OPTIONS & TOOLS
DOI: 10.1200/JCO.2007.15.0375 Journal of Clinical Oncology - published online before print September 21, 2016
Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non–Small-Cell Lung Cancer
Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting.
This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles.
Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.
In advanced-stage (stage IIIB or IV) non–small-cell lung cancer (NSCLC), doublet combinations of platinum compounds (cisplatin or carboplatin) with gemcitabine, vinorelbine, or taxanes (paclitaxel or docetaxel) are reference regimens.1 When compared head-to-head in phase III studies, these doublets have shown comparable efficacy, with differences in toxicity profiles.2-5 Cisplatin plus gemcitabine, in a 3-week schedule, is an effective widely used regimen for first-line treatment of NSCLC.3,6
Pemetrexed is a potent inhibitor of thymidylate synthase7,8 and other folate-dependent enzymes, including dihydrofolate reductase and glycinamide ribonucleotide formyl transferase.9 Pemetrexed is currently approved in combination with cisplatin for first-line treatment of malignant pleural mesothelioma10 and as a single agent for second-line treatment of advanced NSCLC.11
In phase II studies in chemotherapy-naive patients with NSCLC, pemetrexed in combination with cisplatin or carboplatin has yielded efficacy results comparable with other platinum doublets.12-15 In addition, pemetrexed has an excellent safety profile and a convenient administration schedule.
More recently, the addition of bevacizumab, a monoclonal antibody against vascular endothelial growth factor, to paclitaxel and carboplatin led to a significant survival benefit; however, this efficacy benefit was seen with an increased risk of treatment-related deaths.16 In a confirmatory study, the addition of bevacizumab to cisplatin/gemcitabine led to a statistically significant improvement in progression-free survival (PFS).17 In both of these studies, safety issues that emerged from a previous phase II randomized study were considered,18 and consequently, restrictive eligibility criteria were adopted. The primary objective of this phase III noninferiority study was to compare the overall survival of cisplatin/pemetrexed with cisplatin/gemcitabine in chemotherapy-naive patients with advanced NSCLC.
Chemotherapy-naive patients with histologically or cytologically confirmed NSCLC, classified as stage IIIB not amenable to curative treatment or stage IV, with at least one unidimensionally measurable lesion according to the Response Evaluation Criteria in Solid Tumors,19 with an Eastern Cooperative Oncology Group performance status of 0 or 1,20 and at least 18 years of age were eligible. Patients had adequate bone marrow reserve and organ function including calculated creatinine clearance ≥ 45 mL/min based on the standard Cockcroft and Gault formula.21 Prior radiation therapy was permitted if it was completed at least 4 weeks before study treatment and patients had fully recovered from its acute effects.
Exclusion criteria included peripheral neuropathy ≥ National Cancer Institute Common Toxicity Criteria22 grade 1, progressive brain metastases, or uncontrolled third-space fluid retention before study entry. Patients were also excluded if they were unable to interrupt aspirin and other nonsteroidal anti-inflammatory drugs or if they were unable or unwilling to take folic acid, vitamin B12, or corticosteroids.
The protocol was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines23 and was approved by each participating institutional ethics review board. All patients signed written informed consent before treatment.
Eligible patients were randomly assigned to receive either cisplatin 75 mg/m2 on day 1 plus gemcitabine 1,250 mg/m2 on days 1 and 8 or cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 on day 1. Pocock and Simon24 random assignment was used according to disease stage (IIIB v IV), performance status (0 v 1), history of brain metastases (yes v no), sex (male v female), pathologic diagnosis (histologic v cytologic), and investigative center.
Chemotherapy was repeated every 3 weeks for a maximum of six cycles (unless there was earlier evidence of disease progression or intolerance of the study treatment). Patients on both arms received dexamethasone prophylaxis of 4 mg orally twice per day on the day before, the day of, and the day after each day-1 treatment. All patients received oral folic acid (350 to 1,000 μg) daily and a vitamin B12 injection (1,000 μg) every 9 weeks, beginning 1 to 2 weeks before the first dose and continuing until 3 weeks after the last dose of study treatment.
Patients requiring a day-1 dose reduction of pemetrexed, gemcitabine, or cisplatin received the reduced dose for the remainder of the study. Patients who had two dose reductions on day 1 and who experienced toxicity requiring a third dose reduction were discontinued from study therapy. Cycle delays of up to 42 days were permitted for recovery from adverse events. Within-cycle (day 8) dose reductions and omissions were allowed for gemcitabine. Concomitant supportive therapies, such as erythropoietic agents or granulocyte colony-stimulating factors, were allowed according to the American Society of Clinical Oncology guidelines.25
The study protocol requested, in a nonmandatory way, the collection of tumor samples for assessment of candidate biomarkers. Details about these data will be reported separately.
Before entering the study, patients underwent a medical history, physical examination, and tumor measurements of palpable lesions as well as lesions assessed by imaging techniques (positron emission tomography and ultrasound scans were not permitted). The baseline assessment method was repeated every other cycle and then every 6 weeks after treatment discontinuation until disease progression. Disease status was assessed according to Response Evaluation Criteria in Solid Tumors.19
Randomly assigned patients who met the eligibility criteria and who had baseline imaging and at least one scan after starting chemotherapy were considered assessable for tumor response and duration of response. All patients who received at least one dose of pemetrexed, gemcitabine, or cisplatin were considered assessable for safety. Patients were assessed for toxicity according to the National Cancer Institute Common Toxicity Criteria, version 2.0.22 Efficacy analyses, including the primary end point of overall survival, incorporated all randomly assigned patients on an intent-to-treat basis. Secondary end points included PFS, time to progressive disease, time to treatment failure, objective tumor response rate, duration of response, and toxicity.
Using a noninferiority design, this study compared overall survival between the two treatment arms using a fixed margin method. Assuming a hazard ratio (HR) of 1.0 and including all randomly assigned patients, when at least 1,190 deaths occurred, the analysis provided 80% power to reject the null hypothesis (H0). The H0 assumed that cisplatin/gemcitabine would provide a ≥ 15% reduction in the risk of death over cisplatin/pemetrexed, corresponding to a fixed margin of 1.176. Using the Cox proportional hazards model26 (with preplanned adjustments for sex, diagnosis [histologic v cytologic], disease stage, and performance status) and two-tailed 95% CIs for the HR, rejection of the H0 occurred when the upper bound of the HR's 95% CI was less than 1.176.
Cox proportional hazard models were also used to compare the other time-to-event end points between the treatment arms and to test for treatment-by-histology interaction; the Kaplan-Meier27 method was used to estimate the medians for time-to-event parameters. Tests were conducted as follows: noninferiority tests at one-sided α = .025 level; superiority tests at two-sided α = .05 level; and two-sided CIs at 95%. Tumor response was compared using the normal approximation test for superiority. The incidences of toxicities, hospitalizations, and supportive care were analyzed using Fisher's exact test and analysis of variance (as appropriate). Prespecified analyses of overall survival by random assignment factors included age group, race, smoking status, and histology. All HRs are reported as adjusted, unless otherwise specified. P values were not adjusted for multiple comparisons.
From July 2004 to December 2005, a total of 1,725 patients were randomly assigned (863 patients to cisplatin/gemcitabine and 862 patients to cisplatin/pemetrexed). The baseline patient and disease-related characteristics were well balanced between the two treatment arms (Table 1).
All 1,725 patients were evaluated for efficacy, whereas 1,669 patients (cisplatin/gemcitabine, n = 830, 96.2%; cisplatin/pemetrexed, n = 839, 97.3%) were eligible for the safety analyses (Fig 1). As of March 2007, 1,270 of 1,725 patients had died, 647 (75.0%) on the cisplatin/gemcitabine arm and 623 (72.3%) on the cisplatin/pemetrexed arm.
Table 2 indicates that a median number of five cycles was administered on both arms. Dose adjustments (delays, reductions, and omissions) were less frequent in patients treated with cisplatin/pemetrexed compared with cisplatin/gemcitabine, even when considering the more frequent gemcitabine dosing (days 1 and 8 for gemcitabine v only day 1 for pemetrexed). On day 1, cisplatin/pemetrexed dose reductions were much less frequent (cisplatin, n = 64; pemetrexed, n = 54 v cisplatin, n = 154; gemcitabine, n = 362) and were mainly caused by neutropenia, whereas cisplatin/gemcitabine dose reductions were most commonly attributable to neutropenia, thrombocytopenia, febrile neutropenia, and leukopenia. On day 8, 339 gemcitabine doses (9.3%) were omitted. Delivered dose-intensities were higher for cisplatin/pemetrexed (95.0% and 94.8%, respectively) than for cisplatin/gemcitabine (93.5% and 85.8%, respectively).
Overall survival for patients randomly assigned to cisplatin/pemetrexed was noninferior to the overall survival of patients assigned to cisplatin/gemcitabine (median overall survival, 10.3 v 10.3 months; HR = 0.94, 95% CI, 0.84 to 1.05), with the CIs for the HR well below the 1.176 noninferiority margin. Figure 2 shows the Kaplan-Meier curve for overall survival. Survival rates at 12 and 24 months were 43.5% and 18.9% for cisplatin/pemetrexed, respectively, and 41.9% and 14.0% for cisplatin/gemcitabine, respectively.
PFS was also noninferior (cisplatin/pemetrexed median PFS, 4.8 months; cisplatin/gemcitabine median PFS, 5.1 months; HR = 1.04; 95% CI, 0.94 to 1.15; Fig 2), as was time to progressive disease. Objective response rates were comparable for the two arms (cisplatin/pemetrexed = 30.6%; cisplatin/gemcitabine = 28.2%), whereas duration of response was longer for cisplatin/gemcitabine than cisplatin/pemetrexed (4.5 v 5.1 months), although neither comparison was statistically significant.
In a Cox adjusted analysis (similar to the primary analysis of survival) to which smoking status was added, current/former smokers had a significantly higher risk of death compared with never-smokers (HR = 1.74, test for superiority P < .001), even after controlling for treatment and the other four covariates. This effect of smoking status was also demonstrated in unadjusted analyses, in which the median survival time for never-smokers was 15.9 months compared with 10.0 months for former/current smokers on the cisplatin/pemetrexed arm and the median survival time for never-smokers was 15.3 months compared with 10.3 months for former/current smokers on the cisplatin/gemcitabine arm.
Figure 3 shows a plot of Cox adjusted survival HRs (with 95% CIs) for the preplanned analyses that evaluated differences in overall survival with respect to baseline characteristics. The effect on survival of cisplatin/pemetrexed relative to cisplatin/gemcitabine was significantly different according to nonsquamous (large-cell carcinoma plus adenocarcinoma) versus squamous histology. The treatment-by-histology interaction analysis (P = .0011) also showed that overall survival for patients with nonsquamous histology was significantly improved on the cisplatin/pemetrexed arm compared with the overall survival for all other patients with nonsquamous or squamous histology, thus confirming the analysis shown in Figure 3.
The analyses of overall survival by treatment arm for each of three histologic groups (large-cell carcinoma, adenocarcinoma, and squamous) demonstrated that cisplatin/pemetrexed in patients with adenocarcinoma and large-cell carcinoma resulted in significantly better survival than cisplatin/gemcitabine (adenocarcinoma: n = 847, 12.6 v 10.9 months, respectively; HR = 0.84; 95% CI, 0.71 to 0.99; P = .03; large-cell carcinoma: n = 153, 10.4 v 6.7 months, respectively; HR = 0.67; 95% CI, 0.48 to 0.96; P = .03; nonsquamous: n = 1,000, 11.8 v 10.4 months, respectively; HR = 0.81; 95% CI, 0.70 to 0.94; P = .005). Patients with squamous histology assigned to cisplatin/pemetrexed (n = 244) had a median survival time of 9.4 months, whereas patients assigned to cisplatin/gemcitabine (n = 229) had a median survival time of 10.8 months (HR = 1.23; 95% CI, 1.00 to 1.51; P = .05). Figure 2 shows the Kaplan-Meier overall survival by treatment arm for the nonsquamous and the squamous histologic groups. The overall survival for a fourth group, consisting of all those patients in whom a generic cytologic diagnosis of NSCLC without further subtype classification was made (n = 252), did not show a significant difference between the two arms; in this group, patients assigned to cisplatin/pemetrexed had a median survival time of 8.6 months compared with 9.2 months for patients assigned to cisplatin/gemcitabine (HR = 1.08; 95% CI, 0.81 to 1.45; P = .586). When analyzed according to other baseline and disease characteristics, survival was consistent with the overall study results (Table 3). Factors that had a statistically significant (P < .05) prognostic impact on survival (independent of treatment) included sex, race, performance status, disease stage, and histology.
Key hematologic grade 3 or 4 drug-related toxicities were significantly (P ≤ .001) lower for cisplatin/pemetrexed compared with cisplatin/gemcitabine (neutropenia, 15% v 27%; anemia, 6% v 10%, and thrombocytopenia, 4% v 13%, respectively). For cisplatin/pemetrexed versus cisplatin/gemcitabine, drug-related grade 3 or 4 febrile neutropenia (1% v 4%, respectively; P = .002) and alopecia (all grades; 12% v 21%, respectively; P < .001) were also significantly lower, whereas drug-related grade 3 or 4 nausea (7% v 4%, respectively; P = .004) was higher (Table 4). Safety within the histology groups was generally consistent with the overall safety results.
There were no statistically significant differences in hospital admissions or hospital days per patient observed between the study arms. Patients on the cisplatin/pemetrexed arm versus the cisplatin/gemcitabine arm received significantly fewer transfusions (16.4% v 28.9%, respectively; P < .001), including RBC transfusions (16.1% v 27.3%, respectively; P < .001) and platelet transfusions (1.8% v 4.5%, respectively; P = .002); the administration of erythropoietic (10.4% v 18.1%, respectively; P < .001) and granulocyte colony-stimulating factors (3.1% v 6.1%, respectively; P = .004) was significantly lower in favor of cisplatin/pemetrexed.
There was no significant difference (P = .387) between treatment arms in the incidence of or reason for the 116 deaths (7%) that occurred during study treatment. Each investigator categorized the deaths as caused by study disease, possibly caused by study drug, or as a result of other causes. Deaths attributed to study drug toxicity were low and were similar between arms (nine patients [1.0%] for cisplatin/pemetrexed, and six patients [0.7%] for cisplatin/gemcitabine).
Data regarding additional lines of therapy were prospectively collected; decisions regarding which therapies to use were made by the individual investigators. Overall, 56.1% of cisplatin/gemcitabine patients and 52.6% of cisplatin/pemetrexed patients received an additional line of therapy. The types of agents administered were well balanced on the two arms, with the exception of more frequent pemetrexed use on the cisplatin/gemcitabine arm (13.4% v 3.5% on the cisplatin/pemetrexed arm; P < .001) and more frequent gemcitabine use on the cisplatin/pemetrexed arm (16.7% v 8.6% on the cisplatin/gemcitabine arm; P < .001). Docetaxel was administered in 27.6% and 25.4% of patients and epidermal growth factor receptor tyrosine kinase inhibitors were administered in 22.5% and 24.9% of patients on the cisplatin/gemcitabine and cisplatin/pemetrexed arms, respectively. The distribution of postdiscontinuation therapies in each histologic group was similar to that of the overall study group.
In this randomized study, to our knowledge the largest ever conducted in the first-line setting of advanced NSCLC, cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine. Survival, as well as other efficacy outcomes (PFS, 1- and 2-year survival rates, and response rates), for cisplatin/pemetrexed compares favorably with recent, first-line, NSCLC randomized clinical trials evaluating other platinum doublets (median survival time ranging from 7.4 to 10.1 months).2-5 The modest improvement in survival observed on both arms of this study compared with previous studies of platinum-based regimens2-4 may have been influenced by several factors including improvements in NSCLC clinical staging, a relatively higher proportion of stage IIIB patients, or the exclusion of patients with a performance status of 2. In addition, enrollment onto this study reflects the relative increase in the proportion of adenocarcinoma,28 a favorable prognostic factor observed in the overall NSCLC population, which was confirmed in this study. The combination of cisplatin/pemetrexed demonstrated a better safety profile compared with cisplatin/gemcitabine as documented by fewer dose adjustments, lower incidences of drug-related grade 3 or 4 hematologic toxicities, and a significantly lower incidence of febrile neutropenia, even though patients on both arms received a similar number of treatment cycles. In addition, patients treated with cisplatin/gemcitabine required significantly more transfusions and supportive care interventions (ie, hematopoietic growth factor support) than did patients on the cisplatin/pemetrexed arm.
An intriguing aspect of this study occurred in the prespecified analyses for survival with respect to histology, in which a significant survival difference in favor of cisplatin/pemetrexed occurred in two histologic groups (adenocarcinoma, n = 847; and large-cell carcinoma, n = 153). For patients with adenocarcinoma randomly assigned to cisplatin/pemetrexed, survival was significantly better than for those assigned to cisplatin/gemcitabine (12.6 v 10.9 months, respectively; P = .03). One potential explanation may relate to thymidylate synthase expression levels in NSCLC histologic types. Preclinical data have indicated that overexpression of thymidylate synthase correlates with reduced sensitivity to pemetrexed.29,30 A recent study in chemotherapy-naive patients with adenocarcinoma or squamous cell carcinoma of the lung demonstrated that the baseline expression of the thymidylate synthase gene and protein were significantly higher in squamous cell carcinoma compared with adenocarcinoma (P < .0001).31 In addition, thymidylate synthase and S phase kinase–associated protein (Skp2) are transcriptionally regulated in the S phase of the cell cycle by the transcription factor E2F-1.32,33 Like thymidylate synthase, elevated expression of Skp2 has been more commonly found in patients with squamous cell carcinoma of the lung than in patients with adenocarcinoma.34
In a large, randomized, phase II trial of 441 patients that compared docetaxel/gemcitabine with docetaxel/cisplatin, no statistical difference in the efficacy outcomes was seen, but histology was the main predictive factor for response rate in each treatment group.35 In our study, significantly improved overall survival for cisplatin/pemetrexed compared with cisplatin/gemcitabine was also observed in patients with large-cell carcinoma histology (10.4 v 6.7 months, respectively; P = .03). To our knowledge, levels of thymidylate synthase expression in large-cell carcinoma of the lung have not been previously described. Despite the uncommon prevalence of this histologic type, further investigation of this association is warranted.
Although direct comparisons of efficacy across different randomized clinical studies may lead to biased conclusions as a result of differing patient populations, clinicians may consider cisplatin/pemetrexed to be an attractive alternative to bevacizumab-containing regimens (with either paclitaxel/carboplatin16 or gemcitabine/cisplatin17) for patients with nonsquamous tumors. The evaluation of treatment options for these patients must consider both the efficacy of these regimens and the different safety profiles of these combinations. Definitive answers to these relevant clinical questions will only come from controlled clinical trials.
In conclusion, cisplatin/pemetrexed provides similar efficacy to cisplatin/gemcitabine, with better tolerability, a reduced need for supportive therapies, and more convenient administration than cisplatin/gemcitabine, for first-line treatment of patients with advanced NSCLC. Furthermore, to our knowledge, this is the first phase III study in NSCLC to prospectively report survival differences between platinum doublets according to histology. These results are hypothesis generating and warrant a prospective study that is specifically designed to evaluate histology findings, which may potentially guide the selection of patients most likely to benefit from cisplatin/pemetrexed therapy. Lastly, it could be argued that the efficacy to date of cisplatin/pemetrexed in nonsquamous histology should allow it to be a preferred regimen for future studies testing molecular targeted therapies in nonsquamous histology.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Lorinda Simms, Eli Lilly & Co Canada (C); Katherine P. Sugarman, Eli Lilly & Co (C) Consultant or Advisory Role: Giorgio Vittorio Scagliotti, Eli Lilly & Co (C); Purvish Parikh, Eli Lilly & Co (C); Ulrich Gatzemeier, Roche (C), Eli Lilly & Co (C), AstraZeneca (C); Anders Mellemgaard, Sanofi-aventis (C); David Gandara, Bristol-Myers Squibb Co (C), Genentech (C), Sanofi-aventis (C), Bayer (C), Pfizer Inc (C); Johan Vansteenkiste, Eli Lilly & Co (C); Keunchil Park, Eli Lilly & Co (C); Christian Manegold, Eli Lilly & Co (C); Joachim von Pawel, Eli Lilly & Co (C), Roche (C) Stock Ownership: Lorinda Simms, Eli Lilly & Co; Katherine P. Sugarman, Eli Lilly & Co Honoraria: Giorgio Vittorio Scagliotti, Eli Lilly & Co, Roche, Sanofi-aventis; Purvish Parikh, Eli Lilly & Co; Christian Manegold, Eli Lilly & Co; Ulrich Gatzemeier, Pierre Fabre, Roche, Alphacell; Jin S. Lee, Eli Lilly & Co; Anders Mellemgaard, Sanofi-aventis, Eli Lilly & Co, Roche; Filippo de Marinis, Eli Lilly & Co; David Gandara, Eli Lilly & Co, Pfizer Inc; Keunchil Park, Eli Lilly & Co, Roche; Joachim von Pawel, Roche Research Funding: Purvish Parikh, Eli Lilly & Co, AstraZeneca, Pfizer, Roche, Sanofi-aventis, Aveo; Johan Vansteenkiste, Eli Lilly & Co; Christian Manegold, Eli Lilly & Co; Raghunadharao Digumarti, Eli Lilly & Co; Jin S. Lee, Eli Lilly & Co, AstraZeneca; Anders Mellemgaard, Eli Lilly & Co, Roche, Novartis; Tuncay Goksel, Eli Lilly & Co; David Gandara, Bristol-Myers Squibb Co, Abbott Oncology, Eli Lilly & Co, Sunesis Expert Testimony: None Other Remuneration: None
Conception and design: Giorgio Vittorio Scagliotti, Johan Vansteenkiste, Ulrich Gatzemeier, Keunchil Park, David Gandara
Provision of study materials or patients: Giorgio Vittorio Scagliotti, Purvish Parikh, Joachim von Pawel, Bonne Biesma, Johan Vansteenkiste, Christian Manegold, Piotr Serwatowski, Ulrich Gatzemeier, Mauro Zukin, Jin S. Lee, Keunchil Park, Shehkar Patil, Janusz Rolski, Tuncay Goksel, Filippo de Marinis, David Gandara
Collection and assembly of data: Purvish Parikh, Joachim von Pawel, Bonne Biesma, Johan Vansteenkiste, Christian Manegold, Piotr Serwatowski, Raghunadharao Digumarti, Anders Mellemgaard, Keunchil Park, Shehkar Patil, Janusz Rolski, Tuncay Goksel, Lorinda Simms, Katherine P. Sugarman
Data analysis and interpretation: Giorgio Vittorio Scagliotti, Johan Vansteenkiste, Christian Manegold, Ulrich Gatzemeier, Raghunadharao Digumarti, Jin S. Lee, Keunchil Park, Lorinda Simms, Katherine P. Sugarman, David Gandara
Manuscript writing: Giorgio Vittorio Scagliotti, Bonne Biesma, Johan Vansteenkiste, Christian Manegold, Raghunadharao Digumarti, Anders Mellemgaard, Keunchil Park, Lorinda Simms, Katherine P. Sugarman, David Gandara
Final approval of manuscript: Giorgio Vittorio Scagliotti, Purvish Parikh, Joachim von Pawel, Bonne Biesma, Johan Vansteenkiste, Christian Manegold, Piotr Serwatowski, Ulrich Gatzemeier, Raghunadharao Digumarti, Mauro Zukin, Jin S. Lee, Anders Mellemgaard, Keunchil Park, Shehkar Patil, Janusz Rolski, Tuncay Goksel, Filippo de Marinis, Lorinda Simms, Katherine P. Sugarman, David Gandara
The authors wish to thank the investigators in this study (listed in order from highest to lowest enrollment): P. Drings, Thoraxklinik-heidelberg Ggmbh, Germany; B. Raby, Hopital Laval, Canada; K. Syrigos, Sotiria General Hospital, Greece; S. Gans, St. Jansdal Hospital, the Netherlands; B. Balint, Csongrad Megyei Onkormanyzat Mellkasi Betegsegek Szakkorhaza, Mellkasi Betegsegek Szakkorhaza, Hungary; P.P. Bapsy, Kidwai Memorial Institute of Oncology, India; F.J. Kudrik, South Carolina Oncology Associates, United States; R. Labianca, Ospedali Riuniti, Oncologia Medica, Italy; R.G. Martins, Seattle Cancer Care Alliance, University of Washington Medical Center, United States; S. Nag, Jehangir Hospital, Oncology Research Cell, India; M. Blasinska-Morawiec, Wojewodzki Szpital Specjalistyczny Im. M. Kopernika, Poland; D.C. Doval, Oncology Department, Rajiv Gandhi Cancer Institute and Research Center, India; C.-H. Yang, Department of Oncology, National Taiwan University Hospital, Taiwan; J.-Y. Douillard, Centre René Gauducheau, France; P. Klimo, Chemotherapy Clinic, Lions Gate Hospital, Canada; Z. Baliko, Pulmonology Department, County Hospital, Hungary; M. Byrne, Department of Medial Oncology, Sir Charles Gairdner Hospital, Australia; S. Friesland, Klin. F. Onkologi, Karolinska Universitetssjukhuset, Sweden; B. Haim, Oncology Day Care, The Chaim Sheba Medical Center, Israel; H.J.M. Smit, Ziekenhuis Rijnstate, the Netherlands; H. Bozcuk, Akdeniz Universitesi Tip Fakultesimedikal Onkoloji Bilim Dali Kampus Antalya, Akdeniz University, Turkey; S. Cascinu, Clinica Di Oncologia, Ospedale Le Torrette, Italy; L. Freitag, Lungenklinik Hemer, Germany; M. Gottfried, Oncology Day Care, Meir Medical Center, Israel; E. Kaukel, Allgemeines Krankenhaus Harburg, Germany; J.R. Pereira, Instituto Arnaldo Vieira De Carvalho, Centro de Estudos, Brazil; G.-C. Chang, Taichung Veterans General Hospital, Taiwan; N. Davidson, Old School of Nursing, Broomfield Hospital, United Kingdom; F.L.J. Custers, Atrium Medisch Centrumkerkrade, the Netherlands; J.L. Gonzalez-Larriba, Servicio De Oncología, Hospital Clinico San Carlos, Spain; D. Isla Casado, Servicio De Oncología, Hospital Universitario Zaragoza; Spain; L. Paz-Ares, Servicio De Oncología, Hospital 12 De Octubre, Spain; F. Daniel, Plymouth Oncology Centre, Derriford Hospital, United Kingdom; T.-C. Hsia, China Medical University Hospital, Taiwan; O. Merimsky, Oncology Day Care, Tel-Aviv Medical Center, Israel; A. Montes Borinaga, Hospital Duran I Reynals, Spain; C.I. Bagnes, Hospital Dr. Tornu, Argentina; A. Knuuttila, Meilahden Sairaala Keuhkoklinikka, Helsingin Yliopistollinen Keskussairaala, Finland; Y. Neron, Centro De Pesquisa Em Oncologia, Centro De Estudos, Brazil; M. Nicolson, Anchor Unit, Aberdeen Royal Infirmary, United Kingdom; C.-M. Tsai, Department of Chest, Taipei Veterans General Hospital, Taiwan; K. Aigner, Abt. Lungenkrankheiten, Kh Der Elisabethinen Linz, Austria; L. Ek, Hjärt Och Lungdivisionen, Universitetssjukhuset Lungmedicin, Sweden; A. Ferro, Hospital Italiano Regional Del Sur, Argentina; P. Mainwaring, Oncology Department, Mater Adult Hospital, Australia; B. Bergman, Lungkliniken, Sahlgrenska Universitetssjukhuset, Sweden; M. Boyer, Sydney Cancer Centre, Royal Prince Alfred Hospital, Australia; M. Gulhan, Ataturk Gogus Hastaliklari Ve Gogus Cerrahisi Egitim Hastane, Turkey; K. Han-Pin, Chang Gung Memorial, Taiwan; M. Kiyik, Yedikule Gogus Hast. Ve Gogus Cerr. Egitim Ve Arastirma Hast, Turkey; J. Mezger, St. Vincentius-Krankenhäuser, Germany; F. Pimentel, Hospital De Sao Sebastiao, Portugal; E.F. Smit, Vrije Universiteit Medisch Centrum, the Netherlands; P. Astoul, Service Des Maladies Respiratoires, Hopital Sainte Marguerite, France; J.R. Eckardt, Center for Cancer Care and Research, Arch Med. Svcs., Inc, United States; R. Garcia Gomez, Servicio De Oncología, Hospital General Universitario Gregorio Maranon, Spain; M. Hetzel, Universitätsklinikum Ulm, Germany; M.-C. Lin, Chang Gung Memorial Hospital, Taiwan; T. Marsland, Florida Oncology Associates, United States; T. Müller, Kliniken Des Main-Taunus-Kreises, Germany; J. Santos-Dionisio, Serviço De Pneumologia, Instituto Português De Oncologia Dr. Francisco Gentil, Portugal; F. Schnell, Central Georgia Hematology Oncology, United States; E. Ulsperger, Krankenhaus Hietzing, Med. Mit Onkologie, Austria; J.E. Ales Martinez, Servicio De Oncología, Hospital Ruber Internacional, Spain; O. Arrieta, Medicina Interna, Instituto Nacional De Cancerologia, Mexico; F. Bustin, Centre Hospitalier Régional, Belgium; A. Falcone, Divisione Di Oncologia, Azienda Unita Sanitaria Locale 6, Italy; F. Ferraù, Oncologia Medica, Presidio Ospedaliero San Vincenzo, Italy; C. Kalofonos, University General Hospital of Patras, Greece; R.B. Mitchell, Virginia Cancer Institute, United States; S. Reingold, William Osler Health Center, Brampton Memorial Campus, Canada; W. Schuette, Städtisches Krankenhaus Martha-Maria Halle-Dölau GgmbH, Germany; C. Soto Collins, Quimioterapia. Sotano, IMSS Hospital Regional #30 Humberto Torres Sangines, Mexico; C. Steppert, Bezirksklinikum Obermain, Germany; F. Barata, Centro Hospitalar De Coimbra, Portugal; P.R. Clingan, Southern Medial Day Care Centre, Australia; S. Dakhil, Cancer Center of Kansas, United States; E. Felip, Hospital Vall De Hebron, Spain; F. Guichard, Service De Radiothérapie Oncologie, Polyclinique Bordeaux Nord, France; M. Karthaus, Ev. Johannes-Krankenhaus, Germany; M. Krzakowski, Centrum Onkologii, Klinika Nowotworw Puca, Poland; R. Loddenkemper, Krankenhaus Zehlendorf Lungenklinik Heckeshorn, Germany; M. López Brea, Servicio de Oncología, Hospital Universitario Marques De Valdecilla, Spain; D. Maldonado, Policlínica Bancaria, Argentina; B. Milleron, Hopital Tenon, France; D. Moro-Sibilot, Département de Pneumologie, Hopital La Tronche, France; J.-L. Pujol, Service de Pneumologie, Hopital Arnaud De Villeneuve, France; H. Samonigg, Klin. Abt. F. Onkologie, Med. Univ. Graz Lkh-Universitätsklinikum, Austria; P. Soerensen, Odense Universitetshospital, Denmark; G.-J. Timmers, Ziekenhuis Amstelveen, the Netherlands; C. Alexopoulos, Evangelismos Hospital, Greece; A. Araujo, Instituto Português De Oncologia, Portugal; C.H. Barrios, Hospital Mae De Deus, Brazil; A. Brandes, U.O. di Oncologia Medica, Ospedale Bellaria, Italy; R.L. Burkes, Mount Sinai Hospital, Canada; I.W. Burns, Department of Medical Oncology, St Vincents Hospital, Australia; M. Colosimo, IV Chemotherapy Unit, Prince Charles Hospital, Australia; W. Eberhardt, Universitätsklinikum Essen–Westdeutsches Tumorzentrum, Germany; V. Georgoulias, University General Hospital of Heraklion, Greece; D.M. Hayes, Maine Center for Cancer Medicine/Blood Disorders, United States; W. Hilbe, Klin. Abt. Allg. Innere Med., Landeskrankenhaus–Universitätskliniken Innsbruck, Austria; C.S. Karapetis, Department of Medical, Flinders Medical Centre, Australia; R. Orlowski, Northwestern Carolina Oncology, United States; E. Quoix, Hopital Lyautey, France; A.L. Rodríguez, Instituto Jalisciense de Cancerologia, Mexico; W. Urba, Providence Medical Center, United States; A. Welling, Medisch Centrum Alkmaar, Netherlands; U. Yilmaz, Dokuzeyluluni Onkolojienstitusu-balcova, Dokuz Eylul University Hospital, Turkey; D. Amadori, Oncologia Medica, Ospedale Pierantoni-Morgagni, Italy; L. Baez, Veterans’ Affairs Medical Center San Juan, United States; P.F. Conte, Oncologia Medica, Policlinico Universitario Modena, Italy; J. Eckmayr, Abt. F. Lungenkrankheiten, Kh Der Barmherzigen Schwestern Wels, Austria; F. Griesinger, Georg-August-Universität Göttingen, Germany; E. Jaeger, Krankenhaus Nordwest, Germany; C.S.F. Kortsik, St. Hildegardis–Krankenhaus, Germany; Y. Martinet, Chu De Nancy Hop D'Adultes De Brabois, France; G. Marx, Sydney Hematology Oncology Clinic, Australia; B. Massuti, Servicio De Oncología, Hospital Gral. Universitario De Alicante, Spain; C. Mathias, Nucleo De Oncologia De Bahia Ltda., Centro De Estudos, Brazil; J. Montesinos, Consorci Hospitalari Parc Tauli, Spain; C. Sessa, Servizio Oncologico Cantonale, Ospedale San Giovanni, Switzerland; B.E.E.M. van den Borne, Catharina Ziekenhuis, the Netherlands; A. Acosta, Quimioterapia, Hospital General 5 De Diciembre, Mexico; J. Adams, Arlington Cancer Center, United States; D. Capdeville Garcia, Centro Oncológico, Hospital Aranda de la Parra, Mexico; A. Devai, Pulmonologiai Osztaly, Fovarosi Onkormanyzat Uzsoki Utcai Korhaz, Hungary; W.G. Digel, Universitätsklinikum Freiburg, Germany; S. Gupta, Oncology Research Cell, Fortis Hospital, India; M.E. O'Brien, Royal Marsden NHS Trust, United Kingdom; L. Perez-Michel, Hospital Privado San Jose de Ciudad Obregón, Mexico; T. Repka, St. Luke's Cancer Care Center, United States; N.S. Stuart, North West Wales National Health Services Trust, United Kingdom; E. Teixeira, Hospital De Santa Maria, Portugal; S. Arnold, Markey Cancer Center, University of Kentucky, United States; J.T. Beck, Highland Oncology Group, United States; A. Ceribelli, Istituto Regina Elena, Italy; P. Garrido Lopez, Servicio De Oncología, Hospital Ramon Y Cajal, Spain; H. Harper, Hackensack University Medical Center, United States; B. Heinrich, Hämatologisch-Onkologische Praxis Augsburg, Germany; J.M. Lopez-Picazo, Servicio De Oncología, Clinica Universitaria De Navarra, Spain; A. Makalinao, California Hematology and Oncology Medical Group, United States; Z. Mekinda, Service Oncologie, Hopital Universitaire Erasme Brussels, Belgium; A. Ojala, Tampereen Yliopistollinen Keskussairaala, Finland; K. Pavithran, Amrita Institute of Medical Sciences, India; N. Pavlakis, Medical Oncology, Royal North Shore Hospital, Australia; W. Pohl, Abt. F. Lungenkrankheiten, Lkh Grimmenstein, Austria; W.T. Purcell, Deaconess Billings Research Institute, United States; E. Ritanen, Kuopion Yliopistollinen Keskussairaalal, Finland; R. Rosell, Hospital De Badalona Germans Trias I Pujol, Spain; M. Seckl, Department of Oncology, Charing Cross Hospital, United Kingdom; D. Skarlos, Errikos Dynan, Greece; A. Sobrero, Oncologia Medica, Ospedale San Martino Universita’ Genova, Italy; E.R. Arrowsmith, Chattanooga Oncology and Hematology Associates, Memorial Hospital, United States; P. Balcke, first Medical Department of Internal Medicine, Landeskrankenhaus St. Poelten, Austria; A.F. Dowlati, Ireland Cancer Center, Case Western Reserve University, University Hospitals Case Medical Center, United States; T. Eisen, Department of Oncology, Royal Marsden Hospital, United Kingdom; M. Flicker, Pulmologische Abt., Lkh Leoben, Austria; D.S. Lewi, Grupo De Especialistas En Enfermedades Neoplasicas (GEEN), Argentina; A. Sandler, Ingram Cancer Center, Vanderbilt University Medical Center, United States.
|Characteristic||Cisplatin/Pemetrexed (n = 862)||Cisplatin/Gemcitabine (n = 863)|
|No. of Patients||%||No. of Patients||%|
|Age < 65 years||541||62.8||577||66.9|
|Age ≥ 65 years||321||37.2||286||33.1|
|Stage of disease|
|Stage IIIB, dry||138||16.0||159||18.4|
|Stage IIIB, wet||67||7.8||51||5.9|
|ECOG performance status|
|East/South East Asian||116||13.5||104||12.1|
|Squamous cell carcinoma||244||28.3||229||26.5|
|Other: NSCLC, NOS||106||12.3||146||16.9|
Abbreviations: ECOG, Eastern Cooperative Oncology Group; NSCLC, non–small-cell lung cancer; NOS, not otherwise specified.
*Histologic type was reported by the investigative site.
|Cycles and Dose Adjustments||Cisplatin/Pemetrexed (n = 839)||Cisplatin/Gemcitabine (n = 830)|
|No. of cycles per patient|
|Total No. of cycles administered||3,648||3,626|
|% total cycles||8.6||11.3|
|Doses reduced on day 1|
|Doses omitted on day 8||Not applicable|
|Relative dose-intensity, %|
*One patient on the cisplatin/pemetrexed arm received more than six cycles.
†Four patients on the cisplatin/gemcitabine arm received more than six cycles.
|Characteristic||No. of Patients||Survival (months)||Adjusted Hazard Ratio||95% CI|
|Median||95% CI||Median||95% CI|
|< 65 years||1,118||10.3||9.6 to 11.3||10.3||9.6 to 11.3||0.97||0.84 to 1.11|
|≥ 65 years||607||10.1||9.2 to 12.0||10.2||8.5 to 11.2||0.88||0.73 to 1.06|
|Males||1,210||9.6||8.8 to 10.2||9.9||9.1 to 10.6||0.98||0.86 to 1.11|
|Females||515||13.3||12.3 to 15.0||11.4||10.2 to 12.7||0.84||0.68 to 1.03|
|White||1,349||10.0||9.3 to 10.8||10.1||9.3 to 10.8||0.93||0.82 to 1.05|
|East/South East Asian||220||13.8||10.2 to 17.1||11.9||9.0 to 14.7||0.88||0.62 to 1.24|
|All other||156||9.9||8.6 to 12.8||11.5||9.6 to 14.1||1.34||0.89 to 2.01|
|Former/current smoker||1,266||10.0||9.4 to 11.1||10.3||9.5 to 10.9||0.93||0.81 to 1.05|
|Never-smoker||250||15.9||13.8 to 20.2||15.3||12.1 to 22.9||1.00||0.71 to 1.41|
|IIIB||415||11.9||10.0 to 14.2||11.3||9.6 to 13.1||0.89||0.71 to 1.12|
|IV||1,310||10.0||9.3 to 10.8||10.1||9.3 to 10.8||0.95||0.84 to 1.08|
|0||612||13.4||11.9 to 14.9||12.2||11.3 to 13.4||0.91||0.75 to 1.10|
|1||1,110||9.1||8.1 to 9.9||9.0||8.3 to 9.8||0.95||0.83 to 1.09|
*Two hundred nine patients with unknown smoking history were not included in the smoking history analysis.
†Three patients with unknown Eastern Cooperative Oncology Group performance status were not included in the performance status analysis.
|Toxicity||Cisplatin/Pemetrexed (n = 839)||Cisplatin/Gemcitabine (n = 830)||P|
|No. of Patients||%||No. of Patients||%|
|Thrombocytopenia, platelets||34||4.1||105||12.7||< .001|
|Alopecia, any grade||100||11.9||178||21.4||< .001|
|Dehydration, any grade||30||3.6||17||2.0||.075|
*Only toxicities reported in at least 3% of patients on at least one arm are listed.
published online ahead of print at www.jco.org on May 27, 2008.
Supported by Eli Lilly & Co, Indianapolis, IN.
Presented at the 12th World Conference on Lung Cancer, September 1-6, 2007, Seoul, South Korea; and the 14th European Cancer Conference, September 23-26, 2007, Barcelona, Spain.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Clinical Trials repository link available on www.JCO.org.
We thank all of the patients and institutions involved in this study. The authors also thank Patti Moore, Noelle Gasco, Peter Fairfield, Craig Hansen, and Nancy Iturria for assistance with writing, editorial, and statistical analyses.
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