Double-Cycle, High-Dose Ifosfamide, Carboplatin, and Etoposide Followed by Peripheral Blood Stem-Cell Transplantation for Small Cell Lung Cancer*

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1 Double-Cycle, High-Dose Ifosfamide, Carboplatin, and Etoposide Followed by Peripheral Blood Stem-Cell Transplantation for Small Cell Lung Cancer* Yoshinobu Iwasaki, MD, PhD; Kazuhiro Nagata, MD; Masaki Nakanishi, MD; Atsushi Natuhara, MD; Yutaka Kubota, MD; Mikio Ueda, MD; Taichiro Arimoto, MD, PhD; and Hiroshi Hara, MD, PhD Purpose: To determine the tolerability and feasibility of double-cycle, high-dose chemotherapy followed by peripheral blood stem-cell transplantation (PBSCT) after conventional chemotherapy or chemoradiotherapy for small cell lung cancer (SCLC). Patients and methods: Patients with previously untreated SCLC received two cycles of cisplatin, 80 mg/m 2, and etoposide, 300 mg/m 2 (cisplatin-etoposide [PE]). Later, they were administered high-dose etoposide, 1,500 mg/m 2, followed by granulocyte colony-stimulating factor for collection of peripheral blood stem cells. After two additional cycles of PE, the patients received high-dose ifosfamide, 10 g/m 2, carboplatin, 1,200 mg/m 2, and etoposide, 1,000 mg/m 2 (ifosfamidecarboplatin-etoposide [ICE]) followed by PBSCT twice at 3-month to 4-month intervals. Patients with limited disease (LD) concurrently received 50 Gy of irradiation with the last two cycles of PE. Results: Eighteen patients, including 11 patients with LD, were enrolled. Fifteen patients could receive high-dose ICE followed by PBSCT twice, and 3 patients could receive it once. The median number of CD34 cells collected was /kg. The median numbers of days to neutrophil counts > 500/ L and platelet counts > 50,000/ L were 10 days and 14.5 days after the first PBSCT, and 10 days and 15 days after the second PBSCT, respectively. Grade 3 diarrhea occurred in one cycle, and grade 3 renal toxicity occurred in two cycles. The overall response rate was 100%, with an 83.3% rate of complete or near-complete response. The 2-year and 5-year survival rates were 72% and 55% in patients with LD and 43% and 0% in patients with extensive disease, respectively. Conclusion: Double-cycle, high-dose ICE therapy followed by PBSCT is tolerable and feasible even after conventional chemotherapy or chemoradiotherapy in patients with SCLC. (CHEST 2005; 128: ) Key words: high-dose chemotherapy; peripheral blood stem-cell transplantation; small cell lung cancer Abbreviations: ABMT autologous bone marrow transplantation; CR complete response; ED extensive disease; G-CSF granulocyte colony-stimulating factor; ICE ifosfamide-carboplatin-etoposide; LD limited disease; ncr near complete response; PBSC peripheral blood stem cell; PBSCT peripheral blood stem-cell transplantation; PE cisplatin-etoposide; PR partial response; SCLC small cell lung cancer Combination chemotherapy with cisplatin and etoposide (cisplatin-etoposide [PE]) has long been the mainstay of treatment for small cell lung cancer (SCLC). Response rates in extensive disease (ED) range from 51 to 78%, including a7to13% rate of complete response (CR) and a median survival of 8 to 9 months. In patients with limited *From the Division of Pulmonary Medicine, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. Manuscript received January 30, 2005; revision accepted April 26, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). disease (LD), the CR rate is 16 to 18%, with a median survival of 11.7 to 12.4 months. 1 3 Given the exquisite initial sensitivity of SCLC to chemotherapy and the high rate of relapse, some studies have attempted to improve survival by increasing dose intensity. Within conventional ranges, dose intensity can be increased with the support of hematopoietic growth factors. One approach to treatment is the rapid sequencing of several active agents over a short period. 4 6 Another approach is Correspondence to: Yoshinobu Iwasaki, MD, PhD, Division of Pulmonary Medicine, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602, Japan; yiwasaki@koto.kpu-m.ac.jp 2268 Clinical Investigations

2 the use of higher doses of chemotherapy, particularly during the first four cycles of treatment. 7,8 The dose intensity of chemotherapy has also been increased by reducing the interval between chemotherapy cycles with the use of hematopoietic growth factors However, whether such approaches improve survival as compared with standard therapy remains controversial. Autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (PBSCT) have been used in many studies to control the hematologic toxicity of high-dose chemotherapy, thereby permitting a further increase in dose intensity. Most studies have evaluated late intensification strategies, in which a single course of intensive chemotherapy is administered to consolidate the response to standard treatment. A combined analysis 13 revealed no apparent improvement in survival, even though the percentage of complete responders almost doubled. Another study 14 proposed that lateintensification chemotherapy might improve longterm survival in a significant proportion of complete responders with LD. To date, only one randomized, phase III trial 15 of high-dose chemotherapy followed by ABMT or PBSCT has been completed in patients with SCLC. Significant differences favoring highdose chemotherapy were seen with respect to relapse-free survival, 15 suggesting that double-cycle, high-dose chemotherapy with ABMT or PBSCT might prolong survival by reducing the relapse rate. Multiple cycles of high-dose chemotherapy have been used as first-line therapy, 16 not for late intensification. Recently, the safety of high-dose chemotherapy has been enhanced by improvements in supportive care, including the use of hematopoietic growth factors and peripheral blood stem cells (PBSCs). The most recent studies have evaluated ifosfamide, carboplatin, and etoposide (ifosfamide-carboplatin-etoposide [ICE]) therapy, considered to have a favorable therapeutic index A steep dose response coupled with synergistic antitumor activity and a favorable spectrum of nonhematopoietic toxicity makes this combination a natural candidate for high-dose therapy. 20 A phase I dose-escalation study of high-dose ICE therapy followed by ABMT or PBSCT was conducted by Fields et al 21 to determine the maximum tolerated dose. They reported that the maximum tolerated dose of ICE was 20,100 mg/m 2 of ifosfamide, 1,800 mg/m 2 of carboplatin, and 3,000 mg/m 2 of etoposide. The dose-limiting toxicities of ICE were CNS toxicity and acute renal failure. Leyvraz et al 16 showed that three cycles of high-dose ICE therapy could be safely administered as firstline therapy. In their study, three cycles of high-dose ICE therapy with 10 g/m 2 of ifosfamide, 1,200 mg/m 2 of carboplatin, and 1,200 mg/m 2 of etoposide were administered over the course of 4 days at 4-week intervals. We treated patients with double-cycle, high-dose chemotherapy followed by PBSCT after conventional chemotherapy or chemoradiotherapy. Our main objective was to examine whether doublecycle, high-dose chemotherapy with ICE can be delivered with acceptable toxicity after conventional chemotherapy or chemoradiotherapy. Patients Materials and Methods Patients with histologically confirmed SCLC of any stage were eligible for the study. Eligibility criteria included the following: (1) no previous treatment, including radiotherapy, chemotherapy, and surgery; (2) lesions that could be measured or assessed; (3) age 18 to 65 years; (4) an Eastern Cooperative Oncology Group performance status of 0 or 1; (5) a life expectancy of 12 weeks; (6) a blood count within the normal range, and normal cardiac, hepatic, and renal functions; and (7) Pao 2 70 mm Hg in a sample of arterial blood in patients with LD. As for renal function, a serum creatinine level 1.5 mg/dl and a creatinine clearance 60 ml/min were required at entry, immediately before the first high-dose chemotherapy, and immediately before the second high-dose chemotherapy. This study was approved by our institutional review board, and all patients provided their informed consent before enrollment. Before study entry, all patients underwent staging investigations, including physical examination, chest radiography, CT of the chest and abdomen, brain MRI, bone scintigraphy, full blood count, electrolyte measurements, liver and renal function tests, and fiberoptic bronchoscopy with biopsy. LD was defined as tumor confined to one hemithorax with or without ipsilateral supraclavicular lymphadenopathy. All other patients were defined as having ED. Treatment Induction Therapy and PBSC Collection: The treatment scheme is outlined in Figure 1. Patients initially received two cycles of chemotherapy with PE at 3-week intervals. Cisplatin was administered at a dose of 80 mg/m 2 on day 1. Etoposide was administered at a dose of 100 mg/m 2 on days 1, 2, and 3. Four weeks after the first two cycles of PE, patients were administered 300 mg/m 2 of etoposide IV on days 1 to 5, followed by granulocyte colony-stimulating factor (G-CSF), 50 g/m 2 /d subcutaneously, to mobilize stem cells into the blood. PBSCs were collected by leukapheresis and cryopreserved. Collection was performed up to three times, until sufficient PBSCs were obtained to support two cycles of high-dose chemotherapy. Consecutively, two additional cycles of PE were administered at 3-week intervals. High-Dose Therapy Followed by PBSCT: Three weeks after the last two cycles of PE, patients received high-dose ICE therapy. Ifosfamide was administered at 2.5 g/m 2 /d as a 3-h IV infusion for 4 days. Carboplatin was administered at 300 mg/m 2 /d as a 6-h IV infusion for 4 days. Etoposide was administered at 200 mg/m 2 /d as a continuous infusion for 5 days. Mesna, 1,000 mg/m 2, was administered as a 1-h IV infusion 1 h before ifosfamide administration. Subsequently, mesna was adminiswww.chestjournal.org CHEST / 128 / 4/ OCTOBER,

3 Results Patients Characteristics Twenty patients were enrolled at our hospital between 1995 and Two patients were excluded: one patient declined to receive high-dose chemotherapy, and the other patient had a cerebral infarction during the second cycle of PE. The clinical characteristics of the patients data are shown in Table 1. The median age was 58 years (range, 46 to 65 years). Fourteen patients were men. Eleven patients had LD, and 7 patients had ED. Figure 1. Treatment schedule. VP-16 etoposide; PBSCC PBCS collection; TRT thoracic radiotherapy; IFO ifosfamide; CBDCA carboplatin; d1 5 days1to5;d7 day 7. tered at 4,000 mg/m 2 /d as a continuous infusion for 4 days. Forty-eight hours after the end of chemotherapy, PBSCs were reinfused and G-CSF was introduced at 50 g/kg/d, administered subcutaneously until hematopoietic recovery. If sufficient PBSCs were obtained to allow transplantation twice, a second course of high-dose ICE therapy was administered 3 to 4 months after the first course. Radiotherapy: Patients with LD received a total dose of 50 Gy of thoracic radiotherapy concurrently with the last two cycles of PE (2.0 Gy/d in 25 fractions over a period of 5 weeks). The target volume for thoracic radiotherapy included the gross tumor, as defined by the chest CT scan, and the bilateral mediastinal and ipsilateral hilar lymph nodes. If involved by tumor, the supraclavicular lymph nodes were also irradiated. The clinically determined volume was expanded by a 1.5-cm margin. After the first course of high-dose ICE therapy, prophylactic whole-brain irradiation was administered to patients with a CR or near-cr (ncr) from the year The brain irradiation consisted of 15 doses of 2.0 Gy over the course of 3 weeks, for a total dose of 30 Gy. Assessment of Toxicity, Response, and Survival General toxicity was classified according to the National Cancer Institute common toxicity criteria. Response was determined by clinical examination and chest CT. Bronchoscopy with biopsy was performed. Response was defined as follows: (1) CR, if all target lesions disappeared; (2) ncr, if there was a 90% reduction in the sum of the longest diameters of target lesions with persistent radiographic abnormalities; and (3) partial response (PR), if the reduction was at least a 30% reduction in the sum of the longest diameters of target lesions. Response had to be present for 4 weeks with no lesion recurrence. Stable disease was defined as a 30% reduction or 20% increase in the sum of the longest diameters of target lesions for 8 weeks. Restaging was done by chest CT, brain MRI, and bronchoscopy with biopsy in all patients three times: just before the first high-dose ICE therapy, 4 weeks after the first high-dose ICE therapy, and 4 weeks after the second high-dose ICE therapy. In addition, abdomen CT, bone scintigraphy, or both were performed in patients with distant metastasis to evaluate metastatic lesions. Overall survival was calculated from the first day of chemotherapy to the day of death using the Kaplan-Meier method. The patients were followed up for at least 5 years from the start of treatment. Leukaphereses and PBSC Collection After administration of etoposide, 1,500 mg/m 2 IV, over the course of 5 days, G-CSF was administered at 50 g/kg/d for a median of 12 days (range, 10 to 14 days). The interval from day 1 of mobilization to the start of leukapheresis was 17 days (range, 15 to 19 days). The median number of leukaphereses performed per patient was two (range, one to three procedures). The median number of CD34 cells collected was /kg (range, 3.55 to /kg). Grade 4 neutropenia occurred in all patients for a median of 5 days (range, 4 to 6 days), and five patients had febrile neutropenia. Hematopoietic Recovery Among the 18 patients, 15 patients received highdose ICE therapy followed by PBSCT twice. The other three patients did not receive the second course of high-dose ICE: two patients had grade 3 renal toxicity during the first course of high-dose ICE, and the other patient lacked sufficient cells for the second PBSCT. The median number of CD34 cells reinfused was /kg (range, 1.4 to /kg) in the first PBSCT and /kg (range, 1.50 to /kg) in the second PBSCT. The median time from PBSCT to a neutrophil count Table 1 Patient Characteristics (n 18) Characteristics No. Age, yr Median 58 Range Sex Male 14 Female 4 Performance status Disease status LD 11 ED Clinical Investigations

4 500/ L was 10 days (range, 8 to 14 days) in the first PBSCT and 10 days (range, 8 to 13 days) in the second PBSCT. The median time from PBSCT to a platelet count 50,000/ L was 14.5 days (range, 11 to 28 days) in the first PBSCT and 15 days (range, 12 to 24 days) in the second PBSCT. There were no differences in hematopoietic recovery between the first and second PBSCT. Nonhematologic Toxicity A total of 33 cycles of high-dose ICE therapy were analyzed for nonhematologic toxicity (Table 2). Grade 3 diarrhea occurred in one cycle, and grade 3 renal toxicity in two cycles. Infectious complications occurred in 16 cycles. Response and Survival Among the 18 patients evaluated, the response to treatment at study end point was CR in 13 patients, ncr in 2 patients, and PR in 2 patients. PE or PE with concurrent radiotherapy led to a CR or ncr in 10 patients and a PR in 5 patients. Two of the patients with PR had a CR after high-dose ICE therapy. The 2-year and 5-year survival rates were 72% and 55% in patients with LD, and 43% and 0% in those with ED, respectively (Fig 2). Discussion Table 2 Nonhematologic Toxicity in High-Dose ICE (n 33) Variables No. of Cycles Nausea Grade 11/10 Grade 3 10 Vomiting Grade 1/grade 2 2/5 Grade 3/grade 4 3/0 Diarrhea Grade 1/grade 2 6/5 Grade 3/grade 4 1/0 Renal Grade 1/grade 2 4/3 Grade 3/grade 4 2/0 Liver dysfunction Grade 1/grade 2 11/15 Grade 3/grade 4 0/0 Figure 2. Kaplan-Meier survival curves of patients with LD (continuous line) and those with ED (dotted line). 2YS 2-year survival rate; 5YS 5-year survival rate. In the 1980s, high-dose chemotherapy with ABMT was administered as first-line treatment. The rationale of early intensification schedules was to intensify therapy for all patients, while avoiding drug resistance induced by previous chemotherapy In the late 1990s, multicyclic high-dose chemotherapy supported by PBSCT or whole blood transfusions was used as an early intensification strategy. 16,24 This approach resulted in high rates of complete remission (56% to 67%) among patients with LD. Late-intensification schedules, in which conventional chemotherapy is initially administered to debulk the tumor, followed by high-dose chemotherapy to promote consolidation, were also tried. In the 1980s, ABMT was used as hematopoietic support ; PB- SCT has been used more recently. 17,18 High-dose chemotherapy appears to be more toxic when used for late intensification than for early intensification, with much higher treatment-related mortality associated with the former than the latter. However, high-dose chemotherapy can be administered more safely and effectively owing to improvements in supportive care, including the availability of hematopoietic growth factors and improved techniques for PBSCT. We initially administered four cycles of PE with concurrent radiotherapy to patients with LD and four cycles of PE alone to those with ED to derive the full effect of conventional chemotherapy or chemoradiotherapy and decrease tumor volume. The patients then received double-cycle, high-dose ICE therapy. There was no mortality related to high-dose ICE therapy followed by PBSCT. Among the 18 patients evaluated, 10 patients had a CR or ncr after PE or PE with concurrent radiotherapy. Among the five patients with a PR, two had a CR after high-dose ICE therapy. The 2-year and 5-year survival rates were 72% and 55% in patients with LD and 43% and 0% in patients with ED, respectively. In our study, double-cycle, high-dose ICE therapy was administered according to a late-intensification protocol. Our initial concern was that toxicity might cumulatively increase during the second course of high-dose ICE therapy, but this concern proved to CHEST / 128 / 4/ OCTOBER,

5 be unfounded. The doses of ICE were similar to those used in previous studies. 16,18 Among 33 administered cycles of high-dose ICE therapy, reversible severe diarrhea occurred in one cycle and reversible severe renal toxicity occurred in two cycles. The median number of days from PBSCT to a neutrophil count 500/ L was 10 days in both the first and second PBSCTs, and the median number of days from PBSCT to a platelet count 50,000/ L was 14.5 days in the first PBSCT and 15 days in the second PBSCT. The first PBSCT and second PBSCT thus had similar times to hematopoietic recovery. The schedules and dosages of ICE regimens have differed considerably among clinical trials. Although unequivocal conclusions cannot be made, several trends have emerged. First, ICE 16,17 regimens are apparently associated with better results of survival. Our results support a good outcome in terms of survival as well as response. Second, ICE regimens permit double cycles of intensification, without a cumulative increase in toxicity, even after conventional chemotherapy or chemoradiotherapy. We conclude that sequential, double-cycle, high-dose ICE therapy is tolerable and feasible in patients with SCLC, including those who have already received full courses of conventional chemotherapy or chemoradiotherapy. References 1 Roth BJ, Johnson DH, Einhorn LH, et al. Randomized study of cyclophosphamide, doxorubicin and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992; 10: Fukuoka M, Furuse K, Saijo N, et al. Randomized trial of cyclophosphamide, doxorubicin and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 1991; 83: Evans WK, Feld R, Murray N, et al. 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