Surgery xxx (2019) 1-6
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SURGERY NOWEMBER 2018
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Features of synchronous versus metachronous metastasectomy in adrenal cortical carcinoma: Analysis from the US adrenocortical carcinoma database
Katherine M. Prendergast, MDª, Paula Marincola Smith, MDb, Thuy B. Tran, MDC, Lauren M. Postlewait, MDª, Shishir K. Maithel, MDª, Jason D. Prescott, MDe, Timothy M. Pawlik, MD, MPH, PhDe, Tracy S. Wang, MD , Jason Glenn, MDf, Ioannis Hatzaras, MD, MPH8, Rivfka Shenoy, MDg, John E. Phay, MDh, Lawrence A. Shirley, MDh, Ryan C. Fields, MD1, Linda X. Jin, MDi, Sharon M. Weber, MDi, Ahmed Salem, MD, Jason K. Sicklick, MDk, Shady Gad, MDk, Adam C. Yopp, MD’, John C. Mansour, MD’, Quan-Yang Duh, MD™, Natalie Seiser, MD™, Konstantinos I. Votanopoulos, MD”, Edward A. Levine, MD”, George A. Poultsides, MDC, Carmen C. Solórzano, MDb, Colleen M. Kiernan, MD, MPHb,
a Vanderbilt University School of Medicine, Nashville, TN
b Department of Surgery, Vanderbilt University, Nashville, TN
” Department of Surgery, Stanford University School of Medicine, Stanford, CA
d Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA
e Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
Department of Surgery, Medical College of Wisconsin, Milwaukee, WI
% Department of Surgery, New York University School of Medicine, New York, NY
h Department of Surgery, The Ohio State University, Columbus, OH
Department of Surgery, Washington University School of Medicine, St Louis, MO
Department of General Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
k Department of Surgery, University of California San Diego, San Diego, CA
l Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
m Department of Surgery, University of California San Francisco, San Francisco, CA
” Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC
ARTICLE INFO
Article history: Accepted 19 May 2019 Available online xxx
ABSTRACT
Background: Adrenocortical carcinoma is a rare, aggressive cancer. We compared features of patients who underwent synchronous versus metachronous metastasectomy.
Methods: Adult patients who underwent resection for metastatic adrenocortical carcinoma from 1993 to 2014 at 13 institutions of the US adrenocortical carcinoma group were analyzed retrospectively. Patients were categorized as synchronous if they underwent metastasectomy at the index adrenalectomy or metachronous if they underwent resection after recurrence of the disease. Factors associated with overall survival were assessed by univariate analysis.
Results: In the study, 84 patients with adrenocortical carcinoma underwent metastasectomy; 26 (31%) were synchronous and 58 (69%) were metachronous. Demographics were similar between groups. The synchronous group had more T4 tumors at the index resection (42 vs 3%, P < . 001). The metachronous group had prolonged median survival after the index resection (86.3 vs 17.3 months, P < . 001) and metastasectomy (36.9 vs 17.3 months, P = . 007). Synchronous patients with RO resections had improved survival compared to patients with R1/2 resections (P = . 008). Margin status at metachronous meta- stasectomy was not associated with survival (P = . 452).
Presented at the Academic Surgical Congress, Houston, TX, February 5-7, 2019.
* Reprint requests: Colleen M. Kiernan, Vanderbilt University, 597 Preston Research Building, 2220 Pierce Ave, Nashville, TN 37232.
E-mail address: colleenkiernan@gmail.com (C.M. Kiernan).
Conclusion: Select patients with metastatic adrenocortical carcinoma may benefit from metastasectomy. Patients with metachronous metastasectomy have a more durable survival benefit than those under- going synchronous metastasectomy. This study highlights need for future studies examining differences in tumor biology that could explain outcome disparities in these distinct patient populations.
@ 2019 Elsevier Inc. All rights reserved.
Introduction
Adrenocortical carcinoma (ACC) is a rare malignancy with an estimated annual incidence of 2 per million worldwide and 1.02 per million in the United States.1,2 ACC is characterized by an aggressive disease course with more than half of the patients presenting with advanced disease3; the estimated 5-year survival is 58% to 66% for stage I and II disease and 0% and 24% for stage II and IV disease.4,5 Systematic collection of large-scale data elucidating pathogenesis, ideal treatment paradigms, and outcomes of this disease is chal- lenging due to its rarity, resulting in a still limited understanding of prognostic factors in various patient subgroups and limited, evidence-based treatment guidelines.1
Currently, resection is the mainstay of treatment for ACC, of- fering the only curative option for this highly aggressive cancer. Nonetheless, disease recurrence after complete resection occurs in over half of patients.4 It is possible that certain subgroups of pa- tients may benefit from resection of locoregional or distant recur- rence, although data to this effect remain sparse. Schulick and Brennan demonstrated that in patients with locoregional or distant recurrence after their index resection, repeat resection is associated with improved survival.5 In contrast, other investigators have shown that metastasectomy for disease recurrence, a disease-free interval of ≤12 months, the presence of extrapulmonary distant metastasis, or multifocal recurrence seems to be associated with a lesser survival after metastasectomy for ACC recurrence.6,7
Additionally, one-third of patients have metastatic disease at presentation, which is associated with a grim prognosis and a 5-year survival as low as 0%.8,9 Some of these patients may benefit from synchronous or staged resection of extra-adrenal metastases, but little is known about which subgroups are likely to benefit from metastasectomy or which factors portend a poor prognosis within this subpopulation. Improved understanding of patients likely to benefit from these aggressive resections in both the synchronous and metachronous setting may help to improve surgical decision-making and facilitate surgeon-patient discussion of the benefits and risks of pursuing aggressive operative therapy for metastatic ACC.
In this study, we utilized a large, retrospective, multi- institutional database to describe the clinical features and out- comes associated with metastasectomy for ACC in the synchronous and metachronous settings.
Methods
Patient population and data collection
The US Adrenocortical Carcinoma Group (US-ACCG) consists of the following 13 academic medical centers: Vanderbilt University, Emory University, Stanford University, The Johns Hopkins Univer- sity, Medical College of Wisconsin, New York University, the Ohio State University, Washington University in St. Louis, University of Wisconsin, University of California San Diego, University of Texas Southwestern, University of California San Francisco, and Wake Forest University. This collaboration identified all adult patients (≥18 years old) who underwent resection for ACC between 1993 and 2014 at each institution. Data were retrospectively collected
retrospectively at each institution by chart review and then shared amongst the collaborating institutions in a deidentified manner. The institutional review boards at each participating center approved of this study.
A total of 265 patients were included in the US-ACCG database. Patients who underwent resection for synchronous metastatic disease (defined as at least one metastatic lesion at a distant site) or those who underwent a second operation for resection of disease recurrence (either locoregional or distant disease) were included in our analysis (n = 84). Patients who underwent other treatments for metastatic disease, such as Y90 for liver metastases or who un- derwent biopsy but not resection of metastatic disease, were not included in the analysis. Patients were classified as synchronous if they underwent metastasectomy at the time of index resection (n = 26) and metachronous if they underwent metastasectomy after documented locoregional or distant recurrence of the disease (n = 58). Staged index resections (n = 2, one left adrenalectomy fol- lowed by resection of lung metastasis, one left adrenalectomy fol- lowed by resection of liver metastasis) were classified as synchronous, because these lesions were identified at the time of initial diagnosis. Although oftentimes synchronous metastatic le- sions are defined as metastatic lesions occurring within 6 months of diagnosis, for the purposes of this article, we defined synchro- nous lesions as metastatic lesions resected or diagnosed at the time of the index procedure and metachronous if their metastatic or recurrent tumor was diagnosed after the index procedure.
Demographic, preoperative, intraoperative, pathologic, recur- rence, and survival data were collected from medical records at each institution. Preoperative variables included age, race, sex, American Society of Anesthesiologists Classification System class, body mass index, laboratory data (including presence of hormone secretion), and size and laterality of the primary tumor. Intraoperative variables were obtained from the surgeon’s operative report and included operative approach, extent of resection, lymph node dissection, and site of metastasectomy. Pathologic variables were obtained from re- view of the pathologist’s report and included tumor size, tumor- node-metastasis staging, tumor grade, presence of lymphovascular invasion, and resection margin. Recurrence data included date and site of first recurrence. Data on nonsurgical treatments including mitotane, cytotoxic chemotherapy, and external beam radiation therapy were obtained similarly from review of the medical record. The seventh edition of the American Joint Commission on Cancer Staging Manual was used to determine tumor-node-metastasis classification.10 Survival data were determined by chart review and confirmed by review of the Social Security Death Index database.11
Statistical analysis
Categorical variables were presented as frequency and percent- ages. Continuous variables were reported as median values with interquartile ranges and compared using Fisher exact test or if appropriate a t test. Overall survival (OS) and disease-free survival from time of first resection and from time of metastasectomy were calculated using the Kaplan-Meier method and compared using the log-rank test. Data were analyzed using multivariable Cox regression methods. Patients with missing data (n = 17) were excluded from the
| Synchronous (n = 26) | Metachronous (n =58) | P value | |
|---|---|---|---|
| Sex | |||
| Male | 12 (46%) | 25 (43%) | .816 |
| Female | 14 (54%) | 33 (57 %) | |
| Age (median, IQR) | 54 (41,62) | 50 (42,58) | .328 |
| ASA class | |||
| 1 | 5 (19%) | 9 (16%) | .082 |
| 2 | 3 (12%) | 12 (21%) | |
| 3 | 5 (19%) | 23 (40%) | |
| 4 | 3 (12%) | 1 | |
| 5 | 0 | 0 | |
| Race | |||
| White | 23 (89%) | 47 (81%) | .807 |
| Black | 0 | 1 | |
| Hispanic | 1 | 5 (0%) | |
| Asian | 1 | 1 | |
| Other | 0 | 2 (3.4%) | |
| Hormone hypersecreting | |||
| Glucocorticoid | 7 (27%) | 9 (16%) | .304 |
| Mineralocorticoid | 1 | 4 (7%) | |
| Virilizing/feminizing | 5 (19%) | 6 (10%) | |
| Nonsecreting | 12 (46%) | 34 (59%) | |
| Laterality | |||
| Right | 14 (54%) | 23 (0%) | .341 |
| Left | 12 (46%) | 34 (59%) | |
| BMI (median, IQR) | 26 (23,40) | 28 (24,32) | .551 |
| Neoadjuvant | 1 | 1 | .541 |
| chemotherapy | |||
| Adjuvant chemotherapy | 7 (27%) | 9 (16%) | .124 |
| Adjuvant mitotane | 11 (42%) | 18 (31%) | .282 |
| Adjuvant radiation therapy | 1 | 5 (9%) | .656 |
ASA Class, American Society of Anesthesiologists Classification System; IQR, interquartile range. Data presented reflect all available data from the authors’ collaborative database. Percentages may not add up to 100% because data are missing for some variables.
analysis. All statistical analyses were performed using the STATA 15.1 statistical software package (STATA Corp., College Station, TX).
Results
The database contained 265 adult patients with ACC who un- derwent resection between 1993 to 2014, 84 of whom underwent either a synchronous or metachronous metastasectomy and were included in our analysis. Of these patients, 26 (31%) underwent metastasectomy at the time of the index resection and were clas- sified as synchronous, while 58 (69%) underwent metastasectomy after disease recurrence and were classified as metachronous. A comparison of the patient demographics, tumor characteristics, and utilization of neoadjuvant and adjuvant therapies of the 2 groups is summarized in Table I. Patients in each group were similar in age, sex, race, body mass index, and American Society of Anesthesiolo- gists Classification System class. Patients in the synchronous group had a similar percentage of right-sided (54% vs 40%; P = . 34) and glucocorticoid-secreting (27% vs 16%; P = . 31) tumors compared to the metachronous group. There were no differences between groups in the rate of treatment with neoadjuvant chemotherapy (P =. 541), adjuvant chemotherapy (P =. 124), mitotane (P =. 282), or radiation (P = . 656).
The most common site of metastasectomy in the synchronous group was liver (n = 15, 58%) followed by lung (n = 6, 23%). The most common site of metastasectomy in the metachronous group was local (n = 21, 36%) followed by multiple (n = 10, 17 %), lung (n = 8, 14%), and liver (n = 7, 12%). Site of resection by group is summarized in Table II. After synchronous metastasectomy, 31% of patients developed distant recurrence, 12% developed locoregional
| Site | Synchronous (n = 26) | Metachronous (n = 58) |
|---|---|---|
| Bone | 1 | 0 |
| Brain | 0 | 1 |
| Contralateral adrenal | 0 | 3 (5%) |
| Kidney | 0 | 2 |
| Liver | 15 (58%) | 7 (12%) |
| Local | 0 | 21 (36%) |
| Lung | 6 (23%) | 8 (14%) |
| Multiple | 2 %) | 10 (17%) |
| Pancreas | 0 | 1 |
| Peritoneum | 2 | 2 |
| Retroperitoneum | 0 | 1 |
| Soft tissue | 0 | 1 |
| Spleen | 0 | 1 |
Data presented reflect all available data from the authors’ collaborative database. Percentages may not add up to 100% because data are missing for some variables.
recurrence, and 27% developed both. In contrast, those in the metachronous group were more likely to have locoregional (n = 30, 52 %) as opposed to distant (n = 21, 36%) recurrence after the index resection; 6 (10%) had both. Eleven patients (19%) in the meta- chronous group had an additional distant recurrence after meta- stasectomy, including 4 with locoregional recurrence at the time of first metastasectomy, and 7 with distant disease resected at the initial metastasectomy.
At the time of initial resection, 11 patients in the synchronous group (42%) and 2 of 58 in the metachronous group had a T4 pri- mary tumor. Three patients in the synchronous group (12%) and 4
| Synchronous (n = 26) | Metachronous (n = 58) | P value | |
|---|---|---|---|
| Tumor size (median, IQR) | 15 (11, 20) | 11.4 (8.5, 13.9) | .063 |
| T stage | |||
| 1 | 0 | 2 (3.4%) | <. 001 |
| 2 | 3 (11.5%) | 20 (34.5%) | |
| 3 | 7 (26.9%) | 26 (44.8%) | |
| 4 | 11 (42.3%) | 2 (3.4%) | |
| N stage | |||
| X | 14 (53.8%) | 35 (60.3%) | .734 |
| 0 | 6 (23.1%) | 11 (19.0%) | |
| 1 | 3 (11.5%) | 4 (6.9%) | |
| M stage | |||
| 0 | 0 | 50 (86.2%) | <. 001 |
| 1 | 26 (100.0%) | 1 (1.7%)* | |
| Grade | |||
| 1 | 0 | 1 | .264 |
| 2 | 0 | 2 | |
| 3 | 0 | 4 (7%) | |
| 4 | 3 (12%) | 2 | |
| Ki-67 (%) | |||
| 5 | 1 | 0 | 1.000 |
| 10 | 1 | 0 | |
| 20 | 1 | 1 | |
| 50 | 0 | 1 | |
| Lymphovascular invasion | |||
| Yes | 10 (39%) | 13 (22%) | .208 |
| No | 5 (1%) | 18 (31%) | |
| Microvascular invasion | |||
| Yes | 11 (42%) | 19 (33%) | .520 |
| No | 4 (16%) | 12 (21%) | |
| Margin | |||
| R0 | 15 (58%) | 34 (59%) | .718 |
| R1 | 4 (15.4%) | 9 (16%) | |
| R2 | 2 | 2 |
IQR, interquartile range.
Data presented reflect all available data from the authors’ collaborative database. Percentages may not add up to 100% because data are missing for some variables.
Patient presented with pulmonary metastases but did not undergo synchronous meta- stasectomy; patient later underwent metachronous resection of subsequently developed locoregional recurrence.
1.00
Overall Survival Following Index Operation
Proportion Surviving
0.75
0.50
0.25
0.00
0
20
40
Time (months)
60
80
100
Synchronous
Metachronous
in the metachronous group (7%) had nodal involvement (N1 dis- ease). Both groups had similar rates of R0 resection at the time of index operation (58% vs 59%). The pathologic data at the time of index operation are summarized in Table III.
Patients in the synchronous group had a lesser median OS after resection of the index tumor and metastases compared to patients in the metachronous group (17.3 vs 86.3 months, P < . 001; Fig 1).
1.00
Overall Survival Following Metastasectomy
Proportion Surviving
0.75
0.50
0.25
0.00
0
20
Time (months)
40
60
Synchronous
Metachronous
Synchronous patients also had lesser median OS than patients with metachronous resection when comparing OS after the time of metastasectomy (median survival 17.3 vs 36.9 months, P =. 007; Fig 2). This disparity in OS after both the index resection and after the metastasectomy persisted when metachronous patients with locoregional disease were excluded (P < . 001, P = . 0406 respec- tively; Fig 3).
A
Overall Survival Following Index Operation
B
1.00
Overall Survival Following Metastasectomy
1.00
Proportion Surviving
0.75
Proportion Surviving
0.75
0.50
0.50
0.25
0.25
0.00
0.00
0
20
40
60
80
100
0
20
40
60
Time (months)
Time (months)
Synchronous
Metachronous (distant only)
Synchronous
Metachronous (distant only)
A
1.00
Survival Following Synchronous Metastasectomy by Margin Status
B
1.00
Survival Following Metachronous Metastasectomy by Margin Status
Tim
Proportion Surviving
0.75
Proportion Surviving
0.75
0.50
0.50
0.25
0.25
0.00
0.00
0
10
Time (months)
20
30
40
0
20
Time (months)
40
60
RO
R1/2
RO
R1/2
Negative margin status was associated with prolonged OS after synchronous metastasectomy (median survival 19.0 for R0 resec- tion vs 5.5 months for R1/2 resection, P =. 008; Fig 4, A). There was no association between location of metastatic resection (P =. 126), size of primary tumor (P =. 179), T stage (P = . 224), or N stage (P = .561) and OS after synchronous metastasectomy. In this small subset of patients, treatment with neoadjuvant chemotherapy (n = 1), adjuvant chemotherapy (n = 7), adjuvant mitotane (n = 11), or adjuvant radiation (n = 1) were also not associated with any discernable difference in OS, though the total number of patients included in these latter analyses were small.
Factors significantly associated with increased OS after meta- stasectomy in the metachronous group included a disease-free interval >12 months (median OS 56.1 vs 21.5 months, P = . 002; Fig 5) and ≥2 recurrent tumors at the time of metastasectomy (median OS 40.8 vs 7.8 months, P =. 002; Fig 6). Resection margin at the time of metastasectomy (Fig 4, B), type of recurrence and site of resection were not significantly associated with differences in OS after metachronous metastasectomy.
By multivariable Cox regression analysis adjusted for T stage, N stage, and hormone hypersecretion at index operation, metachro- nous metastasectomy was associated with increased OS after the index resection (hazard ratio 0.22; P = . 009) compared to syn- chronous metastasectomy. In contrast, multivariable Cox regression analysis (adjusted for T stage, N stage, and hormone hypersecretion at index operation) demonstrated no difference in OS between groups after metastasectomy (P = . 430).
Discussion
The data in this study suggest that patients with metastatic ACC are a heterogeneous group, and there may be distinct differences in disease course, tumor biology, or therapeutic benefit of operative
1.00
Survival Following Metachronous Metastasectomy by Disease-Free Interval
Proportion Surviving
0.75
0.50
0.25
0.00
0
20
Time (months)
40
60
⇐ 12 months
> 12 months
reinterventions between patients who present with synchronous versus metachronous metastases. Both groups are frequently offered metastasectomy1 and may benefit from these aggressive operations, however, our data suggest that patients with meta- chronous disease derive a greater survival benefit after meta- stasectomy compared to those patients who undergo metastasectomy in the synchronous setting.
In this study, patients in the synchronous group were more likely to present with a higher T stage, suggesting that the lesser OS of patients in this group may be related to more aggressive tumor biology. There were no other differences in pathologic features at initial resection between the 2 groups, however, many pathologic factors, such as Ki-67 staining and nuclear grade, were reported for only a minority of patients. Improved consistency in the reporting of these data may provide more insight into differences in tumor
Survival Following Metachronous Metastasectomy by Number of Recurrent Tumors
1.00
Proportion Surviving
0.75
0.50
0.25
0.00
0
20
Time (months)
40
60
1 or 2
3 or more
biology at presentation between patients who present with syn- chronous versus metachronous metastatic disease.
Previous data have suggested that patients presenting with metastatic disease who do not undergo synchronous meta- stasectomy have a median OS of 8 to 10 months.8,12 In our cohort, patients undergoing synchronous metastasectomy had a median OS of 17.3 months. It is difficult to make a direct comparison be- tween these groups due to inherent differences in the patient populations that led to different treatment strategies. Nevertheless, our data suggest that there may be a survival benefit to synchro- nous resection of metastases in such patients.
Overall in this study, patients in the metachronous group derived a substantial survival benefit after the index resection and subsequent metastasectomy. One recent study showed that reoperation for recurrent ACC had a survival benefit up to the third operation.13 In this cohort, metastatic disease recurrence after the index resection, >2 tumors, and a lesser disease-free interval (<12 months) seem to be important predictors of a lesser OS after metachronous meta- stasectomy. These observations are consistent with previously pub- lished literature which demonstrated decreased OS in patients with disease-free interval of <12 months or with multifocal recurrence.6,7
Final margin resection status seems to have a significant impact on survival after synchronous metastasectomy, whereas the impact of margin status in the metachronous setting is less certain. One previous study of patients undergoing synchronous resection of lung or liver metastases also showed improvement in OS in patients who had an RO resection margin over patients with incomplete resections.14 Although our data show no clear association between margin status and survival in the metachronous group, there is literature suggesting that complete resection improves OS in this group as well.5 The authors continue to think that it is imperative to strive for complete pathologic resection of metachronous metas- tases in patients undergoing resection, in line with international consensus guidelines, because it is possible or likely that our study may be underpowered to detect a survival difference between pa- tients with complete and incomplete resections in the metachro- nous setting. Prospective trials comparing debulking operations to observation alone in patients with recurrent metastatic ACC would be required to definitively determine if there is benefit to incom- plete resection in the metachronous setting.
This study is primarily limited by its retrospective nature which makes conclusions about causality difficult. Additionally, due to the limitations of the US-ACC database which contains data only on those patients who underwent resection for ACC, our analysis does not contain a control cohort who did not undergo intervention. There- fore, it is not possible to ascertain the survival difference attributable
to resection versus observation within our patient cohorts. Third, though the multi-institutional nature of this collaborative is an asset in that it allowed us to examine a relatively large number of ACC patients simultaneously, there is likely inherent inconsistencies in operative practice and reporting of perioperative and pathologic data between institutions that may impact our results. Fourth, although the overall cohort size of our study is relatively large compared to other studies examining ACC, a rare disease, it is possible that our small cohort size (n = 84) limits our ability to detect differences be- tween treatment groups, including differences in tumor location, or hormone secretion status, or other important factors between groups. Next, the pathologic data reported often lacked impactful data points, including Ki67 and tumor grade, making analysis of dif- ferences in tumor biology between groups difficult. Lastly, all participating institutions in the US-ACCG are large tertiary referral centers, perhaps limiting the generalizability of our conclusions.
Overall, our data suggests that ACC patients who undergo metastasectomy for metachronous metastases have a more durable OS benefit after metastasectomy compared to patients with ACC who undergo metastasectomy for synchronous disease. This dif- ference may be due to inherent differences in the tumor biology for those who present with early versus advanced-stage disease, although further investigation comparing the biology of these tu- mors would be necessary to validate such a causation. Despite the uncertainty with regard to the cause of this survival disparity be- tween ACC patients who undergo metastasectomy for synchronous versus metachronous metastases, these data nonetheless may prove helpful in guiding physician-patient conversations about benefits of metastasectomy and expected prognosis after meta- stasectomy in the synchronous and metachronous settings.
Disclosure
There are no conflicts of interest to disclose.
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