Abstract
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an estimated incidence of 0.7–2 cases per million/year. The rarity of this disease, coupled with limited preclinical models and clinical trials, has hindered progress, resulting in poor outcomes, with a 5-year survival rate of approximately 35%. Currently, the only available curative treatment is complete surgical resection of the adrenal tumor. For unresectable or metastatic ACC, the current standard therapeutic modalities are mitotane, chemotherapy, radiotherapy and locoregional treatments; however, these are noncurative. Mitotane has an adrenolytic and anti-steroidogenic effect, and it is used in the adjuvant setting for high-risk patients, as systemic therapy for metastatic disease, and/or to control hormonal secretion. While key pathways in ACC pathogenesis have been identified as potential therapeutic targets, results with targeted therapies remain modest, showing that there is a clinical unmet need for novel treatments or new combinations of exiting drugs. Effective management requires a multidisciplinary team of experts to optimize outcomes for patients. This article presents a multidisciplinary consensus on the diagnosis, management, prognosis and follow-up of patients with ACC, and the approach to two special contexts, ACC in pregnant women and hormone-producing ACC. The consensus was coordinated by the Spanish Society of Endocrinology and Nutrition (SEEN) and the Spanish Group of Neuroendocrine and Endocrine Tumors (GETNE), with contribution from experts from related societies including the Spanish Association of Surgeons (AEC), Spanish Society of Urology (AEU), Anatomic-Pathology (SEAP), Nuclear Medicine (SEMNIM), Medical Oncology (SEOM) and Radiotherapeutic Oncology (SEOR).
Introduction
Adrenal cortical tumors are common, with a prevalence of 1–10%, but most are benign adrenal adenomas discovered incidentally (Araujo-Castro et al. 2020). In contrast, adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 0.7–2 cases per million/year (Bilimoria et al. 2008). ACC exhibits a bimodal distribution predominantly affecting women (55–60%) and presenting in pediatric and adult populations. Approximately 75% of cases involve adrenal hormonal hypersecretion, primarily of cortisol and androgen, while estrogen or mineralocorticoid excess is rare (Abiven et al. 2006).
Due to the rarity of ACC, limited preclinical models and clinical trials have hindered progress, resulting in poor outcomes, with a 5-year survival rate of 35% (Abiven et al. 2006) dropping to less than 15% in metastatic stage (Kerkhofs et al. 2013). Nevertheless, more recent studies reported a slight increase in survival rates, being RO resection cornerstone of curative treatment for ACC. In this regard, estimated 5-year overall survival (OS) for ACC patients undergoing R0 resection was 64.8% compared to 33.8% for patients undergoing an R1 resection (Anderson et al. 2018). Prognosis worsens with advanced age and cortisol hypersecretion (Abiven et al. 2006). ENSAT (European Network for the Study of Adrenal Tumors) staging is currently the most reliable prognostic tool (Fassnacht et al. 2018).
Surgery is the only curative treatment for ACC, with adrenalectomy being the standard approach for localized ACC (Fassnacht et al. 2018). Systemic therapies, including chemotherapy, radiotherapy and mitotane, provide limited efficacy in unresectable or metastatic ACC. Advances in molecular research have identified key drivers such as insulin-like growth factor 2 (IGF2), β-catenin (CTNNB1) and TP53, with integrated genomic analyses revealing distinct molecular subgroups with varied prognoses (Giordano et al. 2009, Assié et al. 2014, Zheng et al. 2016).
This article provides a multidisciplinary update on the diagnosis, management and follow-up of ACC, incorporating contributions from experts in endocrinology, medical and radiotherapeutic oncology, pathology, interventional radiology, urology and surgery. The consensus, coordinated by the Spanish Society of Endocrinology and Nutrition (SEEN) and the Spanish Group of Neuroendocrine and Endocrine Tumors (GETNE), includes contributions of experts belonging to related societies: Spanish Association of Surgeons (AEC), Spanish Society of Urology (AEU), Anatomic-Pathology (SEAP), Medical Oncology (SEOM), Nuclear Medicine (SEMNIM) and Radiotherapeutic Oncology (SEOR). To reach this consensus, the experts of different specialties conducted a review of the literature, analyzed it according to the GRADE (grading of recommendation, assessment, development and evaluation) methodology and made proposals for guidelines, which were rated by other experts. Only the expert opinions with strong agreement were selected.
Diagnostic approach to ACC: hormonal, genetic, radiological and functional (theragnostic) imaging evaluation
Given the aggressive nature of ACC, a prompt and comprehensive diagnosis approach combining clinical, hormonal and radiological assessment by multidisciplinary expert center team is crucial for accurate staging and determining surgical resectability, which can improve patient outcomes (Fassnacht et al. 2011).
Radiological evaluation
Radiological imaging plays a pivotal role in staging, evaluating disease spread and assessing the surgical feasibility. The primary imaging modalities include (Fassnacht et al. 2023b ):
Computed tomography (CT) is the first-line imaging modality for adrenal masses due to its resolution, speed and accessibility (Ilias et al. 2007). ACC typically presents as a large (often >4 cm), irregular mass with heterogeneous features (necrosis, hemorrhage or calcification) and low lipid content, resulting in high Hounsfield units (HU) (>10 on unenhanced CT) (Petersenn et al. 2015, Araujo-Castro et al. 2020, Mínguez Ojeda et al. 2022) (Fig. 1). Contrast-enhanced CT with multiphase imaging aids in evaluating vascularity and differentiating benign from malignant lesions. Some data that may be suggestive of malignancy include an absolute washout of less than 60% and a relative washout of less than 40% (Ahmed et al. 2020). However, some studies found that the sensitivity of these cut-offs of relative and absolute washout is low. For example, according to the Marty M series, sensitivity of these cut-offs of relative and absolute washout was 72.3% and 76.6%, respectively (Marty et al. 2018); and according to the Schloetelburg’s study (Schloetelburg et al. 2021), the established thresholds of 60% for absolute and 40% for relative washout misclassified 35.9% and 35.2% of the masses, respectively.
Radiological features of an ACC. CT of the abdomen with intravenous iodinated contrast with abdominal acquisition in arterial and portal phases: solid left adrenal mass with heterogeneous enhancement (8.2 × 9 × 9.3 cm, CCxTxAP). It displaces the tail of the pancreas cranially and caudally to the ipsilateral kidney. It does not show macroscopic fat foci or calcifications. The findings suggest adrenal carcinoma or pheochromocytoma as the first possibility. Pathological retroperitoneal lymphadenopathy (left paraaortic and interaortocaval) and in the hepatic hilum.
Citation: Endocrine-Related Cancer 32, 5; 10.1530/ERC-25-0034
Staging evaluation assesses local invasion such as involvement of the renal vein, inferior vena cava (IVC) or hepatic vein, and distant metastases, primarily in the liver, lungs and lymph nodes. Liver metastases often necessitate a multiphase study, including arterial, venous and delayed phases, to ensure accurate detection (Ilias et al. 2007).
Abdominal magnetic resonance imaging (MRI) serves as a complementary or alternative tool, particularly when CT contrast is contraindicated, or findings are inconclusive. ACC appears as a heterogeneous mass with hyperintense T2-weighted signals (necrosis/hemorrhage) and hypointense regions on chemical shift imaging, distinguishing lipid-poor adenomas from ACC. MRI is also valuable in assessing venous invasion (IVC or renal veins) and provides enhanced tissue characterization compared to CT (Byung et al. 2007, Shin & Kim 2015).
Hormonal and genetic evaluation
In addition to standard hormonal evaluation for adrenal incidentalomas, the ESE/ENSAT guidelines recommend measuring sex steroids and steroidogenesis precursors, ideally using multisteroid profiling by tandem mass spectrometry in cases where ACC is suspected based on imaging or clinical features (Table 1) (Fassnacht et al. 2023b ). A complete preoperative endocrine work-up is necessary to establish the tumor’s secretory profile, identify biomarkers for recurrence, and optimize perioperative management (e.g., perioperative glucocorticoid therapy in patients with hypercortisolism). Key evaluations include measuring urinary or plasma normetanephrine and metanephrine to rule out pheochromocytoma and prevent intraoperative complications. Cortisol excess should be assessed even in the absence of Cushingoid features to mitigate the risk of life-threatening postoperative adrenal insufficiency in cortisol-secreting ACCs. Aldosterone-secreting tumors should be managed preoperatively to address hypertension and hypokalemia (Gaujoux et al. 2017a , Puglisi et al. 2018a ).
Hormonal evaluation in patients with suspected ACC (Fassnacht et al. 2018).
| Designation purpose | Recommended test |
|---|---|
| Assessment of glucocorticoid secretion disorders | - 1 mg dexamethasone suppression test - 24 h urinary free cortisol - ACTH levels |
| Assessment of mineralocorticoid secretion disorders | - Serum potassium levels - Aldosterone-to-renin ratio (for hypertensive patients) |
| Evaluation of sex hormones and steroid precursors | - DHEA-S, 17-hydroxyprogesterone, androstenedione - Testosterone (for women only), 17β-estradiol (for men and postmenopausal women) - 11-Deoxycortisol |
| Exclusion of pheochromocytoma | - 24 h urinary fractionated metanephrines and/or plasma-free metanephrines |
For all adult patients with ACC, at least a basic clinical genetic evaluation exploring personal and family history for evidence of hereditary predisposition syndrome should be carried out to identify potential hereditary predisposition syndromes (Fassnacht et al. 2018). Germline genetic evaluation should be performed in those patients with clinical and/or family history suggestive of hereditary disorders. Detecting germline mutations impacts patient care and surveillance while allowing identification of at-risk relatives (Fassnacht et al. 2018). The most frequent syndromes associated with ACC in adults are Li Fraumeni (LFS) and Lynch syndromes in 5% and 3% of cases, respectively (Herrmann et al. 2012, Raymond et al. 2013). Nonetheless, LFS accounts for 50–80% of pediatric ACCs (Bougeard et al. 2008). Lynch syndrome screening involves immunohistochemistry for MSH2, MLH1, PMS2, MSH6 and microsatellite instability testing, or direct germline analysis of these genes and EPCAM. LFS diagnosis relies on detecting pathogenic variants in TP53 (Petr & Else 2016). Less frequent genetic syndromes associated with ACC include Beckwith–Wiedemann syndrome (children), familial adenomatous polyposis (APC), Carney complex and MEN1 (Fassnacht et al. 2018).
Functional (theragnostic) imaging evaluation
Nuclear imaging, specifically positron emission tomography with 18F-fluorodeoxyglucose ([18F]FDG PET/CT), has become integral in the diagnosis, staging and management of ACC. This technique helps in distinguishing benign from malignant adrenal lesions and correlates metabolic activity with tumor aggressiveness (Fassnacht et al. 2018). Emerging theragnostic agents, such as fibroblast activation protein inhibitors (FAPI) and C-X-C motif chemokine receptor 4 (CXCR4)-directed radiotracers, hold promise for combining diagnostic imaging with targeted radionuclide therapies, advancing precision medicine in ACC.
[18F]FDG PET/CT in ACC
ACC typically exhibits high metabolic activity, detectable on [18F]FDG PET/CT as areas of increased glucose uptake, correlating with malignancy markers such as Ki67. An adrenal-to-liver SUVmax ratio >1.5 demonstrated 100% sensitivity for malignancy and 87% specificity, establishing it as a robust diagnostic indicator (Libé et al. 2023, Romanisio et al. 2024), excluding pheochromocytoma. Furthermore, [18F]FDG PET/CT aids in evaluating metastatic spread and guiding surgical decisions by providing a more comprehensive disease overview (Table 2). However, we should be aware that although FDG-PET/CT has the advantage of the low risk of false negative results (namely missing a malignant adrenal tumor), it is clearly not zero, and several benign adrenal tumors (e.g., functional adenomas) may be FDG-positive lesions (Fassnacht et al. 2023b , Libé et al. 2023).
Clinical applicability of the [18F]FDG PET/CT in the diagnosis of ACC.
| Clinical scenario | Description |
|---|---|
| Diagnostic accuracy of [18F]FDG PET/CT (Ma et al. 2021) | The specificity and sensitivity of [18F]FDG PET/CT for ACC are high, with several studies recommending an SUVmax cut-off value around 5.65 for differentiating ACC from benign adrenal lesions. The quantification of uptake values, such as the SUVmax and adrenal-to-liver ratio, is crucial for this differentiation |
| Correlation with tumor aggressiveness and Ki67 (Libé et al. 2023, Ma et al. 2021, Romanisio et al. 2024) | In tumors with a Ki67 index exceeding 10%, [18F]FDG uptake tends to be markedly elevated, suggesting a more aggressive disease course and a potentially poorer prognosis |
| Use in differential diagnosis of adrenal lesions (Ma et al. 2021) | In a comparative study, malignant lesions showed a SUVmax mean of 10.0, compared to 5.4 in benign lesions, indicating a significant threshold for malignancy risk assessment. The T/L ratio, or tumor-to-liver ratio, is another useful metric, with malignant lesions often exhibiting ratios >3, in contrast to benign cases, which generally fall below this threshold |
Theragnostic radiotracers in ACC management
Theragnostic represents a transformative approach to ACC management by combining diagnosis imaging with targeted treatment. FAPI and CXCR4-directed agents, such as [68Ga]Ga-pentixafor, exemplify this paradigm, identifying patients for radionuclide therapies and improving outcomes.
FAPI target cancer-associated fibroblasts within the tumor microenvironment present in ACC. FAPI PET/CT has demonstrated high specificity in visualizing tumor-associated stroma, enabling clearer delineation of ACC lesions (Chopra et al. 2023). Moreover, FAPI agents conjugated with therapeutic radionuclides, such as [177Lu]Lu, allow for high-dose radiation directly to the tumor with minimal damage to surrounding tissues, offering a promising approach for recurrent or metastatic ACC (Michalski et al. 2023).
CXCR4 is implicated in tumor progression and metastasis in ACC. Its expression, detectable via [68Ga]Ga-pentixafor PET/CT, predicts poor outcomes, linking high CXCR4 expression with shorter OS (Dreher et al. 2024, Schloetelburg et al. 2024). Patients with CXCR4-positive tumors demonstrated an average survival of 6.4 months compared to 13.3 months in those with lower CXCR4 expression, highlighting its prognostic potential (Schloetelburg et al. 2024).
Radionuclide therapy is effectively used for diagnosis and treatment in various cancers, including neuroendocrine neoplasms, and specific radiotracers for ACC are available. Metomidate, an inhibitor of 11-beta-hydroxylase (CYP11B), has been labeled with 11C, 18F and 131I for SPECT and SPECT/CT scanning, showing good sensitivity and specificity. Other radiotracers that bind CYP11B enzymes include 18F-fluoroetomidate (FETO) and 123I-iodometomidate (IMTO) (Wong et al. 2016). A case series involving 11 patients treated with 123I-IMTO reported one partial response and five stable diseases, with a median progression-free survival (PFS) of 14 months for responding patients and an overall median survival of 13 months for the cohort (Hahner et al. 2012). Another CYP11B-ligand tracer, 131I-IMAZA, has been tested in 13 refractory advanced ACC patients without responses and a PFS of 14 months, warranting cautious interpretation of results (Hahner et al. 2022).
Pathological and molecular markers of prognosis
The rarity of ACC complicates its histopathological differentiation from benign lesions and other neoplasms. Pre-surgical adrenal biopsy is unnecessary when surgery is not an option. Advances in histopathology, ancillary studies and genetics, as reflected in the 2022 WHO classification, have improved diagnostic accuracy (Mete et al. 2022). The modified Weiss scoring system (Weiss et al. 1989) is the most widely used tool, requiring at least three of nine histological parameters for malignancy: high nuclear grade, >5 mitoses/50 high-power fields, atypical mitosis, >75% eosinophilic cytoplasm, >33% diffuse architecture, necrosis or vascular/sinusoidal/capsular invasion.
In pediatric ACC, conventional adult criteria may lead to overdiagnosis of malignancy. The Wieneke score system (Wieneke et al. 2003) provides pediatric-specific parameters, including tumor weight >400 g, size >10.5 cm, local tissue or organ invasion and a high mitotic index, requiring at least four criteria for diagnosis.
Cytopathological variants of ACC include conventional (eosinophilic or lipid-rich), oncocytic, myxoid or sarcomatoid forms. The oncocytic variant, the most common, is characterized by high-grade nuclei and relies on the Lin–Weiss–Bisceglia system (Bisceglia et al. 2004) for malignancy diagnosis, requiring at least one major criterion: >5 mitoses/50 HPF, atypical mitoses or venous invasion.
Immunohistochemistry is essential for confirming ACC and excluding non-adrenal cortical origins. Key markers include SF1, synaptophysin, melan A and inhibin alpha, with SF1 being the most reliable (Bisceglia et al. 2004). High-grade ACC often exhibits molecular alterations, such as IGF2 overexpression, p53 mutations or loss (Mete et al. 2018) and β-catenin accumulation (Borges et al. 2020).
Surgical treatment
Indications of surgery
Complete surgical resection is the only curative treatment for patients with localized ACC. The goal of surgery is to achieve an R0 resection, defined as complete tumor with microscopically negative margins. En bloc resection, including involved organs, is essential to avoid capsular disruption (Chagpar et al. 2014, Fernandez Ranvier & Inabnet 2015, Memeh et al. 2025). Five-year survival rates range from 30 to 50%, while incomplete resection or metastatic disease reduces the median survival to less than 1 year (Fernandez Ranvier & Inabnet 2015, Sinclair et al. 2020, Kwon et al. 2024). Surgical resection is the definitive treatment for stages I–III, including tumors with local invasion into surrounding organs or IVC. Stage III tumors initially deemed unresectable may become resectable following partial response to neoadjuvant therapy. The role of surgery in stage IV metastatic disease is highly individualized (Sinclair et al. 2020).
Principles of surgical treatment for localized stages (ENSAT stages I-III)
Curative treatment requires complete surgical resection with negative margins. Open adrenalectomy remains the gold standard due to superior oncologic outcomes, particularly in cases requiring en bloc resection of adjacent structures or extensive lymphadenectomy (Datta & Roses 2016, Kastelan et al. 2021, McCoy et al. 2022, de Ponthaud et al. 2024).
The deep retroperitoneal location, hypervascular attachments to adjacent organs and fragile capsule of the adrenal glands require meticulous surgical technique to minimize the risk of tumor rupture. These anatomical challenges reinforce the recommendation for open adrenalectomy as the preferred approach, particularly for achieving adequate exposure and optimal oncologic outcomes (Fig. 2) (Gaujoux et al. 2017a ).
Surgery in localized ACC (stage I–III ENSAT). ACC, adrenocortical carcinoma. *Adjuvant chemotherapy may be considered in selected patients with very high risk for recurrence.
Citation: Endocrine-Related Cancer 32, 5; 10.1530/ERC-25-0034
Several studies have defended the superiority of open adrenalectomy over laparoscopic approaches, with higher rates of complete oncologic resection and improved surgical outcomes (Maurice et al. 2017, Dickson et al. 2018). In addition, Hu X meta-analysis (Hu et al. 2020) that included 15 studies incorporating 2,207 patients with ACC found that minimally invasive adrenalectomy surgery (MIS) approaches were likely to have a better recovery, but were associated with earlier recurrence and more positive surgical margin and peritoneal recurrence. Consequently, the Society of Surgical Oncology (SSO), the European Society of Endocrine Surgeons (ESES) and ENSAT strongly recommend open adrenalectomy as the gold standard for confirmed or highly suspected ACC and evidence for local invasion. However, for tumors <6 cm without any evidence of local invasion, laparoscopic adrenalectomy (respecting the principles of oncological surgery) is reasonable if the surgeon has good expertise (Supplementary Material S1 (see section on Supplementary materials given at the end of the article)) (Lombardi et al. 2012, Fassnacht et al. 2018).
In experienced centers, laparoscopic adrenalectomy may be acceptable for suspicious lesions smaller than 8–10 cm without pre- or perioperative evidence of local invasion (stages I–II). However, oncologic principles must be strictly followed, including complete resection with negative surgical margins through en bloc removal of peri-adrenal and retroperitoneal fat, maintenance of capsular integrity by minimizing gland manipulation to prevent rupture or fragmentation and routine performance of regional lymphadenectomy (Leboulleux et al. 2010, Gaujoux & Brennan 2012, Lombardi et al. 2012, Cooper et al. 2013, Donatini et al. 2014, Fassnacht et al. 2018, Wu et al. 2018, Ginsburg et al. 2022).
Surgical treatment for recurrent and/or advanced ACC
Figure 3 shows the algorithm for the management of the patient with recurrent or metastatic ACC. Up to 21–39% of patients with ACC presented with oligo- or multi-metastatic disease at diagnosis. Approximately 80% of those who undergo complete resection will have local or distant recurrence (Datta & Roses 2016, Gaujoux et al. 2017b ). However, the rate of recurrence is lower in more recent series. For example, in the study by Puglisi et al. (Puglisi et al. 2023b ) that included 512 patients with ACC, recurrence free survival was 59% (95% CI, 43–80) for stage I ACC, 36% (95% CI, 29–44) for stage II and 16% (95% CI, 9–27) for stage III.
Surgery in advanced ACC (stage IV ENSAT). ACC, adrenocortical carcinoma.
Citation: Endocrine-Related Cancer 32, 5; 10.1530/ERC-25-0034
While data on surgical treatment in metastatic ACC are scarce, evidence suggests that complete resection of primary lesion and metastases can improve outcomes when technically feasible (Erdogan et al. 2013, Fassnacht et al. 2018, Terzolo et al. 2023). A retrospective study demonstrated an increase in the median OS (28.6 vs 13.0 months) at 1 (69.9 vs 53.0%) and 2 (46.9 vs 22.1%) years for patients undergoing complete resection (Livhits et al. 2014). Neoadjuvant chemotherapy has been shown to enhance 5-year survival (41.7 vs 8.9%) and can help to select patients who are suitable for multimodal management, excluding those with rapidly progressive, chemotherapy-resistant disease (Erdogan et al. 2013, Livhits et al. 2014, Kenney & Hughes 2023). However, it should be noted that data on neoadjuvant chemotherapy in the treatment of ACC is limited by few existing trials, most of which are retrospective. In this regard, the current consensus for its use is to reduce the burden of disease to facilitate complete resection (Kenney & Hughes 2023). In selected cases, particularly in patients with severe hormone excess, debulking surgery might be an option, if >80% of tumor burden can be safely removed (Erdogan et al. 2013, Fassnacht et al. 2018, Terzolo et al. 2023). For patients with poor clinical condition or localized metastatic burden, focal ablative therapies may serve as an alternative (Wood et al. 2003, Cazejust et al. 2010, Ho et al. 2013).
Complete resection of recurrent ACC has been associated with improved PFS and OS. Data from the German Adrenal Carcinoma Registry identified time to first recurrence >12 months as a positive prognostic factor. Surgery should be considered for patients with local or distant recurrence when time to recurrence is ≥6 months, and ideally ≥12 months (Erdogan et al. 2013, Livhits et al. 2014, Fassnacht et al. 2018). Another more recent study of Calabrese et al. (2023) in a series of 106 ACC patients that experienced recurrence described that 60.4% of patients became free of disease, attaining a second remission free survival of 15 months (IQR 6–64) after the treatment of recurrence. Margin status Rx (hazard ratio (HR) 2.62) and R1 (HR 4.37), percent increase in Ki67 (HR 1.03) and recurrence in multiple organs (HR 3.92) were associated with an increased risk of mortality, while adjuvant mitotane treatment (HR 0.30) and longer time to first recurrence (HR 0.93) were associated with reduced risk.
Mitotane and other steroidogenesis inhibitors
Mitotane
Mitotane (o,p′-DDD) is the sole agent that mainly targets adrenal tissue, playing a central role in ACC treatment due to its adrenolytic and anti-steroidogenic effects. It is used in the adjuvant setting for high-risk patients, as systemic therapy for metastatic disease and/or to control hormonal secretion (Allolio & Fassnacht 2006).
Mitotane in adjuvant setting
The ESE/ENSAT guidelines suggest adjuvant mitotane in patients with ACC who have undergone complete surgical resection and have a high risk of recurrence defined as Ki67 > 10%, ENSAT stage III or IV or Rx-R1 resection (Fassnacht et al. 2018). The ADIUVO trial (Terzolo et al. 2023), the first randomized study evaluating adjuvant mitotane in low- to intermediate-risk, showed no significant benefit in recurrence-free survival (RFS) or OS for patients with stage I–III ACC and Ki67 ≤ 10%. In relation to high-risk patients, Calabrese study (Calabrese et al. 2019), including 152 nonmetastatic ACC patients (100 treated with adjuvant mitotane and 52 patients were left untreated following surgery), showed a higher risk of recurrence (HR: 2.79, 95% CI: 1.58–4.91; P < 0.001) in not-treated patients compared to mitotane-treated group. In addition, they observed that adjuvant mitotane treatment reduced significantly the risk of death in patients with elevated Ki67 index (P = 0.005) and in patients with stage III ACC (P = 0.02).
In relation to the situation of adjuvant therapy with mitotane in Spain, it is worth noting the data from the ICARO-GETTHI/SEEN registry. A recent study that included 244 patients nonmetastatic, resectable ACC (TNM stages I-III) who underwent primary tumor resection, of whom 133 (52%) received adjuvant mitotane, indicates a 39% reduced recurrence risk (HR 0.61; 95% CI, 0.39–0.95) for mitotane-treated patients (Carmona-Bayonas et al. 2025). However, the effects have diminished over 24 months. Thus, the Spain data suggests that adjuvant mitotane delays recurrence, but yet questions remain as to its curative capacity.
Adjuvant mitotane is typically initiated within 6–8 weeks post-surgery, and continued long-term, often exceeding 2 years, depending on tolerance. Continuous treatment is advised until there is evidence of disease progression or unacceptable toxicity (Fassnacht et al. 2020a , 2023a ). However, some studies found that the survival curves of patients treated up to 24 months vs patients treated for a longer period, both for RFS and RFS after mitotane, did not show any significant difference (Basile et al. 2021).
Mitotane in patients with metastatic disease
For metastatic ACC, mitotane is utilized as monotherapy or in combination with chemotherapy, depending on the individual patient’s needs and treatment goals (Fassnacht et al. 2020a , 2023a ). As a single agent, it provides symptomatic relief and stabilizing disease in patients unsuitable for combination regimens particularly for those with low tumor burden and a low Ki67 index. Moreover, objective responses in patients with metastatic ACC have been described. For example, Megerle’s study including 127 patients with advanced ACC treated with mitotane monotherapy found that 26 patients (20.5%) experienced objective response, including three with complete remission (Megerle et al. 2018). When combined with chemotherapy, mitotane enhances outcomes by leveraging its adrenolytic properties alongside cytotoxic effects of chemotherapy (phase III FIRM-ACT trial) (Fassnacht et al. 2020a , 2023a ). The use of mitotane in combination with locoregional therapies is another option in low volume metastatic ACC patients. In this regard, a retrospective study of 79 patients with stage IV ACC, with two or fewer tumoral organs who received mitotane (19 in monotherapy and 60 in combination with locoregional therapies (LRT)), showed that OS was statistically longer in the mitotane plus LRT group compared to the mitotane-only group (HR 0.27; 95% CI, 0.14–0.50). In addition, ten (13%) patients achieved complete response, all from the mitotane plus LRT group (Boilève et al. 2021).
Mitotane for hormonal secretion control
Mitotane inhibits steroidogenesis by targeting enzymes such as 11β-hydroxylase, reducing cortisol production (Fassnacht et al. 2018) and alleviating symptoms of hormone excess, including hypertension, weight gain and glucose intolerance (Del Rivero et al. 2024). Moreover, a relevant effect of mitotane on hormonal control is due to the induction of cytochrome P450 3A4 (CYP3A4) and through increased levels of corticosteroid-binding globulin (CBG) (Chortis et al. 2013a ).
For mild hormone secretion, mitotane alone is generally sufficient; although its therapeutic effects typically take several weeks to become evident, severe cases may require additional measures (Fassnacht et al. 2018).
Dosing, monitoring and adverse effects
Mitotane dosing varies based on performance status and mostly on the patient’s and physician’s preferences. However, in general, high-dose regimens should be considered for robust patients and low-dose regimens for those with poorer tolerance (De Filpo et al. 2021, Fassnacht et al. 2025) (Table 3).
Dosing strategies for initiating mitotane therapy (Fassnacht et al. 2025).
| Day 1 | Day 2 | Day 3 | Day 4 | Post day 4 | |
|---|---|---|---|---|---|
| High-dose regimen | 1.5 g/day | 3.0 g/day | 4.5 g/day | 6.0 g/day | Measure blood levels in 2–3 weeks |
| Low-dose regimen | 1.0 g/day | 1.5 g/day | Continue increasing by 0.5 g/day every 3–4 days up to 3.0–4.0 g/day; adjust dose based on mitotane levels and tolerability |
Plasma levels should be maintained above 14 mg/L for efficacy, while levels above 20 mg/L should be avoided due to toxicity risks. Monitoring begins every 3–4 weeks during dose titration and is spaced to 6–12 weeks once levels stabilize (Allolio & Fassnacht 2006). Table 4 describes frequency of adverse effects with mitotane therapy and Table 5 provides some recommendations for monitoring these adverse events.
Secondary adverse effects with mitotane.
| Very common ≥1/10 patients | Common ≥1/100 to 1/10 | Rare ≥1/10,000 to <1/1,000 |
|---|---|---|
| Gastrointestinal Adrenal insufficiency Increase in hepatic enzymes Hepatic microsomal enzyme induction Increase in hormone-binding globulins disturbance of thyroid parameters hypercholesterolemia, hypertriglyceridemia Other: gynecomastia |
CNS Hematological: prolonged bleeding time Leucopenia Primary hypogonadism in men Dermatological |
Liver failure, autoimmune hepatitis Hematological: thrombocytopenia, anemia |
CNS, central nervous system.
Recommendations for monitoring adverse effects of mitotane.
| Type of adverse-effect | Potential adverse effects | Monitoring parameters | Frequency of monitoring |
|---|---|---|---|
| Gastrointestinal | Nausea, vomiting, diarrhea, anorexia | Symptoms diary, nutritional status | Weekly initially, then as needed |
| Adrenal | Adrenal insufficiency | Serum cortisol levels, ACTH levels | Every 2–4 weeks during titration |
| Central nervous system | Lethargy, somnolence, vertigo, ataxia, confusion, depression, dizziness, decreased memory | Neurological assessments, patient reports | Monthly or as symptoms arise |
| Hepatic | Increased hepatic enzymes, liver failure | Increased hepatic enzymes, liver failure | Increased hepatic enzymes, liver failure |
| Hormonal | Disturbance in thyroid parameters, increased hormone-binding globulins | Thyroid function tests, hormone levels | Every 3 months |
| Metabolic | Hypercholesterolemia, hypertriglyceridemia | Lipid panel | Every 3 months |
| Dermatological | Skin rash | Visual skin assessments | As needed, based on patient reports |
| Hematological | Leucopenia, thrombocytopenia, anemia, prolonged bleeding time | Complete blood count | Every 2–4 weeks initially, then every 3 months |
| Gynecomastia | Development of gynecomastia | Patient reports, physical examination | At each follow-up visit |
Adverse events must be carefully managed, including hydrocortisone replacement, which requires high-dose adjustments (2-3×) due to mitotane-induced cytochrome P450 3A4 activation (Kroiss et al. 2011), which accelerates hydrocortisone metabolism and increases cortisol-binding protein (CBG) levels (Chortis et al. 2013b).
Other steroidogenesis inhibitors used in ACC
Additional inhibitors, including metyrapone, osilodrostat, ketoconazole and etomidate, are used for hypercortisolism management (Supplementary Material S2) (Varlamov et al. 2021). Combination regimens or ‘block-and-replace’ approaches with hydrocortisone may be required for rapid cortisol reduction, particularly before surgery or chemotherapy or in advanced disease (Turla et al. 2022). Severe hypercortisolism requires anticoagulation and pneumocystis prophylactic antibiotics until cortisol levels are controlled (Nieman et al. 2015).
In cases of aldosterone-secreting tumors causing hypertension and hypokalemia, mineralocorticoid receptor antagonists such as spironolactone or eplerenone combined with potassium supplementation and electrolyte monitoring are mandatory.
Locoregional therapies
For unresectable or metastatic disease, LRT are recommended by international guidelines (Bechmann et al. 2020, Fassnacht et al. 2018, 2020b ). Although ACC’s rarity and aggressive nature limit large prospective studies, evidence from retrospective analyses suggests that LRT can provide tumor control, symptom relief and potentially prolonged survival (Veltri et al. 2020). Available options include percutaneous thermal ablation (PTA), bland transarterial embolization (TAE), transarterial chemoembolization (TACE), selective internal radiation therapy with yttrium-90 microspheres (SIRT) and radiotherapy (Table 6).
Comparison of TAE, TACE and SIRT in metastatic ACC.
| Aspect | TAE (transarterial embolization) | TACE (transarterial chemoembolization) | SIRT (selective internal radiation therapy) |
|---|---|---|---|
| Mechanism of action | Embolization of blood supply to tumor | Combines chemotherapy with embolization | Delivers localized radiation (yttrium-90 microspheres) |
| Procedure | Injects embolic agents to block arteries | Injects chemotherapy drugs + embolic agents | Radioactive microspheres injected into hepatic arteries |
| Primary effects | Ischemic necrosis of tumor | Cytotoxic chemotherapy + ischemic necrosis | Radiation-induced DNA damage and tumor necrosis |
| Patient selection | Suitable for patients who cannot tolerate chemo | Limited by number and size of liver lesions | Not limited by number and location of metastases |
| Procedure frequency | Repeatable if tolerated | Often requires multiple sessions | Generally one-time per liver lobe |
| Side effects | Post-embolization syndrome (pain, fever) | Post-embolization syndrome + chemo-related si adverse de effects | Transient transaminase increases, mild fatigue, nausea and pain |
| Limitations | Less effective for large hypervascular tumors | Not for large diffuse disease or vascular invasion | Requires preserved liver function |
Radiotherapy
The role of adjuvant radiotherapy in ACC remains controversial. Retrospective studies and older radiotherapy techniques contribute to the uncertainty surrounding its efficacy. However, it might benefit patients at higher risk of relapse, particularly when combined with mitotane in cases of R1 resection, uncertain margins or stage III disease (Ho et al. 2013).
A pooled analysis of four studies in the 2018 ESE/ENSAT guidelines showed mixed results (Fassnacht et al. 2018), with a HR of 0.8 (95% confidence interval (CI): 0.6–1.1) for recurrence and 1.0 (95% CI: 0.7–1.5) for mortality, highlighting the limitations of observational data (Fassnacht et al. 2006, Habra et al. 2013, Else et al. 2014, Sabolch et al. 2015).
Recent studies, such as a meta-analysis by Zhu et al. (2020), demonstrated higher OS and locoregional recurrence- and disease-free survival with radiotherapy. Khosla et al. (2023) identified capsular invasion and positive margins as independent prognostic factors, with only three of 25 experienced local relapses after adjuvant radiotherapy.
Current evidence supports radiotherapy as a safe option to reduce local relapse risk, especially in high-risk patients, although prospective trials are needed to determine its effect on OS. The recommended treatment dose is 50–60 Gy to the tumor bed, with fractionation of 2 Gy per session.
Other locoregional therapies
Image-guided PTA techniques including radiofrequency ablation (RFA), cryoablation, microwave ablation (MWA), irreversible electroporation and laser or external energy-based ablation are effective for controlling primary and metastatic lesions (liver, adrenal glands, kidneys, lungs and bones), particularly those <5 cm. A retrospective study of 66 patients with metastatic ACC reported a 20.5% complete remission rate in treated lesions, with a favorable safety profile (Kimpel et al. 2024). In the Veltri series with 32 patients with oligometastatic ACC (liver and lung metastases) who underwent image-guided ablation, complete ablation was obtained in 97% (29/30) and during follow-up, local tumor progression was registered in 7/29 cases (24.1%), with a median local tumor PFS of 21 ± 12.6 months (Veltri et al. 2020).
Liver-directed therapies, such as TAE, TACE and SIRT, offer tumor control and symptom relief in patients with liver-dominant metastatic ACC. A retrospective study of 65 patients showed significantly longer OS in those treated with TACE or SIRT compared to those without liver-directed therapy (32.4 vs 9.9 months; P = 0.011) (Owen et al. 2019).
In oligometastatic or slowly progressing ACC, combining LRT modalities can prolong time to progression (tTTP) and delay the need for systemic therapy. A study of 132 metastatic lesions found that favorable factors for prolonged tTTP included fewer prior treatments, higher mitotane plasma levels and smaller metastases (<3 cm) (Roux et al. 2022).
Further research is crucial to establish standardized LRT protocols, refine patient selection criteria and improve outcomes. Combining LRT with novel immunotherapies or targeted treatments may enhance outcomes. Personalized, multidisciplinary approaches are essential to optimize treatment decisions based on tumor location, local expertise and patient preferences.
Chemotherapy
Currently, no clinical trial evidence supports adjuvant chemotherapy for ACC in adults. A multicenter ENSAT case–control study of 299 patients with resected ACC suggested potential benefits of platinum-based adjuvant chemotherapy for OS (HR 0.25, 95% CI: 0.09–0.69; P = 0.007) and RFS (HR 0.45, 95% CI: 0.29–0.89; P = 0.021) (Kimpel et al. 2021). In contrast, a retrospective analysis of the National Cancer Database including 577 patients with localized ACC reported no survival advantage from adjuvant chemotherapy in subgroups with lymphovascular invasion, positive margins or T3 tumors (Al Asadi et al. 2021). The ongoing phase III ADIUVO2 trial (NCT03583710) is evaluating 2 years of adjuvant mitotane with or without 3 months of cisplatin and etoposide in high-risk patients (stage I–III, Ki67 > 10%) (Sarvestani et al. 2023). In pediatric ACC, the ARAR0332 study assessed 78 patients with ACC across different stages, using adrenalectomy alone for stage I, adrenalectomy with retroperitoneal lymph node dissection for stage II and mitotane with neoadjuvant chemotherapy for stages III and IV. Five-year event-free survival rates for stages I, II, III and IV were 86.2, 53.3, 81 and 7.1%, respectively, with corresponding OS rates of 95.2, 78.8, 94.7 and 15.6% (Rodriguez-Galindo et al. 2021). Notably, stage III patients who received neoadjuvant treatment demonstrated improved outcomes compared to stage II patients managed with surgery alone, although extrapolation to adults remains uncertain.
Regarding advanced disease, combined chemotherapy regimens with mitotane are more active, although no direct comparisons exist (Fig. 4). Etoposide, doxorubicin and cisplatin combined with mitotane (EDP-M) remains the standard first-line therapy, as established by the phase III FIRM-ACT trial (Fassnacht et al. 2012). This trial randomized 304 patients to EDP-M or streptozotocin-mitotane (STZ-M), with crossover to the alternative regimen upon progression. EDP-M showed superiority in overall response rate (ORR; 23.2 vs 9.2%, P < 0.001) and PFS (5.0 vs 2.1 months; HR, 0.55; 95% CI: 0.43–0.69). OS was similar between groups (14.8 vs 12.0 months; HR, 0.79; 95% CI: 0.61–1.02). In the second-line setting, both regimens produced similar results to first-line therapy, with PFS-2 of 5.6 vs 2.2 months and OS-2 of 10.3 vs 7.4 months (95% CI: 6.3–9.2), favoring EDP-M. Serious adverse events occurred in 58% of EDP-M and 41% of STZ-M group (P = 0.16). For patients unable to tolerate EDP-M, platinum-etoposide is a common alternative, which demonstrated an ORR of 11% and OS of 10 months (Williamson et al. 2000). A phase II trial evaluating cisplatin and docetaxel did not demonstrate superiority over established regimens but may be a viable option for patients unable to receive etoposide or anthracyclines (Urup et al. 2013). The trial reported an ORR of 21%, a median PFS of 3 months (95% CI: 0.7–5.3) and an OS of 12.5 months (95% CI: 6–19), with neutropenia as the most common grade 3/4 toxicity (35%). In addition, continuous infusion doxorubicin, vincristine and etoposide combined with mitotane was investigated in a single-center phase II trial in 35 patients, both as first-line and subsequent therapy (Abraham et al. 2002). This regimen yielded an ORR of 22% and OS of 13.5 months. Prognostic factors included patient performance status and tumor functionality, with functional tumors linked to poorer outcomes.
Comparison of response rates in non-randomized chemotherapy trials with and without mitotane in patients with ACC. A full color version of this figure available at https://doi.org/10.1530/ERC-25-0034.
Citation: Endocrine-Related Cancer 32, 5; 10.1530/ERC-25-0034
Gemcitabine (GEM) with metronomic 5-FU or capecitabine (CAP), combined with mitotane, was evaluated in a phase II Italian trial involving 29 patients in the second- or third-line of treatment (Sperone et al. 2010). This regimen yielded an ORR of 7%, a disease control rate (DCR) of 46.3%, PFS of 5.3 months and OS of 9.8 months, with leukopenia as the most common grade III–IV toxicity (21.4%). In addition, a larger Italian-German cohort study of 145 patients explored clinical and molecular predictors of benefit from GEM-based chemotherapy (Henning et al. 2017). Concomitant mitotane levels above 14 mg/L and GEMCAP therapy were associated with prolonged PFS, while neither line of therapy nor hENT1 or RRM1 expression showed predictive value. Cabazitaxel was examined in an Italian phase II trial of 25 patients in the second or third line after progression on platinum-based therapy, showing no tumor responses, with a PFS of 1.5 months and OS of 6 months (Laganà et al. 2022).
A single-center prospective study of irinotecan in 12 patients treated in the second line showed no objective, clinical or biochemical responses and stabilization in 25% (Baudin et al. 2002). A phase II study in 11 patients with progressive metastatic ACC evaluated cyclophosphamide, doxorubicin and cisplatin (CAP), achieving an ORR of 18.2%, DCR of 72.7% and OS of 10 months (Van Slooten & Van Oosterom 1983). The OPEC regimen (vincristine, cisplatin, teniposide and cyclophosphamide) was evaluated in 11 Swedish patients after failure of streptozocin and mitotane (Khan et al. 2004). The 2-year OS rate was 82%, with an OS of 21 months, ORR of 18% and DCR of 82%. Although the regimen showed activity, significant adverse effects required dose adjustments.
In the Cosentini study (Cosentini et al. 2019) which included 28 patients with ACC, temozolomide achieved a DCR of 35.8%, an ORR of 21.4%, a PFS of 3.5 months and an OS of 7.2 months. The study reported a higher probability of ORR in patients with methylation of O6-methylguanine-DNA methyltransferase (MGMT) gene (50%) than in the non-methylated group (14.3%).
In summary, no clinical trial evidence currently supports adjuvant chemotherapy in adults, although the ADIUVO2 trial is ongoing, and data suggests the benefit of this approach in ACC with high-risk of recurrence. For advanced unresectable disease, EDP-M remains the standard first-line therapy, despite the lack of randomized trials comparing mitotane monotherapy with mitotane plus chemotherapy. Chemotherapy achieves disease control in approximately 30–50% of cases, but benefits are short-lived (median duration ∼5 months) with a median survival of around 1 year. In later lines, the GEMCAP regimen offers a favorable safety profile, although its efficacy remains limited (Table 7).
Chemotherapy in advanced ACC (prospective studies).
| Study | Year | Phase | Regimen | Mitotane | Line | N | ORR (%) | PFS (months) | OS (months) |
|---|---|---|---|---|---|---|---|---|---|
| Van Slooten & Van Oosterom (1983) | 1983 | II | CAP | No | Any | 11 | 18 | N/A | 10 |
| Williamson et al. (2000) | 2000 | II | EP | No | 1st | 37 | 11 | N/A | 10 |
| Abraham et al. (2002) | 2002 | II | Dox, Eto, Vin | Yes | Any | 35 | 11 | N/A | 13.5 |
| Baudin et al. (2002) | 2002 | Prospective, but not clinical trial | Irinotecan | No | 2nd | 12 | 0 | N/A | N/A |
| Sperone et al. (2010) | 2010 | II | GemFU/GEMCAP | Yes | 2/3 | 28 | 7 | 5.3 | 9.8 |
| Fassnacht et al. (2012) | 2012 | III | EDP | Yes | 1st | 151 | 23.2 | 5 | 14.8 |
| 2nd | 101 | 5.6 | 10.3 | ||||||
| Sz | Yes | 1st | 153 | 9.2 | 2.1 | 12 | |||
| 2nd | 84 | 2.2 | 7.4 |
N, number of patients; ORR, objective response rate; PFS, progression-free survival; OS, overall survival; N/A, not available/not reported; CAP, cyclophosphamide, doxorubicin and cisplatin; EP, etoposide and cisplatin; Dox, doxorubicin; Eto, etoposide; Vin, vincristine; GEMFU, gemcitabine and fluorouracil; GEMCAP, gemcitabine and capecitabine; EDP-M, etoposide, doxorubicin and cisplatin with mitotane; STZ, streptozotocin.
Immunotherapy and immunocombinations
The clinical benefit of immune checkpoint inhibitors (ICIs) as second- or subsequent-line treatment in advanced ACC remains unsatisfactory (Araujo-Castro et al. 2021). A phase Ib trial with avelumab, including 50 pretreated patients (median two lines, range 1–6), showed an ORR of 6%, PFS of 2.6 months (95% CI: 1.4–4.0) and OS of 10.6 months (95% CI: 7.4–15.0), with a trend toward longer PFS in patients with PD-L1 expression (Le Tourneau et al. 2018). In a phase II U.S. study with ten patients treated with nivolumab in second or subsequent lines, PFS was 1.8 months with predictable toxicity (Carneiro et al. 2019). A phase II single-center study (Memorial Sloan Kettering Cancer Center) with pembrolizumab in 39 patients showed an ORR of 23%, DCR of 52%, PFS of 2.1 months (95% CI: 2.0–10.7) and OS of 24.9 months (4.2-not reached) (Raj et al. 2020). PD-L1 expression and MSI-H/MMR-D status did not correlate with response. Another phase II single-center study (MD Anderson Cancer Center) with pembrolizumab in 16 patients demonstrated a DCR of 36% at 27 weeks, ORR of 14% and DCR of 50% (Habra et al. 2019). Neither hormonal function, MSI status, nor PD-L1 expression predicted response. A retrospective study with 54 patients treated with ICI across six German centers between 2016 and 2022 reported an ORR of 13.5%, DCR of 24%, PFS of 3.0 months and OS of 10.4 months (Remde et al. 2023). PD-L1 expression and nivolumab treatment compared to pembrolizumab were associated with longer survival.
The combination of nivolumab and ipilimumab in advanced ACC was assessed in a phase II multicohort trial of rare genitourinary cancers in 18 patients (McGregor et al. 2021). ORR was 6% and DCR was 53.3%, with a PFS of 4.5 months (95% CI: 1.8–6.6) and a 12-month PFS rate of 43% (95% CI: 8–75%). In the phase II Australian CA209-538 trial, the combination showed an ORR of 33% and a DCR of 66% (Klein et al. 2021). The phase 1/2 Spencer trial investigated EO2401 (a cancer peptide therapeutic vaccine) combined with nivolumab in 33 patients treated in the first-line (21.2%) or subsequent lines (Baudin et al. 2022). The combination was well-tolerated. The ORR was 12%, DCR 24%, PFS 1.9 months (range 0.4–7.6) and the 6-month OS was 63%. In a post-hoc analysis, patients with clinical benefit had factors such as ECOG ≤1, diagnosis >9 months and ≤3 organs involved. In this group, the DCR was 64%, 6-month PFS 42% and 6-month OS 93%.
The combination of ICI with targeted therapy has been studied in several trials in pretreated patients. A phase II Chinese study with camrelizumab and apatinib in 21 patients showed an ORR of 52%, DCR of 95%, PFS of 12.6 months (95% CI: 8.4–20.9) and OS of 20.9 months (95% CI: 11.0–20.9) (Zhu et al. 2024). The phase II CABATEN trial, conducted by GETNE, included 24 advanced ACC patients treated with atezolizumab and cabozantinib after progression on chemotherapy and/or mitotane (Grande et al. 2024). ORR, the primary endpoint, was 8.3% (95% CI: 1–27), PFS was 2.9 months (95% CI: 2.8–5.7) and OS was 13.5 months (95% CI: 8.8–NR). Grade ≥3 adverse events occurred in 20.8% of patients, with hypertension (12.5%) and elevated transaminases (8.3%) being the most common. Despite limited activity, durable responses emphasize the need to explore predictive factors to optimize patient selection for this combination. In eight pretreated ACC patients of clinical practice, pembrolizumab and lenvatinib showed an ORR of 25%, DCR of 37.5% and PFS of 5.5 months (Bedrose et al. 2020).
A key concern in treating functional ACCs with immunotherapy is potential resistance due to excessive glucocorticoid production (Araujo-Castro et al. 2021). To address this, a phase I trial combining relacorilant with pembrolizumab is ongoing (NCT04373265). A summary of studies with immunotherapy, either as monotherapy, dual immunotherapy or combined with targeted therapy in advanced ACC, is provided in Table 8 and Fig. 5.
Trials with immunotherapy and immunocombinations (2018–2024).
| Author, year | Phase | N | Treatment | Line | ORR (%) | PFS (months) | OS (months) |
|---|---|---|---|---|---|---|---|
| Trials with immunotherapy in monotherapy | |||||||
| Le Tourneau et al. (2018) | Ib | 50 | Avelumab | 2nd | 6 | 2.6 | 10.6 |
| Carneiro et al. (2019) | II | 10 | Nivolumab | ≥2 | 10 | 1.8 | N/A |
| Habra et al. (2019) | II, 1 site | 16 | Pembrolizumab | 2nd | 14 | N/A | N/A |
| Head et al. (2019) | Retrospective | 6 | Pembrolizumab + mitotane | ≥2 | 33 | N/A | N/A |
| Raj et al. (2020) | II, 1 site | 39 | Pembrolizumab | Any | 23 | 2.1 | 24.9 |
| Remde et al. (2023) | Retrospective | 54 | ICI | ≥2 | 13.5 | 3.0 | 10.4 |
| Trials with dual immunotherapy | |||||||
| Klein et al. (2021) | II | 6 | Nivolumab + ipilimumab | Any | 33 | N/A | N/A |
| McGregor et al. (2021) | II | 18 | Nivolumab + ipilimumab | Any | 6 | 4.5 | N/A |
| Baudin et al. (2022) | I/II | 38 | EO2401 + nivolumab | Any | 12 | 1.9 | N/A |
| Trials with ICI and targeted therapy | |||||||
| Bedrose et al. (2020) | Retrospective | 8 | Pembrolizumab + lenvatinib | 2nd or 3rd | 25 | 5.5 | N/A |
| Zhu et al. (2024) | II | 21 | Camrelizumab + apatinib | ≥2 | 52 | 12.6 | 20.6 |
| Grande et al. (2024) | II | 24 | Atezolizumab + cabozantinib | ≥2 | 8.3 | 2.9 | 13.5 |
Abbreviations: ICI, immune checkpoint inhibitors; N, number of patients included; ORR, objective response rate; PFS, progression-free survival; OS, overall survival; 2nd, second; 3rd, third.
Lollipop plot of clinical trials with immunotherapy. PFS, progression-free survival; OS, overall survival. A full color version of this figure available at https://doi.org/10.1530/ERC-25-0034.
Citation: Endocrine-Related Cancer 32, 5; 10.1530/ERC-25-0034
Targeted therapies and future view
Key pathways involved in ACC pathogenesis that could be potentially targetable are in development. However, results from targeted therapies remain modest, highlighting the unmet need for novel treatments or effective drug combinations.
IGF pathway
The IGF1R pathway has been extensively studied, but clinical trials have shown limited efficacy. Linsitinib, an IGF1R and insulin receptor (IR) antagonist, demonstrated two partial responses in a phase I trial with 15 ACC patients (Lee et al. 2020). However, the phase III GALACCTIC trial comparing linsitinib to placebo in 90 patients showed no significant differences in OS or PFS in second line (Fassnacht et al. 2015). Cixutumumab, a monoclonal antibody blocking IGF1R, was investigated with temsirolimus (mTOR inhibitor) in a trial with 26 heavily pretreated patients, resulting in no PRs but stabilization of disease (SD) in 11 patients for over 6 months (Naing et al. 2013). Another trial of cixutumumab monotherapy showed no responses or stabilization (Weigel et al. 2014). A phase II trial of cixutumumab with mitotane included 20 first-line patients and reported an ORR of 5% and a PFS of 6 weeks, which is unfavorable compared to the EDP-M regimen (20 weeks) (Lerario et al. 2014). Figitumumab, another monoclonal IGF1R antibody, also yielded poor results (Haluska et al. 2010). New strategies to enhance IGF1R antibody efficacy include antibody–drug conjugates and radiolabeling with α and β emitters (Solomon et al. 2019, 2020).
mTOR inhibition represents another potential therapeutic target within the IGF1 pathway; however, few ACC patients have been included in trials, with no noted responses (Ganesan et al. 2013, Wagle et al. 2014). A preclinical study using the H295R ACC cell model found that metformin significantly reduced cell viability and proliferation in a dose- and time-dependent manner. This effect was associated with the inhibition of ERK1/2 and mTOR phosphorylation and stimulation of AMPK activity. Metformin-treated cells exhibited lower levels of anti-apoptotic proteins Bcl-2 and Bcl-w, uncleaved caspase 3 and heat shock proteins HSP27, HSP60 and HSP70. In addition, metformin interferes with the IGF2/IGF-1R autocrine loop, which supports adrenal cancer growth. However, no combinations of treatments with metformin have been tested in ACC patients.
Inhibition of peroxisome proliferator-activated receptor (PPAR)-γ, a downstream effector of the IGF1R pathway, is another potential therapeutic target for ACC. Rosiglitazone, the thiazolidinedione with the highest affinity for PPAR-γ, has been shown to induce apoptosis in ACC cell lines and xenograft models while reducing VEGF expression and the anti-apoptotic marker Bcl-2 (Betz et al. 2005, Luconi et al. 2010).
Tyrosine kinase inhibitors
EGFR is strongly expressed in 36% of ACC samples, leading to trials with anti-EGFR molecules. Gefitinib was the first EGFR inhibitor tested in ACC patients who had progressed on standard treatments, but no responses were reported (Samnotra et al. 2007). A combination of erlotinib and gemcitabine was evaluated in ten ACC patients who had undergone multiple cytotoxic therapies, revealing only one minor partial response lasting 8 months (Quinkler et al. 2008).
Derazantinib, an FGFR inhibitor, was tested in a basket phase II trial that included four ACC patients. One patient with FGFR1 amplification achieved a 20% tumor reduction, maintained for 3.5 years, while another patient with no detectable FGFR alterations had disease stabilization for over 12 months (Papadopoulos et al. 2017).
Broad-spectrum TKIs targeting VEGF receptors and other receptors have shown mixed results in ACC (Esteban-Villarrubia et al. 2020). Bevacizumab, combined with capecitabine in ten refractory ACC patients, yielded no objective responses or stabilization (Wortmann et al. 2010). Sunitinib was tried in a phase II study with 39 patients, with no observed responses and a PFS of 83 days; only five patients had disease control for at least 12 weeks (Kroiss et al. 2011, 2012). Axitinib was investigated alone in 13 patients without any responses (O’Sullivan et al. 2014). A phase II trial of dovitinib in 17 patients treated only with mitotane showed one partial response and 23% stabilization for at least 6 months, but the primary endpoint was not met (García-Donas et al. 2014). Cabozantinib was studied in a single-arm phase II trial in 18 patients with ACC, with an ORR of 11% and a PFS of 6 months (Campbell et al. 2024). The main IGF1R and TKI clinical trials are listed in Table 9.
Completed phase 2/3 trials in ACC with I IGF1R antagonist and tyrosine kinase inhibitors.
| Phase | NCT | Patients | Drugs | ORR | PFS | OS |
|---|---|---|---|---|---|---|
| III | NCT00924989 (Fassnacht et al. 2015) | 139 | Linsitinib vs placebo | 3% | 1.46 vs 1.53 m | 10.76 days vs 11.86 m |
| II | NCT00831844 (Weigel et al. 2014) | 10 | Cixutumumab | 0% | NR | NR |
| II | NCT00778817 (Naing et al. 2013) | 20 | Cixutumumab + mitotane | 5% | 1.4 m | NR |
| II | NCT00215202 (Samnotra et al. 2007) | 19 | Gefitinib | 0% | NR | NR |
| II | NCT00453895 (Kroiss et al. 2012) | 35 | Sunitinib ± mitotane | 0% | 2.76 m | 5.4 m |
| II | NCT01255137 (O’Sullivan et al. 2014) | 13 | Axitinib | 0% | 5.48 m | 13.7 m |
| II | NCT01514526 (García-Donas et al. 2014) | 17 | Dovitinib | 5% | 1.8 m | NR |
| II | NCT 03370718 (Campbell et al. 2024) | 18 | Cabozantinib | 11% | 6 m | 24 m |
Abbreviations: NCT, National Clinical Trials Number; ORR, overall response rate; PFS, progression-free survival; OS, overall survival; NR, not reported; m, months.
Future potential new targets
Some molecular pathways involved in ACC may represent potential therapeutic targets, although the low incidence and lack of general knowledge about this disease limit their development.
Inhibiting the Wnt/β-catenin pathway is a potential therapeutic target due to its role in some ACC patients. However, this pathway is ubiquitous, and its inhibition could lead to unknown adverse effects. PNU-74654 (Leal et al. 2015), rottlerin (Zhu et al. 2017), CWP291 (Lee et al. 2020), tegavivint (Cranmer et al. 2022) and porcupine inhibitors have been tested in early phase I studies, although not specifically in ACC (Koo et al. 2015).
p53/Rb pathway plays a central role in ACC pathogenesis, with frequent mutations (TP53, CDKN2A, CDK4, CDK6, MDM2 and RB1) making it a key target for ACC treatment. CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) represent potential treatments; although no ACC-specific CDK inhibitor trials exist yet. Palbociclib has shown significant cell viability reduction and cell cycle arrest in vitro, effects enhanced by combining it with linsitinib (IGF inhibitor) (Liang et al. 2020). Other p53/Rb pathway-related drugs, such as MDM2 inhibitors or mutant p53 inhibitors, are in development (Konopleva et al. 2020, Wang et al. 2023).
Another potential target of future treatments is the inhibition of delta-like noncanonical Notch ligand 1 (DLK1) that is highly expressed in ACC, and growing evidence suggest that DLK1 expression in cancer is associated with worse prognosis and that DLK1 may be a marker of cancer stem cells (Pittaway et al. 2021). An ongoing clinical trial (NCT06041516) is focused on testing the efficacy of an antibody–drug conjugate ADCT-701, which is a humanized antibody directed against DLK1.
Prognosis and follow-up
Prognosis
The prognosis for ACC is generally poor but highly heterogeneous, underscoring the need for reliable prognostic tools to guide follow-up, adjuvant treatment and patient counseling (Elhassan et al. 2021). Prognostic classifications fall into two categories: clinical and molecular.
The clinical classification is based on the TNM-ENSAT staging system, which stratifies patients by tumor extent and guides treatment decisions (Fassnacht et al. 2018). Tumor stage at diagnosis is the strongest predictor of outcome, with metastases indicating the worst prognosis. The ENSAT system relies on comprehensive preoperative imaging, systematic lymph node resection and detailed surgical and pathological reports (Fassnacht et al. 2018).
A modified ENSAT (mENSAT) stage has been proposed for advanced disease, incorporating nodal involvement (equivalent to stage IV) and the number of metastatic organs: IVa (two organs), IVb (three organs) and IVc (>3 organs) (Libé et al. 2015) (Table 10). The GRAS criteria (grade, resection status, age and secretory syndrome) provide an independent framework for predicting relapse and survival across all stages (Elhassan et al. 2021). GRAS factors include grade (Weiss >6 and/or Ki67 ≥ 20%), resection margin status (R0-R2), age (< or ≥50 years) and cortisol excess (S). Elhassan et al. (2021), introduced the S-GRAS score, which assigns points to these variables, and demonstrated superior prognostic accuracy compared to ENSAT staging and Ki67 index alone (Beuschlein et al. 2015). In a multicenter study of 942 ACC patients, 5-year survival decreased from 74% (S-GRAS score 0) to 9% (score 6).
Proposed modified ENSAT stages. Based on Fassnacht et al. (2009) and Libé et al. 2015.
| TNM | mENSAT | |
|---|---|---|
| T1: Tumor located in the adrenal gland ≤5 cm T2: tumor located in the adrenal gland >5 cm T3: tumor infiltrating adipose tissue T4: tumor invasion into adjacent organs or venous tumor thrombus in vena cava or renal vein N0: no positive lymph node N1: positive lymph node M0: no distant metastases M1: presence of distant metastases |
I II III IV |
T1 N0 M0 T2 N0 M0 T3 or T4 N0 M0 Any T, N1 M1: IVa: 2 organs IVb: 3 organs IVc: >3 organs |
T, tumor; N, lymph nodes; M, metastases; mENSAT, modified ENSAT staging.
Molecular analysis is not routinely performed but holds promise for future prognostic tools. In contrast, the S-GRAS score, already part of standard clinical evaluation for surgical patients, requires prospective validation to confirm its role in predicting recurrence and response to mitotane. Future studies should also investigate the integration of GRAS components into mENSAT classification for non-resectable ACC (Elhassan et al. 2021).
Follow-up
Surveillance strategies for ACC remain underexplored (Fassnacht et al. 2010). However, due to its high recurrence rate even after successful treatment, rigorous follow-up is necessary for detecting recurrences, metastases, endocrine dysfunction and evaluating treatment response. A comprehensive approach that includes clinical assessment, imaging and hormonal monitoring is essential (Fig. 6).
Recommendations for ACC follow-up. Based on Fassnacht et al. (2010), (2018), Gaujoux & Brennan (2012). Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; FDG PET, fluorodeoxyglucose positron-emission tomography/computed tomography.
Citation: Endocrine-Related Cancer 32, 5; 10.1530/ERC-25-0034
Postoperative follow-up typically involves regular imaging, clinical assessments and laboratory tests. The ENSAT recommends imaging studies, such as CT or MRI, to monitor local recurrence or distant metastases, particularly during the first 3–5 years post-surgery, when the risk of recurrence is highest. Imaging frequency is more intense in the first 2 years, with intervals of 3–6 months, becoming less frequent after 5 years if the patient remains disease-free (Fassnacht et al. 2018). The S-GRAS score may help determine follow-up intervals (Elhassan et al. 2021).
Special situations in patients with ACC
Pregnancy and ACC
The management of ACC during pregnancy remains challenging due to its rarity and limited evidence. Early, individualized and multidisciplinary treatment involving endocrinology, surgery, obstetrics and psychology is essential (Fassnacht et al. 2018).
A retrospective study of 110 female ACC patients showed that tumors diagnosed during pregnancy or postpartum are more likely to be hormone-secreting and advanced stages, resulting in poorer OS and higher fetal morbidity and mortality compared to non-pregnant women (Abiven-Lepage et al. 2010). ACC in pregnancy is often linked to hypercortisolism, which increases maternal and fetal risks (Puglisi et al. 2023a ) Clinical features of Cushing’s syndrome (CS) often overlap with normal pregnancy, delaying diagnosis. Reliable diagnostic indicators include a more than threefold increase in 24hUFC and elevated nighttime salivary cortisol levels (Hamblin et al. 2022, Morris et al. 2023, Stoinis et al. 2024).
Pregnancy may promote aggressive ACC independently of CS (Abiven-Lepage et al. 2010, Fassnacht et al. 2018). Molecular features, such as elevated IGF2, increased progesterone and estrogen receptor expression and low CREB expression, suggest a unique molecular pattern in pregnancy-associated ACC, although further studies are needed (Faillot & Assie 2016).
Complete tumor resection via adrenal surgery is recommended, regardless of gestational age, following confirmation by MRI. Collaboration with an obstetric team is essential due to increased risk of preterm delivery, particularly in the third trimester.
In first trimester stages III or IV, abortion may need to be discussed. Mitotane is contraindicated during pregnancy due to teratogenic and adrenolytic effects (Baszko-Błaszyk et al. 2011, Tripto-Shkolnik et al. 2013), although metyrapone and ketoconazole have been used to control cortisol secretion. Postpartum, aggressive treatment is advised, even after apparent complete surgical resection. Adjuvant mitotane should begin as soon as possible, and breastfeeding is not recommended (Abiven-Lepage et al. 2010, Fassnacht et al. 2018).
Women on mitotane require effective contraception to prevent pregnancy, as teratogenic effects persist until drug levels are undetectable, a process that may exceed 6 months. Non-estrogenic contraceptives are preferred due to ACC’s potential interaction with estrogen pathways. Pregnancy after successful ACC treatment does not appear to worsen clinical outcomes, but patients should be counseled on the significant risk of recurrence in the first few years post-diagnosis (De Corbière et al. 2015, Fassnacht et al. 2018, Szkodziak et al. 2024).
Hormone-producing ACC
ACC can lead to adrenal hormone overproduction, causing rapid and severe clinical symptoms (Table 1) (Fassnacht et al. 2018). Hormonal phenotypes include cortisol excess (CS), androgen overproduction and less commonly, mineralocorticoid or estradiol secretion. Hormonal assessment, as outlined in the diagnostic section, is critical for identifying secretory profiles and guiding management.
Up to 50–70% of ACCs are hormonally active, the most frequent cortisol. Symptoms include myopathy, hypokalemia, wasting, weight loss, hyperglycemia, osteoporosis facial plethora and edemas. Androgen secretion (20–30%) causes virilization, hirsutism, alopecia and menstrual alterations in women, while estrogen secretion (5% of males) results in painful gynecomastia and testicular atrophy. Mineralocorticoid hypersecretion, with the appearance of hypertension and hypokalemia, is rare (2–3% of ACC) and often due to precursors such as 11-deoxycorticosterone (Berruti et al. 2014, Fassnacht et al. 2018).
Despite inefficient hormone production in some ACCs, elevated metabolites, such as 5-pregnanetriol and tetrahydro-11-deoxycortisol can aid in diagnosis and monitoring. Mass spectrometry offers a promising tool for assessing recurrence and treatment response (Arlt et al. 2011, Chortis et al. 2020, Gadelha et al. 2023, Kimpel et al. 2023, Vogg et al. 2023).
Managing hormone excess requires a multidisciplinary approach tailored to the severity of and symptoms and comorbidities (Fassnacht et al. 2018). Intraoperative and postoperative glucocorticoid replacement therapy, preferably with hydrocortisone, is indicated in all patients, with evidence of possible autonomous cortisol secretion with cortisol post-dexamethasone suppression test >1.8 μg/dL (50 nmol/L). This should follow the suggestions for major stress dose replacement as per recent international guidelines (Araujo Castro et al. 2019, Castinetti et al. 2021). Postoperatively, the dose of glucocorticoid should be tapered on an individualized basis by a physician experienced.
Mitotane is effective for mild hormone excess but requires weeks to achieve therapeutic levels, necessitating faster-acting agents in severe Cushing syndrome (Supplementary Material S2) (Fassnacht et al. 2018).
-
First-line agents: metyrapone (CYP11B1 inhibitor) is well-tolerated, even with mitotane or chemotherapy. Osilodrostat inhibits cortisol and aldosterone synthesis, offering rapid control of cortisol levels with fewer androgenic adverse effects (Bonnet-Serrano et al. 2022, Detomas et al. 2022, Tabarin et al. 2022, Capatina et al. 2024).
-
Alternative therapies: ketoconazole inhibits multiple steroidogenesis steps but is less effective, interacts with mitotane (via CYP3A4/P450 induction) and has hepatotoxicity risks. Levoketoconazole and etomidate are emerging options for selected patients (Fassnacht et al. 2018, Castinetti et al. 2021, Capatina et al. 2024). Etomidate is the only intravenous treatment available for Cushing syndrome
-
Receptor antagonists: mifepristone and relacorilant (selective glucocorticoid receptor antagonist) are used in CS with increased hypertension and hypokalemia.
-
Mineralocorticoid receptor antagonists ( spironolactone and eplerenone): used for specific complications in CS, such as hypertension or hypokalemia (Fassnacht et al. 2018, Castinetti et al. 2021, Capatina et al. 2024).
Doses should be titrated to normalize hormone levels, or in the case of receptor antagonists to improved comorbidities, accepting that assessment of this can be challenging in cancer patients. Block-and-replace therapies are valuable in concomitant treatment with mitotane to avoid acute adrenal insufficiency. Hormonal substitutive therapy and evaluation of the adverse effects must be adapted considering all concomitant therapies and specific CYP-P450 interferences, action on CBG, thyroid and metabolic function (Fassnacht et al. 2018, Castinetti et al. 2021, Capatina et al. 2024).
All patients treated with enzyme inhibitors or receptor antagonists need to be educated about symptoms and signs of adrenal insufficiency (Neumann et al. 2019). All patients at risk for adrenal insufficiency need to be supplied with emergency medication and instructions (Araujo Castro et al. 2019). Glucocorticoid withdrawal syndrome should be taken in account, although diagnosis is difficult (Zhang & Ioachimescu 2024).
Prophylaxis against thromboembolism and infections (e.g., pneumocystis pneumonia) is essential in hypercortisolemic patients. Electrolyte imbalances, including hypokalemia, should be corrected with potassium supplements and monitoring at least once a week (Puglisi et al. 2018b , Fallo et al. 2022, Mehlich et al. 2023, Capatina et al. 2024).
Androgen secretion in women can affect the quality of life, leading to hirsutism and virilization. Treatment options include androgen receptor antagonists such as bicalutamide, flutamide or spironolactone (Fassnacht et al. 2018). Aldosterone-producing tumors are less frequent leading to hypertension and/or hypokalemia. High doses of mineralocorticoid receptor antagonists such as spironolactone and eplerenone are indicated (Fassnacht et al. 2018). Estradiol-producing ACC in male patients can be treated with estrogen receptor antagonists or aromatase inhibitors (Fassnacht et al. 2018).
Conclusions
ACC is a rare endocrine malignancy, with a poor overall prognosis reflected in a 5-year survival rate of approximately 35%. Surgery remains the only curative option when complete resection is feasible. For unresectable or metastatic ACC, current therapeutic standards include mitotane, chemotherapy, radiotherapy and locoregional treatments. Despite advances in understanding ACC pathogenesis, outcomes with emerging therapies, including immunotherapy, tyrosine kinase inhibitors and other targeted agents, are still modest. These findings underscore the need for more studies with innovative treatments and novel combinations of existing drugs. Effective management of ACC requires a multidisciplinary team of specialists, including endocrinologists, surgeons and/or urologists, medical and radiation oncologists, pathologists and nuclear medicine physicians. This collaborative approach is crucial to improve treatment outcomes and care for patients with ACC.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/ERC-25-0034.
Declaration of interest
MAC received speakers’ honoraria and consulting fees from Esteve and Recordati Rare Diseases. ACB received payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, educational events or participation on a data safety monitoring board or advisory board from Astellas, AstraZeneca, BMS, Lilly, MSD, Ipsen, Novartis and Esteve. PJF received honoraria for speakers' bureau participation, and serving on advisory boards from Astellas, AstraZeneca, Bristol-Myers Squibb (BMS), Esteve, Merck Sharp & Dohme (MSD), Novartis, Nutricia, Pfizer, Rovi, Takeda and Viatris and research grants from Astellas, AstraZeneca, BMS and MSD. MRF received honoraria for lectures, manuscript writings, educational events or advisory boards from Telix, Sirtex Medical , Janssen, Novartis and Astellas. FAH received honoraria for lectures and advisor board from HRA Pharma and Recordatti. JLVC received honoraria for lectures, traveling, educational events or advisory boards from Novartis, Sirtex Medical and Terumo. The authors declare no potential conflict of interest.
Funding
This work was funded by Sociedad Española de Endocrinología y Nutrición (SEEN) and the Spanish Group of Neuroendocrine and Endocrine Tumors (GETNE).
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