In the United States, it is estimated that there will be 171,500

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1 ORIGINAL ARTICLE A Randomized Phase II Trial Using Two Different Treatment Schedules of Gemcitabine and Carboplatin in Patients with Advanced Non Small-Cell Lung Cancer Gregory A. Masters, MD,* Athanassios E. Argiris, MD, Elizabeth A. Hahn, MA, J. Thaddeus Beck, MD, P. Gregory Rausch, MD, Zhishen Ye, PhD, Matthew J. Monberg, BS, Leslie P. Bloss, RN, OCD, Rafael E. Curiel, PhD, and Coleman K. Obasaju, MD A related editorial, Pick the Winner Designs in Phase II Cancer Clinical Trials by Sumithra J. Mandrekar appears on page 5 of this issue. Background: Gemcitabine and carboplatin combination therapy is an active and tolerable regimen in the treatment of non small-cell lung cancer (NSCLC). Twenty-eight and 21-day regimens without day-15 administration of gemcitabine are common; however, it remains unclear which offers the optimal therapeutic index. Methods: This trial evaluated two schedules of the combination of gemcitabine and carboplatin: gemcitabine (1100 mg/m 2 on days 1 and 8) plus carboplatin (area under the curve 5 on day 8) every 28 days, or gemcitabine (1000 mg/m 2 on days 1 and 8) plus carboplatin (area under the curve 5 on day 1) every 21 days. Eligible patients in this trial had stage IIIB (with malignant pleural effusion) or stage IV NSCLC with no prior chemotherapy. The primary objective was to evaluate progression-free survival, with secondary objectives of overall survival, response rate, and toxicity. Results: One hundred patients were randomized and enrolled from October of 2000 to January of 2002 into this multi-institutional study (48 for the 28-day regimen and 52 for the 21-day regimen). Baseline demographics were well matched, and a majority of patients (85%) enrolled with stage IV disease. Median progression-free survival and response rates were 3.8 months and 22.9%, respectively, with the 28-day regimen, and 4.9 months and 40.4%, respectively, with the 21-day regimen. Median survival was 8.7 months *Helen Graham Cancer Center, Newark, Delaware; Northwestern University Medical School, Chicago, Illinois; Highlands Oncology Group, Fayetteville, Arkansas; Frederick Memorial Hospital Regional Cancer Therapy Center, Frederick, Maryland; and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. Supported by a grant from Eli Lilly and Company, Indianapolis, Indiana. These data were presented in part at the 2003 American Society of Clinical Oncology meeting. Address for correspondence: Gregory A. Masters, MD, FACP, Associate Professor of Medicine, Thomas Jefferson University Medical School, Medical Oncology Hematology Consultants, Helen Graham Cancer Center, 4701 Ogletown-Stanton Rd - Suite 2200, Newark, DE 19713, Phone: , Fax: , gmasters@cbg.org. Copyright 2006 by the International Association for the Study of Lung Cancer ISSN: /06/ with the 28-day regimen and 8.0 months for the 21-day regimen. One- and 2-year survival rates were 34.7% and 8.7%, respectively, with the 28-day regimen, and 36.5% and 16.8%, respectively, with the 21-day regimen. Differences in progression-free survival (logrank statistic, p ), response rate (Fisher s exact test, p ) and overall survival (log-rank statistic, p ) were not statistically significant. Grade 3 to 4 hematologic toxicities occurred with a greater frequency in the 21-day regimen. No grade 3 to 4 nonhematologic toxicity (except nausea/vomiting with the 28-day regimen) was observed in more than 10% of patients in either treatment arm. Conclusion: Gemcitabine plus carboplatin is active and well tolerated in advanced NSCLC. Both regimens may be considered for further study. Although the 21-day regimen appeared to be associated with preferable outcomes, differences between treatment groups were not statistically significant. Key Words: Gemcitabine, Carboplatin, Non small-cell lung cancer, Combination therapy, Randomized phase II trial. (J Thorac Oncol. 2006;1: 19 24) In the United States, it is estimated that there will be 171,500 new cases of and 156,100 deaths resulting from lung cancer each year, making it the most common cause of cancerrelated death in the United States. 1 Non small-cell lung cancer (NSCLC) constitutes 75% to 80% of all lung cancers. 2 Because the majority of patients present with advanced disease, overall survival and prognosis are poor. Single-agent chemotherapy produces modest response rates in advanced NSCLC. Although two-drug combinations are superior to monotherapy, the addition of a third drug does not improve survival outcomes. 3 Platinum-containing doublets are now considered standard for the treatment of good performance status patients with advanced NSCLC. 4 6 Based on overall survival or progression-free survival, however, no particular regimen has established superior efficacy. 7,8 There- Journal of Thoracic Oncology Volume 1, Number 1, January

2 Masters et al. Journal of Thoracic Oncology Volume 1, Number 1, January 2006 fore, the choice of chemotherapy in advanced NSCLC is often based on potential treatment-related toxicities. Early trials examining the combination of gemcitabine and carboplatin in NSCLC used various treatment schedules Regimens consisted of (1) gemcitabine at a dose of 1000 mg/m 2 on days 1 and 8 with carboplatin at an area under the curve (AUC) of 5.5 on day 1; (2) gemcitabine at 1000 mg/m 2 on days 1, 8, and 15, with carboplatin dosed at an AUC of 5.2 on day 1; and (3) gemcitabine at 1200 mg/m 2 on days 1 and 8 and carboplatin at an AUC of 5.0. In these small trials, response rates ranged from 21% to 50%, with median survival times of approximately 11 months Carrato et al. compared two different schedules of gemcitabine and carboplatin in NSCLC: a 21-day schedule with gemcitabine (1000 mg/m 2 ) given on days 1 and 8 and a 28-day schedule with gemcitabine on days 1, 8, and 15, with carboplatin (AUC 5) on day 1 in both schedules. 11,12 In these trials, there was less hematologic toxicity on the 21-day schedule, with no difference in efficacy. With the 28-day regimen, neutropenia and thrombocytopenia occurred in the majority of patients primarily on or near day 15 of each cycle. On the basis of these results, the 21-day regimen was favored. 13 In a dose-escalation phase I/II study, Iaffaioli et al. studied gemcitabine (1100 mg/m 2 ) on days 1 and 8 and carboplatin (AUC 5) on day 8 of a 28-day cycle. 14 At this dose, 33% and 8% of the patients had grade 3 to 4 neutropenia and thrombocytopenia, respectively, suggesting that this was a well-tolerated regimen. In the study, the objective response rate was 50%, the median duration of response was 13 months, and the median overall survival was 16 months. The 28-day regimen recommended by Iaffaioli et al. and the more conventional 21-day regimen are both widely used to treat advanced NSCLC, but it remains unclear which offers the optimal therapeutic index. The purpose of this study was to use the dosing from these two schedules for comparison in the context of a phase II, randomized clinical trial. PATIENTS AND METHODS Patient Eligibility This multicenter phase II trial randomized patients into treatment arms that received a 28- or 21-day regimen of gemcitabine plus carboplatin. Patients were required to have histologically confirmed stage IIIB (with malignant pleural effusion) or stage IV NSCLC and be 18 years of age or older, be chemotherapy naive, and have measurable (lesions that can be accurately measured as 20 mm in at least one dimension) or assessable disease. Patients were also required to have adequate hematologic (white blood cell count 3500/ mm 3, platelet count 100,000/mm 3, granulocyte count 1500 mm 3, hemoglobin 9 g/liter, and hematocrit 30%), hepatic (serum bilirubin 1.25 times the institutional upper normal limit and aspartate transaminase 2.5 times the institutional upper normal limit), and renal (serum creatinine 2 mg/dl or calculated creatinine clearance 50 ml/min) function and an Eastern Cooperative Oncology Group Performance Status of 0 or 1. No prior radiation to the site to be followed for response was allowed, and any prior radiation therapy had to be completed 3 or more weeks before enrollment. All patients were required to sign informed consent and use an approved method of contraception if of childbearing potential. This study was performed in accordance with the principles stated in the Declaration of Helsinki and regulatory standards for good clinical practice. The institutional review board of each participating center reviewed and approved this study. Treatment Plan Patients were randomized to receive one of the following regimens: Arm A (28-day regimen, as recommended by Iaffaioli et al). Gemcitabine, 1100 mg/m 2, was administered as a 30- minute intravenous infusion on days 1 and 8 followed by carboplatin at a dose of AUC 5 administered over 30 minutes as an intravenous infusion on day 8. This cycle was repeated every 28 days until disease progression. Arm B (21-day regimen). Gemcitabine, 1000 mg/m 2, was administered as a 30- minute intravenous infusion on days 1 and 8 followed by carboplatin at a dose of AUC 5 administered over 30 minutes as an intravenous infusion on day 1. This cycle was repeated every 21 days until disease progression. The total number of cycles administered was at the discretion of the treating physician. No other chemotherapy, immunotherapy, antitumor hormonal therapy (excluding contraceptives and replacement steroids), radiation therapy, or experimental medications were permitted while the patients were on the study. On day 8, platelets, granulocytes, and nonhematologic toxicities were clinically evaluated. If granulocytes were between 500 and 1000/mm 3 or platelets were between 50,000 and 75,000/mm 3, dosages were to be reduced by 25%. If granulocytes were less than 500/mm 3 or platelets were less than 50,000/mm 3, treatment was to be withheld. After grade 3 or 4 nonhematologic events, treatment was withheld at the discretion of the physician. If toxicities resolved to grade 2 or lower, resumption of treatment was allowed during the subsequent cycle. For subsequent cycles, day-1 treatment was only administered when neutrophil counts were greater than 1000/ mm 3, platelet counts were greater than 100,000/mm 3, and all nonhematologic toxicities resolved to grade 2 or lower. Response Criteria Tumor response assessments were based on modified Response Evaluation Criteria in Solid Tumors. 15 Complete response was defined as the disappearance of all known disease (target and nontarget lesions) determined by two observations not less than 4 weeks apart. A partial response (PR) was defined as a 30% reduction from baseline in the sum of the longest diameter (LD) of the target lesions taking as reference the baseline LD sum and a lack of disease progression in nontarget lesions. Progressive disease (PD) was defined as the development of any new lesions or an increase of 20% in the LD sum of target lesions taking as reference the smallest sum LD recorded since the treatment started. Pa- 20 Copyright 2006 by the International Association for the Study of Lung Cancer

3 Journal of Thoracic Oncology Volume 1, Number 1, January 2006 Gemcitabine and carboplatin in patients with NSCLC tients with stable disease (SD) did not meet the criteria for PR or PD. Disease progression was defined as the time from the date of randomization to the first date of documented progression or death from any cause. Progression-free survival was censored at the date of the last follow-up visit for patients who were still alive and whose disease had not progressed. Overall survival time was defined as the time from the date of randomization to the date of death from any cause. Overall survival time was censored at the date of the last follow-up visit for patients who were still alive. Statistical Analysis/Randomization This trial randomized 100 patients with equal probability to either of the two regimens. Patients were stratified by stage of disease and gender. The stratification took place at randomization, to ensure balance with respect to these characteristics in the two arms. The primary analyses was unstratified, to avoid small numbers in the subgroups. The sample size was chosen based on a selection design that used progression-free survival as the primary endpoint. The selection design assumed that a primary goal of the trial was to select a regimen for a larger, phase III trial. For this reason, type I, or alpha, error was not controlled under this design: the procedure was designed to select the regimen with the observed numerical advantage in progression-free survival based on a positive or negative value for the one-sided log-rank statistic. Assuming a hazard ratio of 1.2 or greater, and assuming at least 85 treatment failure events, there was at least an 80% chance of correctly selecting the less hazardous ratio. Kaplan-Meier estimates were calculated for the production of survival curves. 16 Estimates of 1- and 2-year survival were computed from these curves, with 95% confidence intervals (CIs). Demographic characteristics were collected to determine the comparability of the two treatment groups. Adverse events were assessed using National Cancer Institute Common Toxicity Criteria version 2.0. RESULTS One hundred patients were enrolled from October of 2000 to January of 2002 into this multi-institutional study (48 for the 28-day regimen and 52 for the 21-day regimen). All patients enrolled into the study were analyzed for toxicity, survival, time to progression, and best tumor response. Patient Characteristics Patient characteristics at baseline were similar between treatment arms (Table 1). Median age was 66 years (range, years) for the 28-day regimen and 67 years (range, years) for the 21-day regimen. The majority of patients for both groups were men and had an Eastern Cooperative Oncology Group Performance Status of 1, Caucasian racial origin, stage IV disease, and a histologic diagnosis of adenocarcinoma. Dose Administration Patients on the 28-day regimen received a total of 180 cycles of treatment (median, 4.00; mean, 3.75; range, 1 10), compared with 249 cycles (median, 6.00; mean, 4.79; range, TABLE ) for the 21-day regimen. There were a total of 24 dose interruptions (median, 0.00; mean, 0.50; range, 0 3) and 27 dose reductions (median, 0.0; mean, 0.56; range, 0 4) for the 28-day regimen, compared with 39 dose interruptions (median, 0.0; mean, 0.75; range, 0 4) and 43 dose reductions (median, 0.0; mean, 0.83; range, 0 4) for the 21-day regimen. Progression-Free Survival Progression-free survival for both treatment groups is summarized in Figure 1. Median progression-free survival was 3.8 months (95% CI, months) for the 28-day regimen and 4.9 months (95% CI, months) for the 21-day regimen. At 1 year, disease had not progressed in Kaplan-Meier summary of progression-free sur- FIGURE 1. vival. Patient Characteristics 28-Day Regimen (n 48) (%) 21-Day Regimen (n 52) (%) Median age, yr (range) 66 (38 82) 67 (44 82) Gender Male 30 (62.5) 31 (59.6) Female 18 (37.5) 21 (40.4) ECOG PS 0 17 (35.4) 19 (36.5) 1 31 (64.6) 33 (63.5) Racial origin Caucasian 44 (91.7) 46 (88.5) Other 4 (8.3) 6 (11.5) Stage IIIb 7 (14.6) 8 (15.4) IV 41 (85.4) 44 (84.6) Histology Adenocarcinoma 25 (52.1) 28 (53.8) Large-cell 2 (4.2) 1 (1.9) Non small-cell 14 (29.2) 7 (13.5) Squamous 7 (14.6) 16 (30.8) ECOG PS, Eastern Cooperative Oncology Group Performance Status. Copyright 2006 by the International Association for the Study of Lung Cancer 21

4 Masters et al. Journal of Thoracic Oncology Volume 1, Number 1, January % (95% CI, %) of patients in the 28-day regimen and 9.8% (95% CI, ) in the 21-day regimen. Differences in median progression-free survival between the two groups were not statistically significant (log-rank statistic, p ). Tumor Response Objective tumor response is summarized in Table 2. The overall response rate was 22.9% (95% CI, %) for the 28-day regimen and 40.4% (95% CI, %) for the 21-day regimen. There was no statistically significant difference in objective response between the two regimens (Fisher s exact test, p ). The 28-day regimen included no patients with CR, 11 with PR, 21 with SD, and 13 with PD. The 21-day regimen included one patient with a CR, 20 with PR, 20 patients with SD, and 10 with PD. Overall Survival Median survival was 8.7 months (95% CI, months) for the 28-day regimen and 8.0 months (95% CI, months) for the 21-day regimen (Figure 2). Oneyear survival was 34.7% (95% CI, %) for patients receiving the 28-day regimen and 36.5% (95% CI, %) for patients receiving the 21-day regimen. Two-year survival for the 28-day and 21-day regimens was 8.7% (95% CI, %) and 16.8% (95% CI, %), respectively. Differences in median survival time between the two groups were not statistically significant (log-rank statistic, p ). Toxicity Summary As shown in Tables 3 and 4, principal grade 3 to 4 toxicities in both treatment arms were hematologic. Grade 3 to 4 hematologic toxicities were anemia (25.0% versus 4.2%), neutropenia (48.1% versus 27.1%), and thrombocytopenia (50.0% versus 37.5%) in the 21-day and 28-day regimens, respectively. A single patient receiving the 21-day regimen in the study experienced grade 3 neutropenic fever. No grade 3 to 4 nonhematologic toxicity (except nausea/vomiting with the 28-day regimen) was observed in more than 10% of patients in either treatment arm. Grade 2 alopecia was experienced by three patients (6.3%) in the 28-day regimen and two patients (3.8%) in the 21-day regimen. TABLE 2. Objective Response 28-Day Regimen (n 48) (%) 21-Day Regimen (n 52) (%) Complete response 0 1(1.9) Partial response 11 (22.9) 20 (38.5) Stable disease 21 (43.8) 20 (38.5) Progressive disease 13 (27.1) 10 (19.2) Unknown 3 (6.3) 1 (1.9) Overall response rate, % % CI FIGURE 2. Kaplan-Meier summary of overall survival. DISCUSSION We present results of the first randomized study to characterize the efficacy and tolerability of carboplatin and gemcitabine when administered according to the Iaffaioli et al. 14 or 21-day schedules. Both schedules delivered toxicity and efficacy results that are comparable to other platinum doublets in advanced NSCLC. There were no statistically significant differences between schedules with respect to progression-free survival, overall survival (median, approximately 8 months for both schedules), or objective response rates. The insignificant difference in response rates between schedules may have been attributable to small sample size. Although there was no statistical superiority, however, progression-free survival, 1-year survival, and 2-year survival favored the 21-day regimen. Nearly twice as many patients on the 21-day regimen were alive at 2 years as compared with the 28-day regimen. The primary safety concern with both regimens was hematologic; myelosuppression appeared to be more pronounced with the 21-day regimen, yet the rate of neutropenic fever was exceptionally low. Recent studies using combination chemotherapy with gemcitabine and carboplatin in NSCLC show response rates in the range of 30% to 50% and median survival ranging from 6 to 16 months. 4,10,12,14,17 24 For these trials, the main doselimiting toxicities were hematologic. Recent review articles have summarized the results of trials using 28- and 21-day schedules of gemcitabine and carboplatin Many previous studies have used the 21-day regimen of gemcitabine plus carboplatin used in the current trial, with most achieving response rates of greater than 30% and median survival exceeding 9 months. 12,17,28 30 Although the response rates observed in this study are comparable, median survival was slightly less as compared with historical results. This is likely related to the high proportion (85%) of patients enrolled in this study with advanced stage IV disease. The current study was unable to duplicate the initial promising results of the 28-day regimen of Iaffaioli et al. (objective response rate, 50%; median duration of response, Copyright 2006 by the International Association for the Study of Lung Cancer

5 Journal of Thoracic Oncology Volume 1, Number 1, January 2006 Gemcitabine and carboplatin in patients with NSCLC TABLE 3. Summary of Toxicity 28-Day Regimen (n 48) 21-Day Regimen (n 52) Hematologic Grade 3 (%) Grade 4 (%) Grade 3/4 (%) Grade 3 (%) Grade 4 (%) Grade 3/4 (%) Anemia 2 (4.2) 0 2 (4.2) 10 (19.2) 3 (5.8) 13 (25.0) Neutropenia 10 (20.8) 3 (6.3) 13 (27.1) 12 (23.1) 13 (25.0) 25 (48.1) Neutropenic fever (1.9) 0 1 (1.9) Thrombocytopenia 16 (33.3) 2 (4.2) 18 (37.5) 25 (48.1) 1 (1.9) 26 (50.0) Leukopenia 7 (14.6) 3 (6.3) 11 (22.9) 14 (26.9) 7 (13.5) 21 (40.4) Nonhematologic Alopecia* Rash 1 (2.1) 0 1 (2.1) 1 (1.9) 0 1 (1.9) Nausea/vomiting 5 (10.4) 0 8 (16.7) 2 (3.8) 0 2 (3.8) Infection 1 (2.1) 0 1 (2.1) 2 (3.8) 0 2 (3.8) Fatigue 3 (6.3) 0 3 (6.3) 5 (9.6) 0 5 (9.6) *Grade 2 alopecia was experienced by three patients (6.3%) with on the 28-day regimen and two patients (3.8%) on the 21-day regimen. TABLE 4. Summary of Trials Using Similar Schedules and Doses of Gemcitabine and Carboplatin Author No. of Patients Objective Response (%) Survival (mo) 21-day schedules Carratto et al. (12) Edelman et al. (38) Obasaju et al. (32) day schedules Iaffaioli et al. (14) Mott et al. (31) Obasaju et al. (32) months; median overall survival, 16 months). However, as noted by Mott et al., the exceptional results of Iaffiaioli et al. were likely attributable to the inclusion of patients with dry stage IIIB disease. 31 Using the same 28-day regimen as the current study and similar inclusion criteria, Mott et al. reported a median survival of 8.3 months, nearly matching that of the current study. Comparable to this study, 83% of the patients in the study by Mott et al. enrolled with stage IV disease. 31 Data obtained in this trial are also comparable to that of a prior 498-patient surveillance trial reported by Obasaju et al. 32 In that study, patients were nonrandomly assigned on the basis of the treating physician s preference to receive 28- and 21-day regimens of gemcitabine plus carboplatin without day-15 gemcitabine, and dosages were the same as in the current trial. Median survival was slightly greater in the study by Obasaju et al. compared with the current trial. However, response and toxicity were analogous to this study; the overall response rate was 22.8% with the 28-day regimen and 32.7% with the 21-day regimen (favoring the 21-day regimen), but hematologic toxicity was slightly less with the 28-day regimen. The carboplatin plus gemcitabine regimen is associated with a low rate of febrile neutropenia compared with taxanebased regimens. In addition, carboplatin plus gemcitabine rarely results in alopecia; only 5% of patients enrolled in the current study experienced grade 2 alopecia, and no severe neurotoxicity was reported in this trial. This compares favorably with other commonly used doublets in advanced NSCLC, including carboplatin plus paclitaxel 33 or cisplatin plus taxotere 34 or vinorelbine. 35 Toxicity consideration, including alopecia and neurotoxicity, may be important determinants of regimen selection when the efficacy of available regimens is similar. An ongoing randomized trial is comparing carboplatin plus gemcitabine to paclitaxel doublets in advanced NSCLC. 36 Previous research has focused more attention on the use of a 21-day regimen, 12,17,28 30 primarily because of the hematologic toxicity associated with older 28-day regimens (which included day-15 gemcitabine). Although the newer 28-day regimen studied by our regimen (minus day-15 gemcitabine) is comparable in efficacy and toxicity to the 21-day regimen, in practice, we have continued to favor 21-day administration of gemcitabine and carboplatin. The 21-day regimen may offer more consistent dose density (this regimen was associated with fewer dose reductions or interruptions) and a shorter duration of chemotherapy when compared with the 28-day regimen. Although baseline characteristics in this study were generally comparable between treatment arms, 16 of 52 patients had squamous cell histology with the 21-day regimen, compared with 7 of 48 patients with the 28-day regimen. It is unclear whether this discrepancy biased the results of this study in any way. Also, as with most phase II studies, no information on poststudy chemotherapy was collected in this study. Although it is likely that many patients in this study went on to receive additional lines of therapy, it is unclear whether such therapy favored either arm of the study. We conclude that either schedule of gemcitabine plus carboplatin evaluated in the current trial is active, well tolerated, and may serve as a backbone for the integration of targeted agents and investigation in earlier stages of this disease, including the adjuvant setting. In a recent study, the addition of exisulind to a 21-day gemcitabine and carboplatin regimen produced no apparent benefit over standard chemotherapy; however, this combination was well tolerated, with mainly hematologic toxicities. 37 Further trial results are awaited on the benefits of incorporating bevacizumab and Copyright 2006 by the International Association for the Study of Lung Cancer 23

6 Masters et al. Journal of Thoracic Oncology Volume 1, Number 1, January 2006 other vascular endothelial growth factor or epidermal growth factor pathway inhibitors to gemcitabine and carboplatin in advanced NSCLC. ACKNOWLEDGMENTS The authors thank all investigators who enrolled patients into this study, including Jean Peliska, William Luginbuhl, John Smith, William Popovic, Dennis Slater, Paul Schaefer, Doyle Stephens, Bozena Witek, Shaker Dakhil, Cheryl Skinner, Mary Lou Auchus, Madeline Garcia, and Peter Eisenberg. REFERENCES 1. American Cancer Society. Cancer Facts and Figures. New York, NY: American Cancer Society, Ginsberg R, Vokes E, Raben A. Non-small cell lung cancer. In V Devia, S Hellman, S Rogenberg (Eds), Cancer: Principles and Practice of Oncology, 5th Ed. Philadelphia: Lippincott-Raven, Pp Delbaldo C, Michiels S, Syz N, Soria JC, Le Chevalier T, Pignon JP. 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