DOI: 10.33962/roneuro-2023-036 Prospective study of selective intra- arterial cerebral infusion and intra - operative local application of carboplatin for recurrent glioblastoma multiformis Tareq Abdul Ghani Hamid, Abdul Wahab Mahmoud Ibrahim, Ibrahim Ali Awad, Talal Ahmed Youssef Amer, Wael K. Zakaria Romanian Neurosurgery (2023) XXXVII (2): pp. 202-210 DOI: 10.33962/roneuro-2023-036 www.journals.lapub.co.uk/index.php/roneurosurgery Prospective study of selective intra-arterial cerebral infusion and intra-operative local application of carboplatin for recurrent glioblastoma multiformis Tareq Abdul Ghani Hamid1, Abdul Wahab Mahmoud Ibrahim2, Ibrahim Ali Awad3, Talal Ahmed Youssef Amer⁴, Wael K. Zakaria5 1 Assistant Fellow of Neurosurgery, Ahmed Maher Teaching Hospitals, Cairo, EGYPT 2 Professor of Neurosurgery, Department of Neurosurgery, Mansoura University Hospital, Mansoura, EGYPT 3 Professor of Clinical Oncology and Nuclear Medicine, Mansoura University Hospital, Mansoura, EGYPT 4 Professor of Diagnostic Radiology, Faculty of Medicine, Mansoura University, EGYPT 5 Assistant professor of Neurosurgery, Department of Neurosurgery, Mansoura University Hospital, Mansoura, EGYPT ABSTRACT Background. High-grade glioma is the commonest primary malignant brain tumour in adults. Intra-arterially selectively infused chemotherapeutic agents into the tumour bulk is being widely trialled recently with promising results. Methods. This is a prospective study designed between November 2015 and November 2019. Thirty patients were diagnosed with recurrent histo-pathologically proven GBM after one surgery at least and followed by standard radiotherapy and temodal. Patients aged between 37-76 years, 18 males and 12 females were subdivided into group A of 21 patients who underwent intra-arterial delivery of carboplatinand group B of 9 patients who underwent re-surgical resection and local application of carboplatin. Results. The mean age of the included cases was 55.4 years (range, 37-76 years). Selective intra-arterial injection was performed in 21 cases (70%), while the remaining 9 cases (30%) had local application of carboplatin in the tumour bed. Post-treatment vomiting was reported in 7 cases (23.3%). Significant and partial responses were achieved in 2 cases for each (6.7%). Time to tumour progression had a mean of 19.03 weeks (range, 3 – 30 weeks). After receiving carboplatin, the study cases had a mean survival of 26.5 weeks (range, 6 – 70 weeks). Intra-arterial injection had significantly better results compared to local tumour bed infiltration (p = 0.01). Conclusion. Although recurrent glioblastoma multiformis has poor survival, intra- arterial delivery of carboplatin may have a slight positive impact on patient survival. The procedure however is relatively safe with manageable complications. Keywords GBM, carboplatin, intra-arterial injection, tumoricidal, DSA Corresponding author: Wael K. Zakaria Department of Neurosurgery, Mansoura University Hospital, Mansoura, Egypt drwaelmusa@yahoo.com Copyright and usage. This is an Open Access article, distributed under the terms of the Creative Commons Attribution Non–Commercial No Derivatives License (https://creativecommons .org/licenses/by-nc-nd/4.0/) which permits non- commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of the Romanian Society of Neurosurgery must be obtained for commercial re-use or in order to create a derivative work. ISSN online 2344-4959 © Romanian Society of Neurosurgery First published June 2023 by London Academic Publishing www.lapub.co.uk http://www.lapub.co.uk/ 203 Local application of carboplatin for recurrent glioblastoma multiformis INTRODUCTION High grade glioma is the commonest primary malignant brain tumor in adults with an incidence of approximately 5 per 100,000[1]. A published phase III randomized trial showed only 9.8% 5-year survival rate for patients with high grade glioma treated by standard protocol of surgery plus radiation and temozolomide. Intra-arterially selectively infused chemotherapeutic agents into the tumor bulk is being widely trialed recently. Some of the trails showed promising results and point to more investment in the field of selective intra-arterial infusion of tumoricidal agents for treatment of malignant glioma[2].Glioblastoma multiformis which is the high-grade glioma targeted in our study like most malignant carcinoma, its cells possess replicative immortality. Normal cells that undergo DNA damage and telomere shortening have the ends of their DNA strands bind together to stop replication and apoptosis commences. Loss of P53 gene results in over expression of telomerase enzyme that is responsible in maintaining DNA strand length, repairing damage and protecting the ends of chromosomes allowing cells to continuously proliferate [3]. The protocol of maximum safe surgery of GBM followed by adjuvant chemo-radiotherapy and adjuvant chemotherapy is established as usual standard management[9]. But local recurrence is expected, with the majority of cases within 6–9 months of 1ry treatment due to resistant stem cells of GBM [10, 11]. Molecular factors such as mutation of P53,methylation of O-6-methylguanine-DNA methyltransferase (MGMT) and MIB-1 labeling index are associated with GBM recurrence [16]. Controversy exists regarding diagnosing recurrence, with histo - pathological examination of tissue as the ultimate diagnosis .On the other hand, the majority of cases having imaging finding indicative of progression could be unfit for a surgery, hindering diagnosis of recurrence difficult [12,13,17,18]. Surgery is still a significant important strategy in management of GBM. On the other hand, only few cases are recognized appropriate for a complete resection. Re-irradiation (ReRT) has improved in the last years [19].. Chemotherapy is utilized by variable groups to improve survival. Despite this , however , patients of rGBM and GBM still remain fated for poor outcomes[15].The blood–brain barrier (BBB) prevents the deliverance of the majority of the chemotherapeutic drugs [20]. On the other hand, the majority of the regimens of management surfaced via single institute retrospective analysis of phase II clinical trials, thus, there is no standard treatment for those patients non responsive to TMZ [21]. Carboplatin is the drug chosen to target recurrent glioblastoma in our study, it is an analogue of cisplatin containing a platinum atom. Once inside tumorous cells carboplatin becomes activated to produce reactive platinum complexes that form inter-strand and intra-strand cross linking of DNA molecules inhibiting DNA synthesis and replication resulting in cellular death. Its action can occur during any phase of the cell cycle (cycle non-specific). In the brain only malignant cells will be affected and normal cells are spared because they are normally non dividing stable cells [4]. Adverse effects of systemic IV Carboplatin use includes; Bone marrow depression usually reversible within 30days resulting in anemia 71%, febrile neutropenia18%, thrombocytopenia 25% [5]. Nausea (15%) and vomiting (64%)starts within 6- 12 hours after carboplatin injection but can be limited by prior anti-emetics[5].Hepatotoxicity may also occur in the form of elevated alkaline phosphatase (24%), elevated AST (15%), elevated bilirubin (5%) [6]. Selective Intra-arterial Cerebral Infusion of Carboplatin involves its delivery to tumor site via balloon assisted endovascular techniques and prior focal disruption of the blood brain barrier by injecting 10cc of mannitol 20% over 2 mins[7]. Pre-infusion studies and post-infusion studies including magnetic resonance imaging with and without gadolinium to detect the effect on tumor size and magnetic resonance spectroscopy to detect the metabolic response are carried out for candidate patients [8]. IA infusion of chemotherapy refers to the regional delivery of chemotherapy to the CNS, that results in a major rise in plasma peak concentration and in the AUC associated with the 1stpass effect. This leads to a 3– 5.5-fold factor major rise in the concentration of intra-tumoral chemotherapy as theses lesions are vascular in nature[27]. The Fischer animal model [29], found that accumulation of platinum in the tumor cells nuclei was elevated by a 20-fold factor (9 ng platinum/g tissue) when infused via an IA route, when put side by side with the IV route (0.5 ng platinum/g tissue) [30]. 204 Tareq Abdul Ghani Hamid, Abdul Wahab Mahmoud Ibrahim, Ibrahim Ali Awad et al. Clinical trials incorporating patients with GBM who received cisplatin monotherapy or combined with others chemotherapeutic drugs as etoposideor TMZ documented only modest outcomes [27,28]. PATIENTS AND METHODS This is a prospective study designed for patients have recurrent GBM between November 2015 and Novemeber2019 in Neurosurgery department, Mansoura university Hospitals, Egypt. This study aims to evaluate the efficacy of single dose selective intra-arterial cerebral infusion and tumor bed application of carboplatin for such patients.is. Study subject Thirty patients were diagnosed with recurrent histo pathologically proven GBM after a one surgery at least and followed by standard radiotherapy and temodal. They were all referred from the outpatient neurosurgery clinic. Patients aged between 37-76 years , 18 males and 12 females were subdivided into two groups: Group A(21 patients who underwent intra-arterial delivery of carboplatin), Group B(9 patients who underwent re-surgical resection and local application of carboplatin). Inclusion criteria • Age above18 years old • Patients with recurrent glioblastoma multiforme • Karnofsky performance status scale 40 or above Primary outcome measures Evaluating response to both ways of chemotherapy delivery using imaging techniques. Secondary outcome measure 1. Post-treatment complications. 2. Survival. Patients consent A written informed consent was obtained from all patients before the operation after describing and explaining the details and complications of each approach. Procedure Patients were admitted for a variable period of time ranging between 3-7 days. All patients were investigated by a baseline pre and post enhanced MRI and routine lab most notably serum creatinine and a baseline blood picture (CBC). History taking and baseline neurological examination was established as well for all patients. The patients were then grouped into two groups after assessment of the following: • whether or not they require surgical decompression because of significant radiological mass effect and weather the recurrence is surgically accessible or not • history of complications (CSF wound leakage, poor wound healing, poor scalp texture after radiotherapy, deep venous thrombosis ,pulmonary embolism severe chest infection ) related to prior surgery or adjuvant chemo- radiotherapy rendering surgery high risk. Carboplatin dosage was calculated based upon body surface area calculated using the Mostellar Formula BSA (m2) = SQRT ([height (cm) * weight (kg)] / 3600) Body surface area (m2) = square root ( [Height (cm) * weight (kg) ] divided by 3600. The first group (Group A) Selective Intra-Arterial Cerebral Infusion of Carboplatin was performed at a dose of 400 mg/m2 BSA. On table, digital subtraction angiography (DSA) was done to identify the tumor vascular bed then endovascular techniques are employed to reach the vascular bed, followed by injection of 10cc mannitol 20% over to 2 minutes, DSA was redone to detect focal hyperemia indicating successful BBB disruption, after that Carboplatin infusion was commenced through a Marathon flow directed micro-catheter usually within the middle cerebral artery( MCA) or anterior cerebral artery(ACA) or one of their branches as well as a small dosage at the carotid bifurcation. Mostly, this was carried out under local anesthetic with the patient instructed to either report increasing headache, nausea, blurring of vision or increasing tingling or numbness or heaviness of an extremity. The second group (group B) Local application of Carboplatin during re-surgery at a dose 400mg/m2 BS. After sufficient tumor debulking a cotton pack soaked in Carboplatin solution is placed in the tumor cavity before coagulation of the walls of the cavity for 10mins; the pack is then removed and final hemostasis is 205 Local application of carboplatin for recurrent glioblastoma multiformis achieved and lastly the cavity is filled with the rest of Carboplatin solution. Post-procedural follow up MRI with CE was carried out at 2 weeks and at one or two months later. Response to treatment was then determined as a significant response (SR) if CE tumor size was reduced in any of the following MRIs. A partial response PR was considered if the tumor exhibited less mass effect and edema without reduction in the size of CE tumor. A stable disease SD if no changes regarding size or mass effect occurred. A progressive disease PD was established if size or mass effect and edema were increased post procedurally. Data Analysis Statistical analysis of the data in this study was performed using SPSS software, version 20 (Chicago, IL). Descriptive data was expressed as means with standard deviation or medians with ranges according to data distribution. RESULTS The mean age of the included cases was 55.4 years (range, 37-76 years). We included a total of 18 males (60%) as well as 12 females (Figure 1). Figure 1. Gender distribution in the study cases. The Karnofsky Performance Score (KPS) had a mean of 71.33 in the study cases (range, 50-80) (Table1). Table 1. Analysis of KPS in the study cases Items Study cases n=30 KPS Mean ± SD 71.33 ± 8.99 Median (min-max) 70 (50-80) Continuous data expressed as mean ±SD and median (range) All study cases had been commenced on chemo radiotherapy after the first surgery. Evidence of mass effect was present in all study cases (Table2). Table 2 Analysis of the history of the disease in the study cases. ID Hx of radiotherapy Hx of chemotherapy Previous surgery Pre-ttt evidence of mass effect 1 Yes Temodal yes yes 2 Yes Temodal yes yes 3 Yes Temodal yes yes 4 Yes Temodal yes yes 5 Yes Temodal yes yes 6 Yes Temodal yes yes 7 Yes Temodal yes yes 8 Yes Temodal yes yes 9 Yes Temodal yes yes 10 Yes Temodal yes yes 11 Yes Temodal yes yes 12 Yes Temodal yes yes 13 Yes Temodal yes yes 14 Yes Temodal yes yes 15 Yes Temodal yes yes 16 Yes Temodal yes yes 17 Yes Temodal yes yes 18 Yes Temodal yes yes 19 Yes Temodal yes yes 20 Yes Temodal yes yes 21 Yes Temodal yes yes 22 Yes Temodal yes yes 23 Yes Temodal yes yes 24 Yes Temodal yes yes 25 Yes Temodal yes yes 26 Yes Temodal yes yes 27 Yes Temodal yes yes 28 Yes Temodal yes yes 29 Yes Temodal yes yes 30 Yes Temodal yes yes Regarding the method of carboplatin delivery, selective intra arterial injection was performed in 21 cases (70%), while the remaining 9 cases (30%) had local application of carboplatin in the tumour bed (Figure2). Post-treatment vomiting was reported in 7 cases (23.3%), whereas epilepsy was present in 8 cases 0 10 20 Male Female Gender Male Female 206 Tareq Abdul Ghani Hamid, Abdul Wahab Mahmoud Ibrahim, Ibrahim Ali Awad et al. (26.7%). Additionally, hemiparesis was diagnosed only in 2 cases (6.7%) (Figure3). Figure 2. Method of carboplatin delivery in the study cases. Figure 3. Treatment complications in the study cases. More than half of the study cases had progressive disease (16 cases – 53.3%), followed by stable disease (10 cases – 33.3%). Significant and partial responses were achieved in 2 cases for each (6.7%) Time to tumour progression had a mean of 19.03 weeks (range, 3 – 30 weeks).After receiving carboplatin, the study cases had a mean survival of 26.5 weeks (range, 6 – 70 weeks). On dividing our study cases according to the method of carboplatin delivery, no significant difference was detected between the two groups regarding treatment complications (p > 0.05) (Figure 4). Regarding treatment response, it was evident that intra arterial injection had significantly better results compared to local tumor bed infiltration (p = 0.01). All cases in local bed infiltration had progressive disease after treatment, while 2 cases in the other group had significant response (Table3). Figure 4. Treatment complications in both study groups. Table 3. Analysis of response in the two study groups Groups Test of significance Group 1 [Selective IA] (N=21) Group 2 [Local in tumor bed] (N=9) Significant response 2 (9.5%) 0 (0%) 2= 11.250 P= 0.010* Stable disease 10 (47.6%) 0 (0%) Progressive disease 7 (33.3%) 9 (100%) Partial response 2 (9.5%) 0 (0%) P: probability. Categorical data expressed as Number (%) x2= Chi-square test Table 4. Analysis of TTP in the two study groups. Groups Test of significance Group 1 [Selective IA] (N=21) Group 2 [Local in tumor bed] (N=9) TTP (weeks) 19 (6.5 -34) 8 (7.5 -11) t= -1.383 P = 0.178 P: probability. Continuous data expressed as median (IQR). z= Mann Whitney U-test 0 5 10 15 20 25 Selective intraarterial Local in tumour bed Carboplatin delivery Selective intraarterial Local in tumour bed 0 2 4 6 8 10 Treatment complications Vomiting Epilepsy Hemiparesis 0 2 4 6 8 Vomiting Epilepsy Neurological deficit Treatment complications IA injection Local delivery 207 Local application of carboplatin for recurrent glioblastoma multiformis There was no significant difference between the two groups regarding time to disease progression (p = 0.178) although the mean TTP was shorter in the tumor bed infiltration group (8 vs. 19 weeks in the IA group) (Table4). Survival was significantly longer in the IA drug group (35 vs. 14 weeks in the local tumour bed group – p = 0.028) (Figure5). Figure 3. Survival in the study groups. DISCUSSION Even with respect to all advances in aspects of treatment, patients with GBM still remain of poor prognosis[33]. During progression, salvage treatments provide highly modest efficiency. Several agents have been tested concerning this topic, providing low rates of response varying from 5 to 20% and median total survival between 5 and 7.5 months [34]. We included an overall of 30 patients in the current study, having a mean age of 55.4 (range, 37 – 76 years). We included a total of 18 males (60%) as well as 12 females. Another study conducting similar perspective included 24 patients with recurrent GBM. The mean age of the included cases was 44.5 years (range, 26 – 67 years). Investigators comprised 13 males and 11 females in that study [25]. Another study included an overall of 25 patients whose mean age was 37.8 years (range, 22 – 68). A total of 13 males and 12 females were included in that study [26]. In our study, Karnofsky Performance Score (KPS) had a mean of 71.33 in the study cases (range, 50- 80). In a similar study, at the time of initiation of therapy, median KPS was eighty. At the time of disease progression, the median KPS was sixty [35]. Another study reported that the mean KPS score was 66.8 (range, 40 – 90) [26]. In the current study, time to tumor progression had a mean of 19.03 weeks (range, 3 – 30 weeks). Newton and his associates reported that the overall median TTP was 24.2 weeks, while for responders the median TTP was 32 weeks (range 10–174 weeks) [26]. In the current study, more than half of the study cases had progressive disease (16 cases – 53.3%), followed by stable disease (10 cases – 33.3%). Significant and partial responses were achieved in 2 cases for each (6.7%). It was evident that intra-arterial injection had significantly better results compared to local tumor bed infiltration (p = 0.01). All cases in local bed infiltration had progressive disease after treatment, while 2 cases in the other group had significant response. IA injections depend on drug provision throughout capillary networks and finally to the perfused tissue. The tissue concentrations reached by utilizing a selective IA route are significantly greater than those reached following IV administration [36].It is assessed that above 2000 cases were managed with IA chemotherapy for GBM, most of which are parts of Phases I and II trials. There has been small evidence of considerably better results throughout the course of these trials. Numerous series state increased survival by only some weeks, with neurotoxicity or ocular toxicity appearing in 7-50% of the patients [22].In another study, volumetric analysis of serial MRIs revealed decrease in tumor mass in three out of ten cases. A rise in tumor mass in the range of 23% to 230% was detected in the other 7 cases in time extending from 2.3 to 37.7 months after starting of therapy by carboplatin [25]. Additionally, 68.29% of cases had tumor progression while the remaining cases had stable disease in another study [24]. In another study, that utilized criteria of Macdonald in order to categorize tumor responses radio logically, authors detected three full responses, twenty-two partial responses, fourteen stable disorders and twelve progressions [28]. Follézou et al. showed that carboplatin had a partial response in high grade glioma patients using a dose of 400 mg/m2[31, Clocchlatti et al. achieved a 208 Tareq Abdul Ghani Hamid, Abdul Wahab Mahmoud Ibrahim, Ibrahim Ali Awad et al. 74% response rate after 250 mg/m2 IA carboplatin infusion[32], and Cloughesy et al. increased carboplatin dose up to 1400 mg/ hemisphere in a dose-escalation study based on cerebral blood flow[37]. Other authors reported that 45 out of 57 patients evaluated with GBM (79%) experienced SD or better. Authors concluded that along with the use of standard treatment guidelines and protocols, intra-arterial chemotherapy with or without osmotic disruption of the BBB is feasible across several centers with a low incidence of catheter-related complications[23]. After receiving carboplatin, our study cases had a mean survival of 26.5 weeks (range, 6 – 70 weeks). Survival was significantly longer in the IA drug group (35 vs. 14 weeks in the local tumor bed group – p = 0.028).In another study, twenty-three patients (out of 46 cases) died after an average of 205 days; 18 were surviving at an average of 324 days from the start of intra-arterial chemotherapy [24]. Stewart et al. reported the results of intra-carotid infusion of carboplatin (200–400 mg/m2) in 15 patients with either glioblastoma or metastatic tumors. Median survival was 9 weeks [191]. In another study, more than one year survival subsequent to start of IA therapy by carboplatin has been observed in twelve out of the twenty-three cases [25]. Furthermore, in another study, the median total survival from time of diagnosis was twenty-three months with a median survival of eleven months from start of study was detected. The progression- free survival subsequent to therapy was 6.1 months, while a free survival progression of 4.3 months was detected subsequent to the IA therapy [38]. Surgery in case of recurrent GBM may involve either biopsy (for diagnostic purposes) or repeat debulking of tumor. Only approximately 20 to 30 percent of patients with recurrent glioblastoma are candidates for a second surgery [39]. In a patient with recurrent GBM, the indications for a debulking reoperation are still to be definitely recognized. The median survival for cases submitted to operation for recurrent glioblastoma ranges from 8 to 12 months in most series [40.41] and varies from 12 to 18 months for patients with anaplastic astrocytoma [42,43,44]. There is no evidence to suggest that the results of re-surgery are more useful than could be expected with radiation and/or chemotherapy alone. However, selected patients could benefit from reoperation (eg, those with a bulky tumor exerting symptomatic mass effect). Favorable prognostic variables include patients whose age is young, a greater interval from the original operation, and the size of the recurrence as well as extent of the 2nd surgical resection [45,46]. In the current study, post-treatment vomiting was reported in 7 cases (23.3%), whereas epilepsy was present in 8 cases (26.7%). Additionally, hemiparesis was diagnosed only in 2 cases (6.7%). On dividing our study cases according to the method of carboplatin delivery, there was no major difference observed among the 2 groups regarding treatment complications (p > 0.05).Bone marrow suppression (BMS) in the form of thrombocytopenia or leucopenia was not observed in cases in this study and this can be most probably be attributed to the fact that the patients received only a single non incremented dose of carboplatin that the body eliminated too soon before BMS sets in. In the study conducted by Stewart and his associates, three of four patients who received 400 mg/m2 of carboplatin developed retinal toxicity. Three of 9 patients who received 300 mg/m2 had decreased ipsilateral vision and one other developed worsening of a preexisting hemiparesis. Focal seizures and transient aphasia occurred in one patient each [38]. Follezou et al. described 23 patients with malignant glioma who were treated with an intra- arterial infusion of 400 mg/m2 of carboplatin every 4 weeks. One patient developed central neurotoxicity and another developed a reversible decrease in visual acuity [31]. Cloughesy et al. reported the use of escalating doses of carboplatin (up to 1400 mg/hemisphere) infused either in the supra clinoid internal carotid artery or basilar artery above the anterior inferior cerebellar artery in 21 patients with recurrent glioma. One patient had permanent neuromotor decline. The predominant complication was hemopoietic toxicity. The median survival was 39 weeks [37]. In another series of 51 cases, authors detected one grade III anemia, three grades IV and five grade III thrombocytopenia and three grade III neutropenia according to criteria of the National Cancer Institute common toxicity. These toxicities were all manageable easily. 3 cases of carotid spasms were detected and there was a asymptotic. These spasms were elicited by positioning of the catheter, and all 209 Local application of carboplatin for recurrent glioblastoma multiformis resolved spontaneously. No cases of neurotoxicity had been detected in this work [28]. CONCLUSION Although recurrent glioblastoma multiformis has a poor survival, intra-arterial delivery of carboplatin may have a slight positive impact on patient survival. The procedure however is relatively safe with manageable complications. REFERENCES 1. Burkhardt JK, Riina H, Shin BJ, Moliterno J, Hofstetter C, Boockvar JA. Intra-arterial chemotherapy for malignant gliomas: a critical analysis. Interventional Neuroradiology. 2011;17(3):286-95. 2. Khosla D. Concurrent therapy to enhance radiotherapeutic outcomes in glioblastoma. Annals of translational medicine. 2016;4(3). 3. Price SJ, Bulstrode H, Mair R. High-grade gliomas and molecular biology of neurosurgical oncology. Oxford Textbook of Neurological Surgery. 2019:89. 4. Paldor I, Chaichana KL, Brem H, Tyler BM. Targeted local therapy for management of intracranial high-grade gliomas. Intracranial Gliomas Part III-Innovative Treatment Modalities. 32: Karger Publishers; 2018. p. 159-71. 5. Rajeswaran A, Trojan A, Burnand B, Giannelli M. Efficacy and side effects of cisplatin-and carboplatin-based doublet chemotherapeutic regimens versus non- platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: a systematic review of randomized controlled trials. Lung cancer. 2008;59(1):1-11. 6. Thatishetty AV, Agresti N, O'Brien CB. Chemotherapy- induced hepatotoxicity. Clinics in liver disease. 2013;17(4):671-86. 7. Riina H, Knopman J, Greenfield J, Fralin S, Gobin Y, Tsiouris A, et al. Balloon-assisted superselective intra-arterial cerebral infusion of bevacizumab for malignant brainstem glioma: A technical note. Interventional Neuroradiology. 2010;16(1):71-6. 8. Jeon J, Kovanlikaya I, Boockvar J, Mao X, Shin B, Burkhardt J, et al. Metabolic response of glioblastoma to superselective intra-arterial cerebral infusion of bevacizumab: a proton MR spectroscopic imaging study. American journal of neuroradiology. 2012;33(11):2095- 102. 9. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC- NCIC trial. The lancet oncology. 2009;10(5):459-66. 10. Gupta T, Nair V, Paul SN, Kannan S, Moiyadi A, Epari S, et al. Can irradiation of potential cancer stem-cell niche in the subventricular zone influence survival in patients with newly diagnosed glioblastoma? Journal of neuro- oncology. 2012;109(1):195-203. 11. Chen L, Chaichana KL, Kleinberg L, Ye X, Quinones- Hinojosa A, Redmond K. Glioblastoma recurrence patterns near neural stem cell regions. Radiotherapy and Oncology. 2015;116(2):294-300. 12. Iagaru A, Mosci C, Mittra E, Zaharchuk G, Fischbein N, Harsh G, et al. Glioblastoma multiforme recurrence: An exploratory study of 18F FPPRGD2 PET/CT. Radiology. 2015;277(2):497-506. 13. Campos B, Olsen LR, Urup T, Poulsen H. A comprehensive profile of recurrent glioblastoma. Oncogene. 2016;35(45):5819. 14. Noel G, Mazeron J. Reirradiation in primary or secondary brain tumors. Cancer radiotherapie: journal de la Societe francaise de radiotherapie oncologique. 2010;14(6- 7):421-37. 15. Fokas E, Wacker U, Gross MW, Henzel M, Encheva E, Engenhart-Cabillic R. Hypofractionated stereotactic reirradiation of recurrent glioblastomas. Strahlentherapie und Onkologie. 2009;185(4):235-40. 16. Fowler JF, Tomé WA, Fenwick JD, Mehta MP. A challenge to traditional radiation oncology. International Journal of Radiation Oncology* Biology* Physics. 2004;60(4):1241- 56. 17. Archavlis E, Tselis N, Birn G, Ulrich P, Baltas D, Zamboglou N. Survival analysis of HDR brachytherapy versus reoperation versus temozolomide alone: a retrospective cohort analysis of recurrent glioblastoma multiforme. BMJ open. 2013;3(3):e002262. 18. Niyazi M, Ganswindt U, Schwarz SB, Kreth F-W, Tonn J-C, Geisler J, et al. Irradiation and bevacizumab in high-grade glioma retreatment settings. International Journal of Radiation Oncology* Biology* Physics. 2012;82(1):67-76. 19. Ellis JA, Banu M, Hossain SS, Singh-Moon R, Lavine SD, Bruce JN, et al. Reassessing the role of intra-arterial drug delivery for glioblastoma multiforme treatment. Journal of drug delivery. 2015;2015. 20. Hossain SS, Hughes TJ, Decuzzi P. Vascular deposition patterns for nanoparticles in an inflamed patient-specific arterial tree. Biomechanics and modeling in mechanobiology. 2014;13(3):585-97. 21. Boockvar JA, Tsiouris AJ, Hofstetter CP, Kovanlikaya I, Fralin S, Kesavabhotla K, et al. Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Journal of neurosurgery. 2011;114(3):624-32. 22. Newton HB. Intra-arterial chemotherapy of primary brain tumors. Current treatment options in oncology. 2005;6(6):519-30. 23. Doolittle ND, Miner ME, Hall WA, Siegal T, Hanson EJ, Osztie E, et al. Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood‐brain barrier for the 210 Tareq Abdul Ghani Hamid, Abdul Wahab Mahmoud Ibrahim, Ibrahim Ali Awad et al. treatment of patients with malignant brain tumors. Cancer. 2000;88(3):637-47. 24. Chow KL, Gobin YP, Cloughesy T, Sayre JW, Villablanca JP, Viñuela F. Prognostic factors in recurrent glioblastoma multiforme and anaplastic astrocytoma treated with selective intra-arterial chemotherapy. American journal of neuroradiology. 2000;21(3):471-8. 25. Qureshi AI, Fareed M, Suri K, Khan J, Sharma M, Olson K, et al. Superselective intra-arterial carboplatin for treatment of intracranial neoplasms: experience in 100 procedures. Journal of neuro-oncology. 2001;51(2):151-8. 26. Newton HB, Slivka MA, Stevens CL, Bourekas EC, Christoforidis GA, Baujan MA, et al. Intra-arterial carboplatin and intravenous etoposide for the treatment of recurrent and progressive non-GBM gliomas. Journal of neuro-oncology. 2002;56(1):79-86. 27. Newton HB, Slivka MA, Volpi C, Bourekas EC, Christoforidis GA, Baujan MA, et al. Intra-arterial carboplatin and intravenous etoposide for the treatment of metastatic brain tumors. Journal of neuro-oncology. 2003;61(1):35-44. 28. Fortin D, Morin P-A, Belzile F, Mathieu D, Paré F-M. Intra- arterial carboplatin as a salvage strategy in the treatment of recurrent glioblastoma multiforme. Journal of neuro- oncology. 2014;119(2):397-403. 29. Mathieu D, Lecomte R, Tsanaclis AM, Larouche A, Fortin D. Standardization and detailed characterization of the syngeneic Fischer/F98 glioma model. Canadian journal of neurological sciences. 2007;34(3):296-306. 30. Charest G, Sanche L, Fortin D, Mathieu D, Paquette B. Glioblastoma treatment: bypassing the toxicity of platinum compounds by using liposomal formulation and increasing treatment efficiency with concomitant radiotherapy. International Journal of Radiation Oncology* Biology* Physics. 2012;84(1):244-9. 31. Follezou J, Fauchon F, Chiras J. Intraarterial infusion of carboplatin in the treatment of malignant gliomas: a phase II study. Neoplasma. 1989;36(3):349-52. 32. Clocchiatti L, Cartei G, Lavaroni A, Vigevani E, Fabris G, Tommasini G, et al. Intra-Arterial Chemotherapy with Carboplatin (CBDCA) and Vepesid (VP16) in Primary Malignant Brain Tumours: Preliminary Findings. Interventional Neuroradiology. 1996;2(4):277-81. 33. Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nature medicine. 2019;25(3):477-86. 34. Yung WA, Albright R, Olson J, Fredericks R, Fink K, Prados M, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. British journal of cancer. 2000;83(5):588-93. 35. Mrugala MM, Crew LK, Fink JR, Spence AM. Carboplatin and bevacizumab for recurrent malignant glioma. Oncology letters. 2012;4(5):1082-6. 36. Tyler J, Yamamoto Y, Diksic M, Theron J, Villemure J, Worthington C, et al. Pharmacokinetics of superselective intra-arterial and intravenous [11C] BCNU evaluated by PET. J Nucl Med. 1986;27(6):775-80. 37. Cloughesy TF, Gobin YP, Black KL, Viñuela F, Taft F, Kadkhoda B, et al. Intra-arterial carboplatin chemotherapy for brain tumors: a dose escalation study based on cerebral blood flow. Journal of neuro-oncology. 1997;35(2):121-32. 38. Stewart DJ, Belanger JG, Grahovac Z, Curuvija S, Gionet LR, Aitken SE, et al. Phase I study of intracarotid administration of carboplatin. Neurosurgery. 1992;30(4):512-7. 39. Weller M, Van Den Bent M, Tonn JC, Stupp R, Preusser M, Cohen-Jonathan-Moyal E, et al. European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. The lancet oncology. 2017;18(6):e315-e29. 40. Ringel F, group Ss, Pape H, group Ss, Sabel M, group Ss, et al. Clinical benefit from resection of recurrent glioblastomas: results of a multicenter study including 503 patients with recurrent glioblastomas undergoing surgical resection. Neuro-oncology. 2015;18(1):96-104. 41. van Linde ME, Brahm CG, de Witt Hamer PC, Reijneveld JC, Bruynzeel AM, Vandertop WP, et al. Treatment outcome of patients with recurrent glioblastoma multiforme: a retrospective multicenter analysis. Journal of neuro-oncology. 2017;135(1):183-92. 42. Landy H, Feun L, Schwade J, Snodgrass S, Lu Y, Gutman F. Retreatment of intracranial gliomas. Southern medical journal. 1994;87(2):211-4. 43. Ammirati M, Galicich JH, Arbit E, Liao Y. Reoperation in the treatment of recurrent intracranial malignant gliomas. Neurosurgery. 1987;21(5):607-14. 44. Harsh GR, Levin VA, Gutin PH, Seager M, Silver P, Wilson CB. Reoperation for recurrent glioblastoma and anaplastic astrocytoma. Neurosurgery. 1987;21(5):615- 21. 45. Bloch O, Han SJ, Cha S, Sun MZ, Aghi MK, McDermott MW, et al. Impact of extent of resection for recurrent glioblastoma on overall survival. Journal of neurosurgery. 2012;117(6):1032-8. 46. Oppenlander ME, Wolf AB, Snyder LA, Bina R, Wilson JR, Coons SW, et al. An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity. Journal of neurosurgery. 2014;120(4):846-53.