Mitotane is used as a post-operative adjuvant treatment for patients with adrenocortical carcinoma. Monitoring of plasma mitotane concentrations is recommended, but we do not know what impact target concentrations have on patient outcome. To answer this question, we retrospectively analyzed patient records in the Lysosafe Online^® database (HRA Pharma, France) for patients who were treated for ≥6 months and who had ≥3 measurements of plasma mitotane levels during follow-ups at 11 tertiary centers in Italy from 2005 to 2017. We identified 110 patients treated with adjuvant mitotane for a median of 46 months (IQR, interquartile range, 28–62) with a median maintenance dose of 2.0 g/day (IQR 1.5–2.5). Achievement of target mitotane concentrations (≥14 mg/L) required a median of 8 months (IQR 5–19). Female sex was associated inversely with the dose, while body mass index (BMI) was correlated positively. Multivariate analysis showed that the Ki67 index and time to achieve the target range of plasma mitotane were independent predictors of recurrence-free survival (RFS). In a separate multivariate model, considering only the maintenance phase (month 7 to month 36, M7–M36) of treatment, the time in the target range of plasma mitotane was associated with a significantly lower risk of recurrence (Hazard Ratio, HR = 0.93; 0.88–0.98, p < 0.01). The prognostic implications of the time in target range and the time needed to reach target mitotane concentrations support the use of mitotane monitoring and may inform practice.

Mutations in one of the five genes encoding the succinate dehydrogenase (SDHx) or mitochondrial complex II cause the corresponding family syndromes characterized by the occurrence of pheochromocytomas (PHEO) and paragangliomas (PGL). Recently, other solid growths, such as gastrointestinal stromal tumors (GISTs), renal cell carcinomas (RCCs) and pituitary adenomas (PAs) have been associated with these syndromes. In the absence of prospective studies assessing their frequency, at present, their occurrence seems too infrequent to suggest systematic screening for SDHx mutation carriers. However, SDHB immunohistochemistry (IHC) on tumor tissues or SDHx genetic testing on blood or tumor samples should be performed in patients affected by GISTs, RCCs or PAs with clinicopathologic phenotypes suggesting an etiologic role of SDHx genes.

Chromaffin tumors are included among the causes of secondary hypertension because of the release of catecholamines. Nevertheless, the clinical, cardiovascular, and hypertensive picture of patients affected by pheochromocytomas/paragangliomas (PPGL) is extremely variable, due to the different quantitative and qualitative releasing activity of these tumors. A consistent percentage of these patients, about 20%, is normotensive and not affected by the characteristic symptomatic crises due to sudden release of catecholamines. The factors causing such wide clinical variability are many and probably not all known. It is well known that many of these tumors are genetically determined and that the genetic profile influences the biochemical characteristics and the biology of the tumors as well as the clinical presentation of the affected patients. The number of asymptomatic or poorly symptomatic patients is increased after the introduction of genetic screening and the early diagnosis in mutation carriers. In this paper we can review the genotype-phenotype correlation of PPGLs with a focus on the cardiovascular picture.

Purpose of review: In this article, we focus on the current and future treatment options for adrenocortical carcinoma (ACC). Recent findings: Radical surgery remains the only curative treatment for ACC. Recent reports showed a longer overall survival (OS) in patients with high risk of recurrence treated with adjuvant mitotane; the time in target range (14–20 mg/l) is related to low risk of relapse both in adjuvant and in palliative setting. In patients who experience disease progression after etoposide, doxorubicin, cisplatin with mitotane (EDP-M), gemcitabine and metronomic capecitabine, or the less used streptozotocin, represent a second-line chemotherapy option. Temozolomide can be employed as a third-line chemotherapy. To date, unsatisfactory results have been obtained on the efficacy of targeted therapies. Clinical trials are ongoing to evaluate the efficacy of tyrosine kinase and immune checkpoint inhibitors. Summary: ACC is a rare disease with a poor prognosis. The main therapy is represented by radical surgery conducted by an expert surgeon. Adjuvant mitotane has to be started in patients with high risk of recurrence. In patients with inoperable disease, the scheme EDP-M is the most employed. Few data are available on second-line and third-line chemotherapy in patients with disease progression after EDP-M. Currently, the role of targeted therapies is under evaluation.