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    Long-term outcomes with concurrent carboplatin, paclitaxel and radiation therapy for locally advanced, inoperable head and neck cancer. Agarwala S S,Cano E,Heron D E,Johnson J,Myers E,Sandulache V,Bahri S,Ferris R,Wang Y,Argiris A Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Our goal was to evaluate long-term efficacy outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) treated with carboplatin, paclitaxel (Taxol) and radiotherapy. PATIENTS AND METHODS:We conducted a phase II trial in inoperable patients with locally advanced SCCHN. Carboplatin 100 mg/m(2) and paclitaxel 40 mg/m(2) were administered i.v. once a week during external beam radiation therapy (180 cGy per fraction) for 6-7 weeks. Interstitial brachytherapy was used as a boost in selected patients with primary malignancies of the oral cavity and the oropharynx. RESULTS:Fifty-five patients were enrolled. Fifty-two patients (95%) had stage IV and 51 (93%) had technically unresectable disease; 62% had an oropharyngeal primary site. Twenty-one patients underwent brachytherapy boost. Grade 3 or 4 mucositis occurred in 30% of patients. One death occurred during treatment that was related to complications of gastrostomy tube placement. Forty of 50 assessable patients (80%) had an objective response, with a complete response rate of 52%. With a median follow-up of 69 months for surviving patients, the 5-year progression-free survival was 36% and the 5-year overall survival was 35%. Two of the 18 long-term survivors of >50 months were gastrostomy tube feeding dependent. Patients undergoing brachytherapy boost (n = 21) had similar outcomes compared with the rest of the patients. In multivariate analysis, baseline hemoglobin levels and N stage were predictive of survival. CONCLUSION:Treatment with concurrent carboplatin, paclitaxel and radiation is safe and offers curative potential for poor prognosis patients with locally advanced SCCHN. 10.1093/annonc/mdm088
    Evaluation of D-methionine as a novel oral radiation protector for prevention of mucositis. Vuyyuri Saleha B,Hamstra Daniel A,Khanna Divya,Hamilton Christin A,Markwart Sonja M,Campbell Kathleen C M,Sunkara Prasad,Ross Brian D,Rehemtulla Alnawaz Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:Oral mucositis is a common acute morbidity associated with radiation and/or chemotherapy treatment for cancer. D-Methionine (D-Met), the dextro-isomer of the common amino acid l-methionine, has been documented to protect normal tissues from a diverse array of oxidative insults. EXPERIMENTAL DESIGN:We evaluated if D-Met could selectively prevent radiation-induced oral mucositis using in vitro cell culture models as well as an in vivo model of radiation injury to the oral mucosa in C3H mice. RESULTS:Unlike free-radical scavengers, which protected both normal and transformed tumor cells in vitro from radiation-induced cell death, treatment with d-Met in culture protected nontransformed primary human cells from radiation-induced cell death (protective factor between 1.2 and 1.6; P<0.05) whereas it did not confer a similar protection on transformed tumor cells. D-Met treatment also provided significant protection to normal human fibroblasts, but not to tumor cell lines, from radiation-induced loss of clonogenicity (protection factor, 1.6+/-0.15). D-Met treatment did not alter DNA damage (as measured by histone phosphorylation) following irradiation but seemed to selectively mitigate the loss of mitochondrial membrane potential in nontransformed cells, whereas it did not provide a similar protection to tumor cells. Tumor control of implanted xenografts treated with radiation or concurrent cisplatin and radiation was not altered by D-Met treatment. Pharmacokinetics following administration of a liquid suspension of D-Met in rats showed 68% bioavailability relative to i.v. administration. Finally, in a murine model of mucositis, a dose-dependent increase in protection was observed with the protective factor increasing from 1.6 to 2.6 over a range of oral D-Met doses between 200 and 500 mg/kg (P<0.0003). CONCLUSIONS:D-Met protected normal tissues, but not tumor cells, in culture from radiation-induced cell death; it also protected normal cells from radiation-induced mucosal injury in a murine model but did not alter tumor response to therapy. Further studies on the use of D-Met to protect from oral mucositis are warranted. 10.1158/1078-0432.CCR-07-1954
    Radiation treatment breaks and ulcerative mucositis in head and neck cancer. Russo Gregory,Haddad Robert,Posner Marshall,Machtay Mitchell The oncologist Unplanned radiation treatment breaks and prolongation of the radiation treatment time are associated with lower survival and locoregional control rates when radiotherapy or concurrent chemoradiotherapy is used in the curative treatment of head and neck cancer. Treatment of head and neck cancer is intense, involving high-dose, continuous radiotherapy, and often adding chemotherapy to radiotherapy. As the intensity of treatment regimens has escalated in recent years, clinical outcomes generally have improved. However, more intensive therapy also increases the incidence of treatment-related toxicities, particularly those impacting the mucosal lining of the oral cavity, pharynx, and cervical esophagus, and results in varying degrees of ulcerative mucositis. Ulcerative mucositis is a root cause of unscheduled radiation treatment breaks, which prolongs the total radiation treatment time. Alterations in radiotherapy and chemotherapy, including the use of continuous (i.e., 7 days/week) radiotherapy to ensure constant negative proliferative pressure, may improve efficacy outcomes. However, these approaches also increase the incidence of ulcerative mucositis, thereby increasing the incidence of unplanned radiation treatment breaks. Conversely, the reduction of ulcerative mucositis to minimize unplanned breaks in radiotherapy may enhance not only tolerability, but also efficacy outcomes. Several strategies to prevent ulcerative mucositis in radiotherapy for head and neck cancer have been evaluated, but none have demonstrated strong efficacy. Continued investigation is needed to identify superior radiation treatment regimens, technology, and supportive care that reduce unplanned radiation treatment breaks with the goal of improving clinical outcomes in head and neck cancer. 10.1634/theoncologist.2008-0024
    Prospective evaluation to establish a dose response for clinical oral mucositis in patients undergoing head-and-neck conformal radiotherapy. Narayan Samir,Lehmann Joerg,Coleman Matthew A,Vaughan Andrew,Yang Claus Chunli,Enepekides Danny,Farwell Gregory,Purdy James A,Laredo Grace,Nolan Kerry,Pearson Francesca S,Vijayakumar Srinivasan International journal of radiation oncology, biology, physics PURPOSE:We conducted a clinical study to correlate oral cavity dose with clinical mucositis, perform in vivo dosimetry, and determine the feasibility of obtaining buccal mucosal cell samples in patients undergoing head-and-neck radiation therapy. The main objective is to establish a quantitative dose response for clinical oral mucositis. METHODS AND MATERIALS:Twelve patients undergoing radiation therapy for head-and-neck cancer were prospectively studied. Four points were chosen in separate quadrants of the oral cavity. Calculated dose distributions were generated by using AcQPlan and Eclipse treatment planning systems. MOSFET dosimeters were used to measure dose at each sampled point. Each patient underwent buccal sampling for future RNA analysis before and after the first radiation treatment at the four selected points. Clinical and functional mucositis were assessed weekly according to National Cancer Institute Common Toxicity Criteria, Version 3. RESULTS:Maximum and average doses for sampled sites ranged from 7.4-62.3 and 3.0-54.3 Gy, respectively. A cumulative point dose of 39.1 Gy resulted in mucositis for 3 weeks or longer. Mild severity (Grade </= 1) and short duration (</=1 week) of mucositis were found at cumulative point doses less than 32 Gy. Polymerase chain reaction consistently was able to detect basal levels of two known radiation responsive genes. CONCLUSIONS:In our sample, cumulative doses to the oral cavity of less than 32 Gy were associated with minimal acute mucositis. A dose greater than 39 Gy was associated with longer duration of mucositis. Our technique for sampling buccal mucosa yielded sufficient cells for RNA analysis using polymerase chain reaction. 10.1016/j.ijrobp.2008.01.060
    Patient-reported measurements of oral mucositis in head and neck cancer patients treated with radiotherapy with or without chemotherapy: demonstration of increased frequency, severity, resistance to palliation, and impact on quality of life. Elting Linda S,Keefe Dorothy M,Sonis Stephen T,Garden Adam S,Spijkervet F K L,Barasch Andrei,Tishler Roy B,Canty Thomas P,Kudrimoti Mahesh K,Vera-Llonch Montserrat, Cancer BACKGROUND:The risk, severity, and patient-reported outcomes of radiation-induced mucositis among head and neck cancer patients were prospectively estimated. METHODS:A validated, patient-reported questionnaire (OMDQ), the FACT quality of life (QOL), and the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scales were used to measure mucositis (reported as mouth and throat soreness), daily functioning, and use of analgesics. Patients were studied before radiotherapy (RT), daily during RT, and for 4 weeks after RT. RESULTS:Contrary to previous reports, the risk of mucositis was virtually identical in the 126 patients with oral cavity or oropharynx tumors (99% overall; 85% grade 3-4) compared with 65 patients with tumors of the larynx or hypopharynx (98% overall; 77% grade 3-4). The mean QOL score decreased significantly during RT, from 85.1 at baseline to 69.0 at Week 6, corresponding with the peak of mucositis severity. The mean functional status score decreased by 33% from 18.3 at baseline to 12.3 at Week 6. The impact of mucositis on QOL was proportional to its severity, although even a score of 1 or 2 (mild or moderate) was associated with a significant reduction in QOL (from 93.6 at baseline to 74.7 at Week 6). Despite increases in analgesic use from 34% at baseline to 80% at Week 6, mean mucositis scores exceeded 2.5 at Week 6. CONCLUSIONS:Mucositis occurs among virtually all patients who are undergoing radiation treatment of head and neck cancers. The detrimental effects on QOL and functional status are significant, and opioid analgesia provides inadequate relief. Preventive rather than symptom palliation measures are needed. 10.1002/cncr.23898
    Comparison of toxicity associated with early morning versus late afternoon radiotherapy in patients with head-and-neck cancer: a prospective randomized trial of the National Cancer Institute of Canada Clinical Trials Group (HN3). Bjarnason Georg A,Mackenzie Robert G,Nabid Abdenour,Hodson Ian D,El-Sayed Samy,Grimard Laval,Brundage Michael,Wright James,Hay John,Ganguly Pradip,Leong Carson,Wilson Jane,Jordan Richard C K,Walker Melanie,Tu Dongsheng,Parulekar Wendy, International journal of radiation oncology, biology, physics PURPOSE:Based on our demonstration of a circadian rhythm in the human oral mucosa cell cycle, with most cells in the G(1) phase in the morning and M phase at night, we hypothesized that morning radiotherapy (RT) would lead to less oral mucositis than afternoon RT. METHODS AND MATERIALS:A total of 216 patients were randomized to morning (8-10 AM) vs. afternoon (4-6 PM) RT and stratified by radiation dose, smoking status, and center. Patients receiving primary or postoperative RT alone were eligible. Oral mucositis was scored using the Radiation Therapy Oncology Group (RTOG) criteria and a validated scoring system. RESULTS:Of 205 evaluable patients, 52.9% vs. 62.4% developed RTOG Grade 3 or greater mucositis after morning vs. afternoon RT, respectively (p = 0.17). Morning RT was also associated with significantly less weight loss after 5 months (p = 0.024). In a subgroup of 111 patients treated to a dose of 66-70 Gy in 33-35 fractions, exploratory analyses revealed a significant reduction in Grade 3 or greater mucositis with morning RT (44.6% vs. 67.3%, p = 0.022) and a longer interval to the development of Grade 3 or greater mucositis (median, >7.9 vs. 5.6 weeks, p = 0.033). In 53 patients, who smoked during therapy, a significant reduction was found in Grade 3 or greater mucositis with morning RT (42.9% vs. 76%, p = 0.025). CONCLUSION:In this proof of principle study, morning RT was associated with significantly less weight loss after 5 months and an apparent reduction in oral mucositis in a subset of patients receiving >/=66 Gy and in patients who smoked during therapy. 10.1016/j.ijrobp.2008.07.009
    Intensity-modulated radiotherapy in postoperative treatment of oral cavity cancers. Gomez Daniel R,Zhung Joanne E,Gomez Jennifer,Chan Kelvin,Wu Abraham J,Wolden Suzanne L,Pfister David G,Shaha Ashok,Shah Jatin P,Kraus Dennis H,Wong Richard J,Lee Nancy Y International journal of radiation oncology, biology, physics PURPOSE:To present our single-institution experience of intensity-modulated radiotherapy (IMRT) for oral cavity cancer. METHODS AND MATERIALS:Between September 2000 and December 2006, 35 patients with histologically confirmed squamous cell carcinoma of the oral cavity underwent surgery followed by postoperative IMRT. The sites included were buccal mucosa in 8, oral tongue in 11, floor of the mouth in 9, gingiva in 4, hard palate in 2, and retromolar trigone in 1. Most patients had Stage III-IV disease (80%). Ten patients (29%) also received concurrent postoperative chemotherapy with IMRT. The median prescribed radiation dose was 60 Gy. RESULTS:The median follow-up for surviving patients was 28.1 months (range, 11.9-85.1). Treatment failure occurred in 11 cases as follows: local in 4, regional in 2, and distant metastases in 5. Of the 5 patients with distant metastases, 2 presented with dermal metastases. The 2- and 3-year estimates of locoregional progression-free survival, distant metastasis-free survival, disease-free survival, and overall survival were 84% and 77%, 85% and 85%, 70% and 64%, and 74% and 74%, respectively. Acute Grade 2 or greater dermatitis, mucositis, and esophageal reactions were experienced by 54%, 66%, and 40% of the patients, respectively. Documented late complications included trismus (17%) and osteoradionecrosis (5%). CONCLUSION:IMRT as an adjuvant treatment after surgical resection for oral cavity tumors is feasible and effective, with promising results and acceptable toxicity. 10.1016/j.ijrobp.2008.05.024
    Acute normal tissue reactions in head-and-neck cancer patients treated with IMRT: influence of dose and association with genetic polymorphisms in DNA DSB repair genes. Werbrouck Joke,De Ruyck Kim,Duprez Fréderic,Veldeman Liv,Claes Kathleen,Van Eijkeren Marc,Boterberg Tom,Willems Petra,Vral Anne,De Neve Wilfried,Thierens Hubert International journal of radiation oncology, biology, physics PURPOSE:To investigate the association between dose-related parameters and polymorphisms in DNA DSB repair genes XRCC3 (c.-1843A>G, c.562-14A>G, c.722C>T), Rad51 (c.-3429G>C, c.-3392G>T), Lig4 (c.26C>T, c.1704T>C), Ku70 (c.-1310C>G), and Ku80 (c.2110-2408G>A) and the occurrence of acute reactions after radiotherapy. MATERIALS AND METHODS:The study population consisted of 88 intensity-modulated radiation therapy (IMRT)-treated head-and-neck cancer patients. Mucositis, dermatitis, and dysphagia were scored using the Common Terminology Criteria (CTC) for Adverse Events v.3.0 scale. The population was divided into a CTC0-2 and CTC3+ group for the analysis of each acute effect. The influence of the dose on critical structures was analyzed using dose-volume histograms. Genotypes were determined by polymerase chain reaction (PCR) combined with restriction fragment length polymorphism or PCR-single base extension assays. RESULTS:The mean dose (D(mean)) to the oral cavity and constrictor pharyngeus (PC) muscles was significantly associated with the development of mucositis and dysphagia, respectively. These parameters were considered confounding factors in the radiogenomics analyses. The XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes were significantly associated with the development of severe dysphagia (CTC3+). No association was found between the investigated polymorphisms and the development of mucositis or dermatitis. A risk analysis model for severe dysphagia, which was developed based on the XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes and the PC dose, showed a sensitivity of 78.6% and a specificity of 77.6%. CONCLUSIONS:The XRCC3c.722C>T and Ku70c.-1310C>G polymorphisms as well as the D(mean) to the PC muscles were highly associated with the development of severe dysphagia after IMRT. The prediction model developed using these parameters showed a high sensitivity and specificity. 10.1016/j.ijrobp.2008.08.073
    Therapeutic effect of recombinant human epidermal growth factor (RhEGF) on mucositis in patients undergoing radiotherapy, with or without chemotherapy, for head and neck cancer: a double-blind placebo-controlled prospective phase 2 multi-institutional clinical trial. Wu Hong Gyun,Song Si Yeol,Kim Yeon Sil,Oh Young Taek,Lee Chang Geol,Keum Ki Chang,Ahn Yong Chan,Lee Sang-wook Cancer BACKGROUND:We evaluated the efficacy of topically applied human recombinant epidermal growth factor (rhEGF) for the treatment of oral mucositis induced by radiotherapy (RT), with or without chemotherapy, in patients with head and neck cancer. METHODS:Patients receiving definitive chemoradiotherapy, definitive RT, or postoperative RT to the oral cavity or oropharynx were recruited from 6 institutions and enrolled in a randomized, double-blind, placebo-controlled phase 2 trial. Patients were assigned to a placebo group or to 1 of 3 EGF-treatment groups (10, 50, or 100 microg/mL doses, delivered in a spray, twice daily). The grade of mucositis was evaluated using the Radiation Therapy Oncology Group (RTOG) scoring criteria. Responders to EGF were defined as having an RTOG grade of 2 or lower at the fourth- or fifth-week examinations during RT, but an enduring RTOG grade 2 for 2 weeks was an exception. RESULTS:Of the 113 patients included in the study, 28 received placebo and 29 received EGF at 10 microg/mL, 29 at 50 microg/mL, and 27 at 100 microg/mL. EGF significantly reduced the incidence of severe oral mucositis at the primary endpoint (a 64% response was observed with 50 microg/mL EGF vs a 37% response in the control group; P = .0246). CONCLUSIONS:The EGF oral spray may have potential benefit for oral mucositis in patients undergoing RT for head and neck cancer. Phase 3 studies are ongoing to confirm these results. 10.1002/cncr.24414
    Pharmacokinetic analysis and phase 1 study of MRX-1024 in patients treated with radiation therapy with or without cisplatinum for head and neck cancer. Hamstra Daniel A,Eisbruch Avraham,Naidu Maddireddy U R,Ramana Gogula V,Sunkara Prasad,Campbell Kathleen C M,Ross Brian D,Rehemtulla Alnawaz Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:A previous study reported radiation protection from mucosal injury with D-methionine (D-met) in preclinical evaluation; therefore, the pharmacokinetics, safety, and utility of D-met were evaluated clinically. EXPERIMENTAL DESIGN:The pharmacokinetics of D-met following oral administration of a bioavailable formulation (MRX-1024) was evaluated in normal volunteers. Subsequently, 25 patients were enrolled on a phase 1 study of MRX-1024 concurrent with radiation therapy (RT) with or without weekly cisplatinum. Toxicity and mucosal events were evaluated weekly. RESULTS:Oral MRX-1024 resulted in rapid and dose-dependent increases in plasma D-met concentrations with a half-life of 3 hours. When administered concurrent with RT without chemotherapy, it was associated with a modest increase in grade 2 (two of six patients) and grade 3 (one of six patients) emesis. In those treated with MRX-1024 along with RT and weekly cisplatinum, there was no appreciable increase in emesis. Overall, five patients withdrew from the study due to emesis (four grade 2 and one grade 3). Only one incidence of dose-limiting toxicity (grade 3 emesis) was identified in 25 patients (4%). Finally, in 18 evaluable patients treated with MRX-1024 at 100 mg/kg twice daily (BID), the incidence of severe (grade 3) oral mucositis was 6% (1 of 18) with no grade 4 mucositis. CONCLUSIONS:There is a dose-dependent increase in D-met exposure following MRX-1024 administration at 50 and 100 mg/kg, and MRX-1024 is safe for use concurrent with combined radiation and chemotherapy. The observed rate of mucositis seems less than that for similar treatment regimens within the published literature. 10.1158/1078-0432.CCR-09-3318
    Five versus six fractions of radiotherapy per week for squamous-cell carcinoma of the head and neck (IAEA-ACC study): a randomised, multicentre trial. Overgaard Jens,Mohanti Bidhu Kaylan,Begum Naseem,Ali Rubina,Agarwal Jai Prakash,Kuddu Maire,Bhasker Suman,Tatsuzaki Hideo,Grau Cai The Lancet. Oncology BACKGROUND:Several large randomised studies from western Europe and the USA have shown that accelerated fractionation of radiotherapy might be beneficial in the treatment of squamous-cell carcinoma of the head and neck (HNSCC). The aim of this study--the International Atomic Energy Agency (IAEA) ACC trial--was to determine whether accelerated fractionation could be applied in developing countries, where there are fewer therapeutic resources and where tumour burdens can be heavier. METHODS:Between Jan 6, 1999, to March 31, 2004, nine centres from Asia, Europe, the Middle East, Africa, and South America recruited patients with HNSCC of the larynx, pharynx, and oral cavity who were eligible for curative radiotherapy. Patients were randomly assigned in this open-label trial to receive an accelerated regimen of six fractions of radiotherapy per week (n=458) or to receive a conventional radiotherapy regimen of five fractions per week (n=450), receiving a total dose of 66-70 Gy in 33-35 fractions. Patients were stratified by tumour localisation, T classification, histopathological grade, and institution. Randomisation was done by a central computer-generated balanced randomisation algorithm. The primary endpoint was locoregional control, analysed for all eligible patients, irrespective of whether or not they had completed the course of radiotherapy. This trial is registered with ClinicalTrials.gov, number NCT00120211. FINDINGS:Six patients in the accelerated group and two in the conventional group were excluded from analyses because of withdrawal of consent or missing data. The planned total radiotherapy dose was received by 418 (92%) of the 452 eligible patients in the accelerated radiotherapy group and 413 (92%) of the 448 patients in the conventional radiotherapy group. Median treatment time was 40 days in the accelerated group and 47 days in the conventional group. The 5-year actuarial rate of locoregional control was 42% in the accelerated group versus 30% in the conventional group (hazard ratio [HR] 0.63, 95% CI 0.49-0.83; p=0.004). Acute morbidity in the form of confluent mucositis was noted in 45 patients in the accelerated group and 22 patients in the conventional group (2.15, 1.27-3.35); severe skin reactions were noted in 87 patients in the accelerated group and 50 patients in the conventional group (1.91, 1.31-2.79). There were no significant differences in late radiation side-effects. INTERPRETATION:An accelerated schedule of radiotherapy for HNSCC was more effective than conventional fractionation, and since it does not require additional resources, might be a suitable new worldwide standard baseline treatment for radiotherapy of HNSCC. FUNDING:International Atomic Energy Agency, Coordinated Research Project (IAEA-CRP E.3.30.18), the Danish Cancer Society, the Danish Strategic Research Council, and the Lundbeck Centre for Interventional Research in Radiation Oncology (CIRRO). 10.1016/S1470-2045(10)70072-3
    Oral mucositis prevention by low-level laser therapy in head-and-neck cancer patients undergoing concurrent chemoradiotherapy: a phase III randomized study. Gouvêa de Lima Aline,Villar Rosângela Correa,de Castro Gilberto,Antequera Reynaldo,Gil Erlon,Rosalmeida Mauro Cabral,Federico Miriam Hatsue Honda,Snitcovsky Igor Moisés Longo International journal of radiation oncology, biology, physics PURPOSE:Oral mucositis is a major complication of concurrent chemoradiotherapy (CRT) in head-and-neck cancer patients. Low-level laser (LLL) therapy is a promising preventive therapy. We aimed to evaluate the efficacy of LLL therapy to decrease severe oral mucositis and its effect on RT interruptions. METHODS AND MATERIALS:In the present randomized, double-blind, Phase III study, patients received either gallium-aluminum-arsenide LLL therapy 2.5 J/cm(2) or placebo laser, before each radiation fraction. Eligible patients had to have been diagnosed with squamous cell carcinoma or undifferentiated carcinoma of the oral cavity, pharynx, larynx, or metastases to the neck with an unknown primary site. They were treated with adjuvant or definitive CRT, consisting of conventional RT 60-70 Gy (range, 1.8-2.0 Gy/d, 5 times/wk) and concurrent cisplatin. The primary endpoints were the oral mucositis severity in Weeks 2, 4, and 6 and the number of RT interruptions because of mucositis. The secondary endpoints included patient-reported pain scores. To detect a decrease in the incidence of Grade 3 or 4 oral mucositis from 80% to 50%, we planned to enroll 74 patients. RESULTS:A total of 75 patients were included, and 37 patients received preventive LLL therapy. The mean delivered radiation dose was greater in the patients treated with LLL (69.4 vs. 67.9 Gy, p = .03). During CRT, the number of patients diagnosed with Grade 3 or 4 oral mucositis treated with LLL vs. placebo was 4 vs. 5 (Week 2, p = 1.0), 4 vs. 12 (Week 4, p = .08), and 8 vs. 9 (Week 6, p = 1.0), respectively. More of the patients treated with placebo had RT interruptions because of mucositis (6 vs. 0, p = .02). No difference was detected between the treatment arms in the incidence of severe pain. CONCLUSIONS:LLL therapy was not effective in reducing severe oral mucositis, although a marginal benefit could not be excluded. It reduced RT interruptions in these head-and-neck cancer patients, which might translate into improved CRT efficacy. 10.1016/j.ijrobp.2010.10.012
    Phenylbutyrate mouthwash mitigates oral mucositis during radiotherapy or chemoradiotherapy in patients with head-and-neck cancer. Yen Sang-Hue,Wang Ling-Wei,Lin Yi-Hsien,Jen Yee-Min,Chung Yih-Lin International journal of radiation oncology, biology, physics PURPOSE:Deleterious oral mucositis (OM) develops during radiotherapy (RT) or chemoradiotherapy for head-and-neck cancer (HNC) patients. There are currently no effective cytoprotective treatments for OM without a potential risk of tumor protection. This randomized, double-blind, placebo-controlled pilot study aimed to determine the therapeutic safety and efficacy of phenylbutyrate (an antitumor histone deacetylase inhibitor and chemical chaperone) 5% mouthwash for treating OM caused by cancer therapy. METHODS AND MATERIALS:Between September 2005 and June 2006, 36 HNC patients were randomized to standard oral care plus 5 mL of either phenylbutyrate 5% mouthwash (n = 17) or placebo (mouthwash vehicle, n = 19) taken four times daily (swish and spit). Treatment began when mild mucositis (Radiation Therapy Oncology Group Grade 1) occurred, and ended 4 weeks after RT completion. Safety and efficacy were based on adverse events, physical examination, laboratory determinations, vital signs, Oral Mucosa Assessment Scale (OMAS) and World Health Organization scores, the ability to eat, body weight change, local control, and survival. RESULTS:We found no severe drug-related side effect. At RT doses of 5500-7500 cGy, phenylbutyrate significantly mitigated the severity of mucositis compared with placebo, based on both the WHO score (severity ≥ 3; p = 0.0262) and the OMAS scale (ulceration score ≥ 2; p = 0.0049). The Kaplan-Meier estimates for 2- and 3-year local control, and overall survival were 100% and 80.8%, and 78.6% and 64.3%, respectively, in the phenylbutyrate group and 74.2% and 74.2%, and 57.4% and 50.2%, respectively, in the placebo group. CONCLUSIONS:This pilot trial suggested that phenylbutyrate mouthwash significantly decreased the impact of OM in HNC patients receiving RT or chemoradiotherapy and did not confront the tumor control. Larger Phase II randomized trials are needed to confirm these results. 10.1016/j.ijrobp.2011.04.029
    Potential dual role of KGF/KGFR as a target option in novel therapeutic strategies for the treatment of cancers and mucosal damages. Ceccarelli Simona,Romano Ferdinando,Angeloni Antonio,Marchese Cinzia Expert opinion on therapeutic targets INTRODUCTION:Keratinocyte growth factor (KGF) and its receptor KGFR play a pivotal role in regulating cell proliferation, migration, differentiation and survival, in response to injury and tissue repair. Altered expression of this pathway in cancer opened the way to the development of targeted therapy to achieve KGFR inhibition. Nevertheless, KGF administration has been demonstrated to ameliorate oral mucositis resulting from chemoradiotherapy, besides protecting epithelial cells against radiation-induced damage. AREAS COVERED:This review focuses on the potential therapeutic interest of KGF/KGFR in two different areas: selective inhibition of KGFR signaling for the treatment of cancers characterized by upregulation of this pathway and administration of KGF to protect epithelial cells from induced damage. The review presents an overview of therapeutic strategies in both directions. EXPERT OPINION:KGF/KGFR signaling can contribute to enhancing the malignant potential of epithelial cells and to promoting tumorigenesis. On the other hand, the therapeutic use of KGF in cancer patients provides epithelial protection, reducing chemotherapy side effects. FGFRs have become attractive antitumor targets and various inhibitors have been used to contrast tumor cell growth. The identification of KGFR-specific molecules might represent a promising therapeutic strategy that could increase the window of available agents and treatment methods. 10.1517/14728222.2012.671813
    Toll-like receptor 5 agonist protects mice from dermatitis and oral mucositis caused by local radiation: implications for head-and-neck cancer radiotherapy. Burdelya Lyudmila G,Gleiberman Anatoli S,Toshkov Ilia,Aygun-Sunar Semra,Bapardekar Meghana,Manderscheid-Kern Patricia,Bellnier David,Krivokrysenko Vadim I,Feinstein Elena,Gudkov Andrei V International journal of radiation oncology, biology, physics PURPOSE:Development of mucositis is a frequent side effect of radiotherapy of patients with head-and-neck cancer. We have recently reported that bacterial flagellin, an agonist of Toll-like receptor 5 (TLR5), can protect rodents and primates from acute radiation syndrome caused by total body irradiation. Here we analyzed the radioprotective efficacy of TLR5 agonist under conditions of local, single dose or fractionated radiation treatment. METHODS AND MATERIALS:Mice received either single-dose (10, 15, 20, or 25 Gy) or fractioned irradiation (cumulative dose up to 30 Gy) of the head-and-neck area with or without subcutaneous injection of pharmacologically optimized flagellin, CBLB502, 30 min before irradiation. RESULTS:CBLB502 significantly reduced the severity of dermatitis and mucositis, accelerated tissue recovery, and reduced the extent of radiation induced weight loss in mice after a single dose of 15 or 20 Gy but not 25 Gy of radiation. CBLB502 was also protective from cumulative doses of 25 and 30 Gy delivered in two (10 + 15 Gy) or three (3 × 10 Gy) fractions, respectively. While providing protection to normal epithelia, CBLB502 did not affect the radiosensitivity of syngeneic squamous carcinoma SCCVII grown orthotopically in mice. Use of CBLB502 also elicited a radiation independent growth inhibitory effect upon TLR5-expressing tumors demonstrated in the mouse xenograft model of human lung adenocarcinoma A549. CONCLUSION:CBLB502 combines properties of supportive care (radiotherapy adjuvant) and anticancer agent, both mediated via activation of TLR5 signaling in the normal tissues or the tumor, respectively. 10.1016/j.ijrobp.2011.05.055
    Effect of radiotherapy and chemotherapy on the risk of mucositis during intensity-modulated radiation therapy for oropharyngeal cancer. Sanguineti Giuseppe,Sormani Maria Pia,Marur Shanthi,Gunn G Brandon,Rao Nikhil,Cianchetti Marco,Ricchetti Francesco,McNutt Todd,Wu Binbin,Forastiere Arlene International journal of radiation oncology, biology, physics PURPOSE:To define the roles of radiotherapy and chemotherapy on the risk of Grade 3+ mucositis during intensity-modulated radiation therapy (IMRT) for oropharyngeal cancer. METHODS AND MATERIALS:164 consecutive patients treated with IMRT at two institutions in nonoverlapping treatment eras were selected. All patients were treated with a dose painting approach, three dose levels, and comprehensive bilateral neck treatment under the supervision of the same radiation oncologist. Ninety-three patients received concomitant chemotherapy (cCHT) and 14 received induction chemotherapy (iCHT). Individual information of the dose received by the oral mucosa (OM) was extracted as absolute cumulative dose-volume histogram (DVH), corrected for the elapsed treatment days and reported as weekly (w) DVH. Patients were seen weekly during treatment, and peak acute toxicity equal to or greater than confluent mucositis at any point during the course of IMRT was considered the endpoint. RESULTS:Overall, 129 patients (78.7%) reached the endpoint. The regions that best discriminated between patients with/without Grade 3+ mucositis were found at 10.1 Gy/w (V10.1) and 21 cc (D21), along the x-axis and y-axis of the OM-wDVH, respectively. On multivariate analysis, D21 (odds ratio [OR] = 1.016, 95% confidence interval [CI], 1.009-1.023, p < 0.001) and cCHT (OR = 4.118, 95% CI, 1.659-10.217, p = 0.002) were the only independent predictors. However, V10.1 and D21 were highly correlated (rho = 0.954, p < 0.001) and mutually interchangeable. cCHT would correspond to 88.4 cGy/w to at least 21 cc of OM. CONCLUSIONS:Radiotherapy and chemotherapy act independently in determining acute mucosal toxicity; cCHT increases the risk of mucosal Grade 3 toxicity ≈4 times over radiation therapy alone, and it is equivalent to an extra ≈6.2 Gy to 21 cc of OM over a 7-week course. 10.1016/j.ijrobp.2011.06.2000
    A novel Peptide to treat oral mucositis blocks endothelial and epithelial cell apoptosis. Wu Xiaoyan,Chen Peili,Sonis Stephen T,Lingen Mark W,Berger Ann,Toback F Gary International journal of radiation oncology, biology, physics PURPOSE:No effective agents currently exist to treat oral mucositis (OM) in patients receiving chemoradiation for the treatment of head-and-neck cancer. We identified a novel 21-amino acid peptide derived from antrum mucosal protein-18 that is cytoprotective, mitogenic, and motogenic in tissue culture and animal models of gastrointestinal epithelial cell injury. We examined whether administration of antrum mucosal protein peptide (AMP-p) could protect against and/or speed recovery from OM. METHODS AND MATERIALS:OM was induced in established hamster models by a single dose of radiation, fractionated radiation, or fractionated radiation together with cisplatin to simulate conventional treatments of head-and-neck cancer. RESULTS:Daily subcutaneous administration of AMP-p reduced the occurrence of ulceration and accelerated mucosal recovery in all three models. A delay in the onset of erythema after irradiation was observed, suggesting that a protective effect exists even before injury to mucosal epithelial cells occurs. To test this hypothesis, the effects of AMP-p on tumor necrosis factor-α-induced apoptosis were studied in an endothelial cell line (human dermal microvascular endothelial cells) as well as an epithelial cell line (human adult low-calcium, high-temperature keratinocytes; HaCaT) used to model the oral mucosa. AMP-p treatment, either before or after cell monolayers were exposed to tumor necrosis factor-α, protected against development of apoptosis in both cell types when assessed by annexin V and propidium iodide staining followed by flow cytometry or ligase-mediated polymerase chain reaction. CONCLUSIONS:These observations suggest that the ability of AMP-p to attenuate radiation-induced OM could be attributable, at least in part, to its antiapoptotic activity. 10.1016/j.ijrobp.2012.01.006
    Pharmacological protection from radiation ± cisplatin-induced oral mucositis. Cotrim Ana P,Yoshikawa Masanobu,Sunshine Abraham N,Zheng Changyu,Sowers Anastasia L,Thetford Angela D,Cook John A,Mitchell James B,Baum Bruce J International journal of radiation oncology, biology, physics PURPOSE:To evaluate if two pharmacological agents, Tempol and D-methionine (D-met), are able to prevent oral mucositis in mice after exposure to ionizing radiation ± cisplatin. METHODS AND MATERIALS:Female C3H mice, ∼8 weeks old, were irradiated with five fractionated doses ± cisplatin to induce oral mucositis (lingual ulcers). Just before irradiation and chemotherapy, mice were treated, either alone or in combination, with different doses of Tempol (by intraperitoneal [ip] injection or topically, as an oral gel) and D-met (by gavage). Thereafter, mice were sacrificed and tongues were harvested and stained with a solution of Toluidine Blue. Ulcer size and tongue epithelial thickness were measured. RESULTS:Significant lingual ulcers resulted from 5 × 8 Gy radiation fractions, which were enhanced with cisplatin treatment. D-met provided stereospecific partial protection from lingual ulceration after radiation. Tempol, via both routes of administration, provided nearly complete protection from lingual ulceration. D-met plus a suboptimal ip dose of Tempol also provided complete protection. CONCLUSIONS:Two fairly simple pharmacological treatments were able to markedly reduce chemoradiation-induced oral mucositis in mice. This proof of concept study suggests that Tempol, alone or in combination with D-met, may be a useful and convenient way to prevent the severe oral mucositis that results from head-and-neck cancer therapy. 10.1016/j.ijrobp.2011.09.026
    Radiation-free weekend rescued! Continuous accelerated irradiation of 7-days per week is equal to accelerated fractionation with concomitant boost of 7 fractions in 5-days per week: report on phase 3 clinical trial in head-and-neck cancer patients. Skladowski Krzysztof,Hutnik Marcin,Wygoda Andrzej,Golen Maria,Pilecki Boleslaw,Przeorek Wieslawa,Rutkowski Tomasz,Lukaszczyk-Widel Beata,Heyda Alicja,Suwinski Rafal,Tarnawski Rafal,Maciejewski Boguslaw International journal of radiation oncology, biology, physics PURPOSE:To report long-term results of randomized trial comparing 2 accelerated fractionations of definitive radiation therapy assessing the need to irradiate during weekend in patients with head and neck squamous cell carcinoma. METHODS AND MATERIALS:A total of 345 patients with SCC of the oral cavity, larynx, and oro- or hypo-pharynx, stage T2-4N0-1M0, were randomized to receive continuous accelerated irradiation (CAIR: once per day, 7 days per week) or concomitant accelerated boost (CB: once per day, 3 days per week, and twice per day, 2 days per week). Total dose ranged from 66.6-72 Gy, dose per fraction was 1.8 Gy, number of fractions ranged from 37-40 fractions, and overall treatment time ranged from 37-40 days. RESULTS:No differences for all trial end-points were noted. At 5 and 10 years, the actuarial rates of local-regional control were 63% and 60% for CAIR vs 65% and 60% for CB, and the corresponding overall survival were 40% and 25% vs 44% and 25%, respectively. Confluent mucositis was the main acute toxicity, with an incidence of 89% in CAIR and 86% in CB patients. The 5-year rate of grade 3-4 late radiation morbidity was 6% for both regimens. CONCLUSIONS:Results of this trial indicate that the effects of accelerated fractionation can be achieve by delivering twice-per-day irradiation on weekday(s). This trial has also confirmed that an accelerated, 6-weeks schedule is a reasonable option for patients with intermediate-stage head-and-neck squamous cell carcinoma because of the associated high cure rate and minimal severe late toxicity. 10.1016/j.ijrobp.2012.06.037
    Preventive and therapeutic effects of Smad7 on radiation-induced oral mucositis. Han Gangwen,Bian Li,Li Fulun,Cotrim Ana,Wang Donna,Lu Jianbo,Deng Yu,Bird Gregory,Sowers Anastasia,Mitchell James B,Gutkind J Silvio,Zhao Rui,Raben David,ten Dijke Peter,Refaeli Yosef,Zhang Qinghong,Wang Xiao-Jing Nature medicine We report that K5.Smad7 mice, which express a Smad7 transgene under the control of a keratin 5 promoter, were resistant to radiation-induced oral mucositis, a painful oral ulceration. In addition to nuclear factor κB (NF-κB) activation, which is known to contribute to oral mucositis, we found activated transforming growth factor β (TGF-β) signaling in cells from this condition. Smad7 dampened both pathways to attenuate inflammation, growth inhibition and apoptosis. Additionally, Smad7 promoted oral epithelial migration to close the wound. Further analyses revealed that TGF-β signaling Smads and their co-repressor C-terminal binding protein 1 (CtBP1) transcriptionally repressed Rac1, and that Smad7 abrogated this repression. Knocking down Rac1 expression in mouse keratinocytes abrogated Smad7-induced migration. Topical application of Smad7 protein conjugated with a cell-permeable Tat tag to oral mucosa showed prophylactic and therapeutic effects on radiation-induced oral mucositis in mice. Thus, we have identified new molecular mechanisms involved in oral mucositis pathogenesis, and our data suggest an alternative therapeutic strategy to block multiple pathological processes in this condition. 10.1038/nm.3118
    A phase 1 study of everolimus + weekly cisplatin + intensity modulated radiation therapy in head-and-neck cancer. Fury Matthew G,Lee Nancy Y,Sherman Eric,Ho Alan L,Rao Shyam,Heguy Adriana,Shen Ronglai,Korte Susan,Lisa Donna,Ganly Ian,Patel Snehal,Wong Richard J,Shaha Ashok,Shah Jatin,Haque Sofia,Katabi Nora,Pfister David G International journal of radiation oncology, biology, physics PURPOSE:Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. METHODS AND MATERIALS:This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m(2) weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design. RESULTS:Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. CONCLUSIONS:Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins. 10.1016/j.ijrobp.2013.06.2043
    Multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of a mucoadhesive hydrogel (MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck. Allison Ron R,Ambrad Aaron A,Arshoun Youssef,Carmel Richard J,Ciuba Doug F,Feldman Elizabeth,Finkelstein Steven E,Gandhavadi Ranjini,Heron Dwight E,Lane Steven C,Longo John M,Meakin Charles,Papadopoulos Dimitrios,Pruitt David E,Steinbrenner Lynn M,Taylor Michael A,Wisbeck William M,Yuh Grace E,Nowotnik David P,Sonis Stephen T Cancer BACKGROUND:The objective of this trial was to determine how a mucoadhesive hydrogel (MuGard), a marketed medical device, would fare when tested with the strictness of a conventional multi-institutional, double-blind, randomized, placebo-controlled study format. METHODS:A total of 120 subjects planned to receive chemoradiation therapy (CRT) for treatment of head and neck cancers were randomized to receive either MuGard or sham control rinse (SC) during CRT. Subjects completed the validated Oral Mucositis Daily Questionnaire. Weight, opiate use, and World Health Organization (WHO) oral mucositis (OM) scores were recorded. Subjects who dosed at least once daily during the first 2.5 weeks of CRT were included in the efficacy analysis. RESULTS:Of 120 subjects enrolled, 78 (SC, N=41; MuGard, N=37) were eligible for efficacy analysis. Both cohorts were similar in demographics, baseline characteristics, primary tumor type, and planned CRT regimen. MuGard effectively mitigated OM symptoms as reflected by area under the curve of daily patient-reported oral soreness (P=.034) and WHO scores on the last day of radiation therapy (P=.038). MuGard was also associated with nonsignificant trends related to therapeutic benefit including opioid use duration, and OM scores (WHO criteria) at CRT week 4. Rinse compliance was identical between cohorts. No significant adverse events were reported, and the adverse event incidence was similar between cohorts. CONCLUSIONS:Testing MuGard, a rinse marketed as a device, in a standard clinical trial format demonstrated its superiority to SC in mitigating OM symptoms, delaying OM progression, and its safety and tolerability. 10.1002/cncr.28553
    Multifield optimization intensity modulated proton therapy for head and neck tumors: a translation to practice. Frank Steven J,Cox James D,Gillin Michael,Mohan Radhe,Garden Adam S,Rosenthal David I,Gunn G Brandon,Weber Randal S,Kies Merrill S,Lewin Jan S,Munsell Mark F,Palmer Matthew B,Sahoo Narayan,Zhang Xiaodong,Liu Wei,Zhu X Ronald International journal of radiation oncology, biology, physics BACKGROUND:We report the first clinical experience and toxicity of multifield optimization (MFO) intensity modulated proton therapy (IMPT) for patients with head and neck tumors. METHODS AND MATERIALS:Fifteen consecutive patients with head and neck cancer underwent MFO-IMPT with active scanning beam proton therapy. Patients with squamous cell carcinoma (SCC) had comprehensive treatment extending from the base of the skull to the clavicle. The doses for chemoradiation therapy and radiation therapy alone were 70 Gy and 66 Gy, respectively. The robustness of each treatment plan was also analyzed to evaluate sensitivity to uncertainties associated with variations in patient setup and the effect of uncertainties with proton beam range in patients. Proton beam energies during treatment ranged from 72.5 to 221.8 MeV. Spot sizes varied depending on the beam energy and depth of the target, and the scanning nozzle delivered the spot scanning treatment "spot by spot" and "layer by layer." RESULTS:Ten patients presented with SCC and 5 with adenoid cystic carcinoma. All 15 patients were able to complete treatment with MFO-IMPT, with no need for treatment breaks and no hospitalizations. There were no treatment-related deaths, and with a median follow-up time of 28 months (range, 20-35 months), the overall clinical complete response rate was 93.3% (95% confidence interval, 68.1%-99.8%). Xerostomia occurred in all 15 patients as follows: grade 1 in 10 patients, grade 2 in 4 patients, and grade 3 in 1 patient. Mucositis within the planning target volumes was seen during the treatment of all patients: grade 1 in 1 patient, grade 2 in 8 patients, and grade 3 in 6 patients. No patient experienced grade 2 or higher anterior oral mucositis. CONCLUSIONS:To our knowledge, this is the first clinical report of MFO-IMPT for head and neck tumors. Early clinical outcomes are encouraging and warrant further investigation of proton therapy in prospective clinical trials. 10.1016/j.ijrobp.2014.04.019
    Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation-induced oral mucositis. Ortiz Francisco,Acuña-Castroviejo Darío,Doerrier Carolina,Dayoub José C,López Luis C,Venegas Carmen,García José A,López Ana,Volt Huayqui,Luna-Sánchez Marta,Escames Germaine Journal of pineal research Mucositis is a common and distressing side effect of chemotherapy or radiotherapy that has potentially severe consequences, and no treatment is available. The purpose of this study was to analyze the molecular pathways involved in the development of oral mucositis and to evaluate whether melatonin can prevent this pathology. The tongue of male Wistar rats was subjected to irradiation (X-ray YXLON Y.Tu 320-D03 irradiator; the animals received a dose of 7.5 Gy/day for 5 days). Rats were treated with 45 mg/day melatonin or vehicle for 21 days postirradiation, either by local application into their mouths (melatonin gel) or by subcutaneous injection. A connection between reactive oxygen species, generating mitochondria and the NLRP3 (NLR-related protein 3 nucleotide-binding domain leucine-rich repeat containing receptor-related protein 3) inflammasome, has been reported in mucositis. Here, we show that mitochondrial oxidative stress, bioenergetic impairment and subsequent NLRP3 inflammasome activation are involved in the development of oral mucositis after irradiation and that melatonin synthesized in the rat tongue is depleted after irradiation. The application of melatonin gel restores physiological melatonin levels in the tongue and prevents mucosal disruption and ulcer formation. Melatonin gel protects the mitochondria from radiation damage and blunts the NF-κB/NLRP3 inflammasome signaling activation in the tongue. Our results suggest new molecular pathways involved in radiotherapy-induced mucositis that are inhibited by topical melatonin application, suggesting a potential preventive therapy for mucositis in patients with cancer. 10.1111/jpi.12191
    The role of Smad7 in oral mucositis. Bian Li,Han Gangwen,Zhao Carolyn W,Garl Pamela J,Wang Xiao-Jing Protein & cell Oral mucositis, a severe oral ulceration, is a common toxic effect of radio- or chemoradio-therapy and a limiting factor to using the maximum dose of radiation for effective cancer treatment. Among cancer patients, at least 40% and up to 70%, of individuals treated with standard chemotherapy regimens or upper-body radiation, develop oral mucositis. To date, there is no FDA approved drug to treat oral mucositis in cancer patients. The key challenges for oral mucositis treatment are to repair and protect ulcerated oral mucosa without promoting cancer cell growth. Oral mucositis is the result of complex, multifaceted pathobiology, involving a series of signaling pathways and a chain of interactions between the epithelium and submucosa. Among those pathways and interactions, the activation of nuclear factor-kappa B (NF-κB) is critical to the inflammation process of oral mucositis. We recently found that activation of TGFβ (transforming growth factor β) signaling is associated with the development of oral mucositis. Smad7, the negative regulator of TGFβ signaling, inhibits both NF-κB and TGFβ activation and thus plays a pivotal role in the prevention and treatment of oral mucositis by attenuating growth inhibition, apoptosis, and inflammation while promoting epithelial migration. The major objective of this review is to evaluate the known functions of Smad7, with a particular focus on its molecular mechanisms and its function in blocking multiple pathological processes in oral mucositis. 10.1007/s13238-014-0130-4
    Evaluation of the Risk of Grade 3 Oral and Pharyngeal Dysphagia Using Atlas-Based Method and Multivariate Analyses of Individual Patient Dose Distributions. Otter Sophie,Schick Ulrike,Gulliford Sarah,Lal Punita,Franceschini Davide,Newbold Katie,Nutting Christopher,Harrington Kevin,Bhide Shreerang International journal of radiation oncology, biology, physics PURPOSE:The study aimed to apply the atlas of complication incidence (ACI) method to patients receiving radical treatment for head and neck squamous cell carcinomas (HNSCC), to generate constraints based on dose-volume histograms (DVHs), and to identify clinical and dosimetric parameters that predict the risk of grade 3 oral mucositis (g3OM) and pharyngeal dysphagia (g3PD). METHODS AND MATERIALS:Oral and pharyngeal mucosal DVHs were generated for 253 patients who received radiation (RT) or chemoradiation (CRT). They were used to produce ACI for g3OM and g3PD. Multivariate analysis (MVA) of the effect of dosimetry, clinical, and patient-related variables was performed using logistic regression and bootstrapping. Receiver operating curve (ROC) analysis was also performed, and the Youden index was used to find volume constraints that discriminated between volumes that predicted for toxicity. RESULTS:We derived statistically significant dose-volume constraints for g3OM over the range v28 to v70. Only 3 statistically significant constraints were derived for g3PD v67, v68, and v69. On MVA, mean dose to the oral mucosa predicted for g3OM and concomitant chemotherapy and mean dose to the inferior constrictor (IC) predicted for g3PD. CONCLUSIONS:We have used the ACI method to evaluate incidences of g3OM and g3PD and ROC analysis to generate constraints to predict g3OM and g3PD derived from entire individual patient DVHs. On MVA, the strongest predictors were radiation dose (for g3OM) and concomitant chemotherapy (for g3PD). 10.1016/j.ijrobp.2015.07.2263
    Oral toxicity management in head and neck cancer patients treated with chemotherapy and radiation: Dental pathologies and osteoradionecrosis (Part 1) literature review and consensus statement. Buglione Michela,Cavagnini Roberta,Di Rosario Federico,Sottocornola Lara,Maddalo Marta,Vassalli Lucia,Grisanti Salvatore,Salgarello Stefano,Orlandi Ester,Paganelli Corrado,Majorana Alessandra,Gastaldi Giorgio,Bossi Paolo,Berruti Alfredo,Pavanato Giovanni,Nicolai Piero,Maroldi Roberto,Barasch Andrei,Russi Elvio G,Raber-Durlacher Judith,Murphy Barbara,Magrini Stefano M Critical reviews in oncology/hematology Radiotherapy alone or in combination with chemotherapy and/or surgery is the typical treatment for head and neck cancer patients. Acute side effects (such as oral mucositis, dermatitis, salivary changes, taste alterations, etc.), and late toxicities in particular (such as osteo-radionecrosis, hypo-salivation and xerostomia, trismus, radiation caries etc.), are often debilitating. These effects tend to be underestimated and insufficiently addressed in the medical community. A multidisciplinary group of head and neck cancer specialists met in Milan with the aim of reaching a consensus on clinical definitions and management of these toxicities. The Delphi Appropriateness method was used for developing the consensus, and external experts evaluated the conclusions. This paper contains 10 clusters of statements about the clinical definitions and management of head and neck cancer treatment sequels (dental pathologies and osteo-radionecroses) that reached consensus, and offers a review of the literature about these topics. The review was split into two parts: the first part dealt with dental pathologies and osteo-radionecroses (10 clusters of statements), whereas this second part deals with trismus and xerostomia. 10.1016/j.critrevonc.2015.08.010
    Pain management in head and neck cancer patients undergoing chemo-radiotherapy: Clinical practical recommendations. Mirabile A,Airoldi M,Ripamonti C,Bolner A,Murphy B,Russi E,Numico G,Licitra L,Bossi P Critical reviews in oncology/hematology Pain in head and neck cancer represents a major issue, before, during and after the oncological treatments. The most frequent cause of pain is chemo/radiation related oral mucositis, which involves 80% of the patients and worsens their quality of life inhibiting speaking, eating, drinking or swallowing and sometimes reducing the treatment compliance, the maximum dose intensity and thus the potential efficacy of treatment. Nevertheless pain is still often under estimated and undertreated. An Italian multidisciplinary group of head and neck cancer specialists met with the aim of reaching a consensus on pain management in this setting. The Delphi Appropriateness method was used for the consensus. External expert reviewers evaluated the final statements. The paper contains 30 consensus-reached statements about pain management in HNC patients and offers a review of recent literature in these topics. 10.1016/j.critrevonc.2015.11.010
    Mucositis in head and neck cancer patients treated with radiotherapy and systemic therapies: Literature review and consensus statements. De Sanctis Vitaliana,Bossi Paolo,Sanguineti Giuseppe,Trippa Fabio,Ferrari Daris,Bacigalupo Almalina,Ripamonti Carla Ida,Buglione Michela,Pergolizzi Stefano,Langendjik Johannes A,Murphy Barbara,Raber-Durlacher Judith,Russi Elvio G,Lalla Rajesh V Critical reviews in oncology/hematology BACKGROUND:Oral mucositis (OM) due to radiotherapy and systemic therapies in head and neck cancer treatment represents a major problem causing a wide spectrum of clinical signs and symptoms. This adverse event may reduce quality of life, resulting from debilitating oral pain, bleeding, dysphagia, infections, impairment of food intake, high rate of hospitalization and may interfere with the delivery of programmed treatment plans, ultimately jeopardizing patient outcome. Globally, there is a lack of evidence on effective measures for the prevention and treatment of OM, and only scant uniform conclusions and recommendations can be derived from the existing literature and guidelines. A multidisciplinary team of Italian head and neck cancer experts met in Milan 17-18 February 2013 with the aim of reaching consensus on prophylaxis and management of mucositis. The results of the literature review and the statements that achieved consensus are reported and discussed in this paper. MATERIAL AND METHODS:The Delphi Appropriateness Method was used as a structured communication method for achieving consensus. Subsequently, external expert reviewers evaluated the conclusions carefully according to their area of expertise. RESULTS:This paper presents 13 clusters of statements on prophylaxis and treatment of mucositis that achieved consensus. CONCLUSIONS:OM represents a very stressful situation for head and neck cancer patients submitted to chemo-radiation or exclusive radiation treatment. A multidisciplinary approach is mandatory, but there is still no gold-standard protocol that is prominently better than others. 10.1016/j.critrevonc.2016.01.010
    Oral toxicity management in head and neck cancer patients treated with chemotherapy and radiation: Xerostomia and trismus (Part 2). Literature review and consensus statement. Buglione Michela,Cavagnini Roberta,Di Rosario Federico,Maddalo Marta,Vassalli Lucia,Grisanti Salvatore,Salgarello Stefano,Orlandi Ester,Bossi Paolo,Majorana Alessandra,Gastaldi Giorgio,Berruti Alfredo,Trippa Fabio,Nicolai Pietro,Barasch Andrei,Russi Elvio G,Raber-Durlacher Judith,Murphy Barbara,Magrini Stefano M Critical reviews in oncology/hematology Radiotherapy alone or in combination with chemotherapy and/or surgery is a well-known radical treatment for head and neck cancer patients. Nevertheless acute side effects (such as moist desquamation, skin erythema, loss of taste, mucositis etc.) and in particular late toxicities (osteoradionecrosis, xerostomia, trismus, radiation caries etc.) are often debilitating and underestimated. A multidisciplinary group of head and neck cancer specialists from Italy met in Milan with the aim of reaching a consensus on a clinical definition and management of these toxicities. The Delphi Appropriateness method was used for this consensus and external experts evaluated the conclusions. The paper contains 20 clusters of statements about the clinical definition and management of stomatological issues that reached consensus, and offers a review of the literature about these topics. The review was split into two parts: the first part dealt with dental pathologies and osteo-radionecrosis (10 clusters of statements), whereas this second part deals with trismus and xerostomia (10 clusters of statements). 10.1016/j.critrevonc.2016.03.012
    The Chicken or the Egg? Changes in Oral Microbiota as Cause or Consequence of Mucositis During Radiation Therapy. Sonis Stephen T EBioMedicine 10.1016/j.ebiom.2017.03.017
    Single-Arm Phase 2 Trial of Elective Nodal Dose Reduction for Patients With Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck. Maguire Patrick D,Neal Charles R,Hardy Stuart M,Schreiber Andrew M International journal of radiation oncology, biology, physics PURPOSE:To evaluate a novel chemoradiation therapy (CRT) regimen for patients with squamous cell carcinoma of the head and neck (SCCHN) incorporating a lower intensity modulated radiation therapy dose to electively treated neck lymph nodes than is currently standard. METHODS AND MATERIALS:Eligible patients had locally advanced SCCHN of the oral cavity, oropharynx, larynx, or hypopharynx. The 7-week CRT course consisted of weekly cisplatin at 35 mg/m concurrently with sequential-boost intensity modulated radiation therapy: 36 Gy to high- and low-risk planning target volumes followed by a sequential boost to the high-risk planning target volume to 70 Gy. The primary endpoint was elective nodal failure. Secondary endpoints were survival, toxicity, feeding tube duration, and quality of life evaluated by the FACT-HN and QOL-RTI surveys. RESULTS:Between 2011 and 2014, 54 patients were enrolled, 31 (57%) of whom had human papillomavirus (HPV)-positive disease. Of the patients, 35 (65%) had stage IVa disease. The median follow-up period for survivors was 36 months (range, 12-66 months). Elective nodal failure did not develop in any patient. The actuarial 3-year survival rate for the entire cohort was 91% (95% confidence interval [CI] 0.79-0.96); for the HPV-negative group, 85% (95% CI 0.61-0.95); and for the HPV-positive group, 96% (95% CI 0.77-0.99). Common grade 3 toxicities were dysphagia (79%), mucositis and/or stomatitis (41%), nausea (20%), xerostomia (13%), vomiting (11%), and neutropenia (10%). The median feeding tube duration was 142 days. Patient FACT-HN scores were higher at 3, 6, and 12 months versus at the end of treatment (P < .0001). Total FACT-HN scores returned to pretreatment baseline by 6 months. Overall QOL-RTI scores were lower from pretreatment to the end of treatment through 12 months (P = .0001). CONCLUSIONS:This CRT regimen for patients with advanced SCCHN demonstrated the potential feasibility of reducing the elective dose to the neck, a topic that requires additional study in future clinical trials. 10.1016/j.ijrobp.2017.12.277
    Evaluation of XRCC1 Gene Polymorphism as a Biomarker in Head and Neck Cancer Patients Undergoing Chemoradiation Therapy. Nanda Sambit Swarup,Gandhi Ajeet Kumar,Rastogi Madhup,Khurana Rohini,Hadi Rahat,Sahni Kamal,Mishra Surendra Prasad,Srivastava Anoop K,Bhatt Madan Lal Brahma,Parmar Devendra International journal of radiation oncology, biology, physics PURPOSE:We evaluated the correlation of the x-ray repair cross complementing gene 1 (XRCC1) Arg194Trp polymorphism with clinical outcomes in head and neck squamous cell carcinoma (HNSCC) patients treated with concurrent chemoradiation therapy (CCRT). METHODS AND MATERIALS:In this prospective cohort study, we included 101 patients with HNSCC (oral cavity, pharynx, and larynx) who were aged ≥ 18 years, had stage III to IVB disease, had a Karnofsky Performance Status ≥ 80, and were deemed fit for CCRT. DNA extraction was done through polymerase chain reaction, and the genotypes of XRCC1 polymorphism were detected using designed restriction fragment length polymorphism. The genetic polymorphisms were classified into wild and polymorphic variants (Arg194Trp CT and TT). Radiation therapy was delivered with conventional parallel opposed lateral and low anterior neck fields with concurrent weekly cisplatin, 35 mg/m. Acute toxicity was graded per Radiation Therapy Oncology Group criteria, and treatment response was assessed per World Health Organization criteria. Overall survival and progression-free survival (PFS) were estimated using the Kaplan-Meier method. RESULTS:Of the patients, 62 had the wild type and 39 had polymorphic variants. Patients with polymorphic variants had higher rates of grade > 2 oral mucositis, with 35.8% versus 16.0% (odds ratio [OR], 2.91; 95% confidence interval [CI], 1.13-7.46; P = .023); dermatitis, with 30.7% versus 8.0% (OR, 5.076; 95% CI, 1.62-15.8; P = .003); and laryngeal toxicity, with 25.6% versus 6.4% (OR, 5; 95% CI, 1.44-17.54; P = .006). Complete response rates in polymorphic versus wild variants were 76.9% versus 56.0% (P = .209). At a median follow-up of 21 months, the 2-year PFS and overall survival rates for patients with polymorphic versus wild variants were 57.0% versus 42.2% (P = .077) and 73.0% versus 55.5% (P = .143), respectively. CONCLUSIONS:Polymorphic variant XRCC1 HNSCC patients treated with CCRT have significantly increased acute radiation morbidities and may have a trend toward better PFS in comparison with the wild variant. 10.1016/j.ijrobp.2018.03.039
    Interventions for preventing oral mucositis in patients with cancer receiving treatment: oral cryotherapy. Riley Philip,Glenny Anne-Marie,Worthington Helen V,Littlewood Anne,Clarkson Jan E,McCabe Martin G The Cochrane database of systematic reviews BACKGROUND:Oral mucositis is a side effect of chemotherapy, head and neck radiotherapy, and targeted therapy, affecting over 75% of high risk patients. Ulceration can lead to severe pain and difficulty eating and drinking, which may necessitate opioid analgesics, hospitalisation and nasogastric or intravenous nutrition. These complications may lead to interruptions or alterations to cancer therapy, which may reduce survival. There is also a risk of death from sepsis if pathogens enter the ulcers of immunocompromised patients. Ulcerative oral mucositis can be costly to healthcare systems, yet there are few preventive interventions proven to be beneficial. Oral cryotherapy is a low-cost, simple intervention which is unlikely to cause side-effects. It has shown promise in clinical trials and warrants an up-to-date Cochrane review to assess and summarise the international evidence. OBJECTIVES:To assess the effects of oral cryotherapy for preventing oral mucositis in patients with cancer who are receiving treatment. SEARCH METHODS:We searched the following databases: the Cochrane Oral Health Group Trials Register (to 17 June 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue 5), MEDLINE via Ovid (1946 to 17 June 2015), EMBASE via Ovid (1980 to 17 June 2015), CANCERLIT via PubMed (1950 to 17 June 2015) and CINAHL via EBSCO (1937 to 17 June 2015). We searched the US National Institutes of Health Trials Registry, and the WHO Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching databases. SELECTION CRITERIA:We included parallel-design randomised controlled trials (RCTs) assessing the effects of oral cryotherapy in patients with cancer receiving treatment. We used outcomes from a published core outcome set registered on the COMET website. DATA COLLECTION AND ANALYSIS:Two review authors independently screened the results of electronic searches, extracted data and assessed risk of bias. We contacted study authors for information where feasible. For dichotomous outcomes, we reported risk ratios (RR) and 95% confidence intervals (CI). For continuous outcomes, we reported mean differences (MD) and 95% CIs. We pooled similar studies in random-effects meta-analyses. We reported adverse effects in a narrative format. MAIN RESULTS:We included 14 RCTs analysing 1280 participants. The vast majority of participants did not receive radiotherapy to the head and neck, so this review primarily assesses prevention of chemotherapy-induced oral mucositis. All studies were at high risk of bias. The following results are for the main comparison: oral cryotherapy versus control (standard care or no treatment). Adults receiving fluorouracil-based (5FU) chemotherapy for solid cancersOral cryotherapy probably reduces oral mucositis of any severity (RR 0.61, 95% CI 0.52 to 0.72, 5 studies, 444 analysed, moderate quality evidence). In a population where 728 per 1000 would develop oral mucositis, oral cryotherapy would reduce this to 444 (95% CI 379 to 524). The number needed to treat to benefit one additional person (NNTB), i.e. to prevent them from developing oral mucositis, is 4 people (95% CI 3 to 5).The results were similar for moderate to severe oral mucositis (RR 0.52, 95% CI 0.41 to 0.65, 5 studies, 444 analysed, moderate quality evidence). NNTB 4 (95% CI 4 to 6).Severe oral mucositis is probably reduced (RR 0.40, 95% CI 0.27 to 0.61, 5 studies, 444 analysed, moderate quality evidence). Where 300 per 1000 would develop severe oral mucositis, oral cryotherapy would reduce this to 120 (95% CI 81 to 183), NNTB 6 (95% CI 5 to 9). Adults receiving high-dose melphalan-based chemotherapy before haematopoietic stem cell transplantation (HSCT)Oral cryotherapy may reduce oral mucositis of any severity (RR 0.59, 95% CI 0.35 to 1.01, 5 studies, 270 analysed, low quality evidence). Where 824 per 1000 would develop oral mucositis, oral cryotherapy would reduce this to 486 (95% CI reduced to 289 to increased to 833). The NNTB is 3, although the uncertainty surrounding the effect estimate means that the 95% CI ranges from 2 NNTB, to 111 NNTH (number needed to treat in order to harm one additional person, i.e. for one additional person to develop oral mucositis).The results were similar for moderate to severe oral mucositis (RR 0.43, 95% CI 0.17 to 1.09, 5 studies, 270 analysed, low quality evidence). NNTB 3 (95% CI 2 NNTB to 17 NNTH).Severe oral mucositis is probably reduced (RR 0.38, 95% CI 0.20 to 0.72, 5 studies, 270 analysed, moderate quality evidence). Where 427 per 1000 would develop severe oral mucositis, oral cryotherapy would reduce this to 162 (95% CI 85 to 308), NNTB 4 (95% CI 3 to 9).Oral cryotherapy was shown to be safe, with very low rates of minor adverse effects, such as headaches, chills, numbness/taste disturbance, and tooth pain. This appears to contribute to the high rates of compliance seen in the included studies.There was limited or no evidence on the secondary outcomes of this review, or on patients undergoing other chemotherapies, radiotherapy, targeted therapy, or on comparisons of oral cryotherapy with other interventions or different oral cryotherapy regimens. Therefore no further robust conclusions can be made. There was also no evidence on the effects of oral cryotherapy in children undergoing cancer treatment. AUTHORS' CONCLUSIONS:We are confident that oral cryotherapy leads to large reductions in oral mucositis of all severities in adults receiving 5FU for solid cancers. We are less confident in the ability of oral cryotherapy to reduce oral mucositis in adults receiving high-dose melphalan before HSCT. Evidence suggests that it does reduce oral mucositis in these adults, but we are less certain about the size of the reduction, which could be large or small. However, we are confident that there is an appreciable reduction in severe oral mucositis in these adults.This Cochrane review includes some very recent and currently unpublished data, and strengthens international guideline statements for adults receiving the above cancer treatments. 10.1002/14651858.CD011552.pub2
    Chemotherapy-induced oral mucositis is associated with detrimental bacterial dysbiosis. Hong Bo-Young,Sobue Takanori,Choquette Linda,Dupuy Amanda K,Thompson Angela,Burleson Joseph A,Salner Andrew L,Schauer Peter K,Joshi Pujan,Fox Evan,Shin Dong-Guk,Weinstock George M,Strausbaugh Linda D,Dongari-Bagtzoglou Anna,Peterson Douglas E,Diaz Patricia I Microbiome BACKGROUND:Gastrointestinal mucosal injury (mucositis), commonly affecting the oral cavity, is a clinically significant yet incompletely understood complication of cancer chemotherapy. Although antineoplastic cytotoxicity constitutes the primary injury trigger, the interaction of oral microbial commensals with mucosal tissues could modify the response. It is not clear, however, whether chemotherapy and its associated treatments affect oral microbial communities disrupting the homeostatic balance between resident microorganisms and the adjacent mucosa and if such alterations are associated with mucositis. To gain knowledge on the pathophysiology of oral mucositis, 49 subjects receiving 5-fluorouracil (5-FU) or doxorubicin-based chemotherapy were evaluated longitudinally during one cycle, assessing clinical outcomes, bacterial and fungal oral microbiome changes, and epithelial transcriptome responses. As a control for microbiome stability, 30 non-cancer subjects were longitudinally assessed. Through complementary in vitro assays, we also evaluated the antibacterial potential of 5-FU on oral microorganisms and the interaction of commensals with oral epithelial tissues. RESULTS:Oral mucositis severity was associated with 5-FU, increased salivary flow, and higher oral granulocyte counts. The oral bacteriome was disrupted during chemotherapy and while antibiotic and acid inhibitor intake contributed to these changes, bacteriome disruptions were also correlated with antineoplastics and independently and strongly associated with oral mucositis severity. Mucositis-associated bacteriome shifts included depletion of common health-associated commensals from the genera Streptococcus, Actinomyces, Gemella, Granulicatella, and Veillonella and enrichment of Gram-negative bacteria such as Fusobacterium nucleatum and Prevotella oris. Shifts could not be explained by a direct antibacterial effect of 5-FU, but rather resembled the inflammation-associated dysbiotic shifts seen in other oral conditions. Epithelial transcriptional responses during chemotherapy included upregulation of genes involved in innate immunity and apoptosis. Using a multilayer epithelial construct, we show mucositis-associated dysbiotic shifts may contribute to aggravate mucosal damage since the mucositis-depleted Streptococcus salivarius was tolerated as a commensal, while the mucositis-enriched F. nucleatum displayed pro-inflammatory and pro-apoptotic capacity. CONCLUSIONS:Altogether, our work reveals that chemotherapy-induced oral mucositis is associated with bacterial dysbiosis and demonstrates the potential for dysbiotic shifts to aggravate antineoplastic-induced epithelial injury. These findings suggest that control of oral bacterial dysbiosis could represent a novel preventive approach to ameliorate oral mucositis. 10.1186/s40168-019-0679-5
    Salivary Cytokine Levels and Oral Mucositis in Head and Neck Cancer Patients Treated With Chemotherapy and Radiation Therapy. Bossi Paolo,Bergamini Cristiana,Miceli Rosalba,Cova Agata,Orlandi Ester,Resteghini Carlo,Locati Laura,Alfieri Salvatore,Imbimbo Martina,Granata Roberta,Mariani Luigi,Iacovelli Nicola Alessandro,Huber Veronica,Cavallo Anna,Licitra Lisa,Rivoltini Licia International journal of radiation oncology, biology, physics PURPOSE:We assessed the presence of salivary cytokines, their modulation during chemoradiation therapy (CTRT), and their association with oral mucositis severity in patients with head and neck cancer (HNC). METHODS AND MATERIALS:The present prospective observational study enrolled 55 patients with locally advanced HNC requiring CTRT. We also studied 10 healthy volunteers and 10 patients with other cancers. The salivary levels of 13 cytokines were analyzed. We constructed a cytokine predictive score of oral mucositis severity. RESULTS:The baseline salivary cytokine levels were not associated with the severity of treatment-induced oral mucositis. The cytokine levels overall increased during treatment, especially in patients with worse mucositis. In particular, on univariable analysis, an increase of interleukin (IL)-1β (area under the curve [AUC] 0.733; P=.009), IL-6 (AUC 0.746; P=.005), and tumor necrosis factor-α (AUC 0.710; P=.005) at the third week of treatment was significantly associated with the development of severe oral mucositis. On multivariable analysis, the predictive score based on the IL-1β and IL-6 changes from baseline to week 3 was an early strong predictor of higher grade oral mucositis. CONCLUSIONS:The treatment of HNC patients with concurrent CTRT induces a significant increase in the salivary levels of IL-1β, IL-6, and tumor necrosis factor-α, all positively associated with the severity of mucosal toxicity. A greater increase of IL-1β and IL-6 3 weeks after treatment initiation is predictive of worse oral mucositis, representing a potential tool for the early identification of patients at risk. 10.1016/j.ijrobp.2016.08.047
    Oral Cryotherapy for Preventing Oral Mucositis in Patients Receiving Cancer Treatment. Riley Philip,McCabe Martin G,Glenny Anne-Marie JAMA oncology Clinical Question:In patients receiving treatment for cancer, does oral cryotherapy prevent oral mucositis? Bottom Line:Oral cryotherapy is effective for the prevention of oral mucositis in adults receiving fluorouracil-based chemotherapy for solid cancers, and for the prevention of severe oral mucositis in adults receiving high-dose melphalan-based chemotherapy before hematopoietic stem cell transplantation (HSCT). 10.1001/jamaoncol.2016.2680
    Nutritional Status and Its Association With Radiation-Induced Oral Mucositis in Patients With Nasopharyngeal Carcinoma During Radiotherapy: A Prospective Study. Shu Zekai,Zeng Ziyi,Yu Bingqi,Huang Shuang,Hua Yonghong,Jin Ting,Tao Changjuan,Wang Lei,Cao Caineng,Xu Zumin,Jin Qifeng,Jiang Feng,Feng Xinglai,Piao Yongfeng,Huang Jing,Chen Jia,Shen Wei,Chen Xiaozhong,Wu Hui,Wang Xiushen,Qiu Rongliang,Lu Lixia,Chen Yuanyuan Frontiers in oncology Background and Aims:Malnutrition is a concern in patients with nasopharyngeal carcinoma (NPC) during chemoradiotherapy (CRT)/radiotherapy (RT), which is considered to be related with radiation-induced oral mucositis (ROM). The study aimed to evaluate the nutritional status of NPC patients during RT and investigate its association with ROM. Methods:A prospective study was conducted in NPC patients. Patients were divided into three subgroups (mild, moderate, and severe groups) based on the duration of severe ROM (≥ grade 3). Body weight, body mass index (BMI), albumin, prealbumin, NRS2002, and ROM grade were assessed on a weekly basis before and during CRT/RT. The statistical analysis was performed in the overall group and between three subgroups. Results:A total of 176 patients were included. In the overall group, body weight and BMI kept decreasing since week 1 of RT, and NRS2002 score and ROM grade increased (p < 0.001). NRS2002 score and prealbumin levels were significantly different between each subgroup (p ≤ 0.046). Significant differences were observed in the proportion of patients receiving enteral nutrition, duration of parenteral nutrition, and total calories provided by nutritional support among three subgroups (p = 0.045-0.001). Conclusions:Malnutrition occurred early in NPC patients and worsened continuously during RT. ROM was strongly associated with nutritional status. Nutritional support should be provided at the start of RT, especially in patients at high-risk of severe ROM. 10.3389/fonc.2020.594687
    Is skeletal muscle loss associated with chemoradiotherapy toxicity in nasopharyngeal carcinoma patients? A prospective study. Huang Xiao,Lv Li-Na,Zhao Yang,Li Ling,Zhu Xiao-Dong Clinical nutrition (Edinburgh, Scotland) BACKGROUND:Our study explored to investigate whether skeletal muscle loss before concurrent chemoradiotherapy (CCRT) can predict treatment-related toxicity in this population. METHODS:Computed tomography (CT) scan of the third lumbar were used to assess and calculate the SMA (skeletal muscle area), SMI (skeletal muscle index), SMD (skeletal muscle density), SMG (skeletal muscle gauge) and estimate LBM (lean body mass). Handgrip strength (HGS) and daily walk speed were evaluated. Predictive factors linked to toxicity were assessed by logistic regression models and adjusted odds ratios (OR) of treatment toxicity were reported. RESULTS:A total of 82 patients were evaluated (67.1% males, 45.7 ± 10.7 years). Skeletal muscle loss was not associated with severe radiotherapy toxicity. In males, sarcopenia increases the risk of dose-limiting toxicity (DLT) (OR: 4.00, 95% CI = 1.20-13.36, p = 0.024). DLT is associated with reduced SMA (OR: 0.97, 95% CI = 0.94-1.00, p = 0.041), SMI (OR: 0.91, 95% CI = 0.84-0.99, p = 0.042) and LBM (OR: 0.90, 95% CI = 0.81-0.99, p = 0.041). Reduced HGS was significantly associated with grade 3-4 leukopenia (OR: 0.92, 95% CI = 0.86-0.98, p = 0.007), and was associated with any grade 3-4 toxicity (OR: 0.94, 95% CI = 0.89-0.99, p = 0.013). There is a strong correlation between LBM and HGS (Pearson's r = 0.71, p < 0.001). CONCLUSIONS:Skeletal muscle loss was not associated with severe radiation oral mucositis and dermatitis but associated with any grade 3-4 toxicity and severe gastrointestinal reactions in NPC patients. In males, sarcopenia before treatment is predictive of DLT. Increased HGS is independently associated with a reduced risk of hematological toxicity. 10.1016/j.clnu.2020.05.020
    A double-blind phase III trial of immunomodulating nutritional formula during adjuvant chemoradiotherapy in head and neck cancer patients: IMPATOX. Boisselier Pierre,Kaminsky Marie-Christine,Thézenas Simon,Gallocher Olivier,Lavau-Denes Sandrine,Garcia-Ramirez Muriel,Alfonsi Marc,Cupissol Didier,de Forges Hélène,Janiszewski Chloé,Geoffrois Lionnel,Sire Christian,Senesse Pierre, The American journal of clinical nutrition BACKGROUND:In a previous phase II study an immunonutrient supplement was found to reduce severe acute toxicities for head and neck squamous cell cancer (HNSCC) patients treated with concomitant cisplatin and radiotherapy. OBJECTIVES:The primary objective of the present study was to evaluate efficacy of the same immunonutrient supplement on severe mucositis. Secondary objectives included tolerance, compliance to oral supplementation, chemotherapy interruptions and delays, quality of life, and progression-free survival (PFS) and overall survival (OS) at 1, 2, and 3 y. METHODS:Between November 2009 and June 2013, 180 HNSCC patients eligible for adjuvant chemotherapy after surgery with curative intent were included in our double-blind phase III multicenter trial. They were assigned to receive oral supplementation (3 sachets/d) of either a formula enriched with l-arginine and omega-3 (n-3) fatty and ribonucleic acids (experimental arm), or an isocaloric isonitrogenous control (control arm), for 5 d before each of 3 cycles of cisplatin. Intention-to-treat (ITT) and per-protocol (PP) analyses were undertaken, along with subgroup analyses of ≥75% compliant patients, to compare the incidence of acute mucositis (Radiation Therapy Oncology Group and WHO scales) and 36-mo survival. RESULTS:At 1 mo after terminating chemoradiotherapy (CRT), no differences were observed in the incidence of grade 3-4 mucositis between treatment groups, in the ITT, PP (172 patients), and subgroup (≥75% compliance, n = 112) analyses. The immunomodulating supplement did not significantly improve survival in the ITT and PP analyses at 3 y after CRT. Among ≥75% compliant patients, however, OS at 3 y was significantly improved in the immunomodulating formula group (81%; 95% CI: 67%, 89%) compared with controls (61%; 95% CI: 46%, 73%; P = 0.034), as well as PFS (73%; 95% CI: 58%, 83% compared with 50%; 95% CI: 36%, 63%; P = 0.012). CONCLUSIONS:Although this immunomodulating formula failed to reduce severe mucositis during CRT, the findings suggest that the long-term survival of compliant HNSCC patients was improved.This trial was registered at clinicaltrials.gov as NCT01149642. 10.1093/ajcn/nqaa227