Effect on pituitary tumor size
Much attention has been paid to a possible increase in tumor size associated with PEG treatment, but also sometimes under SRL treatment, even though no causal relationship has been established [
44]; however, since tumor enlargements are detected increasingly often thanks to modern techniques, higher consideration should be given to the actual clinical relevance of such enlargements.
Data on tumor volume outcome in patients treated with PEG alone or in combination with SRL are discordant and widely discussed. Some long-term evaluations reported an increased tumor size during PEG in 5–7% of patients [
45]. In the Italian ACROSTUDY patients, according to MRI at local centers (data available for 249 patients), a decrease in tumor volume was reported at least once in 13.7%, an increase in 8.8%, and both increase and decrease in 6.4%, in different treatment phases. Bianchi et al. [
46] observed that none of 35 patients under PEG alone showed significant tumor growth, whereas in one case, MRI documented progressive shrinkage of the adenoma, which was no longer detectable after 6 years of treatment. In the same study, among the 27 patients treated with PEG in combination with SRL, a significant growth (>25%) of the residual adenoma tissue occurred in one case. This patient had from the beginning a very aggressive disease that was difficult if not impossible to control, and, when the tumor enlargement was noted, was receiving PEG 40 mg/day plus lanreotide ATG 120 mg every 4 weeks.
Tumor growth may be observed during the first year of treatment with PEG and may prevalently reflect the disease natural history or the consequence of SRL discontinuation (rebound phenomenon) [
47]. Absence of previous irradiation and shorter duration of SRL therapy before PEG were associated with increased risk of tumor growth [
45]. Changes in tumor size seem not to correlate with IGF-I levels [
48]. Optimal use of PEG with respect to tumor size should take into account the history of the adenoma in terms of aggressiveness and invasiveness, previous tumor response to treatments including SRL and tumor volume at treatment start [
45].
Despite the few reports of increase in tumor size during PEG treatment, there is no clear evidence that PEG may directly promote tumor growth [
47]. Due to the interpersonal variability in pituitary, MRI reading by a single neuroradiologist of all available images before and during PEG therapy is recommended to avoid misinterpretations.
Effect on clinical symptoms and signs, and on quality of life
Recent improvement in the medical treatment of acromegaly has resulted in better biochemical disease control [
49‐
51]. Normalization of both GH and IGF-I levels was demonstrated to restore normal life expectancy in acromegaly patients. However, biochemical control does not necessarily relieve all symptoms [
52,
53]. To quantify the symptoms and the perceived health in patients with acromegaly, the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) and the Acromegaly Quality of Life Questionnaire (AcroQoL) have been developed [
52‐
54]. In particular, the PASQ score is a disease-specific tool that rates five features of acromegaly: headache, excessive perspiration, arthralgia, fatigue, and soft tissue swelling [
52]. On the other hand, the AcroQoL questionnaire contains 22 items divided into two scales, one evaluating physical features and the other assessing psychological aspects [
53,
54]. The use of these questionnaires may improve clinical evaluation of therapeutic interventions, and identification of patients who possibly require further treatment. Both treatments with SRL and PEG showed to be effective in reducing acromegaly signs’ and symptoms’ total scores, and improving health-related quality of life (QoL) [
55‐
57]. However, in patients with more severe disease (IGF-I ≥ 2xULN), a trend toward greater improvements of PASQ and AcroQoL scores was observed with PEG compared with octreotide LAR [
57]. On the other hand, a lower convenience score was observed in patients treated with PEG and evaluated by the Treatment Satisfaction Questionnaire for Medication (TSQM), that may be explained by daily injections [
58].
PEG therapy was widely demonstrated to be effective and safe in acromegalic patients, improving clinical symptoms and systemic complications [
24,
26,
27]. In fact, Trainer et al. reported significant decreases in mean patient-assessed symptom scores, including soft tissue swelling, degree of perspiration and fatigue, as well as in the mean sum scores of all five PASQ items, in patients treated with 15 or 20 mg of PEG per day [
24]. Subsequently, many other studies [
25,
59‐
61] have demonstrated a significant improvement in acromegaly-related QoL, and clinical signs and symptoms in patients treated with PEG in monotherapy or in combination with SRL. However, the improvement was observed in some but not all measures of perceived health or QoL scores. In particular, pain syndrome, joint complaints, and persistent headache seem to persist regardless of type of therapy and/or biochemical control [
24,
52]. A possible explanation for the different responsivity of symptoms to PEG therapy may lie in the nature of symptoms themselves [
52]. Skin manifestations, such as perspiration, soft tissue swelling or numbness, caused by an increase in extracellular volume, edema, dermal glycosaminoglycan accumulation or increased vasoconstriction, are usually rapidly alleviated when GH and IGF-I levels are controlled [
52,
62]. Conversely, joint pain may rather reflect chronic and irreversible changes [
63,
64], so that biochemical control per se may not be sufficient to alleviate them, whereas headache may better respond to centrally active drugs like SRL [
65]. For these reasons, additional pain treatment may be needed to relieve these symptoms.
Overall, 11 independent studies [
9,
14,
24‐
26,
31,
33,
52,
59,
60,
66] specifically focused on headache in acromegalic patients on PEG either as monotherapy or in combination with SRL. Treatment with PEG has been generally reported to negatively impact on headache in acromegalic patients, although not significantly. Actually, the headache score at PASQ was found slightly and not significantly impaired in several studies [
31,
52,
59]. In another study, the headache score in patients on PEG monotherapy was not significantly higher than that of patients on combined SRL and PEG treatment [
60]. In patients receiving PEG monotherapy, headache has been described in a widely variable percentage, ranging from 2% [
14,
26] to 40.7% [
66]. However, the prevalence of severe headache leading to definitive treatment discontinuation ranged from 1.2% [
24] to 28.6% [
31]. Noteworthy, the association between worsening of headache score and increase in tumor size while on PEG therapy is still to be fully elucidated. Two different studies have reported discordant results, with a correlation between worsening of headache and increase in tumor size in the first study [
66] but not in the second one [
33]. Curiously, in a study [
25] comparing long-term therapy with PEG alone, PEG combined with octreotide LAR, and octreotide LAR alone, headache was reported only in patients on octreotide LAR monotherapy and was related to the disease state.
Taken altogether, these data suggest that the normalization of IGF-I may induce an improvement in most acromegaly-related symptoms and QoL. However, normalization of clinical picture from the patient’s perspective not always is obtained, and further studies are needed to investigate the clinical impact of treatment with PEG alone and combined with SRL in larger series of patients.