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Postoperative Mitotane in ACC

Adjuvant Therapy

Postoperative mitotane in adrenocortical carcinoma (ACC) is adjuvant systemic therapy given after macroscopically complete resection to reduce the risk of recurrence in a malignancy with frequent relapse despite apparently curative surgery.12 Within ACC care, it remains the principal established postoperative medical option and is considered alongside surveillance, selective adjuvant radiotherapy for local-control indications, and more limited use of postoperative cytotoxic chemotherapy in very high-risk settings.345

Mitotane’s postoperative role is derived from its adrenolytic activity and its established use in advanced ACC, but the evidence supporting adjuvant treatment is substantially less definitive than its longstanding clinical adoption might imply.67 Most data come from retrospective single-center or multicenter cohorts that are vulnerable to confounding by indication, differences in surgical quality, heterogeneous pathologic risk definitions, and inconsistent drug exposure.8910 Across studies, the most reproducible signal is improved recurrence-free survival in selected patients, whereas overall survival benefit is less consistent.111213

Recent randomized evidence has narrowed the population in whom routine postoperative mitotane appears justified. In low-risk localized ACC after complete resection, the ADIUVO trial did not show a clear recurrence-free or overall survival advantage over surveillance, supporting observation as a reasonable standard in that setting.1415 Current practice has therefore shifted toward risk-adapted selection, with mitotane used mainly for patients with moderate- or high-risk features rather than universally after surgery.1617

Treatment burden is central to this balance. Adjuvant mitotane usually requires prolonged administration, therapeutic drug monitoring, glucocorticoid replacement, and management of frequent gastrointestinal, neurologic, endocrine, hepatic, and metabolic toxicities.181920 The practical implication is that any expected oncologic benefit must be weighed against substantial toxicity and monitoring demands, especially when baseline recurrence risk is low or uncertain.1521

Diagnostic and therapeutic context

Recurrence after resection is common in ACC, including after R0 surgery, which has made adjuvant strategies a persistent focus of postoperative management.222 Mitotane has remained the main systemic adjuvant option largely because no alternative has accumulated stronger postoperative evidence, not because benefit has been definitively established across all resected patients.34

In practice, decisions about adjuvant mitotane are made within a broader framework that includes centralized pathology review, recurrence-risk estimation, and structured surveillance.1623 Retrospective data also suggest that referral-center expertise and completeness of initial surgery may strongly influence outcomes and may partly explain apparent treatment benefit in some series.9 What is relatively reliable is that mitotane should be interpreted in the context of overall care quality; what is less reliable is any simple treated-versus-untreated comparison that does not account for these factors.

This context leads directly to patient selection, which now dominates contemporary postoperative management.

Risk stratification and patient selection

Risk-adapted use is the dominant theme in modern reviews, consensus statements, and guideline-oriented publications.16424 Features commonly associated with greater recurrence risk include stage III disease, positive or indeterminate margins, elevated Ki-67, large tumor burden, vascular or capsular invasion, and cortisol secretion.25226 These factors are used to identify patients in whom the potential benefit of postoperative systemic therapy may justify its toxicity and monitoring requirements.

By contrast, low-risk disease—typically stage I–II, R0 resection, and Ki-67 of 10% or lower—appears less likely to benefit from routine adjuvant mitotane.1627 The ADIUVO randomized trial provides the clearest evidence in this area and supports surveillance alone as an appropriate standard for selected low-risk patients.1415 This is one of the more reliable conclusions in the literature, although it applies primarily to lower-risk localized ACC rather than to all postoperative settings.

Intermediate-risk disease remains less clearly defined and is the area with the greatest practice variation.2829 Available evidence suggests mitotane may be considered, but the magnitude of benefit is uncertain and no single threshold fully captures recurrence risk. The practical implication is that treatment decisions often depend on combined interpretation of pathology, biologic risk markers, patient comorbidity, and center experience rather than on a universally validated algorithm.

Evidence for efficacy

Overall, the literature suggests a stronger effect on recurrence control than on survival. Several retrospective cohorts and pooled analyses have associated adjuvant mitotane with longer recurrence-free survival after complete resection.1111230 Some analyses also suggest improved overall survival, but this finding is less reproducible and may be concentrated in higher-risk subgroups rather than in unselected populations.3113

Neutral and negative studies are also part of the evidence base and define its limits.323334 Their presence reinforces the possibility that observed benefit in favorable series reflects both drug effect and patient selection, especially where treated patients differ in tumor biology, operative management, or specialist follow-up.3529 A relatively reliable conclusion is that adjuvant mitotane may delay recurrence in some patients; a less reliable conclusion is that it consistently improves cure fraction or long-term overall survival across all resected ACC.

More recent registry modeling further suggests that part of the observed benefit may represent recurrence delay rather than definitive eradication of micrometastatic disease.36 Clinically, this distinction matters because recurrence postponement may still be worthwhile in higher-risk disease, but it affects counseling, endpoint interpretation, and expectations about duration of benefit.

Because benefit appears closely linked to treatment intensity and patient selection, delivery of therapy is an important part of the evidence.

Treatment delivery and monitoring

Adjuvant mitotane is generally started after postoperative recovery and continued for a prolonged interval, often about 2 years, although the optimal duration has not been established in comparative trials.3738 Observational data do not clearly support extending treatment beyond 24 months in patients who remain disease-free, particularly in lower- to moderate-risk groups.38 The practical implication is that duration remains based more on convention and retrospective experience than on definitive evidence.

Therapeutic drug monitoring is a defining feature of treatment. Retrospective studies suggest that achieving plasma concentrations in the commonly used 14–20 mg/L range, and spending more time within that range, may be associated with better recurrence outcomes.392340 However, the dose-concentration relationship is variable, subtherapeutic levels are common, and not all patients can safely sustain target exposure.1910 What is reasonably reliable is that inadequate exposure may reduce effectiveness; what remains uncertain is the extent to which concentration targets themselves explain outcome differences independent of patient and tumor factors.

Mitotane also accelerates steroid metabolism and commonly produces adrenal insufficiency, making hormone replacement and biochemical surveillance routine components of care rather than optional adjuncts.1820 This requirement distinguishes adjuvant mitotane from surveillance-only strategies and increases the importance of experienced multidisciplinary follow-up.

Toxicity and practical limitations

Toxicity is frequent and often treatment-limiting. Observational series and randomized data describe common gastrointestinal, neurologic, endocrine, hepatic, and metabolic adverse effects, with adrenal insufficiency expected during effective treatment and treatment discontinuation required in a subset of patients.1420 Dyslipidemia is also increasingly recognized as clinically relevant and may require active monitoring and management.4142 Rare severe reactions, including hypersensitivity syndromes such as DRESS, have been reported but are documented mainly through case-level evidence.43

These adverse effects are a reliable concern because they recur across study designs.1420 By contrast, precise estimates of comparative quality-of-life impact are less reliable because most studies were not designed around patient-reported outcomes. The practical consequence is that toxicity burden becomes a major determinant of shared decision-making, particularly when expected oncologic benefit is modest.

Role relative to other adjuvant strategies

This risk-based perspective helps place mitotane among other postoperative options. Compared with adjuvant radiotherapy, mitotane is intended to address systemic recurrence risk, whereas radiotherapy is generally reserved for selected local-control indications such as positive or close margins or other locally high-risk features.4445 Retrospective data suggest combined approaches may improve some recurrence outcomes in selected patients, but survival effects remain uncertain and selection bias is substantial.4647

Compared with adjuvant cytotoxic chemotherapy, mitotane has broader historical acceptance and stronger incorporation into guideline-based postoperative care.485 Platinum-based combinations may be considered in very high-risk disease or research settings, but evidence remains limited and does not displace mitotane as the default systemic adjuvant comparator.4821 What is relatively reliable is that mitotane remains the reference postoperative systemic therapy; what is less reliable is the optimal way to intensify treatment for very high-risk patients.

Overall, postoperative mitotane remains the adjuvant systemic therapy most often considered after ACC resection, but its use is increasingly selective rather than routine.317 The most supportable current interpretation is that it may be most useful in patients with substantial recurrence risk, while surveillance is appropriate for many low-risk patients and the optimal approach for intermediate- and very high-risk groups remains an active area of research.142924

Included Articles

  • PMID 4050625: This case report describes postoperative cisplatin given after resection of stage II cortisol-secreting adrenocortical carcinoma, with no recurrence observed at about 2 years. The authors emphasize that effective recurrence-prevention strategies were lacking and that the true efficacy of adjuvant cisplatin remained uncertain.49
  • PMID 7736405: This retrospective single-center series of 52 ACC patients found better survival among those treated with surgery followed by immediate long-term mitotane than with surgery alone or delayed mitotane. The report also notes preoperative steroidogenesis inhibition for severe hypercortisolism and limited benefit from small experiences with radiotherapy or cytotoxic chemotherapy.50
  • PMID 8490842: A small retrospective single-center study of 19 patients with localized or regional adrenocortical carcinoma found no improvement in disease-free interval or survival with postoperative adjuvant mitotane; the adjuvant group had the shortest time to recurrence and an unfavorable survival trend despite analysis of several potential confounders.32
  • PMID 9745410: This case series describes four patients treated with low-dose mitotane shortly after surgical resection of ACC, reporting prolonged disease-free follow-up with generally good tolerability. The authors suggest early, long-term postoperative mitotane may be beneficial, while emphasizing the evidence is limited and uncontrolled.51
  • PMID 10199802: This correspondence highlights controversy over postoperative mitotane for localized or regional adrenocortical carcinoma. In a retrospective comparison after complete resection, high-dose mitotane was not associated with significantly improved disease-free interval or overall survival versus no treatment, while low-dose mitotane was argued to be better tolerated but remained unsupported by small numbers.52
  • PMID 11004719: This single-center retrospective series describes mitotane use after resection of adrenocortical carcinoma and reports higher survivor counts when treatment was started immediately after surgery rather than after a delay. The article also outlines replacement steroid support, mitotane level monitoring, and commonly observed toxicities during prolonged therapy.18
  • PMID 12652623: This preliminary pediatric ACC series reports five hormonally active tumors treated with complete surgical resection followed by adjuvant etoposide plus cisplatin, with all patients remaining in complete remission at 29 to 109 months and manageable toxicity. The authors frame cisplatin-etoposide as a promising postoperative approach that warrants further study because chemotherapy had no established role in childhood ACC.53
  • PMID 17554118: In a retrospective multicenter cohort of 177 adults with radically resected ACC, postoperative mitotane was associated with substantially longer recurrence-free survival than surgery alone, with median recurrence-free survival of 42 months versus 10 and 25 months in two control groups. Adverse effects were mostly grade 1 or 2, though some patients required temporary dose reduction.1
  • PMID 17554125: This editorial argues that after macroscopically complete resection of stage I-III adrenocortical carcinoma, adjuvant mitotane has the strongest available supportive evidence from a large multicenter retrospective study, with prolonged recurrence-free survival and potentially lower toxicity when given at relatively low doses of 1 to 3 g per day.54
  • PMID 17881760: This correspondence highlights uncertainty around adjuvant mitotane after complete ACC resection: retrospective multicenter data suggested longer recurrence-free survival, but concerns about selection bias, heterogeneous follow-up, dosing, and incomplete staging remained. The exchange also notes possible earlier benefit in cortisol-secreting tumors and the need for randomized trials.8
  • PMID 18438168: This review addresses postoperative adjunctive treatment after macroscopically complete ACC resection, emphasizing retrospective evidence that adjuvant mitotane may prolong recurrence-free survival and possibly overall survival. It also notes limited evidence that adjuvant radiotherapy can reduce local recurrence, while highlighting persistent controversy, toxicity concerns, and the need for monitoring.6
  • PMID 18842984: This commentary argues that adjuvant mitotane after complete ACC resection remains controversial because supporting data are retrospective and vulnerable to selection bias, heterogeneity, and endpoint limitations. It suggests considering mitotane selectively for higher-risk patients, with serum level monitoring and lower-dose regimens aimed at maintaining therapeutic concentrations and tolerability.35
  • PMID 19494162: This commentary argues that postoperative mitotane may prolong recurrence-free survival after radical ACC resection, while emphasizing that existing evidence is retrospective and hypothesis-generating rather than definitive. It also discusses practical adjuvant use, including serum level-guided dosing, typical 2-3 year treatment duration, and the need for randomized trials such as ADIUVO.37
  • PMID 19558758: This UK multicenter retrospective series found that adjuvant mitotane was commonly used after surgery for ACC, whereas cytotoxic chemotherapy was used in a minority despite frequent metastatic progression. The authors emphasize that the role of adjuvant therapy remained uncertain and supported prospective trials and national databases.55
  • PMID 19851811: In a retrospective single-center series of 218 resected ACC cases, adjuvant mitotane was associated with longer disease-free survival but not a clear overall survival benefit, and this association weakened when analysis was limited to patients operated outside the referral center. The study emphasizes that completeness and expertise of initial surgery may strongly influence recurrence outcomes and complicate interpretation of adjuvant mitotane benefit.9
  • PMID 20026647: In a single-center ACC series using active surgery plus monitored mitotane, achieving serum mitotane levels above 14 mg/l was associated with improved survival in high-stage disease after resection, while low-stage tumors had favorable outcomes without a clear relation to mitotane level. The authors propose adjuvant mitotane as standard care for high-stage completely resected ACC.56
  • PMID 20567001: An international panel position supports selective postoperative mitotane use after radical resection of ACC, recommending it for patients with possible residual disease or Ki-67 greater than 10%, while not considering it mandatory for stage I-II, R0, Ki-67 10% or lower tumors; evidence remains retrospective and a randomized trial was initiated for lower-risk groups.16
  • PMID 20738315: This review outlines postoperative risk-adapted management for apparently nonmetastatic ACC after resection, emphasizing stage, resection status, and Ki-67 for recurrence stratification. It recommends adjuvant mitotane for high-risk patients, selective tumor-bed radiotherapy for very high-risk features such as R1 resection, and observation or trial enrollment for lower-risk cases.57
  • PMID 23549307: This review summarizes evolving postoperative management of ACC, highlighting retrospective support for adjuvant mitotane after resection, risk-based selection using margin status and Ki-67, and limited nonrandomized evidence that adjuvant radiotherapy may reduce local recurrence in selected high-risk patients.22
  • PMID 23704714: In radically resected ACC treated with postoperative mitotane, maintaining plasma mitotane concentrations of at least 14 mg/l was associated with significantly longer recurrence-free survival, while overall survival was not significantly improved. The study supports monitored adjuvant mitotane dosing and level-guided management after surgery.39
  • PMID 24302750: In a large retrospective adult ACC cohort, adjuvant mitotane was associated with longer recurrence-free survival, and this effect was further improved when combined with adjuvant radiation therapy, without a demonstrated overall survival benefit. The study also supports considering open adrenalectomy and identifies cortisol secretion, advanced stage, and high grade as adverse risk factors.46
  • PMID 24458831: This review emphasizes adjuvant mitotane after complete ACC resection for patients at elevated recurrence risk, particularly with stage III or resected stage IV disease, positive margins, or higher Ki-67. It also highlights therapeutic drug monitoring, targeting plasma mitotane concentrations above 14 mg/L, while noting that evidence remains largely retrospective and randomized data were still pending.58
  • PMID 24732405: This review emphasizes postoperative mitotane as adjuvant therapy for ACC, noting retrospective evidence for longer recurrence-free survival and supporting a therapeutic plasma concentration target of 14-20 mg/L, while highlighting loose dose-concentration relationships, monitoring challenges, and uncertain overall survival benefit.19
  • PMID 25392159: This case report describes severe reversible hyper-LDL cholesterolemia during low-dose mitotane used as adjuvant therapy after radical resection of nonfunctional ACC, with subsequent symptomatic three-vessel coronary disease. The report emphasizes the need for careful lipid monitoring during postoperative mitotane treatment.41
  • PMID 26775162: In a 13-institution retrospective cohort of 207 resected ACC patients, adjuvant mitotane was more often given to patients with hormonally secreting and more advanced tumors but was not independently associated with improved recurrence-free or overall survival after multivariable adjustment. The findings question routine postoperative mitotane use and support the need for prospective trials.33
  • PMID 26848413: In a patient with high-grade pT3 adrenocortical carcinoma, intraoperative tumor rupture after adrenalectomy and nephrectomy with IVC resection led to recommendation for long-term adjuvant mitotane. The report also notes substantial toxicity, including chronic adrenal insufficiency requiring replacement therapy and significant hypercholesterolemia.59
  • PMID 26969077: This single-center retrospective ACC series reports that postoperative mitotane was used in a subset of patients, with stage III patients receiving adjuvant therapy showing longer survival than untreated stage III patients in this cohort. The study also notes frequent use of mitotane after recurrence and that therapeutic plasma levels were achieved in most monitored patients.60
  • PMID 27604235: A commentary on a 13-institution retrospective ACC study reports no independent improvement in recurrence-free or overall survival with adjuvant mitotane after curative adrenalectomy, including in high- and low-risk subgroups. It highlights frequent subtherapeutic plasma levels and calls for prospective trials before firm practice recommendations.10
  • PMID 28324035: In a multicenter retrospective landmark analysis of 162 adults with radically resected ACC, adjuvant mitotane was independently associated with longer recurrence-free survival versus two untreated control cohorts, while overall survival benefit was less consistent across controls. The recurrence-free survival benefit appeared irrespective of tumor secretory status, but the retrospective design remained a major limitation.11
  • PMID 28450646: This preclinical study examined mitotane, a standard adjuvant and advanced ACC therapy, and found in mice that it disrupted ovarian follicle maturation, reduced steroidogenic gene expression, impaired ovulation, delayed conception, and lowered litter size, highlighting a potential fertility toxicity relevant to treatment counseling.61
  • PMID 29201509: This single-center ACC series reports that postoperative adjuvant treatment, including mitotane with or without chemotherapy or radiotherapy, was associated with significantly longer overall survival but not disease-free survival. The article also summarizes postoperative mitotane use in higher-risk settings such as R1/Rx resection, stage III disease, or Ki-67 above 10%.62
  • PMID 29967789: A systematic review and meta-analysis of five retrospective studies in resected, nonmetastatic ACC found adjuvant mitotane was associated with longer recurrence-free and overall survival versus no mitotane. The benefit signal is based on adjusted hazard ratios, but the evidence remains limited by retrospective design and the lack of prospective controlled trials.12
  • PMID 30218246: This review summarizes postoperative ACC therapy by emphasizing adjuvant mitotane for residual disease or high-risk completely resected tumors, while noting inconsistent retrospective survival data, the need for therapeutic drug monitoring and steroid replacement, and a possible role for adjuvant radiation mainly to improve local control.44
  • PMID 30540124: This review summarizes postoperative management of ACC, emphasizing selective use of adjuvant mitotane after complete resection for higher-risk disease defined by stage III status, large tumor size, high mitotic activity, Ki-67 greater than 10%, or vascular or capsular invasion. It also notes debated benefit of adjuvant radiotherapy, with evidence mainly for improved local control rather than overall survival.25
  • PMID 30991359: In a retrospective cohort of 152 patients with non-metastatic ACC after complete macroscopic resection, adjuvant mitotane was associated with longer recurrence-free survival versus no adjuvant therapy, with overall survival benefit concentrated in high-risk subgroups defined by stage III disease or elevated Ki67 index. The study also reinforces current high-risk selection concepts used for postoperative mitotane.31
  • PMID 31361313: A National Cancer Database analysis found that use of adjuvant therapy after ACC resection increased after 2007, and patients receiving adjuvant chemotherapy had improved 5-year survival compared with the earlier era, although overall outcomes remained poor and unresectable disease showed no survival improvement after FIRM-ACT.63
  • PMID 31684071: In a retrospective multicenter ACC cohort receiving postoperative mitotane, slower attainment of plasma mitotane levels at or above 14 mg/L and less time spent in range were independently associated with shorter recurrence-free survival. The study supports therapeutic drug monitoring during adjuvant mitotane and suggests earlier target attainment may improve recurrence control.23
  • PMID 32098326: This review summarizes postoperative adjuvant treatment considerations in ACC, emphasizing high recurrence risk after complete resection and key recurrence predictors including stage, margin status, cortisol secretion, Ki-67, and molecular features. It highlights mitotane as the adjuvant mainstay despite retrospective and conflicting evidence, with selective consideration of platinum-based chemotherapy or radiotherapy in higher-risk settings.2
  • PMID 32179008: This review frames mitotane as the principal postoperative systemic therapy for ACC, recommended by ESE-ENSAT mainly for patients at high risk of recurrence after complete resection. It emphasizes that supporting evidence is largely retrospective and heterogeneous, with possible recurrence-free survival benefit most apparent in higher-risk groups such as stage III disease or Ki-67 above 10%.3
  • PMID 33186181: This review emphasizes adjuvant mitotane after curative-intent surgery for patients at high risk of recurrence, particularly stage III disease, R1 resection, or Ki-67 greater than 10%. It highlights the importance of early initiation, maintaining plasma levels in the 14-20 mg/l target range, and prolonged monitoring because time in range is associated with lower relapse risk.40
  • PMID 33260476: This review summarizes postoperative mitotane as the main adjuvant medical therapy for ACC, emphasizing that its routine use remains controversial because supporting studies are largely retrospective. It notes adjuvant treatment is generally reserved for patients with definitively diagnosed ACC at high risk of recurrence, while low to moderate risk cases require individualized decisions.7
  • PMID 33709971: This review of ENSAT stage I-II ACC emphasizes risk-adapted postoperative therapy after complete resection. Adjuvant mitotane is supported mainly for high-risk patients with Ki-67 greater than 10% and/or R1/Rx resection, while adjuvant radiotherapy is not routine but may be considered after positive or uncertain margins.27
  • PMID 33916613: This multicenter retrospective study of radically resected stage I to III ACC found no recurrence-free survival advantage for extending adjuvant mitotane beyond 24 months in patients who remained disease-free at treatment discontinuation, with conclusions mainly applicable to low- to moderate-risk disease.38
  • PMID 34400803: This multicenter retrospective cohort study suggests that adjuvant platinum-based chemotherapy after macroscopically radical ACC resection may prolong recurrence-free and overall survival in patients at very high risk of recurrence, many of whom also received mitotane. The benefit signal was observed after analyses addressing confounding and immortal time bias, with mostly mild to moderate reported toxicities.48
  • PMID 34484430: This review summarizes current adjuvant management after resection of ACC, emphasizing mitotane as the only approved systemic option and the selective use of postoperative treatment in higher-risk patients defined by stage III disease, positive or indeterminate margins, and elevated Ki-67. It also highlights the retrospective and conflicting evidence base, the need for therapeutic drug monitoring, and the ongoing uncertainty pending prospective trial results.4
  • PMID 34881855: This review summarizes mitotane as the cornerstone of postoperative therapy in ACC, noting guideline support for high-risk patients after radical surgery and randomized evidence that low-intermediate risk patients did not gain recurrence-free or overall survival benefit from adjuvant mitotane. It also highlights target plasma concentrations of 14-20 mg/L as the strongest predictor of effectiveness.64
  • PMID 35695575: This review proposes risk-adapted postoperative management for non-metastatic ACC: active surveillance rather than routine adjuvant mitotane for low-risk patients after R0 resection with stage I-II disease and Ki-67 below 10%, adjuvant mitotane for average-risk disease, and consideration of added platinum-based chemotherapy for very high-risk features.28
  • PMID 36009421: In adults with completely resected ENSAT I–III ACC receiving adjuvant mitotane, higher drug concentrations were associated with distinct sex- and menopause-related lipid changes, including consistent HDL increases and variable correlations with total cholesterol, LDL, and triglycerides. The findings support therapeutic drug monitoring and individualized management of mitotane-related dyslipidemia during postoperative treatment.42
  • PMID 36843704: This case report describes a limited-stage T2 ACC with positive margins, lymphovascular invasion, and high mitotic activity that progressed rapidly to metastatic disease despite adrenalectomy followed by external-beam radiotherapy and adjuvant chemotherapy. The report frames high-risk postoperative ACC as a setting where adjuvant treatment is considered, while emphasizing that evidence for radiotherapy and nonstandard adjuvant regimens remains mixed.65
  • PMID 36925185: This review summarizes postoperative and perioperative systemic therapy in ACC, emphasizing that adjuvant mitotane is generally supported for high-risk patients such as those with stage III disease, R1 resection, or Ki-67 greater than 10%, while low- to intermediate-risk patients did not benefit in the Adjuvo trial. It also notes limited evidence for adjuvant cytotoxic therapy, with EDP-mitotane forming the main evidence-based combination for high-risk or advanced disease, and describes neoadjuvant therapy as a selective strategy to facilitate complete resection when upfront R0 surgery is not feasible.5
  • PMID 37435451: This review summarizes risk-adapted adjuvant therapy after ACC resection, emphasizing recurrence risk factors such as stage, Ki-67, margin status, hormonal function, age, and possible molecular features. It notes that adjuvant mitotane is standard in practice, may be unnecessary in low-risk disease per ADIUVO, and remains under prospective study with chemotherapy in high-risk patients.26
  • PMID 37619579: In low-grade, localized ACC after complete resection, the ADIUVO randomized trial found no significant 5-year recurrence-free or overall survival benefit from adjuvant mitotane versus surveillance, while treatment caused universal adverse events among treated patients and a 19% discontinuation rate. The findings support surveillance alone as a reasonable option for selected low-risk patients.14
  • PMID 37619580: This commentary highlights that the ADIUVO randomized trial found no significant 5-year recurrence-free survival benefit for adjuvant mitotane versus surveillance in low- to intermediate-risk localized ACC after complete resection and Ki67 10% or lower. It emphasizes mitotane toxicity and supports avoiding routine adjuvant treatment in this risk group.15
  • PMID 38381694: This review summarizes the evolving postoperative management of ACC, emphasizing that adjuvant mitotane remains controversial and may not benefit low- or intermediate-risk patients after resection. It highlights selective use in high-risk disease, mitotane level monitoring, and unresolved roles for added platinum-based chemotherapy and adjuvant radiotherapy.21
  • PMID 38593446: This case report describes mitotane-induced DRESS after postoperative ACC treatment, with fever, eosinophilia, liver injury, and prolonged immunosuppressive management after drug discontinuation. The toxicity delayed further ACC-directed therapy for about 3 months and highlights the need to recognize rare serious mitotane adverse effects during adjuvant treatment.43
  • PMID 39037424: This review summarizes mitotane use after ACC resection, noting consensus support for adjuvant treatment mainly in moderate- to high-risk disease while emphasizing conflicting retrospective evidence. It highlights ADIUVO findings against routine adjuvant mitotane in low-risk patients and ongoing uncertainty despite current trial efforts.29
  • PMID 39277812: This retrospective single-center study of 26 patients receiving adjuvant mitotane after R0 ACC resection found universal toxicity, with most patients developing multiple adverse events and 7.7% discontinuing treatment. The report emphasizes the need for structured monitoring, hydrocortisone replacement, and timely management of endocrine, neurologic, gastrointestinal, and hepatic toxicities to support adherence.20
  • PMID 39379210: This systematic review and meta-analysis of localized ACC after adrenalectomy found adjuvant mitotane associated with improved recurrence-free survival, while adjuvant radiotherapy was associated with improved overall survival. Mitotane showed stronger benefit in patients with negative surgical margins, but the evidence base remains limited and partly retrospective.13
  • PMID 39823654: In a National Cancer Database cohort of 388 patients with non-metastatic ACC who underwent R0 resection, adjuvant external-beam radiation was not associated with improved overall survival after adjustment for clinicopathologic factors. Lack of benefit persisted in subgroup analyses of tumors at least 6 cm and high-grade tumors.66
  • PMID 39964565: This review supports selective postoperative therapy after ACC resection: adjuvant mitotane appears to improve recurrence-free and overall survival overall, but low-intermediate risk patients with R0 resection and Ki-67 below 10% did not benefit in ADIUVO. It also argues adjuvant radiotherapy may reduce locoregional recurrence and improve survival, especially for tumors larger than 6 cm, positive margins, or high-grade disease.47
  • PMID 39988973: In a multicenter retrospective registry of 244 resected stage I-III ACC cases, adjuvant mitotane was associated with lower recurrence risk, but the benefit diminished over about 24 months and mixture cure modeling suggested recurrence delay more than clear prevention. Signals of greater benefit were seen in males, younger patients, tumors with higher Ki-67, venous invasion, and possibly with added radiotherapy.36
  • PMID 40610651: This review summarizes postoperative management evidence in ACC, emphasizing adjuvant mitotane for moderate- to high-risk disease, its association with longer recurrence-free survival, and uncertainty in low-risk cases after ADIUVO. It also notes controversial, selectively used adjuvant radiotherapy with limited retrospective support, mainly in higher-risk settings.24
  • PMID 40671642: This review highlights a risk-adapted shift in adjuvant ACC management: routine postoperative mitotane is no longer recommended for low-risk patients after R0 resection with Ki-67 below 10%, while higher-risk features still support adjuvant mitotane, and the roles of chemotherapy and radiotherapy remain selective and evolving.17
  • PMID 40796146: This systematic review and meta-analysis found that adjuvant mitotane was associated with improved overall and recurrence-free survival in ACC, including stage I-III disease, while adjuvant radiotherapy showed significant benefit mainly in localized stage I-III cohorts. The effect of cytotoxic chemotherapy remained uncertain, underscoring the need for randomized trials.30
  • PMID 41552854: This editorial frames postoperative management of localized ACC by highlighting that adjuvant radiotherapy may improve local control after curative-intent surgery, especially in patients with capsular invasion, vascular infiltration, or close or positive margins, while not clearly improving disease-free or overall survival.45
  • PMID 7917941: A 1994 comment endorsed the view that adjuvant mitotane had not been shown to improve survival after complete resection and cited a small institutional series in which treated patients did not have better disease-free interval or survival. The letter also noted difficulty maintaining tolerated doses in patients without measurable disease, reinforcing the limitations of the early postoperative evidence base.34

References

Footnotes

  1. Adjuvant mitotane treatment for adrenocortical carcinoma.. N Engl J Med. 2007. PMID: 17554118. Local full text: 17554118.md ↩ ↩2 ↩3

  2. Adjuvant Therapy in Adrenocortical Carcinoma: Reflections and Future Directions.. Cancers (Basel). 2020. PMID: 32098326. Local full text: 32098326.md ↩ ↩2 ↩3 ↩4

  3. New perspectives for mitotane treatment of adrenocortical carcinoma.. Best Pract Res Clin Endocrinol Metab. 2020. PMID: 32179008. Local full text: 32179008.md ↩ ↩2 ↩3 ↩4

  4. Management of adrenocortical carcinoma: are we making progress?. Ther Adv Med Oncol. 2021. PMID: 34484430. Local full text: 34484430.md ↩ ↩2 ↩3 ↩4

  5. Adrenocortical Carcinoma: Role of Adjuvant and Neoadjuvant Therapy.. Surg Oncol Clin N Am. 2023. PMID: 36925185. Local full text: 36925185.md ↩ ↩2 ↩3

  6. Adjunctive treatment of adrenocortical carcinoma.. Curr Opin Endocrinol Diabetes Obes. 2008. PMID: 18438168. Local full text: 18438168.md ↩ ↩2

  7. Medical Approaches in Adrenocortical Carcinoma.. Biomedicines. 2020. PMID: 33260476. Local full text: 33260476.md ↩ ↩2

  8. Adjuvant mitotane in adrenocortical carcinoma.. N Engl J Med. 2007. PMID: 17881760. Local full text: 17881760.md ↩ ↩2

  9. Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane.. Ann Surg Oncol. 2010. PMID: 19851811. Local full text: 19851811.md ↩ ↩2 ↩3

  10. [Adjuvant mitotane treatment after adrenalectomy is not beneficial for adrenocortical carcinoma].. Chirurg. 2016. PMID: 27604235. Local full text: 27604235.md ↩ ↩2 ↩3

  11. Long-Term Outcomes of Adjuvant Mitotane Therapy in Patients With Radically Resected Adrenocortical Carcinoma.. J Clin Endocrinol Metab. 2017. PMID: 28324035. Local full text: 28324035.md ↩ ↩2 ↩3

  12. Benefits of Adjuvant Mitotane after Resection of Adrenocortical Carcinoma: A Systematic Review and Meta-Analysis.. Biomed Res Int. 2018. PMID: 29967789. Local full text: 29967789.md ↩ ↩2 ↩3

  13. The efficacy of adjuvant mitotane therapy and radiotherapy following adrenalectomy in patients with adrenocortical carcinoma: A systematic review and meta-analysis.. Urol Oncol. 2025. PMID: 39379210. Local full text: 39379210.md ↩ ↩2 ↩3

  14. Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study.. Lancet Diabetes Endocrinol. 2023. PMID: 37619579. Local full text: 37619579.md ↩ ↩2 ↩3 ↩4 ↩5 ↩6

  15. Good news for patients with adrenocortical carcinoma from the ADIUVO trial.. Lancet Diabetes Endocrinol. 2023. PMID: 37619580. Local full text: 37619580.md ↩ ↩2 ↩3 ↩4

  16. Adjuvant therapy in patients with adrenocortical carcinoma: a position of an international panel.. J Clin Oncol. 2010. PMID: 20567001. Local full text: 20567001.md ↩ ↩2 ↩3 ↩4 ↩5

  17. Emerging treatment options for adrenocortical carcinoma.. Curr Opin Endocrinol Diabetes Obes. 2025. PMID: 40671642. Local full text: 40671642.md ↩ ↩2 ↩3

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