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Cancer Research and Treatment 2002;34(6):421-425 Oral Etoposide, Ifosfam ide and Cisplatin in the Treatm ent of Extensive Disease Sm all Cell Lung Cancer Seok Jin Kim, M.D.1, Hwa Jung Sung, M.D.1, Kyong Hwa Park, M.D.1, So Young Yoon, M.D.1, Sang Cheul Oh, M.D.1, Jae Hong Seo, M.D.1, Chul W on Choi, M.D.1, Byung Soo Kim , M.D.1, Sang W on Shin, M.D.1, Yeul Hong Kim , M.D.1, Kwang Taek Kim , M.D.2, Young Ho Choi, M.D.2 and Jun Suk Kim , M.D.1 Departments of 1Internal Medicine and 2Chest Surgery, College of Medicine, Korea University, Seoul, Korea Purpose: The com bination of cisplatin and etoposide has been a com m on first line regim en for the treatm ent of sm all cell lung cancer (SCLC). The schedule depen dence, and equal efficacy, of the oral and intravenous dosing of etoposide has led to prolonged adm inistration of oral etoposide, which is known to produce an encouraging response in SCLC. To im prove the efficacy of the cisplatin/etoposide com bination, we adm inistered oral etoposide, with added ifosfam ide, which had sig nificant single agent activity against SCLC. We conducted this study to evaluate the efficacy and toxicity of the cisplatin, ifosfamide and oral etoposide (PIE) combination in patients with extensive sm all cell lung cancer. M aterials and Methods: Twenty-five patients with histologically confirm ed extensive sm all cell lung cancer were enrolled into this study between January 2000 and M ay 2002. They were treated with, cisplatin at 20 m g/ m 2 /day, ifosfam ide 1.5 g/m 2 /day, with m esna (all given 2 intravenously on Days 1∼3), and oral etoposide 50 mg/m on days 4∼17. This cycle was repeated every 4 weeks for up to 6 cycles. W e evaluated the corresponding disease responses and toxicities. Results: The patients' characteristics were as follows: m edian age 65 years (32∼75), 19 m ales and 6 fem ales. The perform ance stati were ECOG 0 in 3 patients, ECOG 1 in 12 and ECOG 2 in 10. Sixteen patients had a partial response, 2 had a stable disease and 4 had a progressive disease. Thus, the overall objective response rate was 72.7% (95% CI: 49.6∼88.4% ), with a m edian response duration of 7 m onths (95% CI: 3.5∼10.5 m onths). Myelosuppression was the major observed toxicity. Grades III and IV neutropenia were observed in 42 (46.1%) of the 91 cycles. Significant non-hem atological toxicities (≥Grade III) were uncom m on, with the exception of nausea and vom iting. Conclusion: The response rate to the com bination of cisplatin, ifosfamide and oral etoposide was similar to that of other com bination chem otherapy studies in patients with extensive disease small cell lung cancer. The toxicity of the regim en was considered acceptable. (Cancer Research and Treatm ent 2002;34:421-425) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Key W ords: Sm all cell lung cancer, Ifosfamide, Cisplatin, Oral etoposide are modest, and long-term survival and cure are rarely achieved. Etoposide and cisplatin are highly synergistic, and are commonly used as a first-line regimen in patients with SCLC (2). The response to etoposide has proven to be dependent on the administration schedule, which has led to changes in its administration. Thus, the continuous administration of intravenous etoposide improved both the response rate and duration in patients with SCLC compared to a larger single dose (3). The oral administration of etoposide has equal efficacy and toxicity as intravenous dosing in patients with SCLC (4); moreover, high plasma concentrations of etoposide are associated with the development of severe myelotoxicity (5). It is suggested that chronic exposure to relatively low levels of etoposide might potentiate the anticancer effect of etoposide. Thus, the prolonged administration of low dosages of etoposide could help improve its efficacy, and decrease its toxicity. The prolonged oral administration of etoposide was reported to produce an 85% response rate in previously untreated patients with SCLC (6). In order to improve the efficacy of combined cisplatin and INTRODUCTION Small cell lung cancer (SCLC) accounts for approximately 15 to 20% of all lung cancers. Because the malignant cells are characterized by rapid tumor growth and early metastatic dissemination, 65 to 70% of SCLC patients present with an extensive disease (ED). Thus, systemic chemotherapy is the most important treatment modality for this disease (1). Although multiple chemotherapeutic trials have demonstrated response rates of 60 to 80% in ED SCLC, the survival benefits Correspondence: Sang Won Shin, Department of Internal Medicine College of Medicine, Korea University, 126-1, Anamdong 1-ga, Sungbuk-gu, Seoul 136-705, Korea. (Tel) 02-920-5350, 5114, (Fax) 02-922-5974, (E-mail) [email protected] Received August 17, 2002, Accepted November 28, 2002 The abstract of this article was presented at the 28th annual meeting of Korea Cancer Association. 421 422 Cancer Research and Treatment 2002;34(6) etoposide (EP), many other drugs have been additionally used with this standard regimen. Ifosfamide has a significant single agent activity in previously untreated patients with SCLC. The ECOG demonstrated a response rate of 45% in 44 chemotherapy nave patients with the use of ED SCLC (7). Ifosfamide is known to be less myelotoxic than cisplatin and etoposide, and its main dose-limiting toxicity, hemorrhagic cystitis, can be prevented by the administration of mesna. Thus, ifosfamide could be administrated safely with cisplatin and etoposide. Although the combination of etoposide, ifosfamide and cisplatin (VIP) was originally developed as a salvage regimen for relapsed SCLC patients, the Hoosier Oncology Group (HOG) compared the results of a phase III trial of this regimen to those of EP in patients with previously untreated ED SCLC. This study showed a modest survival advantage favoring the VIP based regimen (8). It was reported that ifosfamide, in combination with cisplatin and oral etoposide administration, showed the significant response rate of 93% in patients with ED SCLC (9). In the phase II study, the authors added ifosfamide to the cisplatin and etoposide combination, with the etoposide was administered orally, and found a modest survival benefit, and acceptable toxicity, for this regimen in ED SCLC. However, the chosen patient population had good prognostic features, including good performance stati and a median age of 59 years, which was relatively younger than that of previous studies. Therefore, based on the above results, we conducted a prospective study using the same regimen used in the previous study, and evaluate the efficacy and toxicity of cisplatin, ifosfamide and prolonged oral etoposide in patients with ED SCLC, and included relatively older patients with poorer performance stati. history taking, a physical examination, complete blood cell counts (CBCs) with differential blood counts, routine biochemical profile testing, an electrocardiogram, chest X-rays, computed tomographic (CT) scan of the chest and brain, and an isotope bone scan. Bone marrow aspiration and a biopsy were performed when bone marrow involvement was suspected. During the study, physical examinations, including a neurologic examination, were performed before each treatment cycle. CBCs, with differential blood counts, were performed every two weeks, and immediately before the next treatment cycle. In the case of grade IV neutropenia, or febrile neutropenia, CBCs were performed every 2 days until the ANC was more than 1.0×109/l and all symptoms of infection had subsided. To assess responses, all measurable lesions were re-evaluated by a chest X-ray at every cycle. A chest CT scan was repeated after every other cycle. The toxicity was evaluated after every cycle, according to the NCI criteria. 3) Treatment schedule The treatment protocol is described in Table 1, and each treatment cycle was repeated every 4 weeks. The dosage of ifosfamide was reduced by 25% when patients experienced 9 either grade IV neutropenia (ANC<0.5×10 /l) for more than 7 days, or neutropenic fever lasting more than 3 days, or 9 thrombocytopenia (platelet counts<25×10 /l) or any nonhematologic grade III or IV toxicity. Etoposide was discontinued, 9 if the granulocyte or platelet counts were below 1.0×10 /l or 9 50×10 /l, respectively. Because etoposide was available as 25mg capsules, the dose was calculated for a three or four day period. A total of 6 cycles was planned, but patients had their therapy stopped when the toxicity became non-manageable, or when there was evidence of a progressive disease. 4) Definition of response and statistics MATERIALS AND METHODS 1) Patient selection Patients with histologically confirmed ED SCLC, were enrolled onto the study. ED was defined as a disease beyond the hemithorax of the origin and regional lymph nodes. Each patient was required to meet the following criteria: ECOG performance status 2; adequate bone marrow function (absolute neutrophil count (ANC) 2.0×109/l, platelet count 100×109/l); normal hepatic function (serum total bilirubin 1.5 mg/dl and serum AST and ALT less than 3.0 the upper normal limit (UNL)); normal renal function (serum creatinine 1.5 mg/dl). Patients having previously received systemic chemotherapy for SCLC were excluded. Pregnant, or lactating, patients or those with a history of prior malignancies, other than previously excised or curatively irradiated basal cell skin cancer or in situ cervical cancer, were excluded. Patients with brain metastasis, and in need of imminent brain radiotherapy at the time of diagnosis, were excluded. Patients with severe heart disease, active infection, a past history of significant neurologic or psychiatric disorder, a history of hypersensitivity or uncontrolled medical illness were excluded. 2) Patient evaluation Pretreatment evaluations consisted of complete medical The WHO response criteria were used to define the tumor response. The occurrence of pleural effusion was also considered as a sign of a progressive disease if this was substantiated by positive cytology. Patients were assessed for their response after having received a minimum of 2 cycles of treatment, and at least one follow-up tumor assessment. The duration of a partial response was taken from the date the partial response was documented to the first confirmed date of disease progression, and the duration of a complete response was taken from the moment the complete response was documented. The survival duration was determined by measuring the time between the initial treatment and death; the median survival was calculated using the Kaplan-Meier method. Table 1. Treatment protocol ꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚ Drug administration Dosage Day ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Cisplatin IV for 4 hours 20 mg/m/day D1-3 Ifosfamide continuous IV 1.5 g/m/day D1-3 Mix with Mesna 900 mg/m/day D1-3 Etoposide PO 50 mg/m/day D4-17 ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ *Repeated every 4 weeks Seok Jin Kim, et al:Oral Etoposide, Ifosfamide and Cisplatin in ED SCLC 423 RESULTS 1) Patient characteristics Twenty-five patients were enrolled in this study between January 2000 and May 2002; the patients' characteristics are listed Table 2. The median patient age was 65 years; there were 19 male and 6 female patients. Fifteen patients (60%) had an ECOG performance status of 0-1, and 8 had more than two sites of metastasis. Three patients were not assessable for response. After the first cycle, 2 of these 3 patients dropped out due to the development of pneumonia. The remaining patient withdrew from the study after the second cycle, due to the patient opting for an alternative medication. Therefore, 22 patients were assessable for response, but all 25 were evaluated for toxicity. 2) Response and survival Twenty-two patients were assessable, and no complete responses were observed. Sixteen patients achieved a partial response, with an overall response rate of 72.7% (95% confidence interval: 49.6∼88.4%). Two patients had a stable disease and 4 had a progressive disease (Table 3). Of the 4 patients with progressive disease, 1 patient, who had multiple metastases, which included the liver and bone marrow, died due to neutropenic fever after the first cycle. Of the 3 remaining Table 2. Patient characteristics ꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚ No. ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ No. enrolled 25 No. assessable 22 Age(years) Median 65 Range 32∼75 Gender Male 19 Female 6 ECOG performance status 0 3 1 12 2 10 Site of metastasis Liver 13 Brain 7 Bone 6 Pleura 5 Pancreas 2 Adrenal gland 1 Lung 1 Bone marrow 1 No. of metastatic sites 1 17 2 5 3 3 ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ patients with a progressive disease, 1 had pleural and pericardial effusion, another had liver metastasis, and the third had a brain lesion. These patients were all ECOG performance status 2. The median response duration of all responders was 7 months (95% confidence interval: 3.5∼10.5 months). Of the 2 patients with a stable disease, the disease progression was observed at 4 and 2 months following the diagnosis of a stable disease. The median overall survival of all the patients was 10 months (95% confidence interval: 5.3∼14.7 months). Of the 7 patients with brain metastasis, 5 had a partial response, 1 a stable disease and the other developed a progressive disease. Of the 5 responders, 1 was referred for brain radiotherapy after completing six cycles of chemotherapy. Two of the 5 who showed a progressing brain lesion were removed from the study after the third cycle. The remaining 2 patients were withdrawn from the study because they refused further treatment after the fourth cycle. 3) Toxicity and dose-intensity The toxicity was evaluated in all the 25 patients during all the 91 cycles. The hematologic and non-hematologic toxicities encountered are listed in Table 4. The major hematologic toxicities were: leukopenia, 19 cycles showing grade III and 25 cycles grade IV, and neutropenia, 15 cycles showing grade III and 27 cycles grade IV. Grade III thrombocytopenia occurred Table 3. Response rate ꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚ Assessable patients Response ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ No. of patients % ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Complete response (CR) 0 0 Partial response (PR) 16 72.7 Stable disease (SD) 2 9.1 Progressive disease (PD) 4 18.2 All 22 100 ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Table 4. Hematological and non-hematological toxicity ꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚ Number of cycles (total No.=91 cycles) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Grade ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Toxicity I II III IV ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Leukopenia 10 18 19 25 Neutropenia 6 12 15 27 Thrombocytopenia 2 8 5 3 Anemia 7 8 3 1 Nausea/Vomiting 27 25 12 2 Diarrhea 5 4 2 0 Mucositis 4 3 2 0 Neuropathy 3 0 0 0 ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ 424 Cancer Research and Treatment 2002;34(6) in 5 cycles and grade IV in 3. Six patients experienced febrile neutropenia. Two cases of pneumonia were reported after the first cycle, and these patients were withdrawn from the study. Death related to drug-induced neutropenia occurred in 1 patient after completing the first cycle. The non-hematologic toxicities did not seem to be significant during the treatment courses. Nausea and vomiting were the most common toxicity related events. Fourteen cycles showed grade III and IV nausea and vomiting, although the grade IV occurred in only 2 cycles. Other toxicities included diarrhea, mucositis and neuropathy. No hematuria, a known toxicity of ifosfamide, was observed. The actually delivered doses were 13.4 mg/m2/wk of cisplatin, 139.7 mg/m2/wk of etoposide and 2 0.95 g/m /wk of ifosfamide. The dose-intensity (the actual dose delivered as a proportion of the planned dose) was 89% for cisplatin, 80% for etoposide and 84% for ifosfamide. DISCUSSION Systemic combination chemotherapy has been the mainstay for the treatment of extensive disease small cell lung cancer. The combination of cyclophosphamide, doxorubicin and vincristine (CAV) was common in the 1970s (10). In the 80s, the etoposide and cisplatin (EP) regimen was reported as the first effective second-line therapy, because of the synergy of etoposide and cisplatin (11). Two phase III trials compared the CAV and EP regimens, and by alternating the CAV and EP regimens, in patients with an extensive disease. No differences were observed in the response or survival, but the toxicity of the CAV regimen was greater (12,13). Thus, EP was adapted as the first line treatment, and this remains the case for ED SCLC. However, little improvement has been made over the last two decades in improving the median survivals, of 8 to 10 months, in patients with ED SCLC, despite improved the response rates. Strategies to improve the efficacy of standard chemotherapy include; dose intensification, the use of higher doses, with cytokine support (14), maintenance treatment with other drugs (15,16) and the addition of new drugs in multi-agent combinations. Because SCLC relapses, largely as a result of drug resistance, overcoming drug resistance may be the best way of preventing a relapse and prolonging survival, and therefore, adding a new effective agent to a commonly used regimen may be a strategy for the improvement of the therapeutic efficacy, and to overcome drug resistance development. Although the available data remain unconvincing, three-drug regimens may confer a meaningful benefit over two-drug regimens in SCLC. Ifosfamide has been shown to be synergistic with platinum compounds, by reversing the intracellular mechanisms of resistance, and decreasing DNA repair and the detoxification of reactive cisplatin and glutathione intermediates (17). It has been reported that adding ifosfamide to etoposide and cisplatin improved the median survival from 7.3 to 9.0 months, and resulted in a higher 2-year survival rate of 13% against 5% (7). ECOG, incorporating ifosfamide and carboplatin in combination with prolonged oral etoposide (ICE), was reported to have an overall response rate and 2-year survival rate of 83% and 14%, respectively (18). The previous phase II study on the combination of cisplatin, ifosfamide and prolonged oral administration of etoposide used the same protocol as ours. They reported a 93% overall response rate and a 54 week median survival (9). In our study, the overall response rate was 72.7% and the median survival duration was 10 months. This difference may be due to several reasons. First, there were more patients with an ECOG performance status of 2 in our population, and they were 6 years older than the population of the previous study. Second, the total number of assessable patients in our study was relatively small. Despite the high incidence of grade IV neutropenia (27 cycles per total of 91 cycles), its duration was rarely prolonged. However, there was a death related to drug induced neutropenia occurred, and 2 cases of pneumonia developed after the first treatment cycle, which was thought to be associated with orally administered etoposide-induced myelosuppression. It was reported that the delayed development of myelosuppression on days 16 through to 20 was observed in a study of advanced non-small cell lung cancer with the same regimen as used in this study. They suggested that myelosuppression development could be related with etoposide administration and individual differences in the etoposide absorption rate (19). Thus, careful attention should be paid to monitor the development of etoposide-induced myelosuppression, including CBC follow-up, especially during the first treatment cycle. Several cases of myelosuppression were observed on the days the etoposide was orally administration, causing us to reduce the dosage, or skip etoposide administration altogether. However, the overall drug compliance for the oral etoposide was satisfactory, with a dose intensity of 80%. Nausea and vomiting were the most frequent non-hematological toxicity, and grade IV toxicity was rare. Hemorrhagic cystitis, which is known as the main ifosfamide-induced toxicity, was not observed, due to its effective prevention with mesna. Other toxicities did not seem to be significant in the present study, and the dose-intensity for each drug was over 80%. However, unlike previous reports using the same regimen, our results failed to demonstrate a significant improvement in the response rate and median survival duration, even though the patient population studied had poorer prognostic features. CONCLUSIONS The cisplatin, ifosfamide and oral etoposide combination regimen was tolerated, but its response rate and median survival were similar to other previously documented combination regimens in patients with ED SCLC. 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