Gamma knife radiosurgery for acromegaly--long-term experience.Jezkova J, Clin Endocrinol (Oxf). 2006 May;64(5):588-95. Third Department of Medicine, First Medical Faculty, Charles University, Prague, Czech Republic. OBJECTIVE: The Leksell gamma knife (LGK) is one of the treatment options for pituitary adenomas. We report on our long-term experience treating acromegaly using LGK. DESIGN: Since 1993 we have followed 96 acromegaly patients through periods of from 12 to 120 months. The mean follow-up period was 53.7 +/- 26.8 months. Seventy-two patients were treated with neurosurgery prior to LGK; for 24 LGK was the primary treatment. Thirteen patients were irradiated twice, due to persistent activity of the adenoma or its residue. Pituitary functions were tested at 6-month intervals, post-irradiation. The target tumour volume for radiosurgery was between 93.3 and 12 700 mm3 (median 1350 mm3). RESULTS: Fifty per cent of the patients achieved mean GH < 2.5 microg/l within 42 months, normalized their IGF-I within 54 months, and achieved GH suppression in the oral glucose tolerance test (oGTT) < 1 microg/l with normal IGF-I within 66 months. LGK effectiveness was dependent on initial adenoma hormonal activity (GH and IGF-I serum levels), not on the size of the adenoma. Patients with primary neurosurgery followed by LGK irradiation had better outcomes than those with LGK alone. Irradiation arrested all adenoma growth, causing tumour shrinkage in 62.3% of patients. Twenty-six developed hypopituitarism when irradiated by 15 Gy (or more) on functional peritumoral pituitary tissue. No hypopituitarism appeared using lower doses. CONCLUSIONS: In acromegaly, LGK is a useful adjunct to primary neurosurgery when treating post-surgical residues because it can limit the duration of medical therapy. It can be used as a primary therapy when neurosurgery is not possible. Outcome of gamma knife radiosurgery in 82 patients with acromegaly: correlation with initial hypersecretion.Castinetti F, J Clin Endocrinol Metab. 2005 Aug;90(8):4483-8. Epub 2005 May 1 Federation of Endocrinology, Diabetes, Metabolic Diseases and Nutrition, Hopital de la Timone, Centre Hospitalier Universitaire de Marseille and Faculte de Medecine, Universite de la Mediterranee, Marseille, France. CONTEXT: Because surgical and medical therapies of acromegaly all have specific limitations, radiotherapy has been used as an adjunctive strategy. Stereotactic radiosurgery has not yet been widely evaluated. 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. THE AIMS OF the treatment of acromegaly are to control tumor mass, to decrease hormonal levels of GH and IGF-I, and to alleviate clinical symptoms. Mortality in this disease can be reduced to that of a reference population if GH concentration is less than 1–2 µg/liter and IGF-I level is normal. Surgery remains the first-line reference treatment, but remission rate ranges from 44–74% because of the high prevalence of invasive tumors. Currently available somatostatin agonists control GH and IGF-I excess in about 50–60% of patients. The more recent GH antagonist pegvisomant, although usually able to decrease IGF-I levels to the normal range, has no antitumoral effect. Postoperative conventional fractionated radiotherapy controls the disease in 5–78% of cases but not before several years. Moreover, complications associated with radiotherapy have limited its usefulness; these include hypopituitarism, cranial nerve neuritis, visual-field defects, possible cognitive disturbances or increased cerebrovascular disorders, radiation-induced gliomas, and delayed brain necrosis. The adverse consequences of conventional radiotherapy have been attributed to the inability to accurately deliver adequate doses to a small tumor volume. Such a shortcoming may be addressed by using gamma knife radiosurgery (GK). The hallmark of this procedure is to use cobalt-60 to deliver a single high dose of high-energy beams targeted to stereotactically defined intracranial sites . This kind of radiation induces circumscribed cytotoxic effects on both neoplastic and vascular cells. Several authors have detailed their experience with GK, with efficacy ranging from 23–90%. Most studies reported on short-term effects of GK. Except for a study on few patients, no one, to our knowledge, has addressed the long-term effects of GK in acromegaly in terms of efficacy and tolerance and using strict criteria for assessing endocrinological remission. 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. 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. When GH hypersecretion persists in patients with acromegaly, the risk of mortality was reported to be up to three to four times higher than that of patients in whom GH secretion is controlled. Thus, one of the primary aims of the treatment of acromegaly is to normalize GH and IGF-I levels. For patients to be considered in remission, a recent consensus conference recommended achieving a GH plasma level lower than 2 ng/ml (or a suppressibility <0.3 ng/ml after oral glucose tolerance test) and a normal age-adjusted IGF-I level 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, 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 . As underlined by another recent review 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 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 In contrast with a recent series with fewer cases, we found that initial plasma GH and IGF-I levels were significant predictive factors of outcome. Studies evaluating conventional radiotherapy surgery , and somatostatin agonist therapy 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 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 Nevertheless, we share other investigators’ viewpoint that the treatment should be stopped shortly before GK : 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. 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 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. 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 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. 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 . 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, 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. 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, 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. Gamma-knife radiosurgery in
acromegaly: a 4-year follow-up study. RADIATION AS A treatment modality in pituitary adenomas is as old as surgical removal itself, being attempted in the first years of the past century. Currently it includes, besides fractionated conventional radiotherapy (RT), radiosurgery by gamma-knife (GK) and by specially modified linear accelerators and particle accelerators. In the last 30 yr transsphenoidal surgery has emerged as the initial treatment of choice for acromegaly, because it affords relative safety and the fast reduction of both hormone hypersecretion and tumoral mass. A variety of reasons, including technical difficulty, caution near sensitive structures, and tumor invasion of perisellar structures, hamper successful radical resection in at least 30% of operated patients. Medication, when effective and tolerated, has the drawbacks of a life-long and high cost treatment. RT has been regarded for a long time as the conventional method for adjuvant therapy. Rates of tumor growth control have been reported to vary from 72–97% , whereas control of hormonal hypersecretion is less consistent among different series, ranging from less than 5% of IGF-I normalization to 79%. The major drawbacks of RT include the long delay before the desired effect (often a decade) and serious side-effects, including a relatively high rate of hypopituitarism (13–100%), potential cerebral necrosis (0–3%) , neurobehavioral sequelae, low but still significant risks of optic neuropathy (1–2%) and induction of secondary tumor Radiosurgery, defined as highly precise circumscribed delivery of radiation to a target in a single session, performed by either GK or other stereotactic modalities, has been gaining acceptance in recent years to overcome the limitations of RT. The goal is to collimate selectively to the adenoma a high dose of radiation capable of influencing the growth of the tumor and hypersecretion, with negligible irradiation of surrounding normal tissue. The control of adenoma growth alone that would be enough in other tumoral indications is inadequate in the secreting pituitary adenomas. Radiosurgery of acromegaly to prove a valid therapeutic adjunct ought to correct deranged GH secretion and reverse morbidity and excess mortality by reducing GH below a threshold regarded as safe on the basis of epidemiological studies and decreasing IGF-I to age-adjusted concentrations. Methodology of GK treatment The neurosurgeon and the radiation physicist decided jointly the treatment isodose, the central dose, and the dose to the margin, with the foremost consideration being given to the radiation dose received by optic chiasm, that was always lower than 8 Gy. The median irradiated volume was 1.43 ml (range, 0.2–3.7). All patients were treated with multiple isocenters (mean, 8; range, 3–11). The 50% isodose was used in 27 patients (90%). The median margin dose was 20 Gy (range, 15–35). Patients were discharged from the hospital on the day after treatment. The relative role of alternative therapeutic options in acromegalic patients after surgical failure or in those unsuitable for or unwilling to undergo surgery is still debated, as no single treatment modality seems to afford a cure in all patients. Medical treatment with long-acting SA is very effective in most patients , but it is expensive and life-long. The efficacy of RT, denied by some researchers, is still controversial; its effects are very delayed and are often accompanied by a high incidence of side-effects, such as hypopituitarism, cerebral necrosis, and a low possibility of damage to optic pathways, neuropsychological impairment and perhaps development of secondary tumors Alternative modalities of radiation delivery, such as conformal radiotherapy by modified linear accelerators or particle accelerators, are still under evaluation or are not widely available, respectively. With these techniques the incidence of cerebral necrosis, neurocognitive dysfunctions, and optic damage is reported to be near nil. In the present series GK produced safe GH levels and age-matched IGF-I normalization in about 25% of our patients within 5 yr. The doses employed have uniformly been decided in a defensive approach, backcalculating from the dose considered safe to the sensitive structures (in the order: optic pathways, lower stem, oculomotor nerves, and healthy pituitary) and covering the adenoma by whichever dose was allowed. As a progressive unrestrained decline in hormonal levels was observed in most patients, a more prolonged follow-up is needed to better evaluate the real effectiveness of GK in acromegaly. A comparison with published results is difficult, because most series are either methodologically inhomogeneous or define cure by outdated or unspecified criteria . Only a few employ modern criteria of cure, as defined in the consensus conference the achievement of basal GH levels less than 2.5 µg/liter and suppressibility less than 1 µg/liter after oral glucose load combined with normal age-matched IGF-I levels. Using these criteria, published results about GH and IGF-I normalization vary from 82% (14 of 17) described by Ikeda to 60% (6 of 10) by Jackson and Norén , 43% (39 of 91) by Vladyka , and 29% (17 of 59) by Vance (. Landolt and colleagues) reported a mean time of IGF-I normalization of 2.9 yr in keeping with our results. GK was used in most patients as a second step after surgical failure, i.e. in a selected population, that might not be representative of the previously untreated acromegalic patients. The decrease in GH and IGF-I levels in the three patients treated with GK as primary treatment did not differ from that in surgically treated patients. However, this sample is too small to draw any definitive conclusion. For the comparison with results obtained by RT, it should be underlined that we did not perform a randomized comparative study of the two therapeutic modalities. The previous experience obtained by RT in acromegalic patients by the authors of this paper is not homogeneous; Epaminonda reported its effectiveness, but with the burden of hypopituitarism in a considerable portion of the series, whereas Cozzi observed its substantial failure, due perhaps to methodological differences in the irradiation procedure. It may be of interest that the percentage of patients who normalized IGF-I after a median follow-up similar to that of the present study (4–5 yr) was 24% in the case studies of Epaminonda e(pretreatment GH, 20.2 µg/liter) and 6.7% in the case studies of Cozzi e (pretreatment GH, 18 µg/liter). Only Landolt reported the direct comparison of the two techniques, showing that the percent decrease in GH/IGF-I values from baseline was steeper by GK compared with RT. It is fair to say that a correct comparison should be performed with modern techniques, allowing conformation and precise focusing of radiation on tumoral tissue. In contrast with previous data obtained by RT, showing better outcome in acromegalic patients whose basal GH levels were lower in this series the control of hormonal hypersecretion was not dependent on basal GH values. The observation that four patients reached safe GH levels, but still had high IGF-I concentrations, is in keeping with several previous findings after RT (and might be explained by the persistence of a lower, but continuously released, tonic GH secretion capable of inducing an exaggerated stimulation of hepatic IGF-I synthesis No difference in the outcome was observed between the patients who received SA at the time of GK application and those who did not, in contrast with Landolt et al.’s suggestion of a radioprotective effect of octreotide confirmed later in the retrospective evaluation of another series of patients submitted to RT . However, this study was not designed as a prospective randomized one and, even if the two subgroups seem balanced for age, hormonal levels, and tumor volume, a definitive answer to the issue of whether it is better to administer ionizing radiation to resting or active cells cannot be given. In our series GK was very effective in controlling tumor mass, as demonstrated by the lack of further growth of the adenoma in all patients and by the outstanding shrinkage in most. The control of tumoral growth was already reported in virtually all acromegalic patients, with shrinkage in many The only exception was reported by Pan and colleagues who observed a volumetric increase in the tumor in 3 of 65 patients. A word of caution about size reduction is mandatory. It cannot be ruled out that this effect may be linked to concomitant SA treatment carried on throughout the follow-up period in most patients. On the other hand, neuroradiological evaluation was always performed in the same conditions as those used for treatment withdrawal or its prolongation, to minimize drug interference. Moreover, several reports showed that tumor shrinkage is much less evident or negligible in patients treated with SA after surgery compared with patients treated with these drugs as first line treatment The dissociation between the control of tumor growth and that of hormonal hypersecretion is well known. In fact, it has been reported that the dose of radiation to be administered to the tumor is different if the goal of therapy is to reverse an endocrinopathy or merely to halt growth. Finally, we stress that the procedure seems safe: no major side-effect was observed, no visual impairment developed, and the occurrence of hypopituitarism was very rare. Limiting factors in the delivery of an ablative radiation dose include its proximity to the optic apparatus and the size of the tumor. To avoid visual impairment, the dose of radiation to the optic chiasm should not exceed 10 Gy, and our choice was in agreement with the most restrictive cut-off of 8 Gy to the visual pathways . Accordingly, pituitary tumors with suprasellar extension that abut the optic apparatus cannot receive a tumor ablative dose without the risk of compromising vision. The same restrictions do not apply to tumors extending laterally into the cavernous sinus, where cranial nerves III, IV, V, and VI are much less susceptible to radiation damage than is the optic nerve. In comparison with RT, GK permits conformation of the radiation to the tumor shape, thus limiting the radiation exposure of surrounding tissue. Literature data report the rare occurrence of visual damage which we did not observe, and the variable occurrence of hypopituitarism, ranging from less than 5% , concordant with us, to 10–29% . These differences may be explained by the neurosurgeon’s expertise. As for the development of secondary tumor, previously described as a rare event in the field of irradiation with RT ( it has never been observed after GK, even after a follow-up longer than 30 yr Patients who previously underwent RT did not develop distinctive adverse effects; their hormonal pattern was similar to those of the remaining patients. Thus, previous unsuccessful RT does not seem to constitute a restriction to GK, as previously reported In conclusion, our data show the effectiveness of GK in acromegalic patients, both on the control of hormonal hypersecretion and on tumoral mass. It appears to be at least as efficacious and probably safer than conventional RT. Gamma-knife surgery is effective in normalising plasma insulin-like growth factor I in patients with acromegaly.Gutt B, Exp Clin Endocrinol Diabetes. 2005 Apr;113(4):219-24. Department of Internal Medicine Innenstadt, University of Munich, Munich, Germany. Bodo.Gutt@med.uni-muenchen.de OBJECTIVE: For patients in whom acromegaly persists despite pituitary surgery or drug treatment, gamma-knife surgery represents an additional treatment option. Considering carefully the different reported biochemical outcomes, the central point is whether gamma-knife radiosurgery has advantages compared to conventional radiotherapy or, furthermore, to newer medical therapies, such as long-acting somatostatin analogues or growth hormone receptor antagonists. DESIGN AND METHODS: We report the outcome of 44 patients with acromegaly, who received gamma-knife surgery with the Leksell gamma knife. The median follow-up time was 1.9 years (0.5-4.3 years) post-radiosurgery. 43 of 44 patients had previously undergone pituitary surgery. RESULTS: Immediately prior to gamma-knife surgery, median xULN of patients' serum IGF-I was 1.9 times above upper limit of normal (range: 0.5-8.9 xULN [multiple of upper limit of normal range]). There was a significant decline of serum IGF-I at patients' final follow-up. We found a normal age-adjusted IGF-I in 21/44 patients (xULN of IGF-I<1). Furthermore, as the number of treated patients increased, we found an improvement in remission rate, which let us assume that there was a learning effect for the gamma-knife performing team over time. In addition, the median adenoma size decreased from 1.5 ml (0.1-6.9 ml) prior to gamma-knife therapy to 0.3 ml (no rest vol. detectable-2.4 ml) at patients' last visit. CONCLUSION: We have shown that pituitary gamma-knife surgery is effective in lowering serum IGF-I levels. At the end of the follow-up period, 48 % of our cohort had normal age-adjusted IGF-I levels.
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