© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 13, 1074-1080,
July 5, 2000
© 2000 Oxford University Press
Randomized Trial of Paclitaxel Plus Supportive Care Versus Supportive Care for Patients With Advanced Non-Small-Cell Lung Cancer
Affiliations of authors: M. Ranson, H. Anderson, N. Thatcher, Christie Hospital and Wythenshawe Hospital, Manchester, U.K.; N. Davidson, North Middlesex Hospital, London, U.K.; M. Nicolson, Aberdeen Royal Infirmary, U.K.; S. Falk, Bristol Oncology Centre, U.K.; J. Carmichael, University of Nottingham, U.K.; P. Lopez, North-Eastern Ontario Regional Cancer Centre, Sudbury, Canada; N. Gustafson, A. Jeynes, G. Gallant, T. Washington, Bristol-Myers Squibb Co., Princeton, NJ.
Correspondence to: Malcolm Ranson, Ph.D., F.R.C.P., Cancer Research Campaign Department of Medical Oncology, Christie Hospital National Health Service Trust, Wilmslow Rd., Manchester, U.K. M20 4BX (e-mail: malcolm.ranson{at}man.ac.uk).
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ABSTRACT |
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 TopNotes Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Background: In phase II trials, paclitaxel has been shown to have antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). However, the survival and quality-of-life (QOL) benefits of paclitaxel used as a single agent compared with supportive care alone have not been assessed in a randomized clinical trial. Methods: A total of 157 patients with stage IIIB or IV NSCLC who had received no prior chemotherapy were randomly assigned to receive either best supportive care alone (78 patients) or paclitaxel plus supportive care (79 patients). Paclitaxel was administered as a 3-hour intravenous infusion every 3 weeks. Supportive care included palliative radiotherapy and supportive therapy with corticosteroids, antibiotics, analgesics, antiemetics, transfusions, and other symptomatic therapy as required. The primary end point of the study was survival. Time to disease progression, response rate, adverse events, and QOL were secondary end points. Results: Pretreatment characteristics were evenly distributed between the two arms. Survival was statistically significantly better in the paclitaxel plus supportive care arm than in the supportive care alone arm (two-sided P = .037) (median survival = 6.8 months versus 4.8 months). Cox multivariate analysis showed paclitaxel plus supportive care to be statistically significantly associated with improved survival (two-sided P = .048). QOL was similar for both treatment arms, except for the functional activity score of the Rotterdam Symptom Checklist, where QOL data statistically significantly favored the paclitaxel plus supportive care arm (two-sided P = .043). Conclusion: The addition of paclitaxel to best supportive care significantly improved survival and time to disease progression compared with best supportive care in patients with advanced NSCLC and may improve some aspects of QOL.
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INTRODUCTION |
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TopNotesAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Non-small-cell lung cancer (NSCLC) accounts for 75% of lung cancer cases and is a leading cause of cancer deaths, with a 5-year survival of approximately 10%–15% (1). The vast majority of NSCLC patients present with advanced-stage disease and are treated palliatively. When managed by best supportive care including radiotherapy, patients with advanced NSCLC have a median survival of around 4 months, with a 1-year survival of approximately 15% (2–4). Meta-analyses performed during the mid-1990s demonstrated that the addition of cisplatin-based chemotherapy produces a modest improvement in median survival over that produced by best supportive care alone (2–4). While these results indicated that improved survival could result from cisplatin-based chemotherapy, the quality-of-life (QOL) implications were not defined.
Several new active agents for patients with advanced NSCLC have been identified in recent years. Among these is paclitaxel, a novel cytotoxic agent whose major activity is to promote microtubule assembly and render microtubules resistant to depolymerization (5). Data from clinical trials in which paclitaxel was administered every 3 weeks and encompassing 317 patients with advanced NSCLC from 10 phase II studies have shown an overall tumor response rate of 26% (6). The main toxic effects of paclitaxel comprise reversible alopecia, neutropenia, arthralgia/myalgia, and sensory peripheral neuropathy (5). At the time that the study protocol was designed, two small phase II studies (7,8) had been performed with the use of a 3-hour administration schedule and had demonstrated that paclitaxel at a dose of 200 mg/m2 was suitable for further evaluation.
The phase II data indicate that paclitaxel has promising activity for the treatment of advanced NSCLC and has a more favorable toxicity profile than that of cisplatin-based chemotherapy (6). However, the impact of paclitaxel as a single agent on survival and on QOL in patients with advanced NSCLC has not been hitherto assessed in a randomized phase III clinical trial. The trial reported here was started in February 1995 to compare paclitaxel plus best supportive care (supportive care) with supportive care alone to evaluate if there were survival or QOL differences for these two approaches.
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PATIENTS AND METHODS |
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TopNotesAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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End Points
Overall survival was the primary end point of the study. Secondary objectives were assessment of QOL, time to disease progression, toxicity, and the rate of response of tumors to paclitaxel.
Patient Selection
To be eligible for randomization, patients were required to meet the following criteria: histologically proved NSCLC; bidimensionally or unidimensionally measurable stage IIIB or IV NSCLC (9); age 18 years or older, with a life expectancy of 12 weeks; and an Eastern Cooperative Oncology Group (ECOG) (10) performance status of 0, 1, or 2. Adequate baseline bone marrow function for entry was defined as an absolute neutrophil count of 1.5 x 109/L or higher and a platelet count of 100 x 109/L or higher, adequate hepatic function as total bilirubin level of less than or equal to 1.25 the upper limit of normal, and adequate renal function as serum creatinine level of less than or equal to 1.25 times the upper limit of normal. Patients were allowed to have received prior radiotherapy outside assessable lesion(s) but to fewer than 30% of the marrow-bearing bones and more than 2 months prior to study entry. This latter interval was reduced to 4 weeks in February 1996. Patients had to be English speaking to participate in the QOL questionnaire components of the study.
Patients with the following criteria were ineligible: a history of prior or concomitant malignancy (except for curatively treated nonmelanoma skin cancer or carcinoma in situ of the cervix), prior cytotoxic chemotherapy, a requirement for urgent radiotherapy, pregnancy or lactation, symptomatic brain metastases, serious uncontrolled cardiac disease, myocardial infarction within the previous 6 months, a history of second- or third-degree heart block, known prior allergic reaction to Cremophor EL, dementia, or other serious underlying medical conditions.
Written informed consent was obtained from each patient prior to study entry, and the study protocol was approved by each institution's local research ethics committee. Patients were informed that, although platinum-based chemotherapy had been associated with survival benefit compared with best supportive care, it was unknown whether there would be a net benefit from the addition of paclitaxel to supportive care.
Randomization and Study Treatments
Randomization was performed centrally by Bristol-Myers Squibb Co., Princeton, NY, using a dynamic balancing algorithm of the Pocock–Simon type (11). This procedure minimized imbalance in treatment assignment with respect to the following parameters: study site, disease stage (IIIB versus IV), and performance status (ECOG 0–1 versus 2).
Paclitaxel. In the paclitaxel plus supportive care arm, the patients received dexamethasone (20 mg orally) 12 and 6 hours before paclitaxel, cimetidine (300 mg) or ranitidine (50 mg) intravenously 30 minutes before paclitaxel, and diphenhydramine (50 mg) or chlorpheniramine (10 mg) intravenously 30 minutes prior to paclitaxel.
Paclitaxel was administered intravenously at a starting dose of 200 mg/m2 over a 3-hour period; it was diluted in a minimum of 500 mL 5% dextrose or normal saline. An in-line cellulose acetate filter of 0.22-µm pore size was used. Cycles of treatment were repeated every 21 days or upon recovery from hematologic and nonhematologic toxic effects. There were no dose escalations, and dose reduction was based on toxic effects encountered in the previous treatment course.
The response to paclitaxel was assessed every two cycles according to criteria of the World Health Organization (WHO) (12). Patients with disease progression discontinued chemotherapy. Patients with stable disease were treated until relapse or until unacceptable toxicity. Patients who achieved a complete response (CR) were to be treated until two cycles after confirmation of CR, while patients who achieved a partial response (PR) continued until two cycles beyond the best response or until relapse or unacceptable toxicity occurred.
Supportive care. Best supportive care was given to patients in both arms of the study and included palliative radiotherapy for bronchial obstruction, hemoptysis, bony metastases, superior venacaval obstruction, and brain metastases. In addition, supportive therapy with corticosteroids, antibiotics, analgesics, antiemetics, transfusions, and other symptomatic therapy was given as required.
Monitoring and Follow-up
All patients were followed closely by medical history, physical examination, performance status, QOL assessment, and chest x-ray every 3rd week, and computed tomography scans every 9 weeks until disease progression or until 8 months on study. After treatment discontinuation or reaching 8 months on the study, patients were assessed every 6 weeks until death. Patients in the paclitaxel arm had weekly blood cell counts during chemotherapy.
Quality of Life
QOL was assessed with the Rotterdam Symptom Checklist (RSCL), a validated tool to measure the QOL and the psychologic and physical symptoms of cancer patients (13). Patients completed the questionnaire assessing how they had been affected during the past week by responding to questions on a total of 46 items (nine psychologic, 27 physical, eight functional activity, one general QOL, and one general activity). RSCL questionnaires were to be completed by patients at baseline, every 3 weeks during the study, at the date of leaving the study, and every 6 weeks thereafter.
Statistical Analysis
The target population size for the study was a minimum of 144 assessable patients, such that it would have 80% power with an 
level of .05 to detect a 20% difference in survival at 1 year with an expected 20% 1-year survival in the supportive care arm, 18-month accrual, and a minimum of 2 years' study time. Recruitment was continued to 10% above the target to allow for any nonevaluable patients. Survival was calculated from the date of randomization to the date of death. Patients were stratified at randomization by institution, by performance status (ECOG 0–1 versus 2), and by stage of disease (IIIB versus IV). Patients assigned to paclitaxel plus supportive care were analyzed for response to chemotherapy with the use of WHO criteria (12). Safety data were collected and analyzed for all randomized patients with the use of WHO criteria (12). Survival curves were estimated with the Kaplan–Meier method (14) on the entire randomized population and compared for statistical significance by a two-tailed log-rank test. Cox regression analysis for survival was carried out, stratified on tumor stage and performance status. The model included the following treatment and potential prognostic variables: treatment arm, sex, histology, and prior radiotherapy. All P values were two-sided and were considered to be statistically significant at P<.05.
The comparative analysis of QOL was predetermined to extend until there was less than 30% of total randomly assigned patients remaining available for the QOL assessment. QOL treatment comparisons over time were assessed by longitudinal analysis curves for the median change from baseline for the psychologic, physical, and functional activity scores and the questions of general activity and general QOL with the use of the Wei–Johnson test of stochastic ordering (15,16).
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RESULTS |
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TopNotesAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients and Treatment
During the period from February 1995 through October 1997, a total of 157 patients from six geographic sites were randomly assigned to receive either paclitaxel plus supportive care (n = 79) or supportive care alone (n = 78) (Fig. 1
). At the time of the dataset closure on March 31, 1998, one patient had been lost to follow-up and 15 patients in the paclitaxel plus supportive care arm and seven in the supportive care arm remained alive. The patient characteristics are shown in Table 1. Baseline characteristics were very similar for both groups. Males constituted 75% of the enrolled patients, and the median age was 65 years for the patients in the paclitaxel plus supportive care arm and 64 years for the patients in the supportive care alone arm. The median time from disease diagnosis to randomization was 1.1 months in the paclitaxel plus supportive care arm and 0.9 months in the supportive care arm. All patients except one had histologically proven NSCLC. Squamous cell carcinoma and adenocarcinoma were the most common histologic subtypes. One patient's lung tumor on pathology review was found to consist of metastatic prostatic adenocarcinoma. The performance status of one patient worsened from 2 to 3 between randomization and treatment with paclitaxel. The disease stage and the number and extent of disease sites were similarly distributed between the two treatment arms. Of the patients, 10% had received radiotherapy prior to randomization—15% in the paclitaxel plus supportive care arm and 6% in the supportive care alone arm. No patients had received prior chemotherapy. One patient in the paclitaxel arm had received prior interleukin 4 therapy.
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At the time of data analysis, all patients had completed the study treatment. Patients in the paclitaxel plus supportive care arm had a median on-study duration of 15 weeks (range, 0.4–30.4 weeks); those in the supportive care arm had a median on-study duration of 9.8 weeks (range, 1.9–64 weeks).
Paclitaxel Treatment
Of the 79 patients randomly assigned to receive paclitaxel plus supportive care, one patient withdrew consent before receiving chemotherapy. A total of 357 courses were administered to the 78 remaining patients. The median number of courses per patient was five (range, one to ten). The median cumulative paclitaxel dose per patient was 923 mg/m2 (range, 197–1991 mg/m2). The median dose intensity was 66 mg/m2 per week (range, 34–71 mg/m2 per week), which was very close to the planned dose intensity of 67 mg/m2 per week, and 79% of patients received greater than 90% of the full intended dose intensity. Hematologic and nonhematologic toxic effects led to dose reductions in 25 (32%) of the 78 patients, and dose reductions occurred in a total of 39 (11%) of 357 cycles. Two hundred seventy-nine cycles were administered after cycle 1, which formed the basis for an analysis of treatment delays. Overall, only 16 cycles were delayed; the delay was 3–8 days for 15 cycles and 14 days for one cycle.
Three of the 79 patients in the paclitaxel plus supportive care arm were unevaluable for response assessment: One patient was never treated, one was ineligible because of non-lung-cancer tumor histology, and one had no follow-up tumor re-evaluation. Among the 76 evaluable patients, there was one CR and 11 PRs, which gave an overall response rate of 16% (95% confidence interval [CI] = 8%–26%). The rate of response among patients with stage IIIB disease was 18%; the response rate among patients with stage IV disease was 13%. No responses were seen in the seven patients with large-cell carcinoma or in the 13 patients with an ECOG performance status of greater than 1. The response rate for performance status 0–1 was 19%. Response was seen more frequently in patients 65 years old or older than in younger patients (21% versus 11%). The rate of response in patients without prior radiotherapy was 25% versus 14% in patients who had received prior radiotherapy. These differences were not statistically significant.
Supportive Care
After randomization, 61 (78%) of the 78 patients in the supportive care arm received radiotherapy. Of these 61 patients, 14 received chemotherapy (usually with a cisplatin-based regimen). Two additional patients randomly assigned to the supportive care arm received cisplatin-based chemotherapy alone. Thirty-eight patients (48%) in the paclitaxel plus supportive care arm received radiotherapy during their illness, and additional chemotherapy subsequent to paclitaxel was given to seven patients.
Overall Survival
Overall intent-to-treat survival curves are shown in Fig. 2. At the time of the analysis, 135 patients had died (64 of 79 in the paclitaxel plus supportive care arm and 71 of 78 in the supportive care arm). One patient had been lost to follow-up on the supportive care arm. The median survival time was 6.8 months (95% CI = 5.7–10.2 months) for patients in the paclitaxel plus supportive care arm versus 4.8 months (95% CI = 3.7–6.8 months) for patients in the supportive care arm. Survival was statistically significantly better (log-rank test, P = .037) among patients in the paclitaxel plus supportive care arm than among those in the supportive care arm. The 95% CIs for survival at 1 year were 20%–41% for patients in the paclitaxel plus supportive care arm and 18%–39% for patients in the supportive care alone arm. Cox multivariate analysis for survival with the use of the stratified Cox regression model showed that the assigned treatment arm remained significantly associated with survival (P = .048), with a hazard ratio of 0.68 (95% CI = 0.489–0.996) in favor of paclitaxel plus supportive care.
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Secondary End Points
At the time of the analysis, the disease in 151 of the patients had progressed (74 of 79 in the paclitaxel plus supportive care arm and 77 of 78 in the supportive care alone arm). The median times to disease progression were 3.9 months for patients in the paclitaxel plus supportive care arm (95% CI = 3.3–4.5 months) and 0.5 months for patients in the supportive care arm (95% CI = 0.4–0.7 months; P = .0001). This analysis by the protocol definition of progression includes the need for subsequent radiotherapy in the definition of progression. Following randomization, radiotherapy was sometimes appropriately given for symptomatic reasons (e.g., hemoptysis, bronchial obstruction, superior venacaval obstruction, and bone pain) prior to tumor progression. In total, 64% of the patients in the supportive care alone arm and 9% of the patients in the paclitaxel plus supportive care arm received radiotherapy following randomization and before objective disease progression. Analysis of time to disease progression was, therefore, also performed with patients who received radiotherapy prior to tumor progression being censored at the start of radiotherapy. By this analysis, the median time to disease progression for the patients in the paclitaxel plus supportive care arm was 4.0 months (95% CI = 3.4–5.3 months) versus 1.2 months (95% CI = 1.0–1.7 months) for those in the supportive care alone arm (log-rank test, P = .0001) (Fig. 3).
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Quality of Life
The comparative analysis of QOL was predetermined to extend until less than 30% of randomly assigned patients remained available for QOL assessment, and this point was reached by week 33 of the QOL assessment. Overall compliance with completing the RSCL was good in these patients with advanced NSCLC. At baseline, compliance with questionnaire completion was 95% for patients in the paclitaxel plus supportive care arm and 96% for patients in the supportive care alone arm. Overall questionnaire compliance to week 33 was 64% for patients in the paclitaxel plus supportive care arm and 60% for patients in the supportive care alone arm.
QOL treatment comparisons over time were assessed by longitudinal analysis curves for the median change from baseline for the psychologic, physical, and functional activity scores and the questions of general activity and general QOL with the use of the Wei–Johnson test of stochastic ordering (15,16). This nonparametric analysis requires few assumptions about the shape of the data. However, an important assumption is that there is no informative dropout bias—i.e., patients who contribute only a short period of available data ("dropouts") should have the same trends in score over time as those with longer term data ("completers"). Attrition from studies involving patients with advanced NSCLC is typically quite rapid, and patients contributing short-term data may not have the same QOL trends as those patients who contribute longer term data, and the treatment arms may present differing patterns of incomplete data. Analyses for informative dropout bias using random-effects pattern mixture models (17–19) showed that informative dropout bias was present between "dropouts" (defined as patients contributing no data beyond week 15) and "completers" (patients who contributed data beyond week 15). Random-effects model analyses for each of the five QOL subscores of the RSCL were, therefore, performed separately on dropouts and on completers. The slopes computed from the models for dropouts and completers are shown in Table 2 for the two treatment arms.
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For each of the QOL scores, the slopes are smaller for the dropouts than for the completers. In other words, patients who contributed data beyond week 15 had more favorable QOL trends (higher slopes) than did patients whose QOL data were entirely confined to weeks 0–15. Within both the dropout and completer groups, the slopes were similar for both treatment arms or were in favor of the paclitaxel plus supportive care arm. The only instance in which this difference was statistically significant was for the RSCL functional activity subscore among dropouts, where the QOL results significantly (P = .043) favored the paclitaxel plus supportive care arm. The functional activity subscore assesses the patients' ability for self-care, walking, climbing stairs, housework, shopping, and going to work.
In summary, the analysis of the QOL data indicated that, compared with supportive care alone, there was improvement in the functional activity subscore of RSCL that favored the paclitaxel-containing arm for dropouts. For all other RSCL subscores, there was no statistically significant difference in the patient-assessed QOL between the two arms of the study.
Safety
In the paclitaxel plus supportive care arm, adverse events typical of paclitaxel were observed (namely, reversible alopecia, myelosuppression, gastrointestinal effects, peripheral neuropathy, arthralgia/myalgia, and hypersensitivity reactions). The grade 3–4 adverse events are summarized in Table 3. The most common grade 3–4 adverse events seen with paclitaxel were alopecia (76%), neutropenia (34%), arthralgia/myalgia (22%), asthenia (14%), and infection (10%). More patients in the paclitaxel plus supportive care arm (58%) required hospitalization during the study than those in the supportive care arm (41%), although this may be partly a consequence of the patients in the paclitaxel plus supportive care arm remaining in the study for a median 1.5-fold longer than the patients in the supportive care arm.
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DISCUSSION |
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TopNotesAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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This randomized, prospective, multicenter phase III trial showed that treatment with paclitaxel and supportive care prolonged the life of patients with advanced NSCLC compared with supportive care alone. Time to tumor progression was also statistically significantly prolonged in the paclitaxel-containing arm. Comparative QOL analysis showed that there was no difference between the two arms of the study, except in the functional activity subscore of the RSCL, which showed a statistically significant trend in favor of the paclitaxel-containing arm.
Paclitaxel was generally well tolerated by patients. The protocol dose intensity was maintained in the majority of patients, and apart from reversible alopecia there was a low incidence of grade 3–4 toxic effects. The safety profile of paclitaxel appeared superior to that reported elsewhere for cisplatin-based chemotherapy, which, when compared with supportive care, has been shown to improve survival in patients with advanced NSCLC (2–4).
The median survival of 4.8 months for patients in the supportive care alone arm in this study was very similar to that seen in most other studies published since 1995 (Table 4). Trials prior to 1995 have been reviewed previously by meta-analysis, where management by best supportive care alone was attended by a median survival of 4.0 months.
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The patients enrolled in this study were actively managed for their disease-related symptoms; overall, 61 (78%) of the 78 patients in the supportive care alone arm received radiotherapy subsequent to randomization in addition to other symptomatic supportive measures. The requirement for palliative radiotherapy was reduced for patients who were randomly assigned to receive paclitaxel (38 [48%] of 79 patients).
Multiple small-scale phase II trials have demonstrated that paclitaxel administered on a schedule of every 3 weeks has substantial activity in advanced NSCLC, with an overall objective tumor response rate of 26% (6). The rate of response to paclitaxel in this multicenter trial was 16%. Differences in patient populations may account for such differences, and tumor response rates in small, early phase II trials in advanced NSCLC have typically been higher than those reported subsequently in larger, multicenter trials.
To our knowledge, our randomized trial is the only study that has addressed the question of whether paclitaxel as a single agent has an impact on survival and QOL in advanced NSCLC compared with management by best supportive care alone. Information on QOL derived directly from the patients regarding the impact of cancer and its treatment on the patients' physical, social, and psychologic well-being can assist physicians and patients in selecting among available treatment options. In recognition of the palliative nature of therapy in advanced NSCLC, QOL assessments with the use of validated QOL instruments have become more commonly performed, despite the difficulties that arise from the relatively rapid attrition of patients with advanced NSCLC. Improved methods for data analysis have become available in recent years (17–19), and we have utilized these methodologies in our study. The more widespread investigation of QOL and improved data analysis should facilitate in the future a more complete appraisal of the merits of treatment options in advanced NSCLC.
In conclusion, this study provides important evidence that survival among patients with advanced NSCLC can be statistically significantly improved by the addition of single-agent paclitaxel to best supportive care. Moreover, it demonstrates that this approach also may improve some aspects of QOL above that achievable by radiotherapy and supportive care. Such regimens could be used as the control arm in future studies.
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NOTES |
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Editor's note: M. Ranson, J. Carmichael, H. Anderson, and N. Thatcher have all performed research sponsored by Bristol-Myers Squibb, the manufacturer of paclitaxel; in addition, Drs. Carmichael and Thatcher are on the company's speaker's bureau. A. Jeynes, T. Washington, N. Gustafson, and G. Gallant have all been employed by Bristol-Myers Squibb, and G. Gallant, in addition, owns stock in the company.
We acknowledge all clinicians who referred patients.
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TopNotesAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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