ABSTRACT
Treatment of brain tumors, particularly malignant gliomas, is challenging using only surgical resection and radiation therapy, and medical treatment plays an important role in the management of these malignancies. Temozolomide has been mainly used for the treatment of malignant gliomas over a decade. However, novel therapeutic options, such as molecular-targeted drugs and oncolytic virus therapeutic agents have been introduced in recent years. Classical anticancer medications, such as nitrosoureas and platinum-based drugs, continue to be administered for treatment of some types of malignant brain tumors.
Subject(s)
Antineoplastic Agents , Brain Neoplasms , Glioma , Humans , Brain Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , Glioma/drug therapy , Temozolomide/therapeutic use , Nitrosourea Compounds/therapeutic useABSTRACT
BACKGROUND: The aim of the study was to evaluate pretreatment inflammatory markers as prognostic factors in patients with unresectable uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. PATIENTS AND METHODS: 54 patients (44% male, median age: 61 years) were retrospectively assessed. A median of 3 (range: 1-11) treatment sessions were performed with melphalan (92%) or fotemustin (8%). Inflammatory indices were calculated as follows: neutrophils/nl to lymphocytes/nl ratio (NLR), systemic immune-inflammation index ([platelets/nl × neutrophils/nl]/[lymphocytes/nl]; SII), and platelets/nl to lymphocytes/nl ratio (PLR). The cut-off for dichotomization purposes was set at the median (inflammatory indices, hepatic tumor burden) or the upper level of normal. Kaplan Meier analysis was performed for median overall survival (OS) in months, and Cox proportional hazard model for uni(UVA) and multivariate (MVA) hazard ratio (HR, 95%CI) analyses were performed. RESULTS: Median OS of the study cohort was 7.7 (6.3-10.9) months. In UVA OS was prolonged for low C reactive protein (CRP) (13.5 vs. 5.2; p = 0.0005), low SII (10.8 vs. 5.6; p = 0.0005), low NLR (11.1 vs. 6.3; p = 0.0045), low aspartate aminotransferase (AST) (11.5 vs. 5.6; p = 0.015), alanine aminotransferases (ALT) (11.5 vs. 5.6; p = 0.01), and tumor burden ⦠50% (8.2 vs. 4.8; p = 0.007). MVA confirmed low CRP (HR: 0.29, 0.11-0.7; p = 0.005), low SII (HR: 0.19, 0.11-0.7; p = 0.008), and low ALT (HR: 0.13, 0.02-0.63; p = 0.011) as independent predictors for prolonged OS. Patients with ⦠1, 2, 3 elevated significant MVA-factors survived a median of 14.9, 7.7, and 3.9 months, respectively (p = 0.0001). CONCLUSIONS: Pretreatment inflammatory markers (CRP, SII) and AST were independent prognostic survival markers in patients with uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. A combination of factors may help to identify patients potentially benefitting from treatment.
Subject(s)
Liver Neoplasms/blood , Melanoma/blood , Uveal Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Alanine Transaminase/blood , Antineoplastic Agents/therapeutic use , Aspartate Aminotransferases/blood , Biomarkers, Tumor/blood , Blood Platelets/cytology , C-Reactive Protein/analysis , Chemotherapy, Cancer, Regional Perfusion/methods , Female , Humans , Kaplan-Meier Estimate , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Lymphocytes/cytology , Male , Melanoma/drug therapy , Melanoma/mortality , Melanoma/secondary , Melphalan/therapeutic use , Middle Aged , Neutrophils/cytology , Nitrosourea Compounds/therapeutic use , Organophosphorus Compounds/therapeutic use , Prognosis , Proportional Hazards Models , Retrospective Studies , Tumor Burden , Uveal Neoplasms/bloodABSTRACT
Glioblastoma multiforme (GBM) is a severe brain tumor whose ability to mutate and adapt to therapies is at the base for the extremely poor survival rate of patients. Despite multiple efforts to develop alternative forms of treatment, advances have been disappointing and GBM remains an arduous tumor to treat. One of the leading causes for its strong resistance is the innate upregulation of DNA repair mechanisms. Since standard therapy consists of a combinatory use of ionizing radiation and alkylating drugs, which both damage DNA, targeting the DNA damage response (DDR) is proving to be a beneficial strategy to sensitize tumor cells to treatment. In this review, we will discuss how recent progress in the availability of the DDR kinase inhibitors will be key for future therapy development. Further, we will examine the principal existing DDR inhibitors, with special focus on those currently in use for GBM clinical trials.
Subject(s)
Antineoplastic Agents/pharmacology , Brain Neoplasms/drug therapy , DNA Repair , Drug Resistance, Neoplasm/drug effects , Enzyme Inhibitors/pharmacology , Glioblastoma/drug therapy , Molecular Targeted Therapy , Antineoplastic Agents/therapeutic use , Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Ataxia Telangiectasia Mutated Proteins/metabolism , Brain Neoplasms/genetics , Cell Line, Tumor , Clinical Trials, Phase I as Topic , DNA Breaks, Double-Stranded/drug effects , DNA Breaks, Single-Stranded/drug effects , DNA Damage , DNA, Neoplasm/drug effects , DNA, Neoplasm/genetics , DNA-Activated Protein Kinase/antagonists & inhibitors , DNA-Activated Protein Kinase/metabolism , Drug Screening Assays, Antitumor , Enzyme Inhibitors/therapeutic use , Glioblastoma/genetics , Humans , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Nitrosourea Compounds/pharmacology , Nitrosourea Compounds/therapeutic use , Signal Transduction/drug effects , Temozolomide/pharmacology , Temozolomide/therapeutic useABSTRACT
BACKGROUND: Although a myriad of novel treatments entered the treatment paradigm for advanced melanoma, there is lack of head-to-head evidence. We conducted a network meta-analysis (NMA) to estimate each treatment's relative effectiveness and safety. METHODS: A systematic literature review (SLR) was conducted in Embase, MEDLINE and Cochrane to identify all phase III randomised controlled trials (RCTs) with a time frame from January 1, 2010 to March 11, 2019. We retrieved evidence on treatment-related grade III/IV adverse events, progression-free survival (PFS) and overall survival (OS). Evidence was synthesised using a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbazine was pooled with temozolomide, paclitaxel and paclitaxel plus carboplatin. To increase homogeneity of the study populations, RCTs were only included if patients were not previously treated with novel treatments. RESULTS: The SLR identified 28 phase III RCTs involving 14,376 patients. Nineteen and seventeen treatments were included in the effectiveness and safety NMA, respectively. For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57). CONCLUSIONS: Our NMA identified the most effective treatment options for advanced melanoma and provided valuable insights into each novel treatment's relative effectiveness and safety. This information may facilitate evidence-based decision-making and may support the optimisation of treatment and outcomes in everyday clinical practice.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cancer Vaccines/therapeutic use , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Azetidines/administration & dosage , Azetidines/therapeutic use , Benzimidazoles/administration & dosage , Benzimidazoles/therapeutic use , Carboplatin/administration & dosage , Carboplatin/therapeutic use , Dacarbazine/administration & dosage , Dacarbazine/therapeutic use , Humans , Hydrazines/administration & dosage , Hydrazines/therapeutic use , Imidazoles/administration & dosage , Imidazoles/therapeutic use , Interleukin-2/administration & dosage , Interleukin-2/therapeutic use , Ipilimumab/administration & dosage , Ipilimumab/therapeutic use , Lenalidomide/administration & dosage , Lenalidomide/therapeutic use , Melanoma/immunology , Melanoma/pathology , Network Meta-Analysis , Nitrosourea Compounds/administration & dosage , Nitrosourea Compounds/therapeutic use , Nivolumab/administration & dosage , Nivolumab/therapeutic use , Organophosphorus Compounds/administration & dosage , Organophosphorus Compounds/therapeutic use , Oximes/administration & dosage , Oximes/therapeutic use , Paclitaxel/administration & dosage , Paclitaxel/therapeutic use , Piperidines/administration & dosage , Piperidines/therapeutic use , Progression-Free Survival , Proportional Hazards Models , Pyridones/administration & dosage , Pyridones/therapeutic use , Pyrimidinones/administration & dosage , Pyrimidinones/therapeutic use , Skin Neoplasms/immunology , Skin Neoplasms/pathology , Sorafenib/administration & dosage , Sorafenib/therapeutic use , Survival Rate , Temozolomide/administration & dosage , Temozolomide/therapeutic use , Treatment OutcomeABSTRACT
Alkylating agents have been used since the 60ties in brain cancer chemotherapy. Their target is the DNA and, although the DNA of normal and cancer cells is damaged unselectively, they exert tumor-specific killing effects because of downregulation of some DNA repair activities in cancer cells. Agents exhibiting methylating properties (temozolomide, procarbazine, dacarbazine, streptozotocine) induce at least 12 different DNA lesions. These are repaired by damage reversal mechanisms involving the alkyltransferase MGMT and the alkB homologous protein ALKBH2, and through base excision repair (BER). There is a strong correlation between the MGMT expression level and therapeutic response in high-grade malignant glioma, supporting the notion that O6-methylguanine and, for nitrosoureas, O6-chloroethylguanine are the most relevant toxic damages at therapeutically relevant doses. Since MGMT has a significant impact on the outcome of anti-cancer therapy, it is a predictive marker of the effectiveness of methylating anticancer drugs, and clinical trials are underway aimed at assessing the influence of MGMT inhibition on the therapeutic success. Other DNA repair factors involved in methylating drug resistance are mismatch repair, DNA double-strand break (DSB) repair by homologous recombination (HR) and DSB signaling. Base excision repair and ALKBH2 might also contribute to alkylating drug resistance and their downregulation may have an impact on drug sensitivity notably in cells expressing a high amount of MGMT and at high doses of temozolomide, but the importance in a therapeutic setting remains to be shown. MGMT is frequently downregulated in cancer cells (up to 40% in glioblastomas), which is due to CpG promoter methylation. Astrocytoma (grade III) are frequently mutated in isocitrate dehydrogenase (IDH1). These tumors show a surprisingly good therapeutic response. IDH1 mutation has an impact on ALKBH2 activity thus influencing DNA repair. A master switch between survival and death is p53, which often retains transactivation activity (wildtype) in malignant glioma. The role of p53 in regulating survival via DNA repair and the routes of death are discussed and conclusions as to cancer therapeutic options were drawn.
Subject(s)
Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , DNA Repair/drug effects , Nitrosourea Compounds/pharmacology , Precision Medicine/methods , Temozolomide/pharmacology , Brain Neoplasms/pathology , Cell Death/drug effects , Cell Death/genetics , Humans , Nitrosourea Compounds/therapeutic use , Temozolomide/therapeutic useABSTRACT
We performed an in vivo comparative study of activity of three substances of the nitrosourea group produced in Russia. All substances demonstrated high antitumor activity against various solid and leukemic tumors. Aranosa significantly enhanced life duration in mice with leukemia (by 65-194%) and inhibited the growth of solid tumors (by 49-99.6%). Lisomustine and ormustine showed higher activity than aranose. Single administration of lisomustine increased life span of mice (by 22-114%) and resulted in cure of all animals in four models: lymphoblastic leukemia L-1210, lymphocytic leukemia P-388, Lewis lung carcinoma, and cervical cancer RShM-5. After ormustine treatment, full recovery was observed only in groups with lymphocytic leukemia P-388 and cervical cancer RShM-5. These findings attest to higher activity of lisomustine in the studied models.
Subject(s)
Antineoplastic Agents/therapeutic use , Nitrosourea Compounds/therapeutic use , Animals , Female , Leukemia L1210/drug therapy , Leukemia P388/drug therapy , Male , Mice , Neoplasms, Experimental/drug therapy , Russia , Treatment Outcome , Uterine Cervical Neoplasms/drug therapyABSTRACT
BACKGROUND The aim of this study was to compare nutrition-related adverse events and clinical outcomes of ifosfamide, carboplatin, and etoposide regimen (ICE therapy) and ranimustine, carboplatin, etoposide, and cyclophosphamide regimen (MCEC therapy) instituted as pretreatment for autologous peripheral blood stem cell transplantation. MATERIAL AND METHODS We enrolled patients who underwent autologous peripheral blood stem cell transplantation between 2007 and 2012. Outcomes were compared between ICE therapy (n=14) and MCEC therapy (n=14) in relation to nutrient balance, engraftment day, and length of hospital stay. In both groups, we compared the timing of nutrition-related adverse events with oral caloric intake, analyzed the correlation between length of hospital stay and duration of parenteral nutrition, and investigated the association between oral caloric intake and the proportion of parenteral nutrition energy in total calorie supply. Five-year survival was compared between the groups. RESULTS Compared with the MCEC group, the ICE group showed significant improvement in oral caloric intake, length of hospital stay, and timing of nutrition-related adverse events and oral calorie intake, but a delay in engraftment. Both groups showed a correlation between duration of parenteral nutrition and length of hospital stay (P=0.0001) and between oral caloric intake (P=0.0017) and parenteral nutrition energy sufficiency rate (r=-0.73, P=0.003; r=-0.76, P=0.002). Five-year survival was not significantly different between the groups (P=0.1355). CONCLUSIONS Our findings suggest that compared with MCEC therapy, ICE therapy improves nutrition-related adverse events and reduces hospital stay, conserving medical resources, with no significant improvement in long-term survival. The nutritional pathway may serve as a tool for objective evaluation of pretreatment for autologous peripheral blood stem cell transplantation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma/drug therapy , Nutritional Physiological Phenomena , Peripheral Blood Stem Cell Transplantation , Adult , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carboplatin/therapeutic use , Cyclophosphamide/therapeutic use , Energy Intake , Etoposide/therapeutic use , Female , Humans , Ifosfamide/therapeutic use , Male , Middle Aged , Nitrosourea Compounds/therapeutic use , Survival Analysis , Transplantation, Autologous , Treatment Outcome , Young AdultABSTRACT
Chloroethylating nitrosoureas (CNU), such as lomustine, nimustine, semustine, carmustine and fotemustine are used for the treatment of malignant gliomas, brain metastases of different origin, melanomas and Hodgkin disease. They alkylate the DNA bases and give rise to the formation of monoadducts and subsequently interstrand crosslinks (ICL). ICL are critical cytotoxic DNA lesions that link the DNA strands covalently and block DNA replication and transcription. As a result, S phase progression is inhibited and cells are triggered to undergo apoptosis and necrosis, which both contribute to the effectiveness of CNU-based cancer therapy. However, tumor cells resist chemotherapy through the repair of CNU-induced DNA damage. The suicide enzyme O6-methylguanine-DNA methyltransferase (MGMT) removes the precursor DNA lesion O6-chloroethylguanine prior to its conversion into ICL. In cells lacking MGMT, the formed ICL evoke complex enzymatic networks to accomplish their removal. Here we discuss the mechanism of ICL repair as a survival strategy of healthy and cancer cells and DNA damage signaling as a mechanism contributing to CNU-induced cell death. We also discuss therapeutic implications and strategies based on sequential and simultaneous treatment with CNU and the methylating drug temozolomide.
Subject(s)
Cell Death/drug effects , DNA Damage/drug effects , DNA Repair/drug effects , Neoplasms/drug therapy , Nitrosourea Compounds/pharmacology , Nitrosourea Compounds/therapeutic use , Signal Transduction/drug effects , Animals , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Alkylating/therapeutic use , DNA Replication/drug effects , HumansABSTRACT
Background: The primary objective of this study was to compare the overall survival (OS) of patients with anaplastic astrocytoma (AA) treated with radiotherapy (RT) and either temozolomide (TMZ) or a nitrosourea (NU). Secondary endpoints were time to tumor progression (TTP), toxicity, and the effect of IDH1 mutation status on clinical outcome. Methods: Eligible patients with centrally reviewed, histologically confirmed, newly diagnosed AA were randomized to receive either RT+TMZ (n = 97) or RT+NU (n = 99). The study closed early because the target accrual rate was not met. Results: Median follow-up time for patients still alive was 10.1 years (1.9-12.6 y); 66% of the patients died. Median survival time was 3.9 years in the RT/TMZ arm (95% CI, 3.0-7.0) and 3.8 years in the RT/NU arm (95% CI, 2.2-7.0), corresponding to a hazard ratio (HR) of 0.94 (P = .36; 95% CI, 0.67-1.32). The differences in progression-free survival (PFS) and TTP between the 2 arms were not statistically significant. Patients in the RT+NU arm experienced more grade ≥3 toxicity (75.8% vs 47.9%, P < .001), mainly related to myelosuppression. Of the 196 patients, 111 were tested for IDH1-R132H status (60 RT+TMZ and 51 RT+NU). Fifty-four patients were IDH negative and 49 were IDH positive with a better OS in IDH-positive patients (median survival time 7.9 vs 2.8 y; P = .004, HR = 0.50; 95% CI, 0.31-0.81). Conclusions: RT+TMZ did not appear to significantly improve OS or TTP for AA compared with RT+ NU. RT+TMZ was better tolerated. IDH1-R132H mutation was associated with longer survival.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Astrocytoma/therapy , Brain Neoplasms/therapy , Chemoradiotherapy , Dacarbazine/analogs & derivatives , Nitrosourea Compounds/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Astrocytoma/metabolism , Astrocytoma/pathology , Biomarkers, Tumor/metabolism , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Dacarbazine/therapeutic use , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Prognosis , Prospective Studies , Survival Rate , Temozolomide , Young AdultABSTRACT
Thioredoxin reductase 1 (TrxR1) is an important potential anticancer drug target and closely related to both carcinogenesis and cancer progression. Ethaselen (BBSKE), a novel organoselenium compound inhibiting TrxR1 with selective antitumor effect, while its symmetrical structure results in poor solubility. Carmustine (BCNU), a DNA cross-link agent and also a deactivator of TrxR, is with high toxicity and low selectivity which limit its clinical application to some extents. Herein, a novel compound, 1-(2-chloroethyl)-1-nitroso-3-(2-(3-oxobenzoelenazol-2(3H)-yl)ethyl)urea(4a-1), which was designed through the combination of Ethaselen and Carmustine, showed good solubility, good tagetability, low toxicity and excellent antitumor activity by synergism. Using the structure of 4a-1 as a key active scaffold, a series of novel 1-(2-chloroethyl)-1-nitroso-3-(2-(3-oxobenzoelenazol-2(3H)-yl)ethyl)urea was designed, synthesized and evaluated to explore the structure-activity relationships (SARs) of these inhibitors and to improve their antitumor activities. Notably, 1-(2-chloroethyl)-3-(2-(6-fluoro-3-oxobenzoselenazol-2(3H)-yl)ethyl)-1-nitrosourea(4b-1) was found to exhibit more potent antitumor activities comparable to 4a-1 against all the four cancer cell lines, including Mia PaCa-2, PANC-1, RKO, LoVo. These results have highlighted compound 4b-1 as a new potential lead candidate for future development of novel potent broad-spectrum antitumor agents. In addition, a SAR model was established to conduct further structural modification.
Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Nitrosourea Compounds/therapeutic use , Organoselenium Compounds/therapeutic use , Animals , Body Weight/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Ligands , Molecular Docking Simulation , Neoplasms/pathology , Nitrosourea Compounds/chemical synthesis , Nitrosourea Compounds/chemistry , Nitrosourea Compounds/toxicity , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/chemistry , Organoselenium Compounds/toxicity , Rats , Solubility , Structure-Activity Relationship , Thioredoxin-Disulfide Reductase/antagonists & inhibitors , Thioredoxin-Disulfide Reductase/metabolismABSTRACT
Desmoplastic medulloblastoma is a rare subtype of medulloblastoma in childhood and more rare in adults. Cerebrospinal fluid (CSF) occurrence is frequent and important for treatment and prognosis. We report the CSF cytologic features of recurrent desmoplastic/nodular medulloblastoma in a 30-aged male.
Subject(s)
Cerebellar Neoplasms/cerebrospinal fluid , Cerebellar Neoplasms/diagnosis , Cerebrospinal Fluid/cytology , Medulloblastoma/cerebrospinal fluid , Medulloblastoma/diagnosis , Neoplasm Recurrence, Local/cerebrospinal fluid , Neoplasm Recurrence, Local/diagnosis , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cerebellar Neoplasms/drug therapy , Humans , Male , Medulloblastoma/drug therapy , Neoplasm Staging , Nitrosourea Compounds/therapeutic use , Prognosis , Rare Diseases , Treatment OutcomeABSTRACT
PURPOSE: The treatment of recurrent high-grade gliomas (HGG) is controversial. There are different therapeutic schedules but without a clear orientation about which of them should be used in each clinical situation. In addition, when patients suffer a second recurrence or they have poor performance status, they are excluded from clinical trials, although second recurrences and poor performance status are indeed more and more real and common situations in the clinical setting. In this study, we assessed the efficacy and safety of fotemustine (FTM) in HGG [fundamentally, glioblastomas (GB)], independent of time of recurrence or performance status. METHODS/PATIENTS: Retrospective study in HGG patients treated with FTM in second or further line according to standard, the Addeo or any other scheme, starting treatment prior to 30 November 2012. Included patients reflect the regular situation in which the drug is used in terms of comorbidities and analytic situation (hematologic, renal and hepatic functions). Response assessment was performed by MRI and according to the clinical protocols of each center (every 8-12 weeks). Clinical situation and supportive care drugs were evaluated in each medical consultation. Clinical end-points analyzed, among others, were: PFS-6, PFS, OS, response rates, toxicity, quality of life and neurocognitive impact. RESULTS: In terms of activity, an overall response rate of 8 % was observed: partial response 6 % (7 patients) and complete response 2 % (2 patients). The median time to achieve the greater response with FTM was 73 days (4-841 days). Patients treated according to the Addeo schedule had a shorter time to greater response in comparison with other schedules (85.9 vs 114 days), although without statistical significance. There were no significant differences in progression-free survival (PFS) when comparing different FTM schedules or using FTM in first or second recurrence. Median PFS: 3 months. PFS-6: 30.3 %. Overall survival (OS): although without significant differences, a tendency to better survival when using the Addeo schedule versus other schedules was observed (at 6 months, 44.6 vs 34.5 %; at 12 months, 25 vs 23.6 %; at 18 months, 11.5 vs 7.9 %), as well as if earlier use (second vs third line) concerning OS-12 (33.7 vs 18.2 %). Median OS: 5.2 months. Grades 3-4 toxicity was 28 % (31 patients), being neutropenia (4 %) and thrombocytopenia (17 %) the most frequent adverse reactions. From quality of life and neuro-cognitive function perspectives, 11 patients (10 %) and 16 (14 %) improved the Karnofsky Index and neurological impairment, respectively, after FTM treatment. CONCLUSION: This study has shown that FTM is safe and has a comparable activity with other available therapeutic options of use in the treatment of recurrent HGG.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Glioma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Nitrosourea Compounds/therapeutic use , Organophosphorus Compounds/therapeutic use , Adult , Aged , Brain Neoplasms/mortality , Female , Glioma/mortality , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Retrospective Studies , Treatment Outcome , Young AdultSubject(s)
Antineoplastic Agents/adverse effects , Hydroxyurea/adverse effects , Myeloproliferative Disorders/drug therapy , Panniculitis/chemically induced , Aged, 80 and over , Anti-Bacterial Agents/therapeutic use , Biopsy , Drug Substitution , Female , Glucocorticoids/therapeutic use , Humans , Myeloproliferative Disorders/diagnosis , Nitrosourea Compounds/therapeutic use , Panniculitis/diagnosis , Panniculitis/drug therapy , Remission Induction , Treatment OutcomeABSTRACT
BACKGROUND: In adults, malignant glioma (high-grade glioma) is one of the most common brain tumors. In spite of different types of treatment, the outcome is still not likely to be favorable. The aim of this study was to determine the difference between survival rate in adult patients with high grade glioma treated by radiotherapy only and those treated by a combination of radiotherapy and nitrosurea-based chemotherapy. METHODS: This study was conducted using the records of 48 patients with grade 3 or 4 of glial brain tumor referred to the radiation-oncology ward of Shohada-e-Tajrish Hospital in Tehran, Iran from 2005 to 2012. The patients had undergone radiotherapy alone or adjuvant chemoradiation with nitrosourea. The median survival of patients after receiving the different types of treatment were evaluated using the Kaplan-Meier method and the log -rank exam. Data were analyzed using univariate analysis for median survival regarding to the patients' age, gender, extent of surgery, Karnofsky performance status (KPS) with the Kaplan-Meier method, and the log-rank exam. We used the Cox-model for multivariate analysis. RESULTS: Records of 48 patients were studied (34 men and 14 women). The mean survival were 18 months for men and 15.2 months for women (P=0.05). Around 58% (28 patients) were more than 50 years old, and 42% (20 patients) were less than 50, and mean survival for the two age groups were 13 and 20 months, respectively (P<0.001). Then, the patients were divided into three groups according to the extent of surgery, i.e., excisional biopsy (11 patients), stereotactic biopsy (22 patients), and resection (15 patients), and the mean survival for the three groups were 14.7, 17.3, and 18.8 months, respectively. There was no significant statistical difference for mean survival between the three groups (P=0.23). The KPS was greater than 70% in 23 patients and less than 70% in 21 patients, and the mean survival for the former and latter groups were 17.6 and 16 months, respectively (P=0.67), four patients had unknown KPS. Twenty patients received only radiotherapy, and chemoradiation was done for 28 patients, and the mean survival for the former and latter patients were 14.5 and 19 months, respectively (P=0.15). CONCLUSION: In this study, we concluded that age was the only effective factor in the survival of the patients and that chemotherapy had no significant effect on the survival of the patients.
Subject(s)
Glioma/drug therapy , Glioma/radiotherapy , Nitrosourea Compounds/therapeutic use , Adult , Age Factors , Chemoradiotherapy , Female , Glioma/mortality , Glioma/pathology , Humans , Iran/epidemiology , Male , Middle Aged , Neoplasm Grading , Survival RateABSTRACT
Functional preservation is critical in glioma surgery, and the extent of resection influences survival outcome. Neoadjuvant chemotherapy is a promising option because of its potential to facilitate tumor shrinkage and maximum tumor resection. The object of this study was to assess the utility of the neoadjuvant strategy in a prospective series of gliomas with favorable molecular status. Twenty-six consecutive cases of diffuse gliomas of WHO grade II or III with either 1p19q codeletion or MGMT methylation were treated with upfront chemotherapy following maximal safe removal. In cases of incomplete initial surgery, second-look resection was intended after tumor volume decrease by chemotherapy. Among 22 evaluable cases, chemotherapy led to a median change in the sum of the product of perpendicular diameters of -35 %, and 14 out of the 22 cases (64 %) showed objective response. Second-look resection after tumor volume decrease was performed in 12 out of 19 cases of incomplete initial surgery (GTR/STR 9, removal of residual methionine PET uptake 3). The median progression-free survival among the 22 patients with grade II tumors was 57 months, with some cases showing durable progression-free survival after second-look resection. MIB-1 indices of the second-look resected tumors were lower than those of the initial tumors, and the methylation status of the MGMT gene was unchanged. Neoadjuvant chemotherapy based on molecular guidance often produces significant volume decrease of incompletely resected gliomas. Radical second-look resection is an optional advantage of upfront chemotherapy for chemosensitive gliomas compared with initial radiotherapy.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/surgery , Glioma/drug therapy , Glioma/genetics , Glioma/surgery , Adult , Brain Neoplasms/diagnosis , Chromosome Deletion , Chromosomes, Human, Pair 1 , DNA Methylation , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Dacarbazine/analogs & derivatives , Dacarbazine/therapeutic use , Disease-Free Survival , Female , Glioma/diagnosis , Humans , Male , Middle Aged , Nitrosourea Compounds/therapeutic use , Prospective Studies , Temozolomide , Treatment Outcome , Tumor Suppressor Proteins/geneticsABSTRACT
This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/adverse effects , Carboplatin/therapeutic use , Cyclophosphamide/adverse effects , Cyclophosphamide/therapeutic use , Disease Progression , Doxorubicin/adverse effects , Doxorubicin/therapeutic use , Etoposide/adverse effects , Etoposide/therapeutic use , Female , Humans , Leukemia-Lymphoma, Adult T-Cell/mortality , Leukemia-Lymphoma, Adult T-Cell/pathology , Male , Middle Aged , Nitrosourea Compounds/adverse effects , Nitrosourea Compounds/therapeutic use , Prednisolone/adverse effects , Prednisolone/therapeutic use , Treatment Outcome , Vincristine/adverse effects , Vincristine/therapeutic use , Vindesine/adverse effects , Vindesine/therapeutic useABSTRACT
To evaluate the efficacy of hypofractionated stereotactic radiotherapy performed as reirradiation in combination with fotemustine or bevacizumab as salvage treatment in patients with recurrent malignant glioma. Between May 2006 and December 2013, 54 patients with recurrent malignant glioma received hypofractionated stereotactic radiotherapy (HSRT, 25 Gy in 5-Gy fractions) plus either fotemustine or bevacizumab at University of Rome Sapienza, Sant'Andrea Hospital. All patients had Karnofsky performance score (KPS) ≥ 60 and were previously treated with standard chemoradiotherapy. Forty-two patients had a GBM and 12 patients had an anaplastic astrocytoma (AA). The median overall survival (OS) time and 12-month OS rates after HSRT was 11 months and 30 % for patients treated with HSRT plus bevacizumab and 8.3 months and 5 % for those treated with HSRT plus fotemustine (p = 0.01). Median PFS times were 4 and 6 months for patients treated with HSRT plus fotemustine or bevacizumab, respectively (p = 0.01). KPS > 70 (p = 0.04), AA histology, and the treatment with bevacizumab were independent favourable prognostic factors for OS. In general, both treatments were well tolerated with relatively low treatment-related toxicity. HSRT combined with bevacizumab or fotemustine may represent a feasible treatment option for patients with progressive malignant gliomas, although most of the tumors recur in a few months. Efficacy of bevacizumab or alkylating agents in combination with different radiation schedules needs to be evaluated in prospective studies.
Subject(s)
Antineoplastic Agents/therapeutic use , Bevacizumab/therapeutic use , Brain Neoplasms/therapy , Glioma/therapy , Nitrosourea Compounds/therapeutic use , Organophosphorus Compounds/therapeutic use , Radiosurgery/methods , Adult , Aged , Brain Neoplasms/mortality , Female , Glioma/mortality , Humans , Karnofsky Performance Status , Male , Middle Aged , Radiation Dose Hypofractionation , Retrospective StudiesABSTRACT
Glioblastomas are highly aggressive adult brain tumors with poor clinical outcome. In the central nervous system (CNS) the blood-brain barrier (BBB) is the most important limiting factor for both development of new drugs and drug delivery. Here, we propose a new strategy to treat glioblastoma based on transferrin (Tf)-targeted self-assembled nanoparticles (NPs) incorporating zoledronic acid (ZOL) (NPs-ZOL-Tf). NPs-ZOL-Tf have been assessed on the glioblastoma cell line U373MG-LUC that showed a refractoriness in vitro to temozolomide (TMZ) and fotemustine (FTM). NPs-ZOL-Tf treatment resulted in higher in vitro cytotoxic activity than free ZOL. However, the potentiation of anti-proliferative activity of NPs-ZOL-Tf was superimposable to that one induced by NPs-ZOL (not armed with Tf). On the other hand, NPs-ZOL-Tf showed a higher antitumor efficacy if compared with that one caused by NPs-ZOL in immunosuppressed mice intramuscularly bearing U373MG-LUC xenografts, inducing a significant tumor weight inhibition (TWI). The experiments performed on mice with intracranial U373MG-LUC xenografts confirmed the efficacy of NPs-ZOL-Tf. These effects were paralleled by a higher intratumour localization of fluorescently-labeled-NPs-Tf both in intramuscular and intracranial xenografts. In conclusion, our results demonstrate that the encapsulation of ZOL increases the antitumor efficacy of this drug in glioblastoma through the acquisition of ability to cross the BBB.
Subject(s)
Brain Neoplasms/drug therapy , Diphosphonates/administration & dosage , Drug Delivery Systems/methods , Glioblastoma/drug therapy , Imidazoles/administration & dosage , Nanoparticles/administration & dosage , Animals , Apoptosis/drug effects , Blood-Brain Barrier/drug effects , Cell Growth Processes/drug effects , Cell Line, Tumor , Dacarbazine/analogs & derivatives , Dacarbazine/therapeutic use , Diphosphonates/chemistry , Drug Resistance, Neoplasm , Glioblastoma/immunology , Humans , Imidazoles/chemistry , Male , Mice , Mice, Inbred Strains , Nanoparticles/chemistry , Nitrosourea Compounds/therapeutic use , Organophosphorus Compounds/therapeutic use , Temozolomide , Transferrin/chemistry , Tumor Burden/drug effects , Xenograft Model Antitumor Assays , Zoledronic AcidABSTRACT
Diffuse astrocytomas (DAs) represent less than 10% of all gliomas. They are diffusely infiltrating World Health Organization (WHO) grade II neoplasms that have a median survival in the range of 5-7 years, generally with a terminal phase in which they undergo malignant transformation to glioblastoma (GBM). The goals of treatment in addition to prolonging survival are therefore to prevent progression and malignant transformation, as well as optimally managing symptoms, primarily tumor-associated epilepsy. Available data suggest that the course of this disease is only minimally impacted by adjuvant therapies and that there does not seem to be much difference in terms of outcome of whether patients are treated in the adjuvant setting with irradiation or chemotherapy. We review the experience with chemotherapy as a treatment modality and offer some guidelines for its usage and discuss medical management of arising symptoms.
Subject(s)
Antineoplastic Agents/therapeutic use , Astrocytoma/drug therapy , Supratentorial Neoplasms/drug therapy , Astrocytoma/diagnosis , Astrocytoma/pathology , Dacarbazine/analogs & derivatives , Dacarbazine/therapeutic use , Disease Progression , Humans , Neoplasm Grading , Nitrosourea Compounds/therapeutic use , Prognosis , Supratentorial Neoplasms/diagnosis , Supratentorial Neoplasms/pathology , TemozolomideABSTRACT
BACKGROUND: To date, there is no standard treatment for recurrent glioblastoma. We analyzed the feasibility of second surgery plus carmustine wafers followed by intravenous fotemustine. METHODS: Retrospectively, we analyzed patients with recurrent glioblastoma treated with this multimodal strategy. RESULTS: Twenty-four patients were analyzed. The median age was 53.6; all patients had KPS between 90 and 100; 19 patients (79%) performed a gross total resection > 98% and 5 (21%) a gross total resection > 90%. The median progression-free survival from second surgery was 6 months (95% CI 3.9-8.05) and the median OS was 14 months (95% CI 11.1-16.8 months). Toxicity was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia. CONCLUSION: This multimodal strategy may be feasible in patients with recurrent glioblastoma, in particular, for patients in good clinical conditions.