The side effects of chemotherapeutic agents

The side effects of chemotherapeutic agents

ARTICLE IN PRESS Current Anaesthesia & Critical Care (2008) 19, 70–79 www.elsevier.com/locate/cacc FOCUS ON: ONCOLOGY The side effects of chemother...

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ARTICLE IN PRESS Current Anaesthesia & Critical Care (2008) 19, 70–79

www.elsevier.com/locate/cacc

FOCUS ON: ONCOLOGY

The side effects of chemotherapeutic agents Craig Carr, Julia Ng, Tim Wigmore Department of Anaesthesia, SpR Imperial School of Anaesthesia, The Royal Marsden NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK

KEYWORDS Cancer chemotherapy; Complications cancer

Summary It is becoming increasingly common for patients who have had or who are receiving chemotherapy to present for anaesthesia or for potential admission to the intensive care unit. To effectively manage these patients care, it is important to be aware of both the short- and long-term side effects of chemotherapeutic agents, and to understand the physiological changes that may occur during the course of their treatment. Complications such as nausea and vomiting and diarrhoea are well recognised and may cause metabolic disturbances that are relevant to anaesthesia and critical care. However, many treatments have side effects which are more organ specific and severity may not necessarily be dose related. These include cardiomyopathies and irreversible lung fibrosis. Over 200 chemotherapeutic agents are available, and there has recently been a proliferation of agents such as the monoclonal antibodies (e.g. Herceptin) whose side-effect profile, though potentially of great relevance, is not widely known. & 2008 Elsevier Ltd. All rights reserved.

Introduction Most anaesthetists and intensivists encounter patients receiving anti-cancer chemotherapies on a regular basis. Whether for vascular access surgery, surgical management of a tumour, treatment of a pathological fracture or management of the complications of surgery, chemotherapy or radiation, the patient receiving chemotherapy is an increasingly common sight in our everyday lives. Corresponding author.

E-mail address: [email protected] (T. Wigmore).

To optimise patient safety, we require an awareness of the risks of anaesthesia in terms of potential longterm harm to patients who have received chemotherapy and an awareness of the risk presented by the chemotherapy to the patient’s physiological health. With over 200 chemotherapeutic agents in use and a plethora of reported adverse reactions to each, entire textbooks could be written to describe the nature of drug activity and side effects. The purpose of this article is merely to provide an outline, increasing the awareness of the reader of commonly encountered side effects of chemotherapeutic agents and advances in their treatment where applicable.

0953-7112/$ - see front matter & 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.cacc.2008.01.004

ARTICLE IN PRESS The side effects of chemotherapeutic agents

Classification of chemotherapeutic agents (see Table 1) The major classes of chemotherapeutic agents are outlined below. Their mechanisms of actions and the popular agents of each class with their commonly associated systemic side effects are listed in Table 1. For a fuller discussion of the mechanisms of actions, readers are directed to the references at the end of this overview.

       

Cytotoxic drugs anti-metabolites alkylating agents and related compounds plant derivatives cytotoxic antibiotics Hormones agonists antagonists Other agents biological agents monoclonal antibodies

System perturbations induced by chemotherapy Cardiovascular Cardiovascular complications of chemotherapy are uncommon but potentially life threatening and for agents such as anthracyclines are dose limiting. In addition to direct cardiotoxicity per se, chemotherapy may induce a metabolic stress upon the heart via systemic effects, which demand an increase in cardiac output. In the failing or ischaemic heart, this may in itself prove fatal. The direct cardiotoxic effects include myocyte death and fibrosis with resultant cardiomyopathy and heart failure, induction of arrhythmias and coronary ischaemia via vasospasm, thrombosis or vascular endothelial inflammation.1 The risk of cardiotoxicity with all agents is higher in the presence of pre-existing coronary disease, where combinations of cardiotoxic drugs are used and where there is previous or concomitant radiation therapy (especially radiotherapy for left-sided breast carcinoma). The commonest cytotoxic agents to cause cardiac damage are anthracyclines. 5-Fluorouracil, cyclophosphamide2 and taxanes are also wellrecognised causes of cardiac impairment. As anthracyclines are commonly used in combination with these other agents in the treatment of breast cancer, great care has to be taken to monitor cardiac function and to limit the total dose

71 exposure to each agent. Additionally, a small proportion of women with Her-2 receptor positive disease will also receive Herceptin (trastuzumab) and this has additional cardiotoxic effects of its own. Anthracyclines can cause immediate, early (within 1–6 months) and late (after 6 months but often after several years) cardiotoxicity. While immediate cardiotoxicity is almost always transient and associated with tachycardia and a mild reduction in stroke volume, early and late toxicity are irreversible and result from cell death and (usually dilated) cardiomyopathy.3 Despite aggressive medical therapy for heart failure, mortality still remains above 30% at 1 year following the development of anthracycline-induced symptomatic cardiac failure. Given the incidence of late toxicity, anthracyclines should be used in strictly doselimited fashions in potentially curative chemotherapy regimes to reduce the risk of later death secondary to heart failure. Herceptin appears to have a direct cardiotoxic effect resulting in reduced systolic function in around 5% of patients.4 This is not solely attributable to its role in blocking cardiac Her-2 receptors as blockade of the Her-2 pathway by other molecules does not result in similar cardiotoxicity.5 This risk is markedly increased (around fivefold) in patients co-treated with anthracyclines and taxanes possibly as a result of increased myocardial Her-2 receptor expression induced by these classes of chemotherapy. Most patients respond well to treatment with standard medical therapies for cardiac failure and withdrawal of the agent but some develop irreversible, cardiac impairment. Taxanes and 5-fluorouracil less commonly cause cardiomyopathy, but more often arrhythmias and ischaemic symptoms secondary to vasospasm or thrombosis.6,7 These occur in around 5% of patients receiving these agents. Arrhythmias and ischaemic problems are also more commonly seen in association with platinum-based drugs and biological agents such as interferon.

Respiratory While it is not uncommon for patients to develop respiratory infections secondary to immunosuppression while on chemotherapy, clinically apparent direct lung injury secondary to chemotherapy is fortunately rare compared with side effects such as myelosuppression or renal impairment. Whenever a patient with recoverable malignant disease is receiving chemotherapy and develops respiratory failure, full support and investigations including

ARTICLE IN PRESS 72

C. Carr et al. Table 1 Drug group

Mode of action

Characteristic toxicities

Platinum analogues e.g. carboplatin, cisplatin Taxanes e.g. docetaxel, paclitaxel Topoismerase inhibitors e.g. irinotecan, topotecan

Selective inhibition of tumour DNA synthesis Inhibits mitosis Inhibits DNA replication

Myelosuppression, nephro/oto/ neurotoxicity Conduction defects, peripheral neuropathy, hypersensitivity Acute cholinergic syndrome

Immunomodulators Antiproliferatives Azathioprine Mycophenolate

Immunosuppressant Immunosuppressant

Myelosuppression Myelosuppression

Immunosuppressors Cyclosporine

Calcineurin inhibitor

Nephrotoxic, hypertension, PRES, gum hyperplasia Nephrotoxic, hypertension, PRES Teratogenic, peripheral neuropathy

Tacrolimus Thalidomide Monoclonal antibodies Bevacizumab Cetuximab Rituximab Trastuzumab (Herceptins) Alemtuzumab (Campath) Hormones Oestrogens Progestogens Hormone antagonists Anastrozole Tamoxifen Gonadorelin analogues Buserelin

Calcineurin inhibitor Angiogenesis inhibitor, inhibiting cell growth Inhibits VEGF, inhibiting cell growth Binds To EGFR, inhibits cell division Causes lysis of B cell lymphocytes Binds HER2 receptor, inhibits cell division Causes lysis of mature lymphocytes

Mucocutaneous bleeding, GI perforation Hypersensitivity Cytokine release syndrome Cardiotoxicity, hypersensitivity

Direct cytotoxic effect on tumour cells Or suppress other hormone production

Venous and arterial thromboses

Aromatase Inhibitor Oetrogen receptor antagonist

Post-menopausal symptoms Thrombosis, endometrial Ca, strokes

Mild (nausea, fluid retention)

Similar SE to menopause in women and orchidectomy in men Down regulate pituitary stimulation of Male and female gonads

Goserelin (Zoladexs) Antiandrogens Cyproterone Miscellaneous antineoplastics Asparaginase Procarbazine

Inhibit tumour ‘‘Flare’’

Hepatotoxicity

Breaks down asparagine to aspartic acid and ammonia Causes free radical formation

Anaphylaxis Myelosuppression, hypersensitivity rash

 Posterior reversible encephalopathy syndrome.

broncho-alveolar lavage, testing for pneumocystis jerovecii, fungi, yeasts, viral infections and tuberculosis in addition to exclusion of pulmonary thromboemboli should be initiated.

(i) General pulmonary complications of chemotherapy include pneumonitis, bronchospasm, pleurisy and thrombocytopenic thrombotic purpura with pulmonary involvement. Pneumonitis may be

ARTICLE IN PRESS The side effects of chemotherapeutic agents acute or chronic. It can lead to long-term respiratory failure and is recognised secondary to cytotoxic therapies with several agents including gemcitibine, mitomycin C, busulfan, methotrexate, cyclophosphamide, bleomycin, taxanes and nitrosureas as well as others.8 Chronic low-grade pneumonitis with secondary fibrosis and eventual death may take several years to become apparent following completion of chemotherapy and is more common in patients who have received chest radiotherapy as well as chemotherapy and in those who have received supplemental oxygen therapy at the same time or in the months following their chemotherapy.9 (ii) Bleomycin-induced lung injury mainly describes a condition of acute then chronic fibrosing alveolitis although an acute hypersensitivity pneumonitis may also develop.10 The frequency of clinically apparent lung injury is around 10% following bleomycin exposure. However, latent damage detected on performance of pulmonary function tests may occur in up to 50% of patients. The incidence is higher in patients with renal impairment and in those who have previously been exposed to radiation therapy. The acute fibrosis is believed secondary to the production of free radicals of oxygen in the alveolar interstitial tissues by bleomycin owing to a lack of the enzyme bleomycin hydrolase in lung tissue; this enzyme is present in most other tissues of the body and degrades bleomycin preventing its accumulation elsewhere. In the presence of oxygen, free radical formation is believed to be more rapid and once an inflammatory cascade is established in the injured tissue, the process is self-perpetuating even when oxygen therapy is reduced. Management of bleomycin-induced lung injury is by discontinuation of the drug and administration of corticosteroids although the latter has no proven efficacy. Patients requiring ventilation in treatment of bleomycininduced fibrosing alveolitis have a mortality close to 100%.

Gastrointestinal The gastrointestinal side effects of chemotherapy include (i) (ii) (iii) (iv) (v) (vi) (vii)

mucositis, xerostomia, nausea and vomiting, diarrhoea, constipation, colitis (neutropenic, infective or ischaemic) and perforation of the bowel.

73 (i) Oro-pharyngeal mucositis may follow radiotherapy, chemotherapy or haemopoetic stem cell transplant and effects approximately 30–50% of these patient populations.11 Chemotherapy induced damage to the mucous membranes of the body occurs because of the relatively high turnover of cells in these tissues compared with others and results in local inflammation, cellular apoptosis and ulceration of the membrane with loss of barrier function and opportunistic secondary infection especially with candida and herpes simplex virus. Bacteraemia is also common and may lead to secondary infection of indwelling venous access lines for chemotherapy. Patients with poor dental hygiene or caries and gum disease pre-chemotherapy should be referred to dental hygienist and dental surgeon for urgent care at least 10 days before chemotherapy commences to diminish their increased risk of infective complications both locally and systematically.12 The mouth is often the source of sepsis in febrile neutropenic episodes. Prophylactic treatment with nystatin topically or fluconazole systemically reduces the incidence of secondary fungal infection and should be given routinely to all patients at risk. Similarly, all HSV seropositive patients at high risk of developing mucositis should receive prophylactic acyclovir. In patients with grade 3 or higher mucositis, investigations to exclude HSV infection are advisable as the characteristic blistering lesions are often not apparent in the ulcerated, desquamated field. Wherever doubt exists, treatment with acyclovir can be initiated until the results of viral swabs are available. Mucositis is graded on a five-point scale13 and higher scores should influence decisions to alter chemotherapeutic agents or reduce or withhold doses. Certain drugs (5-fluorouracil, methotrexate, etoposide, doxorubicin and cytarabine) characteristically cause mucositis more frequently than others. Methotrexate and etoposide are secreted actively into saliva and anti-cholinergic drugs, which reduce salivary production, may reduce drug-associated mucositis. The use of ice packs in the mouth for 30 min during 5-fluorouracil infusion induces local vasoconstriction and reduces the incidence of mucositis probably by reducing tissue exposure to the agent in the locality of the mouth. Various other treatments and prophylactics including glutamine, laser therapy, keratinocyte stimulating growth factor, palifermin and granulocyte stimulating growth factor also appear to have beneficial roles and are being assessed in on-going clinical trials.14 Topical analgesics such as lignocaine mouthwash and systemic analgesics such as oromorph are used to control pain. Barrier gels may

ARTICLE IN PRESS 74 be used to try and reduce trauma to the mucous membranes during eating and drinking but often parenteral nutrition or tube feeding may be required. (ii) Xerostomia (dry mouth) is usually associated with radiotherapy damage to salivary glands, but can result from anti-cholinergic treatments given alongside chemotherapy to control nausea or diarrhoea. Unlike radiation-induced xerostomia, that seen secondary to chemotherapy is usually self-limiting and reverses on cessation of the agent responsible. Treatment is symptomatic with regular mouthwashes. (iii) Nausea and vomiting remain among the most distressing and debilitating of chemotherapyassociated side effects. They occur acutely in the first 24 h after drug administration, or have onset after this time when they are called delayed symptoms. Nausea and vomiting can be triggered by activation of the chemoreceptor trigger zone or via afferent inputs to the vomiting centre of the brain in the nucleus tractus solitarius, which receives inputs from the GI tract via the vagus nerve. Additionally, patients can learn to anticipate nausea with chemotherapy and actually feel the symptoms before the agent has been administered. Anti-emetic guidelines15 are published by the American Association of Clinical Oncology, which stratify different chemotherapeutic agents into risk groups for causing nausea and vomiting. The risk can be modified by altered route or rate of prescribing and also by the use of prophylactic anti-emetic agents. Steroids, 5HT3 receptor antagonists, anti-histamines, anti-cholinerigcs, dopamine antagonists and more recently, the neurokinin-1 receptor antagonist Aprepitant, are all used to prevent and treat nausea and vomiting. (iv) Diarrhoea is a common finding with many different forms of chemotherapy, but especially anti-metabolites such as fluorouracil and methotrexate and the ‘‘alkylating agent’’ cisplatin. In many instances, this can be a treatment limiting or life-threatening side effect with dehydration, shock, renal impairment and electrolyte disturbances all commonly seen as a consequence. Clinical scales such as the five-point (0–4) National Cancer Institute Criteria for Chemotherapy-Induced Diarrhoea16 exist but are retrospective in their descriptors e.g. point 3 is reached if there is a need for parenteral fluids and point 4 the need for critical care admission. Thus, these scales do not predict the need for critical care but describe that point when it is reached. However, the scales are useful for guiding chemotherapy modifications. For example, if a patient reaches point 2 (46 stools per day or diarrhoea of between 10 and 15 ml/kg

C. Carr et al. day, the next dose of the responsible chemotherapy agent may be withheld or reduced. This has led to a reduction in deaths associated with certain diarrhoea-inducing chemotherapy regimens. As well as the agents causing diarrhoea directly, destruction of the mucosa can lead to secondary pathologies such as lactose intolerance. Careful dietary modification under the supervision of a dietitian with an interest in cancer chemotherapy may help alleviate the symptoms as well as reducing the likelihood of developing severe dehydration or profound malnutrition. Consideration of other causes such as radiation damage, short-bowel syndrome (post-bowel resection) infective diarrhoea and food/alcohol/caffeine intolerances should always be made to avoid missing important alternative or co-existent diagnoses of the cause. Management of diarrhoea includes adequate rehydration and electrolyte replacement (orally wherever possible) and once infective causes have been ruled out the use of high-dose loperamide, 4 mg starting dose then 2 mg after every bowel motion up to 2-hourly, is indicated. If this fails, consideration of octreotide 100 mg s.c. three times daily increasing if required to 2500 mcg three times daily is indicated. In the future use of epithelial growth factors may develop as these are showing some benefits in animal studies. (v) Constipation usually results from the use of opioid analgesics, anti-emetics of the 5-HT3 family and as a direct hypo-motility effect of thalidomide or vinca alkaloids on the gut. The vinca alkaloids may also cause a (usually) temporary neuropathic ileus. However, more sinister pathologies such as paralytic ileus or pseudo-obstruction of the bowel can develop and need to be excluded by thorough clinical examination and appropriate investigations. Constipation usually responds to simple aperients while ileus tends to require cessation of the offending chemotherapeutic agent and any anti-spasmodics prescribed for colicky pain. Neostigime may have a role in the management of ileus which does not follow recent bowel resection and is sufficiently severe to have warranted critical care admission. (vi) Colitis can result from a variety of infective and drug-induced mechanisms. Both the chemotherapeutic drugs and the medicines administered to provide symptom relief can result in gastrointestinal toxicity.17 Neutropenic colitis may affect the large or small bowel but almost always involves the caecum.18 It is commoner in patients receiving treatment for haematological malignancies and bone marrow or stem cell transplant recipients although it is seen

ARTICLE IN PRESS The side effects of chemotherapeutic agents during treatment of solid tumours too. It is believed that a combination of chemotherapy-induced mucosal injury and immunosuppression allows local microbial invasion and damage in the bowel wall. This may lead to infarction, necrosis, haemorrhage, perforation or a localised colitis. The damage may be confined to the inner mucosa or may spread through all layers of the bowel wall. The management is individualised to the patient and tends to start with conservative therapy with rest of the gastrointestinal tract, broad-spectrum antibiotic and anti-fungal cover and support of the bone marrow with GCSF. Where there is an evidence of peritonitis or ongoing GI bleeding, extensive bowel resection is often required. Infective colitis: CMV colitis may occur in patients receiving immunosuppressive chemotherapy and particularly is found in patients following allogeneic stem cell or bone marrow transplant with on-going immunosuppressive therapy. Over 90% of infections affect the large bowel and less than 10% the small bowel. However, all levels of the GI tract may be affected from mouth to anus.19 Haemorrhage, mucosal ulceration and perforation are all associated. Diagnosis is difficult and ideally is by biopsy and visualisation of CMV inclusion bodies. Treatment is with gangciclovir or foscarnet. IVIg may have a role too. Clostridium difficile colitis can occur either as a result of antibiotic use in patients with other infective complications following chemotherapy or may occur de novo in antibiotic naı¨ve patients following the use of chemotherapy only. Paclitaxel has been implicated as having a higher risk of this complication than other agents. (vi) Perforation of the bowel: In addition to bowel perforation associated with colitis, the chemotherapeutic human recombinant monoclonal antibody Bevacizumab (Avastin) that binds to vascular endothelial growth factor has been associated with bowel perforation de novo. Management generally requires surgical repair although successful conservative management has been described.20 Tyrosine kinase inhibitors used in the treatment of gastrointestinal stromal tumours may also cause perforation of the bowel but unlike Bevacizumab, the perforation usually occurs at the site of necrosing tumour in the bowel wall.

Hepatic (i) Hepatic impairment resulting from systemic chemotherapy is uncommon but unpredictable and idiosyncratic in the majority of cases. Dysfunction secondary to haemopoetic stem cell transplanta-

75 tion is commoner but not always attributable to the chemotherapeutic regimen.21 Damage may be reversible or irreversible and in some instances progresses even on withdrawal of the offending agent. Manifestations vary from mild derangements of biochemical markers of hepatocellular function through cholestasis and jaundice to acute hepatic failure. Reactivation of pre-existing viral hepatitis, de-novo infection with EBV or CMV, and exclusion of other agents or tumour involvement of the liver needs to be undertaken before attributing liver impairment to the chemotherapeutic agent. Care must be taken to consider the dosing regime of chemotherapy in patients with known hepatic impairment as the metabolism and pharmacokinetics of these agents may be altered and systemic toxicity result e.g. doxorubicin is largely eliminated in the bile and cholestasis results in elevation of plasma concentrations. In general, if a significant and sustained alteration of liver function is noted following the introduction of a chemotherapeutic agent and it reverses on withdrawal of the agent, the agent should be substituted by another for the next cycle of chemotherapy. (ii) Hepatic veno-occlusive disease describes a specific condition of progressive obliteration of the hepatic sinusoids and terminal hepatic venules following endothelial injury, intraluminal thrombosis and then fibrosis. In its severe form, it is almost always fatal. Presentation is with ascites, weight gain, jaundice, right-sided abdominal pain and hepatomegaly. Conjugated bilirubin rises and the plasma amino transferases are also elevated. In severe cases, fulminant liver failure with associated renal failure and encephalopathy develop. It usually develops in the first 4 weeks following bone marrow or stem cell transplantation in 30–50% of recipients. However, it is occasionally seen after the administration of chemotherapy or high-dose radiotherapy to the liver too. Risk factors for HVOD include pre-existing liver disease, certain genetic phenotypes, the use of vancomycin or acyclovir during pre-transplant conditioning, radiotherapy to the liver, less wellmatched allografts (it can occur with autografts too) and female sex. Associations between the use of certain drugs (especially alkaloids) in pretransplant conditioning and subsequent HVOD have also been described, but the list is extensive and beyond the scope of this article. Management of HVOD has been transformed in recent years by the introduction of defibrotide,22 a polydeoxyribonucleotide with anti-thrombotic and fibrinolytic activity. With defibrotide in severe HVOD mortalities of 30–70% as opposed to 90–100% have been found. Treatments with heparin, anti-thrombin

ARTICLE IN PRESS 76 III, prostaglandin E1, prostacyclin, human recombinant tissue plasminogen activator and glutathione have also been described with varying degrees of success. Prophylaxis using ursodeoxycholic acid, heparin or defibrotide have all been demonstrated to dramatically reduce the incidence of HVOD posthaemopoetic stem cell transplant and is now standard practice in most centres.

Renal impairment secondary to chemotherapy Many chemotherapeutic agents or their active metabolites undergo renal elimination and chemotherapyassociated diseases of glomeruli, tubules, renal interstitium and renal micro-vasculature are recognised. Effects of chemotherapy can also manifest in the bladder with haemorrhagic cystitis, a common side effect with alkylating agents. Additionally, patients also frequently receive other nephrotoxic drugs concomitantly such as aminoglycoside antibiotics, vancomycin, foscarnet, amphotericin, NSAIDs and these may further damage the kidney. Dehydration due to poor oral intake (stomatitis) or vomiting and diarrhoea can predispose to acute tubular necrosis and the use of contrast for CT scanning and MRI in tumour staging and assessments also can leads to diminution of renal function. As changing renal function will alter the elimination of many agents and their potential for systemic toxicity, regular assessment of renal function should be undertaken during the planned chemotherapy administration period— this can be done measuring plasma urea and electrolytes as well as urinary creatinine clearance and electrolytes. Electrolyte disturbances may be mild or severe, acute or chronic. Transient hypokalaemia secondary to tubular impairment is a feature of many cytotoxic chemotherapies whereas permanent hypomagnesaemia is often seen following cisplatin chemotherapy which results in on-going tubular loss of magnesium.23 Occasionally, electrolyte disturbances are severe, acute and life threatening. This is the case with cyclophosphamide-induced hyponatraemia, which in combination with hyperhydration therapy (e.g. to reduce the risk of haemorrhagic cystitis) can lead to cerebral oedema and death. It is believed that cyclophosphamideinduced vasopressin release from the pituitary causes acute water retention24; a profound drop in plasma osmolality often follows. As different members or the same class of drugs affect the kidney differently, it may be necessary to alter the chemotherapy regime altogether with

C. Carr et al. time. The platinum-based agent cisplatin is highly nephrotoxic causing direct tubular damage, interstitial damage and results in renal tubular acidosis, acute tubular necrosis and chronic renal impairment. By contrast carboplatin is less nephrotoxic causing a (usually) reversible tubular injury and oxaliplatin is less nephrotoxic still being safe to use in patients even when moderate renal impairment antecedes chemotherapy. Haemolytic uraemic syndrome—thrombotic thrombocytopenic purpura describes a spectrum of conditions which are characterised by thrombocytopenia, micro-angiopathic haemolytic anaemia, fever, neurological and renal abnormalities.25 The underlying pathology in the kidney is of endothelial damage and thrombus formation in the glomeruli with subsequent renal impairment. Chemotherapy is a relatively infrequent cause of HUSTTP but the condition is a well-recognised complication of mitomycin C, gemcitabine and cisplatin therapies. It also develops in around 4% of patients receiving haemopoetic stem cell transplants; whether this results from the pretransplant conditioning chemotherapy or from an immunological or infective injury subsequent to the transplant has not been elucidated. While plasma exchange is of benefit in most cases of HUSTTP, in chemotherapy-associated disease, its efficacy is unproven. Nonetheless, it is still used as a treatment in some centres as mortality remains very high in this patient subset and no ideal treatment has been identified.

Neurological26,27 Central and peripheral nervous system injuries and syndromes can result as a direct or indirect effect of chemotherapy and can cause confusion with alternative tumour-related diagnoses such as cerebral metastatic disease, spinal cord compression, paraneoplastic syndromes or co-incidental disease such as infective meningitis and primary epilepsy. Appropriate diagnosis is essential to both guiding on-going therapy and discussion of prognosis. Some chemotherapeutic agents such as methotrexate may be administered intrathecally and differentiation of complications of the therapy (leucoencephalopathy, aseptic meningitis and transverse myelopathy) as opposed to complications of the procedure (infective meningitis/encephalitis, spinal cord trauma, neuropraxia) is desirable. Additionally, recognition that neurological injury may be responsible for other apparently non-neurological side effects such as constipation secondary to neurological injury of the gut (vinca alkaloids) is

ARTICLE IN PRESS The side effects of chemotherapeutic agents useful when considering apparently unrelated problems. (i) Peripheral neurological injuries: Peripheral sensory and motor neuropathies are well-recognised side effects of taxanes, thalidomide, vinca alkaloids and nucleoside analogues. Autonomic neuropathies can also arise causing cardiac arrhythmias, ileus and hyperhydrosis. Sensory neuropathies vary from peri-oral numbness through peripheral paraesthesia to neuropathic burning pain. Certain drugs such as taxanes are generally associated with resolution of the neuropathy on reduction or withdrawal of the drug whereas others such as thalidomide and vinca alkaloids may result in permanent irreparable damage and should be discontinued whenever signs of neurological injury arise. Motor neuropathies may also arise and should lead to reduction or discontinuation of the causative agent. (ii) Central neurological injuries: As well as permanent leucoencephalopathy, transient aseptic meningitis and transverse myelitis seen with intrathecal methotrexate, acute and subacute encephalopathies can develop resulting in confusion, seizures, focal neurological deficits and amnesia several days after therapy. When associated with methotrexate this is usually reversible28,29 but when caused by agents such as cytabarabine30 it may be permanent. Similarly, cerebellar signs and ataxia due to cytarabine tend to be irreversible whereas those arising secondary to 5-fluorouracil and capecitabine usually reverse with time following drug withdrawal. While in certain instances such as ototoxicity secondary to cisplatin, toxicity is predictable and dose related, the vast array of neurotoxicities seen with different agents is often unpredictable. Whenever a patient develops unusual neurological signs in the 6 months following chemotherapy, assessment of the individual chemotherapeutic agents and their side-effect profile should be made and full investigations for other causes undertaken even when a causative relationship seems likely. In acute situations where potentially neurotoxic overdoses or inappropriate intrathecal administration of drugs has occurred, consideration of specific antidotes and CSF exchange31 should be undertaken in consultation with the local and national medicines information centre and poisons unit. Bone marrow suppression and immune deficiency are common features following the administration of both cytotoxic and immunomodulatory chemotherapy.32 Sometimes, such as in pre-haemopoetic stem cell transplant conditioning, the aim of chemotherapy may be marrow ablation. However, in most instances, a drop in the immunocyte,

77 platelet and red cell count in the body merely reflects a side effect of treatment in that as well as leading to death in rapidly replicating tumour cells, it targets the high mitotic rate of bone marrow (especially white cell precursor) cells too. These side effects may be dose limiting or if stem cell harvest or bone marrow harvest has been undertaken before chemotherapy exposure, they may be ignored and the patient receives an autograft following chemotherapy. While platelet and red cell transfusions are relatively simple to administer in treatment of thrombocytopenia and anaemia, they are not without their own risks in terms of infection (especially CMV), hypersensitivity and inflammatory reactions. By contrast, granulocyte transfusions are difficult to procure, have to be administered daily for several days owing to the very short half-life of the cells and have high risks of hypersensitivity reactions. Additionally, the cells must be irradiated before administration to reduce the risk of lymphocyte-induced graft—versus host disease developing. Nonetheless, in leucopenic patients with proven sepsis unresponsive to antibiotics, granulocyte transfusions have been correlated with improvement and survival in several case studies.33,34 Where leucopenia results from chemotherapy it is not uncommon for 3– 4 weeks to elapse prior to the recovery of the white cell population, even following stem cell autograft. Granulocyte colony stimulating factor is often prescribed in an attempt to reduce the duration of this period. During this time, patients remain highly susceptible to opportunistic infection and anti-microbial prophylaxis is often commenced to reduce the risk of sepsis. Reactivation of pre-existing infections with viruses such as CMV, EBV and HSV is well recognised and colonising microbes such as PCP and candida may become invasive. Unfortunately, many of the antimicrobial agents to treat these infections e.g. ganciclovir, co-trimoxazole and macrolides are marrow suppressive in their own right. In addition to routine cytotoxic agents leading to immunosuppression, steroids are frequently coadministered with chemotherapy to reduce hypersensitivity responses, systemic inflammation and as anti-proliferative agents per se. Similarly, following haemopoetic cell allografts, agents such as cyclosporin, tacrolimus and mycophenolate are routinely used to reduce the severity of graft versus host disease via a strategy of deliberate immunosuppression and are associated with an increased risk of opportunistic infection and haematological malignancy. Immunomodulatory agents such as rituximab and alemtuzumab are, respectively, directed against CD20 and CD52 epitopes on white

ARTICLE IN PRESS 78 cells and used primarily to treat lymphoid cancers. Alemtuzumab is particularly highly immunosuppressive and despite recovery of the overall white cell count, clinical immunosuppression may continue for years following treatment. In addition to lymphopenia, both may also cause hypogammaglobulinaemia. In such instances, there is an evidence that administration of immunoglobulin may aid resolution of sepsis. Metabolic disturbances such as mild hyperglycaemia with steroid administration and hyperuricaemia secondary to tumour breakdown are relatively common and usually untroublesome side effects of chemotherapy. An awareness of these problems and the desirability of maintaining patients in a well hydrated, diuretic state is suffice for day-to-day anaesthetic management. Knowledge of tumour lysis syndrome is also desirable as this presents an extreme of physiological disturbance which may prove fatal if not recognised and managed appropriately. Tumour lysis syndrome35 describes a metabolic syndrome of acute uric acid nephropathy and renal impairment with hyperphosphataemia, hypocalcaemia, hyperuricaemia and hyperkalaemia secondary to rapid tumour cell death following the introduction of chemotherapy. The dying cells release large quantities of normally intracellular electrolytes and compounds into the circulation resulting in the metabolic abnormalities seen. Hyperuricaemia leads to hyperuricuria, nephropathy and renal failure. Tumour lysis syndrome is thus a result of rapid tumour cell death and a failure of the body to cope with the metabolic load rather than a side effect of individual chemotherapeutic agents per se. Prevention of the problems by excellent hydration and administration of allopurinol or rasburicase is advised where there is a high risk of TLS. Management of established TLS by maintenance of diuresis, alkalinisation of the urine and renal replacement therapy to normalise electrolyte disturbances may be required before a patient can safely be anaesthetised. Hypersensitivity reactions are well recognised in association with the administration of chemotherapeutic agents especially when administered intravenously.36 These range from mild fever seen with over 50% of bleomycin administrations37 to fulminant anaphylaxis. The commonest causative agents of severe reactions are mono-clonal antibodies such as rituximab and Herceptin but they occur frequently with agents such as asparaginase, carboplatin and etoposide too and infrequently with nearly all other chemotherapeutic drugs. Reactions are usually anaphylactic (type I) or anaphylactoid, but type II–IV hypersensitivity reac-

C. Carr et al. tions occur too. Proper type IgE-mediated reactions generally require cessation of the agent while many of the other reactions can be dealt with by slowing the rate of infusion and pre-treatment with antihistamines and steroids. Certain medications such as bleomycin come with clear guidelines on administration of tiny test doses several hours before the main drug infusion is commenced. Additionally, precautions such as the concomitant administration of paracetamol as an anti-pyretic are often written into individual unit protocols. All agents being administered parenterally should be given in units equipped to deal with type I hypersensitivity reactions and be given by staff trained in resuscitation.

Conclusion By their very nature, chemotherapeutic agents are often associated with dysfunction of a wide variety of organ systems. It is well worth keeping this in mind before either embarking on anaesthesia or while making an assessment in the intensive care unit.

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