This page contains a Flash digital edition of a book.
Trainer_US Endo_Cardiology_book_temp 22/12/2009 10:49 Page 109
Advances in Our Understanding of Acromegaly—Is There an Optimal Management Regimen?
Losa et al. reported that Gamma Knife radiotherapy given to 83 patients Figure 1: Serum Insulin-like Growth Factor I
following debulking surgery resulted in an 85% remission rate at 10 years
Concentration in 19 Patients with Acromegaly
post-surgery, with only 10% of patients developing hypopituitarism.
8
120
Further long-term safety data are required, but the method appears to be
faster-acting at both lowering GH and causing hypopituitarism. In the
100
absence of radiotherapy, there is no prospect of a patient being able to
discontinue medical therapy; therefore, a financial case can be made for
80
the continuing use of radiotherapy because with time patients may be able
60
to stop high-cost medical treatment. That argument aside, as biochemical
IGF-I (nmol/l)
control can be achieved in almost every patient by a combination of
40
surgery and medical therapy, we suggest the role of conventional
radiotherapy in acromegaly is primarily for controlling continuing tumor
20
growth. Stereotactic radiotherapy in its various forms is superseding
multifractional radiotherapy and has a role in the treatment algorithm as
30 40 50 60 70 80
an alternative to medical therapy in those patients who have a Age (years)
well-defined area of residual disease at least 5mm away from the optic
chiasm post-debulking surgery.
Pegvisomant has been used successfully on a weekly basis, albeit in combination with
somatostatin analogs (SSAs). Nineteen patients with an insulin-like growth factor-I (IGF-I) above
the upper limit of normal on maximum-dose SSA had pegvisomant added, initially 25mg/week up
Medical Therapy
to 80mg/week. The addition of pegvisomant led to normalization in 18 of 19 patients. However,
this does not answer whether weekly administration is possible in patients on sole pegvisomant
At some point in their care, the majority of patients with acromegaly will therapy. Serum IGF concentration in 19 patients with acromegaly before (represented by red
receive medical therapy, with the choice of agent and the timing of
dots) and after (blue dots) six weeks of combined somatostatin analog (SSA) and pegvisomant
therapy. The shaded area represents age-adjusted IGF-I reference ranges.
initiation being dependent on a number of factors, including tumor size
37
Adapted from Feenstra et al., 2005.
and location, surgical and radiological intervention, patient choice, side
effects, and funding. Three classes of drug are available—SSAs, dopamine between SSR expression by tumors and response to SSA, but the major
agonists (DAs), and the GH-receptor antagonist—with each having distinct predictors of the likelihood of biochemical control are pre-treatment GH
advantages and drawbacks. and IGF-I levels, with more severe disease being less easily controlled.
9
Somatostatin Analogs SSA are generally well-tolerated, although patients frequently experience
Somatostatin is a widely distributed, naturally occurring 14 or 28 amino abdominal symptoms on commencing the drugs; these usually
acid peptide that acts via a family of somatostatin receptors (SSTRs), of spontaneously resolve. Deterioration in glucose tolerance due to inhibition
which there are five subtypes. The adult human pituitary expresses SSTR- of insulin secretion may result in diabetes. A further significant problem is
1, -2, -3, and -5 subtypes, but the SSTR-2 and to a lesser extent SSTR-5 are that SSAs, by a combination of gallbladder stasis and alteration in the
the principal receptors found on somatotroph adenomas, and their composition of bile, encourage gallstone formation. These are usually
activation inhibits GH secretion. The short half-life of somatostatin (two to asymptomatic until SSAs are stopped, when restored gallbladder
three minutes) means it is not a practical form of treatment. The SSAs contractibility may precipitate gallstone-related problems.
13
octreotide and lanroetide are synthetic peptides with a longer half-life and
greater receptor specificity for SSTR-2 and SSTR-5. SSAs are the first line of Pre-operative Somatostatin Therapy
medical therapy following non-curative TSS; both octreotide and lanreotide SSAs have been used successfully for 20 years as medical therapy
are available as monthly depot formulations and are effective at achieving following non-curative surgery, but evidence is accumulating for their use
biochemical control and induce tumor shrinkage in ≤50% of patients.
9
as a primary treatment with the aim of achieving both biochemical control
and tumor shrinkage without the associated risks for surgery or
It is difficult to judge the true efficacy of SSAs in achieving biochemical radiotherapy. Prospective studies of octreotide LAR in treatment-naïve
control post-surgery because of the varied entry criteria and therapeutic patients with micro- or macroadenomas have demonstrated normalization
goals used by the plethora of publications that have addressed the topic. of GH or IGF-I levels in 25–70% of patients in the first year, with rates
A meta-analysis that suggested that a long-acting repeatable (LAR) improving with longer duration of therapy. A reduction in tumor size of at
octreotide was superior to lanreotide at normalising IGF-I (63 versus 42%) least 20% was seen in 75% of the patients, with a significant improvement
and reducing GH to <2.5ug/l (54 versus 48%)
10
has been criticized, as >50% in signs and symptoms of disease.
14–17
It is unlikely that first-line SSA
of the patients included were from two studies that selected patients with therapy will replace surgery in the majority of patients. However, the only
proven octreotide responsiveness. Furthermore, the trials included were study to randomize patients to either primary medical therapy with
almost exclusively comparing lanreotide slow-release (SR) and not the octreotide or surgery reported overall success rates at week 24 and 48,
more long-acting preparation, lanreotide Autogel
®
. In reality, there is respectively, of 25 and 28% for the octreotide LAR group, and 49 and 39%
probably little difference in rates of biochemical control achievable with for the surgery group.
18
Cure rates in both groups are disappointing and it
the two SSAs and the great majority of patients achieve symptomatic is difficult to advocate a high-cost option that barely achieves disease
benefit, even if biochemical remission is achieved in approximately only control in one-quarter of patients. Patients with acromegaly rarely die from
50% of ‘unselected’ patients.
11
Lanreotide Autogel has the advantage that complications of tumor size; mortality relates to persistently raised GH and
it can be self- or carer-administered.
12
Correlations have been made IGF-I levels. This leaves open the question as to what point in primary
US ENDOCRINOLOGY 109
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100  |  Page 101  |  Page 102  |  Page 103  |  Page 104  |  Page 105  |  Page 106  |  Page 107  |  Page 108  |  Page 109  |  Page 110  |  Page 111  |  Page 112  |  Page 113  |  Page 114  |  Page 115  |  Page 116  |  Page 117  |  Page 118  |  Page 119  |  Page 120  |  Page 121  |  Page 122  |  Page 123  |  Page 124
Produced with Yudu - www.yudu.com