Arianna Ardito

Major Prognostic Role of Ki67 in Localized Adrenocortical Carcinoma After Complete Resection

BACKGROUND Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently. OBJECTIVE The aim of this study was to identify markers with prognostic value for patients in this clinical setting. DESIGN, SETTING, AND PARTICIPANTS From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I-III were identified. As an independent validation cohort, 250 patients from three European countries were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS). RESULTS Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio [HR] for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 <10%, 10-19%, and ≥20% (for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone. CONCLUSION This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.

Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma

BACKGROUND There is a strong rationale in the use of antiangiogenic therapy in the management of adrenocortical carcinoma (ACC). Metronomic administration of chemotherapy and antiangiogenic drugs can be synergistic in targeting endothelial cells. OBJECTIVE We assessed the activity of sorafenib plus metronomic paclitaxel as second/third-line therapy in advanced ACC patients. We also tested the activity of sorafenib and paclitaxel against NCI-H295R in vitro. DESIGN Multicenter, prospective phase II trial. Setting Referral centers for ACC. METHODS Twenty-five consecutive metastatic ACC patients who progressed after mitotane plus one or two chemotherapy lines were planned to be enrolled. The patients received a combination of i.v. paclitaxel (60 mg/m(2) every week) and oral sorafenib (400 mg twice a day) till progression. The primary aim was to measure the progression-free survival rate after 4 months and the secondary aims were to assess the objective response rate and toxicity. RESULTS Tumor progression was observed in nine evaluable patients at the first assessment. These results led to the premature interruption of the trial. The treatment was well tolerated. The most relevant toxicities were fatigue, being grade 2 or 3 in four patients, and hypophosphatemia, being grade 3 in three patients. In the in vitro study, sorafenib impaired the viability of H295R cells with dose-response and time-response relationships. The in vitro sorafenib activity was not increased in combination with paclitaxel. CONCLUSIONS Despite the in vitro activity, sorafenib plus weekly paclitaxel is an inactive salvage treatment in patients with advanced ACC and should not be recommended.

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

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 patients 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.

Management of adrenal cancer: a 2013 update.

Adrenocortical carcinoma (ACC) is a devastating tumor for either patients or their families because of short life expectancy and severe impact on quality of life. Due to the rarity of ACC, with a reported annual incidence of 0.5–2 cases per million population, progress in the development of treatment options beyond surgery has been limited. Up to now, no personalized approach of ACC therapy has emerged, apart from plasma level-guided mitotane therapy, and no simple targetable molecular event has been identified from preclinical studies. Complete surgical removal of ACC is the only potentially curative approach and has the most important impact on patient’s prognosis. Despite the limits of the available evidence, adjuvant mitotane therapy is currently recommended in many expert centers whenever the patients present an elevated risk of recurrence. The management of patients with recurrent and metastatic disease is challenging and the prognosis is often poor. Mitotane monotherapy is indicated in the management of patients with a low tumor burden and/or more indolent disease while patients whose disease show an aggressive behavior need cytotoxic chemotherapy. The treatment of patients with advanced ACC may include loco-regional approaches such as surgery and radiofrequency ablation in addition to systemic therapies. The present review provides an updated overview of the management of ACC patients following surgery and of the management of ACC patients with advanced disease.

Management of adjuvant mitotane therapy following resection of adrenal cancer

Whenever adrenal cancer (ACC) is completely removed we should face the dilemma to treat by means of adjuvant therapy or not. In our opinion, adjuvant mitotane is the preferable approach in most cases because the majority of patients following radical removal of an ACC have an elevated risk of recurrence. A better understanding of factors that influence prognosis and response to treatment will help in stratifying patients according to their probability of benefiting from adjuvant mitotane, with the aim of sparing unnecessary toxicity to patients who are likely unresponsive. However, until significant advancements take place, we have to deal with uncertainty using our best clinical judgement and personal experience in the clinical decision process. In the present paper, we present the current evidence on adjuvant mitotane treatment and describe the management strategies of patients with ACC after complete surgical resection. We acknowledge the limit that most recommendations are based on personal experience rather than solid evidence.

Influence of the CYP2B6 polymorphism on the pharmacokinetics of mitotane.

Objective The aim of this study was to assess the potential impact of the pharmacogenetic variability of CYP2B6 and ABCB1 genes on the pharmacokinetics of mitotane. Methods A retrospective analysis was carried out on 27 patients with adrenocortical carcinoma on postoperative adjunctive mitotane. CYP2B6 and ABCB1 polymorphisms were genotyped and tested for an association with plasma trough concentration after 3, 6, 9, and 12 months of therapy. Results Patients with the GT/TT genotype had higher mitotane plasma concentrations compared with patients with GG at 3 months (14.80 vs. 8.01 &mgr;g/ml; P=0.008) and 6 months (17.70 vs. 9.75 &mgr;g/ml; P=0.015). Multivariate logistic regression analysis showed that only the CYP2B6 rs3745274GT/TT genotype (odds ratio=10.7; P=0.017) was a predictor of mitotane plasma concentrations of at least 14 µg/ml after 3 months of treatment. Mitotane concentrations were not influenced by the polymorphisms of the ABCB1 gene. Conclusion Evaluation of the CYP2B6 polymorphism enabled prediction of the individual response to adjuvant mitotane treatment.

Pros and cons of dexamethasone suppression test for screening of subclinical Cushing’s syndrome in patients with adrenal incidentalomas

The results of dexamethasone suppression tests (DST) in the screening of subclinical hypercortisolism are not readily comparable. Aim of the present study was to review the effectiveness of overnight 1-mg DST and 8-mg DST to look for functional autonomy of clinically inapparent adrenal adenomas. Sixty-eight consecutive patients with clinically inapparent adrenal adenomas were enrolled. All patients underwent 1-mg DST. The 8-mg DST was performed in the 11 patients who had post 1-mg DST cortisol >138 nmol/l and in 11 patients who had post 1-mg DST cortisol between 50 and 138 nmol/l. The a priori probability to have autonomous cortisol secretion was defined by the presence of at least two alterations of the hypothalamic-pituitary-adrenal axis among reduced ACTH concentrations, elevated urinary free cortisol (UFC) or elevated midnight serum cortisol. Cortisol levels >138 nmol/l after the 1-mg DST increases the post-test probability of adrenal functional autonomy to 55%, whereas cortisol levels <50 nmol/l reduce the post-test probability to 8%. Cortisol levels recorded after the 8-mg DST were nonsignificantly lower than after the 1-mg DST and all the patients with cortisol >138 nmol/l after the 1-mg DST maintained cortisol above this cut-point. The 1-mg DST should be considered as the more effective test to detect autonomous cortisol secretion by a clinically inapparent adrenal adenoma when cortisol levels are >138 nmol/l, while cortisol levels <50 nmol/l reduce remarkably the post-test probability of this event. The 8-mg DST seems to replicate by large the results of the 1-mg DST

Cortisol secretion, bone health, and bone loss: a cross-sectional and prospective study in normal nonosteoporotic women in the early postmenopausal period

OBJECTIVE The aim of the study was to evaluate the relationship between cortisol secretion, bone health, and bone loss in a cohort of normal women in the early postmenopausal period. METHODS We measured lumbar and hip bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) and heel ultrasound parameters in 82 healthy, nonosteoporotic (lumbar T-score ≥-2.0) women (median age 52.5 years, range 42-61). These women were examined in two sessions, 1 year apart, in the early postmenopausal period (onset of menopause between 6 and 60 months). Parameters of the hypothalamic-pituitary-adrenal (HPA) axis function were morning serum cortisol, morning and midnight salivary cortisol, 24-h urinary free cortisol (UFC), serum cortisol after 0.5 and 1 mg overnight dexamethasone, and DHEA-S. RESULTS In multiple regression analyses, the following significant inverse correlations were found: i) lumbar BMD and either 24-h UFC (P<0.005) or morning serum cortisol (P<0.05), ii) total femur and femoral neck BMD with morning serum cortisol (P=0.05 and P<0.05), and iii) heel ultrasound stiffness index and midnight salivary cortisol (P<0.005). The annual rate of change in lumbar and femoral BMD did not correlate with any of the above-mentioned hormonal variables. No difference was found in the parameters of HPA axis function in slow (loss of BMD <1%) vs fast (loss of BMD ≥3%) bone losers. CONCLUSIONS HPA axis may contribute to postmenopausal bone health, but differences in cortisol secretion do not influence the differential rate of bone loss between slow and fast bone losers in the early postmenopausal period, at least in healthy women.

Metronomic Therapy Concepts in the Management of Adrenocortical Carcinoma

Metronomic chemotherapy is the administration of cytotoxic drugs at low doses, on a frequent or continuous schedule, with no extended interruption. This treatment approach can target tumor cells indirectly since it can affect the endothelium of the growing tumor vasculature and stimulates the anticancer immune response. Both the antiangiogenetic and the immunomodulatory roles of metronomic chemotherapy favor a tumor dormancy, a condition that may improve the patient outcome. Prospective clinical trials conducted in several malignancies have shown that metronomic chemotherapy can obtain disease stabilization or responses in tumors that had been made resistant in vivo to conventional chemotherapeutic regimens. Three prospective phase II trials have been conducted in patients with adrenocortical carcinoma (ACC). In all of them, patients heavily pretreated with conventional chemotherapy and mitotane have been enrolled. One trial tested the activity of the association of gemcitabine and fluoropyrimidines administered on a metronomic schedule. In this trial, 40% of patients attained a disease stabilization or disease response that was long lasting in some of them. In the remaining two trials, metronomic chemotherapy was administered in association with antiangiogenetic drugs, and the results were disappointing since no response or stable disease was obtained. In conclusion, metronomic chemotherapy can delay tumor progression in advanced ACC and deserves to be further tested. The concomitant administration of antiangiogenetic drugs may be detrimental. Several important questions remain to be addressed such as the optimal dose and most effective dosing interval, when to use the metronomic approach in the natural history of the disease, the choice of cytotoxic drugs, and the most efficacious way to integrate metronomic chemotherapy with standard therapy protocols.

Surgical remission of Cushing's syndrome reduces cardiovascular risk

OBJECTIVE Recent studies have questioned the reversibility of complications of Cushings syndrome (CS) after successful surgical treatment. The aim of this study was to assess the outcome of patients with CS who achieved disease remission compared with those patients with persistent hypercortisolism and matched controls. DESIGN A retrospective study of 75 patients with CS followed at an academic center. METHODS Cardiovascular risk profile was evaluated in 51 patients with CS in remission (group 1) and 24 patients with persistent disease (group 2) and compared with 60 controls. Mortality of patients with CS was compared with the background population. RESULTS In group 1, the frequency of cardiovascular risk factors dropped after disease remission even if it remained higher at the last follow-up than in the control group. In group 2, the frequency of cardiovascular risk factors remained unchanged during follow-up. The rate of cardiovascular and thromboembolic events was higher in group 2 than in group 1, as was the mortality rate (two deaths in group 1 and nine in group 2; ratio of two SMRs, 0.11; 95% CI, 0.011-0.512). Survival was significantly longer in group 1 than in group 2 (87 months, 80-98 vs 48 months, 38-62; P<0.0001). CONCLUSIONS Successful surgical treatment of hypercortisolism significantly improves cardiovascular risk and may reduce the mortality rate. Patients with persistent disease have increased morbidity and mortality when compared with patients in remission.