Platinum-based doublet chemotherapy is the standard firstline

ORIGINAL ARTICLE A Phase II Trial of Carboplatin and Weekly Topotecan in the First-Line Treatment of Patients with Extensive Stage Small Cell Lung Cancer David R. Spigel, MD,* John D. Hainsworth, MD,* Jitendra G. Gandhi, MD, Victor G. Gian, MD, James D. Peyton, MD, Kimberly West-Osterfield, PhD,* Bobby L. Clark, PhD,* Elizabeth R. Vazquez, BA, CCRP,* Suzanne F. Jones, PharmD,* Howard A. Burris, III, MD,* and F. Anthony Greco, MD* Background: Carboplatin and topotecan are commonly used in the treatment of small cell lung cancer (SCLC); however, there are no data for this combination in the first-line setting using weekly topotecan. In this multicenter, community-based phase II trial, we evaluated carboplatin and weekly topotecan in the previously untreated patients with extensive stage SCLC. Methods: This trial was designed to achieve an objective response rate (ORR) of 70% ( 0.05; 0.20); secondary aims were to assess time to progression, toxicity, and overall survival (OS). Patients with Eastern Cooperative Oncology Group performance status 0 to 1, measurable disease, and adequate organ function were eligible. Treatment: carboplatin area under the concentration time curve 5 (intravenous) on day 1 and topotecan 4 mg/m 2 (intravenous) on days 1 and 8, every 21 days for up to six cycles, with restaging every 6 weeks (per RECIST). Results: Between June 2006 and November 2008, 61 patients were enrolled. The median follow-up is 40 weeks (range 27 109 weeks). Patient characteristics were as follows: median age 67 years (range 40 84 years); male, 53%; and Eastern Cooperative Oncology Group performance status 0, 28%. Complete responses were seen in two patients and partial responses in 33 patients; ORR was 57% (95% confidence interval CI 44 70). Stable disease was seen in 12 patients (20%), and progressive disease was seen in two patients (3%). The median time to progression was 5.5 months (95% CI 4.0 6.3 months). The median OS was 8.5 months (95% CI 7.2 11.4 months). One-year OS was 29%. Grade 3/4 toxicity in 5%: neutropenia (66%), thrombocytopenia (48%), leukopenia (40%), *Sarah Cannon Research Institute, Nashville; Tennessee Oncology, PLLC, Nashville; and Associates in Hematology and Oncology, Chattanooga Tennessee. Disclosure: This trial was supported in part by research funding, paid to SCRI, from GlaxoSmithKline. All coauthors state that they have no relevant financial interests in this manuscript. Address for correspondence: David R. Spigel, MD, Sarah Cannon Research Institute, 250, 25th Avenue North, Suite 110, Nashville, TN 37203. E-mail: dspigel@tnonc.com Presented at the 2008 Chicago Multidisciplinary Symposium in Thoracic Oncology, Chicago, IL, 2008. Copyright 2010 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/10/0506-0862 862 anemia (30%), fatigue (13%), dehydration (8%), infection (8%), and pain (7%). Conclusions: The ORR achieved with carboplatin and weekly topotecan was less than the anticipated rate of 70%; however, it was comparable with historical rates seen with other platinum doublets in the first-line extensive stage SCLC setting. This regimen was generally well tolerated, with myelosuppression as its primary toxicity. Key Words: Carboplatin, Topotecan, First-line, Extensive stage, Small cell lung cancer. (J Thorac Oncol. 2010;5: 862 866) Platinum-based doublet chemotherapy is the standard firstline treatment for the patients with extensive stage small cell lung cancer (ES-SCLC). Etoposide/platinum and irinotecan/platinum regimens have been extensively studied and compared, resulting in response rates of 45 to 50%, median time to progression (TTP) of 4 to 5 months, and median survivals of 9 to 10 months. 1 4 Topotecan is a DNA topoisomerase-i inhibitor approved for the treatment of sensitive-relapsed SCLC. This approval was based on a randomized trial comparing a consecutive 5-day every 3-week schedule of intravenous topotecan with a triplet regimen of cyclophosphamide, doxorubicin, and vincristine in the patients with sensitive-relapsed SCLC. 5 Topotecan was found to improve the quality of life and symptom control over cyclophosphamide, doxorubicin, and vincristine, despite having an equivalent response rate (24%) and survival (25 weeks), and notable grade 4 hematologic toxicity (neutropenia, 38%; anemia, 10%; and thrombocytopenia, 18%). Topotecan/platinum doublets have been studied in SCLC in phase II trials using a 5-day intravenous scheduling. 6 8 In addition, a randomized phase III trial of oral topotecan/platinum versus etoposide/platinum was completed. 9 In general, these regimens were well tolerated and result in similar efficacy. Weekly dosing of intravenous topotecan has been studied as an alternate schedule, which could minimize hemato- Journal of Thoracic Oncology Volume 5, Number 6, June 2010

Journal of Thoracic Oncology Volume 5, Number 6, June 2010 Carboplatin and Topotecan in Extensive Stage SCLC logic toxicity while preserving treatment benefit and improving patient convenience. 10,11 Weekly scheduling has been studied extensively in ovarian cancer and has been generally well tolerated at a dose of 4 mg/m 2. 12 16 Our group has studied weekly scheduling in the patients with relapsed SCLC and as first-line SCLC therapy in poor performance status (PS) patients. 17,18 Weekly dosing was well tolerated and associated with relatively low severe hematologic toxicity. Our center conducted a phase I study (unpublished) examining weekly topotecan and carboplatin in patients with refractory/advanced solid tumors. Among 19 patients, grade 3 hematologic toxicity was limited to anemia and leukopenia; no grade 4 hematologic and limited nonhematologic toxicity were seen with topotecan. Herein, we report on a multicenter phase II trial of carboplatin (area under the concentration time curve of 5 every 21) and weekly topotecan (4 mg/m 2 administered on days 1 and 8) as a first-line therapy for the previously untreated patients with ES-SCLC. PATIENTS AND METHODS This trial was initiated in June 2006 and completed enrollment in November 2008. Participating centers included the Sarah Cannon Research Institute and select sites from the Sarah Cannon Oncology Research Consortium, a national community-based research network. Patients Patients with histologically confirmed SCLC were enrolled. Patients with ES disease were eligible. This included patients with stage IIIB and IV disease by the tumor node metastasis system. Patients with large cell neuroendocrine tumors or mixed small cell and non-small cell histologies were ineligible. Patients had measurable disease per RECIST. 19 Other eligibility criteria included the following: age 18 years; no prior chemotherapy, primary radiation, or biologic treatment; absence of active brain metastases; Eastern Cooperative Oncology Group PS 0 to 1; and adequate organ function (defined as absolute neutrophil count (ANC) 1.5 10 9 /liter, platelet count 100 10 9 /liter, serum bilirubin 1.5 the upper limit of normal, serum aspartate aminotransferase and alanine transaminase 3 upper limit of normal, and serum creatinine 1.6 mg/dl). Exclusion criteria included pregnancy or lactation, clinically significant cardiovascular disease, and prior malignancy within 3 years except nonmelanoma skin cancer and cervical carcinoma in situ. All patients provided written informed consent before enrollment. Pretreatment Evaluation Before treatment, patients were evaluated by history, physical examination, and laboratory testing. Baseline tumor staging was performed using computerized tomography (CT) scans of the chest and abdomen, CT or magnetic resonance imaging of the brain, and bone scan or positron emission tomography. Treatment Plan All patients received carboplatin at a dose calculated to produce an area under the concentration time curve of 5.0 FIGURE 1. Trial schema. mg/ml/min, administered intravenously on day 1, and topotecan 4 mg/m 2 intravenously on days 1 and 8 every 21 days for a maximum of six cycles (Figure 1). The carboplatin dose was calculated using the method described by Calvert et al. 20 Patients were restaged with CT scans every two cycles (per RECIST). Dose modifications were based on ANC and platelet counts on days 1 and 8 of each cycle; and doses were not increased once modified. No adjustments were required if the ANC was 1.5 10 9 /lier and platelet count 100 10 9 /liter. If the ANC was 1.0 to 1.49 10 9 /liter or platelets 75 to 99 10 9 /liter, chemotherapy was reduced 25%. If the ANC was 1.0 10 9 /liter or platelets 75 10 9 /liter on day 1, chemotherapy was held until counts recovered to baseline parameters when chemotherapy could be resumed with a 25% dose reduction. If the ANC was 1.0 10 9 /liter or platelets 75 10 9 /liter on day 8, topotecan was omitted, and both drugs were reduced 25% with subsequent cycles. If the counts did not recover within 3 weeks, the patient came off study. Patients requiring hospitalization for neutropenia and fever had 25% dose reductions. Chemotherapy was also reduced 25% for grade 3/4 nonhematologic toxicity. Toxicity assessments were made according to the common terminology criteria for adverse events (version 3.0) of the National Cancer Institute. Cytokines were not administered during the first course of treatment; however, prophylactic granulocyte colony-stimulating factor for patients experiencing febrile neutropenia was permitted at the discretion of the treating physician and was not to substitute for mandated dose reductions. Routine antiemetics were used as premedication. This trial was approved by the institutional review boards of all participating institutions. Topotecan was supplied by GlaxoSmithKline (Philadelphia, PA). A commercially available form of carboplatin was used. Definition of Response All patients were evaluated for response by RECIST criteria. The final response category assigned represented the best response obtained during treatment. Statistical Methods The primary objective of this phase II study was to assess the objective response rate. Secondary objectives were Copyright 2010 by the International Association for the Study of Lung Cancer 863

Spigel et al. Journal of Thoracic Oncology Volume 5, Number 6, June 2010 to assess toxicity, TTP, duration of response, and overall survival (OS). This trial used a MiniMax 2-stage statistical design. For a total of 60 subjects, 28 would be accrued during stage 1 and 32 during stage 2. If 15 or fewer responses were observed during the first stage, then the trial would be stopped early or amended. With an anticipated overall response rate of 70%, there was a 5% probability that the trial would be stopped in stage 1. The alpha level of this design was 0.05, and the power was 0.8. TTP was defined as the interval between the start date of treatment and the date of occurrence of progressive disease (PD). If intolerable toxicity or discontinuation of treatment secondary to toxicity occurred, the patient was considered assessable, but it was classified as a treatment failure. If other antitumor therapy was initiated before PD occurred, the patient was censored on the date on which the other therapy began. If a patient was lost to follow-up, the patient was censored on the date of last contact. OS was measured from the date of study entry until the date of death. Survival curves were estimated using the method of Kaplan and Meier. 21 Toxicity was assessed after the first 10 patients were treated. Expected toxicities during this treatment included myelosuppression and thrombocytopenia. If grade 4 cytopenias were seen in more than 4 of the first 10 patients, further accrual would be stopped and a dose reduction in chemotherapy considered. TABLE 1. Baseline Characteristics Characteristic Patients, n (%) Age (yr) Median 67 Range 40 84 Gender Male 32 (53) Female 29 (47) ECOG PS 0 17 (28) 1 43 (71) a Location of treatment facility Nashville site 28 (46) Consortium sites 33 (54) a One patient had a PS of 2. ECOG, Eastern Cooperative Oncology Group; PS, performance status. TABLE 2. Response Rates (n 61) Response n (%) Complete 2 (3) Partial 33 (54) Stable disease 12 (20) Progression 2 (3) Not evaluable a 12 (20) a Not evaluable due to patient death (five patients), intercurrent illness (one patient), patient request (one patient), poor subjective response (three patients), and treatmentrelated toxicities (two patients). FIGURE 2. Time to progression. RESULTS Patient Characteristics Sixty-one patients were enrolled from June 2006 to November 2008, 54% from outside of our Nashville site. Baseline characteristics for all patients are described in Table 1. The median age was 67 years (range 40 84 years). Thirty-two (53%) patients were men, and 29 patients were women. Eastern Cooperative Oncology Group PS was 0 in 17 (28%) patients and 1 in 43 (71%) patients. Treatment Received The median follow-up is 40 weeks (range 27 109 weeks). Sixty-three percent of planned treatment was administered. Twenty-three (38%) patients completed six cycles of chemotherapy (median 4 cycles, range 1 6 cycles). Seventyfive percent of patients had at least one dose reduction; and most of these (91%) were because of hematologic toxicity. Seventy-three percent of patients received at least one dose of granulocyte colony-stimulating factor. Twenty-five (41%) patients received red blood cell transfusions (median 2); and 13 (21%) patients received platelet transfusions. Twelve (20%) patients were not evaluable for response because of patient death (five patients), intercurrent illness (one patient), patient request (one patient), poor subjective response (three patients), or treatment related toxicity (two patients). All these patients were included in the efficacy analyses. Response Sixty-one patients are included in the response analysis (Table 2). Complete responses were seen in 2 (3%) patients and partial responses in 33 (54%) patients, for an overall response rate of 57% (95% confidence interval CI 44 70). Twelve (20%) patients had stable disease, and two (3%) patients had PD. The median response duration was 4.4 months (95% CI 3.2 6.9 months). Time to Progression and Survival The median TTP was 5.5 months (95% CI 4.0 6.3 months) (Figure 2). The median OS was 8.5 months (95% CI 7.2 11.4 months) (Figure 3). One-year OS was 29%. At the time of this analysis, 15 (25%) patients were alive. 864 Copyright 2010 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 5, Number 6, June 2010 Carboplatin and Topotecan in Extensive Stage SCLC FIGURE 3. Survival. TABLE 3. Grades 3 and 4 Toxicity in 5% of Patients (n 61) Toxicity Grade 3 Grade 4 Anemia 15 (25) 3 (5) Neutropenia 26 (43) 14 (23) Neutropenic fever 1 (2) 2 (3) Leukopenia 17 (28) 7 (12) Thrombocytopenia 11 (18) 18 (30) Dehydration 5 (8) 0 Fatigue 8 (13) 0 Infection 5 (8) 0 Pain 3 (5) 1 (2) Values are expressed as n (%). Treatment-Related Toxicity Treatment-related toxicity is summarized in Table 3. In general, treatment was well tolerated although severe (grade 3/4) myelosuppresion was common, and it included neutropenia (66%), leukopenia (40%), anemia (30%), and thrombocytopenia (48%). Neutropenic fever occurred in three patients overall. Nine (15%) patients were hospitalized for myelosuppression. The most common ( 5%) grade 3/4 nonhematologic toxicities included dehydration (8%), fatigue (13%), infection (8%), and pain (7%). All other grade 3/4 toxicities were uncommon ( 5%). There was one potential treatment-related death because of sepsis related to a perforated diverticulum. DISCUSSION This phase II trial was designed to examine carboplatin and weekly topotecan in the previously untreated patients with ES-SCLC. The 57% response rate was lower than the estimated rate of 70% but similar to other first-line platinum doublet regimens in a first-line ES-SCLC setting. Likewise, the disease control rate of 77%, median TTP, and OS are comparable with outcomes with first-line etoposide/platinum and irinotecan/platinum regimens. Weekly scheduling of topotecan has been studied as a means of reducing myelosuppression, preserving treatment efficacy, and improving patient convenience over consecutive 5-day intravenous dosing. This schedule has been extensively studied in ovarian cancer (at a dose of 4 mg/m 2 ), where it has been shown to be well tolerated and active as a single agent in the relapsed setting. Weekly topotecan (2 2.5 mg/m 2 ) has also been studied in combination with carboplatin in small phase I/II settings in patients with advanced ovarian and peritoneal cancer. 22 24 This regimen has been found to be generally well tolerated and associated with responses in the patients previously treated with platinum-based therapy. Data on weekly scheduling of topotecan in SCLC has been limited to small phase II studies at our center 17,18 and by Shah et al. 25 In each of these trials, weekly topotecan (4 mg/m 2 ) could be safely administered, but response efficacy was low. Indeed, this led to a subsequent phase II trial at our center looking at a higher dose of weekly topotecan (6 mg/m 2 weekly for 6 of 8 weeks). 26 Unfortunately, a higher dose could not be consistently delivered because of hematologic toxicity. In our doublet trial, there were high rates of myelosuppression, necessitating dose modifications and leading to hospitalizations in 15% of patients. Importantly, the rates of neutropenia seem lower than what is often observed with etoposide/platinum regimens where rates can exceed 80%. 1,3 The rates of anemia and thrombocytopenia were higher than expected with etoposide or irinotecan, presumably because of the addition of carboplatin. In conclusion, the objective response rate achieved with carboplatin and weekly topotecan was less than the anticipated rate of 70%; however, it was comparable with historical rates seen with other platinum doublets in the first-line ES-SCLC setting. This regimen was generally safe, with myelosuppression as its primary toxicity. This schedule offers a more convenient administration than consecutive 5-day intravenous dosing, while being well tolerated. ACKNOWLEDGMENTS Supported, in part, by a grant from GlaxoSmithKline, Philadelphia, PA. REFERENCES 1. Hanna N, Bunn PA Jr, Langer C, et al. 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