This retrospective, observational study was conducted in 5 Italian hospitals to characterize the use of PEGV vs. PEGV?+?SSA regimens to manage SSA-resistant acromegaly. We found that combination therapy was more likely to be prescribed for patients with clinical/biochemical/imaging evidence of relatively severe/aggressive disease along with a more substantial (albeit incomplete) IGF-I response to SSA monotherapy. Both regimens were well tolerated, and at the end of follow-up, there was no significant difference between the daily PEGV doses in the two groups. However, outcomes (IGF-I normalization rates and final IGF-I SDS) were significantly worse in the patients receiving PEGV?+?SSA. The only variable significantly related to the final PEGV doses in both groups was treatment duration.
Given the size and nature of our sample, it is difficult to tell whether and to what extent our observations on prescribing practices are indicative of practices in other hospitals in Italy or other countries. The tendency to prescribe PEGV?+?SSA for acromegaly patients with more severe disease has not emerged from previous studies [8, 9, 12, 13, 16, 23, 24]. The only difference noted by Filopanti et al. in the Italian cohort they investigated was that patients on PEGV?+?SSA were more likely to have had macroadenomas at the time of diagnosis . This was not observed in our population, although our Group 2 patients did have higher postoperative rates of residual tumor tissue. The increased disease severity in Group 2 was manifested by GH and IGF-I levels at diagnosis that were significantly higher than those in the group treated with PEGV alone. Our two treatment groups—like those analyzed by Reid et al. —also had similar comorbidity rates when the disease was diagnosed. The exception was sleep apnea, which was roughly three times more common in Group 2. This disorder is being reported with increasing frequency in acromegaly patients , and its correlation with disease activity (IGF-I levels) has been demonstrated . According to Roemmler et al. , our data confirm that sleep apnea is a frequent problem among patients whose disease is poorly controlled, especially those who present with more severe disease activity.
Clear-cut guidelines on the selection of patients for PEGV?+?SSA therapy (instead of PEGV alone) are lacking, although Melmed et al. note that combination therapy might be more cost-effective in patients who would otherwise require high-dose PEGV monotherapy . In our population, the decision to use PEGV?+?SSA was significantly influenced by the extent of the IGF-I reduction observed after?≥?12 months of SSA monotherapy, which was approximately three times higher in Group 2 than in Group 1. This may reflect prescribers’ belief that, as suggested by Colao et al. , the efficacy of SSA therapy (in terms of biochemical control and limitation of tumor growth) may emerge only after several years of therapy, particularly when at least some positive effects have been observed with SSA monotherapy. The most important factor in prescribing decisions, however, was the presence or post-operative persistence of MRI-documented tumor tissue. Recent data indicate that the fear of increased tumor growth during PEGV monotherapy is unfounded [19, 27], and our experience confirms this conclusion. Significant increases in tumor volume were extremely rare during follow-up (median duration 37 months) and showed no relation to the treatment regimen (PEGV vs. PEGV?+?SSA). Transaminase elevation rates were also low, which is consistent with previous reports [11, 27], and, as noted by other investigators , these episodes occurred mainly in diabetics.
The IGF-I normalization rates observed in the two groups were in line with those recently reported by Van der Lely et al. . They differ, however, from those reported in other studies, involving patients who had less severe disease at baseline than ours (especially those on combination therapy) and were followed for shorter periods of time. In these studies IGF-I normalization rates achieved with PEGV and PEGV?+?SSA often exceeded 90%, especially in the early studies with follow-ups of <52 weeks [8, 9, 12, 13] but also in the long-term study conducted by Neggers et al. . Rates more similar to our own were reported in 2011 by Van der Lely et al.  in patients with “partial” SSA-resistance treated PEGV?+?SSA: 78.9% achieved IGF-I normalization at least once, and 58% were still controlled at the end of follow-up. The final PEGV doses in that study were far lower than those recorded in our population, reflecting once again the severity of the disease in our patients. Inadequate dosing by the prescribing physician and/or poor patient compliance may also have contributed to the lower-than-expected normalization rates we observed. As noted by other authors , dose increases to?>?20 mg/day sometimes meet with poor compliance because they require two injections a day.
In contrast to recent data reported by Neggers et al. , we—like VanderLely et al. —found no significant differences between the PEGV and PEGV?+?SSA treatment groups in terms of the PEGV doses used or the number of patients controlled. At the time of diagnosis, Group 2 patients had more marked biochemical derangements than those of Group 1, but when SSA monotherapy was discontinued, the GH and IGF-I levels of the two groups were similar. However, the same dose of PEGV appears to have been more effective when administered alone than it was when administered with an SSA. In all probability, this was due mainly to the fact that patients who received PEGV?+?SSA had more aggressive disease.
Treatment duration was significantly longer in patients being managed with PEGV monotherapy. Many of these were among the first in Italy to be treated with PEGV, and they may well have been selected precisely because their disease was relatively mild, with small tumors / residual tumors and IGF-I and GH levels considered more likely to be controlled safely by the new drug (based on data available at that time). It is important to recall that we did not analyze the reasons for the two groups’ different responses to SSA monotherapy. Multiple biochemical and clinical factors are known to influence the response to these drugs , and an analysis of this type was beyond the scope of our study. In contrast with the findings of Trainer et al. , the final PEGV doses being used by patients who were not controlled (in either group) were no lower than those of the patients with normal IGF-I levels at the end of follow-up. Within Group 2, PEGV doses for the uncontrolled subset of patients were higher than those being used by the normalized subset, which suggests that attempts had been made (albeit unsuccessfully) to achieve control by dose increases. Previous short-term [30, 31] and long-term  studies have demonstrated that the PEGV dose required for IGF-I normalization is influenced by various factors, including body weight, sex, previous radiotherapy, baseline GH and IGF-I levels, and GH-receptor (GHR) polymorphisms, although a more recent study failed to confirm the importance of the last factor in responses to PEGV or to PEGV?+?SSA . According to other authors , our data showed that both monotherapy or combination and final dose of PEGV are not affected by previous radiotherapy, probably because that was performed only in about 26% of patients, whereas the same treatment was reported in a high proportion of patients (58-66%) in previous studies [30, 32]. Our findings are the first that reveal a strong linear relation between the IGF-I-normalizing dose and the duration of PEGV treatment, regardless of whether the latter is combined with SSAs. This correlation was not significant in patients who failed to achieve IGF-I normalization at the end of follow-up, probably because these patients had more aggressive disease with higher levels of GH. Inadequate dose adjustment may also have played a role.
Previous studies [8, 9, 11] indicate that the percentage of patients controlled by PEGV remains stable over time. The earliest studies, which were short-term trials, showed that higher doses were associated with proportionally higher control rates, and that the dose required to achieve normalization depended on pre-PEGV IGF-I levels [14, 23].
In healthy subjects, PEGV, a selective competitive GHR antagonist , decreases plasma IGF-I levels and increases blood GH concentrations . Despite in vitro and in vivo studies have demonstrated a direct action of pegvisomant on different organs and tissues  and a possibile direct role in chemoresistance [36, 37], data concerning direct effects of PEGV on GH secretion by pituitary adenoma are conflicting. Some studies have observed an impairment of GH autofeedback in somatotrophs [38, 39], whereas other investigators have demonstrated that PEGV does not effect pituitary somatotrophs directly and it does not cross the human blood–brain barrier [40, 41], thus favoring GH-secretion indirectly via IGF-I lowering.
In our study, the PEGV dose probably has to be progressively increased over time to maintain IGF-I levels within target ranges, particularly in the documented presence of residual GH-secreting tumor tissue. An “escape” phenomenon of this type has been reported by several groups [32, 42, 43]. Although still poorly defined, it has been linked to diverse factors, including distracted physicians, noncompliant patients, and intrinsic features of the adenoma itself . In our opinion, it may also stem from the increasing GH hypersecretion documented during PEGV therapy [8, 19]. In patients who are SSA-resistant and therefore have persistently high levels of GH and IGF-I produced by an aggressive type of adenoma, it is conceivable that the dose of PEGV (regardless of whether it is given alone or with an SSA) will have to be periodically increased over time to control rising GH production. This hypothesis naturally needs to be confirmed with additional studies in larger populations, but physicians should be aware that ongoing monitoring of treatment responses is essential, even after IGF-I normalization has been achieved.