Chemotherapeutic agents are intended to selectively destroy neoplastic cells by interfering with metabolic pathways not present in normal cells. Such selectivity is usually directed towards malignant cells in division and is difficult to achieve because the cytotoxic effects of chemotherapeutic agents on neoplastic and normal cells are sometimes mediated through various mechanisms of enzyme inhibition .
This is a short review of some of the most commonly used chemotherapeutic drugs and protocols with the intention of clarifying the consequences of their use to anaesthetists who do not prescribe such drugs and who encounter with their sequelae. A thorough understanding of cytostatic pharmacology, drug interactions with anaesthetics, clinical pharmacokinetics and toxic reactions become of great importance for anaesthetists who are regularly involved in the treatment of cancer patients. This article is not intended to teach chemotherapy, but to emphasize some of the consequences of chemotherapy appearing in the perioperative course and affecting the anaesthetist's treatment and diagnostic decisions.
Modalities of chemotherapy
Monotherapy. Chemotherapeutic drugs used as monotherapy may provide long-term or complete control of some acute childhood leukaemias , Hodgkin's disease, some germ-cell carcinomas  and other malignancies. Those neoplastic diseases are now assumed to be chronic diseases, almost like diabetes mellitus, requiring long-term therapy and offering longer survival with increased quality of life [4,5]. A good example of cytostatic monotherapy is idarubicin in childhood acute lymphoblastic leukaemia  or letrozole as first-line endocrine therapy in postmenopausal women with advanced breast cancer . Single-agent docetaxel has been used in therapy of various cancer diseases of the prostate, breast and uterus  and advanced or metastatic malignancies , whose disease has been considered inoperable at initial presentation.
Combinations. Antitumour chemotherapeutic agents are more effective when used in combination. They may be synergistic through biochemical interactions and associated toxicity has become more predictable and manageable, but sometimes additive. Shapiro and colleagues combined carboplatin together with cyclophosphamide to maximize platinum dose intensity in patients with advanced epithelial ovarian cancer . Such active combined treatment is associated with substantial toxicity. Crown reports that trastuzumab, a novel monoclonal antibody directed against the protein product of the HER2/(neu) oncogene, has a powerful synergistic interaction with docetaxel and platinum . Cytotoxicity is still the limiting factor in all chemotherapeutic regimens .
Biochemotherapy. Some novel biochemotherapy regimens combining interferon-α2b  or interferon-α and interleukin-2 , and multiagent chemotherapy did not result in overall survival being different than in standard therapeutic regimens.
Radiotherapy. Radiotherapy and/or its combination with chemotherapy have been used in the therapy of various malignant diseases after surgical treatment. Preoperative or neoadjuvant chemoradiotherapy alone has been reported to achieve similar survival rates to surgery alone in operable oesophageal cancer . Another modality of radiotherapy is intraoperative treatment as described in a series of locally advanced or locally recurrent rectal cancer .
Others. Clinically attractive and promising modalities, such as local intraoperative application of a cytostatic agent into the abdominal cavity , intended to prevent the generation of peritoneal carcinomatosis, and subconjunctival application of drug in the treatment of retinoblastoma  still have to be clinically proven.
The same drugs which are used for cytotoxic anti-tumour therapy have been widely used by a broad spectrum of specialists in therapeutic regimens for non-neoplastic diseases, such as rheumatoid arthritis , sickle cell anaemia, proliferative lupus nephritis , Henoch-Schonlein purpura , anti-infective chemotherapy, idiopathic membranous nephropathy  and psoriasis [21,22].
Advances in diagnosis of neoplastic diseases have led to advances in therapy. Preoperative cytostatic therapy or neoadjuvant chemotherapy is now being used widespread as first-line cancer therapy. Malignancy is, thus, treated earlier in the course of the patient's management when most curable and when the patient is best able to tolerate such treatment. Such an early onset of systemic treatment may be effective in obtaining control of micrometastases and reducing the development of drug-resistant clones . Preoperative chemotherapy with doxorubicin and docetaxel is accepted as highly effective and feasible in primary operable breast cancer . De Mateis and colleagues  conducted a clinical study on patients with locally advanced breast carcinoma including patients with inflammatory breast carcinoma. Neoadjuvant docetaxel plus epidoxorubicin chemotherapy was advocated as a method for tumour down-staging. Neoadjuvant chemotherapy increases the likelihood that the patients may undergo conservative surgery and can make some tumours operable that were initially not operable. Monitoring of a primary tumour's response to chemotherapy may provide a surrogate marker of treatment effect on survival.
Preoperative chemotherapy is appropriate for the treatment of certain patients with stages 1 and 2 of disease, and can be used to study breast cancer biology. Fisher and colleagues  conducted a clinical study and concluded that tumour response to preoperative chemotherapy correlates with outcome, but they did not confirm any statistically significant difference in disease-free survival. Grau and colleagues  studied 204 patients with locally advanced squamous cell carcinoma of the oral cavity who received cisplatin, bleomycin and 5-fluorouracil (5-FU) neoadjuvant chemotherapy. This neoadjuvant chemotherapeutic protocol induced a high response rate that may facilitate definitive surgery or radiotherapy.
A good outcome from perioperative cancer chemotherapy has encouraged some investigators to use such therapy as prolonged chemopreventive therapy. Primary prevention was conducted by the prophylactic use of the anti-oestrogen agent tamoxifen in healthy women who are at risk (BRCA1 and BRCA2 carriers, having positive familial breast cancer markers), and gave modest benefit in BRCA1 carriers but somewhat greater benefit in BRCA2, in both cases with wide confidence intervals . Tamoxifen was tested also in women having breast cancer and positive oestrogen receptors. A study has tried to evaluate chemopreventive effects of tamoxifen in women. The first results did not support such long-term therapy and showed a greater incidence of endometrial cancers as possible side-effects . Tamoxifen still remains the gold standard for adjuvant therapy although some preliminary results of ongoing clinical trials comparing tamoxifen with the aromatase inhibitor anastrozole  suggest that anastrozole may be the superior agent for neoadjuvant, adjuvant and chemopreventive treatment [6,31]. The primary treatment objective of such hormonal therapy is reducing both disease burden and patient suffering.
Chemotherapeutic agents may be divided into five groups: alkylating agents, antimetabolites, natural products (e.g. antibiotics, vinca alkaloids, epipodophylotoxins, enzymes and biological response modifiers), miscellaneous agents and hormones and antagonists. Some of toxic adverse reactions relating to those groups are listed in Table 1.
Most chemotherapeutic agents are potent myelosuppressors. Shapiro and colleagues  combined cisplatin and carboplatin together with cyclophosphamide in patients with advanced epithelial ovarian cancer in a dose-intensive combination treatment (phase 2 study). They observed severe haematological toxicity with significant FIGO grades 3-4 anaemia in 81% of patients, grades 3-4 neutropenia in 92% of patients, and grade 4 thrombocytopenia in 96% of patients. A combination of the antimetabolite gemcitabine with the alkylating agent cisplatin in patients with advanced or metastatic pancreatic cancer was reported to produce grades 3-4 neutropenia and thrombocytopenia without bleeding in 29% and 13% of patients, respectively . Reversible thrombocytopenia was observed with carboplatin/gemcitabine therapy  in patients with advanced non-small lung cell carcinoma. The cisplatin analogue carboplatin has been shown to be less toxic than cisplatin, in previously untreated patients with advanced ovarian cancer. Myelosuppression from carboplatin was the dose-limiting adverse reaction. However, carboplatin has not led to improved survival compared with cisplatin .
Etoposide was found to have a haematotoxic effect correlating with systemic exposure to unbound drug better than total drug amount. Patients with higher systemic exposure to unbound drug experienced greater haematological toxicity. This may be of clinical importance due to the lower plasma protein binding of etoposide in hypoproteinaemic cancer patients .
Prolonged intervals of myelosuppression and high rates of systemic infections were frequently the main reason for delays of treatment with subsequent chemotherapy courses as observed in idarubicine treatment of acute childhood leukaemias. . Non-haematological toxicities including acute cardiac reactions were transient and moderate in this study. Clinical signs of candidiasis were observed in 28.4% of patients during cytostatic therapy for non-Hodgkin's lymphoma or Hodgkin's disease. Cultivation revealed that 62.3% of salivary yeast cultures were positive in the same population . That study showed a correlation between mucosal ulcers and septicaemia.
Reckzeh and colleagues described an interstitial pneumonia in patients treated with paclitaxel combined with radiation probably due to lymphocytopenia . Docetaxel is associated with severe lymphopenia and increased incidence of non-neutropenic infections and febrile episodes. Souglakos and colleagues  investigated the incidence of non-neutropenic infections and febrile episodes in patients with solid tumours receiving docetaxel-based chemotherapy. The risk of non-neutropenic infections in patients receiving docetaxel-based therapy was found to be 2.38 and 2.8 times higher than in patients receiving paclitaxel and non-taxane-based chemotherapy, respectively. De Mateis and colleagues observed a grade 4 neutropenia in 80% of patients and a febrile neutropenia in one-third of patients who were preoperatively treated with epirubicin plus docetaxel for breast carcinoma; no thrombocytopenia or anaemia was seen .
Anthracycline antibiotics (doxorubicin, daunorubicin, epirubicin), alkylating agents (cyclophosphamide) and antimetabolites (5-FU) are known to be cardiotoxic . An acute form is characterized by abnormal ECG changes, including ST-T alterations and dysrhythmias. Severe manifestations of this myocardial damage can be expressed as serious dysrhythmias and congestive heart failure associated with pericardial effusion. Chronic cardiotoxic congestive heart failure is cumulative and dose related and does not respond to digitalis therapy. Frequency of serious cardiomyopathy is 1-10% and increases markedly with dose, irradiation, or when an anthracycline is given concomitantly with other cytostatic drugs. The mortality rate of chronic cardiotoxic failure is in excess of 50% . Although not frequent these manifestations are serious. Acute doxorubicin-induced cardiotoxicity can be prevented in adults by using a continuous infusion of the drug. Lipshultz and colleagues claimed that both bolus and continuous infusion regimens in children were associated with progressive subclinical cardiotoxicity, dilated cardiomyopathy with inadequate left ventricular hypertrophy and significant abnormalities of left ventricular structure and function compared with the normal and with baseline . The mean left ventricular fractional shortening decreased, contractility was depressed and hypertrophy and dilated cardiomyopathy were noted. There was no difference in clinical cardiac manifestations and event-free survival.
ECG changes were observed during chemotherapy with 5-FU. Descending ST depressions with preterminally negative T-waves, ventricular extrasystoles and sinus tachycardia with intermittent atrial fibrillation were recorded and had disappeared a few days after the drug had last been administered .
The administration of several anticancer drugs may be associated with respiratory adverse effects. Paclitaxel and carboplatin in a prospective clinical study produced a significant but clinically silent decrease (≥20% of start values) in diffusion capacity for carbon monoxide, which persisted for 5 months after completion of chemotherapy . Pneumonitis has been described mostly in a number of studies and case reports. Read and colleagues described severe interstitial pneumonitis in patients who were treated with single-agent docetaxel for various cancerous diseases (prostate, breast and uterus) . Two percent of patients treated with docetaxel in this study developed progressive interstitial infiltrates and respiratory failure that required mechanical ventilation of the lungs; two of them died. Broad spectrum antibiotics and corticosteroids were ineffective. Other causes of respiratory failure were not found. Khan and colleagues retrospectively studied 239 patients with malignancies treated with paclitaxel, etoposide and cyclophosphamide . Those authors demonstrated an incidence of bilateral pneumonitis associated with dry cough and dyspnoea of 1%. Symptoms responded to parenteral corticosteroid therapy and the radiological signs resolved in 24-96 h. Although the exact pathophysiology explaining the pneumonitis was unclear, a delayed hypersensitivity reaction has been postulated [45,46] or prolonged lymphocytopenia, resulting in an immunodeficiency state .
Chemotherapy with paclitaxel and carboplatin may alter renal function. The affected individuals usually have non-oliguric renal failure . High doses of carboplatin were implicated as the cause of haemorrhagic cystitis, presumably by toxicity to transitional epithelium of the bladder. Gross haematuria and blood clots, resulting in bilateral ureteral obstruction and hydronephrosis may be observed. High-dose chemotherapy regimens including carboplatin and ifosfamide were associated with comparable or even higher nephrotoxicity to single-day cisplatin/ifosfamide . Carboplatin is a cisplatin analogue clinically preferred as being less nephrotoxic compared to the parent compound .
Methotrexate is another well-known nephrotoxic drug. To prevent this effect at the end of a high-dose methotrexate infusion, patients are given proportional doses of leucovorin, which replenishes intracellular stores of reduced fault and attenuates the toxicity due to high-dose methotrexate . Shapiro and colleagues observed elevations in serum creatinine grade 2 or greater in 27% and grade 2 or greater hypomagnaesaemia after platinum and cyclophosphamide combination therapy in 88% of patients, respectively . Grau and colleagues observed the haemolytic-uremic syndrome in 3% of the patients treated with bleomycin .
Hepatic dysfunction is usually reversible and mild. Cirrhosis was observed after prolonged methotrexate therapy in a patient with breast cancer. A severe illness developed accompanied by progressively increasing transaminase concentrations as the prominent sign. Liver biopsy revealed a grade 2 toxic hepatitis. Liver function tests returned to normal after the drug was withdrawn . In standard doses, methotrexate is excreted unchanged in the urine and in high doses it is partially metabolized by the liver. When used in high doses with leucovorin rescue, methotrexate diffuses into both normal and malignant cells. Leucovorin enters normal cells, blocking the effects of methotrexate. Methotrexate used for maintenance therapy in children with acute leukaemia may promote the development of hepatic cirrhosis and fibrosis .
The anti-androgen flutamide generally causes asymptomatic transaminase concentrations to rise, and rarely severe hepatotoxicity (6% of 65 patients) develops . Jaundice, anorexia, nausea and dark urine, as well high aminotransferase and bilirubin concentrations indicating acute hepatitis  were observed in prostate cancer patients receiving flutamide therapy. Laboratory and clinical signs returned to baseline after the drug was discontinued.
Hypoproteinaemia, which is often seen in cancer patients, may intensify cytotoxic drug effects. More pronounced systemic toxic reactions might result from higher exposure to unbound drug . The systemic toxicity was enhanced for both etoposide and teniposide in patients with decreased serum albumin concentrations and decreased protein binding of the drug. This may be explained by higher exposure to unbound etoposide and unchanged systemic clearance of etoposide in patients with increased bilirubin .
Many patients undergoing therapy with interleukin 2 in the therapy of renal cell carcinoma and melanoma experience elevations of serum bilirubin due to profound and reversible intrahepatic cholestasis. Elevations of aspartate aminotransferase (AST, ALT), and alkaline phosphatase, hypoalbuminaemia and prolonged prothrombin times are also common .
Coagulation disorders are common in cancer patients [57,58]. Thromboembolic incidents may occur in anti-oestrogen therapy due to lower concentrations of anti-thrombin III and protein C together with higher levels of plasminogen activity and tissue plasminogen activator antigen . In postmenopausal women, oestrogen concentrations are maintained primarily via aromatase, a cytochrome P450 enzyme that acts at the final step in the oestrogen synthesis pathway . Inhibition of this enzyme may lead to pulmonary embolism, deep vein thrombosis, and stroke. Quality-of-life studies comparing aromatase inhibitors with tamoxifen have shown that aromatase inhibitors produce a more favourable quality of life due to of lower incidence of thromboembolism and vaginal bleeding . Cancer patients are not only at an increased risk for thromboembolic events, but they also have an increased risk of bleeding complications particularly those receiving oral anticoagulant treatment . Bleeding disorders due to severe impairment of platelet aggregation was noted in melanoma patients treated with interferon α-2b adjuvant therapy. This disorder was not detectable by standard coagulation profile and appears to be dose dependent . Bleeding disorders can be observed in thrombocytopaenic and hypoproteinaemic patients during cytostatic therapy .
Significant gastrointestinal toxicity was observed in 7% of patients (n = 65) treated with androgen suppression before and during pelvic radiation therapy for prostate cancer in a flutamide study . De Mateis and colleagues' study noted a significant proportion of patients having diarrhoea (26.6%) and oral mucositis (43.3%), both common gastrointestinal complications of cancer chemotherapy . Laine and colleagues found the incidence of oral mucosal lesions during cytostatic therapy to be 43.4% of 67 patients, being treated for non-Hodgkin's lymphoma or Hodgkin's disease .
Central nervous toxicity manifests itself in the form of nausea and vomiting. It was observed in 9% of patients receiving chemotherapy based on cisplatin plus bleomycin or 5-FU  and in 26.6% receiving docetaxel plus doxorubicin therapy . Mental status was rarely altered but generalized seizures, paralysis and coma may occur. The alkylating agent busulfan may cause transient central nervous toxic symptoms. Seizures may occur during the course or in the 24 h following the last dose. The neurotoxicity of busulfan is dose dependent in children, and effectively prevented by clonazepam . Central nervous toxic reactions usually disappear after discontinuation or dose adjusting.
Peripheral neurotoxicity is described in many therapeutic protocols using chemotherapeutic agents. Neurotoxicity was one of the dose-limiting adverse reactions in a pharmacokinetic study of paclitaxel conducted by Wiernik and colleagues . This toxicity manifested clinically as a stocking-and-glove sensory disturbance that primarily affected proprioception and was confirmed with objective changes on nerve conduction studies in affected individuals . In high-dose paclitaxel schedules a neuropathy may appear, particularly in patients with underlying diabetic or alcoholic neuropathy. Several neuroprotective agents, such as nerve growth factors, gluthathione and ethiofos, are under investigation to prevent or delay these side-effects and maximize the benefits of treatment regimens .
The vinca alkaloids may produce neurotoxic symptoms. Vincristine has predictable cumulative effects. Numbness and tingling of extremities, loss of deep tendon reflexes and weakness of distal limb musculature are the most common and earliest toxic signs . Rarely, patients may experience vocal cord paralysis and loss of extraocular muscle function. Peripheral neuropathy may worsen after discontinuation of cisplatin therapy . It was observed in patients receiving high doses of cisplatin. The ototoxicity is more frequent and severe when doses are repeated, and may be more pronounced in children.
Carcinogenicity was suspected for several anticancer drugs. Endometrial cancer and uterine sarcoma were more common in patients receiving prolonged tamoxifen therapy. Due to these risks, women taking tamoxifen should be properly monitored . Methotrexate and mitoxantrone-based regimens carry a 10× higher risk of subsequent myelodysplastic syndrome or acute myeloid leukaemia compared to that seen in the general population .
Hormonal changes are the goal of hormonal anticancer therapy. Letrozole decreased concentrations of circulating oestrogen by more than 75-95% from pretreatment values in patients treated with daily doses of 0.1-5 mg. Clinically relevant changes in thyroid and other hormones of the endocrine system were not found .
Biotransformation means that lipid-soluble compounds are enzymatically transformed in a two-phase reaction. In phase 1 there is conversion of functional groups by dehydrogenation, oxidation, hydrolysis, reduction and/or mono-oxygenation. In phase 2, there is conjugation of functional groups by glucuronidation, sulphation, acetylation or methylation into polar, water-soluble and excretable metabolites . The metabolic products are often less active than the parent drug or inactive. However, some metabolites may have enhanced activity or toxic effects. Thus, biotransformation may include both 'detoxication' and 'toxication' processes . One of the major drug metabolizing enzyme systems that determines the organism's capability of dealing with drugs and chemicals is represented by the cytochrome P450 mono-oxygenases . Only six of the numerous cytochromes P450 play a major role in metabolism of drugs in common clinical use. Prominent among them in regard to a number of substrates are CYP3A4 and CYP2D6, with fewer drugs metabolized by CYP2C9, CYP2C19, CYP1A2 and CYP2E1 .
A large number of P450 enzymes and also other drug metabolizing enzymes (such as glucuronyltransferases, epoxide hydrolases, etc.) are selectively induced by drugs, such as phenobarbital, rifampicin, dexamethasone or by cigarette smoking. The induction is dose dependent and reversible. It leads to drug tolerance and clinically significant drug interactions . Drug inhibition may result from competitive binding at the site of drug binding. Well-known potent inhibitors of P450 enzymes are quinidine, amiodarone, erythromycin and cimetidine [69,71].
Cytostatic drug metabolism
Cytostatic prodrugs undergo bioactivation, mostly by the cytochrome P450 enzyme system in the liver and in some other tissues. When bioactivation in the liver does not occur, drug uptake into tumour cells does not necessarily lead to local bioactivation of drug and thus cytostatic effect. Bonnenstengel and colleagues , in a ventilated and perfused human lung model study of cyclophosphamide uptake into bronchial carcinoma and healthy lung tissue, observed lack of local bioactivation in tumour tissue. The CYP2B group of isoenzymes activates the prodrug cyclophosphamide in the liver. Despite its activation by cytochrome P450, cyclophosphamide toxicity in human beings is not altered by pretreatment with P450 inducers (e.g. phenobarbital). Other drugs (e.g. mitomycin C) require metabolic activation catalysed by tumour reductase enzymes to exert their cytotoxic or cytostatic effects. Reductase DT-diaphorase activity concentrations correlate with sensitivity to mitomycin C in the National Cancer Institute human tumour cell panel .
Impairment of normal liver function can lead to alterations in hepatic drug metabolism. Such conditions include biliary cirrhosis, hepatitis, alcoholic liver diseases and hepatocarcinomas. The degree to which cytochrome P450 mono-oxygenase activity is decreased appears to be a function of the severity of the liver function damage. Taxanes undergo extensive P450-mediated metabolism in the liver . Two isoenzymes, CYP3A4 and CYP2C8, are involved in docetaxel and paclitaxel metabolism, respectively. Less than 10% of parent drug is excreted in the urine. Paclitaxel clearance is saturable and decreases in the presence of hepatic metastases or in patients with abnormal hepatic function.
As most drugs have metabolites that are excreted in the urine, renal function must be considered in such patients. Some drugs, such as methotrexate, are mostly excreted unchanged by glomerular filtration and active tubular secretion. Therefore, concurrent use of drugs that reduce renal blood flow (non-steroidal anti-inflammatory drugs, NSAIDs), nephrotoxic drugs (e.g. cisplatin) and acids (e.g. aspirin) can reduce renal excretion and enhance myelosuppression .
The liver cytochrome P450 3A4 plays a major role of in docetaxel biotransformation in human beings . Dexamethasone and rifampicin - both classical CYP3A inducers - can induce docetaxel metabolism in human hepatocytes in vitro. Typical CYP3A substrates and/or inhibitors, such as erythromycin, ketoconazole, nifedipine and midazolam, achieve inhibition of CYP3A4 both in human hepatocytes and in liver microsomes [76,78]. Some Vinca alkaloids and doxorubicin were also shown to inhibit docetaxel metabolism in human hepatocytes and liver microsomes . In plasma concentrations present during anti-neoplastic therapy, the agents docetaxel, cyclophosphamide, ifosfamide, vinblastine and teniposide could possibly cause clinical drug interactions due to inhibition of CYP3A4 [77,78]. These findings may have clinical implications and should be taken into account in the design of combination cancer chemotherapy regimens.
Metabolism of anaesthetics
Most of the inhaled anaesthetics are metabolized in liver by cytochrome 2E1. Halothane, enflurane, isoflurane, methoxyflurane and sevoflurane are metabolized in various amounts by this enzyme system. The toxicity of inhaled anaesthetics is not attributable to the compounds per se but more to metabolites produced by cytochrome P450 mediated biotransformation. Sevoflurane has been shown to be a substrate for hepatic cytochrome P450 and to be metabolized in vivo in anaesthetized patients to the extent of approximately 5% . Non-enzymic degradation of sevoflurane in closed anaesthesia circuits by the carbon dioxide absorbents results in Compound A concentrations that may reach 30-40 ppm. Such concentrations were not proven as hepatotoxic or nephrotoxic in human beings, but have increased sister chromatide exchanges (an in vitro mutagenicity test) at 27 ppm. This concentration was obtained in a low-flow system when sevoflurane was used at concentrations approximating minimum alveolar concentration .
Most of the i.v. anaesthetics, such as the benzodiazepines, alfentanil, fentanyl, local anaesthetics, etc, are metabolized by CYP3A4, 5 and 7. Barbiturates are potent inducers of this enzyme group catalysing biodegradation of the majority of i.v. anaesthetic agents . There are some gender-related differences in enzyme activity. Females exhibit higher baseline CYP3A4 activity than males and there is, therefore, a greater extent of interaction on average .
Even though the neuromuscular relaxants vecuronium and pancuronium are substrates to cholinesterase enzyme, they may lead to inhibition of hepatic cytochrome P450 in a rat model. Atracurium may also lead to such inhibition, although it is predominantly degraded in extrahepatic tissues .
Drug interactions in cancer patients
Various drugs do interact with cytostatics and may enhance toxic reactions. Bilateral cranial nerve palsies, severe peripheral neuropathy involving upper and lower extremities, seizures, hypertension, heart failure and the syndrome of inappropriate antidiuretic hormone secretion have been described after treatment with vincristine (CYP3A substrate ), nifedipine (CYP3A substrate) and itraconazole (CYP3A4, 5 and 7 inhibitor) in a 5-yr-old child with leukaemia . Appropriate management of the above problems including discontinuation of vincristine resulted in recovery from toxic manifestations. This reaction was probably mediated by enzyme inhibition due to itraconazole, which resulted by lack of the antihypertensive effect of nifedipine and pronounced toxic effects of vincristine.
Cytostatics and anaesthetics interaction
Most of the observations due to such reactions are based on in vitro and animal studies because controlled clinical trials on anaesthetics and cytostatic interactions are rare [85,86]. Anaesthetics may influence cytostatic metabolism and toxicity as well as tumour growth. Some results and assumptions based on these findings are listed below.
A significant inhibitory effect on tumour growth in cell lines was observed when cytostatics and anaesthetics were given concomitantly. Clinically achievable concentrations of the local anaesthetic procaine enhanced doxorubicin cytotoxicity in vitro resulting in marked growth inhibition. Both drugs were assessed in non-inhibitory concentrations. An incubating temperature of 40°C enhanced all effects of procaine and doxorubicin on cell growth . Another local anaesthetic, lidocaine, enhanced bleomycin-induced cytotoxicity and deoxyribonucleic acid (DNA) damage. The inhibition of DNA repair processes may be partially responsible for the toxicity and DNA damage when lidocaine is added to bleomycin. The outcome of this study indicates that the modulation of toxicity seen with these drug combinations is reflected by changes in DNA integrity . Lidocaine as a sole agent was found to cause cytotoxic effect on human neuroblastoma cells in a dose-dependent manner. Lower concentrations initiate apoptosis whereas higher concentrations cause cellular necrosis .
Several chemotherapeutic protocols include administration of methotrexate during or shortly after anaesthesia. Clinical observations in patients treated for breast cancer have shown unexpected myelosuppression and mucosal damage. Toxic reactions were more common and severe in patients aged 50 yr or more, and in those who received such therapy within 6 h of mastectomy . The effect of exposure to N2O on the toxicity of methotrexate in rats exposed to 50% N2O/50% O2 was investigated in vivo. Gastrointestinal toxicity resulted in diarrhoea and weight loss, bone marrow depression with leukocytopenia and thrombocytopenia. A significantly reduced 50% lethal dose for methotrexate was observed, probably due to the synergistic inhibitory effects of nitrous oxide and methotrexate on folate metabolism . The cytotoxic effect of methotrexate on proliferating cells was enhanced by N2O. Both drugs decreased intracellular folate coenzyme concentrations, methotrexate by inhibition of dihydrofolate reductase and nitrous oxide by inactivating methionine synthase. Toxic effects of the drug combination were attenuated by leucovorin rescue. The action of nitrous oxide may be tumour selective and that it may enhance the therapeutic effect of other antitumour agents. A delicate balance between the beneficial cytostatic and harmful effects of nitrous oxide is still to be defined .
Halothane exposure for 2 h after cyclophosphamide was found to have no effect on the antitumour activity of cyclophosphamide but to decrease overall survival in an animal study conducted on mice . A body clearance of cyclophosphamide in mice exposed to halothane was 60 mL min−1 kg−1, against 188 mL min−1 kg−1 in non-exposed mice. Rudnick exposed the human colon cancer cell line HT-29 to various concentrations of halothane for 8-72 h with and without co-incubation with the biological response modifier gamma-interferon (IFN-γ). Halothane from 0.5% to 2% markedly augmented the antitumour activities of IFN-γ against HT-29. The cytolytic activity of IFN-γ was increased almost 300% by halothane as low as 1 Vol% .
Both isoflurane-N2O anaesthesia and opioid-fentanyl anaesthesia were proved safe in anthracycline-treated patients with ovarian carcinoma. Not one anthracycline-treated patient who did not have overt evidence of cardiomyopathy showed signs of cardiac toxic actions. An isoflurane-N2O technique achieved better haemodynamic stability than opioid anaesthesia in these patients .
Anaesthetic choice could have some influence on [3H]-methotrexate delivery in brain tissue and brain tumours. Propofol/N2O anaesthesia may be better than isoflurane/O2 for optimizing osmotic blood-brain barrier disruption for delivery of chemotherapeutic drugs to brain tumour and normal brain as observed in an animal study .
The i.v. anaesthetics may also interact with anticancer chemotherapy. In vivo, the combination of lonidamine, a new mitochondrial targeting anticancer drug, and diazepam was significantly more effective in reducing glioblastoma tumour growth than either drug alone. This tumour growth retardation was maintained as long as treatment was given . Benzodiazepines produced some metabolic alterations when used concomitantly with tamoxifen in vivo. Diazepam does not enhance tamoxifen toxicity on simultaneous administration, but produces perturbation in lipid storage and metabolism .
Administration of high inspired oxygen concentrations during anaesthesia or respiratory therapy may aggravate or precipitate pulmonary toxicity in patients previously treated with bleomycin . There is no specific therapy for bleomycin lung injury except for corticosteroid therapy and standard symptomatic management and pulmonary care.
Symptomatic cancer therapy and anaesthetics
Cancer patients are usually given a variety of drugs. Synergism or a supra-additive effect has been demonstrated for several drugs commonly administered in combination, such as opioids and benzodiazepines, in pain therapy. Whether such effects are beneficial or deleterious depends upon the anaesthetist taking the interaction into account when choosing the doses to be administered. Some interactions are clinically favourable like diminished morphine dose progression in the group treated with combination of bupivacaine due to a synergistic effect  in the course of intrathecal patient-controlled co-administration. This interaction can diminish morphine side-effects.
Some drugs used in anaesthesia may facilitate the patient's symptoms or therapy. Propofol was safely used during a 4 week course of radiation therapy in a patient with autism and Hodgkin's disease who required daily anaesthesia for immobilization without any adverse side-effects or tolerance . The anti-emetic effect of propofol was revealed in patients with nausea and vomiting secondary to cisplatin chemotherapy uncontrolled by a serotonin-antagonist and corticosteroid prophylaxis during their first cycle. Nausea and vomiting were prevented in the first 24 h following the first and second propofol-supplemented chemotherapy cycles, respectively. They noted that patients' comfort and appetite were improved by a subhypnotic infusion of propofol during cisplatin and non-cisplatin chemotherapy . The i.v. midazolam rapidly relieved intractable hiccup in cancer patients. This treatment was maintained by continuous midazolam infusion .
The anti-emetic drug ondansetron, a selective 5-HT3 receptor antagonist, when used postoperatively reduced the analgesic effect of tramadol, probably blocking spinal 5-HT3 receptors . However, sedation and ventilatory depression induced by alfentanil were not significantly affected by the subsequent administration of ondansetron .
There are some facts which the anaesthetist should be aware of in cancer patients. The most important is preoperative assessment of the patient's condition according to preoperative anticancer therapy. There is a significant possibility of insidious impaired cardiac, renal or hepatic function. Haemoglobin, white cell count and liver enzymes are usually monitored. Coagulation disorders, platelet count and aggregation must be considered. Renal function must be assessed both before cytostatic drug treatment begins, and in the preoperative course. The type of cancer surgery is also important for the anaesthesiologist. Aggressive and extensive surgery confronts the anaesthetist with the potential for intra- and postoperative massive blood loss, hypothermia, prolonged time of operation and increased postoperative morbidity and mortality.
Cancer patients receiving opioids usually express a variety of cognitive dysfunction ranging from delirium through sedation to unconsciousness . Poorer cognitive performance may be the result of an opioid effect superimposed on the cancer disease process. In these patients each mental alteration should be properly examined in terms of the underlying metabolic disorder, infection, hypoxia, other psychotropic drugs overdosing or brain metastatic process.
The increase in the average age of the population is leading to a growing population which is suffering from various neoplastic diseases and receiving anticancer chemotherapy. Advances resulting from basic pharmacological investigations in cancer chemotherapy, radiotherapy, their clinical combinations and progress in surgical technique have led to an increase in the number of successfully treated cancer patients. Some other indications instead of cancer, such as psoriasis, autoimmune diseases and rheumatoid arthritis where cytostatics are given over prolonged periods, have made this population even greater [17-22].
Neoplastic diseases produce haemostatic alterations and cognitive dysfunction , depress the immune response , compromise the airway and produce debilitated malnourished patients. Chemotherapy, capable of depressing tumour growth is still not selective enough and vital functions in the respiratory, cardiac, renal and gastrointestinal systems deteriorate. They act as a potent bone marrow suppressor causing anaemia, thrombocytopenia and coagulation disorders. Radiotherapy directed at the head and neck, mediastinum, lung or surgical area causes ventilatory changes and local bleeding due to vascular injury.
This is a challenge for anaesthesiologists, who must be familiar with the effects of cancer, chemotherapy and irradiation as well as the effects of cancer surgery, which additionally affect perioperative management and survival . The complex chemotherapeutic regimens produces alterations in physiological, metabolic and electrolyte balance which can affect some anaesthetic techniques as well as making intraoperative fluid management, haemostasis, ventilation and recovery from anaesthesia more of a challenge. Preoperative assessment must consider these alterations in addition to the elective surgical operation effects of metastases causing pathologic bone fractures, etc. Critical organ functions known to be affected by chemotherapeutic drugs must be evaluated preoperatively and carefully monitored both during and after operation.
Preoperative assessment must take into account that some organ damage during the initial course of the therapy may not have been apparent at the time of treatment, e.g. clinically silent decreased cardiac reserve or pulmonary fibrosis . Such injury sometimes develops in organs that were irradiated months or years earlier.
The anaesthesiologist must be familiar with drug interactions concerning the cytostatic drugs used in the course of the treatment and their consequences. A good understanding of drugs used in patient's chemotherapeutic regimens and their side-effects is important. This knowledge must prompt a choice of preoperative tests and highlight the patient's actual condition and assists the anaesthesiologist in the choice of anesthetic technique. Potentially toxic anaesthetic drugs, e.g. local anaesthetics, inhaled anaesthetics and nitrous oxide should be used carefully. Sometimes delaying an operation until critical organ dysfunction is restored should be considered. Appropriate support is necessary, if organ damage is critical or expected to worsen after surgery such as prolonged respiratory therapy, diuretics or haemodialysis in renal failure. Concentrations of inspired oxygen during respiratory therapy must be maintained as low as possible.
Clinical studies have implicated surgery in promoting infections and further compromising immune functions. Hypothermia, a common surgical complication, was thought to underlie some of the deleterious consequences of surgery, such as wound infections , morbid cardiac events  and increased blood loss . Hypothermia under thiopental anaesthesia suppresses natural killer cell activity and compromises host resistance to metastasis formation, possibly via epinephric (adrenergic) mechanisms in animal studies; such suppression may place patients with metastatic tumours or dormant viral infections at greater risk for complications after intraoperative hypothermia . Temperature monitoring and heating devices, thus, should be provided.
Cancer-related systemic immune impairment is a frequent finding in cancer patients . Therefore, special attention must be drawn to protection against opportunistic infections, commonly seen in this population. Therapy with broad spectrum antibiotics for episodes of febrile neutropenia and antifungal drugs in candidiasis  should be considered.
The anaesthesiologist must have adequate facilities to provide rapid supportive therapy, such as blood and platelet transfusion, more powerful anti-emetic agents, such as selective 5-HT3 antagonists, low-molecular-weight heparins  and other drugs used in the postoperative period. Analgesia should be provided with special attention to drug interactions and increased opioid requirement in addicted patients, achieving a balance between good pain control and minimal side-effects, cognitive or non-cognitive. A patient controlled analgesic technique appears to be the best choice in treatment of postoperative pain.
Informed consent containing all treatment data and risks must be obtained before surgery. It is important to educate the patient's family regarding the actual course of a patient's disease as well as the risks and benefits of surgery, particularly, if some perceptual disturbances are evident . The medical oncologist who started the anticancer therapy should be involved during the preoperative assessment and postoperative care because he or she is an important member of the multidisciplinary care team.
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