Showing papers in "Journal of The National Cancer Institute Monographs in 2019"

Salivary Gland Hypofunction and Xerostomia in Head and Neck Radiation Patients.

Abstract: Background The most manifest long-term consequences of radiation therapy in the head and neck cancer patient are salivary gland hypofunction and a sensation of oral dryness (xerostomia). Methods This critical review addresses the consequences of radiation injury to salivary gland tissue, the clinical management of salivary gland hypofunction and xerostomia, and current and potential strategies to prevent or reduce radiation injury to salivary gland tissue or restore the function of radiation-injured salivary gland tissue. Results Salivary gland hypofunction and xerostomia have severe implications for oral functioning, maintenance of oral and general health, and quality of life. Significant progress has been made to spare salivary gland function chiefly due to advances in radiation techniques. Other strategies have also been developed, e.g., radioprotectors, identification and preservation/expansion of salivary stem cells by stimulation with cholinergic muscarinic agonists, and application of new lubricating or stimulatory agents, surgical transfer of submandibular glands, and acupuncture. Conclusion Many advances to manage salivary gland hypofunction and xerostomia induced by radiation therapy still only offer partial protection since they are often of short duration, lack the protective effects of saliva, or potentially have significant adverse effects. Intensity-modulated radiation therapy (IMRT), and its next step, proton therapy, have the greatest potential as a management strategy for permanently preserving salivary gland function in head and neck cancer patients.Presently, gene transfer to supplement fluid formation and stem cell transfer to increase the regenerative potential in radiation-damaged salivary glands are promising approaches for regaining function and/or regeneration of radiation-damaged salivary gland tissue.

Oral Mucositis Due to High-Dose Chemotherapy and/or Head and Neck Radiation Therapy

Abstract: Oral mucositis is a common side-effect associated with conventional cancer therapy and has also recently been reported in association with newly emerging cancer therapies. It is characterized as an inflammation of the oral mucous membranes accompanied by many complex mucosal and submucosal changes. Ulcerative oral mucositis can cause significant oral pain, impair nutritional intake, lead to local or systemic infection, and cause significant economic cost. In addition, it may necessitate interruptions in cancer therapy, thus adversely affecting patient prognosis. This review presents the current understanding of the pathogenesis of mucositis and discusses evidence-based clinical management strategies for oral mucositis. In addition, key research questions for future investigation are identified, followed by a discussion of strategies to promote development and funding of the needed research.

Oral Complications of Chronic Graft-Versus-Host Disease.

Abstract: The increasing clinical indications for hematopoietic stem cell transplantation (HSCT) and improved clinical care throughout and following HSCT have led to not only long-term survival but also to an increasing incidence and prevalence of graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) affects almost 50% of adult patients post-HSCT, with increasing incidence in pediatric patients as well. Oral cGVHD specifically has a reported prevalence ranging from 45% to 83% in patients who develop cGVHD and is more extensive in adult patients than in children. Oral cGVHD affects patients through clinically significant oral symptoms that may lead to significantly decreased caloric intake, oral infections, and increased health service utilization, and may thus affect overall health and survival. The most commonly used therapy for mucosal involvement of oral cGVHD is topical high-dose and ultra-high potency corticosteroids, and calcineurin inhibitors. This review of oral complications of cGVHD presents the clinical significance of oral cGVHD to HSCT survivors, our current understanding of the pathobiology of oral cGVHD and gaps in this evidence, and the global targeted interdisciplinary clinical research efforts, including the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Current challenges regarding the management of oral cGVHD and strategies to advance our scientific understanding of this clinically significant chronic oral disease are presented.

Costs of Oral Complications of Cancer Therapies: Estimates and a Blueprint for Future Study

Abstract: Oral complications of cancer treatment are common; however, their clinical and economic importance is often underappreciated. We reviewed the literature on the economic implications of oral complications, updating a previous report in the predecessor to this issue. We searched the Medline and Scopus databases for papers published as of December 31, 2017 that described the economic consequences of preventing and managing oral complications and reviewed the literature reporting the costs of oral mucositis, xerostomia, and osteonecrosis. Cost estimates were inflated to 2017 US dollars. We identified 16 papers describing the cost of managing mucositis, eight describing the cost of osteoradionecrosis, one describing the cost of bisphosphonate-associate osteonecrosis of the jaw, and four describing the cost of xerostomia. The incremental cost of oral mucositis was approximately $5000-$30 000 among patients receiving radiation therapy and $3700 per cycle among patients receiving chemotherapy. The incremental cost of mucositis-related hospitalization among stem cell transplant recipients exceeded $70 000. Conservative management of osteoradionecrosis (antibiotics, debridement) costs $4000-$35 000, although estimates as high as $74 000 have been reported. Hyperbaric oxygen therapy may add $10 000-$50 000 to the cost of therapy. Sialogogues are required for years for the management of xerostomia at a cost of $40-$200 per month. Serious (hospitalization, hyperbaric oxygen therapy) or long-term (sialogogues) outcomes are the major drivers of cost. Future research should address patients' out-of-pocket costs and the costs of oral complications of new treatments. Multisite studies, particularly those conducted by cooperative groups, should be prioritized.

Late Soft Tissue Complications of Head and Neck Cancer Therapy: Lymphedema and Fibrosis.

Abstract: Head and neck cancer and its treatment result in soft tissue damage secondary to lymphedema and fibrosis. Lymphedema is the result of pathological accumulation of interstitial fluid in tissues. It is caused by the inability of the lymphatic system to transport lymph fluid from the tissues to the central circulatory system and is manifested clinically by tissue swelling. Fibrosis is defined as an overaccumulation of fibrotic tissues within the skin and soft tissues after a single or repetitive injury and is characterized by hardening of the soft tissues with associated loss of elasticity. Lymphedema and fibrosis are common yet overlooked late effects of head and neck cancer and its therapy. They may result in profound long-term symptom burden, loss of critical functions, and altered quality of life. The following review will discuss the current pathobiology, clinical manifestations, and future directions for research related to lymphedema and fibrosis.

Oral Pain in the Cancer Patient.

Abstract: Oral pain due to cancer and associated treatments is common. The prevalence and severity of oral cancer is high. Painful oral mucositis develops in head and neck cancer patients following surgery and associated radiation therapy and/or chemotherapy. In addition, oral pain, including pain from mucositis, occurs in patients receiving chemotherapy for cancers of the hematopoietic system and cancers at other anatomic sites. Despite pain management practices that include high-dose opioid analgesics, patients rarely obtain relief from either head and neck cancer pain or mucositis pain. Because oral pain in cancer patients is likely due to both nociceptive and neuropathic mechanisms, effective management of pain requires treatments for both processes. As knowledge of the pathophysiology of oral pain in cancer patients increases, new approaches for the prevention and management are anticipated. This article focuses on the emerging evidence that supports the molecular mechanisms and the unique oral micro-neuroanatomy that in combination produce the severe oral pain experienced by cancer patients. In addition, this article summarizes the current state of clinical management of oral mucositis pain.

Body Composition in Pediatric Solid Tumors: State of the Science and Future Directions.

Abstract: Sarcopenia (severe skeletal muscle wasting) and sarcopenic obesity (skeletal muscle wasting in the setting of excess fat) have been increasingly recognized as important prognostic indicators in adult oncology. Unfavorable changes in lean and adipose tissue masses manifest early in therapy and are associated with altered chemotherapy metabolism as well as increased treatment-related morbidity and mortality. Existing literature addresses the role of body composition in children with hematologic malignancies; however, data is lacking among solid tumor patients. Advances in imaging techniques for quantification of tissue compartments potentiate further investigation in this highly understudied area of pediatric oncology. The following review presents an in-depth discussion of body composition analysis and its potential role in the care of pediatric solid tumor patients. Integration of body tissue measurement into standard practice has broad clinical implications and may improve quality of life and treatment outcomes in this at-risk population.

Potential Successes and Challenges of Targeted Cancer Therapies.

Abstract: The concept and realization of targeted anticancer therapy (TAT) have existed for at least two decades and continue to expand rapidly. It has become clear that there is no "magic bullet" to cure cancer and that even TATs are unlikely to be successful as single agents, necessitating combination with chemotherapy, radiotherapy, or even other targeting agents. The other promise that has not been fulfilled by TAT is that of reduced toxicity. It was thought that by targeting receptors on or within cells, rather than particular phases of the cell cycle, TATs would not be toxic. However, it turns out that the targets also exist on or within normal cells and that there is even cross-reactivity between receptors on nontarget tissues. All of this results in toxicity, the mechanism of which are the same as the mechanism of action of the drugs, making toxicity reduction or prevention very difficult. This leads to new toxicities with new targeted treatments. Nevertheless, all of the above should not detract from the obvious successes of targeted agents, which have turned several acutely fatal cancers into chronic diseases and rendered some hitherto untreatable cancers into treatable diseases.

Research Frontiers in Oral Toxicities of Cancer Therapies: Osteoradionecrosis of the Jaws

Abstract: The deleterious effects of head and neck radiation on bone, with osteoradionecrosis (ORN) as the major disabling side effect of head and neck cancer treatment, are difficult to prevent and hard to treat. This review focuses on the current state of the science regarding the pathobiology, clinical impact, and management of ORN. With regard to the pathobiology underlying ORN, it is not yet confirmed whether the current radiation schedules by 3-dimensional conformal radiotherapy and intensity modified radiotherapy result in an unchanged, decreased, or increased risk of developing ORN when compared with conventional radiation treatment, the main risk factor being the total radiation dose delivered on any clinically significant surface of the mandible. With regard to the prevention of ORN, a thorough, early pre-irradiation dental assessment is still considered the first step to reduce the hazard of developing ORN post-radiotherapy, and hyperbaric oxygen (HBO) treatment reduces the risk of developing ORN in case of dental surgery in an irradiated field. With regard to the treatment of ORN, the focus is bidirectional: elimination of the necrotic bone and improving the vascularity of the normal tissues that were included in the radiation portal. The cure rate of limited ORN by conservative therapy is approximately 50%, and the cure rate of surgical approaches when conservative therapy has failed is approximately 40%. Whether it is effective to support conservative or surgical treatment with HBO as an adjuvant is not set. HBO treatment is shown to increase the vascularity of hard and soft tissues and has been reported to be beneficial in selected cases. However, in randomized clinical trials comparing the preventive effect of HBO on developing ORN with, eg, antibiotic coverage in patients needing dental surgery, the preventive effect of HBO was not shown to surpass that of a more conservative approach. More recently, pharmacologic management was introduced in the treatment of ORN with success, but its efficacy has to be confirmed in randomized clinical trials. The major problem of performing well-designed randomized clinical trials in ORN is having access to large numbers of patients with well-defined, comparable cases of ORN. Because many institutions will not have large numbers of such ORN cases, national and international scientific societies must be approached to join multicenter trials. Fortunately, the interest of funding organizations and the number researchers with an interest in healthy aging is growing. Research aimed at prevention and reduction of the morbidity of cancer treatment fits well within these programs.

Chronic Systemic Symptoms in Head and Neck Cancer Patients

Abstract: The systemic effects and manifestations of disease and treatment have been of interest for millennium. Until recently, basic and clinical research is just now reaching a watershed. Systemic symptoms usually do not occur in isolation but rather in clusters; however, much of the cutting-edge research pertaining to the etiology, mechanism, manifestations, and moderators of systemic symptoms in humans has been directed at individual symptoms, thus creating silos of knowledge. Breaching these silos and bridging the knowledge from disparate arenas of investigation to build a comprehensive depiction of acute and chronic systemic symptoms has been a challenge. In addition, much of the recent work in systemic symptoms has been conducted in the setting of nonmalignant disease. The degree to which the findings from other chronic disease processes can be translated into the oncologic realm is unknown. This article will explore inflammation as a major contributing factor to systemic symptoms and sickness behavior, discuss the most common manifestations in cancer survivors, and, where available, discuss specific data pertaining to head and neck cancer survivors.

Oral Microbiome and Cancer Therapy-Induced Oral Mucositis.

Abstract: Characterization of the role of oral microbiome in cancer therapy-induced oral mucositis (CTOM) is critical in preventing the clinically deleterious effects on patients' health that are associated with CTOM. Funding initiatives related to the National Institutes of Health human microbiome project have resulted in groundbreaking advancements in biology and medicine during the last decade. These advancements have shown that a human being is in fact a superorganism made of human cells and associated symbiotic or commensal microbiota. In this review, we describe the state of science as it relates to fundamental knowledge on oral microbiome and its role in CTOM. We also discuss how state-of-the-art technologies and systems biology tools may be used to help tackle the difficult challenges ahead to develop effective treatments or preventive therapies for oral mucositis. We make a clear distinction between disease processes pertaining to the oral microbiome, which includes opportunistic pathogens that may be defined as pathobionts, and those infectious disease processes initiated by exogenous pathogens. We also explored the extent to which knowledge from the gastrointestinal tract in disease and intestinal mucositis could help us better understand CTOM pathobiology. Finally, we propose a model in which the oral microbiome participates in the current five-step CTOM pathobiology model. With the advent of more sophisticated metagenomics technologies and methods of analysis, much hope lies ahead to implement an effective holistic approach to treat cancer patients affected by CTOM.

Medication-Related Osteonecrosis of the Jaws.

Abstract: Medication-related osteonecrosis of the jaw is an oral complication in cancer patients being treated with either antiresorptive or antiangiogenic drugs. The first reports of MRONJ were published in 2003. Hundreds of manuscripts have been published in the medical and dental literature describing the complication, clinical and radiographic signs and symptoms, possible pathophysiology, and management. Despite this extensive literature, the pathobiological mechanisms by which medication-related osteonecrosis of the jaw develops have not yet been fully delineated. The aim of this manuscript is to present current knowledge about the complication ragarding to the definition, known risk factors, and clinical management recommendations. Based on this current state of the science, we also propose research directions that have potential to enhance the management of future oncology patients who are receiving these agents.

Mechanisms by Which Obesity Impacts Survival from Acute Lymphoblastic Leukemia

Abstract: The prevalence of obesity has steadily risen over the past decades, even doubling in more than 70 countries. High levels of body fat (adiposity) and obesity are associated with endocrine and hormonal dysregulation, cardiovascular compromise, hepatic dysfunction, pancreatitis, changes in drug metabolism and clearance, inflammation, and metabolic stress. It is thus unsurprising that obesity can affect the development of and survival from a wide variety of malignancies. This review focuses on acute lymphoblastic leukemia, the most common malignancy in children, to explore the multiple mechanisms connecting acute lymphoblastic leukemia, obesity, and adipocytes, and the implications for leukemia therapy.

Dietary and Exercise Interventions for Pediatric Oncology Patients: The Way Forward.

Abstract: This review focuses on diet and exercise interventions that have been conducted in pediatric cancer and pediatric stem cell transplant patients. It examines the different reasons for conducting lifestyle interventions with attention to the different outcome measurements and feasibility of these measures with an argument toward a need for standardization to move the field forward.

Hyperglycemia During Childhood Cancer Therapy: Incidence, Implications, and Impact on Outcomes

Abstract: Hyperglycemia is a known complication of therapies used in the treatment of childhood cancer, particularly glucocorticoids and asparaginase. It has been linked to increased infection and reduced survival. With more limited data on hyperglycemia during childhood cancer treatment compared with adult cancer, impact on outcomes is less clear in this population. As additional glycemic-altering cancer agents including immune checkpoint inhibitors and targeted therapies make their way into pediatric cancer treatment, there is a more pressing need to better understand the mechanisms, risk factors, and adverse effects of hyperglycemia on the child with cancer. Thus, we utilized a systematic approach to review the current understanding of the incidence, implications, and outcomes of hyperglycemia during childhood cancer therapy.

Oral Mucosal Injury Caused by Targeted Cancer Therapies

Abstract: Targeted cancer therapies have fundamentally transformed the treatment of many types of cancers over the past decade, including breast, colorectal, lung, and pancreatic cancers, as well as lymphoma, leukemia, and multiple myeloma. The unique mechanisms of action of these agents have resulted in many patients experiencing enhanced tumor response together with a reduced adverse event profile as well. Toxicities do continue to occur, however, and in selected cases can be clinically challenging to manage. Of particular importance in the context of this monograph is that the pathobiology for oral mucosal lesions caused by targeted cancer therapies has only been preliminarily investigated. There is distinct need for novel basic, translational, and clinical research strategies to enhance design of preventive and therapeutic approaches for patients at risk for development of these lesions. The research modeling can be conceptually enhanced by extrapolating "lessons learned" from selected oral mucosal conditions in patients without cancer as well. This approach may permit determination of the extent to which pathobiology and clinical management are either similar to or uniquely distinct from oral mucosal lesions caused by targeted cancer therapies. Modeling associated with oral mucosal disease in non-oncology patients is thus presented in this context as well. This article addresses this emerging paradigm, with emphasis on current mechanistic modeling and clinical treatment. This approach is in turn designed to foster delineation of new research strategies, with the goal of enhancing cancer patient treatment in the future.

A Global Strategy for Building Clinical Capacity and Advancing Research in the Context of Malnutrition and Cancer in Children within Low- and Middle-Income Countries.

Abstract: Cancer is one of the prominent noncommunicable diseases and is responsible for more than 8 million deaths each year worldwide. It is expected to impact up to 22 million people annually by 2030, and more than 60% of new patient cases will be in Asia, Africa, and Central and South America. Despite improvements in the delivery of care to children in low- and middle-income countries, survival of those with cancer is as low as 10%; a figure that is in stark contrast to overall childhood cancer survival rates in North America and Western Europe. Although many factors are contributing to this disparity, access to well-educated health-care workers, knowledgeable in both antineoplastic and supportive care, particularly nutritional assessment and therapy, is necessary for effective treatment and reduced morbidities of children with cancer. To this end, we identify approaches for advancing nutritional care such as building nutritional capacity and education as well as advancing rigorous nutritional science through the establishment of multicountry research groups among pediatric oncology units located in low- and middle-income countries.

Nutrition & Exercise Interventions in Pediatric Patients with Brain Tumors: A Narrative Review.

Abstract: Brain tumors have been the most common pediatric solid tumor and leading cause of morbidity and mortality. Improved survival emphasizes the importance of adverse treatment effects especially related to nutrition and exercise. Although studies have examined nutrition and exercise outcomes, few randomized trials exist. This narrative review included a systematic literature search with analysis of controlled or single group studies examining clinical and quality-of-life impact of nutrition or exercise interventions. Seven articles were included. Three nutrition studies demonstrated improvement with proactive feeding tubes, nutritional supplementation, and nutritional status. Two exercise studies showed improvement in measures of fitness and neuroanatomy with exercise in pediatric brain tumor survivors; two cohort studies demonstrated a link between quality of life and physical activity. Preliminary studies show nutrition and exercise may improve physical well-being and quality of life, suggesting future controlled studies are warranted to inform clinical care of children with brain tumors.

The Gut Microbiome and Pediatric Cancer: Current Research and Gaps in Knowledge.

Abstract: The human microbiome consists of trillions of microbial cells that interact with one another and the human host to play a clinically significant role in health and disease. Gut microbial changes have been identified in cancer pathogenesis, at disease diagnosis, during therapy, and even long after completion of treatment. Alterations in the gut microbiome have been linked to treatment-related toxicity and potential long-term morbidity and mortality in children with cancer. Such alterations are plausible given immune modulation due to disease as well as exposure to cytotoxic chemotherapy, infections, and antibiotics. The following review presents our current scientific understanding on the role of the gut microbiome in pediatric cancer, identifies gaps in knowledge, and suggests future research goals.

Big Data for Nutrition Research in Pediatric Oncology: Current State and Framework for Advancement.

Abstract: Recognition and treatment of malnutrition in pediatric oncology patients is crucial because it is associated with increased morbidity and mortality. Nutrition-relevant data collected from cancer clinical trials and nutrition-specific studies are insufficient to drive high-impact nutrition research without augmentation from additional data sources. To date, clinical big data resources are underused for nutrition research in pediatric oncology. Health-care big data can be broadly subclassified into three clinical data categories: administrative, electronic health record (including clinical data research networks and learning health systems), and mobile health. Along with -omics data, each has unique applications and limitations. We summarize the potential use of clinical big data to drive pediatric oncology nutrition research and identify key scientific gaps. A framework for advancement of big data utilization for pediatric oncology nutrition research is presented and focuses on transdisciplinary teams, data interoperability, validated cohort curation, data repurposing, and mobile health applications.