GENITOURINARY CANCERS (DP PETRYLAK AND JW KIM, SECTION EDITORS)
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Management of Adrenocortical Carcinoma
Sina Jasim 1 . Mouhammed Amir Habra 2
C Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
Purpose of Review Adrenocortical carcinoma (ACC) is a rare endocrine malignancy typically with poor prognosis. This review aims to summarize the current knowledge regarding the clinical management of ACC.
Recent Findings Surgery remains the cornerstone for localized ACC management. In more advanced cases, debulking surgery when feasible can help with hormonal control and may allow the initiation of systemic therapy. Over the last few years, our understanding of ACC molecular pathogenesis has expanded with no significant change in treatment options. Platinum-based chemotherapy is the gold standard in metastatic ACC despite suboptimal efficacy. Tyrosine kinase inhib- itor use did not result in meaningful benefit in ACC patients. Multiple clinical trials are currently exploring the role of immunotherapy in ACC.
Summary Despite the remarkable improvement in our understanding of the molecular signature and pathways in ACC, this knowledge did not yield a major breakthrough in management of advanced ACC. Multi-institutional and international collab- orations are needed to identify promising treatments and new therapeutic targets to improve the care of ACC patients.
Keywords Adrenocortical carcinoma . Mitotane . Targeted therapy . Immunotherapy . Genomic profiling
Introduction
Adrenocortical carcinoma (ACC) is an orphan malignancy with an annual incidence between 0.7 and 2 cases per million population [1, 2]. ACC is more frequent in women (55-60%) with a peak incidence in the fourth and fifth decades of life. ACC is sporadic in majority of cases though it can be a part of hereditary tumor syndromes, such as multiple endocrine neo- plasia type 1, Li-Fraumeni, Lynch, familial adenomatous polyposis coli, and Beckwith-Wiedeman syndromes [1].
This article is part of the Topical Collection on Genitourinary Cancers
☒ Mouhammed Amir Habra mahabra@mdanderson.org
Sina Jasim s.jasim@wustl.edu
1 Division of Endocrinology, Metabolism and Lipid Research, Washington University, in St. Louis, School of Medicine, 660 S. Euclid Ave., Campus Box 8127, St. Louis, MO 63110, USA
2 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1461, Houston, TX 77030, USA
ACC can be present with signs of excessive adrenal hormone production (60%), pain (30-40%), or incidental- ly discovered on imaging studies (10-15%) [3]. ACC carries a poor prognosis with overall 5-year survival rang- ing from 60-80% in patients with ACC stage I to 13% in patients with stage IV disease [4]. The clinical outcomes are heterogeneous given variable tumor biology, disease presentations, and management options. Multiple clinical and pathological factors can influence the prognosis of ACC. Tumor stage at diagnosis is an independent prog- nostic factor. The combination of tumor size and exten- sion, regional lymph node involvement, and distant me- tastasis (TNM classification) are key elements in ACC staging. Adrenocortical tumors in children are less aggres- sive and tend to have better clinical outcomes after com- plete surgical resection compared to ACC in adults [5, 6]. Even in adults, age was proposed as another variable when categorizing ACC as stage I and II (≤55 and >55 respectively) disease [7]. Cortisol-secreting ACC has worse prognosis with higher recurrence rates and worse survival compared to non-cortisol-producing ACCs [8, 9]. Pathological features such as tumor grade and resection margin status are significant predictors for prognosis. Surgical expertise to achieve complete tumor resection (R0) is critical to improve outcome. The effect of margin
resection status on prognostic outcomes has been de- scribed in few retrospective studies suggesting higher re- currence rate and worse survival in patients with positive margin of resection (R1) [5]. Ki67 proliferation index is a clinically useful pathological marker with strong associa- tion with prognosis [10]. In ACC patients (stages I-III) who underwent complete surgical resection, increased Ki67 by 1% was associated with 4% increase in the risk of recurrence. Furthermore, patients with Ki67 of ≥20% had overall survival 9.4 months compared to overall sur- vival of 53.2 months in patients with Ki67 < 10% [11 .. ].
ACC Genetics and Mutations
Over the past few years, the advances in genomic methods have expanded our knowledge about gene ex- pression, and genetic and epigenetic alterations at the pan-genomic level in various malignancies. Genomic studies led to the identification of tumor subgroups that have distinct biology and variable outcome allowing for the development of prognostic molecular markers [10]. Approximately 5% of all ACCs occur in patients with Li-Fraumeni syndrome (TP53) or Lynch syndrome (MLH1, MSH2, MSH6, PMS2). Germline TP53 mutations are more common in pediatric ACC, as germline TP53 mutations are frequent and associated with worse progno- sis [12]. This highlights the importance of genetic counseling in patients with ACC especially if there is suspicious for hereditary cancer syndrome [13].
Loss-of-function mutations of TP53 occur in about 20% of adult’s ACC [14, 15 .. ] usually associated with loss of hetero- zygosity (LOH) of the 17p13 region, where TP53 is located [16]. CTNNB1 gain-of-function mutations and ZNRF3 dele- tions (a negative regulator of Wnt/CTNNB1 and leads to the activation of the Wnt/CTNNB1 pathway) are seen in 20% of ACC [14, 15 .. ].
Genomics studies revealed major differences between aggressive and less aggressive ACCs. Integrated genome analysis identified distinct molecular subgroups of ACC that are associated with different outcomes. The ENSAT network and The Cancer Genome Atlas (TCGA) consor- tium molecular classification identified two major molec- ular subgroups, corresponding to ACC of “good” and “bad” prognosis [14, 15 .. ].
The advancement in understanding the molecular biol- ogy of ACC has led to the identification of mutation asso- ciated with ACC development and factors determining the risks for recurrence and progression, predict tumor aggres- siveness, and to identify potentially targetable molecular changes to facilitate personalized management approach [13].
Pathways Involved in ACC
Figure 1 illustrates variable pathways and therapeutic targets in ACC and summarizes the drugs studied or used in ACC management.
i. IGF2 overexpression
The insulin-like growth factor (IGF) system is involved in cancer cell growth [17]. IGF2 gene is located on 11p15 and IGF2 gene is maternally imprinted and only expressed from the paternal allele. Over-expression of IGF2 is seen in major- ity of ACCs and the loss of heterozygosity at the 11p15 region is seen more frequently with ACC than adenomas; it is usually associated with poor outcome [18].
IGF2 regulates the growth and apoptosis when interacts with insulin-like growth factor 1 receptor (IGF1R), the latter is also found to be over-expressed in ACC especially in pediatric cases [19]. Activation of IGF-1R results in stimulation of downstream signaling pathways including the mitogen-activated protein kinase (MAPK) and phosphoinositol-3-kinase (PI3-AKT) pathway, leading to increased cell division and survival [20]. Of note, the ge- netic alterations of imprinted domains of chromosome 11p15 are implicated in the pathogenesis of Beckwith- Wiedemann syndrome [1].
ii. WNT signaling
The WNT/ß-catenin signaling pathway is an important de- velopmental pathway in multiple organ systems, and it is es- sential in the embryonic development of the adrenal glands [21]. The Wnt/B-catenin signaling pathway is one of the most frequently altered pathways in ACC.
The ß-catenin is essential in this signaling pathway, includ- ing in cell-cell adhesion, and transcription activation of target genes of the Wnt signaling pathway. Activation of beta- catenin and Wnt signaling pathway is a frequently recognized alteration in both benign and malignant adrenocortical tumors [22]. Activating somatic mutation of the CTNNB1 in ACC is an independent predictor of less favorable disease-free and overall survival [23].
iii. cMET
Hepatocyte growth factor (HGF) activates cMET in an au- tocrine and paracrine fashion, leading to enhanced metastatic potential and resistance to therapy in a variety of malignancies including ACC [24 .. ]. HGF stimulates tumor angiogenesis by direct cMET activation, and by increasing the production of angiogenic cytokines, enhancing endothelial cell motility and proliferation [25, 26].
iv. Other
Multiple other pathways involved in cell cycle were iden- tified or currently investigated in ACC [26]. Pan-genomic studies recognized TP53 as one of ACC driver genes [15 .. ]; therefore, the recovery of p53 function, using MDM2 antag- onist, and the reactivation of mutant TP53 have the potential to be used in ACCs. The Polo-like kinase 1 (PLK-1) is a negative modulator of p53 activity. PLK1 system regulates multiple steps of cell division and DNA stability/repair and is considered a good prognostic marker and candidate for targeted therapy [27].
Hormonal Control in ACC
1. Cushing syndrome
Hypercortisolism in ACC requires immediate and prompt treatment to improve the life-threatening metabolic complications.
a) Mitotane
Mitotane is an adrenolytic drug with an inhibitory effect on adrenal steroidogenesis [28]. It is approved to treat advanced ACC cases and it can be used in combination with other drugs to control cortisol overproduction.
b) Steroidogenesis enzyme blockers
i. Ketoconazole
Ketoconazole inhibits multiple key cytochrome P450 (CYP) enzymes involved in variable steps of steroidogenesis in the adrenal cortex, and can be used in cortisol secreting ACCs. The advantage of using ketoconazole (400-1200 mg/ day) is inhibiting androgen production as well. However, rou- tine monitoring of liver function tests is important especially when using mitotane simultaneously as both can be hepato- toxic [29.].
ii. Metyrapone
Metyrapone decreases cortisol synthesis by blocking 11- beta-hydroxylase function [29.]. Adding metyrapone to che- motherapy is often used to rapidly improve the manifestation of Cushing syndrome in patients with cortisol-producing ACC [30].
c) Glucocorticosteroid receptor blocker
Mifepristone
Mifepristone is a glucocorticoid antagonist approved to manage hyperglycemia in the context of Cushing syndrome. Some patients may have worsening hypertension and hypo- kalemia due to mineralocorticoid receptor activation and may require a concomitant use of high doses of spironolactone or eplerenone to manage hypertension and hypokalemia [31].
2. Hyperaldosteronism
a) Spironolactone and eplerenone
Aldosterone-producing ACCs are rare and cause severe hy- pertension and marked hypokalemia [32]. They are managed with mineralocorticoid receptor antagonists (spironolactone or eplerenone). It is important to monitor potassium level and renal function during therapy to titrate the dose and avoid electrolyte imbalance [29.]. Spironolactone has anti-androgen effect in ad- dition to the mineralocorticoid receptors blockade.
3. Androgen excess
Androgen-secreting adrenal ACC typically produces andro- gens, steroid intermediates, and commonly associated with cortisol excess as well. Androgen excess in women negatively influences the quality of life. Patient may have very high levels with serum testosterone, androstendione, and/or DHEA-S. Generally, treatment may involve androgen receptor antago- nists, including spironolactone, bicalutamide, or flutamide.
4. Estrogen excess
Estrogen-producing ACCs are exceedingly rare (1-2%). Treatment with estrogen receptor antagonists or aromatase inhibitors can be used [33].
Management of Localized Disease
Surgery
i. Primary resection
Surgical resection carries the best chance for cure in pa- tients with localized ACC [3].
Surgery for ACC should be done by a skilled surgical team, in high-volume centers for adrenalectomies with the goal of a microscopically free margin (R0 resection).
Open adrenalectomy is generally the favored approach in ACC cases, although with careful patient selection, laparoscopic approach has been proposed as an alternative approach in some studies [34, 35], many of which are retrospective in nature.
To date, available evidence suggests higher rates and shorter time to develop loco-regional and peritoneal recurrence, worse
CIXUTUMUMAB FIGITUMUMAB
ERLOTINIB GEFITINIB
CABOZANTINIB
DOVITINIB
BEVACIZUMAB
HGF
AXITINIB CABOZANTINIB SORAFENIB SUNITINIB
IGF-2
EGFR
LINSITINIB
C-MET
IGF1R
VEGFR
RAS
FGFR
PEMBROLIZUMAB NIVOLUMAB AVELUMAB
Wnt
W
PKC
PI3K
RAF
PLC-Y
VEGFR
ß-Cat
PD1
PDL1
AKT
MEK
TEMSIROLIMUŞ
FAK
VEGF
EVEROLIMUS
TCR
mTOR
ERK
MHC
Mitochondria
CD28
B7
SF1
Endothelial cell
CTLA-4
MITOTANE
IPILIMUMAB
HRE
T-cell lymphocyte
Nucleus
Cholesterol
131-lodometomidate
ADRENOCORTICAL CARCINOMA CELL
CISPLATIN/DOXORUBICIN/ETOPOSIDE(EDP) STREPTOZOSIN (Sz) GEMCITABINE/CAPECITABINE
recurrence-free, and overall survival following laparoscopic resection [15 .. , 36-38]. As such, the long-term advantage of open resection for suspected adrenal masses > 6 cm outweigh the benefits of a minimally invasive approach when ACC is suspected. The lack of randomized controlled trials makes it hard to compare the laparoscopic approach to the open ap- proach in ACC with a diameter of <6 cm [29., 39, 40].
There is no agreement regarding the optimal extent of re- gional lymph node resection during primary resection of ACC [41]. Although the data supporting routine resection of region- al lymph nodes are derived from retrospective cohort studies [3], removal of at least 5 regional lymph nodes was associated with reductions in the risk of tumor recurrence and disease- related mortality [42, 43].
Neoadjuvant Approach
Limited data are available regarding the use of neoadjuvant systemic therapy in ACC. Neoadjuvant chemotherapy im- proved the outcomes in 15 patients with borderline resectable ACC (defined as having oligometastases, reduced perfor- mance status, or requiring multi-organ resection) and these patients had similar overall survival and disease-free survival compared to 38 patients with more localized ACC who were managed with surgical resection alone [44].
Adjuvant Therapy
There is lower risk of tumor recurrence when patients with ACC undergo surgery in high-volume center and by experi- enced surgeons [45]; however, the risk of recurrence remains high approaching 60-70%, requiring the use of adjuvant ther- apies after surgical resection.
i. Mitotane
The routine use of adjuvant mitotane to improve recurrent- free survival in ACC is controversial and mostly based on retrospective evidence of improved recurrence-free and overall survivals in patients who received adjuvant mitotane [46, 47.].
Currently, an international, multicenter, prospective, ran- domized trial (ADIUVO trial) is enrolling low-risk ACC pa- tients (defined as stages I-III after complete surgical resection with Ki67 <10%) to establish the role of adjuvant mitotane in low-risk ACC (ClinicalTrials.gov Identifier: NCT00777244).
ii. Mitotane with chemotherapy
Mitotane is a fat-soluble oral agent that requires few months of therapy to reach what is considered a therapeutic oncological level. Few high-volume centers offer adjuvant platinum-based chemotherapy with mitotane in the first few
months after surgery in high-risk ACC patients. There is an ongoing international, multicenter trial (ADIUVO-2) compar- ing the two practices of using mitotane alone compared to mitotane with cisplatin and etoposide as adjuvant therapy to treat patient with ACC who are at high risk of recurrence (stages I-III with Ki67 ≥ 10%) (Clinicaltrials.gov ID NCT03583710).
iii. Radiation therapy
The use of adjuvant radiotherapy in ACC relies on retrospec- tive studies. In a recent meta-analysis of multiple cohort studies, there was reduced likelihood of recurrence and prolonged time to recurrence when adjuvant radiation was used in ACC but there was no evidence to support improved overall survival in those patients [48]. More recent data showed survival benefit with radiation use in patients with non-metastatic ACCs who had positive resection margins (R1) [49 .. ].
Management of Recurrent/Metastatic Disease Surgery
There is limited data to support the efficacy of surgical resec- tion in metastatic disease. Despite the low likelihood of com- plete tumor removal in advanced ACC, surgery is still an important therapeutic option in metastatic ACC when feasible. Surgery is associated with better survival, even in advanced ACC [50]. Salvage resection or metastasectomy can be of- fered especially with metastases in single organ [51].
The European Society of Endocrine Surgeons (ESES) and ENSAT recommendations did not support palliative or debulking surgery for metastatic ACC due to insufficient ev- idence [52]; however, a recent study suggested that surgery of the primary site improved overall and cancer-specific survival in metastatic ACC patients [53]. Of note, phase I and II trials using heated intraperitoneal chemotherapy with cisplatin have been done in some tumors that spread primarily to the perito- neal lining of the abdomen. This encouraged the launching of phase II clinical trial of using heated intraperitoneal peritoneal chemotherapy (HIPEC) after surgical debulking of ACCs. The purpose of this trial is to determine if surgical approach followed by intraperitoneal administration of heated cisplatin when tumor volume is minimal can favorably influence the progression-free survival in patients with ACC (ClinicalTrials. gov Identifier: NCT03127774).
Mitotane
Mitotane is a key therapy for inoperable or metastatic ACC. Mitotane monotherapy is usually given in cases of low tumor burden or less aggressive disease, but need to be combined
with cytotoxic chemotherapy in more aggressive disease or advanced ACC as mitotane monotherapy might not be enough [54]. Mitotane therapeutic level target is 14-20 mg/L. Mitotane should be given under the supervision of experi- enced team, as mitotane is associated with adrenal insufficien- cy and often requires higher glucocorticosteroid replacement compared to other patients with adrenal insufficiency from other causes. Moreover, mitotane is a strong cytochrome P450-3A4 (CYP3A4) inducer which leads to significant drug-drug interactions leading to the inactivation of other on- going treatments such as antimicrobials, anti-emetics, anti-de- pressants, and other drugs that are usually metabolized through CYP3A4 [55].
Chemotherapy
Etoposide, doxorubicin, and cisplatin (EDP)-mitotane regi- men is considered the standard chemotherapy in advanced ACC. EDP-mitotane use was associated with longer progression-free survival (5.5 months) compared to the com- bination of streptozocin plus mitotane that had progression- free survival of 2.1 months [56]. However, up to 58% of patients receiving EDP-M had serious adverse events com- pared to 41% in the mitotane plus streptozocin arm [56].
GEM-based chemotherapy (gemcitabine + capecitabine) is well-tolerated, but modestly active, regimen against advanced ACC. This can be used with or without mitotane [57.].
Targeted Therapy
Several kinase inhibitors have been investigated in advanced ACC but the results were largely discouraging. However, the efficacy might have been influenced by increased kinase in- hibitor use with mitotane-induced CYP3A4 activity. To date, no specific tyrosine kinase inhibitor is approved in treating advanced ACC [29.].
1. IGF1R inhibitors
a) Monoclonal antibodies
i. Cixutumumab
Cixutumumab is a recombinant human monoclonal anti- body against IGF-1R. Its efficacy against ACC was studied in combination with mitotane in 20 patients with unresectable or metastatic ACC; however, this combination did not show encouraging outcomes [58].
Cixutumumab in combination with temsirolimus, an mTOR inhibitor, was generally tolerated and about 40% of patients had stable disease more than 6 months despite failing multiple lines of therapy before receiving this combination [59].
ii. Figitumumab
The anti-IGF-1R monoclonal antibody figitumumab was studied in 14 patients with metastatic ACC. Eight patients had stable disease without confirmed responses by RECIST criteria [60].
b) Linsitinib
Linsitinib is an oral inhibitor of the IGF-1R and insulin receptor that showed partial response in two of 15 patients with ACC in early studies [61]. However, linsitinib did not improve progression-free or overall survival when studied in double-blind placebo controlled phase III clinical trial [62 .. ].
2. VEGFR inhibitors
There is increased expression of mediators of tumor angio- genesis and proliferation such as vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), and heparanase- 1 (HPA-1) in ACC [63]. As such, anti-angiogenic agents thought to have promising role in the treatment of ACC.
a) Bevazicumab
Bevacizumab, a monoclonal antibody, binds to VEGF and block the interaction with VEGF receptors [64]. The combi- nation of metronomic capecitabine and bevacizumab was studied in advanced ACC who progressed on prior mitotane and other lines of chemotherapy without clear evidence of clinical benefit [65].
b) Multi-kinase inhibitors
i. Sorafenib
Sorafenib is a multiple kinase inhibitor that inhibits VEGFR2-3, platelet-derived growth factor (PDGFR), and the enzyme RAF-1. Its effectiveness was described in some case reports [66]; however, this was not true when it was studied in combination with metronomic paclitaxel in 25 pa- tients with metastatic ACC who had progressed on mitotane and other chemotherapy regimen and the trial was prematurely stopped due to early disease progression [67].
ii. Sunitinib
Sunitinib is an oral multi-kinase inhibitor which inhibits VEGFR1-2, c-KIT, Fms-like tyrosine kinase 3, and PDGFR. In a phase II study, single-agent sunitinib was given to patients with advanced ACC, only 5/35 patients had stable disease with progression-free survival of 5.6 to 11.2 months and over- all survival of 14.0 to 35.5 months, while 24/35 had
progressive disease or died (6/35). However, as mitotane is known to induce cytochrome CYP3A4, its concomitant or prior use with sunitinib may have influenced the results of this study. Mitotane use increases sunitinib clearance as suggested by having very low serum levels of sunitinib and its active metabolites [68].
iii. Dovitinib
Dovitinib, an oral multi-kinase inhibitor, targets fibroblast growth factor receptors, platelet-derived growth factor recep- tors, and VEGF receptors. Evaluation of this drug efficacy in phase II trial showed no objective response. However, stable disease was seen in 23% of the patients for more than 6 months [69].
iv. Axitinib
Axitinib, selective inhibitor of VGEFRs 1-3, was studied in a phase II trial in 13 patients with metastatic ACC previously treated with chemotherapy with or without mitotane. There were no objective responses during therapy as defined by RECIST criteria; however, stable disease of more than 3 months was seen in 8 patients. The median progression-free and overall survival durations were 5.48 and 26.92 months, respectively. The survival duration thought to reflect patients who had indo- lent nature of the disease as median overall survival was 3 years prior to study enrollment [70].
v. Cabozantinib
Cabozantinib is a multi-kinase inhibitor including cMET that reduced ACC tumor growth in vitro and in mice xeno- grafts [24 .. ].
There is an ongoing phase II trial of using cabozantinib in patients with locally advanced or metastatic unresectable ACC (Clinicaltrials.gov ID: NCT03370718).
3. EGFR inhibitors
Epidermal growth factor receptor (EGFR) is significantly over-expressed in ACC [71].
EGFR inhibitors gefitinib and erlotinib were studied in a phase II trial without evidence to support good clinical effica- cy in ACC [72, 73].
4. mTOR inhibitors
The mTOR pathways play a role in the regulation of cell proliferation, survival, angiogenesis, and resistance to antitu- mor treatments via the phosphoinositide 3-kinase/protein ki- nase B signaling pathway [20]; mTOR inhibitors inhibited cell proliferation and cortisol production in ACC cells [74].
The combination of an mTOR inhibitor (temsirolimus), and an immunomodulatory agent (lenalidomide), was studied in a phase I study of patients with advanced cancers, including 3 patients with ACC. Only one of three patients with ACC had stable disease for at least 6 months [75]. Temsirolimus, in combination with cixutumumab, was discussed above.
A phase I study of pazopanib and everolimus in patients with advanced solid tumors included one patient with ACC. This single patient had a stable disease for 13 months [76].
5. Wnt signaling inhibitors
The Wnt/ß-catenin signaling pathway is an important de- velopmental pathway in many organs, including the adrenal gland. Targeting this pathway showed promising results in multiple malignant tumors [77].
Genetic alteration involving deletions and point mutations in CTNNB1 and activation of Wnt/B-catenin occurs frequently in ACCs. Alterations in Wnt/ß-catenin signaling pathways have a negative effect on overall survival of patients with ACC [78].
In vitro studies to block the Wnt/b-catenin signaling in ACC cell line have shown increased apoptosis and impair- ment of adrenal steroidogenesis [79]. However, it is important to note that 27% of benign adrenocortical tumors have ß- catenin mutations [80]; therefore, the clinical use of Wnt in- hibitors to target this pathway will be challenging.
Immunotherapy and Immune Checkpoint Inhibitors
Immunotherapy has revolutionized cancer therapy. The anti- neoplastic activity of immune checkpoint inhibitors such anti- CTLA-4, anti-programmed death-1 (anti-PD-1), and anti-PD- ligand-1 (PD-L1) antibodies in different solid malignancies has sparked interest to explore their potential efficacy in ACC [20].
PD-L1 expression was assessed through immunohisto- chemistry in patients with surgically treated ACC with no evidence of correlation between PD-L1 expression and clini- cal parameters for survival [81.]. Moreover, IL-13Rx2 is overexpressed in ACC cell; IL-13-PE is a recombinant cyto- toxin consisting of human interleukin-13 (IL-13) and a trun- cated form of pseudomonas exotoxin A (PE) [82].
Multiple ongoing clinical trials are currently evaluating the role of immune checkpoint inhibitors in ACC:
IL-13-PE
In a phase I trial using intravenous infusion of IL-13-PE in ACC patients with IL-13Rx2 expression, stable disease was observed in 1/5 patients who were treated at maximum-
tolerated dose with progression times ranging from 1 to 5.5 months. The drug efficacy might have been limited by the development of neutralizing antibodies in 67% of the pa- tients [83].
Ipilimumab
Two phase II clinical trials are ongoing to test the safety and effectiveness of ipilimumab (anti-CTLA-4 antibody) in combi- nation with nivolumab (anti-PD1 antibody) in patients with rare genitourinary malignancies including ACC (ClinicalTrials.gov Identifier: NCT03333616) and (Clinicaltrials.gov ID: NCT02834013).
Pembrolizumab
Pembrolizumab is a humanized anti-PD1 antibody. Two pembrolizumab-based therapeutic trials are ongoing in ACC (ClinicalTrials.gov Identifiers: NCT02673333 and NCT02721732).
Avelumab
Avelumab is monoclonal antibody that targets PD-L1. In phase 1b expansion cohort, 50 patients with metastatic ACC who were previously treated with platinum-based therapy re- ceived avelumab every 2 weeks. Mitotane was continued in 50% of patients but mitotane levels were not recorded during the study. Avelumab showed clinical activity and a manage- able safety profile. Twenty-one patients (42.0%) had stable disease as best response with median progression-free survival of 2.6 months, and median overall survival of 10.6 months. The 1-year overall survival rate was 43.4% [84.].
Nivolumab
Nivolumab is a monoclonal antibody that targets PD-1 recep- tor on T cells. In a phase II study, nivolumab was used in 7 patients with metastatic ACC who failed other treatments. Nivolumab use was associated with a median time to progres- sion of 8 weeks, 5 of those patients has progressed and 2 were pending evaluation at the time of the study report [85].
Radiopharmaceuticals
131 liodometomidate
About 30% of ACCs have significant uptake of iodometomidate in metastatic ACC [86]. Labeling of iodometomidate with 131I offers targeted radionuclide therapy for advanced ACC. In 11 patients with advanced ACC who had high [123I] iodometomidate on diagnostic scans, using
[131I] iodometomidate resulted in partial response in 1 patient, stable disease in 5 patients, and progressive disease in 4 pa- tients while 1 patient died 11 days after treatment but the death was not related to treatment. [13]]] iodometomidate therapy was associated with progression-free survival of 14 months (range, 5-33) and the main toxicities included adrenal insuf- ficiency and transient bone marrow depression [87, 88].
Radiation Therapy
Radiotherapy is traditionally used as a palliative therapy espe- cially in symptomatic bone, brain, or inferior vena cava in- volvement [89]. Radiotherapy could be used as an alternative to systemic therapy or surgery in highly selected patients with oligo-metastases who are not good candidates for surgery or systemic therapy.
Radiofrequency Ablation
Percutaneous image-guided radiofrequency ablation (RFA) is appealing as minimally invasive, locally effective treatment choice, in patients who are not good candidates for reopera- tion [90].
Available data on loco-regional therapeutic options are generally sparse. However, evidence has shown that RFA can potentially result in effective, short-term local control of primary ACC when tumors are less than 5 cm in size, and close to sensitive tissues or large blood vessels. A small case series of 15 ACC recurrences demonstrated that RFA was well tolerated. Decrease in tumor size or loss of enhancement on imaging was seen in 53% of patients. When the tumor size was smaller than 5 cm, up to 67% had a complete ablation [91].
With advanced technology nowadays, RFA may have a role in treating recurrent ACC in selected patients.
Supportive Therapy
Anti-resorptive Therapy for Bone Metastasis
Bone metastasis is associated with poor quality of life in cancer patients due to bone pain and increased risk of ad- verse skeletal-related events such as hypercalcemia and pathological [29.].
No evidence are available to support the use of anti- resorptive therapy in metastatic ACC compared to other pri- mary malignancy such as breast, prostate, and lung where bone strengthening therapy demonstrated efficacy in the prevention of skeletal-related events in patients with bone metastasis. However, the current European Society of Endocrinology
endorse the administration of denosumab or bisphosphonate therapy in oncological doses along with calcium and vitamin D supplementation in patients with ACC and metastatic bone disease, or in anti-osteoporotic doses, if ACC is associated with glucocorticoid-excess which is known to increase the risk of osteoporotic fractures [29.].
Conclusion
ACC management remains challenging considering the het- erogeneous and often unpredictable nature of this disease. The advances in molecular analysis provided plethora of prognos- tic factors and broadened our understanding about the under- lying molecular changes in ACC. Unfortunately, the advanced molecular understanding of ACC has not yielded a major therapeutic breakthrough yet and EDP-M remains the main systemic therapy option for many patients. Ongoing interna- tional collaborations carry hope to identify better treatments compared to the currently used options.
Compliance with Ethical Standards
Conflict of Interest Sina Jasim declares that she has no conflict of inter- est. Mouhammed Amir Habra has received research funding from Exelixis and has received compensation from HRA Pharma and Eisai for service as a consultant.
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
Publisher’s Note Springer Nature remains neutral with regard to jurisdic- tional claims in published maps and institutional affiliations.
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