ENDOCRINE SOCIETY
OXFORD
The Effect of Adrenalectomy on Overall Survival in Metastatic Adrenocortical Carcinoma
Anis Assad, 10 Reha-Baris Incesu, 1,2[D Simone Morra, 1,3 Lukas Scheipner, 1,4 Andrea Baudo, 1,5,6[D Carolin Siech, 1,7 Mario De Angelis, 1,8 Zhe Tian,1 Sascha Ahyai, 40D Nicola Longo,3 Felix K. H. Chun,7 Shahrokh F. Shariat, 9,10,11,12 Derya Tilki, 2,13,14ID Alberto Briganti,8[D Fred Saad, 1(D and Pierre I. Karakiewicz1
1Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec H2X 0A9, Canada
2Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
3Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II, 80131 Naples, Italy
4Department of Urology, Medical University of Graz, 8036 Graz, Austria
5Department of Urology, IRCCS Ospedale Galeazzi-Sant’Ambrogio, 20157 Milan, Italy
6Department of Urology, IRCCS Policlinico San Donato, 20097 Milan, Italy
Department of Urology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60323 Frankfurt am Main, Germany
8Unit of Urology/Division of Oncology, Gianfranco Soldera Prostate Cancer Lab, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita- Salute San Raffaele University, 20132 Milan, Italy
9Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
10Department of Urology, Weill Cornell Medical College, New York, 10065 NY, USA
11Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
12Hourani Center of Applied Scientific Research, Al-Ahliyya Amman University, 19328 Amman, Jordan
13Department of Urology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
14Department of Urology, Koc University Hospital, 34010 Istanbul, Turkey
Correspondence: Anis Assad, MD, Cancer Prognostics and Health Outcomes Unit, University of Montreal Hospital Center, 900 St Denis, Pavilion R, R08.474, Montreal, Quebec H2X 0A9, Canada. Email: anis.assad10@gmail.com.
Abstract
Context: Although complete surgical resection provides the only means of cure in adrenocortical carcinoma (ACC), the magnitude of the survival benefit of adrenalectomy in metastatic ACC (mACC) is unknown.
Objective: This work aimed to assess the effect of adrenalectomy on survival outcomes in patients with mACC in a real-world setting.
Methods: Patients with mACC aged 18 years or older with metastatic ACC at initial presentation who were treated between 2004 and 2020 were identified within the Surveillance, Epidemiology, and End Results database (SEER 2004-2020), and we tested for differences according to adrenalectomy status. Intervention included primary tumor resection status (adrenalectomy vs no adrenalectomy). Kaplan-Meier plots, multivariable Cox regression models, and landmark analyses were used. Sensitivity analyses focused on use of systemic therapy, contemporary (2012-2020) vs historical (2004-2011), single vs multiple metastatic sites, and assessable specific solitary metastatic sites (lung only and liver only).
Results: Of 543 patients with mACC, 194 (36%) underwent adrenalectomy. In multivariable analyses, adrenalectomy was associated with lower overall mortality without (hazard ratio [HR]: 0.39; P < . 001), as well as with 3 months’ landmark analyses (HR: 0.57; P= . 002). The same association effect with 3 months’ landmark analyses was recorded in patients exposed to systemic therapy (HR: 0.49; P <. 001), contemporary patients (HR: 0.57; P= . 004), historical patients (HR: 0.42; P <. 001), and in those with lung-only solitary metastasis (HR: 0.50; P= . 02). In contrast, no statistically significant association was recorded in patients naive to systemic therapy (HR: 0.68; P= . 3), those with multiple metastatic sites (HR: 0.55; P= . 07), and those with liver-only solitary metastasis (HR: 0.98; P= . 9).
Conclusion: The present results indicate a potential protective effect of adrenalectomy in mACC, particularly in patients exposed to systemic therapy and those with lung-only metastases.
Key Words: adrenalectomy, metastatic, adrenocortical carcinoma, cytoreductive surgery
Abbreviations: ACC, adrenocortical carcinoma; CCR, California Cancer registry; ENSAT, European Network for the Study of Adrenal Tumor database; HR, hazard ratio; mACC, metastatic adrenocortical carcinoma; mTOR, mechanistic target of rapamycin; NCDB, National Cancer Database; OM, overall mortality; OS, overall survival; SEER, Surveillance, Epidemiology, and End Results.
Adrenocortical carcinoma (ACC) is a rare malignancy with a very poor prognosis (1). Approximately 30% to 50% of diagnosed adrenocortical carcinoma (ACC) patients exhibit
metastatic disease, commonly associated with tumor mass ef- fects and excessive hormone production, contributing to in- creased morbidity and impaired quality of life (2, 3). The
treatment of metastatic ACC (mACC) can be challenging, with limited improvements in prognosis over recent decades, as indicated by a 5-year overall survival (OS) rate of less than 15% (4, 5). Although clinical trials have not shown a sig- nificant improvement in OS rates, the mitotane plus EDP (eto- poside, doxorubicin, and cisplatin) chemotherapy regimen continues to be the preferred treatment for mACC (6-8). Other systemic therapies, including mechanistic target of ra- pamycin (mTOR) inhibitors, tyrosine kinase inhibitors, and insulin-like growth factor receptor-targeted therapies, have been investigated, yielding inconclusive results (9-12). More recently, in small phase 2 trials, immune checkpoint inhibitors have demonstrated a modest disease response rate, ranging from 6% to 23% (13, 14).
Given such disappointing outcomes, more institutions are now advocating for multimodal approaches, incorporating primary tumor resection when technically feasible (5, 8, 15, 16). The rationale behind adrenalectomy includes potentially en- hancing systemic therapy response, reducing tumor mass ef- fects, and decreasing symptoms associated with hormone secretion (15). However, the magnitude of the survival benefit of adrenalectomy in mACC is unknown. Large-scale, contem- porary population-based analyses addressing this topic are un- available (4, 15, 17). We addressed this knowledge gap within a large contemporary population database (Surveillance, Epidemiology and End Results, SEER). We hypothesized that adrenalectomy use may be associated with lower overall mortal- ity (OM) relative to no adrenalectomy in mACC patients. Additionally, we hypothesized that adrenalectomy in mACC may exhibit a particularly strong effect both in historical and contemporary patients, systemic therapy-exposed patients, and possibly within specific assessable metastatic locations.
Materials and Methods
Data Source and Study Population
The SEER database, which covers approximately 48% of the US population, is representative of the US population with re- spect to demographic composition and cancer incidence rates. All analyses and their reporting followed the SEER reporting guidelines. Due to the anonymously coded design of the SEER database, informed consent and ethical approval were not applicable for the present retrospective study. Within the SEER database (2004-2020) (18), we identified patients aged 18 years or older, with histologically confirmed ACC (International Classification of Disease for Oncology [ICD-O- 3] site code C74.0/C74.9; histologic code: “8370/3: Adrenal cortical carcinoma,” “8010/3: Carcinoma, NOS,” and “8140/3: Adenocarcinoma, NOS”) and metastatic disease at the diagnosis. The two groups of interest consisted of adrenalec- tomy patients and of no-adrenalectomy patients. Patients with treatment type coded as local tumor ablation, or not otherwise specified, were excluded. Autopsy or death certificate-only cases were also excluded (Fig. 1).
Variables of Interest
Demographic covariates consisted of age at diagnosis (years, continuously coded), sex, race/ethnicity (White, non-White). Tumor characteristics consisted of primary tumor size (milli- meters, continuously coded), tumor side, N stage (Nx, N0, N1), and distant metastasis characteristics (number and sites of distant metastasis). Systemic and radiation therapies were
coded as received, not received or unknown. OM represented the end point of interest.
Statistical Analyses
In all analyses, patients with adrenalectomy were compared to patients without adrenalectomy. Six analytical steps were per- formed. First, descriptive statistics compared adrenalectomy vs no-adrenalectomy patients. Second, estimated annual per- centage changes in adrenalectomy rates were quantified. Third, Kaplan-Meier plots displayed rates of OS according to adrenalectomy vs no-adrenalectomy in the overall cohort. Fourth, to further examine the association between adrenalec- tomy and OM, multivariable Cox regression models were fitted with adjustment variables consisting of age at diagnosis, T stage, N stage, systemic therapy, and number of metastasis sites and site of metastasis (brain, lung, liver, or bone) when as- sessable. Fifth, 3 months’ landmark analyses were applied to all multivariable regression models to address the potential effect of immortal time bias, which may favorably affects patients with adrenalectomy (19). Finally, sensitivity analyses tested the effect of adrenalectomy in patients with mACC according to 1) systemic therapy status (exposed vs naive); 2) contempor- ary (2012-2020) vs historical (2004-2011); 3) single vs multiple metastatic sites; and 4) according to specific solitary metastatic tumor locations (exclusive lung vs exclusive liver).
All statistical analyses were performed in the R software en- vironment for statistical computing and graphics (version 4.2.2 for macOS; www.r-project.org) (20). All tests were 2-sided, with a level of statistical significance set at P less than .05.
Results
Descriptive Characteristics
Of 543 patients with mACC, 194 (36%) underwent adrena- lectomy (Table 1). The rate of adrenalectomy declined signifi- cantly over the study period. It decreased from 48% in 2004% to 29% in 2020. The latter resulted in a negative annual per- centage rate change of 3.5% (P <. 01) (Fig. 2). Patients who underwent adrenalectomy were younger (54 vs 58 years; P =. 046) and had a larger primary tumor size (132 vs 115 mm; P <. 001), higher proportion of more advanced T stage (P < .001), higher proportion of N0 stage (P < .02), and higher rates of systemic therapy (65% vs 54%; P =. 02) and radiation therapy (20% vs 1.7%, P <. 001) exposure. In assessable metastatic sites, patients who underwent adrenalec- tomy had a higher proportion of metastases limited to a single site (70% vs 48%; P <. 001). Regarding specific individual metastatic site locations, patients who underwent adrenalec- tomy had a lower rate of lung (52% vs 63%; P = . 03) and liver (48% vs 63%; P = . 006) metastatic tumor locations. No dif- ferences were found in the rates of bone and brain metastasis, ethnicity (P =. 5), sex (P =. 8), and tumor laterality (P =. 08; see Table 1).
Survival Analyses
The median OS of the entire cohort regardless of the adrena- lectomy status was 6 months (95% CI, 5-7 months). No dif- ferences in median OS were recorded after stratification between historical (6 months; CI, 4-7) vs contemporary (6 months; CI, 5-8) patients (P =. 3).
Surveillance, Epidemiology, and End Results (SEER) database 2004-2020 of adrenocortical carcinoma (ACC) patients n=1619
Excluded:
· Confirmed ACC histology: No/Unknown (n=99)
· Patients <18 yo (n=71)
· Autopsy or death certificate cases (n=1)
ACC with histologic confirmation n=1448
Excluded:
· Non-metastatic ACC (n=860)
· Metastatic status: unkown (n=37)
Metastatic ACC (mACC) n=551
Excluded:
· TO (n=3)
· Adrenalectomy status: Unknown (n=5)
Adrenalectomy vs. no-adrenalectomy in known mACC status n=543
Patients eligible for overall analyses n=543 (Adrenalectomy: 194 vs No-adrenalectomy: 349)
Excluded:
· Metastatic site status: Unknown (n=185)
Patients eligible for subgroups analyses according to type or site of metastases n=358 (Adrenalectomy: 112 vs No-adrenalectomy: 246)
Median OS according to adrenalectomy vs no adrenalec- tomy was 14 vs 4 months (4=10 months; P <. 0001; Fig. 3). After additional 3 months’ landmark analyses, median OS according to adrenalectomy vs no adrenalectomy was 16 vs 7 months (4 =9 months; P <. 0001).
Other-cause mortality rate at 24 months was statistically significantly higher in no-adrenalectomy patients (11% vs 21%; P <. 01). However, after additional 3 months’ land- mark analyses, no significant difference was recorded in the other-cause mortality rates according to adrenalectomy status (10% vs 17%; P =. 07).
In multivariable analyses, adrenalectomy was associated with lower OM, both without (hazard ratio [HR]: 0.39; CI, 0.29-0.53; P <. 001; Fig. 4), as well as with (HR: 0.57; CI, 39-82; P =. 002) additional 3 months’ landmark analyses.
Sensitivity Analyses
Systemic therapy-exposed vs naive patients
Of 543 patients, 316 (58%) received systemic therapy. In 316 patients exposed to systemic therapy, 112 (40%) underwent adrenalectomy. Median OS according to adrenalectomy vs no adrenalectomy was 18 vs 6 months (4=12 months; P < . 001; see Fig. 3). In multivariable analyses, adrenalectomy
was associated with lower OM both without (HR: 0.36; 95% CI, 0.25-0.53; P <. 001; see Fig. 4), as well as with (HR: 0.49; 95% CI, 0.31-0.76; P =. 001) additional landmark analyses.
Of 227 (42%) patients naive to systemic therapy, 68 (30%) underwent adrenalectomy. Median OS according to adrena- lectomy vs no adrenalectomy was 7 vs 2 months (4=5 months; P <. 001; see Fig. 3). In multivariable analyses, adre- nalectomy was associated with lower OM without landmark analyses (HR: 0.34; 95% CI, 0.19-0.58; P <. 001; see Fig. 4). However, in multivariable analyses with additional 3 months’ landmark analyses, no statistically significant difference was recorded in OM according to adrenalectomy status (HR: 0.68; 95% CI, 0.33-1.41; P =. 3).
Contemporary (2012-2020) vs historical (2004-2011) cohort
Of 543 patients, 330 (61%) were treated between 2012 and 2020, and 213 (39%) between 2004 and 2011. Of 330 con- temporary patients, 114 (35%) underwent adrenalectomy. Median OS according to adrenalectomy vs no adrenalectomy was 18 vs 6 months (4 = 12 months; P <. 001; see Fig. 3). In multivariable analyses, adrenalectomy was associated with lower OM both without (HR: 0.40; 95% CI, 0.29-0.55; P <. 001; see Fig. 4), as well as with (HR: 0.57; 95% CI, 0.39-0.84; P = . 004) additional 3 months’ landmark analyses.
| Characteristic | Overall (N = 543)ª | Adrenalectomy N = 194 (36%) | No adrenalectomy N = 349 (64%)ª | pb |
|---|---|---|---|---|
| Age, median (IQR), y | 56 (45-65) | 54 (44-64) | 58 (47-66) | .046 |
| Ethnicity | .5 | |||
| White | 365 (67%) | 134 (69%) | 231 (66%) | |
| Non-White | 178 (33%) | 60 (31%) | 118 (34%) | |
| Sex | .8 | |||
| Female | 115 (59%) | 211 (60%) | 326 (60%) | |
| Primary tumor size, median (IQR), mm | 120 (90-150) | 132 (99-179) | 115 (90-147) | <. 001 |
| Tumor laterality, median (IQR) | .08 | |||
| Left | 276 (54%) | 94 (49%) | 182 (57%) | |
| T stage | <. 001 | |||
| T1-2 | 139 (26%) | 53 (27%) | 86 (25%) | |
| T3-4 | 290 (53%) | 130 (67%) | 160 (46%) | |
| Tx | 114 (21%) | 11 (5.7%) | 103 (30%) | |
| N stage | .02 | |||
| N0 | 318 (59%) | 127 (65%) | 191 (55%) | |
| N1 | 116 (21%) | 39 (20%) | 77 (22%) | |
| Nx | 109 (20%) | 28 (14%) | 81 (23%) | |
| Year of surgery | .5 | |||
| 2004-2011 | 213 (39%) | 80 (41%) | 133 (38%) | |
| 2012-2020 | 330 (61%) | 114 (59%) | 216 (62%) | |
| Systemic therapy | .02 | |||
| Yes | 316 (58%) | 126 (65%) | 190 (54%) | |
| Radiation therapy | <. 001 | |||
| Yes | 44 (8.1%) | 38 (20%) | 6 (1.7%) | |
| No. of distant metastasis sites | <. 001 | |||
| Single | 196 (36%) | 78 (40%) | 118 (34%) | |
| Multiple | 162 (30%) | 34 (18%) | 128 (37%) | |
| Unknown | 185 (34%) | 82 (42%) | 103 (30%) | |
| Site of distant metastasis | ||||
| Brain | 7 (1.8%) | 0 (0%) | 7 (2.8%) | .10 |
| Lung | 228 (59%) | 66 (52%) | 162 (63%) | .03 |
| Liver | 222 (58%) | 62 (48%) | 160 (63%) | .006 |
| Bone | 84 (22%) | 25 (20%) | 59 (23%) | .5 |
Values that represent statistical significance are in bold.
“Median (interquartile range [IQR]); n (%).
“Kruskal-Wallis rank sum test; Pearson chi-square test.
Of 213 (39%) historical patients, 80 (38%) underwent adrenalectomy. Median OS according to adrenalectomy vs no adrenalectomy was 11.5 vs 4 months (4=7.5 months; P <. 001; see Fig. 3). In multivariable analyses, adrenalectomy was associated with lower OM both without (HR: 0.43; 95% CI, 0.29-0.65; P <. 001; see Fig. 4), as well as with (HR: 0.42; 95% CI, 0.26-0.68; P = . 004) additional 3 months’ landmark analyses.
Single vs multiple metastatic sites
Of 543 patients, 196 (36%) exhibited a single metastatic site. Multiple metastatic sites were recorded in 162 (30%) patients, and 185 (34%) patients had no information regarding metastatic site status. Of 196 patients with a single metastatic site, 78 (40%) underwent adrenalectomy. Median OS according to adrenalectomy vs no adrenalectomy was 18 vs 4 months
(4 = 14 months; P <. 001; Fig. 5). In multivariable analyses, adrenalectomy was associated with lower OM both without (HR: 0.37; 95% CI, 0.25-0.55; P <. 001; see Fig. 4), as well as with (HR: 0.57; 95% CI, 0.37-0.90; P =. 01) additional 3 months’ landmark analyses.
Of 162 patients with multiple metastatic sites, 34 (21%) underwent adrenalectomy. Median OS according to adrena- lectomy vs no adrenalectomy was 20 vs 2 months (4=18 months; P < . 001; see Fig. 5). In multivariable analyses with- out 3 months’ landmark analyses, adrenalectomy was associ- ated with lower OM (HR: 0.31; 95% CI, 0.18-0.55; P <. 001; see Fig. 4). In contrast, in multivariable analyses with additional 3 months’ landmark analyses, no statistically sig- nificant difference was recorded in OM according to adrena- lectomy status (HR: 0.55; 95% CI, 0.28-1.07; P =. 07; see Fig. 4).
80
Estimated annual percentage change (EAPC): - 3.51% (CI :- 6.14% to -0.96%, p=0.01)
70
60
Rate of adrenalectomy (%)
50
40
30
20
10
0
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
Year of surgery
Specific assessable solitary metastatic tumor locations
Of 196 patients with a single metastatic site, 90 (46%) har- bored lung-only metastasis and 83 harbored liver-only metas- tasis and were assessable in further analyses. Of 90 patients with lung-only metastasis, 37 (41%) underwent adrenalec- tomy. Median OS according to adrenalectomy vs no adrena- lectomy was 27 vs 4 months (4=23 months; P <. 001; see Fig. 5). In multivariable analyses, adrenalectomy was associ- ated with lower OM both without (HR: 0.34; 95% CI, 0.19-0.58; P <. 001; see Fig. 4), as well as with (HR: 0.50; 95% CI, 0.27-0.91; P <. 02) additional 3 months’ landmark analyses.
Of 83 patients with liver-only metastasis, 33 (40%) under- went adrenalectomy. Median OS according to adrenalectomy vs no adrenalectomy was 8 vs 3 months (4=5 months; P =. 01; see Fig. 5). In multivariable analyses without 3 months’ landmark analyses, adrenalectomy was associated with lower OM (HR: 0.50; 95% CI, 0.26-0.95; P =. 04; see Fig. 4). In contrast, in multivariable analyses with additional 3 months’ landmark analyses, no statistically significant dif- ference was recorded in OM according to adrenalectomy sta- tus (HR: 0.98; 95% CI, 0.42-2.28; P = . 96).
Discussion
The magnitude of the survival benefit of adrenalectomy in mACC is unknown. We addressed this knowledge gap in a very large contemporary population of patients with mACC. We recorded several noteworthy observations.
First, of 1448 patients with ACC, 543 (39%) were diag- nosed with synchronous metastatic disease (see Fig. 1). This
rate is comparable to those reported in other population- based studies (5, 16, 21, 22). For example, Tella et al based on the National Cancer Database (NCDB, 2004-2015, n = 1602), Wang et al based on the SEER database (1974-2014, n = 749), as well as Livhits et al based on the California Cancer registry (CCR, 1999-2008, n = 367) re- spectively reported rates of synchronous metastasis of 47%, 39%, and 46% (16, 21, 22).
Second, of 543 patients with mACC, 194 (36%) underwent adrenalectomy. This rate was lower compared with those re- ported in other population-based studies. For example, Tella et al (21) relied on the NCDB, in which the adrenalectomy rate in mACC was 43% (n =760). Similarly, Livhits et al (16) relied on the CCR, in which the adrenalectomy rate in mACC was 41% (n = 167). The difference between the pre- sent cohort and the 2 previously reported cohorts (NCDB and CCR) may be attributed to the more contemporary nature of the present study. Indeed, within the present study a de- crease in the rate of adrenalectomy over time was also re- corded (48% in 2004% to 29% in 2020, negative annual percentage change of 3.5%). This rate was drastically differ- ent from the rate reported by Libé et al (5) based on the European Network for the Study of Adrenal Tumor database (ENSAT, n = 2000-2009, n = 234) that relied on tertiary care referral centers in which 77% of mACC patients underwent adrenalectomy. One possible explanation for this discrepancy is that in community practices, less strict enforcement of multidisciplinary recommendations may be operational com- pared to tertiary care centers that contributed to the ENSAT cohort. This observation is worrisome since it may reflect a negative indicator of quality of care (4, 23). Ideally, North
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| Entire cohort | Median OS (CI 95%) | OS at 24 mo |
|---|---|---|
| 6 mo (5-7) | 19.8% |
| Adrenalectomy No-adrenalectomy | Median OS (CI 95%) | OS at 24 mo |
|---|---|---|
| 18 mo (14-27) | 42.6% | |
| 6 mo (5-8) | 16.1% |
| Adrenalectomy No-adrenalectomy | Median OS (CI 95%) | OS at 24 mo |
|---|---|---|
| 7 mo (5-10) | 24.7% | |
| 2 mo (1-2) | 3.7% |
Figure 3. Kaplan-Meier plots displaying the overall survival (OS) rates of patients with metastatic adrenocortical carcinoma (mACC) in the A, entire cohort and according to adrenalectomy status; B, overall cohort after 3 months “landmark analyses; C, systemic therapy-exposed patients; D, systemic therapy-naive patients; E, more contemporary (2012-2020) patients; and F, more historical (2004-2011) patients.
American multi-institutional studies from centers of excel- lence should also assess adrenalectomy rates in patients with mACC.
Third, the median OS of the entire cohort regardless of adrenalectomy status was 6 months. No difference was re- corded in median OS, regardless of adrenalectomy status, after stratification between historical vs contemporary pa- tients (6 vs 6 months). These median OS rates are comparable to those reported by Tella et al (21) in NCDB (8 months), Wang et al (22) in SEER (7 months), and Livhits et al (16) in CCR (3.6 months). In contrast, these rates significantly dif- fer from those reported by Libé et al (5) using the ENSAT
database, in which the median OS for patients with 1 to 2, 3, and more than metastatic sites were 21.2 months, 12.1 months, and 13.6 months, respectively. The discrepancy be- tween ENSAT and population-based North American reposi- tories may be explained in the same fashion as the previous explanation proposed for rates of adrenalectomy in mACC.
Fourth, the association between adrenalectomy and median OS was virtually invariably in favor of adrenalectomy patients (HR: 0.57; P = . 002), relative to their no-adrenalectomy coun- terparts, regardless of analyses type. Specifically, the adrena- lectomy survival advantage was 10 months in the overall cohort and ranged from 5 to 23 months according to specific
| Variable | Hazard ratio | Multivariate analysis | 95% CI | p value | |
|---|---|---|---|---|---|
| Overall cohortª | |||||
| No-adrenalectomy | - | - | |||
| Adrenalectomy | 0.39 | 0.29-0.53 | <0.001 | ||
| In three months' landmark analyses | |||||
| Overall cohortª | |||||
| No-adrenalectomy Adrenalectomy | - 0.57 | - 0.39-0.82 | 0.002 | ||
| Systemic therapy exposedb | |||||
| No-adrenalectomy | - | - | |||
| Adrenalectomy | 0.57 | 0.31-0.76 | 0.001 | ||
| Systemic therapy naiveb | |||||
| No-adrenalectomy | - | - | |||
| Adrenalectomy | 0.68 | 0.33-1.41 | 0.3 | ||
| Historical cohort (2004-2011)c | |||||
| No-adrenalectomy | - | - | |||
| Adrenalectomy | 0.42 | 0.26-0.68 | <0.001 | ||
| Contemporary cohort (2012-2018)ª | |||||
| No-adrenalectomy | - | - | |||
| Adrenalectomy | 0.57 | 0.39-0.84 | 0.004 | ||
| Single distant metastatic sited | |||||
| No-adrenalectomy | - | - | |||
| Adrenalectomy | 0.57 | 0.37-0.90 | 0.02 | ||
| Multiple distant metastatic sitesd | |||||
| No-adrenalectomy | - | - | |||
| Adrenalectomy | 0.55 | 0.28-1.07 | 0.07 | ||
| Lung only metastatic sitee | |||||
| No-adrenalectomy | - | - | |||
| Adrenalectomy | 0.50 | 0.27-0.91 | 0.02 | ||
| Liver only metastatic site® | |||||
| No-adrenalectomy | - | - | |||
| Adrenalectomy | 0.98 | 0.42-2.28 | 0.9 | ||
| 0.1 | 0.3 0.5 0.7 1 | 1.2 | |||
| Hazards Ratio | |||||
Adjusted for:
aAge, N stage, T stage, systemic therapy , number of metastasis sites, site of metastasis (brain, lung,liver or bone) and adrenalectomy status.
bAge, N stage, T stage, number of metastasis sites, site of metastasis (brain,lung,liver or bone) and adrenalectomy status.
cAge, N stage, T stage, systemic therapy, number of metastatic sites, and adrenalectomy status.
dAge, N stage, T stage, systemic therapy, site of metastasis (brain,lung,liver or bone) and adrenalectomy status.
eAge, N stage, T stage, systemic therapy and adrenalectomy status.
Figure 4. Depiction of multivariable Cox regression model-derived hazard ratios in 543 patients diagnosed with metastatic adrenocortical carcinoma (mACC), in overall population as well as landmark analyses at 3 months and sensitivity analyses.
subgroup analyses. This benefit invariably translated into independent predictor status in all multivariable analyses, including multivariable analyses that were performed with additional 3 months’ landmark analyses. Specifically, the strongest protective effect was recorded in systemic therapy- exposed patients (HR: 0.49; P <. 001) and in those with lung-only solitary metastasis (HR: 0.50; P =. 02) within both the historical (HR: 0.42; P <. 001) and contemporary (HR: 0.57; P = . 004) cohorts. In contrast, no statistically sig- nificant association was recorded in systemic therapy-naive patients (HR: 0.68; P =. 3), those with multiple metastatic sites (HR: 0.55; P =. 07), and those with liver-only solitary metastasis (HR: 0.98; P = . 9).
The association between adrenalectomy and better survival of patients with mACC recorded in the present study is in agreement with previous studies that relied on the NCDB and CCR databases that have reported differences in median
OS in favor of adrenalectomy ranging from 4 to 16 months (all P <. 01) (16, 21). Similarly, in a recent study that relied on a multi-institutional database (American-Australian- Asian Adrenal Alliance collaborative research group, 1995-2019, n = 239), Srougi et al (15) reported a comparable benefit in favor of adrenalectomy in patients with mACC (4:16 months, P <. 001). However, the strength of the present study lies in its contemporary status, multiple subgroup ana- lyses that addressed specific groups of interest, and in rigorous statistical analyses, including 3 months’ landmark analyses that have not been applied in previous studies.
Several explanations may account for the strong association between primary tumor resection and OS in mACC. First, it may be postulated that the early removal of a primary tumor could eliminate or inhibit pathways associated with metastatic progression, thereby enhancing the immune response and the efficacy of systemic therapies. Moreover, primary tumor
A
Single metastatic site
B
Multiple metastatic sites
os
os
- No-adrenalectomy - Adrenalectomy
- No-adrenalectomy - Adrenalectomy
1.00
1.00
survival probability
0.75
survival probability
0.75
0.50
0.50
0.25
Log-rank
0.25
Log-rank
p ≤ 0.0001
p < 0.0001
14 mo
18 mo
0.00
0.00
:
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
0
4
8
12
16
20
24
28
32
36
40
44
48
56
60
Months
Months
52
Number at risk
Number at risk
118
66
41
31
23
14
10
7
7
6
4
3
2
2
2
1
No-adrenalinctomy
128
49
21
14
11
8
7
6
4
4
4
3
2
2
2
1
78
68
52
44
37
33
28
22
19
15
12
11
9
9
8
8
Atomsectomy
34
31
21
17
14
12
8
8
7
5
4
2
2
2
2
1
.
4
8
12
20
24
28
Months
Na
40
44
56
60
0
4
·
1.2
16
20
24
28
Months
32
30
40
44
40
52
56
C
Lung only metastasis
D
Liver only metastasis
os
os
- No-adrenalectomy - Adrenalectomy
- No-adrenalectomy - Adrenalectomy
1.00
1.00
survival probability
0.75
survival probability
0.75
0.50
0.50
0.25
Log-rank
0.25
Log-rank
p < 0.0001
p = 0.012
23 mo
mo
0.00
0.00
0
4
8
12
16
20
24
28
32
36
40
44
48
Months
52
56
60
0
4
8
12
16
20
24
28
32
36
40
44
48
Months
52
56
60
Number at risk
Number at risk
53
32
18
16
13
9
7
5
5
4
2
2
1
1
1
0
No-adenalectomy
50
24
16
12
7
3
2
1
1
1
1
0
0
0
0
0
37
34
28
26
22
19
16
14
11
9
7
7
6
6
5
5
Adresaiechim
33
27
17
12
10
9
8
6
6
4
3
2
1
1
1
1
6
4
.
12
16
20
24
a
Months
Na
36
40
4
48
52
50
60
·
4
”
1.2
16
20
24
20
Months
12
36
40
44
48
52
56
60
Median OS (CI 95%)
OS at 24 mo
Adrenalectomy
8 mo (6-27)
30.2%
No-adrenalectomy
3 mo (1-6)
13.0%
| Median OS (CI 95%) | OS at 24 mo | |
|---|---|---|
| Adrenalectomy | 18 mo (12-27) | 42.5% |
| No-adrenalectomy | 4 mo (3-6) | 13.5% |
| Median OS (CI 95%) | OS at 24 mo | |
|---|---|---|
| Adrenalectomy | 20 mo (9-32) | 33.7% |
| No-adrenalectomy | 2 mo (2-4) | 6.7% |
| Median OS (CI 95%) | OS at 24 mo | |
|---|---|---|
| Adrenalectomy | 27 mo (16-36) | 51.6% |
| No-adrenalectomy | 4 mo (3-11) | 15.0% |
Figure 5. Kaplan-Meier plots displaying the overall survival (OS) rates of patients with metastatic adrenocortical carcinoma (mACC) and assessable metastatic sites according to adrenalectomy status: A, single metastatic site patients; B, multiple metastatic sites patients; C, lung-only solitary metastasis; and D, liver-only solitary metastasis.
resection can reduce hormone secretion, potentially leading to improved metabolic outcomes. However, selection bias may still be operational, with adrenalectomy patients benefiting from more timely and aggressive treatment compared to their nonadrenalectomy counterparts, who may experience delays in subsequent treatment lines. Although a 3-month landmark analysis was conducted, another possible explanation for the observed differences is that patients undergoing adrenalec- tomy might be in better overall health and have less advanced disease, making them suitable candidates for more aggressive surgical interventions.
Taken together, our results indicate a statistically significant OM advantage in patients with mACC who underwent adre- nalectomy (HR: 0.57; P =. 002). This advantage was shown despite the use of the most stringent statistical methodology that controlled for multiple biases, including multivariable and landmark analyses. Specifically, adrenalectomy resulted in a particularly strong protective effect in systemic therapy- exposed (HR: 0.57; P <. 001) and lung-only solitary (HR: 0.50; P =. 02) metastasis patients. Conversely, it did not show OM benefit in systemic therapy-naive patients, those with multiple metastatic sites, and liver-only metastasis.
Given the limited efficacy of systemic therapy in mACC, the role of adrenalectomy in mACC is of the utmost importance. In consequence, our results exhibiting the potential survival benefit of adrenalectomy mACC should at least prompt strong consideration for adrenalectomy in patients with mACC at multidisciplinary tumor boards (24).
The present study is not devoid of limitations. First, despite strict statistical analyses, potential biases may still be oper- ational due to its retrospective design. Second, the SEER data- base lacks information on potential prognostic factors, including performance status, mitotic index, venous invasion, surgical margin status, and endocrine tumor activity. These limitations apply to all previous population-based analyses addressing adrenalectomy in mACC that were based on the CCR, SEER, NCDB, or other large-scale data repositories. Third, limited details regarding specific treatment were avail- able. Specifically, the SEER database does not provide infor- mation regarding metastasectomy, specific systemic therapy used, as well as the timing of adrenalectomy relative to system- ic therapies. In general, the observational nature of studies that assessed the efficacy of adrenalectomy may be subject to multiple selection biases, limiting the ability to establish causality between adrenalectomy status and improved sur- vival. Unfortunately, no randomized clinical trial testing the efficacy of adrenalectomy on survival has been conducted or is likely to be designed due to the extreme rarity of ACC and surgically treated mACC. In consequence, large-scale ob- servational studies such as the present study will fuel future recommendations and guidelines.
Conclusions
The present results indicate a potential protective effect from adrenalectomy in mACC that remains unchanged after control- ling for immortal time bias. This effect applies both to historical and contemporary patients and was more pronounced in sys- temic therapy-exposed and lung-only metastasis patients.
Author Contributions
Study concept and design: A.A. and P.I.K. Acquisition of data: A.A., R.B.I., S.M., L.S., A.B., C.S., M.D.A., and Z.T. Analysis and interpretation of data: A.A., R.B.I, and Z.T. Drafting of the manuscript: A.A., R.B.I., S.M., L.S., A.B., C.S., and M.D.A. Critical revision of the manuscript for important in- tellectual content: A.A., R.B.I., S.M., L.S., A.B., C.S., M.D.A., Z.T., S.A., N.L., F.K.H.C., S.F.S., D.T., A.Br., F.S., and P.I.K. Statistical analysis: A.A. Supervision: P.I.K.
Disclosures
The authors declare that there is no conflict of interests.
Data Availability
All data generated for this analysis were from the SEER data- base. The code for the analyses will be made available on request.
References
1. Margonis GA, Kim Y, Prescott JD, et al. Adrenocortical carcinoma: impact of surgical margin status on long-term outcomes. Ann Surg Oncol. 2016;23(1):134-141.
2. Wooten MD, King DK. Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer. 1993;72(11):3145-3155.
3. Fassnacht M, Libé R, Kroiss M, Allolio B. Adrenocortical carcin- oma: a clinician’s update. Nat Rev Endocrinol. 2011;7(6):323-335.
4. Fassnacht M, Dekkers OM, Else T, et al. European Society of endo- crinology clinical practice guidelines on the management of adreno- cortical carcinoma in adults, in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol. 2018;179(4):G1-G46.
5. Libé R, Borget I, Ronchi CL, et al. Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European network for the study of adrenal tumor (ENSAT) study. Ann Oncol. 2015;26(10): 2119-2125.
6. Fassnacht M, Terzolo M, Allolio B, et al. Combination chemother- apy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366(23):2189-2197.
7. Terzolo M, Fassnacht M, Perotti P, et al. Results of the ADIUVO study, the first randomized trial on adjuvant mitotane in adreno- cortical carcinoma patients. J Endocr Soc. 2021;5(Suppl 1): A166-A167.
8. Laganà M, Grisanti S, Cosentini D, et al. Efficacy of the EDP-M scheme plus adjunctive surgery in the management of patients with advanced adrenocortical carcinoma: the Brescia experience. Cancers (Basel). 2020;12(4):941.
9. Kroiss M, Quinkler M, Johanssen S, et al. Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial. J Clin Endocrinol Metab. 2012;97(10):3495-3503.
10. Naing A, LoRusso P, Fu S, et al. Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibi- tor temsirolimus in patients with refractory Ewing’s sarcoma family tumors. Clin Cancer Res. 2012;18(9):2625-2631.
11. Fassnacht M, Berruti A, Baudin E, et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adreno- cortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol. 2015;16(4):426-435.
12. Wortmann S, Quinkler M, Ritter C, et al. Bevacizumab plus cape- citabine as a salvage therapy in advanced adrenocortical carcinoma. Eur J Endocrinol. 2010;162(2):349-356.
13. Habra MA, Stephen B, Campbell M, et al. Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical car- cinoma. J Immunother Cancer. 2019;7(1):253.
14. Le Tourneau C, Hoimes C, Zarwan C, et al. Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial. J Immunother Cancer. 2018;6(1):111.
15. Srougi V, Bancos I, Daher M, et al. Cytoreductive surgery of the primary tumor in metastatic adrenocortical carcinoma: impact on patients’ survival. J Clin Endocrinol Metab. 2022;107(4): 964-971.
16. Livhits M, Li N, Yeh MW, Harari A. Surgery is associated with im- proved survival for adrenocortical cancer, even in metastatic dis- ease. Surgery. 2014;156(6):1531-1540. discussion 1540-1.
17. Else T, Kim AC, Sabolch A, et al. Adrenocortical carcinoma. Endocr Rev. 2014;35(2):282-326.
18. Overview of the SEER program. SEER. Accessed September 10, 2022. https://seer.cancer.gov/about/overview.html
19. Duchesneau ED, Jackson BE, Webster-Clark M, et al. The timing, the treatment, the question: comparison of epidemiologic ap- proaches to minimize immortal time bias in real-world data using a surgical oncology example. Cancer Epidemiol Biomarkers Prev. 2022;31(11):2079-2086.
20. The R Project for Statistical Computing. Accessed March 10, 2023. https://www.r-project.org/
21. Tella SH, Kommalapati A, Yaturu S, Kebebew E. Predictors of survival in adrenocortical carcinoma: an analysis from the na- tional cancer database. J Clin Endocrinol Metab. 2018;103(9): 3566-3573.
22. Wang S, Chen SS, Gao WC, et al. Prognostic factors of adrenocort- ical carcinoma: an analysis of the surveillance epidemiology and end results (SEER) database. Asian Pac J Cancer Prev. 2017;18(10): 2817-2823.
23. Shah MH, Goldner WS, Benson AB, et al. Neuroendocrine and adrenal tumors, version 2.2021, NCCN clinical practice
guidelines in oncology. J Natl Compr Canc Netw. 2021;19(7): 839-868.
24. Tizianel I, Caccese M, Torresan F, et al. The overall survival and progression-free survival in patients with advanced adrenocortical cancer is increased after the multidisciplinary team evaluation. Cancers (Basel). 2022;14(16):3904.
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