Surgical management of metastatic adrenocortical carcinoma
Jesse E. Passman1 İD Wajid Amjad1 Sara P. Ginzberg1
Jacqueline M. Soegaard Ballester1
Caitlin Finn1 Heather Wachtel1,2
1Department of Surgery, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA
2Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Correspondence
Jesse E. Passman, 3400 Spruce Street, 4th Floor, Maloney Building, Philadelphia, PA 19104, USA.
Email: Jesse.passman@pennmedicine. upenn.edu
Funding information
National Institutes of Health, NCI, Grant/Award Number: K08 CA270385; NIH T32 Training Program in Surgical Oncology Research at Penn, Grant/Award Number: 5T32CA251063- 02
Abstract
Introduction: Adrenocortical carcinoma (ACC) is a notoriously aggressive cancer with a dismal prognosis, especially for patients with metastatic dis- ease. Metastatic ACC is classically a contraindication to operative man- agement. Here, we evaluate the impact of primary tumor resection and metastasectomy on survival in metastatic ACC.
Methods: We performed a retrospective cohort study of patients with metastatic ACC (2010-2019) utilizing the National Cancer Database. The primary outcome was overall survival (OS). Cox proportional hazard models were developed to evaluate the association between surgical management and survival. Propensity score matching (PSM) was utilized to account for selection bias in receipt of surgery.
Results: Of 976 subjects with metastatic ACC, 38% underwent surgical management. Median OS across all patients was 7.6 months. On multi- variable Cox proportional hazards regression, primary tumor resection alone (HR: 0.523; p < 0.001) and primary resection with metastasectomy (HR: 0.372; p < 0.001) were significantly associated with improved OS. Metastasectomy alone had no association with OS (HR: 0.909; p = 0.740). Primary resection with metastasectomy was associated with improved OS over resection of the primary tumor alone (HR: 0.636; p = 0.018). After PSM, resection of the primary tumor alone remained associated with improved OS (HR 0.593; p < 0.001), and metastasectomy alone had no survival benefit (HR 0.709; p = 0.196) compared with nonoperative man- agement; combined resection was associated with improved OS over pri- mary tumor resection alone (HR 0.575, p = 0.008).
Conclusion: In metastatic ACC, patients may benefit from primary tumor resection alone or in combination with metastasectomy; however, further research is required to facilitate appropriate patient selection.
KEYWORDS ACC, adrenalectomy, adrenocortical carcinoma, metastasectomy
1 INTRODUCTION
Adrenocortical carcinoma (ACC) is a notoriously aggressive cancer. Patients often present with large, high-grade tumors and distant metastases at diagnosis. While disease-specific five-year survival in early-stage ACC may be as high as 60%, patients with metastatic
disease have exceptionally poor outcomes, with a five- year survival as low as 10.2%.1-11 With an estimated annual incidence of two or fewer cases per million, however, ACC remains quite rare. 1,2,4-8
While surgical resection is the mainstay of therapy in nonmetastatic ACC, management of metastatic ACC relies primarily on systemic chemotherapy. Mitotane is
the only drug approved for the treatment of metastatic ACC12 and is often combined with systemic chemo- therapy (etoposide, doxorubicin, and cisplatin (EDP)) following the FIRM-ACT trial.13,14 However, response rates to EDP-mitotane remain relatively poor, 13 and no other broadly effective therapeutic options have been identified. 15 Preliminary research on immunotherapeutic agents and immune checkpoint inhibitors have demon- strated modest efficacy in specific subsets of patients, but overall results have been disappointing. 12,14,15
Classically, metastatic disease is a relative contra- indication to surgical resection in ACC. Extensive study in other metastatic malignancies, however, has demonstrated benefit from both primary tumor resec- tion and metastasectomy.16-18 In ACC, retrospective studies of the California Cancer Registry (CCR) and the Surveillance, Epidemiology, and End Results (SEER) database have likewise demonstrated improved sur- vival with primary tumor resection in metastatic ACC.19,20 Pulmonary and hepatic metastasectomy have also demonstrated benefit in both recurrence-free and overall survival.21-24 However, the evidence in support of these interventions remains limited, and the relative impact of primary tumor resection vs. meta- stasectomy is poorly defined.
Therefore, in this study, we aim to characterize the association between survival and surgical resection of (1) the primary tumor and (2) metastatic disease in a large national cohort with metastatic ACC.
2 METHODS
2.1 Data source
We utilized the National Cancer Database (NCDB) to perform a retrospective cohort study of all patients pre- senting with metastatic ACC. The NCDB is a nationwide, facility-based dataset of cancer diagnoses from over 1500 accredited programs, capturing 72% of incident malignancies in the United States per year.25,26 This study was deemed exempt from review by the Institu- tional Review Board of the University of Pennsylvania.
2.2 Study cohort
All adult patients diagnosed with ACC from 2010 to 2019 were identified for inclusion using the ICD-O-3 histology codes for ACC (8370 and 8373) and ICD-10 diagnosis codes for malignant neoplasm of the adrenal cortex (C74.0). Of 4788 patients with ACC, 1198 (25%) had documented metastatic disease and were included. Patients who did not receive any therapy (n = 161), who underwent debulking surgery (n = 15), or who had missing surgical data (n = 46) were excluded, leaving a final cohort of 976 patients (Figure 1).
4,788 patients with adrenocortical carcinoma
3,590 excluded for non- metastatic disease
1,198 patients with metastatic ACC
· 161 excluded for not receiving any treatment · 15 excluded for receiving debulking
1,022 patients with medical or surgical management of metastatic ACC
46 excluded for missing surgical data
976 patients included in final cohort
2.3 Definitions and outcomes
Patients were categorized by surgical intervention received: (1) primary tumor resection, (2) meta- stasectomy, (3) primary tumor resection with meta- stasectomy, or 4) no surgical intervention. The primary outcome was overall survival (OS). Metastatic disease was determined by the presence of Stage IV disease (in patients staged according to the American Joint Com- mittee on Cancer (AJCC), 8th edition) or by documen- tation of a metastatic site (in patients staged according to the AJCC, 7th edition). Pathologic stage of disease was used if available; otherwise, clinical stage was used. “Number of metastatic sites” was defined using NCDB indicators, available only for metastases specifically to the liver, lung, brain, and/or bone. While the NCDB categorizes the location of surgery as primary site or distant site (metastasectomy), data on the anatomic
location of metastasectomy was unavailable. The NCDB does not capture data regarding the temporal relation- ship of surgeries a subject received and so it was not possible to determine if metastasectomy was performed for synchronous or metachronous disease. It was not feasible to identify and exclude patients undergoing palliative surgery, as it is not possible to determine the site, type, or date of such a procedure within NCDB. Patients treated with mitotane were classified as receiving chemotherapy in the NCDB.
2.4 Statistical analysis
Demographic characteristics, tumor size, number of metastatic sites, and treatment modalities were exam- ined, and descriptive statistics were calculated. Data were reported as means with standard deviations (SD) or medians with interquartile ranges (IQR) for contin- uous variables and frequencies with percentages for categorical variables. Group comparisons were per- formed using x2 tests, Student’s t-tests, and Wilcoxon Rank-Sum tests, as appropriate. Multivariable logistic regression was utilized to determine associations of demographic and clinical characteristics with receipt of surgical intervention.
Kaplan-Meier survival analysis was performed based on clinical and treatment characteristics. Median survival and one-, three-, and five-year survival rates were calculated. Mantel-Haenszel tests were used to compare differences in survival. Univariable and multi- variable Cox proportional hazard models were created to determine associations between demographic and clinical characteristics, treatment receipt, and OS. Vari- ables with significance below p = 0.020 on univariable analysis as well as important demographic factors such as sex and race were incorporated into the multivariable model.
2.5 Propensity score matching
To account for the selection bias regarding which pa- tients underwent surgical management in this cohort, propensity score matching (PSM) was used. Three matched groups were created. Patients who did not receive any surgical intervention were matched to those who received: (1) primary resection only and (2) met- astasectomy. Then, patients who received primary resection only were matched with those who received primary resection with metastasectomy. For each sub- cohort, a 1:1 match using the optimal algorithm without replacement and Mahalanobis distance was used. Age, sex, tumor size, Charlson-Deyo comorbidity index, and number of metastatic sites were selected as covariates.
Statistical analysis was performed utilizing Stata, version 17.027 and R, version 4.2.2, using the ‘Matchlt’ package. 28,29
3 RESULTS
3.1 Cohort characteristics
In total, 976 patients met inclusion criteria. The mean age was 55.2 years (SD: 15.4). Most patients were fe- male (60%) and White race (84%). The median tumor size at presentation was 11.0 cm (IQR: 7.7-15.2). The mean number of metastatic sites was 1.4 (SD: 0.75). Of all patients, 59% had metastases to the lung, 57% to the liver, 20% to the bone, and 3.6% to the brain (Table 1).
3.2 Therapeutic approach
In this cohort, 39% of patients (n = 379) underwent operative management. Among patients who underwent surgery, 75% underwent primary resection only, 8.2% underwent metastasectomy only, and 17% underwent both primary resection and metastasectomy. Female sex (OR: 1.476; 95% CI 1.089-1.999; p = 0.012) was associated with higher odds of primary tumor resection. Older age (OR: 0.988; 95% CI 0.977-0.998; p = 0.022) and a greater number of metastatic sites (OR: 0.426; 95% CI 0.340-0.533; p < 0.001) were associated with lower likelihood of undergoing primary tumor resection. Patients with larger primary tumors trended toward a higher likelihood of surgery (OR: 1.016; 95% CI 1.000- 0.1032; p = 0.050). Most patients underwent radiation therapy (62%) or systemic chemotherapy (69%); few were treated with immunotherapy (4%) or hormonal therapy (4%).
3.3 Unadjusted survival
The median follow-up time was 7.2 months (IQR: 3.1- 20.7). The median OS was 7.6 months (95% CI 6.8-8.7). One-year survival was 40.2% (95% CI 36.8%-43.6%), three-year survival was 17.3% (95% CI 14.7%-20.1%), and five-year survival was 10.3% (95% CI 7.9%- 13.0%). The median survival was higher in patients who underwent any surgery (16 vs. 5.2 months, p < 0.001) compared with those managed nonoperatively.
Survival was longest in patients who underwent primary tumor resection with metastasectomy (26.3 months; 95% CI 13.4-39.6), followed by patients who underwent primary resection only (15.3 months; 95% CI 10.9-18.2) and metastasectomy only (6.6 months; 95% CI 3.5-22.0). Survival was the
| Total cohort (n = 976) | Operative management (n = 379) | Non-operative management (n = 597) | p-value | |
|---|---|---|---|---|
| Mean age, years (SD) | 55.2 (15.4) | 53.9 (15.5) | 56.0 (15.3) | 0.035 |
| Sex, n (%) | ||||
| Male | 394 (40.4) | 142 (37.5) | 252 (42.2) | 0.141 |
| Female | 582 (59.6) | 237 (62.5) | 345 (57.8) | |
| Race, n (%) | ||||
| White | 820 (84.0) | 322 (85.0) | 498 (83.4) | 0.475 |
| Black | 96 (9.8) | 32 (8.4) | 64 (10.7) | |
| Other | 60 (6.2) | 25 (6.6) | 35 (5.8) | |
| Ethnicity, n (%) | ||||
| Hispanic | 111 (11.4) | 33 (8.7) | 78 (13.1) | 0.037 |
| Non-Hispanic | 865 (88.6) | 346 (91.3) | 519 (86.9) | |
| Insurance status, n (%) | ||||
| Private | 491 (51.4) | 202 (53.3) | 289 (48.4) | 0.421 |
| Public | 419 (43.8) | 155 (40.9) | 264 (44.2) | |
| Uninsured | 46 (4.8) | 29 (7.7) | 29 (4.9) | |
| Charlson-Deyo score, n (%) | ||||
| 0 | 699 (71.6) | 272 (71.8) | 427 (71.5) | 0.8416 |
| 1 | 193 (19.8) | 76 (20.1) | 117 (19.6) | |
| 2 | 52 (5.3) | 24 (6.3) | 28 (4.7) | |
| ≥3 | 32 (3.3) | 7 (1.8) | 25 (4.2) | |
| Laterality, n (%) | ||||
| Left | 500 (51.2) | 199 (52.5) | 301 (50.4) | 0.001 |
| Right | 401 (41.1) | 167 (44.1) | 234 (39.2) | |
| Bilateral | 12 (1.2) | 2 (0.5) | 10 (1.7) | |
| Unspecified | 63 (6.5) | 11 (2.9) | 52 (8.7) | |
| Median tumor size, cm (IQR) | 11.0 (7.7-15.2) | 10.9 (7.5-14.6) | 12 (8-17) | 0.004 |
| Mean number of metastatic sites, (SD) | 1.37 (0.75) | 1.15 (0.67) | 1.52 (0.76) | <0.001 |
| Location of metastatic sites | ||||
| Liver, n (%) | 550 (56.3) | 166 (43.8) | 384 (64.3) | <0.001 |
| Lung, n (%) | 568 (58.2) | 200 (52.8) | 368 (61.6) | 0.003 |
| Brain, n (%) | 35 (3.6) | 5 (1.3) | 30 (5.0) | 0.002 |
| Bone, n (%) | 189 (19.4) | 61 (16.1) | 128 (21.4) | 0.037 |
| Medical therapy, n (%) | ||||
| Radiation | 606 (62.1) | 209 (55.1) | 397 (66.5) | <0.001 |
| Chemotherapy | 677 (69.4) | 237 (62.5) | 440 (73.7) | <0.001 |
Note: Bold indicates p < 0.05.
shortest in patients managed non-operatively (5.2 months; 95% CI 4.6-6.0) (Figure 2). All surgical interventions had significantly improved survival over nonoperative management (primary resection with
metastasectomy: p < 0.0001; primary resection only: p < 0.0001, metastasectomy only: p = 0.0471). There were no significant differences in survival between sur- gical interventions on pairwise comparisons.
14322323, 2024, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/wjs.12014 by National Library Of Medicine, Wiley Online Library on [05/04/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1.00
0.75
Survival
0.50
0.25
0.00
0
6
12
18
24
30
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Analysis Time (Months)
No Surgery
Resection of Primary Only
Metastas ectomy Only
Resection of Primary and Metastasectomy
3.4 | Cox proportional hazards modeling
On univariable analysis, several demographic and clin- ical characteristics were associated with survival, as shown in Table 2. Resection of the primary tumor alone (HR: 0.549; 95% CI 0.464-0.650; p < 0.001), meta- stasectomy alone (HR: 0.591; 95% CI 0.377-0.926; p = 0.022), resection of the primary with metastasectomy (HR: 0.405; 95% CI 0.292-0.563; p < 0.001), and chemotherapy (HR: 0.787; 95% CI 0.668-0.927; p = 0.004) were associated with improved survival.
On multivariable modeling, Black race (HR: 0.718; 95% CI 0.542-0.951; p = 0.021), private insurance (HR: 0.586; 95% CI 0.406-0.848; p = 0.005), resection of the primary tumor (HR: 0.523; 95% CI 0.430-0.635; p < 0.001) and resection of the primary tumor with metastasectomy (HR: 0.372; 95% CI 0.260-0.532; p < 0.001) were significantly associated with improved OS. Chemotherapy (HR: 0.645; 95% CI 0.532-0.782; p < 0.001) and radiotherapy (HR: 0.716; 95% CI 0.605- 0.846; p < 0.001) were also associated with improved OS. In contrast, Charlson-Deyo score (HR: 1.2182; 95% CI 1.082-1.372; p = 0.001) and greater number of metastatic sites (HR: 1.301; 95% CI 1.167-1.450; p < 0.001) were associated with worse survival. Meta- stasectomy alone had no association with survival (HR: 0.909; 95% CI 0.518-1.595; p = 0.740) (Table 2). When this model was restricted to only patients receiving primary tumor resection, the addition of met- astasectomy was associated with improved OS over
primary tumor resection alone (HR: 0.636; 95% CI 0.437-0.926; p = 0.018).
3.5 Propensity score matching
PSM was performed to develop three matched co- horts: (1) subjects who underwent primary tumor resection alone matched with subjects who did not receive surgery, (2) subjects who underwent meta- stasectomy alone matched with subjects who did not receive surgery, and (3) subjects who underwent pri- mary tumor resection alone with subjects who under- went primary tumor resection with metastasectomy. All matched cohorts were well balanced with respect to age, sex, race, ethnicity, insurance status, comorbid- ities, tumor size, and number of metastatic sites (Table 3).
In the first matched cohort, subjects undergoing primary tumor resection had significantly lower rates of liver and lung metastases when compared with matched patients managed non-operatively (Table 3). On survival analysis, patients who underwent primary tumor resection had a significantly longer median sur- vival (15.9 months, 95% CI 11.0-18.9) than matched patients managed non-operatively (6.0 months; 95% CI 4.8-7.5; p < 0.001) (Figure 3A). Primary tumor resec- tion was associated with improved survival compared to nonoperative management on Cox proportional haz- ards regression (HR: 0.593; 95% CI 0.486-0.723; p < 0.001).
In the second matched cohort, both cohorts were well matched, except the subjects who underwent metastasectomy had a significantly lower rate of liver metastases compared with matched patients managed non-operatively (Table 3). There was no difference in OS between patients who underwent metastasectomy alone (5.6 months; 95% CI 3.5-22.0) and matched patients treated non-operatively (4.6 months; 95% CI 1.9-11.5; p = 0.271) (Figure 3B). Metastasectomy alone was not associated with a survival advantage compared to nonoperative management on Cox pro- portional hazards regression (HR: 0.709; 95% CI 0.421-1.194; p = 0.196).
In the third matched cohort, both cohorts were well matched except the subjects who underwent primary resection alone had a significantly lower rate of liver metastases and a significantly higher rate of lung me- tastases compared with matched patients who under- went primary resection with metastasectomy (Table 3). On survival analysis, patients who underwent primary tumor resection with metastasectomy had a signifi- cantly longer median survival (26.3 months, 95% CI 13.4-37.3) than matched patients managed non- operatively (10.1 months; 95% CI 6.3-20.0; p = 0.011) (Figure 3C). Primary tumor resection with
| Univariable | Multivariable | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p-value | HR | 95% CI | p-value | |
| Age | 1.008 | 1.003-1.013 | 0.002 | 1.003 | 0.997-1.010 | 0.314 |
| Sex | ||||||
| Male | Ref | -- | -- | -- | -- | -- |
| Female | 0.965 | 0.829-1.123 | 0.644 | 1.104 | 0.933-1.306 | 0.248 |
| Race | ||||||
| White | Ref | -- | -- | -- | -- | -- |
| Black | 0.891 | 0.695-1.142 | 0.360 | 0.718 | 0.542-0.951 | 0.021 |
| Other | 0.935 | 0.681-1.283 | 0.675 | 0.859 | 0.604-1.221 | 0.397 |
| Insurance | ||||||
| Uninsured | Ref | -- | -- | -- | -- | -- |
| Private | 0.741 | 0.534-1.028 | 0.072 | 0.586 | 0.406-0.848 | 0.005 |
| Public | 0.908 | 0.653-1.264 | 0.569 | 0.705 | 0.479-1.037 | 0.076 |
| Charlson-Deyo (per point) | 1.220 | 1.110-1.355 | <0.001 | 1.218 | 1.082-1.372 | 0.001 |
| Tumor size (per cm) | 0.994 | 0.987-1.003 | 0.161 | 0.999 | 0.991-1.006 | 0.745 |
| Number of metastatic sites | 1.357 | 1.231-1.496 | <0.001 | 1.301 | 1.167-1.450 | <0.001 |
| Operative management | ||||||
| Nonoperative | Ref | -- | -- | -- | -- | -- |
| Resection of primary | 0.549 | 0.464-0.650 | <0.001 | 0.523 | 0.430-0.635 | <0.001 |
| Metastasectomy | 0.591 | 0.377-0.926 | 0.022 | 0.909 | 0.518-1.595 | 0.740 |
| Primary + metastasectomy | 0.405 | 0.292-0.563 | <0.001 | 0.372 | 0.260-0.532 | <0.001 |
| Medical therapy | ||||||
| Chemotherapy | 0.787 | 0.668-0.927 | 0.004 | 0.645 | 0.532-0.782 | <0.001 |
| Radiation therapy | 0.873 | 0.751-1.012 | 0.072 | 0.716 | 0.605-0.846 | <0.001 |
Note: Bold indicates p < 0.05.
metastasectomy was associated with improved survival compared to primary tumor resection alone on Cox proportional hazards regression (HR: 0.575; 95% CI 0.383-0.864; p = 0.008).
4 DISCUSSION
In metastatic ACC, effective therapeutic options remain limited. Advancements over the past decade in multi- modal therapy, chemotherapeutics, immunotherapy, and targeted therapy in other malignancies have not yet translated to improved survival within this patient pop- ulation. This has, in part, been hindered by the rarity of ACC, which inherently limits the ability to perform rigorous prospective randomized controlled trials. Therefore, the best available data comes from large, multi-center retrospective studies.
To our knowledge, this is the largest study to date to specifically evaluate the role of metastasectomy either
alone or in combination with primary tumor resection in metastatic ACC. We found that surgical resection of the primary tumor is associated with marked improvements in OS compared with nonoperative management. Met- astasectomy, when added to primary tumor resection, was associated with improved survival over nonopera- tive management or primary tumor resection without metastasectomy. However, metastasectomy alone without primary tumor resection did not improve sur- vival. These findings suggest that the status of the pri- mary tumor may significantly impact disease trajectory regardless of metastatic disease burden, and that metastasectomy is likely beneficial when performed in pursuit of potentially curative resection.
Management of the primary tumor is often one of the first decision points in advanced ACC. In this investiga- tion, we found that resection of the primary tumor alone was associated with improved survival after controlling for extent of metastatic disease. By stratifying patients on receipt of metastasectomy, we isolated the effect of
| Non-operative versus resection match | Primary | Non-operative match | versus Metastasectomy | Surgery with versus without metastasectomy match | |||||
|---|---|---|---|---|---|---|---|---|---|
| Non- operative management | Primary resection only (n = 278) | p- value | Non- operative management (n = 30) | Metastasectomy only | p- | Primary resection only | Primary resection with metastasectomy (n = 63) | p-value | |
| (n = 278) | (n = 30) | value | (n = 63) | ||||||
| Mean age, years | 54.1 (14.7) | 53.8 (15.8) | 0.826 | 56.0 (13.1) | 56.4 (13.9) | 0.909 | 53.0 (13.5) | 51.9 (14.8) | 0.656 |
| (SD) | |||||||||
| Sex, n (%) | |||||||||
| Male | 111 (39.9) | 107 (38.5) | 0.728 | 18 (60.0) | 17 (56.7) | 0.793 | 15 (23.8) | 15 (23.8) | 1.00 |
| Female | 167 (60.1) | 171 (61.5) | 12 (40.0) | 13 (43.3) | 48 (76.2) | 48 (76.2) | |||
| Race, n (%) | |||||||||
| White | 231 (83.1) | 237 (85.3) | 0.153 | 25 (83.3) | 26 (86.7) | 0.237 | 50 (79.4) | 54 (85.7) | 0.642 |
| Black | 35 (12.6) | 23 (8.3) | 3 (10.0) | 0 (0.0) | 8 (12.7) | 6 (9.5) | |||
| Other | 12 (4.3) | 18 (6.5) | 2 (6.7) | 4 (13.3) | 5 (7.9) | 3 (4.8) | |||
| Hispanic origin, n (%) | |||||||||
| Yes | 36 (13.0) | 25 (9.0) | 0.136 | 2 (6.7) | 5 (16.7) | 0.424 | 8 (12.7) | 2 (3.2) | 0.095 |
| No | 242 (87.1) | 253 (91.0) | 28 (93.3) | 25 (83.3) | 55 (87.3) | 61 (96.8) | |||
| Insurance status, n (%) | |||||||||
| Private | 148 (55.2) | 146 (53.5) | 0.919 | 15 (51.7) | 19 (63.3) | 0.220 | 33 (52.4) | 36 (57.1) | 0.254 |
| Public | 107 (39.9) | 113 (41.4) | 11 (37.9) | 11 (36.7) | 23 (36.5) | 25 (39.7) | |||
| Uninsured | 13 (4.9) | 14 (5.1) | 3 (10.3) | 0 (0.0) | 7 (11.1) | 2 (3.2) | |||
| Charlson-Deyo score, n (%) | |||||||||
| 0 | 201 (72.3) | 197 (70.9) | 0.981 | 24 (80.0) | 24 (80.0) | 1.000 | 46 (73.0) | 46 (73.0) | 1.000 |
| 1 | 57 (20.5) | 61 (21.9) | 4 (13.3) | 4 (13.3) | 9 (14.3) | 9 (14.3) | |||
| 2 | 15 (5.4) | 15 (5.4) | 2 (6.7) | 2 (6.7) | 6 (9.5) | 6 (9.5) | |||
| ≥3 | 5 (1.8) | 5 (1.8) | 0 (0.0) | 0 (0.0) | 2 (3.2) | 2 (3.2) | |||
| Laterality, n (%) | |||||||||
| Left | 137 (49.3) | 141 (50.7) | 0.001 | 17 (56.7) | 16 (53.3) | 1.000 | 26 (41.3) | 38 (60.3) | 0.032 |
| Right | 112 (40.3) | 130 (46.8) | 9 (30.0) | 10 (33.3) | 37 (58.7) | 24 (38.1) | |||
| Bilateral | 5 (1.8) | 1 (0.4) | 1 (3.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |||
| Unspecified | 24 (8.6) | 6 (2.2) | 3 (10.0) | 4 (13.3) | 0 (0.0) | 1 (1.6) | |||
| Tumor size, cm (IQR) | |||||||||
| Less than | 33 (11.9) | 32 (11.5) | 0.983 | 3 (10.0) | 3 (10.0) | 1.000 | 5 (7.9) | 6 (9.5) | 0.950 |
| 5 cm | |||||||||
| 5-10 cm | 66 (23.7) | 65 (23.4) | 10 (33.3) | 10 (33.3) | 16 (25.4) | 16 (25.4) | |||
| Greater than 10 cm | 179 (64.4) | 181 (65.1) | 17 (56.7) | 17 (56.7) | 42 (66.7) | 41 (65.1) | |||
| Mean number of metastatic sites, (SD) | 1.14 (0.63) | 1.11 (0.65) | 0.552 | 1.50 (0.86) | 1.50 (0.86) | 1.000 | 1.13 (0.63) | 1.13 (0.63) | 1.000 |
| Location of metastatic sites | |||||||||
| Liver, n (%) | 149 (53.6) | 110 (39.6) | 0.001 | 19 (63.3) | 9 (30.0) | 0.010 | 29 (46.0) | 43 (68.3) | 0.012 |
| Lung, n (%) | 128 (46.0) | 154 (55.4) | 0.027 | 15 (50.0) | 21 (70.0) | 0.114 | 36 (57.1) | 23 (36.5) | 0.020 |
| Brain, n (%) | 5 (1.8) | 0 (0.0) | 0.061 | 3 (10.0) | 5 (16.7) | 0.706 | 0 (0.0) | 0 (0.0) | 1.00 |
| Bone, n (%) | 36 (13.0) | 45 (16.2) | 0.279 | 8 (26.7) | 10 (33.3) | 0.573 | 6 (9.5) | 5 (7.9) | 0.752 |
| Non-operative versus Primary resection match | Non-operative versus Metastasectomy match | Surgery with versus without metastasectomy match | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Non- operative management (n = 278) | Primary resection only (n = 278) | p- value | Non- operative management (n = 30) | Metastasectomy only (n = 30) | p- value | Primary resection only (n = 63) | Primary resection with metastasectomy (n = 63) | p-value | |
| Medical therapy, n (%) | |||||||||
| Radiation | 178 (64.0) | 153 (55.0) | 0.031 | 19 (63.3) | 21 (70.0) | 0.584 | 36 (57.1) | 33 (52.4) | 0.591 |
| Chemotherapy | 213 (76.6) | 174 (62.6) | <0.001 | 21 (70.0) | 15 (50.0) | 0.114 | 33 (52.4) | 43 (68.3) | 0.069 |
Note: Bold indicates p < 0.05.
primary resection independent of metastasectomy. Our finding that resection of the primary tumor confers a survival advantage is consistent with two recent studies that utilized the CCR and SEER databases to examine the role of surgery in metastatic ACC. While both of these investigations were notably limited by selection bias, 19,20 the consistency of this finding across multiple studies and patient populations suggests that there is a physiologic advantage associated with the reduction of primary tumor burden, translating to longer survival. Alternatively, this finding may represent excellent patient selection, with patients with less aggressive tumors or a better prognosis being more likely to undergo surgical resection. After matching patients based on tumor size and number of metastatic sites, however, resection of the primary tumor remained associated with improved survival.
The role of metastasectomy is not well described in ACC. Studies generally demonstrate improved OS, especially in patients with metachronous rather than synchronous metastases.22,30,31 Resection of pulmo- nary21,32 and liver metastases23,33 specifically appears safe and effective; however, recurrence is common. In both of our analyses, we found improved OS in patients undergoing primary tumor resection with meta- stasectomy compared to primary tumor resection alone. Patients who underwent metastasectomy alone did not demonstrate a survival benefit over nonoperative man- agement. These findings likely indicate that, in the face of limited metastatic disease, attempts at complete, curative resection are reasonable and can improve survival.
Whereas combined adrenalectomy and meta- stasectomy may improve survival through complete margin-negative resection, the etiology of improved outcomes through resection of the primary tumor alone is unclear. We postulate that this may be due to improved control of corticosteroid hormonal secretion, mass effect, or tumor thrombus through debulking or that perhaps the primary tumor serves as the principal reservoir for shedding metastatic disease. It may also
be that patients who are being selected for primary resection are fundamentally different than those who do not undergo surgery; for instance, they may have excess hormonal secretion or other locoregional symptoms that allow them to benefit more from resec- tion. Regardless, we would suggest that in carefully selected patients, resection of the primary tumor should be considered, and that in patients where complete R0 resection is achievable, metastasectomy should be utilized in conjunction with primary tumor resection.
Palliative resection of the primary tumor or of me- tastases has not been extensively studied.34 Our cohort did not have an adequate sample of patients undergoing debulking or palliative resection. However, patients un- dergoing metastasectomy alone are likely being treated palliatively for symptomatic control rather than for cura- tive intent. While we cannot discern the role of palliative resection for the primary tumor, subjects undergoing metastasectomy alone did not demonstrate improved survival with surgery.
Our study also identified two unexpected significant relationships between private insurance and Black race and improved survival. Improved insurance coverage, decreased time to surgery, and/or higher socioeco- nomic status associated with private insurance may explain improved survival in this cohort. There may be dissimilarities in tumor phenotype by race or ethnic background explaining differential outcomes by this variable; for instance, altered tumor oncogenetic path- ways may make one group more prone to more aggressive or perhaps more hormonally active tumor phenotypes. Further research is necessary to elucidate the mechanisms behind these relationships.
This retrospective study is primarily limited by se- lection bias. Patients with resectable primary tumors, lower volume metastatic disease, or metachronous metastatic disease may have been selected as good candidates for surgical therapy. Alternatively, there may be fundamental differences in tumor biology between groups selected for surgery and those selected for medical management, such as differences in excess
A.
1.00
0.75
Survival
0.50
0.25
0.00
p<0.001
0
6
12
Analysis Time (Months)
18
24
30
36
No Surgery
Resection of Primary Only
B.
1.00
0.75
Survival
0.50
0.25
0.00
p=0.271
0
6
12
Analysis Time (Months)
18
24
30
36
No Surgery
Metastasectomy Only
0
1.00
0.75
Survival
0.50
0.25
0.00
p=0.008
0
6
12
Analysis Time (Months)
18
24
30
36
Resection of Primary Only
Resection of Primary and Metastasectomy
corticosteroid secretion. In this study, we attempted to account for these disease-level factors through multi- variable Cox regression, as well as propensity score matching. Nonetheless, it is not possible to fully account
for selection bias. Therefore, our findings may reflect excellent surgical decision-making and appropriate pa- tient selection rather than a universal surgical benefit in metastatic ACC. Our study is additionally limited by the data source. The NCDB does not capture data regarding the temporal relationship of surgeries a subject received, and it is therefore not possible to determine if metastasectomy was performed for synchronous or metachronous disease. This limitation is somewhat mitigated by the fact that we determined stages based on initial clinical and/or pathologic staging, which should limit the impact of metachronous disease versus syn- chronous disease on outcomes. The NCDB also does not provide information regarding which specific distant site was resected, nor the number of metastatic sites resected. While we were able to match for the number of metastatic sites, limited sample sizes made it infeasible to match for the specific sites of metastatic disease present, and there were some differences regarding specific metastatic sites within our matched cohorts. Future studies should analyze comparative outcomes based on metastatic site resected. Finally, data regarding hormonal secretion for each patient are not captured in the NCDB. In patients with hormonally active tumors, debulking may improve quality of life or survival through reduction of hormone secretion, but this was unable to be assessed nor controlled for.
In conclusion, we found that resection of the primary tumor alone or in combination with metastasectomy improves OS in metastatic ACC, further supporting the importance of surgical management within this population.
AUTHOR CONTRIBUTIONS
Jesse E. Passman, Wajid Amjad, Sara P. Ginzberg, Jacqueline M. Soegaard Ballester, Caitlin Finn and Heather Wachtel all contributed to conception and design of the study. Jesse E. Passman, Wajid Amjad and Heather Wachtel contributed to acquisition, anal- ysis, and visualization of data. All authors contributed to interpretation of data, as well as drafting and revision of this article. All authors gave final approval for submis- sion and publication.
ACKNOWLEDGMENTS
HW received funding from the National Institutes of Health, NCI grant K08 CA270385. JMSB received funding from the NIH T32 Training Program in Surgical Oncology Research at Penn, grant 5T32CA251063- 02.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
ETHICS STATEMENT
This study was deemed exempt from University of Pennsylvania Institutional Review Board approval.
ORCID Jesse E. Passman ® https://orcid.org/0000-0002-6599- 0397
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