bluuebunny/crossref_metadata_2025 huggingface dataset:
Bonamia sp. (Haplosporidia) Found in Nonnative Oysters Crassostrea ariakensis in Bogue Sound, North Carolina
Authors: Burreson Eugene M. , Stokes Nancy A. , Carnegie Ryan B. , Bishop Melanie J.
Published: August 2004

The Suminoe oyster Crassostrea ariakensis is being considered for introduction into the middle Atlantic coast region of the United States, where diseases have decimated native stocks of the eastern oyster C. virginica. Triploid C. ariakensis produced at the Virginia Institute of Marine Science (VIMS) and transferred to Bogue Sound, North Carolina, experienced high mortality in the summer of 2003. Histopathological examination of oysters collected 9 d after peak mortality in August revealed the presence of intrahemocytic inclusions, suggesting a Bonamia-like parasite infecting hemocytes in 9.1% (2/22) of the oysters. November sampling of a subsequent October 2003 deployment to Bogue Sound revealed that 47% were infected by Bonamia-like microcells. Diagnosis of a second sample from this group by Bonamia-specific polymerase chain reaction primers revealed 60% prevalence, and subsequent DNA sequence data confirmed that the parasite was a Bonamia. Two samples collected during the peak mortality and archived in North Carolina were received by VIMS in January 2004. These samples revealed 90.9% and 100% prevalence of Bonamia sp., 10 of the 14 infections being heavy in intensity. No infections were detected in C. ariakensis from Pamlico Sound, North Carolina, or from the York River, Virginia, which had originated from the same hatchery cohort, suggesting that the parasite originated in Bogue Sound and was not present in the seed transferred from VIMS. Additionally, no Bonamia sp. infections were detected in C. virginica from Bogue Sound, indicating specific susceptibility of C. ariakensis to the parasite. The natural host for this Bonamia sp. is unknown. How, or if, this parasite will affect the suitability of C. ariakensis for resource restoration or aquaculture in the middle Atlantic region must await studies on the temperature and salinity tolerance, transmission, and distribution of the natural host. Nonetheless, C. ariakensis appears to be highly susceptible to a previously unknown local pathogen.
Swimming Endurance of Bull Trout, Lake Trout, Arctic Char, and Rainbow Trout following Challenge with Renibacterium salmoninarum
Authors: Jones Darin T. , Moffitt Christine M.
Published: August 2004

We tested the swimming endurance of juvenile bull trout Salvelinus confluentus, lake trout S. namaycush, Arctic char S. alpinus, and rainbow trout Oncorhynchus mykiss at 9°C and 15°C to determine whether sublethal infection from a moderate challenge of Renibacterium salmoninarum administered months before testing affected the length of time fish could maintain a swimming speed of 5–6 body lengths per second in an experimental flume. Rainbow trout and Arctic char swam longer in trials than did bull trout or lake trout, regardless of challenge treatment. When we tested fish 14–23 weeks postchallenge, we found no measurable effect of R. salmoninarum on the swimming endurance of the study species except for bull trout, which showed a mixed response. We conducted additional trials with bull trout 5–8 weeks postchallenge to determine whether increasing the challenge dose would affect swimming endurance and hematocrit. In those tests, bull trout with clinical signs of disease and those exposed to the highest challenge doses had significantly reduced swimming endurance compared with unchallenged control fish. Fish hematocrit levels measured at the end of all swimming endurance tests varied among species and between test temperatures, and patterns were not always consistent between challenged and control fish.
Vascular Endothelial Growth Factor in Human Colon Cancer: Biology and Therapeutic Implications
Authors: Ellis Lee M. , Takahashi Yutaka , Liu Wenbiao , Shaheen Raymond M.
Published: August 2004

Tumor growth and metastasis are dependent on angiogenesis. Vascular endothelial growth factor (VEGF) plays an important role in the angiogenesis of numerous solid malignancies including colon cancer. Evidence from preclinical and clinical studies indicates VEGF is the predominant angiogenic factor in human colon cancer and is associated with formation of metastases and poor prognosis. Based on these results, it was hypothesized that inhibition of VEGF receptor activity could inhibit colon cancer liver metastasis. To test this hypothesis, the authors evaluated the ability of a small molecule inhibitor specific for the tyrosine kinase VEGF receptor Flk-1/KDR (SU5416) or multiple tyrosine kinase receptors (SU6668) to inhibit tumor angiogenesis and metastasis in a model of colon cancer hepatic metastasis. Both SU5416 and SU6668 inhibited metastases, microvessel formation, and cell proliferation while increasing tumor cell and endothelial cell apoptosis. These results showed that targeting the VEGF receptor/ligand system is a rational approach to inhibiting tumor growth and prolonging survival.
Measuring VEGF-Flk-1 Activity and Consequences of VEGF-Flk-1 Targeting In Vivo Using Intravital Microscopy: Clinical Applications
Authors: Vajkoczy Peter , Thurnher Andreas , Hirth K. Peter , Schilling Lothar , Schmiedek Peter , Ullrich Axel , Menger Michael D.
Published: August 2004

Vascular endothelial growth factor (VEGF)-Flk-1/KDR tyrosine kinase signaling pathway plays a pivotal role in tumor angiogenesis. Targeting this angiogenic signaling pathway presents a promising alternative for the treatment of neoplasms. However, recent experimental and clinical studies have suggested that VEGF-Flk-1/KDR activity is unevenly distributed throughout the tumor microvasculature. To further evaluate this phenomenon, the regional differences in VEGF-Flk-1/KDR signaling activities in vivo were studied using intravital fluorescence videomicroscopy in an experimental murine brain tumor model. Regional VEGF-Flk-1/KDR was assessed using the small molecule inhibitor SU5416, which selectively inhibits the tyrosine kinase receptor Flk-1. C6 glioblastoma cells were implanted into the dorsal skinfold chamber preparation of nude mice. The process of tumor vascularization was repeatedly assessed over 22 days. SU5416 treatment resulted in a significant reduction in tumor vascular density (p < 0.05). Regional microvascular evaluation indicated that the magnitude of this antiangiogenic effect was pronounced in the more angiogenic and better vascularized peritumoral areas than in the intratumoral areas of the tumor microvasculature. These results demonstrate regional differences in Flk-1 activity in vivo that may have significant impact on the susceptibility of tumors to compounds that target VEGF-Flk-1/KDR. This finding should be considered in upcoming clinical trials targeting individual signal transduction systems in cancer patients.
VEGF Receptor Signaling in Tumor Angiogenesis
Authors: McMahon Gerald
Published: August 2004

The growth of human tumors and development of metastases depend on the de novo formation of blood vessels. The formation of new blood vessels is tightly regulated by specific growth factors that target receptor tyrosine kinases (RTKs). Vascular endothelial growth factor (VEGF) and the Flk-1/KDR RTK have been implicated as the key endothelial cell-specific factor signaling pathway required for pathological angiogenesis, including tumor neovascularization. Inhibition of the VEGF tyrosine kinase signaling pathway blocks new blood vessel formation in growing tumors, leading to stasis or regression of tumor growth. Advances in understanding the biology of angiogenesis have led to the development of several therapeutic modalities for the inhibition of the VEGF tyrosine kinase signaling pathway. A number of these modalities are under investigation in clinical studies to evaluate their potential to treat human cancers.
von Hippel-Lindau Syndrome: Target for Anti-Vascular Endothelial Growth Factor (VEGF) Receptor Therapy
Authors: Harris Adrian L.
Published: August 2004

von Hippel-Lindau (VHL) syndrome is a familial cancer syndrome caused by germline mutations in the VHL tumor suppressor gene. Mutations in the VHL gene result in the constitutive stabilization of transcription factors hypoxia-inducible factors 1α and 2α, which bind to specific enhancer elements in the vascular endothelial growth factor (VEGF) gene and stimulate angiogenesis. This increase in angiogenesis under normoxic conditions in key target organs such as the brain, kidney, and eye leads to high morbidity and reduced life expectancy. Drugs designed to block the VEGF signaling pathway may prevent the long-term complications of the disease. To test this hypothesis, a clinical study was initiated to evaluate the effect of the VEGF tyrosine kinase receptor inhibitor SU5416 in patients with VHL syndrome. Preliminary data on SU5416 indicate that it is well tolerated when administered chronically in such patients. However, since little is known about the long-term use of such inhibitors, patients will need careful monitoring. Data obtained from monitoring these patients will provide valuable information for adjuvant treatment trials in cancer patients.
Prognostic Value of Vascular Endothelial Growth Factor in Breast Cancer
Authors: Gasparini Giampietro
Published: August 2004

Angiogenesis, the process leading to the formation of new blood vessels from a preexisting vascular network, is necessary for tumor growth, invasion, and metastasis. Data from experimental and clinical studies indicate that breast carcinoma is an angiogenesis-dependent tumor.

Most retrospective studies evaluating the prognostic value of determination of intratumoral microvessel density (IMD) at the vascular “hot spot” (a surrogate marker of angiogenesis) found that IMD is a significant and independent prognostic indicator in patients with both node-negative and node-positive breast cancers. More recently, the expression of certain endothelial growth factors has been tested. Among these, vascular endothelial growth factor (VEGF), the most potent endothelial cell mitogen and also a regulator of vascular permeability, is emerging as a powerful new prognostic tool. Eight of the nine published retrospective studies reported that VEGF is significantly associated with relapse-free survival, overall survival, or both. Patients with early stage breast cancer who have tumors with elevated levels of VEGF have a higher likelihood of recurrence or death than patients with low-angiogenic tumors, even if treated with conventional adjuvant therapy.

High levels of VEGF can differentiate the subgroups of patients with breast cancer with poor prognosis who benefit minimally from conventional adjuvant therapy but who may benefit from validated anti-VEGF treatments.
Targeting Vascular Endothelial Growth Factor Blockade: Ascites and Pleural Effusion Formation
Authors: Verheul H.M.W. , Hoekman K. , Jorna A.S. , Smit E.F. , Pinedo H.M.
Published: August 2004

Primary Purpose. Formation of ascites and pleural effusion (PE) is a common problem for patients with advanced-stage cancer. These fluid accumulations cause severe symptoms such as abdominal distention, shortness of breath, cachexia, anorexia, and fatigue. Preclinical models have demonstrated that vascular endothelial growth factor (VEGF) plays a pivotal role in the accumulation of malignant PE or ascites. This study investigated whether blockade of VEGF activity would reduce biological activity of PE and ascites on endothelial cells of cancer patients.

Patients and Methods. The activity of VEGF in PE and ascites of 58 patients (39 with PE and 19 with ascites) was measured. An endothelial cell proliferation assay with human umbilical vein endothelial cells was used to determine the biological activity of ascites and PE.

Results. VEGF concentrations ranged from 67-6,245 pg/ml. A significantly higher concentration of VEGF was detected in the ascites and PE of patients with cancer (median, 1,290 pg/ml) than in patients with nonmalignant disease (median, 250 pg/ml; p = 0.02). Of the 58 PE and ascites samples, 41 were biologically active, based on a two- to fourfold stimulation of endothelial cell proliferation in 72 hours. VEGF concentrations were significantly higher in the biologically active samples compared with the 17 nonactive samples (2,056 pg/ml versus 771 pg/ml; p = 0.02). Coincubation of the samples with either a neutralizing polyclonal antibody against VEGF or SU5416, a small molecule inhibitor of the VEGF receptor Flk-1/KDR, inhibited endothelial cell proliferation by 66% and 100%, respectively. The inhibition caused by the antibody and that caused by SU5416 correlated significantly (r = 0.8, p < 0.001).

Conclusion. We conclude that malignant ascites and PE contain high levels of biologically active VEGF. This study strongly supports the hypothesis that blockade of VEGF, such as that afforded by SU5416, may benefit cancer patients with recurrent ascites or PE formation.
Clinical Strategy for the Development of Angiogenesis Inhibitors
Authors: Carter Stephen K.
Published: August 2004

Angiogenesis inhibitors differ from conventional cytotoxic chemotherapy agents by targeting normal cells rather than tumor cells, which may contain multiple mutations. Because of this, the traditional strategy used in clinical development of cytotoxic agents may not be appropriate for these novel agents. Many clinical studies are now evaluating these agents with a new approach, referred to as the cytostatic paradigm. The cornerstone of the cytostatic paradigm is the use of time to progression (TTP) of disease as the decision-making criterion for “go/no go” in the early phases of clinical development. However, the use of TTP as the main criterion for clinical trials is complicated for a variety of reasons, including: A) the lack of standardized criteria accepted by regulatory authorities; B) the heterogeneity of the historical database, and C) the larger number of patients needed for the “go/no go” decision-making process. In addition, clinical trials of cytotoxic agents have traditionally used objective response (despite the controversy regarding objective response as a surrogate for clinical activity) as the main criterion for determining whether the results of phase II studies justify the pivotal phase III studies.

Another aspect of the clinical development strategy is combining angiogenesis inhibitors with cytotoxic chemotherapy. The rationale for combination of angiogenesis inhibitors with cytotoxic agents is based on: A) different targets for these agents; B) lack of cross-resistance patterns; C) lack of myelosuppression with angiogenesis inhibitors allows administration of full doses of all agents, and D) the assumption that combining these agents will result in additive antitumor activity. Combination therapy with angiogenesis inhibitors may be attractive to both clinicians and their patients because it allows cytostatic agents to be used upfront in treatment while contributing to drug registration strategy (cytostatic/cytotoxic combination therapy versus cytotoxic therapy).

The clinical development of the angiogenesis inhibitor SU5416, a small molecule inhibitor of vascular endothelial growth factor, is currently ongoing. In phase I trials, SU5416 demonstrated activity in both colorectal and non-small-cell lung cancer patients. Based on these encouraging results, phase III studies to evaluate combination of SU5416 with established cytotoxic therapy are planned. These studies will include an interim analysis, the equivalent of a phase II evaluation of clinical activity. If successful, this strategic approach will save significant time in the clinical development process.
Radiotherapy-Associated Anemia: The Scope of the Problem
Authors: Harrison Louis B. , Shasha Daniel , White Carol , Ramdeen Beverly
Published: August 2004

The impact of anemia on cancer patients undergoing chemotherapy is well established, but only recently has the prevalence of anemia in patients receiving radiotherapy received much attention. Many cancer patients present with anemia prior to radiotherapy, and even more experience anemia or a worsening of anemia at some point during treatment. However, the problem of anemia is often ignored because patients may experience only functional anemia, defined as a hemoglobin level less than 12 g/dl. Unless physiologic anemia (hemoglobin = 8 g/dl) is discovered, efforts to correct anemia are often not made. Because hemoglobin levels <12 g/dl seem to be associated with tumor hypoxia and poorer outcomes of radiotherapy in a number of patient populations, ignoring even modest anemia can result in decreased locoregional control, overall survival, and quality of life (QOL). Because increasing hemoglobin levels 1-2 g/dl is usually easily accomplished, there exists the potential for improving outcomes by paying greater attention to this problem. This article focuses on the prevalence of anemia, particularly functional anemia, and discusses the impact of anemia on locoregional control, overall survival, and QOL.
The Relationship between Anemia and Quality of Life in Cancer Patients
Authors: Sabbatini Paul
Published: August 2004

Anemia is a common occurrence in patients with cancer, and especially in those who undergo chemotherapy. Traditionally, significantly decreased hemoglobin levels have been considered to be ≤ 8 g/dl and have been associated with physiologic manifestations. More recent data have shown that milder anemia (hemoglobin levels 10-12 g/dl) has functional consequences as well. This article reviews several communitybased studies that have analyzed changes in hemoglobin concentrations, transfusion requirements, and QOL parameters in anemic patients with cancer before and after treatment with epoetin alfa. The results of these studies have been consistent and show an increase in hemoglobin and a reduction in transfusion requirements when compared with baseline. Furthermore, a relationship between increasing hemoglobin levels and an improvement in QOL is suggested that is independent of tumor response. Additional studies are evaluating the optimal hemoglobin levels for the greatest incremental improvement in QOL.
The Impact of Fatigue on Patients with Cancer: Overview of FATIGUE 1 and 2
Authors: Curt Gregory A.
Published: August 2004

Fatigue is a complex, multifactorial disorder with physical, mental, and psychological dimensions that has been associated with diminished quality of life (QOL) in patients with cancer. The prevalence and severity of fatigue, however, has only recently been studied systematically. Two national surveys commissioned by The Fatigue Coalition, a multidisciplinary group of medical practitioners, researchers, and patient advocates, whose mission is to study the importance of fatigue for patients with cancer and their caregivers, have assessed the prevalence, severity, and QOL consequences of fatigue in patients with cancer. The most recent survey, initiated in 1998, sought to confirm and extend observations on the prevalence and impact of fatigue in patients with cancer as part of an initiative to develop guidelines for the differential diagnosis and treatment of fatigue. The FATIGUE 2 study probed the emotional, social, physical, and economic impact of fatigue on patients with cancer and their caregivers. Patient perceptions of the professional response to cancer-related fatigue were also assessed. The key findings of these surveys are reviewed.
New Directions in the Treatment of Non-Small Cell Lung Cancer: An Overview
Authors: Edelman Martin J.
Published: August 2004

Despite unequivocal evidence of activity and tolerability, the potential contribution of vinorelbine to the management of non-small cell lung cancer (NSCLC) has been relatively unappreciated. A phase III trial of vinorelbine as a single agent in the elderly demonstrated clear benefits in terms of survival and quality of life compared with supportive care. Two other phase III trials demonstrated that vinorelbine plus platinum was superior when compared either with one of the older platinum combinations, platinum as a single agent or vinorelbine alone. New vinorelbine-based regimens appear to be active but with less toxicity than older combinations in stage IV disease. Chemotherapy plays an essential role in the management of locally advanced (i.e., stage III) disease with the weight of evidence supporting improved curability of this stage when drugs are employed either preoperatively or as part of a chemoradiotherapy regimen. It has been reported that induction therapy using carboplatin/vinorelbine or carboplatin/paclitaxel followed by accelerated conformal radiation therapy has promising results without causing undue toxicity.

Clearly, vinorelbine is an active agent which is well tolerated and suitable for use in the management of NSCLC. It is likely to play a greater role in the future.
Carboplatin and Vinorelbine in Advanced Non-Small Cell Lung Cancer: A Phase I/II Study
Authors: Masters Gregory
Published: August 2004

Standard options for advanced non-small cell lung cancer have focused on cisplatin-based regimens, including the combination of cisplatin with vinorelbine shown in randomized trials to be at least as effective as comparator regimens. Given its lower incidence of nonhematological toxicity, carboplatin may be an attractive alternative agent in combination with vinorelbine. To determine the tolerability of this regimen, a phase I/II study was conducted in 21 patients with stage IIIB/IV disease. A fixed dose of carboplatin (area under the concentration time curve = 2.5) was administered on days 1 and 8 q 21 days, together with vinorelbine also on days 1 and 8 at doses increasing from 20 mg/m2 to 25 mg/m2. This regimen was very well tolerated: only one case of grade 4 hematological toxicity and one case of grade 3 nonhematological toxicity occurred. Objective responses were seen. Given its tolerability and activity, the combination of carboplatin with vinorelbine at the doses and schedule studied should be further evaluated.
Induction Chemotherapy Followed by Concomitant Chemoradiotherapy for Non-Small Cell Lung Cancer
Authors: Vokes Everett E.
Published: August 2004

Multiple concepts of combined modality therapy for locoregionally advanced inoperable non-small cell lung cancer have been investigated. These include induction chemotherapy, concomitant chemoradiotherapy, and intensified radiation therapy schedules. To date, induction chemotherapy has been validated in randomized prospective trials versus radiotherapy alone. Concomitant chemoradiotherapy has led to promising results when combination chemotherapy regimens were used in the phase II setting. In addition, concomitant chemoradiotherapy has been shown to be superior to induction chemotherapy in direct comparison. Finally, accelerated radiotherapy has been shown to lead to improved locoregional control and survival in one randomized study. Based on these observations, the Cancer and Leukemia Group B (CALGB study 9431) investigated the addition of either vinorelbine, paclitaxel, or gemcitabine to cisplatin. In this trial, patients with locally advanced and inoperable non-small cell lung cancer received two cycles of induction chemotherapy with an additional two cycles of concomitant chemoradiotherapy utilizing the same agents accompanied by standard radiation to a total dose of 66 Gy. One hundred eighty-seven patients were entered on this study. An early analysis showed the median survival time was 17 months for all patients entered on the trial. In the context of other CALGB studies, the data from this trial are encouraging, and the regimens used warrant further study.
The ELVIS Trial: A Phase III Study of Single-Agent Vinorelbine as First-Line Treatment in Elderly Patients with Advanced Non-Small Cell Lung Cancer
Authors: Gridelli Cesare
Published: August 2004

In a phase III trial, 191 patients aged over 70 with stage IIIB/IV non-small cell lung cancer were randomized to receive best supportive care (BSC) alone or BSC plus vinorelbine on days 1 and 8, q 21 days for up to six cycles. Increasing difficulties in recruitment meant that the investigators, blinded to the results, stopped the trial early. Data from 161 patients have been analyzed. The vinorelbine regimen was well tolerated. Grade 3/4 neutropenia occurred in 10% of patients and grade 2/3 anemia in 16%. The principle nonhematological toxicities were constipation and fatigue. An objective response rate was recorded in 19.7% of the 76 patients treated with vinorelbine. The survival experience of these patients was significantly superior to that among control patients. The median duration of survival was longer (28 versus 21 weeks) and patients receiving vinorelbine were significantly more likely to survive to one year (32% versus 14%). The relative risk of death in the vinorelbine group was 0.65 (95% confidence interval: 0.45-0.93). Quality of life was extensively investigated using European Organization for Research and Treatment of Cancer scales. While aspects of quality-of-life issues that were directly related to drug toxicity (such as nausea and constipation) were lower in the vinorelbine group, patients who received vinorelbine fared better than controls on measures related to lung cancer symptoms and pain and on social, cognitive, and physical functioning.
Introduction: The History of Arsenic Trioxide in Cancer Therapy
Authors: Antman Karen H.
Published: August 2004

Although arsenic can be poisonous, and chronic arsenic exposure from industrial or natural sources can cause serious toxicity, arsenic has been used therapeutically for more than 2,400 years. Thomas Fowler's potassium bicarbonate-based solution of arsenic trioxide (As2O3) was used empirically to treat a variety of disorders, and in 1878, was reported to reduce white blood cell counts in two normal individuals and one with “leucocythemia.” Salvarsan, an organic arsenical for treating syphilis and trypanosomiasis, was developed in 1910 by Paul Ehrlich. In the 1930s, arsenic was reported to be effective in chronic myelogenous leukemia. After a decline in the use of arsenic during the mid-20th century, reports from China described a high proportion of hematologic responses in patients with acute promyelocytic leukemia (APL) who were treated with arsenic trioxide. Randomized clinical trials in the U.S. led to FDA approval of arsenic trioxide for relapsed or refractory APL in September 2000.
Arsenic Trioxide: An Emerging Therapy for Multiple Myeloma
Authors: Munshi Nikhil C.
Published: August 2004

Arsenic trioxide can inhibit proliferation and induce apoptosis in multiple myeloma (MM) cells in vitro and in vivo. In addition to affecting tumor growth, arsenic trioxide has been shown to inhibit angiogenesis, suggesting that it may have significant potency in the treatment of MM. Based on these observations, the clinical efficacy of arsenic trioxide was evaluated in patients with advanced refractory MM using a fixed-dose intravenous infusion given daily for a maximum of 60 days. Nine patients were evaluable. All nine had extensive prior therapy; seven had two or more high-dose chemotherapy cycles with autologous stem cell support. All nine patients had cytogenetic abnormalities, and six had chromosome 13 deletions. Of the four patients who completed more than 30 days of arsenic trioxide infusion, two had >50% reduction in myeloma paraprotein, one had stable disease, and one progressed. Of the five patients with <30 days infusion, two had stable disease and three progressed. Thus, on an intent-to-treat basis, two of nine (23%) patients responded (>50% paraprotein reduction). The regimen was well tolerated except for development of cytopenia, which responded to G-CSF, and a grade III pulmonary complication in one patient. In summary, arsenic trioxide has activity in end-stage, high-risk myeloma and deserves further evaluation in earlier-stage disease.
Clinical Trials of Arsenic Trioxide in Hematologic and Solid Tumors: Overview of the National Cancer Institute Cooperative Research and Development Studies
Authors: Murgo Anthony J.
Published: August 2004

Arsenic trioxide inhibits growth and promotes apoptosis in many different cancer cell lines. The National Cancer Institute is working cooperatively with research centers across the U.S. to evaluate its clinical activity in hematologic malignancies, such as acute promyelocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, chronic lymphocytic leukemia, myelodysplastic syndrome, and multiple myeloma. It is also supporting research in solid tumors, such as advanced hormone-refractory prostate cancer and renal cell cancer and in cervical cancer and refractory transitional cell carcinoma of the bladder. The safety and pharmacokinetics of arsenic trioxide are also being evaluated in pediatric patients with refractory leukemia and lymphoma. The results of these ongoing studies should provide important insights into the clinical utility of arsenic trioxide in these diseases.
Risk/Benefit Profile of Arsenic Trioxide
Authors: Rust Deborah M. , Soignet Steven L.
Published: August 2004

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

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

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

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

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

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

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

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

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

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

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

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

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.