SUMMARY Introduction Pituitary adenomas (PA) are benign, accounting for 10-15% of the primary brain tumors. Magnetic resonance imaging (MRI) records the percentage of residual tumor after surgery from 12.8-42% of cases, then the tumor will progress, resurgery in these cases often faces many difficulties. Based on the radiation-sensitive property of the pituitary adenomas, radiotherapy is used to assist in the elimination of residual or recurrent pituitary tumors after surgery. The Gamma knife radiosurgery has been mentioned as one of the effective treatments. In Vietnam, in the years of the last decade, the treatment of pituitary adenomas was mainly by surgery and drugs. The Department of Neurosurgery at Cho Ray Hospital in Ho Chi Minh City is the place to treat many brain and nervous system diseases including pituitary adenomas. There are many difficult cases with the medical or surgical treatment, with Gamma knife radiosurgery equipped, we have the chance to treat those patients. In recent years, a number of medical centers have applied Gamma knife radiosurgery to treat pituitary adenomas, there is a few studies on Gamma knife radiosurgery in this field. However, there have been no studies on Gamma knife radiosurgery for patients with residual or recurrent pituitary adenomas after surgery. Therefore, we have carried out the thesis: "Clinical research and evaluation the results of Gamma knife radiosurgery for residual or recurrent pituitary adenomas.” with the objectives: 1. Describe clinical and subclinical characteristics in patients with residual or recurrent pituitary adenomas after surgery. 2. Evaluation of Gamma knife radiosurgery results in patients with residual or recurrent pituitary adenomas after surgery. The necessary of study Recurrent or residual pituitary adenomas are a challenging treatment. The rate of recurrent pituitary adenomas after surgery is 12.8-42%, a quite high rate. Besides that, resurgery for these patients are very difficult and complicated. Worldwide, there have been reports of treatment for recurrent or residual pituitary adenomas after surgery. In Vietnam, there is still a lack of studies in radiosurgery for pituitary adenomas, especially in recurrent or residual tumors. Therefore, this study was conducted to meet the necesscary for radiosurgery on recurrent or residual pituitary adenomas.
MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE VIETNAM MILITARY MEDICAL ACADEMY NGUYEN VAN DO CLINICAL RESEARCH AND EVALUATION THE RESULTS OF GAMMA KNIFE RADIOSURGERY FOR RESIDUAL OR RECURRENT PITUITARY ADENOMAS Speciality: Surgery Code: 9720104 SUMMARY OF PHD DISSERTATION HA NOI – 2020 SUMMARY Introduction Pituitary adenomas (PA) are benign, accounting for 10-15% of the primary brain tumors Magnetic resonance imaging (MRI) records the percentage of residual tumor after surgery from 12.8-42% of cases, then the tumor will progress, resurgery in these cases often faces many difficulties Based on the radiation-sensitive property of the pituitary adenomas, radiotherapy is used to assist in the elimination of residual or recurrent pituitary tumors after surgery The Gamma knife radiosurgery has been mentioned as one of the effective treatments In Vietnam, in the years of the last decade, the treatment of pituitary adenomas was mainly by surgery and drugs The Department of Neurosurgery at Cho Ray Hospital in Ho Chi Minh City is the place to treat many brain and nervous system diseases including pituitary adenomas There are many difficult cases with the medical or surgical treatment, with Gamma knife radiosurgery equipped, we have the chance to treat those patients In recent years, a number of medical centers have applied Gamma knife radiosurgery to treat pituitary adenomas, there is a few studies on Gamma knife radiosurgery in this field However, there have been no studies on Gamma knife radiosurgery for patients with residual or recurrent pituitary adenomas after surgery Therefore, we have carried out the thesis: "Clinical research and evaluation the results of Gamma knife radiosurgery for residual or recurrent pituitary adenomas.” with the objectives: Describe clinical and subclinical characteristics in patients with residual or recurrent pituitary adenomas after surgery Evaluation of Gamma knife radiosurgery results in patients with residual or recurrent pituitary adenomas after surgery The necessary of study Recurrent or residual pituitary adenomas are a challenging treatment The rate of recurrent pituitary adenomas after surgery is 12.8-42%, a quite high rate Besides that, resurgery for these patients are very difficult and complicated Worldwide, there have been reports of treatment for recurrent or residual pituitary adenomas after surgery In Vietnam, there is still a lack of studies in radiosurgery for pituitary adenomas, especially in recurrent or residual tumors Therefore, this study was conducted to meet the necesscary for radiosurgery on recurrent or residual pituitary adenomas New contributions of the thesis This is the first Vietnamese study on Gamma knife radiosurgery for recurrent or residual pituitary adenomas The study shows epidemiological, clinical and subclinical characteristics of patients with recurrent or residual pituitary adenomas after surgery Research has shown the effectiveness of radiosurgery in the treatment of recurrent or residual pituitary adenomas The control of tumor size by radiosurgery achieved a very good result of 98% Additionally, most residual or recurrent pituitary adenomas with increased hormone secreted have hormone levels returning to normal The response time for hormones to return to normal is from months after Gamma knife radiosurgery Dissertation layout: The thesis consists of 137 pages: Introduction (2 pages), Overview (39 pages), Objects and research methods (25 pages), Results (31 pages), Discussion (37 pages), Conclusion (2 pages), and Proposals (1 page) In this thesis, there are 35 tables, 25 charts, 10 pictures and appendix There are 138 references, including 10 Vietnamese and 128 English CHAPTER 1: OVERVIEW 1.1 Gamma knife radiosurgery in residual or recurrent pituitary adenomas after surgery 1.1.1 Natural progression of pituitary adenomas after surgery The pituitary adenoma recurrence rate is often high, 12.8-42% of cases There are many studies evaluating how the natural progression of residual pituitary adenomas after surgery will develop over time Tanaka Y et al assessed 40 cases of residual pituitary adenoma patients after surgery for the time the pituitary adenoma volume doubled, and the author found that the time of doubled volume were average 1836 days, varying from 506 to 5378 days Honergger J et al published in the European Endocrinology Journal followed up 15 cases of residual pituitary adenoma patients for a period of 7.4 years, the author found that the doubled volume presented after 3.1 years, varies from 0.8 to 27.2 years Ekramullah S.M et al reported that the time of pituitary adenoma volume doubled when studying 14 patients with non-functional pituitary adenomas as 930 days, varying from 200 to 2550 days Table 1.2 The time of doubled volume in residual pituitary adenomas after surgery Author Year Number of Time of Time of patients follow up doubled volume 52.5 Tanaka Y 2003 40 Honergger J 2008 15 7.4 years 3.1 years Ekramullah S.M 1996 14 years 930 days months 1836 days 1.1.2 Research situation in Vietnam and the world In 2007, Jagannathan J et al studied in the US on 90 patients with pituitary adenomas treated with the rotary Gamma knife, an average radiation dose of 23 Gy, and the follow-up time for an average of 45 months, the author found that 80% of patients have reduced the tumor size Tanaka S et al studied the treatment of 22 patients who had PRL secreting pituitary adenomas after surgery with the rotary Gamma knife, an average radiation dose of 25 Gy and the patient was monitored for 60 months The results showed that tumor control reached 100% Yazdani O.S et al evaluated over 100 patients with pituitary adenomas treated with Gamma knife radiosurgery There were 46 patients with non-fuctional pituitary adenomas and 54 patients with functional pituitary adenomas After the radiosurgery, the effective control of the tumor size is 92% (the reduced size by 28%, unchanged by 64%) The response rate for tumor size with GH secreting tumors is 73%, returning normal hormone levels is 48%, with PRL secreting tumors is 67%, returning normal hormone levels is 46%, with ACTH secreting tumors is 70%, returning normal hormone levels is 35% According to Nguyen Thi Minh Phuong et al researched on 73 patients of pituitary adenomas, including 48 patients treated with radiosurgery at the Center for Nuclear Medicine and Oncology Bach Mai Hospital: symptoms clinically decreased over time, the size of the pituitary adenoma decreased significantly after 12, 24 and 36 months Response to tumor size after radiosurgery: complete (6.3%), partial (41.7%), stable disease (43.8%), progressive disease (8.3%) Hormonal response: returning nornal levels after 6, 12, 24 and 36 months, the incidence increased gradually in the hormone secreting tumor group Hypopituitarism after intervention were low with 12.5%, other complications were mild and transient CHAPTER 2: OBJECTS AND METHODS 2.1 Research obbjects The study had 81 patients who had residual or recurrent pituitary adenomas after surgery The patient was examined, treated and monitored at Gamma Knife Unit - Department of Neurosurgery, Cho Ray Hospital from January 2012 to March 2017 2.1.1 Selecting Criterias - Patients who had performed surgery for pituitary adenoma The patient had residual or recurrent tumors after surgery with the largest diameter of the tumor < cm detected by MRI Gamma knife radiosurgery is indicated to prevent the development of pituitary tumors - Patients with adequate tests of pituitary hormones - The general condition is still good: Karnofsky index> 70, not suffering from acute and serious diseases - The patient is indicated for adjuvant treatment by radiosurgery with Leksell Gamma Knife radiosurgery system at Gamma Knife Unit - Neurosurgery Department, Cho Ray Hospital - The patient agreed to participate in the study - Have completed archive records 2.1.2 Exclusion criterias - The patient had performed Gamma kinife radiosurgery previously - The general condition is poor, has consciousness disorder or severe intracranial pressure condition - Patients with other cancers - Women who are pregnant or breastfeeding - Patients using drugs that affect the results of functional tests of the pituitary gland such as psychotropic drugs, glucocorticosteroids, levothyroxine, rifampicine, ketoconazole 2.2 Research Methods 2.2.1 Research design The retrospective study combined with prospective, cross-over follow-up 2.2.2 Research location The project was conducted at Gamma Knife Unit - Neurosurgery Department of Cho Ray Hospital 2.2.3 Research time From January 2012 to March 2017 2.2.4 Sample size We apply the formula for calculating the sample size: n Z (21 / 2) p(1 p) d2 (2.1) - p: tumor control rate of Gamma knife radiosurgery in previous studies We aim to a 95% efficiency so we chose p=0.95 Applying the formula for calculating the sample size (formula 2.1), we calculated the theoretical sample size of 73 patients The expected rate of sample loss is 10%, so the sample size is 80 patients The study recruited 81 patients Following the guidance of RTOG 90-05 (Radiation therapy oncology group) the radiation dose according to the size and volume of the tumor is as below: Table 2.1 Radiation dose according to the diameter and volume Average diameter (mm) tumor Volume tumor (cm3) Max dose (Gy) 12.5 1.02 27.5 15.0 1.77 25.0 17.5 2.81 22.5 20.0 4.19 20.0 22.5 5.96 18.7 25.0 8.18 17.5 27.5 10.9 16.5 30.0 14.1 15.0 32.5 18.0 14.0 (Flickingera J.C., et al, 2013) Table 2.2 Radiation dose according to the type of tumor Type Average dose (Gy) Range dose (Gy) Non-functional PA 15.8 8-22.5 GH-secreting PA 19.4 12-25 ACTH-secreting PA 20.7 15-29.5 PRL-secreting PA 18.7 13.3-33 Other secreting PA 12-28.7 (Flickingera J.C., et al, 2013) Table 2.3 Response to treatment according to the RECIST standard Excellent Totally lesion disappeared The total diameter of the tumors decreased by at least Good 30% compared to the total diameter of tumors measured before treatment The sum of the tumor diameters increased by at least Worse 20% compared to the sum of the original tumor diameters or the sum of the smallest tumor diameters in the study The total diameters are neither smaller nor smaller Stable but are not sufficient to be considered partial or large enough to be considered progressive compared to the smallest total diameter during the study period (Eisenhauera P., et al, 2009) Table 2.4 Response of hormone levels Normal Hormone levels within normal limits Hormone levels have not returned to normal Response limits but decreased by over 50% compared to before treatment Hormones remain unchanged from before Stable treatment or reduce by 50% compared to before treatment Hormone Progressive levels continue to increase compared to before treatment (Castro D.G., et al, 2010) CHAPTER 3: RESULTS 3.1 General characteristics Table 3.1 Distribution of patients by age groups Tumor Age Functional PA Non-functional Total PA n % n % n % < 40 11 47.8 19 32.8 30 37.0 40 – 49 30.4 18 31.0 25 30.9 ≥ 50 Total 21.8 21 36.2 26 32.1 23 100 58 100 81 100 Average age 39.48 ± 12.12 44.88 ± 11.67 43.35 ± 11.98 (min-max) (18-65) (23-73) (18-73) 11 3.3 Results of radiosurgery 81 patients undergoing radiosurgery (radiation group) had to be followed 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after treatment 3.3.1 General characteristics Table 3.4 Radiation dose Functional Non- PA functional (n=23) PA (n=58) Average 17.74 ± 2.28 15.55 ± 2.07 16.17 ± 2.33 Min 13 12 12 Max 22 22 22 ≤ 14 Gy (4.3) 20 (34.5) 21 (25.9) > 14 Gy 22 (95.7) 38 (65.5) 60 (74.1) Memory loss Headache Radiation dose (Gy) Total (n=81) p value