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Mucositis: The impact, biology and therapeutic opportunities of oral mucositis
Oral Oncology 45 (2009) 1015–1020
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Review
Mucositis: The impact, biology and therapeutic opportunities of oral mucositis Stephen T. Sonis * Harvard-Farber Cancer Center, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA
a r t i c l e
i n f o
Article history: Received 7 August 2009 Received in revised form 25 August 2009 Accepted 25 August 2009 Available online 13 October 2009 Keywords: Mucositis Review Toxicity Radiation Chemotherapy
s u m m a r y The history of mucositis is as old as radiation- and chemotherapy. Despite being regularly reported and documented as one of the worst side effects of cancer therapy, relatively little was appreciated about the complexities of mucositis’ pathogenesis until relatively recently. More frustrating for patients and clinicians, no effective treatment existed. Fortunately, the situation is changing; ongoing research is leading to a comprehensive understanding of the biology of mucositis, which has resulted in the development of novel interventions. While the FDA’s approval of palifermin in 2004 was limited to only a small percentage of the at-risk population, the fact that the first registered anti-OM agent derived its efficacy from its pleotropic activities was conceptually demonstrative of the therapeutic potential of drugs that selectively interfere with mucositis’ pathogenesis. A number of eclectic molecules, all designed to interfere with pathways that lead to injury are in pre-clinical and clinical development. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Mucosal injury remains an undesirable, painful, and expensive side effect of cytotoxic cancer therapy,1 and is disheartening for patients and frustrating for caregivers. Despite a surge in research efforts to better understand its pathogenesis and discover effective interventions, oral mucositis (OM) is an unmet need with a high priority for the development of an effective treatment. Currently, palifermin (Kepivance) is the only approved intervention for OM and its use is limited to a very small cohort (4%) of the at-risk population.2 In essence, the management of mucositis has not changed for years.3 Accumulating evidence documents the toll that OM plays on patients’ quality of life3 and its impact on medical resource use and its economic consequences. Amomg patients being treated for cancers of the lung and head and neck OM’s incremental perpatient cost exceeded $17000 (USD).5 Increased inpatient hospitalization was the most significant driver of mucositis-associated costs. OM resulted in patients having more tests and procedures, clinic visits, and medications. Similar outcomes were reported in patients receiving hematopoetic stem cell transplants.6 The incidence of OM is widely underreported by clinicians compared to what patients actually experience. For example, while incidence of oncologist-reported OM is about 15% among patients receiving FOLFOX regimens for colorectal cancers, over 70% of patients being treated with the same regimen reported significant mouth or throat soreness.7
* Tel.: +1 617 732 6570; fax: +1 617 232 8970. E-mail address: [email protected]. 1368-8375/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2009.08.006
Fortunately, there is wide industry and academic interest in developing interventions for OM. A range of compounds are in various stages of pre-clinical and clinical development.8 Simultaneously though, new classes of anti-cancer agents such as mTORinhibitors, receptor modifiers and anti-angiogenic factors are being introduced and with them comes additional OM risk and new types of mucosal injury. For example, OM has been reported in 31% of patients treated with temsirolimus,9 and OM is accelerated in patients receiving erlotinib in combination with gemcitabine.10 The pathobiology of mucositis The realization that mucositis was the consequence of a complex sequence of biological events rather than solely the result of direct clonogenic cell death was a critical step in advancing the science underlying the pathobiology of regimen-related mucosal injury.11,12 This concept contradicted longstanding dogma that stated that mucositis resulted simply from the indiscriminate destruction of rapidly dividing basal epithelial stem cells by radiation- or chemotherapy. The implications of this hypothesis have significant conceptual ramifications on the design of approaches to prevent8,13 or treat mucositis. The idea that OM might be prevented through indirect modulation of radiation- or chemotherapy-initiated pathways created opportunities for the development of mechanism-based interventions. The pathobiologic progression of mucositis has been described in five stages (Fig. 1).14 While no complex physiologic process can be compartmentalized, this stepwise approach provides a conduit to understanding the events that underlie the sequence of OM. Two events characterize the initiation phase. Radiation and chemotherapy directly injure DNA and cause strand breaks resulting
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Figure 1 The pathobiology of mucositis as a five stage process. The key biological processes associated with the pathogenesis of oral mucositis can be arbitrarily divided into five stages: initiation, the primary damage response (messaging and signaling), amplification, ulceration, and healing. Reprinted with permission (J Support Oncol 2007;5(Suppl. 4):3–11).
in clonogenic death of basal epithelial cells. Even more significant from the standpoint of ultimate tissue damage, is the generation of reactive oxygen species (ROS). During the primary damage response phase chemotherapy, radiation, and ROS initiate a series of interacting biological events. Transduction pathways triggered by DNA strand breaks and lipid peroxidation prompt the activation of a number of transcription factors, such as NF-jB, Wnt, p53, and their associated canonical pathways.15 The NF-jB pathway is among one of the most studied relative to mucositis and illustrates the robustness of the biology driving OM.16–18 Chemotherapy and radiation can directly activate NF-jB. Indirectly, it can be activated by ROS. Among the 200 genes whose expression is governed by NF-jB are those associated with the production of molecules which have demonstrated activity in the pathogenesis of mucositis including cytokines and cytokine modulators, stress responders (i.e. COX-2, inducible NO-synthase, superoxide dismutase), and cell adhesion molecules. Importantly, apoptosis is an important consequence of the effects of NF-jB in normal cells. Radiation and chemotherapy also impact other pathways that lead to indirect cell death such as the ceramide pathway.19 As cytotoxic therapy percolates into connective tissue, fibrinolysis occurs which stimulates macrophages to produce damaging matrix metalloproteinases.20 All of the above processes begin within seconds of radiation or chemotherapy administration. While havoc reigns within the sub-
mucosa and both direct and indirect destruction of epithelial stem cells start almost immediately, there is a lag between the damage that is occurring at the molecular and cellular level and its clinical manifestations. In the case of fractionated radiation, the precipitating events that lead to extensive mucositis occur in daily increments. Like a rolling snowball, the accumulation of biological changes induced by radiation results in a biological avalanche that culminates in the obliteration of intact mucosa. Signal amplification: Many of the molecules induced by the primary response have the ability to positively or negatively feedback and alter the local tissue response. For example, TNF may positively feedback on NF-jB to amplify its response, and initiates mitogen-activated protein kinase (MAPK) signaling. None of these mechanisms occur in isolation. Rather, many occur simultaneously and through a series of networks in which some genes are more controlling and critical than others. Analyses of these networks15 have demonstrated a scheme that resembles airline flight maps in which there are busy hubs (like Chicago, London, and Singapore) and nodes (like Bismark, Oslo, and Penang). When gene hubs have many links they may be overwhelmed with feedback signals, and behave in much the same way as does Chicago in a snowstorm, London in bad fog, or Singapore in a typhoon – nothing gets in or out. This stalemate inhibits intermittent resolution and leads to the progression of ulceration. For the patient, clinician, insurance company, and drug company, ulceration is the major event associated with mucositis.
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Prevent ulceration and one can minimize pain, risk of infection, use of feeding tubes, and length of hospital stays. Ulceration develops as a consequence of the direct and indirect mechanisms noted above causing damage and apoptotic changes to mucosal epithelium. Mucositis ulcers are deep and quickly colonized by oral bacteria. In animal models, the number of mucosal bacteria goes up over three-hundred fold in the transition between intact and ulcerated epithelium.21 The bacteria on the ulcer surface are active contributors to the mucositis process. Cell wall products (i.e. lipopolysaccharides, lipoteichoic acid, cell wall antigens, and a-glucans) penetrate into the submucosa, now rich in macrophages, to stimulate those cells to further secrete pro-inflammatory cytokines. In granulocytopenic patients, there is a risk that intact bacteria may invade submucosal vessels to produce bacteremia or sepsis. The majority of cases of OM heal spontaneously. Ulcer resolution is the result of an active biological process in which signaling from the submucosa’s extracellular matrix (ECM) guides the proliferation, migration and differentiation of the epithelium bordering the ulcer. The mechanisms by which the ECM impacts would healing have been and are being extensively studied. It appears that its ability to interact with and activate intrinsic tyrosine kinase activity is important.22 Furthermore, the ECM’s ability to modulate receptors and the expression, organization and activation of intracellular proteins has been shown of functional relevance.23 Disruption of the submucosal ECM is the likely initiator of cases in which healing is delayed or, in rare instances, does not occur at all. For patients being treated with chemotherapy, mucositis is generally an acute event. Symptoms first begin about 3–5 days after drug infusion, ulceration is noted a couple of days later, and resolves within 2 weeks. In contrast, radiation-induced mucositis has a chronic course as patients are treated with incremental doses of radiation over a 7 week period (2 Gy per day to 70 Gy). By 30 Gy, ulceration, often coalescing and covered by a pseudomembrane, is present. Ulcerations last for up to three or four weeks following the completion of treatment.
Risk factors Of new cancer patients, approximately 8% will be at high risk (a greater than 50% chance) of developing ulcerative mucositis. Conversely, 43% (over 500,000) will be at little or no risk for the condition. These patients will be treated with curative surgery, peripheral radiation, or low-dose chemotherapy. The majority of new cancer patients fall into an intermediate category of mucositis risk in which somewhere between 20% and 49% will develop ulcerative mucositis at some time during their treatment. Patients in the high risk group fall into the head and neck cancer population and those individuals being treated with high dose, myeloablative chemotherapy. While the incidence of mucositis is high in this group, it is by no means universal. For patients at ‘some risk’, risk disparity is even more profound. This group is composed of individuals being treated for the most common solid tumors (breast, colon, rectum, and lung). Each cycle of therapy incurs mucositis risk. For patients who develop mucositis in one cycle, the risk of mucositis increases with subsequent cycles. For example, the likelihood that a patient being treated with a conventional regimen for breast cancer will develop ulcerative OM is about 20% during the first cycle of chemotherapy, but jumps to >60% in the second cycle. Historically, mucositis risk has been placed into two buckets, one associated with therapy and the other with the patient.24 Treatment-related variables include those associated with the type of therapy, dose, and route of administration. To a large extent
treatment type and dose can be overwhelming risk factors. Thus for a patient with a tongue cancer who is receiving chemoradiation, the likelihood of mucositis is close to 100%. On the other hand, a patient with a hypopharyngeal cancer, also receiving chemoradiation may see the risk drop to 50% because the tissues of the oral cavity are not primarily included in the radiation field. Patients receiving conditioning regimens in preparation for HSCT have been considered to be at high risk of mucositis. This was true of many regimens, especially those which included total body irradiation and/or high doses of stomatotoxic drugs. In an attempt to ameliorate risk, transplanters have adopted less toxic protocols. Since only 19% of the total annual OM cases occur in the head and neck cancer and HSCT populations, it is clear that other factors are critical is determining risk. Age, body mass, and gender have been identified as possible patient-associated risk factors.24 For the most part these are poorly defined, although data supports that being female confers increased toxicity risk for 5-fluorouracil and methotrexate.25 Preexisting conditions may impact mucositis risk. In a study of patients receiving induction therapy for leukemia, OM risk was compared among individuals who had pre-cancer diagnoses of psoriasis and Addison’s disease.26 The authors hypothesized that the inherent effect of psoriasis on epithelial proliferation could attenuate the probability of mucosal injury. Conversely, they believed that patients with Addison’s disease might be predisposed to OM because of high pre-existing pro-inflammatory cytokine levels. The study results of the study (Table 1) supported the supposition and indicate the potential importance of the patient’s underlying (non-cancer) condition on OM risk. Genetic factors may play a dominant role in determining mucositis risk. The most extensively studied genetic determinants of mucositis risk are of genes associated with chemotherapy metabolism. Schwab et al. assessed the predictive value of three polymorphisms associated with the metabolism of fluorouracil for toxicity risk.27 They found a significant association between dihydropyrimidine dehydrogenase (DPYD) variants and the development of OM, although the sensitivity of DPYD for mucositis was low (7.7%). Other investigators have demonstrated similar findings. While these studies offer proof of concept that toxicity risk is to a large extent genetically controlled, enzymatic deficiencies are relatively rare. Rather, it seems more likely that differences in the expression of genes associated with OM pathogenesis are more likely to impact risk. TNF-a appears to play a role in OM development and a number of polymorphisms control individuals’ TNF-a production. BoguniaKubik et al.28 evaluated the role of the expression of TNFA*1,2 on toxicity risk, including mucositis, among patients undergoing allogeneic HSCT and found that its presence resulted in an odds ratio for toxicity that was more than twice that attributable to the use of aggressive conditioning regimens (Table 2). Their findings are illustrative of the potential application of mechanism-related genes as the basis for risk prediction. Another example of mechanistic gene-based risk is provided by studies of radiation-induced dermatitis, a condition with a pathogenesis that is similar to mucositis. ROS play an important role during the initiation phase. Consequently, Ambrosone et al.29
Table 1
Controls Psoriasis Addison’s disease
60 64 44
No. of patients with oral mucositis
% of patients with oral mucositis
Chi square (v2)
P-value
16 4 14
26.6 6.2 32.0
– 56.9 20.4
– 0.0001 0.001
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Table 2 Risk factors for severe toxicities in allogeneic HSCT. From Bogunia-Kubik et al.28 Donor-recipient gender relation (F ? M) Recipient age (>25 years) Aggressive conditioning regimen TNFA*1,2
OR OR OR OR
4.2 2.1 7.0 17.1
reasoned that differences in polyphormisms that encode for glutathione S-transferase, an enzyme that provides protection from ROS, could impact the extent of radiation-induced dermatitis. Amongst a total of close to 500 patients, they found that low activity of the GSTP genotype was associated with more than two-fold risk for acute skin toxicity. The tumor itself is biologically active and might contribute to OM risk. Both tumor parenchyma and stroma are sources of molecules which influence cell behavior.30 Tumor-derived peptides and protein products could directly modify normal cell response to radiation or chemotherapy,31,32 while others, such as matrix mellatoproteinases enhance the breakdown of the local tissue environment. The interaction of tumors with the host, how the tumor contributes to toxicity risk, and how products associated with tumor cell death during treatment impact the patient are areas ripe for investigation. The oral environment and mucositis The oral cavity is one of the most complex environments in the body. The mucosa is bathed in saliva containing a wide microbiota comprised of bacteria, fungi and viruses. Many studies have evaluated the role of saliva and microorganisms in the development and course of mucositis. Overwhelmingly, these investigations have concluded that while the course of mucositis might be influenced by the local environment, neither changes in saliva or the microflora are significant in the primary etiology of OM. Using DNA–DNA hybridization and quantitative culture techniques, Uzel et al. studied the quantitative and qualitative changes of the oral bacterial flora in an established hamster model of radiation-induced mucositis.21 Importantly, hamsters’ oral bacterial flora that is remarkably similar in composition to that of humans. Peak bacterial loads coincided with peak mucositis scores, but an increase in bacterial numbers lagged behind the development of
500
3.5 3
400
2.5
350 300
2
250 200
1.5
150
1
100
0.5
50 0
AVERAGE MUCOSITS SCORE
MEAN TOTAL BACTERIAL COUNT (10^5)
450
0
7
14 DAY
21
28
0
Figure 2 The relationship between mucositis severity and bacterial colonization. The relationship between quantitative increases in bacteria and the course of mucositis was studied in a hamster model in which an acute dose of radiation was given on day 0. Bacterial sampling and clinical mucositis scoring was performed at weekly intervals. Mucositis development (a score of three indicates ulcerative OM) preceded increases in bacterial numbers suggesting that, at least quantitatively, bacteria do not drive the development of mucosal ulceration. Bacterial colonization of ulcerative lesions is suggested by the synchronous peak of mean bacterial count and mucositis score on day 21.
ulcerative mucositis (Fig. 2). This finding contradicts a hypothesis that would suggest that increases in bacterial numbers drive OM, while the observation that the mean bacterial load increased by over 300% compared to baseline suggested that ulcerated mucosa represented a desirable colonization site. Bacterial numbers decreased as ulcers spontaneously resolved indicating that the presence of large numbers of organisms was not enough to inhibit healing. Consistent with early studies33 increases in gram negative organisms were seen during ulceration, and reestablishment of normal bacterial proportions was a requirement for spontaneous ulcer resolution, irrespective of bacterial numbers. Clinical trial results suggest that anti-bacterial strategies have been ineffective as OM interventions.34 Approaches directed at stimulating salivary flow as OM treatments have largely failed. Pilocarpine was ineffective in modifying the incidence or course of mucositis when studied in both head and neck cancer35 and HSCT36 populations. Roles for fungi (candida) and viruses (herpes simplex 1) in the etiology of mucositis have been the subject of speculation for some time and remain marginally controversial. Candidiasis is a common finding among patients receiving head and neck radiation or myeloablative chemotherapy so it is not unexpected that these organisms can be identified in patients with mucositis as a coincident condition, rather than causal. Anti-fungals as mucositis interventions have not been effective, a finding that is not surprising given the large number of patients who develop mucositis even when they receive routine anti-fungal prophylaxis.37 Speculation that HSV-1 might be associated with the development of mucositis has been mentioned in the literature since at least the 1980s.38 Subsequently, data have emerged which rebut HSV as a primary driver of mucositis. Woo et al.39 showed that OM development was unrelated to HSV antibody status or positive viral cultures, and acyclovir prophylaxis was ineffective in preventing OM. Likewise, while radiation and chemotherapy are successful activators of latent virus in seropositive patients, Djuric et al. noted that the rate of HSV-1 reactivation was no different before or after chemotherapy.40 They also found that there was no relationship between in the rate of viral reactivation and the presence or absence of OM.
Summary and therapeutic opportunities OM falls within the bailiwick of the toxicities associated with cytotoxic cancer therapy. Descriptive and mechanistic research conducted over the past decade have resulted in a series of essential changes about how these undesirable side effects are viewed. First and critical has been the demonstration that toxicities are not simply the by-product of non-specific cell death, but rather represent the clinical manifestation of a culmination of a complex series of interactive biological events. Second, it is becoming increasingly clear that specific toxicities do not occur in isolation – patients who develop OM are likely to simultaneously manifest diarrhea, fatigue, cutaneous lesions or other adverse events. The finding of toxicity clusters is still being defined, but what unites elements of toxicity clusters is their common underlying pathobiology. Third, toxicity risk is multifactorial, predictable, quantifiable and largely genetically determined. Our ability to develop effective risk prediction will be an important step in the development of customized patient interventions. Forth, normal cells and tumor cells do not respond in the same way to cytotoxic therapy, therefore pharmacologic toxicity prevention at the mechanistic level is a realistic goal without jeopardizing tumor response to treatment. Finding an effective mucositis pharmacologic or biologic intervention has not been easy. There have been a number of false starts and disappointments. While some of these negative results can be
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attributed to a compound’s lack of sufficient activity, it also seems that others are the consequence of poor study design or execution. The 2004 approval of palifermin as a first in class agent for mucositis is important, therefore for a number of reasons. First, it is likely that palifermin’s OM efficacy is a manifestation of its robust biological activity.41 Second, the enabling study’s primary endpoint was clinically meaningful, able to be achieved with minimal intersite variability, and frames important trial design elements for new agents. And third, the impact of successful amelioration of clinically scored OM on patient-reported and overall health outcomes was demonstrated.2 A review of ClinicalTrials.gov illustrates the scope of molecules with potential mucositis efficacy currently under investigation. The breadth of activity of these compounds is indicative of the multiple interventional targets provided by OM’s biology. Examples include zinc, an essential trace element, which induces metallothionein to sequester oxygen free radicals,42 GM–CSF, granulocyte-macrophage colony-stimulating factor an immunomodulator with other biological activities,43 SCV-07, a immunostimulating synthetic peptide which mediates its effect through Th1 helper cells,44 ATL-104, a plant-derived mitogen,45 and TRAUMEEL S a homeopathic plant and mineral derived preparation.46 This sampling is illustrative of the diversity of interventional approaches and does not include many other agents in earlier stages of development.8 We are at a time when all of the components necessary to produce effective OM agents seem to be finally coming together: molecules and compounds with sufficient targeted activity are becoming increasingly available, formulations that provide local pharmacologic levels of drug have been developed, studies are becoming more sophisticated in design and disciplined in their execution, and importantly, the clinical need and commercial value for an effective product has stimulated the pharmaceutical industry to take interest.
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Conflict of interest statement 28.
Dr. Sonis received a research grant from Amgen, Inc. and is a partner in Biomodels, LLC. 29.
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Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Review
Mucositis: The impact, biology and therapeutic opportunities of oral mucositis Stephen T. Sonis * Harvard-Farber Cancer Center, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA
a r t i c l e
i n f o
Article history: Received 7 August 2009 Received in revised form 25 August 2009 Accepted 25 August 2009 Available online 13 October 2009 Keywords: Mucositis Review Toxicity Radiation Chemotherapy
s u m m a r y The history of mucositis is as old as radiation- and chemotherapy. Despite being regularly reported and documented as one of the worst side effects of cancer therapy, relatively little was appreciated about the complexities of mucositis’ pathogenesis until relatively recently. More frustrating for patients and clinicians, no effective treatment existed. Fortunately, the situation is changing; ongoing research is leading to a comprehensive understanding of the biology of mucositis, which has resulted in the development of novel interventions. While the FDA’s approval of palifermin in 2004 was limited to only a small percentage of the at-risk population, the fact that the first registered anti-OM agent derived its efficacy from its pleotropic activities was conceptually demonstrative of the therapeutic potential of drugs that selectively interfere with mucositis’ pathogenesis. A number of eclectic molecules, all designed to interfere with pathways that lead to injury are in pre-clinical and clinical development. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Mucosal injury remains an undesirable, painful, and expensive side effect of cytotoxic cancer therapy,1 and is disheartening for patients and frustrating for caregivers. Despite a surge in research efforts to better understand its pathogenesis and discover effective interventions, oral mucositis (OM) is an unmet need with a high priority for the development of an effective treatment. Currently, palifermin (Kepivance) is the only approved intervention for OM and its use is limited to a very small cohort (4%) of the at-risk population.2 In essence, the management of mucositis has not changed for years.3 Accumulating evidence documents the toll that OM plays on patients’ quality of life3 and its impact on medical resource use and its economic consequences. Amomg patients being treated for cancers of the lung and head and neck OM’s incremental perpatient cost exceeded $17000 (USD).5 Increased inpatient hospitalization was the most significant driver of mucositis-associated costs. OM resulted in patients having more tests and procedures, clinic visits, and medications. Similar outcomes were reported in patients receiving hematopoetic stem cell transplants.6 The incidence of OM is widely underreported by clinicians compared to what patients actually experience. For example, while incidence of oncologist-reported OM is about 15% among patients receiving FOLFOX regimens for colorectal cancers, over 70% of patients being treated with the same regimen reported significant mouth or throat soreness.7
* Tel.: +1 617 732 6570; fax: +1 617 232 8970. E-mail address: [email protected]. 1368-8375/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2009.08.006
Fortunately, there is wide industry and academic interest in developing interventions for OM. A range of compounds are in various stages of pre-clinical and clinical development.8 Simultaneously though, new classes of anti-cancer agents such as mTORinhibitors, receptor modifiers and anti-angiogenic factors are being introduced and with them comes additional OM risk and new types of mucosal injury. For example, OM has been reported in 31% of patients treated with temsirolimus,9 and OM is accelerated in patients receiving erlotinib in combination with gemcitabine.10 The pathobiology of mucositis The realization that mucositis was the consequence of a complex sequence of biological events rather than solely the result of direct clonogenic cell death was a critical step in advancing the science underlying the pathobiology of regimen-related mucosal injury.11,12 This concept contradicted longstanding dogma that stated that mucositis resulted simply from the indiscriminate destruction of rapidly dividing basal epithelial stem cells by radiation- or chemotherapy. The implications of this hypothesis have significant conceptual ramifications on the design of approaches to prevent8,13 or treat mucositis. The idea that OM might be prevented through indirect modulation of radiation- or chemotherapy-initiated pathways created opportunities for the development of mechanism-based interventions. The pathobiologic progression of mucositis has been described in five stages (Fig. 1).14 While no complex physiologic process can be compartmentalized, this stepwise approach provides a conduit to understanding the events that underlie the sequence of OM. Two events characterize the initiation phase. Radiation and chemotherapy directly injure DNA and cause strand breaks resulting
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Figure 1 The pathobiology of mucositis as a five stage process. The key biological processes associated with the pathogenesis of oral mucositis can be arbitrarily divided into five stages: initiation, the primary damage response (messaging and signaling), amplification, ulceration, and healing. Reprinted with permission (J Support Oncol 2007;5(Suppl. 4):3–11).
in clonogenic death of basal epithelial cells. Even more significant from the standpoint of ultimate tissue damage, is the generation of reactive oxygen species (ROS). During the primary damage response phase chemotherapy, radiation, and ROS initiate a series of interacting biological events. Transduction pathways triggered by DNA strand breaks and lipid peroxidation prompt the activation of a number of transcription factors, such as NF-jB, Wnt, p53, and their associated canonical pathways.15 The NF-jB pathway is among one of the most studied relative to mucositis and illustrates the robustness of the biology driving OM.16–18 Chemotherapy and radiation can directly activate NF-jB. Indirectly, it can be activated by ROS. Among the 200 genes whose expression is governed by NF-jB are those associated with the production of molecules which have demonstrated activity in the pathogenesis of mucositis including cytokines and cytokine modulators, stress responders (i.e. COX-2, inducible NO-synthase, superoxide dismutase), and cell adhesion molecules. Importantly, apoptosis is an important consequence of the effects of NF-jB in normal cells. Radiation and chemotherapy also impact other pathways that lead to indirect cell death such as the ceramide pathway.19 As cytotoxic therapy percolates into connective tissue, fibrinolysis occurs which stimulates macrophages to produce damaging matrix metalloproteinases.20 All of the above processes begin within seconds of radiation or chemotherapy administration. While havoc reigns within the sub-
mucosa and both direct and indirect destruction of epithelial stem cells start almost immediately, there is a lag between the damage that is occurring at the molecular and cellular level and its clinical manifestations. In the case of fractionated radiation, the precipitating events that lead to extensive mucositis occur in daily increments. Like a rolling snowball, the accumulation of biological changes induced by radiation results in a biological avalanche that culminates in the obliteration of intact mucosa. Signal amplification: Many of the molecules induced by the primary response have the ability to positively or negatively feedback and alter the local tissue response. For example, TNF may positively feedback on NF-jB to amplify its response, and initiates mitogen-activated protein kinase (MAPK) signaling. None of these mechanisms occur in isolation. Rather, many occur simultaneously and through a series of networks in which some genes are more controlling and critical than others. Analyses of these networks15 have demonstrated a scheme that resembles airline flight maps in which there are busy hubs (like Chicago, London, and Singapore) and nodes (like Bismark, Oslo, and Penang). When gene hubs have many links they may be overwhelmed with feedback signals, and behave in much the same way as does Chicago in a snowstorm, London in bad fog, or Singapore in a typhoon – nothing gets in or out. This stalemate inhibits intermittent resolution and leads to the progression of ulceration. For the patient, clinician, insurance company, and drug company, ulceration is the major event associated with mucositis.
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Prevent ulceration and one can minimize pain, risk of infection, use of feeding tubes, and length of hospital stays. Ulceration develops as a consequence of the direct and indirect mechanisms noted above causing damage and apoptotic changes to mucosal epithelium. Mucositis ulcers are deep and quickly colonized by oral bacteria. In animal models, the number of mucosal bacteria goes up over three-hundred fold in the transition between intact and ulcerated epithelium.21 The bacteria on the ulcer surface are active contributors to the mucositis process. Cell wall products (i.e. lipopolysaccharides, lipoteichoic acid, cell wall antigens, and a-glucans) penetrate into the submucosa, now rich in macrophages, to stimulate those cells to further secrete pro-inflammatory cytokines. In granulocytopenic patients, there is a risk that intact bacteria may invade submucosal vessels to produce bacteremia or sepsis. The majority of cases of OM heal spontaneously. Ulcer resolution is the result of an active biological process in which signaling from the submucosa’s extracellular matrix (ECM) guides the proliferation, migration and differentiation of the epithelium bordering the ulcer. The mechanisms by which the ECM impacts would healing have been and are being extensively studied. It appears that its ability to interact with and activate intrinsic tyrosine kinase activity is important.22 Furthermore, the ECM’s ability to modulate receptors and the expression, organization and activation of intracellular proteins has been shown of functional relevance.23 Disruption of the submucosal ECM is the likely initiator of cases in which healing is delayed or, in rare instances, does not occur at all. For patients being treated with chemotherapy, mucositis is generally an acute event. Symptoms first begin about 3–5 days after drug infusion, ulceration is noted a couple of days later, and resolves within 2 weeks. In contrast, radiation-induced mucositis has a chronic course as patients are treated with incremental doses of radiation over a 7 week period (2 Gy per day to 70 Gy). By 30 Gy, ulceration, often coalescing and covered by a pseudomembrane, is present. Ulcerations last for up to three or four weeks following the completion of treatment.
Risk factors Of new cancer patients, approximately 8% will be at high risk (a greater than 50% chance) of developing ulcerative mucositis. Conversely, 43% (over 500,000) will be at little or no risk for the condition. These patients will be treated with curative surgery, peripheral radiation, or low-dose chemotherapy. The majority of new cancer patients fall into an intermediate category of mucositis risk in which somewhere between 20% and 49% will develop ulcerative mucositis at some time during their treatment. Patients in the high risk group fall into the head and neck cancer population and those individuals being treated with high dose, myeloablative chemotherapy. While the incidence of mucositis is high in this group, it is by no means universal. For patients at ‘some risk’, risk disparity is even more profound. This group is composed of individuals being treated for the most common solid tumors (breast, colon, rectum, and lung). Each cycle of therapy incurs mucositis risk. For patients who develop mucositis in one cycle, the risk of mucositis increases with subsequent cycles. For example, the likelihood that a patient being treated with a conventional regimen for breast cancer will develop ulcerative OM is about 20% during the first cycle of chemotherapy, but jumps to >60% in the second cycle. Historically, mucositis risk has been placed into two buckets, one associated with therapy and the other with the patient.24 Treatment-related variables include those associated with the type of therapy, dose, and route of administration. To a large extent
treatment type and dose can be overwhelming risk factors. Thus for a patient with a tongue cancer who is receiving chemoradiation, the likelihood of mucositis is close to 100%. On the other hand, a patient with a hypopharyngeal cancer, also receiving chemoradiation may see the risk drop to 50% because the tissues of the oral cavity are not primarily included in the radiation field. Patients receiving conditioning regimens in preparation for HSCT have been considered to be at high risk of mucositis. This was true of many regimens, especially those which included total body irradiation and/or high doses of stomatotoxic drugs. In an attempt to ameliorate risk, transplanters have adopted less toxic protocols. Since only 19% of the total annual OM cases occur in the head and neck cancer and HSCT populations, it is clear that other factors are critical is determining risk. Age, body mass, and gender have been identified as possible patient-associated risk factors.24 For the most part these are poorly defined, although data supports that being female confers increased toxicity risk for 5-fluorouracil and methotrexate.25 Preexisting conditions may impact mucositis risk. In a study of patients receiving induction therapy for leukemia, OM risk was compared among individuals who had pre-cancer diagnoses of psoriasis and Addison’s disease.26 The authors hypothesized that the inherent effect of psoriasis on epithelial proliferation could attenuate the probability of mucosal injury. Conversely, they believed that patients with Addison’s disease might be predisposed to OM because of high pre-existing pro-inflammatory cytokine levels. The study results of the study (Table 1) supported the supposition and indicate the potential importance of the patient’s underlying (non-cancer) condition on OM risk. Genetic factors may play a dominant role in determining mucositis risk. The most extensively studied genetic determinants of mucositis risk are of genes associated with chemotherapy metabolism. Schwab et al. assessed the predictive value of three polymorphisms associated with the metabolism of fluorouracil for toxicity risk.27 They found a significant association between dihydropyrimidine dehydrogenase (DPYD) variants and the development of OM, although the sensitivity of DPYD for mucositis was low (7.7%). Other investigators have demonstrated similar findings. While these studies offer proof of concept that toxicity risk is to a large extent genetically controlled, enzymatic deficiencies are relatively rare. Rather, it seems more likely that differences in the expression of genes associated with OM pathogenesis are more likely to impact risk. TNF-a appears to play a role in OM development and a number of polymorphisms control individuals’ TNF-a production. BoguniaKubik et al.28 evaluated the role of the expression of TNFA*1,2 on toxicity risk, including mucositis, among patients undergoing allogeneic HSCT and found that its presence resulted in an odds ratio for toxicity that was more than twice that attributable to the use of aggressive conditioning regimens (Table 2). Their findings are illustrative of the potential application of mechanism-related genes as the basis for risk prediction. Another example of mechanistic gene-based risk is provided by studies of radiation-induced dermatitis, a condition with a pathogenesis that is similar to mucositis. ROS play an important role during the initiation phase. Consequently, Ambrosone et al.29
Table 1
Controls Psoriasis Addison’s disease
60 64 44
No. of patients with oral mucositis
% of patients with oral mucositis
Chi square (v2)
P-value
16 4 14
26.6 6.2 32.0
– 56.9 20.4
– 0.0001 0.001
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Table 2 Risk factors for severe toxicities in allogeneic HSCT. From Bogunia-Kubik et al.28 Donor-recipient gender relation (F ? M) Recipient age (>25 years) Aggressive conditioning regimen TNFA*1,2
OR OR OR OR
4.2 2.1 7.0 17.1
reasoned that differences in polyphormisms that encode for glutathione S-transferase, an enzyme that provides protection from ROS, could impact the extent of radiation-induced dermatitis. Amongst a total of close to 500 patients, they found that low activity of the GSTP genotype was associated with more than two-fold risk for acute skin toxicity. The tumor itself is biologically active and might contribute to OM risk. Both tumor parenchyma and stroma are sources of molecules which influence cell behavior.30 Tumor-derived peptides and protein products could directly modify normal cell response to radiation or chemotherapy,31,32 while others, such as matrix mellatoproteinases enhance the breakdown of the local tissue environment. The interaction of tumors with the host, how the tumor contributes to toxicity risk, and how products associated with tumor cell death during treatment impact the patient are areas ripe for investigation. The oral environment and mucositis The oral cavity is one of the most complex environments in the body. The mucosa is bathed in saliva containing a wide microbiota comprised of bacteria, fungi and viruses. Many studies have evaluated the role of saliva and microorganisms in the development and course of mucositis. Overwhelmingly, these investigations have concluded that while the course of mucositis might be influenced by the local environment, neither changes in saliva or the microflora are significant in the primary etiology of OM. Using DNA–DNA hybridization and quantitative culture techniques, Uzel et al. studied the quantitative and qualitative changes of the oral bacterial flora in an established hamster model of radiation-induced mucositis.21 Importantly, hamsters’ oral bacterial flora that is remarkably similar in composition to that of humans. Peak bacterial loads coincided with peak mucositis scores, but an increase in bacterial numbers lagged behind the development of
500
3.5 3
400
2.5
350 300
2
250 200
1.5
150
1
100
0.5
50 0
AVERAGE MUCOSITS SCORE
MEAN TOTAL BACTERIAL COUNT (10^5)
450
0
7
14 DAY
21
28
0
Figure 2 The relationship between mucositis severity and bacterial colonization. The relationship between quantitative increases in bacteria and the course of mucositis was studied in a hamster model in which an acute dose of radiation was given on day 0. Bacterial sampling and clinical mucositis scoring was performed at weekly intervals. Mucositis development (a score of three indicates ulcerative OM) preceded increases in bacterial numbers suggesting that, at least quantitatively, bacteria do not drive the development of mucosal ulceration. Bacterial colonization of ulcerative lesions is suggested by the synchronous peak of mean bacterial count and mucositis score on day 21.
ulcerative mucositis (Fig. 2). This finding contradicts a hypothesis that would suggest that increases in bacterial numbers drive OM, while the observation that the mean bacterial load increased by over 300% compared to baseline suggested that ulcerated mucosa represented a desirable colonization site. Bacterial numbers decreased as ulcers spontaneously resolved indicating that the presence of large numbers of organisms was not enough to inhibit healing. Consistent with early studies33 increases in gram negative organisms were seen during ulceration, and reestablishment of normal bacterial proportions was a requirement for spontaneous ulcer resolution, irrespective of bacterial numbers. Clinical trial results suggest that anti-bacterial strategies have been ineffective as OM interventions.34 Approaches directed at stimulating salivary flow as OM treatments have largely failed. Pilocarpine was ineffective in modifying the incidence or course of mucositis when studied in both head and neck cancer35 and HSCT36 populations. Roles for fungi (candida) and viruses (herpes simplex 1) in the etiology of mucositis have been the subject of speculation for some time and remain marginally controversial. Candidiasis is a common finding among patients receiving head and neck radiation or myeloablative chemotherapy so it is not unexpected that these organisms can be identified in patients with mucositis as a coincident condition, rather than causal. Anti-fungals as mucositis interventions have not been effective, a finding that is not surprising given the large number of patients who develop mucositis even when they receive routine anti-fungal prophylaxis.37 Speculation that HSV-1 might be associated with the development of mucositis has been mentioned in the literature since at least the 1980s.38 Subsequently, data have emerged which rebut HSV as a primary driver of mucositis. Woo et al.39 showed that OM development was unrelated to HSV antibody status or positive viral cultures, and acyclovir prophylaxis was ineffective in preventing OM. Likewise, while radiation and chemotherapy are successful activators of latent virus in seropositive patients, Djuric et al. noted that the rate of HSV-1 reactivation was no different before or after chemotherapy.40 They also found that there was no relationship between in the rate of viral reactivation and the presence or absence of OM.
Summary and therapeutic opportunities OM falls within the bailiwick of the toxicities associated with cytotoxic cancer therapy. Descriptive and mechanistic research conducted over the past decade have resulted in a series of essential changes about how these undesirable side effects are viewed. First and critical has been the demonstration that toxicities are not simply the by-product of non-specific cell death, but rather represent the clinical manifestation of a culmination of a complex series of interactive biological events. Second, it is becoming increasingly clear that specific toxicities do not occur in isolation – patients who develop OM are likely to simultaneously manifest diarrhea, fatigue, cutaneous lesions or other adverse events. The finding of toxicity clusters is still being defined, but what unites elements of toxicity clusters is their common underlying pathobiology. Third, toxicity risk is multifactorial, predictable, quantifiable and largely genetically determined. Our ability to develop effective risk prediction will be an important step in the development of customized patient interventions. Forth, normal cells and tumor cells do not respond in the same way to cytotoxic therapy, therefore pharmacologic toxicity prevention at the mechanistic level is a realistic goal without jeopardizing tumor response to treatment. Finding an effective mucositis pharmacologic or biologic intervention has not been easy. There have been a number of false starts and disappointments. While some of these negative results can be
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attributed to a compound’s lack of sufficient activity, it also seems that others are the consequence of poor study design or execution. The 2004 approval of palifermin as a first in class agent for mucositis is important, therefore for a number of reasons. First, it is likely that palifermin’s OM efficacy is a manifestation of its robust biological activity.41 Second, the enabling study’s primary endpoint was clinically meaningful, able to be achieved with minimal intersite variability, and frames important trial design elements for new agents. And third, the impact of successful amelioration of clinically scored OM on patient-reported and overall health outcomes was demonstrated.2 A review of ClinicalTrials.gov illustrates the scope of molecules with potential mucositis efficacy currently under investigation. The breadth of activity of these compounds is indicative of the multiple interventional targets provided by OM’s biology. Examples include zinc, an essential trace element, which induces metallothionein to sequester oxygen free radicals,42 GM–CSF, granulocyte-macrophage colony-stimulating factor an immunomodulator with other biological activities,43 SCV-07, a immunostimulating synthetic peptide which mediates its effect through Th1 helper cells,44 ATL-104, a plant-derived mitogen,45 and TRAUMEEL S a homeopathic plant and mineral derived preparation.46 This sampling is illustrative of the diversity of interventional approaches and does not include many other agents in earlier stages of development.8 We are at a time when all of the components necessary to produce effective OM agents seem to be finally coming together: molecules and compounds with sufficient targeted activity are becoming increasingly available, formulations that provide local pharmacologic levels of drug have been developed, studies are becoming more sophisticated in design and disciplined in their execution, and importantly, the clinical need and commercial value for an effective product has stimulated the pharmaceutical industry to take interest.
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Conflict of interest statement 28.
Dr. Sonis received a research grant from Amgen, Inc. and is a partner in Biomodels, LLC. 29.
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