Abstract
Introduction: The purpose of this study was to determine the recommended phase II dose (RPTD) of the combination of cyclophosphamide and liposomal doxorubicin (Doxil). Patients and methods: Eligibility criteria included: a diagnosis of non-hematologic cancer with no conventional effective therapy, normal renal, liver and bone marrow function, and ECOG performance status of 0-2. Both drugs were administered intravenously on day 1 of a 21-day cycle. The following doses (mg/m2) of Doxil and cyclophosphamide were tested: 30/500, 40/600, and 48/600. Results: Thirty-seven patients with a median age of 62 years (male:female 21:16) received 119 cycles of Doxil and cyclophosphamide. Hand-foot syndrome and mucositis were the dose limiting toxicities for this combination. Other major toxicities included neutropenia. The side effects to the combination were cumulative. The RPTD of Doxil and cyclophosphamide was 48 mg/m2 and 600 mg/m2, respectively. Three patients with adenocarcinoma of the stomach, fibrosarcoma of the stomach and renal cell carcinoma showed objective antitumor responses. Conclusion: The toxicity profile of the combination of Doxil/cyclophosphamide differs significantly from that of non-liposomal doxorubicin plus cyclophosphamide. Major toxicities of the combination include the hand-foot syndrome, stomatitis and neutropenia.
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References
A'Hern RP, Smith IE, Ebbs SR: Chemotherapy and survival in advanced breast cancer: The inclusion of doxorubicin in Cooper type regimens. Br J Cancer 67: 801-805, 1993
Polychemotherapy for early breast cancer: An overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 352: 930-942, 1998
Sparano JA, Winer EP: Liposomal anthracyclines for breast cancer. Semin Oncol 28: 32-40, 2001
Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R, Martin F, Huang A, Barenholz Y: Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54: 987-992, 1994
Northfelt DW, Martin FJ, Working P, Volberding PA, Russell J, Newman M, Amantea MA, Kaplan LD: Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: Pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi's sarcoma. J Clin Pharmacol 36: 55-63, 1996
Uziely B, Jeffers S, Isacson R, Kutsch K, Wei-Tsao D, Yehoshua Z, Libson E, Muggia FM, Gabizon A: Liposomal doxorubicin: Antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 13: 1777-1785, 1995
Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, Muggia FM: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91: 710-717, 1979
Berry G, Billingham M, Alderman E, Richardson P, Torti F, Lum B, Patek A, Martin FJ: The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi's sarcoma patients treated with pegylated liposomal doxorubicin. Ann Oncol 9: 711-716, 1998
Batist G, Ramakrishnan G, Rao CS, Chandrasekharan A, Gutheil J, Guthrie T, Shah P, Khojasteh A, Nair MK, Hoelzer K, Tkaczuk K, Park YC, Lee LW: Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol 19: 1444-1454, 2001
Vaage J, Donovan D, Wipff E, Abra R, Colbern G, Uster P, Working P: Therapy of a xenografted human colonic carcinoma using cisplatin or doxorubicin encapsulated in long-circulating pegylated stealth liposomes. Int J Cancer 80: 134-137, 1999
Ranson MR, Carmichael J, O'Byrne K, Stewart S, Smith D, Howell A: Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: Results of a multicenter phase II trial. J Clin Oncol 15: 3185-3191, 1997
Holder L, Overmoyer B, Silverman P, Tripathy D, Marrs N: Doxil and oral cyclophosphamide as first line therapy for patients with.62 metastatic breast cancer: Preliminary results of a pilot trial, ASCO proceedings 1, 1998
Silverman P, Overmoyer B, Holder L: Doxil and intravenous cyclophosphamide as first line therapy for patients with advanced breast cancer: Interim analysis of an ongoing pilot trial, ASCO proceeding 1, 1999
Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MF: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707-712, 1989
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783-792, 2001
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El-Rayes, B.F., Ibrahim, D., Shields, A.F. et al. Phase I study of liposomal doxorubicin (Doxil) and cyclophosphamide in solid tumors. Invest New Drugs 23, 57–62 (2005). https://doi.org/10.1023/B:DRUG.0000047106.20104.a7
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DOI: https://doi.org/10.1023/B:DRUG.0000047106.20104.a7