EDITORIAL
Adv Clin Exp Med 2015, 24, 2, 185-193 DOI: 10.17219/acem/30645
@ Copyright by Wroclaw Medical University ISSN 1899-5276
JUSTYNA PRZYTULSKAB-E, NATALIA ROGALAB-D, GRAŻYNA BEDNAREK-TUPIKOWSKAA, E, F Current and Emerging Therapies for Adrenocortical Carcinoma - Review
Department of Endocrinology, Diabetology and Isotope Therapy, Wroclaw Medical University, Poland
A - research concept and design; B - collection and/or assembly of data; C - data analysis and interpretation; D - writing the article; E - critical revision of the article; F - final approval of article; G - other
Abstract
Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Patients may present with hormone excess or a local mass effect. The most common imaging techniques (CT and MRI) use both size and appearance to distinguish between benign and malignant tumors. Open surgery by an expert surgeon with RO target is the treat- ment of choice. Mitotane (alone or in combination with cytotoxic drugs) may be administered after surgery or in patients not amenable to surgery. The role of radiotherapy as an adjuvant treatment is uncertain whereas targeted radionuclide therapy seems to be a promising option. New adjuvant treatment options, even after complete tumor removal, are desired because postoperative disease-free survival at 5 yrs is only around 30%. The establishment of detailed guidelines with the purpose of optimizing therapy with only mitotane but also in combination with other antineoplasmatic drugs is still a task to be done. Future advances in the management of ACC will probably be connected with better understanding of the molecular pathogenesis (Adv Clin Exp Med 2015, 24, 2, 185-193).
Key words: molecular genetics, adrenocortical carcinoma, mitotane, treatment options.
Epidemiology
Adrenocortical tumors are quite common (prev- alence of at least 3% in the population over the age of 50 yrs) whereas adrenocortical carcinoma (ACC) is a rare malignancy (incidence 1-2 per 1 m popula- tion) with poor prognosis. Women are more often affected than man (ratio 1 : 5) [1]. Data concerning the epidemiology of ACC in Poland was not found. The age distribution model is bimodal, the disease is most commonly detected in the 5th decade although there is a second peak in children under 10 yrs. Both groups differ in clinical presentation. In adults, 40% concern a nonsecretory mass detected incidentally or during evaluation for abdominal pain (median tumor size at diagnosis > 10 cm). Only 60% of tumors pres- ent with hormone excess and the most common se- cretory syndrome is mixed Cushing’s syndrome and virilization (35%), followed by pure Cushing’s syn- drome (30%) and pure virilization (20%). Estrogen secreting tumors are rare (10%) and the rarest are al- dosterone-secreting ACCs [2]. In many patients with
a seemingly hormonally inactive ACC, high concen- trations of steroid precursors can be detected [1]. In contrast, in childhood, 90% of ACC present with hor- mone excess, the most common of which is androgen secretion (in 55% of cases as the sole hormone or in combination with cortisol in approximately 30% of cases). Pure Cushing’s syndrome is observed in less than 5% of pediatric ACC cases [2]. An exception- ally high annual incidence of ACC in children has been described in southern Brazil (3.4-4.2 per 1 m children vs estimated worldwide incidence of 0.3 per 1 m children younger than 15 yrs). These cases are re- lated to a TP53 tumor suppressor gene mutation [1].
Molecular Genetics
Clonality and DNA Content
Clonal analysis of tumors plays an important role in determining the cellular origin of the neo- plasm and to uncover the fundamental mechanism
of tumor progression. Monoclonality shows that tumor progression is initiated by internal genet- ic alterations, while polyclonality indicates that local or systemic stimuli influence tumor cells. X-chromosome inactivation analysis has shown that ACCs initiate from a monoclonal population of cells, while ACAs might be both monoclonal and polyclonal [3]. Molecular techniques such as comparative genomic hybridization (CGH) have revealed aneuploidy (a genomic aberration most- ly observed in cancers) in 4 of 4 ACCs, whereas exclusively diploidy or tetraploidy are in normal adrenal cortices and ACAs. Further investigations have not shown any significant difference in over- all survival among patients with ACC presenting aneuploidy and those with ACC presenting diploid neoplasm [4].
Chromosomal Aberrations
Comparative genomic hybridization (CGH) can be used to identify structural chromosom- al alterations in ACCs. A large number of inves- tigations have revealed ACAs have few regions of changes, whereas ACCs demonstrated complex chromosomal mutations. Most of the changes in ACCs concern gains in regions 4q, 4p16, 5p15, 5q12-13, 5q32-qter, 9q34, 12q13, 12q24, and 19p, and chromosomal losses were observed at 1p, 2q, 11q 17p, 22p, and 22q [4]. Microsatellite exami- nations identified a high percentage of loss of het- erozygosity (LOH) and allelic imbalance at 17p13, 11q15 and 2p16 [4, 5]. The most recent study of 138 adrenal neoplasms demonstrated a higher number of alterations in ACCs (44%) compared to ACAs (10%) [4].
All these studies confirm the genetic vari- ety and heterogeneity of chromosomal changes in ACCs, and the frequently-observed mutations at chromosomes 5, 12 and 17 are considered to play a fundamental role in tumorigenesis [4]. More- over, CGH data has confirmed the theory of an adenoma-to-carcinoma progression according to more frequent chromosomal alterations in ACCs than ACAs and a positive correlation between the number of these changes and increasing tumor size [6].
Gene Expression Profiles
Global gene expression studies have identified that ACAs and ACCs have different expression profiles. An initial study reported high expression levels of genes involved in growth factor signal- ing and cell proliferation in ACCs (the so-called
IGF2 cluster), compared to the high expression levels of steroidogenic genes in ACAs (the ste- roidogenic cluster) [7]. Another study of 22 ACAs and 33 ACCs confirmed a significant difference in their expression profiles and found unique tran- scriptionally activated (12q and 5q) and repressed (11q,1p and 17p) chromosomal regions [4]. Re- cent studies have correlated expression profiles in ACC with clinical outcome and demonstrat- ed that tumors with high histological grade were transcriptionally different from low grade tumors and presented decreased overall survival. A cluster analysis of ACCs revealed 2 different groups with distinct transcriptional signatures and clearly dif- ferent clinical outcomes [7]. As a result, the poor outcome group had more genes involved in pro- liferation and the mitotic cell cycle, while the bet- ter outcome group presented an over-expression of genes implicated in differentiation, intracellular transport and metabolism [4].
Gene Mutations
Targeted genetic studies have shown that LOH of 17p13, 11p15, 11q13, 17q22-24 and 2p16 is more common in sporadic ACCs than in adrenocortical adenomas, while CGH analyses have shown that more number copy changes were present in ACCs than in ACAs [8]. Furthermore, a positive correla- tion was observed between the increasing number of genetic changes and increasing tumor size [6, 8].
Epigenetics of Adrenocortical Tumors
DNA Methylation
Changes at the epigenetic level have been in- flected in carcinogenesis and considered diag- nostic markers [4]. DNA methylation, which in- fluences a number of various cellular processes responsible for apoptosis, cell cycle, DNA damage repair, growth factor response, signal transduction and tumor architecture, can bring on tumorigene- sis and its progression [8]. This regulatory mecha- nism is frequently affected in cancer.
Fonesca studied the DNA methylation levels in 6 normal adrenal cortices, 15 ACCs, 27 ACAs and identified that tumor suppressor genes, responsi- ble for cell cycle regulation and apoptosis, such as CDKN2A, GATA4, DLEC1, HDAC10, PYCARD and SCGB3A1, are relevantly hypermethylated in ACCs. Moreover, they found an inverse correla- tion between the levels of methylation and mRNA expression [7].
A recent investigation of 51 ACCs and 84 ACAs observed a correlation between the hypermethyl- ation of promoters in ACCs and poor survival, and described H19, G0S2, PLAGLI and NDRG2 as si- lenced genes. Furthermore, it also provided insight into the possible function of methylation in ACC tumorigenesis, especially in the 11p15 locus com- prising IGF2 and H19 [4].
MicroRNAs
MicroRNAs are conserved small, noncoding RNAs implicated in the epigenetic regulation of cellular processes such as proliferation, apoptosis and differentiation. Alterations of miRNA includ- ing overexpression or deletion may be associated with cancer development and progression [4, 8].
The first examination of 36 adrenocortical samples (10 hormonally inactive ACAs, 9 corti- sol producing ACAs, 10 normal cortical tissues and 7 ACCs) identified differential expression of 22 miRNAs, with 14 miRNAs preferentially ex- pressed in ACCs. Including miR-184, miR-210, and miR-503 were up-regulated in ACCs, whereas miR-214, miR-375 and miR-511 were down-reg- ulated [4]. Assessing levels of miR-184, miR-503 and miR-511 alone helped to distinguish between ACCs and ACAs. [4] Another miRNA analysis of adrenal samples (6 normal tissues, 22 ACAs, and 27 ACCs) revealed that 23 miRNA were differen- tially expressed between ACCs and ACAs, of these 14 up-regulated miRNAs and 9 down-regulated miRNAs uniquely to ACC. [4] Furthermore, the study reported a significant up-regulation of miR- -483 (diagnostic sensitivity of 80% and specifici- ty of 100%) and down-regulation of miR-195 and miR-335 in ACC. [4] In addition, miR-483 is locat- ed exactly within the IGF2 locus and it is supposed that dysregulation of the IGF2 locus affects the ex- pression of miR-483 [7].
All these studies have confirmed that miRNAs may serve as promising biomarkers in ACCs due to their stability and the sensitivity of the detection methods available [8].
Signaling Pathways
IGF Pathway
Significant over-expression of IGF2 and down- regulation of CDKN1C and H19 locus is observed in sporadic ACC [9]. The IGF2 gene is located on 11p15, which is organized into two different clus- ters: a telomeric domain consisting of IGF2 and H19 genes and a centromeric domain including
the CDKN1C, KCNQ1OT1 and KCNQ1 genes [5]. The 11p15 region is subject to parental imprinting, in which specific genes are expressed solely either from the maternal or paternal allele [6].
IGF2 is maternally imprinted and is conse- quently expressed only from the paternal allele, whereas H19 and CDKN1C genes are both pater- nally imprinted and are therefore expressed from the maternal allele only. [4, 5] It has been report- ed that IGF2 over-expression is initiated by somat- ic structural alterations of the 11p15 locus, such as the loss of maternal imprinting or the loss of het- erozygosity (two paternal alleles) [7]. The loss of heterozygosity at the 11p15 region is associated with poor outcome and appears more frequently in ACCs than in ACAs [9]. IGF2 regulates growth and apoptosis by connection with the insulin-like growth factor 1 receptor (IGF1R), which has also been shown to be over-expressed in ACCs, partic- ularly in pediatric cases.
IGF2 genetic alterations of imprinted domains of the 11p15 region are implicated in the patho- genesis of Beckwith-Wiedemann Syndrome [4, 5]. This congenital overgrowth syndrome is charac- terized by macrosomia, macroglossia, organomeg- aly, developmental abnormalities and childhood tumors, which include ACC, nephroblastoma, hepatoblastoma, rhabdomyosarcoma.
The fact of IGF2 over-expression and the high incidence of ACC in BWS make the IGF system an interesting target for pharmacological inhibi- tion [4].
WNT Activation
The WNT/ß-catenin signaling pathway is a principal developmental pathway in multiple organ systems, including the adrenal gland and normally activated during embryonic develop- ment [4].
B-catenin plays the main role in this signal- ing pathway, participating in cell-cell adhesion, as a transcription cofactor with T-cell factor/lym- phoid enhancer factor mediating transcription ac- tivation of target genes of the Wnt signaling path- way [5].
Genetic mutations of the WNT/ß-catenin sys- tem were initially identified in familial adenoma- tous polyposis (FAP). Recent studies of adreno- cortical tumors assume that the WNT/ß-catenin signaling pathway plays a crucial role in sporadic adrenocortical tumorigenesis [4].
Furthermore, gene expression profiling anal- ysis disclosed over-expression of ß-catenin target genes, implying an importance of active ß-catenin signaling in ACCs. ß-catenin alteration was ob- served in both ACAs and ACCs, which indicates
that WNT activation may be an early step in ad- renocortical tumorigenesis, which preludes malig- nant transformation [4].
Pathogenesis
The role of pathologist is to diagnose an adre- nocortical tumor, to differentiate a malignant from a benign tumor and to assess its prognosis [10]. Thus, special diagnostic algorithms have been de- veloped to combine a variety of clinical, histologi- cal and immunohistochemical parameters [4]. The first step is macroscopic examination. Most ACCs weigh more than 100 g and are generally larger than 5-6 cm in diameter, while benign adrenocor- tical tumors weigh less than 50 g and are usually smaller than 5-6 cm. Malignant tumors are often lobulated [10].
A combination of histological parameters is helpful to identify tumors with malignant poten- tial and allow the calculation of a ‘score’ for a giv- en tumor [5, 10]. The Weiss system appears to be the most widely used classification, composed of 9 different items [5]. It is assumed that a score above 3 determines malignant tumors, while tu- mors without these features are less likely to me- tastasize and are considered benign [4, 5]. As men- tioned previously, IGF2 and allelic losses at 17p13 have been considered promising markers [5]. Im- munohistochemical criteria indicate the impor- tance of Ki-67 and cyclin E, which may be useful as diagnostic markers for malignancy in adreno- cortical tumors [5, 10].
The histopathological criteria proposed by Weiss (Weiss, 1984) for establishing a differential diagnosis between ACC and adenoma are shown in Table 1. A score of 3 or more correlates with malignancy.
Prognosis
A combination of various criteria including clinical, biochemical, macroscopic, histological, immunohistochemical and molecular help to as- sess the prognosis of ACCs [10]. Among the clin- ical parameters, the most commonly used is Mc- Farlane staging (Table 2). A prognosis of stages 1 and 2 tumors is better than that of stages 3 or 4 tumors [5].
On the pathological level, tumor size, mitotic count, Ki-67 and cyclin E have been suggested to associate with shorter survival [10]. Tumors larg- er than 12 cm confer a worse prognosis as well as high tumor grade (> 20 mitoses per HPF) and ve- locity of tumor growth [4, 5].
| Histological criteria | Weighted value (0 or 1) |
|---|---|
| High nuclear grade | 1 and 2 0 |
| Mitoses | ≤ 5 per 50 HPF 0 |
| Abnormal mitosis | absent 0 |
| Clear cells | > 25% 0 |
| Diffuse architecture | ≤ 33% surface 0 |
| Necrosis | absent 0 |
| Venous invasion (smooth muscle in wall) | absent 0 |
| Sinusoidal invasion | absent 0 |
| Capsular invasion | absent 0 |
HPF - high power fields.
| Stage I | tumor ≤ 5 cm |
|---|---|
| Stage II | tumor > 5 cm |
| Stage III | any tumor size and mobile nodes or Infiltration locally reaching neighboring organs and no lymph node |
| Stage IV | invasion of neighboring nodes or any tumor size and fixed nodes or any tumor size, any lymph nodes and metastasis |
A better survival is usually associated with younger patients [5]. A cortisol secreting tumor is reported to be an adverse prognostic factor [5].
Imaging
The most common techniques (CT and MRI) and recently also FDG-PET use both size and ap- pearance to distinguish between benign and ma- lignant tumors. The size of an adrenal tumor re- mains one of the best indicators of malignancy [1]. Current guidelines recommend surgical remov- al of tumors greater than 5 cm (though in the post-surgical examination 75% of them turn out to be benign) [2]. Measurement of Hounsfield units (HU) in unenhanced CT is of great value in
differentiating malignant from benign adrenal le- sions. If the lesion density is high (above 20 HU), a malignant tumor or pheochromocytoma should be suspected. For a better discrimination of lip- id-poor adenomas from ACC, a delayed contrast- -enhanced CT can be used, analyzing washout of a contrast medium. Modern MRI with dynam- ic gadolinium enhanced and chemical shift tech- nique is equally effective as CT in distinguishing malignant from benign tumors by assessment of fat content. This technique enables better assess- ment of invasion into adjacent organs and the in- ferior vena cava, which is useful in planning sur- gery. Adrenal scintigraphy with iodocholesterol analogs is not widely used as it is time-consum- ing and is associated with a relatively high dosage of radiation. In contrast, recent studies have dem- onstrated good performance of FDG-PET in dif- ferentiating malignant from benign adrenal lesions in patients with proven or suspected malignancy. A new method for adrenal imaging is 11C-metomi- date-PET [1]. Metomidate binds both to adrenal 11ß-hydroxylase and aldosterone synthase with high specificity and affinity and is therefore an ex- cellent tool to distinguish lesions of adrenocorti- cal origin from other lesions (high tracer uptake in both primary tumor and metastases) [11].
Hormonal Assessment
Some hormone secretion patterns suggest the malignant potential of the evaluated tumor (e.g. es- tradiol in males, high concentrations of DHEA-S or secretion of steroid precursors). Hormone mea- surements enable proper preparation for surgical procedures (e.g. risk of postoperative adrenal in- sufficiency connected with autonomous cortisol secretion by the tumor) and they are also essential
Table 3. Hormonal work-up and imaging in patients with suspected or proven ACC (recommendation of the ACC working group of the European Network for the Study of Adrenal Tumors, May 2005) [1]
Hormonal work-up
Glucocorticoid excess (min 3 of 4 tests)
Sexual steroids and steroid precursors
Mineralocorticoid excess
Exclusion of a pheochromocytoma (1 of 2 tests)
Imaging
CT or MRI of abdomen and thorax
Bone scintigraphy (when suspecting skeletal metastases) FDG-PET (optional)
for the establishment of tumor markers for moni- toring of tumor recurrence [1].
Staging
Until 2004, no official TNM classification was available for ACC and different staging systems were used, most often the Sullivan modification of the Mc- Farlane system. According to the TNM staging sys- tem for ACC proposed by the International Union Against Cancer in 2004, stages I and II describe lo- calized tumors up to 5 cm and larger than 5 cm, re- spectively. Locally invasive tumors or the presence of local lymph nodes are classified as stage III, whereas stage IV consists of tumors invading adjacent organs or presenting with distant metastases. The main pur- pose of the staging system is to predict the disease-free and disease-specific survival in patients with cancer. For many tumors, the TNM system has been modi- fied to improve accuracy. On the basis of the analysis of the German ACC Registry, a revised classification has been proposed (the European Network for the Study of Adrenal Tumor classification). In this sys- tem, stage III ACC is defined by the presence of pos- itive lymph nodes, infiltration of surrounding tissue or presence of tumor thrombus in the vena cava or renal vein (VTT), whereas stage IV is restricted to pa- tients with distant metastases. There is also a sugges- tion that correct staging can be performed only after surgery and that the result of surgery should be tak- en into account (e.g. tumor spillage during surgery represents tumor spread and is connected with worse prognosis, so assignment of these cases to stage III or even IV irrespective of prior surgery staging may be justified) [12].
Surgery
In stage I-III, surgery is recommended and complete resection offers the best chance for cure, though adjuvant therapy may be also required. In stage IV, surgery is also taken under consideration - incomplete resection of the primary tumor or metastatic disease not amenable to surgery are as- sociated with poor prognosis, however tumor de- bunking may help to control hormone excess and in some cases enable other therapeutic options [1]. Surgery for local recurrence or metastatic disease is accepted and is associated with improved sur- vival in retrospectives studies [1, 13]. The best pre- dictors of prolonged survival after the first recur- rence are time to first recurrence (TTFR) over 12 months and tumors amenable to radical resection. When both conditions are fulfilled, surgery is rec- ommended [13].
At present, open surgery is regarded as the standard of care and the use of laparoscopic adre- nalectomy is still a matter of debate [1, 13]. How- ever, according to Martin Fassnacht, the experi- ence of the surgeon is more important than the technique of the procedure (ECE 2014 lecture: ad- renocortical carcinoma - current concepts and fu- ture perspectives).
Therapy
Adjuvant treatment options even after com- plete tumor removal are desired because postop- erative disease-free survival at 5 yrs is only around 30%. At present, no such options have been con- vincingly established [1].
Mitotane
Mitotane (o,p-DDD) is the only adrenal-spe- cific agent available for the treatment of ACC. The first description of its effects was made in 1948, and it concerned adrenal atrophy in dogs [14]. De- spite the long history of mitotane use in ACC, it is not available in all countries. Mitotane has an im- pact (as a cytotoxic agent) on the fascicular and re- ticular zone, leading to their degeneration, where- as changes of the zona glomerulosa are relatively slight. Metabolic activation is essential for its ad- renolytic activity. Oxidative damage through the production of free radicals may contribute to the adrenolytic effect of mitotane. Impairment of ad- renal steroidogenesis is due to a direct inhibito- ry effect on steroidogenic enzymes (inhibition of 11 beta-hydroxylation) [1]. Mitotane is admin- istered per os, and monitoring of blood levels is mandatory for predicting the efficacy and toxici- ty (therapeutic range 14-20 mg/L). The daily dos- age needed to achieve and maintain blood levels greater than 14 mg/L is variable. The response rate fluctuates in different publications. Allolio and Fassnacht have analyzed the efficacy of mitotane treatment in advanced ACC, including only pro- spective studies or reports with more than 10 pa- tients from the last 20 yrs. Based on this analysis, it was concluded that mitotane leads to an objec- tive tumor regression in about 25% of cases and control of hormone excess in the majority of pa- tients. Although a complete response (or even cure) in patients with advanced ACC is extremely rare, long-term survival has been reported [1, 15]. Mitotane has a narrow therapeutic window, and adverse effects occur frequently and are often dose limiting. More than 80% of all patients ex- perience at least one undesirable effect [1]. These
effects are mainly gastrointestinal or neurological. Abnormalities in laboratory tests like leucopenia, hypercholesterolemia, hypertriglyceridemia (very common), thrombocytopenia and anemia (com- mon) may be observed. In general, the adverse ef- fects are reversible after cessation of mitotane. The probability of central neurological system (CNS) adverse effects increases strongly with mitotane blood levels greater than 20 mg/L (above the ther- apeutic range) [1]. In case of overdose, cessation of administration is the only way to reduce drug levels. There is no antidote and the drug cannot be removed by hemodialysis, because it is lipophilic. Patients with renal or liver insufficiency, obesity or those who have lost weight recently are more ex- posed to overdose.
For management of nausea, 5-hydroxytrypta- mine blockers may be useful. In the case of signifi- cant neuropsychiatric side effects, drug treatment is interrupted for a minimum of 1 week and re- started with a lower dose. Treatment with mito- tane, due to its adrenolytic activity, leads to adre- nal insufficiency in the majority of patients and it also increases the metabolic clearance of glucocor- ticoids, and thus high-dose glucocorticoid replace- ment (e.g. 50 mg hydrocortisone daily) is needed. Inadequate glucocorticoid substitution enhances the mitotane-induced adverse effects and reduc- es mitotane tolerance [1]. Mitotane is a therapeu- tic indication in the treatment of inoperable ACC and in preparing for adrenalectomy. However, the high rate of recurrence implies a need for adjuvant therapy following surgical procedures. In Poland, Kasperlik-Załuska described a group of 82 patients with microscopically confirmed adrenocortical carcinoma, who were treated with mitotane af- ter surgical procedure irrespectively of stage at the time of surgery. In conclusion, immediate admin- istration of mitotane after surgery was connected with better survival in comparison to the group with delayed treatment [16]. The topic was also dis- cussed in 2008 by an international panel of experts. Adjuvant therapy with mitotane was unanimously recommended for patients with potential residual disease (R1 or Rx resection) or greater than 10% Ki67 positivity on pathologic examination, where- as adjuvant therapy was not considered mandato- ry in patients fulfilling all of the following criteria: stage I or II (based on ENSAT TNM criteria), his- tologically proven R0 resection and Ki67 expres- sion ≤ 10%. Adjuvant therapy in stage III after R0 resection is still an issue to be resolved [17, 18]. Currently, to evaluate the effectiveness of adju- vant therapy with mitotane, a randomized pro- spective study ADIUVO is ongoing (www.adiu- vo-trial.org). Patients will be randomly assigned to receive mitotane treatment or observational
follow-up only. Mitotane will be administered un- til progression or unacceptable toxicity for a min- imum of 2 years. The administration of any other anticancer agents including chemotherapy and ac- tive biologic agents is not permitted. Two hundred patients (100 per treatment arm) will be enrolled. The duration of the study will be 6 years (enroll- ment period, 4 years; follow-up period, 2 years).
Cytotoxic Chemotherapy
The response rates are generally poor. The best results have been initially described for the so-called Italian protocol (Berutti et al.) which combines mi- totane with etoposide, doxorubicin and cisplatin (EDP-M). According to WHO criteria, the over- all response rate in 72 patients was 49%, including 5 patients with complete response [1, 19]. The sec- ond active regime described was a combination of mitotane and streptozocine (Khan et al.), and com- plete or partial responses were observed in 36% of patients [1, 20]. The promising results of both pro- tocols led to the first ever phase III trial in ACC di- rectly comparing these treatment options [First In- ternational Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treat- ment (FIRM-ACT)]. The publication of the results of FIRM-ACT (2012) showed an advantage to EDP-M in terms of progression-free survival. Based on this data, EDP-M can now be considered the “standard of care” though the 25% response rate (with anoth- er 28% disease stabilization) is less optimistic than data obtained in primary observations by Berutti et al. Additionally, the retrospective reviews of the effects of mitotane as a single agent place the re- sponse rate in a similar range [21]. The limited re- sponse to cytotoxic therapy in ACC is linked to high expression of the multidrug-resistant gene mdr-1, resulting in high concentrations of p-glycoprotein acting as a drug efflux pomp, transporting cytotoxic agents (e.g. doxorubicin) out of the cell. The inhibi- tion of a drug efflux pomp could enhance the effica- cy of cytotoxic chemotherapy, and though early tri- als were not promising, the search for more potent mdr-1 inhibitors is ongoing [1].
Radiotherapy
ACC has been considered radio resistant for a long time, however several reports have de- scribed tumor response rates up to 42%, and it has also been demonstrated that radiotherapy reduces the risk of local failure.
Existing data regarding radiotherapy in ACC indicates that this treatment should be taken un- der consideration especially when microscopic tu- mor residues are detectable after surgery (R1) or
residual tumor dimensions are not known (RX). Whereas macroscopic visible residual tumors (R2) are indication for a second operation [22]. Cur- rently, there are no guidelines for radiotherapy in patients who have undergone complete tumor re- moval (R0), although this treatment is usually not recommended when tumor dimensions are not greater than 8 cm. Radiotherapy may be consid- ered as an additional option after R0 resection for tumors with greater dimensions, blood vessel inva- sion and Ki-67 index ≥ 10%, which are associated with a high recurrence risk. Combined treatment (radiotherapy and cytotoxic drugs, such as mito- tane) is also under investigation [22].
Targeted Radionuclide Therapy
Hahner et al. reported about the attempt of sal- vage treatment with [13]]]iodometomidate. Between 2007 and 2010, [13]]]iodometomidate was adminis- tered to 11 patients. One patient died 11 days af- ter treatment, unrelated to the radionuclide ther- apy. The best response was classified as a partial response in one case, in 5 patients stable disease was observed. Treatment was generally well toler- ated and transient bone marrow depression was ob- served. The study has important limitations due to the small number of treated patients. Radionuclide therapy is a promising treatment option deserving evaluation in prospective clinical trials [11].
Future Treatments
Over-expression of the epidermal growth factor receptor (EGFR) protein in AC has been consid- ered a promising target for the use of EGFR inhibi- tors. Unfortunately, treatment with tyrosine kinase inhibitors revealed limited efficacy [23]. Better re- sults have been noted with targeted therapy of in- sulin-like growth factor 1 receptor (IGF-1R) inhib- itors. The IGF system is seen as an interesting aim for future therapies in advanced ACC and further clinical investigations are currently in progress [24]. Vascular endothelial growth factor (VEGF) has also been reported as an attractive therapeutic approach for ACC, however the results of studies did not meet expectations [23]. A further object of interest is Wnt/ß-catenin pathway and so far, its antagonists remain in preliminary preclinical investigations [8].
Treatment of Hormone Excess
Management of endocrine syndromes is of- ten important because the associated systemic ef- fects may significantly impact patient well-being.
Treatment with mitotane leads to adrenal insuffi- ciency in the majority of patients, though the on- set is delayed, and some other drugs may be re- quired to control hormone excess at the beginning of treatment. Amiloride can be used to correct hy- pokalemia. Based on a case report, the use of spi- ronolactone may impair the antitumor activity of mitotane [1]. Adrenostatic drugs like ketocon- azole, metyrapone, aminoglutethimide and etomi- date can be used to lower cortisol into the normal range. Ketoconazole (400-1200 mg/d) is most of- ten used though the treatment may be connected with serious hepatotoxicity. Metyrapone treatment is limited by poor tolerance. Common side-effects include nausea, vomiting, abdominal discom- fort, headache, dizziness and sedation. Hypoten- sion may be also observed. Intravenous etomidate (e.g. 80 mg/d as a continuous infusion) can be used in emergencies (e.g. glucocorticoid-induced psychosis) but is not suitable for long-term treat- ment due to administration only by intravenous route [1]. Mifepristone may be another thera- peutic option. It is well known for its antiproges- tin activity but it is also a glucocorticoid receptor
antagonist with rapid onset of action and there- fore can be used to treat hypercortisolism. The mechanism of action may lead to severe hypokale- mia and hypertension, as mifepristone blocks on- ly glucocorticoid action (ACTH and cortisol levels remain elevated) whereas the mineralocorticoid activity of cortisol excess is not affected by mife- pristone. The assessment of efficacy of the thera- py and risk of signs of adrenal insufficiency dur- ing treatment is difficult because it is only based on clinical features [25].
Conclusion
Adrenocortical carcinomas (ACCs) are rare, aggressive tumors with dismal prognosis. Consid- ering the rarity and complexity of ACC, significant progress has been made over the past decade to understand its molecular pathogenesis, better di- agnosis and better prediction of prognosis. These advances help to improve the clinical care of pa- tients with ACC and hopefully will also give new perspectives for possible targeted therapies.
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Address for correspondence:
Grażyna Bednarek-Tupikowska Department of Endocrinology, Diabetology and Isotope Therapy Wroclaw Medical University Pasteura 4 50-367 Wrocław Poland Tel .: +48 71 784 25 49
E-mail: grazyna.bednarek-tupikowska@umed.wroc.pl
Conflict of interest: None declared
Received: 10.08.2014
Revised: 26.08.2014
Accepted: 17.10.2014