Abstract
A phase I dose-escalation study of multicyclic, ifosfamide, carboplatin, and etoposide (ICE) with sequential reinfusion of peripheral blood stem cells (PBSCs) was conducted to determine the maximum-tolerated dose (MTD) of ICE. Twenty-four patients with SCLC (LD: 6, ED: 18) were treated with ifosfamide (3000–9000 mg/m2, 24-h infusion), carboplatin (300–400 mg/m2), and etoposide (300 mg/m2) followed by subcutaneous filgrastim (75 μg/day) from day 4 to the day of PBSC collection. PBSC were harvested when the WBC count reached ⩾5 × 109/l. The leukapheresis product was cryopreserved and reinfused on day 4 of the next cycle, which was started 48 h after the last PBSC collection. The ifosfamide dose was escalated as follows: 3000 mg/m2 (level 1), 5000 mg/m2 (level 2), 7000 mg/m2 (level 3), 9000 mg/m2 (level 4). Patients with LD were treated with concurrent radiotherapy at 1.5 Gy twice daily for the initial 3 weeks to a total dose of 45 Gy and MTD, defined separately. Patients were evaluated for hematologic and non-hematologic toxicity, actual dose intensities, as well as response to therapy. The maximum-tolerated dose (MTD) was defined as the dose level at which more than 5 days of grade 4 myelo- suppression or non-hematologic toxicity greater than grade 3 developed in two thirds of the patients. For ED cases, MTD was level 4 and the recommended dose of ifosfamide was 7000 mg/m2. For LD cases, the recommended dose of ifosfamide was 5000 mg/m2. The dose limiting toxicity of multicyclic ICE was hemato- logic toxicity and CNS toxicity which manifested as ataxia. Tumor responses were seen in all patients, with 14 patients showing a complete response. The actual total dose-intensity at the recommended dose level was 2.2 and 1.74, for ED and LD, respectively, compared with previously reported ICE regimens. PBSC support for dose-intensive ICE regimen permitted dose escalation of ifosfamide with a mean interval of 16–17 days. We conclude that this regimen is well tolerated, with acceptable hematological and non-hematological toxicity. Bone Marrow Transplantation (2000) 25, 5–11.
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References
Gurney H, Dodwell D, Thatcher N, Tattersall MH . Escalating drug delivery in cancer chemotherapy: a review of concepts and practice – part 1 Ann Oncol 1993 4: 23–34
Gurney H, Dodwell D, Thatcher N, Tattersall MH . Escalating drug delivery in cancer chemotherapy: a review of concepts and practice – part 2 Ann Oncol 1993 4: 103–115
Coldman AJ, Goldie JH . Impact of dose-intense chemotherapy on the development of permanent drug resistance Semin Oncol 1987 14: (Suppl.4) 29–33
DeVita VT Jr . The influence of information on drug resistance on protocol design Ann Oncol 1991 2: 93–106
Arriagada R, Le Chevalier T, Pignon JP et al. Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer New Engl J Med 1993 329: 1848–1852
Humblet Y, Symann M, Bosly A et al. Late intensification chemotherapy with autologous bone marrow transplantation in selected small-cell carcinoma of the lung: a randomized study J Clin Oncol 1987 5: 1864–1873
Shea TC, Mason JR, Storniolo AM et al. Sequential cycles of high-dose carboplatin administered with recombinant human granulocyte–macrophage colony-stimulating factor and repeated infusions of autologous peripheral blood progenitor cells: a novel and effective method for delivering multiple courses of dose-intensive therapy J Clin Oncol 1992 10: 464–473
Tepler I, Cannistra SA, Frei E et al. Use of peripheral blood progenitor cells abrogates the myelotoxicity of repetitive outpatient high-dose carboplatin and cyclophosphamide chemotherapy J Clin Oncol 1993 11: 1583–1591
Pettengell R, Woll PJ, Thatcher N et al. Multicyclic, dose-intensive chemotherapy supported by sequential reinfusion of hematopoietic progenitors in whole blood J Clin Oncol 1995 13: 148–156
Kohno A, Takeyama K, Narabayashi M et al. Low-dose granulocyte colony-stimulating factor enables the efficient collection of peripheral blood stem cells after disease-oriented, conventional-dose chemotherapy for breast cancer, malignant lymphoma and germ cell tumor Bone Marrow Transplant 1995 15: 49–54
Martinez C, Sureda A, Martino R et al. Efficient peripheral blood stem cell mobilization with low-dose G-CSF (50μg/m2) after salvage chemotherapy for lymphoma Bone Marrow Transplant 1997 20: 855–858
Hryniuk W, Bush H . The importance of dose intensity in chemotherapy of metastatic breast cancer J Clin Oncol 1984 2: 1281–1288
Smith IE, Perren TJ, Ashley SA et al. Carboplatin, etoposide, and ifosfamide as intensive chemotherapy for small-cell lung cancer J Clin Oncol 1990 8: 899–905
Gatzemeier U, Hossfeld DK, Neuhauss R et al. Combination chemotherapy with carboplatin, etoposide, and vincristine as first-line treatment in small-cell lung cancer J Clin Oncol 1992 10: 818–823
Loehrer PJ Sr, Rynard S, Ansari R et al. Etoposide, ifosfamide, and cisplatin in extensive small cell lung cancer Cancer 1992 69: 669–673
Seifter EJ, Ihde DC . Therapy of small cell lung cancer: a perspective on two decades of clinical research Semin Oncol 1988 15: 278–299
Skarlos DV, Samantas E, Kosmidis P et al. Randomized comparison of etoposide-cisplatin vs etoposide-carboplatin and irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group study Ann Oncol 1994 5: 601–607
Thatcher N . Ifosfamide/carboplatin/etoposide (ICE) regimen in small cell lung cancer Lung Cancer 1993 9: S51–S67
Blackstein ME . Advances in chemotherapy for small cell lung cancer Semin Oncol 1994 21: (Suppl. 1) 38–42
Van der Wall E, Richel DJ, Holtkamp MJ et al. Bone marrow reconstitution after high-dose chemotherapy and autologous peripheral blood progenitor cell transplantation: effect of graft size Ann Oncol 1994 5: 795–802
Woll PJ, Hodgetts J, Lomax L et al. Can cytotoxic dose intensity be increased by using granulocyte colony-stimulating factor? A randomized controlled trial of lenograstim in small-cell lung cancer J Clin Oncol 1995 13: 652–659
Thatcher N, Sambrook RJ, Stephens RJ et al . Dose intensification (DI) with G-CSF improves survival in small cell lung cancer (SCLC): results of a randomized trial Proc Am Soc Clin Oncol 1998 18:: (Abstr. 1754) 17456a
Pignon JP, Arriagada R, Ihde DC et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer (see comments) New Engl J Med 1992 327: 1618–1624
Murray N, Coy P, Pater JL et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group J Clin Oncol 1993 11: 336–344
Perry MC, Herndon JE, Eaton WL, Green MR . Thoracic radiation therapy added to chemotherapy for small-cell lung cancer: an update of Cancer and Leukemia Group B Study 8083 J Clin Oncol 1998 16: 2466–2467
Turrisi AT, Kim K, Blum R et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide New Engl J Med 1999 340: 265–271
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We are grateful to Satomi Takeuchi for technical assistance.
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Takahashi, M., Yoshizawa, H., Tanaka, H. et al. A phase I dose escalation study of multicyclic, dose-intensive chemotherapy with peripheral blood stem cell support for small cell lung cancer. Bone Marrow Transplant 25, 5–11 (2000). https://doi.org/10.1038/sj.bmt.1702088
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DOI: https://doi.org/10.1038/sj.bmt.1702088
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