Japanese Journal of Clinical Oncology 32:449-454 (2002)
© 2002 Foundation for Promotion of Cancer Research
Low-dose Weekly Paclitaxel as Second-line Treatment for Advanced Non-small Cell Lung Cancer: a Phase II Study
Departments of 1 Medical Oncology and 2 Neurophysiology, Hospital Arnau de Vilanova, Valencia, Spain
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Purpose: To assess the activity and toxicity of low-dose weekly paclitaxel in patients with non-resectable or metastatic non-small cell lung cancer (NSCLC) and who had disease recurrence or failure with previous chemotherapy.
Patients and methods: Forty patients with NSCLC previously treated with platinum-based chemotherapy received weekly paclitaxel 80 mg/m2 as a 1 h infusion. The median age was 63 years (range 42–77 years); 25 patients had Eastern Cooperative Oncology Group performance status (PS) 1 and 15 had PS 2. Thirty-one patients had stage IV disease and nine stage III (eight stage IIIB and one stage IIIA).
Results: A total of 364 weeks of treatment were administered (median 8 weeks, range 2–17 weeks). There were no episodes of grade 3 or 4 haematological toxicities. Severe non-haematological toxicity was uncommon: grade 1–2 asthenia in 50%; grade 1–2 motor neuropathy in 45% and grade 3 in 10%; grade 1–2 sensory neuropathy in 62% of patients. Alopecia was mild. The overall response rate was 37.5% (95% CI, 23.9–55): 2 CR, 13 PR, 15 SD, 8 PD, 2 NE. Median overall survival was 9.7 months (95% CI, 6.5–12.8). Median time to progression was 5.4 months (95% CI, 1.8–8.9).
Conclusion: A low-dose weekly paclitaxel regimen had good clinical efficacy with low toxicity in this group of patients with poor prognosis. This regimen increases the therapeutic options available for second-line therapy in NSCLC patients.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Over the past few years, a change has occurred in the way patients with advanced non-small cell lung cancer (NSCLC) are treated. Recently, three meta-analyses of randomized studies that compared chemotherapy with best supportive care (1–3) demonstrated a significant, albeit small, survival benefit for chemotherapy patients with an accompanying improvement in quality of life. In addition, the advent of several new agents has furthered the development of novel chemotherapy regimens for the treatment of NSCLC patients. For example, active agents such as paclitaxel, docetaxel, gemcitabine, vinorelbine and irinotecan have shown encouraging results as single agents and in combination regimens. Median survival of 9–11 months and 1 year survival rates of over 40% have been observed. Consequently, most advanced lung cancer patients with good performance status are treated with a chemotherapy regimen containing one or another of these new agents in combination with a platinum compound, i.e. cisplatin or carboplatin. However, most responses to initial chemotherapy regimens are partial and nearly all patients will, eventually, progress. The availability of the new pharmacological agents opens up new possibilities for their use in patients who have retained a good performance status following relapse or progression after first-line chemotherapy. In recent years, an increasing number of articles on second-line chemotherapy in patients with NSCLC have been published (4,5).
Paclitaxel as a single agent or in combination has been demonstrated to have significant activity in chemotherapy-naive NSCLC patients. Responses ranged from 10 to 38% and median survival ranged from 6 to 11 months (6). These promising results stimulated its application as a second-line treatment. Several different administration schedules of paclitaxel, alone or in combination, have been used including 24, 3 and 1 h infusions in addition to weekly dosing (6). However, optimum dosages, administration schedules and duration have yet to be defined. Preclinical data have suggested that duration of exposure is an important factor in the cytotoxic activity of paclitaxel (7) and prolonged exposure can achieve cytotoxicity at relatively low paclitaxel concentrations (0.01 mmol/l) (7–9). Prolonged exposure at these concentrations can be achieved easily, either by infusing paclitaxel over an extended period (96 h infusions) or by administering it on a frequent and repetitive basis, such as in a weekly schedule.
Weekly paclitaxel has been demonstrated to have significant activity in NSCLC (10) and other malignancies. Akerley et al. conducted a phase I trial in chemotherapy-naive patients with NSCLC (11). A maximum tolerated dose of 175 mg/m2 was administered over 3 h for six consecutive weekly schedules of an 8 week cycle. Objective response was observed in 35% of patients with haematological and neurological toxicities limiting further dose escalation. The preliminary data from a phase II trial (10) confirmed the efficacy (56% partial responses). However, optimum dosage has not been established to date. Low-dose weekly paclitaxel (80–100 mg/m2) is effective and well tolerated in advanced breast cancer, neuropathy being the limiting toxicity (9,12,13). Apart from a few abstracts (14–16) or studies with a relatively limited numbers of patients (17), there is, to the best of our knowledge, a paucity of data on low-dose weekly paclitaxel in NSCLC.
Based on this rationale, we initiated a prospective phase II trial to assess the efficacy and toxicity of low-dose weekly paclitaxel for patients with NSCLC who have recurrent disease or who are refractory to previously administered chemotherapy.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility
Patients were required to have histologically or cytologically confirmed non-resectable or metastatic NSCLC that had progressed during or after one or more chemotherapy regimens. Other eligibility criteria were as follows: life expectancy of at least 12 weeks; Eastern Cooperative Oncology Group (ECOG) performance status
2; adequate bone marrow reserve (defined as absolute granulocyte count 
2000/ml and platelet count 100 000/ml); adequate hepatic and renal function (defined as serum creatinine level 2 mg/dl, AST and ALT 1.5 times the upper limit of normal, bilirubin 1.5 mg/dl, alkaline phosphatase values 5 times the upper limit of normal). Exclusion criteria included pre-existing motor or sensory neurological symptoms 2 (NCI-CTC), active infections or serious social conditions that precluded weekly attendance at the hospital. Patients with brain metastases were not excluded from the study. The study was conducted in compliance with institutional review board regulations and was approved by the Ethics Committee of the Centre. All patients were required to provide written informed consent prior to entry into the study.
Pretreatment and Follow-up Evaluation
Pretreatment evaluation included a complete clinical history and physical examination, complete blood cell count, serum chemistries (including liver and renal function tests and electrolytes), prothrombin time and partial thromboplastin time, chest X-ray and computed tomographic (CT) scans of the chest and upper abdomen. If symptoms suggestive of metastasis at other sites were present, additional tests were performed to confirm or refute this possibility. During treatment, patient monitoring included a weekly complete blood cell count during the first 4 weeks and then, if haematological toxicity was not detected, every 4 weeks of therapy. Follow-up history and physical examination, serum chemistries, tumour measurements and toxicity assessment according to the NCI-CTC scale (18) were performed before each 5 week course of therapy. For response evaluation, the pertinent CT scans were repeated after every 8 weeks of treatment.
Treatment Schedule
Treatment consisted of paclitaxel at a dose of 80 mg/m2 administered as a 1 h intravenous infusion in physiological saline at the outpatient chemotherapy clinic. Treatment was given weekly, without a rest period, until disease progression, unacceptable drug toxicity, best response had been achieved, or until the attending physician/investigator considered that there was no benefit accruing from the chemotherapy. Dexamethasone (8 mg), dexchlorpheniramine (5 mg) and ranitidine (50 mg) were prescribed 30 min before paclitaxel infusion. Prophylactic anti-emetics were not routinely provided.
World Health Organization (WHO) response criteria were used for efficacy analysis (19). Patients who were withdrawn from the trial prior to response evaluation because of rapidly progressive lung carcinoma were considered as non-responders. All patients who received at least 1 week of chemotherapy were evaluated for toxicity.
The primary end point of the study was the response rate. Simon’s two-stage optimum design was used to determine sample size and decision criteria (20). It was assumed that a response rate of 30% in eligible patients would indicate potential usefulness while a rate of 10% would be the lower limit of interest and 
= 0.05 and ß = 0.10. Using these design parameters, the first stage of the study was initially to enrol 18 patients and this regimen was rejected if fewer than two patients had an objective response. Under the null hypothesis (for response rate 10%) the probability of early termination was 71%. If two or more patients responded, the accrual was continued until 36 patients. The planned accrual period was 24 months. Secondary end points were toxicity and overall survival. Response and survival rates were both calculated on an intent-to-treat basis. Overall survival and time to progression were measured from the date of entry into the trial up to time of death or up to the date of the last follow-up clinical assessment. Survival curves were constructed using the Kaplan–Meier method.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Demography
A total of 40 patients were entered into this study from August 1998 to December 2001. Patients’ clinical characteristics are presented in Table 1. All 40 patients had received a prior platinum-based chemotherapy regimen (Table 1). Four of these patients had received more than one chemotherapy regimen; in three of them, the subsequent regimen was paclitaxel every 3 weeks. All 40 patients were eligible for toxicity assessment. Two patients had received prior chemotherapy in the neoadjuvant setting. Of the 40 patients, 22 had initially responded to platinum-based therapy, 10 patients had achieved stable disease (SD) and eight had progressive disease (PD). The median time between the last dose of the previous chemotherapy and the start of the weekly paclitaxel was 25 weeks (range 3–104 weeks).
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Compliance and Response
A total of 364 courses of weekly paclitaxel were delivered, with a median of 8 weeks per patient (range 2–17 weeks). Only two patients received less than 4 weeks of treatment: one had a hypersensitivity reaction despite pretreatment measures and the other had poor compliance due to social problems. Both were withdrawn from the study following the second cycle and were considered non-evaluable for response. Eighteen cycles were omitted (5%) owing to toxicity: thrombocytopenia grade 1 (three cycles), fever grade 1 (two cycles), fatigue grade 3 (two cycles), infection without neutropenia (eight cycles) and peripheral neuropathy grade 2 (two cycles). No dose reductions were necessary.
Of the 40 patients entered into the study, 15 (37.5%; 95% CI, 23.9–55%) had an objective response (intent-to-treat) to weekly paclitaxel [complete response (CR) = 2; partial response (PR) = 13]. SD was achieved in 15 patients (37.5%) and eight (20%) experienced PD (Table 2). The two patients with CR had received prior chemotherapy with carboplatin and gemcitabine.
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The response rate to prior chemotherapy was 55% (22 of 40 patients). Ten of the 15 responses occurred in this group of chemo-sensitive patients. Only two responses occurred in patients with SD and, surprisingly, three responses were achieved in patients who had experienced PD in the course of the previous platinum-based chemotherapy (Table 2). Response according to histological subtype and performance status is shown in Table 2.
All 40 patients were included in the survival analysis, with a median follow-up time of 6.4 months (range 1–36 months). The median overall survival for the entire group was 9.7 months (95% CI, 6.6–13) (Fig. 1). The 1 and 2 year survival rates were 37.7 and 18.8%, respectively. The median time to progression was 5.4 months (95% CI, 1.8–8.9).
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Toxicity
The haematological and non-haematological toxicities are described in Table 3. In general, weekly paclitaxel was well tolerated by this group of patients with poor prognosis. There were no grade 3 or 4 haematological toxicities. Non-haematological toxicities were also mild. Fatigue and alopecia were the most common non-haematological treatment-related toxicity: 24 patients had grade 1–2 fatigue and 29 patients had alopecia grade 1–2. Three patients developed severe fatigue (grade 3) and one patient severe alopecia. Other grade 3 non-haematological toxicities were uncommon and included nausea (two patients), motor neuropathy (four patients), sensory neuropathy (one patient) and hypersensitivity reaction (one patient).
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One patient with PR died after 9 weeks of treatment due to pneumonia without neutropenia and was considered a toxic death.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Modest survival benefit has been observed with the administration of platinum-based chemotherapy compared with best supportive care alone in patients with advanced NSCLC (1–3). The advent of several new anti-neoplastic agents with favourable efficacy and toxicity profiles opens up the possibility of new approaches in the treatment of advanced NSCLC. The results of the present phase II trial confirm the efficacy of low-dose weekly paclitaxel in the treatment of pretreated patients with non-resectable or metastatic NSCLC.
Weekly paclitaxel as a 1 h infusion had a favourable toxicity profile and a substantial degree of activity in this group of poor prognosis patients. A median of 8 weeks of therapy at a dose of 80 mg/m2 was delivered, which represents a dose intensity of 240 mg/m2 per 3 week interval. At this high-dose intensity haematological toxicity was mild, no grade 3 or 4 neutropenia, anaemia or thrombocytopenia being observed. Non-haematological toxicity was also mild. Fatigue and anorexia were the most common, most of them being grade 1 or 2. Neurotoxicity is particularly associated with this regimen when the paclitaxel dose is increased to >100 mg/m2, but at the dose in our study only four patients presented grade 3 motor neurotoxicity. Considering that all patients had received platinum-based therapy, the rate of grade 1 or 2 neurotoxicity is acceptable.
Second-line chemotherapy has become almost routine in NSCLC patients with good performance status. Recently, two articles that summarized the results of second-line chemotherapy for NSCLC were published (4,5). Huisman et al. reviewed 34 single-agent studies (17 in abstract form) and 24 multi-drug studies (13 in abstract form). They concluded that the results from both single-agent and multi-drug studies are difficult to assess effectively owing to limited patients’ details such as pretreatment conditions, response to first-line therapy and progression-free interval (5). Response rates from 0 to 38% have been reported for single-agent paclitaxel. The number of patients included has been small, the doses varying between 135 and 250 mg/m2 and the duration of infusion between 1 and 24 h. Few data on weekly paclitaxel as second-line chemotherapy have been reported (14–17).
Our phase II trial indicates that weekly paclitaxel, as a single agent, was active as second-line therapy in this group of 40 extensively pre-treated NSCLC patients. The response rate of 37.5% was comparable to that obtained in phase II studies with chemotherapy-naive patients. The median overall survival (9.7 months) and time to progression (5.4 months) are among the best in phase II second-line chemotherapy trials reported to date. Although high-dose paclitaxel could prove to be more effective, no confirmatory studies comparing high- versus low-dose weekly paclitaxel have been conducted to date. When prospective studies had been conducted to assess the dose–response relationship of several paclitaxel-containing regimens administered every 3 weeks, no statistically significant differences were observed regarding response rate or survival (21,22). Moreover, the dose intensity administered with this regimen is similar to the highest dose delivered with schedules of every 3 weeks (240 mg/m2).
Of interest is an evaluation of response following previous chemotherapy. Two studies (23,24) reported that platinum refractoriness negatively influenced second-line chemotherapy response. Contradictory results come from three other trials (25–27) in which no relationships between response to second-line therapy and platinum-resistant NSCLC were observed. In our study, the likelihood of response to weekly paclitaxel did not appear to be influenced by the response to previous platinum-based therapy; five of our 18 patients (28%) with stable disease or progression following previous chemotherapy responded to the weekly paclitaxel therapy.
Since palliation is the most important goal in advanced NSCLC, the challenge is to devise an active and well-tolerated regimen. The low-dose weekly paclitaxel is effective in the treatment of NSCLC patients and can be safely administered in this group of pretreated patients. Unlike high-dose and other conventional schedules, no grade 3–4 neutropenia was observed. In the first-line setting, PS has been identified as prognostic factor for response and survival. Recently, the CALGB study confirmed the benefit of combination therapy (carboplatin plus paclitaxel) versus single-agent paclitaxel (28). However, one should be cautious in extrapolating these results to second-line therapy. In our study, 15 (37.5%) of the 40 patients included had PS 2. The overall response rate (27%) and the median survival (6.2 months; 95% CI, 1.4–11) of these patients with a PS of 2 shows the clinical benefit in this subset of poor prognosis patients.
In conclusion, the favourable response rate, median time to progression and overall survival observed with low-dose weekly paclitaxel justify its application to patients with advanced NSCLC. The low toxicity profile suggests that this schedule would be promising following first-line chemotherapy or in patients with co-existing clinical conditions that preclude further aggressive combination therapy. Further randomized trials comparing weekly paclitaxel to combination chemotherapy as first-line chemotherapy in advanced NSCLC are warranted.
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FOOTNOTES |
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+ For reprints and all correspondence: Oscar Juan, Department of Medical Oncology, Hospital Arnau de Vilanova, C/ San Clemente 12, 46015 Valencia, Spain. E-mail juan_osc@gva.es
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REFERENCES |
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1 Souquet PJ, Chauvin F, Boisel JP, Cellerino R, Cormier Y, Ganz PA, et al. Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. Lancet 1993;342:19–21.[Web of Science][Medline]
2 Marino P, Pampallona S, Preatoni A, Cantoni A, Invernizzi F. Chemotherapy versus supportive care in advanced non-small cell lung cancer: results of a meta-analysis of the literature. Chest 1994;106:861–5.
3 Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using update data on individual patients from 52 randomized clinical trials. Br Med J 1995;311:899–909.
4 Ferrigno D, Buccheri G. Second-line chemotherapy for recurrent non-small cell lung cancer: do new agents make a difference? Lung Cancer 2000;29:91–104.[Web of Science][Medline]
5 Huisman C, Smit EF, Giacone G, Postmus PE. Second-line chemotherapy in relapsing or refractory non-small-cell lung cancer: a review. J Clin Oncol 2000;18:3722–30.
6 Socinski MA. Single-agent paclitaxel in the treatment of advanced non-small cell lung cancer. Oncologist 1999;4:408–16.
7 Lopes NM, Adams EF, Pitts TW, Bhuyan BK. Cell kill kinetics and cell cycles effects of Taxol on human and hamster ovarian cell lines. Cancer Chemother Pharmacol 1993;32:235–42.[Web of Science][Medline]
8 Jordan MA, Wendell K, Gardiner S, Derry WB, Copp H, Wilson L. Mitotic block induced in HeLa cells by low concentration of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Res 1996;56:816–25.
9 Seidman AD, Hudis CA, Albanel J, Tong W, Tepler I, Currie V, et al. Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 1998;16:3353–61.[Abstract]
10 Akerley W, Choy H, Safran H, Sikov W, Rege V, Sambandam S, et al. Weekly paclitaxel in patients with advanced lung cancer: preliminary data from a phase II trial. Semin Oncol 1997 (suppl 12);4:S12-10–S12-13.
11 Akerley W, Glantz M, Choy H, Rege V, Sambandam S, Joseph P, et al. Phase I trial of weekly paclitaxel in advanced lung cancer. J Clin Oncol 1998;16:153–8.
12 Klaassen U, Wilke H, Strumberg D, Eberhardt W, Korn M, Seeber S. Phase I study of a weekly 1 h infusion of paclitaxel in heavily pretreated patients with metastatic breast and ovarian cancer. Eur J Cancer 1996;32A:547–9.[Web of Science][Medline]
13 Sola C, Lluch A, Garcia-Conde J, Ojeda B, Hornedo J, Benavides M, et al. Phase II study of weekly paclitaxel (P) in recurrent breast cancer after high-dose chemotherapy (HDC). Proc Am Soc Clin Oncol 1998;17:174 (abstr 669).
14 Kies MS, Unger P, Gillenwater HH, Smith S, Peterman A, Achell MJ, et al. Second-line (SL) weekly paclitaxel (P) in patients (Pts) with advanced non-small cell lung cancer (NSCLC) failing first-line carboplatin/paclitaxel (C/P). Proc Am Soc Clin Oncol 2000;19:504 (abstr 1971).
15 Hotton KM, Kim K, McGovern J, Larson ML, Hammes LC, Schiller JH, et al. Preliminary results of two phase II studies of weekly paclitaxel in patients (Pts) with non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2000;18:534 (abstr 2103).
16 Leon L, Cuevas J, Cudel T, Calvo M, Graña B, Padín E, et al. Second line chemotherapy with weekly paclitaxel in advanced non-small cell lung cancer. Ann Oncol 2000;11 (suppl 4):121 (abstr 552).
17 Chang AY, Rubins J, Asbury R, Boros L, Hui LF. Weekly paclitaxel in advanced non-small cell lung cancer. Semin Oncol 2001;14:10–3.
18 Cancer Therapy Evaluation Program. Common Toxicity Criteria, Version 2.0. New York: DCTD, NCI, NIH, DHHS, 1998.
19 WHO Handbook for Reporting Results of Cancer Treatment. Geneva: WHO, 1979.
20 Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1–10.[Web of Science][Medline]
21 Kosmidis P, Mylonakis N, Skarlos D, Bafaloukos D, Kalofonos C, Fountzilas G, 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 trial. Hellenic Cooperative Oncology group. Ann Oncol 2000;11:799–805.
22 Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000;18:623–31.
23 Alexopoulos K, Kuorousis C, Androulakis N, Papadakis E, Vaslamatzis M, Kakolyris S, et al. Docetaxel and granulocyte colony-stimulating factor in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy. A multicentre phase II trial. Cancer Chemother Pharmacol 1999;43:257–62.[Web of Science][Medline]
24 Crino L, Mosconi AM, Scagliotti GV, Selvaggi G, Novello S, Rinaldi M, et al. Gemcitabine as second-line treatment for advanced non-small cell lung cancer. A phase II trial. J Clin Oncol 1999;17:2081–5.
25 Fossella FV, Lee JS, Shin DM, Calayag M, Huber M, Perez-Soler R, et al. Phase II study of docetaxel for advanced or metastatic platinum-refractory non-small-cell lung cancer. J Clin Oncol 1995;13:645–51.
26 Van Kooten M, Traine G, Cinat G, Cazap E, Comba AZ, Vicente H, et al. Single-agent gemcitabine in pretreated patients with non-small-cell lung cancer: results of an Argentinean multicentre phase II trial. Br J Cancer 1999;81:846–9.[Web of Science][Medline]
27 Gandara DR, Vokes E, Green M, Bonomi P, Devore R, Comis R, et al. Activity of docetaxel in platinum-treated non-small-cell lung cancer: results of a phase II trial. J Clin Oncol 2000;18:131–5.
28 Lilenbaum RC, Herndon J, List M, Desch C, Watson J, Holland J, et al. Single-agent (SA) versus combination chemotherapy (CC) in advanced non-small cell lung cancer (NSCLC): a CALGB randomised trial of efficacy, quality of life (QOL) and cost-effectiveness. Proc Am Soc Clin Oncol 2002;21:1a (abstr 2).
Received April 15, 2002; accepted August 1, 2002
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