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Modern Methods of Stereotactic Radiosurgery and Radiotherapy for the Treatment of Cushing Disease
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.287663
Keywords: Conventional-RT, Cushing disease, cyber-knife, fractionated stereotactic radiosurgery, gamma-knife, proton-therapy. stereotactic radiosurgery, radiotherapyKey Message: The modern methods of Radiosurgery and Hypo fractionated radiosurgery allow us to achieve quicker remission in most patients with CD with minimal risk of complications. Is used as adjoining treatment to TSS or alternative treatment for variable severities of CD or as an alternative to bilateral adrenalectomy (in severe cases).
It is severe neuroendocrine disorder associated with chronic hypersecretion of ACTH hormone caused by corticotroph-adenomas of pituitary gland. Increased secretion of ACTH causes hypersecretion of cortisol from the adrenal glands and induces endogenous hyper-cortisolism with clinical features of dysplastic obesity, hypertension, reproductive disorders, glucose metabolism disorders, osteoporosis, cognitive derangements, and behavioral changes. The first choice treatment method is trans-sphenoidal adenomectomy. Remission rates ranges from 65 to 90% even in specialized neuro-endocrinological centers. Radiation treatment modalities are considered second line treatment, in cases of incomplete surgical resection due to allocation of lesion in surgically non accessible allocations and no remission, in cases of recurrence after initial remission, and in cases when there are contraindication to surgical resection.[1] Use of radiation therapy to treat CD has a long history, Harvey Cushing was the first who treated Cushing disease by conventional radiation therapy. Following him, Alfred Pattison implanted radon seeds in the pituitary fossa in order to radiate and treat the lesion.[2] Modern methods of stereotactic radiation therapy includes radiosurgery, hypofractionated and standard fractionated radiation techniques, which have high precision with maximum conformity of radiation on the lesions and a minimum irradiation on the surrounding normal tissues. For planning a radiation therapy, the use of modern neuro-diagnostic techniques is very important. In this literature review the efficiency of different radiation techniques (conventional/modern techniques), and the possible complications of conventional/modern methods to treat Cushing disease have been looked for.
(1) Absence of remission after initial surgical resection, specifically when there is no lesion visible in postoperative follow-up MRI, and when the presence of other ectopic lesions is ruled out by specific investigations. (2) Lesions of Cushing disease which are not amendable to complete surgical resection or when lesions have pervasive behavior with invasion into the surrounding important anatomical structures. (3) For prophylaxis of Nelson's disease, after bilateral adrenalectomy. Radiation therapy can prevent the progressive growth of Corticotroph adenomas, which occurs in response to decrease in the inhibitory effect of cortisol. (4) Patients who cannot tolerate surgical procedure as a first line treatment. (5) In patients who are not willing to undergo surgery.[3],[4],[5] Treatment of recurrent Cushing disease is challenging, repeat surgical resection is the method of choice, but repeat surgery is associated with even higher rates of recurrences in comparison to the primary surgery and is associate with other complications such as development of pan hypopituitarism, persistent diabetes insipidus, and higher rates of postoperative CSF leakages. Radiation therapy for the treatment of recurrence of Cushing disease is effective in around 2 / 3 of patients but also have associating complications which are discussed here in details.[6],[7]
At present radiosurgery is widely used for the treatment of Cushing disease in the form of linear accelerator (Linac, Cyberknife), Gamma Knife, or Proton accelerators, which in spite the ability to control the growth of lesion simultaneously brings hormonal remission.[2],[7] Gamma-knife The first apparatus of Gamma Knife (GK; Elekta, Stockholm, Sweden) was developed by the Swedish neurosurgeon Leksell L. in 1951.[8] In this modality a high dose of radiation is delivered with high accuracy to the intracranial targets in a single session. This modern method of SRS is effective in the treatment of Cushing disease and the remission rate according to different authors ranges between 35 and 83%.[7],[8] In one of the largest studies till date which included 278 patients followed for up to 15 years,[9] the control rate of hypercortisolism was reported close to 80% for gamma knife SRS and final remission was seen in 64% of cases in a period of 10 years. The most important finding of this study was the length of the mean time to reach anti-secretory efficacy which was 14.5 months which also showed that the drug therapy used for the control of hypercortisolims are used for a shorter period of time while awaiting the effects of radiotherapy.[4],[6],[9],[10] In a recent study performed by Joshua D et al., the simultaneous use of adrenalectomy with gamma knife was proposed in cases when severe hypercortisolism was present. The major factor for a simultaneous use of these both techniques was the need for acute control of hypercortisolism.[11] In the literature very little is found about the use of gamma knife radiosurgery as the first line of treatment, however in the study performed by Gautam et al., 22 patients were analyzed who underwent stereotactic hypophysectomy in different centers in the world and it was found that stereotactic hypophysectomy is efficient and the control of hypercortisolism was observed in 68% of patients.[9]
There is very little written about the use of linear accelerators for the treatment of CD. In a study performed by P.J. Wilson carried to compare the results of linear accelerator method with the old conventional EBRT system, better tumor growth control of almost 83% and better control of hypercortisolism was shown with a significant faster control time after radiation in comparison to the older external beam radiation therapy (EBRT) system where the results of tumor growth control were 46%.[12] When analyzed on average after 66 months (range 0-183.6 months), biochemical remission was observed in 5.6% of patients (based on the level of cortisol in the blood) and in 22.2% of patients (based on the level of free cortisol in 24 hour urine collection).[12] In addition, 25–36.1% of patients showed biochemical improvement based on the level of cortisol in the blood or the level of free cortisol in 24 h urine collection, respectively.[12] Further studies are required to compare the efficacy of this stereotactic radiosurgery method in treating Cushing's disease and compare its use with the Gamma knife and cyberknife methods of treatments. Cyberknife Cyberknife (CK) is a robotic-based SRS system developed by Adler et al. in 1987.[13] In this system a linear accelerator which has 6 different free arm movement can target different targets without the use of stereotactic frames for radiation and can target different lesions in any localization.[14] Due to the greater prevalence of hormone-inactive pituitary adenomas, it is used after non-radical removal of lesions.[14] Possible complications are similar to other SRS methods (most often complication is the development of hypopituitarism).[15] Currently, there is little data on the use of the CK for the treatment of Cushing disease. In study carried by Moore JM for the treatment of CD, by CK when performed as an adjuvant therapy in patients with no remission or recurrence of hypercortisolism. Remission of hypercortisolism was achieved in 4 patients (57.1%) on average after 12.5 months post-radiation.[16] Proton therapy It is different radiation modality using high energy particle (protons instead of photons), which are losing their energy fairly slowly through the media it passes through, but then at sudden, at the end of their range of motion they lose whole bunch of energy at ones (Bragg peak effect) at the targeted location. In this form of radiation therapy exposure of normal brain tissue into radiation is extremely low and at the same time the target is receiving higher doses of radiation. It is believed that this modality will be more effective in large volume pituitary adenomas which requires treatment of the entire Sella or even extrasellar regions.[14] Proton therapy can be performed as single session fraction stereotactic radiosurgery (PSRS) or in multiple fractionated stereotactic radiotherapy sessions (PSRT). Proton therapy machines are very expensive, very heavy, and its maintenance is very difficult, not available everywhere and as such the price of treatment is also higher, only few centers have these machines worldwide but now it is getting popular and its use is growing for treatment of adenomas.[17] Very limited studies are present in literature about its use for the treatment of Cushing disease till yet. In a study carried by Joshua H et al., carried on 38 patients with the diagnosis of Cushing disease and Nilsson's syndrome, 52% (17) patient were in complete remission in a median time of 18 months (5–49 months) after treatment, and in a median follow-up of 62 months (range 20–136) in MRI no secondary tumors was noted and no clinical evidence of optic nerve damage, seizure, or brain injury was seen but all these patients developed new pituitary hormone deficits(hypopituitarism). This study concluded that PSRS is effective treatment modality with significant lower morbidity.[18] In another study performed in Russia in which 98 patient of Cushing disease underwent proton therapy with an exposure dose of 80–90 Gy (50–110), 90% of patient showed normal biochemical indices in the absence of any clinical signs of the disease. And in a follow-up after 3 and 5 years 94% patients remained in steady remission.[19] In another study carried by Wattson DA et al. results of proton therapy of 144 patients, including 74 patients with Cushing disease, with a follow-up period of 52 months on average (6–247.2 months) in this study normalization of cortisol level was considered as biochemical remission, and MR signs of tumor absence or regression were considered as tumor control. Remission of hypercortisolism was achieved in 54% of patients on average after 32 months. Tumor growth control was achieved in 98% of patients. The appearance of hypopituitarism was observed in 45% and 62% of patients after 36 and 60 months, respectively. One patient developed Cranial Nerve III Palsy with subsequent regression; and in 3 patients, epileptic seizures (temporo-frontal) were observed.[20]
Fractionate radiotherapy methods has some specific indications, it is used in cases of large pituitary adenoma cases when the risk of visual complications is proportional with the radiation dose which reaches the optic nerves, and definitely larger doses in single session radiotherapy imposes greater radiation to the optic apparatus compared to fractionated sessions and thus the fractionated stereotactic radiosurgery should be preserved for cases where lesions abuts the optic chiasms or optic nerves or either are bigger than 3 cm in size.[20],[21] FSRT is carried out in 3-33 fractions with a total focal dose of 21–59.4 Gy. It is considered that, in contrast to convection radiation therapy, FSRT provides a more local radiation exposure with a minimum load on healthy surrounding tissues, reducing the risk of developing long-term radiation complications.[22],[23],[24],[25] There is little data about the use of FSRT in the treatment of CD in the literature. In a study where 12 patients received FSRT after neurosurgical resection, hormonal remission was observed in 9 / 12 patients (75%) on average after 29 months of treatment, and the remission persisted in 56% of cases, during the follow-up period. In this study, no pituitary deficiency and other radiation complications were seen during the time under observation.[26] In another study of 20 patients with persistent hypercortisolism after surgical adenomectomy, modern FSRT (LINAC) treatment was used at an average dose of 45 Gy, which was summed over 25 fractions, the tumor growth control was 95% with an average follow-up of 37.5 months (ranging from 12 to 144 months), hormonal remission was observed in 75% of patients after 20 months of observation.[24]
Despite the emergence of new and modern methods of radiation therapy, there is a risk of radiation induced complications while treating CD such as development of hypopituitarism, damage to surrounding nerves and blood vessels, malignant transformation of a benign lesions or the development of a secondary (radiation-induced) tumor.[17]
Among the adverse effects of radiation therapy on pituitary lesions hypopituitarism is the most commonly met side effects and this is directly correlated to the length of time after radiation therapy. This complications are encountered in 29, 7% of cases (range 0–69%) by SRS radiotherapy at a mean time of 31 months (range 4–132 months). This is comparatively lower than the complications met with the older XRT method of radiation therapy which was 38.4% (range 0–58%).[27],[28],[29],[30] The rate of hypopituitarism is increased in longer periods after radiation, after 10 years it may raise up to 50–54%.[31] With the development of hypopituitarism, appropriate hormone replacement therapy is necessary. The ability to isolate the pituitary gland from the general tumor tissue while planning radiation therapy can reduce the radiation load on the normal gland and though minimize the risk of hypopituitarism development.
Even though that with the modern radiotherapeutical modalities the radiation-induced damage to the optic nerves has significantly decreased but still this complication can be met with higher doses of radiation into lesions located near to the optic apparatus. In order to decrease the occurrence of this complication maximal optic point dose should be kept in the range of (6–10 Gy) in SRS therapy which preserves damage into the optic apparatus. Radiation-induced damage to other intracranial nerves are very rare but could happen in cases when radiating lesions which are located laterally in the cavernous sinuses. Patient with repeat radiotherapeutical treatments and comorbidities such as prior injuries into the cranial nerves, diabetes mellitus, and vascular diseases are more prone to develop cranial nerve injuries.[32],[33],[34],[35]
Radiation-induced secondary tumors are very rare, the incidence of such tumors decreased significantly after the development of newer radiation therapy modalities. In the conventional methods of radiation therapy the incidence of radiotherapy induced secondary lesions was 2–3% in 10–20 years period after radiation therapy and the most common tumors met were gliomas and meningioma's. Recently a large multicenter study was performed to analyze the rate of secondary intracranial malignancies and malignant transformation of benign tumors post-radiation therapy with the modern stereotactic radiosurgery methods. In this study 14,168 patients who underwent SRS for different benign lesion were included, the results concluded that the risk of malignant transformation or secondary intracranial malignancy remains low at long-term follow-up, and is similar to the risk predisposed to general population for the development of primary CNS tumors.[36]
In literature with the use of conventional method of radiation therapy, radiation-induced necrosis of temporal lobe has been reported but injury to the brain tissue while using the modern stereotactic radiotherapeutic methods is very rare even less the 1% cases. These could be clinically non-symptomatic ones or either present worsening the condition of patient. Risk of radiation-induced local injury into the brain tissue increases after a second course of radiation therapy. Carotid artery stenosis could also present sometimes as a very rare radiation-induced complication. In an analysis of 331 cases of hormone-active and inactive pituitary adenomas treated using the traditional method of radiation therapy, a 5, 10, and 20-year risk of stroke was reported in 4, 11, and 21% of cases, respectively. The frequency of stroke was 4.1 times higher in comparison to normal general population.[17] In the work of Sherlock M et al., examining 501 patients with acromegaly which were treated with conventional radiation therapy and developed post-radiation hypocortisolism, a significant increase in the standardized mortality rate was found in comparison to general population. The increase in mortality was associated with cerebrovascular complications.[17]
Stereotactic radiation remains an effective treatment for patients with Cushing disease after non-radical surgical resection of lesion. Both SRS and FSRT can provide good control of tumor growth in 85-100% of cases, and brings remission of hypercortisolims in up to 75% of cases, but relapse is still possible. In modern clinical practices, SRS in a single dose of 16–25 Gy may be the most effective method of treatment for patients with Cushing disease with small pituitary adenoma, or in cases of residual tumor tissue in the cavernous sinuses after non-radical surgical adenomectomy. The use of FSRT is preferable for large tumors of the pituitary gland which are in close proximity or either involves the optic chiasm and nerves. The use of SRS leads to a faster remission of hypercortisolism and a lower incidence of hypopituitarism. All patients require drug therapy to control hypercortisolism before reaching the control of hypersecretion by radiation therapy, regardless of the method used for achieving this goal. After radiation therapy, a long-term (throughout life) observation is necessary to identify possible recurrences of Cushing disease, as well as the development of post-radiation complications.[37] Hypopituitarism is the most common late complication, while the frequency of other complications of radiation therapy is very low. In the case of hypopituitarism, appropriate hormonal replacement therapy is necessary. Financial support and sponsorship Rudn People Friendship University Grant Number. Conflicts of interest There are no conflicts of interest.
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