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© 1999 American Society for Clinical Oncology Multiple Courses of High-Dose Ifosfamide, Carboplatin, and Etoposide With Peripheral-Blood Progenitor Cells and Filgrastim for Small-Cell Lung Cancer: A Feasibility Study by the European Group for Blood and Marrow TransplantationFrom the Centre Pluridisciplinaire d'Oncologie, Lausanne, and ForMed, Statistics for Medicine, Evolène, Switzerland; Ospedale Civile, Ravenna, and Ospedale Civile Maggiore, Verona, Italy; Hopital Universitaire St-Luc, Brussels, and Centre Hospitalier Regional Citadelle, Liège, Belgium; and K. Dluski Hospital, Wroclaw, Poland. Address reprint requests to Serge Leyvraz, MD, Centre Pluridisciplinaire d'Oncologie, CHUV BH 10, Rue du Bugnon 46, 1011 Lausanne, Switzerland; email serge.leyvraz{at}chuv.hospvd.ch
PURPOSE: To determine the feasibility and safety of multiple sequential courses of high-dose chemotherapy and peripheral-blood progenitor cells (PBPCs) administered in a multicenter setting to patients with small-cell lung cancer. PATIENTS AND METHODS: Sixty-nine patients (limited disease, n = 30; extensive disease, n = 39) treated at 15 European centers were scheduled to receive three courses of high-dose chemotherapy with ifosfamide 10 g/m2, carboplatin 1200 mg/m2, and etoposide 1200 mg/m2 (ICE) divided over 4 days at 28-day intervals. PBPCs were harvested before treatment and mobilized with epirubicin 150 mg/m2 administered via an intravenous bolus divided over 2 days and filgrastim 5 µg/kg/d administered subcutaneously. RESULTS: The performed leukaphereses (one to five per patient) yielded a median of 16.6 x 106/kg (range, 1.0 to 96.6 x 106/kg) CD34+ cells, which was sufficient for three reinfusions. Fifty patients (72%) completed the treatment according to schedule. Nine patients completed two courses, and six patients completed one course of treatment. The increase in dose-intensity was 290% that of a standard ICE regimen. The median duration of myelosuppression was similar between courses, namely 4 days (range, 1 to 12 days) for leukocytes less than 0.5 x 109/L and 4 days (range, 0 to 22 days) for thrombocytes less than 20 x 109/L. Febrile neutropenia developed in 66% of courses, severe diarrhea in 14%, mucositis in 10%, and nausea and vomiting in 21% of courses. There were six cases of toxic death (9%), most of which occurred in the first year of accrual and thus were attributable to the learning curve. The antitumor effect of the regimen was reflected in an 86% remission rate (95% confidence interval [CI], 74% to 93%), with 51% of patients achieving a complete response (95% CI, 38% to 63%). Median overall survival was 18 months for patients with limited disease and 11 months for patients with extensive disease. CONCLUSION: This multiple sequential high-dose ICE regimen could be safely administered on a multicenter basis to patients with small-cell lung cancer. The dose-intensity could be increased to 290% that of standard ICE regimen. The benefit of this approach is currently being tested in a randomized trial that aims to double the long-term rate of survival for patients with small-cell lung cancer.
MORE THAN 25 YEARS ago, it was suggested that small-cell lung carcinoma (SCLC) would be the next on a list of curable cancers, following choriocarcinoma, lymphoma, testicular cancer, and some forms of acute leukemia. It was regarded as a distinct histopathologic entity1 with a high labeling index, a high growth fraction, and a short doubling time, similar to Burkitt's lymphoma.2 These characteristics and the discovery of SCLC's high metastatic potential3 provided the basis for testing chemotherapeutic agents. Researchers found that intermittent high-dose cyclophosphamide (40 mg/kg/mo) led to significant improvements.4 The efficacy of cyclophosphamide was enhanced by applying maximum-tolerated doses instead of low daily doses.5 The next series of improvements came with the introduction of combination regimens, which not only afforded better response rates and higher complete remission rates but also prolonged the median survival even more.6 Multiple agents had to be administered at doses high enough to induce some myelotoxicity.7-9 Combination therapy comprising cyclophosphamide, doxorubicin, and vincristine (CAV) was the first regimen to become an established standard,10 at least until the synergistic association of cisplatin and etoposide (PE) was discovered.11 Response rates in extensive disease were in the 51% to 78% range, including a 7% to 13% complete remission rate and a median survival of 8 to 9 months. The corresponding data for patients with limited disease were 16% to 18% or 11.7 to 12.4 months, respectively.12-14 Early clinical results also suggested some impact of dose on the outcome of SCLC.5,15 However, a relatively recent meta-analysis of combination regimens including CAV and PE failed to confirm any such systematic correlation between dose-intensity and complete response or survival.16 The range of intensity variation was narrow, rarely exceeding 30% to 50% of the standard dose. Randomized studies designed to clarify this issue actually added to the confusion; some studies yielded negative results,17-19 whereas the more recent studies have tended to yield positive results.20-23 These discrepancies may, of course, be due to differences in patient selection, size of the patient sample, and rate of intensification. Moreover, the study designs also differed in terms of end points, depending on whether their focus was response rates, median survival, or long-term survival. To further increase the dose-intensity, autologous bone marrow cells (ABMT) or peripheral-blood progenitor cells (PBPCs) were used to control the hematologic toxicity of high-dose chemotherapy. Unfortunately, most of these trials were uncontrolled and comprised small patient numbers with heterogeneous prognostic factors. Those studies mainly tested late intensification strategies, in which a single course of intensive chemotherapy is administered in an attempt to consolidate the response to standard treatment. A combined analysis did not reveal an apparent improvement in survival, even though the percentage of complete responders almost doubled.24 At the same time, it was proposed that late intensification might improve the long-term survival in a significant proportion of complete responders with limited disease.25 A randomized trial suggested an improvement in median survival among limited-disease patients from 14 to 19 months.26 These results were not statistically significant, however, presumably because of the small sample size and the high toxic death rate (18%) in the intensified group. High-dose chemotherapy with ABMT was also administered up front as first-line treatment. The rationale of this was to intensify therapy for all patients while avoiding drug resistance induced by previous chemotherapy. Although this approach resulted in impressive rates of complete remission (56% to 67%) among limited-disease patients,27-29 the impact on median or long-term survival could not be reliably assessed because of insufficient sample sizes and the absence of control groups. This prompted us to prepare a randomized trial comparing standard chemotherapy regimens with high-dose combination regimens to elucidate the role of dose-intensity in chemotherapy for SCLC. The main objective of the present study was to test the feasibility of the high-dose regimen across various European centers in preparation for a multicenter randomized trial. The requirements defined for the high-dose regimen were that it had to be (1) three times more dose-intensive than the standard regimen,30 (2) safe and simple enough to be administered to patients up to 65 years old, and (3) suitable to be carried out on a multicenter basis. It consisted of a sequential combination regimen supported by PBPCs and granulocyte colony-stimulating factor (G-CSF).
Patients Patients were eligible for the study if they had newly diagnosed and untreated SCLC. Inclusion criteria included age of 18 to 65 years, performance status of less than 2, blood count within the normal range, and normal cardiac, hepatic, and renal function. All patients were required to give informed consent. Cerebral metastasis was not an exclusion criterion. Before study entry, all patients underwent staging investigations, including physical examination, chest x-ray, computerized tomography (CT) of chest and abdomen, bone scintigraphy, full blood count, electrolyte measurements, liver and renal function tests, fiberoptic bronchoscopy with biopsy, and bone marrow biopsy. Brain CT scans and serum neuron-specific enolase (NSE) levels were obtained optionally. Limited disease was defined as tumor confined to one hemithorax with or without ipsilateral supraclavicular lymphadenopathy or pleural effusion. All other patients were defined as having extensive disease. During the follow-up, patients underwent weekly clinical examinations, including a full blood count. Patients who developed fever during granulopenia were admitted to the hospital for parenteral antibiotics. A biochemical profile, renal function tests, and chest x-ray were obtained before each treatment cycle. After the end of treatment, patients underwent clinical examinations every month and radiodiagnostic assessment every 3 months.
Mobilization and Collection of PBPCs Quantitation of CD34+ cells was subjected to quality assurance at the beginning of the study. The exact equipment and technique was selected by the various centers to best suit their experience. The 13 centers participating in the standardization scheme were supplied with the same sample for CD34+ cell quantitation. The same antibody (HPCA-2, Becton Dickinson, Rutherford, NJ) was used in 11 centers, but the measurements were performed with different flow cytometers. Quantitation was performed on the day of collection (n = 3 centers), on day 2 (n = 4), on day 3 (n = 5), or on day 4 (n = 1). Figure 1 shows that 12 laboratories (92%) were within two SDs, so that the results could be pooled for direct comparison. Colony assays such as granulocyte-macrophage colony-forming units (GM-CFU) were performed in only a few centers and were not standardized.
High-Dose Treatment Regimen
Fourty-eight hours after the end of chemotherapy, PBPCs were reinfused and G-CSF was introduced at 5 µg/kg/d administered subcutaneously until the leukocytes rose to
Subsequent cycles were delayed by 1 or 2 weeks until recovery of leukocytes to
Assessment of Toxicity, Response, and Survival Progression-free survival and overall survival were calculated from the first day of chemotherapy to first progression or death, whichever occurred first. The study was approved by the ethics committees in charge of the various centers.
Statistics
Differences in distribution of continuous and categoric variable were assessed using the Kruskal-Wallis and
Patient Characteristics Sixty-nine patients were enrolled at 15 European centers between March 1994 and October 1997. Six centers included the majority of patients and nine centers enrolled one or two patients. Pertinent patient data are listed in Table 1. Of these 69 patients, 43% showed limited disease and 57% showed extensive disease. Of the patients with extensive disease, 69% had two or more metastatic sites and 59% had liver metastases. Three patients presented with brain metastases. LDH levels were elevated in more than one half of all patients. Only 16% of patients were female.
Mobilization and Collection of PBPCs Collection of mononuclear cells yielded 6.3 x 108/kg (range, 2.2 to 21.3 x 108/kg), which corresponded to a median of 16.6 x 106/kg CD34+ cells (range, 1.0 to 96.6 x 108/kg). The quality control allowed comparison between CD34+ counts obtained across centers. GM-CFU assays were performed in 47 patients, but the results were highly variable because of the absence of any standardization and hence were unsuitable for direct comparison (data not shown). Hematologic toxicity was minimal, with median nadirs for leukocytes at 3.8 x 109/L (range, 0.1 to 11.9 x 109/L), platelets at 120 x 109/L (range, 14 to 323 x 109/L), and hemoglobin at 105 g/L (range, 8.8 to 142 g/L). Fever occurred in 12 patients (17%), eight of whom had proven infection, including catheter infection (n = 1), lung abscess (n = 1), pararectal abscess (n = 1), sepsis (n = 4), and unknown cause of infection (n = 1). Mucositis occurred in six patients but did not reach WHO grade 3 except in one case. Due to antiemetic premedication, nausea and vomiting was not a major toxicity and was grade 3 in five patients. Nine patients had diarrhea, of whom one had grade 3 diarrhea. One patient died of acute heart failure, and one patient with sepsis died of septic shock. In 49 patients, the antitumor effect could be assessed by standard chest x-ray. None of these x-rays showed tumor progression. Twenty-one patients (43%) responded to a single cycle of high-dose epirubicin, including one complete responder. All other patients showed stable disease (three with minor response).
Sequential High-Dose Chemotherapy The treatment plan was to accomplish an increase in average dose-intensity based on dose per time unit or single dose-intensity to 310% of the standard ICE regimen.22 Ifosfamide was planned to be increased by a factor of 2, carboplatin by a factor of 4, and etoposide by a factor of 3.3. Treatment could be given as planned every 4 weeks and was delayed in only 39 cycles (23%). The reasons were asthenia or patient refusal (n = 7), toxicity (n = 11), and lack of available beds in some centers (n = 21). Owing to treatment delays and missing cycles, the actual delivered median dosages were reduced to ifosfamide 2,380 mg/m2/wk (range, 1,560 to 2,780 mg/m2/wk), carboplatin 282 mg/m2/wk (range, 185 to 335 mg/m2/wk), and etoposide 282 mg/m2/wk (range, 205 to 335 mg/m2/wk).39 Based on all three drugs, the implemented dose-intensity was 94% of the planned dose-intensity.
Toxicity
The median interval in terms of severe leukopenia (leukocytes < 0.5 x 109/L) was 4 days (range, 1 to 12 days), with no differences between cycles (P = .290). Severe thrombocytopenia (thrombocytes < 20 x 109/L) also lasted for a median of 4 days (range, 0 to 22 days). Repeated treatment cycles involved no cumulative thrombocytopenia, as confirmed by similar rates of platelet transfusion per patient per cycle (P > .3). Febrile neutropenia developed in 74%, 63%, and 60% (P = .254) and proven infection developed in 43%, 36%, and 37% (P = .674) of cycles 1, 2, and 3, respectively. Major infection ( Treatment with IV antibiotics lasted for a median of 8 days (range, 0 to 62 days) with no difference between cycles. The median number of 20 days (range, 5 to 75 days) of hospitalization was also similar across cycles (P = .213).
Based on severe (
Response and Survival Bronchoscopy with or without biopsy was performed in 23 of the 33 complete responders and was invariably found to be normal. Based on the 24 partial responders, bronchoscopy was performed in 18 patients and found to be normal in 13. The radiotherapy policies adopted in the various centers were not uniform. Radiation was administered to the primary site in 37 patients and in a prophylactic cranial approach in 24 patients. Five partial responders became complete responders after radiotherapy was administered to the chest. All 69 patients were analyzed for progression-free survival and overall survival over a median follow-up of 45 months. Twelve deaths without tumor progression and 47 cases of disease progression resulted in a median progression-free survival time of 9.2 months. The median progression-free survival was higher in patients with limited disease than in patients with extensive disease (11 v 7 months; P = .001) and in patients with normal LDH levels than in patients with abnormal LDH levels (9.5 v 7.6 months; P = .0011). The main first site of tumor progression was the brain in 21 patients (30%), one of whom had carcinomatous meningitis. Locoregional progression was diagnosed in 17 patients (25%). Other sites of progression were liver (n = 9), distant lymph nodes (n = 7), bone (n = 4), pleura (n = 2), adrenal (n = 2), bone marrow (n = 2), skin (n = 1), chest wall (n = 1), and breast (n = 1).
The overall survival extended to a median of 13.5 months. As is apparent in Fig 2,
SCLC is a potentially curable disease, even though the 5-year survival rate after current strategies of standard combination chemotherapy and radiotherapy does not exceed 3% to 5%.40-42 Among the various possible approaches to improving outcome for patients with SCLC, intensification of chemotherapy is a particularly promising option. Unfortunately, the experience with this strategy has never transcended the level of uncontrolled trials focusing on early or late intensification programs. Whereas these numerous small studies have tended to reveal increased rates of complete remission, the long-term outcome was simply beyond their scope. The only randomized study on late intensification did suggest but could not demonstrate an improvement in survival, because the patient sample was too small and the death rate in the intensified group was too high.26 In recent years, more randomized trials were performed to study early intensification regimens involving increases in dose-intensity of 7% to 33%.20-23 These studies did reveal encouraging improvements in 2-year survival, even though both CR and median survival remained unchanged in some studies. These trials thus far have a short follow-up period, but genuine data on long-term survival can be expected in the foreseeable future. Experimental data have shown that drug concentrations must be increased to 300% to 500% in vitro to effect cell kill in resistant cell lines on a similar scale as in sensitive ones.43 As hematopoietic growth factors and peripheral stem cells became available for clinical use, increases in dose-intensity by at least a factor of 3 became realistic.30 Patients with lung cancer, however, tend to suffer from cardiovascular and pulmonary comorbidities that might be limiting to high-dose regimens,44 which made it necessary before embarking on a randomized trial to test the feasibility of the high-dose approach in a multicenter setting.
The present study demonstrates that intensive sequential chemotherapy under the cover of PBPCs, filgrastim, and prophylactic antibiotics is indeed feasible. The actual implemented dose-intensity of ICE was 94% of the planned dose-intensity. Moreover, 72% of all patients completed the treatment program according to schedule. This compares very favorably with results obtained in a series of younger breast cancer patients, only 40% to 67% of whom completed all cycles of sequential chemotherapy as planned,45,46 or with a 56% rate of completion of six treatment cycles administered to another group of SCLC patients.29 The 9% rate of toxic deaths was high in our series but was within the range of other intensification regimens.22,25,29,47 The high rate of toxic deaths might be due to the frequently associated comorbidities observed in these patients and also to the limited experience of some centers in administering sequential intensive therapy. Indeed, among the 15 centers, nine treated only The ICE combination of chemotherapeutic agents has a favorable therapeutic index. A steep dose response combined with the potential of synergistic antitumor activity and a favorable spectrum of nonhematopoietic toxicity makes this combination a natural candidate for high-dose therapy.48 Intensification of ICE in SCLC has been tested under the cover of hematopoietic growth factors with a cumulative dose-intensity during the first three cycles that was increased to 134%.21 The dose-intensity could be doubled by adding hematopoietic progenitor cells.29 Our study demonstrates that further intensification of up to 290% of standard ICE can be achieved at an acceptable toxicity profile that compares favorably with less intensive regimens.21,22,29 If in this study the dose of carboplatin was administered on a mg/m2 basis in order to have a simple comparison with the standard ICE regimen, then in the ongoing randomized EBMT trial, it is based on the area under the curve to avoid individual variation in dose and toxicity. Our initial concern that administration of multiple sequential cycles might progressively and cumulatively exhaust hematopoiesis proved to be unfounded. There were no differences between treatment cycles regarding the duration or time until recovery of leukopenia and thrombocytopenia, nor were there any differences regarding the number of erythrocyte and platelet transfusions. This is in contrast to the patterns observed with whole blood29 as the source of hematopoietic progenitors or even hematopoietic growth factors only.21 Those studies were characterized by a progressive decrease in platelet nadirs starting during the second cycle with an increase in the requirement for platelet transfusion.29 One way of explaining this phenomenon would be that the hematopoietic progenitors collected after each high-dose chemotherapy course were declining in both quality and quantity.49 In our own series, we did not have this problem, thanks to a large-scale collection of progenitors (median CD34+ cells, 16.6 x 106/kg) harvested after the administration of combined high-dose epirubicin and filgrastim before high-dose ICE therapy was started. In accordance with EBMT recommendations for safe reinfusion, 93% of our patients received at least 2 x 106/kg of CD34+ cells.31 Furthermore, our policy of harvesting hematopoietic progenitors before therapy also reduced the number of leukaphereses. Considering the different techniques used in the various centers, it is remarkable that a median of three leukaphereses were enough to obtain the targeted collection, with only 15 patients (30%) needing four or five leukaphereses. Previous dose-intensive multiple approaches have, by comparison, required at least six to eight leukaphereses,29,45,46 which is both more expensive and renders the procedure as a whole cumbersome. The constraints inherent in any multicenter randomized trial required us to develop a simpler and more economical design. The main objective of this study was to ascertain whether the adopted strategy of sequential high-dose chemotherapy of SCLC was feasible, and, therefore, the criteria for patient selection remained broad. Certain adverse prognostic factors such as brain metastases or multiple metastatic sites were not considered to be exclusion criteria. Likewise, the use of radiotherapy was not standardized but left within the discretion of the various centers. Given these broad criteria, the achieved rates of complete remission of 51% in the absence and 58% in the presence of radiotherapy was in the range of other intensive approaches. This rate was significantly higher in patients with limited disease (70%) than in patients with extensive disease (36%), and all complete responders were tumor-free as determined by bronchoscopy and histopathology. These results are obviously better than those usually reported for standard treatment, where the rate of CR does not tend to exceed approximately 20% in limited disease and 10% in extensive disease.12-14 They are in the range, however, of what is obtained after other intensive treatment programs such as two cycles of high-dose cyclophosphamide, whether alone27 or in combination.24,28 Equally high rates of complete remission have been put forward in relatively recent randomized trials,20-22 and interestingly not only for the intensified chemotherapy arms but also for the standard arms. Two explanations are possible for these puzzling data. First, the method of assessing response may not have been sensitive enough to discriminate between CR and good partial response, which would be consistent with the fact that these studies relied solely on standard chest x-ray. Second, there is evidence that the prognosis of patients with limited SCLC has improved in recent years.50 Viewed in this way, the rate of complete remission would not be a surrogate for long-term survival, a notion that is accepted for most tumors. Despite similar rates of CR, the intensified arm of these studies showed an improvement at 2 years.20-22 Furthermore, the figures on median survival were comparable but were not predictive of long-term outcome.21 This suggests that improvement in long-term survival, rather than response rate or median survival, should be the main end point in designing a randomized trial for SCLC.
The present study resulted in a median survival of 18 months among patients with limited disease, and 32% of them were alive at 2 years. The corresponding results in extensive disease were 11 months for median survival, with 5% of patients alive at 2 years. In the published randomized trials, the 2-year survival rate in the intensive arm was 32% to 42% in limited disease19,20 and
Additional participating institutions include the following: Centre de Santé des Fagnes, Chimay, Belgium (Hamdan Oussama, MD); Clinique Notre Dame, Charleroi, Belgium (Jean-Luc Canon, MD); Ospedale San Francesco, Nuoro, Italy (Attilio Gabbas, MD); Centre Régional Léon Bérard, Lyon, France (Paul Rebattu, MD); Istituto Europeo di Oncologia, Milano, Italy (Giovanni Martinelli, MD); Centre Hospitalier St-Joseph Espérance, Liège, Belgium (Luc Longrée, MD); Ospedale San Giovanni, Bellinzona, Switzerland (Michele Ghielmini, MD); Ospedale San Giovanni, Torino, Italy (Mario Airoldi, MD); and Klinikum Rechts der Isar der Technischen Universität, München, Germany (Michael Fromm, MD).
We thank Marianne Gonin for secretarial assistance and all of the data managers for precise collection of the data.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
0.5 x 109/L. After the first cases of septic death had occurred, the recommendation was issued to prophylactically administer oral antibiotics (methylpenicillin and ciprofloxacin). 
120 µmol/L or creatinine clearance to 
2 tests, respectively.
