Clinical experiences and success rates of acromegaly treatment: the single center results of 62 patients

Acromegaly is a rare condition with a prevalence of around 60 in 1,000,000 [1]. The cause in most patients is a pituitary adenoma that produces growth hormone (GH). Serum insulin-like growth factor 1 (IGF-1) concentration increases when its production is stimulated by GH over-secretion. The clinical features of the disease occur because of the peripheral effects of excessive GH and IGF-1, as well as tumor pressure. Diagnosis is made based on increased serum basal GH level, an IGF-1 level higher than normal limits for gender and age, and an absence of suppression in serum GH levels (>1.0 ng/ml) by the oral glucose tolerance test (OGTT). In acromegaly, progressive deformations occur in the body, especially in the face and extremities, the severity of which are associated with the time to diagnosis. The condition may also cause other morbidities such as arterial hypertension, cardiomyopathy, sleep apnea syndrome, diabetes mellitus (DM), menstrual irregularities, arthropathy, and peripheral neuropathy. Sometimes acromegaly occurs together with hyperprolactinemia [2]. The risk of malignancy, particularly colon cancer, is increased in acromegalic patients [3, 4]. The first treatment option for acromegaly is removal of the pituitary adenoma by an experienced surgeon at a specialist center for pituitary surgery. If surgery is unsuccessful, treatment using somatostatin analogs (SA), dopamine agonists, GH antagonist and/or Gamma Knife radiosurgery can be used [5]. For the disease to be considered under control, the basal GH level should be <2.5 ng/ml, GH levels should be <1.0 ng/ml by the OGTT, and the IGF-1 levels should be within normal limits based on the patient’s age and gender [6, 7].

In this study, we report the clinical and outcome data from a large cohort of acromegalic patients who were diagnosed and followed up over a 20-year period at our institution.

Our study has made it possible to review the most important findings and challenges in managing a large cohort of acromegaly patients over a 20-year period. Although acromegaly can be seen in all ages, the average age of onset is 32 years. However, as it progresses subclinically, the diagnosis is delayed by between 4 and 10 years [1, 2]. This duration has decreased recently, for example, in a study of 100 patients, the delay in diagnosis was found to be 3.2 years [9]. More frequent MRI performed for different reasons may be one explanation for earlier incidental diagnosis of acromegaly [10]. In our patients, the age average at the time of diagnosis was found to be 38.8 ± 1.4 years, and the time to diagnosis was found to be 4.5 ± 0.3 years.

The typical features of acromegaly develop over time, and their severity is associated with a patient’s age, GH and IGF-1 levels, tumor diameter and delay in diagnosis. Indeed the delay in diagnosis can be explained, in part, by the fact that any facial changes are often attributed to aging; old photographs of the patient are therefore a useful diagnostic tool. Skeletal and soft tissue changes, organomegaly and typical facial changes are also common [11]. The most common symptoms of our patients, seen in 92%, were growth in hands and feet, and facial dysmorphism. Additionally, acromegaly patients have an increased incidence of DM, hypertension, cardiovascular diseases, breathing problems, osteoporosis and osteoarticular dysfunctions compared with the normal population. The incidence of glucose intolerance is 16–46%, and the incidence of DM is 19–56% [12, 13]. The anti-insulinergic effects of GH are considered to be responsible for the pathogenesis of acromegaly. In many cases, when acromegaly is cured, DM is also cured [14]. The most common conditions that coexisted with acromegaly in our patients were DM (35%) and hypertension (20.9%), in keeping with the literature.

The incidence of hyperprolactinemia in pituitary acromegaly patients is approximately 30–40%. The reasons for hyperprolactinemia are pressure on the pituitary stalk or simultaneous secretion of prolactin from tumor cells [15‐17]. Incidence of simultaneous secretion of GH and prolactin is around 25% [18]. In our cohort, 13 patients (21%) were found to have hyperprolactinemia at the time of diagnosis, a significantly higher rate than that described in the study by Moyes et al. (13%) [19].

Around 40% of patients are diagnosed in clinics other than endocrinology for symptoms and findings of increased cranial pressure. For instance, neurological symptoms and vision problems may occur because of growth of a pituitary adenoma [11]. The incidence of visual field defect owing to increased pressure is around 19–20% in the literature [20]. The rate of visual field defect in our patients was 32%. In keeping with the published literature, imaging detected macroadenomas in 54 of our patients (87%) [7, 21].

In acromegaly, serum basal GH measurement, post-OGTT GH measurement and IGF-I levels measurement are the gold standard assays for measuring disease activity and monitoring the effectiveness of treatment. While GH measurement has become more sensitive in the recent decades, IGF-1 measurements can be misleading in situations such as malnutrition, liver disease and kidney failure [22, 23]. In particular, inconsistencies between GH and IGF-1 measurements can be seen throughout SA treatment [17]. Our patients usually showed a positive correlation between the average GH levels and IGF-1 levels at the time of diagnosis and during SA treatment.

The first treatment option in acromegaly is transsphenoidal tumor excision, particularly for intrasellar microadenomas and noninvasive macroadenomas. In situations such as patient non-consent, existence of serious cardiomyopathy and respiratory disease or absence of an experienced surgeon, then other treatment options are considered. The finding of visual field defect or neurological deficit is almost always an urgent surgical indication [24, 25]. We also apply transsphenoidal surgery as the first treatment option for many of our patients.

In a previous retrospective study of 100 patients who underwent transsphenoidal surgery with a remission criterion of GH <5 mU/l, 42% of the patients achieved postoperative remission. In this study, the remission rates were associated with tumor diameter and preoperative GH levels, and 21 patients were found to have pituitary hormone deficiency [26]. The postoperative cure rate of patients who underwent transsphenoidal surgery was 12.9%. In studies where remission criteria were considered to be either GH <2.5 ng/ml, post-OGTT GH <2 ng/ml or IGF-1 within normal limits based on age and gender, the remission rates after transsphenoidal surgery were found to be 38, 57 and 37%, respectively, and the anterior pituitary hormone deficiency rates were found to be 35, 8 and 10%, respectively [7, 27, 28]. Currently, the reported success of intrasellar surgery varies between 75 and 95% for intrasellar microadenomas, and between 45 and 68% for noninvasive macroadenomas, if undertaken by experienced surgeons who perform at least 50 case surgeries per year [24, 29]. When our patients were evaluated, four of 31 patients who were operated transsphenoidally attained postoperative cure. Three of these patients had microadenoma, and one had macroadenoma. While anterior pituitary hormone deficiency was found only in one patient before surgery, it was found in 37% of the patients after surgery. The rate of post-operative pituitary hormone deficiency was found to be lower in our cohort compared with the study by Sheaves et al., but higher than that observed by Swearingan et al. [26, 27].

Although the first approach in treatment is transsphenoidal surgery, a transcranial approach is required in some situations such as suprasellar tumor expansion. In another study with remission criteria similar to ours with a follow-up period of 19 years, 26 of 668 acromegaly patients underwent transcranial surgery. The postoperative remission rate of these was 7.7%, the anterior pituitary hormone deficiency rate was 5%, and the rate of permanent DI was 11.5%. In the latter series, 140 patients were re-operated, and the remission rate increased to 27.1% [30]. In our study, two of the 20 patients who were operated on transcranially attained postoperative cure, one of whom had macroadenoma and the other microadenoma. In the patients who did not achieve cure after transsphenoidal surgery and then underwent transcranial surgery, none attained cure, with only one developing secondary hypothyroidism. Although our data on pituitary hormone deficiency before transcranial surgery was insufficient, the rate of patients with anterior pituitary hormone deficiency after transcranial surgery was 85%, a markedly higher rate compared with similar published cohorts. Additionally, the rate of anterior pituitary hormone deficiency in our patients who underwent transcranial surgery was significantly higher than in the patients who underwent transsphenoidal surgery (p < 0.001).

The success of treatment in acromegaly is negatively correlated with tumor diameter and basal GH levels and positively correlated with the experience of the surgeon. Additionally, if the tumor is invasive, this decreases the likelihood of successful surgery [24, 31]. Indeed, when we assessed our results based on tumor size, 50% of those with microadenoma and 15% of those with macroadenoma were cured. Unfortunately, owing to small sample numbers, assessment of significance was not feasible. Precise tumor diameter was significantly associated with GH level (p = 0.002), but did not correlate with cure rate (p = 0.06). Additionally, only 20 of 32 patients whose tumor diameters reduced developed biochemical remission. Twenty-five of our patients also had cavernous sinuous invasion.

Another important factor that affects success rate is the number of surgeons who can perform this surgery, and the number of pituitary surgeries performed by the surgeons. Additionally, a greater number of years of surgical experience also increases the surgical success rate [25]. Our cure rate after transsphenoidal and transcranial surgery was very low compared with the literature. More than half of our patients (n = 34) were operated on in our center by one of two surgeons while the others were operated on in several external centers. The lack of experience of our surgeons in pituitary surgery, the absence of a single specialist operating center and the existence of macroadenoma or cavernous sinuous invasion at the time of diagnosis are therefore likely contributors to our low surgical success rate.

Radiotherapy is preferred in situations where surgery is contraindicated or unsuccessful, or when medical treatment is insufficient in controlling GH secretion [32]. An average of 60% of patients who receive conventional radiotherapy attain GH and IGF-1 normalization, but the maximum response is seen after 10–15 years [24, 33]. While conventional radiotherapy is preferred in large recidive tumors or in tumors close to the optical nerve, Gamma Knife radiosurgery is preferred in smaller tumors. The 5-year remission rates following Gamma Knife is between 29 and 60% [34]. The incidence of pituitary deficiency for both methods is similar [28, 31]. Some of our patients who did not achieve cure after surgery received radiotherapy. Thirty percent of the patients who received conventional radiotherapy or Gamma Knife attained cure, and a further 50% entered biochemical remission. The time to cure was 5–10 years for the two patients who received conventional radiotherapy, and 3–5 years in the four patients who received Gamma Knife. Thus, our rate of cure with surgical treatment and radiotherapy was 19.3% (12 patients), which is in keeping with the literature.

It has been shown in vitro that natural somatostatin inhibits GH secretion in many GH-secreting tumors. For this reason, SAs have been developed for treating acromegaly. Somatostatin analogs work by activating somatostatin receptors. There are, however, major gastrointestinal side effects associated with these drugs. Long-lasting forms of somatostatin analogs are preferred, and octreotide LAR and lanreotide autogel are in current clinical use in Turkey, but not pasireotide. Pegvisomant is a GH receptor antagonist, which can be used alone or in combination with SAs [17]. Somatostatin analogs can be used for situations when there is little possibility of surgical cure such as large extrasellar tumors without pressure effect, in patients who cannot be controlled biochemically with surgery, and to provide biochemical control while waiting for the effect of radiotherapy. Although there are data that show that preoperative SA use has benefits on GH and IGF-1 normalization and on postoperative hospitalization, some studies have concluded that it does not [24, 35]. Some studies have shown that with use of somatostatin analogs, biochemical remission is attained, and tumors become smaller in size [36, 37]. Several long-term retrospective studies have reviewed the effects of SA given postoperatively and/or primarily, and have reported a wide variation of biochemical remission rates of between 34 and 95% [38, 39]. Investigations comparing efficacy of lanreotide and octreotide treatments have reported a similar rate of cure of symptoms and biochemical cure for both agents [40‐42].

It should be kept in mind that our study is not a study for evaluating response to primary SA treatment. In our study, we used serum GH <2.5 ng/ml and IGF-1 normalization as biochemical remission criterion, and the serum GH and IGF-1 levels of our patients who received drug treatment decreased significantly compared with the baseline (p < 0.001). When we review all our patients with regards to biochemical remission, we see that 32/52 patients (61.5%) who received octreotide treatment and 2/5 patients (40%) who received lanreotide treatment are in biochemical remission. However, it should be noted that 10 of the patients who achieved biochemical remission received Gamma Knife, and five received conventional radiotherapy; therefore, the cause of remission may be multifactorial in these patients.

In a recent study by Coloa et al., which followed up 45 acromegalic patients, no improvement in glucose intolerance or DM prevalence was seen [37]. However, we observed improvement in DM in four of the 22 patients in our cohort who were initially diagnosed with DM. Two of these patients, whose blood glucose levels improved were in remission and one of them was cured.

A notable restriction of our study was that the file archiving system was more irregular and insufficient in previous years, and therefore we did not have access to a full range of data for all patients. For example, the initial IGF-1 level was the most important predictor of adequate response to treatment [43]; however, this measurement was not available for some patients. Furthermore, we did not have access to data concerning presence or absence of pituitary hormone deficiency before treatment. Additionally, the majority of our patients were operated on in different centers by different surgeons and some patients did not attend our hospital for assessment with optimum regularity. Indeed, infrequent monitoring may be an additional contributing factor to the low rate of cure in our cohort compared with the literature.

In conclusion, we believe the rate of successful treatment of acromegaly will increase with earlier diagnosis, greater surgical experience and regular and appropriate follow-up after surgery. Future prospective studies of large cohorts will help to provide further information on appropriate treatment strategies in this disease.