6 Emerging treatment options for adrenocortical URRENT PINION carcinoma
Olga Papalou, Stylianos Tsagarakis and Dimitra Argyro Vassiliadi
Purpose of review
Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options and poor prognosis. This review highlights recent advances in risk stratification, systemic therapies, surgical approaches and personalized treatment strategies to improve outcomes in ACC.
Recent findings
Significant progress has been made in molecular characterization of ACC, enabling more precise risk stratification and prognostication. Novel biomarkers and integrated scoring systems now complement traditional staging methods. Therapeutic advances include refinements in surgical approaches for both localized and metastatic disease, while systemic treatment options are expanding beyond traditional mitotane-based regimens. Immunotherapy and targeted agents show emerging promise, particularly in molecularly selected patients. The role of adjuvant therapy continues to evolve, with recent evidence supporting more selective application based on individual risk assessment. Multimodal strategies combining locoregional and systemic therapies are demonstrating improved outcomes in advanced disease.
Summary
The ACC treatment landscape is undergoing significant transformation, moving toward personalized approaches guided by molecular profiling and risk-adapted strategies. While challenges remain in overcoming treatment resistance and validating new biomarkers, the integration of advanced diagnostics with innovative therapies offers hope for improved patient outcomes. Future progress will depend on collaborative research efforts and the development of robust clinical trials.
Keywords
adrenocortical carcinoma, multimodal treatment, precision medicine, risk stratification, targeted therapy
INTRODUCTION
Adrenocortical cancer (ACC) is a rare malignancy originating in the adrenal cortex with an estimated incidence of approximately one to two cases per million people per year [1]. It has a slight female predominance and follows a bimodal age distribu- tion, peaking in childhood and again between ages 40 and 50 years [2]. ACC has long been recognized as a highly aggressive cancer with poor prognosis - marked by high rates of recurrence and progression. Nearly one-third of patients present with distant metastases at diagnosis [3,4]. However, more inci- dental cases are detected, leading to earlier diagnosis and the potential for more effective intervention [5]. While surgical resection remains the cornerstone of curative therapy, particularly for early-stage disease, the role of adjuvant mitotane - long considered standard practice - has been questioned following recent evidence showing limited benefit in low-risk patients [6”]. For high-risk or advanced cases, mito- tane with or without chemotherapy remains the standard-of-care, yet response rates are low, and
long-term outcomes remain poor [7]. These thera- peutic limitations, combined with the unpredictable clinical course of ACC, underscore the urgent need for robust prognostic markers and individualized treatment strategies. This review explores emerging approaches, including advancements in risk-adapted therapy, systemic treatments, loco-regional interven- tions, and individualized care models.
RISK STRATIFICATION
Traditionally, several staging systems have been employed to predict prognosis. The ENSAT and the recently introduced modified ENSAT (mENSAT) that
Department of Endocrinology, Diabetes and Metabolism, European Reference Network on Rare Endocrine Conditions (ENDO-ERN), Evangelismos Hospital, Athens, Greece
Correspondence to Stylianos Tsagarakis, 22A Vas. Sofias Avenue, Athens, Greece. Tel: +30 21 0770 3201; e-mail: stsagara@otenet.gr
Curr Opin Endocrinol Diabetes Obes 2025, 32:201-209 DOI:10.1097/MED.0000000000000921
KEY POINTS
· Advances in molecular profiling are enabling precision risk stratification and personalized treatment approaches for ACC.
· Emerging systemic therapies, including immunotherapy combinations and targeted agents, show promise beyond traditional mitotane-based regimens.
· Surgical innovations and cytoreductive strategies are expanding treatment options for both localized and metastatic disease.
· Multimodal integration of locoregional and systemic therapies demonstrates improved outcomes in advanced ACC.
· Artificial intelligence-powered tools and novel biomarkers are refining prognostic accuracy and therapeutic decision-making.
incorporates nodal status and metastatic burden [8], as well as the AJCC (2017) [9], are widely used. However, they do not perfectly discriminate prog- nosis - some stage IV patients survive long-term, while aggressive disease can occur in stage I-II. Other markers, such as Ki67, have shown independ- ent prognostic value. Efforts to integrate Ki67, sur- gical and clinical parameters led to the development of the S-GRAS (Grading, Resection status, Age, and Symptoms) score [8], which demonstrated superior prognostic accuracy in stratifying patients [10]. A similar score, using age, stage, resection status, and Ki67, for pediatric ACC (pediatric S- GRAS-ps-SGRAS), was recently validated in a fairly large pediatric cohort and was found to strongly predict survival [11”]. Despite these advances, clin- ical and histological features still miss ~25% of out- come predictions [12].
To bridge this prognostic gap, molecular and genetic profiles have been increasingly explored. Initial pan-genomic investigations identified two main transcriptomic subtypes: C1A, associated with poor prognosis, and C1B, associated with more favor- able outcomes [13]. Building upon these findings, Zheng et al. [14] expanded the list of driver genes and described three distinct molecular subgroups, each linked to unique clinical behaviors. More recently, a transcriptomic analysis identified 45 genes associ- ated with poor survival, uncovering previously unrecognized interactions with key oncogenic regu- lators, including POLD1, AURKA, KIF23, and notably, TP53 - the most frequently mutated gene in ACC germline cases [15”]. Based on these studies, four major molecular clusters have been delineated:
Wnt/ß-catenin signaling pathway (e.g. CTNNB1 mutations, ZNRF3 deletions), p53/Rb1 cell cycle reg- ulation pathway (e.g. TP53, RB1, MDM2, and CDK4 alterations), chromosomal maintenance and chro- matin remodeling pathway (e.g. ATRX, DAXX, and MEN1 mutations), mismatch repair (MMR) pathway (e.g. MLH1, MSH2, and MSH6 mutations) [16]. In addition to genetic alterations, epigenetic modifica- tions have emerged as crucial prognostic markers. A CpG island methylator phenotype (CIMP), charac- terized by widespread hypermethylation, is associ- ated with aggressive disease. Hypermethylation of GOS2 and, more recently, PAX5 has also been corre- lated with worse clinical outcomes [17].
Efforts to translate these molecular insights into routine clinical practice have shown promise. Tar- geted next-generation sequencing (NGS) and pyro- sequencing, applicable to formalin-fixed, paraffin- embedded (FFPE) samples, have identified both known and novel recurrent mutations (e.g. NOTCH1, CIC, KDM6A, and BRCA1/2) [18]. Integrating molec- ular alterations with clinical and pathological data has led to the development of the COMBI score, which provides robust predictions of progression- free survival (PFS) and overall survival (OS). Targeted biomarker analyses, including gene expression profiling (e.g. BUB1B and PINK1) and methylation signatures (e.g. PAX5, GSTP1, PYCARD, and PAX6), have further refined prognostic models, especially in early-stage (I-III) ACC [19]. However, their prognos- tic utility is more limited in stage IV disease. Impor- tantly, combining the S-GRAS score with two critical molecular markers - alterations in Wnt/ß-catenin and p53/Rb pathways, and PAX5 hypermethylation - provides the best discriminatory performance to stratify patients by risk of early recurrence, PFS, and OS [20]. Based on these findings, the ENSAT group has proposed an updated S-GRAS system incorporat- ing molecular high-risk markers to better identify aggressive ACC subtypes [20].
Recent advances in artificial intelligence and machine learning offer additional opportunities for individualized risk prediction. Kong et al. [21] devel- oped a pathomic-based nomogram that integrates histopathological features with clinical variables, enhancing the precision of survival prediction and supporting personalized treatment planning. Simi- larly, Saygili et al. developed a machine learning model using the published S-GRAS dataset, resulting in a publicly available web-based tool for individu- alized risk prediction of mortality and disease pro- gression (https://acc-survival.streamlit.app) [22]. These emerging methodologies are anticipated to complement molecular and clinical risk models, pro- viding more accurate and personalized prognostica- tion for patients with ACC.
ADJUVANT THERAPY
Mitotane, an adrenolytic agent specifically targeting adrenal cortical cells, has long been the cornerstone of adjuvant therapy in ACC. Nonetheless, the recently completed ADIUVO trial, a prospective, multicenter, randomized study, challenged this para- digm. In patients with low-risk features - defined as a Ki67 proliferation index less than 10% and R0 (com- plete) surgical resection - the trial demonstrated no statistically significant improvement in PFS or OS for patients treated with mitotane compared to those who underwent simple observation. These findings have led to a pivotal change in clinical practice: routine adjuvant mitotane is no longer recom- mended for patients with low-risk disease character- istics. Instead, a surveillance strategy with close clinical and radiological follow-up is now considered appropriate for this subset of patients. Conversely, for patients with higher risk features - including stage III disease, R1 resection (microscopic residual disease), vascular invasion, or a Ki67 index greater than 10% - adjuvant mitotane therapy remains a strongly recommended standard of care. Current guidelines advocate for mitotane treatment for a minimum of 2 years, with the possibility of extend- ing therapy to up to 5 years in patients deemed at exceptionally high risk for recurrence. Long-term mitotane administration requires careful monitoring for therapeutic plasma levels and management of associated toxicities.
The role of adjuvant chemotherapy in ACC, particularly the use of platinum-based regimens (e.g. cisplatin or carboplatin combined with etopo- side and/or doxorubicin), remains an area of active investigation. Retrospective studies have suggested that patients with very high-risk disease, especially those with Ki67 indices exceeding 30% or with other aggressive pathological features, may obtain addi- tional benefit from systemic chemotherapy in con- junction with mitotane. However, these findings are largely based on retrospective series with inherent biases. Thus, no definitive consensus has been reached regarding the routine use of adjuvant che- motherapy in ACC. The ongoing ADIUVO-2 trial seeks to address this important clinical question by comparing outcomes of mitotane alone versus mito- tane combined with platinum-based chemotherapy in high-risk patients. Results from this pivotal study are eagerly anticipated by the end of 2025 and are expected to significantly transform future treatment algorithms.
The utility of adjuvant radiotherapy in ACC remains a topic of debate. Historically, the role of postoperative radiotherapy was controversial, largely due to the rarity of the disease, the absence of randomized controlled trials, and the conflicting
results from retrospective studies. However, a recent retrospective analysis involving 105 patients has provided compelling evidence supporting the bene- fit of adjuvant radiotherapy. This study demon- strated a significant improvement in both OS and disease-free survival (DFS) for patients who received postoperative radiotherapy compared to those who underwent surgery alone. Despite these promising results, prospective validation remains necessary to establish adjuvant radiotherapy as a standard of care. At present, adjuvant radiotherapy is primarily con- sidered for patients with specific indications, includ- ing: incomplete R1 or R2 resections, presence of local residual disease, cases of surgical resection for local recurrence and, patients at high risk for locoregional recurrence in the absence of distant metastases. Mod- ern radiotherapy techniques, including intensity- modulated radiation therapy (IMRT) and image- guided radiation therapy (IGRT), may further enhance treatment precision and minimize toxicity, potentially increasing the role of radiotherapy in future multidisciplinary management of ACC.
SYSTEMIC THERAPIES
Surgical resection remains the cornerstone of treat- ment for adrenocortical carcinoma (ACC), but its curative potential is often limited. Even in patients with localized disease, recurrence is common - reach- ing rates as high as 85% in advanced stages - while many others present de novo with inoperable or metastatic disease. Historically, systemic therapies have offered only modest benefit. Mitotane, either as monotherapy or in combination with chemother- apy (most commonly the EDP regimen: etoposide, doxorubicin, cisplatin), remains the standard of care [7,23,24]. However, its efficacy is limited [objective response rate (ORR) ~23%], and its use is complicated by high toxicity, a narrow therapeutic window, and significant interpatient pharmacokinetic variability. Alternative cytotoxic agents such as streptozocin, gemcitabine, capecitabine, and temozolomide have shown limited effectiveness, typically achieving transient disease stabilization rather than durable responses [25].
Given the highly vascular nature of ACC, angio- genesis inhibitors have garnered interest. Tumors often exhibit upregulation of VEGF and its receptors, prompting the investigation of tyrosine kinase inhib- itors (TKIs) and multitargeted kinase inhibitors (MTKIs) that block VEGFRs and related pathways. Unfortunately, agents such as sunitinib [26] and axitinib [27] have shown only modest benefit in phase II studies, with median PFS ranging from 2 to 6 months. Combination of paclitaxel and sorafe- nib [28] was inefficient as second-third-line
treatment in a small cohort. A key challenge is mito- tane-induced CYP3A4 upregulation, which acceler- ates the metabolism of TKIs and reduces systemic drug exposure. To mitigate this, concurrent mitotane is often avoided in TKI-based regimens. Among emerging therapies, has shown a 14% objective response rate (ORR) and a 57% disease control rate (DCR), while cabozantinib [29”] demonstrated mod- est efficacy with 72.2% of patients remaining pro- gression-free at 4 months, and the median PFS was 6 months.
A small salvage therapy study evaluated lenvati- nib [30], a multikinase inhibitor targeting VEGF, fibroblast growth factor (FGF), and rearranged during transfection (RET), in seven patients with advanced ACC. Two patients achieved partial responses, result- ing in a disease control rate of 57% and a median PFS of 6months. In a small cohort of 10 ACC patients treated with bevacizumab plus capecitabine, no objective responses or disease stabilization were observed, with a median survival of just 124 days and poor tolerability in some cases [31].
Therapies aimed at the IGF2/IGF1R axis emerged from the observation that IGF2 is overexpressed in approximately 90% of ACCs. Despite promising
preclinical data, clinical trials with IGF1R inhibitors like cixutumumab and linsitinib have failed to dem- onstrate survival benefit [32-34]. These disappoint- ing outcomes are likely due to the absence of molecular preselection and the intrinsic heterogene- ity of ACC.
Immunotherapy, while transformative in several solid tumors, has thus far produced limited success in ACC. A rationale for immune checkpoint inhibition was initially based on the presence of mismatch repair deficiency (dMMR) in a subset of cases and its emerging recognition as a Lynch syndrome-asso- ciated cancer [35]. Yet these subtypes account for less than 5% of all ACC cases. Early-phase trials evaluat- ing immune checkpoint inhibitors (ICIs) such as nivolumab, pembrolizumab, and avelumab in meta- static ACC report overall response rates in the range of 13-23%, Although only a minority of patients responded, those who did often experienced durable clinical benefit lasting for years (Fig. 1) [36"",37]. In a phase II trial by Habra et al. [38], pembrolizumab achieved an ORR of 14% in ACC patients, including those with cortisol-producing tumors - despite the known immunosuppressive effects of glucocorti- coids. A larger study of 39 patients [37] reported a
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23% ORR and a 52% DCR, but with a short median PFS of 2.1 months. Similarly, nivolumab [39] and avelumab [40] demonstrated minimal activity in small cohorts, with median OS values of 10-25 months depending on the study. Combination immunotherapy appears more promising. In the CA209-538 trial, ipilimumab plus nivolumab was given to six patients with advanced ACC [41]; two achieved partial responses (both MSI-high) lasting over 10 and 25 months, and two more had stable disease, yielding a DCR of 66%. A retrospective study combining pembrolizumab with lenvatinib [42] showed encouraging results in heavily pretreated patients, including some previously resistant to both TKIs and ICIs. The ORR was 25%, with a median PFS of 5.5 months, suggesting potential synergy.
Several challenges temper enthusiasm for immu- notherapy in ACC. Biomarkers such as PD-L1 expres- sion, tumor mutational burden (TMB), and MSI status have yielded inconsistent predictive value [37,43]. Moreover, around 60% of ACCs produce glucocorticoids, which suppress immune responses and likely contribute to immune evasion. These findings have fueled interest in strategies to convert immunologically ‘cold’ tumors into ‘hot’ ones. Com- binations with radiotherapy (e.g. HDR brachyther- apy), TKIs, or steroidogenesis inhibitors are under investigation. The SPENCER trial evaluated EO2401, a microbiome-derived peptide vaccine, in combina- tion with nivolumab for advanced adrenal malignan- cies, including ACC. While objective responses were limited, the treatment was well tolerated in most patients, with some ACC cases achieving disease control beyond 6 months [44]. Meanwhile, innova- tive modalities such as CAR-T-cell therapy are being explored. ROR1 is a promising target for CAR-T therapy in ACC due to its marked overexpression and its induction by autocrine glucocorticoid signal- ing. However, glucocorticoids produced by the tumor suppress immune responses and impair CAR-T-cell efficacy. A recent study addressed this by using genetically engineered CAR-T cells lacking the glucocorticoid receptor, which resisted glucocor- ticoid-mediated suppression and conferred complete remission of glucocorticoid-producing ACC xeno- grafts in vivo[45]. Although this study has not under- gone scientific peer review, its inclusion here is primarily due to the novel insights it offers into emerging therapeutic strategies.
In parallel, peptide receptor radionuclide therapy (PRRT) has shown some promise. Treatment with Iodine-131 Iodometomidate (131I-MTO) led to one partial response and stable disease in five of 11 patients [46]. A study using Yttrium-90/177 Lu-DOTA- TOC in 19 patients with somatostatin-expressing tumors reported radiometabolic uptake in eight
cases, with two patients achieving prolonged disease control [47].
Genomic studies have identified frequent alter- ations in chromatin remodeling genes (e.g. ATRX, DAXX, MEN1) and epigenetic regulators, sparking interest in histone deacetylase (HDAC) inhibitors [48] and DNA methyltransferase inhibitors [49]. These agents may reactivate silenced tumor suppressor genes or sensitize tumors to conventional therapies. Likewise, a synergistic combination of MELK and CDK inhibitors significantly reduced tumor growth and invasiveness in ACC preclinical models [50].
These approaches are largely investigational but hold promise, particularly in molecularly selected patients or in combination regimens. In this context, mitotane may have additional value - not only through its adrenolytic effect but also as a potential synergistic partner that enhances the cytotoxicity of various agents, particularly in tumors with high steroidogenic activity.
EMERGING SURGICAL PARADIGMS AND MULTIMODAL INTEGRATION IN ADRENOCORTICAL CARCINOMAS
Minimally invasive and robotic-assisted adrenalectomy
Complete resection (R0) remains essential for long- term survival in ACC. Although open adrenalectomy has been the traditional standard, recent evidence supports minimally invasive adrenalectomy (MIA) in select cases, provided oncologic principles are strictly followed [7,51”]. A meta-analysis of 1617 patients showed similar survival and complication rates between open and laparoscopic approaches, though open surgery yielded fewer positive margins [52]. Con- version from laparoscopic to open surgery (required in ~20% of cases) is linked to worse outcomes, emphasiz- ing the importance of proper patient selection [53]. MIA is recommended only for small, noninvasive tumors (<6cm) in high-volume centers [54]. Robotic-assisted adrenalectomy may offer advantages over laparoscopy, including lower conversion and mar- gin positivity rates, making it a promising [54].
Cytoreductive surgery in locally advanced and metastatic adrenocortical carcinomas
Cytoreductive surgery is increasingly recognized as a valuable option for select patients with advanced ACC, offering both symptomatic relief and potential survival benefits. Recent retrospective studies demon- strate improved outcomes when surgical resection is integrated into multimodal treatment plans. More specifically, analysis of 543 patients in the SEER
database revealed adrenalectomy conferred a 10- month median survival advantage overall, extending to 23 months for patients with isolated lung metasta- ses. The benefit was most pronounced when com- bined with systemic therapy, showing a hazard ratio of 0.49) and in those with lung-only solitary meta- stasis [55”]. Multicenter studies further support this approach, with one demonstrating 26.3 months median survival for patients undergoing combined primary tumor resection and metastasectomy com- pared to 5.2months for nonsurgical management [56]. The A5 (American-Australian-Asian Adrenal Alliance) consortium data on 325 metastatic ACC patients showed cytoreduction doubled median sur- vival from 9.0 to 25.2 months, particularly benefiting those with limited metastatic burden [57]. Overall, optimal candidates typically exhibit good perform- ance status, oligometastatic disease (especially pulmo- nary-only metastases), and responsiveness to systemic therapy. Additionally, cytoreduction appears partic- ularly valuable for hormone-secreting tumors where symptom control is needed. Prospective studies are needed to better define selection criteria and quantify benefits, but existing evidence supports judicious use of surgical cytoreduction in appropriately selected cases. The strongest outcomes occur when complete resection is achieved and combined with systemic treatment modalities.
Integration of neoadjuvant and adjuvant therapies
Neoadjuvant chemotherapy is under investigation for locally advanced or borderline resectable ACC. A recent study conducted at a high-volume reference center in Italy reported partial radiological response in 50% of patients treated with EDP-M, with half achieving disease-free status postsurgery. However, only 7% showed a pathological complete response. Patients who underwent resection had better sur- vival outcomes [58], though selection bias limits generalizability. Similar results have been observed in earlier studies [59,60], but prospective, multicen- ter trials are needed for validation.
The role of adjuvant therapeutic strategies in ACC and in particular mitotane, due to its high propensity for recurrence, is more established and reflects the prevailing clinical practice across most expert centers [7,51”]. While adjuvant mitotane remains standard for most patients with completely resected ACC, the ADIUVO trial demonstrated active surveillance may be appropriate for low-risk cases (stage I-II, Ki-67 ≤10%), with both groups showing 75% 5-year recurrence-free survival [54]. For high- risk patients, the ongoing ADIUVO-2 trial is evaluat- ing mitotane combined with cisplatin/etoposide, as
current evidence for adjuvant chemotherapy remains limited to small studies. Finally, given the high incidence of local recurrence in patients with ACC, adjuvant radiotherapy has also been integrated in therapeutic protocols, particularly after R1/R2 resection or after local recurrence surgery. Literature suggest that this approach is effective in reducing the risk of local recurrence. However, only a limited number of these studies have reported a statistically significant improvement in recurrence-free survival (RFS) and overall survival (OS), and the evidence remains largely retrospective and heterogeneous, warranting further prospective validation [61"",62].
Local and regional therapies
Locoregional therapies play an important role in managing advanced ACC, offering both palliative benefits and local tumor control, particularly for oligometastatic disease [7,51”]. Radiofrequency abla- tion (RFA) and cryoablation demonstrate high rates of complete tumor destruction (61% in some series) with minimal toxicity, making them valuable for limited metastases in liver, lung, or bone [63,64]. Data on transarterial embolization (TAE) and trans- arterial chemoembolization (TACE) in patients with advanced ACC are very limited and mainly deriving from retrospective studies. Based on the largest cohort of patients (n=29) treated with TACE for advanced ACC by Cazejust et al. TACE shows modest efficacy (30% partial response), with better outcomes in smaller lesions (<3 cm) [63,65]. Finally, selective internal radiation therapy (SIRT) may offer promis- ing therapeutic outcomes in carefully selected patients, achieving prolonged PFS. However, data are limited and primarily based on case reports or small case series [66,67].
COMBINATION THERAPIES AND CLINICAL TRIALS
Despite therapeutic advances, response remains poor for patients who present with or develop metastatic ACC, with over half progressing within 6 months of first-line therapy - highlighting the urgent need for more effective treatment strategies. Combination therapies - particularly those pairing ICIs with tar- geted agents - have shown promise in improving outcomes. For instance, camrelizumab plus apatinib yielded a 52% response rate and a median PFS of 13.3 months. Though overall response to combined administration of ipilimumab and nivolumab was modest (13%), some patients had durable benefits. Combining systemic therapies with locoregional treatments like surgery or SBRT has also extended PFS to about 15 months in oligometastatic cases.
| Standard of care | Available nonstandard options for advanced disease | Investigational therapies |
|---|---|---|
| Resectable disease: | ||
| Surgery (aim for R0) | Targeted therapies: | Hormonal modulators: |
| + | Tyrosine kinase inhibitors (cabozantinib, | Relacorilant (GR antagonist) |
| Adjuvant mitotane | lenvatinib, apatinib) | Combination strategies: |
| or | Antiangiogenic agents (Bevacizumab - limited | Pembrolizumab + Lenvatinib |
| Surveillance (low-risk; ADIUVO trial) | efficacy) | Camrelizumab + Apatinib |
| or | Checkpoint Inhibitors: | ICIs + radiotherapy/TKI/Relacorilant |
| Adjuvant radiotherapy (R1/R2, recurrence) | Pembrolizumab, Nivolumab, Ipilimumab | Cancer vaccines: |
| Advanced/metastatic disease: | Durable response in select cases | EO2401 + nivolumab (SPENCER trial) |
| Mitotane | IGF-1R Inhibitors: | CAR-T Therapy: |
| or | Cixutumumab, Linsitinib (limited benefit) | ROR 1-targeted CAR-T |
| Mitotane+chemotherapy | Cytoreductive surgery | GC-resistant CAR-T (preclinical success) |
| EDP | May improve survival and symptom control in selected patients with good performance | Cell cycle/chromatin targeting: "MELK + CDK Inhibitors HDAC and DNA methylation inhibitors Machine learning algorithms # |
| streptozocin, gemcitabine, capecitabine, | ||
| temozolomide | status and limited metastatic burden Locoregional therapies: Radiofrequency ablation (RFA) | |
| Cryoablation TACE/SIRT (liver metastases) | more accurate and personalized prognostication and individualized treatment plans |
GC, glucocorticoid.
Managing hormone excess, especially hypercortiso- lism, may enhance immunotherapy efficacy, as tested in trials combining relacorilant with pembro- lizumab. Emerging agents such as cixutumumab, an IGF-1R inhibitor, and temsirolimus, an mTOR inhib- itor, and others are under investigation. Ongoing trials will clarify the role of these combinations in improving ACC outcomes.
PERSONALIZED MULTI-TASKED APPROACH
Given the profound heterogeneity and aggressive course of ACC, a personalized multitask approach is essential. This strategy should integrate validated clin- ical risk stratification tools (e.g. S-GRAS) with molecular profiling-such as mutations in Wnt/ß-catenin and p53 pathways, and epigenetic alterations like PAX5 hyper- methylation - to refine prognostic accuracy and guide therapeutic decisions. Treatment should be adapted based on individual tumor biology, disease burden, and functional status. For localized disease, a tailored combination of surgery (preferably R0 resection), adju- vant therapy (e.g. mitotane or radiotherapy based on resection margins and Ki67 index), and surveillance is key. In advanced or metastatic settings, systemic thera- pies should be dynamically adjusted to incorporate mitotane, cytotoxic chemotherapy, or novel agents like multikinase inhibitors or ICIs, depending on tumor molecular profile and treatment response. Emerging tools such as machine learning-based nomograms and individualized survival prediction platforms further
enable a data-driven, patient-centric approach, enhancing the precision of therapeutic selection. Ultimately, successful management requires seamless integration of surgical, systemic, and locoregional modalities, coordinated through high-volume, multi- disciplinary centers equipped to interpret complex molecular data and clinical dynamics (Table 1).
CONCLUSION
Despite recent advances, ACC remains a clinical chal- lenge marked by biological complexity and limited treatment responsiveness. Integrating molecular risk markers, refined surgical approaches, and evolving systemic strategies - alongside AI-supported prognos- tication - has the potential to transform management from a one-size-fits-all model into a truly individual- ized, multimodal paradigm. As prospective validation of emerging tools and therapies advances, a precision oncology framework rooted in molecular insight and multidisciplinary care will be critical to improving outcomes for patients with ACC.
Acknowledgements
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Conflicts of interest
There are no conflicts of interest.
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