EJE
Psychosocial burden in adrenocortical carcinoma patients
Otilia Kimpel,1.+D Senta Kiermeier,2,1 [D Emely Stahl,1 Barbara Altieri, 1,3D Martin Fassnacht, 1,3,4,*,+(D and Imad Maatouk2,3,4,tiD
1Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany 2Division of Psychosomatic Medicine, Psychotherapy and Psychooncology, Department of Internal Medicine II, Julius-Maximilian University Würzburg, 97080 Würzburg, Germany
3Bavarian Cancer Research Center (BZKF), University Hospital, University of Würzburg, 97080 Würzburg, Germany
4Comprehensive Cancer Center Mainfranken, University of Würzburg, 97080 Würzburg,Germany
*Corresponding author: Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany. Email: fassnacht_m@ukw.de
Abstract
Objective: Distress, fear of progression (FOP), and depression are common in cancer patients and negatively impact patients’ health-related quality of life (HRQOL). However, no studies have explored these aspects in adrenocortical carcinoma (ACC), yet.
Methods: We conducted a single-centre observational study in adults (≥18 years) with ACC. We analysed questionnaires addressing FOP, distress (National Comprehensive Cancer Network distress thermometer), depression (patient health questionnaire, PHQ-9), and HRQOL (EORTC-QLQ-C30). Potentially influencing factors were evaluated. Multiple linear regression on HRQOL subscales was performed to identify associated psychosomatic correlations.
Results: Within 12 months, 105 patients were included (56.2% female; median age 49 years, 14.3% newly diagnosed, 46.7% tumour-free, 39.0% metastatic). The majority experienced an elevated level of distress (62%) and of FOP (59%). PHQ-9 results suggested major depression in 41%. Of note, these results were neither influenced significantly by tumour burden, hormone excess nor by cancer treatment. Patients reported moderate functioning scores (median 62.2) and moderate symptom burden (median 33.3) in the EORTC-QLQ-C30. Fatigue and insomnia were prominent symptoms. Tumour burden and treatment affected functioning and symptoms, with significant differences in appetite loss, diarrhoea, nausea, vomiting, and financial difficulties. Hormone excess showed no significant impact on these measures. Our questionnaires indicated a need for psychosomatic counselling in 80% of patients.
Conclusions: Patients with ACC show high values for distress, FOP, and depression, which can only partly be explained by clinical characteristics. Our study suggests that psychosomatic support should be offered to all patients with ACC.
Keywords: adrenocortical cancer, distress, fear of progression, quality of life, psychosomatic therapy
Significance
This study highlights a substantial psychosocial burden in patients with adrenocortical carcinoma (ACC), characterized by high levels of distress, fear of progression, and depression, which significantly impair health-related quality of life (HRQOL). Importantly, these psychosomatic symptoms occur independently of tumour burden, hormone excess, or treatment status, underscoring that clinical factors alone do not predict patient well-being. With 80% of patients expressing a need for psy- chosomatic counselling, our findings underscore the urgent necessity to incorporate routine psychosomatic assessment and supportive interventions in ACC care. Addressing these unmet needs may enhance HRQOL and overall patient outcomes, advocating for a more holistic, patient-centred approach in managing this rare malignancy.
Introduction
Adrenocortical carcinoma (ACC) is an aggressive endocrine tumour with a variable clinical course between individual cases.1-3 Survival in ACC depends on tumour stage, resection status, tumour grading, and hormone excess, all of which were recently combined to form the new prognostic S-GRAS score.2 In its early stages, and with limited risk factors, some patients can be surgically cured, but as the disease progresses to more
advanced stages, the prognosis becomes increasingly un- favourable, with 5-year survival rates dropping to less than 20% for those with metastatic disease.1,2,4,5 However, some patients survive many years, and cases with complete treat- ment responses have been reported even in patients presenting with stage IV disease.6,7
Treatment for ACC is determined by the stage of the disease. For solitary tumours, the preferred approach is surgical resec- tion. When there is a high risk of recurrence, such as in stage III disease, R1 or Rx resections, or cases with Ki67 >10%,
+ O.K., S.K., M.F., and I.M. shared first author and last author.
surgery is typically followed by at least two years of adjuvant mitotane monotherapy or even platinum-based therapies8,9 For metastatic or unresectable tumours, treatment options in- clude mitotane monotherapy, local therapies, chemotherapy, or immunotherapy, either alone or in combination with mitotane. 3,8,10-12
In about 60% of patients with ACC, the tumour autono- mously secretes cortisol. There is clear evidence that cortisol influences the mental state and that cortisol excess is associ- ated with an increased rate of depression and reduced quality of life. 13
Both the disease and its treatment options can negatively af- fect patients’ health-related quality of life (HRQOL). Until now, only one prospective randomized study ADIUVO included the HRQOL assessment with the EORTC QLQ-C30 in ACC.14 ADIUVO demonstrated a significant impairment of quality of life in tumour-free patients with a low risk of recurrence treated with an adjuvant mitotane therapy. Furthermore, in this trial, mitotane treatment led to a worsening in quality of life.14
In addition, the recent European Society for Endocrinology (ESE) and European Network for the Study of Adrenal Tumours (ENSAT) guideline on ACC management and a study by Steenaard et al. highlight the need for a deeper under- standing of HRQOL in ACC patients to enhance patient- centred care.8,15,16
Beyond the effects of cancer treatment, psychosocial factors such as distress and fear of progression (FOP) are important contributors to impaired HRQOL.17,18 The term “distress” describes an unpleasant emotional experience triggered by psychological, social, or spiritual factors.19 Psychosocial dis- tress is common in cancer patients and survivors and includes a broad range of concerns and psychological symptoms.17,18 Moreover, FOP is one of the most frequently identified factors that affect HRQOL in patients with cancer.2º Fear of progres- sion is defined as a persistent anxiety that the illness may wor- sen or return, which can significantly affect a patient’s emotional well-being and HRQOL.21 Distress and FOP can become a chronic problem, and are associated with symptoms of depression and anxiety.
There are already some studies in other cancer types and cancer predisposition syndrome investigating these aspects.18,22-25 These studies showed high levels of FOP, dis- tress, and, accordingly, a negative effect on HRQOL. Due to these results, these authors suggest a screening for FOP and distress in cancer patients. Additionally, they recommend pro- viding psychosocial support for patients with high levels of FOP or distress. 18,22,26
To date, no study has explored these aspects in ACC. The aim of our study is to investigate FOP, distress, and depression, as well as their impact on HRQOL in patients with ACC. We want to improve our understanding of whether and how men- tal and physical HRQOL are impaired in this group and to what degree FOP, distress, and depression are relevant factors.
Methods
Design and participants
In September 2023, we implemented this cross-sectional evaluation of patient-reported outcomes as part of our routine clinical care of adult patients with ACC. This observational study was conducted as part of the ENSAT registry study (www.ensat.org/registry) in our ACC centre in Würzburg, Germany. This registry study was approved by the ethics
committee of the University of Würzburg (Würzburg #88/ 11). All patients who participated in this study and the registry provided written informed consent. Trained personnel tried to contact as many patients as possible who visited our clinic un- til August 2024. Of the 108 approached patients, 3 declined participation.
Measures
Data collection included demographic (eg, sex, age at evalu- ation, and at diagnosis), clinical, and histological parameters, and the socioeconomic status sourced from both the ENSAT ACC registry and patients’ medical records. This included evi- dence of hormonal overproduction and ENSAT tumour stage.5 For various subanalyses, patients were divided accord- ing to (a) tumour burden, (b) current treatment modalities, and (c) hormone excess. For (a), tumour burden at the time of evaluation, patients were divided in 2 subgroups: tumour free vs. active disease and additionally for a supplementary analysis in 4 subgroups: recently diagnosed patients (time be- tween primary diagnosis and evaluation <3 months), patients without evidence of disease (tumour-free), patients with only 1 tumoural lesion, or patients with ≥2 tumoural lesions. For (b), the following treatment modalities were analysed: only sur- gery vs. mitotane mono therapy and in a second approach mi- totane monotherapy, cytotoxic chemotherapy (± mitotane), immunotherapy (± mitotane), radiotherapy (± mitotane), or no current treatment. For (c), hormone excess, we discrimi- nated cortisol (± other hormones), androgen, oestrogen, al- dosterone excess, and no current hormone excess.
In order to assess psychosocial variables (distress, FOP, depres- sive symptoms, and HRQOL) of patients with ACC, we included the following 4 validated questionnaires in our evaluation: Psychological distress was measured using the distress thermom- eter (DT), an ultra-brief screening tool developed by the National Comprehensive Cancer Network (NCCN). The scale is visual- ized as a thermometer ranging from 0 (“not distressed at all”) to 10 (“extremely distressed”), referring to the level of distress ex- perienced in the past week, including today. We used the German version, validated for cancer patients.19 We selected the Patient Health Questionnaire-9 Item Depression Module (PHQ-9) to assess symptoms of depression, which is a short form of the Patient Health Questionnaire.27 Patients rate how often they ex- perienced symptoms in the past 2 weeks on a 4-point scale: 0 (“not at all”), 1 (“on several days”), 2 (“on more than half the days”), and 3 (“nearly every day”). The summed scores classify depression severity as follows: 0-4 (none), 5-9 (mild), 10-14 (moderate), 15-19 (moderately severe), and 20-27 (severe). We utilized a cut-off score of ≥10 to indicate elevated levels of depres- sive symptoms.28 To assess FOP in our study, we used the vali- dated Fear of Progression-Questionnaire in its 12-item short form (FOP-Q-12).25 It was developed for cancer patients and other chronic conditions.25-30 Patients rate items on a 5-point Likert scale from 1 (“never”) to 5 (“very often”). A sum score is calculated, with a cut-off of >34 indicating a high level of FOP as previously suggested in cancer patients.31 We measured HRQOL with the EORTC-QLQ-30, a cancer-specific tool devel- oped by the European Organization for Research and Treatment of Cancer. The questionnaire consists of 30 items, divided into 9 multi-item scales and 6 single-item scales, covering a broad range of aspects of quality of life. The multi-item scales include 5 func- tional scales (physical, role, emotional, cognitive, and social), 3 symptom scales (fatigue, nausea/vomiting, and pain), and one
global health/quality of life scale.32 Single items address issues like appetite loss or financial difficulties. Except for the global health and quality of life scale, all items use a 4-point scale ran- ging from “not at all” (1 point) to “very much” (4 points). The global health/quality of life scale uses a 7-point scale from “very poor” to “excellent”.33 Scores are transformed into values between 0 and 100. High scores on functional or global health scales indicate better functioning or quality of life, whereas high scores on symptom scales indicate greater symptom bur- den.32 We defined a need for psychosomatic counselling if one or more cut-off scores in DT, PHQ-9, and/or FOP-Q-12 were reached. Participants for whom this was applicable were offered a psychological consultation within a short interval. If accepted, the consultation was conducted in-house by psychologists with specialized training in psychosomatic and psycho-oncological care. The conducting psychologists were informed about the need but did not receive details on questionnaire results. The con- tent of the psychological consultation was not prespecified. The timing of the psychological consultation varied and was sched- uled according to patients’ preferences.
Statistical analysis
We performed descriptive analyses to explore sample charac- teristics of relevant variables. Categorical variables were pre- sented as frequencies and percentages, while continuous variables were presented as means and SDs. Patients were as- signed to different groups according to their tumour mass, hormone excess, and cancer therapy as previously described. Statistical analysis included the use of Fisher’s exact test or the Wilcoxon rank-sum test where appropriate. To answer re- search questions, we conducted 2 multiple linear regression models to explore regressive associations of HRQOL sub- scales: “total symptoms” and “total functioning”. The sub- scale “total symptoms” included questions addressing fatigue, nausea and vomiting, dyspnoea, insomnia, appetite loss, constipation, and diarrhoea. The subscale “total func- tioning” included questions addressing physical, role, emo- tional, cognitive, and social functioning. We adjusted for sex, age, presence of the primary tumour or metastases, and cancer therapies (dummy-codings) and added psychosocial variables (FOP, distress, depressive symptoms) as predictors.
All reported P-values are two-sided, and statistical signifi- cance was considered when P <. 05. Data analysis was con- ducted using SPSS version 29 (IBM SPSS Statistics).
Results
Patient characteristics
A total of 105 patients were included in our study, 15 of whom had recently been diagnosed with ACC for the first time and of whom 49 were tumour-free. Median age was 49 years and most of the patients were female (56.2%). The patients’ charac- teristics, including cancer treatment and information on current or past psychotherapeutic treatment, are presented in Table 1.
In order to look for possible influencing factors, we divided the patients according to their tumour burden and, in another approach, according to their cancer therapy (Tables S1 and S2). Median age, sex, socioeconomic status, psychotherapy, and the intake of psychotherapeutic drugs did not differ ac- cording to cancer treatment or tumour burden. In both ana- lyses (tumour burden and cancer treatment), tumour stage, resection status, median time since diagnosis, cancer
treatment, and the type of hospitalization revealed to be sig- nificantly different between patient groups (Tables S1 and S2).
The descriptive results of assessed psychosocial variables are shown in Table 2.
Most of the patients demonstrated an elevated level of dis- tress (62%) and also high levels of FOP (59%). Symptoms of a major depression, according to PHQ-9, were present in 41% of participants. The EORTC-QLQ-30 showed a median of 62.2 for functioning and a median of 33.3 for symptom burden.
Furthermore, we performed statistical analyses including the use of Fisher’s exact test to analyse if assessed psychosocial variables differ according to tumour burden (tumour free vs. active disease) (Table 3 and table S3), cancer treatment (only surgery vs. mitotane mono therapy) (Table 4 and table S4) or hormone excess (Table S5). Only patients treated with mi- totane showed a tendency for a higher fear of progression and a significantly higher symptom burden compared to patients treated surgery only. None of the other variables revealed sig- nificant P-values.
We used the scores of the instruments we used to assess fear of progression (FOP-Q-12), distress (DT) and depressive symptoms (PHQ-9) as screening tools for the need for add- itional psychosomatic counselling and offered support to pa- tients with elevated levels in one or more of these questionnaires (see Table 2). Most of our patients (80%) ful- filled our criteria for a need for psychosomatic counselling ac- cording to our approach. Out of all participants to whom we made the offer for counselling, 33% accepted it. Descriptive differences in psychosomatic needs and acceptance of counsel- ling are depicted in Table 5. There was no significant differ- ence between these subgroups.
Furthermore, we evaluated HRQOL with the EORTC-QLQ-30 questionnaire according to functional and symptom scales. Our cohort showed high scores with a me- dian of 80 for physical functioning and a median of 50 for role, emotional, and social functioning, indicating that our co- hort had better physical functioning compared to role, emo- tional, and social functioning. The EORTC-QLQ-30 symptom subcategories showed high scores for fatigue and in- somnia in our patients, pointing to a symptom burden (see Table S6).
In another approach, we analysed the EORTC-QLQ-30 functional and symptom subcategories according to tumour burden, cancer treatment, and hormone excess. We saw sig- nificant differences between patients with a recent initial diag- nosis in comparison to patients without any tumour or with low/high tumour burden (Tables S7 and S8). However, there were no significant differences between patients with or with- out a hormone excess (Table S9).
In addition, the subcategories for symptoms showed only for the category appetite loss, diarrhoea, nausea and vomiting, and for financial difficulties, significant differences between the patient groups divided into tumour burden and cancer treatment (Tables S10 and S11). Again, there were no signifi- cant differences between patients with or without a hormone excess (Table S12).
Data of 88 individuals were included for the multiple linear regression analysis for HRQOL “total functioning” and “to- tal symptoms.” We included age, sex, presence of metastases, cancer therapy (mitotane, chemotherapy, immunotherapy, radiotherapy), and psychosocial variables (FOP, distress, de- pressive symptoms) into each regression model. The model
| n =105 | |
|---|---|
| Median age at primary diagnosis- years (range) | 49 (17-78) |
| Sex-n (%) | |
| Male | 46 (43.8) |
| Female | 59 (56.2) |
| Marital status-n (%) | |
| Single | 28 (26.7) |
| Married | 71 (67.6) |
| Divorced | 4 (3.8) |
| Widowed | 2 (1.9) |
| Occupational status-n (%) | |
| Student | 4 (3.8) |
| Stay-at-home parent | 2 (1.9) |
| Employee or freelancer | 42 (40.0) |
| Retired | 32 (30.5) |
| Unemployed | 5 (4.8) |
| Unknown | 20 (19.0) |
| Highest school-leaving qualification-n (%) | |
| Basic school | 14 (13.3) |
| 10th grade | 21 (20.0) |
| 12th/13th grade | 12 (11.4) |
| University degree | 37 (35.2) |
| Unknown | 21 (20.0) |
| Insurance status-n (%) | |
| Compulsory | 94 (89.5) |
| Private | 11 (10.5) |
| ENSAT stage at primary diagnosis-n (%) | |
| 1 | 12 (11.4) |
| 2 | 39 (37.1) |
| 3 | 24 (22.9) |
| 4 | 28 (26.7) |
| Unknown | 2 (1.9) |
| Resection status at primary diagnosis-n (%) | |
| 0 1 2 | 66 (62.9) |
| 10 (9.5) | |
| 0 (0) | |
| X | 27 (25.7) |
| No resection | 2 (1.9) |
| Median age at evaluation-years (min-max) | 55 (18-82) |
| Median time elapsed since primary diagnosis-months (range) | 34 (1-349) |
| Disease stage at evaluation-n (%) | |
| Tumour free | 49 (46.7) |
| Recurrence | 18 (17.1) |
| Advanced ACC | |
| Stable disease | 29 (27.6) |
| Progressive disease | 8 (7.6) |
| Tumour burden at evaluation-n (%) | |
| Recent initial diagnosis | 14 (13.3) |
| Tumour-free | 49 (46.7) |
| 1 tumour lesion | 15 (12.3) |
| ≥ 2 tumour lesions | 27 (25.7) |
| Treatment at evaluation-n (%) | |
| Only surgery | 45 (42.9) |
| Mitotane mono | 30 (28.6) |
| Chemotherapy (±mitotane) | 13 (12.4) |
| Immunotherapy (±mitotane) | 15 (14.3) |
| Radiotherapy (+mitotane) | 2 (2.0) |
| Hormone excess at evaluation-n (%) | |
| No hormone excess | 52 (49.5) |
| Cortisol excess | 22 (20.9) |
| Androgen excess | 11 (10.5) |
| Cortisol+ androgen excess | 10 (9.5) |
| Oestrogen excess | 1 (1.0) |
| Aldosterone excess | 1 (1.0) |
| Unknown | 8 (7.6) |
| Type of hospitalization-n (%) | |
| Outpatient | 70 (66.7) |
| Inpatient | 35 (33.3) |
| (continued) |
| n = 105 | |
|---|---|
| Secondary extra-adrenal malignancyª | 1 (1.0) |
| Psychotherapy-n (%) | |
| Currently receiving psychotherapy | 27 (25.7) |
| Previously received psychotherapy | 8 (7.6) |
| No history of psychotherapy | 61 (58.1) |
| Medication of psychotropic drugs-n (%) | |
| No medication | 87 (82.9) |
| Currently under medication | 9 (8.6) |
aOne patient with breast cancer before ACC.
n, number.
on HRQOL “total symptoms” was significant (F(10, 78) = 10.646, P <. 001) and revealed a medium model fit (R2orr= 0.523). Depressive symptoms according to PHQ-9 revealed to be the only variable significantly associated with “total symptoms” (Bs = 0.620, P <. 001). Multiple linear regression on HRQOL “total functioning” was also significant (F(10, 78) = 22.159, P <. 001) and revealed a medium to high model fit (Rcorr = 0.706). Depressive symptoms demonstrated a sig- nificant negative association with “total functioning” (Bs = -0.673, P <. 001). Additionally, presence of metastases (Bs =- 0.162, P =. 016) and age (Bs =- 0.244, P <. 001) were also revealed to be significant variables concerning “total functioning.” With variance inflation factors ranging from 1.121 to 2.474, multicollinearity is likely not indicated for the included variables in both regressions. Results of the 2 multiple linear regressions in detail are depicted in tables S13 and S14.
Discussion
This study is the first to investigate fear of progression (FOP), distress, and depression in a large sample of patients with ACC, as well as the association with health-related quality of life (HRQOL). More than half of our participants reported high levels of distress and FOP, and 40% showed clinically relevant depressive symptoms.
In our sample, 59% of patients reported a distress thermom- eter (DT) score greater than 5, exceeding the proportions ob- served in studies of breast cancer (45%),34 lung cancer (52%)35, and mixed cancer populations.36 However, findings from a multicentre study including over 1000 patients with various cancer types showed a comparable prevalence of dis- tress (63%).37 Even higher distress levels have been reported in patients with Li-Fraumeni syndrome, with a median DT score of 5.7% and 69.1% scoring above the threshold.22
Compared to previously studied cancer populations, our co- hort showed even higher FOP scores .. 23,25 The rarity of ACC and the limited treatment options, similar to other metastatic cancer types or rare syndromes like Li-Fraumeni-syndrome, might be an explanation for the high FOP and distress scores in our cohort.
In addition, 41% of our patients showed a highly clinically relevant level of depressive symptoms according to PHQ-9.
In line with our objective to explore associations between psychosocial variables and HRQOL, depressive symptoms emerged as the only significant predictor for the HRQOL sub- scale “total symptoms” in our regression model. This associ- ation remained robust even after adjusting for treatment type and metastatic status. Our results demonstrate the relevance
| na | Median (range) | Mean (SD) | Thresholdb indicating high symptom level | Threshold n (%) | |
|---|---|---|---|---|---|
| Distress last week, including today | 92 | 5.5 | 5.6 | ≥5 | 62 (59.0) |
| (0-10) | (2.9) | ||||
| Fear of Progression (sum score) | 105 | 35 | 34.7 | ≥34 | 59 (56.2) |
| (14-55) | (9.2) | ||||
| PHQ-9 Depression | 101 | 7 | 8.2 | ≥10 | 41 (39.0) |
| (0-26) | (5.9) | ||||
| Quality of Life-functional | 103 | 62.2 | 59.8 | — | — |
| (6.7-97.8) | (23.5) | ||||
| Quality of Life-symptoms | 103 | 33.3 | 33.8 | — | — |
| (0-87.2) | (21.6) |
ªSome patients did not fill in all the questionnaires explaining the different number of patients.
Thresholdb: The number of patients whose scores exceed the specified threshold. Threshold values indicative of elevated symptom levels are: distress thermometer: scores ≥5; fear of progression: scores ≥34; PHQ-9 Depression Scale: scores ≥10. n, number.
| Tumour Free n =49 | Active Diseaseª n = 55 | P | |
|---|---|---|---|
| Distress last week, including today | |||
| n | 44 | 47 | |
| Mean (SD) | 5.1 (3.0) | 5.9 (2.8) | 0.30 |
| Median (range) | 5 (0-10) | 6.0 (2-10) | |
| Above threshold n (%) | 25 (51.0) | 36 (66.7) | 0.75 |
| Fear of progression (sum score) | |||
| n | 49 | 55 | |
| Mean (SD) | 34.0 (9.3) | 35.5 (9.1) | 0.22 |
| Median (min-max) | 33 (14-50) | 36 (15-55) | |
| Above threshold n (%) | 24 (49.0) | 33 (60.0) | 0.32 |
| PHQ-9 depression | |||
| n | 48 | 54 | |
| Mean (SD) | 7.6 (5.8) | 8.9 (5.9) | 0.69 |
| Median (range) | 6.5 (0-20) | 8 (1-16) | |
| Above threshold n (%) | 18 (36.7) | 29 (53.3) | 0.22 |
| Quality of life-functional | |||
| n | 49 | 55 | |
| Mean (SD) | 63.1 (24.1) | 56.7 (22.8) | 0.55 |
| Median (range) | 64.4 (13.3-97.8) | 57.7 (6.6-97.8) | 0.65 |
| Quality of life-symptoms | |||
| n | 49 | 55 | |
| Mean (SD) | 31.3 (24.2) | 35.7 (18.1) | 0.23 |
| Median (range) | 25.6 (0-87.2) | 38.4 (0-87.1) | 0.15 |
Threshold: the number of patients whose scores exceed the specified threshold. Threshold values indicative of elevated symptom levels are: distress thermometer: scores ≥5; fear of progression: scores ≥34; PHQ-9 depression scale: scores ≥10. n, number.
ªIncluding patients with low and high tumour burden.
of assessing and treating depressive symptoms in patients with ACC not only to increase well-being and general quality of life but also for limiting physical symptoms and decreasing pos- sible treatment-associated adverse effects like nausea or pain.
An essential part of our study was to screen our participants for a need for psychosomatic counselling, which the majority of our patients fulfilled. Despite the high level of indicated need, only one third accepted support, suggesting potential barriers to psychosomatic care. One contributing factor may be the considerable travel distance reported by many partici- pants, which likely posed a substantial barrier to attending additional psychological consultations.
The underutilization of psycho-oncological services may be attributed to several barriers. One potential factor may be an in- sufficient provision of information regarding the procedures and
possible content of psycho-oncological support. Additionally, a lack of confidence in the potential benefits of psychological con- sultations and concerns related to stigmatization may also have contributed to the low uptake of these services. Also, a lack of organizational integration into routine care cannot be ruled out. Which barriers specifically apply to the unique group of ACC patients’ need to be further investigated to develop targeted interventions aimed at mitigating these obstacles.38,39 Our re- sults also revealed a high need for counselling in patients who are currently tumour-free or have a low tumour burden. Therefore, our findings highlight that psychosocial burden is widespread among patients with ACC and there is no clear rela- tion to tumour characteristics or other clinical variables.
Of note, patients with higher tumour burden, cancer treat- ment that was more aggressive or a hormonal overproduction
| Only Surgery n = 45 | Mitotane Mono therapy n=30 | P | |
|---|---|---|---|
| Distress last week, including today | |||
| n | 40 | 27 | |
| Mean (SD) | 5.4 (3.2) | 6.2 (2.8) | 0.49 |
| Median (min-max) | 5 (0-10) | 7 (0-10) | 0.32 |
| Above threshold n (%) | 25 (55.6) | 18 (60.0) | |
| Fear of progression (sum score) | |||
| n | 45 | 30 | |
| Mean (SD) | 34.2 (9.7) | 37.4 (8.3) | 0.19 |
| Median (min-max) | 33 (14-54) | 39 (17-50) | 0.053 |
| Above threshold n (%) | 22 (48.9) | 22 (73.3) | |
| PHQ-9 depression | |||
| n | 45 | 28 | |
| Mean (SD) | 7.1 (5.6) | 9.6 (5.9) | 0.76 |
| Median (min-max) | 4 (0-26) | 8 (1-26) | 0.24 |
| Above threshold n (%) | 16 (35.6) | 13 (43.3) | |
| Quality of life-functional | |||
| n | 45 | 30 | |
| Mean (SD) | 67.2 (29.3) | 55.7 (21.8) | 0.39 |
| Median (min-max) | 83.4 (13.3-97.8) | 56.6 (6.7-88.9) | 0.20 |
| Quality of life-symptoms | |||
| n | 45 | 30 | |
| Mean (SD) | 28.8 (22.8) | 41.7 (21.8) | 0.23 |
| Median (min-max) | 16.6 (0-87.2) | 42.3 (7.7-87.2) | 0.007 |
Threshold: The number of patients whose scores exceed the specified threshold. Threshold values indicative of elevated symptom levels are: distress thermometer: scores ≥5; fear of progression: scores ≥34; PHQ-9 depression scale: scores ≥10. n, number.
| Psychosomatic counselling needs- n (%) | Acceptance of the offer-n (%) | |
|---|---|---|
| Overall n =105 | 84 (80.0) | 28 (33.3) |
| Tumour-free n = 49 | 36 (73.5) | 10 (27.7) |
| Recent initial diagnosis n =15 | 13 (86.7) | 7 (53.8) |
| Low tumour burden n =27 | 24 (88.9) | 7 (29.2) |
| High tumour burden n =13 | 10 (76.9) | 4 (40.0) |
| No treatment n = 45 | 33 (73.3) | 9 (27.3) |
| Mitotane mono n =30 | 27 (90.0) | 10 (37.0) |
| Chemotherapy (±mitotane) n=13 | 10 (76.9) | 5 (50.0) |
| Immunotherapy (±mitotane) n =15 | 12 (80.0) | 4 (33.3) |
n, number.
caused by ACC had similar values in the questionnaires com- pared to ACC patients who were tumour-free, had a therapy with less adverse events or no hormonal excess. The diagnosis of ACC itself may be a mutual burdening factor. Effective sys- temic therapy options are limited in this disease, which may cause high levels of FOP, depression, and loss of control, mak- ing tumour burden and hormonal excess less significant in these measures.
The published studies on other cancer types showed contro- versial results regarding the correlation of these questionnaires with clinical characteristics. Geerse et al. detected a higher
level of distress in lung cancer patients with more symptoms and a shorter median survival.35
However, repeated findings in psycho-oncological research indicate that differences in distress, for example, across vari- ous tumour stages or treatment modalities and timings, are not necessarily significant.40,41 A retrospective study by de Mol et al. could not demonstrate that distress is dependent on clinical criteria.42 A study investigating fear of cancer re- currence in cervical cancer identified only anxiety disorders as a predictor for a higher fear of recurrence.23 These findings may suggest that psycho-oncological support should be uni- versally offered to patients regardless of these factors. The ex- tent to which this is the case in the ACC group requires further investigation, particularly given the limited sample size of our study.
We also investigated HRQOL by using the EORTC QLQ-C30. This questionnaire showed moderate levels of functioning and a moderate symptom burden in our ACC pa- tients. Until now, there are only few other studies that meas- ured HRQOL in overall 468 patients with ACC, all indicating a reduced HRQOL compared to the general population.10,14,16,43-48 Three of these studies used the EORTC QLQ-C30 questionnaire.10,14,16 In the FIRM-ACT trial in patients with metastatic ACC, a median EORTC QLQ-C30 score at baseline of 58.3/100 (n =204),10 suggest- ing that our cohort was not better off than these patients with advanced disease. The ADIUVO trial showed a signifi- cant impairment in quality of life due to the treatment with mi- totane in patients with ACC detected by the assessment of EORTC QLQ-C30 questionnaires, but these results are based on only 18 patients.14 Another study demonstrated in 118 ACC patients that the overall score was significantly lower for patients who underwent active treatment within the last 1000 days, including surgery, adjuvant radiotherapy, mito- tane therapy, or chemotherapy (mean overall EORTC
QLQ-C30 score 72.2). These patient groups reported a signifi- cantly lower HRQOL in several domains, including lower role, emotional and cognitive functioning, and a higher fatigue score on the EORTC QLQ-C30, but the inclusion of only pa- tients treated for more than 1000 days might have introduced a bias. 16
In contrast, there are several studies on other cancer types using the EORTC-QLQ-C30 questionnaire. A study with over 5000 breast cancer patients reported differences in HRQOL scores between stages, performance status, and co- morbidities. While early breast cancer patients presented bet- ter HRQOL with high baseline functioning scores and low prevalence of symptoms, metastatic breast cancer patients re- ported worse HRQOL with lower functioning scores and more prevalence of symptoms. In metastatic breast cancer pa- tients, poor performance status and the presence of comorbid- ities reflected worse baseline HRQOL. With reservations, this is in line with our study, as metastases seemed to contribute to HRQOL total functioning. No consistent differences were found for age and countries. 49 Koch et al. investigated the psy- chosocial burden and quality of life in lung cancer patients by using the EORTC-QLQ-C30 questionnaire. The mean score for quality of life was 47.8. As our symptom score was even more impaired, this indicates the unique burden of ACC pa- tients, as half of our cohort was actually tumour free.50
Strengths and limitations
Still, little is known about patients with ACC and accompany- ing psychosocial aspects. It is a rare disease, with an incidence of 1 per million per year, our cohort is an important and much- needed contribution to research for this understudied group. We developed a new approach in ACC care to identify patients with a need for psychosomatic counselling. Our concept re- vealed a surprisingly high number of those in need of counsel- ling. In addition to this, an assessment of qualitative data would have been beneficial. The possibly unique aspects of pa- tients with ACC need to be further identified to improve their health care. Also, an evaluation of the offered psychosomatic counselling and reasons for declining should have been in- cluded in order to make adjustments accordingly. Another im- portant limitation is that we did not systematically assess the reasons why patients have declined the psychological support, despite the objective need. Understanding these factors would have provided valuable insights for improving access to and acceptance of psychological care.
This study also has some methodological limitations that should be acknowledged. Although we did not find an associ- ation regarding hormone excess, the EORTC QLQ-C30 was not originally designed to offer a comprehensive assessment of cognitive functioning.51 As a result, the impact of hormone excess on cognitive symptoms may have been underestimated.
Additionally, regarding statistical analysis, the low number of participants in the subgroup analysis limits the statistical power and robustness of our between-group comparisons. Our cross-sectional study design precludes causal relation- ships, as all variables were assessed at a single time point. Consequently, we cannot capture temporal changes in psycho- logical symptoms, which are suggested to change over time due to the diagnostic work-up and treatment course. Another important limitation is that certain potentially influ- ential covariates were not captured or controlled for in the present analysis, such as duration of cortisol excess prior to
evaluation. Although no current hormone excess may be de- tected at the time of evaluation, residual effects of prior corti- sol overexposure cannot be excluded and may still influence patients’ current mental or physical well-being.52 Moreover, psychological burden was assessed using only self-assessment tools. We did not use any clinical interviews. As a last limita- tion, we need to mention the lack of validation of the results by a specialist regarding the results derived from the questionnaires.
Conclusion
Our results imply that patients with ACC experience several psychosomatic burdens, including symptoms of distress, de- pression, and fear of progression, with depressive symptoms seemingly contributing most to impairment of HRQOL. In our study, we detected a need for psychosomatic counselling in 80% of participants. The observation that merely one-third of these 80% accepted psychological counselling underscores the need to better understand and address barriers to psycho- logical care in this population.
Therefore, regular screening for distress and depression is highly recommended for all patients with ACC, regardless of their current clinical state (eg, disease-free or low tumour bur- den). Psychosomatic counselling needs to be established for this vulnerable group.
Larger-scale studies, ideally multicentre, are required to val- idate our preliminary observations regarding subgroup- specific effects. Nevertheless, the rarity of the disease poses a significant challenge to achieving the required sample sizes. Longitudinal research is needed to establish whether psycho- logical distress in ACC reflects a stable psychological trait or indeed varies according to disease stage and timing. Furthermore, standardized clinical interviews conducted by specialists should be implemented in the future.
Acknowledgments
We are thankful for the continuous help in data documenta- tion from Michaela Haaf.
Authors’ contributions
Otilia Kimpel (Conceptualization [equal], Data curation [equal], Formal analysis [equal], Visualization [equal], Writing-original draft [equal]), Senta Kiermeier (Conceptualization [equal], Data curation [equal], Formal analysis [equal], Visualization [equal], Writing-original draft [equal]), Emely Stahl (Data curation [equal], Formal analysis [equal]), Barbara Altieri (Writing-review & editing [equal]), Martin Fassnacht (Conceptualization [equal], Funding acqui- sition [equal], Supervision [equal], Writing-review & editing [equal]), and Imad Maatouk (Conceptualization [equal], Funding acquisition [equal], Supervision [equal], Writing- review & editing [equal])
Supplementary material
Supplementary material is available at European Journal of Endocrinology online.
Conflict of interest: OK received speaker honoraria from HRA Pharma Rare Diseases. All other authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
Funding
This study was supported by the Clinician Scientist Programme RISE, funded by the Else Kroner-Fresenius-Stiftung and the Eva Luise und Horst Köhler Stiftung and the German Research Foundation (DFG) project 314061271 (TRR-CRC 205), and the Habilitations programme for women by the interdisciplin- ary centre for clinical research (IZKF) in Würzburg.
Data availability
ACC is an ultra-rare disease and patient privacy is important. However, we are committed to sharing data with all qualified external researchers. Requests have to be sent to the corre- sponding authors. All data provided are anonymized to re- spect the privacy of the patients.
Ethics approval and consent to participate
This study was part of the ENSAT registry study (www.ensat. org/registry) in Würzburg, Germany. It was conducted in ac- cordance with the Declaration of Helsinki and approved by the ethics committee in Würzburg (#88/11) on 17 May 2011. Informed consent was obtained from all subjects in- volved in the study.
References
1. Vaidya A, Nehs M, Kilbridge K. Treatment of adrenocortical car- cinoma. Surg Pathol Clin. 2019;12(4):997-1006. https://doi.org/ 10.1016/j.path.2019.08.010
2. Elhassan YS, Altieri B, Berhane S, et al. S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multi- center ENSAT study. Eur J Endocrinol. 2021;186(1):25-36. https:/doi.org/10.1530/EJE-21-0510
3. Fassnacht M, Assie G, Baudin E, et al. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(11):1476-1490. https://doi.org/10.1016/j.annonc. 2020.08.2099
4. Berruti A, Fassnacht M, Haak H, et al. Prognostic role of overt hy- percortisolism in completely operated patients with adrenocortical cancer. Eur Urol. 2014;65(4):832-838. https://doi.org/10.1016/j. eururo.2013.11.006
5. Fassnacht M, Johanssen S, Quinkler M, et al. Limited prognostic value of the 2004 International Union Against Cancer staging clas- sification for adrenocortical carcinoma: proposal for a revised TNM classification. Cancer. 2009;115(2):243-250. https://doi. org/10.1002/cncr.24030
6. Schulick RD, Brennan MF. Long-term survival after complete resec- tion and repeat resection in patients with adrenocortical carcinoma. Ann Surg Oncol. 1999;6(8):719-726. https://doi.org/10.1007/ s10434-999-0719-7
7. Pommier RF, Brennan MF. An eleven-year experience with adreno- cortical carcinoma. Surgery. 1992;112(6):963-970; discussion 70-1.
8. Fassnacht M, Dekkers OM, Else T, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018;179(4):G1-G46. https://doi.org/10.1530/EJE- 18-0608
9. Kimpel O, Bedrose S, Megerle F, et al. Adjuvant platinum-based chemotherapy in radically resected adrenocortical carcinoma: a
cohort study. Br J Cancer. 2021;125(9):1233-1238. https://doi. org/10.1038/s41416-021-01513-8
10. Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366(23): 2189-2197. https://doi.org/10.1056/NEJMoa1200966
11. Kimpel O, Dischinger U, Altieri A, et al. Current evidence on local therapies in advanced adrenocortical carcinoma. Horm Metab Res. 2023;56(1):91-98. https://doi.org/10.1055/a-2209-6022
12. Fassnacht M, Puglisi S, Kimpel O, Terzolo M. Adrenocortical car- cinoma: a practical guide for clinicians. Lancet Diabetes Endocrinol. 2025;13(5):438-452. https://doi.org/10.1016/S2213- 8587(24)00378-4
13. Alcalar N, Ozkan S, Kadioglu P, et al. Evaluation of depression, quality of life and body image in patients with Cushing’s disease. Pituitary. 2013;16(3):333-340. https://doi.org/10.1007/s11102- 012-0425-5
14. Terzolo M, Fassnacht M, Perotti P, et al. Adjuvant mitotane versus sur- veillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study. Lancet Diabetes Endocrinol. 2023;11(10): 720-730. https://doi.org/10.1016/S2213-8587(23)00193-6
15. Steenaard RV, Michon LA, Haak HR. Health-related quality of life in adrenocortical carcinoma. Cancers (Basel). 2019;11(10):1500. https://doi.org/10.3390/cancers11101500
16. Steenaard RV, Kerkhofs TMA, Zijlstra M, et al. Health-related quality of life in adrenocortical carcinoma: development of the disease-specific questionnaire ACC-QOL and results from the PROFILES registry. Cancers (Basel). 2022;14(6):1366. https://doi. org/10.3390/cancers14061366
17. Herschbach P, Britzelmeir I, Dinkel A, et al. Distress in cancer pa- tients: who are the main groups at risk? Psychooncology. 2020;29(4):703-710. https://doi.org/10.1002/pon.5321
18. Hass HG, Seywald M, Wöckel A, Muco B, Tanriverdi M, Stepien J. Psychological distress in breast cancer patients during oncological in- patient rehabilitation: incidence, triggering factors and correlation with treatment-induced side effects. Arch Gynecol Obstet. 2023;307(3):919-925. https://doi.org/10.1007/s00404-022-06657-3
19. Mehnert A, Müller D, Lehmann C, Koch U. Die deutsche version des NCCN distress-thermometers. Z Psychiatr Psychol Psychother. 2006;54(3):213-223. https://doi.org/10.1024/1661- 4747.54.3.213
20. Simard S, Thewes B, Humphris G, et al. Fear of cancer recurrence in adult cancer survivors: a systematic review of quantitative studies. J Cancer Surviv. 2013;7(3):300-322. https://doi.org/10.1007/ s11764-013-0272-z
21. Herschbach P, Dinkel A. Fear of progression. Recent Results Cancer Res. 2014;197:11-29. https://doi.org/10.1007/978-3-642- 40187-9_2
22. Kiermeier S, Schott S, Nees J, et al. Health-related quality of life and fear of progression in individuals with Li-Fraumeni syndrome. J Genet Couns. 2024;34(1):e1859. https://doi.org/10.1002/jgc4.1859
23. Hanprasertpong J, Geater A, Jiamset I, Padungkul L, Hirunkajonpan P, Songhong N. Fear of cancer recurrence and its predictors among cervical cancer survivors. J Gynecol Oncol. 2017;28(6):e72. https://doi.org/10.3802/jgo.2017.28.e72
24. Koch L, Jansen L, Brenner H, Arndt V. Fear of recurrence and dis- ease progression in long-term (≥5 years) cancer survivors-a sys- tematic review of quantitative studies. Psychooncology. 2013;22(1):1-11. https://doi.org/10.1002/pon.3022
25. Mehnert A, Berg P, Henrich G, Herschbach P. Fear of cancer pro- gression and cancer-related intrusive cognitions in breast cancer survivors. Psychooncology. 2009;18(12):1273-1280. https://doi. org/10.1002/pon.1481
26. Erdoğan Yüce G, Döner A, Muz G. Psychological distress and its as- sociation with unmet needs and symptom burden in outpatient can- cer patients: a cross-sectional study. Semin Oncol Nurs. 2021;37(5):151214. https://doi.org/10.1016/j.soncn.2021.151214
27. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9): 606-613. https://doi.org/10.1046/j.1525-1497.2001.016009606.x
28. Gräfe K, Zipfel S, Herzog W, Löwe B. Screening psychischer Störungen mit dem “Gesundheitsfragebogen für Patienten (PHQ-D)“. Diagnostica. 2004;50(4):171-181. https://doi.org/10. 1026/0012-1924.50.4.171
29. Dankert A, Duran G, Engst-Hastreiter U, et al. Fear of progression in patients with cancer, diabetes mellitus and chronic arthritis. Rehabilitation (Stuttg). 2003;42(3):155-163. https://doi.org/10. 1055/s-2003-40094
30. Zimmermann T, Herschbach P, Wessarges M, Heinrichs N. Fear of progression in partners of chronically ill patients. Behav Med. 2011;37(3):95-104. https://doi.org/10.1080/08964289.2011.605399
31. Herschbach P, Berg P, Waadt S, et al. Group psychotherapy of dys- functional fear of progression in patients with chronic arthritis or cancer. Psychother Psychosom. 2010;79(1):31-38. https://doi.org/ 10.1159/000254903
32. Fayers P, Bottomley A. Quality of life research within the EORTC-the EORTC QLQ-C30. European Organisation for Research and Treatment of Cancer. Eur J Cancer. 2002;38 Suppl 4:S125-S133. https://doi.org/10.1016/S0959-8049(01)00448-8
33. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-376. https://doi.org/ 10.1093/jnci/85.5.365
34. Sun H, Lv H, Zeng H, Niu L, Yan M. Distress Thermometer in breast cancer: systematic review and meta-analysis. BMJ Support Palliat Care. 2022;12(3):245-252. https://doi.org/10.1136/bmjspcare- 2021-002960
35. Geerse OP, Brandenbarg D, Kerstjens HAM, et al. The distress thermometer as a prognostic tool for one-year survival among pa- tients with lung cancer. Lung Cancer. 2019;130:101-107. https:/ doi.org/10.1016/j.lungcan.2019.02.008
36. Tonsing KN, Vungkhanching M. Assessing psychological distress in cancer patients: the use of distress thermometer in an outpatient can- cer/hematology treatment center. Soc Work Health Care. 2018;57(2): 126-136. https://doi.org/10.1080/00981389.2017.1402844
37. Fabian A, Rühle A, Domschikowski J, et al. Psychosocial distress in cancer patients undergoing radiotherapy: a prospective na- tional cohort of 1042 patients in Germany. J Cancer Res Clin Oncol. 2023;149(11):9017-9024. https://doi.org/10.1007/s00432- 023-04837-5
38. Neumann M, Galushko M, Karbach U, et al. Barriers to using psycho-oncology services: a qualitative research into the perspec- tives of users, their relatives, non-users, physicians, and nurses. Support Care Cancer. 2010;18(9):1147-1156. https://doi.org/10. 1007/s00520-009-0731-2
39. Dilworth S, Higgins I, Parker V, Kelly B, Turner J. Patient and health professional’s perceived barriers to the delivery of psychosocial care to adults with cancer: a systematic review. Psychooncology. 2014;23(6):601-612. https://doi.org/10.1002/pon.3474
40. Maatouk I, He S, Hummel M, et al. Patients with precursor disease exhibit similar psychological distress and mental HRQOL as pa- tients with active myeloma. Blood Cancer J. 2019;9(2):9. https:// doi.org/10.1038/s41408-019-0172-1
41. Mayer S, Fuchs S, Fink M, et al. Hope and distress are not associ- ated with the brain tumor stage. Front Psychol. 2021;12:642345. https://doi.org/10.3389/fpsyg.2021.642345
42. de Mol M, den Oudsten BL, Aarts M, Aerts J. The distress therm- ometer as a predictor for survival in stage III lung cancer patients treated with chemotherapy. Oncotarget. 2017;8(22):36743-36749. https://doi.org/10.18632/oncotarget.14151
43. Pikkarainen L, Sane T, Reunanen A. The survival and well-being of patients treated for Cushing’s syndrome. J Intern Med. 1999;245(5):463-468. https://doi.org/10.1046/j.1365-2796.1999. 00483.x
44. Von Essen L, Larsson G, Öberg K, Sjödén PO. Satisfaction with care’: associations with health-related quality of life and psycho- social function among Swedish patients with endocrine gastrointes- tinal tumours. Eur J Cancer Care (Engl). 2002;11(2):91-99. https:/ doi.org/10.1046/j.1365-2354.2002.00293.x
45. Sippel RS, Elaraj DM, Kebebew E, Lindsay S, Tyrrell JB, Duh QY. Waiting for change: symptom resolution after adrenalectomy for Cushing’s syndrome. Surgery. 2008;144(6):1054-1060; discussion 60-1. https://doi.org/10.1016/j.surg.2008.08.024
46. Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C. Mifepristone, a glucocorticoid receptor antagonist, produ- ces clinical and metabolic benefits in patients with Cushing’s syn- drome. J Clin Endocrinol Metab. 2012;97(6):2039-2049. https:// doi.org/10.1210/jc.2011-3350
47. Katznelson L, Loriaux DL, Feldman D, Braunstein GD, Schteingart DE, Gross C. Global clinical response in Cushing’s syndrome pa- tients treated with mifepristone. Clin Endocrinol (Oxf). 2014;80(4):562-569. https://doi.org/10.1111/cen.12332
48. Dovirak O, Mao J, Taylor K, Chang P, Wagner AA. How to quan- tify recovery after laparoscopic adrenalectomy: an assessment of patient-reported health-related quality of life. Surg Laparosc Endosc Percutan Tech. 2016;26(4):290-294. https://doi.org/10. 1097/SLE.0000000000000290
49. Mierzynska J, Taye M, Pe M, et al. Reference values for the EORTC QLQ-C30 in early and metastatic breast cancer. Eur J Cancer. 2020;125:69-82. https://doi.org/10.1016/j.ejca.2019.10.031
50. Koch M, Gräfenstein L, Karnosky J, Schulz C, Koller M. Psychosocial burden and quality of life of lung cancer patients: re- sults of the EORTC QLQ-C30/QLQ-LC29 questionnaire and horn- heide screening instrument. Cancer Manag Res. 2021;13: 6191-6197. https://doi.org/10.2147/CMAR.S314310
51. Cusatis R, Balza J, Uttke Z, et al. Patient-reported cognitive func- tion among hematopoietic stem cell transplant and cellular therapy patients: a scoping review. Qual Life Res. 2023;32(4):939-964. https://doi.org/10.1007/s11136-022-03258-0
52. Puglisi S, Perini AME, Botto C, Oliva F, Terzolo M. Long-term con- sequences of Cushing syndrome: a systematic literature review. J Clin Endocrinol Metab. 2024;109(3):e901-e919. https://doi.org/ 10.1210/clinem/dgad453
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