High Fear of Disease Occurrence Is Associated With Low Quality of Life in Patients With Multiple Endocrine Neoplasia Type 1: Results From the Dutch MEN1 Study Group

High Fear of Disease Occurrence Is Associated With Low Quality of Life in Patients With Multiple... Abstract Objective Multiple endocrine neoplasia type 1 (MEN1) is a hereditary disease characterized by a high risk of developing primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors, and pituitary tumors (PITs). It is unclear if having MEN1 leads to psychological distress because of fear of disease occurrence (FDO), thereby potentially affecting quality of life. Design A cross-sectional study was performed using the Dutch MEN1 cohort. All patients received the Cancer Worry Scale (a score ≥14 reflects high FDO), the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36), and questions on sociodemographic and medical history. Results A total of 227 of 285 (80%) eligible patients with MEN1 completed the questionnaire. The mean (± standard deviation) age was 47 ± 15 years. Overall, patients experienced an FDO of 15.1 ± 4.7, with 58% of patients having a score ≥14. This is higher than reported in previous studies assessing fear of cancer recurrence in different cancer populations (31% to 52%). Adjusted for age and sex, the FDO score was negatively associated with almost all SF-36 subscales. In multivariable analysis, the diagnosis of a PIT, a pancreatic neuroendocrine tumor, and not being employed were associated with FDO (P < 0.05). Patients had higher FDO scores for their family members than for themselves. Conclusion The majority of patients with MEN1 have FDO for themselves and even more for their relatives. This psychological distress is associated with a lower health-related quality of life. Therefore, in the medical care for MEN1, emphasis should also be placed on FDO and quality of life. Multiple endocrine neoplasia type 1 (MEN1) is a hereditary disease with an autosomal dominant inheritance pattern caused by a germline mutation on chromosome 11q13 (1). MEN1 is characterized by a lifetime risk of developing primary hyperparathyroidism (pHPT) of almost 100%, a lifetime risk of developing duodenopancreatic neuroendocrine tumors (dpNETs) of >80%, and a lifetime risk of developing pituitary tumors (PITs) of 70% (1–4). The mean ages at diagnosis for the three main manifestations, pHPT, dpNET, and PIT, in the Dutch MEN1 population are 36, 41, and 40 years, respectively (5). Other neoplasms, such as adrenal tumors; neuroendocrine tumors of gastric, bronchial, or thymic origin; skin and subcutaneous tumors; smooth muscle tumors; and, as recently discovered, breast cancer, can occur during the course of the disease (6, 7). These manifestations cause significant morbidity; dpNETs and thymic neuroendocrine tumors lead to premature death (4, 8, 9). The average life expectancy in the Dutch MEN1 population is 73 years, which is 10 years shorter than the general Dutch population (4). The young age at which MEN1 mutation carriers are confronted with an MEN1-related disease makes lifelong screening and intensive monitoring indispensable for early tumor detection to prevent morbidity and mortality (10). A diagnosis of MEN1 has a considerable impact on an individual and might lead to psychological distress and worry about disease occurrence. Considering the autosomal inheritance pattern, theoretically 50% of family members are MEN1 carriers. For individuals with MEN1, this implies that 50% of their children potentially have MEN1. As with other autosomal-dominant hereditary diseases, the stress caused by MEN1 could extend to fear of disease occurrence (FDO) in family members. Fear of cancer occurrence has been studied in other hereditary cancer syndromes with the same inheritance pattern as MEN1 (11–13). Patients with Von Hippel Lindau (VHL) disease reported frequent concerns about VHL-related tumors developing in themselves or in a family member with VHL (12). Moreover, more patients with Li-Fraumeni syndrome expressed greater concern about cancer occurrence in family members than about the chance of developing cancer themselves (11). The quality of life (QoL) of patients with Li-Fraumeni and VHL syndrome was comparable to an age- and sex-matched reference group from the general population (11), with the exception that patients with VHL had a significantly lower score for general health (12). Few studies have addressed QoL in patients with MEN1, and these studies had a limited or selected study population (14, 15). These limitations reflect the difficulty in performing research in rare tumor syndromes, such as MEN1, which has a prevalence of 3 to 4 per 100,000 (1). This highlights the need for QoL studies in an unselected MEN1 population with an adequate sample size to assess the impact of MEN1 on patients and to determine whether there is a need for more psychological support. To address this important aspect for patients with MEN1, the primary aim of this study was to evaluate MEN1-related FDO in patients themselves and for their family members with MEN1. The secondary aim was to assess the association of MEN1-related fear on health-related QoL. In addition, we aimed to identify variables that were significantly related to MEN1-related fear. Methods Study population Patients were selected from the Dutch MEN1 study group database. This longitudinal database includes >90% of all Dutch patients with MEN1, aged 16 years and older at the end of 2013, treated at one of the Dutch University Medical Centers between 1990 and 2013. Patients were eligible for the current study if they had a confirmed MEN1 mutation. Demographic and clinical data (e.g., age, sex, and MEN1-related medical history) were retrieved from this database. Study design A cross-sectional study was performed from April 2015 to December 2016 in which all eligible patients were invited to complete a questionnaire. After 2 weeks, a reminder e-mail was sent to the participants. The questionnaire could be completed by hand or as a web-based questionnaire. All patients with MEN1 who participated in the study provided written informed consent. Questionnaires Sociodemographic data (e.g., marital status, offspring, education, and employment) were obtained. MEN1-related fear MEN1-related fear of FDO was assessed with an eight-item questionnaire adapted from the Cancer Worry Scale (CWS) (16, 17). The eight items of the CWS are rated on a four-point Likert scale ranging from “never” to “almost always.” The total sum score ranges from 8 to 32, with higher scores indicating more frequent worries about cancer. Cronbach α in this study was 0.89. A diagnostic cut-off score of 14 or higher (sensitivity, 77%; specificity, 81%) indicates severe FDO (17). The CWS has previously been used in different hereditary tumor syndrome populations, which included healthy subjects (noncarriers), mutation carriers with disease manifestations, and mutation carriers at risk. These studies showed that the CWS in these populations is a valid tool with high internal consistency (11–13). Five similar questions regarding FDO in family members were added to the original scale. These questions were from the original scale but addressed fear of family members instead of fear of the patients themselves. These additional questions did not affect the outcome of the original FDO score because they were used in a separate analysis. Cronbach α for these additional questions was 0.87, which reflects a high internal consistency of the questions. Perceived risk Respondents were asked to report their perceived risk of developing an (additional) tumor compared with that of an “average person in the Dutch population” of their age [item adapted from Lerman et al. (16)]. Response categories ranged from “lower” to “much higher” on a five-point scale. Health-related QoL Health-related QoL was assessed with the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) composed of eight multi-item scales assessing physical functioning, role limitations due to physical health problems and emotional problems, bodily pain, general health perceptions, vitality, social functioning, and general mental health. Scale scores range from 0 to 100, with higher scores indicating better levels of functioning and well-being. Cronbach α for the SF-36 scales ranged from 0.84 (social functioning) to 0.93 (physical pain). Only general health perception had a low Cronbach α (0.55), which is therefore of low significance. Statistical analysis Descriptive statistics were applied to characterize the study population. Univariate analyses (independent sample t test, χ2 test/Fisher exact test, Pearson correlation) were used to evaluate which MEN1-related manifestations and sociodemographic variables were associated with cancer worry and health-related QoL. To compare FDO of the patients for themselves with FDO in first-degree relatives, we performed the Wilcoxon signed rank test. Binary logistic regression was performed to assess the association between low (<14) and high (≥14) FDO scores with the eight different SF-36 subscales adjusted for age and sex. A multivariable analysis was carried out using multiple linear regression to assess which patient characteristics were associated with FDO. Collinearity was tested using variance inflation factors. In the linear models, none of the variance inflation factor values was >1.20, suggesting that collinearity was not a problem. Multiple imputation was used for missing data in the CWS. Analyses were conducted using SPSS 22.0. P values <0.05 were considered statistically significant. Results Response rate A total of 285 patients (120 men and 165 women) were eligible for inclusion, of whom 252 (102 men and 150 women) received the questionnaire. The questionnaire was completed by 227 individuals [84 (70%) men and 143 (87%) women], resulting in a total response rate of 80% (Fig. 1). Figure 1. View largeDownload slide Flowchart of the study population. Figure 1. View largeDownload slide Flowchart of the study population. Sample characteristics The mean [± standard deviation (SD)] age of the study population was 47 ± 15 years. All patients had a confirmed MEN1 mutation or one or more MEN1-related manifestations and a first-degree relative with MEN1. Eighty-three percent of patients had ever had pHPT. More than half of the patients had ever had a pancreatic neuroendocrine tumor (pNET) (55%), and 38% of patients had ever had a PIT (Table 1). Table 1. Baseline Characteristics (N = 227) Characteristic No. (%)a Sex  Female 143 (63)  Male 84 (37) Mean age, y (SD) 47 (15) Education  Primary school 6 (3)  High school 149 (65)  College or university 66 (29) Employment  Yes 159 (70)  No 64 (28) Children  Yes 139 (61)  No 69 (30)  Unknown 19 (8) Index case  Yes 51 (23)  No 173 (76) Presymptomatic diagnosis  Yes 98 (44)  No 125 (56) Years since MEN1 diagnosis  <5 27 (12)  ≥5 190 (84) pHPT  Yes 187 (83)  No 38 (17) PT  Yes 85 (38)  No 139 (62) pNET  Yes 123 (55)  No 101 (45) Characteristic No. (%)a Sex  Female 143 (63)  Male 84 (37) Mean age, y (SD) 47 (15) Education  Primary school 6 (3)  High school 149 (65)  College or university 66 (29) Employment  Yes 159 (70)  No 64 (28) Children  Yes 139 (61)  No 69 (30)  Unknown 19 (8) Index case  Yes 51 (23)  No 173 (76) Presymptomatic diagnosis  Yes 98 (44)  No 125 (56) Years since MEN1 diagnosis  <5 27 (12)  ≥5 190 (84) pHPT  Yes 187 (83)  No 38 (17) PT  Yes 85 (38)  No 139 (62) pNET  Yes 123 (55)  No 101 (45) a Values in parentheses are percentage unless noted otherwise. View Large Table 1. Baseline Characteristics (N = 227) Characteristic No. (%)a Sex  Female 143 (63)  Male 84 (37) Mean age, y (SD) 47 (15) Education  Primary school 6 (3)  High school 149 (65)  College or university 66 (29) Employment  Yes 159 (70)  No 64 (28) Children  Yes 139 (61)  No 69 (30)  Unknown 19 (8) Index case  Yes 51 (23)  No 173 (76) Presymptomatic diagnosis  Yes 98 (44)  No 125 (56) Years since MEN1 diagnosis  <5 27 (12)  ≥5 190 (84) pHPT  Yes 187 (83)  No 38 (17) PT  Yes 85 (38)  No 139 (62) pNET  Yes 123 (55)  No 101 (45) Characteristic No. (%)a Sex  Female 143 (63)  Male 84 (37) Mean age, y (SD) 47 (15) Education  Primary school 6 (3)  High school 149 (65)  College or university 66 (29) Employment  Yes 159 (70)  No 64 (28) Children  Yes 139 (61)  No 69 (30)  Unknown 19 (8) Index case  Yes 51 (23)  No 173 (76) Presymptomatic diagnosis  Yes 98 (44)  No 125 (56) Years since MEN1 diagnosis  <5 27 (12)  ≥5 190 (84) pHPT  Yes 187 (83)  No 38 (17) PT  Yes 85 (38)  No 139 (62) pNET  Yes 123 (55)  No 101 (45) a Values in parentheses are percentage unless noted otherwise. View Large FDO Patients with MEN1 had a mean (± SD) FDO score of 15.1 ± 4.7, which can be considered as a high level of fear, in comparison with other types of cancer (Fig. 2). The same CWS (consisting of the original eight questions) was used in this comparison with the other cross-sectional studies. A total of 58% of patients with MEN1 had an FDO score ≥14. Figure 2. View largeDownload slide Fear of cancer recurrence scores in different (hereditary) tumor syndromes. Figure 2. View largeDownload slide Fear of cancer recurrence scores in different (hereditary) tumor syndromes. FDO occurrence in relation to QoL Adjusted for age and sex, the FDO score was significantly associated with all scales of the SF-36. Table 2 shows the mean (SD) SF-36 health-related QoL scores stratified by high or low FDO. Patients with high FDO showed lower QoL on all subscales, except for the physical functioning subscale (P = 0.05), compared with patients with low FDO. Table 2. Means and SDs of the SF-36 Scale Stratified by Age and Sex Low Fear for Cancer Recurrence (CWS <14; n = 90) High Fear for Cancer Recurrence (CWS ≥14; n = 120) P Value SF-36 Physical functioning 87.3 (18.7) 80.4 (24.6) 0.05 Role functioning 80.6 (35.3) 56.7 (43.2) <0.001 Emotional functioning 91.7 (22.8) 63.8 (42.6) <0.001 Social functioning 85.7 (20.3) 70.5 (25.7) <0.001 Mental health 80.3 (13.5) 66.8 (18.6) <0.001 Vitality 64.6 (21.0) 51.2 (21.5) <0.001 Bodily pain 88.8 (14.7) 76.1 (23.2) <0.001 General health 51.6 (15.7) 47.3 (21.8) 0.11 Low Fear for Cancer Recurrence (CWS <14; n = 90) High Fear for Cancer Recurrence (CWS ≥14; n = 120) P Value SF-36 Physical functioning 87.3 (18.7) 80.4 (24.6) 0.05 Role functioning 80.6 (35.3) 56.7 (43.2) <0.001 Emotional functioning 91.7 (22.8) 63.8 (42.6) <0.001 Social functioning 85.7 (20.3) 70.5 (25.7) <0.001 Mental health 80.3 (13.5) 66.8 (18.6) <0.001 Vitality 64.6 (21.0) 51.2 (21.5) <0.001 Bodily pain 88.8 (14.7) 76.1 (23.2) <0.001 General health 51.6 (15.7) 47.3 (21.8) 0.11 Data were obtained using the Mann-Whitney U test. View Large Table 2. Means and SDs of the SF-36 Scale Stratified by Age and Sex Low Fear for Cancer Recurrence (CWS <14; n = 90) High Fear for Cancer Recurrence (CWS ≥14; n = 120) P Value SF-36 Physical functioning 87.3 (18.7) 80.4 (24.6) 0.05 Role functioning 80.6 (35.3) 56.7 (43.2) <0.001 Emotional functioning 91.7 (22.8) 63.8 (42.6) <0.001 Social functioning 85.7 (20.3) 70.5 (25.7) <0.001 Mental health 80.3 (13.5) 66.8 (18.6) <0.001 Vitality 64.6 (21.0) 51.2 (21.5) <0.001 Bodily pain 88.8 (14.7) 76.1 (23.2) <0.001 General health 51.6 (15.7) 47.3 (21.8) 0.11 Low Fear for Cancer Recurrence (CWS <14; n = 90) High Fear for Cancer Recurrence (CWS ≥14; n = 120) P Value SF-36 Physical functioning 87.3 (18.7) 80.4 (24.6) 0.05 Role functioning 80.6 (35.3) 56.7 (43.2) <0.001 Emotional functioning 91.7 (22.8) 63.8 (42.6) <0.001 Social functioning 85.7 (20.3) 70.5 (25.7) <0.001 Mental health 80.3 (13.5) 66.8 (18.6) <0.001 Vitality 64.6 (21.0) 51.2 (21.5) <0.001 Bodily pain 88.8 (14.7) 76.1 (23.2) <0.001 General health 51.6 (15.7) 47.3 (21.8) 0.11 Data were obtained using the Mann-Whitney U test. View Large Manifestations and FDO Patients who had a pNET had a higher FDO than patients without a pNET, with scores of 15.6 ± 4.8 and 14.4 ± 4.5, respectively (P < 0.01). Having pHPT also led to a slightly higher FDO than never having had pHPT (15.2 ± 4.6 vs 14.4 ± 5.0, respectively; P = 0.15). Patients with a PIT had more fear than patients without a PIT, with FDO scores of 16.2 ± 4.5 and 14.4 ± 4.7 (P < 0.01). A total of 41 patients had small incidentalomas (<1 cm) not requiring intervention (medication or surgery), 12 patients had undergone surgery, and 32 patients were on medication (hormonal supplementation because of pituitary insufficiency, dopamine agonists, or somatostatin analogs). The FDO values were 15.9 ± 4.4, 15.4 ± 4.7, and 17.9 ± 4.9, respectively. Patients who were employed had an FDO of 14.8 ± 4.3, in comparison with an FDO of 15.6 ± 5.4 for unemployed patients (P < 0.01). Presymptomatic patients (e.g., patients who did not have an MEN1-related manifestation at time of diagnosis) had an FDO of 15.5 ± 4.7, in comparison with an FDO of 14.7 ± 4.6 in nonpresymptomatic patients (P < 0.01). There were no differences in FDO for sex, age, and education level. Multivariable analysis In a multivariable analysis including age, sex, pNET, pHPT, PIT, number of MEN1-related manifestations, employment (yes/no), and presymptomatic diagnosis (yes/no), the diagnosis of a PIT, a pNET, and being unemployed were associated with FDO (P < 0.05). Multiple MEN1 manifestations An increasing number of manifestations led to more FDO (P = 0.02 for trend). The FDO was lower between respondents without a manifestation (13.8 ± 5.4; n = 24) and patients who were already affected by the disease with one or more manifestations (15.2 ± 4.6; P < 0.01). Respondents without or with one manifestation had scores of 13.8 ± 5.4 and 13.7 ± 4.0, respectively. Patients with two or three manifestations had scores of 15.6 ± 4.5 and 16.1 ± 4.), respectively. FDO in family members On five different items of the FDO scale, patients had significantly more fear for their family members than for themselves. However, the effect sizes ranged from 0.10 to 0.22 (Cohen d), which can be considered a small-to-medium effect (Table 3). Table 3. Comparison of Fear of Cancer Occurrence in Patients and in Their Family Members r P Value Regular thoughts about tumor recurrence (self vs family) −0.15 0.02 Thoughts about tumor recurrence have influenced mood −0.14 0.03 Thoughts about tumor recurrence interfered in daily activities −0.10 0.14 How concerned are you about recurrence of a tumor? −0.22 <0.01 How often have you worried about tumor recurrence −0.22 <0.01 Is this worry a problem for you? −0.20 <0.01 r P Value Regular thoughts about tumor recurrence (self vs family) −0.15 0.02 Thoughts about tumor recurrence have influenced mood −0.14 0.03 Thoughts about tumor recurrence interfered in daily activities −0.10 0.14 How concerned are you about recurrence of a tumor? −0.22 <0.01 How often have you worried about tumor recurrence −0.22 <0.01 Is this worry a problem for you? −0.20 <0.01 Wilcoxon signed-rank test (r using Cohen criteria of 0.1 = small effect, 0.3 = medium effect, 0.5 = large effect). View Large Table 3. Comparison of Fear of Cancer Occurrence in Patients and in Their Family Members r P Value Regular thoughts about tumor recurrence (self vs family) −0.15 0.02 Thoughts about tumor recurrence have influenced mood −0.14 0.03 Thoughts about tumor recurrence interfered in daily activities −0.10 0.14 How concerned are you about recurrence of a tumor? −0.22 <0.01 How often have you worried about tumor recurrence −0.22 <0.01 Is this worry a problem for you? −0.20 <0.01 r P Value Regular thoughts about tumor recurrence (self vs family) −0.15 0.02 Thoughts about tumor recurrence have influenced mood −0.14 0.03 Thoughts about tumor recurrence interfered in daily activities −0.10 0.14 How concerned are you about recurrence of a tumor? −0.22 <0.01 How often have you worried about tumor recurrence −0.22 <0.01 Is this worry a problem for you? −0.20 <0.01 Wilcoxon signed-rank test (r using Cohen criteria of 0.1 = small effect, 0.3 = medium effect, 0.5 = large effect). View Large Disease perception and FDO Respondents were asked whether they believed they had an equal, slightly higher, moderately higher, or severely higher chance of developing an MEN1-related tumor in the next 10 years in comparison with the general Dutch population. Thirty-nine percent of patients responded that they had an equal or slightly higher chance, and 40% considered their chances as being much higher. Patients who considered themselves to have a severely higher chance had the greatest FDO. Patients who considered themselves to have an equal chance had the lowest FDO (Table 4). Table 4. Cancer Worry and the Chance of MEN1-Related Tumor Development in the Next 10 Years in Comparison With the General Population CWS n (%) Equal chance 11.9 33 (15) Slightly higher chance 12.8 53 (24) Moderately higher chance 14.7 46 (21) Severely higher chance 17.7 90 (40) CWS n (%) Equal chance 11.9 33 (15) Slightly higher chance 12.8 53 (24) Moderately higher chance 14.7 46 (21) Severely higher chance 17.7 90 (40) Kruskal-Wallis P < 0.01 (3 degrees of freedom). View Large Table 4. Cancer Worry and the Chance of MEN1-Related Tumor Development in the Next 10 Years in Comparison With the General Population CWS n (%) Equal chance 11.9 33 (15) Slightly higher chance 12.8 53 (24) Moderately higher chance 14.7 46 (21) Severely higher chance 17.7 90 (40) CWS n (%) Equal chance 11.9 33 (15) Slightly higher chance 12.8 53 (24) Moderately higher chance 14.7 46 (21) Severely higher chance 17.7 90 (40) Kruskal-Wallis P < 0.01 (3 degrees of freedom). View Large Discussion In this study, we focused on FDO in patients and their family members in a large and representative cohort of patients with MEN1. The high FDO that was found in this study can be interpreted as a substantial fear of further implications of the disease. High fear can be characterized as chronic worry, excessive monitoring for signs of disease occurrence, seeking medical reassurance, avoidance of disease reminders, intrusive thoughts and images about occurrence, and difficulties planning for the future (18–23). Patients with high FDO had lower scores on the SF-36 scale, indicating a lower QoL. In addition, an increase in the of number of manifestations of MEN1 was directly correlated to higher FDO scores. FDO has been derived from fear of cancer recurrence, which has been a topic of increasing interest in recent years (24–27). Fear of cancer recurrence has been defined as “fear, worry or concern relating to the possibility that cancer will come back or progress” (28). Because some patients with MEN1 have not experienced an MEN1 manifestation, “recurrence” was replaced with “occurrence,” and “cancer” was replaced with “disease” because pHPT and PITs are not recognized as cancer. The FDO score was high in comparison with other types of cancer. The outcome of 15.1 is comparable with patients with the VHL syndrome (15.6) (12). Fear in patients with breast cancer, for example, was lower, with an average score of 13.4 (17). This reflects the major impact of MEN1 because fear in breast cancer patients is generally considered high. Patients with Li-Fraumeni and familial adenomatous polyposis also have lower scores compared with patients with MEN1 (13.9 and 12.4, respectively) (11, 13) (Fig. 2). Patients who considered their chance of occurrence of an MEN1-related tumor as comparable with the general population had less FDO than respondents considering themselves as having a severely higher chance. Regarding the high age-related penetrance of the disease, patients with a higher number of manifestations had more FDO. In this study, the diagnosis of a PIT, pNET, and being unemployed were related to elevated FDO. pNETs lead to the most morbidity and mortality in MEN1, and therefore it seems obvious that patients with a pNET diagnosis have greater FDO (4, 8, 29–31). However, it is interesting that patients with a PIT diagnosis have greater FDO because PITs in MEN1 are generally benign and have a slow growth rate. In addition, the majority of patients with PITs are successfully managed by pharmacological treatment or by a watchful waiting strategy (32, 33). Patients who had an operation in the past had the lowest FDO, whereas patients with a current PIT had greater FDO. This suggests that present disease status is more relevant than past severe pituitary disease. This finding could suggest that patients were not aware of the indolent course of PITs or that the knowledge of having a tumor near their brain is a high burden. Adequate patient information on the expected course of individual MEN1 manifestations is therefore mandatory. Unemployment was associated with FDO, which is in line with previous research. Employment status in general has proved to be beneficial for health and in particular for mental health (34). Cancer survivors who continued working had better health and QoL than those who were not able to work (35). Age was not associated with FDO, although a younger age has been indicated to be a predictor for elevated FDO in other studies (20, 21, 26). In MEN1 there is an age-related effect, with young patients with MEN1 generally having fewer manifestations (4). This could explain why young age is not related to high FDO in this cohort. Patients were more worried about their family members than about themselves. This underlines the necessity of an integral familial approach in identifying FDO and in supporting of the family as a whole. Limitations A limitation of this study is its cross-sectional design, which did not allow assessing changes of FDO or QoL over time. In hereditary tumor syndromes, FDO could vary over time, and it would be interesting to study the course of FDO in MEN1. MEN1-related fear was assessed by an adapted CWS that has not been validated in an MEN1 population. However, the CWS has been validated in patients with breast cancer (17) and has been used in other hereditary syndromes with similar inheritance patterns, such as VHL (12), Li-Fraumeni (11), and familial adenomatous polyposis (13). Another limitation is that the questions regarding FDO in patients themselves in comparison with their family members have not been validated in other studies. Because there was a trend toward greater FDO for family members, this could be relevant for other hereditary diseases and necessitates further research. Strengths All respondents are from the population-based Dutch MEN1 study group database, which consists of >90% of the total Dutch MEN1 population. The high response rate of 80% contributes to the generalizability and validity of the study results, which can be considered a major strength. This response rate is much higher than similar studies (11, 13, 17, 19, 25, 36). This is the largest MEN1 cohort in which FDO associated with QoL has been studied, which makes the data unique. In accordance with recent findings, only MEN1 mutation–positive patients were included. MEN1 mutation–negative patients have a different phenotype, a different clinical course, and no family members with an MEN1 mutation, and therefore we excluded these patients to prevent heterogeneity (4). Clinical implications The high percentage of patients with MEN1 (58%) with a high FDO highlights the need for more attention and support for aspects of fear and worry regarding the disease. This topic has been largely neglected, which is incomprehensible considering the results regarding FDO and its impact on QoL. MEN1 is a diagnosis that often affects multiple family members, and therefore the high FDO for patients’ family members requires that regular follow-up visits include addressing worries about relatives with MEN1-related problems, and psychosocial support should be provided when needed. A study in women with an increased risk of breast cancer who expressed a high level of unmet need in support showed that women were mostly interested in attending a support group where they could participate in discussions and receive more information (37). Identifying the need for support in patients with MEN1 would be the first step toward interventions to reduce fear and improve QoL, especially because the prevalence rate for high FDO is higher in patients with MEN1 [58%, in comparison with 52% in patients with gastrointestinal stromal tumors (36), 38% in patients with colorectal tumors (38), 36% in patients with prostate cancer (25), and 31% of patients with breast cancer (17)]. A psychological intervention has shown efficacy to reduce fear in patients with curable breast and colorectal cancer and melanoma. Similar interventions could be beneficial for selected patients with MEN1 after gaining more knowledge on FDO and performing evidence-based interventional studies in patients with MEN1 (39). In summary, there is high FDO in patients with MEN1, which is associated with a lower QoL. Future studies should focus on interventions that improve QoL and thereby improve care and subsequently the QoL of patients with MEN1. Abbreviations: Abbreviations: CWS Cancer Worry Scale dpNET duodenopancreatic neuroendocrine tumor FDO fear of disease occurrence MEN1 multiple endocrine neoplasia type 1 pHPT primary hyperparathyroidism PIT pituitary tumor pNET pancreatic neuroendocrine tumor QoL quality of life SD standard deviation SF-36 Medical Outcomes Study 36-item Short-Form Health Survey VHL Von Hippel Lindau Acknowledgments Disclosure Summary: The authors have nothing to disclose. References 1. Chandrasekharappa SC , Guru SC , Manickam P , Olufemi SE , Collins FS , Emmert-Buck MR , Debelenko LV , Zhuang Z , Lubensky IA , Liotta LA , Crabtree JS , Wang Y , Roe BA , Weisemann J , Boguski MS , Agarwal SK , Kester MB , Kim YS , Heppner C , Dong Q , Spiegel AM , Burns AL , Marx SJ . Positional cloning of the gene for multiple endocrine neoplasia-type 1 . Science . 1997 ; 276 ( 5311 ): 404 – 407 . Google Scholar CrossRef Search ADS PubMed 2. Kouvaraki MA , Lee JE , Shapiro SE , Gagel RF , Sherman SI , Sellin RV , Cote GJ , Evans DB . Genotype-phenotype analysis in multiple endocrine neoplasia type 1 . Arch Surg . 2002 ; 137 ( 6 ): 641 – 647 . Google Scholar CrossRef Search ADS PubMed 3. Trump D , Farren B, Wooding C, Pang JT, Besser GM, Buchanan KD, Edwards CR, Heath DA, Jackson CE, Jansen S, Lips K, Monson JP, O'Halloran D, Sampson J, Shalet SM, Wheeler MH, Zink A, Thakker RV . Clinical studies of multiple neoplasia type 1 . Q J Med . 1997 ; 90 : 19 – 25 . Google Scholar CrossRef Search ADS 4. de Laat JM , van der Luijt RB , Pieterman CRC , Oostveen MP , Hermus AR , Dekkers OM , de Herder WW , van der Horst-Schrivers AN , Drent ML , Bisschop PH , Havekes B , Vriens MR , Valk GD . MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients . BMC Med . 2016 ; 14 ( 1 ): 182 . Google Scholar CrossRef Search ADS PubMed 5. de Laat JM , van der Luijt RB , Pieterman CRC , Oostveen MP , Hermus AR , Dekkers OM , de Herder WW , van der Horst-Schrivers AN , Drent ML , Bisschop PH , Havekes B , Vriens MR , Valk GD . MEN1 redefined: a clinical comparison of mutation-positive and mutation-negative patients. Results from the DutchMEN1 study group . BMC Medicine . 2016 ; 14 : 182 . 6. Dreijerink KM , Goudet P , Burgess JR , Valk GD ; International Breast Cancer in MEN1 Study Group . Breast-cancer predisposition in multiple endocrine neoplasia type 1 . N Engl J Med . 2014 ; 371 ( 6 ): 583 – 584 . Google Scholar CrossRef Search ADS PubMed 7. Ito T , Igarashi H , Uehara H , Berna MJ , Jensen RT . Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors . Medicine (Baltimore) . 2013 ; 92 ( 3 ): 135 – 181 . Google Scholar CrossRef Search ADS PubMed 8. Goudet P , Murat A , Binquet C , Cardot-Bauters C , Costa A , Ruszniewski P , Niccoli P , Ménégaux F , Chabrier G , Borson-Chazot F , Tabarin A , Bouchard P , Delemer B , Beckers A , Bonithon-Kopp C . Risk factors and causes of death in MEN1 disease. A GTE (Groupe d’Etude des Tumeurs Endocrines) cohort study among 758 patients . World J Surg . 2010 ; 34 ( 2 ): 249 – 255 . Google Scholar CrossRef Search ADS PubMed 9. Doherty GM , Olson JA , Frisella MM , Lairmore TC , Wells SA Jr , Norton JA . Lethality of multiple endocrine neoplasia type I . World J Surg . 1998 ; 22 ( 6 ): 581 – 586, discussion 586–587 . Google Scholar CrossRef Search ADS PubMed 10. Pieterman CRC , Schreinemakers JMJ , Koppeschaar HPF , Vriens MR , Rinkes IH , Zonnenberg BA , van der Luijt RB , Valk GD . Multiple endocrine neoplasia type 1 (MEN1): its manifestations and effect of genetic screening on clinical outcome . Clin Endocrinol (Oxf) . 2009 ; 70 ( 4 ): 575 – 581 . Google Scholar CrossRef Search ADS PubMed 11. Lammens CRM , Aaronson NK , Wagner A , Sijmons RH , Ausems MG , Vriends AH , Ruijs MW , van Os TA , Spruijt L , Gómez García EB , Kluijt I , Nagtegaal T , Verhoef S , Bleiker EM . Genetic testing in Li-Fraumeni syndrome: uptake and psychosocial consequences . J Clin Oncol . 2010 ; 28 ( 18 ): 3008 – 3014 . Google Scholar CrossRef Search ADS PubMed 12. Lammens CRM , Bleiker EM , Verhoef S , Hes FJ , Ausems MG , Majoor-Krakauer D , Sijmons RH , van der Luijt RB , van den Ouweland AM , Van Os TA , Hoogerbrugge N , Gómez García EB , Dommering CJ , Gundy CM , Aaronson NK . Psychosocial impact of Von Hippel-Lindau disease: levels and sources of distress . Clin Genet . 2010 ; 77 ( 5 ): 483 – 491 . Google Scholar CrossRef Search ADS PubMed 13. Douma KFL , Aaronson NK , Vasen HF , Gerritsma MA , Gundy CM , Janssen EP , Vriends AH , Cats A , Verhoef S , Bleiker EM . Psychological distress and use of psychosocial support in familial adenomatous polyposis . Psychooncology . 2010 ; 19 ( 3 ): 289 – 298 . Google Scholar CrossRef Search ADS PubMed 14. Berglund G , Lidén A , Hansson MG , Öberg K , Sjöden PO , Nordin K . Quality of life in patients with multiple endocrine neoplasia type 1 (MEN1) . Fam Cancer . 2003 ; 1 : 27 – 33 . Google Scholar CrossRef Search ADS 15. Goswami S , Peipert BJ , Helenowski I , Yount SE , Sturgeon C . Disease and treatment factors associated with lower quality of life scores in adults with multiple endocrine neoplasia type I . Surgery . 2017 ; 162 ( 6 ): 1270 – 1277 . Google Scholar CrossRef Search ADS PubMed 16. Lerman C , Daly M , Masny A , Balshem A . Attitudes about genetic testing for breast-ovarian cancer susceptibility . J Clin Oncol . 1994 ; 12 ( 4 ): 843 – 850 . Google Scholar CrossRef Search ADS PubMed 17. Custers JA , van den Berg SW , van Laarhoven HW , Bleiker EM , Gielissen MF , Prins JB . The Cancer Worry Scale: detecting fear of recurrence in breast cancer survivors . Cancer Nurs . 2014 ; 37 ( 1 ): E44 – E50 . Google Scholar CrossRef Search ADS PubMed 18. Lebel S , Tomei C , Feldstain A , Beattie S , McCallum M . Does fear of cancer recurrence predict cancer survivors’ health care use ? Support Care Cancer . 2013 ; 21 ( 3 ): 901 – 906 . Google Scholar CrossRef Search ADS PubMed 19. Custers JA , Gielissen MF , de Wilt JH , Honkoop A , Smilde TJ , van Spronsen DJ , van der Veld W , van der Graaf WT , Prins JB . Towards an evidence-based model of fear of cancer recurrence for breast cancer survivors . J Cancer Surviv . 2017 ; 11 ( 1 ): 41 – 47 . Google Scholar CrossRef Search ADS PubMed 20. Crist JV , Grunfeld EA . Factors reported to influence fear of recurrence in cancer patients: a systematic review . Psychooncology . 2013 ; 22 ( 5 ): 978 – 986 . Google Scholar CrossRef Search ADS PubMed 21. Simard S , Thewes B , Humphris G , Dixon M , Hayden C , Mireskandari S , Ozakinci G . Fear of cancer recurrence in adult cancer survivors: a systematic review of quantitative studies . J Cancer Surviv . 2013 ; 7 ( 3 ): 300 – 322 . Google Scholar CrossRef Search ADS PubMed 22. Lee-Jones C , Dixon R . Fear of cancer recurrence: a literature review and proposed cognitive formulation to explain exacerbation of recurrent fears . Psychooncology . 1996 ; 1997 ( 6 ): 95 – 105 . 23. Thewes B , Butow P , Bell ML , Beith J , Stuart-Harris R , Grossi M , Capp A , Dalley D ; FCR Study Advisory Committee . Fear of cancer recurrence in young women with a history of early-stage breast cancer: a cross-sectional study of prevalence and association with health behaviours . Support Care Cancer . 2012 ; 20 ( 11 ): 2651 – 2659 . Google Scholar CrossRef Search ADS PubMed 24. Thewes B , Butow P , Zachariae R , Christensen S , Simard S , Gotay C . Fear of cancer recurrence: a systematic literature review of self-report measures . Psychooncology . 2012 ; 21 : 571 – 587 . Google Scholar CrossRef Search ADS PubMed 25. van de Wal M , van Oort I , Schouten J , Thewes B , Gielissen M , Prins J . Fear of cancer recurrence in prostate cancer survivors . Acta Oncol . 2016 ; 55 ( 7 ): 821 – 827 . Google Scholar CrossRef Search ADS PubMed 26. Thewes B , Kaal SEJ , Custers JAE , Manten-Horst E , Jansen R , Servaes P , van der Graaf WTA , Prins JB , Husson O . Prevalence and correlates of high fear of cancer recurrence in late adolescents and young adults consulting a specialist adolescent and young adult (AYA) cancer service [published online ahead of print November 22, 2017]. Support Care Cancer . doi:10.1007/s00520-017-3975-2 . 27. Thewes B , Husson O , Poort H , Custers JAE , Butow PN , McLachlan SA , Prins JB . Fear of cancer recurrence in an era of personalized medicine . J Clin Oncol . 2017 ; 35 ( 29 ): 3275 – 3278 . Google Scholar CrossRef Search ADS PubMed 28. Lebel S , Ozakinci G , Humphris G , Mutsaers B , Thewes B , Prins J , Dinkel A , Butow P ; University of Ottawa Fear of Cancer Recurrence Colloquium attendees . From normal response to clinical problem: definition and clinical features of fear of cancer recurrence . Support Care Cancer . 2016 ; 24 ( 8 ): 3265 – 3268 . Google Scholar CrossRef Search ADS PubMed 29. Triponez F , Dosseh D , Goudet P , Cougard P , Bauters C , Murat A , Cadiot G , Niccoli-Sire P , Chayvialle JA , Calender A , Proye CA . Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas . Ann Surg . 2006 ; 243 ( 2 ): 265 – 272 . Google Scholar CrossRef Search ADS PubMed 30. Geerdink EAM , Luijt RB Van Der , Lips CJM . Do patients with multiple endocrine neoplasia syndrome type 1 benefit from periodical screening? 2003;149(6):577–582 . 31. Dean PG , van Heerden JA , Farley DR , Thompson GB , Grant CS , Harmsen WS , Ilstrup DM . Are patients with multiple endocrine neoplasia type I prone to premature death ? World J Surg . 2000 ; 24 ( 11 ): 1437 – 1441 . Google Scholar CrossRef Search ADS PubMed 32. Giusti F , Cianferotti L , Boaretto F , Cetani F , Cioppi F , Colao A , Davì MV , Faggiano A , Fanciulli G , Ferolla P , Ferone D , Fossi C , Giudici F , Gronchi G , Loli P , Mantero F , Marcocci C , Marini F , Masi L , Opocher G , Beck-Peccoz P , Persani L , Scillitani A , Sciortino G , Spada A , Tomassetti P , Tonelli F , Brandi ML . Multiple endocrine neoplasia syndrome type 1: institution, management, and data analysis of a nationwide multicenter patient database . Endocrine . 2017 ; 58 ( 2 ): 349 – 359 . Google Scholar CrossRef Search ADS PubMed 33. de Laat J , Dekkers OM , Pieterman CRC , Kluijfhout WP , Hermus AR , Pereira AM , van der Horst-Schrivers AN , Drent ML , Bisschop PH , Havekes B , de Herder WW , Valk GD . Long-term natural course of pituitary tumors in patients with MEN1: results from the Dutch MEN1 study group (DMSG) . J Clin Endocrinol Metab . 2015 ; 100 ( 9 ): 3288 – 3296 . doi: Google Scholar CrossRef Search ADS PubMed 34. van der Noordt M , IJzelenberg H , Droomers M , Proper KI . Health effects of employment: a systematic review of prospective studies . Occup Environ Med . 2014 ; 71 ( 10 ): 730 – 736 . Google Scholar CrossRef Search ADS PubMed 35. Duijts SFA , Kieffer JM , van Muijen P , van der Beek AJ . Sustained employability and health-related quality of life in cancer survivors up to four years after diagnosis . Acta Oncol . 2017 ; 56 ( 2 ): 174 – 182 . Google Scholar CrossRef Search ADS PubMed 36. Custers JA , Tielen R , Prins JB , de Wilt JH , Gielissen MF , van der Graaf WT . Fear of progression in patients with gastrointestinal stromal tumors (GIST): is extended lifetime related to the Sword of Damocles ? Acta Oncol . 2015 ; 54 ( 8 ): 1202 – 1208 . Google Scholar CrossRef Search ADS PubMed 37. Thewes B , Meiser B , Tucker M , Tucker K . The unmet information and support needs of women with a family history of breast cancer: a descriptive survey . J Genet Couns . 2003 ; 12 ( 1 ): 61 – 76 . Google Scholar CrossRef Search ADS PubMed 38. Custers JAE , Gielissen MFM , Janssen SHV , de Wilt JHW , Prins JB . Fear of cancer recurrence in colorectal cancer survivors . Support Care Cancer . 2016 ; 24 ( 2 ): 555 – 562 . Google Scholar CrossRef Search ADS PubMed 39. Butow PN , Turner J , Gilchrist J , Sharpe L , Smith AB , Fardell JE , Tesson S , O’Connell R , Girgis A , Gebski VJ , Asher R , Mihalopoulos C , Bell ML , Grunewald Zola K , Beith J , Thewes B . Randomized trial of ConquerFear: a novel, theoretically based psychosocial intervention for fear of cancer recurrence . J. Clin. Oncol . 2017 ; 35 ( 36 ): 4066 – 4077 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

High Fear of Disease Occurrence Is Associated With Low Quality of Life in Patients With Multiple Endocrine Neoplasia Type 1: Results From the Dutch MEN1 Study Group

Loading next page...
 
/lp/ou_press/high-fear-of-disease-occurrence-is-associated-with-low-quality-of-life-Ar6M50qIPy
Publisher
Oxford University Press
Copyright
Copyright © 2018 Endocrine Society
ISSN
0021-972X
eISSN
1945-7197
D.O.I.
10.1210/jc.2018-00259
Publisher site
See Article on Publisher Site

Abstract

Abstract Objective Multiple endocrine neoplasia type 1 (MEN1) is a hereditary disease characterized by a high risk of developing primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors, and pituitary tumors (PITs). It is unclear if having MEN1 leads to psychological distress because of fear of disease occurrence (FDO), thereby potentially affecting quality of life. Design A cross-sectional study was performed using the Dutch MEN1 cohort. All patients received the Cancer Worry Scale (a score ≥14 reflects high FDO), the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36), and questions on sociodemographic and medical history. Results A total of 227 of 285 (80%) eligible patients with MEN1 completed the questionnaire. The mean (± standard deviation) age was 47 ± 15 years. Overall, patients experienced an FDO of 15.1 ± 4.7, with 58% of patients having a score ≥14. This is higher than reported in previous studies assessing fear of cancer recurrence in different cancer populations (31% to 52%). Adjusted for age and sex, the FDO score was negatively associated with almost all SF-36 subscales. In multivariable analysis, the diagnosis of a PIT, a pancreatic neuroendocrine tumor, and not being employed were associated with FDO (P < 0.05). Patients had higher FDO scores for their family members than for themselves. Conclusion The majority of patients with MEN1 have FDO for themselves and even more for their relatives. This psychological distress is associated with a lower health-related quality of life. Therefore, in the medical care for MEN1, emphasis should also be placed on FDO and quality of life. Multiple endocrine neoplasia type 1 (MEN1) is a hereditary disease with an autosomal dominant inheritance pattern caused by a germline mutation on chromosome 11q13 (1). MEN1 is characterized by a lifetime risk of developing primary hyperparathyroidism (pHPT) of almost 100%, a lifetime risk of developing duodenopancreatic neuroendocrine tumors (dpNETs) of >80%, and a lifetime risk of developing pituitary tumors (PITs) of 70% (1–4). The mean ages at diagnosis for the three main manifestations, pHPT, dpNET, and PIT, in the Dutch MEN1 population are 36, 41, and 40 years, respectively (5). Other neoplasms, such as adrenal tumors; neuroendocrine tumors of gastric, bronchial, or thymic origin; skin and subcutaneous tumors; smooth muscle tumors; and, as recently discovered, breast cancer, can occur during the course of the disease (6, 7). These manifestations cause significant morbidity; dpNETs and thymic neuroendocrine tumors lead to premature death (4, 8, 9). The average life expectancy in the Dutch MEN1 population is 73 years, which is 10 years shorter than the general Dutch population (4). The young age at which MEN1 mutation carriers are confronted with an MEN1-related disease makes lifelong screening and intensive monitoring indispensable for early tumor detection to prevent morbidity and mortality (10). A diagnosis of MEN1 has a considerable impact on an individual and might lead to psychological distress and worry about disease occurrence. Considering the autosomal inheritance pattern, theoretically 50% of family members are MEN1 carriers. For individuals with MEN1, this implies that 50% of their children potentially have MEN1. As with other autosomal-dominant hereditary diseases, the stress caused by MEN1 could extend to fear of disease occurrence (FDO) in family members. Fear of cancer occurrence has been studied in other hereditary cancer syndromes with the same inheritance pattern as MEN1 (11–13). Patients with Von Hippel Lindau (VHL) disease reported frequent concerns about VHL-related tumors developing in themselves or in a family member with VHL (12). Moreover, more patients with Li-Fraumeni syndrome expressed greater concern about cancer occurrence in family members than about the chance of developing cancer themselves (11). The quality of life (QoL) of patients with Li-Fraumeni and VHL syndrome was comparable to an age- and sex-matched reference group from the general population (11), with the exception that patients with VHL had a significantly lower score for general health (12). Few studies have addressed QoL in patients with MEN1, and these studies had a limited or selected study population (14, 15). These limitations reflect the difficulty in performing research in rare tumor syndromes, such as MEN1, which has a prevalence of 3 to 4 per 100,000 (1). This highlights the need for QoL studies in an unselected MEN1 population with an adequate sample size to assess the impact of MEN1 on patients and to determine whether there is a need for more psychological support. To address this important aspect for patients with MEN1, the primary aim of this study was to evaluate MEN1-related FDO in patients themselves and for their family members with MEN1. The secondary aim was to assess the association of MEN1-related fear on health-related QoL. In addition, we aimed to identify variables that were significantly related to MEN1-related fear. Methods Study population Patients were selected from the Dutch MEN1 study group database. This longitudinal database includes >90% of all Dutch patients with MEN1, aged 16 years and older at the end of 2013, treated at one of the Dutch University Medical Centers between 1990 and 2013. Patients were eligible for the current study if they had a confirmed MEN1 mutation. Demographic and clinical data (e.g., age, sex, and MEN1-related medical history) were retrieved from this database. Study design A cross-sectional study was performed from April 2015 to December 2016 in which all eligible patients were invited to complete a questionnaire. After 2 weeks, a reminder e-mail was sent to the participants. The questionnaire could be completed by hand or as a web-based questionnaire. All patients with MEN1 who participated in the study provided written informed consent. Questionnaires Sociodemographic data (e.g., marital status, offspring, education, and employment) were obtained. MEN1-related fear MEN1-related fear of FDO was assessed with an eight-item questionnaire adapted from the Cancer Worry Scale (CWS) (16, 17). The eight items of the CWS are rated on a four-point Likert scale ranging from “never” to “almost always.” The total sum score ranges from 8 to 32, with higher scores indicating more frequent worries about cancer. Cronbach α in this study was 0.89. A diagnostic cut-off score of 14 or higher (sensitivity, 77%; specificity, 81%) indicates severe FDO (17). The CWS has previously been used in different hereditary tumor syndrome populations, which included healthy subjects (noncarriers), mutation carriers with disease manifestations, and mutation carriers at risk. These studies showed that the CWS in these populations is a valid tool with high internal consistency (11–13). Five similar questions regarding FDO in family members were added to the original scale. These questions were from the original scale but addressed fear of family members instead of fear of the patients themselves. These additional questions did not affect the outcome of the original FDO score because they were used in a separate analysis. Cronbach α for these additional questions was 0.87, which reflects a high internal consistency of the questions. Perceived risk Respondents were asked to report their perceived risk of developing an (additional) tumor compared with that of an “average person in the Dutch population” of their age [item adapted from Lerman et al. (16)]. Response categories ranged from “lower” to “much higher” on a five-point scale. Health-related QoL Health-related QoL was assessed with the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) composed of eight multi-item scales assessing physical functioning, role limitations due to physical health problems and emotional problems, bodily pain, general health perceptions, vitality, social functioning, and general mental health. Scale scores range from 0 to 100, with higher scores indicating better levels of functioning and well-being. Cronbach α for the SF-36 scales ranged from 0.84 (social functioning) to 0.93 (physical pain). Only general health perception had a low Cronbach α (0.55), which is therefore of low significance. Statistical analysis Descriptive statistics were applied to characterize the study population. Univariate analyses (independent sample t test, χ2 test/Fisher exact test, Pearson correlation) were used to evaluate which MEN1-related manifestations and sociodemographic variables were associated with cancer worry and health-related QoL. To compare FDO of the patients for themselves with FDO in first-degree relatives, we performed the Wilcoxon signed rank test. Binary logistic regression was performed to assess the association between low (<14) and high (≥14) FDO scores with the eight different SF-36 subscales adjusted for age and sex. A multivariable analysis was carried out using multiple linear regression to assess which patient characteristics were associated with FDO. Collinearity was tested using variance inflation factors. In the linear models, none of the variance inflation factor values was >1.20, suggesting that collinearity was not a problem. Multiple imputation was used for missing data in the CWS. Analyses were conducted using SPSS 22.0. P values <0.05 were considered statistically significant. Results Response rate A total of 285 patients (120 men and 165 women) were eligible for inclusion, of whom 252 (102 men and 150 women) received the questionnaire. The questionnaire was completed by 227 individuals [84 (70%) men and 143 (87%) women], resulting in a total response rate of 80% (Fig. 1). Figure 1. View largeDownload slide Flowchart of the study population. Figure 1. View largeDownload slide Flowchart of the study population. Sample characteristics The mean [± standard deviation (SD)] age of the study population was 47 ± 15 years. All patients had a confirmed MEN1 mutation or one or more MEN1-related manifestations and a first-degree relative with MEN1. Eighty-three percent of patients had ever had pHPT. More than half of the patients had ever had a pancreatic neuroendocrine tumor (pNET) (55%), and 38% of patients had ever had a PIT (Table 1). Table 1. Baseline Characteristics (N = 227) Characteristic No. (%)a Sex  Female 143 (63)  Male 84 (37) Mean age, y (SD) 47 (15) Education  Primary school 6 (3)  High school 149 (65)  College or university 66 (29) Employment  Yes 159 (70)  No 64 (28) Children  Yes 139 (61)  No 69 (30)  Unknown 19 (8) Index case  Yes 51 (23)  No 173 (76) Presymptomatic diagnosis  Yes 98 (44)  No 125 (56) Years since MEN1 diagnosis  <5 27 (12)  ≥5 190 (84) pHPT  Yes 187 (83)  No 38 (17) PT  Yes 85 (38)  No 139 (62) pNET  Yes 123 (55)  No 101 (45) Characteristic No. (%)a Sex  Female 143 (63)  Male 84 (37) Mean age, y (SD) 47 (15) Education  Primary school 6 (3)  High school 149 (65)  College or university 66 (29) Employment  Yes 159 (70)  No 64 (28) Children  Yes 139 (61)  No 69 (30)  Unknown 19 (8) Index case  Yes 51 (23)  No 173 (76) Presymptomatic diagnosis  Yes 98 (44)  No 125 (56) Years since MEN1 diagnosis  <5 27 (12)  ≥5 190 (84) pHPT  Yes 187 (83)  No 38 (17) PT  Yes 85 (38)  No 139 (62) pNET  Yes 123 (55)  No 101 (45) a Values in parentheses are percentage unless noted otherwise. View Large Table 1. Baseline Characteristics (N = 227) Characteristic No. (%)a Sex  Female 143 (63)  Male 84 (37) Mean age, y (SD) 47 (15) Education  Primary school 6 (3)  High school 149 (65)  College or university 66 (29) Employment  Yes 159 (70)  No 64 (28) Children  Yes 139 (61)  No 69 (30)  Unknown 19 (8) Index case  Yes 51 (23)  No 173 (76) Presymptomatic diagnosis  Yes 98 (44)  No 125 (56) Years since MEN1 diagnosis  <5 27 (12)  ≥5 190 (84) pHPT  Yes 187 (83)  No 38 (17) PT  Yes 85 (38)  No 139 (62) pNET  Yes 123 (55)  No 101 (45) Characteristic No. (%)a Sex  Female 143 (63)  Male 84 (37) Mean age, y (SD) 47 (15) Education  Primary school 6 (3)  High school 149 (65)  College or university 66 (29) Employment  Yes 159 (70)  No 64 (28) Children  Yes 139 (61)  No 69 (30)  Unknown 19 (8) Index case  Yes 51 (23)  No 173 (76) Presymptomatic diagnosis  Yes 98 (44)  No 125 (56) Years since MEN1 diagnosis  <5 27 (12)  ≥5 190 (84) pHPT  Yes 187 (83)  No 38 (17) PT  Yes 85 (38)  No 139 (62) pNET  Yes 123 (55)  No 101 (45) a Values in parentheses are percentage unless noted otherwise. View Large FDO Patients with MEN1 had a mean (± SD) FDO score of 15.1 ± 4.7, which can be considered as a high level of fear, in comparison with other types of cancer (Fig. 2). The same CWS (consisting of the original eight questions) was used in this comparison with the other cross-sectional studies. A total of 58% of patients with MEN1 had an FDO score ≥14. Figure 2. View largeDownload slide Fear of cancer recurrence scores in different (hereditary) tumor syndromes. Figure 2. View largeDownload slide Fear of cancer recurrence scores in different (hereditary) tumor syndromes. FDO occurrence in relation to QoL Adjusted for age and sex, the FDO score was significantly associated with all scales of the SF-36. Table 2 shows the mean (SD) SF-36 health-related QoL scores stratified by high or low FDO. Patients with high FDO showed lower QoL on all subscales, except for the physical functioning subscale (P = 0.05), compared with patients with low FDO. Table 2. Means and SDs of the SF-36 Scale Stratified by Age and Sex Low Fear for Cancer Recurrence (CWS <14; n = 90) High Fear for Cancer Recurrence (CWS ≥14; n = 120) P Value SF-36 Physical functioning 87.3 (18.7) 80.4 (24.6) 0.05 Role functioning 80.6 (35.3) 56.7 (43.2) <0.001 Emotional functioning 91.7 (22.8) 63.8 (42.6) <0.001 Social functioning 85.7 (20.3) 70.5 (25.7) <0.001 Mental health 80.3 (13.5) 66.8 (18.6) <0.001 Vitality 64.6 (21.0) 51.2 (21.5) <0.001 Bodily pain 88.8 (14.7) 76.1 (23.2) <0.001 General health 51.6 (15.7) 47.3 (21.8) 0.11 Low Fear for Cancer Recurrence (CWS <14; n = 90) High Fear for Cancer Recurrence (CWS ≥14; n = 120) P Value SF-36 Physical functioning 87.3 (18.7) 80.4 (24.6) 0.05 Role functioning 80.6 (35.3) 56.7 (43.2) <0.001 Emotional functioning 91.7 (22.8) 63.8 (42.6) <0.001 Social functioning 85.7 (20.3) 70.5 (25.7) <0.001 Mental health 80.3 (13.5) 66.8 (18.6) <0.001 Vitality 64.6 (21.0) 51.2 (21.5) <0.001 Bodily pain 88.8 (14.7) 76.1 (23.2) <0.001 General health 51.6 (15.7) 47.3 (21.8) 0.11 Data were obtained using the Mann-Whitney U test. View Large Table 2. Means and SDs of the SF-36 Scale Stratified by Age and Sex Low Fear for Cancer Recurrence (CWS <14; n = 90) High Fear for Cancer Recurrence (CWS ≥14; n = 120) P Value SF-36 Physical functioning 87.3 (18.7) 80.4 (24.6) 0.05 Role functioning 80.6 (35.3) 56.7 (43.2) <0.001 Emotional functioning 91.7 (22.8) 63.8 (42.6) <0.001 Social functioning 85.7 (20.3) 70.5 (25.7) <0.001 Mental health 80.3 (13.5) 66.8 (18.6) <0.001 Vitality 64.6 (21.0) 51.2 (21.5) <0.001 Bodily pain 88.8 (14.7) 76.1 (23.2) <0.001 General health 51.6 (15.7) 47.3 (21.8) 0.11 Low Fear for Cancer Recurrence (CWS <14; n = 90) High Fear for Cancer Recurrence (CWS ≥14; n = 120) P Value SF-36 Physical functioning 87.3 (18.7) 80.4 (24.6) 0.05 Role functioning 80.6 (35.3) 56.7 (43.2) <0.001 Emotional functioning 91.7 (22.8) 63.8 (42.6) <0.001 Social functioning 85.7 (20.3) 70.5 (25.7) <0.001 Mental health 80.3 (13.5) 66.8 (18.6) <0.001 Vitality 64.6 (21.0) 51.2 (21.5) <0.001 Bodily pain 88.8 (14.7) 76.1 (23.2) <0.001 General health 51.6 (15.7) 47.3 (21.8) 0.11 Data were obtained using the Mann-Whitney U test. View Large Manifestations and FDO Patients who had a pNET had a higher FDO than patients without a pNET, with scores of 15.6 ± 4.8 and 14.4 ± 4.5, respectively (P < 0.01). Having pHPT also led to a slightly higher FDO than never having had pHPT (15.2 ± 4.6 vs 14.4 ± 5.0, respectively; P = 0.15). Patients with a PIT had more fear than patients without a PIT, with FDO scores of 16.2 ± 4.5 and 14.4 ± 4.7 (P < 0.01). A total of 41 patients had small incidentalomas (<1 cm) not requiring intervention (medication or surgery), 12 patients had undergone surgery, and 32 patients were on medication (hormonal supplementation because of pituitary insufficiency, dopamine agonists, or somatostatin analogs). The FDO values were 15.9 ± 4.4, 15.4 ± 4.7, and 17.9 ± 4.9, respectively. Patients who were employed had an FDO of 14.8 ± 4.3, in comparison with an FDO of 15.6 ± 5.4 for unemployed patients (P < 0.01). Presymptomatic patients (e.g., patients who did not have an MEN1-related manifestation at time of diagnosis) had an FDO of 15.5 ± 4.7, in comparison with an FDO of 14.7 ± 4.6 in nonpresymptomatic patients (P < 0.01). There were no differences in FDO for sex, age, and education level. Multivariable analysis In a multivariable analysis including age, sex, pNET, pHPT, PIT, number of MEN1-related manifestations, employment (yes/no), and presymptomatic diagnosis (yes/no), the diagnosis of a PIT, a pNET, and being unemployed were associated with FDO (P < 0.05). Multiple MEN1 manifestations An increasing number of manifestations led to more FDO (P = 0.02 for trend). The FDO was lower between respondents without a manifestation (13.8 ± 5.4; n = 24) and patients who were already affected by the disease with one or more manifestations (15.2 ± 4.6; P < 0.01). Respondents without or with one manifestation had scores of 13.8 ± 5.4 and 13.7 ± 4.0, respectively. Patients with two or three manifestations had scores of 15.6 ± 4.5 and 16.1 ± 4.), respectively. FDO in family members On five different items of the FDO scale, patients had significantly more fear for their family members than for themselves. However, the effect sizes ranged from 0.10 to 0.22 (Cohen d), which can be considered a small-to-medium effect (Table 3). Table 3. Comparison of Fear of Cancer Occurrence in Patients and in Their Family Members r P Value Regular thoughts about tumor recurrence (self vs family) −0.15 0.02 Thoughts about tumor recurrence have influenced mood −0.14 0.03 Thoughts about tumor recurrence interfered in daily activities −0.10 0.14 How concerned are you about recurrence of a tumor? −0.22 <0.01 How often have you worried about tumor recurrence −0.22 <0.01 Is this worry a problem for you? −0.20 <0.01 r P Value Regular thoughts about tumor recurrence (self vs family) −0.15 0.02 Thoughts about tumor recurrence have influenced mood −0.14 0.03 Thoughts about tumor recurrence interfered in daily activities −0.10 0.14 How concerned are you about recurrence of a tumor? −0.22 <0.01 How often have you worried about tumor recurrence −0.22 <0.01 Is this worry a problem for you? −0.20 <0.01 Wilcoxon signed-rank test (r using Cohen criteria of 0.1 = small effect, 0.3 = medium effect, 0.5 = large effect). View Large Table 3. Comparison of Fear of Cancer Occurrence in Patients and in Their Family Members r P Value Regular thoughts about tumor recurrence (self vs family) −0.15 0.02 Thoughts about tumor recurrence have influenced mood −0.14 0.03 Thoughts about tumor recurrence interfered in daily activities −0.10 0.14 How concerned are you about recurrence of a tumor? −0.22 <0.01 How often have you worried about tumor recurrence −0.22 <0.01 Is this worry a problem for you? −0.20 <0.01 r P Value Regular thoughts about tumor recurrence (self vs family) −0.15 0.02 Thoughts about tumor recurrence have influenced mood −0.14 0.03 Thoughts about tumor recurrence interfered in daily activities −0.10 0.14 How concerned are you about recurrence of a tumor? −0.22 <0.01 How often have you worried about tumor recurrence −0.22 <0.01 Is this worry a problem for you? −0.20 <0.01 Wilcoxon signed-rank test (r using Cohen criteria of 0.1 = small effect, 0.3 = medium effect, 0.5 = large effect). View Large Disease perception and FDO Respondents were asked whether they believed they had an equal, slightly higher, moderately higher, or severely higher chance of developing an MEN1-related tumor in the next 10 years in comparison with the general Dutch population. Thirty-nine percent of patients responded that they had an equal or slightly higher chance, and 40% considered their chances as being much higher. Patients who considered themselves to have a severely higher chance had the greatest FDO. Patients who considered themselves to have an equal chance had the lowest FDO (Table 4). Table 4. Cancer Worry and the Chance of MEN1-Related Tumor Development in the Next 10 Years in Comparison With the General Population CWS n (%) Equal chance 11.9 33 (15) Slightly higher chance 12.8 53 (24) Moderately higher chance 14.7 46 (21) Severely higher chance 17.7 90 (40) CWS n (%) Equal chance 11.9 33 (15) Slightly higher chance 12.8 53 (24) Moderately higher chance 14.7 46 (21) Severely higher chance 17.7 90 (40) Kruskal-Wallis P < 0.01 (3 degrees of freedom). View Large Table 4. Cancer Worry and the Chance of MEN1-Related Tumor Development in the Next 10 Years in Comparison With the General Population CWS n (%) Equal chance 11.9 33 (15) Slightly higher chance 12.8 53 (24) Moderately higher chance 14.7 46 (21) Severely higher chance 17.7 90 (40) CWS n (%) Equal chance 11.9 33 (15) Slightly higher chance 12.8 53 (24) Moderately higher chance 14.7 46 (21) Severely higher chance 17.7 90 (40) Kruskal-Wallis P < 0.01 (3 degrees of freedom). View Large Discussion In this study, we focused on FDO in patients and their family members in a large and representative cohort of patients with MEN1. The high FDO that was found in this study can be interpreted as a substantial fear of further implications of the disease. High fear can be characterized as chronic worry, excessive monitoring for signs of disease occurrence, seeking medical reassurance, avoidance of disease reminders, intrusive thoughts and images about occurrence, and difficulties planning for the future (18–23). Patients with high FDO had lower scores on the SF-36 scale, indicating a lower QoL. In addition, an increase in the of number of manifestations of MEN1 was directly correlated to higher FDO scores. FDO has been derived from fear of cancer recurrence, which has been a topic of increasing interest in recent years (24–27). Fear of cancer recurrence has been defined as “fear, worry or concern relating to the possibility that cancer will come back or progress” (28). Because some patients with MEN1 have not experienced an MEN1 manifestation, “recurrence” was replaced with “occurrence,” and “cancer” was replaced with “disease” because pHPT and PITs are not recognized as cancer. The FDO score was high in comparison with other types of cancer. The outcome of 15.1 is comparable with patients with the VHL syndrome (15.6) (12). Fear in patients with breast cancer, for example, was lower, with an average score of 13.4 (17). This reflects the major impact of MEN1 because fear in breast cancer patients is generally considered high. Patients with Li-Fraumeni and familial adenomatous polyposis also have lower scores compared with patients with MEN1 (13.9 and 12.4, respectively) (11, 13) (Fig. 2). Patients who considered their chance of occurrence of an MEN1-related tumor as comparable with the general population had less FDO than respondents considering themselves as having a severely higher chance. Regarding the high age-related penetrance of the disease, patients with a higher number of manifestations had more FDO. In this study, the diagnosis of a PIT, pNET, and being unemployed were related to elevated FDO. pNETs lead to the most morbidity and mortality in MEN1, and therefore it seems obvious that patients with a pNET diagnosis have greater FDO (4, 8, 29–31). However, it is interesting that patients with a PIT diagnosis have greater FDO because PITs in MEN1 are generally benign and have a slow growth rate. In addition, the majority of patients with PITs are successfully managed by pharmacological treatment or by a watchful waiting strategy (32, 33). Patients who had an operation in the past had the lowest FDO, whereas patients with a current PIT had greater FDO. This suggests that present disease status is more relevant than past severe pituitary disease. This finding could suggest that patients were not aware of the indolent course of PITs or that the knowledge of having a tumor near their brain is a high burden. Adequate patient information on the expected course of individual MEN1 manifestations is therefore mandatory. Unemployment was associated with FDO, which is in line with previous research. Employment status in general has proved to be beneficial for health and in particular for mental health (34). Cancer survivors who continued working had better health and QoL than those who were not able to work (35). Age was not associated with FDO, although a younger age has been indicated to be a predictor for elevated FDO in other studies (20, 21, 26). In MEN1 there is an age-related effect, with young patients with MEN1 generally having fewer manifestations (4). This could explain why young age is not related to high FDO in this cohort. Patients were more worried about their family members than about themselves. This underlines the necessity of an integral familial approach in identifying FDO and in supporting of the family as a whole. Limitations A limitation of this study is its cross-sectional design, which did not allow assessing changes of FDO or QoL over time. In hereditary tumor syndromes, FDO could vary over time, and it would be interesting to study the course of FDO in MEN1. MEN1-related fear was assessed by an adapted CWS that has not been validated in an MEN1 population. However, the CWS has been validated in patients with breast cancer (17) and has been used in other hereditary syndromes with similar inheritance patterns, such as VHL (12), Li-Fraumeni (11), and familial adenomatous polyposis (13). Another limitation is that the questions regarding FDO in patients themselves in comparison with their family members have not been validated in other studies. Because there was a trend toward greater FDO for family members, this could be relevant for other hereditary diseases and necessitates further research. Strengths All respondents are from the population-based Dutch MEN1 study group database, which consists of >90% of the total Dutch MEN1 population. The high response rate of 80% contributes to the generalizability and validity of the study results, which can be considered a major strength. This response rate is much higher than similar studies (11, 13, 17, 19, 25, 36). This is the largest MEN1 cohort in which FDO associated with QoL has been studied, which makes the data unique. In accordance with recent findings, only MEN1 mutation–positive patients were included. MEN1 mutation–negative patients have a different phenotype, a different clinical course, and no family members with an MEN1 mutation, and therefore we excluded these patients to prevent heterogeneity (4). Clinical implications The high percentage of patients with MEN1 (58%) with a high FDO highlights the need for more attention and support for aspects of fear and worry regarding the disease. This topic has been largely neglected, which is incomprehensible considering the results regarding FDO and its impact on QoL. MEN1 is a diagnosis that often affects multiple family members, and therefore the high FDO for patients’ family members requires that regular follow-up visits include addressing worries about relatives with MEN1-related problems, and psychosocial support should be provided when needed. A study in women with an increased risk of breast cancer who expressed a high level of unmet need in support showed that women were mostly interested in attending a support group where they could participate in discussions and receive more information (37). Identifying the need for support in patients with MEN1 would be the first step toward interventions to reduce fear and improve QoL, especially because the prevalence rate for high FDO is higher in patients with MEN1 [58%, in comparison with 52% in patients with gastrointestinal stromal tumors (36), 38% in patients with colorectal tumors (38), 36% in patients with prostate cancer (25), and 31% of patients with breast cancer (17)]. A psychological intervention has shown efficacy to reduce fear in patients with curable breast and colorectal cancer and melanoma. Similar interventions could be beneficial for selected patients with MEN1 after gaining more knowledge on FDO and performing evidence-based interventional studies in patients with MEN1 (39). In summary, there is high FDO in patients with MEN1, which is associated with a lower QoL. Future studies should focus on interventions that improve QoL and thereby improve care and subsequently the QoL of patients with MEN1. Abbreviations: Abbreviations: CWS Cancer Worry Scale dpNET duodenopancreatic neuroendocrine tumor FDO fear of disease occurrence MEN1 multiple endocrine neoplasia type 1 pHPT primary hyperparathyroidism PIT pituitary tumor pNET pancreatic neuroendocrine tumor QoL quality of life SD standard deviation SF-36 Medical Outcomes Study 36-item Short-Form Health Survey VHL Von Hippel Lindau Acknowledgments Disclosure Summary: The authors have nothing to disclose. References 1. Chandrasekharappa SC , Guru SC , Manickam P , Olufemi SE , Collins FS , Emmert-Buck MR , Debelenko LV , Zhuang Z , Lubensky IA , Liotta LA , Crabtree JS , Wang Y , Roe BA , Weisemann J , Boguski MS , Agarwal SK , Kester MB , Kim YS , Heppner C , Dong Q , Spiegel AM , Burns AL , Marx SJ . Positional cloning of the gene for multiple endocrine neoplasia-type 1 . Science . 1997 ; 276 ( 5311 ): 404 – 407 . Google Scholar CrossRef Search ADS PubMed 2. Kouvaraki MA , Lee JE , Shapiro SE , Gagel RF , Sherman SI , Sellin RV , Cote GJ , Evans DB . Genotype-phenotype analysis in multiple endocrine neoplasia type 1 . Arch Surg . 2002 ; 137 ( 6 ): 641 – 647 . Google Scholar CrossRef Search ADS PubMed 3. Trump D , Farren B, Wooding C, Pang JT, Besser GM, Buchanan KD, Edwards CR, Heath DA, Jackson CE, Jansen S, Lips K, Monson JP, O'Halloran D, Sampson J, Shalet SM, Wheeler MH, Zink A, Thakker RV . Clinical studies of multiple neoplasia type 1 . Q J Med . 1997 ; 90 : 19 – 25 . Google Scholar CrossRef Search ADS 4. de Laat JM , van der Luijt RB , Pieterman CRC , Oostveen MP , Hermus AR , Dekkers OM , de Herder WW , van der Horst-Schrivers AN , Drent ML , Bisschop PH , Havekes B , Vriens MR , Valk GD . MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients . BMC Med . 2016 ; 14 ( 1 ): 182 . Google Scholar CrossRef Search ADS PubMed 5. de Laat JM , van der Luijt RB , Pieterman CRC , Oostveen MP , Hermus AR , Dekkers OM , de Herder WW , van der Horst-Schrivers AN , Drent ML , Bisschop PH , Havekes B , Vriens MR , Valk GD . MEN1 redefined: a clinical comparison of mutation-positive and mutation-negative patients. Results from the DutchMEN1 study group . BMC Medicine . 2016 ; 14 : 182 . 6. Dreijerink KM , Goudet P , Burgess JR , Valk GD ; International Breast Cancer in MEN1 Study Group . Breast-cancer predisposition in multiple endocrine neoplasia type 1 . N Engl J Med . 2014 ; 371 ( 6 ): 583 – 584 . Google Scholar CrossRef Search ADS PubMed 7. Ito T , Igarashi H , Uehara H , Berna MJ , Jensen RT . Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors . Medicine (Baltimore) . 2013 ; 92 ( 3 ): 135 – 181 . Google Scholar CrossRef Search ADS PubMed 8. Goudet P , Murat A , Binquet C , Cardot-Bauters C , Costa A , Ruszniewski P , Niccoli P , Ménégaux F , Chabrier G , Borson-Chazot F , Tabarin A , Bouchard P , Delemer B , Beckers A , Bonithon-Kopp C . Risk factors and causes of death in MEN1 disease. A GTE (Groupe d’Etude des Tumeurs Endocrines) cohort study among 758 patients . World J Surg . 2010 ; 34 ( 2 ): 249 – 255 . Google Scholar CrossRef Search ADS PubMed 9. Doherty GM , Olson JA , Frisella MM , Lairmore TC , Wells SA Jr , Norton JA . Lethality of multiple endocrine neoplasia type I . World J Surg . 1998 ; 22 ( 6 ): 581 – 586, discussion 586–587 . Google Scholar CrossRef Search ADS PubMed 10. Pieterman CRC , Schreinemakers JMJ , Koppeschaar HPF , Vriens MR , Rinkes IH , Zonnenberg BA , van der Luijt RB , Valk GD . Multiple endocrine neoplasia type 1 (MEN1): its manifestations and effect of genetic screening on clinical outcome . Clin Endocrinol (Oxf) . 2009 ; 70 ( 4 ): 575 – 581 . Google Scholar CrossRef Search ADS PubMed 11. Lammens CRM , Aaronson NK , Wagner A , Sijmons RH , Ausems MG , Vriends AH , Ruijs MW , van Os TA , Spruijt L , Gómez García EB , Kluijt I , Nagtegaal T , Verhoef S , Bleiker EM . Genetic testing in Li-Fraumeni syndrome: uptake and psychosocial consequences . J Clin Oncol . 2010 ; 28 ( 18 ): 3008 – 3014 . Google Scholar CrossRef Search ADS PubMed 12. Lammens CRM , Bleiker EM , Verhoef S , Hes FJ , Ausems MG , Majoor-Krakauer D , Sijmons RH , van der Luijt RB , van den Ouweland AM , Van Os TA , Hoogerbrugge N , Gómez García EB , Dommering CJ , Gundy CM , Aaronson NK . Psychosocial impact of Von Hippel-Lindau disease: levels and sources of distress . Clin Genet . 2010 ; 77 ( 5 ): 483 – 491 . Google Scholar CrossRef Search ADS PubMed 13. Douma KFL , Aaronson NK , Vasen HF , Gerritsma MA , Gundy CM , Janssen EP , Vriends AH , Cats A , Verhoef S , Bleiker EM . Psychological distress and use of psychosocial support in familial adenomatous polyposis . Psychooncology . 2010 ; 19 ( 3 ): 289 – 298 . Google Scholar CrossRef Search ADS PubMed 14. Berglund G , Lidén A , Hansson MG , Öberg K , Sjöden PO , Nordin K . Quality of life in patients with multiple endocrine neoplasia type 1 (MEN1) . Fam Cancer . 2003 ; 1 : 27 – 33 . Google Scholar CrossRef Search ADS 15. Goswami S , Peipert BJ , Helenowski I , Yount SE , Sturgeon C . Disease and treatment factors associated with lower quality of life scores in adults with multiple endocrine neoplasia type I . Surgery . 2017 ; 162 ( 6 ): 1270 – 1277 . Google Scholar CrossRef Search ADS PubMed 16. Lerman C , Daly M , Masny A , Balshem A . Attitudes about genetic testing for breast-ovarian cancer susceptibility . J Clin Oncol . 1994 ; 12 ( 4 ): 843 – 850 . Google Scholar CrossRef Search ADS PubMed 17. Custers JA , van den Berg SW , van Laarhoven HW , Bleiker EM , Gielissen MF , Prins JB . The Cancer Worry Scale: detecting fear of recurrence in breast cancer survivors . Cancer Nurs . 2014 ; 37 ( 1 ): E44 – E50 . Google Scholar CrossRef Search ADS PubMed 18. Lebel S , Tomei C , Feldstain A , Beattie S , McCallum M . Does fear of cancer recurrence predict cancer survivors’ health care use ? Support Care Cancer . 2013 ; 21 ( 3 ): 901 – 906 . Google Scholar CrossRef Search ADS PubMed 19. Custers JA , Gielissen MF , de Wilt JH , Honkoop A , Smilde TJ , van Spronsen DJ , van der Veld W , van der Graaf WT , Prins JB . Towards an evidence-based model of fear of cancer recurrence for breast cancer survivors . J Cancer Surviv . 2017 ; 11 ( 1 ): 41 – 47 . Google Scholar CrossRef Search ADS PubMed 20. Crist JV , Grunfeld EA . Factors reported to influence fear of recurrence in cancer patients: a systematic review . Psychooncology . 2013 ; 22 ( 5 ): 978 – 986 . Google Scholar CrossRef Search ADS PubMed 21. Simard S , Thewes B , Humphris G , Dixon M , Hayden C , Mireskandari S , Ozakinci G . Fear of cancer recurrence in adult cancer survivors: a systematic review of quantitative studies . J Cancer Surviv . 2013 ; 7 ( 3 ): 300 – 322 . Google Scholar CrossRef Search ADS PubMed 22. Lee-Jones C , Dixon R . Fear of cancer recurrence: a literature review and proposed cognitive formulation to explain exacerbation of recurrent fears . Psychooncology . 1996 ; 1997 ( 6 ): 95 – 105 . 23. Thewes B , Butow P , Bell ML , Beith J , Stuart-Harris R , Grossi M , Capp A , Dalley D ; FCR Study Advisory Committee . Fear of cancer recurrence in young women with a history of early-stage breast cancer: a cross-sectional study of prevalence and association with health behaviours . Support Care Cancer . 2012 ; 20 ( 11 ): 2651 – 2659 . Google Scholar CrossRef Search ADS PubMed 24. Thewes B , Butow P , Zachariae R , Christensen S , Simard S , Gotay C . Fear of cancer recurrence: a systematic literature review of self-report measures . Psychooncology . 2012 ; 21 : 571 – 587 . Google Scholar CrossRef Search ADS PubMed 25. van de Wal M , van Oort I , Schouten J , Thewes B , Gielissen M , Prins J . Fear of cancer recurrence in prostate cancer survivors . Acta Oncol . 2016 ; 55 ( 7 ): 821 – 827 . Google Scholar CrossRef Search ADS PubMed 26. Thewes B , Kaal SEJ , Custers JAE , Manten-Horst E , Jansen R , Servaes P , van der Graaf WTA , Prins JB , Husson O . Prevalence and correlates of high fear of cancer recurrence in late adolescents and young adults consulting a specialist adolescent and young adult (AYA) cancer service [published online ahead of print November 22, 2017]. Support Care Cancer . doi:10.1007/s00520-017-3975-2 . 27. Thewes B , Husson O , Poort H , Custers JAE , Butow PN , McLachlan SA , Prins JB . Fear of cancer recurrence in an era of personalized medicine . J Clin Oncol . 2017 ; 35 ( 29 ): 3275 – 3278 . Google Scholar CrossRef Search ADS PubMed 28. Lebel S , Ozakinci G , Humphris G , Mutsaers B , Thewes B , Prins J , Dinkel A , Butow P ; University of Ottawa Fear of Cancer Recurrence Colloquium attendees . From normal response to clinical problem: definition and clinical features of fear of cancer recurrence . Support Care Cancer . 2016 ; 24 ( 8 ): 3265 – 3268 . Google Scholar CrossRef Search ADS PubMed 29. Triponez F , Dosseh D , Goudet P , Cougard P , Bauters C , Murat A , Cadiot G , Niccoli-Sire P , Chayvialle JA , Calender A , Proye CA . Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas . Ann Surg . 2006 ; 243 ( 2 ): 265 – 272 . Google Scholar CrossRef Search ADS PubMed 30. Geerdink EAM , Luijt RB Van Der , Lips CJM . Do patients with multiple endocrine neoplasia syndrome type 1 benefit from periodical screening? 2003;149(6):577–582 . 31. Dean PG , van Heerden JA , Farley DR , Thompson GB , Grant CS , Harmsen WS , Ilstrup DM . Are patients with multiple endocrine neoplasia type I prone to premature death ? World J Surg . 2000 ; 24 ( 11 ): 1437 – 1441 . Google Scholar CrossRef Search ADS PubMed 32. Giusti F , Cianferotti L , Boaretto F , Cetani F , Cioppi F , Colao A , Davì MV , Faggiano A , Fanciulli G , Ferolla P , Ferone D , Fossi C , Giudici F , Gronchi G , Loli P , Mantero F , Marcocci C , Marini F , Masi L , Opocher G , Beck-Peccoz P , Persani L , Scillitani A , Sciortino G , Spada A , Tomassetti P , Tonelli F , Brandi ML . Multiple endocrine neoplasia syndrome type 1: institution, management, and data analysis of a nationwide multicenter patient database . Endocrine . 2017 ; 58 ( 2 ): 349 – 359 . Google Scholar CrossRef Search ADS PubMed 33. de Laat J , Dekkers OM , Pieterman CRC , Kluijfhout WP , Hermus AR , Pereira AM , van der Horst-Schrivers AN , Drent ML , Bisschop PH , Havekes B , de Herder WW , Valk GD . Long-term natural course of pituitary tumors in patients with MEN1: results from the Dutch MEN1 study group (DMSG) . J Clin Endocrinol Metab . 2015 ; 100 ( 9 ): 3288 – 3296 . doi: Google Scholar CrossRef Search ADS PubMed 34. van der Noordt M , IJzelenberg H , Droomers M , Proper KI . Health effects of employment: a systematic review of prospective studies . Occup Environ Med . 2014 ; 71 ( 10 ): 730 – 736 . Google Scholar CrossRef Search ADS PubMed 35. Duijts SFA , Kieffer JM , van Muijen P , van der Beek AJ . Sustained employability and health-related quality of life in cancer survivors up to four years after diagnosis . Acta Oncol . 2017 ; 56 ( 2 ): 174 – 182 . Google Scholar CrossRef Search ADS PubMed 36. Custers JA , Tielen R , Prins JB , de Wilt JH , Gielissen MF , van der Graaf WT . Fear of progression in patients with gastrointestinal stromal tumors (GIST): is extended lifetime related to the Sword of Damocles ? Acta Oncol . 2015 ; 54 ( 8 ): 1202 – 1208 . Google Scholar CrossRef Search ADS PubMed 37. Thewes B , Meiser B , Tucker M , Tucker K . The unmet information and support needs of women with a family history of breast cancer: a descriptive survey . J Genet Couns . 2003 ; 12 ( 1 ): 61 – 76 . Google Scholar CrossRef Search ADS PubMed 38. Custers JAE , Gielissen MFM , Janssen SHV , de Wilt JHW , Prins JB . Fear of cancer recurrence in colorectal cancer survivors . Support Care Cancer . 2016 ; 24 ( 2 ): 555 – 562 . Google Scholar CrossRef Search ADS PubMed 39. Butow PN , Turner J , Gilchrist J , Sharpe L , Smith AB , Fardell JE , Tesson S , O’Connell R , Girgis A , Gebski VJ , Asher R , Mihalopoulos C , Bell ML , Grunewald Zola K , Beith J , Thewes B . Randomized trial of ConquerFear: a novel, theoretically based psychosocial intervention for fear of cancer recurrence . J. Clin. Oncol . 2017 ; 35 ( 36 ): 4066 – 4077 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 Endocrine Society

Journal

Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Mar 30, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off