Experience about Chemoradiation treatment with or without Concurrent Tumor-Treating Fields (TTFields) in Newly Diagnosed Glioblastoma (GBM) Patients in China

Experience about Chemoradiation treatment with or without Concurrent Tumor-Treating Fields (TTFields) in Newly Diagnosed Glioblastoma (GBM) Patients in China | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Experience about Chemoradiation treatment with or without Concurrent Tumor-Treating Fields (TTFields) in Newly Diagnosed Glioblastoma (GBM) Patients in China Liping Liang, Lingchao Chen, Chunxia Ni, Wenyin Shi, Zhirui Zhou, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4350426/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 Background: Tumor-Treating Fields (TTFields) and radiotherapy may have synergistic anti-glioma effect based on preclinical study. Chemoradiation concurrent with TTFields has become a hot topic in clinicians. This study provided preliminary experience about the clinical outcomes of patients with newly diagnosed Glioblastoma (GBM) received concurrent and adjuvant TTFields with chemoradiation or adjuvant TTFields only based on a cohort of patients treated at Huashan Hospital, China. Methods: This is a retrospective study analyzing clinical outcomes for newly diagnosed GBM patients treated at Huashan Hospital who received TTFields treatment. Patients were divided into two groups: one group received TTFields adjuvantly after the completion of chemoradiation (referred to as the A-TTF group), and another group received TTFields concurrently with chemoradiation and continued TTFields after treatment completion (referred to as the CA-TTF group). Treatment efficacy and toxicities were assessed and compared between the two groups. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method. To account for confounding factors, the Cox proportional hazards regression model, data matched by propensity score, and inverse probability of treatment weighting (IPTW) based on the propensity score were used for effectiveness evaluation. Results: A total of 72 patients with ndGBM were included in the study, 41 received concurrent and adjuvant TTFields in combination with chemoradiotherapy (concurrent and adjuvant TTFields group, CA-TTF), and 31 received adjuvant TTFields with temozolomide (adjuvant TTFields group, A-TTF). Skin toxicity was common but tolerated, there was no significant difference between the CA-TTF and A-TTF groups. The two groups were well balanced in age, sex, extent of resection, MGMT methylation status, KPS, as well as compliance and duration of TTFields usage. The TERT promoter mutation rate was 63.4% in the CA-TTF group versus 41.9% in the A-TTF group. With a median follow up of 18.0 months, there was no significant difference in PFS between CA-TTF and A-TTF groups (14.2 and 15.0 months, respectively, p=0.92); or the median OS (20.8 and 20.0 months, respectively, p=0.92). After IPTW, there remained no significant differences in PFS or OS, but the adjusted hazard ratio (HR) for PFS decreased from 0.93 (95% CI: 0.53-1.63, p=0.82) to 0.77 (95% CI: 0.44-1.30, p=0.344), and the adjusted HR for OS decreased from 0.96 (95% CI: 0.52-1.79, p=0.91) to 0.74 (95% CI: 0.40-1.37, p=0.336) for OS. Conclusions: Concurrent chemoradiation and TTFields treatment is safe for ndGBM patients. No survival difference was presented between CA-TTF and A-TTF groups in this series of patients, but a potential advantage for those undergoing concurrent TTFields treatment. This hypothesis need validation through large-scale clinical trials. TTFields glioblastoma concurrent therapy chemoradiotherapy Figures Figure 1 Figure 2 Introduction GBM, characterized by its extensive invasiveness and dismal prognosis, is the most prevalent primary malignant brain tumor in adults 1 . TTFields treatment is a novel anti-mitotic therapeutic modality that utilizes low-intensity, intermediate-frequency electric fields to inhibit cell proliferation and disrupt cancer cell replication 2 . It is approved for patients with newly diagnosed and recurrent GBM 3–7 . The EF-14 clinical trial demonstrated that adding TTFields to maintenance temozolomide chemotherapy after radiotherapy significantly improved the PFS and OS in patients with ndGBM. Consequentlyu, TTFields plus temozolomide was recommended as the first-line standard adjuvant therapy for ndGBM after completing radiotherapy 5,6 . Many basic studies have investigated the mechanisms of TTFields treatment. Besides anti-mitotic effect, TTFields has also been found to have other mechanisms of action, such as increased cell permeability, activation autophagy, stimulation of immune response, and inhibition DNA damage repair 8 . Preclinical studies indicate that the combination of TTFields and irradiation has a synergistic anti-glioma effect via inhibition of the repair of radiation- induced DNA damage. When glioma cells treated with TTFields after RT, more than 40% of the initial DNA damage remained unrepaired when TTFields were subsequently applied. as assessed by comet assy. After TTFields treatment, the BRCA1 DNA-damage response was significantly down-regulated and DNA double-strand break (DSB) repair was reduced. These results provided a strong rationale for the application of the combination of concurrent TTFields with chemoradiation therapy 9–13 . Based on these findings, early clinical trials were conducted to evaluate the safety and feasibility of this combination. The SPARE trial was the first study reporting the feasibility of concurrent TTFields with chemoradiation in patients with ndGBM. The skin toxicities were common; however they were mild and well tolerated, with 83.3% of patients experiencing grade 1 or 2 skin adverse events. The median PFS and OS were 9.3 months and 15.8 months, respectively, which compares favorably to historical benchmark 14,15 . Bokstain et al also conducted a phase 1/phase 2 and reported the safety and feasibility concurrent TTFields and radiotherapy of 10 patients in the phase 1 portion. The findings are similar, most patients (80%) experienced mild to moderate skin toxicities (grade 1–2) caused by TTFields. There was no grade 3 or higher toxicities and the combination is considered well tolerated. The median PFS was 8.9 months, but the median OS was not yet reached 16 . Based on these two early phase trials, an international phase 3 randomized trial (EF-32, NCT04471844) is currently enrolling, comparing concurrent TTFields vs maintenance TTFields only 17 , but the results are yet to be reported. In this retrospective study, we aimed to determine the clinical benefits between concurrent and adjuvant TTFields with chemoradiotherapy (CA-TTF group) or adjuvant TTFields after chemoradiotherapy only (A-TTF group) in our real clinical practice. We reviewed a cohort of ndGBM patients treated at Huashan Hospital, China between 2020 and 2021. These patients underwent concurrent and adjuvant TTFields with chemoradiotherapy (CA-TTF group) or adjuvant TTFields after chemoradiotherapy only (A-TTF group). We presented and shared our primary experiences about these two regimens. Methods and materials Patients This retrospective study included ndGBM patients who received radiotherapy and underwent TTFields treatment in Huashan Hospital, Fudan University, China, from Jan 2020 to Dec 2021. All the patients included would match this criterias: ( 1 ) age > = 18 year with newly diagnosed IDH1/2 wild type GBM; ( 2 ) TTFields treatment more than four weeks; ( 3 ) completed the standard Stupp regimen chemoradiotherapy. Participants were administered temozolomide concurrently with radiotherapy at a dose of 75 mg/m^2 daily for 6 weeks. Following the concurrent phase, during the adjuvant phase, temozolomide was given at a dose of 150–200 mg/m^2 for the first 5 days of each 28-day cycle, for a total of 6 cycles. This study was approved by the Ethics Committee of Huashan Hospital, Fudan University (Approval N0. KY2023-1007). The baseline characteristics, such as age, sex, Karnofsky performance status score (KPS), the extent of resection, MGMT promoter methylation status, TERT promoter methylation status, TTFields usage, adverse events, grade evaluation, PFS, and OS, were collected. The extent of resection was classified as gross tumor resection (GTR), subtotal resection (STR) and biopsy 18 . Radiation Therapy All patients were immobilized in a supine position using a thermoplastic mask. For the CA-TTF group, a customized 5 mm thickness latex-free open-cell styrene butadiene rubber foam was fitted under the mask to accommodate the TTFields transducer arrays. Treatment planning computed tomography (CT) scans were performed for all patients without TTFields arrays and fused with post-operative magnetic resonance imaging (MRI). The target volumes were contoured according to the Radiation Therapy Oncology Group (RTOG) guidelines. The radiation prescription was 60 Gy in 30 fractions for all patients. For CA-TTF group, scalp that was defined as a 5-mm thickness area from the skin surface above the level of the foramen magnum which the SPARE trial 14 was also contoured and defined as organ at risk (OAR) in radiation planning. The sclap constraints were also adopted from SPARE trial14, that were: mean < 20Gy, D20cc < 50Gy, D30cc < 40Gy; All patients’ radiotherapy plans were done with eclipse v15.5 (Varian, Palo Alto, CA). All patients were treated with Truebeam (Varian, Palo Alto, CA) by weekly CBCT verification. In the initial phase of our study, TTFields arrays were removed daily for the first five patients to closely monitor skin conditions and ensure safety. However, after observing no significant adverse skin effects and consulting findings from the SPARE study, we adjusted our protocol. For subsequent patients, arrays were not removed daily during the radiation therapy period, facilitating a more continuous application of TTFields therapy. Tumor Treating Fields Treatment For CA-TTF group, TTFields treatment started at the beginning of radiotherapy (within 1 week), and for A-TTF group, started (4–7 week) after completing radiotherapy. The follow-up began on the first day after surgery in both groups. The array placement was shifted between two alternate sites at every array change. Monthly device logs and average daily use (ADU) were obtained for all patients. The scalp reaction was inspected by the physician and/or patient/care giver during transducer array changes 14 . Toxicity The Common Terminology Criteria for Adverse Events (CTCAE) 5.0 was used to grade the scalp toxicity 19 . Statistical analysis Continuous variables were analyzed using Student’s t-test or Wilcoxon rank-sum test. Categorical variables at baseline were analyzed by chi-squared or Fisher’s exact test. The propensity data set generated the inverse probability of treatment weighting (IPTW) dataset, which balanced all observable characteristics for the patients in the CA-TTF group to compare to the A-TTF group. The Kaplan-Meier method and multivariate Cox regression model were implemented for survival analysis. The IPTW dataset was analyzed with Cox regression model for sensitivity analysis. The results were expressed as adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs). The R software version 4.2.0 ( http://cran.rproject.org , accessed on 1st May 2022, was used for statistical analysis. Results Study Population A total of 72 patients were included in this retrospective study; 41 received concurrent and adjuvant TTFields in combination with chemoradiotherapy (CA-TTF group), and 31 received adjuvant TTFields after chemoradiotherapy (A-TTF group). All patients had GBM, were IDH wild type, and were classified as WHO grade 4. The patient characteristics were well balanced between the two groups (Table 1 ). In the CA-TTF group, 31.7% of patients underwent STR or biopsy, versus 25.8% in the A-TTF group. The TERT promoter mutation rate was 63.4% in the CA-TTF group versus 41.9% in the A-TTF group. The MGMT promoter methylation rate was 36.6% in the CA-TTF group versus 32.3% in the A-TTF group (Table 1 ). Table 1 Patient characteristics. TTFields P-value CA-TTF (N = 41) A-TTF (N = 31) Sex Female 13 (31.7%) 13 (41.9%) 0.518 Male 28 (68.3%) 18 (58.1%) Age (years) Median [Min, Max] 53.0 [22.0, 76.0] 48.0 [19.0, 74.0] 0.615 Extent of resection GTR 28 (68.3%) 23 (74.2%) 0.777 STR/Biopsy 13 (31.7%) 8 (25.8%) MGMT promoter methylation Methylated 15 (36.6%) 10 (32.3%) 0.907 Unmethylated 24 (58.5%) 19 (61.3%) unknown 2 (4.9%) 2 (6.5%) TERT promoter mutation status Wild-type 12 (29.3%) 14 (45.2%) 0.192 Mutation 26 (63.4%) 13 (41.9%) unknown 3 (7.3%) 4 (12.9%) Baseline KPS Median [Min, Max] 90.0 [60.0, 90.0] 80.0 [60.0, 90.0] 0.443 compliance with TTFields (hours) Median [Min, Max] 21.1 [8.88, 23.0] 21.6 [15.8, 23.3] 0.491 Duration of TTFields(months) Median [Min, Max] 10.0 [1.00, 31.0] 10.4 [1.00, 35.0] 0.203 Temozolomide intake All patients included in this study underwent the standard treatment protocol, which consists of a Concomitant Phase and an Adjuvant Phase. During the radiation therapy of the Concomitant Phase, patients took Temozolomide orally every day; this phase typically lasted six weeks. In the Adjuvant Phase, therapy generally involved cycles of Temozolomide administered for 5 consecutive days followed by a 23-day rest period, with each cycle spanning 28 days. TTFields Treatment Compliance and Duration In the CA-TTF group, the initial five patients had TTField arrays removed daily with radiation delivery, the rest kept the TTFields arrays on during radiation treatment. Scalp sparing radiation treatment was administered to thirty-five (83.3%). Regarding TTFields compliance, both groups achieved more than 75% (18 hours every day) 20 . The median compliance is 21.1 hours a day for the CA-TTF group, and 21.6 hours for the A-TTF group. The median durations of TTFields treatment were similar, 10.0 and 10.4 months in CA-TTF and A-TTF group, respectively (Table 1 ). Toxicity Skin adverse events (Skin AEs) were assessed in this study. These events included dermatitis, pruritus, electric sensation, and skin burning sensation. Dermatitis, which included scalp irritation, dry skin, folliculitis, erythema, color change, or rash, was similar in both groups, with Grade 1 AEs occurring in 21.95% of CA-TTF group patients and 25.81% of A-TTF group patients. Grade 2 AEs were seen in 34.15% of CA-TTF group patients and 32.26% of A-TTF group patients. Grade 3 skin AEs were rare, occurring only in 2.44% of CA-TTF group patients and 3.23% of A-TTF group patients. Pruritus, another skin-related adverse event, was noted in both groups as well. Grade 1 AEs were observed in 9.76% of CA-TTF group patients and 9.68% of A-TTF group patients. Grade 2 AEs were less frequent, affecting 4.88% of CA-TTF group patients and 3.22% of A-TTF group patients. Electric sensation occurred in 2.44% of CA-TTF group patients. Skin burning sensation, another infrequent event, was reported in both groups, with Grade 1 AEs documented in 2.44% of CA-TTF group patients and 3.22% of A-TTF group patients (Table 4 ). Other toxicities like electric sensation were recorded by one patient (2.44%) in the CA-TTF group, and skin burning sensation was found only in one patient in both groups. Survival With a median follow-up of 18.0 months, there was no significant difference in median progression-free survival (PFS) between the two groups. The PFS was 14.2 months (95% CI: 11.1–20.4) in the CA-TTF group and 15.0 months (95% CI: 8.0-NA) in the A-TTF group, with a proportional hazard ratio (HR) of 0.97 (95% CI: 0.55–1.70, p = 0.92) (Fig. 1 ). Similarly, there was no significant difference in overall survival (OS) between the groups, with 20.8 months (95% CI: 17.8-NA) in the CA-TTF group versus 20.0 months (95% CI: 17.0-NA) in the A-TTF group, HR of 0.97 (95% CI: 0.51–1.80, p = 0.92) (Fig. 1 ). In the CA-TTF group, the 1-year PFS and OS rates were 61.0% (95% CI: 47.7–77.9%) and 82.9% (95% CI: 72.2–95.3%), respectively. Conversely, the A-TTF group demonstrated a 1-year PFS rate of 51.6% (95% CI: 36.7–72.6%) and a 1-year OS rate of 80.6% (95% CI: 67.9–95.8%) (Fig. 1 ). After conducting inverse probability treatment weighting (IPTW) to balance the baseline between the CA-TTF and A-TTF groups, there remained no significant differences in PFS and OS. However, the adjusted hazard ratio (HR) for PFS decreased from 0.93 (95% CI: 0.53–1.63, p = 0.82) to 0.77 (95% CI: 0.44–1.30, p = 0.344), and the adjusted HR for OS decreased from 0.96 (95% CI: 0.52–1.79, p = 0.91) to 0.74 (95% CI: 0.40–1.37, p = 0.336) for OS. For subgroup analysis, age, sex, extent of resection, MGMT promotor methylation status, TERT promotor mutation status, baseline KPS and duration of TTFields usage were evaluated. There was almost no difference in PFS or OS between CA-TTF and A-TTF (Table S1 , S2). The median PFS values were 8.5 months (95% CI: 5.3-NA) for the A-TTF plus STR/Biopsy group, 13.0 months (95% CI: 4.9-NA) for the CA-TTF plus STR/Biopsy group, 16.0 months (95% CI: 9.0-NA) for the A-TTF plus GTR group, and 17.1 months (95% CI: 11.1-NA) for the CA-TTF plus GTR group (p = 0.052) (Figure S1 A). The corresponding median OS values were 13.6 months (95% CI: 10.0-NA), 17.9 months (95% CI: 14.9-NA), 26.3 months (95% CI: 17.0-NA), and NA (95% CI: 17.0-NA), respectively (p = 0.043) (Figure S1 B). In the entire cohort, MGMT promotor methylation status is associated with PFS and OS. The median PFS for the MGMT promoter methylated group was indeterminate (95% CI: 14.2-NA), while for the MGMT promoter unmethylated group, it was 10 months (95% CI: 7.5–17.9) (p = 0.0042) (Fig. 2 A). The median OS was indeterminate in the MGMT methylated group (95% CI: 18.0-NA), whereas it was 17.8 months (95% CI: 14.9–30) in the unmethylated group (p = 0.039) (Fig. 2 B). In the entire cohort, the median PFS for the TERT mutation group was 10.5 months (95% CI: 8.0-17.2), while for the TERT wild-type group, it was 20.0 months (95% CI: 12.8-NA) (p = 0.036) (Fig. 2 C). The median OS for the TERT mutation group was 17.9 months (95% CI: 14.9-NA), whereas it was 30.0 months (95% CI: 18.0-NA) for the wild-type group (p = 0.095) (Fig. 2 D). On the other hand, in patients with TERT mutations, there was no difference in PFS or OS between CA-TTF and A-TTF. The median PFS for the CA-TTF group was 11.9 months (95% CI: 8.9–20.4), and for the A-TTF group, it was 7.5 months (95% CI: 6.0-NA) (p = 0.85) (Fig. 2 E). The median OS for the CA-TTF group was 18.1 months (95% CI: 14.6-NA), whereas for the A-TTF group, it was 17.0 months (95% CI: 14.6-NA) (p = 0.48) (Fig. 2 F). Univariate and multivariate analysis were performed in the CA-TTF group to evaluate the impact of age, sex, extent of surgery, MGMT promoter methylation status, TERT promotor methylation status, baseline KPS, patient compliance with TTFields and duration of TTFields. In Cox regression analyses, four patients were excluded from the analysis due to missing molecular status data. Univariate analysis revealed that the duration of TTFields had a significant impact on OS (HR = 0.93, 95% CI: 0.87–0.99, p = 0.019), this effect remained significant in multivariate analysis (HR = 0.89, 95% CI: 0.81–0.98, p = 0.013). STR/Biopsy was associated with shorter PFS compared to GTR in multivariate analyses (HR = 5.28, 95% CI: 1.47–18.91, p = 0.011). Multivariate Cox regression analysis also revealed a significant association between longer mean patient compliance with TTFields (hours/day) and extended progression-free survival (PFS) with a hazard ratio (HR) of 0.68 (95% CI: 0.49–0.93, p = 0.016) (Tables 2 and 3 ). Table 2 Univariate and multivariate analyses of progression-free survival (PFS) and overall survival (OS) in CA-TTF group patients. Univariate (95% CI, Crude p value) Multivariate (95% CI, Crude p value) n(%) PFS OS PFS OS Age Median (Min, Max) 53.0(22.0,76.0) 1.01 (0.98–1.04, p = 0.523) 1.01 (0.98–1.04, p = 0.523) 1.01 (0.96–1.07, p = 0.670) 1.01 (0.96–1.07, p = 0.670) Sex female 11 (29.7) - - - - male 26 (70.3) 3.29 (1.22–8.88, p = 0.019 ) 3.29 (1.22–8.88, p = 0.019 ) 3.63 (1.18–11.18, p = 0.025) 3.63 (1.18–11.18, p = 0.025) Extent of resection GTR 26 (70.3) - - - - STR/Biopsy 11 (29.7) 2.13 (0.92–4.89, p = 0.076) 2.13 (0.92–4.89, p = 0.076) 5.28 (1.47–18.91, p = 0.011) 5.28 (1.47–18.91, p = 0.011) MGMT promoter region methylation methylated 15 (40.5) - - - - unmethylated 22 (59.5) 1.77 (0.76–4.12, p = 0.183) 1.77 (0.76–4.12, p = 0.183) 2.34 (0.79–6.95, p = 0.125) 2.34 (0.79–6.95, p = 0.125) TERT promoter mutation status mutation 25 (67.6) - - - - wild-type 12 (32.4) 0.51 (0.20–1.28, p = 0.152) 0.51 (0.20–1.28, p = 0.152) 0.32 (0.08–1.26, p = 0.104) 0.32 (0.08–1.26, p = 0.104) Baseline KPS ≥ 90 NO 11 (29.7) - - - - YES 26 (70.3) 0.64 (0.28–1.44, p = 0.280) 0.64 (0.28–1.44, p = 0.280) 1.29 (0.41-4.00, p = 0.665) 1.29 (0.41-4.00, p = 0.665) Patient compliance with TTF (hours) Median (Min, Max) 20.12(16.8,23.0) 0.82 (0.61–1.10, p = 0.191) 0.82 (0.61–1.10, p = 0.191) 0.68 (0.49–0.93, p = 0.016 ) 0.68 (0.49–0.93, p = 0.016 ) Duration of TTF(months) Median (Min, Max) 10.0(1.0,31.0) 0.97 (0.93–1.02, p = 0.260) 0.97 (0.93–1.02, p = 0.260) 0.94 (0.86–1.03, p = 0.203) 0.94 (0.86–1.03, p = 0.203) Table 3 TTFields-Related Adverse Events CA-TTF (N = 41) A-TTF (N = 31) Skin AEs, n (%) Dermatitis* Grade 1 AEs, n (%) 9(21.95%) 8(25.81%) Grade 2 AEs, n (%) 14(34.15%) 9(32.26%) Grade 3 AEs, n (%) 1(2.44%) 1(3.23%) Pruritus Grade 1 AEs, n (%) 4(9.76%) 3(9.68%) Grade 2 AEs, n (%) 2(4.88%) 1(3.22%) Electric sensation Grade 1 AEs, n (%) 1(2.44%) skin burning sensation Grade 1 AEs, n (%) 1(2.44%) 1(3.22%) *Dermatitis included scalp irritation, dry skin, folliculitis, erythema, color change, or rash. Table 4 PFS and OS analysis after inverse probability treatment weighting (IPTW). PFS TTFields concurrent HR p Value 95% CI Lower Upper 0.77 0.344 0.44 1.3 OS TTFields concurrent HR p Value 95% CI Lower Upper 0.74 0.336 0.4 1.37 Discussion This is the first retrospective study to compare the clinical benefit of chemoradiation therapy with or without concurrent TTFields in patients with ndGBM in China. Our experience confirmed the feasibility and safety of concurrent TTFields and chemoradiation in Chinese patient population. Both CA-TTF and A-TTF groups exhibited similar low grade skin toxicities. There were no significant differences in PFS or OS between the CA-TTF and A-TTF groups, but our data confirmed the PFS and OS benefit with TTFields. The PFS ~ 14m and OS ~ 20 m compared, similar or to EF-14 and favorable to historical benchmark with TTFields, confirming the benefit in Chinese patient population. Although preclinical studies showed a synergistic effect between TTFields and radiation, many clinicians also concern about the dosimetric consequences of applying TTFields treatment during radiation. Guberina et al. reported their dosimetry study; they found that the dose distribution within the clinical target volume (CTV) is below 2% and therefore not clinically relevant 21 . In our previous dosimetry study 22 , we detected the dosimetric distribution when wearing the TTFields arrays and the 5 mm thickness latex-free open-cell styrene butadiene rubber foam that fitted the mask. We found that the dose distribution for the CTV variated below 1%, which was not clinical significant; however, the scalp dose was elevated as Guberina reported. Therefore, when applying the TTFields during radiation, we strongly suggest to contouring the scalp and defining it as OAR in radiation planning, using the constraints recommended by SPARE trial. Several clinical trials also have investigated the safety and efficacy of the concurrent TTFields therapy. Such combination appeared to be feasible and well tolerated. Scalp toxicity is still common, about 80%, but mild (grade 1 or grade 2) 16 14 . In the current study of 72 patients, 41 received concurrent TTFields with CRT (CA-TTF group), and 31 received adjuvant TTFields with TMZ after CRT (A-TTF group). We also observed common but mild scalp irritation, about 55–60%. Dermatitis, including scalp irritation, dry skin, folliculitis, erythema, color change, or rash, was the most common cutaneous adverse event. Pruritus was the second most frequently reported skin adverse event, while electric sensation and skin burning sensation were rare. There was no significant difference in skin toxicity between the CA-TTF and A-TTF groups. One patient (2.4%) in the CA-TTF group experienced grade 3 skin toxicity, as this patient did not apply the scalp-preserving procedure and the transducer arrays were not removed during radiation treatment. The radiation plan was suspended but the skin reaction was improved in three days by using topical corticosteroids ointment. Other patients who suffered scalp toxicity did not interrupt their radiation plan but just suspend TTFields treatment for about three days, and their skin reaction also recovered by using topical corticosteroids ointment and then restarted the TTFields treatment. Our result confirmed that concurrent use of TTFields and CRT is safe and well-tolerated for patients with newly diagnosed GBM. Preclinical studies have indicated the synergistic effects between TTFields and irradiation 10 , which provide the scientific rationale for concurrent use of TTFields with CRT. DNA damage, particularly double-strand DNA damage is the main mechanism of action of radiation treatment. TTFields can inhibit DNA damage repair and promote cell death, potentially increasing the efficacy of RT. In conditions where TTFields were used after irradiation, chromatid aberrations increased, and the DNA repair capacity declined, enhancing the sensitivity to irradiation. However, there is a critical temporal relationship of TTFields and RT. The radiation sensitization effect is maximized when TTFields initiated soon after radiation treatment 10 . In order to minimize the interruption of TTFields treatment after radiation, we adopted the solution of irradiate through the TTFields arrays, which is first developed in the SPARE trial 14 . The other two separate pilot studies, which investigated the combination of TTFields with concurrent chemoradiotherapy (CRT), reported median progression-free survival (PFS) of 8.9 months and 9.3 months, respectively 16,23 . These results were higher than the 6.7 months observed in the EF-14 study, which TTFields were administered during the temozolomide adjuvant chemotherapy phase. This suggests that initiating TTFields treatment earlier during the CRT phase may potentially lead to improved survival outcomes compared to the temozolomide adjuvant phase. In our study, the baseline characteristics were similar between both groups, but no significant differences were found in either median OS or PFS. The PFS was 14.2 months (95% CI: 11.1–20.4) in the CA-TTF group and 15.0 months (95% CI: 8.0-NA) in the A-TTF group, with a proportional hazard ratio (HR) of 0.97 (95% CI: 0.55–1.70, p = 0.92) (Fig. 1 ). The PFS was 20.8 months (95% CI: 17.8-NA) in the CA-TTF group versus 20.0 months (95% CI: 17.0-NA) in the A-TTF group, HR of 0.97 (95% CI: 0.51–1.80, p = 0.92) (Fig. 1 ). After IPTW analysis, the baseline characteristics of both groups were balanced, and the survival benefits remained insignificantly different. The adjusted hazard ratio (HR) for PFS decreased from 0.93 (95% CI: 0.53–1.63, p = 0.82) to 0.77 (95% CI: 0.44–1.30, p = 0.344), and the adjusted HR for OS decreased from 0.96 (95% CI: 0.52–1.79, p = 0.91) to 0.74 (95% CI: 0.40–1.37, p = 0.336) for OS. This result showed the hazard ratios for PFS and OS in the CA-TTF group decreased, suggesting a potential advantage for those undergoing concurrent TTFields treatment. This hypothesis necessitates validation through large-scale clinical trials. When comparing molecular markers between both groups, we observed an even distribution of the MGMT promoter region status. MGMT promoter methylation is typically associated with a better prognosis because it reduces tumor cell resistance to alkylating agents, such as TMZ 24 . In this study, a benefit in terms of PFS and OS was observed in the MGMT promoter methylation group compared to the unmethylated group across all populations. Regarding TERT mutation, in the CA-TTF group, the proportion of TERT promoter mutation was 63.4%, higher than that in the A-TTF group (41.9%). Previous studies have reported an association between TERT promoter mutation and poor prognosis in patients with glioblastoma 25 . Nevertheless, despite the poorer prognosis in the concurrent treatment group, they achieved survival rates comparable to those of the A-TTF group. This observation suggests that, although TERT promoter mutations were more prevalent in the CA-TTF group, other factors, including the concurrent use of TTFields, may have had a positive impact on patient survival. This suggests a potential improved survival outcome for TERT mutation patients treating with CA-TTF, which requires larger patient cohorts and a longer clinical practice period to be conclusively demonstrated. The ongoing phase 3 randomized clinical trial EF-32 aims to investigate the clinical benefits of combining TTFields with CRT and may provide definitive answers 26 . The residual lesions in patients may affect the degree of benefit from the concurrent use of TTFields. In Figure S1 A, the use of CA-TTF, compared to the A-TTF group, appears to improve PFS in the STR/Biopsy subgroup (median PFS of 13 months vs. 8.5 months). In the GTR subgroup, the median PFS with the use of CA-TTF and A-TTF is similar. A similar trend is observed in median OS. The P-values between the two groups in the figure are not suitable for comparison due to the limited number of samples. However, observed trends in both PFS and OS suggest that CA-TTF may aid in controlling disease recurrence and impacting patient survival outcomes in the presence of residual lesions. Further validation with a larger sample size is needed. In CA-TTF group, surgery extension significantly improved PFS in multivariate analyses, while the duration of TTFields treatment was associated with better survival outcomes in both univariate and multivariate analyses. Previous studies have shown that longer usage durations of TTFields are associated with higher survival rates 27,28 . The post hoc analysis of the EF-11 trial data demonstrated that recurrent glioblastoma (GBM) patients treated with TTFields and a compliance rate of ≥ 75% had a longer median overall survival (7.7 vs. 4.5 months; p = 0.042) compared to those with a compliance rate of < 75% 20,29 . Patients are advised to wear the device for a minimum of 18 hours per day with an adherence rate exceeding 75%. Both EF-11 and EF-14 trials demonstrated adherence rates surpassing 75%, while our data revealed a median adherence rate of 85%. The CA-TTF and A-TTF groups exhibited comparable overall survival rates, with medians of 20.8 and 20.0 months, respectively, consistent with those observed in EF-14 (20.9 months). In the CA-TTF group, 5 patients (12.2%) experienced early disease progression in less than 6 months, which negatively impacted the overall survival rate. The current findings support previous reports emphasizing the importance of surgical extension and TTFields utilization for GBM patients’ prognosis 29 . There were no significant differences in PFS or OS between the CA-TTF and A-TTF groups. There may be several reasons. This is a retrospective study, there certainly may be selection bias. Though there is no statistical difference in patient characteristics between the two groups. The proportion of TERT promoter mutation in the CA-TTF group was higher than that in the A-TTF group, so the CA-TTF group likely has worse prognosis comparing to A-TTF group, since it included patients with early progression. Data from large perspective trials indicated about 10–15% patients may have early progression or clinical decline after chemoradiation and did not proceed with further treatment. In the A-TTF group, since TTFields treatment initiated after finishing chemoradiation, patients with early progression or clinical decline were excluded. Limitation The study has several limitations, primarily due to its retrospective design, which introduces potential patient selection bias. This method was selected in response to the inconsistent and limited insurance coverage for TTFields. Additionally, the relatively small sample size of 72 patients and a median follow-up duration of 18.0 months (IQR: 12.1) may affect the robustness of the results, particularly as the survival data for patients still alive at the last follow-up are yet to be fully updated. Conclusion This study presents the first real-world analysis evaluating the survival benefits of concurrent versus adjuvant TTFields treatment combined with chemoradiotherapy in newly diagnosed GBM patients. Our findings confirm the safety of administering TTFields concurrently with chemoradiotherapy in Chinese patients and show no significant differences in survival outcomes between those receiving combined TTFields and those undergoing adjuvant TTFields therapy alone (CA-TTF and A-TTF groups). The results suggest that patients with a greater burden of residual disease may benefit more from concurrent therapy, though further research is needed to validate these observations. In summary, this study not only shares valuable clinical experiences with synchronous electric field therapy but also provides practical guidance for medical professionals worldwide. The potential benefits of combining TTFields with chemoradiation are being further explored in the ongoing phase 3 trial (TRIDENT, NCT04471844), which is expected to provide more definitive answers. Declarations Data Availability Statement: The datasets utilized in this study can be obtained from the corresponding author upon a reasonable request. Author Contributions: Liping Liang and Lingchao Chen collected the datas, analysed the datas and wrote the main manuscript text. Chunxia Ni, Shu Chen, Zhirui Zhou, Wenjia Zhu and Jiabing Liu collected the datas. Xianxin Qiu and Wanzun Lin prepared the Figs and tables. Wenyin Shi and Junyan Zhang reviewed and edited the manuscript. Zhiyong Qin and Yang Wang supervised the study. All authors reviewed and agreed to publish the manuscript. Funding: Beijing Xisike Clinical Oncology Research Foundation Y-zai2021/qn-0204 and Y-zai2021/zd-0207. Institutional Review Board Statement: This study was performed in line with the principles of the declaration of Helsinki. Approval was granted by the Ethics Committee of Huashan Hospital, Fudan University Shanghai, China 200040 (Approval N0. KY2023-1007). Inform Consent Statement: Informed consent was obtained from all individual participants included in the study. The authors affirm that human research participants provided informed consent for publication of the clinical data. Conflicts of Interest: The authors have no relevant financial or non-financial interests to disclose. References Horbinski C, Nabors LB, Portnow J, et al. NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022: Featured Updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2023;21(1):12–20. Fonkem E, Wong ET. NovoTTF-100A: a new treatment modality for recurrent glioblastoma. Expert Rev Neurother. 2012;12(8):895–9. Stupp R, Mason WP, Van Den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–66. Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;318(23):2306–16. Stupp R, Taillibert S, Kanner AA, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. 2015;314(23):2535–43. Chen C, Xu H, Song K, et al. Tumor Treating Fields Combine with Temozolomide for Newly Diagnosed Glioblastoma: A Retrospective Analysis of Chinese Patients in a Single Center. J Clin Med. 2022;11(19):5855. Rominiyi O, Vanderlinden A, Clenton SJ, Bridgewater C, Al-Tamimi Y, Collis SJ. Tumour treating fields therapy for glioblastoma: Current advances and future directions. Br J Cancer. 2021;124(4):697–709. Karanam NK, Srinivasan K, Ding L, Sishc B, Saha D, Story MD. Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines. Cell Death Dis. 2017;8(3):e2711–2711. Giladi M, Munster M, Schneiderman RS, et al. Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells. Radiat Oncol. 2017;12(1):1–13. Gutin PH, Wong ET. Noninvasive application of alternating electric fields in glioblastoma: a fourth cancer treatment modality. Am Soc Clin Oncol Educational Book. 2012;32(1):126–31. Hong P, Kudulaiti N, Wu S, Nie J, Zhuang D. Tumor treating fields: a comprehensive overview of the underlying molecular mechanism. Expert Rev Mol Diagn. 2022;22(1):19–28. Li T, Shukla G, Peng C, Lockamy V, Liu H, Shi W. Dosimetric impact of a tumor treating fields device for glioblastoma patients undergoing simultaneous radiation therapy. Front Oncol. 2018;8:51. Miller R, Song A, Ali A, et al. Scalp-Sparing Radiation With Concurrent Temozolomide and Tumor Treating Fields (SPARE) for Patients With Newly Diagnosed Glioblastoma. Front Oncol. 2022;12:896246. Song A, Bar-Ad V, Martinez N, et al. Initial experience with scalp sparing radiation with concurrent temozolomide and tumor treatment fields (SPARE) for patients with newly diagnosed glioblastoma. J Neurooncol. 2020;147:653–61. Bokstein F, Blumenthal D, Limon D, Harosh CB, Ram Z, Grossman R. Concurrent tumor treating fields (TTFields) and radiation therapy for newly diagnosed glioblastoma: a prospective safety and feasibility study. Front Oncol. 2020;10:411. Shi W, Kleinberg L, Jeyapalan SA, et al. Abstract CT061: TRIDENT phase 3 study (EF-32): First-line Tumor Treating Fields (TTFields; 200 kHz) therapy concomitant with chemo-radiation, followed by maintenance TTFields/temozolomide in newly diagnosed glioblastoma. Cancer Res. 2023;83(8Supplement):CT061–061. Brown TJ, Brennan MC, Li M, et al. Association of the extent of resection with survival in glioblastoma: a systematic review and meta-analysis. JAMA Oncol. 2016;2(11):1460–9. Shah S. Common terminology criteria for adverse events. 2022. Kanner AA, Wong ET, Villano JL, Ram Z, investigators E-. Post hoc analyses of intention-to-treat population in phase III comparison of NovoTTF-100A™ system versus best physician’s choice chemotherapy. Paper presented at: Seminars in oncology2014. Guberina N, Pöttgen C, Kebir S, et al. Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial. Radiat Oncol. 2020;15:1–11. Lei H, Yang W, Chunxia N, Xiaoyang H, Hongwei L, Dongxiao Z. Effects of Tumor Treating Fields (TTF) Arrays on Radiation Dose of Glioblastoma was Verified by the Compass. China Med Device Inform. 2021;27(9):3. Ali AS, Lombardo J, Niazi MZ, et al. Concurrent chemoradiation and Tumor Treating Fields (TTFields, 200 kHz) for patients with newly diagnosed glioblastoma: patterns of progression in a single institution pilot study. J Neurooncol. 2022;160(2):345–50. Wick W, Weller M, Van Den Bent M, et al. MGMT testing—the challenges for biomarker-based glioma treatment. Nat Reviews Neurol. 2014;10(7):372–85. Olympios N, Gilard V, Marguet F, Clatot F, Di Fiore F, Fontanilles M. TERT promoter alterations in glioblastoma: a systematic review. Cancers. 2021;13(5):1147. Shi W, Kleinberg L, Jeyapalan SA, et al. Phase III TRIDENT trial: Radiation and temozolomide+/-tumor treating fields in newly diagnosed glioblastoma. In: American Society of Clinical Oncology; 2020. Ballo MT, Urman N, Lavy-Shahaf G, Grewal J, Bomzon Ze, Toms S. Correlation of tumor treating fields dosimetry to survival outcomes in newly diagnosed glioblastoma: a large-scale numerical simulation-based analysis of data from the phase 3 EF-14 randomized trial. Int J Radiation Oncology* Biology* Phys. 2019;104(5):1106–13. Toms S, Kim C, Nicholas G, Ram Z. Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial. J Neurooncol. 2019;141:467–73. Mrugala MM, Engelhard HH, Tran DD et al. Clinical practice experience with NovoTTF-100A™ system for glioblastoma: the Patient Registry Dataset (PRiDe). Paper presented at: Seminars in oncology2014. 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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-4350426","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":297530667,"identity":"c4b02940-12c7-4789-801b-7c89e0f69291","order_by":0,"name":"Liping Liang","email":"","orcid":"","institution":"Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Liping","middleName":"","lastName":"Liang","suffix":""},{"id":297530668,"identity":"be515248-7048-43a9-bb3e-7e52952f6db6","order_by":1,"name":"Lingchao Chen","email":"","orcid":"","institution":"Fudan 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University","correspondingAuthor":true,"prefix":"","firstName":"Yang","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-04-30 16:21:56","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4350426/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4350426/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56102239,"identity":"612b7094-07cb-4d33-aeb4-cf7abe3c21d5","added_by":"auto","created_at":"2024-05-08 14:52:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":69745,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of Progression-Free Survival (A) and Overall Survival (B) between CA-TTF and A-TTF Groups. CA-TTF: concurrent and adjuvant TTFields group; A-TTF: adjuvant TTFields with temozolomide.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4350426/v1/ce4359730c30f0233ee1edef.png"},{"id":56102238,"identity":"7965cdfe-22e0-4f9f-8a1d-039685ea2787","added_by":"auto","created_at":"2024-05-08 14:52:11","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":205628,"visible":true,"origin":"","legend":"\u003cp\u003eImpact of \u003cem\u003eMGMT\u003c/em\u003e Promoter Methylation (A, B), \u003cem\u003eTERT\u003c/em\u003e Status (C, D) and \u003cem\u003eTERT\u003c/em\u003e Mutation (E, F) on Progression-Free Survival and Overall Survival.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4350426/v1/9e5c7ca9d70ea51abc48732e.png"},{"id":57676197,"identity":"e29a90ca-3e43-4b04-93c8-c7ef84b1e157","added_by":"auto","created_at":"2024-06-04 07:46:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1009520,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4350426/v1/08ee25b4-9055-44b5-b9fa-7be51b3673bb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Experience about Chemoradiation treatment with or without Concurrent Tumor-Treating Fields (TTFields) in Newly Diagnosed Glioblastoma (GBM) Patients in China","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGBM, characterized by its extensive invasiveness and dismal prognosis, is the most prevalent primary malignant brain tumor in adults\u003csup\u003e1\u003c/sup\u003e. TTFields treatment is a novel anti-mitotic therapeutic modality that utilizes low-intensity, intermediate-frequency electric fields to inhibit cell proliferation and disrupt cancer cell replication \u003csup\u003e2\u003c/sup\u003e. It is approved for patients with newly diagnosed and recurrent GBM \u003csup\u003e3\u0026ndash;7\u003c/sup\u003e. The EF-14 clinical trial demonstrated that adding TTFields to maintenance temozolomide chemotherapy after radiotherapy significantly improved the PFS and OS in patients with ndGBM. Consequentlyu, TTFields plus temozolomide was recommended as the first-line standard adjuvant therapy for ndGBM after completing radiotherapy \u003csup\u003e5,6\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMany basic studies have investigated the mechanisms of TTFields treatment. Besides anti-mitotic effect, TTFields has also been found to have other mechanisms of action, such as increased cell permeability, activation autophagy, stimulation of immune response, and inhibition DNA damage repair\u003csup\u003e8\u003c/sup\u003e. Preclinical studies indicate that the combination of TTFields and irradiation has a synergistic anti-glioma effect via inhibition of the repair of radiation- induced DNA damage. When glioma cells treated with TTFields after RT, more than 40% of the initial DNA damage remained unrepaired when TTFields were subsequently applied. as assessed by comet assy. After TTFields treatment, the BRCA1 DNA-damage response was significantly down-regulated and DNA double-strand break (DSB) repair was reduced. These results provided a strong rationale for the application of the combination of concurrent TTFields with chemoradiation therapy\u003csup\u003e9\u0026ndash;13\u003c/sup\u003e. Based on these findings, early clinical trials were conducted to evaluate the safety and feasibility of this combination. The SPARE trial was the first study reporting the feasibility of concurrent TTFields with chemoradiation in patients with ndGBM. The skin toxicities were common; however they were mild and well tolerated, with 83.3% of patients experiencing grade 1 or 2 skin adverse events. The median PFS and OS were 9.3 months and 15.8 months, respectively, which compares favorably to historical benchmark \u003csup\u003e14,15\u003c/sup\u003e. Bokstain et al also conducted a phase 1/phase 2 and reported the safety and feasibility concurrent TTFields and radiotherapy of 10 patients in the phase 1 portion. The findings are similar, most patients (80%) experienced mild to moderate skin toxicities (grade 1\u0026ndash;2) caused by TTFields. There was no grade 3 or higher toxicities and the combination is considered well tolerated. The median PFS was 8.9 months, but the median OS was not yet reached \u003csup\u003e16\u003c/sup\u003e. Based on these two early phase trials, an international phase 3 randomized trial (EF-32, NCT04471844) is currently enrolling, comparing concurrent TTFields vs maintenance TTFields only\u003csup\u003e17\u003c/sup\u003e, but the results are yet to be reported.\u003c/p\u003e \u003cp\u003eIn this retrospective study, we aimed to determine the clinical benefits between concurrent and adjuvant TTFields with chemoradiotherapy (CA-TTF group) or adjuvant TTFields after chemoradiotherapy only (A-TTF group) in our real clinical practice. We reviewed a cohort of ndGBM patients treated at Huashan Hospital, China between 2020 and 2021. These patients underwent concurrent and adjuvant TTFields with chemoradiotherapy (CA-TTF group) or adjuvant TTFields after chemoradiotherapy only (A-TTF group). We presented and shared our primary experiences about these two regimens.\u003c/p\u003e"},{"header":"Methods and materials","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis retrospective study included ndGBM patients who received radiotherapy and underwent TTFields treatment in Huashan Hospital, Fudan University, China, from Jan 2020 to Dec 2021. All the patients included would match this criterias: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) age\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;18 year with newly diagnosed \u003cem\u003eIDH1/2\u003c/em\u003e wild type GBM; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) TTFields treatment more than four weeks; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) completed the standard Stupp regimen chemoradiotherapy. Participants were administered temozolomide concurrently with radiotherapy at a dose of 75 mg/m^2 daily for 6 weeks. Following the concurrent phase, during the adjuvant phase, temozolomide was given at a dose of 150\u0026ndash;200 mg/m^2 for the first 5 days of each 28-day cycle, for a total of 6 cycles. This study was approved by the Ethics Committee of Huashan Hospital, Fudan University (Approval N0. KY2023-1007).\u003c/p\u003e \u003cp\u003eThe baseline characteristics, such as age, sex, Karnofsky performance status score (KPS), the extent of resection, \u003cem\u003eMGMT\u003c/em\u003e promoter methylation status, \u003cem\u003eTERT\u003c/em\u003e promoter methylation status, TTFields usage, adverse events, grade evaluation, PFS, and OS, were collected. The extent of resection was classified as gross tumor resection (GTR), subtotal resection (STR) and biopsy \u003csup\u003e18\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eRadiation Therapy\u003c/h2\u003e \u003cp\u003eAll patients were immobilized in a supine position using a thermoplastic mask. For the CA-TTF group, a customized 5 mm thickness latex-free open-cell styrene butadiene rubber foam was fitted under the mask to accommodate the TTFields transducer arrays. Treatment planning computed tomography (CT) scans were performed for all patients without TTFields arrays and fused with post-operative magnetic resonance imaging (MRI). The target volumes were contoured according to the Radiation Therapy Oncology Group (RTOG) guidelines. The radiation prescription was 60 Gy in 30 fractions for all patients. For CA-TTF group, scalp that was defined as a 5-mm thickness area from the skin surface above the level of the foramen magnum which the SPARE trial\u003csup\u003e14\u003c/sup\u003e was also contoured and defined as organ at risk (OAR) in radiation planning. The sclap constraints were also adopted from SPARE trial14, that were: mean\u0026thinsp;\u0026lt;\u0026thinsp;20Gy, D20cc\u0026thinsp;\u0026lt;\u0026thinsp;50Gy, D30cc\u0026thinsp;\u0026lt;\u0026thinsp;40Gy; All patients\u0026rsquo; radiotherapy plans were done with eclipse v15.5 (Varian, Palo Alto, CA). All patients were treated with Truebeam (Varian, Palo Alto, CA) by weekly CBCT verification.\u003c/p\u003e \u003cp\u003eIn the initial phase of our study, TTFields arrays were removed daily for the first five patients to closely monitor skin conditions and ensure safety. However, after observing no significant adverse skin effects and consulting findings from the SPARE study, we adjusted our protocol. For subsequent patients, arrays were not removed daily during the radiation therapy period, facilitating a more continuous application of TTFields therapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eTumor Treating Fields Treatment\u003c/h2\u003e \u003cp\u003eFor CA-TTF group, TTFields treatment started at the beginning of radiotherapy (within 1 week), and for A-TTF group, started (4\u0026ndash;7 week) after completing radiotherapy. The follow-up began on the first day after surgery in both groups. The array placement was shifted between two alternate sites at every array change. Monthly device logs and average daily use (ADU) were obtained for all patients. The scalp reaction was inspected by the physician and/or patient/care giver during transducer array changes\u003csup\u003e14\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eToxicity\u003c/h2\u003e \u003cp\u003eThe Common Terminology Criteria for Adverse Events (CTCAE) 5.0 was used to grade the scalp toxicity\u003csup\u003e19\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were analyzed using Student\u0026rsquo;s t-test or Wilcoxon rank-sum test. Categorical variables at baseline were analyzed by chi-squared or Fisher\u0026rsquo;s exact test. The propensity data set generated the inverse probability of treatment weighting (IPTW) dataset, which balanced all observable characteristics for the patients in the CA-TTF group to compare to the A-TTF group.\u003c/p\u003e \u003cp\u003eThe Kaplan-Meier method and multivariate Cox regression model were implemented for survival analysis. The IPTW dataset was analyzed with Cox regression model for sensitivity analysis. The results were expressed as adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs). The R software version 4.2.0 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://cran.rproject.org\u003c/span\u003e\u003cspan address=\"http://cran.rproject.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, accessed on 1st May 2022, was used for statistical analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy Population\u003c/h2\u003e\n\u003cp\u003eA total of 72 patients were included in this retrospective study; 41 received concurrent and adjuvant TTFields in combination with chemoradiotherapy (CA-TTF group), and 31 received adjuvant TTFields after chemoradiotherapy (A-TTF group). All patients had GBM, were \u003cem\u003eIDH\u003c/em\u003e wild type, and were classified as WHO grade 4. The patient characteristics were well balanced between the two groups (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). In the CA-TTF group, 31.7% of patients underwent STR or biopsy, versus 25.8% in the A-TTF group. The \u003cem\u003eTERT\u003c/em\u003e promoter mutation rate was 63.4% in the CA-TTF group versus 41.9% in the A-TTF group. The \u003cem\u003eMGMT\u003c/em\u003e promoter methylation rate was 36.6% in the CA-TTF group versus 32.3% in the A-TTF group (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePatient characteristics.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eTTFields\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eP-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCA-TTF (N\u0026thinsp;=\u0026thinsp;41)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eA-TTF (N\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSex\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e13 (31.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e13 (41.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.518\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e28 (68.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e18 (58.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge\u0026nbsp;(years)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedian [Min, Max]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e53.0 [22.0, 76.0]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e48.0 [19.0, 74.0]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.615\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eExtent of resection\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGTR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e28 (68.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23 (74.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.777\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSTR/Biopsy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e13 (31.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e8 (25.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMGMT promoter methylation\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMethylated\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15 (36.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10 (32.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.907\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnmethylated\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e24 (58.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e19 (61.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eunknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2 (4.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2 (6.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTERT promoter mutation status\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWild-type\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12 (29.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e14 (45.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.192\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMutation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e26 (63.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e13 (41.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eunknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3 (7.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4 (12.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline KPS\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedian [Min, Max]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e90.0 [60.0, 90.0]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e80.0 [60.0, 90.0]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.443\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ecompliance with TTFields\u0026nbsp;(hours)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedian [Min, Max]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e21.1 [8.88, 23.0]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e21.6 [15.8, 23.3]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.491\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDuration of TTFields(months)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedian [Min, Max]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10.0 [1.00, 31.0]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10.4 [1.00, 35.0]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.203\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eTemozolomide intake\u003c/h2\u003e\n\u003cp\u003eAll patients included in this study underwent the standard treatment protocol, which consists of a Concomitant Phase and an Adjuvant Phase. During the radiation therapy of the Concomitant Phase, patients took Temozolomide orally every day; this phase typically lasted six weeks. In the Adjuvant Phase, therapy generally involved cycles of Temozolomide administered for 5 consecutive days followed by a 23-day rest period, with each cycle spanning 28 days.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eTTFields Treatment Compliance and Duration\u003c/h2\u003e\n\u003cp\u003eIn the CA-TTF group, the initial five patients had TTField arrays removed daily with radiation delivery, the rest kept the TTFields arrays on during radiation treatment. Scalp sparing radiation treatment was administered to thirty-five (83.3%). Regarding TTFields compliance, both groups achieved more than 75% (18 hours every day)\u003csup\u003e20\u003c/sup\u003e. The median compliance is 21.1 hours a day for the CA-TTF group, and 21.6 hours for the A-TTF group. The median durations of TTFields treatment were similar, 10.0 and 10.4 months in CA-TTF and A-TTF group, respectively (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eToxicity\u003c/h2\u003e\n\u003cp\u003eSkin adverse events (Skin AEs) were assessed in this study. These events included dermatitis, pruritus, electric sensation, and skin burning sensation. Dermatitis, which included scalp irritation, dry skin, folliculitis, erythema, color change, or rash, was similar in both groups, with Grade 1 AEs occurring in 21.95% of CA-TTF group patients and 25.81% of A-TTF group patients. Grade 2 AEs were seen in 34.15% of CA-TTF group patients and 32.26% of A-TTF group patients. Grade 3 skin AEs were rare, occurring only in 2.44% of CA-TTF group patients and 3.23% of A-TTF group patients. Pruritus, another skin-related adverse event, was noted in both groups as well. Grade 1 AEs were observed in 9.76% of CA-TTF group patients and 9.68% of A-TTF group patients. Grade 2 AEs were less frequent, affecting 4.88% of CA-TTF group patients and 3.22% of A-TTF group patients. Electric sensation occurred in 2.44% of CA-TTF group patients. Skin burning sensation, another infrequent event, was reported in both groups, with Grade 1 AEs documented in 2.44% of CA-TTF group patients and 3.22% of A-TTF group patients (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eOther toxicities like electric sensation were recorded by one patient (2.44%) in the CA-TTF group, and skin burning sensation was found only in one patient in both groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eSurvival\u003c/h2\u003e\n\u003cp\u003eWith a median follow-up of 18.0 months, there was no significant difference in median progression-free survival (PFS) between the two groups. The PFS was 14.2 months (95% CI: 11.1\u0026ndash;20.4) in the CA-TTF group and 15.0 months (95% CI: 8.0-NA) in the A-TTF group, with a proportional hazard ratio (HR) of 0.97 (95% CI: 0.55\u0026ndash;1.70, p\u0026thinsp;=\u0026thinsp;0.92) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Similarly, there was no significant difference in overall survival (OS) between the groups, with 20.8 months (95% CI: 17.8-NA) in the CA-TTF group versus 20.0 months (95% CI: 17.0-NA) in the A-TTF group, HR of 0.97 (95% CI: 0.51\u0026ndash;1.80, p\u0026thinsp;=\u0026thinsp;0.92) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). In the CA-TTF group, the 1-year PFS and OS rates were 61.0% (95% CI: 47.7\u0026ndash;77.9%) and 82.9% (95% CI: 72.2\u0026ndash;95.3%), respectively. Conversely, the A-TTF group demonstrated a 1-year PFS rate of 51.6% (95% CI: 36.7\u0026ndash;72.6%) and a 1-year OS rate of 80.6% (95% CI: 67.9\u0026ndash;95.8%) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). After conducting inverse probability treatment weighting (IPTW) to balance the baseline between the CA-TTF and A-TTF groups, there remained no significant differences in PFS and OS. However, the adjusted hazard ratio (HR) for PFS decreased from 0.93 (95% CI: 0.53\u0026ndash;1.63, p\u0026thinsp;=\u0026thinsp;0.82) to 0.77 (95% CI: 0.44\u0026ndash;1.30, p\u0026thinsp;=\u0026thinsp;0.344), and the adjusted HR for OS decreased from 0.96 (95% CI: 0.52\u0026ndash;1.79, p\u0026thinsp;=\u0026thinsp;0.91) to 0.74 (95% CI: 0.40\u0026ndash;1.37, p\u0026thinsp;=\u0026thinsp;0.336) for OS.\u003c/p\u003e\n\u003cp\u003eFor subgroup analysis, age, sex, extent of resection, \u003cem\u003eMGMT\u003c/em\u003e promotor methylation status, \u003cem\u003eTERT\u003c/em\u003e promotor mutation status, baseline KPS and duration of TTFields usage were evaluated. There was almost no difference in PFS or OS between CA-TTF and A-TTF (Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e, S2). The median PFS values were 8.5 months (95% CI: 5.3-NA) for the A-TTF plus STR/Biopsy group, 13.0 months (95% CI: 4.9-NA) for the CA-TTF plus STR/Biopsy group, 16.0 months (95% CI: 9.0-NA) for the A-TTF plus GTR group, and 17.1 months (95% CI: 11.1-NA) for the CA-TTF plus GTR group (p\u0026thinsp;=\u0026thinsp;0.052) (Figure \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003eA). The corresponding median OS values were 13.6 months (95% CI: 10.0-NA), 17.9 months (95% CI: 14.9-NA), 26.3 months (95% CI: 17.0-NA), and NA (95% CI: 17.0-NA), respectively (p\u0026thinsp;=\u0026thinsp;0.043) (Figure \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003eB).\u003c/p\u003e\n\u003cp\u003eIn the entire cohort, MGMT promotor methylation status is associated with PFS and OS. The median PFS for the \u003cem\u003eMGMT\u003c/em\u003e promoter methylated group was indeterminate (95% CI: 14.2-NA), while for the \u003cem\u003eMGMT\u003c/em\u003e promoter unmethylated group, it was 10 months (95% CI: 7.5\u0026ndash;17.9) (p\u0026thinsp;=\u0026thinsp;0.0042) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA). The median OS was indeterminate in the \u003cem\u003eMGMT\u003c/em\u003e methylated group (95% CI: 18.0-NA), whereas it was 17.8 months (95% CI: 14.9\u0026ndash;30) in the unmethylated group (p\u0026thinsp;=\u0026thinsp;0.039) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e\n\u003cp\u003eIn the entire cohort, the median PFS for the \u003cem\u003eTERT\u003c/em\u003e mutation group was 10.5 months (95% CI: 8.0-17.2), while for the \u003cem\u003eTERT\u003c/em\u003e wild-type group, it was 20.0 months (95% CI: 12.8-NA) (p\u0026thinsp;=\u0026thinsp;0.036) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC). The median OS for the \u003cem\u003eTERT\u003c/em\u003e mutation group was 17.9 months (95% CI: 14.9-NA), whereas it was 30.0 months (95% CI: 18.0-NA) for the wild-type group (p\u0026thinsp;=\u0026thinsp;0.095) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eD). On the other hand, in patients with \u003cem\u003eTERT\u003c/em\u003e mutations, there was no difference in PFS or OS between CA-TTF and A-TTF. The median PFS for the CA-TTF group was 11.9 months (95% CI: 8.9\u0026ndash;20.4), and for the A-TTF group, it was 7.5 months (95% CI: 6.0-NA) (p\u0026thinsp;=\u0026thinsp;0.85) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eE). The median OS for the CA-TTF group was 18.1 months (95% CI: 14.6-NA), whereas for the A-TTF group, it was 17.0 months (95% CI: 14.6-NA) (p\u0026thinsp;=\u0026thinsp;0.48) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eF).\u003c/p\u003e\n\u003cp\u003eUnivariate and multivariate analysis were performed in the CA-TTF group to evaluate the impact of age, sex, extent of surgery, \u003cem\u003eMGMT\u003c/em\u003e promoter methylation status, \u003cem\u003eTERT\u003c/em\u003e promotor methylation status, baseline KPS, patient compliance with TTFields and duration of TTFields. In Cox regression analyses, four patients were excluded from the analysis due to missing molecular status data. Univariate analysis revealed that the duration of TTFields had a significant impact on OS (HR\u0026thinsp;=\u0026thinsp;0.93, 95% CI: 0.87\u0026ndash;0.99, p\u0026thinsp;=\u0026thinsp;0.019), this effect remained significant in multivariate analysis (HR\u0026thinsp;=\u0026thinsp;0.89, 95% CI: 0.81\u0026ndash;0.98, p\u0026thinsp;=\u0026thinsp;0.013). STR/Biopsy was associated with shorter PFS compared to GTR in multivariate analyses (HR\u0026thinsp;=\u0026thinsp;5.28, 95% CI: 1.47\u0026ndash;18.91, p\u0026thinsp;=\u0026thinsp;0.011). Multivariate Cox regression analysis also revealed a significant association between longer mean patient compliance with TTFields (hours/day) and extended progression-free survival (PFS) with a hazard ratio (HR) of 0.68 (95% CI: 0.49\u0026ndash;0.93, p\u0026thinsp;=\u0026thinsp;0.016) (Tables\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eUnivariate and multivariate analyses of progression-free survival (PFS) and overall survival (OS) in CA-TTF group patients.\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\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eUnivariate (95% CI, Crude p value)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMultivariate (95% CI, Crude p value)\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\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003en(%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOS\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedian (Min, Max)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53.0(22.0,76.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.01 (0.98\u0026ndash;1.04, p\u0026thinsp;=\u0026thinsp;0.523)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.01 (0.98\u0026ndash;1.04, p\u0026thinsp;=\u0026thinsp;0.523)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.01 (0.96\u0026ndash;1.07, p\u0026thinsp;=\u0026thinsp;0.670)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.01 (0.96\u0026ndash;1.07, p\u0026thinsp;=\u0026thinsp;0.670)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (29.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26 (70.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.29 (1.22\u0026ndash;8.88, p\u0026thinsp;=\u0026thinsp;\u003cstrong\u003e0.019\u003c/strong\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.29 (1.22\u0026ndash;8.88, p\u0026thinsp;=\u0026thinsp;\u003cstrong\u003e0.019\u003c/strong\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.63 (1.18\u0026ndash;11.18, p\u0026thinsp;=\u0026thinsp;0.025)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.63 (1.18\u0026ndash;11.18, p\u0026thinsp;=\u0026thinsp;0.025)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eExtent of resection\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGTR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26 (70.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSTR/Biopsy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (29.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.13 (0.92\u0026ndash;4.89, p\u0026thinsp;=\u0026thinsp;0.076)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.13 (0.92\u0026ndash;4.89, p\u0026thinsp;=\u0026thinsp;0.076)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.28 (1.47\u0026ndash;18.91, p\u0026thinsp;=\u0026thinsp;0.011)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.28 (1.47\u0026ndash;18.91, p\u0026thinsp;=\u0026thinsp;0.011)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMGMT promoter region methylation\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emethylated\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (40.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eunmethylated\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (59.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.77 (0.76\u0026ndash;4.12, p\u0026thinsp;=\u0026thinsp;0.183)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.77 (0.76\u0026ndash;4.12, p\u0026thinsp;=\u0026thinsp;0.183)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.34 (0.79\u0026ndash;6.95, p\u0026thinsp;=\u0026thinsp;0.125)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.34 (0.79\u0026ndash;6.95, p\u0026thinsp;=\u0026thinsp;0.125)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTERT promoter mutation status\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emutation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25 (67.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ewild-type\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (32.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.51 (0.20\u0026ndash;1.28, p\u0026thinsp;=\u0026thinsp;0.152)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.51 (0.20\u0026ndash;1.28, p\u0026thinsp;=\u0026thinsp;0.152)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.32 (0.08\u0026ndash;1.26, p\u0026thinsp;=\u0026thinsp;0.104)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.32 (0.08\u0026ndash;1.26, p\u0026thinsp;=\u0026thinsp;0.104)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline KPS\u0026thinsp;\u0026ge;\u0026thinsp;90\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNO\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (29.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eYES\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26 (70.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.64 (0.28\u0026ndash;1.44, p\u0026thinsp;=\u0026thinsp;0.280)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.64 (0.28\u0026ndash;1.44, p\u0026thinsp;=\u0026thinsp;0.280)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.29 (0.41-4.00, p\u0026thinsp;=\u0026thinsp;0.665)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.29 (0.41-4.00, p\u0026thinsp;=\u0026thinsp;0.665)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient compliance with TTF\u0026nbsp;(hours)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedian (Min, Max)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.12(16.8,23.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.82 (0.61\u0026ndash;1.10, p\u0026thinsp;=\u0026thinsp;0.191)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.82 (0.61\u0026ndash;1.10, p\u0026thinsp;=\u0026thinsp;0.191)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.68 (0.49\u0026ndash;0.93, p\u0026thinsp;=\u0026thinsp;\u003cstrong\u003e0.016\u003c/strong\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.68 (0.49\u0026ndash;0.93, p\u0026thinsp;=\u0026thinsp;\u003cstrong\u003e0.016\u003c/strong\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDuration of TTF(months)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedian (Min, Max)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.0(1.0,31.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97 (0.93\u0026ndash;1.02, p\u0026thinsp;=\u0026thinsp;0.260)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97 (0.93\u0026ndash;1.02, p\u0026thinsp;=\u0026thinsp;0.260)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.94 (0.86\u0026ndash;1.03, p\u0026thinsp;=\u0026thinsp;0.203)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.94 (0.86\u0026ndash;1.03, p\u0026thinsp;=\u0026thinsp;0.203)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eTTFields-Related Adverse Events\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\"\u003e\n\u003cp\u003eCA-TTF (N\u0026thinsp;=\u0026thinsp;41)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eA-TTF (N\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSkin AEs, n (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDermatitis*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade 1 AEs, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9(21.95%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e8(25.81%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade 2 AEs, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e14(34.15%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9(32.26%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade 3 AEs, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1(2.44%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1(3.23%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePruritus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade 1 AEs, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4(9.76%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3(9.68%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade 2 AEs, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2(4.88%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1(3.22%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eElectric sensation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade 1 AEs, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1(2.44%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eskin burning sensation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade 1 AEs, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1(2.44%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1(3.22%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\"\u003e*Dermatitis included scalp irritation, dry skin, folliculitis, erythema, color change, or rash.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePFS and OS analysis after inverse probability treatment weighting (IPTW).\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003ePFS\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eTTFields concurrent\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eHR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e Value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e95% CI\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLower\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUpper\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.77\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.344\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eOS\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eTTFields concurrent\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eHR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e Value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e95% CI\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLower\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUpper\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.74\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.336\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.37\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first retrospective study to compare the clinical benefit of chemoradiation therapy with or without concurrent TTFields in patients with ndGBM in China. Our experience confirmed the feasibility and safety of concurrent TTFields and chemoradiation in Chinese patient population. Both CA-TTF and A-TTF groups exhibited similar low grade skin toxicities. There were no significant differences in PFS or OS between the CA-TTF and A-TTF groups, but our data confirmed the PFS and OS benefit with TTFields. The PFS\u0026thinsp;~\u0026thinsp;14m and OS\u0026thinsp;~\u0026thinsp;20 m compared, similar or to EF-14 and favorable to historical benchmark with TTFields, confirming the benefit in Chinese patient population.\u003c/p\u003e \u003cp\u003eAlthough preclinical studies showed a synergistic effect between TTFields and radiation, many clinicians also concern about the dosimetric consequences of applying TTFields treatment during radiation. Guberina et al. reported their dosimetry study; they found that the dose distribution within the clinical target volume (CTV) is below 2% and therefore not clinically relevant\u003csup\u003e21\u003c/sup\u003e. In our previous dosimetry study\u003csup\u003e22\u003c/sup\u003e, we detected the dosimetric distribution when wearing the TTFields arrays and the 5 mm thickness latex-free open-cell styrene butadiene rubber foam that fitted the mask. We found that the dose distribution for the CTV variated below 1%, which was not clinical significant; however, the scalp dose was elevated as Guberina reported. Therefore, when applying the TTFields during radiation, we strongly suggest to contouring the scalp and defining it as OAR in radiation planning, using the constraints recommended by SPARE trial. Several clinical trials also have investigated the safety and efficacy of the concurrent TTFields therapy. Such combination appeared to be feasible and well tolerated. Scalp toxicity is still common, about 80%, but mild (grade 1 or grade 2) \u003csup\u003e16 14\u003c/sup\u003e. In the current study of 72 patients, 41 received concurrent TTFields with CRT (CA-TTF group), and 31 received adjuvant TTFields with TMZ after CRT (A-TTF group). We also observed common but mild scalp irritation, about 55\u0026ndash;60%. Dermatitis, including scalp irritation, dry skin, folliculitis, erythema, color change, or rash, was the most common cutaneous adverse event. Pruritus was the second most frequently reported skin adverse event, while electric sensation and skin burning sensation were rare. There was no significant difference in skin toxicity between the CA-TTF and A-TTF groups. One patient (2.4%) in the CA-TTF group experienced grade 3 skin toxicity, as this patient did not apply the scalp-preserving procedure and the transducer arrays were not removed during radiation treatment. The radiation plan was suspended but the skin reaction was improved in three days by using topical corticosteroids ointment. Other patients who suffered scalp toxicity did not interrupt their radiation plan but just suspend TTFields treatment for about three days, and their skin reaction also recovered by using topical corticosteroids ointment and then restarted the TTFields treatment. Our result confirmed that concurrent use of TTFields and CRT is safe and well-tolerated for patients with newly diagnosed GBM.\u003c/p\u003e \u003cp\u003ePreclinical studies have indicated the synergistic effects between TTFields and irradiation\u003csup\u003e10\u003c/sup\u003e, which provide the scientific rationale for concurrent use of TTFields with CRT. DNA damage, particularly double-strand DNA damage is the main mechanism of action of radiation treatment. TTFields can inhibit DNA damage repair and promote cell death, potentially increasing the efficacy of RT. In conditions where TTFields were used after irradiation, chromatid aberrations increased, and the DNA repair capacity declined, enhancing the sensitivity to irradiation. However, there is a critical temporal relationship of TTFields and RT. The radiation sensitization effect is maximized when TTFields initiated soon after radiation treatment\u003csup\u003e10\u003c/sup\u003e. In order to minimize the interruption of TTFields treatment after radiation, we adopted the solution of irradiate through the TTFields arrays, which is first developed in the SPARE trial\u003csup\u003e14\u003c/sup\u003e. The other two separate pilot studies, which investigated the combination of TTFields with concurrent chemoradiotherapy (CRT), reported median progression-free survival (PFS) of 8.9 months and 9.3 months, respectively\u003csup\u003e16,23\u003c/sup\u003e. These results were higher than the 6.7 months observed in the EF-14 study, which TTFields were administered during the temozolomide adjuvant chemotherapy phase. This suggests that initiating TTFields treatment earlier during the CRT phase may potentially lead to improved survival outcomes compared to the temozolomide adjuvant phase. In our study, the baseline characteristics were similar between both groups, but no significant differences were found in either median OS or PFS. The PFS was 14.2 months (95% CI: 11.1\u0026ndash;20.4) in the CA-TTF group and 15.0 months (95% CI: 8.0-NA) in the A-TTF group, with a proportional hazard ratio (HR) of 0.97 (95% CI: 0.55\u0026ndash;1.70, p\u0026thinsp;=\u0026thinsp;0.92) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The PFS was 20.8 months (95% CI: 17.8-NA) in the CA-TTF group versus 20.0 months (95% CI: 17.0-NA) in the A-TTF group, HR of 0.97 (95% CI: 0.51\u0026ndash;1.80, p\u0026thinsp;=\u0026thinsp;0.92) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). After IPTW analysis, the baseline characteristics of both groups were balanced, and the survival benefits remained insignificantly different. The adjusted hazard ratio (HR) for PFS decreased from 0.93 (95% CI: 0.53\u0026ndash;1.63, p\u0026thinsp;=\u0026thinsp;0.82) to 0.77 (95% CI: 0.44\u0026ndash;1.30, p\u0026thinsp;=\u0026thinsp;0.344), and the adjusted HR for OS decreased from 0.96 (95% CI: 0.52\u0026ndash;1.79, p\u0026thinsp;=\u0026thinsp;0.91) to 0.74 (95% CI: 0.40\u0026ndash;1.37, p\u0026thinsp;=\u0026thinsp;0.336) for OS. This result showed the hazard ratios for PFS and OS in the CA-TTF group decreased, suggesting a potential advantage for those undergoing concurrent TTFields treatment. This hypothesis necessitates validation through large-scale clinical trials.\u003c/p\u003e \u003cp\u003eWhen comparing molecular markers between both groups, we observed an even distribution of the \u003cem\u003eMGMT\u003c/em\u003e promoter region status. \u003cem\u003eMGMT\u003c/em\u003e promoter methylation is typically associated with a better prognosis because it reduces tumor cell resistance to alkylating agents, such as TMZ\u003csup\u003e24\u003c/sup\u003e. In this study, a benefit in terms of PFS and OS was observed in the \u003cem\u003eMGMT\u003c/em\u003e promoter methylation group compared to the unmethylated group across all populations. Regarding \u003cem\u003eTERT\u003c/em\u003e mutation, in the CA-TTF group, the proportion of \u003cem\u003eTERT\u003c/em\u003e promoter mutation was 63.4%, higher than that in the A-TTF group (41.9%). Previous studies have reported an association between \u003cem\u003eTERT\u003c/em\u003e promoter mutation and poor prognosis in patients with glioblastoma\u003csup\u003e25\u003c/sup\u003e. Nevertheless, despite the poorer prognosis in the concurrent treatment group, they achieved survival rates comparable to those of the A-TTF group. This observation suggests that, although \u003cem\u003eTERT\u003c/em\u003e promoter mutations were more prevalent in the CA-TTF group, other factors, including the concurrent use of TTFields, may have had a positive impact on patient survival. This suggests a potential improved survival outcome for \u003cem\u003eTERT\u003c/em\u003e mutation patients treating with CA-TTF, which requires larger patient cohorts and a longer clinical practice period to be conclusively demonstrated. The ongoing phase 3 randomized clinical trial EF-32 aims to investigate the clinical benefits of combining TTFields with CRT and may provide definitive answers \u003csup\u003e26\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe residual lesions in patients may affect the degree of benefit from the concurrent use of TTFields. In Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eA, the use of CA-TTF, compared to the A-TTF group, appears to improve PFS in the STR/Biopsy subgroup (median PFS of 13 months vs. 8.5 months). In the GTR subgroup, the median PFS with the use of CA-TTF and A-TTF is similar. A similar trend is observed in median OS. The P-values between the two groups in the figure are not suitable for comparison due to the limited number of samples. However, observed trends in both PFS and OS suggest that CA-TTF may aid in controlling disease recurrence and impacting patient survival outcomes in the presence of residual lesions. Further validation with a larger sample size is needed.\u003c/p\u003e \u003cp\u003eIn CA-TTF group, surgery extension significantly improved PFS in multivariate analyses, while the duration of TTFields treatment was associated with better survival outcomes in both univariate and multivariate analyses. Previous studies have shown that longer usage durations of TTFields are associated with higher survival rates\u003csup\u003e27,28\u003c/sup\u003e. The post hoc analysis of the EF-11 trial data demonstrated that recurrent glioblastoma (GBM) patients treated with TTFields and a compliance rate of \u0026ge;\u0026thinsp;75% had a longer median overall survival (7.7 vs. 4.5 months; p\u0026thinsp;=\u0026thinsp;0.042) compared to those with a compliance rate of \u0026lt;\u0026thinsp;75%\u003csup\u003e20,29\u003c/sup\u003e. Patients are advised to wear the device for a minimum of 18 hours per day with an adherence rate exceeding 75%. Both EF-11 and EF-14 trials demonstrated adherence rates surpassing 75%, while our data revealed a median adherence rate of 85%. The CA-TTF and A-TTF groups exhibited comparable overall survival rates, with medians of 20.8 and 20.0 months, respectively, consistent with those observed in EF-14 (20.9 months). In the CA-TTF group, 5 patients (12.2%) experienced early disease progression in less than 6 months, which negatively impacted the overall survival rate. The current findings support previous reports emphasizing the importance of surgical extension and TTFields utilization for GBM patients\u0026rsquo; prognosis\u003csup\u003e29\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere were no significant differences in PFS or OS between the CA-TTF and A-TTF groups. There may be several reasons. This is a retrospective study, there certainly may be selection bias. Though there is no statistical difference in patient characteristics between the two groups. The proportion of \u003cem\u003eTERT\u003c/em\u003e promoter mutation in the CA-TTF group was higher than that in the A-TTF group, so the CA-TTF group likely has worse prognosis comparing to A-TTF group, since it included patients with early progression. Data from large perspective trials indicated about 10\u0026ndash;15% patients may have early progression or clinical decline after chemoradiation and did not proceed with further treatment. In the A-TTF group, since TTFields treatment initiated after finishing chemoradiation, patients with early progression or clinical decline were excluded.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eLimitation\u003c/h2\u003e \u003cp\u003eThe study has several limitations, primarily due to its retrospective design, which introduces potential patient selection bias. This method was selected in response to the inconsistent and limited insurance coverage for TTFields. Additionally, the relatively small sample size of 72 patients and a median follow-up duration of 18.0 months (IQR: 12.1) may affect the robustness of the results, particularly as the survival data for patients still alive at the last follow-up are yet to be fully updated.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study presents the first real-world analysis evaluating the survival benefits of concurrent versus adjuvant TTFields treatment combined with chemoradiotherapy in newly diagnosed GBM patients. Our findings confirm the safety of administering TTFields concurrently with chemoradiotherapy in Chinese patients and show no significant differences in survival outcomes between those receiving combined TTFields and those undergoing adjuvant TTFields therapy alone (CA-TTF and A-TTF groups). The results suggest that patients with a greater burden of residual disease may benefit more from concurrent therapy, though further research is needed to validate these observations. In summary, this study not only shares valuable clinical experiences with synchronous electric field therapy but also provides practical guidance for medical professionals worldwide. The potential benefits of combining TTFields with chemoradiation are being further explored in the ongoing phase 3 trial (TRIDENT, NCT04471844), which is expected to provide more definitive answers.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u003c/strong\u003e The datasets utilized in this study can be obtained from the corresponding author upon a reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLiping Liang and Lingchao Chen collected the datas, analysed the datas and wrote the main manuscript text. Chunxia Ni, Shu Chen, Zhirui Zhou, Wenjia Zhu and Jiabing Liu collected the datas. Xianxin Qiu and Wanzun Lin prepared the Figs and tables. Wenyin Shi and Junyan Zhang reviewed and edited the manuscript. Zhiyong Qin and Yang Wang supervised the study. All authors reviewed and agreed to publish the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBeijing Xisike Clinical Oncology Research Foundation\u0026nbsp;Y-zai2021/qn-0204 and Y-zai2021/zd-0207.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement:\u0026nbsp;\u003c/strong\u003eThis study was performed in line with the principles of the declaration of Helsinki. Approval was granted by the Ethics Committee of Huashan Hospital, Fudan University Shanghai, China 200040 (Approval N0. KY2023-1007).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInform Consent Statement:\u003c/strong\u003e Informed consent was obtained from all individual participants included in the study. The authors affirm that human research participants provided informed consent for publication of the clinical data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHorbinski C, Nabors LB, Portnow J, et al. NCCN Guidelines\u0026reg; Insights: Central Nervous System Cancers, Version 2.2022: Featured Updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2023;21(1):12\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFonkem E, Wong ET. NovoTTF-100A: a new treatment modality for recurrent glioblastoma. Expert Rev Neurother. 2012;12(8):895\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStupp R, Mason WP, Van Den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;318(23):2306\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStupp R, Taillibert S, Kanner AA, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. 2015;314(23):2535\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen C, Xu H, Song K, et al. Tumor Treating Fields Combine with Temozolomide for Newly Diagnosed Glioblastoma: A Retrospective Analysis of Chinese Patients in a Single Center. J Clin Med. 2022;11(19):5855.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRominiyi O, Vanderlinden A, Clenton SJ, Bridgewater C, Al-Tamimi Y, Collis SJ. Tumour treating fields therapy for glioblastoma: Current advances and future directions. Br J Cancer. 2021;124(4):697\u0026ndash;709.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaranam NK, Srinivasan K, Ding L, Sishc B, Saha D, Story MD. Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines. Cell Death Dis. 2017;8(3):e2711\u0026ndash;2711.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiladi M, Munster M, Schneiderman RS, et al. Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells. Radiat Oncol. 2017;12(1):1\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGutin PH, Wong ET. Noninvasive application of alternating electric fields in glioblastoma: a fourth cancer treatment modality. Am Soc Clin Oncol Educational Book. 2012;32(1):126\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHong P, Kudulaiti N, Wu S, Nie J, Zhuang D. Tumor treating fields: a comprehensive overview of the underlying molecular mechanism. Expert Rev Mol Diagn. 2022;22(1):19\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi T, Shukla G, Peng C, Lockamy V, Liu H, Shi W. Dosimetric impact of a tumor treating fields device for glioblastoma patients undergoing simultaneous radiation therapy. Front Oncol. 2018;8:51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiller R, Song A, Ali A, et al. Scalp-Sparing Radiation With Concurrent Temozolomide and Tumor Treating Fields (SPARE) for Patients With Newly Diagnosed Glioblastoma. Front Oncol. 2022;12:896246.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSong A, Bar-Ad V, Martinez N, et al. Initial experience with scalp sparing radiation with concurrent temozolomide and tumor treatment fields (SPARE) for patients with newly diagnosed glioblastoma. J Neurooncol. 2020;147:653\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBokstein F, Blumenthal D, Limon D, Harosh CB, Ram Z, Grossman R. Concurrent tumor treating fields (TTFields) and radiation therapy for newly diagnosed glioblastoma: a prospective safety and feasibility study. Front Oncol. 2020;10:411.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShi W, Kleinberg L, Jeyapalan SA, et al. Abstract CT061: TRIDENT phase 3 study (EF-32): First-line Tumor Treating Fields (TTFields; 200 kHz) therapy concomitant with chemo-radiation, followed by maintenance TTFields/temozolomide in newly diagnosed glioblastoma. Cancer Res. 2023;83(8Supplement):CT061\u0026ndash;061.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrown TJ, Brennan MC, Li M, et al. Association of the extent of resection with survival in glioblastoma: a systematic review and meta-analysis. JAMA Oncol. 2016;2(11):1460\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShah S. Common terminology criteria for adverse events. 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanner AA, Wong ET, Villano JL, Ram Z, investigators E-. Post hoc analyses of intention-to-treat population in phase III comparison of NovoTTF-100A\u0026trade; system versus best physician\u0026rsquo;s choice chemotherapy. Paper presented at: Seminars in oncology2014.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuberina N, P\u0026ouml;ttgen C, Kebir S, et al. Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial. Radiat Oncol. 2020;15:1\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLei H, Yang W, Chunxia N, Xiaoyang H, Hongwei L, Dongxiao Z. Effects of Tumor Treating Fields (TTF) Arrays on Radiation Dose of Glioblastoma was Verified by the Compass. China Med Device Inform. 2021;27(9):3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAli AS, Lombardo J, Niazi MZ, et al. Concurrent chemoradiation and Tumor Treating Fields (TTFields, 200 kHz) for patients with newly diagnosed glioblastoma: patterns of progression in a single institution pilot study. J Neurooncol. 2022;160(2):345\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWick W, Weller M, Van Den Bent M, et al. MGMT testing\u0026mdash;the challenges for biomarker-based glioma treatment. Nat Reviews Neurol. 2014;10(7):372\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOlympios N, Gilard V, Marguet F, Clatot F, Di Fiore F, Fontanilles M. TERT promoter alterations in glioblastoma: a systematic review. Cancers. 2021;13(5):1147.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShi W, Kleinberg L, Jeyapalan SA, et al. Phase III TRIDENT trial: Radiation and temozolomide+/-tumor treating fields in newly diagnosed glioblastoma. In: American Society of Clinical Oncology; 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBallo MT, Urman N, Lavy-Shahaf G, Grewal J, Bomzon Ze, Toms S. Correlation of tumor treating fields dosimetry to survival outcomes in newly diagnosed glioblastoma: a large-scale numerical simulation-based analysis of data from the phase 3 EF-14 randomized trial. Int J Radiation Oncology* Biology* Phys. 2019;104(5):1106\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eToms S, Kim C, Nicholas G, Ram Z. Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial. J Neurooncol. 2019;141:467\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMrugala MM, Engelhard HH, Tran DD et al. Clinical practice experience with NovoTTF-100A\u0026trade; system for glioblastoma: the Patient Registry Dataset (PRiDe). Paper presented at: Seminars in oncology2014.\u003c/span\u003e\u003c/li\u003e\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":"TTFields, glioblastoma, concurrent therapy, chemoradiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-4350426/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4350426/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003eTumor-Treating Fields (TTFields) and radiotherapy may have synergistic anti-glioma effect based on preclinical study. Chemoradiation concurrent with TTFields has become a hot topic in clinicians. This study provided preliminary experience about the clinical outcomes of patients with newly diagnosed Glioblastoma (GBM) received concurrent and adjuvant TTFields with chemoradiation or adjuvant TTFields only based on a cohort of patients treated at Huashan Hospital, China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This is a retrospective study analyzing clinical outcomes for newly diagnosed GBM patients treated at Huashan Hospital who received TTFields treatment. Patients were divided into two groups: one group received TTFields adjuvantly after the completion of chemoradiation (referred to as the A-TTF group), and another group received TTFields concurrently with chemoradiation and continued TTFields after treatment completion (referred to as the CA-TTF group). Treatment efficacy and toxicities were assessed and compared between the two groups. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method. To account for confounding factors, the Cox proportional hazards regression model, data matched by propensity score, and inverse probability of treatment weighting (IPTW) based on the propensity score were used for effectiveness evaluation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eA total of 72 patients with ndGBM were included in the study, 41 received concurrent and adjuvant TTFields in combination with chemoradiotherapy (concurrent and adjuvant TTFields group, CA-TTF), and 31 received adjuvant TTFields with temozolomide (adjuvant TTFields group, A-TTF). Skin toxicity was common but tolerated, there was no significant difference between the CA-TTF and A-TTF groups. The two groups were well balanced in age, sex, extent of resection, \u003cem\u003eMGMT\u003c/em\u003e methylation status, KPS, as well as compliance and duration of TTFields usage. The \u003cem\u003eTERT\u003c/em\u003e promoter mutation rate was 63.4% in the CA-TTF group versus 41.9% in the A-TTF group. With a median follow up of 18.0 months, there was no significant difference in PFS between CA-TTF and A-TTF groups (14.2 and 15.0 months, respectively, p=0.92); or the median OS (20.8 and 20.0 months, respectively, p=0.92). After IPTW, there remained no significant differences in PFS or OS, but the adjusted hazard ratio (HR) for PFS decreased from 0.93 (95% CI: 0.53-1.63, p=0.82) to 0.77 (95% CI: 0.44-1.30, p=0.344), and the adjusted HR for OS decreased from 0.96 (95% CI: 0.52-1.79, p=0.91) to 0.74 (95% CI: 0.40-1.37, p=0.336) for OS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eConcurrent chemoradiation and TTFields treatment is safe for ndGBM patients. No survival difference was presented between CA-TTF and A-TTF groups in this series of patients, but a potential advantage for those undergoing concurrent TTFields treatment. This hypothesis need validation through large-scale clinical trials.\u003c/p\u003e","manuscriptTitle":"Experience about Chemoradiation treatment with or without Concurrent Tumor-Treating Fields (TTFields) in Newly Diagnosed Glioblastoma (GBM) Patients in China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-08 14:44:06","doi":"10.21203/rs.3.rs-4350426/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":"c9fd63f9-bfea-4a22-8fb8-1ca062b275f5","owner":[],"postedDate":"May 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-04T07:46:02+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-08 14:44:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4350426","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4350426","identity":"rs-4350426","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}