Prognostic Role of Overt Hypercortisolism in Completely Operated Patients with Adrenocortical Cancer

Abstract

Background

Although prognostic parameters are important to guide adjuvant treatment, very few have been identified in patients with completely resected adrenocortical carcinoma (ACC).

Objective

To assess the prognostic role of clinical symptoms of hypercortisolism in a large series of patients with completely resected ACC.

Design, setting, and participants

A total of 524 patients followed at referral centers for ACC in Europe and the United States entered the study. Inclusion criteria were ≥18 yr of age, a histologic diagnosis of ACC, and complete surgery (R0). Exclusion criteria were a history of other malignancies and adjuvant systemic therapies other than mitotane.

Intervention

All ACC patients were completely resected, and adjuvant mitotane therapy was prescribed at the discretion of the investigators.

Outcome measurements and statistical analysis

The primary end point was overall survival (OS). The secondary end points were recurrence-free survival (RFS) and the efficacy of adjuvant mitotane therapy according to cortisol secretion.

Results and limitations

Overt hypercortisolism was observed in 197 patients (37.6%). Patients with cortisol excess were younger (p = 0.002); no difference according to sex and tumor stage was observed. The median follow-up of the series was 50 mo. After adjustment for sex, age, tumor stage, and mitotane treatment, the prognostic significance of cortisol excess was highly significant for both RFS (hazard ratio [HR]: 1.30; 95% confidence interval [CI], 1.04–2.62; p = 0.02) and OS (HR: 1.55; 95% CI, 1.15–2.09; p = 0.004). Mitotane administration was associated with a reduction of disease progression (adjusted HR: 0.65; 95% CI, 0.49–0.86; p = 0.003) that did not differ according to the patient's secretory status. A major limitation is that only symptomatic patients were considered as having hypercortisolism, thus excluding information on the prognostic role of elevated cortisol levels in the absence of a clinical syndrome.

Conclusions

Clinically relevant hypercortisolism is a new prognostic factor in patients with completely resected ACC. The efficacy of adjuvant mitotane does not seem to be influenced by overt hypercortisolism.

Introduction

Adrenocortical carcinoma (ACC) is a rare tumor characterized by a dismal prognosis with <50% of patients surviving >5 yr after diagnosis [1]. Complete surgical resection of ACC offers the best chance for prolonged survival, particularly in patients diagnosed at an early stage and with low proliferating tumors [1]; however, a significant number of patients without objective and biochemical evidence of residual disease after surgery are destined to relapse [2], [3], [4].

The aggressive behavior and the high recurrence rate of most of the ACC patients provide the rationale for adjuvant therapy. For decades mitotane has been the only approved drug for ACC therapy [5]. In a case-control study involving 177 patients, the outcome in 47 patients treated in Italian reference centers systematically using adjuvant mitotane therapy after radical surgery was significantly improved (in terms of both recurrence-free survival [RFS] and overall survival [OS]) compared with 55 Italian patients and 75 German patients treated at institutions not administering adjuvant mitotane therapy [6].

Although these data cannot be considered conclusive, mitotane is recommended [7] and increasingly prescribed in ACC patients who have undergone a complete resection and are at high risk of recurrence. However, only very few prognostic factors are currently available to identify patients at risk. A few molecules have been proposed as prognostic and predictive markers [8], [9], [10], [11], [12], but none of them are used in clinical practice. Currently only disease stage, completeness of initial resection, and proliferation index are widely accepted prognostic factors [13], [14]. However, they are not sufficiently accurate to predict the outcome of every individual, and risk stratification remains challenging, at least for a subset of patients. Consequently, new prognostic factors are needed.

Two previous reports suggested cortisol secretion as a negative prognostic factor in ACC patients. In a large single-institution French series including 202 patients with different disease stages, cortisol excess was found to be an independent prognostic factor for OS [15]. Similar results were obtained from a series of 72 Italian patients submitted to chemotherapy with etoposide, doxorubicin, and cisplatin plus mitotane [16]. In the French series a significant interaction was found between cortisol overproduction and mitotane therapy, and in a subsequent letter on the same series the authors reported a trend toward improved outcomes for patients with cortisol-overproducing tumors subjected to adjuvant mitotane therapy [17]. Conversely, cortisol excess failed to be associated with prognosis in another series involving metastatic ACC patients [18]. It is not actually known whether or not hypercortisolism has a prognostic role in radically resected patients.

In the current study, the prognostic role of overt cortisol excess at diagnosis was investigated in a large multicenter multinational series of patients who underwent complete resection. A secondary aim of the study was to explore the efficacy of adjuvant mitotane therapy, classifying patients according to their cortisol excess status.