the Medical Oncology Department, Venezia
    Medical Oncology Department, Centro Riferimento Oncologico, Aviano
    Medical Oncology Department, Azienda Ospedaliera, Padova
    Medical Oncology Department, San Giuseppe Hospital, Milano
    Medical Oncology Department, Policlinico Universitario Modena
    General Medicine Department, Pavia
    Cardio-Thoracic Department, Universita di Pisa, Pisa
    Oncology Department, Istituto di Ricerca e Cura a Caratiere Scientifico San Raffaele, Milano
    Medical Oncology Department, Pordenone
    Medical Oncology Department, Forlì
    Institute for Scientific Intercharge Foundation, Torino, Italy
    for the Gruppo di Studio Tumori Polmonari del Veneto (GSTPV)

    ABSTRACT

    PURPOSE: Paclitaxel/carboplatin (PC) is one of the reference combinations in the treatment of non–small-cell lung cancer (NSCLC). No triplet novel agent combination has until now shown superiority over a two-drug combination for advanced NSCLC. We therefore conducted a clinical trial to test if paclitaxel/carboplatin/gemcitabine (PCG) increases overall survival (OS) and response rate (RR) over PC.

    METHODS: Stage IIIB patients not suitable for radical radiation treatment and stage IV chemotherapy-naive patients with measurable disease and performance status of 0 to 2 were randomly assigned to PC arm (paclitaxel 200 mg/m2 and carboplatin area under the concentration-time curve 6 day 1/q21 days) or the PCG arm (paclitaxel 200 mg/m2 and carboplatin area under the concentration-time curve 6 day 1, and gemcitabine 1,000 mg/m2 days 1 and 8 every 21 days).

    RESULTS: A total of 324 patients were randomly assigned to the two arms. The RR for PC arm and PCG arm were 20.2% and 46% (P < .0001). The median time to the progression was 5.1 months in the PC group and 7.6 months in the PCG group (P = .012; hazard ratio [HR] 1.34; 95% CI: 1.06 to 1.72). Median OS was 8.3 months and 10.8 months (P = .032; HR 1.309; 95% CI: 1.03 to 1.67) in favor of the PCG arm. One-year survival was 34% (PC arm) and 45% (PCG arm; P = .032). Only hematologic toxicity (neutropenia, thrombocytopenia, and anemia) was significantly increased in the PCG arm and the experimental arm required more platelet and red blood cell transfusions, and more granulocyte colony-stimulating factor usage. No toxic/early deaths were observed.

    CONCLUSION: The PCG regimen offers a significant survival advantage over PC in advanced NSCLC, making PCG a treatment option for advanced NSCLC patients.

    INTRODUCTION

    Platinum-based chemotherapy results in a small improvement in survival in patients with advanced non–small-cell lung cancer (NSCLC).1 With the introduction of newer, third-generation nonplatinum based agents like vinorelbine, gemcitabine, paclitaxel, docetaxel, and irinotecan, combination drug therapy became possible. Studies have shown that two-drug combinations are more efficacious than single-agent treatment. Presently, two-drug combinations are usually employed as first-line chemotherapy for advanced NSCLC. A series of phase III randomized studies has shown that doublets give similar results in terms of response rate (RR; 20% to 30%), time to progression (3 to 4 months), and overall survival (OS; 7.5 to10 months) and minimal differences in toxicity with a slight advantage for the paclitaxel/carboplatin (PC) combination as nonhematologic toxicities are considered.2-8 Until now, no randomized trial has demonstrated that adding a third drug improves overall survival.9-11

    PC combination is the reference treatment in many North American and European centers. In a preclinical study performed using three NSCLC cell lines, paclitaxel was shown to be synergistic with gemcitabine and carboplatin, regardless of the sequence of administration.12 This provided a rationale for studying this triple-agent combination in patients with NSCLC.

    We conducted a phase I-II study to test the paclitaxel/carboplatin/gemcitabine (PCG) combination in advanced NSCLC. Among the 31 patients treated in the phase II part of the study, an RR of 57%, a median survival of 17.2 months, and a 1-year survival of 60%, were observed.13 Based on these encouraging efficacy results, a phase II or III randomized study was planned. The primary objective of this randomized, open-label, multicenter study was to compare RR and OS in chemotherapy-naive patients with stage IIIB or IV NSCLC. The secondary objectives of this study were time to progression and toxicity evaluation.

    PATIENTS AND METHODS

    Eligibility Criteria

    Chemotherapy-naive patients with measurable histologic or cytologic confirmed stage IIIB not suitable for radical radiation treatment (pleural effusion and/or supraclavicular lymphoadenopathy) or stage IV NSCLC were eligible. Patients with recurrent/metastatic disease after surgery who were not suitable for locoregional therapy were also included. Prior radiation therapy at symptomatic sites was allowed provided that the indicator sites had not been irradiated. Patients with asymptomatic brain metastases were eligible. All patients had to be more than 18 years old, with a WHO performance status (PS) of 0 to 2, and with adequate hematologic, hepatic, and renal functions. Life expectancy had to be  12 weeks.

    The institutional ethics committee of the Coordinating Oncology Centre of Padua, approved the protocol. All patients gave consent before random assignment.

    Treatment Schedule

    Patients were stratified according to center and the stage of disease (IIIB v IV). Patients were randomly assigned to one of two study arms: the reference (PC) arm was paclitaxel 200 mg/m2 administered intravenously over a 3 hour period, followed by carboplatin area under the concentration-time curve of 6 every 3 weeks; and the experimental (PCG) arm was gemcitabine 1,000 mg/m2 administered intravenously (after PC) over 30 to 60 minutes on days 1 and 8, plus PC combination at the same doses as reference treatment on day 1 every 21 days. Premedication for paclitaxel in both arms was dexamethasone 16 mg, diphenhydramine 50 mg, and an H2 receptor blocker (such as ranitidine 50 mg intravenously), all administered intravenously 30 to 60 minutes before the paclitaxel infusion.

    In the absence of progressive disease after the third cycle, the patients were treated for a minimum of six cycles. Second-line chemotherapy was unplanned and administered according to individual center policy.

    Dose Schedule Modification

    Patients were required to have a white blood cell count (WBC) of more than 4,000/μL and platelets more than 100,000/μL before receiving the next course of therapy. In case of lower values, the next cycle was delayed for 7 days, and if the counts did not recover, a 25% dose reduction was permitted for a WBC count of less than 4,000/μL and/or a platelet count less than 100,000/μL. Gemcitabine day 8 was omitted for absolute neutrophil count less than 500/μL and/or platelet count less than 50,000/μL, and a 25% dose reduction was required for absolute neutrophil count from 500 to 990/μL and/or platelet count from 50,000 to 90,000/μL. There was no dose modification for uncomplicated nadirs.

    Prophylactic granulocyte colony-stimulating factor (G-CSF) was not allowed. G-CSF therapy was administered according to the 1997 American Society Clinical Oncology guidelines.

    Treatment was interrupted in case of creatinine clearance less than 60 mL/min, allergic reactions, and neurologic toxicity greater than grade 2, and for grade 4 nonhematologic toxicity, except alopecia. Patients were also discontinued from treatment in case of patient refusal or disease progression.

    Baseline and Treatment Assessment

    Staging was done according to the International Union Against Cancer (UICC) 1997 TNM classification. Before entry onto the study, all patients were required to have a radiographic work-up, including chest and abdominal computed tomography scans and complete blood tests. Brain and bone scans were required in presence of specific symptoms. Complete blood cell counts were performed weekly during treatment, while hepatic and renal functions were determined before each chemotherapy cycle. Tumor assessment for response was performed at the end of the third chemotherapy cycle and after the sixth cycle in nonprogressing patients. Patients thereafter were followed-up every 2 months.

    Standard WHO bidimensional response criteria were used.14 Survival was calculated from the date of random assignment to the date of death or the date when the patient was last known to be alive. The time to the progression of disease was calculated from the date of enrollment to the date of progression or death. Patients who were alive and relapse free were censored as of the date of the last known follow-up visit. Toxicity was classified in accordance with the WHO toxicity grading criteria.15 All 324 patients were included for survival analysis on an intention to treat basis, and those patients who were eligible for the study and received at least one cycle were included in the efficacy and toxicity analysis.

    Statistical Analysis

    RR was the main original end point. Statistical analyses followed the principle of intention to treat. To detect a difference of at least 20% in RR in favor of the experimental arm (from 30% to 50%), with a power of 0.8 and a two-sided statistical significance level of .05, 220 patients (110 per arm) were initially planned. At the end of the planned randomization, the protocol was amended to further evaluate the impact of the two chemotherapy regimens on OS. It was planned to randomly assign 324 patients to detect a minimal hazard ratio of 1.33 (which is equivalent to a one third higher risk of death for patients treated with PC) with a power of 0.8 and an  error of two-sided .05. Data for treatment responses and toxic effects were compared with the use of 2 or Fisher's exact test when appropriate. All time to event distributions were estimated by Kaplan-Meier methods16 and comparisons were made with the use of the log-rank test. The adjusted hazard ratio (HR) for OS and time to progression was assessed by the Cox's model, which was created to identify independent predictors of survival factors (stage, number of metastatic site, brain metastases, PS, sex, age, histologic subtype, weight loss, therapy).17

    RESULTS

    Patient Characteristics

    Between February 1998 and October 2004, 324 patients were enrolled in this study, 159 in the standard arm (PC), and 165 in the experimental arm (PCG). Of the enrolled patients, seven (2.1%) were subsequently found to be ineligible: four patients in the PC arm (one patient with concomitant second neoplasm, one patient progression before treatment and two had inadequate information) and three patients in the PCG arm (one incorrect histology, two inadequate information; Fig 1).

    The median age was 62 years (range, 25 to 80 years) and most patients had performance status of 0 or 1 (44.7% and 49%, respectively). Two thirds of the patients (78%) were men. Patient characteristics for the two groups are summarized in Table 1.

    Dose Administration and Response

    A total number of 1,347 chemotherapy cycles were administered, 620 in the PC arm and 727 in the PCG arm. Patients received a median number of five cycles (range, 0 to eight cycles) in the PCG arm compared to four cycles (range, 0 to eight cycles) in the PC arm (mean, 4.4 [standard deviation: 1.8] and 3.9; [SD, 1.9] P = .022). Dose reductions were required for 12.4% of the patients in the PC arm and for 44.5% in the PCG arm (P = < .0001), during 19 cycles and 113 cycles respectively. Median delay due to toxicity was 9.5 days in PC arm (12 patients, 14 cycles) and seven days in PCG arm (31 patients, 45 cycles). Gemcitabine administration on day 8 was omitted in 21 patients due to hematologic or nonhematologic toxicities (39 cycles).

    The overall RR was 20% in the PC arm and 43.6% in the PCG arm (P = < .0001) (Table 2). In the PC arm only partial responses were observed while in the PCG arm 10 complete responses (6.3%) and 59 partial responses (37.3%) were registered. Stable disease was 32% in the PC arm and 27.2% in the PCG arm. Interestingly, 48% of the patients who received the PC combination were withdrawn from the study because of progressive disease, as compared to 29.1% of the patients who received PCG (P = .001). Early death rate, defined as death occurring during the 30 days following the last chemotherapy administration, was similar in the two groups: 6.4% and 4.3% in the PC and the PCG arm, respectively (P = .40). Following chemotherapy treatment, a locoregional treatment (palliative radiotherapy) was feasible for 15.8% of patients in the PC group and for 18.1% of patients in the PCG group, and 24.7% of PC patients and 23.6% in the experimental arm, underwent second-line chemotherapy (Table 3).

    Time to Event Measures

    The median follow-up period was 19 months. The median time to the progression of disease was 5.1 months in the PC group, as compared with 7.6 months in the PCG group (P = .012; HR 1.34; 95% CI, 1.06 to 1.72). Adjusting for baseline prognostic factors with Cox proportional hazard method, the HR was 1.35 (95% CI, 1.07 to 1.72) and the P = .013 (Fig 2).

    The median survival time for intention to treat was 8.3 months for the patients who received PC and 10.8 months for those who received PCG (P = .032; HR 1.309; CI, 1.02 to 1.67; Fig 2.) Adjusted for baseline prognostic factors with Cox proportional hazard method, the HR was 1.31 (CI, 1.02 to 1.68) and P = .044 (Fig 2). The one and two-year survival rate, according to intention to treat basis, was, respectively, 34% and 11% in PC arm and 45% and 19% in the experimental arm. In multivariate analysis, PS and treatment were the only independent prognostic factors (Table 4).

    Toxicity

    Table 5 shows grade 3 to 4 WHO hematologic toxicity in the two arms. Grade 3 to 4 neutropenia, anemia, and thrombocytopenia were significantly higher in the PCG arm; for grade 1 to 2 anemia, a trend was also observed (18.3% v 28%; P = .050). Febrile neutropenia (4.2% v 9.3%; P = .08) and hemorrhage (1.4% v 4.7%; P = .17) were higher in the PCG arm, although not significantly. Patients in the PCG arm also required more platelet (6% v 0%; P = .004) and red-cell transfusions (21.5% v 8.4%; P = .002). G-CSF use was required in 12 patients (8%) in PC arm and in 23 patients (15%) in PCG arm.

    There were no significant differences in WHO nonhematologic toxicities between the two arms (Table 6) . Delays in the treatment due to toxicity were higher in the PCG arm (28% v 13.1%; P = .0021).

    DISCUSSION

    Our randomized trial showed a significant difference in OS in favor of the PCG arm with an increase in median, 1-year, and 2-year survival. For the experimental arm (PCG) the advantage in OS was 11% at 1 year and 8% at 2 years, and the median OS increased by 2.5 months. It is noteworthy that the results for RR, time to progression, median, and one and two-year survival in the control arm (PC), are similar to those obtained in many randomized studies in a similar subset of patients with the same PC regimen.2,5,8,28 The RR we observed with PCG more than doubled that observed with the PC combination from 20% to 43.6%, making this regimen potentially useful in clinical studies when response rate is an important goal, and in particular, in preoperative treatment of locally advanced NSCLC. Patients in the PCG arm received a higher median number of cycles compared with the reference treatment, more likely due to the lower disease progression rate during chemotherapy, and resulted in the benefit observed in the time to progression in the PCG arm. Although there was higher hematologic toxicity in the PCG arm, it was manageable, as shown by the higher median number of cycles administered. Due to higher hematologic toxicity, dose reduction, dose delays, and red cell and platelet transfusions were significantly higher in the PCG arm. However, nonhematologic toxicities and toxic/early death were not different in the two arms.

    There is evidence that for RR, platinum-based, three-drug combinations are generally superior to the two-drug regimens in advanced NSCLC.9-11,18,19 However, no triplet regimen has so far shown superiority in OS over doublet combination regimen. Adding targeted drugs, such as getifinib or erlotinib, to a third generation two-drug combination has also not resulted in any advantage in RR and OS.20-22

    Three literature-based meta-analyses exploring the two-drug regimen versus the three-drug regimen were recently published.23-25 Delbaldo et al23 evaluated 30 clinical trials published between January 1980 and October 2003, comparing two-drug with three-drug regimens. They reported that adding a drug to a doublet regimen yielded significant advantage in RR (P = < .001) without any benefit for one-year survival (P = .88) or for median survival time (P = .97). However, a significant heterogeneity was observed in the treatment effect on survival when three-drug combinations were considered. This probably due to dose reduction planned in some trials for the three-drug regimens. Of the triplet chemotherapy combinations analyzed in Delbaldo's meta-analyses, only two studies, by Greco et al and by Hussein et al, included a combination with a platinum compound, a taxane, and gemcitabine. Both of them showed a superiority in median survival for the three-drug combinations: 12.7 v 9.2 months and 11.4 v 8.5 months, respectively.26,27 Both are, however, phase II randomized trials with an inadequate number of patients (135 and 71, respectively) to detect a significant difference between the two analyzed regimens (PC and PCG).

    To our knowledge, this is the first phase III study showing an OS superiority for a triple-agent regimen over a standard doublet regimen combining platinum with a third-generation drug. Several hypotheses could be put forward to explain our finding. It should be noted that a full dose of gemcitabine (1,000 mg/m2 day 1 and day 8) was added to the full doses of paclitaxel (200 mg/m2 day 1)/carboplatin (area under the concentration-time curve, 6) combination, which is different from the three-drug combination trials included in Delbaldo et al meta-analyses.

    Data from preclinical studies have shown that gemcitabine increases paclitaxel and platinum concentration and stabilizes the platinum damage to DNA in cancer cells.12 Pharmacokinetic and pharmacodynamic interaction between gemcitabine and the other two drugs (PC) could also explain the increased effectiveness of PCG.29 Several reports have shown that the sequence of administration of gemcitabine and paclitaxel may also affect the efficacy of this combination chemotherapy, since paclitaxel increases the concentration of active metabolite of gemcitabine (dFdCTP) when administered first.30 The paclitaxel dose was also an important factor in our study because the dFdCTP level is increased at the higher paclitaxel dose and in our study the paclitaxel dose was not reduced in comparison to the dose adopted for the two-drug regimen.

    An alternative explanation for the superiority of the PCG regimen over PC could be the presence of gemcitabine. A recent meta-analysis reports the superiority of platinum-based regimens containing gemcitabine over regimens without it. An analyses from 13 randomized trials with 4,556 patients by Le Chevalier et al showed an absolute benefit in one year OS (3.9%) in favor of regimens containing gemcitabine and platinum, with a significant reduction in overall mortality and disease progression.28

    Based on the results of our study, we suggest that triple agent PCG chemotherapy could be used in early stage NSCLC patients when RR is an important goal, to allow a following locoregional treatment. In metastatic disease the PCG regimen should be also considered for palliation and for the possibility to obtain a moderate increase in OS in patients with a good PS and no relevant comorbidities.

    In conclusion, PCG regimen offers a significant survival advantage over PC in advanced NSCLC, making PCG a treatment option for advanced but fit NSCLC patients.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Author Contributions

    Conception and design: Adriano Paccagnella, Adolfo Favaretto

    Provision of study materials or patients: Adriano Paccagnella, Francesco Oniga, Alessandra Bearz, Adolfo Favaretto, Maurizia Clerici, Fausto Barbieri, Alberto Riccardi, Antonio Chella, Umberto Tirelli, Giovanni Ceresoli, Salvatore Tumolo, Ruggero Ridolfi, Rita Biason, Paolo Belloni, Maria Ornella Nicoletto, Maria Grazia Ghi

    Collection and assembly of data: Adriano Paccagnella, Francesco Oniga, Adolfo Favaretto, Rita Biason, Paolo Belloni, Maria Ornella Nicoletto, Maria Grazia Ghi

    Data analysis and interpretation: Fabrizio Veglia

    Manuscript writing: Adriano Paccagnella, Francesco Oniga, Maria Grazia Ghi

    Final approval of manuscript: Adriano Paccagnella, Francesco Oniga, Alessandra Bearz, Adolfo Favaretto, Maurizia Clerici, Fausto Barbieri, Alberto Riccardi, Antonio Chella, Umberto Tirelli, Giovanni Ceresoli, Salvatore Tumolo, Ruggero Ridolfi, Rita Biason, Paolo Belloni, Maria Ornella Nicoletto, Fabrizio Veglia, Maria Grazia Ghi

    Acknowledgment

    We thank Laura McMahon and Anna Luise for data management and for assistance in manuscript preparation.

    NOTES

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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