Anesthesia Experts | Anesthetic Techniques and Cancer Outcomes: What Is the Current Evidence?

Authors: Ramly, Mohd S. MD, FCAI et al

Anesthesia & Analgesia 140(4):p 768-777, April 2025.

Abstract

It is almost 2 decades since it was first hypothesized that anesthesia technique might modulate cancer biology and thus potentially influence patients’ long-term outcomes after cancer surgery. Since then, research efforts have been directed towards elucidating the potential pharmacological and physiological basis for the effects of anesthetic and perioperative interventions on cancer cell biology. In this review, we summarize current laboratory and clinical data. Taken together, preclinical studies suggest some biologic plausibility that cancer cell function could be influenced. However, available clinical evidence suggests a neutral effect. Observational studies examining cancer outcomes after surgery of curative intent for many cancer types under a variety of anesthetic techniques have reported conflicting results, but warranting prospective randomized clinical trials (RCTs). Given the large patient numbers and long follow-up times required for adequate power, relatively few such RCTs have been completed to date. With the sole exception of peritumoral lidocaine infiltration in breast cancer surgery, these RCTs have indicated a neutral effect of anesthetic technique on long-term oncologic outcomes. Therefore, unless there are significant new findings from a few ongoing trials, future investigation of how perioperative agents interact with tumor genes that influence metastatic potential may be justified. In addition, building multidisciplinary collaboration to optimize perioperative care of cancer patients will be important.

Cancer presents a major global health care and socioeconomic burden. An estimated 20 million new cases were diagnosed and almost 10 million cancer-related deaths were reported worldwide in 2022.¹ The World Health Organization (WHO) projects over 28 million new cancer diagnoses per year by 2040, an increase of 60%. Cancer will become the leading cause of death worldwide in the coming years. Surgery remains the mainstay of curative treatment for most solid organ cancers and approximately 65% of cancer patients will require at least 1 diagnostic or therapeutic surgical procedure during their illness.² Unsurprisingly, cancer-related procedures form a large component of surgical and anesthetic workload and consume considerable health care resources, generating a very significant societal and economic cost alongside the enormous personal burdens that cancer patients and their families endure.

Unfortunately, cancer often recurs after surgery. Despite optimum surgical technique, some microscopic residual tumor disease remains, and even with significant and continuing advances in medical oncology, metastatic cancer recurrence is often fatal and is the most frequent cause of cancer-related deaths.³^,⁴ Undoubtedly, any perioperative interventions that could reduce subsequent recurrence risk would potentially save many lives. It has been hypothesized that events occurring during and after surgery may influence pathophysiological processes that in turn, could modulate recurrence risk.⁴ These include the stress and inflammatory responses to surgery which drive wound healing, but also may paradoxically promote residual tumor growth, stimulating recurrence and metastases (see Figure 1).

Figure 1.:

Schematic of perioperative development of metastatic disease. (Created using Biorender.com.)

What has gained much attention in the recent past is whether anesthetic agents and techniques may also influence cancer outcomes. Some preclinical experiments examining anesthetic technique and perioperative management have suggested potential influences on cancer behavior in vitro or in animal models. Early observational clinical studies suggested a potential benefit associated with certain techniques.⁵ This narrative review presents an overview of the current evidence base regarding the effects of various anesthetic agents and techniques on cancer outcomes, the limitations of conclusions that can be drawn, and possible future research in this area.

SCIENTIFIC RATIONALE

Although Paget’s original concept of “seed and soil” to explain cancer metastasis, first proposed in 1889, still holds true, our understanding of the pathological processes by which cancer cells (the “seed”) become modified, released into the circulation and lodge in distant receptive organ tissues (the “soil”) is more nuanced.⁶^,⁷ For example, the ability of primary tumors to genetically reprogram distant tissues into “premetastatic niches” remotely through the release of extracellular vesicles to make them more receptive hosts of arriving tumor cells is becoming clearer.⁸ How these tumor microenvironments and the relationships between cancer, stromal, and immune cells behave in response to surgery is better understood now, alongside the processes of inflammation, angiogenesis, neural activation, and immune response.⁹

Figure 2.:

Hypothetical mechanisms of effects of anesthesia on cancer biology. (Created using Biorender.com.)

In attempts to understand how cancer development and metastasis are affected by anesthesia, many laboratory experiments have examined the effects of anesthetic and analgesic agents on cancer cells, stromal tissue, and immune cells in vitro. Early studies led to the hypotheses that certain agents possessed potentially harmful effects (eg, opioids impairing innate immune cell function), and some possessed potentially beneficial effects (eg, propofol suppressing inflammation), see Figure 2.¹⁰ These studies were limited because they evaluated cellular processes in isolation without considering the interactions with the tumor microenvironment. Recently, focus has turned to examining anesthesia effects on NETosis, the process by which neutrophils can extrude decondensed chromatin to form web-like structures called neutrophil extracellular traps (NETs). This process is implicated in neoplasia with elevated serum markers of NETosis associated with poorer prognosis and poorer postoperative outcomes in some cancers.¹¹ How this may lead to metastatic progression is uncertain—NETs possibly trap cancer cells without killing them and shield them from immune attack. In addition to NETosis, the influence of epigenetics on cancer cell and immune response to anesthesia has attracted significant research interest in recent years.

METHODS

The keywords “anesthesia cancer” were used to search the Medical Literature Analysis and Retrieval System (MEDLINE), Excerpta Medica database (EMBASE), and Web of Science databases. Studies from January 1, 1994 up to March 1, 2024 were included in addition to any referenced articles deemed significant irrespective of date of publication. Prospective studies, retrospective studies, meta-analyses, and systematic reviews were included. Articles were assessed for relevance by both authors and data were qualitatively analyzed and presented in a narrative format.

Propofol Total Intravenous Anesthesia (TIVA) or Volatile Anesthesia?

In vitro studies suggest that propofol has potentially beneficial antineoplastic effects, with candidate mechanisms including suppression of angiogenesis and inflammation, preservation of immune cell function, and direct inhibitory effects on cancer cells.¹² Moreover, some researchers found laboratory evidence that volatile anesthetic agents may possess proangiogenic and immunosuppressive effects, findings which, theoretically, may stimulate the malignant progression of residual cancer cells postoperatively.¹³ Propofol downregulates expression of the transcription factor hypoxia-inducible factor 1-alpha (HIF-1α), a key driver of angiogenesis, in cancer cells.¹⁴^,¹⁵ In contrast, volatile agents stimulate HIF-1α and vascular endothelial growth factor (VEGF) expression and promote cancer cell proliferation in vitro.¹⁶ The activity of natural killer (NK) cells, innate immune cells responsible for cancer detection and elimination, was found to be relatively preserved in serum from breast cancer patients undergoing excisional surgery under a propofol-paravertebral technique, compared to a volatile-opioid technique.¹⁷ Additionally, propofol may suppress neoplastic activity via effects on expression of microribonucleic acids (micro-RNAs) or oncogenes, amongst other potential pathways.¹⁸^,¹⁹ However, volatile agents can promote these pathways, potentially stimulating malignant cells.²⁰

Not all studies are supportive of the “propofol good, volatile bad” narrative. Propofol has also been found to stimulate breast cancer cell migration and proliferation.²¹ Recent randomized clinical trials (RCTs) have detected no difference in postoperative circulating tumor cells, NK or T-cells when patients were randomized to propofol total intravenous anesthesia (TIVA) versus sevoflurane in breast cancer or colorectal cancer, respectively.²²^,²³ Similarly, serum NETosis markers were no different between patients undergoing breast cancer surgery who were randomized to receive volatile-opioid or paravertebral-propofol techniques.²⁴ Despite preclinical studies suggesting that propofol may have anti-inflammatory benefits, a meta-analysis of 23 studies (n = 1611 patients) examining the effect of propofol TIVA versus sevoflurane on serum concentrations of perioperative inflammatory markers interleukin-6 and -10 (IL-6, IL-10), tumor-necrosis factor alpha (TNF-α), and C-reactive protein (CRP) found no difference.²⁵

Many retrospective clinical studies have examined cancer outcomes in cohorts of patients undergoing a range of cancer surgery, who received propofol TIVA or volatile-based techniques. A large Danish registry study of colorectal cancer patients (n = 4347 in propensity-score matched groups) found no difference in overall survival associated with propofol or volatile use, but a weak association between volatile exposure and cancer recurrence (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.02–1.23).²⁶ A larger study (n > 190,000) in Japan among gastrointestinal tract cancer patients showed overall survival and recurrence-free survival were similar between propofol- and volatile-based anesthesia.²⁷ Another, even larger (n > 310,000) registry study in Korea also detected no association between anesthetic technique and overall, 1- and 5-year survival after surgery for a wide range of cancers.²⁸

Whether propofol TIVA has a causal impact on postoperative cancer outcomes requires data from appropriately powered, prospective RCTs. Several such trials have been recently completed. The first reported on breast cancer patients (n = 2132) receiving either a propofol-paravertebral technique or a sevoflurane-opioid technique.²⁹ After an interim analysis, the trial was halted on the grounds of futility with no difference in recurrence detected (HR, 0.97; 95% CI, 0·74–1·28). It should be noted that the combination of techniques analyzed in this RCT makes it difficult to establish the relative contributions of propofol and volatile to the outcome measures. The CAN (Cancer and Anesthesia, NCT01975064) study randomized breast cancer patients (n = 1764) to propofol TIVA or sevoflurane and found that survival after a median follow-up of 77 months was no different between the groups (HR, 0.97; 95% CI, 0.72–1.29). Follow-up of a multicenter RCT in China randomizing patients (n = 1195 in the intention-to-treat analysis) aged 65 to 90 years to either propofol or volatile anesthesia for major cancer surgery showed no difference in overall survival (HR, 1.02; 95% CI, 0.83–1.26) or recurrence-free survival (HR, 1.07; 95% CI, 0.89–1.30) after a median follow-up period of 43 months.³⁰

While it remains possible that a significant effect may be found in other cancers, the best available evidence indicates that the choice of propofol or volatile has no bearing on long-term cancer outcomes. Ongoing RCTs that will add to this field include the General Anesthetics in Cancer Resection Surgery (GA-CARES, NCT03034096) trial and the colorectal arm of the Cancer and Anesthesia (CAN) trial.

Neuraxial and Regional Anesthesia

Some of the earliest clinical studies to suggest an association between anesthesia technique and cancer outcomes were small, retrospective cohort studies suggestive of a benefit attributable to regional anesthesia (RA) or neuraxial anesthesia (NA): specifically, the use of paravertebral anesthesia in breast cancer surgery and epidural in prostatectomy for prostate cancer were associated with reduced postoperative recurrence rates.⁵^,³¹ If such a beneficial effect is real, then the biologic basis underpinning it is likely to be multifactorial. RA could blunt the sympathetic stress response to tissue trauma and pain, inhibiting the procancer aspects of the inflammatory response by reducing serum cortisol and inflammatory cytokine levels.³² LA-absorbed systemically may have direct inhibitory effects on cancer cells and contribute to preservation of native NK and T-cell antineoplastic functions.³³ Improved analgesia resulting from effective RA/NA can reduce the need for postoperative opioid treatment, which potentially has deleterious immunosuppressive effects.³⁴

Until the recent completion of relevant RCTs, the bulk of evidence regarding RA/NA and cancer outcomes came from small retrospective clinical studies. However, the formation of national cancer registries in some countries has enabled the analysis of much larger cohorts. One propensity-score matched (PSM) study of a Danish registry, matching 2980 cancer patients receiving GA with epidural analgesia for colorectal cancer resection versus 2980 who received GA alone, found no difference in recurrence or survival.³⁵ Meta-analyses have attempted to consolidate retrospective studies, typically in a cancer-specific manner, with some showing potential benefit with RA/NA. One meta-analysis of 8 studies (n = 3764, 2117 NA vs 1647 GA) comparing NA and GA in bladder cancer, concluded that NA reduced recurrence (RR, 0.84; 95% CI, 0.72–0.98; P = .03).³⁶ Most retrospective studies compare GA and RA together with GA alone, however, 1 meta-analysis compared studies that examined GA alone to RA alone. This included 10 retrospective studies (n = 9708, 4567 GA vs 5141 RA), and found no difference in recurrence, time to recurrence, or overall survival, although the meta-analysis was hampered by an underpowered trial sequential analysis and a low level of evidence resulting from the quality of the included studies.³⁷

Again, higher quality evidence than retrospective studies is required to prove any causal association with cancer outcomes. A small number of prospective observational studies, follow-up studies to prior RCTs examining noncancer outcomes, and most usefully, prospective trials examining survival and/or recurrence as the primary outcome have been completed. The largest RCT (n = 2108) examining RA was the breast cancer trial randomizing patients to propofol-paravertebral or volatile-opioid techniques and finding no difference in recurrence rates (see previous section).²⁹ The second largest trial to date is a large RCT randomizing patients aged 60 to 90 years undergoing major thoracic or abdominal cancer surgery to either GA-epidural or GA alone. The coprimary outcome was delirium. Among 1712 cancer patients, epidural use conveyed no benefit in terms of cancer-specific survival (adjusted HR, 1.09; 95% CI, 0.93–1.28) or recurrence-free survival (adjusted HR, 0.97; 95% CI, 0.84–1.12).³⁸ The other available RCT on RA examined 400 patients undergoing VATS for lung cancer, randomized to GA or GA-epidural, with a median follow-up of 32 months. Again, there was no difference in survival or recurrence rates.³⁹

Although some preclinical and retrospective studies continue to be published showing beneficial effects of RA/NA on cancer outcomes, recent large prospective RCT data has not reproduced these findings. The initial hypothesis that RA/NA would reduce cancer recurrence risk by preserving innate immune response, reducing surgical stress-induced inflammation, and avoiding harmful effects of opioids, has not convincingly been proven to have a meaningful effect. Overall, the most robust current evidence points towards RA/NA not having a significant influence on cancer outcomes.

Intravenous Lidocaine

Lidocaine is commonly used perioperatively as an analgesic. Laboratory studies investigating lidocaine’s effects on biomarkers of angiogenesis and inflammation, immune cell function, and cancer cell biology, demonstrate a signal that intravenous lidocaine may possess beneficial antineoplastic effects.^40–42 Comparatively little in the way of clinical evidence currently exists. Only one large retrospective study examining clinical outcomes has been published: among 2239 patients undergoing resection of pancreatic carcinoma, Zhang et al⁴³ found that those who received intravenous lidocaine had improved overall survival at 1 and 3 years (68.0% vs 62.6%, P < .001; 34.1% vs 27.2%; P = .011), although disease-free survival was no different. The same authors went on to perform an RCT randomizing pancreatic cancer patients to receive either intravenous lidocaine or placebo perioperatively, enrolling 563 patients and following them for 3 years postoperatively. After a familiar pattern, the results seen in the retrospective study were not replicated in the RCT—intravenous lidocaine had a neutral effect on overall survival (HR, 0.98; 95% CI, 0.81–1.17) and disease-free survival (HR, 0.91; 95% CI, 0.71–1.17).⁴⁴ It is difficult to know how far this result can be extrapolated to other cancer types. Certainly, more high-quality RCT evidence is required across a range of cancer types; unfortunately, there are no large-scale trials currently underway which examine this topic.

Infiltration Lidocaine

Lidocaine can provide local anesthesia by tissue infiltration. However, in cancer surgery, this use is largely limited to excision of skin lesions and breast tumors. It is in the latter role that a large RCT has shown a surprising result. In an Indian multicenter study, Badwe et al⁴⁵ randomized patients with early breast cancer (n = 1600) to receive peritumoral lidocaine infiltration (0.5%, up to 4.5 mg.kg^–1) or no infiltration immediately before surgery. The results were significant—those who received LA showed an improvement in both 5-year disease-free survival (HR, 0.74; 95% CI, 0.58–0.95) and 5-year overall survival (HR, 0.71; 95% CI, 0.53–0.94), relative risk reductions of 26% and 29%, respectively. Local recurrence and distant metastasis were significantly reduced. The study is not without its flaws—there was no placebo injection in the “no LA” arm, study investigators were not blinded, and the overall oncological treatment of the enrolled patients may not mirror that of Western practice. Interestingly, the outcome benefits were seen in the mastectomy subgroup, where the dissection planes were outside of the infiltrated tissue—suggesting perhaps that the benefits were attributable to systemic absorption of lidocaine rather than any analgesic effects. Whatever the mechanism and despite the criticisms, this study remains the only large, appropriately powered RCT to show a significant causal association between an anesthetic technique and improved cancer outcome.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs are widely used as analgesics in the perioperative period. Through inhibition of cyclo-oxygenase enzymes, reduced production of prostanoids (prostaglandins, prostacyclins, and thromboxane) inhibits inflammation as well as the surgical stress response. This has analgesic benefits but also inhibits the inflammatory stimulus which is inextricably linked with the pathophysiology of cancer cell proliferation.⁴⁶ Numerous laboratory studies have demonstrated the possible antineoplastic effects of NSAIDs via effects on inflammation, angiogenesis, and a wide variety of other cellular pathways.⁴⁷^,⁴⁸ Clinically, the potential beneficial effects of NSAIDs on cancer outcomes are seen in observational epidemiologic studies suggesting that regular use is associated with reduced cancer incidence (esp. colorectal cancer), although prospective trial evidence remains limited.⁴⁹^,⁵⁰ A systematic review of these studies published up to 2021 (19 studies involving a total of 12,994 participants) found that perioperative NSAID use was associated with longer disease-free survival (HR, 0.84; 95% CI, 0.73–0.97) and overall survival (HR, 0.78; 95% CI, 0.64–0.94), particularly among breast cancer and ovarian cancer patients.⁵¹ The authors cautioned that the level of certainty of these results is low as many of the included studies were retrospective and highly heterogenous. In fact, the authors of a slightly older systematic review in 2017 (involving most of the same studies) did not even attempt a meta-analysis as they considered it inappropriate due to these quality and heterogeneity issues.⁵² One small trial (n = 203) examined the effect of single-dose preincisional ketorolac compared to placebo on disease-free survival in breast cancer patients and did not detect any outcome difference, although the study was underpowered due to a lower-than-expected recurrence rate.⁵³

Two large RCTs have examined the effect of long-term postoperative celecoxib therapy on cancer outcomes. One trial compared celecoxib to placebo for 2 years in addition to standard adjuvant treatment in postresection breast cancer patients (n = 2639) and found no benefit in terms of disease-free survival.⁵⁴ The other trial examined the effect of celecoxib versus placebo added to standard adjuvant therapy in postoperative Stage III colon cancer patients (n = 2526), and again found no beneficial effect of celecoxib on recurrence or disease-free survival.⁵⁵ It should be noted that these 2 RCTs were not perioperative studies per se and the interval between resection and trial enrollment was not specified. A recent meta-analysis of 20 studies examining adjuvant NSAID use in the treatment or prevention of cancer recurrence concluded that overall they have not demonstrated clinical benefit.⁵⁶

Overall, long-term adjuvant use of these agents has not been shown to have an effect on cancer outcomes and the small body of prospective trial data regarding perioperative NSAIDs is unconvincing.⁵⁷ Therefore, there is currently no high-quality evidence that perioperative NSAID use affects cancer outcomes and indeed none seems warranted.

Opioids

Opioids remain one of the cornerstones of perioperative analgesia worldwide, despite a recent body of opinion suggesting that “opioid-free anesthesia” is desirable for patients as it avoids familiar adverse effects. In addition, some early laboratory data signaled that opioids might have detrimental effects on cancer cell biology or an immunosuppressive effect,⁵⁸ the latter involving both innate and adaptive immune systems via inhibition of NK cell cytotoxicity, and neutrophil and macrophage phagocytosis, amongst others.⁵⁹^,⁶⁰ These effects on the immune system could possibly favor tumor growth, metastasis, and recurrence.⁵⁸^,⁶¹ Many cancers express µ-opioid receptors (MOR) in a highly dysregulated fashion, activation of which alters cellular signaling pathways associated with neoplastic proliferation and metastasis.^62–64 However, preclinical evidence is conflicting—some researchers have detected opioid-related inhibition of angiogenesis and tumor growth inhibition, suggestive of potentially beneficial effects in certain contexts.⁶⁵^,⁶⁶ In addition, different opioids may have differential effects: in a rat model of cancer surgery, morphine and fentanyl decreased NK cytotoxicity and promoted metastasis, whereas the MOR partial-agonist buprenorphine had an opposite effect.⁶⁷ Tramadol on the other hand, appears to have immune-stimulating properties and has been shown to enhance NK cytotoxicity in vivo and ameliorate the suppression of NK cells induced by surgery.⁶⁸ The potential for MOR antagonists (eg, naltrexone) to inhibit cancer cell function has also been suggested, with some outcome benefits noted in a few small clinical studies conducted to date.⁶⁹^,⁷⁰

Retrospective studies of the effect of perioperative opioids on cancer outcomes, consistent with other anesthetic-analgesic techniques, have unsurprisingly shown a large disparity in results.⁷¹^,⁷² These disparities may (at least in part) have an epigenetic basis. Recent retrospective data has correlated the effect of various routine perioperative techniques with gene expression from actual excised tumors of breast cancer and nonsmall cell lung cancer (NSCLC) patients. One concluded that higher intraoperative opioid dose was in fact associated with improved cancer outcomes in lung cancer patients when some genes are present, and worse outcomes with others.⁷³ Another found an association between higher intraoperative opioid use and better outcome in triple-negative breast cancer, a particularly challenging subtype to treat.⁷⁴ A further retrospective study found that reduced intraoperative opioid dose was associated with improved recurrence-free survival and overall survival after excision of renal cell carcinoma.⁷⁵

Only 2 prospective RCTs in the last 2 years have specifically investigated the effects perioperative opioids. In a small trial, (n = 146), no difference was observed in biochemical recurrence between the opioid-free versus opioid-based anesthesia in a prostatectomy cohort.⁷⁶ And a further prospective, noninferiority RCT comparing sufentanil-dominant anesthesia versus epidural anesthesia (n = 81 each arm) found no difference between the groups for tumor-related immune alterations and cancer-related outcomes (metastasis, recurrence, and survival).⁷⁷ Therefore, the current picture of perioperative use of opioids in the context of cancer surgery is nuanced, with emerging evidence that variability in gene expression may play a role in determining whether opioids have overall detrimental or beneficial effects on long-term cancer outcomes. In essence, there is equivalence of data and therefore decisions around perioperative use of opioids for cancer resection patients should be made without reference to any potential oncologic effect.

Other Agents: Ketamine, Dexamethasone, Alpha-2 Agonists, and Acetaminophen

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is frequently used as a perioperative analgesic agent, and occasionally as an induction agent. In the laboratory, ketamine has demonstrated potentially beneficial anti-inflammatory and antiangiogenic effects, as well as direct inhibitory effects on cancer cells.^78–80 Again, other preclinical studies have yielded contrary results, with some showing it may actually promote cancer progression, possibly via impaired NK function.⁸¹ A meta-analysis of data from small RCTs of cancer patients evaluating surrogate outcomes, such as biomarkers, found that ketamine had no effect on reducing postoperative IL-6, but a significant effect on reducing postoperative CRP, suggestive of a modest beneficial anti-inflammatory effect. However, this involved only 3 studies with 120 patients for IL-6, and 2 studies with 178 patients for CRP.⁸² One small RCT randomizing 100 patients undergoing laparoscopic colorectal cancer excision to receive intraoperative ketamine infusion or placebo, showed that ketamine did not convey any favorable impact on NK cell activity, inflammatory markers (IL-6, CRP, TNF-α) or cancer recurrence at 2 years.⁸⁰ Therefore, there is no conclusive evidence that ketamine has a significant effect on cancer outcomes.

Similarly, much of our knowledge regarding the perioperative effects of dexamethasone (and other glucocorticoids) on cancer biology derives from preclinical studies showing highly variable effects depending on cancer type and disease setting.⁸³ Dexamethasone potentially possesses beneficial antineoplastic effects due to its anti-inflammatory properties; however, at higher doses, it may also cause harmful suppression of the immune response.⁶¹ A recent large retrospective cohort study (n > 30,000) of patients who had solid tumors resected found that intraoperative dexamethasone was associated with both a reduced 1-year mortality risk and increased recurrence-free survival.⁸⁴ These findings appear to have been modified by tumor immunogenicity and were only present in the cohort of patients who did not meet the criteria for immunotherapy. However, retrospective data as a whole is very mixed, with a meta-analysis of such studies reporting that dexamethasone did not affect cancer recurrence but that the evidence regarding overall or disease-free survival was too heterogenous to be reliable.⁸⁵ Prospective trial data is limited to a follow-up study of a previous RCT, which suggested a weak association between perioperative dexamethasone use and improved oncologic outcome.⁸⁶ However, in light of the conflicting laboratory and observational data, and the absence of any further prospective RCT, no conclusions can be made regarding the effect of dexamethasone on long-term cancer outcomes.

Alpha-2 adrenergic agonists (dexmedetomidine, clonidine) are used as adjuncts to analgesia, as sedatives, or as sympatholytics in the perioperative period. Laboratory data is mixed, with some studies showing that these agents are implicated in cellular proliferation, migration, and metastasis in some cancer types, and inhibition of cancer cell activity in others.^87–89 Clinical evidence is scarce. One retrospective study found that dexmedetomidine use decreased overall survival after lung cancer surgery.⁹⁰ Older patients enrolled in an RCT examining delirium after major noncardiac surgery (n = 620) were followed up regarding cancer outcomes. Patients who received dexmedetomidine were found to have improved recurrence-free survival but overall survival was unaffected.⁹¹ An underpowered prospective feasibility study (n = 150) randomizing breast cancer patients to dexmedetomidine or placebo intraoperatively found no difference in recurrence-free or overall survival between the groups.⁹² Therefore, the clinical evidence regarding the effects of alpha-2 agonist therapy on cancer outcomes is inadequate and consequently, these agents should be chosen for their analgesic and sympatholytic effects alone.

Acetaminophen (or paracetamol) is one of the most commonly used perioperative analgesic agents. Despite this, surprisingly little research has examined the influence of acetaminophen on cancer biology or outcomes. One laboratory study showed acetaminophen exhibits antiproliferative properties on ovarian cancer cells in vitro via effects on a number of cellular signaling pathways, 4 of which were identified in genomic datasets as being correlated with overall survival in ovarian cancer patients.⁹³ Other laboratory studies found that acetaminophen inhibited proliferation and stimulated apoptosis, but had no effect on migration, when tested on pancreatic cancer cells in vitro.⁹⁴^,⁹⁵ To date, no RCT has specifically examined the effects of acetaminophen on cancer outcomes. Although not perioperative studies per se, several large observational studies failed to demonstrate an association between pre- or postdiagnosis acetaminophen use and overall survival in ovarian cancer.^96–99 In summary, there is very little clinical evidence that acetaminophen has any effect on cancer outcome, therefore it is likely that it will continue in use as an important component of multi-modal perioperative analgesia.

CONCLUSIONS

While this clinical question remains of great interest, prospective, randomized trials are the pinnacle of evidence-based clinical decision-making. Trials in this field require large numbers of patients for sufficient statistical power and a prolonged postenrolment follow-up period, to account for oncologic outcomes such as cancer-specific disease-free survival, which are typically 3 to 5 years. Emerging trials of some routinely used anesthetic-analgesic techniques evaluated to date are indicating a consistent message that no perioperative intervention during cancer surgery has yet to show any long-term oncologic effect. One exception is peritumoral lidocaine infiltration in breast cancer, but this finding needs to be confirmed in other trials, some of which are ongoing. Future research, particularly in the field of epigenetics, will greatly expand our understanding and may reveal a role for tailoring anesthetic techniques depending on an individual’s genome. Pending any further significant trial data however, the choice of anesthetic-analgesic technique for cancer resection patients should be made without reference to any potential oncologic effect.

REFERENCES

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–263.

2. Sullivan R, Alatise OI, Anderson BO, et al. Global cancer surgery: delivering safe, affordable, and timely cancer surgery. Lancet Oncol. 2015;16:1193–1224.

3. Mehlen P, Puisieux A. Metastasis: a question of life or death. Nat Rev Cancer. 2006;6:449–458.

4. Hiller JG, Perry NJ, Poulogiannis G, Riedel B, Sloan EK. Perioperative events influence cancer recurrence risk after surgery. Nat Rev Clin Oncol. 2018;15:205–218.

5. Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI, Buggy DJ. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology. 2008;109:180–187.

6. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3:453–458.

7. Alix-Panabières C. Circulating tumor cells: finding rare events for a huge knowledge of cancer dissemination. Cells. 2020;9:661.

8. Tao SC, Guo SC. Role of extracellular vesicles in tumour microenvironment. Cell Commun Signal. 2020;18:163.

9. Raskov H, Orhan A, Salanti A, Gögenur I. Premetastatic niches, exosomes and circulating tumor cells: early mechanisms of tumor dissemination and the relation to surgery. Int J Cancer. 2020;146:3244–3255.

10. Heaney A, Buggy DJ. Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis? Br J Anaesth. 2012;109(Suppl 1):i17–i28.

11. Masucci MT, Minopoli M, Del Vecchio S, Carriero MV. The Emerging role of neutrophil extracellular traps (NETs) in tumor progression and metastasis. Front Immunol. 2020;11:1749.

12. Jiang S, Liu Y, Huang L, Zhang F, Kang R. Effects of propofol on cancer development and chemotherapy: potential mechanisms. Eur J Pharmacol. 2018;831:46–51.

13. Ramirez MF, Cata JP. Anesthesia techniques and long-term oncological outcomes. Front Oncol. 2021;11:788918.

14. Huang H, Benzonana LL, Zhao H, et al. Prostate cancer cell malignancy via modulation of HIF-1alpha pathway with isoflurane and propofol alone and in combination. Br J Cancer. 2014;111:1338–1349.

15. Gao M, Guo R, Lu X, Xu G, Luo S. Propofol suppresses hypoxia-induced esophageal cancer cell migration, invasion, and EMT through regulating lncRNA TMPO-AS1/miR-498 axis. Thorac Cancer. 2020;11:2398–2405.

16. Benzonana LL, Perry NJ, Watts HR, et al. Isoflurane, a commonly used volatile anesthetic, enhances renal cancer growth and malignant potential via the hypoxia-inducible factor cellular signaling pathway in vitro. Anesthesiology. 2013;119:593–605.

17. Buckley A, McQuaid S, Johnson P, Buggy DJ. Effect of anaesthetic technique on the natural killer cell anti-tumour activity of serum from women undergoing breast cancer surgery: a pilot study. Br J Anaesth. 2014;113:i56–i62.

18. Peng Z, Zhang Y. Propofol inhibits proliferation and accelerates apoptosis of human gastric cancer cells by regulation of microRNA-451 and MMP-2 expression. Genet Mol Res. 2016;15:1–9.

19. Zhou CL, Li JJ, Ji P. Propofol suppresses esophageal squamous cell carcinoma cell migration and invasion by down-regulation of sex-determining region Y-box 4 (SOX4). Med Sci Monit. 2017;23:419–427.

20. Iwasaki M, Zhao H, Jaffer T, et al. Volatile anaesthetics enhance the metastasis related cellular signalling including CXCR2 of ovarian cancer cells. Oncotarget. 2016;7:26042–26056.

21. Meng C, Song L, Wang J, Li D, Liu Y, Cui X. Propofol induces proliferation partially via downregulation of p53 protein and promotes migration via activation of the Nrf2 pathway in human breast cancer cell line MDA-MB-231. Oncol Rep. 2017;37:841–848.

22. Hovaguimian F, Braun J, Z’graggen BR, et al. Anesthesia and circulating tumor cells in primary breast cancer patients: a randomized controlled trial. Anesthesiology. 2020;133:548–558.

23. Oh C-S, Park H-J, Piao L, et al. Expression profiles of immune cells after propofol or sevoflurane anesthesia for colorectal cancer surgery: a prospective double-blind randomized trial. Anesthesiology. 2022;136:448–458.

24. Aghamelu O, Buggy P, Smith G, Inzitari R, Wall T, Buggy DJ. Serum NETosis expression and recurrence risk after regional or volatile anaesthesia during breast cancer surgery: A pilot, prospective, randomised single-blind clinical trial. Acta Anaesthesiol Scand. 2021;65:313–319.

25. O’Bryan LJ, Atkins KJ, Lipszyc A, Scott DA, Silbert BS, Evered LA. Inflammatory biomarker levels after propofol or sevoflurane anesthesia: a meta-analysis. Anesth Analg. 2022;134:69–81.

26. Hasselager RP, Hallas J, Gögenur I. Inhalation or total intravenous anaesthesia and recurrence after colorectal cancer surgery: a propensity score matched Danish registry-based study. Br J Anaesth. 2021;126:921–930.

27. Makito K, Matsui H, Fushimi K, Yasunaga H. Volatile versus total intravenous anesthesia for cancer prognosis in patients having digestive cancer surgery. Anesthesiology. 2020;133:764–773.

28. Yoon S, Jung SY, Kim MS, Yoon D, Cho Y, Jeon Y. Impact of propofol-based total intravenous anesthesia versus inhalation anesthesia on long-term survival after cancer surgery in a nationwide cohort. Ann Surg. 2023;278:1024–1031.

29. Sessler DI, Pei L, Huang Y, et al.; Breast Cancer Recurrence Collaboration. Recurrence of breast cancer after regional or general anaesthesia: a randomised controlled trial. Lancet. 2019;394:1807–1815.

30. Cao SJ, Zhang Y, Zhang YX, et al.; First Study of Perioperative Organ Protection (SPOP1) investigators. Long-term survival in older patients given propofol or sevoflurane anaesthesia for major cancer surgery: follow-up of a multicentre randomised trial. Br J Anaesth. 2023;131:266–275.

31. 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.

32. Vicente D, Patino M, Marcus R, et al. Impact of epidural analgesia on the systemic biomarker response after hepatic resection. Oncotarget. 2019;10:584–594.

33. Wei Q, Xia M, Zhang Q, Wang Z. Effect of intravenous lidocaine infusion on perioperative cellular immunity and the quality of postoperative recovery in breast cancer patients: a randomized controlled trial. Gland Surg. 2022;11:599–610.

34. Wigmore T, Farquhar-Smith P. Opioids and cancer: friend or foe? Curr Opin Support Palliat Care. 2016;10:109–118.

35. Hasselager RP, Hallas J, Gogenur I. Epidural analgesia and recurrence after colorectal cancer surgery: a Danish retrospective registry-based cohort study. Anesthesiology. 2022;136:459–471.

36. Wang Y, Song Y, Qin C, Zhang C, Du Y, Xu T. Effect of regional versus general anesthesia on recurrence of non-muscle invasive bladder cancer: a systematic review and meta-analysis of eight retrospective cohort studies. BMC Anesthesiol. 2023;23:201.

37. Ang E, Ng KT, Lee ZX, Ti LK, Chaw SH, Wang CY. Effect of regional anaesthesia only versus general anaesthesia on cancer recurrence rate: a systematic review and meta-analysis with trial sequential analysis. J Clin Anesth. 2020;67:110023.

38. Du YT, Li YW, Zhao BJ, et al.; Peking University Clinical Research Program Study Group. Long-term survival after combined epidural-general anesthesia or general anesthesia alone: follow-up of a randomized trial. Anesthesiology. 2021;135:233–245.

39. Xu ZZ, Li HJ, Li MH, et al. Epidural anesthesia-analgesia and recurrence-free survival after lung cancer surgery: a randomized trial. Anesthesiology. 2021;135:419–432.

40. Wall TP, Buggy DJ. Perioperative intravenous lidocaine and metastatic cancer recurrence—a narrative review. Front Oncol. 2021;11:688896.

41. Castro I, Carvalho P, Vale N, Monjardino T, Mourão J. Systemic anti-inflammatory effects of intravenous lidocaine in surgical patients: a systematic review and meta-analysis. J Clin Med. 2023;12:3772.

42. Ren B, Cheng M, Liu C, et al. Perioperative lidocaine and dexmedetomidine intravenous infusion reduce the serum levels of NETs and biomarkers of tumor metastasis in lung cancer patients: a prospective, single-center, double-blinded, randomized clinical trial. Front Oncol. 2023;13:1101449.

43. Zhang H, Yang L, Zhu X, et al. Association between intraoperative intravenous lidocaine infusion and survival in patients undergoing pancreatectomy for pancreatic cancer: a retrospective study. Br J Anaesth. 2020;125:141–148.

44. Zhang H, Qu M, Guo K, et al. Intraoperative lidocaine infusion in patients undergoing pancreatectomy for pancreatic cancer: a mechanistic, multicentre randomised clinical trial. Br J Anaesth. 2022;129:244–253.

45. Badwe RA, Parmar V, Nair N, et al. Effect of peritumoral infiltration of local anesthetic before surgery on survival in early breast cancer. J Clin Oncol. 2023;41:3318–3328.

46. Todoric J, Antonucci L, Karin M. Targeting inflammation in cancer prevention and therapy. Cancer Prev Res (Phila). 2016;9:895–905.

47. Zhang X, Feng Y, Liu X, et al. Beyond a chemopreventive reagent, aspirin is a master regulator of the hallmarks of cancer. J Cancer Res Clin Oncol. 2019;145:1387–1403.

48. Rodrigues P, Bangali H, Hammoud A, et al. COX 2-inhibitors; a thorough and updated survey into combinational therapies in cancers. Med Oncol. 2024;41:41.

49. Lichtenberger LM. Using aspirin to prevent and treat cancer. Inflammopharmacology. 2024;32:903–908.

50. Shah D, Di Re A, Toh JWT. Aspirin chemoprevention in colorectal cancer: network meta-analysis of low, moderate, and high doses. Br J Surg. 2023;110:1691–1702.

51. Shaji S, Smith C, Forget P. Perioperative NSAIDs and long-term outcomes after cancer surgery: a systematic review and meta-analysis. Curr Oncol Rep. 2021;23:146.

52. Cata JP, Guerra CE, Chang GJ, Gottumukkala V, Joshi GP. Non-steroidal anti-inflammatory drugs in the oncological surgical population: beneficial or harmful? A systematic review of the literature. Br J Anaesth. 2017;119:750–764.

53. Forget P, Bouche G, Duhoux FP, et al. Intraoperative ketorolac in high-risk breast cancer patients. A prospective, randomized, placebo-controlled clinical trial. PLoS One. 2019;14:e0225748.

54. Coombes RC, Tovey H, Kilburn L, et al.; Randomized European Celecoxib Trial (REACT) Trial Management Group and Investigators. Effect of celecoxib vs placebo as adjuvant therapy on disease-free survival among patients with breast cancer: the REACT randomized clinical trial. JAMA Oncol. 2021;7:1291–1301.

55. Meyerhardt JA, Shi Q, Fuchs CS, et al. Effect of celecoxib vs placebo added to standard adjuvant therapy on disease-free survival among patients with stage III colon cancer: the CALGB/SWOG 80702 (alliance) randomized clinical trial. JAMA. 2021;325:1277–1286.

56. Benjamin DJ, Haslam A, Prasad V. Cardiovascular/anti-inflammatory drugs repurposed for treating or preventing cancer: a systematic review and meta-analysis of randomized trials. Cancer Med. 2024;13:e7049.

57. Bosch DJ, Nieuwenhuijs-Moeke GJ, van Meurs M, Abdulahad WH, Struys M. Immune modulatory effects of nonsteroidal anti-inflammatory drugs in the perioperative period and their consequence on postoperative outcome. Anesthesiology. 2022;136:843–860.

58. Ackerman RS, Luddy KA, Icard BE, Pineiro Fernandez J, Gatenby RA, Muncey AR. The effects of anesthetics and perioperative medications on immune function: a narrative review. Anesth Analg. 2021;133:676–689.

59. Plein LM, Rittner HL. Opioids and the immune system—friend or foe. Br J Pharmacol. 2018;175:2717–2725.

60. Moorthy A, Eochagáin AN, Buggy DJ. Can acute postoperative pain management after tumour resection surgery modulate risk of later recurrence or metastasis? Front Oncol. 2021;11:802592.

61. Wall T, Sherwin A, Ma D, Buggy DJ. Influence of perioperative anaesthetic and analgesic interventions on oncological outcomes: a narrative review. Br J Anaesth. 2019;123:135–150.

62. Bhoir S, Uhelski M, Guerra-Londono JJ, Cata JP. The role of opioid receptors in cancer. Adv Biol (Weinh). 2023;7:e2300102.

63. Wang X, Zhang S, Jin D, et al. mu-opioid receptor agonist facilitates circulating tumor cell formation in bladder cancer via the MOR/AKT/Slug pathway: a comprehensive study including randomized controlled trial. Cancer Commun (Lond). 2023;43:365–386.

64. Sezer G, Caner A, Onal MG, Cumaoglu A. Morphine counteracts the effects of paclitaxel in triple-negative breast cancer cells. Indian J Med Res. 2022;156:70–76.

65. Koodie L, Yuan H, Pumper JA, et al. Morphine inhibits migration of tumor-infiltrating leukocytes and suppresses angiogenesis associated with tumor growth in mice. Am J Pathol. 2014;184:1073–1084.

66. Khabbazi S, Nassar ZD, Goumon Y, Parat MO. Morphine decreases the pro-angiogenic interaction between breast cancer cells and macrophages in vitro. Sci Rep. 2016;6:31572.

67. Franchi S, Panerai AE, Sacerdote P. Buprenorphine ameliorates the effect of surgery on hypothalamus-pituitary-adrenal axis, natural killer cell activity and metastatic colonization in rats in comparison with morphine or fentanyl treatment. Brain Behav Immun. 2007;21:767–774.

68. Gaspani L, Bianchi M, Limiroli E, Panerai AE, Sacerdote P. The analgesic drug tramadol prevents the effect of surgery on natural killer cell activity and metastatic colonization in rats. J Neuroimmunol. 2002;129:18–24.

69. Janku F, Johnson LK, Karp DD, Atkins JT, Singleton PA, Moss J. Treatment with methylnaltrexone is associated with increased survival in patients with advanced cancer. Ann Oncol. 2016;27:2032–2038.

70. Vijayakumar J, Haddad T, Gupta K, Sauers J, Yee D. An open label phase II study of safety and clinical activity of naltrexone for treatment of hormone refractory metastatic breast cancer. Invest New Drugs. 2023;41:70–75.

71. Belltall A, Mazzinari G, Garrido-Cano I, et al. Opioid receptor expression in colorectal cancer: a nested matched case-control study. Front Oncol. 2022;12:801714.

72. Belltall A, Zuniga-Trejos S, Garrido-Cano I, et al. Solid tumor opioid receptor expression and oncologic outcomes: analysis of the cancer genome atlas and genotype tissue expression project. Front Oncol. 2022;12:801411.

73. Connolly JG, Tan KS, Mastrogiacomo B, et al. Intraoperative opioid exposure, tumour genomic alterations, and survival differences in people with lung adenocarcinoma. Br J Anaesth. 2021;127:75–84.

74. Montagna G, Gupta HV, Hannum M, et al. Intraoperative opioids are associated with improved recurrence-free survival in triple-negative breast cancer. Br J Anaesth. 2021;126:367–376.

75. Silagy AW, Hannum ML, Mano R, et al. Impact of intraoperative opioid and adjunct analgesic use on renal cell carcinoma recurrence: role for onco-anaesthesia. Br J Anaesth. 2020;125:e402–e404.

76. Rangel FP, Auler JOC Jr, Carmona MJC, et al. Opioids and premature biochemical recurrence of prostate cancer: a randomised prospective clinical trial. Br J Anaesth. 2021;126:931–939.

77. Guan Y, Song H, Li A, et al. Comparison of the effects of sufentanil-dominant anaesthesia/analgesia and epidural anaesthesia/analgesia on postoperative immunological alterations, stress responses and prognosis in open hepatectomy: a randomized trial. J Gastrointest Oncol. 2023;14:2521–2535.

78. Rodriguez Arango JA, Zec T, Khalife M. Perioperative ketamine and cancer recurrence: a comprehensive review. J Clin Med. 2024;13:1920.

79. Li T, Yang J, Yang B, et al. Ketamine inhibits ovarian cancer cell growth by regulating the lncRNA-PVT1/EZH2/p57 axis. Front Genet. 2020;11:597467.

80. Saito J, Zao H, Wu L, et al.; ESA-IC Onco-Anaesthesiology Research Group. “Anti-cancer” effect of ketamine in comparison with MK801 on neuroglioma and lung cancer cells. Eur J Pharmacol. 2023;945:175580.

81. Chen LK, Chen SS, Shih CH, Huang ZX, Chen L, Chen KB. Ketamine promoted breast cancer invasion and metastasis through up-regulating Wnt, BMP, and EGFR signaling. Anticancer Res. 2023;43:5415–5424.

82. Alhayyan A, McSorley S, Roxburgh C, Kearns R, Horgan P, McMillan D. The effect of anesthesia on the postoperative systemic inflammatory response in patients undergoing surgery: a systematic review and meta-analysis. Surg Open Sci. 2020;2:1–21.

83. Mayayo-Peralta I, Zwart W, Prekovic S. Duality of glucocorticoid action in cancer: tumor-suppressor or oncogene? Endocr Relat Cancer. 2021;28:R157–R171.

84. Blank M, Katsiampoura A, Wachtendorf LJ, et al. Association between intraoperative dexamethasone and postoperative mortality in patients undergoing oncologic surgery: a multicentric cohort study. Ann Surg. 2023;278:e105–e114.

85. Rosenkrantz Hölmich E, Petring Hasselager R, Tvilling Madsen M, Orhan A, Gögenur I. Long-term outcomes after use of perioperative glucocorticoids in patients undergoing cancer surgery: a systematic review and meta-analysis. Cancers (Basel). 2019;12:76.

86. Singh PP, Lemanu DP, Taylor MH, Hill AG. Association between preoperative glucocorticoids and long-term survival and cancer recurrence after colectomy: follow-up analysis of a previous randomized controlled trial. Br J Anaesth. 2014;113(Suppl 1):i68–i73.

87. Cai Q, Liu G, Huang L, et al. The role of dexmedetomidine in tumor-progressive factors in the perioperative period and cancer recurrence: a narrative review. Drug Des Devel Ther. 2022;16:2161–2175.

88. Nair AS, Saifuddin MS, Naik V, Rayani BK. Dexmedetomidine in cancer surgeries: present status and consequences with its use. Indian J Cancer. 2020;57:234–238.

89. Dong J, Che J, Wu Y, et al. Dexmedetomidine promotes colorectal cancer progression via Piwil2 signaling. Cell Oncol (Dordr). Published online April 9, 2024. doi: 10.1007/s13402-024-00944-8.

90. Cata JP, Singh V, Lee BM, et al. Intraoperative use of dexmedetomidine is associated with decreased overall survival after lung cancer surgery. J Anaesthesiol Clin Pharmacol. 2017;33:317–323.

91. Xing MW, Li CJ, Guo C, Wang BJ, Mu DL, Wang DX. Effect of intraoperative dexmedetomidine on long-term survival in older patients after major noncardiac surgery: 3-year follow-up of a randomized trial. J Clin Anesth. 2023;86:111068.

92. Luo J, Xuan W, Sun J, et al. The effects of dexmedetomidine on postoperative tumor recurrence and patient survival after breast cancer surgery: a feasibility study. Anesthesiol Perioper Sci. 2023;1:37.

93. Bush SH, Tollin S, Marchion DC, et al. Sensitivity of ovarian cancer cells to acetaminophen reveals biological pathways that affect patient survival. Mol Clin Oncol. 2016;4:399–404.

94. Malsy M, Hackl C, Graf B, Bitzinger D, Bundscherer A. The effects of analgesics on the migration of pancreatic cancer cells. In Vivo. 2022;36:576–581.

95. Malsy M, Graf B, Bundscherer A. Effects of metamizole, MAA, and paracetamol on proliferation, apoptosis, and necrosis in the pancreatic cancer cell lines PaTu 8988 t and Panc-1. BMC Pharmacol Toxicol. 2017;18:77.

96. Nagle CM, Ibiebele TI, DeFazio A, Protani MM, Webb PM; Australian Ovarian Cancer Study Group. Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, acetaminophen and ovarian cancer survival. Cancer Epidemiol. 2015;39:196–199.

97. Majidi A, Na R, Jordan SJ, et al. Common analgesics and ovarian cancer survival: the Ovarian cancer Prognosis And Lifestyle (OPAL) Study. J Natl Cancer Inst. 2023;115:570–577.

98. Dixon SC, Nagle CM, Wentzensen N, et al.; Australian Ovarian Cancer Study Group. Use of common analgesic medications and ovarian cancer survival: results from a pooled analysis in the Ovarian Cancer Association Consortium. Br J Cancer. 2017;116:1223–1228.

99. Merritt MA, Rice MS, Barnard ME, et al. Pre-diagnosis and post-diagnosis use of common analgesics and ovarian cancer prognosis (NHS/NHSII): a cohort study. Lancet Oncol. 2018;19:1107–1116.