Anesthesia and recurrence of cancer

These studies were already posted in Sassy's thread on ketorolac, but I thought I would pull them out, because there's already enough going on in that thread! I don't want anyone reading this to think: "Oh no, I got the wrong anesthesia!" Whatever keeps us from feeling pain reduces stress on our bodies, and decreases the factors that lead to recurrence. But it may be that some forms of anesthesia are better than others. And I apologize if the bolding is messed up (I'm computer challenged).

I would love to see BC centers come up with an anesthetic protocol that would incorporate everything that is being learned about the effects of anesthesia on recurrence. The Mayo Clinic has created "enhanced recovery pathways" that are meant to help patients recover more quickly (which are pretty much the same things that may prevent recurrence). Their plan might be a good model to build off of.

The Mayo Clinic uses: preoperative analgesics to help prevent pain , nonsteroidal anti-inflammatories (don't know if they use as ketorolac), use of nerve-numbing agent liposomal bupivacaine in the surgical site during surgery, avoiding postoperative opioids, giving preventive nausea treatment, resuming food and walking soon after surgery, and avoiding routine intensive care unit monitoring (http://www.sciencedaily.com/releases/2014/03/140303143345.htm)

In a nutshell: surgery is often necessary for the removal of cancer, but it also causes inflammation and immunosuppression, and can increase the chance of cancer recurrence. Anesthesia may contribute to these effects or lessen them.

Good overview articles

Effect of anaesthetic technique and other perioperative factors on cancer recurrence
Really good article that covers the effects of a lot of different anesthesia drugs, and regional anesthesia on long term outcome and gives a good overview of the metastatic process. A few highlights:
"Surgery can inhibit important host defences and promote the development of metastases. Anaesthetic technique and drug choice can interact with the cellular immune system and effect long-term outcome."
"Tumour cells that survive (immune defences) will become trapped in the capillary beds of distant organs, extravasate, proliferate, and ultimately develop their own blood supply. The mediators of this process of angiogenesis include vascular epidermal growth factor (VEGF) and prostaglandin E2 (PGE2)."
"Animal studies have shown that stress-induced reduction of NK cell activity can cause enhanced tumour development."
"Natural killer (NK) cells are the primary defence against cancer cells. Animal studies have shown that stress-induced reduction in NK cell activity can cause enhanced tumour development."
This article also looks at NSAIDS: "Non-steroidal anti-inflammatory drugs inhibit prostaglandin sythesis via the inhibition of the COX enzyme. Tumour cells have been shown to secrete prostaglandins, and this may be a mechanism to evade host cell-mediated immunity. COX-2 inhibitors have anti-tumour and anti-angiogenic properties in a rat model. Breast cancer cells over-express COX-2. Women on long-term COX-2 inhibitors may have a lower incidence of breast cancer. " (However, a phase III trial of an aromatase inhibitor combined with celecoxib in women with advanced breast cancer did not result in a significant advantage to the aromatase inhibitor alone.)
http://bja.oxfordjournals.org/content/105/2/106.full
(Snyder, 2010)

Cancer recurrence after surgery: direct and indirect effects of anesthestic agents
"Despite meticulous surgical technique including minimal handling of the neoplasm, surgical resection of tumors causes measurable release of cancerous cells into the circulation. In addition to this seeding effect, undetectable micrometastases may already exist even in localized disease."
"Natural killer (NK) cells, a subset of the CMI (cell-mediated immune) system are of key importance to this phenomenon. These are MHC-independent cytotoxic lymphocytes that are uniquely able to detect and destroy circulating tumor cells and micrometastases. Intratumoral NK-cell levels have a prognostic significance in a range of neoplasms."
"Melamed et al. investigated the effects of propofol, thiopental, ketamine and halothane: all agents reduced the number of circulating NK-cells and all except propofol depressed NK-cell cytotoxicity (to cancer cells). Ketamine has notable adrenergic activity and is profoundly immunosuppressive."
"Opioids are widely used in anesthesia to provide both intra- and postoperative pain relief. Although undoubtedly efficacious analgesics, there is growing evidence of their potential for exerting negative consequences in those undergoing surgery. Administration of morphine to mice in clinically relevant doses leads to increased angiogenesis and growth of breast tumors."
"...morphine has been demonstrated to reduce NK-cell activity in a dose-dependent fashion in rats and also reduces NK-activity following intravenous administration in humans, the effects persisting 24 hr. after the cessation of the infusion." (However, in other studies morphine acted to promote apoptosis and cell death, and lessened the tumor promoting effect of surgery)
"Although inhalational anesthestics and opioids appear to negatively affect immune parameters, growing evidence suggests the use of RA (regional anesthesia) lessens the immunosuppressive burden of surgery."
"...regional anesthesia reduces intra- and postoperative opioid requirement. By reducing opiate-induced immunosuppression, RA may also abrogate opiate-induced NK-cell suppression."
http://onlinelibrary.wiley.com/doi/10.1002/ijc.26448/pdf
(Tavare, 2011)

The effects of anesthesia on tumor progression
"Retrospective studies suggest that regional anesthesia reduces the risk of tumor metastasis and recurrence. This benefit may be due to the attenuation of immunosuppression by regional anesthesia. On the other hand, accumulating evidence points to a direct role of anesthetics in tumor progression. A variety of malignancies exhibit increased activity of voltage-gated sodium channels. Blockade of these channels by local anesthetics may help inhibit tumor progression. Opioids promote angiogenesis, cancer cell proliferation and metastasis."
"Except propofol, volatile anesthetics and intravenous anesthetics are known to depress all aspects of immunity system. This depression augments the surgically-induced immunosuppression."
"Anesthetics act on neoplasms both directly and indirectly. Past studies have been focused more on the indirect aspect, the immune suppression . Recently, growing evidence demonstrates that anesthetics directly regulate tumor molecular and cell biology."
"A good approach is to avoid regimens that are potentially harmful and favor these potentially beneficial. The former includes volatile anesthetics, systemic opioids, and ketamine; while the latter includes regional block, local anesthetics, and propofol. In addition, multidisciplinary strategies need to be implemented to reduce perioperative stress."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601457/#b58
(Mao, 2013)

The perioperative period and promotion of cancer metastasis: New outlooks on mediating mechanisms and immune involvement

"A recent epidemiological historical study had compared two databases of breast cancer patients, showing that while untreated patients exhibited only one peak of mortality 3–4 years after diagnosis, operated patients showed an additional distinct peak at 7–8 years after surgery, suggesting that beside its important beneficial outcomes, surgery may indeed have long-term deleterious effects."
"Opiate administration, and endogenously secreted opioids in response to nociception, were shown to facilitate tumor proliferation, promote tumor angiogenesis, and enhance tumor blood supply through nitric-oxide (NO) release. Opiates were also shown to suppress NK and phagocytic activity, the production of antibodies, and the release of pro-CMI cytokines." (Although at lower doses opiates have beneficial effects)
In comparing general anesthesia (GA) to regional anesthesia (RA), "several experimental studies in humans have recently shown that the GA approach as a whole can directly affect the malignant tissue and promote its growth. In two studies, breast cancer patients were randomly assigned to undergo either GA or RA. Only the GA approach (which includes opiate administration) was shown to directly increase serum levels of VEGF , MMP-3, and MMP-9. In another study, sera taken from patients who were randomly allocated to undergo GA, rather than RA, promoted the in vitro proliferation of a breast cancer cell line). Other studies have reported that the use of RA had resulted in a reduced perioperative stress response, and spared postoperative immunity."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423506/
(Neeman, 2013)

Anesthetic Techniques and Cancer Recurrence after Surgery
"Anesthesia technique could differentially affect cancer recurrence in oncologic patients undergoing surgery, due to immunosuppression, stimulation of angiogenesis, and dissemination of residual cancer cells. Data support the use of intravenous anesthetics, such as propofol anesthesia, thanks to antitumoral protective effects inhibiting cyclooxygenase 2 and prostaglandins E2 in cancer cells, and stimulation of immunity response; a restriction in the use of volatile anesthetics; restriction in the use of opioids as they suppress humoral and cellular immunity, and their chronic use favors angiogenesis and development of metastases; use of locoregional anesthesia compared with general anesthesia, as locoregional appears to reduce cancer recurrence after surgery. However, these findings must be interpreted cautiously as there is no evidence that simple changes in the practice of anesthesia can have a positive impact on postsurgical survival of cancer patients."
http://www.hindawi.com/journals/tswj/2014/328513/
(Fodale, 2014)

Are we causing the recurrence-impact of perioperative period on long-term cancer prognosis: Review of currrent evidence and practice
This review gives a good explanation of the immune system and pro and anti-inflammatory cytokines, then looks at the effects of intavenous agents, barbituates, propofol, midazolam, ketamine, volatile agents, opioids, NSAIDS/COX-2 inhibitors, local and regional anesthesia, steroids and statins, and other perioperative factors.
"On reviewing the current literature, we can suggest to modify our practice more towards preoperative anxiolysis, use of 'safer' drugs like propofol, tramadol, NSAIDS, and use of regional anesthesia wherever possible along with adequate pain control. In our institute, which caters to approximately 7,000 oncosurgeries a year, we are trying to follow the same and are in the process of formulating a comprehensive institutional oncoanesthesia protocol based on current evidences. Whether these will help our patients, only data from long-term follow-up reports will tell."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC400963...
(Das, 2014)

Anesthesia and cancer recurrence: What is the evidence?
Summarizes the studies on the effect of anesthesia on various cancers, and points out a lack of randomized controlled trials. The authors come to a conservative conclusion: "Thus, while the basic science literature does point towards a potential effect of anesthetic technique on cancer outcomes, current data do not call for a drastic change in the perioperative management of cancer patients."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009629/
(Divatia, 2014)

Improving patient outcomes through state-of-the-art pain control in breast cancer surgery

"A multimodal analgesic regimen that consists of 2 or more nonopioid medications and is initiated in the preoperative phase and continued during the intraoperative and acute postoperative phases may provide the best patient outcomes. These nonopioid medications include, but are not limited to, local anesthetics, acetaminophen, nonsteroidal anti-inflammatory drugs, antiepileptics, alpha-2-adrenergic antagonists, N-methyl-D-aspartate antagonists, and glucocorticoids. This multimodal approach can be a stand-alone protocol or a part of a more comprehensive enhanced recovery after surgery (ERAS) protocol" - See more at: http://www.gotoper.com/publications/ajho/2015/2015...

Cancer surgery: how may anesthesia influence outcome?
"Surgery is the main treatment for potentially curable solid tumors, but most cancer-related deaths in patients who have received previous surgical treatment are caused by metastatic disease. There is increasing evidence that anesthetic technique has the potential to affect long-term outcome after cancer surgery."

Inhaled anesthetics induce immunosuppression and activate inflammatory cascade activation, whereas propofol has a protective action. Opioids might promote cancer recurrence and metastasis. In vitro and in vivo studies have demonstrated that local anesthetics inhibit proliferation and migration of cancer cells and induce apoptosis."
"Anesthesiologists should follow current best clinical practice and include all strategies that effectively decrease pain and attenuate stress. Regional anesthesia and multimodal analgesia, adding anti-inflammatory drugs, play an unquestionable role in the control of perioperative pain and may improve recurrence-free survival.
http://www.ncbi.nlm.nih.gov/pubmed/25769963
(Cassinello, 2015)

"Non-opiate surgical anesthesia: a paradigm shift?"
This includes a non-opiate surgical protocol developed by one of the authors of the Forget study on pre-op ketorolac. It involves clonidine, ketamine at low dose, and esmolol, which is a beta-adrenergic, and counteracts ketamine's immunosuppressiveness.

http://publicationslist.org/data/jan.mulier/ref-37..

Links to BCO threads that are related to this topic:

Topic: Toradol (ketorolac) and Recurrence Prevention July 2015, sas-schatzi

https://community.breastcancer.org/forum/73/topic/...

Topic: Paravertebral Nerve Block and Propofol Sept. 2015, by Falleaves

https://community.breastcancer.org/forum/73/topic/834546?page=1#idx_15

Topic: Effects of opioids on cancer progression Sept. 2015, by Falleaves

https://community.breastcancer.org/forum/73/topic/835291?page=1#idx_

Topic: ketorolac to reduce recurrence Mar. 2014, by Falleaves

https://community.breastcancer.org/forum/91/topic/818961?page=1#post_3936891

Topic: NSAIDS and Breast Cancer Sept. 2015, by 123JustMe

https://community.breastcancer.org/forum/73/topic/835343