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Discovery Medicine Feb 2017Checkpoint inhibitors, like ipilimumab, nivolumab, and pembrolizumab, have provided a breakthrough in cancer immunotherapy, such as in the treatment of melanoma and... (Review)
Review
Checkpoint inhibitors, like ipilimumab, nivolumab, and pembrolizumab, have provided a breakthrough in cancer immunotherapy, such as in the treatment of melanoma and colorectal and lung cancer. The close relationship between the number of mutations (mutational load) and the response to checkpoint immunotherapy has been convincingly demonstrated in these cancers. Hypermutations in tumors are caused by environmental factors, like UV radiations or cigarette smoking, or by germinal mutations affecting genes of the Mismatch Repair (MMR) machinery, as in the Lynch syndrome. In the context of a high mutational load, a number of neoantigens become visible to the immune system, creating the basis for effective T cell responses. In low- and high-grade gliomas, the most frequent brain tumors, germinal MMR defects are rare; however, hypermutations associated with mutations or decreased expression of MMR genes are rather frequent, occurring in 20-60% of the tumors at recurrence after alkylating chemotherapy with temozolomide. Ongoing clinical trials and genomic investigations will clarify if temozolomide-induced hypermutations, which usually occur in the presence of methylation of the methylguanine methyltransferase gene (MGMT), will be effectively targeted by immunotherapy with checkpoint inhibitors or dendritic cell immunotherapy, thus improving the survival expectations for patients affected by these tumors.
Topics: Animals; Antineoplastic Agents, Alkylating; Dacarbazine; Glioma; Humans; Immunotherapy; Mutation; Temozolomide
PubMed: 28371614
DOI: No ID Found -
Neuroendocrinology 2015Alkylating agents, such as streptozocin and dacarbazine, have been reported as active in neuroendocrine neoplasms (NENs). Temozolomide (TMZ) is an oral, potentially less... (Review)
Review
Alkylating agents, such as streptozocin and dacarbazine, have been reported as active in neuroendocrine neoplasms (NENs). Temozolomide (TMZ) is an oral, potentially less toxic derivative of dacarbazine, which has shown activity both as a single agent and in combination with other drugs. Nevertheless, its role in NENs has not been well defined. Several retrospective and prospective phase I-II studies have been published describing its use in a variety of NENs. In a retrospective series, the combination of capecitabine and TMZ was reported to be associated with a particularly high tumour response in pancreatic NENs as a first-line treatment. Although in NENs, determination of the O6-methylguanine-DNA methyltransferase (MGMT) status has been suggested as a predictive biomarker of response, its role still remains investigational, awaiting validation along with the establishment of the optimal detection method. Metronomic schedules have been reported to potentially overcome MGMT-related drug resistance. Toxicity is manageable if well monitored. We reviewed the literature regarding pharmacological and clinical aspects of TMZ, focusing on specific settings of NENs, different schedules, toxicity and safety profiles, and potential predictive biomarkers of response.
Topics: Antineoplastic Agents, Alkylating; Dacarbazine; Humans; Neuroendocrine Tumors; Temozolomide
PubMed: 25924937
DOI: 10.1159/000430816 -
Drugs & Aging Aug 2018Clinical research in neuro-oncology frequently classifies patients over 60-70 years of age as 'elderly', a designation intended to identify patients with the disease... (Review)
Review
Clinical research in neuro-oncology frequently classifies patients over 60-70 years of age as 'elderly', a designation intended to identify patients with the disease characteristics, psychosocial changes, and susceptibility to treatment toxicities associated with advancing age. The elderly account for a large proportion of patients diagnosed with glioblastoma (GBM), and this population is projected to increase. Their prognosis is inferior to that of GBM patients as a whole, and concerns over treatment toxicity may limit the aggressiveness with which they are treated. Recent clinical studies have assisted with therapeutic decision making in this cohort. Hypofractionated radiation with concurrent and adjuvant temozolomide has been shown to increase survival without worsened quality of life in elderly patients with good functional status. Single modality radiation therapy or temozolomide therapy are frequently used in this population, and while neither has demonstrated superiority, O-methylguanine-DNA methyltransferase (MGMT) methylation status is predictive of improved survival with temozolomide over radiation therapy. Despite these advances, ambiguity as to how to best define, assess, and treat this population remains. The specific response of elderly patients to emerging therapies, such as immunotherapies, is unclear. Advancing outcomes for elderly patients with GBM requires persistent efforts to include them in translational and clinical research endeavors, and concurrent dedication to the preservation of function and quality of life in this population.
Topics: Aged; Brain Neoplasms; Chemotherapy, Adjuvant; Dacarbazine; Glioblastoma; Humans; O(6)-Methylguanine-DNA Methyltransferase; Prognosis; Quality of Life; Temozolomide
PubMed: 30039343
DOI: 10.1007/s40266-018-0568-9 -
International Journal of Circumpolar... Dec 2023Glioblastoma (GBM), WHO grade IV, is the most common primary malignant brain tumour among adults with a devastating overall survival of 14-22 months. Standard...
Glioblastoma (GBM), WHO grade IV, is the most common primary malignant brain tumour among adults with a devastating overall survival of 14-22 months. Standard treatment of GBM includes maximum safe resection, radiotherapy plus concomitant and adjuvant temozolomide (TMZ), given over a period of approximately 9 months. Treatment and follow-up for Greenlandic patients with GBM are managed at Rigshospitalet (RH), Copenhagen. Greenlandic GBM patients, therefore, travel back and forth to RH, often unaccompanied, and challenged by cognitive failure or other symptoms from their disease and/or treatment. Few Greenlandic patients are diagnosed with GBM annually, but considering the poor prognosis and short remaining lifespan, it would be preferable to limit their travels. TMZ is administrated as capsules. Health personnel at Queen Ingrid's Hospital (DIH), Nuuk, are trained in treating other oncological diseases and handling side effects. Hence, it could be investigated whether administration of adjuvant TMZ at DIH could be feasible after personnel education as well as economic consideration and compensation, in close collaboration with neuro oncologists at RH. In this article, we describe the Greenlandic cancer treatment, and the typical workflow from diagnosis of GBM to treatment to progression.
Topics: Adult; Humans; Glioblastoma; Antineoplastic Agents, Alkylating; Dacarbazine; Chemotherapy, Adjuvant; Brain Neoplasms; Temozolomide
PubMed: 37992407
DOI: 10.1080/22423982.2023.2285077 -
Progress in Neurological Surgery 2018Fractionated radiotherapy (FRT) plays a critical role in the management of gliomas. For glioblastoma, the irradiation dose of 60 Gy in 30 fractions with concomitant and... (Review)
Review
Fractionated radiotherapy (FRT) plays a critical role in the management of gliomas. For glioblastoma, the irradiation dose of 60 Gy in 30 fractions with concomitant and adjuvant temozolomide is currently considered as a standard of treatment, and further dose escalation has failed to be of benefit in clinical trials. Hypofractionated radiation schedules may be applied in elderly patients or those with poor performance status. For anaplastic gliomas, the high-risk region is typically irradiated to a total dose of approximately 60 Gy in 1.8-2 Gy per fraction. For patients with 1p/19q co-deleted WHO grade III tumors (i.e., anaplastic oligodendrogliomas), FRT alone is currently not considered as an acceptable therapeutic approach. The use of adjuvant irradiation for low-grade gliomas is controversial; in high-risk patients, treatment with a dose of 45-54 Gy in 1.8 Gy per fraction is usually used. Long-term risks of FRT include radiation necrosis, neurocognitive decline, and neuroendocrine dysfunction. Modern techniques, such as intensity-modulated radiation therapy (IMRT) and proton therapy allow for modifications in radiation dosing and delivery while improving conformality and limiting irradiation of normal tissue.
Topics: Adult; Brain Neoplasms; Dacarbazine; Dose Fractionation, Radiation; Glioblastoma; Glioma; Humans; Male; Middle Aged; Radiotherapy Dosage; Temozolomide
PubMed: 29393175
DOI: 10.1159/000466922 -
Pituitary Apr 2018Non-functioning pituitary adenomas (NFPAs) are in general large tumors that present with symptoms secondary to local pressure on adjacent structures. Transsphenoidal... (Review)
Review
INTRODUCTION
Non-functioning pituitary adenomas (NFPAs) are in general large tumors that present with symptoms secondary to local pressure on adjacent structures. Transsphenoidal surgery is the first line of treatment but residual tumor mass is often detected post-operatively. Medical therapy, in any stage of tumor management, is not well established.
METHODS
A literature search was performed to review the available data on medical treatment of NFPAs.
RESULTS
Medications investigated for the treatment of NFPAs include dopamine receptor agonists (DA) and somatostatin receptor ligands. Randomized controlled trials are lacking, but available data suggest that DA have a positive effect on tumor remnant stabilization after surgery and could be considered in this setting. Temozolomide is reserved for aggressive tumors, although future studies are required.
CONCLUSIONS
NFPA are often not amenable to complete surgical resection. Conservative follow-up after surgery is associated with a high prevalence of tumor remnant progression. DA therapy may prevent residual tumor enlargement in over 85% of these patients, with a substantial consequent reduction in the need for repeat surgery or radiation therapy. It is our view that DA treatment should be routinely considered for the management of NFPA patients with incompletely resected tumors.
Topics: Adenoma; Dacarbazine; Dopamine Agonists; Female; Humans; Male; Pituitary Neoplasms; Temozolomide
PubMed: 29344905
DOI: 10.1007/s11102-018-0865-7 -
Journal of Hepato-biliary-pancreatic... Aug 2015Advanced neuroendocrine tumors are incurable, and most patients will succumb to the disease. Chemotherapies with cytotoxic agents such as streptozocin, 5-fluorouracil,... (Review)
Review
Advanced neuroendocrine tumors are incurable, and most patients will succumb to the disease. Chemotherapies with cytotoxic agents such as streptozocin, 5-fluorouracil, or temozolomide have been frequently used as drug therapies for neuroendocrine tumors. Streptozocin, which is the only approved cytotoxic agent available for the treatment of this disease in many countries, has been considered a key agent for the treatment of advanced neuroendocrine tumors based on the results of phase III studies. However, the widespread acceptance of streptozocin-based chemotherapy for this indication has been limited by concerns regarding toxicity. Recent prospective and retrospective studies showed the promising activity of a temozolomide-based regimen, although an adequate prospective controlled study defining the role of temozolomide in the treatment of neuroendocrine tumors is lacking. The promising activity of cytotoxic agents awaits confirmation; solid evidence-based recommendations and treatment decisions are needed for the optimal use of chemotherapy against this disease.
Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Dacarbazine; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Streptozocin; Temozolomide
PubMed: 25940377
DOI: 10.1002/jhbp.257 -
Current Neurology and Neuroscience... Feb 2016Nitrosoureas represent one of the most active classes of agents in the treatment of high-grade gliomas and glioblastoma. In clinical practice, the most commonly used... (Review)
Review
Nitrosoureas represent one of the most active classes of agents in the treatment of high-grade gliomas and glioblastoma. In clinical practice, the most commonly used compounds are lomustine (either alone or in combination with procarbazine and vincristine), carmustine, and fotemustine. Given their toxicity profile and subsequent to the introduction of temozolomide in clinical practice, most of these agents were moved to the recurrent setting. This review focuses on the role of the nitrosoureas currently used in clinical practice for the treatment of malignant gliomas.
Topics: Dacarbazine; Glioma; Humans; Lomustine; Nitrosourea Compounds; Organophosphorus Compounds; Procarbazine; Temozolomide; Vincristine
PubMed: 26750128
DOI: 10.1007/s11910-015-0611-8 -
Current Opinion in Neurology Aug 2014This study summarizes recent advances in neuroimaging of therapy-related brain tissue abnormalities. (Review)
Review
PURPOSE OF REVIEW
This study summarizes recent advances in neuroimaging of therapy-related brain tissue abnormalities.
RECENT FINDINGS
Pseudoprogression constitutes a typical posttherapeutic phenomenon in patients with glioblastoma treated with radiochemotherapy with temozolomide. Advanced MRI techniques, such as diffusion MRI and perfusion MRI, can be helpful to distinguish it from true tumor progression. In clinical trials on amyloid-modifying therapies in Alzheimer's disease patients, previously unknown, characteristic nonhemorrhagic and hemorrhagic amyloid-related imaging abnormalities have been observed. Awareness of this phenomenon is essential for therapy monitoring. Posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome can both occur as a complication of a variety of systemic drug therapies and present with a wide spectrum of clinical and imaging findings. The pathomechanisms underlying these different therapy-related brain tissue changes are only poorly understood.
SUMMARY
Neuroimaging, including advanced MRI techniques, plays a key role in the identification and monitoring of therapy-associated brain tissue abnormalities. However, future imaging studies should focus on the pathomechanism underlying these phenomena.
Topics: Antineoplastic Agents, Alkylating; Brain Diseases; Chemoradiotherapy; Dacarbazine; Glioblastoma; Humans; Neuroimaging; Temozolomide
PubMed: 24950012
DOI: 10.1097/WCO.0000000000000108 -
Neuro-oncology Apr 2023
Topics: Humans; Temozolomide; Methotrexate; Dacarbazine; Lymphoma; Brain
PubMed: 36655502
DOI: 10.1093/neuonc/noad015