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From the Clinical Research Centers |
Pituitary and Neuroendocrine Center, Division of Endocrinology and Metabolism, Department of Internal Medicine (A.L.B., I.H., C.A.J., R.D.F.), Division of Neurosurgery, Department of Surgery (W.F.C.), and Department of Radiation Oncology (H.M.S., K.J.D.), University of Michigan Medical Center, and the Department of Veterans Affairs Medical Center, Ann Arbor, Michigan 48109
Address all correspondence and requests for reprints to: Ariel Barkan, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, 3920 Taubman Center, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0354.
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Abstract |
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We reviewed hospital charts of 140 patients with acromegaly seen in our institution between 1975 and 1996. Data on plasma GH and IGF-I were extracted and tabulated longitudinally together with the information about the concomitant medical therapy. We included data from the patients who received radiotherapy as a part of their treatment and whose IGF-I was monitored for more than 1 yr afterward. To avoid the potential bias, the data for patients who were referred to us for medical therapy, having failed radiation elsewhere, were excluded.
A total of 38 datasets were submitted for the final analysis. The average follow-up was 6.8 ± 0.8 yr (range, 1–19). Only 2 patients achieved age- and sex-adjusted normal IGF-I levels while off medical therapy. Noncured patients had a mean plasma GH level of 4.6 ± 1.1 µg/L but still elevated plasma IGF-I levels (219 ± 26% of the upper normal limit) at the last follow-up visit. A random GH concentration below 1.5 µg/L was associated with a pathologically high plasma IGF-I concentration in 43% of instances.
Radiotherapy appears to be ineffective in normalizing plasma IGF-I levels in acromegaly. A multicenter study to reevaluate the future use of this modality in patients with acromegaly is warranted.
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Introduction |
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Over the past few years, it has become clear that the criterion of 5 µg/L is very liberal. Plasma GH fluctuates widely throughout the day, and the majority of GH concentrations in normal individuals are below 0.2 µg/L (10). Measurement of plasma insulin-like growth factor I (IGF-I) was proposed for evaluation of acromegaly almost 20 yr ago (11). Plasma IGF-I is regulated primarily by the prevailing level of circulating GH and is responsible for the majority of the clinical manifestations of acromegaly (12). Due to its longer half-life, plasma IGF-I reflects integrated GH secretion over the previous day (13) and is elevated even in patients with minimally active disease (14, 15). Measurements of plasma IGF-I currently are the "gold standard" for assessing the efficacy of medical therapy for acromegaly (16, 17, 18, 19).
Unfortunately, at the time when the previous studies of radiotherapy were conducted, plasma IGF-I assays were not widely available. Thus, we conducted a review of cases treated in our institution to provide the first analysis of the true efficacy of radiotherapy for acromegaly, using plasma IGF-I as a marker of disease control.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Plasma GH concentrations were measured over the years either by the RIAs with the stated limit of detection (1.5 µg/L) or by the immunoradiometric assay (Nichols Institute, San Juan Capistrano, CA) with a detectability level of 0.5 µg/L. For the purposes of this study, all GH data were treated similarly, and all unmeasurable plasma GH concentrations were assigned a value of 1.5 µg/L. Plasma IGF-I concentrations were measured by a variety of methodologies in different laboratories. For example, between 1985 and 1996, plasma IGF-I in our institution was measured in succession by the Nichols Laboratories, Smith-Kline Laboratories (Van Nuys, CA), Endocrine Sciences (Calabasas Hills, CA), and, finally, locally using kits purchased from Nichols Institute Diagnostics. Also, patients followed elsewhere had their IGF-I measured by A.R.U.P. (Salt Lake City, UT), American Medical Laboratories (Chantilly, VA), Mayo Medical Laboratories (Rochester, MN), Metpath (Teterborough, NJ), and Roche Biochemical Laboratories (Burlington, NC). The normal age- and sex-adjusted ranges differed widely. For example, the upper limit of the normal range for a 55-yr-old man was reported as 1.9 U/mL or 318 µg/L by the old and the current Nichols assays, respectively; as 46.01 nmol/L by American Medical Laboratories; as 178 µg/L by Smith-Kline; as 100 µg/L by the Mayo Medical Laboratories; as 463 µg/L by Metpath; as 290 µg/L by the Roche Laboratories; and as 449 µg/L by Endocrine Sciences. Thus, the absolute reported IGF-I values could not be compared directly between the patients or even in the same patient during a long term follow-up. To normalize the data, we expressed every plasma IGF-I value as a percentage of the upper limit of the normal age- and sex-adjusted range as reported by the actual laboratory.
Most of the patients were treated with bromocriptine and/or octreotide to lower GH hypersecretion while awaiting its normalization postradiotherapy. Normal IGF-I (and their corresponding GH) values during medical therapy were omitted from the final analysis. In these patients, the medications were withdrawn periodically, plasma GH and IGF-I were measured 2–3 weeks later, and these values were included in the analysis. Persistently elevated plasma IGF-I (and their corresponding GH) values during medical therapy were included in the final analysis.
Statistical analysis
Data were analyzed by paired or unpaired t test with Bonferroni’s protection when appropriate. Data are shown as the mean ± SE. P < 0.05 indicated statistical significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Despite differences in some
individual pairs of data, overall there was a good correlation (r
= 0.89; P < 0.0001) between the mean 24-h GH
concentration and a single GH value at 1600 h. Thus, a single GH
value can serve as a valid estimate of the magnitude of GH
hypersecretion in patients with active acromegaly. The entire set of
the actual plasma GH and IGF-I concentrations in all 38 patients is
shown in Fig. 2. Data on presurgery IGF-I
(and their corresponding GH) values were available for 22 patients.
Surgery alone decreased plasma GH from 78.3 ± 25.7 µg/L (range,
8–544 µg/L) to 13.1 ± 3.4 µg/L (range, 1.5–59.4 µg/L;
P < 0.001). Plasma IGF-I declined from 442 ±
29% of the upper limit of normal (ULN; range, 230–755%) to 289
± 23% of the ULN (range, 104–416%; P < 0.001).
Approximately 2 yr after radiotherapy, 11 of 20 patients (55%) had
random GH measurements below 5 µg/L off medical therapy; after 5 yr,
this proportion increased to 65% (11 of 17). Only 2 patients achieved
persistently normal IGF-I concentrations off medical therapy 4.5 and 5
yr after radiation. Another 3 patients exhibited high normal IGF-I
(90–98% of the ULN) on 1 occasion each, but these were followed by
elevated values on subsequent visits. Thus, only 5% of the patients
could be regarded as truly cured by the radiotherapy. To ascertain the
time course of IGF-I and GH decline postradiation, we analyzed the data
obtained off medical therapy (Fig. 3) in
the 20 patients for whom preradiotherapy IGF-I data were available. The
postradiation GH and IGF-I values within the intervals 0–2, 2–5, and
5–10 yr were expressed as percentages of the respective preradiation
values. In each patient, only the latest value within each time
interval was included. Plasma GH declined gradually to 41 ± 8.5%
at 3.7 ± 0.3 yr and to 19.3 ± 4.4% of the preradiation
values at 7 ± 0.7 yr. In contrast, plasma IGF-I declined only
modestly to 77 ± 9.9% and 83.2 ± 10.9% of the
preradiation values at the same time intervals. This analysis included
the data from the two cured patients. Individual dynamics of plasma GH
and IGF-I in these patients are shown in Fig. 4. To ascertain whether IGF-I declined in
the noncured patients, we extracted data from the 17 patients whose
off-medication IGF-I and GH levels were measured preradiation and at
least 2 yr postradiation. At their last follow-up visits (4.5 ±
0.5 yr), plasma GH declined from 10.1 ± 1.7 to 4.6 ± 1.1
µg/L (P < 0.001), and plasma IGF-I declined from
257 ± 29% to 219 ± 26% of the ULN (P
< 0.05).
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Discussion |
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We undertook this study to ascertain the rate of normalization of plasma IGF-I after pituitary irradiation in patients with acromegaly. The number of patients studied and the duration of follow-up are similar to those in the previously reported series (1, 2, 3, 4, 5, 6, 7, 8). We found that pituitary irradiation was very effective in lowering plasma GH, with about 80% reduction achieved between 5–10 yr of follow-up. Between 55–65% of the patients had plasma GH below 5 µg/L 5 yr after the radiation, which is even better than the 25–30% rate reported in earlier studies (9). This is due to the efficient surgical debulking of the tumor, so that a third of our patients had plasma GH below 5 µg/L even before radiation. Despite the salutary effects of radiation on plasma GH, it was disturbingly unsuccessful in normalizing plasma IGF-I; only 2 of 38 patients achieved normal IGF-I values. It appears, therefore, that plasma GH levels significantly lower than what was previously thought are sufficient to maintain pathologically high IGF-I levels. The single GH estimate in our study is not as accurate a reflection of the prevailing GH milieu as the mean of four or five values used by other groups (3, 4, 5, 7). Even though a single GH measurement faithfully reflected the prevailing GH milieu in untreated patients with mean daily GH level above 5 µg/L, its diagnostic utility was lost in the low range. In almost half of the instances when a random GH measurement was reported to be below 1.5 µg/L, the concomitant IGF-I level was still elevated. This is similar to the postoperative data reported by Lindholm et al. (22), who found invariably low IGF-I values in patients with GH below 0.5 µg/L, but a 62% rate of elevated IGF-I values associated with GH between 0.5–5.0 µg/L. This discrepancy between low GH and elevated IGF-I probably explains the persistence of acromegalic cardiomyopathy (22) and arthropathy (24) in patients thought to be successfully treated by radiotherapy. Recently (25, 26), a mean daily GH level of 2.5 µg/L was proposed as a cut-off below which acromegalic complications were unlikely to occur. However, the mortality rate in these patients, although seemingly statistically normal, was still 42% higher than that expected in the normal population (25). It is likely that there was still a considerable heterogeneity in the outcome within the low GH group between the patients with low and high IGF-I levels.
Even though as a group plasma IGF-I levels did not decline substantially over time, in some patients they were markedly lowered (albeit not normalized) years after radiotherapy. Although a direct answer is not yet available, some circumstantial evidence suggests that even mild elevation of IGF-I may be undesirable. First, in GH-treated adult hypopituitary patients or the elderly, an increase in IGF-I into the young normal range is associated with a high incidence of the side-effects characteristic of acromegaly: carpal tunnel syndrome, fluid retention, arthralgia, hyperinsulinemia, hyperglycemia, and hypertension (27). Second, the age adjustment of IGF-I values by the laboratories usually stops at 55 yr. As plasma IGF-I in normal subjects continues to decline beyond that point as a consequence of aging (28, 29), the reported modest increase in IGF-I in a 65- to 75-yr-old individual may be, in fact, quite significant in relation to his/her actual age. In our study, 31% of patients were older than 55 yr during the long term follow-up. The exclusion of the 12 patients treated elsewhere did not introduce a bias in favor of our results; on the contrary, had these patients been included, the rate of normalization of IGF-I postradiotherapy would have fallen from the reported 5.2% (2 of 38 patients) to 4% (2 of 50 patients).
Most of our patients were treated with conventional external pituitary
irradiation. The differences in the doses administered and in the
techniques employed by different treatment sites are unlikely to be of
major importance. Radiation doses as low as 20 Gy and the standard
doses of 45–50 Gy produce identical degrees and rates of GH decline
(3, 30). None of our patients treated with a proton beam technique
achieved normal IGF-I levels. This technique was used to treat almost
500 patients with acromegaly (31), but assessment of its efficacy based
on the plasma IGF-I data is not available. In the only study directly
comparing the proton beam and conventional radiation methods (32), the
techniques yielded identical results in terms of GH suppression, but a
higher incidence of pituitary failure and oculomotor palsies was seen
in the proton beam group. Stereotactic radiosurgery of pituitary tumors
using a 
-knife will probably become more widespread in the near
future due to commercial availability of the equipment. Early data show
no advantage of this technique over the conventional methodology in
normalizing plasma GH levels in patients with acromegaly (33, 34). Even
the previously used interstitial pituitary irradiation employing direct
90Y bead implantation and delivering 500–1500 Gy to the
tumor bed does not appear to be any better in terms of GH suppression
than conventional external radiotherapy (35).
In view of our data, should radiotherapy be used at all? In the past, when no alternatives were available, the answer would be unquestionably in the affirmative. Even if it is only minimally effective in normalizing plasma IGF-I, radiotherapy may prevent regrowth of the tumor remnants (3, 5, 6). The current availability of pharmacological agents, especially the long acting somatostatin analogs (17, 36, 37) that are capable of suppressing GH hypersecretion, normalizing plasma IGF-I, and shrinking pituitary somatotropinomas, may obviate the need for radiotherapy in patients noncured by surgery. Whether there is a subset of pituitary somatotropinomas exquisitely sensitive to radiation (38, 39) is unknown, and this question can be answered only when the biology of these tumors is better understood. On the other hand, Newman et al. (40) have shown that the rate of normalization of plasma IGF-I with octreotide related inversely to the pretreatment GH levels and that higher drug doses were needed for the patients with high plasma GH levels. Perhaps, radiation may be useful in octreotide-unresponsive patients with high GH levels who may become drug responsive when their GH concentrations decline significantly as a result of radiotherapy.
In summary, our data confirm the previously reported efficacy of pituitary irradiation as a suppressor of GH hypersecretion in acromegaly. However, despite this effect, plasma IGF-I remained elevated in 95% of the patients even after a long follow-up. The relatively low number of subjects in this study and the variability of IGF-I assays require a degree of caution in reaching final conclusions. A need for a multicenter study to verify these results in a methodologically uniform protocol involving a larger number of patients is obvious. If the true efficacy of radiotherapy is as low as that seen in our study, the utility of this treatment should be reassessed.
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Acknowledgments |
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Footnotes |
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Received April 23, 1997.
Revised June 3, 1997.
Accepted June 9, 1997.
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References |
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, Values obtained off medical therapy;
•, values obtained during medical therapy (for details see
Materials and Methods). The shaded area
for GH is less than or equal to 5 µg/L; the shaded
area for IGF-I is less than or equal to the ULN of the age- and
sex-adjusted range.
, P <
0.05 (vs. preradiation value).
