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A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma
Author(s) -
Abraham Jame,
Bakke Susan,
Rutt Ann,
Meadows Beverly,
Merino Maria,
Alexander Richard,
Schrump David,
Bartlett David,
Choyke Peter,
Robey Rob,
Hung Elizabeth,
Steinberg Seth M.,
Bates Susan,
Fojo Tito
Publication year - 2002
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.10487
Subject(s) - medicine , adrenocortical carcinoma , chemotherapy , surgical resection , oncology , carcinoma
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/m 2 /day), etoposide (75 mg/m 2 /day), and vincristine (0.4 mg/m 2 /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