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ORIGINAL ARTICLE - ENDOCRINE TUMORS
Adjuvant Radiation is Associated with Improved Survival for Select Patients with Non-metastatic Adrenocortical Carcinoma
Daniel W. Nelson, DO1, Shu-Ching Chang, PhD2, Brad C. Bandera, MD1, Trevan D. Fischer, MD1, Robert Wollman, MD3, and Melanie Goldfarb, MD, MS, FACS, FACE1,4
1Division of Surgical Oncology, John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA; 2Department of Biostatistics, Medical Data Research Center at Providence Health and Services Center, Portland, OR; 3Department of Radiation Oncology, Providence Saint John’s Health Center, Santa Monica, CA; 4Center for Endocrine Tumors and Disorders, John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA
ABSTRACT
Background. Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy for which surgery is the mainstay of treatment and for which adjuvant radiation is infrequently employed; however, small, single-institution series suggest adjuvant radiation may improve outcomes. Methods. All patients with non-metastatic ACC treated with either surgery alone or surgery followed by adjuvant radiation were identified in the 2004-2013 National Cancer Database. Factors associated with receipt of radiation and the impact of adjuvant radiation on survival were deter- mined by multivariable analysis.
Results. Of 1184 patients, 171 (14.4%) received adjuvant radiation. Patient demographics were similar between the two groups, but those receiving radiation were more likely to have had positive margins following surgery (37.4 vs. 14.6%; p < 0.001), evidence of vascular invasion (14.0 vs. 5.1%; p = 0.05), and receive concurrent chemotherapy (57.3 vs. 28.8%; p < 0.001). After adjustment for tumor and other treatment factors, only positive margins follow- ing surgery was associated with an increased likelihood of receiving adjuvant radiation (odds ratio 3.84, 95% confi- dence interval [CI] 1.95-7.56). Radiation therapy did not confer a difference in median overall survival in the
general cohort. However, for patients with positive mar- gins, adjuvant radiation was associated with a 40% decreased yearly risk of death after adjustment for con- current chemotherapy (hazard ratio 0.60, 95% CI 0.40-0.92; p = 0.02). This survival advantage was not evident for other traditional high-risk features.
Conclusion. Adjuvant radiation appears to decrease the risk of death in ACC patients with positive margins fol- lowing surgical resection, but only a small percentage are currently receiving radiation. Multidisciplinary treatment with surgery and radiation should be considered for these patients.
Adrenocortical carcinoma (ACC) is well-recognized as a rare but highly aggressive malignancy. Although the annual incidence ranges between just 0.5 and 2.0 per mil- lion,” patients commonly present at advanced stages, leading to poor overall prognosis,2 which has not signifi- cantly changed over the last 4 decades.1,3,4 Based on the European Network for the Study of Adrenal Tumors (ENSAT) staging classification, estimates of 5-year dis- ease-specific survival are 82% for stage I, 61% for stage II, 50% for stage III, and 13% for stage IV.5
The mainstay of treatment for ACC is complete radical resection with negative margins; however, local recurrence is common and, in historical series, has been reported to occur in as many as 85% of patients.º Repeat resection of recurrent disease has been shown to improve survival7 and has often been relied upon as ‘adjuvant therapy’ due to limited options for efficacious systemic alternatives.8,9
Adjuvant radiation has been proposed as a means to reduce high recurrence rates in ACC following surgery with curative intent. Early series examining the utility of
Poster presented at the 125th Annual Meeting of the Western Surgical Association, Scottsdale, AZ, USA, 5 November 2017.
@ Society of Surgical Oncology 2018 First Received: 2 February 2018
M. Goldfarb, MD, MS, FACS, FACE e-mail: goldfarbm@jwci.org
radiation in ACC demonstrated disappointing results, which led many investigators to conclude that ACC was a relatively radiation-resistant cancer.10 However, due to the rarity of this disease, these studies were often limited to retrospective case series with small numbers of patients collected over several decades.6,11,12 More recent small studies utilizing modern radiation techniques have demonstrated that tumor bed irradiation may be associated with improved local recurrence-free survival, and, in at least one series, lack of adjuvant radiotherapy was asso- ciated with a nearly fivefold increased risk of local failure.13-17 Unfortunately, these studies have also been limited by small numbers of patients, ranging from just 10 to 58 patients. Therefore, this study utilizes a large, pop- ulation-based dataset to examine the utility of adjuvant radiation in the treatment of ACC.
METHODS
Cohort Selection
The National Cancer Database (NCDB) is a joint project of the American College of Surgeons and the American Cancer Society. A nationwide cancer registry, the NCDB gathers data from more than 1500 Commission on Cancer- accredited facilities, tracking patients with cancer, their treatments and outcomes, and, in the process, capturing more than 70% of all newly diagnosed malignancies in the US annually.18 The data used in this study are derived from a de-identified NCDB file. The American College of Sur- geons and Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigator.
Using the NCDB 2004-2013 participant user file, all patients with ACC were identified, on the basis of the
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International Classification of Diseases for Oncology, 3rd edition (ICD-0-3), by site and histology. Adrenal cortical carcinoma is identified as site C74.0 (adrenal cortex) with histology 8010, 8140, and 8370, or C74.9 (adrenal gland, NOS) with histology 8370. Only patients with primary, histologically confirmed, invasive ACC who had a surgical resection, either total surgical removal of the primary site or removal of the primary site with resection in continuity with other organs (radical/en bloc resection), were included for analysis. Patients with early postoperative mortality (< 30 days) and those with unknown information regard- ing receipt of adjuvant radiation therapy were excluded. Patients with clinically (cM1) presumed or pathologically (pM1) confirmed metastatic disease were also excluded. After all exclusion criterion, except for tumor size, were applied, 1312 patients remained in the study cohort (1127 surgery alone vs. 185 surgery plus adjuvant radiation) of whom three patients had tumor sizes < 1 cm, 1184 had tumor sizes between 1 and 20 cm, 81 had tumor sizes > 20 cm, and 44 patients had unknown tumor sizes. To avoid contaminating the patient sample with incidental ACC discovered following adrenalectomy for another indication as well as incorrectly coded tumor sizes, all tumors smaller than 1 cm, as well as unknown tumor sizes, were excluded. In addition, to avoid potential bias towards a treatment effect, tumor sizes > 20 cm were excluded as these would inherently be associated with higher risk for positive margins or distant metastasis. However, analyses were also performed when tumors > 20 cm were included, but the data are not presented since it did not change the results. This study received Institutional Review Board exemption status after independent regulatory review due to the de-identified nature of the data.
Statistical Analysis
Patients were stratified into two groups: surgery alone versus surgery followed by adjuvant radiation. Descriptive data that included patient and sociodemographic variables, as well as tumor and treatment-related factors, were sum- marized by median (range) for continuous data and count (percentage) for categorical data. Univariate comparisons between groups were performed using the Chi-square test and nonparametric Kruskal-Wallis rank-sum test for cate- gorical and continuous covariates, respectively, followed by multivariable regression analysis to determine inde- pendent factors for use of adjuvant radiation.
Overall survival was compared between groups using the Kaplan-Meier method with log-rank test. Multivariable Cox proportional hazards modeling was then performed to examine for independent effects of adjuvant radiation therapy and other covariates on the risk of death. A priori subgroup analysis was planned for patients with positive
| Variable | Surgery [N = 1013] | Surgery + radiation [N = 171] | p-Value |
|---|---|---|---|
| Age, years | |||
| Median (Q1, Q3) | 54.0 (43.0, 66.0) | 54.0 (43.0, 63.0) | 0.68 |
| ≤ 55 | 555 (54.8) | 92 (53.8) | 0.88 |
| > 55 | 458 (45.2) | 79 (46.2) | |
| Race | 0.42 | ||
| White | 841 (83) | 141 (82.5) | |
| Black | 79 (7.8) | 15 (8.8) | |
| Hispanic | 55 (5.4) | 7 (4.1) | |
| Asian Pacific Islander | 22 (2.2) | 7 (4.1) | |
| Other/unknown | 16 (1.6) | 1 (0.6) | |
| Sex | 0.93 | ||
| Male | 390 (38.5) | 67 (39.2) | |
| Female | 623 (61.5) | 104 (60.8) | |
| Comorbid conditions | 0.10 | ||
| No | 762 (75.2) | 139 (81.3) | |
| Yes | 251 (24.8) | 32 (18.7) | |
| Facility type | 0.58 | ||
| Academic | 448 (44.2) | 67 (39.2) | |
| Community | 323 (31.9) | 59 (34.5) | |
| Other | 48 (4.7) | 8 (4.7) | |
| Missing | 194 (19.2) | 37 (21.6) | |
| Distance to treatment facility | |||
| Median (Q1, Q3) | 15.3 (5.9, 44.2) | 14.2 (5.0, 47.0) | 0.42 |
| Range | 0.92 | ||
| ≤ 50 | 772 (76.2) | 129 (75.4) | |
| 50-100 | 120 (11.8) | 22 (12.9) | |
| > 100 | 101 (10) | 18 (10.5) | |
| Missing | 20 (2) | 2 (1.2) | |
| Insurance status | 0.38 | ||
| Uninsured | 38 (3.8) | 6 (3.5) | |
| Private | 607 (59.9) | 112 (65.5) | |
| Public | 353 (34.8) | 49 (28.7) | |
| Unknown | 15 (1.5) | 4 (2.3) | |
| Size, cm | |||
| Median (Q1, Q3) | 10.0 (7.0, 13.5) | 9.7 (7.2, 13.4) | 0.76 |
| ≤ 5 | 135 (13.3) | 17 (9.9) | 0.27 |
| > 5 | 878 (86.7) | 154 (90.1) | |
| Grade | 0.51 | ||
| I/II well-differentiated | 94 (9.3) | 16 (9.4) | |
| III/IV poor to undifferentiated | 160 (15.8) | 33 (19.3) | |
| Unknown | 759 (74.9) | 122 (71.3) | |
| Lymph node status | 0.20 | ||
| Positive | 65 (6.4) | 5 (2.9) | |
| Negative | 189 (18.7) | 34 (19.9) | |
| Unknown | 759 (74.9) | 132 (77.2) |
| Variable | Surgery [N = 1013] | Surgery + radiation [N = 171] | p-Value |
|---|---|---|---|
| Margin status | <0.001 | ||
| Positive | 148 (14.6) | 64 (37.4) | |
| Negative | 749 (73.9) | 90 (52.6) | |
| Unknown | 116 (11.5) | 17 (9.9) | |
| Vascular invasion | 0.05 | ||
| Yes | 52 (5.1) | 24 (14.0) | |
| No | 210 (20.7) | 53 (31.0) | |
| Missing | 751 (74.1) | 94 (55.0) | |
| Type of surgical procedure | 0.44 | ||
| Total | 789 (77.9) | 128 (74.9) | |
| Radical | 224 (22.1) | 43 (25.1) | |
| Chemotherapy | <0.001 | ||
| Yes | 292 (28.8) | 98 (57.3) | |
| No | 690 (68.1) | 68 (39.8) | |
| Missing | 31 (3.1) | 5 (2.9) |
Data are expressed as n (%) unless otherwise specified
tumor margins, large tumor size (> 5 cm), and high-grade histology, since they are mentioned as high risk in the latest National Comprehensive Cancer Network (NCCN) guide- lines, as well as age > 55 years and node-positive status, which are known to decrease survival.19 All tests were two- sided and statistical significance was set at p < 0.05. All statistical analysis was performed using R software (R Core Team 2016, Vienna, Austria).
RESULTS
Of 1184 patients with non-metastatic ACC who had an attempted complete surgical resection, the majority of patients were White (82.9%) and female (61.4%), with a median age of 54 years (interquartile range [IQR] 43-65 years). Median tumor size was 10 cm (IQR 7.0-13.5 cm), high-grade histology was identified in 16.3% of patients, and 5.9% of patients had positive lymph nodes on final pathology. Following surgical resection, only 14.4% (n = 171) of patients went on to receive adjuvant radiation, with a median time to adjuvant radiation after surgery of 55.5 days (IQR 44-75.3 days). Chemotherapy was administered in 32.9% of cases.
Patient and tumor characteristics were similar between patients undergoing surgery alone and those receiving adjuvant radiation after surgery (Table 1). Only patients with positive margins (37.4 vs. 14.6%; p < 0.001) and who had chemotherapy as part of their treatment regimen (57.3 vs. 28.8%; p < 0.001) were more likely to have received adjuvant radiation compared with those with negative margins and no chemotherapy, respectively. After adjust- ment for tumor- and other treatment-related factors, only
positive margin status following surgery was associated with an increased likelihood of receiving adjuvant radiation (odds ratio [OR] 3.84, 95% confidence interval [CI] 1.95-7.56; p < 0.001). Conversely, evidence of nodal metastases was associated with a decreased likelihood of receiving adjuvant radiation (OR 0.10, 95% CI 0.01-0.91; p = 0.04).
The NCDB does not collect data regarding disease recurrence. Unadjusted overall survival was 60.1 months for surgery alone versus 37.3 months for those who received adjuvant radiation (p = 0.16) [Fig. 1]. However, overall survival was lower for patients aged > 55 years, high-grade histology, nodal metastases, positive resection margins, evidence of vascular invasion, and chemotherapy as part of their treatment regimen (all p < 0.05) before adjustment for confounding factors (Table 2). After adjustment, only high-grade histology (hazard ratio [HR] 4.33, 95% CI 1.44-12.99; p = 0.01) and vascular invasion (HR 1.85, 95% CI 1.12-3.05; p = 0.02) independently decreased survival.
Subgroup analysis with adjustment for confounding factors was performed for each of the above known high- risk characteristics. Adjuvant radiation provided no sig- nificant benefit for patients aged > 55 years and with node- positive disease or high-grade histology (all p > 0.05). However, after adjustment for other treatment-related characteristics, adjuvant radiation was associated with a 40% decreased risk of death (HR 0.60, 95% CI 0.40-0.92; p = 0.02) in patients with positive margins (Fig. 2a). Among margin-negative patients, no survival difference was demonstrated between treatment groups (p = 0.36) [Fig. 2b].
| Variable | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p-Value | HR | 95% CI | p-Value | |
| Treatment | ||||||
| Surgery | Ref | Ref | ||||
| Surgery + radiation | 1.20 | 0.93-1.53 | 0.16 | 0.80 | 0.47-1.37 | 0.42 |
| Age, years | ||||||
| ≤ 55 | Ref | Ref | ||||
| > 55 | 1.47 | 1.24-1.74 | <0.001 | 1.46 | 0.93-2.27 | 0.10 |
| Size, cm | ||||||
| ≤ 5 | Ref | Ref | ||||
| >5 | 1.19 | 0.91-1.56 | 0.19 | 1.13 | 0.57-2.24 | 0.72 |
| Grade | ||||||
| I/II | Ref | Ref | ||||
| III/IV | 3.08 | 2.03-4.67 | <0.001 | 4.33 | 1.44-12.99 | 0.01 |
| Unknown | 2.34 | 1.60-3.44 | <0.001 | 2.7 | 0.97-7.55 | 0.06 |
| Comorbid conditions | ||||||
| No | Ref | Ref | ||||
| Yes | 1.21 | 0.99-1.47 | 0.06 | 1.17 | 0.70-1.96 | 0.54 |
| Lymph node status | ||||||
| Negative | Ref | Ref | ||||
| Positive | 2.92 | 2.06-4.14 | <0.001 | 0.78 | 0.27-2.23 | 0.64 |
| Unknown | 1.06 | 0.84-1.33 | 0.64 | 0.62 | 0.37-1.05 | 0.07 |
| Margin status | ||||||
| Negative | Ref | Ref | ||||
| Positive | 2.14 | 1.73-2.63 | <0.001 | 1.53 | 0.85-2.73 | 0.15 |
| Unknown | 1.64 | 1.27-2.10 | <0.001 | 1.36 | 0.60-3.05 | 0.46 |
| Vascular invasion | ||||||
| No | Ref | Ref | ||||
| Yes | 1.94 | 1.24-3.04 | 0.004 | 1.85 | 1.12-3.05 | 0.02 |
| Chemotherapy | ||||||
| No | ||||||
| Yes | 1.30 | 1.08-1.55 | 0.005 | 1.11 | 0.71-1.76 | 0.64 |
DISCUSSION
The current study represents the largest series of ACC comparing the outcome of surgery alone and surgery with adjuvant radiation, and is the first to demonstrate a sig- nificant survival advantage in select groups of patients with ACC, namely those with positive margins. Additionally, it highlights the infrequent use of adjuvant radiation, even in those patients who experienced a survival benefit.
ACC is a highly aggressive malignancy, with less than half of all newly diagnosed patients presenting with early- stage disease.5 Although complete surgical resection is the mainstay of treatment for curative intent, the overwhelm- ing majority of patients will experience a recurrence.6 Efficacious adjuvant therapeutic options remain limited. The most widely studied agent in the adjuvant setting has been the synthetic adrenolytic mitotane, which, in
retrospective series, demonstrated improved recurrence- free survival;8,20 however, mitotane is associated with significant toxicity and requires frequent drug monitoring, which may limit its use.21 Although cytotoxic chemother- apy,9 as well as several novel targeted therapies, have been explored, these agents have been limited to the rapidly progressive recurrent and metastatic settings.22
In the present series, patients who received adjuvant radiation were nearly twice as likely to also receive chemotherapy as part of their treatment regimen (57.3 vs. 28.8%; p < 0.001). Due to limitations of the NCDB, we were unable to determine the specific indication for initi- ation of systemic therapy. However, based on current practice guidelines, one might safely assume that chemotherapy was initiated following disease recurrence or development of metastatic disease as chemotherapy was associated with a 30% increased risk of death on univariate
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analysis (HR 1.30, CI 1.08-1.55; p = 0.005) and had no effect on survival on multivariable analysis. This finding further illustrates the importance of obtaining early and definitive locoregional control.
Early investigations exploring the therapeutic potential of adjuvant radiation to the tumor bed in hopes of improving local control had disappointing results, leading many clinicians to consider ACC to be a relatively radioresistant tumor type.10 However, recent series using modern radiation technology have renewed interest in this treatment modality, and have demonstrated radiation to be effective in decreasing local recurrence in both the adju- vant and palliative settings in small series.13-17 Given the rarity of the disease, it has been difficult to assemble a large enough cohort of patients that would provide adequate power to truly study the effectiveness of adjuvant radiation for ACC, which is the strength of the present series.
There are several limitations of this study that are inherent to any large, population-based national dataset. First, the analysis is restricted to the variables collected and the accuracy of the recorded data. Therefore, some factors that may contribute to patient outcomes, in this case tumor functionality and any inherited tumor syndrome, are not available. Additionally, granular data, such as the extent of surgery, specific chemotherapeutic regimens, and admin- istered adjuvant radiation schedules, are not available. However, most importantly, the NCDB lacks data related to disease recurrence and thus disease-specific survival outcomes cannot be assessed. Despite these limitations, these results, along with those of modern retrospective case series, collectively reaffirm the need for prospective investigation to clarify the role of adjuvant radiation in ACC.
CONCLUSION
Using a large national dataset, this study demonstrated that although only a small percentage of patients are cur- rently receiving radiation therapy, adjuvant radiation was correlated with a decreased risk of death in ACC patients with positive margins following surgical resec- tion. Prospective examination of this treatment modality is warranted based on these findings.
ACKNOWLEDGMENT The results and opinions expressed in this article are those of the authors and do not reflect the opinions or official policy of the United States Army or the Department of Defense.
DISCLOSURE Dr. Daniel W. Nelson is the Harold McAlister Charitable Foundation Fellow at the John Wayne Cancer Institute.
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Adjuvant Radiation is Associated with Improved Survival
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