Efficacy and Toxicity of Belotecan for Relapsed Or Refractory Small Cell Lung Cancer Patients

View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector Original Article

Efficacy and Toxicity of Belotecan for Relapsed or Refractory Small Cell Lung Cancer Patients

Gun Min Kim, MD,*† Young Sam Kim, MD, PhD,† Young Ae Kang, MD, PhD,† Jae-Heon Jeong, MD,‡ Sun Mi Kim, PhD,§ Yun Kyoung Hong, MS,|| Ji Hee Sung, MS,|| Seung Taek Lim, MD,† Joo Hang Kim, MD, PhD,*† Se Kyu Kim, MD, PhD,† and Byoung Chul Cho, MD, PhD,*†

mall cell lung cancer (SCLC) comprises approximately Introduction: Belotecan (Camtobell, CKD602) is a new camp- 15% of all lung cancers and is strongly associated with tothecin-derivative antitumor agent that belongs to the topoi- S smoking.1 SCLC is highly responsive to initial chemotherapy somerase inhibitors. The aim of this study was to evaluate the or radiotherapy. However, approximately 80% of the limited- efficacy and safety of belotecan monotherapy as a second-line stage and nearly all extensive-stage patients develop recur- therapy in patients with relapsed or refractory small cell lung can- rence. The patients who relapse after initial chemotherapy cer (SCLC). have a poor prognosis. The median survival is 2 to 3 months Methods: Between June 2008 and August 2011, a total of 50 patients for the patients who do not receive salvage therapy.2 The with relapsed or refractory SCLC were treated with belotecan 0.5mg/ 2 results of second-line chemotherapy are also disappointing, m for 5 consecutive days, every 3 weeks. We evaluated the overall with low response rates and short survival times.3 response rate (ORR), the progression-free survival (PFS), and the The efficacy of salvage chemotherapy depends on the overall survival (OS), and toxicity according to sensitivity to initial response and the duration of the response to initial chemo- chemotherapy. therapy. The patients who recur more than 3 months after Results: The median age was 66 years (range, 43–84 years) and completion of the initial therapy are often termed as “sensitive Eastern Cooperative Oncology Group performance was 0 or 1 in 34 relapse” patients. In contrast, the patients whose tumor does patients (68%) and 2 in 16 patients (32%). Twenty patients (40%) not respond or progress through treatment or who develop a had sensitive relapse and 30 patients (60%) had refractory disease. recurrence within 3 months after completion of initial therapy The ORR, PFS, and OS for sensitive patients were 20% (95% confi- are considered to be “refractory or resistant relapse” patients. dence interval [CI], 8–40), 2.8 months (95% CI, 0.53–5.06), and 6.5 Refractory patients have a dismal prognosis, with a survival of months (95% CI, 1.58–11.42), respectively. In the refractory group, 3 to 5 months and overall response rates (ORRs) of approxi- the ORR, PFS, and OS were 10% (95% CI, 1–21), 1.5 months (95% mately 10% or less.4 CI, 1.25–1.75), and 4.0 months (95% CI, 3.40–4.60), respectively. Currently, topotecan is the only drug approved for sin- Most commonly reported grade-3 or -4 adverse events included neu- gle-agent second-line SCLC treatment in the United States and tropenia (54%), thrombocytopenia (38%), and anemia (32%). is considered the standard second-line regimen in many coun- Conclusion: Belotecan showed modest activity with an acceptable tries. Topotecan showed an ORR of 24% and a median over- safety profile as a second-line therapy in patients with relapsed or all survival (OS) of 6 months in sensitive patients. However, refractory SCLC. topotecan seems to have only minimal activity in refractory Key Words: Belotecan, Relapsed, Refractory, Small cell lung disease, producing ORRs of 4 to 12% and an OS of 3.4 to 4-6 cancer. 5.8 months. In terms of toxicity, topotecan showed significant adverse events, including grade-3 or -4 myelosuppression (J Thorac Oncol. 2012;7: 731–736) (neutropenia, 86–89%, thrombocytopenia, 43–57%, and anemia 31–40%), diarrhea (6–8%), and fatigue (5–8%).4-8 More recently, amrubicin has shown favorable efficacy in relapsed *Department of Medical Oncology, Yonsei Cancer Center, †Department of Internal Medicine, Yonsei University College of Medicine, Seoul, SCLC patients (ORR, 17–60%, median survival, 5.3–12 9 Korea; ‡Department of Medical Oncology and Hematology, Kyung-Hee months) and is also currently in phase-III clinical evaluations. University School of Medicine, Seoul, Korea; §Brain Korea 21 Project for 12 Therefore, the development of new strategies for the man- Medical Sciences, Yonsei University College of Medicine, Seoul, Korea; agement of this disease is urgently needed. and JE UK Institute for Cancer Research, Gumi City, Kyungbuk, Korea. Disclosure: The authors declare no conflicts of interest. Belotecan (Camtobell, CKD602, 7-[-2(N-isopropy Address for correspondence: Byoung Chul Cho MD, PhD, Yonsei Cancer lamino)ethyl]-(20S)-camptothecin, Chong Keun Dang Corp., Center, Division of Medical Oncology, Yonsei University College of Seoul, Korea) is a new camptothecin analog, in which a Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120–752, Korea. E-mail: water-solubilizing group is introduced at the position of the B [email protected] 13 Copyright © 2012 by the International Association for the Study of Lung ring. In the preclinical studies, belotecan was a more potent Cancer topoisomerase-I inhibitor and had superior antitumor activity ISSN: 1556-0864/12/0704-0731 compared to other camptothecin agents including topotecan.

Journal of Thoracic Oncology • Volume 7, Number 4, April 2012 731 Kim et al. Journal of Thoracic Oncology • Volume 7, Number 4, April 2012

Recently, several phase-II trials showed that belotecan was ment by the physician, and unacceptable toxicity which makes active and well tolerated as a single agent or in combination treatment interruption for more than 3 weeks. with cisplatin in untreated patients with SCLC.14 17 Two phase- II trials of belotecan in second-line treatment of SCLC also Evaluation showed modest efficacy and tolerable toxicity.18,19 However, All patients underwent a history-taking and physical these two studies had a small number of patients and had little examination, including documentation of concomitant medi- data for refractory patients. One had only sensitive-relapsed cations, performance status, and history of smoking, labora- patients (n = 27) and the other study (n = 25) had no infor- tory tests (complete blood count, biochemistry profile, and mation on the type of relapse. Therefore, we evaluated the urinalysis), and computed tomography scans of chest and efficacy and toxicity of belotecan as a second-line chemother- abdomen electrocardiogram before the start of belotecan apy for a relatively large number of patients with relapsed or monotherapy. Tumor assessments were carried out once every refractory SCLC. two cycles. Toxicity was assessed twice every cycle (D+1 and D+14). Tumor response was assessed by the Response PATIENTS AND METHODS Evaluation Criteria in Solid Tumors version 1.0. Data Source and Analytic Variables Statistical Consideration Between June 2008 and August 2011, we identified 56 We analyzed the ORR, PFS, OS, and toxicity profiles. patients who received belotecan monotherapy for refractory or The distribution of baseline patient characteristics and a relapsed SCLC at the Yonsei Cancer Center, Seoul, Korea. We relapse pattern was evaluated by using Mantel-Haenszel 2 excluded one patient who received the first-line chemotherapy tests for categorical variables and analysis of variance for con- after surgery and those who received a belotecan as third-line tinuous variables. We performed univariate and multivariate or later-line settings. Thus, 50 patients were left for analysis. logistic regressions to evaluate the association between the We retrospectively collected and analyzed the data of these patient characteristics and the efficacy. Survival curves were patients. generated using the Kaplan Meier method and compared by Patient characteristics were sex, age, performance sta- the log rank test. Logistic regression and Cox’s proportional tus, stage at diagnosis, initial chemotherapy regimen, the hazard model were used to determine the contribution of the response of the initial chemotherapy, and the duration of clinico-pathological factors to response and survival, respec- the response to initial chemotherapy. A complete history of tively. All tests were two-sided, with a p-value of less than 0.05 the treatment each patient had received for SCLC was being considered statistically significant. The data were pre- recorded, including the start and stop dates of chemotherapy, sented with 95% CIs and calculated using standard methods dose of chemotherapy agents, reason for discontinuation, based on a binomial distribution. Data analysis was done by best response, and date of progressive disease (PD). The the SPSS software (version 18.0). study was approved by the Institutional Review Board of the Severance Hospital. RESULTS Patient Characteristics Treatment From June 2008 to August 2011, a total of 50 patients Belotecan was administered intravenously for more were treated with belotecan monotherapy as a second-line than 30 minutes once a day on days 1 to 5 for every 3 weeks. treatment for relapsed or refractory SCLC. The baseline char- The dose of belotecan was 0.5 mg/m2/d during the first cycle, acteristics of the patients are listed in Table 1. Four patients but a dose adjustment for the subsequent cycles was made were women and 46 were men, and their median age was 66 according to the greatest degree of toxicity developed during years (range, 43–84 years). Among the 50 patients, 34 (68%) the previous cycle. The dose was adjusted as follows: the dose had a PS of 0 or 1 before belotecan monotherapy. Sixteen would be decreased to 0.4 mg/m2/d in the event of (1) abso- patients (32%) had limited disease at diagnosis. Thirteen lute neutrophil count nadir of less than 500 /mm3 for 4 days patients had received thoracic irradiation simultaneously with or more (2) febrile neutropenia (3) platelet nadir of less than first-line chemotherapy. Twenty patients (40%) had sensitive 50,000 /mm3 for 4 days or more (4) thrombocytopenia asso- relapse and 30 patients (60%) had refractory relapse. Almost ciated with bleeding episode or requiring transfusion or (5) all the patients (98%) had received etoposide-containing che- grade-3 or higher nonhematological toxicity except alopecia, motherapy and two patients had received an irinotecan-based nausea, and vomiting. Dose increment was not allowed. The regimen. next cycle of treatment was started when absolute neutrophil count was 1500/mm3, platelet count was 100,000/mm3, and all Treatment Delivery nonhematologic toxicity except alopecia, nausea, and vomiting Two patients died during the first cycle of treatment recovered to grade 2 or less. Otherwise, the next cycle would because of PD. Therefore, 48 patients received more than be delayed for up to 3 weeks. Granulocyte colony-stimulating one cycle of treatment. In total, 130 cycles of treatment (68 factor was used as a therapeutic intervention for neutropenia cycles for sensitive group and 62 cycles for refractory group) but not used as a prophylactic. Treatment was continued until were administered, with a median of two cycles (range, one to one of the following events occurred: PD, termination of treat- nine cycles). The median duration of treatment was 6.5 weeks

TABLE 1. Baseline Characteristics Total Sensitive Group Refractory Group (n = 50) (n = 20) (n = 30) Parameter No. of Patients % No. of Patients % No. of Patients % p-Value Sex 0.67 Male 46 92 18 90 28 93 Female 4 8 2 10 2 7 Age, yrs 0.827 Median 66 67 66 Range 43–84 47–84 43–80 Performance status (ECOG) 0.677 0 2 4 1 5 1 3 1 32 64 14 70 18 60 2 16 32 5 25 11 37 Stage at diagnosis 0.001 Limited 16 32 12 60 8 13 Extensive 34 68 4 40 26 87 Previous chemotherapy 0.012 Etoposide + carboplatin 30 60 7 35 23 77 Etoposide + cisplatin 18 36 12 60 6 20 Irinotecan + carboplatin 2 2 1 5 1 3 Response to prior chemotherapy 0.83 CR or PR 39 78 18 90 21 70 SD or PD 11 22 2 10 9 30

ECOG, Eastern Cooperative Oncology Group; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

(range, 3–31 weeks). Dose reduction and cycle delays of (7 patients), follow-up loss (1 patient), treatment-related tox- more than 7 days occurred in 6 patients (12%) and 15 patients icity (1 sepsis and 1 cerebral hemorrhage), and 2 patients were (30%), respectively. The median relative dose intensity was not yet evaluated. All these 12 patients were included in the 0.92 (range, 0.4–1.0). Reasons for discontinuation of treatment efficacy analyses. were disease progression (n = 39), patient withdrawal (n = 2), The ORR was 14% (95% CI, 4–24%). There was no unacceptable toxicity (n = 1), and others (n = 4). Among the complete response. The ORR of patients with sensitive relapse 43 patients who experienced disease progression after belo- (20%; 95% CI, 8–40%) was higher than that of patients with tecan chemotherapy, 12 (28%) received third-line salvage chemotherapy. refractory relapse (10%; 95% CI, 1–21%) (Table 2). The median follow-up time is 4.2 months (range, 0.1– Efficacy 19.2). At the time of analysis, 11 patients (22%) were alive. The We were not able to evaluate the treatment response of 10 median progression-free survival (PFS) and the OS were 1.6 patients because of death caused by early disease progression months (95% CI, 1.17–2.03) and 4.5 months (95% CI, 3.53– 5.47), respectively (Fig.�� 1��). The OS of the patients with sensitive relapse was significantly longer than that of the patients TABLE 2. Response with refractory relapse (6.5 versus 4.0 months, p = 0.003, Fig. Sensitive Relapse Refractory 2A). The PFS of the patients with sensitive relapse had a trend Total (n = 50) (n = 20) Relapse (n = 30) toward a longer PFS than that of the patients with refractory No. % No. % No. % relapse (2.8 versus 1.5 months, p = 0.053). The OS of the patients Complete 0 0 0 0 0 0 with good performance status (Eastern Cooperative Oncology response Group [ECOG] 0 or 1) was significantly longer than that of the Partial response 7 14 4 20 3 10 patients with poor performance status (ECOG 2) (5.1 versus Stable disease 10 20 5 25 5 16.7 3.5 months, p = 0.045, Fig. 2B). In multivariate analysis, only Progressive 21 42 7 35 14 46.7 the type of relapse was identified as an independent prognostic disease factor for PFS (hazard ratio [HR], 2.25; p = 0.035). The type Not evaluable 12 24 4 20 8 26.7 of relapse (HR, 3.78; p = 0.003) and response to prior chemo- Response rate 7 14 4 20 3 10 95% CI 4–24% 8–40% 1–21% therapy (HR, 0.285; p = 0.003) were identified as independent prognostic factors for OS (Appendix Table 1 , Supplemental CI, confidence interval. Digital Content 1, http://links.lww.com/JTO/A256).

Figure 1. Overall survival and progression-free survival. PFS, progression-free survival; OS, overall survival; CI, confidence interval.

Toxicity The toxicity profile is summarized inTable 3. The most common grade-3 to -4 hematologic toxicity was neutropenia that developed in 54% of the patients. Febrile neutropenia was observed in two patients. Grade-3 or -4 thrombocytopenia and anemia were developed in 38% and 32 % of the patients, respectively. The most frequent grade-3 or -4 nonhematological toxicity was asthenia (6%). One patient died because of treatment-related toxicity, which was septic shock combined with pneumonia. Thrombocytopenia was the most frequent reason for dose reduction and neutropenia was the most common reason for cycle delay. Nonhematological toxicities were generally mild. There were no patients who had grade-3 to -4 gastrointestinal toxicities. Figure 2. Comparison of overall survival according to (A) the type of relapse and (B) the performance status. DISCUSSION We examined the efficacy and toxicity of belotecan, a report of belotecan as a second-line treatment for the refractory- new camptothecin analog, as a second-line treatment in a rela- relapsed SCLC in a relatively large number of patients. tively large number of relapsed or refractory SCLC patients. The type of relapse and performance status are well- We observed modest antitumor activity of belotecan mono- known prognostic factors for relapsed SCLC patients. In our therapy in relapsed SCLC: an ORR of 14%, a median OS of study, the ratio of the refractory-relapsed patient was 60% and 4.5 months, and a median PFS of 1.6 months. The most com- the patients with the poor performance status (ECOG = 2) was mon toxicity was myelosuppression (neutropenia 54%), and relatively higher than those of two recent phase-II trials (32 nonhematological toxicity was minimal. versus 4–8%).18,19 The primary factor determining the likeli- Recently, Jeong et al18 reported that belotecan showed hood of response to second-line salvage therapy is whether modest activity and manageable toxicities in sensitive-relapsed the patient has refractory or sensitive relapse. In one report, patients after first-line irinotecan chemotherapy O( RR, 22%; OS, the performance status was the second-most important predic- 13.1 months). Rhee et al19 also reported that belotecan induced tor of response to second-line salvage therapy.10 In this study, an ORR of 24% and a median OS of 9.9 months. However, the the OS of the patients with sensitive relapse was significantly Jeong et al had no refractory patients and Rhee et al had no longer than that of the patients with refractory relapse (6.5 information on the type of relapse. Thus, our study was the first versus 4.0 months, p = 0.003). The OS of the patients with a

The major toxicity of belotecan was myelosuppression. TABLE 3. Toxicities (NCI-CTC Version 3.0) Grade-3 or -4 hematological toxicities included neutropenia All Grades Grade 3/4 in 56.5% of the patients, thrombocytopenia in 40%, and ane- CTC AE Terminology No. % No. % mia in 35%. Previous studies have also demonstrated that the Hematological toxicity major toxicity of belotecan is myelosuppression. In phase-II Neutropenia 38 76 27 54 studies of belotecan as second-line chemotherapy for relapsed Anemia 47 94 16 32 SCLC patients, rates of grade-3 or -4 neutropenia, thrombo- Thrombocytopenia 35 70 19 38 cytopenia, and anemia were 88 to 90%, 40 to 48%, and 29 to 18,19 Nonhematological toxicity 36% of the patients, respectively. In addition, in phase-II Asthenia 28 56 3 6 studies of belotecan monotherapy as a first-line treatment, Anorexia 11 22 2 4 grade-3 or -4 neutropenia, thrombocytopenia, and anemia Nausea 17 34 0 0 developed in 70 to 74%, 13 to 30%, and 18 to 20% of the 14,17 Vomiting 14 28 0 0 patients, respectively. The incidence of thrombocytopenia 18,19 Diarrhea 12 24 0 0 and anemia was consistent with that in previous studies. Constipation 15 30 0 0 However, the incidence of grade-3 or -4 neutropenia was rela- Dyspnea 28 56 3 6 tively lower than that in previous studies. This may be because Infection 13 26 3 6 of relatively high incidence of early progression. Fourteen Liver enzyme elevation 14 28 0 0 patients (30%) had a PD after the first cycle of chemotherapy. Nonhematological toxicities in our study were generally NCI-CTC, National Cancer Institute-Common Toxicity Criteria; AE, adverse event. favorable to manage. This is consistent with the results of previous clinical trials.18,19 Only two patients showed grade-3 anorexia and none of the patients reported grade-3 or -4 gas- good performance status (ECOG 0 or 1) was also significantly trointestinal toxicities (nausea, vomiting, and diarrhea). This longer than that of the patients with a poor performance status is favorable compared with that of grade-3 or -4 diarrhea for (5.1 versus 3.5 months, p = 0.045 Fig. 2). topotecan, ranging from 0.9 to 7.9% as a second-line trial.7,8 Topotecan has been considered the standard second-line Hematological toxicity of belotecan was comparable to that regimen in many countries. Recently, amrubicin has been consid- of topotecan and of amrubicin, and nonhematological toxicity ered as an alternative choice for relapsed SCLC patients, based of belotecan was milder than that of topotecan and amrubicin on the recent trials of amrubicin that showed a favorable efficacy (Appendix Table 2, Supplemental Digital Content 1, http:// and toxicity.9-11 A randomized phase-II trial comparing amrubicin links.lww.com/JTO/A256). with topotecan in relapsed SCLC patients showed better response Although several studies have shown belotecan to have rates for both sensitive (53% versus 21%) and refractory (17% a modest efficacy in patients with sensitive relapsed SCLC, versus 0%) relapsed patients.12 A preliminary report of a phase- there is a limitation of their adoption as standard treatment for III trial comparing amrubicin with topotecan as a second-line relapsed SCLC, especially in refractory SCLC. This limitation treatment for SCLC showed that amrubicin had significantly might reflect that SCLC was the genetically complex human improved ORR and PFS compared to those of topotecan.20 We cancer. With regard to the complex biology of SCLC, the compared these two drugs with belotecan in second-line treat- probability of developing a potent single novel drug against ment for relapsed SCLC (Table 4). According to the historical refractory SCLC was very low. Therefore, we should focus on data review, the overall efficacy of belotecan was comparable to identifying the driver mutations and the underlying mecha- that of topotecan and slightly lower than that of amrubicin. nism for rapid development of drug resistance for further

TABLE 4. Comparison of Efficacy Topotecan Intravenous Oral Amrubicin Belotecan Pawel8 Eckardt7 O’Brien5 Eckardt7 Inoue12 Onoda11 Kaira10 Ettinger9 Jeong18 Rhee19 Current Study Type of relapse No data 10%* 57%* 9%* S R S R S R R only S only No data S R Number of patients 107 151 70 153 17 12 44 16 10 19 75 27 25 20 30 Poor performance 23 12 27 13 13 1 3 5 17 4 8 25 37 (%) (ECOG > 2) Efficacy oRR (%) 24 18.3 7 21.9 53 17 52 50 60 37 21.3 22 24 20 10 PFS (months) 3.3 3.0 4.1 3.8 3.9 2.6 4.2 2.6 4 4 3.2 4.7 2.2 2.8 1.5 oS (months) 6.3 8.3 6.5 8.8 9.9 5.3 11.610.3 12 11 6 13.1 9.9 6.5 4

*The ratio of refractory-relapse patients. S, sensitive relapse; R, resistance-relapse or refractory patients; ECOG, Eastern Cooperative Oncology Group; ORR, overall response rate; PFS, progression-free survival; OS, overall survival.

clinical trials of second-line treatment in patients with refrac- Cooperative Group. J Clin Oncol 1997;15:2090–2096. tory SCLC. Advanced technology such as next-generation 5. O Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients sequencing should be introduced to identify such key genetic with relapsed small-cell lung cancer. J Clin Oncol 2006;24:5441–5447. events. Based on gene-expression profiling and toxicity of 6. Park SH, Cho EK, Kim Y, et al. Salvage treatment with topotecan drugs, we should select a proper combination of regimens for in patients with irinotecan-refractory small cell lung cancer. Cancer further investigations of refractory SCLC. Chemother Pharmacol 2008;62:1009–1014. The main limitation of the present study resides in its 7. Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung retrospective nature. Another limitation is the relatively high cancer. J Clin Oncol 2007;25:2086–2092. incidence of early progression in our study, mainly because 8. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus of inclusion of a large number of refractory SCLC patients cyclophosphamide, doxorubicin, and vincristine for the treatment of with poor performance status. Furthermore, the toxicity of recurrent small-cell lung cancer. J Clin Oncol 1999;17:658–667. the belotecan might not be adequately reflected in this study 9. Ettinger DS, Jotte R, Lorigan P, et al. Phase II study of amrubicin as second-line therapy in patients with platinum-refractory small-cell lung because of early progression in many patients. Thus, we are cancer. J Clin Oncol 2010;28:2598–2603. currently conducting a randomized phase-II study comparing 10. Kaira K, Sunaga N, Tomizawa Y, et al. A phase II study of amrubicin, a belotecan with topotecan. It will reveal more precise informa- synthetic 9-aminoanthracycline, in patients with previously treated lung tion about the efficacy and toxicity of belotecan in relapsed or cancer. Lung Cancer 2010;69:99–104. refractory SCLC. 11. Onoda S, Masuda N, Seto T, et al. Thoracic Oncology Research Group Study 0301. Phase II trial of amrubicin for treatment of refractory or In conclusion, belotecan showed modest activity and relapsed small-cell lung cancer: Thoracic Oncology Research Group manageable toxicity as a second-line treatment in patients Study 0301. J Clin Oncol 2006;24:5448–5453. with relapsed or refractory SCLC. Considering the limited 12. Inoue A, Sugawara S, Yamazaki K, et al. Randomized phase II trial activity of belotecan for refractory relapsed patients, an effort comparing amrubicin with topotecan in patients with previously treated has to be made to find key genetic events for further studies of small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0402. J Clin Oncol 2008;26:5401–5406. belotecan in refractory SCLC. 13. Crul M. CKD-602. Chong Kun Dang. Curr Opin Investig Drugs 2003;4:1455–1459. 14. Lee DH, Kim SW, Suh C, et al. Belotecan, new camptothecin analogue, Acknowledgments is active in patients with small-cell lung cancer: results of a multicenter This study was supported in part by a grant of the Korea early phase II study. Ann Oncol 2008;19:123–127. Health Technology R&D Project, Ministry of Health & Welfare, 15. Lee DH, Kim SW, Suh C, et al. Multicenter phase 2 study of belotecan, a new Republic of Korea (A100580) and by a faculty research grant camptothecin analog, and cisplatin for chemotherapy-naive patients with of Yonsei University College of Medicine for 6-2010-0061. extensive-disease small cell lung cancer. Cancer 2010;116:132–136. 16. Kim SJ, Kim JS, Kim SC, et al. A multicenter phase II study of belotecan, new camptothecin analogue, in patients with previously untreated extensive REFERENCES stage disease small cell lung cancer. Lung Cancer 2010;68:446–449. 1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of 17. Hong J, Jung M, Kim YJ, et al. Phase II study of combined belotecan and small-cell lung cancer in the United States over the last 30 years: analysis cisplatin as first-line chemotherapy in patients with extensive disease of of the surveillance, epidemiologic, and end results database. J Clin Oncol small cell lung cancer. Cancer Chemother Pharmacol 2012;69:215–220. 2006;24:4539–4544. 18. Jeong J, Cho BC, Sohn JH, et al. Belotecan for relapsing small-cell 2. Kim YH, Mishima M. Second-line chemotherapy for small-cell lung lung cancer patients initially treated with an irinotecan-containing cancer (SCLC). Cancer Treat Rev 2011;37:143–150. chemotherapy: a phase II trial. Lung Cancer 2010;70:77–81. 3. Jackman DM, Johnson BE. Small-cell lung cancer. Lancet 19. Rhee CK, Lee SH, Kim JS, et al. A multicenter phase II study of belotecan, 2005;366:1385–1396. a new camptothecin analogue, as a second-line therapy in patients with 4. Ardizzoni A, Hansen H, Dombernowsky P, et al. Topotecan, a new active small cell lung cancer. Lung Cancer 2011;72:64–67. drug in the second-line treatment of small-cell lung cancer: a phase II 20. von Pawel J, Jotte R, Spigel DR, et al. Randomized phase III trial of amrubicin study in patients with refractory and sensitive disease. The European versus topotecan (Topo) as second-line treatment for small cell lung cancer Organization for Research and Treatment of Cancer Early Clinical (SCLC). Proceedings of the Annual Meeting of the American Society of Studies Group and New Drug Development Office, and the Lung Cancer Clinical Oncology 2011. J Clin Oncol 2011;29:(Suppl; abstr 7000).