ENDOCRINE SOCIETY
OXFORD
Efficacy and Safety of Radiotherapy and Systemic Treatments in Adrenocortical Carcinoma: Systematic Review and Meta-Analysis
Anita Pfeffer,1,2 Nóra Beke,2 Dorottya Bakó,2 Márk Hernádfői,2,3 Tamás Kói,2,4 András Fogarasi,2,3 Andrea Parniczky,2,5,6 Peter Hegyi,2,6,7 and Miklós Garami1,2(D
1Pediatric Center, Tűzoltó Street Department, Semmelweis University, Budapest 1094, Hungary
2Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary
3Department of Neurology, Bethesda Children’s Hospital, Budapest 1146, Hungary
4Department of Stochastics, Institute of Mathematics, Budapest University of Technology and Economics, Budapest 1111, Hungary 5Department of Pulmonology, Heim Pál National Pediatric Institute, Budapest 1089, Hungary
6Institute of Pancreatic Diseases, Semmelweis University, Budapest 1085, Hungary
7Institute for Translational Medicine, Medical School, University of Pécs, Pécs 7624, Hungary
Correspondence: Miklós Garami, MD, MSc, PhD, Pediatric Center, Semmelweis University, 7-9 Tűzoltó utca, Budapest 1094, Hungary. Email: garami.miklos@ semmelweis.hu.
Abstract
Context: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with a high recurrence and mortality rate even after complete resection. Therefore, intensification of adjuvant therapies is crucial, although their effectiveness remains controversial.
Objective: This study aimed to determine the efficacy and safety of available treatments by considering the prognostic factors affecting disease outcomes.
Methods: The search was conducted across 3 databases (PubMed, Embase, and CENTRAL) in October 2024. Eligible studies compared overall survival (OS) and recurrence-free survival (RFS) in patients with ACC treated with and without systemic (mitotane, cytotoxic chemotherapy) or localized (radiotherapy) nonsurgical treatments. In total, 86 studies met the inclusion criteria for the systematic review, and 62 for the meta- analysis. Two reviewers extracted data independently. Adjusted hazard ratios (aHR) with 95% CI were calculated for survival outcomes.
Results: Mitotane significantly improves OS (aHR: 0.54; CI: 0.41-0.70) and RFS (aHR: 0.60; CI: 0.43-0.84), even in stage I-III disease (OS aHR: 0.71; CI: 0.52-0.98; RFS aHR: 0.65; CI: 0.50-0.85). Radiotherapy showed a trend toward improved OS (aHR: 0.66; CI: 0.38-1.15) and RFS (aHR: 0.65; CI: 0.35-1.23), with significant benefits in stage I-III (OS aHR: 0.68; CI: 0.50-0.93; RFS aHR: 0.71; CI: 0.63-0.81). The impact of cytotoxic chemotherapy on OS remains uncertain (aHR: 0.61; CI: 0.08-4.78).
Conclusion: Mitotane significantly improves survival outcomes in patients with ACC, while radiotherapy exhibits potential benefits, particularly in localized disease. Further research is needed to verify the efficacy of cytotoxic chemotherapy, and randomized controlled trials are required to provide robust evidence of different treatment approaches.
Key Words: adrenocortical carcinoma, cytotoxic chemotherapy, irradiation, mitotane, radiotherapy, targeted therapy
Abbreviations: ACC, adrenal cortical carcinoma; aHR, adjusted hazard ratio; CENTRAL, Cochrane Central Register of Controlled Trials; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; HR, hazard ratio; LRFS, local recurrence-free survival; NCDB, National Cancer Database; OR, odds ratio; OS, overall survival; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT, randomized controlled trial; RFS, recurrence-free survival; SEER, Surveillance, Epidemiology, and End Results.
Adrenocortical carcinoma (ACC) is a rare and aggressive ma- lignancy, with an annual incidence estimated at 0.7 to 2 cases per million individuals (1, 2). Despite improvements over time in the clinical management of ACC, its prognosis remains largely unfavorable (1, 3) due to its aggressive biological behav- ior (4) and limited therapeutic options (5). The 5-year survival rate ranges from 15% to 40% (6); however, there is significant heterogeneity in individual outcomes (7) influenced by stage, surgical margin, and hormone secretion of the tumor (7, 8).
The only potentially curative treatment is surgical removal of the primary tumor with regional lymph node dissection (4). Nevertheless, more than 50% of patients experience
recurrence, even after complete R0 resection (9, 10), leading to a poor prognosis. Treatment options for inoperable or metastatic disease are limited (11). Therefore, intensification of adjuvant therapies is an unmet clinical need to prevent dis- ease recurrence and improve survival outcomes (1, 3, 12).
Available therapies include mitotane, radiotherapy, cyto- toxic chemotherapy, and targeted therapies (13). Mitotane, an adrenolytic agent, has been widely used in clinical practice since 1960 (14, 15). It is administered alone or in combination with cytostatic chemotherapy in adjuvant and palliative care settings (16). However, the effectiveness of this treatment shows conflicting outcomes (13, 17) and significant side
effects (18, 19). Evidence for adjuvant radiotherapy is even more limited than for mitotane, and the role of adjuvant chemotherapy remains poorly defined (20).
Due to the rarity of ACC, prospective randomized studies are limited (21), and there is a need for level I evidence to guide clinical practice and decision-making about adjuvant therapies (8).
This meta-analysis aimed to comprehensively assess the im- pact and tolerability of current therapeutic modalities on overall survival (OS) and recurrence-free survival (RFS) in pa- tients with ACC, considering prognostic factors that affect disease outcomes.
Materials and Methods
We utilized the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to present the results of our research (Table S1) (22). We adhered to the methodological guidance outlined in the Cochrane Handbook (23, 24). Our study protocol was registered on PROSPERO (CRD42023475740), and we fully adhered to the protocol.
Search Strategy and Selection Criteria
On November 15, 2023, we performed a comprehensive search of 3 scientific databases: PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). We up- dated our search on October 18, 2024. In addition, we screened reference lists of eligible articles using “citationchaser” to identify all pertinent studies (25). Our search key focused on domains of adrenocortical carcinoma and various treatment approaches ((“adrenocortical” OR (“adrenal” AND cort*) AND (carcinoma* OR cancer*)) AND (“therapy” OR “treat- ment” OR “chemotherapy” OR “adjuvant” OR “radiotherapy” OR “irradiation” OR “radiation” OR “mitotan” OR “mito- tane” OR (“targeted” AND “therapy”) OR (“personalized” AND “therapy”) OR “immunotherapy” OR “cisplatin*” OR “doxorubicin” OR “etoposid*”)). No language or further re- strictions were applied during the systematic search.
After automatic and manual removal of duplicates with the assistance of reference management software (EndNote X9), 2 reviewers independently screened publications by title, ab- stract, and full text according to predefined eligibility criteria. Inter-rater agreement during selection was evaluated using Cohen’s kappa coefficient. Any conflicts in selection were re- solved by a third author.
Randomized controlled trials (RCT) and observational stud- ies were included in the analysis. Conference abstracts report- ing relevant data were also included in the analysis. Eligible articles compared the outcomes of patients with ACC receiving systemic (mitotane, cytotoxic chemotherapy, immunotherapy, targeted therapy) or localized (radiotherapy) nonsurgical ther- apy to those who did not. There were no restrictions on the age or extent of the disease in the patients enrolled. The primary outcomes of the eligible studies involved the assessment of sur- vival measures, such as OS, RFS, and local recurrence-free sur- vival (LRFS). These studies reported on survival duration or proportion in patients with ACC and presented results using unadjusted or adjusted Cox hazard models.
Articles examining the effectiveness of investigated therap- ies based on factors such as stage, surgical margin, hormone secretion, and serum mitotane levels were also included.
In addition, we considered secondary outcomes related to treatment side effects.
Case reports, case series, review articles, and studies with- out comparison groups were excluded.
Data Extraction
Two independent reviewers (A.P. and N.B.) extracted data from eligible studies using a predefined Excel datasheet (Office 365, Microsoft, Redmond, WA, USA). An independ- ent third reviewer (D.B.) resolved any disagreements. Data ex- tracted included first author, publication year, digital object identifier, study design, study duration, sample size in each comparison group, demographic data, outcome measures such as hazard ratios (HR) for adjuvant therapy with corre- sponding 95% CI in terms of RFS and OS derived from uni- variate or multivariate Cox regression analyses, along with survival durations and associated CIs, potential prognostic factors adjusted for in multivariate Cox regression model, and follow-up times.
Risk of Bias and Quality of Evidence Assessment
Two independent review authors (A.P. and N.B.) evaluated the risk of bias according to the Cochrane Collaboration rec- ommendation: the Risk of Bias-2 tool (26) was employed for RCTs, the ROBINS-I tool (27) for non-randomized, and QUIPS (28) for prognostic studies. Any disagreements were resolved by involving a third investigator (D.B.).
We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach (29) and GRADEpro software to assess the quality of evidence in our findings.
Statistical Analyses
To take into account the differences in the circumstances of the studies, we included random effect terms in all the analyses.
To pool the HRs, we used classical inverse variance random- effects meta-analysis on the logarithms of the HRs with the REML tau estimator and Hartung-Knapp adjustment. We vi- sualized the pooled outcomes and their 95% CIs on forest plots. Due to the low number of studies involved in the analysis, we did not provide prediction intervals. Heterogeneity was assessed by calculating the (univariate) I 2 measure and its CI and per- forming the Cochrane Q test. Subgroup analyses based on stage, hormone secretion, and surgical margin were also performed.
In observational studies, the unadjusted HR can be mislead- ing due to potential confounders; for example, certain treat- ments may be administered to patients with more severe conditions. Therefore, we pooled unadjusted and adjusted HRs separately. We pooled adjusted HRs (aHRs) from the multivariate Cox regression together with HRs of studies using matching-based adjustment. As randomization avoids con- founding, HRs of RCTs were included in the adjusted analyses. The studies involved used similar variables for the adjustments. Nevertheless, as differences in the covariates used may cause heterogeneity, following the approach of Renehan et al (30) for odds ratios, we created a table showing the covariates in- volved in the adjustment for each study.
Except for studies utilizing well-established large databases (National Cancer Database [NCDB] and Surveillance, Epidemiology, and End Results [SEER]), when clearly identi- fiable and significant overlap in patient populations was
Identification of new studies via databases and registers
Identification of new studies via other methods
Identification
Records identified from *: Databases (n = 19,183)
Records removed before screening: Duplicate records removed (n = 4,084) Records marked as ineligible by automation tools (n = 0) Records removed for other reasons (n = 0)
Records identified from: Citation searching (n = 686)
Records screened (n = 15,099)
Records excluded ** (n = 14,977)
Screening
Reports sought for retrieval (n = 122)
Reports not retrieved (n = 1)
Reports sought for retrieval (n = 11)
Reports not retrieved (n = 0)
Reports excluded: Insufficient data (n = 13) Duplicates of study cohort (n = 9) Without control group (n = 10) Wrong outcome (n = 2) Wrong study design (n = 5) Wrong intervention (n = 1)
Reports assessed for eligibility (n = 121)
Reports assessed for eligibility (n = 111
Reports excluded: Insufficient data (n = 3) Duplicates of study cohort (n = 1) Wrong study design (n = 2)
Studies included in systematic review (n = 86)
Included
Studies included in meta- analysis (n = 62)
*Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). ** If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.
Source: Page MJ, et al. BMJ 2021;372:n71. doi: 10.1136/bmj.n71.
This work is licensed under CC BY 4.0. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
observed, the study with the smaller sample size was excluded. However, in cases where overlap was not suspected but could not be definitively determined, the studies were retained.
The handling of publications utilizing the NCDB or SEER database required careful consideration. These databases cov- er an extensive timeframe; different studies used different sub- periods and patient inclusion criteria, leading to the varying extents of overlapping timeframes. Consequently, retaining only the largest study would result in significant loss of patient data. Using all the studies with a multivariate meta-analysis approach was also not feasible since the strength of the corre- lations between the published HRs presumably differs sub- stantially depending on the extent of the overlaps. Instead of the multivariate approach, to minimize selection bias, we con- ducted several sensitivity analyses using different nonoverlap- ping study sets. The analysis with the highest number of patients for a specific outcome was considered the primary re- sult and presented in the results section of the manuscript. The results from the sensitivity analysis with a smaller sample size for the corresponding primary result are provided in the Supplemental Material (22).
A few involved HRs were calculated by digitizing the Kaplan-Meier curves with the WebPlotDigitizer tool (31).
Publication bias analyses were conducted for the main out- comes when at least 10 studies were available (32). Publication bias was visually assessed using funnel plots and formally evaluated using Egger’s test.
A leave-one-out sensitivity analysis was performed for the main outcomes to explore the contribution of individual stud- ies to overall heterogeneity.
Statistical analyses were performed using packages “IPDfromKM” (v0.1.10), “meta” (v6.2.1), “metaSurvival” (v0.1.0), and “survival” (v3.3.1) of the R statistical software
(version 4.2.1.). A P value of less than 0.05 was considered sig- nificant for all statistical analyses.
Results
Study Selection
The systematic search yielded 19 183 articles. Of these, 86 met the eligibility criteria for inclusion in the systematic review, and 62 were included in the meta-analysis. The PRISMA flow- chart presents the selection process in Fig. 1 (33).
Characteristics of the Included Studies
The studies analyzed consisted of cohort studies and 2 RCTs. The basic characteristics are summarized in Table S2 (22). The geographical distribution of the included studies is illustrated in Fig. S1 (22).
Due to the limited number of articles comparing side effects of different therapies, conducting a meta-analysis on adverse effects was not feasible.
A summary of the findings from the systematic review is presented in Table S3 (22).
Effect of Mitotane on Overall and Recurrence-Free Survival
Fifteen articles provided univariate and 16 multivariate HRs for mortality risk in patients treated with mitotane. This ther- apy was significantly associated with prolonged OS in both unadjusted (HR: 0.62, CI: 0.45 to 0.85; heterogeneity I 2 : 63%; Fig. S2) (22) and adjusted analyses (aHR =0.54, CI: 0.41 to 0.70; I 2 : 50%; Fig. 2).
In stage I to III patients, adjuvant mitotane significantly re- duced the risk of death in multivariate analysis (aHR = 0.71,
| Author | Intervention | Control | Patients in | | Patients in C | Adjusted HR | aHR | 95%-CI |
|---|---|---|---|---|---|---|---|
| Stage I-IV | |||||||
| Loncar et al. 2015 | mitotane+operation | operation | 30 | 17 | 0.11 | [0.04; 0.29] | |
| Pan et al. 2023 | mitotane | no mitotane | 49 | 18 | 0.27 | [0.11; 0.68] | |
| Nowak et al. 2018 | mitotane | no mitotane | 57 | 7 | 0.29 | [0.09; 0.93] | |
| Berruti et al. 2017 | mitotane+operation | operation | 47 | 45 | 0.49 | [0.28; 0.85] | |
| Pedersen et al. 2024 | mitotane | no mitotane | 68 | 26 | 0.50 | [0.28; 0.88] | |
| Grubbs et al. 2010 | mitotane+operation | operation | 22 | 196 | 0.63 | [0.30; 1.33] | |
| Postlewait et al. 2016 | mitotane+operation | operation | 88 | 119 | 0.70 | [0.31; 1.57] | |
| Abiven et al. 2016 | mitotane | no mitotane | NA | NA | 1.29 | [0.60; 2.78] | |
| Random effects model (HK) | 0.46 | [0.25; 0.83] | |||||
| Heterogeneity: /2 = 63.4% [21.4%; 82.9%], +2 = 0.3107, p = Test for effect in subgroup: t7 = - 3.10 (p = 0.017) | 0.008 | ||||||
| Stage I-III | |||||||
| Fassnacht et al., 2010 | mitotane+operation | operation | 35 | 114 | 0.38 | [0.12; 1.24] | |
| Beuschlein et el. 2015 (G) | mitotane+operation | operation | 63 | 256 | 0.41 | [0.21; 0.80] | |
| Terzolo et al. 2023 | mitotane+operation | operation | 45 | 46 | 0.46 | [0.09; 2.25] | |
| Beuschlein et al. 2015 (E) | mitotane+operation | operation | 117 | 133 | 0.80 | [0.48; 1.34] | |
| Berruti et al. 2014 | mitotane+operation | operation | 251 | 273 | 0.82 | [0.61; 1.11] | |
| Calabrese et al. 2019 | mitotane+operation | operation | 100 | 52 | 0.82 | [0.41; 1.64] | |
| Random effects model (HK) | 0.71 | [0.52; 0.98] | |||||
| Heterogeneity: /2 = 3.8% [ 0.0%; 75.6%], [2 = 0.0111, p = Test for effect in subgroup: ts = - 2.75 (p = 0.040) | 0.392 | ||||||
| Stage IV | |||||||
| Debets et al. 2024 | mitotane | no mitotane | 59 | 108 | 0.48 | [0.25; 0.93] | |
| Recurrent disease | |||||||
| Calabrese et al. 2023 | mitotane+operation | operation | 64 | 42 | 0.30 | [0.11; 0.81] | |
| Unknown | |||||||
| Steenard et al. 2021 | mitotane | no mitotane | NA | NA | 0.61 | [0.37; 1.00] | |
| Random effects model (HK) | 0.54 | [0.41; 0.70] | |||||
| Heterogeneity: /2 = 49.6% [11.8%; 71.2%], +2 = 0.1103, p = Test for overall effect: t16 = - 4.91 (p < 0.001) | 0.011 | ||||||
| 0.1 0.5 1 2 10 favour intervention favour | control | ||||||
Abbreviations: aHR, adjusted hazard ratio; NA, not applicable.
CI: 0.52 to 0.98; I 2 : 4%; Fig. 2). Univariate analysis revealed a similar trend without statistical significance (HR = 0.80, CI: 0.43 to 1.49; I 2 : 40%; Fig. S2) (22).
Significantly improved survival was observed in patients who achieved a target plasma mitotane concentration of 14 mg/L compared to those who did not, based on both uni- variate (HR = 0.46, CI: 0.27 to 0.80; 12: 58%; Fig. S3) (22) and multivariate results (aHR = 0.47, CI: 0.33 to 0.67; I 2 : 0%; Fig. S4) (22). No significant difference in the effectiveness of mitotane on OS between hormone-producing and non-hormone-producing subgroups was observed (HR = 0.62, CI: 0.14-2.63; I 2 : 61%; Fig. S5) (22).
Adjuvant mitotane demonstrated a tendency to improve survival in patients who underwent RO resection (HR = 0.70, CI: 0.42 to 1.17; I 2 : 61%; Fig. S6) (22).
A total of 9 articles reported unadjusted and 10 reported ad- justed HRs on the risk of tumor recurrence in patients treated with adjuvant mitotane. Its use was significantly associated with prolonged RFS in adjusted analysis (aHR =0.60, CI: 0.43 to 0.84; I 2 : 64%; Fig. 3). A similar trend was observed in the unadjusted analysis at the border of statistical signifi- cance (HR = 0.72, CI: 0.48 to 1.06; I 2 : 75%; Fig. S7) (22).
Adjuvant mitotane significantly improved RFS in stages I to III based on multivariate analysis (aHR = 0.65, CI: 0.50 to 0.85; I 2 : 32%; Fig. 3). Univariate analysis showed a similar trend without statistical significance (HR = 0.79, CI: 0.51 to 1.22; 12: 55%; Fig. S7) (22).
It prolonged RFS in both the hormone-producing and non-hormone-producing subgroups (HR = 0.47, CI: 0.21 to 1.03; I 2 : 55%; Fig. S8) (22) and also significantly improved RFS in patients who underwent RO resection (HR =0.72, CI: 0.58-0.89; I 2 : 0%; Fig. S9) (22).
Effect of Radiotherapy on Overall, Recurrence-Free, and Local Recurrence-Free Survival
The analysis of 8 studies that reported adjusted HRs for OS in patients with ACC indicated that adjuvant radiotherapy pro- vided a clinically relevant benefit compared to surgery alone. This result was not statistically significant due to 2 outlier stud- ies with few participants (aHR = 0.66, CI: 0.38 to 1.15; Fig. 4). A similar result was observed in the analysis of 9 studies inves- tigating OS in patients treated with and without radiotherapy (aHR =0.76, CI: 0.47 to 1.22; Fig. S10) (22). Adjuvant radio- therapy improved OS in patients with ACC, with an odds ratio (OR) of 2.03 (CI: 0.60 to 6.84; I 2 : 49%; Fig. S11) (22).
In the adjusted analysis, adjuvant radiotherapy significantly increased OS in patients with stage I to stage III disease compared with surgery without radiotherapy (aHR =0.68, CI: 0.50 to 0.93; I 2 : 42%; Fig. 4). A similar trend was seen without statistical significance in the unadjusted analysis (HR = 0.79, CI: 0.50 to 1.27; I 2 : 37%; Fig. S12) (22) and the evaluation of OS in patients treated with and without radiotherapy based on adjusted HRs (aHR = 0.77, CI: 0.50 to 1.20; I 2 : 46%; Fig. S13) (22).
aHR
95%-CI
0.15
[0.04; 0.56]
0.34
[0.20; 0.58]
0.51 [0.28; 0.94]
1.40 [0.81; 2.42]
0.48 [0.12; 1.99]
| Author | Intervention | Control | Patients in I | Patients in C |
|---|---|---|---|---|
| Stage I-IV | ||||
| Nowak et al. 2018 | mitotane+operation | operation | 36 | 5 |
| Berruti et al. 2017 | mitotane+operation | operation | 47 | 45 |
| Grubbs et al. 2010 | mitotane+operation | operation | 22 | 196 |
| Postlewait et al. 2016 | mitotane+operation | operation | 88 | 119 |
| Random effects model (HK) | ||||
| Heterogeneity: 12 = 83.3% [57.5%; 93.4%], +2 = 0.5993, p < Test for effect in subgroup: t3 = - 1.63 (p = 0.201) | 0.001 | |||
| Stage I-III | ||||
| Calabrese et al. 2019 | mitotane+operation | operation | 100 | 52 |
| Puglisi et al. 2023 | mitotane+operation | operation | 226 | 134 |
| Fassnacht et al. 2010 | mitotane+operation | operation | 35 | 114 |
| Berruti et al. 2014 | mitotane+operation | operation | 251 | 273 |
| Beuschlein et al. 2015 (G) | mitotane+operation | operation | 63 | 256 |
| Terzolo et al. 2023 | mitotane+operation | operation | 45 | 46 |
| Beuschlein et al. 2015 (E) | mitotane+operation | operation | 117 | 133 |
| Random effects model (HK) | ||||
| Heterogeneity: /2 = 32.3% [ 0.0%; 71.2%], [2 = 0.0255, p = 0.181 Test for effect in subgroup: t6 = - 3.96 (p = 0.007) | ||||
| Random effects model (HK) | ||||
| Heterogeneity: 12 = 63.5% [30.2%; 80.9%], +2 = 0.1278, p = 0.002 Test for overall effect: t10 = - 3.40 (p = 0.007) | ||||
Adjusted HR
0.1
0.5 1
2
10
favour intervention
favour control
0.36 [0.20; 0.64]
0.55 [0.34; 0.88]
0.58 [0.29; 1.15]
0.66 [0.53; 0.83]
0.70 [0.47; 1.05]
0.74 [0.30; 1.84]
0.97 [0.65; 1.43]
0.65 [0.50; 0.85]
0.60 [0.43; 0.84]
Figure 3. Forest plot with pooled adjusted hazard ratio, representing the risk of tumor recurrence in patients treated with and without mitotane treatment based on disease stage.
Abbreviation: aHR, adjusted hazard ratio.
| Author | Patients in I | Patients in C | Database |
|---|---|---|---|
| Stage I-IV | |||
| Gharzai et al. 2019 | 39 | 39 | own data |
| Zhu et al. 2020 | 12 | 12 | own data |
| Test for effect in subgroup: t1 = - 0.18 (p = 0.890) | |||
| Stage I-III | |||
| Wu et al. 2023 | 46 | 59 | own data |
| Sabolch et al. 2015 | 20 | 20 | own data |
| Wu et al. 2021 | NA | NA | SEER |
| Ginsburg et al. 2021 | 259 | 1174 | NCDB |
| Else et al. 2014 | 59 | 217 | MEOR |
| Habra et al. 2013 | 16 | 32 | own data |
Random effects model (HK)
Heterogeneity: /2 = 41.7% [ 0.0%; 76.9%], [2 = < 0.0001, p = 0.127
Test for effect in subgroup: t5 = - 3.17 (p = 0.025)
Random effects model (HK)
Test for overall effect: t7 = - 1.77 (p = 0.121)
Adjusted HR
aHR
95%-CI
0.28
[0.12;
0.64]
2.81
[0.65;
12.12]
0.29
[0.11;
0.80]
0.51
[0.15;
1.74]
0.52
[0.29;
0.92]
0.68
[0.55;
0.85]
0.83
[0.50;
1.38]
1.59
[0.71;
3.59]
0.68
[0.50;
0.93]
0.66
[0.38;
1.15]
0.02
0.1
0.5
1
2
10
50
favour intervention
favour control
Abbreviations: aHR, adjusted hazard ratio; MEOR, Michigan Endocrine Oncology Repository; NA, not applicable; NCDB, National Cancer Database; SEER, Surveillance, Epidemiology, and End Results.
The effect of radiotherapy on OS in patients with stage IV disease was assessed across 3 studies reporting univariate HRs. Although we observed a clinical benefit in prolonging OS among stage IV patients, statistical significance was not reached due to high heterogeneity (HR = 0.59, CI: 0.21 to 1.69; I 2 : 60%; Fig. S14) (22).
The results of the sensitivity analysis for OS in radiotherapy-treated patients are presented in the Supplementary Material (Figs. S15-S29) (22).
Our results support the efficacy of adjuvant radiotherapy in improving OS in patients who underwent R1 resection (Fig. S30) (22).
Seven studies reported adjusted HRs for tumor recurrence risk in patients with ACC treated with adjuvant radiotherapy. Adjuvant radiotherapy provided a clinical benefit in prolong- ing RFS, although without statistical significance due to high heterogeneity (aHR = 0.65, CI: 0.35 to 1.23; I 2 : 56%; Fig. 5). Patients who received adjuvant radiotherapy showed
| Author | Intervention | Control | Patients in I | Patients in C | |
|---|---|---|---|---|---|
| Stage I-IV | |||||
| Gharzai et al. 2019 | irrad+operation | operation | 39 | 39 | |
| Zhu et al. 2020 | irrad+operation | operation | 10 | 11 | |
| Test for effect in subgroup: t1 = - 0.06 (p = 0.959) | |||||
| Stage I-III | |||||
| Sabolch et al. 2015 | irrad+operation | operation | 20 | 20 | |
| Wu et al. 2024 | irrad+operation | operation | 46 | 59 | |
| Else et al. 2014 | irrad+operation | operation | 59 | 217 | |
| Habra et al. 2013 | irrad+operation | operation | 16 | 32 | |
| Random effects model | (HK) | ||||
| Heterogeneity: 12 = 0% [ 0.0%; 84.7%], +2 = 0, p = 0.975 Test for effect in subgroup: t3 = - 8.33 (p = 0.004) | |||||
| Unknown | |||||
| Hatzaras et al. 2016 | irrad+operation | operation | 20 | 188 | |
Adjusted HR
aHR
95%-CI
0.39
[0.21;
0.71]
#
2.58
[0.85;
7.85]
0.66
[0.29;
1.49]
0.67
[0.38;
1.18]
0.74
[0.50;
1.10]
0.87
[0.24;
3.12]
0.71
[0.63;
0.81]
Random effects model (HK)
0.65
[0.35;
1.23]
0.01
0.1
0.5
1
2
10
favour intervention
favour control
Figure 5. Forest plot with pooled adjusted hazard ratio, representing the risk of tumor recurrence in patients treated with and without radiotherapy based on disease stage.
Abbreviation: aHR, adjusted hazard ratio.
| Author | Intervention | Control | Patients in I | Patients in C | Stage |
|---|---|---|---|---|---|
| Kimpel et al. 2021 | chemo+operation | operation | 31 | 31 | Stage II-IV |
| Margonis et al. 2015 | chemo+operation | operation | 17 | 148 | Stage I-IV |
| Pan et al. 2023 | chemo+operation | operation | 21 | 46 | Stage I-IV |
| Random effects model (HK) | |||||
| Heterogeneity: /2 = 64.4% [0.0%; 89.8%], +2 = 0.4725, p = 0.060 Test for overall effect: t2 = - 1.03 (p = 0.411) | |||||
| 0.01 | |||||
0.13
[0.03;
0.60]
Heterogeneity: /2 = 55.6% [0.0%; 80.9%], +2 = 0.1494, p = 0.036
Test for overall effect: t6 = - 1.66 (p = 0.148)
Adjusted HR
HR
95%-CI
0.26
[0.09; 0.74]
0.61
[0.15; 2.45]
1.26
[0.57; 2.79]
0.61 [0.08; 4.78]
0.1
0.5
1
2
10
favour intervention
favour control
Figure 6. Forest plot with pooled adjusted hazard ratio, representing the risk of death in patients treated with and without cytotoxic chemotherapy. Abbreviation: aHR, adjusted hazard ratio.
higher odds of RFS than those who did not (OR: 1.89, CI: 0.75 to 4.75; I 2 : 17%; Fig. S31) (22). Adjuvant radiotherapy significantly improved RFS in patients with stage I to III dis- ease (aHR = 0.71, CI: 0.63 to 0.81; I 2 : 0%; Fig. 5).
Five articles presented multivariate HRs for LRFS in pa- tients with ACC treated with adjuvant radiotherapy, showing a clear clinical benefit in prolonging LRFS without statistical significance due to high heterogeneity and small sample size (aHR = 0.55, CI: 0.16 to 1.90; I 2 : 56%; Fig. S32) (22). The pooled analysis showed a preference for adjuvant radiother- apy in improving LRFS, with an OR of 4.10 (CI: 0.89 to 18.87; I 2 : 68%; Fig. S33) (22).
Effect of Adjuvant Cytotoxic Chemotherapy, Chemoradiotherapy, and Systemic Therapy on Overall Survival
Three studies examined the effect of adjuvant cytotoxic chemotherapy on OS. The adjusted analysis suggested a po- tential clinical benefit in reducing the risk of mortality, but this finding lacked statistical significance (aHR = 0.61, CI: 0.08 to 4.78; I 2 : 64%; Fig. 6). Furthermore, the wide CI caused by an outlier study published by Pan et al (7) should be considered when interpreting this finding.
Adjuvant chemoradiotherapy prolonged OS without statis- tical significance (aHR = 0.78, CI: 0.44 to 1.36; I 2 : 8%; Fig. S34) (22).
Systemic therapy significantly improved OS (aHR = 0.74, CI: 0.57 to 0.97; I 2 : 0%; Fig. S35) (22).
Risk of Bias Assessment, Certainty of Evidence, and Assessment of Heterogeneity
Of the articles, 6% showed a low, 54% moderate, and 40% high risk of bias, primarily due to confounding factors such as missing adjustments for age and stage (Figs. S36-S38) (22).
As most of the included studies were observational, the lev- els of certainty were generally very low based on the findings and comprehensive assessment of the evidence (Table S4) (22).
During the assessment of publication bias, we found that in all but one case, the Egger test did not detect a significant small-study effect. For the adjusted mitotane OS HR, the P value was slightly below 0.05 (P =. 0397). Considering that no significant small-study effect was found for the adju- vant mitotane RFS HR, whose meta-analysis included a slight- ly different set of studies, we found no strong evidence for a small-study effect overall (Fig. S39-S41) (22).
Most analyses showed statistical heterogeneity due to underlying differences in study design and patient popula- tions, as well as small sample sizes and imbalances between intervention and control groups. In univariate analyses, het- erogeneity was likely largely attributable to differences in pa- tient characteristics and the absence of adjustment for prognostic factors. Subgroup analysis revealed that, among studies performing multivariate analysis to investigate the ef- fect of radiotherapy, small-sample institutional studies con- tributed disproportionately to heterogeneity compared to large database studies (Figs. S42-S44) (22). Additionally, leave-one-out analyses revealed that certain individual studies investigating the effect of mitotane on overall survival had a notable influence on heterogeneity. This pattern was not ob- served in studies evaluating recurrence-free survival outcomes related to adjuvant mitotane or in the radiotherapy subgroup. Furthermore, the pooled effect size did not change substantial- ly in any of the analyses (Figs. S45-S48) (22).
Discussion
Translational science plays a key role in translating research findings into routine medical practice (34, 35). This systematic review and meta-analysis addresses a gap by evaluating the ef- ficacy and safety of radiotherapy and available systemic ther- apies for ACC, considering the prognostic factors that influence disease outcomes.
Mitotane is the primary adjuvant therapy in ACC (36); however, its use remains controversial, and predictors of re- sponse are lacking (37). Two previous meta-analyses have ex- amined its effect in an adjuvant setting: both found a significant benefit for OS (38, 39), while only one showed a significant improvement in RFS (38). Our meta-analysis dem- onstrated that mitotane significantly improves OS and RFS, reducing the risk of death and tumor recurrence by 47% and 40%, respectively.
Current guidelines recommend adjuvant mitotane after ACC resection for patients at a high risk of recurrence (stage III-IV, R1 resection, or Ki-67> 10%). Nevertheless, for pa- tients at low or moderate risk (stage I-II, R0 resection, or Ki-67 ≤10%), its use should be discussed individually (36, 39). The ADIUVO trial, the first RCT comparing adjuvant mi- totane therapy to surveillance in resected ACC patients with low to intermediate risk (stage I-III, R0 resection, Ki67 ≤ 10%), reported no significant benefit of adjuvant mitotane in improving RFS or OS (40). However, this study was limited by the small sample size, and the recurrence rate was much lower than expected. Our subgroup analysis revealed that ad- juvant mitotane significantly prolonged OS and RFS in pa- tients with stage I to III disease. Nevertheless, it is important to emphasize that we were unable to adjust for other key prog- nostic factors, such as R status or Ki67, that influence disease outcomes. As a result, we could not clearly differentiate be- tween low- and high-risk groups concerning recurrence risk. Some of the patients included in our analysis might have been at higher risk of tumor recurrence, which could explain the more pronounced benefit of adjuvant mitotane observed in our study compared to its effect in low-risk patients.
According to the GRADE assessment (29), the certainty of evidence for the effect of mitotane on OS and RFS-both in the overall population and the subgroup with stage I to stage III-was rated as very low, mainly due to the retrospective na- ture of the included studies and lack of adjustment for key
clinical variables in several analyses. These factors substantial- ly reduce confidence in the estimated effect sizes, highlighting the need for prospective, well-controlled studies to better clar- ify the role of mitotane in ACC treatment.
Recent guidelines emphasize reaching mitotane blood levels above 14 mg/L (39). Our findings support this recommenda- tion and show that achieving this serum level significantly pro- longs OS. Based on the GRADE assessment (29), the certainty of evidence for this association was rated as moderate.
Hormone secretion by the tumor, especially hypercortiso- lism, is associated with poor prognosis (41, 42). Previous stud- ies have provided conflicting results on whether tumor hormone production affects the effectiveness of adjuvant mito- tane (43-45). Our results indicate that adjuvant mitotane may contribute to prolonged RFS regardless of the hormonal activ- ity of the tumor, with no significant difference observed in OS between hormone-producing and non-hormone-producing subgroups. Therefore, this treatment can be considered irre- spective of ACC hormone status.
Our findings suggest that adjuvant mitotane is associated with improved OS and RFS in patients with negative surgical margins, supporting its role in the management of this patient subgroup.
Our meta-analysis found side effects similar to previous re- ports, including gastrointestinal, neurological, hematological, and endocrine symptoms in mitotane-treated patients, some- times leading to treatment discontinuation (7, 40).
The findings of studies on adjuvant radiotherapy are incon- sistent (46). ACC was traditionally considered radio-resistant based on mixed results from case reports and series published until 2006 (47, 48). However, modern radiation techniques and high-quality retrospective studies have changed the per- ception of radiotherapy in the treatment of ACC (49).
Of the 4 previous meta-analyses that explored the impact of adjuvant radiotherapy in ACC, 3 concluded that it significant- ly prolongs LRFS (49-51). Of the 3 reviews that also evaluated its effectiveness in enhancing OS and RFS, 1 reported im- provements in both (49), whereas the 2 others found no sig- nificant difference (39, 50).
Our results suggest that adjuvant radiotherapy has a poten- tial clinical benefit in reducing the risk of local and distant re- currence and mortality. However, our findings were not statistically significant due to the high heterogeneity and small sample size of some studies. As indicated in previous reports, large patient cohorts are required to demonstrate a significant survival benefit from adjuvant radiation (46, 52), as individ- ual patient outcomes can heavily influence small trials.
Current guidelines do not establish a definitive consensus on using adjuvant radiotherapy. Its use in patients with R1/ Rx resection or stage III disease has been recommended only on an individual basis (36, 39). We found that adjuvant radio- therapy significantly prolonged OS and RFS in stages I to III and showed a clinical benefit in reducing the risk of mortality in stage IV disease. However, the evidence supporting its effi- cacy in stage IV is limited due to the low number of included studies. Several large retrospective cohorts using data from the NCDB have demonstrated its positive impact on survival in patients with R1 resection (8, 53).
According to the GRADE assessment (29), the certainty of evidence for the effect of radiotherapy on OS was rated as very low across all stages, including stage I to III and stage IV. For RFS, the certainty was moderate overall but very low within the stage I to stage III subgroup. Regarding LRFS, the
certainty of evidence was rated as low. These ratings reflect the retrospective observational nature of the included studies and the lack of reported event numbers in several analyses, which limits the robustness and interpretability of the findings.
The studies included in our meta-analysis described mild, tolerable adverse effects, such as nausea, fatigue, and skin tox- icities (52, 54).
Our findings suggest that radiotherapy should be consid- ered in both stage I to III and stage IV ACC, such as those with R1 resection. Nevertheless, RCTs are necessary to con- firm its efficacy.
The use of cytotoxic chemotherapy alone or with mitotane in an adjuvant setting remains a matter of debate (37). Platinum-based chemotherapy, such as EDP-M, is the stand- ard regimen (55), and is supported by the FIRM-ACT trial (56). Current guidelines do not agree on the routine use of ad- juvant cytotoxic chemotherapy; it should be considered on an individual basis in selected patients at a very high risk of recur- rence (36, 39). Our analysis did not confirm the efficacy of ad- juvant chemotherapy in reducing the risk of death, limited by a small patient sample and wide CIs. These findings highlight the need for robust, large-scale studies to clarify its role in the treatment of ACC. The ongoing randomized ADIUVO 2 trial, evaluating adjuvant mitotane alone vs its combination with cisplatin/etoposide after surgical resection, may provide fu- ture guidance for treating high-risk ACC patients (57). Cytotoxic chemotherapy can cause mild to severe side effects, including hematological, gastroenterological toxicity, alope- cia, and fatigue, as confirmed by our reviewed studies (20, 56).
Experimental studies have shown that mitotane and radio- therapy have synergetic effects (58), confirmed by several retro- spective cohorts (8, 59). Our findings indicate that adjuvant chemoradiotherapy tends to prolong OS without increasing the risk of side effects compared to radiotherapy alone (60).
In our study, we could not assess treatment strategies for pediatric ACC separately from adult cases due to the lack of data and comparative trials evaluating therapeutic efficacy in children. Current treatment protocols for pediatric ACC are primarily derived from adult management approaches (61). Surgery remains the cornerstone of therapy (62); however, in advanced stages, no standardized treatment guidelines are cur- rently available (63). Mitotane has demonstrated benefit par- ticularly in advanced stages, although it is poorly tolerated and requires close monitoring due to potential neurotoxicity and challenges in maintaining therapeutic levels (64). For high- risk or metastatic cases, mitotane is typically combined with chemotherapy, such as CED (cisplatin, etoposide, doxorubicin) (64), or regimens based on the German Society for Pediatric Oncology and Hematology for Malignant Endocrine Tumors (GPOH-MET) protocol (65). The use of radiotherapy in pedi- atric ACC remains controversial; although it may be beneficial in certain cases, its use should be carefully considered due to the high prevalence of germline TP53 mutations in this population, which substantially increases the risk of secondary malignan- cies (65). Targeted therapies have shown limited efficacy to date, underlining the need for improved molecular character- ization and the identification of novel therapeutic targets (63). Our findings underscore the urgent need for larger, more comprehensive studies specifically focused on the pediat- ric population to improve evidence-based management strat- egies in this vulnerable group.
Our study has several strengths, including a rigorous meth- odology and a comprehensive analysis of key ACC
treatments. Broad inclusion criteria were utilized, making the study population representative of the overall patient population and allowing for a large sample size despite the rarity of the disease. Our meta-analysis is the first to include subgroup analyses based on prognostic factors such as stage, surgical margin, and hormone secretion, and assess their im- pact on treatment efficacy.
To highlight the limitations, most of our findings were de- rived from retrospective cohorts, some of which, with small patient numbers, have the potential to introduce bias. Another limitation is the high heterogeneity among studies, which mainly results from differences in patient selection, baseline characteristics, study design, and methodological ap- proaches. Treatments with potentially severe side effects are typically offered to patients with more serious diseases, which may cause selection bias within the studies. The lack of con- sistent adjustment for relevant prognostic factors led to imbal- ances between intervention and control groups and further contributed to the variability in treatment outcomes. These findings highlight the need for future prospective studies in- vestigating the impact of different prognostic factors on the ef- ficacy of various therapeutic modalities. Additionally, the analysis of the effect of mitotane on OS may be influenced by publication bias. Most of our findings were based on evi- dence of low or very low certainty, which further limits the strength and generalizability of our conclusions. It is import- ant to highlight that developing appropriate treatment proto- cols would require evaluating the efficacy of each therapy at all stages; however, the current literature lacks adequate data to perform such an analysis.
Our findings indicate that mitotane significantly improves oncological outcomes in patients with ACC, while radiotherapy demonstrates potential advantages, especially in localized dis- ease. Monitoring serum mitotane levels is essential for maintain- ing mitotane concentrations above 14 mg/L and preventing toxicity. This drug may be effective regardless of hormonal activ- ity; however, this remains uncertain due to limited data, under- scoring the need for further research. It also improves oncological outcomes in patients with negative surgical margins.
Further research is essential to evaluate the efficacy and safety of adjuvant cytotoxic chemotherapy, as well as the combined use of adjuvant mitotane and radiotherapy. Additionally, more studies are needed to analyze the effective- ness of adjuvant treatments at different stages and in pediatric patients, and to identify novel therapeutic targets to improve patient outcomes. In addition, larger RCTs are required to minimize selection bias and balance confounding factors.
In conclusion, our results highlight the positive impact of mi- totane in improving recurrence-free and overall survival in the entire patient population, including those with localized tu- mors. Radiotherapy demonstrates potential advantages in en- hancing oncological outcomes, especially for stage I to III disease. These findings suggest broader consideration of each therapy in clinical practice. However, further research is needed to assess the efficacy and safety of the combined use of these therapies. Additional research is also required to confirm the ef- fectiveness of adjuvant cytotoxic chemotherapy, evaluate the stage-specific efficacy of radiotherapy and systemic treatments, and establish treatment protocols for childhood ACC.
The main conclusion of our study is that there is currently a lack of comprehensive and high-quality studies in the litera- ture, which is essential to improve evidence-based treatment protocols for this aggressive malignancy. Our findings
underscore the urgent need for more randomized controlled trials and well-designed, rigorous studies to support clinical decision-making and improve patient outcomes.
Acknowledgments
During the preparation of this work the authors used ChatGPT (OpenAI, version 4, 2024) in order to improve read- ability. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.
Funding
This study did not receive any funding or financial support.
Author Contributions
A.P., M.H., and M.G. designed the research and the study concept. A.P. performed the search and was the first reviewer for article screening and performed data extraction, risk as- sessment, and quality appraisal. N.B. was the second reviewer for article screening, data extraction, risk assessment, and quality appraisal. Any disagreements during the article selec- tion, risk assessment, and quality appraisal were resolved by D.B. T.K. analyzed and interpreted the data. A.P. and T.K. wrote the first draft of the manuscript with input from M.G., and M.H. M.H. provided methodological guidance, and M.G. supervised the research. M.G., A.F., A.P., and P.H. conducted a critical revision of the manuscript for im- portant intellectual content. All authors confirm that they had full access to all the data in the study and have contributed sufficiently to the work, including involvement in the concept, design, analysis, writing, or revision of the manuscript. All au- thors have read and agreed to the published version of the manuscript.
Disclosures
The authors have nothing to disclose.
Data Availability
Original data generated and analyzed during this study are in- cluded in this published article or in the data repositories listed in References.
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