How to Position Pasireotide LAR Treatment in Acromegaly

Eva C. Coopmans; Ammar Muhammad; Aart J. van der Lely; Joseph A. M. J. L. Janssen; Sebastian J. C. M. M. Neggers

Disclosures

J Clin Endocrinol Metab. 2019;104(6):1978-1988. 

In This Article

Recommendation for Medical Management of Acromegaly

First-line Treatment

Transsphenoidal surgery is the primary treatment modality for most patients with acromegaly.[2,6,41] In Figure 1 we provide recommendations for the medical management of acromegaly after surgery or as primary treatment strategy if surgery is contraindicated or if patients prefer pharmacological treatment. In accordance with the consensus criteria,[3] first-generation SRLs such as lanreotide autogel (ATG) and octreotide LAR are considered the first-line medical treatment of acromegaly (Figure 1). The effects of long-acting lanreotide ATG and octreotide LAR on biochemical control and tumor shrinkage are considered to be equivalent.[42–45] The package insert of first-generation SRL recommends a starting dosage of either 90 mg lanreotide ATG or 20 mg octreotide LAR every 4 weeks.[8,9] In contrast to the package insert, we recommend starting with maximum dosages of either lanreotide ATG or octreotide LAR every 4 weeks for 6 months until IGF-1 normalization is achieved, defined as IGF-1 ≤1.3 × ULN.[46] Extension of dosing intervals or dosing reduction is recommended for patients achieving biochemical control with first-generation SRLs.[47] Because of the modest efficacy of dopamine agonists in acromegaly, cabergoline monotherapy can be considered as first-line medical therapy postsurgery only for patients with modestly elevated GH and IGF-1 levels, independent of the presence of hyperprolactinemia.[3,6,48]

Figure 1.

Proposed algorithm for the medical management of acromegaly. Radiotherapy is not mentioned in this algorithm, but it should be considered for patients with biochemically persistent disease or tumor growth despite surgery or medical therapy. DA, dopamine agonist.

Second-line and Alternative Treatments

In line with the consensus criteria,[3] we recommend PEGV combined with or substituted for first-generation SRL therapy as the second-line treatment of choice for patients with <20% IGF-1 reduction (no significant response) during first-generation SRL monotherapy (Figure 1).

PEGV, alone or in combination with first-generation SRL, can normalize IGF-1 levels in the majority of patients, provided that the PEGV dosage is sufficiently increased. In combination therapy the recommended starting dosage with either lanreotide ATG or octreotide LAR every 4 weeks is the highest approved dosage. To determine the optimal PEGV starting dosage to achieve IGF-1 normalization, we advise using the prediction formulas of Franck et al..[49] It is noteworthy that if patients were pretreated with first-generation SRL and then switched to PEGV monotherapy, the expected washout time and the carryover effect of first-generation SRLs are ~15 to 20 weeks.[50–52] Therefore, a slow and gradual increase in serum IGF-1 levels can be expected after discontinuation of first-generation SRLs, and for that reason gradual PEGV uptitration will be necessary.

The current consensus criteria[3] recommend pasireotide LAR as a second-line treatment for patients without biochemical response to first-generation SRLs, with clinically relevant residual tumor. However, we recommend first-generation SRL and PEGV combination therapy as the second-line treatment of choice in all nonresponders (Figure 1). Combination therapy has the potential advantage that a lower PEGV dosage is needed to normalize IGF-1 levels compared with PEGV monotherapy, which may decrease the number of injections for patients.[53–55] In a subset of patients, combination therapy of PEGV with first-generation SRL might have favorable effects on quality of life compared with first-generation SRL monotherapy, including those whose disease is biochemically controlled.[56] Moreover, although PEGV monotherapy does not reduce tumor size, combination therapy with first-generation SRLs results in tumor size control or even tumor shrinkage in most patients.[55] Another advantage of the combination therapy is that first-generation SRLs are generally effective in resolving headaches through a proposed mechanism of inhibition of nociceptive peptides, which makes it the preferred treatment for patients with headaches.[57,58] In general, if patients report improvements in clinical symptoms during first-generation SRL monotherapy, we recommend initiating combination therapy with first-generation SRLs and PEGV, except in patients who show poor control of diabetes during monotherapy with first-generation SRLs. Such patients are good candidates for PEGV monotherapy because PEGV may improve glucose metabolism by reducing insulin resistance.[59–61] This latter recommendation is in accordance with the current consensus criteria,[3] which recommend PEGV monotherapy for patients without biochemical response to monotherapy with first-generation SRLs but with impaired glucose metabolism.

For patients with partial response to first-generation SRLs, defined as a significant reduction in IGF-1 levels but without normalization, we recommend combination therapy with cabergoline (if IGF-1 ≤ 1.5 × ULN)[48] (Figure 1). In contrast to the current consensus criteria, which propose considering cotreatment with cabergoline (if IGF-1 < 2.5 × ULN) for patients with inadequate control on first-generation SRL therapy, we recommend cotreatment with cabergoline only if IGF-1 levels are modestly elevated (IGF-1 ≤1.5 × ULN), because IGF-1 normalization has been observed only for these patients.[48] Besides, cabergoline is recommended for patients who have no access to PEGV. In the current consensus criteria, use of PEGV combined with or substituted for first-generation SRL therapy in partial responders is not covered.[3] Nevertheless, we recommend for this indication combination therapy with first-generation SRLs and PEGV as the second-line treatment of choice (Figure 1). Moreover, because of the marginal additional efficacy in our experience of first-generation SRL dosage escalation and of shortening of the SRL dosing intervals for patients with partial response to first-generation SRLs,[52,62,63] we recommend switching patients to combination therapy with first-generation SRLs and PEGV or pasireotide LAR monotherapy according to the proposed algorithm (Figure 1).

Switching to pasireotide LAR monotherapy can be considered as an alternative to PEGV monotherapy or combination therapies for patients with the following baseline clinical features (Figure 1):

  • Young patients (aged <40 years) with macro-adenomas that show tumor growth during first-generation SRL monotherapy (i.e., clinically aggressive tumors).[64] For young patients with resistant tumors, pasireotide LAR monotherapy can be considered as an early treatment option before radiotherapy is started. This strategy is in accordance with the current consensus criteria,[3] which recommend switching from first-generation SRL monotherapy to pasireotide LAR monotherapy for patients with a clinically relevant residual tumor that is unsuitable for resection.

  • The same argument can be applied for patients whose disease was previously not controlled by first-generation SRLs with tumor growth during PEGV monotherapy. Tumor growth may reflect the presence of more aggressive tumors, and pasireotide LAR monotherapy can be considered as a next treatment step before starting with radiotherapy.

  • Patients whose disease was previously not controlled by first-generation SRLs, who experience side effects, or who cannot tolerate PEGV monotherapy may benefit from switching to pasireotide LAR monotherapy.

  • Patients with severe headache not responsive to first-generation SRL therapy. These patients have a high likelihood of improvement in headache symptoms after beginning pasireotide LAR treatment.

Switching to pasireotide LAR therapy combined with PEGV can be considered as a third-line treatment option in patients with the following baseline clinical features (Figure 1):

  • Patients without diabetes who use low PEGV dosages (≤80 mg/week) during combination therapy with first-generation SRLs. Because of the PEGV sparing effect of pasireotide LAR, the PEGV dosages can be reduced or sometimes even discontinued.

  • Patients with tumor growth during first-generation SRL and PEGV combination therapy. We postulate that pasireotide LAR monotherapy may improve tumor size control or even tumor shrinkage. However, at present there are no good data on tumor response to pasireotide LAR and PEGV combination therapy.

  • Patients whose disease is biochemically controlled during first-generation SRL and PEGV combination therapy, who have symptoms of active acromegaly in the fourth week after first-generation SRL administration, may experience symptomatic improvement after switching to pasireotide LAR and PEGV combination therapy.

Both the EMA and the FDA recommend starting pasireotide LAR 40 mg every 4 weeks,[8,9] but we recommend starting with either 40 or 60 mg pasireotide LAR every 4 weeks. We expect that patients with partial response to first-generation SRLs will need lower dosages of pasireotide LAR, and we recommend starting with 40 mg pasireotide LAR monotherapy. For those on combination therapy we recommend initiating pasireotide LAR at a dosage of 60 mg every 4 weeks while tapering down the PEGV dosage by 33%. Our recommendation to initiate the maximum dosage of pasireotide is based on our experience that these patients probably do not need dosage reduction. In fact, only 1 of 46 patients in the PAPE study who used pasireotide LAR 60 mg in combination with PEGV therapy switched to pasireotide LAR monotherapy during the extension phase, and further dosage reduction to pasireotide LAR 40 mg was possible.[12] Moreover, we postulate that if the maximum dosage of 60 mg is used, there is a reasonable chance that PEGV dosage reduction can be achieved.

In our experience, IGF-1 levels decrease after the start of treatment more rapidly with pasireotide LAR than with octreotide LAR or lanreotide ATG. Although it can take ≤6 months for IGF-1 levels to normalize with first-generation SRL therapy, pasireotide LAR may induce a significant reduction in IGF-1 levels within 2 months,[11] and this early response is associated with a longer-lasting response at 48 weeks of treatment.[12] Switching to PEGV monotherapy or combination therapy with first-generation SRL should be considered when biochemical control cannot be achieved by pasireotide LAR monotherapy (Figure 1). When biochemical control cannot be achieved by combination therapy of pasireotide LAR and PEGV, patients can be switched back to their previous PEGV dosage, either as monotherapy or in combination with first-generation SRL therapy.

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