Microsoft Word - 10MusaWael_Surgery 272 | Musa et al - Surgery for recurrent high-grade gliomas             DOI: 10.2478/romneu-2018-0033 Surgery for recurrent high-grade gliomas: the dilemma of debate Wael Musa, Ahmed N. Taha Department of Neurosurgery, Mansoura Medical School, EGYPT Abstract: Background: Treating recurrent gliomas is a big dilemma in the literature and no uniform protocol is approved to treat such disappointing problem. Although improvement in the RT techniques, new CTX techniques and new techniques including targeted therapy and gene therapy; all fail to dramatically improve the outcome and solve the problem of significant mass effect when the recurrent tumor is big So resurgery play a role in treating such challenging problem. The aim of the study: to assess the goal and outcome of surgery in treatment of recurrent malignant glioma. Methods: We retrospectively analyzed the data of 56 patients who were operated upon for recurrent or progressed high grade gliomas in the Mansoura neurosurgery department allover 2007 to 2016. We have excluded patients with recurrent thalamic gliomas and patients with Kps score less than 70. Results: 12 patient underwent sterotactic biopsy for their tumor and were sent for adjuvant radiotherapy, 29 patients underwent partial tumor resection and gross total resection was done in 15 patients. The median time to progression was 5 months. All patients were sent after surgery for poster radiotherapy and chemotherapy. The median overall survival was 4 months. Conclusion: Recurrent high grade glioma is one of unsolved problem and optimal management is no longer available. Redo surgery is quiet challenging with higher minorities and no add to overall survival. Surgery is indicated to relieve significant mass effect. Outcome of surgery is better for those who did aggressive surgical resection at initial surgery than those who did only partial resection. Key words: RT radiotherapy, CTX chemotherapeutic, kps karnofsky performance status Introduction High grade gliomas are the most common primary brain tumor and the most challenging regarding the treatment opportunities.¹⁻²⁻³ Safe gross total resection followed by adjuvant treatment including radiotherapy and chemotherapy (temozolomide) is the standard treatment that could be offered to such dismal tumors.4 Despite advancement in the treatment modalities; the outcome is improved mostly in the functional status but Romanian Neurosurgery (2018) XXXII 2: 272 - 282 | 273             the potential survival has not significantly improved and recurrence is mostly inevitable. Treating recurrent gliomas is a big dilemma and no uniform protocol is approved to treat such disappointing problem. Although improvement in the radiotherapeutic techniques making re-irradiation for recurrent gliomas is potentially safe and new chemotherapeutic techniques and the development of new techniques including targeted therapy and gene therapy; all fail to dramatically improve the outcome and solve the problem of significant mass effect when the recurrent tumor is big making redo surgery play a role in treating such challenging problem. 5⁻6 Surgery for recurrent high-grade glioma should be tailored and individualized based on the patient’s age, clinical status, Karnofsky Performance Status score. The extent of resection and numbers of redo surgeries played an important role regarding the quality of life and expected survival for recurrent grade III or IV gliomas.6 The aim of this retrospective study is to assess the goal and outcome of surgery in treatment of recurrent malignant glioma. Patients and methods We retrospectively analyzed the data of 56 patients who were operated up on for recurrent or progressed high grade gliomas in the neurosurgery department, Mansoura University during the period from 2007 to 2016. Previous treatment for those cases was surgery followed by adjuvant treatment in the form of radiotherapy with or without chemotherapy. We have excluded patients with recurrent thalamic gliomas and patients with Karnofsky Performance Status score less than 70. Results Patient characteristics are shown in Table 1. Median age was 47.79 years. Thirty-three patients were male, and 23 were female. Histology was WHO Grade 4 in 44 patients and Grade 3 in 12 patients. At last follow-up, 32 of 56 patients had died. Median follow-up from the date of reoperation was 7 months (range, 0–94 months) for all patients and 11 months (range, 0–94 months) for surviving patients. Predictors of survival We chose certain factors to predict the survival of our patient from diagnosis and from reoperation to be included in this study, and these factors are; age, size of 2ry tumor, interval between operation, pathology of 2ry tumor and treatment offered after reoperation. As regard age of patients, median survival rate from diagnosis for patients less than 50 years was 11.00 and 9.00 for patients more than 50 years( p value 0.034) figure 1-A; median survival rate from reoperation for patients less than 50 years was 5.00 and 4.00 for patients more than 50 years( p value 0.060) figure 1-B   274 | Musa et al - Surgery for recurrent high-grade gliomas             TABLE 1 Patient characteristics AGE Mean ± SD 47.79 9.81 Size of 1ry_tumor (CM) Median Min – Max 5.00 3-7 Time to recurrence (m) Median Min – Max 5.00 2-15 Size of recurrence (CM) Median Min – Max 4.00 2.5-7 Survival time (m) Median Min – Max 5.00 1-13 Sex Male 33 58.9% Female 23 41.1% Tumor location RT frontal 8 14.3% RT T/P 4 7.1% LF F/T/P 3 5.4% LF F/T 5 8.9% LF TEMPORAL 4 7.1% RT TEMPORAL 4 7.1% RT P/O 2 3.6% LF F/P 2 3.6% RT F/T/P 5 8.9% CORPUS CALLOSUM 9 16.1% LF P/O 2 3.6% LF P 3 5.4% LF T/P 2 3.6% LF F 1 1.8% RT F/P 1 1.8% RT P 1 1.8% Pathology of 1ry tumor GBM 39 69.6%% G3 8 14.3% Primary TTT GTR RT 19 33.9% PTR RT CH 7 12.5% GTR RT CH 10 17.9% PTR RT 9 16.1% STB RT CH 3 5.4% STB RT 8 14.3% Pathology of 2dry T GBM 44 78.6% G3 12 21.4% Surgery complication NO 22 39.3% Lt hemiparesis 7 12.5% Coma 6 10.7% Aphasia 2 3.6% Rt hemiparesis 9 16.1% Seizures 9 16.1% CSF leakage 1 1.8% Romanian Neurosurgery (2018) XXXII 2: 272 - 282 | 275             Figure 1-A - median survival rate from diagnosis according patients age Figure 1-B - median survival rate from reoperation according patients age Survival from diagnosis and from reoperation acording to size of 2ry tumor is shown in figure 2-A,B. Median survival rate from diagnosis for 2ry tumor less than 5cm in size was 11.00 and for more than 5 cm was 7.00 with p value 0.004,while it was from reoperation for tumor less than 5cm 5.00 and 3.00 for larger tumor size with p value < 0.001. Figure 2-A - Survival from diagnosis according to size of 2ry tumor Figure 2-B - Survival from reoperation according to size of 2ry tumor On the other hand, if we are looking for Survival from diagnosis and from reoperation according to interval between operation as shown in figure 3-A, B. We found that the median survival rate from diagnosis for patients whom underwent another surgery for the tumors in less than 6 months from the primary surgery was 8.00 and its increase to 18.00 for patients did 2nd surgery in period more than 6 months from first tumor attacking with p value 0.001. While median survival rate from reoperation for patients whom underwent 276 | Musa et al - Surgery for recurrent high-grade gliomas             another surgery for the tumors in less than 6 months from the primary surgery was 4.00 and its increase to 7.00 for patients did 2nd surgery in period more than 6 months from first tumor attacking with p value < 0.001. Figure 3-A - Survival from diagnosis according to interval between operation Figure 3-B - Survival from reoperation according to interval between operation According to pathology of 2ry tumor, Survival from diagnosis and from reoperation shown figure 4-A, B. We found that the median survival rate from diagnosis for patients whom 2ry tumor pathology was GBM was 9.00 and its 15.00 for patients whom 2ry tumor pathology was grade 3 with p value 0.003.While median survival rate from reoperation for patients whom 2ry tumor pathology was GBM was 4.00 and its 7.00 for patients whom 2ry tumor pathology was grade 3 with p value 0.011. Figure 4-A - Survival from diagnosis according to pathology of 2ry tumor Figure 4-B - Survival from reoperation according to pathology of 2ry tumor Romanian Neurosurgery (2018) XXXII 2: 272 - 282 | 277             Finally, According to treatment offered after reoperation, Survival from diagnosis (Table 2, figure 5-A) and from reoperation (Table 3, figure 5-B). TABLE 2 Survival from diagnosis according to treatment offered after reoperation TTT_offered Total N N of Events Censored Median survival time P N Percent GTR_RT_CHT 6 6 0 0.0% 12.000 ˂0.001 PTR 2 2 0 0.0% 6.000 GTR_CHT 15 15 0 0.0% 18.000 PTR_RT 1 1 0 0.0% 11.000 PTR_CHT 18 18 0 0.0% 9.000 PTR_RT_CHT 8 8 0 0.0% 9.000 PTR_DC 6 6 0 0.0% 4.000 Overall 56 56 0 0.0% 9.000 Figure 5-A - Survival from diagnosis according to treatment offered after reoperation 278 | Musa et al - Surgery for recurrent high-grade gliomas             TABLE 3 Survival from reoperation according to treatment offered after reoperation TTT_offered Total N N of Events Censored Median survival time P N Percent GTR_RT_CHT 6 6 0 0.0% 7.000 ˂0.001 PTR 2 2 0 0.0% 1.000 GTR_CHT 15 15 0 0.0% 8.000 PTR_RT 1 1 0 0.0% 6.000 PTR_CHT 18 18 0 0.0% 4.000 PTR_RT_CHT 8 8 0 0.0% 3.000 PTR_DC 6 6 0 0.0% 1.000 Overall 56 56 0 0.0% 5.000 Figure 5-B - Survival from reoperation according to treatment offered after reoperation Romanian Neurosurgery (2018) XXXII 2: 272 - 282 | 279             In our current study we have different patient complications varied from hemiparesis, coma, CSF leakage, and aphasia (Table 4) TABLE 4 Patient complications Sex Male Female Surgery complication NO Count 14 8 % 63.6% 36.4% Lt hemiparesis Count 6 1 % 85.7% 14.3% Coma Count 4 2 % 66.7% 33.3% Aphasia Count 1 1 % 50.0% 50.0% Rt hemiparesis Count 5 4 % 55.6% 44.4% Seizures Count 3 6 % 33.3% 66.7% CSF leakage Count 0 1 % 0.0% 100.0% Treating recurrent high-grade gliomas is a big dilemma and debate still exist in the literature about the value of redo surgery in improving the overall prognosis of such dismal tumors. Patient age and Karnofsky Performance Status (KPS) are very important detectors for the quality and duration of survival after reoperation. Patients with recurrent high-grade glioma with KPS more than 70 have better outcome than those less than 70. Age and preoperative KPS score had a significant effect on duration of high-quality survival after reoperation.8⁻¹²⁻¹³⁻¹4⁻¹5⁻¹6⁻¹7⁻¹9⁻²º⁻²¹ Some studies compared the quality of survival and duration of survival for patients with recurrent high-grade gliomas who offered re-operation to those who not operated up on. One study found a 9-month survival (operated group) compared with 5.75 months (Non-operated group). 9⁻²²⁻²5⁻²6⁻²7 Many published data showed 5-50% 280 | Musa et al - Surgery for recurrent high-grade gliomas             improvement in KPS after re-operation for recurrent high-grade gliomas. Improvement in the adjuvant treatment protocols with the use of conformal fractionated radiotherapy with the use of temozolomide chemotherapy helped to improve the clinical outcome and overall survival for high-grade glioma. Despite such improvement; the chance of tumor progression or recurrence still exist and still there is a big debate if adjuvant treatment alone is enough for recurrence or there is a role for re-operation.4 In a one retrospective study done by on 65 patients who underwent re- operation for progressing high grade gliomas. Median time to second surgery was 7.1 months. The indications to reoperation were increase in the tumor size on magnetic resonance imaging, new neurological deficit, manifestation of increased intracranial pressure and epilepsy. The authors found better overall survival for those who did re- operation the those who did not.9 Many other reports addressed such controversial problem and they found that outcome of re-operation for recurring high-grade gliomas is multifactorial and more favorable outcome was found for those patients with age 50 years or less, time interval more than 9 months between operations, achieving gross total resection (GTR), and KPS scores 70 at reoperation.9⁻²²⁻²5 Some studies addressed the role of either radiotherapy plus temozolimide or temozolimide alone for treating progressing high-grade gliomas and despite initial good results; the found less capabilities of achieving good tumor control and overall survival compared to re-operation with adjuvant treatment. However; there was no difference in outcome of the patient functional status.¹¹ Improvement in neurosurgical techniques, neuro-anesthesia, and post-operative ICU care minimized procedure related morbidities and mortalities. However, proper patient selection is very important to choose the case who might get benefit from re-operation. Beside the patient age, KPS, the time to recurrence; other factors may play an important role be considering the outcome. 5⁻7⁻8⁻¹º⁻¹²⁻¹³⁻¹5⁻¹8⁻²¹⁻²³⁻²8 The tumor size and the degree of central necrosis play an important role regarding the outcome and it was found in some studies that the prognosis was favorable with patients having tumor necrosis rather than tumor recurrence. Smaller tumor volume had a more favorable outcome compared with bigger tumor volume at time of re-operation. The extent of tumor removal is another prognostic indicator for the outcome which is also dependent on the tumor size and location with more favorable outcome occur with achieving adequate gross total resection at both the time of primary and re-operations. It was found the re-operation for recurrent tumor after initial gross total resection has a better outcome than after partial resection or just biopsy.²4 Gross total resection (GTR) is recognized by many studies as an independent predictor of improved survival in patients with recurrent high-grade glioma. It was found that the residual tumor volume has its impact on outcome of temozolomide chemotherapy after re-operation.² One study on recurrent high- grade gliomas reported a median survival of Romanian Neurosurgery (2018) XXXII 2: 272 - 282 | 281             11months after GTR compared to 5 months after only partial resection disregarding patient age and performance status.²³ In another study; authors analyzed a series of 107 patients with re-operation for recurring high- grade glioma. They addressed the value of the extent of tumor resection at the initial and subsequent surgery. The found the best survival outcome with subtotal resection at the initial surgery and GTR at re-operation with median overall survival of 16.7-month and the worst outcome with partial resection at both surgery with 7.4 median overall survival.5 Patients age play an important role in overall prognosis for recurrent high-grade gliomas and the younger the age the better the prognosis. Although some centers did not offer surgery for elderly with recurrent high- grade gliomas; some studies concluded that surgery should be considered for all patients with favorable KPS disregarding the age of the patient.²9 The goal of surgery for recurrent high- grade gliomas is to do safe adequate resection with limited morbidities. The potential morbidities for re-operation was studied in many case series. Some studies showed no difference in the incidence of morbidities while others showed higher chance of surgery related morbidities. 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