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Impact of Micro- and Macroscopically Positive Surgical Margins on Survival after Resection of Adrenocortical Carcinoma
Kevin L. Anderson Jr., MHS1, Mohamed A. Adam, MD2, Samantha M. Thomas, MS3,4, Linda Youngwirth, MD2, Michael T. Stang, MD1,2,4, Randall P. Scheri, MD1,2,4, Sanziana A. Roman, MD1,2,4, and Julie A. Sosa, MD, MA1,2,4,5
1Duke University School of Medicine, Durham, NC; 2Department of Surgery, Duke University School of Medicine, Durham, NC; 3Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC; 4Duke Cancer Institute, Durham, NC; 5Duke Clinical Research Institute, Durham, NC
ABSTRACT
Purpose. Adrenocortical carcinoma (ACC) is a rare, aggressive cancer; complete surgical resection offers the best chance for long-term survival. The impact of surgical margin status on survival is poorly understood. Our objective was to determine the association of margin status with survival.
Methods. Patients with ACC were identified from the National Cancer Data Base, 1998-2012, and stratified based on surgical margin status (negative vs. microscopi- cally positive [+] vs. macroscopically [+]). Univariate/multivariate regression/survival analyses were utilized to determine factors associated with margin status and overall survival (OS).
Results. A total of 1553 patients underwent surgery at 589 institutions: 86% had negative, 12% microscopically (+), and 2% macroscopically (+) margins. Those with micro- scopically (+) and macroscopically (+) margins more often received adjuvant chemotherapy (39.4% macro- scopically (+) vs. 38.5% microscopically (+) vs. 25.2% negative margins, p < 0.001). For unadjusted analysis, there was a significant difference in OS between the groups (log-rank p < 0.001), with median survival times of 58 months (95% confidence interval [CI] 49-66) for those with negative margins, 22 months (95% CI 18-34)
microscopically (+), and 14 months (95% CI 6-27) macroscopically (+) margins. After adjustment, both microscopically (+) (HR 1.76, p < 0.001) and macro- scopically (+) (HR 2.10, p = 0.0019) margin status were associated with compromised survival.
Conclusions. Having micro- or macroscopically (+) margin status after ACC resection is associated with dose- dependent compromised survival. These results underscore the importance of achieving negative surgical margins for optimizing long-term patient outcomes.
Adrenocortical carcinoma (ACC) is a rare and lethal disease, with an estimated annual incidence of 0.50-2.0 per million.1 The prognosis for patients with ACC is poor; 5-year survival rates ranged between 82 and 13% for Stages I and IV disease, respectively.2 4 Early diagnosis is uncommon; therefore, many patients present with large, advanced tumors that invade nearby organs or with distant metastases.5,6
Complete surgical resection remains the only chance for cure for ACC; adjuvant treatment with chemotherapy and/ or radiation results in a modest improvement in survival for patients with locoregional and metastatic disease.1,7-9 Even when patients present with resectable tumors, 70-85% will demonstrate recurrence, potentially as a result of residual disease.3,10 The best opportunity for a favorable outcome that is durable is for patients to present with early-stage disease (Stage I or II cancers) and then undergo complete resection. Unfortunately, there have been no significant improvements in outcomes for patients with ACC at a population level in the United States over the past two decades.11 Studies in colorectal and hepatocellular carci- nomas have demonstrated that (+) surgical margin status is associated with compromised short- and long-term patient
A portion of these data was presented at the 2016 American College of Surgeons Clinical Congress, Washington, DC, October 19, 2016.
@ Society of Surgical Oncology 2018 First Received: 7 December 2017
R. P. Scheri, MD e-mail: r.scheri@duke.edu
outcomes.12-14 There are currently limited data examining resectional margin status (complete vs. incomplete resec- tion) and its potential association with survival among patients with ACC.15-17 Those studies that have assessed margin status were limited to single or multi-institutional studies or case series at high-volume, experienced aca- demic medical centers from which conclusions might not be generalizable. 8,10,18
The objectives of this study were to gain the first national perspective on the impact of surgical margin status (negative vs. microscopically positive vs. macroscopically positive) on overall survival of patients undergoing adrenalectomy for ACC and to understand the factors that are associated with having positive surgical margins.
METHODS
The Institutional Review Board granted exempt status to this retrospective analysis of the National Cancer Database (NCDB). The NCDB, established in 1989, is administered by the American College of Surgeons and the American Cancer Society. At present, it contains data from approximately 1500 Commission on Cancer-accredited programs across all 50 states, Puerto Rico, and the District of Columbia.19
Data were coded in accordance with the Commission on Cancer Registry Operations and Data Standards Manual, the International Classification of Disease for Oncology 3rd Edition (ICD-O-3), and the AJCC Manual for Staging of Cancer. All submitted data to the NCDB were de-identified in compliance with the Health Insurance Portability and Accountability Act.
The NCDB participant user files from 1998 to 2012 were used to identify all adult patients (age ≥ 18 years) who underwent an adrenalectomy procedure for a diagnosis of ACC (ICD-O-3 code: 8370.3). Patients with more than one cancer diagnosis were excluded to ensure that out- comes were not confounded by other diagnoses and/or treatments. Due to a high degree of missing data regarding the presence of distant metastases and clinical and patho- logic stage, we excluded these factors from the analysis. Patients then were stratified based on their postoperative margin status: negative versus microscopically positive versus macroscopically positive margins. Annual hospital volume was calculated as the total number of adult patients with only a single cancer diagnosis of ACC who were seen at a given facility, regardless of type of surgical procedure they received, divided by the total number of years that facility reported treating at least one of these patients to the NCDB. Due to small annual case volumes, this value was multiplied by 3 to obtain the estimated 3-year ACC case volume for each facility, and this calculated hospital vol- ume was used throughout this analysis.
Statistical Analysis
Patient demographic, clinical, pathologic and treatment variables, including gender, age at diagnosis, race, annual income, insurance status, comorbidity score, year of diag- nosis, tumor size, use of chemotherapy, use of hormonal therapy, use of external beam radiation therapy (EBRT), and surgical approach (laparoscopic, open, converted to open, or performed at another hospital), along with facility variables, including type of facility (community, comprehensive community, or academic), 3-year hospital volume, and facility location (midwest, northeast, south, or west) were extracted from the database. Comorbidity was represented by the modified Charlson-Deyo scoring system (1992).20 Annual patient income was assigned by the NCDB by matching the patient’s ZIP code to previous United States census tract data. Median annual income data in the patient’s ZIP code is reported in quartiles: the lower two quartiles were for median annual incomes of < 35,000.
Baseline characteristics and outcomes were compared between groups using the Kruskal-Wallis test for contin- uous variables and Chi Square or Fisher’s exact tests for categorical variables, as appropriate. The primary outcome was overall survival; given the high degree of lethality associated with ACC, this is a reasonable proxy for dis- ease-specific survival. The secondary goal was to identify factors associated with positive surgical margins after adrenalectomy for ACC.
Overall survival was defined as the time from diagnosis to time of death or last follow-up. Patients who had no follow-up were excluded from the analysis. Median overall survival and 95% confidence intervals (CI) were estimated using the Kaplan-Meier method. Survival distributions were compared across surgical margin groups using the log-rank test. Cox proportional hazards modeling was used to estimate the association of surgical margin status with overall survival after adjustment for patient age, gender, facility type, race, insurance status, annual income, hospital volume, comorbidity score, hospital volume, chemotherapy use, EBRT use, and tumor size. This model incorporated a robust sandwich covariance matrix to account for the cor- relation of patients treated at the same hospital.
Multivariate logistic regression models were used to identify factors associated with (microscopically and macroscopically) positive surgical margins. The model adjusted for the effects of patient demographic and clinical variables, including age at diagnosis, race, facility type, insurance status, comorbidity score, tumor size, chemotherapy use, EBRT use, and hospital volume. This model was built in the generalized estimating equations framework and included an exchangeable correlation structure to account for the correlation of patients treated at
| Negative margins (N = 1341) (%) | Microscopically (+) margins (N = 179) (%) | Microscopically (+) margins (N = 33) (%) | p value | |
|---|---|---|---|---|
| Age (years) | 0.06 | |||
| Median (IQR) | 52 (42-64) | 51 (40-63) | 57 (47-70) | |
| Gender | 0.18 | |||
| Female | 827 (61.7) | 117 (65.4) | 16 (48.5) | |
| Male | 514 (38.3) | 62 (34.6) | 17 (51.5) | |
| Race | 0.41 | |||
| White | 1196 (89.2) | 155 (86.6) | 30 (90.9) | |
| Black | 97 (7.2) | 14 (7.8) | 2 (6.1) | |
| Asian | 24 (1.8) | 8 (4.5) | 1 (3) | |
| Other | 12 (0.9) | 2 (1.1) | 0 (0) | |
| Annual income | 0.83 | |||
| < $35,000 | 366 (27.3) | 51 (28.5) | 7 (21.2) | |
| ≥ $35,000 | 911 (67.9) | 118 (65.9) | 21 (63.6) | |
| Insurance status | 0.50 | |||
| None | 53 (4) | 8 (4.5) | 1 (3) | |
| Government | 414 (30.9) | 57 (31.8) | 16 (48.5) | |
| Private | 839 (62.6) | 110 (61.5) | 16 (48.5) | |
| Unknown | 35 (2.6) | 4 (2.2) | 0 (0) | |
| Year of diagnosis | 0.39 | |||
| 1998-2000 | 206 (15.4) | 18 (10.1) | 5 (15.2) | |
| 2001-2003 | 237 (17.7) | 27 (15.1) | 7 (21.2) | |
| 2004-2006 | 266 (19.8) | 33 (18.4) | 7 (21.2) | |
| 2007-2009 | 301 (22.4) | 53 (29.6) | 8 (24.2) | |
| 2010-2012 | 331 (24.7) | 48 (26.8) | 6 (18.2) | |
| Facility type | 0.60 | |||
| Community program | 76 (5.7) | 9 (5) | 3 (9.1) | |
| Comprehensive community program | 523 (39) | 63 (35.2) | 14 (42.4) | |
| Academic program | 740 (55.2) | 107 (59.8) | 16 (48.5) | |
| Facility location | 0.33 | |||
| Midwest | 361 (26.9) | 54 (30.2) | 8 (24.2) | |
| Northeast | 297 (22.1) | 40 (22.3) | 7 (21.2) | |
| South | 472 (35.2) | 55 (30.7) | 8 (24.2) | |
| West | 211 (15.7) | 30 (16.8) | 10 (30.3) | |
| Hospital volume (3-year) | 0.06 | |||
| Median (IQR) | 3.7 (3-5) | 3.8 (3-4.8) | 3 (3-4) |
Percentages have been rounded and may not add up to 100% NCDB National Cancer Database, IQR interquartile range
the same hospital. A two-sided, p value < 0.05 was used to indicate statistical significance. No adjustments were made for multiple comparisons. All statistical analyses were performed using SPSS Version 22.0 (IBM Corp., Armonk, NY) or SAS version 9.4 (SAS Institute, Cary, NC).
RESULTS
Patient Demographic, Treatment-Level, and Clinicopathologic Characteristics
A total of 1553 patients met inclusion criteria for this study; 1,341 (86%) had negative surgical margins, 179 (12%) had microscopically positive surgical margins, and 33 (2%) had macroscopically positive margins. There were
| Negative margins (N = 1341) (%) | Microscopically (+) margins (N = 179) (%) | Macroscopically (+) margins (N = 33) (%) | p value | |
|---|---|---|---|---|
| Charlson-Deyo score | 0.14 | |||
| 0 | 769 (57.3) | 117 (65.4) | 16 (48.5) | |
| 1 | 172 (12.8) | 18 (10.1) | 7 (21.2) | |
| ≥ 2 | 47 (3.5) | 9 (5) | 1 (3) | |
| Unknown | 353 (26.3) | 35 (19.6) | 9 (27.3) | |
| Surgical approach (2010-2012) | 0.68 | |||
| Laparoscopic | 77 (5.7) | 11 (6.1) | 0 (0) | |
| Open | 209 (15.6) | 28 (15.6) | 5 (15.2) | |
| Converted to open | 8 (0.6) | 1 (0.6) | 0 (0) | |
| Chemotherapy | 338 (25.2) | 69 (38.5) | 13 (39.4) | <0.001 |
| Hormonal therapy | 33 (2.5) | 5 (2.8) | 1 (3) | 0.76 |
| Radiation therapy | < 0.001 | |||
| None | 1199 (89.4%) | 133 (74.3%) | 23 (69.7%) | |
| EBRT | 117 (8.7%) | 43 (24%) | 10 (30.3%) | |
| Tumor size (cm) | 0.11 | |||
| Median (IQR) | 11.0 (7.5-15.0) | 10.5 (7.8-14.5) | 14.3 (8.5-17.8) | |
| Laterality | 0.34 | |||
| Unilateral (NOS) | 5 (0.4) | 1 (0.6) | 0 (0) | |
| Left | 741 (55.3) | 99 (55.3) | 17 (51.5) | |
| Right | 580 (43.3) | 74 (41.3) | 15 (45.5) | |
| Bilateral | 1 (0.1) | 0 (0) | 0 (0) | |
| Unknown | 13 (1) | 5 (2.8) | 1 (3) | |
| Regional LNs examined | 0 (0-0) | 0 (0-0) | ||
| Median (IQR) | 0 (0-0) | |||
| Regional LNs (+) | < 0.001 | |||
| Median (IQR) | 0 (0-0) | 0 (0-3) | 0 (0-1) | |
| Positive LN status | 61 (4.5) | 22 (12.3) | 3 (9.1) | < 0.001 |
Percentages have been rounded and may not add up to 100%
NOS not otherwise specified, LN lymph node, EBRT external beam radiation therapy
no significant differences between the three groups in terms of patient age, gender, race, annual income, insurance status, Charlson-Deyo comorbidity score, or year of diag- nosis (p > 0.05; Table 1). Those who had macroscopically positive margins were more likely to receive adjuvant chemotherapy (39.4% vs. microscopically positive [38.5%] vs. negative [25.2%], p <0.001) and EBRT (30.3% vs. microscopically positive [24.0%] vs. negative [8.7%], p < 0.001). Those with negative margins were less likely to have positive regional lymph nodes (4.5% vs. micro- scopically positive [12.3%] vs. macroscopically positive [9.1%], p <0.001). There were no differences in other treatment-level characteristics between margin status groups based on facility type and location, surgical approach, and use of hormone therapy (including mitotane) (p > 0.05; Table 2). There also was no difference in tumor
characteristics between the three groups, including tumor size, laterality, or number of regional lymph nodes exam- ined (p> 0.05; Table 2).
No demographic, clinical, or treatment covariates were found to be associated with positive margins after surgery. This included patient age and race, facility type, insurance status, comorbidity score, tumor size, and hospital volume (p >0.05).
Impact of Surgical Margin Status on Overall Survival
Median overall survival time was 49.7 months (95% CI 44.1-57.6). In univariate analysis, there was a significant difference between the three margin status groups; those patients with negative margins had a longer median sur- vival of 57.6 months (95% CI 48.5-66.0) compared with
1.0
Surgical Margins
- Negative
0.8
Microscopically Positive
Macroscopically Positive
Survival Probability
0.6
0.4
Log-Rank p<0.001
0.2
0.0
0
24
48
72
96
120
144
168
192
Survival Time (Months)
those with microscopically positive margins, who survived 22.4 months (95% CI 17.6-33.5) and those with macro- scopically positive margins, who survived a median of 13.7 months (95% CI 5.8-26.8) (log-rank p < 0.001; Fig. 1). More patients (48.8%, 95% CI 45.7-51.8%) with negative surgical margins survived 5 years compared with those with microscopically positive (28.6%, 95% CI 21.0-36.8%) and macroscopically positive margins (22.6%, 95% CI 9.4-39.2%).
After adjustment for patient age, gender, race, facility type, insurance status, annual income, comorbidity score, 3-year hospital volume status, chemotherapy use, radiation use, and tumor size, both microscopically positive (hazards ratio [HR] 1.76; 95% CI 1.37-2.26, p < 0.001) and macroscopically positive (HR 2.10; 95% CI 1.21-3.65, p = 0.009) margins were associated with compromised survival (Table 3).
DISCUSSION
Surgical resection continues to represent the only cura- tive option for patients with ACC.21 Previous studies have evaluated short- and long-term outcomes after adrenalec- tomy, but they have been limited to institutional level analyses, many of which evaluated resection margin as a binary variable, allocating patients either to negative (R0) or positive (R1) surgical resection margins.8,15-17 This study represents the first national level analysis to estimate the association between surgical margin status and overall survival after resection of ACC. The present study is unique in its characterization of margins as negative,
microscopically positive, or macroscopically positive margins. The presence of microscopic residual disease was shown to be associated with compromised survival com- pared to negative surgical margins from a 5-year overall survival perspective (48.8-28.6%, respectively), with macroscopically positive margins associated with even more compromised 5-year overall survival (22.6%).
The important association between surgical resection margin status and patient survival has been demonstrated for several surgical procedures and for a variety of different cancers.12-14 The case for ACC has been unclear until now, however. In a 15-year retrospective analysis of 98 Aus- tralian patients, Ip et al. found that surgical margin status was not associated with recurrence free-survival (HR 2.4, 95% CI 0.9-6.1, p = 0.08) in the multivariate analysis.22 In another retrospective analysis of 330 patients at a high- volume tertiary hospital in the United States, Ayala- Ramirez et al. also found that surgical margin status was not an independent predictor of overall survival after ACC resection (p = 0.09); 275 patients (83.3%) ultimately underwent resection of their tumors.8 Both studies may have been underpowered to detect the possible effect that margin status had on survival.
More recent analyses have suggested a prominent role for surgical margin status with regard to long-term prog- nosis. In a multi-institutional report by Margonis et al., patients with R0 and R1 margin status after ACC resection were compared with regard to overall and recurrence-free survival.18 The presence of positive resection margins was associated with compromised overall survival (HR 2.22, 95% CI 1.03-4.77; p = 0.04). However, in the adjusted multivariate analysis, a positive surgical margin status was not an independent predictor of recurrence-free survival (HR 1.06, 95% CI 0.58-1.94, p = 0.84).18 Using the same multi-institutional registry, Amini et al. also noted in an analysis of 180 patients undergoing curative-intent resec- tion of ACC that having a positive surgical margin was not independently associated with recurrence-free survival (HR 0.85, 95% CI 0.39-1.83, p = 0.68).23 These studies potentially have limited generalizability, because each of the 13 participating institutions included were high-volume academic centers. In a larger analysis using the NCDB, Bilimoria et al. illustrated that positive surgical margins were associated with compromised prognosis among patients with ACC (HR 1.81, 95% CI 1.44-2.27; p < 0.001).1º This study was limited, because it did not adjust for other important characteristics, such as comor- bidity score, facility type, tumor size, and hospital volume, any of which conceivably could be associated with margin status or survival.
Our current study should be considered in light of cer- tain limitations. As with any large national database, in the NCDB there is the possibility of coding errors despite the
| Variable | Hazards ratio | 95% CI | p value | |
|---|---|---|---|---|
| Margin status | ||||
| Microscopically (+) | 1.76 | 1.37 | 2.26 | < 0.001 |
| Macroscopically (+) | 2.10 | 1.21 | 3.65 | 0.009 |
| Age (per decade) | 1.11 | 1.04 | 1.19 | 0.002 |
| Gender | ||||
| Female | 0.99 | 0.83 | 1.17 | 0.88 |
| Facility type | ||||
| Comprehensive cancer center | 0.83 | 0.69 | 1.00 | 0.04 |
| Community hospital | 0.59 | 0.39 | 0.90 | 0.01 |
| Race | ||||
| Black | 0.90 | 0.65 | 1.26 | 0.55 |
| Asian | 0.42 | 0.18 | 0.98 | 0.04 |
| Other | 0.61 | 0.16 | 2.34 | 0.47 |
| Insurance status | ||||
| Private | 0.96 | 0.60 | 1.54 | 0.87 |
| Government | 1.16 | 0.71 | 1.90 | 0.56 |
| Unknown | 0.98 | 0.48 | 2.01 | 0.96 |
| Annual income | ||||
| ≥ $35,000 | 1.06 | 0.89 | 1.27 | 0.44 |
| Comorbidity score | ||||
| 1 | 1.24 | 0.97 | 1.60 | 0.09 |
| ≥ 2 | 1.26 | 0.78 | 2.03 | 0.34 |
| Unknown | 1.31 | 1.08 | 1.58 | 0.006 |
| Hospital volume (3-Year) | 0.97 | 0.92 | 1.01 | 0.14 |
| Chemotherapy | 1.57 | 1.31 | 1.87 | < 0.001 |
| EBRT | 1.09 | 0.81 | 1.46 | 0.57 |
| Tumor size (cm) | 1.01 | 1.00 | 1.02 | 0.008 |
Model accounts for the correlation of patients treated at the same hospital
References include negative margins, male gender, academic facility, white race, uninsured status, annual income < $35,000 and comorbidity score of 0
NCDB National Cancer Database, EBRT External Beam Radiation Therapy
scrutiny of trained coders. The NCDB does not collect information about intent-to-treat, so does not account for patient selection bias. This study also was limited based on the variables that are included in the database; for example, we were unable to identify the location of the positive margin (peritoneal surface) or measure characteristics, such as microscopic capsular invasion, tumor functionality (especially with regard to cortisol secretion), presence of distant metastases, and recurrence-free survival. The lack of available information on metastatic disease potentially influences our measurement of both overall and disease- free survival. The strength of this study is in its general- izability due to its national perspective and large patient cohort. It also is unique for its pathologic detail; it was able to afford our examining both microscopically and macro- scopically positive resection margin status.
Both microscopically and macroscopically positive surgical margins after resection of ACC were associated with compromised overall survival, in a dose-response fashion. Because a number of tumor characteristics and patient demographics were not significant predictors of survival, including race and number of comorbidities, surgeons should not limit patients from undergoing resec- tion with curative intent when it is felt to be feasible to obtain negative margins.
ACKNOWLEDGMENT This research was supported by a NIH TL-1 clinical and translational science award (CTSA), Grant number 1UL1-TR001117-01 (NCATS). J. A. S. is a member of the data monitoring committee of the Medullary Thyroid Cancer Consortium Registry supported by NovoNordisk, GlaxoSmithKline, Astra Zeneca, and Eli Lilly. The other authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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