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Journal of Clinical Oncology, Vol 24, No 27 (September 20), 2006: pp. 4397-4404 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.4163 Simultaneous Chemoradiotherapy Compared With Radiotherapy Alone After Induction Chemotherapy in Inoperable Stage IIIA or IIIB Non–Small-Cell Lung Cancer: Study CTRT99/97 by the Bronchial Carcinoma Therapy Group
From the Pneumologie, Medizinische Klinik Innenstadt, and Strahlentherapie, University of Munich; Institut für Medizinische Statistik und Epidemiologie, Technical University of Munich, Munich; Klinik und Poliklinik für Strahlentherapie, and Pneumologie, Medizinische Klinik, University of Wuerzburg, Wuerzburg; and the Robert-Koch-Klinik, Leipzig; Germany Address reprint requests to Rudolf M. Huber, PhD, MD, Pneumologie, Medizinische Klinik Innenstadt, University of Munich, Ziemssenstrasse 1, 80336 Munich, Germany; e-mail: huber{at}med.uni-muenchen.de
PURPOSE: The aim of this study was to examine whether, after preceding induction chemotherapy, simultaneous chemoradiotherapy is superior to radiotherapy alone. PATIENTS AND METHODS: Patients with non–small-cell lung cancer in inoperable stage IIIA or IIIB received induction chemotherapy with two cycles of paclitaxel 200 mg/m2 and carboplatin area under the curve 6 every 3 weeks. Patients without progression at restaging after induction chemotherapy were randomly assigned to radiotherapy (60 Gy) or chemoradiotherapy (paclitaxel 60 mg/m2 weekly). The primary end point was overall survival; secondary end points were time to progression, response, and toxicity. RESULTS: Three hundred three patients entered the study, and 276 completed induction chemotherapy. Two hundred fourteen patients were randomly assigned (radiotherapy alone: n = 113; simultaneous chemoradiotherapy: n = 101). Median follow-up time of all randomly assigned patients was 13.6 months (interquartile range [IQR], 6.4 to 29.0 months), and median follow-up time of the subgroup of censored patients (n = 52) was 37.4 months (IQR, 5.9 to 57.0 months; maximum, 76.1 months). Toxicities during the induction phase were mild. During radiotherapy, overall toxicity rates were not significantly different between the two arms. Median survival times in the radiotherapy group and chemoradiotherapy group were 14.1 months (95% CI, 11.8 to 16.3 months) and 18.7 months (95% CI, 14.1 to 23.3 months; difference not statistically significant, P = .091). Median time to progression significantly favored simultaneous chemoradiotherapy (11.5 months; 95% CI, 8.3 to 14.7 months) versus radiotherapy alone (6.3 months; 95% CI, 5.0 to 7.6 months; P < .001, log-rank test). CONCLUSION: Induction chemotherapy followed by chemoradiotherapy with weekly paclitaxel is feasible. Response, time to progression, and survival favor chemoradiotherapy compared with radiotherapy alone.
Lung cancer is one of the most frequent tumors in Western societies. In Germany, approximately 40,000 new patients are diagnosed every year, with a 5-year survival rate of approximately 13%. The most frequent histologic subtype is non–small-cell lung cancer (NSCLC), composing approximately 75% of lung cancers. The majority of NSCLCs in Germany are still squamous cell carcinomas. In the 40% of patients with local disease and involved mediastinal lymph nodes, chemotherapy and radiotherapy and/or surgery are used. In locally advanced inoperable disease, the combination of two to three cycles of platinum-containing chemotherapy followed by conventionally fractionated radiotherapy with 60 to 65 Gy has proven superior to radiotherapy alone in several randomized trials and a meta-analysis.1-4 Adding carboplatin concurrent with radiation treatment did not result in a clear-cut difference compared with sequential treatment alone.5 Several new active agents, such as taxanes, gemcitabine, and vinorelbine, in the mid-1990s led to better tolerance. At the time when this study was planned, paclitaxel had been evaluated in phase II studies. At doses between 200 and 250 mg/m2 every 3 weeks, partial and complete response rates were 21% to 24%, and median survival time was 24 to 40 weeks.6-8 Three-hour paclitaxel infusions were better tolerated than 24-hour infusions. In combination with cisplatin or carboplatin, paclitaxel demonstrated remission rates between 40% and 50%.9-11 In a phase I study, combined daily radiotherapy (total dose to the tumor = 60 Gy) with weekly paclitaxel (10 to 70 mg/m2) resulted in a promising response rate of 74%.12 Esophagitis was the dose-limiting toxicity, with a maximum-tolerated paclitaxel dose of 60 mg/m2. Our group tested this concept after induction with two cycles of paclitaxel and carboplatin in a phase II study and demonstrated promising results.13 In this phase III study, we evaluated whether, after induction chemotherapy, subsequent simultaneous chemoradiotherapy with weekly administration of paclitaxel is superior to radiotherapy alone.
The study was designed and conducted in accordance with Good Clinical Practice Guidelines, the German Drug Law, the relevant regulations on the performance of clinical studies, and the Declaration of Helsinki. The study was approved by the local ethics committees. Before inclusion in the study, all patients provided written informed consent.
Patients
Patients with previous or concomitant malignancies, apart from nonmelanoma skin cancer or curatively treated in situ carcinoma of the cervix, a Karnofsky performance score of less than 70, severe motor or sensory neuropathy (WHO grade
Treatment Doses were reduced to paclitaxel 175 or 150 mg/m2 and/or carboplatin AUC 5 or 4 as a result of an absolute neutrophil count of less than 0.5 g/L for more than 7 days or of less than 0.1 g/L for more than 3 days, febrile neutropenia, WHO grade 3 thrombocytopenia, WHO grade 3 GI adverse effects, and WHO grade 2 or 3 neurological adverse effects. Treatment was stopped and patients went off study in case of insufficient hematologic recovery, significant hypersensitivity to paclitaxel, grade 4 esophagitis, cardiac arrhythmia, heart block apart from grade 1 atrioventricular block, or WHO grade 3 to 4 major organ toxicity (with the exception of predefined alopecia, vomiting, and musculoskeletal pain). After two cycles, patients were restaged in study week 7. Patients showing progressive disease went off study. Patients with a good response were re-evaluated for operability. Patients now operable left the study. The other patients were randomly assigned to radiotherapy alone or to chemoradiotherapy. Patients were to receive three-dimensional conformal radiotherapy (> 6 MeV) in multiple-field technique, with a minimal target dose of 60 Gy for the primary tumor and enlarged lymph nodes (> 1.5 cm transversal diameter). Radiation of 50 Gy was administered to the mediastinum and the primary tumor, followed by boost irradiation of 10 to 16 Gy to macroscopic disease. Increasing the boost to 16 Gy was at the discretion of the radiotherapist in relation to estimated pneumonitis risk. The supraclavicular area was irradiated in case of enlarged upper mediastinal nodes. Total dose to the spinal canal was kept to less than 42 Gy. Radiation was documented on specific data forms and centrally reviewed after treatment. Patients in the chemoradiotherapy group received 1-hour infusions of paclitaxel 60 mg/m2 in weekly intervals over 6 weeks, up to 6 hours before radiotherapy, starting on day 1 of radiotherapy. Patients received premedication as during induction therapy. The paclitaxel dose was chosen in accordance with the results of a preceding dose-finding study.13 Paclitaxel was delayed by 1 week for an absolute neutrophil count of less than 2 g/L or a thrombocyte count of less than 100 g/L. Radiotherapy was stopped for an absolute neutrophil count less than 1 g/L and was not restarted until the absolute neutrophil count recovered to more than 1.5 g/L. Patients could receive antiemetics, if required, but no cytotoxic, hormone, or immune therapy and no regular supportive treatment with granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor.
Assessments and Outcomes
Random Assignment
Statistical Analysis
Determination of Sample Size
Patients Between July 1997 and May 2002, 303 patients were recruited, of whom 276 completed induction chemotherapy. Two hundred eighty-eight patients received at least one cycle and were thus assessable for toxicity; 269 patients were assessable for response after induction chemotherapy. Two hundred nineteen patients were randomly assigned (115 patients to radiotherapy alone and 104 patients to simultaneous chemoradiotherapy). After careful review, five patients were excluded (three patients were randomly assigned despite progressive disease, and two patients showed brain metastasis before the start of treatment), leading to 214 patients (radiotherapy alone: n = 113; simultaneous chemoradiotherapy: n = 101). Two patients were completely lost from follow-up. Survival analyses are limited to 212 patients (99 receiving chemoradiotherapy and 113 receiving radiotherapy alone; Fig 1).
Patient characteristics and reasons for not being randomly assigned are listed in Tables 1 and 2. Treatment was administered per protocol or with minor variations in the vast majority of eligible patients and without differences between the treatment arms. Mean and median time for radiotherapy was 43 days (± 7 days). Median dose of radiotherapy administered was 60 Gy, with 88% of patients receiving a dose greater than 57 Gy. The analysis reported here was performed after a minimal potential follow-up time of 3 years.
Response Induction chemotherapy achieved a complete response in 1.1% of the patients; 39.1% demonstrated a partial response; 42.0% had stable disease; and 15.2% experienced disease progression (Table 1). Evaluation of response 3 months after the end of radiotherapy alone or chemoradiotherapy suggested advantages for chemoradiotherapy; more complete responses and less progressive disease were seen (Table 3). However, the number of deceased patients within the first 3 months was greater in the chemoradiotherapy arm. These differences between both treatment groups were statistically significant (P = .02).
Relapses were less frequent in the chemoradiotherapy group compared with the radiotherapy alone group (65.7% v 85.9%, respectively; P < .001). There was no difference in the distribution of relapse locations. In multivariate analysis, only stage (P = .005) and response to induction chemotherapy (P = .006) predicted response at 3 months after end of treatment.
Time to Progression
Overall Survival Median survival time in the group receiving radiotherapy alone was 14.1 months (95% CI, 11.8 to 16.3 months); in the group receiving simultaneous chemoradiotherapy, the median survival time was 18.7 months (95% CI, 14.1 to 23.3 months), leading to a hazard ratio of 0.76 (95% CI, 0.56 to 1.05). This difference was not statistically significant (P = .091, log-rank test; Fig 3).
Response after induction chemotherapy was correlated with overall survival (P = .010 in multivariate analysis). In a post hoc subgroup analysis, only patients with partial response after induction chemotherapy had a benefit from weekly paclitaxel during radiotherapy (median survival time, 32.6 v 16.6 months for patients with at least a partial response; log-rank P = .041; Fig 4).
Toxicity Induction chemotherapy was well tolerated, with 2.1% of patients with grade 3 nausea and vomiting and 3.8% of patients with grade 3 or 4 leukopenia/neutropenia (grade 4, 2.1%). Toxicities during radiotherapy alone or chemoradiotherapy are listed in Table 4. The most frequent grade 3 or 4 toxicity observed was esophagitis, which occurred in 12.8% of patients in the chemoradiotherapy arm and in 6.5% of patients in the radiotherapy arm. Overall toxicity, however, was not statistically significantly different between the two groups.
After induction chemotherapy with two cycles of carboplatin and paclitaxel, combined chemoradiotherapy with weekly paclitaxel was superior to radiotherapy alone. This difference was highly significant for time to progression and nearly significant for overall survival (P = .091). Induction chemotherapy with platinum-containing regimens has been shown to increase survival in inoperable stage III NSCLC patients2 compared with radiotherapy alone. A median survival time of approximately 14 months has been consistently reproduced by trials using induction therapy with cisplatin and vinblastine and locoregional radiotherapy with 60 Gy.14 This survival range was also achieved in our induction chemotherapy and then radiotherapy alone arm. Because the toxicity of this approach is low, trials were started that added single-agent chemotherapy concurrent with radiotherapy after two to three cycles of chemotherapy. Weekly schedules were preferred as a compromise between possible radiosensitization and feasibility. Cancer and Leukemia Group B (CALGB) 9130 trial randomly assigned 350 patients to radiotherapy 63 Gy alone versus radiotherapy plus carboplatin 100 mg/m2 weekly after two cycles of cisplatin and vinblastine. Survival was identical in both groups, with a median survival time of 13 months and a 3-year survival rate of 20%.5 This negative result was confirmed by a recent French trial that used daily carboplatin (15 mg/m2) concurrent with radiotherapy (66 Gy) in the experimental arm after induction chemotherapy with cisplatin/vinorelbine.15 Median survival time was approximately 15 months, and the 3-year survival rate was 19% in both groups. These data are in contrast to the findings of our trial. Radiosensitizer properties of paclitaxel have been shown both in vitro and in animal models.16-18 Clinically, however, no chemotherapy combination has proven superiority in a combined-modality setting. CALGB 9431 was a three-arm randomized phase II study that tested induction chemotherapy with platinum plus paclitaxel, gemcitabine, or vinorelbine followed by concurrent chemoradiotherapy with weekly application of the respective novel agent. Median overall survival time was promising (14.8 to 17.3 months), although the trial was not aimed to demonstrate survival differences.19 The combination of carboplatin and paclitaxel was tested in a similar fashion and led to rather equivalent outcome.20 Because of its favorable toxicity profile, it was chosen for CALGB 39801, which randomly assigned patients to two cycles of induction chemotherapy followed by weekly paclitaxel (50 mg/m2) and carboplatin AUC 2 concurrent with radiotherapy 66 Gy versus concurrent chemoradiotherapy only.21 The feasibility and tolerance of this approach are confirmed in our trial. Patients profited to an extent of 4.6 and 5.2 months from combined chemoradiotherapy (differences compared with the radiotherapy group in median survival time and median progression-free survival time, respectively) without major increases in toxicity. No dose-limiting effects for bone marrow toxicity and no increase in pneumonitis were observed in our multicenter study. Only the incidence of grade 3 or 4 esophagitis was higher with simultaneous chemoradiotherapy versus radiotherapy alone (12.8% v 6.5%, respectively; P = not significant). Compared with concurrent chemoradiotherapy with full-dose conventional chemotherapy, the rate of esophagitis seems rather low and tolerable.22,23 However, in CALGB 39801,21 there was no difference seen between the arms, challenging the importance of induction chemotherapy. Median survival time was 14 months, and 3-year survival rate was 19% in both arms. These results were worse than expected. The major difference to former trials was a higher portion of patients with a performance status of 2. The data presented in this publication show an increase in median survival time from 14.1 to 18.7 months and an improvement of 3-year survival rate from 16.8% to 29.7% in the arm with additional weekly paclitaxel during radiotherapy. The major difference to the cited negative trials is that random assignment was performed after induction chemotherapy only for patients showing at least stable disease. Thus nearly one third of registered patients did not qualify for random assignment. The importance of this is highlighted by the observation that only patients responding to induction chemotherapy had a significant benefit from weekly concurrent chemoradiotherapy. Regimens similar to our experimental arm have yielded nearly identical results. Lau et al24 reported a median survival time of 17 months in stage IIIA or IIIB NSCLC patients after paclitaxel 30 mg/m2 twice weekly and carboplatin AUC 1.5 once weekly for 6 weeks, together with radiotherapy for a total dose of 61 Gy. Patients without progression received two cycles of paclitaxel 200 mg/m2 and carboplatin AUC 6. The randomized Radiotherapy Oncology Group 98-01 trial explored the ability of amifostine to reduce mucosal and pulmonary toxicity during concurrent chemoradiotherapy (69.6 Gy bid, paclitaxel 50 mg/m2, and carboplatin AUC 2) after two cycles of paclitaxel (225 mg/m2) and carboplatin (AUC 6). No benefit for amifostine was shown. Median survival time was 17.5 months, and estimated 3-year survival rate was 24%.25 Our trial adds data to the question of how to sequence chemoradiotherapy. Induction chemotherapy may select patients who will benefit from concurrent chemoradiotherapy and may spare patients from intensive treatment who will experience early treatment failure. Nevertheless, given the evidence from randomized studies, upfront concurrent chemoradiotherapy represents the current standard for stage III inoperable patients with NSCLC and good performance status. Toxicities using chemotherapy without dose adjustments are more pronounced. This was first shown in a Japanese trial22 using a split-course design and confirmed by the Radiotherapy Oncology Group 9410 trial, which randomly assigned patients to induction chemotherapy with cisplatin and vinblastine followed by radiotherapy versus the same chemotherapy simultaneous with 60 Gy of radiation.23 A Czech study26 and two not fully published European trials27,28 yield at least a trend supporting concurrent treatment. Data from a three-arm, randomized, phase II trial20 suggest marginal superiority of chemoradiotherapy followed by consolidation chemotherapy (carboplatin and paclitaxel) over the same treatment using induction chemotherapy. This conclusion is supported by data from the phase II Southwest Oncology Group 9504 trial, which administered three courses of docetaxel after full-dose concurrent chemoradiotherapy with vinblastine and cisplatin,29 and seems to parallel the experience from small-cell lung cancer that early initiation of local treatment is beneficial. Whether consolidation chemotherapy really adds to the efficacy of full-dose concurrent chemotherapy is being investigated by the Hoosier Oncology Group and the present trial from our group, which administers two cycles of oral vinorelbine and cisplatin during radiotherapy and randomly assigns responding patients between two further cycles of chemotherapy and observation only. In conclusion, induction chemotherapy remains an option for patients with locally advanced disease who may initially be thought not to be candidates for intensive concurrent chemoradiotherapy. According to our results, responding patients could receive weekly chemotherapy concomitant with radiotherapy.
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)
Supported by Bristol-Myers Squibb Co GmbH, Munich, Germany. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31 to June 3, 2003; and at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Le Chevalier T, Arriagada R, Quoix E, et al: Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non-small lung carcinoma. J Natl Cancer Inst 83:417-423, 1991 2. Dillman RO, Herndon J, Seagren SL, et al: Improved survival in stage III non-small-cell lung cancer: Seven year follow up of CALGB 8433 trial. J Natl Cancer Inst 88:1210-1215, 1966 3. Havemann K, Wolf M, Goerg C, et al: Paclitaxel and simultaneous radiation in the treatment of stage III A/B non-small cell lung cancer. Semin Oncol 22:19-22, 1995 (suppl 14)[Medline] 4. 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 randomized clinical trials. BMJ 311:899-909, 1995 5. Clamon G, Herndon J, Cooper R, et al: Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: A phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol 17:4-11, 1999 6. Gatzemeier U, Heckmayer M, Neuhauss R, et al: Chemotherapy of advanced inoperable non-small cell lung cancer with paclitaxel: A phase II trial. Semin Oncol 22:24-28, 1995 (suppl 15)[Medline] 7. Johnson DH, Chang AY, Ettinger DS: Taxol (paclitaxel) in the treatment of lung cancer: The Eastern Cooperative Oncology Group experience. Ann Oncol 5:S45-S50, 1994 (suppl 6) 8. Murphy WK, Fossella FV, Winn RJ, et al: Phase II study of Taxol in patients with untreated advanced non-small cell lung cancer. J Natl Cancer Inst 85:384-388, 1993 9. Bunn PA: The North American experience with paclitaxel combined with cisplatin or carboplatin in lung cancer. Semin Oncol 23:18-25, 1996 (suppl 16)[Medline] 10. Langer CJ, Millenson M, O'Dwyer P, et al: Combination paclitaxel (1-hour) and carboplatin (AUC 7.5) in advanced non-small cell lung cancer: A phase II study by the Fox Chase Cancer Center Network. Semin Oncol 23:35-41, 1996 (suppl 16)[Medline] 11. Splinter TA: Paclitaxel and carboplatin as neoadjuvant chemotherapy in operable (stage I and II) and locally advanced (stage IIIa-N2) non small cell lung cancer. Semin Oncol 23:59-61, 1996 (suppl 16)[Medline] 12. Choy H, Akerley W, Safran H, et al: Phase I trial of outpatient weekly paclitaxel and concurrent radiation therapy for advanced non-small-cell lung cancer. J Clin Oncol 12:2682-2686, 1994 13. Willner J, Schmidt M, Kirschner J, et al: Sequential chemo- and radio-chemotherapy with weekly paclitaxel (Taxol) and 3D-conformal radiotherapy of stage III inoperable non-small cell lung cancer: Results of a dose escalation study. Lung Cancer 32:163-171, 2001[CrossRef][Medline] 14. 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 15. Gervais R, Ducolone A, Lechevalier T, et al: Conventional radiation (RT) with daily carboplatin (Cb) compared to RT alone after induction chemotherapy (ICT) [vinorelbine (Vr)-cisplatin (P)]: Final results of a randomized phase III trial in stage III unresectable non small cell lung (NSCLC) cancer—Study CRG/BMS/NPC/96 of the French Lung Cancer Study Group FNCLCC and IFCT. J Clin Oncol 23:625s, 2005 (suppl 16, abstr 7016) 16. Mote PA, Davey MW, Davey RA, et al: Paclitaxel sensitizes multidrug resistant cells to radiation. Anticancer Drugs 7:182-188, 1996[Medline] 17. Geard CR, Jones JM, Schiff PB: Taxol and radiation. J Natl Cancer Inst Monogr 15:89-94, 1993[Medline] 18. Leonard CE, Chan DC, Chou TC, et al: Paclitaxel enhances in vitro radio-sensitivity of squamous carcinoma cell lines of the head and neck. Cancer Res 56:5198-5204, 1996 19. 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 20. Belani CP, Choy H, Bonomi P, et al: Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: A randomized phase II locally advanced multi-modality protocol. J Clin Oncol 23:5883-5891, 2005 21. Vokes EE, Herndon JE, Kelley MJ, et al: Induction chemotherapy followed by concomitant chemoradiotherapy (CT/XRT) versus CT/XRT alone for regionally advanced unresectable non-small cell lung cancer (NSCLC): Initial analysis of a randomized phase III trial. J Clin Oncol 22:618s, 2004 (suppl 14, abstr 7005) 22. 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 23. Curran WJ, Scott CB, Langer CJ, et al: Long term benefit is observed in a phase III comparison of sequential vs. concurrent chemoradiation for patients with unresected stage III NSCLC: RTOG 9410. Proc Am Soc Clin Oncol 22:621, 2003 (abstr 2499) 24. Lau D, Leigh B, Gandara D, et al: Twice-weekly paclitaxel and weekly carboplatin with concurrent thoracic radiation followed by carboplatin/paclitaxel consolidation for stage III non–small-cell lung cancer: A California Cancer Consortium phase II trial. J Clin Oncol 19:442-447, 2001 25. Movsas B, Scott C, Langer C, et al: Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: Radiation Therapy Oncology Group Trial 98-01. J Clin Oncol 23:2145-2154, 2005 26. Zatloukal P, Petruzelka L, Zemanova M, et al: Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: A randomized study. Lung Cancer 46:87-98, 2004[CrossRef][Medline] 27. Pierre F, Maurice P, Gilles R, et al: A randomized phase III trial of sequential chemo-radiotherapy versus concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (GLOT-GFPC NPC 95-01). Proc Am Soc Clin Oncol 20:312a, 2001 (abstr 1246) 28. Zemanova M, Petruzelka L, Zemanova M, et al: Concurrent versus sequential radiochemotherapy with vinorelbine plus cisplatin (V-P) in locally advanced non-small cell lung cancer: A randomized phase II study. Proc Am Soc Clin Oncol 21:310a, 2002 (abstr 1159) 29. Gandara DR, Chansky K, Albain KS, et al: Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non–small-cell lung cancer: Phase II Southwest Oncology Group Study S9504. J Clin Oncol 21:2004-2010, 2003 Submitted December 28, 2005; accepted July 11, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2), cardiac arrhythmias, congestive heart failure (New York Heart Association grades 3 or 4), recent myocardial infarction, complete intestinal obstruction, acute infections, or psychiatric disorders were excluded. At study entry, all patients were required to present adequate physiologic, hematologic, renal, and hepatic function, as well as a forced expiratory volume in 1 second of 
2 test, respectively. (Fisher’s exact test was used if asymptotic requirements for 
= 5% was used. All tests were performed two sided. 
