Reviews & Analysis

The identification of somatic mutations in the epidermal growth factor receptor (EGFR) gene and promising clinical trial data showing a favorable clinical response to associated gefitinib and erlotinib in non-small-cell lung cancer patients was a major breakthrough in the field. Should patient selection for treatment with these drugs, however, be solely based on mutational EGFR status? Giaccone and Rodriguez discuss ways in which mutational analysis could be optimized, highlight factors that might help define sensitivity to EGFR inhibitors, and comment on how to select those patients who would benefit from treatment.

Prodrugs of 5-fluorouracil (5-FU) have been shown to be as effective as bolus 5-FU and folinic acid (FA) both in the metastatic and adjuvant setting for colon cancer treatment. Currently, oxaliplatin/5-FU is regarded as the standard adjuvant treatment, and improved response rates and prolonged survival support the use of irinotecan or oxaliplatin combined with 5-FU/FA. The use of oral compounds of 5-FU with irinotecan and oxaliplatin in patients with metastatic disease, however, is questionable due to toxicity concerns. Folprecht and Köhne explain why fluoropyrimidines remain an important component of first-line treatment and discuss which patients would benefit from monotherapy with fluoropyrimidines.

Based on preclinical data, it has been suggested that antiangiogenic compounds could improve cytotoxic drug delivery because of their effects on tumor endothelium. Most of the early clinical testing of these agents was conducted in patients with advanced disease resistant to standard therapies, and while some of the phase III trial data were disappointing, recent studies validated in large clinical trials with the anti-VEGF antibody, bevacizumab, demonstrated significant clinical benefit and renewed enthusiasm for this therapeutic strategy. This review highlights the challenges related to choosing appropriate strategies for the selection of patients, study design, and choice of appropriate endpoints for the study development of these agents.

Evaluating the prognostic value of a tumor marker is an important component of oncology research and has an important impact on treatment decisions. The authors discuss whether the usual statistical approach used to assess prognostic markers can enhance predictive accuracy, and they describe the merits of a more direct approach.

The best practice for use of oncology guidelines is discussed in this Viewpoint article. Clinical practice guidelines should not be used as cost-savings devices, but as tools for ensuring the best care of each individual patient. Guidelines should be accessible, flexible and allow participation of those intended to use them.

The treatment of head and neck cancer requires a multidisciplinary approach, and positron emission tomography/CT is a rapidly evolving technique that is profoundly altering the staging, radiation treatment planning and clinical management decisions for this disease. Franket al. discuss the use of PET/CT for staging and detecting both primary or recurrent head and neck cancer and its applications in radiotherapy treatment planning.

Biochemical markers of bone turnover are considered useful in the diagnosis and follow-up of patients with malignant bone disease. Although many markers of bone turnover are elevated in patients with established bone metastases, available evidence does not allow any final conclusions to be made regarding the accuracy and validity of these markers for early diagnosis. The diagnostic and prognostic value of bone markers for clinical outcome when used in combination with new diagnostic techniques could pave the way for improvements of clinical assessment, as discussed in this review.

The development of new drugs that are both safe and effective is paramount for the future of cancer chemoprevention. Sporn and Liby critically discuss the issues that have hampered the advances of chemoprevention in the oncology field, and emphasize the need for discovery of new targets and chemopreventive agents, offering new insights into how new approaches tested in the scientific setting could be introduced in clinical practice.

In this provocative Viewpoint the authors challenge the concept that patients in clinical trials have a better survival and quality of life than those managed routinely. For instance, phase III trials of breast cancer that restrict access to post-study salvage chemotherapy have yielded 'superior' survival data for investigational drug combinations compared with single-agent therapy, despite poor survival in all cohorts. Should such studies set new standards of care for our patients?

Differences in cancer survival rates throughout Europe are difficult to interpret, but declines in cancer mortality rates from breast cancer and colorectal cancer occurring in many developed countries reflect the great advances in cancer control that have been made in recent years.

In oncology, hundreds of prognostic marker studies are published each year, yet few markers have been demonstrated to be clinically useful. Altman and Riley discuss the pitfalls associated with publication bias, inadequate reporting and retrospective studies, and advocate that an evidence-based approach should be adopted. The authors comment on the advantages of making individual patient data available and improving the reporting of the results of prognostic marker studies.

Most modern medical centers worldwide now offer sentinel lymph node (SLN) biopsy for treating melanoma and breast cancer, yet debate continues regarding whether SLN biopsy should be routinely used in clinical practice. The authors assert that SLN biopsy is an accurate, safe and minimally invasive staging technique that is an extremely powerful prognostic tool, and should be considered a staging procedure, not a therapeutic one. This review provides a concise overview of the current literature on SLN biopsy and discusses the controversies associated with technical and patient management issues.

Some molecular targeted therapies can confer radiation response and minimize toxicity compared with chemoradiation regimens. Many of these molecular targeted drugs are being tested in clinical trials in combination with radiotherapy; however, for the optimal translation of these drugs in the clinical setting, their safety must be demonstrated in phase I clinical trials. The combination of new molecular targeted therapies and radiation might not necessarily be equivalent to the toxicity of the targeted drug plus the usual toxicity of radiation. Deutschet al. discuss the need for specific and long-term clinical evaluation and the necessity to reassess phase I strategies, toxicity endpoints, and trial concepts in order to fully optimize these regimens.

Asia, Africa and Latin America are at particular risk of marketing efforts by tobacco companies, with children being the most vulnerable. The Framework Convention on Tobacco Control has now become legally binding in the countries that have adopted it. John Seffrin discusses the global measures designed to prevent tobacco companies gaining a stronghold in developing countries, and reiterates why the US needs to be at the forefront in implementing these measures.

Epithelial polyps of the colorectum have traditionally been classified into two main groups: neoplastic polyps or adenomas, and hyperplastic polyps. Serrated adenomas display features intermediate between hyperplastic polyps and adenomas. The absence of serrated adenomas in recently published series of colorectal polyps indicates that some pathologists do not recognize them. Yet, it is becoming increasingly clear that serrated adenoma serves as the precursor lesion for a major subset of colorectal cancers. It is likely that a significant proportion of these lesions do not evolve through the adenoma-to-carcinoma sequence, but through a largely independent 'serrated-polyp pathway' in which DNA methylation is a key genetic hallmark. Jass discusses the importance of the 'CpG-island-methylator phenotype' and the morphological and molecular correlations of serrated adenomas.

Despite the plethora of reports on tumor markers in oncology, the number of markers that have emerged as clinically useful is disappointing. There is considerable evidence that the quality of reporting of studies of biomarkers, particularly tumor prognostic markers, is generally poor. McShaneet al. present guidelines that provide helpful suggestions on study design, patient characteristics, statistical analysis methods, and guidance on how to present data. The authors advocate the importance of transparent and complete reporting of tumor marker prognostic studies in order to increase accessibility and interpretability of trial data, which should help to improve patient treatment and management.

Patients with HIV infection are at an increased risk of malignancies, especially Kaposi's sarcoma and certain B-cell lymphomas. Highly active antiretroviral therapy has helped to reduce the incidence of many HIV-associated tumors, but as the number of people living with AIDS is increasing, AIDS-associated malignancies will probably rise, posing a significant treatment challenge. Yarchoanet al. discuss the pathogenesis of AIDS-related malignancies, and describe the successful treatments for Kaposi's sarcoma and lymphomas using treatments based on viral, vascular or other pathogenesis-based targets.

Ablative therapies such as cryotherapy, Mohs' micrographic surgery and radiation have long been considered the standard of care for actinic keratoses and superficial basal cell carcinomas, but imiquimod is now approved for these indications in the US and Europe. Daniel Sauder discusses the mechanisms of action and clinical potential of this promising agent.

Although the current classification schemes and prognostic algorithms for defining myelodysplastic syndromes (MDS) are valid for defining disease subgroups, they do not take into consideration the significant biological diversity of MDS. Numerous pathophysiological pathways involved in MDS are being unraveled, and new molecular targets are being identified. This review provides a concise update of some of the most up-to-date targeted agents being investigated in MDS that may offer durable benefits to patients with MDS.