Clinical Target Volume Based on Disease Extension Risk Atlas and Computer-aided Delineation in Nasopharyngeal Carcinoma

Study Overview
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Brief Summary
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The purpose of this study is to compare individualized clinical target volume (CTV) based on disease extension risk atlas and computer-aided delineation with traditional CTV in intensity modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC), in order to confirm the efficacy and safety.

Detailed Description
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Patients with non-keratinizing NPC T1-4N0-3M0 (AJCC/UICC staging system 7th edition) are randomly assigned to receive IMRT using individualized clinical target volume (CTV) based on disease extension risk atlas and computer-aided delineation or IMRT using traditional CTV. IMRT is given as 2.13 Gray (Gy) per fraction with five daily fractions per week for 6-7 weeks to a total dose of 70.29 Gy to the primary tumor. Patients with T1N0M0 NPC receive IMRT only. For patients with stage T2-4N0-3M0 NPC, concurrent chemoradiotherapy (CCRT) is required and induction chemotherapy (IC) before CCRT is optional.Patients who participate in another randomized trial (NCT01872962) at the same time receive the protocol chemotherapy. Induction chemotherapy regimens are as follows: gemcitabine (1000 mg/m² d1,8) plus cisplatin (80mg/m² d1) or docetaxel (75mg/m² d1) plus cisplatin (75mg/m², total dose average to d1-d3) every 3 weeks for three cycles. concurrent chemotherapy include cisplatin (100mg/m² d1 or 80mg/m², total dose average to d1-d3) every 3 weeks for three cycles. Our primary endpoint is loco-regional recurrence-free survival (LRRFS) rate. Secondary end points include overall survival (OS) rate, distant metastasis-free survival (DMFS) rate, constituent ratio of local and regional recurrence pattern, toxic effects, quality of life scores and dosimetric parameters of IMRT planning. All efficacy analyses are conducted in the intention-to-treat population, and the safety population include only patients who receive their randomly assigned treatment.

Official Title
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Prospective Non-inferiority Randomized Trial Comparing Clinical Target Volume Based on Disease Extension Risk Atlas and Computer-aided Delineation and Traditional Clinical Target Volume in Radiotherapy for Nasopharyngeal Carcinoma

Conditions
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Nasopharyngeal Neoplasms

Intervention / Treatment
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* Radiation: IMRT using individualized CTV
* Radiation: IMRT using traditional CTV
* Drug: Gemcitabine and cisplatin (induction chemotherapy)
* Drug: Docetaxel and cisplatin (induction chemotherapy)
* Drug: Cisplatin 100mg/m² concurrent chemotherapy
* Drug: Cisplatin 80mg/m² concurrent chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with newly histologically confirmed non-keratinizing (according to WHO histologically type). Tumor staged as T1-4N0-3M0 (according to the 7th AJCC edition), based upon the following minimum diagnostic workup within 4 weeks prior to registration:(1) history/physical examination;(2)chest X-ray, PA and lateral OR chest CT OR PET/CT;(3) pre-treatment magnetic resonance imaging (MRI) of nasopharynx and neck, pre-treatment MRI must be done at Sun Yat-sen University Cancer Center;(4) sonography OR CT of upper abdoman OR PET/CT;(5) Bone scan OR PET/CT. Satisfactory performance status: Karnofsky scale (KPS) ≥ 70. Adequate bone marrow function based upon the complete blood count within 2 weeks prior to registration: leucocyte count ≥ 4000/μL, hemoglobin ≥ 90g/L and platelet count ≥ 100000/μL. Adequate hepatic function within 2 weeks prior to registration: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) < 1.5×upper limit of normal (ULN) concomitant with alkaline phosphatase (ALP) ≤ 2.5×ULN, and bilirubin ≤ ULN. Adequate renal function within 2 weeks prior to registration: serum creatinine ≤ 133 umol/L or calculated creatinine clearance ≥ 60 ml/min. Women of childbearing potential and male participants must agree to use a medically effective means of birth control throughout their participation in the treatment phase of the study. Patients must be informed of the investigational nature of this study and sign a written informed consent. Exclusion Criteria: Age > 65 or < 18. Prior malignancy except adequately treated basal cell or squamous cell skin cancer outside head and neck region, in situ cervical cancer. Pregnancy or lactation (consider pregnancy test in women of child-bearing age and emphasize effective contraception during the treatment period). History of previous RT (except for non-melanomatous skin cancers outside intended RT treatment volume). Prior chemotherapy or surgery (except fine needle aspiration biopsy) to primary tumor or nodes. Hearing loss due to sensorineural deafness（except tumor induced conductive hearing loss). Any severe intercurrent disease, which may bring unacceptable risk or affect the compliance of the trial, for example, unstable cardiac disease requiring treatment, renal disease, chronic hepatitis, diabetes with poor control (fasting plasma glucose > 1.5×ULN), emotional disturbance, untreated active infectious disease, and acquired immune deficiency syndrome. Prior allergic reaction to the study drugs involved in this protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Individualized CTV<br>Patients receive IMRT using individualized CTV based on disease extension risk atlas and computer-aided delineation. Gemcitabine and cisplatin induction chemotherapy or docetaxel and cisplatin induction chemotherapy and cisplatin 100mg/m² concurrent chemotherapy or cisplatin 80mg/m² concurrent chemotherapy are optional based on clinical classification. | Radiation: IMRT using individualized CTV<br>* Intensity modulated radiotherapy (IMRT) using individualized CTV based on disease extension risk atlas and computer-aided delineation is given as 2.13 Gy per fraction with five daily fractions per week for 6-7 weeks to a total dose of 70.29 Gy to the primary tumor.<br>Drug: Gemcitabine and cisplatin (induction chemotherapy)<br>* Induction chemotherapy is optional for patients with T2-4N0-3M0 NPC. Patients who participate in another randomized trial (NCT01872962) at the same time receive gemcitabine (1000 mg/m² d1,8) and cisplatin (80mg/m² d1) every 3 weeks for 3 cycles before radiotherapy.<br>* Other names: Gemcitabine and cisplatin (GP);Drug: Docetaxel and cisplatin (induction chemotherapy)<br>* Induction chemotherapy is optional for patients with T2-4N0-3M0 NPC. Patients who haven't participated in other trials receive docetaxel (75 mg/m² d1) and cisplatin (75mg/m²,total dose average to d1-d3) every 3 weeks for 3 cycles before radiotherapy.<br>* Other names: Docetaxel and cisplatin (TP);Drug: Cisplatin 100mg/m² concurrent chemotherapy<br>* Cisplatin concurrent chemotherapy is required for patients with T2-4N0-3M0 NPC. Patients who participate another clinical trial (NCT01872962) at the same time receive cisplatin (100mg/m² d1) every 3 weeks for 3 cycles concurrently with radiotherapy.<br>* Other names: DDP 100mg/m²;Drug: Cisplatin 80mg/m² concurrent chemotherapy<br>* Cisplatin concurrent chemotherapy is required for patients with T2-4N0-3M0 NPC.Patients who haven't participated in other trials receive cisplatin (80mg/m²,total dose average to d1-d3) every 3 weeks for 3 cycles concurrently with radiotherapy.<br>* Other names: DDP 80mg/m²;|
| Active Comparator: Traditional CTV<br>Patients receive IMRT using traditional CTV. Gemcitabine and cisplatin induction chemotherapy or docetaxel and cisplatin induction chemotherapy and cisplatin 100mg/m² concurrent chemotherapy or cisplatin 80mg/m² concurrent chemotherapy are optional based on clinical classification. | Radiation: IMRT using traditional CTV<br>* Intensity modulated radiotherapy(IMRT) using traditional CTV is given as 2.13 Gy per fraction with five daily fractions per week for 6-7 weeks to a total dose of 70.29 Gy to the primary tumor.<br>Drug: Gemcitabine and cisplatin (induction chemotherapy)<br>* Induction chemotherapy is optional for patients with T2-4N0-3M0 NPC. Patients who participate in another randomized trial (NCT01872962) at the same time receive gemcitabine (1000 mg/m² d1,8) and cisplatin (80mg/m² d1) every 3 weeks for 3 cycles before radiotherapy.<br>* Other names: Gemcitabine and cisplatin (GP);Drug: Docetaxel and cisplatin (induction chemotherapy)<br>* Induction chemotherapy is optional for patients with T2-4N0-3M0 NPC. Patients who haven't participated in other trials receive docetaxel (75 mg/m² d1) and cisplatin (75mg/m²,total dose average to d1-d3) every 3 weeks for 3 cycles before radiotherapy.<br>* Other names: Docetaxel and cisplatin (TP);Drug: Cisplatin 100mg/m² concurrent chemotherapy<br>* Cisplatin concurrent chemotherapy is required for patients with T2-4N0-3M0 NPC. Patients who participate another clinical trial (NCT01872962) at the same time receive cisplatin (100mg/m² d1) every 3 weeks for 3 cycles concurrently with radiotherapy.<br>* Other names: DDP 100mg/m²;Drug: Cisplatin 80mg/m² concurrent chemotherapy<br>* Cisplatin concurrent chemotherapy is required for patients with T2-4N0-3M0 NPC.Patients who haven't participated in other trials receive cisplatin (80mg/m²,total dose average to d1-d3) every 3 weeks for 3 cycles concurrently with radiotherapy.<br>* Other names: DDP 80mg/m²;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local-regional recurrence-free survival rate | Local-regional recurrence-free survival is calculated from the date of randomization to the date of local or regional recurrence, whichever is first. | 3-year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival rate | Overall survival is calculated from the date of randomization to the date of death from any cause. | 3-year | 
| Distant metastasis-free survival rate | Distant metastasis-free survival is calculated from the date of randomization to the date of the first distant metastasis. | 3-year | 
| Constituent ratio of local and regional recurrence pattern | Constituent ratio of local and regional recurrence pattern is defined as the proportion of in-field,marginal and out-field recurrence. | 3-year | 
| Number of participants with adverse events | Incidence of acute and late toxicity | 3-year | 
| Quality of life score measured by EORTC QLQ-C30 | Quality of life is measured by European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30). | 3-year | 
| Quality of life score measured by EORTC H&N35 | Quality of life is measured by European Organization for Research and Treatment of Cancer Quality of Life Head and Neck Questionnaire (EORTC QLQ-H&N35). | 3-year | 
| Target volumes' dose coverage and doses irradiated to organs at risk | For example, relative volume of planning target volume (PTV) receive 110%,95%,93% of the prescription doses;max dose or dose receive by 1% volume of brainstem; et,al. | 3-year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nasopharyngeal carcinoma, Intensity modulated radiotherapy, Clinical target volume, Clinical trial