Local and Systemic Pathogenesis and Consequences of Regimen-Induced Inflammatory Responses in Patients with Head and Neck Cancer Receiving Chemoradiation

Local and Systemic Pathogenesis and Consequences of Regimen-Induced Inflammatory Responses in Patients with Head and Neck Cancer Receiving Chemoradiation Elvio G. Russi,1 Judith E. Raber-Durlacher,2 and Stephen T. Sonis3 1Department of Radiation Oncology, University Teaching Hospital A.O. “S. Croce e Carle”, Via M. Coppino 26, 12100 Cuneo, Italy 2Department of Oral and Maxillofacial Surgery, Academic Medical Center, University of Amsterdam, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands 3Division of Oral Medicine, Brigham and Women's Hospital and the Dana-Farber Cancer Institute and Biomodels, LLC, 75 Francis Street, Boston, MA 02115, USA Received 8 December 2013; Accepted 27 January 2014; Published 16 March 2014 Academic Editor: Inger von Bultzingslowen Copyright © 2014 Elvio G. Russi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Treatment-related toxicities are common among patients with head and neck cancer, leading to poor clinical outcomes, reduced quality of life, and increased use of healthcare resources. Over the last decade, much has been learned about the pathogenesis of cancer regimen-related toxicities. Historically, toxicities were separated into those associated with tissue injury and those with behavioural or systemic changes. However, it is now clear that tissue-specific damage such as mucositis, dermatitis, or fibrosis is no longer the sole consequence of direct clonogenic cell death, and a relationship between toxicities that results in their presentation as symptom clusters has been documented and attributed to a common underlying pathobiology. In addition, the finding that patients commonly develop toxicities representing tissue injury outside radiation fields and side effects such as fatigue or cognitive dysfunction suggests the generation of systemic as well as local mediators. As a consequence, it might be appropriate to consider toxicity syndromes, rather than the traditional approach, in which each side effect was considered as an autonomous entity. In this paper, we propose a biologically based explanation which forms the basis for the diverse constellation of toxicities seen in response to current regimens used to treat cancers of the head and neck. 1. Introduction The past decade has seen major shifts in how we view the biology and consequences of regimen-related toxicities associated with cancer therapy. Tissue-specific damage such as mucositis, dermatitis, or fibrosis is no longer thought to be the sole consequence of direct clonogenic cell death. A relationship between toxicities that results in their presentation as symptom clusters has been documented and attributed to common underlying pathobiology [1, 2]. Active roles for the local microbiota and tumour as biologically active contributors and modifiers of toxicity development are being assessed. Genomic differences among patients have been identified which are major determinants of toxicity risk [3–5]. And the finding that patients commonly develop toxicities representing tissue injury (i.e., diarrhoea) outside radiation fields and side effects such as fatigue or cognitive dysfunction suggests the generation of systemic and local mediators. Cumulatively, this information has formed the basis for a robust pipeline of investigative agents that offer the hope of effective toxicity interventions. Among cancer patients, those being treated for cancers of the head and neck (HNCPs) represent one of the most robust populations to evaluate and analyse focal tissue injury such as mucositis or dermatitis or systemic side effects such as fatigue, cachexia, or cognitive dysfunctions [6–9]. Furthermore, rarely do patients have a single toxicity. Rather, treatment-related complications appear to occur as nonrandom clusters [1, 2], which share a common underlying pathobiological basis. In fact, it might be most appropriate to consider the study of “toxicity syndromes,” rather than the traditional approach in which each side effect was considered as an autonomous entity. The historical reductionist view that attributed iatrogenic damage solely to the clonogenic cell death of tissue stem cells, mostly in the epithelium of the entire gastrointestinal tract, has been experimentally reevaluated to reveal that iatrogenic toxicities including mucositis [10, 11], dermatitis [12], and pneumonitis [13, 14] represent the culmination of a series of biologically complex events that occur in all directly and indirectly injured tissues [15]. In addition, the observation of toxicities, which are systemically manifested, have provided a rationale for the application of the abscopal effect to normal tissues in addition to tumours [16]. This hypothesis suggests that focal radiation, even in the absence of concomitant chemotherapy (CT), can result in biologically active mediators that have diffuse targets at remote sites. The clustering of CT- and radiotherapy (RT)-induced toxicities sharing common pathobiology reported by Aprile et al. [1] provided a biological basis for clinical observations. Understanding the nature of the genesis of these toxicities is critical to establishing an effective interventional strategy. Based on the pathobiology of diseases which result in similar phenotypes (i.e., chronic fatigue syndrome, Crohn’s disease, and Sjogren’s syndrome as examples), it seems that inflammatory pathways and mediators are likely candidates for this role. It is becoming increasingly clear that the wide variety of proteins elicited by CT or RT to cause local toxicities may have significant abscopal effects that put the patient at risk for a systemic inflammatory reaction that, in many ways, resembles what is seen clinically in sepsis. While the true definition of sepsis is not satisfied in cases with no identifiable microbial invasion, the scope of a systemic inflammatory response can result in marked clinical morbidity or even death [17–21]. Moreover, bacteraemia, due to the loss of integrity of a physical barrier (mucosa, skin), are not always associated with sepsis [22, 23] but may lead to sepsis when they are associated with a panoply of nonspecific inflammatory responses [24]. In addition, it has been postulated that an inflammatory response induced by the tumour itself [25] may play a role and, together with inflammation induced by iatrogenic cytolysis, may contribute to the main adverse events in CT-RT-treated HNCPs. In this manuscript, we attempt to develop a biologically based explanation which forms the basis for the diverse constellation of toxicities seen in response to current regimens used to treat cancers of the head and neck. 2. Mucosal Injury Until the late 1990’s [26], the historical paradigm of cancer regimen-related epithelial injury held that damage was essentially the consequence of nons (...truncated)