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Differences in life expectancy of adrenocortical carcinoma patients vs. age- and sex-matched population controls
Letizia Maria Ippolita Jannello 1,2,3 D · Andrea Baudo1,4 . Lukas Scheipner1,5 . Mario de Angelis1,6,7 . Carolin Siech 1,8 . Francesco Di Bello1,9 . Jordan A. Goyal1 . Kira Vitucci1,8 . Zhe Tian1 . Stefano Luzzago2,10 . Francesco A. Mistretta2,10. Matteo Ferro2,10 . Fred Saad1 . Felix K. H. Chun8 . Alberto Briganti6,7 . Luca Carmignani4,11 . Nicola Longo9 . Ottavio de Cobelli2,10 . Gennaro Musi2,10 . Pierre I. Karakiewicz1
Received: 31 May 2024 / Accepted: 6 August 2024 / Published online: 12 August 2024 @ The Author(s), under exclusive licence to Springer Nature B.V. 2024
Abstract
Purpose To quantify to what extent the 5-year overall survival (OS) of adrenocortical carcinoma (ACC) patients differs from age- and sex-matched population-based controls, especially when stage is considered.
Methods We relied on the Surveillance, Epidemiology, and End Results database (2004-2020) to identify newly diagnosed (2004-2014) ACC patients. Subsequently, we compared OS between ACC patients relative to simulated age- and sex-matched controls (Monte Carlo simulation), according to Social Security Administration Life Tables (2004-2020).
Results Of all 742 ACC patients, 301 (41%) harbored localized stage, 173 (23%) locally advanced stage, and 268 (36%) metastatic stage. At 5-years follow-up, ACC patients’ OS was 33%. After stratification for stage, the 5-years OS was 55 vs. 31 vs. 8% in localized, locally advanced, and metastatic stages, respectively. Conversely, after Monte Carlo simulation of age- and sex-matched controls, OS at five-years was 93% in the entire simulated cohort vs. 94% in the simulated localized cohort vs. 92 and 92% in locally advanced and metastatic stage, respectively. The resulting differences in OS between ACC patients and age- and sex-matched population-based controls were 60 vs. 39 vs. 61 vs. 84% respectively in the overall cohort vs. localized vs. locally advanced vs. metastatic stage.
Conclusion The most pronounced life expectancy detriment (84%) was recorded in metastatic ACC followed by locally advanced ACC patients (61%). Unfortunately, even in patients with localized ACC, life expectancy was 39% lower than that of the general population. Therefore, regardless of stage, ACC diagnosis results in a very pronounced detriment in life expectancy relative to the general population.
Keywords SEER . Social security administration · Adrenocortical carcinoma . Overall survival · Life tables
☒ Letizia Maria Ippolita Jannello
1 Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Centre, Montréal, Québec, Canada
2 Department of Urology, IEO European Institute of Oncology, IRCCS, Via Ripamonti 435, Milan, Italy
3 Università degli Studi di Milano, Milan, Italy
4 Department of Urology, IRCCS Policlinico San Donato, Milan, Italy
5 Department of Urology, Medical University of Graz, Graz, Austria
6 Vita-Salute San Raffaele University, Milan, Italy
7 Division of Experimental Oncology/Unit of Urology, URI; IRCCS Ospedale San Raffaele, Milan, Italy
8 Department of Urology, Goethe University Frankfurt, University Hospital, Frankfurt Am Main, Germany
9 Department of Neurosciences, Science of Reproduction and Odontostomatology, University of Naples Federico II, 80131 Naples, Italy
10 Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, Italy
11 Department of Urology, IRCCS Ospedale Galeazzi- Sant’Ambrogio, Milan, Italy
Introduction
Adrenocortical carcinoma (ACC) is known for its aggres- siveness and patients’ survival is usually poor, regardless of stage [1]. Despite generally well-known dismal sur- vival in ACC patients, specific analyses quantifying the effect of ACC diagnosis on life expectancy have not been reported. Consequently, to what extent ACC diagnosis may decrease life expectancy relative to age- and sex-matched population-based controls is unknown.
It is equally unknown whether the life expectancy detri- ments attributable to ACC vary in a stage-specific fashion, namely in localized vs. locally advanced vs. metastatic stage. We addressed this knowledge gap and hypothesized that important differences in life expectancy, expressed as overall survival (OS), may distinguish ACC patients from age- and sex-matched population-based controls after diagnosis of metastatic or locally advanced ACC. Conversely, we postulated that substantially smaller dif- ferences may be recorded in individuals with newly diag- nosed localized ACC.
To address these hypotheses, we tabulated five-year OS in ACC patients identified within the Surveillance Epide- miology and End Results (SEER) database from 2004 to 2014. Subsequently, we relied on a Monte Carlo simula- tion based on the United States Social Security Adminis- tration (SSA) Life Tables (2004-2020), which determined OS of age- and sex-matched population-based controls. Finally, we repeated all analyses according to ACC stages: localized vs. locally advanced vs. metastatic.
Materials and methods
Data source and study population
The SEER database (2004-2020) was used to identify newly diagnosed (2004-2014) and histopathologically confirmed ACC patients (site code C74.0/C74.9; histologic code: “8370/3: Adrenal cortical carcinoma,” “8010/3: Carcinoma, NOS,” and “8140/3: Adenocarcinoma of the adrenal, NOS”) aged ≥ 18 years across all stages [2]. Death certificates only or autopsy cases were excluded. Subse- quently, the survival of the controls was computed using a Monte Carlo simulation and a Markov chain of natural progression, according to SSA Life Tables’ derived prob- abilities of survival at five years of follow-up [3]. Here, for each ACC patient, we simulated age- and sex-marched controls in a one-to-one fashion, according to the previ- ously described methodology [4-8]. Thus five years OS estimates for each age- and sex-matched control were
derived and will hereafter be referred to as “population- based controls”. Since SEER is entirely anonymous, study- specific ethics approval was waived by the institutional review board [9, 10].
Descriptive statistics included frequencies and propor- tions for categorical variables. Kaplan-Meier plots graphi- cally depicted OS of ACC patients and corresponding popu- lation-based controls in a stage-specific fashion. All analyses were first applied to the overall population of ACC patients and subsequently repeated in localized ACC stage as well as locally advanced ACC stage, and finally in metastatic ACC stage. Ultimately, we performed subgroup analyses in young vs. old (≤55 vs.>55 years) ACC patients within each of the three stages as well as surgical performed vs. not performed in the metastatic ACC patients. All statistical tests were two-sided, with the level of significance set at p<0.05, and were performed with R Software Environment for Statistical Computing and Graphics (R version 4.1.3; R Foundation for Statistical Computing, Vienna, Austria) [11].
Results
Descriptive characteristics
Of 742 ACC patients, 301 (41%) harbored localized stage, 173 (23%) locally advanced stage, and 268 (36%) metastatic stage. In the overall cohort, the median age was 56 years (IQR 45-66 years) and the majority of patients were female (61%; Table 1).
Overall survival in all ACC patients vs population-based controls
The overall population median OS was 23 months and 33% of patients survived at five years of follow-up. After Monte Carlo simulation that relied on the SSA Life Tables’ derived estimates of population-based controls in a one-to-one fash- ion, the median survival was not reached and the simulated OS was 93% at five years. The difference in OS between ACC patients vs. simulated population-based controls was 60% at five years of follow-up (Fig. 1).
Overall survival in localized ACC patients vs. population-based controls
In localized ACC patients, median OS was not reached and 55% survived at five years of follow-up. After Monte Carlo simulation that relied on the SSA Life Tables’ derived esti- mates of population-based controls in a one-to-one fashion, the median survival was not reached and the simulated OS was 94% at five years. The difference in OS between ACC patients vs. simulated population-based controls was 39%
| Overall, (n=742) | Localized, (n=301; 41%) | Locally advanced, (n=173; 23%) | Metastatic, (n=268; 36%) | |
|---|---|---|---|---|
| Age at diagnosis, (years) | 56 (45-66) | 55 (44-66) | 57 (47-65) | 56 (45-65) |
| Sex, (female) | 451 (61%) | 193 (64%) | 102 (59%) | 156 (58%) |
| Surgery performed | 598 (81%) | 294 (98%) | 164 (95%) | 140 (52%) |
| Year of diagnosis | ||||
| 2004 | 42 (100%) | 17 (40%) | 10 (24%) | 15 (36%) |
| 2005 | 58 (100%) | 28 (48%) | 8 (14%) | 22 (38%) |
| 2006 | 64 (100%) | 21 (33%) | 22 (34%) | 21 (33%) |
| 2007 | 55 (100%) | 29 (53%) | 9 (16%) | 17 (31%) |
| 2008 | 75 (100%) | 32 (43%) | 20 (27%) | 23 (31%) |
| 2009 | 74 (100%) | 27 (36%) | 20 (27%) | 27 (36%) |
| 2010 | 84 (100%) | 34 (40%) | 24 (29%) | 26 (31%) |
| 2011 | 72 (100%) | 29 (40%) | 14 (19%) | 29 (40%) |
| 2012 | 74 (100%) | 28 (38%) | 17 (23%) | 29 (39%) |
| 2013 | 68 (100%) | 25 (37%) | 11 (16%) | 32 (47%) |
| 2014 | 76 (100%) | 31 (41%) | 18 (24%) | 27 (36%) |
Adrenocortical carcinoma patients - - Population-based controls
1.00
93%
Percentage Survival
0.75
abs ..= 56%
abs ..= 60%
0.50
Log-rank
40%
0.25
33%
p < 0.0001
0.00
0
12
24
36
48
60
Months
Number at risk
Adrenocortical carcinoma patients
742
470
358
296
255
235
Population-based controls
742
733
724
714
704
691
0
12
24
36
48
60
Months
at five years of follow-up (Fig. 2A). Subsequently, we per- formed subgroup analyses according to age (young vs. old). At five years of follow-up, OS differences between young localized ACC patients vs. population-based controls was
65 vs 94%; A =31% (Fig. 3A1). Conversely, at five years of follow-up, differences in OS between old localized ACC patients vs. population-based controls was 44 vs 86%; 4 =41% (Fig. 3A2).
(A)
(B)
(C)
Localized ACC - - Population-based controls
Locally advanced ACC - - Population-based controls
Metastatic ACC - - Population-based controls
1.00
94%
1.00
95%
92%
1.00
95%
92%
0.75
abs ..= 32%
0.75
0.75
Percentage Survival
abs ..= 39%
Percentage Survival
abs ..= 54%
Percentage Survival
63%
abs ..= 61%
0.50
55%-
abs ..= 81%
0.50
0.50
abs ..= 84%
40%
0.25
Log-rank
Log-rank p < 0.0001
0.25
31%
0.25
Logi-rank
p < 0.0001
p <0.0001
13%
0.00
0.00
0.00
8%
0
12
24
Months
36
48
60
0
12
24
Months
36
48
60
0
12
24
Months
36
48
60
Number at risk
Number at risk
Number at risk
Localized ACC
301
258
219
192
171
161
Locally advanced ACC 173
119
84
67
59
52
Metastatic ACC
268
93
55
37
25
22
Population-based control
301
298
293
287
286
283
Population-based controls
173
170
166
164
161
160
Population-based controls
268
265
261
254
249
247
0
12
24
Months
36
48
60
0
12
24
Months
38
48
60
0
12
24
Months
38
48
60
(A1)
(B1)
(C1)
- Young localized ACC - - Population-based controls
Young locally advanced ACC - - Population-based controls
- Young metastatic ACC - - Population-based controls
1.00
1.00
1.00
abs ..= 26%
abs ..= 31%
0.75
0.75
0.75
Percentage Survival
73%
Percentage Survival
abs ..= 52%
abs ..= 59%
Percentage Survival
65%
abs ..= 79%
0.50
0.50
0.50
abs ..= 83%
44%
Log-rank
Log-rank p < 0.0001
37%
0.25
Log-rank p < 0.0001
p < 0.0001
0.25
0.25
18%
13%
0.00
0.00
0.00
0
12
24
36
48
60
0
12
24
Months
Months
36
48
60
0
12
24
Months
36
48
60
Number at risk
Number at risk
Number at risk
Ybung localized ACC
156
145
129
114
106
98
Young locally advanced ACC
78
62
42
32
30
27
Young metastatic ACC
132
59
35
25
19
16
Population-based control
156
155
154
154
154
151
Population-based controls
78
76
76
75
75
75
Population-based controls
132
130
129
128
128
126
0
12
24
38
0
Months
48
60
12
24
Months
36
48
60
0
12
24
Months
38
48
60
(A2)
(B2)
(C2)
Old localized ACC - - Population-based controls
Old locally advanced ACC . - Population-based controls
Old metastatic ACC - - Population-based controls
1.00-
91%
1.00-
92%
1.00
86%
88%
88%
85%
0.75
abs ..= 38%
0.75
0.75
Percentage Survival
abs ..= 41%
Percentage Survival
abs ..= 54%
Percentage Survival
abs ..= 62%
0.50
53%
0.50
0.50
abs ..= 79%
abs ..= 81%
44%
37%
0.25
Log-rank
0.25
Log-rank
Lbg-rank
p < 0.0001
p < 0.0001
27%
0.25
0.0001
0.00
0.00
0.00
9%
0
12
24
Months
36
48
60
0
12
24
Months
36
48
60
0
12
24
Months
36
48
60
Number at risk
Number at risk
Number at risk
Old localized ACC
145
113
90
78
66
63
Old locally advanced ACC 95
57
42
36
29
25
Old metasitatie ACC
136
34
20
12
6
6
Population-based control
145
143
134
132
130
124
Population-based control
95
94
90
87
85
84
Population-based controls
136
130
124
120
116
116
0
12
24
Months
36
48
60
0
12
24
Months
36
48
60
0
12
24
Months
36
48
60
Overall survival in locally advanced ACC patients vs. population-based controls
In locally advanced ACC patients, the median OS was 24 months and 31% of the patients survived at five years of follow-up. After Monte Carlo simulation that relied on the SSA Life Tables’ derived estimates of population- based controls in a one-to-one fashion, the median sur- vival was not reached and the simulated OS was 92% at five years. The difference in OS between ACC patients
vs. simulated population-based controls was 61% at five years of follow-up (Fig. 2B). Subsequently, we performed subgroup analyses according to age (young vs. old). At five years of follow-up, minimal differences in OS were recorded between young locally advanced ACC patients and population-based controls vs. old locally advanced ACC patients and population-based controls. The observed OS differences for these two scenarios were 59 vs. 62%. (Fig. 3 B1-2).
Overall survival in metastatic ACC patients vs. population-based controls
In metastatic ACC patients, the median OS was 7 months and 8% of the patients survived at five years of follow-up. After Monte Carlo simulation that relied on the SSA Life Tables’ derived estimates of population-based controls in a one-to-one fashion, the median survival was not reached and the simulated OS was 92% at five years. The difference in OS between ACC patients vs. simulated population-based controls was 84% at five years of follow-up (Fig. 2C). Sub- sequently, we performed subgroup analysis according to age (young vs. old). At five-year follow-up, minimal differences in OS were reported between young metastatic ACC patients and population-based controls vs. old metastatic ACC patients and their population-based controls counterparts. The observed OS differences were 81 vs. 83%, respectively. (Fig. 3 C1-2). Additionally, after stratification according to surgical status (performed vs. not performed), substantial differences in OS were reported. For instance, at five years of follow-up, differences in OS between surgically treated metastatic ACC patients vs. population-based controls was 14 vs 89%; A= 75% (Fig. 4A). Conversely, at five years of follow-up, OS differences between not surgically treated metastatic ACC patients vs. population-based controls was 3 vs 89%; 4 = 86% (Fig. 4B).
(A)
Surgically-treated metastatic ACC - - Population-based controls
1.00
91%
89%
0.75
Percentage Survival
Percentage Survival
abs ..= 70%
0.50
abs ..= 75%
Log-rank p < 0.0001
0.25
21%
14%
0.00
0
12
24
36
48
60
Months
Number at risk
Surgically-treated metastatic ACC
140
71
47
31
21
19
Population-based controls
140
137
133
128
125
124
0
12
24
Months
36
48
60
Discussion
It is unknown to what extent the diagnosis of ACC under- mines life expectancy. We addressed this knowledge gap and quantified life expectancy detriments in newly diagnosed ACC of all stages. Subsequently, we repeated all analyses in a stage-specific fashion as well as in subgroups of young vs. old patients. We made several noteworthy observations.
ACC is a rare entity. Its annual incidence in North America is 0.7 per million [1]. Large-scale epidemiologi- cal analyses of ACC survival are equally rare. Based on the rarity of ACC, it is unknown to what extent ACC diagnosis may affect patients’ life expectancy relative to the general population. We addressed this hypothesis and based our analyses on one of the largest cohorts of ACC patients. Spe- cifically, 742 ACC patients were identified across all stages over a period of 11 years (SEER 2004-2014). The majority of our population harbored localized stage 301 (41%), fol- lowed by metastatic stage 268 (36%), and locally advanced ACC stage 173 (23%). Those proportions are comparable to more historical SEER cohorts (1973-2000) [12] as well as to other large-scale population databases such as the National Cancer Database (NCDB) 2004-2015 [13] and European multi-institutional databases [14, 15]. Moreover, all previous reports that focused on ACC demonstrated similar median age and predominant female sex distribution. To the best of our knowledge, no previous investigators addressed life expectancy detriment in newly diagnosed ACC patients.
We examined OS of ACC patients. In the overall cohort, five years OS was poor 33%, with a median of 23 months. Poor survival predominantly originates from patients with
(B)
Non surgically-treated metastatic ACC - - Population-based controls
1.00
92%
89%
0.75
0.50
abs ..= 87%
abs ..= 86%
Log-rank
0.25
p < 0.0001
0.00
5%
0
12
24
36
48
60
Months
Number at risk
Non surgically-treated metastatic ACC
128
22
8
6
4
3
Population-based controls
128
124
119
118
116
114
0
12
24
Months
36
48
60
metastatic stage (median 7 months) and those with locally advanced stage (median 24 months). Conversely, for those with localized ACC, the median survival was not reached. However, only 55% of individuals were alive a five years of follow-up. Similar survival rates were reported in other pub- lications from more historical large-scale population data- sets, namely NCDB, as well as multi-institutional European datasets [13, 15]. These observations validate the findings recorded in the SEER database relative to NCDB.
We simulated five years OS of population-based controls. The simulations were based on Monte Carlo and Markov chain of natural progression methodologies. These steps were first applied to the overall ACC population. Subse- quently, separate simulations were applied to localized, locally advanced, and metastatic ACC patients, for a total of four separate simulations. In the simulation applied to the overall cohort of ACC patients, five years OS was 93%. Conversely, five years OS was 94 vs. 92 vs. 92% in simula- tions based on localized, locally advanced, and metastatic ACC patients.
We compared and quantified differences in life expec- tancy, defined as OS, between ACC patients relative to simu- lated population-based controls. The comparison between the overall ACC cohort and population-based controls revealed values of 33 vs. 93% at five years of follow-up, resulting in a difference of 60%. The latter is interpreted as a life expectancy detriment of 60% for a newly diagnosed ACC patient, regardless of stage. However, since important OS differences distinguish ACC patients according to stage, the overall comparison lacks specificity. In consequence, we repeated the same comparisons for each of the three ACC stages, namely: localized, locally advanced, and metastatic. The most pronounced difference was expectedly recorded for metastatic ACC patients. Here life expectancy detriment was 84%, followed by 61% in locally advanced, and 39% in localized. It is noteworthy that even in localized ACC life expectancy exhibits very pronounced detriment. To the best of our knowledge, this is the first time this data has been published. However, this observation is critical for newly diagnosed ACC patients, since severely decreased life expectancy should be communicated to patients based on the severity of its impact on their lives and the lives of their families.
We confirmed the initial hypothesis about pronounced differences between five years OS in ACC patients and relative to age- and sex-matched population-based con- trols. Moreover, we quantified the extent of life lost in ACC patients, which ranged from 39 to 84%, relative to popula- tion-based controls. These findings emphasize the critical need for early detection, accurate staging, and personalized treatment strategies to improve patient outcomes.
Despite its novelty, our study is not devoid of limitations. Our study shares the limitations of all similar studies that
were based on the SEER database and relied on a retrospec- tive data design, with the potential for selection biases [16, 17]. Despite a large patient population, the amount of detail is limited. Indeed, only survival rates were available. For exam- ple, no data regarding the Weiss score [18], the Ki-67 score [19], lymph-vascular invasion [20], and the presence of tumor necrosis [21] that may affect ACC patients’ survival were available. Additionally, the nature of the SEER database did not allow us to address early cancer control outcomes such as relapse rates or metastatic progression rates. Therefore, the lack of inclusion of more detailed information and endpoints precludes the generalizability of our results. The comparison group that consisted of age- and sex-matched controls rep- resented a simulated population in whom OS was defined according to SSA Life Tables. Although this methodology has been used in various previous publications and is well accepted, it only represents a surrogate for true population- based controls without the trait of interest, namely ACC. Finally, data derived from SSA Life Tables does not provide a specific cause of death. In consequence, the comparison to the SSA Life Tables only allows for investigating OS. Similarly, further adjustments for patient characteristics other than age and sex could also not be made, since the SSA Life Tables do not provide this type of stratification.
Conclusion
The most pronounced life expectancy detriment (84%) was recorded in metastatic ACC followed by locally advanced ACC patients (61%). Unfortunately, even in patients with localized ACC, life expectancy was 39% lower than that of the general population. Therefore, regardless of stage, ACC diagnosis results in a very pronounced detriment in life expec- tancy relative to the general population.
Author contributions Conceptualization and Methodology: LMIJ, AB (Andrea Baudo); Acquisition of the data: LMIJ, LS, CS, MdA, FDB, KV; Formal analysis: LMIJ, ZT; Investigation and Data Curation: LMIJ, SL, FAM, MF; Writing- Original Draft: LMIJ, JAG; Visualiza- tion: FS, LC, AB (Alberto Briganti), NL, FKHC,; Funding acquisition: N/A; Supervision: OdC, GM, PIK; Project administration: PIK.
Data availability No datasets were generated or analysed during the current study.
Declarations
Conflict of interest The authors have declared no conflicts of interest.
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