sequence (15). The therapeutic ratio in vivo was improved when paclitaxel preceded CDDP, and it was greatest when the interval was 48 h (16). Based on these reports regarding the optimal sequence schedule, we administered paclitaxel on day 1 and CDDP on day 2 in this study.
Paclitaxel is a promising drug for use in combination with CDDP or carboplatin, because these drugs have different mechanisms of action. Several studies have described the antitumor activity of the combination of a 3-h infusion of paclitaxel and CDDP in advanced NSCLC, and the overall response rates have ranged from 21% to 38% (6,7,13). Although the number of patients in this study was small, the response rate (29.2%, seven PRs) was considered to be reasonable in comparison with previous studies. In addition, the survival outcome (MST, 17.9 months) in this study was relatively high and favorable in comparison to the conventional platinum-based chemotherapy.
CDDP/paclitaxel is not commonly used in clinical practice and future trial using this regimen is not strongly recommended as it offers few advantages over carboplatin/paclitaxel in terms of the problems with the inconvenience in drug administration and increased and redundant toxicity in peripheral neuropathy. However, in terms of patient survival, CDDP/paclitaxel has been shown to be equal to other platinum-based chemotherapy (17). A phase III trial directly comparing carboplatin/paclitaxel with CDDP/paclitaxel in the treatment of advanced NSCLC has been reported (13). The median survival was 8.2 months in the carboplatin/paclitaxel arm and 9.8 months in the CDDP/paclitaxel arm with 2-year survival rates of 9% and 15%, respectively. Although the response rate in both arms was similar, the significantly longer MST obtained with CDDP/paclitaxel indicates that CDDP-based chemotherapy should be the first treatment option for advanced NSCLC.
In conclusion, the combination of paclitaxel 210 mg/m2 on day 1 and CDDP 80 mg/m2 on day 2, every 3–4 weeks, was found to be a well-tolerated active regimen in Japanese patients with advanced NSCLC.
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FOOTNOTES |
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+ For reprints and all correspondence: Tomohide Tamura, Division of Internal Medicine, National Cancer Center Hospital, 5–1–1, Tsukiji Chuo-ku, Tokyo 104-0045, Japan. E-mail: ttamura{at}ncc.go.jp
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REFERENCES |
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1 Non-small Cell Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized trials. Br Med J 1995;311:899–909.
2 Pazdur R, Kudelka AP, Kavanagh JJ, Cohen PR, Raber MN. The taxoids: paclitaxel (Taxol) and docetaxel (Taxotere). Cancer Treat Rev 1993;19:351–86.[CrossRef][Web of Science][Medline]
3 Rowinsky EK, Cazenave LA, Donehower RC. Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst 1990;82:1247–59.
4 Tamura T, Sasaki Y, Nishiwaki Y, Saijo N. Phase I study of paclitaxel by three-hour infusion: hypotension just after infusion is one of the major dose-limiting toxicities. Jpn J Cancer Res 1995;86:1203–9.[CrossRef][Web of Science]
5 Sekine I, Nishiwaki Y, Watanabe K, Yoneda S, Saijo N. Phase II study of 3-h infusion of paclitaxel in previously untreated non-small cell lung cancer. Clin Cancer Res 1996;2:941–5.[Abstract]
6 Kurata T, Tamura T, Shinkai T, Ohe Y, Kunitoh H, Kodama T, et al. Phase I and Pharmacological Study of Paclitaxel Given Over 3 h with Cisplatin for Advanced Non-small Cell Lung Cancer. Jpn J Clin Oncol 2001;31:93–9.
7 Belli L, LeChevalier T, Gottfried M, Adams D, Ruffie P, LeCesne A, et al. Phase I/II study of paclitaxel plus cisplatin as first-line chemotherapy for advanced non-small cell lung cancer: preliminary results. Semin Oncol 1995;22:29–33.[Medline]
8 Huizing MT, Giaccone G, van Warmerdam LJ, Rosing H, Bakker PJ, Vermorken JB, et al. Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre. J Clin Oncol 1997;15:317–29.
9 Kosmidis P, Mylonakis N, Skarlos D, Samantas E, Dimopoulos M, Papadimitriou C, et al. Paclitaxel (175 mg/m2) plus carboplatin (6 AUC) versus paclitaxel (225 mg/m2) plus carboplatin (6 AUC) in advanced non-small-cell lung cancer (NSCLC): a multicenter randomized trial. Ann Oncol 2000;11:799–805.
10 Bookman MA, Kloth DD, Kover PE, Smolinski S, Ozols RF. Short-course intravenous prophylaxis for paclitaxel-related hypersensitivity reactions. Ann Oncol 1997;8:611–4.
11 Markman M, Kennedy A, Webster K, Peterson G, Kulp B, Belinson J. An effective and more convenient drug regimen for prophylaxis against paclitaxel-associated hypersensitivity reactions. J Cancer Res Clin Oncol 1999;125:427–9.[CrossRef][Web of Science][Medline]
12 Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207–14.[CrossRef][Web of Science][Medline]
13 Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, et al. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol 2002;13:1539–49.
14 Vanhoefer U, Harstrick A, Wilke H, Schleucher N, Walles H, Schroder J, et al. Schedule-dependent antagonism of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines in vitro. Eur J Cancer 1995;31:92–7.
15 Rowinsky EK, Gilbert MR, McGuire WP, Noe DA, Grochow LB, Forastiere AA, et al. Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol 1991;9:1692–703.[Abstract]
16 Milross CG, Peters LJ, Hunter NR, Mason KA, Milas L. Sequence-dependent antitumor activity of paclitaxel (taxol) and cisplatin in vivo. Int J Cancer 1995;62:599–604.[Web of Science][Medline]
17 Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;10:92–8.
Received July 21, 2003; accepted November 3, 2003
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