Anesthetic technique and cancer recurrence is there a link?

Questions about the potential influence of surgery and the perioperative period on cancer outcomes dates back to Dr Alfred Velpeau’s (1795–1867) work “A Treatise on cancer of the breast and of the mammary region” in 1856. Velpeau observed that there is a hereditary component to breast cancer, that there is hormonal influence to the disease, that radical resection with surrounding integument structures can be curative in certain patients, there is the possibility of lymphatic system influencing local and distant metastasis, microscopic spread of cancer cells could contribute to recurrence, and that there are certain patients who will suffer from delayed and distant metastasis.

Question if the anesthetic technique could possibly influence oncological outcomes was raised by Seebacher et al in their article titled “Comparative analysis of narcosis and local anesthesia in surgery of malignant melanoma of the skin “. This was a nonrandomized single institution trial [Hautarzt. 1990 Mar; 41(3):137-4] comparing survival rates in patients with malignant melanoma who underwent surgical resections under general anaesthesia (GA) or with local anaesthesia (LA) only. Study period was between 1972 and 1987. 190 patients were operated under GA between 1972 to 1980, and 376 patients operated under only LA between 1981 to 1987. The 5-year survival rates across all Breslow’s thickness: up to 1.50 mm (pT1 and pT2); 1.51-3.00 mm (pT3a); and over 3.00 mm (pT3b and pT4) favored LA over GA.

Women with pT3a melanoma had more benefit from the operation than did men (71.6% to 55.2%) under LA. The authors concluded that the explanation for the difference in survival between the two groups could be due to a favorable host defense response with LA. These findings were seconded by Melchi and colleagues five years later [Dermatol Surg. 1995 Sep; 21(9):786-8] in their article titled “Prognostic value of anesthesia type for patients treated for cutaneous melanoma”. The 5-year survival proportions were 81% for patients treated under local anesthesia, compared to 71.9% for patients receiving halothane isoflurane or enflurane (P < .05). After multiple adjustment for other prognostic variables (tumor thickness, presence of ulceration, age, sex, cross-sectional profile), using patients treated under local anesthesia as a reference group, the relative risk for general anesthesia with volatile agents was 1.3 (95% CI, 0.84-2.10).

This interest and debate of anesthetic technique possibly influencing oncological outcomes was rekindled with the publication by Exadaktylos et al in 2006 [Anesthesiology. 2006 Oct; 105(4):660-4] titled “Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis?”. In this single institution retrospective study, the authors examined the medical records of 129 consecutive patients undergoing mastectomy and axillary clearance for breast cancer between September 2001 and December 2002. Fifty patients had surgery with paravertebral anesthesia and analgesia combined with general anesthesia, and 79 patients had general anesthesia combined with postoperative morphine analgesia.

The follow-up time was 32 +/- 5 months (mean +/- SD). There were no significant differences in patients or surgical details, tumor presentation, or prognostic factors. Recurrence- and metastasis-free survival was 94% (95% confidence interval, 87-100%) and 82% (74-91%) at 24 months and 94% (87-100%) and 77% (68-87%) at 36 months in the paravertebral and general anesthesia patients, respectively (P = 0.012). The authors concluded that paravertebral anesthesia and analgesia for breast cancer surgery reduces the risk of recurrence or metastasis during the initial years of follow-up, and that prospective trials evaluating the effects of regional analgesia and morphine sparing on cancer recurrence are warranted. Two other larger retrospective studies by Tsigonis et al. Are Cure Rates for Breast Cancer Improved by Local and Regional Anesthesia? [Reg Anesth Pain Med 2016; 41: 339–347], and Cata et al. The Impact of Paravertebral Block Analgesia on Breast Cancer Survival After Surgery [Reg Anesth Pain Med 2016; 41(6): 696-703] had different results, showing no survival benefit for regional analgesia in breast cancer surgery.

Currently there are no randomized controlled studies, which offer clear benefits of one anesthetic technique (or perioperative strategy) over the other in terms of recurrence free survival or overall survival after cancer surgery. Published retrospective studies offer contradictory results and most of the studies have not taken the oncological factors (tumor stage and type, tumor burden, lympho vascular space invasion (LVSI), response to therapy, etc..), nutritional state, inflammatory burden and functional status into account in the design of published studies or analysis of the current anesthesia literature. Furthermore, one has to acknowledge the known shortcomings (bias in treatment allocation to the study groups) of a retrospective study despite the strengths of the clinical end points. In-vitro and animal data similarly cannot be correlated with, or translated to clinical experience although they form the basis for future research models and can guide appropriate clinical protocols. Published literature from in-vitro and animal models usually involves studying the effects of individual cell lines in a controlled environment.

It is further difficult to collaborate animal studies to the clinical environment for the following reasons: the experiments are frequently conducted in an engineered model (knock-out species), single cell lines are studied for tumor retention and growth of the introduced cell lines, and the effects of a particular drug (morphine for example) tested are affected by dose of the drug, route of administration, frequency of administration and the metabolic pathway of the drug in the animal model (active metabolite or not, as an example). We now also understand that the cancer biology for each of the tumors is different, and also that within each tumor there is phenotypic and genotypic heterogeneity and plasticity that explains the differences in response to therapy amongst different patients and also the existence of cancer stem cells (CSC’s). Our growing understanding of the concept of CSC’s offer one of the possible explanations for the tenacity of some of the tumors in escaping the innate immunity of the host with resultant loco-regional and distant clinical metastasis years after the primary therapeutic interventions that were deemed curative. A randomized controlled trial (NCT00418457) comparing the effect of a combination of paravertebral blockade and propofol general anesthesia with sevoflurane GA and opioid analgesia on cancer outcomes is currently underway. It is too early to conclude if regional anesthesia based anesthetic techniques minimizing the use of opioids will lead to improved survival after cancer surgery.

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