Online version at https://www.minervamedica.it
ORIGINAL ARTICLE
Regional differences in stage distribution and rates of treatment for adrenocortical carcinoma across United States SEER registries
Andrea PANUNZIO 1, 2 *, Stefano TAPPERO 2, 3, 4, Mattia PICCINELLI 2, 5, Cristina CANO GARCIA 2, 6, Francesco BARLETTA 2, 7, Reha-Baris INCESU 2, 8, Kyle W. LAW 2, Zhe TIAN 2, Alessandro TAFURI 1, Fred SAAD 2, Shahrokh F. SHARIAT 9, 10, 11, 12, Derya TILKI 8, 13, 14, Alberto BRIGANTI 7, Felix K. CHUN 6, Ottavio DE COBELLI 5, Carlo TERRONE 3, 4, Isabelle BOURDEAU 15, Maria A. CERRUTO 1, Alessandro ANTONELLI 1, Pierre I. KARAKIEWICZ 2
1Department of Urology, University Hospital of Verona, Verona, Italy; 2Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Canada; 3Department of Surgical and Diagnostic Integrated Sciences (DISC), University of Genoa, Genoa, Italy; 4Department of Urology, IRCCS San Martino Polyclinic Hospital, Genoa, Italy; 5Department of Urology, IEO European Institute of Oncology IRCCS, Milan, Italy; 6Department of Urology, University Hospital Frankfurt, Frankfurt am Main, Germany; 7Department of Urology and Division of Experimental Oncology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy; 8Martini-Klinik Prostate Cancer Center, University Hospital of Hamburg-Eppendorf, Hamburg, Germany; 9Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; 10Department of Urology, Weill Cornell Medical College, New York, NY, USA; 11Department of Urology, University of Texas Southwestern, Dallas, TX, USA; 12Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, Jordan; 13Department of Urology, University Hospital of Hamburg- Eppendorf, Hamburg, Germany; 14Department of Urology, Koc University Hospital, Istanbul, Türkiye; 15Division of Endocrinology, Department of Medicine and Research Center, Centre Hospitalier de l’Université de Montreal (CHUM), Montreal, Canada
*Corresponding author: Andrea Panunzio, Department of Urology, University Hospital of Verona, piazzale A. Stefani 1, 37126 Ve- rona, Italy. E-mail: panunzioandrea@virgilio.it
ABSTRACT
BACKGROUND: We tested for regional differences across United States (US) in rates of adrenalectomy, systemic thera- py, and adrenalectomy and systemic therapy combination for adrenocortical carcinoma (ACC) patients. We hypothesized that no differences exist, especially after accounting for baseline patient and tumor characteristics.
METHODS: Within Surveillance, Epidemiology, and End Results (SEER) database (2004-2018), 1275 ACC patients were identified. Distribution of patient age, tumor size, ENSAT (European Network for the Study of Adrenal Tumors) stages, and treatments were tabulated and graphically displayed, according to nine geographical registries, corresponding to the population of specific states, cities or macro areas of the US on which the data are based on. Multinomial models predicted treatment probability for each patient according to registries.
RESULTS: Patients count according to registries ranged from 62 to 509. Differences across registries existed for age (range 54-59 years; P=0.4), tumor size (8.5-11.0 cm; P=0.2), ENSAT stage (1-11% vs. 17-35% vs. 18-32% vs. 24-44%, in respectively ENSAT stage I, II, III, and IV), and treatment distribution (35-53% vs. 5-21% vs. 23-42%, in respectively adrenalectomy, systemic therapy, and adrenalectomy and systemic therapy combination; P=0.039). After adjustment for age, stage and year of diagnosis, clinically meaningful residual differences across registries remained for adrenalectomy (33-54%), systemic therapy (4-19%), and adrenalectomy and systemic therapy combination (20-38%). However, most variability originated from registries with smallest sample sizes.
CONCLUSIONS: We identified important variability in ACC treatment according to SEER geographical registries, even
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REGIONAL DIFFERENCES IN ACC TREATMENT
after considering baseline patient and tumor characteristics. These findings may be indicative of differences in quality of care or expertise in ACC management.
(Cite this article as: Panunzio A, Tappero S, Piccinelli M, Cano Garcia C, Barletta F, Incesu RB, et al. Regional differences in stage distribution and rates of treatment for adrenocortical carcinoma across United States SEER registries. Minerva Urol Nephrol 2023;75:443-51. DOI: 10.23736/S2724-6051.23.05342-9)
KEY WORDS: Adrenalectomy; United States; Therapeutics.
A drenocortical carcinoma (ACC) is a rare and aggressive malignancy, with a high rate of recurrence and a dismal prognosis.1-4 Ac- cording to stage at presentation, treatment may consist of adrenalectomy, systemic therapy, or combination of both.5-9 Currently, international ACC guidelines recommend a multidisciplinary approach, and treatment at referral centers.10 In- deed, in primaries other than ACC, centraliza- tion of care to high-volume centers is associated with better cancer control outcomes.11-16 This concept was validated among several genitouri- nary primaries, including bladder,12 prostate, 13 and testicular cancer.14 However, it received little attention in ACC.
Recently, a large population-based study, re- lying on National Cancer Database (NCDB), showed that ACC patients treated at academic centers exhibited lower overall mortality than their counterparts treated at community hospi- tals, due to existing differences in practice pat- terns between the two institution types.17 We revisited this topic and postulated that it is also possible that differences in selected treatment type may also depend on geography: specifical- ly, in some regions combination of adrenalec- tomy and systemic therapy may be used more frequently than single treatment options and vice versa; such phenomenon may be related to different stage distribution across the coun- try or may be even indicative of differences in quality of care or expertise in ACC manage- ment.
The Surveillance, Epidemiology, and End Re- sults (SEER) database (2004-2018) is divided into 13 different geographical registries cor- responding to the population of specific states, cities or macro areas of the United States (US) on which the data are based on. In the present study we tested for differences in rates of adre- nalectomy only, systemic therapy only, and ad-
renalectomy and systemic therapy combination, according to SEER geographical registries. We hypothesized that no interregional differences exist in patient and tumor characteristics or treat- ment rates, either in unadjusted or case mix ad- justed analyses.
Materials and methods
Study population
The SEER database samples 48% of the US and approximates the US in terms of its demo- graphic composition, as well as its cancer inci- dence.18 Within the SEER database (2004-2018), we identified patients aged >18 years with his- tologically confirmed ACC (International Clas- sification of Disease for Oncology [ICD-O-3] site code C74.0/C74.9; histologic code: “8370/3: Adrenal cortical carcinoma”, “8010/3: Carci- noma, NOS”, and “8140/3: Adenocarcinoma, NOS”). Cases identified only at autopsy (N .= 2), or without information on T, N, and M stages (N .= 5), as well as patients with unknown treat- ment (N .= 11) were excluded. Due to limited sample size (N .< 50) that prevented us in report- ing data from five registries, these registries were grouped and analyzed as one. Additionally, in accordance with the SEER data agreements and limitations, 18 names of individual registries were censored. These selection criteria resulted in an overall cohort of 1275 assessable patients within nine SEER registries, renamed from SEER Reg- istry 1 to SEER Registry 9 in ascending order of patients count.
Statistical analysis
Descriptive statistics included frequencies and proportions for categorical variables. Medians and interquartile ranges (IQR) were reported for continuously coded variables. Statistical
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to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access
REGIONAL DIFFERENCES IN ACC TREATMENT
analyses relied on two steps. First, baseline patient and ACC characteristics namely 1) age at initial diagnosis; 2) primary tumor size; 3) ENSAT (European Network for the Study of Adrenal Tumors19) stage groupings (I vs. II vs. III vs. IV vs. unknown); and 4) treatment types (adrenalectomy only vs. systemic therapy only vs. adrenalectomy and systemic therapy com- bination) were tabulated and graphically dis- played according to the above defined SEER registries. The Kruskall-Wallis Rank Sum Test, and the Pearson’s x2 test examined the statisti- cal significance of differences in medians and proportions distribution according to registries, respectively.
Second, we repeated the analyses for types and rates of treatment after multivariable adjust- ment for age at initial diagnosis, ENSAT stage, and year of diagnosis coded as a continuous vari- able, in a multinomial model.20 Here, a predicted treatment probability was calculated for each pa- tient. Afterwards, treatment probabilities of each patient were averaged for each treatment type in the separate SEER registries. All tests were two sided with a level of significance set at P<0.05 and R software environment for statistical com- puting and graphics (version 4.1.2, R foundation for Statistical Computing, Vienna, Austria) was used for all analyses.21
Results
Differences in patient and tumor characteristics, across SEER registries
Demographics, tumor features, and distribu- tion of treatment types for the overall cohort of 1275 ACC patients are listed in Table I. In five of thirteen registries, patient count (N .= 2, N .= 15, N .= 27, N .= 32, and N .= 50) was too low to in- dividually analyze each registries data. These five registries were combined into a single pa- tient group (N .= 126), which was renamed SEER Registry 6, based on ascending order of patient count. The remaining eight SEER registries ex- hibited individual patient counts that ranged from 62 (4.9%) in SEER Registry 1 to 509 (39.9%) in SEER Registry 9 (Figure 1).
Median age at initial diagnosis ranged from 54 (IQR 43-62) years in SEER Registry 5 to 59
| Characteristic | Overall ACC population N .= 1275* |
|---|---|
| Age at diagnosis (years) | 56 (45, 66) |
| Sex | |
| Female | 774 (61%) |
| Male | 501 (39%) |
| Primary tumor size (cm) ** | 10.5 (7.5, 14.5) |
| ENSAT stage | |
| Stage I | 53 (4%) |
| Stage II | 365 (29%) |
| Stage III | 303 (24%) |
| Stage IV | 483 (38%) |
| Stage unknown | 71 (5%) |
| Treatment type | |
| Adrenalectomy only | 556 (44%) |
| Adrenalectomy+systemic therapy | 372 (29%) |
| Systemic therapy only | 178 (14%) |
| None/other treatment | 169 (13%) |
ENSAT: European Network for the Study of Adrenal Tumor. *Median (IQR); N. (%); ** available for 1145 patients.
(IQR 47 - 68) years in SEER Registry 1 (P=0.4; Figure 2A). Female proportion ranged from 52% in SEER Registry 3 to 65% in SEER Registry 5 (P=0.7). Median primary tumor size ranged from 8.8 cm (IQR 6.9-13.1) in SEER Registry 1 to 11.0 cm (IQR 7.9-15) in SEER Registry 9 (Figure 2B; P=0.2). ENSAT stage proportions ranged from 1% (SEER Registry 6) to 11% (SEER Registry 4) for stage I, from 17% (SEER Registry 3) to 35% (SEER Registry 2) for stage II, from 18% (SEER Registry 8) to 32% (SEER Registries 3 and 4) for stage III, and from 24%
4.9%
4.9%
5.1%
SEER registries
5.2%
SEER registry 1 (N .= 62)
SEER registry 2 (N .= 63)
5.6%
39.9%
SEER registry 3 (N .= 65)
SEER registry 4 (N .= 66)
SEER registry 5 (N .= 72)
SEER registry 6 (N .= 126)
9.9%
SEER registry 7 (N .= 154)
SEER registry 8 (N .= 158)
SEER registry 9 (N .= 509)
12.1%
12.4%
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REGIONAL DIFFERENCES IN ACC TREATMENT
90 80 70 60 50 40 30 20 SEER (N .= 72) A 80 70 60 o 50 40 30 25 o 20 Primary tumor size (cm) Age at diagnosis 10 5 SEER B 100 4 11 75 29 50 32 25 Age at diagnosis 24 0 SEER C cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher. to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access 15 This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically (Ň .= 52)
Distribution of age at diagnosis in ACC patients according to SEER registries
P=0.4
0
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8
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Distribution of primary tumor size in ACC patients according to SEER registries
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ENSAT stage distribution in ACC patients according to SEER registries
4 6
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SEER registries
| SEER registry 5 (N .= 72) | 54 (43-62) |
| SEER registry 2 (N .= 63) | 56 (46-64) |
| SEER registry 3 (N .= 65) | 56 (45-62) |
| SEER registry 4 (N .= 66) | 56 (41-64) |
| SEER registry 8 (N .= 158) | 56 (49-65) |
| SEER registry 9 (N .= 509) | 56 (45-66) |
| SEER registry 7 (N .= 154) | 57 (46-67) |
| SEER registry 6 (N .= 126) | 58 (45-68) |
| SEER registry 1 (N .= 62) | 59 (47-68) |
| SEER registry 5 (N .= 72) | 8.8 (6.9-13.1) |
| SEER registry 4 (N .= 62) | 9.9 (6.9-15.0) |
| SEER registry 3 (N .= 58) | 10.0 (7.0-17.0) |
| SEER registry 5 (N .= 69) | 10.0 (7.6-13.0) |
| SEER registry 7 (N .= 142) | 10.0 (6.7-14.5) |
| SEER registry 8 (N .= 126) | 10.1 (7.1-14.0) |
| SEER registry 6 (N .= 113) | 10.7 (8.3-14.0) |
| SEER registry 2 (N .= 60) | 11.0 (7.4-14.3) |
| SEER registry 9 (N .= 465) | 11.0 (7.9-15.0) |
Figure 2 .- Box and whisker plots and stacked bar plots depicting (A) patient age at initial diagnosis, (B) primary tumor size (available for 1145 patients), and (C) ENSAT stage distribution in 1275 adrenocortical carcinoma (ACC) patients according to nine Surveillance, Epidemiology, and End Results (SEER) registries.
REGIONAL DIFFERENCES IN ACC TREATMENT
Rates of adrenalectomy only according to SEER registries
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(N .= 154)(N .= 158)(N .= 509) (N .= 65) (N .= 66) (N .= 63) (N .= 62) (N .= 126) (N .= 72)
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Rates of combination of adrenalectomy and systemic therapy according to SEER registries
Adjusted probability of combination of adrenalectomy and systemic therapy according to SEER registries
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(N .= 65) (N .= 72) (N .= 126)(N .= 154)(N .= 158)(N .= 509) (N .= 62) (N .= 66) (N .= 63)
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Rates (%) Rates (%) B C This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically Rates (%) to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
49 52 42 35 42 42 48 48 SEER SEER SEER SEER SEER SEER SEER SEER registry registry registry registry registry registry registry registry registry (N .= 62) (N .= 63) (N .= 72) (N .= 158) (N .= 509) (N .= 66) (N .= 126)(N .= 154) (N .= 65) 2 5 8 9 4 6 7 3 SEER registries 17 21 16 16 6 15 13 10 SEER SEER SEER SEER SEER SEER SEER SEER registry registry registry registry registry registry registry registry registry (N .= 65) (N .= 66) (N .= 154) (N .= 63) (N .= 509) (N .= 62) (N .= 158)(N .= 126) (N .= 72) 7 2 9 1 8 6 5 SEER registries 25 25 27 29 38 41 27 37 6 7 8 9 1 4 2 (N .= 65) (N .= 72) (N .= 126)(N .= 154)(N .= 158) (N .= 509) (N .= 62) (N .= 66) (N .= 63) SEER registries cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher. ER SEER SEER SEER SEER SEER SEER SEER SEER registry registry registry registry registry registry registry registry registry
100 75 50 25 35 0 SEER 1 A 100 75 50 25 0 5 SEER 3 4 100 75 50 25 23 0 SEER 3 or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access 5
(SEER Registry 4) to 44% (SEER Registry 5) for stage IV (Figure 2C).
Unadjusted and adjusted differences in treat- ment rates, across SEER registries
Rates of adrenalectomy only ranged from 35% in SEER Registries 1 and 2 to 52% in SEER Reg- istry 3 (Figure 3A). Rates of systemic therapy only ranged from 5% in SEER Registry 3 to 21% in SEER Registry 5 (Figure 3B). Rates of adre- nalectomy and systemic therapy combination ranged from 23% in SEER Registry 3 to 41% in SEER Registry 2 (Figure 3C; P=0.039).
After adjustment for age, ENSAT stage, and year of diagnosis, residual differences remained
for adrenalectomy only rates: 33-54%; systemic therapy only rates: 4 - 19%; and adrenalectomy and systemic therapy combination rates: 20-39% (Figure 3D-F).
In subgroup analyses focusing on smaller vs. larger SEER registries further differences were identified. Specifically, wider variability was re- corded in rates of adrenalectomy only (33-54%), systemic therapy only (4-19%), and adrenalecto- my and systemic therapy combination (20-39%) within smaller registries count (SEER Registry 1 to 6). Conversely, less pronounced variability was recorded in rates of adrenalectomy only (43- 46%), systemic therapy only (13-14%), and ad- renalectomy and systemic therapy combination
REGIONAL DIFFERENCES IN ACC TREATMENT
(26-30%) within larger registries count (SEER Registry 7 to 9, Figure 3G-I).
Discussion
Centralization of care to high-volume centers is associated with better perioperative and onco- logical outcomes in many urological and non- urological primaries.11 This concept received little if any attention in the ACC context. Based on extrapolation from primaries with higher incidence than ACC, international guidelines recommend ACC treatment at referral centers with high expertise in adrenal tumors.10 How- ever, those recommendations are based on very limited contemporary data. Due to absence of specific and large-scale analyses to support the importance of centralization of oncological care in ACC patients, we focused on this concept within the SEER database. We hypothesized that no regional differences exist in active treatment rates between geographical SEER registries. We further postulated that adjustment for baseline patient and tumor characteristics, as well as for year of diagnosis will obliterate any differences, if such differences were identified prior to such adjustment. Our analyses resulted in several noteworthy observations.
First, we observed important differences in patient numbers, as well as in baseline patients and tumor characteristics between SEER regis- tries. The most pronounced differences applied to interregional ENSAT stages proportion, where rates of stage I ranged from 1% to 11%, rates of stage II ranged from 17% to 35%, rates of stage III ranged from 18% to 32%, and rates of stage IV ranged from 24% to 44%. Besides ENSAT stage, the remaining differences in patients age, sex and primary tumor size were marginal and not statis- tically significant. Although none of these differ- ences exhibited statistical significance, important combined heterogeneity within the current cohort required multivariable adjustment as was done in the subsequent analytical steps. To the best of our knowledge, no previous investigators focused on regional differences in ACC patient and tumor characteristics. However, the same methodologi- cal approach was previously applied to patients with localized prostate cancer.22
Second, we also identified very important dif- ferences in rates of treatment, according to SEER registries. Adrenalectomy only rates ranged from 35% to 52%, systemic therapy only rates ranged from 5 to 21%, and adrenalectomy and systemic therapy combination rates ranged from 23% to 41%. All of these differences significantly ex- ceeded what would be expected by chance alone (P=0.039). These findings validated the objective and hypothesis of the current study and might be indicative of differences in expertise or quality of care in ACC patients, across SEER registries.
Third, based on these observations, we re- lied on multinomial regression analyses to test whether after adjustment for patient and tumor characteristics the variability in treatment rates persisted beyond what would be expected by chance alone. After multivariable adjustment for age, stage at presentation, and year of diagno- sis, differences in adrenalectomy only, systemic therapy only, and adrenalectomy and systemic therapy combination not only persisted but also maintained virtually the same magnitude: the absolute difference in adrenalectomy only rates was 21% after adjustments vs. 17% prior to ad- justments; the absolute difference in systemic therapy only rates was 15% after adjustments vs. 16% prior to adjustments; the absolute dif- ference in adrenalectomy and systemic therapy combination rates was 19% after adjustments vs. 18% prior to adjustments. In consequence, we rejected the initial hypothesis that no regional differences in treatment types and rates existed between the nine examined SEER registries in either unadjusted or adjusted analyses. The pres- ence and persistence of such differences may at- test to the variability in patients care that should ideally not exist, provided the use of standard- ized treatment decision making that is recom- mended by guidelines.
Finally, we relied on subgroup analyses to further examine treatment rates’ variability be- tween smaller vs. larger registries. Specifically, six registries (SEER Registry 1 to 6) were de- fined as smaller in size, based on patient counts that ranged between 2 and 72. Conversely, three registries (SEER Registry 7 to 9) were defined as larger in size, based on patient counts that ranged between 154 and 509. After adjustment,
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to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access
REGIONAL DIFFERENCES IN ACC TREATMENT
PANUNZIO
in smaller size registries, absolute differences in rates of adrenalectomy only, systemic therapy only, and adrenalectomy and systemic therapy combination were 21%, 15%, and 19%, respec- tively. Conversely, after adjustment, in larger size registries, absolute differences in rates of ad- renalectomy only, systemic therapy only, and ad- renalectomy and systemic therapy combination were 3%, 1%, and 4%, respectively. The drastic discrepancy between very pronounced variabil- ity recorded in smaller size registries, and very marginal if any variability recorded in larger size registries might supports the homogeneity in patients care in larger size registries relative to smaller ones regardless of age, stage, and year of diagnosis.
The results of the current study cannot be di- rectly compared to other analyses, since neither group of investigators specifically focused on regional differences in ACC management. How- ever, our findings complement, and strength the findings reported by previous studies, that ad- dressed the importance of centralization of care in ACC.17, 23-25 For example, Stone et al.17 within NCDB (2004-2016), identified a large cohort of ACC patients (N .= 2886) and demonstrated that differences in treatment existed across differ- ent type of facilities. Specifically, rates of open adrenalectomy and systemic therapy, either administered alone or in combination as a part of multimodal and more aggressive treatment protocols, were higher at academic/research cancer hospitals than at the community cancer counterparts. These differences also translated in a statistically significant survival advantage for ACC patients treated at academic centers, even after adjustment for baseline patients and tumor characteristics (Hazard Ratio [HR]: 0.78, P=0.021). Similarly, Hermsen et al.23 relied on a more historical (1965-2008) patient cohort (N .= 175), within a multi-institutional database, and showed that surgically treated patients oper- ated outside of ACC national hospitals network exhibited worse overall survival than those who underwent surgery at ACC referral centers (HR: 1.74, P=0.014). Additionally, the survival disad- vantage was more pronounced for patients with metastatic disease.
Taken together, the combined contribution of
the current study, as well as those of the other more historical reports, provide more robust jus- tifications and support for the recommendation of centralization of care in ACC.
Limitations of the study
Several limitations should be acknowledged. First, despite the large scale of the SEER data- base, a suboptimal low number of ACC individu- als were identified in the overall, as well as in reg- istry specific analyses. This limitation prevented us to describe baseline ACC characteristics and rates of treatment in registries with low obser- vation counts, and to further examine survival differences according to individual registries that would surely have been just as important. Second, the current SEER version provides sam- pling of patient from only 13 specific registries. This sample may not perfectly reflect the entire US population. Additionally, since the SEER da- tabase is designed with the intent of providing a representation of the US population, our findings cannot be applicable to patients from other coun- tries and should be ideally validated after adjust- ment for ACC characteristics using large-scale database in multi-collaborative studies even in other countries or macro areas. Third, limited detail regarding treatment type was available. Specifically, the SEER database does provide information on adrenalectomy, but not on surgi- cal approach or potential cytoreduction in more advanced disease stages. Similarly, the SEER database does provide information on systemic therapy. However, it does not have the granular- ity to allow the distinction between mitotane and cytotoxic systemic therapy and does not provide information on cycles number and duration of its administration. Fourth, multivariable adjustment relied only on clinically meaningful available variables. It is also possible, that other not avail- able variables, such as patient comorbidities, as well as other potentially prognostic factors such as mitotic index, venous invasion, and surgical margins status after adrenalectomy,26-28 or even patient will or denial, have influenced treat- ment decision making, translating in regional differences in treatment types and rates. These as other limitations related to the retrospective nature of the SEER, with potentially high selec-
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REGIONAL DIFFERENCES IN ACC TREATMENT
tion bias apply to the current study, as well as to other analyses based on similar large-scale data repositories.
Conclusions
In ACC, important differences may be identified in rates of adrenalectomy, systemic therapy, or adrenalectomy and systemic therapy combina- tion, within the examined SEER geographical registries. The observed differences are not virtu- ally entirely explained by differences in baseline patient and ACC characteristics. Additionally, most of the recorded geographical variability in treatment type and rates originated from regis- tries with the smallest sample size. These find- ings may be indicative of regional differences in quality of care or expertise in ACC management, corroborating the importance of centralization of care as recommended by ACC international guidelines.
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Conflicts of interest
The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manu- script.
Authors’ contributions
Andrea Panunzio and Pierre I. Karakiewicz contributed to the study conception and design; Andrea Panunzio, Stefano Tappero, Mat- tia Piccinelli, Cristina Cano Garcia, Francesco Barletta, Reha-Baris Incesu, and Kyle W. Law contributed to material preparation and data collection; formal analysis was performed by Andrea Panunzio and Zhe Tian; the first draft of the manuscript was written by Andrea Panunzio and all authors commented on previous versions of the manuscript; Alessandro Tafuri, Fred Saad, Shahrokh Shariat, Alberto Briganti, Derya Tilki, Ottavio De Cobelli, Felix K. Chun, Carlo Terrone, Isabelle Bourdeau, Maria A. Cerruto, Alessandro Antonelli and Pierre I. Karakiewicz provide critical revision of the manuscript for important intellectual content. All authors contrib- uted equally to the manuscript. All authors read and approved the final version of the manuscript.
Manuscript accepted: June 16, 2023. - Manuscript revised: May 16, 2023. - Manuscript received: March 10, 2023.
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