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The efficacy of adjuvant mitotane therapy and radiotherapy following adrenalectomy in patients with adrenocortical carcinoma: A systematic review and meta-analysis
Ichiro Tsuboja,b,c, Mehdi Kardoust Parizia,d, Akihiro Matsukawaa,e, Stefano Mancona,f, Marcin Miszczyka,8, Robert J. Schulza,h, Tamás Fazekasª,1, Anna Cadenara,j, Ekaterina Laukhtinaª,k, Tatsushi Kawadaa,C, Satoshi Katayamaa,C, Takehiro Iwataa,c, Kensuke Bekkua,C, Koichiro Wadaa,b, Mesut Remziª, Pierre I. Karakiewicz , Motoo Araki“, Shahrokh F. Shariata,k,m,n,o,p,q,i,r,*
a Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
” Department of Urology, Shimane University Faculty of Medicine, Shimane, Japan
” Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
d Department of Urology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
e Department of Urology, Jikei University School of Medicine, Tokyo, Japan Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy § Collegium Medicum - Faculty of Medicine, WSB University, Dąbrowa Górnicza, Poland
h Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Department of Urology, Semmelweis University, Budapest, Hungary
¿ Unit of Oncologic Minimally Invasive Urology and Andrology, Department of Experimental and Clinical Medicine, Careggi Hospital, University of Flor- ence, Florence, Italy
k Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
l Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre, Montreal, Quebec, Canada ” Department of Urology, University of Texas Southwestern, Dallas, TX ” Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic ° Division of Urology, Department of Special Surgery, Jordan University Hospital, The University of Jordan, Amman, Jordan P Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria
9 Research center of Evidence Medicine, Urology department Tabriz University of Medical Sciences, Tabriz, Iran “Department of Urology, Weill Cornell Medical College, New York, NY
Received 15 August 2024; received in revised form 29 August 2024; accepted 15 September 2024
Abstract
Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with a high recurrence rate after surgical therapy with cura- tive intent. Adjuvant radiotherapy (RT) and mitotane therapy have been proposed as options following the adrenalectomy. However, the efficacy of adjuvant RT or mitotane therapy remains controversial. We aimed to evaluate the efficacy of adjuvant therapy in patients who underwent adrenalectomy for localised ACC. The PubMed, Scopus, and Web of Science databases were queried on March 2024 for studies evaluating adjuvant therapies in patients treated with surgery for localized ACC (PROSPERO: CRD42024512849). The endpoints of interest were overall survival (OS) and recurrence-free survival (RFS). Hazard ratios (HR) with 95% confidence intervals (95%CI) were pooled in a random-effects model meta-analysis. One randomized controlled trial (n = 91) and eleven retrospective studies (n = 4,515) were included. Adjuvant mitotane therapy was associated with improved RFS (HR: 0.63, 95%CI: 0.44-0.92, p = 0.016), while adjuvant RT did not reach conventional levels of statistical significance (HR:0.79, 95%CI:0.58-1.06, p = 0.11). Conversely, Adjuvant RT was associated with improved OS (HR:0.69, 95%CI:0.58-0.83, p<0.001), whereas adjuvant mitotane did not (HR: 0.76, 95%CI: 0.57-1.02, p = 0.07). In the subgroup analyses, adjuvant mitotane was
*Corresponding author.
E-mail address: shahrokh.shariat@meduniwien.ac.at (S.F. Shariat).
associated with better OS (HR:0.46, 95%CI: 0.30-0.69, p < 0.001) and RFS (HR:0.56, 95%CI: 0.32-0.98, p = 0.04) in patients with negative surgical margin. Both adjuvant RT and mitotane were found to be associated with improved oncologic outcomes in patients treated with adrenalectomy for localised ACC. While adjuvant RT significantly improved OS in general population, mito- tane appears as an especially promising treatment option in patients with negative surgical margin. These data can support the shared decision-making process, better understanding of the risks, benefits, and effectiveness of these therapies is still needed to guide tailored management of each individual patient. @ 2024 The Author(s). Published by Elsevier Inc. This is an open access arti- cle under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
1. Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive cancer with an incidence rate of approxi- mately 1-2 cases per million people annually [1]. The 5-year survival rates are 60%-80% for tumors confined to the adrenal gland, 35%-50% for locally advanced disease, and 0% and 28% for metastatic disease [1]. Sur- gical resection is the primary treatment option for clini- cally localized and locally advanced ACC with curative intent [2].
However, the recurrence rate following adrenalec- tomy can be as high as 60%-80%, highlighting the need for multimodal treatment for most of these cancers [3]. Indeed, even with complete surgical resection and negative margins, approximately 30% of patients may still experience local recurrence of ACC [4]. In patients with positive surgical margins on the adrenalectomy specimen, the rate of local recurrence rates is as high as 60% [3]. The guidelines [1] recommend the using adjuvant mitotane for patients with a high risk of recur- rence (stage III, or positive surgical margin, or Ki67 >10%). Although the effect of adjuvant radiotherapy (RT) has been controversial [5], novel data support the addition of adjuvant RT to adjuvant mitotane therapy for ACC patients with positive surgical margins or stage III disease [1]. While those 2 strategies seem promising, strong evidence is lacking. Therefore, we conducted this systematic review and meta-analysis to clarify the oncologic efficacy of adjuvant therapies with RT and/or mitotane following adrenalectomy for local- ized ACC.
2. Evidence acquisition
We registered the study with the International Prospec- tive Register of Systematic Reviews (PROSPERO: registra- tion number: CRD 42024512849). This systematic review and meta-analysis was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (PRISMA 2020 checklist, Supple- mentary Table 1).
2.1. Search strategy
On March 2024, the MEDLINE, Scopus, and Web of Science databases were searched to identify studies investi- gating the efficacy of adjuvant therapy following adrenalec- tomy for ACC. The search terms included: “adjuvant” and “adrenocortical carcinoma”. The detailed search strategy for each database is shown in the Supplementary Appendix 1. In addition, searches of reference lists were performed to identify additional studies of interest. Two investigators independently performed an initial screening based on the titles and abstracts and noted the cause of exclusion of ineli- gible reports. Full texts were retrieved and evaluated for eli- gibility. In the case of discrepancies, they were solved by consensus among the authors.
2.2. Inclusion and exclusion criteria
We used the population, interventions, comparator, out- comes, and study design (PICOS) framework to define the eligibility criteria (Supplementary Table 2) [6]. We included studies that evaluated the efficacy of adjuvant ther- apy following the adrenalectomy for ACC. We compared these patients with patients who did not undergo adjuvant therapy following the adrenalectomy to assess recurrence- free survival (RFS) and overall survival (OS). Adjuvant therapy included mitotane therapy, radiotherapy. We did not include other adjuvant therapy, including chemother- apy, immunotherapy. We excluded studies that lacked orig- inal patient data, along with reviews, letters, editorial remarks, responses from authors, case reports, and articles not written in English. When encountering duplicate cohorts, we selected either the more recent or the higher- quality publication.
2.3. Data extraction
Two reviewers independently extracted data on baseline study and patient’s characteristics. From each study, we gathered essential details: the first author’s name, publica- tion year, country, design of the study, type of adjuvant therapy, criteria for both inclusion and exclusion, the main endpoint, the number of participants, the median duration of follow-up, proportion of sex, their median age, median
Ki67 index, hormone secretion, surgical margin status, and oncological outcomes including RFS and OS. All discrep- ancies were resolved by consensus with co-authors.
2.4. Quality assessment and risk of bias
Risk of bias were evaluated using the Risk-of-Bias (ROB version 2) tool as outlined in the Cochrane Handbook for Systematic Reviews of Interventions [7]. We used the Risk Of Bias In Nonrandomized Studies - of Interventions (ROBINS-I) tool to evaluate bias in nonrandomized studies [8]. The RoB2 and ROBINS-I assessment of each study was performed by 2 authors independently, any disagree- ments were resolved by consensus with a third author.
2.5. Statistical analysis
All statistical analyses were performed using R version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria, 2023; meta). Statistical significance was estab- lished at P < 0.05. To evaluate the oncological effect of adjuvant therapy following adrenalectomy in patients with ACC, we generated and analyzed forest plots presenting adjusted multivariable hazard ratios (HR) with 95% confi- dence intervals (CI). Subgroup analyses were performed according to the types of control group. A random-effects model was utilized to calculate the pooled HR considering the differences in study population and designs. Cochrane’s Q test and the I-square test were used to evaluate the hetero- geneity. Significant heterogeneity was indicated by a P- value <0.05 in the Cochrane’s Q-tests and I statistics greater than 50%. When significant heterogeneity was observed, we attempted to investigate the causes of hetero- geneity [9]. We preformed sensitivity analyses to increase homogeneity and confirm the reliability of our results.
3. Evidence synthesis
3.1. Study selection and characteristics
Our search strategy was depicted in Supplementary Fig. 1. We identified 1 randomized controlled trial (RCT) and 11 retrospective studies comprising 4,606 eligible patients for meta-analyses [10-21]. Adjuvant therapies included RT and mitotane. One RCT [11] and 2 retrospective studies [16,17] conducted a comparison between adjuvant mitotane and surveillance (without both adjuvant mitotane and RT), while other studies [10,12-15,18-21] included the patients who underwent either adjuvant RT or adjuvant mitotane. Regarding tumor stage diagnosis, 5 studies [10,11,13,15,18,19] employed European Network for the Study of Adrenal Tumors (ENSAT) staging classification [22], while 4 studies [12,14,16,17] utilized the TNM classi- fication. Among these, 4 studies [10,11,13,16] specifically focused on patients with tumor stage III or lower, as diag- nosed by the ENSAT staging classification. Additionally, 3
studies [11,13,16] exclusively included patients with a neg- ative surgical margin. The detail of patient’s characteristics are summarized in Table 1. The dose of mitotane and RT were summarized in Supplementary Table 3.
3.2. Risk of bias assessment
Authors’ judgments about each domain for each included study were presented in Supplementary Table 4 and Supplementary Fig. 2. Although there was no concern in 1 RCT, the other nonrandomized studies presented con- cerns in certain domains. Funnel plots of each analysis are depicted in Supplementary Fig. 3.
3.3. Meta-analysis
The results of our analyses are summarized in Table 2.
3.3.1. Overall survival (OS)
3.3.1.1. Adjuvant RT. Five studies [10,13,14,19,20], compris- ing 2,342 patients, were analyzed to compare OS in patients who underwent adjuvant RT to those who did not. 652 (27.8%) patients who underwent adjuvant RT and 1690 (72.2%) who did not. Among both groups, a significant pro- portion of patients administered adjuvant mitotane therapy (Table 1). Adjuvant RT significantly improved OS com- pared to no-adjuvant RT (HR: 0.69, 95%CI: 0.58-0.83, P < 0.001; Fig. 1A). Cochran’s Q tests and the 12 statistics showed no significant heterogeneity.
3.3.1.2. Adjuvant mitotane. Eight studies [11,12,15-18,21], comprising 2,655 patients, were analyzed to compare OS in patients who were administrated adjuvant mitotane to those who did not. The study included 931 (35.1%) patients who underwent adjuvant mitotane therapy and 1,353 (51%) patients who did not. Among these, 4 studies [11,12,15,16] did not include the patients (n = 682) who underwent any other adjuvant therapy, while the other studies included patients (n = 671) who underwent other adjuvant therapies, including RT or chemotherapy, in conjunction with adju- vant mitotane therapy. There was no significant difference in OS between the 2 groups (HR: 0.76, 95% CI: 0.57-1.02, P = 0.7; Fig. 1B). Subgroup analysis indicated that there was no significant difference in OS between adjuvant mito- tane therapy and no other therapy (without any adjuvant therapy) (HR:0.80, 95%CI: 0.48-1.32; Fig. 1B) versus no- adjuvant mitotane (HR:0.72, 95% CI: 0.57-1.01; Fig. 1B). Subgroup analysis in patients with negative surgical mar- gins revealed that adjuvant mitotane significantly improved OS compared to no-adjuvant mitotane (HR: 0.46, 95% CI: 0.30-0.69, P < 0.001; Fig. 1C). Cochran’s Q tests and the I 2 statistic showed no significant heterogeneity.
| Characteristics of included studies. | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Author/ | Country | Period | Number of patients | Median follow-up duration, mo | Sex M:F | Median age, | Tumor stage (%) | Median | Ki67 | Hormone | secretion Margin status (%) | ||||
| Year/ | Total | Adjuvant RT | No Adjuvant RT | Adjuvant mitotane | No Adjuvant mitotane | years | index (%) | (%) | |||||||
| study design | |||||||||||||||
| Wu et al. 2024/ | China | 2015-2021 | 105 | 46 (44) | 59 (56) | 70 (67) | 35 (33) | I:34.1 | I:20:26 | I:42 C:55 | ENSAT | I:15 | I:11(24) | I: R0:35 (76) R1:6 | |
| retrospective | C:39.2 | C:31:28 | I:I:2 (4) II:35 (76) | C:20 | C:19 (32) | (13) | |||||||||
| III:8 (17) | C: R0:47 (80) R1:5 | ||||||||||||||
| C:I:5 (8) II:35 (59) | (8) | ||||||||||||||
| III:8 (14) | |||||||||||||||
| Terzolo et al. | Italy, Germany, | 2008-2018 | 91 | 0 | 0 | 45 (49) | 46 (51) | 48 | I:12 (27):33 (73) | I:51 C:50.5 | ENSAT | I:5 | I:20 (44) C:16 | (36) R0 100% | |
| 2023/ | France, | C:15 (33):31 | I:I:9 (20) II:30 (67) | C:5 | |||||||||||
| open label, | Canada, USA, | (67) | III:6 (13) | ||||||||||||
| randomized, | Brazil, | C:I:12 (26) II:29 (63) | |||||||||||||
| phase 3 trial | Switzerland | III:5 (11) | |||||||||||||
| NCT00777244 | |||||||||||||||
| ADIUVO | |||||||||||||||
| Passman et al | USA | 2010-2019 | 1175 | 104(9.3) | 539(48.3) | 275(24.6) | 539(48.3) | 37 | 445 (37.9): | 54.1 | TNM | N/A | N/A | R0: 866 (80.9) | |
| 2023/ | 730 (62.1) | I:113 (9.6) II:539 | R1or2:204 (19.1) | ||||||||||||
| retrospective/ | (45.9) III:523 | ||||||||||||||
| utilizing the | (45.5) | ||||||||||||||
| NCDB | |||||||||||||||
| Wu et al. 2021/ | USA | 2004-2016 | 365 | 55 (15) | 310 (85) | N/A | N/A | 26 | I: 26 (47):29 (53) | I:53 C:54.5 | ENSAT | N/A | N/A | N/A | |
| retrospective/ | C: 112 (36):198 | I:I/II:25 (45) III:30 | |||||||||||||
| utilizing the SEER | (64) | (55) C:I/II:189 | |||||||||||||
| database | (61) III: 121 (39) | ||||||||||||||
| Ginsburg et al. | USA | 2004-2017 | 1433 | 259(18) | 1174(82) | N/A | N/A | 38.7 | I: 104 (40):155 | I:53 C:54 | TNM | N/A | N/A | I:R0:141 (54) | |
| 2021/ | (60) C: 468 | I: I/II 89 (35) III/ | R1:118 (46) C: | ||||||||||||
| retrospective/ | (40):707 (60) | IV:92 (35) | R0:949 (81) | ||||||||||||
| utilizing the | Missing78 (30) | R1:225 (19) | |||||||||||||
| NCDB | C:I/II 322 (27) III/ | ||||||||||||||
| IV:202 (17) | |||||||||||||||
| Missing650 (55) | |||||||||||||||
| Calabrese et al. | Italy | 2001-2015 | 152 | 0 | 0 | 100 (66) | 52 (34) | I:57 | I: 37 (37):63 (63) | I: 45 | ENSAT | I :< 10:23 | I:51(51) C:21 | (40) I:R0:71 (74) R1:22 | |
| 2019 | C:45 | C: 21 (40.4):31 | C: 49.5 | I:I/II 77 (77) III:23 | (25.3) C :< | 10:21 | (23) C:R0:40 | ||||||||
| retrospective | (59.6) | (23) | (48.8) | (77) R1:12 (23) | |||||||||||
| C:I/II 38 (73) III/ | |||||||||||||||
| IV:14 (27) | |||||||||||||||
| Berruti et al. 2017 | Italy | 1985-2003 | 102 | 0 | 0 | 47 (46) | 45 (44) | I:141 | I: 11 (23):36 (77) | I: 42 C:44 | TNM | N/A | I:24(51) C:17 | (38) R0 100% | |
| retrospective | C:142 | C:18 (40):27 | I:I:3 (6) II:27 (57) | ||||||||||||
| (60) | III: 11 (24) IV:6 | ||||||||||||||
| (13) | |||||||||||||||
C: I:4 (9) II: 25 (57) III: 11 (25) IV:4 (9)
(continued on next page)
I. Tsuboi et al. / Urologic Oncology: Seminars and Original Investigations 43 (2025) 297-306
| Author/ Country Year/ study design | Period | Number of patients | Median follow-up duration, mo | Sex M:F | Median age, Tumor stage (%) years | Median Ki67 index (%) | Hormone secretion (%) | Margin status (%) | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | Adjuvant RT | No Adjuvant RT | Adjuvant mitotane | No Adjuvant mitotane | |||||||||
| Postlewait et al. USA | 1993-2014 | 207 | 18 (9) | 189 (91) | 88 (43) | 119 (57) | 44 | I: 45 (38):73 (62) | I: 51 C:53 | TNM | N/A | I:48(58) C:35(32) | I:R0:51 (65) R1:23 |
| 2016 | C:35 (39):53 | I:I:2 (2) II:22 (27) | (30) R2:4 (5) | ||||||||||
| retrospective | (61) | III:24 (29) IV:34 | C:R0:76 (72) | ||||||||||
| (42) | R1:24 (23) R2:6 | ||||||||||||
| C: I:9 (8) II: 41 (37) III:24 (29) IV:25 | (6) | ||||||||||||
| (23) | |||||||||||||
| Beuschiein et al. German | 1979-2011 | 319 | 30 (9) | 289 (91) | 84 (26) | 235 (74) | 43.7 | 112:207 | 46.3 ENSAT I:27 (9) II:202 (63) | 10 | 101 (32) | R0: 100% | |
| 2015 | |||||||||||||
| retrospective | III:90 (28) | ||||||||||||
| German cohort | |||||||||||||
| Else et al. 2014 USA | 1979-2013 | 391 | 276 (71) | 115 (29) | 264 (68) | 127 (32) | 35.2 | 158:233 | 47.4 | ENSAT | N/A | 167(43) | R0:164 (42) |
| retrospective | I:12 (3) II:169 (43) | R1: 227 (58) | |||||||||||
| III: 110 (28) | |||||||||||||
| IV:100 (26)ª | |||||||||||||
| Habra et al. 2013 USA | 1998-2011 | 48 | 16 (33) | 32 (67) | 14 (29) | 34 (71) | I:22 | I:11 (34):21 (66) | I: 48 C:44 N/A | N/A | I:8(50) C:15(47) | I:R0:7 (44) R1:6 | |
| retrospective | C:33 | C:6 (38):10 (62) | I:II:9 (56) III:7 (44) | (38):R2:1 (6) C: | |||||||||
| C:II: 17 (53) III:15 | R0:13 (41) | ||||||||||||
| (47) | R1:11 (34)R2:2 (6) | ||||||||||||
| Grubbs et al. 2010 USA | 1991-2008 | 218 | N/A | N/A | 28 (13) | 190 (87) | 88 | I:14:8 | I: 50 C:46 Lee classification | N/A | I: 14(63) | I: R0:22 (100) | |
| retrospective | C128:68 | system | C: 107(54) | C: R0:184 (94) | |||||||||
| I:I/II 5 (26) III:14 | R1:12 (0.6) | ||||||||||||
| (74) | |||||||||||||
| C:I/II 77 (45) III/ | |||||||||||||
| IV:95 (55) | |||||||||||||
Stage IV was excluded from the adjuvant setting.
C = control, ENSAT = European Network for the Study of Adrenal Tumors, I = interventions, R0 = negative surgical margin, R1 = positive surgical margin.
I. Tsuboi et al. / Urologic Oncology: Seminars and Original Investigations 43 (2025) 297-306
| Adjuvant therapy | Overall survival | Recurrence-free survival |
|---|---|---|
| Radiotherapy (RT) | vs nonadjuvant RT | vs nonadjuvant RT |
| HR: 0.69, 95%CI: | HR: 0.79, 95%CI: | |
| 0.58-0.83, P < | 0.58-1.06, P = | |
| 0.001, | 0.11, | |
| I 2 = 52%, P = 0.08 | I 2 = 73%, P = 0.001 | |
| Mitotane | vs control group | vs control group |
| HR: 0.76, 95% CI: | HR: 0.63, 95% CI: | |
| 0.57-1.02, P = | 0.44-0.92, P = | |
| 0.07, | 0.016, | |
| I 2 = 58%, P = 0.02 | I 2 = 10%, P = 0.3 | |
| vs surveillance | vs surveillance | |
| HR: 0.80, 95%CI: | HR: 0.40, 95% CI: | |
| 0.48-1.32 | 0.28-0.57 | |
| vs nonadjuvant mitotane | vs nonadjuvant mitotane | |
| HR: 0.72, 95% CI: | HR: 0.80, 95% CI: | |
| 0.57-1.02 | 0.55-1.17 | |
| Studies included only negative surgical margin | Studies included only negative surgical margin | |
| HR: 0.46, 95% CI: | HR: 0.56, 95% CI: | |
| 0.30-0.69, p < | 0.32-0.98, P = | |
| 0.001, | 0.04, | |
| I 2 = 0%, P = 0.9 | I 2 = 66%, P = 0.052 |
3.3.2. Recurrence-free survival (RFS)
3.3.2.1. Adjuvant RT. Three studies [10,19,20], comprising 544 patients, were analyzed to compare RFS in patients who underwent adjuvant RT to those who did not; 338 (62.1%) underwent adjuvant RT and 206 (37.9%) did not. Among both groups, some patients were administered adjuvant mitotane therapy in conjunction with adjuvant RT. Adju- vant RT did not significantly improve RFS compared to no- adjuvant RT (HR: 0.79, 95%CI: 0.58-1.06, P = 0.11; Fig. 2A). Cochran’s Q tests and the I statistic showed no significant heterogeneity.
3.3.2.2. Adjuvant mitotane. Seven studies [11,15-19,21], com- prising 1,480 patients, were analyzed to compare RFS in patients who received adjuvant mitotane to those who did not; 656 (44.3%) patients received adjuvant mitotane ther- apy and 814 (55%) did not. Three studies [11,15,16] did not include the 143 (17.6%) patients who received additional adjuvant therapy, while other studies included 671 (82.4%) patients who did it (i.e., RT or chemotherapy in conjunction with adjuvant mitotane therapy). Adjuvant mitotane therapy significantly improve RFS compared to no-adjuvant mito- tane therapy (HR: 0.63, 95% CI: 0.44-0.92, P = 0.016; Fig. 2B). Subgroup analyses indicated that adjuvant mito- tane therapy significantly improved RFS compared to sur- veillance (HR: 0.40, 95% CI: 0.28-0.57; Fig. 2B), while there was no significant difference between adjuvant
mitotane therapy and no-adjuvant mitotane therapy (HR: 0.80, 95% CI: 0.55-1.17; Fig. 2B). The subgroup analysis in patients with negative surgical margin at time of adrenal- ectomy, revealed that adjuvant mitotane significantly improved OS compared to no-adjuvant mitotane (HR: 0.56, 95% CI: 0.32-0.98, P = 0.042; Fig. 2C). Cochran’s Q tests showed no significant heterogeneity
4. Discussion
In this systematic review and meta-analyses, we ana- lyzed the impact on oncologic outcomes of adjuvant thera- pies after adrenalectomy in patients treated surgically for localized ACC. We identified 3 clinically important find- ings. First, adjuvant RT significantly improved OS. Second, adjuvant mitotane therapy significantly improved RFS com- pared to surveillance, although it had no significant impact on OS in whole study population. Third, in patients with negative surgical margins, adjuvant mitotane therapy sig- nificantly improved both OS and RFS.
To date, 3 meta-analyses [1,5,23] have reported the effi- cacy of adjuvant RT. Fassnacht et al. [1] and Viani et al. [5] reported no significant differences in OS and RFS between adjuvant RT and no-adjuvant RT (OS: HR: 1.0, 95%CI: 0.7 -1.5, P = 0.4 and RFS: HR: 0.8, 95%CI: 0.6-1.1, P = 0.4, respectively) (OS: Risk Ratio (RR): 0.77, 95%CI: 0.49 -1.22, P = 0.27 and RFS: RR: 0.94, 95%CI: 0.77-1.13, P = 0.15, respectively). On the other hand, Zhu et al. [23] reported adjuvant RT significantly improve OS and RFS compared to radical surgery without adjuvant RT (Odd ratio (OR): 0.41, 95%CI: 0.23-0.75, P = 0.004, OR: 0.44, 95%CI: 0.24-0.81, P = 0.009). The differences between the studies [1,5,23] were in the number of patients they included, resulting in limited power of the analyses to detect significant differences. However, as our analysis included the largest number of studies and patients, we believe that it provides currently the most accurate meta- analytic estimate based on available literature data. A remaining challenge is to explain the beneficial impact of adjuvant RT on OS but not RFS. Previous 2 studies [5,23] demonstrated that adjuvant RT improves local, but not dis- tant disease control, which can be attributed to the local mechanism of action of RT. Thus, our hypothesis is that the inclusion of both local and distant recurrences in our RFS analysis might have hindered our ability to show an improvement in RFS, but controlling local RFS still has a long-term effect on OS.
A previous study [24] indicated that mitotane could potentially enhance the efficacy of RT. Some patients included in our analyses underwent both adjuvant RT and adjuvant mitotane therapy. The data suggests that combin- ing both adjuvant therapies could lead to better OS and RFS. Indeed, Else et al. [19] reported that combination of RT and mitotane significantly improve RFS (HR: 0.41, 95%CI: 0.18-0.93, P = 0.3), although there was no signifi- cant improvement in OS. Conversely, Passman et al. [12]
(A) Adjuvant RT
Study
Wu et al. 2024
Wu et al. 2021
Ginsburg et al. 2021
Else et al. 2014
Habra et al. 2013
Random effects model
Heterogeneity: /2 = 52%, +2 < 0.0001, 2 = 8.34 (p = 0.080)
Test for overall effect: z = - 4.03 (p < 0.001)
Hazard Ratio
HR
95%-CI Weight
0.29
[0.11; 0.80]
3%
0.52
[0.29; 0.92]
10%
0.68
[0.55; 0.85]
69%
0.83
[0.50; 1.38]
13%
1.59 [0.71; 3.59]
5%
0.69 [0.58; 0.83]
100%
0.2
0.5
1
2
Favours [Adjuvant RT] Favours [No Adjuvant RT]
(B) Adjuvant mitotane
Study
subgroup = surveillance
Terzolo et al. 2023
Passman et al 2023
Calabrese et al. 2019
Berruti et al. 2017
Random effects model
Heterogeneity: /2 = 68%, 12 = 0.1534, x2 = 9.43 (p = 0.024)
subgroup = No Adjuvant mitotane
Postiewait et al. 2016
Beuschiein et al. 2015
Else et al. 2014
Grubbs et al. 2010
Random effects model
Heterogeneity. 1 = 33%, 12 = 0.0418, x3 = 4.51 (p = 0.211)
Random effects model
Heterogeneity: /2 = 58%, 12 = 0.0896, x2 = 16.80 (p = 0.019)
Test for overall effect: z =- 1.82 (p = 0.069)
Test for subgroup differences: x2 = 0.11, df = 1 (p = 0.740)
Hazard Ratio
HR
95%-CI
Weight
0.46
[0.09; 2.25]
3%
1.19
[0.94; 1.51]
21%
0.89
[0.45; 1.77]
11%
0.49
[0.28; 0.85]
13%
0.80
[0.48; 1.32]
48%
0.88
[0.49; 1.57]
13%
0.41
[0.21; 0.80]
11%
0.89
[0.62; 1.27]
18%
0.63
[0.30; 1.33]
10%
0.72
72 [0.51; 1.01]
52%
0.76 [0.57; 1.02]
100%
02
0.5
1
2
Favours [Adjuvant mitotane] Favours [control]
| (C) Adjuvant mitotane with negative surgical margins | ||||
|---|---|---|---|---|
| Study | Hazard Ratio | HR | 95%-CI | Weight |
| subgroup = surveillance | ||||
| Terzolo et al. 2023 | 0.46 | [0.09; 2.25] | 7% | |
| Berruti et al. 2017 | 0.49 | [0.28; 0.85] | 55% | |
| Random effects model | 0.49 | [0.29; 0.82] | 62% | |
| Heterogeneity: /2 = 0%, 12 = 0. %} = 0.01 (p = 0.936) | ||||
| subgroup = No Adjuvant mitotane | ||||
| Beuschiein et al. 2015 | 0.41 | [0.21; 0.80] | 38% | |
| Random effects model | 0.46 | [0.30; 0.69] | 100% | |
| Heterogeneity: /2 = 0%, 12 = 0, 2 = 0.17 (p = 0.917) | ||||
| Test for overall effect: z = - 3.75 (p < 0.001) | 0.2 0.5 | 1 2 | ||
| Test for subgroup differences: x2 = 0.17, df = 1 (p = 0.682) | Favours [Adjuvant mitotane] | Favours [control] | ||
reported no OS benefit to the combination of adjuvant RT and mitotane therapy in a retrospective study (HR: 0.89, 95%CI: 0.67-1.18, P = 0.4). Further prospective studies are needed to investigate the efficacy of combination adju- vant therapies for improvement of both OS and RFS.
To the best of our knowledge, regarding the effect of adjuvant mitotane therapy, this is the first analysis to include a RCT [11]. We found that adjuvant mitotane
therapy does not improve OS compared to no-adjuvant mitotane therapy. Two meta-analyses [1,25] reported the efficacy of adjuvant mitotane therapy. Base on retrospective data only, Fassnacht et al. [1] and Tang et al. [25] found an OS benefit to adjuvant mitotane therapy compared to no- adjuvant mitotane therapy (HR: 0.7, 95%CI: 0.5-0.9, and HR: 0.69, 95%CI: 0.55-0.88, P = 0.003, respectively). Although our analysis including all the patients in those
| (A) Adjuvant RT | ||||
|---|---|---|---|---|
| Study | Hazard Ratio | HR | 95%-CI | Weight |
| Wu et al. 2024 | 0.67 | [0.38; 1.18] | 27% | |
| Else et al. 2014 | 0.74 | [0.50; 1.10] | 57% | |
| Habra et al. 2013 | 1.32 | [0.62; 2.82] | 16% | |
| Random effects model | 0.79 | [0.58; 1.06] | 100% | |
| Heterogeneity: /2 = 10%, +2 < 0.0001, x2 = 2.21 (p = 0.331) | ||||
| Test for overall effect: z = - 1.58 (p = 0.113) | 0.2 0.5 1 2 | |||
| Favours [Adjuvant RT] Favours [No Adjuvant | RT] | |||
| (B) Adjuvant mitotane | ||||
| Study | Hazard Ratio | HR | 95%-CI | Weight |
| subgroup = surveillance | ||||
| Terzolo et al. 2023 | 0.74 | [0.30; 1.84] | 9% | |
| Calabrese et al. 2019 | 0.38 | [0.21; 0.67] | 14% | |
| Berruti et al. 2017 | 0.34 | [0.20: 0.57] | 14% | |
| Random effects model | 0.40 | [0.28; 0.57] | 37% | |
| Heterogeneity: /2 = 10%, 12 = < 0.0001, x2 = 2.22 (p = 0.330) | ||||
| subgroup = No Adjuvant mitotane | ||||
| Postiewait et al. 2016 | 1.40 | [0.90; 2.19] | 16% | |
| Beuschiein et al. 2015 | 0.75 | [0.50; 1.12] | 16% | |
| Else et al. 2014 | 0.72 | [0.53; 0.98] | 18% | |
| Grubbs et al. 2010 | 0.51 | [0.28; 0.94] | 13% | |
| Random effects model | 0.80 | [0.55; 1.17] | 63% | |
| Heterogeneity: /2 = 65%, 12 = 0.0977. x2 = 8.65 (p = 0.034) | ||||
| Random effects model | 0.63 | [0.44; 0.92] | 100% | |
| Heterogeneity: /2 = 73%, +2 = 0.1805, x= = 22.11 (p = 0.001) | ||||
| Test for overall effect: z = - 2.40 (p = 0.016) | 0.2 0.5 1 | 2 | ||
| Test for subgroup differences: x2 = 7.07, df = 1 (p = 0.008) | Favours [Adjuvant mitotane] | Favours [Contorl] | ||
| (C) Adjuvant mitotane with negative surgical margins | ||||
| Study | Hazard Ratio | HR | 95%-CI | Weight |
| subgroup = surveillance | ||||
| Terzolo et al. 2023 | 0.74 | [0.30; 1.84] | 22% | |
| Berruti et al. 2017 | 0.34 | [0.20; 0.57] | 36% | |
| Random effects model | 0.46 | [0.21; 0.97] | 58% | |
| Heterogeneity: /2 = 54%, 12 = 0.1679, x7 = 2.16 (p = 0.142) | ||||
| subgroup = No Adjuvant mitotane | ||||
| Beuschiein et al. 2015 | 0.75 | [0.50; 1.12] | 42% | |
| Random effects model | 0.56 | [0.32; 0.98] | 100% | |
| Heterogeneity: /2 = 66%, 12 = 0.1527, x2 = 5.90 (p = 0.052) | ||||
| Test for overall effect: z = - 2.03 (p = 0.042) | 0.2 0.5 1 | 2 | ||
| Test for subgroup differences: x- = 1.31, df = 1 (p = 0.253) | Favours [Adjuvant mitotane] | Favours [Contorl] | ||
analyses, the addition of the RCT data could not show the improvement of OS with adjuvant mitotane therapy. How- ever, subgroup analysis in patients with negative surgical margins revealed a benefit to adjuvant mitotane therapy. This would suggest that adjuvant mitotane therapy is very unlikely to improve OS in patients with positive surgical margins. Although the current guidelines recommend adju- vant mitotane therapy for ACC patients with a high risk of recurrence, including those with positive surgical margins,
this consensus is based on weak evidence, such as the observed tumor response to mitotane therapy in 20% patients with metastatic ACC [1]. We believe that adjuvant mitotane therapy is insufficient to achieve a radical cure for residual tumors. Given these results, we think adjuvant mitotane therapy may be benefit in patients with negative surgical margins but with a high risk of recurrence.
Recent prospective studies [26] have evaluated the effects of immunotherapy, including agents such as
avelumab, nivolumab, and pembrolizumab, in patients with metastatic ACC. However, these studies are limited by small sample sizes and short follow-up durations. More- over, the oncological outcomes, including progression-free survival and response rates, have not been particularly promising. Therefore, additional studies are essential to fur- ther assess the role of immunotherapy in ACC. In the future, immunotherapy may hold potential as an adjuvant therapy following radical adrenalectomy for ACC, but more robust data are required to support its efficacy in this setting.
4.1. Limitations
Our analysis has many limitations. First, all studies [10,12-21] except 1 RCT [11], included in our analyses, were of retrospective nature. As ACC is a rare carcinoma, it is difficult to conduct prospective studies, and there are con- cerns regarding potential biases, such as selection bias, loss to follow-up, confounding factors, and reporting bias, and so on. Notably, adjuvant mitotane therapy and RT are often performed for patients with a high risk of disease recurrence [1], characterized by invasion in other organs, metastasis to local lymph nodes, and/or positive surgical margins, poten- tially introducing selection bias into the studies. Moreover, some studies did not repeat the regimens of mitotane ther- apy or RT. Finally, the staging system for diagnosing the ACC varied overtime and across studies, with studies using either the TNM or ENSAT staging classifications. This makes an adjustment for disease stage impossible.
5. Conclusions
We found that adjuvant RT significantly improve OS compared to no-adjuvant RT in patients with ACC follow- ing adrenalectomy with curative intent. Although there was no significant difference in OS between adjuvant mitotane therapy and no-adjuvant mitotane therapy, adjuvant mito- tane therapy improved OS in patients with negative surgical margins. Therefore, we recommend, based on our data, to consider adjuvant mitotane therapy in patients with nega- tive surgical margins but still a high-risk recurrence. In all high-risk patients, we also recommend considering adjuvant RT, specifically those likely to suffer from local recurrence.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
CRediT authorship contribution statement
Ichiro Tsuboi: Writing - original draft, Investigation, Formal analysis, Data curation, Conceptualization. Mehdi Kardoust Parizi: Writing - review & editing,
Conceptualization. Akihiro Matsukawa: Writing - review & editing. Stefano Mancon: Writing - review & editing. Marcin Miszczyk: Writing - review & editing. Robert J. Schulz: Writing - review & editing. Tamás Fazekas: Writing - review & editing. Anna Cadenar: Writing - review & editing. Ekaterina Laukhtina: Writing - review & editing. Tatsushi Kawada: Writing - review & editing. Satoshi Katayama: Writing - review & editing. Takehiro Iwata: Writing - review & editing. Kensuke Bekku: Writ- ing - review & editing. Koichiro Wada: Writing - review & editing. Mesut Remzi: Writing - review & editing. Pierre I. Karakiewicz: Writing - review & editing. Motoo Araki: Writing - review & editing, Supervision. Shahrokh F. Shariat: Writing - review & editing, Supervision.
Patient Summary
Our analysis suggests that adjuvant radiotherapy reduces the mortality compared to control group in patients with adrenocortical carcinoma after adrenalectomy. Adjuvant mitotane therapy also reduce the mortality and recurrence after adrenalectomy.
Funding statement
No external funding provided.
Acknowledgments
Tamás Fazekas was supported by the EUSP Scholarship of the European Association of Urology (Scholarship S- 2023-0006).
Marcin Miszczyk was supported by NAWA - Polish National Agency for Academic Exchange in cooperation with Medical Research Agency under the Walczak Pro- gramme, grant number BPN/WAL/2023/1/00061/DEC/1
Supplementary materials
Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j. urolonc.2024.09.014.
References
[1] Fassnacht M, Dekkers OM, Else T, Baudin E, Berruti A, de Krijger R, et al. European Society of Endocrinology Clinical Practice Guide- lines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2018;179:G1-g46.
[2] Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol 2003;169:5-11.
[3] Meyer A, Behrend M. Long-term survival over 28 years of a patient with metastatic adrenal cortical carcinoma: case report. Anticancer Res 2004;24:1901-4.
[4] Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, et al. Adrenocortical carcinoma. Endocr Rev. 2014;35:282-326.
[5] Viani GA, Viana BS. Adjuvant radiotherapy after surgical resection for adrenocortical carcinoma: a systematic review of observational studies and meta-analysis. J Cancer Res Ther 2019;15:S20-s6.
[6] Schardt C, Adams MB, Owens T, Keitz S, Fontelo P. Utilization of the PICO framework to improve searching PubMed for clinical ques- tions. BMC Med Inform Decis Mak 2007;7:16.
[7] Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928.
[8] Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswa- nathan M, et al. ROBINS-I: a tool for assessing risk of bias in non- randomised studies of interventions. Bmj 2016;355:14919.
[9] Assel M, Sjoberg D, Elders A, Wang X, Huo D, Botchway A, et al. Guidelines for reporting of statistics for clinical research in urology. Eur Urol 2019;75:358-67.
[10] Wu LM, Chen JY, Su TW, Jiang L, Han YM, Zhang C, et al. Efficacy and safety of adjuvant radiation therapy in localized adrenocortical carcinoma. Front Endocrinol 2024;14:8.
[11] Terzolo M, Fassnacht M, Perotti P, Libé R, Kastelan D, Lacroix A, et al. 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;11:720-30.
[12] Passman JE, Amjad W, Soegaard Ballester JM, Ginzberg SP, Wach- tel H. Defining optimal management of non-metastatic adrenocortical carcinoma. Ann Surg Oncol 2024;31:1097-107.
[13] Wu K, Liu X, Liu ZH, Lu YP, Wang XD, Li X. Benefit of postopera- tive radiotherapy for patients with nonmetastatic adrenocortical carci- noma: a population-based analysis. J Nat Comprehens Canc Netw 2021;19:1425-32.
[14] Ginsburg KB, Chandra AA, Schober JP, Handorf EA, Uzzo RG, Greenberg RE, et al. Identification of oncological characteristics associated with improved overall survival in patients with adrenocor- tical carcinoma treated with adjuvant radiation therapy: insights from the National Cancer Database. Urol Oncol 2021;39:791.e1-.e7.
[15] Calabrese A, Basile V, Puglisi S, Perotti P, Pia A, Saba L, et al. Adju- vant mitotane therapy is beneficial in non-metastatic adrenocortical carcinoma at high risk of recurrence. Eur J Endocrinol 2019;180:387-96.
[16] Berruti A, Grisanti S, Pulzer A, Claps M, Daffara F, Loli P, et al. Long-term outcomes of adjuvant mitotane therapy in patients with
radically resected adrenocortical carcinoma. J Clin Endocrinol Metab 2017;102:1358-65.
[17] Postlewait LM, Ethun CG, Tran TB, Prescott JD, Pawlik TM, Wang TS, et al. Outcomes of adjuvant mitotane after resection of adreno- cortical carcinoma: a 13-institution study by the US Adrenocortical Carcinoma Group. J Am Coll Surg 2016;222:480-90.
[18] Beuschlein F, Weigel J, Saeger W, Kroiss M, Wild V, Daffara F, et al. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab 2015;100:841-9.
[19] Else T, Williams AR, Sabolch A, Jolly S, Miller BS, Hammer GD. Adjuvant therapies and patient and tumor characteristics associated with survival of adult patients with adrenocortical carcinoma. J Clin Endocrinol Metab 2014;99:455-61.
[20] Habra MA, Ejaz S, Feng L, Das P, Deniz F, Grubbs EG, et al. A retro- spective cohort analysis of the efficacy of adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma. J Clin Endocrinol Metab 2013;98:192-7.
[21] Grubbs EG, Callender GG, Xing Y, Perrier ND, Evans DB, Phan AT, et al. Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane. Ann Surg Oncol 2010;17:263-70.
[22] Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocri- nol 2016;175:G1-g34.
[23] Zhu JW, Zheng ZY, Shen J, Lian X, Miao Z, Shen J, et al. Efficacy of adjuvant radiotherapy for treatment of adrenocortical carcinoma: a retro- spective study and an updated meta-analysis. Radiat Oncol 2020;15:10.
[24] Cerquetti L, Bucci B, Marchese R, Misiti S, De Paula U, Miceli R, et al. Mitotane increases the radiotherapy inhibitory effect and indu- ces G2-arrest in combined treatment on both H295R and SW13 adre- nocortical cell lines. Endocr Relat Cancer 2008; 15:623-34.
[25] Tang Y, Liu Z, Zou Z, Liang J, Lu Y, Zhu Y. Benefits of adjuvant mitotane after resection of adrenocortical carcinoma: a systematic review and meta-analysis. Biomed Res Int 2018;2018:9362108.
[26] Padua TC, Marandino L, Raggi D, Hallanger-Johnson J, Kutikov A, Spiess PE, et al. A systematic review of published clinical trials in the systemic treatment of adrenocortical carcinoma: an initiative led on behalf of the global society of rare genitourinary tumors. Clin Genitourin Cancer 2023;21:1-7.