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2013
Adrenal Glands
Prognostic Role of Overt Hypercortisolism in Completely Operated Patients with Adrenocortical Cancer
Alfredo Berrutiª,*, Martin Fassnachtb,g, Harm Haak, Tobias Elseª, Eric Baudin e, Paola Sperone5, Matthias Kroiss&, Thomas Kerkhofsc, Andrew R. Williams d, Arianna Ardito h, Sophie Leboulleux®, Marco Volante’, Timo Deutschbeing, Richards Feelders, Cristina Ronchig, Salvatore Grisanti ª, Hans Gelderblomk, Francesco Porpiglia’, Mauro Papotti’, Gary D. Hammerª, Bruno Allolio&, Massimo Terzoloh
a Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Spedali Civili Hospital, Brescia, Italy; b Department of Internal Medicine IV, University Clinic, Munich, Germany; “Internal Medicine, Maxima Medical Centre, Eindhoven, The Netherlands; d Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA; e Endocrine Oncology and Nuclear Medicine, Gustave Roussy Institute, Villejuif, France; ‘ Department of Oncology, University of Turin, Medical Oncology Unit, San Luigi Gonzaga Hospital, Orbassano, Italy; % Department of Medicine I, Endocrine Unit, University Hospital of Würzburg, Germany; h Department of Clinical and Biological Sciences, University of Turin, Internal Medicine I, S. Luigi Gonzaga Hospital, Orbassano, Italy; ` Department of Oncology, University of Turin, Pathology Unit, S. Luigi Gonzaga Hospital, Orbassano, Italy; Erasmus MC, Rotterdam, The Netherlands; k Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; l Department of Oncology, University of Turin, Urology Unit, S. Luigi Gonzaga Hospital, Orbassano, Italy
Article info
Article history: Accepted November 4, 2013 Published online ahead of print on November 13, 2013
Keywords: Adrenocortical cancer Adjuvant therapy Cushing syndrome Mitotane
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 associ- ated 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.
@ 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Oncologia Medica, Azienda Ospedaliera Spedali Civili, Piazzale Spedali Civili 1, 20123 Brescia, Italy. Tel. +39 030 3995410; Fax: +39 030 3700017. E-mail address: alfredo.berruti@gmail.com (A. Berruti).
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1. Introduction
Adrenocortical carcinoma (ACC) is a rare tumor character- ized 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 [2-4].
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 administer- ing 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 [8-12], 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.
2. Methods
This retrospective analysis was carried out in five cohorts of patients with ACC collected from several centers in Italy, Germany, and the Netherlands and from two single institutions in France (Gustave Roussy Institute) and the United States (University of Michigan), respectively. All patients had undergone radical surgery. None of the patients included in this study has been included in previous published series [15-18]. The patients were recruited between 1990 and 2008. Median follow-up was 50 mo.
The primary aim was to evaluate the prognostic role of clinical symptoms and signs of hypercortisolism for survival in ACC patients who had undergone complete resection. Secondary aims were the prognostic role of overt hyper- cortisolism on progression-free survival and the efficacy of adjuvant mitotane therapy classifying patients according to their cortisol excess status.
To be included in the study the patients had to meet these inclusion criteria: ≥18 yr of age, histologic diagnosis of ACC, complete surgery (R0), and a postoperative Eastern Cooperative Oncology Group performance status of 0-1. Exclusion criteria were incomplete resection, history of other malignancies within the previous 5 yr, and adjuvant systemic therapies other than mitotane (ie, cytotoxic chemotherapy). Adjuvant radiation therapy of the tumor bed was allowed.
All data were obtained by reviewing patient medical records. Data were retrieved by trained medical personnel using specifically tailored data forms. We collected data on patient clinical and demographic characteristics, date of diagnosis, tumor stage at diagnosis, physical examination, clinical symptoms and signs of hormone hypersecretion, date and type of surgery, pathology report, date of recurrence, and either date of death or date of the last follow-up visit. In all cases, the presence of clinical signs and syndromes prompted a hormone work-up. The institutional ethics committee at each clinical center approved the study.
Complete resection was defined as no evidence of macroscopic residual disease on the basis of surgical reports and histopathologic analysis. The great majority of diagnoses were confirmed by reference pathologists. Staging at diagnosis was based on imaging studies and corroborated by the findings at surgery. Staging was reported according to the European Network for the Study of Adrenal Tumors staging system [19]. Disease recurrence was defined as unequivocal radiologic evidence of a new tumor lesion during follow-up. Definition of the functional status of ACC was based on clinical symptoms and signs of hormone excess. Patients with elevated hormone levels without a clinical syndrome were not considered to be hypersecreting.
2.1. Statistical analysis
All statistical analyses were performed using Statistica software (StatSoft Inc., Tulsa, OK, USA). Rates and proportions
were calculated for categorical data, and medians and ranges were calculated for continuous data. Differences in contin- uous variables were analyzed by the two-tailed Mann- Whitney U test. For categorical variables, differences were analyzed by the chi-square test. RFS was measured from the date of surgery to the date of recurrence; for patients who did not have a relapse, the data were censored at the date of the last follow-up visit. OS was measured from the date of surgery to the date of death, and the data were censored at the date of the last follow-up visit. Survival curves were computed using the Kaplan-Meier method and compared using the log-rank test. The independent prognostic role of the overt secretory status was also assessed in multivariate analysis according to the Cox model. RFS and OS were the dependent variables; the covariates included were cortisol excess, age, sex, and mitotane treatment. Due to the limited number of patients with mitotic count available and the risk of biased data, mitotic and proliferation indexes were not added in the multivariate model. The Cox analysis was also used to assess the presence of heterogeneity in the prognostic effect of the hormone excess status in patients stratified according to various prognostic factors and the prognostic role of mitotane treatment according to the secretory status. A modification of prognostic effect in these subgroups was assessed by including the appropriate covariate interaction terms in the model. This procedure is equivalent to a test of the homogeneity of the hazard ratios (HRs) associated with functional status or mitotane treatment in the strata. Missing data led to patient exclusion from particular analyses. All p values reported are the result of two-sided tests. The p values <0.05 were considered to indicate statistical significance.
3. Results
A total of 524 patients entered the study. Table 1 shows the patient characteristics. No patient had metastases. Recur- rence was documented in 339 patients (64.7%). Death occurred in 204 patients (38.9%). Clinical signs of cortisol plus or minus other hormone excess were observed in 197 patients (37.6%) and clinical hyperandrogenism in 58 patients (11.1%). Seven patients (1.3%) had symptoms and signs of pure mineralocorticoid excess, 9 patients (1.8%) had clinical evidences of estrogen excess, and the remaining 247 patients (47.2%) had clinically nonfunc- tional tumors.
The distribution of cortisol excess according to demog- raphy showed no difference according to sex (125 of 321 [38.9%] in women; 72 of 203 [35.5%] in men; p = 0.42), whereas an inverse relationship was found with age (divided according to tertile distribution) (p = 0.002). The distribution of overt cortisol secretion did not differ when stratifying patients according to stage (126 of 336 [37.5%] in patients with stage I and II; 71 of 188 [37.8%] in patients with stage III; Table 2). No relationship was also found between cortisol excess and mitotic index (in the patient subset in whom both parameters were available) and patients with or without adjuvant mitotane (Table 2).
| Total patients | 524 |
| Participating countries, n (%) | |
| Italy | 191 (36.4) |
| France | 37 (7.1) |
| Holland | 65 (12.4) |
| United States: Michigan | 77 (14.7) |
| Germany | 154 (29.4) |
| Sex, n (%) | |
| Female | 321 (61.2) |
| Male | 203 (38.8) |
| Age, yr, median (range) | 45 (18-77) |
| Stage, n (%) | |
| 1-2 | 336 (64.1) |
| 3 | 188 (35.9) |
| Mitosis in 50 HPF, n (%) | |
| <5 | 84 (31.8) |
| <10 | 69 (26.2) |
| >10 | 111 (42.0) |
| Missing | 260 |
| Secretory status, n (%) | |
| No secretion | 249 (47.5) |
| Cortisol | 150 (28.7) |
| Cortisol and androgens | 43 (8.3) |
| Androgens | 58 (11.1) |
| Estrogens | 9 (1.7) |
| Mineralocorticoid | 7 (1.3) |
| Cortisol and mineralocorticoid | 2 (0.4) |
| Cortisol and estrogen | 2 (0.4) |
| Androgen and mineralocorticoid | 3 (0.6) |
| Adjuvant mitotane, n (%) | |
| No | 273 (52.1) |
| Yes | 251 (47.9) |
| HPF = high-power field. |
3.1. Prognostic role of overt cortisol secretory status
In the univariate analysis, cortisol excess was associated with a decreased RFS (just failing to attain the statistical significance; p = 0.088) (Fig. 1a) and a significant decrease in OS (p = 0.044) (Fig. 1b). The prognostic significance of the overt secretory status was highly significant after adjust- ment for sex, age, tumor stage, and adjuvant mitotane treatment in the multivariate analysis for both RFS (hazard ratio [HR]: 1.30; 95% confidence interval [CI], 1.04-1.62; p = 0.02) and OS (HR: 1.55; 95% CI, 1.15-2.09; p = 0.004) (Table 3).
3.2. Variation in the prognostic role of overt hypercortisolism according to participating country, sex, age, and tumor stage
We performed a further explorative analysis to assess the heterogeneity of the prognostic role of cortisol excess status according to country, sex, age, and tumor stage. The data are displayed in Table 4.
Despite some variability, there was no significant difference of cortisol excess among the HRs for recurrence and death across the subgroups from the different countries ( p for interaction 0.58 and 0.20, respectively).
Stratifying patients according to demographic and clinical parameters, the HR for clinical cortisol excess versus no cortisol excess in terms of RFS did not significantly differ by classifying patients according to age, sex, and tumor stage (Table 4). In terms of OS, however,
| No overt cortisol excess, n (%) | Overt cortisol excess, n (%) | p | |
|---|---|---|---|
| Sex | 0.42 | ||
| Female | 196/321 (61.1) | 125/321 (38.9) | |
| Male | 131/203 (64.5) | 72/203 (35.5) | |
| Age, yr | 0.002 | ||
| Tertile 1, 18-40 | 94/179 (52.5) | 85/179 (47.5) | |
| Tertile 2, 41-53 | 117/177 (66.1) | 60/177 (33.9) | |
| Tertile 3, 54-77 | 115/167 (68.8) | 52/167 (31.2) | |
| Stage | 0.95 | ||
| I-II | 210/336 (62.5) | 126/336 (37.5) | |
| III | 117/188 (62.2) | 71/188 (37.8) | |
| Mitosis in 50 HPF | 0.56 | ||
| <5 | 53/84 (63.1) | 31/84 (36.9) | |
| <10 | 46/69 (66.7) | 23/69 (33.3) | |
| >10 | 66/111 (59.5) | 45/111 (40.5) | |
| Mitotane use | 0.80 | ||
| No | 169/273 (61.90) | 104/273 (38.10) | |
| Yes | 158/251 (62.95) | 93/251 (37.05) | |
| HPF = high-power field. * Chi-square test for trend. |
a greater HR for death was observed in more advanced stage (III) versus early stage (I-II) of disease (interaction test p = 0.018) (Table 4).
3.3. Prognostic role of mitotane therapy according to the cortisol excess status
Adjuvant mitotane (Lysodren, Bristol-Myers Squibb, New York, NY, USA; HRA Pharma, Paris, France) was prescribed to 251 patients (47.9%): 105 patients in the Italian series (55.0%), 34 patients in the French series (91.4%), 30 patients in the Netherlands series (46.2%), 28 patients in the Michigan series (36.4%), and 54 patients in the German series (35.1%).
In the overall series, mitotane administration was associated with a significant reduction of disease relapse in multivariate analysis adjusting for sex, age, and stage (HR: 0.65; 95% CI, 0.49-0.86; p = 0.003). The prognostic impact on RFS of mitotane therapy did not differ according to the overt hypercortisolism status (no cortisol excess HR: 0.68; 95% CI, 0.51-0.90; cortisol excess HR: 0.65; 95% CI, 0.46-0.93; interaction test p = 0.79) (Fig. 2a). Con- versely, mitotane treatment failed to be significantly associated with a lower risk of death (adjusted HR: 0.82; 95% CI, 0.60-1.10; p = 0.18), without any difference stratifying patients according to their clinical hypercorti- solism status (cortisol excess HR: 0.85; 95% CI, 0.57-1.28; no cortisol excess HR: 0.71; 95% CI, 0.44-1.13; interaction test p = 0.67) (Fig. 2b).
4. Discussion
One of the major determinants of the variability in the clinical presentation of ACC is the presence and type of hormone secretion [14]. Hormone-secreting tumors most frequently produce cortisol. In this multinational study we demonstrated for the first time in a large series of radically resected ACC patients that the presence of clinical
signs of cortisol excess is prognostically relevant either in terms of RFS or in terms of OS applying a multivariate analysis after adjustment for commonly recognized prog- nostic factors. This is an important observation because very few prognostic parameters are known in this subset (7-10). The mechanism underlying this relationship, however, is not clear. Although in patients with metastatic disease, hypercortisolism leads to increased mortality due to immunosuppression, catabolismand infection [15,16], these issues cannot play such a role in patients who underwent complete resection and in whom the Cushing syndrome has attained a complete remission.
Our data are consistent with the hypothesis that cortisol excess is associated with a more aggressive disease, although no correlation was found between cortisol excess and mitotic index in the subset of patients in whom such information was available. These data suggest that other mechanisms than tumor proliferation activity must be taken into account to support the association between overt hypercortisolism and tumor aggressiveness. For instance, it was recently suggested that SKG1 protein expression is inversely associated with cortisol hypersecretion and that low SGK1 represents a negative prognostic factor in ACC [20]. In addition, the chronic exposure to elevated cortisol levels before surgery, leading to immunosuppression, may favor the development of micrometastases leading to an increased rate of recurrent disease.
A limitation of this study is that only symptomatic patients were considered as having hypercortisolism, thus excluding information on the prognostic role of elevated hormone levels in the absence of a clinical syndrome. It should be noted, however, that our data can be generalized in ACC patients undergoing surgery outside of reference centers in which a complete hormone work-up is not routinely performed in the absence of symptoms. A prospective study testing the prognostic role of cortisol levels in either symptomatic or asymptomatic patients should be of interest.
Cumulative proportion relapse free surviving 0)
1,0
Relapse-free survival
0,9
0,8
No secretion
Cortisol secretion
0,7
0,6
0,5
0,4
p = 0.0888
0,3
0,2
0,1
0
20
40
60
80
100
120
Months
| No. of patients at risk | 0 | 20 | 40 | 60 | 80 | 100 | 120 |
| No secretion | 327 | 164 | 98 | 51 | 29 | 17 | 11 |
| Cortisol secretion | 197 | 84 | 44 | 24 | 18 | 11 | 8 |
Cumulative proportion overall surviving
1,0
Overall survival
0,9
0,8
No secretion
Cortisol secretion
0,7
0,6
0,5
0,4
0,3
0,2
p = 0.044
0,1
0,0
0
20
40
60
80
100
120
Months
| No. of patients at risk | 0 | 20 | 40 | 60 | 80 | 100 | 120 |
| No secretion | 327 | 252 | 159 | 106 | 71 | 45 | 40 |
| Cortisol secretion | 197 | 146 | 97 | 60 | 37 | 22 | 17 |
Fig. 1 - Prognostic role of clinical cortisol hypersecretion in terms of (a) relapse-free survival and (b) overall survival in patients with adrenocortical carcinoma who underwent radical resection.
| n = 518 | Relapse-free survival | Overall survival | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p | HR | 95% CI | p | |
| Cortisol excess | 1.30 | 1.04-1.62 | 0.020 | 1.55 | 1.15-2.09 | 0.004 |
| Sex | 1.02 | 0.82-1.27 | 0.84 | 0.87 | 0.64-1.17 | 0.34 |
| Age | 1.00 | 0.99-1.01 | 0.51 | 1.01 | 1.00-1.02 | 0.049 |
| Stage | 1.63 | 1.31-2.03 | <0.001 | 2.64 | 1.97-3.55 | 0.000 |
| Mitotane therapy | 0.66 | 0.53-0.83 | <0.001 | 0.82 | 0.60-1.10 | 0.19 |
CI = confidence interval; HR = hazard ratio.
Age is a continuous variable; the other variables are categorized. Reference: Sex: males; stage: I-II; mitotane therapy: no therapy.
| Relapse-free survival | Overall survival | |||||||
|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | p | p interaction | HR | 95% CI | p | p interaction | |
| Countries | 0.580 | 0.204 | ||||||
| Italy | 1.225 | 0.836-1.796 | 0.298 | 1.303 | 0.765-2.217 | 0.330 | ||
| France | 0.867 | 0.393-1.911 | 0.723 | 0.810 | 0.276-2.379 | 0.701 | ||
| The Netherlands | 1.178 | 0.517-2.686 | 0.697 | 3.242 | 1.467-7.165 | 0.004 | ||
| United States: Michigan | 1.604 | 0.916-2.811 | 0.098 | 1.760 | 0.950-3.261 | 0.072 | ||
| Germany | 1.032 | 0.686-1.553 | 0.878 | 0.785 | 0.435-1.415 | 0.420 | ||
| Sex | 0.871 | 0.668 | ||||||
| Male | 1.364 | 0.948-1.962 | 0.094 | 1.394 | 0.879-2.212 | 0.158 | ||
| Female | 1.252 | 0.947-1.656 | 0.114 | 1.504 | 1.042-2.171 | 0.029 | ||
| Age, yr | 0.320 | 0.666 | ||||||
| Tertile 1 (18-40) | 1.182 | 0.822-1.698 | 0.366 | 1.717 | 1.056-2.793 | 0.029 | ||
| Tertile 2 (41-53) | 1.141 | 0.762-1.710 | 0.522 | 1.048 | 0.622-1.765 | 0.861 | ||
| Tertile 3 (54-77) | 1.557 | 1.063-2.281 | 0.023 | 1.526 | 0.934-2.493 | 0.092 | ||
| Stage | 0.980 | 0.018 | ||||||
| I-II | 1.328 | 1.000-1.763 | 0.050 | 1.033 | 0.688-1.551 | 0.875 | ||
| III | 1.259 | 0.882-1.797 | 0.205 | 2.095 | 1.394-3.150 | 0.000 | ||
CI = 95% confidence interval; HR = hazard ratio; p interaction = p interaction test.
* Adjusted HR.
Proliferative activity was found to be a strong prognostic factor in patients with radically resected ACC [7-9]. Due to the limited proportion of patients having mitosis assessed in the present study, this parameter was not added to the independent variables included in the multivariate analysis, which is a further limitation. The absence of correlation between cortisol secretion and mitosis, however, makes the
a
Overall patients
No overt cortisol hypersecretion
Overt cortisol hypersecretion
Interaction test p = 0.79
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
Hazard ratio
b
Overall patients
No overt cortisol hypersecretion
Overt cortisol hypersecretion
Interaction test p = 0.71
0
0.1
0.2
0.3
.4
0.5
0.6
0.7
0.8
0.9
1.0
1.11.2
1.1
Hazard ratio
dependency between the two parameters in the multivari- ate prognostic model improbable.
The HR for progression and death showed a high variation among participating centers reflecting patient selection, but these HRs did not significantly differ at the interaction test.
In our series, adjuvant mitotane after surgery was generally prescribed in patients at higher risk of relapse, but the criteria adopted were not uniform across centers. This is the reason why the proportion of patients who received the drug varied substantially according to coun- tries. The French series was recruited in only one oncology center that had a policy to administer mitotane in most patients. This explains why the great majority of French patients received mitotane. These limitations notwith- standing, in this multinational study patients receiving adjuvant mitotane showed a better prognosis in terms of RFS and a nonsignificant survival improvement compared with patients who did not, confirming the results of a previously published case-control study [6].
In a French series of 166 radically resected patients, the efficacy of mitotane administration on disease-free survival (DFS) improvement was not demonstrated in the overall population, although in the subgroup of patients with hypercortisolism a beneficial tendency was evident [17].
In the present study, the efficacy of mitotane adminis- tration on DFS did not differ when patients were stratified according to the presence or absence of cortisol excess. These data further support the antineoplastic activity of mitotane irrespective of the cortisol excess status.
5. Conclusions
The present study demonstrates that overt hypercortiso- lism is a new prognostic factor in patients with radically
resected ACC. The mechanisms underlying the relationship between cortisol secretion and prognosis in this patient subset deserve further elucidation.
Author contributions: Alfredo Berruti had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Berruti, Terzolo.
Acquisition of data: Sperone, Kroiss, Kerkhofs, Williams, Ardito, Leboulleux, Else, Deutschbein, Feelders, Ronchi, Gelderblom, Porpiglia, Papotti, Volante.
Analysis and interpretation of data: Fassnacht, Haak, Else, Baudin, Hammer, Allolio, Terzolo.
Drafting of the manuscript: Berruti, Fassnacht, Haak, Else, Baudin, Kerkhofs, Terzolo.
Critical revision of the manuscript for important intellectual content: Porpiglia, Papotti, Volante, Allolio, Ronchi.
Statistical analysis: Grisanti, Sperone.
Obtaining funding: Berruti, Terzolo.
Administrative, technical, or material support: Berruti, Terzolo, Fassnacht, Baudin, Haak, Else.
Supervision: Hammer, Allolio, Papotti.
Other (specify): None.
Financial disclosures: Alfredo Berruti certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultan- cies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Martin Fassnacht, Eric Baudin, Harm Haak, Gary D. Hammer, Bruno Allolio, and Massimo Terzolo participated in a study on the pharmacokinetics of mitotane in a subgroup of patients who were enrolled in the FIRM-ACT study. This substudy was funded by HRA Pharma. Alfredo Berruti, Martin Fassnacht, Eric Baudin, Harm Haak, Gary D. Hammer, and Bruno Allolio participated in a clinical trial on OSI-906 in adrenocortical carcinoma sponsored by Astellas Pharma. Gary D. Hammer consults for ISIS, Orphagen, Embara, and Atterocor; holds stocks in Orphagen, Embara, and Atterocor; and is a partial owner of Atterocor. The remaining authors have nothing to disclose.
Funding/Support and role of the sponsor: This study is a collaborative effort of the ACC working group of the European Network for the Study of Adrenal Tumors (ENS@T) and the University of Michigan (USA). The study was supported in part by Regione Piemonte Ricerca Sanitaria Finalizzata 2008 no. 20889/DA20.01, by a donation of Bortolotti Marilena in memory of Ridon Carlo, and the ENS@T (FP7/2007-2013 under grant agreement 259735). In addition, this study was supported by grants of the Deutsche Krebshilfe (#106 080 to Bruno Allolio and #107 111 to Martin Fassnacht).
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