Oncology: Adrenal/Bladder
JU Insight
Disparate Practice Patterns and Survival Outcomes: The Impact of Centralization of Cancer Care for Adrenocortical Carcinoma in the United States
Benjamin V. Stone, Jacob E. Tallman Kelvin A. Moses
Correspondence: Kelvin A. Moses (email: kelvin.a.moses@vumc.org).
Full-length article available at https://doi.org/10.1097/JU.0000000000001871.
Study Need and Importance: Adrenocortical carci- noma (ACC) is a rare but aggressive malignancy. Studies of other urological malignancies have shown superior outcomes associated with centralization of care-shifting cancer treatment to high-volume referral centers with multidisciplinary expertise. However, centralization of care remains under studied in ACC. In this study we sought to evaluate differences in practice patterns and overall survival (OS) in patients with ACC across types of treating facilities.
What We Found: We identified 2,886 patients diag- nosed with ACC from 2004-2016 in the National Cancer Database (NCDB). Median OS was 21.8 months (95% CI 19.8-23.8). Academic centers had improved OS versus community centers on unadjusted Kaplan-Meier analysis (p <0.05) and had higher rates of adrenalectomy or radical en bloc resection (p <0.001), performed more open surgery (p <0.001), administered more systemic therapy (p <0.001) and had lower rates of positive surgical margins (p=0.03, see table). On multivariable analysis controlling for
treatment modality, academic centers were associated with significantly decreased risk of death (HR 0.779, 95% CI 0.631-0.963, p=0.021).
Limitations: This study is retrospective in nature and is subject to limitations inherent to the NCDB, including missing data, possible coding errors, and a lack of central pathological review. We are unable to report recurrence rates or disease-specific survival, instead reporting OS, though we are importantly able to adjust for age and medical comorbidities.
Interpretations for Patient Care: Treatment of ACC at an academic center is associated with improved OS compared to community programs. There are significant differences in practice patterns, including more aggressive surgical treatment at academic fa- cilities, but the survival benefit persists on multi- variable analysis controlling for treatment modality. Further studies are needed to identify the most important predictors of survival in this at-risk population.
| Community (%) | Comprehensive Community Cancer Center (%) | Academic (%) | Integrated Network Cancer Program (%) | p Value | |
|---|---|---|---|---|---|
| Systemic therapy: | 30.7 | 34.6 | 40.1 | 34.3 | <0.001 |
| Adjuvant systemic therapy | 13.6 | 20.2 | 28.8 | 23.9 | <0.001 |
| Radiation: | 15.1 | 14.7 | 14.7 | 18.2 | 0.046 |
| Adjuvant radiation | 10.8 | 10.6 | 11.5 | 13.8 | 0.507 |
| Surgery: | <0.001 | ||||
| Ablation | 0.6 | 0.1 | 0.1 | 0.3 | |
| Partial adrenalectomy | 2.4 | 3.2 | 3.5 | 4.1 | |
| Adrenalectomy | 40.4 | 50.2 | 54.7 | 55.1 | |
| Radical surgery | 12.7 | 11.1 | 15.5 | 8.8 | |
| Open surgery* | 43.8 | 49.7 | 61.4 | 50.0 | <0.001 |
| Pos surgical margins* | 21.7 | 18.2 | 19.1 | 20.3 | 0.032 |
| Lymph node dissection* | 30.4 | 16.8 | 26.1 | 17.2 | <0.001 |
* Among patients undergoing partial adrenalectomy, adrenalectomy, or radical surgery (1,993)
@ 2021 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
of THE JOURNAL UROLOGY ®
Disparate Practice Patterns and Survival Outcomes: The Impact of Centralization of Cancer Care for Adrenocortical Carcinoma in the United States
Benjamin V. Stone,1 Jacob E. Tallman1 and Kelvin A. Moses1,*
1 Department of Urology, Vanderbilt University Medical Center, Nashville, Tennessee
Purpose: Adrenocortical carcinoma is a rare but aggressive malignancy. While centralization of care to referral centers improves outcomes across common urological malignancies, there exists a paucity of data for low-incidence cancers. We sought to evaluate differences in practice patterns and overall survival in patients with adrenocortical carcinoma across types of treating facilities.
Materials and Methods: We identified all patients diagnosed with adrenocortical carcinoma from 2004-2016 in the National Cancer Database. The Kaplan-Meier method was used to evaluate overall survival and multivariable Cox regression analysis was used to investigate independent predictors of overall survival. The chi-square test was used to analyze differences in practice patterns.
Results: We identified 2,886 patients with adrenocortical carcinoma. Median overall survival was 21.8 months (95% CI 19.8-23.8). Academic centers had improved overall survival versus community centers on unadjusted Kaplan- Meier analysis (p <0.05) and had higher rates of adrenalectomy or radical en bloc resection (p <0.001), performed more open surgery (p <0.001), administered more systemic therapy (p <0.001) and had lower rates of positive surgical mar- gins (p=0.03). On multivariable analysis, controlling for treatment modality, academic centers were associated with significantly decreased risk of death (HR 0.779, 95% CI 0.631-0.963, p=0.021).
Conclusions: Treatment of adrenocortical carcinoma at an academic center is associated with improved overall survival compared to community programs. There are significant differences in practice patterns, including more aggressive surgical treatment at academic facilities, but the survival benefit persists on multivariable analysis controlling for treatment modality. Further studies are needed to identify the most important predictors of survival in this at-risk population.
Abbreviations and Acronyms
ACC = adrenocortical carcinoma
CCP = Community Cancer Program
CCCP = Comprehensive Commu- nity Cancer Program
INCP = Integrated Network Cancer Program NCDB = National Cancer Database
OS = overall survival
Accepted for publication January 25, 2021.
* Correspondence: Department of Urology, Vanderbilt University Medical Center, A-1302 Medical Center North, Nashville, Tennessee 37232 (telephone: 615-343-1317; FAX: 615-322- 8990; email: kelvin.a.moses@vumc.org).
Editor’s Note: This article is the first of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtain- ing credits are given with the questions on pages 1074 and 1075.
Key Words: adrenal gland neoplasms, survival analysis, quality of health care, guideline adherence
ADRENOCORTICAL carcinoma (ACC) is a rare malignancy with an incidence of approximately 2 per million people, but is an aggressive disease with poor prognosis. While centralization of care-shifting of cancer treatment to high-volume referral centers with coordi- nated multidisciplinary expertise-has been shown to improve outcomes across
common urological malignancies,1 the same has not been demonstrated for ACC.
The survival benefit of centraliza- tion of care would be expected to be more pronounced for rare malig- nancies such as ACC, and guidelines for ACC recommend multidisciplinary management among specialized teams
with expertise in adrenal tumors.2 ACC is a surgical disease, and both the National Comprehensive Can- cer Network® (NCCN®) and the European Society of Endocrinology recommend open adrenalectomy and regional lymphadenectomy with en bloc resection of locally invasive disease, and cite an increased risk for local recurrence with laparoscopic adrenalectomy.2,3 While complete surgical resection is the mainstay of ACC treatment, the NCCN and European Society of Endocrinology also recommend consideration of adjuvant mitotane and external beam radiation therapy in high-risk disease.
The National Cancer Database (NCDB), with data from over 1,500 Commission on Cancer- accredited facilities across the United States, is an excellent resource for investigating rare malig- nancies. Further, the characterization of facilities at which patients receive care enables comparison of practice patterns and outcomes across practice set- tings. We hypothesized that in patients with ACC, adherence to guidelines and best practices would differ between types of treating facilities, and that there would be improved overall survival (OS) associated with care at academic centers.
METHODS
Cohort, Outcome and Variables
We identified all patients with ACC diagnosed at Com- mission on Cancer-accredited facilities from 2004-2016 using the International Classification of Disease for Oncology, Third Edition, Code 8370 and site-specific code C74. Our primary outcome was OS. Demographic vari- ables included age, race, gender, insurance status, and metropolitan/urban/rural residence. The proportion of adults in the patient’s home ZIP code without a high school education was obtained from the American Com- munity Survey. Median household income from the pa- tient’s home ZIP code was similarly obtained. Distance to hospital was reported as the distance in miles from the patient’s residence to the reporting hospital. Charlson/ Deyo score was calculated based upon ICD-9-CM diag- nosis codes, and reported as 0, 1, or >2. Oncologic data included tumor size, tumor extension (localized, invasive into adjacent connective tissue/Gerota’s fascia, invasive into adjacent organs) and presence of metastatic disease; clinical/pathological nodal staging was not included due to missing data in over 40% of patients. Treatment data included performance of regional lymphadenectomy, type of surgery (ablation, partial adrenalectomy, adrenalec- tomy, radical surgery including en bloc resection of adja- cent organs), surgical approach (laparoscopic/robotic versus open), administration of radiation therapy, and administration of systemic therapy.
Reporting facilities were designated as Community Cancer Program (CCP), Comprehensive Community Cancer Program (CCCP), Academic/Research Program (which includes National Cancer Institute-designated comprehensive cancer centers), and Integrated Network Cancer Program (INCP). CCPs report 100-500 newly
diagnosed cancer cases per year. CCCPs report ≥500 newly diagnosed cancer cases per year. Academic pro- grams report ≥500 newly diagnosed cancer cases per year and participate in multidisciplinary postgraduate medical education. INCPs do not have a minimum caseload requirement but own or operate a multi-facility network which provides integrated cancer care and comprehensive services with a unified cancer committee. To qualify for INCP status, at least 1 facility in the INCP group must be a hospital-based Commission on Cancer-accredited cancer program and they typically participate in cancer-related clinical research, though participation in graduate medi- cal education is optional. For patients receiving treatment at more than one facility, the NCDB uses the best report based upon completeness of coding and recency of patient contact; the final report includes the cumulative treat- ments administered by any facility.
Analysis
OS for the entire cohort, stratified by facility type, was calculated using the Kaplan-Meier method with log-rank test used for comparisons between groups. Pairwise comparisons were further made to distinguish between each survival curve. We used a chi-square test of inde- pendence to analyze the differences in practice patterns across types of facilities including administration of chemotherapy, administration of radiation, type of sur- gery, surgical approach (laparoscopic/robotic versus open), surgical margin status, and regional lymph node dissection. We performed multivariable Cox regression analysis to investigate independent predictors of OS. The model included age, race, gender, insurance status, edu- cation, ZIP-code based median income, metropolitan/ urban/rural residence, facility type, Charlson/Deyo score, distance to hospital, tumor size, tumor extension, metastatic disease, performance of lymph node dissection, surgery, radiation treatment, and treatment with sys- temic therapy. Surgical approach (laparoscopic/robotic versus open) was not included in this model due to missing data in 42% of the cohort. Missing data were excluded listwise. Multicollinearity was tested using variance inflation factors. This study received institu- tional review board approval (IRB No. 200030). Analyses were performed using SPSS version 20.0.
RESULTS
There were 3,476 patients diagnosed with ACC in centers reporting to the NCDB from 2004 to 2016; 585 had missing data on facility type and were excluded from analysis, and we further excluded 5 patients coded as clinical T0, leaving 2,886 patients in the analytical cohort. Treatment was received at more than 1 facility in 14.2% of patients. Table 1 shows the baseline demographic and oncologic data across facility types. Patients treated at aca- demic centers were younger, more racially diverse, and had higher rates of private insurance; patients treated at academic centers also presented with larger tumors and had lower rates of clinically localized disease.
| Community | CCCP | Academic | INCP | Total | p Value | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| No. | 166 | 904 | 1,475 | 341 | 2,886 | ||||||
| Median age (IQR) | 63 | (51-71) | 60 | (51-70) | 57 | (50-66) | 61 | (51-71) | 59 | (50-68) | <0.001 |
| No. race (%): | 0.001 | ||||||||||
| White | 146 | (88.0) | 813 | (89.9) | 1,229 | (83.3) | 292 | (85.6) | 2,480 | (85.9) | |
| Black | 11 | (6.6) | 65 | (7.2) | 158 | (10.7) | 37 | (10.9) | 271 | (9.4) | |
| Asian/Pacific Islander | 4 | (2.4) | 17 | (1.9) | 45 | (3.1) | 5 | (1.5) | 71 | (2.5) | |
| Other/unknown | 5 | (3.0) | 9 | (1.0) | 43 | (2.9) | 7 | (2.1) | 64 | (2.2) | |
| Hispanic ethnicity | 12 | (7.9) | 44 | (5.3) | 99 | (7.0) | 19 | (5.9) | 174 | (6.4) | 0.36 |
| No. gender (%): | 0.83 | ||||||||||
| Male | 66 | (39.8) | 385 | (42.6) | 615 | (41.7) | 137 | (40.2) | 1,203 | (41.7) | |
| Female | 100 | (60.2) | 519 | (57.4) | 860 | (58.3) | 204 | (59.8) | 1,683 | (58.3) | |
| No. insurance status (%): | <0.001 | ||||||||||
| Uninsured | 7 | (4.2) | 42 | (4.6) | 56 | (3.8) | 13 | (3.8) | 118 | (4.1) | |
| Private | 63 | (38.0) | 440 | (48.7) | 788 | (53.4) | 174 | (51.0) | 1,465 | (50.8) | |
| Medicaid | 10 | (6.0) | 44 | (4.9) | 88 | (6.0) | 18 | (5.3) | 160 | (5.5) | |
| Medicare | 78 | (47.0) | 347 | (38.4) | 439 | (29.8) | 133 | (5.3) | 997 | (34.5) | |
| Other government | 6 | (3.6) | 11 | (1.2) | 27 | (1.8) | 0 (0) | 44 | (1.5) | ||
| Unknown | 2 | (1.2) | 20 | (2.2) | 77 | (5.2) | 3 | (0.9) | 102 | (3.5) | |
| No. urban/rural (%): | <0.001 | ||||||||||
| Metropolitan | 117 | (70.5) | 720 | (79.6) | 1,192 | (80.8) | 286 | (83.9) | 2,315 | (80.2) | |
| Urban | 39 | (23.5) | 135 | (14.9) | 232 | (15.7) | 35 | (10.3) | 441 | (15.3) | |
| Rural | 4 | (2.4) | 29 | (3.2) | 22 | (1.5) | 4 | (1.2) | 59 | (2.0) | |
| Unknown | 6 | (3.6) | 20 | (2.2) | 29 | (2.0) | 16 | (4.7) | 71 | (2.5) | |
| No. Charlson/Deyo score (%): | |||||||||||
| 0 | 124 | (74.7) | 613 | (67.8) | 1,090 | (73.9) | 249 | (73.0) | 2,076 | (71.9) | 0.190 |
| 1 | 31 | (18.7) | 210 | (23.2) | 274 | (18.6) | 66 | (19.4) | 581 | (20.1) | |
| 2 | 7 | (4.2) | 56 | (6.2) | 79 | (5.4) | 16 | (4.7) | 158 | (5.5) | |
| ≥3 | 4 | (2.4) | 25 | (2.8) | 32 | (2.2) | 10 | (2.9) | 71 | (2.5) | |
| Median miles distance to hospital (IQR) | 6.7 | (2.2-15.5) | 8.9 | (4.1-21.4) | 21.8 | (8.1-57.0) | 8.3 | (4.0-20.6) | 13.2 | (5.4-36.8) | <0.001 |
| Median mm tumor size (IQR) | 100 | (66-144) | 97 | (65-135) | 105 | (72-149) | 100 | (70-130) | 100 | (70-140) | 0.006 |
| No. tumor extension (%): | <0.001 | ||||||||||
| Localized | 72 | (43.4) | 405 | (44.8) | 619 | (42.0) | 165 | (48.4) | 1,261 | (43.7) | |
| Adjacent tissue, Gerota's fascia | 20 | (12.0) | 133 | (14.7) | 312 | (21.2) | 53 | (15.5) | 518 | (17.9) | |
| Adjacent organs | 40 | (24.1) | 190 | (21.0) | 338 | (22.9) | 69 | (20.2) | 637 | (22.1) | |
| Unknown | 34 | (20.5) | 176 | (19.5) | 206 | (14.0) | 54 | (15.8) | 470 | (16.3) | |
| No. metastases (%): | 0.001 | ||||||||||
| M0 | 79 | (47.6) | 485 | (53.7) | 902 | (61.2) | 206 | (60.4) | 1,672 | (57.9) | |
| M1 | 59 | (35.5) | 307 | (34.0) | 414 | (28.1) | 104 | (30.5) | 884 | (30.6) | |
| Unknown | 28 | (16.9) | 112 | (12.4) | 159 | (10.8) | 31 | (9.1) | 330 | (11.4) | |
There were 1,785 all-cause deaths, and median OS was 21.8 months (95% CI 19.8-23.8 months). There was a significant difference in unadjusted OS based upon type of treating facility, as shown in the figure (log-rank p=0.024). The 3-year OS estimates for CCP, CCCP, academic, and INCP facilities were 37%, 37%, 41%, and 42%, respectively. Using pair- wise comparisons, academic centers had a statisti- cally significant survival benefit over both CCPs and CCCPs (median OS 23.3 months vs. 15.8 months, p=0.023 and 23.3 months vs. 18.8 months, p=0.012, respectively). No other pairwise compari- sons were statistically significant.
We evaluated trends in practice patterns across facility types that may, in part, explain the unad- justed differences in OS. These results are shown in table 2. Academic centers performed adrenalectomy or radical surgery in 70% of patients compared to 53% and 61% at CCPs and CCCPs, respectively (p <0.001). Among patients who underwent surgery, open surgery was performed in 61.4% of patients at academic centers compared to 44% and 50% at CCPs and CCCPs, respectively (p <0.001).
Academic centers and CCCPs were associated with the lowest rates of positive surgical margins, 19.1% and 18.2%, respectively, versus 21.7% at CCPs and 20.3% at INCPs (p=0.03). Academic centers and CCPs had the greatest frequency of regional lym- phadenectomy (p <0.001), though this was only performed in 26.1% and 30.4% of patients at these facilities, respectively. Academic centers were associated with a significantly greater frequency of systemic therapy (p <0.001), administered in 40.1% of patients versus 30.7% at community centers. Of note, only 3.9% of patients in this cohort were re- ported to have not received chemotherapy due to patient risk factors or contraindications.
Multivariable Cox regression analysis was per- formed to determine independent predictors of OS (table 3). Variance inflation factors for covariates in the model ranged from 1.0-1.9, indicating absence of significant multicollinearity. Treatment at an aca- demic facility was associated with a 22% reduction in hazard of death compared to treatment at a com- munity program (HR 0.779, 95% CI 0.631-0.963) even when controlling for treatment modality
Overall Survival, All Patients with Adrenocortical Carcinoma
1.0-
log rank=0.024
Facility Type
Community Cancer Program
Comprehensive
Community Cancer
Program
0.8
Academic/Research
Program
Probability of Survival
Integrated Network Cancer Program
0.6
0.4
0.2
0.0-
.00
50.00
100.00
150.00
200.00
Time Since Diagnosis (months)
Community
151
39
15
1
Comprehensive Community
825
176
63
7
Academic
1349
324
102
6
Integrated Network
316
85
22
3
Numbers at risk
including type of surgery and receipt of systemic therapy or radiation. Other significant independent predictors of OS included younger age, nonMedicaid insurance status, lower Charlson/Deyo score, lower stage disease, and receipt of surgery or systemic therapy. We performed a subgroup analysis for the cohort diagnosed from 2004 to 2009 (1,181) and for the cohort diagnosed from 2010 to 2016 (1,705). There was no survival benefit associated with treatment at aca- demic centers from 2004 to 2009 (HR 0.970, 95% CI 0.715-1.315; supplementary table 1, https://www. jurology.com). From 2010 to 2016, treatment at an academic facility was associated with a 30% reduction
in hazard of death compared to treatment at a com- munity program (HR 0.701, 95% CI 0.516-0.951; supplementary table 2, https://www.jurology.com). Practice patterns over these time periods are shown in supplementary table 3 (https://www.jurology.com).
DISCUSSION
ACC is a rare, aggressive malignancy with a scar- city of literature regarding clinical outcomes. In this study we found improved OS associated with centralization of care to academic centers compared with community programs, particularly for patients diagnosed from 2010 to 2016. There were significant
| Community (%) | CCCP (%) | Academic (%) | INCP (%) | p Value | |
|---|---|---|---|---|---|
| Systemic therapy | 30.7 | 34.6 | 40.1 | 34.3 | <0.001 |
| Adjuvant systemic therapy | 13.6 | 20.2 | 28.8 | 23.9 | <0.001 |
| Radiation | 15.1 | 14.7 | 14.7 | 18.2 | 0.046 |
| Adjuvant radiation | 10.8 | 10.6 | 11.5 | 13.8 | 0.507 |
| Surgery: | <0.001 | ||||
| Ablation | 0.6 | 0.1 | 0.1 | 0.3 | |
| Partial adrenalectomy | 2.4 | 3.2 | 3.5 | 4.1 | |
| Adrenalectomy | 40.4 | 50.2 | 54.7 | 55.1 | |
| Radical surgery | 12.7 | 11.1 | 15.5 | 8.8 | |
| Open surgery* | 43.8 | 49.7 | 61.4 | 50.0 | <0.001 |
| Pos surgical margins* | 21.7 | 18.2 | 19.1 | 20.3 | 0.032 |
| Lymph node dissection* | 30.4 | 16.8 | 26.1 | 17.2 | <0.001 |
* Among patients undergoing partial adrenalectomy, adrenalectomy or radical surgery (1,993).
| HR (95% CI) | p Value | |
|---|---|---|
| Age | 1.018 (1.013-1.024) | <0.001 |
| Race: | ||
| White | Reference | |
| Black | 1.018 (0.855-1.213) | 0.839 |
| Asian/Pacific Islander | 0.590 (0.414-0.840) | 0.003 |
| Other/unknown | 1.277 (0.857-1.904) | 0.230 |
| Hispanic ethnicity | 1.097 (0.885-1.359) | 0.400 |
| Gender: | ||
| Male | Reference | |
| Female | 0.940 (0.851-1.038) | 0.224 |
| Insurance status: | ||
| Uninsured | Reference | |
| Private insurance | 1.077 (0.831-1.395) | 0.575 |
| Medicaid | 1.389 (1.019-1.916) | 0.038 |
| Medicare | 1.178 (0.891-1.558) | 0.249 |
| Other government | 1.214 (0.743-1.983) | 0.438 |
| Education, % without high school degree: | ||
| ≥21 | Reference | |
| 13.0-20.9 | 0.885 (0.751-1.043) | 0.146 |
| 7.0-12.9 | 0.871 (0.730-1.040) | 0.128 |
| <7.0 | 0.875 (0.711-1.076) | 0.206 |
| Median $ income: | ||
| <38,000 | Reference | |
| 38,000-47,999 | 1.049 (0.884-1.245) | 0.584 |
| 48,000-62,999 | 1.126 (0.939-1.351) | 0.201 |
| ≥63,000 | 1.038 (0.843-1.277) | 0.726 |
| Urban/rural residence: | ||
| Metropolitan | Reference | |
| Urban | 0.920 (0.790-1.071) | 0.282 |
| Rural | 0.868 (0.602-1.250) | 0.446 |
| Facility type: | ||
| Community | Reference | |
| Comprehensive Community | 0.825 (0.664-1.025) | 0.083 |
| Academic | 0.779 (0.631-0.963) | 0.021 |
| Integrated Network | 0.822 (0.643-1.050) | 0.117 |
| Charlson/Deyo Score: | ||
| 0 | Reference | |
| 1 | 1.326 (1.172-1.500) | <0.001 |
| 2 | 1.562 (1.277-1.910) | <0.001 |
| ≥3 | 1.833 (1.358-2.472) | <0.001 |
| Distance to hospital | 1.000 (1.000-1.000) | 0.764 |
| Tumor size | 1.000 (1.000-1.000) | 0.405 |
| Tumor extension: | ||
| Localized | Reference | |
| Adjacent tissue, Gerota's fascia | 1.561 (1.359-1.795) | <0.001 |
| Adjacent organs | 1.540 (1.350-1.758) | <0.001 |
| Metastases: | ||
| M0 | Reference | |
| M1 | 2.743 (2.393-3.144) | <0.001 |
| Lymph node dissection | 1.030 (0.885-1.199) | 0.705 |
| Surgery: | ||
| None | Reference | |
| Ablation | 0.263 (0.036-1.890) | 0.184 |
| Partial adrenalectomy | 0.337 (0.247-0.460) | <0.001 |
| Adrenalectomy | 0.386 (0.331-0.451) | <0.001 |
| Radical surgery | 0.432 (0.357-0.524) | <0.001 |
| Radiation | 1.023 (0.887-1.179) | 0.759 |
| Systemic therapy | 0.823 (0.733-0.924) | 0.001 |
differences between facility types regarding practice patterns including aggressiveness of surgical man- agement, rate of positive surgical margins, and provision of systemic therapy that may in part explain these differences. Importantly, on multi- variable analysis controlling for treatment modal- ity, there remained a significant survival benefit associated with academic centers, which may indi- cate other important benefits of provision of care at
these centers beyond the observed differences in practice patterns.
Our results are largely in line with previously published single-center series and population-based analyses regarding outcomes of ACC.4-6 Tella et al previously evaluated survival for patients with ACC in the NCDB and found that surgical treatment was associated with improved OS and that adjuvant systemic therapy and radiation were associated with improved survival in advanced disease.7 This study did not investigate differences in survival based on the type of treating facility. A prior anal- ysis using the NCDB for patients diagnosed with ACC from 1998-2011 compared OS between high- volume centers (>4 cases annually, 90th percen- tile) and low-volume centers and, similar to our results, found more aggressive surgical and adju- vant treatment at high-volume centers.5 However, this study found no corresponding significant dif- ference in OS between high-volume and low-volume centers and did not distinguish between academic and community programs. Our contrasting results suggest that the multidisciplinary infrastructure of academic centers, as opposed to the individual hos- pital’s case volume, may be driving the associated improvement in OS. Similar trends have been shown in the Netherlands in a study by Kerkhofs et al demonstrating improved survival among pa- tients managed at multidisciplinary Dutch Adrenal Network hospitals versus nonDutch Adrenal Network hospitals.8 Within the United States, Grubbs et al evaluated 218 patients with ACC managed at MD Anderson Cancer Center and found that those who underwent surgery at the index institution had significantly greater OS compared to those resected at outside institutions and subse- quently referred for additional management; in addition, the patients undergoing surgical resection at this tertiary referral center had higher rates of radical surgery, lower rates of positive margins, and lower risk of recurrence.º Our study adds to the growing literature on the importance of centralizing care for ACC with a nationwide administrative data analysis similarly demon- strating the importance of initial referral to aca- demic centers capable of achieving an R0 resection and performing complex multidisciplinary management.
Our subgroup analysis based upon year of diag- nosis revealed that the survival benefit associated with centralization of care to academic centers was driven by patients diagnosed from 2010-2016. Interestingly, there was no significant survival benefit associated with systemic therapy before 2010. While the differences in survival over time are likely multifactorial, this change corresponds to emerging research on the use of mitotane,
particularly in the adjuvant setting,10 and corre- sponding increases in the use of adjuvant systemic therapy from 19.7% of patients from 2004-2009 to 27.0% of patients from 2010-2016. These data suggest that as more nuanced multidisciplinary treatment has become the standard of care for pa- tient with ACC, the benefit of centralization of care has become more pronounced.
Prior studies have evaluated the impact of centralization of care in other urological malig- nancies. Treatment at high-volume centers has been associated with improved survival and clinical outcomes in bladder, prostate, penile, and testicular cancer,1,11 though it should be noted that these studies defined centralized care based only on hos- pital volume without evaluating the importance of multidisciplinary expertise or the presence of post- graduate medical training. In nonmuscle invasive bladder cancer, care at academic centers and private/Medicare insurance have been shown to be associated with guideline-based care.12 A recent study using the NCDB also showed that treatment at academic centers is associated with improved OS in primary urethral cancer.13 The present study adds to this growing base of literature in demon- strating a survival benefit associated with care at academic centers for patients with ACC.
This study must be interpreted in light of several important limitations. First, the study is retro- spective in nature and is subject to limitations inherent to the NCDB, including missing data, possible coding errors, and a lack of central patho- logical review. Though reports to the NCDB are meant to include all cumulative treatment across
facilities, it is possible that further treatment may have been received at a nonCommission on Cancer facility, which would not be captured; to our knowledge, only 14% received care at multiple fa- cilities. Further, the NCDB does not include gran- ular detail on case complexity, and since more complex cases are likely referred to high-volume academic centers, the actual survival benefits may be underestimated in this analysis. While we are able to discern how many patients received systemic therapy, we are unable to determine the type of systemic therapy given so cannot differentiate mitotane from cytotoxic chemotherapy or differen- tiate between treatment regimens or number of cy- cles. We are additionally unable to report recurrence rates or disease-specific survival due to inherent limitations of the NCDB data set, instead reporting OS though we are importantly able to adjust for age and medical comorbidities.
CONCLUSIONS
In patients with ACC, treatment at an academic facility is associated with greater OS. There are significant differences in management between practice settings, including provision of multimodal treatment and aggressiveness of surgical resection. However, the survival differences persist on multi- variable analysis even when controlling for treat- ment modality, indicating unmeasured benefits associated with provision of care at these in- stitutions. Further studies are needed to elucidate the primary drivers of survival in this patient population.
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