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Journal of Clinical Oncology, Vol 26, No 15 (May 20), 2008: pp. 2457-2463 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.7371 Randomized Phase II Trial of Induction Chemotherapy Followed by Concurrent Chemotherapy and Dose-Escalated Thoracic Conformal Radiotherapy (74 Gy) in Stage III Non–Small-Cell Lung Cancer: CALGB 30105
From the Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill; Wake Forest University School of Medicine, Winston-Salem; Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham; Southeast Cancer Control Consortium Inc Community Clinical Oncology Program, Goldsboro, NC; State University of New York Upstate Medical University, Syracuse, NY; Helen F. Graham Cancer Center and Christiana Care CCOP, Wilmington, DE; and the University of Chicago, Chicago, IL Corresponding author: Mark A. Socinski, MD, Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, CB# 7305, Chapel Hill, NC 27599; e-mail: socinski{at}med.unc.edu
Purpose: To evaluate 74 Gy thoracic radiation therapy (TRT) with induction and concurrent chemotherapy in stage IIIA/B non–small-cell lung cancer (NSCLC). Patients and Methods: Patients with stage IIIA/B NSCLC were randomly assigned to induction chemotherapy with either carboplatin (area under the curve [AUC], 6; days 1 and 22) with paclitaxel (225 mg/m2; days 1 and 22; arm A) or carboplatin (AUC, 5; days 1 and 22) with gemcitabine (1,000 mg/m2; days 1, 8, 22, and 29; arm B). On day 43, arm A received weekly carboplatin (AUC, 2) and paclitaxel (45 mg/m2) while arm B received biweekly gemcitabine (35 mg/m2) both delivered concurrently with 74 Gy of TRT utilizing three-dimensional treatment planning. The primary end point was survival at 18 months. Results: Forty-three and 26 patients were accrued to arms A and B, respectively. Arm B was closed prematurely due to a high rate of grade 4 to 5 pulmonary toxicity. The overall response rate was 66.6% (95% CI, 50.5% to 80.4%) and 69.2% (95% CI, 48.2% to 85.7%) on arm A and B, respectively. The median survival time (MST) and 1-year survival rate was 24.3 months (95% CI, 12.3 to 36.4) and 66.7% (95% CI, 50.3 to 78.7) and 12.5 months (95% CI, 9.4 to 27.6) and 50.0% (95% CI, 29.9 to 67.2) for arms A and B, respectively. The primary toxicities included esophagitis, pulmonary, and fatigue. Conclusion: Arm A reached the primary end point with an estimated MST longer than 18 months and will be compared with a standard dose of TRT in a planned randomized phase III trial in the United States cooperative groups.
Lung cancer remains the leading cause of cancer-related mortality in the United States.1,2 In patients with good performance status (PS), stage IIIA/B NSCLC, combined-modality therapy is the standard of care.3 Several randomized phase II and III trials have shown that the concurrent administration of chemoradiotherapy results in modestly improved survival outcomes compared with sequential approaches.4-7 There is not universal agreement as to the optimal strategy nor the optimal chemotherapeutic agent(s)/regimen. The strategy of induction chemotherapy followed by low-dose concurrent chemotherapy has been most often evaluated using carboplatin and paclitaxel and has been tested in multiple phase II and III trials.8-11 Historically, 60 Gy using two-dimensional planning techniques was established as the standard in the Radiation Therapy Oncology Group Trial (RTOG) 73-01.12-14 Subsequent attempts at dose escalation were complicated by the lack of accurate tumor targeting and the fear of toxicity. The advent of three-dimensional (3-D) planning techniques led to the ability to more accurately target the tumor volume and establish dose-volume relationships for healthy tissues at risk for toxicity.15 The possibility of enhanced local control by more effective dose delivery to the target volume, escalation of thoracic radiation therapy (TRT) dose, as well as less healthy tissue toxicity, was realized.16-20 Socinski et al21-23 escalated the dose of TRT from 60 to 74 Gy using 3-D planning with induction and concurrent carboplatin and paclitaxel. The outcomes of this phase I/II trial were promising as the median survival time (MST) was 24 months and 26% of patients survived 5 years.24 The rate of grade 3 to 4 esophagitis was less than 10% and no grade 3 to 4 pulmonary toxicity was observed. Subsequently, these investigators demonstrated that further escalation of the TRT dose was feasible (with concurrent chemotherapy) using 3-D planning.25 Others have also explored dose-escalation TRT strategies using 3-D planning either alone or in combination with other chemotherapy regimens.26-33 The Cancer and Leukemia Group B (CALGB) designed a randomized phase II trial exploring the use of 74 Gy with 3-D planning. This report summarizes the results of CALGB 30105.
Eligibility Patients had a histologic or cytologic diagnosis of stage IIIA or IIIB NSCLC and a staging chest computed tomography (CT) scan which included the liver and adrenal glands, radionuclide bone scan, and either a head CT scan or magnetic resonance imaging (MRI) brain scan. Patients with palpable supraclavicular adenopathy, malignant pleural effusions or direct invasion of vertebral bodies were excluded. Patients had to have an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1. No prior chemotherapy for lung cancer or prior radiation therapy to the chest was allowed. Other required parameters included: absolute neutrophil count  1,500/µL, platelet count 100,000/µL, hemoglobin 10 gm/dL, calculated creatinine clearance (estimated by the Crockoft-Gault formula) 20 mL/min, AST lower than two times the upper limit of institutional normal, and bilirubin lower than 1.5 mg/dL. The forced vital capacity in 1 second (FEV1) had to be higher than 1.2 L. This trial was approved by the institutional review boards of the CALGB institutions that participated in this trial. Patients were required to give informed consent (Fig 1).
Treatment Plan Patients in arm A received induction chemotherapy with carboplatin (area under the concentration curve [AUC] of 6 using the Calvert equation34 by intravenous infusion [IV]) and paclitaxel (225 mg/m2 IV over 3 hours) on days 1 and 22. On day 43, patients received weekly carboplatin (AUC, 2 IV) and paclitaxel (45 mg/m2 IV) for 7 weeks during TRT. Standard premedications for paclitaxel administration were used. Patients in arm B received two cycles of induction carboplatin (AUC 5 using the Calvert equation34 IV) and gemcitabine (1,000 mg/m2 IV over 30 minutes on days 1 and 8 of each cycle). On day 43, patients received twice-weekly gemcitabine (35 mg/m2 IV) for 7 weeks during TRT. Standard dose reduction/omission parameters were used for hematologic and nonhematologic toxicities during induction chemotherapy. During concurrent therapy, if the neutrophil count was higher than 1,000/µL, full doses of all drugs were administered. If the neutrophil count was either higher than 500/µL but lower than 999/µL or lower than 500/µL, then all drugs were reduced by 50% or held, respectively. Similarly, if the platelet count was higher than 75,000/µL, full doses of all drugs were administered. If the platelet count was higher than 50,000/µL but lower than 75,000/µL or lower than 50,000/µL, then all drugs were reduced by 50% or held, respectively. For grade 3 esophagitis, both the paclitaxel and gemcitabine was held until the esophagitis resolved to less than grade 2. Subsequently, both paclitaxel and gemcitabine doses were reduced by 50%. Radiation treatment breaks were strongly discouraged for grade 3 esophagitis. For grade 4 esophagitis, all treatment was held until the esophagitis resolved to less than grade 2. Once this occurred, paclitaxel and gemcitabine doses were reduced by 50%. 3-D conformal TRT was initiated on day 43. Beam arrangements, immobilization devices, and treatment techniques that minimized the dose to healthy tissues were encouraged. An approved 3-D benchmark was on file at the quality assurance review center for all radiation centers participating in this study. A contrast-enhanced treatment planning CT was required for target volume determination and radiation therapy planning. Although the above method for obtaining a planning CT scan was preferred, it was acceptable to use the prestudy CT scan obtained for diagnostic purposes, provided that it was performed on a flat tabletop. All patients were treated with linac-based radiation units with nominal photon beam energy of 4 MV or higher.
Target Volume Definitions The prescription point was defined at or near the isocenter. The PTV received a dose of 40 Gy (2 Gy/d) to the prescription point. The boost volume PTV received 34 Gy (2 Gy/d) to the prescription point. Treatment planning utilizing inhomogeneity corrections was required. The maximum dose to any point in the spinal cord could not exceed 49 Gy. No specific volume or dose restrictions as it related to the normal lung or esophagus were mandated.
Response and Toxicity Evaluation
Statistical Design
The difference of response rates between arms were tested by
Patients Between March 15, 2002, and November 30, 2004, 69 patients were enrolled (43 in arm A and 26 in arm B). One patient on arm A had a hypersensitivity reaction and was deemed nonassessable. The patient demographics are summarized in Table 1. The median age was 61 years (range, 38 to 79 years). Adenocarcinoma and squamous cell histology were seen in 35% of patients each. The median FEV1 was 2.08 L (range, 1.24 to 3.72 L). Arm B was closed prematurely on March 15, 2004, after 26 patients were enrolled. This was due to a high rate of grade 4 to 5 toxicities (grade 4/5 pneumonitis in four patients and grade 5 gastrointestinal bleeding in one patient).
Treatment Administration During induction chemotherapy, 40 (95%) of 42 and 24 (92%) of 26 patients on arms A and B, respectively, completed both cycles. Initiation of concurrent chemoradiotherapy beginning on day 43 was accomplished in 39 patients (92.8%) on arm A and 23 patients (88.4%) on arm B. No unexpected toxicities were noted on either arm during induction chemotherapy. During concurrent chemoradiotherapy, 32 (76%) of the 42 assessable patients on arm A completed all seven weekly treatments of carboplatin and paclitaxel while 18 (69%) of the 26 patients on arm B completed all 7 weeks of twice weekly gemcitabine. Thirty-nine (92.8%) and 23 (88.4%) received combined chemoradiotherapy on arms A and B, respectively. The median volume of lung receiving 20 Gy (V20) was 32% on arm A (range, 18% to 52%) and 32% on arm B (range, 20% to 50%). On arm A, the median dose of TRT delivered was 74 Gy with an average dose delivered of 72.7 Gy (range, 34.0 to 77.9). Thirty-four (87.2%) of 39 patients completed therapy to at least 74 Gy. On arm B, the median dose of TRT delivered was 74 Gy with and average dose delivered of 70.6 Gy (range, 22.0 to 77.7). Eighteen (78.3%) of 23 patients completed therapy to at least 74 Gy. The reasons for going off protocol treatment on arms A and B were completion of protocol treatment, 76% and 69%, respectively; adverse events, 14% and 11%, respectively; death, 2% and 4%, respectively; progressive disease, 0% and 4%, respectively; and other reasons, 7% and 12%, respectively.
Toxicity
Response and Survival The response rate to induction chemotherapy was 28.6% on arm A and 19.2% on arm B (Table 4). The overall response rates were 66.6% and 69.2% for arms A and B, respectively.
The median follow-up for all patients was 44 months (42 months on arm A and 49 months on arm B). The survival outcomes are presented in Table 5 including the overall survival for patients with stage IIIA versus IIIB. The median progression-free survival on arm A was 14.9 months and 7.7 months on arm B (Fig 2A). The MST on arm A was 24.3 months and the 1-year survival rate was 66.7%. On arm B, the MST was 12.5 months and the 1-year survival rate was 50.0% (Fig 2B).
The optimal combined modality strategy in stage IIIA/B NSCLC remains undefined. This trial was designed after several trials suggested that 74 Gy could be delivered after induction and with concurrent chemotherapy and were associated with favorable survival outcomes.21,23,27,28 The encouraging survival results seen in those trials mandated multi-institutional evaluation. The survival outcome observed on arm A of this trial exceeded the predefined benchmark of 18 months, which was chosen as this had been the best MST achieved by CALGB.36 Vokes et al36 evaluated paclitaxel, vinorelbine, and gemcitabine in combination with cisplatin using an induction and concurrent strategy with 66 Gy of standard TRT (CALGB 9431). The MSTs on the three arms were 14.8, 17.7, and 18.3 months, respectively. The CALGB has also reported a phase II (9534)8 and a III (39801) trial11 using induction and low-dose concurrent paclitaxel with 66 Gy of standard TRT. The MSTs on both of these trials were approximately 14 months. In another trial, CALGB 30106, which ran concurrently with CALGB 30105 and which used the identical chemotherapy strategy but only 66 Gy without defined 3-D planning guidelines, the MST was 14 months.37 The Lung Advanced Multimodality Protocol (LAMP 9) trial and RTOG 98-0110 used a similar design of induction and concurrent carboplatin and paclitaxel and used either 63 Gy (1.8 Gy/d) or 69.6 Gy (1.2 Gy twice per day). The MST on these two trials was 12.7 months and 17.5 months, respectively. The major differences between CALGB 30105 and the other trials mentioned were the use of 3-D radiation planning and a higher total dose of 74 Gy. The gemcitabine-containing arm of this trial was closed early due to excessive treatment-related deaths. In reviewing the TRT parameters for these patients, the V20s exceeded 40% in two of three patients who died. Graham et al18 initially described the relationship between the V20 and the risk of radiation pneumonitis. Gemcitabine is a potent radiation sensitizer and may also sensitize healthy tissue to radiation-related toxicity.27,28 Given this experience, prospective definitions of healthy tissue constraints (particularly lung) should be a mandatory part of any trial in which aggressive TRT is employed with or without concurrent chemotherapy agents. The distribution of stage IIIA versus IIIB was similar on this trial compared with the historical experiences of CALGB.3 However, given the fact that more stage IIIB patients were randomly assigned to arm B (Table 1), potentially larger tumor volumes could have predisposed this arm to more toxicity, particularly in the presence of gemcitabine. The treatment volume was also undoubtedly influenced by the details of nodal irradiation, which will be reported subsequently. In an analysis of 694 patients with stage IIIA/B NSCLC treated on previous CALGB trials3 and the data presented in Table 5, there were no significant differences between the survival of patients with stage IIIB versus IIIA, making it unlikely that stage significantly influenced survival outcomes on this trial. Two other experiences have explored the use of 74 Gy. The RTOG reported a phase I trial (RTOG 0117) and defined 74 Gy as the maximum-tolerated dose.38 A MST of 21.6 months was reported. The North Central Cancer Treatment Group (NCCTG) reported a phase I trial escalating the dose of TRT with 3-D planning between 70 and 78 Gy.30 They defined the maximum-tolerated dose as 74 Gy and reported an impressive MST of 37 months. In both trials, the dose-limiting toxicities were mainly pulmonary. One concern of using more aggressive TRT strategies is the risk of late toxicity. Lee et al39 reviewed several trials employing dose-escalated (70 to 90 Gy in 2 Gy/d fractions) TRT. In general, the rates of late pulmonary, esophageal, cardiac, and osseous complications were lower than 10%. However, unusual complications, such as bronchial stenosis,40 pulmonary hemorrhage, and osseous insufficiency fractures (ribs and vertebral bodies), were reported. In conclusion, these results suggest that the dose and technical aspects of TRT delivery are important in the combined modality approach to stage III NSCLC. This trial corroborated the results reported by Socinski et al22,24 and met the prespecified survival hurdle set forth in the original trial design. Given this as well as the results reported in the trials performed by NCCTG30 and RTOG,38 we believe that dose-escalation using 3-D planning should be tested in the phase III setting. Toward that end, RTOG, NCCTG, and CALGB are planning a randomized phase III trial comparing 60 Gy versus 74 Gy in a strategy of concurrent followed by consolidation chemotherapy.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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. Employment or Leadership Position: None Consultant or Advisory Role: A. William Blackstock, Eli Lilly Oncology (C), Sanofi-Aventis (C), Protheries/Genentech (C) Stock Ownership: None Honoraria: Mark A. Socinski, Lilly; A. William Blackstock, Eli Lilly Oncology Research Funding: Mark A. Socinski, BMS, Lilly; A. William Blackstock, Astra-Zeneca, Sanofi-Aventis Expert Testimony: None Other Remuneration: None
Conception and design: Mark A. Socinski, A. William Blackstock, Jeffrey A. Bogart, Mark Green, Antonius A. Miller, Everett E. Vokes Administrative support: Mark A. Socinski, Jeffrey A. Bogart, Everett E. Vokes Provision of study materials or patients: Mark A. Socinski, Julian Rosenman, Gregory A. Masters, Peter Ungaro, Arthur Sleeper, Antonius A. Miller Collection and assembly of data: Mark A. Socinski, Michael Munley Data analysis and interpretation: Mark A. Socinski, A. William Blackstock, Jeffrey A. Bogart, Xiaofei Wang, Michael Munley, Julian Rosenman, Lin Gu, Mark Green, Everett E. Vokes Manuscript writing: Mark A. Socinski, A. William Blackstock, Jeffrey A. Bogart, Michael Munley, Mark Green, Everett E. Vokes Final approval of manuscript: Mark A. Socinski, A. William Blackstock, Jeffrey A. Bogart, Michael Munley, Julian Rosenman, Mark Green, Antonius A. Miller, Everett E. Vokes
The following institutions participated in this study: Christiana Care Health Services Inc CCOP, Wilmington, DE, Stephen Grubbs, MD, supported by CA45418; Duke University Medical Center, Durham, NC, Jeffrey Crawford, MD, supported by CA47577; Kansas City Community Clinical Oncology Program CCOP, Kansas City, MO, Jorge C. Paradelo, MD; Roswell Park Cancer Institute, Buffalo, NY, Ellis Levine, MD, supported by CA02599; University of California at San Diego, San Diego, CA, Joanne Mortimer, MD, supported by CA11789; University of Minnesota, Minneapolis, MN, Bruce A. Peterson, MD, supported by CA16450; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO, Michael C. Perry, MD, supported by CA12046; Wake Forest University School of Medicine, Winston-Salem, NC, David D. Hurd, MD, supported by CA03927; Southeast Cancer Control Consortium Inc CCOP, Goldsboro, NC, James N. Atkins, MD, supported by CA45808; University of North Carolina at Chapel Hill, Chapel Hill, NC, Thomas C. Shea, MD, supported by CA47559; University of Massachusetts Medical School, Worcester, MA, William V. Walsh, MD, supported by CA37135.
Supported by Grants No. CA47559, CA03927, CA21060, CA33601, CA45418, CA45808, and CA41287; by grant no. CA31946 from the National Cancer Institute to the Cancer and Leukemia Group B (Richard L. Schilsky, MD) and by grant no. CA33601 to the Cancer and Leukemia Group B Statistical Center (Stephen George, PhD). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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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] 19. Senan S, De Ruysscher D: Critical review of PET-CT for radiotherapy planning in lung cancer. Crit Rev Oncol Hematol 56:345-351, 2005[Medline] 20. Yorke ED, Jackson A, Rosenzweig KE, et al: Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 54:329-339, 2002[Medline] 21. Socinski MA, Rosenman JG, Halle JS, et al: Induction carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal thoracic radiation therapy in unresectable stage IIIA/B non-small cell lung cancer: A modified phase I trial. Cancer 89:534-542, 2000[CrossRef][Medline] 22. Socinski MA, Rosenman JG, Halle JS, et al: Dose-escalating conformal thoracic radiation therapy with induction and concurrent carboplatin/paclitaxel in unresectable stage IIIA/B non-small cell lung carcinoma: A modified phase I/II trial. Cancer 92:1213-1223, 2001[CrossRef][Medline] 23. Rosenman JG, Halle JS, Socinski MA, et al: High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: Technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys 54:348-356, 2002[CrossRef][Medline] 24. Socinski MA, Halle JS, Morris DE, et al: Long-term results of aggressive combined modality therapy employing induction and concurrent carboplatin/paclitaxel with dose-escalated thoracic conformal radiation therapy. Lung Cancer 41:S239, 2003 (suppl 2; abstr P-585) 25. Socinski MA, Morris DE, Halle JS, et al: Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non–small-cell lung cancer: A dose-escalation phase I trial. J Clin Oncol 22:4341-4350, 2004 26. Belderbos JS, De Jaeger K, Heemsbergen WD, et al: First results of a phase I/II dose escalation trial in non-small cell lung cancer using three-dimensional conformal radiotherapy. Radiother Oncol 66:119-126, 2003[CrossRef][Medline] 27. 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] 28. Blackstock AW, Ho C, Butler J, et al: Phase Ia/Ib chemo-radiation trial of gemcitabine and dose-escalated thoracic radiation in patients with stage III A/B non-small cell lung cancer. J Thorac Oncol 1:434-440, 2006[CrossRef][Medline] 29. Bradley JD, Graham MV, Winter KW, et al: Acute and late toxicity results of RTOG 9311: A dose escalation study using 3D conformal radiation therapy in patients with inoperable non-small cell lung cancer. Int J Radiat Oncol Biol Phys 57:S137-S138, 2003 30. Schild SE, McGinnis WL, Graham D, et al: Results of a phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 65:1106-1111, 2006[CrossRef][Medline] 31. Sim S, Rosenzweig KE, Schindelheim R, et al: Induction chemotherapy plus three-dimensional conformal radiation therapy in the definitive treatment of locally advanced non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 51:660-665, 2001[CrossRef][Medline] 32. Wu KL, Jiang GL, Liao Y, et al: Three-dimensional conformal radiation therapy for non-small-cell lung cancer: A phase I/II dose escalation clinical trial. Int J Radiat Oncol Biol Phys 57:1336-1344, 2003[CrossRef][Medline] 33. Marks LB, Garst J, Socinski MA, et al: Carboplatin/paclitaxel or carboplatin/vinorelbine followed by accelerated hyperfractionated conformal radiation therapy: Report of a prospective phase I dose escalation trial from the Carolina Conformal Therapy Consortium. J Clin Oncol 22:4329-4340, 2004 34. Calvert A, Newell D, Gumbrell L, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756, 1989[Abstract] 35. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organisation for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 36. Vokes EE, Herndon JE 2nd, 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 37. Ready N, Herndon J, Vokes E, et al: Initial cohort toxicity evaluation for chemoradiotherapy (CRT) and ZD1839 in stage III non–small-cell lung cancer (NSCLC): A CALGB stratified phase II trial. J Clin Oncol 22:7078, 2004 38. Bradley JD, Graham M, Suzanne S, et al: Phase I results of RTOG L-0117: A phase I/II dose intensification study using 3DCRT and concurrent chemotherapy for patients with Inoperable NSCLC. J Clin Oncol 23:636s, 2005 (abstr 7063) 39. Lee CB, Socinski MA, Lin L, et al: High-dose 3D chemoradiotherapy trials in stage III non–small-cell lung cancer (NSCLC) at the University of North Carolina: Long-term follow up and late complications. J Clin Oncol 24:400s, 2006 (abstr 7145) 40. Miller KL, Shafman TD, Anscher MS, et al: Bronchial stenosis: An underreported complication of high-dose external beam radiotherapy for lung cancer? Int J Radiat Oncol Biol Phys 61:64-69, 2005[CrossRef][Medline] Submitted October 22, 2007; accepted February 7, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. Progression-free survival is defined as the time from study entry to the date of disease progression or death. Overall survival is defined as the time from study entry to the date of death of any causes. Kaplan-Meier curves were used to characterize overall survival and progression-free survival. Median survival and survival rate at certain landmark time as well as their 95% CIs were computed. Log-rank test was used to test the survival difference between treatment arms. All P value reported are two sided without adjusting for multiple comparisons. 
