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Improved Metastatic Uterine Papillary Serous Cancer Outcome With Treatment of Mast Cell Activation SyndromeA 71-year-old woman not on hormone replacement therapy presented with uterine bleeding. Dilation and curettage revealed complex hyperplasia with atypia, focal clear-cell features, and endocervicitis. Endometrial intraepithelial carcinoma was suspected.
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Erlotinib: Preclinical InvestigationsErlotinib (Tarceva) is an orally available selective small-moleculeinhibitor of HER1/EGFR tyrosine kinase with a 50% inhibitory concentrationof 2 nM for purified tyrosine kinase. This agent has beenshown to produce stasis or regression of tumor growth in human cancerxenograft models, including non-small-cell lung cancer models.Ongoing preclinical investigations indicate that inhibition of the MAPKand Atk signaling pathways downstream of HER1/EGFR may be requiredfor optimal antitumor effects. Erlotinib exhibits inhibition ofMAPK and Atk kinases at concentrations higher than those requiredfor HER1/EGFR tyrosine kinase inhibition; such findings suggest thatmaximal inhibition of HER1/EGFR, requiring high erlotinib doses, isnecessary for optimum antitumor activity. These considerations aresupported by tumor models, including non-small-cell lung cancermodels, showing dose-related antitumor effects up to high doses oferlotinib. Erlotinib exhibits additive antitumor effects when combinedwith chemotherapeutic agents (cisplatin, doxorubicin, paclitaxel,gemcitabine [Gemzar], and capecitabine [Xeloda]), radiation therapy,and other targeted agents (eg, bevacizumab [Avastin]). Recent studiesindicate that erlotinib inhibits the EGFRvIII mutant at concentrationshigher than those required for inhibition of wild-type receptor. Ongoinginvestigation will help to determine optimal dosing and dose frequencyof erlotinib in various cancers in the clinical setting.
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Apoptosis Mechanisms: Implications for Cancer Drug DiscoveryDefects in the regulation of apoptosis (programmed cell death) makeimportant contributions to the pathogenesis and progression of mostcancers and leukemias. Apoptosis defects also figure prominently inresistance to chemotherapy, radiotherapy, hormonal therapy, andimmune-based treatments. Apoptosis is caused by activation ofintracellular proteases, known as caspases, that are responsible directlyor indirectly for the morphologic and biochemical events thatcharacterize the apoptotic cell. Numerous proteins that regulate thesecell death proteases have been discovered, including proteins belongingto the Bcl-2, inhibitor of apoptosis, caspase-associated recruitmentdomain, death domain, and death effector domain families. Thesecaspase-regulating proteins provide mechanisms for linkingenvironmental stimuli to cell death responses or to maintenance of cellsurvival. Alterations in the expression and function of several apoptosisregulatinggenes have been demonstrated in cancer, suggesting targetsfor drug discovery. Knowledge of the molecular details of apoptosisregulation and the three-dimensional structures of apoptosis proteinshas revealed new strategies for identifying small-molecule drugs thatmay yield more effective treatments for malignancies. Apoptosisregulatinggenes are also beginning to find utility as targets for antisenseoligonucleotides.
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Topoisomerase I Inhibitors in the Combined-Modality Therapy of Lung CancerLocally advanced non–small-cell lung cancer represents 30% to 40%of all pulmonary malignancies. Most patients will die of the diseaseafter aggressive contemporary treatments. Therefore, significant improvementin therapeutic methods must be implemented to improveoverall survival rates. The arrival of a new generation of chemotherapeuticagents-including the taxanes, gemcitabine (Gemzar), andtopoisomerase inhibitors such as irinotecan (Camptosar) and topotecan(Hycamtin)-offers the hope of significant advances in the treatmentof lung cancer. Irinotecan and topotecan are camptothecin derivativesthat inhibit topoisomerase I enzyme. It is believed that topoisomerase Iinhibitors stabilize a DNA/topoisomerase I complex and interact withreplication machinery to cause cell death. A significant amount of datademonstrates that these topoisomerase I inhibitors also act asradiosensitizers. With the increasing data that support concurrentchemoradiation treatment for malignancies, including lung cancer andhead and neck cancers, there is an impetus to pursue the additionaldrugs that may potentially improve local control and survival. Irinotecanis undergoing early clinical trials in the combined-modality setting inseveral different disease sites. This paper will review the data on therole of camptothecin derivatives as a radiosensitizer and as a componentof combined-modality therapy for lung cancer. It is hoped thatnewer treatment strategies, like the combination of radiation andtopoisomerase I inhibitors, will have a significant impact on cure ratesin the future.
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Topoisomerase I Inhibitors in the Combined-Modality Therapy of Lung CancerLocally advanced non–small-cell lung cancer represents 30% to 40%of all pulmonary malignancies. Most patients will die of the diseaseafter aggressive contemporary treatments. Therefore, significant improvementin therapeutic methods must be implemented to improveoverall survival rates. The arrival of a new generation of chemotherapeuticagents-including the taxanes, gemcitabine (Gemzar), andtopoisomerase inhibitors such as irinotecan (Camptosar) and topotecan(Hycamtin)-offers the hope of significant advances in the treatmentof lung cancer. Irinotecan and topotecan are camptothecin derivativesthat inhibit topoisomerase I enzyme. It is believed that topoisomerase Iinhibitors stabilize a DNA/topoisomerase I complex and interact withreplication machinery to cause cell death. A significant amount of datademonstrates that these topoisomerase I inhibitors also act asradiosensitizers. With the increasing data that support concurrentchemoradiation treatment for malignancies, including lung cancer andhead and neck cancers, there is an impetus to pursue the additionaldrugs that may potentially improve local control and survival. Irinotecanis undergoing early clinical trials in the combined-modality setting inseveral different disease sites. This paper will review the data on therole of camptothecin derivatives as a radiosensitizer and as a componentof combined-modality therapy for lung cancer. It is hoped thatnewer treatment strategies, like the combination of radiation andtopoisomerase I inhibitors, will have a significant impact on cure ratesin the future.
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Final AVAiL results confirm longer PFS with bevacizumabSTOCKHOLM-Final analysis of the phase III Avastin in Lung Study (AVAiL), which evaluated bevacizumab (Avastin) as first-line therapy for advanced nonsmall- cell lung cancer, showed that adding bevacizumab to gemcitabine/cisplatin significantly extends progression-free survival, Christian Manegold, MD, of Heidelberg University in Mannheim, Germany, reported at ESMO 2008 (abstract LBA1).
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Histologic Subtype in NSCLC: Does It Matter?Since the publication of a meta-analysis in 1995 that demonstrated a modest survival benefit compared to best supportive care, platinum-based chemotherapy became the cornerstone of therapy in the first-line setting in advanced-stage non–small-cell lung cancer (NSCLC) for patients with good performance status.[1] A recent meta-analysis of 16 randomized trials including 2,714 patients demonstrated an advantage of chemotherapy over best supportive care with an absolute improvement in survival of 9% at 12 months.[2]
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What is the Clinical Role of Induction Therapy in Locally Advanced Squamous Cell Cancer of the Head and Neck?Induction chemotherapy has led to improved survival and organ preservation. Combining induction therapy with other treatment modalities is critical for treating this complex disease and attaining optimal outcomes.
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Small-Cell Lung Cancer: Is There a Standard Therapy?For more than 25 years, chemotherapy has been the cornerstone of treatment for small-cell lung cancer. Many studies have tested a wide variety of drugs in different combinations, resulting in a number of standard
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Small-Cell Lung Cancer: Is There a Standard Therapy?For more than 25 years, chemotherapy has been the cornerstone of treatment for small-cell lung cancer. Many studies have tested a wide variety of drugs in different combinations, resulting in a number of standard
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Antifungal Prophylaxis in Hematopoietic Stem Cell Transplant RecipientsEfforts at preventing and treating fungal infection in hematopoietic stem cell transplant (HSCT) recipients must take into account the types of infections likely to be encountered during the different risk periods in hosts with different underlying risks. Given the emergence of molds as prevalent pathogens and the long duration of risk in allogeneic HSCT recipients, optimal antifungal prophylaxis would consist of treatment that can be given over a prolonged period and that would provide both anti-Candida and anti-Aspergillus activity. Optimal empiric therapy would consist of a broad-spectrum agent in the absence of more sensitive and specific methods for microbial diagnosis. Fluconazole (Diflucan) is currently the standard prophylactic agent for candidiasis, although mold-active agents and alternative strategies for polyene administration are being investigated. The gold standard for empiric therapy is currently a polyene antifungal, yet an increased appreciation for amphotericin B-resistant yeasts and molds, and less toxic mold-active alternatives, might lead to the use of other compounds in the future. The recent development of multiple alternatives emphasizes our need to establish treatment algorithms that consider both the likely pathogens and potential toxicities. [ONCOLOGY 15(Suppl 9):15-19, 2001]
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Rationale and Dose-Finding Studies of the Combination of Irinotecan and a Taxane on a Weekly ScheduleCisplatin (Platinol)-based chemotherapy has been the standard systemic therapy for both non-small-cell and small-cell lung cancer for the past 2 decades, though the efficacy and benefit remain modest. Recently, several novel
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Rationale and Dose-Finding Studies of the Combination of Irinotecan and a Taxane on a Weekly ScheduleCisplatin (Platinol)-based chemotherapy has been the standard systemic therapy for both non-small-cell and small-cell lung cancer for the past 2 decades, though the efficacy and benefit remain modest. Recently, several novel
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Evolution of Combined Modality Therapy for Stage III Non–Small-Cell Lung CancerA number of randomized clinical trials and meta-analyses now support the conclusion that combined modality regimens that include cisplatin (Platinol)-based chemotherapy improve survival in stage III non–small-cell lung
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Evolution of Combined Modality Therapy for Stage III Non–Small-Cell Lung CancerA number of randomized clinical trials and meta-analyses now support the conclusion that combined modality regimens that include cisplatin (Platinol)-based chemotherapy improve survival in stage III non–small-cell lung
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Paclitaxel, Carboplatin, and Radiation Therapy for Non-Small-Cell Lung CancerPreclinically, the taxanes appear to potentiate radiation more effectively than do the platinum compounds. In our phase I trial (LUN-17) in patients with advanced non-small-cell lung cancer, we defined the maximum tolerated
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Paclitaxel, Carboplatin, and Radiation Therapy for Non-Small-Cell Lung CancerPreclinically, the taxanes appear to potentiate radiation more effectively than do the platinum compounds. In our phase I trial (LUN-17) in patients with advanced non-small-cell lung cancer, we defined the maximum tolerated
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Postmastectomy Radiation: Then and NowWith the increased use of doxorubicin-based chemotherapy, chemoendocrine therapy, and high-dose chemotherapy with autologous bone marrow transplantation or peripheral blood progenitor-cell reinfusion, the role
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Irinotecan in Combined-Modality Therapy for Locally Advanced Non-Small-Cell Lung CancerThe management of non-small-cell lung cancer is undergoing rapid evolution. Although the advent of combined-modality therapy has led to improved survival, most patients eventually succumb to the disease. The arrival of a
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High-Dose Therapy for Follicular LymphomaMost patients with advanced-stage follicular non-Hodgkin’s lymphoma (NHL) are not cured with conventional therapy. The use of high-dose therapy and autologous stem-cell transplantation in patients with relapsed follicular
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Novel Concepts in Radioimmunotherapy for Non-Hodgkin's LymphomaTositumomab/iodine-131 tositumomab (Bexxar) and ibritumomab tiuxetan (Zevalin) are radioimmunoconjugates targeting the CD20 antigen. Both agents are approved in the United States for use in relapsed or refractory, indolent or transformed, B-cell lymphoma. These agents are well tolerated and have the highest levels of single-agent activity observed in these histologies. This review will summarize the key trials that led to approval of both I-131 tositumomab and ibritumomab tiuxetan, and then focus on four novel therapeutic concepts in radioimmunotherapy: retreatment, therapy of de novo indolent lymphoma, therapy of aggressive histologies, and incorporation in high-dose therapy programs utilizing autologous stem cell support.
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Management of Renal Cell CarcinomaSurgical resection remains the cornerstone of management for localized renal cell carcinoma. No effective postsurgical adjuvant therapy has been established for
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Clinical Status and Optimal Use of Rituximab for B-Cell LymphomasRituximab (IDEC-C2B8 [Rituxan]) is a chimeric anti-CD20 monoclonal antibody (MoAb) that was recently approved by the FDA for the treatment of patients with low-grade or follicular B-cell non-Hodgkin’s lymphoma. Its potential efficacy in other B-cell malignancies is currently being explored. This article reviews the mechanisms of action of rituximab, as well as preclinical data and results of the clinical trials that led to its approval. Also discussed are the mechanics of administering rituximab on the recommended weekly ´ 4 outpatient schedule. Finally, the article describes ongoing and planned trials of rituximab in other dosage schedules, in other B-cell neoplasms, and in conjunction with chemotherapy. As the first MoAb to gain FDA approval for the treatment of a malignancy, rituximab signals the beginning of a promising new era in cancer therapy. [ONCOLOGY 12(12):1763-1770, 1998]
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Clinical Status and Optimal Use of Rituximab for B-Cell LymphomasRituximab (IDEC-C2B8 [Rituxan]) is a chimeric anti-CD20 monoclonal antibody (MoAb) that was recently approved by the FDA for the treatment of patients with low-grade or follicular B-cell non-Hodgkin’s lymphoma. Its potential efficacy in other B-cell malignancies is currently being explored. This article reviews the mechanisms of action of rituximab, as well as preclinical data and results of the clinical trials that led to its approval. Also discussed are the mechanics of administering rituximab on the recommended weekly ´ 4 outpatient schedule. Finally, the article describes ongoing and planned trials of rituximab in other dosage schedules, in other B-cell neoplasms, and in conjunction with chemotherapy. As the first MoAb to gain FDA approval for the treatment of a malignancy, rituximab signals the beginning of a promising new era in cancer therapy. [ONCOLOGY 12(12):1763-1770, 1998]
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Recent Progress in Radioimmunotherapy for CancerRadioimmunotherapy allows for the delivery of systemically targeted radiation to areas of disease while relatively sparing normal tissues. Despite numerous challenges, considerable progress has been made in the application of radioimmunotherapy to a wide variety of human malignancies. The greatest successes have occurred in the treatment of hematologic malignancies. Radioimmunotherapy, with or without stem-cell transplant support, has produced substantial complete remission rates in chemotherapy-resistant B-cell lymphomas. Nonmyeloablative regimens have shown so much promise that they are now being tested as initial therapy for low-grade B-cell lymphomas. Although solid tumor malignancies have been less responsive to radioimmunotherapy, encouraging results have been obtained with locoregional routes of administration, especially when the tumor burden is small. Greater tumor-to-normal tissue ratios are achievable with regional administration. Even with intraperitoneal and intrathecal administration, bone marrow suppression remains the dose-limiting toxicity. Ongoing research into new targeting molecules, improved chelation chemistry, and novel isotope utilization is likely to extend the applications of this strategy to other tumor types. The potential for radioimmunotherapy will be enhanced if this modality can be optimally adapted for integration with other agents and if the administration method can be tailored to the type and distribution of malignancy. [ONCOLOGY 11(7):979-987, 1997]
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Trimodality Therapy for Non–Small-Cell Lung CancerProspects for the multimodality treatment of non–small-cell lung cancer have improved substantially with the demonstration of fairly dramatic results, in terms of 5-year survival, in several phase III trials that employed
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Concomitant Cisplatin, Vinorelbine, and Radiation in Advanced Chest MalignanciesNewer chemotherapy drugs have shown encouraging activity in advanced non-small-cell lung cancer. Based on these improved outcomes, as well as the high rate of distant relapse in patients with locally advanced disease, several recent studies have evaluated the use of systemic therapy in patients with earlier-stage disease.
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Concomitant Cisplatin, Vinorelbine, and Radiation in Advanced Chest MalignanciesNewer chemotherapy drugs have shown encouraging activity in advanced non-small-cell lung cancer. Based on these improved outcomes, as well as the high rate of distant relapse in patients with locally advanced disease, several recent studies have evaluated the use of systemic therapy in patients with earlier-stage disease.
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Transplant Registries: Guiding Clinical Decisions and Improving OutcomesAbout 50,000 hematopoietic stem cell transplantations are performed yearly, primarily for malignancies. Use of this therapy increased dramatically over the past 30 years due to its proven and potential efficacy in diverse
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Transplant Registries: Guiding Clinical Decisions and Improving OutcomesAbout 50,000 hematopoietic stem cell transplantations are performed yearly, primarily for malignancies. Use of this therapy increased dramatically over the past 30 years due to its proven and potential efficacy in diverse
