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Does regional anaesthesia and analgesia or opioid analgesia influence recurrence after primary cancer surgery? An update of available evidence

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Cancer continues to be a key cause of morbidity and mortality worldwide and its overall incidence continues to increase. Anaesthetists are increasingly faced with the challenge of managing cancer patients, for surgical resection to debulk or excise the primary tumour, or for surgical emergencies in patients on chemotherapy or for the analgesic management of disease- or treatment-related chronic pain. Metastatic recurrence is a concern. Surgery and a number of perioperative factors are suspected to accelerate tumour growth and potentially increase the risk of metastatic recurrence. Retrospective analyses have suggested an association between anaesthetic technique and cancer outcomes, and anaesthetists have sought to ameliorate the consequences of surgical trauma and minimise the impact of anaesthetic interventions. Just how anaesthesia and analgesia impact cancer recurrence and consequent survival is very topical, as understanding the potential mechanisms and interactions has an impact on the anaesthetist's ability to contribute to the successful outcome of oncological interventions. The outcome of ongoing, prospective, randomized trials are awaited with interest.

Introduction

Cancer continues to be a key cause of morbidity and mortality worldwide and its overall incidence continues to increase, despite growing efforts towards its prevention and considerable advances in its treatment.

Worldwide in 2008, it was estimated that almost 13 million new cancer cases were diagnosed and over 7 million people died from cancer. In the UK, over a third of people will develop some form of cancer during their lifetime and over 150,000 people died due to the disease in 2010 (http://www.cancerresearchuk.org/cancer-info/cancerstats/keyfacts (accessed 20 July 2013)). In the USA in 2013, it is estimated that over 1.6 million new cases will be diagnosed, and every day over 1500 people will die from cancer [1].

Anaesthetists are increasingly faced with the challenge of managing cancer patients, either for surgical resection to debulk or excise the primary tumour, the mainstay of treatment in many forms of cancer (particularly solid tumours), or for the analgesic management of disease- or treatment-related chronic pain in a proportion of the increasing number of people living with or overcoming cancer, concurrent with improvements in oncological therapies [2], [3], [4].

Metastatic recurrence is a concern and occurs commonly. While the pattern of tumour growth is usually non-linear, with periods of dormancy alternating with periods of growth, surgery potentially alters this pattern [5], [6], [7], [8]. Examination of the hazard rate of recurrence subsequent to primary tumour resection has shown that while progression of initially dormant micrometastases does not seem to be subject to direct induction by surgery, early recurrence during the first two postoperative years may be [9], [10], [11], [12], [13].

As surgery is suspected to accelerate tumour growth and potentially increase the risk of metastatic recurrence, anaesthetists have sought to ameliorate the consequences of surgical trauma and minimise the impact of anaesthetic interventions [14]. A number of perioperative factors have been suggested to directly affect tumour cells and have an impact on cell-mediated immunity, thereby potentially enhancing the risk of metastatic recurrence [15], [16], ∗[17]. There is, therefore, a strong rationale for the development of perioperative techniques to lower the risk of cancer recurrence.

How anaesthesia and analgesia impact cancer recurrence and consequent survival is very topical [4], [18], ∗[19], [20], [21], as understanding the potential mechanisms and interactions influences the anaesthetist's ability to contribute to the successful outcome of oncological interventions.

Section snippets

How does metastasis occur and how it might be influenced

The metastatic process is intricate. Beginning with the detachment of metastatic cells from the primary tumour, metastasis depends on the essential processes of, first, angiogenesis, to establish an independent blood supply, and, second, evasion of the host's immune mechanisms. This culminates in the proliferation of metastasis within a distant organ(s) [15].

Cancer cells result from a single cell that is rendered ‘genetically unstable’ by multiple cycles of division, mutated and susceptible to

Interaction between the immune system and cancer cells

The developing tumour induces an inflammatory state resulting in the recruitment of immune cells. Cell-mediated immunity forms the principle defence against cancer cell invasion, with <1 in a 1000 invading cancer cells viable after 24 h. However, even with an intact immunity, some cancer cells will elude the host's defences and continue to grow.

The major components of cell-mediated immunity include natural killer (NK) cells, cytotoxic T-cells (CTCs), mononuclear cells, macrophages and dendritic

How surgery may influence recurrence

While the surgical excision of a primary tumour forms an essential part of multimodal oncological treatment, offering a particular prognostic advantage in the treatment of solid tumours, the surgical process can inadvertently aid the metastatic process [56]. Animal models have demonstrated surgical enhancement of tumour growth and metastasis, including a significant increase in the number of metastases and tumour retention [32], [33], [34], [57], [58]. Colorectal cancer metastases to the liver

How anaesthesia and analgesia may influence recurrence

Before discussing the potential mechanisms by which anaesthesia and analgesia may affect cancer recurrence, with or without modulation of the immune system, it is important to note that effective postoperative analgesia may facilitate resistance to metastasis [82] and that a high level of perioperative immune suppression has been observed in animal models, where acute postoperative pain was highest [34], [83], [84], [85], [86].

Several studies have suggested that perioperative anaesthetic and

How opioids may influence cancer recurrence

Opioids are routinely used as postoperative analgesics, forming a key part of the armamentarium for the management of cancer pain, whether disease- or treatment-related chronic pain or acute postoperative pain.

Clinical evidence surrounding the effect of opioids on cancer processes is limited. However, in addition to their analgesic effects, opiates are known to exert immunomodulatory effects which may impact on cancer progression and recurrence. A range of mechanisms and cancer effects have

How NSAIDs may influence cancer recurrence

Owing to their effects on COX-2 and PGE2, which are major mediators in cancer progression [38], NSAIDs have a strong, potential anticancer effect [27]. The inhibition of PGE2 production, secondary to COX-2 inhibition, may have a direct impact on cancer cell mutation, proliferation and survival. Its suppression may also have beneficial effects on cell-mediated immunity, increasing the cytotoxicity of NK cells and CTCs [9]. Key enzymes that control the production of prostaglandins,

How regional anaesthesia and analgesia may influence cancer recurrence

The proposed theoretical benefits of regional anaesthesia may be indirect, including a decreased surgical stress response with subsequent amelioration of the associated effects on host immunity, reduced opioid and intra-operative volatile anaesthetic requirements, optimised analgesia and the aforementioned potential anticancer effects of the LA agents themselves ∗[107], [165], [166]. The combination of some or all of these proposed effects could theoretically alter the perioperative balance of

Conclusion

There is some in vitro and in vivo experimental and retrospective clinical evidence linking anaesthetic/analgesic techniques with cancer outcomes and recurrence. Opioids, LAs and NSAIDs exert effects on cancer biology and NSAIDs and regional techniques may be beneficial through their avoidance of opioids. However, it is unclear as to whether avoidance of opioid analgesia may always benefit cancer patients, whether NSAIDs can be safely used or how regional anaesthesia and analgesia should be

Conflict of interest statement

None.

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