A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma

Continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycoprotein antagonist

Authors

  • Jame Abraham M.D.,

    1. Medicine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Susan Bakke R.N.,

    1. Medicine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Ann Rutt R.N.,

    1. Medicine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Beverly Meadows R.N.,

    1. Medicine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Maria Merino M.D.,

    1. Surgical Pathology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Richard Alexander M.D.,

    1. Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • David Schrump M.D.,

    1. Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • David Bartlett M.D.,

    1. Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Peter Choyke M.D.,

    1. Department of Radiology, Clinical Center, National Institutes of Health, Bethesda, Maryland
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  • Rob Robey M.S.,

    1. Medicine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Elizabeth Hung M.S., M.P.H.,

    1. Medicine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Seth M. Steinberg Ph.D.,

    1. Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Susan Bates M.D.,

    1. Medicine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Tito Fojo M.D., Ph.D.

    Corresponding author
    1. Medicine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    • Medicine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 12N226, 9000 Rockville Pike, Bethesda, MD 20892
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    • Fax: (301) 402-1608


Abstract

BACKGROUND

Adrenocortical carcinoma (ACC) is rare, nearly always fatal, and to the authors' knowledge has few nonsurgical treatment options. Based on in vitro studies demonstrating the efficacy of mitotane as a P-glycoprotein (Pgp) antagonist, and expression of high levels of Pgp in ACC, the authors conducted a study of infusional doxorubicin, vincristine, and etoposide with oral mitotane ± surgical resection in patients with metastatic ACC.

METHODS

Thirty-six patients with metastatic ACC received daily oral mitotane (mean, 4.6 g/day) and 96-hour infusional doxorubicin (10 mg/m2/day), etoposide (75 mg/m2/day), and vincristine (0.4 mg/m2/day). Four responding patients (11%) underwent surgery.

RESULTS

Thirty-five patients were evaluable; all had metastatic disease. Eleven patients had not undergone resection of the primary tumor. Approximately 53% of patients had functional tumors. A total of 190 cycles were administered to 36 patients. Responses were observed in 8 patients (22%): 1 complete, 4 partial, and 3 minor responses. The mean duration of response was 12.4 months. Using a landmark method, the median survival of patients who did not respond to chemotherapy was 11.6 months from a point 4 months after the initiation of therapy, whereas that of 8 patients who demonstrated a response to chemotherapy was 34.3 months from that same landmark. High levels of Pgp expression were documented in nine of nine tumors. Mitotane levels > 10 μg/mL, previously shown to antagonize Pgp in vitro, were achieved in 25 of 36 patients (69%). However, rhodamine efflux from CD56-positive cells was not impaired, suggesting poor in vivo Pgp inhibition. The predominant Grade 3/4 toxicity (according to the Common Toxicity Criteria of the National Cancer Institute) was neutropenia in 66% of cycles; however, fever occurred in only 3% of cycles. Daily mitotane was associated with Grade 1/2 nausea, diarrhea, fatigue, and neuropsychiatric changes in 31 of 36 patients (86%).

CONCLUSIONS

Using a combination regimen of daily mitotane with infusional doxorubicin, vincristine, and etoposide in patients with metastatic ACC, responses were observed in 22% of patients. The superiority of this combination over single-agent mitotane is uncertain. The side effects of mitotane made treatment difficult. More effective Pgp antagonists are needed. Cancer 2002;94:2333–43. © 2002 American Cancer Society.

DOI 10.1002/cncr.10487

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