It is expected that by 2030, there will be 21.7 million new cancer cases and 13 million cancer-related deaths worldwide.1 According to the Centers for Disease Control and Prevention and the International Agency for Research on Cancer, cancer is the second leading cause of death in the United States and around the globe.2,3 In adults 45 years or older, the prevalence of cancer is 6.7%, it increases to 15.8% in subjects 65 years or older, and it is the highest in those older than 75 years of age (21.8%).2 Surgery is still one of the primary treatments for cancers; in fact, the “Lancet Oncology Commission” called surgery as “one of the major pillars of cancer care and control.”4 If we take into consideration that pediatric and adult patients with cancer might need surgery at least once, to diagnose, initiate treatment, or palliate their disease, millions of subjects worldwide will be exposed to the unwanted physiological consequences of the surgical trauma itself (psychological or physical stress), pain, or the effects of perioperative drugs such as anesthetics and analgesics.
It was more than a century ago when Marie and Clunet and others suggested that surgery could enhance the growth of distant metastasis.5 These authors and other investigators hypothesized that “athrepsia” was the mechanism behind that phenomenon; however, in 1907, Bashford presented the concept of “concomitant immunity.”6 Around the 1950s, different groups of investigators indicated that “dormant or latent tumors” could become metastasis after being stimulated by a “growth factor” released during surgery. Several years later, Gorelik suggested the concept of “concomitant resistance” to overcome some of the pitfalls of the hypothesis of “concomitant immunity.”7 Later experimental studies would demonstrate that the inflammatory and angiogenic changes (“angiogenic switch”) that normal tissues undergo as the result of the surgical trauma would facilitate the seeding and growth of circulating tumor cells. It was not until the late 1900s that studies investigated the role of anesthetics and analgesics drugs on tumor progression.8–10 In 2006, Exadaktylos et al11 published a study suggesting an association between the use of regional anesthesia and propofol and a decrease in the rate of recurrence after breast cancer surgery. This publication sparked the interest of many investigators worldwide to conduct similar studies but unfortunately with mixed results.
In this issue of Anesthesia & Analgesia, Sekandarzad et al12 elegantly present a review of the literature in which they discuss the impact of “perioperative anesthesia care” on “tumor progression.” The authors thoughtfully examine the effects of IV anesthetics, regional anesthesia, local anesthetics, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and nutrition on the immune system and cancer cells. Furthermore, they address how pain and anxiety can contribute to immunosuppression and cancer progression. Last, they effectively argue about the role of potential treatment interventions that can stimulate the immune system, modulate the surgical stress response, and improve the survival of patients with cancer.
WHAT IS THE QUESTION?
I think that the central issue in the developing field of onco-anesthesiology is: Can the perioperative anesthesia care of patients with cancer affect their long-term oncological outcomes? The answer is yes, but it apparently depends on the clinical intervention and clinical outcome of interest. The perioperative period is a continuum process of planned and unplanned events that go beyond a particular type of anesthesia or analgesia technique or drug. Based on the clinically available evidence from other areas of perioperative medicine, it is possible to hypothesize that a single intervention might have a significant impact on long-term outcomes such as survival.
Experimental animal data and human studies agree that the perioperative period is a critical point in the biology of many cancers. The complex interplay between inflammation, immunosuppression, hypothermia, angiogenesis, and a high adrenergic state can facilitate the growth of the so-called minimal residual disease and promote the seeding of circulating tumor cells. Hence, different investigators have suggested that any intervention that could modulate all those factors in a significant degree would have a major impact on cancer progression and the formation of metastasis. For instance, there is convincing evidence to conclude that perioperative blood transfusions have an adverse impact on the survival of patients with colorectal cancer. However, the assumption that perioperative blood transfusions should have the same impact on all cancers is not accurate based on the current evidence. A similar scenario can be proposed for anesthetics and analgesics. Thus, it cannot be expected that the same anesthetic agent, analgesic drug, or anesthesia technique will have the same effect on all cancers. If we believe so, our understanding of the role of the perioperative period on cancer progression is oversimplistic and can lead to false conclusions.
I think that the experimental nonclinical evidence is clear on the negative impact of some volatile anesthetics on the immune system and the beneficial effects of NSAIDs, propofol, and nonselective beta-blockers on the reduction of perioperative metastasis formation. Unfortunately, the role of opioids is less well understood and it depends on the type of cancer model used to study the impact of these drugs on the metastatic biological process. Readers should know that, as pointed out by Sekandarzad et al, there is a lack of convincing clinical evidence to indicate one particular treatment option or anesthesia technique to reduce cancer recurrence or improve other cancer-related outcomes.
In my opinion, the following reasons can be proposed to explain the discrepancies in the results between the different studies that have investigated the impact of anesthetics and analgesics on cancer recurrence or other oncological outcomes. First, most of the published clinical studies are retrospective or have conducted unplanned analyses of the data in cases of randomized controlled trials. Therefore, most of those studies suffered from different types of biases. Furthermore, none of these studies were designed to test the efficacy or impact of one anesthetic technique (or drug) over another on cancer recurrence or cancer-related survival. Second, the lack of standardized definitions of survival outcomes adds further confusion to the interpretation of the results. When recurrence or progression was studied as the primary end points, there were no descriptions, for instance, on how nonmeasurable disease (ie, leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung) or chemoradiation regimens were handled in the analysis of survival. Third, some of the studies have included different cancer stages and histologies but data on mutations are missing; all these factors also complicate the interpretation of the results. Based on these premises, I am forced to doubt the validity of the findings from those studies.
HOW TO ANSWER THE QUESTION?
I believe that the research community will be able to respond to the proposed question by conducting well-designed randomized controlled trials. These studies should be large enough to enroll in either arm of treatment patients with similar demographics, tumor-related variables, neoadjuvant or adjuvant therapy, and neither of them should interfere with the potential effects of the allocated anesthesia or analgesia technique. While we wait for the results of the ongoing clinical studies to give us an answer (or not), it is important to consider the role of experimental studies that closely resemble the effects of anesthetics and analgesics in the context of surgery.13 I think that there is a role of carefully conducting longitudinal and observational cohort studies that can integrate perioperative information with the so-called “omics” data. The results from this type of studies will be hypothesis generating and, in cases of rare cancers, will help to test associations between the use of specific perioperative interventions and cancer-related outcomes.
To date, only a few perioperative interventions (ie, blood transfusions and surgical approach) have shown to the have a strong impact on the survival of patients with particular types of cancer. However, it is possible to think that anesthesiologists, in the near future, will become a key component of the personalized perioperative care of patients with cancer in which a targeted anesthesia care will be designed to provide the most effective treatment of the oncological patient. As indicated by Sekandarzad et al, I have to conclude that there is no evidence to recommend one type of anesthetic or analgesic over another; however, the perioperative care of the patient with cancer should be comprehensive and targeted to maintain homeostasis.
Name: Juan P. Cata, MD.
Contribution: This author wrote the manuscript.
This manuscript was handled by: Markus W. Hollmann, MD, PhD.
2. National Center for Health Statistics. Health, United States, 2015: With Special Feature on Racial and Ethnic Health Disparities, 2015. DHHS Publication No. 2016-1232.
3. American Cancer Society. Global Cancer Facts & Figures, 2015.
4. Sullivan R, Alatise OI, Anderson BO, et al. Global cancer surgery: delivering safe, affordable, and timely cancer surgery. Lancet Oncol. 2015;16:1193–1224.
5. Apolant H. The question of athrepsia. J Exp Med. 1911;14:316–321.
6. Bashford EF, Murray JA, Cramer W. The natural and induced resistance of mice to the growth of cancer. Proc Roy Soc Lond Ser B. 1907;79:164–187.
7. Gorelik E. Concomitant tumor immunity and the resistance to a second tumor challenge. Adv Cancer Res. 1983;39:71–120.
8. Micheels J, Degiovanni G, Cayet AM. Effect of surgery and anesthesia on cell mediated immunity. Clinical human evaluation and evaluation in mice. Acta Anaesthesiol Belg. 1979;30 Suppl:33–43.
9. Micheels J, Degiovanni G, Castermans A. Effect of various types of anesthesia, combined with surgery, on cell mediated immunity. Acta Anaesthesiol Belg. 1978;29:151–163.
10. Lovett EJ 3rd, Varani J, Lundy J. Suppressor cells and increased primary tumor growth rate induced by thiopental. J Surg Oncol. 1983;22:26–32.
11. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology. 2006;105:660–664.
12. Sekandarzad MW, van Zundert AAJ, Lirk PB, Doonerbal CW, Hollmann MW. Perioperative anesthesia care and tumor progression. Anesth Analg2017;124:1697–1708.
13. Afsharimani B, Doornebal CW, Cabot PJ, Hollmann MW, Parat MO. Comparison and analysis of the animal models used to study the effect of morphine on tumour growth and metastasis. Br J Pharmacol. 2015;172:251–259.