Efficacy of Adjuvant Mitotane Treatment (ADIUVO)

Study Rationale Adrenocortical carcinoma (ACC) is a very rare disease with a high risk of relapse after radical surgery. The efficacy of adjuvant mitotane treatment is suggested by a retrospective multicenter international study showing that postoperative mitotane treatment was associated with a significant reduction of the risk of relapse and death. However, these promising results need confirmation in a randomized prospective study. Caution should be adopted particularly in patients with low risk of disease relapse, in whom the benefit of therapy should be weighted against the side effects. Even if an adjuvant treatment seems justified in patients at high risk of relapse, a randomised prospective study is needed to assess whether such a treatment is efficacious in patients at low-intermediate risk.

The purpose of the present study is to determine whether adjuvant mitotane treatment is effective in prolonging the disease free survival in patients with adrenocortical carcinoma at low-intermediate risk of progression who underwent radical resection

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.

Eligibility Criteria:
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.