Anaesthesia for Cancer Patients Mujeebullah Rauf Arain and Donal J

Anaesthesia for cancer patients Mujeebullah Rauf Arain and Donal J. Buggy

Purpose of review Introduction Cancer is beginning to outpace cardiovascular disease as Cancer is the second leading cause of death in the devel- the primary cause of death in the developed world. A oped world, accounting in 2004 for over half a million majority of cancer patients will require anaesthesia either for deaths. Cancers at four organ sites – lung/bronchus, colo- primary debulking tumour removal or to treat an adverse rectal, breast and prostate – accounted for 56% of all consequence of the malignant process or its treatment. cancer cases and 53% of all cancer deaths [1]. Approxim- Therefore we outline here the pathophysiology of cancer, ately half of patients diagnosed with cancer will develop generalized metastatic disease and systemic chemotherapy metastatic disease. Over 70% of all cancer patients develop and radiotherapy on major organ systems. The anaesthetic symptoms from either their primary or metastatic disease considerations for optimum perioperative management of [2]. The overall metastatic burden and the number and cancer patients are discussed, and the possibility of location of the sites involved by disease influence prog- anaesthetic technique at primary cancer surgery affecting nosis. There is an increasing surgical intervention rate long-term cancer outcome is mentioned. in cancer patients, both for primary tumour excision Recent findings and emergency intervention for intercurrent illness. Cancer and its therapy can adversely affect every major Coupled with the increased use of chemotherapeutic organ system with profound implications for perioperative agents over the past decade, cancer patients requiring management. Retrospective analysis suggests an surgery present particular challenges for the anaesthe- association between regional anaesthetic techniques at tist [2]. This review outlines acute perioperative care for primary cancer surgery and reduced incidence of cancer patients. Early research reports suggest a possible metastatic disease. association between perioperative anaesthetic technique Summary and cancer outcome. Chronic pain management of cancer Optimum perioperative patient care requires individual patients, and acute cancer pain management outside the assessment of the impact of cancer and its treatment on the context of the postoperative period, is beyond the scope of functional reserve of all major organ systems. The potential this work. of anaesthetic technique at cancer surgery to influence long-term cancer outcome merits investigation. Systemic effects of cancer and metastasis Keywords Pain is one of the most common and feared symptoms cancer, cancer treatment, chemotherapy, general associated with cancer. It occurs in 25% of patients with anaesthesia, radiotherapy, regional anaesthesia newly diagnosed malignancies, and in 75% of those with advanced disease [3]. Curr Opin Anaesthesiol 20:247–253. ß 2007 Lippincott Williams & Wilkins. Measurable psychological distress and depression affects Division of Anaesthesia, Intensive Care and Pain Medicine, Mater Misericordiae up to 70% of all oncology patients. Interest has increased University Hospital, Dublin, Ireland intherolethatpsychologicaldistressmayplayin Correspondence to Dr Donal J. Buggy, Consultant in Anaesthesia, MD, MSc, DipMedEId, FRCPI, FCARCSI, FRCA, Division of Anaesthesia, Intensive Care and complicating the presentation, treatment and prognosis Pain Medicine, Mater Misericordiae University Hospital and National Cancer of patients with cancer [4]. Screening Service Eccles Unit, Dublin 7, Ireland Tel: +353 1 8301122/8302281; fax: +353 1 8300080; e-mail: [email protected] Approximately half of all cancer patients develop Current Opinion in Anaesthesiology 2007, 20:247–253 cachexia [5], characterized by anorexia, weight loss, weak- ness, poor performance and impaired immune function [6]. ß 2007 Lippincott Williams & Wilkins 0952-7907 Adequate vascular access is required for effective administration of chemotherapeutic agents, blood products, nutritional support and the multiple blood tests needed for monitoring cancer patients [7]. Central line insertion may be difficult in patients with cancer because of coagulopathy, multiple previous attempts in the same vessels, or difficulty in placing patients supine where there is respiratory distress.

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Cardiac side effects of cancer therapy provide a consider- it occurs in approximately 10% of all cancer patients [15]. able challenge to the clinician. Arrhythmias, radiation- It is most commonly seen in squamous cell carcinoma induced myocardial ischemia, congestive heart failure, of the bronchus in the absence of bony metastasis, anthracycline and radiation-induced cardiomyopathy, suggesting a humoral factor in its aetiology. Breast cancer peripheral vascular disease and pericardial disease can causes excessive calcium mobilization from bone in the all be caused by different cancer therapies [8]. presence of multiple osseous metastasis, and multiple myeloma is associated with local bone destruction and It is estimated that 5–10% of patients taking chemother- abnormal renal function [15]. apy may experience an adverse pulmonary reaction. The clinical syndrome of radiation pneumonitis develops Hyponatraemia (serum sodium >145 mmol/l) results in 5–20% of all irradiated patients. Factors that increase from an impaired ability to excrete a water load, due the incidence of lung toxicity include concomitant to inability to produce dilute urine. Arginine vasopressin administration of oxygen, radiation therapy, IV route of activity is increased in patients with hyponatraemia of administration, going above an established cumulative malignancy [16]. Syndrome of inappropriate antidiuretic threshold dose, pre-existing respiratory morbidity and hormone (SIADH) is the most common cause of hypo- advanced age [9]. natraemia among cancer patients. Neoplasms associated with SIADH are small cell carcinoma of lung, and carci- Mechanisms of renal failure include pre-renal failure noma of the pancreas, bladder, prostate, breast and colon. secondary to inadequate renal perfusion from fever- induced dehydration or cardiac failure. Intrinsic renal Tumour lysis syndrome (TLS) is a spectrum of metabolic failure in the cancer setting may result from generalized derangement usually associated with the cytotoxic sepsis syndrome or nephrotoxic therapy, including anti- therapy of malignancy. It is characterized by numerous biotics. Urinary obstruction commonly occurs with locally metabolic abnormalities (including hyperuricemia, advanced pelvic cancers, for example, prostate and cer- hyperphosphatemia, hypocalcaemia, hyperkalaemia and vical cancers [10]. uraemia) and frequently leads to acute renal failure. Malignancies associated with TLS are acute and chronic Neutropenia is common in cancer patients either because lymphoid and myeloid leukaemia, small cell carcinoma of the malignant process interferes with bone marrow func- the lung, and testicular and breast cancers [17]. tion or because chemotherapeutic regimens administered to treat the disease cause myelosuppression. Since the Haematological problems neutrophil is an important host defence against many Anaemia tends to increase in severity as the stage of the pathogens, neutropenic patients are at increased risk of disease progresses. Malignancy-associated anaemia is developing opportunistic infection. The frequency of designated as an anaemia of chronic disease. Serum infectious complications is related to the degree and erythropoietin levels are inappropriately low for a given duration of neutropenia [11]. level of anaemia in patients with cancer. It is possible that erythropoietin-producing cells are either directly sup- Infection in hospitalized oncology patients poses a pressed by the malignancy itself or that these cells are serious challenge and may lead to unfavourable impact functionally impaired by chemotherapy or radiation on successful cancer treatment outcomes. In addition, therapy [18]. nosocomial infections are well recognized predictors of prolonged hospital stay and increased cost [12]. Leukopenia is associated with cytotoxic treatment in 20–50% of patients with solid tumours. The probability More than 75% of patients receiving combination che- of clinical infection is proportional to its severity and motherapy are affected [13]. The chemoreceptor trigger duration [19]. zone, located in the area postrema at the ventral aspect of the fourth ventricle, can be stimulated by drugs including Thrombocytopenia in cancer patients is usually attribu- opiates, anaesthetic agents, and cancer chemotherapy. table to chemotherapy and radiation therapy. However, Metabolic abnormalities, for example, uraemia, hypoxia thrombocytopenia may also be due to splenic sequestration and ketoacidosis, may also cause nausea and vomiting. in patients in whom splenomegaly is part of the primary neoplastic process [20]. Acute abdomen or bowel obstruction, bleeding and ﬁstula formation can present as emergent surgical problems in The incidence of thrombosis is 2–10% of all patients with cancer patients [14]. cancer. Most thrombotic complications occur postoperatively. Thrombosis can be the ﬁrst symptom of an Hypercalcaemia (serum calcium >2.7 mmol/l) is the occult malignancy. Patients with adenocarcinoma are at major metabolic abnormality seen in malignant disease: increased risk [20].

Local effects of cancer and metastases sensory and motor deficits, developing after a latent Superior vena cava syndrome may occur as an acute or period [28]. subacute process with characteristic features including facial oedema, plethora, dilatation of chest wall and neck In the lungs, fibrosis from radiation therapy may develop veins, respiratory difficulty, conjunctival oedema, head- late, for example, after 2–6 months. Clinical signs or ache, visual disturbance and altered states of conscious- symptoms of acute radiation pneumonitis are reduced ness. Diagnosis is based on clinical findings. It is usually pulmonary compliance, progressive dyspnoea and dry due to a neoplastic obstruction of venous return from the cough. head and neck, primary lung carcinoma being the most prominent [21]. In the kidney, radiation nephropathy usually manifests as proteinuria, hypertension and impairment in urine Spinal cord compression is diagnosed in more than 30% of concentration. Angiotensin converting enzyme (ACE) all patients with disseminated cancer. Back pain virtually inhibitors or angiotensin II antagonists may significantly always precedes neurological injury. It has a devastating ameliorate radiation nephropathy [28]. impact on quality of life and is frequently diagnosed late. The presence of new or worsening back pain in a patient In the heart, the most common type of radiation-induced with cancer should be a clarion call to action, including injury is pericarditis with a pericardial effusion, which MRI scan and spinal decompression surgery [22]. occurs within 6 months to 2 years. It is often asymptomatic.

In the liver, two phases of radiation hepatopathy are Systemic effects of cancer therapy recognized. The acute phase develops approximately During recent decades, the number of anticancer drugs 2–6 weeks after irradiation, with liver enlargement and has grown dramatically, paralleled by an increasing num- portal hypertension (ascites). Liver function tests are ber of patients receiving such therapy. Chemotherapeutic abnormal. The chronic phase occurs 6 months–1 year agents are intended to selectively destroy neoplastic cells post-irradiation, and shows progressive cirrhotic changes by interfering with a metabolic pathway not present in [28]. normal cells [23]. Often there are signiﬁcant negative side effects including nausea, vomiting, hair loss, anorexia, Anticancer drugs and interaction with anaesthetics fatigue, peripheral neuropathy and anaemia. It has been Most studies on interactions between anticancer estimated that 33% of patients undergoing systemic chemotherapeutic agents and anaesthetic substances chemotherapy have cognitive dysfunction that interferes have been in vitro. A signiﬁcant inhibitory effect on with their quality of life [24]. Various anticancer drugs tumour growth in cell lines was observed when cytostatics may be associated with different organ toxicity, as out- and anaesthetics were given concomitantly. Lidocaine lined in Table 1 [25,26]. enhanced bleomycin-induced cytotoxicity and deoxy- ribonucleic acid (DNA) damage. A 50% reduction in Radiotherapy has replaced surgery for the long-term lethal dose for methotrexate was observed, when it was control of many tumours of the head and neck, cervix, combined with nitrous oxide, probably due to the bladder, prostate and skin, in which it often achieves synergistic inhibitory effects of nitrous oxide and reasonable tumour control with good cosmetic results. In methotrexate on folate metabolism [29]. addition, many patients gain valuable palliation by radiation [27]. Whenever radiation therapy is given with Symptomatic cancer therapy and anaesthetics curative intent, there is the risk of serious damage to Propofol was safely used during a 4-week course of normal tissues. radiation therapy in patients with Hodgkin’s disease who required daily anaesthesia for treatment [30]. The With modern megavoltage equipment, epidermal reac- antiemetic effect of propofol was therapeutic in patients tions are usually limited to dry desquamation and with nausea and vomiting secondary to cisplatin che- increased pigmentation. Late changes are characterized motherapy [31]. Intravenous midazolam rapidly relieved by atrophy leading to contraction of the irradiated area intractable hiccup in cancer patients [32]. [28]. Anaesthetic considerations in the cancer patient Acute mucositis frequently occurs, with clinical symp- There are a number of factors to be considered for the toms such as diarrhoea or gastritis. cancer patient.

The nervous system is less sensitive to radiation injury Preoperative assessment than other tissues such as the lung or kidney. Radiation- Determining the risks associated with a given surgical induced peripheral neuropathy is characterized by mixed operation in a cancer patient is a complex process based

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 250 Anaesthesia and medical disease immunosuppression Coag, MS, HC, GI Organ toxicity MS, CNS, GI, HC, Ca R, MS, HC, CNS,N, GI, D, D CNS, R,Ca, IPC MS, PN, C, SIADH, HC, MS, GI, D, R, N, Ca MS, GI, HC, D GI, MS, CNS, C,MS, D GI, HC, immunosuppression CNS, Coag, Ca Coag, HC, D PN, GI, C, D MS, R, CNS, GI,MS, MS, GI, PN, HC, N, immunosuppression C CNS, MS, GI, C, D GI, MS, D, C,GI, red MS, urine D, C C, MS, HC, D MS, C n; D, dermatotoxicity (dermatitis, alopecia); MS, rhagic cystitis; SIADH, syndrome of inappropriate with glucocorticoid fi brosis, cardiac toxicity MS, R, D Coag, coagulatio increase in purine andcausing pyrimidine uric acid nephropathy for various leukaemias require substitution during perioperative period and autonomic neuropathy Side effects Rapid tumour destruction produces Due to myelodepressive effects, used Leukopenia, neurotoxicity, peripheral Pulmonary Myelosuppression ma cholinesterase; HC, haemor fi c enzymes, c and systemic effects nucleic acids inhibit that enzyme andcannot cell function normally binding to intracellular microtubular protein causing mitotic arrest of complex with DNA,DNA inhibiting or RNA synthesis or both Mechanism Cytotoxic effect by alkylating Interacts with speci Antitumour effects caused by Breast cancers, prostate cancer Patients treated Tumoricidal effect is due to formation GI, gastrointestinal system; C, cardiotoxicity; Ca, carcinogenic; hanism of action, speci fi nervous system; R, respiratory system; IPC, inhibition of plas Cyclophosphamide, Thiotepa, Melphalan, Isofosfamide Fluorouracil, 5-FU, Gemcitabine Docetaxel Paclitaxel, Etoposide aromatase inhibitors, oestrogen Daunorubicin, Mixantrone Methotrexate, Mercaptopurine, Bleomycin, Doxorubicin, Idarubicin, Drugs Vinblastine, Vincristine, Tamoxifen, Letrozole, Flutamide, Busulfan, Chlorambucil, er of biological responsea Interferon- Alkaloids Epipodophylatoxins Class Alkylating agents Table 1 Anticancer chemotherapeutic agents, mec Antimetabolites Natural products, Vinca CNS, central nervousmyelosuppression; system N, (including nephrotoxicity; nauseaantidiuretic PN, hormone. peripheral and vomiting); Antibiotics Taxanes Modi fi Hormones

on a number of factors. The physical status of the patient, reduction in infectious complications, protein catabolism, including nutritional assessment and comorbid con- and inflammatory markers with preoperative or early ditions, morbidity inherent to a specific operation and postoperative feeding. the goal of surgery are all relevant. The assessment should balance the risk associated with disease pro- Further investigations should be undertaken at the dis- gression and those associated with treatment [33]. The cretion of the attending anaesthetist as indicated, follow- preoperative cancer patient is frequently in relatively ing a thorough history and physical examination. For poor physical condition. Patients often present with poor major procedures in most cancer patients, laboratory nutritional status, considerable pain, physiologic abnor- studies should include a complete blood count, serum malities (e.g. electrolyte disorders), and significant co- electrolyte, liver function tests, and coagulation profile. A morbid conditions. Nutritional deficiencies should be 12-lead electrocardiogram may be advisable [35]. Chest corrected prior to surgery if possible with hyperalimen- radiograph should not be conducted routinely unless tation or total parenteral nutrition. Consideration should there is a specific clinical indication. be given to replenishing depleted blood volume if major blood loss is anticipated, and correcting electrolyte Intraoperative management abnormalities prior to major surgical resections. The published standards for basic anaesthetic monitoring should be applied. Additional monitoring should be Physiological status related to cardiopulmonary reserve deployed as indicated to maintain physiologic homeo- and hepatic and renal function should also be assessed stasis or to provide early warning of worsening organ and optimized. The underlying disease, as well as the system function and to direct appropriate interventions. procedure itself, must be considered in the preoperative Temperature monitoring should be routine, because risk assessment [33]. Involvement of the heart by inadvertent perioperative hypothermia is associated with primary malignancy, metastatic disease or anticancer a number of deleterious consequences, such as wound treatment has important implications. Patients with a infections, morbid cardiac events and increased blood history of cardiotoxicity should undergo echocardiogra- loss [36]. Forced convective air-warming devices actively phy. Further cardiac evaluation such as stress testing and heat patients during anaesthesia and aim to restore angiography should be considered in specific conditions normothermia. [33]. Cancer patients with tumour involving head, neck, and Several endocrine system disorders can have a major mediastinum may present with established or potential impact on perioperative morbidity and mortality. These airway compromise. Assessment of the airway by physical include diabetes mellitus, diabetes insipidus, hypopitui- examination and appropriate imaging is of paramount tarism, thyroid disorders, abnormalities of adrenal cortex importance. Awake fiberoptic intubations should be the and medullary function, and calcium disorders. Failure to technique of choice for large head and neck tumours identify these disorders in the preoperative period can where there is a risk of airway compromise on induction lead to acute medical problems in the intraoperative or of general anaesthesia. Elective tracheostomy should be postoperative periods [34]. Prior cancer therapy and its considered where fiberoptic intubation is deemed potential complications are also important aspects of impossible or hazardous, for example, large nasopharyn- preoperative assessment. Although it may be preferable geal tumour. Continuing postoperative endotracheal to anaesthetize patients only after any coexisting medical intubation is often prudent until airway patency is conditions have been successfully mitigated, some cancer assured [37]. operations, while not true emergencies, cannot wait excessively for interventions that could delay surgery Perioperative blood component therapy should be and allow cancer to spread. Appropriate support may guided by clinical judgement, considering the benefits be necessary if organ damage is critical or expected to and risks of such therapy. Cytomegalovirus infection worsen after surgery. has been a substantial cause of morbidity and mortality in oncology patients who are immunocompromised. Identification of correctable causes of anaemia, leuo- Patients at risk are those who received allogenic bone poenia and thrombocytopenia, and appropriate therapy, marrow/stem cell transplantation. Guidelines for blood including replacement of blood elements, bone marrow transfusion recommend that blood should not be trans- stem cell stimulation and maintenance of coagulation fused prophylactically and suggest that in patients with- homeostasis, improve patient’s survival [34]. out risk factors, the threshold for transfusion should be a haemoglobin level of 6–8 g/dl, whereas a threshold of Assessment of preoperative nutritional status and plan- 10–11 g/dl can be justified for patients who are con- ning for perioperative support merit attention [35]. sidered at risk [38]. Thrombocytopenia remains a signifi- Studies assessing nutrition in cancer patients suggest a cant clinical problem for patients with cancer. Although

platelet transfusion remains the gold standard for pro- intraoperatively may also be indicated, bearing in mind phylaxis and treatment of thrombocytopenia, transfusion- that tolerance is commonly present. The presence of transmitted disease, infection and platelet refractoriness tolerance may necessitate frequent and higher dosing. are associated with its use [39]. Adequate doses of opioids should be provided with at least an additional 30% for the acute postoperative period Benzodiazepines are increasingly recognized as having [48,49]. immunomodulatory actions mediated via the central nervous system. There are some data to suggest that Conclusion cytokines released in response to surgical stress may be Optimum perioperative care of the cancer patient reduced by midazolam [40]. Clinical concentration of requires assessment of the impact of cancer and its nitrous oxide and enflurane transiently depress natural treatment on the functional reserve of all major organ killer-cell activity [41]. However, there is no evidence to systems in the individual patient. Although various support the use of one volatile anaesthetic agent over anaesthetic agents and surgery itself have important another. Thiopentone decreases neutrophil chemotaxis, effects on immune function, their clinical significance while etomidate inhibits basal cortisol production, is not well established. Available evidence suggests that abolishes the stress response and increases mortality from anaesthetic agents have short-term reversible effects on wound infection in trauma patients admitted to intensive host immunity, and there is as yet no evidence to suggest care [42]. Intraoperatively, high dose fentanyl (in the that one anaesthetic technique is associated with better order of 20 mg/kg) and morphine suppress natural outcomes in cancer patients. killer-cell activity for 24–48 h [43]. References There are no studies evaluating the influence of anaes- Additional references related to this topic can also be found in the Current thetic technique on cancer outcome. However, exper- World Literature section in this issue (p. 288). imental studies from Ben-Eliyahu and colleagues demon- 1 Schottenfeld D. Epidemiology. In: Abeloff MD, Armitage JO, Lichter AS, strated that rats injected with a breast cancer cell line had editors. Clinical Oncology, 2nd ed. New York: Churchill Livingstone; 2000. pp. 494–518. decreased metastases when the animals had a laparotomy 2 Huettemann E, Sakka SG. Anaesthesia and anti cancer chemotherapeutic under regional anaesthesia compared with general anaes- drugs. Curr Opin Anaesthesiol 2005; 18:307–314. thesia [44]. 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