Evaluation of Effects of Silymarin on Cisplatin Induced Nephrotoxicity in Upper Gastrointestinal Adenocarcinoma

Study Overview
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Brief Summary
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Cisplatin is a potent chemotherapeutic agent that has been widely used to treat many solid tumours. acute renal failure, despite conservative fluid and electrolyte management, frequently reported adverse event and limiting cisplatin use. Silymarin, a flavonolignan complex isolated from Silybum marianum, has a strong antioxidant, hepatoprotective, anticancer and in animal model nephroprotective properties. Neutrophil gelatinase-associated lipocalin (NGAL) protein is a promising biomarker to detect acute kidney injury due to cisplatin. Milk thistle extract inhibitory effects on epidermal growth factor receptor, vascular endothelial growth factor and insulin-like growth factor-I have shown in the previous in-vitro studies.The aim of present study,a randomized double-blind placebo- controlled clinical trial, to investigate the therapeutic effect of silymarin on cisplatin induced nephrotoxicity and it's impact on chemotherapy. Fifty-eight patients with diagnosed upper gastrointestinal tract carcinomas randomized to silymarin (420mg) or placebo plus chemotherapy [cisplatin 50-60 mg/m2, 5-fluorouracil mg/m2, docetaxel 60-80 mg/m2 every 21 days] for 63 day after inclusion. serum creatinin, blood urea nitrogen (BUN), serum and urine electrolyte will be measured daily during chemotherapy. changes in urine NGAL, serum vascular endothelial growth factor (VEGF)and caspase activity assessed up to 64 days.

Detailed Description
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This study will look for possible protective effects silymarin on kidney injury in patients receiving cisplatin.

Official Title
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Phase 2-3 Study of Silymarin on Cisplatin Induced Nephrotoxicity

Conditions
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Upper GI Cancer, Cisplatin Adverse Reaction

Intervention / Treatment
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* Drug: Silymarin
* Drug: Placebo
* Drug: chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age>18 years diagnosed measurable upper gastrointestinal adenocarcinoma swallow problem would like to participate in the study Glomerular filtration rate(GFR)>45ml/min/1.73m2 Exclusion Criteria: end stage renal disease requiring dialysis post transplantation receiving contrast media during last 72 hours chronic use of corticosteroids chronic use of angiotensin-converting enzyme inhibitor(ACEI ) untreated hypo-and hyperthyroidism ejection fraction<60% active urinary tract infection iver disease ( five fold increase of liver enzyme in asymptomatic or 3 fold increase in symptomatic use of other nephrotoxic agents such as aminoglycoside, amphotericin karnofsky performance status <70

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control arm<br>Placebo 420 mg daily in three divided doses for 65 days as control along with [cisplatin 50-60mg/m2 + fluorouracil 750 mg/m2 +docetaxel 60-80 mg/m2] | Drug: Placebo<br>* placebo tablets: 420 mg in 3 divided dose<br>* Other names: Identical inert tablet to mimic silymarin (140 mg);Drug: chemotherapy<br>* All patients will receive standard chemotherapy: cisplatin 50-60mg/m2 + fluorouracil 750 mg/m2 + docetaxel 60-80 mg/m2<br>* Other names: Docetaxel;|
| Active Comparator: Exprimental: Silymarin and chemotherapy<br>silymarin 420 mg daily in three divided doses for 65 days along with standard chemotherapy [cisplatin 50-60mg/m2 + fluorouracil 750 mg/m2 +docetaxel 60-80 mg/m2 control | Drug: Silymarin<br>* Silymarin 420 mg in 3 divided dose plus standard chemotherapy<br>* Other names: Milk thistle;Drug: chemotherapy<br>* All patients will receive standard chemotherapy: cisplatin 50-60mg/m2 + fluorouracil 750 mg/m2 + docetaxel 60-80 mg/m2<br>* Other names: Docetaxel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine concentration of NGAL | All subject receive silymarin at dose of 420mg or placebo in three dose for 65 consecutive day, urine NGAL concentration will be measured. | up to 9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in VEGF Serum concentration | To assess interaction between silymarin and cancer chemotherapy serum vascular endothelial growth factor will be measured. | up to 9 weeks | 
| Tissue activity of caspase 3 | To assess interaction between silymarin and cancer chemotherapy Tissue activity of caspase 3will be measured. | up to 9 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cisplatin, nephrotoxicity, antioxidant, urine neutrophil gelatinase-associated lipocalin (NGAL)