Introduction
Adrenocortical carcinoma (ACC) is a rare endocrine tumor with a poor prognosis.
Recurrences are common even in patients with localized disease. The annual incidence
is estimated to be between 0.7 and 2.0 cases per 1 million population. It can occur
at any age, with a peak incidence between 40 and 50 years. ACC corresponds to
1.3% of all childhood cancer allowing to conclude for a higher relative
incidence early in life. The incidence in children is particularly high in southern
Brazil due to the high prevalence of a specific TP53 germline mutation [1]. In the adult as well as in the pediatric
population, there is a predilection for the female gender [2]
[3]
[4]
[5].
ACC is, in most cases, a steroid hormone-producing tumor. The steroidogenic pattern
is dominated by steroid precursor metabolites that are not measured by routine
evaluation rather than end products of steroidogenesis [6]. Hypercortisolism (Cushing syndrome) or
mixed Cushing and virilizing syndromes are the most common presentations in patients
presenting with hormone excess; 30–40% of patients experience
mass-effect symptoms, and 10% are incidentally found [3].
Stage at presentation is a crucial prognostic factor. Five-year survival is
60–80% for tumors limited to adrenal, 35–50% for
locally advanced disease and much lower in case of metastatic disease ranging from
0% to 28%. Nonetheless, this condition is very heterogeneous, and
even patients with metastatic disease may have a long survival [7].
Surgical resection is the only curative option. However, it is only a realistic
option for stage I and II tumors (rarely stage III). Even after apparently
successful surgery, local or metastatic recurrence is frequent [3]. As a matter of fact, as many as
75–85% have a relapse after radical resection [8]
[9].
Recently, a nomogram incorporating age at diagnosis, T stage, N stage, and M stage
has been proposed to predict overall survival of adult ACC patients after surgery
[10].
Using the National Cancer Database (NCDB) and on Cox multivariate analysis, Tella SH
et al. [11] concluded that increasing age,
higher comorbidity index, high tumor grade, stage IV and no surgical therapy were
associated with worse survival. Concerning the type of surgery –
laparoscopic resection versus open adrenalectomy – in stage I–III
disease, the presence of R0 resections was similar in either type of surgery.
Adjuvant treatment to reduce the risk of ACC recurrence after surgery is widely
advocated, and several studies have taken place in an attempt to guide the optimal
regimen [12]. Mitotane,
[1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane
(o,p′-DDD)], an analogue of the insecticide
dichlorodiphenyltrichloroethane (DDT), has been used in the treatment of ACC since
1959 taking advantage of its cytotoxic effect on adrenal tissue and its potential to
inhibit steroidogenesis [13]. Adjuvant
mitotane may prolong recurrence-free survival in patients with radically resected
adrenocortical carcinoma [14]. It is the only
Food and Drug Administration (FDA) approved treatment of ACC. In advanced disease,
mitotane is usually combined with etoposide, doxorubicin, and cisplatin (EDP) in a
first-line attempt.
The response rates of mitotane monotherapy are estimated to be 10–30%
[15]. A randomized phase III study of
mitotane combined with EDP in patients with unresectable ACC without prior treatment
(except mitotane) presented an ORR of 23.2%, a disease-control rate (DCR) of
58.3%, a median progressive free survival (mPFS) of 5 months and a median OS
of 14.8 months [16].
The poor prognosis despite adjuvant therapy with mitotane with or without concurrent
different chemotherapeutic regimens has led to the exploration of novel therapies
[5]
[17]. Abnormal activation of insulin-like growth factor receptor 1 (IGF1R)
is one of the first and the most frequent molecular abnormalities described in
sporadic adult ACC, with a very high prevalence. Therefore, the use of IGF1R
inhibitors in association with mitotane appeared as an alternative treatment,
however, with low therapeutic efficacy [18]
[19].
The use of ICI has transformed the therapeutic approach of multiple human
malignancies. Some of them, such as pembrolizumab, are already approved by FDA for
all mismatch repair-deficient (MMRd) or high microsatellite instability (MSI-H)
mutated solid tumors (independent of the histological findings) [20]. Some studies reported the use of mTKI in
advanced ACC pointing for a modest efficacy [21]
[22]. Herein, we review new
strategies for the management of patients with advanced ACC with a particular focus
on immunotherapy: molecular rationale, outcomes, limitations, and adverse
effects.
Molecular markers and targeted therapies
The majority of ACC are sporadic, but some cases occur as part of hereditary
syndromes such as Li–Fraumeni Syndrome, Beckwith–Wiedemann
Syndrome, Carney Complex or Multiple Endocrine Neoplasia type I [3]. Patients with Lynch Syndrome (LS)
present a prevalence of ACC up to 3.2% [12].
As one of the rare cancer projects of The Cancer Genome Atlas (TCGA) a
comprehensive genomic characterization of ACC was performed resulting in the
identification of different genetic alterations from an expanded list of driver
genes: IGF2, TP53, ZNFR3, CTNNB1, TERT,
PRKAR1A, CCNE1, and TERF2
[23]. The same study revealed frequent
occurrence of massive DNA loss followed by whole-genome doubling (WGD)
associated with ACC progression and reinforced the prognostic value of the
methylation pattern.
A better understanding of the molecular pathogenesis of ACC offer hope that
targeted therapies can be developed. The diversity of genomic alterations
suggests the need for combined therapies.
Tyrosine Kinase Inhibitors
Molecular rationale
Selective and multi-kinase inhibitors are effective in the targeted treatment
of various malignancies. They share the same mechanism of action however
they differ from each other in the spectrum of targeted kinases. These drugs
potentially inhibit a cascade of signaling events that regulate cell growth
and angiogenesis. Overexpression of tyrosine kinase receptors was documented
in ACC particularly vascular endothelial growth factors and receptors
(VEGF/VEGFR), epidermal growth factor and receptor
(EGF/EGFR) and insulin-like growth factor (IGF) system comprised by
the IGF ligands (IGF-1, IGF-2, insulin) and their cell surface receptors
(IGF-1R, IGF-2R and insulin receptor) [23]
[24]
[25].
Signaling pathways such as PI3K/AKT/mTOR and MAPK
(Ras/Raf/MEK/ERK) resulting in cell survival,
proliferation and tumor growth, are activated through IGF-1R and EGF-R in
ACC [25].
Clinical trials
Multikinase inhibitors like cabozantinib (C-Met, VEGFR2, AXL, and RET mTKI),
levantinib (VEGFR1, VEGFR2, and VEGFR3 mTKI) and pazopanib (VEGFR, PDGFR and
c-Kit) have been tested in advanced ACC with modest efficacy. Nonetheless, a
small subset of patients, resistant to cytotoxic agents, may achieve partial
remission [7]
[22]
[26].
A randomized phase III trial enrolling 139 patients showed no significant
effect for linsitinib – an oral small molecule inhibitor of both
insulin-like growth factor 1 receptor and the insulin receptor –
compared to placebo in metastatic ACC [19]. The SIRAC-study (Sunitinib In Refractory Adrenocortical
Carcinoma) showed that sunitinib had modest activity in advanced ACC [28].
Since mitotane is used in the vast majority of patients with advanced ACC and
knowing that it has a strong and durable inducing effect on CYP3A4 activity
likely to interfere with the efficacy of other therapies including TKI,
analysis of TKI benefits has to take into account prior use of mitotane.
Megerle et al. suggest the use of TKIs only when the levels of mitotane are
<2 mg/l [29].
Immunotherapy
Molecular rationale
Tumor mutational burden is characterized by the presence of more than 10
mutations per megabase. ACC has an intermediate tumor mutation burden
particularly a high frequency of inactivating somatic or germline mutations
of genes of the DNA mismatch repair (MMR) system that originate enhanced
instability of microsatellite loci. Since the MMR-deficient cancers are
associated with the presence of neoantigens, ACC was considered amenable to
immunotherapy [30]
[31]
[32]
[33].
The immunotherapy is based on blocking key regulators of T cells (T-cell
checkpoint molecules) using anti PD-1 or anti PD-L1. Programmed cell death-1
(PD-1) is an immune-checkpoint receptor expressed by T cells, and programmed
cell death ligand-1 and 2 (PD-L1 and PD-L2) are expressed in the
microenvironment of a number of cancers. An estimated 11% of ACCs
express PD-L1 on tumor cell membranes, and 70% of tumor-infiltrating
monocytes are PD-L1 positive [34]. The
binding of PD-1 to PD-L1 or PD-L2 negatively regulates T-cell effector
functions.
The over-expression of PD-L1 in several cancers as melanoma, non-small-cell
lung carcinoma, and renal cell carcinoma have been regarded as good
prognostic factor in terms of the response to PD-1 inhibitors therapy.
However, there are studies reporting good overall response rates (ORR) to
immunotherapy even in PD-L1 negative tumors. PD-L1 expression may not be the
only determinant factor to immunotherapy response and more clinical trials
are essential to determine the benefits of these drugs in advanced ACC [5]
[35].
The hypercortisolism state of many ACC is pointed as a factor of
immunotherapy resistance. The steroid phenotype is associated with lower
overall survival (OS) when compared to non-functional ACCs [5]. Glucocorticoids have
immunosuppressive function through inhibition of circulating and
tumor-infiltrating immune cells. The presence of circulating and/or
T lymphocytes is known to be correlated with favorable outcome on
patients’ OS in various malignancies as melanoma or lung cancer.
These malignancies are highly responsive to immune checkpoint therapies
[36]. In contrast, ACC displays
the lowest pathological immune scores in cancer stromal cells infiltrates
among different human neoplasms. But the real contribution of
hypercortisolism state to the ineffectiveness of immunotherapy is uncertain
[5].
Specific genetic alterations are possible indicators of immunotherapy
resistance. β-Catenin gene (CTNNB1) and TP53 gene are frequently
mutated in ACCs. Overactivation of β-catenin pathway and loss of p53
protein function are potential tumor-intrinsic factors that may alter the
ability of ACC cells to recruit dendritic cells, leading to T-cell exclusion
[2].
Clinical trials
In recent literature, we found 4 clinical trials using ICI to treat advanced
ACC: a clinical trial phase Ib using avelumab – an anti-PD-L1
antibody; a phase II clinical trial using nivolumab – an anti-PD-1
antibody; and 2 phase II trials with pembrolizumab – another
anti-PD-1 antibody [37]
[38]
[39]
[40] ([Table 1]).
Table 1 Clinical trials of immunotherapy in patients
with advanced adrenocortical carcinoma.
|
Avelumab
|
Pembrolizumab
|
Nivolumab
|
Pembrolizumab
|
|
ClinicalTrials. Gov Identifier
|
NCT01772004
|
NCT02721732
|
NCT02720484
|
NCT02673333
|
|
Phase
|
1b
|
2
|
2
|
2
|
|
n
|
50
|
16
|
10
|
39
|
|
Female (%)
|
26 (52%)
|
8 (50%)
|
7 (70%)
|
23 (59%)
|
|
Age (median)
|
50
|
48
|
57
|
62
|
|
Non-Functioning Tumor (%)
|
NR
|
6 (37.5%)
|
6 (60%)
|
NR
|
|
PDL 1/PD1 (%)
|
15 (30%)
|
0 (0%)
|
6 (60%)
|
7 (18%)
|
|
MSI/MMR-D (%)
|
NR
|
1 (6.2%)
|
NR
|
6 (15%)
|
|
≥2 lines of previous treatment (%)
|
37 (74%)
|
10 (63%)
|
3 (30%)
|
NR
|
|
Concomitant mitotane (%)
|
25 (50%)
|
0 (0%)
|
0 (0%)
|
0 (0%)
|
|
mPFS (months)
|
2.6
|
NR
|
1.8
|
2.1
|
|
mOS (months)
|
10.6
|
NR
|
21.2
|
24.9
|
|
Disease control rate
|
48%
|
57%
|
NA
|
52%
|
|
ORR
|
6%
|
14%
|
NA
|
23%
|
|
Outcome
|
PD 23 (46%)
|
SD 7 (43%)
|
PD 7 (70%)
|
PD 15 (38%)
|
|
SD 21 (42%)
|
PD 5 (31%)
|
SD 2 (20%)
|
PR 9 (23%)
|
|
PR 3 (6%)
|
PR 2 (12.5%)
|
PR 1 (10%)*
|
SD 7 (18%)
|
|
CR 0 (0%)
|
CR 0 (0%)
|
CR 0 (0%)
|
CR 0 (0%)
|
|
Final status (deaths) (%)
|
6 (12%)
|
10 (63%)
|
1 (10%)
|
20 (51%)
|
|
Follow-up (months)
|
16.5
|
6.75
|
4.5
|
17.8
|
|
Reference
|
Le Tourneau et al. [40]
|
Habra et al. [38]
|
Carneiro et al. [39]
|
Raj et al. [37]
|
MMR-D: Mismatch repair deficiency; MSI: Microsatellite instability;
PDL1: Programmed death receptor 1 ligand; n: Number of patients;
mPFS: Median progression-free survival; mOS: Median overall
survival; ORR: Objective response rate; NR: Not reported; NA: Not
applicable; PD: Progressive disease; SD: Stable disease; PR: Partial
response; CR: Complete response. * Unconfirmed
partial response.
A multicenter, single-arm, open-label, phase 2 study to assess the ORR to
nivolumab enrolled 10 patients with advanced ACC. Nivolumab demonstrated a
modest efficacy; just 1 patient achieved unconfirmed partial response (PR)
[39].
Avelumab is a human IgG1 monoclonal antibody that specifically bind and block
PD-L1. The JAVELIN trial assessed Its efficacy in patients with previously
treated metastatic adrenocortical carcinoma with a DCR of 48% and
ORR of 6%. Results should be carefully interpreted because half of
patients were treated with concomitant mitotane. From the 3 patients with
PR, 2 were treated with double therapy [40].
The two trials with pembrolizumab presented better results than the trial
with Avelumab. Pembrolizumab was used as single-agent therapy. The trials
showed a promising efficacy regardless of tumor’s hormonal function
and MSI or PD-L1 status. A DCR of 57 and 52% and an ORR of 14 and
23% were described [37]
[38]. Isolated cases reporting the use
of pembrolizumab reinforce the heterogeneity in terms of response [30] ([Table 2]).
Table 2 Case series investigating immunotherapy or
TKIs in patients with advanced adrenocortical
carcinoma.
|
Characteristics
|
Cabozantinib
|
Pembrolizumab
|
Pembrolizumab
|
Pembrolizumab
|
Pembrolizumab
|
Nivolumab plus ipilimumab
|
Lenvantinib plus pembrolizumab
|
Cabozantinib or levantinib or pembrolizumab
|
|
n
|
16
|
2
|
6
|
1
|
1
|
1
|
8
|
15
|
|
Female (%)
|
13 (81%)
|
2 (100%)
|
6 (100%)
|
1 (100%)
|
0 (0%)
|
0 (0%)
|
4 (50%)
|
7 (47%)
|
|
Age (median)
|
42
|
34
|
44
|
58
|
29
|
38
|
38
|
43
|
|
Functioning Tumor (%)
|
13 (81%)
|
NR
|
3 (50%)
|
1 (100%)
|
1 (100%)
|
1 (100%)
|
3 (37.5%)
|
5 (33%)
|
|
Lynch syndrome
|
NR
|
NR
|
2 (33%)
|
1 (100%)
|
0 (0%)
|
1 (100%)
|
0 (0%)
|
1 (6.7%)
|
|
PDL 1/PD1
|
NR
|
1 (50%)
|
NR
|
0 (0%)
|
1 (100%)
|
NR
|
NR
|
NR
|
|
MSI/MMR-D
|
NR
|
NR
|
1 (20%)
|
1 (100%)
|
1 (100%)
|
1 (100%)
|
NR
|
NR
|
|
≥2 lines of previous treatment
|
At least 10 (62%)
|
2 (100%)
|
1 (16%)
|
0 (0%)
|
1 (100%)
|
0 (0%)
|
8 (100%)
|
14 (93%)
|
|
Concomitant mitotane
|
0%
|
0%
|
6 (100%)
|
1 (100%)
|
1 (100%)
|
0 (0%)
|
0 (0%)
|
0 (0%)
|
|
mPFS (months)
|
4
|
NR
|
NR
|
NA
|
NA
|
NA
|
5.5
|
mTKI 6.3
|
|
|
|
|
|
|
|
Pem 1.4
|
|
mOS (months)
|
14.5
|
NR
|
NR
|
NA
|
NA
|
NA
|
NR
|
mTKI 17.2
|
|
|
|
|
|
|
|
Pem 5.3
|
|
Disease control rate
|
50%
|
50%
|
100%
|
0%
|
100%
|
100%
|
25%
|
mTKI 63%
|
|
|
|
|
|
|
|
Pem 17%
|
|
ORR
|
18.7%
|
50%
|
33%
|
0%
|
100%
|
100%
|
37.5%
|
mTKI 25%
|
|
|
|
|
|
|
|
Pem 8%
|
|
Outcome
|
PD 8 (50%)
|
CR 1 (50%)
|
SD 4 (67%)
|
PD 1 (100%)
|
PR 1 (100%)
|
PR 1 (100%)
|
PD 5 (62.5%)
|
mTKI
|
|
SD 5 (31%)
|
PD 1 (50%)
|
PR 2 (33%)
|
|
|
|
PR 2 (25%)
|
PD 3 (37,5%)
|
|
PR 3 (18,7%)
|
SD 0 (0%)
|
PD 0 (0%)
|
|
|
|
SD 1 (12.5%)
|
SD 3 (37,5%)
|
|
CR 0 (0%)
|
PR 0 (0%)
|
CR 0 (0%)
|
|
|
|
CR 0
|
PR 2 (25%)
|
|
|
|
|
|
|
|
CR 0 (0%)
|
|
|
|
|
|
|
|
Pem
|
|
|
|
|
|
|
|
PD 10 (83,4%)
|
|
|
|
|
|
|
|
SD 1 (8,3%)
|
|
|
|
|
|
|
|
PR 1 (8,3%)
|
|
|
|
|
|
|
|
CR 0 (0%)
|
|
Final status (deaths) (%)
|
9 (56%)
|
1 (50%)
|
2 (33%)
|
1 (100%)
|
0 (0%)
|
0 (0%)
|
2 (25%)
|
10 (67%)
|
|
Follow-up (months)
|
NR
|
26
|
21.3
|
4
|
6
|
24
|
NR
|
NR
|
|
Reference
|
Kroiss et al. [22]
|
Mota et al. [30]
|
Head et al. [41]
|
Casey et al. [46]
|
Caccese et al. [31]
|
Nevgi et al. [32]
|
Bedrose et al. [27]
|
Miller et al. [26]
|
MMR-D: Mismatch repair deficiency; MSI: Microsatellite instability;
PDL1: Programmed death receptor 1 ligand; n: Number of patients;
mPFS: Median progression-free survival; mOS: Median overall
survival; ORR: Objective response rate; NR: Not reported; NA: Nnot
applicable; PD: Progressive disease; SD: Stable disease; PR: Partial
response; CR: Complete response; mTKI: Multi-Tyrosine Kinase
Inhibitors; Pem: embrolizumab.
Combined therapies have also been assayed. The association of mitotane and
pembrolizumab was used by Head et al. [41] in 6 patients and a partial response was observed in 2 of
them. The association of pembrolizumab and levantinib conducted to a partial
response in 1 out of 8 heavily pre-treated patients [27]. The rationale for this type of
combination is that MKI modulate a variety of interferon-signaling related
genes and in this way activate CD8+ T cells in tumoral
microenvironment.
The association of pembrolizumab and chemotherapy (i. e.,
cyclophosphamide or gemcitabine/doxetaxel) was reported by Miller et
al. [26] in 4 patients and all had
disease progression.
A better characterization of the genomic, molecular and immune profiles of
the good responders will facilitate the selection of candidates for these
therapies. So far, it seems that microsatellite instability and Lynch
Syndrome related germline mutations may be predictive biomarkers of response
to immunotherapy. Germline mutations in the CDKN2A gene might also be
associated with a favorable response to immunotherapy [2]
[26]
[42]. On the other hand,
cortisol secretion has been associated with more aggressive ACC tumors and
potentially poor responses to immunotherapy [43].
Adverse Effects (AE)
In general, the adverse effects observed in patients with advanced ACC
treated with TKI or ICI are the same reported in the setting of other
malignancies [39]
[44]
[45]. However, the frequent association with mitotane that has a
toxicity profile including hepatic, gastrointestinal, neurological, and
hematologic effects increases the risk of adverse effects. Patients
receiving concomitant mitotane have a higher rate of grade ≥3
treatment related adverse effects (TRAEs) than those with single therapy,
particularly liver enzymes elevation [40].
From the literature, the occurrence of TRAEs in ACC patients is estimated to
range between 58.9% and 100% but in most of the cases the
severity of symptoms were mild without the need to stop treatment. A death,
possible related to pembrolizumab, was reported [46].
The TRAEs observed in 55 patients with pembrolizumab, retrieved from the
literature, are outlined in [Table
3]. Grade 3 or higher were observed in 11 patients (20%) which
is much lower than the rate of 58% reported in patients submitted to
EDP treatment [37]. Nonetheless, close
clinical and biochemical monitoring are indicated.
Table 3 Treatment related adverse events of
Pembrolizumab trials.
|
Adverse Event
|
Raj et al. [37]
|
Habra et al. [38]
|
Total n (%)
|
|
All Grades n (%)
|
Grade ≥3 n (%)
|
All Grades n (%)
|
Grade ≥3 n (%)
|
|
Increased AST/ALT
|
9 (23)
|
4 (10)
|
2 (13)
|
|
11 (20)
|
|
Fatigue
|
8 (20)
|
|
3 (19)
|
|
11 (20)
|
|
Pruritus
|
7 (18)
|
|
|
|
7 (12)
|
|
Rash, maculo-papular
|
3 (8)
|
|
2 (13)
|
|
5 (9)
|
|
Hypothyroidism
|
3 (8)
|
|
2 (13)
|
|
5 (9)
|
|
Hypocalcemia
|
4 (10)
|
1 (3)
|
|
|
4 (7)
|
|
Increased alkaline phosphatase
|
4 (10)
|
|
|
|
4 (7)
|
|
Nausea
|
2 (5)
|
|
1 (6)
|
|
3 (5)
|
|
Anorexia
|
1 (3)
|
|
2 (13)
|
|
3 (5)
|
|
Dry skin
|
2 (5)
|
|
1 (6)
|
|
3 (5)
|
|
Lymphopenia
|
2 (5)
|
|
|
|
2 (4)
|
|
Increased creatinine
|
2 (5)
|
|
|
|
2 (4)
|
|
Hypoalbuminemia
|
2 (5)
|
1 (3)
|
|
|
2 (4)
|
|
Hyperpigmentation
|
2 (5)
|
|
|
|
2 (4)
|
|
Chills
|
2 (5)
|
|
|
|
2 (4)
|
|
Oral mucositis
|
1 (3)
|
|
1 (6)
|
|
2 (4)
|
|
Pneumonitis
|
1 (3)
|
|
1 (6)
|
1 (6)
|
2 (4)
|
|
Anemia
|
1 (3)
|
|
1 (6)
|
|
2 (4)
|
|
Dyspnea
|
|
|
1 (6)
|
|
1 (2)
|
|
Arthralgia
|
|
|
1 (6)
|
|
1 (2)
|
|
Myalgia
|
|
|
1 (6)
|
|
1 (2)
|
|
Colitis
|
|
|
1 (6)
|
1 (6)
|
1 (2)
|
|
Thrombocytopenia
|
1 (3)
|
|
|
|
1 (2)
|
|
Neutropenia
|
1 (3)
|
|
|
|
1 (2)
|
|
Hyperglycemia
|
1 (3)
|
|
|
|
1 (2)
|
|
Hypokalemia
|
1 (3)
|
1 (3)
|
|
|
1 (2)
|
|
Hypophosphatemia
|
1 (3)
|
1 (3)
|
|
|
1 (2)
|
|
Hypomagnesemia
|
1 (3)
|
1 (3)
|
|
|
1 (2)
|
|
Hyponatremia
|
1 (3)
|
|
|
|
1 (2)
|
|
Increased bilirubin
|
1 (3)
|
|
|
|
1 (2)
|
|
Peripheral edema
|
1 (3)
|
|
|
|
1 (2)
|
|
Limbs edema
|
1 (3)
|
|
|
|
1 (2)
|
|
Pain
|
1 (3)
|
|
|
|
1 (2)
|
|
Decreased libido
|
1 (3)
|
|
|
|
1 (2)
|
|
Fever
|
1 (3)
|
|
|
|
1 (2)
|
|
Malaise
|
1 (3)
|
|
|
|
1 (2)
|
|
Other general toxicities
|
1 (3)
|
|
|
|
1 (2)
|
|
Hyperthyroidism
|
1 (3)
|
|
|
|
1 (2)
|
|
Adrenal insufficiency
|
1 (3)
|
|
|
|
1 (2)
|
|
Vomiting
|
1 (3)
|
|
|
|
1 (2)
|
|
Constipation
|
1 (3)
|
|
|
|
1 (2)
|
|
Diarrhea
|
1 (3)
|
|
|
|
1 (2)
|
|
Duodenitis
|
1 (3)
|
|
|
|
1 (2)
|
|
Alopecia
|
1 (3)
|
|
|
|
1 (2)
|
|
Skin and subcutaneous tissue disorder
|
1 (3)
|
|
|
|
1 (2)
|
|
Dry eyes
|
1 (3)
|
|
|
|
1 (2)
|
|
Conjunctivitis
|
1 (3)
|
|
|
|
1 (2)
|
|
Dizziness
|
1 (3)
|
|
|
|
1 (2)
|
|
Infusion reaction
|
1 (3)
|
|
|
|
1 (2)
|
n: Number of patients; AST: Aspartate transaminase; ALT: Alanine
transaminase.
Conclusions
ACC is a rare, aggressive and heterogeneous endocrine tumor. The standard treatment
with mitotane with or without EDP has limited efficacy and important AEs. Recurrence
is the most common outcome. Early recurrence is associated with an advanced stage of
disease at diagnosis, incomplete surgical resection, cortisol production, and a few
genetic alterations.
The low incidence of the disease and high cost of clinical trials are the major
constraints in the search for improved treatment strategies. That is why new
concepts for clinical trials such as registry-based randomized trials, as proposed
by the European Network for the Study of Adrenal Tumours (ENSAT) [47], will probably facilitate future
studies.
Pembrolizumab is the most often used checkpoint inhibitor and the one that showed the
best results in patients with advanced ACC. In some series, the ORR reached
33% in patients in whom other previous treatments had failed. Identification
of biomarkers allowing to select the candidates for immunotherapy are likely to
improve results. Putative candidates might be those with mutations in DNA
repair-related genes [30]. Whether the high
intratumoral concentrations of glucocorticoids might interfere in the response to
this class of medications remains to be answered.
Clinical trials exposed weaknesses of the single pathway,
“one-size-fits-all” therapy, that could be anticipated, due to the
high mutational burden of ACC, thus, reinforcing the need for combined
therapies.
In summary, immunotherapy and/or multi-kinase inhibitors may be a salvage
therapeutic option to ACC patients with limited options. However, this approach
requires the improved patient selection and future studies aiming to identify
biomarkers that predict response.
While awaiting an effective treatment for this orphan disease, a prompt diagnosis of
relapse remains the best alternative to care for the patients. Therefore,
development of liquid biopsies, including steroid metabolomics, cell-free DNA or
microRNA, to use on a clinical ground are promising tools for the postoperative
follow-up and early detection of relapse. It is conceivable that a biochemical
detection of relapse, prior to the evidence of structural disease will have a
positive impact on treatment efficacy.
