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Surgical management of metastatic adrenocortical carcinoma: Is there a role for multivisceral resection?
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Omair A. Shariq, MD, PhDa, Benjamin Kensing, MDª, Jace P. Landry, MDª, Ching-Wei D. Tzeng, MDª, Mouhammad Amir Habra, MDb, Matthew T. Campbell, MDC, Sarah B. Fisher, MDª, Nancy D. Perrier, MDª, Jeffrey E. Lee, MDa, Paul H. Graham, MDª,*
a Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX
b Department of Endocrine Neoplasia and Hormonal Disorders, MD Anderson Cancer Center, Houston, TX
Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, TX
ARTICLE INFO
Article history: Accepted 7 August 2025 Available online 26 September 2025
ABSTRACT
Background: Recent data suggest that cytoreductive surgery in metastatic adrenocortical carcinoma) may improve survival. However, successful removal of locally invasive primary tumors in such patients may require complex en bloc and/or multivisceral resection, for which the survival benefits remain unclear.
Methods: We retrospectively analyzed 153 patients with metastatic adrenocortical carcinoma treated at our institution from 1998 to 2024. Patients were categorized into 3 groups based on treatment approach: multivisceral resection, adrenalectomy alone, and nonoperative management. Kaplan-Meier analysis and Cox proportional hazards models were used to evaluate overall survival across these groups. Results: Among 153 patients (52% female; median age 49 years, interquartile range: 36-59 years), 24% underwent multivisceral resection, 18% had adrenalectomy alone, and 58% were managed non- operatively. Overall, 68% of tumors were functional. The most frequent metastatic sites were the lung (71%) and liver (66%). The most frequent en bloc procedures included radical nephrectomy (64%) and partial hepatectomy (47%). The median overall survival was 33 months after multivisceral resection, 22 months after adrenalectomy alone, and 7 months with nonoperative management (P < . 0001). On multivariable analysis, multivisceral resection (hazards ratio = 0.31, 95% confidence interval: 0.18-0.50, P < . 0001) and adrenalectomy alone (hazards ratio = 0.50, 95% confidence interval: 0.28-0.88, P = . 017) were independently associated with longer overall survival compared with nonoperative management. Conclusion: Cytoreductive surgery, including multivisceral resection, may be associated with improved survival in metastatic adrenocortical carcinoma compared with nonoperative management. However, given the potential risks of these complex operations, they should be judiciously performed in select patients by experienced multidisciplinary teams.
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Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive endo- crine malignancy with an estimated worldwide annual incidence
of approximately 1-2 cases per million.1,2 Approximately one- third of patients present with metastatic disease at diagnosis, which portends a poor prognosis, with a 5-year overall survival (OS) rate of only 2%-15%.3 Many of these patients experience additional morbidity and impaired quality of life secondary to excess hormone secretion.
In the setting of metastatic ACC, current guidelines recommend systemic therapy with the adrenolytic agent mitotane in combi- nation with etoposide, doxorubicin, and cisplatin.4 Although this regimen represents the current standard of care and may improve recurrence-free survival in some patients,5 response rates remain low at 23%, and a beneficial effect on OS has not consistently been
Presented at the 45th Annual Meeting of the American Association of Endo- crine Surgeons, Milwaukee, WI, May 17-19, 2025.
* Reprint requests: Paul H. Graham, MD, Department of Surgical Oncology, the University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1484, Houston, TX 77030.
E-mail address: phgraham@mdanderson.org (P.H. Graham); Twitter: @OmairShariq, @CDTzeng, @DrNancyPerrier
demonstrated.6 Furthermore, administration of these drugs may be associated with a plethora of side effects. Although newer molecular targeted therapies, such as multikinase inhibitors,7 have shown promise in small phase 2 trials, no breakthrough agents have emerged to date.
The paucity of effective systemic treatment options for meta- static ACC has led to growing interest in the role of surgical cytoreduction of the primary tumor in select patients.8 The rationale for this approach includes the potential to enhance the effectiveness of systemic therapy, prolong the window of oppor- tunity for future treatment options, and alleviate symptoms caused by hormone secretion. Recent literature suggests that pri- mary tumor resection may be associated with prolonged OS in patients with metastatic ACC when compared with nonoperative management.9-11 However, many of the studies published to date are derived from national databases, which lack the granularity required to capture endocrine-specific variables, such as tumor functionality, surgical margin status, and the nature and timing of systemic therapy. In addition, patients with advanced ACC can present with neoplasms that have invaded adjacent organs in approximately 40%-55% of cases,12,13 which may necessitate complex en bloc and/or multivisceral resection for successful removal, a factor not accounted for in previous studies. Finally, multivisceral resection frequently requires nephrectomy, impact- ing decisions regarding nephrotoxic chemotherapy (eg, cisplatin) administration. Whether these patients also benefit from primary tumor resection in the setting of metastatic disease remains un- clear. Therefore, we aimed to compare survival outcomes across treatment approaches for metastatic ACC, including multivisceral resection, adrenalectomy alone, and nonoperative management.
Methods
Study population
After obtaining institutional review board approval, we per- formed a retrospective cohort study of patients aged ≥18 years with stage IV (synchronously metastatic) ACC who were managed at the University of Texas MD Anderson Cancer Center between January 1, 1998, and December 31, 2024. Staging was based on the eighth edition of the American Joint Committee on Cancer staging system.14 The diagnosis of ACC was made histologically, through pathologic analysis of a surgical specimen or tumor biopsy or clinically based on imaging findings of a locally invasive or meta- static adrenal mass, accompanied by excess hormone secretion. Patients with other active primary malignancies and/or missing survival data were excluded.
Patients considered for surgical resection during the study period were typically evaluated by a multidisciplinary team that included endocrinology, endocrine surgery, medical oncology, radiology, and, where appropriate, hepatobiliary and thoracic surgery. Our institutional approach generally followed a stepwise workflow: 1) initial assessment to determine resectability or borderline resectability (eg, due to the perceived need for multi- organ or vascular resection); 2) consideration of neoadjuvant systemic therapy in patients deemed borderline resectable; 3) periodic restaging after every 2 cycles to assess for radiographic stability or response; 4) completion of neoadjuvant therapy and optimization of comorbidities, if applicable; and 5) surgical consideration in patients who demonstrated disease stability or response and remained appropriate candidates based on func- tional status and likelihood of achieving meaningful cytoreduction and/or symptom control. The decision to proceed with surgery after neoadjuvant therapy was made on a case-by-case basis. Notably, local progression into adjacent structures such as the
renal hilum did not uniformly preclude surgery, particularly when other favorable findings were present, such as a decrease in the extent of a vena cava thrombus and stabilization of distant disease.
Data collection
Demographic, clinical, pathologic, and treatment-related data were extracted from electronic medical records in compliance with the Health Insurance Portability and Accountability Act. Tumor-specific variables included tumor laterality, size (measured as the greatest dimension on final pathology or, for patients who did not undergo surgery, on diagnostic cross-sectional imaging), hormone production, and metastatic sites. For patients who un- derwent surgery, we recorded the extent of resection, receipt and timing of systemic therapy, and whether curative-intent resection (ie, removal of the primary tumor and all identified metastases) was performed.
Outcomes and statistical analysis
The cohort was categorized into 3 groups: 1) patients who underwent multivisceral resection (eg, adrenalectomy with en bloc and/or concomitant resection of adjacent involved organs such as the kidney, liver, pancreas, and/or lung), 2) adrenalectomy alone, or 3) nonoperative management. Baseline characteristics were compared between treatment groups using x2 or Fisher exact tests for categorical variables and Kruskal-Wallis tests for continuous variables. The primary outcome of this study was OS, defined as the time from ACC diagnosis to the date of last follow-up or death from any cause. Kaplan-Meier survival analysis was used to esti- mate OS, with log-rank tests comparing survival distributions between treatment approaches. Cox proportional hazards regres- sion was used to assess the association between treatment approach and OS. Univariable Cox models were first constructed for each covariate, and variables with clinical relevance or P < . 05 were included in the multivariable model. The final multivariable model was adjusted for age at diagnosis, tumor functionality, treatment approach, use of any systemic therapy (either neo- adjuvant or adjuvant), presence of liver metastases, and number of metastatic sites. To assess whether resection of the primary ad- renal tumor in the setting of unresected metastasis was inde- pendently associated with survival, a sensitivity analysis was performed by excluding patients who underwent resection of all
known disease within the multivisceral resection group. Multi- variable Cox models were then reconstructed using the same covariates as the primary analysis. In addition, we performed a subgroup analysis limited to patients in the multivisceral resection cohort, comparing OS between those who underwent resection of all known disease and those who underwent margin-negative resection of the primary tumor in the setting of residual distant metastatic disease.
All values are reported as mean + standard deviation or median (interquartile range [IQR]), when appropriate, for continuous data and percentages for categorical data. A 2-tailed P value of <. 05 was considered statistically significant. All statistical analyses were performed using Prism v10.3.0 (GraphPad Software, San Diego, CA). UpSet plots were generated using RStudio v2024.12.0 + 467 (Posit Software, Boston, MA) and the “UpSetR” package (version 1.4.0).
Results
Cohort characteristics
A total of 153 patients with stage IV ACC were identified over the study period and met the inclusion criteria. Of these patients,
51.6% (79 of 153) were female. The median age at diagnosis was 49 years (IQR: 36-59 years). The majority of the cohort (67% [103 of 153]) had functioning tumors, and 53% (81 of 153) were left- sided. The median tumor size at presentation was 12.2 cm (IQR: 10-15 cm), and the median number of metastatic sites was 2 (range: 1-7). Inferior vena cava tumor thrombus was present in 16% (25 of 153) of patients. The lungs were the most frequent site of metastasis (71% [108 of 153]), followed by the liver (66% [101 of 153]). Demographic and clinical details are shown in Table I.
Treatment approaches
In this cohort, 42% (n = 64) of patients underwent surgical resection of the primary tumor, whereas 58% (n = 89) were managed nonoperatively. Among those treated surgically, 56% (n = 36) underwent multivisceral resection, whereas 44% (n = 28) had adrenalectomy alone. Patients who underwent multivisceral resection were significantly younger at diagnosis compared with those who had adrenalectomy alone or were managed non- operatively (median age: 39.5, 54.5, and 51 years, respectively; P = . 0073). The median tumor size at diagnosis was larger in the multivisceral resection group compared with the adrenalectomy and nonoperative groups (14.4 cm, 11 cm, and 12 cm, respectively; P = . 001). Patients managed nonoperatively were significantly more likely to have liver metastases at diagnosis (76%, n = 68) compared with those who underwent multivisceral resection (69%, n = 25) or adrenalectomy alone (29%, n = 8; P < . 0001). Similarly, bone metastases at diagnosis were more prevalent in the nonoperative group (29%, n = 26) compared with the adre- nalectomy (14%, n = 4) and multivisceral resection groups (6%, n = 2; P = . 006). Patients who underwent multivisceral resection were significantly more likely to have received preoperative sys- temic therapy compared with those who had adrenalectomy
alone (44.4% vs 23.8%, P = . 032). The most frequently used adju- vant systemic therapy was mitotane in both surgical groups (Figure 1). Adjuvant radiotherapy to the resection bed was administered to 5.6% (n = 2) of patients in the multivisceral resection group and 17.9% (n = 5) in the adrenalectomy group (P = . 225). There were no significant differences in sex distribu- tion, tumor laterality, or patterns of hormone excess among the 3 groups (Table I).
Of the patients who underwent multivisceral resection, 31% (n = 11) had resection of the primary tumor and all known me- tastases, whereas 69% (n = 25) underwent surgical resection of the primary tumor with residual unresected distant disease. The most frequent en bloc procedures included radical nephrectomy (64%, n = 23) and partial hepatectomy (47%, n = 17) (Figure 2).
Survival analysis
The mean follow-up duration for the entire cohort was 19 ± 27 months (median: 10 months, IQR: 4-23 months), with estimated 1-, 2-, and 5-year survival rates of 42.5% (95% confidence interval [CI]: 34.7%-50.5%), 26.2% (95% CI: 18.9%-33.6%), and 6.3% (95% CI: 1.3%-11.3%), respectively. The median OS was 33 months after multivisceral resection, 22 months after adrenalectomy alone, and 7 months in the nonoperative management group. Survival was significantly longer after multivisceral resection or adrenalectomy compared with nonoperative management (log- rank P < . 0001 for both). There was no significant difference in median OS between the 2 surgical groups (log-rank P = . 097) (Figure 3).
On univariate analysis, performance of multivisceral resection (hazards ratio [HR] = 0.25, 95% CI: 0.15-0.39, P < . 001), adrenal- ectomy alone (HR = 0.38, 95% CI: 0.24-0.60, P < . 001), and use of any systemic therapy (HR = 0.63, 95% CI: 0.42-0.98, P =. 032) were
| Characteristic | Overall cohort (N = 153) | Multivisceral resection (n = 36) | Adrenalectomy alone (n = 28) | Nonoperative management (n = 89) | P |
|---|---|---|---|---|---|
| Age at diagnosis, median (IQR) (yr) | 49 (36-59) | 39.5 (29-48) | 54.5 (41-61) | 51 (36.5-59.5) | .0073 |
| Sex: female, n (%) | 79 (52) | 20 (56) | 9 (32) | 50 (56) | .08 |
| BMI, mean ± SD | 28.7 ± 7.5 | 28.1 ± 7.2 | 26.9 ± 4.7 | 29.5 ± 8.3 | .336 |
| Tumor laterality: right, n (%) | 72 (47) | 21 (58) | 10 (36) | 41 (46) | .20 |
| Tumor size at diagnosis, median (IQR) (cm) | 12.2 (10-15) | 14.4 (11-20.2) | 11 (7.6-14) | 12 (9.5-14.3) | .001 |
| Hormone excess, n (%) | |||||
| Absent | 49 (32) | 14 (39) | 9 (32) | 26 (29) | .19 |
| Cortisol alone | 65 (43) | 12 (33) | 14 (50) | 39 (44) | |
| Androgens alone | 12 (8) | 2 (6) | 0 | 10 (11) | |
| Cortisol + androgens | 23 (15) | 8 (22) | 4 (14) | 11 (12) | |
| Aldosterone or other | 4 (3) | 0 | 1 (3) | 3 (3) | |
| Sites of metastases, n (%) | |||||
| Liver | 101 (66) | 25 (69) | 8 (29) | 68 (76) | <. 0001 |
| Lung | 108 (71) | 23 (64) | 20 (74) | 65 (73) | .54 |
| Bone | 32 (21) | 2 (6) | 4 (14) | 26 (29) | .006 |
| Other | 41 (27) | 7 (19) | 7 (25) | 27 (30) | .45 |
| IVC tumor thrombus, n (%) | 25 (16) | 9 (25) | 4 (14) | 12 (13) | .29 |
| Any systemic therapy, n (%) | 127 (83) | 33 (92) | 26 (93) | 68 (76.4) | .21 |
| Neoadjuvant systemic | — | 16 (44) | 5 (18) | — | .03 |
| Adjuvant systemic | — | 32 (89) | 24 (86) | — | .72 |
| Adjuvant radiation, n (%) | — | 2 (6) | 5 (18) | .22 | |
| En bloc resected organs, n (%) | |||||
| Nephrectomy | — | 23 (64) | — | — | |
| Partial hepatectomy | — | 17 (47) | — | — | |
| Splenectomy | — | 4 (11) | — | — | |
| Distal pancreatectomy | — | 2 (5.6) | — | — | |
| Other | — | 7 (19.4) | — | — | |
| Duration of follow-up, mean ± SD (mo) | 19 ± 27 | 37 ± 38 | 26 ± 32 | 10 ± 12 | <. 0001 |
BMI, body mass index; IQR, interquartile range; IVC, inferior vena cava; SD, standard deviation.
A
Adrenalectomy only
6
6
Number of patients
5
4
2
2
2
2
1
1
1
1
1
1
1
1
1
0
Neoadjuvant mitotane
●
●
●
Neoadjuvant EDP
●
●
●
●
Adjuvant other
●
●
●
●
Adjuvant TKI
●
●
●
●
●
Adjuvant IO
●
●
●
●
●
●
Adjuvant EDP
●
●
●
●
●
Adjuvant mitotane
●
●
●
●
●
●
●
●
●
●
20
15
10
5
0
Number of patients
B
Multivisceral resection
8
7
Number of patients
6
5
4
2
2
2
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
Neoadjuvant IO
●
Adjuvant TKI
●
Adjuvant IO
●
●
●
●
●
Adjuvant other
●
●
●
●
●
●
●
●
●
Neoadjuvant mitotane
●
●
●
●
●
●
●
●
Adjuvant EDP
●
●
●
●
●
●
●
●
Neoadjuvant EDP
●
●
●
●
●
●
●
●
●
●
●
Adjuvant mitotane
●
●
●
●
●
●
●
●
●
●
●
25
20
15
10
5
0
Number of patients
associated with significantly longer OS. In contrast, older age at diagnosis (HR = 1.05, 95% CI: 1.01-1.08, P =. 008), presence of liver metastases (HR = 1.42, 95% CI: 1.01-2.01, P =. 045), and increasing number of metastatic sites (HR = 1.32, 95% CI: 1.12-1.56, P =. 001) were associated with poorer survival. Conversely, male sex (HR = 1.23, 95% CI: 0.88-1.71, P =. 23), presence of lung metastases (HR = 1.28, 95% CI: 0.88-1.86, P =. 19), tumor size (HR = 0.98, 95% CI: 0.95-1.02, P = . 273), and tumor functionality (HR = 0.28, 95% CI: 0.08-0.65, P = . 131) were not significantly associated with OS (Table II).
On multivariable Cox regression, performance of multivisceral resection (HR = 0.31, 95% CI: 0.18-0.50, P < . 0001), adrenalec- tomy alone (HR = 0.50, 95% CI: 0.28-0.88, P = . 017), and use of any systemic therapy (HR = 0.44, 95% CI: 0.27-0.76, P = . 002) remained independently associated with longer OS. An increasing number of metastatic sites (HR = 1.28, 95% CI: 1.05-1.55, P =. 013) continued to be associated with poorer OS. In contrast, age at diagnosis (HR = 1.01, 95% CI: 1.00-1.03, P =. 069), tumor functionality (HR = 1.51, 95% CI: 1.00-2.32, P = . 057), and presence of liver metastases (HR = 1.04, 95% CI: 0.67-1.64,
Liver (n = 17)
9
Kidney (n = 23)
Spleen (n = 4)
0
0
4
0
0
0
13
1
0
0
0
0
0
2
0
1
0
0
0
0
1
1
0
0
0
2
0
0
2
0
Other (n = 7)
Pancreas (n = 2)
P =. 85) were not significantly associated with OS in the adjusted model (Table II).
To determine whether the observed longer survival after mul- tivisceral resection was primarily attributable to patients who underwent resection of all identified disease, we performed a sensitivity analysis by excluding the 11 patients who had curative- intent resection. In this adjusted model, multivisceral resection remained significantly associated with longer OS compared with nonoperative management (HR = 0.31, 95% CI: 0.17-0.52,
P < . 0001). In addition, a subgroup analysis of the multivisceral resection cohort found no significant difference in survival be- tween patients who underwent complete resection of all disease and those who underwent surgical cytoreduction of the primary adrenal tumor in the setting of unresected metastases, with a median OS of 37 and 31 months, respectively (log-rank P = . 477) (Figure 4).
Discussion
Metastatic ACC presents unique management challenges due to its aggressive behavior and an absence of effective systemic ther- apies.15 In recent years, surgical resection of the primary tumor has gained interest as a potential strategy to improve survival in these patients. Our study demonstrates that this approach, whether through adrenalectomy alone or, when necessary, multivisceral resection, is associated with longer OS compared with nonopera- tive management. Notably, this association persisted even in pa- tients who did not undergo resection of all sites of distant metastasis, suggesting a potential role for debulking through sur- gical resection of the primary site in select cases.
Prior retrospective studies using large databases, including the California Cancer Registry,16 the National Cancer Database,1º and the Surveillance, Epidemiology, and End Results dataset,9,17,18 have reported that adrenalectomy is associated with a median OS improvement of approximately 4-16 months in patients with metastatic ACC. However, these studies are limited by the inherent constraints of large-scale data repositories, including the absence of information regarding the timing and nature of systemic ther- apies, as well as the extent of metastatic disease present at the time of surgery. Nevertheless, a recent multicenter, non-registry- based study of 239 patients with metastatic ACC, conducted by the American Australian Asian Adrenal Alliance (A5) network, also demonstrated a comparable survival benefit in patients who un- derwent cytoreductive surgery of the primary tumor compared with nonsurgical management.11 Yet, none of these studies have specifically examined the role of multivisceral resection in this setting.
A small number of investigations have evaluated outcomes after en bloc resection of extra-adrenal organs during index
100
Multivisceral resection (n=36)
☐
- Adrenalectomy alone (n=28)
n.s.
- Non-operative management (n=89)
☐
Overall survival (%)
50
0
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
Time (months)
| Variable | Univariable HR (95% CI) | P | Multivariable HR (95% CI) | P |
|---|---|---|---|---|
| Age at diagnosis | 1.05 (1.01-1.08) | .008 | 1.01 (1.00-1.03) | .069 |
| Sex (male) | 1.23 (0.88-1.71) | .23 | — | — |
| Functioning tumor (yes) | 0.28 (0.08-0.65) | .131 | 1.51 (1.00-2.32) | .057 |
| Tumor size (cm) | 0.98 (0.95-1.02) | .273 | — | — |
| Management approach | ||||
| Multivisceral resection | 0.25 (0.15-0.39) | .001 | 0.31 (0.18-0.50) | .0001 |
| Adrenalectomy alone | 0.38 (0.24-0.60) | .001 | 0.50 (0.28-0.88) | .017 |
| Lung metastases (yes) | 1.28 (0.88-1.86) | .19 | — | — |
| Liver metastases (yes) | 1.42 (1.01-2.01) | .045 | 1.04 (0.67-1.64) | .85 |
| Number of metastatic sites | 1.32 (1.12-1.56) | .001 | 1.28 (1.05-1.55) | .013 |
| Any systemic therapy (yes) | 0.63 (0.42-0.98) | .032 | 0.44 (0.27-0.76) | .002 |
CI, confidence interval; HR, hazards ratio.
surgery for ACC.12,13,19 The largest series, by Marincola Smith et al,13 included 68 patients, with the most frequently resected en bloc organs being the kidney (56%) and liver (28%). Despite having more advanced tumors, patients who underwent en bloc re- sections to avoid violating the tumor capsule, or to achieve clear margins, had comparable survival rates to those who underwent adrenalectomy alone. However, unlike our study, this series only included patients with nonmetastatic disease. Our findings sug- gest that multivisceral resection of the primary tumor may still confer a survival benefit even when it is not feasible to resect all distant sites of disease. There are several possible explanations for this observation. Resection of primary tumor bulk may leave behind smaller, well-perfused lesions that could be more responsive to systemic therapies.20 This could also enhance anti- tumoral immune responses, a phenomenon previously reported after nephrectomy in stage IV renal cell carcinoma.21 In addition, cytoreduction of the primary tumor may prevent it serving as a reservoir for shedding additional metastatic cells. In patients experiencing symptoms from tumor mass effect or hormone excess, surgical resection may also alleviate morbidity and enhance quality of life, potentially facilitating either the initiation or continuation of systemic therapy. In contrast to our findings, Dy
100
Overall survival (%)
All disease resected (n=11)
Cytoreduction with unresected distant metastases (n=25)
n.s.
50
0
0
12
24
36
48
60
72
84
96
108
120
132
144
Time (months)
et al22 and Prendergast et al23 reported worse OS in patients who underwent primary surgery for synchronously metastatic ACC without resection of all known disease, compared with those who achieved complete resection. These discrepancies could be attributed to the small overall sample sizes in these series (n = 27 and n = 26, respectively) and the absence of adjusted analyses. In addition, differences in surgical morbidity, such as intraoperative tumor rupture and seeding, or variations in treatment approaches, including the use of neoadjuvant therapy, may have influenced outcomes in these cohorts.
In the current study, 44% of patients who underwent multi- visceral resection received neoadjuvant chemotherapy before surgery, a relatively high proportion compared with the 18% re- ported in the A5 network study.11 This likely reflects prior work from our institution, which demonstrated that among 15 patients with ACC who was deemed “borderline resectable”, 87% (13 of 15) were able to proceed to surgery after neoadjuvant therapy due to tumor downstaging or disease stability, with the majority requiring multivisceral resection.19 Beyond facilitating complete extirpation of the primary tumor and potentially reducing the extent of resection required, neoadjuvant therapy can allow nephrotoxic chemotherapy delivery in the presence of 2 func- tioning kidneys, provides an opportunity to medically optimize associated comorbidities (eg, hormone overproduction and pul- monary emboli), and enables the assessment of tumor biology, allowing patients likely to experience early postoperative disease progression to avoid the morbidity of an extensive operation.
Despite the survival benefit associated with multivisceral resection in our cohort, it is important to recognize that not all patients with metastatic ACC are appropriate candidates for this approach. In our multivariable Cox analysis, the number of meta- static sites was independently associated with worse OS, sug- gesting that patients with high metastatic burden may derive limited benefit from cytoreductive surgery and that the decision to operate should be carefully considered in the context of the overall extent of disease. Furthermore, the potential for selection bias cannot be understated, as patients who underwent multivisceral resection were younger and may have had better performance status, fewer comorbidities, and a higher likelihood of receiving systemic therapy, which could have contributed to improved survival. Although we attempted to control for some of these factors using multivariable Cox modeling, residual confounding remains likely. Importantly, the findings of this study should not be interpreted as an unequivocal recommendation that all patients with metastatic ACC will benefit from complex multiorgan resection of the primary tumor. Operative decision-making in this setting is complex and influenced by factors such as details of preoperative imaging, tumor size, extent of vascular involvement,
underlying tumor biology, and the overall condition of the patient. Furthermore, these procedures can be associated with significant morbidity, with Clavien-Dindo grade III/IV (severe) complications reported in 15% of patients undergoing multivisceral resection in the series by Marincola Smith et al.13 This is particularly relevant, as prolonged postoperative recovery may delay the initiation of adjuvant systemic therapy, which could be detrimental for pa- tients who are most likely to benefit from it. Given these risks, it is imperative that such decisions are made in experienced, special- ized centers with surgical expertise and an established multidis- ciplinary framework.
In addition to the potential for selection bias highlighted above, the present study has several limitations. First, its retrospective nature inherently limits causal inferences, as treatment decisions were made at the discretion of treating physicians rather than through a standardized protocol. The sample size, although reasonable for a single-institution cohort of metastatic ACC, re- mains relatively small, precluding the ability to perform subgroup analyses, such as the impact of neoadjuvant therapy on post- operative survival. Information regarding baseline clinical perfor- mance status was not recorded, and although our study focuses on OS, other clinically relevant outcomes, such as symptom control, quality of life, and postoperative morbidity, were not evaluated. These may provide further insight into the risks and benefits associated with multivisceral resection in metastatic ACC. Finally, details regarding nonsurgical treatment of metastatic lesions were not ascertained.
In conclusion, this study demonstrates that multivisceral resection of the primary tumor may improve survival in patients with metastatic ACC compared with nonoperative management. Although our findings align with emerging evidence supporting cytoreductive surgery in selected patients, prospective studies are needed to refine patient selection criteria and better delineate the role of surgery within the evolving landscape of multimodal ACC treatment. Given the complexity and potential risks of these pro- cedures, they should be performed judiciously by experienced multidisciplinary teams to optimize oncologic outcomes, while minimizing morbidity.
Funding/Support
O.A.S. is supported by a Mayo Foundation Scholarship.
Conflict of Interest/Disclosure
The authors have no related conflicts of interest to declare.
CRediT authorship contribution statement
Omair A. Shariq: Writing - review & editing, Writing - orig- inal draft, Software, Project administration, Investigation, Formal analysis, Data curation, Conceptualization. Benjamin Kensing: Writing - review & editing, Methodology, Data curation, Conceptualization. Jace P. Landry: Writing - review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Ching-Wei D. Tzeng: Writing - review & editing, Writing - original draft, Formal analysis. Mouhammad Amir Habra: Writing - review & editing, Writing - original draft, Formal analysis, Conceptualization. Matthew T. Campbell: Writing - review & editing, Writing - original draft, Conceptualization. Sarah B.
Fisher: Writing - review & editing, Writing - original draft. Nancy D. Perrier: Writing - review & editing, Writing - original draft, Conceptualization. Jeffrey E. Lee: Writing - review & editing, Writing - original draft, Supervision, Formal analysis, Conceptu- alization. Paul H. Graham: Writing - review & editing, Writing - original draft, Supervision, Formal analysis, Data curation, Conceptualization.
References
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Discussion
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Dr Michael J. Demeure (Hoag Family Cancer Institute, Newport Beach): I think you brought up the limitation with the selection bias. I don’t think you should gloss by that. Because if somebody has multiple neuroendocrine liver metastases, it has been shown pretty nicely that if you resect the bulk of disease, 80%, 90% or more, then there’s benefit. So, is there an equation where you say, if we can resect, you know, 90-100%, what’s the bulk of the disease left behind? Does that influence your decision? My second ques- tion is do you treat these people for a while with neoadjuvant therapy before you do resection? If so, how does the pace of their disease affect the cohort presented here? Isn’t there concern for selection bias?
Speaker: Omair Shariq: Thank you Dr Demeure, those ques- tions are very relevant here. So to address your first question, I wish there was a well-defined algorithm that could be applied. In reality, each of these cases is discussed on an individualized basis, and there are a number of factors to consider. One factor that is particularly relevant to ACC is whether the patient has a func- tioning tumor that’s resulting in significant morbidity, and in that situation, one may consider primary tumor resection, even in the presence of more extensive metastases, with the knowledge that the patient may be able to go on systemic or locoregional therapy that could help them address those metastases in the future. With regard to your second question regarding neoadjuvant therapy, our practice is based on prior work from our institution, and the landscape of treatment has evolved. In more recent years, patients have been more likely to go on neoadjuvant therapy for an average of 4-6 cycles, with periodic reassessment of tumor response or stability every couple of months. In those who do demonstrate stability, tumor biology may be seen as being more favorable with a higher likelihood of benefitting from surgery. Regarding your point about selection bias, we do acknowledge that inherently, the fact that these patients are progressing to surgery means that we are selecting a cohort of patients who are likely to do better. We did attempt to adjust for this in our study. However, we acknowledge that there is going to be residual confounding and your point about selection bias is well taken.
Dr Matthew Nehs (Harvard University, Boston): This is phenomenal work. Congratulations to you and Dr Graham and your whole team. How many of your parents got immunotherapy, and how many of those had hypercortisolism within each? Because I think that resecting a large bulk of the mass of a tumor that over produces cortisol (which inhibits your immune system) may improve immune surveillance and thus response to immu- notherapy. So I think there’s an interaction between use of immunotherapy and hypercortisolism in the survival for these patients.
Speaker: Omair Shariq: Thank you Dr Nehs, that’s a really good question. If I could move on to a supplementary slide here. So, in terms of the neoadjuvant systemic therapy, about 45% of patients did receive that in our cohort. The majority of this cohort did have evidence of hormone excess, including hypercortisolism. In terms of your question about the breakdown of immunotherapy, this
figure shows the different distributions of systemic therapy regi- mens that were used. And as you can see, immunotherapy in the neoadjuvant setting was very infrequently used. I think that there’s a role for it, perhaps in the adjuvant setting.
Dr Kristen E. Limbach: (Tulane University, New Orleans): Thank you again for this wonderful presentation. I am excited to see you’re prepared with a supplemental slide regarding your new adjuvant regimens. My question was regarding the large number of years from which patients were selected from this study and that our management of ACC has changed fairly substantially over that time. Are you able to add any additional subanalysis comparing these different regimens and how they played into the success of your multivisceral resection?
Speaker: Omair Shariq: That’s a really good question, and something that we’ve thought about. As I had mentioned earlier, there has been an increasing trend toward utilizing neoadjuvant chemotherapy for this disease. As a result of studies like the FIRM- ACT study, the most commonly used regimen in the neoadjuvant setting, as you can see from the figure, was EDP plus mitotane. In more recent years, there have been some patients who have been selected for immunotherapy. We weren’t able to control for this due to the small numbers that precluded adjusted statistical analysis.
Dr Barbra Miller (Ann Arbor, Michigan): I’m glad you brought up tempo of disease in considering treatment for these patients, because it is not only just about quantity of life, but also quality of life. We don’t want to see somebody’s disease burden blossom rapidly immediately after surgery, especially with the potential for significant complications from some of these procedures and lengthy recovery periods that would preclude additional therapy. I would like you to comment on the complications noted in this study. Also, were all of these patients managed the entire time at MD Anderson? Because so much care is suboptimal in centers unfamiliar with this rare disease. You really need that multidisci- plinary team-based care to say, yes, these patients are getting optimal care overall, and we can use these data when designing guidelines for care. Are they getting the best care that they can with consideration and/or use of all available modalities as a comprehensive package rather than just a great operation stand- ing alone?
Speaker: Omair Shariq: Thank you Dr Miller. Fifteen percent of patients who undergo multivisceral resections experience Clav- ien-Dindo class 3 or 4 complications, and we know this from work done by the US ACC Study Group. We didn’t specifically look at complications in this cohort. The natural corollary of this study is to look at complications. In terms of your second point about the proportion of patients who were treated outside of MD Anderson, I don’t have a specific percentage that comes to mind, but it wasn’t an insignificant number of patients who initially received their care elsewhere. However, in recent years, an increasing number of patients have been referred to centers that are more experienced with this condition so that they get the appropriate treatment from the outset.