Patient characteristics
113 patients from 12 centers were included, of whom 111 were considered evaluable in the analysis. Two patients were excluded because their duration of pharmacological treatment was lower than 6 months.
Table 2 summarizes demographic and clinical characteristics of patients. Macroadenoma was present in most patients (82.7%) at diagnosis (Table 2). However, in 97.1% of patients, tumour was not visible or had not changed in volume since prior MRI and only 3 patients (2.9%) had experienced a slight increase (≤20%) since prior MRI (Table 2). IGF-1 levels were within normal limits in 64.0% of patients, above ULN but below 1.2 ULN in 16.2% of patients and above 1.2 ULN in 19.8% of patients.
The main co-morbidity was cardiac disease (54.1%), followed by arthropathy (42.7%), diabetes (36.0%) and sleep apnoea (20.9%) (Table 2). Main comorbidities were controlled in most patients. However, 11.5% of patients presented an uncontrolled cardiac disease and 14.3% an uncontrolled sleep apnoea.
Disability was present in 23.6% of patients (Table 2) and 8.8% of patients were on work leave at the study visit. Most patients had undergone pituitary surgery (75.7%), a third of patients (35.1%) received radiotherapy (34.2% of patients had undergone surgery and radiotherapy), and 23.4% of patients had not undergone surgery nor radiotherapy.
Disease activity
According to ACRODAT®, 48.2% of patients were classified as controlled (S) and 51.8% as having active disease: 31.8% M-DA and 20.0% S-DA (Figure 1A).
S-DA patients were significantly younger, had a significantly higher headache severity, had a significantly higher number of medication changes in the last two years and their last change in medication was significantly more recent compared to S patients (Table 2). Both M-DA and S-DA patients presented significantly higher values of IGF-1 compared with S patients (p<0.001) (Table 2, Figure 2A). Consistently with the algorithm behind ACRODAT®, 100% of S-DA patients had IGF-1 levels >1.2 ULN (Table 2, Figure 2A). There were no statistically significant differences in comorbidities or tumour status among S, M-DA or S-DA patients (Table 2, Figure 2B-C). Symptoms (phPASQ) were significantly more severe (p=0.004) and QoL significantly worse (p=0.005) in M-DA patients compared to S patients, and, in some items (joint pain and fatigue severity and physical component of AcroQoL) compared to S-DA patients (Table 2, Figure 2D-E).
According to physicians’ clinical evaluation, 73.9%, 17.1% and 9.0% were classified as S, M-DA or S-DA respectively (Figure 1B). ACRODAT® classification of disease activity significantly correlated with physicians’ opinion (Pearson's correlation coefficient 0.621, p<0.001), with a moderate inter-rater agreement [kappa agreement coefficient 0.569; 95% confidence interval (CI95%): 0.402-0.678]. Predictive analysis between controlled (S) or active disease (M-DA + S-DA) groups according to ACRODAT vs. physicians’ opinion showed a fair inter-rater agreement (kappa agreement 0.356; CI95% 0.207-0.506) a specificity value of 92.5% (CI95%: 84.4-100), sensitivity 43.9% (CI95%: 30.1- 57.6), PPV 86.2% (CI95%: 71.9-100) and NPV 60.5% (CI95%: 49.2-71.8).
Discrepancies between ACRODAT® classification of disease activity and physicians’ criteria were observed in patients with IGF-1 levels above ULN (p<0.001), patients with higher symptomatology [joint pain (p<0.05), numbness or tingling (p<0.05) and global symptomatology (p<0.01) according to phPASQ, fatigue (p<0.05) according to paPASQ], worse health status [according to paPASQ (p<0.001) and phPASQ (p<0.01)] and patients showing higher QoL impairment (p<0.05). Moreover, discrepancies were also observed in patients with longer time since diagnosis (p<0.05) or since the beginning of treatment (p<0.05). A multivariant analysis showed that the existence of discrepancies between ACRODAT® classification and physicians’ criteria relied on IGF-1, phPASQ and time since diagnosis (p<0.05).
Quality of life
Overall, patients reported mild impairment in their QoL with a mean (SD) AcroQoL total score of 65.7 (19.2) (Table 2 and Table 3). Patients scored worse in the physical domain and in the psychological-appearance domain (Table 2 and Table 3).
According to ACRODAT® levels of severity for QoL (Table 1), 33.7% of patients presented a mild to moderate (21.2%) or significant (12.5%) impairment on QoL.
No correlation was found between IGF-1 levels and AcroQoL (Pearson's correlation coefficient 0.084, p=0.395).
Among the 65 patients (60.7%) with controlled IGF-I and tumour status (IGF-I < ULN and tumour not visible or without changes), 1 (1.5%) and 7 (10.8%) presented a significant and mild to moderate impairment of QoL respectively. These patients presented a significant higher time since diagnosis than patients with no or minimal impairment of QoL (p=0.012).
Symptoms
Overall, patients suffered from mild-moderate acromegaly symptoms [mean (SD) phPASQ total score 12.9 (8.6)] (Table 4). According to ACRODAT® levels of severity for symptoms (Table 1), 73,6% of patients showed moderate (51.8%) or severe (21.8%) symptoms.
Physicians rated patient symptoms significantly lower in severity than patients (p<0.001). However, phPASQ significantly correlated with paPASQ with a substantial inter-rater agreement in both PASQ total score and individual symptoms sub-scores (Table 4). No characteristic traits in patients with discrepancies between phPASQ and paPASQ were found.
No correlation was found between IGF-1 levels and phPASQ (Pearson's correlation coefficient: 0.049, p=0.615) or paPASQ (Pearson's correlation coefficient: -0.011, p=0.911) neither in the total score nor in symptoms or health status sub-scores.
Among the 65 patients (60.7%) with controlled IGF-I and tumour status (IGF-I < ULN and tumour not visible or without changes), 13 (20.0%) and 34 (52.3%) presented severe and moderate symptoms respectively according to their phPASQ (32.3 % and 53.8% respectively according to their paPASQ). No characteristic demographic traits were found for these populations of patients.
Therapeutic action
Overall, a therapeutic action regarding acromegaly management was taken in 28.0% of patients in the visit before study visit. A significantly higher rate of action was taken on patients with IGF-1 > 1.2 ULN than in patients with normal IGF-1 (71.4% vs 13.4; p<0.001) or IGF-1 > ULN but < 1.2 ULN at the visit before study visit (71.4% vs 33.3%; p<0,01).
Results of the therapeutic action taken in the previous visit was not successful in most of the patients: 88.9% (n=16) of patients with no IGF-I and/or tumour control, remained uncontrolled at the study visit. Similarly, 82.8% (n=53) of patients in which no action was taken in the last visit remained in the same control status. Most of them (83.9%, n=47) were controlled and remained controlled. 14.1% (n=9) of patients were controlled in terms of IGF-I and tumor status and, spontaneously, lost control at the study visit.
At the study visit, therapeutic action was taken in 27.9% of patients overall and a change of medication (dose or drug) was the most frequent action taken (20,7% of patients) (Table 5). In S-DA patients, therapeutic actions were taken on a significantly greater proportion (77.3%) compared to M-DA (22.9%, p<0.001) and S patients (11.3%, p<0.001) (Figure 3). However, no action was taken on 22.7% (n=5) of S-DA patients and in 77.1% (n=27) of M-DA patients.
In 3 of those 5 S-DA patients, a change in treatment (dose or drug) was taken in the last visit, that took place a mean (SD) of 5.2 (2.7) months. In the other 2 patients, no action was taken neither in the last visit nor in the study visit. Both presented IGF-I levels above ULN at both visits, but one of them was considered stable according to physician criteria.
Differences between M-DA patients in which no action was taken (n=27) vs patients in which action was taken (n=8) at the study visit were found regarding the disease activity classification by physician’s criteria (4 vs 24 classified as S-DA, p<0.05), time since the beginning of treatment (mean time 5.87 vs 10.41 years, p<0.05) and time since the last visit (mean time 3.96 vs 6.70 years, p<0.05).
Criteria that marked the decision to take a therapeutic action on S-DA and M-DA patients were IGF-1 levels and IGF-1 + tumour control at the last visit and at the study visit (p<0.01).