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Cancers Oct 2022Adrenocortical cancer (ACC) typically presents in advanced stages of disease and has a dismal prognosis. One of the foremost reasons for this is the lack of available... (Review)
Review
Adrenocortical cancer (ACC) typically presents in advanced stages of disease and has a dismal prognosis. One of the foremost reasons for this is the lack of available systemic therapies, with mitotane remaining the backbone of treatment since its discovery in the 1960s, despite underwhelming efficacy. Surgery remains the only potentially curative option, but about half of patients will recur post-operatively, often with metastatic disease. Other local treatment options have been attempted but are only used practically on a case-by-case basis. Over the past few decades there have been significant advances in understanding the molecular background of ACC, but this has not yet translated to better treatment options. Attempts at novel treatment strategies have not provided significant clinical benefit. This paper reviews our current treatment options and molecular understanding of ACC and the reasons why a successful treatment has remained elusive. Additionally, we discuss the knowledge gaps that need to be overcome to bring us closer to successful treatment and ways to bridge them.
PubMed: 36358665
DOI: 10.3390/cancers14215245 -
The Oncologist Jun 2019Adrenocortical carcinoma (ACC) is a rare endocrine cancer with treatments limited in efficacy for metastatic disease. New molecular targeted therapies have yet to...
BACKGROUND
Adrenocortical carcinoma (ACC) is a rare endocrine cancer with treatments limited in efficacy for metastatic disease. New molecular targeted therapies have yet to improve patient outcomes. In contrast, established treatment regimens of adrenolytics and chemotherapy have demonstrated treatment benefit, although admittedly in a minority of patients. Identification of microRNAs (miRNAs) in patients responsive to adjuvant therapy may offer a means to sensitize patients with progressive disease to existing adjuvant regimens.
MATERIALS AND METHODS
Samples from primary ACC tumors of 10 Stage IV patients were examined for differentially expressed miRNAs between a "sensitive" and "resistant" cohort. Candidate microRNAs were restored via transfection in two functional ACC cell lines. Gain of function and effects on apoptosis and cell cycle were assessed.
RESULTS
microRNA-431 (miR-431) was underexpressed in patients with ACC with progressive disease undergoing adjuvant therapy. Restoration of miR-431 in vitro decreased the half maximal inhibitory concentrations of doxorubicin and mitotane, with markedly increased apoptosis. We found that a reversal of epithelial-mesenchymal transition underlies the action of miR-431 with doxorubicin treatment, with implicated as the molecular target of miR-431 in ACC.
CONCLUSION
This is the first report of the potential of miRNA therapy to sensitize ACC to current established adjuvant therapy regimens, which may mitigate the resistance underlying treatment failure in patients with advanced ACC. Effective and well-studied methods of targeted miRNA delivery in existence hints at the imminent translatability of these findings.
IMPLICATIONS FOR PRACTICE
Adrenocortical carcinoma (ACC) is a rare endocrine cancer with outcomes not improving despite extensive research and new targeted therapies. Mitotane and etoposide/doxorubicin/cisplatin chemotherapy is trial validated for improved recurrence-free survival. However, a minority of patients experience sustained benefit. Significant side effects exist for this regimen, with patients often unable to attain target drug doses shown to give survival benefit. This preclinical study examines the role of microRNAs in sensitizing ACC to doxorubicin or mitotane. This study offers an important bridge between new and existing cancer treatments, offering an imminently translatable approach to the treatment of adrenocortical carcinoma.
Topics: Adolescent; Adrenal Cortex; Adrenal Cortex Neoplasms; Adrenalectomy; Adrenocortical Carcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biopsy; Cell Line, Tumor; Chemotherapy, Adjuvant; Doxorubicin; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; MicroRNAs; Middle Aged; Treatment Outcome; Young Adult; Zinc Finger E-box-Binding Homeobox 1
PubMed: 30918109
DOI: 10.1634/theoncologist.2018-0849 -
Journal of the Endocrine Society Sep 2022Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis for both locally advanced and metastatic disease. Standard treatment with combination...
CONTEXT
Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis for both locally advanced and metastatic disease. Standard treatment with combination etoposide-doxorubicin-cisplatin-mitotane (EDP-M) is highly toxic and some patients benefit from mitotane monotherapy. However, identification of these patients remains challenging.
OBJECTIVE
We present a summary of the Israeli national referral center's 20 years of experience in treating advanced ACC, with the aim of identifying prognostic factors and assisting in treatment decision making.
METHODS
We conducted a retrospective multivariate analysis of patients treated for metastatic or locally advanced ACC at Hadassah Medical Center between 2000 and 2020 to determine clinical, pathological, and treatment factors correlated with overall survival (OS).
RESULTS
In our cohort of 37 patients, a combination of modified European Network for the study of Adrenal Tumors (mENSAT) staging with either grade and R status, or age and symptoms was validated to stratify prognosis ( = .01 and = .03, respectively). Patients who underwent R0 resection followed by radiotherapy or metastasectomy for oligometastatic disease had longer OS than patients with residual disease: median OS of 55 months vs 14 months, respectively, hazard ratio 3.1 (CI 1.4-6.7, = .005). Patients treated with mitotane monotherapy had a significantly better prognosis, yet this result was attenuated in a multivariate analysis controlling for mENSAT and R status. Of patients treated with EDP-M, 41.4% experienced grade 3 or higher adverse events.
CONCLUSION
Patients with advanced ACC achieving R0 status have a better prognosis and might benefit from mitotane monotherapy.
PubMed: 35949453
DOI: 10.1210/jendso/bvac112 -
Frontiers in Oncology 2022Mitotane is the only drug approved to treat adrenocortical carcinoma (ACC), and a relationship of pharmacokinetic/pharmacodynamic has been characterized. However,...
Mitotane is the only drug approved to treat adrenocortical carcinoma (ACC), and a relationship of pharmacokinetic/pharmacodynamic has been characterized. However, limited evidence concerning affecting factors in large interindividual variability of the pharmacokinetics of mitotane is available. To address this question, a retrospective analysis was performed on ACC Chinese patients treated with mitotane for more than 3 months. Mitotane plasma trough concentrations were detected at the steady state, and CYP2B6, CYP3A4, and pregnane X receptor (PXR) polymorphisms were genotyped. After examining homogeneous pharmacologic data, we restricted the analyses to 36 patients that received mitotane for a median (interquartile range, IQR) of 9 months (5.00-22.50) with a median dose of 2 g/day (2.00-2.50). As a result, drug exposure was significantly influenced by the cumulative dose of mitotane, and CYP2B6 516GG and CYP2B6 26570CC were at high risk to be below the therapeutic range of mitotane. No association was found between mitotane concentrations with CYP3A4 or PXR polymorphism. Our data firstly indicated that the cumulative dose of mitotane and polymorphisms of CYP2B6 516 and CYP2B6 26570 might significantly affect mitotane plasma trough concentrations in Chinese ACC patients.
PubMed: 35847963
DOI: 10.3389/fonc.2022.919027 -
Hormones & Cancer Aug 2020Advanced adrenocortical cancer (ACC) is a rare, highly aggressive malignancy, which typically has a poor prognosis. In advanced ACC, the overall trend is toward a short... (Review)
Review
Advanced adrenocortical cancer (ACC) is a rare, highly aggressive malignancy, which typically has a poor prognosis. In advanced ACC, the overall trend is toward a short PFS interval following first-line systemic therapy, highlighting a clear need for improved second-/third-line treatment strategies. We conducted a review of the literature and relevant scientific guidelines related to systemic therapy for advanced ACC. Public indexes including PubMed/MEDLINE were searched. Treatment selection in the second-line setting is based on small phase 2 trials, case reports, and pre-clinical evidence. The best data available for initial second-line therapy selection supports the use of gemcitabine and capecitabine (G + C) or streptozotocin (S), both with or without mitotane. G + C is becoming increasingly recommended based on phase 2 clinical trial data in patients of good PS, due to the inferred superior PFS and OS from non-comparative trials. Alternatively, streptozotocin was better tolerated than EDP + M in the FIRM-ACT study and remains an option when warranted. Beyond this, further treatment approaches should be tailored to individual patient characteristics, utilizing a mixture of systemic therapies, local therapies, and enrolment in clinical trials where available. Additionally, the role of molecular stratification, predictive biomarkers, and immune checkpoint inhibitors in specific individuals, such as Lynch syndrome, is evolving and may become increasingly utilized in clinical practice. Advanced ACC necessitates a multidisciplinary approach and is best managed in a specialist center. Although there is no one definitive second-line treatment strategy, there are some favorable approaches, which require further validation in larger clinical trials.
Topics: Adrenocortical Carcinoma; Humans
PubMed: 32303972
DOI: 10.1007/s12672-020-00385-3 -
European Journal of Endocrinology Jun 2019Objective Many patients with adrenocortical carcinoma (ACC) suffer from tumor recurrence despite radical surgery. Evidence on the post-operative use of mitotane is...
Objective Many patients with adrenocortical carcinoma (ACC) suffer from tumor recurrence despite radical surgery. Evidence on the post-operative use of mitotane is controversial and no predictors of response are available. We aimed to assess whether adjuvant mitotane treatment may prolong survival in patients with non-metastatic ACC following complete resection and whether ACC patients at high risk of recurrence may benefit from treatment. Design and methods We retrospectively reviewed data from 152 non-metastatic ACC patients followed at the San Luigi Gonzaga Hospital: 100 patients were treated with adjuvant mitotane and 52 patients were left untreated following surgery. We assessed a number of potential predictive factors of recurrence and death. Mitotane effect was explored stratifying patients by staging (stage I-II vs stage III), hormone secretion (yes vs no) and Ki67 index. Results The non-treated group had a higher risk of recurrence (HR: 2.79, 95%CI: 1.58-4.91; P < 0.001) than mitotane-treated group, while overall survival was not significantly different between groups. Hormone secretion, elevated Weiss score and elevated Ki67 index confer a higher risk of both recurrence and death and stage III ACC of death. Adjuvant mitotane treatment reduced significantly the risk of death in patients with elevated Ki67 index (P = 0.005) and in patients with stage III ACC (P = 0.02). Conclusions Adjuvant mitotane may prolong recurrence-free survival in radically resected ACC patients with acceptable toxicity and may also prolong overall survival in a subgroup of ACC patients at high risk of recurrence.
Topics: Adolescent; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mitotane; Neoplasm Recurrence, Local; Risk Factors; Survival Rate; Young Adult
PubMed: 30991359
DOI: 10.1530/EJE-18-0923 -
Annals of Pediatric Endocrinology &... Sep 2022Mitotane is an adrenolytic drug that exhibits therapeutic effects within a narrow target range (14-20 μg/dL). Various complications develop if the upper limit is...
Mitotane is an adrenolytic drug that exhibits therapeutic effects within a narrow target range (14-20 μg/dL). Various complications develop if the upper limit is exceeded. We present the case of a 5-year-old girl with breast development, acne, and pubic hair who was diagnosed with an adrenal mass that was subsequently excised. The pathological finding was adrenocortical carcinoma with a high risk of malignancy, and adjuvant therapy (combined mitotane and radiation therapy) was recommended. Mitotane was initiated at a low dose to allow monitoring of the therapeutic drug level, and high-dose hydrocortisone was also administered. However, the patient exhibited elevated adrenocorticotropic hormone levels and vague symptoms such as general weakness and difficulty concentrating. It was important to determine if these symptoms were signs of the neurological complications that develop when mitotane level is elevated. Encephalopathy progression and pubertal signs appeared 6 months after diagnosis, induced by high mitotane level. The mitotane decreased to subtherapeutic level several months after its discontinuation, at which time endocrinopathy (central hypothyroidism, hypercholesterolemia, and secondary central precocious puberty) developed. The case shows that low-dose mitotane can trigger neurological and endocrinological complications in a pediatric patient, indicating that the drug dose should be individualized with frequent monitoring of the therapeutic level.
PubMed: 34670067
DOI: 10.6065/apem.2142044.022 -
Journal of Personalized Medicine Apr 2021A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question,...
A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence.
PubMed: 33916613
DOI: 10.3390/jpm11040269 -
Journal of Oncology 2019Adrenocortical carcinoma (ACC) is a rare, highly aggressive cancer, often insensitive to conventional chemotherapeutics agents. Early diagnosis, followed by radical... (Review)
Review
Adrenocortical carcinoma (ACC) is a rare, highly aggressive cancer, often insensitive to conventional chemotherapeutics agents. Early diagnosis, followed by radical surgical resection plus/minus adjuvant mitotane therapy, is nowadays the only valuable option. Unfortunately, one out of four patients has metastatic disease at diagnosis and most of radically resected ACC patients are destined to recur with local or metastatic disease. Numerous efforts aimed at identifying molecular alterations crucial for ACC pathogenesis have been extensively conducted, with the hope to develop new treatments. Indeed, multiple genes and pathways have been identified as potentially targetable in ACC patients; however, despite the strong preclinical rationale, translational findings to clinical trials led to date to disappointing results. The immunotherapeutic intervention targeting T-cell checkpoint molecules has been proposed as well, but results obtained in early studies indicate that ACC patients would be unlikely to benefit from immunotherapy. Genetic alterations of different pathways involved in ACC carcinogenesis are also known substrates of resistance to immunotherapy. Among them, -catenin gene CTNNB1 and TP53 gene are frequently mutated in ACC samples. Overactivation of the -catenin pathway and loss of p53 protein function are potential tumor-intrinsic factors that, impacting on the ability of ACC cells to recruit dendritic cells, leading to T-cell exclusion, put this tumor among those that are potentially resistant to immunotherapy. Moreover, the steroid phenotype, which implies glucocorticoids hypersecretion in a subset of ACC, contributes to generating an immunosuppressive microenvironment. Here, we review clinical results of immunotherapy in ACC and we highlight molecular mechanisms driving immunotherapy failure in ACC, suggesting possible approaches to overcome resistance.
PubMed: 31057613
DOI: 10.1155/2019/6072863 -
Experimental and Clinical Endocrinology... Feb 2019Despite advances in diagnostic and therapeutic approach, Cushing's disease (CD) presents a challenging situation for the treating physician. (Review)
Review
BACKGROUND
Despite advances in diagnostic and therapeutic approach, Cushing's disease (CD) presents a challenging situation for the treating physician.
AIMS
To elucidate current challenges, present strengths and pitfalls of existing diagnostic tests, enlighten the need for new diagnostic approaches, appraise the effects of surgery and available pharmacological agents and identify future perspectives regarding CD.
MATERIALS AND METHODS
Systematic search to PubMed and Medline databases for publications mainly over the last five years.
RESULTS
Mutations in the ubiquitin specific peptidase 8 gene have been recently identified in functional sporadic corticotroph adenomas causing CD. Since the prevalence of obesity and metabolic syndrome is rapidly increasing, new diagnostic tests are necessary to differentiate these conditions. Next to the traditional tests, a cutoff of preoperative ACTH/cortisol ratio, an ultrasensitive late night salivary cortisol assay and the desmopressin test have been suggested as valid tools for the diagnosis and differential diagnosis of CD. Transsphenoidal surgery with variable remission and recurrence rates presents the treatment of choice for CD. Medical therapy consists of adrenal-targeted drugs e. g. ketoconazole, metyrapone, etomidate and mitotane and pituitary-targeted drugs e. g. pasireotide, cabergoline and retinoic acid.
CONCLUSIONS
CD is associated to a significant clinical burden, since numerous comorbidities persist after long-term biochemical control. These chronically ill patients show an increased mortality despite disease remission. Clinicians should treat comorbidities aggressively and seek for appropriate consultations. Structured consultation hours and expert excellence networks are needed in order to allow optimal, individualized care for affected patients, reverse increased morbidity and mortality and identify tumor recurrence early.
Topics: Comorbidity; Humans; Pituitary ACTH Hypersecretion
PubMed: 30130808
DOI: 10.1055/a-0664-7632