Efficacy of adjuvant Mitotane treatment in prolonging recurrence-free survival in patients with Adrenocortical Carcinoma at low-intermediate risk of recurrence submitted to radical resection

Study design and objectives in brief

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.

Study objectives


To compare the efficacy of adjuvant Mitotane treatment vs observation only in prolonging recurrence free survival (RFS) in patients with ACC at low-intermediate risk of recurrence after complete resection.

  • Comparison of Overall Survival (OS);
  • Comparison of quality of life;
  • Assessment of toxicity;
  • Assessment of the impact of mitotane serum levels on the efficacy of treatment;
  • Assessment of the efficacy of the mitotane administration on subgroups of patients stratified according to: type of hormone secretion, stage of disease, histopathologic characteristics.



To compare RFS, 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.
  • To compare OS, 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 RFS and OS in patients who achieve or not serum mitotane concentrations > 14 mg/l;
  • To compare RFS and OS between the 2 arms in patients subgroups stratified according to: type of hormone secretion, stage of disease, histopathologic characteristics.

Study design

Prospective, randomized, controlled, open label, multi-center phase III trial.

Treatment administered

Patients will be randomly assigned to receive Mitotane treatment or observational follow up only. Mitotane will be administered till progression or unacceptable toxicity for a minimum of 2 years. Mitotane will be provided by HRA Pharma.

Concomitant treatments

All patients treated with Mitotane will receive concomitant administration of glucocorticoids to prevent adrenal insufficiency. Fludrocortisone may be added depending on blood pressure, serum potassium levels and plasma renin activity/concentration.

The administration of any other anticancer agents including chemotherapy and active biologic agents is NOT permitted.

Statistical analysis

The sample size is calculated using the primary end point recurrence-free survival. The main statistical analysis of the primary end point will be based on the intention-to-treat (ITT) population. Based on the results of previous studies, in patients with low-intermediated recurrence risk it is estimated a recurrence free survival rate after 2 years of about 0.60 with surgery only. The sample size is calculated to provide an 80% chance of detecting an increase of non-progressing patients at 2 years from 0.60 to 0.75. Taking 0.05 as the level of significance (alpha) and using a two-sided log rank test for analysis, it is calculated that approximately 180 patients will be randomized considering 4 years of accrual and 2 years of follow-up after entry of the last patient. Assuming a lost-to-follow-up rate of maximum 10%, a total of 200 patients (100 per treatment arm) will be needed.

An interim analysis will be performed after occurrence of 29 events.

The primary analysis on recurrence free survival will be conducted as follows: for each group, the RFS distribution and the median RFS time will be estimated using the Kaplan-Meier method. The two-sided logrank test will be used to compare the survival times between the two arms. The Cox's proportional hazard model will be used to estimate the hazard ratio (HR) with 95% confidence intervals. To verify the proportional hazard assumption both graphical checks and statistical tests (as introducing into the model an interaction term between the treatment variable and a function of time) will be applied. The stratification employed to randomize the patients should prevent unbalances between the two arms, however an adjusted HR standardised for the most important prognostic factors will also be estimated. The final analysis will be conducted after each patient enrolled will have at least a 2 year follow-up or experienced a failure. The primary analysis will be based on the ITT analysis set. However, a sensitivity analysis will be conducted on a per protocol analysis set. The latter only serves to confirm the robustness of the results. Toxicities will be compared between the two groups with usual statistical methods, however, to take into account competitive risks (due to death or disease recurrence), a cumulative incidence proportion of severe toxicities will be calculated using the method described by Gooley et al and compared with Gray's test. Further analyses of the secondary endpoints are sensitivity analyses, or they are descriptive or explorative. Subgroup analyses will be performed by including in the Cox model interaction terms between the treatment and subgroup variables.

Sample size and study duration

200 patients (100 per treatment arm) will be enrolled. The duration of the study will be: 6 years (enrollment period, 4 years; follow-up period, 2 years).


Coordinating Centers

  • Dipartimento di Scienze Cliniche e Biologiche Università degli Studi di Torino
    Medicina Interna I, AOU San Luigi Gonzaga, Orbassano (TO) - Italy
    Massimo TERZOLO, MD
  • Oncologia Medica, AOU San Luigi Gonzaga, Orbassano (TO) - Italy
    Alfredo BERRUTI, MD

Steering committee and scientific support

Study Chairs
International study coordinator

Department of Internal Medicine
University of Wuerzburg
Josef-Schneider-Str. 2 - D-97080 Wuerzburg - Germany

European study coordinators
  • Harm HAAK, MD
    Department of Internal Medicine
    Maxima Medisch Centrum
    5600 PD Eindhoven - The Netherlands
  • Eric BAUDIN, MD
    Département de Médecine Nucléaire et de Cancérologie Endocrinienne
    Institut Gustave Roussy
    39 Bis, Rue Camille Desmoulins - F-94800 Villejuif - France
Protocol committee


Statistical design of the Study, Center of collection and data analysis

Statistical Board
Data management

Independent data monitoring committe

  • Ulrich MANNSMANN
  • Vincenzo TOSCANO