Review Articles in 2006

Post-therapy prostate-specific antigen (PSA) changes have been associated with improved survival in castrate metastatic patients, but currently no drug has been approved strictly on the basis of a post-treatment decline in PSA, as it is unproven that such PSA changes are surrogates for true clinical benefits. Fleming and coauthors address the critical question of whether PSA post-therapy decline reflects true clinical benefit, and if it should be used as an intermediate endpoint for accelerated approval. The authors emphasize the importance of recognizing that there are a range of clinical benefits to patients that can favorably improve the quality and possibly the duration of survival independent of PSA.

Experimental data indicate that lymphodepletion prior to adoptive transfer of tumor specific T-lymphocytes plays a key role in enhancing treatment efficacy by eliminating regulatory T-cells and competing elements of the immune system. Newly emerging animal data suggest that more profound lymphoablative conditioning with autologous hematopoetic stem-cell rescue might further enhance treatment results. The authors review the recent advances in adoptive immunotherapy of solid tumors and discuss the rationale for lymphodepleting conditioning, and also address the safety issues of translating experimental animal results of total lymphoid ablation into clinical practice.

Vascular disrupting agents (VDAs) are designed to disrupt the already established abnormal vasculature, and induce rapid shutdown of tumor blood supply causing subsequent tumor death from hypoxia and nutrient deprivation. The authors discuss the strategies to improve drug delivery, and suggest that further clinical trials need to evaluate novel treatment strategies that combine VDAs with radiotherapy, cytotoxic drugs, anti-angiogenic agents, and other novel targeted therapies. Close attention to the cardiovascular side effect profile of these agents is also imperative during their clinical development.

Surgery and chemotherapy form the cornerstone in the treatment of ovarian cancer. The standard of care for primary ovarian cancer is platinum and taxane-based chemotherapy. Despite the favorable response characteristics, however, most women with advanced-stage ovarian cancer will relapse. Herzog and Pothuri discuss the treatment options available and highlight the issues surrounding how these patients should be managed with surgical, chemotherapy, biological targeted agents and radiation therapy.

Adjuvant chemotherapy improves survival for patients with early-stage disease but this benefit is not equal for all patients. Molecular characteristics of the cancer affect sensitivity to chemotherapy. In general, estrogen receptor (ER)-negative disease is more sensitive to chemotherapy than ER-positive tumors. Before any new molecular classification (or predictive test) is adopted for routine clinical use, however, several criteria need to be met. This review describes the current limitations and future promises of gene-expression-based molecular classification of breast cancer and how it might impact selection of adjuvant therapy for individual patients.

It is unclear whether stressful life events, work-related stress, or perceived global stress are differentially associated with breast cancer incidence and breast cancer relapse in prospective studies. In this review systematic and explicit methods were used to identify, select, and critically appraise relevant studies. Despite the heterogeneity in the results obtained, the authors conclude that stress does not seem to increase the risk of breast cancer incidence but emphasize that larger studies on stress and breast cancer relapse are required to determine if stress affects the progression of breast cancer.

The development of the 70-gene prognosis signature for breast cancer was evaluated in the MINDACT (Microarray In Node negative Disease may Avoid ChemoTherapy) trial to assess the clinical relevance of the 70-gene prognosis signature, and how this compares with traditional prognostic factors for assigning adjuvant chemotherapy for patients with node-negative breast cancer. This review outlines the background work and rationale behind the final design of the MINDACT trial and how these considerations can help to optimize future trials and aim to improve individualization of cancer therapy.

Owing to cardiovascular and thromboembolic toxicities, oral estrogens were abandoned as treatments for prostate carcinoma; however, it is now recognized much of this toxicity can be avoided by parenteral (intramuscular or transdermal) estrogen administration. Ockrim and coauthors highlight the cost and protective andropause advantages of estrogen therapy, advocating a re-evaluation of this promising, but forgotten therapy.

The established role of theRETproto-oncogene in the development of medullary thyroid carcinoma makes this gene an attractive target for selective cancer therapy. The current evidence of RET involvement in the etiology of medullary thyroid carcinoma, and the therapeutic targeting of this process in preclinical and clinical studies are discussed, and the authors propose why targeting the RET proto-oncogene with small-molecule drugs is very likely to be successful in clinical applications.

The importance of positive N2 lymph node staging for prognosis and treatment decisions is now recognized for patients with Pancoast tumors. The authors of this review assert that a multi-disciplinary management strategy is needed for these patients, and that survival advantages have been observed using combined and multimodality regimens. The role of surgery in the context of viable treatment options and the use of imaging for assessing treatment response is critically discussed.

Sedation is used in multiple settings in palliative care, such as transient controlled sedation, respite sedation, and sedation for refractory psychological or existential suffering; however, it is a controversial technique that can diminish the capacity of the patient to interact, function, and, in some cases, to live. Cherny provides a comprehensive account of the risks associated with different sedation approaches and also highlights the controversies and ethical considerations for palliative care medicine.

Advances in the fields of genetics and gene-expression profiling and the advent of microarray technology have revolutionized the concept of patient tailored treatment. Before microarrays qualify as a useful clinical tool, however, they must demonstrate reliability and reproducibility. Limitations of microarray technology include sample acquisition and methods of biostatistical analysis required to analyze the enormous quantities of data obtained. Abdullah-Sayaniet al.overview the current status of microarray technology in clinical practice and propose how advances in this technology will help eliminate some of these limitations and improve patient management.

As more aggressive cytotoxic agents and targeted therapies become the standard treatment approach in oncology, tumor lysis syndrome (TLS) will be more frequently encountered. Not only should the metabolic abnormalities of acute TLS and its complications be treated, but it is critical for prevention that patients at risk are identified as early as possible. This review discusses the symptoms and clinical features of this syndrome and the authors highlight the issues related to appropriate monitoring of treatment and the use of prophylaxis.

The oncogene addition concept was established to explain how some cancers that contain multiple genetic, epigenetic, and chromosomal abnormalities are dependent on or are “addicted” to one or more genes for both maintenance of the malignant phenotype and cell survival. Weinstein and Joe summarize current experimental and clinical evidence of this concept and describe some of the molecular mechanisms of this phenomenon. The use of molecular targeted agents in combination with cytotoxic agents, and the advances in systems biology and network theory can help to facilitate an optimal treatment approach.

The incidence of male breast cancer is rising, and the treatment of this disease has been extrapolated from the knowledge of female breast cancer despite multiple differences in the pathogenesis, biology and genetics of these two disease entities. Although there have been major advances in hormonal manipulation for the treatment of breast cancer, an improved understanding of the potential differences between male and female breast cancer is essential to providing new opportunities for therapeutic intervention and likely improved outcome, as discussed in this review.

Despite recent progress in oncology, the continuing high incidence and mortality rates illustrate that our overall approach to tackling this disease is still inadequate. While the emphasis on treatment of end-stage disease is crucial, chemoprevention approaches could be regarded as the 'Cinderella' of the cancer field; largely neglected from cancer research and practice. This review elaborates on fundamental dichotomies in our outlook between traditional and revisionist viewpoints and presents a new synthesis, which builds on old strengths but also encourages a holistic approach to the entire cancer problem aimed at improving quality of life.

Regulation of cell death pathways is pivotal to cancer development and progression. Much knowledge has been gained from basic research efforts to understand the complex molecular mechanisms that drive cell turnover, leading to several strategies that modulate the cell death machinery. This article discusses these strategies, which include development of epigenetic modifiers of gene expression, gene therapy approaches, and compounds that induce pro-apoptotic events, and overviews the recent progress on some of these strategies that are being explored and tested in clinical trials.

Bortezomib is a protease inhibitor and is the first compound in this drug class to be used in clinical practice, with trials demonstrating efficacy in patients with relapsed/refractory multiple myeloma. Mature clinical data on the efficacy of bortezomib in solid tumors are not yet available, but early clinical data indicate this could be a promising drug for the treatment of advanced solid tumors. This Review summarizes the principal clinical trials of bortezomib and discusses its efficacy in solid and hematologic tumors.

Hemopoietic stem-cell transplantation (HSCT) remains an important curative therapy for many malignant and non-malignant conditions and its use worldwide is increasing. Although many advances have been made in this field, graft-versus-host disease (GvHD), or its treatment, is responsible for causing high morbidity and mortality in patients potentially cured from their primary disease. This review summarizes the successful treatment of steroid refractory-dependent acute and chronic GvHD with extracorporeal photochemotherapy.

Locoregional techniques have become the mainstay of therapy for patients with unresectable hepatocellular carcinoma (HCC). These include catheter-based approaches and locoregional ablative techniques. These therapies are mainly utilized for palliation, but have also been used with curative intent. This review outlines the current status of the most commonly used image-guided loco-regional interventions for the treatment of HCC, and describes recent research and advances related to image-guided interventions for HCC.