Review Articles in 2010

This Review focuses on the adverse effects of radical radiotherapy for localized prostate cancer. The authors discuss the methodological issues that make comparison between the different treatment modalities problematic, and describe the pattern of adverse effects that occur over time after radiotherapy. Recent technical advances, such as intensity modulation and image guidance, will hopefully further improve the toxicity profile of prostate radiotherapy.

Inhibitors of poly(ADP-ribose)polymerase (PARP) have shown promise as therapeutic agents for the treatment of ovarian cancers with mutations inBRCA1 or BRCA2. By exploiting the synthetic lethal interaction that exists between PARP inhibition and BRCA mutations, these agents specifically kill cancer cells by targeting their DNA repair system. The authors of this Review describe the importance of BRCAmutations for the efficacy of PARP inhibitors. They also discuss the preclinical and clinical trial results of PARP inhibitors, the challenges related to the use of these agents, and future directions.

This Review discusses the advantages and disadvantages of weekly paclitaxel for the treatment of relapsed ovarian cancer. When compared with the 3 weekly schedule, weekly paclitaxel is better tolerated, with a reduced frequency of toxic effects; however, response duration can be short. Importantly, patients with tumors that are resistant to 3-weekly paclitaxel have responded to treatment with weekly paclitaxel. Current research focuses to increase response duration include the combination of weekly paclitaxel with molecular-targeted agents and the use of molecular profiling to better select patients for treatment.

Brain metastases are a frequent complication in patients with advanced breast cancer. Whole-brain radiation therapy (WBRT) is the standard treatment for these patients, but it can cause neurocognitive damage, and results are suboptimal. Therapies that reduce toxic effects, improve local control, and prevent recurrences are needed. The authors of this Review outline the current strategies and novel developments in WBRT, and discuss new irradiation modalities that are improving outcomes in breast cancer patients with brain metastases.

Chronic lymphocytic leukemia has long been regarded as an incurable disease of the elderly. Consolidation strategies using non-cross resistant agents have improved the success rates of patients with residual disease at the end of induction treatment. This Review discusses chemoimmunotherapy regimens that contain purine analogs and rituximab and considers new developments in induction and consolidation strategies that are leading the path towards cure.

Castleman's disease is an infectious disease of the lymph node that causes either local symptoms or a systemic inflammatory syndrome. This Review discusses the viral causes of the disease and the mechanisms of its subsequent progression. The efficacy of established treatment options for this disease and of potential novel therapies is outlined.

Sentinel lymph-node biopsy is an accurate staging procedure for patients with melanoma. However, this procedure followed by immediate completion lymph-node dissection (CLND) does not seem to improve survival, based on data from the MSLT-1 randomized trial. Patients with micrometastases <0.1 mm have a similar clinical course to sentinel-node-negative patients and routine CLND may not be indicated in these patients. The authors discuss the issue of prognostic false positivity and explain how the Rotterdam Criteria could be useful for the measurement of sentinel node tumor burden.

The rapid pace of research in cancer biology, and the advent of molecular targeted therapies has made personalized medicine a reality. This knowledge has generated a vast panel of molecular biomarkers. This Review presents the molecular, prognostic and predictive factors for the six solid tumors associated with the highest mortality. The authors discuss the key biomarkers for each disease site according to its associated clinicopathological presentation and specific associated molecular interactions.

The use of azanucleosides has altered the treatment paradigm of myelodysplastic syndromes. Recently, treatment with 5-azacitidine was demonstrated to prolong survival in patients with myelodysplastic syndromes for the first time. This Review discusses the potential of these forms of treatment as monotherapy and in combination, and assesses the most recent clinical data.

EGFR is one of the most studied targets in oncology, and several inhibitors have shown promising results in selected patient populations. However, intrinsic and acquired resistance to these targeted therapies is increasingly recognized. The authors of this Review describe the successful translation of EGFR inhibitors to the clinic, and highlight the mechanisms of resistance to these agents that limit their long-term efficacy. Understanding these processes will allow researchers to develop therapies that overcome resistance and ultimately lead to more successful outcomes.

Survival outcomes for advanced or metastatic non-small-cell lung cancer remain poor; however, molecular targeted agents offer new opportunities provided that patients are selected for treatment according to their tumor profile. This Review highlights the promising activity shown with novel targeted therapies that interfere with the IGF-1R pathway and agents that inhibit the EML4-ALK fusion protein. Aberrations in other key signaling pathways that have been identified as crucial targets, especially in resistant patients, are also discussed.

Metronomic chemotherapy is the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and with no prolonged drug-free breaks. This type of chemotherapy inhibits tumor growth primarily through anti-angiogenic mechanisms. The latest clinical trials of metronomic chemotherapy in adult and pediatric cancer patients are discussed and the authors highlight the research efforts that need to be made to facilitate the optimal development of metronomic chemotherapy in the clinic.

The number of young cancer survivors is increasing owing to advances in cancer therapeutics, but many face infertility as a result of their treatment. Teresa Woodruff highlights the obstacles to fertility preservation in young cancer patients and describes how the Oncofertility Consortium is addressing these issues by integrating a multidisciplinary network of specialists to assess the impact of treatment, allows research advances in fertility-saving options, and provides patients with the best possible care.

Two gene-expression-based reference laboratory tests, MammaPrint^® and Oncotype Dx^®, are available for prognostication of patients diagnosed with breast cancer. This Review provides a conceptual and practical overview of these two tests and describes the clinical contexts for which these assays were developed so oncologists can select the most appropriate assay based on specific clinical contexts.

Many men diagnosed with prostate cancer as a consequence of PSA testing have clinically insignificant disease. In this Review, Peter Albertsen discusses risk assessment in prostate cancer and strategies to identify these patients at low-risk of disease progression. The benefits of active surveillance are considered as an option for these men, as opposed to either surgery or radiation that are recommended for men who have a significant risk of disease progression.

Prognostic and predictive markers in colon cancer might help define which patients with stage II disease are likely to benefit from adjuvant therapy. In this Review, Tara Gangadhar and Richard Schilsky discuss the recent clinical development of such markers, including microsatellite instability and 18q loss of heterozygosity. Further validation of these markers could potentially lead to the individualization of adjuvant therapy in colon cancer.

Well-developed and validated genomic signatures can lead to personalized treatment decisions resulting in improved patient management. However, the pace of acceptance of these signatures in clinical practice has been slow because many of the signatures have been developed without clear focus on the intended clinical use, and proper independent validation studies establishing their medical utility have rarely been performed. The authors of this Review focus on guidelines that physicians could refer to when evaluating studies on prognostic gene-expression signatures.

Imaging ovarian cancer and its metastases is important for diagnosis, staging and follow-up. The authors of this Review describe functional imaging techniques that are currently used in the experimental and clinical setting, including their advantages and limitations compared with conventional imaging. In the future, these imaging modalities will provide noninvasive biomarkers of therapeutic response and patient prognosis, which will allow improved patient management and outcome.

Elevations in CA125 measurements often antedate any signs, symptoms or radiographic evidence of disease. Unfortunately, data favoring early therapeutic intervention for recurrent ovarian cancer are lacking. The results of a clinical trial suggest that withholding treatment in the event of isolated rising CA125 levels will not negatively impact overall survival. Women with no clinical evidence of disease should be informed about the usefulness and drawbacks of CA125 measurements, and offered the choice to pursue periodic measurements as well as other surveillance.

Mutations inVHL cause von Hippel–Lindau (VHL) disease, and are common in sporadic clear-cell renal-cell carcinoma (ccRCC). Drugs that modulate the downstream targets of the pVHL/HIF pathway have proven benefit in treating ccRCC. This Review, therefore, discusses the potential role of VHLalterations as prognostic and predictive markers in ccRCC.