Adjuvant Temozolomide In Patients Research Articles

500O Trotabresib (CC-90010) combined with concomitant temozolomide (TMZ) plus radiotherapy (RT) and adjuvant TMZ in patients (pts) with newly diagnosed primary glioblastoma (ndGBM): Updated results from a phase Ib/II study

500O Trotabresib (CC-90010) combined with concomitant temozolomide (TMZ) plus radiotherapy (RT) and adjuvant TMZ in patients (pts) with newly diagnosed primary glioblastoma (ndGBM): Updated results from a phase Ib/II study

Efficacy and Toxicity of Different Target Volume Delineations of Radiotherapy Based on the Updated RTOG/NRG and EORTC Guidelines in Patients with High Grade Glioma: A Randomized, Controlled Clinical Trial

Postoperative radiotherapy with concomitant and adjuvant temozolomide (TMZ) is the standard of care for newly diagnosed high grade glioma, but the optimal method for target volume delineations for intensity modulated radiation therapy (IMRT) is still unclear. We hypothesized that compared with the EORTC guidelines, IMRT based on the updated RTOG/NRG guidelines was equally effective, without increasing toxicities for patients with high-grade glioma. The purpose of this randomized phase 2 study was to compare the efficacy and toxicity of IMRT based on different target volume delineations (updated RTOG/NRG versus EORTC guidelines) with concomitant and adjuvant TMZ for patients with high grade glioma. A total of 302 patients with newly diagnosed high-grade glioma (WHO grade 3-4) were randomly assigned (1:1) to receive postoperative IMRT based on either updated RTOG/NRG guidelines (RTOG/NRG group, n = 151) or EORTC guideline (EORTC group, n = 151), with concomitant and adjuvant TMZ. In the RTOG/NRG group, an initial volume consisting of enhancement, postoperative cavity, plus surrounding edema (or fluid-attenuated inversion recovery [FLAIR] abnormality defined by magnetic resonance imaging [MRI]) and a 2-cm margin received 46 Gy in 23 fractions followed by a boost of 14 Gy in 7 fractions to the area of enhancement plus the cavity and a 2-cm margin. In the EORTC group, a single planning volume was used to deliver 60 Gy in 30 fractions to the area of enhancement and the cavity with a 2-cm margin. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS) and toxicities associated with each treatment. No statistically significant differences were observed between groups for 1-year OS (71.8% for RTOG/NRG group and 69.9% for EORTC group, respectively; P = 0.759) or 1-year PFS (46.7% for RTOG/NRG group and 43.6% for EORTC group, respectively; P = 0.674). Efficacy did not differ by MGMT methylation status. There were no differences in grade 3-4 toxicities (leukopenia, lymphopenia, neutropenia, thrombocytopenia, fatigue, nausea and vomiting) between the two groups. No grade 5 toxicities were observed in both groups. Multivariate analyses showed that tumor MGMT status (methylated vs unmethylated) and WHO grade (grade 3 vs grade 4) were associated with OS and PFS. However, radiation type (RTOG/NRG group vs EORTC), sex, age, and Karnofsky scale did not significantly influence OS or PFS. Compared with EORTC guidelines for postoperative radiotherapy, IMRT based on RTOG/NRG guidelines was equally effective, without increasing toxicities for patients with high-grade glioma. This trial is registered with chictr.org.cn, number ChiCTR2100046667.

Updated systematic review and meta-analysis of extended adjuvant temozolomide in patients with newly diagnosed glioblastoma.

Contemporary standard-of-care for newly diagnosed glioblastoma (GBM) is maximal safe resection followed by postoperative focal conformal radiotherapy (RT) plus concurrent temozolomide (TMZ) and 6-cycles of adjuvant TMZ (Stupp regimen). However, many patients continue to receive extended adjuvant TMZ (beyond 6-cycles) without solid scientific evidence. This review pools data from nonrandomized studies and randomized controlled trials (RCTs) comparing extended adjuvant TMZ (>6-cycles) to standard adjuvant TMZ (6-cycles) in patients with newly diagnosed GBM for updated evidence-synthesis. This systematic review and meta-analysis was carried out in accordance with the Cochrane methodology including quality assessment of primary studies. Primary outcome of interest was comparative efficacy defined as progression-free survival (PFS) and overall survival (OS). Hazard ratios (HRs) for PFS and OS with corresponding 95% confidence interval (CIs) were extracted/computed from individual primary studies and pooled using random-effects model. Any p-value <0.05 was considered statistically significant. Evidence-synthesis was based on pooling of data from 2578 patients enrolled in 16 nonrandomized comparative studies and 5 RCTs. Overall, extended adjuvant TMZ was associated with statistically significant reduction in the risk of progression (HR = 0.72, 95%CI: 0.60-0.87; p = 0.007) and death (HR = 0.71, 95%CI: 0.57-0.90; p = 0.004) compared to standard adjuvant TMZ. However, on subgroup analysis, survival benefit of extended adjuvant TMZ was limited to data synthesized from retrospective nonrandomized comparative studies with no statistically significant difference in outcomes seen after pooling of data from RCTs only. Apparent survival benefit of extended adjuvant TMZ in newly diagnosed GBM is largely driven by nonrandomized comparative studies with high inherent potential for multiple biases.

CTNI-47. INTERIM RESULTS OF NCT03011671: A MULTI-INSTITUTIONAL PHASE I STUDY OF ACETAZOLAMIDE WITH TEMOZOLOMIDE IN ADULTS WITH NEWLY DIAGNOSED MGMT-METHYLATED MALIGNANT GLIOMA

Abstract Preclinical studies indicate that up-regulation of carbonic anhydrase (CA) by temozolomide (TMZ), via a mechanism requiring the proto-oncogene BCL-3, promotes resistance to therapy in glioblastoma (GBM) cells. Moreover, the CA inhibitor, acetazolamide (ACZ), sensitizes patient-derived GBM cells and xenografts to TMZ. These findings led to the current Phase I study investigating the safety and efficacy of adding ACZ to adjuvant TMZ in patients with newly diagnosed, MGMT-methylated malignant glioma. 24 patients were enrolled (23 GBM and one Grade III IDH-mutant astrocytoma), median age was 53.5 and mean KPS 91. ACZ was given on days 1-21 of each adjuvant TMZ cycle (250 mg BID days 1-7, increased to 500 mg BID days 8-21). No patient experienced the primary outcome of regimen limiting toxicity (RLT) and there were only three grade III adverse events deemed likely unrelated to ACZ. For the secondary endpoints of overall and progression free survival (OS and PFS, respectively), only the 23 GBM patients were included (22 IDH-wildtype and 1 IDH-mutant). From diagnosis, median PFS was 18.8 months (95% CI: 10.4-23.0) and median OS was 25.0 months (95% CI: 19.9-28.4). Median time from diagnosis to consent was 2.9 months. As of April 2021, only 7 of 23 deaths had occurred. 2-year OS% was 68.2%. Further analysis of secondary endpoints including 6-month objective response rate (ORR) and biomarker analysis of BCL-3 by IHC will be available in the coming months. In sum, the data indicate that addition of ACZ to TMZ is safe and does not lead to reduced TMZ dosing. Also, compared to historical data, interim outcomes suggest that addition of ACZ may substantially improve PFS and 2-year overall survival. These findings support the hypothesis that ACZ acts as a chemosensitizer of alkylating chemotherapy in GBM and support examination of this regimen in a randomized, placebo-controlled study.

A Randomized Trial of Short-Course Versus Conventional Radiotherapy With Concomitant and Adjuvant Temozolomide in Patients 18 to 70 Years of Age With Glioblastoma

<h3>Purpose/Objective(s)</h3> Patients 70 years old or younger with good performance status with glioblastoma often are treated with radiotherapy (RT) over 6 weeks with concurrent and adjuvant temozolomide. Whether short-course hypofractionated RT using the same total dose over a shorter time has similar clinical efficacy without increased toxicity is presently not known. Primary objective was to compare outcomes between conventional and short-course RT regimens. <h3>Materials/Methods</h3> We conducted a randomized noninferiority trial for patients aged 18-70 years with histologically confirmed, newly diagnosed glioblastoma and ECOG 0-2. Patients were randomized in a 1:1 ratio, stratified by extent of surgical resection, to conventional RT of 60 Gy in 30 fractions over 6 weeks or short-course RT of 60 Gy in 20 fractions over 4 weeks, with concomitant and maintenance temozolomide in both arms. Primary endpoint was overall survival defined as time from randomization until death. Secondary endpoints included acute and late toxicity graded according to NCI CTCAE version 4.0, and patient-reported quality of life assessed by EORTC QLQ-C30 and QLQ-BN20 questionnaires. Survival outcomes were analyzed by intention to treat. Noninferiority margin was 14.5% (hazard ratio, < 1.57). <h3>Results</h3> One hundred thirty-three patients were randomized to short-course arm (n = 68) or conventional arm (n = 65). Median age was 58 years (range 24-70); 69% male; 91% had ECOG 0-1; 88% had resection. In prospective molecular analysis of suitable specimens, IDH1 mutation was seen in 13/131 patients (9.9%) and MGMT promotor methylation in 68/126 patients (54.0%). Age (< 60 vs. ≥60 years), ECOG (0-1 vs. 2), extent of resection (resection vs. biopsy), IDH1 status (wildtype vs. mutated), MGMT status (methylated vs. unmethylated), and extent of disease (unifocal vs. multifocal) were not different between two arms. Median overall survival was 14.4 months (95% CI 12.7 – 16.1 months) in the short-course arm; 11.0 months (95% CI 9.2 – 12.8 months) in the conventional arm (HR 0.94, 95% CI 0.64 – 1.38, <i>P</i>-value for superiority = 0.751, <i>P</i>-value for non-inferiority < 0.01). In 97 patients without multifocal disease, median overall survival was 15.3 months (95% CI 13.0 - 17.7 months) in the short-course arm; 11.8 months (95% CI 9.4 -14.2 months) in the conventional arm (HR 0.95, 95% CI 0.62 – 1.46, <i>P</i> = 0.816). With median follow-up time of 18.7 months, no significant differences were detected between arms for any grade ≥2 toxicity. No patients had reoperation for radionecrosis in the short-course arm. In the conventional arm, one patient had reoperation for radionecrosis. Quality of life between both arms at the end of RT, and at 12 weeks and 16 weeks post-RT was not different. <h3>Conclusion</h3> The short-course RT regimen used in this trial was not inferior to conventional RT and was not associated with increased toxicity or reduced quality of life. Short-course RT is more convenient for patients and may be recommended as a treatment option for patients 70 years old or younger with newly diagnosed glioblastoma.

Predicting Recurrent Patterns After Radiotherapy Plus Concomitant and Adjuvant Temozolomide in Patients With High-Grade Gliomas Incorporating Multimodal Magnetic Resonance Imaging and Molecular Biomarkers

This study aimed to establish a multivariable logistic regression model based on multimodal magnetic resonance (MR) imaging and molecular biomarkers to provide individualized prediction of recurrent patterns (RPs) in patients with high-grade glioma (HGG) after temozolomide-based chemoradiotherapy.We retrospectively analyzed 152 patients with recurrent HGG who had contemporaneous diffusion tensor imaging (DTI) and MR spectroscopy (MRS) at initial diagnose. Patients were randomly divided into training (n = 102) and internal validation cohorts (n = 50). Local and distant recurrent were assessed, with the pattern of recurrence of individual lesions defined relative to the 95% isodose line. DTI parameters of the tumor, including fractional anisotropy (FA) and apparent diffusion coefficient were calculated. N-acetylaspartate and choline (Cho) values of the tumor were measured from MRS and normalized as ratios to creatine (Cr). Clinical data collected were grade, location and molecular status. Logistic regression analysis was used to identify risk factors for building the prediction model in training cohorts. The results were internally validated by assessment of discrimination and calibration using the validation cohorts.For all the patients, local recurrences occurred in 105 (69.08%) patients, and distant recurrent developed in 47 (30.92%) patients. Multivariable logistic analysis indicated that grade (OR: 4.585; 95% CI: 1.082-19.436), subventricular zone (SVZ) contact (OR: 6.893; 95% CI: 1.325-35.868), FA value of tumor (OR: 6.989; 95% CI: 1.310-37.271), Cho/Cr ratio (OR: 14.327; 95% CI: 2.697-76.112) and O6-methylguanine-DNA methyltransferase (MGMT) methylation status (OR: 5.467; 95% CI: 1.453-20.577) were independent predictors of RPs. A prediction model was developed as following: Logit (P) = -7.038 + 1.523XGrade + 1.931XSVZ + 1.944XFA + 2.662XCho/Cr + 1.699XMGMT. Our model showed superior discriminatory power in the training cohort (AUC = 0.897, P < 0.001). Calibration curves indicated favorable consistency between the model prediction and the actual outcomes (Hosmer-Lemeshow test = 0.853). Moreover, the decision curve analyses exhibited satisfactory clinical utility. The favorable performance of this prediction model was confirmed in the internal validation cohorts.Multimodal MR imaging can be integrated with molecular biomarkers to provide better RPs prediction for HGG patients. The developed model could help the clinicians to make decision-making in patients with HGG undergoing (chemo) radiotherapy.S. Nie: None. Y. Wang: None. X. Ding: None. Z. Zhou: None. Y. Guo: None. M. Hu: None.

The duration of adjuvant temozolomide in patients with glioblastoma and the law of diminishing returns.

The duration of adjuvant temozolomide in patients with glioblastoma and the law of diminishing returns.

Randomized phase III study of high-dose methotrexate and whole brain radiotherapy with or without concomitant and adjuvant temozolomide in patients with newly diagnosed primary central nervous system lymphoma: JCOG1114C.

2500 Background: Temozolomide (TMZ) is an oral alkylating agent that penetrates the blood-brain barrier with moderate toxicity, and has shown anti-tumor activity in primary central nervous system lymphoma (PCNSL) in single arm studies. Our goal was to determine whether the addition of concomitant and adjuvant TMZ chemotherapy to standard treatment of high-dose methotrexate (HD-MTX) and whole brain radiotherapy (WBRT) for PCNSL improves survival in a randomized controlled trial. Methods: We did an open-label, randomized phase III trial at 30 hospitals in Japan enrolling immunocompetent patients (pts) aged 20-70 years with histologically confirmed newly diagnosed PCNSL. Pts enrolled at step 1 registration received HD-MTX (MTX; 3.5 g/m2 at day 1, 15, 29). Pts who received at least 1 cycle of HD-MTX were randomly assigned (1:1) at step 2 registration to receive WBRT (30 Gy) ± 10 Gy boost (control arm: A) or WBRT ± boost with concomitant TMZ (75 mg/m2 daily) and adjuvant TMZ (150-200 mg/m2 daily for 5 days every 28 days) for two years after initiation of HD-MTX or until tumor progression (experimental arm: B). Randomization was adjusted by institution, PS (0-1 / 2-3), age (≤60/≥61 years), presence or absence of intraparenchymal tumor after HD-MTX. The primary endpoint was overall survival (OS). The planned sample size was 130 pts in total, to provide an 80% power to detect a 0.52 hazard ratio (65% vs 80% in 2y-OS) for arm B to A and a one-sided alpha of 5%. Results: Between September 29, 2014 and October 15, 2018, 134 pts were enrolled, of whom 122 were randomly assigned and analyzed; 62 to arm A and 60 to arm B. At the planned interim analysis, the 2-y OS was 86.8% (95% CI: 72.5-94.0) in arm A and 71.4% (56.0-82.2) in arm B. The hazard ratio was 2.18 (95% CI: 0.95 to 4.98) with predictive probability for showing the superiority of arm B at the final analysis was calculated to be 1.3%. The study was terminated due to futility. The 2-y progression-free survival was 60.6% (43.6-73.8) in arm A and 49.9% (34.4-63.5) in arm B with a hazard ratio of 1.54 (0.88 to 2.70). The most common grade 3 and 4 toxicities were lymphopenia, observed in 7 (11.5%) pts during WBRT in arm A, 18 (30%) pts during WBRT + concomitant TMZ and 18 (37.5%) pts during adjuvant TMZ in arm B. Conclusions: This study failed to demonstrate the benefit of the addition of TMZ to WBRT and adjuvant TMZ in newly diagnosed PCNSL. Possible biomarkers including methylation status of the MGMT promoter in the tumors will be analyzed. Clinical trial information: jRCTs031180207 .

ACT-25 CLINICAL TRIALS BY THE JCOG BRAIN TUMOR STUDY GROUP

Ongoing brain tumor clinical trials by the Japan Clinical Oncology Group (JCOG) are:JCOG1016, phase III randomized study in patients with anaplastic glioma of radiotherapy with temozolomide versus nimustine hydrochloride (ACNU) followed by temozolomide, is to prove superiority of post-operative radiotherapy with ACNU. JCOG1114, phase III study of high-dose methotrexate and whole brain radiotherapy with or without concomitant and adjuvant temozolomide in patients with primacy CNS lymphoma, is to prove usefulness and get insurance approval of TMZ for primary CNS lymphoma. JCOG1303, randomized phase III study for unresectable WHO Grade II diffuse astrocytoma with radiotherapy alone or chemoradiotherapy with temozolomide, is to prove superiority of STUPP regimen over simple radiotherapy for newly diagnosed and unresectable diffuse astrocytoma. JCOG1308, a multicenter randomized phase III study for recurrent glioblastoma comparing bevacizumab alone with dose-dense temozolomide followed by bevacizumab, is to prove usefulness of dose-dense, 7 days on/7 days off, TMZ, and to approve insurance coverage for recurrent GBM. JCOG1703, a multicenter randomized phase III study for newly-diagnosed maximally resected glioblastoma comparing carmustine wafer implantation followed by Stupp regimen with Stupp regimen alone, is to prove the survival advantage of surgery of GBM using carmustine wafer.

A Phase 2 Trial of Neoadjuvant Temozolomide (TMZ) Followed By Accelerated Hypofractionated Radiation Therapy (AHRT) and TMZ Followed By Adjuvant TMZ in Patients with Newly Diagnosed Glioblastoma (GBM): Long Term Survival and Toxicity Analysis

Purpose: Encouraging results were observed on analysis of a phase II of neoadjuvant temozolomide (TMZ) followed by AHRT and TMZ followed by adjuvant TMZ in patients with newly diagnosed GBM. Here, we report long term outcomes. Fifty patients were accrued: age >18 years, histologically-proven GBM, KPS ≥ 60 and adequate hematologic, renal, and hepatic functions. Three to 4 weeks post-surgery patients started neoadjuvant TMZ for 2 weeks, followed by concomitant AHRT and TMZ followed by adjuvant TMZ. GTV was surgical cavity and/or postoperative contrast-enhancing lesion on MRI. PTV60 included GTV plus 0.5 cm and PTV 40 included GTV plus 2.0 cm. PTV60 received 60 Gy in 20 fractions, while PTV40 received 40 Gy. From March 2009 and July 2013, 50 patients were accrued with a median age of 60 years. MGMT gene promoter was methylated in 21 patients and unmethylated in 27. Gross total and partial resection were performed in 46, and biopsy in 4 patients. With a median follow up of 71 months for patients at risk, median OS is 22 months with PFS of 13.2 months. At 3 and 5 years, actuarial OS was 34% and 23%, respectively. Methylated MGMT gene promoter patients have OS of 57% and 40.9% at 3 and 5 years, respectively compared to 18.5% and 11.1% for unmethylated MGMT. Eleven patients had reoperation for suspected recurrence, 5 were found to have radiation effects with no evidence of recurrence. The actuarial freedom from necrosis is 82.5% at 78 months, with a plateau after 32.9 months. One patient had a grade 5 hematological toxicity without evidence of disease recurrence at time of death. Another patient developed a grade 4 hepatotoxicity which reversed back to normal after discontinuation of TMZ. As of the date of this report, 10 patients are alive at present with ECOG status of 0 in 4, ECOG 1 in 2, ECOG 2 in 3, and ECOG 3 in one patient. Of the 10 patients 7 are not receiving corticosteroids, while 3 are receiving dexamethasone doses varying between 0.5 mg and 4 mg QD. With a longer follow up, the initially observed OS was further confirmed, and compares favorably to OS reported by large clinical trials. The long-term toxicity continues to be monitored closely, especially for this special group of patients with long survival. Laboratory, in-vitro and in-vivo, experiments are currently underway to further understand the molecular basis of the interactions of neoadjuvant TMZ and AHRT. Future plans are to conduct a phase III randomized clinical trial to compare the current approach versus the standard Stupp’s regimen.

P01.005 The impact of thrombocytopenia from concomitant and adjuvant temozolomide in patients with glioblastoma

P01.005 The impact of thrombocytopenia from concomitant and adjuvant temozolomide in patients with glioblastoma

Interim Results of a Phase II Study of Hypofractionated Radiotherapy with Concurrent Temozolomide Followed by Adjuvant Temozolomide in Patients over 70 Years Old with Newly Diagnosed Glioblastoma

Objective: In this phase II study, we investigate clinical outcomes and tolerability of hypofractionated radiotherapy (HRT) combined with temozolomide (TMZ) to treat elderly patients with glioblastoma (GBM). Methods: Patients 70 years of age or older with newly diagnosed GBM received HRT to a dose of 34 Gy given in ten fractions over 2 weeks, delivered with concurrent and adjuvant TMZ. Results: In this interim analysis, ten patients were enrolled on trial from 12/1/2015 to 4/5/2017. With a median follow-up of 9 months (range 3–12 months), median progression-free survival (PFS) was 6 months. The median overall survival (OS) has not been reached. Estimated 1-year OS and PFS rates were 53.3 and 44.4%, respectively. All patients completed the full course of RT, with no patients developing grade 3 or higher adverse events from treatment. Conclusions: The preliminary results of our phase II trial suggest HRT delivered over 2 weeks with concurrent and adjuvant TMZ is well tolerated in elderly patients with GBM without compromising clinical outcomes.

A search for the "Goldilocks zone" with regard to the optimal duration of adjuvant temozolomide in patients with glioblastoma.

A search for the "Goldilocks zone" with regard to the optimal duration of adjuvant temozolomide in patients with glioblastoma.

A Phase 2 Trial of Neoadjuvant Temozolomide Followed by Hypofractionated Accelerated Radiation Therapy With Concurrent and Adjuvant Temozolomide for Patients With Glioblastoma

We performed a phase 2 trial of neoadjuvant temozolomide (TMZ), followed by hypofractionated accelerated radiation therapy (HART) with concurrent TMZ, and adjuvant TMZ in patients with newly diagnosed glioblastoma to determine whether neoadjuvant TMZ would safely improve outcomes in this group of patients prior to subsequent cytotoxic therapy. Adult patients with newly diagnosed glioblastoma and a Karnofsky Performance Status >60 were eligible. Neoadjuvant TMZ administration started 2 to 3weeks from surgery at a daily dose of 75mg/m2 for 2weeks prior to delivery of HART (60Gy in 20 daily fractions) with concurrent and adjuvant TMZ. The primary endpoints were feasibility and toxicity. The secondary endpoints included overall survival (OS) and progression-free survival. Fifty patients were accrued. The median follow-up period was 44.0months for patients at risk and 22.3months for all 50 patients. Except for 1 patient in whom infection developed and another patient with progression during HART, all patients completed protocol therapy as planned. The median OS and progression-free survival were 22.3months (95% confidence interval, 14.6-42.7months) and 13.7months (95% confidence interval, 8.0-33.3months), respectively. The 4-year OS rates were 30.4% for the entire cohort and 53.3% and 14.0% for patients with methylated (n=21) and unmethylated (n=27) MGMT gene promoter tumors, respectively. One patient had grade 5 pancytopenia during HART, and another patient had transient grade 4 hepatotoxicity. A second surgical procedure was performed in 13 patients: 2 had intracranial infection, 3 had recurrences, 4 had recurrences and radiation-induced damage, and 4 had only radiation-induced damage. This novel approach of neoadjuvant TMZ is associated with an encouraging favorable long-term survival with acceptable toxicity. A future comparative trial of the efficacy of this regimen is warranted.

PRM5 - To Evaluate the Outcomes of Concomitant Chemoradiotherapy Followed by Extended Adjuvant Temozolomide in Patients with Newly Diagnosed Glioblastoma - A Retrospective Study

PRM5 - To Evaluate the Outcomes of Concomitant Chemoradiotherapy Followed by Extended Adjuvant Temozolomide in Patients with Newly Diagnosed Glioblastoma - A Retrospective Study

Benefits, limitations and opportunities of NOTCH inhibitors for treatment of glioma

: High grade gliomas are associated with worse prognosis and treatment failure. In glioma, the anti-tumor effect of Notch inhibition in combination with the standard care of treatment has been shown in vitro and in pre-clinical research. Now, a phase 0/1 trial by Xu et al., evaluated for the first time the efficacy of a previously available NOTCH inhibitor (RO4929097) in combination with standard treatment consisting of radiation therapy (RT) with daily temozolomide (TMZ) followed by adjuvant TMZ in patients with glioblastoma (GBM) or anaplastic astrocytoma (AA). Quite impressively the authors also studied the in vivo pharmacokinetics of RO4929097 and tumor perfusion in glioma prior to RT + TMZ and in resections using contrast-enhanced MRI and noted tumor progression in several patients during treatment. However, defining disease progression versus pseudoprogression (psPD) as a result of therapy-induced alteration of blood-brain-barrier (BBB) can be difficult. While sufficient drug target inhibition was achieved in the initial tumor, recurrence occurred. Surprisingly, recurrent tumors exhibited increased expression of angiogenesis markers despite low NOTCH activity contrasting the pro-angiogenic role of NOTCH. While the authors concluded a NOTCH-independent form of angiogenesis, it is possible that therapy-induced inflammation and necrosis resulted into break down of the BBB causing the upregulation of pro-angiogenic markers. Given the disappointing outcome of the sustained NOTCH inhibition, their effect could potentially be enhanced when used in conjunction with angiogenesis inhibitors. Importantly, in this study it was not stated if GBM tumors originated de novo (primary) or progressed from low grade glioma (secondary). This is crucial due to their different cell of origin and molecular profile, which can lead to different treatment response and outcome. Further investigating different scheduling to allow normal tissue recovery, optimizing the sequence of multimodal treatments, combined with patient selection and monitoring seems necessary to move NOTCH therapeutics forward.

A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme

Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.

Results of a Phase 2 Clinical Trial of Neo-Adjuvant Temozolomide (TMZ), Followed by Concurrent TMZ and Hypofractionated Accelerated External Beam Radiation Therapy (Ac-EBRT) With Limited Margins, and Adjuvant TMZ for Patients With Glioblastoma Multiforme (GBM)

Results of a Phase 2 Clinical Trial of Neo-Adjuvant Temozolomide (TMZ), Followed by Concurrent TMZ and Hypofractionated Accelerated External Beam Radiation Therapy (Ac-EBRT) With Limited Margins, and Adjuvant TMZ for Patients With Glioblastoma Multiforme (GBM)

Temozolomide added to whole brain radiotherapy in patients with multiple brain metastases of non-small-cell lung cancer: a multicentric Austrian phase II study

This multicentric randomized phase II study investigated the feasibility and toxicity of temozolomide (TMZ) added to whole brain radiotherapy (WBRT) followed by adjuvant TMZ in patients with multiple brain metastases of non-small-cell lung cancer (NSCLC). Patients with multiple brain metastases from NSCLC aged ≥ 18 years, classified according to recursive partitioning analysis class I or II and with adequate organ functions were eligible. Treatment consisted of WBRT + TMZ 75 mg/m² for 2 weeks followed at day 28 by TMZ 100 mg/m²/day 2 weeks on/2 weeks off for up to 6 months (radiochemotherapy, RCT) or WBRT alone (radiotherapy, RT). The study enrolled only 35 patients (22 patients in RCT and 13 in RT) and had to be closed prematurely due to poor accrual. The toxicity was mainly due to TMZ with WHO grade 3 and 4 thrombocytopenia in 3/22 versus 0/13, leucocytopenia in 1/22 versus 0/13 and lymphocytopenia in 7/22 versus 12/13 patients in RCT and RT respectively. Thirteen patients in RCT and six in RT progressed systemically and dropped out before first restaging of the response in brain. Median time to progression (TTP) was 2.4 months (95 % CI: 2-2.6 months) and 2.0 months (95 % CI: 0.5-3.5 months), median overall survival (OAS) was 3 months (95% CI: 1.7-3.1 months) and 6.3.months (95 % CI: 0.2-7.6 months) in RCT and RT, respectively. Like other studies before on patients with brain metastases, insufficient number of recruited patients does not allow conclusions on efficacy and toxicity as the study closed prematurely.

Phase I study of hypofractionated intensity modulated radiation therapy with concurrent and adjuvant temozolomide in patients with glioblastoma multiforme

PurposeTo determine the safety and efficacy of hypofractionated intensity modulated radiation therapy (Hypo-IMRT) using helical tomotherapy (HT) with concurrent low dose temozolomide (TMZ) followed by adjuvant TMZ in patients with glioblastoma multiforme (GBM).Methods and materialsAdult patients with GBM and KPS > 70 were prospectively enrolled between 2005 and 2007 in this phase I study. The Fibonacci dose escalation protocol was implemented to establish a safe radiation fractionation regimen. The protocol defined radiation therapy (RT) dose level I as 54.4 Gy in 20 fractions over 4 weeks and dose level II as 60 Gy in 22 fractions over 4.5 weeks. Concurrent TMZ followed by adjuvant TMZ was given according to the Stupp regimen. The primary endpoints were feasibility and safety of Hypo-IMRT with concurrent TMZ. Secondary endpoints included progression free survival (PFS), pattern of failure, overall survival (OS) and incidence of pseudoprogression. The latter was defined as clinical or radiological suggestion of tumour progression within three months of radiation completion followed by spontaneous recovery of the patient.ResultsA total of 25 patients were prospectively enrolled with a median follow-up of 12.4 months. The median age at diagnosis was 53 years. Based on recursive partitioning analysis (RPA) criteria, 16%, 52% and 32% of the patients were RPA class III, class IV and class V, respectively. All patients completed concurrent RT and TMZ, and 19 patients (76.0%) received adjuvant TMZ. The median OS was 15.67 months (95% CI 11.56 - 20.04) and the median PFS was 6.7 months (95% CI 4.0 – 14.0). The median time between surgery and start of RT was 44 days (range of 28 to 77 days). Delaying radiation therapy by more than 6 weeks after surgery was an independent prognostic factor associated with a worse OS (4.0 vs. 16.1 months, P = 0.027). All recurrences occurred within 2 cm of the original gross tumour volume (GTV). No cases of pseudoprogression were identified in our cohort of patients. Three patients tolerated dose level I with no dose limiting toxicity and hence the remainder of the patients were treated with dose level II according to the dose escalation protocol. Grade 3–4 hematological toxicity was limited to two patients and one patient developed Grade 4 Pneumocystis jiroveci pneumonia.ConclusionHypo-IMRT using HT given with concurrent TMZ is feasible and safe. The median OS and PFS are comparable to those observed with conventional fractionation. Hypofractionated radiation therapy offers the advantage of a shorter treatment period which is imperative in this group of patients with limited life expectancy.