VEGF: Effects of Analgesia Methods on Vascular Endothelial Growth Factor* and Inflammatory Responses in Breast Cancer Surgery

• Sponsor: Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT04689945
• Collaborator: (none)
• Enrollment: 91
• Location: 1
• Actual Duration (Months): 8
• Patients Per Site Per Month: 11.4

Study Details

Study Description

Brief Summary

Worldwide, breast cancer is the most common cancer among women, and its incidence and mortality rates are expected to increase significantly in the next years. It remains a major health problem. There is a vast area on breast cancer and immunity that still needs to be researched. Do anesthetic techniques and medication preferences effect immune responses? If so how they effect breast cancer outcomes is unclear.

On this trial, the investigators are searching anesthetic techniques affect on inflammatory and immune responses.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Morphine; Procedure: Erector Spinae Block; Drug: Control

Detailed Description

Breast cancer is the most frequently encountered surgery among all cancer surgeries. Although it is a well known procedure for anesthesiologists, it is still unclear whether anesthesiology effects immune responses. Cancer therapies often use immune therapies such as Bevacizumab (a monoclonal antibody which targets Vascular Endothelial Growth Factor), Trastuzumab(a monoclonal antibody for Herceptin (HER2/Neu) mutation) how anesthetics effect VEGF stays unclear.

Opioids are commonly used to provide analgesia for cancer pain, and functional opioid receptors have been identified on natural killer (NK) cells, the lymphocytes responsible for surveillance and elimination of cancer cells.[4] Anesthesiologists have well founded concerns about using morphine during cancer surgeries.

Regional anesthetic techniques commonly used on cancer surgeries.The activation of sensory neurons during pain enhances tumor progression and metastatic potential. Regional anesthesia blocks somatic nociception and inhibits sympathetic preganglionic outflow (functional sympathectomy) during surgery. Moreover regional anesthesia, by blocking sympathetic nervous system output, induces a prevalence of parasympathetic tone. Local anesthetics can also modulate autonomic receptors. For these reasons, more studies are needed to investigate the action of regional anesthetic neuromodulation on cancer progression.[11]

The Erector Spinae Plane Block (ESP block) is most often performed on thoracic paraspinal levels, causes sympathetic blockage. Sympathetic block has been studied on central neuraxial blocks but the sympathetic block caused by the ESP block and immune responses remain unclear.

Sympathetic block inhibits hyperbolic immune responses after surgery, therefore enhances postoperative rate of acceleration on cytokine levels. The investigators propose that ESP block improves immune responses and improved immune responses have better clinical outcomes for patients with breast cancer. Improved immune responses decrease length of stay (LOS), enhance postoperative recovery, analgesia and quality of life. Therefore allows better patient experience about procedures.

The investigators will take 90 patients who will undergo a breast cancer operation and compare vitals (heart rate, blood pressure, oxygen saturation), Numeric Rating Scales (NRS), Vascular Endothelial Growth Factor (VEGF) responses, systemic immune inflammatory indexes, cortisol levels, CRP and Procalcitonin levels between three groups; opioid analgesia group(group M), ESP block group(group E), non-opioid non-ESP group (group P).

The investigators' main focus is immune alterations after anesthesia techniques. Anesthesiologist keep track of pain scores after surgery. this trials secondary outcome focuses on pain management after surgery.

Study Design

• Study Type: Observational
• Actual Enrollment: 91 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Do Analgesic Techniques and Preferences Affect Postoperative Vascular Endothelial Growth Factor and Inflammatory Responses on Breast Cancer Surgery?
• Actual Study Start Date: Feb 1, 2021
• Actual Primary Completion Date: May 1, 2021
• Actual Study Completion Date: Oct 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Morphine 30 patients who received intravenous morphine intraoperatively, without regional block application	Drug: Morphine; PREOPERATIVE ANALGESIA: None INTRAOPERATİVE ANALGESIA: Paracetamol 1000 mg IV Morphine 0,1 mg/kg IV POSTOPERATIVE ANALGESIA IV Morphine Patient-Controlled Analgesia (PCA) Rescue analgesic: IV paracetamol; Other Names: Opioid
Erector Spinae Block 30 patients who had preoperative esp block but did not use morphine during or after surgery	Procedure: Erector Spinae Block; PREOPERATIVE ANALGESIA: Ultrasonography (USG) guided ESP block:T4 spinal level, %0,25 concentration 20 ml, single injection INTRAOPERATİVE ANALGESIA: Paracetamol 1000 mg IV dexketoprofen 50 mg IV POSTOPERATIVE ANALGESIA IV PCA with tramadol Rescue analgesic: IV paracetamol; Other Names: Plane block
Control 30 patients who received multimodal analgesia methods other than ESP block or IV morphine	Drug: Control; PREOPERATIVE ANALGESIA: none INTRAOPERATİVE ANALGESIA: Paracetamol 1000 mg IV Dexketoprofen 50 mg IV POSTOPERATIVE ANALGESIA IV PCA with tramadol Rescue analgesic: IV paracetamol; Other Names: other

Outcome Measures

Primary Outcome Measures

1. Defining the change in preoperative (baseline), postoperative hour 24 Vascular Endothelial Growth Factor (VEGF) levels between the morphine group (group M), the ESP block group (group E), and the control group (group c). [change from baseline VEGF at 24 hours postoperatively]

   The investigators will measure VEGF preoperative(baseline), postoperative hour 24 from blood analysis. Normal ranges of serum VEGF were 62-707 pg/ml.

Secondary Outcome Measures

1. Defining the change in preoperative (baseline), postoperative hour 0, postoperative hour 24 cortisol levels between the morphine group (group M), the ESP block group (group E), and the control group (group c). [change from baseline cortisol up to 24 hours postoperatively]

   The investigators will measure cortisol preoperative(baseline),postoperative hour 0, postoperative hour 24 from blood analysis. Serum cortisol normal range for adults 8 am to 4pm: 5-25 mcg/dL

2. Defining the change in preoperative (baseline), postoperative hour 0, postoperative hour 24 C-reactive Protein levels between the morphine group (group M), the ESP block group (group E), and the control group (group c). [change from baseline CRP up to 24 hours postoperatively]

   The investigators will measure CRP preoperative(baseline), postoperative hour 0, postoperative hour 24 from blood analysis. CRP normal reading is less than 10mg/L.

3. Defining the change in preoperative (baseline), postoperative hour 0, postoperative hour 24 procalcitonin levels between the morphine group (group M), the ESP block group (group E), and the control group (group c). [change from baseline procalcitonin up to 24 hours postoperatively]

   The investigators will measure Procalcitonin preoperative(baseline), postoperative hour 0, postoperative hour 24 from blood analysis. procalcitonin normal range: 0-0.15 ng/mL

4. Defining the change in preoperative (baseline), postoperative hour 0, postoperative hour 24 systemic immune-inflammatory index levels between the morphine group (group M), the ESP block group (group E), and the control group (group c). [change from baseline systemic immune inflammatory index at 24 hours postoperatively]

   The investigators will measure systemic immune inflammatory index preoperative(baseline), postoperative hour 0, postoperative hour 24 from blood analysis. Mean value for SII: 459 (189-1168).

5. Defining the change in preoperative (baseline), postoperative hour 0, postoperative hour 24 neutrophil/lymphocyte ratio (NLR) levels between the morphine group (group M), the ESP block group (group E), and the control group (group c). [change from baseline NLR up to 24 hours postoperatively]

   The investigators will measure neutrophil/lymphocyte ratio (NLR) preoperative(baseline), postoperative hour 0, postoperative hour 24 from blood analysis. Mean value for the NLR:1.76 (0.83-3.92)

6. Defining the change in preoperative (baseline), postoperative hour 0, postoperative hour 24 platelet/lymphocyte ratio (PLR) levels between the morphine group (group M), the ESP block group (group E), and the control group (group c). [change from baseline PLR up to 24 hours postoperatively]

   Defining preoperative (baseline), postoperative hour 0, postoperative hour 24 platelet/lymphocyte ratio (PLR) on patients who undergo breast cancer surgery with the ESP block or morphine analgesia. Mean value for PLR: 120 (61-239)

7. Defining the change in preoperative (baseline), postoperative hour 0, postoperative hour 24 ferritin levels between the morphine group (group M), the ESP block group (group E), and the control group (group c). [change from baseline ferritin up to 24 hours postoperatively]

   Defining preoperative (baseline), postoperative hour 0, postoperative hour 24 ferritin levels on patients who undergo breast cancer surgery with the ESP block or morphine analgesia, or control group. The normal range for ferritin: 10-291 mg/L

8. Defining the change in preoperative (baseline), postoperative hour 0, postoperative hour 24 Lactate dehydrogenase (LDH) levels between the morphine group (group M), the ESP block group (group E), and the control group (group c). [change from baseline LDH up to 24 hours postoperatively]

   Defining preoperative (baseline), postoperative hour 0, postoperative hour 24 LDH levels on patients who undergo breast cancer surgery with the ESP block or morphine analgesia, or control group. Normal LDH levels range: 140-280 U/L

9. Defining analgesic effects between the morphine group (group M), the ESP block group (group E), and the control group (group c) on patients who had breast cancer surgery. [End of surgery up to 24 hours postoperatively]

   The investigators will evaluate patients' pain score with numeric rating scale (NRS) postoperative hour 0, 1, 4, 12, 24 and compare NRS between the control group (group c), the ESP block group (group E) and intravenous morphine group (group M) The investigators will compare NRS between two groups at postoperative hour 0, 1, 4,12, 24. The most common form of NRS is a horizontal line with an eleven point numeric range, from 0 (patient with no pain) to 10 (patient with the worst pain possible).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Should be female

2. Should be between 18-65 years old

3. Diagnosed with unilateral primary breast cancer

4. Are decided to have mastectomy surgery

5. Stage 1-2 breast cancer (T0-1-2, N0-1, M0)

Exclusion criteria from the:

1. Being allergic to the anesthetics

2. Previously had breast operation other than diagnostic biopsy

3. Presence of a malignancy history on the other breast

4. Diagnosed with Inflammatory breast cancer

5. Having a risk score of The American Society of Anaesthesiologists (ASA) risk score 3 and above

6. Contraindications for regional block(Allergies for local anesthetics, Anatomic application difficulties, Coagulopathies)

7. Hormone usage

8. NRS score greater than 3 before the operation

9. Opioid or steroid usage before the operation

10. Rheumatologic history

11. Sickness or drug usage that might cause immunosuppression

12. Chemotherapy and/or radiotherapy history

13. Concomitant history of previous malignancy

14. History of Coronary Artery Disease, Peripheral Vascular Disease that may affect VEGF

15. Chronic smoking

16. Chronic obstructive pulmonary disease

17. Presence of infection at the time of surgery

18. Hypothalamus, Pituitary, adrenal gland dysfunction

19. Autoimmune diseases

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dr.Abdurrahman Yurtaslan Ankara Oncology Train and Research Hospital	Ankara		Turkey	06200

Sponsors and Collaborators

• Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital

Investigators

• Principal Investigator: hazal ekin güran aytug, resident, Dr. Abdurrahman Yurtaslan Oncology Train and Research Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bates JP, Derakhshandeh R, Jones L, Webb TJ. Mechanisms of immune evasion in breast cancer. BMC Cancer. 2018 May 11;18(1):556. doi: 10.1186/s12885-018-4441-3. Review.
• Deegan CA, Murray D, Doran P, Moriarty DC, Sessler DI, Mascha E, Kavanagh BP, Buggy DJ. Anesthetic technique and the cytokine and matrix metalloproteinase response to primary breast cancer surgery. Reg Anesth Pain Med. 2010 Nov-Dec;35(6):490-5. doi: 10.1097/AAP.0b013e3181ef4d05.
• Demirci U, Yaman M, Buyukberber S, Coskun U, Baykara M, Uslu K, Ozet A, Benekli M, Bagriacik EU. Prognostic importance of markers for inflammation, angiogenesis and apoptosis in high grade glial tumors during temozolomide and radiotherapy. Int Immunopharmacol. 2012 Dec;14(4):546-9. doi: 10.1016/j.intimp.2012.08.007. Epub 2012 Aug 29.
• Forget P, Aguirre JA, Bencic I, Borgeat A, Cama A, Condron C, Eintrei C, Eroles P, Gupta A, Hales TG, Ionescu D, Johnson M, Kabata P, Kirac I, Ma D, Mokini Z, Guerrero Orriach JL, Retsky M, Sandrucci S, Siekmann W, Štefančić L, Votta-Vellis G, Connolly C, Buggy D. How Anesthetic, Analgesic and Other Non-Surgical Techniques During Cancer Surgery Might Affect Postoperative Oncologic Outcomes: A Summary of Current State of Evidence. Cancers (Basel). 2019 Apr 28;11(5). pii: E592. doi: 10.3390/cancers11050592. Review.
• Gürkan Y, Aksu C, Kuş A, Yörükoğlu UH, Kılıç CT. Ultrasound guided erector spinae plane block reduces postoperative opioid consumption following breast surgery: A randomized controlled study. J Clin Anesth. 2018 Nov;50:65-68. doi: 10.1016/j.jclinane.2018.06.033. Epub 2018 Jul 2.
• Harbeck N, Gnant M. Breast cancer. Lancet. 2017 Mar 18;389(10074):1134-1150. doi: 10.1016/S0140-6736(16)31891-8. Epub 2016 Nov 17. Review.
• Maher DP, Walia D, Heller NM. Morphine decreases the function of primary human natural killer cells by both TLR4 and opioid receptor signaling. Brain Behav Immun. 2020 Jan;83:298-302. doi: 10.1016/j.bbi.2019.10.011. Epub 2019 Oct 15.
• Sen S, Koyyalamudi V, Smith DD, Weis RA, Molloy M, Spence AL, Kaye AJ, Labrie-Brown CC, Morgan Hall O, Cornett EM, Kaye AD. The role of regional anesthesia in the propagation of cancer: A comprehensive review. Best Pract Res Clin Anaesthesiol. 2019 Dec;33(4):507-522. doi: 10.1016/j.bpa.2019.07.004. Epub 2019 Jul 31. Review.
• Sen Y, Xiyang H, Yu H. Effect of thoracic paraspinal block-propofol intravenous general anesthesia on VEGF and TGF-β in patients receiving radical resection of lung cancer. Medicine (Baltimore). 2019 Nov;98(47):e18088. doi: 10.1097/MD.0000000000018088.
• Sultan SS. Paravertebral block can attenuate cytokine response when it replaces general anesthesia for cancer breast surgeries. Saudi J Anaesth. 2013 Oct;7(4):373-7. doi: 10.4103/1658-354X.121043.

• Responsible Party: Hazal Ekin GÜRAN AYTUĞ. MD, Anesthesiology Resident, MD, Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital
• ClinicalTrials.gov Identifier: NCT04689945
• Other Study ID Numbers: 2020-12/898
• First Posted: Dec 30, 2020
• Last Update Posted: Oct 28, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Hazal Ekin GÜRAN AYTUĞ. MD, Anesthesiology Resident, MD, Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital: erector spinae plane block; breast cancer; anesthesia and cancer; nerve block and cancer; cancer prognosis
• Additional relevant MeSH terms: Breast Neoplasms; Morphine

Study Results

No Results Posted as of Oct 28, 2021