The Australian Childhood Cancer Registry reports that, on average, approximately 810 children, aged 0–14 years old, are diagnosed with cancer in Australia each year, and 45% of them were of ages 0–4 years old (1). The National Cancer Institute reports similar statistics for childhood cancer in the United States, estimating that 9,620 children aged 0–14 years will be diagnosed with cancer in 2024 (2).

Cancer survival in children has improved significantly with overall 5-year survival rates of 86% in Australia (1). As a result of high survival rates, the quality of survival has become increasingly important. Cancer treatment modalities including surgery, chemotherapy, radiotherapy, and immunotherapy may result in long-term, multi-organ chronic health conditions (1). Cancer treatment in children can also result in significant psychological and financial burdens on patients and their families. Prevention of both metastases and recurrence in pediatric cancers is an evolving and essential strategy in reducing mortality and optimizing outcomes.

The impact of perioperative interventions, particularly the type of anesthesia administered, on cancer recurrence and survival in adults has been widely considered (3, 4). Given the increased frequency of exposure to anesthesia in children, in addition to the potential longer period for cancer recurrence, and the personal and financial implications of cancer-related morbidity, any interaction between anesthesia and pediatric oncological outcomes is vital to consider.

The three most common types of childhood cancer are acute lymphoid leukemia (24%), astrocytoma (10%), and neuroblastoma (6%) (1). This contrasts with cancers in adults in which solid organ tumors predominate (5). As a result, there is significant heterogeneity in the treatment modalities and outcomes between adults and children. Data obtained through studies in the adult population may have little, if any, application to children.

Consideration must also be given for confounding factors when studying the impacts of anesthesia on both tumor growth and recurrence. There is considerable variability in tumor size and growth, toxic effects of chemotherapy and radiation therapy, and their interaction with anesthetic agents as well as the heterogeneity of the pediatric population which includes neonates through to adolescents, and the presence of complications from cancers including sepsis, thromboembolism, tumor lysis syndrome, and multi-organ failure.

Pediatric anesthetists are regularly involved in the care of pediatric oncology patients, including the facilitation of treatment, vascular access, imaging, and surgical resection. Therefore, it is necessary to be aware not only of the continually evolving changes in treatment but also any impact that anesthetic technique may have on patients’ long-term outcomes, particularly given that children commonly have a high cumulative burden of anesthetic exposure over a relatively short period of time.

This review article investigates the currently available evidence assessing the immunomodulatory effects of anesthesia in the pediatric oncology population. Where that information is unavailable, we discuss the applicability or correlation of data extrapolated from the adult population.

Cancer is described as the unregulated proliferation of abnormal cells. Tumor initiation is caused by a genetic alteration resulting in an abnormal cell. Unregulated proliferation then occurs due to abnormalities of multiple cell regulatory systems. Cancers can be classified as carcinomas—malignancies of epithelial cells, sarcomas—solid tumors of connective tissues, and leukemias/lymphomas—malignancies of hemopoietic cells or cells of the immune system.

The innate and adaptive immune systems act together to protect the body against tumor growth. The components of the innate immune system that directly target cancer cells include natural killer cells, dendritic cells, macrophages, polymorphonuclear leukocytes, mast cells, and cytotoxic T-lymphocytes. The innate immune system activates the adaptive immune system through the activation of T-cells and B-cells (6). Abnormalities in immune regulatory mechanisms prevent the natural immune response of selectively killing cancer cells. The developing tumor induces an inflammatory state, which is conducive to the recruitment of immune cells. These immune cells typically do not exhibit the normal protective anti-tumor response and may release pro-inflammatory cytokines, resulting in tumor progression (7).

Anesthetic agents are often administered during a vulnerable period in the establishment of metastasis. During surgical resection of a solid tumor, neoplastic cells may inadvertently be dispersed into the lymphatic system and circulation due to tissue damage and tumor handling, thereby establishing metastases. The neuroendocrine and cytokine stress response associated with a major surgery and the effects of cancer treatment modalities may result in the transient suppression of cell-mediated immunity, creating an immune system that is susceptible to further influences from anesthetic agents and/or techniques (7). Cancer recurrence or metastases depend on both the presence of residual cancer cells and the ability of those residual cancer cells to escape the host’s immune system response (4). Several postoperative changes have been described, which may aid the survival of cancer cells in the circulation. Experimental models have shown that reduced natural killer cytotoxicity and impaired macrophage function were both associated with increased tumor growth after surgery (8).

Hematological malignancies predominate in children. While they may not require an extensive surgical resection, with a prolonged general anesthetic and exposure to the associated neuroendocrine stress response, children often require several interventions necessitating repeated general anesthetics. This cumulative burden, even in the absence of surgical resection, can be significant with numerous radiotherapy or chemotherapy treatments, imaging, and vascular access procedures. This is an important consideration for our evaluation of the current evidence and the impact of anesthesia on oncological outcomes.

Volatile anesthetics affect many organ systems, including the immune system (3). Volatiles suppress the innate immune system by reducing circulating neutrophils, dendritic cells, natural killer cells, and tissue macrophages (9). They also cause suppression of the adaptive immune system by limiting the proliferation of lymphocytes (9). In addition, volatiles have been shown to indirectly modulate the immune system through their enhanced effect on stress hormone release (10). In cancer patients, it has been proposed that this volatile-mediated immunosuppression contributes to tumor growth, recurrence, and metastases (9). Several studies have shown that volatile anesthetics increase the expression of prometastatic and protumorigenic factors on tumor cells via signaling pathways, including hypoxia inducible factor-1-alpha and transforming growth-factor-beta (11–14).

In contrast, propofol mainly has an anti-tumor effect, predominantly occurring through reduced cancer cell proliferation and invasion and increased cancer cell apoptosis through the downregulation of matrix metalloproteinases and various immunosuppressing cytokines (14–16).

Most of the current research assessing the impact of anesthesia on tumor growth and recurrence are based on retrospective studies in adults, animal models, or in vitro studies. This data shows a trend toward a beneficial effect of propofol-based TIVA outcomes, specifically overall survival and recurrence rates (3). There are, however, important considerations assessing the applicability of the currently available evidence to children. Pediatric oncology patients often undergo many general anesthetics to facilitate treatment, vascular access, or imaging over a relatively short period of time. While the duration of anesthesia is often short, the cumulative effect may be significant. Additionally, particularly in the younger pediatric oncology patient cohort, repeated interventions may result in significant periprocedural anxiety and distress, which may perpetuate the sympathetic stress response and further influence immune surveillance (17). Furthermore, studies often consider anesthetic agents as if used alone, while in clinical practice they are almost always used in combination with other medications such as opioids.

A systematic review and meta-analysis of 19 retrospective observational studies in adults determined that patients receiving propofol-based TIVA during cancer surgery had significantly better overall survival than those receiving volatile anesthesia (HR: 0.79, 95% CI: 0.66–0.94, p = 0.008). There was, however, no statistically significant difference in recurrence-free survival between groups (HR: 0.81, 95% CI: 0.61–1.07, p = 0.137). In the subgroup analysis, patients in the TIVA group had better overall survival compared to those receiving desflurane, but there was no statistically significant difference in overall survival when compared to those receiving sevoflurane (14).

A retrospective analysis of over 7,000 adults undergoing cancer surgery found that patients had a worse outcome if they received volatile anesthesia irrespective of their ASA score, surgical severity, or whether they had recorded metastases at the time of surgery. In 2,607 propensity-score-matched patients, overall mortality was 22.8% with volatile and 11.2% with TIVA, with an adjusted hazard ratio of 1.46 (95% CI: 1.29 to 1.66) (18).

A further retrospective analysis of patients undergoing a modified radical mastectomy for breast cancer found no difference in overall survival between patients receiving TIVA or sevoflurane-based anesthesia but a lower rate of cancer recurrence in the propofol group (19). A multi-center randomized controlled trial of 1,764 breast cancer patients similarly found no difference in overall survival between propofol or sevoflurane groups (20).

A meta-analysis of TIVA versus volatile anesthesia in adults with breast, esophageal, and non-small cell lung cancer found that the use of TIVA was associated with improved recurrence-free survival in all cancer types (pooled HR: 0.78, 95% CI: 0.65–0.94, p < 0.01) and improved overall survival (pooled HR: 0.76, 95% CI: 0.63–0.92, p < 0.01) (21). These findings have been further supported by another retrospective observational study in adults with esophageal cancer (22).

A prospective randomized trial comparing the immunosuppressive effects of propofol compared to sevoflurane using blood samples collected from women undergoing breast cancer surgery determined that changes in immune cells were similar in both the propofol and sevoflurane groups (23). These findings are supported by a retrospective cohort study of over 7,000 patients who had breast cancer surgery which found that inhalational anesthesia had no significant impact on recurrence-free survival (HR: 0.96, 95% CI: 0.69–1.32, p = 0.782) or overall survival (HR: 0.96, 95% CI: 0.69–1.33, p = 0.805) when compared with TIVA (24). Additionally, these findings align with a national-registry-based study of 11,598 patients with stages 1–3 colorectal cancer (25). Similarly, a more recent study of 536 adults undergoing hepatectomy for hepatocellular carcinoma found that intraoperative anesthesia technique did not affect postoperative recurrence or overall survival. It is worth noting that in the subgroup undergoing open hepatectomy, there was a significantly lower risk of tumor recurrence or death identified in the TIVA group (HR: 0.49, 95% CI: 0.25–0.95, p = 0.034). This contrasts with the subgroup undergoing laparoscopic surgery, where no significant difference was observed (HR: 1.14, 95% CI: 0.73–1.80, p = 0.558) (26).

A study comparing the effects of various anesthetic agents (ketamine, thiopental, halothane, and propofol) on natural killer cell activity and on resistance to experimental metastasis found that all anesthetic agents, except propofol, significantly reduced natural killer activity and increased MADB106 lung tumor retention or lung metastases (27). Table 1 summarizes the adult studies comparing volatile agents and TIVA.

Comparable data from pediatric oncology populations is scarce and severely lacking. One small study in the pediatric population compared the analgesic and anti-stress effects of inhalational and intravenous anesthesia in 49 children with various types of cancer undergoing tumor resection surgery. They studied the patients’ hemodynamic responses, level of cortisol, proinflammatory cytokines, and heart rate variability indicators and found no statistically significant difference in the level of intraoperative stress between the sevoflurane and propofol groups (28). It is worth noting that this is a small study with a very heterogenic cohort. Thus, it is unlikely to show statistically significant differences. In addition, this study did not report cancer outcomes.

A retrospective study performed on 150 pediatric patients with acute lymphoblastic leukemia (ALL) undergoing anesthesia for intrathecal chemotherapy found that the group receiving a combination of propofol and sevoflurane demonstrated greater recovery of T/B cell subset activity, thereby alleviating immunosuppression and impairing ALL progression, compared to the use of sevoflurane or propofol alone (29).

Furthermore, a small cohort study of 20 children with ALL undergoing bone marrow aspiration and lumbar puncture with methotrexate assessed the immunomodulatory activity of a combination of propofol and ketamine sedation on proinflammatory and anti-inflammatory cytokines. They found that propofol ketamine sedation had no effect on the plasma concentration of most measured cytokine levels and the T helper 1/2 ratio in children with ALL (30).

Regional anesthesia reduces the sympathetically driven surgical stress response and associated perioperative pain (3). Therefore, it has been hypothesized that regional anesthesia should minimize immunosuppression and has an anesthetic and analgesic-sparing effect with a beneficial effect on cancer outcomes. Additionally, in vitro studies have shown that amide local anesthetics, particularly the anti-inflammatory properties of lignocaine, may inhibit cancer cell activity and have beneficial effects on the immune system (31, 32).

A multi-center randomized controlled trial of 2,132 patients having potentially curative primary breast cancer resections found no difference in breast cancer recurrence between the paravertebral block and propofol group and the sevoflurane and opioids group (33). Similarly, a meta-analysis that included six RCTs investigating the effect of perioperative regional anesthesia in adults demonstrated no significant difference in the rate of cancer recurrence in patients receiving the adjunctive use of regional anesthesia compared to those receiving general anesthesia alone. However, the authors cautioned that these results were based on a low level of evidence (34).

Another systematic review and meta-analysis that included 15 RCTs, again based on an adult population, found that regional anesthesia did not have a positive effect on recurrence-free survival or overall survival when compared with general anesthesia (35).

In contrast, a retrospective review of medical records of patients with invasive prostate cancer who underwent an open radical prostatectomy found that the group who received an epidural in addition to general anesthesia had an estimated 57% (95% CI: 17%–78%) lower risk of recurrence compared with the group who received a general anesthetic and opioids with no epidural (HR: 0.43, 95% CI: 0.22–0.83, p = 0.012) (36).

Similarly to general anesthetic agents, there is a marked lack of evidence investigating the effects of regional anesthesia and cancer in the pediatric cohort.

A retrospective cohort study of 126 children undergoing primary resection of either neuroblastoma (51.6%), hepatoblastoma (13.5%), or sarcoma (34.9%) over 16 years investigated if an intraoperative epidural was associated with relapse-free survival in children with solid organ tumors (37). There was no statistically significant association between epidural use and improved relapse-free survival. In a subgroup (sarcoma group), there was a clinically meaningful lower risk of relapse with combined general anesthetic/epidural (37).

There remains, however, inadequate scientific evidence to demonstrate a beneficial effect of regional anesthesia on cancer outcomes in children. Despite this, regional anesthesia remains useful as part of a multimodal analgesia regimen and, as such, improves patient comfort and satisfaction (3).

Opioids are widely used in the treatment of both perioperative and cancer-related pain. Like regional anesthesia, it may be suggested that by reducing perioperative pain and stress, opioids should be immunostimulating with beneficial effects on cancer outcomes (38). Evidence from in vitro and animal studies appear inconsistent, with differing effects of opioids on the immune system demonstrated. Immunosuppressive opioids include fentanyl and morphine, while tramadol appears to augment natural killer cell proliferation. Buprenorphine, hydromorphone, and oxycodone appear to have a neutral effect on the immune system (39). Methadone improves the efficacy of cancer treatment agents in glioblastoma and leukemia by inducing cell death and apoptosis (39).

A Danish cohort study of 34,000 women with breast cancer found no correlation between opioid prescription and breast cancer recurrence during an 8-year follow-up period, irrespective of opioid type, duration of use, or cumulative dose (40).

With respect to evidence in children, a small retrospective study of 75 patients <19 years who underwent cytoreductive surgery with hyperthermic intraperitoneal chemotherapy found no statistically significant association between opioid consumption (total amount of opioid consumed during the entire admission) and recurrence-free survival (HR: 1.0, 95% CI: 0.99–1.03, p = 0.55) or overall survival (HR: 1.01; 95% CI: 0.99–1.03, p = 0.22) (41). The patients typically received a continuous infusion of fentanyl or sufentanil and an epidural infusion of bupivacaine 0.075% with hydromorphone at 2–5 mcg/mL.

Blood transfusion-related immunomodulation is postulated to result in unfavorable cancer outcomes for patients, predominantly by enhancing the suppression of natural killer cells (42). Packed red cells are known to contain several biological substances that are implicated in immunosuppression and tumor promotion. These substances include biologically active cytokines, non-polar lipids, residual leukocytes, and a mixture of proinflammatory lysophosphatidylcholines which may stimulate the production of proinflammatory cytokines (43).

Original studies investigating the effect of perioperative blood transfusion on oncological outcomes suggested an association between allogeneic blood transfusion and increased cancer recurrence and mortality. However, these studies were predominantly retrospective in nature and widely disputed (44, 45).

A large Cochrane review from 2006, which included over 12,000 patients from 36 different studies, supported the hypothesis that perioperative blood transfusion is associated with an increased incidence of recurrence for patients with colorectal cancer. These findings were consistent across different tumor stages although less evident in more advanced stages, which was likely due to the inherent negative effect of advanced disease on the risk of recurrence. Perioperative blood transfusion and colorectal cancer recurrence yielded an odds ratio of 1.42 (95% CI: 1.2–1.67) against transfused patients (46).

A retrospective multicenter study of children undergoing surgery for neuroblastoma found that the intraoperative administration of erythrocyte concentrates was associated with a reduction in recurrence-free survival (HR: 7.59, 95% CI: 1.36–42.2, p = 0.004). However, overall survival was unaffected (HR: 5.37, 95% CI: 0.42–68.4, p = 0.124) (42).

The effects of the administration of autologous blood on oncological outcomes during tumor surgery remain unclear. A randomized controlled trial of 475 patients with colorectal cancer found no significant difference in prognosis between the allogenic transfusion group and the autologous transfusion group (47). This contrasts with a small retrospective study of 165 head and neck cancer patients, which found that recipients of heterologous blood had a 40% increased risk of cancer recurrence (48).

The known immunosuppressive effects of transfused blood, together with the recognized complications of blood transfusion, have led to the development and widespread implementation of patient blood management programs with the aim of avoiding unnecessary blood transfusion and improving patient safety and outcomes.

There is mounting evidence supporting an association between perioperative interventions such as anesthetic techniques and oncological outcomes in adults. Evidence suggests a trend toward an effect rather than a definitive answer. TIVA and NSAIDs in the perioperative period may be beneficial, while perioperative blood transfusion appears to be associated with more harm.

The significant differences between adult and pediatric oncology populations, in terms of immune system maturation, underlying malignancy, treatment regimens, and frequency of anesthetic exposure, make it difficult to extrapolate findings from adults to children. However, evidence from adults is important to consider as children share more physiological similarities with adults than with experimental animal models.

In addition, the potential impacts of anesthesia on pediatric oncological outcomes may be influenced by different cancer types, stages, and even treatments. There is a distinct lack of data on this topic in the pediatric population, and it is therefore an important topic for future evaluation. A large, high-quality randomized, controlled trial is warranted to further our understanding of the effects of anesthesia in pediatric oncology patients.