Radiation-induced Mucositis Research Articles

Sa2002 Therapeutic Usefulness of an Herbal Preparation, STW 5, in Protecting Against Radiation-Induced Intestinal Mucositis

Sa2002 Therapeutic Usefulness of an Herbal Preparation, STW 5, in Protecting Against Radiation-Induced Intestinal Mucositis

Sa2004 Effects of AVX-470m, an Oral Polyclonal Anti-TNF Antibody, on Survival and Biomarkers in a Murine Model of Gastrointestinal Acute Radiation Syndrome

Intestinal mucositis is a common side-effect in patients undergoing radiotherapy and poses a severe dose-limiting factor in treatment1. Identification of compounds that prevent radiationinduced mucositis and improve intestinal restitution may offer new therapeutic strategies for maintaining intestinalmucosal integrity in patients undergoing radiotherapy. Pathogenesis of mucositis involves production of pro-inflammatory cytokines and reactive oxygen metabolites2,3 and increased apoptosis in intestinal epithelium, leading to loss of intestinal structure and function4. STW 5 is an herbal multi-component preparation having potent anti-oxidant and anti-inflammatory properties in intestinal inflammatory disorders,5,6, making it an attractive candidate to study its potential usefulness in mucositis. Intestinal mucositis was induced experimentally in rats by exposing them to whole body irradiation from a Caesium 137 source at a radiation dose of 6 Gray. Three days later, rats developed intestinal mucositis, judged by histological examination of the small intestine and measurement of associated parameters in intestinal homogenates and serum. STW5 was given orally for 5 days to rats in graded doses of 2 10 ml/kg before exposing them to radiation and continued for 3 days after exposure. Animals were sacrificed 24h later. Pretreatment with STW 5 led to dosedependent reduction in histological changes. A dose of 5 ml/kg was chosen to study in detail the protective effects of the preparation on relevant associated parameters. Histologically, irradiation caused shortening and fusion of villi, activation of mucus secreting glands, inflammatory cell infiltration of lamina propria and mucosal atrophy. Inflammation markers: tumor necrosis factor and myeloperoxidase activity in homogenates were also raised. The changes were associated with a rise in thiobarbituric acid reactive substances, reduction in glutathione and in protein content of intestinal homogenates. Biomarkers of intestinal tissue injury: plasma diamineoxidase was raised while citrulline7 was significantly reduced. Apoptosis was evidenced by a rise in cytosolic calcium, depletion of mitochondrial cytochrome c and B-cell lymphoma 2. Most histological changes and associated derangement in the parameters tested were largely prevented by STW 5. The findings pave the way to a new therapeutic approach in management of radiation induced mucositis. 1Costa G and Donaldson SS (1979) N Engl J Med 300, 1471-1474, 2MacNaughton WK (2000) Aliment Pharmacol Ther. 14, 523-528, 3Linard C et al (2003) Am J Physiol Gastrointest Liver Physiol. 285, 556-565, 4Wong TC et al (2006) J Pain Symptom Manage. 32, 27-37, 5Khayyal MT et al (2006) Phytomedicine. 13 Suppl 5, 56-66, 6Schempp H et al (2006) Phytomedicine. 2006;13 Suppl 5, 36-44 7Lutgens L and Lambin P (2007) World J. Gastroenterol., 13, 3033 3042

Assessment of the effect of local application of amifostine on acute radiation-induced oral mucositis in guinea pigs

The aim of present study was to assess the radioprotective effects of the local application of amifostine to treat acute buccal mucositis in guinea pigs. A total of 32 guinea pigs were randomized into four groups: (Group A) topically administered 50 mg of amifostine plus radiotherapy (RT); (Group B) 100 mg amifostine plus RT; (Group C) normal saline plus RT; and (Group D) normal saline plus sham RT. The opportunity for administration was 15 min before irradiation. When administered, the cotton pieces that had been soaked with 0.5 ml amifostine solution or saline were applied gently on the buccal mucosa of each guinea pig for 30 min. The animals in Groups A, B and C were irradiated individually with a single dose of 30 Gy to the bilateral buccal mucosa. Eight days after irradiation, the animals were scored macroscopically; they were then euthanized, and the buccal mucosal tissues were processed for hematoxylin–eosin staining and ICAM-1 immunohistochemical analysis. In Groups A and B, the mean macroscopic scores were 2.9 ± 0.6 and 2.4 ± 1.1, respectively. There was no significant difference between the two groups (P > 0.05). However, when they were separately compared with Group C (4.4 ± 0.7), a noticeable difference was obtained (P < 0.05). No mucositis was observed in Group D. Comparisons of the expression of ICAM-1 were in agreement with the macroscopic data. Histologically, superficial erosion, exudate and ulcer formation were all observed in the RT groups; only the severity and extent were different. The microscopic observations in the amifostine-treated groups were better than in Group C. The results demonstrated that topical administration of amifostine to the oral mucosa is effective treatment of acute radiation-induced mucositis.

Role of oral glutamine in alleviation and prevention of radiation-induced oral mucositis: A prospective randomized study

Background:Oral mucositis is the most frequently occurring painful and dose-limiting side-effect of radiation of the head and neck region. Few studies demonstrated that oral glutamine suspension may significantly reduce the duration and severity of objective oral mucositis during radiotherapy.Materials and Methods:A randomized, prospective single institutional case control study was performed between April 2012 and November 2012 comparing the influence of oral glutamine on radiation induced mucositis in head and neck malignancy patients. Seventy biopsy proven patients with head and neck cancer receiving primary or adjuvant radiation therapy were randomized to receive either oral glutamine suspension daily 2h before radiation in the study arm (10 g in 1000 ml of water) (n = 35) or nothing before radiation; control arm (n = 35).Results and Analysis:Total 32 patients (91.43%) in the glutamine arm and total 34 patients (97.15%) developed mucositis. Grade 3 mucositis (14.29%) and grade 4 mucositis (2.86%) in the study arm (who received oral glutamine) were significantly less (P = 0.02 and P = 0.04, respectively) in the glutamine arm. The mean duration of grade 3 or worse mucositis (grade 3 and grade 4) was significantly less (6.6 days vs. 9.2 days) in study arm with P < 0.001. Mean time of onset of mucositis was significantly delayed in patients who took glutamine in comparison to control arm with P < 0.001.Conclusion:Glutamine delays oral mucositis in the head neck cancer patients. Moreover, it reduces the frequency and duration of grade 3 and grade 4 mucositis.

A novel synthetic compound 3-amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione (KR22332) exerts a radioprotective effect via the inhibition of mitochondrial dysfunction and generation of reactive oxygen species.

PurposeAcute side effects of radiation such as oral mucositis are observed in most patients. Although several potential radioprotective agents have been proposed, no effective agent has yet been identified. In this study, we investigated the effectiveness of synthetic compound 3-amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione (KR22332) as a radioprotective agent.Materials and MethodsCell viability, apoptosis, the generation of reactive oxygen species (ROS), mitochondrial membrane potential changes, and changes in apoptosis-related signaling were examined in human keratinocyte (HaCaT).ResultsKR22332 inhibited irradiation-induced apoptosis and intracellular ROS generation, and it markedly attenuated the changes in mitochondrial membrane potential in primary human keratinocytes. Moreover, KR22332 significantly reduced the protein expression levels of ataxia telangiectasia mutated protein, p53, and tumor necrosis factor (TNF)-α compared to significant increases observed after radiation treatment.ConclusionKR22332 significantly inhibited radiation-induced apoptosis in human keratinocytes in vitro, indicating that it might be a safe and effective treatment for the prevention of radiation-induced mucositis.

Effect of Iranian Propolis on Salivary Total Antioxidant Capacity in Gamma-irradiated Rats.

Background and aims. The antioxidant and anti-inflammatory properties of propolis were studied. Since saliva containsantioxidants and radiotherapy of the head and neck mainly affects the saliva, salivary antioxidant defensive mechanism iscompromised with oxidative stress produced by radiation therapy. Therefore, the aim of the present study was to investigatethe effect of propolis on salivary total antioxidant capacity in irradiated rats.Materials and methods. The study was conducted on 28 rats, 7-11 weeks of age (160±20 g), divided into four groups:saline with no radiation (S), saline and radiation (SR), propolis with no radiation (P) [400 mg/kg IP], propolis and radiation(PR) [400 mg/kg IP]. SP and PR were exposed to 15 Gy of gamma irradiation for 7 minutes and 39 seconds. The rats received intraperitoneal injections each day for 10 days, and their tongues and lips were daily examined for mucositis; salivasample were also taken three times on days 0, 6, and 10.Results. Mucositis incidence appeared to be delayed in the PR compared to the SR, and the severity was significantlyhigher in the SR compared to the PR. No significant alterations were observed in salivary antioxidant levels during the ex-periment, except the SR group in which a significant reduction was found.Conclusion. Propolis might reduce and delay radiation-induced mucositis in animal models; it might be able to prevent thereduction in salivary antioxidant levels in irradiated rats as well.

A randomized placebo-controlled trial of manuka honey for radiation-induced oral mucositis

Few treatments have the potential to reduce the severity of radiation-induced mucositis in head and neck cancer patients. Some small studies have suggested that organic honey may be a useful preventive treatment. This investigator-initiated double-blind randomized placebo-controlled trial investigated whether honey reduced the severity of radiation-induced oral mucositis (ROM). One hundred six head and neck cancer patients from the Vancouver and Sudbury Cancer Centers in Canada were randomized to swish, hold, and swallow either 5 ml of irradiated organic manuka honey or a placebo gel, four times a day throughout radiation treatment, plus seven more days. Severity of oral mucositis according to the Radiation Therapy Oncology Group (RTOG), World Health Organization (WHO), and Oral Mucositis Assessment Scale scales, weight, and subjects' symptom severity and quality of life were assessed weekly. Sialometry was performed at baseline and at the last study visit. One hundred six patients were recruited. Twenty-four did not attend any mucositis assessments. One was removed from the study because of off-study consumption of store-bought manuka honey. The remaining 81 patients had at least one mucositis assessment and were included in the analysis. Sixty-two percent of subjects received concurrent chemotherapy; 81 % were male. The groups were well-matched, and blinding was excellent. Dropouts were mostly due to nausea and were similar in both arms, with 78 % being able to tolerate the study products for more than 1 week. The dropout rate was 57 % in those who received honey and 52 % in those who received placebo gel. The dropout rate in those who had concurrent chemotherapy was 59 % and in those who only received radiation was 47 %. There was no statistically significant difference between the honey and placebo arms in any of the outcome indicators. Those who completed the study in both treatment arms had low rates of RTOG greater than or equal to grade 3 mucositis; 35 % in the honey group and 43 % in the placebo group. Despite promising earlier reports, manuka honey was not tolerated well by our patients and, even when used as directed, did not have a significant impact on the severity of ROM.

The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer

Radiation-induced oral mucositis is an acute morbidity seen in patients undergoing treatment for head and neck cancers. In this study, we evaluated the efficacy of turmeric in preventing radiation-induced mucositis. This was a single-blinded, randomized, controlled clinical trial and was conducted with head and neck cancer patients requiring 70 Gy of radiation or chemoradiotherapy (daily radiotherapy plus carboplatin once a week). Eligible patients (n = 80) were randomly assigned to receive either turmeric gargle (n = 40) or povidone-iodine ([n = 40] active comparator condition) during chemo/radiotherapy during the period of treatment. Oral mucositis was assessed using the RTOG (Radiation Therapy Oncology Group) grading system before the start, during, and at the end of the treatment by an investigator unaware of the treatment. The primary endpoint of this study was the incidence of mucositis every week during the 7-week period. The secondary endpoint was the effect of turmeric gargle on the incidence of treatment breaks, loss of scheduled treatment days, and decrease in body weight at the end of the treatment. This study clearly suggests that when compared with the cohorts using povidone-iodine gargle, the group using turmeric as a mouthwash had delayed and reduced the levels of radiation-induced oral mucositis and was statistically significant at all time points (P< 0.001 toP< 0.0001). Additionally, the cohorts using turmeric had decreased intolerable mucositis (P< 0.001) and lesser incidence of treatment breaks in the first half of the treatment schedule before 4 weeks (P< 0.01) and reduced change in body weight (P< 0.001). Gargling with turmeric by head and neck cancer patients undergoing radiation therapy provided significant benefit by delaying and reducing the severity of mucositis. Turmeric is readily available, relatively inexpensive, and highly accepted making it useful in cancer treatment.

Effect of Epicatechin against Radiation-Induced Oral Mucositis: In Vitro and In Vivo Study

PurposeRadiation-induced oral mucositis limits the delivery of high-dose radiation to head and neck cancer. This study investigated the effectiveness of epicatechin (EC), a component of green tea extracts, on radiation-induced oral mucositis in vitro and in vivo.Experimental DesignThe effect of EC on radiation-induced cytotoxicity was analyzed in the human keratinocyte line HaCaT. Radiation-induced apoptosis, change in mitochondrial membrane potential (MMP), reactive oxygen species (ROS) generation and changes in the signaling pathway were investigated. In vivo therapeutic effects of EC for oral mucositis were explored in a rat model. Rats were monitored by daily inspections of the oral cavity, amount of oral intake, weight change and survival rate. For histopathologic evaluation, hematoxylin-eosin staining and TUNEL staining were performed.ResultsEC significantly inhibited radiation-induced apoptosis, change of MMP, and intracellular ROS generation in HaCaT cells. EC treatment markedly attenuated the expression of p-JNK, p-38, and cleaved caspase-3 after irradiation in the HaCaT cells. Rats with radiation-induced oral mucositis showed decreased oral intake, weight and survival rate, but oral administration of EC significantly restored all three parameters. Histopathologic changes were significantly decreased in the EC-treated irradiated rats. TUNEL staining of rat oral mucosa revealed that EC treatment significantly decreased radiation-induced apoptotic cells.ConclusionsThis study suggests that EC significantly inhibited radiation-induced apoptosis in keratinocytes and rat oral mucosa and may be a safe and effective candidate treatment for the prevention of radiation-induced mucositis.

Tissue-engineered oral mucosa to study radiotherapy-induced oral mucositis

Purpose: Oral mucositis is a severe and often dose-limiting side-effect of cancer therapy that occurs in patients receiving radiotherapy for head and neck cancers. Although radiation-induced effects on keratinocytes have been studied, little is known about its effect on fibroblasts or endothelial cells or, more importantly, when all these cells are combined in an engineered oral mucosal model.Materials and methods: Monolayer cultures of normal oral keratinocytes, normal oral fibroblasts, human dermal microvascular endothelial cells or tissue-engineered oral mucosa (TEOM) were exposed to 20 Gy irradiation. Cell damage and cytokine release was measured for 72 h for monolayer cultures and for up to 21 d for TEOM.Results: Compared to non-irradiated cells, the viability of all monolayer and co-cultures was significantly reduced 72 h post-irradiation while levels of secreted interleukin IL-6 and CXCL8 were increased. The viability of irradiated TEOM models was significantly reduced compared to controls at all time-points. Histologically, irradiated TEOM displayed thinner epithelium, increased apoptosis and more extensive damage than non-irradiated models. IL-6, CXCL8 and granulocyte macrophage colony-stimulating factor release was reduced whereas IL-1α levels were increased in irradiated TEOM models compared to controls.Conclusions: TEOM models comprising of mixed cell populations may prove useful in examining the pathobiology of radiation-induced mucositis.

Prevention and management of radiation-induced dermatitis, mucositis, and xerostomia

Current strategies for preventing and managing radiation-induced dermatitis, mucositis, and xerostomia are reviewed, with an emphasis on pharmacologic interventions. Nearly two thirds of all patients with cancer receive radiation therapy during the course of treatment, frequently resulting in acute skin and mucosal toxicities. The severity of radiotherapy-associated toxicities varies according to multiple treatment- and patient-related factors (e.g., total radiation dose and dose fractionation schedule, volume of organ or tissue irradiated, use of concurrent versus sequential chemotherapy, comorbid conditions, functional performance status). Three major radiation toxicities encountered in clinical practice are (1) radiation dermatitis, typically managed with a variety of topical agents such as water-based moisturizing creams or lotions, topical steroids, antiinflammatory emulsions, and wound dressings, (2) radiation-induced oral mucositis, which can be managed through proper basic oral care practices, appropriate pain management, and the use of medicated mouthwashes and oral rinses and gels, and (3) radiation-induced xerostomia, which can be alleviated with saliva substitutes, moistening agents, and sialagogues. Pharmacists involved in the care of patients receiving radiotherapy can play an important role in optimizing symptom control, educating patients on self-care strategies, and adverse effect monitoring and reporting. Radiation-induced dermatitis, mucositis, and xerostomia can cause significant morbidity and diminished quality of life. Pharmacologic interventions for the prevention and treatment of these toxicities include topical agents for dermatitis; oral products, analgesics, and palifermin for mucositis; and amifostine, saliva substitutes, and pilocarpine for xerostomia.

Antioxidant capacity of calendula officinalis flowers extract and prevention of radiation induced oropharyngeal mucositis in patients with head and neck cancers: a randomized controlled clinical study

This study was designed to determine the effect of Calendula officinalis flowers extract mouthwash as oral gel on radiation-induced oropharyngeal mucositis (OM) in patients with head-and-neck cancer. Forty patients with neck and head cancers under radiotherapy or concurrent chemoradiotherapy protocols were randomly assigned to receive either 2% calendula extract mouthwash or placebo (20 patients in each group). Patients were treated with telecobalt radiotherapy at conventional fractionation (200 cGy/fraction, five fractions weekly, 30–35 fractions within 4–7 weeks). The oropharyngeal mucositis was evaluated by two clinical investigators (a radiation oncologist and a dentist), using the oral mucositis assessment scale (OMAS). Trying to find out the possible mechanism of action of the treatment, total antioxidant, polyphenol and flavonoid contents, and quercetin concentration of the mouth wash were measured. Calendula mouthwash significantly decreased the intensity of OM compared to placebo at week 2 (score: 5.5 vs. 6.8, p = 0.019), week 3 (score: 8.25 vs. 10.95, p < 0.0001) and week 6 (score: 11.4 vs. 13.35, p = 0.031). Total antioxidant, polyphenol and flavonoid contents and quercetin concentration of the 2% extract were 2353.4 ± 56.5 μM, 313.40 ± 6.52 mg/g, 76.66 ± 23.24 mg/g, and 19.41 ± 4.34 mg/l, respectively. Calendula extract gel could be effective on decreasing the intensity of radiotherapy- induced OM during the treatment and antioxidant capacity may be partly responsible for the effect.

Damped sinusoidal function to model acute irradiation in radiotherapy patients

In the paper, we suggest a damped sinusoidal function be used to model a regenerative response of mucosa in time after the radiotherapy treatment. The medical history of 389 RT patients irradiated within the years 1994–2000 at the Radiotherapy Department, Cancer Center, Maria Skłodowska-Curie Memorial Institute of Oncology, Gliwice, Poland, was taken into account. In the analyzed group of patients, the number of observations of a single patient ranged from 2 to 25 (mean = 8.3, median = 8) with severity determined by use of Dische's scores from 0 to 24 (mean = 7.4, median = 7). Statistical modeling of radiation-induced mucositis was performed for five groups of patients irradiated within the following radiotherapy schedules: CAIR, CB, Manchester, CHA–CHA, and Conventional. All of the regression parameters of the assumed model, i.e. amplitude, damping coefficient, angular frequency, phase of component, and offset, estimated in the analysis were statistically significant (p-value < 0.05) for the radiotherapy schedules. The model was validated using a non-oscillatory function. Following goodness-of-fit statistics, the damped sinusoidal function fits the data better than the non-oscillatory damped function. Model curves for harmonic characteristics with confidence intervals were plotted separately for each of the RT schedules and together in a combined design. The suggested model might be helpful in the numeric evaluation of the RT toxicity in the groups of patients under analysis as it allows for practical comparisons and treatment optimization. A statistical approach is also briefly described in the paper.

Changes of tumor and normal structures of the neck during radiation therapy for head and neck cancer requires adaptive strategy

The treatment period over which radiation therapy is administered extends over several weeks. Since tumor shrinkage in response to radiation therapy and weight loss due to radiation-induced mucositis may impact on the dose distribution in both target and organ at risk in patients with head and neck cancer, the anatomical changes of tumor and neck volumes during this period should be taken into consideration. We investigated the anatomical changes that occurred in the target and normal structure of the neck during radiation therapy for pharyngeal cancer, and evaluated the necessity of an adaptive strategy. Ten patients with pharyngeal cancer who underwent radical chemoradiation therapy using 3-dimensional conformal radiation therapy RT (66-70 Gy in 33-35 fractions) between April 2009 and September 2010 were enrolled in the study. Patients underwent CT scans every week during their course of treatment. We analyzed the CT data in the radiation treatment planning system and measured changes of tumor, organ at risk, and neck volume. Gross tumor volume (GTV) was rapidly reduced by 28% of the original volume on average in the first 3 weeks. The right and left submandibular glands volume decreased to 70% and 63% of their initial volumes on average, respectively. The volume of the neck in the radiation fields decreased to 89% of its initial volume on average by the sixth week mainly caused by body weight loss due to acute radiation morbidity. Considerable anatomical change in the radiation filed that will affect dose distribution of the target and organ at risk was observed during radiation therapy for head and neck cancer.

Ozone applications in dentistry: an overview

Ozone therapy has been successfully used in the medical field for treatment of various diseases, for more than 100 years. Researches have shown the efficacy of both gaseous and dissolved ozone in eradicating a wide range of bacteria, bacterial spores and viruses. Ozone could also help in healing wounds, treatment of radiation-induced mucositis and osteoradionecrosis by increasing the blood supply and through modulation of inflammatory mediators. Despite of these advantages, therapeutic ozone’s application in dentistry is limited because of its possible side effects on upper respiratory system. Dental practitioners need to know the proper usage of modern pharmaceutical methods like ozone, that can provide better patient care and considerably cut down the time and cost of treatment.

WS10-2 - A Pilot Randomized Trial Comparing Standard Pain Control with or without Gabapentin for the Treatment of Pain Related to Radiation-Induced Mucositis in Head and Neck Cancer

ABSTRACT Background Radiation-induced mucositis (RIM) in chemoradiation (CRT) for head and neck cancer (HNC) causes severe pain and worsens CRT compliance and outcome. Following retrospective reports that gabapentin might improve RIM-associated pain during CRT, we conducted a randomized phase II trial to analyze the safety and efficacy of gabapentin for RIM-associated pain. Methods HNC patients (pts) receiving CRT were randomized to receive standard pain control (SPC) or SPC plus gabapentin (SPC + G). Pts in the SPC arm received acetaminophen and opioids as analgesic, while those in the SPC + G arm received gabapentin in addition to SPC. Gabapentin maintained at dose of 900 mg/day till 4 weeks after CRT. The prescribed RT dose was 66-70 Gy/33-35Fr. Concurrent chemotherapy consisted of a three-week cycle of cisplatin. Primary endpoint was maximum VAS score during CRT. Secondary endpoints were total dose of opioids, change in QOL (EORTC QLQ-C30 and EORTC QLQ-HN 35) from base line to 4 weeks after CRT, and adverse events. Results From Apr 2010 to Oct 2011, 22 eligible pts were randomly assigned to receive SPC (n = 11) or SPC + G (n = 11). All pts were Stage III or IV. Twelve were treated in a locally advanced setting and 10 in a postoperative setting. No statistically significant differences were seen in median maximum VAS scores between arms (47 in SPC vs. 74 in SPC + G; p = 0.517). Median total dose of opioids at maximum VAS and total dose of opioids at 4 weeks after CRT did not statistically differ but appeared higher in the SPC + G arm (215 mg vs. 745.3 mg; p = 0.880, 1260 mg vs. 1537.5 mg; p = 0.9438). QOL analysis showed significantly worse scores in the SPC + G arm for weight gain (p = 0.005). Adverse events related to gabapentin were manageable. One-year survival rate in both arms was equivalent. Conclusions This is the first prospective randomized trial to analyze the safety and efficacy of gabapentin for RIM-associated pain. While survival data was equivalent in both arms, gabapentin may have detrimental effects for RIM and further investigation is warranted. Disclosure N. Kiyota: an advisory board member on proper usage of cetuximab for head and neck cancer in Japan (Merck Serono) All other authors have declared no conflicts of interest.

MTOR Inhibition Prevents Epithelial Stem Cell Senescence and Protects from Radiation-Induced Mucositis

The integrity of the epidermis and mucosal epithelia is highly dependent on resident self-renewing stem cells, which makes them vulnerable to physical and chemical insults compromising the repopulating capacity of the epithelial stem cell compartment. This is frequently the case in cancer patients receiving radiation or chemotherapy, many of whom develop mucositis, a debilitating condition involving painful and deep mucosal ulcerations. Here, we show that inhibiting the mammalian target of rapamycin (mTOR) with rapamycin increases the clonogenic capacity of primary human oral keratinocytes and their resident self-renewing cells by preventing stem cell senescence. This protective effect of rapamycin is mediated by the increase in expression of mitochondrial superoxide dismutase (MnSOD), and the consequent inhibition of ROS formation and oxidative stress. mTOR inhibition also protects from the loss of proliferative basal epithelial stem cells upon ionizing radiation in vivo, thereby preserving the integrity of the oral mucosa and protecting from radiation-induced mucositis.

Relief with Rapamycin: mTOR Inhibition Protects against Radiation-Induced Mucositis

In this issue of Cell Stem Cell, Iglesias-Bartolome et al. (2012) show that mTOR inhibition with rapamycin protects against mucositis in mice, suggesting potential treatment strategies against this harmful side effect of anticancer therapies. In normal tissues, rapamycin prevents epithelial stem cell senescence by reducing oxidative stress through increased MnSOD.

1581P - A Randomized Phase II Trial Comparing Standard Pain Control with or Without Gabapentin for the Treatment of Pain Related to Radiation-Induced Mucositis in Head and Neck Cancer

ABSTRACT Background Radiation-induced mucositis (RIM) in chemoradiation (CRT) for head and neck cancer (HNC) causes severe pain and worsens CRT compliance and outcome. Following retrospective reports that gabapentin might improve RIM-associated pain during CRT, we conducted a randomized phase II trial to analyze the safety and efficacy of gabapentin for RIM-associated pain. Methods HNC patients (pts) receiving CRT were randomized to receive standard pain control (SPC) or SPC plus gabapentin (SPC + G). Pts in the SPC arm received acetaminophen and opioids as analgesic, while those in the SPC + G arm received gabapentin in addition to SPC. Gabapentin maintained at dose of 900 mg/day till 4 weeks after CRT. The prescribed RT dose was 66-70 Gy/33-35Fr. Concurrent chemotherapy consisted of a three-week cycle of cisplatin. Primary endpoint was maximum VAS score during CRT. Secondary endpoints were total dose of opioids, change in QOL (EORTC QLQ-C30 and EORTC QLQ-HN 35) from base line to 4 weeks after CRT, and adverse events. Results From Apr 2010 to Oct 2011, 22 eligible pts were randomly assigned to receive SPC (n = 11) or SPC + G (n = 11). All pts were Stage III or IV. Twelve were treated in a locally advanced setting and 10 in a postoperative setting. No statistically significant differences were seen in median maximum VAS scores between arms (47 in SPC vs. 74 in SPC + G; p = 0.517). Median total dose of opioids at maximum VAS and total dose of opioids at 4 weeks after CRT did not statistically differ but appeared higher in the SPC + G arm (215 mg vs. 745.3 mg; p = 0.880, 1260 mg vs. 1537.5 mg; p = 0.9438). QOL analysis showed significantly worse scores in the SPC + G arm for weight gain (p = 0.005). Adverse events related to gabapentin were manageable. One-year survival rate in both arms was equivalent. Conclusions This is the first prospective randomized trial to analyze the safety and efficacy of gabapentin for RIM-associated pain. While survival data was equivalent in both arms, gabapentin may have detrimental effects for RIM and further investigation is warranted. Disclosure N. Kiyota: an advisory board member on proper usage of cetuximab for head and neck cancer in Japan (Merck Serono) All other authors have declared no conflicts of interest.

1059 - Anti Oxidant Capacity of Calendula Officinalis Flowers Extract and Prevention of Radiation Induced Oropharyngeal Mucositis in Patients with Head and Neck Cancers: A Randomized Controlled Clinical Study

ABSTRACT To determine the effect of Calendula officinalis flower extract mouthwash as gel formulation on radiation-induced oropharyngeal mucositis (OM) in patients with head-and-neck cancer. Forty patients with neck and head cancers who were treated with radiotherapy or chemoradiotherapy were randomly assigned to receive either 2% calendula extract mouthwash or placebo (20 patients in each group). The subjects were treated with telecobalt radiotherapy at conventional fractionation (2 Gy/fraction, five fractions weekly, 20–35 fractions within 4–7 weeks). Oropharyngeal mucositis was evaluated by two doctors (a radiation oncologist and a dentist), using the oral mucositis assessment scale (OMAS). The patients also received concurrent chemotherapy. Calendula mouthwash significantly decreased the intensity of OM compared to placebo at week 2 (score: 5.5 vs. 6.8, p = 0.019), week 3 (score: 8.25 vs. 10.95, p Disclosure All authors have declared no conflicts of interest.