Background:

• Adrenocortical cancer (ACC) is a rare disease with an extremely poor prognosis.

• Treatment of advanced ACC has never been adequately standardized and the choice of therapy is based on personal experience and data from uncontrolled trials.

• Previous studies including streptozotocin plus mitotane (Sz/M) regimen and etoposide, doxorubicin, cisplatin plus mitotane (EDP/M) regimen appear to have some activity in ACC and were recommended as best choices until better data arise.

• Previous reports with EDP/M suggest that it is possible to achieve with this regimen a higher response rate than with the Sz/M regimen, but that it may be more toxic. No survival data is available for comparison from these studies.

Objectives:

-To investigate whether etoposide, doxorubicin, cisplatin plus mitotane (EDP/M) as first line treatment will prolong survival as compared to streptozocin plus mitotane (Sz/M) as first line treatment in advanced ACC.

Eligibility:

• Histologically confirmed diagnosis of adrenocortical carcinoma.

• Locally advanced or metastatic disease not amenable to radical surgery resection (Stage III-IV).

• Radiologically measurable disease.

• ECOG performance status 0 - 2.

• Life expectancy greater than 3 months.

• Age greater than or equal to 18 years.

• Adequate bone marrow reserve (neutrophils greater than 1500/mm(3) and platelets greater than 100,000/mm(3)).

• Previous palliative surgery, radiotherapy or radiofrequency ablation is acceptable as long as disease that can be monitored and verified radiologically has not been treated.

Design:

• Phase III, randomized, open-label, multi-national trial.

• 300 patients will be accrued for the study.

• Patients will be randomized to receive therapy with etoposide, doxorubicin, cisplatin plus mitotane (EDP/M) or streptozotocin plus mitotane (Sz/M) as first line treatment.

• Evaluation of response is scheduled every 8 weeks in the first 6 months after beginning first line and second line treatment, respectively, and afterwards every 12 weeks. In case of documented disease progression or unacceptable toxicity, subjects will be switched to the alternative regimen.

• INCLUSION CRITERIA:

Clinical inclusion criteria

• Histologically confirmed diagnosis of adrenocortical carcinoma.

• Locally advanced or metastatic disease not amenable to radical surgery resection (Stage III-IV).

Other inclusion criteria

• Radiologically monitorable disease.

• ECOG performance status 0-2.

• Life expectancy greater than 3 months.

• Age greater than or equal to 18 years.

• Adequate bone marrow reserve (neutrophils greater than or equal to 1500/mm(3) and platelets greater than or equal to 100.000/mm(3)).

• Effective contraception in pre-menopausal female and male patients.

• Patient’s written informed consent.

• Ability to comply with the protocol procedures (including availability for follow-up visits).

• Previous palliative surgery, radiotherapy or radiofrequency ablation is acceptable as long as radiologically monitorable disease is verifiably afterwards.

EXCLUSION CRITERIA:

• History of prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, or other cancers treated with no evidence of disease for at least five years.

• Previous cytotoxic chemotherapy (prior therapy with mitotane is allowed) for adrenocortical carcinoma.

• Renal insufficiency (serum creatinine greater than or equal to 2 mg/dl or creatinine clearance less than or equal to 50 ml/min).

• Hepatic insufficiency (serum bilirubin greater than or equal to 2 times the institutional upper limit of normal range and/or serum transaminases greater than or equal to 3 times the institutional upper limit of normal range; exception: in patients on mitotane transaminase levels up to 5 times the institutional upper limit of normal range are acceptable).

• Pregnancy or breast feeding.

• Known hypersensitivity to any drug included in the treatment protocol.

• Presence of active infection.

• Any other severe clinical condition that in the judgment of the local investigator would place the patient at undue risk or interfere with the study completion.

• Decompensated heart failure (ejection fraction less than 50 percent), myocardial infarction or revascularization procedure during the last 6 months, unstable angina pectoris, and uncontrolled cardiac arrhythmia.

• Current treatment with other experimental drugs and/or previous participation in clinical trials with other experimental agents for adrenocortical carcinoma.

• Prisoners