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Oral toxicities of cancer treatment
16 Oral toxicities of cancer treatment Richard M. Logan Oral and Maxillofacial Pathology, Adelaide Dental School, The University of Adelaide, Adelaide, SA, Australia
Abstract The oral cavity is a unique environment; it includes a range of different tissue types that rely on maintenance of a constant environment or homeostasis. The health of the mucosa and teeth relies on maintenance of good salivary function and also integrity of the mucosa. Toxicities associated with cancer treatments presenting in the mouth do not occur in isolation from each other or other systemic toxicities. Oral toxicities broadly include mucosal damage (mucositis), changes in salivary gland function (most notably by causing reduced salivary flow), and also can affect the integrity of bone (osteonecrosis of the jaws). These effects can have additional outcomes which affect quality of life including loss of taste, difficulty swallowing, compromised nutrition, increased dental caries, and oral infections. For most patients, the most debilitating acute toxicity is oral mucositis, and this is the main focus of this chapter. Important chronic toxicities include long-term salivary hypofunction and osteonecrosis of the jaws.
Introduction Although improvements in cancer treatment have improved outcomes for many patients with a diagnosis of cancer, there continues to be a potentially wide range of bystander side effects or toxicities of treatment that manifest throughout the body. Those toxicities affecting the oral cavity are important for a variety of reasons, not the least of which is the significant impact that they have on the quality of life of patients during and after their treatment.1,2 Furthermore, the effect of these oral toxicities, as well as toxicities more generally, on the ability for clinicians to provide optimal cancer treatment is obviously also importantdpositive treatment outcomes can be compromised if toxicities cannot be prevented or adequately managed.2
Translational Systems Medicine and Oral Disease. https://doi.org/10.1016/B978-0-12-813762-8.00016-5 Copyright © 2020 Elsevier Inc. All rights reserved.
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The oral cavity is a unique environment in the body, in that it includes a range of different tissue types that rely on maintenance of a constant environment or homeostasis. More specifically, the health of the mucosa and teeth relies on maintenance of good salivary function and also integrity of the mucosa. For example, it is well known that a reduction in salivary flow can increase the risk of mucosal infections, increase the risk of trauma, and increase rates of dental caries. A breakdown in the integrity of the mucosa increases the risk of infections and in patients at risk, systemic infectionsdan important broad effect of cancer treatment is the effect that it has on the oral environment. Furthermore the environmental changes in the mouth, caused by the effect of cancer treatment, also impacts on the resident oral microflora. There is increasing interest in the role of the oral microbiome and its interplay with oral tissues and the impact that this interplay has on cancer treatment toxicity.3 Oral toxicities of cancer treatment are diverse (Fig. 16.1) and generally well described in the literaturedthis attests to the ease at which they can be identified by clinicians and also, as stated previously, the impact that they have on the quality of life of patients and the limitations they place on the ability to provide optimum cancer treatment. The ability to effectively eat, drink, talk, and sleep can be significantly affected by oral toxicities that involve the head and neck region, particularly within the oral cavity. Despite the easy clinical recognition of many of these toxicities, they are frequently underreported in the literature.4 Cancer treatment toxicities that occur in the oral cavity are dependent on a variety of factors, both treatment-related and patient-related.5
(A)
(B)
(C)
Other effects of oral toxicity: • Xerostomia • Difficulty Swallowing (Dysphagia) • Taste changes (Dysgeusia)
(D)
(E)
(F)
• Speech difficulties • Appetite loss • Weight loss
Figure 16.1 Range of oral adverse events resulting from cancer treatment. (A) Mucositis and candida infection; (B) dry mouth and candida infection; (C) and (D) dry mouth and radiation caries; (E) osteoradionecrosis; and (F) mucositis.
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These factors are key driving forces that influence the sort of problems that patients may experience. The patient-related factors, while potentially influencing the outcome of treatment (Table 16.1), are highly variable and have been reported to be somewhat unreliable in terms of predicting risk.6 More recently, genetic studies have highlighted a genetic risk for developing toxicities during treatment.7 Importantly, it has become increasingly evident over the years that toxicities presenting in the mouth do not occur in isolation from each other or other systemic toxicities.4,8 These include a wide range of conditions including, for example, anorexia, fatigue, and more general gastrointestinal symptoms. Oral toxicities broadly include mucosal damage (mucositis), changes in salivary gland function (most notably by causing reduced salivary flow), and also can affect the integrity of bone (osteonecrosis of the jaws). These effects can have additional outcomes which compound adverse effects on quality of life including loss of taste, difficulty swallowing, compromised nutrition, increased risk of dental caries, and oral infections. Toxicities can also be considered in terms of acute and chronic effects of treatment (Table 16.2).9,10 For most patients, by far, the most debilitating acute toxicity is oral mucositis and this is the main focus of this chapter. Important chronic toxicities include long-term salivary hypofunction and osteonecrosis of the jaws.
Table 16.1 Treatment- and patient-related risk factors influencing the development of cancer toxicities during cancer treatment. Treatment-related risk factors
Patient-related risk factors
Type of treatment Radiation type, dose, and field Chemotherapy agent
Genetics
Neutropenia
Nutritional status Oral health Salivary flow Preexisting oral disease and infections Age, gender Type of tumor
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Table 16.2 Acute and chronic oral toxicities associated with cancer treatment.9 Acute oral toxicities
Chronic oral toxicities
Mucositis
Mucosal atrophy or fibrosis
Infections (fungal or bacterial)
Reduced salivary gland function
Reduced salivary gland function
Osteonecrosis (þ/ soft tissue necrosis)
Taste loss or change
Dental caries Temporomandibular joint dysfunction Dysphagia Infections (fungal or bacterial)
Oral mucositis Mucositis is the mucosal damage that can occur as a result of chemotherapy, radiotherapy, and also with targeted chemotherapy treatments.6 The development of mucositis in patients undergoing chemotherapy or radiation to the head and neck often has a relatively predictable clinical course and presents as a spectrum of signs and symptoms ranging from mild mucosal erythema through to widespread mucosal ulceration (Fig. 16.2). This can cause significant pain and discomfort resulting in the inability to eat, swallow, or speak and in turn increases the risk of many other adverse effects including oral and systemic infections, weight loss, poor nutrition, and poor sleep patterns.
Figure 16.2 Spectrum of clinical presentation of oral mucositis, ranging from erythema through to widespread ulceration of the mucosa; the appearance of normal mucosa is seen on the far left.
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Historically, it was considered that cancer treatments in addition to targeting neoplastic cells with high replication rates also adversely affected healthy tissues with high cell turnoverdthis includes the basal cell layer within the oral mucosa epithelium. This simplistic historical view that cancer treatment attenuates the rapidly dividing basal cells causing epithelial atrophy and ulceration has been effectively discounted over the last 15 years or so.11,12 While it is acknowledged that this does occur, the degree of damage that is clinically seen in the mucosa cannot be accounted for by this simplistic explanation. Increasing evidence from both animal and human studies now provides a compelling case supporting a significantly more complex model of the pathobiology of mucositis (Fig. 16.3)11 involving both local and systemic effects. The pathobiology of mucositis can be considered in five overlapping phases involving a complex interplay that occurs between all components of the oral mucosadchanges occur not only to the epithelium but also the underlying components within the lamina propria including endothelial cells and
Figure 16.3 Pathobiology of mucositis.
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fibroblasts as well as effects on other cells including macrophages and platelets.12 In fact, effects on endothelial cells may be the first indication of tissue damage in the mucosa before there is any effect on the epithelium.12 This model better accounts for the degree of damage that occurs to the mucosa compared with that that could result from simple clonogenic cell death. The first of the phases is described as the initiation phase and is characterized by the initial direct damage that occurs to cells in different mucosal compartments. To some extent, this manifests as direct cell death, particularly of basal epithelial cells; however, the nonlethal DNA damage to various cell types and the production of reactive oxygen species (ROS) that also occurs following radiation exposure or through the effects of some chemotherapy agents also precipitates a cascade of events at the cellular level that potentiates the degree of damage that occurs accounting for the degree of damage to the mucosa that is observed clinically. The second and third phases described in the process, the upregulation and messenger generation and signal amplification phases, are characterized by the upregulation of various pathways resulting in the production of endogenous damage-associated pattern molecules including mitogen-activated protein kinase signaling, toll-like receptor (TLR) signaling, and importantly nuclear factor-kappa B (NF-kB) pathway.3 The role of NF-kB in mucositis is probably the most well described.6 Importantly, this pathway can be directly activated by the cancer treatments themselves, through DNA damage, or by the ROS that result from treatment.6 NF-kB is a transcription factor, that when upregulated can cause a wide range of outcomes including cellular apoptosis which is seen in the epithelium in the context of mucositis,13 and the upregulation of proinflammatory cytokines such as interleukin 1 beta (IL-1b), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Furthermore, TNF can also contribute to cellular apoptosis through activation of caspase pathways.6 Additionally, altered expression of matrix metalloproteinase expression the mucosa has also been shown to contribute to tissue damage through increased breakdown of the connective tissues.14 The upregulation of these pathways have positive feedback effects on NF-kB resulting in an amplification of molecular signaling within the tissues resulting in sufficient tissue damage to cause complete breakdown of the epithelial barrier of the mucosa. The breakdown of the epithelial barrier manifests clinically as ulceration and characterizes the fourth phase in the pathobiology of mucositis which is referred to appropriately as the ulcerative phase. It is at this point that mucositis is clinically evident and where the effects for patients and clinicians are most problematic. Patients are often well into their course of cancer treatment, they may be neutropenic and accordingly are at increased risk of
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infections. Colonization of oral ulcers by oral bacteria contributes to the mucosal damage by potentiating positive feedback pathways that upregulate NF-kB and cause further production of proinflammatory cytokines,3,6 which as described earlier potentiates the degree of tissue damage. Finally, with the cessation of treatment, the final phase is initiated and characterized by healing of tissues. This occurs through expression of various signals from the extracellular matrix; eventually reepithelialization of the mucosa occurs and for most patients function is restored. While clinically ulcers heal and, for most patients, pain resolves, at the cellular level there is persistent ultrastructural damage of mucosal cells13 as well as residual angiogenesis6 which means that the resilience of tissues to further damage is affecteddthis is evident in patients who undergo subsequent treatment such as further chemotherapy cycles where severity of mucositis is often increased.15
Differences between different treatment modalities Given the limited response that mucosa has to injury, the underlying pathobiology of mucositis is similar for different treatment modalities. Despite this, there are obvious differences between the clinical presentation of mucosal damage according to cancer treatments with respect to timing, degree of mucosal involvement, and also the clinical appearance of ulceration. The clinical presentation of chemotherapy-associated mucositis is largely dependent on the type of chemotherapy agent that is used. Some drugs such as antimetabolites (for example, 5-fluorouracil, methotrexate, and capecitabine), alkylating agents such as cyclophosphamide, and other specific drugs such as irinotecan, a topoisomerase 1 inhibitor, are well recognized as “mucotoxic” drugs.16 Chemotherapy-associated mucositis is also influenced by other physiological factors such as renal and hepatic function which can affect drug metabolism.6 The likelihood that a patient develops mucositis is also influenced somewhat by concurrent administration of radiotherapy or targeted treatments6 as well as, as mentioned previously in this chapter, whether the patient has had previous cycles of chemotherapy. Mucositis associated with radiotherapy, on the other hand, is generally a more localized effect of treatment, and oral mucositis is seen in almost all patients undergoing radiation to the head and neckdif the oral cavity is within the field of radiation (Fig. 16.4). Again, though the type of radiation will affect the degree of mucositis, the addition of concurrent chemotherapy increases risk.6 Interestingly, while the direct effects of radiation are well characterized, radiation to the head and neck has been reported to cause indirect effects to other parts of the gastrointestinal tract presenting as symptoms of abdominal bloating and pain.17
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Figure 16.4 A clinical photograph of a male patient undergoing radiotherapy for tongue squamous cell carcinoma. The tongue shows widespread ulceration typical of radiation-induced mucositisdthe well-demarcated skin erythema clearly illustrates the field of radiation that is used to treat the tumor (dotted line).
Targeted treatment agents including mammalian target of rapamycin (mTOR) inhibitors,18 tyrosine kinase inhibitors (TKIs), and antibodies have all been reported to cause mucosal injury often when prescribed in conjunction with conventional treatment such as radiation. Mucosal injury associated with mTOR inhibitors is well described presenting as aphthous-like ulcers (Fig. 16.5), which are generally less severe and often self-limiting lesions compared with that seen in conventional cancer treatments.18 The pathobiology of these lesions is unclear with respect to how they develop compared with conventional mucositis.
Figure 16.5 Clinical appearance of stomatitis associated with targeted cancer treatments.
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Interactions with the host microbiome As mentioned previously in this chapter, cancer treatments, as well as affecting different cells and tissues in the oral cavity, can cause changes in the oral microbiome through alterations in the local environment (as a result of loss of mucosal integrity and also reduced salivary flow, impaired oral hygiene, the presence of intraoral tumors, and surgery) and also as a result of systemic changes such as myelosuppression and poor nutrition.3 In the current model of mucositis pathobiology, it is suggested that the impact of oral microflora on the pathobiology of mucositis is through effects of bacteria extending into ulcerated mucosa.3 The dynamic nature of the oral environment corresponds to a changing microbial population in the mouth.3 It was highlighted in an earlier part of this chapter that various molecular pathways are upregulated through the production of endogenous damage-associated pattern molecules.6 TLR expression can be potentially initiated through interactions between bacteria and the mucosa.3 Stimulation of mucosal cells through bacterially initiated TLR signaling can potentially activate NF-kB and produce proinflammatory cytokines such as IL-1b, IL-6, and TNF which as described previously is involved in pathobiology of mucositis.6 Despite this, the use of antimicrobial agents in the treatment of mucositis has not been shown to be consistently effective in controlling mucosal damage.
Systemic effects The evidence supporting the model of mucositis pathobiology has been derived from a wide variety of sources including clinical studies, animal trials, and in vitro models. The evidence indicates that the damage associated with mucositis is driven not just by effects on the basal cell layer of the epithelium but represents a multisystem process and additionally can be applied to not only oral mucosal damage but other mucosal sites such as the rest of the gastrointestinal tract. Mucosal damage can be seen in the upper aerodigestive tract, beyond the oral cavity extending along the gastrointestinal tract. The clinical signs and symptoms particularly in terms of timing of damage is related to the type of structure of the mucosa that is affecteddstratified squamous epithelium in the mouth, upper aerodigestive tract, and rectal mucosa compared with a thin single layer of epithelial cells in the small and large intestine. The processes leading to damage, however, are the same. A key factor in the pathobiology model of mucositis is the amplification of damage that generates regimen-induced inflammatory responses which have effects extending beyond the oral cavity.17
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Salivary gland hypofunction Changes in salivary gland function can be precipitated by a wide range of events including the effect of medications and physiological change. Changes in function of the salivary glands are reported in all types of cancer treatment; however, the effects are most profound in patients undergoing radiotherapy to the head and neck. A significant number of patients undergoing radiation treatment that involves the head and neck develop reduced salivary gland function.19,20 It is not only the quantity of saliva produced that is affected but also the quality which has impacts on the ability to maintain a stable oral environment. Good quality and quantity of saliva is important for maintaining mucosal integrity and tooth integrity (e.g., risk of caries and other forms of tooth structure loss). Adequate saliva is also important in helping to control infections within the oral cavitydparticularly opportunistic fungal infections (Fig. 16.6). Loss of salivary gland function therefore can exacerbate mucosal damage from mucositis and impact more broadly on functional aspects such as eating, swallowing, and speaking and contributing to loss of appetite, weight loss, and poor nutrition. Accordingly, changes in salivary gland function can result in a wide range of local and systemic effects that can affect quality of life both acutely during treatment and longer term. Inherent to the clinical effects of altered salivary gland function is the effect of treatment on the acinar cells within the salivary glands. These cells produce saliva which is then modified in its composition as it drains through the
Figure 16.6 Clinical appearance of oral candida infection superimposed on oral and pharyngeal mucositis.
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glands’ ductal systems. Minor salivary glands which are present throughout the oral mucosa are also affected. The exact effect of radiation on the acinar cells is unclear, unlike mucosal epithelial cells which are naturally susceptible to clonogenic death because of their high rate of division, acinar cells are not rapidly dividing. Despite this, various animal studies have shown that acinar cell death does occur in the salivary gland parenchyma either through necrosis or apoptosis.19 In addition, the acini show structural changes including cytoplasmic vacuolation which reflect metabolic changes with the cells and hypovascularization, fibrosis, and edema. It is this more chronic radiation damage that is attributed to the long-term chronic changes in function experienced by patients. But how does this occur? As in the context of mucositis, it is likely that salivary gland damage can be attributed to various molecular pathways stimulated by nonlethal radiationinduced DNA damage and also the production of ROS.21 Also similar to mucosal injury is the suggestion that proinflammatory cytokine production and amplification of these molecular pathways leads to further tissue damage. It has been suggested that salivary gland acinar cell apoptosis is mediated through a p53-dependent pathway as a result of p53-dependent cellular senescence triggered by radiation-induced DNA damage.19,22
Osteonecrosis of the jaws Another chronic toxicity of cancer treatment associated particularly with radiation to the head and neck is osteonecrosis of the jaws23e25 (Fig. 16.7). In the context of radiation treatment, this is referred to as osteoradionecrosis (ORN) and has been recognized as a complication of treatment for many years.23,26 ORN can cause significant decreases in quality of life as well as ongoing functional problems. More recently, the use of antiresorptive and antiangiogenic agent a part of cancer treatments has resulted in sporadic reports of osteonecrosis either as a result of the use of the agent alone or in combination with radiation.23
Osteoradionecrosis ORN is defined as ischemic necrosis of bone with associated soft tissue necrosis but not associated with the presence of tumor.23,26 It is more likely to occur as radiation doses increase and subsequent to trauma such as tooth extraction post radiotherapy. Histologically, ORN shows a range of changes including an initial hyperemic phase with actually increased activity of endothelial cells and an associated inflammatory response, followed by atypical fibroblastic activity and finally
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(A)
(B)
Figure 16.7 (A) Clinical photograph showing osteoradionecrosis involving the mandible following spontaneous breakdown of a skin graft to reconstruct the floor of mouth subsequent to radiation treatment. (B) Histologically, osteoradionecrosis shows a fragment of nonvital mature lamellar bone and adjacent bacteria and debris.
remodeling and loss of bone osteocytes.26 This pattern of histological change results in bone that is hypocellular and hypovascular and as a result hypoxic and unable to respond to remodeling and repair.23,27 In addition to this model, the concept of radiation-induced fibroatrophy (RIF) has been proposed as well as the role of dysregulation of bone turnover, depletion of osteoclasts (as per the hypocellular theory above), and role of local tissue injury and infection.23,28 RIF is interesting in that this process has similarities to that described in the pathobiology of mucositis, namely that endothelial cells may play a role in initial phases of tissue damage through stimulation of a nonspecific inflammatory response and for also suggesting that the effect of ROS produced by radiation may play a role in tissue damage.28 Like the mucositis pathobiology model, the effect of ROS in tissues may trigger cell death through either apoptotic pathways or necrosis clinically manifesting in the production of nonvital bone. Fortunately, improvements in techniques delivering more targeted radiation (for example, intensity-modulated radiotherapy) mean that the volumes of tissue exposed to radiation is less and the risk of toxicities such as ORN is reduced.10 Other factors such as basic oral care are also important in reducing these toxicities.
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Medication-related osteonecrosis Medication-related osteonecrosis is defined as persistent bone exposure lasting for a period of 8 weeks or more in patients who have had previous or current treatment with antiresorptive and or antiangiogenic agents with no history of radiotherapy to the jaws.25 The exact pathophysiology of bone necrosis is yet to be determined, although decreased bone turnover through osteoclast inhibition and inhibition of angiogenesis as well as the role of infection (especially with Actinomyces species) have all been discussed.23 These agents are used to control tumor-associated osteolysis and metastatic disease.29 Broadly, antiresorptive drugs include bisphosphonates, which are well described in the literature and inhibitors of receptor activator for NF-kB ligand (RANK-L) such as denosumab.24,25 Antiresorptive drugs exert their effects on osteoclasts inhibiting their function resulting in reduced bone resorption and remodeling.25 The inability of alveolar bone to respond to inflammation, trauma, and infection through impeded ability to remodel increases the risk of jaw bones to become necrotic24,30 as well as explaining why nonjaw bones are less affected.23 Antiangiogenic agents implicated in osteonecrosis of the jaws include bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor and the TKI, sunitinib25,29,31; other drugs have also been implicated in sporadic reports in the literature including mTOR inhibitors. As their name suggests, these antiangiogenic drugs affect the formation of new blood vessels25 either through directly targeting VEGF32 or through inhibiting downstream molecular pathways of VEGF.29 While inhibiting osteoclast function and inhibition of angiogenesis seem to be key factors in the pathogenesis of osteonecrosis of the jaws, other factors such as soft tissue toxicity, in terms of effects of these agents on epithelium, and impaired immune function have also been implicated.25,32
Conclusion Oral toxicities associated with different cancer treatment modalities are well recognized in terms of their effects on the patient’s quality of life during cancer treatment and also their impact on the ability of clinicians to provide optimal cancer treatment for patients. As more is understood about the complexities of all cancer treatment toxicities, not just those that occur in the mouth, it is becoming more evident that there are most likely similar mechanisms at play that influence toxicities in a variety of different tissues. The key issue underlying the development of toxicities in patients undergoing cancer treatment is that it is not only one factor that can be considered in the development of toxicities, the dynamic nature of the host, the
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changing microbiome, and the complex interactions between different pathways mean that a systems medicines approach is required to not only fully understand the mechanisms behind the toxicity but also to ensure effective cancer management.
References 1. Staudenmaier T, Cenzer I, Crispin A, Ostermann H, Berger K. Burden of oral mucositis in stem cell transplant patients-the patients’ perspective. Support Care Canc. 2018;26:1577e1584. 2. Villa A, Akintoye SO. Dental management of patients who have undergone oral cancer therapy. Dent Clin N Am. 2018;62:131e142. 3. Stringer AM, Logan RM. The role of oral flora in the development of chemotherapyinduced oral mucositis. J Oral Pathol Med. 2015;44:81e87. 4. Aprile G, Rihawi K, De Carlo E, Sonis ST. Treatment-related gastrointestinal toxicities and advanced colorectal or pancreatic cancer: a critical update. World J Gastroenterol. 2015;21:11793e11803. 5. Villa A, Sonis ST. Mucositis: pathobiology and management. Curr Opin Oncol. 2015;27:159e164. 6. Cinausero M, Aprile G, Ermacora P, et al. New frontiers in the pathobiology and treatment of cancer regimen-related mucosal injury. Front Pharmacol. 2017;8:354. 7. Coller JK, White IA, Logan RM, et al. Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer: a pilot study. Support Care Canc. 2015;23:1233e1236. 8. Aprile G, Ramoni M, Keefe D, Sonis S. Application of distance matrices to define associations between acute toxicities in colorectal cancer patients receiving chemotherapy. Cancer. 2008;112:284e292. 9. Board PSPCE. Oral complications of chemotherapy and head/neck radiation (PDQ). PDQ Cancer Information Summaries. 2016. 10. Strojan P, Hutcheson KA, Eisbruch A, et al. Treatment of late sequelae after radiotherapy for head and neck cancer. Cancer Treat Rev. 2017;59:79e92. 11. Sonis ST. The pathobiology of mucositis. Nat Rev Canc. 2004;4:277e284. 12. Sonis ST. Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol. 2007;5:3e11. 13. Gibson RJ, Cummins AG, Bowen JM, Logan RM, Healey T, Keefe DMK. Apoptosis occurs early in the basal layer of the oral mucosa following cancer chemotherapy. Asian Pac J Cancer Oncol. 2006;2:39e49. 14. Al-Azri AR, Gibson RJ, Bowen JM, Stringer AM, Keefe DM, Logan RM. Involvement of matrix metalloproteinases (MMP-3 and MMP-9) in the pathogenesis of irinotecaninduced oral mucositis. J Oral Pathol Med. 2015;44:459e467. 15. Elting LS, Cooksley C, Chambers M, Cantor SB, Manzullo E, Rubenstein EB. The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer. 2003;98:1531e1539. 16. Logan RM, Stringer AM, Bowen JM, Gibson RJ, Sonis ST, Keefe DM. Is the pathobiology of chemotherapy-induced alimentary tract mucositis influenced by the type of mucotoxic drug administered? Cancer Chemother Pharmacol. 2009;63:239e251. 17. Russi EG, Raber-Durlacher JE, Sonis ST. Local and systemic pathogenesis and consequences of regimen-induced inflammatory responses in patients with head and neck cancer receiving chemoradiation. Mediat Inflamm. 2014;2014:518261. 18. Lo Muzio L, Arena C, Troiano G, Villa A. Oral stomatitis and mTOR inhibitors: a review of current evidence in 20,915 patients. Oral Dis. 2018;24:144e171.
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19. Acauan MD, Figueiredo MA, Cherubini K, Gomes AP, Salum FG. Radiotherapy-induced salivary dysfunction: structural changes, pathogenetic mechanisms and therapies. Arch Oral Biol. 2015;60:1802e1810. 20. Mizrachi A, Cotrim AP, Katabi N, Mitchell JB, Verheij M, Haimovitz-Friedman A. Radiation-induced microvascular injury as a mechanism of salivary gland hypofunction and potential target for radioprotectors. Rad Res. 2016;186:189e195. 21. Choi JS, Shin HS, An HY, Kim YM, Lim JY. Radioprotective effects of Keratinocyte Growth Factor-1 against irradiation-induced salivary gland hypofunction. Oncotarget. 2017;8:13496e13508. 22. Avila JL, Grundmann O, Burd R, Limesand KH. Radiation-induced salivary gland dysfunction results from p53-dependent apoptosis. Int J Radiat Oncol Biol Phys. 2009;73:523e529. 23. Omolehinwa TT, Akintoye SO. Chemical and radiation associated jaw lesions. Dent Clin N Am. 2016;60:265e277. 24. Japanese Allied Committee on Osteonecrosis of the J, Yoneda T, Hagino H, et al. Antiresorptive agent-related osteonecrosis of the jaw: position paper 2017 of the Japanese allied committee on osteonecrosis of the jaw. J Bone Miner Metab. 2017;35:6e19. 25. Ruggiero SL, Dodson TB, Fantasia J, et al. American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jawd2014 update. J Oral Maxillofac Surg. 2014;72:1938e1956. 26. Sroussi HY, Epstein JB, Bensadoun RJ, et al. Common oral complications of head and neck cancer radiation therapy: mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease, and osteoradionecrosis. Cancer Med. 2017;6:2918e2931. 27. Marx RE. Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg. 1983;41:283e288. 28. Delanian S, Lefaix J-L. The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway. Radiother Oncol. 2004;73:119e131. 29. Lombard T, Neirinckx V, Rogister B, Gilon Y, Wislet S. Medication-related osteonecrosis of the jaw: new insights into molecular mechanisms and cellular therapeutic approaches. Stem Cell Int. 2016;2016:8768162. 30. Cheng A, Daly CG, Logan RM, Stein B, Goss AN. Alveolar bone and the bisphosphonates. Aust Dent J. 2009;54(Suppl 1):S51eS61. 31. Abel Mahedi Mohamed H, Nielsen CEN, Schiodt M. Medication related osteonecrosis of the jaws associated with targeted therapy as monotherapy and in combination with antiresorptives. A report of 7 cases from the Copenhagen Cohort. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125:157e163. 32. Aghaloo T, Hazboun R, Tetradis S. Pathophysiology of osteonecrosis of the jaws. Oral Maxillofac Surg Clin. 2015;27:489e496.
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Abstract The oral cavity is a unique environment; it includes a range of different tissue types that rely on maintenance of a constant environment or homeostasis. The health of the mucosa and teeth relies on maintenance of good salivary function and also integrity of the mucosa. Toxicities associated with cancer treatments presenting in the mouth do not occur in isolation from each other or other systemic toxicities. Oral toxicities broadly include mucosal damage (mucositis), changes in salivary gland function (most notably by causing reduced salivary flow), and also can affect the integrity of bone (osteonecrosis of the jaws). These effects can have additional outcomes which affect quality of life including loss of taste, difficulty swallowing, compromised nutrition, increased dental caries, and oral infections. For most patients, the most debilitating acute toxicity is oral mucositis, and this is the main focus of this chapter. Important chronic toxicities include long-term salivary hypofunction and osteonecrosis of the jaws.
Introduction Although improvements in cancer treatment have improved outcomes for many patients with a diagnosis of cancer, there continues to be a potentially wide range of bystander side effects or toxicities of treatment that manifest throughout the body. Those toxicities affecting the oral cavity are important for a variety of reasons, not the least of which is the significant impact that they have on the quality of life of patients during and after their treatment.1,2 Furthermore, the effect of these oral toxicities, as well as toxicities more generally, on the ability for clinicians to provide optimal cancer treatment is obviously also importantdpositive treatment outcomes can be compromised if toxicities cannot be prevented or adequately managed.2
Translational Systems Medicine and Oral Disease. https://doi.org/10.1016/B978-0-12-813762-8.00016-5 Copyright © 2020 Elsevier Inc. All rights reserved.
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The oral cavity is a unique environment in the body, in that it includes a range of different tissue types that rely on maintenance of a constant environment or homeostasis. More specifically, the health of the mucosa and teeth relies on maintenance of good salivary function and also integrity of the mucosa. For example, it is well known that a reduction in salivary flow can increase the risk of mucosal infections, increase the risk of trauma, and increase rates of dental caries. A breakdown in the integrity of the mucosa increases the risk of infections and in patients at risk, systemic infectionsdan important broad effect of cancer treatment is the effect that it has on the oral environment. Furthermore the environmental changes in the mouth, caused by the effect of cancer treatment, also impacts on the resident oral microflora. There is increasing interest in the role of the oral microbiome and its interplay with oral tissues and the impact that this interplay has on cancer treatment toxicity.3 Oral toxicities of cancer treatment are diverse (Fig. 16.1) and generally well described in the literaturedthis attests to the ease at which they can be identified by clinicians and also, as stated previously, the impact that they have on the quality of life of patients and the limitations they place on the ability to provide optimum cancer treatment. The ability to effectively eat, drink, talk, and sleep can be significantly affected by oral toxicities that involve the head and neck region, particularly within the oral cavity. Despite the easy clinical recognition of many of these toxicities, they are frequently underreported in the literature.4 Cancer treatment toxicities that occur in the oral cavity are dependent on a variety of factors, both treatment-related and patient-related.5
(A)
(B)
(C)
Other effects of oral toxicity: • Xerostomia • Difficulty Swallowing (Dysphagia) • Taste changes (Dysgeusia)
(D)
(E)
(F)
• Speech difficulties • Appetite loss • Weight loss
Figure 16.1 Range of oral adverse events resulting from cancer treatment. (A) Mucositis and candida infection; (B) dry mouth and candida infection; (C) and (D) dry mouth and radiation caries; (E) osteoradionecrosis; and (F) mucositis.
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These factors are key driving forces that influence the sort of problems that patients may experience. The patient-related factors, while potentially influencing the outcome of treatment (Table 16.1), are highly variable and have been reported to be somewhat unreliable in terms of predicting risk.6 More recently, genetic studies have highlighted a genetic risk for developing toxicities during treatment.7 Importantly, it has become increasingly evident over the years that toxicities presenting in the mouth do not occur in isolation from each other or other systemic toxicities.4,8 These include a wide range of conditions including, for example, anorexia, fatigue, and more general gastrointestinal symptoms. Oral toxicities broadly include mucosal damage (mucositis), changes in salivary gland function (most notably by causing reduced salivary flow), and also can affect the integrity of bone (osteonecrosis of the jaws). These effects can have additional outcomes which compound adverse effects on quality of life including loss of taste, difficulty swallowing, compromised nutrition, increased risk of dental caries, and oral infections. Toxicities can also be considered in terms of acute and chronic effects of treatment (Table 16.2).9,10 For most patients, by far, the most debilitating acute toxicity is oral mucositis and this is the main focus of this chapter. Important chronic toxicities include long-term salivary hypofunction and osteonecrosis of the jaws.
Table 16.1 Treatment- and patient-related risk factors influencing the development of cancer toxicities during cancer treatment. Treatment-related risk factors
Patient-related risk factors
Type of treatment Radiation type, dose, and field Chemotherapy agent
Genetics
Neutropenia
Nutritional status Oral health Salivary flow Preexisting oral disease and infections Age, gender Type of tumor
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Table 16.2 Acute and chronic oral toxicities associated with cancer treatment.9 Acute oral toxicities
Chronic oral toxicities
Mucositis
Mucosal atrophy or fibrosis
Infections (fungal or bacterial)
Reduced salivary gland function
Reduced salivary gland function
Osteonecrosis (þ/ soft tissue necrosis)
Taste loss or change
Dental caries Temporomandibular joint dysfunction Dysphagia Infections (fungal or bacterial)
Oral mucositis Mucositis is the mucosal damage that can occur as a result of chemotherapy, radiotherapy, and also with targeted chemotherapy treatments.6 The development of mucositis in patients undergoing chemotherapy or radiation to the head and neck often has a relatively predictable clinical course and presents as a spectrum of signs and symptoms ranging from mild mucosal erythema through to widespread mucosal ulceration (Fig. 16.2). This can cause significant pain and discomfort resulting in the inability to eat, swallow, or speak and in turn increases the risk of many other adverse effects including oral and systemic infections, weight loss, poor nutrition, and poor sleep patterns.
Figure 16.2 Spectrum of clinical presentation of oral mucositis, ranging from erythema through to widespread ulceration of the mucosa; the appearance of normal mucosa is seen on the far left.
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Historically, it was considered that cancer treatments in addition to targeting neoplastic cells with high replication rates also adversely affected healthy tissues with high cell turnoverdthis includes the basal cell layer within the oral mucosa epithelium. This simplistic historical view that cancer treatment attenuates the rapidly dividing basal cells causing epithelial atrophy and ulceration has been effectively discounted over the last 15 years or so.11,12 While it is acknowledged that this does occur, the degree of damage that is clinically seen in the mucosa cannot be accounted for by this simplistic explanation. Increasing evidence from both animal and human studies now provides a compelling case supporting a significantly more complex model of the pathobiology of mucositis (Fig. 16.3)11 involving both local and systemic effects. The pathobiology of mucositis can be considered in five overlapping phases involving a complex interplay that occurs between all components of the oral mucosadchanges occur not only to the epithelium but also the underlying components within the lamina propria including endothelial cells and
Figure 16.3 Pathobiology of mucositis.
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fibroblasts as well as effects on other cells including macrophages and platelets.12 In fact, effects on endothelial cells may be the first indication of tissue damage in the mucosa before there is any effect on the epithelium.12 This model better accounts for the degree of damage that occurs to the mucosa compared with that that could result from simple clonogenic cell death. The first of the phases is described as the initiation phase and is characterized by the initial direct damage that occurs to cells in different mucosal compartments. To some extent, this manifests as direct cell death, particularly of basal epithelial cells; however, the nonlethal DNA damage to various cell types and the production of reactive oxygen species (ROS) that also occurs following radiation exposure or through the effects of some chemotherapy agents also precipitates a cascade of events at the cellular level that potentiates the degree of damage that occurs accounting for the degree of damage to the mucosa that is observed clinically. The second and third phases described in the process, the upregulation and messenger generation and signal amplification phases, are characterized by the upregulation of various pathways resulting in the production of endogenous damage-associated pattern molecules including mitogen-activated protein kinase signaling, toll-like receptor (TLR) signaling, and importantly nuclear factor-kappa B (NF-kB) pathway.3 The role of NF-kB in mucositis is probably the most well described.6 Importantly, this pathway can be directly activated by the cancer treatments themselves, through DNA damage, or by the ROS that result from treatment.6 NF-kB is a transcription factor, that when upregulated can cause a wide range of outcomes including cellular apoptosis which is seen in the epithelium in the context of mucositis,13 and the upregulation of proinflammatory cytokines such as interleukin 1 beta (IL-1b), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Furthermore, TNF can also contribute to cellular apoptosis through activation of caspase pathways.6 Additionally, altered expression of matrix metalloproteinase expression the mucosa has also been shown to contribute to tissue damage through increased breakdown of the connective tissues.14 The upregulation of these pathways have positive feedback effects on NF-kB resulting in an amplification of molecular signaling within the tissues resulting in sufficient tissue damage to cause complete breakdown of the epithelial barrier of the mucosa. The breakdown of the epithelial barrier manifests clinically as ulceration and characterizes the fourth phase in the pathobiology of mucositis which is referred to appropriately as the ulcerative phase. It is at this point that mucositis is clinically evident and where the effects for patients and clinicians are most problematic. Patients are often well into their course of cancer treatment, they may be neutropenic and accordingly are at increased risk of
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infections. Colonization of oral ulcers by oral bacteria contributes to the mucosal damage by potentiating positive feedback pathways that upregulate NF-kB and cause further production of proinflammatory cytokines,3,6 which as described earlier potentiates the degree of tissue damage. Finally, with the cessation of treatment, the final phase is initiated and characterized by healing of tissues. This occurs through expression of various signals from the extracellular matrix; eventually reepithelialization of the mucosa occurs and for most patients function is restored. While clinically ulcers heal and, for most patients, pain resolves, at the cellular level there is persistent ultrastructural damage of mucosal cells13 as well as residual angiogenesis6 which means that the resilience of tissues to further damage is affecteddthis is evident in patients who undergo subsequent treatment such as further chemotherapy cycles where severity of mucositis is often increased.15
Differences between different treatment modalities Given the limited response that mucosa has to injury, the underlying pathobiology of mucositis is similar for different treatment modalities. Despite this, there are obvious differences between the clinical presentation of mucosal damage according to cancer treatments with respect to timing, degree of mucosal involvement, and also the clinical appearance of ulceration. The clinical presentation of chemotherapy-associated mucositis is largely dependent on the type of chemotherapy agent that is used. Some drugs such as antimetabolites (for example, 5-fluorouracil, methotrexate, and capecitabine), alkylating agents such as cyclophosphamide, and other specific drugs such as irinotecan, a topoisomerase 1 inhibitor, are well recognized as “mucotoxic” drugs.16 Chemotherapy-associated mucositis is also influenced by other physiological factors such as renal and hepatic function which can affect drug metabolism.6 The likelihood that a patient develops mucositis is also influenced somewhat by concurrent administration of radiotherapy or targeted treatments6 as well as, as mentioned previously in this chapter, whether the patient has had previous cycles of chemotherapy. Mucositis associated with radiotherapy, on the other hand, is generally a more localized effect of treatment, and oral mucositis is seen in almost all patients undergoing radiation to the head and neckdif the oral cavity is within the field of radiation (Fig. 16.4). Again, though the type of radiation will affect the degree of mucositis, the addition of concurrent chemotherapy increases risk.6 Interestingly, while the direct effects of radiation are well characterized, radiation to the head and neck has been reported to cause indirect effects to other parts of the gastrointestinal tract presenting as symptoms of abdominal bloating and pain.17
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Figure 16.4 A clinical photograph of a male patient undergoing radiotherapy for tongue squamous cell carcinoma. The tongue shows widespread ulceration typical of radiation-induced mucositisdthe well-demarcated skin erythema clearly illustrates the field of radiation that is used to treat the tumor (dotted line).
Targeted treatment agents including mammalian target of rapamycin (mTOR) inhibitors,18 tyrosine kinase inhibitors (TKIs), and antibodies have all been reported to cause mucosal injury often when prescribed in conjunction with conventional treatment such as radiation. Mucosal injury associated with mTOR inhibitors is well described presenting as aphthous-like ulcers (Fig. 16.5), which are generally less severe and often self-limiting lesions compared with that seen in conventional cancer treatments.18 The pathobiology of these lesions is unclear with respect to how they develop compared with conventional mucositis.
Figure 16.5 Clinical appearance of stomatitis associated with targeted cancer treatments.
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Interactions with the host microbiome As mentioned previously in this chapter, cancer treatments, as well as affecting different cells and tissues in the oral cavity, can cause changes in the oral microbiome through alterations in the local environment (as a result of loss of mucosal integrity and also reduced salivary flow, impaired oral hygiene, the presence of intraoral tumors, and surgery) and also as a result of systemic changes such as myelosuppression and poor nutrition.3 In the current model of mucositis pathobiology, it is suggested that the impact of oral microflora on the pathobiology of mucositis is through effects of bacteria extending into ulcerated mucosa.3 The dynamic nature of the oral environment corresponds to a changing microbial population in the mouth.3 It was highlighted in an earlier part of this chapter that various molecular pathways are upregulated through the production of endogenous damage-associated pattern molecules.6 TLR expression can be potentially initiated through interactions between bacteria and the mucosa.3 Stimulation of mucosal cells through bacterially initiated TLR signaling can potentially activate NF-kB and produce proinflammatory cytokines such as IL-1b, IL-6, and TNF which as described previously is involved in pathobiology of mucositis.6 Despite this, the use of antimicrobial agents in the treatment of mucositis has not been shown to be consistently effective in controlling mucosal damage.
Systemic effects The evidence supporting the model of mucositis pathobiology has been derived from a wide variety of sources including clinical studies, animal trials, and in vitro models. The evidence indicates that the damage associated with mucositis is driven not just by effects on the basal cell layer of the epithelium but represents a multisystem process and additionally can be applied to not only oral mucosal damage but other mucosal sites such as the rest of the gastrointestinal tract. Mucosal damage can be seen in the upper aerodigestive tract, beyond the oral cavity extending along the gastrointestinal tract. The clinical signs and symptoms particularly in terms of timing of damage is related to the type of structure of the mucosa that is affecteddstratified squamous epithelium in the mouth, upper aerodigestive tract, and rectal mucosa compared with a thin single layer of epithelial cells in the small and large intestine. The processes leading to damage, however, are the same. A key factor in the pathobiology model of mucositis is the amplification of damage that generates regimen-induced inflammatory responses which have effects extending beyond the oral cavity.17
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Salivary gland hypofunction Changes in salivary gland function can be precipitated by a wide range of events including the effect of medications and physiological change. Changes in function of the salivary glands are reported in all types of cancer treatment; however, the effects are most profound in patients undergoing radiotherapy to the head and neck. A significant number of patients undergoing radiation treatment that involves the head and neck develop reduced salivary gland function.19,20 It is not only the quantity of saliva produced that is affected but also the quality which has impacts on the ability to maintain a stable oral environment. Good quality and quantity of saliva is important for maintaining mucosal integrity and tooth integrity (e.g., risk of caries and other forms of tooth structure loss). Adequate saliva is also important in helping to control infections within the oral cavitydparticularly opportunistic fungal infections (Fig. 16.6). Loss of salivary gland function therefore can exacerbate mucosal damage from mucositis and impact more broadly on functional aspects such as eating, swallowing, and speaking and contributing to loss of appetite, weight loss, and poor nutrition. Accordingly, changes in salivary gland function can result in a wide range of local and systemic effects that can affect quality of life both acutely during treatment and longer term. Inherent to the clinical effects of altered salivary gland function is the effect of treatment on the acinar cells within the salivary glands. These cells produce saliva which is then modified in its composition as it drains through the
Figure 16.6 Clinical appearance of oral candida infection superimposed on oral and pharyngeal mucositis.
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glands’ ductal systems. Minor salivary glands which are present throughout the oral mucosa are also affected. The exact effect of radiation on the acinar cells is unclear, unlike mucosal epithelial cells which are naturally susceptible to clonogenic death because of their high rate of division, acinar cells are not rapidly dividing. Despite this, various animal studies have shown that acinar cell death does occur in the salivary gland parenchyma either through necrosis or apoptosis.19 In addition, the acini show structural changes including cytoplasmic vacuolation which reflect metabolic changes with the cells and hypovascularization, fibrosis, and edema. It is this more chronic radiation damage that is attributed to the long-term chronic changes in function experienced by patients. But how does this occur? As in the context of mucositis, it is likely that salivary gland damage can be attributed to various molecular pathways stimulated by nonlethal radiationinduced DNA damage and also the production of ROS.21 Also similar to mucosal injury is the suggestion that proinflammatory cytokine production and amplification of these molecular pathways leads to further tissue damage. It has been suggested that salivary gland acinar cell apoptosis is mediated through a p53-dependent pathway as a result of p53-dependent cellular senescence triggered by radiation-induced DNA damage.19,22
Osteonecrosis of the jaws Another chronic toxicity of cancer treatment associated particularly with radiation to the head and neck is osteonecrosis of the jaws23e25 (Fig. 16.7). In the context of radiation treatment, this is referred to as osteoradionecrosis (ORN) and has been recognized as a complication of treatment for many years.23,26 ORN can cause significant decreases in quality of life as well as ongoing functional problems. More recently, the use of antiresorptive and antiangiogenic agent a part of cancer treatments has resulted in sporadic reports of osteonecrosis either as a result of the use of the agent alone or in combination with radiation.23
Osteoradionecrosis ORN is defined as ischemic necrosis of bone with associated soft tissue necrosis but not associated with the presence of tumor.23,26 It is more likely to occur as radiation doses increase and subsequent to trauma such as tooth extraction post radiotherapy. Histologically, ORN shows a range of changes including an initial hyperemic phase with actually increased activity of endothelial cells and an associated inflammatory response, followed by atypical fibroblastic activity and finally
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(A)
(B)
Figure 16.7 (A) Clinical photograph showing osteoradionecrosis involving the mandible following spontaneous breakdown of a skin graft to reconstruct the floor of mouth subsequent to radiation treatment. (B) Histologically, osteoradionecrosis shows a fragment of nonvital mature lamellar bone and adjacent bacteria and debris.
remodeling and loss of bone osteocytes.26 This pattern of histological change results in bone that is hypocellular and hypovascular and as a result hypoxic and unable to respond to remodeling and repair.23,27 In addition to this model, the concept of radiation-induced fibroatrophy (RIF) has been proposed as well as the role of dysregulation of bone turnover, depletion of osteoclasts (as per the hypocellular theory above), and role of local tissue injury and infection.23,28 RIF is interesting in that this process has similarities to that described in the pathobiology of mucositis, namely that endothelial cells may play a role in initial phases of tissue damage through stimulation of a nonspecific inflammatory response and for also suggesting that the effect of ROS produced by radiation may play a role in tissue damage.28 Like the mucositis pathobiology model, the effect of ROS in tissues may trigger cell death through either apoptotic pathways or necrosis clinically manifesting in the production of nonvital bone. Fortunately, improvements in techniques delivering more targeted radiation (for example, intensity-modulated radiotherapy) mean that the volumes of tissue exposed to radiation is less and the risk of toxicities such as ORN is reduced.10 Other factors such as basic oral care are also important in reducing these toxicities.
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Medication-related osteonecrosis Medication-related osteonecrosis is defined as persistent bone exposure lasting for a period of 8 weeks or more in patients who have had previous or current treatment with antiresorptive and or antiangiogenic agents with no history of radiotherapy to the jaws.25 The exact pathophysiology of bone necrosis is yet to be determined, although decreased bone turnover through osteoclast inhibition and inhibition of angiogenesis as well as the role of infection (especially with Actinomyces species) have all been discussed.23 These agents are used to control tumor-associated osteolysis and metastatic disease.29 Broadly, antiresorptive drugs include bisphosphonates, which are well described in the literature and inhibitors of receptor activator for NF-kB ligand (RANK-L) such as denosumab.24,25 Antiresorptive drugs exert their effects on osteoclasts inhibiting their function resulting in reduced bone resorption and remodeling.25 The inability of alveolar bone to respond to inflammation, trauma, and infection through impeded ability to remodel increases the risk of jaw bones to become necrotic24,30 as well as explaining why nonjaw bones are less affected.23 Antiangiogenic agents implicated in osteonecrosis of the jaws include bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor and the TKI, sunitinib25,29,31; other drugs have also been implicated in sporadic reports in the literature including mTOR inhibitors. As their name suggests, these antiangiogenic drugs affect the formation of new blood vessels25 either through directly targeting VEGF32 or through inhibiting downstream molecular pathways of VEGF.29 While inhibiting osteoclast function and inhibition of angiogenesis seem to be key factors in the pathogenesis of osteonecrosis of the jaws, other factors such as soft tissue toxicity, in terms of effects of these agents on epithelium, and impaired immune function have also been implicated.25,32
Conclusion Oral toxicities associated with different cancer treatment modalities are well recognized in terms of their effects on the patient’s quality of life during cancer treatment and also their impact on the ability of clinicians to provide optimal cancer treatment for patients. As more is understood about the complexities of all cancer treatment toxicities, not just those that occur in the mouth, it is becoming more evident that there are most likely similar mechanisms at play that influence toxicities in a variety of different tissues. The key issue underlying the development of toxicities in patients undergoing cancer treatment is that it is not only one factor that can be considered in the development of toxicities, the dynamic nature of the host, the
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changing microbiome, and the complex interactions between different pathways mean that a systems medicines approach is required to not only fully understand the mechanisms behind the toxicity but also to ensure effective cancer management.
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19. Acauan MD, Figueiredo MA, Cherubini K, Gomes AP, Salum FG. Radiotherapy-induced salivary dysfunction: structural changes, pathogenetic mechanisms and therapies. Arch Oral Biol. 2015;60:1802e1810. 20. Mizrachi A, Cotrim AP, Katabi N, Mitchell JB, Verheij M, Haimovitz-Friedman A. Radiation-induced microvascular injury as a mechanism of salivary gland hypofunction and potential target for radioprotectors. Rad Res. 2016;186:189e195. 21. Choi JS, Shin HS, An HY, Kim YM, Lim JY. Radioprotective effects of Keratinocyte Growth Factor-1 against irradiation-induced salivary gland hypofunction. Oncotarget. 2017;8:13496e13508. 22. Avila JL, Grundmann O, Burd R, Limesand KH. Radiation-induced salivary gland dysfunction results from p53-dependent apoptosis. Int J Radiat Oncol Biol Phys. 2009;73:523e529. 23. Omolehinwa TT, Akintoye SO. Chemical and radiation associated jaw lesions. Dent Clin N Am. 2016;60:265e277. 24. Japanese Allied Committee on Osteonecrosis of the J, Yoneda T, Hagino H, et al. Antiresorptive agent-related osteonecrosis of the jaw: position paper 2017 of the Japanese allied committee on osteonecrosis of the jaw. J Bone Miner Metab. 2017;35:6e19. 25. Ruggiero SL, Dodson TB, Fantasia J, et al. American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jawd2014 update. J Oral Maxillofac Surg. 2014;72:1938e1956. 26. Sroussi HY, Epstein JB, Bensadoun RJ, et al. Common oral complications of head and neck cancer radiation therapy: mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease, and osteoradionecrosis. Cancer Med. 2017;6:2918e2931. 27. Marx RE. Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg. 1983;41:283e288. 28. Delanian S, Lefaix J-L. The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway. Radiother Oncol. 2004;73:119e131. 29. Lombard T, Neirinckx V, Rogister B, Gilon Y, Wislet S. Medication-related osteonecrosis of the jaw: new insights into molecular mechanisms and cellular therapeutic approaches. Stem Cell Int. 2016;2016:8768162. 30. Cheng A, Daly CG, Logan RM, Stein B, Goss AN. Alveolar bone and the bisphosphonates. Aust Dent J. 2009;54(Suppl 1):S51eS61. 31. Abel Mahedi Mohamed H, Nielsen CEN, Schiodt M. Medication related osteonecrosis of the jaws associated with targeted therapy as monotherapy and in combination with antiresorptives. A report of 7 cases from the Copenhagen Cohort. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125:157e163. 32. Aghaloo T, Hazboun R, Tetradis S. Pathophysiology of osteonecrosis of the jaws. Oral Maxillofac Surg Clin. 2015;27:489e496.
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