Concurrent chemoradiotherapy (CCRT) and intravenous drip of ulinastatin, the details are as follows:
Intensity modulated radiation therapy combined with concurrent chemotherapy of cisplatin 100mg/m2 on day 1 and day 22 of RT;
Ulinastatin through intravenous drip at a dose of one hundred thousand units added to 100 ml of 0.9% normal saline, 3 times every radiation day, until the end of radiotherapy.

Concurrent chemoradiotherapy (CCRT) alone:
Intensity modulated radiation therapy combined with concurrent chemotherapy of cisplatin 100mg/m2 on day 1 and day 22 of RT.

Oral Mucositis (Ulcerative) Due to Radiation

Patients in both arms received concurrent cisplatin chemotherapy:
100 mg/m² cisplatin given intravenously every 3 weeks on days 1, 22 concurrently with radiotherapy.

Cisplatin

Patients in both arms received Intensity Modulated Radiation Therapy:
All target volumes were outlined slice by slice on the axial contrast-enhanced CT with MR fusion images in the treatment planning system. The target volumes were defined in accordance with the International Commission on Radiation Units and Measurements Reports 50 and 62. The prescribed dose was 68-72 Gy to PTVnx (Planning target volume of the primary tumor), 64-68 Gy to GTVnd (Gross tumor volume of the cervical lymph node), 60- 64Gy to PTVnd and PTV1 (Planning target volume 1), and 54-58 Gy to PTV2 (Planning target volume 2) in 30-32 fractions. The details of dose limits for organs at risk were based on the study 0225 from The Radiation Therapy Oncology Group (RTOG 0225).

Intensity Modulated Radiation Therapy

Patients in the experimental group were received ulinastatin:
Ulinastatin (UTI): ulinastatin was intravenous drip at a dose of one hundred thousand units added to 100 ml of 0.9% normal saline every time, 3 times every radiation day, and until the end of radiotherapy.

Ulinastatin

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Cancer Center, Sun Yat-sen University

Efficacy of Ulinastatin for Reducing Radiation-Induced Oral Mucositis in Nasopharyngeal Carcinoma Patients

A Phase 3, Open Label, Multicenter, Randomized Controlled Clinical Trial to Evaluate the Efficacy of Ulinastatin in the Reduction of Acute Oral Mucositis Caused by Concurrent Chemoradiotherapy(CCRT) for Patients With Localregionally Advanced Nasopharyngeal Carcinoma (NPC).

The primary outcome measures planned in the protocol were the incidence of actue oral mucositis grade greater than or equal to 3 using the Common Terminology Criteria for Adverse Events of Version 4.03 (CTCAE 4.03) in the experimental group and control group. CTCAE 4.03 grade 3 = severe pain; interfering with oral; CTCAE 4.03 grade 4 = Life-threatening consequences; urgent intervention indicated; CTCAE 4.03 grade 5 = death. Mucositis will be assessed weely during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. The whole observation time may up to 19 weeks.

Weeks to onset is the duration from the start of radiotherapy to the week of first severe oral mucositis occurred. Severe oral mucositis was defined as a Grade 3 or above of Common Terminology Criteria For Adverse Events of Version 4.03 (CTCAE 4.03). CTCAE 4.03 grade 3 = severe pain; interfering with oral; CTCAE 4.03 grade 4 = Life-threatening consequences; urgent intervention indicated; CTCAE 4.03 grade 5 = death. Mucositis will be assessed weekly during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. Time to onset of severe mucositis will be recorded. The whole observation time may up to 19 weeks.

The Oral Assessment Guide (OAG) score is calculated based on the following categories: ability of swallow; the appearance of lips; the appearance of tongue; the appearance of oral mucous membranes; the appearance of gingivae; the appearance of teeth; and the change of voice. There are three grades in every category. The details about Oral Assessment Guide is available in: http://www.rch.org.au/rchcpg/hospital_clinical_guideline_index/Mouth_Care_of_the_paediatric_oncology_patient/. The OAG score will be assessed weekly during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. The whole observation time may up to 19 weeks.

The Oral Mucositis Score of World Health Organization (WHO) was classified based on the changes of patients' oral mucosa and ability to eat, and are classified to 4 grades. WHO scale for oral mucositis (available in: Peterson DE, Boersdoets CB, Bensadoun RJ, et al. Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Annals of Oncology 2015; 26(supply5). https://doi.org/10.1093/annonc/mdv202): Grade 0 = no oral mucositis; Grade 1 = erythema and soreness; Grade 2 = ulcers, able to eat solids; Grade 3 = ulcers, requires liquid diet (due to mucositis); Grade 4 = ulcers, alimentation not possible (due to mucositis). The WHO score will be assessed weekly during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. The whole observation time may up to 19 weeks.

Participants with a duration of 5 days or more without an administration of radiotherapy or who discontinue radiotherapy prior to completion of planned radiotherapy were considered to have an unplanned break in radiotherapy. The rate of unplanned break was calculated for both arms.

The quality of life for all participants was evaluated according to The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) (available in: Grønvold M. EORTC QLQ-C30 Scoring Manual 2014.). The EORTC QLQ-C30 shoule be completed weekly during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. The whole observation time may up to 19 weeks.

The functional status for all participants was assessed according to Karnofsky Performance Status Scale (KPS Scale) (available in: Friendlander AH, Ettinger RL. Karnofsky performance status scale[J]. Special Care in Dentistry, 2009, 29(4):147.). The KPS Scale was range from 0 to 100, and were averagely divided into eleven grades begin with 0. The KPS Scale will be recoreded weekly during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. The whole observation time may up to 19 weeks.

The pain caused by oral mucositis for all participants was assessed according to Numeric Rating Scale (NRS scale), by which a respondent selects a whole number (0-10 integers) that best reflects the intensity of their pain. And an 11-point scale where 0 indicates no pain and 10 indicates the worst imaginable pain. The scale for each patient was recorded. The NRS scale will be assessed weekly during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. The whole observation time may up to 19 weeks.

Efficacy was estimated according to Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST 1.1) (available in: Watanabe H, Okada M, Kaji Y, et al. New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1. European Journal of Cancer, 2009, 45(2):228-247.). The efficacy was divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). And CR was defined as disappearance of all target lesions, PR was defined as at least a 30% reduction in the sum of the longest diameter of target lesions. Overall response rate (ORR) is the sum rate of patients with CR and PR for the total number of evaluable patients.

The adverse events related to ulinastatin based on medicine specification of ulinastatin was observed and recorded down according to Common toxicity criteria, version 2.0. (available in: Version CTC, Version CTC, Date P, et al. Common toxicity criteria (ctc) 1999.).

Zhao Chong

Clinical Professor

Sun Yat-sen University

Affiliated Cancer Hospital & Institute of Guangzhou Medical University

First People's Hospital of Foshan

People's Hospital of Zhongshan

Fifth Affiliated Hospital, Sun Yat-Sen University

All patients will receive two Iohexol clearance tests, 5 mL each time before cycle 1 and 4 of HDMTX

Patients receive 5 mL of Iohexol prior to cycle 1 and 4 of HDMTX

IOHEXOL

Ann & Robert H. Lurie Children's Hosptial of Chicago

Prediction of Excretion and Toxicity of High Dose Methotrexate in Children and Adolescents With ALL

Prediction of Excretion and Toxicity of High Dose Methotrexate in Children and Adolescents With Acute Lymphoblastic Leukemia and Lymphoma

A change from baseline Iohexol clearance results after about six weeks

A change from baseline serum creatinine results after about six weeks

Amy Walz, MD

Attending Physician-Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplant

Ann & Robert H Lurie Children's Hospital of Chicago

Cryotherapy during conditioning treatment with chemotherapy prior to HSCT

Standard oral Care. No Cryotherapy during conditioning treatment prior to HSCT

Oral Mucositis

Pain

Infection

Nutrition Aspect of Cancer

Cryotherapy with ice-chips, ice cream or ice water is given during conditioning treatment with chemotherapy prior to HSCT.

Cryotherapy

Pediatric Oncology Department, Queen Silvia Childrens´ Hospital

Departent of Pediatric Oncology, Lund University Hospital

Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Hudding

Department of pediatrics B78, Karolinska University Hospital

Department of Hematology, Uppsala University Hospital

Cryotherapy for Prevention of Oral Mucositis in Children Undergoing Hematopoietic Stem Cell Transplantation

A Randomized Controlled Trial of Cryotherapy for Prevention and Reduction of Severity of Oral Mucositis in Children Undergoing Hematopoietic Stem Cell Transplantation.

WHO-Oral toxicity scale Grade 0 - No mucositis Grade 1 - Erythema and/or soreness Grade 2 - Erythema and/or ulcers. Can eat solid food. Grade 3 - Erythema and/or Ulcers. No solid food but can ingest liquids. Grade 4 - Oral alimentation not possible.

Mouth Pain measured with Numerical Rating scale(NRS)for children >7 years and parents and Facial Pain Scale(FPS) for children < 7 years

Beck youth inventories for depression and anxiety

Days with, and dose of morphine-equivalent opioids

Weight Loss in kilograms from admission to date of engraftment

Counted from day 0 until discharge either home or to region hospital.

Level of p-CRP in comparison to grade of mucositis

In correlation to grade of Oral Mucositis

mucositis/protease

Efficacy of Ulinastatin for Reducing Radiation-Induced Oral Mucositis in Nasopharyngeal Carcinoma Patients

Prediction of Excretion and Toxicity of High Dose Methotrexate in Children and Adolescents With ALL

Cryotherapy for Prevention of Oral Mucositis in Children Undergoing Hematopoietic Stem Cell Transplantation

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