Abstract
Objective
To describe the treatment and long-term outcomes of patients with acromegaly from all healthcare regions in Sweden.
Design and methods
Analysis of prospectively reported data from the Swedish Pituitary Register of 698 patients (51% females) with acromegaly diagnosed from 1991 to 2011. The latest clinical follow-up date was December 2012, while mortality data were collected for 28.5 years until June 2019.
Results
The annual incidence was 3.7/million; 71% of patients had a macroadenoma, 18% had visual field defects, and 25% had at least one pituitary hormone deficiency. Eighty-two percent had pituitary surgery, 10% radiotherapy, and 39% medical treatment. At the 5- and 10-year follow-ups, insulin-like growth factor 1 levels were within the reference range in 69 and 78% of patients, respectively. In linear regression, the proportion of patients with biochemical control including adjuvant therapy at 10 years follow-up increased over time by 1.23% per year. The standardized mortality ratio (SMR) (95% CI) for all patients was 1.29 (1.11–1.49). For patients with biochemical control at the latest follow-up, SMR was not increased, neither among patients diagnosed between 1991 and 2000, SMR: 1.06 (0.85–1.33) nor between 2001 and2011, SMR: 0.87 (0.61–1.24). In contrast, non-controlled patients at the latest follow-up from both decades had elevated SMR, 1.90 (1.33–2.72) and 1.98 (1.24–3.14), respectively.
Conclusions
The proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy, while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly.
Introduction
The diagnosis of acromegaly is often delayed since symptoms and signs generally develop slowly (1, 2). Therefore, associated comorbidities such as diabetes mellitus, hypertension, sleep apnea, and bone/joint disorders are frequent before diagnosis (3, 4, 5). Measurements of serum insulin-like growth factor 1 (IGF-I) as a marker of integrated GH secretion are recommended as the initial screening method for acromegaly, as well as for monitoring treatment response (6). According to guidelines, transsphenoidal surgery is the first-line treatment (6, 7). Pharmacological treatments with somatostatin analogs, GH receptor antagonists, or dopamine agonists are second-line treatments that are often needed to achieve biochemical control and can be used as primary therapy in selected cases (3, 6). Radiotherapy is generally considered an adjuvant therapy in a patient who is biochemically uncontrolled after surgery and medical therapy (6, 8). Increased mortality mainly from cardiovascular, cerebrovascular, and respiratory diseases and, in some reports, malignancy has been reported (9, 10). However, mortality was found to have gradually declined in recent decades (11, 12). In a recent meta-analysis involving more than 16 000 patients with acromegaly in 19 registries, large variations in data collection were noticed, and the importance of national registries for a correct interpretation of epidemiology and disease characteristics across countries was underscored (13). In Sweden, patients diagnosed with acromegaly have been prospectively registered in the Swedish Pituitary Register (SPR) since 1991.
The aim of the present study was to evaluate Swedish patients with acromegaly diagnosed between 1991 and 2011 regarding disease characteristics, treatment, biochemical outcomes, and time trends of mortality during long-term follow-up.
Patients and methods
The Swedish Pituitary Register
SPR is based on the national Information Network for Cancer treatment IT platform located on the Regional Cancer Center (RCC) Stockholm-Gotland, Sweden, and financially supported by the government. SPR is organized by endocrinologists, neurosurgeons, oncologists, pathologists, ophthalmologists, neuroradiologists, and endocrine nurses from all six health care regions in Sweden.
Study design
Prospectively reported data were retrieved from the SPR for patients with acromegaly diagnosed between 1991 and 2011. The diagnoses were made according to typical features of acromegaly, increased age-adjusted IGF-I levels, non-suppressible growth hormone (GH) after oral glucose tolerance test (OGTT), and histopathological findings. Missing data were obtained retrospectively from medical records when available. The latest date for the clinical follow-up was December 31, 2012, while mortality data were collected until June 30, 2019.
Registered variables and definitions
Data analyzed were date and age at diagnosis, sex, radiological findings of the tumor, ophthalmological findings, pituitary function, pituitary tumor treatment (pharmacological, surgical, and radiotherapy), and hormone replacement therapy.
Biochemical control at follow-ups was defined as serum IGF-I within the reference range for age, including both patients with and without medical therapy.
A pituitary tumor with largest diameter <10 mm was considered a microadenoma and a tumor with largest diameter ≥ 10 mm macroadenoma. Tumor volume was calculated as (length × width × height)/2 and was reported as cm3. Suprasellar grades 0–4 according to SIPAP (suprasellar, infrasellar, parasellar, anterior, posterior) classification (14) and Knosp parasellar grades 0–4 (15) were used to evaluate pituitary adenoma extension.
SPR was approved by the Ethics Committee at Karolinska Institute (Stockholm, Sweden), 2003 (No: 515/03) and 2012 (No: 2012/915-32). Since the SPR is a quality register supported by the government, we do not need written approval for inclusion in the register, but the patients must be informed, with an opt-out possibility, either orally or by written information.
Statistical analysis
Quantitative data are described as the mean ± s.d. or median and interquartile range (IQR; Q1–Q3) depending on the skewness and kurtosis of the data.
Age-standardized incidence rates were calculated using the Swedish age distribution year 2000 as the standard population. All-cause mortality in the study group was compared to the mortality of the Swedish population by means of the standardized mortality ratio (SMR). To estimate SMR, we used deaths rates, stratified by 1-year interval age and 1-year interval calendar year and sex.
A non-parametric K-sample test on the equality of medians was used to detect possible differences in tumor size across age groups. Possible differences between categorical data were evaluated using Fisher’s exact test.
Regression analysis of the trend in the proportion of biochemically controlled patients at 1, 5, and 10 years after diagnosis throughout the study period was performed using the year of diagnosis as an explanatory variable.
Odds ratios (ORs) for being categorized as not biochemically controlled were assessed using uni- and multivariate logistic regression at the 1- and 5-year follow-ups. Survival times were calculated from the date of diagnosis until the date of death from all causes, and patients were censored at the last date of follow-up. To compare mortality between two decades, 1991–2000 and 2001–2011, the follow-up time was censored to 10 years after diagnosis in all cases.A Cox proportional hazards regression model was fitted to evaluate survival, adjusting for factors such as biochemical status at the latest available time point during follow-up, age, and sex.
The results are presented as ORs) and hazard ratios (HRs) with corresponding 95% CIs. P-values <0.05 were considered statistically significant.
All statistical calculations were performed using Stata/MP Version 15.1 (StataCorp LLC, College Station, TX, USA).
Results
Population
A total of 698 patients with acromegaly were reported in the SPR from 1991 to 2011 (345 males and 353 females). The median (IQR) age at diagnosis was 51 (40–66) years overall, 53 years among females and 49 years among males, and the age at diagnosis did not change between 1991 and 2011. The incidence of acromegaly in Sweden from 1991 to 2011 was 3.7/million/year, based on the SPR and population census in Sweden in 2000. On June 30, 2019, 512 patients (73%) were alive.
Patients at follow-up
Data on clinical characteristics and different treatments, as well as patient outcomes at follow-up times, were designated as 1 (range: 8 months–2.5 years), 5 (range: 2.5–7.5 years), and 10 years (range: 7.5–15 years) after diagnosis. The median (IQR) times to follow-up were 1.2 (1.0–1.5), 5.1 (4.7–5.6), and 10.1 (9.6–11.0) years after diagnosis.
Based on possible number of patients according to follow-up time after diagnosis, 1-year follow-up was reported for 80% (533/665) of patients, 5-year follow-up for 87% (467/532), and 10-year follow-up for 82% (296/353) of patients. The median (IQR) time to follow-up overall was 10.3 years (5.4–15.2).
Baseline characteristics
MRI
The majority of patients (71%) had a macroadenoma at diagnosis, with no significant sex difference. The proportion of supra- and parasellar grades is shown in Table 1. Tumor volume was reported for 81% (565/698) of the patients. Younger patients had larger tumor volumes than older patients, but there was no significant difference in sex among the different age groups (Fig. 1).
Tumor volumes in relation to age at diagnosis: 0–39 years (n = 142), 40–60 years (n = 255), and >60 years (n = 168). Younger patients with acromegaly had larger tumor volumes (0–39 vs 40–60 years, P = 0.002; 0–39 vs >60 years, P < 0.001; 40–60 vs >60 years, P= 0.004). There was no significant sex difference within the different age groups. The median, IQR, and whiskers (within 1.5 times the IQR from the first and third quartiles) are shown. Values above or below these limits are considered outliers, and no distinction is made between mild or extreme outliers in different age groups. Volume is missing for 18, 22, and 15%, and outlier rates are 11, 11, and 14% of the patients in the three age groups, respectively.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
Tumor volumes in relation to age at diagnosis: 0–39 years (n = 142), 40–60 years (n = 255), and >60 years (n = 168). Younger patients with acromegaly had larger tumor volumes (0–39 vs 40–60 years, P = 0.002; 0–39 vs >60 years, P < 0.001; 40–60 vs >60 years, P= 0.004). There was no significant sex difference within the different age groups. The median, IQR, and whiskers (within 1.5 times the IQR from the first and third quartiles) are shown. Values above or below these limits are considered outliers, and no distinction is made between mild or extreme outliers in different age groups. Volume is missing for 18, 22, and 15%, and outlier rates are 11, 11, and 14% of the patients in the three age groups, respectively.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
Tumor volumes in relation to age at diagnosis: 0–39 years (n = 142), 40–60 years (n = 255), and >60 years (n = 168). Younger patients with acromegaly had larger tumor volumes (0–39 vs 40–60 years, P = 0.002; 0–39 vs >60 years, P < 0.001; 40–60 vs >60 years, P= 0.004). There was no significant sex difference within the different age groups. The median, IQR, and whiskers (within 1.5 times the IQR from the first and third quartiles) are shown. Values above or below these limits are considered outliers, and no distinction is made between mild or extreme outliers in different age groups. Volume is missing for 18, 22, and 15%, and outlier rates are 11, 11, and 14% of the patients in the three age groups, respectively.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
Baseline characteristics of 698 patients (345 males and 353 females) with acromegaly diagnosed from 1991 to 2011.
| Age, years, median (IQR) | 51 (40–66) |
| Microadenoma, n (%) | 174/607 (29) |
| Macroadenoma, n (%) | 433/607 (71) |
| Supra- and para-sellar grades 0–2, n (%) | 401/542 (74) |
| Supra- or para-sellar grades 3–4, n (%) | 98/542 (18) |
| Supra- and para-sellar grades 3–4, n (%) | 45/542 (8.3) |
| Visual field defect, n (%) | 126/628 (20) |
| Visual impairment, n (%) | 63/628 (10) |
| Ophtalmoplegia, n (%) | 6/628 (1) |
| Optic nerve atrophy, n (%) | 13/628 (2) |
Visual disturbances
Data regarding visual disturbances are shown in Table 1. In total, 76% had no visual disturbances at diagnosis. In the analysis by age group, 27% of patients (46/173) aged <40 years had visual field defects at diagnosis, in contrast to 17% (55/328) aged 40–60 years and 13% (25/197) >60 years of age (P= 0.001).
Pituitary hormone deficiencies
At diagnosis, at least one pituitary hormone deficiency was reported in 25% of the patients (Table 2). Two percent had four deficiencies reported: gonadotropin, adrenocorticotrophic hormone (ACTH), thyroid-stimulating hormone, and antidiuretic hormone. Younger patients had more deficiencies than older patients (age groups: 0–39, 40–60, and >60 years) (P< 0.001).
Pituitary deficiencies in different pituitary axes at different time points during the study in patients. Data are presented as n (%).
| Pituitary deficiency | Diagnosis | 1 year | 5 years | 10 years | c2 test for trend, P |
|---|---|---|---|---|---|
| ACTH | 42 (6) | 46 (9) | 46 (10) | 33 (11) | 0.006 |
| LH/FSH | 140 (20) | 93 (17) | 93 (20) | 62 (21) | 0.770 |
| TSH | 48 (7) | 48 (9) | 61 (13) | 50 (17) | <0.001 |
| GH | 0 | 7 (1) | 14 (3) | 10 (3) | 0.048¥ |
| ADH | 7 (1) | 25 (5) | 19 (4) | 11 (4) | 0.008 |
¥Excluding GH at diagnosis.
Treatment
Surgery
Eighty-two percent (572/698) of the patients underwent pituitary surgery at least once during the study period (478 patients had 1 surgery and 94 patients had ≥2 surgeries), with no difference between the time periods 1991–2000 and 2001–2011. There was a shift in surgical techniques between the time periods 1991–2000 and 2001–2011 (Table 2). Patients who received more than one surgery (tumor volume available in 83/94 patients) had larger tumor volume (1.64 cm3 (0.5–5)) at diagnosis than those operated once (tumor volume available in 376/478 patients) (0.81 cm3 (0.25–3)); P= 0.024.
Medical treatment
Thirty-nine percent of the patients received medical therapy for acromegaly at some point during the study period. Ongoing medical treatment was reported for 29 (155/533), 30 (142/467), and 23% (69/296) of the patients at the 1-, 5-, and 10-year follow-ups after diagnosis. Monotherapy with somatostatin analogs was the most common (73% of all medical therapies reported) (Table 3).
Different treatment modalities and numbers of different surgical and radiotherapeutic techniques reported until December 31, 2012, among patients diagnosed from 1991 to 2000 or 2001 to 2011. Data are presented as n (%). Fisher’s exact test, two-sided, 2001–2011 vs 1991-2000.
| Treatments | 1991–2000 | 2001–2011 | 1991–2011 |
|---|---|---|---|
| n | 334 | 364 | 698 |
| Surgery overall | 273 (82) | 299 (82) | 572 (82) |
| Surgery only | 159 (48) | 195 (54) | 354 (51) |
| Radiotherapy overall | 48 (14) | 24 (7)*** | 72 (10) |
| Radiotherapy only | 2 (0.6) | 0 (0) | 2 (0.3) |
| Medical therapy overall | 136 (41) | 139 (38) | 275 (39) |
| Medical therapy only | 34 (10) | 37 (10) | 71 (10) |
| Surgery and radiotherapy | 19 (6) | 5 (1.4)** | 24 (3.4) |
| Surgery and medical therapy | 75 (22) | 83 (23) | 158 (23) |
| Medical and radiotherapy | 7 (2) | 3 (0.8) | 10 (1.4) |
| Surgery, medical, and radiotherapy | 20 (6) | 16 (4.4) | 36 (5) |
| No therapy reported | 18 (5) | 25 (7) | 43 (6) |
| Transcranial surgery | 3 (0.9) | 2 (0.6) | 5 (0.7) |
| Lateral rhinotomy | 66 (20) | 40 (11)*** | 106 (15) |
| Transseptal/sublabial | 168 (50) | 47 (13)*** | 215 (31) |
| Transnasal/endonasal | 36 (11) | 210 (58) *** | 246 (35) |
| Fractionated radiotherapy | 22 (6.6) | 8 (2.2) ** | 30 (4.3) |
| Gamma knife surgery | 25 (7.5) | 16 (4.4) | 41 (6) |
**P < 0.01; ***P < 0.001.
Radiotherapy
Radiotherapy was given to 10% (72/698) of the patients during the whole study period. There was a decrease in the use of conventional fractionated radiotherapy over time (Table 3).
Combination therapy
Thirty-three percent of the patients received a combination of two different treatment modalities to achieve IGF-I normalization and 5% were treated with triple therapy (Table 3).
Outcome
Biochemical control
Biochemical control, defined as IGF-I within the reference range (including both patients with and without medical therapy), was achieved in 53% (280/533) of patients at 1 year, 69% (324/467) at 5 years, and 78% (232/296) at 10 years after diagnosis, as well as in 74% of the patients at the latest follow-up reported (range: 0.7–14.9 years). Biochemical control without medical therapy was achieved in 41, 48, and 60% of patients at the 1-, 5-, and 10-year follow-ups, respectively. In total, 71 patients received medical therapy only. In these patients, biochemical control was achieved in 33 (19/57), 56 (31/55), and 50% (12/24) at 1-, 5-, and 10-year of follow-ups, respectively, and the biochemical control at the latest follow-up was 55% (39/71). The proportion of all biochemically controlled patients 10 years after diagnosis increased significantly during the study period as did that of controlled patients without medical therapy 5 and 10 years after diagnosis (Fig. 2A and B).
(A and B) Patients with acromegaly had biochemical control at the 1-, 5-, and 10-year follow-ups. The dotted lines represent the 5-year moving average with a significant trend at 10 years (P< 0.001), with an increase in the proportion of biochemically controlled patients of 1.23% each year. There was a weakly positive but not significant trend at 1 and 5 years (A). The proportion of patients with biochemical control without medical therapy increased significantly at both the 5- and 10-year follow-ups, with increases of 0.93 and 2.24% each year, respectively (B). *P < 0.05, **P < 0.01; ***P < 0.001.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
(A and B) Patients with acromegaly had biochemical control at the 1-, 5-, and 10-year follow-ups. The dotted lines represent the 5-year moving average with a significant trend at 10 years (P< 0.001), with an increase in the proportion of biochemically controlled patients of 1.23% each year. There was a weakly positive but not significant trend at 1 and 5 years (A). The proportion of patients with biochemical control without medical therapy increased significantly at both the 5- and 10-year follow-ups, with increases of 0.93 and 2.24% each year, respectively (B). *P < 0.05, **P < 0.01; ***P < 0.001.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
(A and B) Patients with acromegaly had biochemical control at the 1-, 5-, and 10-year follow-ups. The dotted lines represent the 5-year moving average with a significant trend at 10 years (P< 0.001), with an increase in the proportion of biochemically controlled patients of 1.23% each year. There was a weakly positive but not significant trend at 1 and 5 years (A). The proportion of patients with biochemical control without medical therapy increased significantly at both the 5- and 10-year follow-ups, with increases of 0.93 and 2.24% each year, respectively (B). *P < 0.05, **P < 0.01; ***P < 0.001.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
Biochemical control in surgical patients
Biochemical control at 1-, 5-, and 10-years of follow-up in patients treated with surgery only for microadenoma was achieved in 62 (58/93), 66 (56/85), and 64% (39/61), respectively and in 46 (131/286), 45 (114/255), and 47% (71/152) of the patients with macroadenoma. For all operated patients, including patients who also received medical therapy or radiotherapy, biochemical control was achieved in 71 (66/93), 82 (70/85), and 87% (53/61) in microadenomas and 54 (154/286), 71 (180/255), and 80% (121/152) in macroadenomas, at the same follow-up points.
The difference in biochemical control between micro- and macro-adenoma was significant only at the 1-year follow-up (P= 0.003) and within the macroadenoma group between 1 and 5 and 1 and 10 years, respectively (P< 0.001).
Predictive factors for biochemical control
Surgery-predicted biochemical control in both the univariate and multivariate analysis with biochemical control at 1 and/or 5 years after diagnosis as the dependent variable. Suprasellar grades 3–4, parasellar grades 3–4, a combination of supra- and parasellar grades 3–4 or a volume >2.0 cm3 at diagnosis were all negative predictors for biochemical control in the univariate analysis, while the combination of supra- and parasellar grades 3–4 significantly predicted no biochemical control in the multivariate analysis (n = 368 at 1 year and n = 314 at 5 years). Neither age nor sex had a significant effect on biochemical control at follow-up.
Pituitary hormone deficiencies during follow-up
No pituitary hormone deficiency was reported in 70 (373/533), 65 (305/467), or 62% (184/296) of patients at the 1-, 5-, and 10-year follow-ups, respectively. The development of specific pituitary deficiencies during the study period is shown in Table 2.
Mortality
Causes of death
In total, 186 patients (86 men and 100 women) died before June 30, 2019.
The main reported causes of death were cardiovascular diseases (total: 69; ischemic heart disease: 31, intracranial vascular disease: 19, other heart disease: 18, and pulmonary vascular disease: (1) and tumors (total: 55; malignant: 51, benign: 2, and not specified: (2) followed by endocrine disorders (12), trauma (9), respiratory disorders (7), gastrointestinal disorders (7), and psychiatric disorders (6). Only a few neurologic (3), kidney (2), and infectious diseases (1) were recorded. For 15 patients, the cause of death was not specified (8) or not available at the time of data retrieval (7). The proportion of deaths due to cardio/cerebrovascular diseases was similar during the years 1991–2000, 2001–2010, and 2011–June 2019, that is 41, 42, and 39%, as well as deaths due to neoplasia 36, 32, and 32%, respectively.
SMR evaluation until June 30, 2019
The SMR (95% CI) for all patients diagnosed between 1991 and 2011 was 1.29 (1.11–1.49), 1.31 (1.10–1.56) among patients diagnosed between 1991 and 2000, and 1.24 (0.97–1.60) among patients diagnosed between 2001 and 2011. In patients with biochemical control at the latest follow-up, SMR was not increased; 1.06 (0.85–1.33) for patients diagnosed between 1991 and 2000 and 0.87 (0.61–1.24) for patients diagnosed between 2001 and 2011 (Table 4).
Standardized mortality ratio (SMR, 95% CI) of biochemically controlled and uncontrolled patients at the latest follow-up during the two decades and of patients with no follow-up in the register up to June 30, 2019. In total, 512 patients survived and 186 patients died before June 30, 2019. SMR was increased in not controlled patients and in patients with no status/follow-up. No significant differences between the two decades were seen among controlled, not controlled, and patients with no status/follow-up.
| Group | Year of diagnosis | Deaths | Expected deaths | SMR (lower–upper) |
|---|---|---|---|---|
| Controlled | 1991–2000 | 78 | 73 | 1.06 (0.85–1.33) |
| Not controlled | 1991–2000 | 30 | 16 | 1.90 (1.33–2.72) |
| No status/follow-up | 1991–2000 | 18 | 7 | 2.55 (1.61–4.04) |
| Controlled | 2001–2011 | 30 | 35 | 0.87 (0.61–1.24) |
| Not controlled | 2001–2011 | 18 | 9 | 1.98 (1.24–3.14) |
| No status/follow-up | 2001–2011 | 12 | 5 | 2.63 (1.50–4.64) |
| Controlled | 1991–2011 | 108 | 108 | 1.00 (0.83–1.21) |
| Not controlled | 1991–2011 | 48 | 25 | 1.93 (1.45–2.56) |
| No status/follow-up | 1991–2011 | 30 | 12 | 2.58 (1.80–3.69) |
Influence of sex, age, micro/macroadenoma, pituitary surgery, pituitary radiotherapy, and pituitary deficiency
The SMR (95% CI) did not differ significantly between men and women or between patients with micro- or macroadenomas. There were no significant differences in SMR among patients who were diagnosed at <40 years of age, 40–60 years, or >60 years. Patients who never underwent pituitary surgery for acromegaly had a higher SMR (1.90 (1.53–2.37)) than surgically treated patients (1.03 (0.85–1.25)); (P< 0.001). A lower proportion of non-surgically treated patients was biochemically controlled at the latest follow-up (65%, 69/106) compared to the operated patients (91%, 491/537). There was no significant difference in mortality between patients with pituitary deficiencies or ACTH deficiency and patients with no deficiencies. Patients treated with pituitary radiotherapy (n =72) did not have significantly different SMR (1.13 (0.67–1.90)) compared to the reference population.
Hazard ratios for premature death
Age at diagnosis, lack of biochemical control, and loss of biochemical status/no report of follow-up were all associated with higher hazards for premature death in the multivariate Cox model (Fig. 3).
Hazard ratios (HRs) with 95% CIs for the outcome of overall death in patients with acromegaly until June 30, 2019. Estimates from Cox proportional hazards models with biochemical status at the latest available time point during follow-up. Other covariates included in the model were age at diagnosis (continuous), sex, and time periods (1991–2000; 2001–2011). Statistically significant categories of biochemical control were non-controlled and no status/follow-up, which had HRs of 2.31 (P < 0.001) and 3.24 (P < 0.001), respectively. Age at diagnosis was associated with an HR of 1.10 (P < 0.001). ***P < 0.001.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
Hazard ratios (HRs) with 95% CIs for the outcome of overall death in patients with acromegaly until June 30, 2019. Estimates from Cox proportional hazards models with biochemical status at the latest available time point during follow-up. Other covariates included in the model were age at diagnosis (continuous), sex, and time periods (1991–2000; 2001–2011). Statistically significant categories of biochemical control were non-controlled and no status/follow-up, which had HRs of 2.31 (P < 0.001) and 3.24 (P < 0.001), respectively. Age at diagnosis was associated with an HR of 1.10 (P < 0.001). ***P < 0.001.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
Hazard ratios (HRs) with 95% CIs for the outcome of overall death in patients with acromegaly until June 30, 2019. Estimates from Cox proportional hazards models with biochemical status at the latest available time point during follow-up. Other covariates included in the model were age at diagnosis (continuous), sex, and time periods (1991–2000; 2001–2011). Statistically significant categories of biochemical control were non-controlled and no status/follow-up, which had HRs of 2.31 (P < 0.001) and 3.24 (P < 0.001), respectively. Age at diagnosis was associated with an HR of 1.10 (P < 0.001). ***P < 0.001.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
Observed survival
Overall survival until June 30, 2019, was better among biochemically controlled patients than in uncontrolled patients and patients with missing status information at the latest follow-up or without any follow-up in the SPR (P< 0.001) (Fig. 4).
Kaplan–Meier plot showing standardized overall survival until June 30, 2019, per the biochemical status of the 698 patients diagnosed with acromegaly in the years 1991–2011. There was a difference in observed survival between biochemically controlled and uncontrolled patients (P < 0.001) or patients with no status or follow-up (P < 0.001). Overall survival was 60.8% at 25 years after diagnosis.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
Kaplan–Meier plot showing standardized overall survival until June 30, 2019, per the biochemical status of the 698 patients diagnosed with acromegaly in the years 1991–2011. There was a difference in observed survival between biochemically controlled and uncontrolled patients (P < 0.001) or patients with no status or follow-up (P < 0.001). Overall survival was 60.8% at 25 years after diagnosis.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
Kaplan–Meier plot showing standardized overall survival until June 30, 2019, per the biochemical status of the 698 patients diagnosed with acromegaly in the years 1991–2011. There was a difference in observed survival between biochemically controlled and uncontrolled patients (P < 0.001) or patients with no status or follow-up (P < 0.001). Overall survival was 60.8% at 25 years after diagnosis.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
Comparison of 10-year mortality of patients diagnosed from 1991 to 2000 and 2001 to 2011
The SMR was significantly lower in biochemically controlled patients than in uncontrolled patients during both decades (P= 0.015 and P< 0.001) (Fig. 5). In biochemically controlled patients, the SMR was not higher than that in the general population up to 10 years after acromegaly diagnosis in patients diagnosed in either of the two decades (Fig. 5).
The standardized mortality ratio (SMR, 95% CI) of patients with acromegaly having biochemical control or no biochemical control 10 years after the diagnosis of acromegaly diagnosed in the years 1991–2000 and 2001–2011 and for the whole period from 1991 to 2011. The SMR (95% CI) in biochemically controlled patients was equal to that in the Swedish population in both decades. There was a difference between biochemically controlled and uncontrolled patients during both decades (P= 0.015 and P< 0.001). In total, 265 and 295 biochemically controlled patients from 1991 to 2000 and 2001 to 2011, respectively, and 42 and 41 uncontrolled patients from 1991 to 2000 and 2001 to 2011, respectively were included.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
The standardized mortality ratio (SMR, 95% CI) of patients with acromegaly having biochemical control or no biochemical control 10 years after the diagnosis of acromegaly diagnosed in the years 1991–2000 and 2001–2011 and for the whole period from 1991 to 2011. The SMR (95% CI) in biochemically controlled patients was equal to that in the Swedish population in both decades. There was a difference between biochemically controlled and uncontrolled patients during both decades (P= 0.015 and P< 0.001). In total, 265 and 295 biochemically controlled patients from 1991 to 2000 and 2001 to 2011, respectively, and 42 and 41 uncontrolled patients from 1991 to 2000 and 2001 to 2011, respectively were included.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
The standardized mortality ratio (SMR, 95% CI) of patients with acromegaly having biochemical control or no biochemical control 10 years after the diagnosis of acromegaly diagnosed in the years 1991–2000 and 2001–2011 and for the whole period from 1991 to 2011. The SMR (95% CI) in biochemically controlled patients was equal to that in the Swedish population in both decades. There was a difference between biochemically controlled and uncontrolled patients during both decades (P= 0.015 and P< 0.001). In total, 265 and 295 biochemically controlled patients from 1991 to 2000 and 2001 to 2011, respectively, and 42 and 41 uncontrolled patients from 1991 to 2000 and 2001 to 2011, respectively were included.
Citation: European Journal of Endocrinology 186, 3; 10.1530/EJE-21-0729
Patients with no follow-up until June 30, 2019
For a small proportion (n = 25, median age of 62 years at diagnosis vs 50 years at diagnosis in the group with follow-up (P< 0.001)), no follow-up was reported to the SPR after the initial diagnosis registration. This group of patients had a markedly elevated SMR (95% CI): 4.28 (2.69–6.79) (P< 0.001 vs the whole study population). Eighteen patients in this group died before June 30, 2019, and six of these patients died within 1 year after diagnosis at a median age of 71.5 years, vs 77.5 years in the follow-up group (NS).
Discussion
The incidence of acromegaly, with nearly four cases/million/year reported in the present study, is similar to most other studies (16) and earlier studies from Sweden, Denmark, and Finland (17, 18, 19) which indicates that the vast majority of Swedish patients with acromegaly were included in the SPR. The long follow-up time, with over 80% of the possible patients reported 10 years after diagnosis, made it possible to study long-term outcome and time trends. Patients were well characterized regarding tumor size/extension, ophthalmological findings, pituitary deficiencies, different treatments (surgery, radiotherapy, and medical treatment), and biochemical control at follow-up. The main findings in the present report were the increasing proportion of patients with verified acromegaly who achieved biochemical control over time and in parallel normalization of SMR in biochemically controlled patients. In agreement with earlier reports, a shortened life span was seen in patients who not were biochemically controlled (20, 21, 22, 23). Furthermore, there was no clear shift from cardiovascular to neoplastic deaths suggested by other studies (24, 25), but in line with an Italian survey (20).
The overall mortality was higher among patients with acromegaly than in the reference population during the study period. This is in agreement with recent studies from Finland, Denmark, and Sweden (12, 17, 26), while others have found no overall increase in the SMR (24, 27). A meta-analysis of 26 studies providing SMR data found that in studies published before 2008, mortality from acromegaly was increased, while in studies published after 2008, mortality was not different from that in the general population (SMR: 1.35, CI: 0.99–1.85) (11, 28). The SMR found in the present study was in accordance with the recalculated mortality data in a recently published Swedish paper (12), where 1089 patients diagnosed with acromegaly between 1987 and 2013 using solely ICD codes according to the Swedish National Health Registries, were investigated. The difference in methods explains the difference in patient numbers, and the major strength of the present study from the SPR is that the acromegaly diagnosis was validated with the medical charts, thereby excluding the risk of including patients with other pituitary tumor types and patients in whom acromegaly initially was suspected but ruled out at further work-up. Another strength is the correlation to clinical characteristics and outcome and the long follow-up time in the majority of the patients.
We observed that the 25 patients who were lost to follow-up in the SPR had a high mortality rate. These were older at diagnosis and may have had other comorbidities that could explain the high death rate. The French study ACROSPECT (29) in which 21% of patients were lost to follow-up ‘traced’ 362 patients and found that 62 had died, and the authors concluded that the patients were not receiving optimal follow-up.
Our mortality analysis, conducted up to 10 years after the acromegaly diagnosis in all patients, revealed no clear differences between the two decades of diagnosis. However, patients who were not biochemically controlled had an increased mortality ratio compared with biochemically controlled patients. In fact, our data demonstrate that a long follow-up time is necessary when analyzing time trends in mortality between different time periods for a rare disease such as acromegaly, especially for patients diagnosed at a relatively young age.
As previously reported (30), the sex distribution was equal in the present study, while other registries have reported a predominance of female patients (21, 30, 31). The median age of Swedish acromegaly patients at diagnosis seems to be higher than in other studies (17, 20, 24, 32, 33, 34). The high proportion of older patients (the oldest being >80 years at diagnosis) could partly explain this finding, which is in accordance with the reported higher age at diagnosis in the German Acromegaly Register (34). The median age has not changed since the start of the register, indicating no change in patients’ and doctors’ delay in the diagnosis of acromegaly. However, one can speculate if the younger patients have a shorter diagnostic delay because of a more aggressive course due to larger tumors found in this study.
In the current study, with over 80% follow-up at 10 years after diagnosis, we found that the percentage of patients achieving biochemical control after treatment was similar to or higher than that in previous multicenter studies or acromegaly register reports (20, 21, 23, 24, 27, 32, 33, 35, 36). The proportion of biochemically controlled patients increased with time. The best positive predictor for biochemical control was surgical treatment of pituitary adenoma, and 82% of Swedish patients underwent surgery, in line with 80% reported in the meta-analysis by Maione et al. (13). Similar to other studies (17, 18, 21, 31), the majority of patients in the present study had a macroadenoma. Both suprasellar grades 3–4 (SIPAP) and parasellar grades 3–4 (Knosp) were negative predictors for biochemical control in the univariate analysis, and a combination of these was a negative predictor in the multivariate analysis concurrent with other reports (37). Large volume was a negative predictor only in the univariate analysis in contrast to a recent report where maximum tumor diameter was a determinant of both short- and long-term remission in a multivariate analysis (38). In contrast to the report from the Liège Acromegaly Survey Database (2), there was no sex difference in tumor size in any of the age groups, while younger patients had larger tumors than older patients, which was similar to the Liège Survey.
The reported use of radiotherapy was lower than that in other reports (17, 20, 21, 24, 26, 27, 35, 36) and was less frequent during the last decade, particularly conventional fractionated radiotherapy. Few patients received radiation therapy alone, and no deaths due to secondary brain tumors were reported. The use of medical treatment for acromegaly did not change during the study period, while the pattern changed with lower use of dopamine agonists due to the introduction of long-acting somatostatin analogs in the late 1990s and pegvisomant in 2004. Furthermore, there was a shift in surgical techniques between the two decades, with the introduction of endoscopic techniques in several centers and a corresponding decrease in the transseptal, sublabial, and lateral rhinotomy approaches. One can speculate that changed treatment modalities may contribute to better biochemical control over time, as in the recent French report (24).
Pituitary hormone deficiency in at least one hormone axis was reported in a quarter of the patients at diagnosis, in accordance with other European acromegaly registries (17, 20, 23, 24, 39), furthermore, there was an increase over time. In line with earlier publications (40, 41), gonadotropin deficiency was the most common deficiency and was more common in men than in women, most likely because hypogonadotropic hypogonadism is biochemically more obvious in men than in postmenopausal women. Alternatively, gonadotropin deficiency in postmenopausal women was not reported. Pituitary deficiency was more pronounced in younger patients, which is probably explained by larger tumors in this age group (42, 43). Furthermore, the rate of pituitary deficiencies increased over time with disease duration.
The acromegaly diagnosis was established according to clinical routine and clinical guidelines. Limitations in the present study were that a few missing data were entered in the SPR retrospectively and that data on one of five patients were not available at each time point. The 25 patients with the worst outcomes were lost to follow-up, and 6 (24%) of them were deceased within a year of diagnosis. In addition, it was not possible to evaluate individual causes of deaths in comparison with the background population. Another limitation was that only serum IGF-1 was used as the marker for biochemical control at follow-ups, since serum GH or OGTT is not always used in routine clinical follow-ups. Additionally, the binary registration of biochemical control did not allow for the evaluation of a potential relation between degrees of persistent biochemical disease activity and clinical consequences. Moreover, the accuracy of the different commercial IGF-I assays available varied over time, which might have influenced the results.
In conclusion, the proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy, while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.
Funding
The Swedish Pituitary Register has financial support from the Swedish Association of Local Authorities and Regions.
Data availability
The data generated or analyzed during this study are available from the corresponding author upon reasonable request.
Author contribution statement
All authors are associated with the Swedish Pituitary Group and were active in the collection of register data and in the planning and management of the study. S A, B E E, and B E drafted the manuscript. All authors reviewed and revised the manuscript for intellectual content and approved the final manuscript.
Acknowledgements
The authors would like to thank the participating endocrine nurses, physicians, and other staff members at all participating hospitals who have contributed to the Swedish Pituitary Register. In addition, the authors thank the team at RCC Stockholm/Gotland and the staff at the six Regional Cancer Centers in Sweden.
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