FRCA Notes

Malignancy

The curriculum asks for knowledge on 'the effects of chemotherapy/radiotherapy, and the implications for anaesthesia' as well as the 'anaesthetic relevance of drugs used in malignancy'.

Although the curriculum doesn't explicitly ask for knowledge on the impact of anaesthesia on oncological outcomes, this is included because of the BJA Education article on the topic.

Resources

  • Cancer is a leading cause of death worldwide, accounting for approximately 1 in 6 deaths
  • Over 80% of patients with cancer undergo either curative or palliative surgery
  • There a growing, albeit not necessarily always conclusive, body of evidence about the impact of anaesthetic practice on post-operative cancer outcomes
  • Naturally the clinical manifestations of any given cancer will depend on the primary organ system affected, whether it has metastasised and the stage of cancer
  • There are, however, some clinical manifestations of malignancy which are more common amongst any patient with cancer

Neurological

  • Cancer pain (75%)
  • Psychological distress & depression (70%)

Renal

  • Pre-renal AKI from dehydration or cardiac failure
  • Intrinsic AKI as a side-effect of drugs or from sepsis
  • Post-renal AKI from obstructive effects e.g. pelvic malignancy

Nutritional and metabolic

  • Cancer cachexia (50%); anorexia | weight loss | weakness | impaired immunity
  • Hypercalcaemia (10%)
    • May be hormonal e.g. bronchial carcinoma
    • May be from bony destruction e.g. breast cancer, myeloma
  • Hyponatraemia, often an SIADH e.g. in small cell lung cancer

Haematological

  • Anaemia
  • Neutropaenia, either from bone marrow infiltration or as a drug side-effect
  • Hypercoagulable state

Effects of local compression

  • Superior vena cava obstruction (SVCO)
    • E.g. from primary lung tumours or mediastinal lymphoma
    • Symptoms include facial oedema, plethora and headache
    • This can be associated with tracheal compression

  • Spinal cord compression


Class Examples
Alkylating agents Cyclophosphamide
Melphalan
Mitomycin C
Platinum-based agents Cisplatin
Carboplatin
Oxaliplatin
Anti-metabolites Methotrexate
5-fluorouracil
Gemcitabine
Capecitabine
'Natural' products Vinca alkaloids (vincristine)
Taxanes (paclitaxel, docetaxel)
Etoposide
Topoisomerase inhibitors Topotecan
Irinotecan
Anthracyclines Doxorubicin
Idarubicin
Cytotoxic antibiotics Bleomycin
Mitomycin
Monoclonal antibodies Trastuzumab (Herceptin)
Bevacizumab (Avastin)

Immunotherapy

  • Immunotherapies comprise a class of drugs which manipulate the immune system to (re)activate the anti-tumour immune response
  • They can be classified as:
    • Interferons
    • Immune checkpoint inhibitors e.g. Ipilimumab, Tremelimumab, Pembrolizumab, Nivolumab, Atezolizumab, Avelumab or Durvalumab
    • Chimeric antigen receptor T-cells (CAR-T therapy)

Airway

  • Patients may experience peri-oral changes affecting ease of airway management, such as:
    • Mucositis
    • Dry mouth
    • Lack of dentition
    • Osteonecrosis of the jaw
  • Trismus
  • Reduced tongue mobility
  • Reduced neck mobility
  • Glottic or epiglottic oedema

Respiratory

  • Chemotherapy-induced pneumonitis
    • A pulmonary toxicity syndrome characterised by cough, dyspnoea, low-grade fever and hypoxaemia
    • CXR shows reticular markings, consolidation or ground-glass changes; CT is sensitive but not specific
    • Treatment is with cessation of the offending agent, systemic corticosteroids and supportive therapy
    • Implicated chemotherapeutic agents include alkylating agents, gemcitabine, taxanes and platinum-based compounds
  • Radiotherapy can cause a pneumonitis:
    • Acute radiation pneumonitis (hours or days post-irradiation)
    • Sub-acute radiation pneumonitis (2-6 months post-irradiation)
    • Chronic lung fibrosis (9-12 months post-irradiation)
  • Immunotherapies can also cause a pneumonitis

  • Bleomycin-induced lung fibrosis
    • Occurs in 5 - 16% of patients receiving >400 IU/m2 of the drug
    • Develops within 6 months after treatment and risk remains lifelong
    • Induced and potentiated by oxygen therapy
      • Keep FiO2 to minimum to achieve target saturations
      • If hypoxic, target sats 88 - 92%
      • Only use high oxygen concentrations for immediate life-saving indications
    • If I&V is required, mortality is nearly 100%

  • Bronchospasm (mitomycin C)
  • Diffuse alveolar haemorrhage (alkylating agents, anti-metabolites)
  • PE due to hypercoagulable state in cancer
  • Secondary respiratory infection i.e. pneumonia due to immunosuppression from chemotherapy

Cardiovascular

  • Chemotherapy can cause cardiac toxicity
    • Higher incidence in those with pre-existing cardiac disease, or concurrent use of radiotherapy
    • Herceptin causes direct cardiotoxicity in 5% of patients
    • 5-fluorouracil causes myocardial ischaemia in 10% of patients
    • Cardiac myocyte necrosis leads to cardiac failure and/or arrhythmia

  • QTc-prolongation is a common feature
  • Arrhythmias (typically AF or other supraventricular arrhythmia)
    • Anthracyclines (2-10%)
    • Cisplatin (12-32%)
    • Melphalan (7-12%)

  • Anthracyclines-induced cardiomyopathy
    • A late, irreversible cardiotoxicity which occurs in 9-18%
    • Carries a 30% mortality so require strict dose limitation in therapy for curative intent
    • Characterised initially by ECG changes (non-specific ST and T-wave changes, prolonged QT interval)
    • Progresses to supraventricular arrhythmias and (transient) LV dysfunction
    • Continuous decline in LV function may lead to a chronic dilated cardiomyopathy

  • Cardiomyopathy
  • Myopericarditis

  • Radiotherapy can cause endothelial damage, oxidative stress, inflammation and mitochondrial DNA damage
  • Any component of the heart can be damaged, although features usually include:
    • Cardiomyopathy
    • Pericardial effusion and exudative pericarditis (typically self-limiting)
    • Conducting system abnormalities (typically self-limiting)
    • Coronary artery disease (late)

  • Immunotherapies can cause cardiac disease:
    • Myocarditis (1.14%)
    • Pericarditis
    • Cardiac fibrosis
    • Arhhythmias
    • Heart failure

Neurological

  • Higher risk of neurotoxicity in those with diabetes mellitus, of increased age, existing neuropathy or previous neurotoxicity from chemotherapy
  • Vincristine is especially good at causing neurotoxicity

  • Peripheral (often sensory) neuropathy
  • Autonomic neuropathy
  • Seizures
  • Encephalopathy e.g. methotrexate
  • Acute cerebellar syndrome
  • PRES
  • Aseptic meningitis
  • Chemotherapy-induced cognitive impairment (BJA, 2022)
  • Immunotherapy-induced neuropsychiatric disorders

Renal

  • Chemotherapeutic agents are often eliminated by the kidneys, risking chemotherapy-induced AKI
  • May have an additive effect with dehydration (from nausea and vomiting), NSAID use (for cancer pain) and other causes of renal disease
  • Typically presents with reduced GFR/raised creatinine and clinical features of proximal tubular injury:
    • Proteinuria
    • Hypophosphataemia
    • Hypomagnesaemia
    • Fanconi syndrome (hypophosphataemia, hypokalaemia, glycosuria, proteinuria)

  • Platinum-based agents are particularly nephrotoxic; 33% experience dose-related cisplatin-induced nephrotoxicity
  • Ifosfamide can cause renal failure (80%), Fanconi syndrome (66%) and nephrogenic DI

  • Radiotherapy-induced nephropathy, which can lead to hypertension and proteinuria although may respond to ACE-inhibitors

Gastrointestinal

  • Dysphagia, which may increase likelihood of aspiration

  • Chemotherapeutic agents are mostly metabolised by the liver
  • Hepatotoxicity is typically asymptomatic and manifests as raised liver enzymes
  • In some cases it can present with inflammatory hepatitis, cholestasis, steatosis, hepatocellular necrosis and hepatic cirrhosis/fibrosis
  • Classically caused by alkylating agents, 5-fluorouracil and topoisomerase inhibitors
  • Sinusoidal obstruction syndrome can also occur due to hepatic sinusoidal injury (e.g. oxaliplatin, busulfan)

  • Radiotherapy-induced hepatopathy
    • Acute hepatomegaly and deranged LFT's
    • Chronic, progressive liver cirrhosis

  • Immunotherapies can cause nausea, diarrhoea and anorexia

Metabolic

  • Tumour lysis syndrome is a metabolic complication following the onset of treatment for lymphomas and leukaemia
  • Widespread cell destruction causes: hyperuricaemia | hyperkalaemia | uraemia
  • Can cause AKI
  • Should not routinely administer steroids (e.g. for PONV) for patients with untreated lymphoma
  • Treatment includes hydration, allopurinol and rasburicase
  • Some patients will require RRT for refractory hyperkalaemia

Haematological

  • Bone marrow suppression by chemotherapeutic agents can lead to:
    • Pancytopaenia
    • Anaemia
    • Thrombocytopaenia
    • Neutropaenia
    • Lymphopaenia or in some cases lymphocytosis
  • Immunotherapies can also cause thrombocytopaenia and leukopaenia
  • May require G-CSF or other marrow-stimulating drugs

  • Both cancer and chemotherapy induces an inflammatory, procoagulant, anti-fibrinolytic and pro-aggregative response
  • This increases the risk of venous thrombosis, which is sustained for up to 6 months post-treatment

  • Vascular permeability is increased by radiotherapy-induced damage if doses >10Gy per fraction are used
  • This causes vessel wall cellular apoptosis, triggering platelet aggregation, fibrosis and increasing risk of vascular thrombus

Endocrine

  • Immunotherapies can cause endocrinopathies
  • Hypophysitis, an inflamed pituitary gland, is the most common endocrine effect, presenting variably as:
    • Hypothyroidism
    • Adrenal insufficiency
    • Hypogonadism
    • Central diabetes insipidus

  • Other immunotherapy-related endocrinopathies include:
    • Hypothyroidism (which may also be caused by radiotherapy to the head/neck)
    • Hyperthyroidism
    • Primary adrenal insufficiency
    • Diabetes mellitus

Immunological

  • The effect on the immune system varies among different agents, affecting both innate and adaptive arms
  • Myelosuppression can cause chemotherapy-induced neutropaenia and risks neutropaenic sepsis
  • The incidence of neutropaenia with fever ranges from 50% (solid organ tumours) to 80% (haematological malignancies)

  • Radiotherapy can activate both innate and adaptive immune responses by triggering cell apoptosis in response to DNA damage
  • This results in a systemic, pro-inflammatory, anti-tumour response which is responsible for the abscopal effect
  • Irradiation can inactivate NK cells and dendritic cells, leading to immunosuppression

  • Laboratory models suggest that cancer surgery generates a pathophysiological milieu conducive to poor outcomes
  • Surgery-related physiological changes which can inadvertently promote tumour survival, progression, proliferation and metastasis include:
    1. The surgical stress response
    2. Immunosuppression
    3. Tissue inflammation
    4. Tissue hypoxia and enhanced angiogenesis

  • These changes can drive an 'epithelial-to-mesenchymal transition', allowing epithelial cancer cells to develop a mesenchymal phenotype and thus cellular motility & metastatic potential
  • Cancer recurrence post-operatively can occur:
    • Locally at the resection site due to proliferation of residual cells
    • In lymph nodes due to tumour cells being released into the lymphatic system perioperatively
    • Distantly due to seeding by circulating tumour cells
    • In body cavities due to seeding perioperatively e.g. the peritoneal cavity

Surgical stress response

  • Both natural killer (NK) cells and CD8+ T-cells are a prominent feature of the adaptive immune system's ability to eliminate cancer cells
  • Activation of both the neuroendocrine-metabolic and cytokine-inflammatory-immune arms of the surgical stress response promote a pro-tumour environment by
    • Suppressing cell-mediated immunity by inhibiting the proliferation and anti-tumour activity of NK cells, CD8+ T-cells and CD4+ Type 1 T-helper cells
    • Proliferation of regulatory T-cells and Type 2 T-helper cells, which have pro-tumour effects (reduced Th1:Th2 ratio)
    • Increasing levels of interleukin-6 and prostaglandin E2, further impairing NK cell cytotoxicity
    • Activation of adrenoreceptors on tumour cells, triggering expression of pro-metastatic factors such as VEGF, interleukin-6 and matrix metalloproteases

Immunosuppression

  • In addition to the immunosuppressive effects of the surgical stress response, a post-operative effect on neutrophils can influence cancer recurrence
  • The post-operative inflammatory state increases circulating neutrophil count, raising the neutrophil-to-lymphocyte ratio (NLR)
  • An elevated NLR is associated with poor cancer survival in some cancers

  • Once neutrophils migrate into the tumour microenvironment, they adopt either an:
    • N1 anti-tumour phenotype which phagocytoses cancer cells
    • N2 pro-tumour phenotype which can promote cancer in various ways:
      • Reshaping of peritumour stroma
      • Expression of VEGF and MMP-9
      • Extrusion of neutrophil extracellular traps (NETs), elevated serum markers of which are associated with poorer prognosis in certain cancers

Inflammation

  • Trauma to surrounding (normal) tissue during tumour removal leads to inflammation
  • As part of the inflammatory process, various molecules are released which recruit cells such as macrophages, neutrophils, dendritic cells and fibroblasts
  • These in turn release further cytokines, growth factors and induce cellular pathways
  • The pathways and mechanisms involved include:
    • COX-2 pathways and increased prostaglandin release
    • The effect of other enzymes such as matrix metalloproteases (MMP-2, MMP-9)
    • Cytokines such as interleukin-6
    • Various chemokines e.g. CXC chemokine receptor 2
    • TNFɑ
    • Transcription factors such as hypoxia-inducible factor 1- alpha (HIF1ɑ), nuclear factor kappa-B (NF-κB)

  • Although the intended net effect is promotion of tissue healing, negative sequelae of this process include:
    • Promotion of residual cancer cell viability
    • Promotion of cancer cell migration
    • Depression of NK cell cytotoxicity
    • Increased risk of seeding of circulating tumour cells at distant sites of inflammation (inflammatory oncotaxis)

Angiogenesis

  • Disrupted perfusion of injured tissue at the surgical site leads to a hypoxic cellular environment
  • This in turn up-regulates expression of HIF1ɑ
  • Downstream effects include increased expression of VEGF amongst other components of tissue repair pathways
  • The results of this process include:
    • Angiogenesis, which promotes proliferation of residual cancer cells
    • VEGF-induced lymphatic dilation, which may increase risk of lymphatic spread
  • Indeed, iver-expression of HIF1ɑ or VEGF is associated with poor prognosis in various cancer types


Molecule/pathway Effects
Hypoxia inducible factor-1-alpha (HIF1ɑ) Angiogenesis
Glycolysis
Cell proliferation
Insulin-like growth factor (IGF) Cell proliferation
Suppresses apoptosis
Epithelial growth factor receptor (EGFR) Cell proliferation
Growth
Nuclear factor kappa B (NF-κB) Suppression of apoptosis
Chemoresistance
Tumourigenesis
Vascular endothelial growth factor (VEGF) Angiogenesis
Tumourigenesis
Neuroepithelial transforming 1 gene (NET1) Cancer and tumour invasion
Tissue necrosis factor alpha (TNFɑ) Activation of Src kinase and disruption of endothelial tight junctions
Natural killer cells (NK cell) Lyses tumour cells
Cytotoxic T-lymphocytes (CTL) Directly eliminate tumour cells
T-helper 1 cell to T-helper 2 cell ratio (Th1:Th2) T-helper 1 cells release IFN-ɣ and TNFɑ, which activate and induce CTL
T-helper 2 cells release Il-4, 5, 6 and 10 which are immunosuppressive + promote tumour production


Perioperative management of the patient undergoing cancer surgery


History and examination

  • Type, grade and stage of cancer
  • Treatment to date inc. previous surgeries

Investigations

  • Baseline saturations
  • Consider CXR ± lung function tests if suspicion of pneumonitis or other drug-induced pulmonary pathology

  • Baseline HR, blood pressure
  • 12-lead ECG, esp. with respect to QTc
  • TTE if any suspicion of drug-induced cardiomyopathy
  • Consider NT-pro-BNP

  • Liver function
  • Renal function and electrolytes

  • If suspicion of endocrinopathy may need liaison with Endocrinology

Optimisation

  • The time to surgery after neoadjuvant therapy is generally advised to be 4-6 weeks, allowing:
    • Reduction in disease volume
    • Recovery from cytotoxic effects of therapy

  • Prehabilitation, ideally in the window between neoadjuvant therapy and surgery
  • Airway planning, especially in those with head and neck tumours or previous head and neck radiotherapy
  • Drug cessation e.g. anticoagulants in those with existing VTE
  • Management of anaemia, thrombocytopaenia or other marrow dyscrasia if present
  • Optimise cell counts e.g. G-CSF for neutropaenia if appropriate

Monitoring and access

  • AAGBI
  • Consider 5-lead ECG if cardiotoxicity
  • Consider arterial line

Airway and ventilatory management

  • Consider RSI in some cases e.g. dysphagia, autonomic neuropathy
  • Patients with difficult airways may require awake tracheal intubation

  • Lung-protective ventilation, especially if pneumonitis
  • Titrate oxygenation accordingly, especially if previous bleomycin therapy

Anaesthetic technique

  • See below sections for influence of anaesthetic technique on cancer outcomes
  • Meticulous asepsis for regional/neuraxial techniques and central access due to immunosuppression
  • Blood conservation strategies; transfusion associated with poorer outcomes

Drug management

  • May need stress dosing of steroids in the perioperative period e.g. in those taking steroids for the cancer itself or the side-effects of SOL e.g. cerebral oedema
  • Consider avoidance of QT-prolonging drugs
  • Avoid suxamethonium in those with hyperkalaemia e.g. tumour lysis syndrome, nephrotoxicity
  • Blood components may need to be irradiated and/or CMV-negative
  • Consider impact of hepatic impairment on drug metabolism
  • Consider avoiding renally-eliminated drugs if chemotherapy-induced nephrotoxicity

Care bundle

  • Meticulous pressure care, especially in those with cachexia and/or neuropathy
  • Appropriate intra-operative VTE
  • Temperature management

  • Patients undergoing major resections may need higher level care post-operatively e.g. HDU
  • VTE prophylaxis
  • Analgesia
    • Be mindful patients may be on long-term opioid therapy for cancer pain and therefore need greater doses perioperatively
    • See below for effect of analgesics on cancer outcomes
  • Anti-emesis

  • The field of onco-anaesthesia is growing, although to date much of the literature and many of the clinical trials are of lower quality (e.g. retrospective, observational, non-randomised etc.)
  • In time, it seems likely we'll see the focus moving towards cancer subtypes or even patient-specific tumour genomics in order to understand the influence of anaesthetic and analgesic drugs on oncological outcomes

Volatile agents

  • Volatile agents demonstrate a number of in vitro characteristics which could have pro-tumour effects, such as:

    • Theoretical pro-tumour effects of volatiles
    Inhibition of NK cell activity in rodents
    Induction of HIF1ɑ expression, as part of their protective effect against ischaemia-reperfusion injury
    ↑ VEGF levels
    ↑ IGF levels
    ↓ CTL activity
    ↓ Th1:Th2 ratio
    Potentially ↑ cancer cell proliferation, migration and other pro-metastatic processes

  • However, clinical trials of the effect of volatile agents on cancer outcomes are equivocal
  • Some demonstrate no difference vs. propofol, although others demonstrate increased risk of recurrence and decreased overall survival (BJA, 2021)

Propofol

  • Compared to volatile agents, propofol demonstrates a number of in vitro characteristics which may lead to beneficial effects on cancer outcomes, such as:

    • Theoretical anti-tumour effects of volatiles
    Down-regulates HIF1ɑ levels
    Inhibits oncogenes such as NET1 and SOX4
    ↓ VEGF levels
    Suppression of cytokine and prostaglandin production
    Suppression of MMPs, reducing cancer cell migration
    ↑ NK cell activity
    ↓ cancer cell motility and degree of invasiveness

  • These apparent benefits have not universally translated into clinical studies, with several showing no difference compared to volatile-based anaesthetics
  • However, the available evidence does suggest overall propofol may have beneficial effects regarding risk of metastasis and overall survival

TIVA vs. volatile maintenance

  • Studies have shown no difference between the two techniques with regards to perioperative levels of:
    • Inflammatory cytokines/markers (IL-6, IL-10, TNFɑ, CRP)
    • NETs
    • Circulating tumour cell counts
    • NK cell or T-cell levels

  • There are multiple studies showing no difference in cancer recurrence or mortality between the two techniques (e.g. BJA, 2023)
  • The overall signal from retrospective studies suggests propofol TIVA may be associated with improved short- and longer-term survival and reduced cancer recurrence
  • However, this is not necessarily borne out in evidence from RCTs
  • For example, the CAN study (2023) found no difference in survival between propofol and volatile maintenance
  • There are relevant RCTs ongoing:

Regional anaesthesia

  • Multiple theoretical benefits to RA for reducing cancer outcomes such as:
    • Replace exposure to other anaesthetics e.g. volatiles
    • Attenuation of the surgical stress response
    • Reduce perioperative pain, which is associated with NK cell progression and metastasis
    • Reduced opioid consumption
    • Reduced surgical stress response (via neuro-endocrine arm, but no reduction in inflammatory response)
    • Direct immunomodulatory and anti-tumour effects of local anaesthetics

  • Evidence from retrospective studies of regional anaesthesia is inconclusive, and a 2014 Cochrane review found evidence for benefit of RA 'inadequate'
  • Indeed, RCTs and meta-analyses have failed to show improved oncological outcomes (BJA, 2021)

Return to oncological treatment (RIOT)

  • Reduced time to RIOT, e.g. adjuvant therapy post-operatively, may increase likelihood of recurrence-free survival
  • Therefore (in general) use of anaesthetic techniques aimed at reducing surgical recovery times may improve cancer outcomes

  • Post-operative pain control in patients undergoing cancer surgery may be more challenging due to existing chronic opioid use, additional anxiety or more extensive surgery
  • Evidence from one RCT found persistent moderate-severe post-operative pain was associated with higher risk of cancer recurrence and mortality
  • Optimisation of post-operative pain has multiple theoretical benefits relating to cancer outcomes:
    • Reductions in surgical stress response
    • Reduced long-term opioid exposure
    • Reduced time to RIOT

Opioids

In vitro effects of opioids which may be detrimental for cancer outcomes
Suppression of both cell-mediated and humoral immunity in mouse and human studies
Inhibition of NK cell cytotoxicity and neutrophil activity
↑ VEGF levels
Directly influencing cancer cell growth, proliferation and migration via the MOP
Immunosuppression via stimulation of the HPA axis and consequent cortisol release
  • Other factors potentially implicating opioids in poor cancer outcomes include:
    • MOP over-expression may be associated with poorer outcomes in some cancer types, such as prostate or oesophageal
    • MOP antagonism is associated with tumour-inhibiting effects in some murine models
  • There is some clinical evidence suggests that (excessive) opioid use may be harmful with respect to cancer outcomes
    • Longer term use of opioids in chronic pain patients is associated with a higher risk of cancer (BJA, 2022)
    • High intra-operative opioid exposure may be associated with worse overall survival in early-stage lung adenocarcinoma (BJA, 2021)
    • Long-term opioid use for chronic pain prior to cancer diagnosis may be associated with poorer cancer survival (BJA, 2022)

  • However, there is laboratory evidence that morphine exerts anti-tumour effects, while buprenorphine and tramadol may have beneficial effects too
  • Meta-analysis of animal cancer models concluded opioids do not influence metastasis
  • Furthermore, opioids have beneficial effects such as reducing post-operative pain and attenuating the surgical stress response
  • Indeed, some of the available evidence suggests a neutral or sometimes beneficial effect of opioids:
    • Higher doses of opioids was associated with less colorectal adenocarcinoma recurrence in DNA MMR-deficient tumours (BJA, 2022)
    • Other studies found no association between opioid dose and survival in colorectal cancer patients
    • Opioid use was not associated with outcomes in patients undergoing radical prostatectomy for prostate cancer (BJA, 2021)
    • Intra-operative opioid use had a protective effect in triple-negative breast cancer (BJA, 2021)

NSAIDs

  • NSAIDs/COX-2 inhibitors demonstrate multiple potential benefits in vitro:
    • Anti-tumour and anti-angiogenic activities in animal models
    • Reduced metastasis in animal models
    • Reductions in expression of VEGF, EGFR and NF-κB
    • Down-regulation of the SOX2 oncogene
  • Other known benefits include an opioid-sparing effect and inhibition of prostaglandin-induced immunosuppression

  • Theoretical benefits not necessarily borne out in clinical trials
  • Regular NSAID use pre-diagnosis may reduce incidence of cancer occurrence, recurrence and improve recurrence-free survival
  • Post-operative NSAID use has not been shown to benefit oncologic outcomes in trials of breast and colorectal cancer
  • Overall the evidence base is of poor quality, heterogenous and it is difficult to draw firm conclusions

Local anaesthetics

Beneficial effects of amide LA in vitro
Direct cytotoxic on tumour cells
Reductions in cancer cell proliferation, migration and viability
Down-regulation of EGFR
Decreased expression of NF-κB, IL-1, IL-6 and TNFɑ
Enhanced NK cell cytotoxicity
Preserved Th1:Th2 ratio
Inhibition of HIF1ɑ and VEGF pathways
Modulation of NETosis
Reduction in cancer cell MMP release
  • Putative mechanisms for these findings include sodium channel inhibition, DNA demethylation or Src oncogene inhibition
  • Other perioperative benefits include:
    • Opioid-sparing effect
    • Reduce surgical stress response if used in regional techniques
    • Attenuation of sympathetic response and analgesic effect when lidocaine is used directly IV (1.5mg/kg then 1.5-2.0mg/kg/hr)

  • Evidence from clinical trials is less concrete, with mixed albeit potentially promising results:
    • Use of IV lidocaine wasn't associated with better overall or disease-free survival in pancreatic cancer resection
    • IV lidocaine reduces perioperative inflammatory markers, attenuates surgical stress response and NETosis expression
    • Intraperitoneal infiltration of ropivacaine was associated with reduced time to RIOT following ovarian cancer resection
    • IV lidocaine was associated with improved 5-yr overall and disease-free survival after curative breast cancer surgery

Ketamine

  • Mixed findings from studies of its effects on the microcellular environment:
    • Inhibits NK cell activity in rodents
    • Suppresses pro-inflammatory cytokines such as IL-6, IL-8 and TNFɑ
    • Improves Th1:Th2 ratio
  • RCT evidence of ketamine vs. control found no difference in NK cell activity or pro-inflammatory cytokine levels after colorectal surgery
  • Ketamine use was associated with improved recurrence-specific survival in renal cell carcinoma and lung adenocarcinoma patients (BJA, 2021)
  • Opioid-sparing effects may be beneficial

Alpha-2-adrenoreceptor agonists

  • Theoretically these agents might have a cancer-promoting effect via adrenoreceptor activation
  • Laboratory studies show mixed results:
    • Pro-tumour effects such as increases in tumour growth, metastasis and a detrimental effect on innate immunity
    • Activation of HIF1ɑ, increased production of MMP-2, MMP-9 and VEGF, and up-regulation of survivin
    • Conversely, modulation of CD4+ T-cells, CD8+ T-cells and NK cells which may have indirect anti-tumour effects (BJA, 2023)

  • Clinical perioperative benefits include:
    • Volatile-sparing anaesthetic effect
    • Reduced post-operative catecholamine and pro-inflammatory cytokine levels
    • Opioid-sparing analgesic effect
  • Evidence base is poor-quality and overall relatively equivocal with respect to dexmedetomidine's effect on cancer outcomes

Nitrous oxide

  • Supresses neutrophil and mononuclear cell function
  • Accelerated lung and liver metastases in a rodent model

Corticosteroids

  • Immunosuppressive effect decreases NK cell activity
  • Anti-inflammatory affect helps attenuate surgical stress response
  • Perhaps unsurprising that the poor-quality evidence base demonstrates mixed outcomes with regards to the effect of dexamethasone on cancer outcomes

Allogeneic blood transfusion

  • Associated with transfusion-associated immunomodulation/immunosuppression in vitro
  • Reduced cellular immunity by compromised macrophage activity and a lower Th1:Th2 ratio
  • Cytokine release from transfused blood products contributes to inflammation
  • May be associated with increased risk of tumour recurrence (colorectal, bladder, gastric and prostate cancers)