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Cancer Jun 2010Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. The authors report safety, activity, and angiogenic profiling results...
Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma.
BACKGROUND
Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. The authors report safety, activity, and angiogenic profiling results with the rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide (RT-PEPC) regimen in patients with recurrent mantle cell lymphoma (MCL).
METHODS
RT-PEPC included induction (Months 1-3) of rituximab 4 times weekly, daily thalidomide (50 mg), and PEPC followed by maintenance thalidomide (100 mg), oral PEPC titrated to the neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies, including tumor angiogenic phenotyping, plasma vascular endothelial growth factor (VEGF), and circulating endothelial cells.
RESULTS
Twenty-five patients were enrolled, and 22 were evaluable. The median age was 68 years (range, 52-81 years), 24 patients (96%) had stage III or IV disease, 18 patients (72%) had an International Prognostic Index (IPI) score of 3 to 5, and 20 patients (80%) had high-risk Mantle Cell International Prognostic Index (MIPI) scores. Patients had received a median of 2 previous therapies (range, 1-7 previous therapies), and 15 patients (60%) had progressed on bortezomib. At a median follow-up of 38 months, the overall response rate was 73% (complete response [CR]/unconfirmed CR rate, 32%; partial response [PR] rate, 41%; n = 22 patients), and the median progression-free survival was 10 months. Four CRs were ongoing (> or =6 months, > or =31 months, > or =48 months, and > or =50 months). Toxicities included grade 1 and 2 fatigue, rash, neuropathy, and cytopenias, including grade 1 and 2 thrombocytopenia (64%) and grade 3 and 4 neutropenia (64%). Two thromboses and 5 episodes of grade 3 or 4 infections occurred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGF A and VEGF receptor 1) and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF levels and circulating endothelial cells trended down with treatment.
CONCLUSIONS
RT-PEPC had significant and durable activity in MCL with manageable toxicity and maintained QoL. Novel, low-intensity approaches warrant further evaluation, potentially as initial therapy in elderly patients.
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Etoposide; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Neovascularization, Pathologic; Prednisone; Procarbazine; Quality of Life; Recurrence; Rituximab; Thalidomide; Treatment Outcome
PubMed: 20235190
DOI: 10.1002/cncr.25055 -
Journal of the Royal College of... Jan 1971
Review
Topics: Adult; Antineoplastic Agents; Asparaginase; Carmustine; Child; Cyclophosphamide; Cytarabine; Cytosine; Daunorubicin; Drug Therapy, Combination; Hodgkin Disease; Humans; Immunotherapy; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Male; Mechlorethamine; Mercaptopurine; Methotrexate; Nitrogen Mustard Compounds; Prednisolone; Prednisone; Procarbazine; Remission, Spontaneous; Vincristine
PubMed: 4950464
DOI: No ID Found -
Blood Feb 1999
Review
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow Transplantation; Cardiomyopathies; Clinical Trials as Topic; Cohort Studies; Combined Modality Therapy; Dacarbazine; Doxorubicin; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Infections; Laparotomy; Lung Diseases, Interstitial; Lymphography; Mechlorethamine; Middle Aged; Neoplasm Staging; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Prednisone; Procarbazine; Prognosis; Radiation Injuries; Radiotherapy; Remission Induction; Salvage Therapy; Vinblastine; Vincristine
PubMed: 9920825
DOI: No ID Found -
Pharmaceutics Sep 2023The present study aimed to evaluate the stability of active pharmaceutical ingredients (APIs) from different pharmacological classes in a compounded oral suspending...
The present study aimed to evaluate the stability of active pharmaceutical ingredients (APIs) from different pharmacological classes in a compounded oral suspending vehicle. Oral suspensions of amoxicillin trihydrate (50 mg/mL), clozapine (25 mg/mL), indomethacin (5.0 mg/mL), levodopa/carbidopa (10.0/2.5 mg/mL), levothyroxine sodium (T4, 25 µg/mL), lomustine (4.0 and 10.0 mg/mL), methyldopa (25 mg/mL) and procarbazine (10.0 mg/mL) were formulated in SyrSpend SF PH4 and the stability was monitored for up to 90 days, except for amoxicillin trihydrate, which was evaluated for 30 days only. The APIs' stability was determined by measuring percent recovery using stability-indicating high-performance liquid chromatography (HPLC or UHPLC) or titration (amoxicillin trihydrate only). The stability of amoxicillin trihydrate, clozapine, indomethacin and levodopa/carbidopa were studied at both refrigerated (2-8 °C) and room temperature (20-25 °C). Lomustine, procarbazine, and methyldopa were studied at refrigerated temperature only. Our data demonstrated promising stability for the compounded suspensions containing various APIs, investigated in SyrSpend SF PH4, as all APIs exhibited stability throughout the study duration and met content uniformity criteria. These findings lead to the conclusion that the tested compounded oral suspensions present a viable approach for creating personalized, age-appropriate formulations. The capacity to ensure dose consistency and stability using APIs from diverse pharmacological classes renders them suitable choices for both pediatric and geriatric patients.
PubMed: 37896148
DOI: 10.3390/pharmaceutics15102388 -
Blood Nov 2018The HD18 study for patients with newly diagnosed advanced-stage Hodgkin lymphoma (HL) used positron emission tomography (PET) after 2 cycles (PET-2) of bleomycin,...
The HD18 study for patients with newly diagnosed advanced-stage Hodgkin lymphoma (HL) used positron emission tomography (PET) after 2 cycles (PET-2) of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses (eBEACOPP) to guide further treatment. Here, we analyzed the impact of PET-2 results in the context of eBEACOPP according to the Deauville score (DS) in patients treated within the HD18 trial. Residual tissue was visually compared with reference regions according to DS. We analyzed the association between PET-2 uptake and baseline characteristics, progression-free survival (PFS), and overall survival (OS). One thousand five patients (52%) had DS1 or DS2, 471 (24%) had DS3, and 469 (24%) DS4. PET-2 uptake was associated with baseline risk factors large mediastinal mass, extranodal disease, and high International Prognostic Score ( < .0001 each). Among 722 patients receiving standard therapy with 6 cycles of eBEACOPP, 3-year PFS rates were 92.2%, 95.9%, and 87.6% with DS1-2, DS3, and DS4, respectively. Univariate hazard ratio (HR) for PFS in patients with DS4 vs DS1-3 was 2.3 (1.3-3.8; = .002). DS4 was the only factor remaining significant for PFS in a multivariate analysis including the associated baseline risk factors. Three-year OS rates were 97.6% for DS1-2, 99.0% for DS3, and 96.8% for DS4, with a univariate HR for DS4 vs DS1-3 of 2.6 (1.0-6.6; = .04). Residual uptake above that in the liver at PET-2 (ie, DS4) is an important risk factor regarding survival outcomes for patients treated with eBEACOPP upfront. We thus recommend DS4 as the cutoff value for PET-2 positivity. This trial was registered at www.clinicaltrials.gov as #NCT00515554.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Doxorubicin; Etoposide; Female; Hodgkin Disease; Humans; Male; Middle Aged; Positron-Emission Tomography; Prednisone; Procarbazine; Survival Analysis; Treatment Outcome; Vincristine; Young Adult
PubMed: 30166329
DOI: 10.1182/blood-2018-05-852129 -
Journal of Clinical Oncology : Official... Jan 2013Intrinsic glioma subtypes (IGSs) are molecularly similar tumors that can be identified based on unsupervised gene expression analysis. Here, we have evaluated the... (Randomized Controlled Trial)
Randomized Controlled Trial
Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951.
PURPOSE
Intrinsic glioma subtypes (IGSs) are molecularly similar tumors that can be identified based on unsupervised gene expression analysis. Here, we have evaluated the clinical relevance of these subtypes within European Organisation for Research and Treatment of Cancer (EORTC) 26951, a randomized phase III clinical trial investigating adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study includes gene expression profiles of formalin-fixed, paraffin-embedded (FFPE) clinical trial samples.
PATIENTS AND METHODS
Gene expression profiling was performed in 140 samples, 47 fresh frozen samples and 93 FFPE samples, on HU133_Plus_2.0 and HuEx_1.0_st arrays, respectively.
RESULTS
All previously identified six IGSs are present in EORTC 26951. This confirms that different molecular subtypes are present within a well-defined histologic subtype. Intrinsic subtypes are highly prognostic for overall survival (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance status, and tumor location), molecular (1p/19q loss of heterozygosity [LOH], IDH1 mutation, and MGMT methylation), and histologic parameters. Combining known molecular (1p/19q LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (proportion of explained variation, 30% v 23% for each individual group of factors). Specific genetic changes (IDH1, 1p/19q LOH, and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p/19q LOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone versus 12.8 years after RT/PCV (P = .0349; hazard ratio, 2.18; 95% CI, 1.06 to 4.50).
CONCLUSION
Intrinsic subtypes are highly prognostic in EORTC 26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Glioma; Humans; Kaplan-Meier Estimate; Lomustine; Male; Middle Aged; Procarbazine; Prognosis; Transcriptome; Treatment Outcome; Vincristine; Young Adult
PubMed: 23269986
DOI: 10.1200/JCO.2012.44.1444 -
Environmental and Molecular Mutagenesis Jul 2019Procarbazine hydrochloride (PCH) is a DNA-reactive hematopoietic carcinogen with potent and well-characterized clastogenic activity. However, there is a paucity of in...
Integrated In Vivo Genotoxicity Assessment of Procarbazine Hydrochloride Demonstrates Induction of Pig-a and LacZ Mutations, and Micronuclei, in MutaMouse Hematopoietic Cells.
Procarbazine hydrochloride (PCH) is a DNA-reactive hematopoietic carcinogen with potent and well-characterized clastogenic activity. However, there is a paucity of in vivo mutagenesis data for PCH, and in vitro assays often fail to detect the genotoxic effects of PCH due to the complexity of its metabolic activation. We comprehensively evaluated the in vivo genotoxicity of PCH on hematopoietic cells of male MutaMouse transgenic rodents using a study design that facilitated assessments of micronuclei and Pig-a mutation in circulating erythrocytes, and lacZ mutant frequencies in bone marrow. Mice were orally exposed to PCH (0, 6.25, 12.5, and 25 mg/kg/day) for 28 consecutive days. Blood samples collected 2 days after cessation of treatment exhibited significant dose-related induction of micronuclei in both immature and mature erythrocytes. Bone marrow and blood collected 3 and 70 days after cessation of treatment also showed significantly elevated mutant frequencies in both the lacZ and Pig-a assays even at the lowest dose tested. PCH-induced lacZ and Pig-a (immature and mature erythrocytes) mutant frequencies were highly correlated, with R values ≥0.956, with the exception of lacZ vs. Pig-a mutants in mature erythrocytes at the 70-day time point (R = 0.902). These results show that PCH is genotoxic in vivo and demonstrate that the complex metabolism and resulting genotoxicity of PCH is best evaluated in intact animal models. Our results further support the concept that multiple biomarkers of genotoxicity, especially hematopoietic cell genotoxicity, can be readily combined into one study provided that adequate attention is given to manifestation times. Environ. Mol. Mutagen. 60:505-512, 2019. © 2018 Her Majesty the Queen in Right of Canada.
Topics: Animals; Carcinogens; Cell Nucleus; DNA Damage; Erythrocytes; Hematopoietic Stem Cells; Lac Operon; Male; Mice; Micronucleus Tests; Mutagenesis; Mutagenicity Tests; Mutagens; Mutation; Procarbazine; Reticulocytes
PubMed: 30592561
DOI: 10.1002/em.22271 -
Acta Medica Portuguesa 1990After an historical review of the progressive improvement of Radiotherapy of Hodgkin's Disease, the authors present the actual management concepts with special reference... (Review)
Review
After an historical review of the progressive improvement of Radiotherapy of Hodgkin's Disease, the authors present the actual management concepts with special reference to prognostic factors. So, the actual strategy of Hodgkin's Disease aims above all not to lower the "cure" values lately reached but to reduce the iatrogenic pathology trying not to treat to much the good prognosis subgroups. These are susceptible of a less aggressive therapy by the knowledge of the relation cost/benefit of the intensive radiotherapy and the several multidrug regimens.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Combined Modality Therapy; Dacarbazine; Doxorubicin; Hodgkin Disease; Humans; Mechlorethamine; Prednisone; Procarbazine; Radiotherapy Dosage; Vinblastine; Vincristine
PubMed: 1692179
DOI: No ID Found -
Journal of the National Medical... Oct 1985An update in cancer chemotherapy that deals with the various therapies of lung cancer is described. At present, the stage of the disease and cell type are the major... (Review)
Review
An update in cancer chemotherapy that deals with the various therapies of lung cancer is described. At present, the stage of the disease and cell type are the major factors that determine the treatment. Important differences in the biological behavior and response to treatment exist between small cell and non-small cell cancers. The small cell type is sensitive to many chemotherapeutic agents. Differences in response to chemotherapy and survival have been less among the non-small cell types.The treatment of non-small cell carcinomas including squamous cell, large cell, and adenocarcinoma are reviewed in Part I of this paper. Small cell lung cancer will be described in Part II, which will be published in a future issue of the journal.
Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; BCG Vaccine; Bleomycin; Carcinoma; Carcinoma, Squamous Cell; Cyclophosphamide; Dactinomycin; Doxorubicin; Fluorouracil; Humans; Lomustine; Lung Neoplasms; Mechlorethamine; Methotrexate; Mitomycin; Mitomycins; Neoplasm Staging; Peptichemio; Prednisone; Procarbazine; Prognosis; Vincristine
PubMed: 2414458
DOI: No ID Found -
Brain Tumor Research and Treatment Oct 2014A 49-year-old female patient was admitted due to memory disturbances. Magnetic resonance (MR) imaging suggested gliomatosis cerebri (GC), which had spread to both...
A 49-year-old female patient was admitted due to memory disturbances. Magnetic resonance (MR) imaging suggested gliomatosis cerebri (GC), which had spread to both insular lobes, both frontal and basal ganglia and the brain stem. A stereotactic biopsy was performed at the high signal intensity area of the T2-weighted MR image, and the revealed a diffuse astrocytoma. Radiation therapy was judged not to be an appropriate treatment for the patient because of her cognitive impairment. A combinatorial chemotherapy regiment consisting of Procarbazine, CCNU, and Vincristine (PCV) was agreed upon after discussion. The patient underwent six cycles of PCV chemotherapy (a full dose was applied until the 3rd cycle, and dose then was reduced to 75% for the remaining cycles). Although the patient exhibited side effects such as bone marrow suppression and gastrointestinal symptoms, these were managed by medication. Over the 28 months following initiation of treatment, the high signal area in the right frontal and temporal lobes in the T2-weighted MR image decreased, and the patient's cognitive function [global deterioration scale (GDS) 4 points, mini-mental state examination (MMSE) 25 point] also improved (GDS 1 points, MMSE 29 points). PCV chemotherapy can therefore be an alternative therapeutic option for patients with GC who cannot be treated with radiation therapy or other chemotherapies.
PubMed: 25408934
DOI: 10.14791/btrt.2014.2.2.102