When approaching a patient with inoperable non-small

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1 ORIGINAL ARTICLE Gemcitabine, Cisplatin, and Hyperfractionated Accelerated Radiotherapy for Locally Advanced Non-small Cell Lung Cancer Matjaz Zwitter, PhD, MD, Viljem Kovac, MSc, MD, Uros Smrdel, MD, and Primoz Strojan, PhD, MD Background: Due to potent radiosensitization and potential serious or fatal toxicity, concurrent gemcitabine and irradiation should only be applied within clinical trials. We here present experience from a phase I-II clinical trial for patients with locally advanced non-small cell lung cancer (NSCLC) treated with hyperfractionated accelerated radiotherapy and concurrent low-dose gemcitabine. Methods: Eligible patients had locally advanced inoperable NSCLC without pleural effusion, Eastern Cooperative Oncology Group performance status 0-1, were chemotherapy naïve and had no previous radiotherapy to the chest, and had adequate hematopoietic, liver, and kidney function. Routine brain computed tomography was not performed, and positron emission tomography/computed tomography was not available. Treatment consisted of three parts: induction chemotherapy with gemcitabine and cisplatin in standard doses, local treatment with concurrent chemotherapy and radiotherapy, and consolidation chemotherapy. Patients were irradiated with opposed AP-PA and oblique fields, using 2.5-D treatment planning. Although corrections for inhomogeneous tissue were made, volume of total lung receiving 20 Gy (V20) could not be determined. The trial started as phase I, aimed to determine the dose-limiting toxicity and maximal tolerated dose (MTD) for concurrent hyperfractionated radiotherapy (1.4 Gy twice daily) and gemcitabine 55 mg/m 2 twice weekly as a radiosensitizer. Phase II of the trial then continued at the level of MTD. Results: Twenty-eight patients with NSCLC, nine patients with stage IIIA, 16 patients with IIIB, and three patients with an inoperable recurrence after previous surgery, entered the trial. The first 12 patients entered Phase I of the trial at the initial level of 42 Gy in 30 fractions in 3 weeks. Dose-limiting toxicity was acute esophagitis; 47.6 Gy in 34 fractions in 3.5 weeks was the MTD for this regimen of concurrent chemotherapy and radiotherapy. In phase II of the trial, this dose was applied to the next 16 patients. Among all 28 patients, 13 had grade 3 or 4 acute toxicity: esophagitis (eight patients), neutropenia (eight patients), thrombocytopenia (four patients), and anemia (two patients). No pulmonary toxicity and no persistent or serious late toxicity were seen. Local and/or regional relapse was documented in nine patients, distant in five and both locoregional and distant in 10 patients. The most common sites of Institute of Oncology, Ljubljana, Slovenia. Address for correspondence: Dr. Matjaz Zwitter, Institute of Oncology, Zaloska 2, 1000 Ljubljana, Slovenia. mzwitter@onko-i.si Copyright 2006 by the International Association for the Study of Lung Cancer ISSN: /06/ distant spread were the brain and lung in eight and six patients, respectively. At 2 years, progression-free survival was 43% and overall survival was 57%. After 43 to 85 months of follow-up, seven patients are alive, of whom six (21%) are without evidence of disease and may be regarded as long-term survivors. Among the long-term survivors, one was in the group irradiated to 42 Gy and six in the groups irradiated to 47.6 Gy. Conclusion: Judging from current standards, the methods used in diagnostics and in planning of radiotherapy were suboptimal. Using modern radiotherapy planning, a higher MTD, possibly a different profile of toxicity, and better long-term results may be expected. The high incidence of brain relapse emphasizes the need for careful screening for unsuspected brain disease before treatment and the importance of clinical studies on prophylactic cranial irradiation for patients with locally advanced NSCLC. Although the small number of patients in this study precludes any definitive conclusion, it appears that our program of concurrent chemotherapy and radiotherapy offers a chance for disease control at least comparable to previously described programs for inoperable lung cancer. Key Words: non-small cell lung cancer, gemcitabine, cisplatin, sensitization, radiotherapy, hyperfractionation. (J Thorac Oncol. 2006;1: ) When approaching a patient with inoperable non-small cell lung cancer (NSCLC), two problems must be addressed: the problem of local tumor control and the problem of distant micrometastases. The standard approach is combination of chemotherapy and radiotherapy. 1,2 When compared to sequential treatment, concurrent radiotherapy and chemotherapy are associated with higher toxicity but lead to superior time to progression and overall survival. 3 5 The past decade brought progress in local and in systemic treatment. Regarding local treatment, there is evidence in favor of hyperfractionated accelerated radiotherapy (HART), as compared to standard fractionation regimens. 6,7 The same trend in favor of HART was reported in a recent trial of combined chemotherapy and irradiation. 8 Regarding systemic treatment, chemotherapy with the third-generation of cytotoxic drugs (gemcitabine, taxanes, vinorelbine) in combination with cisplatin or carboplatin offers higher activity and often less toxicity when compared to older cisplatinbased combinations Journal of Thoracic Oncology Volume 1, Number 7, September 2006

2 Journal of Thoracic Oncology Volume 1, Number 7, September 2006 Chemotherapy and Hyperfractionated Accelerated Radiotherapy for NSCLC The objective of this trial was to assess toxicity and efficacy of a novel approach of combined treatment for locally advanced NSCLC. Treatment program consisted of induction chemotherapy, local treatment with concurrent hyperfractionated accelerated radiotherapy and low-dose gemcitabine as a radiosensitizer and consolidation chemotherapy. PATIENTS AND METHODS Patients Staging included chest x-ray, computed tomography (CT) for chest and upper abdomen, bronchoscopy, abdominal ultrasonography, and bone scintigraphy. In the absence of neurologic symptoms, brain CT was not performed; positron emission tomography or positron emission tomography/ct was not available. Patients eligible for this trial had histologic or cytologic diagnosis of NSCLC, stage IIIA or IIIB inoperable cancer without malignant pleural effusion, Eastern Cooperative Oncology Group performance status 0-1, were chemotherapy naïve and had no previous radiotherapy to the chest, and had adequate hematopoietic, liver, and kidney function. All patients were fully informed and consented to participate in the trial. The trial was approved by the Institutional Protocol Review Board and by the National Committee for Medical Ethics. Induction Chemotherapy Treatment started with two cycles of chemotherapy with gemcitabine (1250 mg/m 2, days 1 and 8) and cisplatin (70 mg/m 2, day 1). Local treatment The target volume included the gross tumor and involved lymph nodes with margin of 2 to 3 cm in craniocaudal and 1 to 1.5 cm in other directions. The dose was prescribed to the isodose line, which encompassed the target volume; dose variations of 5% inside this volume were considered acceptable. Using 2.5 D treatment planning system, corrections were made for tissue inhomogeneities. Patients were treated on linear accelerator with 5 to 10 MeV x-rays with AP-PA and one or two opposed oblique fields. The total dose to the spinal cord was kept under 45 Gy. Due to limitations of the planning system, volume of total lung receiving 20 Gy or more (V20) was not determined. Patients underwent irradiation twice daily with 1.4 Gy per fraction to a weekly dose 14 Gy. Phase I of the trial started at 42 Gy in 3 weeks. According to the plan for dose escalation, first three patients would receive a total dose of 42 Gy in 3 weeks, after which groups of six patients would receive a total dose of 47.6 Gy, 50.4 Gy, 53.2 Gy, and 56 Gy in 3.5 to 4 weeks. Our initial plan was to include 27 patients in Phase I of the trial. After establishing the maximal tolerated dose (MTD) for the concomitant chemotherapy/radiotherapy part of the protocol, the trial should continue as phase II and include a total of 80 patients. Monitoring for acute toxicity included regular weekly hematology, biochemistry, body weight, and physical examination. In the absence of pulmonary symptoms, routine pulmonary tests were not performed. The MTD was defined as the radiation dose level at one cohort below that, which resulted in more than 33% of patients experiencing any grade 3 or greater acute toxicity. During radiotherapy, gemcitabine at a dose of 55 mg/m 2 was given twice weekly. Consolidation Chemotherapy After an interval of 2 to 3 weeks, patients continued with two to four cycles of systemic treatment with gemcitabine and cisplatin in the same doses as during induction chemotherapy. RESULTS From February 1999 to November 2002, 28 patients (19 men, nine women, age 33 to 72 years, median age 52 years) entered the trial. Histology was squamous in 14 patients, adenocarcinoma in nine patients, and large cell or poorly differentiated in five patients. The stage were IIIA (nine patients), IIIB (16 patients, of whom two had superior vena cava syndrome), and inoperable recurrence after previous surgery (three patients). Induction Chemotherapy No grade 3 toxicity from the induction chemotherapy was recorded. Of 21 patients who were assessable for response, there were no complete responses, 12 partial remissions, and nine minimal responses or stable disease. Local Treatment The first 12 patients entered Phase I of the trial and were treated with escalating total doses of irradiation: 42 Gy in 3 weeks (three patients), 47.6 Gy in 3.5 weeks (six patients), and 50.4 Gy in 4 weeks (three patients). All three patients irradiated to 50.4 Gy had grade 3 acute toxicity: esophagitis in two patients (one of whom also had grade 3 neutropenia) and thrombocytopenia in one. Based on this admittedly limited experience, acute esophagitis was defined as the dose-limiting toxicity. Subsequent 16 patients were treated as Phase II of the trial to 47.6 Gy as our estimate of the maximal tolerated dose. An overview of acute toxicity is presented in Table 1. In nine patients, some applications of gemcitabine as a radiosensitizer had to be omitted due to hematologic toxicity, general malaise, and/or nausea. Based on a plan to combine irradiation with twice-weekly low-dose gemcitabine, on average 94% (range 40% 100%) of radiotherapy was actually covered by gemcitabine. Most patients experienced general malaise and nausea (grade 2, 20 patients). Grade 2 and 3 esophagitis was present in 14 and eight patients, respectively. Median loss of body weight was 3 kg (range 0 12 kg) or 5% (range 0% 15%) of body weight. After a median interval of 10 days (range 6 25 days) from the end of radiotherapy, patients could eat normally and were again gaining weight. No lasting consequences of esophagitis were seen. Anemia (grades 2 and 3 in 16 and two patients, respectively) was common, with mean hemoglobin nadir at 94 g/l. Grade 2, 3, and 4 neutropenia occurred in 14, five, and three Copyright 2006 by the International Association for the Study of Lung Cancer 663

3 Zwitter et al. Journal of Thoracic Oncology Volume 1, Number 7, September 2006 TABLE 1. Number of patients with grade 2, 3, or 4 toxicity Phase I Phase II All Dose level (Gy) No. of patients Esophagitis Grade Grade Anemia Grade Grade Neutropenia Grade Grade Grade Thrombocytopenia Grade Grade Grade Any grade 3 or 4 toxicity Due to a small number of patients in each group, percentages are not presented. patients, with one case of febrile neutropenia. Grade 2, 3, and 4 thrombocytopenia was seen in six, two, and two patients, respectively. In all cases, neutrophil and platelet counts returned to normal within 13 days. One patient died 3 weeks after radiotherapy. A 71-yearold man with a recurrence of lung cancer after surgery and destruction of the vertebral body suffered ventricular fibrillation and heart arrest. The relationship between the treatment and the fatal outcome remains unclear. Consolidation Chemotherapy No grade 3 toxicity was seen during consolidation chemotherapy. Long-term toxicity Eight months after completing treatment with 42 Gy as the total dose to the spinal cord, one patient developed transient paraparesis of the lower limbs. Myelography and magnetic resonance imaging were negative for tumor invasion. After treatment with corticosteroids, the symptoms resolved and did not recur in the next 3 years. No other late toxicity was seen. Disease progression and survival No patient was lost to follow-up. The median follow-up for patients alive at close-out date (March 1, 2006) was 60 months (range months). Among all 28 patients who entered the trial, seven patients are alive, six (21%) of whom are currently without evidence of disease and may be regarded as long-term survivors. In addition to four patients who never had a relapse, two had surgery and radiotherapy for brain metastases and are without evidence of disease 28 and 47 months later, respectively. Among the long-term survivors, one was in the group irradiated to 42 Gy and six in the groups irradiated to 47.6 Gy. Local and/or regional relapse was documented in nine patients, distant in five, and both locoregional and distant in 10 patients. The most common sites of distant spread were the brain and lung in eight and six patients, respectively. Median time to progression and survival were 16 and 28 months, respectively. At 2 years, progression-free survival was 43% (95% CI: 25 61%) and overall survival was 57% (95% CI: 39 75%). At 3 years, progression-free survival was 18% (95% CI: 4 32%) and overall survival was 43% (95% confidence interval: 25% 61%) (Figure 1). DISCUSSION The objective of this trial was to explore the feasibility of a novel approach of combined treatment with gemcitabine and cisplatin and radiotherapy in locally advanced NSCLC. Our induction and consolidation chemotherapy followed the standard schedule used in many other trials of locally advanced or metastatic NSCLC. The innovative part of the protocol was the local treatment with hyperfractionated accelerated radiotherapy and concurrent gemcitabine as a radiosensitizer. We start the discussion with an explanation of the design of this part of the treatment protocol. Comments on actual performance of the trial and on our experience are then presented. Early experience with radiotherapy and concurrent gemcitabine revealed serious and even fatal toxicity. It is now clear that both modalities in full doses cannot be used simultaneously Further laboratory and clinical studies confirmed potent radiosensitizing properties of gemcitabine. 15,16 Radiosensitization is seen even at very low doses of approximately 35 to 60 mg/m 2 and last for as long as 72 hours, much longer than the short-lived effect of the older sensitizers such as cisplatin. In routine clinical practice, simultaneous use of gemcitabine and irradiation should be avoided and a 2-week gap between the two modalities is recommended. However, in clinical research, several phase I/II trials were developed to test the potential clinical benefit of a carefully designed combined treatment for patients with inoperable cancers of the lung, pancreas, head and neck, cervix, or bladder. When used as a radiosensitizer, gemcitabine is given either once weekly at 300 to 1000 mg/m 2 or twice weekly at a single dose of 40 to 60 mg/m In our trial, gemcitabine at 55 mg/m2 was given twice weekly to cover the whole week of radiotherapy. Unconventional fractionation of irradiation was chosen since we preferred acute (and usually reversible) rather than late (and often irreversible) dose-limiting toxicity of the concurrent gemcitabine/radiotherapy. With the standard 2 Gy per fraction and considering the factor of radiosensitization of gemcitabine, the biologic dose per fraction would be approxi- FIGURE 1. Progression-free survival and overall survival. 664 Copyright 2006 by the International Association for the Study of Lung Cancer

4 Journal of Thoracic Oncology Volume 1, Number 7, September 2006 Chemotherapy and Hyperfractionated Accelerated Radiotherapy for NSCLC mately 3 Gy and the risk of late toxicity substantially increased. Twice-daily fractionation was chosen to avoid a very prolonged course of irradiation, a factor that may lead to poor survival. 24 Our primary aim was to define the MTD and the dose-limiting toxicity for a regimen of concurrent hyperfractionated irradiation and low-dose gemcitabine. Our estimate is that 47.6 Gy in 34 fractions in 17 treatment days is the dose that most patients can tolerate and that will not lead to serious late toxicity. This dose is biologically equivalent to 46 Gy delivered in 23 daily fractions of 2 Gy over 31 days (standard fractionation; calculation on biologic equivalence based on / 10 Gy). Thus, the total dose in our trial is 77% of the standard regimen of 60 Gy in 30 fractions in 6 weeks. The reduction of the MTD in our trial corresponds to 1.3 as the factor of radiosensitization due to concurrent gemcitabine, a figure that compares well with the published data on gemcitabine-enhanced radiosensitivity. 25,26 A detailed look at the actual performance of our trial reveals four areas of criticism and, at the same time, of potential for improvement of results: staging, radiotherapy planning, attention to anemia, and small sample. There is little doubt that PET/CT, not available to the patients in our trial, would detect clinically silent distant spread in a substantial proportion of patients. When dealing with apparently locally advanced disease, careful staging is essential to select only those patients for whom a potentially curative treatment with significant acute toxicity is justified. Judging from the present standards, the radiotherapy part of the treatment was suboptimal. Dose calculations and therapy planning were done without three-dimensional CTassisted treatment planning. These factors contributed to dose inhomogeneity and, consequently, to more pronounced treatment-related side effects and suboptimal tumor control. Most of the dose was delivered through opposed AP-PA fields, an approach that explains a high incidence of acute esophagitis and possibly also absence of pulmonary toxicity in our trial. With modern treatment planning, we could expect a higher MTD, possibly a different profile of side effects, and improved tumor control. 27,28 Anemia is the third area for potential improvement of our results. Mean hemoglobin levels were 116 g/l after induction chemotherapy and 93 g/l at the nadir during concurrent chemotherapy/radiotherapy. Anemia lowers radiosensitivity and is a well-recognized prognostic factor for tumor control after radical radiotherapy. 29,30 We would expect that correction of anemia before radiotherapy would further improve long-term results. The fourth obvious weak point of our trial is the small number of patients. In December 2002, accrual to the trial closed prematurely. The decision was made after serious technical problems on two linear accelerators led to temporary substantial limitations in the access to radiotherapy in Slovenia. In , a modern system for treatment planning and four new accelerators were installed; an additional new unit is expected within the next eight months. Although we can now offer new modern facilities for routine treatment and for clinical research, a gap of 4 years was considered too long to reopen accrual to this particular trial. We believe that experience with this small group of patients deserves to be presented, and a new trial will test this approach using new technology. As local and systemic treatment for NSCLC improves, the risk of brain metastases increases. In our series, eight patients (29 %) developed brain metastases as the most frequent site of distant spread. Two recommendations follow. First, screening for clinically silent brain metastases should be a routine part of staging before intensive chemotherapy/ radiotherapy for locally advanced lung cancer. 31 Second, prophylactic cranial radiotherapy should be considered for patients in remission. This emphasizes the importance of the ongoing Radiation Therapy Oncology Group 0214 trial of prophylactic cranial radiotherapy in stage III NSCLC. Our trial offers a new and hitherto unreported approach to the treatment of inoperable NSCLC. The acute side effect of grade 3 esophagitis was common but transient, and no severe late toxicity was seen. Overall survival at 2 and 3 years was 57% and 42%, respectively; six patients (21%) may be regarded as long-term survivors. Although the small number of patients precludes any definitive conclusion, it appears that our program of concurrent chemotherapy/radiotherapy offers a chance for disease control at least comparable to that in previously described programs for inoperable lung cancer. ACKNOWLEDGMENTS Partly supported by grants J and J , Ministry of Science and Technology, Republic of Slovenia. REFERENCES 1. Rinaldi M, Crino L. Induction chemotherapy with gemcitabine and cisplatin in stage III non-small cell lung cancer. Lung Cancer 2001; 34(suppl 4):S25 S Santo A, Pedersini R, Pasini F, et al. A phase II study of induction chemotherapy with gemcitabine (G) and cisplatin (P) in locally advanced non-small cell lung cancer: interim analysis. Lung Cancer 2001;34(suppl 4):S15 S 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 2004;46: Rowell N, O Rourke N. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2004:CD Reboul FL. Radiotherapy and chemotherapy in locally advanced nonsmall cell lung cancer: preclinical and early clinical data. Hematol Oncol Clin North Am 2004;18: Baumann M. Accelerated radiation therapy in non-small cell lung cancer. Radiother Oncol 1999;52: Saunders M, Dische S, Barrett A, et al. Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee. Radiother Oncol 1999;52: Belani CP, Wang W, Johnson DH, et al. Phase III study of the Eastern Cooperative Oncology Group (ECOG 2597): induction chemotherapy followed by either standard thoracic radiotherapy or hyperfractionated accelerated radiotherapy for patients with unresectable stage IIIA and B non-small-cell lung cancer. J Clin Oncol 2006;23: Baggstrom MQ, Socinski MA, Hensing TA, et al. Third generation chemotherapy regimens (3GR) improve survival over second generation regimens (2GR) in stage IIIB/IV non-small cell lung cancer (NSCLC): a meta-analysis of the published literature. Proc Am Soc Clin Oncol 2002;21:306a. 10. Socinski MA, Morris DE, Masters GA, et al. American College of Chest Copyright 2006 by the International Association for the Study of Lung Cancer 665

5 Zwitter et al. Journal of Thoracic Oncology Volume 1, Number 7, September 2006 Physicians. Chemotherapeutic management of stage IV non-small cell lung cancer. Chest 2003;123(1 suppl):226s 243S. 11. Le Chevalier T, Scagliotti G, Natale R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer 2006;47: Chen Y, Okunieff P. Radiation and third-generation chemotherapy. Hematol Oncol Clin North Am 2004;18: Curran JrWJ Combined-modality therapy for inoperable non-small-cell lung cancer using gemcitabine. Clin Lung Cancer 2002;3(suppl 1):S17 S Langer CJ. The emerging role of gemcitabine in combination with radiation in locally advanced, unresectable non-small-cell lung cancer. Clin Lung Cancer 2003;4(suppl 2):S45 S Lawrence TS, Blackstock AW, McGinn C. The mechanism of action of radiosensitization of conventional chemotherapeutic agents. Semin Radiat Oncol 2003;13: Mose S, Class R, Weber HW, et al. Radiation enhancement by gemcitabine-mediated cell cycle modulations. Am J Clin Oncol. 2003;26: Pauwels B, Korst AE, Pattyn GG, et al. Cell cycle effect of gemcitabine and its role in the radiosensitizing mechanism in vitro. Int J Radiat Oncol Biol Phys 2003;57: Robinson BW, Ostruszka L, Im MM, et al. Promising combination therapies with gemcitabine. Semin Oncol 2004;31(2 suppl 5): 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 2003;9: 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 2002;20: McGinn CJ, Zalupski MM. Radiation therapy with once-weekly gemcitabine in pancreatic cancer: current status of clinical trials. Int J Radiat Oncol Biol Phys 2003;56(4 suppl): Joensuu TK, Kiviluoto T, Karkkainen P, et al. Phase I-II trial of twice-weekly gemcitabine and concomitant irradiation in patients undergoing pancreaticoduodenectomy with extended lymphadenectomy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2004;60: Martenson JA, Vigliotti AP, Pitot HC, et al. A phase I study of radiation therapy and twice-weekly gemcitabine and cisplatin in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2003;55: Eisbruch A, Shewach DS, Bradford CR, et al. Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study. J Clin Oncol 2001;19: Zarba JJ, Jaremtchuk AV, Gonzalez Jazey P, et al. A phase I-II study of weekly cisplatin and gemcitabine with concurrent radiotherapy in locally advanced cervical carcinoma. Ann Oncol 2003;14: Machtay M, Hsu C, Komaki R, et al. Effect of overall treatment time on outcomes after concurrent chemoradiation for locally advanced nonsmall-cell lung carcinoma: analysis of the Radiation Therapy Oncology Group (RTOG) experience. Int J Radiat Oncol Biol Phys 2006;63: 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 doseescalation phase I trial. J Clin Oncol 2004;22: Schild SE, Bogat JA. Innovations in the radiotherapy of non-small cell lung cancer. J Thorac Oncol 2006;1: Harrison L, Shasha D, Shiaova L, et al. Prevalence of anemia in cancer patients undergoing radiation therapy. Semin Oncol 2001;28(2 suppl 8): Pradier O, Lederer K, Hille A, et al. Concurrent low-dose cisplatin and thoracic radiotherapy in patients with inoperable stage III non-small cell lung cancer: a phase II trial with special reference to the hemoglobin level as prognostic parameter. J Cancer Res Clin Oncol 2006;131: Shi AA, Digumarthy SR, Temel JS, et al. Does initial staging or tumor histology better identify asymptomatic brain metastases in patients with non-small cell lung cancer? J Thorac Oncol 2006;1: Copyright 2006 by the International Association for the Study of Lung Cancer