Author: Frederic Castinetti
Institution: Department of Endocrinology, La Timone Hospital
Address: Marseille, France
Author: Thierry Brue
Institution: Department of Endocrinology, La Timone Hospital
Address: Marseille, France
Abstract: Pituitary adenomas are benign tumors that can be either secreting (acromegaly, Cushing's disease, prolactinomas) or non-secreting. Transsphenoidal neurosurgery is the gold standard treatment; however, it is not always effective. Gamma Knife radiosurgery is a specific modality of stereotactic radiosurgery, a precise radiation technique. Several studies reported the efficacy and low risk of adverse effects induced by this technique: in secreting pituitary adenomas, hypersecretion is controlled in about 50% of cases and tumor volume is stabilized or decreased in 80-90% of cases, making Gamma Knife a valuable adjunctive or first-line treatment. As hormone levels decrease progressively, the main drawback is the longer time to remission (12-60 months), requiring an additional treatment during this period. Hypopituitarism is the main side effect, observed in 20-40% cases. Gamma Knife is thus useful in the therapeutic algorithms of pituitary adenomas in well-defined indications, mainly low secreting small lesions well identified on magnetic resonance imaging (MRI).
Pituitary adenomas are usually benign tumors that can be either secreting (growth hormone in acromegaly, adrenocorticotropin hormone in Cushing’s disease, prolactin in prolactinomas) (Biller et al., 2008; Chanson et al., 2009b; Klibanski, 2010) or non-secreting (in this latter case, adenomas are frequently responsible for local compression after several years of progressive volume increase) (Dekkers et al., 2008). Despite major advances in the treatment of pituitary adenomas, definite cure remains challenging. Transsphenoidal surgery, considered as the first line treatment, induces remission in 50-80% of cases, depending on the adenoma volume, its extension to peripheral structures, the neurosurgeon’s experience, and so on. Adjunctive treatments are thus necessary, but their efficacy and tolerance are less than satisfactory. For instance, somatostatin analogs generally lead to a 50-60% remission rate in acromegaly, but relapse is the rule after withdrawal (Chanson et al., 2009a); dopamine agonists lead to a 80-90% remission rate in prolactinomas, but are sometimes poorly tolerated (Casanueva et al., 2006). Fractionated radiotherapy, another possible adjunctive treatment, though highly effective, induces a high risk of hypopituitarism (Brada and Jankowska, 2008).
Stereotactic radiosurgery has been used for years in the treatment of secreting and non-secreting pituitary adenomas, either as a primary non-surgical or as an adjunctive post-surgical treatment (Castinetti et al., 2010). Stereotactic radiosurgery is characterized by a highly precise definition of the target. It can be delivered as a single fraction using a multi-headed cobalt unit (Gamma Knife) or a linear accelerator (LINAC), or as a fractionated procedure using linear accelerator (stereotactic conformal radiotherapy). Recent studies also reported the possibility of Cyberknife multi-session radiosurgery, but data on the efficacy and adverse effects of this technique in pituitary adenomas are preliminary (Castinetti et al., 2010). The majority of the studies published to date were based on Gamma Knife: we thus decided to focus only on this approach. Reports based on other stereotactic procedures, though infrequent, reported similar levels of efficacy and risks of adverse effects compared to Gamma Knife. This latter point should allow extending the conclusions of this review to the overall role of stereotactic radiosurgery in the management of pituitary adenomas.
What Is Gamma Knife Radiosurgery?
Gamma knife stereotactic radiosurgery is a radiation therapy technique using a source of 60Cobalt where narrow ionizing beams, given in a single high-dose fraction, are used either to destroy a predetermined target volume or to induce a desired biological effect in the target volume (in other words normalize or decrease the secretion of an over-secreted pituitary hormone) (Castinetti et al., 2010). The procedure is performed without opening the skull and with minimal damage to the surrounding brain. Sparing the critical structures around the target relies on the high conformity and anatomical selectivity of the dose delivery. In contrast with stereotactic radiosurgery, conventional radiotherapy covers the lesion and the surrounding structures with a fractionated dose; its aim is to minimize the injury of the surrounding structures included in the field of irradiation by the fractionation, creating a gradient of toxicity between target cells and normal tissue. The mechanism of both techniques is thus different, leading to complementary indications that will be detailed later in this review. To obtain optimal efficacy, Gamma Knife should thus be reserved to small well-defined lesions.
Who to Treat with Gamma Knife Radiosurgery?
Several studies have been published on the use of Gamma Knife in secreting and non-secreting pituitary adenomas. Recent reports gave more clues about the long-term efficacy in secreting pituitary adenomas, i.e., acromegaly, Cushing’s disease, and prolactinomas: in most series, remission, defined by normalized hormone secretion, was observed in about 30-50% of cases after a mean follow-up of 60-96 months (Castinetti et al., 2009; Hoybye et al., 2004; Jagannathan et al., 2008; Jagannathan et al., 2007; Jezkova et al., 2006; Kobayashi et al., 2002; Kobayashi et al., 2005; Losa et al., 2008; Pollock et al., 2008a; Pouratian et al., 2006; Ronchi et al., 2009; Vik-Mo et al., 2007). Anti-tumoral efficacy, in both secreting and non-secreting pituitary adenomas, was observed in more than 90% cases, with decrease or stabilization of the tumor volume (Castinetti et al., 2009; Hoybye and Rahn, 2009; Jagannathan et al., 2009; Jezkova et al., 2006; Minniti and Brada, 2007; Pollock et al., 2008b; Ronchi et al., 2009; Sheehan et al., 2005). These results clearly demonstrate the efficacy of the procedure which was reported either as a primary non-surgical or as an adjunctive post-surgical treatment.
The efficacy of the technique is highly correlated to the definition of the target, and according to some studies, to the target volume (Jagannathan et al., 2007; Pouratian et al., 2006) — as previously mentioned, Gamma Knife radiosurgery should be reserved to small well-defined lesions. Most of the studies did not report that target volume was a predictive factor of remission due to a bias of selection of patients (in the way that most of the patients treated by Gamma Knife present a small tumor volume). The less precise the target is, the higher the risk of adverse effects is, mainly hypopituitarism. Other positive predictive factors have been reported, including initial hormone levels and radiation dose (Castinetti et al., 2009; Jezkova et al., 2006; Pollock et al., 2008a) — but results are contradictory and do not allow to draw any firm conclusion. Previous studies also reported a so-called radioprotective effect of anti-secretory drugs given at the time of radiosurgery: for instance, patients treated by somatostatin agonists at the time of Gamma Knife were presumed to be less likely to achieve remission compared to patients without the treatment (Jagannathan et al., 2008; Jagannathan et al., 2007; Landolt et al., 2000; Landolt and Lomax, 2000; Pollock et al., 2007; Pouratian et al., 2006). The pathophysiological mechanism is unclear and results are also contradictory. As a consequence, to our knowledge, the best criterion to evaluate whether radiosurgery is the appropriate treatment is the level of definition of the target on MRI.
The main drawback of Gamma Knife is the delay to remission, and this has to be taken into account at the time of disease management decision. Due to the slow decrease of hormone levels, mean time to remission after radiosurgery is usually about 30-50 months in patients with acromegaly, and 15-30 months in patients with Cushing’s disease and prolactinomas (Castinetti et al., 2010). This delay to remission implies that Gamma Knife should either be used in patients with low secreting tumors, or in patients for whom an anti-secretory drug is at least partially effective. In this latter case, the drug should be given immediately after the procedure; regular withdrawal will allow to determine hormone levels without any anti-secretory drug, and to determine the need for maintaining the treatment (and also the efficacy of the radiosurgical procedure). In our studies, we observed that the time to remission was frequently correlated to the initial hormone levels without anti-secretory drugs (Castinetti et al., 2007; Castinetti et al., 2009; Castinetti et al., 2005). We thus think that a pre-radiosurgical evaluation of the level of hypersecretion should be performed without medical treatment. In our opinion, Gamma Knife should be reserved to tumors with a relatively low level of hypersecretion. Interestingly, the anti-tumoral effect is observed shortly after radiosurgery: in the majority of the studies, volume stabilization was reported during the first year after the procedure (Jagannathan et al., 2008; Jagannathan et al., 2007; Jezkova et al., 2006; Pamir et al., 2007; Pouratian et al., 2006). Of note, this does not justify the use of Gamma Knife radiosurgery in rapidly expanding lesions close to the optic chiasm; these lesions should still highly benefit from surgery if operable, or anti-secretory drugs as a first line treatment.
There is no major contra-indication to Gamma Knife radiosurgery. The focalized high dose delivered by radiosurgery was initially thought to be dangerous for the optical pathways; this involved the need for a minimal distance between the target volume and the chiasm and a dose to the chiasm not superior to 8 Gy. This risk seems low presently, taking into account new target definition methods and improvements in the accuracy of the radiosurgical procedure (Castinetti et al., 2010).
How to Follow Up the Patients Treated by Gamma Knife Radiosurgery?
As mentioned previously, radiosurgery has a delayed maximal efficacy, requiring effective anti-secretory treatments during this latency period. MRI evaluation should be performed 3 months after the procedure, and then yearly. Some rare cases of immediate or delayed increase of the tumor volume have been reported, which justifies the need for a prolonged follow-up (Castinetti et al., 2010; Jagannathan et al., 2008; Jagannathan et al., 2007; Jezkova et al., 2006; Pouratian et al., 2006). Usually, hormone levels tend to decrease progressively to a stable level: withdrawal of anti-secretory drugs has to be performed regularly to assess the efficacy of the procedure, and, as a consequence, to determine the appropriate time for discontinuation of the drug. Interestingly, recent long-term follow-up studies reported a risk of late recurrence in patients treated for Cushing’s disease (Castinetti et al., 2009; Jagannathan et al., 2007). In our long-term study based on 76 patients, 2 out of 10 patients considered in remission of Cushing’s disease presented recurrence 6 and 8 years after Gamma Knife (Castinetti et al., 2009). This point emphasizes the need for a prolonged follow-up, particularly in patients with Cushing’s disease, even after long-term remission.
Radiation induced hypopituitarism is the most frequent side effect. It is usually reported in 10-30% of cases, depending on the dose to the target and the stalk, the visualization of the target, previous surgical or radiotherapy procedures, etc. (Castinetti et al., 2009; Jezkova et al., 2006; Minniti and Brada, 2007; Pollock et al., 2008b; Ronchi et al., 2009; Sheehan et al., 2005). These adverse effects have been reported as early as within a year after Gamma Knife, or much later, up to ten years after the procedure (Castinetti et al., 2009; Ronchi et al., 2009). Systematic pituitary hormone evaluations should thus be performed yearly in all patients. There is also a theoretical risk of optic neuritis, evaluated to be about 2% of cases in former published series. This risk currently seems to be lower due to more precise definition techniques, and improvement of the stereotactic procedure (Ove et al., 2000; Stafford et al., 2003; Tishler et al., 1993). Other side effects, described with long-term follow-up studies of fractionated radiotherapy for brain tumors, memory loss, and cerebro-vascular accidents, seem to be rare with Gamma Knife: it could either be because the technique is more precise and harmless for the surrounding tissues, or because the length of follow-up is too short to date to detect such adverse effects.
Why to Use Gamma Knife Radiosurgery Rather Than Fractionated Radiotherapy?
Efficacy of conventional radiotherapy in controlling hormone hypersecretion is estimated to be about 50-90% of cases, regardless of the type of secretion (Brada and Jankowska, 2008). Interestingly, to our knowledge, no recurrence has ever been reported after radiotherapy. Efficacy of radiosurgery is seemingly lower, particularly for Cushing’s disease, where a 50% rate of remission was reported, which might be further decreased by potential late recurrences (Castinetti et al., 2009; Jagannathan et al., 2008). In terms of anti-tumoral efficacy, results of conventional radiotherapy are comparable to those of Gamma Knife, with unchanged or decreased tumor volume in the majority of cases. However, conventional radiotherapy has two main drawbacks: the first one is the time to remission, equal to 5-10 years which is longer than that of Gamma Knife, requiring an effective medical treatment during this period. The second drawback of radiotherapy is the risk of side effects, including hypopituitarism (in more than 80% of cases), optic neuritis, radiation induced cerebral tumors, cerebral infraction, cognitive dysfunctions, etc. (Brada and Jankowska, 2008). These latter side effects occurred after a mean time of 10-20 years, and were not (at least not yet) described with the use of Gamma knife (Ayuk and Stewart, 2009; Borson-Chazot and Brue, 2006; Jenkins et al., 2006; Kong et al., 2007; Langsenlehner et al., 2007; Minniti et al., 2009; Snead et al., 2008).
Fractionated radiotherapy and stereotactic radiosurgery should be considered as two different modalities to treat different types of tumors. We think that stereotactic radiosurgery should be reserved to small and well defined tumors, in contrast with conventional, fractionated radiotherapy for larger and/or imprecisely defined tumors. To minimize the risk of adverse effects, a discussion between the endocrinologist, the neurosurgeon, the radiotherapist, and the radiosurgery specialist is necessary to choose the most appropriate radiation therapy.
Gamma Knife radiosurgery (and more generally stereotactic radiosurgery) is an effective and safe technique for treating pituitary adenomas. It has a reasonable good anti-secretory and a high anti-tumoral efficacy, making it a valuable treatment in case of contra-indication or partial efficacy of transsphenoidal surgery. Due to its mechanism of action being based on a precise single high dose fraction, stereotactic radiosurgery should be reserved to small lesions well defined on imaging techniques. A regular follow-up is required after the procedure, and should take into account the risk of late recurrence, particularly in Cushing’s disease.
Compared to fractionated radiotherapy, the main advantages of stereotactic radiosurgery are the relative rapidity of the effects (with a shorter time to remission) and a theoretically lower risk of adverse effects (this latter point will have to be proven by studies with a more prolonged follow-up, identical to the ones reporting fractionated radiotherapy studies). However, as indications of both techniques are different, stereotactic radiosurgery and fractionated radiotherapy should not be considered as mutually exclusive, but more as complementary ways to treat different kinds of pituitary adenomas.
The authors would like to thank Prof. J. Regis and Prof. H. Dufour, Department of Functional neurosurgery and Department of Neurosurgery, La Timone Hospital, Marseille, France, for their support.
Ayuk J, Stewart PM. Mortality following pituitary radiotherapy. Pituitary 12(1):35-9, 2009.
Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: A consensus statement. J Clin Endocrinol Metab 93(7):2454-62, 2008.
Borson-Chazot F, Brue T. Pituitary deficiency after brain radiation therapy. Ann Endocrinol (Paris) 67(4):303-9, 2006.
Brada M, Jankowska P. Radiotherapy for pituitary adenomas. Endocrinol Metab Clin North Am 37(1):263-275, xi, 2008.
Casanueva FF, Molitch ME, Schlechte JA, Abs R, Bonert V, Bronstein MD, Brue T, Cappabianca P, Colao A, Fahlbusch R, Fideleff H, Hadani M, Kelly P, Kleinberg D, Laws E, Marek J, Scanlon M, Sobrinho LG, Wass JA, Giustina A. Guidelines of the pituitary society for the diagnosis and management of prolactinomas. Clin Endocrinol (Oxf) 65(2):265-73, 2006.
Castinetti F, Nagai M, Dufour H, Kuhn JM, Morange I, Jaquet P, Conte-Devolx B, Regis J, Brue T. Gamma knife radiosurgery is a successful adjunctive treatment in Cushing’s disease. Eur J Endocrinol 156(1):91-98, 2007.
Castinetti F, Nagai M, Morange I, Dufour H, Caron P, Chanson P, Cortet-Rudelli C, Kuhn JM, Conte-Devolx B, Regis J, Brue T. Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J Clin Endocrinol Metab 94(9):3400-7, 2009.
Castinetti F, Regis J, Dufour H, Brue T. Role of stereotactic radiosurgery in the management of pituitary adenomas. Nat Rev Endocrinol 6(4):214-23, 2010.
Castinetti F, Taieb D, Kuhn Jm, Chanson P, Tamura M, Jaquet P, Conte-Devolx B, Regis J, Dufour H, Brue T. Outcome of gamma knife radiosurgery in 82 patients with acromegaly: Correlation with initial hypersecretion. J Clin Endocrinol Metab 90(8):4483-8, 2005.
Chanson P, Bertherat J, Beckers A, Bihan H, Brue T, Caron P, Chabre O, Cogne M, Cortet-Rudelli C, Delemer B, Dufour H, Gaillard R, Gueydan M, Morange I, Souberbielle JC, Tabarin A. French consensus on the management of acromegaly. Ann Endocrinol (Paris) 70(2):92-106, 2009a.
Chanson P, Salenave S, Kamenicky P, Cazabat L, Young J. Pituitary tumours: Acromegaly. Best Pract Res Clin Endocrinol Metab 23(5):555-74, 2009b.
Dekkers OM, Pereira AM, Romijn JA. Treatment and follow-up of clinically nonfunctioning pituitary macroadenomas. J Clin Endocrinol Metab 93(10):3717-26, 2008.
Hoybye C, Grenback E, Thoren M, Hulting AL, Lundblad L, Von Holst H, Anggard A. Transsphenoidal surgery in cushing disease: 10 years of experience in 34 consecutive cases. J Neurosurg 100(4):634-8, 2004.
Hoybye C, Rahn T. Adjuvant gamma knife radiosurgery in non-functioning pituitary adenomas; low risk of long-term complications in selected patients. Pituitary 12(3):211-6, 2009.
Jagannathan J, Sheehan JP, Pouratian N, Laws ER, Jr, Steiner L, Vance ML. Gamma knife radiosurgery for acromegaly: Outcomes after failed transsphenoidal surgery. Neurosurgery 62(6):1262-9, discussion 1269-70, 2008.
Jagannathan J, Sheehan JP, Pouratian N, Laws ER, Steiner L, Vance ML. Gamma knife surgery for Cushing’s disease. J Neurosurg 106(6):980-7, 2007.
Jagannathan J, Yen CP, Pouratian N, Laws ER, Sheehan JP. Stereotactic radiosurgery for pituitary adenomas: A comprehensive review of indications, techniques and long-term results using the gamma knife. J Neurooncol 92(3):345-56, 2009.
Jenkins PJ, Bates P, Carson MN, Stewart PM, Wass JA. Conventional pituitary irradiation is effective in lowering serum growth hormone and insulin-like growth factor-i in patients with acromegaly. J Clin Endocrinol Metab 91(4):1239-45, 2006.
Jezkova J, Marek J, Hana V, Krsek M, Weiss V, Vladyka V, Lisak R, Vymazal J, Pecen L. Gamma knife radiosurgery for acromegaly — long-term experience. Clin Endocrinol (Oxf) 64(5):588-95, 2006.
Klibanski A. Clinical practice. Prolactinomas. N Engl J Med 362(13):1219-26, 2010.
Kobayashi T, Kida Y, Mori Y. Gamma knife radiosurgery in the treatment of Cushing disease: Long-term results. J Neurosurg 97(Suppl 5):422-8, 2002.
Kobayashi T, Mori Y, Uchiyama Y, Kida Y, Fujitani S. Long-term results of gamma knife surgery for growth hormone-producing pituitary adenoma: Is the disease difficult to cure? J Neurosurg 102(Suppl):119-23, 2005.
Kong DS, Lee JI, Lim DOH, Kim KW, Shin HJ, Nam DH, Park K, Kim JH. The efficacy of fractionated radiotherapy and stereotactic radiosurgery for pituitary adenomas: Long-term results of 125 consecutive patients treated in a single institution. Cancer 110(4):854-60, 2007.
Landolt AM, Haller D, Lomax N, Scheib S, Schubiger O, Siegfried J, Wellis G. Octreotide may act as a radioprotective agent in acromegaly. J Clin Endocrinol Metab 85(3):1287-9, 2000.
Landolt AM, Lomax N. Gamma knife radiosurgery for prolactinomas. J Neurosurg 93(Suppl 3):14-8, 2000.
Langsenlehner T, Stiegler C, Quehenberger F, Feigl GC, Jakse G, Mokry M, Langsenlehner U, Kapp KS, Mayer R. Long-term follow-up of patients with pituitary macroadenomas after postoperative radiation therapy: Analysis of tumor control and functional outcome. Strahlenther Onkol 183(5):241-7, 2007.
Losa M, Gioia L, Picozzi P, Franzin A, Valle M, Giovanelli M, Mortini P. The role of stereotactic radiotherapy in patients with growth hormone-secreting pituitary adenoma. J Clin Endocrinol Metab 93(7):2546-52, 2008.
Minniti G, Brada M. Radiotherapy and radiosurgery for Cushing’s disease. Arq Bras Endocrinol Metabol 51(8):1373-80, 2007.
Minniti G, Gilbert DC, Brada M. Modern techniques for pituitary radiotherapy. Rev Endocr Metab Disord 10(2):135-44, 2009.
Ove R, Kelman S, Amin PP, Chin LS. Preservation of visual fields after peri-sellar gamma-knife radiosurgery. Int J Cancer 90(6):343-50, 2000.
Pamir MN, Kilic T, Belirgen M, Abacioglu U, Karabekiroglu N. Pituitary adenomas treated with gamma knife radiosurgery: Volumetric analysis of 100 cases with minimum 3 year follow-up. Neurosurgery 61(2):270-80, discussion 280, 2007.
Pollock BE, Brown PD, Nippoldt TB, Young WF, Jr. Pituitary tumor type affects the chance of biochemical remission after radiosurgery of hormone-secreting pituitary adenomas. Neurosurgery 62(6):1271-6, discussion 1276-8, 2008a.
Pollock BE, Cochran J, Natt N, Brown PD, Erickson D, Link MJ, Garces YI, Foote RL, Stafford SL, Schomberg PJ. Gamma knife radiosurgery for patients with nonfunctioning pituitary adenomas: Results from a 15-year experience. Int J Radiat Oncol Biol Phys 70(5):1325-9, 2008b.
Pollock BE, Jacob JT, Brown PD, Nippoldt TB. Radiosurgery of growth hormone-producing pituitary adenomas: Factors associated with biochemical remission. J Neurosurg 106(5):833-8, 2007.
Pouratian N, Sheehan J, Jagannathan J, Laws ER, Jr, Steiner L, Vance ML. Gamma knife radiosurgery for medically and surgically refractory prolactinomas. Neurosurgery 59(2):255-66, discussion 255-66, 2006.
Ronchi CL, Attanasio R, Verrua E, Cozzi R, Ferrante E, Loli P, Montefusco L, Motti E, Ferrari DI, Giugni E, Beck-Peccoz P, Arosio M. Efficacy and tolerability of gamma knife radiosurgery in acromegaly: A 10-year follow-up study. Clin Endocrinol (Oxf), epub ahead of print, Mar. 28, 2009.
Sheehan JP, Niranjan A, Sheehan JM, Jane JA, Jr, Laws ER, Kondziolka D, Flickinger J, Landolt AM, Loeffler JS, Lunsford LD. Stereotactic radiosurgery for pituitary adenomas: An intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium. J Neurosurg 102(4):678-91, 2005.
Snead FE, Amdur RJ, Morris CG, Mendenhall WM. Long-term outcomes of radiotherapy for pituitary adenomas. Int J Radiat Oncol Biol Phys 71(4):994-8, 2008.
Stafford SL, Pollock BE, Leavitt JA, Foote RL, Brown PD, Link MJ, Gorman DA, Schomberg PJ. A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 55(5):1177-81, 2003.
Tishler RB, Loeffler JS, Lunsford LD, Duma C, Alexander E, 3rd, Kooy HM, Flickinger JC. Tolerance of cranial nerves of the cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys 27(2):215-21, 1993.
Vik-Mo EO, Oksnes M, Pedersen PH, Wentzel-Larsen T, Rodahl E, Thorsen F, Schreiner T, Aanderud S, Lund-Johansen M. Gamma knife stereotactic radiosurgery for acromegaly. Eur J Endocrinol 157(3):255-63, 2007.
[Discovery Medicine (Discov Med), Volume 10, Number 51, August 2010. Pre-published.]