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Originally published as JCO Early Release 10.1200/JCO.2008.19.0892 on October 6 2008 © 2008 American Society of Clinical Oncology.
High-Dose Etoposide: From Phase I to a Component of Curative Therapy
Meharry Medical College, Nashville, TN
Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN In 1983, we reported in Journal of Clinical Oncology1 a phase I high-dose escalation study of the chemotherapeutic agent etoposide. By reinfusing autologous bone marrow to assure hematopoietic recovery, we were able to identify the nonmyeloid dose-limiting toxicity of this agent. At the same time, other chemotherapy agents were similarly studied, based on the concept that high-dose therapy might be superior treatment for cancers that were not successfully treated with standard-dose cytotoxic therapy.2-8 The results of these single-agent studies led to the development of the combination regimens that today remain integral to high-dose anticancer therapy. The intravenous infusion of marrow-derived hematopoietic stem cells to facilitate marrow ablative cytotoxic therapy was under intense investigation in the 1980s. The fundamentals of such therapy were pioneered, during the previous decade, by Nobel laureate E. Donnell Thomas, MD, and George Santos, MD.9 They hypothesized that supra-maximal therapy could overcome resistance to standard-dose therapy and began to unravel the immunologic aspects of allogeneic graft-versus-host disease. Patients with resistant acute leukemia were initially treated, using fresh allogeneic marrow and cytotoxic therapy consisting of total whole-body irradiation (TBI) with cyclophosphamide or busulfan with cyclophosphamide. These therapies provided two predominant functions: (1) profound immunosuppression to allow engraftment of allogeneic cells and (2) cytoreduction to eradicate leukemia refractory to standard-dose treatment. Despite substantial toxicity, a minority of patients with otherwise incurable acute leukemia achieved long-term complete remission. Autologous cryopreserved marrow-derived stem-cell transplantation was similarly developed to allow patients to donate their own stem cells, thus avoiding the allogeneic consequences of graft-versus-host disease. The first reports of cryopreserved autologous transplantation, in the 1980s, used large aliquots of marrow aspirates as the cell source with adequate marrow recovery and cure of some patients with resistant lymphoma.10,11 In this era, improvements in supportive care for the consequences of neutropenia and thrombocytopenia reduced the morbidity and mortality of transplantation. Gradually, other cancers became targets of high-dose therapy as autologous transplantation and supportive care became more refined. Recently, the preferred source for hematopoietic stem cells are mobilized peripheral-blood cells collected by large-volume leukapheresis.12,13 Etoposide (VP-16-213), a semi-synthetic congener of epidophyllotoxin, has a broad spectrum of clinical activity in hematologic and solid tumors. The standard dose of etoposide is 300 to 500 mg/m2 administered in divided doses over 3 to 5 days and repeated every 3 weeks. With this dose, grade 4 neutropenia and thrombocytopenia (usually of brief duration) is produced in 10% to 15% of patients. We chose this agent to dose escalate because myelosuppression was its dose-limiting toxicity, with other toxicities being infrequent or mild. Our trial escalated etoposide using a modified Fibonacci scheme from the previous highest dose ever administered to humans (1,500 mg/m2) to 2,700 mg/m2 (900 mg/m2 per day for 3 consecutive days). A total of 28 patients underwent four dose escalations, with four patients treated at the highest dose and 13 patients at the prior dose level. At 2,700 mg/m2, severe mucositis was observed in three of three courses. At the next highest dose (2,400 mg/m2), only two (11%) of 18 courses resulted in severe mucositis, thus defining this dose as the maximally tolerated dose based on extramedullary toxicities. In reviewing these observations 25 years later, it is conceivable that further dose escalation may have been achieved with current methods to mitigate mucous membrane toxicity and prevent herpes simplex virus reactivation.14 As anticipated, myelotoxicity was severe, but based on the kinetics of marrow recovery, etoposide at these doses appeared not to be marrow ablative. Etoposide produced a prolonged duration of cytopenias at all dose levels, but peripheral blood count recovery (defined as > 500 neutrophils/µ L and > 20,000 platelets/µ L) occurred before three weeks after transplantation in all except one patient. During this time, we did not routinely measure stem cell content using CD34+ cell number as a surrogate and therefore could not, beyond measuring total nucleated cell count, determine the quality of the marrow infusion. The duration of neutropenia (< 500 neutrophils/µL) was similar at all dose levels with a median of 11 days. Our suspicion that dose escalated etoposide was not myeloablative was confirmed in a subsequent study, when high-dose dose of etoposide (1.8 to 4.8 g/m2 by continuous infusion) was administered with high-dose cyclophosphamide (50 mg/kg/d x 3-4 days).15 In this trial, patients with refractory leukemia or lymphoma recovered their blood counts without autologous stem cell support. In our study, patients with refractory hematologic or solid tumors were eligible, and objective responses were seen in acute lymphocytic leukemia, germ cell tumor, glioblastoma multiforme, and Hodgkin's lymphoma. Overall, tumor responses occurred in 36% of all patients, but most responses were of brief duration. Five of six patients with refractory germ cell tumors responded, four of whom were refractory to regimens containing standard-dose etoposide. We therefore concluded, based on responses observed in this study, that high-dose etoposide should be explored in phase II studies or used in combination chemotherapy. Dose escalation of cytotoxic therapy may alter the pharmacokinetics measured with standard-dose therapy by increasing peak levels or the area under the concentration-time curve. Regional distribution can be improved, especially to "sanctuary" sites with high-dose therapy. As part of our study, we measured plasma, urine, and CSF etoposide concentrations in 12 adult patients to determine the pharmacokinetics of this drug at these elevated dosages.16 Increasing the etoposide dose produced proportionally higher peak plasma etoposide concentrations (27 to 114 µg/mL) and total areas under the concentration-time curve. The etoposide mean terminal half-life and plasma clearance, however, were independent of the dosage given. CSF etoposide concentrations were 1.8% ± 1.7% of the simultaneously measured plasma levels. Pleural fluid removed from one patient at 18 hours post-therapy contained etoposide at 1.8 µg/mL. Our data, combined with previously published data, indicated that the pharmacokinetics of high-dose etoposide are linear within the dosage range tested. They also suggested that etoposide penetrates poorly into the CSF. High-dose etoposide in combination with other cytotoxics continues to be a component of high-dose therapy for the treatment of refractory hematologic neoplasms, including acute leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.17-24 These regimens produce substantial myelotoxicity and mucositis, as well as occasional pulmonary and hepatic toxicity.25 Whether adding etoposide to other high-dose regimens or to TBI regimens (eg, cyclophosphamide and TBI) yields superior results to these regimens without etoposide has not been determined.26,27 Nonetheless, it is generally believed that maximal antitumor cytotoxicity should be delivered with autologous transplantation. However, the profound antitumor effect of allogeneic graft-versus leukemia has led to the evaluation of reduced-intensity preparative regimens designed for immunosuppression rather than cytotoxicity for patients not projected to be able to tolerate allogeneic marrow transplantation with full-dose preparative regimens.28 In contrast to the continued role of high-dose therapy in the treatment of hematologic malignancies, this approach has not been useful in most solid tumors. Early studies with high-dose etoposide produced higher response rates, but responses were of brief duration.29-33 Randomized trials have subsequently failed to demonstrate any advantage of high-dose therapy when compared with standard dose in metastatic breast or ovarian cancer.34,35 An exception may be testicular cancer. A recent report suggested improved survival (compared with historical controls) when patients in first or second relapse received two successive treatments with high-dose etoposide plus carboplatin followed by autologous stem-cell support.36 Twenty-five years after the first dose-escalation studies, high-dose etoposide remains a routine component of potentially curative high-dose therapy for patients with several hematologic malignancies. However, the administration of high-doses of etoposide (as well as other cytotoxic agents) has made no contribution to the therapy of common solid tumors. Recent improved understanding of cancer stem cells suggests that these quiescent cells are resistant to standard cytotoxic agents, regardless of dose.37 Further improvements in therapy will require continued definition and exploration of molecular mechanisms unique to cancer cells. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Steven N. Wolff, John D. Hainsworth, F. Anthony Greco Manuscript writing: Steven N. Wolff, John D. Hainsworth, F. Anthony Greco Final approval of manuscript: Steven N. Wolff, John D. Hainsworth, F. Anthony Greco ACKNOWLEDGMENTS Supported by Minnie Pearl Cancer Foundation (F.A.G. and J.D.H.) and National Institutes of Health/National Cancer Institute Grants No. 5 U54 CA091408 08 and 5 U10 CA107612 05 (S.N.W.). NOTES published online ahead of print at www.jco.org on October 6, 2008 REFERENCES 1. Wolff SN, Fer MF, McKay CM, et al: High-dose VP-16-213 and autologous bone marrow transplantation for refractory malignancies: A phase I study. J Clin Oncol 1:701-705, 1983[Abstract] 2. Phillips GL, Fay JW, Herzig GP, et al: Intensive 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), NSC #4366650 and cryopreserved autologous marrow transplantation for refractory cancer A phase I-II study. Cancer 52:1792-1802, 1983[CrossRef][Medline] 3. Phillips GL, Wolff SN, Fay JW, et al: Intensive 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) monochemotherapy and autologous marrow transplantation for malignant glioma. J Clin Oncol 4:639-645, 1986 4. Lazarus HM, Herzig RH, Graham-Pole J, et al: Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer. J Clin Oncol 1:359-367, 1983[Abstract] 5. Lazarus HM, Phillips GL, Herzig RH, et al: High-dose melphalan and the development of hematopoietic stem-cell transplantation: 25 years later. J Clin Oncol 26:2240-2243, 2008 6. Lazarus HM, Gottfried MR, Herzig RH, et al: Veno-occlusive disease of the liver after high-dose mitomycin C therapy and autologous bone marrow transplantation. Cancer 49:1789-1795, 1982[CrossRef][Medline] 7. Wolff SN, Herzig RH, Fay JW, et al: High-dose N,N',N'-triethylenethiophosphoramide (thiotepa) with autologous bone marrow transplantation: Phase I studies. Semin Oncol 17:2-6, 1990[Medline] 8. Shea TC, Flaherty M, Elias A, et al: A phase I clinical and pharmacokinetic study of carboplatin and autologous bone marrow support. J Clin Oncol 7:651-661, 1989[Abstract] 9. Appelbaum FR: Hematopoietic-cell transplantation at 50. N Engl J Med 357:1472-1475, 2007 10. Phillips GL, Herzig RH, Lazarus HM, et al: Treatment of resistant malignant lymphoma with cyclophosphamide, total body irradiation, and transplantation of cryopreserved autologous marrow. N Engl J Med 310:1557-1561, 1984[Abstract] 11. Philip T, Armitage JO, Spitzer G, et al: High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med 316:1493-1498, 1987[Abstract] 12. Brunvand MW, Bensinger WI, Soll E, et al: High-dose fractionated total-body irradiation, etoposide and cyclophosphamide for treatment of malignant lymphoma: Comparison of autologous bone marrow and peripheral blood stem cells. 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Blood 85:1391-1395, 1995 18. Fleming DR, Wolff SN, Fay JW, et al: Protracted results of dose-intensive therapy using cyclophosphamide, carmustine, and continuous infusion etoposide with autologous stem cell support in patients with relapse or refractory Hodgkin's disease: A phase II study from the North American Marrow Transplant Group. Leuk Lymphoma 35:91-98, 1999[Medline] 19. Phillips GL, Wolff SN, Herzig RH, et al: Treatment of progressive Hodgkin's disease with intensive chemoradiotherapy and autologous bone marrow transplantation. Blood 73:2086-2092, 1989 20. Horning SJ, Chao NJ, Negrin RS, et al: The Stanford experience with high-dose etoposide cytoreductive regimens and autologous bone marrow transplantation in Hodgkin's disease and non-Hodgkin's lymphoma: Preliminary data. Ann Oncol 2:47-50, 1991 (suppl 1) 21. Horning SJ, Negrin RS, Chao JC, et al: Fractionated total-body irradiation, etoposide, and cyclophosphamide plus autografting in Hodgkin's disease and non-Hodgkin's lymphoma. J Clin Oncol 12:2552-2558, 1994 22. Long GD, Chao NJ, Hu WW, et al: High dose etoposide-based myeloablative therapy followed by autologous blood progenitor cell rescue in the treatment of multiple myeloma. Cancer 78:2502-2509, 1996[Medline] 23. Weaver CH, Appelbaum FR, Petersen FB, et al: High-dose cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation in patients with lymphoid malignancies who have received dose-limiting radiation therapy. J Clin Oncol 11:1329-1335, 1993 24. Weaver CH, Petersen FB, Appelbaum FR, et al: High-dose fractionated total-body irradiation, etoposide, and cyclophosphamide followed by autologous stem-cell support in patients with malignant lymphoma. J Clin Oncol 12:2559-2566, 1994 25. Wolff SN: High-dose carmustine and high-dose etoposide: A treatment regimen resulting in enhanced hepatic toxicity. Cancer Treat Rep 70:1464-1465, 1986[Medline] 26. Stein RS, Greer JP, Goodman S, et al: Intensified preparative regimens and autologous transplantation in refractory or relapsed intermediate grade non-Hodgkin's lymphoma. Bone Marrow Transplant 25:257-262, 2000[CrossRef][Medline] 27. Stein RS, Greer JP, Goodman S, et al: Is total body irradiation a necessary component of preparative therapy for autologous transplantation in non-Hodgkin's lymphoma. Leuk Lymphoma 41:97-103, 2001[Medline] 28. Baron F, Storb R: Allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning as treatment for hematologic malignancies and inherited blood disorders. Mol Ther 13:26-41, 2006[CrossRef][Medline] 29. Giannone L, Wolff SN: Phase II treatment of central nervous system gliomas with high-dose etoposide and autologous bone marrow transplantation. Cancer Treat Rep 71:759-761, 1987[Medline] 30. Greco FA, Johnson DH, Hande KR, et al: High-dose etoposide (VP-16) in small-cell lung cancer. Semin Oncol 12:42-44, 1985[Medline] 31. Wolff SN, Birch R, Sarma P, et al: Randomized dose-response evaluation of etoposide in small cell carcinoma of the lung: A Southeastern Cancer Study Group Trial. Cancer Treat Rep 70:583-587, 1986[Medline] 32. Wolff SN, Johnson DH, Hainsworth JD, et al: High-dose VP-16-213 monotherapy for refractory germinal malignancies: A phase II study. J Clin Oncol 2:271-274, 1984[Abstract] 33. Wolff SN, Johnson DH, Hande KR, et al: High-dose etoposide as single-agent chemotherapy for small cell carcinoma of the lung. Cancer Treat Rep 67:957-958, 1983[Medline] 34. Crump M, Gluck S, Tu D, et al: Randomized trial of high-dose chemotherapy with autologous peripheral-blood stem-cell support compared with standard-dose chemotherapy in women with metastatic breast cancer: NCIC MA.16. J Clin Oncol 26:37-43, 2008 35. Möbus V, Wandt H, Frickhofen N, et al: Phase III trial of high-dose sequential chemotherapy with peripheral blood stem cell support compared with standard dose chemotherapy for first-line treatment of advanced ovarian cancer: Intergroup trial of the AGO-Ovar/AIO and EBMT. J Clin Oncol 25:4187-4193, 2007 36. Einhorn LH, Williams SD, Chamness A, et al: High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 357:340-348, 2007 37. Reya T, Morrison SJ, Clarke MF, et al: Stem cells, cancer, and cancer stem cells. Nature 414:105-111, 2001[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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