title: 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.
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/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 microg/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.
authors.affiliation: Medicine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jame
authors.initials: J
authors.lastname: Abraham
authors.forename: Susan
authors.initials: S
authors.lastname: Bakke
authors.forename: Ann
authors.initials: A
authors.lastname: Rutt
authors.forename: Beverly
authors.initials: B
authors.lastname: Meadows
authors.forename: Maria
authors.initials: M
authors.lastname: Merino
authors.forename: Richard
authors.initials: R
authors.lastname: Alexander
authors.forename: David
authors.initials: D
authors.lastname: Schrump
authors.forename: David
authors.initials: D
authors.lastname: Bartlett
authors.forename: Peter
authors.initials: P
authors.lastname: Choyke
authors.forename: Rob
authors.initials: R
authors.lastname: Robey
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hung
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Susan
authors.initials: S
authors.lastname: Bates
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000097:blood; D000284:Administration, Oral; D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery*; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery*; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019002:CD56 Antigen / Q000032:analysis; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000008:administration & dosage* / Q000009:adverse effects; D009362:Neoplasm Metastasis; D012235:Rhodamines / Q000378:metabolism; D015996:Survival Rate; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D019002:CD56 Antigen; D012235:Rhodamines; D014750:Vincristine; D005047:Etoposide; D008939:Mitotane; D004317:Doxorubicin