The Role of Radiotherapy in Acromegaly
A. J. van der Lely and
W. W. de Herder
S. W. J. Lamberts
Department of Internal Medicine
Erasmus University
Rotterdam, Netherlands
Address correspondence and requests for reprints to: A. J. van der Lely, Dept. of Medicine, University Hospital Dijkzigt, 40 Dr. Molewaterplein, 3015 GD Rotterdam, The Netherlands. E-mail:
vanderlely{at}inw3.azr.nl
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Introduction
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The manuscript of Barkan et al. (1), in
this issue of JCEM (see page 3187), in which they describe
the inefficacy of pituitary irradiation in normalizing serum
insulin-like growth factor I (IGF-I) concentrations in patients with
acromegaly, is interesting because it is the first report that uses
IGF-I instead of GH as the parameter for the efficacy of radiotherapy
in acromegaly. Most previous reports use GH as the parameter in the
long-term follow-up of acromegalic patients after radiotherapy (2, 3, 4).
Roughly, these studies indicate that, after two yr, GH concentrations
decrease by about 50% from baseline levels, and by five yr the GH
concentrations are about 25% of the initial values. Speirs et
al. (5) reported that radiotherapy is equally efficacious whether
an earlier unsuccessful ablative procedure had been used or not.
Acromegalic patients frequently do have abnormally large frontal air
sinuses, which allow increased anterior beam transmission. This can
cause an increased dose to the optic nerve and chiasm with potentially
damaging effects. The resultant overdosage can be greater than 5% of
the intended dose (6). These authors recommended therefore that
acromegalic patients should be treated with a more acurately directed
beam, which avoids the air sinuses altogether. Despite this,
radiotherapy for acromegaly is a safe procedure in the long-term, with
few reports of damage to the optic nerves (7, 8). The incidence of
second brain tumors after pituitary irradiation is also low (9). Little
is known, however, about the long-term effect of irradiation of the
pituitary area on neuro-psychological functions (9, 10, 11). The
relationship between GH and IGF-I levels in patients with acromegaly
does not follow a straight line. Only in GH concentrations up to 4060
µg/L do GH and IGF-I demonstrate a close correlation, but higher GH
concentrations do not lead to a further increase in IGF-I levels in
most patients (12, 13). However, many patients demonstrate increased
serum IGF-I levels in the follow-up, while GH concentrations are within
the normal range and vice versa (13). After the introduction of
somatostatin analogs in the treatment of acromegaly, the need for
radiotherapy has decreased. The somatostatin analogs available
(octreotide and lanreotide) decrease GH and IGF-I levels to normal
levels in about 60% of patients (14). The recently developed
long-acting somatostatin analogs will simplify therapy for these
patients and will encourage their compliance, while the effectiveness
of normalizing GH and IGF-I levels might be higher (15, 16, 17, 18, 19, 20). With
better medical treatment available, fewer acromegalic patients who fail
surgical therapy will need radiotherapy. This is especially true for
elderly patients, who are more sensitive to somatostatin analog therapy
(13). One of the shortcomings of the study by Barkan and coworkers (1),
as they themselves pointed out, is that no uniform radiotherapy
technique was used in this retrospective study. Both proton beam
radiotherapy and conventional radiation techniques were used, and
patients were treated in several centers. The relatively low number of
subjects in this study and the variability of the IGF-I assays used
make it hard to draw final conclusions. In our own database, we looked
for the course of serum IGF-I concentrations in acromegalic patients.
In a group of 37 patients who were not cured after transsphenoidal
surgery and radiotherapy and who could be followed for a period of 7
yr, we found that IGF-I concentrations had not normalized, even after a
follow-up period of 7 yr. In the same group, anterior pituitary
insufficiency had developed in about 40% (39% thyroidal
insufficiency; 33% gonadal insufficiency; 42% adrenal insufficiency).
This clearly demonstrates that pituitary damage frequently occurs after
radiotherapy. The lowering of GH levels further supports the damaging
effect of radiotherapy on the pituitary fossa. Why then do serum IGF-I
concentrations not normalize, and what does this mean from a clinical
viewpoint?
One of the major problems in assessing disease activity in acromegaly
is the fact that neither serum GH nor IGF-I concentrations have been
shown to be reliable parameters, although recently some investigators
suggested a possible role for IGFBP-3 (21, 22, 23, 24). There is consensus,
however, that in patients with normal serum GH and IGF-I
concentrations, disease activity is absent or low. It remains uncertain
whether one or several GH samples or 24 hr GH profiles are necessary to
obtain an impression of GH secretory reserve (21, 23). Why did serum
IGF-I levels demonstrate such a disappointing decrease after
radiotherapy?
One might speculate on a role of IGF-I modulating tissue repair after
irradiation or ischemia. In acromegalics IGF-I levels are increased,
which in theory might influence the outcome of radiotherapy. Several
reports demonstrated that IGF-I can decrease cellular damage in cases
of ischemia (25, 26, 27). IGF-I might be a potent neuronal rescue agent
when injury is imminent in case of ischemia. When tissue damage is
caused by irradiation, however, the role of IGF-I could be less
beneficial (28). By inducing changes in chromatin confirmation IGF-I
inhibits repair of irradiation-damaged DNA. Whether this plays a role
where radiotherapy in acromegaly is concerned is not known. It would
not explain why tumorous GH levels decrease after radiotherapy in these
patients, while IGF-I concentrations do so to a much lesser extent. If
these findings by Barkan and coworkers turn out to be correct, while we
do not know the long-term adverse effect of radiotherapy on
neuropsychiatric functions, we probably should reserve irradiation of
the pituitary tumor (remnants) in acromegalic patients with active
disease to those in whom other treatments like somatostatin analogs
have failed to control disease activity.
However, more studies should be carried out to find the optimal
biochemical parameters to be used in defining a "cure" of
acromegaly. Also the high costs of long-term somatostatin analog
therapy should be considered. In the meantime we reserve radiotherapy
only for acromegalics with large, infiltrating pituitary tumors that
cannot be cured surgically and that are also not controlled by
somatostatin analog treatment with repeated long-acting depot
preparations. This means that fewer patients will receive radiotherapy
in future. Up till now, in many centers, including ours, patients who
are not cured after neurosurgery are still treated with radiotherapy.
With the report by Barkan et al. (1), however, the discussion about the
role of radiotherapy is again intensified.
Received July 15, 1997.
Accepted July 18, 1997.
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