Efficacy of an Oral Immunomodulatory Nutrient on Survival During Postoperative Concomitant Chemoradiotherapy in Head and Neck Cancer

Study Overview
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Brief Summary
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The investigators designed a prospective randomized double-blind trial to determine if the oral immunomodulating formula could improve the disease-free survival rate in high-risk locally-advanced head and neck Squamous Cell Carcinoma patients treated with Chemoradiotherapy.

Detailed Description
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The primary objective is to evaluate the efficacy on disease-free survival of a formula enriched with L-arginine, omega-3 fatty acids, and ribonucleic acids, taken for 5 days before each cycle of chemotherapy, in patients with high-risk locally-advanced HNSCC treated with postoperative concomitant chemoradiotherapy (CRT). This study is a national, multicentric double blinded, randomised phase III trial. A total of 306 patients (102 patients in group control vs 204 patients in group Oral Impact®) will be required including 10% of lost-to-follow-up patients. An immunomodulating oral supplementation compound (Oral Impact®) is compared to an isocaloric isonitrogenous control. The compound to be assessed contains 334kcal/bag and 18.1g of proteins, as well as immunomodulatory nutrients such as L-Arginine, RNA and omega-3. The control has the same formula to that of the Oral Impact®, but not enriched with specific nutrients. Each patient has to take Oral Impact® or a sip feed control during 5 days before each cycle of chemotherapy. DFS will be measured from the time of randomization to the time of the first evidence of progression (local, regional, metastatic, or second primary) or death from any cause. Patients alive without carcinologic event were censored at last follow-up date. Patients treated with postoperative CRT are expected to have a 2-year DFS rate of 60% without specific diet (pControl). Including a ratio 1:2, an expected recruitment of 90 patients per year, the current study will require 131 events to detect an absolute improvement of 15% (HR=0.56, pExperimental=75%) with 0.90 statistical power using a two-sided test and a significance level of 0.05. A total of 306 patients (102 vs 204) will be required including 10% of lost of follow-up patients. The inclusion period would be 4 years, for an expected total duration of study about 8 years.

Official Title
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Double-blind Multicenter Phase III Trial Evaluating the Efficacy of an Oral Immunomodulatory Nutrient on Survival During Postoperative Concomitant Chemoradiotherapy in Head and Neck Squamous Cell Carcinoma (HNSCC)

Conditions
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Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Dietary Supplement: Immunomodulating oral supplementation
* Dietary Supplement: Sip feed control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Surgically resected primary squamous cell carcinomas (HNSCC) of the hypopharynx, oropharynx, larynx and oral cavity with pathological stage pT1-2 pN+ (pathological stage 1 ou 2 with node) or pT3-4 any pN (pathological stage 3 ou 4 with or without node) (UICC 7th edition, 2010), Postoperative concomitant CRT based on radiotherapy and on cisplatinum, 3 cycles, 100mg/m² by cycle, Patients who undergone macroscopically complete resection, High-risk characteristics patients with one or more following criteria: such as invasion of two or more regional lymph nodes, extracapsular extension of nodal disease or microscopically-involved mucosal margins of resection, perineural involvement, vascular tumor embolism, WHO (World Health Organization) performance status 0, 1 or 2, Age: 18 years old up to 75 years old including, Exclusion Criteria: Nasopharyngeal, paranasal sinuses, nasal cavity tumours or thyroid cancers Sepsis at baseline Distant metastasis Other immunomodulating diets in the last month before inclusion Parenteral nutrition at baseline History of hypersensitivity and/or allergy to any component of Oral Impact ® Patients with history of malignancies who are not disease-free for more than 5 years.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immunomodulating oral supplementation<br>The immunomodulating oral supplementation compound (Oral Impact®) contains 334kcal/bag and 18.1g of proteins, as well as immunomodulatory nutrients such as L-Arginine, RNA and omega-3. Each bag of product containing powder (74g/bag) will be diluted in 250 millilitres of water by the patients and drunk at home. Three doses will be drunk at home by the patients daily, during the 5 days before each chemotherapy cycle. | Dietary Supplement: Immunomodulating oral supplementation<br>* Per os administration, 3 times / day, 5 days before each cycle of chemotherapy.<br>|
| Active Comparator: Sip feed control<br>The control has the same formula to that of the Oral Impact®, but not enriched with specific nutrients: it is an isocaloric isonitrogenous control. Each bag of product containing powder (74g/bag) will be diluted in 250 millilitres of water by the patients and drunk at home. Three doses will be drunk at home by the patients daily, during the 5 days before each chemotherapy cycle. | Dietary Supplement: Sip feed control<br>* Per os administration, 3 times / day, 5 days before each cycle of chemotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-Free Survival (DFS) | 2-years DFS rate | From date of randomization until the date of the first documented progression (local, regional, metastatic) or date of death from any cause, whichever came first, assessed up to 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS at 1, 2 and 3 years | From date of randomization until the date of death from any cause, assessed up to 3 years. | 
| Rate of drug compliance | the compliance is defined as the taking of more than 75 % of study product prescription | up to 45 days | 
| Adverse events rate | graded based on NCI-CTCAE v4.03 | until 3 months after radiotherapy | 
| Quality of life by using the general quality of life questionnaire about cancer (QLQ-C30). | The EORTC QLQ-C30 uses for the questions 1 to 28 a 4-point scale. The scale scores from 1 to 4: 1 (Not at all), 2 (A little), 3 (Quite a bit) and 4 (Very much). Half points are not allowed. The range is 3. For the raw score, less points are considered to have a better outcome. The EORTC QLQ-C30 uses for the questions 29 and 30 a 7-points scale. The scale scores from 1 to 7: 1 (very poor) to 7 (excellent). Half points are not allowed. The range is 6. First of all, raw score has to be calculated with mean values. Afterwards linear transformation is performed to be comparable. More points are considered to have a better outcome. | Quality of life will be assessed up to 2 years after the last day of radiotherapy. | 
| Quality of life by using the specific quality of life questionnaire about head and neck cancer (HN35) | The EORTC HN35 uses a 4-point scale. The scale scores from 1 to 4: 1 (Not at all), 2 (A little), 3 (Quite a bit) and 4 (Very much). Half points are not allowed. The range is 3. For the raw score, less points are considered to have a better outcome. | Quality of life will be assessed up to 2 years after the last day of radiotherapy. | 
| Cachexia | Cachexia will be evaluated with weight (in kilograms) | Cachexia will be assessed up to 3 years after the last day of radiotherapy. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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head and neck squamous cell carcinoma (HNSCC), immunomodulatory nutrient, concomitant chemoradiotherapy, survival