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Chinese Clinical Oncology Aug 2021
Topics: Australia; Dacarbazine; Glioblastoma; Humans; Temozolomide
PubMed: 32075395
DOI: 10.21037/cco.2020.02.05 -
Current Oncology Reports Oct 2017Glioblastoma is the most common primary malignant brain tumor diagnosed in the USA and is associated with a poor prognosis. The outcomes in elderly patients (more than... (Review)
Review
Glioblastoma is the most common primary malignant brain tumor diagnosed in the USA and is associated with a poor prognosis. The outcomes in elderly patients (more than 65 years of age) are worse when compared to those younger than age 65 at the time of diagnosis. Older patients are not always offered treatments that would otherwise be considered standard of care due to comorbidities and concerns about toxicity and tolerability. The initial European Organization for Research and Treatment of Cancer study that led to approval of temozolomide in glioblastoma excluded patients more than 70 years of age. This review outlines challenges that arise in the treatment of glioblastoma in the elderly population and discusses results of recent studies that established the role of adjuvant chemotherapy in addition to radiation and surgery. There is evidence that these patients can benefit from a more aggressive and safe resection, from hypofractionated radiation treatments, and from adjuvant temozolomide.
Topics: Aged; Aged, 80 and over; Combined Modality Therapy; Dacarbazine; Disease-Free Survival; Glioblastoma; Humans; Prognosis; Temozolomide
PubMed: 29075865
DOI: 10.1007/s11912-017-0644-z -
Progress in Neurological Surgery 2018Malignant gliomas have been historically considered unresponsive to chemotherapy due to their intrinsic resistance to conventional anticancer medications and the role of... (Review)
Review
Malignant gliomas have been historically considered unresponsive to chemotherapy due to their intrinsic resistance to conventional anticancer medications and the role of the blood-brain barrier in preventing access of the cytotoxic agents to the tumor. However, recent studies have demonstrated the efficacy of specific drugs in subsets of patients with high-grade astrocytomas that has revived the enthusiasm for the role of systemic chemotherapy against these neoplasms. Temozolomide, a monofunctional alkylator, was the first chemotherapeutic agent to definitively improve survival in adults with newly diagnosed glioblastoma used in combination with radiation therapy with the most pronounced effect being in a subgroup of tumors with MGMT promoter methylation. Various other cytotoxic drugs and their combinations have been tested in this population with mostly anecdotal reports of benefit. Current efforts are directed towards identifying the subsets of patients most likely to benefit from chemotherapy and to determine the most effective treatment regimens likely to improve outcome. In addition, specific strategies in order to overcome resistance mechanisms to cytotoxic drugs and to disable cellular adaptive pathways are being explored to enhance cell kill and antitumor effects of chemotherapeutic agents.
Topics: Adult; Astrocytoma; Brain Neoplasms; Dacarbazine; Glioblastoma; Glioma; Humans; Neoplasm Grading; Temozolomide
PubMed: 29393181
DOI: 10.1159/000467374 -
Journal of the College of Physicians... Sep 2015Melanoma is one of the most malignant forms of skin cancer; with a rapidly increasing prevalence. Early-stage melanoma is curable, but advanced metastatic melanoma is... (Review)
Review
Melanoma is one of the most malignant forms of skin cancer; with a rapidly increasing prevalence. Early-stage melanoma is curable, but advanced metastatic melanoma is almost always fatal, and patients with such advanced disease have short median survival. Surgery and radiotherapy play a limited role in the treatment of metastatic melanoma. Rather, chemotherapy remains the mainstay of treatment, although other approaches, including biotherapy and gene therapy, have been attempted. The authors hereby, evaluated the use of temozolomide (TMZ) for treating metastatic melanoma compared to dacarbazine (DTIC), the effectiveness of TMZ for treating brain metastases, as well as TMZ resistance and how the efficacy of TMZ in malignant melanoma can be increased. Two chemotherapeutic regimens are commonly used for palliative treatment of malignant melanoma: intravenous administration of DTIC and oral administration of the alkylating agent temozolomide (TMZ). Compared to DTIC, TMZ is very well tolerated and has an advantage in terms of improving the quality of life of patients with metastatic melanoma. While the prognosis is currently unpromising, chemotherapy plays a palliative role for patients with metastatic melanoma. The toxicity of treatment regimens based on DTIC and TMZ do not differ significantly, although TMZ is costlier. These findings provide a reference for future researchers via a comprehensive analysis of the relevant literature.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Dacarbazine; Humans; Melanoma; Quality of Life; Skin Neoplasms; Temozolomide; Treatment Outcome; Melanoma, Cutaneous Malignant
PubMed: 26374366
DOI: No ID Found -
Biochemistry. Biokhimiia Feb 2016Glioblastoma multiforme (GBL) is the most common and aggressive brain neoplasm. A standard therapeutic approach for GBL involves combination therapy consisting of... (Review)
Review
Glioblastoma multiforme (GBL) is the most common and aggressive brain neoplasm. A standard therapeutic approach for GBL involves combination therapy consisting of surgery, radiotherapy, and chemotherapy. The latter is based on temozolomide (TMZ). However, even by applying such a radical treatment strategy, the mean patient survival time is only 14.6 months. Here we review the molecular mechanisms underlying the resistance of GBL cells to TMZ including genetic and epigenetic mechanisms. Present data regarding a role for genes and proteins MGMT, IDH1/2, YB-1, MELK, MVP/LRP, MDR1 (ABCB1), and genes encoding other ABC transporters as well as Akt3 kinase in developing resistance of GBL to TMZ are discussed. Some epigenetic regulators of resistance to TMZ such as microRNA and EZH2 are reviewed.
Topics: Animals; Antineoplastic Agents, Alkylating; Blood-Brain Barrier; Brain; Brain Neoplasms; Dacarbazine; Drug Resistance, Neoplasm; Epigenesis, Genetic; Glioblastoma; Humans; Temozolomide
PubMed: 27260389
DOI: 10.1134/S0006297916020036 -
JAMA Neurology Nov 2014Glioblastoma is the most common primary malignant brain tumor, but despite multimodal treatment with surgery, radiotherapy, and temozolomide chemotherapy, the prognosis... (Review)
Review
IMPORTANCE
Glioblastoma is the most common primary malignant brain tumor, but despite multimodal treatment with surgery, radiotherapy, and temozolomide chemotherapy, the prognosis is poor, with a median survival of 16 to 19 months and poor quality of life throughout the disease course. New treatments are needed.
EVIDENCE REVIEW
Articles were identified through a search of PubMed references from March 2005 through January 2014, using the terms glioblastoma, glioma, malignant glioma, and brain neoplasm, as well as by search of the authors' files. Clinical trials were identified in the Clinicaltrials.gov registry.
FINDINGS
Advances in the understanding of the molecular biology of glioblastoma are being rapidly translated into innovative clinical trials, capitalizing on improved genomic, epigenetic, transcriptional, and proteomic characterization of glioblastomas as well as host factors, including the brain microenvironment and immune system interactions. Therapies targeting tumor growth factor receptors and downstream pathways, angiogenesis, modulation of cancer stemlike cells, cell cycle regulation, oncolytic viruses, new radiotherapy techniques, and immunotherapy, including vaccines and modulation of immune checkpoints (eg, programmed cell death 1 and cytotoxic T-lymphocyte antigen 4), are under investigation. In addition to novel agents, techniques to circumvent the blood-brain barrier to facilitate central nervous system drug exposure are being developed.
CONCLUSIONS AND RELEVANCE
Glioblastoma is an aggressive tumor with heterogeneous molecular features and complex host interactions, many of which are amenable to therapeutic intervention. Meaningful treatment advances will depend on identifying agents that target mechanistic vulnerabilities that are relevant to specific subgroups of patients; increasing patient enrollment into clinical trials is essential to accelerate the development of patient-tailored treatments.
Topics: Animals; Blood-Brain Barrier; Brain Neoplasms; Cell- and Tissue-Based Therapy; Dacarbazine; Glioblastoma; Humans; Immunotherapy; Temozolomide
PubMed: 25244650
DOI: 10.1001/jamaneurol.2014.1701 -
Neurologia Medico-chirurgica 2015Glioblastoma (GBM) has proven to be incurable despite recent progress on its standard of care using temozolomide (TMZ) as the main trunk of initial therapy for newly... (Review)
Review
Glioblastoma (GBM) has proven to be incurable despite recent progress on its standard of care using temozolomide (TMZ) as the main trunk of initial therapy for newly diagnosed GBM. One of the main reasons accounting for the dismal prognosis is attributed to lack of active therapeutic regimens at recurrence. Since TMZ is the most active cytotoxic agent against GBM, and the standard dosing of TMZ has shown favorable safety profile in clinical trials, re-challenge with TMZ in increased dose density schedules for recurrent tumors that have evaded from prior standard TMZ therapy appears to be a rational approach and has been intensively exploited. A number of phase II clinical trials using different alternating scheduling of dose-dense TMZ (ddTMZ) have shown superior efficacy over the standard TMZ or historical controls with other alkylating agents including nitrosoureas and procarbazine. One ddTMZ schedule, consisting of a 21-days on/7-days off regimen was applied to newly-diagnosed GBM as the adjuvant monotherapy after completion of combined radiation and TMZ and failed to demonstrate survival benefit in a large phase III trial (RTOG 0525). Thus its role in TMZ-pretreated, recurrent GBM should be carefully pursuit in randomized trials, e.g., planned JCOG 1308 trial comparing a 7-days on/7-days off ddTMZ regimen used upfront at the first relapse followed by bevacizumab on progression versus bevacizumab alone, investigating whether insertion of ddTMZ prior to bevacizumab could bestow better outcome in the recurrent setting. In this article, mode of action, past trials, and future directions of ddTMZ therapy are discussed.
Topics: Antineoplastic Agents, Alkylating; Clinical Trials as Topic; Dacarbazine; Disease Progression; Dose-Response Relationship, Drug; Glioblastoma; Humans; Recurrence; Temozolomide
PubMed: 25744349
DOI: 10.2176/nmc.ra.2014-0277 -
Expert Opinion on Biological Therapy May 2017Malignant gliomas are highly invasive tumors, associated with a dismal survival rate despite standard of care, which includes surgical resection, radiotherapy and... (Comparative Study)
Comparative Study Review
Malignant gliomas are highly invasive tumors, associated with a dismal survival rate despite standard of care, which includes surgical resection, radiotherapy and chemotherapy with temozolomide (TMZ). Precision immunotherapies or combinations of immunotherapies that target unique tumor-specific features may substantially improve upon existing treatments. Areas covered: Clinical trials of single immunotherapies have shown therapeutic potential in high-grade glioma patients, and emerging preclinical studies indicate that combinations of immunotherapies may be more effective than monotherapies. In this review, the authors discuss emerging combinations of immunotherapies and compare efficacy of single vs. combined therapies tested in preclinical brain tumor models. Expert opinion: Malignant gliomas are characterized by a number of factors which may limit the success of single immunotherapies including inter-tumor and intra-tumor heterogeneity, intrinsic resistance to traditional therapies, immunosuppression, and immune selection for tumor cells with low antigenicity. Combination of therapies which target multiple aspects of tumor physiology are likely to be more effective than single therapies. While a limited number of combination immunotherapies are described which are currently being tested in preclinical and clinical studies, the field is expanding at an astounding rate, and endless combinations remain open for exploration.
Topics: Animals; Brain Neoplasms; Cancer Vaccines; Combined Modality Therapy; Dacarbazine; Genetic Therapy; Glioma; Humans; Immunotherapy; Temozolomide
PubMed: 28286975
DOI: 10.1080/14712598.2017.1305353 -
Chinese Clinical Oncology Aug 2017Glioblastoma is the most common primary CNS malignancy and it is becoming more frequently diagnosed in the elderly population. Glioblastoma is associated with a dismal... (Review)
Review
Glioblastoma is the most common primary CNS malignancy and it is becoming more frequently diagnosed in the elderly population. Glioblastoma is associated with a dismal prognosis and remains a huge challenge for the neuro-oncology community. Surgical resection/biopsy is well defined as an important first approach in the care of this disease, for tumor diagnosis, molecular analysis and maximum resection. MGMT promoter methylation status has proved to be a useful indicator of whether single modality (RT or TMZ alone) or combined modality treatment may achieve better outcomes. Post-operative treatment options include: (I) hypofractionated radiotherapy (HRT) with concurrent and adjuvant temozolomide (TMZ) or (II) HRT alone (MGMT unmethylated patients); (III) TMZ alone (MGMT methylated patients) when combined modality is not feasible due to patient poor performance status or multiple comorbidities. Following the positive survival outcomes of the CCTG CE.6/EORTC 26062-22061 phase III trial which randomized newly diagnosed glioblastoma patients aged 65 or older to HRT (40 Gy/15 fractions) with concurrent and adjuvant temozolomide to HRT alone, combined modality therapy (CMT) with HRT with concurrent temozolomide as the initial post-surgical approach should be considered in patients well enough to have treatment. In meantime, future trials addressing new approaches are needed to improve outcomes in this fatal disease.
Topics: Aged; Antineoplastic Agents, Alkylating; Brain Neoplasms; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Dacarbazine; Glioblastoma; Humans; Prognosis; Radiation Dose Hypofractionation; Randomized Controlled Trials as Topic; Temozolomide
PubMed: 28841801
DOI: 10.21037/cco.2017.06.03 -
Advanced Science (Weinheim,... Jan 2023Glioblastoma (GBM) is the most aggressive type of cancer. Its current first-line postsurgery regimens are radiotherapy and temozolomide (TMZ) chemotherapy, both of which...
Glioblastoma (GBM) is the most aggressive type of cancer. Its current first-line postsurgery regimens are radiotherapy and temozolomide (TMZ) chemotherapy, both of which are DNA damage-inducing therapies but show very limited efficacy and a high risk of resistance. There is an urgent need to develop novel agents to sensitize GBM to DNA-damaging treatments. Here it is found that the triterpene compound stellettin B (STELB) greatly enhances the sensitivity of GBM to ionizing radiation and TMZ in vitro and in vivo. Mechanistically, STELB inhibits the expression of homologous recombination repair (HR) factors BRCA1/2 and RAD51 by promoting the degradation of PI3Kα through the ubiquitin-proteasome pathway; and the induced HR deficiency then leads to augmented DNA damage and cell death. It is further demonstrated that STELB has the potential to rapidly penetrate the blood-brain barrier to exert anti-GBM effects in the brain, based on zebrafish and nude mouse orthotopic xenograft tumor models. The study provides strong evidence that STELB represents a promising drug candidate to improve GBM therapy in combination with DNA-damaging treatments.
Topics: Animals; Mice; Humans; Glioblastoma; Recombinational DNA Repair; Dacarbazine; Phosphatidylinositol 3-Kinases; Antineoplastic Agents, Alkylating; Zebrafish; Drug Resistance, Neoplasm; Brain Neoplasms; Temozolomide; Triterpenes; DNA Damage
PubMed: 36453577
DOI: 10.1002/advs.202205529