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Phase I-II Study of Gemcitabine and Carboplatin in Stage IIIB-IV Non–Small-Cell Lung Cancer

From the Cattedra di Oncologia Medica, Università di Cagliari, Cagliari; Fondazione "G. Pascale," Istituto Nazionale Tumori Napoli, Naples; Chirurgia Toracica, Università Federico II, Naples; ASL Bari Policlinico, Bari; and Ospedale V. Monaldi, Naples, Italy.

Address reprint requests to Prof R.V. Iaffaioli, II Clinica Medica, Via S. Pansini, 5 80131 Napoli, Italy

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Platinum-based chemotherapy currently represents standard treatment for advanced non–small-cell lung cancer. Gemcitabine is one of the most interesting agents currently in use in advanced non–small-cell lung cancer, and high response rates have been reported when it is administered in combination with cisplatin. The aim of the present study was to evaluate the combination of gemcitabine and carboplatin in a phase I-II study.

PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB-IV non–small-cell lung cancer received carboplatin at area under the concentration-time curve (AUC) 5 mg/mL/min and gemcitabine at an initial dose of 800 mg/m², subsequently escalated by 100 mg/m² per step. Gemcitabine was administered on days 1 and 8 and carboplatin on day 8 of the 28-day cycle. Dose escalation proceeded up to dose-limiting toxicity (DLT), which was defined as grade 4 neutropenia or thrombocytopenia or grade 3 nonhematologic toxicity.

RESULTS: Neutropenia was DLT, inasmuch as it occurred in three of five patients receiving gemcitabine 1,200 mg/m². Nonhematologic toxicities were mild. Gemcitabine 1,100 mg/m² plus carboplatin AUC 5 was recommended for phase II studies. An objective response was observed in 13 (50%) of 26 patients, including four complete responses (15%) and nine partial responses (35%). Median duration of response was 13 months (range, 3 to 23 months). Median overall survival was 16 months (range, 3 to 26 months).

CONCLUSION: The combination of gemcitabine and carboplatin is well tolerated and active. Neutropenia was DLT. The observed activity matches that observable in cisplatin-gemcitabine studies, whereas duration of response and survival are even higher. A phase II trial is under way.

	INTRODUCTION

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LUNG CARCINOMA CURRENTLY represents the leading cause of death from malignant disease in western countries.¹ Non–small-cell lung cancer (NSCLC) constitutes approximately three quarters of primary malignant lung tumors and is unresectable in 70% of cases. In spite of decades of clinical research, the role of chemotherapy in advanced NSCLC is still controversial, because only a few drugs have shown reproducible response rates of more than 15%.¹ The issue of the benefit of chemotherapy over the best supportive care in advanced NSCLC has been addressed by several randomized trials. Three important meta-analyses of these trials have been published^2-4 and have demonstrated a small but significant survival benefit for chemotherapy with concurrent improvement in quality of life. In one meta-analysis,⁵ cisplatin-based chemotherapy for NSCLC resulted in both a higher response rate and better survival than non–cisplatin-containing combinations. In another study,⁶ the use of cisplatin was an independent predictor of improved survival in stage IV disease.

In the last few years, there has been a surge of interest in a number of new agents that have displayed activity in advanced NSCLC.⁷ Among these, gemcitabine (2',2'-difluorodeoxycytidine) is one of the most promising. Although structurally similar to cytarabine, gemcitabine has a different spectrum of antitumor activity, probably as a result of the different kinetics of accumulation and elimination. Gemcitabine is a prodrug with a greater membrane permeability and a higher affinity for deoxycytidine kinase than the parent compound. This leads to the intracellular synthesis of the active metabolite, gemcitabine triphosphate, which achieves higher concentrations and is retained significantly longer than other pyrimidine analogs.⁸

A number of phase II studies of gemcitabine in advanced NSCLC have been performed, and a consistent reproducible response rate of 20% to 26% has been demonstrated, with mean response durations and median overall survival times of approximately 9 months. In all of these studies, in which gemcitabine was used at weekly doses ranging from 800 to 1,250 mg/m² for 3 weeks every 28 days, toxicity was considered mild.^9-11

Among the issues to be addressed in the further development of gemcitabine for treatment of lung cancer, the combined administration with platinum compounds is probably the most valid. Evidence of synergism between cisplatin and gemcitabine exists and is probably the result of gemcitabine's ability to block cellular mechanisms that are necessary for repairing cisplatin-induced DNA damage.¹² A few clinical trials of cisplatin and gemcitabine in advanced NSCLC have been carried out thus far; they have reported response rates averaging 50% and median survival times of approximately 1 year.^13-18

Carboplatin is a platinum analog that, although retaining antitumor activity, has significantly less nephrotoxicity and neurotoxicity than cisplatin. Phase III trials have shown the equivalence of the two agents in the treatment of ovarian cancer.¹⁹ In view of the mild toxicity profile of gemcitabine, its efficacy when combined with cisplatin, and the reduced toxicity of carboplatin compared with cisplatin, we started a phase I-II study of carboplatin and gemcitabine in stage IIIB-IV NSCLC.

	PATIENTS AND METHODS

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Patient Selection
Eligibility criteria for study entry included histologically or cytologically confirmed stage IIIB or IV NSCLC; age 18 to 75 years; no prior chemotherapy; an Eastern Cooperative Oncology Group performance status of 0 to 2; adequate baseline organ function, defined as a WBC count of at least 3,000/µL, a platelet count of at least 100,000/µL, a bilirubin level of less than 1.5 mg/dL, serum transaminase levels of less than 2 times the upper limit of normal, and a creatinine value of less than 1.4 mg/dL; and a life expectancy of at least 12 weeks. Prior palliative radiotherapy to symptomatic metastases was allowed, provided that these lesions were not monitored for tumor response. The study was approved by the ethics committees of participating centers, and written informed consent was required from each patient.

Treatment Plan
Treatment consisted of gemcitabine alone by 30-minute intravenous infusion in 250 mL of normal saline solution on day 1 and gemcitabine followed by carboplatin, each given in a 30-minute intravenous infusion in 250 mL of normal saline solution on day 8 of the 28-day cycle. 5-Hydroxytryptamine-3 receptor antagonists were routinely used as antiemetics on day 8. Carboplatin dose was fixed at area under the curve (AUC) 5 mg/mL/min²⁰ for all patients; gemcitabine was started at a dose of 800 mg/m², which was then escalated by 100 mg/m² per step, with a percentage increase that was much lower than according to the common Fibonacci's modified scheme, because of the high starting gemcitabine dose. The gemcitabine dose-escalation scheme is shown in Table 1. Doses were assigned at registration, and no dose escalation was permitted in individual patients. Full doses of chemotherapy were given on days 1 and 8 if neutrophil and platelet counts were at least 2 x 10⁹/L and 100 x 10⁹/L, respectively. In cases of World Health Organization grade 1 or higher neutropenia or thrombocytopenia on day 1 or day 8, treatment was delayed 1 week. In patients with persistent grade 1 neutropenia or thrombocytopenia after 1 week, treatment was given at doses reduced by 25% on both day 1 and day 8. Patients with persisting higher-grade toxicity after 1 week were taken off study. Cohorts of at least three patients were treated at each dose level. Dose escalation proceeded if no patients had dose-limiting toxicity (DLT) after the first cycle. If one of the three patients had DLT, three more patients were enrolled at that level. Dose escalation was stopped if at least one third of patients of a given cohort had DLT, which was defined as grade 4 neutropenia or thrombocytopenia or grade 3 or 4 nonhematologic toxicity (except for nausea and alopecia). Maximum-tolerated dose was defined as the dose level immediately below that causing DLT in one third of patients or more.

Patient Evaluation
A complete history, physical examination, recording of performance status, complete blood cell count with differential, serum biochemistry, urinanalysis, and ECG were obtained at baseline for each patient. Patients were monitored weekly throughout treatment by physical examination, recording of toxic effects, and complete blood cell count with differential; the serum chemistry determination and ECG were repeated at the beginning of each cycle. Evaluation of tumor response was performed every three cycles, with repetition of all tests that were abnormal at baseline. A complete response (CR) was defined as the complete disappearance of all symptoms and signs of disease. A partial response (PR) was defined as a reduction of more than 50% in the sum of the products of the perpendicular diameters of all measurable lesions; both CRs and PRs were required to persist for at least 4 weeks. Stable disease was defined as a less than 50% reduction or a less than 25% increase in the sum of the products of two perpendicular diameters of all measured lesions. Progressive disease was defined as an increase in the product of two perpendicular diameters of any measured lesion by more than 25% or the appearance of new lesions. Patients with stable or responsive disease after three courses of chemotherapy received additional treatment up to a maximum of six courses; patients with progressive disease were withdrawn from the study. No radiation consolidation was planned for stage IIIB patients. Duration of response was measured from the date of documentation of first response to the date of first evidence of progressive disease. Time to progression was measured from the date of initial treatment to the date of disease progression. Overall survival was measured from the date of initial treatment to the date of death or last follow-up examination and was estimated by the method of Kaplan and Meier.²¹

	RESULTS

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Patient Characteristics
From July 1996 to August 1997, 26 patients were enrolled onto the study. Their median age was 62 years (range, 43 to 70 years); the Eastern Cooperative Oncology Group performance status was 0 in five patients, 1 in 15 patients, and 2 in six patients. Seventeen patients had stage IIIB disease, and nine patients had stage IV disease. Adenocarcinoma was the predominant histologic subtype. No patient had previously received radiation therapy. Patient characteristics are listed in Table 2. A total of 131 courses of treatment were given, for a median of six courses per patient (range, three to six courses).

Hematologic Toxicity
Neutropenia was not observed in the patients treated at the first two dose levels; two of three patients treated at the third dose level had grade 2 neutropenia; and nine patients treated at the fourth dose level had neutropenia, but it reached grade 3 in three patients and grade 4 in only one patient. All of the five patients who were treated at dose level 5 had neutropenia; in particular, three patients had grade 4 neutropenia, which was never febrile, lasted a median of 4 days (range, 2 to 6 days), and resolved spontaneously in all cases without overwhelming infections. Therefore, neutropenia was considered DLT, dose escalation was stopped at this step, and the dose level immediately below was considered the maximum-tolerated dose. Neutropenia was not cumulative, and its severity was not related to patient pretreatment characteristics. Thrombocytopenia was not observed at the first dose level and reached grade 1 in one patient each at the second and third dose levels; six of 12 patients treated at the fourth dose level had grade 1 or 2 thrombocytopenia, and one patient had grade 3 thrombocytopenia. Among the five patients who were treated at the fifth dose level, two had grade 1 to 2 thrombocytopenia, two had grade 3 thrombocytopenia, and one had grade 4 thrombocytopenia, which required platelet transfusions but was not complicated by hemorrhage.

Nonhematologic Toxicity
Nonhematologic side effects were generally mild. Alopecia was common; nausea and vomiting occurred frequently but reached grade 3 in only two patients. Liver enzyme derangement was observed in three patients, and mild renal abnormalities occurred in two patients. Grade 1 peripheral neuropathy occurred in only one patient. Supraventricular ectopic beats were recorded in one completely asymptomatic patient during a routine ECG. All nonhematologic toxic effects were reversible and vanished rapidly after treatment interruption. Details on toxic effects are listed in Tables 3 and 4.

Treatment Delays
Treatment was delayed 1 week in 30 courses because of neutropenia and/or thrombocytopenia. No drug dose reductions were performed. Gemcitabine mean delivered dose-intensity at the fourth step was 518 mg/m²/wk. No patient was withdrawn from the study because of failure to achieve hematologic recovery.

Response Evaluation
All patients completed at least three cycles and were evaluated for response. The drug combination exhibited a significant degree of antitumor activity. The overall response rate was 50% (95% confidence interval, 31% to 69%). In particular, four complete responses (15%) and nine partial responses (35%) were observed among the 26 patients. At the first dose level, one patient achieved a CR, and at the second dose level, one patient achieved a PR; at the third dose level, one CR and one PR were observed. Among the 12 patients treated at the fourth dose level, two CRs and four PRs were observed. Finally, three PRs were achieved among the five patients treated at the fifth dose level. Responses by dose level are listed in Table 5. Median duration of response was 13 months (14 months in stage IIIB, 13 months in stage IV) (range, 3 to 23 months). Among the 12 patients with adenocarcinoma, eight objective responses (three CRs and five PRs) were recorded; one CR and two PRs occurred among the nine patients with squamous cell carcinoma, while two PRs were achieved among the five patients with anaplastic large-cell carcinoma. An objective response was recorded in eight of 17 patients with stage IIIB disease (two CRs) and in five of nine patients with stage IV disease (two CRs); three of five patients with performance status 0, nine of 15 patients with performance status 1, and one of six patients with performance status 2 achieved an objective response. Median time to progression was 10 months (range, 3 to 26 months). Median overall survival was 16 months (range, 3 to 26 months), and the 1-year survival was 62%.

Recommended Dose for Phase II Studies
Dose escalation was stopped at the fifth step because of DLT in more than one third of patients. The recommended gemcitabine dose for phase II studies in this combination regimen with carboplatin AUC 5 is 1,100 mg/m² on days 1 and 8. Treatment should be recycled at 28-day intervals, depending on the observed toxicity.

	DISCUSSION

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Gemcitabine is one of the most promising new drugs for the treatment of NSCLC. There is evidence of a possible synergistic effect between gemcitabine and alkylating agents; the molecular basis of this synergism probably lies in gemcitabine's inhibition of the excision repair mechanism, through which tumor cells can overcome platinum-induced cytotoxicity (DNA-DNA cross-links).¹² Because of the importance of platinum in the treatment of NSCLC, the synergistic effect of combined cisplatin and gemcitabine in several preclinical models, and the non-overlapping toxicity profile of the two agents, there has been great interest in exploring the combination of cisplatin and gemcitabine. Currently, a few phase II trials of gemcitabine and cisplatin have been completed, and a consistent objective response rate averaging 50% has been reported.^13-18 In particular, Crinò et al¹³ obtained a 54% response rate and a median survival time of 61.5 weeks in 48 assessable patients treated with gemcitabine at a dose of 1 g/m²/wk (days 1, 8, and 15), followed by a 1-week rest and cisplatin at a dose of 100 mg/m² on day 2 of each 28-day cycle. In the study by Abratt et al,¹⁴ cisplatin was administered on day 15, and gemcitabine was administered at a dose of 1 g/m²/wk on days 1, 8, and 15. In this study, a 52% response rate was obtained, with a median survival duration of 13 months. Data from the six studies have been pooled and analyzed with the aim of assessing the impact of various prognostic factors.²² This analysis showed that the cisplatin schedule and sex were the only statistically significant variables. Regression analysis showed that cisplatin delivery on day 2 or 15 was associated with a better response rate and survival than delivery on day 1 or fractionated delivery on days 1, 8, and 15.

Carboplatin is a platinum analog that, although retaining antitumor activity, has significantly less neurotoxicity and nephrotoxicity than cisplatin. The lack of severe myelosuppression with carboplatin suggests that a modestly myelosuppressive agent, such as gemcitabine, may be safely added to carboplatin. In our study, the combination of carboplatin and gemcitabine proved feasible, well tolerated, and active. The rationale for the schedule used in this study is based on classical cytokinetic theory with the initial fractionated administration of a phase-specific agent aimed at eradicating the initially proliferating cells and those subsequently recruited into proliferation, followed by a cycle-specific agent that will destroy the residual nonproliferating cells.^23,24 The subsequent rest period allows for normal tissue repopulation. As expected, in our study, neutropenia was the DLT; in fact, grade 4 neutropenia occurred in three of five patients treated at a dose of carboplatin AUC 5 and gemcitabine 1,200 mg/m². However, neither treatment-related deaths nor overwhelming infections occurred, and neutropenia recovered in no more than 6 days without growth factor support. Thrombocytopenia was significant only at the last step, with three of five patients having grade 3 to 4 toxicity. However, no patients had hemorrhage, and only in one patient were prophylactic platelet transfusions required. We decided to recycle treatment every 28 days, instead of every 21 days, which is the most common treatment interval when gemcitabine is used on days 1 and 8. This schedule was chosen because we thought that carboplatin recycling every 21 days, along with the high gemcitabine dose-intensity that would have been achieved with an every-3-week schedule, would likely translate into high bone marrow toxicity.

Although evaluation of antitumor activity was not a primary end point in our study, we can state that the combination of carboplatin and gemcitabine is definitely active. No substantial differences in terms of objective responses were reported among patients treated at different dose levels; in fact, a CR was observed even at the first dose level. At the fourth dose level, which was expanded to 12 patients to obtain a more reliable estimate of the activity of the regimen, objective responses were reported in six of 12 patients, and two of these responses were CRs. This apparent lack of correlation between gemcitabine dose and response rate is in keeping with the previous observation that a clear dose-response curve for gemcitabine is not evident and the response rate to the drug does not seem to differ substantially above a "threshold" dose.²⁵ We think that both duration of response and overall survival in our trial are worth emphasizing and are above those reported in cisplatin-gemcitabine studies,^13,14 although the majority of patients in our study had stage IIIB disease. Furthermore, the response rate achieved in adenocarcinoma seems very encouraging, even if the low number of cases prevents these data from achieving statistical significance.

It is difficult to compare the results of our study with those of similar studies, since no final publications of this combination have appeared in the literature thus far. A few phase I or II studies of carboplatin and gemcitabine have been initiated. In the first study,²⁶ gemcitabine was administered weekly for 3 weeks every 28 days at a fixed dose of 1,000 mg/m²; carboplatin was given immediately before gemcitabine on day 1 at an initial AUC dose of 4 mg/mL/min. As no toxicity was observed in the three patients treated at the first dose level, nine additional patients were entered at the next level (AUC 5.2 mg/mL/min). At this dose, two patients experienced grade 4 neutropenia and two patients had grade 4 thrombocytopenia. Actual carboplatin AUC correlated with decrease in platelet counts, although no pharmacokinetic interactions between the two compounds were observed. Four of 12 patients (33%) achieved a PR; median survival for the patients was 45 weeks, which compares favorably with the generally accepted figures for platinum-based combination chemotherapy in advanced NSCLC.⁴ In the second study, which is still ongoing,²⁷ gemcitabine is given at a starting dose of 1,000 mg/m² on a weekly basis for 3 weeks every 28 days; carboplatin, in this study, is given after gemcitabine once every 4 weeks on day 1, at an initial AUC dose of 5.2 mg/mL/min. The Hoosier Oncology Group has recently reported severe thrombocytopenia, which has led to premature discontinuation of a phase II study in which gemcitabine was administered at 1,000 mg/m² on days 1, 8, and 15 every 4 weeks, and carboplatin at an AUC dose of 5 mg/mL/min on day 1 of the 28-day cycle.²⁸ Only seven patients have been accrued and evaluated in this study. However, such a severe hematologic toxicity was entirely unexpected and hard to explain, as the authors acknowledged. The higher gemcitabine dose-intensity in comparison to that reached in our study might be an explanation for the platelet toxicity, which was much more impressive than in our study. Finally, Martinez et al²⁹ are currently conducting a phase I study in which gemcitabine (administered on days 1 and 8) and carboplatin (administered on day 1 of a 21-day cycle) are alternately escalated. This study has accrued 12 patients thus far, and DLT has not yet been reached at gemcitabine doses of 1,000 mg/m² and carboplatin at AUC 5.2 mg/mL/min.

In conclusion, the combination of gemcitabine administered at a dose of 1,100 mg/m² on days 1 and 8 and carboplatin at AUC 5 on day 8, every 28 days, is feasible, well tolerated, and active. A large phase II trial is currently under way to obtain a more reliable estimate of the response rate achievable with this regimen and to evaluate its impact on overall survival and quality of life.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Ihde DC: Chemotherapy of lung cancer. N Engl J Med 327:1434-1441, 1992[Medline]

2. Grilli R, Oxman AD, Julian JA: Chemotherapy for advanced non-small cell lung cancer: How much benefit is enough? J Clin Oncol 11:1866-1872, 1993[Abstract/Free Full Text]

3. Souquet PJ, Chauvin F, Boissel JP, et al: Polychemotherapy in advanced non small cell lung cancer: A meta-analysis. Lancet 342:19-21, 1993[Medline]

4. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials—Non-Small Cell Lung Cancer Collaborative Group. BMJ 311:899-909, 1995[Abstract/Free Full Text]

5. Donnadieu N, Paesmans M, Sculier JP, et al: Chemotherapy of non-small cell lung cancer according to disease extent: A meta-analysis of the literature. Lung Cancer 7:243-252, 1991

6. Albain KS, Crowley JJ, LeBlanc M, et al: Survival determinants in extensive-stage non-small-cell lung cancer: The Southwest Oncology Group experience. J Clin Oncol 9:1618-1626, 1991[Abstract]

7. Lilenbaum RC, Green MR: Novel chemotherapeutic agents in the treatment of non-small-cell lung cancer. J Clin Oncol 11:1391-1402, 1993[Abstract/Free Full Text]

8. Heinemann V, Hertel LW, Grindey GB, et al: Comparison of the cellular pharmacokinetics and toxicity of 2',2'-difluorodeoxycytidine and 1-D-arabinofuranosylcytosine. Cancer Res 48:4024-4031, 1988[Abstract/Free Full Text]

9. Anderson H, Lund B, Back F, et al: Single-agent activity of weekly gemcitabine in advanced non-small cell lung cancer: A phase II study. J Clin Oncol 12:1821-1826, 1994[Abstract/Free Full Text]

10. Abratt RP, Bezwoda WR, Falkson G, et al: Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: A phase II study. J Clin Oncol 12:1535-1540, 1994[Abstract/Free Full Text]

11. Gatzemeier U, Shepherd FA, Le Chevalier T, et al: Activity of gemcitabine in patients with non-small cell lung cancer: A multicentre, extended phase II study. Eur J Cancer 32A:243-248, 1996

12. Peters GJ, Bergman AM, Ruiz van Haperen VWT, et al: Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 22:72-79, 1995

13. Crinò L, Scagliotti G, Marangolo M, et al: Cisplatin-gemcitabine combination in advanced non-small-cell lung cancer: A phase II study. J Clin Oncol 15:297-303, 1997[Abstract/Free Full Text]

14. Abratt RP, Bezwoda WR, Goedhals L, et al: Weekly gemcitabine with monthly cisplatin: Effective chemotherapy for advanced non-small-cell lung cancer. J Clin Oncol 15:744-749, 1997[Abstract/Free Full Text]

15. Anton A, Artal A, Carrato A, et al: Gemcitabine plus cisplatin in advanced non-small cell lung cancer: Final phase II results. Proc Am Soc Clin Oncol 16:461a, 1997 (abstr)

16. Cardenal F, Rosell R, Anton A, et al: Gemcitabine + cisplatin vs etoposide + cisplatin in advanced non-small cell lung cancer patients: Preliminary randomized phase III results. Proc Am Soc Clin Oncol 16:458a, 1997 (abstr)

17. Sandler A, Nemunaitis J, Denham C, et al: Phase III study of cisplatin with or without gemcitabine in patients with advanced non small cell lung cancer. Proc Am Soc Clin Oncol 17:1747a, 1998 (abstr)

18. Shepherd FA, Cormier Y, Burkes R, et al: Phase II trial of gemcitabine and weekly cisplatin for advanced non-small cell lung cancer. Semin Oncol 24:S827-S830, 1997 (suppl 8)

19. Alberts DS, Green S, Hannigan EV, et al: Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: Final report of the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol 10:706-717, 1992[Abstract/Free Full Text]

20. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756, 1989[Abstract]

21. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958

22. Shepherd FA, Anglin G, Abratt R, et al: Influence of gemcitabine and cisplatin schedule on response and survival in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 17:1816a, 1998 (abstr)

23. Valeriote FA, Edelstein MB: The role of cell kinetics in cancer chemotherapy. Semin Oncol 4:217-226, 1977[Medline]

24. Tannock IF: Cell kinetics and chemotherapy: A critical review. Cancer Treat Rep 62:1117-1133, 1978[Medline]

25. Eli Lilly: New Drug Submission. Canadian Comprehensive Summary Clinical Synopsis (part 3, vol 1). Indianapolis, IN, Eli Lilly, 1994, p 38

26. Carmichael J, Allerheiligen S, Walling J: A phase I study of gemcitabine and carboplatin in non-small cell lung cancer. Semin Oncol 23:55-59, 1996 (5 suppl 10)

27. Pedersen AG: Phase I studies of gemcitabine combined with carboplatin or paclitaxel. Semin Oncol 24:S764-S768, 1997 (2 suppl 7)

28. Ng EW, Sandler AB, Einhorn LH: A phase II study of carboplatin plus gemcitabine in non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 17:1801a, 1998 (abstr)

29. Martinez J, Panizo A, Alonso MA, et al: Gemcitabine plus carboplatin in advanced non-small cell lung cancer (NSCLC): A phase I trial. Proc Am Soc Clin Oncol 17:1903a, 1998 (abstr)

Submitted June 17, 1998; accepted November 11, 1998.

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