Complications in the oncological patient

Complications in the Oncological Patient David P. Myers, Kathleen A. O'Leary, and Mark J. Lema

OMPLICATIONS in the oncological patient undergoing surgery comprise three major areas of concern for the anesthesiologist. First, the type and extent of the tumor and whether organs are involved can have a profound impact on the management and outcome of the anesthetic. Second, the patient's chemotherapy regimen can interact with drugs given by the anesthesiologist. Third, radiation treatment can markedly alter the course of surgery and recovery. As with all patients undergoing surgery, a preoperative assessment should address the patient's general background health, extent of cancer growth, and treatment history. A close scrutiny of these areas will help to select an appropriate management course. This evaluation of the major organ system function may alter the need for invasive monitoring as well as for postoperative pain requirements (patient-controlled analgesia [PCA] v epidural analgesia).

C

TUMOR INVOLVEMENT

Knowing the extent of cancer involvement is vital to proper intraoperative anesthetic management. The review of diagnostic studies such as the computed tomography (CT) scan or magnetic resonance imaging (MRI) will show the extent of tumor invasion. Involvement of vital structures such as the vena cava, aorta, right atrium, or major arteries will necessitate large-bore intravenous catheters. These studies should also help anticipate the blood products needed for the surgery, because major debulking procedures can rapidly deplete blood product reserves. Compression of the trachea or direct erosion of tumor into the trachea or bronchi will necessitate fiberoptic or awake endotracheal intubation.

generated by highly toxic intermediates such as superoxide or hydroxyl radicals, which then bind to and disrupt cellular DNA. In contrast to most antitumor agents, bleomycin has little myelosuppressive activity. The primary toxicity of bleomycin is subacute or chronic pneumonitis that rapidly progresses to interstitial fibrosis. The exact pathogenesis of bleomycin lung injury is not fully understood. However, some studies implicate a direct toxic effect to pneumocytes, f'2 whereas others implicate nitrous oxide as a cotoxin. 3 The first signs of pulmonary toxicity are cough, dyspnea, and pleuritic chest pain. Carbon monoxide diffusion capacity of the lung (DLCO) decreases progressively, with total doses of the drug reaching 250 #g/m 2. The incidence of clinically significant pulmonary toxicity reaches 10% at total doses of 450 #g/m 2 or higher. 4 Toxicity is most frequently seen in older patients (>70 years of age), those with underlying lung disease such as emphysema, and those previously treated with pulmonary or mediastinal irradiation. Streptomyces antibiotics. Bleomycin appears to predispose patients to respiratory failure after surgery, particularly if high concentrations of inspired 02 are used during the procedure. The Goldiner et alS study suggested that the use of oxygen in concentrations greater than 28% greatly increased the risk of postoperative adult respiratory distress syndrome, s Although there appears to be a close relationship between total dose and risk of pulmonary toxicity, well-documented cases have been observed at total doses lower than 100 #g/m 2. There are anecdotal cases, but no definite proof regarding the use of steroids to treat bleomycin toxicity. Thus, pulmonary fibrosis can neither be prevented nor reversed with corticosteroids.

CHEMOTHERAPEUTIC AGENTS Antibiotics

The use of cytotoxic antibiotics such as bleomycin, mitomycin, and the anthracyclines (daunorubicin and doxorubicin) is critical information for the anesthesiologist. Bleomycin effects are

From the State University of New York at Buffalo, Roswell Park Cancer Institute, Buffalo, NY. Address reprint requests to David P. Myers, AID, Roswell Park Cancer Institute, Buffalo, New York 14263-0001. Copyright 9 1996 by W.B. Saunders Company 0277-0326/96/1503-000855.00/0

Seminars in Anesthesia, Vol 15, No 3 (September),1996: pp 283-287

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284 At our Institute, patients receiving bleomycin and mitomycin are treated in the same manner. We administer low oxygen concentrations (<30%) while monitoring 02 saturation by pulse oximetry. Both bleomycin- and mitomycintreated patients often maintain 90% to 95% oxygen saturation while being administered air/O2 concentrations under general anesthesia. Anthracyclines. Anthracyclines (doxorubicin, daunorubicin, idarubicin) exert their effects by producing oxygen free radical formation, causing DNA fragmentation. The heart is most susceptible to the toxic actions of anthracyclines. The one condition that can occur is an acute syndrome that can be seen for hours to days after a dose of doxorubicin or daunorubicin. This acute reaction is idiosyncratic and unrelated to the cumulative dose. It can manifest as conduction and rhythm disturbances, or in rare cases, cardiac failure. Electrocardiographic examinations have shown supraventricular arrhythmias, heart block, and ventricular tachycardia. Most of these changes are reversible after discontinuation of the agent but may take up to 1 to 2 months for complete resolution. The more common toxicity is a cumulative, dose-dependent cardiomyopathy that can lead to congestive heart failure in up to 10% of the patients who receive a total dose of 550 mg/m 2 of doxorubicin. Patients receiving anthracycline therapy are monitored routinely with echocardiography or multigated angiogram (MUGA) scans. Therapy is discontinued if serial studies demonstrate progressively worsening ejection fraction.

Alkylating Agents Alkylating agents were among the first compounds used for chemotherapy. They are administered both as single agents and in combination therapy regimens. Their chemotherapeutic effect is derived from their ability to alter DNA structure and function, causing cellular dysfunction. 9 These agents include nitrogen mustard, melphalan, cyclophosphamide, busulfan, ifosfamide, chlorambucil, lomustine (CCNU), carmustine (BCNU), and Thiotepa. One of the most common therapies used is MOPP. This consists of nitrogen mustard, vincristine (oncovin), procarbazine, and prednisone. The major side effects of nitrogen mustard and melphalan are myelosuppression, anemia, and thrombocytopenia.

MYERS, O'LEARY, AND LEMA Cyclophosphamide can produce significant leukopenia and immunosuppression. Excretion of active metabolites in the urine can also lead to hemorrhagic cystitis, l~ A syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and direct action on renal tubules can cause severe hyponatremia, seizures, and death. In addition to these side effects, patients receiving high-dose cyclophosphamide ( > 1.55 g/m 2) can experience cardiac necrosis caused by extensive uptake and metabolism of the drag in susceptible patients. Busulfan has been known to cause pulmonary fibrosis or hepatocellular dysfunction. In highdose transplantation regimens, busulfan has caused hepatic venoocclusive disease, mucositis, hemorrhagic cystitis, seizures, and pneumonitis. T M

Ifosfamide and cyclophosphamide have both a closely related structure and a similar spectrum of antitumor activity. Ifosfamide has the advantage of causing less myelosuppression and doselimiting cystitis. Another significant effect common to both is cerebellar-hepatic dysfunction. The chloroethylnitroureas, CCNU and BCNU, have as their most notable toxic effect delayed myelosuppression. Prolonged treatment with BCNU and CCNU has also been associated with pulmonary fibrosis. In addition, high-dose BCNU is associated with cardiovascular toxicity, including hypotension, tachycardia, and flushing. 13

Thiotepa is administered by intravenous and, most commonly, intracavitary routes. It has also been used by interpleural, intraperitoneal, or most commonly intrafascicular instillation. 14,15In routine dosing, the most common side effects associated with thiotepa are nausea, vomiting, and headaches. In high-dose regimens, delayed myelosuppression has been observed. 16

Platinum Analogs Cisplatinum and carboplatinum work by interfering with the DNA function. Platinum analog toxicity includes renal dysfunction, nausea and vomiting, neuropathy in a stocking and glove distribution, auditory and visual impairment, and myelosuppression. 1728 When these agents are used in the format of a single dose per cycle, the dose-limiting toxicity of cisplatinum has been nephrotoxicity. Renal dysfunction may be mani-

COMPLICATIONS IN THE ONCOLOGICAL PATIENT

fested as reduction of glomerular filtration rate (GFR), and electrolyte imbalance, especially hypomagnesemia. Acute renal failure may occur within 24 hours of drug administration, especially in patients receiving inadequate pretreatment hydration. Fortunately, in most patients receiving conventional doses of platinum analogs, renal dysfunction is mild and reversible.

Antimetabolites Methotrexate remains the most widely used antifolate in both cancer chemotherapy and noncancerous conditions such as psoriasis, graft-versus-host disease, and bacterial and parasitic conditions. It is available in both oral and intravenous forms. The side effects of methotrexate include myelosuppression, nephrotoxicity and neurotoxicity, and acute and chronic hepatotoxicity, which is usually reversible. The most common syndrome after methotrexate is injected intrathecally is that of acute chemical arachnoiditis. 5-Fluorouracil (5-FU) is most commonly administered in combination therapy, because it has antitumor activity against many tmnors and synergistic interactions with other antineoplastic agents and radiation. The primary effect of 5-FU is myelosuppression. Less common side effects include dermatologic and neurological symptoms. Cytosine Arabinase (ARA-C) is most commonly used in patients with acute myeloblastic leukemia (AML). It is occasionally used in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma. Its main toxic effects are myelosuppression, gastrointestinal epithelial injury, and sloughing. Antimicrotubule Agents Taxol (Paclitaxel; Bristol-Myers Squibb Co, Princeton, N J), a natural product derived from the bark of a yew tree, is most widely used in ovarian, breast, and lung cancers. 6 Taxol works by actually increasing the rate of microtubular assembly, promoting tubular dysfunction and G2 and M phase arrest. 7 The most common side effects are type 1 hypersensitivity reaction, dyspnea, bronchospasm, urticaria, flushing, and hypotension. 8 Also, myelosuppression and peripheral neuropathy (glove-stocking distribution) have occurred. In patients with preexisting neu-

285 Table 1. Toxic Effects of Radiation

Organ

Toxic Effects

Skin (epidermis) Gastrointestinal t r a c t Hair follicles Bone marrow Vaginal/oral mucosa

Radiation burn Nausea/vomiting, adhesions Alopecia Pancytopenia Mucositis

ropathy, Taxol has been reported to cause motor and autonomic dysfunction. The vinca alkyloids, vincristine and vinblastine, disrupt microtubule formation by binding to tubulin and causing metaphase arrest. These compounds are widely used for lymphomas, leukemias, sarcomas, and other solid tumors. Their major dose-limiting adverse effect is a mixed sensorimotor neuropathy, especially in the arms and legs. Alopecia, bone marrow suppression, and gastrointestinal (GI) irritation are also known to occur after using these drugs. RADIATION THERAPY

Two general types of radiation techniques are used clinically; brachytherapy and teletherapy. In brachytherapy, the radiation device is placed within or close to the target tissue. Most commonly these are gynecologic and pulmonary tumors. In teletherapy, a device is located some distance from the patient, and a varying dose of ionizing radiation is emitted. Patients may receive radiation therapy for either curative or palliative reasons. Palliative radiation therapy is designed to reduce cancer pain secondary to bone metastases, alleviate obstruction by tumor, or reduce hemorrhage from an ulcerating tumor. Anesthesiologists should ascertain where and when the radiation was given. Radiation may produce acute or chronic complications (Table 1). Radiation effects on vital organs are of great importance to the anesthesiologist. Mediastinal, lung, or breast cancers requiring radiation therapy can expose cardiac tissue to ionizing radiation. Shielding the heart is difficult during radiation therapy. Fortunately, the heart is somewhat radioresistant. Complications arise because of vascular or pericardial damage. Anthracyclines and radiotherapy (RT) can synergistically produce cardiomyopathy. Noninvolved tissue can

MYERS, O'LEARY, A N D LEMA

286 Table 2. Other Complications of Radiation Therapy Hepatic Renal Bone

Venoocclusive disease Radiation hepatitis Radiation nephritis Renal failure Hypertension Scoliosis (children) Thoracic cage deformities (children)

also be injured b y R T used to treat mediastinal, lung, and breast cancers. These complications are rare but include radiation pneumonitis, p u l m o nary fibrosis, p a t h o l o g i c a l rib fractures, pleural effusion, t r a c h e o - e s o p h a g e a l (TE) fistulae, and h y p o x e m i a . Other c o m p l i c a t i o n s to vital organs are listed in T a b l e 2. The m o s t c o m m o n complications o f radiation therapy to h e a d and neck tumors are l a r y n g e a l edema, fibrosis, scarring, skin tethering, and laryngeal cartilage necrosis. Close e x a m i n a t i o n and a p r e o p e r a t i v e conversation with the surgeon are m a n d a t o r y in such cases to assist in anesthetic m a n a g e m e n t o f the airway.

completed, and m a y b e c o m e a serious sequela o f an otherwise u n c o m p l i c a t e d m i n o r surgical procedure. It is important to realize that m a n y patients will never k n o w which chemotherapeutic agents they have received. T h e y only k n o w they have had " c h e m o t h e r a p y . " In certain circumstances, it m a y be i m p o s s i b l e to locate records concerning their treatment. In those cases, it is best to at least be familiar with which drugs are most c o m m o n l y used for their type of malignancy. Then, if any of those drugs have anesthetic implications, assume they were used and adjust the anesthetic plan accordingly. Finally, one should not underestimate the psychological state o f the cancer patient presenting for surgery. W h e t h e r their anxieties are obvious or not, they are virtually always present. S o m e times just an a c k n o w l e d g m e n t that it is normal to be nervous goes a long w a y toward m a k i n g them feel m o r e at ease. This, a c c o m p a n i e d b y intravenous m i d a z o l a m , m a y m a k e a stressful preoperative situation m o r e tolerable and help the patient to better c o p e with the " e m o t i o n a l b a g g a g e " associated with his or her surgery.

CONCLUSION W i t h the current p r e v a l e n c e o f cancer and the successes in cancer therapy, it has b e c o m e m u c h m o r e c o m m o n to see cancer patients in the operating room. T h e y m a y be presenting for diagnostic surgery, resection o f tumor, surgery relating to c o m p l i c a t i o n s o f chemotherapy, or radiation, or surgery unrelated to their malignancy. W h a t e v e r the scenario, it is important for all anesthesiologists to be aware o f the p h y s i o logical implications o f the m a l i g n a n c y itself, and the toxicities associated with the treatment. Certain therapies m a y have long-lasting effects on the b o d y and m a y be a p r o b l e m long after a m a l i g n a n c y has been cured. A classic e x a m p l e is A d r i a m y c i n - i n d u c e d c a r d i o m y o p a t h y (Pharmacia, Dublin, OH), which m a y be present years after a child has been successfully treated for leukemia. Similarly, the successfully treated H o d g k i n s ' l y m p h o m a patient m a y very likely have been treated with mantle radiation. On rare occasions, this m a y p r e d i s p o s e a patient to the d e v e l o p m e n t o f p u l m o n a r y e d e m a after liberal intravenous hydration, as sometimes occurs intraoperatively. This c o m p l i c a t i o n m a y h a p p e n years after the radiation treatments have been

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