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Journal of Clinical Oncology, Vol 25, No 21 (July 20), 2007: pp. 3124-3129 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.9606 Results of a Phase II Study of High-Dose Thoracic Radiation Therapy With Concurrent Cisplatin and Etoposide in Limited-Stage Small-Cell Lung Cancer (NCCTG 95-20-53)
From the Mayo Clinic Arizona, Scottsdale, AZ; University of Alabama at Birmingham, Birmingham, AL; Mayo Clinic and Mayo Foundation, Rochester, MN; Cedar Rapids Community Clinical Oncology Program (CCOP), Cedar Rapids; Siouxland Hematology-Oncology Associates, Sioux City, IA; Carle Cancer Center CCOP, Urbana; Illinois Oncology Research Association, CCOP, Peoria, IL; Missouri Valley Cancer Consortium, Omaha, NE; Rapid City Regional Oncology Group, Rapid City, SD; and Roswell Park Cancer Institute, Buffalo, NY Address reprint requests to Steven E. Schild, MD, Mayo Clinic, Department of Radiation Oncology, 13400 E Shea Blvd, Scottsdale, AZ 85259; e-mail: sschild{at}mayo.edu
Purpose: To evaluate the outcome of patients with limited-stage small-cell lung cancer (L-SCLC) treated with cisplatin and etoposide (PE), early prophylactic cranial irradiation (PCI), and high-dose twice-daily thoracic radiotherapy (bid RT). Patients and Methods: A total of 76 assessable patients were treated on this phase II trial, which included six cycles of PE. PCI (25 Gy/10 fractions) was delivered during cycle 3 to responding patients. Cycles 4 and 5 included concurrent chemotherapy and thoracic RT (30 Gy/20 bid fractions, a 2-week break, and another 30 Gy/20 bid fractions). Results: Of the 76 assessable patients, 74 patients (97%) suffered grade 3 or greater (3+) toxicity and 61 patients (80%) had grade 4 or greater (4+) toxicity. Of these adverse events, grade 3+ hematologic toxicity occurred in 72 patients (95%), and grade 3+ nonhematologic toxicity occurred in 55 patients (72%). Only one (2%) of the 61 patients who received PCI experienced treatment failure in the brain. The 5-year survival rate of the 76 assessable patients was 24% (median, 20 months). The 5-year survival rate of the 64 patients who received thoracic RT was 29% (median, 22 months). The 5-year cumulative incidence of in-field treatment failure was 34%. Conclusion: This regimen included a high total dose of bid TRT, which resulted in a favorable 5-year survival rate. Local failure remains a problem that will require additional investigation. Newer technology should allow the safe administration of greater doses of RT, which should improve patient outcome. Data from eight trials were combined to demonstrate a relationship between RT dose fractionation and 5-year survival.
Lung cancer is the leading cause of cancer deaths in the United States, and caused an estimated 169,440 deaths in 2006.1 Approximately 15% of patients with lung cancer have small-cell lung cancer (SCLC) and of these, 30% have limited-stage disease.2 The natural history of untreated SCLC includes rapid tumor progression and a median survival of 2 to 4 months.3 The first major treatment breakthrough was the recognition that SCLC was more responsive to chemotherapy than non–small-cell lung cancer.4 Since that time, the standard of care for SCLC patients has included systemic chemotherapy. In 1992, two meta-analyses addressed the role of thoracic radiotherapy (RT) in addition to chemotherapy in limited-stage SCLC (L-SCLC).2,5 Pignon et al5 reported a 3-year survival rate of 14.3% with combined-modality therapy compared with 8.9% with chemotherapy alone (P = .001). This 5.4% difference in 3-year survival was equivalent to the 5.4% difference in 2-year survival (P < .001) reported by Warde and Payne.2 Prophylactic cranial irradiation (PCI) has also improved survival of patients who achieve a complete response. Auperin et al6 performed a meta-analysis and found that the 3-year survival rate was 5.4% better for those who received PCI (P = .01). With regard to the specifics of RT administration, twice-daily thoracic RT (bid TRT) was found to improve the outcome of patients with L-SCLC. Turrisi et al7 reported the findings of the Intergroup Trial 0096, a phase III trial that compared etoposide and cisplatin plus once-daily RT (45 Gy in 25 daily fractions) versus etoposide and cisplatin plus bid TRT (45 Gy in 30 bid fractions). The 5-year survival rate was 16% (median, 19 months) for daily RT compared with 26% (median, 23 months) for bid TRT (P = .04). Local treatment failure continued to be relatively frequent (36%) despite bid TRT, which has led investigators to try higher doses of RT.8-11 Mayo-North Central Cancer Treatment Group (NCCTG) investigators performed a phase II study for unresectable stage III non–small-cell lung cancer. This trial included split-course bid TRT with a total dose of 60 Gy in 40 fractions of 1.5 Gy, with concurrent cisplatin and etoposide administered in 28-day cycles. The median survival was 26 months, with only 35% of the patients experiencing grade 3 or 4 toxicity and no treatment-related deaths.12 This regimen was believed to be promising and was used as the basis for the present trial in SCLC. The goals were to assess the survival, local control, and tolerability of concurrent chemotherapy with this high-dose bid TRT approach.
Before therapy, each patient had a history, physical examination, and the following tests: biopsy or sputum sample, computed tomography of the chest and upper abdomen, computed tomography or magnetic resonance imaging of the brain, CBCs, serum chemistries, pulmonary function studies, bone scan, and bone marrow biopsy. Patients eligible for this trial had the following characteristics: pathologic verification of SCLC, limited disease (which can be encompassed within reasonable RT fields) with no pleural effusion greater than minimal, Eastern Cooperative Oncology Group performance status of 0 to 2, weight loss less than 10% in the previous 6 months, and an forced expiratory volume at 1 second of more than 1 L. Central review of all tumor samples was performed to confirm the pathologic diagnosis. In addition, each patient had adequate organ function verified with the following laboratory findings: WBC count more than 3,500/mL, platelet count more than 100,000/µL, hemoglobin more than 10 g/dL, creatinine less than 1.5x the upper limit of normal, and alkaline phosphatase less than 1.5x the upper limit of normal. Patients were deemed ineligible for the following health problems: severe preexisting or active cardiac disease, prior cancer history (with the exceptions of nonmelanomatous skin cancers or in situ cervical cancer), prior therapy for this cancer, evidence of infection, or pregnancy. Written informed consent was obtained from all patients per institutional guidelines. Chemotherapy included a total of six cycles of cisplatin and etoposide administered at 28-day intervals. Cycles 1 through 3 were administered before any RT and included the intravenous (IV) administration of cisplatin 30 mg/m2 and etoposide 130 mg/m2 on days 1 through 3. Doses were modified based on blood counts, serum chemistry values, and toxicity levels. PCI was administered beginning on day 12 of cycle 3 before thoracic RT. PCI was administered to patients having had any degree of tumor shrinkage noted on chest x-ray. PCI was administered with 4- to 6-MV x-rays and included the delivery of 25 Gy in 10 fractions to the entire brain with opposed lateral fields. Cycles 4 and 5 included concurrent chemotherapy and thoracic RT. The RT was started at this point because it was hoped that the tumor response from chemotherapy would allow the use of smaller radiation portals, resulting in less toxicity. During cycles 4 and 5, IV cisplatin 4 mg/m2 was administered on days 1 through 5 and 8 through 12. Etoposide 50 mg daily was administered orally on day 1 through 12 with variation in the number of days administered based on body-surface area. Thoracic RT was delivered with 6- to 10-MV x-rays and included a total of 60 Gy in 40 bid fractions of 1.5 Gy each administered at least 6 hours apart. The thoracic RT was administered in a split-course fashion with 30 Gy in 20 bid fractions followed by a 2-week break and another 30 Gy in 20 bid fractions. Each half of the RT began on the first day of cycles 4 and 5 of chemotherapy, respectively. RT was administered in an anteroposterior/posteroanterior manner until spinal cord tolerance (36 Gy) was approached. At that point, RT was continued with opposed off-cord obliques until 60 Gy was administered to the isocenter. The anteroposterior/posteroanterior fields included the following structures with 2-cm margins to the block edge: primary tumor with ipsilateral hilar, mediastinal, and supraclavicular nodes. The initial oblique fields included RT to 51 Gy administered to the primary tumor, ipsilateral hilum, mediastinum, and supraclavicular nodes if initially involved. The final oblique fields to 60 Gy included only the primary tumor, ipsilateral hilum, a reduced volume of mediastinum, and supraclavicular nodes if initially involved. The sixth and last cycle of chemotherapy was identical to that administered during cycles 1 through 3 and included the IV administration of cisplatin 30 mg/m2 and etoposide 130 mg/m2 on days 1 through 3. Follow-up evaluations were performed every 3 to 4 months for 2 years and then every 6 months for 3 additional years. These included history and physical examination, CBCs, chemistry panels, and chest x-rays. Other tests were performed as clinically indicated. Toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria version 1. This study used a one-stage design to test the null hypothesis that after this regimen, the true 2-year survival rate without thoracic failure is at most 20% versus the alternative hypothesis that this rate is at least 36%. Forty-nine patients were needed to assess this hypothesis. Additional patients were enrolled to protect against expected attrition. If 15 or more patients survived without thoracic failure for 2 years or more after study entry, additional testing of the regimen in future studies would be recommended; if 14 or fewer were observed, no such consideration for additional study would be warranted. A total of 82 patients were enrolled; however, there was a higher rate of attrition than expected. After enrolling 82 patients, only 39 patients completed all chemotherapy and radiotherapy, and thus we were unable to evaluate the originally stated efficacy criteria. Instead we evaluated the entire sample of eligible patients as well as the subset of patents who received some of the planned thoracic radiation therapy for all efficacy end points. Survival probabilities were calculated from the time of registration using the Kaplan-Meier method. Cumulative incidence methods were used to calculate the local (in field) and distant failure rates (treatment failures occurring elsewhere). This methodology was used to account for competing risks when determining treatment failure rates because only first sites of treatment failure were recorded.
Eighty-two patients were enrolled between November 1996 and March 1999. Six of these patients were deemed ineligible (five patients had incorrect histology and one patient had extensive stage SCLC). Therefore, 76 patients were assessable for toxicity, disease control, and survival end points. Patient characteristics are summarized in Table 1.
Thirty-nine (51%) of the 76 assessable patients completed all six cycles of chemotherapy and RT. Of the 37 patients who did not complete six cycles of treatment, five patients had progression of disease, 16 patients had toxicity, six patients refused additional therapy, five patients died during chemotherapy, and five patients were removed from the study because of other reasons (Table 2). Of the 76 eligible patients, 61 (80%) of the patients received PCI based on the presence of any tumor response on chest x-ray after the first three cycles of chemotherapy. Sixty-four (84%) of the 76 patients received thoracic RT, which was administered during cycles 4 and 5 of chemotherapy. Sixty-one patients received the full dose of thoracic RT, whereas three patients received a partial dose.
Toxicity Severe toxicity was evaluated in detail (Tables 3 and 4). Of the 76 assessable patients, 74 patients (97%) suffered grade 3 or greater (3+) toxicity and 61 patients (80%) had grade 4 or greater (4+) toxicity. Adverse events were divided further into both hematologic and nonhematologic toxicity. Grade 3+ hematologic toxicity occurred in 72 patients (95%) and grade 4+ hematologic toxicity occurred in 57 patients (75%). Grade 3+ nonhematologic toxicity occurred in 55 patients (72%) and grade 4+ nonhematologic toxicity occurred in 22 patients (29%). Of these patients, three (4%) died as a result of grade 5 toxicity because of renal, pulmonary, and esophageal damage.
Efficacy Of the 76 assessable patients, 57 have died and 56 have experienced disease progression. Patients were observed for a maximum of 5 years (range, 1.5 to 5 years; median, 5 years). Eighteen of the 19 surviving patients (95%) were observed for 4 years or more. The 2- and 5-year cumulative incidences of progression at any site were 71% (95% CI, 62% to 78%) and 74% (95% CI, 65% to 80%). The 2- and 5-year cumulative incidences of locoregional failure (all those occurring in the chest) were 45% (95% CI, 32% to 55%) and 47% (95% CI, 34% to 58%). The 2- and 5-year cumulative incidences of distant (out of chest) failures were 26% (95% CI, 13% to 37%) and 26% (95% CI, 13% to 37%). Five of the 76 patients (7%; 95% CI, 2% to 15%) had the first site of treatment failure in the brain. However, only one of the 61 patients (2%; 95% CI, 0.04% to 9%) who received PCI had the first site of treatment failure in the brain. The median survival of the 76 assessable patients was 20 months. The 2- and 5- year survival rates were 43% (95% CI, 33% to 56%) and 24% (CI, 16% to 36%; Fig 1).
The median survival of the 64 patients who received thoracic radiotherapy (TRT) was 22 months. The 2- and 5-year survival rates were 46% (95% CI, 36% to 60%) and 29% (95% CI, 20% to 43%). The 2- and 5-year cumulative incidences of in-field treatment failure were 33% (95% CI, 19% to 45%) and 34% (95% CI, 20% to 46%). The 2- and 5-year cumulative incidences of distant (out of field) treatment failures were 36% (95% CI, 22% to 47%) and 38% (95% CI, 24% to 49%), respectively.
SCLC is an aggressive malignancy characterized by rapid growth with a short and fulminate natural history. It has been long recognized that SCLC is responsive to chemotherapy. In addition, both TRT and PCI have been shown to enhance further the survival of patients with L-SCLC.2,5,6 Thoracic RT affects the patient outcome by decreasing the tumor burden within the chest, resulting in enhanced local control and survival.2,5 Despite the addition of thoracic RT to chemotherapy, local treatment failures occur in approximately one third of patients treated with the currently accepted optimal therapy. Long-term survival occurs in about one fourth of patients so treated.7 These results indicate the need for improved treatment strategies to combat this disease. In all situations in which RT affects a response, there exists a dose-response relationship. Local control and subsequent survival are associated with both the timing of RT and dose-fractionation parameters.7,13,14
When attempting to improve therapy, the goal should be to obtain the longest possible patient survival with the least toxicity. Altering the fractionation pattern is one method used to improve the therapeutic index of RT. Some of the parameters used to develop a fractionation pattern include overall time, total dose, and fraction size. These factors can be adjusted for the proliferative nature of the tumor in question and the tolerance of the surrounding normal tissues. The biologically effective dose (BED) can be used to compare the efficacy of various dose-fractionation regimens in providing tumor control.15-17 The first portion of the formula accounts for the efficacy provided by a particular fractionation program and the second part accounts for the decrease in efficacy related to the overall time radiotherapy is delivered compared with the potential doubling time of the tumor cells.
 /ß = 10 for acute effects and tumor control and 3 for chronic effects17; = 0.3 Gy; t = total days in which radiotherapy is delivered; and Tpot = potential doubling time (5.6 days). The potential doubling time (Tpot) for SCLC has been reported in the radiobiology literature to range from 2.6 to 8.6 days.18-20 Thus, a break in the RT decreases the BED and the efficacy of the regimen because a greater overall time of RT allows tumor repopulation to occur. The potential relationship between BED of thoracic RT and 5-year survival was evaluated for this trial and the randomized trials that included various thoracic RT programs.7,11,21-23 Studies selected included only phase III trials that administered platinum plus etoposide concurrently with thoracic RT reported between 1997 and 2004. The Intergroup Trial 0096 compared once-daily RT to bid TRT and found that the bid TRT approach resulted in significantly better survival.7 The NCCTG trial 892052 compared once-daily RT versus split-course bid TRT and found similar survival rates for both groups.11 The trials reported by Qiao et al21 and Takada et al23 compared sequential versus concurrent administration of chemotherapy plus RT and concluded that concurrent therapy was superior. The trial by Jeremic et al22 compared the early versus late administration of bid TRT and concluded that the early administration of bid TRT was better. For the purposes of the following analysis, the early RT arm from Jeremic et al22 was included, as were the concurrent therapy arms from Qiao et al21 and Takada et al.23 The RT regimens and 5-year survival rates derived from the 904 patients included in these trials are listed in Table 5. Then, the BED of the TRT was plotted against the resulting 5-year survival reported in these studies (Fig 2). The Pearson correlation coefficient between BED and 5-year survival was 0.81, indicating a strong positive correlation.
Survival was used in this analysis rather than local control because of difficulties in objectively comparing local control rates reported in various studies. Some studies use chest radiographs and others use computed tomography. Positron emission tomography or rebiopsy is likely to be more accurate in determining local control. However, survival is an objective end point that is difficult to misjudge. In addition, there is at least one major trial that found that dose fractionation significantly influences survival.7 The available data related to the timing of TRT include conflicting reports but generally support the concept that TRT should begin early and be completed quickly.13,14 The TRT in this study began with cycle 4, which may have negatively influenced the outcome. Future trials should be designed with the early administration of TRT. Most studies in L-SCLC include PCI for favorable responders after the chemotherapy is completed. The early PCI employed in the present study seemed to decrease the rate of brain metastases, which could enhance survival. However, whole-brain RT impairs function of approximately 12% of the body's bone marrow found in the skull, which may have contributed to the high fraction of patients with severe hematologic toxicity. In the present trial, 75% of patients had grade 4+ hematologic toxicity compared with 43% in NCCTG trial 892052, which included either bid TRT or once-daily RT with the same doses of etoposide and cisplatin but PCI at the end.11 The results of this trial do provide lessons that can be used to improve future therapy. The 5-year survival rate was quite favorable at 24% for the entire cohort and 29% for those who received TRT. However, although the split-course TRT probably lessened the risk of severe esophagitis, it may have contributed to less favorable survival than would have been achieved with continuous-course RT. The break in TRT likely negated some of the value of increasing the overall TRT dose. The literature suggests early and intense courses of TRT are most efficacious.7,13,14 Despite the low rate of patients who developed brain metastases and also received early PCI, PCI should likely be administered after all planned chemotherapy has been administered. This would likely allow more chemotherapy to be delivered safely. The concept of BED can be used by investigators to design innovative RT programs that potentially are more effective. More intensive RT regimens can be used in the future if technical advances allow better sparing of the normal surrounding structures to prevent toxicity. This is important because merely increasing the doses of RT will not necessarily improve patient survival if increased toxicity occurs and results in a greater frequency of patient death. Technologic advances that have the potential to provide the safe escalation of TRT dose or intensity include the following: involved-field three-dimensional RT, stereotactic body RT, hadron (heavy particle) RT, intensity-modulated RT, tomotherapy (a form of intensity-modulated RT), and CyberKnife RT (Accuracy, Sunnyvale, CA). In addition, the North American Lung Cancer Intergroup is planning a phase III trial for patients with L-SCLC that compares bid TRT (45 Gy/30 fractions from the Intergroup trial 0096) versus higher dose RT regimens.
The author(s) indicated no potential conflicts of interest.
Conception and design: Steven E. Schild, James A. Bonner, Shauna Hillman, Timothy F. Kozelsky, Antonio P.G. Vigliotti, Randolph S. Marks Administrative support: Shauna Hillman, Randolph S. Marks, David Graham, Gamini S. Soori, John W. Kugler, Richard C. Tenglin, Donald B. Wender, Alex A. Adjei Provision of study materials or patients: Steven E. Schild, James A. Bonner, Timothy F. Kozelsky, Antonio P.G. Vigliotti, Randolph S. Marks, David Graham, John W. Kugler, Richard C. Tenglin, Donald B. Wender, Alex A. Adjei Collection and assembly of data: Steven E. Schild, James A. Bonner, Shauna Hillman, Antonio P.G. Vigliotti, Gamini S. Soori, Donald B. Wender, Alex A. Adjei Data analysis and interpretation: Steven E. Schild, James A. Bonner, Shauna Hillman Manuscript writing: Steven E. Schild, James A. Bonner, Shauna Hillman, Timothy F. Kozelsky, Antonio P.G. Vigliotti, Randolph S. Marks, David Graham, Gamini S. Soori, Richard C. Tenglin, Alex A. Adjei Final approval of manuscript: Steven E. Schild, James A. Bonner, Shauna Hillman, Timothy F. Kozelsky, Antonio P.G. Vigliotti, Randolph S. Marks, David Graham, Gamini S. Soori, John W. Kugler, Richard C. Tenglin, Donald B. Wender, Alex A. Adjei
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group (NCCTG) and Mayo Clinic. Additional participating institutions include: MedCenter One Health Systems, Bismarck, ND (Edward J. Wos, DO); Meritcare Hospital CCOP, Fargo, ND (Preston D. Steen, MD); Duluth CCOP, Duluth, MN (Daniel A. Nikcevich, MD); Geisinger Clinic & Medical Center CCOP, Danville, PA (Albert M. Bernath, MD); Iowa Oncology Research Association CCOP, Des Moines, IA (Roscoe F. Morton, MD); Ochsner CCOP, New Orleans, LA (Carl G. Kardinal, MD); Toledo Community Hospital Oncology Program CCOP, Toledo, OH (Paul L. Schaefer, MD); Sioux Community Cancer Consortium, Sioux Falls, SD (Loren K. Tschetter, MD); Rapid City, SD (Larry P. Ebbert, MD); Altru Health Systems, Grand Forks, ND (Tudor Dentchev, MD); CentreCare Clinic, St Cloud, MN (Harold E. Windschitl, MD).
Supported in part by Public Health Service Grants No. CA-25224, CA-37404, CA-63849, CA-35113, CA-35103, CA-37417, CA-35269, CA-35448, CA-35101, CA-35272, CA-35415, CA-35101, CA-52352, and CA-60276. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2006. CA Cancer J Clin 56:106-130, 2006 2. Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10:890-895, 1992[Abstract] 3. National Cancer Institute: Small cell lung cancer (PDQ): treatment. http://www.cancer.gov/cancertopics/pdq/treatment/small-cell-lung/healthprofessional 4. Green RA, Humphrey E, Close H, et al: Alkylating agents in bronchogenic carcinoma. Am J Med 46:516-525, 1969[CrossRef][Medline] 5. Pignon JP, Arriagada R, Ihde DC, et al: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327:1618-1624, 1992[Abstract] 6. Aupérin A, Arriagada R, Pignon JP, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission: Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341:476-484, 1999 7. Turrisi AT III, Kim K, Blum R, et al: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265-271, 1999 8. Komaki R, Swann RS, Ettinger DS, et al: Phase I study of thoracic radiation dose escalation with concurrent chemotherapy for patients with limited small-cell lung cancer: Report of Radiation Therapy Oncology Group (RTOG) protocol 97-12. Int J Radiat Oncol Biol Phys 62:342-350, 2005[CrossRef][Medline] 9. Bogart JA, Herndon JE II, Lyss AP, et al: 70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: Analysis of Cancer and Leukemia Group B study 39808. Int J Radiat Oncol Biol Phys 59:460-468, 2004[CrossRef][Medline] 10. Bonner JA, Hillman S, Vigliotti A, et al: High dose, twice-daily thoracic radiotherapy (TRT) with daily chemotherapy in limited stage small cell lung cancer. Presented at the Annual Meeting of the International Association for the Study of Lung Cancer, Lung Cancer 42:23, 2003 (abstr 0-73)[CrossRef][Medline] 11. Schild SE, Bonner JA, Shanahan TG, et al: Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 59:943-951, 2004[CrossRef][Medline] 12. Shaw EG, McGinnis WL, Jett JR, et al: Pilot study of accelerated hyperfractionated thoracic radiation therapy plus concomitant etoposide and cisplatin chemotherapy in patients with unresectable stage III non-small-cell carcinoma of the lung. J Natl Cancer Inst 85:321-323, 1993 13. De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al: Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 24:1057-1063, 2006 14. Fried DB, Morris DE, Poole C, et al: Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 22:4837-4845, 2004 15. Hall EJ: Radiology for the Radiologist (ed 5). Philadelphia, PA, Lippincott Williams and Wilkins, 2000 16. Fowler JF: Biological factors influencing optimum fractionation in radiation therapy. Acta Oncol 40:712-717, 2001[CrossRef][Medline] 17. Fowler JF: The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 62:679-694, 1989[Medline] 18. Tinnemans MM, Schutte B, Lenders MH, et al: Cytokinetic analysis of lung cancer by in vivo bromodeoxyuridine labelling. Br J Cancer 67:1217-1222, 1993[Medline] 19. Shibamoto Y, Ike O, Mizuno H, et al: Proliferative activity and micronucleus frequency after radiation of lung cancer cells as assessed by the cytokinesis-block method and their relationship to clinical outcome. Clin Cancer Res 4:677-682, 1998[Abstract] 20. Kerr KM, Lamb D: Actual growth rate and tumour cell proliferation in human pulmonary neoplasms. Br J Cancer 50:343-349, 1984[Medline] 21. Qiao TK, Zhou DA, Xin L, et al: Concurrent radiotherapy combined with carboplatin and etoposide in limited stage small cell lung cancer. Zhonghua Jie He He Hu XiZa Zhi 27237-239, 2004 22. Jeremic B, Shibamoto Y, Acimovic L, et al: Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: A randomized study. J Clin Oncol 15:893-900, 1997 23. Takada M, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: Results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20:3054-3060, 2002 Submitted November 15, 2006; accepted April 18, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
