Primary Medical Therapy for Acromegaly

Pamela U. Freda and Sharon L. Wardlaw

Columbia University College of Physicians & Surgeons New York, New York 10032

Address correspondence and requests for reprints to: Dr. Sharon L. Wardlaw, Department of Medicine, Columbia University College of Physicians & Surgeons, 630 West 168th Street, New York, New York 10032.


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 Introduction
 References
 
Twenty-five years ago therapeutic options for patients with pituitary tumors were limited to surgery and radiotherapy. This approach changed dramatically for prolactinomas when it became apparent that long-acting dopamine agonists were very effective in reducing prolactin levels and restoring endocrine function in most patients with prolactinomas. In addition, these drugs caused significant tumor shrinkage in approximately 75% of patients. In some patients with large invasive tumors, the tumor shrinkage was dramatic. Today, medical therapy has replaced surgery and radiotherapy as the first line of treatment in the majority of patients with prolactin-secreting micro- and macroadenomas (1). The success with prolactinomas has raised the hope that other similarly effective medical treatments will eventually be found for other types of pituitary tumors. There is now considerable evidence that analogues of somatostatin, which normally inhibits GH release, provide an effective medical option for the treatment of acromegaly (2, 3). These analogues have, however, been studied primarily as secondary or adjunctive therapy in patients who had already been treated with surgery or radiotherapy. In this issue of JCEM (see page 3034), Newman and colleagues (4) present an important study that focuses on the use of the somatostatin analogue octreotide as a primary therapy for acromegaly.

In a large multicenter study, Newman and colleagues (4) compare the efficacy of octreotide treatment in two groups of patients with acromegaly. One group of 26 patients received octreotide as primary treatment, and a second group of 81 patients received octreotide as secondary treatment after unsuccessful surgery and/or radiotherapy. They demonstrate that an equivalent biochemical response, in terms of lowering IGF-I levels, can be achieved with octreotide in these two groups. Over a mean treatment period of 39 months, GH levels were no more than 2 µg/L during at least 4 study visits in 43% of the primary treatment group and in 22% of the secondary treatment group. IGF-I levels were normalized during at least half of the study visits in 68% of patients in the primary and 62% of the secondary treatment groups. There was also equivalent improvement in clinical symptoms in both groups. Pituitary magnetic resonance images were available in 13 of 26 patients in the primary treatment group. Tumor shrinkage was observed in 6 of 13 patients, but reduction in tumor volume greater than 25% was seen in only 3 patients. Importantly, the degree of tumor shrinkage did not correlate with the percent reduction in GH or IGF-I. The authors conclude that "While surgery is the treatment of choice in patients with tumors likely to be completely resected, our results suggest that, if the possibility of surgical cure is low, as in patients with large or invasive tumors, then octreotide may be a reasonable primary therapeutic modality, provided that the tumor does not threaten vision or neurological function."

Although this is clearly an important study, it would, at this time, be premature to make general clinical recommendations about the use of octreotide as primary therapy for acromegaly. As acknowledged by the authors, the interpretation of this study must be tempered by the fact that the patients who entered this study were not randomized to primary therapy with octreotide vs. surgery. It is unclear how the 26 patients were chosen to receive octreotide as primary therapy. Although the primary and secondary treatment groups had similar mean GH and IGF-I levels before the study, it is unknown how the two groups compared as to tumor size and invasiveness. Imaging studies are available on only 13 of the 26 primary therapy patients, of which 11 were reported to be macroadenomas and 2 were microadenomas. Without information regarding tumor size and invasiveness it is impossible to compare the clinical outcome in these patients with the expected outcome after transsphenoidal surgery.

To be considered as suitable primary therapy for acromegaly, the efficacy of somatostatin analogues must be compared with transsphenoidal surgery, the traditional first line of therapy for this disease. Based on data from several recent series, transsphenoidal surgery for acromegaly is successful in many patients and is associated with very low morbidity and a low recurrence rate (5, 6, 7). Although the results of transsphenoidal surgery for acromegaly have been reported from many centers over the last 20 years, the results are difficult to compare with our current clinical practice for two reasons. Over the years, the criteria used to define "cure" in acromegaly has changed, and the success of transsphenoidal surgery has improved with the increasing experience of the surgeons and the improvement of surgical techniques (6). Most earlier series reported cure rates based on a definition of post-operative GH of less than 5.0 µg/L, but it is now clear that some patients with "normal" basal GH levels of less than 5.0 µg/L measured by a polyclonal RIA still have excess GH secretion and active acromegaly. Therefore, we and others have recently evaluated the results of transsphenoidal surgery more stringently and have defined biochemical cure as a normalization of IGF-I level and/or a basal or glucose-suppressed GH of not more than 2.0 µg/L (5, 6). In our recent series of 115 patients who underwent transsphenoidal surgery for acromegaly and who were followed for a mean of 5.4 yr, 61% of patients were in remission after surgery alone; the remission rate was 88% for microadenomas and 53% for macroadenomas (5). Although surgery alone was unsuccessful for most invasive macroadenomas, 67% of noninvasive macroadenomas were in remission after transsphenoidal surgery alone (5). Using criteria very similar to ours, Swearingen et al. (6) report an overall remission rate for transsphenoidal surgery of 57%; remission rate was 91% for microadenomas and 48% for macroadenomas. In addition to the initial success of transsphenoidal in nearly all microadenomas and most noninvasive macroadenomas, these recent series have documented very low recurrence rates after surgery, ranging from 2–7% overall (5, 6, 7). Transsphenoidal surgery has also proven to be a very safe procedure with no mortality in these series and low complication rates of up to 8% (5, 6, 7). In the hands of an experienced neurosurgeon, cerebral spinal fluid leaks, meningitis, and new hypopituitarism in particular are now extremely unlikely to result from transsphenoidal surgery.

Thus for microadenomas, which make up approximately 20–25% of patients with newly diagnosed acromegaly, transsphenoidal surgery by an experienced pituitary surgeon is curative in close to 90% of patients. We therefore routinely recommend surgery to most patients with microadenomas unless severe medical problems preclude surgery. The majority of GH secreting tumors are, however, macroadenomas with cure rates as high as 67% if the tumor is noninvasive, but with markedly diminished success rates if the tumor is invasive (5). How might primary or secondary medical therapy affect overall outcome in these patients? Newman et al. (4) report a 68% or 62% success rate for normalizing IGF-I with octreotide as either primary or secondary therapy, respectively. If the 50% of patients with macroadenomas who are not cured by surgery are then treated with octreotide, normalization of IGF-I should be achieved in 62%; thus the overall success rate for patients with macroadenomas who undergo surgery followed by octreotide would be 81% vs. 68% for patients with macroadenomas who receive primary therapy with octreotide. The overall success rate for similarly treated noninvasive macroadenomas would be even higher at 87%. Thus initial transsphenoidal surgery still appears to be the best option for many patients with GH-secreting macroadenomas. If there is a reasonable chance of achieving a surgical cure, transsphenoidal surgery should usually be recommended to avoid the inconvenience and expense of life-long somatostatin analogue injections. Patients with large invasive tumors, however, are very unlikely to be cured surgically. It has been standard clinical practice to operate on these patients even though biochemical cure is unlikely. Newman and colleagues question this practice and suggest that octreotide may be a reasonable primary therapeutic modality in these patients. To recommend octreotide as primary treatment for these patients we need to consider the effect of octreotide on tumor size and growth, especially with these large invasive tumors. Unfortunately, in contrast to dopamine agonist treatment of prolactinomas, octreotide does not cause a large degree of tumor shrinkage in the majority of patients. In the study by Newman et al, follow up imaging studies after 6 months showed some tumor shrinkage in 6 of 13 patients, but reduction in tumor volume greater than 25% was seen in only 3 patients. Importantly, biochemical response was not predictive of tumor shrinkage. More long-term data are clearly needed to determine the effects of primary medical therapy on the progression of large or invasive tumors.

Although the somatostatin analogues have been a significant advance in the treatment of acromegaly, the study by Newman et al. (4) shows that 38% of patients who received octreotide as secondary treatment after previous surgery and/or radiotherapy still did not achieve biochemical remission. Additional therapeutic strategies for acromegaly are clearly still needed as accumulating data suggest that successful treatment of this disease is associated with decreased long-term morbidity and mortality. Newer forms of stereotactic radiotherapy (a computer assisted linear accelerator or cobalt-60, the gamma knife) may be more effective than conventional radiotherapy but long-term experience with these techniques for treating GH secreting pituitary tumors is limited. The long acting somatostatin analogues, which will soon be available in the U.S.A., will certainly make treatment more convenient, but remission rates do not appear to be very different from the short acting preparations. It is hoped that response rates may improve with the development of more potent and specific somatostatin analogues. Dopamine agonists have been found to be only minimally effective for the treatment of acromegaly, and their success has been limited by the need for high doses with associated side effects. There is evidence that the longer acting and better tolerated dopamine agonist, cabergoline, may be somewhat more effective (8). Additional therapeutic benefit can sometimes be achieved by combination therapy with somatostatin analogues and dopamine agonists. On the horizon is a novel therapeutic agent, a growth hormone antagonist, which is currently being evaluated in clinical trials for the treatment of acromegaly and may potentially be a very useful future therapeutic option for this disease (9).

At present the somatostatin analogues provide the most effective medical option for the treatment of acromegaly, and the possibility of using these drugs as primary therapy, as suggested by Newman and colleagues (4), is very appealing. In selected patients this approach may well be preferable to surgery. However, a prospective study comparing the long-term benefits of primary somatostatin analogues vs. primary surgical therapy in two groups of patients carefully matched in terms of tumor size and invasiveness, preoperative GH level, and other parameters needs to be done. Outcome needs to be examined in terms of biochemical control, quality of life, cost of therapy, as well as long term morbidity. Hopefully the long acting somatostatin analogues will provide the therapeutic efficacy and tolerability that would make them a viable option for primary treatment. The timely and careful study by Newman et al. (4) demonstrates the feasibility of primary somatostatin therapy for acromegaly and highlights the need for a prospective study answering the remaining questions about tumor shrinkage and comparison of the long-term clinical outcomes vs. transsphenoidal surgery, the traditional primary therapy for acromegaly.

Received June 29, 1998.

Accepted July 8, 1998.


    References
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 Introduction
 References
 

  1. Molitch ME, Thorner MO, Wilson C. 1997 Management of prolactinomas. J Clin Endocrinol Metab. 82:996–1000.[Free Full Text]
  2. Newman CB, Melmed S, Snyder PJ, et al. 1995 Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients. J Clin Endocrinol Metab. 80:2768–2775.[Abstract]
  3. Lamberts SWJ, Van der Lely A-J, De Herder WW, Hofland LJ. 1996 Octreotide. N Engl J Med. 334:246–253.[Free Full Text]
  4. Newman CB, Melmed S, George A, et al. 1998 Octreotide as primary therapy for acromegaly. J Clin Endocrinol Metab. 83:3034–3040.[Abstract/Free Full Text]
  5. Freda PU, Wardlaw SL, Post KD. 1998 Long-term endocrinologic follow-up after transsphenoidal surgery for acromegaly. J Neurosurg. 89:353–358.[CrossRef][Medline]
  6. Swearingen B, Barker FG, Katznelson L, et al. 1998 Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab. In press.
  7. Abosch A, Tyrell JB, Lamborn KR, Hannegan LT, Applebury CB, Wilson CB. 1998 Transsphenoidal microsurgery for growth-hormone secreting pituitary adenomas: initial outcome and long-term results. J Clin Endocrinol Metab. In press.
  8. Abs R, Verhelst J, Maiter D, et al. 1998 Cabergoline in the treatment of acromegaly: a study in 64 patients. J Clin Endocrinol Metab. 83:374–378.[Abstract/Free Full Text]
  9. van der Lely AJ, Lamberts SWJ, Barkan A, et al. A six-week, double-blind placebo controlled study of a growth hormone antagonist, B2036-PEG (Trovert), in acromegalic patients. 80th Annual Meeting of The Endocrine Society, New Orleans, LA, 1998, Abstract OR4–1.