Trial Design Priorities in ACC

Clinical Trials and Evidence Gaps

Trial design priorities in adrenocortical carcinoma (ACC) refer to methodological choices intended to produce interpretable evidence in a rare, biologically heterogeneous endocrine malignancy. Within ACC research, these priorities span metastatic systemic therapy, postoperative and adjuvant treatment, surgery-related questions, radiotherapy, and translational biomarker development.¹² Because ACC is uncommon and often presents with advanced or recurrent disease, trial results are especially vulnerable to distortion by selection bias, variable tumor tempo, and inconsistent prior treatment exposure.¹³

The current evidence base is limited and uneven. Prospective studies are few, randomized trials are rare, and many published datasets are small single-arm cohorts or retrospective analyses that mix clinically distinct populations.⁴³ This makes it difficult to separate treatment effect from prognosis, particularly when studies include both indolent and rapidly progressive disease or combine first-line and salvage settings.¹⁵

Across treatment settings, a recurring finding is that many investigated therapies yield low response rates and short progression-free intervals, so endpoint choice and population definition strongly influence whether a study is clinically informative.⁶⁷ At the same time, radiographic response alone may not capture all clinically relevant outcomes in ACC, where endocrine manifestations, resection status, and recurrence risk may substantially affect management and prognosis.⁸⁹ The literature therefore generally supports tighter eligibility criteria, disease-specific outcome measures, and stronger biologic annotation than would typically be required in more common solid tumors.¹²

Diagnostic and methodological context

ACC poses several challenges for conventional oncology trial design because prognostic heterogeneity is substantial even within the same nominal disease category. Stage, completeness of resection, Ki-67 and other markers of proliferation, hormone secretion, prior mitotane or chemotherapy exposure, and baseline growth rate may all influence outcome and apparent treatment benefit.¹⁵ When these factors are not accounted for, uncontrolled efficacy signals may reflect underlying biology rather than drug activity.

This problem is most apparent in small phase II and salvage studies, where stable disease can be difficult to interpret without proof of recent progression before enrollment.¹⁰¹¹ Retrospective and exploratory studies are useful for identifying recurring design flaws and generating hypotheses, but they are less reliable for estimating comparative benefit. In practice, advanced-disease trials are more informative when they require measurable progressive disease and distinguish first-line from later-line populations.³⁷

These background issues shape the main design priorities discussed below, particularly population selection, endpoint choice, and biomarker strategy.

Key design priorities

Population selection and stratification

Clear definition of the study population is a central requirement in ACC trials. In metastatic disease, interpretability improves when studies specify prior systemic therapy exposure, mitotane use, performance status, and whether disease is both measurable and progressing at baseline.⁸³ In the postoperative setting, enrichment for patients at high risk of recurrence, including use of Ki-67-based criteria, may improve feasibility and increase the likelihood that a treatment effect can be detected.⁵

Stratification is also important for features that may influence both prognosis and treatment delivery, such as hormone excess, tumor burden, and prior therapies.¹² The general principle is well supported, but the precise set of mandatory stratifiers remains incompletely standardized. Clinically, broad mixed-population studies may consume scarce patient numbers without clarifying which subgroup, if any, benefits.

Endpoints and benchmarks

Endpoint selection is especially important because absolute gains in metastatic ACC are often small. A meta-analysis of prospective metastatic trials reported a pooled objective response rate of 9.0%, median progression-free survival of 2.6 months, and median overall survival of 9.9 months, providing contemporary benchmarks for future studies.⁷ Earlier prospective experiences with nonstandard cytotoxic regimens likewise showed low response rates and short disease control, supporting caution in interpreting uncontrolled activity claims.¹²⁶

In metastatic disease, progression-free survival may be more informative than response rate alone when tumor shrinkage is uncommon, whereas overall survival is often confounded by subsequent therapies and small sample sizes.⁶⁷ In adjuvant studies, recurrence-free or disease-free survival is generally more practical than overall survival, although long follow-up and baseline prognostic imbalance remain major limitations.⁴⁵ Endocrine outcomes may be clinically relevant in functioning tumors, but available evidence suggests that biochemical control should complement rather than replace standard oncologic endpoints.¹³ The most reliable approach is therefore predefined efficacy thresholds with consistent imaging and transparent reporting of duration of benefit, rather than reliance on isolated stable disease or exceptional response narratives.

Biomarkers and biologic enrichment

Biomarker integration is repeatedly identified as a major unmet need in ACC trial design. Targeted therapies have often been evaluated without validated predictive markers, and early biologic rationale, including interest in IGF signaling, has not translated into durable benefit in unselected populations.¹⁴¹ Uncertainty around mitotane further illustrates this problem, as questions remain about which patients benefit, how resistance develops, and how toxicity and drug interactions influence outcome assessment.⁸

The need for biomarker-guided development is a robust conclusion, but currently available predictive tools remain weak. Exceptional responder reports may generate useful hypotheses, yet they do not establish general efficacy or a dependable enrichment strategy.¹¹ In addition, some molecular prognostic claims may be unreliable unless independently reproduced, as highlighted by a recent retraction involving an ACC gene-signature report.¹⁵ The practical implication is that future trials may benefit from mandatory biospecimen collection, standardized molecular annotation, and prospective correlation of biomarkers with response and resistance.²

Evidence across treatment settings

The consequences of these design issues differ by clinical setting. In metastatic systemic therapy, the dominant pattern is modest activity across prospective studies, with targeted approaches generally underperforming in unselected populations.³⁷ This makes randomized designs, progression-based eligibility, and explicit comparison against historical benchmarks particularly important. Small single-arm studies and case reports may identify signals worth testing, but they are not reliable for changing routine care.¹⁰¹¹

In postoperative management, rarity is compounded by long recurrence timelines and substantial heterogeneity after resection. Reviews consistently describe unresolved questions regarding adjuvant mitotane, chemotherapy intensification for high-risk disease, and the role of adjuvant radiotherapy.¹⁴ Current efforts to restrict adjuvant trials to higher-risk populations, such as those with Ki-67 greater than 10%, reflect a move toward more explicit risk enrichment.⁵ Here, randomization and careful baseline stratification are more reliable than single-arm postoperative series because prognosis varies widely even after apparently curative surgery.

For local-regional and surgery-related questions, the main limitation is confounding by case selection and institutional expertise. This is evident in debates around prophylactic lymph node dissection and in the sparse literature on local ablation, where feasibility may be shown but oncologic benefit remains uncertain.⁹¹⁶ In these settings, prospective registries or pragmatic multicenter studies may be more feasible than conventional randomized trials, although causal inference will remain limited.

Limitations and implications for research

The main methodological risks in ACC research are false-positive conclusions from underpowered uncontrolled studies and false-negative conclusions from biologically unselected populations.⁸³ Variable concomitant mitotane exposure, inconsistent eligibility criteria, and treatment toxicity that may be substantial relative to benefit further complicate interpretation.¹³² These constraints are consistently recognized across reviews and evidence syntheses, even when precise treatment estimates remain uncertain.

Taken together, the literature supports an ACC trial strategy centered on international collaboration, harmonized eligibility criteria, benchmark-based endpoint selection, and prospective biologic sampling.¹⁷ Compared with routine clinical decision-making, this framework is less about endorsing a specific therapy than about making future evidence interpretable. In ACC, where patient numbers are limited and standard therapies often provide narrow margins of benefit, trial design itself is a major determinant of whether research can meaningfully inform care.³²

Included Articles

• PMID 7955436: A multicenter series of nine patients with metastatic ACC found that suramin produced transient partial responses or short-term disease stabilization in some patients, but efficacy depended on maintaining serum levels near 200 to 250 mg/l and did not reliably reduce steroid excess. Serious toxicity was frequent, including coagulopathy, thrombocytopenia, neuropathy, allergic reactions, and possible treatment-related deaths, supporting the authors’ conclusion that suramin should not be first-line and that controlled prospective trials were urgently needed.¹³

• PMID 12419755: In a single-center prospective study of 12 patients with progressive metastatic ACC treated with irinotecan, no objective responses were observed and only three brief stabilizations occurred, with occasional significant toxicity. The findings argue against a major role for CPT-11 in ACC and highlight the need to test other systemic agents in this rare disease.¹²

• PMID 22415797: This review identifies adrenocortical carcinoma as one of the tumor types with early signals of potential interest for IGF-1R–targeted therapy, while emphasizing that larger clinical development of IGF-1R inhibitors was broadly disappointing and lacked validated predictive biomarkers or clear resistance mechanisms.¹⁴

• PMID 22522572: A small exploratory clinical series suggests that metronomic oral etoposide or cyclophosphamide may occasionally produce durable partial responses in heavily pretreated metastatic ACC, particularly in selected patients with indolent, hormone-secreting tumors. The authors emphasize that additional chemotherapy lines should not be routinely recommended outside prospective clinical trials.¹⁰

• PMID 22920388: This editorial argues that mitotane should not be used broadly in ACC simply because it is approved, citing limited overall survival benefit, toxicity, uncertain mechanisms, and CYP3A4-mediated drug interactions highlighted after FIRM-ACT. It emphasizes the need for predictive markers of response and resistance and for development of new, biomarker-informed treatment strategies.⁸

• PMID 23652308: A prospective phase II trial in advanced ACC found that first-line docetaxel plus cisplatin produced a 21% response rate, median progression-free survival of 3 months, and median overall survival of 12.5 months, with neutropenia as the main grade 3/4 toxicity. The regimen did not meet its prespecified efficacy target and was not recommended, underscoring the difficulty of improving systemic therapy in this rare disease.⁶

• PMID 24821394: A pediatric systematic review identified only two adrenocortical carcinoma cases among 28 children treated with local ablation, within a small heterogeneous literature of primary, recurrent, and metastatic tumors. The review concluded that ablation appears feasible and promising in selected pediatric malignancies, but efficacy remains unestablished and requires large multicenter prospective trials.¹⁶

• PMID 26728470: This review emphasizes that ACC therapeutic progress depends on multinational collaborative trials because available evidence is limited and many targeted approaches have shown little benefit. It highlights unresolved questions in adjuvant mitotane use, the uncertain survival impact of adjuvant radiotherapy, and the need for biomarker-guided trial design.¹

• PMID 28277340: This review emphasizes that ACC management is constrained by limited prospective evidence, with unresolved questions around routine adjuvant mitotane, radiotherapy, and chemotherapy after surgery. It also highlights the modest efficacy of current systemic regimens and the need for multicenter trials to test targeted and immunotherapy strategies.⁴

• PMID 33967965: This case report describes an exceptional prolonged response to second-line temozolomide in metastatic ACC after progression on EDP-mitotane, with complete remission of lung metastases and progression-free survival beyond 14 months. It highlights the absence of validated predictive biomarkers, as MGMT and progesterone receptor testing were unavailable and broad NGS was non-informative.¹¹

• PMID 34893201: This commentary argues that prophylactic locoregional lymph node dissection in ACC remains insufficiently defined, with major methodological limitations in existing studies regarding adequacy of node retrieval, nodal stations, and interpretation of nodal disease. It concludes that prospective studies are needed before routine prophylactic lymphadenectomy can be recommended.⁹

• PMID 36305989: This letter outlines a recruiting phase III trial testing adjuvant mitotane alone versus mitotane plus cisplatin and etoposide after resection of stage I-III ACC at high risk of recurrence, defined by Ki-67 greater than 10%. It highlights the lack of prospective evidence guiding postoperative systemic therapy in this setting.⁵

• PMID 36376169: This systematic review of prospective systemic-therapy trials in ACC found only 24 studies, including one adjuvant randomized trial and very few phase III data overall. Evidence remains limited by small, nonrandomized cohorts, with modest activity for immunotherapy and targeted agents and a need for international multicenter collaboration.³

• PMID 40343066: This editorial frames advanced ACC as a rare disease with slow therapeutic progress due to limited patient numbers, late-stage presentation, and modest activity of current standard systemic therapy. It highlights unresolved questions across targeted therapy, immunotherapy, mitotane toxicity monitoring, and adjuvant radiotherapy, emphasizing the need for prospective studies and continued trial-oriented research.²

• PMID 40937275: This meta-analysis of 24 prospective trials in metastatic ACC establishes contemporary systemic-therapy benchmarks, with pooled objective response rate 9.0%, median progression-free survival 2.6 months, and median overall survival 9.9 months. Targeted therapies performed worst, underscoring limited actionable biomarkers and the need for future trials to exceed these benchmarks.⁷

• PMID 38550181: A 2024 retraction notice reported that an ACC necroptosis-associated gene-signature study was withdrawn because of multiple indicators of publication-process manipulation and unreliable content. In this note, it supports caution toward unvalidated biomarker claims used for prognosis or therapeutic efficacy prediction in ACC research.¹⁵

References

Footnotes

1. 5th International ACC Symposium: Future and Current Therapeutic Trials in Adrenocortical Carcinoma.. Horm Cancer. 2016. PMID: 26728470. Local full text: 26728470.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰

2. Editorial: Adrenocortical carcinoma: advancing treatment beyond surgery for a rare disease.. Front Endocrinol (Lausanne). 2025. PMID: 40343066. Local full text: 40343066.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷

3. A Systematic Review of Published Clinical Trials in the Systemic Treatment of Adrenocortical Carcinoma: An Initiative Led on Behalf of the Global Society of Rare Genitourinary Tumors.. Clin Genitourin Cancer. 2023. PMID: 36376169. Local full text: 36376169.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸

4. Update on adrenocortical carcinoma management and future directions.. Curr Opin Endocrinol Diabetes Obes. 2017. PMID: 28277340. Local full text: 28277340.md ↩ ↩² ↩³ ↩⁴

5. Mitotane With or Without Cisplatin and Etoposide for Patients with a High Risk of Recurrence in Stages 1-3 Adrenocortical Cancer After Surgery.. Ann Surg Oncol. 2023. PMID: 36305989. Local full text: 36305989.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

6. Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma, a phase II study.. Br J Cancer. 2013. PMID: 23652308. Local full text: 23652308.md ↩ ↩² ↩³ ↩⁴

7. Efficacy of systemic therapy in metastatic adrenocortical carcinoma: a meta-analysis of prospective clinical trials.. Endocr Oncol. 2025. PMID: 40937275. Local full text: 40937275.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷

8. A fly in the ointment: reassessing mitotane’s role in the treatment of adrenocortical carcinoma.. Pharmacogenomics. 2012. PMID: 22920388. Local full text: 22920388.md ↩ ↩² ↩³ ↩⁴ ↩⁵

9. Commentary: Locoregional metastasis of adrenocortical carcinoma and lymphadenectomy - Disease clearance or identification of high-risk features?. Am J Surg. 2022. PMID: 34893201. Local full text: 34893201.md ↩ ↩² ↩³

10. Metronomic chemotherapy may be active in heavily pre-treated patients with metastatic adreno-cortical carcinoma.. J Endocrinol Invest. 2013. PMID: 22522572. Local full text: 22522572.md ↩ ↩² ↩³

11. Case Report: Exceptional Response to Second Line Temozolomide Therapy in a Patient With Metastatic Adrenocortical Carcinoma.. Front Endocrinol (Lausanne). 2021. PMID: 33967965. Local full text: 33967965.md ↩ ↩² ↩³ ↩⁴

12. Use of a topoisomerase I inhibitor (irinotecan, CPT-11) in metastatic adrenocortical carcinoma.. Ann Oncol. 2002. PMID: 12419755. Local full text: 12419755.md ↩ ↩²

13. Suramin in adrenocortical cancer: limited efficacy and serious toxicity.. Clin Endocrinol (Oxf). 1994. PMID: 7955436. Local full text: 7955436.md ↩ ↩² ↩³

14. Clinical development of insulin-like growth factor receptor—1 (IGF-1R) inhibitors: at the crossroad?. Invest New Drugs. 2012. PMID: 22415797. Local full text: 22415797.md ↩ ↩²

15. Retracted: Prognosis and Therapeutic Efficacy Prediction of Adrenocortical Carcinoma Based on a Necroptosis-Associated Gene Signature.. Biomed Res Int. 2024. PMID: 38550181. Local full text: 38550181.md ↩ ↩²

16. Systematic review of ablation techniques for the treatment of malignant or aggressive benign lesions in children.. Pediatr Radiol. 2014. PMID: 24821394. Local full text: 24821394.md ↩ ↩²