- Angiogenesis inhibitors in tackling recurrent glioblastoma. [Journal Article]
- ERExpert Rev Anticancer Ther 2017 Apr 24
- Despite aggressive multimodality treatment of glioblastoma, outcome remains poor and patients mostly die of local recurrences. Besides reoperation and occasionally reirradiation, systemic treatment o...
Despite aggressive multimodality treatment of glioblastoma, outcome remains poor and patients mostly die of local recurrences. Besides reoperation and occasionally reirradiation, systemic treatment of recurrent glioblastoma consists of alkylating chemotherapy (lomustine, temozolomide), bevacizumab and combinations thereof. Unfortunately, antiangiogenic agents failed to improve survival either as a monotherapy or in combination treatments. This review provides current insights into tumor-derived escape mechanisms and other areas of treatment failure of antiangiogenic agents in glioblastoma. Areas covered: We summarize the current literature on antiangiogenic agents in the treatment of glioblastoma, with a focus on recurrent disease. A literature search was performed using the terms "glioblastoma", "bevacizumab", "antiangiogenic", "angiogenesis", "resistance", radiotherapy", "chemotherapy" and derivations thereof. Expert commentary: New insights in glioma neoangiogenesis, increasing understanding of vascular pathway escape mechanisms, and upcoming immunotherapy approaches might revitalize the therapeutic potential of antiangiogenic agents against glioblastoma, although with a different treatment intention. The combination of antiangiogenic approaches with or without radiotherapy might still hold promise to complement the therapeutic armamentarium of fighting glioblastoma.
- Patterns of care and outcomes of multi-agent versus single-agent chemotherapy as part of multimodal management of low grade glioma. [Journal Article]
- JNJ Neurooncol 2017 Apr 21
- For high-risk low-grade gliomas (LGGs), adjuvant radiotherapy (RT) with procarbazine/lomustine/vincristine (PCV) chemotherapy increases overall survival (OS) over RT alone. However, in practice, temo...
For high-risk low-grade gliomas (LGGs), adjuvant radiotherapy (RT) with procarbazine/lomustine/vincristine (PCV) chemotherapy increases overall survival (OS) over RT alone. However, in practice, temozolomide (TMZ) is often used instead of PCV. Using the National Cancer Data Base (NCDB), we provide the first investigation of practice patterns and outcomes of chemoradiotherapy with single-agent chemotherapy (SAC, analogous to TMZ) or multi-agent chemotherapy (MAC, analogous to PCV) for LGG. Patients with high-risk Grade II LGGs were queried in the NCDB. Inclusion was limited to patients treated with definitive RT and chemotherapy. Patients were divided into cohorts receiving SAC or MAC. Kaplan-Meier analysis compared overall survival (OS), and Cox proportional hazards models determined variables independently associated with OS. Of 1029 patients, 989 (96.1%) received SAC, while 40 (3.9%) received MAC. Patients treated more recently (2010-2012) were less likely to receive MAC (p = 0.029). No differences in median OS were observed between patients treated with MAC and SAC (45.3 vs. 59.2 months, p = 0.861). Independent predictors of worse OS included age >40, high Charlson-Deyo index, other governmental/unrecorded insurance status, biopsy only, astrocytoma histology, Western geographical region, and higher income. Substuting MAC with SAC had no impact on OS (p = 0.804). There is a significantly greater utilization of SAC compared to MAC in the US. There were no differences in OS between patients receiving SAC and MAC, nor did this factor impact OS on multivariate analysis, suggesting that the practice of substituting MAC with SAC for management of LGG may not adversely affect outcome.
- Lomustine induced acute pulmonary toxicity in a pediatric medulloblastoma survivor. [Journal Article]
- SASouth Asian J Cancer 2017 Jan-Mar; 6(1):38-39
- Prolonged Temozolomide Maintenance Therapy in Newly Diagnosed Glioblastoma. [Journal Article]
- OOncologist 2017 Mar 30
- CONCLUSIONS: Our data do not support a general extension of TMZ maintenance therapy beyond six cycles. The Oncologist 2017;22:1-6 IMPLICATIONS FOR PRACTICE: Radiation therapy with concomitant and adjuvant temozolomide (TMZ) maintenance therapy is still the standard of care in patients below the age of 65 years in newly diagnosed glioblastoma. However, in clinical practice, many centers continue TMZ maintenance therapy beyond six cycles. The impact of this continuation is controversial and has not yet been addressed in prospective randomized clinical trials. We compared the effect of more than six cycles of TMZ in comparison with exactly six cycles on overall survival (OS) and progression-free survival (PFS) by multivariate analysis and found a benefit in PFS but not OS. Thus, our data do not suggest prolonging TMZ maintenance therapy beyond six cycles, which should be considered in neurooncological practice.
- Bevacizumab for Patients with Recurrent Gliomas Presenting with a Gliomatosis Cerebri Growth Pattern. [Journal Article]
- IJInt J Mol Sci 2017 Mar 29; 18(4)
- Bevacizumab has been shown to improve progression-free survival and neurologic function, but failed to improve overall survival in newly diagnosed glioblastoma and at first recurrence. Nonetheless, b...
Bevacizumab has been shown to improve progression-free survival and neurologic function, but failed to improve overall survival in newly diagnosed glioblastoma and at first recurrence. Nonetheless, bevacizumab is widely used in patients with recurrent glioma. However, its use in patients with gliomas showing a gliomatosis cerebri growth pattern is contentious. Due to the marked diffuse and infiltrative growth with less angiogenic tumor growth, it may appear questionable whether bevacizumab can have a therapeutic effect in those patients. However, the development of nodular, necrotic, and/or contrast-enhancing lesions in patients with a gliomatosis cerebri growth pattern is not uncommon and may indicate focal neo-angiogenesis. Therefore, control of growth of these lesions as well as control of edema and reduction of steroid use may be regarded as rationales for the use of bevacizumab in these patients. In this retrospective patient series, we report on 17 patients with primary brain tumors displaying a gliomatosis cerebri growth pattern (including seven glioblastomas, two anaplastic astrocytomas, one anaplastic oligodendroglioma, and seven diffuse astrocytomas). Patients have been treated with bevacizumab alone or in combination with lomustine or irinotecan. Seventeen matched patients treated with bevacizumab for gliomas with a classical growth pattern served as a control cohort. Response rate, progression-free survival, and overall survival were similar in both groups. Based on these results, anti-angiogenic therapy with bevacizumab should also be considered in patients suffering from gliomas with a mainly infiltrative phenotype.
- Procarbazine, Lomustine, and Vincristine (PCV) Regimen for Central Nervous System Tumors. [Journal Article]
- HPHosp Pharm 2017; 52(2):98-104
- The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensin...
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: firstname.lastname@example.org. The information presented in this review is based on published data and clinical expertise and includes information not included in the product labeling. Incorporation of such published data provides a more robust assessment of the drugs and assists pharmacists in evaluation of orders for off-label use of these agents.
- Glioma Subclassifications and Their Clinical Significance. [Review]
- NNeurotherapeutics 2017; 14(2):284-297
- The impact of targeted therapies in glioma has been modest. All the therapies that have demonstrated a significant survival benefit for gliomas in Phase III trials, including radiation, chemotherapy ...
The impact of targeted therapies in glioma has been modest. All the therapies that have demonstrated a significant survival benefit for gliomas in Phase III trials, including radiation, chemotherapy (temozolomide and PCV [procarbazine, lomustine, vincristine]), and tumor-treating fields, are based on nonspecific targeting of proliferating cells. Recent advances in the molecular understanding of gliomas suggest some potential reasons for the failure of more targeted therapies in gliomas. Specifically, the histologic-based glioma classification is composed of multiple different molecular subtypes with distinct biology, natural history, and prognosis. As a result of these insights, the diagnosis and classification of gliomas have recently been updated by the World Health Organization. However, these changes and other novel observations regarding glioma biomarkers and subtypes highlight several clinical challenges. First, the field is faced with the difficulty of reinterpreting the results of prior studies and retrospective data using the new classifications to clarify prognostic assessments and treatment recommendations for patients. Second, the new classifications and insights require rethinking the design and stratification of future clinical trials. Last, these observations provide the essential framework for the development and testing of new specific targeted therapies for particular glioma subtypes. This review aims to summarize the current literature regarding glioma subclassifications and their clinical relevance in this evolving field.
- Is CCNU (lomustine) valuable for treatment of cutaneous epitheliotropic lymphoma in dogs? A critically appraised topic. [Review]
- BVBMC Vet Res 2017 Feb 21; 13(1):61
- CONCLUSIONS: CCNU leads to a complete remission of signs in approximately one-third of dogs with CTCL, but such remissions are of short duration. The median survival time after CCNU appears longer than that without treatment, but other drugs appear to provide a better long-term prognosis. Further studies are required to investigate the effect of CCNU, alone or in combination, on remission rates, survival times and impact on quality of life.
- Chloroethylating nitrosoureas in cancer therapy: DNA damage, repair and cell death signaling. [Review]
- BBBiochim Biophys Acta 2017 Jan 29; 1868(1):29-39
- Chloroethylating nitrosoureas (CNU), such as lomustine, nimustine, semustine, carmustine and fotemustine are used for the treatment of malignant gliomas, brain metastases of different origin, melanom...
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 O(6)-methylguanine-DNA methyltransferase (MGMT) removes the precursor DNA lesion O(6)-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.
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- Addition of Androgens Improves Survival in Elderly Patients With Acute Myeloid Leukemia: A GOELAMS Study. [Journal Article]
- JCJ Clin Oncol 2017; 35(4):387-393
- Purpose Elderly patients with acute myeloid leukemia (AML) have a poor prognosis, and innovative maintenance therapy could improve their outcomes. Androgens, used in the treatment of aplastic anemia,...
Purpose Elderly patients with acute myeloid leukemia (AML) have a poor prognosis, and innovative maintenance therapy could improve their outcomes. Androgens, used in the treatment of aplastic anemia, have been reported to block proliferation of and initiate differentiation in AML cells. We report the results of a multicenter, phase III, randomized open-label trial exploring the benefit of adding androgens to maintenance therapy in patients 60 years of age or older. Patients and Methods A total of 330 patients with AML de novo or secondary to chemotherapy or radiotherapy were enrolled in the study. Induction therapy included idarubicin 8 mg/m(2) on days 1 to 5, cytarabine 100 mg/m(2) on days 1 to 7, and lomustine 200 mg/m(2) on day 1. Patients in complete remission or partial remission received six reinduction courses, alternating idarubicin 8 mg/m(2) on day 1, cytarabine 100 mg/m(2) on days 1 to 5, and a regimen of methotrexate and mercaptopurine. Patients were randomly assigned to receive norethandrolone 10 or 20 mg/day, according to body weight, or no norethandrolone for a 2-year maintenance therapy regimen. The primary end point was disease-free survival by intention to treat. Secondary end points were event-free survival, overall survival, and safety. This trial was registered at www.ClinicalTrials.gov identifier NCT00700544. Results Random assignment allotted 165 patients to each arm; arm A received norethandrolone, and arm B did not receive norethandrolone. Complete remission or partial remission was achieved in 247 patients (76%). The Schoenfeld time-dependent model showed that norethandrolone significantly improved survival for patients still in remission at 1 year after induction. In arms A and B, respectively, 5-year disease-free survival was 31.2% and 16.2%, event-free survival was 21.5% and 12.9%, and overall survival was 26.3% and 17.2%. Norethandrolone improved outcomes irrelevant to all prognosis factors. Only patients with baseline leukocytes > 30 × 10(9)/L did not benefit from norethandrolone. Conclusion This study demonstrates that maintenance therapy with norethandrolone significantly improves survival in elderly patients with AML without increasing toxicity.