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Journal of Clinical Oncology, Vol 23, No 33 (November 20), 2005: pp. 8380-8388 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.2781 Phase III Trial of Gemcitabine Plus Carboplatin Versus Single-Agent Gemcitabine in the Treatment of Locally Advanced or Metastatic Non–Small-Cell Lung Cancer: The Swedish Lung Cancer Study GroupFrom the Department of Pulmonary Medicine and Oncologic Center, University Hospital, Linköping; Department of Pulmonary Medicine, Karolinska University Hospital, Stockholm; Department of Pulmonary Medicine, Akademiska Hospital University of Uppsala, Uppsala; Ronny Westberg Clinical Research, Sundbyberg, Sweden; and Eli Lilly and Company, Indianapolis, IN. Address reprint requests to Christer Sederholm, MD, Department of Pulmonary Medicine, University Hospital, S-581 85 Linköping, Sweden; e-mail: christer.sederholm{at}lio.se
PURPOSE: This phase III study compared overall survival in patients with locally advanced or metastatic non–small-cell lung cancer (NSCLC) when treated with single-agent gemcitabine versus gemcitabine/carboplatin. Secondary objectives were to compare response, time to progression, toxicity, and quality of life. PATIENTS AND METHODS: Chemotherapy-naive patients received either gemcitabine alone (1,250 mg/m2 on days 1 and 8; gemcitabine arm) or with carboplatin (area under the curve 5 on day 1; GC arm) every 21 days. RESULTS: Demographics and disease characteristics of 334 randomly assigned patients were comparable on both arms. An intent-to-treat analysis showed significantly better overall survival (log-rank P = .0205) and 2-year survival (15% v 5%; P = .009) favoring the GC arm. Per Cox multivariate analysis, only two covariates, treatment arm (GC v G) and baseline performance status (0 or 1 v 2), independently influenced survival. Per-protocol analyses showed significantly longer median time to progression (5.7 v 3.9 months; P = .0001) and significantly higher objective response rate (29.6 v 11.3%; P < .0001) in the GC arm. Grade 3 to 4 leucopenia and thrombocytopenia were significantly more pronounced in the GC arm (P for both variables < .001) but importantly without associated increases in fever, infection, bleeding, or hospitalizations. There was no discernible difference in global quality-of-life patterns between treatment arms. CONCLUSION: In advanced NSCLC, gemcitabine/carboplatin therapy resulted in significant survival benefit compared with single-agent gemcitabine without undue increase in toxicity.
A majority of patients with non–small-cell lung cancer (NSCLC) present with locally advanced or metastatic disease that is incurable with existing treatment modalities.1 Platinum-based chemotherapy offers a modest survival benefit and better quality of life (QoL) compared with best supportive care, yet only 20% to 25% of patients survive beyond l year.2 Many new drugs, such as the taxanes, vinorelbine, gemcitabine, and irinotecan have shown single-agent efficacy with lower toxicity.
Experience with single-agent gemcitabine in NSCLC, including more than 500 patients in six phase II studies, showed a response rate of Cisplatin-based doublets are the accepted standard palliative treatment in good-performance patients with advanced NSCLC; however, nonhematologic toxicities and complexity of administration contraindicate use of cisplatin in a substantial proportion of patients, mostly older patients or those with comorbid conditions. Its analog, carboplatin, has a more favorable toxicity profile, especially regarding nausea/emesis, fatigue, nephrotoxicity, neurotoxicity, and ototoxicity, and is easy to administer in an outpatient setting. Studies comparing cisplatin and carboplatin doublets suggest roughly similar efficacy in advanced NSCLC, at least in terms of survival.7-9 Although still a controversial issue, carboplatin has been substituted for cisplatin in a number of regimens including gemcitabine/cisplatin for improved tolerability in a strictly palliative treatment setting. Initial phase II studies of the gemcitabine/cisplatin combination used a 28-day schedule with gemcitabine administered on days 1, 8, and 15. The activity was promising, but frequent thrombocytopenia and neutropenia occurred. Hence a modified 21-day schedule was developed by eliminating the day-15 gemcitabine dose, thus achieving preserved activity and manageable hematologic toxicity.10-12 A recent pilot study evaluating the feasibility and activity of gemcitabine plus carboplatin using a 21-day schedule, showed a promising response of 43%, median survival of 12 months and 2-year survival of 17%, with good tolerability in 35 patients, mostly with stage IV disease.13 Therefore, we decided to conduct a randomized study exploring the combination of gemcitabine/carboplatin versus gemcitabine alone in advanced NSCLC for superiority in overall survival (OS) without undue increase in toxicity or impairment in QoL. OS was the primary objective, with secondary end points being QoL, safety, time to progression, and objective response.
Eligibility Criteria Chemotherapy-naive patients diagnosed with histologic or cytologic stage IIIB or IV NSCLC (according to American Joint Committee on Cancer) not amenable to surgery or radiation of curative intent were enrolled. Stage IIIB specifically referred to patients with malignant pleural effusion or tumor extension of such degree that encompassment into a radiation field with curative intent was prohibitive. Other enrollment criteria were as follows: age  18 years with no upper age restriction, WHO performance status 0 to 2, and acceptable liver and kidney functions. The most important exclusion criteria were uncontrolled hypercalcemia, known CNS metastases, or secondary malignancy within the last 5 years. Signed informed consent was obtained from all patients before randomization. The study was approved by the ethics committee at the University of Linköping and participating regional ethics committees and was conducted per the guidelines of good clinical practice and the Declaration of Helsinki.
Treatment Plan
Dose Adjustments
Dose adjustments within a cycle were made based on weekly hematology. Day 8 gemcitabine was given in full for actual WBC
Baseline and Treatment Assessments Performance status was determined using the WHO scale. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30–Lung Cancer-13 was used for QoL assessment and administered within 1 week before start of chemotherapy before randomization and during the rest week in each new cycle. All eligible patients who received treatment with at least one dose of gemcitabine or GC were evaluated before each cycle for efficacy and safety using WHO criteria.14 All recorded tumor responses were intramurally reviewed and rejected or accepted in consensus by the study group. Survival was measured from date of randomization until date of death or date of last follow-up for living patients. Time to progressive disease was measured from date of randomization until date of documented progressive disease/death or date of last follow-up for progression-free living patients. Patients were followed up after completion of chemotherapy every second month during the first year and then every third month, until disease progression or death. In the event of progressive disease, patients were given the following treatment options at the discretion of the responsible physician: best supportive care (including palliative radiotherapy), reinduction with the primary chemotherapy (provided a treatment-free interval > 3 months), or second-line therapy with docetaxel. Cross-over from primary single-agent gemcitabine to second-line treatment with a platinum-containing regimen was not allowed.
Statistical Analysis
The main objective (ie, OS) was investigated according to an intent-to-treat (ITT) analysis on all 334 randomly assigned patients. Secondary objectives (ie, ORR, TTP, toxicity, and QoL) were investigated according to per-protocol (PP) analyses on eligible and assessable patients. Time-dependent variables (OS, TTP) were plotted using Kaplan-Meier estimates and differences between groups were calculated according to the log-rank test; in addition, survival hazard ratios were calculated. A Cox proportional hazards regression model was used in a multivariate analysis of relations between OS and prognostic factors. Differences between groups regarding ORR, baseline characteristics, and toxicity were analyzed with the
Patient Characteristics A total of 334 patients from 17 clinics in Sweden were randomly assigned between October 1998 and January 2001 to receive either gemcitabine alone (gemcitabine arm, 170 patients) or in combination with carboplatin (GC arm, 164 patients). Two thirds of the patients were recruited from four major centers: Karolinska University Hospital (102 patients), Linköping University Hospital (56 patients), Västerås Regional Hospital (39 patients), and Academic University Hospital Uppsala (26 patients). The study was regularly monitored by the same research nurse from the Department of Pulmonary Medicine at the University Hospital in Linköping. The most prominent histology was adenocarcinoma (51%). More than one third of patients (37%) were 70 years of age or older; the majority (59%) had stage IV disease, 85% had PS of 0 to 1 at baseline, and one third reported weight loss greater than 5% in the preceding 3 months. The two arms were well balanced in terms of patient demographics and disease characteristics (Table 1), yet there were minor imbalances. The gemcitabine arm had a small excess of females (48% v 40%), less occurrence of weight loss exceeding 5% (29% v 35%), and fewer patients with PS of 2 at baseline (12% v 18%), but more stage IV patients (63% v 54%) than the GC arm. All of these small differences were nonsignificant.
Treatment Administration Nine of the 334 enrolled patients did not receive a single dose of study drug; four patients suffered from deteriorating PS and early death, and five patients had different violations of protocol eligibility rules. The remaining 325 patients (gemcitabine, n = 169; GC, n = 156) received a total of 1,416 treatment cycles. The median number of cycles per patient was five cycles for the gemcitabine arm and six cycles for the GC arm. Fifty-six percent of patients on the gemcitabine arm and 47% on the GC arm discontinued treatment before completing six cycles of therapy. The main reason for discontinuation was disease progression (gemcitabine, n = 68%; GC, n = 50%). Study treatment was prematurely stopped because of adverse events in 10% of patients (gemcitabine, n = 9%; GC, n = 12%). Both drugs had high values for recorded DI; gemcitabine mean DI was 1.0 (range, 0.5 to 1.2) on the G arm and 0.9 (range, 0.5 to 1.0) on the GC arm, whereas carboplatin mean DI was 0.9 (range, 0.5 to 1.1). No patients received bone marrow support with granulocyte colony-stimulating factor or erythropoietin.
ITT Analysis
PP Analyses A total of eight patients did not fulfill the protocol eligibility criteria as a result of inadequate renal and hepatic function (three patients); PS of 3 (two patients); more than 30 days between randomization and start of treatment (one patient); diagnosis of other primary tumor (eg, pulmonary metastasis from primary breast cancer; one patient); and pathology report missing (one patient). These eight patients, in addition to nine patients who never received study treatment, made up a total of 17 unassessable patients, leaving 317 patients (gemcitabine, n = 167; GC, n = 150) eligible for PP analyses.
Similar to the ITT analysis, PP analysis revealed a significant difference in OS favoring the GC arm (log-rank P = .0043). In an unadjusted univariate analysis, median survival seemed better among females (10.3 v 8.8 months in males), in patients with baseline PS 0 or 1 (10.0 v 4.0 months for PS 2), in those with stage IIIB disease (10.5 v 8.3 months for stage IV), and in those with weight loss
OS for patients with PS of 0 to 1 was significantly better on the GC arm (log-rank P = .0015). Survival in the small fraction of patients with PS of 2 (24 and 20 patients on GC and gemcitabine arms, respectively) was not significantly different (log-rank P = .6) but seemed better on the GC arm (median survival, 5.1 v 3.5 months for the gemcitabine arm).
Time to Progression
ORR Response evaluations could not be performed in 16 of 317 eligible patients because of inadequate baseline or follow-up tumor assessments, leaving 301 patients eligible for ORR analysis. Of 142 patients on the GC arm, there were two complete responders and 40 partial responders. Of 159 patients on the gemcitabine arm, 18 patients had a partial response. The ORR of 29.6% (95% CI, 22.2 to 37.8) in the GC arm was significantly higher (P < .0001) than the 11.3% (95% CI, 6.9 to 17.3) rate in the gemcitabine arm.
Toxicity
Grade 3 to 4 nonhematologic toxicities were infrequent, usually less than 5%; however, grade 3 pulmonary events were slightly greater than 10% in both treatment arms (Table 4). The proportion of patients requiring all types of transfusions (RBCs or platelets) was significantly higher (P < .0001) in the GC arm (45%; 127 transfusions) than the gemcitabine arm (14%; 33 transfusions). Nine patients (6%) on the GC arm required prophylactic platelet transfusions totaling 0.07 transfusion events per patient (11 of 156). The proportion of patients hospitalized for any reason was 27% in the gemcitabine arm and 25% in the GC arm. Median hospital stay per hospitalized patient for any reason was equally long in both groups (gemcitabine, 9 days; GC, 7 days). There was no difference between treatment arms in the proportion of patients hospitalized because of study-related adverse events (8.9% in the gemcitabine arm v 9.6% in the GC arm). However, the median hospital stay per hospitalized patient resulting from study-related adverse events was significantly longer (P = .025) in the gemcitabine arm (9 days v 4 days in GC arm). This observation is somewhat surprising. A plausible explanation might be that patients in the gemcitabine arm initially hospitalized with what appeared to be study drug–related dyspnea might have suffered from mainly progressive disease-related dyspnea, prolonging their hospital stay. No toxic deaths were registered on either treatment arm.
QoL
Subgroup Analysis of Older Patients
ORR was more or less the same in both age groups: 18.6% (< 70 years) versus 22.1% (
Second-Line Treatment Approximately one third of patients in each arm received some form of second-line chemotherapy. Docetaxel was given to 18% and 16% of patients in the gemcitabine and GC arms, respectively. Reinduction with the primary treatment was offered to 8% of patients on the gemcitabine arm and 14% in the GC arm. Platinum-based second-line treatment or other chemotherapy regimens were given to less than 8% of patients in either group.
In our randomized study, the GC combination showed significantly higher efficacy in terms of OS, 2-year survival, TTP, and ORR compared with gemcitabine alone in the treatment of patients with advanced NSCLC. Gemcitabine has well-documented single-agent activity in NSCLC, offering significant sustained benefit in QoL and disease-related symptoms in comparison to best supportive care or several other oncolytic regimens.5,6,15,16 Our efficacy results for single-agent gemcitabine (median survival, 8.6 months; 1-year survival rate, 32%; TTP, 3.9 months; and ORR, 11%) fall clearly within the range for those respective values previously seen in several trials evaluating gemcitabine monotherapy in advanced NSCLC.3,17-19 The GC regimen showed considerable advantage over single-agent gemcitabine. Although our ORR (29.6%) is slightly on the lower side when compared with phase II studies of this combination,20,21 the median survival of 10 months and 1-year survival of 40% represent typical values reported in earlier studies. Interestingly, both ORR and median survival in this study are quite similar to those reported in recently published phase III trials evaluating the GC combination.22,26 Because our results for both gemcitabine and GC are within the observed and expected range, the benefit seen with the GC regimen seems to be substantiated. Although some variations were noticed based on sex, disease stage, weight loss, and so on according to a Cox multivariate analysis of prognostic factors in relation to survival, only PS at baseline and treatment regimen directly influenced survival. For patients with PS of 2 or those on the gemcitabine arm, the risk of dying increased by 1.5 to two times in comparison with those treated on the GC arm or with PS 0 to 1, respectively. The prominent toxicity was hematologic, with the GC arm showing significantly higher occurrence of grade 3 to 4 leucopenia and thrombocytopenia. However, the incidence of these toxicities was consistent with expectations based on previous reports for this combination, were manageable, and did not lead to higher incidence of fever/infection or bleeding episodes.21,23,24 The proportion of patients receiving transfusions and overall number of mostly RBC transfusions were significantly higher in the GC arm. Carboplatin, and gemcitabine in both treatment arms, achieved almost full DIs, indicating successful administration of these drugs with minimum dose adjustments, once again a reflection of the favorable toxicity profile. Despite the addition of carboplatin to gemcitabine and a higher incidence of hematologic toxicities and transfusions, the frequency and length of hospital stay was not higher in the GC arm. There was also no discernible difference between treatment arms for global QoL patterns. Our results are in agreement with many other previous trials evaluating the GC combination,10,22,26 in other words, that the 3-week schedule of this combination is feasible and efficacious in the treatment of advanced NSCLC. Moreover, our results show that this combination significantly improves ORR, TTP, and OS compared with gemcitabine alone, while keeping the toxicity profile manageable.
Lung cancer is prevalent in older individuals, and approximately one third of these patients are 70 years of age or older. As a function of age, these patients may have different reactions to drugs compared with a younger population, and it is crucial to ascertain the efficacy of any key regimen in older patients. With this rationale, we performed a retrospective subgroup analysis on patients
A retrospective analysis of phase II studies25 reported the safety and efficacy profile for single-agent gemcitabine was similar in the age groups
In summary, the GC combination given as a 3-week schedule in patients with advanced NSCLC is more efficacious than single-agent gemcitabine. The combination is well tolerated and does not lead to an increase in hospitalizations or drug-related adverse events. This study also illustrates that administration of GC is feasible in the
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank the following participating institutions: Departments of Pulmonary Medicine at Karolinska and Huddinge in Stockholm, Linköping, Uppsala, Västerås, Gävle, Kalmar, Jönköping, Visby, Falun, Lund, Växjö, Malmö, and Ängelholm, and Departments of Oncology in Karlstad, Eskilstuna, and Uppsala. We thank Birgitta Johansson (Uppsala) for assistance with quality-of-life analysis.
Supported by grant from Eli Lilly and Company, Indianapolis, IN. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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6. Vansteenkiste J, Vandebroek J, Nackaerts K, et al: Clinical-benefit response in advanced non-small-cell lung cancer: A multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine. Ann Oncol 12:1221-1230, 2001 7. 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 8:1556-1562, 1990[Abstract] 8. Jelic S, Mitrovic L, Radosavljevic D, et al: Survival advantage for carboplatin substituting cisplatin in combination with vindesine and mitomycin C for stage IIIB and IV squamous-cell bronchogenic carcinoma: A randomized phase III study. Lung Cancer 34:1-13, 2001[Medline] 9. Klastersky J, Sculier JP, Dabouis G, et al: A randomized trial of two platinum combinations in patients with advanced non-small cell lung cancer: A preliminary report—European Organization for the Research and Treatment of Cancer–Lung Cancer Working Party. Semin Oncol 17:20-24, 1990 (suppl 2)[Medline] 10. Carrato A, Garcia-Gomez J, Alberola V, et al: Carboplatin (CARBO) in combination with gemcitabine (GEM) in advanced non-small cell lung cancer (NSCLC): Comparison of two consecutive phase II trials using different schedules. Proc Am Soc Clin Oncol 18:498a, 1999 (abstr 1922) 11. Parente B, Barrosa A, Conde S, et al: A prospective study of gemcitabine and carboplatin as first-line therapy in advanced non-small cell lung cancer: Toxicity of a three- versus a four-week schedule. Semin Oncol 28:10-14, 2001 (suppl 10) 12. Crino L, Calandri C: Gemzar platinum combinations: Phase III trials in non-small cell lung cancer. Lung Cancer 38:9-12, 2002 (suppl 2)[Medline] 13. Sederholm C: A phase II study of gemcitabine plus carboplatin in chemonaive patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 18:490a, 1999 (abstr 1889) 14. World Health Organization: WHO handbook for Reporting the Results of Cancer Treatment (vol 48). Geneva, Switzerland, World Health Organization, 1979 15. Anderson H, Hopwood P, Stephens RJ, et al: Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer: A randomized trial with quality of life as the primary outcome—UK NSCLC Gemcitabine Group. Br J Cancer 83:447-453, 2000[CrossRef][Medline] 16. ten Bokkel Huinink WW, Bergman B, Chemaissani A, et al: Single-agent gemcitabine: An active and better tolerated alternative to standard cisplatin-based chemotherapy in locally advanced or metastatic non-small cell lung cancer. Lung Cancer 26:85-94, 1999[CrossRef][Medline] 17. LeChevalier T, Gottfried M, Gatzemeier U, et al: A phase II multicenter study of gemcitabine in non-small cell lung cancers. Bull Cancer 84:282-288, 1997[Medline] 18. Gatzemeier U, Shepherd FA, LeChevalier T: Activity of gemcitabine in patients with non-small cell lung cancer: A multicentre, extended phase II study. Eur J Cancer 32A:243-248, 1996 19. Gatzemeier U, Peters H-D: The use of gemcitabine in non-small cell lung cancer, in Schiller JH (ed): Updates in Advances in Lung Cancer (vol 29). Progress in Respiratory Research. Basel, Switzerland, Karger, 1997, pp 91-105 20. Edelman MJ: Past, present, and future of gemcitabine and carboplatin regimens in advanced non-small cell lung cancer. Lung Cancer 38:S37–S43, 2002 (suppl 2)[CrossRef]
21. Iaffaioli RV, Tortoriello A, Facchini G: Phase I-II study of gemcitabine and carboplatin in Stage IIIB-IV non-small cell lung cancer. J Clin Oncol 17:921-926, 1999 22. Zatloukal P, Petruzelka L, Zemanova M, et al: Gemcitabine plus cisplatin vs. gemcitabine plus carboplatin in stage IIIB and IV non-small cell lung cancer: A phase III randomized trial. Lung Cancer 41:321-331, 2003[CrossRef][Medline] 23. Harper P: Update on gemcitabine/carboplatin in patients with advanced non-small cell lung cancer. Semin Oncol 30:2-12, 2003 (suppl 10) 24. Gandara DR, Lau DH, Lara PN, et al: Gemcitabine/carboplatin combination regimens: Importance of dose schedule. Oncology 14:26-30, 2000 (suppl 4) 25. Shepherd FA, Abratt RP, Anderson H, et al: Gemcitabine in the treatment of elderly patients with advanced non-small cell lung cancer. Semin Oncol 24:S7-S50-S7-S55, 1997 (suppl 7)
26. Rudd RM, Gower NH, Spiro SG, et al: Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non–small-cell lung cancer: A phase III randomized study of the London Lung Cancer Group. J Clin Oncol 23:142-153, 2005 Submitted January 21, 2005; accepted August 9, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5% in the preceding 3 months), and performance status (PS; 0 to 1 v 2). 
2 test. Median, mean, and 95% CIs were calculated when appropriate. For each patient, the dose-intensity (DI) was calculated as the ratio of the actual dose delivered per unit time divided by the planned dose per unit time. Cycle length of 21 days was used in the calculation. QoL data were analyzed using repeated measures of analysis of covariates. 
