Dataset Information

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series.

ABSTRACT:

Objectives

To report on the tolerability and efficacy of olaparib with temozolomide (TMZ) for glioma METHODS: Single-center retrospective series of glioma patients treated with olaparib/TMZ September 2018-December 2021 RESULTS: Twenty patients (median age: 42, median Karnofsky Performance Status: 90) received olaparib/TMZ for diagnoses of IDH-mutant oligodendroglioma (n=5), IDH-mutant astrocytoma grade 2-3 (n=4), IDH-mutant astrocytoma grade 4 (n=7), or IDH-wildtype glioma (n=4). One patient was treated upfront and 19 at recurrence (median=3). Olaparib 150mg was administered three times/week concurrent with TMZ 50-75mg/m² daily. Fatigue, gastrointestinal symptoms, and hematologic toxicity were common. 6/20 patients required dose reduction (n=4) or discontinuation (n=2) due to toxicity. Radiographic response was evaluable in 16 and observed (complete + partial) in 4/8 with IDH-mutant grade 2-3 glioma. No responses were seen in patients with grade 4 IDH-mutant astrocytomas (0/5) or IDH-wildtype gliomas (0/3). Progression-free survival was 7.8, 1.3, and 2.0 months, respectively.

Discussion

Olaparib/TMZ resulted in objective radiographic response in 50% of evaluable patients with recurrent IDH-mutant grade 2-3 gliomas with encouraging PFS and manageable toxicity. This supports a prospective trial of olaparib/TMZ for this population.

Classification of evidence

This case series provides Class IV evidence that treatment with olaparib/TMZ may result in radiographic response in patients with glioma.

SUBMITTER: Schaff LR

PROVIDER: S-EPMC9620814 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series.

Schaff Lauren R LR Kushnirsky Marina M Lin Andrew L AL Nandakumar Subhiksha S Grommes Christian C Miller Alexandra Michelle AM Gavrilovic Igor T IT Nolan Craig C Pentsova Elena E Mellinghoff Ingo K IK Kaley Thomas J TJ

Neurology 20221024 17

<h4>Background and objectives</h4>To report the tolerability and efficacy of olaparib with temozolomide (TMZ) for glioma.<h4>Methods</h4>Single-center retrospective series of patients with glioma treated with olaparib/TMZ from September 2018 to December 2021.<h4>Results</h4>Twenty patients (median age: 42 years, median Karnofsky Performance Status: 90) received olaparib/TMZ for diagnoses of <i>IDH</i>-mutant oligodendroglioma (n = 5), <i>IDH-</i>mutant astrocytoma grade 2-3 (n = 4), <i>IDH</i>-m ...[more]

PMID: 35948444

Similar Datasets

Project description:For pediatric patients with high-grade gliomas, standard-of-care treatment includes surgery, chemotherapy, and radiation therapy; however, most patients ultimately succumb to their disease. With advances in genomic characterization of pediatric high-grade gliomas, the use of targeted therapies in combination with current treatment modalities offer the potential to improve survival in this patient population. In this report, we present the case of a 3-year-old girl with glioblastoma who continues to experience an exceptional and durable response (>2?years) to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib. Our patient presented with persistent and progressive seizure activity that upon workup was the result of a large heterogeneously enhancing, mixed cystic and solid mass in the left frontal-parietal-temporal region. Histopathologic analysis of resected tumor tissue confirmed the diagnosis of glioblastoma, and comprehensive genomic profiling demonstrated absence of any BRAF or H3F3A mutations. Genomic profiling, however, did reveal a probable germline heterozygous BRCA2 Lys3326Ter (K3226*) nonsense variant. After debulking surgery, the patient received standard-of-care treatment with radiation and temozolomide. Nine months later the PARP inhibitor olaparib was administered in combination with temozolomide for 16 cycles. This regimen was well tolerated by the patient and serial imaging showed reduction in tumor size. Since completion of the regimen, the patient remains neurologically intact with no evidence of tumor recurrence. To our knowledge, this represents the first case of a pediatric glioblastoma that maintains a durable response to a therapeutic strategy that included the PARP inhibitor olaparib and more generally highlights the potential clinical utility of incorporating these agents into the treatment of pediatric high-grade gliomas. KEY POINTS: Germline mutations detected in pediatric gliomas may represent a cancer predisposition syndrome. Integrating molecular testing into routine clinical care for pediatric patients with glioma is critical to identify therapeutic targets and patients with a cancer predisposition syndrome. Patients with glioma with defects in DNA repair pathway components (e.g., BRCA1/2) may show increased responsiveness to poly (ADP-ribose) polymerase (PARP) inhibitors. Combining PARP inhibitors with temozolomide (standard-of-care treatment) revealed no adverse events or toxicities over the course of 18 months.

Project description:Anti-angiogenic agents, such as bevacizumab (BEV), can induce normalization of the blood brain barrier, which may influence the penetration and activity of a co-administered cytotoxic drug. However, it is unknown whether this effect is associated with a benefit in overall survival. This study employed intracranial human glioma models to evaluate the effect of BEV alone and in combination with temozolomide (TMZ) and/or radiation therapy (XRT) on overall survival. One hundred eight male athymic rats were intracranially injected with either U251 or U87 human glioma. Ten or eleven days after tumor inoculation, animals bearing U251 and U87, respectively, were treated with: TMZ alone (50 mg/kg for 5 consecutive days, P.O.), BEV alone (15 mg/kg, I.V.), a combination of TMZ and BEV, or a combination of TMZ, BEV, and a single fraction of XRT (20 Gy). Controls received no treatment. The U87 experiment was repeated and the relationship between survival and the extent of anti-angiogenesis via anti-laminin antibodies for the detection of blood vessels was assessed. In both U87 glioma experiments, all of the treatment groups had a statistically significant increase in survival as compared to the control groups. Also, for both U87 experiments the combination groups of TMZ and BEV had significantly better survival when compared to either treatment administered alone, with 75% of animals demonstrating long-term survival (LTS) (defined as animals alive 120 days after tumor implantation) in one experiment and 25% LTS in the repeat experiment. In the U251 glioma experiment, all treated groups (except BEV alone) had significantly improved survival as compared to controls with minimal statistical variance among groups. The percent vessel area was lowest in the group of animals treated with BEV alone. The addition of BEV to TMZ and/or XRT had variable effect on prolonging survival in the two human glioma models tested with reduced tumor vascularity in groups treated with BEV. These results indicate that BEV has anti-angiogenic activity and does not seem to hinder the effect of TMZ.

Project description:Non-tubal ectopic pregnancies are a rare subgroup of ectopic pregnancies implanted at sites other than the Fallopian tube. Mortality from non-tubal ectopic pregnancies is higher compared with that for tubal ectopic pregnancies, and they are becoming more common, partly due to the rising incidence of Caesarean sections and use of assisted reproductive technologies. Non-tubal ectopic pregnancies can be especially difficult to treat. Surgical treatment is complex, and follow-up after medical treatment is usually protracted. There is therefore a need for more effective medical therapies to resolve non-tubal ectopic pregnancies and reduce operative intervention. We have recently reported successful use of combination gefitinib (an orally available epidermal growth factor receptor inhibitor) and methotrexate for treatment of tubal pregnancies. To our knowledge, this combination has not been used to treat non-tubal pregnancies. Here we report the use of combination gefitinib and methotrexate to treat eight women with stable, non-tubal ectopic pregnancies at two tertiary academic teaching hospitals (Edinburgh, UK and Melbourne, Australia); five interstitial and three Caesarean section scar ectopic pregnancies. Pretreatment serum hCG levels ranged from 2458 to 48 550 IU/l, and six women had pretreatment hCG levels >5000 IU/l. The women were co-administered 1-2 doses of i.m. methotrexate (50 mg/m² on Day 1, ± Day 4 or Day 7) with seven once daily doses of oral gefitinib (250 mg). The women were monitored until complete resolution of the ectopic pregnancy, defined as a serum hCG <15 IU/l. Time to resolution (days from first methotrexate dose until serum hCG <15 IU/l), safety and tolerability, complication rates and subsequent fertility outcomes were also recorded. All eight women were successfully treated with combination gefitinib and methotrexate. The most common side effects were transient acne/rash and diarrhoea, known side effects of gefitinib. All women promptly resumed menstruation and importantly, three women subsequently conceived spontaneously. Two have delivered a healthy infant at term and the third is currently in her second trimester of pregnancy. Hence, our case series supports a future clinical trial to determine the efficacy of combination gefitinib and methotrexate to treat non-tubal ectopic pregnancies.

Dataset Information

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series.

Objectives

Discussion

Classification of evidence

Publications

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets