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Federation of Endocrinology, Diabetes, Metabolic Diseases and Nutrition (F.C., D.T., P.J., B.C.-D., T.B.), Department of Neurosurgery and Functional Neurosurgery (M.T., J.R., H.D.), and Department of Neurosurgery (H.D.), Hôpital de la Timone, Centre Hospitalier Universitaire de Marseille and Faculté de Médecine, Université de la Méditerranée, 13385 Marseille, France; Department of Endocrinology and Metabolic Diseases (J.-M.K.), Centre Hospitalier Universitaire de Rouen, 76031 Rouen, France; and Department of Endocrinology and Reproductive Diseases (P.C.), Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre and Faculté de Médecine Paris XI, 94270 Le Kremlin Bicêtre, France
Address all correspondence and requests for reprints to: Prof. T. Brue, Department of Endocrinology, Hôpital de la Timone, 264 rue St. Pierre, cedex 5, 13385 Marseille, France. E-mail: thierry.brue{at}mail.ap-hm.fr.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Objective: The objective was to perform an analysis of long-term hormonal effects and tolerance of gamma knife radiosurgery.
Design: Eighty-two patients were prospectively studied over a decade, with a mean follow-up of 49.5 months.
Setting: All patients were treated at the Department of Functional Neurosurgery of Marseille, France.
Patients: The patients included 82 with active acromegaly, of whom 63 had previous transsphenoidal surgery.
Intervention: Intervention included radiosurgery using the Leksell Gamma Unit B model.
Main Outcome Measures: Remission was diagnosed when mean GH levels were less than 2 ng/ml and IGF-I was normal for age off somatostatin agonists (at least 3 months).
Results: Seventeen percent of the patients were in remission without any treatment. Twenty-three percent previously uncontrolled on somatostatin agonists fulfilled the same criteria after gamma knife while maintained on medical treatment. Initial GH and IGF-I levels off somatostatin agonists were significantly higher in uncured than in remission group (P = 0.01 and 0.047, respectively). Withdrawal of somatostatin agonists at the time of radiosurgery had no incidence on the outcome. No significant difference was found in success rate whether patients had previously been treated or not. Long-term side effects included complete (n = 2) or partial (n = 12) hypopituitarism diagnosed 1–7 yr after gamma knife.
Conclusions: Gamma knife radiosurgery may represent a therapeutic approach in patients with moderate initial or residual GH hypersecretion.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The aim of the present study was to analyze our 10-yr experience with GK in a single radiosurgical center as either first nonmedical treatment or an adjunctive treatment after transsphenoidal surgery for acromegaly. We thus evaluated the clinical and hormonal outcome in 82 patients, with a mean follow-up of 49.5 months.
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Patients and Methods |
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A total of 99 patients with active acromegaly were consecutively treated with GK between February 1993 and May 2003 at the Department of Functional Neurosurgery of Hôpital de la Timone (Marseille, France). The diagnosis of acromegaly was based on the association of clinical features of the disease, elevated baseline plasma GH not suppressible less than 1 µg/liter after a glucose load, and increased IGF-I levels. Active disease was defined on the basis of GH levels in excess of 2 ng/ml and elevated age-adjusted IGF-I. These patients had been referred from different centers in France (n = 89, 23 centers) and abroad (n = 10, 6 centers). Each center agreed to monitor the patients’ outcome according to the standardized investigation described below. Immediate preradiosurgical and postradiosurgical evaluations were performed in the same Endocrinology Department in Marseille. In the present study, we did not analyze data from the 10 patients referred from foreign centers and from seven French patients who were all lost to follow-up. For data analysis, 82 patients were thus entered into this prospective study. Sixty-three of them were treated after unsuccessful transsphenoidal surgery. Two also previously received conventional radiotherapy. Nineteen patients had received only medical treatments (somatostatin or dopamine agonists) before GK in case of unresectable adenomas (such as small intrasellar adenomas with laterosellar extension), of contraindication (due to the patient’s general condition), or of refusal of surgery. Only two patients had two consecutive GK.
At the time of GK, 42 patients (51.3%) were treated with somatostatin agonists. In the others, the treatment with somatostatin analogs was discontinued at least 3 months or 2 wk before surgery for long-acting and sc forms, respectively. In the only patient treated with cabergoline, treatment was stopped 6 wk before the procedure.
Radiosurgical procedure
For the radiosurgical procedure, the Gamma Unit B model of the Leksell stereotactic system (Elekta Instruments, Stockholm, Sweden) was used. Irradiation was performed by cross-firing the target region with 201 beams of cobalt-60 distributed within a spherical sector. To delineate the lesion, a Leksell stereotactic head frame was used to perform both magnetic resonance imaging (MRI) and computed tomography scans to minimize metric distortion. For 43 patients treated between February 1993 and July 1997, dose planning was done with the KULA dose-planning software, and, for the 39 remaining patients treated after May 2000, it was done with the more recent Leksell Gamma-Plan system (Elekta Instruments), 18 of them with Automated Positioning System. In each case, the decision to treat by GK was made collectively by the endocrinological, neurosurgical, and radiosurgical teams. Before treatment, the target was delineated by two neurosurgeons. The radiosurgical planning was conducted jointly as part of the GK procedure. The treatment parameters and dose selection varied with the tumor size and the proximity of the tumor to the optic apparatus. Tumor margin was covered within the 50% isodose line (margin dose). Multiple isocenters were used for all of the patients. The prescribed margin dose ranged from 12–40 Gy according to several factors: tumor volume, distance to the visual pathways, age, and previous treatment with fractionated radiotherapy. In all cases, the dose delivered to the optic chiasm and nerves was less than 9 Gy. In each case, marginal dose and dose delivered to the optic chiasm were recorded.
Clinical and hormonal evaluation
Each patient had a complete clinical and hormonal evaluation before GK, including ophthalmological evaluation using Goldman’s campimetry in the same department (Endocrinology Department, Hôpital de la Timone). Initial pre-GK levels of GH, IGF-I, ACTH, urinary free cortisol, prolactin, LH, FSH, testosterone or estradiol, TSH, and free T3 and T4 were determined. The same evaluation was then performed in each center 3 and 6 months after GK, every 6 months during 2 yr, and then yearly. During follow-up, GH and IGF-I levels were determined without any medical therapy or after at least 3 months of discontinuation of the treatment with somatostatin agonists. Results obtained earlier than 3 months or later than 3 months after the last injection of somatostatin agonists were considered as "on" treatment or "off" treatment, respectively. All pre-GK evaluations were performed off treatment, and at least one off treatment evaluation was performed during the first year after GK. Subsequently, intervals from 1–3 yr between off-treatment evaluations were decided on by each investigator according to clinical and hormonal evaluations on treatment. Patients were considered in remission if they had a mean GH level of less than 2 µg/liter and a normal age-adjusted IGF-I in off-treatment period. Those who were still on somatostatin agonists were considered uncured. Mean GH levels were determined by averaging eight hourly determinations between 0800 and 1500 h. GH and IGF-I concentrations were measured in the same laboratory immediately before and after GK in all patients and at each subsequent time point in the subset of patients (n = 42) followed in the Endocrine Department in Marseille. For these assays, the characteristics of the kits used were as follows. Serum GH levels were measured by an immunoradiometric assay (Immunotech, Marseille, France). The sensitivity is 0.05 ng/ml. The intraassay and interassay coefficients of variation are 0.66–1.5 and 13.1–14.0%, respectively. Serum IGF-I was measured by immunoradiometric assay (Immunotech). The sensitivity is 3 ng/ml. The intraassay and interassay coefficients of variation are 2.6–7.4 and 7.8–15.5%, respectively. All other determinations in the 22 other centers were done using commercial kits, and normal IGF-I values for each laboratory were taken into account.
Gonadotroph deficiency was defined by low plasma testosterone with nonelevated gonadotrophin levels in men, amenorrhea with low plasma estradiol and low or normal gonadotrophins in nonmenopausal women, and a lack of increased gonadotrophins in menopausal women. Corticotroph deficiency was established by subnormal response of cortisol during an insulin tolerance test (peak, <550 nmol/liter). The diagnosis of thyrotroph deficiency was based on low free plasma T4 level with normal or diminished plasma TSH.
Initial pituitary neuroimaging
Pituitary imaging was performed by MRI to define dose planning and to evaluate the limits of the lesion. The MRI sequences were coronal postgadolinium T1-weighted spin-echo (SE), T2-weighted SE, and, for most patients, a postgadolinium three-dimensional magnetization prepared acquisition gradient echo sequence.
Statistical analysis
Data were analyzed by parametric or nonparametric tests. Continuous data with normal distribution were analyzed by t test, and those with uneven distribution were analyzed by Mann-Whitney U test. Categorical data were analyzed by Fisher’s exact test. Longitudinal evaluations were performed by Kaplan-Meier method.
All statistical tests were two tailed, and P < 0.05 was considered significant.
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Results |
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Long-term effects of GK
At the end of the study, 17 patients (20.7%) had GH levels less than 2 ng/ml after an average of 35.3 months, and 21 patients (25.6%) had normal age-adjusted IGF-I after an average of 35.5 months. Based on both criteria, 14 of 82 patients (17%) were considered to be in remission after an average of 36 months (Fig. 1
and Table 1). Thanks to GK, 19 other patients (23%), considered uncured, were controlled by somatostatin agonists, whereas they were not controlled with the same treatment before GK. The two patients who had two consecutive GK treatments were not in the remission group.
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, the profile of GH decrease was similar in both outcome groups, who differed mainly by their initial hormone levels.
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Nineteen patients had GK as a primary nonmedical treatment. In Table 3 are presented the data on patients treated primarily with GK or treated with GK as adjunct of transsphenoidal surgery (n = 63). No difference was found between the two groups in terms of sex ratio, marginal dose, prevalence of macroadenomas, mixed or isolated secretion, and initial GH or IGF-I levels. The only difference was median age, reflecting that older patients often had contraindications to transsphenoidal surgery. GK given as a primary treatment or in adjunct of transsphenoidal surgery appears to be similarly effective, resulting in remission in 4 of 19 (21%) and 10 of 63 (16%) patients, respectively.
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At least one new pituitary deficiency was observed after GK in 14 patients: TSH deficiency in three (1, 3, and 7 yr after GK), ACTH deficiency in three (4, 5, and 6 yr after GK), LH and FSH deficiency in seven (between 5 and 7 yr after GK), and complete hypopituitarism in two (3 and 2 yr after GK). One of these two cases had conventional radiotherapy 10 yr before. The mean margin dose for these 14 patients was 27.5 vs. 26 Gy for patients without adverse effects (P > 0.05). One patient, previously treated by conventional radiotherapy, presented 1 month after GK (marginal dose, 40 Gy; dose delivered to the optic chiasm, <8 Gy) a trigeminal neuralgia that disappeared under carbamazepine treatment, and, 2 months later, the same patient displayed an impaired central visual field, which was alleviated after 3 months of steroid treatment. Overall, patients in remission (4.7 Gy) or uncured (4 Gy) did not differ in terms of dose delivered to the optic chiasm. Only a few patients had other transient adverse effects, including headaches or vomiting.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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With reference to these stringent basal GH and IGF-I criteria, 17% of the patients were in remission after an average of 36 months. In addition, based on the same criteria for GH and IGF-I levels, 23% of our patients (n = 19) achieved normal values after GK while treated with somatostatin agonists, whereas they were not controlled with the same treatment before. Although some of them might have been found in remission after an appropriate withdrawal of their medical treatment, we considered all of them as uncured. A longer follow-up would obviously be helpful to better evaluate the real effectiveness of GK. In this regard, 36 of our patients had a final off-treatment evaluation less than 36 months after GK, i.e. less than the average time for normalization. In a recent review of currently published series (18), 37.7% of 361 patients reported in 19 studies on 4–68 patients were found to have "complete response" to GK after a corrected median follow-up of 29 months. These series, however, differed widely in the types of tumors treated, the time between last administration of medical treatment and hormonal evaluation, and the criteria for biological remission, among other factors (9, 12, 13, 19). As underlined by another recent review (20), comparison of results is indeed difficult, mainly because of the variable criteria of cure: in the series with at least 10 patients and a median follow-up of 2 yr, success rates ranged from 20–96%. For example, in the single largest series on 68 patients in 2000 by Zhang et al. (13), patients were considered in remission when GH levels were less than 12 ng/ml, with a reported cure rate of 96%, whereas the second largest series reported a 25% remission rate based on normalization of age- and sex-matched IGF-I (21).
In contrast with a recent series with fewer cases (12), we found that initial plasma GH and IGF-I levels were significant predictive factors of outcome. Studies evaluating conventional radiotherapy (22, 23), surgery (24, 25), and somatostatin agonist therapy (26, 27) had also shown a better outcome in acromegalic patients whose pretreatment plasma GH levels were lower. The importance of initial hormonal level was confirmed in our study by the lack of difference in mean percentage of GH decrease between the two groups. In our patients, the final outcome depended mainly on GH and IGF-I initial levels off somatostatin agonists.
No difference in the outcome was observed between patients who received somatostatin agonists at the time of GK (20% patients in remission) and those who did not (15% patients in remission). This result does not confirm that of a nonrandomized study by Landolt et al. (28) concluding that the use of octreotide might decrease the efficacy of radiation therapy if used at the time of the procedure. Our results are in accordance with those of a recent study (12). Nevertheless, we share other investigators’ viewpoint that the treatment should be stopped shortly before GK (9, 13, 29): somatostatin agonist withdrawal indeed allows further comparison of off-treatment GH secretion.
In most patients, GK was indicated because transsphenoidal surgery failed to achieve remission. Our study found no significant difference in success rate whether GK was used as primary treatment (16%) or after surgery (21%). When performed in other centers as a primary treatment, GK was mainly used for microadenomas (9, 30). In our study, GK was used as primary treatment for microadenomas or small (10–15 mm) enclosed macroadenoma with laterosellar extension. The overall success rate remains low, in contrast with the study of Zhang et al. (13) in which more than 90% of patients treated with GK as primary nonmedical treatment were in remission. In that study, however, the criteria for remission were not precisely defined. To our knowledge, no other study has tried to compare the efficacy of GK as primary or adjunctive treatment on a large number of patients.
As observed in other series, our patients showed no increase in tumor volume (12, 31, 32). Tumor size, however, was not systematically monitored during long-term follow-up because the treatment was not primarily aimed at reducing tumor volume of usually small adenoma remnants. According to a recent review, tumor growth control was obtained in 92–100% of patients in all but one series (20).
The mean margin dose we used was 25.8 Gy. Higher success rates were observed with higher margin dose but with the drawback of more severe complications (13, 33). The doses used in our center were chosen by comparing the benefits of decreasing GH secretion and the risks of secondary effects, i.e. onset of new pituitary deficiency. Dose prescription was also adapted to the tumor volume, the distance separating the tumor and the visual pathway, the aggressiveness of the disease, and previous treatment.
We found a mean time of GH and IGF-I normalization of 36 months. This latency is longer than that in most series evaluating GK in acromegaly (13, 29, 33, 34). This difference can probably be explained by the higher marginal doses used by other researchers. Because GK patients often have lower pretreatment GH concentrations than conventionally treated patients and different types of tumors, it is difficult to compare the rate of decline between GK and conventional radiotherapy.
As shown in many studies (12, 16, 35), GK induces far fewer complications than conventional radiotherapy: 82% patients in our series had no side effects after GK vs. less than 50% with conventional radiotherapy in most studies (7, 36). A longer follow-up would probably be useful to better evaluate long-term effects of GK. In the present series, only one severe visual regressive trouble with cavernous syndrome was observed (dose to the optic chiasm, 8 Gy). As recommended previously (37), the dose delivered to the optic chiasm was inferior or equal to 8 Gy in all but one patient. A 9-Gy dose had to be delivered in one case because of the conformation and size of the lesion.
In conclusion, after a mean follow-up of more than 4 yr, GK was able to decrease GH and IGF-I concentrations to so-called "safe" (1) levels in 40% (17% in remission and 23% under somatostatin agonists) of our patients. This treatment was thus helpful in this population who had failed to achieve hormonal control with either surgery alone or a combined treatment of surgery and somatostatin agonists at the time of their irradiation. GK represents a safe and efficacious treatment in well-defined indications: small postsurgical remnants, sufficiently distant from the optic chiasm, and with moderate initial GH hypersecretion. In view of the high rate of IGF-I control obtained with currently available medical therapies, the place of GK in the treatment of acromegaly may, however, need to be redefined in the future. In particular, the cost effectiveness of a potentially lifelong medical approach will have to be compared in the context of each particular country with an approach that offers long-term remission and possibly cure in a subset of patients with acromegaly.
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Acknowledgments |
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Footnotes |
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Abbreviations: GK, Gamma-knife radiosurgery; MRI, magnetic resonance imaging.
Received February 11, 2005.
Accepted May 5, 2005.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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