Efficacy and Safety of FORRAD® for the Management of Radiation-induced Mucositis in Patients With Nasopharyngeal Carcinoma Receiving IMRT

Efficacy and Safety of FORRAD® for the Management of Radiation-induced Mucositis in Patients With Nasopharyngeal Carcinoma Receiving IMRT: A Single-center, Randomized Controlled Trial

Radiation therapy remains the principal treatment for nasopharyngeal carcinoma (NPC). The most frequently occurred radiation-related side effect is probably the radiation-induced oral mucositis (OM), which affects up to 100% of NPC patients receiving radiation therapy. When severe, oral mucositis increases the risk of infection and may compromise clinical outcomes by necessitating treatment breaks, dosage reductions, and reduced therapy compliance. In China, a quadruple mixture, composed of dexamethasone, gentamicin, vitamin B12, and procaine, is commonly prescribed when NPC patients begin to suffer from radiation-induced OM. However, the incidence of radiation-induced OM is still quite high. Oral Ulcer Gargle (FORRAD®) is a proprietary viscous liquid mucoadhesive hydrogel formulation. It creates a palliative barrier over injured mucosa, to prevent and to cure radiation-induced OM. The objective of this randomized phase II study is to assess the efficacy and safety of Oral Ulcer Gargle (FORRAD®) as an intervention for radiation-induced OM in the treatment of NPC, compared with the commonly used quadruple mixture, which is composed of dexamethasone, gentamicin, vitamin B12, and procaine.

Study Overview

• Status: Unknown
• Conditions: Nasopharyngeal Neoplasms; Stomatitis
• Intervention / Treatment: Drug: Oral Ulcer Gargle (FORRAD®); Drug: Quadruple mixture, composed of dexamethasone, gentamicin, vitamin B12, and procaine

Detailed Description

Nasopharyngeal carcinoma (NPC) is one of the most common malignances in South China. Radiation therapy remains the principal treatment for NPC. The most frequently occurred radiation-related side effect is probably the radiation-induced oral mucositis (OM), which affects up to 100% of NPC patients receiving radiation therapy. Although intensity modulated radiation therapy (IMRT) has been widely used in China nowadays, the incidence of radiation-induced oral mucositis is still high. OM can decrease patients' oral intake and nutrition, leading to dehydration, weight loss, and declining performance status that may require intravenous fluid hydration, feeding tube placement, and hospitalization. OM also may increase opioid use. When severe, oral mucositis increases the risk of infection and may compromise clinical outcomes by necessitating treatment breaks, dosage reductions, and reduced therapy compliance. Common clinical management strategies include bland rinses, topical anesthetics and analgesics, mucosal coating agents, and systemic analgesics. However, none of these interventions has been supported by conclusive evidence. In China, a quadruple mixture, composed of dexamethasone, gentamicin, vitamin B12, and procaine, is commonly prescribed when NPC patients begin to suffer from radiation-induced OM.

Oral Ulcer Gargle (FORRAD®) is a proprietary viscous liquid mucoadhesive hydrogel formulation. It creates a palliative barrier over injured mucosa, to prevent and to cure radiation-induced OM.

The objective of this randomized phase II study is to assess the efficacy and safety of Oral Ulcer Gargle (FORRAD®) as an intervention for radiation-induced OM in the treatment of NPC, compared with the commonly used quadruple mixture, which is composed of dexamethasone, gentamicin, vitamin B12, and procaine.

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Department of Radiation Oncology, Sun Yat-Sen University Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Pathologically confirmed and previously untreated nasopharyngeal carcinoma.
2. Age ≥ 18 years and ≤ 65 years.
3. Karnofsky performance status (KPS) score ≥ 70.
4. Planned to receive radiotherapy alone or concurrent chemoradiotherapy, with intensity-modulated radiation therapy (IMRT).
5. Adequate bone marrow function: while blood cell >= 3,000/μL, absolute neutrophil count >= 1,500/μL, hemoglobin >= 100g/L, platelet >= 75,000/μL.
6. Life expectancy of >= 3 months.

Exclusion Criteria:

1. Known allergic reaction to any component of Oral Ulcer Gargle (FORRAD®) or quadruple mixture, which is composed of dexamethasone, gentamicin, vitamin B12, and procaine, or severe allergic constitution.
2. Other conditions that the investigators consider as inappropriate for enrolling into this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FORRAD group; This group of patients will receive Oral Ulcer Gargle (FORRAD®) during study for prevention and treatment of acute radiation-induced oral mucositis (OM). This is the experimental group.	Drug: Oral Ulcer Gargle (FORRAD®); Oral Ulcer Gargle (FORRAD®) is prescribed at the beginning of radiotherapy for free. Patients are asked to start application of Oral Ulcer Gargle (FORRAD®) at the onset of radiotherapy, four times a day (after meals and before bedtime), until completion of their radiotherapy. All patients will receive conventional health education and medical care for prevention and treatment of radiation-induced oral mucositis. When grade > 3 OM happened, other interventions, such as prophylactic or therapeutic antibacterial therapy, will be used, and radiotherapy should be interrupted.
Active Comparator: Quadruple mixture group; This group of patients will receive quadruple mixture, which is composed of dexamethasone, gentamicin, vitamin B12, and procaine, during study for prevention and treatment of acute radiation-induced oral mucositis (OM). This is the active comparator group.	Drug: Quadruple mixture, composed of dexamethasone, gentamicin, vitamin B12, and procaine; Quadruple mixture is prescribed at the beginning of radiotherapy. Patients are asked to start application of quadruple mixture at the onset of radiotherapy, four times a day (before meals and before bedtime), until completion of their radiotherapy. All patients will receive conventional health education and medical care for prevention and treatment of radiation-induced oral mucositis. When grade > 3 OM happened, other interventions, such as prophylactic or therapeutic antibacterial therapy, will be used, and radiotherapy should be interrupted.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EORTC QLQ-C30	EORTC QLQ-C30 is a Quality-of-Life Instrument proposed by the European Organization for Research and Treatment of Cancer (EORTC), for use in International Clinical Trials in Oncology. The QLQ-C30 incorporates nine multi-item scales: five functional scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life scale.	Day 56 after completion or termination of radiotherapy
WHO score	The World Health Organization (WHO) Oral Toxicity score combines both elements into a single score that grades the severity of the condition from 0 (no oral mucositis) to 4 (swallowing not possible such that patient needs supplementary nutrition).	Day 56 after completion or termination of radiotherapy
OMDQ MTS question 2 (Q2) score	Oral Mucositis Daily Questionnaire (OMDQ) mouth and throat soreness (MTS) question 2 (Q2) is a 5-point categorical scale in which patients grade MTS from 0 (no soreness) to 4 (extreme soreness)3 which is a component of the OMDQ in that it tracks very well with objective (WHO score and opioid use) and subjective measurement of OM severity.	Day 56 after completion or termination of radiotherapy
OMAS	Oral Mucositis Assessment Scale (OMAS) provides an objective assessment of oral mucositis based on assessment of the appearance and extent of redness and ulceration in various areas of the mouth.	Day 56 after completion or termination of radiotherapy
Incidence of grade ≥ 3 mucositis	Incidence of grade ≥ 3 mucositis according to CTCAE version 4.0	Day 56 after completion or termination of radiotherapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Interruption time during the schedule of radiotherapy	The cumulative interruption time during the schedule of radiotherapy because of grade 4 or higher radiation-induced oral mucositis.	Through radiotherapy completion or termination, an average of 7 weeks
Time for healing of radiation-induced oral mucositis	Time until healing of radiation-induced oral mucositis, after the completion or the termination of radiotherapy.	Through study completion, an average of 15 weeks
The cumulative dose of opioid used	The cumulative dose of opioid used from the beginning of radiotherapy until the completion of study.	Through study completion, an average of 15 weeks
The cumulative time using opioid	The cumulative time using opioid from the beginning of radiotherapy until the completion of study.	Through study completion, an average of 15 weeks
The change of body weight from baseline.	The change of body weight before radiotherapy and the day when radiotherapy is completed or terminated.	Baseline and 7 weeks

Collaborators and Investigators

• Sponsor: Yun-fei Xia

Publications and helpful links

General Publications

• Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90. doi: 10.3322/caac.20107. Epub 2011 Feb 4. Erratum In: CA Cancer J Clin. 2011 Mar-Apr;61(2):134.
• Blanchard P, Lee A, Marguet S, Leclercq J, Ng WT, Ma J, Chan AT, Huang PY, Benhamou E, Zhu G, Chua DT, Chen Y, Mai HQ, Kwong DL, Cheah SL, Moon J, Tung Y, Chi KH, Fountzilas G, Zhang L, Hui EP, Lu TX, Bourhis J, Pignon JP; MAC-NPC Collaborative Group. Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol. 2015 Jun;16(6):645-55. doi: 10.1016/S1470-2045(15)70126-9. Epub 2015 May 6.
• Chen L, Hu CS, Chen XZ, Hu GQ, Cheng ZB, Sun Y, Li WX, Chen YY, Xie FY, Liang SB, Chen Y, Xu TT, Li B, Long GX, Wang SY, Zheng BM, Guo Y, Sun Y, Mao YP, Tang LL, Chen YM, Liu MZ, Ma J. Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial. Lancet Oncol. 2012 Feb;13(2):163-71. doi: 10.1016/S1470-2045(11)70320-5. Epub 2011 Dec 7.
• Zhang LF, Li YH, Xie SH, Ling W, Chen SH, Liu Q, Huang QH, Cao SM. Incidence trend of nasopharyngeal carcinoma from 1987 to 2011 in Sihui County, Guangdong Province, South China: an age-period-cohort analysis. Chin J Cancer. 2015 May 14;34(8):350-7. doi: 10.1186/s40880-015-0018-6.
• Mao YP, Yin WJ, Guo R, Zhang GS, Fang JL, Chi F, Qi ZY, Liu MZ, Ma J, Sun Y. Dosimetric benefit to organs at risk following margin reductions in nasopharyngeal carcinoma treated with intensity-modulated radiation therapy. Chin J Cancer. 2015 May 20;34(5):189-97. doi: 10.1186/s40880-015-0016-8.
• Zheng Y, Han F, Xiao W, Xiang Y, Lu L, Deng X, Cui N, Zhao C. Analysis of late toxicity in nasopharyngeal carcinoma patients treated with intensity modulated radiation therapy. Radiat Oncol. 2015 Jan 13;10:17. doi: 10.1186/s13014-014-0326-z.
• Porock D. Factors influencing the severity of radiation skin and oral mucosal reactions: development of a conceptual framework. Eur J Cancer Care (Engl). 2002 Mar;11(1):33-43.
• Rodriguez-Caballero A, Torres-Lagares D, Robles-Garcia M, Pachon-Ibanez J, Gonzalez-Padilla D, Gutierrez-Perez JL. Cancer treatment-induced oral mucositis: a critical review. Int J Oral Maxillofac Surg. 2012 Feb;41(2):225-38. doi: 10.1016/j.ijom.2011.10.011. Epub 2011 Nov 8.
• Wu F, Wang R, Lu H, Wei B, Feng G, Li G, Liu M, Yan H, Zhu J, Zhang Y, Hu K. Concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: treatment outcomes of a prospective, multicentric clinical study. Radiother Oncol. 2014 Jul;112(1):106-11. doi: 10.1016/j.radonc.2014.05.005. Epub 2014 Jun 2.
• Guo R, Tang LL, Mao YP, Zhou GQ, Qi ZY, Liu LZ, Lin AH, Liu MZ, Ma J, Sun Y. Clinical Outcomes of Volume-Modulated Arc Therapy in 205 Patients with Nasopharyngeal Carcinoma: An Analysis of Survival and Treatment Toxicities. PLoS One. 2015 Jul 6;10(7):e0129679. doi: 10.1371/journal.pone.0129679. eCollection 2015.
• Allison RR, Ambrad AA, Arshoun Y, Carmel RJ, Ciuba DF, Feldman E, Finkelstein SE, Gandhavadi R, Heron DE, Lane SC, Longo JM, Meakin C, Papadopoulos D, Pruitt DE, Steinbrenner LM, Taylor MA, Wisbeck WM, Yuh GE, Nowotnik DP, Sonis ST. 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. Cancer. 2014 May 1;120(9):1433-40. doi: 10.1002/cncr.28553.

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Anticipated): June 1, 2017
• Study Completion (Anticipated): June 1, 2017

Study Registration Dates

• First Submitted: March 27, 2016
• First Submitted That Met QC Criteria: April 6, 2016
• First Posted (Estimate): April 12, 2016

Study Record Updates

• Last Update Posted (Estimate): April 12, 2016
• Last Update Submitted That Met QC Criteria: April 6, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: radiotherapy; Nasopharyngeal carcinoma (NPC); oral mucositis (OM)
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Diseases; Gastroenteritis; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Mouth Diseases; Carcinoma; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Mucositis; Stomatitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Sensory System Agents; Anesthetics; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Micronutrients; Anti-Bacterial Agents; Anesthetics, Local; Protein Synthesis Inhibitors; Vitamins; Vitamin B Complex; Hematinics; Dexamethasone; Gentamicins; Vitamin B 12; Hydroxocobalamin; Procaine
• Other Study ID Numbers: B2015-074-01