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Pituitary Unit, Department of Neurosurgery, Istituto Scientifico San Raffaele, Università Vita-Salute, 20132 Milano, Italy
Address all correspondence and requests for reprints to: Marco Losa, M.D., Department of Neurosurgery, Istituto Scientifico San Raffaele, Via Olgettina 60, 20132 Milano, Italy. E-mail: losa.marco{at}hsr.it.
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Abstract |
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Objective: We analyzed the safety and efficacy of SR in patients who had previously received maximal surgical debulking at our center.
Design: The study was a retrospective analysis of hormonal, radiological, and ophthalmologic data collected in a predefined protocol from 1994 through 2006.
Setting: The study was performed at a university hospital.
Patients: Eighty-three acromegalic patients, 52 women and 31 men, with a mean age of 42.6 ± 1.2 yr, participated in the study. The median follow-up was 69 months (interquartile range 44–107 months).
Intervention: The patients were treated with SR for residual or recurrent GH-secreting adenoma.
Main Outcome Measure: Normalization of age- and sex-adjusted IGF-I levels together with a basal GH level below 2.5 µg/liter without concomitant GH-suppressive drugs was the goal of therapy.
Results: Fifty patients (60.2%) reached the main outcome of the study. The rate of remission was 52.6% at 5 yr [95% confidence interval (CI) 40.6–64.6%]. Another 13 patients (15.7%), who were resistant to somatostatin analogs, were in remission after SR. Multivariate analysis showed that low basal GH and IGF-I levels were associated with a favorable outcome. No serious side effects occurred after SR. The 5-yr cumulative risk of new onset hypogonadism, hypothyroidism, or hypoadrenalism was 3.6% (95% CI 0–8.6%), 3.3% (95% CI 0–7.7%), and 4.9% (95% CI 0–10.4%), respectively.
Conclusion: In a highly selected group of acromegalic patients, SR treatment had good efficacy and safety. This may lead to reconsider the role of SR in the therapeutic algorithm of acromegaly.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Single-session stereotactic radiotherapy (SR), also known as Leksell 
-knife, permits to deliver high-dose radiation to a targeted volume. The surrounding normal structures are spared because of the steep fall-off of radiation at the margins of the lesion. Landolt et al. (13) showed that the highly precise and potent radiation delivered by SR caused a more rapid fall of GH levels than fractionated radiotherapy. However, SR is a relatively new technique, and there are few published data about the long-term results in acromegalic patients.
The aim of our study was to evaluate the efficacy and safety of SR in a homogeneous cohort of acromegalic patients who had previously undergone maximal surgical debulking at our center.
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Patients and Methods |
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We included in the study all consecutive patients who, between January 1994 and December 2006, were treated with SR for residual or recurrent acromegaly after having received their last surgical treatment at our department. Diagnosis of active acromegaly was based on the clinical picture, GH levels not suppressed less than 1 µg/liter after a glucose load, and an elevated age- and sex-adjusted IGF-I level. Moreover, magnetic resonance imaging (MRI) showed a residual or recurrent pituitary tumor in each patient.
From 1994 through 2000, concomitant therapy with SSA was permitted according to patient’s preference. After the release of one study that suggested a radioprotective effect of SSA (14), we advised, when feasible, to quit such treatment before SR. Because of this policy, 17 patients (20.5%) were receiving SSA at the time of SR. Medical treatment was not initiated (45 patients) or was discontinued (21 patients) at least 4 months or 2 wk before SR, depending on the formulation of the drug. Three patients (3.6%) continued taking dopamine agonists until treatment with SR.
Standard informed consent was obtained from each patient undergoing SR.
Clinical and hormonal evaluation
Evaluation of pituitary function included measurement of free urinary cortisol excretion and basal serum GH, IGF-I, free T3, free T4, TSH, LH, FSH, prolactin (PRL), cortisol, testosterone (in men) and 17-β-estradiol levels (in premenopausal women). Neuroophthalmological examination included visual acuity testing, oculomotor function, and automated perimetry. During follow-up, GH and IGF-I levels determined without any concomitant medical therapy or after at least 4 months of discontinuation of SSA were considered as off treatment. Scheduled follow-up studies included MRI and neuroophthalmological examination 6, 12, 24, 36, and 48 months after SR and then at 2-yr intervals, whereas GH, IGF-I, and pituitary function were determined at 6-month intervals for the first 2 yr and then yearly thereafter or when clinically indicated. All examinations were performed at the Istituto Scientifico San Raffaele whenever possible. Otherwise, the referring physicians performed testing at a local facility, and results were sent to us for review. During the study period, a variety of assays were used to determine IGF-I levels. When indicated, we converted IGF-I levels into the multiple of the upper normal limit (mUNL).
The criterion for remission of acromegaly after SR was achievement of normal age- and sex-adjusted IGF-I in combination with GH level less than 2.5 µg/liter without concomitant treatment with GH-suppressive drugs. Patients who still needed GH-suppressive drugs were not considered in remission, irrespective of IGF-I and GH levels.
Hypogonadotropic hypogonadism was diagnosed in premenopausal women with amenorrhea and in men with subnormal testosterone levels. Low or normal gonadotropin levels were also required in both sexes. Hypogonadism was also assigned to postmenopausal women with inappropriately normal gonadotropin levels; three premenopausal women taking estrogens were excluded from the analysis of gonadal function. Secondary hypothyroidism was diagnosed in patients with low free T4 level and normal or suppressed TSH concentration; four patients, already on T4 replacement therapy because of other thyroid disorders, were excluded from this analysis. Secondary hypoadrenalism was diagnosed by low 24-h free urinary cortisol and morning serum cortisol (<50 µg/liter) levels. Moreover, patients with serum cortisol levels in the lower half of the normal range were also started on replacement therapy if they had symptoms of hypoadrenalism.
Radiosurgical treatment
Patients underwent placement of the Leksell stereotactic head frame (model G; Elekta Instruments, Stockholm, Sweden) under mild sedation and after application of a local anesthetic agent. High-resolution gadolinium-enhanced MRI was performed to obtain precise information on the three-dimensional coordinates of the residual tumor. Treatment was then planned with the KULA dose-planning software until 1995 and the Leksell GammaPlan system (Elekta Instruments) thereafter. SR was performed using a 201-source 60Co -knife (model B until December 2001 and model C thereafter). Two neurosurgeons delineated the target and one radiotherapist approved the definitive radiosurgical planning. The entire residual tumor was covered within the 50% isodose line. The goal of treatment was to deliver 25 Gy to the margin of the tumor. Multiple isocenters were distributed throughout the target volume to conform the dose to the tumor margins. To this aim, small collimator sizes (4 and 8 mm) were used, and frequent source blocking was applied to obtain a sharper dose decrease toward the optic nerves, chiasm, and pituitary stalk. The dose to the tumor was decreased, when necessary, to keep a maximal dose of 10 Gy to the optical pathway. All patients were discharged the day after SR treatment.
Statistical analysis
Continuous variables were examined for homogeneity of variance by the Kolmogorov-Smirnov test. For continuous variables with a normal distribution, the mean (± SEM) is reported. For variables not normally distributed, the median and interquartile ranges (IQRs) are reported. The Wilkonson signed rank test for paired data was used to compare GH and IGF-I levels before and after SR. Estimates of the cumulative event rate were calculated by the Kaplan-Meier method, and differences in subgroups of patients were tested by the log-rank test. Data for patients who were lost to follow-up or who did not reach remission of disease were censored at the time of the last hormonal evaluation. Adjusted analysis of the primary outcome, i.e. remission of acromegaly, was performed with the use of a Cox proportional-hazards regression model with the factors that had a P < 0.10 in the univariate analysis plus preidentified covariates of interest.
A probability value of less than 0.05 was considered to indicate statistical significance and all reported values are two sided. All calculations were performed using a commercially available statistical software package (SPSS 11.0 for Mac OS X; SPSS Inc., Chicago, IL).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The main clinical characteristics are summarized in Table 1
. Altogether, 83 patients with active acromegaly, 52 women (62.6%) and 31 men (37.4%), were evaluated. Seventy-eight patients (94.0%) had residual adenoma after surgery, whereas five patients (6.0%) had recurrence of disease. Sixty-four (77.1%) had undergone surgery once, 17 (20.5%) twice, and the remaining two patients (2.4%) four times. Immunocytochemistry, available in 71 patients (85.5%), demonstrated the presence of a pure GH-secreting adenoma in 55 patients (77.5%) and a mixed GH-PRL-secreting tumor in 16 patients (22.5%). Thirty-eight patients (45.8%) had received SSA before SR: sc. octreotide in 14, octreotide LAR (10–30 mg/month) in nine, and lanreotide (30–120 mg once or twice a month) in 15 patients. IGF-I and GH levels normalized during medical therapy in three patients (7.9%), whereas GH levels decreased to more than 50% of pretreatment value in 12 patients (31.6%).
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Neuroophthalmological examination was normal in 80 patients (96.4%) and abnormal in three (3.6%).
Long-term effects of SR on GH and IGF-I levels
Total follow-up was 507 patient-yr. The median follow-up was 69 months (IQR 44–107 months; range 6–158 months). Five patients (6.0%) did not continue the scheduled follow-up 6, 11, 12, 14, and 37 months after SR, respectively.
Fifty-seven patients did not receive medical treatment at the last follow-up. Their median serum GH level fell from a baseline value of 5.5 µg/liter (IQR 2.9–11.7) to 1.0 µg/liter (IQR 0.6–1.9; P < 0.001). Similarly, the median IGF-I level fell from 787 µg/liter (IQR 606–985) to 198 µg/liter (IQR 144–263; P < 0.001). Eighteen patients, 15 in remission and 3 not in remission, underwent an oral glucose tolerance test during follow-up. Eleven of the 15 patients in remission had GH nadir less than 1 µg/liter after oral glucose tolerance test, whereas the other four had GH nadir comprised between 1 and 1.2 µg/liter.
Remission of disease occurred in 50 patients (60.2%). Survival analysis (Fig. 1) showed that the probability to achieve remission of acromegaly was 30.5% at 3 yr [95% confidence interval (CI) 20.0–40.9%] and 52.6% at 5 yr (95% CI 40.6–64.6%). Further cases of remission occurred during prolonged follow-up so that the estimated 8- and 10-yr rates of remission were 71.0 (95% CI 58.2–83.7%) and 84.8% (95% CI 72.2–97.3%), respectively. One patient had recurrence of acromegaly 1 yr after remission. She was successfully treated with SSA. No other recurrence occurred in the other 49 patients after a further median follow-up of 34 months.
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. As a whole, 70 patients (84.3%) were in remission after treatment with SR alone or in combination with drugs.
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). Patients with a basal GH of 7.0 µg/liter or lower reached remission a median of 37 months after SR (95% CI 28–46), as compared with 93 months (95% CI 72–114) in patients with basal GH level higher than 7.0 µg/liter (P < 0.001). Similarly, patients with basal mUNL IGF-I of 1.83 or lower reached remission a median of 36 months after SR (95% CI 27–45), as compared with 90 months (95% CI 59–121) in patients with basal mUNL IGF-I value higher than 1.83 (P < 0.001). Patients who were treated with a dose to the tumor margin of 21.5 Gy or higher reached remission a median of 44 months after SR (95% CI 39–49), as compared with 77 months (95% CI 39–115) in the group of patients who received less than 21.5 Gy (P < 0.02). Concomitant treatment with SSA had a borderline negative effect on outcome. Patients who were receiving SSA at the time of SR reached remission of disease after a median time of 77 months after SR (95% CI 42–112), whereas the group not treated with SSA reached remission after a median time of 46 months (95% CI 31–61; P = 0.08). Age at SR, sex, year of SR (categorized as before or after 2000), volume of the irradiated lesion, mixed or pure GH-secreting nature of the adenoma, and reduction of tumor size after SR were not associated with outcome.
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Tumor growth
At last follow-up, tumor size remained unchanged in 43 patients (51.8%) and decreased in 38 patients (45.8%). Two patients (2.4%) had growth of tumor tissue 4 and 5 yr after SR, respectively. Recurrence occurred in an area that was not covered by SR because MRI at the time of treatment did not show any pathological tissue in that location. Both patients were treated with SSA and had no further tumor growth.
Side effects of SR
No serious side effects occurred after SR. Eight patients (9.6%), three of whom already symptomatic before SR, complained of severe headache for at least 1 month after SR. No patient had deterioration of visual function or oculomotor function. One patient had rhinoliquorrhea necessitating surgical repair 18 months after SR.
Seven of 82 patients (8.5%) experienced a new deficit of pituitary function (the remaining patient had hypopituitarism before SR). In more detail, new cases of hypogonadism occurred in three of the 63 patients at risk (4.8%). New cases of hypothyroidism occurred in three of the 75 patients at risk (4.0%), and new cases of hypoadrenalism occurred in six (7.4%) of the 81 patients at risk. In all cases, replacement therapy was initiated accordingly. No cases of diabetes insipidus occurred after SR. The 5-yr cumulative risk of new-onset hypogonadism, hypothyroidism, or hypoadrenalism was 3.6% (95% CI 0–8.6%), 3.3% (95% CI 0–7.7%), and 4.9% (95% CI 0–10.4%), respectively (Fig. 3). Ten years after SR, the incidence of new pituitary defects was estimated at 7.7% (95% CI 0–16.7%), 7.5% (95% CI 0–16.6%), and 13.6% (95% CI 2.9–24.2%) for gonadal, thyroid, and adrenal function, respectively (Fig. 3).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Our data, in a selected population of patients, show that remission occurred throughout the follow-up period, approaching almost 85% 10 yr after SR (Fig. 1
). Moreover, 13 patients, who had complete or partial resistance to SSA, achieved remission of disease while continuing the drug after SR. Recurrence of disease once remission had been achieved was quite uncommon. At variance with other studies (19, 20, 21, 22, 23, 24), we included only patients who, before SR, had been operated on at our center, aiming in each case at reducing GH and IGF-I levels as much as possible. Therefore, our results might not apply to other patients, especially those with high GH and IGF-I levels before SR.
Previous studies reported mixed results (19, 20, 21, 22, 23, 24). Using biochemical criteria similar to ours, remission of acromegaly occurred at 5 yr in 56–60% of cases (22, 23), whereas lower rates (29–30%) have been reported by other authors (19, 20). Minor differences in the criteria of remission are unlikely to explain these differences because normalization of age- and sex-adjusted IGF-I levels was common to all these series. We, as other authors, did not require suppression of GH levels after oral glucose tolerance test as a criterion of remission because radiation therapy may alter GH feedback regulation, thus making the interpretation of GH dynamic testing more difficult (25). Indeed, Powell and coworkers (26) showed a clear overlap in the postglucose GH levels in 15 irradiated patients, whose disease status was defined by IGF-I levels.
GH and IGF-I levels before SR treatment and in the absence of concomitant GH-suppressive therapy were inversely associated with remission. The other variables, including sex, age, year of SR, concomitant treatment with SSA, and radiation dose to the tumor margin, were not independently associated with outcome. In a univariate analysis, basal GH and IGF-I levels off medication were inversely related to a successful outcome in two series (20, 22), whereas Pollock et al. (23), who also used a multivariate analysis, found that only baseline IGF-I levels had an independent predictive value. Interestingly, the same relationship between baseline hormone levels and remission of acromegaly also exists after conventional radiotherapy (12, 27, 28, 29). Despite some exceptions to this supposition (19, 24, 18, 30), it seems reasonable that the less hormonally active tumors will normalize earlier because the kinetic of GH reduction after radiation seems to be independent of the starting GH level (20). Therefore, maximal surgical debulking before SR should enhance the subsequent probability of success. In keeping with another series (23), we found that the marginal dose to the tumor was not independently associated with remission of disease.
The role of concomitant therapy with SSA has been debated after the report of Landolt et al. (14), which showed a clearly reduced efficacy of SR in patients while on medication. The supposed radioprotective effect of SSA has been confirmed by some (23) but not all authors (19, 20). Our multivariate analysis failed to show any detrimental effect of concomitant treatment with SSA on SR outcome. However, our analysis might be flawed by the nonrandom decision to quit prior medication that we implemented, starting in 2000. Only a randomized prospective study would give the final answer to this question. In the meantime and in keeping with other authors’ view (20, 31, 32), we prefer quitting SSA before SR treatment, when clinically feasible.
Reduction of tumor size after SR occurred in 45.8% of our patients, but it was not related to biochemical outcome, as already reported by Jezkova et al. (22). Two patients showed growth of residual tumor located outside the area initially covered by SR. We described two similar cases in patients with a nonfunctioning pituitary adenoma (33). Continuous MRI follow-up is therefore mandatory, especially in patients without remission of disease.
Determining the safety of SR is of paramount importance to broaden its use in acromegaly. No serious side effect attributable to SR has occurred after more than 507 patient-yr of follow-up: SR does not seem to have had any role in the development of a single case of rhinoliquorrhea. No transient or permanent dysfunction of optic or oculomotor nerves occurred in this study. A similar safety profile has been described by others (19, 22). Only two series (20, 23) reported serious side effects in three patients. However, they all had received conventional radiotherapy before SR, suggesting that the cumulative exposure to radiation rather than SR itself was the principal risk factor for serious complications.
New deficit of pituitary function occurred rarely in our series. In one study with a mean follow-up of 54 months (22), new cases of hypogonadism, hypothyroidism, and hypoadrenalism occurred in 41.1, 31.7, and 14% of the patients at risk, respectively. The rather high rate of hypopituitarism in that study might be attributed to a higher percentage of patients (12.5%) who had previously received conventional radiotherapy, compared with only 1.2% in our study and to the higher median radiation dose to the tumor margin (35 vs. 21.5 Gy). The latter factor is probably the most important because another series that used a median margin dose similar to ours (20 Gy) had 5.3, 0, and 7.7% new cases of hypogonadism, hypothyroidism, and hypoadrenalism, respectively (19). Pollock et al. (23) reported that 13 of 39 patients (33%) suffered a new pituitary deficit after a median follow-up of 63 months. From these rough data, it is, however, difficult to ascertain whether damage to the normal pituitary is progressive with time. To this aim, we analyzed the data with survival analysis methods. The estimated probability of new onset hypogonadism, hypothyroidism, and hypoadrenalism slightly increased with time but remained around 10% at 10 yr. Only a longer follow-up will clarify whether the risk of hypopituitarism will further increase after this period.
A direct comparison between the results of SR and fractionated radiotherapy is difficult to perform because patients selected to undergo SR may have more favorable characteristics, i.e. smaller tumor size and lower GH levels, than those receiving fractionated radiotherapy. A faster normalization of IGF-I levels has been found in patients treated by SR than in a group of historical controls treated at the same institution by fractionated radiotherapy (13). The risk of new-onset hypopituitarism seems, on average, to be lower for SR than fractionated radiotherapy. Only prospective, randomized, controlled studies would clarify the issue but are unlikely to be performed.
In conclusion, our study demonstrates that, in a highly selected group of acromegalic patients subjected to previous surgery at our center, SR treatment was effective and safe. This may lead to reconsider the role of SR in the therapeutic algorithm of acromegaly. SR treatment might be considered as an alternative to lifelong treatment with SSA or GH receptor antagonists, particularly in patients with small tumor residue located away from the optic pathway and the residual normal pituitary gland.
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Footnotes |
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First Published Online April 15, 2008
Abbreviations: CI, Confidence interval; IQR, interquartile range; MRI, magnetic resonance imaging; mUNL, multiple of the upper normal limit; PRL, prolactin; SR, stereotactic radiotherapy; SSA, somatostatin analog.
Received January 18, 2008.
Accepted April 9, 2008.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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-Knife radiosurgery in acromegaly: a 4-year follow-up study. J Clin Endocrinol Metab 88:3105–3112-knife radiosurgery in 82 patients with acromegaly: correlation with initial hypersecretion. J Clin Endocrinol Metab 90:4483–4488-Knife surgery is effective in normalising plasma insulin-like growth factor I in patients with acromegaly. Exp Clin Endocrinol Diabetes 113:219–224[CrossRef][Medline]-Knife radiosurgery for acromegaly—long term experience. Clin Endocrinol (Oxf) 64:588–595[CrossRef][Medline]-Knife stereotactic radiosurgery for acromegaly. Eur J Endocrinol 157:255–263 knife radiosurgery in acromegaly. Pituitary 2:71–77[CrossRef][Medline]-Knife radiosurgery for residual nonfunctioning pituitary adenomas after surgical debulking. J Neurosurg 100:438–444[Medline]This article has been cited by other articles:
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  F M Swords, J P Monson, G M Besser, S L Chew, W M Drake, A B Grossman, and P N Plowman Gamma knife radiosurgery: a safe and effective salvage treatment for pituitary tumours not controlled despite conventional radiotherapy Eur. J. Endocrinol., December 1, 2009; 161(6): 819 - 828. [Abstract] [Full Text] [PDF]
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 F. Castinetti, M. Nagai, I. Morange, H. Dufour, P. Caron, P. Chanson, C. Cortet-Rudelli, J.-M. Kuhn, B. Conte-Devolx, J. Regis, et al. Long-Term Results of Stereotactic Radiosurgery in Secretory Pituitary Adenomas J. Clin. Endocrinol. Metab., September 1, 2009; 94(9): 3400 - 3407. [Abstract] [Full Text] [PDF]
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