Small cell lung cancer (SCLC) accounts for 13 to 15% of

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1 ORIGINAL ARTICLE Randomized Phase II Study of Maintenance Irinotecan Therapy Versus Observation Following Induction Chemotherapy with Irinotecan and Cisplatin in Extensive Disease Small Cell Lung Cancer Ji-Youn Han, MD, Heung Tae Kim, MD, Kun Young Lim, MD, Sung Jin Yoon, RN, Dae Ho Lee, MD, and Jin Soo Lee, MD Introduction: To determine whether irinotecan maintenance therapy in extensive disease-small cell lung cancer can improve survival of patients who responded to irinotecan plus cisplatin (IP) induction therapy. Methods: A total of 120 chemo-naive patients with adequate organ functions and Eastern Cooperative Oncology Group performance status of 0 to 2 were enrolled from March 2003 through April After IP induction therapy, with either schedule A (I: 60 mg/m 2 intravenously (IV) on days 1, 8, and 15; P: 30 mg/m 2 IV on days 1 and 8, every 4 weeks for six cycles) or schedule B (I: 60 mg/m 2 and P: 30 mg/m 2 IV on days 1, and 8, every 3 weeks for eight cycles), responding patients were randomized to either maintenance with irinotecan 100 mg/m 2 IV on days 1, 8, and 15, every 4 weeks up to six cycles, or observation. Results: Overall, 100 (83%) of 120 patients achieved objective tumor responses (12 complete responses, 88 partial responses) after IP induction therapy. Of those patients who remained in remission upon completion of planned cycles of induction therapy, 45 were randomized to maintenance (n 21) or observation (n 24). Median progression-free survival (PFS) and overall survival (OS) for all patients were 7.2 and 14.0 months, respectively. For the maintenance arm, median PFS and OS were 12.0 and 17.6 months, respectively. For the observation arm, median PFS and OS were 9.9 and 20.5 months, respectively, which was not significantly different from the maintenance arm. Conclusions: IP chemotherapy is very useful for the treatment of small cell lung cancer. However, maintenance irinotecan therapy did not seem to further affect the clinical outcome of patients who had responded to IP induction therapy. Key Words: Maintenance chemotherapy, SCLC, irinotecan. (J Thorac Oncol. 2008;3: ) Research Institute and Hospital, National Cancer Center, Goyang, Korea. Disclosure: The authors declare that no conflict of interest exists for any of the authors. Address for correspondence: Jin Soo Lee, MD, Lung Cancer Branch, National Cancer Center, 809 Madu-dong, Ilsan-gu, Goyang, Gyeonggi , Korea. jslee@ncc.re.kr Copyright 2008 by the International Association for the Study of Lung Cancer ISSN: /08/ Small cell lung cancer (SCLC) accounts for 13 to 15% of all lung cancer and more than 60 to 70% of patients present with extensive disease (ED). 1 Although etoposide plus cisplatin (EP) regimen has been the mainstay of ED- SCLC treatment, median survival is about 9 months, with 5 to 10% surviving 2 years and only 1% of patients achieving a long-term disease-free survival. 2 To improve this outcome further, various attempts have been made, which included dose intensification with stem cell supports, 3,4 maintenance chemotherapy, 5 19 and also searches for a better chemotherapy regimen. 20 Irinotecan has been demonstrated to have significant activity against SCLC and a phase II trial conducted by the West Japan Thoracic Oncology Group showed irinotecan plus cisplatin (IP) regimen had promising results. For previously untreated patients with ED-SCLC, the objective response rate was 86% with complete response (CR) rate of 26%. 21 A subsequent randomized phase III from the Japanese Cooperative Oncology Group reported a statistically superior benefit of IP combination over the standard EP chemotherapy. The median survival and 2-year survival rates on IP and EP arms were 12.8 months versus 9.4 months and 19.5% versus 5.2%, respectively. 22 From a separate randomized phase III trial, however, Hanna et al. 23 reported no significant difference between IP and EP in response rate and survival in 331 patients enrolled from the United States, Australia, and Canada. On the other hand, Hermes et al. reported in 2007 a randomized phase III study of irinotecan plus carboplatin versus etoposide plus carboplatin in 220 Norwegian and Swedish patients with ED-SCLC. Similar to the Japanese Cooperative Oncology Group data, they found a statistically significant difference in overall survival (OS) in favor of the irinotecan-containing regimen. Moreover, significantly more CRs were observed with irinotecan plus carboplatin therapy. 24 These findings suggest that irinotecan plus platinum agent chemotherapy can improve the survival of ED-SCLC. Regarding the role of maintenance chemotherapy in SCLC, there have been about 14 randomized phase III trials since Although its role remains unresolved until recently and quite controversial, at least five studies had found better progression-free survival (PFS) with maintenance chemotherapy 12,15,16,18,19 and three trials demonstrated Journal of Thoracic Oncology Volume 3, Number 9, September

2 Han et al. Journal of Thoracic Oncology Volume 3, Number 9, September 2008 statistically significant advantage for OS with maintenance chemotherapy when only the patients who achieved objective responses to induction chemotherapy were included. 6,8,14 Given the documented contribution of irinotecan in the treatment of SCLC, we postulated that irinotecan maintenance therapy might improve the outcome of ED-SCLC patients who achieved objective responses after IP induction therapy. Therefore, we conducted a randomized phase II trial to examine whether the irinotecan maintenance therapy would improve the survival of ED-SCLC patients who responded to IP induction chemotherapy. PATIENTS AND METHODS Eligibility criteria were as follows: (1) histologically confirmed SCLC; (2) extensive-stage disease; (3) Eastern Cooperative Oncology Group performance status (PS) of 0 to 2; (4) age 18 years old; (5) adequate function of bone marrow (white blood cell count 4000/mm 3 and platelet count 100,000/mm 3 ), liver (bilirubin level 1.5 mg/dl, AST, and ALT 2 the upper limit of normal), and kidney (creatinine level 1.5 mg/dl); (6) at least one bidimensionally measurable disease; (7) absence of active infection; (8) no prior chemotherapy or radiotherapy; (9) no history of myocardial infarction in the last 6 months, no congestive heart failure or significant arrhythmia; (10) no second primary cancer, except skin cancer. Patients with CNS metastasis were eligible as long as neurologic symptoms were controlled by corticosteroid. All patients signed informed consent. The study was approved by the institutional review board of our institution and was conducted in compliance with institutional review board regulations. Treatment Treatment was given in the outpatient setting, the schema of which is shown in Figure 1. The first 40 patients were treated with irinotecan 60 mg/m 2 intravenously (IV) on days 1, 8, and 15, and cisplatin 30 mg/m 2 IV on days 1 and 8 of a 28-day cycles (schedule A). Because of frequent omission of day 15 irinotecan and delay in the next cycle of chemotherapy, next 80 patients were treated with irinotecan 60 mg/m 2 and cisplatin 30 mg/m 2 IV on days 1 and 8 of a 21-day cycle (schedule B). Patients received IP indu chemotherapy up to maximum six (schedule A) or eight cycles (schedule B) for a total of 24 weeks unless there were disease progression or undue toxicity. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. Response assessment was performed every three cycles or whenever clinically indicated according to the World Health Organization criteria. Approximately 3 to 4 weeks after the last course of induction IP chemotherapy, responding patients were randomized to receive either irinotecan maintenance or observation alone. Stratification factors were response to induction chemotherapy [CR versus partial response (PR)] and number of metastasis site (0 1 versus 2 or more). Previously a phase I study reported that the recommended dose of single-agent irinotecan was 100 to 125 mg/m 2 once a week. 25 Additionally, Masuda used irinotecan 100 mg/m 2 every week to treat Induction chemotherapy Schedule A (n=40) Irinotecan (60 mg/m 2 ) IV on day 1, 8, & 15 Cisplatin (30 mg/m 2 ) IV on day 1 & 8 Every 4 weeks X 6 cycles or Schedule B (n=80) Irinotecan (60 mg/m 2 IV on day 1 & 8 Cisplatin (30 mg/m 2 ) IV on day 1 & 8 Every 3 weeks X 8 cycles CR or PR (n=100) Treatment failure (SD or PD/death ) (n=20) Randomization (n=45) Stratified by; CR v PR No of metastasis 0 or 1 v 2 or more Non-randomization (n=55) PD after 1 st evaluation Toxicity Patients refusal FIGURE 1. Study scheme. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. Observation (n=24) or Maintenance (n=21) Irinotecan (100 mg/m2) IV on day 1, 8, & 15 Every 4 week X 6 cycles Off study (n=75) 1040 Copyright 2008 by the International Association for the Study of Lung Cancer

3 Journal of Thoracic Oncology Volume 3, Number 9, September 2008 Irinotecan Maintenance Chemotherapy in ED-SCLC 16 patients with refractory or relapsed SCLC, and 7 of 15 evaluable patients responded to irinotecan. 26 Based on these data, patients received irinotecan 100 mg/m 2 IV on days 1, 8, and 15, every 4 weeks up to six cycles as the maintenance therapy. Follow-up consisted of physical examination, blood cell counts, and chest radiographs every cycle and chest CT every three cycles. The same follow-up was applied to both arms when treatment was terminated. Choice of subsequent treatment for progression was left to the discretion of the investigator. Statistical Analysis Patients were randomized to one of two treatment arms (maintenance or observation) following irinotecan/cisplatin induction in equal proportions using a stratified permuted block randomization. Patients were stratified according to response to induction chemotherapy (CR versus PR) and number of metastasis site (0 or 1 versus 2 or more). The primary endpoint of the study was PFS. The secondary end point was evaluation of the toxicity to maintenance irinotecan following irinotecan/cisplatin induction chemotherapy and OS. This trial was designed to detect an increase in median PFS from 7 to 12 months in responding patients receiving maintenance chemotherapy ( 0.05, 0.02, one-tailed test) and required accrual of 50 assessable patients for each arm. Assuming the objective response rate of 85%, we initially planned accrue a total of 120 patients. Survival time and PFS were defined from the date on which the study began until date of death (or date last seen) or date of progression, respectively. Survival curves were constructed using the Kaplan Meier product limit method. RESULTS Patients From March 2003 through April 2006, 120 patients were entered in this trial. Patients characteristics are listed in Table 1. Out of 100 responding patients (CR or PR), 63 patients maintained objective tumor responses after a total of six or eight cycles of IP induction therapy. The other 37 initially responding patients became not eligible for randomization because of disease progression during induction therapy. Among 63 patients maintaining tumor responses, 45 patients were randomized to either maintenance irinotecan single therapy or observation. The other 18 patients were not randomized for the following reasons: 14 patients refusal due to either declined PS or toxicities, and 4 due to follow-up loss. Twenty-one patients were randomized to irinotecan maintenance arm and 24 were to observation arm. Patient characteristics at the time of randomization are also depicted in Table 1. Treatment Delivery The median number of induction IP chemotherapy cycles delivered was six (range, 1 8). By treatment schedule, 80% (32/40) of patients completed six cycles of IP chemotherapy in schedule A. In schedule B, 38% (30/80) of patients completed eight cycles and 63% (50/80) of patients received more than six cycles of IP chemotherapy. The reasons for treatment discontinuation were disease progression (5% for schedule A, 34% for TABLE 1. Characteristics Patients Characteristics Total (n 120) n (%) Maintenance (n 21) n (%) Observation (n 24) n (%) Age, median (range) 63 (33 79) 63 (51 77) 63 (51 77) Sex Male 107 (89) 19 (91) 23 (96) Female 13 (11) 2 (9) 1 (4) ECOG PS 0 24 (20) 4 (19) 4 (17) 1 64 (53) 12 (57) 16 (66) 2 32 (27) 5 (24) 4 (17) No. of metastatic sites 1 68 (57) 16 (76) 18 (75) 1 52 (43) 5 (24) 6 (25) Induction schedule Every 4 wk 40 (33) 11 (52) 13 (54) Every 3 wk 80 (67) 10 (48) 11 (56) Response to induction CR 12 (10) 4 (19) 6 (25) PR 88 (73) 17 (81) 18 (75) SD 3 (3) 0 0 PD 5 (4) 0 0 NA 12 (10) NA, nonassessable. schedule B), toxicity (5% for schedule A, 23% for schedule B), and follow-up loss (10% for schedule A, 6% for schedule B). The median number of maintenance irinotecan single chemotherapy cycles delivered was three (range, 1 6). Only 5 of 21 (24%) of patients completed all six cycles. The remaining patients did not complete maintenance irinotecan therapy because of PD (nine), pneumonia (two), poor PS (two), prolonged thrombocytopenia (one), acute myocardial infarction (one), and patient s refusal (one). Toxicity One hundred nineteen patients were included in evaluation of toxicity of induction IP chemotherapy. Overall, toxicity of induction therapy with IP was similar to our previous report. 4 Myelosuppression was the most common grade 3 or 4 toxicity and grade 3 diarrhea developed in 13 (12%) patients (Table 2). There were five treatment-related deaths (4%) that occurred after the first cycle of IP, three due to sepsis with neutropenia, and two due to pneumonia. Maintenance with irinotecan was well tolerated. Myelosuppression was the most common grade 3 or 4 toxicity, with anemia reported in 28.6% of patients and granulocytopenia in 28.6% of patients (Table 3). Nonhematologic toxicity was mild. There was no treatment-related death during maintenance irinotecan therapy. Response Of a total 120 patients, 12 patients (10%) achieved CR and 88 patients (73%) achieved a PR, for an overall response rate of 83%. Three patients (3%) maintained SD, and 17 Copyright 2008 by the International Association for the Study of Lung Cancer 1041

4 Han et al. Journal of Thoracic Oncology Volume 3, Number 9, September 2008 TABLE 2. Maximal Hematologic and Nonhematologic Toxicity of Induction Chemotherapy per Patient (n 119) Grade by NCI-CTC Version n (%) n (%) n (%) n (%) n (%) Hematologic toxicity Neutropenia 6 (5.0) 4 (3.4) 33 (27.7) 52 (43.7) 24 (20.2) Anemia 4 (3.4) 27 (22.7) 59 (49.6) 28 (23.5) 1 (0.8) Thrombocytopenia 49 (41.2) 43 (36.1) 17 (14.3) 9 (7.6) 1 (0.8) Nonhematologic toxicity Infection (without neutropenia) 113 (95.0) 0 (0) 0 (0) 3 (2.5) 3 (2.5) Infection (with neutropenia) 116 (97.5) 0 (0) 0 (0) 1 (0.8) 2 (1.7) AST 87 (73.1) 29 (24.4) 1 (0.8) 1 (0.8) 1 (0.8) ALT 83 (69.7) 29 (24.4) 4 (3.4) 2 (1.7) 1 (0.8) Asthenia 2 (1.7) 29 (24.4) 85 (24.4) 3 (2.5) 0 (0.0) Alopecia 11 (9.2) 73 (61.3) 35 (2.94) 0 (0.0) 0 (0.0) Anorexia 0 (0.0) 40 (33.6) 74 (62.2) 5 (4.2) 0 (0.0) Nausea/vomiting 8 (6.7) 32 (26.9) 78 (65.6) 0 (0.0) 0 (0.0) Constipation 49 (41.2) 31 (26.1) 30 (26.1) 9 (7.6) 0 (0.0) Creatinine 82 (68.9) 35 (29.4) 1 (0.8) 1 (0.8) 0 (0.0) Diarrhea 21 (17.6) 49 (41.2) 35 (29.4) 14 (11.7) 0 (0.0) Mucositis 43 (36.1) 54 (45.4) 21 (17.6) 1 (0.8) 0 (0.0) TABLE 3. Maximal Hematologic and Nonhematologic Toxicity of Maintenance Chemotherapy per Patient (n 21) Grade by NCI-CTC Version n (%) n (%) n (%) n (%) n (%) Hematologic toxicity Neutropenia 3 (14.3) 4 (19.0) 8 (38.1) 1 (4.8) 5 (23.8) Anemia 1 (4.8) 6 (28.6) 8 (38.1) 6 (28.6) 0 (0.0) Thrombocytopenia 8 (38.1) 10 (47.6) 3 (14.3) 0 (0.0) 0 (0.0) Nonhematologic toxicity Infection (without neutropenia) 20 (95.2) 0 (0.0) 0 (0.0) 1 (4.8) 0 (0.0) Infection (with neutropenia) 20 (95.2) 0 (0.0) 0 (0.0) 1 (4.8) 0 (0.0) AST 18 (85.7) 2 (9.5) 1 (4.8) 0 (0.0) 0 (0.0) ALT 20 (95.2) 0 (0.0) 1 (4.8) 0 (0.0) 0 (0.0) Asthenia 1 (4.8) 8 (38.1) 12 (57.1) 0 (0.0) 0 (0.0) Alopecia 1 (4.8) 7 (33.3) 13 (61.9) 0 (0.0) 0 (0.0) Anorexia 1 (4.8) 6 (28.6) 14 (66.7) 0 (0.0) 0 (0.0) Nausea/vomiting 6 (28.6) 2 (9.5) 13 (61.9) 0 (0.0) 0 (0.0) Constipation 12 (57.1) 6 (28.6) 3 (14.3) 0 (0.0) 0 (0.0) Creatinine 11 (52.4) 10 (47.6) 0 (0.0) 0 (0.0) 0 (0.0) Diarrhea 4 (19.0) 7 (33.3) 9 (42.9) 1 (4.8) 0 (0.0) Mucositis 15 (71.4) 5 (23.8) 1 (4.8) 0 (0.0) 0 (0.0) patients (14%) had treatment failure, which include 5 patients who developed PD during IP chemotherapy, 7 who stopped therapy due to toxicity or noncompliance, and 5 patients who died during the first cycle of IP chemotherapy. Of the 21 patients randomized to maintenance irinotecan therapy, all were evaluable for response: 2 remain in CR, 7 remained in PR, whereas 12 had PD during the 6-month period of maintenance irinotecan therapy. In the observation arm (n 24), 2 remained in CR, 3 remained in PR, whereas 19 had PD during the same 6-month period (Table 4). Survival After median follow-up of 39.1 month (range, ), 19 of 120 patients were known alive at the time of this report. Median OS for all patients was 14 months [95% confidence interval (CI), ] with 1- and 2-year sur Copyright 2008 by the International Association for the Study of Lung Cancer

5 Journal of Thoracic Oncology Volume 3, Number 9, September 2008 Irinotecan Maintenance Chemotherapy in ED-SCLC TABLE 4. Responses During Maintenance Irinotecan Single Therapy Versus Observation Maintenance (n 21) No. of Patients Observation (n 24) Maintained CR 2 2 Maintained PR 7 3 Achieved CR from induction PR 0 0 PD TABLE 5. Times Median Progression-Free and Overall Survival PFS (95% CI) OS (95% CI) Overall n 120 n 120 Median (mo) 7.2 ( ) 14.0 ( ) 1 yr (%) 20.3 ( ) 59.2 ( ) 2 yr (%) 6.2 ( ) 17.8 ( ) Randomization maintenance n 21 n 21 Median (mo) 12.0 ( ) 17.6 ( ) 1 yr (%) 47.6 ( ) 85.7 ( ) 2 yr (%) 19.6 ( ) Observation n 24 n 24 Median (month) 9.9 ( ) 20.5 ( ) 1 yr (%) 29.2 ( ) 83.3 ( ) 2 yr (%) 33.7 ( ) FIGURE 2. Kaplan Meier plot for time to progression by randomization. PFS, progression-free survival; OS, overall survival. vival rates were 59.2% (95% CI, ) and 17.8% (95% CI, ), respectively, as shown in Table 5. Median PFS was 7.2 months (95% CI, ) with 1- and 2-year PFS rates were 20.3% (95% CI, ) and 6.2% (95% CI, ), respectively. Figures 2 and 3 show the progression-free and OS curves for the patients who participated in the maintenance versus observation study. Second-Line Therapy Overall, 77 patients received salvage chemotherapy after PD, including 14 of 21 patients (66.7%) in the maintenance arm, and 19 of 24 patients (79.2%) in the observation arm. The most commonly used regimens were IP, AIV (adriamycin, ifosfamide, and vincristine), CAV (cyclophosphamide, adriamycin, and vincristine), etoposide and cisplatin, paclitaxel and gemcitabine, and others. Table 6 summarized the commonly used second-line treatments and their response rates. DISCUSSION Encouraged by a phase III trial results that had showed better survival outcome after IP chemotherapy when compared with EP, we previously reported promising activity of IP regimen for LD-SCLC and also for ED-SCLC. 27,28 In this study, overall response rate was 83% with a CR rate of 10%. The median survival was 14 months (95% CI, ) with 1- and 2-year survival rates of 59.2 and 17.8%. The median PFS was 7.2 months with 1- and 2-year PFS rates of FIGURE 3. Kaplan Meier plot for overall survival by randomization and 6.2%. These results are comparable with those of two studies of IP regimen for ED-SCLC, which have reported a median survival time of 13 and 12.8 months. 21,22 In addition, they are better than those of recent standard EP chemotherapy. Two recent studies of EP regimen have reported a median survival of 8.9 and 10.2 months. 22,23 Indeed, these findings suggest that there was significant progress in the treatment of SCLC with the introduction of IP regimen. Copyright 2008 by the International Association for the Study of Lung Cancer 1043

6 Han et al. Journal of Thoracic Oncology Volume 3, Number 9, September 2008 TABLE 6. Second-Line Treatment Overall (n 77) Randomization Maintenance (n 14) Observation (n 19) Nonrandomization (n 44) n RR (%) n RR (%) n RR (%) n RR (%) IP 25 8 (32.0) (33.3) 9 3 (33.3) AIV 22 6 (27.3) 6 1 (16.7) (33.3) CAV 13 5 (38.5) 3 2 (66.7) (33.3) EP 8 3 (37.5) 1 1 (100) (33.3) PG 6 4 (66.7) 2 2 (100) (66.7) PC VIP RR, response rate; IP, irinotecan and cisplatin; AIV, adriamycin, ifosfamide, and vincristine; CAV, cyclophosphamide, adriamycin, and vincristine; EP, etoposide and cisplatin; PG, paclitaxel and gemcitabine; PC, paclitaxel and carboplatin; VIP, vincristine, ifosfamide, and cisplatin. Nevertheless, irinotecan maintenance therapy for responding patients after six or eight cycles of induction IP chemotherapy did not further influence either PFS or OS in this study. The role of maintenance chemotherapy in patients with SCLC has been debated for many years. So far, three randomized trials have shown a survival benefit of maintenance chemotherapy. 6,8,14 Interestingly, two of them used different chemotherapy regimens, CAV regimen for induction therapy and EP regimen for maintenance therapy. 8,14 These findings suggest that addition of a noncross resistant regimen as maintenance therapy may improve the therapeutic efficacy. In addition, five trials have found improved PFS. 12,15,16,18,19 Nevertheless, most studies failed to detect a benefit for maintenance chemotherapy. 7,9 11,13,14,17 Nevertheless, a recent meta-analysis on maintenance therapy in SCLC revealed that maintenance therapy improved 1- and 2-year OS by 9% (from 30 to 39%) and 4% (from 10 to 14%), respectively. Similarly, 1- and 2-year PFS were also improved. 29 This finding suggests that some questions about the role of maintenance chemotherapy in SCLC are still awaiting more definite answers. The emergence of novel targeted agents with different action mechanisms makes the questions more interesting and has recently been proposed as possible alternatives to maintenance chemotherapy. Interferons, 30,31 metalloproteinase inhibitors, 32 and thalidomide, 33 have been evaluated as maintenance therapy in SCLC, however, failed to prolong survival of patients with SCLC. Our result regarding the role of maintenance irinotecan therapy in ED-SCLC patients deserves a word of caution since full patients accrual target was not reached. The optimum number of chemotherapy in ED-SCLC has not been clearly defined yet. General consensus is that there is no obvious improvement in survival when the duration of drug administration exceeds 6 months. 5 Indeed, most randomized trials of maintenance chemotherapy consisted of four to six cycles of induction chemotherapy In the current study, initial 40 patients received six cycles of 4-week IP induction. Because of frequent omission of day 15 irinotecan and delay in the next cycle of chemotherapy, we changed the schedule as a 3-week cycle using the same doses of irinotecan and cisplatin on days 1 and 8. Instead we increased the number of induction therapy from six to eight cycles to match the whole duration of induction therapy. Because of the study design in which randomization took place after six or eight cycles of induction therapy, many patients became not eligible for randomization because they went off study mainly due to disease progression during the initial six to eight cycles of induction therapy, especially among those patients treated on schedule B. It is interesting to note that 32 (80%) of 40 patients treated with schedule A received all six cycles of induction therapy, whereas only 30 (38%) of 80 patients treated with schedule B received all eight cycles of induction therapy. It was quite unexpected to see many patients in schedule B developed PD by the time of response re-evaluation after six cycles of IP chemotherapy. This was the major reason why we could not accrue the target sample size to examine the role of irinotecan maintenance therapy even though we completed the patient accrual as initially planned. Although our study did not demonstrate the survival benefit of irinotecan maintenance therapy over six or eight cycles of IP induction therapy, IP chemotherapy seems to be associated with better survival than old regimens in SCLC. Therefore, the value of irinotecan single or IP regimen as maintenance should be evaluated in larger number of patients with adequate power. In summary, although IP chemotherapy showed significant activity and favorable survival outcome in SCLC, maintaining irinotecan as a single therapy in patients with objective tumor responses after six or eight cycles of IP chemotherapy failed to show any additional survival benefit. ACKNOWLEDGMENTS Supported in part by NCC grants NCC and NCC REFERENCES 1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics. CA Cancer J Clin 2007;57: Ettinger D, Johnson B. Update: NCCN small cell and non-small cell lung cancer clinical practice guidelines. J Natl Compr Cancer Net 2005;3:S17 S Woll PJ, Thatcher N, Lomax L, et al. Use of hematopoietic progenitors in whole blood to support dose-dense chemotherapy: a randomized phase II trial in small-cell lung cancer patients. J Clin Oncol 2001;19: Leyvraz S, Perey L, Rosti G, et al. Multiple courses of high-dose ifosfamide, carboplatin, and etoposide with peripheral-blood progenitor 1044 Copyright 2008 by the International Association for the Study of Lung Cancer

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