Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas

Abstract BACKGROUND The optimal management of high risk WHO grade II gliomas after surgery is still debated. The efficacy of initial temozolomide to delay radiotherapy and risk of cognitive defects could vary across the molecular subgroups of WHO 2016, but information on this issue are lacking. PATIENTS AND METHODS A post-hoc analysis has been performed on a cohort of high risk WHO grade II gliomas, who received initial temozolomide alone in phase II multicenter study, with the objective of re-evaluating the long-term results across the different molecular subgroups of the WHO 2016 classification. The primary endpoint of the study, carried out between 2007 and 2010, was response rate according to RANO, being seizure response, PFS and OS secondary endpoints. RESULTS Response rate (partial and minor responses) among oligodendrogliomas IDH-mutant and 1p/19q codeleted (76%) was significantly higher than that among diffuse astrocytomas either mutant (55%) or wild-type (36%). A reduction of seizure frequency >50% was observed in 87% patients and a seizure freedom in 72%. The probability of seizure reduction >50% was significantly associated with the presence of an IDH mutation. Median PFS, PFS at 5 and 10 years, median OS and OS at 5 and 10 years were all significantly longer in oligodendrogliomas IDH-mutant and 1p/19q codeleted. Of patients who did not recur or delay radiotherapy at recurrence for a median follow-up of 8.2 years, 67% and 59%, respectively, were oligodendrogliomas IDH-mutant and 1p/19q codeleted. CONCLUSIONS The post-hoc analysis of this phase II trial suggests that the beneficial effects of initial temozolomide prevail in oligodendrogliomas IDH-mutant and 1p/19q codeleted: thus, these tumors, when incompletely resected or progressive after surgery, especially when suffering from pharmacoresistant seizures, could receive temozolomide as initial treatment with radiotherapy and chemotherapy at recurrence. The trial was registered with EU Clinical Trials Register, EudraCT n. 2007/000386-38.

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Lack of complete 1p19q deletion in a consecutive series of 12 WHO grade II gliomas involving the insula: a marker of worse prognosis?

Journal of Neuro-Oncology ◽

10.1007/s11060-008-9680-8 ◽

2008 ◽

Vol 91 (1) ◽

pp. 1-5 ◽

Cited By ~ 35

Author(s):

C. Gozé ◽

V. Rigau ◽

L. Gibert ◽

T. Maudelonde ◽

H. Duffau

Keyword(s):

Consecutive Series ◽

Who Grade ◽

Grade Ii ◽

Who Grade Ii Gliomas ◽

Worse Prognosis

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Influence of 1p19q status and Ki67 index to predict extent of resection in WHO grade II gliomas: a virtual patient model

Journal of Neuro-Oncology ◽

10.1007/s11060-015-1790-5 ◽

2015 ◽

Vol 123 (2) ◽

pp. 317-318 ◽

Cited By ~ 3

Author(s):

Dominik Cordier ◽

Sabine Schädelin ◽

Hugues Duffau

Keyword(s):

Extent Of Resection ◽

Virtual Patient ◽

Ki67 Index ◽

Who Grade ◽

Patient Model ◽

Grade Ii ◽

Who Grade Ii Gliomas

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Surgery for Diffuse WHO Grade II Gliomas: Volumetric Analysis of a Multicenter Retrospective Cohort From the German Study Group for Intraoperative Magnetic Resonance Imaging

Neurosurgery ◽

10.1093/neuros/nyz397 ◽

2019 ◽

Vol 86 (1) ◽

pp. E64-E74 ◽

Cited By ~ 6

Author(s):

Moritz Scherer ◽

Hajrulla Ahmeti ◽

Constantin Roder ◽

Florian Gessler ◽

Christine Jungk ◽

...

Keyword(s):

Regression Models ◽

Cox Regression ◽

Study Group ◽

Incomplete Resection ◽

Who Grade ◽

German Study ◽

Significant Survival ◽

Idh Mutations ◽

Grade Ii ◽

Who Grade Ii Gliomas

Abstract BACKGROUND In diffuse WHO grade II gliomas (LGG), the extent of resection (EOR) required to achieve significant survival benefits remains elusive. OBJECTIVE To evaluate the association of residual volume (RV) and EOR with progression-free survival (PFS) or overall survival (OS) in LGG in a retrospective, multicenter series by the German study group of intraoperative MRI (GeSGIM). METHODS Consecutive cases were retrospectively assessed from 5 centers. Tumors were volumetrically quantified before and after surgery, and clinical data were analyzed, including IDH mutations and neurologic deficits. Kaplan–Meier estimates, accelerated failure time models (AFT), and multivariate Cox regression models were calculated to identify determinants of survival. RESULTS A total of 140 cases were analyzed. Gross total resection (GTR) was associated with significantly longer PFS compared to any incomplete resection (P = .009). A significant survival disadvantage was evident even for small (>0-5 ml) residuals and increased for moderate (>5-20 ml) and large remnants (>20 ml) P = .001). Accordingly, PFS increased continuously for 20% incremental steps of EOR (P < .001). AFT models supported the notion of a continuous association of RV and EOR with PFS. Multivariate Cox regression models confirmed RV (P = .01) and EOR (P = .005) as continuous prognosticators of PFS. Univariate analysis showed significant associations of RV and EOR with OS. CONCLUSION Our data support the hypothesis of a continuous relationship of RV and EOR with survival for LGG with superiority seen for GTR. Hence, GTR should be achieved whenever safely feasible, and resections should be maximized whenever tumor has to be left behind to spare function.

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PVAG (Prednisone, Vinblastine, Doxorubicin and Gemcitabine) In Elderly Patients with Intermediate or Advanced Stage Hodgkin Lymphoma: Final Results of a Phase II Study of the German Hodgkin Study Group (GHSG).

Blood ◽

10.1182/blood.v116.21.2827.2827 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2827-2827

Author(s):

Boris Böll ◽

Teresa Halbsguth ◽

Helen Görgen ◽

Henning Bredenfeld ◽

Hans Eich ◽

...

Keyword(s):

Elderly Patients ◽

Hodgkin Lymphoma ◽

Phase Ii ◽

Poor Prognosis ◽

Progressive Disease ◽

Phase Ii Study ◽

Advanced Stage ◽

Who Grade ◽

Who Grade Iii ◽

Grade Iii

Abstract Abstract 2827 About 20% of all patients diagnosed with Hodgkin lymphoma (HL) are older than 60 years. These patients have a rather poor prognosis, particularly when presenting in intermediate or advanced stages. Besides a biologically more aggressive disease, the main reason is a drastically increased toxicity of chemo- and radiotherapy resulting in a higher treatment-related mortality and insufficient dosing of the applied treatment. In the GHSG-HD9 trial, elderly patients did not benefit from the BEACOPP regimen in terms of overall survival due to a high toxicity related death rate. In order to improve tolerability, the PVAG regimen (prednisone, vinblastine, doxorubicin, and gemcitabine) was developed. This is a modification of the ABVD regimen in which bleomycin and dacarbazine were replaced by prednisone and gemcitabine. Here we report for the first time on the final analysis of this multi-center phase II study for elderly HL patients. 61 patients were recruited between 2004 and 2007. 2 patients were excluded due to histology review not confirming HL, resulting in 59 patients with intermediate- or advanced-stage HL aged between 60 and 75 years. Treatment consisted of 6 cycles PVAG in patients achieving a complete remission (CR) after 4 cycles or 8 cycles PVAG in case of partial remission (PR) after 4 cycles. Patients who did not achieve CR after the end of chemotherapy received additional radiotherapy. Primary endpoints were administration of adequate dose without excessive delays, and response rate 3 months after end of treatment. Secondary endpoints included WHO grade III/IV toxicities, and occurrence of early progression. 59 patients with a median age of 68 years were evaluated, of which 59% were male and 93% had advanced stage disease. The relative dose intensity (relative dose divided by relative chemotherapy duration) was at least 80% in 44 patients (76%). Regarding the single cycles, of which 85% started without major delay (max. 1 day), the mean relative dose of all agents was slightly decreasing over time but always exceeded 90%. WHO grade III/IV toxicities were documented in 43 patients (75%). Only 3 patients terminated CT because of excessive toxicity. 10 Patients (17%) received consolidating radiotherapy. In total, 46 patients responded with CR/CRu (78%; 95% CI: 65% to 88%), 2 with PR (3%), 2 with no change (3%) and 4 with progressive disease (7%). 3 patients died before restaging with unknown response and in 2 patients treatment outcome is unknown. With a median observation time of 37 months, 6 patients (10%) had progressive disease and 9 patients (15%) relapsed. In total, 10 patients died from relapsing or progressing HL, 2 from second malignancies (one of lung cancer after 23 months, and one of AML after 25 months) and 5 patients due to other reasons. Overall 17 patients (29%, 95% CI: 18% to 42%) have died so far. In conclusion, PVAG is safe and feasible in Hodgkin patients older than 60. The PFS indicates activity of this regimen in this poor prognosis patient cohort. However, a controlled randomized trial to determine the best treatment in this patient population is warranted. This trial was registered at www.clinicaltrials.gov as #NCT00147875. Disclosures: No relevant conflicts of interest to declare.

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BMX-HGG: Phase II trial of newly diagnosed high-grade glioma treated with concurrent radiation therapy, temozolomide, and BMX-001.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps2577 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS2577-TPS2577

Author(s):

Katherine B. Peters ◽

Adam Louis Cohen ◽

Nicholas A. Butowski ◽

John L. Villano ◽

Pierre Giglio ◽

...

Keyword(s):

Radiation Therapy ◽

White Matter ◽

Cancer Therapy ◽

Phase Ii ◽

Functional Assessment ◽

Phase Ii Study ◽

High Grade Glioma ◽

High Grade ◽

Newly Diagnosed ◽

Who Grade

TPS2577 Background: Patients diagnosed with malignant high-grade gliomas (WHO grade III-IV) experience significant morbidity and mortality associated with these cancers. While the mainstay of therapy for patients with newly diagnosed high-grade glioma is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain very poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. Early preclinical studies demonstrated BMX-001’s ability to act as a radioprotectant to healthy tissue such as a central nervous white matter and as a radiosensitizer to cancer cells, in particular, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase I study of newly diagnosed high-grade glioma patients, and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase II study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints include cognitive performance as assessed by standardized cognitive testing, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase II study has enrolled 64 of 160 high-grade glioma patients at six sites with future sites planned to be implemented. Clinical trial information: NCT02655601 .

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