Cycles Of Adjuvant Temozolomide Research Articles

Therapy Intensity Outweighs the Prognostic Importance of the Timing of Chemoradiotherapy in Newly Diagnosed Glioblastoma Patients.

To investigate the significance of the timing of chemoradiotherapy together with clinical and laboratory features in newly diagnosed glioblastoma. Clinical and laboratory parameters of 209 patients with glioblastoma potentially influencing overall (OS) and progression-free (PFS) survival were analyzed in univariable and multivariable models. On univariable analyses, Karnofsky performance status (p<0.001), recursive partitioning analysis (RPA) class (p<0.001), O6-methylguanine-DNA methyltransferase (MGMT)-status (p<0.001), extent of resection (p<0.001), radiotherapy dose (p=0.01), and the number of adjuvant temozolomide (TMZ) cycles (p<0.001) were significantly associated with OS. Additionally, MGMT-status (p<0.001), extent of resection (p=0.03), surgical site infections (p=0.02), and the number of adjuvant TMZ cycles (p<0.001) were significantly associated with PFS. Multivariable analysis identified radiotherapy dose as the only independent predictor (p=0.049) of OS. MGMT-status (p=0.02) and the number of adjuvant TMZ cycles (p<0.001) were independent predictors of PFS. The timing of chemoradiotherapy did not play a prognostic role. For OS, the radiotherapy dose, and for PFS, MGMT-status and the number of adjuvant TMZ cycles were identified as independent prognostic factors.

Extended cycles of adjuvant temozolomide improves survival outcomes in glioblastoma: a retrospective analysis

Aim: Standard treatment includes post-surgical chemoradiotherapy and adjuvant temozolomide (TMZ) for glioblastoma (GBM). There is no consensus on the optimal duration for adjuvant TMZ. This study assessed whether prolonging adjuvant TMZ improved survival outcomes. Methods: We retrospectively analyzed data of GBM patients who met inclusion criteria at our institute from September 2013 to December 2022. Patients who received 6 cycles of maintenance TMZ constituted the standard group, whereas those who underwent &gt; 6 cycles were classified into the extended group. Kaplan-Meier method was used to estimate the median progression-free survival (PFS) and overall survival (OS). Independent predictors of OS and PFS were explored by Cox regression analyses. Results: 100 patients were enrolled. Extended adjuvant TMZ significantly improved OS (28.0 vs. 10.0 months, P &lt; 0.001) and PFS (22.0 vs. 8.0 months, P &lt; 0.001) in newly diagnosed GBM patients. Subgroup analysis showed that patients with MGMT promoter methylation who received &gt; 6 cycles of adjuvant TMZ experienced a significant increase in OS (34.0 vs. 9.0 months, P &lt; 0.001) and PFS (26.0 vs. 9.0 months, P = 0.008). Additionally, in the extended group, patients with MGMT promoter methylation had better survival outcomes compared to MGMT promoter unmethylated patients (OS: 34.0 vs. 17.0 months, P = 0.013; PFS: 26.0 vs. 12.0 months, P = 0.025). In patients with solitary GBM, extended adjuvant TMZ resulted in better OS (11.0 vs. 32 months, P = 0.007) and PFS (9.0 vs. 24.0 months, P &lt; 0.001). For patients with multiple GBM, undergoing six or more cycles of adjuvant TMZ did not significantly impact OS (P = 0.100) and PFS (P = 0.067). The Karnofsky Performance Status (KPS) is employed to assess the health condition of surgical patients. Patients with KPS &gt; 70 exhibited better survival outcomes in the extended group. Nausea and vomiting were the main adverse events reported in both cohorts. However, fatigue emerged as the most severe side effect, specifically within the extended group. Conclusion: This study indicated that prolonged adjuvant TMZ significantly enhanced OS and PFS in GBM, and the adverse events were acceptable. The benefits were particularly notable in those with MGMT promoter methylation, solitary GBM, and high KPS. The optimal cycles of adjuvant TMZ require large prospective studies to further validate and identify which patient groups benefit the most based on molecular subtyping and clinical characteristics.

Phase I clinical trial of peposertib plus radiation in adults with newly diagnosed MGMT-unmethylated glioblastoma.

2076 Background: DNA-dependent protein kinase (DNA-PK) is a pivotal component of DNA damage repair (DDR) pathways and is an attractive target in glioblastoma because its expression renders tumors less vulnerable to radiotherapy. Peposertib is a small molecule DNA-PK inhibitor that has been pre-clinically shown to potentiate radiotherapy and regress glioblastoma tumors. We conducted a two-stage phase I trial of peposertib plus radiation in patients with newly-diagnosed MGMT-unmethylated glioblastoma (NCT04555577). Methods: In stage 1, patients received concurrent peposertib plus standard-of-care radiotherapy to determine the maximum-tolerated dose (MTD) based on the Bayesian Optimal Interval design (maximum n=24). Stage 2 is a window-of-opportunity expansion cohort and will include 5 surgical patients to evaluate intratumoral drug concentration. Both groups receive 6 cycles of adjuvant temozolomide. Results: Eighteen patients completed the 10-week dose-limiting toxicity (DLT) period; 3@50mg, 3@100mg, 3@200mg, 9@300mg. One DLT (G3 radiation necrosis [RN] at 300mg) was observed. Enrollment of the last three patients into the 300mg dose level began in December 2023 and will complete stage 1. To date, most notable toxicity was transient G3 dermatitis of the scalp (2@200mg, 1@300mg; not a DLT per protocol). Therefore, radiation dose constraints to the skin were incorporated and subsequent patients did not experience this toxicity. After a median follow up of 14.3 months (9.3-18.4), the median OS was 22.9 months [95% CI (16-NR)] and median PFS was 12.7 months [95% CI (9-NR)]. Next-generation sequencing (NGS) was available for 16 archival tumor tissue specimens from patients treated on this trial. Two patients had pathology-proven RN (one within and one outside of the DLT period). Both tumors had baseline mutations in DDR genes (i.e. ATRX, DICER1). Recurrent tissue was available for 4 patients after treatment with peposertib, 2 of which demonstrated gain of DDR gene mutations (2 ATM mutations in one patient and gain of MAD2L2 mutation in another patient). Conclusions: The initial safety data of peposertib plus radiation in patients with newly-diagnosed MGMT unmethylated glioblastoma is favorable. The cases with RN in tumors with DDR mutations, the gain of DDR mutations in recurrent tumors, and the cases of scalp dermatitis suggest peposertib activity may correlate with DDR function, and possibly potentiates the effect of radiation. Stage I is an independent stage of the protocol that will enable MTD determination. Complete safety and survival data and correlations with genomics and spatial transcriptomics for Stage I patients will be presented at the meeting. The study was supported by EMD Serono (CrossRef Funder ID: 10.13039/100004755). Clinical trial information: NCT04555577 .

Efficacy and safety of anlotinib combined with the STUPP regimen in patients with newly diagnosed glioblastoma: a multicenter, single-arm, phase II trial.

Glioblastomas are highly vascularized malignant tumors. We determined the efficacy and safety of the anti-angiogenic multi-kinase inhibitor, anlotinib, for a newly diagnosed glioblastoma. This multicenter, single-arm trial (NCT04119674) enrolled 33 treatment-naïve patients with histologically proven glioblastomas between March 2019 and November 2020. Patients underwent treatment with the standard STUPP regimen [fractionated focal irradiation in daily fractions of 1.8-2 Gy given 5 d/w × 6 w (total = 54-60 Gy)] or radiotherapy plus continuous daily temozolomide (TMZ) (75 mg/m2 of body surface area/d, 7 d/w from the first to the last day of radiotherapy), followed by 6 cycles of adjuvant TMZ (150-200 mg/m2 × 5 d during each 28-d cycle) plus anlotinib (8 mg/d on d 1-14 of each 3-w cycle for 2 cycles during concomitant chemoradiotherapy, 8 maximal cycles as adjuvant therapy, followed by maintenance at 8 mg/d. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AEs). Thirty-three patients received the planned treatment. The median PFS was 10.9 months (95% CI, 9.9-18.7 months) and the 12-month PFS rate was 48.5%. The median OS was 17.4 months (95% CI, 14.5-21.1 months) and the 12-month OS rate was 81.8%. The most common AEs included hypertriglyceridemia [58% (n = 19)], hypoalbuminemia [46% (n = 15)], and hypercholesterolemia [46% (n = 15)] during concurrent chemoradiotherapy and leukopenia [73% (n = 24)], hypertriglyceridemia [67% (n = 22)], and neutropenia [52% (n = 17)] during adjuvant therapy. Five patients discontinued treatment due to AEs. HEG1 (HR, 5.6; 95% CI, 1.3-23.7; P = 0.021) and RP1L1 alterations (HR, 11.1; 95% CI, 2.2-57.2; P = 0.004) were associated with a significantly shorter PFS. Anlotinib plus the STUPP regimen has promising anti-tumor activity against glioblastoma and manageable toxicity. HEG1 and RP1L1 alterations might be novel predictive biomarkers of the response to anlotinib.

INNV-07. ADJUVANT POST-SURGERY TREATMENT OF RECURRENT IDH2 MUTANT ANAPLASTIC OLIGODENTROGLIOMA (AO) WITH IDH2 INHIBITOR, ENASIDENIB: A CASE REPORT

Abstract INTRODUCTION Recent phase III trial presented by Mellinghoff at 2023 ASCO demonstrated successful treatment of Isocitrate dehydrogenase (IDH)–mutant grade 2 gliomas with Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes. Ivosidenib and enasidenib are separate inhibitors of mutant IDH1 and IDH2, which have shown single-agent activity for the treatment of IDH1- or IDH2-mutant acute myeloid leukemia but the effect in the treatment of glioma is uncertain. Here we report a case of IDH2 mutant AO, who was treated with enasidenib for about two years with fair tolerance and was postponed the next intervention. CASE REPORT A 36 yo female was diagnosed anaplastic ogligodentroglioma in 2006, 17 yrs ago. The patient underwent surgery resection, radiation and Temozolomide (TMZ), and 4 cycles of adjuvant TMZ. In 2021, fifteen years later, she was found tumor recurrence. She had a second surgery with near gross total resection. Pathology confirmed anaplastic oligodentraglioma with negative IDH1 mutation but positive IDH2 R172K mutation. To avoid re-radiation nor re-challenge with TMZ, the patient opted IDH2 inhibitor therapy after surgery. The patient tolerated the treatment, and her brain MRI demonstrated no tumor recurrence until one year later when her brain MRI showed vague sub-centimeter nodular non-enhancing lesion at surgical area. Enasidenib was continued for additional 6 months until recent MRI showed small and slow growth. Total therapy is 20 months. Clinically, the patient has no symptoms from tumor. DISCUSSION Our case review found post-surgery therapy with IDH2 inhibitor Enasidenib for IDH2 mutant recurrent AO is tolerated and could postpone next intervention such as re-radiation or re-challenge with TMZ.

Low Dose Fractionated Radiation Therapy as a Chemo-Potentiator of Salvage Temozolomide (TMZ) for Recurrent Anaplastic Astrocytoma (AA) and Glioblastoma Multiforme (GBM): A Single-Arm Phase I/II Trial

Cell survival curves demonstrate low-dose radiation hypersensitivity, with steepest cell kill at 0.3-0.5 Gy/fx. This phase 1/2 study assessed the safety and efficacy of low-dose fractionated radiation therapy (LDFRT) as a chemopotentiator of concurrent TMZ for patients with recurrent GBM or AA. Patients with recurrent GBM or AA s/p standard of care therapy and ≥12 months from prior RT and ≥2 months from prior TMZ were eligible to receive 0.5 Gy of RT twice daily for 10 fx with concurrent TMZ (150-200 mg/m2), both delivered in 5 consecutive days of a 28-day cycle for up to 6 cycles, followed by 6 more cycles of adjuvant TMZ. In phase 1, hematologic toxicity was assessed 1 month after starting therapy. Brain MRIs were obtained every 2 months, or every 1 month in cases of potential progression. Progression was defined by RANO criteria. Pseudoprogression consisted of MRI changes independent of clinical deterioration or steroid use that stabilize/reverse without oncologic intervention. The primary endpoint was 1-year overall survival (OS), with a lower bound of an 80% CI >28% deemed promising for further study based on historical data. Secondary endpoints were rates of pseudoprogression and hematologic toxicity. Thirty-one patients were enrolled/analyzed. Grade 3-4 acute hematologic toxicity was seen in 8 (27%) patients. Median follow-up was 9.5 (range: 0.1-66.3) months (mos). Median and 1-yr OS were 9.6 (95% CI = 7.0-15.4) mos and 34.5% (95% CI = 20.9%-57.0%). The lower bound of the 80% CI for 1-yr OS was 24.8%. 77% of patients experienced pseudoprogression, with a median time to pseudoprogression from start of LDFRT of 1.9 (95% CI = 1.7-4.4) mos and median duration of 3.6 (95% CI = 1.6-Not estimable) mos. Patients with pseudoprogression had improved OS vs. those without (N = 6; median 10.6 vs 3.9 mos, HR = 0.12 [95% CI = 0.03-0.40]; P < 0.01). LDFRT in the re-irradiation setting for GBM or AA was safe. High rates of pseudoprogression were observed at strikingly low RT doses, with improved OS amongst patients with vs. without pseudoprogression. While pseudoprogression is common at definitive doses of brain RT, it is rare at palliative doses (e.g., 30 Gy/10 fx). Thus, low-dose RT hypersensitivity may be elicited by LDFRT with TMZ for patients with GBM/AA. Further study is needed to optimally apply this radiobiological property to improve patient outcomes.

A multicenter retrospective study of the duration of adjuvant temozolomide in IDH-mutant gliomas.

e14048 Background: Gliomas with isocitrate dehydrogenase (IDH) mutations have improved prognosis and are more treatment responsive compared to IDH wild-type gliomas. For glioblastoma (IDH wild-type glioma), Stupp protocol has demonstrated superiority with 6 cycles of adjuvant temozolomide (TMZ). However, recommended duration of TMZ for IDH mutant gliomas is not well-defined, with studies such as RTOG 0424, CATNON, and CODEL extending treatment up to 12 cycles. Prolonged TMZ duration following radiation therapy (RT) is associated with increased toxicity including both financial (cost of drug, lab work, and visits) and drug side effects including cytopenias. We aimed to evaluate for any differences in survival between patients treated with more than 6 cycles of TMZ and those treated with 6 or fewer. Methods: We conducted a multicenter retrospective study of patients treated at the University of Washington and Stanford Medical Center for oligodendrogliomas (oligo) and IDH mutated astrocytomas (astro) using World Health Organization 2016 molecular diagnostic criteria including IDH mutation. Other inclusion criteria were grades 2 and 3, as well as treatment with RT (with or without concurrent TMZ) followed by adjuvant TMZ monotherapy with number of cycles documented. Survival probability, mean overall survival (mOS) and mean progression-free survival (mPFS), were calculated using Kaplan-Meier method with distributions compared using log-rank test in Prism GraphPad comparing &gt;6 cycles of adjuvant TMZ and ≤6 cycles. Results: Of 153 patients treated with both XRT and adjuvant TMZ, 88 were treated with between 1 and 6 cycles of adjuvant TMZ, while 91 were treated with &gt;6 cycles Treatment duration ranged from 1-12 cycles for oligos, 4-12 cycles for grade 2 astros, and 1-14 cycles for grade 3 astros. mOS of oligos was undefined for those treated with 1-6 cycles and 84 months (m) for those treated with &gt;6 cycles (p=0.1448). mOS of grade 2 astros was 154m for those treated with 1-6 cycles and 162.9m for those treated with &gt;6 cycles (p=0.8864). mOS of grade 3 astros was undefined for those treated with 1-6 cycles and 117m for those treated with &gt;6 cycles (p=0.8003). mPFS of oligos was 93m for those treated with 1-6 cycles and undefined for those treated with &gt;6 cycles (p=0.584). mPFS of grade 2 astros was 79.6m for those treated with 1-6 cycles and 144.56m for those treated with &gt;6 cycles (p=0.610). mPFS of grade 3 astros was 72m for those treated with 1-6 cycles and 79.4m for those treated with &gt;6 cycles (p=0.9596). Conclusions: While this study is limited by power, there was no difference in mOS or mPFS with greater than 6 cycles of TMZ among patients with oligodendrogliomas and IDH mutant astrocytomas. More data is needed to evaluate the optimal treatment duration to maximize survival without over-exposing these patients to toxicities.[Table: see text]

Final results of phase 2 trial of personal dendritic cell (DC) vaccines loaded with autologous tumor antigens (ATA) in newly diagnosed glioblastoma (GBM).

2047 Background: Standard GBM therapy is associated with early progression and poor overall survival (OS). DC-ATA AV-GBM-1, a personal vaccine consisting of autologous DC pulsed with ATA, was investigated in a multicenter trial in patients with newly diagnosed GBM. Methods: Key eligibility criteria for surgical collection of tumor were clinical suspicion of new primary GBM &amp; age 18-70 years. ATA lysate was prepared from irradiated tumor cells that were self-renewing in serum-free media. Autologous monocytes (MC) were collected by leukapheresis. Prior to initiating concurrent radiation therapy (RT) and temozolomide (TMZ), patients were enrolled with intent-to-treat (ITT) with DC-ATA after RT/TMZ. Eligibility included confirmation of primary GBM, availability of ATA &amp; MC, KPS &gt; 70 and plans for RT/TMZ. DC-ATA was manufactured during RT/TMZ. MC were differentiated into DC by culturing with IL-4 &amp; GM-CSF, then DC were incubated with ATA. DC-ATA was suspended in 500 mg GM-CSF just prior to s.c. injections at weeks 1, 2, 3, 8, 12,16, 20, &amp; 24 (8 doses). Patients were not excluded based on apparent disease progression or PFS. Standard adjuvant TMZ regimens were started after the 3 weekly injections. Primary endpoint was &gt; 75% OS 14.6 months from ITT enrollment. Secondary endpoints included median OS &amp; progression-free survival (PFS). Results: Cell line and MC collection were successful for 97% of patients. Median age of the 60 ITT enrollees was 59 years. 3 patients withdrew before starting DC-ATA; 57 received 392 injections; 68% received all 8. Most common AE attributed to DC-ATA were local injection site reactions (16%) &amp; flu-like symptoms (10%), but 33% experienced seizures. After 3 years of follow up, OS at 14.6 mos is 52.7% (95% CI 39.8,65.8), median OS 16.0 mos (95% CI 12.9,21.7) &amp; median PFS 10.4 mos (95% CI 8.6,11.6). OS rates at 1, 2, &amp; 3 years are 70.1%, 32.4%, &amp; 23.2%. Longer OS was associated with 8 DC-ATA doses (p &lt; 0.0001), on &lt; 2 mg/day dexamethasone (dex) at start of DC-ATA (p = 0.005), &gt; 6 cycles of adjuvant TMZ (p = 0.0054), &amp; KPS 90 or 100 (p = 0.010) at enrollment. Independent variables per multivariate Cox regression analysis were 8 DC-ATA doses, dex dose, IDH mutated, TMZ &gt; 6 cycles, &amp; MGMT promoter methylated. Concurrent TMZ regimens included TMZ alone (n = 28), TMZ + anti-VEGF(n = 14), &amp; TMZ + tumor treating fields (TTF) (n = 10); 8 received no concurrent TMZ. OS was longer in patients treated with concurrent TMZ alone compared to no TMZ (p = 0.0003), TMZ + anti-VEGF (p = 0.045) or TMZ + TTF (p = 0.045). The only common features among 7 patients progression-free at 3 years are 8 DC-ATA injections, age &lt; 60, &amp; &lt; 2 mg dex. Conclusions: DC-ATA was reliably produced and injections well-tolerated in combination with various TMZ-based regimens, but the primary OS objective was not achieved. PFS was encouraging, but did not translate into improved OS, perhaps because DC-ATA was limited to 8 injections. Clinical trial information: NCT03400917 .

Concurrent chemoradiation and adjuvant chemotherapy in newly diagnosed glioblastoma multiforme: A retrospective analysis of single center.

e14053 Background: The standard of care of glioblastoma multiforme (GBM) first line therapy is maximum safe debulking and posterior treatment based in concurrent chemo-radiation (Qt-Rt) followed by temozolomide-based chemotherapy. Despite a complete resection and adjuvant treatment, overall survival (OS) in patients (pts) with GBM is poor and it depends on tumor biology and patient characteristics. We analyzed retrospectively clinical and tumor biology characteristics of pts with GBM treated in our center with Qt-Rt +/- adjuvant Qt and their impact in OS. Methods: From November-2016 to October-2022, we collected data for 82 pts (median age: 60 years) who underwent Qt-Rt exclusively (25 patients) or Qt-Rt and adjuvant temozolomide (57 patients). Pts characteristics are detailed. Results: In multivariate analysis, significant difference of OS were observed in function of type of surgery (better OS in R0; p=0.015), performance status (better OS in PS 0-1; P=0.006), MGMT methylation (better OS in methylated; p=0.037), ATRX status (better OS in negative; p=0.05). No differences were founded in function of TERT (p=0.47) or p53 status (p=0.57). OS was significantly increased in pts treated with Qt-Rt and adjuvant Qt (17.7 +/- 1.7 months) vs Qt-Rt exclusively (11.35 +/-1.62 months) (p=0.013). After Qt-Rt treatment, radiological response was (%): no evidence of disease 13.4/partial response 6.1/stable disease 58.5/progressive disease 18.3/not evaluated 2.4. Most relevant adverse event G3/4 during Qt-Rt (%): thrombocytopenia 7.31, neutropenia 8, leukopenia 3.65, anemia 2.4, thrombosis 2.4. There were 2 toxic death (infection grade 5). After Qt-Rt, 57 pts received adjuvant treatment (median number of cycles: 5; range 1-15). Most relevant toxicity G3/4 during this therapy was (%): asthenia 3.05, anorexia 1.75, thrombocytopenia 5.26, neutropenia 3.05, leukopenia 1.75. There was 1 toxic death (infection G5). Pts that received 4 or more cycles of adjuvant temozolomide had a significant impact on OS versus those that completed 3 or less cycles (19.28 +/- 2 months vs. 12.05 +/- 1.5 months; p=0.022). Conclusions: Temozolomide-based chemotherapy in GBM is an effective and safe therapy and the premature interruption of this treatment may impact on OS. It is essential to know patient characteristics and tumor biology in order to identify patients that will beneficiate from this treatment.[Table: see text]

Abstract LB127: VAL-083 in patients with recurrent glioblastoma treated under expanded access program

Abstract Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) and adjuvant TMZ. Almost all GBM patients experience recurrent/progressive disease despite upfront standard of care treatment, with a median overall survival of 3-9 mo. after recurrence. There are limited treatment options available upon progression of disease which may include potential participation in clinical trials. However, patients may not meet the strictly defined entry criteria to participate in these clinical trials. VAL-083 is a first-in-class bifunctional alkylating agent that acts independent of O6-methylguanine-DNA-methyltransferase (MGMT) methylation status. Under an Expanded Access (EA) program, we have treated 24 patients with recurrent GBM, who were not eligible to participate in clinical trials with VAL-083. Four (4/24; 17%) patients had leptomeningeal disease (LMD) at time of enrolment. While safety data was assessed for all patients, those without LMD (20 patients) were evaluated for efficacy. All patients evaluated for efficacy received chemoradiation with TMZ, and the mean number of adjuvant TMZ cycles was 5 (± 6.2). The median time from last progression to start of VAL-083 was 0.65 mo. (95%CI: 0.32-1.55) and median KPS was 80 (25-75P: 70-90). Eight (8/20; 40%) patients had 2 or more prior recurrences, 9/20 (45%) patients had multifocal disease, and 5/20 (25%) had prior lomustine. Eighteen (18/20; 90%) patients had unmethylated promoter status for MGMT and 18/20 (90%) were IDH wild type. All patients had at least 1 mutation, with 11/20 (55%) having 5 or more mutations, and one patient had hypermutator phenotype with MSH6 mutation. The most common mutations were, TERT 11/20 (55%), PTEN 9/20 (45%), and TP53 6/20 (30%). All patients started treatment with VAL-083 at 30 mg/m2 administered on 3 consecutive days every 21 days. Seven patients received bevacizumab concurrently with VAL-083. VAL-083 was well tolerated and the main adverse events were consistent with prior experience, i.e., thrombocytopenia and neutropenia. Eight (8/24; 33%) patients had a dose reduction, 7 of which were due to thrombocytopenia, and 1 due to neutropenia. Five patients with thrombocytopenia had prior lomustine. As of cut-off date (05 Jan, 2023), median progression free survival (mPFS) and median overall survival (mOS) from last disease progression was 5.9 mo (95%CI: 3.9-7.9) and 9.4 mo (95%CI: 3.0-14.3), respectively. In patients without multifocal disease mOS was even longer, 14.3 mo (95%CI: 3.9-14.3). Use of VAL-083 in this expanded access study showed benefit in the treatment of recurrent GBM patients even those who have had multiple recurrences and were not candidates for the treatment through clinical trial. Additional safety and efficacy measures will be presented at the meeting.Clincialtrials.gov Identifier: NCT03138629. All EA treatment requests and plans were approved by MD Anderson Cancer Center IRB. Citation Format: Carlos Kamiya-Matsuoka, Shiao-Pei Weathers, Rebecca A. Harrison, Nazanin K. Majd, Ashley E. Aaroe, Stephanie Knight, Teresa Hanna, Timothy A. Gregory, John Langlands, Dennis Brown, Vinay K. Puduvalli. VAL-083 in patients with recurrent glioblastoma treated under expanded access program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB127.

Adjuvant Treatment of Grade 4 Glioma, Outcomes at a UK Tertiary Center

Aim: The 5-year overall survival (OS) for Glioblastoma (GBM) remains low. The cohort had a lower percentage of completing adjuvant treatment than those reported in trials. Therefore unplanned 6 cycles of adjuvant treatment and the effect on survival outcomes were assessed. Survival data for patients with Gliadel wafer insertion at the time of primary surgery was also assessed. The combination of these factors on survival outcomes was also assessed. Methods: The retrospective cohort study of 110 patients who underwent neurosurgery followed by chemoradiotherapy (CRT) 60 Gray in 30 fractions and adjuvant Temozolomide (TMZ) was carried out from 2007 to 2016. Overall survival (OS) and progression-free survival (PFS) were assessed and a number of subset analyses were carried out. Results: The period of OS was 16 months and PFS was 11.9 months. 57% of patients completed 4-6 cycles of adjuvant TMZ 43% received 3 or fewer cycles of TMZ. Those unable to complete planned adjuvant TMZ had a poorer OS (10 vs 20 months, Cox analysis P-value 0.0003). For patients having maximal safe debulking plus Gliadel wafer insertion, median OS was improved, 19.5 months P=0.06. In the group with the combination of significant factors, the median OS was 2 months greater than those that did not receive Gliadel wafers and could not complete 4 cycles of adjuvant TMZ. Conclusion: Survival outcomes were improved with Gliadel wafer insertion and completing 4-6 cycles of TMZ. Consequently, the combination of these factors led to improved outcomes.

Impact of Extended Adjuvant Temozolamide Beyond 6 Months in the Management of Glioblastoma Patients.

Our study aimed to assess the benefit of prolonging adjuvant temozolomide (TMZ) therapy beyond 6 cycles in glioblastoma multiform patients. The medical records of 329 patients in 2 cancer centers in Egypt were reviewed from January 2008 to December 2018 who were diagnosed with diffuse gliomas. Data were collected on patient demographics, presenting complaints, tumor size, treatment modalities (extent of surgery, radiotherapy dose and technique, concomitant TMZ, and the number of adjuvant TMZ cycles), and reported adverse events. In the studied cohort, 105 patients were treated with adjuvant TMZ, 33 patients received <6 cycles (TMZL), 41 patients received the standard 6 cycles (TMZS), and 31 patients received >6 cycles (TMZE). Our results showed the median overall survival in the TMZL arm was 8.47 months compared with 15.83 months in the TMZS arm and 27.33 months in the TMZE arm ( P < 0.001). Furthermore, a median progression-free survival of 6.35 months was reported in the TMZL group versus, 12.7 and 22.90 months in (TMZS) and (TMZE) groups, respectively( P < 0.001). In the multivariate analysis, the extended adjuvant TMZ with a hazard ratio of 3.106 (95% CI: 2.43-14.46; P < 0.001) was statistically significantly associated with a better outcome. Extended adjuvant TMZ therapy beyond 6 cycles may significantly improve the progression-free survival and overall survival in patients with glioblastoma multiform.

Phase II trial of concurrent sunitinib, temozolomide, and radiotherapy with adjuvant temozolomide for newly diagnosed MGMT unmethylated glioblastoma.

The overall prognosis of glioblastoma (GBM) remains dismal, particularly for patients with unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter. In this phase II trial, we tested the combination of the antiangiogenic agent sunitinib with radiotherapy and temozolomide (TMZ) for newly diagnosed unmethylated MGMT GBM patients. We enrolled 37 patients with unmethylated MGMT promoter GBM, age 18-70, and KPS ≥70. Patients received 12.5 mg of daily sunitinib for 7 days, followed by concurrent chemoradiation plus 12.5 mg sunitinib, then adjuvant TMZ. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), safety, and neutrophil-to-lymphocyte ratio (NLR) biomarker. At a median follow-up time of 15.3 months (range: 3.1-71.3 months), the median PFS was 7.15 months (95% CI: 5.4-10.5) and the 6-month PFS was 54.0%. Median OS was 15.0 months (95% CI: 13.8-19.4) and 2-year OS rate was 17.1%. Patients receiving >3 cycles of adjuvant TMZ, undergoing surgery at progression, and presenting a post-concurrent NLR ≤6 experienced a significant improved OS with hazard ratios of 0.197 (P = .001), 0.46 (P = .049), and 0.38 (P = .021), respectively, on multivariable analysis. Age >65 years predicted for worse OS with hazard ratio of 3.92 (P = .037). Grade ≥3 thrombocytopenia occurred in 22.9%, grade ≥3 neutropenia in 20%, and grade ≥3 thromboembolic events in 14.3% of patients. There were no grade 5 events. Our findings suggest a potential benefit of combining sunitinib with chemoradiation in newly diagnosed GBM patients with unmethylated MGMT status and provide a strong rationale to test this combination in future studies.

Extending adjuvant-temozolomide does not necessarily improve survival in patients with newly-diagnosed glioblastoma: a fifthteen-year territory-wide multi-centre retrospective cohort study

Background: First-line treatment for glioblastoma after surgery consists of concurrent chemo-radiation (CCRT) followed by 6 cycles of adjuvant-temozolomide. This study investigates the association between the duration of adjuvant-temozolomide and overall survival (OS) in glioblastoma patients.

Extended adjuvant temozolomide in newly diagnosed glioblastoma: A single-center retrospective study.

To investigate whether extending adjuvant temozolomide (TMZ) improved the prognosis of newly diagnosed glioblastoma (GBM) patients with different mutation statuses of O6-methylguanine DNA methyltransferase (MGMT), isocitrate dehydrogenase 1 (IDH1), p53 and different expression level of Ki67. This study was a retrospective cohort study that postoperative patients with newly diagnosed GBM who did not progress after receiving radiotherapy with concomitant and 6 cycles of adjuvant TMZ were enrolled in control group, and those received more than 6 cycles of adjuvant TMZ were incorporated in extended group. Patients were stratified by MGMT expression, IDH1 mutation, p53 mutation and expression level of Ki67. The primary endpoints were overall survival (OS) and progression-free survival (PFS). A total of 93 postoperative patients with newly diagnosed GBM were included in this study, 40 and 53 cases were included in control group and extended group, respectively. On the whole, extended adjuvant TMZ chemotherapy significantly prolonged OS and PFS of patients with newly diagnosed GBM [median OS (mOS): 29.00 months vs. 16.70 months, P < 0.001; median PFS (mPFS): 13.80 months vs. 9.60 months, P = 0.002]. The results of subgroup analysis showed that patients with methylated MGMT in extended group had significantly longer OS and PFS than those in control group; patients with IDH1 mutation benefited more from extended adjuvant TMZ chemotherapy than those with wild-type IDH1; there was no significant difference in the effect of extended TMZ chemotherapy on OS between GBM patients with wild-type p53 and those with mutant p53; compared with GBM patients with lower expression of Ki67, extended adjuvant TMZ treatment dramatically improved the OS and PFS of those with higher expression of Ki67. The therapeutic schedule of extended adjuvant TMZ significantly prolonged OS and PFS of patients with newly diagnosed GBM regardless of p53 mutation status, and patients with different MGMT methylation, IDH1 mutation and Ki67 expression level benefited differently from extended adjuvant TMZ chemotherapy.

NCOG-34. METASTATIC PAPILLARY TUMOR OF THE PINEAL REGION: ROLE OF STEREOTACTIC IRRADIATION AND ADJUVANT TEMOZOLOMIDE

Abstract INTRODUCTION Papillary tumor of the pineal region (PTPR) is a very rare tumor comprising &amp;lt; 1% of all intracranial neoplasms. It was first included as a distinct tumor entity in the 2007 World Health Organization classification. Due to its rarity, only anecdotal data is currently available to guide management. However, with these tumors being recognized more frequently, further molecular observations and therapeutic experiences are necessary. Herein, we report an unusual case of PTPR with a previously treated leptomeningeal metastasis (LM) whom we successfully managed with Gamma Knife Radiosurgery (GKRS) and adjuvant temozolomide at time of distant brain parenchymal tumor progression. CASE REPORT: A 41-year-old man presented with headache and diplopia in 2015, MRI brain revealed a large cystic enhancing lesion in the pineal region protruding into the third ventricle and causing obstructive hydrocephalus. He had a ventriculoperitoneal shunt placed and underwent partial tumor resection. He then transferred care to our institution and a gross total resection was achieved. Pathology confirmed PTPR. A repeat MRI 15 months later showed evidence of radiographic LM in the cerebellum and he underwent craniospinal proton radiation therapy. He remained stable until January 2020 when a new left temporal heterogeneously enhancing multicystic lesion was identified on surveillance MRI. He underwent subtotal resection of this intra-axial lesion. Histological features of the tumor were similar to his initial tumor. Somatic tumor mutation testing using FoundationOne®CDx did not reveal targetable molecular alterations. Following surgery, he received GKRS and six cycles of adjuvant temozolomide. At 21-month follow up, patient continues to do well. CONCLUSION To our knowledge, this is the first case to describe a metastatic brain intraparenchymal PTPR. We also describe a first case of successful therapeutic strategy for a distant recurrence of PTPR.

Standard or extended STUPP? Optimal duration of temozolomide for patients with high-grade gliomas: a retrospective analysis.

Brain radiotherapy combined with concomitant and six cycles of adjuvant temozolomide (TMZ) is the standard treatment for newly diagnosed high-grade gliomas (HGGs). However, the optimal number of cycles of TMZ is still controversial. We conducted this retrospective cohort study to evaluate whether prolonging adjuvant TMZ beyond six cycles resulted in better survival outcomes. Patients with high-grade gliomas treated with standard brain radiotherapy combined with TMZ were retrospectively analysed. The duration of adjuvant TMZ ranged from 6 to 12 cycles. Those with 6 cycles of adjuvant TMZ were defined as the standard STUPP group, and those with 7-12 cycles were called the extended STUPP group. Median progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. The Cox proportional hazards model was adopted to estimate the Hazard ratio (HR) associated with PFS and OS. From September 2011 to May 2021, 372 patients were eligible (143 in the standard group, 229 in the extended group). Patients who received extended STUPP had better PFS and OS compared with standard STUPP. The median PFS for the standard STUPP group was 12 months and for the extended STUPP group 22 months (log-rank P < 0.001). The median OS for the standard STUPP group and extended STUPP group were 12 months and 36 months, respectively (log-rank P < 0.001). In the subgroup analysis, the two treatments did not differ in IDH-mutated patients, while patients with IDH wild-type had a significantly better response to extended treatment than to standard treatment (PFS: log-rank P = 0.004; OS log-rank P = 0.001). Patients with MGMT promoter methylation treated with extended STUPP obtained longer PFS and OS than those treated with standard STUPP (PFS: log-rank P = 0.015; OS log-rank P = 0.010). Adverse events including leukopenia (P < 0.001), thrombocytopenia (P = 0.090), fatigue (P < 0.001) and nausea/vomiting (P = 0.004) were more frequent in the extended group. Extended TMZ treatment was superior to standard 6-cycle TMZ for both PFS and OS. The incidence of toxicities in extended group was higher but tolerable.

A Phase II Trial of Concurrent Sunitinib, Temozolomide and Radiation Therapy Followed by Adjuvant Temozolomide for Newly Diagnosed Glioblastoma Patients with an Unmethylated MGMT Gene Promoter

<h3>Purpose/Objective(s)</h3> Despite advances in treatment modalities, the overall prognosis of Glioblastoma remains dismal, particularly for patients with unmethylated MGMT promoter. In this phase II trial, we tested for the first time the combination of Sunitinib with radiotherapy and Temozolomide in newly diagnosed MGMT unmethylated Glioblastoma patients. We hypothesized that this combination therapy would be safe and yield superior survival outcomes than the current standard of care for MGMT unmethylated Glioblastoma patients. <h3>Materials/Methods</h3> 37 patients diagnosed with WHO-Grade IV Glioblastoma and unmethylated MGMT promoter, age 18-70 and KPS ≥70 were eligible from two institutions. Patients received 12.5 mg of daily Sunitinib for 7 days, followed by concurrent chemoradiation and 12.5 mg Sunitinib x6 weeks, then adjuvant Temozolomide x6 cycles. Primary objective was progression-free-survival (PFS) as per RANO criteria, secondary objectives were overall survival (OS), safety and Neutrophil-to-Lymphocyte ratio (NLR). <h3>Results</h3> Median follow-up time was 15.3 months (95% CI: 13.8-19.4). Median PFS was 7.15 months (95% CI: 5.4-10.5 months) and 6-month PFS was 54.0%. Median OS was 15.0 months (95% CI: 13.8-19.4 months) and 2-year OS was 17.1%. Having received >3 cycles of adjuvant Temozolomide and surgery at progression significantly predicted for better OS with hazard ratios of 0.32 (p=0.017) and 0.46 (p=0.049) respectively, whereas age >65 and post-treatment NLR>6 predicted for worse OS with hazard ratios of 3.92 (p=0.037) and 2.64 (p = 0.021) respectively. Grade ≥3 thrombocytopenia occurred in 22.9%, grade ≥3 neutropenia in 20% and grade ≥3 thromboembolic events in 14.3% of patients. There were no grade 5 events. <h3>Conclusion</h3> Addition of Sunitinib to RT and Temozolomide was safe and survival outcomes are promising compared to the standard of care for GBM patients with unmethylated MGMT promoter status.

A new approach to delineating clinical target volume for radiotherapy of glioblastoma: A phase II trial.

No consensus has currently been reached regarding the optimal radiation volume for radiotherapy of glioblastoma. Here, we have proposed a new delineation approach to delineating clinical target volume based on the relationship between the growth patterns of glioblastoma and neural pathways. Its safety and efficacy were evaluated in a phase II clinical trial. A total of 69 patients with histologically confirmed glioblastoma were enrolled. All patients underwent tumor resection, followed by focal radiotherapy and concomitant temozolomide (TMZ), and then received six cycles of adjuvant TMZ. The gross tumor volume (GTV) was defined as the surgical resection cavity plus any residual enhancing tumor, on contrast enhanced T1-weighted MRI. The clinical target volume (CTV) was delineated through our new approach. The median recurrence-free survival (RFS) and overall survival (OS) were 11.4 months and 18.2 months, which were better than the previous reports. Relapse was found in 47 patients, of whom 41 patients (87.2%) failed in central, two patients (4.3%) failed in field, and four patients (8.5%) failed in distance. No marginal recurrence was found. Our regimen showed a trend of lower rates of marginal recurrence, and the brain volume of high-dose radiation fields in our regimen was similar to that of EORTC (p = 0.257). We have proposed a novel method for the delineation of clinical target volume by referencing the nerve fiber bundles for radiotherapy of glioblastoma. The results of the present phase II clinical trial suggest that this approach may be feasible and effective.

Can Extended Chemotherapy Improve Glioblastoma Outcomes? A Retrospective Analysis of Survival in Real-World Patients.

Standard treatment for glioblastoma multiforme (GBM) is surgery followed by radiotherapy plus concurrent chemotherapy with daily temozolomide (TMZ), and six subsequent TMZ 5/28-day cycles. Research has focused on identifying more effective alternatives to the current protocol, including extension of the number of adjuvant TMZ cycles. We performed a retrospective analysis of all GBM patients treated in our hospital (160 patients, 2011–2020). Median follow-up was 16.0 months. Analysis of prognostic factors was performed with a particular focus on the benefit of extending TMZ chemotherapy. Improved survival correlated with younger age, female gender, good performance status, absence of cognitive dysfunctions, no steroid use, and total tumor resection. Median progression-free survival (PFS) was 12 months and median overall survival (OS) was 20.0 months for the entire cohort. Median OS by adjuvant TMZ was 10.0 months if no adjuvant chemotherapy given (group 0), 15.0 months for patients that did not complete six TMZ cycles (group A), 24.0 months for those that did (group B), and 29.0 months for patients having received more than six cycles (group C) (p < 0.0001). At the three-year mark, 15.9% patients were alive in group A, 24.4% in group B and 38.1% in group C. Carefully selected GBM patients may derive benefit from extending the standard adjuvant chemotherapy beyond six TMZ cycles, but more data is required.