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Octreotide May Act as A Radioprotective Agent in Acromegaly

Neurosurgery Section, Gamma Knife Unit, Klinik im Park, 8021 Zürich, Switzerland

Address correspondence and requests for reprints to: A. M. Landolt M.D., Neurosurgery Section, Klinik im Park, Seestrasse 220, 8021 Zürich, Switzerland. E-mail: 100023.1666{at}compuserve.com

	Abstract

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Clinical experience shows that an increasing number of patients undergoing radiation treatment for recurring acromegaly or acromegaly persisting after surgery are treated with octreotide. We, therefore, performed a follow-up study of patients undergoing stereotactic radiosurgery (Gamma Knife) to determine whether this medication has an influence on the ultimate result of radiation therapy in either a positive or negative sense. It has been suggested that the combination of radiation with antisecretory drugs may increase the effectiveness of radiation. A follow-up study of 31 patients suffering from recurrent acromegaly and acromegaly persisting after surgery, and who had been treated with stereotactic radiosurgery, showed that patients treated with octreotide at the time of radiation application simultaneously reached a normal level of growth hormone and insulin-like growth factor-I only after a significantly longer interval than patients who did not receive the drug. The two groups of patients did not demonstrate significant differences in the main clinical findings (age, sex, target volume, radiation dose, baseline growth hormone, and baseline insulin-like growth factor-I).

	Introduction

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THE GOALS of acromegaly treatment are normal levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I), as well as relief of compression effects of the pituitary mass on the surrounding nervous structures. Therapeutic options include microsurgery, treatment with antisecretory drugs, particularly octreotide, and radiation therapy. Flow charts for selecting the appropriate therapeutic cascade usually rank transsphenoidal microsurgery as first choice (1); followed by treatment with octreotide, particularly in younger patients in their fertile period of life (2, 3). Radiation treatment is used primarily in the older age group and often ranks as third choice (2, 3). However, an Endocrine Society Workshop, held in 1994, ranked the different types of radiation treatment (conventional x-irradiation, proton beam therapy, or Gamma Knife) as second choice (4).

Because of the rapid onset of its beneficial effect and its tendency to spare other endocrine functions (5), stereotactic radiosurgery has replaced fractionated radiotherapy in our institution for treating patients who suffer from recurrent disease or elevated GH that persists after surgery. We rank stereotactic radiosurgery as our first choice after failed surgery, because this treatment can control the disease permanently, whereas octreotide lowers GH and IGF-I only as long as the drug is used (6).

We see an increasing number of patients in our institution who, at the time of referral for stereotactic radiosurgery, are being treated with octreotide, particularly its new, long-acting, microencapsulated form (7). We decided to investigate, in a retrospective study, a possible influence of the drug on the result of stereotactic radiosurgery, because a cytocidal effect has been described in in-vitro experiments (8) and may therefore have a beneficial, therapeutic effect.

	Subjects and Methods

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Subjects

Thirty-one adult patients (16 women, 15 men) were followed for 0.3–3.7 yr (mean 1.6 yr) after Gamma Knife treatment of their adenoma remnants. Their relevant data are summarized in Table 1.

Methods

The dose planning was similar in all patients. The planning aimed to cover the tumor margin, as defined on the magnetic resonance image (MRI) with the 50% isodose, with 100% being the maximum dose within the target. The prescription dose was 25 Gy to the 50% isodose (tumor margin). This differed in only six patients: four received a lower dose (13.5, 15, 20, 22.5 Gy, all without octreotide treatment) because of previous fractionated radiotherapy, and two received a higher dose (30, 35 Gy, one octreotide treated). The target coverage (the percentage of the target volume covered by the prescription isodose) is quoted in Table 1.

We did not influence the decision of whether or not octreotide should be used on an individual patient. The previously initiated treatment scheme (with or without octreotide) was always continued. The patients were followed at 3-month intervals with determination of random GH and IGF-I levels. The patients were continued on octreotide until the IGF-I and GH values approached the upper limit of normal. The drug was then stopped or progressively decreased until the defined end point of the study (normal values without drug treatment) was reached.

Simultaneous lowering of GH below 5 µg/L and IGF-I below the age-related limit were used to define normalization in this group of adult patients. The cut-off IGF-I value was 492 ng/mL in the age group below 39 yr (7 patients), 360 ng/mL in the age group 40–54 yr (18 patients), and 290 ng/mL in the age group above 55 yr (6 patients).

GH and IGF-I were determined using commercial kits. Glucose tolerance tests with GH determination were not done routinely, but only in special cases if the random GH level did not allow a clear end-point definition.

The Imulite hGH, a solid-phase, two-phase chemiluminiscent enzyme immunometric assay (DPC, Diagnostic Products Corporation, Los Angeles, CA) was used to determine GH levels, and the Nichols Institute Diagnostics (San Juan Capistano, CA) assay by extraction was used to determine IGF-I determination.

The paired samples t test (for comparing pre- and postoctreotide hormone levels), the independent samples t test with variance analysis (for comparison of the groups of treated and untreated patients), Pearson’s -square cross tabulation (for comparison of nonparametric results), the cumulative distribution function (Kaplan-Meier), and the Cox regression model were used for statistical analysis.

	Results

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The initial basal GH and IGF-I levels of untreated patients and of those treated with octreotide showed a wide overlap. No significant differences could be detected (Fig. 1, groups A and C). However, we cannot exclude the possibility that some of the referring physicians may have had a tendency to treat patients with higher GH levels with octreotide (Fig. 1, group A left panel; Table 1). No similar tendency can be suspected if the IGF-I levels are reviewed (Fig. 1, A and C, right panel; Table 1). There is no apparent relationship between the pretreatment GH and IGF-I levels, as shown in Fig. 2.

View larger version (23K): [in this window] [in a new window]   Figure 1. Box plot (median, interquartile range, 1.5 x midspread, and outliers) of GH (left) and IGF-I values (right). A: before octreotide treatment, 9 patients; B: the same 9 octreotide-treated patients immediately before the Gamma Knife treatment; C: GH and IGF-I levels in the group of 22 patients not treated with octreotide.

View larger version (22K): [in this window] [in a new window]   Figure 2. Scatter plot of pretreatment GH and IGF-I levels of all patients.

The cumulative distribution function (Kaplan-Meier estimate) of the two groups (with and without octreotide) is shown in Fig. 3. The curves show a smaller fraction of the patients reaching normal GH and IGF-I levels in the group treated with octreotide at the time of stereotactic radiosurgery, with a progressive separation in the course of the follow-up period. A log-rank test shows a significant difference (significance, 0.042).

View larger version (26K): [in this window] [in a new window]   Figure 3. Cumulative distribution function (Kaplan-Meier estimate) showing endocrine control in 31 acromegalic patients treated with Gamma Knife radiosurgery while receiving or not receiving simultaneous octreotide medication.

	Discussion

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The radiation doses used in our groups of patients were quite uniform. The lower dose given to four patients (not treated with octreotide) would actually have favored the octreotide treated group.

The cumulative distribution function (Fig. 3) shows that octreotide, in contrast to the assumption based on in vitro studies mentioned above (8), can actually protect pituitary adenomas of acromegalic patients from the effects of stereotactic radiosurgery. This may be due to a reduction of the metabolic activity of the adenomas, caused by octreotide, as in the case of pentobarbital in normal brain (9), or as hypoxia and hypothermia in other tissues (10). This effect is of course undesirable in our patients.

Barkan et al. (11) found that pituitary irradiation suppressed GH hypersecretion in 38 patients suffering from acromegaly. Radiation led to GH levels below 5 µg/L in 55% after 5 yr, whereas only 2 of a total of 22 patients (9%) achieved normal IGF-I levels. This seems to contradict our previously published results, obtained with fractionated radiotherapy and with radiosurgery, using a lowering of both parameters into the normal range as criterion for success (12). The fact that Barkan and coworkers used a large variety of radiation treatment techniques with different beam energies (11) may explain part of this difference. Barkan used octreotide in some of his patients, which may have added to his failures.

Our observations led us to change our approach. We administer stereotactic radiosurgery only during an octreotide gap. The last injection of microencapsulated octreotide is given about 4 months before the Gamma Knife treatment. Three daily injections of 100 mg of the short-lasting formula are started 6 weeks later and continued until 2 weeks before radiation treatment. This allows a short gap in octreotide treatment (about 2 weeks). Octreotide is restarted immediately afterwards, with the usual precautions (7). Patients who are treated with the short-acting form of the drug undergo only a 2-week pre-irradiation break in the drug treatment.

Our results and conclusions are preliminary as indicated above, because the study is neither prospective nor randomized. These results must be confirmed by future studies involving not only stereotactic radiosurgery with the Gamma Knife but fractionated radiotherapy as well, because similar mechanisms may be active in all types of radiation treatment of pituitary adenomas causing acromegaly.

	Acknowledgments

 
We thank Professor J. Girard, Endocrinologic Laboratory, Basel, Switzerland, for the IGF-I determinations as well as for his advice in the interpretation of the results. We also thank Dr. U. Helfenstein, Biostatistics Center, University of Zürich, Switzerland, for his help and advice in the statistical evaluation of our data.

Received July 1, 1999.

Revised November 19, 1999.

Accepted December 1, 1999.

	References

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