History
In 1951, Lars Leksell, a Swedish professor of neurosurgery, was the first to introduce the concept of “Stereotactic
Radiosurgery”. He conceived the idea of using a single burst of high-energy radiation to accurately destroy intracranial tissue without craniotomy, with the normal brain tissue surrounding the lesion receiving minimal radiation due to the rapidly decreasing dose, thus providing a surgical-like effect on the lesion. Accordingly, the first gamma knife was designed [1]. Zhang Nan, Department of Neurosurgery, Huashan Hospital, Fudan University
At the beginning of clinical trials, the gamma knife was used in the saddle area to perform pituitary resection by radiation to treat cancer pain, and on January 27, 1968, Backlund et al. used the gamma knife to treat pituitary tumors. This was the first time in history that the gamma knife was used to treat brain tumors [2]. A growing body of literature in recent years has demonstrated that gamma knife is an important and effective option for the treatment of pituitary adenomas [1-3].
Advantages of Gamma Knife for pituitary adenomas
Gamma knife treatment offers many advantages when choosing among the multiple treatment options for pituitary tumors. The development of computer technology, combined with the use of a stereotactic headstock, allows the accuracy of Gamma Knife radiosurgery to be controlled to 0.3 mm. the mechanical isocentric accuracy of the Gamma Knife device is higher than that of the linear gas pedal; the Leksell stereotactic headstock, combined with the Gamma Knife collimator attachment device, keeps the pendulum accuracy with minimal error; the Gamma
PlanWizard has been upgraded and improved year by year so that CT and MRI can be integrated in one dose plan, and the 3D reconstructed target design allows the complete accuracy of dose coverage to be demonstrated, thus ensuring the highest accuracy of target position in radiosurgery planning systems. The unique hole plugging technique minimizes potential damage to vital structures such as the eye, visual pathway, and brainstem from radiation.
Gamma Knife treatment does not require general or intravenous anesthesia, making the procedure more acceptable and tolerable to the patient. Gamma knife treatment can avoid a series of complications such as internal carotid artery injury and temporal lobe radiation damage after external radiation therapy. Because of the intuitive and calculable dose parameters during gamma knife treatment, thus making it possible to re-gamma knife treatment when the tumor recurs after radiation therapy will gamma knife treatment.
Indications for Gamma Knife treatment
Kurita referred to gamma knife treatment of pituitary adenomas as a “class I indication” for gamma knife that provides true and complete tumor control, given the multiple effects of gamma knife treatment on pituitary adenoma growth control, shrinkage, and normalization of hormone levels [4].
Ganz stated that the goals of gamma knife treatment of pituitary adenomas are (1) to control abnormal hormone levels and improve clinical symptoms, (2) to shrink or control tumor growth, and (3) to preserve normal pituitary tissue [5]. A growing body of literature reports the satisfactory therapeutic results of gamma knife therapy as the treatment of choice for pituitary adenomas [1-3].
Pituitary adenomas that can be treated with gamma knife therapy are.
1, postoperative residual or recurrent pituitary adenomas; (pituitary macroadenoma with optic bundle and optic cross spacing >3 ~ 5mm)
2.Pituitary adenoma patients who cannot tolerate surgery due to old age or associated medical diseases (such as hypertension, diabetes, heart disease or coagulation disorders);
3, patients with pituitary microadenoma who are ineffective in drug therapy, cannot tolerate the side effects of drug therapy or do not want to undergo surgery.
4, pituitary tumors with invasion of the cavernous sinus or skull base, postoperative residual recurrence or preferred treatment.
Radiobiological characteristics of gamma knife for pituitary adenoma
Unlike radiation therapy for malignant tumors, the main goal in radiation therapy for benign brain tumors is complete coverage of the lesion with high doses of radiation. The dose plan needs to be designed to protect the brainstem, optic nerve optic crossings, cavernous sinus and the trigeminal nerve passing through it, internal carotid artery or other adjacent cranial nerves.
A series of radiobiological changes occur after gamma knife treatment of pituitary adenomas. The early effect is double-stranded deconvolution and breakage of the DNA strand in the nucleus of the tumor cells. The late subsequent changes include alterations such as occlusion of the microvasculature within the tumor or the supply vessels to the tumor [3]. In our practice, we found that in pathological specimens of pituitary adenomas that were surgically resected again after gamma knife treatment: although significantly more tumor cells were seen at the tumor margins than at the center of the tumor, they were accompanied by vitreous changes in the vessel walls and fibrous proliferation of the tissue.
Dose selection and efficacy
Backlund [2] found that normal pituitary tissue can withstand irradiation doses of up to 185Gy. Based on his experience with gamma knife treatment of PRL, GH, and ACTH adenomas at Stockholm: the central dose should be above 50 Gy, and no tumor shrinkage occurs at peripheral doses below 15 Gy. Ganz [5] concluded that the dose that shrinks pituitary adenomas is significantly lower than the dose that restores hormone levels to normal. He found that a peripheral dose of 25 Gy cured three patients with acromegaly and Cushing’s disease. He suggested that a peripheral dose of 10-12 Gy is needed to control adenoma growth and a dose of at least 35 Gy is needed to induce complete normalization of hormone levels. recent literature has focused on the therapeutic doses needed for different types of pituitary tumors.
Non-functioning adenomas
Because non-functioning adenomas are not associated with abnormal hormone levels, they are often found in clinical practice when they are already large and have a high residual surgical resection rate. Gamma knife treatment, as long as the tumor with the optic nerve optic intersection has a distance of 3 ~ 5 mm, and make the optic path to radiation dose is less than 10Gy, take a lower peripheral dose can control tumor growth. The purpose of treatment can be achieved. The peripheral dose of gamma knife for the treatment of non-functional adenoma in our hospital ranges from 10 to 21 Gy. The tumor growth was controlled during the follow-up [9]. Hayashi et al. reported the average peripheral dose of 19.5 Gy for the treatment of non-functional adenoma [10].
Growth hormone adenoma
GH adenoma is the most radiation sensitive of the secretory pituitary adenomas. It is also the most suitable for preferred gamma knife treatment [6-8,10-11,22]. Surgical resection is somewhat unsafe because patients with acromegaly often have multiple concomitant medical disorders. Our hospital experience has shown [6-8]:
Although excellent clinical outcomes can be obtained with peripheral doses of 30 Gy or more. The patient’s extremity hypertrophy symptoms improved and hypertension and diabetes were simultaneously controlled. The rate and extent of tumor shrinkage were related to the dose level. However, there was no statistical difference between the two groups with a peripheral dose of 30 Gy at more than three years of follow-up, and a peripheral dose of 25 Gy may be more appropriate according to Landolt et al, who subsequently noted that no tumor shrinkage was seen in the one patient in that group with a peripheral dose of 13 Gy [4,12].
Prolactin adenoma
Also secretory adenomas, prolactin adenomas are less sensitive to radiation than GH and ACTH adenomas [6-8,10-11]. 20 Gy of peripheral dose did not induce tumor shrinkage [6]. Statistical analysis showed that gamma knife treatment with a peripheral dose of 30 Gy or more resulted in better tumor growth control and normalization of hormone levels [7]. It was shown in the data [7] that a woman with infertility in her 40s delivered normally even with a peripheral dose higher than 30 Gy. The normal pituitary gland is able to tolerate higher radiation doses and avoiding excessive radiation to the normal pituitary gland during dose planning protects the normal physiological function of the patient.
Adrenocorticotropic Hormone Adenoma
ACTH adenomas are mostly pituitary microadenomas, which have been reported in the past to be insensitive to radiation, but gamma knife treatment is second only to growth hormone adenomas [6-8,10-11,22]. thoren concluded that the central dose of gamma knife treatment should be 70-100Gy [13].
Seo [14] et al. reported good outcomes in a group of patients with Cushing’s disease whose pituitary adenomas were treated with a peripheral dose of 20-35 Gy of gamma knife, suggesting that a better prognosis can be obtained with a lower central dose based on current localization methods and treatment planning levels.
Our institution [6] also achieved tumor growth control, improvement of clinical symptoms and normalization of hormone levels using peripheral doses of 23-34 Gy.
Thyrotropin adenoma
Oaki [15] reported a patient with TSH adenoma treated with Gamma Knife at a central dose of 33.3Gy and a peripheral dose of 17Gy, with 16 months of follow-up and normalization of hormone levels and tumor shrinkage. We had a similar experience [9].
Pituitary tumor invading the cavernous sinus
The rate of total surgical resection of pituitary tumors decreases after pituitary tumor invasion of the cavernous sinus. Gamma knife treatment of cavernous sinus meningioma has achieved good therapeutic results [16] and provides a good reference for the treatment of pituitary tumors [17].Shin et al. concluded that gamma knife treatment of pituitary tumors in the cavernous sinus is slightly better than external radiation therapy, while the complication rate is extremely low [17].
The motor branch of the cranial nerve is better tolerated by radiation than the sensory branch. Patients with cavernous sinus pituitary tumors can present with motoneural, talipes, trigeminal and abducens nerve symptoms. The exact ability of these cranial nerves to withstand radiation doses remains to be explored [16], and Leber et al. concluded that these cranial nerves can withstand radiation doses up to 20 Gy [18]. These cranial nerves travel through the lateral wall of the cavernous sinus, and excessive doses to this region should be avoided during dose planning. Although the optic nerve and optic cross are extremely sensitive to radiation. the 8th Annual International Conference of Leksell Gamma Knife (Marseille, France) in 1996 confirmed by a panel discussion and by the experience of several centers that it is safe to irradiate the optic path with a dose less than 10 Gy, combined with simulated plugging to change the shape of the scattered rays. Secondly, by choosing a dose plan with small collimators and multiple targets, the radiation dose to the optic path is lower and safer. At our institution, we chose a dose of less than 10 Gy to the optic path and did not see any loss of vision in patients at long-term follow-up [6-9]. Data showed [6-7,16-18] that the incidence of vision loss was 26.7% at doses of 10-15 Gy to the optic pathway, and more than 77.8% at doses higher than 15 Gy.
Pharmacological treatment after gamma knife treatment
Bergen et al. reported [2] that after gamma knife treatment for prolactin adenoma, those who were previously resistant to the drug recovered more quickly after treatment with drug sensitivity and hormonal abnormalities. The results of our treatment were similar to theirs [8]. However.
Landolt et al. suggested that the decrease in tumor cell secretion after drug administration would decrease the sensitivity of pituitary tumors (prolactin adenoma and growth hormone adenoma) to radiation and recommended that drug treatment should be discontinued before gamma knife treatment, but the article did not detail the relevant case data [19].
During follow-up, many women of childbearing age discontinued medication due to side effects and improved their symptoms with improvement in endocrine parameters after gamma knife treatment. They were able to resume menstruation and childbirth and delivery without medication. We found that some patients with persistent endocrine index abnormalities despite a long period of conservative drug treatment had their hormonal abnormalities drop quickly after gamma knife treatment and delivered normally (The 6th Annual Leksell Gamma Knife Conference, Tokyo, 1994).
We believe that: the DNA strand in the nucleus of pituitary tumor cells breaks after gamma knife treatment and loses the ability to reproduce, but various intracellular organelles continue to function. The cells remain functional until the end of the cell cycle. Administration of bromocriptine after gamma knife treatment
can restore the abnormal endocrine level as early as possible. When the tumor cell cycle is over, apoptosis breaks down. Taking bromocriptine during this period may improve the therapeutic effect and even reduce the swelling caused by radioactive changes in the tumor during the early stage of Gamma Knife treatment. There is no trial evidence that drugs such as bromocriptine reduce the radiosensitivity of pituitary tumors. The drug dose should be decreased with symptomatic improvement during follow-up, and discontinuation should be monitored according to endocrine indicators.
Complications of Gamma Knife treatment
The complication rate of gamma knife treatment of pituitary adenomas is significantly lower than that of surgery, conventional radiation therapy, and LINAC therapy [1]. However, as the follow-up time increases and the number of cases treated with gamma knife increases, some individual cases of complications after treatment have been reported. Care should be taken when carrying out treatment.
Headache, nausea
During the first 24-72 hours after Gamma Knife treatment, a small number of patients experience nausea, vomiting or complain of headache. Symptoms will disappear in the short term with appropriate fluid support, oral corticosteroids and vasodilators. Mannitol dehydration therapy does not reduce symptoms during this period. The above symptoms occur due to multiple factors such as high dose during gamma knife treatment of pituitary adenoma, long treatment time, dose amplitude to the brainstem and the vomiting center at the base of the four ventricles, and changes in hormone levels in the early post-radical treatment producing vascular headache.
Pituitary crisis
Liang Junchao et al [20] reported a case of pituitary crisis 2 months after pituitary tumor treatment, and surgery confirmed massive tumor necrosis and ultimately death. The causes of pituitary crisis are related to excessive irradiation range, high dose selection, and individual patient radiation tolerance differences.
Internal carotid artery injury
Lim [21] reported a case of a 35-year-old patient with pituitary tumor who died 4 years after treatment due to massive cerebral infarction. This is thought to be related to gamma knife treatment. In our treatment practice for patients with a history or potential risk of cerebral infarction, we should avoid overextending and straining the carotid artery when positioning the head and developing atherosclerotic dislodgement secondary to cerebral infarction. When invasive pituitary tumors involve the cavernous sinus, the dose plan should be designed with care to avoid large exposures to the internal carotid artery. Post-treatment mannitol dehydration therapy increases blood viscosity, and given the extracerebral location of pituitary adenomas and the low incidence of cerebral edema, dehydration therapy should be administered as needed.
Vision loss
Rocher treated 36 pituitary tumors with a stereotactic radiosurgery (LINAC) approach and 12 (33%) developed severe visual loss shortly after treatment, including two cases of bilateral total blindness [1]. Izawa et al.
et al. reported a case of vision loss 10 months after gamma knife treatment [22]. A patient with a growth hormone adenoma at our hospital received an optic nerve irradiation dose higher than 12 Gy. During follow-up, although his hormone levels were completely normalized and his blood glucose was normalized, his visual acuity was significantly reduced [7]. When a pituitary macroadenoma or giant adenoma involves the optic cross, the tumor should be surgically removed as much as possible first, followed by stereotactic radiosurgery applied to treat the residual tumor after surgery. When this tumor compresses and wraps around the optic cross for a long time, even if the tumor is surgically reduced, the patient’s vision will still be diminished with optic nerve atrophy. Patients with long-term diabetes mellitus or recurrence after conventional external radiotherapy may also suffer from secondary vision loss. A dramatic loss of visual acuity during follow-up cannot exclude pituitary stroke.
Pituitary stroke
Intratumoral tissue necrosis and intratumoral hemorrhage can occur after gamma knife treatment of pituitary adenomas. A patient with a prolactin adenoma at our hospital had significant intratumoral hemorrhage 36 months after treatment, an enlarged tumor, and a dramatic loss of vision, which was reoperatively removed and confirmed as a pituitary stroke [10]. Izawa et al. also reported a case of cystic degeneration 4 months after gamma knife treatment [22].
Hypopituitarism or hypopituitarism
Although many patients suffering from infertility in cases of gamma knife treated prolactin adenomas have normal pregnancies or deliveries [8,19]. Similarly, other secretory pituitary adenomas showed significant clinical improvement with normal hormone levels. However, the following symptoms were still found during follow-up: e.g., loss of libido, secondary amenorrhea, and weakness and dullness. Moreover, patients’ MRI images also showed manifestations similar to empty pteroid saddle [7-8].Kim reported that gamma knife treatment of ACTH adenoma with a peripheral dose of 35 Gy resulted in pituitary insufficiency in 55% of patients [23].
Empty saddle syndrome can be secondary to intra-saddle surgery or radiotherapy. Pituitary necrosis or pituitary stroke is also a cause of the development of empty pterygoid saddle in the saddle region. In addition, the longer duration of patients with pituitary adenomas and the prolonged compression of the normal pituitary gland and pituitary stalk by the tumor have an impact on normal pituitary function.
The extent of some pituitary adenomas is difficult to distinguish from normal pituitary tissue in imaging. Patients with postoperative residual pituitary adenomas and patients with residual recurrent adenomas after conventional external radiotherapy may have their blood supply to normal pituitary tissue affected by mechanical or physical factors during prior treatment, making them more susceptible to decreased pituitary function. The correct choice of treatment dose is important when performing gamma knife treatment for post-radiotherapy or postoperative residual pituitary tumors.
Brain radionecrosis
Izawa, Japan, reported [22] a case of significant cerebral necrosis in the temporal lobe 6 months after gamma knife treatment for PRL adenoma. The case had been treated with 48 Gy of external radiation. It is difficult to explain the above phenomenon by gamma knife treatment itself. For the occurrence of delayed brain tissue radionecrosis after external radiation therapy should be recognized, after radiotherapy in gamma knife treatment, attention should be paid to the choice of dose and the extent of the dose coverage area. The positioning of the stereotactic head frame, the accuracy of the positioning film and the accuracy of the target point during the treatment operation are the basis for avoiding damage to brain tissue by treatment errors.
Actinic nerve damage
Gamma Knife can treat pituitary adenomas in the paracavernous or eroding cavernous sinus without damaging the cranial nerves. The nerves within the cavernous sinus are resistant to 20 Gy of radiation. Two patients in our institution showed damage to the actinic nerve 1 month after gamma knife treatment [6-7], and the cavernous sinus was irradiated with a dose much lower than 20 Gy, but they still developed ptosis. After 3-6 months of symptomatic treatment with small doses of hormones and drugs such as vitamin B, the actinic nerve damage completely improved. It is suggested that the nerve damage in the early stage after gamma knife treatment can be recovered. The cause of nerve damage may be related to demyelination changes. Tumor invasion and compression can affect and reduce the ability of cranial nerves to tolerate radiation.
Outlook
Our experience shows [6-8] that (i) peripheral doses of 30 Gy or more can induce shrinkage of pituitary adenomas and normalization of abnormal hormone levels in a relatively short period of time. ②The following factors should be considered when choosing the peripheral dose: endocrine type of adenoma, size, whether postoperative residual, history of external radiotherapy, and whether it affects the cavernous sinus, brainstem or optic nerve optic cross. An objective evaluation of the role of gamma knife in the treatment of pituitary adenomas can provide patients with safe and effective treatment options. Complications accompanying treatment should also be taken seriously and avoided by choosing the most optimal treatment regimen and dose. In addition, proper diagnosis and gamma knife treatment of adolescent pituitary adenomas should be carried out carefully to avoid the pitfalls associated with hypopituitarism. In conclusion, the development of radiosurgery techniques is very beneficial to improve the treatment outcome of pituitary adenomas.