Clinical Score Predicting Overall Survival After Surgery for Synchronous Metastatic Adrenocortical Carcinoma: A Surveillance, Epidemiology, and End Result-Based Study
The American Surgeon 2020, Vol. 0(0) 1-7 C The Author(s) 2020 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/0003 134820956275 journals.sagepub.com/home/asu SSAGE
Kan Wu, MD’,*, Zhihong Liu, MD’,*, Xiang Li, MD’, and Yiping Lu, MD’
Abstract
Surgery remains the only potential option for prolonging survival in synchronous metastatic adrenocortical carcinoma (ACC). The purpose of this study is to identify patients who may benefit from adrenalectomy. Using the Surveillance, Epidemiology, and End Results (SEER) database (2010-2015), we identified synchronous metastatic ACC patients who underwent adrenalectomy. Cox regression analysis was performed to identify prognostic factors associated with overall survival. A clinical scoring system was created to predict survival after surgery. Sixty-two patients underwent adre- nalectomy for synchronous metastatic ACC. Median age was 54.5 years. Median overall survival was 12 months. In univariable analysis revealed that age 652years, tumor stage: T3/4, multiple metastases, liver metastases, and no chemotherapy were associated with poor survival. In the multivariable Cox analysis, liver metastases (P = . 017) and no chemotherapy (P = . 039) remained independent predictors of worse prognosis. A clinical scoring system including of 1-point each for the 2 predictors demonstrated good discrimination in predicting survival after adrenalectomy (3-year survival: 45.9% for 0 points and 0% for 1 or 2 points; P < . 001, area under the curve = . 78). Prolonged survival after adrenalectomy combined with chemotherapy can be potentially achieved in synchronous metastatic ACC patients without liver metastases. Patients with liver metastases should be carefully evaluated for surgery.
Keywords
metastatic adrenocortical carcinoma, synchronous, adrenalectomy, overall survival
Introduction
Adrenocortical carcinoma (ACC) is a rare and highly aggressive malignancy with an estimated incidence of 1/1 000 000 individuals annually.1,2 About one-third of patients present with synchronous metastases at initial diagnosis,3 and the 5-year survival rate is as low as 0% in metastatic ACC patients.4 Currently, the main treatment modality for synchronous metastatic ACC is mitotane plus chemotherapy regimen based on the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment study.5 It was considered to be a promising result, whereas for overall survival, it remains dismal. The administration of this aggressive regimen usually comes with the risk of toxicity and side effects, and some patients cannot tolerate the entire course of treatment. Therefore, surgical intervention is thought to be a feasible option for prolonging survival in patients with synchronous metastases if technically possible.
Some investigators demonstrated that complete en bloc resection could improve survival in selected pa- tients with metastatic ACC.6-9 A population-based study revealed that adrenal surgery is also associated with improved overall survival in synchronous meta- static ACC patients, even in the presence of metasta- ses.1º Recently, the current guideline suggests adrenalectomy in patients presenting with limited metastatic diseases at initial diagnosis if operative in- tervention seems feasible.11 Obviously, some patients
‘Department of Urology, Institute of Urology, West China Hospital, Sichuan University, China
*These authors contributed equally to this work
Corresponding Author:
Yiping Lu, Professor of Urology, Department of Urology, Institute of Urology, West China Hospital, Sichuan University, 37 Guoxue Lane, Chengdu 610041, Sichuan, China. Email: yipinglu@163.com
with synchronous metastases may benefit from ag- gressive adrenalectomy, but there are limited data about which subgroups can benefit from aggressive operative therapy.
Thus, we utilized a population-based database to evaluate the clinicopathologic features and survival out- comes of patients who underwent adrenalectomy for synchronous metastatic ACC. Besides, we generated a clinical score that can be used by surgeons to improve surgical decision-making and select patients with meta- static diseases who likely to benefit from surgical resection.
Methods
Study Population
We extracted data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database which collects and publishes cancer-specific outcomes for approximately 28% of the American pop- ulation. Using the SEER database, we identified patients diagnosed with metastatic ACC from January 1, 2010 to 20 December 31, 2015.
Inclusion criteria included the following: (1) patients with a primary site labeled as codes: C740: Cortex of the adrenal gland and C749: Adrenal gland, not otherwise specified, and the histology code: 8370 according to the International Classification of Disease for Oncology, third edition; (2) patients diagnosed with a unilateral tumor, and pathology-confirmed ACC; (3) patients older than 18 years of age; (4) patients who underwent surgery for the primary tumor, which defined as codes 40, total surgical removal of the primary site; and 60, radical surgery. Patients who had unknown metastatic sites (lung, liver, bone, and brain) or unknown surgery information were excluded in the cohort. Patients who underwent local tumor excision (such as radio-frequency ablation, cryoa- blation, partial or debulking surgery) also were excluded.
Demographic and Clinical Variables
Study variables included age, sex, race, marital status, laterality, tumor size, tumor grade, tumor stage, treatment modality (surgery, radiotherapy, or chemotherapy), site of metastatic disease, survival months, and vital status. The tumor stages were reevaluated based on the European Network for the Study of Adrenal Tumors (ENSAT) staging system.12
Statistical Analysis
Basic clinicopathologic characteristics are described using continuous variables, or categorical variables. Comparisons were performed by the ANOVA, and Fisher exact test, as appropriate. Overall survival was
estimated using the Kaplan-Meier method and compared by using the log-rank test. A univariate and multivariate Cox proportional hazards model was applied to identify the independent predictors associated with overall survival and expressed as hazard ratios (HR) with 95% confidence intervals (CIs). Independent prognostic factors of overall survival were entered into a clinical score that assigned points to each identified factor based on their ß-coefficients. The predictive value of the clinical score was determined by assessing the area under curve (AUC) of the receiver operating characteristics curve obtained by using the ad- justed risk factor model. An AUC of .5 represents no predictive value and an AUC of 1 represents perfect dis- crimination. P values <. 05 were determined as statistically significant. All statistical analyses were performed with SPSS software version 23.0 (IBM, Armonk, New York).
Results
Figure 1 illustrates the inclusion and exclusion processes in this study. A total of 62 patients who underwent radical adrenal surgery for synchronous metastatic ACC were enrolled in the study cohort. The majority of metastasis sites were the lung metastases (30.6%), followed by liver metastases (25.8%), multiple metastases (25.8%), other metastases (11.3%), and bone metastases (6.5%).
The baseline demographic and clinicopathological characteristics of the entire patients and the subgroups according to the site of metastasis are presented in Table 1. The median age at initial diagnosis was 54.5 years (in- terquartile range (IQR) 43-62 years). The majority of patients were females (56.6%), white race (88.7%), right- sided tumors (53.2%), and lymph node negative (80.6%). Median tumor size was 13.5 cm (IQR 9.9-18.7 cm) and one-fifth of patients underwent metastasectomy for distant diseases. Chemotherapy was more common than radiation in adjuvant therapy for metastatic ACC patients (chemotherapy 62.9%, radiation 22.6%). As showed in
Exclusion criteria:
1. Unknown metastatic sites (N=1)
2. Unknown surgery information (N=3)
Inclusion criteria:
3. Local tumor excision (N= 12)
1. Adrenocortical carcinoma aged 18+
2. Diagnosed in 2010-2015
3. ENSAT Stage: IV
4. Unilateral tumor, and positive histology
5. Underwent primary site surgery (N=78)
Lung metastasis (N=19) Liver metastasis (N=16)
Final population (N=62)
Bone metastasis (N=4) Brain metastasis (N=0) Other metastasis (N=7) Multiple metastasis (N=16)
| Characteristic | Total (n = 62) | Lung metastasis (n = 19) | Liver metastasis | Bone or other metastasis Multiple metastasis Sites | ||
|---|---|---|---|---|---|---|
| (n = 16) | (n = 11) | (n = 16) | P value | |||
| Age, y, median | 54.5 (43-62) | 54 (43-67) | 56.5 (38-66) | 55 (47-62) | 48.5 (42-58.5) | .753 |
| (IQR) | ||||||
| Sex, n (%) | ||||||
| Male | 27 (43.5) | 7 (36.8) | 8 (50.0) | 3 (27.3) | 9 (56.3) | .442 |
| Female | 35 (56.6) | 12 (63.2) | 8 (50.0) | 8 (72.7) | 7 (43.7) | |
| White race, n (%) | 55 (88.7) | 17 (89.5) | 14 (87.5) | 9 (81.8) | 15 (93.8) | .862 |
| Primary tumor location, n (%) | ||||||
| Left | 29 (46.8) | 11 (57.9) | 8 (50.0) | 3 (27.3) | 7 (43.8) | .440 |
| Right | 33 (53.2) | 8 (42.1) | 8 (50.0) | 8 (72.7) | 9 (56.3) | |
| Tumor size,cm, median (IQR) | 13.5 (9.9-18.7) | 14.0 (11.0-19.5) | 16.0 (8.8-23.9) | 10.0 (9.6-14.0) | 13.7 (8.1-18.0) | .128 |
| T3/4 stage, n (%) | 46 (74.2) | 13 (68.4) | 14 (87.5) | 8 (72.7) | 11 (68.8) | .547 |
| N stage, n (%) | ||||||
| N0 | 50 (80.6) | 18 (94.7) | 12 (75.0) | 8 (72.7) | 12 (75.0) | .275 |
| N1 | 8 (12.9) | 1 (5.3) | 2 (12.5) | 2 (18.2) | 3 (18.8) | |
| Nx | 4 (6.5) | 0 (0) | 2 (12.5) | 1 (9.1) | 1 (6.3) | |
| Tumor grade, n (%) | ||||||
| I/II | 6 (9.7) | 2 (10.5) | 0 (0) | 2 (18.2) | 2 (12.5) | .093 |
| III/IV | 11 (17.7) | 3 (15.8) | 4 (25.0) | 2 (18.2) | 2 (12.5) | |
| Unknown | 45 (72.6) | 14 (73.7) | 12 (75.0) | 7 (63.6) | 12 (75.0) | |
| Surgery of metastatic | ||||||
| site, n (%) | ||||||
| Yes | 13 (21.0) | 4 (21.1) | 5 (31.3) | 1 (9.1) | 3 (18.8) | .634 |
| No/unknown | 49 (79.0) | 15 (78.9) | 11 (68.7) | 10 (90.9) | 13 (81.2) | |
| Radiation, n (%) | ||||||
| Yes | 14 (22.6) | 2 (10.5) | 3 (18.8) | 4 (36.4) | 5 (31.3) | .322 |
| No/unknown | 48 (77.4) | 17 (89.5) | 13 (81.2) | 7 (63.6) | 11 (68.7) | |
| Chemotherapy, n (%) | ||||||
| Yes | 39 (62.9) | 16 (84.2) | 5 (31.3) | 8 (72.7) | 10 (62.5) | .013 |
| No/unknown | 23 (37.1) | 3 (15.8) | 11 (68.7) | 3 (27.3) | 6 (37.5) | |
Abbreviation: IQR, interquartile range.
Table 1, patients in each group well matched for age, sex distribution, race, tumor size, tumor grade, tumor stage, and adjuvant therapy. Whereas, compared with liver metastases patients, patients with lung metasta- ses tended to receive chemotherapy (84.2% vs. 31.1%, P = . 002).
Among the 62 patients finally recruited, 39 patients had died during the follow-up. The median survival was 12 months (IQR 6-36 months). The 1-, 2-, and 3-year overall survival rates for the entire patients were 49.4%, 35.4%, and 18.8%, respectively. Table 2 shows the results of a univariable analysis of prognostic factors associated with overall survival after primary site surgery for syn- chronous metastatic ACC. Risk factors for worse prog- noses included age older than 65 years (3-year survival 0% vs. 23.7%; P = . 041), ENSAT stage: T3/4 (10.7% vs. 59.1%; P = . 037), multiple metastases (8.5% vs. 24.5%; P = . 026), liver metastases (0% vs. 37.5%; P < . 001), and
no chemotherapy (0% vs. 31.2%; P < . 001). Sex, race, surgery of metastatic site, primary tumor location, tu- mor size, tumor grade, local lymph node status, and administration of radiation were not significantly as- sociated with overall survival. Figure 2 displayed the Kaplan-Meier curves of overall survival after primary site surgery according to the 5 prognostic factors mentioned above.
In the multivariable Cox analysis, liver metastases (HR = 2.606, 95% CI 1.185-5.732; P = . 017) and no chemotherapy (HR = 2.191, 95% CI 1.040-4.614; P = .039) remained independent predictors of worse sur- vival (Table 2). To predict overall survival after pri- mary site surgery, all 2 predictors were incorporated into a clinical score (1 point for each predictor). Additional analysis demonstrated that this clinical score had good discrimination (AUC = . 78) in pre- dicting overall survival after adrenalectomy: 3-year
| Variable | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| 3-y overall survival, % | HR (95% CI) | P-value | β | HR (95% CI) | P-value | |
| Age, y | ||||||
| <65 | 23.7 | Ref | Ref | Ref | ||
| ≥65 | 0 | 2.286 (1.134-4.608) | .041 | .447 | 1.564 (.707-3.463) | .270 |
| Sex | ||||||
| Male | 21.3 | Ref | ||||
| Female | 18.4 | 1.046 (.551-1.988) | .887 | — | ||
| Race | ||||||
| White | 19.6 | Ref | ||||
| Other | 42.8 | 1.447 (.433-4.829) | .462 | — | ||
| Primary tumor location | ||||||
| Left | 28.2 | Ref | ||||
| Right | 0 | 1.584 (.837-2.997) | .139 | — | ||
| Tumor size, cm | ||||||
| <20 | 15.3 | Ref | ||||
| ≥20 | 31.8 | .633 (.294-1.359) | .281 | — | ||
| T stage | ||||||
| T1/2 | 59.1 | Ref | Ref | Ref | ||
| T3/4 | 10.7 | 2.786 (1.327-5.849) | .037 | .395 | 1.484 (.482-4.566) | .491 |
| N stage | ||||||
| N0 | 23.8 | Ref | ||||
| N1 | 0 | 1.802 (.655-4.954) | .141 | — | ||
| Tumor grade | ||||||
| I/II | 62.5 | Ref | ||||
| III/IV | 16.4 | 2.395 (.666-8.621) | .240 | — | ||
| Metastatic tumors | ||||||
| Single | 24.5 | Ref | Ref | Ref | ||
| Multiple | 8.5 | 2 (1.009-3.964) | .026 | .345 | 1.412 (.586-3.400) | .442 |
| Site of metastasis | ||||||
| Distant (except liver) | 37.5 | Ref | Ref | Ref | ||
| Liver | 0 | 3.547 (1.822-6.903) | <. 001 | .958 | 2.606 (1.185-5.732) | .017 |
| Surgery of metastatic site | ||||||
| Yes | 23.1 | Ref | ||||
| No/unknown | 14.7 | .754 (.335-1.696) | .441 | — | ||
| Radiation | ||||||
| Yes | 24.4 | Ref | ||||
| No/unknown | 16.2 | 1.567 (.76-3.231) | .263 | — | ||
| Chemotherapy | ||||||
| Yes | 31.2 | Ref | Ref | Ref | ||
| No/unknown | 0 | 3.293 (1.552-6.988) | <. 001 | .784 | 2.191 (1.040-4.614) | .039 |
Abbreviation: HR, hazard ratios; CI, confidence interval.
ªVariables with P < . 05 in univariate analysis were included in the multivariate model.
survival 45.9% for 0 points and 0% for 1 or 2 points (Figure 3; P < . 001).
Discussion
In this study, we identified 2 independent predictors of poor survival after adrenalectomy of synchronous
metastatic ACC, including liver metastases and no che- motherapy. Furthermore, we constructed a clinical score as a risk prediction tool that can be used to provide reliable prognostic information in these pa- tients. This study finding supports radical adrenalec- tomy combined with systemic chemotherapy, which may improve survival outcomes in carefully selected
A
100
P=0.041
B
100
P=0.037
Percent survival (%)
80
Percent survival (%)
80
60
60
T1/2
40
Age<65y
40
20
Age≥65y
20
T3/4
0
0
0
12
24
36
48
60
0
12
24
36
48
60
Months
Months
C
100
P=0.026
D
100
P<0.001
Percent survival (%)
80
Percent survival (%)
80
60
60
Single
Chemotherapy
40
40
20
20
No chemotherapy
Multiple
0
0
0
12
24
36
48
60
0
12
24
36
48
60
Months
Months
E
100
P<0.001
F
100
P<0.001
Percent survival (%)
80
Percent survival (%)
80
60
60
Lung
40
40
Other site
Bone or other sites
20
20
Liver
Liver
0
Multiple
0
0
12
24
36
48
60
0
12
24
36
48
60
Months
Months
patients with synchronous metastatic ACC (except for liver metastases).
In our study, a novel finding is that the site of the ACC metastasis has significant prognostic implications on the survival outcomes after adrenal surgery. Liver metastases were found to represent inferior situations and were as- sociated with poor survival. On the contrary, other distant sites (such as lung metastases and bone metastases) were associated with favorable outcomes. These observations
are supported by a multi-institutional study that dem- onstrated a significant difference in long-term outcomes by location of distant metastasis; they found liver me- tastases were associated with worse survival.13 This outcome was in accordance with a previously published study that reported 28 ACC patients who underwent metastasectomy for liver metastases eventually developed recurrent diseases and died of disease during the follow- up period.14 In addition, the number of involved organs
100
P<0.001
Percent survival (%)
80
60
0 Point
40
20
1 or 2 Points
0
0
12
24
36
48
60
Months
should be considered as a prognostic factor for overall survival in synchronous metastatic ACC. Our results showed that multiple metastases have a significant neg- ative effect on survival in univariate analysis. Several previous studies also confirmed that the number of metastatic sites is indeed a predictive factor for survival in metastatic ACC.9,15,16
The benefit of radical adrenalectomy on survival for patients with synchronous metastatic ACC remains controversial. Several previous studies have displayed a survival benefit from aggressive operative in- tervention,6-8 but the majority of their patients with metachronous metastases received metastasectomy, and the influence of the adrenalectomy was not assessed. Given their overall dismal prognosis, few institutions offered aggressive surgical intervention in these patients. However, recently published studies show that radical adrenalectomy had a more favorable survival in selected patients with synchronous metastatic ACC, even in the presence of metastases.9,10 These outcomes are supported by international consensus guidelines that suggest adrenal surgery in patients with limited metastatic lesions but against the routine use of adrenalectomy in cases with widespread metastatic diseases at initial diagnosis.11 Therefore, we acknowledge that in carefully selected patients, adrenalectomy might confer survival benefit if technically possible.
The influence of adjuvant or neoadjuvant chemo- therapy on survival in patients with metastatic ACC remains a subject of debate. Because of heterogeneity in metastatic ACC, many reports based on single-arm studies resulted in different therapeutic regimens and limited by the inherent selection bias. The final standard chemotherapy regimen for advanced ACC cannot be given by the current guidelines. Several previous published studies showed that chemotherapy had no significant impact on survival outcomes in
advanced ACC patients, whether administration be- fore or after surgery.8,13,17 Nevertheless, a US study by Mayo Clinic and MD Anderson Cancer Center showed that neoadjuvant chemotherapy might be as- sociated with improved survival after operative in- tervention in patients with synchronous metastatic diseases.º In terms of this study, we demonstrated that patients who received chemotherapy had an improved outcome. But there is no clear evidence to support the use of neoadjuvant chemotherapy before surgery for synchronous metastatic ACC in our study due to lack of sufficient information on the type of chemo- therapy in the SEER database. Given the efficacy of chemotherapy based on current data, we suggest ne- oadjuvant treatment might have survival advantages and should be tested in future clinical trials for met- astatic ACC.
There are several limitations in this study. First, despite this study based on the SEER database cov- ering approximately 28% of the American population, the sample size is still small and also limited by the inherent bias of a retrospective study. Second, in- formation on patient performance status, patient co- morbid conditions, postoperative complications, the 30-day mortality rates, and detailed information on systemic treatment are unavailable. These variables may have an impact on therapeutic decision-making. There is a definite need for further studies to identify suitable surgery candidates. Third, several prognostic parameters, such as the Weiss score, Ki-67 index, surgical margin status, and hormonal functional status were not recorded, but these have been considered as independent prognostic factors for metastatic ACC patients.18,19 Fourth, in our cohort, only included patients underwent surgery of primary sites but excluded patients who did not undergo surgery. Therefore, it is not possible to compare the survival difference between these groups. Lastly, the predictive value of this clinical score is limited by the small size of our cohort, but this clinical scoring system may be used to improve the understanding of the benefits of aggressive intervention in the synchronous setting. Consequently, given these limitations of this study, more future studies are urgently needed to explore a power prognostic model for synchronous metastatic ACC.
Conclusions
Utilizing the SEER database, we find that adrenalectomy combined with systemic chemotherapy may be justified in synchronous metastatic ACC patients without liver me- tastases. Given dismal survival, patients with liver me- tastases should be carefully evaluated for surgery based on prognostic factors, multidisciplinary discussion, and pa- tient’s preference.
Acknowledgments
The authors appreciate the Surveillance, Epidemiology, and End Results database in providing high-quality clinical data for our research.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with re- spect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University.
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