Need of Safer Anaesthetic Drug for Oncoanaesthesia

Editorial

The medical science has always looking not only for newer drugs but also for safer drugs having least adverse effects. This has prompted the research and development to look for the drug molecules with better safety profile. But in spite of improved safety profile, certain drugs has been implicated in some or the other adverse issues. Recently, there has been reports on implication of anesthetic drugs on increased incidence of cancer metastasis and cancer recurrence [1,2]. Such implications of cancer metastasis and recurrence due to drugs might not be acceptable. The oncoanaesthesia is always challenging in view of extensive surgical intervention superimposed on preexisting implications of chemotherapy and radiotherapy. The comorbidities and general status of cancer patients are also concern in perioperative management. With the improvement in surgical procedures, improved chemotherapy and radiotherapy, cancer patients are considered potential curable. However, if certain interventions during the management of cancer impose issues on increased risk of cancer recurrence or cancer metastases remains unacceptable. This mandates a search of a safe molecule for anaesthetic practice that may be considered absolute safe for cancer patients undergoing anaesthetic management for oncosurgical intervention.

The factors for cancer recurrence related to management in the perioperative period appear to be multifaceted and is not very clear. The reported factor responsible for cancer recurrence includes metabolic, hematological, inflammatory/immunological responses and neuroendocrine factors [2-4]. These body responses are protective and assist in elimination of tumor cells shed into the body during surgical intervention [5-8]. However, the perioperative and specially surgical stress leads to body immune suppression and thus obtundation of protective responses for prevention of tumor cell spread. This implies a tight balance of the metastatic potential of the tumour and the antimetastatic host defenses. The body response alteration is a lead factor for cancer recurrence or tumor metastasis [9,10]. Apart from these surgical response, certain anaesthetic drugs have been implicated for cancer recurrence or metastasis. This has been implicated due to alteration on body immunity response and effect on cellular mechanisms (e.g. cell apoptosis) or influence on the endocrine and sympathetic systems [11]. The various agents used in perioperative period like opioids, midazolam, α2 agonists like clonidine, dexmedetomidine are prone of risk for cancer recurrence [12]. Also, the drugs of similar groups like fentanyl and morphine among the opioids have different risk for cancer recurrence. On the other hand, agents like COX-inhibitor (ketorolac), β blockers has been reported to reduce cancer metastasis in oncosurgery [13-15]. Opioids promotes endothelial cell proliferation, migration of cells, increase angiogenesis and induce a defect in the barrier function of cells [16,17]. The angiogenic effect is due to reciprocal activation of VEGF (vascular endothelial growth factor) [17]. However, the peripherally acting μ receptor antagonists attenuates pro-tumor effects of opioids [18,19]. So it appears there is a need of a molecule that blocks the tumor inducing effect of the opioid molecule. The future exploration needs to be done for therapeutic potential of peripheral opioid antagonist. Though the potential for cancer spread with volatile agents are conflicting, but some data regarding its relation has been reported [20,21]. The hypoxia inducible factor-1α (HIF-1α) promotes tumor cell survival and is up-regulated by the volatile agents [20]. The increased level of HIF-1α leads to the possibility of relapse in breast cancer. In specific, isoflurane, a volatile anaesthetic agent is reported to have protective effect of colon cancer from [21,22]. So, again, the volatile agent molecule needs to have all protective effect against spread of cancer cells. The other anaesthetic agents have also been implicated in tumor cells. The midazolam and ketamine interfere with host immunity and thus may promote spread of tumor cell whereas propofol have protective effect [23,24]. These effects have been related to immunosupression by ketamine and prevention of surgical stress induced immunosuppressant and promotion of T lymphocyte activities by propofol [24,25]. The morphine induced stimulation of COX-2 expression in tumour cells may be overcome by NSAIDS especially those with COX-2 selection inhibition [26]. The multimodal analgesic management in perioperative period balances the adverse profile of tumor spread related to drugs. Te beneficial role of ketorolac by preventing recurrence after breast cancer surgery has been reported [26]. However, it would be interesting to look for a molecule with combined action i.e. opioid like analgesic action with COX inhibition. The local anaesthetics and beta blockers have also been reported to have protective effect by their action on voltage gated sodium channels, potassium or calcium channels and beta receptors (also by reducing surgical stress response) respectively [27,28].

Though these data of anaesthetic drugs and cancer recurrence are reported in literature but not in a robust randomized clinical trial. However, still it becomes essential this possible risk implicated due to anaesthetic drugs. Pharmacogenomics is an emerging concept for drug development. The occurrence of cancer recurrence due to implicated anaesthetic drugs is not universal [1,2]. There appears role of genetic factors in addition to various other factors related to surgery and anesthetic management in the perioperative period. This phenomenon is applicable for various anesthetics as well and emphasizes the need of newer drugs with better efficacy and lesser side effect profile [29]. Also the era of ‘personalized medicine’ and need of individualized drug therapy is an emerging concept [11]. It is dire need for the researches to look for anaesthetic drug molecule which remains safer for its use in cancer surgery with regards to potential for cancer recurrence or metastasis. The literature mentions regarding the variability in response to anaesthetic agents like induction agents, opioids resulting from genetic factors [30]. In future the phenomenon of pharmacogenetics probably would identify patient at risk for cancer recurrence to a particular anaesthetic drugs.

To conclude, the implication of anaesthetic agents for spread of tumor cells leading to possibility of recurrence after cancer surgery cannot be ignored. A more robust data by well designed prospective randomized clinical trial of optimal sample size is desirable to assess the risk associated with various anesthetic drug molecule for its role in cancer recurrence and metastasis. The role of genetic factors for cancer recurrence or metastasis needs further elucidation. This may probably lead to development of cancer safe anaesthetic molecule in future.

References

1. Camara O, Kavallaris A, Nöschel H, Rengsberger M, Jörke C, Pachmann K. Seeding of epithelial cells into circulation during surgery for breast cancer: the fate of malignant and benign mobilized cells. See comment in PubMed Commons below World J Surg Oncol. 2006; 4: 67.
2. Eschwège P, Dumas F, Blanchet P, Le Maire V, Benoit G, Jardin A, et al. Haematogenous dissemination of prostatic epithelial cells during radical prostatectomy. See comment in PubMed Commons below Lancet. 1995; 346: 1528-1530.
3. Goodnough LT, Shander A. Patient blood management. Anesthesiology. 2012; 116: 1367-1376.
4. Shakhar G, Ben-Eliyahu S. Potential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological atients? Ann SurgOncol. 2003; 10: 972-992.
5. Bauer M, George JE 3rd, Seif J, Farag E. Recent advances in epidural analgesia. See comment in PubMed Commons below Anesthesiol Res Pract. 2012; 2012: 309219.
6. Tsui BCH, Green JS. Type of anaesthesia during cancer surgery and cancer recurrence. Regional anaesthesia has short term benefits over general anaesthesia, but cancer related effects are unknown. BMJ 2011; 342: 1605.
7. Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI, Buggy DJ. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. See comment in PubMed Commons below Anesthesiology. 2008; 109: 180-187.
8. Carson JL, Grossman BJ, Kleinman S, Tinmouth AT, Marques MB, Fung MK, et al. Red blood cell transfusion: a clinical practice guideline from the AABB*. See comment in PubMed Commons below Ann Intern Med. 2012; 157: 49-58.
9. Humphrey JA, Sedensky MM, Morgan PG. Understanding anesthesia: making genetic sense of the absence of senses. See comment in PubMed Commons below Hum Mol Genet. 2002; 11: 1241-1249.
10. Sato Y, Seo N, Kobayashi E. Genetic background differences between FVB and C57BL/6 mice affect hypnotic susceptibility to pentobarbital, ketamine and nitrous oxide, but not isoflurane. See comment in PubMed Commons below Acta Anaesthesiol Scand. 2006; 50: 553-556.
11. Sweeney BP. Pharmacogenomics and anaesthesia: explaining the variability in response to opiates. See comment in PubMed Commons below Eur J Anaesthesiol. 2007; 24: 209-212.
12. Cascio M, Xing Y, Gong D, Popovich J, Eger EI 2nd, Sen S, et al. Mouse chromosome 7 harbors a quantitative trait locus for isoflurane minimum alveolar concentration. See comment in PubMed Commons below Anesth Analg. 2007; 105: 381-385.
13. Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes. See comment in PubMed Commons below Ann Pharmacother. 1995; 29: 619-624.
14. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, et al. The sequence of the human genome. See comment in PubMed Commons below Science. 2001; 291: 1304-1351.
15. Uhl GR, Sora I, Wang Z. The mu opiate receptor as a candidate gene for pain: polymorphisms, variations in expression, nociception, and opiate responses. See comment in PubMed Commons below Proc Natl Acad Sci U S A. 1999; 96: 7752-7755.
16. Sacerdote P. Opioid-induced immunosuppression. See comment in PubMed Commons below Curr Opin Support Palliat Care. 2008; 2: 14-18.
17. Welters ID, Menzebach A, Goumon Y, Langefeld TW, Teschemacher H, Hempelmann G, et al. Morphine suppresses complement receptor expression, phagocytosis, and respiratory burst in neutrophils by a nitric oxide and m3 oipate receptor-dependent mechanism. J Neuroimmunol. 2000; 111: 139–145.
18. Chen C, Farooqui M, Gupta K. Morphine stimulates vascular endothelial growth factor-like signaling in mouse retinal endothelial cells. See comment in PubMed Commons below Curr Neurovasc Res. 2006; 3: 171-180.
19. Cata JP, Wang H, Gottumukkala V, Reuben J, Sessler DI. Inflammatory response, immunosuppression, and cancer recurrence after perioperative blood transfusions. BJA. 2013; 110: 690-701.
20. Ma D, Lim T, Xu J, Tang H, Wan Y, Zhao H, et al. Xenon preconditioning protects against renal ischemic-reperfusion injury via HIF-1alpha activation. See comment in PubMed Commons below J Am Soc Nephrol. 2009; 20: 713-720.
21. Fleischmann E, Marschalek C, Schlemitz K, Dalton JE, Gruenberger T, Herbst F, et al. Nitrous oxide may not increase the risk of cancer recurrence after colorectal surgery: a follow-up of a randomized controlled trial. See comment in PubMed Commons below BMC Anesthesiol. 2009; 9: 1.
22. Lindholm ML, Granath F, Eriksson LI, Sandin R. Malignant disease within 5 years after surgery in relation to duration of sevoflurane anesthesia and time with bispectral index under 45. See comment in PubMed Commons below Anesth Analg. 2011; 113: 778-783.
23. Ohta N, Ohashi Y, Takayama C, Mashimo T, Fujino Y. Midazolam suppresses maturation of murine dendritic cells and priming of lipopolysaccharide-induced t helper 1-type immune response. See comment in PubMed Commons below Anesthesiology. 2011; 114: 355-362.
24. Ren XF, Li WZ, Meng FY, Lin CF. Differential effects of propofol and isoflurane on the activation of T-helper cells in lung cancer patients. See comment in PubMed Commons below Anaesthesia. 2010; 65: 478-482.
25. Inada T, Kubo K, Shingu K. Possible link between cyclooxygenase-inhibiting and antitumor properties of propofol. See comment in PubMed Commons below J Anesth. 2011; 25: 569-575.
26. Farooqui M, Li Y, Rogers T, et al. COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumor growth, metastasis and mortality, without compromising analgesia. Br J Cancer. 2007; 97:1523–1531.
27. Fraser SP, Diss JK, Chioni AM, Mycielska ME, Pan H, Yamaci RF, et al. Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis. See comment in PubMed Commons below Clin Cancer Res. 2005; 11: 5381-5389.
28. Powe DG, Voss MJ, Zänker KS, Habashy HO, Green AR, Ellis IO, et al. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. See comment in PubMed Commons below Oncotarget. 2010; 1: 628-638.
29. Nagele P. Perioperative genomics. See comment in PubMed Commons below Best Pract Res Clin Anaesthesiol. 2011; 25: 549-555.
30. Humphrey JA, Sedensky MM, Morgan PG. Understanding anesthesia: making genetic sense of the absence of senses. See comment in PubMed Commons below Hum Mol Genet. 2002; 11: 1241-1249.