Adrenocortical carcinoma : a study on epidemiology diagnostics and treatment of a rare endocrine malignancy

The adrenal gland is an important hormone-producing organ which, like any other organ, can develop cancer. Adrenal gland cancer is rare, with only twenty new cases being diagnosed in the Netherlands each year. The disease is generally quite aggressive in nature. This dissertation describes the prevalence of this disease and the survival rate among adults and children in the Netherlands. It also examines a diagnostic tool that uses a urine test to distinguish between benign and malignant tumours in the adrenal gland. Finally, this dissertation contains studies on the properties of mitotane, the only registered medication for adrenal gland cancer, with the aim of finding a more efficient and individualised dosage system for this medicine

Health-related quality of life in adrenocortical carcinoma:Development of the disease-specific questionnaire ACC-QOL and results from the PROFILES registry

We aimed to develop a disease-specific adrenocortical carcinoma (ACC) health-related quality of life (HRQoL) questionnaire (ACC-QOL) and assess HRQoL in a population-based cohort of patients with ACC. Development was in line with European Organization for Research and Treatment of Cancer (EORTC) guidelines, though not an EORTC product. In phase I and II, we identified 90 potential HRQoL issues using literature and focus groups, which were reduced to 39 by healthcare professionals. Pilot testing resulted in 28 questions, to be used alongside the EORTC QLQ-C30. In Phase III, 100 patients with ACC were asked to complete the questionnaires twice in the PROFILES registry (3-month interval, respondents: first 67, second 51). Confirmatory factor analysis demonstrated the structural validity of 26 questions with their scale structure (mitotane side-effects, hypercortisolism/hydrocortisone effects, emotional effects). Internal consistency and reliability were good (Cronbach's alpha 0.897, Interclass correlation coefficient 0.860). Responsiveness analysis showed good discriminative ability (AUC 0.788). Patients diagnosed more than 5 years ago reported a good HRQoL compared with the Dutch reference population, but experienced residual fatigue and emotional problems. Patients who underwent recent treatment reported a lower HRQoL and problems in several domains. In conclusion, we developed an ACC-specific HRQoL questionnaire with good psychometric properties

Developing treatment for adrenocortical carcinoma

Cancer of the adrenal cortex (ACC) is a rare endocrine malignancy with limited treatment options. Patients typically present with autonomous hormonal overproduction and/or a large abdominal mass. Hormonal assays and medical imaging can be diagnostic, but urinary steroid profiling might be a more sensitive technique to assess malignancy in adrenal tumours. The stage of the disease at diagnosis is the most important prognostic factor. The current staging system needs refinement, especially to separate aggressive from indolent disease in stage IV patients and to select patients who need adjuvant treatment after complete surgical resection. Regarding the latter, assessing the proliferation index Ki-67 seems the best tool currently available. Genomic profiling is expected to become of clinical relevance in the future. Medical therapy is centred on the adrenolytic drug mitotane, which carries considerable toxicity and is not easy to manage. Its tolerability and long plasma level build-up phase may be improved by therapeutic drug monitoring based on pharmacokinetic modelling and intensive counselling of patients. Current chemotherapy regimens can offer disease stabilization in about 50% of patients, but an objective response should be expected in ! 25%. Research on targeted therapy and immunotherapy is difficult in this rare disease with often heavily pre-treated patients and has not yet been successful. Quality of care should be ensured by treating patients in centres with established experience in multi-disciplinary oncologic care, who adhere to prevailing guidelines and state-of-the-art in diagnostic and treatment concepts. International collaboration in fundamental research and clinical trials is the key to further elucidate the pathogenesis and to improve patient care

How close are we to personalized mitotane dosing in the treatment of adrenocortical carcinoma? State of the art and future perspectives

Introduction Mitotane is the only drug registered specifically for adrenocortical carcinoma. Finding the optimal dose for a patient is difficult due to large differences in bioavailability, toxicity and effect. We therefore look to improve personalized dosing of mitotane. Areas covered We searched PubMed for studies related to mitotane dosing, pharmacokinetics, pharmacogenetics and combination therapy. Comparison of different dosing strategies have not resulted in an optimal advice. Several computerized pharmacokinetic models have been proposed to predict plasma levels. The current pharmacokinetic models do not explain the full variance in plasma levels. Pharmacogenetics have been proposed to find the unexplained variance. Studies on combination therapy have not yet led to a potential dose adjustment for mitotane. Expert opinion Computerized pharmacokinetics models are promising tools to predict plasma levels, further validation is needed. Pharmacogenetics are introduced in these models, but more research is required before clinical application. We believe that in the near future, personalized mitotane dosage will be aided by a validated web-based pharmacokinetic model with good predictive ability based primarily on clinical characteristics, adjustable for actual plasma levels and dosage

Diagnostic Value of Urinary Steroid Profiling in the Evaluation of Adrenal Tumors

Radiological examination may unexpectedly reveal an adrenal mass. Current algorithms for differentiating between benign and malignant lesions mainly rely on size and densitometry on unenhanced CT, which have limited specificity. We examined the diagnostic value of urinary steroid profiling by gas chromatography/mass-spectrometry (GC/MS) in differentiating between benign and malignant adrenal tumors. A retrospective study in two referral centers for patients with adrenal disease was performed. All urinary steroid profiles ordered for evaluation of an adrenal tumor between January 2000 and November 2011 were examined. Patients were diagnosed with adrenal cortical carcinoma (ACC), adrenal cortical adenoma (ACA), or other adrenal mass. Results of hormonal measurements, imaging studies, pathology reports, and clinical outcome were retrieved from medical records. The diagnostic value of individual urinary steroid metabolites was determined by receiver operating characteristics analysis. Cut-off values were compared to reference values from an age and gender-standardized population of healthy controls. Eighteen steroid metabolites were excreted in significantly higher concentrations in patients with ACC (n = 27) compared to patients with ACA (n = 107) or other adrenal conditions (n = 18). Tetrahydro-11-deoxycortisol (THS) at a cut-off value of 2.35 mu mol/24 h differentiated ACC from other adrenal disorders with 100 % sensitivity and 99 % specificity. Elevated urinary excretion of THS was associated with a very high sensitivity and specificity to differentiate between an ACC and a benign adrenal mass. Urinary steroid profiling might be a useful diagnostic test for the evaluation of patients with an adrenal incidentaloma

Development of a Pharmacokinetic Model of Mitotane: Toward Personalized Dosing in Adrenocortical Carcinoma

Personalised Therapeutic

Development of a Pharmacokinetic Model of Mitotane: Toward Personalized Dosing in Adrenocortical Carcinoma

Personalised Therapeutic

Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring

Objective: Mitotane is the drug of choice in patients with adrenocortical carcinoma. The anti-neoplastic effect is correlated with mitotane plasma levels, which render it crucial to reach and maintain the concentration above 14 mg/l. However, mitotane pharmacokinetics is poorly understood. The aim of this study was to investigate the variation in plasma mitotane levels during the day and the influence of a single morning dose. Design: A prospective case-control study was conducted to investigate the variation in plasma mitotane levels. Methods: Patients who had been treated for at least 24 weeks and had reached the therapeutic plasma level (14 mg/l) at least once were eligible. In the first group, mitotane levels were determined hourly for the duration of 8 h after administration of a single morning dose. In the second group, mitotane levels were assessed similarly without administration of a morning dose. Results: Ten patients were included in this study, and three patients participated in both groups. Median plasma level at baseline was 16.2 mg/l (range 11.3-23.3 mg/l) in the first group (n=7) and 17.0 mg/l (13.7-23.8) in the second group (n=6). Plasma levels displayed a median increase compared with baseline of 24% (range 6-42%) at t=4 after morning dose and a change of 13% (range K14 to 33%) at t=4 without morning dose (P=0.02). Conclusion: A substantial increase in mitotane plasma levels was observed in steady-state patients within a period of 8 h after morning dosing. Without morning dose, mitotane curves showed a variable profile throughout the day. This implies that random sampling could yield incidentally high levels. For this reason, we recommend early-morning trough sampling as standard management in monitoring mitotane treatment

Adrenocortical carcinoma in children: First population-based clinicopathological study with long-term follow-up

Adrenocortical carcinoma (ACC) is rare in both adult and pediatric populations. Literature suggests significant differences between children and adults in presentation, histological properties and outcome. The aim of this first nationwide study on pediatric ACC was to describe the incidence, presentation, pathological characteristics, treatment and survival in The Netherlands. All ACC patients aged = 5 years, 3 presented with distant metastases and 1 with locally advanced disease. For all patients, histological examination displayed malignant characteristics. All patients aged = 5 years died; the median survival was 6 months (0-38 months). Pediatric ACC is extremely rare in the Western world. The clinical outcome was remarkably better in patients aged <= 4 years. This is in accordance with less advanced stage of disease at presentation, yet contrasts with the presence of adverse histological characteristics. Clinical management in advanced disease is adapted from adult practice in the absence of evidence regarding pediatric ACC