Ignite Creation Date:
2024-05-06 @ 6:15 PM
Last Modification Date:
2024-10-26 @ 2:44 PM
Study NCT ID:
NCT05595109
Status:
ENROLLING_BY_INVITATION
Last Update Posted:
2022-10-26
First Post:
2022-10-22
Brief Title:
Role of Silymarin in Chemotherapy Toxicity and Cognition Improvement in Breast Cancer Patients
Sponsor:
Tanta University
Organization:
Tanta University
Study Overview
Official Title:
The Possible Protective Role of Silymarin Against Chemotherapy Induced Toxicities and Cognitive Impairment in Breast Cancer Patients
Status:
ENROLLING_BY_INVITATION
Status Verified Date:
2022-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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 n28 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 n28 which will receive the same regimen plus silymarin 140mg once daily
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 n28 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 n28 which will receive the same regimen plus silymarin 140mg once daily
Detailed Description:
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 388 of cancers in this population with the estimated number of breast cancer cases nearly 22700 in 2020 and forecasted to be approximately 46000 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 aminotransferaseIn 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
Silymarin administration in a lipopolysaccharide induced animal model of peripheral neuropathy prevented the dopaminergic neuro-degeneration through inhibiting the activation of microglia Other in-vitro studies revealed that silymarin attenuates the activation of glial cell activation in cellular models possibly through inhibition of inducible nitric oxide synthase iNOS production Silymarin was also reported to protect both microglia and astroglia from oxidative insults induced by peroxide in ex vivo system
Treatment with silymarin prevents the increase in AST and creatine kinase CK serum activity and myocardial excitability in rats caused by doxorubicin It also significantly reduces doxorubicin-pro-oxidative activity and decreases histological changes in liver and heart tissue The hepato-protective and cardio-protective effects of silymarin may be attributed to its antioxidant capacity its ability to prevent lipid peroxidation and its ability to increase glutathione concentration
Cognitive impairment in patients with breast cancer began to appear in the literature in the 1990s coincident with the increasing use of postoperative adjuvant chemotherapy In two recent preclinical studies silymarin was reported to improve cognitive impairment in mice and these former studies suggested that silymarin may be a therapeutic agent for cognitive decline
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 n28 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 n28 which will receive the same regimen plus silymarin 140mg once daily
Blood sample collection and biochemical assessment
1 N-terminal prohormone of brain naturetic peptide NT-proBNP and liver panel
2 myeloperoxidase MPO
3 neurofilament light chain NFL
4 andnuclear factor- Kabba B p65 NF-ĸB p65 or TNF-alpha
Clinical assessment of chemotherapy induced toxicities
Doxorubicin related cardiotoxicity will be assessed through - Echocardiography at baseline and after the last doxorubicin cyclophosphamide AC cycle
Paclitaxel induced peripheral sensory neuropathy will be done through - The implication of National Cancer Institute Common Terminology Criteria for Adverse Events NCI-CTCAE Version 5 2017 for grading of neuropathy at baseline and by the end of every two paclitaxel cycles
The use of Neurotoxicity- 12 item questionnaire score Ntx-12 from the validated Functional Assessment of Cancer TherapyGynecologic Oncology Group FACTGOG-Ntx-12 at baseline and by the end of every two paclitaxel cycles
The assessment of the severity of neuropathic pain through brief pain inventory short form BPI-SF worst item Severity of neuropathic pain will be assessed at baseline and by the end of every two paclitaxel cycles
Cognitive impairment will be assessed using the brief assessment of impaired Cogentin questionnaire BASIC-Q
Primary and secondary outcomes
The primary outcome is the change in ejection fraction and 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 The secondary outcome is the changes in serum levels of the measured biological markers
- Sample size calculation According to the results of a previous study the total number of subjects required to detect the cardio-protective effect of silymarin in patients with different types of cancer receiving anthracyclines containing chemotherapy was 25 patients With 5 significance level 80 statistical power and an attrition rate of 10 the initial sample size required for the current study is 28 patients in each group
-Ethical approval The study will be approved by the Research Ethics Committee of Tanta University The study will be registered as a clinical trial at ClinicalTrialsgov All participants will be informed about the benefits and risks of the study Any unexpected risks that will appear during the course of the research will be clarified to the participants and to the ethical committee on time The data of the enrolled patients will be confidential All enrolled patients will give their written informed consents The study will be conducted between October 2022 and October 2024
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 aminotransferaseIn 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
Silymarin administration in a lipopolysaccharide induced animal model of peripheral neuropathy prevented the dopaminergic neuro-degeneration through inhibiting the activation of microglia Other in-vitro studies revealed that silymarin attenuates the activation of glial cell activation in cellular models possibly through inhibition of inducible nitric oxide synthase iNOS production Silymarin was also reported to protect both microglia and astroglia from oxidative insults induced by peroxide in ex vivo system
Treatment with silymarin prevents the increase in AST and creatine kinase CK serum activity and myocardial excitability in rats caused by doxorubicin It also significantly reduces doxorubicin-pro-oxidative activity and decreases histological changes in liver and heart tissue The hepato-protective and cardio-protective effects of silymarin may be attributed to its antioxidant capacity its ability to prevent lipid peroxidation and its ability to increase glutathione concentration
Cognitive impairment in patients with breast cancer began to appear in the literature in the 1990s coincident with the increasing use of postoperative adjuvant chemotherapy In two recent preclinical studies silymarin was reported to improve cognitive impairment in mice and these former studies suggested that silymarin may be a therapeutic agent for cognitive decline
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 n28 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 n28 which will receive the same regimen plus silymarin 140mg once daily
Blood sample collection and biochemical assessment
1 N-terminal prohormone of brain naturetic peptide NT-proBNP and liver panel
2 myeloperoxidase MPO
3 neurofilament light chain NFL
4 andnuclear factor- Kabba B p65 NF-ĸB p65 or TNF-alpha
Clinical assessment of chemotherapy induced toxicities
Doxorubicin related cardiotoxicity will be assessed through - Echocardiography at baseline and after the last doxorubicin cyclophosphamide AC cycle
Paclitaxel induced peripheral sensory neuropathy will be done through - The implication of National Cancer Institute Common Terminology Criteria for Adverse Events NCI-CTCAE Version 5 2017 for grading of neuropathy at baseline and by the end of every two paclitaxel cycles
The use of Neurotoxicity- 12 item questionnaire score Ntx-12 from the validated Functional Assessment of Cancer TherapyGynecologic Oncology Group FACTGOG-Ntx-12 at baseline and by the end of every two paclitaxel cycles
The assessment of the severity of neuropathic pain through brief pain inventory short form BPI-SF worst item Severity of neuropathic pain will be assessed at baseline and by the end of every two paclitaxel cycles
Cognitive impairment will be assessed using the brief assessment of impaired Cogentin questionnaire BASIC-Q
Primary and secondary outcomes
The primary outcome is the change in ejection fraction and 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 The secondary outcome is the changes in serum levels of the measured biological markers
- Sample size calculation According to the results of a previous study the total number of subjects required to detect the cardio-protective effect of silymarin in patients with different types of cancer receiving anthracyclines containing chemotherapy was 25 patients With 5 significance level 80 statistical power and an attrition rate of 10 the initial sample size required for the current study is 28 patients in each group
-Ethical approval The study will be approved by the Research Ethics Committee of Tanta University The study will be registered as a clinical trial at ClinicalTrialsgov All participants will be informed about the benefits and risks of the study Any unexpected risks that will appear during the course of the research will be clarified to the participants and to the ethical committee on time The data of the enrolled patients will be confidential All enrolled patients will give their written informed consents The study will be conducted between October 2022 and October 2024
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None