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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 464-468

Anesthetics impact on cancer recurrence: What do we know?


1 Department of Anesthesiology, Dr. BRAIRCH, All India Institute of Medical Sciences, New Delhi, India
2 Department of Anesthesiology and Perioperative Medicine, University of Manitoba, Winnipeg, Canada
3 Department of Anesthesiology and Neurological Surgery, Wexner Medical Center, Ohio State University, Columbus, Ohio, USA
4 Department of Anaesthesiology and Intensive Therapy, University of Pecs, Pecs, Hungary

Date of Web Publication25-Jul-2016

Correspondence Address:
Tumul Chowdhury
Department of Anesthesiology and Perioperative Medicine Health Sciences Center, University of Manitoba, 2nd Floor, Harry Medovy House, 671 - William's Ave., Winnipeg, R3E 0Z2
Canada
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.148670

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 > Abstract 


Surgery is an important component of treatment in cancer patients. However, surgical stress, anesthesia, and perioperative analgesia interfere with the host immune defense mechanisms and may contribute to metastatic dissemination of malignant tumors and cancer progression. Little is known about the effects of anesthesia on tumor recurrence. In vivo studies and clinical data show some evidence that regional anesthesia is beneficial for cancer patients as it may decrease the risk of metastasis. This short review summarizes the clinical data on the possible association between anesthesia, perioperative analgesia, and the risk of cancer recurrence. Most of the clinical reports are based on retrospective studies, and properly designed prospective trials including a sufficient number of patients is required to reveal the interaction of various anesthetic drugs and methods and cancer progression.

Keywords: Anesthetics, cancer, immunomodulation, recurrence


How to cite this article:
Bharati SJ, Chowdhury T, Bergese SD, Ghosh S. Anesthetics impact on cancer recurrence: What do we know?. J Can Res Ther 2016;12:464-8

How to cite this URL:
Bharati SJ, Chowdhury T, Bergese SD, Ghosh S. Anesthetics impact on cancer recurrence: What do we know?. J Can Res Ther [serial online] 2016 [cited 2019 Dec 9];12:464-8. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/464/148670




 > Introduction Top


Despite significant advances in medicine, cancer remains one of the leading causes of mortality world-wide. According to the recently published report from the International Agency for Research on Cancer, the specialized cancer research agency of the World Health Organization, the global burden of cancer is expected to almost double in the next decade.[1]

Surgery is an important component of cancer therapy, specifically, for solid tumors. The effective perioperative management can be challenging for oncological patients, who commonly suffer from toxic sequel of cancer progression, immunosuppression, and side effects of radio- and chemotherapy. Team effort and close cooperation between the anesthesiologists, surgeons, intensivists, and other specialists are mandatory to avoid the apparent risks of this period in cancer patients.

One of the important determinants of overall therapeutic efficacy is cancer recurrence. In this regard, most often the surgical factors have been previously shown to be contributory. Until recently, the role of anesthesia and related factors in cancer recurrence was not appreciated and explored despite its importance.

The present short review focuses on the possible role of anesthesia in regards to cancer recurrence and discussion of recent developments in research in the area.


 > Role of Surgery Top


A strong association exists between inflammatory processes, immune dysfunction, neo-angiogenesis, and neoplastic growth.[2],[3] For solid tumors, surgery remains an important treatment modality apart from chemotherapy and radiotherapy. Cancer recurrence after surgery is primarily associated with already established local invasion and micro-metastases as components of the minimal residual disease as well as development of new metastatic foci triggered by surgical manipulation. In many cases, the surgical treatment of cancer carries the best prospects for the long-term cure, however, it may also support tumor progression via impairment of cellular immunity, predispose to cancer recurrence, and worsen the long-term outcome.[2],[3] Thus, perioperative immunosuppression is an important contributory factor for tumor progression after surgery.


 > Role of Anaesthesia Top


Anesthetic agents and analgesic techniques may substantially modify the systemic inflammatory processes and modulate the immunological mechanisms, which will indirectly affect the tumor growth rate and recurrence. The role of anesthesia in cancer progression, metastasis, and survival, is still an unsolved quarry, but evidences are building up that suggest a possible role of anesthetics in tumor recurrence. It is postulated that the anesthetics accelerate cell growth and hence cancer recurrence via impairment of cellular immunity.[4],[5],[6],[7],[8],[9],[10],[11],[12],[13]

Presumably, the regional anesthesia is superior in blocking the stress response to surgical trauma, reduction in requirements of perioperative opioids and better preservation of immune function.[14],[15] Regional anesthesia, in particular – central-neuraxial-blockade, have been shown to be anti-inflammatory, preserve the functionality of natural killer (NK) cells, and hence provide anticancer immunity.[8] Those effects become more evident in patients undergoing major surgeries.[14],[15] Data from retrospective studies have shown that patients undergoing cancer surgeries under regional anesthesia have lower recurrence rates when compared with patients operated on under general anesthesia.[4],[5],[7],[10],[11],[12],[13] Currently, well-conducted prospective randomized studies still lack to confirm or disprove these findings.

Compelling evidence lacks on anesthetic drugs such as barbiturates, inhalational agents, propofol, and etomidate as potential causes for tumor recurrence. In high doses, ketamine is indirectly associated with cancer recurrence via suppression of cellular immunity, while there are no sufficient data on alpha two agonists.[8] At present, it is still unclear which anesthetic technique (intravenous, regional or neuraxial-blockade) or analgesics play a clinically significant role in cancer recurrence, nevertheless, the available evidence indicate that regional and neuraxial-blockade may have favorable antimetastatic properties owing to better preservation of cellular immunity. There is some evidence associating opioid use and tumor recurrence.[8],[16],[17] Opioid analgesics have been most extensively studied with regard to their effect on the perioperative immune response. This drug group produces dual effects on immune function: Suppression of the NK cellular activity and reduction of pain-induced immunosuppression.[16],[17] Abrupt opioid withdrawal is another promoter of immunosuppression.[16] In addition, opioids have been implicated in stimulating wound healing via neo-angiogenesis, and this mechanism may also play a role in tumor progression.[16] However, the significance of opioids in cancer recurrence is still not clear and needs further research.[17]


 > Probable Mechanisms Top


The NK cells act to protect against metastatic dissemination, and any factors suppressing their function will indirectly increase the chances of metastatic spread and cancer recurrence.[18] It is known that these cells are suppressed in the perioperative period.[2] Some analgesics, anesthetics, and various techniques used in the perioperative period may alter the postoperative inflammatory response and diminish NK cell suppression.[19] There is some evidence indicating that analgesics and regional techniques used during surgery may improve the survival in cancer patients.[4],[5],[6],[7]

Trans-membrane proteins like toll-like receptor 4 (TLR4) mediated signaling have recently been found to play a crucial modulator role in tumor cell survival and metastasis and their down-regulation could potentially contribute to the attenuation of cancer growth.[20] Rodríguez-González et al. have shown in their recent in vitro model that human endothelial cells when exposed to 3% sevoflurane decreased TLR4 expression indicating a downstream regulation of the MyD88 signaling pathway involving nuclear factor kappa B, tumor necrosis factor, and interleukins (ILs).[21] Recent evidence also shows that not just volatile anesthetic agents but propofol under controlled conditions inhibits the up-regulation of TLR4.[22] Hence, there is considerable factual evidence supporting that anesthesia does manipulate the immune system affecting survival in cancer. But how does that relate to recurrence of the malignant state?

The biology of tumor recurrence primarily depends on the invasive and metastatic potential of tumor cells and normal functioning of the immune defense mechanisms.[23],[24],[25],[26],[27] Disruption of the delicate balance between these opposing processes may lead to tumor recurrence.

Perioperative period is a vulnerable part in the natural history of cancer recurrence. Surgical stress inhibits cellular immunity and favors metastasis.[8],[20],[21],[28],[29],[30],[31],[32],[33] It may facilitate the tumor spread via local invasion or systemic dissemination. In turn, the anesthetic agents, analgesic technique, and postoperative pain management may play their role in tumor recurrence and this role, whether protective or detrimental, needs clarification in well-controlled and sufficiently powered prospective trials, even though it will be extremely challenging to properly design such studies and exclude the effects of multiple covariates that will always be present in cancer patients undergoing massive surgeries.

Cytotoxic T-lymphocytes, NK cells, dendritic cells, and macrophages provide cellular immunity against tumor spread. On the other hand, the inflammatory mediators such as interferon-α and ILs (IL-12, Th 1 cytokines) promote the cytotoxic activity of T-lymphocytes and NK cells. Factors suppressing angiogenesis under normal conditions (angiotensin, endostatin, etc.) are found to be reduced due to surgical stress.[30],[31],[32],[33]

The overall combined effects of immunosuppression and enhanced neoangiogenesis seen during the surgical trauma predispose to tumor invasion and metastatic dissemination.

It is known that general anesthetics can directly suppress the cellular immunity (neutrophils, macrophages, dendritic cells, T-lymphocytes, and NK cells).[34],[35],[36],[37],[38],[39],[40],[41]

In fact, in vivo studies have shown that ketamine, thiopental, and halothane reduce cell-mediated immunity, while propofol does not act in such a way.[37],[38] Perioperative opioids, particularly, morphine was shown to inhibit both the humoral and cellular immunity. Although the picture is less clear with synthetic opioids, sufentanil, and fentanyl were found to act inhibitory on NK cells while tramadol preserves the NK activity.[34],[36],[37],[38],[39],[40],[41] Again, these associations of anesthetic agents and opioids with cancer recurrence are based on the animal studies, and properly designed clinical trials are still awaited to address the question.[37]

Regional anesthetics and analgesia can attenuate the surgical stress response by decreasing the noxious stimulation, thus minimizing the requirements in general anesthetics, sedatives, and opioids in the perioperative period. Concomitantly, properly performed local and regional anesthesia reduces the risk of anesthesia-associated adverse reactions and the extent of surgical stress with better functioning of cell-mediated immunity.[42],[43] Evidences are building up on the association of regional anesthesia and reduction in recurrence rate of solid tumors. Since the majority of published data are from retrospective studies, prospective randomized trials are still in the pipeline. Currently, two multicenter, prospective randomized trials are ongoing: One in breast cancer patients and the second one in colorectal cancer patients. Hopefully, the results of these two trials will enlighten the role of regional anesthesia and analgesia with a broader perspective.[4],[5],[7],[8],[10],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54] The presentable literature on role of anesthetics and cancer recurrence on breast cancer,[3],[6],[7] prostate cancer,[4],[11],[13],[47] colorectal cancer,[4],[5],[9],[10],[48] and ovarian cancer [50],[51] is available in the form of retrospective studies.

In a recently published prospective cohort study conducted on 766 patients, Lindholm et al. showed that neither the duration of anesthesia nor increased cumulative time with profound sevoflurane anesthesia was associated with an increased risk for new malignant disease or death within 5 years after surgery in patients with earlier or existing malignant disease at the time of surgery.[55]

Before year 2000, the available literature for the role of anesthetic agents and techniques on cancer recurrence is very scant but in recent years, over the last decade, it have evolved immensely.[4],[5],[6],[7],[8],[10],[13],[34],[38],[44],[45],[47],[48],[49],[50],[51],[52],[53],[54],[55]

In previous years, there have been extensive data on the role of humoral and cell-mediated immunity on cancer biology in terms cancer occurrence and recurrence.[9],[14],[15],[23],[24],[25],[27],[28],[29],[30],[31],[40],[41]

Cancer recurrence is a result of different factors in the perioperative period.[56] Factors implicated for cancer recurrence apart from the stage of diseases and extents of tumor excision are the factors primarily affecting the cellular immunity in the perioperative period. The evidence available so far on the relationship between cancer recurrence and anesthetic techniques used is equivocal.[57],[58],[59],[60],[61] But the techniques of providing analgesia in the perioperative period have a definite link between cancer recurrences.[57],[58],[59],[60],[61] Recent systemic review on role of regional anesthesia on cancer recurrence in various surgeries highlights that though there are mixed responses in various studies; the benefits of regional anesthesia cannot be ignored and found to be useful in very few of the trials.[62] Therefore, it is still very early to apply our understanding for any particular anesthetic techniques in the context to cancer recurrence.


 > What Do We Know? Top


Based on the extensive literature available after 2000, we may infer that some of the factors do have a definitive role in reference to cancer growth and recurrence. First, stress response has some link with cancer growth and recurrence. Second, perioperative pain mechanisms do have some interactions with tumor recurrence. Finally, regional anesthesia (blunting stress and pain responses) has a definite role in the prevention of cancer recurrence.[62],[63]


 > What Do We not Know? Top


There are some points, which require further attention and related research. Is regional anesthesia effective in some specific type of cancer surgery and what is the underlying mechanism behind it? Role of various anesthetics should be further explored in human trials. Whether or not these results can be applied during radiotherapy procedures is still a matter of research.


 > Conclusion Top


Clinical reports and in vivo studies indicate that the surgical stress and general anesthesia can alter the immune response, specifically, by suppressing the cell-mediated immune defense. This, in turn, will predispose to tumor progression and metastases development. Even though, it is challenging to separate anesthesia effects from adverse reactions induced by the primary disease, chemo-and radiotherapy, and surgical stress, there is some evidence that local and regional anesthesia may be beneficial in reducing the risks of cancer metastases and recurrence. The vast majority of currently available data are derived from animal studies while clinical trials are mostly retrospective, underpowered, and inconclusive. Further prospective multicenter trials might be able to find associations between anesthesia, cancer recurrence and survival if they exist.

 
 > References Top

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