Fig. 1.1
Adapted from Neurosurg Focus 29(4):E15, Fleseriu, M., Delashaw, J.B., and Cook, D.M. Acromegaly: a review of current medical therapy and new drugs on the horizon, page 3, Copyright (2010), with permission from Journal of Neurosurgery Publishing Group and American Association of Neurological Surgeons
Pituitary tumor patients are best cared for by a multidisciplinary neuroendocrine team at a specialized center; one that includes neurosurgeons, endocrinologists, radiation oncologists, neuro-ophthalmologists, and otolaryngologists. No single treatment algorithm applies to all patients. Treatment should be individualized and include long-term follow-up. Treatment models for individual pituitary adenomas vary and are summarized above (Fig. 1.1).
Prolactinomas
Prolactinomas are the most common type of hormone-secreting pituitary tumor. First-line therapy is with DAs. Surgery is generally reserved for patients who do not respond to medical therapy, with severe pituitary hemorrhage, are pregnant with progressive tumor enlargement or are not responding to DA therapy.
Treatment aims to normalize PRL levels, restore fertility in those of child-bearing age, decrease tumor mass, save or improve the residual pituitary function, and inhibit disease relapse. Dopamine agonists available in the United States (US) are bromocriptine and cabergoline.
Cabergoline is usually better tolerated (less headache, nausea, postural hypotension, and fatigue) and offers the convenience of twice-a-week administration; starting dose is usually 0.25 mg up to a maximum dose of 1 mg. Cabergoline appears to be more effective in lowering PRL levels within the first 2–3 weeks of treatment in about 90 % of patients and in restoring ovulation. The drug usually decreases the size of micro- and macroadenomas (several weeks to months to observe detectable decreases). In cases whereby the adenoma affects vision, improvement may be observed within days of starting treatment. If tumor response to drug is therapeutically good, medical therapy can be withdrawn after 3–5 years. Hyperprolactinemia will not recur in two-thirds of these patients.
The best treatment to restore fertility in women with a microadenoma is a DA. Cabergoline is less used in women attempting conception or in pregnancy. Bromocriptine does not appear to increase the risk of miscarriage or birth defects when discontinued early in pregnancy. Before attempting pregnancy, a detailed discussion with patients should include when to discontinue bromocriptine, the chances that the adenoma will grow during pregnancy and further treatment details as necessary. Microadenomas rarely increase in size during pregnancy. On the other hand, if the adenoma is large or is affecting vision, surgery is usually recommended before attempting to conceive.
Acromegaly
Treatment of GH-secreting adenomas should include a comprehensive treatment strategy to alleviate pituitary tumor effects, normalize GH and insulin-like growth factor-1 (IGF-1) hypersecretion, improve associated comorbidities, and reverse the increase in mortality risk, all while preserving normal pituitary function. Surgery is the first-line treatment choice for acromegaly patients, with two caveats, an experienced surgeon is available and tumor is visible on MR imaging. If the tumor has invaded the cavernous sinus, or has been determined to be not completely resectable, medical therapy can be also offered as first-line treatment in addition to surgery. The treatment of patients with persistently active acromegaly has been facilitated over the past decade by the advent of highly specific and selective pharmacological agents that are sometimes used in combination. Radiation therapy is a potential adjuvant therapy, usually reserved for patients who have some remaining tumor postsurgery. These patients often concomitantly take medications to lower GH levels as there is usually a long waiting period before radiation is effective. Decrease in pituitary function (hypopituitarism) is a significant complication. Radiotherapy remains a third-line treatment option for acromegaly in the US.
Three classes of medical therapy are available to treat acromegaly, each with unique advantages and disadvantages. In patients with uncontrolled hormone levels after surgery, SSAs are the first-line treatment choice. Dopamine agonists and GH receptor antagonists are generally indicated after failure of SSAs or in combination with SSAs (Fig. 1.1).
Somatostatin Analogues
There are three SSAs approved for use in the US: octreotide short release, octreotide long acting release (LAR) or Sandostatin LAR, and lanreotide ATG (Somatuline depot). It is difficult to appreciate the true efficacy of SSAs in achieving biochemical control due to varied clinical trial study entry criteria and “desirable” cut-off goals. Although early on a study data meta-analysis showed that overall GH and IGF-1 were normalized in 49–56 % and 48–66 % of patients, respectively. Other study results suggest symptom control in a large majority, with biochemical control only being achieved in approximately half of patients if “unselected” for responsiveness. Somatostatin analogues are generally safe and well tolerated. The most frequent adverse events of SSA treatment are abdominal symptoms, which usually improve over time glucose intolerance and gallbladder sludge/stones. The distinctions between different types of GH-secreting tumors (sparsely vs. densely granulated tumors), and presence of somatostatin receptor type 2a (SSTR2a) can impact response to therapy as well as prognosis; therefore, accurate classification is important.
It has been suggested that SSA treatment prior to surgery can reduce surgical risks and potentially improve surgical cure rates. Conversely, tumor debulking is often used with SSA therapy when GH is partially but not completely controlled with treatment. In these cases, debulking the tumor may allow SSA therapy to reduce GH and IGF-1 into the normal age-adjusted range.
A number of studies have reported tumor shrinkage in patients with acromegaly treated with SSA therapy, both adjunctive and primary. This shrinkage can be significant (20–80 % in about one-third of patients), however results are unpredictable.
Dopamine Agonists
Dopamine agonists inhibit GH secretion in some acromegaly patients. The beneficial effects could occur even when pretreatment PRL levels are normal and/or there is no evidence of tumor PRL staining. A lower IGF-1 level at the start of treatment seems overall to be the best predictor of efficacy. Cabergoline is administered orally and is thus more convenient, although not as effective as other medical therapies.
Growth Hormone Receptor Antagonists
The GH receptor antagonist, pegvisomant, (Somavert) directly inhibits the peripheral action of GH by interfering with functional dimerization of the two GH receptors subunits and thus blocks the signal for IGF-1 production. In early clinical trials, normalized IGF-1 levels were observed in approximately 90 % of patients, however, data from large observational studies has revealed a much lower IGF-1 normalization rate (70 % of patients), most probably due to inadequate dosage. Pegvisomant adverse events include disturbed liver function tests and injection site reactions. Tumor growth has not been proven to be a concern, but continued long-term surveillance of tumor volume is needed, especially in nonirradiated patients. It is recommended that pegvisomant be reserved for SSA nonresponders or patients intolerant of SSAs, patients whose diabetes is worsened by SSAs or considered in combination therapy.
For acromegaly patients who are poorly or non-responsive to, presently available single drug therapies, the use of combination drug therapy holds promise. However, currently the use of combination therapy is not approved by the Federal Drug Administration (FDA) in the US.
Monitoring Therapy
General consensus is to lower the IGF-1 levels to within the reference range for the patient’s age and gender and to lower the random serum GH levels to <1 ng/mL or <0.4 ng/mL (depending on the assay) after a glucose load (oral glucose tolerance test; OGTT). Pegvisomant is unique in that the drug does not lower GH levels (levels are raised, due to feed-back mechanics), thus making IGF-1 the only available marker for disease activity.
It is recommended that all patients undergo biochemical testing and pituitary MR imaging during long-term follow-up, irrespective of medical treatment.
Drugs in Clinical Trial
The role of SSTRs and dopamine receptors (DR) as molecular targets for the treatment of pituitary adenomas is well established.
Pasireotide (SOM 230; Signifor) is a unique somatotropin release-inhibiting factor with a high binding affinity to SSTR subtypes 1, 2, 3, and 5 and up to a 40-fold greater affinity for SSTR5 than octreotide. Phase III clinical trials results show that subjects treated with pasireotide LAR were significantly more likely to achieve disease control than those treated with octreotide LAR. Also, approximately 20 % of subjects uncontrolled on octreotide achieved full disease control after switching to pasireotide LAR. However, a higher degree and frequency of hyperglycemia has been observed and reported with pasireotide use. The long-term and future role of pasireotide in treating acromegaly remains to be determined.
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