First-Line Cytotoxic Therapy for Advanced ACC

Systemic Therapy Backbone

First-line cytotoxic therapy for advanced adrenocortical carcinoma (ACC) refers to initial multiagent chemotherapy used for unresectable, metastatic, or rapidly progressive disease, usually in combination with mitotane.¹²³ Within ACC management, it occupies the principal systemic treatment role when surgery is not feasible or is unlikely to provide durable control. The regimen most commonly used as the reference standard is etoposide, doxorubicin, and cisplatin plus mitotane (EDP-mitotane), which serves as both the prevailing clinical backbone and the benchmark comparator for newer systemic approaches.⁴⁵

The purpose of first-line cytotoxic therapy is mainly palliative rather than curative. It may reduce tumor burden, improve cancer-related symptoms, and help control hormone-mediated morbidity in functioning tumors; in a minority of cases, treatment response may create an opportunity for subsequent surgery or other local therapy.¹⁶³⁷ Compared with mitotane alone, combination chemotherapy appears to produce faster and more frequent radiographic responses, which is clinically relevant in bulky, symptomatic, or biologically aggressive disease.⁸⁴

The evidence base is limited by the rarity of ACC. Most data derive from phase II studies, retrospective series, and reviews, with only one major randomized first-line trial directly comparing cytotoxic regimens.⁹⁴¹⁰ As a result, short-term endpoints such as objective response and progression-free survival are better supported than overall survival, optimal sequencing, or biomarker-guided patient selection. Case reports describe occasional exceptional responses, but these are not generalizable and mainly illustrate uncommon possibilities rather than expected outcomes.⁷¹¹¹²

Clinical context

Advanced ACC is clinically heterogeneous, but outcomes are generally poor once disease is metastatic or unresectable.¹⁶ Systemic therapy is therefore used to pursue overlapping goals: palliation, temporary disease control, endocrine stabilization, and, less commonly, cytoreduction before additional local treatment. What is relatively reliable is that durable complete remissions from drug therapy alone are uncommon; the practical implication is that first-line treatment is usually framed around control of disease tempo and symptoms rather than cure.⁶²

Mitotane remains central to this setting because it has both adrenolytic and steroid-lowering effects, making it relevant even when cytotoxic chemotherapy is added.¹³¹ Review-level and retrospective evidence suggests that therapeutic drug monitoring is clinically important, as higher serum levels have been associated with greater activity, although the exact magnitude and consistency of this effect are not fully established across all treatment contexts.¹³¹⁴³ In practice, mitotane is often continued alongside chemotherapy rather than viewed as a competing strategy when rapid tumor shrinkage is needed.

Against this background, first-line treatment selection usually centers on whether the patient requires intensive combination therapy for prompt cytoreduction or may reasonably begin with a less intensive mitotane-based approach because disease appears more indolent.

Major first-line approaches

EDP-mitotane

EDP-mitotane is the most established first-line cytotoxic regimen for advanced ACC.¹⁵⁴ Prospective studies and the randomized FIRM-ACT trial indicate that it can produce objective responses in a meaningful minority of patients and offers better response rates and progression-free survival than streptozotocin plus mitotane.⁸¹⁵⁴ This is the strongest direct comparative evidence available for any first-line cytotoxic strategy in ACC.

Its limits are equally important. The randomized trial did not demonstrate a clear overall survival advantage, likely influenced by crossover and the methodological constraints of rare-cancer trials, so the regimen is best regarded as improving initial disease control rather than definitively prolonging survival.⁴⁵ The practical implication is that EDP-mitotane is generally favored for fit patients when rapid tumor shrinkage or early disease stabilization is a priority.

Alternative cytotoxic regimens

Earlier platinum- and doxorubicin-based combinations established that ACC is not uniformly chemoresistant, but activity has been inconsistent and durable benefit has usually been limited.¹⁶¹⁷¹⁸ Streptozotocin plus mitotane remains the best-known alternative because it was tested in the randomized setting, but comparative data suggest it is less active than EDP-mitotane for response and progression control.⁴⁵

Evidence supporting nonstandard combinations is much weaker. Isolated reports of marked benefit with other regimens, including platinum-taxane therapy, mainly show that rare outlier responses can occur rather than supporting routine first-line substitution.¹⁹ Clinically, deviation from EDP-based treatment is usually driven by contraindications, tolerability concerns, or individual patient factors rather than equivalent efficacy data.

Mitotane monotherapy in selected patients

Mitotane alone remains a first-line option for some patients with lower-volume, slower-growing, or less symptomatic disease, and for those who are poor candidates for combination chemotherapy.¹³⁶³ Available evidence suggests lower response rates and a slower onset of antitumor effect than with multiagent cytotoxic therapy.¹⁷⁶ This makes mitotane monotherapy less suitable when immediate disease control is needed, but still reasonable in selected indolent presentations where treatment burden is a major concern.

Outcomes and patterns of benefit

Across prospective and retrospective series, first-line cytotoxic therapy can induce objective responses in a minority of patients, but median progression-free and overall survival remain limited.¹⁵⁴¹⁰ The most consistent finding is that EDP-mitotane improves the probability of radiographic response and delays progression relative to older comparators.⁸⁴ Contemporary retrospective data broadly resemble the prospective experience, which supports the reality of this effect even though overall outcomes remain modest.¹⁰

What remains unreliable is prediction of who will obtain prolonged benefit. Reviews consistently note the absence of validated predictive biomarkers, and available subgroup observations are not strong enough to guide confident regimen selection.⁶¹⁴² Functioning tumors and endocrine complications may affect prognosis and treatment tolerance, but current evidence does not define a clearly chemotherapy-sensitive phenotype.¹⁰²⁰

Occasional reports describe conversion to resection, pathologic complete response, or unusually prolonged disease control after first-line therapy.⁷¹² These outcomes are best interpreted as uncommon exceptions rather than representative expectations for most patients.

Toxicity and treatment selection

The greater cytoreductive activity of combination chemotherapy is balanced by substantial toxicity. Common adverse effects include myelosuppression, infection risk, fatigue, gastrointestinal toxicity, and cumulative anthracycline- and platinum-related harms; serious events and rare treatment-related death have been reported in prospective studies.¹⁸¹⁵⁴ These risks are well supported by the evidence and directly shape regimen choice, dose intensity, and patient selection.

Mitotane contributes a separate toxicity burden that may include gastrointestinal symptoms, neurocognitive effects, metabolic abnormalities, and adrenal insufficiency.¹³⁸¹⁰ Hormone excess from the tumor itself, especially hypercortisolism, may further complicate chemotherapy delivery and supportive care.¹⁰³ The practical implication is that first-line EDP-mitotane is usually reserved for patients with adequate performance status and access to close oncologic and endocrine co-management.

This toxicity profile also explains why mitotane alone, treatment modification, or less intensive approaches may still be chosen in selected patients despite the stronger efficacy signal for EDP-mitotane.

Role in current management and research

In contemporary ACC care, first-line cytotoxic therapy is mainly used for patients with metastatic or unresectable disease who are fit for combination treatment and require prompt control of tumor burden or hormone-related symptoms.⁶² Relative to surgery, its role is usually noncurative; relative to mitotane monotherapy, it offers greater expected antitumor activity at the cost of higher toxicity.⁷³

In research, EDP-mitotane remains the established systemic backbone against which newer strategies are measured.⁵²³ What is reliable is that it is the best-supported first-line comparator in advanced ACC; what remains unresolved is how to personalize its use, identify predictive markers, and improve outcomes after progression.¹⁴² Further advances will likely depend on multicenter collaboration and trial designs that address both tumor control and endocrine disease burden.

Included Articles

• PMID 1494808: This case report describes two young women with metastatic or recurrent functioning ACC who achieved partial remissions on etoposide, adriamycin, and cisplatin chemotherapy, including one prolonged response beyond 21 months. The authors also report that combining EAP with ongoing mitotane appeared feasible with mainly moderate toxicity.²¹

• PMID 9233519: This review describes mitotane as first-line therapy for incompletely resected or metastatic ACC, emphasizing serum level monitoring because concentrations above 14 mg/L were associated with higher response rates and longer survival. It also summarizes cisplatin-based regimens, with cisplatin plus etoposide presented as a reference combination despite substantial toxicity and limited durable responses.¹³

• PMID 9716042: A small clinical trial in advanced ACC evaluated etoposide plus cisplatin given every 4 weeks, with mitotane continued in most patients. The regimen produced a 33% overall response rate with non-life-threatening toxicity, including responses in some patients progressing despite effective-dose mitotane.¹⁶

• PMID 9827725: This multicenter Phase II trial in advanced, inoperable ACC found that etoposide, doxorubicin, and cisplatin combined with continuous mitotane produced objective responses in 53.5% of patients, with a 24.4-month time to progression among responders. Treatment was generally manageable, though mitotane added neurologic, gastrointestinal, and lipid abnormalities and often required dose reduction.⁸

• PMID 10699907: A phase II SWOG trial in locally advanced or metastatic ACC found cisplatin plus etoposide had limited activity, with an 11% objective response rate and median survival of 10 months. Among 16 mitotane-naive patients treated with mitotane after progression, the objective response rate was 13%, supporting the need for more effective systemic strategies.¹⁷

• PMID 11572034: This review summarizes early systemic treatment experience in advanced ACC, emphasizing mitotane for unresectable disease, the need for serum level monitoring, and the limited efficacy of most single-agent chemotherapy. Among combination regimens, etoposide, doxorubicin, cisplatin plus mitotane showed the highest reported response rate, though evidence remained retrospective and toxicities were substantial.⁹

• PMID 12015757: In metastatic ACC, a phase II regimen of continuous-infusion doxorubicin, vincristine, and etoposide plus daily mitotane produced objective responses in 22% of evaluable patients, with substantial neutropenia and frequent mitotane-related gastrointestinal and neuropsychiatric toxicity. The study concluded that benefit over single-agent mitotane remained uncertain.¹⁸

• PMID 16172198: This prospective phase II trial in advanced, unresectable ACC found that etoposide, doxorubicin, and cisplatin plus mitotane produced an objective response rate of 48.6%, with leukopenia as the dose-limiting toxicity and one treatment-related septic death. Median time to progression among responders was 18 months.¹⁵

• PMID 16840836: This case report describes metastatic, androgen-secreting ACC initially considered unresectable that showed complete radiographic regression of lung metastases, hormonal normalization, and pathologic complete response in the adrenal primary after etoposide, doxorubicin, cisplatin plus mitotane, followed by surgery and prolonged disease-free survival.⁷

• PMID 19153517: This review describes mitotane as the recommended first-line medical treatment for advanced ACC when complete resection is not feasible or disease recurs, notes its steroid-lowering and adrenolytic effects, and summarizes the historical chemotherapy backbone of EDP-mitotane or streptozotocin-mitotane with limited survival benefit.¹

• PMID 22551107: In a randomized phase 3 trial of advanced ACC, first-line etoposide, doxorubicin, cisplatin plus mitotane produced higher objective response rates and longer progression-free survival than streptozocin plus mitotane, without a significant overall survival difference and with similar serious adverse event rates.⁴

• PMID 22614717: A commentary on the FIRM-ACT randomized trial reports that etoposide, doxorubicin, cisplatin, and mitotane improved objective response rate and progression-free survival versus streptozocin plus mitotane in advanced ACC, with similar adverse-event rates. Despite no significant overall survival advantage, the article states EDP-mitotane should be considered the standard first-line cytotoxic regimen and benchmark for future therapies.⁵

• PMID 28723406: This review frames mitotane and etoposide, doxorubicin, cisplatin plus mitotane as the only systemic treatments with demonstrated efficacy in advanced ACC, highlighting FIRM-ACT evidence favoring EDP-mitotane over streptozotocin-mitotane for response and progression-free survival. It also notes mitotane monotherapy as a possible option for more indolent disease and emphasizes the need for predictive markers.⁶

• PMID 28777782: This review and case report emphasizes that no approved standard exists after progression on first-line chemotherapy plus mitotane in metastatic ACC. It supports EDP-mitotane as the main first-line reference regimen, notes the uncertain benefit of later-line chemotherapy, and highlights therapeutic mitotane levels as a possible prognostic factor.¹⁴

• PMID 29903850: This case report describes recurrent, inoperable metastatic ACC with bilateral adrenal, liver, lung, and abdominal wall involvement achieving rapid symptomatic improvement and radiologic partial response after three cycles of etoposide, doxorubicin, cisplatin, plus mitotane. The report also frames EDP-mitotane as the standard regimen for advanced or metastatic ACC.¹¹

• PMID 34468885: This single-institution retrospective series of 17 Japanese patients with metastatic ACC found first-line EDP-mitotane produced median progression-free survival of 6.2 months and overall survival of 15.4 months, broadly similar to FIRM-ACT. Toxicity included frequent treatment-limiting adrenal insufficiency and complications related to hypercortisolism, highlighting the need for endocrine co-management during therapy.¹⁰

• PMID 35748231: This case report describes recurrent metastatic ACC after complete resection and adjuvant mitotane, with prolonged disease control after 15 courses of EDP plus mitotane and no new lesions at reporting. It also notes EDP-mitotane as the current standard systemic regimen for metastatic ACC, while emphasizing limited evidence for postoperative recurrent disease.¹²

• PMID 35795129: A case of mitotane-refractory metastatic ACC reported marked response to paclitaxel and carboplatin plus mitotane, with complete remission of liver metastases after three cycles, subsequent resection of the primary tumor, and 20-year survival. The report highlights this regimen as a rare salvage chemotherapy experience outside standard first-line EDP-mitotane.¹⁹

• PMID 37760461: In metastatic or unresectable ACC with low performance status, adding megestrol acetate to first-line EDP-mitotane was reported as feasible, with similar progression-free and overall survival to matched EDP-mitotane controls despite poorer baseline performance status. Megestrol caused additional toxicities including vaginal bleeding, weight gain, and occasional thromboembolic or metabolic events.²²

• PMID 38381366: This review summarizes systemic treatment for advanced ACC, identifying EDP plus mitotane as the current first-line standard based on improved response rate and progression-free survival in FIRM-ACT, while emphasizing the limited evidence and modest activity of mitotane monotherapy and later-line cytotoxic options.²

• PMID 39066856: This 2024 review summarizes systemic treatment for advanced ACC, emphasizing EDP plus mitotane as the evidence-supported first-line standard for metastatic or unresectable disease, while noting mitotane level-response relationships and the limited activity of most later-line cytotoxic regimens.³

• PMID 39550299: This corrigendum to a population-based metastatic ACC study reports corrected counts for hormone-producing tumors and shows that, in patients diagnosed from 2014 onward, hormone production was associated with a median overall survival of 8 months versus 12 months for nonfunctioning tumors, with no significant univariate survival difference.²⁰

References

Footnotes

1. Adrenocortical cancer treatment.. Horm Res. 2009. PMID: 19153517. Local full text: 19153517.md ↩ ↩² ↩³ ↩⁴ ↩⁵

2. Current Status and Future Direction in the Treatment of Advanced Adrenocortical Carcinoma.. Curr Oncol Rep. 2024. PMID: 38381366. Local full text: 38381366.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷

3. Systemic Management of Advanced Adrenocortical Carcinoma.. Curr Treat Options Oncol. 2024. PMID: 39066856. Local full text: 39066856.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸

4. Combination chemotherapy in advanced adrenocortical carcinoma.. N Engl J Med. 2012. PMID: 22551107. Local full text: 22551107.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹

5. Adrenal gland: adrenocortical carcinoma-first RCT.. Nat Rev Endocrinol. 2012. PMID: 22614717. Local full text: 22614717.md ↩ ↩² ↩³ ↩⁴ ↩⁵

6. Systemic Therapy in Locally Advanced or Metastatic Adrenal Cancers: A Critical Appraisal and Clinical Trial Update.. Eur Urol Focus. 2016. PMID: 28723406. Local full text: 28723406.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸

7. Long-term disease free survival in a patient with metastatic adreno-cortical carcinoma after complete pathological response to chemotherapy plus mitotane.. J Endocrinol Invest. 2006. PMID: 16840836. Local full text: 16840836.md ↩ ↩² ↩³ ↩⁴ ↩⁵

8. Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group for the Study of Adrenal Cancer.. Cancer. 1998. PMID: 9827725. Local full text: 9827725.md ↩ ↩² ↩³ ↩⁴ ↩⁵

9. Cytotoxic treatment of adrenocortical carcinoma.. World J Surg. 2001. PMID: 11572034. Local full text: 11572034.md ↩ ↩²

10. Clinical management and outcomes associated with etoposide, doxorubicin, and cisplatin plus mitotane treatment in metastatic adrenocortical carcinoma: a single institute experience.. Int J Clin Oncol. 2021. PMID: 34468885. Local full text: 34468885.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷

11. Long-term survival in recurrent adrenocortical cancer.. BMJ Support Palliat Care. 2019. PMID: 29903850. Local full text: 29903850.md ↩ ↩²

12. [A Case Report of a Patient with Metastatic Adrenocortical Carcinoma who Received the Combination Etoposide, Doxorubicin, Cisplatin, and Mitotane Therapy and Achieved Remission].. Hinyokika Kiyo. 2022. PMID: 35748231. Local full text: 35748231.md ↩ ↩² ↩³

13. Adrenocortical carcinoma.. Ann Oncol. 1997. PMID: 9233519. Local full text: 9233519.md ↩ ↩² ↩³ ↩⁴ ↩⁵

14. [Palliative chemotherapy in metastatic adrenal carcinoma beyond the first line: a case report and literature review].. Medwave. 2017. PMID: 28777782. Local full text: 28777782.md ↩ ↩² ↩³ ↩⁴

15. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial.. Endocr Relat Cancer. 2005. PMID: 16172198. Local full text: 16172198.md ↩ ↩² ↩³ ↩⁴ ↩⁵

16. Cytotoxic therapy with etoposide and cisplatin in advanced adrenocortical carcinoma.. Br J Cancer. 1998. PMID: 9716042. Local full text: 9716042.md ↩ ↩²

17. Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma: a Southwest Oncology Group Study.. Cancer. 2000. PMID: 10699907. Local full text: 10699907.md ↩ ↩² ↩³

18. A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycoprotein antagonist.. Cancer. 2002. PMID: 12015757. Local full text: 12015757.md ↩ ↩² ↩³

19. Long-term survival of a patient with refractory advanced adrenocortical carcinoma after combination chemotherapy with paclitaxel and carboplatin plus mitotane.. IJU Case Rep. 2022. PMID: 35795129. Local full text: 35795129.md ↩ ↩²

20. Corrigendum to “Impact of EDP-M on survival of patients with metastatic adrenocortical carcinoma: A population-based study” [Eur J Cancer 196 (2024) 113424].. Eur J Cancer. 2024. PMID: 39550299. Local full text: 39550299.md ↩ ↩²

21. Favorable response of metastatic adrenocortical carcinoma to etoposide, adriamycin and cisplatin (EAP) chemotherapy. Report of two cases.. Tumori. 1992. PMID: 1494808. Local full text: 1494808.md ↩

22. Feasibility and Activity of Megestrol Acetate in Addition to Etoposide, Doxorubicin, Cisplatin, and Mitotane as First-Line Therapy in Patients with Metastatic/Unresectable Adrenocortical Carcinoma with Low Performance Status.. Cancers (Basel). 2023. PMID: 37760461. Local full text: 37760461.md ↩