OXFORD
ENDOCRINE SOCIETY
Time trends in incidence, treatment, and survival of patients with adrenocortical carcinoma, a nationwide study
Rebecca V. Steenaard ( 1,2,3, J. Sofie de Wit1, Marieke Rutjens1, Babs van der Bruggen1, Karin Blijdorp1, Pleun Wouters - van Poppel1, Richard A. Feelders @D 4,5, and Harm R. Haak [D 1,2on behalf of the Dutch Adrenal Network
1Department of Internal Medicine, Máxima MC, Eindhoven/Veldhoven 5504 DB, The Netherlands
2CAPHRI School for Public Health and Primary Care, Ageing and Long-Term Care, Maastricht University, Maastricht 6229 HX, The Netherlands
3Department of Research, Netherlands Comprehensive Cancer Organization (IKNL), Utrecht 3511 DT, The Netherlands
4Department of Internal Medicine, Section Endocrinology, Erasmus Medical Center, Rotterdam 3015 GD, The Netherlands
5Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NewYork University Langone Medical Center, New York, NY 10016, USA
Correspondence: Rebecca V. Steenaard, MSc, Department of Internal Medicine, Máxima MC, De Run 4600, Veldhoven 5504DB, The Netherlands. Email: Rebecca.Steenaard@mmc.nl.
Abstract
Purpose We aimed to determine time trends in incidence, treatment, and survival of patients with adrenocortical carcinoma in the Netherlands.
Methods All 685 adult patients with adrenocortical carcinoma diagnosed between 1993 and 2020 in the Netherlands were included, using the nationwide prospective Netherlands Cancer Registry.
Results The median age-adjusted incidence rate based on the European Standard Population was 1.62 per million person- years [0.83-2.11] and was stable over time. We saw a gradual increase in stage III on diagnosis (13%-25%) with a stable proportion of stage IV (40%). The 5-year survival remained stable over time for stage I-II at 65% and stage III at 35%, whereas the survival for stage IV increased from 3% in 1993 through 1996 to 11% in 2017 through 2020. Since the Dutch Adrenal Network was founded in 2004, more patients were referred to an expert center (P < . 001), which was associated with increased survival (adjusted HR 0.70; 95% CI, 0.57-0.85). Multivariate Cox regression showed increased survival in all stages when treated with adrenalectomy (adjusted HR 0.53; 95% CI, 0.43-0.65) and mitotane therapy (adjusted HR 0.73; 95% CI, 0.55-0.98). In stage IV disease, adrenalectomy, surgical control of disease, chemotherapy, and mitotane therapy were associated with increased survival. However, only 58% of mitotane users reached a therapeutic drug level and 59.5% discontinued treatment prematurely.
Conclusion The incidence of adrenocortical carcinoma is stable over time. The 5-year survival for stage I-III remained stable, whereas the survival for stage IV increased. Factors associated with increased survival are centralization of care, adrenalectomy, surgical control of disease, chemotherapy, and mitotane therapy.
Keywords adrenocortical carcinoma, incidence, survival, centralization, treatment
Abbreviations: ACC, adrenocortical carcinoma; DAN, Dutch Adrenal Network; EoD, extent of disease; HR, hazard ratio; NCR, Netherlands Cancer Registry.
Adrenocortical carcinoma (ACC) is a cancer originating from the adrenal cortex. Because the adrenal cortex produces cortisol, aldosterone, and adrenal androgens, a subset of patients with ACC presents with hormonal overproduction such as Cushing syndrome, hyperaldosteronism, virilization, or feminization (1, 2). Patients with nonfunctional ACC can present with symptoms
of tumor mass effect or complaints caused by metastases. A proportion of patients is found incidentally with abdominal imaging for another indication. Treatment modalities for ACC include surgery, mitotane therapy, chemotherapy, and radio- therapy (1, 2). Even with these treatment modalities and the introduction of new anticancer treatments in recent years,
prognosis is still poor, especially for patients diagnosed with metastatic disease (3).
ACC is a rare disease, which makes reliable epidemiological studies on incidence, survival, and effects of treatment more dif- ficult. The nationwide prospective Netherlands Cancer Registry (NCR) includes information on every patient in the Netherlands ever diagnosed with ACC since 1989. This provides unique real- life data on this rare disease. A previous study using this registry determined that the incidence of ACC in the Netherlands varied between 0.8 and 2.0 between 1993 and 2010 (4). Our aim is to de- termine whether the incidence and survival of ACC changed over time, with an update until 2020. We further aimed to determine the current use of treatment strategies and their effect on sur- vival in this real-life population-based cohort using newly added disease-specific data to the registry from 2014 onward. Last, it is recommended to treat patients with ACC in an expert center (1, 2). In 2004, the Dutch Adrenal Network (DAN) was founded to unite all clinical and research expert centers on adrenal dis- eases in the Netherlands. We aimed to determine whether this had an effect on centralization of care and more importantly on survival.
Methods
The NCR is a prospective registry with data on all cancer patients diagnosed in the Netherlands from 1989 onward. All pathology diagnoses of malignancy are recorded in a national pathology database. Diagnoses without pathology confirmation are col- lected through hospital declaration data. Survival is documented through national death records. Treatment and referral hospital are collected from the hospital declaration data. Additional data are collected by trained data collectors directly from the hospital records. Use of the data for this specific study was approved by the NCR board of directors and the NCR adrenal scientific com- mittee consisting of Dutch experts on ACC.
From 1989 to 2013, the NCR includes data on extend of disease (EoD), treatment modality (including surgery, chemotherapy, radiotherapy, immunotherapy) and hospital for patients with ACC. Together with experts on ACC within DAN, we determined which new items specific to ACC were helpful to record from 2014 onward. These items are: ENSAT stage, ASA status (1-5), ALAT (U/L), creatinine (umol/L), hormone production (cortisol, adrenal androgens, estrogens, aldosterone from medical records or laboratory measurements), 24-hour urine cortisol (elevated or normal compared to local laboratory normal range), dexametha- sone suppression test (not suppressed or suppressed compared to local laboratory normal range), ENSAT stage (I-IV), surgical ap- proach to adrenalectomy (open or laparoscopic), resection status (complete or not complete as stated in pathology and surgery re- ports), vena cava infiltration (from pathology, surgery, and radi- ology reports), Weiss score (0-9 from pathology reports), KI-67 index (% from pathology reports), mitotic index (number of mitosis per high power field or mm2 from pathology reports, converted to mitosis per 50 high power fields), maximum mitotane dose (mg/day), maximum mitotane level (mg/L), mitotane discontinu- ation or adjustment other than for plasma levels (from medical re- cords), reason for mitotane discontinuation or adjustment (from medical records), and imaging modality (from radiology reports).
Before 2014, only EoD stage localized disease in the tissue of origin was registered, without information on tumor size.
Therefore, before 2014 no distinction can be made between ENSAT stage I localized disease less than 5 cm and ENSAT stage II localized disease more than 5 cm. Therefore, in analysis using all data between 1989 and 2020, we used ENSAT stages I and II combined. There was no difference between the EoD and ENSAT system in the registration of stage III locally advanced dis- ease and IV metastatic disease. Additional surgery was defined as resection of tumor growth in surrounding organs during adre- nalectomy, resection of local recurrence, or additional lymph node resection other than routine locoregional lymphadenec- tomy during adrenalectomy. Treatment in an expert center was defined as 1 or more treatments performed in 1 of the DAN hospitals. These hospitals did not change over the course of the study.
Statistical analysis was done using STATA version 17 and SPSS version 29. Incidence was calculated as age-standardized inci- dence per million person-years using the European Reference Population 1993 to 2020 data for all patients aged 18 and older upon diagnosis. Childhood ACC in this population was described in a previous project and not included in the current analysis (5). Data between 1989 and 1992 were discarded for this analysis be- cause only a few cases were registered in those years. Evaluation of the trend in incidence was performed by calculating the esti- mated annual percentage of change. Survival was determined using Kaplan-Meier curves and life tables’ 1993 to 2020 data. Time trends in ENSAT stage, 1-year survival, and 5-year survival were calculated by comparing means of 8 predetermined time periods (1993-1996, 1997-2000, 2001-2004, 2005-2008, 2009-2012, 2013-2016, 2017-2020).
Multivariate Cox regression was used to determine adjusted hazard ratios (HR) on the 1989 to 2020 data. The proportional hazard assumption was met and treatment covariates were not time-dependent. Presented adjusted HR for all stages were adjusted for age, sex, ENSAT stage (I-II, III, IV), adrenalectomy, additional surgery, mitotane therapy, adjuvant radiotherapy, and referral center. Presented adjusted HR for stage IV disease were adjusted for age, sex, adrenalectomy, additional surgery, metastasis surgery, mitotane therapy, chemotherapy, and radio- therapy. Ki-67, resection status, and hormone overproduction are also known determinants of survival. These data, however, were only available from 2014 to 2019 and had missing data be- cause of poor hospital recordkeeping (3). These parameters were therefore not used in the adjusted HR because there were insuf- ficient data for a robust survival analysis.
The current situation in adrenocortical carcinoma treatment in the Netherlands was analyzed using descriptive statistics, chi- square, ANOVA analysis, and t-tests on the 2014 to 2019 data. This time period was chosen because it contained the complete detailed data on the new ACC-specific items. At the time of data analyses, the detailed data of 2020 had not been recorded yet.
Results Time trends in ACC
All 685 adult patients with ACC diagnosed between 1993 and 2020 in the Netherlands were included in the analyses of time trends in ACC. Median age at diagnosis was 58 years (range, 18-89 years) and 56.8% were female. The age-adjusted incidence rate based on the European Standard Population varied between 0.83 and 2.11 per
A
Age-standardized incidence (European reference population) per million person-years
B Percentage of ENSAT stage upon diagnosis per time-period
2.5
60
50
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40
1.5
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1993-1996
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2011
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2019
Stage I+II - - Stage III … Stage IV
C
One-year survival percentage per ENSAT stage per time-period
D Percentage of patients treated in a general hospital or expert center per time-period
100
100
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60
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1993-1996
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1993-1996
1997-2000
2001-2004
2005-2008
2009-2012
2013-2016
2017-2020
Stage I+II - - Stage III … Stage IV
General hospital
Expert center
million person-years with a median of 1.62 per million person- years (Fig. 1A). This incidence was stable over time (estimated an- nual percentage of change, -1.52%; 95% CI, -16.7 to 13.4).
We saw a gradual increase in the proportion of ENSAT stage III upon diagnosis (13%-25%), with a similar decrease in stage I-II and a stable proportion of stage IV (40%) (P for trend .001) (Fig. 1B). Even with this change in ENSAT stage upon diagnosis, the survival for stage I-II and III remained stable over time (1-year survival stage I-II 90%, stage III 67%; 5-year survival stage I-II 65%, stage III 35%; P for trend .43) (Fig. 1C). Although the 1-year survival for stage IV remained stable at 24% (P of trend .77), the 5-year survival increased from 3% to 11% in the last period from 2017 to 2020 (P for trend .01).
Since the founding of the Dutch Adrenal Network in 2004, more patients were referred to an expert center (P <. 001) (Fig. 1D). Between 2014 and 2019, 85% of adrenalectomies and 95% of med- ical treatments were performed in an expert center. Treatment in an expert center was associated with a survival benefit for the to- tal population (adjusted HR 0.70; 95% CI, 0.57-0.85) (Fig. 2A).
Current situation
Localized and locally advanced disease, stage I-III Between 2014 and 2019, 89 patients were diagnosed with local- ized and locally advanced ACC stage I-III. Of the patients
diagnosed in this period, 6.6% had ENSAT stage I, 33.8% stage II, and 25.0% stage III disease upon diagnosis. The diagnostic de- tails such as hormone production, pathology data, and perform- ance status are shown in Table 1. Adrenalectomy was performed in 85 patients. The majority of adrenalectomies was performed by open resection (91.6%), with the exception of stage I disease (77.8% laparoscopic surgery). Complete resection was accom- plished in 86.1% of adrenalectomies for stage I-II disease and only 46.4% for stage III disease. Surgery for ACC was performed in DAN centers 85.1% of the time. There was no difference in resection status between DAN centers and non-DAN centers (P =. 363). Additional surgical resection in stage III disease in- cluded additional lymph node resection other than lymph node resection as part of the adrenalectomy (n =5) and sur- rounding organ resection (n = 34, various combinations of dia- phragm, kidney, liver, gallbladder, pancreas, stomach, spleen, colon, omentum, peritoneum resection, and unspecified abdom- inal surgery). Adjuvant radiotherapy was administered to 6 pa- tients with ENSAT stage II or III. Multivariate Cox regression showed a survival benefit for adrenalectomy (adjusted HR 0.53; 95% CI, 0.43-0.65) in all stages (Fig. 2B). This survival benefit was not found for adjuvant radiotherapy (adjusted HR 0.94; 95% CI, 0.61-1.46). The survival benefit from additional surgery did not reach significance (adjusted HR 0.67; 95% CI, 0.42-1.07).
Adjuvant mitotane was given to 17 patients with stage II and 18 patients with stage III disease. One patient with stage I was
A
Treatment in an expert center or general hospital
B Adrenalectomy
1,0
1,0
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Cumulative Survival Probability
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| Number at risk | Number at risk | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Expert center | 400 | 106 | 46 | 23 | 9 | 0 | 0 | Adrenal ectomy | 436 | 146 | 74 | 50 | 26 | 3 | 0 | ||
| General hospital | 285 | 58 | 38 | 29 | 18 | 5 | 0 | No | 249 | 18 | 10 | 2 | 1 | 0 | 0 | ||
C Mitotane
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Cumulative Survival Probability
0,8
0,6
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Mitotane
113
19
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572
145
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51
28
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prescribed mitotane due to a Ki-67 index of 20% and later proved to have rapidly progressive disease. Multivariate Cox regression showed a survival benefit from adjuvant mitotane therapy (ad- justed HR 0.73; 95% CI, 0.55-0.98) in all stages (Fig. 2C).
Metastasized disease, stage IV
Between 2014 and 2019, 47 patients had stage IV disease upon diagnosis (34.6%). Of these patients, 24 received an open adrena- lectomy and 1 a laparoscopic adrenalectomy. Indications for sur- gery such as debulking or hormone production were not collected. Of the 21 adrenalectomies with complete data, 13 re- sulted in complete resection of the primary tumor (61.9%). Metastasis surgery included 5 lung (video-assisted thoracoscopic surgery or wig-resection), 7 liver (segmental or hemihepatec- tomy), 1 omentum, 2 peritoneum, and 4 resections at an un- known location. Of the 13 metastasectomies with complete
data, only 1 was registered as a complete resection of the metas- tasis (7.7%). For liver metastases, local therapies were used in 6 patients, including 3 microwave ablations, 1 radiofrequency ab- lation, and 2 transarterial radio-embolizations. Multivariate Cox regression showed a survival benefit from adrenalectomy, add- itional surgery and metastasis surgery in stage IV disease (ad- justed HR 0.39; 95% CI, 0.29-0.54; 0.40, 95% CI, 0.18-0.91; 0.37, 95% CI, 0.22-0.63, respectively) (Fig. 3A-3C). No survival benefit has yet been found for local therapies because of the low number of patients.
Palliative mitotane was prescribed 65 times (2 times for irre- sectable stage III disease, 63 times for stage IV disease). Mitotane was mostly prescribed in DAN centers (96.0%) and only 4 times in a non-DAN center. Multivariate Cox regression showed a survival benefit from palliative mitotane therapy in stage IV disease (adjusted HR 0.69; 95% CI, 0.47-0.99) (Fig. 3D).
| N | % | |
|---|---|---|
| Sex | 136 | |
| Female | 86 | 63.2 |
| Male | 50 | 36.8 |
| Primary tumor | 136 | |
| Right adrenal | 75 | 55.1 |
| Left adrenal | 61 | 44.9 |
| Hormone production | 109 | |
| Nonfunctional | 37 | 34.0 |
| Cortisol | 24 | 22.0 |
| Androgens | 17 | 15.6 |
| Cortisol + androgens | 12 | 11.0 |
| Estrogens | 3 | 2.8 |
| Aldosterone | 1 | 0.9 |
| Unknown | 15 | 13.8 |
| Cortisol 24-hour urine | 108 | |
| Elevated | 38 | 35.2 |
| Normal | 32 | 29.6 |
| Unknown | 38 | 35.2 |
| Dexamethasone suppression test | 108 | |
| Not suppressed | 16 | 14.8 |
| Suppressed | 15 | 13.9 |
| Unknown | 77 | 71.3 |
| Pathology | 108 | |
| Weiss 2-3 | 9 | 8.3 |
| Weiss >4 | 50 | 46.3 |
| Weiss unknown | 49 | 45.4 |
| Vena cava invasion | 110 | |
| Yes | 14 | 12.7 |
| No | 96 | 87.3 |
| Ki-67 | 75 | |
| ≥10% | 52 | 69.3 |
| <10% | 23 | 30.7 |
| Mitosis per 50/high powered field | 84 | |
| ≥5 | 78 | 92.9 |
| <5 | 6 | 7.1 |
| Imaging | 109 | |
| CT of the abdomen | 78 | 71.6 |
| CT of the thorax | 63 | 57.8 |
| CT not otherwise specified | 10 | 9.2 |
| PET | 37 | 33.9 |
| MRI | 14 | 12.8 |
| Ultrasound | 2 | 1.8 |
| Unknown | 10 | 9.2 |
| ASA score | 108 | |
| No disease and medication, perfect health | 5 | 4.6 |
| Minor disease or medication, no influence on health | 44 | 40.7 |
| Major disease or medication, minor influence on health | 25 | 23.1 |
| Major disease or medication, major influence on health | 0 | 0 |
| Major disease or medication, dead expected <24 hours | 0 | 0 |
| Unknown | 34 | 31.5 |
| Creatinine (mean, range) | 103 | 75.3 (40-200) |
| ALAT (mean, range) | 90 | 47 (8-390) |
Abbreviations: ACC, adrenocortical carcinoma; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography. Description of the new ACC-specific variables added to the registry after 2014. Data include the 136 patients diagnosed with ACC between 2014 and 2019.
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A Adrenalectomy
B Additonal surgery
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Adrenale
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D Mitotane
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Chemotherapy
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Chemother
73
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apy
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| Number at risk | Number at risk | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Metastasec | 22 | 3 | 1 | 0 | 0 | 0 | Mitotane | 47 | 1 | 0 | 0 | 0 | 0 | |||
| tomy | ||||||||||||||||
| No | 217 | 13 | 10 | 8 | 2 | 0 | ||||||||||
| No | 242 | 11 | 8 | 8 | 2 | 0 | ||||||||||
Figure 3 Kaplan-Meier curves in stage IV patients between 1993 and 2020.
In total, 26 patients received chemotherapy for stage IV dis- ease. The FIRMACT scheme with etoposide-doxorubicin-cisplatin with or without mitotane was prescribed in 18 patients (6). Other regimes were less common in the population (2 etoposide/
carboplatin, 1 streptozocin, 2 temozolomide, 3 unknown). Only 1 patient received chemotherapy in a non-DAN center; however, this center is known to have ongoing online consultations with 1 of the DAN centers. Multivariate Cox regression showed a survival
benefit from chemotherapy in stage IV disease (adjusted HR 0.64; 95% CI, 0.45-0.91) (Fig. 3E).
Immunotherapy was prescribed in 5 patients (2 atezolizumab, 1 olaparib, 1 pembrolizumab, 1 unknown). In the Netherlands, immunotherapy for ACC is only available in clinical trials. Because the largest trial within the study period was in a non-DAN center, 4 of the patients were treated with immunother- apy outside a DAN center (7). No survival benefit has yet been found for immunotherapy because of the low number of patients.
Palliative radiotherapy was administered 14 times: 7 bone, 2 lung, 1 liver, 3 metastasis unknown, 1 internal radiation with Lutetium therapy. Radiotherapy, both adjuvant and palliative, was performed in a DAN center 12 times (60.0%) and 8 times in a non-DAN center. No survival benefit was found for radiotherapy in stage IV disease (adjusted HR 0.70; 95% CI, 0.44-1.12).
There were 21 patients with stage IV disease who did not re- ceive any treatment. The reasons were high tumor load or pro- gression (n =8), poor physical condition (n=3), dead before start of treatment (n = 2), patient preference (n = 1), or unknown (n = 7). One third of these patients were never referred to a DAN center.
Mitotane therapy in practice
As demonstrated in the previous sections, both adjuvant and pal- liative mitotane treatment is associated with a survival benefit. In real-life, however, mitotane therapy is often complicated be- cause of difficult dosing and its (severe) side effect profile, result- ing in impaired therapy adherence. Of all mitotane users between 2014 and 2019, both palliative and adjuvant, only 58% reached mitotane levels above 14 mg/L (range of maximum level reached: 1-36.9 mg/L) with a mean maximum dose of 6672 mg/day (range of maximum dosage used: 500-9000 mg/ day). Of the 96 counts of mitotane treatment with known follow- up, 22% were discontinued before the predetermined treatment period (18% in adjuvant use and 24% in palliative use). In an- other 37.5%, the dose was reduced or temporary discontinued, often with resumption at a lower dose, for reasons other than plasma level correction. Progression of disease accounted for 21% of adjustments and discontinuations (12% in adjuvant use and 27% in palliative use). However, 61% of adjustments and discontinuations was attributed to toxicity, including gastro- intestinal complaints, liver toxicity, skin problems, thrombotic events, infections, hematological, cardiac or renal toxicity, hypertension, and general physical decline. In 8 patients, signifi- cant elevations in ALAT levels during or after mitotane therapy were registered. In 4 of the 8 patients, the ALAT levels normalized after mitotane discontinuation or dose reduction. The remaining 18% discontinued for unknown reasons. Notably, discontinu- ation was not associated with maximum dose (P = . 61) or max- imum plasma levels (P = . 87).
Discussion
This unique nationwide registry study on ACC provides longitu- dinal real-life data on the incidence, survival over time according to tumor stage, and the effects of various treatment modalities on survival. Every patient in the Netherlands diagnosed between 1993 and 2020 was included in this study, which provides the true
incidence of 1.62 per million person-years for adult ACC. This in- cidence was stable over time. Although the proportion of the dif- ferent ENSAT stages upon diagnosis was generally in line with other larger ACC cohort, it was not stable over time (8, 9). We hy- pothesized that the percentage of stage I and II disease might in- crease at the expense of more advanced stages due the increase in use of abdominal imaging resulting in a higher rate of ACC pre- senting as incidentaloma. On the contrary, we found that the proportion of stage III disease increased from 13% to 25% at the expense of stage I-II disease. This finding is also different from the study of Daher et al, who found an increase in stage IV disease upon diagnosis between 1998 and 2019 (10). However, this was based on a single-center experience; there- fore, referral bias might have been present. Our study is a nation- wide registry including all diagnosed patients in the Netherlands in this period and is therefore not influenced by referral bias. However, we have no data on whether the increase in stage III is caused by a recategorization of stage I-II due to better imaging techniques to correctly identify lymph node and adjacent organ involvement.
The current guidelines recommend adrenalectomy of stage I-III disease (1, 2). The ADIUVO trial concluded that for low-grade localized disease adjuvant mitotane therapy does not increase 5-year recurrence-free and 5-year overall survival (11). For high- grade or locally advanced disease, when a high risk of recurrence exists, the guideline does recommend adjuvant mitotane ther- apy after adrenalectomy. The data in this study confirm that adrenalectomy and mitotane therapy are associated with in- creased survival in all stages of disease (adjusted HR 0.53; 95% CI, 0.43-0.65; adjusted HR 0.73; 95% CI, 0.55-0.98, respectively). These practices did not change over time, potentially explaining why survival for stage I-III disease remained stable over time with a 1-year survival of 90% at stage I-II and 67% at stage III. There is, however, still room for improvement. The current ADIUVO-2 trial proposes the use of adjuvant etoposide-cisplatin chemotherapy in addition to adjuvant mitotane to increase the survival of pa- tients with high risk of recurrence (NCT03583710). The results of this trial, however, are not expected for another couple of years.
Another potential for improvement is the actual use of mito- tane. As in our clinical experience, the ACC population data re- flect the real-life problems with mitotane therapy adherence because of drug toxicity. The data showed that only 58% of pa- tients ever reached therapeutic mitotane levels above the rec- ommended 14 mg/L and only 2 in every 5 patients completed mitotane therapy for the predetermined period (12). In 61% of patients, the reason for discontinuation or dose reduction was toxicity. A recent study on health-related quality of life in the Dutch ACC population found that patients experience a lower quality of life with mitotane therapy, which persists even after discontinuation (13). Careful monitoring and treatment of side effects, for example by means of patient-reported outcome measures, might help improve health-related quality of life, pre- vent early discontinuation, and thereby improve survival.
Although the 1-year survival of stage IV disease also remained stable over time at 24%, the 5-year survival increased from 3% to 11% in the most recent time period. This is concurrent with the study of Daher et al, who also found an increased survival for stage IV disease between 1998 and 2019 (10). For stage IV dis- ease, the current guidelines recommend either chemotherapy
in the FIRMACT scheme (etoposide, doxorubicin, cisplatin, mito- tane) or local therapy with or without mitotane therapy (1, 2). In our population, both chemotherapy and palliative mitotane were associated with increased survival in stage IV disease (adjusted HR 0.64; 95% CI, 0.45-0.91; adjusted HR 0.69; 95% CI, 0.47-0.99, respectively). The data on chemotherapy use in this population were analyzed previously in more detail in the study by Debets et al (14). Our data further confirm the results from re- cent studies on the benefit of local therapies in metastatic ACC, including the benefit of primary tumor resection in metastasized disease (15-19). In this population, adrenalectomy, additional surgery and metastasis surgery were all associated with a sur- vival benefit in stage IV disease (adjusted HR 0.39; 95% CI, 0.29-0.54]; 0.40, 95% CI, 0.18-0.91; 0.37, 95% CI, 0.22-0.63, respectively). The number of patients (n =6) who received microwave ablation, radiofrequency ablation, or transarterial ra- dioembolization for liver metastases was too small to determine survival benefit from other local therapies. However, the data confirm that for selected patients, surgical control of disease is possible and can indeed improve survival of stage IV disease. Radiotherapy has also been described as beneficial for local re- currence in adjuvant setting and local tumor control in palliative setting (20, 21). However, only high-dose radiotherapy in ad- vanced ACC has been associated with increased overall survival (20). In our population, we also found no overall survival benefit from radiotherapy, both adjuvant and palliative. However, the registry only holds data on overall survival and no data on local tumor control or symptom relief due to radiotherapy, both of which can be as important to patients as overall survival.
The finding that the 5-year survival for stage IV disease did in- crease, whereas the 1-year survival did not, might suggest that the survival benefit from the changes in chemotherapy and local therapies of the recent years only benefit patients with less ag- gressive stage IV disease who have survived the first year. This verifies the need for new or better tailored treatment options for ACC. Immunotherapy as monotherapy or added to other treatments is one of the newly proposed treatment options (22). This current study did not include sufficient number of pa- tients treated with immunotherapy to draw any conclusions on its survival benefit and no data on treatment response other than survival was present.
The current ACC guidelines recommend patients to be re- ferred to an expert center at least once during the course of the disease (1, 2). We have confirmed that treatment in an ex- pert center is indeed associated with an improved survival in all stages (adjusted HR 0.70; 95% CI, 0.57-0.85). In 1993, the ma- jority of Dutch patients was treated in a general hospital, but this decreased slowly in the following years. The centralization rate increased considerably after 2004 when DAN was founded. From that moment, the majority of patients is treated in an ex- pert center. Currently 85% of adrenalectomies are performed in an expert center and 96% of medical treatments. For medical treatment, especially in stage IV disease with poor prognosis, patients might prefer treatment closer to home over improved survival. There are nonexpert centers in the Netherlands that provide medical therapy locally with electronic consultations from one of the expert centers. The true number of medical treatments with involvement of an expert center may therefore be closer to 100%. For surgery however, there is still room for improvement.
The current study is a nationwide study on ACC without influ- ence of the referral bias that occurs in a single or multicenter registry. Patient identification is performed through the national pathology data and hospital declaration data to ensure no miss- ing cases; survival is based on national records. Because the study is observational, selection bias is always present. However, the aim of our study was to determine the real-life in- cidence, treatment strategies, and centralization of care and its effects on survival in the total population of patients with ACC in the Netherlands. We aimed to correct for selection bias using a multivariate Cox regression model. The quality of this more de- tailed data is dependent on the quality of the hospital record keeping and the ability of the data collectors to find the data. We trained the data collectors specifically on ACC from 2014 on- ward, which might introduce a slight difference in the data col- lection before and after 2014. However, even with this training, we saw a lot of missing data in the ACC-specific items and diag- nostic characteristics recorded from 2014 onward, suggesting it was poorly recorded in the hospital records. This did not influ- ence the analysis of the 1993 to 2020 data on incidence, stages, treatment, and survival. However, the survival models could not be adjusted of Ki-67, resection status, and hormone production because of the lack of collected data so far. These factors are known to influence survival and would be interesting to include in a couple of years, when more patients in the registry have de- tailed data available (3).
Conclusion
This unique nationwide registry study provides real-life longitudin- al data on the incidence, treatment, and survival of patients with ACC. The true incidence of adult ACC was 1.62 per million person- years and was stable between 1993 and 2020. The 5-year survival for stage I-III remained stable, whereas the survival for stage IV in- creased in the most recent years. Centralization of care has im- proved since the founding of the DAN, which was associated with increased survival. Adrenalectomy and mitotane therapy are associated with increased survival in all stages of disease. Adrenalectomy, surgical control of disease, chemotherapy, and mitotane therapy are associated with increased survival in stage IV disease. Even with this survival benefit, the 1-year survival re- mained stable over time, verifying the need for new or better tail- ored treatment options. For example, currently only 58% of patients on mitotane therapy reach therapeutic drug levels and only 41.5% complete the treatment as planned. Better guidance during mitotane therapy might improve treatment adherence with to intent to reach a survival benefit in more patients.
Disclosures
No disclosures.
Data availability
Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author
will on request detail the restrictions and any conditions under which access to some data may be provided.
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