Check for updates
ORIGINAL ARTICLE Clinical Investigation
Impact of Adjuvant Radiotherapy and Mitotane on Survival in Localized Adrenocortical Carcinoma: A Retrospective Cohort Study
Aysenur Elmali1 | Ozan Cem Guler2 | Gokhan Ozyigit3 | Pervin Hurmuz3 D | Cem Onal1,3 (D
1Department of Radiation Oncology, Baskent University Faculty of Medicine, Ankara, Turkiye | 2Department of Radiation Oncology, Baskent University Faculty of Medicine, Adana Dr Turgut Noyan Research and Treatment Center, Adana, Turkiye | 3Department of Radiation Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkiye
Correspondence: Cem Onal (hcemonal@hotmail.com)
Received: 10 September 2025 | Revised: 17 November 2025 | Accepted: 3 December 2025
Keywords: adrenocortical carcinoma | mitotane | radiotherapy | survival outcomes | toxicity
ABSTRACT
Objectives: Adrenocortical carcinoma (ACC) is a rare, aggressive tumor with high recurrence rates after surgery. Although radiotherapy (RT) has historically been underutilized in ACC, modern RT techniques have renewed interest in its potential role for improving local control (LC). This study evaluated long-term outcomes and prognostic factors in high-risk localized ACC treated with adjuvant RT and mitotane.
Methods: In this multicenter retrospective study, 23 patients with localized, high-risk ACC who underwent complete surgi- cal resection followed by adjuvant RT between 2003 and 2023 were analyzed. All received mitotane, and 21.6% also received platinum-based chemotherapy. RT was delivered using image-guided IMRT or VMAT to a median dose of 50.4 Gy, targeting the tumor bed with or without regional lymphatics. Survival was estimated using the Kaplan-Meier method, and prognostic factors were assessed with Cox regression analyses.
Results: At a median follow-up of 84.7 months, the 5-year LC, overall survival (OS), and disease-free survival (DFS) rates were 85.5%, 58.6%, and 45.6%. Locoregional recurrence occurred in two patients (8.6%), with isolated local failure in one (4.3%). Distant metastasis (DM) developed in 47.8% and was the predominant failure pattern. On univariable analysis, age > 55 years predicted worse OS and DFS, while female sex independently predicted inferior DFS. Treatment was well tolerated, with no grade ≥ 3 RT- related toxicities.
Conclusions: Adjuvant RT achieves excellent LC with minimal toxicity in high-risk localized ACC. These exploratory findings, limited by small cohort size, retrospective design, and absence of a comparator group, warrant confirmation in larger prospective multicenter studies.
1 Introduction
Adrenocortical carcinoma (ACC) is a rare and highly aggres- sive malignancy arising from the adrenal cortex, with an esti- mated annual incidence of 0.5-2 cases per million population 1]. Despite its rarity, ACC is associated with a poor prognosis ☒
due to its propensity for early recurrence and limited respon- siveness to systemic therapies, with 5-year overall survival (OS) rates ranging from 15% to 60% [2, 3]. Most patients are diagnosed with localized or locally advanced disease with- out distant metastases (DM), for which complete surgical re- section (R0) remains the cornerstone of potentially curative
@ 2025 The Japanese Urological Association.
treatment. However, even after R0 resection, up to one-third of patients experience locoregional recurrence (LR), under- scoring the need for effective adjuvant treatment strategies [4, 5].
The most commonly utilized adjuvant therapies are mitotane and external beam radiotherapy (RT). Mitotane, an adrenolytic agent, is typically recommended for hormonally active tumors and high-risk pathological features. European guidelines fur- ther support its use in stage III disease and resected tumors with Ki-67 indices > 10% [6, 7]. The role of adjuvant RT, however, re- mains controversial. Historically, ACC has been considered ra- dioresistant, which has limited RT utilization [8]. Nevertheless, recent retrospective studies and institutional series suggest that modern RT techniques may enhance local control (LC) and potentially improve OS, especially in high-risk patients with positive surgical margins, capsular invasion, or bulky tumors [7, 9,10].
Current guidelines from the European Society of Endocrinology (ESE), the European Network for the Study of Adrenal Tumors (ENSAT), and the National Comprehensive Cancer Network (NCCN) acknowledge the potential benefit of adjuvant RT in select high-risk cases [9, 11, 12]. However, these recommen- dations are primarily based on retrospective analyses and expert consensus in the absence of randomized data. While some meta-analyses report an OS benefit with adjuvant RT compared to surgery alone [13, 14], findings from other studies remain inconsistent [15]. Many of these studies are limited by their reliance on cancer registry databases that lack critical in- formation on RT technique, timing, dose, and treatment fields [15-17]. Furthermore, most retrospective reports involve het- erogeneous patient populations treated with various combina- tions of surgery, mitotane, chemotherapy, and RT, often without standardized protocols or long-term follow-up [18-20]. Data on treatment-related toxicity are also largely lacking, further limit- ing interpretation of safety and efficacy.
Given these limitations, the role of postoperative RT in local- ized ACC remains poorly defined. This multicentric study aims to evaluate outcomes in patients with localized, nonmetastatic ACC who underwent surgical resection followed by adjuvant mitotane and RT. By focusing on a homogeneous patient pop- ulation and incorporating detailed RT parameters, this study seeks to overcome limitations of prior research and to identify clinicopathologic factors associated with survival.
2 Methods
I
2.1 Patient Population I
This retrospective cohort study included patients with histolog- ically confirmed ACC who underwent curative-intent surgical resection between January 2003 and December 2023 at Baskent University and Hacettepe University. Clinical data were ob- tained through a comprehensive review of institutional elec- tronic medical records.
Eligible patients had localized, nonmetastatic disease at diag- nosis, tumor larger than 5 cm, and received adjuvant treatment
with both mitotane and RT. Patients were excluded if they had lymph node or DM at diagnosis, underwent R2 resection (macroscopic residual disease), or received RT with palliative intent. Staging was performed according to the 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM classification.
Patients were classified as high-risk according to established clinicopathologic criteria outlined in current ESE and European Network for the Study of Adrenal Tumors (ENSAT) guidelines. High-risk features included one or more of the following: posi- tive or close surgical margins (R1 resection), capsular or vascu- lar invasion, intraoperative tumor spillage, renal vein thrombus, tumor size > 5 cm, or a Ki-67 proliferation index exceeding 10%. Functional (hormone-secreting) tumors were also considered high-risk.
This study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board and all patient records were reviewed in accordance with the approved protocol. Informed consent was waived because of the retrospective nature of the study.
2.2 | Adjuvant Treatment
Mitotane was initiated postoperatively in all patients, typically within 6-10 weeks after surgery (median, 8 weeks). The start- ing dose was 2-3 g/day and was titrated according to tolerance, aiming for serum trough levels of 14-20mg/L, consistent with current guideline recommendations. Serum concentrations were monitored at regular intervals during follow-up to ensure therapeutic exposure. The median duration of mitotane ther- apy was 24 months (range, 12-48 months). In selected high-risk cases (5 patients, 21.6%), platinum-based chemotherapy was ad- ministered concomitantly with or following mitotane initiation. These decisions were made in multidisciplinary tumor board discussions for patients exhibiting multiple adverse features or early signs of biochemical recurrence risk.
Adjuvant RT was delivered postoperatively using advanced tech- niques, including intensity-modulated RT (IMRT) or volumetric modulated arc therapy (VMAT). The prescribed dose (45-54 Gy in 1.8-2.0Gy daily fractions) was normalized to cover the planning target volume (PTV), which encompassed the tumor bed with or without regional lymphatics. Treatment planning adhered to institutional and international dose-volume con- straints for adjacent organs at risk (kidneys, liver, spinal cord, and bowel). All patients were treated with daily image guidance, predominantly cone-beam CT (CBCT), to ensure accurate target localization and minimize setup uncertainties.
2.3 | Follow-Up and Outcome Assessment
Patients were monitored through clinical evaluations, imaging studies, and biochemical assessments every 3-6 months during the first 2years, and annually thereafter. The primary endpoint was OS, defined as the time from surgical resection to the date of death or last follow-up. Secondary endpoints included disease- free survival (DFS), defined as the time from diagnosis to the
first documented occurrence of LR or DM following RT, as well as treatment-related toxicity.
Toxicity data were retrospectively abstracted from electronic medical records and follow-up clinical documentation. Acute and late adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. While toxicity grading was based on clinician documentation rather than prospective patient-reported outcomes, all records were systematically reviewed to capture treatment-related events.
2.4 | Statistical Analysis
All statistical analyses were conducted using SPSS software, version 25 (IBM Corp., Armonk, NY, USA). Descriptive sta- tistics were used to summarize patient demographics, tumor characteristics, and treatment parameters. Continuous variables were presented as medians with interquartile ranges (IQRs), and categorical variables as frequencies and percentages. OS and DFS were estimated using the Kaplan-Meier method. Survival outcomes between groups were compared using the log-rank test. Univariate analyses were performed to evaluate potential prognostic factors, including: age, sex, functional status of the tumor, extent of resection, tumor diameter, tumor grade, atypi- cal mitoses, T stage, interval between surgery and RT, RT field, and total RT dose. Univariable and multivariable Cox propor- tional hazards regression models were used to identify factors associated with OS and DFS. Variables with p <0.10 in univari- able analysis were included in the multivariable model. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported. A p-value <0.05 was considered statistically significant.
I
3 Results
Of 31 patients with localized ACC identified, eight were ex- cluded (four with nodal metastasis, three without mitotane, one palliative RT), leaving 23 for analysis. Baseline characteristics are summarized in Table 1. The median age was 49 years (range, 19-78), with 12 males (52.2%). Eight patients (34.8%) had hor- monally functional tumors, mostly cortisol-secreting. The me- dian tumor diameter was 11 cm (range, 6-19). All patients met at least one criterion for high-risk disease, most commonly a tumor size greater than 5 cm (100%) and a Ki-67 index above 10% (65.2%), followed by positive or close surgical margins (43.5%) and capsular invasion (30.4%). The distribution of high-risk pathological features is detailed in Table S1.
All patients underwent adrenalectomy, and 4 (17.9%) also had nephrectomy. Postoperative RT was initiated a median of 2 months after surgery (range, 0.9-4.9). IMRT was used in 16 patients (69.6%) and VMAT in 7 (30.4%). Eleven patients (47.8%) received RT to the tumor bed only, while 12 (52.2%) also had elective nodal irradiation. The median prescribed dose was 50 Gy (range, 45-60) in 23-30 fractions. Mitotane was started a median of 8 weeks postoperatively (range, 5-14) and continued for a median of 24 months. Five patients (21.6%) also received
| Characteristic | n | % |
|---|---|---|
| Age (years, median, range) | 49 (19-78) | |
| Sex | ||
| Male | 12 | 52.2 |
| Female | 11 | 47.8 |
| Tumor diameter (cm, median, range) | 11 (6-19) | |
| Resection extent | ||
| R0 | 13 | 56.5 |
| R1 | 10 | 43.5 |
| Capsule perforation during surgery | ||
| Absent | 16 | 69.6 |
| Present | 7 | 30.4 |
| Surgical tumor spillage | ||
| Absent | 20 | 87 |
| Present | 3 | 13 |
| Renal vein thrombus | ||
| Absent | 20 | 87 |
| Present | 3 | 13 |
| Grade | ||
| Low | 8 | 34.8 |
| High | 15 | 65.2 |
| Atypical mitosis | ||
| Absent | 15 | 65.2 |
| Present | 8 | 34.8 |
| Tumor necrosis | ||
| Absent | 6 | 26.1 |
| Present | 17 | 73.9 |
| Vascular invasion | ||
| Absent | 7 | 30.4 |
| Present | 14 | 60.9 |
| Unknown | 2 | 8.7 |
| Capsular involvement | ||
| Absent | 7 | 30.4 |
| Present | 15 | 65.3 |
| Unknown | 1 | 4.3 |
| T stage | ||
| T2 | 16 | 49.6 |
| T3 | 5 | 21.7 |
| T4 | 2 | 8.7 |
platinum-based chemotherapy. Exploratory subgroup analyses showed no clear differences in OS or DFS by chemotherapy use or RT field. Because all patients in this cohort received adju- vant RT, formal subgroup comparisons between RT-treated and non-RT groups were not feasible; therefore, only exploratory within-cohort analyses were performed, which consistently demonstrated high LC across all clinicopathologic subgroups.
At a median follow-up of 84.7 months (IQR 72.1-97.3), 11 pa- tients (47.8%) relapsed, with median time to progression of 15 months. DM occurred in 10 patients (43.4%), while two (8.6%) developed LR (one isolated, one with DM). At last follow-up, 11 patients (47.8%) were disease-free, two (8.7%) alive with disease, and 10 (43.5%) had died (9 from ACC, one unrelated).
The 2- and 5-year OS rates were 70.3% and 58.6%, and DFS rates were 62.7% and 45.6%, respectively (Figure 1). Median OS and DFS were not reached. LC was 95.0% at 2years and 85.5% at 5 years. Results of the Cox proportional hazards analyses are summarized in Tables 2 and 3. On univariable analysis, age > 55 years was significantly associated with inferior overall and DFS (p=0.02 and 0.04, respectively) (Figure 2A,B), while female sex also predicted shorter DFS (p=0.05). Tumor size ≥11 cm showed a trend toward poorer outcomes, though not statistically significant (Figure 2C,D). In multivariable analysis, female sex remained an independent predictor of worse DFS (p=0.04), whereas no variables retained significance for OS (Table 3).
Treatment was well tolerated across the entire cohort. As sum- marized in Table 4, most acute toxicité 1-2 and transient, consisting mainly of mild nausea (39.1%), fatigue (17.4%), and occasional abdominal discomfort or anorexia. Only one patient (4.3%) experienced grade 2 nausea requiring tempo- rary antiemetic therapy. No grade ≥3 acute toxicity- served. Late toxicity was minimal, limited to a single case (4.3%) of mild gastrointestinal symptoms, with no hepatic, renal, or other organ-related late effects reported. No grade ≥3 acute or late toxicities were observed.
4 Discussion I
This multicenter retrospective analysis demonstrates that the integration of adjuvant RT with mitotane is a safe and effective strategy for achieving durable LC in patients with localized ACC
presenting with high-risk pathological features. The remarkably low incidence of LR, despite the predominance of adverse prog- nostic factors, underscores the ability of modern RT techniques to overcome the historical perception of ACC as a radioresistant malignancy. However, DM remained the predominant pattern of failure, highlighting the persistent challenge of systemic dis- ease control. These findings suggest that while adjuvant RT can reliably prevent locoregional relapse, optimizing systemic therapy remains essential to improve long-term outcomes. The absence of severe acute or late toxicities reinforces the feasibil- ity of incorporating RT into multimodal treatment protocols for appropriately selected high-risk patients. While adjuvant RT im- proves LC, systemic recurrence remains the major driver of poor outcomes in ACC. Therefore, RT should be considered part of multimodal management, ideally in combination with systemic agents such as mitotane or novel targeted therapies. These find- ings suggest that while adjuvant RT can reliably prevent locore- gional relapse, optimizing systemic therapy remains essential to improve long-term outcomes.
The biological rationale for incorporating adjuvant RT lies in its capacity to eradicate microscopic residual disease within the tumor bed, a common source of local relapse after surgery. Advances in image-guided IMRT and VMAT enable precise dose delivery to the target while sparing adjacent critical struc- tures such as the bowel, liver, and kidneys. This precision allows adequate tumor bed coverage with curative-intent doses, trans- lating into high LC rates with minimal toxicity. However, the role of adjuvant RT in ACC still remains uncertain; the rarity of the disease has precluded randomized trials, and available evi- dence is largely confined to small retrospective series, many de- rived from national registries, with heterogeneous cohorts and incomplete RT details [5, 10, 15, 16, 21-23] (Table 5). Historically, RT was infrequently used because of perceptions of radioresis- tance. Advances in treatment delivery and image guidance now allow precise targeting of the tumor bed and regional lymphat- ics while minimizing dose to critical organs. In our series, only two patients (8.6%) experienced LR, despite a high prevalence of adverse pathological features such as capsular invasion, vas- cular involvement, and high-grade histology. These results are consistent with Sabolch et al. [23], who reported markedly lower local relapse rates in RT-treated patients (1 of 20) compared with surgery alone (12 of 20). Similarly, a meta-analysis by Wu et al. [24] demonstrated significantly improved OS and DFS in ACC patients receiving adjuvant RT. At the population-level, Zhan
100
80-
OS
60-
40-
20-
0
0
24
48
72
96
120
Time (months)
No at risk 23
12
10
9
4
2
100
80-
DFS
60
40
20-
0
0
24
48
72
96
120
Time (months)
No at risk
23
11
8
7
4
2
| Patient characteristics | n | OS | DFS | ||
|---|---|---|---|---|---|
| HR (95% CI) | p | HR (95% CI) | p | ||
| Age | |||||
| ≤ 55 years | 15 | 1 | 0.02 | 1 | 0.04 |
| > 55 years | 8 | 4.25 (1.17-15.48) | 3.25 (1.06-10.97) | ||
| Sex | |||||
| Male | 11 | 1 | 0.06 | 1 | 0.05 |
| Female | 12 | 4.54 (0.96-21.55) | 3.79 (1.02-14.06) | ||
| Tumor functional status | |||||
| Nonfunctional | 15 | 1 | 0.63 | 1 | 0.63 |
| Functional | 8 | 0.72 (0.19-2.78) | 1.32 (0.42-4.18) | ||
| Surgical resection | |||||
| R0 | 13 | 1 | 0.31 | 1 | 0.25 |
| R1 | 10 | 1.94 (0.55-6.90) | 1.96 (0.62-6.20) | ||
| Tumor size | |||||
| ≤11 cm | 12 | 1 | 0.09 | 1 | 0.07 |
| >11 cm | 11 | 3.19 (0.81-12.53) | 2.91 (0.87-9.78) | ||
| Tumor grade | |||||
| Low | 8 | 1 | 0.19 | 1 | 0.09 |
| High | 15 | 2.85 (0.60-13.50) | 3.73 (0.82-17.11) | ||
| Atypical mitoses | |||||
| Absent | 15 | 1 | 0.39 | 1 | 0.3 |
| Present | 8 | 1.75 (0.49-6.25) | 1.86 (0.58-5.87) | ||
| Stage | |||||
| <T3 | 16 | 1 | 0.15 | 1 | 0.3 |
| ≥T3 | 7 | 2.49 (0.71-8.65) | 1.85 (0.58-5.87) | ||
| Interval between surgery and RT | |||||
| <2 months | 12 | 1 | 0.35 | 1 | 0.17 |
| ≥ 2 months | 11 | 0.55 (0.15-1.95) | 0.43 (0.13-1.43) | ||
| Radiation field | |||||
| Tumor bed | 11 | 1 | 0.69 | 1 | 0.8 |
| Tumor bed and lymphatics | 12 | 1.29 (0.37-4.52) | 1.16 (0.37-3.64) | ||
| Total RT dose | |||||
| > 50 Gy | 10 | 1 | 0.19 | 1 | 0.84 |
| ≤ 50 Gy | 13 | 0.63 (0.60-13.50) | 0.89 (0.28-2.77) | ||
et al. [16] found adjuvant RT to be an independent predictor of OS and cancer-specific survival, leading to a validated prognos- tic nomogram that incorporates RT as a significant factor. Our findings, demonstrating a 5-year LC rate of 85.5% and an ab- sence of severe RT-related toxicity, are consistent with previous
institutional and population-based studies supporting the effi- cacy of postoperative RT. Furthermore, our study adds to this growing body of evidence by providing detailed dosimetric, technical, and outcome data from two tertiary centers using standardized IMRT/VMAT-based RT protocols.
14422042, 2026, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/iju.70319 by National Library Of Medicine, Wiley Online Library on [02/04/2026]. See the Terms and Conditions (https://onlinelibrary. wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
| Variables | Risk factor | HR (95% CI) | p |
|---|---|---|---|
| Overall survival | |||
| Age | ≤ 55 vs. > 55 years | 2.24 (0.55-9.11) | 0.26 |
| Sex | Male vs. female | 3.36 (0.67-16.85) | 0.14 |
| Tumor size | <11 vs. ≥ 11 cm | 2.15 (0.51-9.12) | 0.3 |
| Disease free survival | |||
| Age | ≤ 55 vs. > 55 years | 0.80 (0.73-23.47) | 0.11 |
| Sex | Male vs. female | 4.45 (1.04-19.12) | 0.04 |
| Tumor size | <11 vs. ≥ 11 cm | 2.43 (0.60-9.85) | 0.21 |
| Tumor grade | Low vs. high | 4.15 (0.73-23.45) | 0.11 |
Despite excellent LC rates, DM occurred in nearly half of pa- tients, consistent with prior studies showing systemic dissemi- nation as the major determinant of long-term survival [23, 25]. The high rate of DM underscores the limitations of current sys- temic strategies, particularly mitotane monotherapy, in erad- icating micrometastatic disease. Although mitotane remains the guideline-recommended cornerstone of adjuvant systemic therapy, its benefit is modest, and achieving therapeutic serum levels is challenging [9, 12]. All patients in our series received mitotane in line with ESE and ENSAT recommendations, and 21.6% also received platinum-based adjuvant chemotherapy, reflecting individualized treatment for those at greatest risk of early systemic relapse. Retrospective data suggest that adequate mitotane dosing may reduce recurrence risk, but more active regimens, including platinum-based chemotherapy, immune checkpoint inhibitors, and molecularly targeted agents should be explored alongside RT to improve distant disease control. Several ongoing clinical trials are addressing these gaps in both the adjuvant and advanced settings. Notably, the ADIUVO-2 trial (NCT03583710) is a randomized, multicenter study com- paring adjuvant mitotane alone with mitotane plus cisplatin- etoposide in patients with completely resected, high-risk ACC, with the goal of improving recurrence-free survival. In parallel, multiple institutional and registry-based initiatives, including those at the Mayo Clinic (e.g., NCT02673333) and the University of Michigan Rogel Cancer Center, are prospectively collecting clinical and biospecimen data and evaluating early-phase agents such as TKM-080301. Collectively, these efforts aim to optimize adjuvant systemic therapy, explore integration of immunother- apy, and clarify the role of RT within contemporary multimodal management of ACC.
Patient selection remains critical for optimizing the benefit of adjuvant RT. Current ESE/ENSAT and NCCN guidelines rec- ommend consideration of postoperative RT for patients with
high-risk pathological features such as positive or close margins, capsular invasion, vascular infiltration, tumor spillage, or high Ki-67 index. Nearly all patients in our cohort exhibited one or more of these features, and RT achieved excellent LC even in this high-risk population, reinforcing its value in selected cases.
Because adjuvant RT was administered to all patients, direct comparative subgroup analyses between RT and non-RT cohorts could not be performed; as a result, only exploratory within- cohort comparisons were undertaken, which uniformly demon- strated sustained LC across diverse risk groups. Exploratory subgroup analyses indicated that adjuvant RT achieved consis- tently high LC across all clinicopathologic subgroups, including patients with adverse features such as positive or close surgical margins, capsular invasion, or large tumor size. Neither tumor size, resection status, nor RT field significantly influenced lo- coregional outcomes, suggesting that modern RT techniques effectively mitigate the risk of local recurrence even in unfavor- able settings. Our analysis also identified older age (> 55 years) as a significant adverse prognostic factor for both OS and DFS in univariable analysis, aligning with prior studies [16]. Female sex emerged as the only independent predictor of shorter DFS in multivariable analysis, a novel finding that may warrant further investigation into biological or treatment-related differences. Tumor size > 11 cm showed a nonsignificant trend toward infe- rior OS and DFS, consistent with previous reports linking larger tumor burden to worse prognosis [26]. The lack of statistical significance for tumor size and grade likely reflects the small sample size and the predominance of high-risk features across the cohort. These results highlight the importance of intensified surveillance and potentially more aggressive systemic therapy in older patients, females, and those with large tumors.
Potential risks of RT, including gastrointestinal, hepatic, and renal toxicity, must be considered. Historically, upper abdominal RT was associated with significant morbidity; however, modern IMRT/VMAT techniques, daily image guidance, and strict ad- herence to dose-volume constraints have greatly reduced these complications. In our study, the combination of adjuvant RT and mitotane was well tolerated, with no grade ≥3 acute tox- icities and no late RT-related adverse events during long-term follow-up. This compares favorably with earlier series reporting higher rates of gastrointestinal and constitutional side effects, often related to less conformal techniques [23, 25].
From a clinical perspective, our findings support consideration of adjuvant RT in patients with high-risk pathological features after complete resection of localized ACC, particularly those with positive or close surgical margins, capsular or vascular in- vasion, high proliferative index, or intraoperative tumor spillage. These patients are at greatest risk for LR, and RT can provide effective LC with minimal toxicity. Integration of RT with ad- juvant mitotane should be individualized based on recurrence risk, performance status, and organ function, ideally within a multidisciplinary framework. Looking forward, prospective tri- als should explore combined-modality strategies incorporating RT with intensified systemic therapies, such as platinum-based regimens, immunotherapy, or targeted agents, to address both local and distant disease components. Such approaches may ul- timately improve overall disease outcomes while maintaining the excellent LC achieved with modern RT.
14422042, 2026, 1, Downloaded from https://onlinelibrary. wiley.com/doi/10.1111/iju.70319 by National Library Of Medicine, Wiley Online Library on [02/04/2026]. See the Terms and Conditions (https://onlinelibrary. wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
A
100
B
100
1
80
80
OS
60
DFS
60
40
40
20
20
0
0
0
24
48
72
96
120
0
24
48
72
96
120
Time (months)
Time (months)
≤ 55 years
15
9
8
8
4
2
≤ 55 years
15
9
8
7
4
2
> 55 years
8
3
2
1
0
0
> 55 years 8
2
0
0
0
0
C
100
D 100
80
80
8
60
DFS
60
T
40
40
20
20
0
0
0
24
48
72
96
120
0
24
48
72
96
120
Time (months)
Time (months)
< 11 cm
12
7
6
6
4
2
< 11 cm
12
6
6
5
4
2
≥11 cm
11
5
4
3
0
0
≥11 cm
11
5
2
2
0
0
| Toxicity type | Toxicity | Grade 1 | Grade 2 | Grade ≥3 | Total, n (%) |
|---|---|---|---|---|---|
| Acute | Nausea | 8 (34.8%) | 1 (4.3%) | 0 | 9 (39.1%) |
| Fatigue | 4 (17.4%) | 0 | 0 | 4 (17.4%) | |
| Anorexia | 2 (8.7%) | 0 | 0 | 2 (8.7%) | |
| Abdominal pain/discomfort | 2 (8.7%) | 0 | 0 | 2 (8.7%) | |
| Diarrhea | 1 (4.3%) | 0 | 0 | 1 (4.3%) | |
| Late | Gastrointestinal | 1 (4.3%) | 0 | 0 | 1 (4.3%) |
| Hepatic/renal | 0 | 0 | 0 | 0 | |
| Other | 0 | 0 | 0 | 0 |
This study has some limitations. The rarity of ACC inherently restricts cohort sizes, and this limitation must be considered when interpreting our findings. The retrospective design in- troduces potential selection bias, and the small number of events limits the statistical power of subgroup and multivari- able analyses, which may result in wide confidence intervals
and unstable estimates. In addition, potential selection bias must be acknowledged, as patients referred for adjuvant RT may have had higher baseline risk features, which could influ- ence observed outcomes. The observed association between female sex and inferior DFS, for example, may represent a chance finding rather than a true biological effect. The lack of
| Study (year) | Design & setting | N | Treatment/comparison | RT technique/dose | Survival | Local control | Key takeaway |
|---|---|---|---|---|---|---|---|
| Sabolch et al. (2015) [23] | Case-matched, single/multi- institution retrospective | 62 | Adjuvant RT vs. surgery alone | 45-60Gy; 3D- CRT or IMRT | 5-year OS ~66% | 1/20 vs. 12/20 local relapses | Strong LC benefit of adjuvant RT in high-risk patients |
| Gharzai et al. (2019) [10] | Retrospective, multi-institution | 105 | Adjuvant RT vs. no RT | Median 50.4Gy; IMRT/3D-CRT | 5-year OS ~60% | Improved LC; numeric rates NR | Survival benefit beyond LC |
| Wu et al. (2024) [24] | Retrospective cohort | 105 | Adjuvant RT vs. surgery alone | Median 50 Gy; IMRT | 3-year OS 83%, DFS 71% | 3-year LC ~90% | Modern RT effective in early-stage high- risk patients |
| Zhan et al. (2025) [16] | Population- based registry | 426 | Adjuvant RT vs. no RT | NR | NR | NR | Population- level evidence supporting RT |
| Ginsburg et al. (2021) [21] | Registry analysis | 365 | Adjuvant RT vs. no RT | NR | NR | NR | Helps refine RT candidate selection |
| Zhu et al. (2020) [22] | Retrospective series + meta- analysis | — | Adjuvant RT vs. surgery alone | NR | NR | NR | Multi-study synthesis supports RT |
| Current study (2025) | Multicenter retrospective | 23 | Surgery+ adjuvant RT + mitotane ± chemo | Median 50.4Gy (range 45-54 Gy); IMRT/VMAT with IGRT | 5-year OS 58.6%, PFS 45.6% | 5-year LC 85.5% | Modern image-guided RT with mitotane achieves excellent LC and minimal toxicity; systemic failure remains main challenge |
Abbreviations: 3D-CRT, three-dimensional conformal radiotherapy; ACC, adrenocortical carcinoma; CSS, cancer-specific survival; DFS, disease-free survival; IGRT, image-guided radiotherapy; IMRT, intensity-modulated radiotherapy; LC, local control; N/A, not applicable; NR, not reported; OS, overall survival; RFS, recurrence-free survival; VMAT, volumetric modulated arc therapy.
a comparator group treated with surgery and mitotane alone also prevents definitive attribution of benefit to RT. In addi- tion, variability in mitotane dosing, treatment duration, and serum monitoring may have influenced systemic disease con- trol. Treatment heterogeneity, including the use of adjuvant chemotherapy in some patients and variation in RT fields, may likewise have affected outcomes. Although exploratory anal- yses did not reveal significant differences, the limited sample size precludes firm conclusions. Finally, the use of multivari- able Cox regression with few outcome events raises the risk of model overfitting. As such, findings such as the apparent association between female sex and DFS should be considered hypothesis-generating. In this rare disease setting, univari- able analyses may provide more reliable insights, while ro- bust multivariable modeling will require larger, collaborative datasets.
Despite the retrospective design, small sample size, and lack of a comparator group, this study provides valuable real-world evidence from a homogeneous cohort uniformly treated with surgery, adjuvant RT, and mitotane. The use of modern image- guided RT techniques ensured precise target coverage and opti- mal sparing of organs at risk. Comprehensive clinicopathologic, treatment, and toxicity data were systematically collected from two high-volume tertiary centers, enabling reliable long-term outcome assessment. The extended follow-up of more than 7 years provides mature survival and safety data, while the multicenter design highlights the reproducibility of treatment approaches across institutions with established expertise in ACC management. These strengths enhance the robustness and clinical relevance of our findings, which, although exploratory, support further investigation of combined adjuvant strategies in high-risk localized ACC.
This multicenter retrospective study demonstrates that adju- vant RT, when combined with mitotane, achieves excellent LC with minimal toxicity in patients with localized, high-risk ACC. These results challenge the historical perception of ACC radioresistance and support selective integration of RT into multimodal treatment strategies. However, given the small sample size, retrospective design, and absence of a comparator cohort, these findings should be regarded as exploratory and hypothesis-generating rather than definitive. The persistently high incidence of DM despite effective local therapy underscores the urgent need for more active systemic approaches, including optimized mitotane dosing, cytotoxic combinations, and novel targeted or immunotherapeutic agents. Future collaborative, prospective, multicenter trials and robust registry-based analy- ses will be essential to validate these results, refine patient se- lection, and establish evidence-based guidelines for the use of adjuvant RT in ACC.
Author Contributions
Aysenur Elmali: conceptualization, data curation, validation, writ- ing - original draft, writing - review and editing. Ozan Cem Guler: data curation, software, investigation. Gokhan Ozyigit: supervision, visualization, validation. Pervin Hurmuz: conceptualization, data cu- ration, validation, visualization. Cem Onal: writing - original draft, writing - review and editing, formal analysis, validation, investigation, visualization.
Acknowledgments
The authors alone are responsible for the content and writing of the paper.
Funding
The authors alone are responsible for the content and writing of the paper.
Ethics Statement
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or na- tional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed con- sent was obtained from all individuals included in the study.
Consent
All patients provided written informed consent.
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
Data available on request from the corresponding author.
References
1. K. Y. Bilimoria, W. T. Shen, D. Elaraj, et al., “Adrenocortical Carci- noma in the United States: Treatment Utilization and Prognostic Fac- tors,” Cancer 113 (2008): 3130-3136.
2. E. Sharma, S. Dahal, P. Sharma, et al., “The Characteristics and Trends in Adrenocortical Carcinoma: A United States Population Based Study,” Journal of Clinical Medical Research 10 (2018): 636-640.
3. P. Icard, P. Goudet, C. Charpenay, et al., “Adrenocortical Carcinomas: Surgical Trends and Results of a 253-Patient Series From the French Association of Endocrine Surgeons Study Group,” World Journal of Sur- gery 25 (2001): 891-897.
4. S. Gaujoux and M. F. Brennan, “Recommendation for Standardized Surgical Management of Primary Adrenocortical Carcinoma,” Surgery 152 (2012): 123-132.
5. K. Wu, Z. Liu, X. Li, and Y. Lu, “Adrenal Surgery for Synchronously Metastatic Adrenocortical Carcinoma: A Population-Based Analysis,” World Journal of Surgery 45 (2021): 1457-1465.
6. M. Terzolo, A. Angeli, M. Fassnacht, et al., “Adjuvant Mitotane Treat- ment for Adrenocortical Carcinoma,” New England Journal of Medicine 356 (2007): 2372-2380.
7. M. Fassnacht, O. M. Dekkers, T. Else, et al., “European Society of En- docrinology Clinical Practice Guidelines on the Management of Adre- nocortical Carcinoma in Adults, in Collaboration With the European Network for the Study of Adrenal Tumors,” European Journal of Endo- crinology 179 (2018): G1-G46.
8. R. Vassilopoulou-Sellin and P. N. Schultz, “Adrenocortical Carci- noma. Clinical Outcome at the End of the 20th Century,” Cancer 92 (2001): 1113-1121.
9. M. H. Shah, W. S. Goldner, A. B. Benson, et al., “Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology,” Journal of the National Comprehensive Cancer Network 19 (2021): 839-868.
10. L. A. Gharzai, M. D. Green, K. A. Griffith, et al., “Adjuvant Radi- ation Improves Recurrence-Free Survival and Overall Survival in
Adrenocortical Carcinoma,” Journal of Clinical Endocrinology and Me- tabolism 104 (2019): 3743-3750.
11. M. Fassnacht, S. Tsagarakis, M. Terzolo, et al., “European Society of Endocrinology Clinical Practice Guidelines on the Management of Adrenal Incidentalomas, in Collaboration With the European Network for the Study of Adrenal Tumors,” European Journal of Endocrinology 189 (2023): G1-G42.
12. M. Fassnacht, G. Assie, E. Baudin, et al., “Adrenocortical Carcino- mas and Malignant Phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up,” Annals of Oncology 31 (2020): 1476-1490.
13. I. Tsuboi, M. Kardoust Parizi, A. Matsukawa, et al., “The Efficacy of Adjuvant Mitotane Therapy and Radiotherapy Following Adrenalec- tomy in Patients With Adrenocortical Carcinoma: A Systematic Review and Meta-Analysis,” Urologic Oncology 43 (2025): 297-306.
14. G. A. Viani and B. S. Viana, “Adjuvant Radiotherapy After Surgical Resection for Adrenocortical Carcinoma: A Systematic Review of Ob- servational Studies and Meta-Analysis,” Journal of Cancer Research and Therapeutics 15 (2019): S20-S26.
15. B. C. Greenspun, Y. J. Lee-Saxton, C. E. Egan, et al., “Adjuvant Radi- ation Therapy Is Not Associated With a Survival Benefit After R0 Resec- tion in Non-Metastatic Adrenocortical Carcinoma,” American Journal of Surgery 242 (2025): 116194.
16. K. Zhan, X. Ruan, and H. Jia, “Adjuvant Radiation Improves Sur- vival Outcomes in Adrenocortical Carcinoma: A Population-Based Study,” Medicine (Baltimore) 104 (2025): e41313.
17. S. Ma, L. Wu, L. Ye, M. A. Habra, V. Balderrama-Brondani, and W. Wang, “Adjuvant Radiation Therapy Improves Outcome of Patients With Surgical Resected Adrenocortical Carcinoma,” Endocrine 88 (2025): 597-606.
18. O. Kimpel, P. Schindler, L. Schmidt-Pennington, et al., “Efficacy and Safety of Radiation Therapy in Advanced Adrenocortical Carcinoma,” British Journal of Cancer 128 (2023): 586-593.
19. P. Şişman, A. B. Şahin, H. Peynirci, et al., “Adrenocortical Carci- noma: Single Center Experience,” Turkish Journal of Urology 43 (2017): 462-469.
20. L. H. Pan, C. C. Yen, C. J. Huang, X. N. Ng, and L. Y. Lin, “Prognostic Predictors of Adrenocortical Carcinoma: A Single-Center Thirty-Year Experience,” Frontiers in Endocrinology (Lausanne) 14 (2023): 1134643.
21. K. B. Ginsburg, A. A. Chandra, J. P. Schober, et al., “Identification of Oncological Characteristics Associated With Improved Overall Sur- vival in Patients With Adrenocortical Carcinoma Treated With Adju- vant Radiation Therapy: Insights From the National Cancer Database,” Urologic Oncology 39 (2021): 791.e1-e7.
22. J. Zhu, Z. Zheng, J. Shen, et al., “Efficacy of Adjuvant Radiotherapy for Treatment of Adrenocortical Carcinoma: A Retrospective Study and an Updated Meta-Analysis,” Radiation Oncology 15 (2020): 118.
23. A. Sabolch, T. Else, K. A. Griffith, et al., “Adjuvant Radiation Ther- apy Improves Local Control After Surgical Resection in Patients With Localized Adrenocortical Carcinoma,” International Journal of Radia- tion Oncology, Biology, Physics 92 (2015): 252-259.
24. L. Wu, J. Chen, T. Su, et al., “Efficacy and Safety of Adjuvant Ra- diation Therapy in Localized Adrenocortical Carcinoma,” Frontiers in Endocrinology (Lausanne) 14 (2023): 1308231.
25. B. Polat, M. Fassnacht, L. Pfreundner, et al., “Radiotherapy in Adre- nocortical Carcinoma,” Cancer 115 (2009): 2816-2823.
26. T. Else, A. R. Williams, A. Sabolch, S. Jolly, B. S. Miller, and G. D. Hammer, “Adjuvant Therapies and Patient and Tumor Characteristics Associated With Survival of Adult Patients With Adrenocortical Car- cinoma,” Journal of Clinical Endocrinology and Metabolism 99 (2014): 455-461.
Supporting Information
Additional supporting information can be found online in the Supporting Information section. Table S1: High-risk pathological and clinical features in the study cohort.
14422042, 2026, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/iju.70319 by National Library Of Medicine, Wiley Online Library on [02/04/2026]. See the Terms and Conditions (https://onlinelibrary. wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License