Efficacy of Adjuvant Mitotane Treatment (ADIUVO)

Endpoints Primary : To compare DFS (Disease Free Survival), defined as the time between the
date of randomization until documentation of any of the following failures (whichever occurs
first): -local or distant recurrence of disease;-death from any cause or completion of
follow-up.

Secondary:

To compare OS (Overall Survival), defined as the time interval between the date of
randomization and the date of death from any cause or the last known alive date;· To compare
quality of life measured by EORTC-QLQ-C30· To compare toxicity, graded according to the
NCI-CTG criteria;· To compare DFS and OS in patients who achieve or not serum mitotane
concentrations > 14 mg/L;· To compare DFS and OS between the 2 arms in patients subgroups
stratified according to: type of hormone secretion, stage of disease, histopathologic
characteristics.

Inclusion Criteria:

- Histologically confirmed diagnosis of ACC according to Weiss system by a national
reference pathologist who has to be nominated before study initiation.

- Low-intermediate risk of relapse defined as:

- Stage I-III (according to ENSAT classification 2008; see Appendix 2)

- Microscopically complete resection, defined as no evidence of microscopic
residual disease based on surgical reports, histopathology and post-operative
imaging. Detailed pathological and surgical reports prepared according to
guidelines detailed in appendix x and y should be available for assessment.

- Ki 67 < 10%

- Post-operative imaging (thoracic and whole abdominal CT with contrast medium or MRI)
demonstrating no evidence of disease within 4 weeks from randomization

- Age > 18 years

- ECOG performance status 0-2 (Appendix 3)

- Adequate bone marrow reserve (neutrophils > 1000/mm3 and platelets > 80000/ mm3)

- Ability to comply with the protocol procedures (including geographic accessibility)

- Written informed consent

Exclusion Criteria:

- Time between primary surgery and randomization > 3 months.

- Repeat surgery for recurrence of disease

- Presence of autonomous adrenocortical hormone secretion despite the absence of
disease detectable with imaging techniques

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

- Renal insufficiency (creatinine clearance < 40 ml/min) or liver insufficiency (serum
bilirubin > 2 times the upper normal range and/or serum transaminases (AST/SGOT,
ALT/SGPT, but not gamma Glutamyl Transpeptidase) >3 times the upper normal range).
Creatinine clearance may be calculated according to validated formulas (Crockoft's or
MDRD)

- Pregnancy or breast feeding

- Previous or current treatment with mitotane or other antineoplastic drugs for ACC

- Previous radiotherapy of the tumor bed (for ACC).

- Any other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that would impart, in the judgment of the investigator, excess risk
associated with study participation or study drug administration, or which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study.