The majority of patients with extensive-stage small-cell

Transcription

1 ORIGINAL ARTICLE Irinotecan, Carboplatin, and Imatinib in Untreated Extensive-Stage Small-Cell Lung Cancer: A Phase II Trial of the Minnie Pearl Cancer Research Network David R. Spigel, MD,* John D. Hainsworth, MD,* Lisa Simons,* Christina Meng,* Howard A. Burris III, MD,* Denise A. Yardley, MD,* Richard Grapski, MD, Marshall Schreeder, MD, Padmaja V. Mallidi, MD, and F. Anthony Greco, MD,* Introduction: The tyrosine kinase KIT has variable expression in small-cell lung cancer (SCLC) and may be a prognostic factor. Imatinib targets KIT expression, providing rationale for studying its role in combination with chemotherapy in SCLC in a multicenter phase II trial. Methods: Patients with untreated extensive-stage SCLC received carboplatin area under the concentration-time curve of 4 on day 1; irinotecan 6 mg/m 2 on days 1, 8, and 15; and imatinib 6 mg/day. Treatment cycles were 28 days. Patients remained on imatinib until progressive disease or significant toxicity. Results: Between September 22 and May 24, 68 patients were enrolled in this multicenter trial. Median age was 6 years (range, 37 81). The objective response rate was 66% (95% confidence interval: 54% 76%). Median progression-free survival was 5.4 months (95% CI: months). Median overall survival was 8.4 months (95% CI: months). Thirty-five percent of patients were alive at 1 year. Grade 3/4 hematologic toxicity included neutropenia (43%), anemia (16%), and thrombocytopenia (9%). Grade 3 nonhematologic toxicity included diarrhea (19%), fatigue (24%), and nausea (26%). Forty-eight of 56 patients (86%) with available tumor specimens had KIT expression detected. KIT expression did not appear to correlate with progression-free survival or overall survival in a retrospective analysis. Conclusions: Irinotecan, carboplatin, and imatinib is a safe and generally well-tolerated regimen in patients with SCLC. However, the addition of imatinib did not improve results from those expected with chemotherapy alone. *Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, Tennessee; Thompson Cancer Survival Center, Knoxville, Tennessee; Clearview Cancer Institute, Huntsville, Alabama; Oncology and Hematology Associates of SW Virginia, Roanoke, Virginia. Disclosure: The authors declare no conflict of interest. Preliminary data presented at the American Society of Clinical Oncology 24 and 25 annual meetings. Address for correspondence: David R. Spigel, MD, Sarah Cannon Research Institute, 25 25th Avenue North, Suite 11, Nashville, TN dspigel@tnonc.com Copyright 27 by the International Association for the Study of Lung Cancer ISSN: /7/ Key Words: Imatinib, Small-cell lung cancer, extensive-stage, KIT, Carboplatin, Irinotecan. (J Thorac Oncol. 27;2: ) The majority of patients with extensive-stage small-cell lung cancer (ES-SCLC) will not survive beyond 2 years. 1 Despite high response rates with chemotherapy, modern combination regimens have not dramatically affected mortality with median survival times averaging 8 to 1 months. 2 4 Likewise, triplet combinations have not improved survival when compared with doublet regimens, although toxicity is increased. 5,6 Newer treatment strategies incorporating novel biologic agents are needed. Imatinib is an oral inhibitor of several kinases including KIT, which is variably expressed in SCLC and may be an important target for treatment. 7,8 Inhibition of KIT activation has proven to be a successful strategy in the treatment of gastrointestinal stromal tumors. 9 The published experience with imatinib in SCLC has been limited to date. Single-agent studies and a small phase I experience in combination with chemotherapy have not suggested benefit Given the variable expression of KIT in SCLC and the ability of imatinib to inhibit this expression, a multicenter phase II trial of chemotherapy and imatinib was initiated in previously untreated patients with ES-SCLC. The platform chemotherapy used in this study was carboplatin and irinotecan, a generally well-tolerated and active regimen studied by our group and others in SCLC treatment METHODS This multicenter phase II trial was initiated in September 22. Participating centers in the trial included the Sarah Cannon Cancer Center and selected sites from the Minnie Pearl Cancer Research Network (Appendix). This trial was approved by the institutional review boards of all participating institutions. Patient Eligibility Patients with cytologically or histologically confirmed ES-SCLC were enrolled. Patients had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) Journal of Thoracic Oncology Volume 2, Number 9, September 27

2 Journal of Thoracic Oncology Volume 2, Number 9, September 27 Irinotecan, Carboplatin, Imatinib in SCLC Other eligibility criteria included no previous systemic chemotherapy, primary radiation, or biologic treatment; Eastern Cooperative Oncology Group (ECOG) performance status or 1; adequate organ function (defined as absolute neutrophil count [ANC] /L and platelet count /l, total bilirubin 3. mg/dl, aspartate aminotransferase (SGOT) three times or less the institutional upper limit of normal, and creatinine 1.6 mg/dl); absence of active brain metastases; and age 18 years or older. Patients were excluded if they had a previous malignancy within 3 years with the exception of skin cancer (excluding melanoma), cervical carcinoma in situ, in situ breast carcinoma, or early-stage prostate cancer. Women who were pregnant or lactating were also excluded. Patients with reproductive potential were required to use barrier contraception during treatment. All patients were required to provide written informed consent before study entry. Pretreatment Evaluation Before beginning therapy, all patients were evaluated with routine histories, physical examinations, chemistry profiles, and complete blood counts. Tumor staging with computed tomography scans of the chest and upper abdomen and bone scanning was required. Computed tomography or magnetic resonance imaging of the head was also required. Bone marrow biopsy was not required if ES-SCLC could be confirmed by other staging procedures. Treatment Plan At the time this study was designed, experience with irinotecan and carboplatin in SCLC was emerging. Our center previously studied this combination in a phase I study in patients with refractory malignancies and determined the regimen used for this study in previously untreated patients with ES-SCLC. 18 All patients received irinotecan 6 mg/m 2 administered by intravenous (IV) infusion on days 1, 8, and 15, IV carboplatin at an area under the concentration-time curve of 4 on day 1, and imatinib 6 mg/day orally. Irinotecan was infused prior to carboplatin, with each administered over 3 to 6 minutes. The carboplatin dose was calculated using the method described by Calvert et al. 19 Treatment cycles were repeated every 28 days for four to six cycles. After four cycles, in selected patients based on clinical judgment, two additional cycles of treatment could be administered. Patients remaining in remission or with stable disease after completion of four to six cycles continued imatinib 6 mg daily until tumor progression or for a maximum of 24 months, with re-evaluation at 2-month intervals. Because imatinib is a local irritant, patients were instructed to take this in a sitting position with a large (25 ml) glass of water. It was advised that imatinib not be taken with grapefruit juice. If a patient had significant gastrointestinal intolerance, the dose could be split into twice-daily dosing. Cytokines were not administered with the first course of treatment. Prophylactic granulocyte colony-stimulating factor for patients experiencing febrile neutropenia was permitted at the discretion of the treating physician, but was not to substitute for mandated dose reductions. Routine antiemetics were used as premedication. Patients were seen and examined by their physicians on a monthly basis. After 8 weeks of treatment, patients were evaluated for response. At restaging, repeat computed tomography scans of all measurable lesions were performed. Based on this evaluation, all patients were assigned a response category. Patients who had objective response or stable disease continued to receive additional treatment. Patients with tumor progression were removed from the study. Patients with symptomatic bone metastases could receive concomitant palliative radiation therapy during study treatment. Imatinib was supplied by Novartis AG (Basel, Switzerland) as 1-mg capsules packaged in bottles. Medication labels complied with federal legal requirements and were printed in English. Bottles were stored in a safe and secure central location and were then distributed to participating sites. Commercially available forms of irinotecan and carboplatin were used. Dose modifications were based on absolute neutrophil and platelet counts on day 1 of each cycle. Dose adjustments at the beginning of each cycle were not made based on nadir blood counts. No dose adjustments were required if the ANC was /l and the platelet count was /l. If the ANC was /l, but /l or platelets /l, but /l, irinotecan and carboplatin were reduced 25%, and imatinib was lowered to 4 mg. If the ANC was /l or platelets /l, all therapy was held up to 2 weeks. When counts recovered, irinotecan and carboplatin were reduced 25% and imatinib lowered to 4 mg. If counts did not recover within 2 weeks, the patient came off study. Chemotherapy doses were not increased once modified; however, imatinib could be increased to 6 mg once counts recovered to the entry criteria level. Missed doses were not made up. Dose modifications for irinotecan and imatinib on days 8 and 15 were made according to the same parameters. Patients requiring hospitalization for neutropenia and fever had 25% dose reductions for irinotecan and carboplatin, and imatinib was reduced to 4 mg. Patients experiencing grade 3/4 nonhematologic toxicity had treatment held until the toxicity resolved to less than grade 2; chemotherapy was then resumed with 25% dose reductions of the offending agents. Imatinib was held until the toxicity resolved to grade 1 or lower and then resumed at 4 mg. If grade 3/4 toxicity recurred, imatinib was withheld until toxicity resolved to grade 1 or lower and resumed at 2 mg. If grade 3/4 toxicity recurred a third time, imatinib was discontinued. Patients experiencing any grade 4 nonhematologic toxicity could be removed from the study at the discretion of the treating physician. Patients who developed grade 2 or 3 diarrhea had irinotecan and imatinib held up to 2 weeks until the diarrhea improved to grade 1 or lower. Both agents were resumed at full dose. Definition of Response All patients were reevaluated for response by RECIST. 17 All patients with major responses had confirmation of response on repeat scans performed at 8-week intervals. Pa- Copyright 27 by the International Association for the Study of Lung Cancer 855

3 Spigel et al. Journal of Thoracic Oncology Volume 2, Number 9, September 27 tients with stable disease or minor responses at 8 weeks were reevaluated at 2-month intervals as treatment continued. The final response category assigned to these patients represented the best response obtained during their treatment course. Statistical Methods This nonrandomized phase II study was designed to assess the tumor response rate. We considered the achievement of a 7% objective response rate to be a level of efficacy commensurate with irinotecan and carboplatin alone A higher response rate would be worthy of additional development of this combination regimen. Achievement of 48 responses among a total of 68 patients would indicate a true response rate of 7%. The level of this design was.5 and the power was.85. Progression-free survival (PFS) was defined as the date of study entry until the date that tumor progression was documented. Overall survival (OS) was measured from the date of study entry until the date of death. Survival curves were constructed by using the method of Kaplan and Meier. 2 Comparisons of PFS and OS for various subsets of patients based on KIT expression were accomplished by using twosided log-rank analysis. 21 KIT expression by immunohistochemistry was scored by one pathologist who was blinded to treatment outcome. Immunohistochemistry analyses were performed using the Pathway Anti-c-KIT (9.7) Primary Antibody (Ventana Medical Systems, Inc., Tucson, AZ), a purified rabbit monoclonal antibody directed against the intracellular domain of the c-kit oncoprotein. Expression was scored two ways: positive (1, 2, or3 ) or negative (). Toxicity was evaluated in all patients who received at least one dose of therapy. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria, version 3.. RESULTS Patient Characteristics Between September 22 and May patients were enrolled by 15 participating sites in the Minnie Pearl Cancer Research Network (Appendix). Patient characteristics are summarized in Table 1. Patients in this trial had a median age of 6 years; the majority had ECOG 1 performance status. Treatment Received Fifty-nine patients (87%) completed the planned four courses of irinotecan, carboplatin, and imatinib, and were evaluated for response. Nine patients were withdrawn from treatment before completing two courses for the following reasons: rapid tumor progression (two patients), treatmentrelated death (one patient), intercurrent illness (three patients), poor subjective response (one patient), treatmentrelated toxicity (carboplatin hypersensitivity reaction, one patient), and poor compliance (one patient). The median number of chemotherapy cycles received was four (range, one to six). Twenty-four patients (35%) completed six courses of combination chemotherapy, and 26 patients (38%) TABLE 1. Patient Characteristics (n 68) Characteristic Patients Age, yr Median 6 Range Gender Male 39 (57%) Female 29 (43%) Racial/ethnic origin White 64 (94%) African descent 4 (6%) ECOG performance status 16 (24%) 1 52 (76%) Previous treatment for brain metastases 1 (1%) Location of treatment facility Sarah Cannon Cancer Center 37 (54%) Network sites 31 (46%) ECOG, Eastern Cooperative Oncology Group. went on to receive imatinib alone for a median of 2 months (range, 1 5). Response to Treatment The intent-to-treat responses of the 68 patients enrolled in this trial are shown in Table 2. Forty-five of 68 patients (66%, 95% confidence interval [CI]: 54% 76%) had objective responses (partial response, 42; complete response, three including one unconfirmed complete response). An additional eight patients (12%) had stable disease. Eight patients (12%) had disease progression by the time of their first reevaluation (8 weeks). With a median follow-up of 24 months, PFS and OS for the entire group of patients are shown in Figures 1 and 2, respectively. The median PFS was 5.4 months (95% CI: ). The median OS for the entire group was 8.4 months (95% CI: ). Thirty-five percent of patients were alive at 1 year. KIT expression was not a requirement for enrollment. Tissue blocks were available for KIT analysis on 56 patients (82%) (Table 3). Figures 3 6 compare PFS and OS in patients by KIT expression as measured by different scoring scales. No comparison shows statistically significant differences in PFS or OS when stratified by KIT expression. TABLE 2. Response to Treatment (n 68) Response No. (%) Complete 3 a (4) Partial 42 (62) Stable disease 8 (12) Progression 8 (12) Unassessable 7 (1) a One unconfirmed complete response. 856 Copyright 27 by the International Association for the Study of Lung Cancer

4 Journal of Thoracic Oncology Volume 2, Number 9, September 27 Irinotecan, Carboplatin, Imatinib in SCLC FIGURE 1. Progression-free survival (PFS) for the entire group (n 68). FIGURE 2. Overall survival for the entire group (n 68). CI, confidence interval; pts, patients. TABLE 3. KIT Expression Scoring (n 56) KIT Expression No. % Positive Negative Treatment-Related Toxicity Treatment-related toxicity is summarized in Table 4. The most common grade 3/4 toxicity during combination therapy was neutropenia, which occurred in 43% of patients. Grade 3/4 anemia occurred in 16% of patients. Five patients (7%) required hospitalization for treatment of neutropenia and fever. Granulocyte colony-stimulating factor, granulocyte-macrophage colonystimulating factor, or erythropoietin agents were used in 85% of patients at some time during treatment. There was one (1%) treatment-related death, possibly due to hypokalemia. FIGURE 3. Progression-free survival (PFS) by KIT expression: positive or negative. pt, patient. Copyright 27 by the International Association for the Study of Lung Cancer 857

5 Spigel et al. Journal of Thoracic Oncology Volume 2, Number 9, September 27 FIGURE 4. Overall survival by KIT expression: positive or negative. pt, patient. FIGURE 5. Progression-free survival (PFS) by KIT expression:, 1, 2, 3. pt, patient. FIGURE 6. Overall survival by KIT expression:, 1, 2, 3. pts. patients. Severe nonhematologic toxicity, other than alopecia, was relatively uncommon. Nineteen percent of patients had grade 3 diarrhea (, grade 4) and 24% had grade 3 fatigue/weakness (, grade 4). Twenty-six percent had grade 3 nausea (, grade 4), and 15% had grade 3 vomiting (, grade 4). Ten percent had grade 3 anorexia (, grade 4) and dehydration (, grade 4), and 12% had grade 3 dyspnea (, grade 4). Other nonhematologic toxicities occurred in less than 1% of patients. Nonhematologic toxicities specific to imatinib (rash, edema) were uncommon. DISCUSSION The tyrosine kinase KIT plays an important role in cell development and growth regulation in some tumors. Ninety 858 Copyright 27 by the International Association for the Study of Lung Cancer

6 Journal of Thoracic Oncology Volume 2, Number 9, September 27 Irinotecan, Carboplatin, Imatinib in SCLC TABLE 4. Grade 3/4 Treatment-Related Toxicity During Irinotecan, Carboplatin, and Imatinib (n 68) Patients Toxicity a Grade 3, No. (%) Grade 4, No. (%) Hematologic Neutropenia 19 (28) 1 (15) Thrombocytopenia 6 (9) Anemia 9 (13) 2 (3) Febrile neutropenia 4 (6) 1 (1) Platelet transfusion 1 (1) RBC transfusion 16 (24) Nonhematologic Anorexia 7 (1) Atrial fibrillation 2 (3) Dehydration 7 (1) Diarrhea 13 (19) Dyspnea 8 (12) Edema 2 (3) Fatigue/weakness 16 (24) Hypokalemia 6 (9) 2 (3) Infection 3 (4) Nausea 18 (26) Vomiting 1 (15) Weight loss 2 (3) RBC, red blood cell. a Grade 3 and 4 toxicities occurring in 3% of patients. percent of gastrointestinal stromal tumors express KIT in an activated form because of a mutation in c-kit, the protooncogene that encodes for the receptor. 22 Several gain-offunction mutations have been identified, involving exons 9, 11, 13, and 17, which account for this ligand-independent receptor activation. 23,24 Imatinib inhibits KIT and is associated with disease control in 8% of gastrointestinal stromal tumors patients. 9 KIT and its ligand, stem cell factor, are expressed in the majority of SCLCs This coexpression may lead to autocrine or paracrine activation and consequent cell proliferation. 31 Recently, exon 9 and 11 mutations have been identified in a subset of patients with SCLC, 32 potentially explaining other mechanisms for KIT activation in this disease. Studies examining KIT s value as a prognostic factor in SCLC have been mixed. 25,26 In a multivariate analysis of 23 SCLC patients, KIT expression was found to be an independent prognostic factor, along with stage and performance status. However, increased KIT expression was associated with improved survival compared with decreased or no expression. Other retrospective analyses have found opposite conclusions. 33,34 Micke et al. 33 examined tumor samples from SCLC patients and correlated clinical outcomes with KIT expression. In ES-SCLC patients who had only minor responses to chemotherapy and positive KIT expression, survival was shorter (median, 71 days; 95% CI: 237) compared with similar patients with KIT-negative tumors (median, 288 days; 95% CI: ; log rank test, p.3). Additional support for targeting KIT comes from in vitro studies in which Japanese investigators used antisense adenovirus vectors expressing c-kit transcripts in KIT expressing SCLC cell lines. Infection of these cells resulted in reduced KIT expression and cellular growth inhibition compared to uninfected cells. 35 The published experience with imatinib in the treatment of SCLC has been limited. There have been three studies in which imatinib has been used as a single agent, 1 12 and more recently, a phase I trial in which imatinib was combined with chemotherapy 36 (Table 5). Johnson et al. 36 administered imatinib to 19 patients, nine of whom had no previous treatment and 1 with sensitive relapse. Four patients could not be confirmed to have had SCLC with central review. There were no objective responses; however, only four patients had evidence of KIT expression. Similarly, two phase II studies that required KIT expression for enrollment found no objective responses in patients with relapsed disease treated with imatinib alone. Recently, phase I data were published on previously untreated patients (n 9) with ES-SCLC who received imatinib in combination with cisplatin and irinotecan. KIT expression was identified in three of nine patients, and five of six assessed patients responded. The present study was designed to combine imatinib with an active chemotherapy regimen. Several studies have found TABLE 5. Published ES-SCLC Studies With Imatinib Study No. Setting ORR Median Time to progression KIT Expression Comments Johnson et al No previous therapy, 9 Sensitive relapse, 1 Dy et al Sensitive relapse, 22 Refractory relapse, 7 Krug et al Sensitive relapse, 6 Refractory relapse, 6 Johnson et al No previous therapy. Imatinib administered with cisplatin/irinotecan, 1 patient (KIT negative) had SD for 4.1 mo 83% (5 of 6 assessable for response).8 mo 1.2 mo 1mo 1.1 mo All with PD by4wk All with PD by 3 5 mo 21% (4 patients) SCLC not confirmed in 5 patients 1% (required for enrollment) 1% (required for enrollment) 33% (3 of 9 assessed) Information on KIT status in responders not available ORR, objective response rate; SD, stable disease. Copyright 27 by the International Association for the Study of Lung Cancer 859

7 Spigel et al. Journal of Thoracic Oncology Volume 2, Number 9, September 27 irinotecan and carboplatin to be an active and well-tolerated regimen in SCLC, with response rates of approximately 7% In our multicenter phase II trial, treatment with irinotecan, carboplatin, and imatinib was found to be safe and generally well tolerated, with an objective response rate of 66% and a disease control rate (objective response rate stable disease) of 78%. Neutropenia, nausea, fatigue, and diarrhea were significant toxicities; however, grade 4 toxicity was rare. Fiftysix specimens (82%) were available for KIT analysis and 86% of these had 1 or higher expression by immunohistochemical scoring. KIT expression did not appear to correlate with improved PFS or OS, although few KIT-negative patients (n 8, 14%) were available for comparison. Compared with historical outcomes for first-line treatment of ES-SCLC with platinumbased chemotherapy alone, the addition of imatinib does not appear to offer any advantage. This study is limited by its nonrandomized design and small subsets for KIT expression to adequately assess KIT s value as a predictive marker. Additionally, this trial design cannot readily distinguish the effects of imatinib from those of combination chemotherapy. Despite these limitations, these results do not support further investigation of imatinib in SCLC. KIT expression does not appear to be a valid target for drug development in SCLC. Unlike in gastrointestinal stromal tumors in which activating mutations account for constitutive receptor activity and consequent tumor growth, KIT expression in SCLC may be more reflective of downstream, rather than upstream, signaling. Identifying other targets, such as the vascular endothelial growth factor, the insulin-like growth factor-i receptor, and the mammalian target of rapamycin kinase may prove to be more successful strategies in improving SCLC treatment. ACKNOWLEDGMENTS Supported in part by grants from Novartis AG, Basel, Switzerland, and The Minnie Pearl Cancer Foundation, Nashville, TN. REFERENCES 1. Govindan R, Page N, Morgensztern D, et al. Changing Epidemiology of Small-Cell Lung Cancer in the United States Over the Last 3 Years: Analysis of the Surveillance, Epidemiologic, and End Results Database. J Clin Oncol 26;24; Hanna N, Bunn PA, Jr., Langer C, et al. Randomized phase III trial comparing irinotecan/cisplatin with ebottomoside/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 26;24: Eckardt JR, von Pawel J, Papai Z, et al. Open-label, multicenter, randomized, phase III study comparing oral bottomotecan/cisplatin versus ebottomoside/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer. J Clin Oncol 26;24: Socinski MA, Weissman C, Hart LL, et al. Randomized phase II trial of pemetrexed combined with either cisplatin or carboplatin in untreated extensive-stage small-cell lung cancer. J Clin Oncol 26;24: Niell HB, Herndon JE, 2nd, Miller AA, et al. Randomized phase III intergroup trial of ebottomoside and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial J Clin Oncol 25;23: Greco FA, Thompson DS, Morrissey LH, et al. Paclitaxel/carboplatin/ ebottomoside versus paclitaxel/bottomotecan for extensive-stage small cell lung cancer: a Minnie Pearl Cancer Research Network randomized, prospective phase II trial. Oncologist 25;1: Heinrich MC, Blanke CD, Druker BJ, et al. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KITpositive malignancies. J Clin Oncol 22;2: Rossi G, Cavazza A, Marchioni A, et al. Kit expression in small cell carcinomas of the lung: effects of chemotherapy. Modern Pathol 23; 16: Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 22;347: Dy GK, Miller AA, Mandrekar SJ, et al. A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study. Ann Oncol 25;16: Johnson BE, Fischer T, Fischer B, et al. Phase II study of imatinib in patients with small cell lung cancer. Clin Cancer Res 23;9: Krug LM, Crapanzano JP, Azzoli CG, et al. Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: a phase II clinical trial. Cancer 25;13: Hirose T, Horichi N, Ohmori T, et al. Phase II study of irinotecan and carboplatin in patients with the refractory or relapsed small cell lung cancer. Lung Cancer 23;4: Kinoshita A, Fukuda M, Soda H, et al. Phase II study of irinotecan combined with carboplatin in previously untreated small-cell lung cancer. Br J Cancer 26;94: Schmittel A, Fischer von Weikersthal L, Sebastian M et al. A randomized phase II trial of irinotecan plus carboplatin versus ebottomoside plus carboplatin treatment in patients with extended disease small-cell lung cancer. Ann Oncol 26;17: Spigel DR, Greco FA. Evolving role of irinotecan in small-cell lung cancer. Clin Adv Hematol Oncol 23;1: Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2;92: Jones SF, Burris HA, 3rd, Hainsworth JD, et al. Phase I. Trial of irinotecan plus carboplatin in two dose schedules. Oncology (Huntington) 23;17(5 Suppl 5): Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7: Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53: Mantel N, Haenszel W. Statistical aspects of the analyses of data from the retrospective study of disease. J Natl Cancer Inst 1959;27: Bono P, Krause A, von Mehren M, et al. Serum KIT and KIT ligand levels in patients with gastrointestinal stromal tumors treated with imatinib. Blood 24;13: Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279: Lux ML, Rubin BP, Biase TL, et al. KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am J Pathol 2;156: Rohr UP, Rehfeld N, Pflugfelder L, et al. Expression of the tyrosine kinase c-kit is an independent prognostic factor in patients with small cell lung cancer. Int J Cancer 24;111: Camps C, Sirera R, Bremnes RM, et al. Analysis of c-kit expression in small cell lung cancer: prevalence and prognostic implications. Lung Cancer 26;52: Plummer H, 3rd, Catlett J, Leftwich J, et al. c-myc expression correlates with suppression of c-kit protooncogene expression in small cell lung cancer cell lines. Cancer Res 1993;53: Sekido Y, Obata Y, Ueda R, et al. Preferential expression of c-kit protooncogene transcripts in small cell lung cancer. Cancer Res 51: Sekido Y, Takahashi T, Ueda R, et al. Recombinant human stem cell factor mediates chemotaxis of small-cell lung cancer cell lines aberrantly expressing the c-kit protooncogene. Cancer Res 1993;53: Krystal GW, Hines SJ, Organ CP. Autocrine growth of small cell lung 86 Copyright 27 by the International Association for the Study of Lung Cancer

8 Journal of Thoracic Oncology Volume 2, Number 9, September 27 Irinotecan, Carboplatin, Imatinib in SCLC cancer mediated by coexpression of c-kit and stem cell factor. Cancer Res 1996;56: Tamborini E, Bonadiman L, Negri T, et al. Detection of overexpressed and phosphorylated wild-type kit receptor in surgical specimens of small cell lung cancer. Clin Cancer Res 24;1: Boldrini L, Ursino S, Gisfredi S, et al. Expression and mutational status of c-kit in small-cell lung cancer: prognostic relevance. Clin Cancer Res 24;1: Micke P, Basrai M, Faldum A, et al. Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications. Clin Cancer Res 23;9: Naeem M, Dahiya M, Clark JI, et al. Analysis of c-kit protein expression in small-cell lung carcinoma and its implication for prognosis. Hum Pathol 22;33: Yamanishi Y, Maeda H, Hiyama K, et al. Specific growth inhibition of small-cell lung cancer cells by adenovirus vector expressing antisense c-kit transcripts. Jpn J Cancer Res 1996;87: Johnson FM, Krug LM, Tran HT, et al. Phase I studies of imatinib mesylate combined with cisplatin and irinotecan in patients with small cell lung carcinoma. Cancer 26;16: APPENDIX: MINNIE PEARL CANCER RESEARCH NETWORK PARTICIPATING SITES Tennessee Oncology, PLLC, Nashville, TN; Clearview Cancer Institute, Huntsville, AL; Wellstar Health System Cancer Research, Marietta, GA; Consultants in Blood Disorders and Cancer, Louisville, KY; Louisiana Oncology Associates, Lafayette, LA; Grand Rapids Clinical Oncology Program, Grand Rapids, MI; ICON Florida Oncology Associates, Orange Park, FL; Northeast Alabama Regional Medical Center, Anniston, AL; Oncology & Hematology Associates of SW Virginia, Roanoke, VA; Thompson Cancer Survival Center, Knoxville, TN; Central Georgia Cancer Care, P.C., Macon, GA; Consultants in Medical Oncology & Hematology, P.C., Drexel Hill, PA; Kingsport Hematology-Oncology Associates, Kingsport, TN; Florida Cancer Specialists, Fort Myers, FL. Copyright 27 by the International Association for the Study of Lung Cancer 861