The Possible Protective Role of Silymarin Against Chemotherapy Induced Toxicities and Cognitive Impairment in Breast Cancer Patients
试验速览
- 阶段
- 2 期
- 状态
- Enrolling By Invitation
- 入组人数
- 56
- 试验地点
- 1
- 主要终点
- change in ejection fraction
研究概览
简要总结
Aim of the work This study aims to evaluate the possible beneficial role of silymarin in attenuating both doxorubicin related cardiac and hepatic toxicities and paclitaxel associated peripheral neuropathy and improving cognitive impairment in patients with breast cancer.
This study will be a randomized placebo controlled parallel study. The study will be performed in accordance with the ethical standards of Helsinki declaration in 1964 and its later amendments.
Group one: (Placebo group; n=28) which will receive four cycles of AC regimen (doxorubicin and cyclophosphamide; each cycle was given every 21 day) followed by 12 cycles of paclitaxel (each cycle was given in a weekly basis) plus placebo tablets once daily.
Group two: (Silymarin group; n=28) which will receive the same regimen plus silymarin 140mg once daily
详细描述
Breast cancer represents the most frequently diagnosed malignancy and the second most common cause of cancer death worldwide. In Egypt, breast cancer is the most common malignancy in women, accounting for 38.8% of cancers in this population, with the estimated number of breast cancer cases nearly 22,700 in 2020 and forecasted to be approximately 46,000 in 2050 .
Paclitaxel and doxorubicin are cytotoxic agents that are commonly used for treatment of breast cancer. Despite their effectiveness, both paclitaxel and doxorubicin are associated with cumulative and potential neurotoxicity and cardiotoxicity respectively . Paclitaxel induced peripheral neuropathy (PN) is a consequence of activation of the inflammatory cascade with subsequent increased pro-inflammatory cytokines production including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) . Moreover, paclitaxel can up-regulate matrix metalloproteinase-3 (MMP3) which plays an important role in the inflammatory and degenerative processes following nerve injury .
Oxidative stress plays a critical role in doxorubicin associated cardiotoxicity through direct cellular damage, induction of apoptosis and activation of nuclear factor- Kabba B (NF-ĸB) which in turn stimulates the production and release of inflammatory mediators .
Hepatotoxicity from doxorubicin was reported and it is likely due to direct toxic injury to the liver. Doxorubicin and its analogues are metabolized in the liver via microsomal enzymes, and production of a toxic or immunogenic intermediate may trigger liver injury with subsequent elevation of Serum aminotransferase.In addition, it was reported that, doxorubicin related hepatotoxicity is a consequence of free radical formation and oxidative stress and antioxidants may protect against doxorubicin-induced toxicity in the liver .
Although, the underlying neuro-protective mechanism of silymarin is mainly due to its capacity to inhibit oxidative stress in the brain, it also confers additional neuro-protection by influencing other pathways such as inflammatory pathways . Silymarin has been implicated in protecting neurons against oxidative stress and nitrosative stress . Silymarin was reported to exert direct effect on neuronal oxidant status .
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years old.
- •Patients with biopsy confirmed diagnosis breast cancer and with stage II and stage III breast cancer according to the American Joint Committee on Cancer (TNM staging system of breast cancer).
- •Patients with performance status <2 according to Eastern Cooperative Oncology Group (ECOG) score.
- •Adequate baseline hematologic values (absolute neutrophilic count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L and hemoglobin level ≥ 10 g/dl).
- •Patients with adequate liver function (serum bilirubin < 1.2 mg/dl) and adequate renal function (serum creatinine< 1.5 mg/d).
排除标准
- •Patients with prior exposure to anthracyclines and neurotoxic agents (Cis-platin, vincristine, paclitaxel, docetaxel, foscarnet ,INH, etc..) in the last 6 months.
- •Patients with evidence of metastasis at the initial assessment.
- •Concomitant use of antioxidant vitamins (vitamin A, C, E),anticonvulsants, tricyclic antidepressants, other medications used for neuropathic pain (gabapentin, lamotrigine, carbamazepine).
- •Presence of clinical evidence for severe cardiac illness (angina pectoris, uncontrolled hypertension, arrhythmias and left ventricular ejection fraction <50%).
- •Preexisting peripheral neuropathy resulting from other causes such as diabetes and brain disorders, hypothyroidism, autoimmune diseases, hepatitis C.
- •Patients with diabetes.
- •Patients with inflammatory diseases (ulcerative colitis, rheumatoid arthritis).
- •Patients with conditions associated with oxidative stress (smoking, tuberculosis, obesity).
- •Patients with liver disease (fatty liver, hepatitis C, etc..).
- •Patients who are candidates for monoclonal antibodies such as Trastuzumab and other targeted therapy (HER2 positive patients).
- •Pregnant and breast feeding women.
研究组 & 干预措施
Group one: (Placebo group)
which will receive four cycles of AC regimen (doxorubicin and cyclophosphamide; each cycle was given every 21 day)
followed by 12 cycles of paclitaxel (each cycle was given in a weekly basis) plus placebo tablets once daily.
干预措施: Placebo (Drug)
Group two: (Silymarin group)
which will receive the same regimen plus silymarin 140mg once daily.
干预措施: Silymarin (Drug)
结局指标
主要结局
change in ejection fraction
时间窗: 6 months
Doxorubicin related cardiotoxicity will be assessed through :Echocardiography at baseline, Before starting the first chemotherapy cycle (baseline), after the last AC cycle (for assessment of N-terminal prohormone of brain naturetic peptide "NT-proBNP" ) and after the last doxorubicin/ cyclophosphamide (AC) cycle.
change in percentage of patients with peripheral sensory neuropathy
时间窗: 6 months
change in percentage of patients with peripheral sensory neuropathy grade ≥ 2 with the variation of both 12-item neurotoxicity questionnaire (Ntx-12) total score and pain rating scale score.
次要结局
- changes in serum levels of the measured biological markers.(6 months)
研究者
Azza Ahmed Abdelkader Abu El-atta
principal investigator
Tanta University