Prediction of mucositis risk secondary to cancer therapy: a systematic review of current evidence and call to action.

PURPOSE: Despite advances in personalizing the efficacy of cancer therapy, our ability to identify patients at risk of severe treatment side effects and provide individualized supportive care is limited. This is particularly the case for mucositis (oral and gastrointestinal), with no comprehensive risk evaluation strategies to identify high-risk patients. We, the Multinational Association for Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) Mucositis Study Group, therefore aimed to systematically review current evidence on that factors that influence mucositis risk to provide a foundation upon which future risk prediction studies can be based. METHODS: We identified 11,018 papers from PubMed and Web of Science, with 197 records extracted for full review and 113 meeting final eligibility criteria. Data were then synthesized into tables to highlight the level of evidence for each risk predictor. RESULTS: The strongest level of evidence supported dosimetric parameters as key predictors of mucositis risk. Genetic variants in drug-metabolizing pathways, immune signaling, and cell injury/repair mechanisms were also identified to impact mucositis risk. Factors relating to the individual were variably linked to mucositis outcomes, although female sex and smoking status showed some association with mucositis risk. CONCLUSION: Mucositis risk reflects the complex interplay between the host, tumor microenvironment, and treatment specifications, yet the large majority of studies rely on hypothesis-driven, single-candidate approaches. For significant advances in the provision of personalized supportive care, coordinated research efforts with robust multiplexed approaches are strongly advised.

Placebo effect in burning mouth syndrome: a systematic review.

Placebo controls play a critical role in the evaluation of any pharmacotherapy. This review surveys the placebo arm in 12 randomized controlled trials (RCTs) investigating burning mouth syndrome (BMS) and documents a positive placebo response in 6 of them. On average, treatment with placebos produced a response that was 72% as large as the response to active drugs. The lack of homogeneity in the use of placebos adds to the difficulty in comparing results and aggregating data. Future RCTs investigating BMS would benefit from larger sample sizes, adequate follow-up periods, and use of a standard placebo.

New thoughts on the initiation of mucositis.

It has been slightly more than a decade since the classic mechanistic paradigm that defined the pathogenesis of mucositis was revised. A five-stage sequence of linked biological events forms the basis for our current understanding of how regimen-related mucosal injury occurs. The first stage is the initiation phase, although the gateway to toxicity has been the least studied. This essay proposes new thoughts on the phase's components, how they might interact, and how they present new opportunities for treatment interventions and mucositis risk prediction.

Subgingival and tongue microbiota during early periodontitis.

Periodontal infections have a microbial etiology. Association of species with early disease would be useful in determining which microbes initiate periodontitis. We hypothesized that the microbiota of subgingival and tongue samples would differ between early periodontitis and health. A cross-sectional evaluation of 141 healthy and early periodontitis adults was performed with the use of oligonucleotide probes and PCR. Most species differed in associations with sample sites; most subgingival species were associated with subgingival samples. Few species were detected more frequently in early periodontitis by DNA probes. Porphyromonas gingivalis and Tannerella forsythia (Tannerella forsythensis) were associated with early periodontitis by direct PCR. In conclusion, the microbiota of tongue samples was less sensitive than that of subgingival samples in detecting periodontal species, and there was overlap in species detected in health and early periodontitis. Detection of periodontal pathogens in early periodontitis suggests an etiology similar to that of more advanced disease.

Prevention of chemotherapy-induced ulcerative mucositis by transforming growth factor beta 3.

Mucositis is a common, dose-limiting complication in patients receiving cancer chemotherapy, which appears to be a consequence of the rate of epithelial proliferation. The beta transforming growth factors have been shown to be negative regulators of epithelial cell proliferation. Here we show that transforming growth factor beta 3 administration reduced proliferation of oral epithelium in vitro and in vivo. Topical application of transforming growth factor beta 3 to the oral mucosa of the Syrian golden hamster prior to chemotherapy significantly reduced the incidence, severity, and duration of oral mucositis, reduced chemotherapy-associated weight loss, and increased survival.

Host-Microbiome Cross-talk in Oral Mucositis.

Oral mucositis (OM) is among the most common, painful, and debilitating toxicities of cancer regimen-related treatment, resulting in the formation of ulcers, which are susceptible to increased colonization of microorganisms. Novel discoveries in OM have focused on understanding the host-microbial interactions, because current pathways have shown that major virulence factors from microorganisms have the potential to contribute to the development of OM and may even prolong the existence of already established ulcerations, affecting tissue healing. Additional comprehensive and disciplined clinical investigation is needed to carefully characterize the relationship between the clinical trajectory of OM, the local levels of inflammatory changes (both clinical and molecular), and the ebb and flow of the oral microbiota. Answering such questions will increase our knowledge of the mechanisms engaged by the oral immune system in response to mucositis, facilitating their translation into novel therapeutic approaches. In doing so, directed clinical strategies can be developed that specifically target those times and tissues that are most susceptible to intervention.

Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation.

PURPOSE: To explore the relationship between oral mucositis and selected clinical and economic outcomes in blood and marrow transplant patients. PATIENTS AND METHODS: Subjects consisted of 92 transplant patients from eight centers who participated in a multinational pilot study of a new oral mucositis scoring system (Oral Mucositis Assessment Scale [OMAS]). In the pilot study, patients were evaluated for erythema and ulceration/pseudomembrane formation beginning on the first day of conditioning and continuing for 28 days. We examined the relationship between patients' peak OMAS scores and days with fever (body temperature > 38.0 degrees C), the occurrence of significant infection, days of total parenteral nutrition (TPN), and days of injectable narcotic therapy (all over 28 days), days in hospital (over 60 days), total hospital charges for the index admission, and vital status at 100 days. RESULTS: Patients' peak OMAS scores spanned the full range of possible values (0 to 5) and were significantly (P <.05) correlated with all of the outcomes of interest except days with fever (P =.21). In analyses controlling for type of graft (autologous v allogeneic) and study center, a 1-point increase in peak OMAS score was associated with (1) 1.0 additional day with fever (P <.01), (2) a 2.1-fold increase in risk of significant infection (P <.01), (3) 2.7 additional days of TPN (P <.0001), (4) 2.6 additional days of injectable narcotic therapy (P <.0001), (5) 2.6 additional days in hospital (P <.01), (6) $25,405 in additional hospital charges (P <.0001), and (7) a 3.9-fold increase in 100-day mortality risk (P <.01). Mean hospital charges were $42,749 higher among patients with evidence of ulceration compared with those without (P =.06). CONCLUSION: Oral mucositis is associated with significantly worse clinical and economic outcomes in blood and marrow transplantation.

Assessment of oral mucositis in clinical trials: impact of training on evaluators in a multi-centre trial.

In the assessment of mucositis, the inter-evaluator variability needs to be minimised and would likely to be best accomplished by training. The aim of this study was to evaluate the effect of training on concordance of evaluators in scoring oral mucositis. The evaluators were informed about the pathobiology and clinical appearance of mucositis and were trained in scoring mucositis according the Oral Mucositis Assessment Scale (OMAS). The effect of the training was evaluated by a pre- and post-training test. Each test consisted of 15 slides depicting oral mucositis. The pre- and post-training scores were compared to the reference standard. During 8 months at 6 meetings, 65 evaluators were trained. The mean percentage correctly scored slides according the OMAS increased significantly between the pre- and post-training test (P<0.001). Training evaluators in scoring oral mucositis has a significant improvement on the outcome of mucositis assessment.

The gene expression sequence of radiated mucosa in an animal mucositis model.

Oral mucositis is a common, dose-limiting, acute toxicity of radiation therapy administered for the treatment of cancers of the head and neck. Accumulating data would suggest that the pathogenesis of mucositis is complex and involves the sequential interaction of all cell types of the oral mucosa, as well as a number of cytokines and elements of the oral environment. While a number of studies have reported on gene expression of particular cell types in response to radiation, the overall response of irradiated mucosa has only been evaluated in a limited way. The present study was undertaken to evaluate the expression of a target group of genes using RNA quantification assays and, more broadly, to assess patterns of mucosal gene expression using DNA microarray hybridization. Our results demonstrate the sequential upregulation of a series of genes that, when taken collectively, suggest an intricate functional interaction.

The role of effector cells and antiserum in the inhibition of cell-mediated cytotoxicity of allogeneic tumor cells.

Previous experiments in this laboratory demonstrated a progressive decrease in cell-mediated cytotoxicity (CMC) against allogeneic tumor cells by immune spleen cells from mice repeatedly immunized with those tumor cells. In the present study, immune spleen cells, obtained at specified intervals during the course of multiple immunizations of BALB/c mice with EL-4 lymphoma cells, were tested for CMC against EL-4 target cells pretreated with anti-EL-4 serum which had been obtained from singly or repeatedly immunized animals. Cytolysis of EL-4 cells was measured by a 51Cr-release assay. The results indicate that blocking of CMC in an allogeneic tumor model may occur by two pathways. First, antigen or antigen-antibody complexes present in the immunized animal may bind in vivo to the antigen receptor sites of of sensitized effector cells that are used in the in vitro CMC assay, thereby blocking their interaction with tumor cells. Second, immune serum that is added to the in vitro CMC assay may contain highly avid antibodies, as well as antigen-antibody complexes, that bind to tumor cells and thereby block interaction with sensitized effector cells. The identification of these elements may be of prognostic significance in certain clinical situations.

The immune response of mice repeatedly injected with allogeneic tumor cells.

The development and kinetics of cell-mediated cytotoxicity (CMC), antibody-mediated complement-dependent cytotoxicity (C'DC), and antibody-dependent cellular cytotoxicity (ADCC) were studied in an allogeneic model. Using microcytotoxic assays of 51Cr release from labeled EL-4 tumor cells, C'DC, ADCC, and CMC were measured at 14 intervals during the 77-day course of the experiment. The results obtained demonstrate the oscillating nature of the immune response. The rise and fall of activity was almost synchronous for the three functions studied. A generalized trend of increasing antibody-dependent functions and a simultaneous dampening of CMC was noted.

Modification of in vitro and in vivo immune function by acute inflammatory cells.

The ability of adoptively transferred, syngeneic polymorphonuclear leukocyte-rich (PMNLr) inflammatory cells to influence lymphocyte-mediated cytotoxicity (LMC), complement-dependent cytotoxicity (CDC), and skin allograft survival was studied in a murine model. BALB/c mouse PMNLr, stimulated by i.p. injection of either glycogen (G/PMNLr) or thioglycollate (T/PMNLr), were transferred to other BALB/c mice at the time of primary or secondary immunization with a cellular alloantigen (C57BL/6 spleen cells) or after skin allografting (C57BL/6 tailskin). The metabolic activity of each PMNLr population was determined by measuring glucose utilization in the hexose monophosphate shunt. It appeared that metabolic activity of the T/PMNLr was significantly greater than that of the G/PMNLr. Our results indicate that, while the infusion of G/PMNLr tended to suppress the primary cell-mediated immune response and the secondary humoral immune response, the infusion of T/PMNLr stimulated both of these responses. Furthermore, i.p. infusion of mice with G/PMNLr at a time approximating grafting resulted in prolonged graft survival, but neither T/PMNLr nor syngeneic thymocytes effect graft survival. Our data demonstrate that both cellular and humoral immunity can be modified by acute inflammatory cells. The metabolic status of the acute inflammatory cells seems to be critical in determining their immunoregulatory potential.

Transplantation of polarized type 2 donor T cells reduces mortality caused by experimental graft-versus-host disease.

Acute graft-versus-host disease (GVHD) is thought to be initiated by alloreactive type 1 T cells that secrete gamma-interferon (IFN-gamma). IFN-gamma induces the production of inflammatory cytokines, e.g., tumor necrosis factor-alpha and interleukin (IL)-1, which are the distal mediators of GVHD. We demonstrate that the transplantation of polarized type 2 murine T cells (i.e., cells secreting IL-4 but not IFN-gamma) together with T-cell-depleted bone marrow results in a significant increase in survival (P<0.001) after bone marrow transplantation across minor histocompatibility barriers (B10.BR-->CBA/J). Further analysis demonstrated that increased survival in recipients of polarized type 2 T cells correlated with diminished production of both IFN-gamma and tumor necrosis factor-alpha but with increases in IL-4 2 weeks after transplantation. Despite improved survival, histologic changes of GVHD were evident in oral mucosal and hepatic tissues at 7 weeks after bone marrow transplantation. These data provide further evidence that inflammatory cytokines in the immediate posttransplant period are pivotal to the development of mortality but that they do not correlate with individual target organ damage.

Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity.

Mucositis induced by antineoplastic drugs is an important, dose-limiting and costly side effect of cancer therapy. The ulcerative lesions which result are frequent systemic portals of entry for microorganisms which inhabit the mouth and consequently are often sources of systemic infection in the myelosuppressed patient. A number of clinical observations and the inconsistency of responses to a broad range of treatment modalities suggests a physiological complexity to mucositis which has not previously been comprehensively considered. We now propose a hypothesis as to the mechanism by which mucositis develops and resolves, which is based on four phases: an initial inflammatory/vascular phase; an epithelial phase; an ulcerative/bacteriological phase; and a healing phase. The role of cytokines as initiators and ampliers of the process is discussed, as is the potential influence of genetic factors in establishing risk and modifying the course of stomatotoxicity.

Transforming growth factor-beta 3 mediated modulation of cell cycling and attenuation of 5-fluorouracil induced oral mucositis.

Mucositis is a common, dose-limiting complication in patients receiving cancer chemotherapy, which derives from damage to the epithelial cell layer. We have shown that transforming growth factor-beta 3 (TGF-beta 3) negatively regulates epithelial cell proliferation and reduces the incidence of oral mucositis. Here, we report the findings of a large study examining the effects of TGF-beta 3 administration in a hamster model on oral epithelial cell cycling in vivo, on oral mucositis, on weight retention and on survival. Topical application of TGF-beta 3 to the buccal mucosa significantly reduced basal cell proliferation, as measured by proliferating cell nuclear antigen (PCNA) immunohistochemistry and DNA ploidy. Administration of topical TGF-beta 3 prior to chemotherapy with 5-fluorouracil (5-FU) significantly reduced the severity of mucositis with respect to time, reduced chemotherapy-associated weight loss and increased survival.

The relationship between mucosal cyclooxygenase-2 (COX-2) expression and experimental radiation-induced mucositis.

Although cycloooxygenase-2 (COX-2) is upregulated by factors associated with oral mucositis, its role in the pathogenesis of mucositis has not been studied. We investigated the kinetics of mucosal COX-2 expression following radiation exposure, and assessed its relationship to the development of oral mucositis in an established animal model using immunohistochemical endpoints. While little or no COX-2 expression was observed in unirradiated mucosa or in tissue taken 2 days after radiation, COX-2 expression was dramatic on days 10 and 16, especially in submucosal fibroblasts and endothelium. The kinetics of COX-2 expression paralleled mucositis severity. A burst of angiogenic activity was seen on day 21 following peak COX-2 expression. The kinetics of COX-2 expression relative to mucositis progression suggests that COX-2 is not a primary driver of radiation injury, but instead plays an amplifying role.

Defining mechanisms of action of interleukin-11 on the progression of radiation-induced oral mucositis in hamsters.

Oral ulcerative mucositis is a common toxicity associated with drug and radiation therapy for cancer. It impacts on quality of life and economic outcomes, as well as morbidity and mortality. Mucositis is often associated with dose limitations for chemotherapy or is a cause for dose interruption for radiation. The complexity of mucositis as a biological process has only been recently appreciated. It has been suggested that the condition represents a sequential interaction of oral mucosal cells and tissues, pro-inflammatory cytokines and local factors such as saliva and the oral microbiota. The recognition that the pathophysiology of mucositis is a multifactorial process was partially suggested by the observation that interleukin-11 (IL-11), a pleotropic cytokine, favorably altered the course of chemotherapy-induced mucositis in an animal model. In the current study, we evaluated a series of biologic and morphologic outcomes to determine their roles and sequence in the development of experimental radiation-induced mucositis and to evaluate the effects of IL-11 in attenuating them. Our results suggest that IL-11 favorably modulates acute radiation-induced mucositis by attenuating pro-inflammatory cytokine expression. Data are also presented which help define the pathobiological sequence of mucositis.

Interaction of Ia antigen-bearing polymorphonuclear leukocytes and murine splenocytes.

Polymorphonuclear leukocytes (PMN) were induced in the peritoneum of a Balb/c mouse by ip injection of Fusobacterium nucleatum (FN) (greater than 95% PMN). A subpopulation of PMN harvested bore Ia surface antigens and stimulated a mixed lymphocyte reaction (MLR) when cultured with C57B1/6J splenocytes. The reaction was blocked by a short prior incubation of PMN with anti-Ia antibody or PMN cell depletion by the same antibody plus complement. The Ia antigen-bearing PMN were capable of antigenic modulation since incubation of PMN for 24 h rendered the cells incapable of stimulating an MLR. The Ia antigen-bearing PMN produced a soluble material that enhanced the phytohemagglutinin (PHA) response of murine splenocytes and the active material was a product of live cells since the supernatants contained no detectable lactate dehydrogenase activity. The data suggest that murine PMN subpopulations, defined by surface Ia antigen, can modulate mitogenic responses by production of an enhancing factor(s).

Effects of supernatants of polymorphonuclear neutrophils recruited by different inflammatory substances on mitogen responses of lymphocytes.

Two different substances, glycogen and thioglycollate, were used to recruit early peritoneal exudate cells (4h). In the acute phase of the inflammatory response the cellular infiltrate is large, and the predominant cell (greater than 95%) is the polymorphonuclear neutrophil. Supernatant had differing effects on lymphocyte responses to the mitogens PHA and LPS, also carried out in serum-free media, depending on recruiting substance and time of culture. While glycogen-recruited PMN supernatant (GPMN-S) always enhanced splenocyte responses to PHA, thioglycollate-recruited cells (TPMN-S) did not produce an enhancing factor until the cells had been in culture for 24 h. Whereas GPMN-S enhanced the splenocyte response to LPS only after 1 or 4 h of culture, TPMN-S failed to have any significant effect. Thymocyte responses to PHA were facilitated by all supernatants. Dilution of the soluble PMN factors resulted in a suppressive effect on splenocyte responses to both PHA and LPS, regardless of whether PMN were recruited by the thioglycollate or glycogen or of the time of cell incubation. These results indicate that PMN-rich cell populations of different types of activity are recruited by glycogen and thioglycollate and that these cells produce factors capable of potentiating, enhancing, or suppressing responses to T- or B-cell mitogens by normal syngeneic lymphocytes.