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Cancer Treatment and Research Communications

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cancer TREATMENT AND RESEARCH COMMUNICATIONS

Adrenocortical carcinoma: Diagnosis, prognostic classification and treatment of localized and advanced disease

Rossella Libé ª, Olivier Huillard b,

a Service Endocrinologie, AP-HP, Hôpital Cochin, French National Network, ENDOCAN-COMETE, F-75014, Paris, France

b Institut du Cancer Paris CARPEM, AP-HP, Department of medical oncology, Hôpital Cochin, F-75014, Paris, France

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ABSTRACT

Keywords: Adrenocortical carcinoma Diagnostic Mitotane

Adrenocortical carcinoma (ACC) is a rare cancer with an estimated incidence of 0.7 to 2.0 cases per 1 million population per year in the United States. It is an aggressive cancer originating in the cortex of the adrenal gland with a poor prognosis. The 5-year survival rate is less than 15% among patients with metastatic disease. In this article, we review the epidemiology and pathogenesis of ACC, the diagnostic procedures, the prognostic clas- sification of ACC, and the treatment options from localized and resectable forms to advanced disease detailing recent therapeutic developments such as immunotherapy and molecularly targeted therapy.

Introduction

Epidemiology and pathogenesis

Adrenocortical carcinoma (ACC) is a rare tumor of the adrenal cor- tex. Data from the United States and the Netherlands show that the incidence of ACC is 1-2 case per 1 million person- years in the general population and 0.21 cases per 1 million person- years in children and young adults. By contrast, in the United States, the age- standardized general cancer incidence is 4,500 cases per 1 million person- years in adults and 150 cases per 1 million person- years in children. The inci- dence of ACC follows a bimodal age distribution, with a peak in child- hood and a plateau occurring between 40 and 50 years of age. The incidence is more frequent in women (sex ratio 1.5). ACC constitute about 8-11% of adrenal tumors in clinical and surgical series [1]. Conversely, about 80% of adrenal tumors are adrenocortical adenomas, 7-10% are pheochromocytomas derived from the adrenal medulla and 5-7% are adrenal metastases from other type of cancer (Fig. 1). The circumstances of discovery are: (1) hormonal hypersecretion (40-74% of cases), (2) tumor syndrome (40-60% of cases), (3) an “adrenal inci- dentaloma” (10- 20% of cases), (4) more rarely a paraneoplastic syn- drome (fever, poor general condition, hypoglycemia) [2-4].

ACC is almost always sporadic, except when congenital (Beckwith- Wiedemann) and/or hereditary (Li-Fraumeni syndrome, MEN1, Gardner syndrome, Lynch syndrome). In recent years, several multicenter studies on the pathogenesis of ACC have been performed and ‘multi-omic’

studies reveal that only a minority of ACC cases have pathogenic driver mutations. Two large consortia have characterized the landscape of molecular alterations in ACC. They included deregulated cell-cycle and apoptosis pathways (p53 and RB), impaired chromatin and DNA main- tenance (mismatch and double stranded DNA repair as well as TERT overexpression or alternative lengthening of telomeres), altered adre- nocortical differentiation, signaling pathway activation (most commonly WNT-ß-catenin signaling but also cAMP and the mitogen- activated protein kinase pathways) [5].

Diagnostic procedures in ACC

Due to the potentially poor prognosis of ACC, it is critical to rapidly perform the diagnosis based on clinical, biological, hormonal, and radiological assessment.

1) Clinical, biological, and hormonal assessment

A clinical examination and a biological work-up are recommended. The aim is to search for: (1) the signs of steroid hypersecretion: Cush- ing’s syndrome, hyperandrogenism in women, hyperestrogenism in men, arterial hypertension with hypokalemia, (2) a tumor syndrome (abdominal mass, pain or signs of compression related to the primary or distant metastases), (3) a genetic context, (4) the absence of arguments for another cancer, possibly metastatic, or a pheochromocytoma. The diagnosis of pheochromocytoma will be ruled out by measuring plasma

* Corresponding author.

E-mail address: olivier.huillard@aphp.fr (O. Huillard).

https://doi.org/10.1016/j.ctarc.2023.100759

Fig. 1. Overview of the different type of adrenal tumors.

Adrenal gland

Adrenal medulla

Adrenal cortex

Adrenocortical adenomas 55-80% *

Adrenocortical carcinomas 8-11% *

Metastases 5-7% *

Phechromocytoma 7-10% *

and/or urinary metanephrines and normetanephrines [2]. The profile of urinary steroids measured by mass spectrometry could be of interest to confirm the secretion of steroids metabolites [6]. A standardized bio- logical and hormonal assessment for diagnosis is shown in Table 1.

2) Initial imaging work-up

The initial imaging work-up allows to assess the initial clinical staging (cTNM), the possibility of complete resection of the primary tumor, and its locoregional involvement (organs and lymph nodes), venous vascular extension and the presence of metastases.

a Thoraco-abdomino-pelvic (TAP) computed tomography (CT)

ACC are most often > 4 cm, heterogeneous (including areas of ne- crosis) and/or presenting a spontaneous density > 10 HU on TAP CT (sensitivity 97%, specificity 52%) [7]. The study of the kinetics of the contrast product uptake and the absolute and relative wash-out (WO) of the adrenal lesion provides diagnostic information. An absolute WO after injection of the contrast product < 60% (88% sensitivity and 89% specificity) and a relative WO < 40% (100% sensitivity and 100% specificity) suggest a suspicious lesion (not typical of benignity) [7]. Advanced “radiomic” analysis are being evaluated in search of predic- tive factors of malignancy in imaging [8]. TAP CT is also used to assess the presence of locoregional invasion or distant metastases.

Table 1

Hormonal/biochemical investigations.
Type of hormonal secretion	Hormonal/biochemical evaluation
Hypersecretion of glucocorticoids	· Basal cortisol (plasma) at 0h (in hospitalization) or salivary cortisol at 0h · Basal (plasma) ACTH · Cortisol after dexamethasone 1 mg at 11 p.m. (must be considered as pathological a plasma cortisol level, taken the next morning at 8 a.m., greater than 50 nmol/L) · 24-hour urinary cortisol (with creatinine) · Hypersecretion of androgens or precursors · DHEA- S (serum)
	· 17-OH-progesterone, compound S (serum) · Androstenedione (serum) · Testosterone (serum)
	· 17ß-estradiol (serum), only in men and postmenopausal women
	· DOC
	· Urinary metabolites on 24-hour urine
Hypersecretion of	· Kalaemia
mineralocorticoids	· Aldosterone and plasma renin (if arterial hypertension and/or hypokalaemia)
Catecholamine	· Plasma or urinary metanephrines and
hypersecretion	normetanephrines

b 18F-FDG PET

18F-FDG PET should be systematic before surgery for an adrenal tumor if ACC is suspected since it may provide elements in favor of malignancy and helps determine disease extension. In the event of a localized adrenal mass, various criteria have been studied, such as SUVmax and the SUVmax tumour/SUVliver ratio: several cut-offs have been proposed with different thresholds of sensitivity and specificity but are not routinely validated. Generally, ACC have a max tumour/SUV liver uptake ratio > 1.5 [2] (Fig. 2).

c Abdominal MRI

Abdominal MRI can be used as to assess locoregional extension. ACC usually show an isointense to hypointense signal on T1-weighted im- ages, a hyperintense signal on T2-weighted images and a heterogeneous signal drop on chemical shift. It can replace injected CT, especially in patients with renal insufficiency, children and pregnant women [2].

3) Role of the adrenal biopsy

Adrenal biopsy is generally not recommended if the primary tumor is secreting and resectable, to avoid the risk of tumor dissemination. It cannot distinguish ACC from an atypical adrenocortical adenoma. It should be discussed in case of: (1) non-secreting adrenal cancer, (2) suspicious non-adrenocortical tumor (for example to exclude an adrenal metastasis of unknown primary or lymphoma or sarcoma), (3) protocols including molecular analyzes. It must be performed by an experienced radiologist, in an expert center, guided by CT or ultrasound, according to the methodology applied to retroperitoneal sarcomas (trans-retroperi- toneal approach with a coaxial technique to avoid the risk of

0

CT

0

18F-FDG TEP

Size (cm)	15	5
Spontaneous density (SD)	25	20
Absolute Wash out (WO)%	30	42
Adrenal/liver SUV ratio	7,5	3,5

Fig. 2. Aspects of a large and a small ACC at computed tomography scans and 18F- FDG PET.

Localized and resectable ACC

Fig. 3. Flow-chart of the clinical management of localized and resectable ACC.

Surgery by laparotomy

Complete Resection (R)

Incomplete resection (R1,Rx)

Low risk ENSAT 1-2, Ki67≤10%

Intermediate risk ENSAT 1-2, Ki67 10-20%

High risk ENSAT 3, Ki67 > 20%

Observational

Adjuvant treatment (Mitotane)

Adjuvant treatment (Mitotane) +/- Radiotherapy if stage 3 Chemotherapy if Ki>20%

Mitotane +/- Radiotherapy

Follow-up every 3 months Hormonal and radiological assessment

dissemination) [9].

4) Pathological work-up

Histopathology is the gold standard of diagnosing ACC and should, in principle, be obtained in all patients. For patients deemed operable, this will be done on the basis of the resection specimen and for those patients who are inoperable, a biopsy will be performed [2]. As the ACC diag- nosis can be challenging and misdiagnoses are relatively frequent, it’s recommended that all adrenal tumors, which cannot be readily classi- fied, and all suspected ACC, should be reviewed by an expert adrenal pathologist [10]. The pathological analysis can confirm the adrenocor- tical origin as immunohistochemistry with the steroidogenic factor 1 (SF1), which is the most sensitive and specific marker currently avail- able (sensitivity of 98% and specificity of 100%). The Weiss score is currently the most widely used. It is based on 9 criteria rated 0 or 1 each depending on their absence or presence: (1) diffuse architecture >1/3 of the tumor surface, (2) tumor necrosis, (3) ≤ 25% of clear cells of spongiocyte aspect, (4) Führman nuclear grade III or IV, (5) mitotic count > 5 mitoses / 50 fields x400, (6) presence of atypical mitosis, (7) capsular invasion, (8) venous invasion, and (9) sinusoidal invasion. Tumors with a score ≥ 3 are considered to have metastatic potential and are diagnosed as ACC [11]. The Lin Weiss Bisceglia score is applied to adrenocortical tumors with oncocytic cells for which the Weiss score is unsuitable and overestimates the potential for malignancy. This score is based on histological criteria divided into 3 major criteria and 4 minor criteria. The presence of at least one major criterion is in favor of the malignancy of the tumor. In the absence of a major criterion, the pres- ence of at least one minor criterion is in favor of a tumor of uncertain malignant potential (borderline) [12,13]. The Helsinki score [14] is an alternative diagnostic and prognostic score applicable conventional adrenocortical and oncocytic tumors [14,15]. It combines two weighted histological parameters with Ki67. A score > 8.5 seems to predict met- astatic potential and >17 presents a poor prognosis.

ACC prognostic classification

There are two prognostic classifications: clinical and molecular. The clinical classification is based on TNM-ENSAT stage. Moreover,

four prognostic criteria independently predict the risk of relapse and overall survival whatever the stage: Grade (Weiss > 6 and/or Ki67 > 20%) (G), primary resection status (R), the patient’s age (A), the pres- ence of a secretory syndrome, characterized by cortisol excess (S). These parameters are grouped under the acronym GRAS [16]. The TNM stage is assessed preoperatively (cTNM) or postoperatively (pTNM) and then grouped into UICC 8th Edition stages (equivalent to the ENSAT stage) [17]. It’s defined as follow: 1) stage 1 [tumor located in the adrenal gland ≤ 5 cm (T1)], 2) stage 2 [(tumor located in the adrenal gland > 5 cm (T2)], 3) stage 3 [(tumor infiltrating adipose tissue (T3), adjacent organs (T4), renal vein and/or vena cava (T4) regardless of lymph node status (N0-N1); Tumor (T1-T2) with invasion of loco-regional lymph nodes (N1)], 4) stage 4 [tumor, whatever the size (T1-T4), whatever the lymph node status (NO-N1) in the event of distant metastases (M1)]. It’s a major prognostic factor for relapse and survival of ACC. The risk of relapse at 5 years is estimated at 18-47%, 36-62%, 50-81%, respectively for stages 1, 2 or 3. The 5-year survival varies according to the stages from 63-88% for stages 1 to 38-73% for stage 2, 19-54% for stage 3 and 0-21% for stage 4 [18,19]. Recent data show that nodal involvement has an unfavorable prognosis identical to stage 4 [16]. The primary resec- tion status (R) is defined as follows: - RO: “microscopically complete” -R1: “microscopically incomplete”- R2: “macroscopically incomplete”- Rx: unknown. The R status of the primary tumor is associated with the risk of relapse and survival. Overall survival at 5 years is 73% vs 64% vs 26% vs 13% in case of R0 vs Rx vs R1 vs R2 status, respectively [19]. The notion of intraoperative capsular rupture has not given rise to impact studies, even if intuitively it is attributed an identical pejorative effect. This status is also a prognosis for overall survival at the metastatic stage [16]. The Grade is characterized by the cell proliferation index (Ki67%) and number of mitoses. Ki67 immunohistochemistry has been proposed for prognostic purposes. Higher Ki67 levels are consistently associated with poor prognosis. Threshold levels of 10 and 20% have been considered for discriminating low from high Ki67 labeling index. In localized ACC (stages 1 and 2 and 3), a Ki-67 index >10%, whatever the stage or R status, presents an intermediate risk of recurrence (30-70% for a Ki-67 11- 20%) and high (50-80% for Ki-67 >20%) [20]. In locally advanced and metastatic ACC (stage 3-4) a Ki-67 index ≥20% is asso- ciated with a reduction in overall survival [16]. A number of mitoses > 20/50 high magnification fields (GC) is pejorative in some studies on

metastatic ACC [21]. Age is a prognostic factor associated with a risk of recurrence in localized ACC and lower overall survival in metastatic ACC, but different cut-offs have been used [16,19]. Finally, the excess cortisol is an independent pejorative prognostic factor in localized and advanced ACC. In a European multicenter study including 524 patients with localized ACC (stage 1-2-3), excess cortisol was confirmed as a poor prognostic factor on the risk of recurrence after complete surgery and on overall survival [22]. These results have been confirmed in both local- ized and metastatic ACC [16,19].

TNM and Grade (G), Resection (R), Age (A), Secretion (S) factors (i.e. GRAS) are currently the best validated prognostic parameters and represent the best prognostic clinical model in localized and metastatic ACC. In a recent study of 943 localized ACC, the authors proposed the same GRAS model to stratify the risk of relapse after surgery [19]. In a European multicenter study concerning 444 stage 3 and 4 ACC, the GRAS model led to better stratify the patients in this group, even after adjustment for tumor volume [16].

The second is the molecular prognostic classification. In fact, genomic approaches - including pan-genomic studies, gene expression (transcriptome), recurrent mutations (exome or whole genome sequencing), chromosomal alterations, DNA methylation (methylome), expression of miRNAs (miRnome) - converge towards a new classifica- tion of ACC characterized by distinct molecular profiles. Recently, a study reported that molecular markers (including expression markers- BUB-1-PINK-1, methylation-PAX5, GSTP1, PYCARD, and PAX6) can be used as independent prognostic markers in localized ACC [23]. Inter- estingly, these studies led to define three molecular subtypes of ACC the first with poor outcome characterized by the presence of alterations in driver genes, as ZNRF3, MEN1 and MMR- related genes, the second one with intermediate prognosis characterized by the presence of alterations in genes as CDKN2A, NF1, PRKAR1A, TP53 and the third one with better prognosis, characterized by alterations in CDK4, CTNNB1, MLL4, RB1 [5].

Treatment of localized, resectable forms (Fig. 3)

These are the forms of ACC for which complete surgery seems possible, i.e. stages 1, 2 and some stages 3, with an objective of R0 resection in more than 95% of cases.

1) Complete surgery

Complete resection is of utmost importance for all ACC and suc- cessful surgery is a prerequisite for cure. It must be performed according to the principles of oncological surgery with, as a principle, complete ‘en bloc’ excision of the entire gland and the periadrenal fat without tumor rupture. Sometimes, complete surgery may require the sacrifice of neighboring organs. The standard approach is laparotomy [2,24]. In addition to laparotomy, minimally invasive approaches (laparoscopy, laparo-robot assisted, retroperitoneoscopy) have been described and have become the reference for benign adrenal tumors. However, given the aggressiveness of ACC and the extremely pejorative nature of the prognosis of an R1 resection or a tumor rupture [25,26], the possible cosmetic and recovery benefits of the laparoscopic approaches cannot outweigh the risk to affect the oncological prognosis. At present, not only laparoscopy has not demonstrated its non-inferiority versus lapa- rotomy but several series report a negative prognostic impact [27-29]. An exception to this rule could be a small tumor (< 4 cm) [29], not clearly malignant on preoperative exams, if these conditions are respected: (i) the center is very experienced in oncological surgery (ii) the type of surgery leads to the same excision as done by laparotomy (enlarged surgery with fat dissection), (iii) the part is extracted in a bag and without fragmenting in order to analyze the margins. Even in the absence of suspicious lymph nodes, lymphadenectomy should be sys- tematically performed, at least for staging purposes. This dissection should at least involve the periadrenal and perirenal lymph nodes, as

well as those of the hilum of the kidney [30,31]. All suspicious lymph nodes must be resected. Lymph node status is a major prognostic factor [16]. In the series by Panjwani et al., 16% of N+ patients are alive at 5 years compared to 63% of N- patients [31]. Two independent studies showed that lymphadenectomy reduced the risk of local recurrence (Hazard ratio = 0.65 [0.43-0.98]) [30] and it was associated with better OS (Hazard ratio: 0.17 [0.05-0.61] [32].

2) Adjuvant therapy

Even following initial resection, disease specific 5-year survival for patients with ACC is variable, ranging from 60-80% for stage 1-2 to 40-60% for stage 3. Therefore, a discussion of adjuvant therapies is necessary. Adjuvant therapy options include mitotane and/or radiation therapy.

a Mitotane

Mitotane, 1,1-(o,p’-Dichlorodiphenyl)-2,2-dichloroethane (o,p’- DDD), commercially available as Lysodren® (HRA Pharma Rare Dis- eases, Paris, France), is a parent compound of the insecticide dichlor- odiphenyltrichloroethane. It acts primarily on the adrenal cortex by two mechanisms: 1) steroidogenesis enzyme inhibition in mitochondria 2) endoplasmatic reticulm stress, leading to impairment of steroidogenesis and cell destruction (Fig. 4). Recently, the multicenter, international, randomized ADIUVO study evaluated the efficacy of mitotane treatment compared to simple monitoring in ACC at low-intermediate risk of relapse (defined by a Ki67 index < 10% R0). The primary endpoint was disease-free survival. It showed that there was no benefit in terms of progression-free survival (PFS) or OS of treatment with mitotane. Adjuvant treatment with mitotane is therefore not routinely recom- mended in this group of ACC patients [33]. Once mitotane treatment has been decided, it should be started as soon as possible after surgery [4]. Monitoring of plasma mitotane levels is recommended at least monthly initially. Mitotane is a drug with a very long half-life and a narrow therapeutic window. At present, it is advisable to obtain a mitotanemia between 14-20 mg/L. Indeed, several retrospective analyzes have shown that mitotane blood concentrations ≥14 mg/L are associated with a disease response in both advanced and adjuvant ACC treatment [4]. The upper limits are more uncertain; in fact, central neurological toxicity has been more frequently associated with elevated mitotane levels (>20 mg/L), but mild symptoms can be observed even with lower plasma levels. Pragmatically, clinicians titrate mitotane to the highest dose or level a patient can tolerate without substantial adverse events [4]. Mitotane is a powerful enzymatic inducer, in particular of cytochrome CYP3A4, responsible for the metabolism of many drugs (Table 2) [34]. Mitotane side effects include non-endocrine adverse effects and endo- crinopathies [4]. Common non-endocrine adverse effects of mitotane treatment include nausea, vomiting, diarrhea, and fatigue; however, these side effects can overlap with signs and symptoms of adrenal insufficiency and hypothyroidism (discussed below). At higher levels or doses of mitotane, the risk of neurologic side effects increases, including ataxia, memory loss, and depression. Hepatotoxicity can occur at any level or dose of mitotane and can range from a mild increase in liver enzymes to severe hepatic synthetic dysfunction. Mitotane can cause substantial hypercholesterolemia, bone marrow suppression, and drug-induced rash. In addition, mitotane is known to cause several complicated endocrinopathies. The most important is the mitotane-induced adrenal insufficiency. As mitotane have an adreno- lytic or adrenostatic effect on the residual contralateral adrenal gland where endogenous adrenal steroidogenesis is insufficient or deficient. For this reason, mitotane treated patients require high doses glucocor- ticoids treatment (sometimes up to 80-100 mg/d), and sometimes, mineralocorticoids as well. There is no evidence for the ideal duration of treatment with mitotane. Most authors suggest that treatment should be continued for at least 2 years, as the frequency of recurrences is very

Fig. 4. Mitotane action in adrenal cells.

Mitotane

Endoplasmatic Reticulum (ER)

Mitochondria

ER stress

Steroidogenesis enzymes inhibition CYP11A1

CYP11B1 CYP17A1

Apoptosis

CYP17B1

Tumor growth inhibition

Steroids production inhibition

Adrenal cell

high during this period. Beyond this period, the maintenance of mito- tane is assessed according to the risk of relapse, individual tolerance, and the plasma mitotane levels obtained.

b Adjuvant radiotherapy

The interest of adjuvant radiotherapy after surgery, in combination or not with mitotane, in particular for R1 or R2, remains subject to debate [35,36]. It is discussed in patients with ACC with a high risk of recurrence (stage 3 and/or R1-RX resection or in the event of capsular rupture) or large ACC operated by a non-expert operator or by an inappropriate approach [36]. Among the most recent studies (with modern irradiation techniques), a significant improvement in local PFS has been described in patients at high risk of local recurrence, in particular when R1. These observations are independent of the concomitant treatment with mitotane, which was administered in 40 to 70% of these patients, with a median follow-up of 3 to 5 years [36-40]. A single study from 2019 showed an improvement in OS, with a median follow-up of 4 years (2.8-4.9) [37]. However, other older retrospective studies show no efficacy on local PFS or OS [36,41].

Treatment of advanced disease

For advanced diseases with low tumor burden and slow growing disease, local treatment can be discussed. Nevertheless, for most patients with locally advanced non-resectable or metastatic disease, systemic treatment is required.

1 Mitotane

Mitotane has been the standard of care first line treatment in the metastatic setting for many years based on low level data [42]. More recently in 2018, a multicenter cohort study of three referral centers specifically evaluated the efficacy of mitotane in 127 patients with advanced ACC showing an overall response rate (ORR) of 20.5% (including 3 patients with complete response), a median PFS of 4.1 months, and a median OS of 18.5 months [43]. In multivariate analysis two favorable prognostic factors were identified: a low tumor burden (< 10 lesions) and recurrence more than 1 year after initial definitive local

treatment. For patients with both those favorable prognostic factors, ORR was over 30%, median PFS was 8.8 months and median OS was 29.6 months. As previously described for the adjuvant treatment with mitotane, patients who achieved mitotane levels >14 mg/L had signif- icantly longer OS than other patients.

2 First line chemotherapy

In 2012, the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM- ACT) study set the standard of care first line treatment in the metastatic setting [44]. In this randomized, controlled, open label trial, 304 pa- tients with advanced ACC received mitotane plus either etoposide, doxorubicin, and cisplatin (EDP) or streptozocin. An objective tumor response occurred in 35 of 151 patients in the EDP- mitotane group, as compared with 14 of 153 patients in the other group (23.2% vs. 9.2%, p < 0.001). The median PFS was 5.0 months in the EDP-mitotane group, as compared with 2.1 months in the other group (hazard ratio, 0.55; 95% CI, 0.43 to 0.69; p < 0.001). Among patients receiving first-line therapy, there were 108 deaths in the EDP-mitotane group and 124 in the streptozocin-mitotane group with a median duration of survival of 14.8 months (95% CI, 11.3 to 17.1) and 12.0 months (95% CI, 10.3 to 13.6) respectively, corresponding to a reduction in the risk of death of 21%, as compared with streptozocin plus mitotane (hazard ratio, 0.79; 95% CI, 0.61 to 1.02; p = 0.07). EDP plus mitotane therefore became the standard first line therapy but it should be highlighted that doxorubicin and etoposide being both topoisomerase inhibitors, the clinical rele- vance of combining these drugs is uncertain concerning efficacy while toxic effects are cumulative. Therefore, the combination of cisplatin (or carboplatin in case of renal clearance less than 60 ml/m2) and etoposide is routinely used rather than EDP combination. Furthermore, as previ- ously described, mitotane is a potent CYP3A4 inducer which can result in decrease in etoposide serum concentration. A pilot study evaluated this drug-drug interaction in metastatic ACC patients [45]: etoposide clearance was two-fold higher with concomitant mitotane than after mitotane discontinuation, and 2.5-fold higher than that in a reference population not treated with mitotane. In this study, etoposide dose escalation was performed in four patients under mitotane, resulting in two minor tumor responses and one severe toxicity. Tumor response was

Table 2 Potential drug interactions with mitotane in patients treated for ACC (from Kroiss et al. Clin Endocrinol 2011).

Indication	Substrates of CYP3A4	Alternatives with lesser likelihood of drug interaction with mitotane
Insomnia	Benzodiazepines Alprazolam	Titration of the drug to a clinically desirable effect
	Diazepam	TDM during long-term use or
	Midazolam	If Ineffective
	And others
Insomnia	Z-Drugs	Titration of the drug to a
	Zopiclone	clinically desirable effect
	Zolpidem
Contraception Steroid hormones	Oral contraceptives	Mechanical contraception Titration to a clinically
	Glucocorticoids
	Hydrocortisone	desirable effect in the setting
	Prednisone	of hormone replacement
	Dexamethasone	Dose adjustment following
	Testosterone	hormone measurement
	Oestradiol
Antiemetics	5HT3-receptor	Metociopramide
	antagonists	Diphenhydramine
	Ondansetron
	Granisetron
Analgesia	Certain opioids	Morphine
	Fentanyl	Oxymorphine
	Methadone	Hydromorphone
	Oxycodone
	Tramadol
Hypertension	Dihydropyridines	ACE inhibitors
	Amlodipine	a-adrenoreceptor antagonists
	Nifedipine	B-adrenoreceptor antagonists
	Nitrendipine	Angiotensin 2 antagonists
	And others	Loop diuretics Thiazide diuretics
Hypertension class I antiarrhythmics Antipsychotic	Verapamil	ACE inhibitors
	Diltazem	B-adrenoreceptor antagonists
	Haloperidol	Elevate the dose based on therapeutic drug monitoring
Hypercholesterolaemia	Certain HMG-CoA-	Pravastatin Rosuvastatin
	reductase Inhibitors
	Atorvastatin
	Cerivastatin
	Lovastatin
	Simvastatin
Antibiotic (atypical pathogens)	Macrolide antibiotics	Azithromycin Moxifoxacin
	Erythromycin
	Clarithromycin	Ciprofoxacin

associated with higher etoposide AUC.

3 Optional second line chemotherapy

Multiple drug regimens have been studied in this setting with little efficacy as streptozocin, gemcitabine, capecitabine, thalidomide, temo- zolomide or trofosfamide [42]. In the FIRM-ACT study [44], of those who crossed over from the EDP + mitotane group to the streptozocin + mitotane group, the median ORR was 7.6%, with a median PFS of 2.2 months showing little efficacy of streptozocin. The combination of gemcitabine and capecitabine was studied in a phase II study with 28 patients with heavily pre-treated advanced ACC who had progressive disease following mitotane together with at least one cytotoxic chemo- therapy [46]. There was 1 complete response (CR), 1 partial response (PR) and 11 patients with stable disease (SD) (39%), with 15 patients (54%) having progressive disease (PD). Median PFS was 5.3 months and OS was 9.8 months. In another study, 145 patients with advanced ACC were treated with gemcitabine based chemotherapy, of which 132 received concomitant capecitabine [47]. The median PFS was 12 weeks (range, 1 to 94). An ORR of 4.9% was noted and 25% of patients had SD. All together this reflects limited efficacy of this treatment strategy.

4 Insulin-like growth factor-1 receptor inhibitors

Since preclinical studies demonstrated that inhibition of IGF1R signaling in ACC had antiproliferative effects, the IGF1R inhibitor cix- utumumab in association with mitotane was evaluated as first-line treatment in a multicenter, randomized double-arm phase II trial [48]. This study was terminated before the randomization phase due to slow accrual and limited efficacy. Twenty patients were enrolled. Therapeutic effects were observed in 8/20 patients, including one PR and seven SD. The median PFS was 6 weeks (range 2.66-48). In another international, double-blind, placebo-controlled phase III study, patients were randomly assigned linsitinib a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor or placebo [49]. Of 139 patients enrolled, 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded in March 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase efficacy. At database lock and based on 92 deaths, no difference in OS was noted between linsitinib and placebo.

5 Tyrosine kinase inhibitors (TKI)

In 2012, an open label phase II trial evaluated the efficacy of suni- tinib, a multitargeted TKI with predominant anti-angiogenic effect [50]. Thirty-five patients could be evaluated for response. Five patients experienced SD, 24 had PD, and six patients died from ACC before the first evaluation. The median PFS was 2.8 months. In responders, PFS ranged from 5.6 to 11.2 months and OS from 14.0 to 35.5 months. Concomitant mitotane appeared to negatively impact on outcome. Furthermore, a negative correlation between the serum concentrations of sunitinib plus its active metabolite N-desethylsunitinib (SU12662) and mitotane was observed in seven evaluable patients suggestive of a relevant drug-drug interaction. More recently, in 2020, cabozantinib an inhibitor of c-MET, vascular endothelial growth factor receptor 2, AXL, and RET was evaluated in a retrospective cohort study [51]. Mitotane was discontinued in all patients before cabozantinib therapy to avoid drug-drug interaction. Sixteen patients received cabozantinib. Best response was PR in 3, SD in 5, and PD in 8 patients. Median progression-free and OS was 16 and 58 weeks, respectively.

6 Immune checkpoint inhibitors (ICI)

The recent development of ICI for the treatment of most cancers also concerned ACC.

Habra et al. [52] reported a pre-specified cohort of a phase II using pembrolizumab in patients with rare malignancies. Sixteen patients with ACC were included. Ten patients (63%) had hormonal overproduction (seven had cortisol-producing ACC which could theoretically limit the efficacy of immunotherapy). Non-progression rate at 27 weeks was evaluable in 14 patients. Non-progression rate at 27 weeks was 36%, 95% confidence interval 13-65%. Of the 14 patients evaluable, two had PR (including one with cortisol-producing ACC), seven had SD (including three with cortisol-producing ACC), and five had PD, repre- senting an ORR of 14% (95% confidence interval 2-43%). Of those who had SD, six had disease stabilization that lasted at least 4 months. In another phase II study [53], 39 patients received pembrolizumab with a median follow-up of 17.8 months (from 5.4 months to 34.7 months). The ORR was 23% and the disease control rate was 52%. The median duration of response was not reached (lower 95% CI, 4.1 months). Two of six patients with microsatellite instability-High / mismatch repair-Deficient tumors responded. The other seven patients with objective responses had microsatellite stable tumors. The median PFS was 2.1 months (95% CI, 2.0 months to 10.7 months), and the median OS was 24.9 months (95% CI, 4.2 months to not reached). Nivolumab was also evaluated in a single-arm, phase II [54] enrolling ten patients. The median number of doses of nivolumab administered was only two. Three patients only received one treatment [one died of disease pro- gression, one discontinued due to adverse events, one withdrew after beginning treatment]. The median PFS was 1.8 months. The median

follow-up was 4.5 months (range, 0.1 to 25.6 months). Two patients had SD for a duration of 48 and 11 weeks, respectively. One patient had an unconfirmed partial response but discontinued the study due to an adverse event. Avelumab was also evaluated in a phase 1b expansion cohort [55] in patients with metastatic ACC and prior platinum-based therapy. Fifty patients received avelumab and were followed for a me- dian of 16.5 months. Prior treatment included >2 lines in 74.0%; mitotane was continued in 50.0%. The ORR was 6.0% (95% CI, 1.3% to 16.5%; PR in 3 patients). Twenty-one patients (42.0%) had SD as best response (disease control rate of 48.0%). Median PFS was 2.6 months (95% CI, 1.4 to 4.0), median OS was 10.6 months (95% CI, 7.4 to 15.0), and the 1-year OS rate was 43.4% (95% CI, 27.9% to 57.9%). In evaluable patients with PD-L1+ (n = 12) or PD-L1- (n = 30) tumors (≥5% tumor cell cutoff), ORR was 16.7% vs 3.3% (p = 0.192). ICI based combination were also tested. In the CA209-538 prospective multicenter clinical trial, ipilimumab plus nivolumab was evaluated in patients with advanced rare cancers [56]. Six patients with ACC were enrolled. Two patients (33%) had an ongoing PR (at least 10 and 25 months) and two patients (33%) had SD leading to a disease control rate of 66%. Both responders had tumors with a microsatellite instability. Finally, a retrospective case series describing the use of lenvatinib plus pem- brolizumab as salvage therapy was published [57]. Eight patients were treated with the lenvatinib plus pembrolizumab combination therapy. Three (37.5%) patients had hormonally active ACC. The median number of prior lines of systemic therapy was 4 (range 2-9). Six (75%) patients had had disease progression on prior ICI and five (62.5%) patients had progressed on prior TKI therapy. The median PFS was 5.5 months (95% CI 1.8-not reached) and median duration of therapy was 8.5 months (range 2-22). Two (25%) patients had a PR, one (12.5%) patient had SD, and five (62.5%) patients had PD.

7 Other approaches

In 2006, Papewalis et al. [58] evaluated a dendritic cells immuno- therapy protocol. Autologous dentritic cells were pulsed with autolo- gous tumor lysate. Two patients with metastasized hypersecretory ACC were vaccinated twice. Although this strategy resulted in increases in T-cell proliferation and induction of cytotoxic T-cells, no impact on tumor growth was observed and clinical outcome was not improved.

Another approach is peptide-based vaccination that delivers immu- nogenic peptides, corresponding to tumor-associated or tumor-specific antigens, to elicit a T-cell immune response. The NCT04187404 SPENCER multicenter, phase 1/2, first-in-human trial evaluated the EO2401 vaccine against ACC in combination with nivolumab. This vaccine includes three microbiome-derived epitopes: the interleukin receptor alpha 2 (IL13R2), survivin (BIRC5), and the mammalian fork- head box M1 (FOXM1) [59]. These antigens are overexpressed and linked to clinical outcomes in ACC. The preliminary results have been reported in 2022 showing a specific immune response in all tested pa- tients and efficacy in a subpopulation [60].

Finally, promising data exists concerning peptide receptor radionu- clide therapy. A study on Iodine-131 Iodometomidate (131I MTO) tar- geted radionuclide therapy demonstrated one partial response and five patients with stable disease in a cohort of 11 patients [61]. In another study, 19 patients with advanced somatostatin expressing tumors, Yttrium-90/177 Lu-DOTATOC was tested. Eight patients showed radio- metabolic uptake of Yttrium-90/177Lu-DOTATOC and two patients showed strong uptake and disease control lasting 4 and 12 months [62].

Conclusion

ACC is a rare disease with clearly established diagnostic procedures that do not rely only on tumor biopsy. When diagnosed at a local stage, ACC can be cured with radical surgery and discussion on adjuvant mitotane or radiotherapy. At a locally advanced non-resectable or metastatic stage, ACC is a highly aggressive disease with very poor

prognosis. Given the complexity of the oncologic and endocrinologic situations, a multidisciplinary management in specialized centers is recommended for these patients.

CRediT authorship contribution statement

Rossella Libé: Conceptualization, Methodology, Writing - original draft, Writing - review & editing. Olivier Huillard: Conceptualization, Methodology, Writing - original draft, Writing - review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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