bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk/Benefit Profile of Arsenic Trioxide
Authors: Rust Deborah M. , Soignet Steven L. 
Published: August 2004

Abstract
Approximately 20%-30% of patients with acute promyelocytic leukemia (APL) who are treated with the current standard all-trans retinoic acid and anthracycline-based chemotherapy regimen suffer relapse. In the mid-1990s, studies from China reported the effective use of arsenic trioxide in achieving complete remission in patients with APL. In the United States, a multicenter trial of this agent in 40 patients with relapsed APL following conventional therapy confirmed the positive safety and efficacy outcomes of a smaller 12-patient pilot study. Common adverse events were hyperleukocytosis, APL differentiation syndrome, prolonged QT interval on electrocardiogram, skin rash, and hyperglycemia.
Docetaxel: Overview of an Active Drug for Breast Cancer
Authors: Crown John 
Published: August 2004

Abstract
Docetaxel and paclitaxel differ in their precise molecular targets and pharmacokinetics. Docetaxel is more avidly taken up by tumor cell lines than paclitaxel, and its efflux is slower. Comparative cytotoxicity data suggest greater potency. These factors may help explain the clinical differences that have been observed between the taxanes in patients with breast cancer.
Docetaxel and Epirubicin in Advanced Breast Cancer
Authors: Sessa Cristiana , Pagani Olivia 
Published: August 2004

Abstract
In an International Breast Cancer Study Group phase I/II program, 70 patients with advanced breast cancer received up to eight courses of 75 mg/m2 docetaxel combined with 90 mg/m2 epirubicin, every 3 weeks. G-CSF was not administered prophylactically. Grade 4 neutropenia occurred in 88% of cycles that were not supported by G-CSF. However, febrile neutropenia affected only 24% of cycles. It occurred after the first cycle in 56% of cases and was managed by oral antibiotics in 52% of cases. When supportive G-CSF was administered, the incidence of febrile neutropenia fell to 3% and grade 4 neutropenia to 41%. Only 6% of patients experienced a greater than 20% reduction in left ventricular ejection fraction and no severe, irreversible cardiotoxicity was observed. The overall response rate (RR) was 66% and median time to progression was 4.5 months. The RR was similar in patients with prior adjuvant chemotherapy and patients with predominantly visceral disease. These data and those of comparable series suggest that the combination of epirubicin and docetaxel is tolerable and active, and that it should be further developed clinically.
Docetaxel and Herceptin: Foundation for Future Strategies
Authors: Pegram Mark D. 
Published: August 2004

Abstract
Randomized controlled studies have demonstrated that both docetaxel and Herceptin are capable of increasing survival in patients with metastatic breast cancer. The two agents show synergy in vitro, and their use in combination is not likely to be associated with the problem of enhanced cardiotoxicity. In two trials of Herceptin plus docetaxel in patients with advanced breast cancer, preliminary data are available for 35 patients. These early results show that the combination is well-tolerated. No symptomatic cardiotoxicity has occurred. The preliminary response rates (RR) in these first- and second-line patients are 44% in one study and 63% in the other. In the subgroups of patients who were HER-2 3+ overexpressers, the RRs are currently 55% and 73%. In an attempt to maximize the efficacy of Herceptin, its use has also been studied in combination with docetaxel and a platinum salt, producing a preliminary RR of 78% in patients positive for HER-2 on the fluorescence in situ hybridization assay. These data are sufficiently promising to justify a study of the role of Herceptin in combination with adjuvant chemotherapy regimens containing docetaxel or docetaxel plus a platinum. The combination of Herceptin with adjuvant therapy containing docetaxel and a platinum may provide a helpful alternative to the potentially cardiotoxic Herceptin/anthracycline-containing regimens currently under investigation.
Weekly Docetaxel in Breast Cancer: Applying Clinical Data to Patient Therapy
Authors: Baselga Jose , Tabernero Josep M. 
Published: August 2004

Abstract
The use of weekly 35-40 mg/m2 docetaxel, typically on a schedule of 6 weeks of therapy followed by a 2-week break, has produced response rates ranging from 33%-50% in patients with advanced breast cancer, the majority of whom have already received chemotherapy. These encouraging levels of response are seen across disease sites and in patients with prior anthracycline exposure. Importantly, the weekly administration of docetaxel allows prolonged treatment to a high cumulative dose: the weekly regimen is minimally myelotoxic, and neuropathy and other adverse events are infrequent. Weekly single-agent docetaxel may be a useful therapy in particular groups of patients such as those with reduced bone marrow reserve. It may also be a helpful means of delivering a highly active cytotoxic drug in combination with radiation therapy, other proven chemotherapy agents such as doxorubicin, and new, highly promising biological agents such as Herceptin.
Theoretical Concepts and the Emerging Role of Taxanes in Adjuvant Therapy
Authors: Norton Larry 
Published: August 2004

Abstract
The proven benefits of adjuvant chemotherapy on disease-free and overall survival in breast cancer can be explained by concepts of cell kill. Interventions which result in greater log kill can be expected to produce improved clinical results. The application of log-kill concepts to human breast cancer growth, which appears to follow Gompertzian kinetics, suggests not only that the use of non-cross-resistant drugs is important, but that dose-dense schedules may have an advantage over conventional schedules of drug administration. Sequential therapy may allow dose-dense administration of cytotoxic agents and encourage the integration of new biological agents into combination regimens, particularly with the taxanes. Ongoing trials in these concepts are reviewed.
Novel Compounds in the Therapy of Breast Cancer: Opportunities for Integration with Docetaxel
Authors: Tolcher Anthony W. 
Published: August 2004

Abstract
Increasingly, novel agents are being developed specifically at inhibition of growth factor receptors and events within the signal transduction pathway. These agents include the epidermal growth factor tyrosine kinase inhibitors, the farnesyl transferase inhibitors, and bcl-2 antisense oligonucleotides. Along with these new approaches to molecular targeting, it will be necessary to develop new study designs for drug evaluation. Target validation in both normal surrogate tissues and tumor tissue becomes increasingly relevant in early clinical trials. Furthermore, antitumor efficacy may no longer correlate with normal hematological or nonhematological toxicity, and it may be more appropriate in phase I trials to identify the maximum target inhibition dose rather than the maximum tolerated dose. Moreover, measures of cytoreduction, such as complete and partial response, may be less relevant than disease stabilization for some of these novel agents which have limited cytotoxic effects and would be considered cytostatic agents. Assessment of single-agent activity and the future role in conjunction with cytostatic agents represents the single most important challenge facing the clinical development of these molecular targeted therapies.
Answering Patients' Needs: Oral Alternatives to Intravenous Therapy
Authors: Borner Markus , Scheithauer Werner , Twelves Chris , Maroun Jean , Wilke Hansjochen 
Published: August 2004

Abstract
Metastatic colorectal cancer has traditionally been treated with i.v. 5-fluorouracil (5-FU), with or without leucovorin (LV). 5-FU is administered as either an i.v. bolus or a protracted infusion. Although schedules using the latter method offer efficacy benefits (objective response rate, time to disease progression), protracted infusion schedules are often associated with medical complications, inconvenience, high costs, and poor quality of life. Issues such as quality of life and convenience have influenced treatment decisions, but the availability of oral fluoropyrimidines represents a new development in this domain.
Studies have confirmed that the majority of patients prefer oral to i.v. chemotherapy. Questionnaire-based studies have also demonstrated a preference for home-based rather than hospital-/clinicbased therapy. This preference was one of the driving forces behind the development of the oral fluoropyrimidines capecitabine (Xeloda®) and uracil plus tegafur (UFT). Oral agents offer patients a more convenient treatment option that can be administered at home, providing patients with a greater sense of control over their therapy, while avoiding the medical complications and psychological distress associated with venous access.
This article highlights some of the problems associated with i.v. therapy and reviews the available data on patient preference, including results of a recent, randomized, phase II study. It also provides a critical evaluation of the efficacy and safety profiles of the only two oral fluoropyrimidines approved for prescription, capecitabine and UFT/LV (UFT/LV not available in Germany and the U.S.), compared with those of two infused, 5-FU-based regimens. Finally, the results of an interactive debate exploring the opinions of approximately 400 oncologists on the issues of oral versus i.v. therapy are presented.
Optimizing the Use of Irinotecan in Colorectal Cancer
Authors: Cunningham David , Maroun Jean , Vanhoefer Udo , Van Cutsem Eric 
Published: August 2004

Abstract
The introduction of new agents with novel mechanisms of action has led to considerable changes in the management of colorectal cancer in recent years. One of these novel agents, irinotecan, has been shown to offer survival benefits in both the first- and second-line treatment of advanced/metastatic colorectal cancer. Irinotecan monotherapy improves survival compared with both best supportive care and infused 5-fluorouracil (5-FU) in patients with 5-FU-pretreated disease, without impacting negatively on patients' quality of life. As a result, irinotecan monotherapy is now considered to be the standard treatment in this setting. Irinotecan in combination with 5-FU/leucovorin (LV) was subsequently evaluated as first-line therapy for metastatic colorectal cancer in two randomized, phase III studies. Both trials confirmed that irinotecan plus infused or bolus 5-FU/leucovorin LV provide a modest survival benefit without compromising patients' quality of life. Combined irinotecan/5-FU/LV represents a new standard in the first-line treatment of metastatic colorectal cancer.
In an attempt to further improve efficacy and tolerability, recent studies have investigated irinotecan in combination with capecitabine as first-line treatment for colorectal cancer. The replacement of infused 5-FU with oral capecitabine provides a more convenient treatment option. A phase I study was conducted to establish the maximum tolerated dose, and demonstrated encouraging antitumor activity and a manageable safety profile with the combination. This article provides a brief overview of the pivotal clinical trial data for irinotecan and discusses how irinotecan-based therapy may be improved in the future. It also discusses potential optimization of irinotecan use through identification of patient subpopulations most likely to benefit from combination or sequential strategies, and the potential of new, oral agents such as capecitabine to replace i.v. 5-FU as a combination partner for irinotecan.
Targeted Approaches for the Treatment of Thrombocytopenia
Authors: Demetri George D. 
Published: August 2004

Abstract
Molecular targeting of novel therapies has the promise of inducing very specific biologic effects. In clinical hematology and oncology, molecular targeting of specific cell surface receptors with erythropoietin, G-CSF, or GM-CSF has been used to stimulate erythropoiesis and granulopoiesis, respectively. Although anemia and neutropenia can be corrected with targeted therapy, safe and effective treatment of thrombocytopenia remains an unmet medical need. While platelet transfusions still represent the standard of care for severe thrombocytopenia, there are several negative aspects associated with their use, including issues of availability, transient effectiveness, costs, adverse effects, negative perception by patients, and infection considerations. Despite extensive investigations of cytokines which act primarily on primitive levels of hematopoiesis, pharmacologic interventions to date have failed to elevate platelet counts in a reliable, highly effective, and well-tolerated fashion. Recombinant human interleukin-11 has been approved by the U.S. Food and Drug Administration for the treatment of chemotherapy-induced thrombocytopenia but has only modest efficacy and significant side effects. The identification of c-Mpl as the thrombopoietin receptor has opened new avenues for the therapeutic manipulation of thrombopoiesis. The development of specific c-Mpl ligands, including recombinant human thrombopoietin (rHuTPO), has allowed investigators to target this receptor for the treatment of chemotherapy-induced thrombocytopenia and other medical disorders characterized by extremely low platelet counts. As a potent stimulator of platelet production, rHuTPO has the potential to reduce the need for platelet transfusions and their attendant complications.
Vascular Endothelial Growth Factor Signaling Pathway as an Emerging Target in Hematologic Malignancies
Authors: List Alan F. 
Published: August 2004

Abstract
Angiogenesis is important in a variety of physiologic and pathologic disorders. It is a central element in embryogenesis, ovulation, wound healing, diabetic retinopathy, and rheumatoid arthritis and in the establishment and spread of malignant tumors. Angiogenic factors include direct angiogens, indirect angiogens, and integrins. Direct angiogens stimulate the formation of new blood vessels directly. Indirect angiogens promote neovascular formation by paracrine stimulation of direct angiogens. Integrins mediate interactions between the developing vessels and components of the extracellular matrix. Vascular endothelial growth factor (VEGF) is a principal direct angiogen. By binding to 1 of 3 receptors (VEGFR-1, -2, or -3), it influences vasculogenesis during embryogenesis, physiologic and neoplastic angiogenesis, and lymphangiogenesis. Although the importance of angiogenesis in solid tumors has been recognized for some time, its exact significance in hematologic malignancies is less clear. Evidence now suggests that VEGF has a major role in the development and progression of hematologic malignancies such as acute leukemia, chronic leukemia, myelodysplasia, non-Hodgkin's lymphoma, and multiple myeloma. Potential therapeutic interventions to interrupt the VEGF signaling pathway of malignancy include antibodies that neutralize the growth factor and small molecules that inhibit the receptor tyrosine kinase activity of VEGF receptors.
The Vascular Endothelial Growth Factor (VEGF) Signaling Pathway: A Therapeutic Target in Patients with Hematologic Malignancies
Authors: Giles Francis J. 
Published: August 2004

Abstract
Angiogenesis is an important component in the progression and metastasis of solid tumors. We now appreciate that angiogenesis is also critically involved in the pathogenesis of hematologic malignancies. Current data suggest important prognostic and therapeutic implications of angiogenesis in a variety of malignancies of the hematopoietic system, including acute and chronic leukemias, myeloproliferative diseases, multiple myeloma, non-Hodgkin's lymphomas, and Hodgkin's disease. Vascular endothelial growth factor (VEGF) is a major angiogenic factor that regulates multiple endothelial cell functions, including mitogenesis. Cellular and circulating levels of VEGF are elevated in hematologic malignancies and are adversely associated with prognosis. Angiogenesis is a very complex, tightly regulated, multistep process, the targeting of which may well prove useful in the creation of novel therapeutic agents. Current approaches being investigated include the inhibition of angiogenesis stimulants (e.g., VEGF), or their receptors, blockade of endothelial cell activation, inhibition of matrix metalloproteinases, and inhibition of tumor vasculature. Preclinical, phase I, and phase II studies of both monoclonal antibodies to VEGF and blockers of the VEGF receptor tyrosine kinase pathway indicate that these agents are safe and offer potential clinical utility in patients with hematologic malignancies.
Targeting Hypomethylation of DNA to Achieve Cellular Differentiation in Myelodysplastic Syndromes (MDS)
Authors: Silverman Lewis R. 
Published: August 2004

Abstract
Considerable progress has been made recently in defining and understanding the diverse members of the group of hematologic disorders now known as the myelodysplastic syndrome (MDS). New systems of classification, based on the latest cytogenetic methodologies, have generated better prognostic data, and basic research has more closely associated molecular mechanisms with clinical subgroups. The mechanisms underlying most cases of myelodysplasia appear to be an array of chromosomal abnormalities leading to suppression of normal myeloid cell differentiation and dominance of abnormal, immature cells. The process is progressive and is mediated by a variety of cytokines, potential loss of tumor suppressor genes, aberrations in signal transduction pathways, and perhaps immune mechanisms. Hypermethylation of specific DNA sequences has been implicated in the pathogenesis of MDS. Until recently, treatment options have been few, high risk, and mostly ineffective. New discoveries, particularly in the area of stimulating remaining normal myeloid cells to resume growth and differentiation, hold promise for safer treatment regimens and improved outcomes. Among the promising new agents are nucleoside analogues, such as 5-azacytidine and decitabine, which reactivate tumor suppressor gene transcription through effects on DNA methylation.
Molecular Targets of Arsenic Trioxide in Malignant Cells
Authors: Miller Wilson H. 
Published: August 2004

Abstract

Learning Objectives
After taking all of the CME courses in this supplement the reader will be able to: Describe the basic biology of various leukemias, multiple myeloma, and myelodysplastic syndrome (MDS).Discuss new targeted treatment strategies for hematologic malignancies.Understand the rationale for the use of nontraditional cytotoxic agents such as arsenic trioxide in the treatment of hematologic malignancies.Examine the role of arsenic trioxide and other novel agents in early-versus accelerated-stage hematologic disease.Discuss the preclinical and clinical efficacy of arsenic trioxide and various agents in treating acute promyelocytic leukemia, MDS, and multiple myeloma.
Access CME test online and receive one hour category 1 credit at CME.TheOncologist.com
Arsenic trioxide (As2O3; ATO) has considerable efficacy in the treatment of relapsed acute promyelocytic leukemia (APL), inducing partial differentiation and promoting apoptosis of malignant promyelocytes. Although initial studies focused on the role of the characteristic APL fusion protein, PML-RARα, in mediating response to ATO, subsequent investigations have revealed that ATO acts on numerous intracellular targets. ATO broadly affects signal transduction pathways and causes a wide range of alterations leading to apoptosis. Key mediators of sensitivity to ATO-induced apoptosis include intracellular glutathione and hydrogen peroxide (H2O2). The loss of inner mitochondrial membrane potential is also an important step in ATO-mediated cell killing. Cellular and physiologic pathways affected by ATO provide some clues as to the mechanisms for the biologic effects of ATO. Recent research has shown that hematologic cancers other than APL and solid tumors derived from several tissue types may be responsive to monotherapy or combination therapy with ATO. A better understanding of the mechanisms of action of ATO may help guide the use of ATO for the treatment of a wide variety of malignancies and allow its potential in cancer therapy to be fully realized.
Nontraditional Cytotoxic Therapies for Relapsed/Refractory Multiple Myeloma
Authors: Hussein Mohamad A. 
Published: August 2004

AbstractLearning ObjectivesAfter taking all of the CME courses in this supplement the reader will be able to:Describe the basic biology of various leukemias, multiple myeloma, and myelodysplastic syndrome (MDS). Discuss new targeted treatment strategies for hematologic malignancies. Understand the rationale for the use of nontraditional cytotoxic agents such as arsenic trioxide in the treatment of hematologic malignancies. Examine the role of arsenic trioxide and other novel agents in early-versus accelerated-stage hematologic disease. Discuss the preclinical and clinical efficacy of arsenic trioxide and various agents in treating acute promyelocytic leukemia, MDS, and multiple myeloma.Access CME test online and receive one hour category 1 credit at CME.TheOncologist.comMultiple myeloma remains an incurable disease, with median survival rates of 4-6 years even with aggressive, high-dose chemotherapy, bone marrow transplantation, and intensive supportive care. Additionally, multiple myeloma is primarily a disease of the elderly, many of whom cannot tolerate aggressive chemotherapy. Thus, newer treatments with good safety profiles are needed to improve the quality of responses and, hopefully, to translate into prolonged progression and overall survival. The pathophysiology of multiple myeloma is complex, involving many pathways and interactions among cytokines, adhesion molecules, angiogenesis, and mechanisms of resistance, which, taken together, provide multiple targets for novel therapeutic modalities. Agents currently under investigation for treating multiple myeloma include thalidomide and its successors, PS-341, and arsenic trioxide. Thalidomide and immunomodulatory drugs both exhibit activity against multiple myeloma by affecting different levels of the immune system. PS-341 is a proteasome inhibitor that halts the cell cycle, resulting in apoptosis; it also inhibits a key transcription factor and may have antiangiogenic activity. Arsenic trioxide activates multicellular mechanisms to induce apoptosis, inhibit angiogenesis, and stimulate immune responses. Preclinical and early clinical data suggest that combination regimens should be pursued, given the different mechanisms of action of these compounds on the immune system and their non-overlapping toxicities at low dosages.