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Plenary Session, May 25, 2000

Plenary Session, May 25, 2000 The May 25, 2000, plenary session highlighted discussions that emerged from each of the workgroups. The workgroups themselves had been organized on the basis of the following scientific themes: Mucosal Biology I: Mouth and Esophagus Mucosal Biology II: Intestine Mucosal Immunology Infection and Mucosal Injury Gene Expression and Inflammation Biology of Mucosal Pain Mucosal Drug Delivery Quality of Life and Economics The “Appendix” section lists the guidelines that were used for each of the workgroups. Conference participants attended a May 24, 2000, plenary session conducted before the workgroups, at which time invited speakers addressed these subjects. A summary of plenary session outcomes follows. Common Workshop Themes Several themes common to all workgroups evolved during plenary discussion in relation to mucosal injury in cancer: Mucositis in cancer patients is multifactorial in nature. A balance exists at the clinical level between the need to treat cancer and the relationship of that treatment to causing mucosal injury. It is important to interface appropriate patient-oriented outcomes with objective outcomes relative to clinical trial design and Federal regulatory mandates. There is need for innovative in vitro, in vivo, and clinical models for mucosal injury. These models could include identification of surrogate markers; examination of relationships of oral to other gastrointestinal mucositis; interrelationships of pain models with those for mucositis; patient-related risk factors, including the potential role of genomics in risk for and cause of mucositis; mucositis scoring systems; mucositis as a model for wound healing; and economic models relative to acute and chronic complications associated with mucositis, with attention paid to the variety of health care models that exist internationally. Ultimately, the best model is the human model. Considerable opportunities exist for academic, clinical, industrial, and government collaborations. It is critically important that standardized approaches be utilized, including mucositis nomenclature as well as scoring system techniques. Effective communication and multiprofessional education are essential to advance the research agenda. Examples by which this can occur include publication of the enclosed conference proceedings; development of a listserve linked to a website directed to research and clinical issues regarding mucosal injury in cancer; and participation in the activities of professional organizations, including the Multinational Association of Supportive Care in Cancer, currently operating in alliance with the International Society for Oral Oncology. In addition to these common themes, issues specific to a given workgroup were also addressed in the plenary session. A summary of these discussions follows. Mucosal Biology I: Mouth and Esophagus— Dr. Christopher A. Squier, Chair Because mucositis is a multifactorial disease, it is essential that endpoints be standardized. In addition to scientific advantages, this will reduce potential regulatory conflicts when multiple Federal and institutional review groups are involved. Relative to laboratory models, there appears to be value in studying the unique contributions of connective tissue, epithelium, and oral microorganisms. In vitro models should compare oral epithelial injury in relation to intestinal mucositis, including the role of inflammatory infiltrates and the measurement of apoptotic changes in the two respective anatomic sites. The hamster model currently used for several mucositis studies has represented an important contribution to science. However, the model itself is only as effective as the questions being asked. Furthermore, it will be important to determine what relevant cellular and molecular components in the mucositis model are conserved across species. Clinical models should address differences in mucositis signs and symptoms across all mucosal surfaces, correlation between morphologic changes and subjective feeling of pain, possible role of tobacco as a risk factor for mucositis, and long-term sequelae of mucosal damage. Definitions for stomatitis are not uniformly applied in relation to mucositis caused by radiation therapy versus chemotherapy. This disparity is reflected in current measurement systems, including the National Cancer Institute's Common Toxicity Criteria. Mucosal Biology II: Intestine—Dr. Christopher S. Potten, Chair Recent research has been principally directed to causes and management of oral mucositis. Additional research studies are needed relative to mucositis occurring at other gastrointestinal sites. This research should include Improved characterization of cell biology and innate mechanisms for injury and repair. Selected studies should specifically explore the possible influence of circadian rhythms associated with small and large intestine kinetics. These rhythms appear to differ between rodents and humans. Systemic and topical drug delivery systems to nonoral alimentary tract sites. These systems could be coupled by agents that preserve mucosal barrier function through protecting cells in replicative phase and by activating cellular repair processes. This could occur via incorporation of DNA repair genes into intestinal stem cells and via tissue engineering, modeled after research involving skin grafts for burn patients. Development of novel diagnostic approaches, to supplement currently used indirect measures including pain and diarrhea. Mucosal Immunology—Dr. Leo Lefrancois, Chair Additional research is needed regarding: The role of the immune system relative to damage and repair during the multiple phases of oral mucositis. The hierarchy of loss and the recovery of immune components during mucositis. Examples of these phenomena include loss of lymphocytes, antigen-processing cells, and polymorphonuclear leukocytes, followed by their subsequent resurgence, and the relationship of peripheral blood-immune components to tissue-based elements. The delineation of cellular and molecular factors potentially responsible for induction and repair of tissue damage, including cytokines (e.g., those principally responsible for modulation of epithelial cell kinetics) and the relationship to destruction of stem cells. The mechanisms governing tissue-specific effects, to better understand why selected mucosal sites are commonly affected while other sites are not. Application of current models of inflammatory bowel disease may be useful in this regard. Chemotherapy regimens for humans do not translate well to study in nonhuman primates and other animals. Improved animal models for oral mucositis and gut diseases are thus needed. The rat may be particularly relevant to this research. Infection and Mucosal Injury—Dr. John R. Wingard, Chair Basic research should address both transgenic knockout mice as an important technology to examine mucosal stem cell biology and mechanisms that render oral mucosa more vulnerable to injury than other, nonoral, mucosal tissue. Differences could be related to cell cycling, microbial flora, degree of physical trauma, kinetics of drug delivery, and/or salivary contributions in the oral cavity. Several agents exist relative to mucositis prevention or treatment. It is important to study the most promising interventions via randomized clinical trials. Critical attention must be paid to the definition and selection of endpoints in these clinical trials, including the strength of the data justifying use of the specific endpoint, the feasibility of measurements, and the clinical significance of differences generated via different mucosal scoring systems. An important goal is to develop precision in endpoint design and implementation consistent with clinical trials in noncancer cohorts. The hypertension model appears to be an effective example of such precision. Mucositis is clearly related to increased risk for systemic infection in the neutropenic cancer patients. In addition to research relative to mucosal biology and disease, further study of locally injurious mechanisms directly mediated via oral bacteria or fungi is important. Mucositis in cancer patients can compromise delivery of cancer therapy. This is a serious risk, since maintenance of cancer therapy dose intensity is important for maximizing patient survival. Gene Expression and Inflammation—Dr. David A. Williams, Chair In vitro systems, including clonogenic assays, are at present relatively limited in sophistication. Strategic new technology development in this arena is required. Important research issues to be pursued include defining the role of genetics and the potential that genes amplify and thus alter susceptibility to mucositis; the mechanisms by which endothelial damage may lag behind that observed in epithelium; the role of the stem cell in oral mucosal health and disease; the relationship between systemic myeloablation and mucosal disease; potential therapeutics, with attention paid to technologic and biologic barriers; and relationships between chemotherapy-induced mucositis and disease processes in other cancer and noncancer patients. Biology of Mucosal Pain—Dr. Christine Miaskowski, Chair Key research issues relating to both laboratory and clinical studies include identification of fundamental mechanisms of pain causation throughout the alimentary tract, the immunopathogenic basis of pain, potential biomarkers for pain measurement, the means by which patients discriminate types of pain and pain intensity, and relationships between acute and chronic pain experiences and their sequelae. Improvement in animal systems for study of pain is needed, including The extension of current animal models for pain to new models for pain associated with mucosal injury. For example, current technology in which phantom limb pain following amputation is reduced by prophylactic analgesics may have relevance to mucositis pain studies. The role of genetic variability relative to tissue response to injury. Clinical research needs to address The relationship of risk factors to early identification of patients likely to experience significant pain secondary to mucositis. The subjective assessments of pain, including incorporation of changes in patient perception as cancer therapy continues. For example, a patient may report a high pain score early in the treatment process. Subsequently, the patient's report may exceed the scale parameters if more severe pain develops. The appropriate measures of the effect of pain in relation to economics of healthcare in cancer patients. The improvement in strategies to collect and interpret data regarding the influence of pain medication on pain reporting in clinical trials. The efficacy of topical versus systemic application of pain medication, including patient education relative to goals of pain treatment and importance of compliance with medication dosing. New delivery systems for pain medication, including the potential utility of a microchip-based dermal or mucosal patch system. Mucosal Drug Delivery—Dr. Vincent H. L. Lee, Chair The potential full value of a mucoprotective drug may be realized by successfully tailoring its delivery to mucosa. Important research issues necessary to achieve this goal include The development of new in vitro models to better define pathogenesis of mucositis in relation to strategies for drug formulation and dosing frequency. The enhancement of drug delivery to mucosal surfaces in order to maximize drug efficacy, including drug distribution within tissue and increased patient tolerability via improvements in formulation. A variety of scientific expertise is needed to effectively develop new drug delivery systems. Scientists, including geneticists, biomaterial scientists, bioinformatics specialists, and tissue engineers, should participate in this research in partnership with the appropriate health professionals. Understanding the full scope of the mechanism by which cancer chemotherapeutic drugs are delivered to mucosal surfaces may permit identification of new approaches to reduce mucosal injury in patients. Quality of Life and Economics—Dr. David Cella, Chair Future research is needed in the following areas: Efficacy of treatments to improve quality of life (QOL) in cancer patients. QOL assessment and management in pediatric cancer populations. Effect of mucositis in relation to long-term cancer patient outcomes, including survival. Relationships of global versus subcategory measures of QOL to the acute effects of mucositis. Potentially different responses to pain and analgesic medications based on sex. Although there is no apparent variation in susceptibility to mucositis between males and females, level of pain and response to therapy may differ between the sexes. Assessment and management of gastrointestinal toxicity at anatomic sites other than the oral cavity. Correlation of patient assessment of QOL with objective measures to define clinically important changes. QOL associated with mucositis across different cancer populations. In addition, study of these issues in relation to QOL in noncancer cohorts including those with chronic pain, gut diseases with an inflammatory component, or chronic fatigue syndrome may be valuable. New cost models are needed relative to management of oral mucositis in cancer patients. In addition, potential cost savings associated with an institutional oral care program should be examined. These QOL and economic studies need to address multiple variables, including underlying disease diagnosis, patient demographics, and type of cancer treatment. Development of a multi-institutional registry for oral complications in cancer, including mucositis, may be useful at both scientific and clinical levels. Appendix Guidelines for Workgroup Discussion (Distributed in Advance to Conference Participants) Conference objective. To strategically advance basic, translational, and applied knowledge needed to ultimately prevent or ameliorate significant mucosal injury associated with intense cytotoxic cancer therapy. Workgroup objective. To generate specific basic, translational, and applied research ideas involving the workgroup's topic in relation to mucosal toxicity. Discussion points for each workgroup. (Please note: dialogue should be based on the collective experience of the group as well as the reviews presented in the May 24 plenary session. The report from each workgroup should follow the format below. Additional questions and discussion can be reported in Section 6. The report will be presented by the workgroup chair at the May 25 plenary session. Each presentation will consist of a 10-minute summary followed by an open discussion.) What is the strength of data relative to the following factors as studied in laboratory or clinical models for mucosal injury in cancer? Degree of risk (low, moderate, or high) Cause Diagnosis Prevention and treatment Clinically significant local or systemic sequelae Impact on quality of life and health care costs Relationship to cancer cure or remission What models of mucosal injury exist in noncancer settings that could define new strategies for research in relation to mucosal injury in cancer? What key research questions could substantially advance knowledge of mucosal injury in cancer? What is the degree of relevance of the research questions (Section 3) to important clinical outcomes? In what ways could current and proposed research regarding mucosal injury in cancer enhance understanding of mucosal injury in noncancer models? What additional questions and discussion did the workgroup address? © Oxford University Press http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

Plenary Session, May 25, 2000

JNCI Monographs , Volume 2001 (29) – Oct 1, 2001

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Oxford University Press
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© Oxford University Press
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1052-6773
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1745-6614
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10.1093/oxfordjournals.jncimonographs.a003441
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Abstract

The May 25, 2000, plenary session highlighted discussions that emerged from each of the workgroups. The workgroups themselves had been organized on the basis of the following scientific themes: Mucosal Biology I: Mouth and Esophagus Mucosal Biology II: Intestine Mucosal Immunology Infection and Mucosal Injury Gene Expression and Inflammation Biology of Mucosal Pain Mucosal Drug Delivery Quality of Life and Economics The “Appendix” section lists the guidelines that were used for each of the workgroups. Conference participants attended a May 24, 2000, plenary session conducted before the workgroups, at which time invited speakers addressed these subjects. A summary of plenary session outcomes follows. Common Workshop Themes Several themes common to all workgroups evolved during plenary discussion in relation to mucosal injury in cancer: Mucositis in cancer patients is multifactorial in nature. A balance exists at the clinical level between the need to treat cancer and the relationship of that treatment to causing mucosal injury. It is important to interface appropriate patient-oriented outcomes with objective outcomes relative to clinical trial design and Federal regulatory mandates. There is need for innovative in vitro, in vivo, and clinical models for mucosal injury. These models could include identification of surrogate markers; examination of relationships of oral to other gastrointestinal mucositis; interrelationships of pain models with those for mucositis; patient-related risk factors, including the potential role of genomics in risk for and cause of mucositis; mucositis scoring systems; mucositis as a model for wound healing; and economic models relative to acute and chronic complications associated with mucositis, with attention paid to the variety of health care models that exist internationally. Ultimately, the best model is the human model. Considerable opportunities exist for academic, clinical, industrial, and government collaborations. It is critically important that standardized approaches be utilized, including mucositis nomenclature as well as scoring system techniques. Effective communication and multiprofessional education are essential to advance the research agenda. Examples by which this can occur include publication of the enclosed conference proceedings; development of a listserve linked to a website directed to research and clinical issues regarding mucosal injury in cancer; and participation in the activities of professional organizations, including the Multinational Association of Supportive Care in Cancer, currently operating in alliance with the International Society for Oral Oncology. In addition to these common themes, issues specific to a given workgroup were also addressed in the plenary session. A summary of these discussions follows. Mucosal Biology I: Mouth and Esophagus— Dr. Christopher A. Squier, Chair Because mucositis is a multifactorial disease, it is essential that endpoints be standardized. In addition to scientific advantages, this will reduce potential regulatory conflicts when multiple Federal and institutional review groups are involved. Relative to laboratory models, there appears to be value in studying the unique contributions of connective tissue, epithelium, and oral microorganisms. In vitro models should compare oral epithelial injury in relation to intestinal mucositis, including the role of inflammatory infiltrates and the measurement of apoptotic changes in the two respective anatomic sites. The hamster model currently used for several mucositis studies has represented an important contribution to science. However, the model itself is only as effective as the questions being asked. Furthermore, it will be important to determine what relevant cellular and molecular components in the mucositis model are conserved across species. Clinical models should address differences in mucositis signs and symptoms across all mucosal surfaces, correlation between morphologic changes and subjective feeling of pain, possible role of tobacco as a risk factor for mucositis, and long-term sequelae of mucosal damage. Definitions for stomatitis are not uniformly applied in relation to mucositis caused by radiation therapy versus chemotherapy. This disparity is reflected in current measurement systems, including the National Cancer Institute's Common Toxicity Criteria. Mucosal Biology II: Intestine—Dr. Christopher S. Potten, Chair Recent research has been principally directed to causes and management of oral mucositis. Additional research studies are needed relative to mucositis occurring at other gastrointestinal sites. This research should include Improved characterization of cell biology and innate mechanisms for injury and repair. Selected studies should specifically explore the possible influence of circadian rhythms associated with small and large intestine kinetics. These rhythms appear to differ between rodents and humans. Systemic and topical drug delivery systems to nonoral alimentary tract sites. These systems could be coupled by agents that preserve mucosal barrier function through protecting cells in replicative phase and by activating cellular repair processes. This could occur via incorporation of DNA repair genes into intestinal stem cells and via tissue engineering, modeled after research involving skin grafts for burn patients. Development of novel diagnostic approaches, to supplement currently used indirect measures including pain and diarrhea. Mucosal Immunology—Dr. Leo Lefrancois, Chair Additional research is needed regarding: The role of the immune system relative to damage and repair during the multiple phases of oral mucositis. The hierarchy of loss and the recovery of immune components during mucositis. Examples of these phenomena include loss of lymphocytes, antigen-processing cells, and polymorphonuclear leukocytes, followed by their subsequent resurgence, and the relationship of peripheral blood-immune components to tissue-based elements. The delineation of cellular and molecular factors potentially responsible for induction and repair of tissue damage, including cytokines (e.g., those principally responsible for modulation of epithelial cell kinetics) and the relationship to destruction of stem cells. The mechanisms governing tissue-specific effects, to better understand why selected mucosal sites are commonly affected while other sites are not. Application of current models of inflammatory bowel disease may be useful in this regard. Chemotherapy regimens for humans do not translate well to study in nonhuman primates and other animals. Improved animal models for oral mucositis and gut diseases are thus needed. The rat may be particularly relevant to this research. Infection and Mucosal Injury—Dr. John R. Wingard, Chair Basic research should address both transgenic knockout mice as an important technology to examine mucosal stem cell biology and mechanisms that render oral mucosa more vulnerable to injury than other, nonoral, mucosal tissue. Differences could be related to cell cycling, microbial flora, degree of physical trauma, kinetics of drug delivery, and/or salivary contributions in the oral cavity. Several agents exist relative to mucositis prevention or treatment. It is important to study the most promising interventions via randomized clinical trials. Critical attention must be paid to the definition and selection of endpoints in these clinical trials, including the strength of the data justifying use of the specific endpoint, the feasibility of measurements, and the clinical significance of differences generated via different mucosal scoring systems. An important goal is to develop precision in endpoint design and implementation consistent with clinical trials in noncancer cohorts. The hypertension model appears to be an effective example of such precision. Mucositis is clearly related to increased risk for systemic infection in the neutropenic cancer patients. In addition to research relative to mucosal biology and disease, further study of locally injurious mechanisms directly mediated via oral bacteria or fungi is important. Mucositis in cancer patients can compromise delivery of cancer therapy. This is a serious risk, since maintenance of cancer therapy dose intensity is important for maximizing patient survival. Gene Expression and Inflammation—Dr. David A. Williams, Chair In vitro systems, including clonogenic assays, are at present relatively limited in sophistication. Strategic new technology development in this arena is required. Important research issues to be pursued include defining the role of genetics and the potential that genes amplify and thus alter susceptibility to mucositis; the mechanisms by which endothelial damage may lag behind that observed in epithelium; the role of the stem cell in oral mucosal health and disease; the relationship between systemic myeloablation and mucosal disease; potential therapeutics, with attention paid to technologic and biologic barriers; and relationships between chemotherapy-induced mucositis and disease processes in other cancer and noncancer patients. Biology of Mucosal Pain—Dr. Christine Miaskowski, Chair Key research issues relating to both laboratory and clinical studies include identification of fundamental mechanisms of pain causation throughout the alimentary tract, the immunopathogenic basis of pain, potential biomarkers for pain measurement, the means by which patients discriminate types of pain and pain intensity, and relationships between acute and chronic pain experiences and their sequelae. Improvement in animal systems for study of pain is needed, including The extension of current animal models for pain to new models for pain associated with mucosal injury. For example, current technology in which phantom limb pain following amputation is reduced by prophylactic analgesics may have relevance to mucositis pain studies. The role of genetic variability relative to tissue response to injury. Clinical research needs to address The relationship of risk factors to early identification of patients likely to experience significant pain secondary to mucositis. The subjective assessments of pain, including incorporation of changes in patient perception as cancer therapy continues. For example, a patient may report a high pain score early in the treatment process. Subsequently, the patient's report may exceed the scale parameters if more severe pain develops. The appropriate measures of the effect of pain in relation to economics of healthcare in cancer patients. The improvement in strategies to collect and interpret data regarding the influence of pain medication on pain reporting in clinical trials. The efficacy of topical versus systemic application of pain medication, including patient education relative to goals of pain treatment and importance of compliance with medication dosing. New delivery systems for pain medication, including the potential utility of a microchip-based dermal or mucosal patch system. Mucosal Drug Delivery—Dr. Vincent H. L. Lee, Chair The potential full value of a mucoprotective drug may be realized by successfully tailoring its delivery to mucosa. Important research issues necessary to achieve this goal include The development of new in vitro models to better define pathogenesis of mucositis in relation to strategies for drug formulation and dosing frequency. The enhancement of drug delivery to mucosal surfaces in order to maximize drug efficacy, including drug distribution within tissue and increased patient tolerability via improvements in formulation. A variety of scientific expertise is needed to effectively develop new drug delivery systems. Scientists, including geneticists, biomaterial scientists, bioinformatics specialists, and tissue engineers, should participate in this research in partnership with the appropriate health professionals. Understanding the full scope of the mechanism by which cancer chemotherapeutic drugs are delivered to mucosal surfaces may permit identification of new approaches to reduce mucosal injury in patients. Quality of Life and Economics—Dr. David Cella, Chair Future research is needed in the following areas: Efficacy of treatments to improve quality of life (QOL) in cancer patients. QOL assessment and management in pediatric cancer populations. Effect of mucositis in relation to long-term cancer patient outcomes, including survival. Relationships of global versus subcategory measures of QOL to the acute effects of mucositis. Potentially different responses to pain and analgesic medications based on sex. Although there is no apparent variation in susceptibility to mucositis between males and females, level of pain and response to therapy may differ between the sexes. Assessment and management of gastrointestinal toxicity at anatomic sites other than the oral cavity. Correlation of patient assessment of QOL with objective measures to define clinically important changes. QOL associated with mucositis across different cancer populations. In addition, study of these issues in relation to QOL in noncancer cohorts including those with chronic pain, gut diseases with an inflammatory component, or chronic fatigue syndrome may be valuable. New cost models are needed relative to management of oral mucositis in cancer patients. In addition, potential cost savings associated with an institutional oral care program should be examined. These QOL and economic studies need to address multiple variables, including underlying disease diagnosis, patient demographics, and type of cancer treatment. Development of a multi-institutional registry for oral complications in cancer, including mucositis, may be useful at both scientific and clinical levels. Appendix Guidelines for Workgroup Discussion (Distributed in Advance to Conference Participants) Conference objective. To strategically advance basic, translational, and applied knowledge needed to ultimately prevent or ameliorate significant mucosal injury associated with intense cytotoxic cancer therapy. Workgroup objective. To generate specific basic, translational, and applied research ideas involving the workgroup's topic in relation to mucosal toxicity. Discussion points for each workgroup. (Please note: dialogue should be based on the collective experience of the group as well as the reviews presented in the May 24 plenary session. The report from each workgroup should follow the format below. Additional questions and discussion can be reported in Section 6. The report will be presented by the workgroup chair at the May 25 plenary session. Each presentation will consist of a 10-minute summary followed by an open discussion.) What is the strength of data relative to the following factors as studied in laboratory or clinical models for mucosal injury in cancer? Degree of risk (low, moderate, or high) Cause Diagnosis Prevention and treatment Clinically significant local or systemic sequelae Impact on quality of life and health care costs Relationship to cancer cure or remission What models of mucosal injury exist in noncancer settings that could define new strategies for research in relation to mucosal injury in cancer? What key research questions could substantially advance knowledge of mucosal injury in cancer? What is the degree of relevance of the research questions (Section 3) to important clinical outcomes? In what ways could current and proposed research regarding mucosal injury in cancer enhance understanding of mucosal injury in noncancer models? What additional questions and discussion did the workgroup address? © Oxford University Press

Journal

JNCI MonographsOxford University Press

Published: Oct 1, 2001

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