Q J Med 2000; 93: 1-6
© 2000 Association of Physicians
Editorial |
Modern approaches to treating acromegaly
Department of Endocrinology, Radcliffe Infirmary, Oxford
Only a couple of months ago in the Times, acromegaly was described as a serious disease causing grotesque appearances and crippling arthritis.1 The aim of this article is to discuss the recent advances and developments in management of acromegaly that make the likelihood of this situation developing vanishingly small.
Acromegaly leads to reduced life-expectancy, with a 2–3-fold increase in mortality. However, patients with post-treatment growth hormone (GH) of <5 mU/l have been shown to have the same mortality as the general population2–4 and recently, normalization of IGF-1 has also been shown to reduce mortality to that of the general population.5 Therefore the main aims of management of patients with acromegaly are to control the tumour and its effects, and to reduce GH and IGF-1 levels. There have been many recent developments, in currently accepted modalities of treatment as well as novel approaches to therapy.
Trans-sphenoidal adenomectomy remains the initial treatment of choice for the majority of patients with acromegaly. Auditing the outcome from this procedure is important, but requires appropriate definition of successful treatment. Much of the older literature contains reports where `cure' is reported when GH levels reach <10 mU/l (5 ng/ml). The epidemiological data available demonstrate that this level of GH secretion is still associated with an increased mortality and morbidity, and therefore a more stringent value of GH <5 mU/l has been introduced. This is not normal, so `cure' is not strictly accurate. We prefer to refer to `safe' GH levels. Application of these criteria to various different centres, and taking into account tumour size, reveals startlingly different outcomes from surgery.6
It has recently become clear that the number of surgeons operating in a particular centre influences the rate of achievement of `safe' post-operative GH levels. Perhaps this is intuitive, but in a report from Manchester, 73 patients were operated on by nine different surgeons between 1994 and 1997.7 Only 39% patients with microadenomas and 12% with macroadenomas were cured, in contrast to the Oxford series—where a single neurosurgeon operated on 139 patients and cured 91% microadenomas and 46% macroadenomas.7,8 In support of this, Yamada and colleagues report an almost doubling of the cure rate following the replacement of several surgeons with a single pituitary surgeon9 and in Birmingham the experience is the same.10
As expected increasing surgical expertise also has a bearing on outcome. In Oxford, the success rate rose from 48% over 15 years ago to 74%, and for microadenomas rose from 50% 15 years ago, to 100% currently.8 Similar results are reported from Newcastle11 and London.12 Increases in the rates of improvement in post-operative pituitary function have also occurred, rising from 16% to 34%. During this time, there was no change in rate of post-operative complications.
The implications of these data are that it is imperative to have an experienced dedicated pituitary surgeon operating in a specialized centre.13 This will lead to the optimal outcome for the patient, but also makes economic sense, as fewer patients will require further treatment in the form of radiotherapy and/or long-term expensive drug treatment to lower persistently elevated GH levels.14
Medical therapy is taking on an increasingly important role in the management of acromegaly, as the importance of achieving tight control of GH, and the limitations particularly of radiotherapy are recognized.15 Studies using dopamine agonists for acromegaly using the better-tolerated drug cabergoline, still demonstrate limited effectiveness, with only 20–40% patients achieving normalization of IGF-1 despite high dosage.16,17
The somatostatin analogue octreotide has, until recently, usually been administered subcutaneously 3 times daily, and leads to normalization of IGF-1 in approximately 53% patients with acromegaly. The recent licensing of two new long-acting depot somatostatin preparations has increased the convenience and acceptability of long-term drug treatment. Lanreotide SR is injected intra-muscularly every 7–14 days, and octreotide LAR is administered every 28 days. Several reports have assessed the efficacy of lanreotide and octreotide LAR. In studies aiming for a mean GH <5 mU/l, this is achieved in a similar proportion (50–70%) of patients whether they are selected for prior response to somatostatin analogues18,19 or not.20
Comparisons between responsiveness to the two somatostatin analogues in terms of GH and IGF-1 suppression show no difference between mean GH achieved on subcutaneous octreotide and octreotide LAR,20–22 or between subcutaneous octreotide and lanreotide.20,23 However, we have recently demonstrated that although there is no difference in terms of the proportion of patients suppressing GH to `safe' levels (78% lanreotide vs. 80% octreotide LAR), within-patient comparison shows that lower GH levels are achieved when octreotide LAR is administered compared with lanreotide.20 Whether this is important in terms of outcome is not known.
Prolonged suppression of GH and IGF-1 has been noted in some patients following both lanreotide and octreotide LAR. This suggests that the dose frequency may be reduced in some patients without compromising overall disease control, further improving convenience and increasing cost-effectiveness of treatment. Studies are needed in this area.
Tolerability and side-effects of the different preparations appear to be similar. It is known that subcutaneous octreotide leads to gall-stones in up to 50% patients, but it has been suggested that this may be less common with the longer-acting sustained release preparations. However there are insufficient follow-up data to confirm this at present. We have demonstrated that both lanreotide and octreotide LAR lead to inhibition of gall bladder emptying, and that this is significantly greater in patients receiving octreotide LAR.24 Whether this means that lanreotide should be recommended for patients with gall-stones is unclear.
There has been recent interest in the possibility of using medical therapy as primary treatment for patients with acromegaly. Newman and colleagues recently reported that 43% of patients achieved GH <2 µg/l while receiving primary therapy with subcutaneous octreotide.25 However, as discussed by the authors and in the accompanying editorial,26 this was not a randomized study and there were data on tumour size in only half the patients. A comparison with surgery is therefore difficult, but since the cure rate for trans-sphenoidal surgery should be 80–90% for microadenomas and 40–50% for macroadenomas, most endocrinologists would continue to refer patients for surgery in the first instance.
Perhaps a more relevant role of somatostatin analogues may be to consider them as sole secondary therapy following non-curative surgery where radiotherapy is unlikely to cure the patient (within the medium term anyway), and in particular where the remaining pituitary function is intact and needed in the future, for example for fertility.
The achievement of `safe' GH only occurs at best in 60–70% patients when treated with subcutaneous or depot preparations of somatostatin analogues, and dopamine agonists lead to satisfactory results in up to 40%. There is thus an urgent need for the development of alternative therapeutic options.
A novel growth hormone receptor antagonist (B-2036-PEG) has recently been developed and is undergoing evaluation for the treatment of acromegaly. Reversible binding to the GH receptor leads to inhibition of signal transduction and therefore lowering of IGF-1. This drug is a recombinant protein with structural similarity to wild-type human GH, but mutations have been made at the sites of interaction with the GH receptor to leave the GH receptor inactivated and unresponsive to endogenous GH.27 Eight mutations at site 1 lead to increased affinity for the receptor compared to endogenous GH, and the mutation at site 2 prevents binding with a second GH receptor and receptor dimerization. Pegylation increases the half-life from 11 min to 72 h and reduces immunogenicity. B2036 is administered subcutaneously, and since it does not lower circulating GH, serum IGF-1 is the principal biochemical means of monitoring effectiveness of treatment.28 The drug was initially administered subcutaneously on a weekly basis, which demonstrated that reduction in IGF-1 was possible, however daily dosage was required to lead to satisfactory IGF-1 control. The results of preliminary studies show that over 90% patients (including those who did not respond to somatostatin analogue therapy) achieve IGF-1 within the reference range with daily dosing.28,29
The drug has been well tolerated in general, with no significant change in pituitary MRI appearances, or the development of B2036-PEG or GH antibodies. There has been concern that blocking short-loop GH feedback at the hypothalamus may stimulate endogenous GH secretion and possibly tumour growth (as is seen when Nelson's syndrome follows bilateral adrenalectomy in Cushing's disease). Although no pituitary tumour growth has been observed thus far, the majority of patients included in the studies have received pituitary surgery and radiotherapy. Thorner and colleagues, however, have recently demonstrated that GH did not change when B2036-PEG was administered to normal males, although IGF-1 levels were reduced by 49%.30 These data are reassuring in that they suggest that B2036-PEG may simply block peripheral action of GH without influencing hypothalamic GH receptors, and therefore without leading to enhanced pituitary GH secretion and tumour enlargement.
Further work with this exciting new therapeutic agent may help differentiate specific effects of IGF-1 and GH, as well as potentially leading to control of acromegaly in the majority of patients requiring medical treatment.
Pituitary radiotherapy is often recommended for control of excess growth hormone secretion in acromegaly, particularly following non-curative surgery. The conventional dose is a total of 4500 Gy in 26 fractions given through three portals. Radiotherapy leads to a predictable lowering of GH in the majority of patients—with the maximum fall occurring in the first 2 years.31 The major determinant of the time taken to normalize GH to `safe' levels is the pre-radiation GH level.
However, although there are a number of series in the literature reporting GH response to radiotherapy in patients with acromegaly, there are few data concerned with achievement of what are currently recognized as `safe' GH levels (mean GH <5 mU/l), and normalization of IGF-1. There has been a suggestion that although radiotherapy is effective in lowering GH, it infrequently leads to cure or safe GH levels, and in particular that it does not normalize IGF-1.15,32 Thalassinos and colleagues used the achievement of mean GH <2.5 ng/ml as criterion for cure, and showed that only 7/28 (25%) achieved this at 5 years, and 4/19 (21%) at 10 years. Of a total of 48 patients followed for a mean of 7.6 years (range 2–22 years), only 21% showed mean GH <2.5 ng/ml at their latest follow-up. IGF-1 was normalized in 4/14 (29%) patients followed for over 10 years. However the majority of these patients had not undergone prior surgical debulking of the tumour. Similar results were reported by Barkan, who showed that despite lowering of GH (to 19.3% of pre-radiation values at 7 years), only minimal lowering of IGF-1 was seen (83.2% of pre-radiation values at 7 years).15 Only 2/38 patients (5%) achieved normalization of IGF-1 during a mean follow-up of 6.8 years.
These recent results have led to further discussion regarding the role of pituitary radiotherapy in treating acromegaly. More data are required on larger series of patients, and information acquired from databases such as the UK Acromegaly Database (currently involving 14 different endocrine centres) will be very useful in this regard.
Stereotactic radiosurgery uses focused radiation to deliver a precise dose of radiation to the tumour with little radiation to the surrounding tissue. There are three forms currently used: the gamma knife, which involves ionizing radiation from a Cobalt-60 source delivered by convergent collimated beams focused on a stationary point; linear acceleration, where photons are focused on a stationary point from a moving gantry; and proton beam therapy, where protons generated in a cyclotron are focused on a moving point.
The gamma knife technique has been used by a few centres to treat different types of pituitary tumour, but recent interest in its use has been following non-curative pituitary surgery;33 for example, where inaccessible tumour extends into the cavernous sinus. The advantages of its use are the high dose of radiation that is sharply focused on the tumour in a single session, and the steep fall-off of radiation at the periphery, reducing the likelihood of radiation damage to surrounding tissue. It has been suggested that this may lead to reduced likelihood of the complications occasionally seen following conventional radiotherapy in terms of second tumour development and possible cognitive changes. However long-term data are required to substantiate this. The potential for optic nerve damage when treating tumours with suprasellar extension limits its usage, and visual deterioration is the major complication.34
There have been very few data published on the efficacy of this form of treatment in terms of endocrine outcome, and in particular there is a lack of any long-term data. Proponents of this technique suggest that it is associated with more rapid resolution of tumour hypersecretion than conventional radiotherapy.33,35,36 Although this technique is promising and may prove to be particularly useful in situations of surgical inaccessibility, there is an urgent need for more long-term follow-up data.34
An increased incidence and mortality from colon cancer has been demonstrated in both retrospective and prospective studies of patients with acromegaly.4,37 Although the mechanism is as yet unclear, acromegaly leads to a higher prevalence of tubulovillous adenomas, which are known to be pre-malignant. It is therefore important to not only screen and treat patients with acromegaly for the factors associated with increased cardiovascular risk and respiratory disorders such as sleep apnoea, but also to perform routine surveillance colonoscopy. Further data on the possibility of increased risk of other malignancy, for example breast cancer (standardized mortality rate 1.6, p=0.07)4 remains to be seen, as the life-expectancy of patients increases with improvement in therapy.
An international workshop in February 1999 has led to the most recent consensus on criteria for cure of acromegaly.38 These state that the aims of therapy are to use safe treatment to remove tumour mass or control its growth, and to restore GH secretion and action to normal. The biochemical goals of treatment were stated as reduction of circulating IGF-1 to normal age- and sex-matched values and to reduce serum GH concentrations to a nadir <1 µg/l (2 mU/l) after an oral glucose load.
With currently available commercial assays, the suppression of GH to <2 mU/l (1 µg/l) on oral glucose tolerance testing, is used to separate normals from those with acromegaly. However, newer more sensitive assays are likely to lead to redefinition with a lower cut-off in the future.
Whether it is appropriate to use normalization of IGF-1 and nadir GH on an oral glucose tolerance test to define `cure', when the majority of the epidemiological data on morbidity and mortality are based on serum GH or mean of several GH values, requires further study. This is another area where databases are likely to provide useful information.
The aim of therapy has been to reverse the increased mortality associated with active disease. Aiming for `safe' GH levels may prove to be inadequate as it becomes clear that the secretory pattern of GH as well as the actual amount produced may influence IGF-1 levels. This becomes pertinent as we accrue data on the long-term effects of GH deficiency, and also the increased mortality associated with elevated IGF-1.5 Clayton has suggested that absolute biochemical cure should be defined as a restoration of physiological patterns of GH secretion with (i) restoration of secretory dynamics, (ii) abolition of paradoxical responses, and (iii) return of basal GH and IGF-1 values to age and sex-matched normal range.39 In practice, such stringent criteria are rarely achieved, but consideration of them may explain some of the findings discussed above.
The data on post-operative GH pulsatility suggest restoration of paradoxical responses, in conjunction with normalization of mean GH and IGF-1, but some report normalization of GH pulse frequency,40 while others suggest persistent abnormalities.41 Abnormal pulse frequency may lead to subsequent elevation of IGF-1 during follow-up due to more frequent or continuous stimulation of secretion. Following pituitary irradiation of pituitary tumours, GH deficiency is commonly encountered. However, even in GH-deficient elderly patients following radiotherapy, GH secretion can still be shown to be pulsatile.42 In contrast, Peacey and Shalet have demonstrated abnormal GH release following radiotherapy in acromegaly, where a large proportion of the GH release is non-pulsatile. This may explain the dichotomy between normalization of GH and IGF-1 levels, and also suggests that normalization of IGF-1 in these patients may be associated with significantly lower GH secretion.43 Although pulsatility of GH is altered with somatostatin analogue therapy, the marked disparity between GH and IGF-1 normalization is seen less frequently. Inhibition of persistent GH secretion from the tumour, as well as hypothalamic effects, may lead to less disruption of GH pulsatility, although further data are required.
The real significance of altered GH pulsatility remains to be explored. However the possible existence of a `U-shaped curve' to describe the relationship between GH levels and mortality in acromegaly has been recently suggested.43 As might be expected, many patients with `safe' GH following radiotherapy have been shown to reach agreed criteria for GH deficiency44 which is associated with increased morbidity and mortality. The suggestion that treatment designed to reduce the risk of long-term complications of acromegaly, such as increased cardiovascular mortality, might ironically then be associated with increased cardiovascular morbidity (and probably mortality) due to GH deficiency remains to be fully addressed.
Future developments within the field of acromegaly are likely to involve further refinement of the assays used to measure GH and IGF-1, which may lead to even more stringent criteria for successful outcome from treatment, with the aim of further reducing the morbidity and mortality associated with the condition.
Epidemiological data accrued from databases such as the UK Acromegaly Register, will enable outstanding issues such as efficacy of radiotherapy, long-term risk of different malignancies, the importance of IGF-1 levels and the relevance of post-treatment GH deficiency, to be answered.
There is still considerable room for improvement in the therapy of these patients. The new GH receptor antagonists, and perhaps more specific somatostatin receptor agonists, in addition to improved and appropriate use of surgical expertise, re-evaluation of the use of radiation, and newer radiation techniques, may enable the outcome from this condition to be improved further and associated with a normal life expectancy.
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