bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vascular Endothelial Growth Factor as a Target for Anticancer Therapy
Authors: Ferrara Napoleone 
Published: August 2004

Abstract

Learning Objectives
After completing this course, the reader will be able to:
Explain the biology of angiogenesis. Identify the role of VEGF in normal and tumor angiogenesis. Describe the key ways in which VEGF has been targeted in cancer therapy.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit atCME.TheOncologist.com
The development of a vascular supply is a critical factor in the growth and metastatic spread of malignant tumors. Of the multitude of growth factors that regulate physiological and pathological angiogenesis, vascular endothelial growth factor (VEGF) is believed to be the most important. There is evidence that overexpression of VEGF is correlated with an adverse prognosis, at least in some tumors. Tumor-expressed VEGF is particularly attractive as a target for anticancer therapy because its angiogenesis-promoting activity is at the level of the endothelial cell and, compared with agents that directly target tumor cells, tumor penetration is less critical for VEGF inhibitors. Moreover, recent work has shown that inhibiting tumor angiogenesis increases the effectiveness of coadministered chemotherapy and radiotherapy. This suggests that drugs that target VEGF or its receptors can be combined with traditional treatment modalities to ensure maximum effectiveness. A variety of agents aimed at blocking VEGF or its receptor-signaling system are currently being developed for the treatment of cancer. Of these, bevacizumab, a humanized monoclonal antibody directed at VEGF, is the most advanced in clinical development and has shown promising results in clinical trials.
Expanding the Clinical Development of Bevacizumab
Authors: Chen Helen X. 
Published: August 2004

Abstract

Learning Objectives
After completing this course, the reader will be able to:
Describe the clinical development of bevacizumab. Summarize the clinical trials conducted using bevacizumab. Discuss the anticipated role of bevacizumab in cancer treatment and future directions for research.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit atCME.TheOncologist.com
Bevacizumab (AvastinTM; Genentech, Inc.; South San Francisco, CA) is a recombinant, humanized monoclonal antibody to vascular endothelial growth factor, a key regulator of tumor angiogenesis. Bevacizumab demonstrated potent antitumor activity in preclinical models and has also shown biologic activity and clinical benefit in clinical studies. Notably, a randomized, placebo-controlled phase II trial in renal cell carcinoma demonstrated a significantly longer time to tumor progression with bevacizumab monotherapy. Furthermore, in a phase III trial for untreated advanced colorectal cancer, the addition of bevacizumab to chemotherapy led to significantly longer overall survival and progression-free survival times than chemotherapy alone. The clinical development of bevacizumab has been expanded to include confirmatory phase III trials and exploratory phase II trials in a variety of solid tumors and hematologic malignancies. Treatment regimens being examined include bevacizumab alone and in combination with conventional chemotherapy, radiation, immune therapy, and biologically targeted agents.
Maximizing the Potential of Bevacizumab in Cancer Treatment
Authors: Bergsland Emily , Dickler Maura N. 
Published: August 2004

Abstract

Learning Objectives
After completing this course, the reader will be able to:
Identify the major side effects of bevacizumab treatment. Describe the drug combinations, doses, and sequencing options that have been investigated to date and discuss further studies that are needed to fully define optimal therapy. Explain the challenges to using biological surrogates as outcome measures.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit atCME.TheOncologist.com
Promising results have been obtained with bevacizumab (AvestinTM; Genentech, Inc.; South San Francisco, CA) in clinical trials in patients with a range of solid tumors; however, to maximize the potential of this agent, further research is needed to clarify a number of important issues. These include the optimization of bevacizumab dosage and schedule of administration, the potential value of this agent in combination with other treatment modalities like chemotherapy and radiation, the management of toxicities, and the selection of patients most likely to benefit from treatment. Intriguing results from two recent phase III trials highlight the need for a better understanding of the best ways to incorporate bevacizumab into clinical practice. Ultimately, maximizing the potential value of this agent may require a more thorough understanding of bevacizumab's mechanism of action and the pathways mediating resistance.
Bevacizumab in the Treatment of Breast Cancer: Rationale and Current Data
Authors: Rugo Hope S. 
Published: August 2004

Abstract

Learning Objectives
After completing this course, the reader will be able to:
Explain the role of VEGF in the tumor biology of breast cancer. Outline the data from clinical trials of bevacizumab conducted in patients with breast cancer. Discuss the interpretation of the phase III study of capecitabine alone or in combination with bevacizumab.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit atCME.TheOncologist.com
Vascular endothelial growth factor (VEGF) has emerged as a key target for the treatment of cancer. As the ligand to the VEGF receptor, it plays a central role in promoting tumor angiogenesis. Overexpression of VEGF leads to poor outcomes in patients with breast cancer and other tumors.
Preclinical studies have shown that the humanized monoclonal antibody to VEGF, bevacizumab (AvastinTM; Genentech, Inc., South San Francisco, CA), can reduce tumor angiogenesis and inhibit the growth of solid tumors, either alone or in combination with chemotherapy. As a single agent or added to vinorelbine, bevacizumab has produced encouraging results in phase II clinical trials in patients with refractory metastatic breast cancer. When added to capecitabine chemotherapy in a phase III trial, bevacizumab produced a greater response rate, but did not prolong progression-free survival. This may reflect the late disease stage and poor prognostic factors in the patient population. A large, ongoing, phase III, cooperative group trial is evaluating the effect of bevacizumab in combination with paclitaxel as first-line therapy for metastatic disease. The adverse effect profile of bevacizumab differs from that of cytotoxic chemotherapy and includes hypertension, proteinuria, thrombosis, and epistaxis.
Taxane-Platinum Combinations in Advanced Non-Small Cell Lung Cancer: A Review
Authors: Rigas James R. 
Published: August 2004

Abstract

Learning Objectives
After completing this course, the reader will be able to:
Describe the rationale for and use of taxanes in NSCLC. Identify key efficacy findings from the four large randomized trials assessing platinum-taxane combinations in advanced NSCLC. Discuss adverse event and quality-of-life results from four large randomized trials assessing platinum-taxane combinations in advanced NSCLC.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
Platinum-based chemotherapy is the treatment of choice for patients with non-small cell lung cancer (NSCLC). As a result of their single-agent activities and synergistic effects, taxane-platinum combinations are often used as first-line therapy for this disease. Four large, multicenter, randomized phase III clinical trials (the TAX 326 trial, the Southwest Oncology Group 9509 trial, the Italian Lung Cancer Project, and the Eastern Cooperative Oncology Group 1594 trial) have compared taxane-platinum combinations (docetaxel and paclitaxel) with other platinum combinations (vinorelbine and gemcitabine) in chemotherapy-naïve patients with good performance status scores and advanced disease. The end points for these large randomized clinical trials were survival, response rate, adverse events, and quality of life (QOL). Of the taxane-platinum combinations tested, docetaxel-cisplatin was the only platinum combination to yield survival and response rates superior to another platinum combination. In adverse event terms, the taxane-platinum combination of paclitaxel-carboplatin demonstrated less grade 3 or 4 neutropenia and lower rates of febrile neutropenia than other taxane-platinum combinations but higher rates of irreversible grade 3 or 4 peripheral neuropathy than any of the other taxane-platinum combinations. Additional differences emerged when QOL data were evaluated. The docetaxel-platinum combination demonstrated broad QOL benefits for patients receiving this combination, and this benefit was not observed with the other platinum or taxane-platinum combinations. As our use of these taxane-platinum combinations expands, these differences in survival, response rate, adverse events, and QOL will permit us to better balance our treatment goals for all patients with all stages of NSCLC.
Docetaxel and Paclitaxel in the Treatment of Breast Cancer: A Review of Clinical Experience
Authors: Crown John , O'Leary Michael , Ooi Wei-Seong 
Published: August 2004

Abstract

Learning Objectives
After completing this course, the reader will be able to:
Describe randomized trial data from studies evaluating taxanes in anthracycline-naïve or anthracycline-pretreated metastatic breast cancer patients. Discuss recent findings of randomized trials evaluating docetaxel as neoadjuvant therapy. Compare and contrast efficacy end point data from three adjuvant taxane trials with mature results.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
In the 10 years since their initial licensing in Europe, the taxanes, paclitaxel and docetaxel, have emerged as fundamental drugs in the treatment of breast cancer. Clinically meaningful benefits were first shown in the metastatic setting, and large-scale exploration of their roles in the adjuvant therapy of early-stage disease is ongoing. Benefits have been seen in the neoadjuvant setting as well, mainly with docetaxel. This paper reviews the current roles of the taxanes in the treatment of metastatic and early-stage breast cancer. Also addressed are outstanding issues involving optimal dosing and sequencing, as well as a discussion of the relative merits of each agent in this setting. Clinicians should choose a taxane-based regimen for their patients with breast cancer based on consideration of the pharmacokinetics, clinical activity, and dosing schedule that best meets the patients' needs. At the current time, the pharmacokinetic profile, consistent positive clinical results, and convenience of an intermittent, short-infusion schedule have made docetaxel the preferred taxane for many clinicians treating patients with breast cancer.
Preclinical Pharmacology of the Taxanes: Implications of the Differences
Authors: Gligorov Joseph , Lotz Jean Pierre 
Published: August 2004

Abstract

Learning Objectives
After completing this course, the reader will be able to:
Identify the differences in molecular pharmacology of the taxanes. Describe the impact of the pharmacokinetic and pharmacodynamic profiles of the taxanes on their administration and toxicity. Outline the toxicity profiles of paclitaxel and docetaxel.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
Taxanes are one of the most powerful classes of compounds among all chemotherapeutic drugs. Only 30 years separate the isolation of the first taxane from the results of direct clinical comparisons in metastatic breast, ovarian, and lung cancer between the two taxanes available in routine clinical practice. These results suggest a more favorable benefit-to-risk ratio for docetaxel compared to paclitaxel when these drugs are used as single agents or in combination with other chemotherapeutic agents in an every-3-week dosing regimen. Pharmacological data support the difference between the taxanes, likely explaining the clinical results. Considering the molecular pharmacology of the two drugs, docetaxel appears to bind to β-tubulin with greater affinity and has a wider cell cycle activity than paclitaxel. Docetaxel also appears to have direct antitumoral activity via an apoptotic effect mediated by bcl-2 phosphorylation. In addition, docetaxel has a longer retention time in tumor cells than paclitaxel because of greater uptake and slower efflux. Pharmacokinetics and pharmacodynamics of the taxanes show both agents to be extensively metabolized in the liver, and paclitaxel has a nonlinear pharmacokinetic behavior while docetaxel has linear pharmacokinetics. These differences explain the more simple treatment schedule and favorable results for docetaxel as a single agent and in combination therapy. Last, but not least, there is a pharmacokinetic interaction between paclitaxel and the anthracyclines, an active class of compounds commonly used in the treatment of breast cancer. This pharmacokinetic interaction is associated with greater cardio- and myelotoxicities, which are sequence dependent. These pharmacological data likely explain the different clinical development strategies for the two molecules as well as the different clinical results from individual trials and direct comparisons.
The Treatment of Advanced Gastric Cancer: New Findings on the Activity of the Taxanes
Authors: Van Cutsem Eric 
Published: August 2004

Abstract

Learning Objectives
After completing this course, the reader will be able to:
Explain the role and evolution of chemotherapy for advanced gastric cancer. Discuss results of phase II trials evaluating taxanes in advanced gastric cancer. Describe the results and clinical implications of a phase III trial of docetaxel, cisplatin, and fluorouracil in advanced gastric cancer.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
Globally, gastric cancer is one of the most common types of cancer and one of the most frequent causes of cancer-related death. Despite many advances in the diagnosis and treatment of this disease, the prognosis for gastric cancer remains poor, especially in more advanced stages. In metastatic disease, benefits in survival and quality of life have been demonstrated in patients with unresectable or metastatic gastric cancer receiving chemotherapy plus best supportive care versus best supportive care alone. The taxanes, which are among the most promising cytotoxic agents in clinical use, have shown encouraging activity in early-phase studies as single agents and in combination regimens in the treatment of advanced gastric cancer. Recently, interim results of a randomized phase III trial comparing the triplet of docetaxel, cisplatin, and 5-fluorouracil with a standard reference regimen of cisplatin and 5-fluorouracil were reported. Patients treated with the docetaxel-containing regimen had a statistically superior response rate and time to disease progression as well as a clinically significant prolongation of survival. This study underscores the importance of developing new therapeutic options for patients with advanced gastric cancer.
Dual Kinase Inhibition in the Treatment of Breast Cancer: Initial Experience with the EGFR/ErbB-2 Inhibitor Lapatinib
Authors: Burris Howard A. 
Published: August 2004

Abstract

Learning Objectives
After completing this course, the reader will be able to:
Identify the rationale for the development of dual ErbB receptor inhibitors. Describe safety data from early-phase clinical trials of the dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib. Describe evidence of biologic and clinical activity from early-phase clinical trials of the dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
Dual inhibition of ErbB-1 (EGFR) and ErbB-2 (HER-2) tyrosine kinases has been found to exert greater biologic effects in the inhibition of signaling pathways promoting cancer cell proliferation and survival than inhibition of either receptor alone. The novel dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib (GlaxoSmithKline; Research Triangle Park, NC) has been shown to inhibit tumor cell growth in vitro and in xenograft models for a variety of human tumors. Preliminary findings in a phase I study of lapatinib in patients with solid tumors indicate doses up to 1,800 mg per day are well tolerated. No grade 4 toxicities were observed and only two of 43 patients had grade 3 toxicity (diarrhea). Clinical activity of lapatinib was observed in these patients; nine patients with a variety of tumors remained on study for ≥4 months, one with a complete response (head and neck cancer). In a phase IB study in pretreated metastatic cancer patients with disease that could be biopsied, grade 1 or 2 diarrhea and rash were the most common adverse events. Three patients with breast cancer refractory to trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA) had partial responses and 12 patients with a variety of tumors had stable disease. Assessment of biologic correlates in these patients indicates that increased tumor cell apoptosis on the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay correlates with clinical response. Lapatinib currently is being evaluated in phase II and phase III trials in patients with metastatic breast cancer.
The Role of ErbB Inhibitors in Trastuzumab Resistance
Authors: Miller Kathy D. 
Published: August 2004

Abstract

Learning Objectives
After completing this course, the reader will be able to:
Discuss mechanisms of resistance to EGFR inhibitor monotherapy. Cite potential treatment strategies and ongoing clinical trials to prevent or delay the development of resistance to EGFR inhibitors. Describe results of clinical trials using EGFR inhibitors in patients with metastatic breast cancer.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
The ErbB family of receptors and ligands is a complex, delicately balanced system involved in the growth and differentiation of normal human cells as well as neoplasms. Targeting this system with therapies that inhibit ErbB receptor activity in cancer patients has been somewhat successful, but resistance to ErbB inhibitor monotherapy is substantial. An understanding of the biology of ErbB receptor inhibitors is necessary to determine how best to utilize them in treatment regimens. Experimental evidence has provided valuable insights regarding mechanisms involved in resistance, and indicates that resistance can be reversed in some models. Ongoing studies in patients are evaluating whether agents that target both the epidermal growth factor (EGFR, ErbB-1) and ErbB-2 (HER-2) receptors can prevent or delay resistance in patients with metastatic breast cancer that overexpresses HER-2. With a better understanding of the biology of breast cancer, and with several novel ErbB receptor inhibitors in development, continued progress for improved patient outcomes is expected.
Overcoming Endocrine Therapy Resistance by Signal Transduction Inhibition
Authors: Ellis Matthew 
Published: August 2004

Abstract

Learning Objectives
After completing this course, the reader will be able to:
Discuss patterns of resistance to endocrine therapy for breast cancer. Relate differences in resistance patterns in early and advanced disease settings. Identify potential treatment strategies to overcome resistance and/or restore endocrine therapy efficacy.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
Endocrine therapy is the most effective systemic treatment for patients with hormone-receptor-positive (HR+) breast cancer. Unfortunately, efficacy is often limited by the onset of resistance, which is almost inevitable for patients with advanced disease. Several patterns of endocrine resistance are recognizable clinically, including: A) tumors that are inherently insensitive to all attempts at estrogen receptor (ER) targeting despite expression of ER (pan-endocrine therapy resistance); B) tumors that are estrogen dependent but resistant to one or more specific endocrine therapies (agent-selective resistance); and C) tumors that initially respond but subsequently progress (acquired resistance). Current insights into the molecular basis for these resistance patterns are rudimentary, but are most clearly illuminated by investigations that focus on the crosstalk between the ErbB or HER peptide growth factor family and the ER. The data are sufficiently compelling to be addressed by ongoing clinical trials that examine combinations of endocrine agents and either trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA) or ErbB-specific tyrosine kinase (TK) inhibitors. Preliminary data from a small “proof of concept” phase II study of letrozole (Femara®; Novartis Pharmaceuticals Corporation; East Hanover, NJ) and trastuzumab demonstrated durable responses despite tamoxifen (Nolvadex®; AstraZeneca Pharmaceuticals; Wilmington, DE) resistance. Efficacy was variable, however, despite the selection of patients on the basis of ER and ErbB-2 coexpression. Complicating matters further, resistance often occurs in the absence of any evidence for ErbB TK family member expression. In the absence of a clear target, common downstream signal transduction proteins that are known to intersect with the ER pathway can be inhibited to address resistance, including G proteins with farnesyltransferase inhibitors and molecular target of rapamycin (mTOR) with rapamycin analogues. With a number of phase III clinical trials now under way, major advances in the endocrine treatment of advanced disease are possible.
Monoclonal Antibodies, Small Molecules, and Vaccines in the Treatment of Breast Cancer
Authors: Esteva Francisco J. 
Published: August 2004

Abstract

Learning Objectives
After completing this course, the reader will be able to:
Describe the specificity and benefits of the monoclonal antibody trastuzumab in treating patients with metastatic breast cancer. Identify the potential advantages of dual HER tyrosine kinase inhibitors over single HER receptor inhibitors for treating metastatic breast cancer. Explain the design considerations of clinical trials for therapeutic vaccines to assess effect in patients with various stages of breast cancer.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
The human epidermal growth factor receptor (HER, ErbB) family of receptors is considered an important therapeutic target, and various types of molecularly based small molecules, including monoclonal antibodies, protein tyrosine kinase inhibitors, and therapeutic vaccines, are in development as potential therapies for metastatic breast cancer. Trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA), the first approved monoclonal antibody for HER-2 (ErbB-2)-overexpressing metastatic breast cancer, provided the proof of principle that targeting specific receptors results in clinical benefit. Other monoclonal antibodies and the small molecule dual protein tyrosine kinase inhibitors show great promise as treatments for metastatic breast cancer but require evaluation in clinical trials to assess their benefits. Therapeutic vaccines may have a role, particularly in early-stage disease, but they are associated with greater limitations and study design issues that make their evaluation difficult. Optimum combination therapy regimens with a variety of novel approaches that incorporate small molecule targeted therapies need to be developed, and the population most likely to benefit from targeted therapies needs to be identified.