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Editorial

Editorial Prevention of mucositis in cancer patients is the ultimate goal of the research addressed in this conference. As the proceedings demonstrate, regimen-related mucosal injury is a multifaceted entity that crosses many disciplines at both scientific and clinical levels. Consequently, it is likely that effectively understanding the etiology and biology of mucositis, as well as developing successful interventions, will depend on collaboration among a diverse group of scientists and clinicians. As with most clinical problems, three major areas of investigational activity for mucositis have evolved to date. These areas are 1) discovery of mechanisms contributing to its underlying pathogenesis, 2) translational studies in models to evaluate potential efficacy of new interventions, and 3) clinical trials to bring new treatments to patients or to evaluate the effect on economic issues and quality of life (QOL). It is clear from the conference outcomes that mucositis as a biological entity is complex. Research has progressed from a collection of observational and descriptive studies to examination of the condition at cellular and molecular levels. There are thus vast opportunities to study the biology of regimen-related mucosal injury. For example, investigators have preliminary information at present regarding changes that occur in tissue following challenge with radiation or chemotherapeutic agents. However, knowledge levels remain comparatively limited relative to identifying specifically which cellular and molecular changes occur in various mucosal tissues. For example, what, when, and which receptors are expressed? How do the answers to these questions change over time? These are important issues. Research has demonstrated that a relationship exists between mucositis and venoocclusive disease and that endothelial changes occur in both. What is the contribution of endothelial injury, expression of intercellular adhesion molecules, and changes in permeability to mucosal injury? Morphologic changes in connective tissue suggest that this tissue may serve as a trigger to epithelial damage. How does that occur? What is the sequence? Why is gut epithelium so susceptible? Why are selected mucosal sites more prone to injury than other mucosal sites? These are but some of the questions that require further systematic pursuit. Genetic models may provide a key to fruitful investigation. For example, the role of transcription factors such as NF-κB in triggering cellular injury may be important for understanding initial events that lead to tissue damage. While it appears that certain proteins such as proinflammatory cytokines may have a role in the pathophysiology of the condition, studies have not yet reported how intracellular metabolism or structure is affected by antineoplastic agents. The clinical observation that there is diversity of mucosal response among patients receiving identical therapy for similar tumors suggests that there may be a genetic predisposition for some forms of mucosal injury. Increasing use of pharmacogenetics as well as assessment by genetic determinants of susceptibility will play substantial roles in understanding patient-to-patient variability relative to occurrence and severity of mucositis. In addition, identification of genetic bases of mucosal cell growth, survival, and differentiation will allow future refinement of animal models. Thus, genetic determinants will become increasingly important in understanding both pathophysiology and therapeutics. A different but ultimately related approach seeks to define the effect of new antineoplastic therapies as initiators, promoters, or effectors of mucosal damage. There is obviously a fine line between developing an optimal antitumor agent and minimizing its deleterious impact on normal tissue. Defining biologic differences between healthy and malignant tissue holds potential benefit for new approaches to antitumor treatment. This strategy also, at the same time, promises to minimize “collateral damage” to normal bystander cells and tissue. Definition of mechanisms will lead to opportunities for new interventions. While current animal models provide an important translational tool for drug development, they are time consuming and relatively expensive. Thus, the models do not provide an opportunity for rapid evaluation of test compounds, and they thereby impair the ability to screen large numbers of potential agents in the context of drug development. Opportunities exist for development of culture-based assays as a means of initially evaluating potential interventions for mucosal injury. On a fundamental level, manipulated cultures also could serve as the basis for targeted mechanistic studies. Mucosal drug delivery to prevent or treat mucositis offers potential advantages over systemic forms of therapy. Transmucosal therapy, especially with molecules of significant size, is a challenge. Studies on formulation, use of permeability enhancers, and techniques to provide locally concentrated levels of drug are all opportunities for future study. Mucositis is also a unique and excellent model for pain studies. The relationship between tissue injury and both activation and sensitization of primary afferent nociceptors provides an important link between objective and subjective findings among patients with mucositis. As each component of mucositis tissue injury is defined, its particular relationship to pain can, in turn, be established and evaluated. Consequently, an opportunity exists for development of directed therapy for pain control. Another area ripe for potential investigation relies on animal modeling of the mechanisms for mucositis-induced pain. Clinical opportunities for pain studies also abound in this arena, both from the standpoint of deriving new techniques to evaluate and accurately record pain as well as from that of developing new forms of pain control. Mucositis carries with it a substantial cost in QOL and economics. Both of these content areas are potentially fertile areas for future research. As a common and representative regimen-related toxicity, mucositis is a prototypical example of how the “tail can wag the dog” with respect to QOL and cost of care. For example, while the patient's tumor may be responding well to treatment, toxicity can be sufficiently severe to preclude the patient's compliance with cancer therapy. The obvious solution to this problem rests with an adequate treatment for mucositis. In the meantime, adequate definition of QOL issues related to mucositis may provide opportunity for interim strategies. It is important that these issues become potential endpoints for clinical trials of mucositis interventions. While work to date has initially defined economic and health care costs of mucositis, there is considerable need for additional study. In particular, economic modeling for mucositis associated with a range of protocols has yet to be completed. Scientists, health care providers, and many patients live in a dot-com society, yet there has been relatively little use of the power of the computer to archive, analyze, or model the frequency and basis for mucosal toxic effects. Use of multiagent therapies has complicated risk prediction for mucosal toxic effects. However, there is little sharing of data, short of case reports. A centralized database is an opportunity waiting to happen. Clearly, the scope of mucosal injury provides an exciting area for innovative, imaginative research in a multiprofessional setting. We earnestly hope that this conference has provided a useful context in which to pursue these investigations. Editor's note: D. A. Williams receives royalty payments from Children's Hospital, Boston, MA, based on milestone agreements between Children's Hospital and Genetics Institute related to the licensing of interleukin 11. © Oxford University Press http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

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Publisher
Oxford University Press
Copyright
© Oxford University Press
ISSN
1052-6773
eISSN
1745-6614
DOI
10.1093/oxfordjournals.jncimonographs.a003432
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Abstract

Prevention of mucositis in cancer patients is the ultimate goal of the research addressed in this conference. As the proceedings demonstrate, regimen-related mucosal injury is a multifaceted entity that crosses many disciplines at both scientific and clinical levels. Consequently, it is likely that effectively understanding the etiology and biology of mucositis, as well as developing successful interventions, will depend on collaboration among a diverse group of scientists and clinicians. As with most clinical problems, three major areas of investigational activity for mucositis have evolved to date. These areas are 1) discovery of mechanisms contributing to its underlying pathogenesis, 2) translational studies in models to evaluate potential efficacy of new interventions, and 3) clinical trials to bring new treatments to patients or to evaluate the effect on economic issues and quality of life (QOL). It is clear from the conference outcomes that mucositis as a biological entity is complex. Research has progressed from a collection of observational and descriptive studies to examination of the condition at cellular and molecular levels. There are thus vast opportunities to study the biology of regimen-related mucosal injury. For example, investigators have preliminary information at present regarding changes that occur in tissue following challenge with radiation or chemotherapeutic agents. However, knowledge levels remain comparatively limited relative to identifying specifically which cellular and molecular changes occur in various mucosal tissues. For example, what, when, and which receptors are expressed? How do the answers to these questions change over time? These are important issues. Research has demonstrated that a relationship exists between mucositis and venoocclusive disease and that endothelial changes occur in both. What is the contribution of endothelial injury, expression of intercellular adhesion molecules, and changes in permeability to mucosal injury? Morphologic changes in connective tissue suggest that this tissue may serve as a trigger to epithelial damage. How does that occur? What is the sequence? Why is gut epithelium so susceptible? Why are selected mucosal sites more prone to injury than other mucosal sites? These are but some of the questions that require further systematic pursuit. Genetic models may provide a key to fruitful investigation. For example, the role of transcription factors such as NF-κB in triggering cellular injury may be important for understanding initial events that lead to tissue damage. While it appears that certain proteins such as proinflammatory cytokines may have a role in the pathophysiology of the condition, studies have not yet reported how intracellular metabolism or structure is affected by antineoplastic agents. The clinical observation that there is diversity of mucosal response among patients receiving identical therapy for similar tumors suggests that there may be a genetic predisposition for some forms of mucosal injury. Increasing use of pharmacogenetics as well as assessment by genetic determinants of susceptibility will play substantial roles in understanding patient-to-patient variability relative to occurrence and severity of mucositis. In addition, identification of genetic bases of mucosal cell growth, survival, and differentiation will allow future refinement of animal models. Thus, genetic determinants will become increasingly important in understanding both pathophysiology and therapeutics. A different but ultimately related approach seeks to define the effect of new antineoplastic therapies as initiators, promoters, or effectors of mucosal damage. There is obviously a fine line between developing an optimal antitumor agent and minimizing its deleterious impact on normal tissue. Defining biologic differences between healthy and malignant tissue holds potential benefit for new approaches to antitumor treatment. This strategy also, at the same time, promises to minimize “collateral damage” to normal bystander cells and tissue. Definition of mechanisms will lead to opportunities for new interventions. While current animal models provide an important translational tool for drug development, they are time consuming and relatively expensive. Thus, the models do not provide an opportunity for rapid evaluation of test compounds, and they thereby impair the ability to screen large numbers of potential agents in the context of drug development. Opportunities exist for development of culture-based assays as a means of initially evaluating potential interventions for mucosal injury. On a fundamental level, manipulated cultures also could serve as the basis for targeted mechanistic studies. Mucosal drug delivery to prevent or treat mucositis offers potential advantages over systemic forms of therapy. Transmucosal therapy, especially with molecules of significant size, is a challenge. Studies on formulation, use of permeability enhancers, and techniques to provide locally concentrated levels of drug are all opportunities for future study. Mucositis is also a unique and excellent model for pain studies. The relationship between tissue injury and both activation and sensitization of primary afferent nociceptors provides an important link between objective and subjective findings among patients with mucositis. As each component of mucositis tissue injury is defined, its particular relationship to pain can, in turn, be established and evaluated. Consequently, an opportunity exists for development of directed therapy for pain control. Another area ripe for potential investigation relies on animal modeling of the mechanisms for mucositis-induced pain. Clinical opportunities for pain studies also abound in this arena, both from the standpoint of deriving new techniques to evaluate and accurately record pain as well as from that of developing new forms of pain control. Mucositis carries with it a substantial cost in QOL and economics. Both of these content areas are potentially fertile areas for future research. As a common and representative regimen-related toxicity, mucositis is a prototypical example of how the “tail can wag the dog” with respect to QOL and cost of care. For example, while the patient's tumor may be responding well to treatment, toxicity can be sufficiently severe to preclude the patient's compliance with cancer therapy. The obvious solution to this problem rests with an adequate treatment for mucositis. In the meantime, adequate definition of QOL issues related to mucositis may provide opportunity for interim strategies. It is important that these issues become potential endpoints for clinical trials of mucositis interventions. While work to date has initially defined economic and health care costs of mucositis, there is considerable need for additional study. In particular, economic modeling for mucositis associated with a range of protocols has yet to be completed. Scientists, health care providers, and many patients live in a dot-com society, yet there has been relatively little use of the power of the computer to archive, analyze, or model the frequency and basis for mucosal toxic effects. Use of multiagent therapies has complicated risk prediction for mucosal toxic effects. However, there is little sharing of data, short of case reports. A centralized database is an opportunity waiting to happen. Clearly, the scope of mucosal injury provides an exciting area for innovative, imaginative research in a multiprofessional setting. We earnestly hope that this conference has provided a useful context in which to pursue these investigations. Editor's note: D. A. Williams receives royalty payments from Children's Hospital, Boston, MA, based on milestone agreements between Children's Hospital and Genetics Institute related to the licensing of interleukin 11. © Oxford University Press

Journal

JNCI MonographsOxford University Press

Published: Oct 1, 2001

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