Biomedical subjects

Jacqueline Williams

Publications and source records attributed to Jacqueline Williams.

3 recordsLinked to original sources

PubMed2003

Normal tissue effects: reporting and analysis.

Any effective cancer therapy developed to date is associated with a spectrum of normal tissue effects of varying incidence and severity. With an increasing number of novel therapeutic approaches undergoing clinical testing and an increased effort to optimize the established treatment modalities, methods for reliable quantification of normal tissue effects have become a key element in advancing cancer care. Here, we present a review of many of the issues involved in reporting and analyzing clinical normal tissue effect data. A distinction is introduced between explorative (science-driven) and pragmatic (patient-centered) studies. The desirable properties of criteria for reporting and grading toxicity are discussed from a biological and clinical perspective. Validation of toxicity criteria and the statistical issues involved in analyzing this type of data are presented with special emphasis on descriptors of the time evolution of toxicity. Finally, we discuss surrogate markers for late effects, mechanistic studies, and the design of clinical studies with normal tissue endpoints as a primary outcome. It is concluded that a consensus is required on guidelines for the reporting of normal tissue effects to improve the comparability of published reports on treatment outcome.

Antineoplastic Agents↗

PubMed2003

The biological basis of a comprehensive grading system for the adverse effects of cancer treatment.

As described in the previous article in this issue by Trotti et al, there have been major changes in the philosophy and scope of the new National Cancer Institute comprehensive grading system for treatment-related toxicities, Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0). The most prominent changes are the merging of early and late effects criteria into a single uniform document and the development of criteria that cover all treatment modalities. In this article, we briefly outline the biological support for the new grading system in the context of our current knowledge base. The clinical consequences of radiotherapy in normal tissue have been classically grouped temporally, into early and late effects, using a somewhat arbitrary dividing line, 90 days after commencement of radiotherapy. This definition was developed in an era of standard fractionation used alone or in simple sequential programs involving other modalities. However, most patients are now managed with multiple highly integrated modalities, often augmenting tissue injury and limiting our ability to ascribe any given effect to a particular modality. The use of complex concurrent or hybrid (concurrent/sequential) schedules also undermines the usefulness of a simplistic temporally defined early-late construct. Moreover, there is growing recognition that chemotherapy and surgery produce inherent long-term biologic and clinical effects as well. Our basic understanding of the roles that surgery, chemotherapy, and radiation play in normal tissue response has expanded over the last decade because of vastly improved molecular techniques. The original biologic paradigm viewing acute and late tissue injury as a continuum of response and repair has been strengthened by these additional laboratory investigations. The expression of toxicity over time has been shown to be caused by a variety of cellular, tissue, environmental, and host factors. We continue to elucidate the roles of DNA damage, cytokines, chemokines, and associated inflammation, which lead in some cases to perpetuation of the wound-healing response, progressive tissue fibrosis, and vascular compromise. The continuum model of tissue injury supports the recent changes in the common toxicity grading system. It also provides insights into potential targets and strategies for modulating response, which may in turn lead to effective interventions for altering the therapeutic ratio.

Antineoplastic Agents↗

PubMed2002

Radiation pneumonitis and early circulatory cytokine markers.

Radiation pneumonitis is a distinct clinical entity that differs from other pulmonary symptoms such as allergic pneumonitis, chemical pneumonitis, or pneumonia by various infectious agents. Recent research has supported the mechanism of cellular interaction between lung parenchymal cells and circulating immune cells mediated through a variety of cytokines including proinflammatory cytokines, chemokines, adhesion molecules, and profibrotic cytokines. Identifying reliable biomarkers for radiation pneumonitis will allow us to identify individuals at risk for pneumonitis before or during the early stage of therapy. Prospective blood sampling, scoring of respiratory symptoms, and chest imaging were conducted for patients receiving thoracic radiotherapy for malignancy. Serial plasma specimens were analyzed for circulating cytokine changes before, during, and up to 12 weeks after radiation. Radiation pneumonitis was diagnosed using National Cancer Institute (NCI) common toxicity criteria. Cytokine analysis was assayed for interleukin 1alpha (IL-1alpha), interleukin 6 (IL-6), monocyte chemotactic protein 1 (MCP-1), E-selectin, L-selectin, transforming growth factor beta1 (TGF-beta1), and basic fibroblast growth factor (bFGF) using enzyme linked immmunosorbant assay (ELISA). Twenty-four patients had clinical follow-up longer than 12 months after radiotherapy. Thirteen had symptomatic pneumonitis (NCI grade 2). The peak incidence of symptoms was between 6 and 13 weeks after radiotherapy. Six patients had only radiographic infiltrates (NCI grade 1). Five patients did not have clinical or radiographic pneumonitis. Both IL-1alpha and IL-6 levels were significantly higher before, during, and after radiotherapy for those who had pneumonitis. The pattern of changes of MCP-1, E-selectin, L-selectin, TGF-beta1, and bFGF varied, but none of these cytokines correlated with radiation pneumonitis. Analysis of a panel of circulating cytokines with different putative functions in radiation pulmonary injury identified IL-1alpha and IL-6 as early circulating cytokine markers for radiation pneumonitis.

Adult↗