|Ahead of print
Regional anesthesia prevents cancer recurrence after oncosurgery! What is wrong with the hypothesis?
Abhijit S Nair1, Vibhavari Naik2, Mohammed Salman Saifuddin2, Harini Narayanan2, Basanth Kumar Rayani2
1 Department of Anaesthesiology, Ibra Hospital, Ministry of Health-Oman, Ibra-414, Sultanate of Oman
2 Department of Anaesthesiology, Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad, Telangana, India
|Date of Submission||13-Apr-2020|
|Date of Decision||24-Apr-2020|
|Date of Acceptance||27-Aug-2020|
|Date of Web Publication||02-Jul-2021|
Abhijit S Nair,
Department of Anaesthesiology, Ibra Hospital, Ministry of Health-Oman, Ibra-414
Sultanate of Oman
Source of Support: None, Conflict of Interest: None
Several studies have investigated the hypothesis of the efficacy of regional anesthesia (RA) techniques in preventing cancer recurrence when used perioperatively during oncological surgeries. Although theoretically, the association appears beneficial, the patient outcomes after cancer surgeries with or without RA were comparable, that is, the use of RA did not improve patient survival or prevent cancer recurrence after surgery. Another problem with this data is its retrospective nature which makes its interpretation difficult. Moreover, there are a lot of other confounding factors like comorbidities, tumor biology, nosocomial infections, duration of hospital stay, and baseline immunity, which is not comparable, and hence make standardization for a well-designed prospective study difficult. Return to intended oncologic therapy (RIOT) involves treatment in the form of radiation or chemotherapy which, if received on time after the planned oncosurgery, could provide a better chance of preventing cancer recurrence and improved survival. However, none of the retrospective studies have correlated cancer recurrence with delay in RIOT or not receiving RIOT as a cause of cancer recurrence. This paper discusses why even a well-designed, prospective trial could possibly never establish the efficacy of RA in preventing cancer recurrence and improving survival due to the complexities involved in a patient undergoing oncosurgery.
Keywords: Chemotherapy, neoplasm recurrence, postoperative care, radiation oncology, regional anesthesia, surgical oncology
|How to cite this URL:|
Nair AS, Naik V, Saifuddin MS, Narayanan H, Rayani BK. Regional anesthesia prevents cancer recurrence after oncosurgery! What is wrong with the hypothesis?. Indian J Cancer [Epub ahead of print] [cited 2021 Jul 27]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=320438
| » Introduction|| |
Anesthetic techniques leading to cancer recurrence is a hypothesis that has been explored for more than a decade now. Anesthesia management has a role to play in the surgical outcome. Volatile anesthetics and opioids when used for general anesthesia are considered unfavorable. Experimental and retrospective studies have shown that they could facilitate cancer recurrence. It has been demonstrated that opioids and volatile anesthetics inhibit the function of natural killer (NK) cells, thereby stimulating cancer cell proliferation by facilitating angiogenesis and tumor cell signaling pathways. Several authors have published retrospective data wherein they have tried to establish an association between the use of inhalational anesthetics and systemic opioids leading to cancer recurrence., Anesthetic agents like thiopentone sodium and ketamine are also considered to have unfavorable effects on NK cells and the immune system. Although this association has been studied (in-vitro studies), the association was never proven in humans convincingly. However, total intravenous anesthesia (TIVA) using propofol has been shown to have many desirable effects like preserving immunity and recurrence-free survival.
Perioperative period after oncosurgery
The perioperative period after major oncological surgery leads to a cascade of events like immunosuppression, angiogenesis, extensive tissue handling, inflammation, and possible dissemination of cancer cells. This period is critical because if immunosuppression and angiogenesis are not obtunded by proper measures, there could be malignant cell proliferation, invasion, and eventually recurrence in the long run.,,
Oncosurgeries are complex surgeries that involve major resections, prolonged duration of surgery/anesthetic exposure, postoperative immunosuppression due to surgery per se, and due to the use of preoperative use of neoadjuvant chemotherapy/radiation., Tumor handling and resection release malignant cells into the blood circulation and in the lymphatics and the extent of cells taking this course is unpredictable. The decrease in the activity of NK cells and macrophages in the perioperative period due to surgery and anesthetics further adds to the insult thereby providing a nidus to these disseminated cells. Perioperative immunosuppression facilitates angiogenesis and thus theoretically facilitates the growth of these disseminated cells. Perioperative blood transfusion also can lead to transfusion-related immunomodulation which can also impact underlying immunity thereby giving way to recurrence along with many other factors. Core hypothermia which is a consequence of prolonged surgery is multifactorial and inevitable. It occurs in spite of using several intraoperative warming measures like warm fluids, warming blankets, forced air warmers, and humidified gases., Hypothermia leads to immunosuppression which is directly proportional to the temperature and duration of hypothermia. Hypothermia causes platelet dysfunction and coagulopathy. In the perioperative period, if a coagulopathy is profound, it is managed by blood and blood products. Thus, one insult leads to another which leads to a vicious cycle.
Associated preoperative comorbidities increase patient's stay in the intensive care unit and overall hospital stay, thereby increasing susceptibility to infections. Surgical site infections (SSI) also contribute to an increased hospital stay and significant morbidity. SSI, after oncosurgeries, has been shown to have adverse outcomes in the long run.,
Regional anesthesia benefits in oncosurgery
Theoretically, regional anesthesia (RA) techniques have been found to be beneficial during oncosurgeries as it is believed that due to several mechanisms, RA could prevent cancer recurrence. In 2008, Sessler et al. raised the question about the role of RA in preventing cancer recurrence., This hypothesis was based on several advantages that RA confers when used alone or as a part of multimodal analgesia (MMA) during oncosurgery. RA is proposed to reduce the incidence of cancer recurrence by attenuating the sympathetic nervous system's response to surgical insult, by reducing the perioperative requirement of opioids, and lastly by the direct effects of local anesthetics, possibly by systemic absorption.
The attenuation of the sympathetic system is a direct effect of RA. It has been shown that the amide local anesthetics used in RA (lidocaine, bupivacaine, ropivacaine) have anticancer properties and they enhance NK cell activity by activating apoptotic pathways. This has been shown in breast, gastric, and prostate malignancy. However, the data are at present experimental and based mostly on animal and cell line studies.,,,
Many researchers have investigated this interesting association by analyzing retrospective data and tried to establish an association of RA and cancer recurrence. Although there are a lot of beneficial mechanisms that come into play when RA is used, the literature does not support the hypothesis convincingly.,,,,, Several surgical factors, heterogeneous patient population, anesthetic factors, disease biology, perioperative issues, and associated comorbidities influence directly or indirectly the overall recurrence process. Thus, the hypothesis that RA in oncosurgeries could reduce recurrence postoperatively sounds quite oversimplified. As a technique and its effects, the possibility of RA to influence the disease recurrence after oncosurgery, in the presence of so many factors, sounds quite impractical. Although researchers have addressed specific cancers, tumor biology is different for cancers of various organs.
RA technique which is used for breast surgeries could be different from that used for esophagectomy, ovarian malignancy, or colorectal surgeries. This means sympathetic blockade by epidural analgesia for gastric surgery could be different from that for colorectal surgeries. Surgical factors such as duration of surgery, hospital stay; SSI, baseline nutritional status, etc., cannot be standardized. Response to stress is different and baseline immunity could be different.
Every published paper mentions that upcoming research in the form of well-designed, multicentric, randomized controlled trials might be able to explore the association of RA in preventing cancer recurrence. Kairaluoma et al. retrospectively analyzed the efficacy of perioperative RA in preventing recurrence after breast cancer surgery in 86 patients. Although the authors concluded that there was no antimetastatic effect of RA, the study was limited by a small sample size and hence, further studies were suggested.
Myles et al. prospectively followed up 445 patients who were undergoing abdominal surgeries with or without epidural block to compare long-term cancer recurrence and survival. They concluded that epidural block was not associated with improved cancer-free survival. Limitations of the study were the number of patients analyzed, that is, 230 patients in the epidural group and 215 patients in no block group, and a lack of power to reliably detect smaller effects that might still be of considerable clinical importance. Hiller et al. retrospectively analyzed data of 140 patients undergoing gastroesophageal surgeries over 6 years which were analyzed for 2 years postoperatively (97 patients had an epidural block and 43 were without epidural). Although on analysis the study found an association between effective postoperative epidural analgesia and medium-term benefit on cancer recurrence and survival following esophageal surgery, authors recommended adequately powered, randomized controlled studies to understand this more effectively.
However, the correlation of RA and cancer recurrence after surgery is too complicated, and even well designed, adequately powered studies might not be able to prove the association.
MMA is used by anesthesiologists to provide comprehensive analgesia which is also different based on the type of surgery, institutional preferences, availability, contraindications to certain analgesics, etc. Avoiding MMA for the sake of standardizing a methodology in major oncological surgery is not only unethical but also impractical. Nonsteroidal anti-inflammatory drugs (NSAIDs) are an essential part of MMA and provide opioid-sparing analgesia unless there is a contraindication. The cyclooxygenase inhibitory properties of NSAIDs conferring anti-inflammatory effects have been extrapolated in oncosurgical patients. It has been shown in animal and epidemiological studies that the use of NSAIDs perioperatively has anticancer effects in breast, gastrointestinal, and reproductive cancers of either gender. In this group of patients, if the role of RA in cancer recurrence is to be investigated, NSAIDs should be omitted. However, if there are no contraindications and evidence favor the use of NSAIDs in preventing recurrence, NSAIDs cannot be excluded from the methodology. NSAIDs are contraindicated in elderly patients, having an underlying renal impairment and in those who have risk factors for cardiovascular and cerebrovascular diseases. On ethical grounds, patients should be offered MMA, as it cannot be denied. This just adds to the difficulty in arriving at a plausible conclusion.
Present status on association of RA and cancer recurrence
Sessler et al. published the data of the first-ever well-designed, multicentric (13 hospitals), prospective randomized controlled study. They tested the hypothesis that breast cancer recurrence after potentially curative surgery is lower with RA-analgesia using paravertebral blocks and the anesthetic propofol than with general anesthesia with the volatile anesthetic sevoflurane and opioid analgesia. In reference to what has been mentioned earlier, it is thus no surprise that paravertebral block and propofol anesthesia did not reduce breast cancer recurrence after potentially curative surgery compared with volatile anesthesia (sevoflurane) and opioids. In the study by Sessler et al., less than 1% of patients in either arm received preoperative radiation and 6–7% received preoperative neoadjuvant chemotherapy which was not statistically significant. Also, around 40% of patients were subjected to radiation and around 55% of patients received chemotherapy postoperatively. With this data, authors have cleared the air of doubt as far as the association of breast cancer recurrence after surgery and RA is concerned. Perioperative factors such as American Society of Anesthesiologists'-physical status (ASA-PS), prolonged duration of surgery leading to more dissection, handling and subsequent spread, blood transfusion, surgery-induced neuroendocrine and paracrine responses leading to reduced immunity, SSIs, hypothermia, nosocomial infections either by itself or in combination could contribute to further affecting immunity and thus provide an opportunity for recurrence.
There are a lot of trials going on using more or less the same methodology to establish an association between RA and cancer recurrence when compared to general anesthesia and opioid technique. (https://clinicaltrials.gov/ct2/show/NCT02840227, https://clinicaltrials.gov/ct2/show/NCT03941223, https://clinicaltrials.gov/ct2/show/NCT01318161).
Several prospective studies have highlighted the importance of RA in breaking this cascade by providing good quality analgesia. In a randomized study comparing propofol anesthesia with an ultrasound-guided paravertebral block with sevoflurane anesthesia and fentanyl (121 versus 126 patients in respective groups), Pei et al. demonstrated that perioperative analgesia was better in the first group compared to second. Abdallah et al. randomized 66 patients in two groups, one received inhalational anesthesia with opioids and the other received propofol based anesthesia with thoracic paravertebral block. On analysis, authors found that multilevel paravertebral block (PVB) with propofol provides reliable anesthesia, improves postoperative analgesia, enhances the quality of recovery, and expedites discharge compared with inhalational gas- and opioid-based general anesthesia for ambulatory breast tumor resection. Several studies and reviews have highlighted the importance of the use of RA techniques during oncosurgeries which lead to better pain control, less opioids use perioperatively, and lesser incidence of chronic postoperative pain., The beneficial effects of good perioperative analgesia lead to a reduction in surgical stress, less requirement of perioperative opioids, and intraoperative volatile anesthetics all of which are responsible for immunosuppression, angiogenesis, and recurrence. This beneficial effect is believed to be due to the effect of RA on the activity of NK cells function thereby reducing the load of inflammatory mediators like cytokines.
However, the present data is mostly retrospective and predominantly mentions the efficacy of thoracic epidural and paravertebral blocks mostly in patients undergoing breast surgeries, epidural analgesia for colorectal, esophageal, prostate, bladder, and ovarian surgeries [Table 1]. The efficacy is described in the form of a reduction in the inflammatory response and not in preventing cancer recurrence or tumor-free survival. At this moment, there is no data on the use of peripheral nerve blocks or the interfascial plane blocks in reducing cancer recurrence when used either alone or with general anesthesia.,,,,,,,,,,
|Table 1: Papers which prospectively and retrospectively analyzed patients undergoing oncological surgeries for different organs and association of regional anesthesia in preventing cancer recurrence or having better survival in those patients|
Click here to view
Well designed, prospective, and multicentric studies when done and analyzed might be able to answer this perplexing question, that is, the role of RA in preventing cancer recurrence.
Return to intended oncologic treatment (RIOT) and its role in cancer recurrence
Return to intended oncologic treatment (RIOT) involves postoperative treatment in the form of chemotherapy, radiation, biological, or hormonal therapies after the surgery for a certain type of malignancies. The timing of RIOT is usually 4–6 weeks after the surgical resection. When a patient undergoes a major oncological surgery and ends up with certain postoperative issues such as SSI, lung infection, sepsis, undergoes reexploration, develops paralytic ileus, the hospital stay is increased thereby delaying the discharge from the hospital. This also affects RIOT in this group of patients because they are not able to report for the proposed plan after surgery. The inability of RIOT was found to be an independent predictor for survival. In this group of patients, whatever the intraoperative anesthetic plan was used, recurrence is inevitable as they could not undergo the adjuvant treatment due to certain unavoidable reasons. Delay in RIOT after major oncological surgeries due to medical and surgical causes and its association with a recurrence have not been validated in papers yet but is a serious issue which could solely or in association with other factors can be held responsible for recurrence. Enhanced recovery protocols by surgical team and anesthesiologists are not enough to avoid adverse perioperative outcomes but can definitely streamline patient management and can have evidence-based protocols to have better and enhanced recovery.,,
| » Conclusion|| |
It might not be correct to quote after looking at current literature that RA solely could prevent cancer recurrence. There are many advantages conferred by the use of RA during oncosurgeries. Therefore, wherever possible RA must be used as a part of MMA. Perioperative physicians should provide comprehensive MMA and comply with current enhanced recovery pathways to facilitate early recovery, rehabilitation, and discharge of the patient.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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