Effect of Anthracyclines and Cyclophosphamide on Cardiovascular Responses

Breast Cancer Clinical Trial

Official title:

Chronic Effect of Doxorubicin and Cyclophosphamide on Neurovascular Control and Blood Pressure in Women in Adjuvant Treatment for Breast Neoplasia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04568161
• Other study ID #: Breast Cancer Chemotherapy
• Status: Recruiting
• Phase: N/A
• Start date: August 3, 2020
• Est. completion date: March 3, 2025

Study information

• Verified date: June 2023
• Source: University of Sao Paulo General Hospital
• Contact: Raphaela VR Groehs, PhD
• Phone: 551126615699
• Email: rapha_vilar[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The present study aims to investigate the chronic effect of treatment with doxorubicin and cyclophosphamide on neurovascular control and blood pressure in women undergoing adjuvant treatment for breast cancer.

Description:

The development of new drugs and different adjuvant therapeutic regimens, based on the combination of anthracycline (A) and cyclophosphamide (C), have contributed greatly to improve survival rate in breast cancer patients. Despite the clinical benefits of this therapy, AC treatment can cause cardiovascular acute and chronic changes. In a recent investigation, we observed that an acute AC chemotherapy session increases sympathetic nervous activity and blood pressure in patients with breast cancer.

The present study aims to investigate the chronic effects of AC regimen on sympathetic nervous activity, peripheral vasoconstriction, endothelial microparticles and blood pressure, in women with breast cancer.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 15
• Est. completion date: March 3, 2025
• Est. primary completion date: September 3, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 45 Years to 60 Years

Eligibility

Inclusion Criteria:

• diagnosis of stage II-III breast cancer

• starting adjuvant chemotherapy

Exclusion Criteria:

• metastatic disease,

• hypercholesterolemia, diabetes,

• hypertension,

• severe lymphedema,

• organic disorders (renal failure, heart failure and chronic liver disease),

• obesity (BMI> 30) and,

• who are under pharmacological treatment with statins, angiotensin-converting enzyme inhibitors, losartan potassium, beta blockers or antioxidants

Related Conditions & MeSH terms

• Breast Cancer
• Cardiotoxicity
• Cardiovascular Disease
• Cardiovascular Diseases
• Endothelial Disfunction
• Neurovascular Disorder

Intervention

Procedure:
• Physical Characteristics
Body weight, height and waist circumference
• Muscular Sympathetic Nervous Activity
Microneurography technique.

Diagnostic Test:
• Cardiac Function
Echocardiography.
• Heart rate
Electrocardiography
• Blood pressure
Non-invasive photoplethysmography.
• Blood Assessments
Serum and Plasma will be extracted by centrifugation. Endothelial microparticles by flow cytometry Interleukin-6 and tumor necrosis factor a by ELISA, High-sensitive reactive serum C-reactive protein by immunoturbidimetric assay, NT- ProBNP According to Central Laboratory, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo. Endothelin-1 by immunoenzymatic method Nitric oxide by gas chemiluminescence Lipoperoxidation by fluorimetry Carbonyl by spectrophotometer, and Superoxide Dismutase (SOD) by colorimetry.
• Muscle blood flow
Venous occlusion plethysmography
• Endothelium-dependent vascular function
Brachial ultrasound
• Vascular intima-media thickness
Carotid ultrasound
• Physical Capacity
Cardiopulmonary exercise test

Drug:
• Anthracycline & Cyclophosphamide treatment scheme
Four session of intravenous (in bolus) infusion of doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 with an interval of 21 days between sessions.

Locations

Country	Name	City	State
Brazil	Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo	Sao Paulo

Sponsors (3)

Lead Sponsor	Collaborator
University of Sao Paulo General Hospital	Hospital Israelita Albert Einstein, Universidade Federal Fluminense

Country where clinical trial is conducted

Brazil, 

References & Publications (14)

Abdel-Sayed S, Nussberger J, Aubert JF, Gohlke P, Brunner HR, Brakch N. Measurement of plasma endothelin-1 in experimental hypertension and in healthy subjects. Am J Hypertens. 2003 Jul;16(7):515-21. doi: 10.1016/s0895-7061(03)00903-8. — View Citation

Barretto AC, Santos AC, Munhoz R, Rondon MU, Franco FG, Trombetta IC, Roveda F, de Matos LN, Braga AM, Middlekauff HR, Negrao CE. Increased muscle sympathetic nerve activity predicts mortality in heart failure patients. Int J Cardiol. 2009 Jul 10;135(3):302-7. doi: 10.1016/j.ijcard.2008.03.056. Epub 2008 Jun 26. — View Citation

Dolci A, Dominici R, Cardinale D, Sandri MT, Panteghini M. Biochemical markers for prediction of chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use. Am J Clin Pathol. 2008 Nov;130(5):688-95. doi: 10.1309/AJCPB66LRIIVMQDR. — View Citation

Granger DL, Anstey NM, Miller WC, Weinberg JB. Measuring nitric oxide production in human clinical studies. Methods Enzymol. 1999;301:49-61. doi: 10.1016/s0076-6879(99)01068-x. No abstract available. — View Citation

Jenkins NT, Padilla J, Boyle LJ, Credeur DP, Laughlin MH, Fadel PJ. Disturbed blood flow acutely induces activation and apoptosis of the human vascular endothelium. Hypertension. 2013 Mar;61(3):615-21. doi: 10.1161/HYPERTENSIONAHA.111.00561. Epub 2013 Jan 14. — View Citation

Jensen BV, Skovsgaard T, Nielsen SL. Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol. 2002 May;13(5):699-709. doi: 10.1093/annonc/mdf132. — View Citation

Kovachich GB, Mishra OP. Lipid peroxidation in rat brain cortical slices as measured by the thiobarbituric acid test. J Neurochem. 1980 Dec;35(6):1449-52. doi: 10.1111/j.1471-4159.1980.tb09022.x. — View Citation

Laterza MC, de Matos LD, Trombetta IC, Braga AM, Roveda F, Alves MJ, Krieger EM, Negrao CE, Rondon MU. Exercise training restores baroreflex sensitivity in never-treated hypertensive patients. Hypertension. 2007 Jun;49(6):1298-306. doi: 10.1161/HYPERTENSIONAHA.106.085548. Epub 2007 Apr 16. — View Citation

Negrao CE, Rondon MU, Tinucci T, Alves MJ, Roveda F, Braga AM, Reis SF, Nastari L, Barretto AC, Krieger EM, Middlekauff HR. Abnormal neurovascular control during exercise is linked to heart failure severity. Am J Physiol Heart Circ Physiol. 2001 Mar;280(3):H1286-92. doi: 10.1152/ajpheart.2001.280.3.H1286. — View Citation

Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf. 2000 Apr;22(4):263-302. doi: 10.2165/00002018-200022040-00002. — View Citation

Sales ARK, Negrao MV, Testa L, Ferreira-Santos L, Groehs RVR, Carvalho B, Toschi-Dias E, Rocha NG, Laurindo FRM, Debbas V, Rondon MUPB, Mano MS, Hajjar LA, Hoff PMG, Filho RK, Negrao CE. Chemotherapy acutely impairs neurovascular and hemodynamic responses in women with breast cancer. Am J Physiol Heart Circ Physiol. 2019 Jul 1;317(7):H1-H12. doi: 10.1152/ajpheart.00756.2018. Epub 2019 Apr 19. — View Citation

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019 Jan;69(1):7-34. doi: 10.3322/caac.21551. Epub 2019 Jan 8. — View Citation

Soultati A, Mountzios G, Avgerinou C, Papaxoinis G, Pectasides D, Dimopoulos MA, Papadimitriou C. Endothelial vascular toxicity from chemotherapeutic agents: preclinical evidence and clinical implications. Cancer Treat Rev. 2012 Aug;38(5):473-83. doi: 10.1016/j.ctrv.2011.09.002. Epub 2011 Oct 6. — View Citation

Thijssen DHJ, Bruno RM, van Mil ACCM, Holder SM, Faita F, Greyling A, Zock PL, Taddei S, Deanfield JE, Luscher T, Green DJ, Ghiadoni L. Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans. Eur Heart J. 2019 Aug 7;40(30):2534-2547. doi: 10.1093/eurheartj/ehz350. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Muscle sympathetic nerve activity	Change in muscular sympathetic nerve activity measured by microneurography	15-20 days after the end of AC regimen
Secondary	Muscle blood flow	Change in muscle blood flow measured by venous oclusion plethysmography	15-20 days after the end of AC regimen
Secondary	Blood Pressure	Change in blood pressure measured by finometer	15-20 days after the and of AC regimen
Secondary	Physical capacity	Change in physical capacity measured by cardiopulmonary exercise test	15-20 days after the end of AC regimen
Secondary	Cardiac Function Impairment	Change in cardiac function measured by echocardiography	15-20 days after the end of AC regimen