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Current Anaesthesia & Critical Care (2008) 19, 96–104

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FOCUS ON: ONCOLOGY

The cancer critical care paradox

Paul Kelly

Anaesthesia and Intensive Care Medicine, The Royal Marsden NHS Foundation Trust, Fulham Road,London SW3 6JJ, UK

KEYWORDSCancer;Critical illness;Immune system;SIRS;CARS

ee front matter & 2008acc.2008.01.002

ess: drpaulkelly@gmail.

Summary A normal inflammatory response is a necessary reaction to injury orinfection. It has proinflammatory components, intended to promote healing andrepair, and anti-inflammatory components, to terminate and limit the response.The response is complex with significant inter-individual variability. It may bemodulated by multiple factors including cancer and its treatment. Cancer causesconsiderable immune dysfunction through a number of mechanisms. Cancertherapies, including surgery, chemotherapy, radiotherapy and transplantation, alsohave profoundly detrimental immunomodulatory effects. The resultant abnormalinflammatory response may cause excessive activation of proinflammatory or anti-inflammatory components, with consequent progression to critical illness. Aderanged inflammatory response may also affect carcinogenesis by proinflammatorypromotion of cancer growth and spread or anti-inflammatory suppression of anti-tumour immunity. In addition, techniques and medications used to provide organsupport during cancer-related critical illness may unwittingly further disorderinflammatory responses and have negative effects on the underlying cancer.

This review article explores this complex relationship between inflammation,critical illness and cancer and introduces the concept that critical illness and itsmanagement may influence cancer growth and spread.& 2008 Published by Elsevier Ltd.

Introduction

Cellular pathways involved in the pathogenesis ofinflammation, critical illness and cancer are intri-cately entwined. As a result, any alteration in oneis likely to affect the other. A dysfunctional immunesystem, secondary to the cancer itself or cancertherapies, is central to a cancer patient’s predis-position to critical illness. Once established, the

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progression of critical illness and the critical careinterventions, intended to treat the illness, mayhave paradoxical detrimental effects on the under-lying cancer.

To the best of our knowledge, the hypotheticalconcept that critical illness and critical caremanagement may influence carcinogenesis has notbeen reviewed. This article is an attempt to fill thathiatus by exploring the mechanisms and conse-quences of interactions between cancer, criticalillness and the immune system.

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Critical illness and the immune system

The inflammatory response is considered pivotal tothe onset and progression of critical illness.An inflammatory response is a normal responseto either injury, such as surgery, or infectionwhich involves rapid activation of the immunesystem. There is a local proinflammatory response,necessary for healing and repair, and a parallel,peripheral immunosuppressive anti-inflammatoryresponse, to contain and terminate the response.If left unchecked, uncontrolled recruitment ofimmune cells, and production of inflammatorymediators, may result in damage to normal organsand tissues. The normal course of events seesa return to baseline once healing, repair andhomeostasis have been achieved. However, incritically ill patients an excessive and prolongedproinflammatory response, often called SIRS(Systemic Inflammatory Response Syndrome), orexcessive and prolonged anti-inflammatoryresponse, often called CARS (CounterregulatoryAnti-inflammatory Response Syndrome), may causeMultiple Organ Dysfunction Syndrome (MODS) orimmunosuppression, respectively.1 MODS accountsfor the majority of the critical care deaths.The cause of the progression to critical illness andMODS is unclear. Dysregulation of intracellularinflammatory control pathways has been impli-cated. One of the most important componentsis Nuclear Factor-kB (NFkB), a group of transcrip-tion factors responsible for regulating over 150genes whose products control both innate andacquired inflammatory responses. These productsinclude tumour necrosis factor (TNF), interleukin 6(IL-6), IL-8, COX2, iNOS, LPS binding protein, CRP,growth factors and adhesion molecules. Its activa-tion appears to play a central role in the develop-ment of ARDS, sepsis and MODS. NFkB inhibition hasbeen shown to limit organ damage in animalmodels.2

Why some patients exhibit an abnormal inflam-matory response and develop critical illness andMODS is unknown. Indeed, whether it is abnormalor just inappropriate is still a matter of debate. Theresponse is highly complex and varies from indivi-dual to individual. The response may vary due topredispositions such as gender, age, premorbidillness and genetic polymorphisms in the inflamma-tory pathways. Site, type and extent of infection orinjury also shape the response. In addition,external influences such as drugs and surgery haveimmunomodulatory effects. Deviation from a nor-mal inflammatory response may modulate theprogression of certain disease states includingcancer.

Cancer and the immune system

The link between cancer and the immune system isdemonstrated by carcinogenesis at sites of chronicinflammation or as a result of cytokine polymorph-isms. The interaction occurs at multiple levels in acomplex bi-directional relationship. Cancer cellsprovoke an immune response and an immuneresponse can promote cancer. There is now nodoubt that immune cells, such as NK cells andcytotoxic T cells, are able to detect and kill cancercells. Suppression of any of these immune compo-nents may influence cancer growth. Cancers devel-op multiple immunosuppressive mechanisms toavoid immune mediated death. These includesecretion of soluble immunosuppressive factors,recruitment of immunosuppressive immune cells,suppression of cell-mediated immunity and induc-tion of immune tolerance.3,4 Other immune cells,including dendritic cells, macrophages, neutrophilsand mast cells, are also recruited into the tumourmicroenvironment. The complexity is introducedwhen considering carcinogenic effects of theproducts of this cancer-induced immune activation.The immune cells produce free radicals, cytokines,growth factors, angiogenic factors and matrixmetalloproteinases. These products can promotecancer initiation, growth and spread throughmodification of cellular apoptotic and proliferativemechanisms. Cancer growth and migration,is therefore not only genetically determined, but isalso regulated by environmental inflammatory media-tors. The net effect is a product of anti-tumourigenicimmunosurveillance and pro-tumourigenic inflamma-tory mediators.

However, it is not only cancer-induced inflamma-tion that may influence cancer growth. Inflamma-tion in response to other triggers such as infection,surgery and trauma may also occur. The effect of asecond inflammatory process occurring at the siteof an established cancer, as seen in infection,surgery or trauma, is less clear. Anecdotal evidencesuggests that a secondary inflammatory process,occurring at the site of the cancer, may lead totumour regression. In 2600 BC Imhotep is describedas incising over tumour sites to encourage infec-tion, an inflammatory response and a reduction intumour size. In the late 1800s, similar dramaticresponses were produced by Dr. William Coley.5 Hedeveloped a killed bacterial vaccine and injectedthis directly into the tumour or metastasis daily, for6 months, with remarkable success. Several morerecent publications suggested regression of cancerafter infection, including acute myeloid leukaemiaafter aspergillosis and lung cancer after an empye-ma. However, reports of spontaneous cancer

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regression have reduced since the 1930s and theintroduction of antibiotics and antipyretics.

A localised inflammatory reaction may alsoinfluence cancer at a distant site. This is demon-strated by the epidemiological link between peri-odontal disease and pancreatic cancer.6 This maybe due to the peripheral immunosuppressiveeffects of a local inflammatory reaction.

This association of the immune system withcancer is not entirely surprising. Many of theintracellular mechanisms involved in inflammation,healing and repair, are also involved in cell growthand death. They converge at vital cellular junc-tions. NFkB, mentioned as central to critical illnessand MODS, not only controls genes involved ininflammation, but also those responsible for cel-lular apoptosis and proliferation.7–9 It is activatedby proinflammatory cytokines, such as TNF andinterleukin-1 (IL-1), bacterial cell-wall compo-nents, such as lipopolysaccharide, viruses andDNA-damaging agents. Activation of NFkB in in-flammatory cells promotes an inflammatory re-sponse and production of mediators that maypromote carcinogenesis. Activation of NFkB innon-immune cells, such as epithelial cells, pro-motes survival, proliferation, invasion and metas-tasis. Effects may therefore differ betweenhaematological and solid cancers. They may alsovary between primary and metastasis.

In addition to the immunomodulatory effects ofcancer, cancer therapies may also significantly alterthe immune response and are responsible for manyof the admissions to a critical care unit. Cancertherapies include surgery, chemotherapy, radio-therapy and transplantation.

Surgery has profound immunomodulatory effectsand may promote infections and paradoxicallycancer. Various animal models have demonstratedthat surgery directly promotes metastasis. Parallelhuman studies are understandably non-existent andonly indirect evidence or anecdotal exists. Severalstudies have shown an early peak in death rate postmastectomy when compared to those managedexpectantly.10 Others have demonstrated increasedmetastatic growth after primary cancer excision.The mechanisms underlying these putative detri-mental effects are likely to be multifactorial.Surgical release of cancer cells into the circulation,stress response induced cell-mediated immunosup-pression, removal of primary tumour-induced an-giostatic effects and proinflammatory promotion ofcancer growth have all been implicated.

Chemotherapy and radiotherapy are broadlyimmunosuppressive. Cytotoxic agents can cause asignificant reduction in number and function ofimmune cells reducing the immune systems ability

to target cancer cells, fight infection and coordi-nate a normal inflammatory response. Preoperativechemotherapy has been shown to increase the SIRSresponse post oesophagectomy.11

Proponents of cancer immunotherapy have ar-gued that traditional chemotherapy is, therefore,self-defeating. However, some of these agents mayalso enhance the immunogenicity of cancer cells,trigger anti-tumour immunity and therefore im-prove immune-mediated cancer cell death.4

The immunology of bone marrow and stem celltransplantation is complex and beyond the scope ofthis commentary. Briefly, the use of transplanttechnology has allowed escalation of cytotoxicagents above the limits imposed by bone marrowsuppression. This allows enhanced tumour celldeath but at the cost of increased immunosuppres-sion and organ toxicity. The use of immunosuppres-sive drugs to reduce rejection further contributesto immune dysfunction. Among the interestingimmunological phenomena is graft-versus-hostdisease and the observation that donor cellsfrom allogeneic transplants may exhibit a graft-versus-tumour response.

Critical illness, cancer and the immunesystem

Cancer may alter immune responses during criticalillness and the inflammatory perturbations involvedin the onset and progression of critical illness mayaffect carcinogenesis. A generalised excessiveproinflammatory immune response, as seen in SIRS,may promote cancer growth. Indeed, a SIRSresponse was associated with a decreased 5-yearsurvival after lung cancer surgery.12 The oppositemay be true of CARS. In addition, critical careinterventions, such as drugs, inotropes, ventilationand filtration, may unwittingly alter cancer growthand spread. This may occur through direct action onhaematological or solid cancer cells, or indirectlythrough modification of the inflammatory response.

The following section provides a few examples ofhow the critical illness and critical care interven-tions may influence the immune system and cancer.

Cardiovascular system

Cells of the immune system express receptors andcontain enzymes influenced by many drugs usedin the treatment of critically ill patients. Theseinclude dopamine receptors, adrenoreceptors,phosphodiesterase (PDE) and angiotensin convertingenzyme (ACE). Dopamine has immunomodulatory

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properties. Its immune actions are mediateddirectly through D3, D4 and D5 dopamine receptorson lymphocytes and indirectly by inhibiting pituitaryprolactin production. T cell proliferation, proin-flammatory cytokine production and antibody re-sponse are attenuated.13,14 The production of anti-inflammatory cytokines is increased.13,14 This mayexplain increased mortality in septic shock treatedwith dopamine.15 Dopamine is also able to directlyinfluence malignant cell growth. It has antiangio-genic properties and seems to act by suppressingVEGF.16

Adrenaline causes an initial, transient increase inlymphocyte and NK cell numbers due to mobilisation.However, numbers and function are then suppressed.Most immune cells also express b adrenoreceptors.Lymphocyte and NK cell adrenoreceptors are b2subtype. b2 Adrenoreceptor stimulation suppressesNK cell function in vitro17 Animal models suggest thatstress-induced metastases can be increased by b1and b2 adrenoreceptor stimulation and decreased byb-blockade.18 In addition, human epidemiologicalstudies suggest a reduction in cancer risk withb-Blocker treatment.19,20 The effect may not onlybe due to direct immune cell receptor interactionsbut also to direct cancer cell interactions. b2Adrenoreceptors are expressed by various cancersincluding breast, colon and prostate.

Noradrenaline also suppresses NK cell function.Although, constitutive a1 or a2 expression onimmune cells is debatable, they appear to beupregulated in certain disease states, includingcancer. a Adrenoreceptor stimulation modulatesthe actions of various transcription factors, includ-ing NFkB and AP-1. Noradrenaline has beendemonstrated to inactivate NFkB in lymphocytes.21

Noradrenaline infusions induce metastases in ani-mal models but appear to have no effect on growthof the primary22 This effect is attenuated byb-blockade indicating the action may be mediatedthrough b adrenoreceptors.

Clonidine may also influence inflammation, andtherefore modulate cancer, by attenuating catecho-lamine release. It may have direct effects on cancerprogression. A2 adrenoreceptors have been demon-strated on breast cell lines and their activation wasassociated with increased cell proliferation.23

PDE inhibitors, such as milrinone and sildenafil,inhibit PDE in both immune cells and cancer cells.They cause inhibition of proinflammatory cytokinerelease and have antiproliferative and proapoptoticproperties. There is increasing evidence thatspecific PDE inhibitors may be useful in thetreatment of haematological malignancies.24,25

ACE is present in lymphocytes and NK cells. ACEinhibitors have been demonstrated to induce

apoptosis in T lymphocytes.26 ACE receptors arealso expressed in cancer cells and may be involvedin growth and angiogenesis.27

The immunomodulatory effects of statins havebeen the subject of several recent reviews.28

Oncologists are also attempting utilise their anti-proliferative and antiangiogenic properties as anadjunct to chemotherapy.29

Respiratory system

Hypoxia is immunosuppressive and may promotegrowth, invasion and metastasis of cancer cells. TCell and NK cell cytotoxicity is reduced underhypoxic conditions.30 Hypoxia can influence cellsurvival via the expression of the transcriptionfactor Hypoxia Inducible Factor (HIF). Its expres-sion is upregulated under hypoxic conditions and isresponsible for regulating multiple genes includingthose involve in angiogenesis, cell proliferation andcell survival.2 Von Hippel-Lindau (VHL) tumoursuppressor protein targets HIF and is responsiblefor its degradation in the presence of oxygen.Mutations in the VHL gene have been implicated inthe development of various cancers including clearcell renal cancer. VHL and HIF have also beenimplicated in cancer cells acquiring metastaticpotential. HIF increases expression of chemokinereceptors on cancer cells. Chemokine receptor–li-gand interactions are thought to be one of themechanisms by which cancer cells home to distantsites.31

Attempts to correct hypoxia by ventilation mayalso alter immune function. The potential forventilation to cause lung injury is well recognised.It not only causes mechanical injury, but alsoinitiates an inflammatory response within the lung.This response varies with mode of ventilation.However, the effects are not restricted to the lung.Increases in proinflammatory cytokines are detect-able in the peripheral circulation. Suppression ofperipheral immune cells, including NK cells, hasalso been demonstrated. It has been suggested thatthese peripheral effects may contribute to theonset of multiorgan failure in ventilated pa-tients.32,33 A lung protective ventilatory and fluidstrategy for oesophagectomy patients has beenshown to reduce the proinflammatory response.34

The effect of such strategies on cancer outcome isnot known.

Gastrointestinal system and metabolism

The gastrointestinal tract contains an extensiveimmune system. Amplification of this vital immune

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component may result from disruption of themucosal barrier, with possible translocation ofbacteria and toxins, or through modulation byintraluminal contents, including food and bacteria.The resultant effects on systemic inflammation maycontribute to the pathogenesis of critical illness,multiorgan failure and could in theory influencecancer growth and spread.

Cancer patients frequently suffer from a dis-rupted mucosal barrier. Mucositis is triggered bychemotherapy and radiotherapy. Traditionally itwas thought to be due to damage to epithelialcells. However, it has become apparent that thatthe process is significantly more complex andinvolves activation of proinflammatory and apopto-tic pathways within endothelial and epithelialcells. Again, NFkB activation may be a key player.High levels of proinflammatory cytokines and tissueNFkB are present in patients with mucositis.35

Both critically ill and cancer patients arefrequently nutritionally deplete. Poorly nourishedindividuals suffer from immune dysfunction. Nutri-tional management may therefore have profoundeffects on immune function. Nutrition in criticalcare patients is becoming more than just caloricsupport. The ability of specific nutritional compo-nents to modulate systemic immune function hasbeen termed immunonutrition. Glutamine, argi-nine, Omega 3 oils, antioxidants, selenium andprobiotics have been used with variable effects.Several, including glutamine and fish oils, havedemonstrated that immunonutrition may be able toattenuate inflammation, including NFkB activation,improve organ function and reduce mortality.36,37

Utilising similar mechanisms to prevent initiationand progression of cancer is under investigation.38

Omega 3 oils have been shown to reduce proin-flammatory cytokine production and tumour load intumour bearing rats.39

Disordered metabolism is also common in cancerand critical illness. Derangements include insulinresistance, hyperinsulinaemia, high insulin-likegrowth factor 1 (IGF-1) and hyperglycaemia. Thesehave all been implicated in modulating bothinflammatory responses and carcinogenesis.40 Glu-cose control seems to play an important role inmaintaining immunocompetence. Diabetics andcritically ill patients with poor glucose control havean increased susceptibility to infection. Diabeticsmay also be at increased risk of developing cancerand have a worse prognosis once diagnosed.41

Hyperglycaemia is known to promote pathologicalcellular proliferation by promoting free radicalproduction and impairing DNA repair. It may alsosuppress anti-tumour immunity. Insulin has anti-inflammatory properties and acts at a growth factor

and promotes the production and mitogenicactivity of other insulin-like growth factors.42

Interestingly, remission of tumours is anecdotallydemonstrated during long-term insulin-inducedcoma for treatment of psychosis.41

Drugs used to manipulate the gastrointestinalsystem have immunomodulatory and tumour-mod-ulating effects. Metoclopramide, for instance,protects haemorrhaging mice from immunosuppres-sion. Its effects may be due to antagonism ofimmune cell dopamine receptors or increasedprolactin secretion from the pituitary gland.43,44

Prolactin, also produced in extrapituitary tissues,has immunostimulatory properties, protects againststress-induced immune alterations and promotesanti-tumour immunity. It is also able to influencecell growth, proliferation, apoptosis and survi-val.45,46 Other antiemetics, particularly serotoninreceptor antagonists, are able to influence immunefunction. Lymphoid tissues are innervated byserotinergic nerves and serotonin receptors arepresent on immune cells. Serotonin is able toinfluence immune cell apoptosis and disorders ofserotonin uptake are thought to be important in thepathogenesis of malignancies such as BurkittsLymphoma and Myeloma.13 Histamine receptorsare also present throughout the immune system.H2-antagonists have been shown to preserve cell-mediated immunity in post-surgical and traumapatients.47,48

Renal system and fluids

The relationship between the immune system andthe kidney is complex. Increased proinflammatoryand anti-inflammatory cytokines are seen in acuterenal failure (ARF). This may be related todecreased renal clearance of cytokines or adisordered inflammatory response secondary toretention of organic and inorganic compounds.49

Acidosis and uraemia interfere with normal immunecell and endothelial cell function. ARF increasessusceptibility to infection and increases cytokinedysregulation that may further contribute tocritical illness and MODS. Infection is the cause ofdeath in up to 40% of those critically ill patientswith ARF.50,51

Renal replacement therapy (RRT) also causesimmune perturbations.52 This may be due toinappropriate activation of immune componentsin an extracorporeal circuit or the removal ofinflammatory mediators. However, removal ofinflammatory mediators is limited by rapid filtersaturation and does not offer a survival benefit in

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sepsis unless high volume exchanges or adsorptionfilters are used.53

So what about cancer? Firstly, cancer risk isincreased in patients with end stage renal failure.54

Some of the excess incidence may be attributableto immune dysfunction or impaired DNA repair.Although the effect of ARF and RRT in cancerpatients is unknown, it may be hypothesisedto influence cancer growth. In an animal model,NK activity was increased by adsorption basedfiltration and survival in tumour bearing ratsimproved.55,56 Removal of tumour secreted immu-nosuppressive and growth factors may also occurduring RRT. Anticoagulation, necessary for RRT, hasalso been implicated as causing immune dysfunc-tion and influencing cancer spread. Heparin bindsto various cytokines, including IFNg, therebyprolonging their half-life.57 In animal modelsheparin demonstrates an ability to reduce metas-tases. This effect is possibly due to inhibition ofadhesion molecules.58,59

The choice of fluid may also influence immunefunction. The most obvious example is blood withwell-documented effects on cancer. A CochraneMeta analysis in 2006 supported the hypothesis thatblood transfusions have a detrimental effect oncolorectal cancer recurrence.60 Blood transfusionhas been shown to suppress several components ofthe immune system, including NK cell activity.61

This is clinically demonstrated by the observationof increased renal transplant survival after transfu-sion. Animal models have shown an increasedmetastatic rate after transfusion. Multiple humanstudies have found transfusion to be an indepen-dent negative prognostic indicator. A recent pro-spective observational study of colorectal cancersurgery suggested that blood transfusions mayworsen prognosis.62

Central nervous system

The commonly used sedatives, analgesic andanaesthetic agents and anxiolytics have profoundimmunomodulatory properties.

Probably the most notorious anaesthetic agent isEtomidate. Infusions, used in the 1980s, were foundto increase mortality secondary to suppressed adre-nocortical synthesis of cortisol. Cortisol is probablynecessary to limit a proinflammatory response.

Thiopentone, Ketamine, Propofol and volatileagents have been shown to suppress a wide range ofimmune components. These include neutrophils,lymphocytes and macrophages.63,64 Propofol ap-pears to be the least immunosuppressive. Theyhave all been demonstrated to significantly sup-

press NK cell activity with a corresponding increasein metastasis in animal models.65–67 Mechanismsare unclear. Their respective carriers have beenblamed. However, Thiopentone has been shown toinhibit NFkB in vitro.68 In addition, Ketamine’sactions may be due to direct interaction withimmune cells with a1 and b2 adrenoreceptors orindirectly through stimulating sympathetic activity.Ketamine induced tumour retention was shown tobe significantly reduced by b-blockade. Finally,volatiles, with the exception of Desflurane, havebeen reported to induce apoptosis in T lymphocytesin vitro.69 The mechanisms remain elusive butinhibition of IL-2 receptor expression and thetranscription factor AP-1 have been suggested.70

Clinically relevant infusions of Propofol or Mid-azolam may have almost opposite effects. Propofolcauses a significant increase in proinflammatorycytokines after a 48-h infusion in critically illpatients. Midazolam caused a reduction. This wouldsuggest that Midazolam has greater anti-inflamma-tory properties that may be useful in excessiveinflammatory conditions such as SIRS.71 However,such immunosuppressive qualities may predispose toinfection and influence cancer growth and spread.

Analgesic drugs that modify pain also influenceinflammation. Opioids are the most commonly useanalgesic drugs in critical care.72 Their immuno-suppressive properties have been recognised sinceopium became popular as a substance of abuse.Exogenous administration results in decreasedhumoral and cell-mediated responses, NK cellactivity, cytokine production and phagocytosis.Their action is mediated through opiate receptorsin the CNS and on immune cells. Despite theirimmunosuppressive properties, their exact effectson immune function during critical illness or in thepostoperative setting are not known. Their effecton tumour promotion and progression is alsocomplex. Some may contribute to progression,while others, including methadone and morphine,may result in apoptosis of tumour cells. This may bedue to differential opioid receptor stimulation orthrough non-opioid mechanisms. For example,Methadone inhibits the activity of the bcl-2oncogene, possibly via stimulation of the somatos-tatin receptor. This receptor is known to beimportant in the initiation of lung cancer.

Epidurals are reputed to have beneficial effectsin attenuating stress-induced immunosuppres-sion.73 When used in addition to a generalanaesthetic for hip replacements epidurals wereshown to alleviate monocyte and lymphocytedysfunction seen with a general anaesthetic alone.The addition of a spinal blockade, in animalstudies, appears to reduce metastasis after surgery.

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In human studies, NK cell activity was improved byepidural use but the effect on outcome aftercancer surgery has not been studied.74 The onlyhuman study that actually demonstrates a possiblelink between outcome from cancer surgery andnerve blockade was performed by Exadactyloset al. It is a retrospective analysis of breast cancerpatients undergoing a mastectomy under generalanaesthetic with and without paravertebral blocks.Those without paravertebral blocks had a signifi-cantly increased recurrence rate.75

Infection and sepsis

Interestingly, various drugs used in the treatment ofsepsis may directly affect immune function andcancer growth.

For instance, macrolides appear to have anti-metastatic and antiangiogenic effects. Lung cancerpatients demonstrated a survival advantage aftertreatment with clarithromycin.76

Steroids remain controversial in critical care.While they may be advantageous in suppressing thedetrimental effects of an excessive proinflamma-tory response, they also suppress natural immunityand predispose to subsequent infections.77 Suchimmunomodulatory properties may also influencecancer growth. Glucocorticoids directly influencecell survival by modifying apoptotic pathways.Glucocorticoids promote apoptosis in haematologi-cal cancer cells but may increase survival andchemotherapy resistance in solid cancer cells. Themechanisms of action are diverse but includesregulation of NFkB.78

Antipyretics, such as paracetamol, also haveimmunomodulatory effects. Fever has persistentlybeen demonstrated to be beneficial in the hostresponse to infection. Despite this, antipyretics areroutinely used. Endogenous pyrogens, including IL-1and PGE2, may trigger anti-inflammatory processesand be necessary for limiting the inflammatoryresponse. Pyrexia has also been shown to have anumber of beneficial immune effects.79 A trendtowards increased mortality in critically ill patientstreated with aggressive antipyretic therapy hasbeen demonstrated.80 In the same study, there wasa paradoxical increase in SIRS score in theaggressively treated group. Fever-induced changesin the inflammatory response are likely to influencecancer growth. There is certainly anecdotal evi-dence to support this theory. Coley insisted thatinduction of fever was necessary for his tumourvaccines to be effective. Conversely, hypothermiacompromises resistance to metastases in animalmodels.81

Conclusion

Critical illness and its treatment may paradoxicallyexacerbate cancer growth and metastasis. Sup-pressed immunosurveillance and enhanced inflam-matory mediator-induced, or drug-induced, cancercell survival, proliferation, invasion and metastasisare putative mechanisms. The challenge is toinvestigate whether this theory translates intoreality. Advancements in our understanding of theimmune system, critical illness and cancer willhopefully unravel these mysteries and allow us tomodify critical care of cancer patients to improvesurvival.

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