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Acta Biomaterialia Feb 2021The treatment for glioblastoma multiforme (GBM) has not changed for more than 20 years while the prognosis for the patients is still poor and most of them survive less... (Review)
Review
The treatment for glioblastoma multiforme (GBM) has not changed for more than 20 years while the prognosis for the patients is still poor and most of them survive less than 1 year after diagnosis. The standard of care for GBM is comprised of surgical resection followed by radiotherapy and oral chemotherapy with temozolomide. The placement of carmustine wafers in the brain after tumour removal is added in cases of recurrent glioma. Significant research is underway to improve the GBM therapy outcome and patient quality of life. Biomaterials are in the front line of the research focus for new treatment options. Specially, biocompatible polymers have been proposed in hydrogel-based formulations aiming at injectable and localized therapies. These formulations can comprise many different pharmacological agents such as chemotherapeutic drugs, nanoparticles, cells, nucleic acids, and diagnostic agents. In this manuscript, we review the most recent formulations developed and tested both in vitro and in vivo using different types of hydrogels. Firstly, we describe three common types of thermo-responsive polymers addressing the advantages and drawbacks of their formulations. Then, we focus on formulations specifically developed for GBM treatment.
Topics: Brain Neoplasms; Carmustine; Glioblastoma; Humans; Neoplasm Recurrence, Local; Polymers; Quality of Life
PubMed: 33227487
DOI: 10.1016/j.actbio.2020.11.030 -
Turkish Neurosurgery 2014The aim of this study was to a conduct a systematic review of carmustine wafers (Gliadel wafers) for the treatment of glioblastoma multiforme (GBM) to assess the... (Review)
Review
The aim of this study was to a conduct a systematic review of carmustine wafers (Gliadel wafers) for the treatment of glioblastoma multiforme (GBM) to assess the survival benefit and safety of this therapy. The inclusion criteria were 1) prospective or retrospective clinical trial; 2) patients who had undergone resection for primary GBM or first recurrence of GBM with or without carmustine wafer implantation; 3) patients with malignant gliomas that included GBM; 4) outcomes including survival analysis of the GBM population. Six trials met the inclusion criteria; four were randomized, controlled trials and two were retrospective. The trials varied with regard to the type of patients and interventions. In three of the trials, patients with GBM who received carmustine wafers had significantly longer median survival than patients who did not receive wafers. Implantation of carmustine wafers did not significantly improve progression-free survival. Carmustine wafers did not increase adverse effects. This systematic review suggests that carmustine wafers have demonstrated promise as an effective and tolerable treatment in comparison to other treatment strategies in patients with GBM.
Topics: Antineoplastic Agents, Alkylating; Carmustine; Glioblastoma; Humans; Randomized Controlled Trials as Topic; Survival Analysis
PubMed: 25269031
DOI: 10.5137/1019-5149.JTN.8878-13.1 -
Drug Design, Development and Therapy 2015Standard treatment for high-grade glioma (HGG) includes surgery followed by radiotherapy and/or chemotherapy. Insertion of carmustine wafers into the resection cavity as... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Standard treatment for high-grade glioma (HGG) includes surgery followed by radiotherapy and/or chemotherapy. Insertion of carmustine wafers into the resection cavity as a treatment for malignant glioma is currently a controversial topic among neurosurgeons. Our meta-analysis focused on whether carmustine wafer treatment could significantly benefit the survival of patients with newly diagnosed glioblastoma multiforme (GBM).
METHOD
We searched the PubMed and Web of Science databases without any restrictions on language using the keywords "Gliadel wafers", "carmustine wafers", "BCNU wafers", or "interstitial chemotherapy" in newly diagnosed GBM for the period from January 1990 to March 2015. Randomized controlled trials (RCTs) and cohort studies/clinical trials that compared treatments designed with and without carmustine wafers and which reported overall survival or hazard ratio (HR) or survival curves were included in this study. Moreover, the statistical analysis was conducted by the STATA 12.0 software.
RESULTS
Six studies including two RCTs and four cohort studies, enrolling a total of 513 patients (223 with and 290 without carmustine wafers), matched the selection criteria. Carmustine wafers showed a strong advantage when pooling all the included studies (HR = 0.63, 95% confidence interval (CI) = 0.49-0.81; P = 0.019). However, the two RCTs did not show a statistical increase in survival in the group with carmustine wafer compared to the group without it (HR = 0.51, 95% CI = 0.18-1.41; P = 0.426), while the cohort studies demonstrated a significant survival increase (HR = 0.59, 95% CI = 0.44-0.79; P < 0.0001).
CONCLUSION
Carmustine-impregnated wafers play a significant role in improving survival when used for patients with newly diagnosed GBM. More studies should be designed for newly diagnosed GBM in the future.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Brain Neoplasms; Carmustine; Chemistry, Pharmaceutical; Decanoic Acids; Dosage Forms; Glioblastoma; Humans; Middle Aged; Neoplasm Grading; Polyesters; Risk Factors; Survival Analysis; Time Factors; Treatment Outcome; Young Adult
PubMed: 26170620
DOI: 10.2147/DDDT.S85943 -
Cytotherapy May 2024The combination therapy of autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell (CART) therapy has been employed to improve...
Prognostic differences between carmustine, etoposide, cytarabine and melphalan (BEAM) and carmustine, etoposide, cytarabine, melphalan and fludarabine (BEAMF) regimens before autologous stem cell transplantation plus chimeric antigen receptor T therapy in patients with refractory/relapsed B-cell...
BACKGROUND AIMS
The combination therapy of autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell (CART) therapy has been employed to improve outcomes for relapsed or refractory (R/R) B-cell non-Hodgkin-lymphoma (B-NHL). The widely used conditioning regimen before ASCT plus CART therapy reported in the literature was carmustine, etoposide, cytarabine and melphalan (BEAM). However, whether adding fludarabine to the BEAM regimen (BEAMF) can improve the survival of patients with R/R B-NHL remains unknown.
METHODS
In total, 39 and 19 patients with R/R B-NHL were enrolled to compare clinical outcomes in the BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy, respectively.
RESULTS
The objective response (OR) rates at 3 months to BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy were 71.8% and 94.7%, respectively (P = 0.093). The BEAMF regimen showed a trend towards a superior duration of response compared with the BEAM regimen (P = 0.09). After a median follow-up of 28 months (range: 0.93-51.9 months), the BEAMF regimen demonstrated superior 2-year progression-free survival (PFS) (89.5% versus 63.9%; P = 0.048) and 2-year overall survival (OS) (100% vs 77.3%; P = 0.035) compared with the BEAM regimen. In the multivariable Cox regression analysis, OR at month 3 (responders) was remarkably correlated with better OS (hazard ratio: 0.112, P = 0.005) compared with OR (non-responders).
CONCLUSIONS
For patients with R/R B-NHL, the BEAMF regimen before ASCT plus CD19/22 CART therapy was correlated with superior PFS and OS than the BEAM regimen, and the BEAMF regimen is a promising alternative conditioning regimen for ASCT plus CAR-T therapy.
Topics: Humans; Male; Carmustine; Melphalan; Cytarabine; Female; Hematopoietic Stem Cell Transplantation; Middle Aged; Adult; Transplantation, Autologous; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Vidarabine; Prognosis; Aged; Lymphoma, B-Cell; Podophyllotoxin; Immunotherapy, Adoptive; Young Adult; Combined Modality Therapy; Transplantation Conditioning; Receptors, Chimeric Antigen
PubMed: 38385909
DOI: 10.1016/j.jcyt.2024.01.012 -
Biology of Blood and Marrow... Sep 2012Total body irradiation has been the mainstay of conditioning since the inception of allogeneic hematopoietic cell transplantation, but toxicity often precludes its use....
Radiation-free allogeneic conditioning with fludarabine, carmustine, and thiotepa for acute lymphoblastic leukemia and other hematologic malignancies necessitating enhanced central nervous system activity.
Total body irradiation has been the mainstay of conditioning since the inception of allogeneic hematopoietic cell transplantation, but toxicity often precludes its use. For less-fit patients with acute lymphoblastic leukemia and other hematologic malignancies frequently affecting the central nervous system, we designed a radiation-free regimen with fludarabine (25 mg/m2/day on days -6 to -4), carmustine (400 mg/m2 on day -6), and thiotepa (5 mg/kg twice daily on days -5 and -4), all of which readily penetrate the blood-brain barrier and have potent antileukemic and lymphotoxic activity. Here we present a series of 30 consecutive patients with high-risk or relapsed disease who underwent allogeneic hematopoietic cell transplantation with this protocol. The median patient age was 60 years (range, 42-70 years), and the median follow-up was 968 days (range, 58-1989 days). Graft-versus-host disease prophylaxis consisted of cyclosporine A and alemtuzumab (10-20 mg). At 2 years, overall survival was 52% (95% confidence interval [CI], 34%-71%), event-free survival was 39% (95% CI, 22%-57%), cumulative incidence of relapse/progression was 30% (95% CI, 17%-52%), and treatment-related mortality was 31% (95% CI, 18%-53%). Neurologic toxicity is a concern, especially in older and heavily pretreated patients. Our experience indicates the feasibility of this regimen as an alternative to total body irradiation and a potentially curative option for less-fit patients who need a highly central nervous system-active conditioning.
Topics: Adult; Aged; Alemtuzumab; Antibodies, Monoclonal, Humanized; Carmustine; Central Nervous System; Cyclosporine; Drug Administration Schedule; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Recurrence; Survival Analysis; Thiotepa; Transplantation Conditioning; Transplantation, Homologous; Vidarabine
PubMed: 22430085
DOI: 10.1016/j.bbmt.2012.02.016 -
The Oncologist 2011The 2-year survival rate of patients with glioblastoma accrued to research studies increased from 10% to nearly 40% from 2000 to 2010. These improvements began with the... (Review)
Review
The 2-year survival rate of patients with glioblastoma accrued to research studies increased from 10% to nearly 40% from 2000 to 2010. These improvements began with the demonstration of a survival benefit when daily temozolomide was administered with 6 weeks of standard radiation and for 6 months thereafter. This treatment regimen is often associated with significant lymphopenia, thrombocytopenia, and progressive blood-brain barrier dysfunction that can result in clinical and radiologic deterioration without true tumor progression ("pseudoprogression"). With new evidence that combining this cytotoxic agent with radiation improves survival in this malignancy, many investigators have modified the regimen to further improve patient outcomes. These largely uncontrolled studies highlight controversies regarding the optimal therapy of this disease. This review focuses on the following selected controversies: (a) What is the appropriate temozolomide dose, schedule, and duration in the postradiation period? (b) How should other U.S. Food and Drug Administration-approved therapies (such as carmustine wafers and bevacizumab) be incorporated into this treatment regimen? (c) Should the results in glioblastoma be extrapolated to patients aged >70 and to patients with lower grade gliomas? and (d) How should novel therapeutic approaches be added to radiation and temozolomide in clinical trials for patients with newly diagnosed glioblastoma?
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Alkylating; Bevacizumab; Carmustine; Chemotherapy, Adjuvant; Female; Glioblastoma; Humans; Male; Treatment Outcome
PubMed: 21339260
DOI: 10.1634/theoncologist.2010-0335 -
The Cochrane Database of Systematic... Mar 2011Standard treatment for high grade glioma (HGG) usually entails surgery (either biopsy or resection) followed by radiotherapy plus or minus temozolomide. Implanting... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Standard treatment for high grade glioma (HGG) usually entails surgery (either biopsy or resection) followed by radiotherapy plus or minus temozolomide. Implanting wafers impregnated with chemotherapy agents into the resection cavity represents a novel means of delivering drugs directly to the resection cavity with potentially fewer systemic side effects. It is not clear how effective this modality is or whether it should be recommended as part of standard care for patients with HGG.
OBJECTIVES
To estimate the clinical effectiveness of chemotherapy wafers for patients with HGG.
SEARCH STRATEGY
The following databases were searched: CENTRAL (issue 4. 2010); MEDLINE and EMBASE. The original search strategy also included: Science Citation Index; Physician Data Query; and the meta-Register of Controlled Trials. Reference lists of all identified studies were searched. The Journal of Neuro-Oncology and Neuro-oncology were hand searched from 1999 to 2010, including all conference abstracts. Neuro-oncologists, trial authors and drug manufacturers were contacted regarding ongoing and unpublished trials.
SELECTION CRITERIA
Patients included those of all ages with a histologically proven diagnosis of HGG (using intra-operative analysis when undergoing first resection). Therapy could be instigated for either newly diagnosed disease (primary therapy) or at recurrence. Interventions included insertion of chemotherapy wafers to the resection cavity. Included studies had to be randomised controlled trials (RCTs).
DATA COLLECTION AND ANALYSIS
Two independent review authors assessed the search results for relevance and undertook critical appraisal according to pre-specified guidelines.
MAIN RESULTS
In primary disease two RCTs assessing the effect of carmustine impregnated wafers (Gliadel®) and enrolling a total of 272 participants were identified. Survival was increased with Gliadel® compared to placebo (hazard ratio (HR) 0.65, 95% Confidence Interval (CI) 0.48 to 0.86, P = 0.003). In recurrent disease a single RCT was included comparing Gliadel® with placebo and enrolled 222 participants. It did not demonstrate a significant survival increase (HR 0.83, 95% CI 0.62 to 1.10, P = 0.2). There was no suitable data for any of the secondary outcome measures. Adverse events were not more common in either arm and are presented in a descriptive fashion.
AUTHORS' CONCLUSIONS
Carmustine impregnated wafers (Gliadel®) result in improved survival without an increased incidence of adverse events over placebo wafers when used for primary disease therapy. There is no evidence of benefit for any other outcome measures. In recurrent disease Gliadel® does not appear to confer any additional benefit.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Carmustine; Combined Modality Therapy; Decanoic Acids; Drug Carriers; Glioma; Humans; Neoplasm Recurrence, Local; Polyesters; Randomized Controlled Trials as Topic
PubMed: 21412902
DOI: 10.1002/14651858.CD007294.pub2 -
Cancer Jan 2006The objective of this study was to compare the response rates, ability to mobilize autologous hematopoietic (peripheral blood) stem cells (PBSCs), and progression-free...
Similar response rates and superior early progression-free survival with gemcitabine, dexamethasone, and cisplatin salvage therapy compared with carmustine, etoposide, cytarabine, and melphalan salvage therapy prior to autologous stem cell transplantation for recurrent or refractory Hodgkin...
BACKGROUND
The objective of this study was to compare the response rates, ability to mobilize autologous hematopoietic (peripheral blood) stem cells (PBSCs), and progression-free survival (PFS) after second-line chemotherapy with either gemcitabine, dexamethasone, and cisplatin (GDP) or carmustine, etoposide, cytarabine, and melphalan (mini-BEAM) followed by high-dose therapy and hematopoietic stem cell transplantation (ASCT) for patients with recurrent or refractory Hodgkin lymphoma.
METHODS
The outcomes of 68 consecutive patients who were referred for salvage therapy (34 patients received mini-BEAM, and 34 patients received GDP) were compared retrospectively. Patients received mini-BEAM as inpatient treatment every 3-4 weeks, whereas GDP was administered on an outpatient basis every 3 weeks. Responding patients proceeded to stem cell mobilization, followed by high dose etoposide and melphalan, and ASCT. Patients who had disease bulk at recurrence that measured > 5 cm received involved-field radiation post-ASCT.
RESULTS
The response rate to GDP prior to ASCT (complete responses, unconfirmed complete responses, and partial responses) was 62% (95% confidence interval [95% CI], 45-78%) compared with 68% (95% CI, 52-83%) for mini-BEAM (P = 0.61). After mobilizing chemotherapy, the proportion of patients for whom the target PBSC number of > or = 5 x 10(6) CD34-positive cells/kg was obtained was 97% after GDP and 57% after MB (P = 0.0003). More patients completed collection with a single apheresis procedure after GDP than after mini-BEAM (73% vs. 36%; P = 0.004), and fewer patients in the GDP group required bone marrow harvesting to proceed to ASCT. After a median follow-up of 1.8 years after ASCT, PFS was significantly better for patients who received GDP compared with patients who received mini-BEAM (74% vs. 35% at 1.5 yrs, respectively; P = 0.005). Overall survival at 1.5 years was 91% after GDP and 82% after mini-BEAM (P = 0.23).
CONCLUSIONS
Although this was a retrospective analysis, response to GDP and early PFS after ASCT compared favorably with mini-BEAM salvage chemotherapy. Based on these data, the authors believe that a Phase III trial comparing GDP with mini-BEAM or other platinum-containing regimens is warranted.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cisplatin; Cytarabine; Deoxycytidine; Dexamethasone; Disease Progression; Disease-Free Survival; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Male; Melphalan; Middle Aged; Prognosis; Recurrence; Retrospective Studies; Salvage Therapy; Treatment Outcome; Gemcitabine
PubMed: 16329112
DOI: 10.1002/cncr.21587 -
Nanomedicine (London, England) Nov 2010Once metastatic, melanoma remains one of the most aggressive and morbid malignancies. Moreover, in past decades, the overall survival for advanced unresectable melanoma... (Review)
Review
Once metastatic, melanoma remains one of the most aggressive and morbid malignancies. Moreover, in past decades, the overall survival for advanced unresectable melanoma exhibited a constancy of poor prognosis. Low response rates and serious adverse effects have been characteristic of standard therapy based on a combination of chemotherapeutic agents or immunotherapy with IL-2. For example, the chemotherapy including dacarbazine, carmustin, cisplatin and tamoxifen is known as 'Dartmouth regimen' while the CVD regimen comprises carmustine, vinblastine and dacarbazine. Thus, there is an urgent and critical need to reformulate these bioactive agents using nanoscience and nanotechnology as alternative strategies. This article overviews current design and evaluation of nanomedicine undertaken to address this unmet medical need. The nanomedicines studied include polymeric nanoparticles, liposomes, polymersomes, dendrimers, cubosomes, niosomes and nanodiamonds. In this preclinical article, nanotechnology provides hope for effective treatment of this aggressive and largely treatment-resistant disease.
Topics: Antineoplastic Agents; Carmustine; Cisplatin; Dacarbazine; Drug Delivery Systems; Humans; Melanoma; Nanomedicine; Tamoxifen
PubMed: 21128721
DOI: 10.2217/nnm.10.117 -
International Journal of Cancer Oct 2016Despite established androgen receptor (AR) antagonists, AR/AR-variants signaling remain a major obstacle for the successful treatment of castration resistant prostate...
Combination of carmustine and selenite effectively inhibits tumor growth by targeting androgen receptor, androgen receptor-variants, and Akt in preclinical models: New hope for patients with castration resistant prostate cancer.
Despite established androgen receptor (AR) antagonists, AR/AR-variants signaling remain a major obstacle for the successful treatment of castration resistant prostate cancer (CRPC). In addition, CRPC cells adapt to survive via AR-independent pathways to escape next generation therapies. Therefore, there is an urgent need for drugs that can target these signaling pathways in CRPC. In this study, we sought to determine whether carmustine and selenite in combination could induce apoptosis and inhibit growth of CRPC in-vitro and in-vivo. CRPC (22Rv1, VCaP, and PC-3) cell lines in culture and xenograft mouse were used. Combination of carmustine and selenite treatment significantly increased reactive oxygen species, apoptosis and growth inhibition in CRPC cells with down regulation of anti-apoptotic (Bcl-2 and Mcl-1) and proliferative proteins (c-Myc and cyclin-D1). This effect was associated with complete reduction of AR/AR-variants, AR-V7, PSA and significant induction of p27Kip1. Combination treatment substantially abolished phospho-Akt, phospho-GSK-3β, and anchorage-independent growth in AR-positive and AR-negative cells. Consistent with in-vitro results, combination treatment effectively induced apoptosis and completely inhibited xenograft tumor growth and markedly reduced AR/AR-variants, AR-V7, PSA, and Bcl-2 in xenograft tumors without causing genotoxicity in host mice. Individual agent treatment showed only partial effect. The combination treatment showed a significant synergistic effect. The present study is the first to demonstrate that the combination of carmustine and selenite treatment completely suppressed CRPC tumor growth by reducing AR/AR-variants and Akt signaling. Our findings suggest that the combination of carmustine and selenite could constitute a promising next-generation therapy for successful treatment of patients with CRPC.
Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carmustine; Cell Line, Tumor; Cell Proliferation; Humans; Male; Mice; Mice, Nude; Molecular Targeted Therapy; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-akt; Receptors, Androgen; Signal Transduction; Sodium Selenite; Xenograft Model Antitumor Assays
PubMed: 27198552
DOI: 10.1002/ijc.30189