Does limited-margin radiotherapy change the recurrence pattern and survival of patients with high-grade gliomas? Analysis and validation of a different approach

Does limited-margin radiotherapy change the recurrence pattern and survival of patients with high-grade gliomas? 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Analysis and validation of a different approach Volkan Semiz, Oğuz Çetinayak, Şeyda Kınay, Doğukan Akçay, Nuri Karabay, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3909937/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: We aimed to analyze our radiotherapy protocol by evaluating its effect on recurrence patterns and survival outcomes. Methods: We assessed 89 patients diagnosed with high-grade gliomas (HGGs) who underwent chemoradiotherapy at our institution from January 2014 to January 2021. A high-risk clinical target volume (CTV high) was created with a 1 cm margin in all directions from the GTV, while a low-risk clinical target volume (CTV low) was established with a 2 cm margin. Planned treatment volumes with a 2-3 mm margin in all directions were created, and doses of 60 Gy and 46-50 Gy were prescribed in 30 fractions. Recurrence patterns were classified as central, in-field, marginal, or distant based on the 60 and 50 Gy D95 isodose lines. Results: With a median follow-up of 29 months, 77.5% of patients experienced recurrence. Recurrence patterns were central in 65.2%, in-field in 16%, marginal in 4.3%, and distant in 14.5%. The overall survival rates at 1, 2, and 5 years were 87.6%, 60.3%, and 26.8%, respectively. The progression-free survival rates at the same intervals were 53.9%, 32.6%, and 20.7%, respectively. Conclusion: The recurrence pattern remained unchanged with our protocol. With longer survival times, distant recurrence rates increase, yet central and in-field recurrences remain dominant. Despite the decrease in the volume that received the 60 Gy dose, marginal recurrences remained at a notably low level. High-grade glioma Recurrence pattern Limited margin Radiotherapy Figures Figure 1 Introduction The context of radiotherapy (RT) for high-grade glioma (HGG) has changed considerably. Long-standing practices involving whole-brain irradiation were called into question in 1989 when Shapiro et al. showed no significant difference in survival between whole-brain RT and partial brain irradiation[ 1 ]. Subsequent advancements in imaging and RT techniques prompted the gradual abandonment of whole-brain irradiation in favor of more targeted treatment volumes. Currently, the Radiation Therapy Oncology Group (RTOG) and European Society for Therapeutic Radiology and Oncology-Advisory Committee for Radiation Oncology Practice (ESTRO-ACROP) guidelines are commonly employed in RT planning for HGG, with a notable distinction being the inclusion of peritumoral edema within the treatment area[ 2 , 3 ]. In addition to these guidelines, alternative protocols with various volume definitions have emerged. Despite the evolution of treatment paradigms, disease recurrence frequently originates from the surgical bed and within the RT field. According to initial studies assessing recurrence patterns, 70–90% of recurrences occurred within 2 cm of the surgical cavity [ 4 ]. Studies employing smaller treatment volumes continue to highlight recurrence from the treatment area as the most prevalent scenario [ 5 – 9 ]. Stupp et al.'s study marked a turning point in the treatment of HGG and increased survival rates[ 10 ]. As survival increases, the long-term consequences of treatment become more critical. Treatment techniques and imaging advancements have led to an increase in reirradiation, and the importance of the dose received from the first treatment applied to organs at risk has also increased. For these reasons, RT applications with smaller volumes have emerged in different clinics. In 2014, the Dokuz Eylul University Neuro-oncology Group (DENOG) established a treatment protocol for HGG involving the use of smaller volumes and partially lower doses compared to frequently used treatment guidelines (RTOG, ESTRO-ACROP). In this study, we aimed to validate our protocol by evaluating its effect in terms of recurrence pattern and survival. Methods We conducted a retrospective analysis of records detailing the treatment, survival, and recurrence patterns of HGG patients who treated according to the DENOG protocol from 2014 to 2021. This study included adult patients who had at least 12 weeks of follow-up after RT. Patients treated outside the clinical protocol or those who died before treatment response evaluation were excluded. Histopathological grading of the patients was performed according to the 2016 WHO Classification. Patients treated before 2016 were reclassified accordingly. Ethical approval was obtained from our university review board. All eligible patients underwent surgery. Those unsuitable for surgical intervention, including biopsy, were treated through radiological diagnosis. Patients were evaluated with multiparametric brain MRI (contrast-enhanced MRI, diffusion MRI, perfusion MRI, and MR spectroscopy) three to four weeks after surgery. All patients received concomitant and adjuvant temozolomide (TMZ) according to the Stupp protocol [ 10 ]. For patients in good general condition and with good drug tolerance or residual disease after 6 cycles, additional cycles of TMZ were given. The dose was reduced, or chemotherapy was suspended in the presence of disease recurrence or grade 3–4 toxicity. Radiotherapy Protocol Radiotherapy was started 4–6 weeks after surgery. Treatment planning was performed with the Varian© Eclipse Treatment Planning System. Patient immobilization was ensured through a thermoplastic head mask, and CT images were obtained at 2–3 mm cross-sectional intervals with contrast agent. Subsequently, treatment planning CT images were coregistered with postoperative contrast-enhanced MR scans using Velocity software. Within the registered images, the resection cavity and residual tumor were delineated as the gross tumor volume (GTV). The clinical target volume (CTV) was established in two phases. First, a high-risk CTV (CTVhigh) was created by including a 1 cm margin around the GTV. Next, a low-risk CTV (CTVlow) with a 2 cm margin from the GTV was defined. While the adjacent edema area was not included in the CTVs, T2/FLAIR changes, which are thought to be associated with low-grade tumors, were included in the low-risk CTV. Both volumes underwent further editing based on anatomical constraints such as bone, ventricle, falx cerebri, and tentorium cerebri, adhering to the ESTRO-ACROP guideline [ 3 ]. Planning target volumes (PTVlow, PTVhigh) were created by expanding the CTVs by 2–3 mm. In the case of treatments involving three-dimensional conformal radiotherapy (3D-CRT), patients received a dosage of 46 Gy in 23 fractions for PTVlow, followed by an additional 14 Gy in seven fractions for PTVhigh. On the other hand, for those treated with intensity-modulated radiotherapy or volumetric arc therapy (IMRT/VMAT) with a simultaneous integrated boost (SIB) technique, the prescribed dose was as follows: 50 Gy over 30 fractions for PTVlow and 60 Gy for PTVhigh, both simultaneously administered in 30 fractions. Evaluation of the Recurrence Pattern The patients underwent systematic assessments for recurrence through multiparametric MRI at intervals of 3 months for the initial 2 years, followed by assessments every 6 months thereafter. The Neuro-Oncology Working Group's Response Assessment in Neuro-Oncology (RANO) criteria were used to determine treatment response and tumor recurrence [ 11 ]. In cases of recurrence, the contrast-enhanced brain MR scan was coregistered with the initial planning CT images at the time with Velocity software. The progressive tumor was delineated as the GTVr on the treatment planning CT. To characterize the type of recurrence pattern, the association of the GTVr with isodose lines was. Because of the presence of two separate CTVs, we defined the recurrence pattern similarly to that used in the study by Minniti et al. [ 7 ]. Accordingly, recurrence patterns were classified as follows: central, if more than 95% of the GTVr was within the 95% isodose line of 60 Gy; in-field, if more than 95% of the GTVr was within the 95% isodose line of 50 Gy; marginal, if less than 95% of the GTVr was within the 95% isodose line of 50 Gy; and distant, if the GTVr extended beyond the 20% isodose line of 60 Gy (Fig. 1). Since the majority of treatments in the study were applied with VMAT, the 20% isodose line encompassed a substantial portion of the brain parenchyma. Consequently, instances of recurrence without invasion into the contralateral hemisphere, infratentorial structures, or brainstem were also regarded as distant recurrences. To evaluate differences between the DENOG protocol and the RTOG and ESTRO-ACROP guidelines, target volumes were recontoured on the planning CT according to these guidelines. The GTV, CTV, and PTV data were subsequently compared with the corresponding volumes from the DENOG protocol. Assessment of Adverse Events The National Cancer Institute Common Terminology Criteria for Adverse Events version 5 (NCI CTCAE v.5) was used to assess patients for cutaneous, neurological, and hematological early and late adverse events. Early adverse events were defined as those that occurred within three months of RT, while late adverse events occurred six months after RT. Notably, patients who experienced disease recurrence while receiving adjuvant systemic therapy were excluded from the evaluation of late adverse events to avoid potential confounding symptoms caused by disease recurrence or salvage therapies. Statistical analysis The statistical analysis was performed with IBM SPSS 24.0. The survival data were estimated by the Kaplan‒Meier method, and the effects of variables on survival were assessed by the log-rank test and Cox regression analysis. To analyze recurrence patterns, we used either the chi-square test or Fisher's exact test for small sample sizes. A t test was used to examine differences between target volumes. Results Within the scope of this study, we assessed 115 newly diagnosed HGG patients, and 89 patients meeting the study criteria were included in the analysis. Table 1 displays the demographic and histopathological characteristics of the patients. The median age of the cohort was 55 (22–77) years. Three patients were deemed unsuitable for surgery due to tumor localization. RT started at a median of 41 (18–98) days after surgery. Although concurrent TMZ was prescribed for all patients, 8 patients (9%) were unable to tolerate concurrent treatment due to hematological and liver toxicity. Table 1 Patient demographic and treatment characteristics n = 89 (%) Gender Female Male 35 (39,3%) 54 (60,7%) Karnofsky Performance Status < 70 80 90 6 (6,8%) 10 (11,2%) 73 (82,0%) Extend of Surgery No surgery Biopsy only Subtotal resection Gross total resection 3 (3,4%) 4 (4,5%) 21 (23,6%) 61 (68,5%) Grade of Tumor* Grade 3 Grade 4 17 (19,1%) 69 (77,5%) IDH mutation Wild Mutant 74 (83,1%) 12 (13,4%) 1p/19q codeletion Wild Mutant 78 (89,6%) 6 (6,7%) Radiotherapy technique 3DCRT IMRT-VMAT 13 (14,6%) 76 (85,4%) IDH: Isocitrate dehydrogenase, 3DCRT: Three-dimensional conformal radiation therapy, IMRT: Intensity-modulated radiotherapy, VMAT: Volumetric modulated arc therapy After RT, a median of 11 cycles (1–18) of adjuvant TMZ were administered to 84 patients (94.3%). Adjuvant treatment was withheld in five patients (5.7%) due to intolerance to concurrent TMZ. Seven patients were unable to complete six cycles of TMZ, five (5.7%) of whom progressed at the first follow-up after radiotherapy, and one (1%) of whom developed severe thrombocytopenia. Table 2 provides the mean values of the target volumes according to the RTOG and ESTRO-ACROP guidelines in comparison to those in this study. We observed a significant difference in the irradiated volumes (p < 0.001). Table 2 Mean target volumes Mean Volume (range) RT Dose DENOG GTV CTVhigh CTVlow PTVhigh PTVlow 52,76 (2,0-196,5) cm 3 138,62 (31,2-368,0) cm 3 246,14 (60,7-614,1) cm 3 184,27 (61,9-446,2) cm 3 310,02 (108,4-725,7) cm 3 60 Gy/30 fr. 50 Gy/30 fr. ESTRO/ACROP GTV CTV PTV 52,76 (2,0-196,5) cm 3 245,84 (60,7-604,4) cm 3 309,82 (108,4-715,2) cm 3 60 Gy/30 fr. RTOG GTV 1 GTV 2 CTV 1 CTV 2 PTV 1 PTV 2 88,87 (8,5-246,3) cm 3 52,76 (2,0-196,5) cm 3 318,94 (119,9-816,8) cm 3 245,84 (60,7-604,4) cm 3 409,95 (170,5-970,5) cm 3 309,82 (108,4-715,2) cm 3 46 Gy/23 fr. 60 Gy/30 fr. GTV: gross tumor volume; CTV: clinical target volume; PTV: planning target volume; DENOG: Dokuz Eylul Neurooncology Group; ESTRO-ACROP: European Society for Therapeutic Radiology and Oncology-Advisory Committee for Radiation Oncology Practice; RTOG: Radiation Therapy Oncology Group Recurrence pattern Recurrence was identified in 24 patients (27%) during adjuvant systemic therapy and in 45 patients (50.5%) posttreatment. Recurrences were categorized as central in 45 patients (65.2%), in-field in 11 patients (16%), marginal in 3 patients (4.3%), or distant in 10 patients (14.5%). Five patients exhibited both central and distant recurrence, but these were considered central recurrences. The tumor volumes for central, in-field, marginal, and distant recurrence were 50.85 cm³, 58.98 cm³, 63.7 cm³, and 24.8 cm³, respectively. The median times to recurrence were 9 (3–79) months for central and in-field recurrence, 25 (3–32) months for marginal recurrence, and 12 (3–28) months for distant recurrence. Notably, only one of the distant recurrences occurred in the same hemisphere, with the remaining lesions distributed as one in the brainstem, one in the infratentorial area, and seven in the contralateral hemisphere. There were no significant differences in overall or progression-free survival among the various recurrence patterns (p = 0.630; p = 0.664). Furthermore, there was no significant difference in the recurrence pattern based on the extent of surgery or radiotherapy technique (p = 0.628; p = 0.630). Survival The median follow-up duration was 29 (7–86) months. The overall survival rates at 1, 2, and 5 years were 87.6%, 60.3%, and 26.8%, respectively. Two patients died from nondisease causes—one from pulmonary embolism and the other from a cardiac cause—with no evidence of recurrence in their latest imaging. The median time from the end of RT to recurrence was 14 months (range 3–83). The progression-free survival rates at 1, 2, and 5 years were 53.9%, 32.6%, and 20.7%, respectively. The prognostic factors for overall and progression-free survival are detailed in Table 3 . Performance status, IDH mutation status, and tumor grade emerged as the most significant prognostic factors for overall survival. Conversely, for progression-free survival, the most influential factors were IDH mutation, 1p/19q codeletion, and tumor grade. Table 3 Prognostic factors for overall and progression-free survival Univariate analyze Multivariate analyze 2-y OS (%) P 2-y PFS (%) p HR for OS p HR for PFS p Gender Male Female 68,3 55,0 0.651 35,5 30,6 0,740 N/A N/A N/A N/A Age > 55 ≤ 55 51,6 68,7 0,031 27,0 37,5 0,637 1.332 (0,785-2,303) 0,297 N/A N/A KPS > 70 ≤ 70 63,5 16,7 0,002 34,2 16,1 0,024 0.306 (0,115-0,818) 0,018 0,466 (0,220-1,527) 0,118 Extent of surgeryª Partial Total 38,1 66,6 0,040 27 33,5 0, 268 0,840 (0,505-1,278) 0,427 0,654 (0,402-1,057) 0,124 Grade of Tumor b III IV 88,2 51,5 < 0,001 69,7 21,5 < 0,001 8,708 (2,874 − 27,625) 0,041 4,723 (1,952 − 11,426) < 0,001 İDH mutation Mutant Wild 53,4 82,5 < 0,001 25,3 66,7 0,004 0,167 (0,040 − 0,699) 0,014 0,304 (0,109-0,703) 0,014 1p/19q codeletion Codeleted Wild 54,6 100 0,006 25,4 100 0,003 N/A N/A N/A N/A RT technique 3DCRT IMRT-VMAT 53,8 61,4 0,063 30,8 32,8 0,304 0,827 (0,535-1,276) 0,372 N/A N/A a = Patients who underwent biopsy were accepted as STR b = According to the 2016 WHO Classification KPS: Karnofsky Performance Scale, IDH: Isocitrate dehydrogenase, 3DCRT: Three-dimensional conformal radiation therapy, IMRT: Intensity-modulated radiotherapy, VMAT: Volumetric modulated Arc therapy Adverse Events The most common adverse events were hematological. Throughout the treatment and the initial 3-month posttreatment period, 74.8% of patients experienced hematological adverse events. TMZ had to be discontinued in five patients during RT and in one patient during adjuvant therapy due to severe grade III and IV hematological complications. Additionally, the dosage was adjusted, or treatment was temporarily halted in six patients. Late adverse events were examined in 65 patients, revealing a sole incidence of grade 4 thrombocytopenia occurring 25 months after RT. No other late adverse events of Grade 3 or 4 severity were documented in the patient cohort. Discussion Despite advancements in imaging and radiotherapy technologies, a general consensus on target volumes in the treatment of HGG has not yet been reached. In this study, our aim was to validate our treatment approach, which involves the use of smaller target volumes, by evaluating its impact on recurrence patterns and survival. The primary objective is to reduce the brain's exposure to high doses without compromising recurrence or survival. This reduction in high-dose volume seeks to minimize long-term side effects in patients with extended survival. An additional 1 cm margin in the CTV can increase the irradiated volume by 1.5-2 times, and considering the direct link between the irradiated brain volume and adverse outcomes such as neurotoxicity, radionecrosis, and cognitive functions, quality of life may be affected in these patients. Minniti et al. reported that the CTV of patients receiving 60 Gy in treatments following their protocol was 177.8 cm3, whereas it was 214.3 cm3 in treatments following the RTOG guidelines, and they observed fewer side effects when less brain tissue was irradiated with high-dose radiation [ 7 ]. Similarly, Kumar et al. reported a notable reduction in volume and an improvement in long-term quality of life in patients treated according to their own protocols compared to those treated according to the RTOG guidelines [ 12 ]. In this study, the CTV receiving 60 Gy was 44% smaller than that recommended by the ESTRO-ACROP and RTOG guidelines, while the CTV receiving 46–50 Gy was 23% smaller than RTOG guideline (Table 2 ). A significant reduction in treatment volume led to a substantial decrease in early adverse effects, and in the long term, no patients experienced grade 3–4 neurological adverse effects. However, the impact on cognitive functions could not be evaluated in this study. High-grade gliomas often relapse within 2 years after treatment, and local recurrence has a significant impact on survival. Recurrence mostly occurs in the tumor bed and within 2–3 cm of the tumor [ 4 , 13 – 15 ]. An overview of studies evaluating recurrence patterns across treatments with varying volumes and doses is shown in Table 4 . The findings of this study appear to be similar to those of studies conducted in the post-TMZ period. The rate of central and in-field recurrences in this study was 81.2%, which is consistent with the findings of previous studies ([ 4 , 6 , 7 , 16 – 20 ]). Similarly, central and in-field recurrences often develop early during the follow-up period, but some long-surviving patients also experience central and in-field recurrences years later. Recurrences that occur after a relatively long time may be caused by the molecular or genomic characteristics of the tumor, but a definitive comment cannot be made on this issue in this study [ 21 , 22 ]. The majority of recurrences in this study which involved the delineation of CTVs in dual volumes, manifested in the central area approximately 12–13 mm from the GTV. However, 14% of recurrences were found within the low-risk CTV (10 to 20 mm from the GTV). Despite the fact that there are treatments in the literature that use a 5 mm CTV, omitting radiotherapy in this specific region was thought to potentially escalatory for the risk of recurrence. Therefore, in our treatment approach, a dose equivalent to 46 Gy was administered to this area. The primary concern with smaller treatment volumes is the increased risk of disease recurrence arising from the treatment area's borders. The marginal recurrence rate reported in treatments applied according to the ACROP and RTOG guidelines is approximately 6–15% [ 17 , 19 , 20 ]. However, McDonald et al. reported a marginal recurrence rate of 5% in patients treated with a CTV limited to 5–10 mm [ 6 ]. Similarly, Paulsson et al. reported no difference in marginal recurrence patterns between treatments with 5, 10, or 15–20 mm CTV margins [ 23 ]. In our study, three patients had lesions that met our definition of marginal recurrence. Only one of these has 37.5% of the lesion above the 50 Gy isodose line. In two of these patients, the majority of the lesions (approximately 84%) were located within the center of the treatment area and grew outward, but according to our definition of recurrence pattern, these two lesions were classified as marginal recurrences. Even considering all three lesions as marginal recurrences, the rate reached 4.3%, lower than that reported in many studies. In the literature, distant recurrence rates have been reported to vary between 2% and 21.5% depending on the follow-up duration, with distant recurrence rates increasing as survival extends [ 6 , 7 , 14 , 16 – 19 ]. As a result of the long follow-up period and survival rates in this study, the distant recurrence rate was 14.5%. Compared to other recurrence types, it occurs later, with a median of 12 (3–28) months, and is observed in smaller volumes, with an average tumor volume of 24.8 (1-108) cm3. During the assessment of recurrence patterns, we observed that a substantial portion of the brain in patients treated with the VMAT technique received a dose of 1200 cGy (20% isodose line). This posed challenges in evaluating relapses within the opposite hemisphere that spread without invading anatomical barriers. Consequently, the definition of distant recurrence in our study did not rely solely on isodose curves; instead, lesions in these areas were also considered as distant recurrences. This novel definition may prove beneficial in analyzing recurrence patterns among patients undergoing treatment with arc techniques. Table 4 Summary of studies on recurrence patterns of HGG Study (year) Patients İnitial Treatment Boost treatment Recurrence pattern Hochberg et al (1980)[ 15 ] 42 GBM Whole-Brain RT None 90% within 2 cm from tumor 10% outside 2 cm from tumor Wallner et al (1989)[ 24 ] 32 HGG Whole-Brain RT: Dose:40–60 Gy 10 Gy boost to tumor bed in 25 patients %78 within 2 cm from tumor %22 outside 2 cm from tumor Hess et al (1994)[ 25 ] 66 HGG GTV + 2 cm, Dose:60Gy in 30 fr None %86 İFR, %14 DR Aydın et al (2001)[ 4 ] 46 HGG GTV + 2 cm Dose:60Gy in 30 fr None %73 within 2 cm from tumor %94 within 3 cm from tumor Chan et al (2002)[ 26 ] 34 HGG GTV + 2,5 cm Dose:44Gy in 22 fr GTV + 1,5 cm Dose:60Gy in 30 fr GTV + 0,5 cm Dose:90Gy in 45fr %78 CR, %91 IFR + CR, %9 MR, %0 DR Brandes et al (2009)[ 20 ] 95 GBM GTV + 2 cm Dose:60 Gy in 30 fr None %72,2 IFR, %6,3 MR, %21,5 DR Milano et al (2010)[ 17 ] 54 GBM GTV + edema in MRI + 2 cm2cm Dose:46 Gy in 23 fr GTV + 2–2,5 cm, Dose:60 Gy in 30 fr IFR %92, MR%15, DR %13 (first recurrence) Minniti et al (2010)[ 7 ] 105 GBM GTV + 2 cm Dose:60Gy in 30 fr (if CTV > 250 cm 3 50 Gy in 25 fr) GTV + 1 cm (İf CTV > 250 cm 3 ) Dose:60 Gy in 30 fr %75 CR, %81 IFR, %6 MR, %13 DR Mcdonald et al (2011)[ 6 ] 62 GBM GTV + edema + 5–12 mm Dose:46–54 Gy in 23–30 fr GTV + 5–10 mm, Dose:60 Gy in 30 fr %93 IFR, %5 MR %2 DR Kumar et al (2012)[ 12 ] 25 GBM GTV + 2 cm Dose:50 Gy in 25 fr GTV Dose:60Gy in 30 fr %87,2 IFR, %6,2 MR %6,2 DR Ogura et al (2013)[ 14 ] 21 GBM GTV + 2 cm Dose:50–54 Gy in 25–30 fr GTV Dose:60 Gy in 30 fr %85,7 IFR + CR, %9,5 out-field recurrence, %19 DR Gebhardt et al (2014)[ 5 ] 95 GBM GTV + edema + 5 mm Dose:46 Gy in 23 fr GTV + 5 mm Dose:60 Gy in 30 fr %87 IFR, %6 MR, %28 DR Buglione et al (2016)[ 19 ] 68 GBM GTV + 2 cm Dose:60 Gy in 30 fr None %88 IFR, %10 MR, %2 DR Zheng et al (2021)[ 27 ] 55 GBM GTV + 2 cm Dose:54 Gy in 30fr GTV + 1 cm Dose:60 Gy/30 fr (with SİB technique) %80 CR, %83,6 IFR + CR, %1,8 MR, %20 DR This study 89 HGG GTV + 2 cm Dose:46–50 Gy in 23-30fr GTV + 1 cm Dose:60 Gy in 30 fr (85% with SİB technique) %65,2 CR, %81,1 IFR + CR, %4,3 MR, %14,5 DR fr: fraction HGG: high-grade glioma, GBM: glioblastoma multiforme, GTV: gross tumor volume, CTV: clinical target volume, SIB: simultaneous integrated boost, CR: central recurrence, IFR: in-field recurrence, MR: marginal recurrence, DR: distant recurrence In their study evaluating recurrence patterns based on the RT technique, Paulsson et al. and Buglione et al. reported no difference in recurrence patterns between patients treated with IMRT or 3BKRT [ 19 , 23 ]. Similarly, we found no significant relationship between the RT technique and the recurrence pattern. When evaluated according to tumor grade, 66.7% of Grade 3 gliomas experienced central recurrence, and 33.3% of them experienced distant recurrence. Although distant recurrence is more common in Grade 3 gliomas, definitive conclusions are limited by the small number of Grade 3 patients and the fact that just over one-third (35.3%) experienced recurrence during the follow-up period. There are publications with different results regarding the relationship between surgical extent and recurrence pattern. Yoo et al. reported a lower incidence of in-field recurrence after total and supratotal resection [ 28 ]. In this study, the survival rate increased with total resection according to univariate analysis, but no relationship was found between the extent of surgery and the recurrence pattern. The overall and progression-free survival rates in our study were slightly greater than those in the literature. The primary reason for this difference is thought to be the exclusion of patients who died before evaluating the response after RT. Furthermore, the success rate of salvage treatments contributes significantly to increased overall survival rates. This study has several limitations. First, being a retrospective study introduces potential bias in patient selection. However, the similarity of patient characteristics with those of other studies reduces this potential bias. Second, after the recruitment of patients was completed, the World Health Organization (WHO) published a new grading system for high-grade glial tumors. Since patient recruitment and analyses were completed, patients were evaluated according to the 2016 WHO classification. Third, due to the lack of O6-methylguanine-DNA methyltransferase (MGMT) status data available from our clinic, the impact of MGMT status on the recurrence pattern was not assessed. In conclusion, the recurrence pattern remained unchanged with the DENOG protocol, which is distinguished by a lower brain volume irradiation than standard guidelines. With longer survival times, distant recurrence rates increase, yet central and in-field recurrences remain dominant. Despite the decrease in the volume that received the 60 Gy dose, marginal recurrences remained at a notably low level. The absence of significant long-term side effects in our study is thought to be related to the decrease in this volume. This retrospective study supports the hypothesis that smaller volumes have a negligible impact on relapse patterns. However, prospective studies are still needed to assess how a reduction in brain volume following exposure to high doses impacts quality of life. Declarations Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests: The authors declare no competing interests. Author Contributions: All the authors contributed to the material preparation, data collection, and analysis. The first draft of the manuscript was written by Volkan Semiz., and all the authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript. Data Availability: The datasets are available from the corresponding author on reasonable request. Ethics approval: This study was approved by the Institutional Review Board of Dokuz Eylul University Faculty of Medicine. Consent to participate: Informed consent was obtained from all individual participants included in the study. 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Neuro Oncol 14:vi134–vi135 Zhou X, Liao X, Zhang B, et al (2016) Recurrence patterns in patients with high-grade glioma following temozolomide-based chemoradiotherapy. Mol Clin Oncol 5:289–294. https://doi.org/10.3892/mco.2016.936 Ogura K, Mizowaki T, Arakawa Y, et al (2013) Initial and cumulative recurrence patterns of glioblastoma after temozolomide-based chemoradiotherapy and salvage treatment: a retrospective cohort study in a single institution. Radiat Oncol 8:. https://doi.org/10.1186/1748-717X-8-97 Hochberg FH, Pruitt A (1980) Assumptions in the radiotherapy of glioblastoma. Neurology 30:907–911. https://doi.org/10.1212/WNL.30.9.907 Guram K, Smith M, Ginader T, et al (2019) Using Smaller-Than-Standard Radiation Treatment Margins Does Not Change Survival Outcomes in Patients with High-Grade Gliomas. Pract Radiat Oncol 9:16–23. https://doi.org/10.1016/j.prro.2018.06.001 Milano MT, Okunieff P, Donatello RS, et al (2010) Patterns and timing of recurrence after temozolomide-based chemoradiation for glioblastoma. Int J Radiat Oncol Biol Phys 78:1147–1155. https://doi.org/10.1016/J.IJROBP.2009.09.018 Zheng L, Zhou Z-R, Yu Q, et al (2021) The Definition and Delineation of the Target Area of Radiotherapy Based on the Recurrence Pattern of Glioblastoma After Temozolomide Chemoradiotherapy. Article 615368 1 Front Oncol 10:615368. https://doi.org/10.3389/fonc.2020.615368 Buglione M, Pedretti S, Poliani PL, et al Pattern of relapse of glioblastoma multiforme treated with radical radio-chemotherapy: Could a margin reduction be proposed? J Neurooncol 128:. https://doi.org/10.1007/s11060-016-2112-2 Brandes AA, Tosoni A, Franceschi E, et al (2009) Recurrence Pattern After Temozolomide Concomitant With and Adjuvant to Radiotherapy in Newly Diagnosed Patients With Glioblastoma: Correlation With MGMT Promoter Methylation Status. Journal of Clinical Oncology 27:1275–1279. https://doi.org/10.1200/JCO.2008.19.4969 Yoon HG, Cheong JH, Ryu J Il, et al (2023) The genes significantly associated with an improved prognosis and long-term survival of glioblastoma. PLoS One 18:. https://doi.org/10.1371/JOURNAL.PONE.0295061 Jovčevska I (2019) Genetic secrets of long-term glioblastoma survivors. Bosn J Basic Med Sci 19:116–124. https://doi.org/10.17305/BJBMS.2018.3717 Paulsson AK, McMullen KP, Peiffer AM, et al (2014) Limited margins using modern radiotherapy techniques does not increase marginal failure rate of glioblastoma. American Journal of Clinical Oncology: Cancer Clinical Trials 37:177–181. https://doi.org/10.1097/COC.0B013E318271AE03 Wallner KE, Galicich JH, Krol G, et al (1989) Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 16:1405–1409. https://doi.org/10.1016/0360-3016(89)90941-3 Hess CF, Schaaf JC, Kortmann RD, et al (1994) Malignant glioma: patterns of failure following individually tailored limited volume irradiation. Radiother Oncol 30:146–149. https://doi.org/10.1016/0167-8140(94)90044-2 Chan JL, Lee SW, Fraass BA, et al (2002) Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy. J Clin Oncol 20:1635–1642. https://doi.org/10.1200/JCO.2002.20.6.1635 Zheng L, Zhou Z-R, Yu Q, et al (2021) The Definition and Delineation of the Target Area of Radiotherapy Based on the Recurrence Pattern of Glioblastoma After Temozolomide Chemoradiotherapy. Article 615368 1 Front Oncol 10:615368. https://doi.org/10.3389/fonc.2020.615368 Yoo J, Yoon S-J, Kim KH, et al (2021) Patterns of recurrence according to the extent of resection in patients with IDH-wild-type glioblastoma: a retrospective study. J Neurosurg 1–11. https://doi.org/10.3171/2021.10. JNS211491 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3909937","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":270122704,"identity":"6b0be3c8-81b3-4f1d-8dad-975a00c50b54","order_by":0,"name":"Volkan Semiz","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYJCCA0AsI8HAwPgAyODhI1YLD1ALswGIwUasTSAtbBIgFkEt8u3diQd/ttnwSLafPVb5NcdOho2B+eGjG3i0GJw5u+GAZFsajzRPXtpt2W3JQIexGRvn4NMikbvhgMGZwzxyDDlmtyW3MQO18LBJ49MiP//thgMJIC38b8yKJbfVE9bCcIN3w4EDFYd5pCVyzBg/bjtMWIvBmdwNBxsq0ngkZ7wxlmbcdpyHjZmAX+Tbz27++MPARk7ifI7hx5/bqu352ZsfPsbrMGTAzAMmiVUOAow/SFE9CkbBKBgFIwYAAF6tRMsOe4fmAAAAAElFTkSuQmCC","orcid":"","institution":"Dokuz Eylül University","correspondingAuthor":true,"prefix":"","firstName":"Volkan","middleName":"","lastName":"Semiz","suffix":""},{"id":270122706,"identity":"88570660-25ed-4b08-ad8d-61feac338219","order_by":1,"name":"Oğuz Çetinayak","email":"","orcid":"","institution":"Dokuz Eylül University","correspondingAuthor":false,"prefix":"","firstName":"Oğuz","middleName":"","lastName":"Çetinayak","suffix":""},{"id":270122708,"identity":"3ed9ae1f-a9da-405d-8422-641c8c17f602","order_by":2,"name":"Şeyda Kınay","email":"","orcid":"","institution":"Dokuz Eylül University","correspondingAuthor":false,"prefix":"","firstName":"Şeyda","middleName":"","lastName":"Kınay","suffix":""},{"id":270122709,"identity":"a13936ac-d586-46f0-893e-225a367ff4a5","order_by":3,"name":"Doğukan Akçay","email":"","orcid":"","institution":"Dokuz Eylül University","correspondingAuthor":false,"prefix":"","firstName":"Doğukan","middleName":"","lastName":"Akçay","suffix":""},{"id":270122710,"identity":"5f428a3f-9e60-42be-89a0-2d116c36bb2f","order_by":4,"name":"Nuri Karabay","email":"","orcid":"","institution":"Dokuz Eylül University","correspondingAuthor":false,"prefix":"","firstName":"Nuri","middleName":"","lastName":"Karabay","suffix":""},{"id":270122711,"identity":"8d9eab5d-61d5-483d-a377-b08bea69ad9f","order_by":5,"name":"Fadime Akman Can","email":"","orcid":"","institution":"Dokuz Eylül University","correspondingAuthor":false,"prefix":"","firstName":"Fadime","middleName":"Akman","lastName":"Can","suffix":""}],"badges":[],"createdAt":"2024-01-30 08:08:51","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3909937/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3909937/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50513644,"identity":"4d7f7661-86c6-47bf-9fde-f547daa390c2","added_by":"auto","created_at":"2024-02-01 16:28:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1244983,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3909937/v1/b3063b39ed0006a24c5833dd.png"},{"id":50998182,"identity":"de7055ef-a0d7-4378-a7a1-32a84bf7fe65","added_by":"auto","created_at":"2024-02-12 12:36:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1215723,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3909937/v1/54754695-d82d-4393-8101-a488cf724c05.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Does limited-margin radiotherapy change the recurrence pattern and survival of patients with high-grade gliomas? Analysis and validation of a different approach","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe context of radiotherapy (RT) for high-grade glioma (HGG) has changed considerably. Long-standing practices involving whole-brain irradiation were called into question in 1989 when Shapiro et al. showed no significant difference in survival between whole-brain RT and partial brain irradiation[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Subsequent advancements in imaging and RT techniques prompted the gradual abandonment of whole-brain irradiation in favor of more targeted treatment volumes. Currently, the Radiation Therapy Oncology Group (RTOG) and European Society for Therapeutic Radiology and Oncology-Advisory Committee for Radiation Oncology Practice (ESTRO-ACROP) guidelines are commonly employed in RT planning for HGG, with a notable distinction being the inclusion of peritumoral edema within the treatment area[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In addition to these guidelines, alternative protocols with various volume definitions have emerged.\u003c/p\u003e \u003cp\u003eDespite the evolution of treatment paradigms, disease recurrence frequently originates from the surgical bed and within the RT field. According to initial studies assessing recurrence patterns, 70\u0026ndash;90% of recurrences occurred within 2 cm of the surgical cavity [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Studies employing smaller treatment volumes continue to highlight recurrence from the treatment area as the most prevalent scenario [\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStupp et al.'s study marked a turning point in the treatment of HGG and increased survival rates[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. As survival increases, the long-term consequences of treatment become more critical. Treatment techniques and imaging advancements have led to an increase in reirradiation, and the importance of the dose received from the first treatment applied to organs at risk has also increased. For these reasons, RT applications with smaller volumes have emerged in different clinics.\u003c/p\u003e \u003cp\u003e In 2014, the Dokuz Eylul University Neuro-oncology Group (DENOG) established a treatment protocol for HGG involving the use of smaller volumes and partially lower doses compared to frequently used treatment guidelines (RTOG, ESTRO-ACROP). In this study, we aimed to validate our protocol by evaluating its effect in terms of recurrence pattern and survival.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe conducted a retrospective analysis of records detailing the treatment, survival, and recurrence patterns of HGG patients who treated according to the DENOG protocol from 2014 to 2021. This study included adult patients who had at least 12 weeks of follow-up after RT. Patients treated outside the clinical protocol or those who died before treatment response evaluation were excluded. Histopathological grading of the patients was performed according to the 2016 WHO Classification. Patients treated before 2016 were reclassified accordingly. Ethical approval was obtained from our university review board.\u003c/p\u003e\n\u003cp\u003eAll eligible patients underwent surgery. Those unsuitable for surgical intervention, including biopsy, were treated through radiological diagnosis. Patients were evaluated with multiparametric brain MRI (contrast-enhanced MRI, diffusion MRI, perfusion MRI, and MR spectroscopy) three to four weeks after surgery. All patients received concomitant and adjuvant temozolomide (TMZ) according to the Stupp protocol [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. For patients in good general condition and with good drug tolerance or residual disease after 6 cycles, additional cycles of TMZ were given. The dose was reduced, or chemotherapy was suspended in the presence of disease recurrence or grade 3\u0026ndash;4 toxicity.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eRadiotherapy Protocol\u003c/h2\u003e\n \u003cp\u003eRadiotherapy was started 4\u0026ndash;6 weeks after surgery. Treatment planning was performed with the Varian\u0026copy; Eclipse Treatment Planning System. Patient immobilization was ensured through a thermoplastic head mask, and CT images were obtained at 2\u0026ndash;3 mm cross-sectional intervals with contrast agent. Subsequently, treatment planning CT images were coregistered with postoperative contrast-enhanced MR scans using Velocity software. Within the registered images, the resection cavity and residual tumor were delineated as the gross tumor volume (GTV).\u003c/p\u003e\n \u003cp\u003eThe clinical target volume (CTV) was established in two phases. First, a high-risk CTV (CTVhigh) was created by including a 1 cm margin around the GTV. Next, a low-risk CTV (CTVlow) with a 2 cm margin from the GTV was defined. While the adjacent edema area was not included in the CTVs, T2/FLAIR changes, which are thought to be associated with low-grade tumors, were included in the low-risk CTV. Both volumes underwent further editing based on anatomical constraints such as bone, ventricle, falx cerebri, and tentorium cerebri, adhering to the ESTRO-ACROP guideline [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]. Planning target volumes (PTVlow, PTVhigh) were created by expanding the CTVs by 2\u0026ndash;3 mm.\u003c/p\u003e\n \u003cp\u003eIn the case of treatments involving three-dimensional conformal radiotherapy (3D-CRT), patients received a dosage of 46 Gy in 23 fractions for PTVlow, followed by an additional 14 Gy in seven fractions for PTVhigh. On the other hand, for those treated with intensity-modulated radiotherapy or volumetric arc therapy (IMRT/VMAT) with a simultaneous integrated boost (SIB) technique, the prescribed dose was as follows: 50 Gy over 30 fractions for PTVlow and 60 Gy for PTVhigh, both simultaneously administered in 30 fractions.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eEvaluation of the Recurrence Pattern\u003c/h2\u003e\n \u003cp\u003eThe patients underwent systematic assessments for recurrence through multiparametric MRI at intervals of 3 months for the initial 2 years, followed by assessments every 6 months thereafter. The Neuro-Oncology Working Group\u0026apos;s Response Assessment in Neuro-Oncology (RANO) criteria were used to determine treatment response and tumor recurrence [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]. In cases of recurrence, the contrast-enhanced brain MR scan was coregistered with the initial planning CT images at the time with Velocity software. The progressive tumor was delineated as the GTVr on the treatment planning CT.\u003c/p\u003e\n \u003cp\u003eTo characterize the type of recurrence pattern, the association of the GTVr with isodose lines was. Because of the presence of two separate CTVs, we defined the recurrence pattern similarly to that used in the study by Minniti et al. [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. Accordingly, recurrence patterns were classified as follows: central, if more than 95% of the GTVr was within the 95% isodose line of 60 Gy; in-field, if more than 95% of the GTVr was within the 95% isodose line of 50 Gy; marginal, if less than 95% of the GTVr was within the 95% isodose line of 50 Gy; and distant, if the GTVr extended beyond the 20% isodose line of 60 Gy (Fig.\u0026nbsp;1). Since the majority of treatments in the study were applied with VMAT, the 20% isodose line encompassed a substantial portion of the brain parenchyma. Consequently, instances of recurrence without invasion into the contralateral hemisphere, infratentorial structures, or brainstem were also regarded as distant recurrences.\u003c/p\u003e\n \u003cp\u003eTo evaluate differences between the DENOG protocol and the RTOG and ESTRO-ACROP guidelines, target volumes were recontoured on the planning CT according to these guidelines. The GTV, CTV, and PTV data were subsequently compared with the corresponding volumes from the DENOG protocol.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eAssessment of Adverse Events\u003c/h2\u003e\n \u003cp\u003eThe National Cancer Institute Common Terminology Criteria for Adverse Events version 5 (NCI CTCAE v.5) was used to assess patients for cutaneous, neurological, and hematological early and late adverse events. Early adverse events were defined as those that occurred within three months of RT, while late adverse events occurred six months after RT. Notably, patients who experienced disease recurrence while receiving adjuvant systemic therapy were excluded from the evaluation of late adverse events to avoid potential confounding symptoms caused by disease recurrence or salvage therapies.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eThe statistical analysis was performed with IBM SPSS 24.0. The survival data were estimated by the Kaplan‒Meier method, and the effects of variables on survival were assessed by the log-rank test and Cox regression analysis. To analyze recurrence patterns, we used either the chi-square test or Fisher\u0026apos;s exact test for small sample sizes. A t test was used to examine differences between target volumes.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eWithin the scope of this study, we assessed 115 newly diagnosed HGG patients, and 89 patients meeting the study criteria were included in the analysis. Table \u003cspan\u003e1\u003c/span\u003e displays the demographic and histopathological characteristics of the patients. The median age of the cohort was 55 (22\u0026ndash;77) years. Three patients were deemed unsuitable for surgery due to tumor localization. RT started at a median of 41 (18\u0026ndash;98) days after surgery. Although concurrent TMZ was prescribed for all patients, 8 patients (9%) were unable to tolerate concurrent treatment due to hematological and liver toxicity.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003ePatient demographic and treatment characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;89 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (39,3%)\u003c/p\u003e\n \u003cp\u003e54 (60,7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKarnofsky Performance Status\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;70\u003c/p\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (6,8%)\u003c/p\u003e\n \u003cp\u003e10 (11,2%)\u003c/p\u003e\n \u003cp\u003e73 (82,0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExtend of Surgery\u003c/p\u003e\n \u003cp\u003eNo surgery\u003c/p\u003e\n \u003cp\u003eBiopsy only\u003c/p\u003e\n \u003cp\u003eSubtotal resection\u003c/p\u003e\n \u003cp\u003eGross total resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3,4%)\u003c/p\u003e\n \u003cp\u003e4 (4,5%)\u003c/p\u003e\n \u003cp\u003e21 (23,6%)\u003c/p\u003e\n \u003cp\u003e61 (68,5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade of Tumor*\u003c/p\u003e\n \u003cp\u003eGrade 3\u003c/p\u003e\n \u003cp\u003eGrade 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (19,1%)\u003c/p\u003e\n \u003cp\u003e69 (77,5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIDH mutation\u003c/p\u003e\n \u003cp\u003eWild\u003c/p\u003e\n \u003cp\u003eMutant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e74 (83,1%)\u003c/p\u003e\n \u003cp\u003e12 (13,4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1p/19q codeletion\u003c/p\u003e\n \u003cp\u003eWild\u003c/p\u003e\n \u003cp\u003eMutant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78 (89,6%)\u003c/p\u003e\n \u003cp\u003e6 (6,7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRadiotherapy technique\u003c/p\u003e\n \u003cp\u003e3DCRT\u003c/p\u003e\n \u003cp\u003eIMRT-VMAT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (14,6%)\u003c/p\u003e\n \u003cp\u003e76 (85,4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003eIDH: Isocitrate dehydrogenase, 3DCRT: Three-dimensional conformal radiation therapy, IMRT: Intensity-modulated radiotherapy, VMAT: Volumetric modulated arc therapy\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\u003cbr\u003e\u003c/div\u003e\n\u003cp\u003eAfter RT, a median of 11 cycles (1\u0026ndash;18) of adjuvant TMZ were administered to 84 patients (94.3%). Adjuvant treatment was withheld in five patients (5.7%) due to intolerance to concurrent TMZ. Seven patients were unable to complete six cycles of TMZ, five (5.7%) of whom progressed at the first follow-up after radiotherapy, and one (1%) of whom developed severe thrombocytopenia.\u003c/p\u003e\n\u003cp\u003eTable \u003cspan\u003e2\u003c/span\u003e provides the mean values of the target volumes according to the RTOG and ESTRO-ACROP guidelines in comparison to those in this study. We observed a significant difference in the irradiated volumes (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 2\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eMean target volumes\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eMean Volume (range)\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eRT Dose\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eDENOG\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGTV\u003c/p\u003e\n \u003cp\u003eCTVhigh\u003c/p\u003e\n \u003cp\u003eCTVlow\u003c/p\u003e\n \u003cp\u003ePTVhigh\u003c/p\u003e\n \u003cp\u003ePTVlow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52,76 (2,0-196,5) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e138,62 (31,2-368,0) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e246,14 (60,7-614,1) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e184,27 (61,9-446,2) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e310,02 (108,4-725,7) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 Gy/30 fr.\u003c/p\u003e\n \u003cp\u003e50 Gy/30 fr.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eESTRO/ACROP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGTV\u003c/p\u003e\n \u003cp\u003eCTV\u003c/p\u003e\n \u003cp\u003ePTV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52,76 (2,0-196,5) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e245,84 (60,7-604,4) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e309,82 (108,4-715,2) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 Gy/30 fr.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eRTOG\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGTV\u003csub\u003e1\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003eGTV\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003eCTV\u003csub\u003e1\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003eCTV\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003ePTV\u003csub\u003e1\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003ePTV\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88,87 (8,5-246,3) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e52,76 (2,0-196,5) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e318,94 (119,9-816,8) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e245,84 (60,7-604,4) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e409,95 (170,5-970,5) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e309,82 (108,4-715,2) cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46 Gy/23 fr.\u003c/p\u003e\n \u003cp\u003e60 Gy/30 fr.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eGTV: gross tumor volume; CTV: clinical target volume; PTV: planning target volume; DENOG: Dokuz Eylul Neurooncology Group; ESTRO-ACROP: European Society for Therapeutic Radiology and Oncology-Advisory Committee for Radiation Oncology Practice; RTOG: Radiation Therapy Oncology Group\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003eRecurrence pattern\u003c/h2\u003e\n \u003cp\u003eRecurrence was identified in 24 patients (27%) during adjuvant systemic therapy and in 45 patients (50.5%) posttreatment. Recurrences were categorized as central in 45 patients (65.2%), in-field in 11 patients (16%), marginal in 3 patients (4.3%), or distant in 10 patients (14.5%). Five patients exhibited both central and distant recurrence, but these were considered central recurrences. The tumor volumes for central, in-field, marginal, and distant recurrence were 50.85 cm\u0026sup3;, 58.98 cm\u0026sup3;, 63.7 cm\u0026sup3;, and 24.8 cm\u0026sup3;, respectively. The median times to recurrence were 9 (3\u0026ndash;79) months for central and in-field recurrence, 25 (3\u0026ndash;32) months for marginal recurrence, and 12 (3\u0026ndash;28) months for distant recurrence. Notably, only one of the distant recurrences occurred in the same hemisphere, with the remaining lesions distributed as one in the brainstem, one in the infratentorial area, and seven in the contralateral hemisphere.\u003c/p\u003e\n \u003cp\u003eThere were no significant differences in overall or progression-free survival among the various recurrence patterns (p\u0026thinsp;=\u0026thinsp;0.630; p\u0026thinsp;=\u0026thinsp;0.664). Furthermore, there was no significant difference in the recurrence pattern based on the extent of surgery or radiotherapy technique (p\u0026thinsp;=\u0026thinsp;0.628; p\u0026thinsp;=\u0026thinsp;0.630).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\"\u003e\n \u003ch2\u003eSurvival\u003c/h2\u003e\n \u003cp\u003eThe median follow-up duration was 29 (7\u0026ndash;86) months. The overall survival rates at 1, 2, and 5 years were 87.6%, 60.3%, and 26.8%, respectively. Two patients died from nondisease causes\u0026mdash;one from pulmonary embolism and the other from a cardiac cause\u0026mdash;with no evidence of recurrence in their latest imaging. The median time from the end of RT to recurrence was 14 months (range 3\u0026ndash;83). The progression-free survival rates at 1, 2, and 5 years were 53.9%, 32.6%, and 20.7%, respectively.\u003c/p\u003e\n \u003cp\u003eThe prognostic factors for overall and progression-free survival are detailed in Table \u003cspan\u003e3\u003c/span\u003e. Performance status, IDH mutation status, and tumor grade emerged as the most significant prognostic factors for overall survival. Conversely, for progression-free survival, the most influential factors were IDH mutation, 1p/19q codeletion, and tumor grade.\u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 3\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003ePrognostic factors for overall and progression-free survival\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eUnivariate analyze\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eMultivariate analyze\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e2-y\u003c/strong\u003e \u003cstrong\u003eOS (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e2-y\u003c/strong\u003e \u003cstrong\u003ePFS (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR for OS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR for PFS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68,3\u003c/p\u003e\n \u003cp\u003e55,0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.651\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35,5\u003c/p\u003e\n \u003cp\u003e30,6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,740\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;55\u003c/p\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51,6\u003c/p\u003e\n \u003cp\u003e68,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,031\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27,0\u003c/p\u003e\n \u003cp\u003e37,5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,637\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.332\u003c/p\u003e\n \u003cp\u003e(0,785-2,303)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,297\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKPS\u003c/p\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;70\u003c/p\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63,5\u003c/p\u003e\n \u003cp\u003e16,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34,2\u003c/p\u003e\n \u003cp\u003e16,1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,024\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.306\u003c/p\u003e\n \u003cp\u003e(0,115-0,818)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,018\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,466\u003c/p\u003e\n \u003cp\u003e(0,220-1,527)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,118\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExtent of surgery\u0026ordf;\u003c/p\u003e\n \u003cp\u003ePartial\u003c/p\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38,1\u003c/p\u003e\n \u003cp\u003e66,6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,040\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003cp\u003e33,5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0, 268\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,840\u003c/p\u003e\n \u003cp\u003e(0,505-1,278)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,427\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,654\u003c/p\u003e\n \u003cp\u003e(0,402-1,057)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,124\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade of Tumor\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88,2\u003c/p\u003e\n \u003cp\u003e51,5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0,001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69,7\u003c/p\u003e\n \u003cp\u003e21,5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0,001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8,708\u003c/p\u003e\n \u003cp\u003e(2,874\u0026thinsp;\u0026minus;\u0026thinsp;27,625)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,041\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4,723\u003c/p\u003e\n \u003cp\u003e(1,952\u0026thinsp;\u0026minus;\u0026thinsp;11,426)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0,001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eİDH mutation\u003c/p\u003e\n \u003cp\u003eMutant\u003c/p\u003e\n \u003cp\u003eWild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53,4\u003c/p\u003e\n \u003cp\u003e82,5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0,001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25,3\u003c/p\u003e\n \u003cp\u003e66,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,167\u003c/p\u003e\n \u003cp\u003e(0,040\u0026thinsp;\u0026minus;\u0026thinsp;0,699)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,014\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,304\u003c/p\u003e\n \u003cp\u003e(0,109-0,703)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,014\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1p/19q codeletion\u003c/p\u003e\n \u003cp\u003eCodeleted\u003c/p\u003e\n \u003cp\u003eWild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54,6\u003c/p\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,006\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25,4\u003c/p\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRT technique\u003c/p\u003e\n \u003cp\u003e3DCRT\u003c/p\u003e\n \u003cp\u003eIMRT-VMAT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53,8\u003c/p\u003e\n \u003cp\u003e61,4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,063\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30,8\u003c/p\u003e\n \u003cp\u003e32,8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,304\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,827\u003c/p\u003e\n \u003cp\u003e(0,535-1,276)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0,372\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003ea\u0026thinsp;=\u0026thinsp;Patients who underwent biopsy were accepted as STR\u003c/p\u003e\n \u003cp\u003eb\u0026thinsp;=\u0026thinsp;According to the 2016 WHO Classification\u003c/p\u003e\n \u003cp\u003eKPS: Karnofsky Performance Scale, IDH: Isocitrate dehydrogenase, 3DCRT: Three-dimensional conformal radiation therapy, IMRT: Intensity-modulated radiotherapy, VMAT: Volumetric modulated Arc therapy\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\"\u003e\n \u003ch2\u003eAdverse Events\u003c/h2\u003e\n \u003cp\u003eThe most common adverse events were hematological. Throughout the treatment and the initial 3-month posttreatment period, 74.8% of patients experienced hematological adverse events. TMZ had to be discontinued in five patients during RT and in one patient during adjuvant therapy due to severe grade III and IV hematological complications. Additionally, the dosage was adjusted, or treatment was temporarily halted in six patients.\u003c/p\u003e\n \u003cp\u003eLate adverse events were examined in 65 patients, revealing a sole incidence of grade 4 thrombocytopenia occurring 25 months after RT. No other late adverse events of Grade 3 or 4 severity were documented in the patient cohort.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eDespite advancements in imaging and radiotherapy technologies, a general consensus on target volumes in the treatment of HGG has not yet been reached. In this study, our aim was to validate our treatment approach, which involves the use of smaller target volumes, by evaluating its impact on recurrence patterns and survival. The primary objective is to reduce the brain's exposure to high doses without compromising recurrence or survival. This reduction in high-dose volume seeks to minimize long-term side effects in patients with extended survival. An additional 1 cm margin in the CTV can increase the irradiated volume by 1.5-2 times, and considering the direct link between the irradiated brain volume and adverse outcomes such as neurotoxicity, radionecrosis, and cognitive functions, quality of life may be affected in these patients.\u003c/p\u003e \u003cp\u003eMinniti et al. reported that the CTV of patients receiving 60 Gy in treatments following their protocol was 177.8 cm3, whereas it was 214.3 cm3 in treatments following the RTOG guidelines, and they observed fewer side effects when less brain tissue was irradiated with high-dose radiation [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Similarly, Kumar et al. reported a notable reduction in volume and an improvement in long-term quality of life in patients treated according to their own protocols compared to those treated according to the RTOG guidelines [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In this study, the CTV receiving 60 Gy was 44% smaller than that recommended by the ESTRO-ACROP and RTOG guidelines, while the CTV receiving 46\u0026ndash;50 Gy was 23% smaller than RTOG guideline (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e2\u003c/span\u003e). A significant reduction in treatment volume led to a substantial decrease in early adverse effects, and in the long term, no patients experienced grade 3\u0026ndash;4 neurological adverse effects. However, the impact on cognitive functions could not be evaluated in this study.\u003c/p\u003e \u003cp\u003eHigh-grade gliomas often relapse within 2 years after treatment, and local recurrence has a significant impact on survival. Recurrence mostly occurs in the tumor bed and within 2\u0026ndash;3 cm of the tumor [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. An overview of studies evaluating recurrence patterns across treatments with varying volumes and doses is shown in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The findings of this study appear to be similar to those of studies conducted in the post-TMZ period.\u003c/p\u003e \u003cp\u003eThe rate of central and in-field recurrences in this study was 81.2%, which is consistent with the findings of previous studies ([\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]). Similarly, central and in-field recurrences often develop early during the follow-up period, but some long-surviving patients also experience central and in-field recurrences years later. Recurrences that occur after a relatively long time may be caused by the molecular or genomic characteristics of the tumor, but a definitive comment cannot be made on this issue in this study [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The majority of recurrences in this study which involved the delineation of CTVs in dual volumes, manifested in the central area approximately 12\u0026ndash;13 mm from the GTV. However, 14% of recurrences were found within the low-risk CTV (10 to 20 mm from the GTV). Despite the fact that there are treatments in the literature that use a 5 mm CTV, omitting radiotherapy in this specific region was thought to potentially escalatory for the risk of recurrence. Therefore, in our treatment approach, a dose equivalent to 46 Gy was administered to this area.\u003c/p\u003e \u003cp\u003eThe primary concern with smaller treatment volumes is the increased risk of disease recurrence arising from the treatment area's borders. The marginal recurrence rate reported in treatments applied according to the ACROP and RTOG guidelines is approximately 6\u0026ndash;15% [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, McDonald et al. reported a marginal recurrence rate of 5% in patients treated with a CTV limited to 5\u0026ndash;10 mm [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Similarly, Paulsson et al. reported no difference in marginal recurrence patterns between treatments with 5, 10, or 15\u0026ndash;20 mm CTV margins [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In our study, three patients had lesions that met our definition of marginal recurrence. Only one of these has 37.5% of the lesion above the 50 Gy isodose line. In two of these patients, the majority of the lesions (approximately 84%) were located within the center of the treatment area and grew outward, but according to our definition of recurrence pattern, these two lesions were classified as marginal recurrences. Even considering all three lesions as marginal recurrences, the rate reached 4.3%, lower than that reported in many studies.\u003c/p\u003e \u003cp\u003eIn the literature, distant recurrence rates have been reported to vary between 2% and 21.5% depending on the follow-up duration, with distant recurrence rates increasing as survival extends [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. As a result of the long follow-up period and survival rates in this study, the distant recurrence rate was 14.5%. Compared to other recurrence types, it occurs later, with a median of 12 (3\u0026ndash;28) months, and is observed in smaller volumes, with an average tumor volume of 24.8 (1-108) cm3. During the assessment of recurrence patterns, we observed that a substantial portion of the brain in patients treated with the VMAT technique received a dose of 1200 cGy (20% isodose line). This posed challenges in evaluating relapses within the opposite hemisphere that spread without invading anatomical barriers. Consequently, the definition of distant recurrence in our study did not rely solely on isodose curves; instead, lesions in these areas were also considered as distant recurrences. This novel definition may prove beneficial in analyzing recurrence patterns among patients undergoing treatment with arc techniques.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of studies on recurrence patterns of HGG\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy (year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eİnitial Treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBoost treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRecurrence pattern\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHochberg et al (1980)[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 GBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWhole-Brain RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90% within 2 cm from tumor\u003c/p\u003e \u003cp\u003e10% outside 2 cm from tumor\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWallner et al\u003c/p\u003e \u003cp\u003e(1989)[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003cp\u003eHGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWhole-Brain RT:\u003c/p\u003e \u003cp\u003eDose:40\u0026ndash;60 Gy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 Gy boost to tumor bed in 25 patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%78 within 2 cm from tumor\u003c/p\u003e \u003cp\u003e%22 outside 2 cm from tumor\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHess et al (1994)[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66\u003c/p\u003e \u003cp\u003eHGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;2 cm,\u003c/p\u003e \u003cp\u003eDose:60Gy in 30 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%86 İFR, %14 DR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAydın et al (2001)[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003cp\u003eHGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;2 cm\u003c/p\u003e \u003cp\u003eDose:60Gy in 30 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%73 within 2 cm from tumor\u003c/p\u003e \u003cp\u003e%94 within 3 cm from tumor\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChan et al\u003c/p\u003e \u003cp\u003e(2002)[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003cp\u003eHGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;2,5 cm\u003c/p\u003e \u003cp\u003eDose:44Gy in 22 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;1,5 cm\u003c/p\u003e \u003cp\u003eDose:60Gy in 30 fr\u003c/p\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;0,5 cm\u003c/p\u003e \u003cp\u003eDose:90Gy in 45fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%78 CR, %91 IFR\u0026thinsp;+\u0026thinsp;CR, %9 MR, %0 DR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrandes et al (2009)[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95 GBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;2 cm\u003c/p\u003e \u003cp\u003eDose:60 Gy in 30 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%72,2 IFR, %6,3 MR, %21,5 DR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMilano et al (2010)[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 GBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;edema in MRI\u0026thinsp;+\u0026thinsp;2 cm2cm\u003c/p\u003e \u003cp\u003eDose:46 Gy in 23 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;2\u0026ndash;2,5 cm,\u003c/p\u003e \u003cp\u003eDose:60 Gy in 30 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIFR %92, MR%15, DR %13 (first recurrence)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinniti et al (2010)[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e105 GBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;2 cm\u003c/p\u003e \u003cp\u003eDose:60Gy in 30 fr\u003c/p\u003e \u003cp\u003e(if CTV\u0026thinsp;\u0026gt;\u0026thinsp;250 cm\u003csup\u003e3\u003c/sup\u003e 50 Gy in 25 fr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;1 cm (İf CTV\u0026thinsp;\u0026gt;\u0026thinsp;250 cm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e \u003cp\u003eDose:60 Gy in 30 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%75 CR, %81 IFR, %6 MR, %13 DR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMcdonald et al (2011)[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 GBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;edema\u0026thinsp;+\u0026thinsp;5\u0026ndash;12 mm\u003c/p\u003e \u003cp\u003eDose:46\u0026ndash;54 Gy in 23\u0026ndash;30 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;5\u0026ndash;10 mm,\u003c/p\u003e \u003cp\u003eDose:60 Gy in 30 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%93 IFR, %5 MR %2 DR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKumar et al (2012)[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 GBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;2 cm\u003c/p\u003e \u003cp\u003eDose:50 Gy in 25 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGTV\u003c/p\u003e \u003cp\u003eDose:60Gy in 30 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%87,2 IFR, %6,2 MR %6,2 DR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOgura et al (2013)[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 GBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;2 cm\u003c/p\u003e \u003cp\u003eDose:50\u0026ndash;54 Gy in 25\u0026ndash;30 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGTV\u003c/p\u003e \u003cp\u003eDose:60 Gy in 30 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%85,7 IFR\u0026thinsp;+\u0026thinsp;CR, %9,5 out-field recurrence, %19 DR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGebhardt et al (2014)[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95 GBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;edema\u0026thinsp;+\u0026thinsp;5 mm\u003c/p\u003e \u003cp\u003eDose:46 Gy in 23 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;5 mm\u003c/p\u003e \u003cp\u003eDose:60 Gy in 30 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%87 IFR, %6 MR, %28 DR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBuglione et al (2016)[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 GBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;2 cm\u003c/p\u003e \u003cp\u003eDose:60 Gy in 30 fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%88 IFR, %10 MR, %2 DR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZheng et al\u003c/p\u003e \u003cp\u003e(2021)[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 GBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;2 cm\u003c/p\u003e \u003cp\u003eDose:54 Gy in 30fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;1 cm\u003c/p\u003e \u003cp\u003eDose:60 Gy/30 fr\u003c/p\u003e \u003cp\u003e(with SİB technique)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%80 CR, %83,6 IFR\u0026thinsp;+\u0026thinsp;CR, %1,8 MR, %20 DR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThis study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89\u003c/p\u003e \u003cp\u003eHGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;2 cm\u003c/p\u003e \u003cp\u003eDose:46\u0026ndash;50 Gy in 23-30fr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGTV\u0026thinsp;+\u0026thinsp;1 cm\u003c/p\u003e \u003cp\u003eDose:60 Gy in 30 fr\u003c/p\u003e \u003cp\u003e(85% with SİB technique)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%65,2 CR, %81,1 IFR\u0026thinsp;+\u0026thinsp;CR, %4,3 MR, %14,5 DR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003efr: fraction HGG: high-grade glioma, GBM: glioblastoma multiforme, GTV: gross tumor volume, CTV: clinical target volume, SIB: simultaneous integrated boost, CR: central recurrence, IFR: in-field recurrence, MR: marginal recurrence, DR: distant recurrence\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn their study evaluating recurrence patterns based on the RT technique, Paulsson et al. and Buglione et al. reported no difference in recurrence patterns between patients treated with IMRT or 3BKRT [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Similarly, we found no significant relationship between the RT technique and the recurrence pattern.\u003c/p\u003e \u003cp\u003eWhen evaluated according to tumor grade, 66.7% of Grade 3 gliomas experienced central recurrence, and 33.3% of them experienced distant recurrence. Although distant recurrence is more common in Grade 3 gliomas, definitive conclusions are limited by the small number of Grade 3 patients and the fact that just over one-third (35.3%) experienced recurrence during the follow-up period.\u003c/p\u003e \u003cp\u003eThere are publications with different results regarding the relationship between surgical extent and recurrence pattern. Yoo et al. reported a lower incidence of in-field recurrence after total and supratotal resection [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In this study, the survival rate increased with total resection according to univariate analysis, but no relationship was found between the extent of surgery and the recurrence pattern.\u003c/p\u003e \u003cp\u003eThe overall and progression-free survival rates in our study were slightly greater than those in the literature. The primary reason for this difference is thought to be the exclusion of patients who died before evaluating the response after RT. Furthermore, the success rate of salvage treatments contributes significantly to increased overall survival rates.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, being a retrospective study introduces potential bias in patient selection. However, the similarity of patient characteristics with those of other studies reduces this potential bias. Second, after the recruitment of patients was completed, the World Health Organization (WHO) published a new grading system for high-grade glial tumors. Since patient recruitment and analyses were completed, patients were evaluated according to the 2016 WHO classification. Third, due to the lack of O6-methylguanine-DNA methyltransferase (MGMT) status data available from our clinic, the impact of MGMT status on the recurrence pattern was not assessed.\u003c/p\u003e \u003cp\u003e In conclusion, the recurrence pattern remained unchanged with the DENOG protocol, which is distinguished by a lower brain volume irradiation than standard guidelines. With longer survival times, distant recurrence rates increase, yet central and in-field recurrences remain dominant. Despite the decrease in the volume that received the 60 Gy dose, marginal recurrences remained at a notably low level. The absence of significant long-term side effects in our study is thought to be related to the decrease in this volume. This retrospective study supports the hypothesis that smaller volumes have a negligible impact on relapse patterns. However, prospective studies are still needed to assess how a reduction in brain volume following exposure to high doses impacts quality of life.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eAll the authors contributed to the material preparation, data collection, and analysis. The first draft of the manuscript was written by Volkan Semiz., and all the authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability:\u0026nbsp;\u003c/strong\u003eThe datasets are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e This study was approved by the Institutional Review Board of Dokuz Eylul University Faculty of Medicine.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish:\u003c/strong\u003e Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShapiro WR, Green SB, Burger PC, et al (1989) Randomized trial of three chemotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. 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Strahlenther Onkol 177:424\u0026ndash;431. https://doi.org/10.1007/PL00002424\u003c/li\u003e\n\u003cli\u003eGebhardt BJ, Dobelbower MC, Ennis WH, et al (2014) Patterns of failure for glioblastoma multiforme following limited-margin radiation and concurrent temozolomide. https://doi.org/10.1186/1748-717X-9-130\u003c/li\u003e\n\u003cli\u003eMcDonald MW, Shu HKG, Curran WJ, Crocker IR (2011) Pattern of failure after limited margin radiotherapy and temozolomide for glioblastoma. Int J Radiat Oncol Biol Phys 79:130\u0026ndash;136. https://doi.org/10.1016/J.IJROBP.2009.10.048\u003c/li\u003e\n\u003cli\u003eMinniti G, Amelio D, Amichetti M, et al (2010) Patterns of failure and comparison of different target volume delineations in patients with glioblastoma treated with conformal radiotherapy plus concomitant and adjuvant temozolomide. Radiotherapy and Oncology 97:377\u0026ndash;381. https://doi.org/10.1016/J.RADONC.2010.08.020\u003c/li\u003e\n\u003cli\u003eGuram K, Smith M, Ginader T, et al (2019) Using Smaller-Than-Standard Radiation Treatment Margins Does Not Change Survival Outcomes in Patients with High-Grade Gliomas. Pract Radiat Oncol 9:16\u0026ndash;23. https://doi.org/10.1016/j.prro.2018.06.001\u003c/li\u003e\n\u003cli\u003eGuberina N, Padeberg F, P\u0026ouml;ttgen C, et al (2023) Location of Recurrences after Trimodality Treatment for Glioblastoma with Respect to the Delivered Radiation Dose Distribution and Its Influence on Prognosis. Cancers (Basel) 15:. https://doi.org/10.3390/cancers15112982\u003c/li\u003e\n\u003cli\u003eStupp R, Mason WP, Van Den Bent MJ, et al Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma\u003c/li\u003e\n\u003cli\u003eWen PY, Macdonald DR, Reardon DA, et al (2010) Updated response assessment criteria for high-grade gliomas: Response assessment in neuro-oncology working group. Journal of Clinical Oncology 28:1963\u0026ndash;1972\u003c/li\u003e\n\u003cli\u003eKumar N, Sharma S, Mukherjee K, et al (2012) To compare the treatment outcomes of two different target volume delineation guidelines (RTOG vs MD anderson) in glioblastoma multiforme patients: a prospective randomized study. Neuro Oncol 14:vi134\u0026ndash;vi135\u003c/li\u003e\n\u003cli\u003eZhou X, Liao X, Zhang B, et al (2016) Recurrence patterns in patients with high-grade glioma following temozolomide-based chemoradiotherapy. Mol Clin Oncol 5:289\u0026ndash;294. https://doi.org/10.3892/mco.2016.936\u003c/li\u003e\n\u003cli\u003eOgura K, Mizowaki T, Arakawa Y, et al (2013) Initial and cumulative recurrence patterns of glioblastoma after temozolomide-based chemoradiotherapy and salvage treatment: a retrospective cohort study in a single institution. Radiat Oncol 8:. https://doi.org/10.1186/1748-717X-8-97\u003c/li\u003e\n\u003cli\u003eHochberg FH, Pruitt A (1980) Assumptions in the radiotherapy of glioblastoma. Neurology 30:907\u0026ndash;911. https://doi.org/10.1212/WNL.30.9.907\u003c/li\u003e\n\u003cli\u003eGuram K, Smith M, Ginader T, et al (2019) Using Smaller-Than-Standard Radiation Treatment Margins Does Not Change Survival Outcomes in Patients with High-Grade Gliomas. Pract Radiat Oncol 9:16\u0026ndash;23. https://doi.org/10.1016/j.prro.2018.06.001\u003c/li\u003e\n\u003cli\u003eMilano MT, Okunieff P, Donatello RS, et al (2010) Patterns and timing of recurrence after temozolomide-based chemoradiation for glioblastoma. Int J Radiat Oncol Biol Phys 78:1147\u0026ndash;1155. https://doi.org/10.1016/J.IJROBP.2009.09.018\u003c/li\u003e\n\u003cli\u003eZheng L, Zhou Z-R, Yu Q, et al (2021) The Definition and Delineation of the Target Area of Radiotherapy Based on the Recurrence Pattern of Glioblastoma After Temozolomide Chemoradiotherapy. Article 615368 1 Front Oncol 10:615368. https://doi.org/10.3389/fonc.2020.615368\u003c/li\u003e\n\u003cli\u003eBuglione M, Pedretti S, Poliani PL, et al Pattern of relapse of glioblastoma multiforme treated with radical radio-chemotherapy: Could a margin reduction be proposed? 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Radiother Oncol 30:146\u0026ndash;149. https://doi.org/10.1016/0167-8140(94)90044-2\u003c/li\u003e\n\u003cli\u003eChan JL, Lee SW, Fraass BA, et al (2002) Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy. J Clin Oncol 20:1635\u0026ndash;1642. https://doi.org/10.1200/JCO.2002.20.6.1635\u003c/li\u003e\n\u003cli\u003eZheng L, Zhou Z-R, Yu Q, et al (2021) The Definition and Delineation of the Target Area of Radiotherapy Based on the Recurrence Pattern of Glioblastoma After Temozolomide Chemoradiotherapy. Article 615368 1 Front Oncol 10:615368. https://doi.org/10.3389/fonc.2020.615368\u003c/li\u003e\n\u003cli\u003eYoo J, Yoon S-J, Kim KH, et al (2021) Patterns of recurrence according to the extent of resection in patients with IDH-wild-type glioblastoma: a retrospective study. J Neurosurg 1\u0026ndash;11. https://doi.org/10.3171/2021.10. JNS211491\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"High-grade glioma, Recurrence pattern, Limited margin, Radiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-3909937/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3909937/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003eWe aimed to analyze our radiotherapy protocol by evaluating its effect on recurrence patterns and survival outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe assessed 89 patients diagnosed with high-grade gliomas (HGGs) who underwent chemoradiotherapy at our institution from January 2014 to January 2021. A high-risk clinical target volume (CTV high) was created with a 1 cm margin in all directions from the GTV, while a low-risk clinical target volume (CTV low) was established with a 2 cm margin. Planned treatment volumes with a 2-3 mm margin in all directions were created, and doses of 60 Gy and 46-50 Gy were prescribed in 30 fractions. Recurrence patterns were classified as central, in-field, marginal, or distant based on the 60 and 50 Gy D95 isodose lines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e With a median follow-up of 29 months, 77.5% of patients experienced recurrence. Recurrence patterns were central in 65.2%, in-field in 16%, marginal in 4.3%, and distant in 14.5%. The overall survival rates at 1, 2, and 5 years were 87.6%, 60.3%, and 26.8%, respectively. The progression-free survival rates at the same intervals were 53.9%, 32.6%, and 20.7%, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThe recurrence pattern remained unchanged with our protocol. With longer survival times, distant recurrence rates increase, yet central and in-field recurrences remain dominant. Despite the decrease in the volume that received the 60 Gy dose, marginal recurrences remained at a notably low level.\u003c/p\u003e","manuscriptTitle":"Does limited-margin radiotherapy change the recurrence pattern and survival of patients with high-grade gliomas? Analysis and validation of a different approach","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-01 16:28:20","doi":"10.21203/rs.3.rs-3909937/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b242cffc-99e1-46b8-a044-43fdf9e16f83","owner":[],"postedDate":"February 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-02-12T12:36:31+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-01 16:28:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3909937","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3909937","identity":"rs-3909937","version":["v1"]},"buildId":"J0_U0BvcaRcwD8yVFaRlm","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}