A Trial On 4 Cycles Of Neoadjuvant Chemotherapy Plus Concurrent Chemoradiation In N2-3 Nasopharyngeal Carcinoma

Study Overview
=================
Brief Summary
-----------------
The standard treatment strategy of locally advanced nasopharyngeal carcinoma (NPC) nowadays is concurrent chemoradiation (CCRT) based on intensity-modulated radiation therapy (IMRT). However, distant metastasis remains the major cause of treatment failure, especially in patients with T1-4N2-3M0 diseases (N2-3 NPC). The investigators inferred that it was more appropriate to consider N2-3 NPC as a systemic disease instead of a local disease. NACT of sufficient intensity such as 4 cycles might be effective enough for control of the pre-existing micrometastases. Therefore, the objective of this phase 3 multicenter randomized controlled trial is to make a comparison between NACT of 4 cycles plus CCRT based on IMRT and CCRT alone in N2-3 NPC on distant metastasis, survival and adverse reaction.

Detailed Description
-----------------
The standard treatment strategy of locally advanced nasopharyngeal carcinoma (NPC) nowadays is concurrent chemoradiation (CCRT), which is based on intensity-modulated radiation therapy (IMRT) and achieves a satisfactory local-regional control and a 5-year overall survival (OS) of 83.0%. However, distant metastasis remains the major cause of treatment failure, especially in patients with T1-4N2-3M0 diseases (N2-3 NPC). The distant metastasis reaches 35-48% after CCRT alone. To decrease distant metastasis of locally advanced NPC so as to improve survival, approaches on modifying timing of chemotherapy have been made to mainly 2 types: one was CCRT plus adjuvant chemotherapy (ACT), the other was neoadjuvant chemotherapy (NACT) plus CCRT. It was proved that CCRT plus ACT could not improve survival of locally advanced NPC further. Some clinical trials indicated that locally advanced NPC patients with 2-3 cycles of NACT plus CCRT had a better survival than those with CCRT alone though the roles of NACT remain controversial. It is known that N stage is by far the most significant predicting factor of metastasis risk for NPC. N2-3 NPC was also proved to have a quite great risk of distant failure. 51.4% of distant metastases happened within 1 year after CCRT. The investigators inferred that subclinical micrometastases were already present before treatment starting. Hence, it was more appropriate to consider N2-3 NPC as a systemic disease instead of a local disease. NACT of sufficient intensity such as 4 cycles might be effective enough for control of the pre-existing micrometastases. Therefore, this phase 3 multicenter randomized controlled trial is conducted to enroll 144 patients with N2-3 NPC. After stratification by N stage, the patients will be allocated into 2 treatment groups randomly at a ratio of 1:1 and applied with different treatment strategies to make a comparison between NACT of 4 cycles plus CCRT based on IMRT and CCRT alone in N2-3 NPC on distant metastasis, survival and adverse reaction.

Official Title
-----------------
4 Cycles Of Neoadjuvant Chemotherapy Plus Concurrent Chemoradiation Versus Concurrent Chemoradiation Alone In Patients With Stage N2-3 Nasopharyngeal Carcinoma: A Phase 3 Multicenter Randomised Controlled Trial

Conditions
-----------------
Nasopharyngeal Carcinoma

Intervention / Treatment
-----------------
* Drug: Docetaxel (DOC)
* Drug: Cisplatin (DDP)
* Radiation: Concurrent chemoradiation (CCRT)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with pathological diagnosis of nasopharyngeal carcinoma Union Internationale Contre le Cancer/American Joint Cancer Committee (UICC/AJCC) 2010 Stage T1-4 N2-3 M0 through magnetic resonance imaging of head and neck, whole-body bone scan and thoracoabdominal computed tomography Male or female with age no older than 70 years old Karnofsky Performance Scores ≥ 80 Expected survival ≥ 3 months Exclusion Criteria: Patients with distant metastasis before or during radiotherapy Severe dysfunction of heart, lung, liver, kidney or hematopoietic system Severe neurological, mental or endocrine diseases History of other malignancies Prior chemotherapy, radiotherapy or application of monoclonal antibodies Patients participated in clinical trials of other drugs within last 3 months Pregnant or lactating women Those who are considered by the researchers unsuitable to participate

Ages Eligible for Study
-----------------
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CCRT group (Group A)<br>Patients who are allocated into in this group will be treated with concurrent chemoradiation (CCRT). | Radiation: Concurrent chemoradiation (CCRT)<br>* The technology of radiotherapy is intensity-modulated radiation therapy (IMRT). A total dose of 66-72Gy is given to gross tumor of nasopharynx (GTVnx), 60-70Gy to positive neck lymph nodes (GTVnd), 60Gy to high-risk region (CTV1), and 50-54Gy to prophylactic irradiation region (CTV2). The regimen of concurrent chemotherapy is single-agent cisplatin 40mg/m2 weekly.<br>|
| Experimental: NACT-CCRT group (Group B)<br>Patients who are allocated into in this group will be treated with 4 cycles of neoadjuvant chemotherapy (NACT, docetaxel plus cisplatin) followed by CCRT. | Drug: Docetaxel (DOC)<br>* Neoadjuvant chemotherapy (NACT) is administrated every 3 weeks with the regimen comprised of docetaxel plus cisplatin. A total of 4 cycles of NACT is applied. Docetaxel is given at a dose of 75mg/m2 on the first day of every cycle.<br>* Other names: Docetaxel Injection;Drug: Cisplatin (DDP)<br>* Neoadjuvant chemotherapy (NACT) is administrated every 3 weeks with the regimen comprised of docetaxel plus cisplatin. A total of 4 cycles of NACT is applied. Cisplatin is given at a dose of 75mg/m2 on the first day of every cycle.<br>* Other names: Cisplatin Injection;Radiation: Concurrent chemoradiation (CCRT)<br>* The technology of radiotherapy is intensity-modulated radiation therapy (IMRT). A total dose of 66-72Gy is given to gross tumor of nasopharynx (GTVnx), 60-70Gy to positive neck lymph nodes (GTVnd), 60Gy to high-risk region (CTV1), and 50-54Gy to prophylactic irradiation region (CTV2). The regimen of concurrent chemotherapy is single-agent cisplatin 40mg/m2 weekly.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year overall survival (5y-OS) | Percentage of patients in a treatment group who are alive for a 5-year period of follow-up after the date of pathologic diagnosis | 5 years after the date of pathologic diagnosis | 
| 5-year distant-metastasis-free survival (5y-MFS) | Percentage of patients in a treatment group who are alive without distant metastasis for a 5-year period of follow-up after the date of pathologic diagnosis | 5 years after the date of pathologic diagnosis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year local-relapse-free survival (5y-RFS) | Percentage of patients in a treatment group who are alive without local recurrence for a 5-year period of follow-up after the date of pathologic diagnosis | 5 years after the date of pathologic diagnosis | 
| 5-year disease-free survival (5y-DFS) | Percentage of patients in a treatment group who are alive without disease-related events (local recurrence, distant metastasis) for a 5-year period of follow-up after the date of pathologic diagnosis | 5 years after the date of pathologic diagnosis | 
| Incidence of grade 3/4 adverse event | Incidence of patients in a treatment group who manifest a specific adverse event (such as myelosuppression) of grade 3/4. Incidence is calculated for each adverse event respectively and severity is evaluated on basis of Common Terminology Criteria for Adverse Events (CTCAE) 4.0 criteria. | Once a week during therapy, up to 7 weeks (Group A) or 19 weeks (Group B) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Survival, Nasopharyngeal carcinoma, Neoadjuvant chemotherapy, Concurrent chemoradiation, Distant metastasis