Clinical research and evaluation the results of gamma knife radiosurgery for residual or recurrent pituitary adenomas

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 6 months after Gamma knife radiosurgery. Dissertation layout: 3 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 1 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. 4 Table 1.2. The time of doubled volume in residual pituitary adenomas after surgery Author Year Number of patients Time of follow up Time of doubled volume Tanaka Y. 2003 40 52.5 months 1836 days Honergger J. 2008 15 7.4 years 3.1 years Ekramullah S.M. 1996 14 5 years 930 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 5 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 < 4 cm detected by MRI. Gamma knife radiosurgery is indicated to prevent the development of pituitary tumors. - Patients with adequate tests of pituitary hormones. 6 - 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. 7 2.2.4. Sample size We apply the formula for calculating the sample size: 2 2 )2/1( )1( d ppZ n    (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 tumor Average diameter (mm) Volume tumor (cm 3 ) 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) 8 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. Good The total diameter of the tumors decreased by at least 30% compared to the total diameter of tumors measured before treatment. Worse The sum of the tumor diameters increased by at least 20% compared to the sum of the original tumor diameters or the sum of the smallest tumor diameters in the study. Stable The total diameters are neither smaller nor smaller 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) 9 Table 2.4. Response of hormone levels Normal Hormone levels within normal limits. Response Hormone levels have not returned to normal limits but decreased by over 50% compared to before treatment. Stable Hormones remain unchanged from before treatment or reduce by 50% compared to before treatment. Progressive Hormone 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 PA Total n % n % n % < 40 11 47.8 19 32.8 30 37.0 40 – 49 7 30.4 18 31.0 25 30.9 ≥ 50 5 21.8 21 36.2 26 32.1 Total 23 100 58 100 81 100 Average age (min-max) 39.48 ± 12.12 (18-65) 44.88 ± 11.67 (23-73) 43.35 ± 11.98 (18-73) 10 Table 3.2. Gender Tumor Gender Functional PA Non-functional PA Total n % n % n % Male 11 47.8 27 46.6 38 46.9 Female 12 52.2 31 53.4 43 53.1 Total 23 100 58 100 81 100 3.2. Clinical characteristics Table 3.3. Clinical symptoms Synptoms Patients (n=81) Number (N) % Compressing syndrome Memory loss 13 16 Headache 68 84 Visual disturbances 44 54.3 Paralysis III 4 4.9 Paralysis IV 4 4.9 Visual field defect 42 51.9 Endocrine Syndrome Lactation 6 13.9 Hypopituitarism 25 30.9 Menstrual disorders 8 18.6 Erectile dysfunction 11 13.6 Acromegaly 14 17.3 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 Radiation dose (Gy) Functional PA (n=23) Non- functional PA (n=58) Total (n=81) p value Average 17.74 ± 2.28 15.55 ± 2.07 16.17 ± 2.33 <0.001 Min 13 12 12 Max 22 22 22 ≤ 14 Gy 1 (4.3) 20 (34.5) 21 (25.9) 0.005 > 14 Gy 22 (95.7) 38 (65.5) 60 (74.1) Chart 3.1. Clinical characteristics in functional PA (n=23) 4.3 78.3 73.9 52.2 13 0 0 0 0 0 0 0 30.4 30.4 21.7 8.7 8.7 8.7 8.7 9.5 15.4 12.5 0 10 20 30 40 50 60 70 80 90 T0 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 Memory loss Headache Visual disturbances 12 Chart 3.2. Clinical characteristics in non-functional PA (n=58) Chart 3.3. Response of tumor size according to the RECIST standard In this study, 2 patients increased tumor size after the follow-up time, so the rate of tumor control was 79/81 = 97.5%. 0 20 40 60 80 100 T0 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 Memory loss Headache Visual disturbances 13.6 50.6 2.5 33.3 0 10 20 30 40 50 60 Totally Partial Progress Stable 13 3.3.2. Response of hormone levels 3.3.2.1. Response of PRL, GH levels Chart 3.4. Average PRL, GH levels in functional PA (n= 23) Chart 3.5. Rate of the new hypopituitarism after radiosurgery 121.8 105.72 89.57 75.23 59.82 48.57 38.48 36.79 38.14 41.32 17.24 22.56 19.25 16.62 14.16 11.11 9.24 6.79 5.55 4.6 3.65 3.02 0 20 40 60 80 100 120 140 T0 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 PRL (ng/ml) GH (ng/ml) 0 10 20 30 40 50 60 T0 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 14 3.3.4. Rate of complications Table 3.5: Rate of complications Complications Functional PA (n=23) Non- functional PA (n=58) All (n=81) p value Overal complications Yes 16 (69.9) 38 (65.5) 54 (66.7) 0.727 No 7 (30.4) 20 (34.5) 27 (33.3) Headache Yes 5 (21.7) 12 (20.7) 17 (21.0) 0.917 No 18 (78.3) 46 (79.3) 64 (79.0) Nausea Yes 5 (21.7) 10 (17.2) 15 (18.5) 0.638 No 18 (78.3) 48 (82.8) 66 (81.5) Anorexia Yes 6 (26.1) 16 (27.6) 22 (27.2) 0.891 No 17 (73.9) 42 (72.4) 59 (72.8) Dry mouth Yes 8 (34.8) 18 (31.0) 26 (32.1) 0.745 No 15 (65.2) 40 (69.0) 55 (67.9) Insomnia Yes 4 (17.4) 15 (25.9) 19 (23.5) 0.417 No 19 (82.6) 43 (74.1) 62 (76.5) Alopecia Yes 7 (30.4) 6 (10.3) 13 (16.0) 0.026 No 16 (69.6) 52 (89.7) 68 (84.0) 15 CHAPTER 4: DISCUSSION 4.1. General characteristics 4.1.1. Gender Several epidemiological studies show that in the pituitary adenomas, the ratio of male to female depends on the different types of tumors, generally more in women than men. A study of 219 pituitary adenomas on sex and other factors showed that the numbers of women with small pituitary and prolactin-free tumors was higher than in men. When studying recurrent or residual pituitary adenomas after surgery, we found that the male to female ratio was 1: 1, of which females accounted for 53.1%. When analyzing the function of pituitary adenomas, we found that there was no statistically significant difference between the male and female ratio. Our results are similar to other authors in the world. Chen Y.H. et al reported 22 recurrent or residual pituitary adenomas after Gamma knife radiosurgery in Taiwan showed that the ratio of male to female was 2: 1. However, Bir S.C. et al. studied 57 without increased hormone secreting pituitary adenomas treated with Gamma knife radiosurgery, of which 53 patients were recurrent or residual tumors after surgery showed the ratio male: female is equal (56.1% and 43.9%). Sheehan J.P. reported a multicenter report that the non-functional pituitary adenomas were treated with Gamma knife radiosurgery in the US, in which 93.6% of pituitary adenomas had at least a surgical removal or biopsy, showing that the percentage of men is 55.9% and women are 44.1%, equivalently. Thus, in terms of gender distribution, we found that the proportion of men and women is equal 16 4.2 Evaluate the results of Gamma knife radiosurgery in pituitary adenomas 4.2.1. Result of tumor size control 4.2.1.1. Evaluate tumor size control according to the RECIST standard After follow-up, we noted that the pituitary adenoma fully responded to Gamma knife radiosurgery accounted for 13.6%, partially response accounted for 50.6%, stable disease accounted for 33.3% and had 2.5 % of tumor progression increased in size. Nguyen Thi Minh Phuong noted the tumor response with Gamma knife radiosurgery according to the RECIST standard in 44 pituitary adenomas showed that: complete response accounted for 6.3%, partial response accounted for 41.7%, stable disease accounted for the highest rate of 43.8%, progressive disease met 8.3%. In the treatment of 30 pituitary adenomas, Sallabanda K. showed that 63% of patients had tumors that did not change in size after Gamma knife radiosurgery, 30% of tumors decreased in size and 7% of tumors increased in size after radiosurgery. Through results of the above studies, we found that the effect of Gamma knife radiosurgery was positive, the ability to reduce the size of the tumor and keep disease stable high, only less than 10% of patients have progressed after Gamma knife radiosurgery. 17 4.2.1.2. Evaluation of tumor size control by Gamma knife radiosurgery Table 4.1. Proportion of tumor size control Authors Number of patients Radiation dose Time of follow-up Rate of tumor size control Chen Y.H. et al (2013) 22 patient of recurrent or residual PA 25 Gy 58.1 months 100% Grant R.A. et al (2014) 31 cases of functional PA: 15 ACTH, 13 GH, 2 PRL, 1 TSH 35 Gy 40.2 months 100% Sheehan J.P. et al (2013) 512 cases of non-functional PA 16 Gy (5-35 Gy) 36 months 3 years: 98%; 5 years: 95%; 8 years: 91%; 10 years: 85%. Elshirbiny M.F. et al (2015) 40 cases of functional PA: 16 PRL, 16 GH, 8 ACTH PRL: 18-22 Gy GH: 20-25 Gy ACTH: 25-30 Gy 20 months (12-60 months) PRL: 100% GH: 87% ACTH: 100% Hafez R.F. et al (2014) 54 cases of functional PA PRL: 18-22 Gy GH: 20-25 Gy ACTH: 25-30 Gy 28 months (12 – 84 months) PRL: 96% GH: 90% ACTH: 100% Yazdani S.O. et al (2015) 100 patients: 46 cases of non- functional PA, 54 cases of functional PA non- functional PA: 18 Gy functional PA: 24 Gy 24 months Overall: 92% non-functional PA: 93%. PRL: 80% GH: 96% ACTH: 84% 18 We noted that the overall control rate of tumor size in the study was 97.5%. In general, the effectiveness of controlling is higher than 90% and has the time long in controlling tumor size after Gamma knife radiosurgery. 4.2.2. Evaluate the outcome of hormone levels 4.2.2.1. The endocrine response of functional pituitary adenomas Table 4.2. Comparison of treatment results for functional pituitary adenomas Authors Number of patients Radiation dose Time of follow up Results Our study 23 cases 17.74 ± 2.28 Gy 60 months Returning normal endocrine levels PLR: 20% GH: 46.7% Nguyễn Thị Minh Phương (2018) 21 cases 14.05 ± 2.89 Gy 36 months 40% cases return normal endocrine levels Elshibiny M.F. et al (2015) 40 cases PRL-secreting PA: 18-22 Gy GH-secreting PA: 20-25 Gy ACTH-secreting PA: 25-30 Gy 20 months (12-60 months) Hormonal control: PRL 56%, GH: 62%, ACTH: 62% Yazdani S.O. et al (2015) 56 cases 24 Gy 24 months Returning normal endocrine levels / Good control: GH: 48% / 73% PLR: 46% / 67% ACTH: 35% / 70% 19 Authors Number of patients Radiation dose Time of follow up Results Iwai Y. et al (2009) 26 GH- secreting PA 20 Gy (14-30 Gy) 84 months (36-144 months) Returning normal endocrine levels : 42% Good control: 50% Raef H.F. et al (2014) 54 cases PRL-secreting PA: 18-22 Gy GH-secreting PA: 20-25 Gy ACTH-secreting PA: 25-30 Gy 12 – 84 months Returning normal endocrine levels: PRL: 62% GH: 60% ACTH: 70% 4.2.2.2. The time of hormonal response When analyzing the response time to PRL and GH hormones, we found that the time for PRL to start responding to treatment was at the 6 th month and the 12 th month for GH. The time when the hormone responds to treatment returns to normal for PRL is 18 months, GH is 30 months after Gamma knife radiosurgery. Nguyen Thi Minh Phuong noted that the time when hormones returned to normal was the 6 th month after Gamma knife radiosurgery. Sallabanda et al analyzed 30 pituitary adenomas including 26 functional pituitary adenomas, showing 65.4% of cases returned to normal and 15.3% of cases had an improvement in concentration levels of blood, the time of hormonal response to normal or improved with an average of 12.3 months for GH and 61.8 months for ACTH. Grant R.A. et al. reported that 31 patients of functional pituitary adenomas receiving Gamma knife radiosurgery with an average follow-up time of 40.2 months found that 70% of the patients had an endocrine levels returning normal after the average 17.7 months’ follow-up period. The author showed that the average time of 20 hormonal levels returning normal: ACTH is 11.7 months, GH is 18.4 months and PRL is 57 months. Thus, the response of endocrine to Gamma knife radiosurgery returned to normal levels in our study similar to other authors in the world. The endocrine response is usually slow starting at the 6 th and 12 th months after treatmenr. More than half of all cases will have a complete endocrine response to Gamma knife radiosurgery after follow-up. Patients with functional pituitary tumors after radiosurgery should be treated with the adjuvant endocrine drugs to quickly improve the endocrine concentration of blood and improve clinical symptoms due to the increase of hormone levels. 4.2.2.3. Hypopituitarism Hypopituitarism is a symptom that needs attention during the radiosurgery of pituitary by Gamma knife. Besides radiation, medical treatment also contributes significantly to the outcome of treatment. Before Gamma knife radiosurgery, the rate of hypopituitarism in our study was 53.1%. After Gamma knife radiosurgery, the rate of hypopituitarism decreases gradually in the 3 rd months and by the 6 th month is 30.9%. However, these cases of hypopituitarism are adjuvant treated with hormonal drugs (except in the case of impaired GH function and sex hormones). This rate remained stable until the end of the 36 th month follow-up visit, after that from the 36 th month, the rate of hypopituitarism increased gradually until the 48 th month at 67.6% and the 54 th month at 54.2%. This can be explained when the tumor responds to Gamma knife radiosurgery help reduce the size of the tumor, thereby reducing the compression of the anterior pituitary gland, reducing the rate of hypopituitarism. Additionaly, because of hormonal drug supplements helped to reduce this rate. 21 However, in the latter stage, pituitary cells degenerated by Gamma knife radiosyrgery will increase the rate of hypopituitarism. This is also an important late complication of pituitary Gamma knife radiosurgery. We noted that the time of new hypopituitarism after radiosurgery occurred was the 24 th month after treatment. It is noted that the proportion of hypopituitarism that appears after radiosurgery increases and stabilizes at about 32-35% after 42 months of treatment. Tanaka S. et al studied 22 PRL-secreting patients who had received Gamma knife radiosurgery, average dose of 22 Gy (16-30 Gy), median follow-up time was 60 months (16-129 months) found that 100% of the patients had decreased PRL level, the average level from 88.4 ng/ml to an average of 28.4 ng/ml. The difference was statistically significant with p=0.001. However, after the follow-up period, the author noticed that 8 patients appeared a new hypopituitarism. The average time of occurrence of new hypopituitarism is 19 months (4-40 months). The rate of hypopituitarism after 2 years is 23% and after 4 years is 42%. Castinetti F. et al. reported on 76 patients with different types of pituitary adenomas, with a minimum follow-up of 5 years and a third of patients was followed for more than 10 years, the author found that 21% patients develop a new hypopituitarism during an average of 48 months, which again reinforces the importance of long-term monitoring of hypopituitarism. The sensitivity of the hormonal axes varies among patients, except for GH, which is always the most sensitive to the timing of deficiency. Zibar T.L. et al. reported 27 pituitary adenomas receiving Gamma knife radiosurgery, the average tumor volume was 4.73 cm3, the average radiation dose was 20 Gy, the average follow-up time 22 was 72 months showed 30% patients appear with new hypopituitarism after Gamma knife radiosurgery, the cumulative chart shows that the frequency of new hypopituitarism after Gamma knife radiosurgery is 42% and the average time of occurrence of new hypopituitarism is 41.5 months (3 -96 months). Sheehan J.P. reported that 512 non-functional pituitary adenoma patients undergo Gamma knife radiosurgery showed that the rate of hypopituitarism before treatment was 58%. After the 120-month follow-up period, the author reported a new incidence of hypopituitarism was 21.1%. The author conducted a univariate and multivariate analysis of risk factors for new or worsening pituitary dysfunction including: increased radiation dose Gamma knife radiosurgery at the edge of the tumor (OR = 1.07 [95% CI 1.01 - 1,12], p = 0,018) and previous history of Gamma knife radiosurgery (OR = 2.44 [95% CI 1.04-5.77], p = 0.041). Patients with new visual disorders are also more likely to have new pituitary dysfunction after treatment (OR = 2.39 [95% CI 1.19-4.83], p = 0.015) 4.2.3. Radiosurgery complications Our study did not record any visual complications. According to the study of Sebastian P. et al on 94 patients in radiosurgery, visual complications after treatment had the rate of 5.3%. Multivariate analysis showed that the risk factors for visual complications after Gamma knife radiosurgery is conformal Gamma knife radiosurgery (OR = 10.36, p = 0.04). Gopalan R. noted that the visual complication after Gamma knife radiorurgery is 6.2% (3/48 patients), of which 2 patients had visual disturbances before surgery, 2 out of 3 patients had advanced tumors after Gamma knife radiosurgery. 23 CONCLUSION During the study period from January 2012 to March 2017, we collected a total of 81 cases of residual or recurrent pituitary adenomas after surgery. We divided two types of patients: - Functional pituitary adenomas: 23 patients (28.4%) - Non-functional pituitary adenomas: 58 patients (71.6%) 1. Clinical and subclinical characteristics of pituitary adenoma - The average age is 43.35 ± 11.9, the youngest is 18-year-old and the largest is 73-year-old. - The rat