Treatment Of Oligodendrogliomas Research Articles

Abstract 476: MEK inhibitors for treatment of oligodendroglioma

Abstract Oligodendroglioma (OD) is defined by the 2016 WHO classification as IDH mutant gliomas with 1p19q co-deletion. Although ODs are sensitive to chemotherapy, they eventually recur leading to functional deficits and ultimately death. CIC gene mutations, located on chromosome 19q are seen in 60% of 1p19q co-deleted OD and have been linked to worse survival. Despite our growing knowledge of the molecular characteristics of OD, all recurrent OD patients are treated similarly mainly using radiation and/or poorly tolerated cytotoxic chemotherapy with modest benefit. There is therefore an urgent unmet medical need to understand the molecular consequence of recurrent mutations in OD in order to improve patient outcomes. CIC gene mutations result in truncated, degraded or non-functional CIC protein, disrupting CIC protein repressor functions. This leads to upregulation of ETS-Pea3 family of transcription factors which are known oncogenes in a variety of solid cancers. MAPK signaling pathway has been shown to directly activate ETS family of proteins in drosophila. However, the link between MAPK signaling, ETS proteins and CIC in OD is elusive. Here, we propose a model of aggressiveness in CIC mutant OD in which these cells are dependent on MAPK axis for activation of their augmented ETS proteins (i.e ETV1, ETV4) and therefore are sensitive to MAPK inhibition. To test our model, we evaluated mRNA and protein expression of ETS family of proteins in CIC mutant and CIC wild-type mouse OD cell lines and show that ETV1 and ETV4 have elevated protein and mRNA expression in CIC mutant OD cells, respectively. Consistent with our hypothesis, two different MEK inhibitors, trametinib and pimasertib, reduce cell viability of OD cell lines with greater reduction in CIC mutant than wild-type cells. As proof of concept, we demonstrate that CIC mutant cells have increased pERK expression when compared with CIC wild-type cells indicating that MAPK pathway is more active in CIC mutant cells. Overall, we were able to show that MEK inhibitors have anti-tumor effects in OD cell lines, with greater sensitivity seen in CIC mutant cells. This work lays the foundation for repurposing the widely clinically used MEK inhibitors for treatment oligodendroglioma patients with CIC mutation. Citation Format: Nazanin Majd, Soon Young Park, Marisela Martinez de Kraatz, Veerakumar Balasubramaniyan, Mittal Sandeep, Jian Hu, Jihye Paik, John de Groot. MEK inhibitors for treatment of oligodendroglioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 476.

Retrospective review for outcomes of IDH mutant, 1p/19q co-deleted gliomas based on initial treatment.

2063 Background: Treatment for oligodendroglioma in the molecular era is based on trials that used histologic criteria alone and has evolved over time to include observation and a combination of radiation (RT) and chemotherapy. In particular, treatment for high-risk patients is variable including sequential RT followed by temozolomide (TMZ) or procarbazine, lomustine, and vincristine (PCV) or chemoradiation with TMZ. This is a single institutional review of outcomes of molecular IDH mutant, 1p19q co-deleted oligodendroglioma based on initial treatment. Methods: Using both Palantir Foundry and direct record review, we stratified adult patients with grade II/III gliomas diagnosed from 1997-2017 harboring an IDH mutation and 1p/19q co-deletion based on initial treatment and excluded patients without molecular testing. Overall survival (OS) and progression free survival (PFS) were calculated by Kaplan-Meier analysis. Results: 187 patients were initially managed as: 55 (31%) observation, 16 (9%) RT alone, 51 (29%) chemotherapy alone, 39 (22%) sequential RT and chemotherapy, and 17 (10%) chemoradiation. For all patients, a subtotal (STR) or gross total resection (GTR) was associated with prolonged OS vs biopsy (NR vs 123 mos, p = 0.007). Age < 40 did not correlate with OS (p = 0.87). In the chemotherapy group, although PCV demonstrated improved PFS vs TMZ (157 vs 45 mos, p = 0.004) there was no difference in OS, only 3 patients received PCV. For patients treated sequentially with RT and PCV or TMZ vs chemoradiation, there were no differences in OS (NR vs 140 mos; p = 0.87) or PFS (49 vs 45 mos, p = 0.52), though sequential treatment trended toward prolonged survival. Conclusions: This data supports both STR and GTR as prognostic for overall survival. Despite the prolonged PFS observed with patients treated with PCV alone which did not translate to improved OS, the small PCV sample size limits the strength of this evidence. We did not find significant survival differences between sequential RT and chemotherapy vs concurrent, but interestingly, there was a trend toward improved OS in sequentially treated patients.

Eighty percent survival rate at 15years for 1p/19q co-deleted oligodendroglioma treated with upfront chemotherapy irrespective of tumor grade.

Chromosomes 1p/19q co-deletion is a robust molecular marker for the diagnosis of oligodendroglial tumors, and has been included in the 2016 WHO modified classification. Although treatment for oligodendroglioma is controversial, upfront chemotherapy is regarded as one of the treatment option for low-grade tumor. We have treated all the 1p/19q co-deleted oligodendrogliomas, both grades II and III, with upfront chemotherapy without conventional radiotherapy for 20years. The clinical experience from this trial may be suggestive for understanding of the biological features of oligodendroglioma with 1p/19q co-deletion toward precision medicine. This is a long-term retrospective data of the non-selected patients with 1p/19q co-deleted oligodendrogliomas uniformly treated with up-front chemotherapy. Seventy consecutive patients (48 with grade II and 22 with grade III tumors) were included. The median follow-up period was 13years. The 5-, 10-, and 15-year progression-free survival (PFS) rates were 85.7%, 54.8%, and 31.5%, respectively, and the median PFS was 146months. In most cases, tumor recurrence was remained local and could be controlled by salvage surgery and/or chemotherapy. The 5-, 10-, and 15-year overall survival (OS) rates were 96.8%, 88.7%, and 80.0%, respectively, and the median OS was not reached. These survival data compared favorably with previous large clinical studies employing radiotherapy. Tumor grades based on World Health Organization classification, extent of surgery, and age affected neither PFS nor OS. Most patients were able to return to their premorbid social life. The long-term results drawn from 20-years of single institution experience show that the patients with 1p/19q co-deleted oligodendrogliomas can be successfully treated with up-front chemotherapy alone without compromising OS.

The role of surgery in grade II/III oligodendroglial tumors.

Supratentorial gliomas WHO grade II and III with an oligodendroglial phenotype are highly infiltrative lesions that preferentially originate in lobar location. Open tumor resection represents one of the mainstays of management as beneficial decompressive effects for large space-occupying lesions and oncologically relevant cytoreductive effects from complete resection can be expected. In patients not eligible for safe tumor resection meticulous histological and molecular-genetic evaluation can be obtained from advanced stereotactic biopsy techniques. In this perspective, important aspects of open tumor surgery and stereotactic biopsy are discussed within the context of diagnosis, prognosis and treatment of oligodendrogliomas and oligoastrocytomas WHO grade II and III. Practical considerations are provided in order to integrate the place of surgery into an increasingly personalized management concept. For highly selected patients interstitial brachytherapy is introduced as an alternative surgically performed treatment option.

Therapy-related myelodysplastic syndrome presenting as fulminant heart failure secondary to myeloid sarcoma

Rapidly progressive heart failure is commonly caused by an extensive myocardial infarction, a mechanical complication of infarction, myocarditis, or acute valvular insufficiency. We present an unusual case that was caused by a diffuse infiltration of the myocardium with leukemic cells (myeloid sarcoma). The patient presented with episodic shortness of breath, he was anemic and thrombocytopenic, and his bone marrow biopsy revealed myelodysplastic syndrome from treatment for oligodendroglioma. His clinical course was characterized by a chronic leak of cardiac enzymes, a new right bundle branch block, and a large pericardial effusion causing tamponade and death from fulminant heart failure and ventricular arrhythmias within 2weeks. At autopsy, the heart was massively infiltrated with myeloblasts and other immature myeloid cells. There was no evidence of acute leukemia in the bone marrow or peripheral blood. Cardiac infiltration in a patient with myelodysplastic syndrome is extremely rare, especially in the absence of bone marrow involvement by blasts. The recognition of this entity is becoming increasingly important as the incidence of cardiac myeloid sarcoma may be on the rise as the number of patients receiving chemotherapy increases.

Chemotherapy as first line treatment for oligodendroglioma

Chemotherapy as first line treatment for oligodendroglioma

Treatment of newly diagnosed symptomatic pure low‐grade oligodendrogliomas with PCV chemotherapy

Based on studies relating to anaplastic oligodendroglioma (OG) chemosensitivity and benefit of time to progression or overall survival, chemotherapy for pure OG has been proposed. Several studies have reported the efficacy of various chemotherapeutic agents in a small number of patients with low-grade gliomas, e.g. pure astrocytomas, OG or mixed histologies. The 5-year survival rate varies from 61% to 89% with a mean time to progression of 5 years. We report the outcome of 33 consecutive patients with pure low-grade OG diagnosed between 1990 and 2006 systematically treated for residual or non-removable tumor with PCV chemotherapy regimen as the front-line treatment after surgery. All the tumors were low grade (grade II) pure OG according to the WHO classification. All patients were symptomatic at presentation and underwent neurosurgical procedure for histological diagnosis. Response was evaluated by clinical assessment and brain magnetic resonance imaging. Twenty-one men and 12 women with a mean age at pathological diagnosis of 46.5 years were studied. The most common first symptom was partial epileptic seizure (73.7%). Six patients (18%) had initial gadolinium enhancement, associated with methoxyisobutyl (MIBI) hypermetabolism (P < 0.001). The resection was partial in seven cases (21%), and 26 patients (79%) had biopsy only. Eleven patients (36%) had a malignant transformation during the follow-up with a median time to progression of 19 months. Favorable prognostic factors were lack of contrast enhancement (P < 0.0001), and age <40 years (P < 0.0003); 90% of patients were progression-free at 1 year. Survival rates at 2, 5 and 10 years were 85%, 75% and 50%, respectively. Up-front chemotherapy with PCV regimen is a good treatment for symptomatic pure low-grade OG, as it increases the number of progression-free patients and time to progression. These results suggest that radiotherapy could be postponed until the malignant transformation occurs to delay cognitive side effects of irradiation.

Recent advances in the treatment of oligodendrogliomas

The optimal treatment for patients with oligodendrogliomas is unknown, and current management strategies remain controversial. This past year, further exploration of the molecular genetics of the tumors and its prognostic implications for outcome, evaluation of the utility of positron emission tomography imaging, and the role of radiation and chemotherapy in the treatment of oligodendrogliomas have been reported. It is becoming increasingly apparent that oligodendrogliomas are several distinct diseases on a molecular level, and that key genetic derangements can signify a response to treatment and favorable outcome. The added contributions of recent publications consolidates these emerging impressions. Ultimately, the combination of improved imaging techniques, molecular profiling, and new therapies should result in improved outcome with reduced treatment-related toxicity for patients with newly diagnosed, progressive, and recurrent oligodendrogliomas.

Advances in the biology and treatment of oligodendrogliomas

The sensitivity of oligodendroglioma to chemotherapy and the prognostic significance of combined loss of 1p/19q in these tumors are now well established. This review discusses recent molecular, genetic and clinical advances made in studies on oligodendroglioma and mixed oligoastrocytoma. Methylation of genes is a frequent event in oligodendroglioma (OD), but no specific methylation sites have been discovered. In contrast to earlier reports, the expression of the basic helix-loop-helix transcription factors is not specific for OD, but may occur in glial tumors of all lineages. In a number of studies, the prognostic relevance of 1p/19q loss has been confirmed, and several studies have shown that loss of 1p/19q are early events in OD. No candidate genes have so far been identified on 1p36 and 19q13. Gene expression profiling using gene arrays allows the separation of glial tumors according to histology, tumor grade and prognosis. A number of genes have been identified that are significantly more highly expressed in OD. On MRI imaging, OD with combined 1p/19q loss has typical characteristics, including indistinct borders and a mixed signal intensity on T2-weighted images. Despite the large increase in knowledge on the molecular abnormalities in OD, the therapeutic options for these tumors have not improved significantly since the introduction of temozolomide. The increased survival after chemotherapy has been clearly established, but the timing of chemotherapy seems less critical. It is clear that temozolomide is a good alternative to procarbazine, CCNU and vincristine (PCV) chemotherapy, in particular, because it is better tolerated. No randomized trials, however, have compared PCV-chemotherapy to temozolomide. New agents--and probably more targeted therapies--are needed to further improve treatment. Chemo-irradiation deserves further study in anaplastic OD. The progress in the understanding of genetic and molecular abnormalities of OD has improved the recognition of treatment-sensitive OD, although this has not yet been mirrored in improved therapies or new treatment options. While chemotherapy improves the outcome of OD, further improvements will likely require new drugs or new treatment concepts.

Current diagnosis and treatment of oligodendroglioma

The strategies used to diagnose and treat oligodendroglial tumors have changed significantly over the past decade. The purpose of this paper is to review the topic of oligodendroglioma, emphasizing the new developments. Information was obtained by conducting a Medline search in which the term oligodendroglioma was used. Recent editions of standard textbooks were also studied. Because of tools such as magnetic resonance imaging, oligodendrogliomas are being diagnosed earlier, and they are being recognized more frequently histologically than in the past. Seizures are common in these patients. Functional mapping and image-guided surgery may now allow for a safer and more complete resection, especially when tumors are located in difficult areas. Genetic analysis and positron emission tomography may provide data that supplement the standard diagnostic tools. Unlike other low-grade gliomas, patients in whom residual or recurrent oligodendroglioma (World Health Organization Grade II) is present may respond to chemotherapy. Although postoperative radiotherapy prolongs survival of the patient, increasingly this therapeutic modality is being delayed until tumor recurrence, especially if a gross-total tumor resection has been achieved. Oligodendrogliomas are the first type of brain tumor for which "molecular" characterization gives important information. The most significant finding is that allelic losses on chromosomes 1p and 19q indicate a favorable response to chemotherapy. Whereas surgery continues to be the primary treatment for oligodendroglioma, the scheme for postoperative therapy has shifted, primarily because of the lesion's relative chemosensitivity. Molecular characterization of oligodendrogliomas may become a standard practice in the near future.

Treatment of oligodendroglioma: An update

Oligodendrogliomas are rare primary brain tumors. Significant attention has recently been focused on these interesting neoplasms because of their unique chemosensitivity and the durability of some of these responses. Surgery and radiation continue to play important roles in the treatment of oligodendrogliomas. Molecular genetic analyses have given new insight into the allelic deletions that distinguish these tumors and their progression from indolent to more aggressive forms. In the future, molecular genetic analysis may guide therapeutic decisions concerning patients with oligodendroglioma and may help us learn more about how to best treat other malignant brain neoplasms.

Chimioradiothérapie concomitante et tumeurs gliales malignes de l'adulte

The prognosis of adult patients with malignant gliomas remains poor despite advances in neurosurgery and radiotherapy. Even if chemotherapy has done little to improve on these results, except in the treatment of oligodendrogliomas, many authors have proposed to test the effect of radiotherapy by adding concomitant chemotherapy. Unfortunately, the analysis of these studies is difficult because all these protocols are different with a small number of patients. Furthermore, there are only a few studies evaluated in well controlled clinical trials with homogeneous patient population. Important factors such as tumor grade, patient age, and Karnofsky score, which have a strong influence on survival in malignant gliomas, are not clearly evaluated. Whatever, all these studies suggest that concomitant radio-chemotherapy seems not be promising in the treatment of malignant gliomas.

Treatment of oligodendrogliomas with or without postoperative irradiation.

The authors have reviewed the treatment results in 42 patients with intracranial oligodendroglioma treated from 1940 through 1983 at the University of California, San Francisco. Two patients who died postoperatively were excluded from analysis. Eleven patients had mixed tumors, with a minor astrocytic component. The overall survival rates for the 29 patients with pure oligodendroglioma were 61% and 33% at 5 and 10 years, respectively; these rates for the 11 patients with mixed tumors were 57% and 38% at 5 and 10 years, respectively. The 10-year survival rate for 14 patients with pure oligodendroglioma who received greater than 45 Gy irradiation was 56% versus 18% for 11 patients who did not receive postoperative irradiation (p = 0.09). Nine patients with mixed tumor who received more than 45 Gy postoperatively had survival rates similar to those for the 14 patients with pure tumors irradiated with more than 45 Gy (p = 0.89). All patients who died of their tumor had evidence of intracranial recurrence. One patient, who did not receive initial postoperative irradiation, also had clinical and myelographic evidence of spinal seeding. All five patients examined postmortem had tumor recurrence at the primary site; one patient also had intraventricular seeding. Six of the 10 patients with pure oligodendroglioma who had a repeat biopsy at the time of tumor recurrence or at postmortem examination showed histological progression to an anaplastic astrocytoma or glioblastoma multiforme. Based on this study, adult patients with pure or mixed oligodendroglioma currently are treated with partial-brain irradiation to a dose of about 60 Gy. In general, children are treated with partial-brain irradiation to about 50 Gy.

Intracarotid infusion of ACNU and BCNU as adjuvant therapy of malignant gliomas. Clinical aspects and critical considerations.

Thirty patients with malignant gliomas were treated by operation, radiotherapy and additional intracarotid infusions of ACNU and BCNU. Positive results were obtained in the treatment of oligodendrogliomas and astrocytomas grade III and IV. On the contrary, the results in cases of glioblastoma multiforme were disappointing: neither survival time nor quality of life had been significantly improved. The protective effect of phenobarbitone against systemic toxicity by ACNU was not always confirmed in this study. Based on literature reports and our own experience the indications, technical aspects, unexpected complications and results of this therapeutic approach are discussed.