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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 -
JCO Oncology Practice Jul 2022The shortage of dacarbazine (DTIC) has created an acute and unprecedented crisis in the management of patients with classical Hodgkin lymphoma, with DTIC being an... (Review)
Review
The shortage of dacarbazine (DTIC) has created an acute and unprecedented crisis in the management of patients with classical Hodgkin lymphoma, with DTIC being an essential component of doxorubicin, bleomycin, vinblastine, and DTIC (ABVD) and prior attempts at omitting DTIC from ABVD leading to substantial loss of efficacy. In this review, we discuss the strategies to manage classical Hodgkin lymphoma during the DTIC shortage and propose a treatment algorithm on the basis of fitness and ability to receive anthracyclines safely.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Dacarbazine; Doxorubicin; Hodgkin Disease; Humans; Vinblastine
PubMed: 35254922
DOI: 10.1200/OP.21.00890 -
Profiles of Drug Substances,... 2016Dacarbazine is a cell cycle nonspecific antineoplastic alkylating agent used in the treatment of metastatic malignant melanoma. This chapter contains the descriptions of... (Review)
Review
Dacarbazine is a cell cycle nonspecific antineoplastic alkylating agent used in the treatment of metastatic malignant melanoma. This chapter contains the descriptions of the drug: nomenclature, formulae, chemical structure, elemental composition, and appearance. The uses and applications of dacarbazine and the methods that were used for its preparation are reported. The methods which were used for the physical characterization of the drug are ionization constant, solubility, X-ray powder diffraction pattern, crystal structure, melting point, and differential scanning calorimetry. The profile contains the spectra of the drug: ultraviolet spectrum, vibrational spectrum, nuclear magnetic resonance spectra, and mass spectrum. The compendial methods of analysis for dacarbazine include the United States Pharmacopeia methods, British Pharmacopeia methods, and International Pharmacopeia methods. Other reported methods that are used for the analysis of the drug are high-performance liquid chromatography, high-performance liquid chromatography-mass spectrometry, and polarography. Metabolism, pharmacokinetics, and stability studies on dacarbazine are also included. Reviews of some analytical methods and physicochemical properties of the drug as well as the most important enzymes that are involved in the prodrug activation are provided. Sixty-four references are listed at the end of this monograph.
Topics: Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Dacarbazine; Humans
PubMed: 26940170
DOI: 10.1016/bs.podrm.2015.12.002 -
Gene Dec 2015The MTT assay (to a less degree MTS, XTT or WST) is a widely exploited approach for measuring cell viability/drug cytotoxicity. MTT reduction occurs throughout a cell...
The MTT assay (to a less degree MTS, XTT or WST) is a widely exploited approach for measuring cell viability/drug cytotoxicity. MTT reduction occurs throughout a cell and can be significantly affected by a number of factors, including metabolic and energy perturbations, changes in the activity of oxidoreductases, endo-/exocytosis and intracellular trafficking. Over/underestimation of cell viability by the MTT assay may be due to both adaptive metabolic and mitochondrial reprogramming of cells subjected to drug treatment-mediated stress and inhibitor off-target effects. Previously, imatinib, rottlerin, ursolic acid, verapamil, resveratrol, genistein nanoparticles and some polypeptides were shown to interfere with MTT reduction rate resulting in inconsistent results between the MTT assay and alternative assays. Here, to test the under/overestimation of viability by the MTT assay, we compared results derived from the MTT assay with the trypan blue exclusion assay after treatment of glioblastoma U251, T98G and C6 cells with three widely used inhibitors with the known direct and side effects on energy and metabolic homeostasis - temozolomide (TMZ), a DNA-methylating agent, temsirolimus (TEM), an inhibitor of mTOR kinase, and U0126, an inhibitor of MEK1/2 kinases. Inhibitors were applied shortly as in IC50 evaluating studies or long as in studies focusing on drug resistance acquisition. We showed that over/underestimation of cell viability by the MTT assay and its significance depends on a cell line, a time point of viability measurement and other experimental parameters. Furthermore, we provided a comprehensive survey of factors that should be accounted in the MTT assay. To avoid result misinterpretation, supplementation of the tetrazolium salt-based assays with other non-metabolic assays is recommended.
Topics: Animals; Biological Assay; Cell Count; Cell Line, Tumor; Cell Survival; Dacarbazine; Female; Formazans; Humans; Inhibitory Concentration 50; Rats; Rats, Wistar; Sirolimus; Temozolomide; Tetrazolium Salts
PubMed: 26260013
DOI: 10.1016/j.gene.2015.08.009 -
Cancer Treatment and Research 2016Prior to the recent therapeutic advances, chemotherapy was the mainstay of treatment options for advanced-stage melanoma. A number of studies have investigated various... (Review)
Review
Prior to the recent therapeutic advances, chemotherapy was the mainstay of treatment options for advanced-stage melanoma. A number of studies have investigated various chemotherapy combinations in order to expand on the clinical responses achieved with single-agent dacarbazine, but these have not demonstrated an improvement in overall survival. Similar objective responses were observed with the combination of carboplatin and paclitaxel as were seen with single-agent dacarbazine. The combination of chemotherapy and immunotherapy, known as biochemo-therapy, has shown high clinical responses; however, biochemo-therapy has not been shown to improve overall survival and resulted in increased toxicities. In contrast, palliation and long-term responses have been observed with localized treatment with isolated limb perfusion or infusion in limb-isolated disease. Although new, improved therapeutic options exist for first-line management of advanced-stage melanoma, chemotherapy may still be important in the palliative treatment of refractory, progressive, and relapsed melanoma. We review the various chemotherapy options available for use in the treatment and palliation of advanced-stage melanoma, discuss the important clinical trials supporting the treatment recommendations, and focus on the clinical circumstances in which treatment with chemotherapy is useful.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Dacarbazine; Humans; Melanoma; Neoplasm Staging; Palliative Care; Taxoids; Temozolomide
PubMed: 26601864
DOI: 10.1007/978-3-319-22539-5_8 -
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 -
Pituitary Jun 2023Refractory pituitary adenomas are those that have progressed following standard of care treatments. Medical therapy options for these challenging tumors are limited. (Review)
Review
INTRODUCTION
Refractory pituitary adenomas are those that have progressed following standard of care treatments. Medical therapy options for these challenging tumors are limited.
PURPOSE
To review the landscape of tumor directed medical therapies and off-label investigational approaches for refractory pituitary adenomas.
METHODS
Literature on medical therapies for refractory adenomas was reviewed.
RESULTS
The established first-line medical therapy for refractory adenomas is temozolomide, which importantly may increase survival, but clinical trial data are still needed to clearly establish its efficacy, identify biomarkers of response, and clarify eligibility and outcome criteria. Other therapies for refractory tumors have only been described in case reports and small case series.
CONCLUSION
There are currently no approved non-endocrine medical therapies for refractory pituitary tumors. There is an urgent need for identifying effective medical therapies and studying them in multi-center clinical trials.
Topics: Humans; Pituitary Neoplasms; Dacarbazine; Antineoplastic Agents, Alkylating; Adenoma; Temozolomide
PubMed: 37115295
DOI: 10.1007/s11102-023-01320-9 -
Progress in Neurological Surgery 2018Oligodendrogliomas are therapy-responsive tumors, which have better prognosis compared to their astrocytic counterparts. The goal of treatment in such cases is not only...
Oligodendrogliomas are therapy-responsive tumors, which have better prognosis compared to their astrocytic counterparts. The goal of treatment in such cases is not only prolongation of the patients' survival, but maintaining high neurologic functioning and quality of life. Traditionally, after maximal surgical resection fractionated radiation therapy was given. However, prospective randomized trials comparing irradiation alone and its combination with chemotherapy demonstrated strong impact of the latter on prolongation of overall survival in 1p/19q co-deleted anaplastic and "high-risk" low-grade gliomas. In such cases the median survival of patients is well beyond a decade. The optimal chemotherapy regimen (PCV or temozolomide) remains an active clinical trial question, which may be resolved after completion of the ongoing phase III CODEL study (clinicaltrials.gov identifier NCT00887146). Additional investigations should also refine further the prognostic and predictive role of molecular markers in oligodendroglial tumors.
Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemotherapy, Adjuvant; Dacarbazine; Glioma; Humans; Oligodendroglioma; Temozolomide
PubMed: 29393183
DOI: 10.1159/000467376 -
International Journal of Radiation... Apr 2021
Topics: Animals; Dacarbazine; Temozolomide; Wolves
PubMed: 33714524
DOI: 10.1016/j.ijrobp.2020.07.2319