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Journal of Clinical Oncology, Vol 23, No 27 (September 20), 2005: pp. 6664-6673 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.519 Phase I/IIa Study of Cisplatin and Gemcitabine As Induction Chemotherapy Followed by Concurrent Chemoradiotherapy With Gemcitabine and Paclitaxel for Locally Advanced Non–Small-Cell Lung CancerFrom the University of Alabama at Birmingham; and Birmingham Veterans Administration Medical Center, Birmingham, AL Address reprint requests to Francisco Robert, MD, FACP, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 Sixth Ave S, Birmingham, AL 35294-3300; e-mail: pacorobertuab{at}cs.com
PURPOSE: This is a phase I/IIa study to assess tolerance of gemcitabine and paclitaxel with radiotherapy in locally advanced non–small-cell lung cancer after induction chemotherapy. PATIENTS AND METHODS: Fifty-seven patients with stage III non–small-cell lung cancer were treated with cisplatin 80 mg/m2 on days 1 and 22 and gemcitabine 1,250 mg/m2 on days 1, 8, 22, and 28. Chemoradiotherapy began on day 43 as follows: cohort 1 (n = 9), gemcitabine 300 mg/m2 and paclitaxel 35 mg/m2 weekly (except week 9); cohort 2 (n = 9), gemcitabine 150 mg/m2 and paclitaxel 35 mg/m2 weekly (except week 9); cohort 3 (n = 10) and the 25 phase IIa patients, gemcitabine 300 mg/m2 and paclitaxel 135 mg/m2 every 21 days. Patients were treated with three-dimensional thoracic radiotherapy concurrently to 60 Gy.
RESULTS: Weekly chemotherapy resulted in grade 4 esophageal and grade 3 or higher pulmonary toxicities. Reduction in dose density (cohort 3) led to a tolerable toxicity profile and was chosen as the phase IIa regimen. The response rate to induction was 49%, with stable disease in 40% of the patients. The response rate after consolidation therapy was 75% (94% for weekly chemotherapy v 82% for every 3 weeks). Median survival was 23 months, and 3-year survival was 45% for eligible patients. Local relapse occurred in 20% of the patients. Performance status of more than 1 predicted for poor outcome, but baseline pulmonary function did not. Dosimetric parameters including V15, V20, V30 (percent lung volume receiving CONCLUSION: Additional investigation with the 3-week schedule is warranted in patients with a good performance status based on the safety profile and preliminary efficacy data observed in this study.
For approximately 25% to 30% of patients with non–small-cell lung cancer (NSCLC) who present with locally advanced tumors (stage IIIa or IIIb), treatment represents a modern therapeutic dilemma. Most patients will die from distant metastases, but a frequent failure to produce a cure is based, at least in part, on the inability of conventional combined modality regimens to eradicate locoregional disease.1-5 Recent data suggest a survival benefit from concomitant chemoradiotherapy2-8; however, the optimal timing and sequence remains undefined. Gemcitabine (Gemzar; Eli Lilly, Indianapolis, IN) and paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) have significant single-agent activity and radiation-sensitizing effects in NSCLC.9-13 Their different mechanisms of action and the partially nonoverlapping toxicities make them attractive for additional clinical exploration in this setting.14,15 Gemcitabine has significant activity as a radiosensitizer in vitro and in human studies.16,17 This occurs at subcytotoxic doses, and the mechanism is thought to be through depletion of deoxyribonucleoside triphosphate pools.18,19 Paclitaxel causes cytokinetic stabilization of the spindle microtubule resulting in G2-M cell-cycle arrest and increased radiosensitization.20-22 Kroep et al23 have shown a pharmacologic interaction of gemcitabine-paclitaxel combination, resulting in an increased cellular accumulation of gemcitabine triphosphate (dFdCTP) in mononuclear cells of NSCLC patients. This interaction might enhance the antitumor and radiosensitizing effects of gemcitabine. We conducted a phase I/II study combining gemcitabine and paclitaxel with concurrent thoracic radiotherapy in the treatment of patients with locally advanced, unresectable NSCLC. Our goal was to test the hypothesis that these agents could improve the efficacy of radiotherapy as a definitive treatment for NSCLC. To minimize distant failure, we induced all patients with a regimen previously studied in the advanced setting that consisted of two 21-day cycles of cisplatin and gemcitabine.24 The primary objective of this study was to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of the gemcitabine-paclitaxel doublet when given concurrently with three-dimensional radiotherapy. The secondary objective was to collect preliminary efficacy data including response rate, time to progression, survival, and failure pattern. In addition, we evaluated clinical and dosimetric parameters associated with the development of treatment-related esophagitis and pulmonary toxicity.
Eligibility Patients with pathologically confirmed NSCLC and clinically evaluated unresectable stage IIIa/b (N2, N3, or T4) disease with no prior chemoradiotherapy were eligible. Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 were enrolled, including those with weight loss of  5% in the 3 months before diagnosis. Initial laboratory tests included an absolute granulocyte count of 1,500/µL, hemoglobin of 10 g/dL, platelet count of 100,000/µL, serum creatinine of  1.5 mg/dL, liver-function tests 1.5x the upper limit of normal, and a forced expiratory volume in 1 second (FEV1) of greater than 800 mL. All patients provided informed consent.
Treatment Plan
Radiotherapy began on day 43 for all cohorts. Target volumes were based on the postinduction chemotherapy tumor volumes. Radiation was delivered in 2-Gy fractions daily for 5 days each week to a total dose of 60 Gy. The initial large-field target volume included all visible tumor and involved lymph nodes ( 1.0 cm) with a 2-cm margin for each, as well as ipsilateral hilar, superior mediastinal, and subcarinal nodes. Supraclavicular nodes were included in the setting of an upper lobe lesion. This large-field target volume received 40 to 44 Gy over 4.5 to 5 weeks. The boost target volume, which consisted of the primary tumor and any gross adenopathy, received 10 additional Gy over 5 days. All radiation was delivered with megavoltage linear accelerators. Isodose curves and dose-volume histograms (DVHs) were calculated for the lungs and the esophagus. The maximum dose to any level of the spinal cord did not exceed 45 Gy. Local control was defined as no evidence of progressive disease within the planned radiation fields.
Assessment Procedure Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, Version 2.26 Pulmonary and esophageal toxicities were graded according to the Radiation Therapy Oncology Group (RTOG)/European Organisation for Research and Treatment of Cancer radiation-morbidity criteria. Acute and late esophageal and pulmonary toxicities (grades 3 to 5) are listed in Table 1 . Standard World Health Organization criteria were used to determine response.27
The DLT was defined as any of the following: grade 4 neutropenia (for > 5 days); febrile neutropenia requiring hospitalization; grade 4 thrombocytopenia; grade 4 esophagitis; grade 3 to 4 pneumonitis or any other toxicity resulting in a delay of radiotherapy more than 14 days; or inability to deliver 80% of the projected doses of chemotherapy. The MTD was defined as the dose and schedule of gemcitabine and paclitaxel when given concomitantly with radiotherapy that produced DLTs in three of nine patients within a given cohort. Once the MTD has been reached, an additional 25 patients were treated at the recommended phase IIa dose schedule.
Statistical Analysis The individual relationships between patient age, pretreatment pulmonary function tests, cohort assignment, and dosimetry variables to the observed pulmonary and esophageal toxicities were examined by using Kendall correlation coefficients, Fisher's exact tests, and univariate logistic regressions as indicated. The response rate and its 95% CI were calculated. Time to progression, median, overall survival, and patterns of failure were determined. The Kaplan-Meier method was used to estimate median survival and the proportion of patients surviving at 1, 2, and 3 years.28 All calculations were performed by using SAS.29
The phase IIa section of this study was for the purpose of collecting preliminary efficacy data (response and survival) using a tolerable chemoradiotherapy regimen (recommended phase II dose). Our goal was to increase the median survival by at least 30%, taking into consideration a median survival from 14 to 17 months from previous studies. A sample size of 25 would provide a 95% CI on increased survival (
Patient Characteristics Between February 1998 and December 2002, a total of 63 patients were enrolled: 37 patients onto the phase I component and an additional 26 patients onto the phase IIa study. This lengthy period of accrual was secondary to the necessary interval (3 months) between each cohort of patients to exclude late toxicities. Fifty-seven patients were assessable for toxicity and response. Six patients were excluded: two patients refused chemoradiotherapy after signing consent, and four patients were ineligible because of stage IV disease. Four patients had early deterioration and death: acute myocardial infarction (1), massive hemoptysis (1), obstructive pneumonia (1), and acute respiratory failure (1). These clinical events occurred early during the first cycle of induction chemotherapy in the phase I portion of the study (cohort 1, n = 2; cohort 2, n = 2). Patient characteristics are listed in Table 2. The median age was 62 years and ranged from 35 to 78 years. Eleven patients (21%) were 70 years old. A significant number of patients with high-risk features were enrolled, including 23% with a performance status of 2% and 32% with 5% weight loss in the preceding 3 months. With the exception of four patients who had T4 primary lesions, all patients had clinical involvement of N2 or N3 disease at presentation. Thirty-four patients had histologic confirmation of mediastinal nodal involvement.
Toxicity Induction chemotherapy. Fifty-seven patients received induction chemotherapy and were assessable for toxicity and response. Selected hematologic and nonhematologic toxicities are listed in Table 3. Toxicity was predictable and acceptable and consisted mainly of nonfebrile neutropenia and clinically insignificant thrombocytopenia.
Chemoradiotherapy. Toxicities during chemoradiotherapy are summarized in Tables 4 and 5. Fifty-one patients were assessable for consolidation therapy, 11 (22%) of which required treatment delays. There were notable differences between the weekly (cohorts 1 and 2) versus 3-week schedules in terms of esophageal and pulmonary toxicities. Significant esophageal and pulmonary toxicities were encountered as a result of chemoradiotherapy in cohort 1. Of the nine patients, seven developed grade 3 or higher esophagitis (78%), three of which required gastrostomy-tube placement for a brief duration. One patient developed dose-limiting esophagitis, causing an esophageal stricture that required endoscopic dilation. Three patients in cohort 1 also developed dose-limiting acute pulmonary toxicity (grade 3). They presented with fever, dyspnea, and infiltrates on days 37, 49, and 90 of consolidation, respectively, requiring breaks or discontinuation of radiotherapy and treatment with oral steroids and oxygen. One of these patients died of progressive respiratory failure at 50 Gy. Four additional patients developed cough and dyspnea that required treatment delays or brief courses of oral corticosteroids. Two patients in this cohort had persistent symptoms and radiographic changes consistent with late, grade 3 pulmonary toxicity.
Because of the findings listed above, patients in cohort 2 were treated with a dose de-escalation of gemcitabine of 150 mg/m2/wk, which resulted in a modest improvement in esophageal toxicity. Three patients received intravenous hydration, but no patients required gastrostomy tubes or esophageal dilation. However, significant dose-limiting pulmonary toxicity was noted again (Table 4). Two patients experienced reversible grade 3 and 4 toxicities at 42 and 52 Gy, respectively, requiring treatment delays and oral steroids. A third patient developed rapidly progressive respiratory failure at 36 Gy and died on day 73 despite support with mechanical ventilation. Two patients experienced late grade 3 and 4 pulmonary toxicity, respectively. Both of these patients were treated with oral corticosteroids, with adequate stabilization of their symptoms.
Because regimen-related toxicities in cohort 2 were still unacceptable and additional dose reductions were thought to compromise systemic efficacy, the chemotherapy schedule for cohort 3 was changed to 3-week intervals (gemcitabine 300 mg/m2 and paclitaxel 135 mg/m2). On this schedule, no cases of significant acute or late pulmonary toxicity were seen in the 10 assessable patients accrued. Grade 3 esophageal toxicity was observed in 33% of the patients. Therefore, the 3-week schedule of gemcitabine and paclitaxel, at the doses used in cohort 3, was chosen as the recommended phase IIa regimen. Twenty-five additional patients were enrolled onto the phase IIa portion of the study. No episodes of grade
Tumor response.
Median follow-up was 27 months (4 to
Sites of initial relapse are listed in Table 7. Only 20% of patients assessable for the chemoradiotherapy phase relapsed within the radiation fields. Distant failure represented the most common pattern of relapse. Brain metastases occurred in 15 patients (nine women; six men), and 67% represented the first site of failure.
Clinical and dosimetric correlates for pulmonary and esophageal toxicities. One of the end points of this study was to assess the physiologic impact of chemoradiotherapy on pulmonary function. These changes were measured as reductions in the percentages of predicted values of ventilatory function indices (FEV1 and forced vital capacity) and diffusion capacity to carbon monoxide (DLCO). In general, DLCO was the only parameter showing a significant change, with a 25% reduction. However, no significant correlation between the grade of pulmonary toxicity (acute or late) and the individual change in the post-treatment DLCO was observed.
Tables 8 and 9 summarize the association of pertinent clinical and dosimetric parameters with the development of significant pulmonary toxicity. In the univariate analyses for the clinical factors and acute pulmonary toxicity (grade
In the univariable analysis for late pulmonary toxicity (Table 9), a performance status of 2 and dosimetric parameters (V15, V20, and V30) were associated with significant (grade 3) toxicity, with V30 being the most statistically significant factor (P = .031). There was also a relationship between the mean lung dose (MLD) and late pulmonary toxicity, which was most significant with grade 2 or higher toxicity (P = .009). Regarding esophageal toxicity, treatment schedule (weekly v 3-week schedule) was the only clinical parameter associated with toxicity. We found no association between DVH (V15, V30, or V54) and the grade of esophagitis.
To our knowledge, this is the first trial that incorporates two of the most potent radiosensitizing agents commonly used to treat NSCLC with thoracic irradiation. Given the encouraging activity of paclitaxel and gemcitabine in advanced disease and the feasibility of delivering each of these agents concurrently with radiotherapy,7,12,13,30,31 we postulated that the incorporation of both agents in a chemoradiotherapy regimen might lead to an improved locoregional control and overall survival. In this study the MTD was reached with the weekly administration of gemcitabine (150 to 300 mg/m2) and paclitaxel (35 mg/m2) when given with concurrent thoracic irradiation. The main DLT in these cohorts of patients was pulmonary toxicity: 22% to 23% acute events and 22% late events in cohorts 1 and 2. Esophagitis was dose limiting in cohort 1 as well.
The incidence of esophageal and pulmonary toxicities with the 3-week schedule is comparable with that reported in a number of similar platinum- or taxane-based chemoradiotherapy regimens.6-8,32,33 Only two of the patients treated on the 3-week schedule (5.7%) developed long-term sequelae in the form of significant (grade This narrow therapeutic window may be explained by the pharmacokinetics of gemcitabine, as evidenced by several studies that have examined it in combination with thoracic irradiation.32,34-37 The MTD ranged from 70 to 350 mg/m2/wk. An Italian group reported an MTD of 350 mg/m2/wk in combination with a subtherapeutic radiation dose of 56 Gy.35 Fosella et al36 reported an MTD of gemcitabine of 190 mg/m2/wk using larger radiation volumes and a total dose of 63 Gy, followed by adjuvant cisplatin-gemcitabine. van Putten et al34 reported an MTD of gemcitabine of 300 mg/m2/wk and total dose of 60 Gy, with treatment volumes not exceeding 2,000 mL. Blackstock et al37 found an MTD for gemcitabine at only 70 mg/m2/wk when administered as twice-weekly doses with 60 Gy of thoracic irradiation. Whether gemcitabine at these low doses has a systemic effect is not known, but it seems unlikely. In a phase II trial, Vokes et al32 were able to administer four doses of gemcitabine at 600 mg/m2 in combination with cisplatin over 6 weeks of thoracic irradiation (66 Gy) with only a 14% incidence of grades 3 or higher dyspnea. The heterogeneity of treatment volumes, dosing schedules, and toxicity parameters from these studies complicates the overall interpretation. However, as suggested in our study, the risk of pulmonary toxicity seems to increase with short intertreatment intervals to a greater extent than with the dose intensity of gemcitabine. The impact of treatment-related pulmonary toxicity was elucidated in a long-term follow-up analysis of RTOG 92-04.38 In this report, radiation pneumonitis was the only toxicity that was found to influence survival adversely. Several retrospective studies have related the risk and severity of radiation pneumonitis with clinical and dosimetric parameters.39-43 Hernando et al39 analyzed clinical and dosimetric parameters in 201 patients with lung cancer who underwent three-dimensional planning radiotherapy. Of the clinical factors examined (age, sex, tumor site, performance status, tobacco use, chemotherapy, weight loss, and pre-FEV1), only active smoking was associated with fewer cases of radiation pneumonitis. Dosimetric factors (including V30), MLD, and normal tissue complication probability according to the Lyman and Kutcher models were the best predictor of radiation-induced pulmonary toxicity. Graham et al42 found a reasonable correlation between the V20 and MLD and the incidence of radiation pneumonitis. The V20 was also found to be associated with the severity of this complication. The clinical factors, preradiation pulmonary-function tests and chemotherapy exposure, were also tested for association with radiation pneumonitis, but none was found.
In this study, performance status of more than 1 was the best clinical factor associated with acute or late pulmonary toxicities. More straightforward dosimetric parameters such as V15, V20, V30, and MLD were also correlated with pulmonary toxicity. The MLDs for patients with or without toxicity were slightly higher, but the risk seemed to rise above 30 Gy. We found equivalent association for V15, V20, or V30, probably because of all patients received concurrent chemoradiotherapy. The use of weekly chemotherapy during radiotherapy was only correlated with severe (grade We found no association between V15, V30, or V54 and the development of esophagitis. Although other studies have suggested that dosimetric parameters correlate with esophagitis, we believe that the addition of concurrent chemotherapy is by far the most important determinant of outcome. With radiotherapy alone, significant esophageal toxicity occurs in less than 5% of patients treated for NSCLC in the absence of hyperfractionation.2,3 However, in a review of more than 1,000 patients, the RTOG found that the addition of chemotherapy increased the incidence 12-fold.44 A recent study by Bradley et al45 confirmed these findings; for any given DVH, concurrent chemotherapy doubled the risk of acute esophagitis. The response rate, time to progression, and median survival observed in this study are comparable with or higher than those reported by most other sequential or concomitant combined-modality trials,8,32,33,46,47 which may be because of an improvement in local control; few patients (20%) relapsed locally at their first site. The induction regimen of cisplatin and gemcitabine also may have contributed to this outcome, because it was shown recently to be more active than nongemcitabine containing cisplatin doublets.48 Most early deaths in the phase I portion (cohorts 1 and 2) were secondary to pulmonary toxicity, which has not been seen with the 3-week regimen of chemoradiotherapy. As in most studies of locally advanced NSCLC, control of micrometastatic disease and subsequent distant relapse remains a problem in this study. In particular, brain metastases were a significant source of morbidity. Hopefully the ongoing RTOG-0214 study will help to clarify the role of prophylactic cranial irradiation in NSCLC. On the basis of our experiences, additional studies of gemcitabine- and paclitaxel-containing chemotherapy regimens given concurrently with radiotherapy should proceed with caution, especially if large radiotherapy ports are likely to be involved. Although the available data support the efficacy of concomitant chemoradiotherapy over sequential approaches (albeit at the cost of increased toxicity), the most tolerable and efficacious method of combining this modality with induction or consolidation chemotherapy has not been elucidated. A phase IIb portion of this study is being conducted to address this issue by reversing the sequence used in the phase IIa component. Future patients enrolled will be treated with gemcitabine/paclitaxel on weeks 1, 4, and 7 with concomitant thoracic radiotherapy followed by two consolidation cycles of gemcitabine and cisplatin at the same doses used in the induction regimen.
The authors indicated no potential conflicts of interest.
Supported by P30CA13148, awarded from the National Cancer Institute (National Institutes of Health, Bethesda, MD) and Eli Lilly Oncology (Indianapolis, IN). Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 311:899-909, 1995
2. Dillman RO, Herndon J, Seagren SL, et al: Improved survival in stage III non-small-cell lung cancer: Seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst 88:1210-1215, 1996
3. Sause WT, Scott C, Taylor S, et al: Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 87:198-205, 1995
4. Le Chevalier T, Arriagada R, Quoix E, et al: Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: First analysis of a randomized trial in 353 patients. J Natl Cancer Inst 83:417-423, 1991 5. Gordon GS, Vokes EE: Chemoradiation for locally advanced, unresectable NSCLC: New standard of care, emerging strategies. Oncology (Williston Park) 13:1075-1088; discussion 1088, 1091–1094, 1999
6. Albain KS, Crowley JJ, Turrisi AT III, et al: Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non–small-cell lung cancer: A Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol 20:3454-3460, 2002 7. Choy H, Akerley W, Safran H, et al: Multi-institutional phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non–small-cell lung cancer. J Clin Oncol 16:3316-3322, 1998[Abstract] 8. Curran W, Scott C, Langer C: Phase III comparison of sequential versus concurrent chemoradiation for patients with unresectable stage III non-small-cell lung cancer: Report of Radiation Therapy Oncology Group 9410. Lung Cancer 29:93, 2000 (suppl 1; abstr 303) 9. Blackstock AW, Lesser G, Tucker D, et al: Twice weekly gemcitabine and concurrent thoracic radiotherapy: A phase I/II study in patients with advanced non-small-cell lung cancer. Proc Am Soc Clin Oncol 19:470, 2000 (abstr 1846)
10. Chen Y, Pandya K, Keng PC, et al: Phase I/II clinical study of pulsed paclitaxel radiosensitization for thoracic malignancy: A therapeutic approach on the basis of preclinical research of human cancer cell lines. Clin Cancer Res 9:969-975, 2003 11. Choy H, Rodriguez FF, Koester S, et al: Investigation of Taxol as a potential radiation sensitizer. Cancer 71:3774-3778, 1993[CrossRef][Medline] 12. Choy H, Safran H, Akerley W, et al: Phase II trial of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small-cell lung cancer. Clin Cancer Res 4:1931-1936, 1998[Abstract]
13. Natale RB: Experience with new chemotherapeutic agents in non-small-cell lung cancer. Chest 113:32S-39S, 1998 (suppl 1) 14. Peters GJ, Ackland SP: New antimetabolites in preclinical and clinical development. Expert Opin Investig Drugs 5:637-679, 1996
15. Rowinsky EK, Donehower RC: Paclitaxel (Taxol). N Engl J Med 332:1004-1014, 1995 [Erratum: N Engl J Med 333:75, 1995] 16. Shewach DS, Lawrence TS: Radiosensitization of human solid tumor cell lines with gemcitabine. Semin Oncol 23:65-71, 1996 (suppl 10) 17. Latz D, Fleckenstein K, Eble M, et al: Radiosensitizing potential of gemcitabine (2',2'-difluoro-2'-deoxycytidine) within the cell cycle in vitro. Int J Radiat Oncol Biol Phys 41:875-882, 1998[CrossRef][Medline] 18. Heinemann V, Xu YZ, Chubb S, et al: Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2',2'-difluorodeoxycytidine. Mol Pharmacol 38:567-572, 1990[Abstract]
19. Shewach DS, Hahn TM, Chang E, et al: Metabolism of 2',2'-difluoro-2'-deoxycytidine and radiation sensitization of human colon carcinoma cells. Cancer Res 54:3218-3223, 1994 20. Milas L, Hunter NR, Kurdoglu B, et al: Kinetics of mitotic arrest and apoptosis in murine mammary and ovarian tumors treated with taxol. Cancer Chemother Pharmacol 35:297-303, 1995[Medline]
21. Milross CG, Mason KA, Hunter NR, et al: Relationship of mitotic arrest and apoptosis to antitumor effect of paclitaxel. J Natl Cancer Inst 88:1308-1314, 1996 22. Sinclair WK, Morton RA: X-ray sensitivity during the cell generation cycle of cultured Chinese hamster cells. Radiat Res 29:450-474, 1996[CrossRef]
23. Kroep JR, Giaccone G, Voorn DA, et al: Gemcitabine and paclitaxel: Pharmacokinetic and pharmacodynamic interactions in patients with non–small-cell lung cancer. J Clin Oncol 17:2190-2197, 1999
24. Crino 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
25. Mountain CF: Revisions in the international system for staging lung cancer. Chest 111:1710-1717, 1997 26. Cancer Therapy Evaluation Program: \?\Common toxicity criteria, version 2. Bethesda, MD, National Cancer Institute, 1998. Available at: https://webapps.ctep.nci.nih.gov/ctcv2/plsql/ctc000w$.startup. 27. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline] 28. Lee ET: Statistical Methods for Survival Data Analysis. New York, NY, John Wiley and Sons, 1992 29. SAS Institute, Inc: SAS/STAT User's Guide (4th ed). Version 9. Cary, NC, SAS Institute Inc, 2002 30. Vokes EE, Gregor A, Turrisi AT: Gemcitabine and radiation therapy for non-small-cell lung cancer. Semin Oncol 25:66-69, 1998 (suppl 9) 31. Vokes EE, Leopold KA, Herndon JE, et al: A CALGB randomized phase II study of gemcitabine or paclitaxel or vinorelbine with cisplatin as induction chemotherapy (Inc CT) and concomitant chemoradiotherapy (XRT) in stage IIIB non-small-cell lung cancer (NSCLC): Feasibility data (CALGB study 9431). Proc Am Soc Clin Oncol 16:455, 1997 (abstr 1636)
32. Vokes EE, Herndon JE II, Crawford J, et al: Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non–small-cell lung cancer: Cancer and Leukemia Group B study 9431. J Clin Oncol 20:4191-4198, 2002 33. Gaspar L, Gandara D, Chansky K, et al: Consolidation docetaxel following concurrent chemoradiotherapy in pathologic IIIB non-small-cell lung cancer (SWOG 9504): Patterns of failure and updated survival. Proc Am Soc Clin Oncol 20:315, 2001 (abstr 1255)
34. van Putten JW, Price A, van der Leest AH, et al: A phase I study of gemcitabine with concurrent radiotherapy in stage III, locally advanced non-small-cell lung cancer. Clin Cancer Res 9:2472-2477, 2003
35. Trodella L, Granone P, Valente S, et al: Phase I trial of weekly gemcitabine and concurrent radiotherapy in patients with inoperable non–small-cell lung cancer. J Clin Oncol 20:804-810, 2002 36. Fosella FV, Zinner RG, Komaki R, et al: Gemcitabine (G) with concurrent chest radiation (XRT) followed by consolidation chemotherapy with gemcitabine plus cisplatin (CDDP): A phase I trial for patients with stage III non-small-cell lung cancer. Proc Am Soc Clin Oncol 20:312, 2001 (abstr 1243) 37. Blackstock AW, Lesser GJ, Fletcher-Steede J, et al: Phase I study of twice-weekly gemcitabine and concurrent thoracic radiation for patients with locally advanced non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 51:1281-1289, 2001[CrossRef][Medline] 38. Komaki R, Seiferheld W, Ettinger D, et al: Randomized phase II chemotherapy and radiotherapy trial for patients with locally advanced inoperable non-small-cell lung cancer: Long-term follow-up of RTOG 92-04. Int J Radiat Oncol Biol Phys 53:548-557, 2002[CrossRef][Medline] 39. Hernando ML, Marks LB, Bentel GC, et al: Radiation-induced pulmonary toxicity: A dose-volume histogram analysis in 201 patients with lung cancer. Int J Radiat Oncol Biol Phys 51:650-659, 2001[CrossRef][Medline] 40. Martel MK, Ten Haken RK, Hazuka MB, et al: Dose-volume histogram and 3D treatment planning evaluation of patients with pneumonitis. Int J Radiat Oncol Biol Phys 28:575-581, 1994[Medline] 41. Oetzel D, Schraube P, Hensley F, et al: Estimation of pneumonitis risk in three-dimensional treatment planning using dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 33:445-460, 1995 42. Graham MV, Purdy JA, Emami B, et al: Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 45:323-329, 1999[Medline] 43. Kwa SL, Lebesque JV, Theuws JC, et al: Radiation pneumonitis as a function of mean lung dose: An analysis of pooled data of 540 patients. Int J Radiat Oncol Biol Phys 42:1-9, 1998[Medline] 44. Werner-Wasik M, Scott C, Graham ML: Interfraction interval does not affect survival of patients with non-small-cell lung cancer treated with chemotherapy and/or hyperfractionated radiotherapy: A multivariate analysis of 1076 RTOG patients. Int J Radiat Oncol Biol Phys 44:327-331, 1999[CrossRef][Medline] 45. Bradley J, Deasy JO, Bentzen S, et al: Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma. Int J Radiat Oncol Biol Phys 58:1106-1113, 2004[CrossRef][Medline] 46. Schaake-Koning C, van den Bogaert W, Dalesio O, et al: Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 326:524-530, 1992[Abstract]
47. Furuse K, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non–small-cell lung cancer. J Clin Oncol 17:2692-2699, 1999 48. Natale RB: Gemcitabine-containing regimens vs. others in first-line treatment of NSCLC. Oncology (Williston Park) 18:27-31, 2004 (suppl 5) Submitted October 19, 2004; accepted May 25, 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
= .05) ranging from 0.441 to 0.819 (14 months) to 0.503 to 0.867 (17 months). 
