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Radiation techniques for acromegaly

Radiation techniques for acromegaly Radiotherapy (RT) remains an effective treatment in patients with acromegaly refractory to medical and/or surgical interventions, with durable tumor control and biochemical remission; however, there are still concerns about delayed biochemical effect and potential late toxicity of radiation treatment, especially high rates of hypopituitarism. Stereotactic radiotherapy has been developed as a more accurate technique of irradiation with more precise tumour localization and consequently a reduction in the volume of normal tissue, particularly the brain, irradiated to high radiation doses. Radiation can be delivered in a single fraction by stereotactic radiosurgery (SRS) or as fractionated stereotactic radiotherapy (FSRT) in which smaller doses are delivered over 5-6 weeks in 25- 30 treatments. A review of the recent literature suggests that pituitary irradiation is an effective treatment for acromegaly. Stereotactic techniques for GH-secreting pituitary tumors are discussed with the aim to define the efficacy and potential adverse effects of each of these techniques. Keywords: acromegaly, fractionated stereotactic radiotherapy, radiosurgery, toxicity, GH-secreting pituitary tumors Introduction Despite its efficacy, there are concerns about the neces- Acromegaly is a disorder caused by a pituitary GH- sity and potential toxicity of RT and its use remains secreting adenoma and characterized by high circulating matter of debate. levels of GH and IGF-I. It is associated with increased More recently, stereotactic radiation techniques have morbidity and mortality rates, especially due to respira- been employed in patients with acromegaly with the aim tory, cardiovascular disease, and malignant diseases [1]. of treating less normal brain and of minimizing the Surgery, medical therapy, and radiotherapy (RT) are the long-term consequences of RT while improving its available treatments employed with the aim of normaliz- effectiveness [7]. Stereotactic radiotherapy can be given ing GH and IGF-I hypersecretion, controlling pituitary as a single treatment (stereotactic radiosurgery-SRS) tumor mass effects, preventing recurrences, and improv- using either cobalt-60 gamma radiation-emitting sources ing morbidity. Transsphenoidal surgery is the procedure (Gamma-Knife) or linear accelerator (LINAC), or as of choice for the initial management of acromegaly, fractionated stereotactic radiotherapy (FSRT). Although leading to the remission of disease in 42-65% of patients stereotactic techniques have the clear advantage to offer [2], and achieving a rapid improvement of metabolic a more precise radiation delivery compared with con- and cardiovascular abnormalities [3,4]. Medical therapy, ventional RT, the question regarding their superiority mainly with long-acting somatostatin analogs, permits a and efficacy in the management of patients with acro- normalization of GH/IGF-I hypersecretion in up to 70% megaly remains to be demonstrated. of cases with an apparently low incidence of side effects In this review, we present a critical analysis of the more recent available literature in the management of [5]. RT is currently proposed to a subset of patients patients with acromegaly, in an attempt to define rea- with persistent active disease after surgery and/or during medical therapy. In most of published studies conven- sonably objective and comparative information on the tional RT achieves tumor growth control in 85-95% of safety and efficacy of the individual techniques. cases, dropping out GH/IGF-I levels to less than 5 ng/ ml in up to 80% of patients 10-15 years after RT [6]. Fractionated Radiotherapy Modern RT even without the recourse to stereotactic techniques has seen advances in all aspects of treatment * Correspondence: gminniti@ospedalesantandrea.it with better immobilization, imaging, planning and treat- Department of Neuroscience, Neuromed Institute, Pozzilli (IS), Italy ment. Patients are typically immobilized in a custom Full list of author information is available at the end of the article © 2011 Minniti et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Minniti et al. Radiation Oncology 2011, 6:167 Page 2 of 8 http://www.ro-journal.com/content/6/1/167 made plastic mask with movement limited to 2-5 mm. [8-15]. Differing from earlier series based on basal GH Tumour localization, initially based on plain X-ray levels < 5-10 μg/liter to evaluate the biochemical remis- visualization of the pituitary fossa, has improved with sion of acromegaly after pituitary irradiation, more strin- the routine use of fused CT/MRI imaging. A margin of gent criteria for disease control are currently used [16]. 3-10 mm beyond the visible extent of tumour is In a series of 45 patients with active acromegaly trea- included in the treatment planning to allow for patient ted with external beam RT at University of Rome La movement and set-up variation during the treatment. Sapienza between 1982 and 1994 survival rates were 98%, 95%, and 93%, and local tumor control rates 95% Three-dimensional (3D) treatment planning provides at 5, 10 and 15 years after treatment [14]. Biochemical more accurate visualization of dose distribution as com- pared with 2D planning, with the option of giving a remission of disease as defined by GH levels below 1 more homogeneous dose within the target and lower ng/ml during an oral glucose tolerance test (OGTT) was dose to the organs at risk of radiation toxicity. More seen in 9% of patients at 2 years, 29% at 5 years, 52% at precise delivery is achieved conforming the radiation 10 years, and 77% at 15 years, respectively. IGF-I levels beams to the shape of tumor (conformal radiotherapy) were normal in 8% of patients 2 years after RT, and this and increasing the number of beams. This results either proportion increased to 23%, 42% and 61% after 5,10 in reduction of volume of normal brain receiving high and 15 years, respectively. In a large retrospective series dose of radiation or in a greater dose differential of 656 patients with acromegaly treated with conven- between the target and normal brain tissue. The total tional pituitary irradiation in the United Kingdom the dose of 45-55Gyisachievedbydaily dosesof1.8-2.0 proportion of patients who achieved a safe GH (< 2.5 Gy, with treatment lasting for 5-6 weeks. ng/ml) was 22% at 2 years, 36% at 5 years, 60% at 10 Published series assessing the long term effectiveness years, and 74% at 15 years [15]. The biochemical remis- of conventional RT in patients with acromegaly report sion rates were 35%, 49%, 73%, and 88% at 2, 5, 10, and tumor control and normalization of GH/IGF-I levels in 15 years for patients with a preirradiation GH levels less the region of 80-90% and 50-60% at 10 years, respec- than 10 ng/ml, compared with 11%, 27%, 51%, and 69% tively. The reported results are summarized in Table 1 for patients with preirradiation GH levels of 10-30 ng/ Table 1 Summary of results of recent series on fractionated radiotherapy for GH-secreting pituitary adenoma Authors type patients total follow-up tumor biochemical remission late toxicity (%) of dose control RT (Gy) median % % visual hypopituitarism (months) Barkan et al., 1997 [8] CRT 38 46 80 NA 5 NA NA Thalassinos et al., 1998 CRT 46 45-50 86 100 25 and 21 at 5 and 10 0 30 at 10 years [9] years Barrande et al., 2000 [10] CRT 128 52 137 NA 35 and 53 at 5 and 10 3 50 at 10 years years Biermasz et al., 2000 [11] CRT 36 40 130 NA 40 and 61 at 5 and 10 0 29 and 54 at 5 and 10 years years Cozzi et al., 2001 [12] CRT 49 45 168 96 10 at 10 years 4 12 Epaminonda et al., 2001 CRT 67 40-75 120 NA 65 at 15 years 0 NA [13] Jenkins et al., 2006 [15] CRT 656 45 84 NA 36 and 64 at 5 and 10 0 58 at 10 years° years 74 at 15 years Minniti et al., 2005 [14] CRT 45 45 144 95 29 and 52 at 5 and 10 0 45 at 10 years years 77 at 15 years Milker-Zabel et al.,2004 FSRT 20 52.2 61 100 55 5 15 [26] Colin et al., 2005 [27] FSRT 31* 50.4 80 99 20 and 50 at 5 and 10 037 years Minniti et al., 2006 [28] FSRT 18* 45 39 98 50 at 5 years* 0 22 Roug et al., 2010 [29] FSRT 34 54 45 91 30 NA 29 CRT, conventional radiotherapy; FSRT, fractionated stereotactic radiotherapy. *acromegalic patients included in series of FSRT for either secreting or non secreting pituitary tumors. °hypogonadism 58%, hypothyroidism 27%, and hyposurrenalism 15%, respectively. Minniti et al. Radiation Oncology 2011, 6:167 Page 3 of 8 http://www.ro-journal.com/content/6/1/167 ml. Normalization of IGF-I was observed in 38% of FSRT is a refinement of high conformal RT with patients at 2 years, 50% at 5 years, 63% at 10 years, and further improvement in immobilization and delivery. 56% at 15 years, respectively. Similar effects of pituitary Patients undergoing FSRT are usually immobilized in a irradiation on GH and IGF-I levels have been reported highly precision frameless stereotactic mask fixation sys- in some other retrospective series [10,11]. tem with a reported accuracy of 1-2 mm [25], so that it Analysis of rate of declining of individual GH levels is possible to administrate stereotactic irradiation in a number of small doses/fractions. Thus, the principal aim shows that plasma GH declines gradually to approxi- of FSRT is to deliver more localized irradiation as com- mately 50% of the preirradiation value at 2 years, to 20% pared with conventional RT, leading to a reduction of at 5 years, and to 10% at 10 years, with a slower decline of IGF-I concentration in the range of 50%-60% at 10 thevolumeofnormalbrain tissueirradiated to high years [10,11,14]. This means that the interval to achieve radiation doses, possibly minimizing the long-term con- biochemical remission of acromegaly mainly depends on sequences of treatment. GH/IGF-I preirradiation levels. Although RT was found Only few series report on the use of FSRT in patients effective in the majority of treated patients in most ser- with GH-secreting pituitary adenomas showing tumor ies, few studies reported a less favourable outcome control and biochemical remission rates of 90-100% and [8,9,12]. Differences in the length of follow-up, disease 8-55% at a variable follow-up of 30-60 months [26-29] activity, and biochemical testing procedures may, at (Table 1). In a series of 18 patients with acromegaly trea- least in part, be responsible for these discrepancies. ted with FSRT at Royal Marsden Hospital biochemical The risk of late normal central nervous system toxicity remission was achieved in 35% after a median follow-up of external beam RT to doses less than 50 Gy at 2 Gy of 39 months [28]. Actuarial normalization of GH/IGF-I per fraction is low, with a reported incidence of optic levels was 20% at 3 years and 50% at 5 years. Milker- neuropathy resulting in visual deficits of 1-5%, and a Zabel et al. [26] reported 5-year local and hormonal con- risk of necrosis of normal brain structures of 0-2%. trol rates of 100% and 80%, respectively, in 20 patients Hypopituitarism represents the most commonly with acromegaly. At a median follow-up of 30 months reported late complication of RT, and its frequency Roug et al. [29] observed biochemical remission of dis- increases with longer follow-up, occurring in up to 60% ease, as defined by suppressed GH at OGTT and normal of irradiated patients 10 years after treatment (Table 1). IGF-I levels adjusted for age, in 30% of 34 patients with An increased incidence of cerebrovascular accidents active acromegaly, being 24%, 38% and 64% after 1,3 and 5 years, respectively. An additional 20% of patients (CVA) and related mortality has been reported in achieved normal GH and IGF-I levels with the use of patients with acromegaly treated with conventional RT [17,18]. Brada et al [17] found an increased mortality in somatostatin analogs during the follow-up. a series of 334 irradiated patients with a 1.6-fold excess A low radiation-induced toxicity has been reported of CVA, and similar results have been reported by after FSRT. Hypopituitarism is the most common com- others [18]. Since other possible risk factors include plication of treatment and has been reported in 15-37% GH/IGF-/excesses, hypopituitarism, and extensive sur- of patients at median follow-up ranging from 39 to 80 gery, a direct link between RT and cerebrovascular months, whereas the reported incidence of optic neuro- events remains to be proven. Conventional radiation of pathy is 1-5%. The incidence of hypopituitarism is likely pituitary tumors has been associated with the develop- to remain the major late effect of FSRT since it does ment of secondary radiation-induced neoplasm, usually not result in a significant reduction of dose to the a glioma or a meningioma [19,20]. In a cohort of 426 hypothalamus and the residual normal pituitary tissue. patients with pituitary adenomas [20] who received CRT Although no cases of CVA and second tumors have at the Royal Marsden Hospital (RMH) between 1962 been reported after FSRT, the incidence of the former and 1994, the cumulative risk of second brain tumours increases with time, and secondary tumors usually occur was 2.0% (95% CI: 0.9-4.4%) at 10 years and 2.4% (95% with many years delay. Although treating less normal CI: 1.2-5.0%) at 20 years. The results are in consistent brain at high radiation doses may translate in a reduc- with the reported cumulative risk of secondary glioma tion of the development of such radiation induced com- after radiation of 2.7% at 15 years in a cohort of 305 plications, large series and longer follow-ups need to patients with pituitary adenomas [19]. Developmental demonstrate these potential clinical advantages. Simi- problems leading to neurocognitive impairment, particu- larly, the lack of formal cognitive function testing and quality of life assessment in all published series does not larly in children, is a recognized consequence of large allow for definitive conclusion about the potential super- volume cranial irradiation [21]; however, there is little iority of stereotactic techniques as compared with 3D evidence that fractionated irradiation for pituitary ade- nomas may significantly alters cognitive function conformal RT, and this will need to be addressed in [22-24]. future studies. Minniti et al. Radiation Oncology 2011, 6:167 Page 4 of 8 http://www.ro-journal.com/content/6/1/167 Intensity-modulated radiation therapy (IMRT) repre- treat pituitary adenomas. In its most common design, a sents an advanced form of 3D conformal RT with the total of 201 sources of Co are arranged in a hemi- potential to achieve a much higher degree of target con- sphere and focused with a collimator helmet on a single formity while minimizing radiation exposure to sur- or multiple fixed points (isocenters). CT localization and rounding normal tissues, especially for tumors with computerized 3D planning are used to determine the complex shapes and concave regions close to sensitive optimal number and distribution of isocenters, and this structures. IMRT uses a series of multiple subfields cre- can be aided by selective occlusion of collimator aper- ated by a multileaf collimator (MLC) which move under tures. During SRS, patients are usually immobilized in a computer control creating modulated fields. IMRT treat- fixed frame with a positioning accuracy of < 1 mm. ment plans are generated using inverse planning system, Similar dose distribution can be obtained with a LINAC which uses computer optimization techniques to modu- using multiple noncoplanar arcs of rotation or multiple late intensities across the target volume and sensitive noncoplanar fixed beams. normal structures, starting from a specified dose distri- SRS has been extensively employed in the last two bution. IMRT may result in a more conformal and bet- decades in patients with residual pituitary tumors. At a ter coverage than 3D conformal RT and therefore is median follow-up ranging between 31 and 60 months able to spare more normal brain. In 34 patients with the reported tumor growth control following SRS in pituitary adenoma treated with IMRT at a median fol- patients with acromegaly is between 88 and 97% [34-48] low-up of 42 months local control was 89% [30]. How- (Table 2). A variable reduction in tumor size has been ever, there are no reported clinical data on IMRT in observed in 30-60% of patients after the treatment. acromegaly, and currently, it is not possible to conclude Biochemical remission of disease has been reported in that IMRT confers any advantage over other techniques 35-100% of patients with GH-secreting adenomas. The with respect to either hormonal control or toxicity. variable rate of control disease may reflect the different Particle radiation has been also applied successfully in lengths of follow-up and criteria used to define the bio- the treatment of pituitary adenomas. The physical prop- chemical control of disease, making difficult the evalua- erties of proton irradiation can offer superior conformal- tion of the real efficacy of SRS. Nevertheless, when ity in dose distribution when compared to 3D conformal stringent criteria of cure as defined by suppressed GH RT and IMRT. Distribution of low and intermediate levels during OGTT and normal age-corrected IGF-I dosestoportionsofthe braininchildrenirradiatedfor levels are considered, the 5-year actuarial biochemical common brain tumors are significantly lower with pro- remission has been reported in 30-60% of patients fol- tons when compared with photons [31], and the advan- lowing SRS, including patients who achieved normal tage becomes more apparent for large volumes. Proton GH/IGF-I levels during medical treatment with soma- therapy can be delivered as SRS or as FSRT with the tostatin analogs, and normalization of GH/IGF-I levels same immobilization systems and target accuracy of continues throughout the follow-up period [36,40-42,44] photon techniques. (Table 2). Petit JH et al [32] reported on 22 patients with persis- Losa et al [44] in a retrospective analysis of 83 tent acromegaly who were treated with single fraction patients with acromegaly treated with GK SRS at Uni- proton radiosurgery at Massachusetts General Hospital. versity of Milan San Raffaele between 1994 and 2006 Using a median dose of 20 GyE biochemical remission have reported actuarial biochemical remission rates of was achieved in 50% of patients, with a median time to 30%, 52% and 85% at 3, 5 and 10 years, respectively. complete response of 30.5 months. One-third of patients Jagannathan et al [43] observed normalization of the developed at least one new pituitary deficiency, requir- serum IGF-1 in 53% of 95 patients treated with GK SRS ing medical therapy. In a small series of 11 acromegalic and at least 18 months of follow-up. The mean time to patients treated with fractionated proton beam irradia- remission was 30 months; twelve patients achieved tion at a median time of 83 months hormonal normali- endocrine remission within the first year of treatment, zation occurred in 45% of patients, with an actuarial 28 within 2 years, and 34 within 3 years, respectively. rate of 23% at 5 years [33]. Currently, no data suggest Jezkova et al [39] in a series of 96 patients reported hor- the superiority of protons in the treatment of pituitary monal remission rates of 45% at 3 years, 58% at 5 years, tumors as compared with other radiation techniques. and 57% at 8 years, respectively. The median time to achieve GH suppression < 1 μg/l during an OGTT and Stereotactic radiosurgery (SRS) normal IGF-I was 66 months. Similar biochemical SRS is given using either a multiple cobalt-60 ( Co) remission rates in the range of 45-60% at 5 years have gamma radiation-emitting sources gamma knife (GK) or been shown by others [41,42], although lower rates have been reported in some series [34,36,40,48]. There are a modified linear accelerator (LINAC). GK is the most only few studies on the efficacy of LINAC SRS for the widely published radiosurgical methodology used to Minniti et al. Radiation Oncology 2011, 6:167 Page 5 of 8 http://www.ro-journal.com/content/6/1/167 Table 2 Summary of results of recent series on stereotactic radiosurgery for GH-secreting pituitary adenomas Authors patients type of total follow-up tumor biochemical remission late toxicity (%) dose SRS (Gy) median control (%) visual hypopituitarism (months) (%) Attanasio et al., 2003 [34] 30 GK SRS 20 46 100 30 at 5 years 0 6.7 Jane et al., 2003 [35] 64 GK SRS 15 > 18 NA 36 0 28 Castinetti et al., 2005 [36] 82 GK SRS 26 49.5* NA 17 1.2 17 Gutt et al., 2005 [37] 44 GK SRS 23 22 100 48 NA NA Kobayashi et al., 2005 67 GK SRS 18,9 63 100 17 11 15 [38] Jezkova et al., 2006 [39] 96 GK SRS 32 53.7 100 44 at 5 years 0 27.1 Voges et al., 2006 [40] 64 LINAC 16,5 54.3 97 14 and 33 at 3 and 5 1.4 13 and 18 at 3 and 5 SRS years years Petit et al., 2007 [32] 22 PSRS 20 GyE 75.6 100 59 0 38 Pollock et al., 2007 [41] 46 GK SRS 20 63 100 11 and 60 at 2 and 5 0 33 at 5 years years Vik-Mo et al., 2007 [42] 53 GK SRS 26.5 67 100 58 and 86 at 5 and 10 3.8 10 at 5 years years Jagannathan et al., 2008 95 GK SRS 22 57 98 53 4 34 [43] Losa et al., 2008 [44] 83 GK SRS 21,5 69 97 52 and 85 at 5 and 10 0 10 at 10 years years Ronchi et al., 2009 [45] 35 GK SRS 20 114 100 46 at 10 years 0 50 Wan et al., 2009 [46] 103 GK SRS 21,4 67 95 37 0 6 Hayashi et al., 2010 [47] 25 GK SRS 25.2 36 100 40 0 0 Iwai et al., 2010 [48] 26 GK SRS 20 84 96 17 and 47 at 5 and 10 08 years *mean follow-up; NA not assessed. SRS, stereotactic radiosurgery; GKS, Gamma Knife radiosurgery. PSRS; proton stereotactic radiosurgery. treatment of GH-secreting pituitary adenomas [40]; in normal, and 23% and 38% with IGF-I levels greater than general, they show comparable efficacy to GK SRS. 2.25 times the upper limit of normal, respectively. Several factors including preirradiation GH/IGF-I Although no relationship between baseline hormonal levels, the use of somatostatin analogs, and radiosurgical levels and remission of acromegaly has been reported in dose have been correlated with the endocrinological few series [34,42], it seems reasonable that patients with outcome after SRS, although disagreement exists across near-normal GH and IGF-I levels are more likely to the published series. achieve hormonal remission than patients with markedly High GH and/or IGF-I levels have been found inde- abnormal pretreatment levels. pendently associated with worse SRS outcome in some Whether the concomitant use of somatostatin analogs series [36,39,41,44], similar to that reported after con- at the time of SRS is a negative predictor of endocrine ventional RT [10,11,14,15]. Losa et al [44] reported a normalization remains matter of debate. In Landolt at median time for remission of 37 months for patients al. [49] and Pollock et al. [41] series the use of suppres- with pre-treatment GH levels ≤ 7 μg/liter as compared sive medications at the time of SRS negatively correlated with 93 months for patients with GH levels > 7 μg/liter. with biochemical remission of disease and increased the IGF-I levels ≤ 1.8 times the upper limit of normal time to hormonal normalization. In contrast, other reached remission at a median time of 36 months as authors failed to show any detrimental effect of medical compared with 90 months for patients with > 1.8 times treatment on outcome [34,36,44]. Although somatostatin analogs withdrawal before SRS has gained an increase the upper limit of normal. Similarly, in a retrospective analysis of 46 consecutive patients treated by SRS acceptance in clinical practice, future prospective studies between 1991 and 2004 at Mayo Clinic, preirradiation are needed to elucidate the issue. IGF-I levels were independently correlated with bio- A variable dose of 18-32 Gy has been employed for chemical remission. The 3-year and 5 year biochemical SRS in acromegaly. With some exceptions, marginal remission rates were 40% and 90% for patients with dose to the tumor was not independently associated IGF-I levels less than 2.25 times the upper limit of with higher rate of remission or faster normalization of Minniti et al. Radiation Oncology 2011, 6:167 Page 6 of 8 http://www.ro-journal.com/content/6/1/167 hormone hypersecretion [34-48].Currently,amarginal up of 25.4 months [53]. The efficacy of hypofractionated dose of about 20-25 Gy seems appropriate to achieve treatment schedules which may offer a reduced risk of either tumor control or hormonal normalization. radiation-related adverse effects as compared to single The reported overall rate of serious complications fraction radiosurgery needs to be evaluated in future after SRS is low (Table 2). The main complication is studies. hypopituitarism which is reported in 0-47% of patients, A comparison of SRS with FSRT in terms of endocri- nological outcome and toxicity is difficult to perform with higher rates in those series with longer median fol- since the choice of the different stereotactic treatment low-up (Table 2). Pollock et al. [41] reported that one modalities is based on different tumor characteristics: third of 39 patients with acromegaly had a new pituitary deficit following GK SRS, with an actuarial incidence of patients with large tumors in close proximity of optic new anterior pituitary deficits of 10% at 2 years and 33% apparatus are likely to be treated with FSRT than SRS. at 5 years, respectively. In a series of 95 patients with In current practice SRS is usually offered to patients acromegaly treated with GK SRS new endocrine defi- with relatively small adenomas less than 3 cm in size ciencies were observed in 34% of patients. Incidence was and more than 2-3 mm away from the optic apparatus only 5% at 12 months after SRS, however increased to in order to avoid irradiation of the optic apparatus more than 1/3 in patients with a follow-up longer than beyond single doses of 8-10 Gy. In contrast, there is no 49 months. A similar incidence of hypopituitarism at 5 restriction to the size and the position of adenomas sui- years in the region of 20-40% has been observed in few table for standard dose fractionated RT, since the treat- other series [39,42,45], suggesting that it will likely ment is delivered within the radiation tolerance limits of increase significantly over time. neural tissue, including the optic apparatus. Although Other treatment-related complications occur rarely early series reported a faster decline of serum GH con- after SRS. To minimize visual complications the dose centration after GK SRS as compared with FSRT received by optic apparatus is usually restricted to less [49,54], the superiority of SRS in terms of time to hor- than 8-10 Gy. In clinical practice this means that a dis- monal normalization remains to be demonstrated. tance between tumor margin and optic apparatus should Recent series have in fact showed that the rate of be at least of 2-3 mm to avoid the risk of visual dete- decline of GH/IGF-I levels observed following SRS is in rioration while delivering an effective dose of 16-20 Gy the same region of that observed following fractionated to the tumor. Cavernous sinus is frequently irradiated at RT, suggesting that the variable time to hormonal nor- malization is more dependent on preirradiation GH/ high dose in patients with residual pituitary tumor, IGF-I levels than differences in radiation techniques although cranial neuropathies, brain radionecrosis, and carotid artery stenosis have been reported infrequently [34,36]. A lower incidence of hypopituitarism has been following SRS. Loeffler et al. [50] reported two cases of suggested with the use of SRS as compared with FSRT, secondary brain tumors after SRS for a pituitary ade- although this is likely to reflect different patient selec- noma. The risk to develop a new tumor after SRS tion. SRS is usually used to treat patients with smaller appears to be significantly less than that seen following tumors than those treated with FSRT. Prospective stu- fractionated RT [20], however the relatively short length dies comparing SRS with fractionated stereotactic radio- of follow-up of most published series does not allow for therapy in patients with pituitary adenomas similar in any definitive conclusion. size would be of value to help define the long-term effi- CyberKnife (Accuray, Sunnyvale, CA) is a relatively cacy and toxicity of the techniques. new technological advancement in radiation therapy in which a miniaturized low energy linear accelerator is Conclusion mounted on a robotic arm. The main advantage of Radiation is highly effective in the management of Cyberknife system is that it allows for frameless image- patients with persistent active acromegaly after surgery guided radiation treatments achieving the same level of and/or during medical therapy. Long-term data clearly targeting precision as frame-based SRS. It can be used indicate that conventional RT is able to achieve bio- for multisession SRS (hypofractionated stereotactic chemical remission of disease in 50-60% of patients after radiotherapy) in patients with tumors involving the 10 years, with an acceptable incidence of complications. optic apparatus and who are not suitable for SRS [51]. Stereotactic techniques (SRS and FSRT) offer a more Initial experiences with the application of CyberKnife localized irradiation compared with conventional RT SRS or hypofractionated SRT in treating patients with and have the potential of reducing the risk of long term acromegaly are promising [52,53]. In a report of nine radiation induced morbidity. Currently, SRS and FSRT patients with acromegaly treated with CyberKnife to represent common treatment modalities of irradiation doses of 18-24 Gy in one to three fractions, biochemical for GH-secreting pituitary tumors, providing a compar- remission was observed in 4 patients at a mean follow able high rates of tumor control and endocrinological Minniti et al. Radiation Oncology 2011, 6:167 Page 7 of 8 http://www.ro-journal.com/content/6/1/167 (ALS) and IGFBP-3 levels in acromegaly. Clin Endocrinol (Oxf) 2001, remission with low morbidity. The choice of the radia- 55:183-189. tion technique should be based on tumor characteristics. 14. Minniti G, Jaffrain-Rea ML, Osti M, Esposito V, Santoro A, Solda F, Gargiulo P, In most centres SRS represent a convenient treatment Tamburrano G, Enrici RM: The long-term efficacy of conventional radiotherapy in patients with GH-secreting pituitary adenomas. Clin for patients with relatively small residual adenomas not Endocrinol (Oxf) 2005, 62:210-216. in close proximity of the optic chiasm, while FSRT is 15. Jenkins PJ, Bates P, Carson MN, Stewart PM, Wass JA: Conventional usually reserved to patients with larger GH-secreting pituitary irradiation is effective in lowering serum growth hormone and insulin-like growth factor-I in patients with acromegaly. J Clin Endocrinol tumors not amenable to SRS. Efficacy and toxicity of Metab 2006, 91:1239-1245. hypofractionated treatment schedules need to be 16. Giustina A, Chanson P, Bronstein MD, Klibanski A, Lamberts S, Casanueva FF, explored in future studies. Trainer P, Ghigo E, Ho K, Melmed S: Acromegaly Consensus Group. A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab 2010, 95:3141-3148. 17. Brada M, Ashley S, Ford D, Traish D, Burchell L, Rajan B: Cerebrovascular Author details mortality in patients with pituitary adenoma. Clin Endocrinol (Oxf) 2002, Department of Neuroscience, Neuromed Institute, Pozzilli (IS), Italy. 57:713-717. Department of Radiation Oncology, Sant’ Andrea Hospital, University 18. Erfurth EM, Bülow B, Svahn-Tapper G, Norrving B, Odh K, Mikoczy Z, Björk J, Sapienza, Rome, Italy. Hagmar L: Risk factors for cerebrovascular deaths in patients operated and irradiated for pituitary tumors. J Clin Endocrinol Metab 2002, Authors’ contributions 87:4892-4899. GM and CS performed the database search, critically reviewed the existing 19. Tsang RW, Laperriere NJ, Simpson WJ, Brierley J, Panzarella T, Smyth HS: data and drafted the manuscript. RME critically reviewed/revised the article. Glioma arising after radiation therapy for pituitary adenoma. A report of All authors read and approved the final manuscript. four patients and estimation of risk. Cancer 1993, 72:2227-2233. 20. 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Cognitive dysfunction in patients treated for pituitary tumours. J Clin Exp 2. Minniti G, Jaffrain-Rea ML, Esposito V, Santoro A, Tamburrano G, Cantore G: Neuropsychol 1997, 19:1-6. Evolving criteria for post-operative biochemical remission of acromegaly: 23. Noad R, Narayanan KR, Howlett T, Lincoln NB, Page RC: Evaluation of the can we achieve a definitive cure? An audit of surgical results on a large effect of radiotherapy for pituitary tumours on cognitive function and series and a review of the literature. Endocr Relat Cancer 2003, 10:611-619. quality of life. Clin Oncol (R Coll Radiol) 2004, 16:233-237. 3. Minniti G, Moroni C, Jaffrain-Rea ML, Esposito V, Santoro A, Affricano C, 24. 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Epaminonda P, Porretti S, Cappiello V, Beck-Peccoz P, Faglia G, Arosio M: management of persistent acromegaly. Endocr Pract 2007, 13:726-734. Efficacy of radiotherapy in normalizing serum IGF-I, acid-labile subunit Minniti et al. Radiation Oncology 2011, 6:167 Page 8 of 8 http://www.ro-journal.com/content/6/1/167 33. Ronson BB, Schulte RW, Han KP, Loredo LN, Slater JM, Slater JD: 54. Morange-Ramos I, Regis J, Dufour H, Andrieu JM, Grisoli F, Jaquet P, Fractionated proton beam irradiation of pituitary adenomas. Int J Radiat Peragut JC: Gamma-knife surgery for secreting pituitary adenomas. Acta Oncol Biol Phys 2006, 64:425-434. Neurochir (Wien) 1998, 140:437-443. 34. Attanasio R, Epaminonda P, Motti E, Giugni E, Ventrella L, Cozzi R, doi:10.1186/1748-717X-6-167 Farabola M, Loli P, Beck-Peccoz P, Arosio M: Gamma-knife radiosurgery in Cite this article as: Minniti et al.: Radiation techniques for acromegaly. acromegaly: a 4-year follow-up study. J Clin Endocrinol Metab 2003, Radiation Oncology 2011 6:167. 88:3105-3112. 35. Jane JA Jr, Vance ML, Woodburn CJ, Laws ER Jr: Stereotactic radiosurgery for hypersecreting pituitary tumors: part of a multimodality approach. Neurosurg Focus 2003, 14:e12. 36. Castinetti F, Taieb D, Kuhn JM, Chanson P, Tamura M, Jaquet P, Conte- Devolx B, Régis J, Dufour H, Brue T: Outcome of gamma knife radiosurgery in 82 patients with acromegaly: correlation with initial hypersecretion. J Clin Endocrinol Metab 2005, 90:4483-4488. 37. Gutt B, Wowra B, Alexandrov R, Uhl E, Schaaf L, Stalla GK, Schopohl J: Gamma-knife surgery is effective in normalising plasma insulin-like growth factor I in patients with acromegaly. Exp Clin Endocrinol Diabetes 2005, 113:219-224. 38. 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 2005, 102(Suppl):119-123. 39. 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Neurosurgery 2008, 62:1262-1269. 44. 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 2008, 93:2546-2552. 45. 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) 2009, 71:846-852. 46. Wan H, Chihiro O, Yuan S: MASEP gamma knife radiosurgery for secretory pituitary adenomas: experience in 347 consecutive cases. J Exp Clin Cancer Res 2009, 28:36. 47. Hayashi M, Chernov M, Tamura N, Nagai M, Yomo S, Ochiai T, Amano K, Izawa M, Hori T, Muragaki Y, Iseki H, Okada Y, Takakura K: Gamma Knife robotic microradiosurgery of pituitary adenomas invading the cavernous sinus: treatment concept and results in 89 cases. J Neurooncol 2010, 98:185-194. 48. Iwai Y, Yamanaka K, Yoshimura M, Kawasaki I, Yamagami K, Yoshioka K: Gamma knife radiosurgery for growth hormone-producing adenomas. J Clin Neurosci 2010, 17:299-304. 49. Landolt AM, Haller D, Lomax N, Scheib S, Schubiger O, Siegfried J, Wellis G: Stereotactic radiosurgery for recurrent surgically treated acromegaly: comparison with fractionated radiotherapy. J Neurosurg 1998, 88:1002-1008. Submit your next manuscript to BioMed Central 50. Loeffler JS, Niemierko A, Chapman PH: Second tumors after radiosurgery: and take full advantage of: tip of the iceberg or a bump in the road? Neurosurgery 2003, 52:1436-1440. • Convenient online submission 51. Adler JR Jr, Gibbs IC, Puataweepong P, Chang SD: Visual field preservation after multisession cyberknife radiosurgery for perioptic lesions. • Thorough peer review Neurosurgery 2006, 59:244-254. • No space constraints or color figure charges 52. Kajiwara K, Saito K, Yoshikawa K, Kato S, Akimura T, Nomura S, Ishihara H, • Immediate publication on acceptance Suzuki M: Image-guided stereotactic radiosurgery with the CyberKnife for pituitary adenomas. Minim Invasive Neurosurg 2005, 48:91-96. • Inclusion in PubMed, CAS, Scopus and Google Scholar 53. Roberts BK, Ouyang DL, Lad SP, Chang SD, Harsh GR, Adler JR Jr, Soltys SG, • Research which is freely available for redistribution Gibbs IC, Remedios L, Katznelson L: Efficacy and safety of CyberKnife radiosurgery for acromegaly. Pituitary 2007, 10:19-25. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Radiation techniques for acromegaly

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Copyright © 2011 by Minniti et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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10.1186/1748-717X-6-167
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22136376
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Abstract

Radiotherapy (RT) remains an effective treatment in patients with acromegaly refractory to medical and/or surgical interventions, with durable tumor control and biochemical remission; however, there are still concerns about delayed biochemical effect and potential late toxicity of radiation treatment, especially high rates of hypopituitarism. Stereotactic radiotherapy has been developed as a more accurate technique of irradiation with more precise tumour localization and consequently a reduction in the volume of normal tissue, particularly the brain, irradiated to high radiation doses. Radiation can be delivered in a single fraction by stereotactic radiosurgery (SRS) or as fractionated stereotactic radiotherapy (FSRT) in which smaller doses are delivered over 5-6 weeks in 25- 30 treatments. A review of the recent literature suggests that pituitary irradiation is an effective treatment for acromegaly. Stereotactic techniques for GH-secreting pituitary tumors are discussed with the aim to define the efficacy and potential adverse effects of each of these techniques. Keywords: acromegaly, fractionated stereotactic radiotherapy, radiosurgery, toxicity, GH-secreting pituitary tumors Introduction Despite its efficacy, there are concerns about the neces- Acromegaly is a disorder caused by a pituitary GH- sity and potential toxicity of RT and its use remains secreting adenoma and characterized by high circulating matter of debate. levels of GH and IGF-I. It is associated with increased More recently, stereotactic radiation techniques have morbidity and mortality rates, especially due to respira- been employed in patients with acromegaly with the aim tory, cardiovascular disease, and malignant diseases [1]. of treating less normal brain and of minimizing the Surgery, medical therapy, and radiotherapy (RT) are the long-term consequences of RT while improving its available treatments employed with the aim of normaliz- effectiveness [7]. Stereotactic radiotherapy can be given ing GH and IGF-I hypersecretion, controlling pituitary as a single treatment (stereotactic radiosurgery-SRS) tumor mass effects, preventing recurrences, and improv- using either cobalt-60 gamma radiation-emitting sources ing morbidity. Transsphenoidal surgery is the procedure (Gamma-Knife) or linear accelerator (LINAC), or as of choice for the initial management of acromegaly, fractionated stereotactic radiotherapy (FSRT). Although leading to the remission of disease in 42-65% of patients stereotactic techniques have the clear advantage to offer [2], and achieving a rapid improvement of metabolic a more precise radiation delivery compared with con- and cardiovascular abnormalities [3,4]. Medical therapy, ventional RT, the question regarding their superiority mainly with long-acting somatostatin analogs, permits a and efficacy in the management of patients with acro- normalization of GH/IGF-I hypersecretion in up to 70% megaly remains to be demonstrated. of cases with an apparently low incidence of side effects In this review, we present a critical analysis of the more recent available literature in the management of [5]. RT is currently proposed to a subset of patients patients with acromegaly, in an attempt to define rea- with persistent active disease after surgery and/or during medical therapy. In most of published studies conven- sonably objective and comparative information on the tional RT achieves tumor growth control in 85-95% of safety and efficacy of the individual techniques. cases, dropping out GH/IGF-I levels to less than 5 ng/ ml in up to 80% of patients 10-15 years after RT [6]. Fractionated Radiotherapy Modern RT even without the recourse to stereotactic techniques has seen advances in all aspects of treatment * Correspondence: gminniti@ospedalesantandrea.it with better immobilization, imaging, planning and treat- Department of Neuroscience, Neuromed Institute, Pozzilli (IS), Italy ment. Patients are typically immobilized in a custom Full list of author information is available at the end of the article © 2011 Minniti et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Minniti et al. Radiation Oncology 2011, 6:167 Page 2 of 8 http://www.ro-journal.com/content/6/1/167 made plastic mask with movement limited to 2-5 mm. [8-15]. Differing from earlier series based on basal GH Tumour localization, initially based on plain X-ray levels < 5-10 μg/liter to evaluate the biochemical remis- visualization of the pituitary fossa, has improved with sion of acromegaly after pituitary irradiation, more strin- the routine use of fused CT/MRI imaging. A margin of gent criteria for disease control are currently used [16]. 3-10 mm beyond the visible extent of tumour is In a series of 45 patients with active acromegaly trea- included in the treatment planning to allow for patient ted with external beam RT at University of Rome La movement and set-up variation during the treatment. Sapienza between 1982 and 1994 survival rates were 98%, 95%, and 93%, and local tumor control rates 95% Three-dimensional (3D) treatment planning provides at 5, 10 and 15 years after treatment [14]. Biochemical more accurate visualization of dose distribution as com- pared with 2D planning, with the option of giving a remission of disease as defined by GH levels below 1 more homogeneous dose within the target and lower ng/ml during an oral glucose tolerance test (OGTT) was dose to the organs at risk of radiation toxicity. More seen in 9% of patients at 2 years, 29% at 5 years, 52% at precise delivery is achieved conforming the radiation 10 years, and 77% at 15 years, respectively. IGF-I levels beams to the shape of tumor (conformal radiotherapy) were normal in 8% of patients 2 years after RT, and this and increasing the number of beams. This results either proportion increased to 23%, 42% and 61% after 5,10 in reduction of volume of normal brain receiving high and 15 years, respectively. In a large retrospective series dose of radiation or in a greater dose differential of 656 patients with acromegaly treated with conven- between the target and normal brain tissue. The total tional pituitary irradiation in the United Kingdom the dose of 45-55Gyisachievedbydaily dosesof1.8-2.0 proportion of patients who achieved a safe GH (< 2.5 Gy, with treatment lasting for 5-6 weeks. ng/ml) was 22% at 2 years, 36% at 5 years, 60% at 10 Published series assessing the long term effectiveness years, and 74% at 15 years [15]. The biochemical remis- of conventional RT in patients with acromegaly report sion rates were 35%, 49%, 73%, and 88% at 2, 5, 10, and tumor control and normalization of GH/IGF-I levels in 15 years for patients with a preirradiation GH levels less the region of 80-90% and 50-60% at 10 years, respec- than 10 ng/ml, compared with 11%, 27%, 51%, and 69% tively. The reported results are summarized in Table 1 for patients with preirradiation GH levels of 10-30 ng/ Table 1 Summary of results of recent series on fractionated radiotherapy for GH-secreting pituitary adenoma Authors type patients total follow-up tumor biochemical remission late toxicity (%) of dose control RT (Gy) median % % visual hypopituitarism (months) Barkan et al., 1997 [8] CRT 38 46 80 NA 5 NA NA Thalassinos et al., 1998 CRT 46 45-50 86 100 25 and 21 at 5 and 10 0 30 at 10 years [9] years Barrande et al., 2000 [10] CRT 128 52 137 NA 35 and 53 at 5 and 10 3 50 at 10 years years Biermasz et al., 2000 [11] CRT 36 40 130 NA 40 and 61 at 5 and 10 0 29 and 54 at 5 and 10 years years Cozzi et al., 2001 [12] CRT 49 45 168 96 10 at 10 years 4 12 Epaminonda et al., 2001 CRT 67 40-75 120 NA 65 at 15 years 0 NA [13] Jenkins et al., 2006 [15] CRT 656 45 84 NA 36 and 64 at 5 and 10 0 58 at 10 years° years 74 at 15 years Minniti et al., 2005 [14] CRT 45 45 144 95 29 and 52 at 5 and 10 0 45 at 10 years years 77 at 15 years Milker-Zabel et al.,2004 FSRT 20 52.2 61 100 55 5 15 [26] Colin et al., 2005 [27] FSRT 31* 50.4 80 99 20 and 50 at 5 and 10 037 years Minniti et al., 2006 [28] FSRT 18* 45 39 98 50 at 5 years* 0 22 Roug et al., 2010 [29] FSRT 34 54 45 91 30 NA 29 CRT, conventional radiotherapy; FSRT, fractionated stereotactic radiotherapy. *acromegalic patients included in series of FSRT for either secreting or non secreting pituitary tumors. °hypogonadism 58%, hypothyroidism 27%, and hyposurrenalism 15%, respectively. Minniti et al. Radiation Oncology 2011, 6:167 Page 3 of 8 http://www.ro-journal.com/content/6/1/167 ml. Normalization of IGF-I was observed in 38% of FSRT is a refinement of high conformal RT with patients at 2 years, 50% at 5 years, 63% at 10 years, and further improvement in immobilization and delivery. 56% at 15 years, respectively. Similar effects of pituitary Patients undergoing FSRT are usually immobilized in a irradiation on GH and IGF-I levels have been reported highly precision frameless stereotactic mask fixation sys- in some other retrospective series [10,11]. tem with a reported accuracy of 1-2 mm [25], so that it Analysis of rate of declining of individual GH levels is possible to administrate stereotactic irradiation in a number of small doses/fractions. Thus, the principal aim shows that plasma GH declines gradually to approxi- of FSRT is to deliver more localized irradiation as com- mately 50% of the preirradiation value at 2 years, to 20% pared with conventional RT, leading to a reduction of at 5 years, and to 10% at 10 years, with a slower decline of IGF-I concentration in the range of 50%-60% at 10 thevolumeofnormalbrain tissueirradiated to high years [10,11,14]. This means that the interval to achieve radiation doses, possibly minimizing the long-term con- biochemical remission of acromegaly mainly depends on sequences of treatment. GH/IGF-I preirradiation levels. Although RT was found Only few series report on the use of FSRT in patients effective in the majority of treated patients in most ser- with GH-secreting pituitary adenomas showing tumor ies, few studies reported a less favourable outcome control and biochemical remission rates of 90-100% and [8,9,12]. Differences in the length of follow-up, disease 8-55% at a variable follow-up of 30-60 months [26-29] activity, and biochemical testing procedures may, at (Table 1). In a series of 18 patients with acromegaly trea- least in part, be responsible for these discrepancies. ted with FSRT at Royal Marsden Hospital biochemical The risk of late normal central nervous system toxicity remission was achieved in 35% after a median follow-up of external beam RT to doses less than 50 Gy at 2 Gy of 39 months [28]. Actuarial normalization of GH/IGF-I per fraction is low, with a reported incidence of optic levels was 20% at 3 years and 50% at 5 years. Milker- neuropathy resulting in visual deficits of 1-5%, and a Zabel et al. [26] reported 5-year local and hormonal con- risk of necrosis of normal brain structures of 0-2%. trol rates of 100% and 80%, respectively, in 20 patients Hypopituitarism represents the most commonly with acromegaly. At a median follow-up of 30 months reported late complication of RT, and its frequency Roug et al. [29] observed biochemical remission of dis- increases with longer follow-up, occurring in up to 60% ease, as defined by suppressed GH at OGTT and normal of irradiated patients 10 years after treatment (Table 1). IGF-I levels adjusted for age, in 30% of 34 patients with An increased incidence of cerebrovascular accidents active acromegaly, being 24%, 38% and 64% after 1,3 and 5 years, respectively. An additional 20% of patients (CVA) and related mortality has been reported in achieved normal GH and IGF-I levels with the use of patients with acromegaly treated with conventional RT [17,18]. Brada et al [17] found an increased mortality in somatostatin analogs during the follow-up. a series of 334 irradiated patients with a 1.6-fold excess A low radiation-induced toxicity has been reported of CVA, and similar results have been reported by after FSRT. Hypopituitarism is the most common com- others [18]. Since other possible risk factors include plication of treatment and has been reported in 15-37% GH/IGF-/excesses, hypopituitarism, and extensive sur- of patients at median follow-up ranging from 39 to 80 gery, a direct link between RT and cerebrovascular months, whereas the reported incidence of optic neuro- events remains to be proven. Conventional radiation of pathy is 1-5%. The incidence of hypopituitarism is likely pituitary tumors has been associated with the develop- to remain the major late effect of FSRT since it does ment of secondary radiation-induced neoplasm, usually not result in a significant reduction of dose to the a glioma or a meningioma [19,20]. In a cohort of 426 hypothalamus and the residual normal pituitary tissue. patients with pituitary adenomas [20] who received CRT Although no cases of CVA and second tumors have at the Royal Marsden Hospital (RMH) between 1962 been reported after FSRT, the incidence of the former and 1994, the cumulative risk of second brain tumours increases with time, and secondary tumors usually occur was 2.0% (95% CI: 0.9-4.4%) at 10 years and 2.4% (95% with many years delay. Although treating less normal CI: 1.2-5.0%) at 20 years. The results are in consistent brain at high radiation doses may translate in a reduc- with the reported cumulative risk of secondary glioma tion of the development of such radiation induced com- after radiation of 2.7% at 15 years in a cohort of 305 plications, large series and longer follow-ups need to patients with pituitary adenomas [19]. Developmental demonstrate these potential clinical advantages. Simi- problems leading to neurocognitive impairment, particu- larly, the lack of formal cognitive function testing and quality of life assessment in all published series does not larly in children, is a recognized consequence of large allow for definitive conclusion about the potential super- volume cranial irradiation [21]; however, there is little iority of stereotactic techniques as compared with 3D evidence that fractionated irradiation for pituitary ade- nomas may significantly alters cognitive function conformal RT, and this will need to be addressed in [22-24]. future studies. Minniti et al. Radiation Oncology 2011, 6:167 Page 4 of 8 http://www.ro-journal.com/content/6/1/167 Intensity-modulated radiation therapy (IMRT) repre- treat pituitary adenomas. In its most common design, a sents an advanced form of 3D conformal RT with the total of 201 sources of Co are arranged in a hemi- potential to achieve a much higher degree of target con- sphere and focused with a collimator helmet on a single formity while minimizing radiation exposure to sur- or multiple fixed points (isocenters). CT localization and rounding normal tissues, especially for tumors with computerized 3D planning are used to determine the complex shapes and concave regions close to sensitive optimal number and distribution of isocenters, and this structures. IMRT uses a series of multiple subfields cre- can be aided by selective occlusion of collimator aper- ated by a multileaf collimator (MLC) which move under tures. During SRS, patients are usually immobilized in a computer control creating modulated fields. IMRT treat- fixed frame with a positioning accuracy of < 1 mm. ment plans are generated using inverse planning system, Similar dose distribution can be obtained with a LINAC which uses computer optimization techniques to modu- using multiple noncoplanar arcs of rotation or multiple late intensities across the target volume and sensitive noncoplanar fixed beams. normal structures, starting from a specified dose distri- SRS has been extensively employed in the last two bution. IMRT may result in a more conformal and bet- decades in patients with residual pituitary tumors. At a ter coverage than 3D conformal RT and therefore is median follow-up ranging between 31 and 60 months able to spare more normal brain. In 34 patients with the reported tumor growth control following SRS in pituitary adenoma treated with IMRT at a median fol- patients with acromegaly is between 88 and 97% [34-48] low-up of 42 months local control was 89% [30]. How- (Table 2). A variable reduction in tumor size has been ever, there are no reported clinical data on IMRT in observed in 30-60% of patients after the treatment. acromegaly, and currently, it is not possible to conclude Biochemical remission of disease has been reported in that IMRT confers any advantage over other techniques 35-100% of patients with GH-secreting adenomas. The with respect to either hormonal control or toxicity. variable rate of control disease may reflect the different Particle radiation has been also applied successfully in lengths of follow-up and criteria used to define the bio- the treatment of pituitary adenomas. The physical prop- chemical control of disease, making difficult the evalua- erties of proton irradiation can offer superior conformal- tion of the real efficacy of SRS. Nevertheless, when ity in dose distribution when compared to 3D conformal stringent criteria of cure as defined by suppressed GH RT and IMRT. Distribution of low and intermediate levels during OGTT and normal age-corrected IGF-I dosestoportionsofthe braininchildrenirradiatedfor levels are considered, the 5-year actuarial biochemical common brain tumors are significantly lower with pro- remission has been reported in 30-60% of patients fol- tons when compared with photons [31], and the advan- lowing SRS, including patients who achieved normal tage becomes more apparent for large volumes. Proton GH/IGF-I levels during medical treatment with soma- therapy can be delivered as SRS or as FSRT with the tostatin analogs, and normalization of GH/IGF-I levels same immobilization systems and target accuracy of continues throughout the follow-up period [36,40-42,44] photon techniques. (Table 2). Petit JH et al [32] reported on 22 patients with persis- Losa et al [44] in a retrospective analysis of 83 tent acromegaly who were treated with single fraction patients with acromegaly treated with GK SRS at Uni- proton radiosurgery at Massachusetts General Hospital. versity of Milan San Raffaele between 1994 and 2006 Using a median dose of 20 GyE biochemical remission have reported actuarial biochemical remission rates of was achieved in 50% of patients, with a median time to 30%, 52% and 85% at 3, 5 and 10 years, respectively. complete response of 30.5 months. One-third of patients Jagannathan et al [43] observed normalization of the developed at least one new pituitary deficiency, requir- serum IGF-1 in 53% of 95 patients treated with GK SRS ing medical therapy. In a small series of 11 acromegalic and at least 18 months of follow-up. The mean time to patients treated with fractionated proton beam irradia- remission was 30 months; twelve patients achieved tion at a median time of 83 months hormonal normali- endocrine remission within the first year of treatment, zation occurred in 45% of patients, with an actuarial 28 within 2 years, and 34 within 3 years, respectively. rate of 23% at 5 years [33]. Currently, no data suggest Jezkova et al [39] in a series of 96 patients reported hor- the superiority of protons in the treatment of pituitary monal remission rates of 45% at 3 years, 58% at 5 years, tumors as compared with other radiation techniques. and 57% at 8 years, respectively. The median time to achieve GH suppression < 1 μg/l during an OGTT and Stereotactic radiosurgery (SRS) normal IGF-I was 66 months. Similar biochemical SRS is given using either a multiple cobalt-60 ( Co) remission rates in the range of 45-60% at 5 years have gamma radiation-emitting sources gamma knife (GK) or been shown by others [41,42], although lower rates have been reported in some series [34,36,40,48]. There are a modified linear accelerator (LINAC). GK is the most only few studies on the efficacy of LINAC SRS for the widely published radiosurgical methodology used to Minniti et al. Radiation Oncology 2011, 6:167 Page 5 of 8 http://www.ro-journal.com/content/6/1/167 Table 2 Summary of results of recent series on stereotactic radiosurgery for GH-secreting pituitary adenomas Authors patients type of total follow-up tumor biochemical remission late toxicity (%) dose SRS (Gy) median control (%) visual hypopituitarism (months) (%) Attanasio et al., 2003 [34] 30 GK SRS 20 46 100 30 at 5 years 0 6.7 Jane et al., 2003 [35] 64 GK SRS 15 > 18 NA 36 0 28 Castinetti et al., 2005 [36] 82 GK SRS 26 49.5* NA 17 1.2 17 Gutt et al., 2005 [37] 44 GK SRS 23 22 100 48 NA NA Kobayashi et al., 2005 67 GK SRS 18,9 63 100 17 11 15 [38] Jezkova et al., 2006 [39] 96 GK SRS 32 53.7 100 44 at 5 years 0 27.1 Voges et al., 2006 [40] 64 LINAC 16,5 54.3 97 14 and 33 at 3 and 5 1.4 13 and 18 at 3 and 5 SRS years years Petit et al., 2007 [32] 22 PSRS 20 GyE 75.6 100 59 0 38 Pollock et al., 2007 [41] 46 GK SRS 20 63 100 11 and 60 at 2 and 5 0 33 at 5 years years Vik-Mo et al., 2007 [42] 53 GK SRS 26.5 67 100 58 and 86 at 5 and 10 3.8 10 at 5 years years Jagannathan et al., 2008 95 GK SRS 22 57 98 53 4 34 [43] Losa et al., 2008 [44] 83 GK SRS 21,5 69 97 52 and 85 at 5 and 10 0 10 at 10 years years Ronchi et al., 2009 [45] 35 GK SRS 20 114 100 46 at 10 years 0 50 Wan et al., 2009 [46] 103 GK SRS 21,4 67 95 37 0 6 Hayashi et al., 2010 [47] 25 GK SRS 25.2 36 100 40 0 0 Iwai et al., 2010 [48] 26 GK SRS 20 84 96 17 and 47 at 5 and 10 08 years *mean follow-up; NA not assessed. SRS, stereotactic radiosurgery; GKS, Gamma Knife radiosurgery. PSRS; proton stereotactic radiosurgery. treatment of GH-secreting pituitary adenomas [40]; in normal, and 23% and 38% with IGF-I levels greater than general, they show comparable efficacy to GK SRS. 2.25 times the upper limit of normal, respectively. Several factors including preirradiation GH/IGF-I Although no relationship between baseline hormonal levels, the use of somatostatin analogs, and radiosurgical levels and remission of acromegaly has been reported in dose have been correlated with the endocrinological few series [34,42], it seems reasonable that patients with outcome after SRS, although disagreement exists across near-normal GH and IGF-I levels are more likely to the published series. achieve hormonal remission than patients with markedly High GH and/or IGF-I levels have been found inde- abnormal pretreatment levels. pendently associated with worse SRS outcome in some Whether the concomitant use of somatostatin analogs series [36,39,41,44], similar to that reported after con- at the time of SRS is a negative predictor of endocrine ventional RT [10,11,14,15]. Losa et al [44] reported a normalization remains matter of debate. In Landolt at median time for remission of 37 months for patients al. [49] and Pollock et al. [41] series the use of suppres- with pre-treatment GH levels ≤ 7 μg/liter as compared sive medications at the time of SRS negatively correlated with 93 months for patients with GH levels > 7 μg/liter. with biochemical remission of disease and increased the IGF-I levels ≤ 1.8 times the upper limit of normal time to hormonal normalization. In contrast, other reached remission at a median time of 36 months as authors failed to show any detrimental effect of medical compared with 90 months for patients with > 1.8 times treatment on outcome [34,36,44]. Although somatostatin analogs withdrawal before SRS has gained an increase the upper limit of normal. Similarly, in a retrospective analysis of 46 consecutive patients treated by SRS acceptance in clinical practice, future prospective studies between 1991 and 2004 at Mayo Clinic, preirradiation are needed to elucidate the issue. IGF-I levels were independently correlated with bio- A variable dose of 18-32 Gy has been employed for chemical remission. The 3-year and 5 year biochemical SRS in acromegaly. With some exceptions, marginal remission rates were 40% and 90% for patients with dose to the tumor was not independently associated IGF-I levels less than 2.25 times the upper limit of with higher rate of remission or faster normalization of Minniti et al. Radiation Oncology 2011, 6:167 Page 6 of 8 http://www.ro-journal.com/content/6/1/167 hormone hypersecretion [34-48].Currently,amarginal up of 25.4 months [53]. The efficacy of hypofractionated dose of about 20-25 Gy seems appropriate to achieve treatment schedules which may offer a reduced risk of either tumor control or hormonal normalization. radiation-related adverse effects as compared to single The reported overall rate of serious complications fraction radiosurgery needs to be evaluated in future after SRS is low (Table 2). The main complication is studies. hypopituitarism which is reported in 0-47% of patients, A comparison of SRS with FSRT in terms of endocri- nological outcome and toxicity is difficult to perform with higher rates in those series with longer median fol- since the choice of the different stereotactic treatment low-up (Table 2). Pollock et al. [41] reported that one modalities is based on different tumor characteristics: third of 39 patients with acromegaly had a new pituitary deficit following GK SRS, with an actuarial incidence of patients with large tumors in close proximity of optic new anterior pituitary deficits of 10% at 2 years and 33% apparatus are likely to be treated with FSRT than SRS. at 5 years, respectively. In a series of 95 patients with In current practice SRS is usually offered to patients acromegaly treated with GK SRS new endocrine defi- with relatively small adenomas less than 3 cm in size ciencies were observed in 34% of patients. Incidence was and more than 2-3 mm away from the optic apparatus only 5% at 12 months after SRS, however increased to in order to avoid irradiation of the optic apparatus more than 1/3 in patients with a follow-up longer than beyond single doses of 8-10 Gy. In contrast, there is no 49 months. A similar incidence of hypopituitarism at 5 restriction to the size and the position of adenomas sui- years in the region of 20-40% has been observed in few table for standard dose fractionated RT, since the treat- other series [39,42,45], suggesting that it will likely ment is delivered within the radiation tolerance limits of increase significantly over time. neural tissue, including the optic apparatus. Although Other treatment-related complications occur rarely early series reported a faster decline of serum GH con- after SRS. To minimize visual complications the dose centration after GK SRS as compared with FSRT received by optic apparatus is usually restricted to less [49,54], the superiority of SRS in terms of time to hor- than 8-10 Gy. In clinical practice this means that a dis- monal normalization remains to be demonstrated. tance between tumor margin and optic apparatus should Recent series have in fact showed that the rate of be at least of 2-3 mm to avoid the risk of visual dete- decline of GH/IGF-I levels observed following SRS is in rioration while delivering an effective dose of 16-20 Gy the same region of that observed following fractionated to the tumor. Cavernous sinus is frequently irradiated at RT, suggesting that the variable time to hormonal nor- malization is more dependent on preirradiation GH/ high dose in patients with residual pituitary tumor, IGF-I levels than differences in radiation techniques although cranial neuropathies, brain radionecrosis, and carotid artery stenosis have been reported infrequently [34,36]. A lower incidence of hypopituitarism has been following SRS. Loeffler et al. [50] reported two cases of suggested with the use of SRS as compared with FSRT, secondary brain tumors after SRS for a pituitary ade- although this is likely to reflect different patient selec- noma. The risk to develop a new tumor after SRS tion. SRS is usually used to treat patients with smaller appears to be significantly less than that seen following tumors than those treated with FSRT. Prospective stu- fractionated RT [20], however the relatively short length dies comparing SRS with fractionated stereotactic radio- of follow-up of most published series does not allow for therapy in patients with pituitary adenomas similar in any definitive conclusion. size would be of value to help define the long-term effi- CyberKnife (Accuray, Sunnyvale, CA) is a relatively cacy and toxicity of the techniques. new technological advancement in radiation therapy in which a miniaturized low energy linear accelerator is Conclusion mounted on a robotic arm. The main advantage of Radiation is highly effective in the management of Cyberknife system is that it allows for frameless image- patients with persistent active acromegaly after surgery guided radiation treatments achieving the same level of and/or during medical therapy. Long-term data clearly targeting precision as frame-based SRS. It can be used indicate that conventional RT is able to achieve bio- for multisession SRS (hypofractionated stereotactic chemical remission of disease in 50-60% of patients after radiotherapy) in patients with tumors involving the 10 years, with an acceptable incidence of complications. optic apparatus and who are not suitable for SRS [51]. Stereotactic techniques (SRS and FSRT) offer a more Initial experiences with the application of CyberKnife localized irradiation compared with conventional RT SRS or hypofractionated SRT in treating patients with and have the potential of reducing the risk of long term acromegaly are promising [52,53]. In a report of nine radiation induced morbidity. Currently, SRS and FSRT patients with acromegaly treated with CyberKnife to represent common treatment modalities of irradiation doses of 18-24 Gy in one to three fractions, biochemical for GH-secreting pituitary tumors, providing a compar- remission was observed in 4 patients at a mean follow able high rates of tumor control and endocrinological Minniti et al. Radiation Oncology 2011, 6:167 Page 7 of 8 http://www.ro-journal.com/content/6/1/167 (ALS) and IGFBP-3 levels in acromegaly. Clin Endocrinol (Oxf) 2001, remission with low morbidity. The choice of the radia- 55:183-189. tion technique should be based on tumor characteristics. 14. Minniti G, Jaffrain-Rea ML, Osti M, Esposito V, Santoro A, Solda F, Gargiulo P, In most centres SRS represent a convenient treatment Tamburrano G, Enrici RM: The long-term efficacy of conventional radiotherapy in patients with GH-secreting pituitary adenomas. Clin for patients with relatively small residual adenomas not Endocrinol (Oxf) 2005, 62:210-216. in close proximity of the optic chiasm, while FSRT is 15. Jenkins PJ, Bates P, Carson MN, Stewart PM, Wass JA: Conventional usually reserved to patients with larger GH-secreting pituitary irradiation is effective in lowering serum growth hormone and insulin-like growth factor-I in patients with acromegaly. J Clin Endocrinol tumors not amenable to SRS. Efficacy and toxicity of Metab 2006, 91:1239-1245. hypofractionated treatment schedules need to be 16. Giustina A, Chanson P, Bronstein MD, Klibanski A, Lamberts S, Casanueva FF, explored in future studies. Trainer P, Ghigo E, Ho K, Melmed S: Acromegaly Consensus Group. A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab 2010, 95:3141-3148. 17. Brada M, Ashley S, Ford D, Traish D, Burchell L, Rajan B: Cerebrovascular Author details mortality in patients with pituitary adenoma. Clin Endocrinol (Oxf) 2002, Department of Neuroscience, Neuromed Institute, Pozzilli (IS), Italy. 57:713-717. Department of Radiation Oncology, Sant’ Andrea Hospital, University 18. Erfurth EM, Bülow B, Svahn-Tapper G, Norrving B, Odh K, Mikoczy Z, Björk J, Sapienza, Rome, Italy. Hagmar L: Risk factors for cerebrovascular deaths in patients operated and irradiated for pituitary tumors. J Clin Endocrinol Metab 2002, Authors’ contributions 87:4892-4899. GM and CS performed the database search, critically reviewed the existing 19. Tsang RW, Laperriere NJ, Simpson WJ, Brierley J, Panzarella T, Smyth HS: data and drafted the manuscript. RME critically reviewed/revised the article. Glioma arising after radiation therapy for pituitary adenoma. A report of All authors read and approved the final manuscript. four patients and estimation of risk. Cancer 1993, 72:2227-2233. 20. 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Radiation OncologySpringer Journals

Published: Dec 2, 2011

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