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JAMA Dec 2017Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor.
OBJECTIVE
To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system.
DESIGN, SETTING, AND PARTICIPANTS
In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis.
INTERVENTIONS
Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles).
MAIN OUTCOMES AND MEASURES
Progression-free survival (tested at α = .046). The secondary end point was overall survival (tested hierarchically at α = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group.
RESULTS
Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone.
CONCLUSIONS AND RELEVANCE
In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT00916409.
Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemoradiotherapy; Dacarbazine; Disease-Free Survival; Electric Stimulation Therapy; Female; Follow-Up Studies; Glioblastoma; Humans; Maintenance Chemotherapy; Male; Middle Aged; Mitosis; Survival Analysis; Temozolomide
PubMed: 29260225
DOI: 10.1001/jama.2017.18718 -
The New England Journal of Medicine Mar 2017Glioblastoma is associated with a poor prognosis in the elderly. Survival has been shown to increase among patients 70 years of age or younger when temozolomide... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Glioblastoma is associated with a poor prognosis in the elderly. Survival has been shown to increase among patients 70 years of age or younger when temozolomide chemotherapy is added to standard radiotherapy (60 Gy over a period of 6 weeks). In elderly patients, more convenient shorter courses of radiotherapy are commonly used, but the benefit of adding temozolomide to a shorter course of radiotherapy is unknown.
METHODS
We conducted a trial involving patients 65 years of age or older with newly diagnosed glioblastoma. Patients were randomly assigned to receive either radiotherapy alone (40 Gy in 15 fractions) or radiotherapy with concomitant and adjuvant temozolomide.
RESULTS
A total of 562 patients underwent randomization, 281 to each group. The median age was 73 years (range, 65 to 90). The median overall survival was longer with radiotherapy plus temozolomide than with radiotherapy alone (9.3 months vs. 7.6 months; hazard ratio for death, 0.67; 95% confidence interval [CI], 0.56 to 0.80; P<0.001), as was the median progression-free survival (5.3 months vs. 3.9 months; hazard ratio for disease progression or death, 0.50; 95% CI, 0.41 to 0.60; P<0.001). Among 165 patients with methylated O-methylguanine-DNA methyltransferase (MGMT) status, the median overall survival was 13.5 months with radiotherapy plus temozolomide and 7.7 months with radiotherapy alone (hazard ratio for death, 0.53; 95% CI, 0.38 to 0.73; P<0.001). Among 189 patients with unmethylated MGMT status, the median overall survival was 10.0 months with radiotherapy plus temozolomide and 7.9 months with radiotherapy alone (hazard ratio for death, 0.75; 95% CI, 0.56 to 1.01; P=0.055; P=0.08 for interaction). Quality of life was similar in the two trial groups.
CONCLUSIONS
In elderly patients with glioblastoma, the addition of temozolomide to short-course radiotherapy resulted in longer survival than short-course radiotherapy alone. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00482677 .).
Topics: Aged; Aged, 80 and over; Central Nervous System Neoplasms; Chemoradiotherapy; Dacarbazine; Disease Progression; Female; Glioblastoma; Humans; Male; Quality of Life; Radiotherapy; Survival Analysis; Temozolomide
PubMed: 28296618
DOI: 10.1056/NEJMoa1611977 -
Chinese Clinical Oncology Aug 2021
Topics: Australia; Dacarbazine; Glioblastoma; Humans; Temozolomide
PubMed: 32075395
DOI: 10.21037/cco.2020.02.05 -
Report on Carcinogens : Carcinogen... 2011
Topics: Animals; Antineoplastic Agents, Alkylating; Carcinogens; Dacarbazine; Humans; Neoplasms
PubMed: 21850138
DOI: No ID Found -
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 -
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 -
AJNR. American Journal of Neuroradiology Sep 2010Temozolomide, an oral alkylating agent, is a commonly used medicine in the treatment of anaplastic astrocytoma and glioblastoma multiforme. This paper will present the...
Temozolomide, an oral alkylating agent, is a commonly used medicine in the treatment of anaplastic astrocytoma and glioblastoma multiforme. This paper will present the mechanism of action as well as the clinical role for this chemotherapeutic drug.
Topics: Administration, Oral; Antineoplastic Agents, Alkylating; Astrocytoma; Brain Neoplasms; Dacarbazine; Drug Costs; Glioblastoma; Humans; Temozolomide
PubMed: 20538821
DOI: 10.3174/ajnr.A2170 -
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 -
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