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© 2000 American Society for Clinical Oncology Multi-Institutional Phase I/II Trial of Paclitaxel, Cisplatin, and Etoposide With Concurrent Radiation for Limited-Stage Small-Cell Lung CarcinomaFrom the Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH; The Vanderbilt Clinic, Vanderbilt University, Nashville, TN; Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA; and Interlakes Hematology and Oncology, Rochester, New York, NY. Address reprint requests to Nathan Levitan, MD, Division of Hematology/Oncology, University Hospitals of Cleveland, Cleveland, OH 44106.
PURPOSE: To determine the feasibility of adding paclitaxel to standard cisplatin/etoposide (EP) and thoracic radiotherapy. PATIENTS AND METHODS: Thirty-one patients were enrolled onto this study. During the phase I section of this study, the dose of paclitaxel was escalated in groups of three or more patients. Cycles were repeated every 21 days. For cycles 1 and 2, paclitaxel was administered according to the dose-escalation schema at doses of 100, 135, or 170 mg/m2 intravenously over 3 hours on day 1. Once the maximum-tolerated dose (MTD) of paclitaxel (for cycles 1 and 2, concurrent with radiation) was determined, that dose was used in all subsequent patients entered onto the phase II section of this study. For cycles 3 and 4, the paclitaxel dose was fixed at 170 mg/m2 in all patients. On day 2, cisplatin 60 mg/m2 was administered for all cycles. On days 1, 2, and 3, etoposide 60 mg/m2/d (cycles 1 and 2) or 80 mg/m2/d (cycles 3 and 4) was administered. Chest radiation was given at 9 Gy/wk in five fractions for 5 weeks beginning on day 1 of cycle 1. Granulocyte colony-stimulating factors were used during cycles 3 and 4 only. RESULTS: Twenty-eight patients were assessable. The MTD of paclitaxel was 135 mg/m2, with the dose-limiting toxicity being grade 4 neutropenia. Cycles 1 and 2 were associated with grade 4 neutropenia in 32% of courses, with fever occurring in 7% of courses and grade 2/3 esophagitis in 13%. Cycles 3 and 4 were complicated by grade 4 neutropenia in 20% of courses, with fever occurring in 6% of courses and grade 2/3 esophagitis in 16%. The overall response rate was 96% (complete responses, 39%; partial responses, 57%). After a median follow-up period of 23 months (range, 9 to 40 months), the median survival time was 22.3 months (95% confidence interval, 15.1 to 34.3 months) CONCLUSION: The MTD of paclitaxel with radiation and EP treatment is 135 mg/m2 given over 3 hours. In this schedule of administration, a high response rate and acceptable toxicity can be anticipated.
SMALL-CELL LUNG cancer (SCLC) is a major cause of cancer deaths and accounts for 20% to 25% of all lung cancers. Although this cancer is initially highly responsive to chemotherapy, the vast majority of patients will ultimately relapse and die of resistant disease. Since the introduction of the platinum and etoposide treatment regimen, there has been no progress in the chemotherapeutic management of this disease. Although remission can be obtained in the majority of patients with limited-stage disease, cure rates have remained low and only modestly improved by the addition of radiation to such therapy. The vast majority of patients with limited-stage SCLC are currently treated with chemotherapy and chest radiation. This bimodality therapy was shown to be superior to either modality alone, resulting in increased complete response (CR) rate, decreased local recurrence, and improved survival.1 A meta-analysis of 13 randomized trials showed a modest but a significant 14% reduction in the relative mortality rate for patients who received combined-modality therapy, with 14% of patients alive after 3 years, compared with 9% in the chemotherapy-only group, although in none of these trials was radiation given concurrently with cycle 1.2 Patients who received chemotherapy and chest radiation had more toxicity, but the gain in response and survival is thought to outweigh the increased toxicity in most instances. The optimal chemotherapy regimen for combined-modality approaches has not been defined. The current, most widely used regimen is cisplatin and etoposide.3-7 It has largely replaced the cyclophosphamide, doxorubicin, etoposide regimen of the 1970s because it seems to be less toxic and more effective.8 Paclitaxel is one agent that has recently received intense scrutiny in SCLC. In two single-agent studies from the Eastern Cooperative Oncology Group (ECOG)9 and the North Central Cancer Treatment Group,10 paclitaxel produced response rates of 43% to 68% in patients with SCLC. In these studies, a 24-hour paclitaxel infusion with granulocyte colony-stimulating factor (G-CSF) support was used because the 24-hour infusion was the most commonly used regimen at the time the studies began. A 3-hour paclitaxel infusion was shown to produce equivalent response rates, compared with the 24-hour infusion, in a study in refractory ovarian cancer, and the shorter infusion was less toxic and more convenient.11 In non–small-cell lung cancer, short paclitaxel infusions were shown to be active, and a comparison of phase II studies using 1-, 3-, or 24-hour infusions showed identical response and survival rates.12 Because of the similarity of results, with less toxicity and greater convenience associated with short paclitaxel infusions, we decided to study short paclitaxel infusions in combination with other agents in SCLC. Five phase I/II studies have evaluated the addition of paclitaxel to cisplatin or carboplatin and etoposide therapy. The majority of these have been studies of patients with extensive-stage SCLC, and the majority used carboplatin instead of cisplatin.13-17 The trial described herein is the first published trial of paclitaxel (3-hour infusion), cisplatin, and etoposide with concurrent radiation (given during cycles 1 and 2) in patients with limited-stage SCLC. Paclitaxel doses were escalated during cycles 1 and 2 in cohorts of three or more patients (concurrently with radiation) to determine the MTD of paclitaxel in this schedule of administration. Dose escalation was performed during radiation therapy because prior studies have already determined the safe dose of paclitaxel with etoposide and platinum without radiation in extensive-stage SCLC.14 Cycles 3 and 4 were administered without radiation, and doses of all three chemotherapy agents remained fixed and were chosen on the basis of prior phase II data. The objectives of the current study were (1) to determine the optimal dose of paclitaxel in combination with etoposide and cisplatin with concurrent chest radiation in limited-stage SCLC, (2) to investigate any toxicity associated with this regimen, and (3) to obtain initial data on the efficacy of this regimen in terms of survival and response rates.
Eligibility Criteria All patients had histologically confirmed, limited-stage disease and were previously untreated with chemotherapy or radiation therapy. Limited-stage disease is defined as disease confined to one hemithorax and adjacent nodes and which is treatable by radiotherapy field sizes (portals) tolerated by normal tissues. Patients with supraclavicular node involvement or pleural effusion with positive cytology were considered to have extensive-stage disease and were ineligible. Additional eligibility criteria included the following: measurable or assessable disease; an ECOG performance status of 0, 1, or 2; life expectancy of 12 weeks or longer; age of 18 years or older; adequate hepatic, renal, and cardiac function (left ventricular ejection fraction of 45% or greater); no prior history of malignancy other than basal cell or squamous cell skin cancer or carcinoma in situ of the cervix with a disease-free interval of greater than 5 years. The study was approved by the institutional review boards of the participating institutions, and all patients provided their informed consent before they participated. All patients underwent complete staging for SCLC, including a chest radiograph, chemistry profile, computed tomography (CT) of the chest and abdomen, bone scan, and CT or magnetic resonance imaging of the brain. Bone marrow aspiration or biopsy was not required for staging purposes. Published data suggests that only 2.3% of patients have bone marrow involvement as the only site of metastatic disease.18
Treatment Schema
Actual body weight was used for all body-surface-area calculations. For cycles 1 and 2, paclitaxel was administered according to the dose-escalation schema at doses of 100, 135, or 170 mg/m2 continuous infusion over 3 hours on day 1 (Table 1). On day 2, cisplatin was administered at a dose of 60 mg/m2 over 30 minutes. Etoposide was administered at a dose of 60 mg/m2 on days 1, 2, and 3. This dose of etoposide was chosen because prior phase II data demonstrated that its equivalent oral dose could be administered safely along with paclitaxel and platinum in extensive-stage SCLC.14 Use of premedication, hydration, and antiemetics in cycles 1 and 2 was identical to that in cycles 3 and 4 (see below). Cycles 3 and 4 were administered as follows: Paclitaxel was administered at a dose of 170 mg/m2 over 3 hours on day 1. Cisplatin was administered at a dose of 60 mg/m2 on day 2 over 30 minutes. Etoposide was administered at a dose of 80 mg/m2 on days 1, 2, and 3. These fixed doses of paclitaxel and etoposide for cycles 3 and 4 were chosen because data from Hainsworth et al14 demonstrated that this combination could be given safely at these doses along with platinum. All patients received premedication with dexamethasone 20 mg orally 12 and 6 hours before treatment and with diphenhydramine (50 mg) and ranitidine (50 mg) or cimetidine (300 mg) 30 minutes before paclitaxel administration. Before cisplatin treatment on day 2, patients received 1 L of normal saline over 4 hours and mannitol 12.5 g along with furosemide 20 mg before commencing treatment with cisplatin. Antiemetic therapy was provided as ondansetron 0.15 mg/kg on days 1, 2, and 3. Treatment was repeated every 21 days. G-CSF was administered at a dose of 5 µg/kg from days 5 to 14 of cycles 3 and 4 only. Patients were reevaluated after the first two courses; responding patients and those who had stable lesions received two additional courses, for a maximum of four courses of treatment. Chest radiation was initiated on the same day as the initiation of chemotherapy for cycle 1. Radiation treatment was administered at 9 Gy/wk in five fractions for 5 weeks. A total dose of 45 Gy/5 wk was given. Treatments were started on a Monday with the initiation of cycle 1 of chemotherapy. The radiation therapy portal was based on the tumor size and included the primary lesion. The primary tumor had a minimum of a 1-cm margin and no more than a 1.5-cm margin. The radiation field also included the mediastinum to encompass ipsilateral hilar, mediastinal, and contralateral mediastinal nodes and, in some cases, the ipsilateral supraclavicular nodes. Inclusion of the mediastinum required extension of the field margins 1.5 to 2.0 cm beyond the contralateral border of the vertebral bodies and therefore included the contralateral mediastinal lymph nodes. Ipsilateral supraclavicular irradiation was allowed when necessary for primary tumor coverage or when there was bulky (> 5 cm) pre- or paratracheal adenopathy detected on CT scans of the chest (four patients). Radiation of contralateral hilar or contralateral supraclavicular nodes was not allowed. Prophylactic cranial irradiation was considered in those patients who achieved a CR and was left to the discretion of the treating physician.
Dose Modifications Delays for radiation therapy were allowed only if a patient’s platelet count was lower than 40,000/µL or his or her granulocyte count was lower than 1,000/µL. If so, treatment was delayed in 1-week increments, and the blood counts were rechecked. Any patients whose radiation therapy was delayed for more than 3 weeks were removed from the study. Efforts were made to continue radiation treatment in case of local toxicity (mucositis, esophagitis). If grade 3 or worse nonhematologic toxicity occurred, treatment was delayed for a 1-week period. If toxicity had receded to grade 1 or better after a 1-week treatment delay, then the treatment would resume. If toxicity remained at grade 2 or worse 2 weeks after a patient had discontinued radiotherapy, the patient would be removed from the protocol.
Evaluation
Statistical Considerations
Between May 1995 and December 1997, 31 patients at four centers were enrolled onto this trial. Patients’ characteristics are listed in Table 2. Although an attempt to made to enroll patients with an ECOG performance status of 2, all patients on this trial had a performance status of 0 or 1. Three patients were not assessable for either toxicity or response. One of these patients was enrolled but was never treated. A second patient had an allergic reaction to paclitaxel with the first cycle and did not continue therapy. A third patient received one cycle and was lost to follow-up. Twenty-eight patients were assessable for toxicity, response, and survival. During the first part of this trial, the MTD of paclitaxel was determined to be 135 mg/m2 during cycles 1 and 2. This dose was used for the phase II portion of this study. The dose-limiting toxicity was grade 4 neutropenia. Twenty-five patients completed the full course of treatment. More than 30 days after completing cycle 3, one patient died of sepsis, which had occurred without neutropenia. Two patients received only two cycles: one because of disease progression and the second patient because of an ischemic cerebrovascular event. These patients were considered in the survival analysis. The median follow-up time was 23 months (range, 9 to 40 months).
Toxicity Toxicity data for cycles 1 and 2 were analyzed separately from those of cycles 3 and 4 because of the use of concurrent radiation during cycles 1 and 2, as well as the use of growth factors during cycles 3 and 4. Toxicity data are listed in Table 3. No treatment-related deaths were observed. Twenty-eight patients completed two cycles of therapy. Grade 3 and 4 toxicities were primarily hematologic. Grade 4 neutropenia occurred during 32% of cycles 1 and 2, with neutropenic fever occurring in 7% of courses. Grade 4 thrombocytopenia occurred during only one course. Only one course was complicated by grade 3 esophagitis. A total of 25 patients received four cycles of therapy. In cycles 3 and 4, grade 4 neutropenia occurred during 10 courses (20%), with neutropenic fever occurring during five (10%) of them. In all instances, neutropenia occurred for less than 7 days. However, two courses (4%) were complicated by grade 4 thrombocytopenia and three courses (6%) with grade 3 esophagitis. In all cases, the esophagitis improved within 1 week of the patient’s attaining grade 3 toxicity severity. One patient died of sepsis more than 30 days after undergoing cycle 3 therapy. No patient was removed from the study because of toxicity. Radiation was delayed for 1 week in one patient because of grade 3 esophagitis. Radiation had to be delayed for 1 week in 50% of the patients because of protocol guidelines for hematologic toxicity; however, all patients resumed radiation therapy within 1 week. No patient had thoracic radiation delayed for longer than 1 week. All patients ultimately received the full dose of radiation.
Response and Survival Each patient was evaluated for response after completing cycle 2 (and before cycle 3) and 1 month after completing cycle 4 of chemotherapy. Response data are listed in Table 4. In the 28 assessable patients, 11 (39%) experienced a CR and 16 (57%) a partial response (PR). The overall response rate was 96%. Only one (4%) patient experienced progressive disease while undergoing therapy. The overall survival curve is shown in a Kaplan-Meier plot in Fig 1. The median survival time was 22.3 months (95% CI, 15.1 to 34.3 months). The estimated 1-year survival rate was 70% (95% CI, 52% to 87%). The estimated 2-year survival rate was 47% (95% CI, 25% to 70%).
Since the introduction of effective chemotherapy regimens, the only significant technique to improve survival rates for limited-stage SCLC has been the addition of radiation.2 One theoretical approach to the problem of limited treatment options is the incorporation of new chemotherapeutic agents that have been shown to have significant single-agent activity into the treatment regimens that are currently used. In two consecutive cooperative group studies, paclitaxel has been shown to have significant single-agent activity against extensive-stage SCLC, with response rates between 43% and 68%.9,10 It thus seemed logical to incorporate this drug into the platinum and etoposide regimen. Several studies using this approach are in progress or have been completed, with the majority of patients having had extensive disease at the time of diagnosis. These studies have demonstrated high response rates, but it is yet unclear whether there is any survival advantage with the addition of paclitaxel because no randomized studies have been performed to test the paclitaxel, cisplatin, etoposide combination against the standard platinum/etoposide treatment. Bunn and Kelly,13 using a combination of cisplatin, etoposide, and paclitaxel, reported an overall response rate of 94% (CRs, 22%; PRs, 72%) in patients with extensive-stage disease. The group from the Sarah Cannon Cancer Center used a combination of paclitaxel, carboplatin, and extended-schedule etoposide and showed a 76% response rate (CRs, 26%; PRs, 50%), with a CR of 17% for extensive disease and 40% for limited disease.14 Only 15 patients in their study had limited-stage disease, and carboplatin was substituted in the study for cisplatin. Radiation was administered concurrently with the last two cycles in those patients who had limited-stage disease. Paclitaxel was administered as a 1-hour infusion. Cytokines were not used in this study. Gatzemeier et al15 reported an overall response rate of 88% in patients with limited-stage disease when carboplatin was substituted for cisplatin and paclitaxel was infused over 1 hour. However, none of their patients received radiation and none received growth factors. Glisson et al16 reported a phase I/II study of paclitaxel (3-hour infusion), cisplatin, and etoposide in patients with extensive-stage SCLC. The MTD resulting from dose-limiting neutropenia was achieved at a paclitaxel dose of 130 mg/m2. Growth factors were not administered, and an overall response rate of 96% was observed, with a 19% CR rate. A preliminary report of combined chemoradiation with paclitaxel, etoposide, and cisplatin with radiation has been reported.17 A 95% response rate in 27 patients was reported, with a very high CR rate of 80%. Once again, growth factors were not allowed to be used. The study does, however, differ from ours in that radiation in that study was initiated with the third cycle of chemotherapy (cycles repeated every 3 weeks) and paclitaxel was administered at a higher dose (175 mg/m2) and as a 1-hour infusion. In addition, the study used a lower dose of cisplatin (50 mg/m2). The overall response rate in that trial was equivalent to that determined in our trial; however, we cannot explain the very high CR in their trial, which certainly needs to be confirmed. Because the optimal dose of paclitaxel to be used in this chemoradiation setting was not clear, we first decided to determine the MTD of paclitaxel when it was administered along with cisplatin, etoposide, and concurrent radiation. Grade 4 neutropenia was dose-limiting, and the MTD of paclitaxel was determined to be 135 mg/m2 over 3 hours. The duration of infusion for paclitaxel in our study was 3 hours, rather than the 1-hour infusion used by most of the previously described studies of SCLC. Indeed, phase II comparisons of 3-hour versus 24-hour infusions in the treatment of non–small-cell lung cancer12 have shown that both infusions have equivalent response rates (although the study was not a randomized comparison), and 3-hour and 24-hour infusions have also been shown to be similar in the treatment of ovarian cancer.11 There is little data available on the efficacy of 1-hour infusions of paclitaxel, and we thus decided to use the 3-hour infusion. Thoracic radiation was initiated on day 1 of therapy. Studies have shown that the early administration of radiation, compared with delayed radiation, may improve outcome in limited-stage disease, although it is unclear how early the radiation should begin. Indirect comparisons in an SCLC meta-analysis did not answer definitively whether preference should be given to early or late radiotherapy.2 However, three randomized trials have investigated this question directly. The National Cancer Institute of Canada trial showed a significant difference in favor of early radiotherapy begun at day 22, compared with late radiotherapy begun at day 106.21 The two other trials failed to show a difference with the early administration of radiation,22,23 which may be due in part to the nondelivery of full chemotherapy doses with initial cycles in the early-radiotherapy group arms.24 Given the uncertainty of whether early or late radiotherapy is superior, we chose to begin administering radiation at cycle 1. The toxicity encountered with this regimen was manageable. However, this trial allowed for delays in radiation (see Dose Modifications) and, therefore, the toxicity may have been more severe if radiation had not been withheld in those circumstances. As mentioned for cycles 1 and 2, when radiation was given concurrently, 32% of the courses were complicated with grade 4 neutropenia, but febrile neutropenia occurred during 7%. These toxicities are similar to those observed with the standard platinum/etoposide regimen. Significant thrombocytopenia occurred infrequently. Grade 3 esophagitis occurred in only 2% of courses and grade 2 esophagitis in 11%. During cycles 3 and 4, when radiation was no longer given and G-CSF support was used, the incidence of grade 4 neutropenia was reduced to 20% of courses administered, and febrile neutropenia occurred in only 6%. The incidence of grades 2 and 3 esophagitis rose slightly to 16% of courses. Other clinically significant toxicities, including thrombocytopenia, were infrequent. The low incidence of thrombocytopenia may be related to the lower dose of etoposide used in this study. Indeed, in the study by Hainsworth et al14 of this three-drug combination, the incidence of grade 3/4 thrombocytopenia was 10%, similar to that in our study. Furthermore, grade 2 neurosensory toxicity occurred in only one patient. No higher grade of neurotoxicity was observed. The decrease in grade 3/4 neutropenia with cycles 3 and 4 could be attributed to the use of G-CSF. The increase in grade 3/4 anemia during cycles 3 and 4 suggests cumulative toxicity. No pulmonary toxicity was seen. The increased incidence of grade 3 esophagitis with cycles 3 and 4 (after radiation was completed) may be explained by radiation recall effects of the chemotherapy. The response rates seen with this regimen are very high and are similar to those in other studies in which this three-drug regimen was administered to patients with limited-stage disease. CRs were seen in 39% of our patients. Survival analysis shows a median survival time of 22.3 months (with a median follow-up period of 23 months) and an estimated 2-year survival rate of 47%. This is comparable to the results in a randomized intergroup trial, which reported an overall response rate of 87%, a median survival time of 23 months, and a 47% 2-year survival rate for those patients who received twice-daily radiation.7 Of course, a randomized trial would have to validate these survival data and compare them with the current standard of care. The ECOG recently completed a phase II trial of the same three-drug regimen with radiation starting in cycle 3; the results from this trial are not yet available. The recently completed RTOG study of a three-drug regimen (cisplatin, ifosfamide, oral etoposide) with concurrent accelerated hyperfractionated thoracic radiotherapy for patients with limited-stage SCLC demonstrated an 80% response rate and a median survival time of 21 months.25 The cost of adding a third chemotherapeutic agent, such as paclitaxel, along with G-CSF to our standard two-drug regimen would only be justified if improvements in survival could be demonstrated. We continue to make progress in the treatment of limited-stage SCLC, as documented by the improvements in survival reported by the recent intergroup trial. As with other diseases that are chemosensitive, the incorporation of new active agents into current regimens used for limited-stage SCLC may be an approach for improving the survival rates for this disease. The addition of paclitaxel to cisplatin, etoposide, and radiation treatment induces high response rates for this disease with manageable toxicity. Survival with this treatment is comparable to the best results of platinum and etoposide therapy with concurrent radiotherapy. Further efforts are needed to discover new effective therapies for SCLC.
1. Warde P, Payne D: Dose 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] 2. Pignon JP, Arriagada R, Ihde CE, et al: A meta-analysis of thoracic irradiation for small-cell lung cancer. N Engl J Med 327:1618-1624, 1992[Abstract] 3. McCracken JD, Janaki LM, Crowley JJ, et al: Concurrent chemotherapy/radiotherapy for limited small cell lung carcinoma: A Southwest Oncology Group study. J Clin Oncol 8:892-898, 1990[Abstract] 4. Turrisi AT, Wagner H, Glover B, et al: Limited small-cell lung cancer (LSCLC): Concurrent BID thoracic radiotherapy (TRT) with platinum-etoposide (PE)—ECOG study. Proc Am Soc Clin Oncol 9:230a, 1990 (abstr 887)
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Johnson BE, Bridges JD, Sobczeck M, et al: Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J Clin Oncol 14:806-813, 1996
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Turrisi AT, Kyungmann 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. Albain KS, Crowley JJ, LeBlanc M, et al: Determinants of improved outcome in small-cell lung cancer: An analysis of the 2,850-patient Southwest Oncology Group data base. J Clin Oncol 8:1563-1574, 1990[Abstract] 9. Ettinger DS, Finkelstein DM, Sarma RP, et al: Phase II study of paclitaxel in patients with extensive-disease small-cell lung cancer: An Eastern Cooperative Oncology Group study. Clin Oncol 13:1430-1435, 1995 10. Kirschling RJ, Jung SH, Jett JR, et al: 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 13:326a, 1994 (abstr 1076)
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Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al: European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusions. J Clin Oncol 12:2654-2666, 1994 12. Bunn PA: Defining the role of paclitaxel in lung cancer: Summary of recent studies and implications for future directions. Semin Oncol 24:153-162, 1997 (suppl 12)[Medline] 13. Bunn PA, Kelly K: A phase I trial of cisplatin, etoposide, and paclitaxel in small-cell lung cancer. Semin Oncol 24:144-148, 1997 (suppl 12) 14. Hainsworth JD, Stroup S, Greco FA: Paclitaxel, carboplatin, and extended schedule etoposide in the treatment of small cell lung carcinoma. Cancer 77:2458-2463, 1996[Medline] 15. Gatzemeier U, Jagos U, Kaukel E, et al: Paclitaxel, carboplatin and oral etoposide: A phase II trial in limited-stage small-cell lung cancer. Semin Oncol 24:149-152, 1997 (suppl 12) 16. Glisson BS, Kurie JM, Fox NJ, et al: Phase I-II study of cisplatin, etoposide and paclitaxel (PET) in patients with extensive small-cell lung cancer. Proc Am Soc Clin Oncol 16:455a, 1997 (abstr 1635) 17. Bremnes RM, Sunstrom S, Aasebo U, et al: Paclitaxel in combination with cisplatin, etoposide and thoracic radiotherapy for limited stage small cell lung cancer: A phase II study. Proc Am Soc Clin Oncol 17:475a, 1998 (abstr 1826) 18. Bezwoda W, Lewis D, Livini N: Bone marrow involvement in anaplastic small-cell lung cancer. Cancer 58:1762-1765, 1986 [Medline] 19. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Oncol 5:649-655, 1982 20. National Cancer Institute:Common Toxicity Criteria. Bethesda, MD,National Cancer Institute, 1988
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Murray N, Coy P, Pater JL, et al: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small cell lung cancer. J Clin Oncol 11:336-344, 1993 22. 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[Abstract] 23. Nielsen OS, Fode K, Bentzen SM, et al: Timing of radiotherapy and chemotherapy in limited-stage small-cell lung cancer: Final analysis. Eur J Cancer 2:S182, 1991 (suppl) (abstr)
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Arriagada R, Le Chevalier T, Pignon JP, et al: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329:1848-1852, 1993 25. Glisson B, Scott C, Komaki R, et al: Cisplatin, ifosfamide, prolonged oral etoposide and concurrent accelerated hyperfractionated thoracic radiotherapy for patients with limited small-cell lung cancer: Results of RTOG 93-12. Proc Am Soc Clin Oncol 17:450a, 1998 (abstr 1733) Submitted December 21, 1998; accepted November 10, 1999. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
