URRENT PINION
Update on adrenocortical carcinoma management and future directions
Jeena Varghese and Mouhammed Amir Habra
Purpose of review
To present an update on the management of and future directions in adrenocortical carcinoma (ACC).
Recent findings
ACC is a rare malignancy with high morbidity and mortality. Surgery remains the mainstay treatment for localized disease, but it is often not feasible in more advanced cases. There is an ongoing controversy about the routine use of adjuvant treatments after surgery. Hormonal overproduction can complicate the management and worsen the prognosis of the disease. Systemic therapy with multiple cytotoxic drugs is often combined with the adrenolytic agent mitotane. Genomic analyses of ACC revealed numerous signal transduction pathway aberrations (insulin-like growth factor 2 overexpression, TP53 mutations and Wnt/ B-catenin pathway activation), but so far, there has been no clinically meaningful breakthrough in targeting these genes. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in ACC is being explored in multiple ongoing trials.
Summary
Surgery by experienced team is the key treatment for localized ACC, whereas currently used chemotherapy has limited efficacy in advanced ACC. The improved understanding of the molecular pathways involved in ACC has not been translated into effective therapy. The development of new therapies requires collaborative effort to fight this disease.
Keywords
adrenocortical carcinoma, genomic alterations, immunotherapy, mitotane, targeted therapy
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare malignancy with an annual incidence of one case per million people [1,2]. ACC carries a poor prognosis as most ACC patients present with locally advanced or meta- static disease not amenable to surgical resection. Two-thirds of patients who present with localized disease experience recurrence that often requires systemic therapy [3-5]. Disease burden on presen- tation is one of the key prognostic factors in ACC with an expected 5-year survival of 80% in patients with stage I disease, whereas stage IV disease carries 5-year survival of 13% [6]. Ki67, a marker of cell prolifer- ation, is widely used as an important prognostic marker of ACC behavior; each 1% increase in Ki67 is associated with a 4% increased risk of recurrence and a 5% increased risk of death [7""].
In the past two decades, extensive efforts have been made to uncover the molecular pathways and genomic alterations involved in ACC pathogenesis. In addition to activation of the ß catenin pathway, other discoveries include the overexpression of insu- lin-like growth factor (IGF) 2, increased Telomerase
Reverse Transcriptase expression and mutations in TP53, CKD2A, PRKAR1A, RPL22, TERF2, CCNE1, NF1, RB1 and menin genes[8,9,10""]. Although these discoveries represent a major step toward under- standing the molecular changes in ACC, targeting these pathways and genes currently does little to alter the course of disease.
MANAGEMENT OF LOCALIZED DISEASE
Localized ACC encompasses stages I and II disease and most patients with stage III disease. Stage I is relatively uncommon, representing only 3% of all
Department of Endocrine Neoplasia and Hormonal Disorders, The Uni- versity of Texas MD Anderson Cancer Center, Houston, Texas, USA
Correspondence to Mouhammed Amir Habra, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Ander- son Cancer Center, Unit 1461, 1515 Holcombe Blvd., Houston, TX 77030, USA. Tel: +1 713 792 2841; fax: +1 713 794 4065; e-mail: mahabra@mdanderson.org
Curr Opin Endocrinol Diabetes Obes 2017, 24:000-000 DOI:10.1097/MED.0000000000000332
KEY POINTS
· Complete resection by an expert surgeon is the most important treatment for patients with localized ACC.
. There is no prospective evidence to support the routine use of adjuvant therapy after complete surgical resection of ACC.
. Currently used systemic chemotherapy has suboptimal efficacy and short lived duration of disease control.
. The role of targeted therapy and immunotherapy is still under investigation and multicenter clinical trials are urgently needed to improve the grim outcomes of this disease.
ACC cases, whereas stages II and III make up 37 and 34%, respectively [3]. Surgery is usually the main- stay therapy in these patients, but unfortunately many experience disease recurrence.
Hormonal management of adrenocortical carcinoma
ACC morbidity stems from the combination of disease burden and hormonal excesses, which are seen in almost half of ACC patients. Agents to treat Cushing syndrome such as ketoconazole, metyrapone and mifepristone are often used, with the hope of reducing the morbidity of cortisol excess, whereas spironolac- tone and eplerenone are mineralocorticosteroid receptor antagonists that can be used to counteract edema and hypertension associated with cortisol or aldosterone overproduction. The success of hormonal control is contingent on a synchronized approach to reduce hormonal production, counteract the effects of hormonal overproduction and reduce disease burden via surgery or systemic chemotherapy [11].
Surgery
Surgery is the mainstay treatment in localized ACC and carries the best hope for prolonged survival and potential cure. The goal of surgery is to achieve complete surgical resection that can be validated pathologically with negative resection margins (R0). Considering the large size of most ACCs, it is difficult to achieve this goal. Microscopically positive resection margins (R1) carry increased risk of recur- rence [3]. Over the past few years, there has been an increasing emphasis on performing regional lympha- denectomy at the time of initial resection. Retrospec- tively analyzed data showed reduced recurrence rates and reduced mortality in 47 ACC patients who under- went lymphadenectomy compared with recurrence
rates and mortality in 236 patients who had resection of the primary tumor without regional lymph node resection [12].
In the past decade, technical advances in min- imally invasive surgery have led to an increased use of laparoscopic procedures to remove adrenal masses. Multiple reports have found increased risk of peritoneal carcinomatosis in ACC patients who underwent laparoscopic resection compared with risk in patients who had open adrenalectomy. Although minimally invasive resection can reduce the length of hospital stay after surgery, it is viewed by many as being inferior from an oncological standpoint because it impairs the surgeon’s ability to perform a comprehensive regional lymph node dissection and reduces the chance of having R0 resection margins [13,14]. Surgical expertise is very important to improve clinical outcome in localized ACCs, as shown by the longer recurrence-free sur- vival (RFS) and reduced local recurrence rates in patients treated in high-volume centers (those per- forming 10 or more ACC surgeries annually) com- pared with rates seen in patients treated in low- volume centers, despite the typically larger tumors in patients in the high-volume centers [15].
Adjuvant therapy
Mitotane (o,p’-DDD (1-(o-chlorophenyl)-2, 2- dichloroethane) is a derivative of the insecticide Dichloro Diphenyl Trichloro Ethane that has shown adrenolytic effects in animals. Mitotane exerts hor- monal effects by reducing adrenal steroids pro- duction via blocking 11ß-hydroxylase enzyme in the adrenal cortex. In the periphery, it increases glucocorticoid clearance. For more than five deca- des, mitotane has been used to treat ACC, often in combination with systemic chemotherapy.
The use of mitotane in the adjuvant setting is based on retrospective data from tertiary referral centers in Europe. Mitotane use was associated with longer median RFS of 42 months compared with rates in control groups from Italy and Germany, with median RFS of 10 and 25 months, respectively. Similarly, mitotane use was associated with median overall survival of 110 months compared with 52 and 67 months in the Italian and German control groups, respectively [16]. However, retrospective data from other centers did not confirm the mito- tane benefit, causing an ongoing debate about its use [17,18]. An ongoing prospective randomized clinical trial (ADIUVO, NCT00777244) is exploring the efficacy of adjuvant mitotane in ACC patients deemed to have low/intermediate risk of recurrence after radical surgical resection. The Ki67 prolifer- ation index is used to select patients for this trial
as ACC patients with Ki67 of 10% or less are con- sidered to have lower risk of recurrence compared with patients with a higher Ki67% [7""].
Radiation therapy
In 3982 ACC patients registered in the National Cancer Data Base, radiation therapy in combination with surgery was used in only 238 (6%) [19]. As with mitotane, there are no prospective data with which to define the role of adjuvant radiation therapy in ACC. Although postoperative radiation therapy improved local recurrence rates in two retrospec- tively analyzed cohorts [20,21”], other reports could not confirm these findings [22]. Furthermore, there was no survival benefit associated with adjuvant radiation therapy in all three series. On the basis of these data, we cannot recommend the routine use of adjuvant radiation therapy after initial surgical resection. However, some patients who display a local recurrence pattern without evidence of distant disease might benefit from adjuvant radiation therapy after surgery.
Chemotherapy
The role of adjuvant chemotherapy in ACC has not been defined. On the basis of expert opinion, selected ACC patients received adjuvant chemother- apy, but so far, this practice has not been supported by any well-analyzed data. Platinum-based chemo- therapy is often used in order to sterilize micro- metastases. Efforts are ongoing to establish a randomized phase 3 clinical trial to ascertain whether the use of adjuvant chemotherapy in ACC is efficacious.
MANAGEMENT OF ADVANCED DISEASE
More than half of ACC patients present with locally advanced or metastatic disease [3]. These patients tend to have a poor prognosis and only a limited response to any single treatment modality. Thus, the use of a multidisciplinary approach and different treatment methods when feasible carries the best hope of improving the grim prognosis in these patients.
Neoadjuvant approach
The use of neoadjuvant systemic chemotherapy as a bridge to surgery was associated with favorable out- come in 15 highly selected patients with borderline resectable ACC (defined as having oligometastases, needing multiorgan or vascular resection, or having a poor performance status preventing surgery) who
were treated at a major referral center. Despite these patients having more advanced disease than those who had undergone surgery alone, the outcome of these 15 patients with borderline resectable ACC was comparable with that of patients who had had surgery alone. The patients who received neo- adjuvant systemic chemotherapy were younger and had more advanced stages of disease. Before under- going surgery, 38.5% of these patients had a partial response to neoadjuvant chemotherapy and 53.8% had stable disease, whereas only one (7.7%) had evidence of progression during neoadjuvant chemo- therapy [23].
Surgery
ACC patients who undergo complete surgical resec- tion often experience recurrence in the surgical site or in distant organs. Delayed recurrences that occur more than 6 months after initial surgery can be salvaged occasionally with another resection of the recurrent disease, and this approach has been associated with improved survival compared with patients who experience early recurrences, which are often an indication for systemic therapy [24]. Furthermore, multiple groups showed the benefit of metastasectomy in ACC [25-27]. Proper patient selection and surgical expertise are required to min- imize complications and improve outcome.
Radiation therapy
Palliative radiation therapy can be used to treat selected sites of symptomatic or high-risk metasta- ses. In a retrospective series of 12 ACC patients who received palliative radiation therapy, clinical or radiographic response was seen in 10 patients, and the adverse effects of radiation were limited to grade 3 toxicity or less without any severe com- plications [28].
Systemic therapy for metastatic disease
The lack of highly efficacious systemic therapy is the biggest challenge for many ACC patients. Multiple regimens were studied over the past few decades ranging from single-agent therapy (mitotane) to various combinations of cytotoxic chemotherapy with or without mitotane. In the only completed randomized phase 3 clinical trial in ACC (FIRM- ACT), the two most commonly used regimens [mito- tane combined with etoposide, cisplatin and dox- orubicin (M-EDP) vs. mitotane with streptozocin (M-Sz)] were compared with establish first-line therapy in advanced/metastatic ACC. This multi- center study established M-EDP as the first-line
treatment based on the higher response rate with this regimen (23%) compared with the 9% rate with M-Sz. Furthermore, the median progression-free sur- vival (PFS) was 5 months with M-EDP vs. 2 months with M-Sz [29]. Although these findings were help- ful to guiding clinical care, they also highlighted the need for more effective treatments in this orphan malignancy.
Among ACC patients for whom M-EDP is not effective, there is no well-established line of salvage therapy, and patients are often referred to clinical trials. Gemcitabine (800mg/m2 intravenously on days 1 and 8, every 21 days) has been used in combination with capecitabine (1500 mg orally once daily) or 5-fluorouracil (daily intravenous infu- sion of 200 mg/m2) in 28 patients with previously treated ACC. Complete response was reported in one patient, partial response in one patient, stable disease in 11 patients and progressive disease in 15 patients [30]. In a subsequent attempt to treat the patients whose disease progressed during this trial, eight patients received metronomic chemotherapy (chemotherapy given at low doses on a frequent or continuous schedule), and only two patients showed evidence of clinical benefit (one was treated with oral etoposide at 50 mg daily and one received oral cyclophosphamide at 50 mg daily) [31].
MOLECULARLY TARGETED THERAPY
Experimental and clinical studies have shown that cancer growth and its metastatic spread are closely related to angiogenesis. Vascular endothelial growth factor (VEGF) has an important role in tumor angio- genesis. VEGF signals mainly through VEGF recep- tor 2 (VEGFR-2). VEGF is commonly expressed in many cancers and is often associated with worse prognosis [32]. Activation of the VEGFR pathway has been well documented in ACC and provides the rationale for targeting these receptors [33].
Treatment with sorafenib, a tyrosine kinase inhibitor specific to VEGFR2, along with everolimus targeting the mammalian target of rapamycin (mTOR) protein showed antitumoral effect in mouse xenograft model. This combination was also associated with improved median survival in mouse models [34]. Case reports have described responses to therapy with multiple kinases inhibiting sorafe- nib and sunitinib in patients with metastatic ACC [35,36].
In a phase 2 study, single-agent sunitinib was given at a standard dose in 6-week cycles (50 mg/ day, 4 weeks on followed by 2 weeks off). This was an open-label study with 38 patients who had refrac- tory ACC progressing after treatment with mitotane and multiple cytotoxic chemotherapies. Of the 35
patients who could be evaluated for response, five had stable disease, with PFS ranging from 5.6 to 11.2 months and overall survival ranging from 14.0 to 35.5 months. Of these five patients with stable disease, only one was receiving mitotane therapy; of the 30 patients with progressive disease, 21 had been receiving mitotane treatment [37]. These results suggest that the interaction between sunitinib and mitotane might influence the drugs’ effects. Sunitinib is metabolized in the liver and intestine by CYP3A4. Mitotane is a strong inducer of CYP3A4, which markedly increases the inacti- vation of sunitinib, and therefore reduces serum concentrations of the active drug. Hence, sunitinib without mitotane appears to be an option in the management of refractory ACC [38,39].
In another study, sorafenib along with pacli- taxel was given to 25 patients with metastatic ACC. This phase 2 clinical trial was discontinued because of progressive disease in nine consecutive patients at the first restaging scan obtained 2 months after starting treatment [40].
Dovitinib is an oral multikinase inhibitor target- ing fibroblast growth factor (FGF) receptors, platelet- derived growth factor receptors and VEGF receptors. Its activity against FGF receptors suggests its useful- ness in treating cancers after the failure of VEGF/ VEGF receptor-targeting agents. Results from a phase 2 trial to evaluate the efficacy of this drug in 17 patients showed no objective response. How- ever, clinical benefit was achieved with stable dis- ease for more than 6 months in 23% of the patients [41].
Axitinib is a potent, selective inhibitor of VGEFRs 1, 2 and 3. A phase 2 trial enrolled 13 patients with metastatic ACC previously treated with at least one chemotherapy regimen with or without mitotane. Axitinib was initiated at 5 mg orally twice daily, with dose escalations as tolerated. No objective response was seen as defined by Response Evaluation Criteria in Solid Tumors response (RECIST) criteria, although the tumor growth rate during therapy was reduced in four of the 13 patients [42].
Bevacizumab, an anti-VEGF monoclonal anti- body, has shown encouraging results in advanced colorectal, breast, lung and renal cancers. Hence, protocols containing this drug were adapted for patients with advanced ACC. All patients had undergone several surgeries and had been heavily pretreated with systemic therapies, including mito- tane. Bevacizumab (5 mg/kg every 3 weeks) along with oral capecitabine (950 mg/m2 twice daily for 14 days), followed by 7 days of rest. None of the 10 patients included in this study experienced any objective response or stable disease [43]. mTOR is a
kinase of the phosphoinositide 3-kinase/protein kinase B [or Protien Kinase B (PKB)] signaling path- way and plays a role in the regulation of cell pro- liferation, cell survival, angiogenesis and resistance to antitumor treatments. mTOR pathway dysregu- lation is also common in many malignancies with plethora of preclinical data to support targeting mTOR pathway [44]. In childhood ACC, inhibition of mTOR signaling by everolimus greatly reduces tumor cell growth in vitro and in vivo [45]. A phase 1 study of pazopanib and everolimus in patients with advanced solid tumors (pazopanib at 400 mg and everolimus at 5 mg daily) included one patient with ACC. This patient had a meaningful clinical benefit with stable disease for 13 months [46].
Hepatocyte growth factor (HGF) stimulates angiogenesis by increasing the production of angio- genic cytokines [VEGF and interleukin-8 (IL-8)], and by direct Alternate name for Hepatocyte growth factor receptor (cMET) activation. HGF/cMET appears to enhance ACC growth, angiogenesis, treatment resistance and increase cancer cell sur- vival. Findings also suggest that ACC cells rapidly upregulate cMET expression in response to radiation therapy and chemotherapy. Furthermore, cabozan- tinib (multikinase and cMET inhibitor) has been shown to reduce ACC tumor growth in vitro and in a mouse xenograft model [47""]. Clinical trials to explore the use of cabozantinib in ACC are needed.
The IGF system is involved in cancer cell growth and apoptosis. This system includes proteins, IGF1, IGF2, receptors (IGF-1R, IGF-2R and insulin recep- tor) and various IGF binding proteins [48]. IGF2 is the single most upregulated transcript in 80-90% of ACCs [49]. IGF2 acts primarily through the acti- vation of IGF-1R. Molecular profiling of human adrenal tumors has demonstrated overexpression of two critical components (IGF2 and IGF-1R) of the IGF signaling cascade and concomitant acti- vation of the downstream effector [50].
Preclinical studies antagonizing this pathway with pharmacological agents resulted in inhibition of growth in vitro and in vivo. This inhibition was more potent than that observed with the use of mitotane alone in decreasing xenograft growth, and the combination of IGF inhibition with mito- tane resulted in greater antiproliferative effects than those observed with the use of single-agent treat- ment. These data establish the role of targeted dis- ruption of IGF-1R signaling to obtain a therapeutic advantage when used with mitotane therapy or possibly other chemotherapeutics in ACC patients [51].
The anti-IGF-1R monoclonal antibody figitumu- mab was given to 14 patients with refractory ACC. The drug was administered on day 1 of each 21-day
cycle at the maximal feasible dose (20 mg/kg). Adverse effects to therapy were low, but no con- firmed responses were seen by RECIST criteria. Of the 14 patients, eight had stable disease as their best response. No patients remained in the study past seven cycles, because of progressive disease or adverse events [52]. In a phase 2 clinical trial, the anti-IGF-1R monoclonal antibody cixutumumab was combined with mitotane. Limited therapeutic benefits were observed in eight of 20 enrolled patients [53]. A phase 1 trial with linsitinib, a dual inhibitor of the IGF-1R and insulin receptor, showed partial response in two of 15 patients with ACC [54]. However, in a double-blind, placebo-controlled phase 3 study, linsitinib was terminated early as therapy did not increase overall survival [55].
In another study, 26 heavily pretreated ACC patients received cixutumumab (IGF-1R inhibitor) with temsirolimus (mTOR inhibitor) weekly with restaging at 8 weeks. Of these 26 patients, 11 (42%) had stable disease for greater than 6 months [56].
Epidermal growth factor receptor (EGFR) has a pivotal role in tumorigenesis in many human solid tumors and has become a promising therapeutic target [57]. EGFR is expressed in more than 75% of ACCs [58]. Erlotinib, a currently available EGFR blocker, induced apoptosis in ACC cell lines that express higher EGFR levels than their normal counterpart [59].
Ten patients with advanced ACC were given salvage chemotherapy consisting of erlotinib and gemcitabine. Only one patient experienced a minor response (PFS of 8 months), whereas the other patients had progressive disease at the first staging suggesting limited utility for this combination [60].
Germline TP53 mutations in adults with spora- dic ACC are relatively uncommon, whereas somatic mutations are more common occurring in 21% of cases. Polo-like kinase 1 (PLK-1) is a negative modu- lator of p53 activity. In general, increased PLK-1 expression has been correlated with poor prognosis and aggressiveness of cancers. Preclinical studies with PKL-1 inhibitors have shown decreased levels of mutant p53, whereas wild-type p53 was not affected [61]. Several PLK-1 inhibitors are being developed and are being tested in phase 1 and 2 trials for several heavily pretreated malignancies [62].
B-Catenin alteration with activation of the Wnt signaling pathway is a prevalent defect in adreno- cortical tumorigenesis, specifically, in both adreno- cortical adenomas and ACCs [63]. In-vitro studies blocking Wnt/B-catenin signaling in adrenocortical tumor cells have shown increased apoptosis, decreased cell viability and impairment of adrenal steroidogenesis [64].
IMMUNOTHERAPY
The antineoplastic activity resulting from immuno- therapy with antibodies that target cytotoxic T lymphocyte-associated antigen 4 and the pro- grammed cell death protein 1 pathway (PD-1/PD- L1) for the treatment of solid tumors such as mel- anoma and nonsmall cell lung cancer has prompted interest in exploring its potential clinical efficacy in ACC. PD-L1 expression was evaluated in 28 patients with surgically treated ACC. Positive PD-L1 staining was seen on tumor cell membrane (three of 28) and on tumor-infiltrating mononuclear cells (19 of 27). There was no relationship between PD-L1 expres- sion and clinicopathologic parameters or survival [65]. Clinical trials to evaluate the role of immune checkpoint inhibitors in ACC are currently active.
IL-13 promotes invasion through IL-13R&2 sig- naling. IL-13R&2 is overexpressed in ACC, compared with its expression in benign tumors, and hence serves as a potential therapeutic target. IL-13-Pseu- domonas exotoxin (PE) is a chimeric fusion protein of human IL-13 and a truncated form of Pseudomo- nas exotoxin A (IL-13-PE). IL-13-PE immunotoxin is specific to IL-13Rx2 and inhibited tumor growth in vitro and in a human xenograft ACC animal model [66]. A phase 1 trial, designed to test the safety and effects of systemic IL-13-PE in patients with meta- static ACC, showed stable disease in three of six patients that lasted 2-5.5 months. However, the effectiveness of the treatment might have been lim- ited because of the generation of a neutralizing antibody. Neutralizing antibodies were detected in 67% of patients. It was also noted that baseline anti- PE antibodies were detected in 25% of patients at a low titer before initiation of treatment [67].
OTHER TREATMENTS
ATR-101 is a selective and potent inhibitor of acyl- coenzyme A: cholesterol O-acyltransferase 1 (ACAT1), an enzyme located in the endoplasmic reticulum membrane that catalyzes esterification of intracellular free cholesterol. Inhibition of ACAT1 was initially tested for the treatment of hypercholesterolemia and atherosclerosis. This approach was abandoned because of in-vivo toxicity in multiple animal species. The toxic effects of the ACAT1 inhibitor were mostly related to the adrenal cortex and hence raised the possibility of targeted ACAT1 inhibition for the treat- ment of ACC [68,69]. ATR-101 is currently in phase 1 clinical trial for the treatment of ACC.
CONCLUSION
Advance ACC is a disease that carries poor prognosis and currently does not have effective treatment options. The discovery of various molecular
pathways involved in the pathogenesis of ACC has identified rational targets for therapies; how- ever, there is still no breakthrough in management. Several multinational collaborations are currently working on prospective data collection to better understand this malignancy, which will likely lead to the development of targeted therapies to improve the clinical outcomes in ACC patients.
Acknowledgements
We thank, Tamara K. Locke, scientific editor from the Department of Scientific Publications, for her editorial assistance.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest
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