ABSTRACT
A male patient started PCV chemotherapy (a combination of procarbazine, lomustine and vincristine) for a recurrent oligodendroglioma grade 2. Unfortunately, our patient took an unintended overdose of lomustine during the first PCV course: instead of 160 mg absolute dose of lomustine on day 1 only, he consumed 160 mg absolute dose of lomustine for seven consecutive days to a total dose of 1120 mg. Pancytopenia became evident after 24 days, and several months of severe myelosuppression, infections, reduced general condition, and nutrition difficulties followed. Fortunately, our patient with time recovered his bone marrow function. However, the patient's quality of life was reduced for a long time and several lessons were learnt: oral and written information on chemotherapy is essential, but not always sufficient to ensure the correct dosing of patient-administered chemotherapy. Oral chemotherapeutics should be delivered as a single-dose supply or be administered by experienced health personnel.
Subject(s)
Brain Neoplasms , Drug Overdose , Lomustine , Oligodendroglioma , Humans , Lomustine/administration & dosage , Male , Brain Neoplasms/drug therapy , Oligodendroglioma/drug therapy , Pancytopenia/chemically induced , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/adverse effects , Glioma/drug therapy , Quality of Life , Middle AgedABSTRACT
A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.
Subject(s)
Brain Neoplasms , Cell Differentiation , Isocitrate Dehydrogenase , Mutation , Oligodendroglioma , Oligodendroglioma/genetics , Oligodendroglioma/pathology , Oligodendroglioma/drug therapy , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/antagonists & inhibitors , Humans , Cell Differentiation/drug effects , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Neoplasms/drug therapy , Cell Lineage/drug effects , Receptor, Notch1/genetics , Receptor, Notch1/metabolism , Cell Proliferation/drug effects , Animals , Astrocytes/metabolism , Astrocytes/drug effects , Astrocytes/pathology , Mice , Single-Cell Analysis/methodsABSTRACT
Oligodendrogliomas characterized and defined by 1p/19q co-deletion are slowly growing tumors showing better prognosis than astrocytomas. TP53 mutation is rare in oligodendrogliomas while the vast majority of astrocytomas harbor the mutation, making TP53 mutation mutually exclusive with 1p/19q codeletion in lower grade gliomas virtually. We report a case of 51-year-old woman with a left fronto-temporal oligodendroglioma that contained a small portion with a TP53 mutation, R248Q, at the initial surgery. On a first, slow-growing recurrence 29 months after radiation and nitrosourea-based chemotherapy, the patient underwent TMZ chemotherapy. The recurrent tumor responded well to TMZ but developed a rapid progression after 6 cycles as a malignant hypermutator tumor with a MSH6 mutation. Most of the recurrent tumor lacked typical oligodendroglioma morphology that was observed in the primary tumor, while it retained the IDH1 mutation and 1p/19q co-deletion. The identical TP53 mutation observed in the small portion of the primary tumor was universal in the recurrence. This case embodied the theoretically understandable clonal expansion of the TP53 mutation with additional mismatch repair gene dysfunction leading to hypermutator phenotype. It thus indicated that TP53 mutation in oligodendroglioma, although not common, may play a critical role in the development of hypermutator after TMZ treatment.
Subject(s)
Antineoplastic Agents, Alkylating , Brain Neoplasms , Mutation , Neoplasm Recurrence, Local , Oligodendroglioma , Temozolomide , Tumor Suppressor Protein p53 , Female , Humans , Middle Aged , Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Neoplasms/drug therapy , Chromosomes, Human, Pair 1/genetics , Chromosomes, Human, Pair 19/genetics , Dacarbazine/therapeutic use , Dacarbazine/analogs & derivatives , Isocitrate Dehydrogenase/genetics , Neoplasm Recurrence, Local/genetics , Oligodendroglioma/genetics , Oligodendroglioma/pathology , Oligodendroglioma/drug therapy , Phenotype , Temozolomide/therapeutic use , Tumor Suppressor Protein p53/geneticsABSTRACT
INTRODUCTION: Procarbazine is an oral chemotherapeutic agent used in the treatment of brain malignancies and is associated with hypersensitivity reactions. In case of grade 4 reactions, rechallenge should be avoided, and the agent should be replaced, unless the treatment is curative, in which case the application of a desensitization protocol should be considered. We present a successful case of desensitization in procarbazine anaphylaxis. CASE REPORT: A 53-year-old male patient was diagnosed with recurrent anaplastic oligodendroglioblastoma. The patient received three cycles of procarbazine, lomustine, and vincristine chemotherapy for malignancy recurrence. In the fourth cycle, on the 12th day of procarbazine treatment, the patient developed anaphylaxis. Procarbazine was given together with premedication as part of the 12-step desensitization process, and the fourth cycle was successfully completed. MANAGEMENT AND OUTCOME: Procarbazine hypersensitivity reactions are observed less frequently than reactions to other chemotherapeutics. We presented a case of procarbazine-associated severe anaphylaxis that was able to continue procarbazine chemotherapy with successful desensitization. This case is important in terms of confirming the procarbazine desensitization protocol. DISCUSSION: In literature there is only one protocol developed was successfully applied in one patient with procarbazine anaphylaxis. In the current case, we took this protocol into consideration in the management of our patient. Following the use of this protocol, the patient was able to continue procarbazine chemotherapy successfully. Procarbazine anaphylaxis is rare, and more cases are needed to be reported to confirm the desensitization protocol and when to continue procarbazine treatment.
Subject(s)
Anaphylaxis , Desensitization, Immunologic , Oligodendroglioma , Procarbazine , Humans , Male , Middle Aged , Procarbazine/administration & dosage , Procarbazine/therapeutic use , Anaphylaxis/chemically induced , Oligodendroglioma/drug therapy , Desensitization, Immunologic/methods , Drug Hypersensitivity/etiology , Drug Hypersensitivity/diagnosis , Drug Hypersensitivity/therapy , Neoplasm Recurrence, Local/drug therapy , Brain Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
PURPOSE: Surgery, radiotherapy (RT), and chemotherapy have prolonged the survival of patients with anaplastic oligodendroglioma. However, whether RT induces long-term toxicity remains unknown. We analyzed the relationship between the RT dose to the fornix and symptomatic radiation necrosis (SRN). MATERIALS AND METHODS: A total of 67 patients treated between 2009 and 2019 were analyzed. SRN was defined according to the following three criteria: 1) radiographic findings, 2) symptoms attributable to the lesion, and 3) treatment resulting in symptom improvement. Various contours, including the fornix, were delineated. Univariate and multivariate analyses of the relationship between RT dose and SRN, as well as receiver operating characteristic curve analysis for cut-off values, were performed. RESULTS: The most common location was the frontal lobe (n=40, 60%). Gross total resection was performed in 38 patients (57%), and 42 patients (63%) received procarbazine, lomustine, and vincristine chemotherapy. With a median follow-up of 42 months, the median overall and progression-free survival was 74 months. Sixteen patients (24%) developed SRN. In multivariate analysis, age and maximum dose to the fornix were associated with the development of SRN. The cut-off values for the maximum dose to the fornix and age were 59 Gy (equivalent dose delivered in 2 Gy fractions) and 46 years, respectively. The rate of SRN was higher in patients whose maximum dose to the fornix was >59 Gy (13% vs. 43%, p=0.005). CONCLUSION: The maximum dose to the fornix was a significant factor for SRN development. While fornix sparing may help maintain neurocognitive function, additional studies are needed.
Subject(s)
Brain Neoplasms , Oligodendroglioma , Humans , Oligodendroglioma/drug therapy , Oligodendroglioma/radiotherapy , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Brain Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Vincristine/adverse effects , Radiation Dosage , Necrosis/chemically induced , Necrosis/drug therapyABSTRACT
The median survival time has been reported to vary between 5 and 8 years in low-grade (WHO grade 2) astrocytoma, and between 10 and 15 years for grade 2 oligodendroglioma. Targeted alpha therapy (TAT), using the modified peptide vector [213Bi]Bi/[225Ac]Ac-DOTA-substance P, has been developed to treat glioblastoma (GBM), a prevalent malignant brain tumor. In order to assess the risk of late neurotoxicity, assuming that reduced tumor cell proliferation and invasion should directly translate into good responses in low-grade gliomas (LGGs), a limited number of patients with diffuse invasive astrocytoma (n = 8) and oligodendroglioma (n = 3) were offered TAT. In two oligodendroglioma patients, TAT was applied as a second-line treatment for tumor progression, 10 years after targeted beta therapy using [90Y]Y-DOTA-substance P. The radiopharmaceutical was locally injected directly into the tumor via a stereotactic insertion of a capsule-catheter system. The activity used for radiolabeling was 2-2.5 GBq of Bismuth-213 and 17 to 35 MBq of Actinium-225, mostly applied in a single fraction. The recurrence-free survival times were in the range of 2 to 16 years (median 11 years) in low-grade astrocytoma (n = 8), in which TAT was administered following a biopsy or tumor debulking. Regarding oligodendroglioma, the recurrence-free survival time was 24 years in the first case treated, and 4 and 5 years in the two second-line cases. In conclusion, TAT leads to long-term tumor control in the majority of patients with LGG, and recurrence has so far not manifested in patients with low-grade (grade 2) astrocytomas who received TAT as a first-line therapy. We conclude that targeted alpha therapy has the potential to become a new treatment paradigm in LGG.
Subject(s)
Astrocytoma , Brain Neoplasms , Glioblastoma , Glioma , Oligodendroglioma , Humans , Oligodendroglioma/drug therapy , Oligodendroglioma/pathology , Substance P , Glioma/drug therapy , Glioma/radiotherapy , Astrocytoma/drug therapy , Astrocytoma/pathology , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Brain Neoplasms/pathologyABSTRACT
BACKGROUND: Either deletion or co-deletion of chromosomal arms 1p or 19q is a characteristic and early genetic event in oligodendroglial tumors that is associated with a better prognosis and enhanced response to therapy. Information of 1p/19q status is now regarded as the standard of care when managing oligodendroglial tumors for therapeutic options in anticipation of the increased survival and progression-free survival times associated with it. Keeping this in view, we first time attempted to establish the FISH based detection of 1p/19q deletion in glioma tissue samples to evaluate its role and involvement in the disease. METHOD: Overall 39 glioma cases of different histologies were evaluated by fluorescence in situ hybridization (FISH) technique using specific FISH probes with Olympus BX43 fluorescent microscope to detect chromosomes 1p and 19q or co-deletions therein. RESULTS: Of the 39 glioma samples, overall 27 (69.2%) were found to have deletion either in 1p, 19q or both. Deletions were observed in 23.0%, 7.6% and 38.4% in 1p, 19q and 1p/19q co-deletions respectively. Overall oligidendrioglioma presented with 53.8% (21 of 39) deletions, astrocytoma group showed 12.8% and GBM accounted for 2.5% deletions. Overall survival and disease free survival was seen significantly better in oligidendrioglioma and astrocytoma with deleted tumors as compared to non-deleted ones (p<0.05). CONCLUSION: Allelic losses on 1p and 19q, either discretely or shared, were more frequent in classic oligodendrogliomas than in either astrocytoma or Glioblastoma with better survival and response to therapy.
Subject(s)
Astrocytoma , Brain Neoplasms , Glioma , Oligodendroglioma , Humans , Prognosis , In Situ Hybridization, Fluorescence , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Chromosome Deletion , Glioma/drug therapy , Glioma/genetics , Glioma/pathology , Oligodendroglioma/drug therapy , Oligodendroglioma/genetics , Oligodendroglioma/pathology , Astrocytoma/genetics , Chromosome Aberrations , Chromosomes , Chromosomes, Human, Pair 1/genetics , Chromosomes, Human, Pair 19/geneticsABSTRACT
BACKGROUND: Pseudoprogression in gliomas has been extensively described after radiotherapy with or without chemotherapy, but not after chemotherapy alone. Here we describe the occurrence of pseudoprogression in patients with anaplastic oligodendrogliomas treated with postoperative procarbazine, lomustine and vincristine (PCV) chemotherapy alone. METHODS: We retrospectively reviewed the medical and radiological files of patients with 1p/19q codeleted, IDH-mutant anaplastic oligodendrogliomas treated with PCV chemotherapy alone who presented magnetic resonance imaging (MRI) modifications suggestive of tumour progression and in whom the final diagnosis was a pseudoprogression. RESULTS: We identified six patients. All patients underwent a surgical resection and were treated with PCV chemotherapy without radiotherapy. After a median of 11 months following the initiation of chemotherapy (range: 3-49 months), the patients developed asymptomatic white matter MRI modifications around the surgical cavity leading to the suspicion of a tumour progression. These modifications appeared as hyperintense on T2-fluid-attenuated inversion recovery (FLAIR) sequence, hypointense on T1 sequence, and lacked mass effect (0/6), contrast enhancement (0/6), restriction on diffusion-weighted imaging (0/4), relative cerebral blood volume (rCBV) increase on perfusion MRI (0/4), and hypermetabolism on 18 F-fluoro-L-dopa positron emission tomography (18 F-DOPA PET) scan (0/3). One patient underwent a surgical resection demonstrating no tumour recurrence; the five other patients were considered as having post-therapeutic modifications based on imaging characteristics. After a median follow-up of 4 years all patients were progression-free. CONCLUSIONS: Anaplastic oligodendroglioma patients treated with postoperative PCV chemotherapy alone occasionally develop T2/FLAIR hyperintensities around the surgical cavity that can wrongly suggest tumour progression. Multimodal imaging and close follow-up should be considered in this situation.
Subject(s)
Brain Neoplasms , Oligodendroglioma , Humans , Lomustine/therapeutic use , Lomustine/adverse effects , Vincristine/therapeutic use , Vincristine/adverse effects , Oligodendroglioma/diagnostic imaging , Oligodendroglioma/drug therapy , Oligodendroglioma/surgery , Procarbazine/therapeutic use , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Neoplasm Recurrence, Local , Magnetic Resonance ImagingABSTRACT
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the basis of the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization for the Research and Treatment of Cancer 26951 and Radiation Therapy Oncology Group 9402 phase III trials initiated in 1990s, which both studied radiotherapy with/without neo/adjuvant procarbazine, lomustine, and vincristine (PCV) for newly diagnosed anaplastic oligodendroglial tumors. The median follow-up duration in both was 18-19 years. For European Organization for the Research and Treatment of Cancer 26951, median, 14-year, and probable 20-year overall survival rates without versus with PCV were 2.6 years, 13.4%, and 10.1% versus 3.5 years, 25.1%, and 16.8% (N = 368 overall; hazard ratio [HR] 0.78; 95% CI, 0.63 to 0.98; P = .033), with 1p19q codeletion 9.3 years, 26.2%, and 13.6% versus 14.2 years, 51.0%, and 37.1% (n = 80; HR 0.60; 95% CI, 0.35 to 1.03; P = .063), respectively. For Radiation Therapy Oncology Group 9402, analogous results were 4.8 years, 16.5%, and 11.2% versus 4.8 years, 29.1%, and 24.6% (N = 289 overall; HR 0.79; 95% CI, 0.61 to 1.03; P = .08), with codeletion 7.3 years, 25.0%, and 14.9% versus 13.2 years, 46.1%, and 37% (n = 125; HR 0.61; 95% CI, 0.40 to 0.94; P = .02), respectively. With that, the studies show similar long-term survival even without tumor recurrence in a significant proportion of patients after first-line treatment with radiotherapy/PCV.
Subject(s)
Brain Neoplasms , Oligodendroglioma , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Clinical Trials, Phase III as Topic , Humans , Lomustine/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Oligodendroglioma/drug therapy , Procarbazine/therapeutic use , Vincristine/therapeutic useABSTRACT
BACKGROUND: Given the young age of patients with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive, functional, and quality-of-life impairment with the current aggressive standard of care treatment, chemoradiation with PCV, of the tumour located in the brain optimizing care is the major challenge. METHODS: NOA-18 aims at improving qualified overall survival (qOS) for adult patients with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and temozolomide (CETEG) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for effective salvage treatment and delaying potentially deleterious side effects. QOS represents a new concept and is defined as OS without functional and/or cognitive and/or quality of life deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany. DISCUSSION: qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification. TRIAL REGISTRATION: Clinicaltrials.gov NCT05331521 . EudraCT 2018-005027-16.
Subject(s)
Brain Neoplasms , Oligodendroglioma , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Humans , Lomustine/therapeutic use , Neoplasm Grading , Oligodendroglioma/drug therapy , Oligodendroglioma/genetics , Oligodendroglioma/pathology , Procarbazine/therapeutic use , Quality of Life , Treatment Outcome , Vincristine/therapeutic useABSTRACT
Postoperative management of lower grade gliomas (grade 2 and 3) is heterogeneous. The American Radium Society's brain malignancies panel systematically reviewed and evaluated the literature to develop consensus guidelines addressing timing of postoperative therapy, monotherapy versus combined modality therapy, type of chemotherapy used with radiotherapy, and radiotherapy dose. Thirty-six studies were included. Using consensus methodology (modified Delphi), the panel voted upon representative case variants using a 9-point appropriateness scale to address key questions. Voting results were collated to develop summarized recommendations. Following gross-total surgical resection, close surveillance is appropriate for well-selected grade 2, IDH-mutant oligodendrogliomas or astrocytomas with low-risk features. For grade 2 gliomas with high-risk features or any grade 3 glioma, immediate adjuvant therapy is recommended. When postoperative therapy is administered, radiation and planned chemotherapy is strongly recommended over monotherapy. For grade 2 and 3 IDH-mutant oligodendrogliomas and astrocytomas, either adjunctive PCV (procarbazine, lomustine, vincristine) or temozolomide is appropriate. For grade 3 IDH-mutant astrocytomas, radiotherapy followed by temozolomide is strongly recommended. The recommended radiotherapy dose for grade 2 gliomas is 45-54 Gy/1.8-2.0 Gy, and for grade 3 gliomas is 59.4-60 Gy/1.8-2.0 Gy. While multiple appropriate treatment options exist, these consensus recommendations provide an evidence-based framework to approach postoperative management of lower grade gliomas.
Subject(s)
Astrocytoma , Brain Neoplasms , Glioma , Oligodendroglioma , Radium , Astrocytoma/drug therapy , Brain Neoplasms/pathology , Glioma/drug therapy , Glioma/radiotherapy , Humans , Oligodendroglioma/drug therapy , Radium/therapeutic use , Temozolomide/therapeutic useABSTRACT
We report a case of oligodendroglioma that had consistent histopathological features as well as a distinct change in 1p/19q status in the second recurrence, after temozolomide chemotherapy and radiotherapy. The first tumor recurrence had oligodendroglial morphology, IDH1 R132H and TERT promoter mutations, and 1p/19q codeletion detected by fluorescent in situ hybridization (FISH). Copy number analysis, assessed by next-generation sequencing, confirmed 1p/19q codeletion, and disclosed loss of heterozygosity (LOH) of chromosomes 4 and 9 and chromosome 11 gain. The second recurrence featured not only oligodendroglial morphology but also the appearance of admixed multinucleated giant cells or neoplastic cells having oval nuclei and mitoses and showing microvascular proliferation; it maintained IDH1 R132H and TERT promoter mutations, acquired TP53 mutation, and showed 19q LOH, but disomic 1p, detected by FISH. Copy number analysis depicted LOH of chromosomes 3p, 13, and 19q, 1p partial deletion (1p chr1p34.2-p11), and gain of chromosomes 2p25.3-p24.1, 8q12.2-q24.3, and 11q13.3-q25. B-allele frequency analysis of polymorphic sites disclosed copy-neutral LOH at 1p36.33-p34.2, supporting the initial deletion of 1p, followed by reduplication of 1p36.33-p34.2 alone. These findings suggest that the two tumor recurrences might have originated from an initial neoplastic clone, featuring 1p/19q codeletion and IDH1 and TERT promoter mutations, and have independently acquired other copy number alterations. The reduplication of chromosome 1p might be the result of temozolomide treatment, and gave rise to false negative 1p deletion detected by FISH. The possibility of 1p copy-neutral LOH should be considered in recurrent oligodendrogliomas with altered 1p/19q status detected by FISH.
Subject(s)
Brain Neoplasms , Oligodendroglioma , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Chromosome Aberrations , Chromosome Deletion , Chromosomes, Human, Pair 1/genetics , Chromosomes, Human, Pair 19/genetics , Humans , In Situ Hybridization, Fluorescence , Isocitrate Dehydrogenase/genetics , Neoplasm Recurrence, Local/genetics , Oligodendroglioma/drug therapy , Oligodendroglioma/genetics , Oligodendroglioma/pathology , Temozolomide/therapeutic useABSTRACT
INTRODUCTION: The role of chemotherapy alone in newly diagnosed WHO grade 2 oligodendroglioma after biopsy, incomplete or gross total resection remains controversial. We here analyze the clinical outcome of four patient cohorts being treated with either procarbazine, CCNU and vincristine (PCV) or temozolomide (TMZ) after biopsy, resection only, or wait-and-scan after biopsy. METHODS: Patients (n = 142) with molecularly defined oligodendroglioma (WHO 2016) were assigned to four cohorts: W&S, wait-and-scan after stereotactic biopsy (n = 59); RES, surgical resection only (n = 27); TMZ, temozolomide after biopsy (n = 26) or PCV (n = 30) after biopsy. Presurgical MRI T2 tumor volumes were obtained by manual segmentation. Progression-free survival (PFS), post-recurrence PFS (PR-PFS) and rate of histological progression to grade 3 were analyzed. RESULTS: PFS was longest after PCV (9.1 years), compared to 5.1 years after W&S, 4.4 years after RES and 3.6 years after TMZ. The rate of histological progression from grade 2 to 3 within 10 years was 9% for the PCV, 29% for the W&S, 67% for the RES and 75% for the TMZ group (p = 0.01). In the W&S group, patients treated with PCV at first relapse had a longer PFS from intervention than those treated with TMZ (7.2 vs 4.0 years, p = 0.04). Multivariate analysis identified smaller tumor volume prior to any intervention (p = 0.02) to be prognostic for PFS. CONCLUSIONS: PCV chemotherapy alone is an effective treatment for WHO grade 2 oligodendroglioma, with long PFS and low rate of histological progression.
Subject(s)
Brain Neoplasms , Oligodendroglioma , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/drug therapy , Humans , Lomustine/therapeutic use , Neoplasm Staging , Oligodendroglioma/diagnostic imaging , Oligodendroglioma/drug therapy , Procarbazine/therapeutic use , Temozolomide/therapeutic use , Vincristine , World Health OrganizationABSTRACT
High-grade gliomas, including anaplastic oligodendroglioma, represent the most common malignant neoplasms of the central nervous system in the adult. The standard treatment of anaplastic oligodendroglioma consists of maximum surgical resection, radiotherapy and subsequent chemotherapy. Despite multimodal treatment, theoretically, all cases can relapse. Immune checkpoint inhibitors (ICIs) as pembrolizumab demonstrated promising results in many types of tumors, particularly in the presence of mismatch repair deficiency (MMRd). However, no ICI benefit was demonstrated in high-grade glioma prospective studies, although no biomarker was analyzed. Here, we describe an interesting case of recurrent anaplastic oligodendroglioma with MMRd, reporting a prolonged disease stability during pembrolizumab treatment.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Brain Neoplasms/drug therapy , Colorectal Neoplasms/drug therapy , Neoplastic Syndromes, Hereditary/drug therapy , Oligodendroglioma/drug therapy , Adult , Brain Neoplasms/pathology , Colorectal Neoplasms/pathology , Female , Humans , Neoplasm Recurrence, Local , Neoplastic Syndromes, Hereditary/pathology , Oligodendroglioma/pathologyABSTRACT
BACKGROUND: We report the analysis involving patients treated on the initial CODEL design. METHODS: Adults (>18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm. RESULTS: Thirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months. CONCLUSIONS: TMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.
Subject(s)
Brain Neoplasms , Oligodendroglioma , Adult , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Humans , Isocitrate Dehydrogenase/genetics , Oligodendroglioma/drug therapy , Oligodendroglioma/genetics , Progression-Free Survival , Temozolomide/therapeutic useABSTRACT
One goal of precision medicine is to identify mutations within individual tumors to design targeted treatment approaches. This report details the use of genomic testing to select a targeted therapy regimen of erlotinib and rapamycin for a pediatric anaplastic oligodendroglioma refractory to standard treatment, achieving a 33-month sustained response. Immunohistochemical analysis of total and phosphorylated protein isoforms showed abnormal signaling consistent with detected mutations, while revealing heterogeneity in per-cell activation of signaling pathways in multiple subpopulations of tumor cells throughout the course of disease. This case highlights molecular features that may be relevant to designing future targeted treatments.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Oligodendroglioma/drug therapy , Child , Erlotinib Hydrochloride/administration & dosage , Female , Humans , Prognosis , Remission Induction , Sirolimus/administration & dosageABSTRACT
PURPOSE OF REVIEW: The management of low-grade (grade II) oligodendrogliomas is still controversial, due to their rarity and long-term survival. According to recent WHO 2016 Classification of central nervous system tumors oligodendrogliomas are defined by the coexistence of molecular alterations, such as isocitrate dehydrogenase (IDH)1/2 mutations and 1p/19q codeletion. These tumors have better outcome and higher response to chemotherapy compared with diffuse astrocytomas. RECENT FINDINGS: The association of radiotherapy and procarbazine, lomustine (CCNU), vincristine chemotherapy in low-grade oligodendrogliomas is definitely superior over radiotherapy alone, and yields median progression-free survival and overall survival values exceeding by far 10 years. Chemotherapy alone yields results that are inferior compared with radiotherapyâ+âprocarbazine, CCNU, vincristine but may better preserve cognitive functions from radiotherapy-induced damage. Chemosensitivity of oligodendrogliomas is related to a high percentage of O6-methylguanine-DNA methyltransferase methylation and low expression of DNA repair genes. Recurrent defects in mismatch repair pathways may induce hypermutation and secondary resistance to temozolomide, but not to nitrosoureas. SUMMARY: Reoperation at progression following initial chemotherapy is increasingly adopted, thus allowing a further delay of radiotherapy. In the future targeting IDH1/2 mutations following incomplete surgery may represent a new innovative option.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Lomustine/therapeutic use , Oligodendroglioma/drug therapy , Temozolomide/therapeutic use , Vincristine/therapeutic use , Humans , Treatment OutcomeABSTRACT
BACKGROUND: The cell cycle checkpoint G1/S, dependent on cyclin-dependent kinase (CDK) 4 amplification/overexpression and retinoblastoma phosphorylation, is altered in most anaplastic oligodendrogliomas (AOs). OBJECTIVE: We aimed to evaluate the efficacy of palbociclib, an oral inhibitor of CDK4/6 with proven efficacy in breast cancer, in patients with AO. The primary endpoint was progression-free survival at 6 months. PATIENTS AND METHODS: We conducted a multicenter, open-label, phase II trial evaluating the efficacy and safety of palbociclib in patients with AO who progressed on radiotherapy and chemotherapy with histologically and molecularly confirmed grade 3 oligodendroglioma and conserved retinoblastoma protein (pRb) expression by immunohistochemistry. Patients were treated with palbociclib (125 mg/day) for 3/1 weeks on/off. RESULTS: Overall, 34 patients were enrolled across 10 hospitals in the Spanish Group of Neuro-Oncology (GEINO) study. The study was stopped early owing to the lack of efficacy, with 74% of evaluable patients progressing within 6 months, which was insufficient to consider palbociclib as an active drug in this population. Within the median follow-up of 12 months, the median progression-free survival was 2.8 months [95% confidence interval (CI) 2.6-3.1] and the median overall survival was 32.1 months (95% CI 5.1-59.2). There were no partial or complete responses; only 13 patients (38%) achieved stable disease as the best response. Palbociclib was well tolerated, with neutropenia (grade 3 or higher: 58.8%) and thrombocytopenia (grade 3 or higher: 14.7%) as the most common adverse events (AEs). Both AEs had no significant impact. CONCLUSION: Despite the good tolerance, palbociclib monotherapy did not show favorable efficacy against recurrent AO. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, identifier NCT0253032 (retrospectively registered on 21 August 2015).
Subject(s)
Oligodendroglioma/drug therapy , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyridines/therapeutic use , Retinoblastoma/drug therapy , Adult , Aged , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Oligodendroglioma/pathology , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Retinoblastoma/pathology , Treatment OutcomeABSTRACT
The present report describes the case of a male 17-year-old patient who progressively developed a hydrocephalus and polyradiculopathy due to involvement of central nervous system (CNS) by a diffuse leptomeningeal glioneuronal tumor (DLGNT). The tumor had partial remission in response to the treatment with radiotherapy plus procarbazine, lomustine, and vincristine (PCV) chemotherapy, and the patient had improvement in function and pain levels. The current knowledge about DLGNT, including its clinical manifestations, imaging findings, histological characteristics, and treatment are revised and discussed in the present paper.