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Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032; and Department of Neurosurgery, Mount Sinai Medical Center, New York, New York 10029
Address all correspondence and requests for reprints to: Dr. Pamela U. Freda, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032.
Abstract
Radiation therapy (RT) has traditionally been considered a useful
additional therapy for patients with acromegaly not achieving
biochemical remission after surgery. However, recent evidence has
suggested that RT is not curative in most patients with acromegaly when
normalization of the serum insulin-like growth factor I (IGF-I) level
is used to define remission. Therefore, we evaluated the success of RT
based on IGF-I level in the 47 patients who received RT as part of
their treatment from the cohort of 161 patients with acromegaly seen by
us between 1981 and 1999. Four patients in whom no post-RT IGF-I level
was available were excluded from the analysis. Of the remaining 43
patients, 32 patients received external beam RT, 6 received
fractionated stereotactic radiosurgery, 4 received 
-knife RT, and 1
received proton beam RT. The most recent IGF-I levels in these 43
patients, obtained a mean of 5.2 yr post-RT (range, 0.8–13.2 yr), were
compared to age-adjusted normal ranges.
IGF-I levels were normal in 17 patients (39.5%) without the addition of medical therapy. The percentage of patients with a normal IGF-I level generally increased with time post-RT; 27% of patients less than 6 yr post-RT, but 69.2% of patients 6 yr or more post-RT had normal IGF-I levels. Using the more traditional criterion for cure, a random GH measurement, 74% of patients had a GH level below 5 ng/mL, and 44% had a GH level below 2.5 ng/mL and would have been considered in remission based on these criteria.
We conclude that with time RT remains a useful adjunctive treatment for many patients with acromegaly. RT should be considered along with appropriate medical therapy in selected patients who do not achieve normalization of IGF-I level after surgery or for those resistant to medical therapy.
RADIATION THERAPY (RT) has been used for many years as adjuvant therapy for patients with acromegaly who have failed surgical and in some cases also medical therapy (1, 2, 3, 4, 5, 6, 7, 8, 9, 10). This clinical practice has been supported by data from many studies documenting the lowering of GH levels with time after conventional external beam RT; more than 75% of patients with acromegaly achieve a GH level below 5 ng/mL by 15 yr after RT (10). However, the validity of studies assessing the outcome of RT for acromegaly based on GH levels alone can be questioned. Random GH levels are not adequately representative of disease activity in acromegaly. It has also become clear that excess mortality persists at the GH levels once considered representative of cure (11). In addition, the use of sensitive GH assays in conjunction with measurement of insulin-like growth factor I (IGF-I) levels has shown that some patients had been misclassified as cured by older GH criteria and has provided evidence that our criteria for cure still need refinement (12, 13, 14, 15).
By contrast, the IGF-I level, as an integrated measure of 24-h GH secretion, is now considered to be most representative of overall disease activity in patients with acromegaly and should normalize for cure to be established (13, 16, 17, 18). Some data also suggest that normalization of IGF-I levels will be associated with a return of the excess mortality of patients with acromegaly to that of the general population (19). Thus, mounting evidence for the importance of achieving normalization of the IGF-I level and its widespread clinical use have called for a reassessment of outcome of RT based on this biochemical parameter. A recent study, however, has suggested that RT does not normalize IGF-I levels in most patients with acromegaly (20) and has raised questions about the role of RT in the treatment of acromegaly. To further investigate these findings, we examined the outcome of RT in our cohort. We report here a retrospective analysis in 43 patients who underwent RT as part of their treatment for acromegaly, using normalization of IGF-I as the primary determinant of cure.
Subjects and Methods
Subjects
Between 1981 and 1999, 161 patients were seen by at least 1 of the authors for treatment of acromegaly. All patients had preoperative biochemical documentation of acromegaly, with an elevated IGF-I level and/or a GH level above 5.0 ng/mL, and all patients had pathological confirmation of a GH-secreting pituitary adenoma at surgery.
Forty-seven patients in our cohort underwent RT as part of their treatment in most cases because of persistent disease after surgery. Post-RT IGF-I levels could not be obtained for four patients, and these patients were excluded from further analysis. Thus, 43 patients were included in the final analysis, 23 women and 20 men. The mean age at completion of RT was 41 yr (range, 21–76 yr). The mean follow-up period from completion of RT to most recent IGF-I value was 5.2 yr (range, 0.8–13.2 yr).
Endocrine testing
IGF-I levels post-RT were obtained by us or from each patient’s primary physician; the most recent IGF-I values available were used to determine the outcome of RT. Seven patients were taking octreotide at the time of testing and had normal IGF-I levels; these patients were considered to not be in remission in analysis of the data. Pre-RT IGF-I values were available for 26 patients who were not receiving medical therapy. In these 26 subjects, IGF-I values were also expressed as a percentage of the upper limit of the age-adjusted normal range for each laboratory, and pre- and post-RT values were compared by paired t test.
Basal GH levels were available for 40 patients who had simultaneous GH and IGF-I levels measured. GH data were analyzed in the 34 of these 40 patients who were not receiving medical therapy at the time of testing. In addition, 15 patients underwent a fasting 100-g oral glucose tolerance test to determine GH levels.
Hormone assays
IGF-I. IGF-I levels were measured in 30 of the 43 patients (70%) by acid-ethanol-extracted RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA). In 13 patients IGF-I levels were assessed by a variety of other laboratories. Each laboratory’s reported age-adjusted and gender-adjusted normal ranges of IGF-I levels were used in interpreting the results.
GH. Basal GH levels were measured by polyclonal RIA in a variety of laboratories in 40 patients. In 15 patients who underwent an oral glucose tolerance test, GH was also measured by a highly sensitive immunoradiometric assay (IRMA) with a sensitivity of 0.05 ng/mL (Diagnostics Systems Laboratories, Inc., Webster, TX).
Radiation therapy
Forty-one of the 43 patients included in the final analysis underwent pituitary RT after surgery, 1 patient had surgery 6 months after RT, and another had a first surgery 3 months before RT and a second surgery 3 yr after RT.
Thirty-two patients received conventional external beam irradiation.
The mean dose delivered was 47.4 Gy (range, 45–54 Gy); the mean number
of fractions given was 26 (range, 25–30), and the mean dose per
fraction was 1.8 Gy (range, 1.7–2.0 Gy). Six patients received
stereotactic radiotherapy using a linear accelerator; 5 of the 6
patients received 5 fractionated weekly doses of 6.0 Gy for a total
dose of 30.0 Gy, and the other patient received 1 dose of 18.0 Gy.
Thus, the mean dose for these 6 patients was 28 Gy (range, 18–30 Gy).
Four patients received their radiation therapy via a -knife; the
mean dose administered was 48 Gy (range, 44–53 Gy). One patient
underwent proton beam RT. The RT was performed at a variety of medical
centers.
Results
Of the 43 patients, 17 (39.5%) patients not receiving medical
therapy at the time of testing had a normal serum IGF-I level at the
most recent follow-up. The percentage of patients in remission
generally increased with time from RT (Fig. 1
). For example, 9 of the 13 patients
(69.2%) seen at least 6 yr after RT had a normal IGF-I level off
medical therapy. In 26 patients in whom pre-RT IGF-I values were also
available, IGF-I levels declined from a mean before RT of 268 ±
32% (range, 116–718%) of the upper limit of normal to 122 ±
12% (range, 38–316%) of the upper limit of normal after RT
(P < 0.001; Fig. 2).
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-knife RT (mean follow-up, 1.2 yr), and in 0 of 1
patient evaluated 3.6 yr after proton beam RT.
Cure rates based on GH criteria were higher than by IGF-I criteria. In
our series, 74% (25 of 34) of patients would have been considered in
remission based on a random GH measurement below 5 ng/mL by RIA,
whereas 44% (15 of 34) of patients had a random serum GH measurement
below 2.5 ng/mL by RIA. However, when comparing simultaneous
GH and IGF-I levels in a subset of our patients, we found that
13% (2 of 15) of patients whose basal GH was below 2.5 ng/mL
and 36% (9 of 25) of patients whose basal GH was below 5.0 ng/mL had
elevated IGF-I levels and would have been falsely classified in
remission by GH criteria alone. In a smaller subset of 15 patients, GH
levels determined by highly sensitive IRMA as well as IGF-I levels
could be compared (Table 1). As we have
reported previously, there was overlap in the basal and postglucose GH
levels in subjects whose disease status was defined by IGF-I level.
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Discussion
IGF-I levels are now considered to be the single best available biochemical marker of disease activity in acromegaly and should normalize for cure to be established (13, 14, 15, 16, 17, 18). We set out, therefore, to determine the rate of IGF-I normalization in our series of patients and how this compared with cure rate, as assessed by traditional GH criteria and with other recent series. We found that 39.5% of patients who were not receiving medical therapy had a normal IGF-I level at a mean of 5.2 yr after RT. This figure is higher than that in a previous study (20) and closer to that in two other reports (19, 21). Barkan et al. found that only 5% (2 of 38) patients who underwent external beam or proton beam RT between 1975 and 1996 achieved a normal IGF-I level (20). In other reports IGF-I levels normalized in 42% (19 of 45) of patients followed for a mean of 6.7 yr (19) and in 51% (34 of 67) of patients followed for a mean of 11 yr (21) after RT for acromegaly.
A number of factors may contribute to the differences in outcomes observed in various series. One important factor is the rate of follow-up; a high rate of follow-up of the cohort is necessary to eliminate possible selection for those patients who return for further treatment because of poor outcomes. We were able to obtain a recent follow-up for 43 of 47 (91%) of patients in our cohort who have had RT for acromegaly, which is similar to some reports (19, 21), but higher than that in another recent series (20). Uniformity of biochemical testing is also an important determinant of the accuracy of the various studies (22); we were able to obtain follow-up with a high quality IGF-I assay in the majority of patients. Another important consideration may be when RT was performed. Because RT techniques have improved over the last 20 yr in terms of dose fractionation and distribution and because of imaging techniques that can better define tumor margins (23), it may be misleading to compare the results obtained in patients who underwent RT in the 1970s to those who received it more recently. All of the patients in our study received RT after 1980, and 67% received it since 1990; perhaps older RT techniques could have adversely affected the outcome of some series with longer follow-up periods. Follow-up periods were as long as 19 yr (20) or 26 yr (21) in other recent studies. It is also unclear whether prior surgery affects the outcome of RT. Some work suggests lower cure rates than expected by GH criteria for patients who did not have surgery before RT (24). All of our patients had surgery in addition to RT, which is similar to the distribution in other studies. Although 2 patients in our series had surgery after RT, both patients had elevated IGF-I levels at the most recent follow-up and would not account for a more favorable outcome in our series. Of the 38 patients studied by Barkan et al., only 2 had RT without surgery (20).
Remission rates after the different forms of RT in our series differed,
but this finding must be interpreted cautiously because of two factors;
the follow-up periods and the number of patients who received each type
of RT varied considerably. There are several other larger series
reporting the use of stereotactic radiosurgery, including the
-knife, to treat GH-producing pituitary adenomas (25, 26, 27, 28, 29, 30). In one
series examining -knife RT, the average time to normalization of
both GH and IGF-I in patients treated with the -knife was shorter
than that in patients treated with fractionated RT (25), but not all
other studies have confirmed this yet (26, 27, 28, 29, 30). The fact that RT was
performed at a variety of medical centers and with varying techniques
is a limitation of ours and other series.
Similar to other series, our results show a trend toward a greater efficacy with time from RT. This pattern resembles the trend of an increasing normalization rate of GH levels as number of years post-RT increases (10). Our study and others have been retrospective series, but a longitudinal study would best be able to characterize the time course of biochemical efficacy of RT for acromegaly. The slow rate of biochemical response to RT as demonstrated by many studies is the major disadvantage to the use of RT for the treatment of acromegaly.
Not unexpectedly, the cure rate based on an older GH level cut-off of
5.0 ng/mL or less was higher than when normalization of IGF-I alone was
used to define remission. Interestingly, using a GH cut-off of 2.5
ng/mL by RIA produced only a slightly higher percentage of patients
considered cured compared to using a normal IGF-I level (44%
vs. 39.5%), but some patients with GH levels below 2.5
ng/mL did not have normal IGF-I levels. Active acromegaly, as
demonstrated by persistently high IGF-I levels, can be found even with
GH levels below 1.0 ng/mL (15). After RT, other alterations in GH
feedback regulation may make the interpretation of GH dynamic testing
more difficult (31). It is not surprising, therefore, that the true
efficacy of RT may be better represented by the IGF-I level, which we
believe to be a better parameter of overall disease activity than prior
GH criteria. As we reported previously, there was overlap in GH levels,
including those measured with a highly sensitive GH IRMA, in the cured
and not cured groups of patients (Table 1
). Further studies in a large
number of patients will be needed to determine the nadir GH level (as
measured with a highly sensitive GH assay) that will correlate best
with IGF-I level and most accurately classify disease status in
patients with acromegaly.
The development of hypopituitarism is the most prevalent complication
of the use of RT for acromegaly (10). Our figure of a 32% incidence of
new hypopituitarism after RT is similar to that of several other
previous reports using conventional external beam (10, 32, 33) and
stereotactic radiosurgery with a linear accelerator (34, 35). In one
series, however, new hypopituitarism developed in up to 67% of
patients after RT (36). In studies of -knife therapy for acromegaly,
the rate of new hypopituitarism seems to be lower (25, 27), but the
mean follow-up after treatment is relatively short in some studies, and
long-term follow-up studies are needed to determine whether this holds
true. Other potential, but very rare, complications of RT that we did
not observe in our series are the risk of visual loss and second brain
tumors (37, 38, 39).
In summary, with time, radiotherapy is an effective adjuvant therapy
for acromegaly; in our series, most patients who have been followed for
more than 6 yr will achieve normalization of IGF-I level. Surgery
remains the initial treatment of choice for most patients with
acromegaly. In those patients for whom surgery is not curative, medical
therapy is typically given. Given the expanding array of medical
therapies now or soon to be available for the treatment of acromegaly,
it is likely that most patients will be controlled medically. However,
in those patients with large residual or invasive tumors or those
resistant to medical therapy, RT may be an important treatment
alternative. Given the long lag time to normalization of IGF-I level,
medical therapy until RT takes effect will be necessary for most
patients. It remains to be determined, as the data from more studies
become available, whether newer forms of RT such as the -knife will
provide greater or earlier efficacy for the treatment of acromegaly.
Therefore, the results of our series provide evidence that RT can still
play a role in the treatment of acromegaly even when the IGF-I level is
used to define cure.
Footnotes
1 This work was supported by NIH Grants K08-DK-02561 (to P.U.F) and
RR-00645 (to the Columbia General Clinical Research Center). Presented
in part at the 81st Annual Meeting of The Endocrine Society, San Diego,
California, June 12–15, 1999 (Abstract P3-652). 
Received October 18, 1999.
Revised January 15, 2000.
Accepted January 18, 2000.
References
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