Effect of TIVA Propofol vs Sevoflurane Anaesthetic on Serum Biomarkers and on PBMCs in Breast Cancer Surgery

Effect of TIVA Propofol vs Sevoflurane Anaesthetic on Serum Biomarkers and on PBMCs in Breast Cancer Surgery

A Prospective, Randomized, Controlled Trial to Compare the Effect of TIVA Propofol vs Sevoflurane Anaesthetic on Serumserum Biomarkers and on PBMCs in Patients Undergoing Breast Cancer Resection Surgery

Surgery, perioperative stress, anaesthetics and analgesics may modulate the immunosurveillance mechanisms and overwhelm host defences that normally maintain a balance between immunity & carcinogenesis. This may lead to escape of cancer cells and tilt the scales toward a more protumorigenic microenvironment. Volatile agents, in particular, have been shown to exhibit profound immunosuppressive effects. In comparison, propofol has a favorable profile and inhibits cancer cell activity. Determining "cancer-protective" role of TIVA with propofol presents an exciting window of opportunity that has potential to improve outcomes in cancer patients undergoing resection surgery

For the current study, consenting patients planned for upfront surgery, will be randomly allocated to 2 groups- 20 patients each group: Propofol TCI-based Total Intravenous Anesthesia group (Propofol group) and Sevoflurane group (Sevoflurane group), according to computer generated randomization number. Patients will be monitored routinely with ECG, non invasive blood pressure, and a pulse- oximetery (SPO2), every 5 min. An intravenous access will be established with 20- 22 G cannula. A perioperative antibiotic prophylaxis will be given to all patients. None of the patients will receive any premedication. After preoxygenation with 100% O2 for 3 min: group specific separate interventions will be performed. Patient will be ventilated with TV of 6-8ml/kg,respiratory rate will be adjusted to maintain end-tidal CO2 value between 40 - 45 mmHg. Crystalloids will be used for hydration (4-6 ml/kg/h), and intraoperative volume deficits will be replaced by additional administration of a solution according to clinical needs. For TIVA group, the depth of anaesthesia will be monitored using Bispectral Index, with target BIS value between 40 and 60. For Sevoflurane group, the depth of anaesthesia will be monitored using MAC, with target MAC value between 0.8 and 1. Half hour before conclusion of surgery, all patients will receive 0.1mg/kg of ondansetron as prophylaxis for PONV. At the end of surgery, muscle relaxation will be reversed by glycopyrrolate (10mcg/kg) and neostigmine (50mcg/kg). Patients in both groups will receive intra-venous non-steroidal anti-inflammatory drug 1-1.5mg/kg diclofenac + Paracetamol 1gm just before conclusion of surgery for postoperative analgesia. Postoperative pain & PONV will be managed as per institutional protocols. ASSAY Peripheral blood (5ml) will be collected from patients in EDTA vaccutainer and (5ml) in another vaccutainer containing clot activator. The sample will be collected at following time points. before anaesthesia (Tpre) after removal of tumor intraoperative (Ti) 2 h after surgery (T2h) , and (T24h) 24 hours after surgery Estimation of serum cytokines : by sandwich ELISA and by cytokine bead array (CBA) method. Expression of various lymphocyte subsets (CD3+ T cells, CD4+ helper T cells, CD8+ cytotoxic T cells, γδT cells, NK cells and B cells) by flow cytometry

In Sevoflurane group, anaesthesia will be induced with Thiopental 5 - 7mg/kg, fentanyl citrate 2mcg/kg and atracurium besylate 0.5mg /kg to facilitate LMA placement. Anaesthesia will be maintained with sevoflurane 2-2.2 % to maintain a target MAC value between 0.8 & 1.0.

In Propofol group, anesthesia will be will be induced with Propofol TCI [target controlled infusion pump - Injectomat® TIVA Agilia (Fresenius Kabi)] using Schneider model to achieve target site concentration of 4-6mcg/ml, fentanyl citrate 2mcg/kg and atracurium besylate 0.5mg /kg to facilitate LMA placement. Anaesthesia will be maintained with TCI propofol at 3 - 6 mcg/ml as effect site concentration to maintain BIS 40-60.

In Propofol group, anesthesia will be induced with Propofol TCI using Schneider model to achieve a target site concentration of 4 - 6 mcg/ml. Propofol TCI to achieve BIS (Bispectral Index) between 40-60.

In Sevoflurane group, anesthesia will be induced with 5 - 7mg/kg thiopental, maintenance with O2 with air 50:50%, sevoflurane 2-2.5 %, Further fentanyl, in increments of 1 mcg/kg - and atracurium 0.15 mg/kg, will be given as indicated by the clinical signs and hemodynamic changes.

Change in baseline levels versus 24 hour postoperative levels (Tpre vs T24h ) of serum HIF-1a and VEGF-C in both groups.

The primary objective of this study is to compare the potential effects of inhalation anesthetic (Sevoflurane) with intravenous anesthetic agent (Propofol) on preoperative levels versus 24hour postoperative levels (Tpre vs T24h ) of serum Hypoxia Inducible Factor-1 alpha (HIF-1a) and Vascular Endothelial Growth Factor -C (VEGF-C) in patients with breast cancer undergoing resection surgery.

Change in levels of serum biomarkers HIF-1a & VEGF-C in patients with breast cancer undergoing resection surgery at other time points - intraoperative, at 2hr postoperative. Ti, T2h in both groups.

Change in levels of serum biomarkers TGF-β, IL-17 IFN-g, TNF-a, IL-6 and MMP-2 at the four time points in both groups.

Transforming Growth Factor -beta (TGF-β), Interleukin - 17 (IL-17), Inferferon - gamma (IFN-g), Tumor Necrosis Factor - alpha (TNF-a), Interleukin - 6 (IL-6), Matrix Metalloproteinase - 2 (MMP-2)

Measure expression of various lymphocyte subsets (CD3+ T cells, CD4+ helper T cells, CD8+ cytotoxic T cells, γδT cells, NK cells and B cells peripheral blood lymphocytes at four time points

Inclusion Criteria: Women with histopathologically (biopsy/FNAC) proven breast carcinoma with Resectable disease (T 1-4, N 0-1, M 0) [Stage I-III]. Willing for upfront modified radical mastectomy. ASA Physical Status 1-2 Exclusion Criteria: use of morphine or on steroid therapy upto 3 months before surgery; history of substance abuse or cognitive dysfunction; endocrine disorders- diabetes, hypothyroid; history of HIV, Hep-B or Hep-C infections; Contraindication to analgesics or anaesthetic drugs; Pregnant & lactating women

Dikshit RP, Yeole BB, Nagrani R, Dhillon P, Badwe R, Bray F. Increase in breast cancer incidence among older women in Mumbai: 30-year trends and predictions to 2025. Cancer Epidemiol. 2012 Aug;36(4):e215-20. doi: 10.1016/j.canep.2012.03.009. Epub 2012 Apr 20.

Weigelt B, Peterse JL, van 't Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005 Aug;5(8):591-602. doi: 10.1038/nrc1670.

Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004 Aug;21(2):137-48. doi: 10.1016/j.immuni.2004.07.017.

Tavare AN, Perry NJ, Benzonana LL, Takata M, Ma D. Cancer recurrence after surgery: direct and indirect effects of anesthetic agents. Int J Cancer. 2012 Mar 15;130(6):1237-50. doi: 10.1002/ijc.26448. Epub 2011 Nov 9.

Tsuchiya Y, Sawada S, Yoshioka I, Ohashi Y, Matsuo M, Harimaya Y, Tsukada K, Saiki I. Increased surgical stress promotes tumor metastasis. Surgery. 2003 May;133(5):547-55. doi: 10.1067/msy.2003.141.

Boomsma MF, Garssen B, Slot E, Berbee M, Berkhof J, Meezenbroek Ede J, Slieker W, Visser A, Meijer S, Beelen RH. Breast cancer surgery-induced immunomodulation. J Surg Oncol. 2010 Nov 1;102(6):640-8. doi: 10.1002/jso.21662.

Camara O, Kavallaris A, Noschel H, Rengsberger M, Jorke C, Pachmann K. Seeding of epithelial cells into circulation during surgery for breast cancer: the fate of malignant and benign mobilized cells. World J Surg Oncol. 2006 Sep 26;4:67. doi: 10.1186/1477-7819-4-67.

Divatia JV, Ambulkar R. Anesthesia and cancer recurrence: What is the evidence? J Anaesthesiol Clin Pharmacol. 2014 Apr;30(2):147-50. doi: 10.4103/0970-9185.129990. No abstract available.

Heaney A, Buggy DJ. Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis? Br J Anaesth. 2012 Dec;109 Suppl 1:i17-i28. doi: 10.1093/bja/aes421.

Melamed R, Bar-Yosef S, Shakhar G, Shakhar K, Ben-Eliyahu S. Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: mediating mechanisms and prophylactic measures. Anesth Analg. 2003 Nov;97(5):1331-1339. doi: 10.1213/01.ANE.0000082995.44040.07.

Mammoto T, Mukai M, Mammoto A, Yamanaka Y, Hayashi Y, Mashimo T, Kishi Y, Nakamura H. Intravenous anesthetic, propofol inhibits invasion of cancer cells. Cancer Lett. 2002 Oct 28;184(2):165-70. doi: 10.1016/s0304-3835(02)00210-0.

Looney M, Doran P, Buggy DJ. Effect of anesthetic technique on serum vascular endothelial growth factor C and transforming growth factor beta in women undergoing anesthesia and surgery for breast cancer. Anesthesiology. 2010 Nov;113(5):1118-25. doi: 10.1097/ALN.0b013e3181f79a69.

Xu YJ, Chen WK, Zhu Y, Wang SL, Miao CH. Effect of thoracic epidural anaesthesia on serum vascular endothelial growth factor C and cytokines in patients undergoing anaesthesia and surgery for colon cancer. Br J Anaesth. 2014 Jul;113 Suppl 1:i49-55. doi: 10.1093/bja/aeu148. Epub 2014 Jun 25.

Wigmore TJ, Mohammed K, Jhanji S. Long-term Survival for Patients Undergoing Volatile versus IV Anesthesia for Cancer Surgery: A Retrospective Analysis. Anesthesiology. 2016 Jan;124(1):69-79. doi: 10.1097/ALN.0000000000000936.

Gisterek I, Matkowski R, Kozlak J, Dus D, Lacko A, Szelachowska J, Kornafel J. Evaluation of prognostic value of VEGF-C and VEGF-D in breast cancer--10 years follow-up analysis. Anticancer Res. 2007 Jul-Aug;27(4C):2797-802.