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PURPOSE: (E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite. Preclinical tests have shown antiproliferative activity in various human tumor xenograft models and have also indicated that efficacy is greatest with frequent dosing schedules. We conducted a phase I trial of MDL 101,731 infusion in humans with advanced cancer to determine the maximum tolerated dose and the dose-limiting toxicities of this drug when administered on a twice-weekly schedule. PATIENTS AND METHODS: The drug was administered on a twice-weekly schedule for 3 weeks, followed by a 2-week rest. The initial dose was 16 mg/m2. This was reduced to 12 mg/m2 if persistent neutropenia occurred. All toxicity in the first six patients resolved by the end of the first rest week. The schedule was changed to 3 weeks of therapy followed by 1 rest week for the subsequent four patients. RESULTS: Dose escalation beyond 16 mg/m2 was not feasible because of dose-limiting toxicities, principally hematologic. No irreversible or life-threatening toxicity was seen. Grade 2 noninfectious fever, mucositis, and anorexia were also seen. In patients with stable disease, there was a heavily pretreated patient with rectal cancer in whom a 38% reduction in indicator lesions of 7 months' duration occurred. DISCUSSION: (E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite with evidence of anticancer activity in heavily pretreated patients. The maximum tolerated dose when the agent is given twice weekly is 16 mg/m2. [ABSTRACT FROM AUTHOR]

2010 was not a year of survival breakthroughs in hematologic malignancies. However, in Hodgkin's disease and multiple myeloma new therapies emerged as the standard of care and nilotinib may be considered the treatment choice for newly diagnosed chronic myeloid leukemia. [ABSTRACT FROM AUTHOR]

Primary care physicians must be up-to-date on the new long-term adjuvant treatment options and know how best to minimize long-term effects, particularly on bone health. [ABSTRACT FROM AUTHOR]

Randomized trials have supported a role for radiation therapy in the initial management of Glioblastoma Multiforme (GBM) for over twenty-five years. Although technological advances in imaging and three-dimensional treatment planning have reduced the toxicity for patients and have allowed safe radiation dose escalation, unfortunately they have not produced a correspondingly dramatic improvement in overall survival. The dose of 60 Gy partial brain RT remains the standard of care for patients with newly diagnosed GBM. Recently completed randomized trials of brachytherapy and radiosurgery do not support these modalities in the initial management of GBM, but these and other focal RT techniques such as intensity modulated radiation therapy enable safe retreatment in selected patients. Future studies will need to explore radiation biologic response modification and radiosensitization through targeted therapies. [ABSTRACT FROM AUTHOR]

Unlike most patients with glioblastoma multiforme who survive less than a year, approximately 2% have an unusually long survival after diagnosis and contemporary treatment (> or = 3 or more years); rarely, the disease appears to be "cured." Understanding these rare patients may tell us something important about the biology of glioblastoma multiforme. Patients who are young, have good performance status, and receive multimodalitytherapy (i.e., surgical resection, radiotherapy, and adjuvant chemotherapy) are more likely to have a long survival than older patients with poor performance status who are treated identically. However, the aforementioned clinical characteristics of long-term survivors do not explain why most patients with glioblastoma multiforme who have this same constellation of favorable features succumb to the disease relatively quickly. "Glioblastoma multiforme" is a group of diseases, one subtype of which behaves in a more indolent fashion, or responds well to current therapies, or both. In this review, we summarize the molecular characteristics of glioblastoma multiforme and pay special attention to molecular predictors of survival outcome, an area of research that is still in its infancy. We conclude by suggesting a translational research strategy that is aimed at uncovering the molecular signatures of long survivorship. [ABSTRACT FROM AUTHOR]

Gliomas are characterized by very high levels of neo-vascularization holding out the hope that therapies aimed at angiogenesis will have a significant impact on this intractable family of tumors. Intense research into the molecular mechanisms that drive the formation of new blood vessels in response to tumor growth has revealed a great deal of complexity, at the heart of which are competing pro- and anti-angiogenic influences. The relevant signaling pathways, and how they might be manipulated to interfere in the promotion of vessel growth are discussed. Several types of anti-angiogenic lead compounds are already in clinical trials, but assessing their impact on brain tumors is not straightforward. We discuss in depth some of the practical aspects of using imaging to more meaningfully follow tumor progression and response to treatment, which is particularly relevant to the use of therapies that target blood flow directly, which is fundamental to modern imaging modalities. [ABSTRACT FROM AUTHOR]

Neural stem cells (NSCs) are capable of tremendous migratory potential to areas of pathology in the central nervous system. When implanted into a diseased or injured nervous system, NSCs can travel through great distances to and engraft within areas of discrete as well as diffuse abnormalities. Engraftment is often followed by integration into the local neural milieu, accompanied by stable gene expression from the NSCs. In addition, the pluripotency of NSCs endows them with the capability to replace diseased tissues in an appropriate manner. Recent evidence has also suggested that engrafted exogenous NSCs may have effects on the surrounding microenvironment, such as promoting protection and/or regeneration of host neural pathways. These characteristics of NSCs would seem to make them ideal agents for the treatment of various central nervous system pathologies, especially brain tumors. Brain tumors are generally difficult to treat because of the unique location of the lesions. In primary gliomas, the extensive infiltrative nature of the tumor cells presents a challenge for their effective and total eradication, hence the high rate of treatment failure and disease recurrence. In addition, normal brain structures are distorted and are often destroyed by the growing neoplasm. Even with effective therapy to surgically resect and destroy the neoplastic tissues, the brain is still injured, which often leaves the patient in a debilitated state. The unique ability of NSCs to "home in" on tumor cells followed by the delivery of a desired gene product makes the NSC a very promising agent in brain tumor therapy. Cytolytic viruses and genes coding for anti-tumor cytokines, pro-drug converting enzymes, and various neurotrophic factors have all been engineered into engraftable NSCs for delivery to tumors. When they are specially tagged, such injected NSCs can be visualized with the use of novel imaging techniques and tracked in vivo within living animals over real time. If the NSCs were also capable of participating in the subsequent repair and regeneration of the tumor-afflicted brain-at present a potential but as-yet-unproven aspect of this intervention-then its role in abetting anti-tumor therapy would be complete. It is important to emphasize, however, that the use of NSCs is adjunctive and is not a replacement for other therapies that should be used in parallel. [ABSTRACT FROM AUTHOR]

Purpose: Brain tumors were the first human malignancy to be targeted by therapeutic transfer of nucleic acids into somatic cells, a process also known as gene therapy. Malignant brain tumor cells in the adult brain have some unique biologic features, such as high mitotic activity on an essentially postmitotic background and virtually no tumor spread outside of the central nervous system. Brain tumors seem therefore to offer major advantages in the design of tumor-selective gene therapy strategies, and the role of gene therapy in malignant glioma has been investigated since the late 1980s, initially in numerous laboratory studies and later on in clinical trials.Design: Retrovirus has been one of the earliest recombinant virus vectors used in brain tumors. Experiments in cell culture and in animal models have demonstrated the feasibility of retrovirus-mediated transduction and subsequent killing of glioma cells by toxic transgenes. Phase I and II clinical studies in patients with recurrent malignant glioma have shown a favorable safety profile and some efficacy of retrovirus-mediated gene therapy. However, the only prospective, randomized, phase III clinical study of retrovirus gene therapy in primary malignant glioma failed to demonstrate significant extension of progression-free or overall survival. Adenovirus- and herpes simplex virus type 1-based vectors have been actively investigated along with retrovirus, but their clinical use is still limited, mostly because of safety concerns. To increase efficacy, novel generations of therapeutic adenovirus and herpes simplex virus type 1 rely more on genetically engineered and tumor-selective lytic properties and less on the actual transfer of therapeutic genes.Conclusions: The failure of most clinical gene therapy protocols to produce a significant and unequivocal benefitto brain tumor patients seems to be mainly due to the low tumor cell transduction rates observed in vivo, but it may also depend on the respective physical delivery strategy of the vector. Standard radiologic criteria for assessing the efficacy of clinical treatments may also not be fully applicable to the specific metabolic changes and blood-brain barrier permeability phenomena caused in brain tumors by virus-mediated gene therapy. Clinical trials in malignant glioma have nevertheless produced a substantial amount of data and have contributed to the continuous improvement of vector systems, delivery methods, and clinical protocols. [ABSTRACT FROM AUTHOR]

Malignant gliomas remain amongst the most difficult cancer to treat. Viral-based gene therapies have been employed for the last decade in preclinical and clinical modes as a novel treatment modality. In this review, such therapies are summarized. The overwhelming majority of clinical studies point one to conclude that methodologies that will increase tumor infection/transduction will lead to enhanced therapeutic results. [ABSTRACT FROM AUTHOR]

Despite remarkable advancements in imaging modalities and treatment options available to patients diagnosed with malignant brain tumors, the prognosis for those with high-grade lesions remains poor. The imprecise mechanisms of currently available treatments to manage these tumors do not spare damage to the normal surrounding brain and often result in major cognitive and motor deficits. Immunotherapy holds the promise of offering a potent, yet targeted, treatment to patients with brain tumors, with the potential to eradicate the malignant tumor cells without damaging normal tissues. The T cells of the immune system are uniquely capable of recognizing the altered protein expression patterns within tumor cells and mediating their destruction through a variety of effector mechanisms. Adoptive T-cell therapy is an attempt to harness and amplify the tumor-eradicating capacity of a patients' own T cells and then return these effectors to the patient in such a state that they effectively eliminate residual tumor. Although this approach is not new to the field of tumor immunology, new advancements in our understanding of T-cell activation and function and breakthroughs in tumor antigen discovery hold great promise for the translation of this modality into a clinical success. [ABSTRACT FROM AUTHOR]

Introduction: Glioblastoma multiforme continues to be associated with a dismal prognosis, despite aggressive therapy. What limited therapeutic impact that has been made has come via multimodality treatment in which chemotherapy plays an important role. In this manuscript, we review current chemotherapy options for glioblastomas.Methods: The current literature concerning glioblastoma multiforme chemotherapy was reviewed. In addition to a review of landmark references, a MEDLINE search of the literature published from January 2000 to November 2002 was performed using the key words "chemotherapy AND malignant glioma" and limiting responses to clinical trials.Results: Several cytotoxic chemotherapeutic agents that are efficacious in treating glioblastoma are in common clinical use. These can be classified as first-line or second-line agents, depending on their efficacy. In addition, cytostatic chemotherapy agents are beginning to play a role in glioblastoma treatment. Finally, new methods to deliver high chemotherapy doses to brain tumors hold promise for future therapies.Conclusions: Despite the overall poor prognosis of patients with glioblastoma multiforme, multimodality treatment and chemotherapy in particular improve outcome, and chemotherapeutic options are beginning to have an increased impact. Strategies currently in clinical trials may improve this impact more in the future. [ABSTRACT FROM AUTHOR]

In the past decade, we have witnessed unprecedented changes and some remarkable advances that have enabled true personalized medicine. Nevertheless, many challenges in clinical cancer research remain and need to be overcome if we are to witness similar progress in the next decade. Such hurdles include, but are not limited to, clinical development and testing of multiple agents in combination, design of clinical trials to best accommodate the ever increasing knowledge of heterogeneity of the disease, regulatory challenges relating to drug development and trial design, and funding for basic research. With this in mind, we asked four leading cancer researchers from around the world, and who have been associated with the journal since its launch in November 2004 what, in their opinion, we have learnt over the past 10 years and how we should progress in the next 10 years.

The development of curative chemotherapy regimens for the treatment of Hodgkin's lymphoma (HL) is one of the true success stories in oncology. Most patients diagnosed with HL today can be cured. The major task remaining before us is curing as many patients as possible with their initial therapeutic approach while minimizing the acute toxicities and limiting the lifetime risks of important secondary events such as cardiovascular complications and secondary malignancies. In the 40 years since DeVita et al. developed the mechlorethamine, vincristine, procarbazine, and prednisone chemotherapy regimen, we have learned a great deal about risk stratification to minimize treatment-related toxicity. Positron emission tomography may further assist us in reducing radiation treatment without compromising cures. This review will discuss the development of the chemotherapy regimens used in the management of early and advanced stage HL and the advantages and disadvantages of their use in combination with radiation therapy.

The use of chemotherapy to treat cancer began at the start of the 20th century with attempts to narrow the universe of chemicals that might affect the disease by developing methods to screen chemicals using transplantable tumors in rodents. It was, however, four World War II-related programs, and the effects of drugs that evolved from them, that provided the impetus to establish in 1955 the national drug development effort known as the Cancer Chemotherapy National Service Center. The ability of combination chemotherapy to cure acute childhood leukemia and advanced Hodgkin's disease in the 1960s and early 1970s overcame the prevailing pessimism about the ability of drugs to cure advanced cancers, facilitated the study of adjuvant chemotherapy, and helped foster the national cancer program. Today, chemotherapy has changed as important molecular abnormalities are being used to screen for potential new drugs as well as for targeted treatments.