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Randomized Phase III Trial of Paclitaxel Plus Carboplatin Versus Vinorelbine Plus Cisplatin in the Treatment of Patients With Advanced Non–Small-Cell Lung Cancer: A Southwest Oncology Group Trial

From the University of Colorado, Denver, CO; Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Swedish Medical Center, and University of Washington, Seattle, WA; St Vincent Medical Center, Los Angeles Oncology Institute, and University of Southern California School of Medicine, Los Angeles; University of California Davis, Sacramento, CA; Wayne State University Medical Center, Detroit, MI; University of Texas Health Science Center San Antonio, San Antonio, TX; and Wichita Community Clinical Oncology Program, Wichita, KS.

Address reprint requests to Southwest Oncology Group (SWOG-9509), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217.

	ABSTRACT

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PURPOSE: This randomized trial was designed to determine whether paclitaxel plus carboplatin (PC) offered a survival advantage over vinorelbine plus cisplatin (VC) for patients with advanced non–small-cell lung cancer. Secondary objectives were to compare toxicity, tolerability, quality of life (QOL), and resource utilization.

PATIENTS AND METHODS: Two hundred two patients received VC (vinorelbine 25 mg/m²/wk and cisplatin 100 mg/m²/d, day 1 every 28 days) and 206 patients received PC (paclitaxel 225 mg/m² over 3 hours with carboplatin area under the curve of 6, day 1 every 21 days). Patients completed QOL questionnaires at baseline, 13 weeks, and 25 weeks. Resource utilization forms were completed at five time points through 24 months.

RESULTS: Patient characteristics were similar between the groups. The objective response rate was 28% in the VC arm and 25% in the PC arm. Median survival was 8 months in both arms, with 1-year survival rates of 36% and 38%, respectively. Grade 3 and 4 leukopenia (P = .002) and neutropenia (P = .008) occurred more frequently on the VC arm. Grade 3 nausea and vomiting were higher on the VC arm (P = .001, P = .007), and grade 3 peripheral neuropathy was higher on the PC arm (P < .001). More patients on the VC arm discontinued therapy because of toxicity (P = .001). No difference in QOL was observed. Overall costs on the PC arm were higher than on the VC arm because of drug costs.

CONCLUSION: PC is equally efficacious as VC for the treatment of advanced non–small-cell lung cancer. PC is less toxic and better tolerated but more expensive than VC. New treatment strategies should be pursued.

	INTRODUCTION

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LUNG CANCER IS the leading cause of cancer death in the United States for both men and women. In 2000, it was estimated that 164,000 people would be diagnosed with lung cancer and 157,000 patients would die from their disease.¹ Approximately 80% of these cases represent non–small-cell lung cancer (NSCLC). The low cure rate for NSCLC can be attributed to the high rate of metastasis at diagnosis and the inability of chemotherapy to cure metastatic disease. However, randomized trials and meta-analyses demonstrated that platinum-based chemotherapy increases survival, palliates symptoms, improves quality of life (QOL), and is cost effective.² Recently, several new chemotherapy agents with activity in NSCLC have become available; these include the taxanes (paclitaxel and docetaxel), vinorelbine, gemcitabine, and the topoisomerase inhibitors (topotecan and irinotecan). Vinorelbine in combination with cisplatin was the first novel agent regimen to produce a statistically significant survival benefit over a standard regimen, vindesine plus cisplatin.³ Subsequently, the Southwest Oncology Group (SWOG) confirmed the efficacy of vinorelbine plus cisplatin for patients with metastatic NSCLC.⁴ In this randomized phase III trial, vinorelbine plus cisplatin was superior to single-agent cisplatin in response rates (26% v 12%; P = .0002), progression-free survival (4 months v 2 months; P = .0001), and overall survival (8 v 6 months; P = .0018). The 1-year survival was 36% for patients who received the combination and 20% for patients given cisplatin alone. Thus, vinorelbine plus cisplatin became the new SWOG standard regimen against which to compare new therapeutic approaches.

Paclitaxel is another novel agent with activity in NSCLC. As a single agent, response rates were observed in 20% to 25% of untreated patients with metastatic disease.² Several phase II trials of combined paclitaxel and cisplatin reported encouraging responses and prolonged survival, which led to a phase III trial by the Eastern Cooperative Oncology Group (ECOG).⁵ Patients with advanced stage NSCLC were randomized to paclitaxel at 135 mg/m² (low dose) or 250 mg/m² with granulocyte colony-stimulating factor (G-CSF) support (high dose), each given as a 24-hour infusion, with cisplatin versus cisplatin plus etoposide. Response rates for the 574 assessable patients were 25% and 28% for the paclitaxel-containing arms (P = .002) versus 12.5% for the cisplatin and etoposide arm (P .001). Median survival times were 9.5 and 10.1 months, and 1-year survival rates were 37% and 40% for the low- and high-dose paclitaxel arms, respectively, versus 7.6 months and 32% for cisplatin plus etoposide. When the data from both paclitaxel arms were combined, survival was statistically superior as compared with cisplatin plus etoposide (P = .048). ECOG declared low-dose paclitaxel plus cisplatin its new standard regimen for treatment of advanced-stage NSCLC.

Carboplatin is less toxic than cisplatin and has been demonstrated to be as efficacious in the treatment of NSCLC; however, the optimal dose of carboplatin is not well defined.⁶ Several investigators have evaluated the combination of paclitaxel with carboplatin. Nine early phase I and II trials of paclitaxel plus carboplatin have been conducted.^7-15 Three trials administered paclitaxel over 24 hours,^7,8,14 and six trials administered paclitaxel over 1 to 3 hours^9-13,15 with carboplatin doses that ranged from an area under the curve (AUC) of 5 to 11. Four of the six studies administered paclitaxel over 3 hours and gave carboplatin at an AUC of 6. Several trials observed a tendency toward a dose-response relationship with higher response rates in patients treated at a paclitaxel dose of at least 175 mg/m².^8,12 The response rates in all trials with doses of paclitaxel of 175 mg/m² or more ranged from 29% to 55%, with an average response rate of approximately 46%. Six trials reported median survival times of 6.5, 8.0, 8.5, 9.5, 13, and 14 months, and five trials observed 1-year survival rates of 31%, 35%, 42%, 51%, and 55%. All trials reported acceptable toxicity with infrequent myelosuppression, febrile neutropenia, and thrombocytopenia; however, more hematologic toxicity was observed with the 24-hour schedule. Nonhematologic toxicities were uncommon. Peripheral neuropathy was dose limiting in phase I studies at paclitaxel doses of 235 to 250 mg/m². For paclitaxel administered over 3 hours with carboplatin, the recommended doses for further study were paclitaxel 225 mg/m² with carboplatin AUC of 6.

The consistent encouraging results and favorable toxicity profile of paclitaxel plus carboplatin demonstrated in these trials warranted further investigation. Because the 3-hour schedule of paclitaxel is more convenient and less toxic, it was selected for continued study in this large, randomized multicenter trial. Thus, SWOG 9509 was designed to determine whether the experimental regimen of paclitaxel plus carboplatin offered a survival advantage over the standard regimen of vinorelbine plus cisplatin. Secondary objectives were to compare toxicity, tolerability, QOL, and resource utilization between the two arms.

	PATIENTS AND METHODS

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Patient Population
All patients entered onto this study had histologically or cytologically confirmed NSCLC (primarily squamous cell, large cell, or adenocarcinoma). Patients with stage IV or selected stage IIIB disease by the International Staging System (lung cancer) were eligible. Stage IIIB patients had to have a positive pleural effusion or multiple ipsilateral lung nodules. Patients with brain metastases were ineligible. Other eligibility criteria included the following: bidimensionally measurable or assessable disease, performance status (PS) of 0 or 1, neutrophil count greater than or equal to 1,500/uL, platelet count greater than or equal to institutional lower limits of normal, hemoglobin greater than or equal to 9 mg/dL, serum creatinine less than or equal to 1.5 mg/dL or a calculated creatinine clearance greater than or equal to 60 mL/min, bilirubin level less than or equal to 2.0 mg/dL, AST less than or equal to twice the institutional upper limits of normal, or less than or equal to four times the institutional upper limits of normal if the patient had liver metastases. Patients with grade 2 or higher peripheral neuropathy were excluded. Patients were not allowed to have previous chemotherapy or biologic therapy. Previous surgery and radiotherapy were allowed. All patients gave written informed consent in accordance with institutional and federal regulations. Stratification at the time of registration was by weight loss (< 5% v 5%), lactate dehydrogenase level (normal v abnormal), disease stage (IIIB v IV), disease status (measurable v assessable), previous surgical resection or radiotherapy (yes v no), and histologic diagnosis (squamous cell v large cell v adenocarcinoma v unspecified).¹⁶

Treatment Schedule
Patients were randomized to one of two study arms: arm I, cisplatin 100 mg/m² every 4 weeks and vinorelbine 25 mg/m²/wk; or arm II, paclitaxel 225 mg/m² intravenously for 3 hours plus carboplatin AUC of 6 every 3 weeks. All chemotherapeutic agents were given intravenously. Patients on arm I received pretreatment and posttreatment intravenous hydration of at least 1 to 2 L of saline with mannitol. Appropriate antiemetics were given before and after the administration of cisplatin per the physician’s discretion. Amifostine was not allowed. Patients on arm II received premedication against a hypersensitivity reaction with dexamethasone, diphenhydramine, and ranitidine or cimetidine. Use of additional antiemetics was dictated by the physician.

In the absence of progressive disease or intolerable toxicity, the patients were treated for a minimum of six cycles. Patients who achieved a complete or partial response could receive two additional cycles of therapy after best response, to a maximum of 10 cycles.

Drug Schedule Modification
During treatment on arm I, patients had a weekly complete blood cell (CBC) count, WBC differential, and platelet count. On the day of treatment, patients were required to have a granulocyte count of at least 1,500/µL and platelet count of at least 100,000/µL for administration of full doses of cisplatin with or without vinorelbine. Day-of-treatment doses were reduced by 50% for granulocyte counts of 1,000 to 1,499/µL and platelet counts less than 75,000/µL to 99,999/µL; the drug(s) was withheld when the granulocyte and/or platelet counts were below these levels. There was a 50% dose reduction of both drugs for the next cycle if therapy was delayed more than 1 week but not more than 2 weeks, or if granulocytopenic fever/sepsis occurred in the previous cycle. There was 50% dose reduction of cisplatin if a nadir of less than 500 granulocytes/µL and/or less than 50,000 platelets/µL occurred during the previous cycle, but a dose reduction for vinorelbine was based on the weekly CBC count as outlined above. Patients who required a dose delay for 2 weeks or more were taken off study. G-CSF (Neupogen; Amgen, Inc, Thousand Oaks, CA) was permitted but not mandated after the first course of treatment for patients who experienced grade 3 or 4 granulocytopenia ( 1,000/µL) or who developed neutropenic fever between cycles of chemotherapy. G-CSF was given at a dose of 5 µg/kg/d beginning 24 hours after completion of chemotherapy, and the dose was continued until the total granulocyte count was greater than 10,000/µL in two successive analyses. The G-CSF was not given on the day chemotherapy was administered.

Before each cycle, serum creatinine, calculated creatinine clearance, and serum electrolytes, including magnesium, were analyzed. If the serum creatinine concentration was 1.6 mg/dL or higher but the creatinine clearance was at least 50 mL/min, the cisplatin dose was reduced by 50%; cisplatin was withheld if the creatinine clearance was less than 50 mL/min. If cisplatin was held for any length of time, retreatment was administered at a 50% dose level. If hyperbilirubinemia developed, the dose of vinorelbine was reduced by 40% for a serum bilirubin level of 2.1 to 3.0 mg/dL and 75% for a bilirubin level greater than 3.0 mg/dL. Dose adjustments for neurotoxicity were based on the signs and symptoms on the day of treatment. If grade 2 or greater neurotoxicity occurred, the cisplatin and/or vinorelbine dose was delayed 1 week. If grade 2 or greater toxicity persisted for more than 2 weeks, the patient was taken off study.

For patients on arm II, weekly complete CBC counts, WBC differentials, and platelet counts were obtained. Hematologic dose modifications were based on the nadir counts of the preceding cycle. If the granulocyte nadir count was less than 500/µL, or the platelet nadir count was less than 50,000/µL, and/or the patient had febrile neutropenia, the dose of carboplatin was reduced to an AUC of 5. If the patient continued to have a granulocyte nadir count of less than 500/µL, a platelet nadir count of less than 50,000/µL, and/or febrile neutropenia despite two dose reductions of carboplatin, the dose of paclitaxel was to be reduced to 200 mg/m² and the carboplatin reduced to an AUC of 3. On the day of treatment, patients had to have a granulocyte count of at least 1,500/µL and platelet count of at least 100,000/µL. If this recovery was not achieved, the next cycle of chemotherapy was delayed until recovery occurred or a maximum of 2 weeks. Patients with a delay in recovery of their counts beyond 2 weeks were taken off protocol. G-CSF was permitted after the first course of treatment for patients per the guidelines discussed above.

If a patient developed grade 2 neurotoxicity at any time during a cycle, the dose of paclitaxel was reduced to 200 mg/m². If the patient developed grade 3 neurotoxicity, the dose of paclitaxel was reduced to 175 mg/m². Patients who developed grade 2 or 3 arthralgia/myalgia despite dexamethasone were required to have the dose of paclitaxel decreased to 200 mg/m² or 175 mg/m², respectively. Patients with grade 2 or higher AST or grade 3 or higher bilirubin had their paclitaxel dose withheld. Patients who sustained a moderate hypersensitivity reaction could be retreated; however, a patient who developed a severe reaction was taken off protocol. If a patient developed chest pain or arrhythmia during the infusion, it was stopped immediately and the patient was evaluated appropriately. Patients with symptomatic arrhythmias or atrioventricular block (except first degree) or a documented ischemic event were taken off protocol. Any patient who required a delay in therapy greater than 2 weeks was removed from the study.

Pretreatment and Follow-Up Studies
Before entry onto the study, all patients were required to have a physical examination, chest x-ray, chest and abdominal computed tomographic scan, a brain computed tomographic or magnetic resonance imaging scan, complete blood work-up, and an ECG. Additional radiographs were obtained only if clinically indicated. A physical examination, complete blood work-up, and a chest x-ray were performed before each cycle of therapy. Weekly CBC counts were obtained during each cycle. Once patients came off protocol treatment, they were observed every 3 months.

Response and Toxicity Criteria
Patients were evaluated every two cycles for an objective response. Standard SWOG criteria were used for response determination.¹⁷ Confirmed responses required repeat measurements at 4 weeks; otherwise, the response was coded as unconfirmed. Toxicity grading was performed in accordance with the National Cancer Institute common toxicity criteria, version 2.0.¹⁸ Criteria for removal of patients from the study included progression of disease, unacceptable toxicity as determined by the treating physician in consultation with the study coordinator, a delay in treatment greater than 2 weeks, requirement for palliative radiotherapy, or patient refusal. Appropriate procedures were observed with regard to reports of all unexpected or fatal toxicities (including suspected reactions).

QOL
QOL was measured with the previously validated Functional Assessment of Cancer Therapy-Lung (FACT-L), version 3; the FACT-L has a total of 44 items, 10 of which address lung cancer concerns.^19-21 This questionnaire was completed by patients before randomization and again at 13 and 25 weeks postrandomization. We selected two follow-up assessments to monitor change in QOL during the main treatment period of S9509. Given that the two therapeutic regimens had different treatment schedules, it was important to select assessment times that were "fair" to both arms and that would minimize the extent of missing data. Both treatment arms were to begin a new cycle of therapy at 13 weeks; in addition, a clinic visit occurred at this time with assessment of key clinical outcomes. Twenty-five weeks represented the minimum number of cycles required for patients on both arms, and a clinic visit occurred with assessment of clinical outcomes. Median survival time of 8 months was expected for the vinorelbine plus cisplatin arm. Therefore, continued QOL assessments beyond 6 months would increase the chances that substantial and informative data would be missed.

QOL data presented in this article are summarized in two sets of categories to describe QOL status: one set compared the percentages of patients with improved, stable, and declined QOL status based on the FACT-L score; the other compared the percentages of patients with improved, stable, and declined status but added a fourth category of patients with missing FACT-L scores (considered intermediate to stable and declined status). FACT-L scores to characterize such change are based on the sensitivity of various FACT-L scores to changes of one or more points on the ECOG PS rating from an ECOG trial for patients with NSCLC.²⁰ Although the published data did not include the total FACT-L score, this information was provided for the SWOG trial (D. Cella, personal communication, August 1998): improved QOL status, defined as an increase of 9.0 or more FACT-L points; deteriorated status, defined as a decrease of 8.5 or more points; and no change or stable status (neither of the above). Wilcoxon tests were used to compare the distributions of patients described as improved, stable, or deteriorated in one analysis and improved, stable, missing from the analysis (but not dead), or deteriorated in a second analysis. This second cross-sectional analysis attempted to address bias associated with missing data.

Resource Utilization Measures
Resource utilization forms were completed for five periods: randomization through week 12, weeks 13 to 24, months 7 to 12, months 13 to 18, and months 19 to 24. During the first 25 weeks, four types of resources were tracked: laboratory tests and medical procedures, supportive care medications, blood products, and other medical care. Three types of resources were evaluated during the next 18 months: supportive care medications, blood products, and other medical care. The resource forms that tracked protocol and nonprotocol treatment emphasized resources associated with use of the more expensive cancer-related treatments and agents (eg, those that require parenteral administration). Dollar costs were assigned to resources by use of national databases. Cost estimates were based on a method to account for medical cost censoring, and costs in year 2 were discounted at 3%.

Statistical Design and Analysis
The primary objective of this study was to determine whether the experimental regimen of paclitaxel plus carboplatin produced a survival advantage over the standard regimen of vinorelbine plus cisplatin in patients with advanced NSCLC. To detect a survival benefit that would be of obvious clinical benefit, a 50% increase in survival in the experimental arm of 12 months was chosen, as compared with 8 months for the standard regimen. This required a sample size of 200 patients per arm to detect this difference with a power of .94 by use of a one-sided log-rank test at a level of .025. This sample size is also sufficient for 79% power to detect a difference of 37.5% (8 v 11 months). Survival curves were estimated by the product-limit method and compared by use of the log-rank test, stratified by predetermined prognostic factors.^22-25 Cox regression analysis was used to determine the influence of prognostic factors on survival and to assess treatment-by-factor interactions.²⁶ All reported P values are two-tailed. An interim analysis conducted by the data monitoring committee was performed after 300 patients were accrued. After the data were reviewed, a decision to continue the study was made.

A cost minimization analysis was performed based on the total costs on each treatment arm for 2 years or until death. We compared total costs and outcomes for each treatment arm to cover the period from randomization through 2 years or until death. The original strategy for the economic analysis was to estimate attributable costs per life year gained for paclitaxel/carboplatin compared with vinorelbine/cisplatin; however, the clinical findings dictated that the analysis should be modified so that only costs were compared between treatment arms (ie, a cost minimization analysis).

	RESULTS

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Patient Characteristics
Four hundred forty-four patients were accrued to this trial between April 1996 and January 1998. Thirty-six patients (8%) were ineligible: 12 patients did not have stage IIIB or IV disease, nine patients had insufficient documentation, eight patients did not meet the prestudy requirements, three patients had received previous chemotherapy, two patients had incorrect histology, and two patients had brain metastases. Four hundred eight patients were eligible: 202 patients on arm I and 206 patients on arm II. The patient characteristics are listed in Table 1. There was no important difference in any of the characteristics listed between the two groups. A large proportion of patients were white, male, with measurable stage IV disease. Patients with stage IIIB disease accounted for 11% on arm I and 12% of patients on arm II. There were 11 major protocol deviations on the vinorelbine arm and four on the paclitaxel arm.

View larger version (13K): [in this window] [in a new window]   Fig 1. Survival by treatment arm. Abbreviations: CBDCA + Pac, carboplatin plus paclitaxel (arm I); CDDP + Vin, cisplatin plus vinorelbine (arm II).

Tolerability
Disease progression was the most common reason for discontinuation of treatment; 34% of patients on arm I and 39% of patients on arm II stopped therapy because of tumor progression (Table 4). The second most frequent reason for termination of therapy was toxicity as determined by the physician, patient, or both. Twenty-eight percent of patients who received vinorelbine plus cisplatin versus 15% of patients given paclitaxel plus carboplatin (P = .001) discontinued therapy because of toxicity. Overall, 15% of patients on the vinorelbine arm completed therapy as planned versus 27% of patients on the paclitaxel arm (P = .008). The every-3-weeks schedule of paclitaxel plus carboplatin also was more convenient than weekly vinorelbine with cisplatin.

View larger version (55K): [in this window] [in a new window]   Fig 2. Mean percentage dose by cycle and treatment. Abbreviations: VNR, vinorelbine; CDDP, cisplatin; CBDCA, carboplatin.

	DISCUSSION

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SWOG 9509 was the first completed randomized trial to compare two new agent-platinum regimens in advanced lung cancer. The results achieved were comparable to those seen in other randomized trials of a novel agent plus a platinum compound versus traditional regimens. Trials of vinorelbine, gemcitabine, paclitaxel, or tirapazamine with cisplatin resulted in response rates of 25% to 41%, median survival times of 8 to 10 months, and 1-year survival rates of 30% to 43%.^3-5,27-33 Substitution of carboplatin for cisplatin plus paclitaxel produced similar results, with an objective response rate of 22%, a median survival time of 7.8 months, and a 1-year survival rate of 32% in one trial.³⁴ Gatzemeier et al³⁵ compared paclitaxel plus carboplatin to paclitaxel plus cisplatin. There was no statistical difference in efficacy between the two regimens; response rates for paclitaxel plus carboplatin versus paclitaxel plus cisplatin were 25% versus 28%, median survival times were 8.5 versus 9.8 months, and 1-year survival rates were 33% versus 38%, respectively. The recent ECOG four-arm trial (E1594) also addressed the issue of paclitaxel/cisplatin versus paclitaxel/carboplatin. This trial compared the standard ECOG regimen of low-dose 24-hour paclitaxel with cisplatin with three experimental regimens: gemcitabine plus cisplatin, docetaxel plus cisplatin, and paclitaxel plus carboplatin. There was no difference in response rates (15% to 21%), median survival (7.4 to 8.2 months), or 1-year survival rates (31% to 36%) among any of the arms.³⁶ Specifically, when paclitaxel 225 mg/m² in a 3-hour infusion with carboplatin AUC of 6 was compared with paclitaxel 135 mg/m² given over 24 hours with cisplatin 75 mg/m², the response rates were 15% versus 21%, the median survival time was 8.2 months versus 7.8 months, and 1-year survival rates were 35% versus 31%, respectively. Febrile neutropenia, nausea, and vomiting were statistically less frequent with paclitaxel and carboplatin. Therefore, these data support the use of the 3-hour paclitaxel with carboplatin regimen over the 24-hour schedule of paclitaxel plus cisplatin, which is cumbersome and more toxic for patients with metastatic lung cancer.

Only one randomized trial in advanced NSCLC has demonstrated a median survival greater than 12 months. Masuda et al³⁷ conducted a trial of irinotecan/cisplatin versus cisplatin/vindesine versus irinotecan, and they demonstrated a promising 12.5-month median survival and a 49% 1-year survival rate for the group that received irinotecan plus cisplatin. However, 37% of patients in this trial had stage IIIB disease, which may have been responsible for the prolonged survival. Thus, it seems that any one of several new agents plus a platinum results in similar efficacy, which suggests that further prolongation in survival will require a new therapeutic strategy such as a nonplatinum drug combination, triple-drug therapy administered either concurrently or sequentially, or new biologic agents alone or in combination with chemotherapy.

Although this trial established the efficacy of paclitaxel plus carboplatin and vinorelbine plus cisplatin for the treatment of lung cancer, differences in toxicity were apparent. Vinorelbine plus cisplatin produced significantly more life-threatening episodes of grade 3 and 4 leukopenia and neutropenia. There were also more grade 3 and 4 infections with significant neutropenia and more toxic deaths observed on the vinorelbine/cisplatin arm, although the differences were not significant. With respect to grade 3 nonhematologic toxicities, there were more episodes of nausea and vomiting on the vinorelbine/cisplatin arm, and peripheral neuropathy was increased on the paclitaxel/carboplatin arm. The impact of these differences in toxicity affected the patient’s ability to complete the planned treatment. Twice as many patients who received vinorelbine plus cisplatin refused therapy because of toxicity as compared with those who were given paclitaxel plus carboplatin (28% v 14%). Toxicity concerns also dictated the dose of drugs administered. During the planned six cycles, we were able to infuse 65% of the intended vinorelbine dose and 78% of the planned cisplatin dose, as compared with greater than 90% drug delivery of paclitaxel and carboplatin.

The favorable toxicity profile of paclitaxel plus carboplatin has been observed by other investigators. This regimen was demonstrated to be significantly less toxic than several other new agents plus cisplatin in patients at PS 2. In the ECOG four-arm trial, patients with a PS of 2 were eligible originally, but after 10 months accrual was closed to this subset of patients because of unexpected toxicity. An analysis of this subgroup of 64 patients revealed that the incidence of grade 3 or greater toxicity was significantly less for patients who received paclitaxel and carboplatin (P = .0032) compared with any other cisplatin combination.³⁸ Furthermore, both randomized trials of paclitaxel/cisplatin versus paclitaxel/carboplatin produced more toxicity on the cisplatin arms as compared with the carboplatin arms.^35,36

SWOG 9509 evaluated two other important issues relevant to the treatment of advanced-stage lung cancer: QOL and economics. There were no treatment arm differences in QOL scores at two follow-up assessments, with approximately one quarter to one third of patients categorized as improved or stable. Because a substantial subset of patients in the study had excellent baseline QOL scores, "maintenance" of QOL is a reasonable assessment as defined by an improved or stable status. Analysis of the QOL data was complicated by missing data, however, particularly at 25 weeks. Missing data is problematic if it is associated with deterioration in health and inability or refusal to respond to the QOL questionnaire. Results based on such data sets are biased and overestimate QOL because "healthy survivors" complete the questionnaire. The impact of missing data on this scale has been reported for other QOL studies with advanced-stage patients and specifically for NSCLC patients.^39,40 We attempted to address this problem in the cross-sectional analyses at 13 and 25 weeks as reported in this article. Additional analyses address the missing data bias more thoroughly in the full report of the QOL results for the trial. Analyses reported in this article, however, disclosed no statistically significant treatment arm differences in QOL when patients with missing data were included or not included.

A challenging undertaking in this trial was to conduct a pharmacoeconomic analysis. We hypothesized that the higher drug costs of paclitaxel plus carboplatin would be, in part, offset by reduced administration costs and fewer adverse events related to therapy as compared with the vinorelbine plus cisplatin arm. Although the cost of drug delivery was lower in the paclitaxel arm, other resource use was similar between the two arms, with the result of no overall differences except for drug costs. Two additional factors contributed to higher drug costs for patients on arm II. On average, patients received an additional cycle of chemotherapy and more than 90% of the intended dose of both paclitaxel and carboplatin.

In conclusion, this study demonstrated that the two-drug combination of paclitaxel plus carboplatin and vinorelbine plus cisplatin produced equivalent response rates and survival for the palliative treatment of advanced NSCLC. Paclitaxel plus carboplatin produced fewer life-threatening toxicities and was more convenient and tolerable. It was also associated with higher drug costs. Thus, newer agents plus a platinum have led to a modest increase in survival for patients with advanced lung cancer, and their continued evaluation is important; however, clinical trials are underway of a number of novel, biologically based therapeutic agents to provide us with new molecular targets independent of those associated with standard chemotherapy. Integration of these novel agents into new treatment strategies should be a high priority.

	ACKNOWLEDGMENTS

 
Supported in part by Public Health Service Cooperative Agreement grant nos. CA38926, CA32102, CA42777, CA14028, CA2243, CA35431, CA5882, CA46441, CA04919, CA46282, CA37981, CA20319, CA45807, CA35090, CA96429, CA58415, CA58416, CA68183, CA12644, CA04920, CA45560, CA52654, CA35192, CA46368, CA35178, CA74647, CA35262, CA45450, CA58861, CA46136, CA58348, CA12213, CA58686, CA76448, CA45377, CA63844, CA63845, CA63850, CA45461, CA46113, and CA16385 from the National Cancer Institute, Department of Health and Human Services, and supported in part by Glaxo Wellcome, Inc, and Bristol-Meyers Squibb.

We thank Amgen, Inc, for their assistance in obtaining the dose-intensity data.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted November 27, 2000; accepted March 26, 2001.

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