Review Articles in 2008

Mammalian target of rapamycin (mTOR) is an important and clinically relevant therapeutic target. Temsirolimus has significantly improved overall survival rates in patients with advanced renal cell carcinoma, thereby validating the importance of mTOR in the natural history of this disease. This Review discusses the clinical development of temsirolimus, its novel mechanism of action, and the investigational strategies for targeting mTOR in other tumor types.

Estrogen-deprivation strategies with aromatase inhibitors are superior to tamoxifen in the adjuvant, neoadjuvant and advanced breast-cancer settings in postmenopausal patients. Short-term hormonal resistance especially in the HER2-positive patient population, however, is a significant issue with these endocrine agents. The authors discuss the progress made in our understanding of resistance to endocrine therapy, and provide insights regarding the management of patients with hormone receptor-positive/HER2-positive advanced breast cancer.

There are few treatment options for patients with metastatic HER2-positive breast cancer who are unresponsive to trastuzumab. The combination of lapatinib and capecitabine significantly prolongs time to disease progression in women previously treated with chemotherapy and trastuzumab for HER2-positive advanced disease. The rationale for using this combination and the promising activity of lapatinib in early trials of inflammatory breast cancer is highlighted.

It is unlikely that tumors are entirely dependent on only one abnormally activated signaling pathway and, consequently, treatment with an agent interfering with a single target may be insufficient. This Review discusses the experimental and early-stage clinical evidence to support the relevance of EGFR-dependent and VEGF-dependent pathways, their functional links and the implications of acquired resistance to targeted therapies.

There is a paucity of phase III data comparing chemoradiation with radiation alone for treating invasive bladder cancer; however, an ongoing Australian trial is attempting to address this lack of data. Strategies that combine systemic chemotherapy and radiotherapy have been explored and have yielded better local control than either modality alone. The role of systemic chemotherapy and the controversies surrounding the use of radical surgery versus chemoradiation are discussed.

Bevacizumab, sorafenib, sunitinib and temsirolimus have been approved for use in patients with advanced solid cancers. Many other drugs with activity in preclinical models, however, have failed to show efficacy in clinical trials. The authors of this Review describe the studies that led to the approval of these antiangiogenic agents, discuss the potential value of biomarkers of angiogenesis, and provide rationale for future developments.

Many drugs are used to treat colorectal cancer but there is little information about how predictive factors can be used to improve treatment response and reduce toxic effects related to anticancer treatment. The authors of this Review analyse the main data in this investigation field, and highlight the most important predictive factors that relate to toxic effects in patients with colorectal cancer who are treated with anticancer chemotherapy, both in adjuvant and in advanced setting.

Until recently, the standard of care for the treatment of glioblastoma involved surgical resection followed by radiation therapy with or without nitrosourea-based chemotherapy. In 2005, a large trial established adjuvant temozolomide chemotherapy and radiotherapy as a new standard therapy. This Review summarizes new developments in the treatment of glioblastoma and speculates on possible future treatment strategies for managing this aggressive cancer.

Brain tumors may harbor small subpopulations of cells that share characteristics of neural stem cells. The use of neural stem cells and progenitor cells as delivery vehicles of molecules toxic to tumors offers a promising experimental treatment strategy. This Review summarizes recent advances in the basic understanding of neural stem cell and cancer-stem-cell biology and the progress towards translating these novel concepts into the clinic.

More-effective systemic therapies are needed for colorectal cancer, and particularly for metastatic disease, for which median survival rates remain below 2 years. The addition of panitumumab to best supportive care has improved efficacy in patients with chemotherapy-refractory metastatic disease, and is associated with a favorable safety profile. The authors discuss the available data and ongoing investigations of this agent in the first-line and second-line settings.

Although many studies have investigated the associations between stress-related psychosocial factors and cancer outcomes, the results have been inconclusive. The authors of this Review use meta-analytical methods from 165 studies to determine if there is an association, and discuss the results indicating that stress-related psychosocial factors have an adverse effect on cancer incidence and survival.

Spinal radiosurgery was developed to overcome the limitations associated with invasive surgery and traditional radiotherapetuic approaches for the treatment of these lesions. The authors of this Review discuss the benefits of this new therapeutic technique, such as low rate of complications, durable pain relief and local tumor control while maintaining physical and mental quality of life.

Specific biological markers that reliably predict unfavorable outcome during first-line treatment for patients with Hodgkin lymphoma are lacking. Recent analyses have shown that differences in hematotoxicity exist among male and female Hodgkin lymphoma patients, with a better prognosis observed in female patients. Klimm and Engert discuss the reasons for these differences in hematotoxicity and how these differences relate to patient outcome.

Although cancer is a preventable disease, few medical interventions are completely without risk or adverse effects. It is critical to establish a framework to determine when interventions show sufficient promise of efficacy and sufficient safety to justify their testing in clinical trials. This Review identifies the issues that are critical for decision making and provides a framework that can be applied in making these decisions.

Cancer stem cells often represent a minor, highly self-renewing population within the tumor mass and are thought to be the only cells required for both initiation and maintenance of disease. The biology of cancer stem cells, the mechanisms of therapy resistance, and potential future therapeutic interventions in the clinical setting are discussed.

Allogeneic non-myeloablative stem-cell transplantation is feasible for patients with various refractory and advanced solid tumors. Current data suggest that the graft-versus-tumor effect associated with this approach might prolong survival of some patients with metastatic solid tumors. The authors discuss the latest results from the literature and recent data from the European Bone Marrow Transplantation Solid Tumors Working Party.

Cardiotoxicity is a rare but serious complication of the management of breast cancer, and adjuvant trastuzumab after anthracycline chemotherapy increases congestive heart failure risk. The authors review the efficacy of trastuzumab, its potential for cardiac compromise, and its interaction with anthracyclines. The biological mechanisms that might be responsible for cardiotoxicity are highlighted, and the clinical strategies used to minimize the risk of developing cardiac failure are discussed.

Several toxicities are associated with molecular-targeted drugs including gastrointestinal adverse effects. These adverse effects need to be considered carefully because they can lead to the discontinuation of oral treatment and subsequently compromise cancer control. The authors of this Review discuss the incidence and clinical patterns of the gastrointestinal toxic effects induced by these agents and propose some hypotheses for each adverse event.

Epithelial–mesenchymal transition (EMT) is a phenotypic conversion that facilitates organ morphogenesis and tissue remodeling. The authors of this Review discuss the phenomenon of EMT in relation to tumor development, and the function of EMT in promoting invasion and metastasis. The roles of ERK1, ERK2 and PI3-kinase, as microenvironmental responsive regulators of EMT are also highlighted.

Preclinical and clinical data indicate a number of potential roles of diffusion-weighted MRI in the characterization of malignancy such as determination of lesion aggressiveness and monitoring response to therapy. This Review outlines the biological basis of observations made using this technique and the authors discuss the strength of evidence for adoption of DW-MRI as a biomarker for the assessment of tumor response.