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A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer
original article
Annals of Oncology 21: 540–547, 2010 doi:10.1093/annonc/mdp352 Published online 15 October 2009
A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer J. A. Treat1*, R. Gonin2, M. A. Socinski3, M. J. Edelman4, R. B. Catalano5, D. M. Marinucci5, R. Ansari6, H. H. Gillenwater7, K. M. Rowland8, R. L. Comis5, C. K. Obasaju1 & C. P. Belani9 for the Alpha Oncology Research Network 1
US Medical Division, Lilly USA, Indianapolis, IN; 2Westat, Rockville, MD; 3Division of Hematology/Oncology, Multidisciplinary Thoracic Oncology Group, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; 4Division of Hematology/Oncology, University of Maryland Greenbaum Cancer Center, Baltimore, MD; 5Drexel University College of Medicine, Philadelphia, PA; 6Northern Indiana Cancer Research Consortium, South Bend, IN; 7Department of Hematology/ Oncology, University of Virginia Cancer Center, Charlottesville, VA; 8Department of Medicine, Carle Clinic Cancer Center, Urbana, IL and 9Division of Hematology/ Oncology, Penn State Hershey Cancer Institute, Hershey, PA, USA
Received 2 September 2008; revised 5 June 2009; accepted 10 June 2009
original article
Background: Paclitaxel–carboplatin is used as the standard regimen for patients with advanced or metastatic nonsmall-cell lung cancer (NSCLC). This trial was designed to compare gemcitabine + carboplatin or gemcitabine + paclitaxel to the standard regimen. Patients and methods: A total of 1135 chemonaive patients with stage IIIB or IV NSCLC were randomly allocated to receive gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin area under the concentration–time curve (AUC) 5.5 on day 1 (GC), gemcitabine 1000 mg/m2 on days 1 and 8 plus paclitaxel 200 mg/m2 on day 1 (GP), or paclitaxel 225 mg/m2 plus carboplatin AUC 6.0 on day 1 (PC). Stratification was based on disease stage, baseline weight loss, and presence or absence of brain metastases. Cycles were repeated every 21 days for up to six cycles or disease progression. Results: Median survival (months) with GC was 7.9 compared with 8.5 for GP and 8.7 for PC. Response rates (RRs) were as follows: GC, 25.3%; GP, 32.1%; and PC, 29.8%. The GC arm was associated with a greater incidence of grade 3 or 4 hematologic events but a lower rate of neurotoxicity and alopecia when compared with GP and PC. Conclusions: Non-platinum and non-paclitaxel gemcitabine-containing doublets demonstrate similar overall survival and RR compared with the standard PC regimen. However, the treatment arms had distinct toxicity profiles. Key words: carboplatin, gemcitabine, non-platinum doublets, NSCLC, paclitaxel, phase III
introduction The annual burden of non-small-cell lung cancer (NSCLC) was estimated in 2007 at 181 000 new cases and 136 000 deaths in the United States [1]. At the time of diagnosis, most patients (>80%) have locally advanced stage III or metastatic stage IV disease and are ineligible for potentially curative surgery; and 5year survival is <10% in this patient population [2, 3]. Palliative chemotherapy has become the standard therapy for patients with advanced NSCLC, with platinum-based doublets producing a modest survival benefit and improvement in quality of life compared with best supportive care alone [4–7].
*Correspondence to: Dr J. A. Treat, US Medical Division, Lilly USA, Drop Code 6831, Indianapolis, IN 46285, USA. Tel: +1-317-433-6078; Fax: +1-317-277-3533; E-mail: [email protected]
Several large randomized trials that have compared commonly prescribed platinum doublets did not support any specific regimen as the evidenced-based practice standard for NSCLC [8–11]. Studies indicate non-platinum doublets can also provide benefits similar to platinum doublets [12, 13]. Paclitaxel produces single-agent response rates (RRs) between 20% and 42%, with 1-year survival rates of 40% in advanced NSCLC [14–16]. Eastern Cooperative Oncology Group (ECOG) 5592 formed the basis for paclitaxel + cisplatin use in advanced NSCLC by demonstrating a median survival of 9.9 months in association with this combination (at two dose levels of paclitaxel) compared with 7.6 months with etoposide + cisplatin [17]. Concerns over cisplatin-related neurotoxicity led to the eventual replacement of cisplatin with carboplatin within platinum-based treatment regimens [18, 19].
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Annals of Oncology
As a single agent in advanced NSCLC, gemcitabine has produced RRs between 20% and 28% and survival between 7 and 11 months [20–23]. In combination with gemcitabine, platinum combination regimens have resulted in RRs between 28% and 54% and 1-year survival rates between 35% and 61%, with manageable toxicity [24–26]. Gemcitabine and paclitaxel have shown single-agent activity in advanced NSCLC, lack overlapping toxic effects, and have different mechanisms of action [27]. Trials of the combination of gemcitabine and paclitaxel have resulted in RRs between 27% and 47%, with manageable toxicity [28–31]. Several phase II studies have tested the combination of gemcitabine + carboplatin, demonstrating levels of activity similar to other combinations [32–34]. Given the similarity of response of gemcitabine + paclitaxel to most platinum-containing regimens, the toxicity profile could determine the choice of first-line regimen for future evaluation of chemotherapeutic approaches for advanced or metastatic NSCLC. Therefore, a prospective, randomized comparison of overall survival (OS), efficacy, and toxicity was conducted to determine the role of non-platinum- and nonpaclitaxel-containing regimens in the treatment of NSCLC. In this phase III study, paclitaxel + carboplatin (PC) was chosen as the reference regimen for comparison with either gemcitabine + carboplatin (GC) or gemcitabine + paclitaxel (GP), with the goal of identifying the regimen associated with the best therapeutic index.
patients and methods study design Patients with stage IIIB (with pleural or pericardial effusion), stage IV, or recurrent NSCLC who met all eligibility criteria were randomly allocated to receive one of the three treatment regimens as summarized in Figure 1. Patient stratification by baseline weight loss (<5% versus ‡5% in previous 6 months), stage of disease (IIIB with effusion versus IV), and brain metastasis (presence versus absence) took place at the time of randomization to ensure balance across treatment arms with respect to these characteristics. Patients were randomly allocated to receive one of the three platinum or non-platinum regimens in equal proportions as follows—arm A: gemcitabine 1000 mg/m2 infused over 30 min on days 1
Figure 1. Treatment schema. *Carboplatin dose decreased to AUC 5.0 in all patients with ‡20% of bone marrow previously irradiated (arm A only). AUC, under the concentration–time curve.
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and 8 plus carboplatin AUC 5.5 over 15–30 min on day 1 (GC); arm B: gemcitabine 1000 mg/m2 infused over 30 min on days 1 and 8 plus paclitaxel 200 mg/m2 infused over 3 h on day 1 (GP); or arm C: paclitaxel 225 mg/m2 infused over 3 h on day 1 plus carboplatin AUC 6.0 over 15–30 min on day 1 (PC). Treatment cycles for all three treatment arms were repeated every 21 days for six cycles or until unacceptable toxicity or disease progression. Carboplatin dosing was based on the formula described by Calvert et al. [35]. Guidelines for dose adjustments were provided for chemotherapy-related hematologic, gastrointestinal, cardiovascular, or hepatic toxicity. In arm A, patients with ‡20% of bone marrow previously irradiated received a reduced dose of carboplatin (AUC 5.0). In arms B and C, patients received prophylactic dexamethasone 20 mg orally 12 and 6 h before paclitaxel infusion, diphenhydramine 50 mg i.v. (or equivalent) £1 h before paclitaxel infusion, and cimetidine 300 mg i.v. (or equivalent; ranitidine 50 mg or famotidine 20 mg) £1 h before paclitaxel infusion. Patients who developed brain metastases as the only evidence of progressive disease (PD) were able to be treated with whole-brain radiation and corticosteroids for brain metastases and remain on study. Chemotherapy was resumed 2 weeks after the completion of brain irradiation. However, if the patient’s condition did not recover to an ECOG performance status of zero or one or the patient failed to meet other entry criteria after radiation therapy, the patient was removed from the study. No other chemotherapy, immunotherapy, antitumor hormonal therapy (excluding contraceptives and replacement steroids), or experimental medication was permitted while the patient was on the study and appropriate supportive care was provided. Granulocyte colony-stimulating factors (G-CSF) were only allowed if there was persistent neutropenia despite dose reductions in the previous course. If G-CSF were used, it was in accordance with American Society of Clinical Oncology (ASCO) guidelines [36].
patient selection Patients with a histologically confirmed diagnosis of stage IIIB (with pleural or pericardial effusion), stage IV, or recurrent NSCLC were enrolled in this study [37]. Mixed tumors were categorized by the predominant cell type unless small-cell anaplastic elements were present, in which case the patient was ineligible. All patients were required to be ‡18 years of age and have measurable or evaluable disease (according to ECOG solid tumor criteria); an ECOG performance status of zero or one; and adequate bone marrow reserve (neutrophils >1500/mm3, platelets >100 000/mm3), adequate hepatic function [aspartate transaminase £5· institutional upper limit of normal (ULN) and serum bilirubin £1.5 mg/dl· institutional ULN], and adequate renal function (creatinine clearance ‡40 ml/min or serum creatinine £1.5 mg/dl). Stage IV patients with brain metastases were eligible provided the brain metastases were, in the opinion of the site investigator, clinically stable after treatment with surgery or radiation therapy. No previous irradiation to the only area of measurable or evaluable disease was allowed, unless that site had subsequent progression of disease documented by physical examination, radiograph, or pathology. Patients receiving prior chemotherapy for this diagnosis were excluded from participation. Pregnant or breast-feeding women were not eligible, and all women of childbearing potential and sexually active men were required to use an approved method of birth control. Patients with a known or suspected hypersensitivity to agents that utilize polyoxyethylated castor oil were excluded from participation. This study was reviewed and approved by an ethical review board at each participating institution, and it was conducted in accordance with the precepts established by the Declaration of Helsinki. Patients who were eligible for participation provided written informed consent consistent with
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original article all applicable governing regulations before undergoing any study procedure or receiving any study drug.
statistical analysis The primary end point of this trial was OS. Secondary end points included RRs, time to progression (TTP), and tolerability as assessed by adverse event reporting. Three pairwise comparisons of OS (GC versus GP, GC versus PC, and GP versus PC) were done with a modified Bonferroni adjustment to control for multiplicity [38]. All tests were two sided [39]. To ensure an overall significance level of 0.05, the nominal significance level was set at one-sided 0.0083 for all three adjusted log-rank test comparisons (an one-sided 2.5% significance level is equivalent to a two-sided test at the 5% significance level). To detect a 33.3% increase in median survival between two arms with 83% power, 1080 patients (360 patients per arm) accrued in a 24-month period with 12 months of additional follow-up were required. Assuming a patient drop-out rate of 5%, sample size for the study was set at 1134 patients. Survival and TTP were assessed using the intention-to-treat (ITT) population and calculated from the date of randomization to the date of death or documented progression. Survival and TTP curves were constructed using the Kaplan–Meier product limit method [40]. Standard ECOG criteria were used for response evaluation [41]. Complete clinical response was defined as the radiographic disappearance of all known disease, determined by two observations not less than 4 weeks apart. Tumor measurement occurred at baseline, before each chemotherapy cycle, and every 3 months during the follow-up period. Partial response (PR) was defined as a ‡50% decrease in bidimensional measurements of the target lesions confirmed by two observations ‡4 weeks apart. In addition, there had to be no appearance of new lesions or progression of any lesion. PD was ‡25% increase in the bidimensional measurements of at least one measurable lesion or the appearance of new lesions. RRs were calculated by summing the number of patients with complete responses (CRs) and PRs, and clinical benefit rates were calculated by summing the number of patients with CRs, PRs, and stable disease (SD). Safety of the treatment regimens was assessed by calculating the percentage of patients experiencing grade 3 or 4 toxic effects using National Cancer Institute (NCI) Common Toxicity Criteria version 2.0 [42]. Only patients receiving at least one dose of treatment were included in the safety population. Additional analyses of patient subgroups and quality-of-life outcomes using the Functional Assessment of Cancer Therapy-Lung tool were planned [43].
Annals of Oncology
results Figure 2 summarizes patient disposition in the trial. From July 2000 to November 2005, 1135 patients were screened for eligibility/entry and were randomly assigned to one of the three treatments: GC (N = 379), GP (N = 377), or PC (N = 379), at 80 investigative centers. Of these 1135 patients, 58 (5.1%) did not receive any study therapy; thus, 1077 patients are included in the safety analysis population.
patient characteristics As shown in Table 1, patient characteristics for the ITT population at baseline were well balanced across the three treatment groups. The median age of patients in the ITT population was 64.3 years. Most patients in all arms were male and had an ECOG performance status of one. Within the ITT population, 17.1% had brain metastases and 12.2% were African-American. Ninety percent of patients in all treatment groups had stage IV or recurrent disease, and 17.8% of patients in all treatment groups had squamous histology. dose administration The number of treatment cycles administered did not vary by treatment group. The median number of cycles administered was 4 in all three treatment groups, and the mean number of cycles administered for GC, GP, and PC was 3.9, 3.8, and 3.7, respectively. The percentage of patients receiving a maximum six cycles of therapy was 36.5%, 35.2%, and 30.6% for GC, GP, and PC, respectively. Median relative dose intensity was 82.9% for gemcitabine and 94.6% for carboplatin in the GC arm, 94.9% for gemcitabine and 99.1% for paclitaxel in the GP arm, and 98.2% for paclitaxel and 95.2% for carboplatin in the PC arm. The percentage of patients receiving dose adjustments by treatment was 75.8% for gemcitabine and 62.1% for carboplatin in the GC group, 47.6% for gemcitabine and 31.3% for paclitaxel in the GP group, 32.2% for paclitaxel and 33.9% for carboplatin in the PC group. During therapy,
Figure 2. Patient disposition.
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Table 1. Patient characteristics Characteristic Age (years) Median Range Gender, n (%) Male Female Histology Squamous Nonsquamous Performance status, n (%) 0 1 2 Brain metastases, n (%) Weight loss, n (%) < 5% ‡5% Race or ethnic group, n (%) White Black Other Disease stage, n (%) IIIB with effusion IV or recurrent disease
GC (N = 379) GP (N = 377) PC (N = 379) 64.1 37–89
64.3 33–91
64.1 39–85
221 (58.3) 158 (41.7)
236 (62.6) 141 (37.4)
231 (60.9) 148 (39.1)
67 (17.7) 312 (82.3)
74 (19.6) 303 (80.4)
61 (16.1) 318 (83.9)
124 253 1 66
159 215 2 64
144 231 1 64
(32.7) (66.8) (0.3) (17.4)
(42.2) (57.0) (0.5) (17.0)
(38.0) (60.9) (0.3) (16.9)
236 (62.3) 143 (37.7)
236 (62.6) 141 (37.4)
238 (62.8) 141 (37.2)
326 (86.0) 47 (12.4) 6 (1.6)
329 (87.3) 42 (11.1) 6 (1.6)
317 (83.6) 49 (12.9) 12 (3.2)
38 (10.0) 341 (90.0)
38 (10.1) 339 (89.9)
40 (10.6) 339 (89.4)
GC, gemcitabine + carboplatin; N, number of patients; GP, gemcitabine + paclitaxel; PC, paclitaxel + carboplatin; n, number in group.
the rates of discontinuation due to excessive complication or toxicity were 12.4% for GC, 14.1% for GP, and 15.3% for PC. The rates of death without evidence of PD were 4.2% for GC, 4.5% for GP, and 4.2% for PC.
efficacy Primary efficacy outcomes by treatment group are summarized in Table 2. Length of median follow-up was 8.2 months, and censorship was low for OS (8.9%) and TTP (7.1%) variables. Curves for OS and TTP are summarized in Figure 3. Median survival was 7.9 months for GC [95% confidence interval (CI) 7.1–9.2], 8.5 months for GP (95% CI 7.6–10.0), and 8.7 months for PC (95% CI 7.7–9.9). P values for comparisons between individual treatment groups indicated that differences were not statistically significant (GC versus GP, 0.585; GP versus PC, 0.404; and GP versus PC, 0.849), and the P value for the overall comparison was 0.693. Survival rates at 1 year ranged from 33.9% for GC to 36.2% for GP. Survival rates at 2 years ranged from 11.5% for GC to 13.9% for GP. Survival rates at 3 years ranged from 5.0% for GP to 7.3% for PC. Median TTP (months) for GC, GP, and PC, respectively, was 4.3 (95% CI 4.1–5.1), 4.5 (95% CI 4.0–5.4), and 4.7 (95% CI 4.2–5.5). Differences across treatment arms in TTP were not statistically significant. Overall RRs (CRs + PRs) were 25.3% for GC, 32.1% for GP, and 29.8% for PC. Although GC was associated with the smallest RR among the treatment groups, it was also associated with an SD rate of 39.3%, which was 8% greater than that of
Table 2. Analysis of efficacy parameters Variable Objective response, n (%) CR PR SD Progressive disease Unknown/not done Response rate (CR + PR), n (%) (95% CI) Clinical benefit rate (CR + PR + SD), n (%) (95% CI) OS Failed, n Censored, n (%) Median, months (95% CI) 1 year, % (95% CI) 2 year, % (95% CI) 3 year, % (95% CI) TTP Failed, n Censored, n (%) Median TTP, months, (95% CI)
GC (N = 379)
GP (N = 377)
PC (N = 379)
3 93 149 73 61 96
6 115 114 69 73 121
4 109 121 87 58 113
(0.8) (24.5) (39.3) (19.3) (16.1) (25.3) (21.0–30.0)
(1.6) (30.5) (30.2) (18.3) (19.4) (32.1) (27.4–37.1)
(1.1) (28.8) (31.9) (23.0) (15.3) (29.8) (25.3–34.7)
245 (64.6) (59.6–69.5)
235 (62.3) (57.2–67.2)
234 (61.7) (56.6–66.7)
351 28 7.9 33.9 11.5 6.0
341 36 8.5 36.2 13.9 5.0
342 37 8.7 35.6 13.3 7.3
(7.4) (7.1–9.2) (29.1–38.7) (8.1–14.9) (3.4–8.7)
356 23 (6.1) 4.3 (4.1–5.1)
(9.5) (7.6–10.0) (31.3–41.1) (10.2–17.5) (2.4–7.6)
348 29 (7.7) 4.5 (4.0–5.4)
(9.8) (7.7–9.9) (30.7–40.4) (9.7–16.9) (4.4–10.2)
350 29 (7.7) 4.7 (4.2–5.5)
GC, gemcitabine + carboplatin; N, number of patients; GP, gemcitabine + paclitaxel; PC, paclitaxel + carboplatin; n, number in group; CR, complete response; PR, partial response; CI, confidence interval; SD, stable disease; OS, overall survival; TTP, time to progression.
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Figure 3. Kaplan–Meier estimates of overall survival (A) and time to progression of disease (B). GC, gemcitabine + carboplatin; GP, gemcitabine + paclitaxel; PC, paclitaxel + carboplatin.
the other two groups. As a result, the clinical benefit rates of all treatment arms were similar and exceeded 60%.
neuropathy was 2.0% for GC, compared with 6.5% for GP and 10.9% for PC.
toxicity Grade 3 and 4 hematologic and non-hematologic events are summarized in Table 3. The frequency of grade 3 and 4 hematologic events was greater for GC compared with the other two treatment arms. The grade 3 or 4 neutropenia rate was 39.0% for GC and 34.7% for PC, compared with 20.0% for GP. The grade 3 thrombocytopenia rate was 49.7% for GC compared with 4.8% for GP and 10.9% for PC. The grade 4 thrombocytopenia rate was 14.9% for GC, compared with 0% for GP and 1.9% for PC. The grade 3 or 4 anemia rate was 23.3% for GC, compared with 4.2% for GP and 6.0% for PC. The GC arm was associated with less grade 2 alopecia compared with the other two treatment groups (13.5% with GC compared with 52.7% each in the other two groups). The incidence of grade 3 or 4 sensory
additional analyses The large numbers of patients accrued in this study allowed for statistical analyses of outcomes by specific patient subgroups. These analyses were previously presented as abstracts at the 2007 ASCO Annual Meeting. Notably, OS, RRs, and TTP did not differ among patients stratified by age (>70 or <70 years) [44] or by race [45].
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discussion This prospective, randomized trial, which represents the largest study to date using carboplatin and non-platinum-based doublets, indicates that all three regimens produced similar efficacy in terms of OS, RR, and TTP. Results from this study are largely consistent with other trials comparing doublet
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Table 3. Toxicity according to treatment group (safety population) Type of toxicity Hematologic events, n (%) Neutropenia Febrile neutropenia Thrombocytopenia Platelet transfusion Anemia Red blood cell transfusion Transfusion Non-hematologic events, n (%) Hemorrhage Infection Nausea Vomiting Diarrhea Sensory neuropathy Arthralgia (grade 3 or 4) Alopecia (grade 2) Any nervous system disorder (grade 1–4)
GC (N = 356) Grade 3 89 8 177 27 80 3 31
(25.0) (2.2) (49.7) (7.6) (22.5) (0.8) (8.7)
8 8 23 14 5 6 1 48 153
(2.2) (2.2) (6.5) (3.9) (1.4) (1.7) (0.3) (13.5) (43.0)
Grade 4 50 (14.0) 2 (0.6) 53 (14.9) 3 (0.8)
1 1 0 0 1 1
(0.3) (0.3) (0.0) (0.0) (0.3) (0.3)
GP (N = 355) Grade 3 Grade 4
PC (N = 366) Grade 3 Grade 4
P value for overall comparison
40 11 17 1 15 2 5
(11.3) (3.1) (4.8) (0.3) (4.2) (0.6) (1.4)
49 9 40 1 22 0 9
(13.4) (2.5) (10.9) (0.3) (6.0) (0.0) (2.5)
<0.001 0.697 <0.001 <0.001 <0.001 0.213 <0.001
0 8 19 15 10 22 15 187 239
(0.0) (2.3) (5.4) (4.2) (2.8) (6.2) (4.2) (52.7) (67.3)
0 6 23 13 9 38 7 193 252
(0.0) (1.6) (6.3) (3.6) (2.5) (10.4) (1.9) (52.7) (68.9)
31 (8.7) 3 (0.8) 0 (0.0) 0 (0.0)
0 2 0 0 0 1
(0.0) (0.6) (0.0) (0.0) (0.0) (0.3)
78 (21.3) 2 (0.5) 7 (1.9) 0 (0.0)
0 2 1 1 0 2
(0.0) (0.5) (0.3) (0.3) (0.0) (0.5)
<0.001 0.831 0.757 0.961 0.609 <0.001 0.001 <0.001 <0.001
GC, gemcitabine + carboplatin; N, number of patients; GP, gemcitabine + paclitaxel; PC, paclitaxel + carboplatin; n, number in group.
therapies [9, 11, 12, 15] and with ASCO guidelines, which indicate that decisions with respect to chemotherapy choice in the first-line setting should be made largely on the basis of the toxicity profile and convenience of the drugs [46]. In one phase III trial (N = 512) reported by Kosmidis et al., median survival was 9.97 for GP and 10.49 for GC, which was not statistically different between groups. The two arms had toxicity profiles that were consistent with results from the current study [9]. In a second phase III trial of platinum and non-platinum doublets (N = 441), gemcitabine–docetaxel and gemcitabine–cisplatin had similar activity and OS; however, the non-platinum doublet had a more favorable toxicity profile [47]. It should also be noted that recent meta-analyses have indicated higher response [48] and survival rates [48–50] with third-generation regimens using cisplatin versus carboplatin in patients with advanced disease. Differences that emerged in this trial were related to the toxicity profiles of the treatment regimens studied. The reference arm (PC) demonstrated more neurotoxicity and alopecia, while the GC arm was associated with greater myelosuppression and reduced median dose intensity. The carboplatin dose used in the GC arm was higher than in more recent trials and this is reflected in the myelosuppressive profile. An analysis of 1126 patients receiving first-line GC in randomized trials (including the current study) found that patients receiving carboplatin at AUC 5 experience approximately one-half the incidence of grade 4 neutropenia and thrombocytopenia compared with patients receiving carboplatin at AUC 5.5, without compromising clinical activity [51]. It is noted that even with the higher dose of carboplatin as used in this trial, there were no differences in the rates of bleeding, which were very low in all three arms. The fatal toxicity rate was also very low across all
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three arms and consistent with modern doublets in the phase III setting. While the non-platinum doublet provided similar efficacy outcomes to the platinum-containing arms, the toxicity profile of this particular non-platinum doublet offered no clear advantages. However, other non-platinum doublets containing different agents may offer advantages in terms of toxicity. The role of non-platinum doublets is likely to increase with emerging treatment strategies, particularly in genomically selected therapy, such as the recent development and acceptance of trial designs with molecular markers that predict for platinum resistance [52–54]. As molecular profile data increase, variations in the efficacy and toxicity of commonly used agents will increase and likely lead to more selected therapy. While future trials are likely to look at genomic concerns, many trials have reported on more general factors, such as age and ethnicity. The percentage of African-Americans enrolled in this trial compares favorably to historical rates of accrual to lung cancer trials sponsored by the NCI [55]. A separate report from this trial will follow that will look at detailed outcomes in this generally underrepresented population. The use of PC as the reference arm for this study was supported by the results of ECOG 5592, which showed that paclitaxel + cisplatin was superior to etoposide + cisplatin [17] and several subsequent phase III trials that established the use of PC in advanced or metastatic NSCLC [11, 56–58]. Compared with ECOG 5592, the survival results in all three arms in the current study surpassed the 7.6-month median survival of the etoposide + cisplatin arm, but were less than the 9.9-month median survival of the 250 mg/m2 PC arm [17]. Importantly, ECOG 5592 excluded patients with brain metastases, and <80% of patients receiving paclitaxel in ECOG
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original article 5592 had stage IV disease compared with 90% of patients in the current study. An unexpected observation was the relatively high incidence of brain metastases (17.1% overall) seen in this trial. A limited number of randomized phase III studies of advanced or metastatic NSCLC have included a mixed population of patients with and without brain metastases at presentation. Analyses of patients with lung cancer from the 1970s and 1980s indicated that the incidence of brain metastases at the time of diagnosis was 10% [59, 60]. The higher incidence observed in this trial may be related to the increasing incidence of adenocarcinoma, which is more prone to presentation with brain involvement at time of diagnosis [61]. It is also possible that the increased incidence of BM observed in this trial may have been related to the exclusion of these patients in other first-line trials. None the less, with the increasing sensitivity of imaging modalities and the potential for excluding a current therapeutic choice in advancedstage NSCLC, the management of patients with brain metastases may be an issue of growing importance. Doublet chemotherapy will remain foundational for the treatment of advanced or metastatic NSCLC. Numerous combination regimens have been evaluated for this disease in the setting of large phase III trials. This randomized study reiterates that cytotoxic doublets are approximately equal in terms of their relative efficacy and that, while the regimens do not differ in the rate of death due to treatment-related events, the regimens do have unique toxicity profiles. Differences in these toxicity profiles should continue to be the primary consideration when selecting treatment in advanced or metastatic NSCLC. Identifying the least toxic regimen and defining the role of non-platinum doublets, particularly in molecular selection strategies, will continue as important issues as new treatment approaches emerge.
funding Eli Lilly and Company.
acknowledgements Previous publication: this original report has neither been previously published nor is it under consideration for publication elsewhere. Preliminary results were presented at the 2005 ASCO Annual Meeting. Study identification numbers—Alpha Oncology: A1-99002L; NCI, PDQ: CDR0000270434; ClinicalTrials.gov: NCT00054392.
disclosure Conflicts of interest statement: coauthors of this paper disclose the following—JAT, CKO: employment with Eli Lilly; MAS: honoraria and research funding with Eli Lilly; MJE: consultant, honoraria, and research funding with Eli Lilly; and CPB: consultant with Eli Lilly.
references 1. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2007. CA Cancer J Clin 2007; 57: 43–66. 2. Shepherd FA. Screening, diagnosis, and staging of lung cancer. Curr Opin Oncol 1993; 5: 310–322.
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3. Walling J. Chemotherapy for advanced non-small-cell lung cancer. Respir Med 1994; 88: 649–657. 4. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311: 899–909. 5. Grilli R, Oxman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer: how much benefit is enough? J Clin Oncol 1993; 11: 1866–1872. 6. Marino P, Pampallona S, Preatoni A et al. Chemotherapy vs supportive care in advanced non-small-cell lung cancer. Results of a meta-analysis of the literature. Chest 1994; 106: 861–865. 7. Souquet PJ, Chauvin F, Boissel JP et al. Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 1993; 342: 19–21. 8. Kosmidis P, Mylonakis N, Nicolaides C et al. Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol 2002; 20: 3578–3585. 9. Kosmidis PA, Kalofonos HP, Christodoulou C et al. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol 2008; 19: 115–122. 10. Scagliotti GV, De Marinis F, Rinaldi M et al. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 2002; 20: 4285–4291. 11. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–98. 12. Rajeswaran A, Trojan A, Burnand B, Giannelli M. Efficacy and side effects of cisplatin- and carboplatin-based doublet chemotherapeutic regimens versus non-platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: a systematic review of randomized controlled trials. Lung Cancer 2008; 59: 1–11. 13. D’Addario G, Pintilie M, Leighl NB et al. Platinum-based versus non-platinumbased chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 2005; 23: 2926–2936. 14. Gatzemeier U, Heckmayer M, Neuhauss R et al. Chemotherapy of advanced inoperable non-small cell lung cancer with paclitaxel: a phase II trial. Semin Oncol 1995; 22: 24–28. 15. Murphy WK, Fossella FV, Winn RJ et al. Phase II study of taxol in patients with untreated advanced non-small-cell lung cancer. J Natl Cancer Inst 1993; 85: 384–388. 16. Rowinsky EK, Donehower RC. Taxol: twenty years later, the story unfolds. J Natl Cancer Inst 1991; 83: 1778–1781. 17. Bonomi P, Kim K, Fairclough D et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000; 18: 623–631. 18. Klastersky J, Sculier JP, Lacroix H et al. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer Protocol 07861. J Clin Oncol 1990; 8: 1556–1562. 19. Rowinsky EK, Chaudhry V, Forastiere AA et al. Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: neuromuscular toxicity is dose-limiting. J Clin Oncol 1993; 11: 2010–2020. 20. Abratt RP, Bezwoda WR, Falkson G et al. Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: a phase II study. J Clin Oncol 1994; 12: 1535–1540. 21. Anderson H, Lund B, Bach F et al. Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1994; 12: 1821–1826. 22. Gatzemeier U, Shepherd FA, Le Chevalier T et al. Activity of gemcitabine in patients with non-small cell lung cancer: a multicentre, extended phase II study. Eur J Cancer 1996; 32A: 243–248. 23. Shepherd FA, Abratt R, Crino L et al. The influence of gemcitabine and cisplatin schedule on response and survival in advanced non-small cell lung cancer. Lung Cancer 2000; 30: 117–125.
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24. Abratt RP, Bezwoda WR, Goedhals L, Hacking DJ. Weekly gemcitabine with monthly cisplatin: effective chemotherapy for advanced non-small-cell lung cancer. J Clin Oncol 1997; 15: 744–749. 25. Crino L, Scagliotti G, Marangolo M et al. Cisplatin-gemcitabine combination in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1997; 15: 297–303. 26. Green M, Eisenberg P, Kosty M et al. Activity and tolerability of gemcitabine plus weekly cisplatin in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 1998; 17: 468 (Abstr). 27. Kroep JR, Giaccone G, Voorn DA et al. Gemcitabine and paclitaxel: pharmacokinetic and pharmacodynamic interactions in patients with non-smallcell lung cancer. J Clin Oncol 1999; 17: 2190–2197. 28. Bhatia S, Hanna N, Ansari R et al. A phase II study of weekly gemcitabine and paclitaxel in patients with previously untreated stage IIIb and IV non-small cell lung cancer. Lung Cancer 2002; 38: 73–77. 29. Einhorn L, Raghavan D, Kindler H et al. A phase I trial of gemcitabine plus paclitaxel combination therapy in patients with refractory solid tumors. Proc Am Soc Clin Oncol 1998; 17: 796 (Abstr). 30. Giaccone G, Smit EF, Laan D et al. Phase I/II study of paclitaxel and gemcitabine in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 1998; 17: (Abstr 1869). 31. Rothenberg ML, Sharma A, Weiss GR et al. Phase I trial of paclitaxel and gemcitabine administered every two weeks in patients with refractory solid tumors. Ann Oncol 1998; 9: 733–738. 32. Domine M, Casado V, Esteves L. Phase II study of carboplatin (C)-gemcitabine (G) in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2000; 19: (Abstr 2107). 33. Mott FE, Cable CT, Sharma N. Phase II study of an alternate carboplatin and gemcitabine dosing schedule in advanced non-small-cell lung cancer. Clin Lung Cancer 2003; 5: 174–176. 34. Obasaju CK, Ye Z, Bloss LP et al. Gemcitabine/carboplatin in patients with metastatic non-small-cell lung cancer: phase II study of 28-day and 21-day schedules. Clin Lung Cancer 2005; 7: 202–207. 35. Calvert AH, Newell DR, Gumbrell LA et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7: 1748–1756. 36. American Society of Clinical Oncology. Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based clinical practice guidelines. J Clin Oncol 1996; 14: 1957–1960. 37. Fleming I, Cooper J, Henson D. AJCC Cancer Staging Manual. Philadelphia, PA: Lippincott-Raven 1997. 38. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988; 75: 800–802. 39. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979; 35: 549–556. 40. Kaplan E, Meier P. Nonparametric estimation of incomplete observations. J Am Stat Assoc 1958; 53: 457–481. 41. Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649–655. 42. Cancer Therapy Evaluation Program. NCI Common Toxicity Criteria Version 2.0. 1999. 43. Cella DF, Bonomi AE, Lloyd SR et al. Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Lung Cancer 1995; 12: 199–220. 44. Ansari R, Goning R, Socinski MA et al. Elderly subgroup analysis of a randomized phase 3 trial of gemcitabine (G) in combination with carboplatin (Cb) or paclitaxel (P) compared to paclitaxel plus carboplatin in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC). J Clin Oncol 2007; 25 (Suppl 18): 2007 ASCO Annual Meeting Proceedings Part I(Abstr 7665).
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original article 45. Treat J, Goning R, Edelman M et al. Subgroup analysis of African American patients from a randomized phase 3 trial of gemcitabine (G) in combination with carboplatin (Cb) or paclitaxel (P) compared to P plus Cb in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC). J Clin Oncol 2007; 25 (Suppl 18): 2007 ASCO Annual Meeting Proceedings Part I (Abstr 7665). 46. Pfister DG, Johnson DH, Azzoli CG et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 2004; 22: 330–353. 47. Georgoulias V, Papadakis E, Alexopoulos A et al. Platinum-based and nonplatinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet 2001; 357: 1478–1484. 48. Ardizzoni A, Tiseo M, Boni L et al. CISCA (cisplatin vs. carboplatin) meta-analysis: an individual patient data meta-analysis comparing cisplatin versus carboplatinbased chemotherapy in first-line treatment of advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2006; 24(18S): 2006 ASCO Annual Meeting Proceedings Part I(Abstr 7011). 49. Hotta K, Matsuo K, Ueoka H et al. Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 2004; 22: 3852–3859. 50. Zojwalla N, Raftopoulos H, Gralla R. Are cisplatin and carboplatin equivalent in the treatment of non-small cell lung carcinoma (NSCLC)? Results of a comprehensive review of randomized studies in over 2300 patients. J Clin Oncol 2004; 22(14S): 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition)(Abstr 7068). 51. Treat J, Belani C, Schiller J et al. Gemcitabine (G) plus carboplatin (C) at AUC 5 demonstrates reduced grade 4 thrombocytopenia rate compared to AUC 5.5 in first line therapy of patients with advanced stage NSCLC. J Clin Oncol 2006; 24 (18 Suppl): 2006 ASCO Annual Meeting Proceedings Part I(Abstr 7130). 52. Azuma K, Komohara Y, Sasada T et al. Excision repair cross-complementation group 1 predicts progression-free and overall survival in non-small cell lung cancer patients treated with platinum-based chemotherapy. Cancer Sci 2007; 98: 1336–1343. 53. Cobo M, Isla D, Massuti B et al. Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in nonsmall-cell lung cancer. J Clin Oncol 2007; 25: 2747–2754. 54. Simon G, Sharma A, Li X et al. Feasibility and efficacy of molecular analysisdirected individualized therapy in advanced non-small-cell lung cancer. J Clin Oncol 2007; 25: 2741–2746. 55. Tejeda HA, Green SB, Trimble EL et al. Representation of African-Americans, Hispanics, and whites in National Cancer Institute cancer treatment trials. J Natl Cancer Inst 1996; 88: 812–816. 56. Belani CP, Lee JS, Socinski MA et al. Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer. Ann Oncol 2005; 16: 1069–1075. 57. Kelly K, Crowley J, Bunn PA Jr et al. 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. J Clin Oncol 2001; 19: 3210–3218. 58. Lilenbaum RC, Herndon JE II, List MA et al. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol 2005; 23: 190–196. 59. Newman SJ, Hansen HH. Proceedings: frequency, diagnosis, and treatment of brain metastases in 247 consecutive patients with bronchogenic carcinoma. Cancer 1974; 33: 492–496. 60. Sorensen JB, Hansen HH, Hansen M, Dombernowsky P. Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol 1988; 6: 1474–1480. 61. Shi AA, Digumarthy SR, Temel JS et al. Does initial staging or tumor histology better identify asymptomatic brain metastases in patients with non-small cell lung cancer? J Thorac Oncol 2006; 1: 205–210.
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Annals of Oncology 21: 540–547, 2010 doi:10.1093/annonc/mdp352 Published online 15 October 2009
A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer J. A. Treat1*, R. Gonin2, M. A. Socinski3, M. J. Edelman4, R. B. Catalano5, D. M. Marinucci5, R. Ansari6, H. H. Gillenwater7, K. M. Rowland8, R. L. Comis5, C. K. Obasaju1 & C. P. Belani9 for the Alpha Oncology Research Network 1
US Medical Division, Lilly USA, Indianapolis, IN; 2Westat, Rockville, MD; 3Division of Hematology/Oncology, Multidisciplinary Thoracic Oncology Group, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; 4Division of Hematology/Oncology, University of Maryland Greenbaum Cancer Center, Baltimore, MD; 5Drexel University College of Medicine, Philadelphia, PA; 6Northern Indiana Cancer Research Consortium, South Bend, IN; 7Department of Hematology/ Oncology, University of Virginia Cancer Center, Charlottesville, VA; 8Department of Medicine, Carle Clinic Cancer Center, Urbana, IL and 9Division of Hematology/ Oncology, Penn State Hershey Cancer Institute, Hershey, PA, USA
Received 2 September 2008; revised 5 June 2009; accepted 10 June 2009
original article
Background: Paclitaxel–carboplatin is used as the standard regimen for patients with advanced or metastatic nonsmall-cell lung cancer (NSCLC). This trial was designed to compare gemcitabine + carboplatin or gemcitabine + paclitaxel to the standard regimen. Patients and methods: A total of 1135 chemonaive patients with stage IIIB or IV NSCLC were randomly allocated to receive gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin area under the concentration–time curve (AUC) 5.5 on day 1 (GC), gemcitabine 1000 mg/m2 on days 1 and 8 plus paclitaxel 200 mg/m2 on day 1 (GP), or paclitaxel 225 mg/m2 plus carboplatin AUC 6.0 on day 1 (PC). Stratification was based on disease stage, baseline weight loss, and presence or absence of brain metastases. Cycles were repeated every 21 days for up to six cycles or disease progression. Results: Median survival (months) with GC was 7.9 compared with 8.5 for GP and 8.7 for PC. Response rates (RRs) were as follows: GC, 25.3%; GP, 32.1%; and PC, 29.8%. The GC arm was associated with a greater incidence of grade 3 or 4 hematologic events but a lower rate of neurotoxicity and alopecia when compared with GP and PC. Conclusions: Non-platinum and non-paclitaxel gemcitabine-containing doublets demonstrate similar overall survival and RR compared with the standard PC regimen. However, the treatment arms had distinct toxicity profiles. Key words: carboplatin, gemcitabine, non-platinum doublets, NSCLC, paclitaxel, phase III
introduction The annual burden of non-small-cell lung cancer (NSCLC) was estimated in 2007 at 181 000 new cases and 136 000 deaths in the United States [1]. At the time of diagnosis, most patients (>80%) have locally advanced stage III or metastatic stage IV disease and are ineligible for potentially curative surgery; and 5year survival is <10% in this patient population [2, 3]. Palliative chemotherapy has become the standard therapy for patients with advanced NSCLC, with platinum-based doublets producing a modest survival benefit and improvement in quality of life compared with best supportive care alone [4–7].
*Correspondence to: Dr J. A. Treat, US Medical Division, Lilly USA, Drop Code 6831, Indianapolis, IN 46285, USA. Tel: +1-317-433-6078; Fax: +1-317-277-3533; E-mail: [email protected]
Several large randomized trials that have compared commonly prescribed platinum doublets did not support any specific regimen as the evidenced-based practice standard for NSCLC [8–11]. Studies indicate non-platinum doublets can also provide benefits similar to platinum doublets [12, 13]. Paclitaxel produces single-agent response rates (RRs) between 20% and 42%, with 1-year survival rates of 40% in advanced NSCLC [14–16]. Eastern Cooperative Oncology Group (ECOG) 5592 formed the basis for paclitaxel + cisplatin use in advanced NSCLC by demonstrating a median survival of 9.9 months in association with this combination (at two dose levels of paclitaxel) compared with 7.6 months with etoposide + cisplatin [17]. Concerns over cisplatin-related neurotoxicity led to the eventual replacement of cisplatin with carboplatin within platinum-based treatment regimens [18, 19].
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Annals of Oncology
As a single agent in advanced NSCLC, gemcitabine has produced RRs between 20% and 28% and survival between 7 and 11 months [20–23]. In combination with gemcitabine, platinum combination regimens have resulted in RRs between 28% and 54% and 1-year survival rates between 35% and 61%, with manageable toxicity [24–26]. Gemcitabine and paclitaxel have shown single-agent activity in advanced NSCLC, lack overlapping toxic effects, and have different mechanisms of action [27]. Trials of the combination of gemcitabine and paclitaxel have resulted in RRs between 27% and 47%, with manageable toxicity [28–31]. Several phase II studies have tested the combination of gemcitabine + carboplatin, demonstrating levels of activity similar to other combinations [32–34]. Given the similarity of response of gemcitabine + paclitaxel to most platinum-containing regimens, the toxicity profile could determine the choice of first-line regimen for future evaluation of chemotherapeutic approaches for advanced or metastatic NSCLC. Therefore, a prospective, randomized comparison of overall survival (OS), efficacy, and toxicity was conducted to determine the role of non-platinum- and nonpaclitaxel-containing regimens in the treatment of NSCLC. In this phase III study, paclitaxel + carboplatin (PC) was chosen as the reference regimen for comparison with either gemcitabine + carboplatin (GC) or gemcitabine + paclitaxel (GP), with the goal of identifying the regimen associated with the best therapeutic index.
patients and methods study design Patients with stage IIIB (with pleural or pericardial effusion), stage IV, or recurrent NSCLC who met all eligibility criteria were randomly allocated to receive one of the three treatment regimens as summarized in Figure 1. Patient stratification by baseline weight loss (<5% versus ‡5% in previous 6 months), stage of disease (IIIB with effusion versus IV), and brain metastasis (presence versus absence) took place at the time of randomization to ensure balance across treatment arms with respect to these characteristics. Patients were randomly allocated to receive one of the three platinum or non-platinum regimens in equal proportions as follows—arm A: gemcitabine 1000 mg/m2 infused over 30 min on days 1
Figure 1. Treatment schema. *Carboplatin dose decreased to AUC 5.0 in all patients with ‡20% of bone marrow previously irradiated (arm A only). AUC, under the concentration–time curve.
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and 8 plus carboplatin AUC 5.5 over 15–30 min on day 1 (GC); arm B: gemcitabine 1000 mg/m2 infused over 30 min on days 1 and 8 plus paclitaxel 200 mg/m2 infused over 3 h on day 1 (GP); or arm C: paclitaxel 225 mg/m2 infused over 3 h on day 1 plus carboplatin AUC 6.0 over 15–30 min on day 1 (PC). Treatment cycles for all three treatment arms were repeated every 21 days for six cycles or until unacceptable toxicity or disease progression. Carboplatin dosing was based on the formula described by Calvert et al. [35]. Guidelines for dose adjustments were provided for chemotherapy-related hematologic, gastrointestinal, cardiovascular, or hepatic toxicity. In arm A, patients with ‡20% of bone marrow previously irradiated received a reduced dose of carboplatin (AUC 5.0). In arms B and C, patients received prophylactic dexamethasone 20 mg orally 12 and 6 h before paclitaxel infusion, diphenhydramine 50 mg i.v. (or equivalent) £1 h before paclitaxel infusion, and cimetidine 300 mg i.v. (or equivalent; ranitidine 50 mg or famotidine 20 mg) £1 h before paclitaxel infusion. Patients who developed brain metastases as the only evidence of progressive disease (PD) were able to be treated with whole-brain radiation and corticosteroids for brain metastases and remain on study. Chemotherapy was resumed 2 weeks after the completion of brain irradiation. However, if the patient’s condition did not recover to an ECOG performance status of zero or one or the patient failed to meet other entry criteria after radiation therapy, the patient was removed from the study. No other chemotherapy, immunotherapy, antitumor hormonal therapy (excluding contraceptives and replacement steroids), or experimental medication was permitted while the patient was on the study and appropriate supportive care was provided. Granulocyte colony-stimulating factors (G-CSF) were only allowed if there was persistent neutropenia despite dose reductions in the previous course. If G-CSF were used, it was in accordance with American Society of Clinical Oncology (ASCO) guidelines [36].
patient selection Patients with a histologically confirmed diagnosis of stage IIIB (with pleural or pericardial effusion), stage IV, or recurrent NSCLC were enrolled in this study [37]. Mixed tumors were categorized by the predominant cell type unless small-cell anaplastic elements were present, in which case the patient was ineligible. All patients were required to be ‡18 years of age and have measurable or evaluable disease (according to ECOG solid tumor criteria); an ECOG performance status of zero or one; and adequate bone marrow reserve (neutrophils >1500/mm3, platelets >100 000/mm3), adequate hepatic function [aspartate transaminase £5· institutional upper limit of normal (ULN) and serum bilirubin £1.5 mg/dl· institutional ULN], and adequate renal function (creatinine clearance ‡40 ml/min or serum creatinine £1.5 mg/dl). Stage IV patients with brain metastases were eligible provided the brain metastases were, in the opinion of the site investigator, clinically stable after treatment with surgery or radiation therapy. No previous irradiation to the only area of measurable or evaluable disease was allowed, unless that site had subsequent progression of disease documented by physical examination, radiograph, or pathology. Patients receiving prior chemotherapy for this diagnosis were excluded from participation. Pregnant or breast-feeding women were not eligible, and all women of childbearing potential and sexually active men were required to use an approved method of birth control. Patients with a known or suspected hypersensitivity to agents that utilize polyoxyethylated castor oil were excluded from participation. This study was reviewed and approved by an ethical review board at each participating institution, and it was conducted in accordance with the precepts established by the Declaration of Helsinki. Patients who were eligible for participation provided written informed consent consistent with
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original article all applicable governing regulations before undergoing any study procedure or receiving any study drug.
statistical analysis The primary end point of this trial was OS. Secondary end points included RRs, time to progression (TTP), and tolerability as assessed by adverse event reporting. Three pairwise comparisons of OS (GC versus GP, GC versus PC, and GP versus PC) were done with a modified Bonferroni adjustment to control for multiplicity [38]. All tests were two sided [39]. To ensure an overall significance level of 0.05, the nominal significance level was set at one-sided 0.0083 for all three adjusted log-rank test comparisons (an one-sided 2.5% significance level is equivalent to a two-sided test at the 5% significance level). To detect a 33.3% increase in median survival between two arms with 83% power, 1080 patients (360 patients per arm) accrued in a 24-month period with 12 months of additional follow-up were required. Assuming a patient drop-out rate of 5%, sample size for the study was set at 1134 patients. Survival and TTP were assessed using the intention-to-treat (ITT) population and calculated from the date of randomization to the date of death or documented progression. Survival and TTP curves were constructed using the Kaplan–Meier product limit method [40]. Standard ECOG criteria were used for response evaluation [41]. Complete clinical response was defined as the radiographic disappearance of all known disease, determined by two observations not less than 4 weeks apart. Tumor measurement occurred at baseline, before each chemotherapy cycle, and every 3 months during the follow-up period. Partial response (PR) was defined as a ‡50% decrease in bidimensional measurements of the target lesions confirmed by two observations ‡4 weeks apart. In addition, there had to be no appearance of new lesions or progression of any lesion. PD was ‡25% increase in the bidimensional measurements of at least one measurable lesion or the appearance of new lesions. RRs were calculated by summing the number of patients with complete responses (CRs) and PRs, and clinical benefit rates were calculated by summing the number of patients with CRs, PRs, and stable disease (SD). Safety of the treatment regimens was assessed by calculating the percentage of patients experiencing grade 3 or 4 toxic effects using National Cancer Institute (NCI) Common Toxicity Criteria version 2.0 [42]. Only patients receiving at least one dose of treatment were included in the safety population. Additional analyses of patient subgroups and quality-of-life outcomes using the Functional Assessment of Cancer Therapy-Lung tool were planned [43].
Annals of Oncology
results Figure 2 summarizes patient disposition in the trial. From July 2000 to November 2005, 1135 patients were screened for eligibility/entry and were randomly assigned to one of the three treatments: GC (N = 379), GP (N = 377), or PC (N = 379), at 80 investigative centers. Of these 1135 patients, 58 (5.1%) did not receive any study therapy; thus, 1077 patients are included in the safety analysis population.
patient characteristics As shown in Table 1, patient characteristics for the ITT population at baseline were well balanced across the three treatment groups. The median age of patients in the ITT population was 64.3 years. Most patients in all arms were male and had an ECOG performance status of one. Within the ITT population, 17.1% had brain metastases and 12.2% were African-American. Ninety percent of patients in all treatment groups had stage IV or recurrent disease, and 17.8% of patients in all treatment groups had squamous histology. dose administration The number of treatment cycles administered did not vary by treatment group. The median number of cycles administered was 4 in all three treatment groups, and the mean number of cycles administered for GC, GP, and PC was 3.9, 3.8, and 3.7, respectively. The percentage of patients receiving a maximum six cycles of therapy was 36.5%, 35.2%, and 30.6% for GC, GP, and PC, respectively. Median relative dose intensity was 82.9% for gemcitabine and 94.6% for carboplatin in the GC arm, 94.9% for gemcitabine and 99.1% for paclitaxel in the GP arm, and 98.2% for paclitaxel and 95.2% for carboplatin in the PC arm. The percentage of patients receiving dose adjustments by treatment was 75.8% for gemcitabine and 62.1% for carboplatin in the GC group, 47.6% for gemcitabine and 31.3% for paclitaxel in the GP group, 32.2% for paclitaxel and 33.9% for carboplatin in the PC group. During therapy,
Figure 2. Patient disposition.
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Table 1. Patient characteristics Characteristic Age (years) Median Range Gender, n (%) Male Female Histology Squamous Nonsquamous Performance status, n (%) 0 1 2 Brain metastases, n (%) Weight loss, n (%) < 5% ‡5% Race or ethnic group, n (%) White Black Other Disease stage, n (%) IIIB with effusion IV or recurrent disease
GC (N = 379) GP (N = 377) PC (N = 379) 64.1 37–89
64.3 33–91
64.1 39–85
221 (58.3) 158 (41.7)
236 (62.6) 141 (37.4)
231 (60.9) 148 (39.1)
67 (17.7) 312 (82.3)
74 (19.6) 303 (80.4)
61 (16.1) 318 (83.9)
124 253 1 66
159 215 2 64
144 231 1 64
(32.7) (66.8) (0.3) (17.4)
(42.2) (57.0) (0.5) (17.0)
(38.0) (60.9) (0.3) (16.9)
236 (62.3) 143 (37.7)
236 (62.6) 141 (37.4)
238 (62.8) 141 (37.2)
326 (86.0) 47 (12.4) 6 (1.6)
329 (87.3) 42 (11.1) 6 (1.6)
317 (83.6) 49 (12.9) 12 (3.2)
38 (10.0) 341 (90.0)
38 (10.1) 339 (89.9)
40 (10.6) 339 (89.4)
GC, gemcitabine + carboplatin; N, number of patients; GP, gemcitabine + paclitaxel; PC, paclitaxel + carboplatin; n, number in group.
the rates of discontinuation due to excessive complication or toxicity were 12.4% for GC, 14.1% for GP, and 15.3% for PC. The rates of death without evidence of PD were 4.2% for GC, 4.5% for GP, and 4.2% for PC.
efficacy Primary efficacy outcomes by treatment group are summarized in Table 2. Length of median follow-up was 8.2 months, and censorship was low for OS (8.9%) and TTP (7.1%) variables. Curves for OS and TTP are summarized in Figure 3. Median survival was 7.9 months for GC [95% confidence interval (CI) 7.1–9.2], 8.5 months for GP (95% CI 7.6–10.0), and 8.7 months for PC (95% CI 7.7–9.9). P values for comparisons between individual treatment groups indicated that differences were not statistically significant (GC versus GP, 0.585; GP versus PC, 0.404; and GP versus PC, 0.849), and the P value for the overall comparison was 0.693. Survival rates at 1 year ranged from 33.9% for GC to 36.2% for GP. Survival rates at 2 years ranged from 11.5% for GC to 13.9% for GP. Survival rates at 3 years ranged from 5.0% for GP to 7.3% for PC. Median TTP (months) for GC, GP, and PC, respectively, was 4.3 (95% CI 4.1–5.1), 4.5 (95% CI 4.0–5.4), and 4.7 (95% CI 4.2–5.5). Differences across treatment arms in TTP were not statistically significant. Overall RRs (CRs + PRs) were 25.3% for GC, 32.1% for GP, and 29.8% for PC. Although GC was associated with the smallest RR among the treatment groups, it was also associated with an SD rate of 39.3%, which was 8% greater than that of
Table 2. Analysis of efficacy parameters Variable Objective response, n (%) CR PR SD Progressive disease Unknown/not done Response rate (CR + PR), n (%) (95% CI) Clinical benefit rate (CR + PR + SD), n (%) (95% CI) OS Failed, n Censored, n (%) Median, months (95% CI) 1 year, % (95% CI) 2 year, % (95% CI) 3 year, % (95% CI) TTP Failed, n Censored, n (%) Median TTP, months, (95% CI)
GC (N = 379)
GP (N = 377)
PC (N = 379)
3 93 149 73 61 96
6 115 114 69 73 121
4 109 121 87 58 113
(0.8) (24.5) (39.3) (19.3) (16.1) (25.3) (21.0–30.0)
(1.6) (30.5) (30.2) (18.3) (19.4) (32.1) (27.4–37.1)
(1.1) (28.8) (31.9) (23.0) (15.3) (29.8) (25.3–34.7)
245 (64.6) (59.6–69.5)
235 (62.3) (57.2–67.2)
234 (61.7) (56.6–66.7)
351 28 7.9 33.9 11.5 6.0
341 36 8.5 36.2 13.9 5.0
342 37 8.7 35.6 13.3 7.3
(7.4) (7.1–9.2) (29.1–38.7) (8.1–14.9) (3.4–8.7)
356 23 (6.1) 4.3 (4.1–5.1)
(9.5) (7.6–10.0) (31.3–41.1) (10.2–17.5) (2.4–7.6)
348 29 (7.7) 4.5 (4.0–5.4)
(9.8) (7.7–9.9) (30.7–40.4) (9.7–16.9) (4.4–10.2)
350 29 (7.7) 4.7 (4.2–5.5)
GC, gemcitabine + carboplatin; N, number of patients; GP, gemcitabine + paclitaxel; PC, paclitaxel + carboplatin; n, number in group; CR, complete response; PR, partial response; CI, confidence interval; SD, stable disease; OS, overall survival; TTP, time to progression.
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Figure 3. Kaplan–Meier estimates of overall survival (A) and time to progression of disease (B). GC, gemcitabine + carboplatin; GP, gemcitabine + paclitaxel; PC, paclitaxel + carboplatin.
the other two groups. As a result, the clinical benefit rates of all treatment arms were similar and exceeded 60%.
neuropathy was 2.0% for GC, compared with 6.5% for GP and 10.9% for PC.
toxicity Grade 3 and 4 hematologic and non-hematologic events are summarized in Table 3. The frequency of grade 3 and 4 hematologic events was greater for GC compared with the other two treatment arms. The grade 3 or 4 neutropenia rate was 39.0% for GC and 34.7% for PC, compared with 20.0% for GP. The grade 3 thrombocytopenia rate was 49.7% for GC compared with 4.8% for GP and 10.9% for PC. The grade 4 thrombocytopenia rate was 14.9% for GC, compared with 0% for GP and 1.9% for PC. The grade 3 or 4 anemia rate was 23.3% for GC, compared with 4.2% for GP and 6.0% for PC. The GC arm was associated with less grade 2 alopecia compared with the other two treatment groups (13.5% with GC compared with 52.7% each in the other two groups). The incidence of grade 3 or 4 sensory
additional analyses The large numbers of patients accrued in this study allowed for statistical analyses of outcomes by specific patient subgroups. These analyses were previously presented as abstracts at the 2007 ASCO Annual Meeting. Notably, OS, RRs, and TTP did not differ among patients stratified by age (>70 or <70 years) [44] or by race [45].
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discussion This prospective, randomized trial, which represents the largest study to date using carboplatin and non-platinum-based doublets, indicates that all three regimens produced similar efficacy in terms of OS, RR, and TTP. Results from this study are largely consistent with other trials comparing doublet
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Table 3. Toxicity according to treatment group (safety population) Type of toxicity Hematologic events, n (%) Neutropenia Febrile neutropenia Thrombocytopenia Platelet transfusion Anemia Red blood cell transfusion Transfusion Non-hematologic events, n (%) Hemorrhage Infection Nausea Vomiting Diarrhea Sensory neuropathy Arthralgia (grade 3 or 4) Alopecia (grade 2) Any nervous system disorder (grade 1–4)
GC (N = 356) Grade 3 89 8 177 27 80 3 31
(25.0) (2.2) (49.7) (7.6) (22.5) (0.8) (8.7)
8 8 23 14 5 6 1 48 153
(2.2) (2.2) (6.5) (3.9) (1.4) (1.7) (0.3) (13.5) (43.0)
Grade 4 50 (14.0) 2 (0.6) 53 (14.9) 3 (0.8)
1 1 0 0 1 1
(0.3) (0.3) (0.0) (0.0) (0.3) (0.3)
GP (N = 355) Grade 3 Grade 4
PC (N = 366) Grade 3 Grade 4
P value for overall comparison
40 11 17 1 15 2 5
(11.3) (3.1) (4.8) (0.3) (4.2) (0.6) (1.4)
49 9 40 1 22 0 9
(13.4) (2.5) (10.9) (0.3) (6.0) (0.0) (2.5)
<0.001 0.697 <0.001 <0.001 <0.001 0.213 <0.001
0 8 19 15 10 22 15 187 239
(0.0) (2.3) (5.4) (4.2) (2.8) (6.2) (4.2) (52.7) (67.3)
0 6 23 13 9 38 7 193 252
(0.0) (1.6) (6.3) (3.6) (2.5) (10.4) (1.9) (52.7) (68.9)
31 (8.7) 3 (0.8) 0 (0.0) 0 (0.0)
0 2 0 0 0 1
(0.0) (0.6) (0.0) (0.0) (0.0) (0.3)
78 (21.3) 2 (0.5) 7 (1.9) 0 (0.0)
0 2 1 1 0 2
(0.0) (0.5) (0.3) (0.3) (0.0) (0.5)
<0.001 0.831 0.757 0.961 0.609 <0.001 0.001 <0.001 <0.001
GC, gemcitabine + carboplatin; N, number of patients; GP, gemcitabine + paclitaxel; PC, paclitaxel + carboplatin; n, number in group.
therapies [9, 11, 12, 15] and with ASCO guidelines, which indicate that decisions with respect to chemotherapy choice in the first-line setting should be made largely on the basis of the toxicity profile and convenience of the drugs [46]. In one phase III trial (N = 512) reported by Kosmidis et al., median survival was 9.97 for GP and 10.49 for GC, which was not statistically different between groups. The two arms had toxicity profiles that were consistent with results from the current study [9]. In a second phase III trial of platinum and non-platinum doublets (N = 441), gemcitabine–docetaxel and gemcitabine–cisplatin had similar activity and OS; however, the non-platinum doublet had a more favorable toxicity profile [47]. It should also be noted that recent meta-analyses have indicated higher response [48] and survival rates [48–50] with third-generation regimens using cisplatin versus carboplatin in patients with advanced disease. Differences that emerged in this trial were related to the toxicity profiles of the treatment regimens studied. The reference arm (PC) demonstrated more neurotoxicity and alopecia, while the GC arm was associated with greater myelosuppression and reduced median dose intensity. The carboplatin dose used in the GC arm was higher than in more recent trials and this is reflected in the myelosuppressive profile. An analysis of 1126 patients receiving first-line GC in randomized trials (including the current study) found that patients receiving carboplatin at AUC 5 experience approximately one-half the incidence of grade 4 neutropenia and thrombocytopenia compared with patients receiving carboplatin at AUC 5.5, without compromising clinical activity [51]. It is noted that even with the higher dose of carboplatin as used in this trial, there were no differences in the rates of bleeding, which were very low in all three arms. The fatal toxicity rate was also very low across all
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three arms and consistent with modern doublets in the phase III setting. While the non-platinum doublet provided similar efficacy outcomes to the platinum-containing arms, the toxicity profile of this particular non-platinum doublet offered no clear advantages. However, other non-platinum doublets containing different agents may offer advantages in terms of toxicity. The role of non-platinum doublets is likely to increase with emerging treatment strategies, particularly in genomically selected therapy, such as the recent development and acceptance of trial designs with molecular markers that predict for platinum resistance [52–54]. As molecular profile data increase, variations in the efficacy and toxicity of commonly used agents will increase and likely lead to more selected therapy. While future trials are likely to look at genomic concerns, many trials have reported on more general factors, such as age and ethnicity. The percentage of African-Americans enrolled in this trial compares favorably to historical rates of accrual to lung cancer trials sponsored by the NCI [55]. A separate report from this trial will follow that will look at detailed outcomes in this generally underrepresented population. The use of PC as the reference arm for this study was supported by the results of ECOG 5592, which showed that paclitaxel + cisplatin was superior to etoposide + cisplatin [17] and several subsequent phase III trials that established the use of PC in advanced or metastatic NSCLC [11, 56–58]. Compared with ECOG 5592, the survival results in all three arms in the current study surpassed the 7.6-month median survival of the etoposide + cisplatin arm, but were less than the 9.9-month median survival of the 250 mg/m2 PC arm [17]. Importantly, ECOG 5592 excluded patients with brain metastases, and <80% of patients receiving paclitaxel in ECOG
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original article 5592 had stage IV disease compared with 90% of patients in the current study. An unexpected observation was the relatively high incidence of brain metastases (17.1% overall) seen in this trial. A limited number of randomized phase III studies of advanced or metastatic NSCLC have included a mixed population of patients with and without brain metastases at presentation. Analyses of patients with lung cancer from the 1970s and 1980s indicated that the incidence of brain metastases at the time of diagnosis was 10% [59, 60]. The higher incidence observed in this trial may be related to the increasing incidence of adenocarcinoma, which is more prone to presentation with brain involvement at time of diagnosis [61]. It is also possible that the increased incidence of BM observed in this trial may have been related to the exclusion of these patients in other first-line trials. None the less, with the increasing sensitivity of imaging modalities and the potential for excluding a current therapeutic choice in advancedstage NSCLC, the management of patients with brain metastases may be an issue of growing importance. Doublet chemotherapy will remain foundational for the treatment of advanced or metastatic NSCLC. Numerous combination regimens have been evaluated for this disease in the setting of large phase III trials. This randomized study reiterates that cytotoxic doublets are approximately equal in terms of their relative efficacy and that, while the regimens do not differ in the rate of death due to treatment-related events, the regimens do have unique toxicity profiles. Differences in these toxicity profiles should continue to be the primary consideration when selecting treatment in advanced or metastatic NSCLC. Identifying the least toxic regimen and defining the role of non-platinum doublets, particularly in molecular selection strategies, will continue as important issues as new treatment approaches emerge.
funding Eli Lilly and Company.
acknowledgements Previous publication: this original report has neither been previously published nor is it under consideration for publication elsewhere. Preliminary results were presented at the 2005 ASCO Annual Meeting. Study identification numbers—Alpha Oncology: A1-99002L; NCI, PDQ: CDR0000270434; ClinicalTrials.gov: NCT00054392.
disclosure Conflicts of interest statement: coauthors of this paper disclose the following—JAT, CKO: employment with Eli Lilly; MAS: honoraria and research funding with Eli Lilly; MJE: consultant, honoraria, and research funding with Eli Lilly; and CPB: consultant with Eli Lilly.
references 1. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2007. CA Cancer J Clin 2007; 57: 43–66. 2. Shepherd FA. Screening, diagnosis, and staging of lung cancer. Curr Opin Oncol 1993; 5: 310–322.
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3. Walling J. Chemotherapy for advanced non-small-cell lung cancer. Respir Med 1994; 88: 649–657. 4. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311: 899–909. 5. Grilli R, Oxman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer: how much benefit is enough? J Clin Oncol 1993; 11: 1866–1872. 6. Marino P, Pampallona S, Preatoni A et al. Chemotherapy vs supportive care in advanced non-small-cell lung cancer. Results of a meta-analysis of the literature. Chest 1994; 106: 861–865. 7. Souquet PJ, Chauvin F, Boissel JP et al. Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 1993; 342: 19–21. 8. Kosmidis P, Mylonakis N, Nicolaides C et al. Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol 2002; 20: 3578–3585. 9. Kosmidis PA, Kalofonos HP, Christodoulou C et al. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol 2008; 19: 115–122. 10. Scagliotti GV, De Marinis F, Rinaldi M et al. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 2002; 20: 4285–4291. 11. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–98. 12. Rajeswaran A, Trojan A, Burnand B, Giannelli M. Efficacy and side effects of cisplatin- and carboplatin-based doublet chemotherapeutic regimens versus non-platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: a systematic review of randomized controlled trials. Lung Cancer 2008; 59: 1–11. 13. D’Addario G, Pintilie M, Leighl NB et al. Platinum-based versus non-platinumbased chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 2005; 23: 2926–2936. 14. Gatzemeier U, Heckmayer M, Neuhauss R et al. Chemotherapy of advanced inoperable non-small cell lung cancer with paclitaxel: a phase II trial. Semin Oncol 1995; 22: 24–28. 15. Murphy WK, Fossella FV, Winn RJ et al. Phase II study of taxol in patients with untreated advanced non-small-cell lung cancer. J Natl Cancer Inst 1993; 85: 384–388. 16. Rowinsky EK, Donehower RC. Taxol: twenty years later, the story unfolds. J Natl Cancer Inst 1991; 83: 1778–1781. 17. Bonomi P, Kim K, Fairclough D et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000; 18: 623–631. 18. Klastersky J, Sculier JP, Lacroix H et al. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer Protocol 07861. J Clin Oncol 1990; 8: 1556–1562. 19. Rowinsky EK, Chaudhry V, Forastiere AA et al. Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: neuromuscular toxicity is dose-limiting. J Clin Oncol 1993; 11: 2010–2020. 20. Abratt RP, Bezwoda WR, Falkson G et al. Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: a phase II study. J Clin Oncol 1994; 12: 1535–1540. 21. Anderson H, Lund B, Bach F et al. Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1994; 12: 1821–1826. 22. Gatzemeier U, Shepherd FA, Le Chevalier T et al. Activity of gemcitabine in patients with non-small cell lung cancer: a multicentre, extended phase II study. Eur J Cancer 1996; 32A: 243–248. 23. Shepherd FA, Abratt R, Crino L et al. The influence of gemcitabine and cisplatin schedule on response and survival in advanced non-small cell lung cancer. Lung Cancer 2000; 30: 117–125.
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Annals of Oncology
24. Abratt RP, Bezwoda WR, Goedhals L, Hacking DJ. Weekly gemcitabine with monthly cisplatin: effective chemotherapy for advanced non-small-cell lung cancer. J Clin Oncol 1997; 15: 744–749. 25. Crino L, Scagliotti G, Marangolo M et al. Cisplatin-gemcitabine combination in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1997; 15: 297–303. 26. Green M, Eisenberg P, Kosty M et al. Activity and tolerability of gemcitabine plus weekly cisplatin in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 1998; 17: 468 (Abstr). 27. Kroep JR, Giaccone G, Voorn DA et al. Gemcitabine and paclitaxel: pharmacokinetic and pharmacodynamic interactions in patients with non-smallcell lung cancer. J Clin Oncol 1999; 17: 2190–2197. 28. Bhatia S, Hanna N, Ansari R et al. A phase II study of weekly gemcitabine and paclitaxel in patients with previously untreated stage IIIb and IV non-small cell lung cancer. Lung Cancer 2002; 38: 73–77. 29. Einhorn L, Raghavan D, Kindler H et al. A phase I trial of gemcitabine plus paclitaxel combination therapy in patients with refractory solid tumors. Proc Am Soc Clin Oncol 1998; 17: 796 (Abstr). 30. Giaccone G, Smit EF, Laan D et al. Phase I/II study of paclitaxel and gemcitabine in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 1998; 17: (Abstr 1869). 31. Rothenberg ML, Sharma A, Weiss GR et al. Phase I trial of paclitaxel and gemcitabine administered every two weeks in patients with refractory solid tumors. Ann Oncol 1998; 9: 733–738. 32. Domine M, Casado V, Esteves L. Phase II study of carboplatin (C)-gemcitabine (G) in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2000; 19: (Abstr 2107). 33. Mott FE, Cable CT, Sharma N. Phase II study of an alternate carboplatin and gemcitabine dosing schedule in advanced non-small-cell lung cancer. Clin Lung Cancer 2003; 5: 174–176. 34. Obasaju CK, Ye Z, Bloss LP et al. Gemcitabine/carboplatin in patients with metastatic non-small-cell lung cancer: phase II study of 28-day and 21-day schedules. Clin Lung Cancer 2005; 7: 202–207. 35. Calvert AH, Newell DR, Gumbrell LA et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7: 1748–1756. 36. American Society of Clinical Oncology. Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based clinical practice guidelines. J Clin Oncol 1996; 14: 1957–1960. 37. Fleming I, Cooper J, Henson D. AJCC Cancer Staging Manual. Philadelphia, PA: Lippincott-Raven 1997. 38. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988; 75: 800–802. 39. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979; 35: 549–556. 40. Kaplan E, Meier P. Nonparametric estimation of incomplete observations. J Am Stat Assoc 1958; 53: 457–481. 41. Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649–655. 42. Cancer Therapy Evaluation Program. NCI Common Toxicity Criteria Version 2.0. 1999. 43. Cella DF, Bonomi AE, Lloyd SR et al. Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Lung Cancer 1995; 12: 199–220. 44. Ansari R, Goning R, Socinski MA et al. Elderly subgroup analysis of a randomized phase 3 trial of gemcitabine (G) in combination with carboplatin (Cb) or paclitaxel (P) compared to paclitaxel plus carboplatin in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC). J Clin Oncol 2007; 25 (Suppl 18): 2007 ASCO Annual Meeting Proceedings Part I(Abstr 7665).
Volume 21 | No. 3 | March 2010
original article 45. Treat J, Goning R, Edelman M et al. Subgroup analysis of African American patients from a randomized phase 3 trial of gemcitabine (G) in combination with carboplatin (Cb) or paclitaxel (P) compared to P plus Cb in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC). J Clin Oncol 2007; 25 (Suppl 18): 2007 ASCO Annual Meeting Proceedings Part I (Abstr 7665). 46. Pfister DG, Johnson DH, Azzoli CG et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 2004; 22: 330–353. 47. Georgoulias V, Papadakis E, Alexopoulos A et al. Platinum-based and nonplatinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet 2001; 357: 1478–1484. 48. Ardizzoni A, Tiseo M, Boni L et al. CISCA (cisplatin vs. carboplatin) meta-analysis: an individual patient data meta-analysis comparing cisplatin versus carboplatinbased chemotherapy in first-line treatment of advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2006; 24(18S): 2006 ASCO Annual Meeting Proceedings Part I(Abstr 7011). 49. Hotta K, Matsuo K, Ueoka H et al. Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 2004; 22: 3852–3859. 50. Zojwalla N, Raftopoulos H, Gralla R. Are cisplatin and carboplatin equivalent in the treatment of non-small cell lung carcinoma (NSCLC)? Results of a comprehensive review of randomized studies in over 2300 patients. J Clin Oncol 2004; 22(14S): 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition)(Abstr 7068). 51. Treat J, Belani C, Schiller J et al. Gemcitabine (G) plus carboplatin (C) at AUC 5 demonstrates reduced grade 4 thrombocytopenia rate compared to AUC 5.5 in first line therapy of patients with advanced stage NSCLC. J Clin Oncol 2006; 24 (18 Suppl): 2006 ASCO Annual Meeting Proceedings Part I(Abstr 7130). 52. Azuma K, Komohara Y, Sasada T et al. Excision repair cross-complementation group 1 predicts progression-free and overall survival in non-small cell lung cancer patients treated with platinum-based chemotherapy. Cancer Sci 2007; 98: 1336–1343. 53. Cobo M, Isla D, Massuti B et al. Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in nonsmall-cell lung cancer. J Clin Oncol 2007; 25: 2747–2754. 54. Simon G, Sharma A, Li X et al. Feasibility and efficacy of molecular analysisdirected individualized therapy in advanced non-small-cell lung cancer. J Clin Oncol 2007; 25: 2741–2746. 55. Tejeda HA, Green SB, Trimble EL et al. Representation of African-Americans, Hispanics, and whites in National Cancer Institute cancer treatment trials. J Natl Cancer Inst 1996; 88: 812–816. 56. Belani CP, Lee JS, Socinski MA et al. Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer. Ann Oncol 2005; 16: 1069–1075. 57. Kelly K, Crowley J, Bunn PA Jr et al. 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. J Clin Oncol 2001; 19: 3210–3218. 58. Lilenbaum RC, Herndon JE II, List MA et al. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol 2005; 23: 190–196. 59. Newman SJ, Hansen HH. Proceedings: frequency, diagnosis, and treatment of brain metastases in 247 consecutive patients with bronchogenic carcinoma. Cancer 1974; 33: 492–496. 60. Sorensen JB, Hansen HH, Hansen M, Dombernowsky P. Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol 1988; 6: 1474–1480. 61. Shi AA, Digumarthy SR, Temel JS et al. Does initial staging or tumor histology better identify asymptomatic brain metastases in patients with non-small cell lung cancer? J Thorac Oncol 2006; 1: 205–210.
doi:10.1093/annonc/mdp352 | 547