- Ketchum, ID
The fact that mucositis remains an important toxicity of cancer therapy was reflected in the thirty abstracts dealing with this topic that were included in this year’s MASCC/ISOO symposium. While mucositis has most often been associated with damage to the oral cavity, it is clear that its clinical and scientific import to the rest of the gastrointestinal tract is significant. Abstracts presented fell into a range of topics that spanned preclinical mechanistic studies to interventional clinical trials. Among the major subject categories addressed were techniques and instruments to assess mucositis and observational reports of its behavior, incidence and risk, animal and human studies of the biological basis for mucositis, the burden of illness of mucositis, and clinical trials of specific interventions.
Mucositis Assessment, Incidence, Risk Factors, and Burden
A number of studies reported on the assessment of mucositis, its incidence, risk factors, and impact on quality of life, health, and economic outcomes.
Dudley, et al. reported the application of an innovative statistical approach to quantify parameters of change for patient populations, model individual variability about population parameters, and predict which patients would be most severely affected. Their approach, known as Latent Growth Curve Analysis (LGCA), was applied to estimate parameters of change in erythema in 133 HSCT patients treated with high-dose chemotherapy conditioning regimens. Clinical ratings of erythema from the 20 item Oral Mucositis Index were made 8 times over a 3-week period. The model identified statistically significant individual variability relative to the average slope and quadratic parameters. Additional analyses are planned in the future.
As part of a psychometric analysis, Cheng, et al. administered a 41-item oropharyngeal mucositis quality-of-life scale (OMQoL) questionnaire to 210 patients with oropharyngeal mucositis. Ninety percent of the study population was being treated for solid tumors. Patients were well distributed for mucositis severity (WHO grades 0 to 3). The initial psychometric analysis resulted in four subscales depicting problems with symptoms, diet, social function, and swallowing, which was driven by 31 of the 41 items on the scale. The authors concluded that the 31-item OMQoL was a psychometrically sound measure of measuring the quality of life of patients with oral mucositis. In a second abstract, the same authors demonstrated that the OMQoL was effective in demonstrating that traditionally stomatotoxic chemotherapy or chemoradiation regimens were associated with a poorer quality of life, especially with respect to symptoms, swallowing, and diet. 
Dorr, et al. evaluated the potential impact of gender on the risk of radiation-induced oral mucositis in patients being treated for cancers of the head and neck. In a retrospective analysis of 362 patients of both genders (♀ = 80, 22%) treated in similar fashion, mucosal reactions in females occurred at the same rate as in men, but were diagnosed slightly later among patients receiving conventional fractionation. The authors attributed this observation to more intensive mouth care by women, and concluded that women do not require particular attention in addition to routine supportive care.
Three retrospective studies described the incidence of oral mucositis in various patient populations. Of 39 patients being treated with a range of high-dose chemotherapy regimens, Eilers, et al. reported mucosal barrier breakdown in 38.5% using Oral Assessment Guide criteria. DeMoor, et al. examined symptoms of oral mucositis among 11,537 cancer patients being treated for common, non-head and neck solid tumors with multicycle therapy at six community oncology clinics. Mucositis symptoms were determined using patient reponses on a 10 Likert scale (0 not a problem, 10 as bad as possible) recorded on an e-tablet computer at the time of patients’ office visits. The authors noted that average mouth sore scores peaked by day 40 (Cycle 2), and that patients who reported any symptoms of mouth sores by day 21 (Cycle 1) were five times more likely to develop severe mucositis by day 126 than patients who reported no symptoms. The authors concluded that mucositis is common in community oncology. Finally, in a retrospective chart review of 95 patients being treated for osteosarcoma, Carrillo, et al. noted 70 mucositis episodes (67%) across two treatment protocols.
To assess risk for oral mucositis in children, Cheng, et al. evaluated 102 patients (51 patients with WHO grade ≥2 and 51 controls) in a matched case-control study. The mean age of study participants was 7.6 years and 65% were males. The authors found that decreasing neutrophils and body weight and increasing body height were significant risk factors for mucositis in the study population.
As a means to better understand mechanism and risk for mucositis in patients with acute myelogenous leukemia (AML), Brennan’s group examined changes in gene expression in five patients being treated for AML as detected by microarray analysis of RNA obtained from biopsies of the buccal mucosa before and after chemotherapy. They found that 32 genes were differentially expressed, among them agininosuccinate synthase, an enzyme that has importance in the maintenance of protective levels of nitric oxide. RT-PCR was used to confirm the microarray results. The authors concluded that the down regulation of argininosuccinate synthase following chemotherapy in AML patients may constitute a risk for acquiring oral mucositis.
Grunberg, et al. reported the results of an interim analysis of the first 20 of a planned 150 colorectal cancer patients receiving FOLFOX chemotherapy in a multinational, 44 center investigation. Oral mucositis and diarrhea were identified from patient reports (oral mucositis daily questionnaire modified to add questions about diarrhea) which patients completed at baseline and daily during treatment. In addition, two validated QoL questionnaires were administered at baseline and then weekly during treatment. Sixty-five percent of patients reported mouth and throat soreness, and 35% reported severe MTS. Seventy percent reported diarrhea and 45% had severe diarrhea. The authors noted that MTS and diarrhea often occurred together. Patients with MTS had poorer quality of life outcomes as measured by both FACT-E and FACIT-Fatigue questionnaires.
Dorr and his colleagues evaluated the relationship between patient self-evaluation of their mouths during radiochemotherapy and clinician derived mucositis scores derived in the same patients based on RTOG/EORTC criteria in 366 patients. During treatment, VAS-values significantly decreased. From the third treatment week, subjective VAS values were significantly lower in those patients who were scored with confluent oral mucositis. The authors concluded that RTOG/EORTC clearly mirrors the subjective assessment of patients, and that the agreement indicates that mucositis significantly impacts on patients’ quality of life.
Nicolatou-Galitis, et al. reported the incidence and severity of mucositis among 93 patients receiving radiation therapy for cancers of the head and neck. Of the 93 patients studied, 80 completed treatment as planned; 13 required treatment interruptions. Using EORTC/RTOG criteria, severe mucositis was noted in 57% of patients. Interestingly, 25 (of 53) showed improvement in mucositis score with the administration of an anti-infectious agent (antiviral or antifungal).
In addition to its high incidence, Keefe, et al. reported that oral mucositis is associated with increased resource use among patients receiving treatment for cancers of the head and neck. Sixty-nine patients with cancers of the mouth, oropharynx, hypopharynx, or larynx whose planned treatment included conventional, intensity modulated radiation therapy with or without chemotherapy were enrolled at the start of therapy in a multinational, multiinstitutional study. Mucositis severity was assessed using a validated symptom questionnaire for oral mucositis. Ninety percent of patient reported moderate to severe mucositis. Of these, the majority were being treated for cancers of the mouth or oropharynx. Patients with mouth cancers had slightly more mucositis symptoms than did patients with tumors of the larynx or hypopharynx. Severe mucositis symptoms were reported in 92% of patients with mouth cancers and 82% of patients with larynx/hypopharynx cancers. Resource use exceeded that previously reported. Among patients with moderate to severe mucositis, gastrostomy tubes were required in 25%, unplanned office visits in 37%, hospitalization in 18%, and transfusion in 5%. Even low grade mucositis was associated with unexpectedly high resource utilization.
The Biology of Mucositis
No longer is mucositis viewed as being biologically simple. Rather, it is now recognized that the pathobiology underlying the genesis of regimen-related mucosal injury is complex. A number of abstracts provided data that support that hypothesis and offered evidence of the roles of p53, NF-κB, and inflammatory cytokines in mucositis development.
Yeoh, et al. used a novel animal model in which fractionated radiation was administered to Dark Agouti rats to study the expression of p53, NF-κB, and COX-1 and -2 during the development of mucositis. The authors compared jejunal and colonic samples obtained weekly from animals that had received 2.5Gy of radiation thrice weekly for up to six weeks with unirradiated controls. The TUNEL assay was used to determine apoptosis, and immunohistochemistry was performed to evaluate the expression of p53, NF-κB, and cyclooxygenases. Mucosal injury was noted after only 1 week of RT. P53 was increased in both the jejunum and colon, and this corresponded to levels of apoptosis. NF-κB and COX-2 were also increased in the irradiated tissue. These results confirm the similarity of molecular pathways involved in mucositis throughout the gastrointestinal tract and the early increase in COX-1 suggests its possible role in the pathogenesis of the condition.
In rodent model of irinotecan-induced mucosal injury, Logan and his colleagues evaluated tissue levels of NF-κB, TNF, and interleukins-1b and -6 using standard immunohistochemical techniques. Following the administration of irinotecan, rats were sacrificed from 30 minutes to 72 hours and buccal mucosa, jejunum, and colon were collected and studied. Altered histological features were noted in all of the tissues studied by 72 hours. Subtle changes were also noted in the intestinal sample as soon as 6 hours after chemotherapy injection. Tissue levels of NF-κB, TNF, IL-1b, and IL-6 peaked between 2 and 6 hours in the tissues examined. The authors concluded that their results provide additional evidence to the pivotal role of NF-κB and associated cytokines in the pathogenesis of mucositis.
Xanthinaki and her group evaluated apoptotis and markers of inflammation in head and neck cancer patients with varying levels of radiation- (with or without chemotherapy) induced oral mucositis. Cytologic smears were obtained by brush biopsy from the oral cavities of 35 patients, and the relationship between selected apoptotic and inflammatory markers and the clinical severity of oral mucositis (as measured by EORTC/RTOG criteria) was studied. Whereas the proapoptotic marker, p53, was seen in 6.5% of patients with no mucositis and 43% of patients with severe mucositis (grade 3), antiapoptotic markers (bcl-2 and mcl-1) were highly expressed in patients with no mucositis and less expressed in patients with severe injury. TNF and IL-1β expression were more frequent in patients with clinically significant mucositis than in patients without the condition.
Interventional Studies for the Prevention or Treatment of Mucositis
A number of agents were tested in preclinical and clinical studies. Among these were growth factors, vitamin therapy, a mitogen, cryotherapy, and laser therapy.
The efficacy of palifermin on 5-FU-induced intestinal injury was studied in a rodent model by Butler, et al. Seventy-two hours following three daily subcutaneous injections of palifermin at doses of 5, 10, or 15 mg/kg into groups of 10 Dark Agouti rats, the animals received a single injection of 5-FU (50 mg/kg). Using the 13C sucrose breath test as a marker to evaluate the health of the small intestine, the authors reported that palifermin administration at dose of 15 mg/kg/day resulted in a significant protective effect against 5-FU-induced intestinal injury.
In another study in the same species, Chan, et al. investigated the mechanism by which palifermin exerts its protective effect on irinotecan-induced mucositis. Groups of 6 Dark Agouti rats received palifermin only, saline, irintecan only, or irinotecan plus palifermin. Rats were sacrificed at various times following chemotherapy and jejunal, and colonic expression of KGF and KGF-receptors were studied using immunohistochemical techniques. Goblet cell characteristics were studied using Alcian Blue-Periodic Acid Schiff stain. The expression of KGF and its receptor was not noticeably different among study groups. The goblet cell population was significantly increased in the jejunum of rats that received palifermin, and goblet cells were maintained after chemotherapy in animals that had received palifermin compared with control animals. The authors concluded that palifermin exerts an anti-mucotoxic effect along the gastrointestinal tract by maintaining the number of goblet cells following chemotherapy administration.
Dexpanthenol (provitamin B5) was studied for its ability to modify radiation-induced oral mucositis in 366 patients being treated for cancers of the head and neck. The study, reported by Doerr, et al., compared the efficacy of mouth washes containing dexpanthenol or tap water, with or without additional mechanical debridement, on daily mucositis grades as measured by RTOG/EORTC criteria. The results of the study failed to demonstrate any advantage to dexpanthenol in the reduction of mucositis severity. 
ATL-104 is a recombinant protein of the L-form of phytohemagglutin, a plant lectin that is highly mitogenic for epithelial cells of the GI tract and resistant to acid and protease degradation. The results of a clinical trial were reported by Hunter, et al. in which ATL-104 was tested for its ability to affect oral mucositis in 104 patients receiving stomatotoxic conditioning regimens (high-dose melphalan or BEAM) prior to autologous HSCT. Subjects were randomized to receive one of three doses of ATL-104 (50 mg, 100 mg, 150 mg) or placebo as a 15 mL swish and swallow for three days before and three days after chemotherapy. Mucositis was assessed using WHO and WCCNR criteria for 28 days following dosing or until discharge. ATL-104 administration favorably affected the duration of mucositis compared to placebo, although no advantage was seen with increased concentrations of the test material (median duration of WHO grade 3-4 mucositis with placebo was 10.5 days, ATL 50 mg 2.0 days, ATL 100 mg 2.0 days, ATL 150 mg 3.0 days). No clear effect of ATL-104 on the incidence of severe mucositis was noted. ATL-104 was well-tolerated at all the doses studied. The authors concluded that further investigation of ATL-104 is warranted.
A group from Dalarna and Uppsala Universities reported on the effects of oral cryotherapy on oral symptoms in patients receiving conditioning regimens prior to bone marrow transplantation. Ohrn, et al. compared the responses of a randomized group of 78 patients (half received cryotherapy and the others standard oral care) based on the completion of visual analog scales for 10 conditions of the mouth including pain, dryness, salivary viscosity, ability to talk, dysphagia, taste alterations, condition of the lips and gingival, and ability to perform oral hygiene. The authors found a pattern suggesting that patients who received oral cryotherapy experienced fewer oral symptoms (not statistically significant).
The results of two randomized trials in which low level laser therapy was studied were presented. In a Phase III randomized, double blind, placebo controlled trial, Schubert and his colleagues compared the ability of two different low level GaA1As diode lasers (40 mW 100 nm and 60 nW 780 nm) to prevent oral mucositis in hematopoietic stem cell transplant patients who received stomatotoxic conditioning regimens. Seventy patients were randomized into one of three treatment groups (2 laser therapy, 1 placebo). Patients in the laser groups were treated throughout the mouth beginning on the first day of conditioning and continuing until two days after transplant. The severity of mucositis and oral pain was assessed twice weekly until three weeks after transplant using the Oral Mucositis Index and a VAS pain scale. The authors reported that both lasers were efficacious in reducing mucositis—the 100 nm wavelength being superior—and concluded that additional studies are warranted.
In a different approach, Genot, et al. evaluated the ability of low energy laser treatment to delay the progression of mild mucositis to more severe grades. Thirty-six patients with hematological malignancies who had EORTC mucositis grades of 1 or 2 induced by stomatotoxic chemotherapy with or without radiation prior to HSCT were randomized to receive either treatment with low energy lasers (3J/cm2 ) or sham laser (n=18 per group). The frequency of laser treatment was not specified in the abstract. All patients had mild mucositis at study entry. The authors reported that while only three patients were treated with laser, 16 patients in the sham treated group went on to develop severe mucositis (grade 3). The time of progression of lesions to severe mucositis appeared to be delayed in the laser treated patients. The authors concluded that low level laser therapy appeared to be effective for the treatment of oral mucositis.
Mucosal injury of the gastrointestinal tract is an important and largely unmet side effect of cytotoxic cancer therapy that has broad health and economic ramifications for cancer patients. Interest in the complex biology underlying this condition continues to result in studies that ultimately will define its pathogenesis and provide targets for treatment. Identification of risk factors will permit interventions to be appropriately targeted. The development of effective therapies for the prevention and treatment of mucositis remains a high priority and continues to be aggressively pursued.
 Dudley W, Jasti S, Peterson D, et al. Latent Growth Curve Analysis of Individual Change in Chemotherapy Induced Oral Mucositis. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P33.
 CHENG KF, WONG MC, LEUNG SF, et al. Use of Rasch analysis in evaluation of the oropharyngeal mucositis quality of life scale (OMQoL). Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P35.
 Dörr E, Dörr W, Herrmann T, et al. 1Med. Faculty Carl Gustav Carus, Dept. Radiotherapy and Radiation Oncology, Dresden, Germany. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-41.
 de Moor C, Houts A, Weidner S, et al. Retrospective Analysis of Symptoms of Oral Mucositis (OM) in Community Oncology. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-44.
 Carrillo CM, dos Santos J, Oliveira, et al. Prevalence of mucocitis in patients with osteosarcoma. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-45.
 Leung SF, Cheng KK, Liang RH, et al. Impact of oropharyngeal mucositis on health-related quality of life in patients with cancer therapy. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-46.
 Grunberg S, Hesketh P, Randolph-Jackson P, et al. Risk and quality of life impact of mucosal injury among colorectal cancer patients receiving FOLFOX chemotherapy. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-50.
 Doerr E, Doerr W, Herrmann T, et al. Self-evaluation of the oral cavity by patients during radio(chemo)therapy for head-and-neck tumours. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-54.
 Nicolatou-Galitis O, Xanthinaki A, Kouloulias V, et al. Incidence and severity of mucositis in 93 head and neck cancer patients receiving radiotherapy. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-55.
 Keefe D, Garden A, Barasch A, et al. Oral Mucositis (OM) is associated with increased resource use among patients receiving treatment for cancers of the head and neck (HN). Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-34.
 Yeoh A, Gibson R, Yeoh E, et al. A novel animal model to investigate radiation-induced mucositis: a qualitative assessment of mucosal injury resulting from fractionated radiotherapy. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-25.
 Logan R, Gibson R, Bowen J, et al. Irinotecan causes elevated expression of nf-kb and pro-inflammatory cytokines along the alimentary tract of the dark agouti rat. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-29.
 Xanthinaki A, Nicolatou-Galitis O, Athanassiadou P, et al. Apoptotic and inflammation markers and gradeof mucositis in patients receiving radiotherapy for head/neck cancer: Preliminary report. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-56.
 Butler R, Howarth G, Geier M, et al. Palifermin regulates intestinal function and protects against 5-FU-induced mucositis. . Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-30.
 Chan T, Gibson R, .Bowen J, et al. The protective mechanism of palifermin in alimentaryMucositis. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-42.
 Doerr W, Doerr E, Herrmann T, et al. Effect of dexpanthenol vs. water mouth washes and mechanical cleansing of the mucosa on radiation-induced oral mucositis: Results of a randomized phase III trial in 366 patients. . Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-53.
 Hunter A, Mahendra P, Wilson K, et al. The efficacy of ATL-104, a swallowable mouthwash, in mucositis in patients undergoing peripheral blood stem cell transplantion: a randomised, double-blind, placebo-controlled, multicentre trial. . Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-39.
 Öhrn K, Svanberg A, Birgegård G, The effect of oral cryotherapy on oral symptoms. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-37.
 Schubert MM, Eduardo F, Guthrie K, et al. A Phase III randomized double-blind placebo controlled clinical trial to determine the efficacy of low level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic cell transplantation. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-36.
 Genot M, Awada A, Awada F, et al. A randomized study testing the efficacy of low-energy laser irradiation for treatment of oral mucositis in patients with haematological malignancy treated with intensive chemotherapy with or without radiotherapy and bone marrow transplant. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium. St. Gallen, Switzerland. 2007. Abstract # P-57