Study of Paclitaxel, Etoposide, and Cisplatin Chemotherapy Combined With Twice-Daily Thoracic Radiotherapy for Patients With Limited-Stage S
http://www.100md.com
《临床肿瘤学》
the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
Radiation Therapy Oncology Group
University of Pennsylvania Medical Center
Thomas Jefferson University Hospital
Fox Chase Cancer Center, Philadelphia, PA
Cedars Sinai Medical Center, Los Angeles, CA
Greater Dayton Cancer Center, Kettering, OH
Medical College of Wisconsin, Milwaukee, WI
ABSTRACT
PURPOSE: To determine the response rate, progression-free survival and overall survival, and toxicity of paclitaxel, etoposide, and cisplatin combined with accelerated hyperfractionated thoracic radiotherapy in patients with limited-disease (LD) small-cell lung cancer (SCLC).
PATIENTS AND METHODS: LD-SCLC patients with measurable disease, Karnofsky performance score of 70, and adequate organ function who were previously untreated were eligible for the study. Treatment was as follows. In cycle 1 of chemotherapy, concurrent thoracic radiation therapy was administered. In cycles 2 to 4, chemotherapy was administered alone. In cycle 1, chemotherapy consisted of paclitaxel 135 mg/m2 intravenous over 3 hours on day 1, etoposide 60 mg/m2 intravenous on day 1 and 80 mg/m2 orally on days 2 and 3, and cisplatin 60 mg/m2 intravenous on day 1. In cycles 2 to 4, the paclitaxel dose was increased to 175 mg/m2, with the etoposide and cisplatin doses remaining the same as in cycle 1. The thoracic radiation therapy consisted of 1.5 Gy in 30 fractions (total dose, 45 Gy) administered 5 days a week for 3 weeks.
RESULTS: Fifty-five patients were enrolled onto the study, and 53 were assessable. The major toxicities included grade 3 and 4 acute neutropenia (32% and 43%, respectively) and grade 3 and 4 esophagitis (32% and 4%, respectively). Two patients died as a result of therapy (one died of acute respiratory distress syndrome, and one died of sepsis). There was one late fatal pulmonary toxicity. The median survival time was 24.7 months. The 2-year survival rate was 54.7%. The median progression-free survival time was 13 months, with a 2-year progression-free survival rate of 26.4%.
CONCLUSION: Although this therapeutic regimen is effective in the treatment of patients with LD-SCLC, it is unlikely that the three-drug combination with thoracic radiation therapy will improve the survival times compared with the etoposide plus cisplatin chemotherapy regimen with thoracic radiation therapy in LD-SCLC patients.
INTRODUCTION
Small-cell lung cancer (SCLC) will account for approximately 15% of the estimated 173,770 new lung cancer cases diagnosed in the United States in 2004.1 SCLC is typically staged as either limited disease (LD) or extensive disease (ED). LD is defined as disease confined to one hemithorax and its regional lymph nodes and can be encompassed by a single radiation therapy port. At presentation, roughly 30% to 40% of all SCLC patients will have LD.2
Milestones in the management of LD-SCLC have included recognition of the following2-14: (1) median survival without the use of systemic chemotherapy is severely limited; (2) the disease is quite chemotherapy responsive, and the use of combination chemotherapy increases survival; and (3) the use of thoracic radiation therapy improves both locoregional disease control and long-term survival, and this effect seems to be optimized when the thoracic radiation therapy is introduced early in the course of disease management.
In the 1990s, the use of twice-daily radiation therapy received substantial attention in the management of both non–small-cell lung cancer and SCLC. In regard to the therapy of LD-SCLC, Choi et al15 reported that 45 Gy in 30 fractions administered over 19 elapsed days was the maximum-tolerated dose of twice-daily radiation therapy administered with concurrent chemotherapy (cisplatin, cyclophosphamide, and etoposide).
In a pilot study conducted at the University of Pennsylvania of concurrent etoposide plus cisplatin with thoracic radiation therapy administered in 1.5-Gy fractions twice daily (total dose, 45 Gy) with an interfraction interval of at least 4 hours for patients with LD-SCLC, Turrisi et al16 and Turrisi and Glover17 reported a 94% complete response (CR) rate, a median survival time of 21 months, and disease-free survival rates of 45% to 50%.
These results were confirmed in a phase III, intergroup, randomized study comparing 45 Gy in 25 fractions (1.8 Gy once daily) with 45 Gy in 30 fractions (1.5 Gy bid) with concurrent etoposide plus cisplatin in LD-SCLC patients.18 At the time of a preliminary analysis of the data, bid radiation therapy yielded slightly higher response and survival results, but the results were not statistically significant.18
Pending subsequent long-term analysis of the intergroup study, the Radiation Therapy Oncology Group (RTOG) elected to continue studies of concurrent bid radiation therapy with concurrent etoposide plus cisplatin, with modifications made in the chemotherapy regimen to enhance the therapeutic effect with acceptable toxicity. In the trial reported, the major modification was the addition of a third drug, paclitaxel, to the chemotherapy regimen. At the time, there was no evidence that the three-drug combination would be no better than the two-drug regimen (etoposide plus cisplatin) in treating patients with SCLC.
Paclitaxel was selected to be part of a three-drug regimen to treat LD-SCLC patients for the following reasons: (1) it was active as a single agent in previously untreated ED-SCLC patients, with a response rate of 34% to 41%19,20; (2) there was evidence to suggest that the drug acts as a radiation sensitizer21,22; (3) paclitaxel with cisplatin or carboplatin and etoposide with thoracic radiation therapy has been used to treat patients with stage II or III non–small-cell lung cancer23,24; and (4) two phase I studies evaluated paclitaxel, etoposide, and cisplatin in ED-SCLC patients.25,26 The goals of this RTOG phase II study were to determine the response rate, progression-free and overall survival, and qualitative and quantitative toxicity in patients with LD-SCLC treated with paclitaxel, etoposide, and cisplatin with concurrent accelerated hyperfractionated (bid) thoracic radiation therapy.
PATIENTS AND METHODS
Eligible patients had histologic or cytologic proof of SCLC. Patients had to have LD and a clinical TNM stage of I to IIIb (ie, confined to one hemithorax but excluding T4 tumors based on malignant pleural effusions and N3 disease based on contralateral hilar or contralateral supraclavicular lymph node involvement). Patients with minimal pleural effusion visible on computed tomography scan of the chest but not evident on a chest x-ray were eligible. Patients must have had measurable or assessable disease. The staging work-up included a complete history and physical examination, including performance status, recent weight loss, and percentage of weight loss; CBC count with a differential, platelet count, electrolytes, kidney and liver function tests, and urinalysis; ECG, chest x-ray, computed tomography of chest, abdomen, and brain, radionuclide bone scan, and bone marrow aspiration and biopsy. Patients had to have adequate hematologic, hepatic, and renal function defined as follows: absolute granulocytes 1,500/μL, platelet count 150,000/μL, a serum bilirubin 1.5 mg/dL, a serum creatinine 1.5 mg/dL, and a forced expiration volume in 1 second of at least 1 L. Patients must have been 18 years of age; have had a Karnofsky performance score of 70; had no prior chemotherapy, radiotherapy, or biotherapy; and had to be available for follow-up and be able to give informed consent to participate in the study. This study was approved by the National Cancer Institute, RTOG, and institutional review boards at all participating institutions.
Patients received four cycles of chemotherapy. A cycle lasted 3 weeks. In cycle 1, patients received chemotherapy with concurrent radiation therapy. In cycles 2 to 4, patients received chemotherapy without radiation therapy. For cycle 1, the chemotherapy consisted of paclitaxel 135 mg/m2 intravenously over 3 hours on day 1, etoposide 60 mg/m2 intravenously over 60 minutes on day 1 and 80 mg/m2 orally on days 2 and 3, and cisplatin 60 mg/m2 intravenously on day 1 after the administration of etoposide. Premedication before paclitaxel was administered and consisted of dexamethasone 20 mg orally 12 and 6 hours before paclitaxel administration, diphenhydramine 50 mg intravenously, and cimetidine 300 mg intravenously 30 minutes before the paclitaxel administration. Patients received pre- and posthydration with the administration of cisplatin. For cycles 2 to 4 without the radiotherapy, the paclitaxel dose was increased to 175 mg/m2, with the etoposide and cisplatin doses remaining the same as in cycle 1. No dose adjustments of the chemotherapy were permitted in cycle 1. For cycles 2 to 4, the use of colony-stimulating factor was permitted to protect against febrile neutropenia. Alternately, a dose reduction of the chemotherapy could be instituted. In cycles 2 to 4, for renal toxicity, the cisplatin dose was reduced for serum creatinine levels of 1.6 to 2.0 mg/dL and held for serum creatinine levels of 2.1 to 3.5 mg/dL until the serum creatinine level decreased to less than 2.0 mg/dL. A serum creatinine of more than 3.5 mg/dL necessitated holding cisplatin from all remaining cycles of chemotherapy.
The thoracic radiation therapy consisted of accelerated bid radiation therapy (1.5 Gy in 30 fractions for a total dose of 45 Gy). The bid doses were administered 6 to 8 hours apart for 5 days a week for 3 weeks. The target volume that was to be treated by anteroposterior/posteroanterior and oblique or lateral fields included the primary tumor plus regional (hilar and mediastinal) lymph nodes. In the case of upper lobe tumors, the ipsilateral supraclavicular lymph nodes were to be treated. The primary tumor must have had a minimum of a 1-cm margin and no more than a 1.5-cm margin. Inclusion of mediastinum required extending field margins 1.5 to 2.0 cm beyond the contralateral border of the vertebral bodies. Ipsilateral supraclavicular irradiation was allowed when necessary for primary tumor coverage or when there was bulky (> 5 cm) pre- or paratracheal adenopathy detected on computed tomography scan of the chest (with contrast). Contralateral supraclavicular treatment was not allowed. Contralateral hilar irradiation was allowed if there was demonstrable bulky contralateral mediastinal involvement. The lower field border was two vertebral bodies or 5 cm below the carina for upper and middle lung field lesions. The lower extent of lower lobe lesions was a 1.0- to 1.5-cm margin, which defined the inferior extent of the field. Any mediastinal node detected by computed tomography scan 1.5 cm was to be included with at least a 2-cm cephalad or caudate margin. Linear accelerators were used to deliver the radiation therapy. Simulation to define the radiation ports was mandatory. All complete responders to the therapy as well as partial responders who desired to receive it were to be offered prophylactic cranial irradiation (PCI) using 2.0- to 2.5-Gy daily fractions. PCI was initiated after hematologic recovery from the last cycle of chemotherapy or within 6 weeks of the last cycle of chemotherapy.
Standard response criteria were used to evaluate the patient's response to the therapy. A CR was the complete disappearance of all clinically detectable disease lasting at least 4 weeks at the time of restaging. A partial response (PR) was defined as a 50% decrease in tumor size lasting for at least 4 weeks without an increase of 25% of the product of perpendicular diameters of any lesion and no new areas of disease. In addition, there could be no significant deterioration of symptoms or performance status (> 1 score level). For measurable, unidimensional disease, a PR was defined as a 30% decrease in the linear tumor measurements lasting for at least 4 weeks; stable disease was defined as no significant change in measure or assessable disease for at least 4 weeks. Disease progression was defined as any increase more than 25% in the sum of the products of diameters of any measurable lesion or in the estimated size of nonmeasurable lesions or the appearance of any new lesions.
Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria as well as the RTOG/European Organisation for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme. All patients were evaluated at the end of the concurrent chemotherapy and radiation therapy and then after each cycle of chemotherapy.
The study end points consisted of (1) 1-year survival rate and long-term survival rates, (2) CR and PR rates, and (3) frequency and severity of treatment morbidity. Overall and progression-free survival were estimated by the Kaplan-Meier method.
The sample size for the study was determined by the 1-year survival rate. It was expected that the 1-year survival rate would be 70% estimated with a 90% lower confidence bound of 60%. This required 47 assessable patients. If the observed 1-year survival rate was less than 60%, then no further phase III study was to be proposed unless long-term survival rates turned out to be much better than the survival rates from the bid arm of the intergroup study.20 Assuming a 10% inassessability rate, the total required sample size was 52 patients.
RESULTS
November 1996 to March 1998, 55 patients were entered onto this phase II study. The data from 53 patients were analyzable. Two patients were ineligible; one patient received brachytherapy before protocol therapy, and the other patient had a pleural effusion. Table 1 lists the pretreatment characteristics of the patients. Sixty-eight percent of patients were younger than 60 years of age (median age, 56 years; range, 39 to 76 years); 81% had a Karnofsky performance score of 90 or better; 74% had less than 5% weight loss in the 3 months before entry onto the study; and on the basis of the TNM staging classification, 79% of patients had stage IIIA or IIIB disease. No patients on study had positive contralateral hilar lymph nodes.
Toxicity
Tables 2 and 3 list the acute and late toxicities, respectively. The major toxicities were as follows. Hematologic toxicity included grade 3 and 4 neutropenia (17 and two patients; 32% and 4%, respectively), grade 3 and 4 thrombocytopenia (two and two patients; 4% and 4%, respectively), and grade 3 anemia (five patients; 9%). Nonhematologic toxicity included grade 3 and 4 esophagitis (17 and two patients; 32% and 4%, respectively), grade 3 and 4 nausea/vomiting (eight and two patients; 15% and 4%, respectively), grade 3 lung toxicity (five patients; 9%), and grade 3 neurologic toxicity (three patients; 6%). Two patients died as a result of therapy; one patient died of acute respiratory distress syndrome on day 39, and one died of sepsis on day 74. There was one late fatal pulmonary toxicity, which occurred on day 136.
Treatment Review
Forty (75%) of the 53 eligible patients received the chemotherapy according to the protocol. An additional 10 patients (19%) had acceptable variations (ie, nonprotocol modifications). Eighty-five percent of the patients received all four cycles of chemotherapy.
Fifty (94%) of 53 patients received the prescribed total dose (45 Gy) of radiation therapy. Specifically, 49 patients received their treatment in 18 to 22 days, and one patient was treated in 25 days. A total of 17 patients received PCI (12 CRs and five PRs). Two of these patients (one CR and one PR) experienced disease progression in the brain (at 16 and 11 months, respectively).
Response Rate
Forty patients (75%) achieved a CR, whereas nine patients (17%) achieved a PR. One patient each had stable disease and disease progression. Two patients had no disease assessment; one patient, who died 40 days after entering the study as a result of pneumonia, was reported by the institution as having unassessable disease, whereas the other patient was reported by the institution as having unknown disease status until 19 months after the treatment ended, at which time progression was noted. Disease response was assessed by institutional investigators only.
Survival
The median survival time was 24.7 months (95% CI, 14.6 to 35.1 months). The 2-year survival rate was 54.7%. The median progression-free survival time was 13 months (95% CI, 11.2 to 20.1 months), and the 2-year progression-free survival rate was 26.4%. Forty-one of the 53 eligible patients have died. Survival time of the 12 patients still alive ranges from 29.5 months to 71.3 months. Overall survival was defined as the time between the date the patient was registered onto the study and the date of the patient's death from any cause. Progression-free survival was defined as the time between the date the patient was registered onto the study and the date of the patient's first local, regional, or distant progression or death from any cause. Figures 1 and 2 are the overall and progression-free survival curves. The x-axes in the overall survival and progression-free survival curves go to 6 years because the maximum follow-up observed in the patients on the study at the time of analysis was 71.3 months.
Pattern of Failure
Among the 40 patients achieving a primary CR, 30 (75%) had primary, nodal, and/or distant metastases failure. Distant metastases as a part of their sites of first failure were reported in 25 patients (63%), including seven patients (13%) with brain metastases (none of whom received PCI). Nine (22.5%) and three patients (7.5%) had progression in the primary tumor and node, respectively, as part of their sites of first failure. Overall, 66% of the 53 patients on the study were diagnosed with metastatic disease at some time, and 22.6% were diagnosed with brain metastases.
DISCUSSION
In 1996 when this study was activated, there were no long-term follow-up data for the intergroup study comparing single-dose thoracic radiation therapy to twice-daily thoracic radiation therapy with concurrent chemotherapy for the treatment of LD-SCLC. In addition, there were no data on the effectiveness of the three-drug combination of paclitaxel, etoposide, and cisplatin compared with the two-drug regimen of etoposide and cisplatin in the treatment of ED-SCLC patients.
Besides this phase II trial, there are three other trials that evaluated the three-drug combination with thoracic radiation therapy in LD-SCLC patients.27-29 Bremnes et al27 reported on their phase II study evaluating paclitaxel, etoposide, and cisplatin with 42-Gy thoracic radiation therapy beginning with cycle 3 in 39 LD-SCLC patients. The response rate was 92%, with a median survival time of 21 months. Thirteen percent of the patients had grade 3 esophagitis. In a phase I and II study involving 31 patients receiving the three-drug combination with thoracic radiation therapy (45 Gy given once daily in 25 fractions during cycles 1 and 2), Levitan et al28 report a response rate of 96% and a median survival time of 22.3 months. During cycles 1 and 2, grade 2 and 3 esophagitis occurred in 13% of the courses of therapy administered. Sandler et al,29 in an Eastern Cooperative Oncology Group phase II study involving 63 patients receiving paclitaxel, etoposide, and cisplatin with radiation therapy (63 Gy administered once daily in 35 fractions starting with the third cycle), report a response rate of 64% and a median survival time of 15.7 months. The principal toxicity was grade 4 neutropenia, which occurred in 59% of patients.
In 1999, Turrisi et al30 published the long-term follow-up results of the intergroup randomized phase III LD-SCLC study. The median survival time was 19 months for patients receiving once-daily radiation therapy and 23 months for patients receiving twice-daily radiation therapy. The 2- and 5-year survival rates for the patients receiving once-daily radiation therapy compared with patients receiving twice-daily radiation therapy were 41% and 16% v 47% and 26%, respectively. Grade 3 esophagitis was significantly more frequent with the twice-daily radiation therapy compared with once-daily radiation therapy (27% v 11%, respectively; P < .001).
Mavroudis et al31 reported on the results of a randomized phase II study involving both LD-SCLC and ED-SCLC patients receiving the three-drug combination compared with the two-drug combination. There were no differences in overall response rates or median survivals between the two regimens studied.
In 2002, Niell et al32 reported on the results of an intergroup phase III study comparing paclitaxel, etoposide, and cisplatin with etoposide plus cisplatin in the treatment of patients with ED-SCLC. Five hundred eighty-seven patients were entered onto the study. Because of excessive toxicity in performance status 2 patients, the study was amended to treat only patients with a performance status of 0 or 1. There was no difference in the median survival (10.33 months for the three-drug regimen v 9.84 months for the two-drug regimen, P = .327).
In this study, our regimen was not better than the twice-daily radiation therapy with concurrent etoposide plus cisplatin evaluated in the intergroup study. As in the intergroup study, the major toxicity was esophagitis (grades 3 and 4, 32% and 4%, respectively) and myelosuppression (grades 3 and 4, 32% and 4%, respectively). Given the results of the two trials evaluating paclitaxel, etoposide, and cisplatin in ED-SCLC and the three trials, including this one, studying the three-drug combination with either once-daily or twice-daily thoracic radiation therapy in LD-SCLC patients, it is unlikely that the three-drug combination with thoracic radiation therapy will improve the survival times in LD-SCLC patients.
Despite the results of the intergroup study showing a 5-year survival rate of 26% for patients receiving the accelerated hyperfractionated radiation therapy, the effectiveness of both thoracic irradiation and systemic chemotherapy needs to be improved. The sequencing and timing of chemotherapy and thoracic radiotherapy as well as the radiation dose to the thorax are controversial areas and still need to be studied.
A phase I study in LD-SCLC, RTOG 97-12, was initiated to improve locoregional control by escalating the total dose of radiation therapy using daily fractionation to larger fields and then boost field and bid radiation therapy toward the end of the thoracic radiation therapy with concurrent etoposide and cisplatin.33 After completion of the phase I study, the RTOG is now conducting a phase II study.
In addition, the RTOG is conducting a phase I study of irinotecan and cisplatin in combination with twice-daily thoracic radiotherapy (45 Gy) or once-daily thoracic radiotherapy (70 Gy) in patients with LD-SCLC. These studies, as well as others conducted by other cooperative groups, are being undertaken in an attempt to improve both local and systemic disease.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, the following authors or their immediate family members have 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.
NOTES
Supported by grant Nos. CA21661, CA37423, and CA32115 from the National Cancer Institute, Bethesda, MD.
Presented at the 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 20-23, 2000.
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Jemal A, Tiwari RC, Murray T, et al: Cancer Statistics, 2004. CA Cancer J Clin 54:8-29, 2004
Ihde DC, Pass HI, Glatstein EJ: Cancer of the lung, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer Principles and Practice of Oncology (ed 4). Philadelphia, PA, Lippincott, 1993
Seifter EJ, Ihde DC: Therapy of small cell lung cancer: A perspective on two decades of clinical research. Semin Oncol 15:278-279, 1988
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
Prez CA, Einhorn L, Oldham RF, et al: Randomized trial of radiotherapy to the thorax in limited small cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: A preliminary report. J Clin Oncol 2:1200-1208, 1984
Perry MC, Eaton WL, Propert KJ, et al: Chemotherapy with or without radiation therapy in limited small cell carcinoma of the lung. N Engl J Med 316:912-918, 1987
Bunn PA, Lichter AS, Makuch RW, et al: Chemotherapy alone or chemotherapy with chest radiation therapy in limited stage small cell lung cancer. Ann Intern Med 106:655-662, 1987
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
Lebeau B, Chastang C, Brechot JM, et al: A randomized trial of delayed thoracic radiotherapy in complete responder patients with small cell lung cancer. Chest 104:726-733, 1993
Coy P, Hodson DI, Murray N, et al: Patterns of failure following loco-regional radiotherapy in the treatment of limited stage small cell lung cancer. Int J Radiat Oncol Biol Phys 28:355-362, 1994
Evans WK, Osoba D, Feld R, et al: Etoposide (VP-16) and cisplatin: An effective treatment for relapse in small-cell lung cancer. J Clin Oncol 3:65-71, 1985
Boni C, Cocconi G, Bisagni G, et al: Cisplatin and etoposide (VP-16) as a single regimen for small cell lung cancer: A phase II trial. Cancer 63:638-642, 1989
Evans WK, Shepherd FA, Feld R, et al: VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol 3:1471-1477, 1985
Einhorn LH, Crawford J, Birch R, et al: Cisplatin plus etoposide consolidation following cyclophosphamide, doxorubicin, and vincristine in limited small-cell lung cancer. J Clin Oncol 6:451-456, 1988
Choi NC, Herndon J, Rosenman J, et al: Phase I study to determine the maximum tolerated ose of radiation in standard fractionated and accelerated twice daily radiation schedules with concurrent chemotherapy for limited stage small cell lung cancer (CALGB 8837). Int J Radiat Oncol Biol Phys 30:179, 1994 (suppl 1)
Turrisi AT, Glover DJ, Mason BA, et al: A preliminary report: Concurrent twice-daily radiotherapy plus platinum–etoposide chemotherapy for limited small cell lung cancer. Int J Radiat Oncol Biol Phys 15:183-187, 1988
Turrisi AT, Glover DJ: Thoracic radiotherapy variables: Influence on local control in small cell lung cancer limited disease. Int J Radiat Oncol Biol Phys 19:1473-1479, 1990
Wagner H, Kim K, Johnson DH, et al: Daily vs. twice-daily thoracic irradiation with concurrent cisplatin/etoposide chemotherapy as initial therapy for patients with limited small cell lung cancer: Preliminary results of a phase III prospective intergroup trial. Int J Radiat Oncol Biol Phys 30:178, 1994 (suppl 1)
Ettinger DS, Finkelstein DM, Sarma PP, et al: Phase II study of paclitaxel in patients with extensive-disease stage small-cell lung cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 13:1430-1435, 1995
Kirschling RJ, Jung SH, Jett JR: A phase II trial of Taxol and G-CSF in previously untreated patients with extensive stage small cell lung cancer. Proc Am Soc Clin Oncol 13:326, 1994 (abstr 1076)
Tishler RB, Schiff PB, Geard CR, et al: Taxol: A novel radiation sensitizer. Int J Radiat Oncol Biol Phys 22:613-617, 1992
Liebmann J, Cook JA, Fisher J, et al: In vitro studies of Taxol as a radiation sensitizer in human tumor cells. J Natl Cancer Inst 86:441-446, 1994
Antonia SJ, Wagner H, Williams C, et al: Concurrent paclitaxel/cisplatin with thoracic radiation in patients with stage IIIA/B non small cell carcinoma of the lung. Semin Oncol 22:34-37, 1995 (suppl 9)
Bonomi P, Farber LP, Recine D, et al: Carboplatin/etoposide/radiation plus escalating doses of paclitaxel in stage III non-small cell lung cancer: A preliminary report. Semin Oncol 22:42-47, 1995 (suppl 9)
Levitan N, McKenney J, Tahsildar H, et al: Results of a phase I dose escalation trial of paclitaxel, etoposide and cisplatin followed by filgrastim in the treatment of patients with extensive stage small cell lung cancer. Proc Am Soc Clin Oncol 14:379, 1995 (abstr 1177)
Kelly K, Wood ME, Bunn PA: A phase I study of cisplatin, etoposide and paclitaxel in extensive stage small cell lung cancer. Proc Am Soc Clin Oncol 15:400, 1996 (abstr)
Bremnes RM, Sundstrom S, Vilsik J, et al: Multicenter phase II trial of paclitaxel, cisplatin and etoposide with concurrent radiation for limited-stage small cell lung cancer. J Clin Oncol 19:3532-3538, 2001
Levitan N, Dowlati A, Shina D, et al: Multi-institutional phase I/II trial a paclitaxel, cisplatin and etoposide with concurrent radiation limited-stage small cell lung carcinoma. J Clin Oncol 18:1102-1109, 2000
Sandler A, Declerck L, Wagner H, et al: A phase II study of cisplatin plus etoposide plus paclitaxel and concurrent radiation therapy for previously untreated limited stage small cell lung cancer (E2596): An Eastern Cooperative Oncology Group trial. Proc Am Soc Clin Oncol 19:491a, 2000 (abstr 1920)
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
Mavroudis D, Papadakis E, Veslemes M, et al: A multicenter randomized phase II study comparing paclitaxel, cisplatin, etoposide (TEP) versus cisplatin-etoposide (EP) as front- line treatment in patients with small cell lung cancer (SCLC). Proc Am Soc Clin Oncol 19:484a, 2000 (abstr 1894)
Niell HB, Herndon JE, Miller AD, et al: Randomized phase III intergroup trial (CALGB 9732) of etoposide and cisplatin with or without paclitaxel and G-CSF in patients with extensive stage small cell lung cancer. Proc Am Soc Clin Oncol 21:293a, 2002 (abstr 1169)
Komaki R, Swann S, Ettinger D, et al: Phase I dose-escalation study of thoracic irradiation with concurrent chemotherapy for patients with limited small cell lung cancer (LSCLC): Radiation Therapy Oncology Group (RTOG) protocol 9712. Proc Am Soc Clin Oncol 22:631, 2003 (abstr 2539)(David S. Ettinger, Brian )
Radiation Therapy Oncology Group
University of Pennsylvania Medical Center
Thomas Jefferson University Hospital
Fox Chase Cancer Center, Philadelphia, PA
Cedars Sinai Medical Center, Los Angeles, CA
Greater Dayton Cancer Center, Kettering, OH
Medical College of Wisconsin, Milwaukee, WI
ABSTRACT
PURPOSE: To determine the response rate, progression-free survival and overall survival, and toxicity of paclitaxel, etoposide, and cisplatin combined with accelerated hyperfractionated thoracic radiotherapy in patients with limited-disease (LD) small-cell lung cancer (SCLC).
PATIENTS AND METHODS: LD-SCLC patients with measurable disease, Karnofsky performance score of 70, and adequate organ function who were previously untreated were eligible for the study. Treatment was as follows. In cycle 1 of chemotherapy, concurrent thoracic radiation therapy was administered. In cycles 2 to 4, chemotherapy was administered alone. In cycle 1, chemotherapy consisted of paclitaxel 135 mg/m2 intravenous over 3 hours on day 1, etoposide 60 mg/m2 intravenous on day 1 and 80 mg/m2 orally on days 2 and 3, and cisplatin 60 mg/m2 intravenous on day 1. In cycles 2 to 4, the paclitaxel dose was increased to 175 mg/m2, with the etoposide and cisplatin doses remaining the same as in cycle 1. The thoracic radiation therapy consisted of 1.5 Gy in 30 fractions (total dose, 45 Gy) administered 5 days a week for 3 weeks.
RESULTS: Fifty-five patients were enrolled onto the study, and 53 were assessable. The major toxicities included grade 3 and 4 acute neutropenia (32% and 43%, respectively) and grade 3 and 4 esophagitis (32% and 4%, respectively). Two patients died as a result of therapy (one died of acute respiratory distress syndrome, and one died of sepsis). There was one late fatal pulmonary toxicity. The median survival time was 24.7 months. The 2-year survival rate was 54.7%. The median progression-free survival time was 13 months, with a 2-year progression-free survival rate of 26.4%.
CONCLUSION: Although this therapeutic regimen is effective in the treatment of patients with LD-SCLC, it is unlikely that the three-drug combination with thoracic radiation therapy will improve the survival times compared with the etoposide plus cisplatin chemotherapy regimen with thoracic radiation therapy in LD-SCLC patients.
INTRODUCTION
Small-cell lung cancer (SCLC) will account for approximately 15% of the estimated 173,770 new lung cancer cases diagnosed in the United States in 2004.1 SCLC is typically staged as either limited disease (LD) or extensive disease (ED). LD is defined as disease confined to one hemithorax and its regional lymph nodes and can be encompassed by a single radiation therapy port. At presentation, roughly 30% to 40% of all SCLC patients will have LD.2
Milestones in the management of LD-SCLC have included recognition of the following2-14: (1) median survival without the use of systemic chemotherapy is severely limited; (2) the disease is quite chemotherapy responsive, and the use of combination chemotherapy increases survival; and (3) the use of thoracic radiation therapy improves both locoregional disease control and long-term survival, and this effect seems to be optimized when the thoracic radiation therapy is introduced early in the course of disease management.
In the 1990s, the use of twice-daily radiation therapy received substantial attention in the management of both non–small-cell lung cancer and SCLC. In regard to the therapy of LD-SCLC, Choi et al15 reported that 45 Gy in 30 fractions administered over 19 elapsed days was the maximum-tolerated dose of twice-daily radiation therapy administered with concurrent chemotherapy (cisplatin, cyclophosphamide, and etoposide).
In a pilot study conducted at the University of Pennsylvania of concurrent etoposide plus cisplatin with thoracic radiation therapy administered in 1.5-Gy fractions twice daily (total dose, 45 Gy) with an interfraction interval of at least 4 hours for patients with LD-SCLC, Turrisi et al16 and Turrisi and Glover17 reported a 94% complete response (CR) rate, a median survival time of 21 months, and disease-free survival rates of 45% to 50%.
These results were confirmed in a phase III, intergroup, randomized study comparing 45 Gy in 25 fractions (1.8 Gy once daily) with 45 Gy in 30 fractions (1.5 Gy bid) with concurrent etoposide plus cisplatin in LD-SCLC patients.18 At the time of a preliminary analysis of the data, bid radiation therapy yielded slightly higher response and survival results, but the results were not statistically significant.18
Pending subsequent long-term analysis of the intergroup study, the Radiation Therapy Oncology Group (RTOG) elected to continue studies of concurrent bid radiation therapy with concurrent etoposide plus cisplatin, with modifications made in the chemotherapy regimen to enhance the therapeutic effect with acceptable toxicity. In the trial reported, the major modification was the addition of a third drug, paclitaxel, to the chemotherapy regimen. At the time, there was no evidence that the three-drug combination would be no better than the two-drug regimen (etoposide plus cisplatin) in treating patients with SCLC.
Paclitaxel was selected to be part of a three-drug regimen to treat LD-SCLC patients for the following reasons: (1) it was active as a single agent in previously untreated ED-SCLC patients, with a response rate of 34% to 41%19,20; (2) there was evidence to suggest that the drug acts as a radiation sensitizer21,22; (3) paclitaxel with cisplatin or carboplatin and etoposide with thoracic radiation therapy has been used to treat patients with stage II or III non–small-cell lung cancer23,24; and (4) two phase I studies evaluated paclitaxel, etoposide, and cisplatin in ED-SCLC patients.25,26 The goals of this RTOG phase II study were to determine the response rate, progression-free and overall survival, and qualitative and quantitative toxicity in patients with LD-SCLC treated with paclitaxel, etoposide, and cisplatin with concurrent accelerated hyperfractionated (bid) thoracic radiation therapy.
PATIENTS AND METHODS
Eligible patients had histologic or cytologic proof of SCLC. Patients had to have LD and a clinical TNM stage of I to IIIb (ie, confined to one hemithorax but excluding T4 tumors based on malignant pleural effusions and N3 disease based on contralateral hilar or contralateral supraclavicular lymph node involvement). Patients with minimal pleural effusion visible on computed tomography scan of the chest but not evident on a chest x-ray were eligible. Patients must have had measurable or assessable disease. The staging work-up included a complete history and physical examination, including performance status, recent weight loss, and percentage of weight loss; CBC count with a differential, platelet count, electrolytes, kidney and liver function tests, and urinalysis; ECG, chest x-ray, computed tomography of chest, abdomen, and brain, radionuclide bone scan, and bone marrow aspiration and biopsy. Patients had to have adequate hematologic, hepatic, and renal function defined as follows: absolute granulocytes 1,500/μL, platelet count 150,000/μL, a serum bilirubin 1.5 mg/dL, a serum creatinine 1.5 mg/dL, and a forced expiration volume in 1 second of at least 1 L. Patients must have been 18 years of age; have had a Karnofsky performance score of 70; had no prior chemotherapy, radiotherapy, or biotherapy; and had to be available for follow-up and be able to give informed consent to participate in the study. This study was approved by the National Cancer Institute, RTOG, and institutional review boards at all participating institutions.
Patients received four cycles of chemotherapy. A cycle lasted 3 weeks. In cycle 1, patients received chemotherapy with concurrent radiation therapy. In cycles 2 to 4, patients received chemotherapy without radiation therapy. For cycle 1, the chemotherapy consisted of paclitaxel 135 mg/m2 intravenously over 3 hours on day 1, etoposide 60 mg/m2 intravenously over 60 minutes on day 1 and 80 mg/m2 orally on days 2 and 3, and cisplatin 60 mg/m2 intravenously on day 1 after the administration of etoposide. Premedication before paclitaxel was administered and consisted of dexamethasone 20 mg orally 12 and 6 hours before paclitaxel administration, diphenhydramine 50 mg intravenously, and cimetidine 300 mg intravenously 30 minutes before the paclitaxel administration. Patients received pre- and posthydration with the administration of cisplatin. For cycles 2 to 4 without the radiotherapy, the paclitaxel dose was increased to 175 mg/m2, with the etoposide and cisplatin doses remaining the same as in cycle 1. No dose adjustments of the chemotherapy were permitted in cycle 1. For cycles 2 to 4, the use of colony-stimulating factor was permitted to protect against febrile neutropenia. Alternately, a dose reduction of the chemotherapy could be instituted. In cycles 2 to 4, for renal toxicity, the cisplatin dose was reduced for serum creatinine levels of 1.6 to 2.0 mg/dL and held for serum creatinine levels of 2.1 to 3.5 mg/dL until the serum creatinine level decreased to less than 2.0 mg/dL. A serum creatinine of more than 3.5 mg/dL necessitated holding cisplatin from all remaining cycles of chemotherapy.
The thoracic radiation therapy consisted of accelerated bid radiation therapy (1.5 Gy in 30 fractions for a total dose of 45 Gy). The bid doses were administered 6 to 8 hours apart for 5 days a week for 3 weeks. The target volume that was to be treated by anteroposterior/posteroanterior and oblique or lateral fields included the primary tumor plus regional (hilar and mediastinal) lymph nodes. In the case of upper lobe tumors, the ipsilateral supraclavicular lymph nodes were to be treated. The primary tumor must have had a minimum of a 1-cm margin and no more than a 1.5-cm margin. Inclusion of mediastinum required extending field margins 1.5 to 2.0 cm beyond the contralateral border of the vertebral bodies. Ipsilateral supraclavicular irradiation was allowed when necessary for primary tumor coverage or when there was bulky (> 5 cm) pre- or paratracheal adenopathy detected on computed tomography scan of the chest (with contrast). Contralateral supraclavicular treatment was not allowed. Contralateral hilar irradiation was allowed if there was demonstrable bulky contralateral mediastinal involvement. The lower field border was two vertebral bodies or 5 cm below the carina for upper and middle lung field lesions. The lower extent of lower lobe lesions was a 1.0- to 1.5-cm margin, which defined the inferior extent of the field. Any mediastinal node detected by computed tomography scan 1.5 cm was to be included with at least a 2-cm cephalad or caudate margin. Linear accelerators were used to deliver the radiation therapy. Simulation to define the radiation ports was mandatory. All complete responders to the therapy as well as partial responders who desired to receive it were to be offered prophylactic cranial irradiation (PCI) using 2.0- to 2.5-Gy daily fractions. PCI was initiated after hematologic recovery from the last cycle of chemotherapy or within 6 weeks of the last cycle of chemotherapy.
Standard response criteria were used to evaluate the patient's response to the therapy. A CR was the complete disappearance of all clinically detectable disease lasting at least 4 weeks at the time of restaging. A partial response (PR) was defined as a 50% decrease in tumor size lasting for at least 4 weeks without an increase of 25% of the product of perpendicular diameters of any lesion and no new areas of disease. In addition, there could be no significant deterioration of symptoms or performance status (> 1 score level). For measurable, unidimensional disease, a PR was defined as a 30% decrease in the linear tumor measurements lasting for at least 4 weeks; stable disease was defined as no significant change in measure or assessable disease for at least 4 weeks. Disease progression was defined as any increase more than 25% in the sum of the products of diameters of any measurable lesion or in the estimated size of nonmeasurable lesions or the appearance of any new lesions.
Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria as well as the RTOG/European Organisation for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme. All patients were evaluated at the end of the concurrent chemotherapy and radiation therapy and then after each cycle of chemotherapy.
The study end points consisted of (1) 1-year survival rate and long-term survival rates, (2) CR and PR rates, and (3) frequency and severity of treatment morbidity. Overall and progression-free survival were estimated by the Kaplan-Meier method.
The sample size for the study was determined by the 1-year survival rate. It was expected that the 1-year survival rate would be 70% estimated with a 90% lower confidence bound of 60%. This required 47 assessable patients. If the observed 1-year survival rate was less than 60%, then no further phase III study was to be proposed unless long-term survival rates turned out to be much better than the survival rates from the bid arm of the intergroup study.20 Assuming a 10% inassessability rate, the total required sample size was 52 patients.
RESULTS
November 1996 to March 1998, 55 patients were entered onto this phase II study. The data from 53 patients were analyzable. Two patients were ineligible; one patient received brachytherapy before protocol therapy, and the other patient had a pleural effusion. Table 1 lists the pretreatment characteristics of the patients. Sixty-eight percent of patients were younger than 60 years of age (median age, 56 years; range, 39 to 76 years); 81% had a Karnofsky performance score of 90 or better; 74% had less than 5% weight loss in the 3 months before entry onto the study; and on the basis of the TNM staging classification, 79% of patients had stage IIIA or IIIB disease. No patients on study had positive contralateral hilar lymph nodes.
Toxicity
Tables 2 and 3 list the acute and late toxicities, respectively. The major toxicities were as follows. Hematologic toxicity included grade 3 and 4 neutropenia (17 and two patients; 32% and 4%, respectively), grade 3 and 4 thrombocytopenia (two and two patients; 4% and 4%, respectively), and grade 3 anemia (five patients; 9%). Nonhematologic toxicity included grade 3 and 4 esophagitis (17 and two patients; 32% and 4%, respectively), grade 3 and 4 nausea/vomiting (eight and two patients; 15% and 4%, respectively), grade 3 lung toxicity (five patients; 9%), and grade 3 neurologic toxicity (three patients; 6%). Two patients died as a result of therapy; one patient died of acute respiratory distress syndrome on day 39, and one died of sepsis on day 74. There was one late fatal pulmonary toxicity, which occurred on day 136.
Treatment Review
Forty (75%) of the 53 eligible patients received the chemotherapy according to the protocol. An additional 10 patients (19%) had acceptable variations (ie, nonprotocol modifications). Eighty-five percent of the patients received all four cycles of chemotherapy.
Fifty (94%) of 53 patients received the prescribed total dose (45 Gy) of radiation therapy. Specifically, 49 patients received their treatment in 18 to 22 days, and one patient was treated in 25 days. A total of 17 patients received PCI (12 CRs and five PRs). Two of these patients (one CR and one PR) experienced disease progression in the brain (at 16 and 11 months, respectively).
Response Rate
Forty patients (75%) achieved a CR, whereas nine patients (17%) achieved a PR. One patient each had stable disease and disease progression. Two patients had no disease assessment; one patient, who died 40 days after entering the study as a result of pneumonia, was reported by the institution as having unassessable disease, whereas the other patient was reported by the institution as having unknown disease status until 19 months after the treatment ended, at which time progression was noted. Disease response was assessed by institutional investigators only.
Survival
The median survival time was 24.7 months (95% CI, 14.6 to 35.1 months). The 2-year survival rate was 54.7%. The median progression-free survival time was 13 months (95% CI, 11.2 to 20.1 months), and the 2-year progression-free survival rate was 26.4%. Forty-one of the 53 eligible patients have died. Survival time of the 12 patients still alive ranges from 29.5 months to 71.3 months. Overall survival was defined as the time between the date the patient was registered onto the study and the date of the patient's death from any cause. Progression-free survival was defined as the time between the date the patient was registered onto the study and the date of the patient's first local, regional, or distant progression or death from any cause. Figures 1 and 2 are the overall and progression-free survival curves. The x-axes in the overall survival and progression-free survival curves go to 6 years because the maximum follow-up observed in the patients on the study at the time of analysis was 71.3 months.
Pattern of Failure
Among the 40 patients achieving a primary CR, 30 (75%) had primary, nodal, and/or distant metastases failure. Distant metastases as a part of their sites of first failure were reported in 25 patients (63%), including seven patients (13%) with brain metastases (none of whom received PCI). Nine (22.5%) and three patients (7.5%) had progression in the primary tumor and node, respectively, as part of their sites of first failure. Overall, 66% of the 53 patients on the study were diagnosed with metastatic disease at some time, and 22.6% were diagnosed with brain metastases.
DISCUSSION
In 1996 when this study was activated, there were no long-term follow-up data for the intergroup study comparing single-dose thoracic radiation therapy to twice-daily thoracic radiation therapy with concurrent chemotherapy for the treatment of LD-SCLC. In addition, there were no data on the effectiveness of the three-drug combination of paclitaxel, etoposide, and cisplatin compared with the two-drug regimen of etoposide and cisplatin in the treatment of ED-SCLC patients.
Besides this phase II trial, there are three other trials that evaluated the three-drug combination with thoracic radiation therapy in LD-SCLC patients.27-29 Bremnes et al27 reported on their phase II study evaluating paclitaxel, etoposide, and cisplatin with 42-Gy thoracic radiation therapy beginning with cycle 3 in 39 LD-SCLC patients. The response rate was 92%, with a median survival time of 21 months. Thirteen percent of the patients had grade 3 esophagitis. In a phase I and II study involving 31 patients receiving the three-drug combination with thoracic radiation therapy (45 Gy given once daily in 25 fractions during cycles 1 and 2), Levitan et al28 report a response rate of 96% and a median survival time of 22.3 months. During cycles 1 and 2, grade 2 and 3 esophagitis occurred in 13% of the courses of therapy administered. Sandler et al,29 in an Eastern Cooperative Oncology Group phase II study involving 63 patients receiving paclitaxel, etoposide, and cisplatin with radiation therapy (63 Gy administered once daily in 35 fractions starting with the third cycle), report a response rate of 64% and a median survival time of 15.7 months. The principal toxicity was grade 4 neutropenia, which occurred in 59% of patients.
In 1999, Turrisi et al30 published the long-term follow-up results of the intergroup randomized phase III LD-SCLC study. The median survival time was 19 months for patients receiving once-daily radiation therapy and 23 months for patients receiving twice-daily radiation therapy. The 2- and 5-year survival rates for the patients receiving once-daily radiation therapy compared with patients receiving twice-daily radiation therapy were 41% and 16% v 47% and 26%, respectively. Grade 3 esophagitis was significantly more frequent with the twice-daily radiation therapy compared with once-daily radiation therapy (27% v 11%, respectively; P < .001).
Mavroudis et al31 reported on the results of a randomized phase II study involving both LD-SCLC and ED-SCLC patients receiving the three-drug combination compared with the two-drug combination. There were no differences in overall response rates or median survivals between the two regimens studied.
In 2002, Niell et al32 reported on the results of an intergroup phase III study comparing paclitaxel, etoposide, and cisplatin with etoposide plus cisplatin in the treatment of patients with ED-SCLC. Five hundred eighty-seven patients were entered onto the study. Because of excessive toxicity in performance status 2 patients, the study was amended to treat only patients with a performance status of 0 or 1. There was no difference in the median survival (10.33 months for the three-drug regimen v 9.84 months for the two-drug regimen, P = .327).
In this study, our regimen was not better than the twice-daily radiation therapy with concurrent etoposide plus cisplatin evaluated in the intergroup study. As in the intergroup study, the major toxicity was esophagitis (grades 3 and 4, 32% and 4%, respectively) and myelosuppression (grades 3 and 4, 32% and 4%, respectively). Given the results of the two trials evaluating paclitaxel, etoposide, and cisplatin in ED-SCLC and the three trials, including this one, studying the three-drug combination with either once-daily or twice-daily thoracic radiation therapy in LD-SCLC patients, it is unlikely that the three-drug combination with thoracic radiation therapy will improve the survival times in LD-SCLC patients.
Despite the results of the intergroup study showing a 5-year survival rate of 26% for patients receiving the accelerated hyperfractionated radiation therapy, the effectiveness of both thoracic irradiation and systemic chemotherapy needs to be improved. The sequencing and timing of chemotherapy and thoracic radiotherapy as well as the radiation dose to the thorax are controversial areas and still need to be studied.
A phase I study in LD-SCLC, RTOG 97-12, was initiated to improve locoregional control by escalating the total dose of radiation therapy using daily fractionation to larger fields and then boost field and bid radiation therapy toward the end of the thoracic radiation therapy with concurrent etoposide and cisplatin.33 After completion of the phase I study, the RTOG is now conducting a phase II study.
In addition, the RTOG is conducting a phase I study of irinotecan and cisplatin in combination with twice-daily thoracic radiotherapy (45 Gy) or once-daily thoracic radiotherapy (70 Gy) in patients with LD-SCLC. These studies, as well as others conducted by other cooperative groups, are being undertaken in an attempt to improve both local and systemic disease.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, the following authors or their immediate family members have 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.
NOTES
Supported by grant Nos. CA21661, CA37423, and CA32115 from the National Cancer Institute, Bethesda, MD.
Presented at the 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 20-23, 2000.
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Jemal A, Tiwari RC, Murray T, et al: Cancer Statistics, 2004. CA Cancer J Clin 54:8-29, 2004
Ihde DC, Pass HI, Glatstein EJ: Cancer of the lung, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer Principles and Practice of Oncology (ed 4). Philadelphia, PA, Lippincott, 1993
Seifter EJ, Ihde DC: Therapy of small cell lung cancer: A perspective on two decades of clinical research. Semin Oncol 15:278-279, 1988
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
Prez CA, Einhorn L, Oldham RF, et al: Randomized trial of radiotherapy to the thorax in limited small cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: A preliminary report. J Clin Oncol 2:1200-1208, 1984
Perry MC, Eaton WL, Propert KJ, et al: Chemotherapy with or without radiation therapy in limited small cell carcinoma of the lung. N Engl J Med 316:912-918, 1987
Bunn PA, Lichter AS, Makuch RW, et al: Chemotherapy alone or chemotherapy with chest radiation therapy in limited stage small cell lung cancer. Ann Intern Med 106:655-662, 1987
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
Lebeau B, Chastang C, Brechot JM, et al: A randomized trial of delayed thoracic radiotherapy in complete responder patients with small cell lung cancer. Chest 104:726-733, 1993
Coy P, Hodson DI, Murray N, et al: Patterns of failure following loco-regional radiotherapy in the treatment of limited stage small cell lung cancer. Int J Radiat Oncol Biol Phys 28:355-362, 1994
Evans WK, Osoba D, Feld R, et al: Etoposide (VP-16) and cisplatin: An effective treatment for relapse in small-cell lung cancer. J Clin Oncol 3:65-71, 1985
Boni C, Cocconi G, Bisagni G, et al: Cisplatin and etoposide (VP-16) as a single regimen for small cell lung cancer: A phase II trial. Cancer 63:638-642, 1989
Evans WK, Shepherd FA, Feld R, et al: VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol 3:1471-1477, 1985
Einhorn LH, Crawford J, Birch R, et al: Cisplatin plus etoposide consolidation following cyclophosphamide, doxorubicin, and vincristine in limited small-cell lung cancer. J Clin Oncol 6:451-456, 1988
Choi NC, Herndon J, Rosenman J, et al: Phase I study to determine the maximum tolerated ose of radiation in standard fractionated and accelerated twice daily radiation schedules with concurrent chemotherapy for limited stage small cell lung cancer (CALGB 8837). Int J Radiat Oncol Biol Phys 30:179, 1994 (suppl 1)
Turrisi AT, Glover DJ, Mason BA, et al: A preliminary report: Concurrent twice-daily radiotherapy plus platinum–etoposide chemotherapy for limited small cell lung cancer. Int J Radiat Oncol Biol Phys 15:183-187, 1988
Turrisi AT, Glover DJ: Thoracic radiotherapy variables: Influence on local control in small cell lung cancer limited disease. Int J Radiat Oncol Biol Phys 19:1473-1479, 1990
Wagner H, Kim K, Johnson DH, et al: Daily vs. twice-daily thoracic irradiation with concurrent cisplatin/etoposide chemotherapy as initial therapy for patients with limited small cell lung cancer: Preliminary results of a phase III prospective intergroup trial. Int J Radiat Oncol Biol Phys 30:178, 1994 (suppl 1)
Ettinger DS, Finkelstein DM, Sarma PP, et al: Phase II study of paclitaxel in patients with extensive-disease stage small-cell lung cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 13:1430-1435, 1995
Kirschling RJ, Jung SH, Jett JR: A phase II trial of Taxol and G-CSF in previously untreated patients with extensive stage small cell lung cancer. Proc Am Soc Clin Oncol 13:326, 1994 (abstr 1076)
Tishler RB, Schiff PB, Geard CR, et al: Taxol: A novel radiation sensitizer. Int J Radiat Oncol Biol Phys 22:613-617, 1992
Liebmann J, Cook JA, Fisher J, et al: In vitro studies of Taxol as a radiation sensitizer in human tumor cells. J Natl Cancer Inst 86:441-446, 1994
Antonia SJ, Wagner H, Williams C, et al: Concurrent paclitaxel/cisplatin with thoracic radiation in patients with stage IIIA/B non small cell carcinoma of the lung. Semin Oncol 22:34-37, 1995 (suppl 9)
Bonomi P, Farber LP, Recine D, et al: Carboplatin/etoposide/radiation plus escalating doses of paclitaxel in stage III non-small cell lung cancer: A preliminary report. Semin Oncol 22:42-47, 1995 (suppl 9)
Levitan N, McKenney J, Tahsildar H, et al: Results of a phase I dose escalation trial of paclitaxel, etoposide and cisplatin followed by filgrastim in the treatment of patients with extensive stage small cell lung cancer. Proc Am Soc Clin Oncol 14:379, 1995 (abstr 1177)
Kelly K, Wood ME, Bunn PA: A phase I study of cisplatin, etoposide and paclitaxel in extensive stage small cell lung cancer. Proc Am Soc Clin Oncol 15:400, 1996 (abstr)
Bremnes RM, Sundstrom S, Vilsik J, et al: Multicenter phase II trial of paclitaxel, cisplatin and etoposide with concurrent radiation for limited-stage small cell lung cancer. J Clin Oncol 19:3532-3538, 2001
Levitan N, Dowlati A, Shina D, et al: Multi-institutional phase I/II trial a paclitaxel, cisplatin and etoposide with concurrent radiation limited-stage small cell lung carcinoma. J Clin Oncol 18:1102-1109, 2000
Sandler A, Declerck L, Wagner H, et al: A phase II study of cisplatin plus etoposide plus paclitaxel and concurrent radiation therapy for previously untreated limited stage small cell lung cancer (E2596): An Eastern Cooperative Oncology Group trial. Proc Am Soc Clin Oncol 19:491a, 2000 (abstr 1920)
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
Mavroudis D, Papadakis E, Veslemes M, et al: A multicenter randomized phase II study comparing paclitaxel, cisplatin, etoposide (TEP) versus cisplatin-etoposide (EP) as front- line treatment in patients with small cell lung cancer (SCLC). Proc Am Soc Clin Oncol 19:484a, 2000 (abstr 1894)
Niell HB, Herndon JE, Miller AD, et al: Randomized phase III intergroup trial (CALGB 9732) of etoposide and cisplatin with or without paclitaxel and G-CSF in patients with extensive stage small cell lung cancer. Proc Am Soc Clin Oncol 21:293a, 2002 (abstr 1169)
Komaki R, Swann S, Ettinger D, et al: Phase I dose-escalation study of thoracic irradiation with concurrent chemotherapy for patients with limited small cell lung cancer (LSCLC): Radiation Therapy Oncology Group (RTOG) protocol 9712. Proc Am Soc Clin Oncol 22:631, 2003 (abstr 2539)(David S. Ettinger, Brian )