Originally published as JCO Early Release 10.1200/JCO.2003.12.046 on July 1 2003
Journal of Clinical Oncology, Vol 21, Issue 16
(August), 2003: 3016-3024
© 2003 American Society for Clinical Oncology
Randomized, Multinational, Phase III Study of Docetaxel Plus Platinum Combinations Versus Vinorelbine Plus Cisplatin for Advanced Non–Small-Cell Lung Cancer: The TAX 326 Study Group
Frank Fossella,
Jose R. Pereira,
Joachim von Pawel,
Anna Pluzanska,
Vera Gorbounova,
Eckhard Kaukel,
Karin V. Mattson,
Rodryg Ramlau,
Aleksandra Szcz sna,
Panagiotis Fidias,
Michael Millward,
Chandra P. Belani
From the M.D. Anderson Cancer Center, Houston, TX; Instituto do Câncer Arnaldo Vieira de Carvalho, Sao Paulo, Brazil; Asklepios Fachkliniken München-Gauting, Gauting, Germany; M. Kopernik Memorial Hospital, Lodz, Poland; Cancer Research Center RAMS, Moscow, Russia; AK-Hamburg-Harbug, Hamburg, Germany; Helsinki University Central Hospital, Helsinki, Finland; Regional Lung Diseases Center, Pozna ; Regional Lung Diseases Hospital, Otwock, Poland; Massachusetts General Hospital, Boston, MA; Sydney Cancer Centre, Camperdown, Australia; University of Pittsburgh Cancer Institute, Pittsburgh, PA.
Address reprint requests to Chandra P. Belani, MD, Division of Medical Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center Cancer Pavilion, 5150 Center Ave, Suite 570, Pittsburgh, PA 15232; email: belanicp{at}msx.upmc.edu.
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ABSTRACT
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Purpose: To investigate whether docetaxel plus platinum regimens improve survival and affect quality of life (QoL) in advanced non–small-cell lung cancer (NSCLC) compared with vinorelbine plus cisplatin as first-line chemotherapy.
Patients and Methods: Patients (n = 1,218) with stage IIIB to IV NSCLC were randomly assigned to receive docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks (DC); docetaxel 75 mg/m2 and carboplatin area under the curve of 6 mg/mL • min every 3 weeks (DCb); or vinorelbine 25 mg/m2/wk and cisplatin 100 mg/m2 every 4 weeks (VC).
Results: Patients treated with DC had a median survival of 11.3 v 10.1 months for VC-treated patients (P = .044; hazard ratio, 1.183 [97.2% confidence interval, 0.989 to 1.416]). The 2-year survival rate was 21% for DC-treated patients and 14% for VC-treated patients. Overall response rate was 31.6% for DC-treated patients v 24.5% for VC-treated patients (P = .029). Median survival (9.4 v 9.9 months [for VC]; P = .657; hazard ratio, 1.048 [97.2 confidence interval, 0.877 to 1.253]) and response (23.9%) with DCb were similar to those results for VC. Neutropenia, thrombocytopenia, infection, and febrile neutropenia were similar with all three regimens. Grade 3 to 4 anemia, nausea, and vomiting were more common (P < .01) with VC than with DC or DCb. Patients treated with either docetaxel regimen had consistently improved QoL compared with VC-treated patients, who experienced deterioration in QoL.
Conclusion: DC resulted in a more favorable overall response and survival rate than VC. Both DC and DCb were better tolerated and provided patients with consistently improved QoL compared with VC. These findings demonstrate that a docetaxel plus platinum combination is an effective treatment option with a favorable therapeutic index for first-line treatment of advanced or metastatic NSCLC.
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INTRODUCTION
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NON–SMALL-CELL LUNG cancer (NSCLC) accounts for approximately 80% of all lung cancers, with 1.2 million new cases worldwide each year.1,2 NSCLC resulted in more than 1 million deaths worldwide in 20012 and is the leading cause of cancer-related mortality in both men and women (31% and 25%, respectively).3 Most patients present with locally advanced stage III or metastatic stage IV disease. A meta-analysis of 52 randomized trials indicated an absolute 1-year survival benefit of 10% and a modest improvement in median survival of 1.5 months for patients treated with cisplatin-containing regimens, compared with best supportive care alone.4 Although the current practice for treating patients with metastatic disease includes the addition of newer generation agents such as vinorelbine, gemcitabine, paclitaxel, or docetaxel to a platinum agent, no combination has emerged as a gold standard.4,5 Survival data with the newer combinations have been encouraging, with median survival times of 8.4 to 14.2 months, and 1-year survival rates as high as 54%.6–9
In an analysis of more than 2,500 patients with advanced NSCLC treated in the Southwest Oncology Group (SWOG) trials between 1974 to 1988, cisplatin emerged as an independent prognostic variable predicting improved survival.10 Vinorelbine plus cisplatin (VC) is frequently used as first-line chemotherapy in patients with advanced disease (on the basis of results from four large controlled studies conducted in North America and Europe), with a median survival of 8.0 to 9.2 months; however, it results in considerable toxicity.11–14
There remains a need to provide patients with treatment that not only prolongs survival, but also has acceptable toxicity and improves quality of life (QoL). Docetaxel and the platinums are active as single chemotherapeutic agents in NSCLC.15–17 Phase III trials have proven the activity of docetaxel in advanced NSCLC, including platinum-resistant disease.18–20 The combination of docetaxel with a platinum agent has yielded response rates of 30% to 67% and median survival of 8.4 to 13.9 months in phase II and III trials of chemotherapy-naive patients, indicating that docetaxel plus platinum combinations are active in the first-line treatment of NSCLC.6,21–27 We conducted a large, randomized, phase III study in chemotherapy-naive patients with stage IIIB or IV NSCLC to compare the effect of docetaxel plus cisplatin (DC) and docetaxel plus carboplatin (DCb) against an accepted11,28 standard regimen of VC. The primary end point was overall survival. Secondary end points included overall response rate, time to progression, safety, and QoL.
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PATIENTS AND METHODS
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This was a multicenter, international, prospective, open-label, randomized phase III study. The study protocol was approved by the review board or ethics committee at each of the participating centers. An independent data-monitoring committee ensured that the trial was conducted in an ethical manner. All patients provided written informed consent before enrollment.
Eligibility Criteria
Adults (age  18 years) with histologically or cytologically confirmed locally advanced or recurrent (stage IIIB) or metastatic (stage IV) NSCLC, Karnofsky performance status (KPS) 70%, and at least one measurable or assessable lesion were recruited. Adequate organ function was required, as evidenced by absolute neutrophil count 1.5 x 109/L, platelet count 100 x 109/L, hemoglobin 9.0 g/dL, hepatic enzyme levels  2 x the upper limit of the normal range (ULN), alkaline phosphatase levels 5 x the ULN, total bilirubin levels no more than the ULN, and serum creatinine levels 1.5 mg/dL (or creatinine clearance 60 mL/min).
Exclusion criteria included prior treatment with a biologic response modifier or chemotherapeutic agent, previous or concurrent malignant disease (except cone-biopsied carcinoma-in-situ of the cervix or adequately treated basal or squamous cell carcinoma of the skin), history of brain or leptomeningeal metastases (except if adequately treated and radiologically stable for at least 4 weeks), peripheral neuropathy of National Cancer Institute common toxicity criteria grade 2 or above, major surgery within 2 weeks of study entry, radiotherapy within 4 weeks of study entry, or other serious concomitant illness.
Stratification and Treatment Plan
Before random assignment to treatment, patients were stratified according to disease stage (IIIB v IV) and geographic region (North America v South Africa, New Zealand and Australia v Europe, Lebanon and Israel v South America). Random assignment to treatment was conducted by an independent research organization using computer-generated lists.
Patients were randomly assigned to one of three treatment groups: DC (docetaxel 75 mg/m2 immediately followed by cisplatin 75 mg/m2, both as 1-hour intravenous infusions on day 1, repeated every 3 weeks); DCb (docetaxel 75 mg/m2 as a 1-hour intravenous infusion immediately followed by carboplatin administered intravenously at a dose calculated to produce an area under the concentration-time curve of 6 mg/mL • min, both on day 1, repeated every 3 weeks); VC (vinorelbine 25 mg/m2 as a 6- to 10-minute intravenous infusion on days 1, 8, 15, and 22, plus cisplatin 100 mg/m2 administered intravenously on day 1, repeated every 4 weeks). A total of six doses of dexamethasone 8 mg were given orally to all patients with each docetaxel treatment for prophylaxis against fluid retention and hypersensitivity reactions. The first 8-mg dose was given on the evening before treatment. Three 8-mg doses were given on the day of treatment (day 1) in the morning, 1 hour before the docetaxel infusion, and in the evening. The last two doses were given the day after treatment (day 2), in the morning and evening. Antiemetic prophylaxis was given routinely, and patients receiving cisplatin also received adequate hydration. Secondary prophylaxis with granulocyte colony-stimulating factor was allowed as needed after completion of cycle 1. If toxicity occurred, patients were allowed a maximum of two dose reductions of docetaxel, cisplatin, or vinorelbine (dose reductions of carboplatin were not allowed).
Patients were treated for six cycles (which corresponds to 18 weeks for DC and DCb, and 24 weeks for VC) or until progressive disease, death, or an unacceptable adverse event. Patients could continue treatment beyond six cycles at the discretion of the treating physician. Second-line therapies, also at the treating physician’s discretion, were permitted after the study treatment was discontinued. The nature of any second-line therapies was recorded. After discontinuation of study treatment, patients were monitored at 2-month intervals until death.
Response, Survival, and Toxicity Criteria
Response was determined in comparison with baseline assessment of measurable disease (identifiable tumor margins, measurable in two dimensions) or assessable disease (one identifiable measurable margin). SWOG response criteria were applied and all responses were confirmed by the next treatment cycle (3 weeks later for DC and DCb, and 4 weeks later for VC). The overall response rate was the number of patients with a confirmed response occurring at any point between the start of treatment and their removal from treatment. Time to progression was defined as the time from random assignment to first documentation of progressive disease. Disease was evaluated every 6 weeks (two cycles) in patients who received DCb or DC, and every 8 weeks (two cycles) for patients who received VC. Survival was measured from the time of random assignment to date of death or date of last patient contact if lost to follow-up. Toxicities were assessed at the end of every cycle using the National Cancer Institute common toxicity criteria; toxicities that could not be graded by these criteria were assessed as mild, moderate, severe, or life threatening. Hematologic assessments were carried out on a weekly basis for all treatment arms.
QoL and Other Clinical Assessments
Instruments used for the self-administered QoL assessments included the validated, disease-specific, Lung Cancer Symptom Scale (LCSS),29 and the global QoL scale, EuroQol.30 The LCSS concentrates on physical and functional QoL dimensions. The EuroQol is a validated general measure of health status, and allows the calculation of quality-adjusted survival. QoL assessments were completed before each treatment cycle, at the end of study treatment, and every other month after the end of study treatment. QoL assessments were performed only in the countries in which a translated version of the QoL tool with validation was available. Other clinical benefit parameters included body weight and KPS, which were measured at baseline and at every cycle; changes were compared using a longitudinal analysis model.
Statistical Analysis
The primary end point was overall survival. Both noninferiority and superiority hypotheses were tested. The noninferiority criterion was based on historic data.12 Noninferiority could be concluded if the lower bound of the confidence interval (CI) of the hazard ratio for survival was greater than 0.85, which means that the test treatment preserves at least 50% of the control treatment effect observed in the historic data. The planned sample size of 360 patients per treatment group provided the study with 88% power to detect an increase in median survival from 8 months in the control arm to 10.5 months in either docetaxel arm (ie, an absolute improvement of 2.5 months), with a type I error of 0.05. The same sample size provided 85% power to test the noninferiority hypothesis.
The planned analyses for survival consisted of two independent comparisons of each docetaxel combination versus VC. The Hochberg method31 was applied to account for the two treatment comparisons. Statistical significance would be declared if both comparisons achieved P .05 or if only one of them achieved P .028. This corresponds to the use of a 97.2% CI if noninferiority was achieved for one comparison only. In addition, the type I error rate for each pair-wise comparison was adjusted to 0.047 to account for a prespecified interim analysis.
In the evaluation of the efficacy end points, every patient enrolled onto the study was included and analyzed according to the intention-to-treat principle. Only patients who actually received treatment were assessed for safety. A Cox proportional hazards model stratified for stage of disease and region of centers and adjusted for important prognostic variables (described below) was used to compare the survival curves and to estimate the hazard ratios and respective CIs. The survival estimates (median and survival rates at 1 and 2 years) were adjusted for the following prognostic variables: age, performance status, time from diagnosis of disease to random assignment of treatment, weight loss in the prior 6 months, histologic subtype, level of lactate dehydrogenase, sex, baseline QoL score, liver involvement, bone involvement, prior radiotherapy, and prior surgical procedure. Minor differences in the distribution of prognostic variables for the two independent comparisons could lead to slightly different point estimates for the control group. Superiority was tested using a nonparametric covariate-adjusted log-rank test.32 The survival curves were plotted on the basis of the nonparametric covariate-adjusted survival estimates. Fisher’s exact test was used to compare frequencies of response rates.
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RESULTS
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Patients and Treatment Administration
A total of 1,218 patients with NSCLC from 140 institutions in 28 countries were enrolled and randomly assigned to treatment between July 1998 and January 2000. Of the 1,218 patients, 15 did not receive treatment (nine were ineligible, four withdrew consent, and two died of malignant disease before the first drug infusion) and were excluded from the safety analysis. The median follow-up period was 10 months. Baseline characteristics of patients were well balanced across the three treatment groups with regard to the stratification factors of stage and geography, as well as sex, age, and performance status (Table 1 ). Approximately 67% of the patients in each treatment group had stage IV disease, and 33% of patients had stage IIIB disease. A total of 4.9% (DC), 6.7% (DCb), and 4.5% (VC) of patients were staged with IIIB disease on the basis of malignant pleural effusion. The 28% of stage IIIB patients without pleural effusion were considered unresectable, and therefore, surgery was not deemed an option. Only 2.2% (DC), 1.2% (DCb), and 1.5% (VC) of patients had stable brain metastases.
Patients received between one and 13 cycles of treatment during the study. The median number of treatment cycles delivered was five (over 15 weeks) for DC, six (18 weeks) for DCb, and four (16 weeks) for VC. Compliance to treatment was excellent, particularly for DC and DCb, as indicated by the combined relative dose-intensities, which approached 1 (DC, 0.94; DCb, 0.93; VC, 0.78). A total of 541 patients completed at least six treatment cycles; more patients in the DC (49.8%) and DCb (51.4%) groups completed six cycles of treatment as compared with those in the VC group (33.6%). The main reasons for treatment discontinuation were completion of protocol-planned treatment (DC, 36.0%; DCb, 37.2%; VC, 22.0%) and disease progression (DC, 30.1%; DCb, 36.9%; VC, 32.2%), with only 13 patients (1.1%) in total discontinuing because of a major protocol violation. Patients who received DC or DCb experienced fewer treatment delays than VC-treated patients (11.8%, 11.2%, and 16.1%, respectively). Granulocyte colony-stimulating factor use was higher for patients on the VC arm (18.9% of patients) than for those on the DC (13.8%) and DCb (15.0%) arms. RBC transfusion was required by a greater number of patients treated with VC (19.4%) compared with DC (10.3%) and DCb (10.5%).
After discontinuation or completion of the study, the number of patients who received second-line therapy and the nature of the second-line therapy were well balanced among the groups. In total, 444 patients (36.5%) went on to receive additional chemotherapy (DC, 35.3%; DCb, 36.0%; VC, 38.1%), 498 patients (40.9%) received radiotherapy (DC, 40.9%; DCb, 41.1%; VC, 40.6%), and 41 patients (3.4%) underwent surgery (DC, 3.4%; DCb, 2.5%; VC, 4.2%). The most common second-line chemotherapies were gemcitabine monotherapy (123 patients; 27.7%), docetaxel monotherapy (56 patients; 12.6%), and gemcitabine plus cisplatin (41 patients; 9.2%). A higher number of patients from the VC study group received docetaxel as second-line therapy (35 patients; 8.7%) as compared with patients from the DC group (14 patients; 3.4%) and DCb group (seven patients; 1.7%).
Survival
In the first pair-wise comparison of DC versus VC, the median overall survival was 11.3 months for DC-treated patients and 10.1 months for VC-treated patients. The hazard ratio was 1.183 (97.2% CI, 0.989 to 1.416). The test for superiority using a nonparametric covariate-adjusted log-rank test resulted in P = .044. The survival curves separate beginning at 4 months from random assignment and remain nonoverlapping for the duration of the follow-up period (Fig 1). One- and 2-year survival rates were 46% v 41%, and 21% v 14% (DC and VC, respectively; Table 2).
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Fig 1. Nonparametric covariate-adjusted estimates of overall survival for docetaxel plus cisplatin (DC) versus vinorelbine plus cisplatin (VC).
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In the second pair-wise comparison of DCb versus VC, the overall median survival was 9.4 v 9.9 months, respectively (Fig 2). The hazard ratio was 1.048 (97.2% CI, 0.877 to 1.253). The test for superiority using a nonparametric covariate-adjusted log-rank test resulted in P = .657. One- and 2-year survival rates for DCb versus VC were 38% v 40%, and 18% v 14%, respectively (Table 2 ).
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Fig 2. Nonparametric covariate-adjusted estimates of overall survival for docetaxel plus carboplatin (DCb) versus vinorelbine plus cisplatin (VC).
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Response
In the first pair-wise comparison, the response rate for DC was 31.6% v 24.5% for VC (P = .029; Table 3). In the second pair-wise comparison of DCb versus VC, the response rates were similar (23.9% v 24.5%; P = .870). Median time to disease progression for DC was 22 weeks (95% CI, 21 to 25 weeks), compared with 23 weeks (95% CI, 21 to 27 weeks) for VC (P = .805). Similarly, median time to disease progression for DCb was 20 weeks (95% CI, 19 to 23 weeks) compared with 22 weeks (95% CI, 19 to 25 weeks) for VC (P = .235).
Toxicity
Fewer patients in both the DC (41.4%) and DCb groups (39.9%) experienced grade 3 to 4 adverse events compared with the VC group (48.0%). No differences were seen among the three treatment groups with regard to grade 3 to 4 neutropenia, thrombocytopenia, or infection (Table 4). Febrile neutropenia occurred in less than 5% of patients in each arm (4.9% DC; 3.7% DCb; 4.5% VC). A higher percentage of patients in the VC arm experienced grade 3 to 4 anemia, nausea, and vomiting compared with patients in either docetaxel arm (P < .01; Table 4). Grade 3 to 4 diarrhea occurred more frequently in DC (6.7%) and DCb (5.2%) patients compared with VC patients (2.8%), though the majority of these events were grade 3, and they had a negligible influence on treatment delays and treatment discontinuation. The incidence of grade 3 to 4 sensory neuropathy was 3.8% in the control arm, 3.9% in the DC arm, and 0.7% in the DCb arm. Grade 1 to 4 edema (DC, 32.3%; DCb, 22.7%; VC, 16.2%), nail disorders (DC, 13.5%; DCb, 10.2%; VC, 0.5%), and hypersensitivity reactions (DC, 11.8%; DCb, 11.2%; VC, 4.0%), as well as grade 1 to 3 alopecia (DC, 73.6%; DCb, 68.3%; VC, 41.4%) occurred more frequently with the docetaxel-containing treatments compared with VC; however, the incidence of these adverse events at grade 3 to 4 was similarly low for all treatment arms (< 1% for alopecia [grade 1 to 3], edema, and nail disorders; 3% for hypersensitivity reactions). Fewer patients treated with DC (0.9%) experienced treatment delays caused by hematologic toxicity compared with those treated with VC (4.8%) and DCb (3.1%). Hospitalizations because of adverse events were less frequent in the DC and DCb arm (40.8% and 39.4%, respectively) compared with the VC arms (46.7%). Furthermore, more patients on the VC arm (22.5%) discontinued treatment because of adverse events compared with those on the DC (15.7%) and DCb arms (9.1%).
QoL and Other Clinical Assessments
Translation of the QoL assessment tools into the patient’s native language was available for 926 patients. The baseline EuroQol questionnaire was completed by 831 patients (DC, 281; DCb 279; VC, 271), and 811 patients (DC, 279; DCb, 269; VC, 263) completed the baseline LCSS questionnaire. Patients treated with either docetaxel regimen reported consistently improved global QoL compared with patients treated with VC, who generally experienced a deterioration in QoL (Figs 3 and 4). Longitudinal analyses showed that for patients treated with DCb, this overall advantage in global QoL was statistically significant according to both LCSS (P = .016) and EuroQol (P < .001) assessments. For patients treated with DC, the advantage in global QoL was statistically significant when evaluated by EuroQol (P = .016) but not when evaluated by the LCSS (P = .064).
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Fig 3. Global quality-of-life assessment using the Lung Cancer Symptom Scale instrument. (A) Docetaxel plus cisplatin (DC) versus vinorelbine plus cisplatin (VC). (B) Docetaxel plus carboplatin (DCb) versus VC. Vertical bars represent plus or minus a unit of standard error.
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Fig 4. Global quality-of-life assessment using the EuroQol instrument. (A) Docetaxel plus cisplatin (DC) versus vinorelbine plus cisplatin (VC). (B) Docetaxel plus carboplatin (DCb) versus VC. Vertical bars represent plus or minus a unit of standard error.
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Patients treated with DC or DCb experienced significantly less mean weight loss from baseline through the last on-treatment assessment than those treated with VC (0.29, 0.01, and 2.35 kg, respectively; P < .001 for both comparisons with VC). A separate analysis indicated that fluid retention observed as an adverse event did not account for the maintenance of weight. Furthermore, VC-treated patients experienced a modest but consistently greater decline (of 20% from baseline) in KPS than those treated with DC (P = .028) and DCb (P < .001).
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DISCUSSION
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This phase III trial of 1,218 chemotherapy-naive patients with stage IIIB to IV NSCLC examined the effect of two docetaxel plus platinum regimens against a standard reference regimen of VC. Patients benefited from a better safety profile, improved QoL, and a higher 2-year survival rate in the docetaxel plus platinum arms, as well as a more convenient dosing schedule. In this study, definitive conclusions can be drawn on the effectiveness of the docetaxel plus platinum regimens because both noninferiority and superiority were tested. With the application of a rigorous statistical methodology and the use of conservative criteria to establish noninferiority, it has been demonstrated that DC, at minimum, retained the effect of the control regimen VC. Although superiority was not demonstrated using a significance level of .028, the lower bound of the 97.2% CI of 0.989 indicated that DC was nearly superior to VC. The survival estimates clearly favored DC, with a longer median survival (11.3 v 10.1 months) and a more favorable 2-year survival rate (21% v 14%) than those of VC. DC-treated patients also experienced a higher overall response rate (31.6% v 24.5%; P = .029). Overall response and survival rates were similar for patients treated with DCb and VC. The lower bound of the 97.2% CI of the hazard ratio of 0.877 met the noninferiority margin of 0.85. However, sensitivity analyses indicated that the survival results for DCb were not as robust as those for DC; a formal conclusion could not be reached on noninferiority. We prospectively recorded the nature of second-line treatment and established that this did not confound survival results in favor of therapy with docetaxel plus platinum.
Because the role of chemotherapy in advanced NSCLC is primarily palliative, the influence on patients’ QoL is an important consideration in determining the true value of any new therapy. The complete evaluation of the effects of chemotherapy on health status in metastatic NSCLC requires assessment of chemotherapy on domains of patient health, lung cancer–specific symptoms, and treatment-related toxicity. In this study, the use of both a lung cancer–specific QoL scale (LCSS), and a global health scale (EuroQol), demonstrated that patients treated with DC or DCb had consistently improved QoL, whereas VC-treated patients suffered a deterioration in QoL (for DC v VC, P = .064 [LCSS] and P = .016 [EuroQol]; for DCb v VC, P = .016 [LCSS] and P < .001 [EuroQol]). Thus, the benefits observed in this study extended beyond survival to an improvement in global QoL. Furthermore, patients treated with either docetaxel plus platinum regimen experienced significantly less weight loss and decline in KPS than did VC-treated patients.
This study also showed that the overall safety profile of both DC and DCb compared favorably with that of VC, as indicated by fewer adverse events leading to hospitalizations, treatment discontinuations caused by side effects, and grade 3 to 4 toxicities. Specifically, grade 3 and 4 anemia, nausea, and vomiting were more prevalent in patients who received VC than in those who received DC or DCb. The incidence of infection and febrile neutropenia was similar across the three treatment arms. There was little grade 3 to 4 neurosensory toxicity associated with DCb or DC in the current trial (1% and 4%, respectively). Grade 1 to 4 edema, nail disorders, and hypersensitivity reactions occurred more frequently in the docetaxel-containing arms; however, the incidence of these adverse events at grade 3 to 4 was similarly low for all treatment arms (< 1% for edema and nail disorders; 3% for hypersensitivity reactions).
Three recently published, large, phase III trials also compared modern platinum-based regimens in the first-line treatment of advanced NSCLC, but found no clear advantage for any regimen.5,14,33 SWOG study 9509 enrolled 408 patients and compared the standard regimen of VC, the identical reference regimen used in our study, to paclitaxel plus carboplatin (PCb).14 The median survival was similar for both regimens, 8.1 and 8.6 months (P = .87). One- and 2-year survival rates were also similar: 36% and 16% for VC, and 38% and 15% for PCb. There were grade 3 to 4 toxicity differences between the regimens: VC was associated with significantly more leukopenia, neutropenia, nausea, and vomiting; PCb was associated with significantly more grade 3 sensory neuropathy. QoL, which was measured using the Functional Assessment of Cancer Therapy–Lung questionnaire, showed no statistically significant differences between the arms. Similarly, a study by the Italian Lung Cancer Project (612 patients) compared PCb and gemcitabine plus cisplatin (GC) against VC, and found no significant differences in median survival (9.9, 9.8, and 9.5 months, respectively), 1-year survival rate (43%, 37%, and 37%, respectively), or QoL.33 The survival data from the Italian Lung Cancer Project and SWOG trials are similar to the results observed in our trial and that of other randomized trials using new agent plus platinum combinations, with median survivals of 7.4 to 13.2 months and 1-year survivals in the range 25% to 61%.11,12,34–36
In the Eastern Cooperative Group (ECOG) study 1594, a control arm of paclitaxel and cisplatin (PC) was compared against GC, DC, or PCb.5 A total of 1,155 patients were assessable. None of the regimens tested showed any improvement in median, 1-, or 2-year survivals as compared with the control regimen. For the entire study population, the overall median survival was 7.9 months, and 1- and 2-year survival rates were 33% and 11%, respectively. There were grade 3 to 4 toxicity differences between each comparator and the control. GC was associated with significantly less febrile neutropenia, but significantly more thrombocytopenia, anemia, and renal toxicities than PC. DC was associated with significantly more hypersensitivity reactions than PC. The PCb arm was associated with significantly less febrile neutropenia, nausea, vomiting, and overall grade 3 to 4 toxicities than PC. QoL evaluations were not a part of this study.5
Differences in trial design, patient characteristics, and treatment delivery between ECOG 1594 and this study may account for the differences in survival outcome of the respective DC arms. Compared with ECOG 1594, this study included approximately 100 more patients per treatment arm, enrolled a higher proportion of stage IIIB patients (33% v 13%), and had a lower proportion of patients with brain metastases (2% v 13%). DC-treated patients in our study received a median of five cycles compared with four cycles in ECOG 1594. Furthermore, unlike this study, the nature of second-line chemotherapy in ECOG 1594 was not documented, and thus may have contributed in obscuring potential survival differences among the treatments.
Recent reports indicate that chemotherapy in advanced lung cancer has reached a plateau, with few differences in survival among the various combinations of chemotherapeutic agents.5,14,33,37,38 ECOG 1594, SWOG 9509, and the Italian Lung Cancer Project trial showed similar survival and response rates across all arms, with an average gain of 2 months for median survival in comparison with historic controls. There were some toxicity trade-offs between arms, but no clear advantage with regard to response rate, survival, or QoL (in SWOG 9509 and the Italian Lung Cancer Project trial) emerged.5,14,33 In contrast, this study demonstrated clinically meaningful benefits with the two docetaxel plus platinum regimens. Because this trial was not designed to compare formally cisplatin with carboplatin, the choice of exactly which platinum should be used in combination with docetaxel is likely to be based on the clinician’s preference and individual patient characteristics. There was a strong trend favoring improved survival in patients receiving DC as compared with VC. In addition, patients in either docetaxel arm experienced a more favorable toxicity profile than those in the VC arm. Perhaps most notable was the observation that patients who received either docetaxel regimen also experienced a consistent improvement in QoL and other measures of clinical benefit, including weight loss and performance status. This QoL benefit appears to be unique to docetaxel plus platinum chemotherapy. Randomized clinical trials of paclitaxel combined with either cisplatin or carboplatin failed to detect any significant QoL benefit of paclitaxel plus platinum therapy in patients with advanced NSCLC.14,33,34 These results demonstrate that a docetaxel plus platinum combination is an effective treatment option with a favorable therapeutic index for use in first-line therapy of patients with advanced or metastatic NSCLC. Although cytotoxic chemotherapeutic agents are currently the mainstay of treatment for advanced NSCLC, it is important to explore concurrent or sequential administration of novel targeted therapies to determine whether treatment can be taken to the next level.
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APPENDIX
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The TAX 326 Study Group comprised the authors listed and the following investigators: Drs Mickiewicz, Mosca, Van Kooten, and Vincente Hector, Argentina;Drs Byrne, Clingan, Rischin, and Richardson, Australia; Drs Bosquee, Canon, Dirix, and Vansteenkiste, Belgium; Dr Anelli, Brazil; Dr Chemozemski, Bulgaria;Drs Butts, Champion, Davies, Tang, Laberge, Laplante, Prady, and Lopez, Canada; Drs Kleinmann and Orlandi, Chile; Drs Isokangas, Mali, Nikkanen, Pekonen, and Hujanen, Finland; Drs Knuth, Lodenkemper, Peschel, and Weh, Germany; Drs Effremides, Panagos, Georgoulias, and Fountilas, Greece; Drs Baliko, Boszormenyi, Magyar, and Kraszko, Hungary; Dr Clancy, Ireland; Drs Gottfried and Hayat, Israel; Drs Barone and Gasparini, Italy; Drs Abigerge, Chahine, and Fadel, Lebanon; Drs Gallardo and Lira, Mexico; Drs Erdkamp, Pannekoek, Van der Hoeven, and Van Zandwijk, the Netherlands; Drs Findlay and Mc Keage, New Zealand; Dr Vallejos, Peru; Drs Folcik, Mlodkowska, Oklek, and Wojtukiewicz, Poland; Drs Gershanovich and Moiseyenko, Russian Federation; Drs Abratt, Brennan, Cronje, Du Toit, Heslop, Landers, and Vorobiof, South Africa; Drs Batista, Bover, Guillem, Diaz-Rubio, Moreno, Saigi, Bastus, and Terasa, Spain; Drs Betticher, Cerny, Egli, and Honegger, Switzerland; Drs Celykel and Topuz, Turkey; Drs Agrawal, Ansari, Arcenas, Axelrod, Baez, Bank, Beck, Bukowski, Dobbs, Dolyle, Drehlichman, Dugan, Ellerton, Garewal, George, Geils, Gutheil, Harker, Harper, Hrushesky, Jahanzeb, Kerr, Kincaid, Kotz, Lokich, Lynch, Matthews, McCarley, Mudad, Neitlich, Pandya, Pendergrass, Robertson, Schwartzberg, Sridhar, Tai, Taylor, Tirumali, Wade, Wax, and Wood, United States; Drs Aren and Alles, Uruguay; and Dr Nunez, Venezuela.
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ACKNOWLEDGMENTS
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We thank Francis C. Gamza, MD, Jocelyne Berille, MD, and Yong S. Kim, PhD (statistician), for planning and implementing the study; Antoinette Wozniak, MD, Lionel Bosquee, MD, and Claude Ramazeilles, PhD, for their valuable insights; Luz Hammershaimb, MD, Antoine Yver, MD, and Jean-Pierre Bizzari, MD, for their support of the study; Mark R. Green, MD (Chairman), Lucio Crino, MD, and Boris Iglewicz, PhD, from the Independent Data Monitoring Committee; and Wendy Crist (international study manager), Isabelle Dancy, PhD (study manager), Anthony Rodgers, PhD (statistician), Martin Roessner, MSc (statistician), Sandrine Anneheim-Herbelin, PhD (study manager), and Jean-Luc Schmidt (data manager).
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NOTES
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Supported by a grant from Aventis Pharma.
Previously presented in part at the Annual Meeting of the American Society of Clinical Oncology (ASCO), San Francisco, CA, May 12–15, 2001; the Annual Meeting of ASCO, Orlando, FL, May 18–21, 2002; and the Congress of the European Society for Medical Oncology, Nice, France, October 18–22, 2002.
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Submitted December 9, 2002;
accepted May 1, 2003.
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TOP
ABSTRACT
INTRODUCTION
