ENDOCRINE SOCIETY
OXFORD
Clinical Research Article
Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients’ Survival
Victor Srougi,1,2 Irina Bancos,3 Marilyne Daher,4 Jeffrey E. Lee,5 Paul H. Graham,5 Jose A. Karam,6 Andres Henriquez,3 Travis J. Mckenzie,3,7 Alaa Sada,3,7 Isabelle Bourdeau,8 Jonathan Poirier,8 Anand Vaidya,9 Tiffany Abbondanza,9 Colleen M. Kiernan,1º Sarika N. Rao,11 Oksana Hamidi,12 Nirupa Sachithanandan,13 Ana O. Hoff,14 Jose L. Chambo,1 Madson Q. Almeida, 14,15 Mouhammed Amir Habra,4,* and Maria C. B. V. Fragoso 14,15,*
1Division of Urology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-000, Brazil; 2Division of Urology, Hospital Moriah, São Paulo 04083-002, Brazil; 3Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA; 4Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; 5Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; 6Department of Urology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; 7Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA; 8Division of Endocrinology and Research Center, Centre hospitalier de l’Université de Montréal (CHUM), Montréal, QC H3C 3J7, Canada; 9Center for Adrenal Disorders, Division of Endocrinology Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; 10Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; 11Division of Endocrinology, Mayo Clinic, Jacksonville, FL 85054, USA; 12Division of Endocrinology and Metabolism, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; 13Department of Endocrinology and Diabetes, St Vincent’s Hospital Melbourne, Melbourne 3065, Australia; 14Unidade de Suprarrenal, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil 05403-000; and 15Instituto do Câncer do Estado de São Paulo da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brazil
ORCID numbers: 0000-0001-8346-3833 (V. Srougi); 0000-0001-9332-2524 (I. Bancos); 0000-0002-7367-3885 (0. Hamidi).
*M.A.H. and M.C.B.V.F. share the last author position.
Abbreviations: ACC, adrenocortical carcinoma; CR, cytoreduction; ENSAT, European Network for the Study of Adrenal Tumor; HR, hazard ratio; no-CR, without cytoreduction; OS, overall survival.
Received: 16 August 2021; Editorial Decision: 23 November 2021; First Published Online: 30 November 2021; Corrected and Typeset: 24 December 2021.
Abstract
Context: The role of cytoreduction of adrenocortical carcinoma (ACC) remains poorly understood.
Objective: To analyze the impact of cytoreductive surgery of the primary tumor in patients with metastatic ACC.
Design and Setting: We performed a multicentric, retrospective paired cohort study comparing the overall survival (OS) in patients with metastatic ACC who were treated either with cytoreductive surgery (CR group) or without cytoreductive surgery (no-CR group) of the primary tumor. Data were retrieved from 9 referral centers in the American- Australian-Asian Adrenal Alliance collaborative research group.
Patients: Patients aged ≥18 years with metastatic ACC at initial presentation who were treated between January 1, 1995, and May 31, 2019.
Intervention: Performance (or not) of cytoreductive surgery of the primary tumor. Main outcome and measures: A propensity score match was done using age and the number of organs with metastasis (≤2 or >2). The main outcome was OS, determined from the date of diagnosis until death or until last follow-up for living patients.
Results: Of 339 patients pooled, 239 were paired and included: 128 in the CR group and 111 in the no-CR group. The mean follow-up was 67 months. Patients in the no-CR group had greater risk of death than did patients in the CR group (hazard ratio [HR] = 3.18; 95% CI, 2.34-4.32). Independent predictors of survival included age (HR = 1.02; 95% CI, 1.00-1.03), hormone excess (HR = 2.56; 95% CI, 1.66-3.92), and local metastasis therapy (HR = 0.41; 95% CI, 0.47-0.65).
Conclusion: Cytoreductive surgery of the primary tumor in patients with metastatic ACC is associated with prolonged survival.
Key Words: adrenocortical carcinoma, cytoreduction surgical procedures, surgery, survival
The treatment of adrenocortical carcinoma (ACC) poses multiple clinical challenges. This rare and often lethal malig- nancy is diagnosed with metastasis in 30% to 50% of pa- tients (1, 2). In this setting, the 5-year overall survival (OS) has varied from 2% to 15%, depending on tumor burden (3). The therapeutic options for advanced ACC often result in disappointing outcomes and have not evolved much in dec- ades. The current standard of care for systemic therapy con- sists of a combination of mitotane, etoposide, doxorubicin, and cisplatin, with a response rate of 23% (4). Despite the slight improvement in cancer-specific survival compared with second-line drugs, this combination is associated with high toxicity and no proven benefit on OS. Multiple trials have tested inhibitors for mTOR, tyrosine kinase, and IGF recep- tors, with unsatisfactory results (5-8). Immunotherapy may provide a future perspective; however, current evidence dem- onstrates a low rate of objective disease response for these drugs, ranging from 6% to 23% (9-11).
The suboptimal prognosis and lack of efficient sys- temic therapies have shifted the treatment of metastatic ACC to a multimodal approach, encompassing surgery, chemotherapy, and other therapeutic measures. Livhits et al. (2) evaluated 167 patients with metastatic ACC from
a local registry database and found that combined treat- ment significantly prolonged survival over chemotherapy (hazard ratio [HR] = 0.47) and perhaps over surgery alone (HR = 0.59). Based on previous experience with other ma- lignancies (ie, renal cell carcinoma and ovarian cancer), cytoreduction of the primary tumor may have a role in the management of patients with metastatic disease. Libé et al. (3) demonstrated that European Network for the Study of Adrenal Tumor (ENSAT) III and IV patients with incomplete tumor resection had a 1.6-fold greater risk of death. The rationale for diminishing the tumor burden is that it could reduce metastatic seeding, improve systemic treatment efficacy, and ameliorate symptoms related to hormone excess and local mass effect. Although many institutions commonly use cytoreductive surgery, there is a paucity of studies evaluating its effect in ACC. Hence, the American-Australian-Asian Adrenal Alliance net- work performed a collaborative cohort study to evaluate the impact on survival of resecting the primary tumor in patients with metastatic ACC. Our hypothesis was that cytoreductive surgery is associated with prolonged sur- vival compared with survival in patients who did not undergo cytoreductive surgery.
Patients and Methods
Patients and Data Collection
In this multicentric, retrospective, paired cohort study, we searched the American-Australian-Asian Adrenal Alliance database for patients with ACC whose disease had been diag- nosed between January 1, 1995, and May 31, 2019, and re- trieved data from 9 international institutions. All participating centers had the approval of their local institutional review board, and the patients’ identification was kept confidential. Inclusion criteria consisted of patients aged ≥18 years with metastatic ACC at diagnosis or with a suspect lesion that was confirmed as a metastasis within 90 days of diagnosis that ful- filled the modified ENSAT stage IV classification, and an ACC diagnosis that was confirmed pathologically (in the surgical specimen or tumor biopsy) or a typical clinical presentation for ACC (excess adrenal hormone, adrenal tumor ≥4 cm, and distant metastasis in imaging studies). Lymph node tumor in- volvement was considered as metastasis, in accordance with the modified ENSAT classification. We excluded patients with other active primary malignancies.
We retrieved the following parameters: age, sex, tumor laterality, hormonal production at presentation, tumor size, presence of carcinomatosis, presence of vein tumoral thrombus, number and site of metastasis, nonsurgical treatment of the primary tumor, local metas- tasis therapy, treatment with systemic therapy, number of lines of systemic therapy, and survival status on last follow-up. Among patients who underwent surgery, we also recorded surgical margin status, tumor rupture during surgery, death within 30 days of surgery, and adju- vant radiotherapy. Nonsurgical treatment of the primary tumor consisted of any therapeutic modality used to treat the primary tumor other than surgery (ie, radiotherapy, chemoembolization, cryotherapy, and radiofrequency). For pairing purposes, we stratified patients based on the modified ENSAT staging: 4a = ≤2 organs with metastasis, 4b = 3 organs with metastasis, and 4c = >4 organs with metastasis. The results were reported according to the Strengthening the Reporting of Observational Studies in Epidemiology recommendations.
Statistical Analysis
We performed a descriptive analysis using frequencies, means, and dispersion measures. The measured parameters were compared between groups by using t tests and Mann- Whitney tests for continuous variables or the Fisher exact test or x2 for categorical variables. Normality was assessed by using the Shapiro-Wilk test.
Patients were distributed into two groups according to the treatment performed: (1) primary tumor resection
(cytoreductive surgery) followed (or not) by systemic therapy (cytoreduction group [CR]) and (2) without primary tumor resection followed (or not) by systemic therapy (without cytoreduction group [no-CR]). Systemic therapy included any cytotoxic chemotherapy, with or without concomitant use of mitotane. Patients with incomplete chemotherapy records were considered as not having performed systemic therapy. Complementary treatments to the primary tumor and me- tastasis were allowed for both groups. A propensity match score was applied by using age as a continuous variable and the modified ENSAT classification as a dichotomous variable (4a or >4a). (3) Matching was done by using the R package MatchIT by the exact paring method and applying the logit function to estimate the distance between matches.
The primary end point was OS, defined as the period be- tween the date of diagnosis of ACC and death by any cause. Living patients were censored at the date of last follow-up. Survival was estimated by Kaplan-Meier curves. A subanalysis of OS was performed after the exclusion of patients who were referred to systemic therapy after surgery or as primary treat- ment but had no record of receiving chemotherapy. OS was compared between groups with use of the log-rank test. A Cox proportional hazards model was used to evaluate the relation between the independent variables and OS, aiming to iden- tify predictors of survival. Variables with P values < 0.2 were included in the multivariate analysis. The final model was obtained by using the stepwise regression method. All tests were 2-sided. Result with P values < 0.05 were considered statistically significant. The statistical analysis was performed with use of R software version 3.6.
Results
Demographic and Clinical Characteristics
Among 339 patients with metastatic ACC in the database, 325 met the inclusion criteria. After matching, 128 patients were included in the CR group and 111 were included in the no-CR group (total = 239). The median cohort age was 52 years (range, 19-86 years). Demographic and clinical characteristics are shown in Table 1. Most of the cohort had hormone ex- cess (73.2%) and metastasis to a single organ (54%). The lung was the most frequent site of metastasis (66.9%). Nonsurgical treatment to the primary tumor was performed in 28.8% of patients. A total of 161 subjects had available data on metas- tasis management, 28.6% of whom had undergone an inter- vention. Table 2 summarizes the data regarding local therapies to the primary tumor and metastasis. The no-CR group had smaller tumors (11.7 cm vs 13.6 cm; P = 0.001) and higher frequency of liver metastasis (68.5% vs 42.2%; P < 0.001).
In the CR group, 22% of patients had positive sur- gical margins; in 17.3%, the surgical margin status was
| All cohorts | CR group | No-CR group | P | |
|---|---|---|---|---|
| N = 239 | N = 128 | N = 111 | ||
| Median age (QRT), years | 52 (19-86) | 52 (19-86) | 52 (19-86) | 0.520 |
| Laterality (right) | 107 (45.1%) | 54 (42.2%) | 53 (48.6%) | 0.389 |
| Gender (female) | 136 (56.9%) | 75 (58.6%) | 61 (55%) | 0.663 |
| Diagnosis based on | ||||
| Surgical specimen | 108 (45.2%) | |||
| Biopsy specimen | 49 (20.5%) | |||
| Clinical findings | 82 (34.3%) | |||
| Hormonal excess | 0.170 | |||
| Absent | 88 (36.8%) | 46 (35.9%) | 42 (37.8%) | |
| Corticosteroids | 77 (32.2%) | 39 (30.5%) | 38 (34.2%) | |
| Corticosteroids + androgens | 49 (20.5%) | 33 (25.8%) | 16 (14.4%) | |
| Androgens | 18 (7.5%) | 6 (4.7%) | 12 (10.8%) | |
| Aldosterone and other | 7 (2.9%) | 4 (3.1%) | 3 (2.7%) | |
| Median primary tumor size (QRT), cm | 13 (3-29) | 13.6 (3.5-29) | 11.7 (3-23) | 0.001 |
| Site of metastasis | ||||
| Lung | 160 (66.9%) | 83 (64.8%) | 77 (69.4%) | 0.546 |
| Liver | 130 (54.4%) | 54 (42.2%) | 76 (68.5%) | <0.001 |
| Distant lymph nodes | 35 (14.6%) | 15 (11.7%) | 20 (18%) | 0.234 |
| Bone | 33 (13.8%) | 20 (15.6%) | 13 (11.7%) | 0.492 |
| Other | 28 (11.7%) | 12 (9.4%) | 16 (14.4%) | 0.314 |
| Carcinomatosis | 16 (6.7%) | 7 (5.5%) | 9 (8.1%) | 0.579 |
| Vein thrombus | 66 (29.5%) | 31 (24.6%) | 35 (35.7%) | 0.097 |
| Modified ENSAT classification | ||||
| 4a | 212 (88.7%) | 116 (90.6%) | 96 (86.5%) | 0.422 |
| 4b | 17 (7.1%) | 8 (6.3%) | 9 (8.1%) | |
| 4c | 10 (4.2%) | 4 (3.1%) | 6 (5.4%) | |
| Mean follow-up (mo) | 67 ± 7 | 69 ± 8 | 42 ± 5 |
CR, cytoreductive surgery; ENSAT, European Network for the Study of Adrenal Tumor; QRT, quartile.
unknown. Tumor rupture during the procedure was re- ported in 4 patients. The mortality rate within 30 days after the surgery was 2.3% (3 events). Neoadjuvant systemic therapy was performed in 17.9% of the CR group.
Survival Analysis
The mean follow-up was 67 ± 7 months for living patients. The median OS time for patients in the CR group was 25.2 months (95% CI, 21.0-29.5) and in the no-CR group was 9.0 months (95% CI, 6.7-11.3). The estimated 1-, 2-, and 5-year OS rates of the entire cohort were 57%, 36%, and 14%, respectively. In the CR group, 85 patients (66%) died; in the no-CR group, 98 patients (88%) died.
The estimated 1-, 2-, and 5-year OS rates for the CR group were 77%, 54%, and 22% and for the no-CR group were 34%, 15%, and 5%, respectively (log-rank; P < 0.001) (Fig. 1). Patients in the no-CR group had greater risk of death than did patients in the CR group (HR = 3.18; 95% CI, 2.34-4.32). In the CR and no-CR groups, 20 and 23 patients, respectively, had no record of chemotherapy. After
these patients were excluded, the OS difference remained significant (HR = 2.72; 95% CI, 1.95-3.81) favoring the CR group (log-rank; P < 0.001) (Fig. 2).
Predictors of Survival
The number of systemic therapy lines was equivalent between groups (P = 0.101) (Fig. 3). In the univariate analysis, age (HR = 1.01; 95% CI, 1.00-1.02), hormone excess (HR = 1.61; 95% CI, 1.17-2.21), and liver metas- tasis (HR = 1.34; 95% CI, 1.00-1.80) were associated with decreased survival. Tumor size (HR = 0.97; 95% CI, 0.94-0.99), adjuvant radiotherapy (HR = 0.32; 95% CI, 0.20-0.51), local metastasis therapy (HR = 0.41; 95% CI, 0.26-0.63), performance of systemic therapy (HR = 0.68; 95% CI, 0.47-0.99), and performance of CR (HR = 3.18; 95% CI, 2.34-4.32) were associ- ated with increased survival. On multivariate analysis, age (HR = 1.02; 95% CI, 1.00-1.03), hormone excess (HR = 2.56; 95% CI, 1.66-3.92), local metastasis therapy (HR = 0.41; 95% CI, 0.47-0.65), and performance of CR
| All cohorts | CR group | No-CR group | P | |
|---|---|---|---|---|
| N = 239 | N = 128 | N = 111 | ||
| Nonsurgical treatment of the primary tumor | 69 (28.9%) | |||
| Radiotherapy (adjuvant in CR group) | 45 (18.8%) | 35 (27.3%) | 10 (9%) | 0.001 |
| Chemoembolization | 19 (7.9%) | 11 (8.6%) | 8 (7.2%) | 0.876 |
| Radiofrequency (162 records available) | 4 (2.5%) | 4 (3.1%) | 0 | 0.580 |
| Cryotherapy | 1 (0.4%) | 1 (0.8%) | 0 | 1.0 |
| Metastasis treatment (161 records available) | 47 (29.2%) | 46 | 1 | <0.001 |
| Radiotherapy | 23 (48.9%) | 22 | 1 | |
| Metastasectomy | 19 (40.4%) | 19 | 0 | |
| Radiofrequency | 3 (6.4%) | 3 | 0 | |
| Other | 2 (4.3%) | 2 | 0 | |
| Multiple treatment for metastasis | 23 (14.3%) | 23 | 0 | NA |
| Disease-free after metastasis treatment | 6 (12.8%) | 6 | 0 | 0.574 |
CR, cytoreductive surgery; NA, not available.
Group
- Cytoreduction + No Cytoreduction
100%
80%
Overall survival
60%
40%
20%
0%
Log-rank P <. 001
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
Time (months)
180
Number at risk
Cytoreduction
127
92
54
32
21
13
9
8
6
4
4
3
2
2
1
0
No Cytoreduction
111
35
13
4
2
1
1
0
0
0
0
0
0
0
0
0
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
Time (months)
(HR = 3.26; 95% CI, 2.08-5.12) remained independent predictors of survival.
Discussion
In this retrospective multicenter study, we found that resec- tion of the primary tumor was associated with prolonged OS in patients with metastatic ACC. Likewise, we found that age, hormone excess, and local metastasis therapy were independent predictors of survival.
Currently, there are well-established prognostic param- eters for ACC. Bilimoria et al. (12), after evaluating almost
4000 patients in a national registry database, reported that patient age, tumor grade, resection margin status, and nodal or distant metastasis were associated with a higher likeli- hood of death. Cortisol-secreting tumors, compared with nonfunctioning ACC, are also known to be associated with worse prognosis, increasing mortality from 1.5- to 3.9-fold (13, 14).
Recently, Libé et al. (3) evaluated a multi-institutional cohort comprising 444 patients with ENSAT III and IV ACC, searching for prognostic features, and proposed an acronym for the ones that significantly influenced OS: GRAS, for grade, resection margins status, age, and
Group
- Cytoreduction + No Cytoreduction
100%
80%
Overall survival
60%
40%
20%
0%
Log-rank P <. 001
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
Time (months)
Number at risk
Cytoreduction
107
80
45
25
15
9
6
6
6
4
4
3
2
2
1
0
No Cytoreduction
88
33
12
4
2
1
1
0
0
0
0
0
0
0
0
0
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
Time (months)
180
60
N 48
Cytoreduction Group
50
No Cytoreduction Group
40
N 36
% of patients
30
N 27
N 19
P =. 101
20
N 16
N 11
10
N 10
N9
N5
N1
0
1 Line
2 Lines
3 Lines
4 Lines
>5 Lines
symptoms. They also reported that the number of organs with metastasis was a predictor of OS. Later, these findings were validated in an external cohort and were proposed to be used as a score (15). Our results are in accordance with their findings. However, because part of our popula- tion did not have surgery or biopsy, prognostic parameters from surgical specimens, such as grade and margin status, were not available for comparisons. We used age and the modified ENSAT classification for matching, aiming to mitigate selection bias. The hormonal hypersecretion was not included in the pairing criteria but was balanced between groups.
We also found that treatment of metastasis improved survival. This finding could have favored the CR group, in which local metastasis therapy was significantly more fre- quent. One could expect that patients in whom systemic
therapy was performed, without resection of the primary tumor, will likely not undergo resection of secondary le- sions. An exception would be in the case of symptomatic metastasis. In contrast, those who undergo cytoreduction are more likely to have greater effort to treat metastasis. Resection of the primary tumor and metastasis treatment are part of a maximum cytoreductive intent and share the same rationale. By reducing the metastasis burden, pro- oncogenic inflammation and tumor signaling are impaired, enhancing the patient immune response to cancer and pos- sibly the systemic therapy efficacy (16, 17). This approach may also preclude the primary tumor and metastases from generating new metastases, as happens in other malignan- cies (18). However, this behavior is unknown for ACC.
Patients also benefit from reducing hormonal produc- tion; higher hormonal levels increase morbidity apart from impairing life quality. This finding could also be attrib- uted to selection bias; it is possible that patients selected for metastasis treatment had a better performance status and, consequently, a greater chance of survival. Only small retrospective series have reported that metastasectomy was associated with improved survival (19, 20). Because our study was not designed to evaluate this outcome, we wait for future trials to assess this topic.
The surgical resection of ACC is considered the main- stream of treatment for localized disease (21). In patients with metastatic disease, the absence of efficient systemic therapies has compelled many institutions to empirically adopt primary tumor’s resection as part of the treatment. A small body of evidence supports this approach, based
on retrospective studies done for other purposes. The me- dian survival time of patients with a diagnosis of metastatic ACC who undergo surgery or chemotherapy as mono- therapy is 0.4 or 0.3 years, respectively; survival is 0.1 year for those who receive no treatment and 1.1 years for those who receive a combination of surgery and chemotherapy (2). An analysis of the Surveillance, Epidemiology, and End Results database that assessed 320 patients with advanced ACC demonstrated that 1-year survival for patients with metastasis who underwent tumor resection was 54% and for those who received no treatment was 16% (22).
Despite the lack of robust studies, these numbers en- courage the performance of cytoreduction. Unfortunately, not all patients can tolerate cytoreduction of bulky tu- mors that often require multivisceral resection and have a challenging convalescence period. We did not evaluate the occurrence of surgical complications or chemotherapy tox- icity; however, the mortality rate within 30 days of the pro- cedure (2.4%) was acceptable, considering the severity of disease in the patients enrolled.
In clinical practice, it seems reasonable that specific clus- ters of patients would benefit from cytoreduction, whereas others would not. The treatment plan should be tailored individually. The aforementioned clinical prognostic parameters could be valuable tools for this purpose. Risk estimation nomograms have been proposed but have not been tested for treatment decision-making (23). Deploying neoadjuvant systemic therapy could help in selecting pa- tients with treatment response, who would benefit from a maximum effort approach. However, neoadjuvant reports are limited to small series with modest results; therefore, this approach is not commonly adopted (24). Recently, Assié et al. (25) identified various genetic profiles of ACC significantly associated with patient prognosis. His findings were validated and reported in the same study. We expect in the future to ally the genetic profile and clinical features to select the best candidates for each treatment, especially for patients with metastatic ACC.
This study has the inherent drawbacks of its retro- spective design, with exposure to selection and referral bias. Other limitations are the absence of a clinical performance status parameter for the patients in the matched group, the lack of information regarding the chemotherapeutic agents, the Tumor, Nodes, and Metastasis classification and ACC grade, and the lack of standardized systemic therapy and follow-up protocols. However, by using a propensity match score, we provided the best evidence to date for as- sessing the use of CR for patients with metastatic ACC. Our study encompassed data from 9 institutions in 4 coun- tries (Australia, Brazil, Canada, and the United States of America), which makes our results more generalizable. The number of patients was reasonable for a rare malignancy,
and follow-up was sufficient to assess such a lethal disease. The percentages of liver metastasis in the 2 groups were different; however, this parameter was not associated with survival. The tumor size was also uneven between groups; however, the 2-cm difference would favor the no-CR group, which had worse outcome. Of note, although the CR and no-CR groups were even regarding the modified ENSAT classification, the CR group had a greater frequency of metastasis to a single organ than the no-CR group (67% vs 39%).
In conclusion, after pairing the cohort for age and dis- ease burden, we found that cytoreductive surgery of the primary tumor was associated with prolonged survival of patients harboring metastatic ACC compared with survival in those who did not undergo resection of the primary tumor. Our results support the use of cytoreduction of the primary tumor. Older patients with hormone-secreting ACC typically have worse prognosis, although treatment of metastasis improved survival.
Acknowledgments
The authors acknowledge Vinicius F. Calsavara for the stat- istical support and the American-Australian-Asian Adrenal Alliance members.
Additional Information
Correspondence: Victor Srougi, MD, Hospital das Clinicas de São Paulo, Av. Enéas de Carvalho Aguiar, 255, São Paulo, SP, Bra- zil 05403-000. Email: vsrougi@gmail.com; or Mouhammed Amir Habra, MD, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1461, Houston, TX 77030, USA. Email: mahabra@mdanderson.org; or Maria C.B.V. Fragoso, MD, Hospital das Clinicas de São Paulo, Av. Enéas de Carvalho Aguiar, 255, São Paulo, SP, Brazil 05403-000. Email: maria.villares@hc.fm.usp.br.
Disclosures: A.V. receives research funding from the National Institutes of Health and Ventus Charitable Foundation and re- ports consulting fees from Mineralys, Corcept, and HRA Pharma. O.H. reports research collaboration with Mayo Clinic, Rochester, MN, USA, and advisory board participation with Corcept Thera- peutics, Strongbridge Pharma, and Pfizer Inc outside the submitted work. J.A.K. works reports working as a consultant, on Advisory Boards, and receiving honoraria for Pfizer, Merck, Johnson and Johnson and has received research funding to MD Anderson from Merck, Roche/Genentech, Mirati, Elypta, and stocks of MedTek. All other authors have nothing to declare.
Data Availability: Some or all data generated or analyzed during this study are included in this published article or in the data reposi- tories listed in References.
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