Oncologic emergencies for the internist - Cleveland Clinic Journal of ...

CANCER DIAGNOSIS AND MANAGEMENTWILLIAM S. KRIMSKY, MDJohns Hopkins University/Sinai Hospital Programin Internal Medicine, Baltimore, MDROBERT J. BEHRENS, MDOncology and Hematology Fellow, MedicineBranch, National Cancer Institute, Bethesda, MDMAURIE MARKMAN, MD, EDITORGARY J. KERKVLIET, MDInstructor in Medicine, Johns Hopkins Hospitaland General Internal Medicine Faculty, JohnsHopkins University/Sinai Hospital Program inInternal Medicine, Baltimore, MDPREVENTION,DETECTION, ANDMANAGEMENTFOR THEGENERALISTOncologic emergencies for the internist■ ABSTRACTMost cancer patients experience at least one emergencyduring the course of the disease. This paper reviews thediagnosis and treatment of tumor lysis syndrome,hypercalcemia of malignancy, superior vena cava syndrome,spinal cord compression, strokes and seizures, andtreatment-related emergencies.■ KEY POINTSTo prevent tumor lysis syndrome, patients at risk should bestarted on intravenous fluids and, if possible, allopurinol,several days before chemotherapy.Hypercalcemia of malignancy is treated with hydration andwith bisphosphonates. Diuresis with furosemide should bestarted only after the patient is adequately hydrated.The new onset of back pain in a cancer patient is a red flagfor spinal cord compression. Prompt treatment withcorticosteroids and radiation therapy may preserve thepatient’s ability to walk.In neutropenic fever, antibiotics must be startedimmediately, including a broad-spectrum antipseudomonaldrug such as ceftazidime. Patients should also receivevancomycin to cover resistant gram-positive organisms ifthey have any of the following: severe mucositis, catheterinfection, current quinolone prophylaxis, hypotension, orknown colonization with resistant gram-positive organisms.AS MORE CANCER PATIENTS undergo outpatienttherapy, internists are beingconfronted more often with emergencies relatedto cancer or its treatment. Emergencies incancer patients encompass virtually everymajor organ system. This article focuses on thecommon and critical complications of cancerthat the general internist is most likely to seeand can least afford to miss, specifically:• Tumor lysis syndrome• Hypercalcemia of malignancy• Superior vena cava syndrome• Spinal cord compression• Strokes and seizures• Treatment-related emergencies.Overall, most cancer patients experienceone of these complications at some point inthe course of their disease.■ TUMOR LYSIS SYNDROMETumor lysis syndrome is the set of metabolicabnormalities that results from acute destructionof neoplastic cells and release of theirintracellular products into the circulation. Thehigh rate of cell turnover overwhelms thebody’s normal homeostatic mechanisms forhandling potassium, calcium, phosphorus, anduric acid, leading to hyperuricemia, hyperkalemia,hyperphosphatemia, hypocalcemia,and uremia. These may be seen alone or incombination with one another.Tumor lysis syndrome occurs with a varietyof tumors, most commonly the hematologicmalignancies. Hande and Garrow 1 found anincidence of tumor lysis syndrome of 42%among patients with high-grade non-Hodgkinlymphoma, although it was considered clinicallysignificant in only 6%. The risk depends notonly on the type of tumor, but also on theextent of disease, the type of treatment, and thepatient’s preexisting renal function (TABLE 1). 2CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 3 MARCH 2002 209

ONCOLOGIC EMERGENCIESKRIMSKY AND COLLEAGUESHyperkalemia isthe most lifethreateningproblem intumor lysissyndromeNot available foronline publication.See print version of theCleveland Clinic Journalof MedicineFeatures of tumor lysis syndromeHyperuricemia. Catabolism of largeamounts of both RNA and DNA causes uricacid levels to rise fairly quickly. Normally, uricacid remains in the ionized state in the body;however, increased levels can lead to urateprecipitation in the distal tubule. 3 The resultof precipitation is an overall decrease in renalfunction.Hyperphosphatemia and hypocalcemiaalso result from the above process. Phosphatelevels in neoplastic cells can be as much as fourtimes higher than in normal cells. 4,5 Thebreakdown and release of phosphate is initiallycompensated for by increased renal excretion.However, as the concentration of phosphateincreases, it combines with calcium and precipitatesin the renal tubule as well as in thesoft tissues. Consequently, hypocalcemia andrenal failure develop. 6 Clinically, hypocalcemiacan manifest as agitation, tetany, andbone pain.Hyperkalemia is perhaps the most lifethreateningderangement in tumor lysis syndrome.The sudden increase in potassiumresults in the well-defined clinical presentationof cardiac arrhythmias and death.All the above metabolic derangements aremade worse by preexisting renal insufficiency.Treatment of tumor lysis syndromeProphylaxis is the first step in treatment (TABLE2). 7 If a patient is found to be at high risk fortumor lysis syndrome, he or she shouldpromptly be started on both intravenous fluidand allopurinol if there is no contraindicationto it. Close observation during therapy is alsoessential, as transient, urgent hemodialysismay reverse the toxicity.■ HYPERCALCEMIA OF MALIGNANCYHypercalcemia of malignancy occurs inapproximately 10% to 20% of cancerpatients, 8,9 most often with lung cancer,breast cancer, and the hematologic malignanciessuch as multiple myeloma and lymphoma.10Features of hypercalcemia of malignancySymptoms vary depending on the degree ofhypercalcemia and how quickly it develops.Acute symptoms include nausea, vomiting,constipation, polyuria, polydipsia, muscleweakness, acute renal insufficiency, and mentalstatus changes. Chronic symptoms includekidney stones, bone pain, and depression.Mechanisms of hypercalcemiaof malignancyNormally, calcium levels are maintained bythe interaction of parathyroid hormone, calcitonin,and 1,25(OH) 2 -vitamin D. The disordersof calcium metabolism in malignancyusually represent an alteration in one of thesepathways or extensive lytic bone lesions.Parathyroid hormone-related peptide.The most common cause of hypercalcemia ofmalignancy, classically seen in squamous celllung cancer, is a syndrome mediated by productionof a parathyroid hormone-related peptide(PTHrP). Structurally similar to PTH atthe amino acid terminus, PTHrP binds toparathyroid hormone receptors, mobilizes calciumfrom bones, and increases renal reabsorptionof calcium. Evidence suggests thatthere might be some clinical utility to measuringPTHrP because significant elevations ofPTHrP seem to correlate with poorer outcomes.11–13Abnormal production of calcitriol (1,25-vitamin D). The deregulated conversion of210 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 3 MARCH 2002

Not available for online publication.See print version of theCleveland Clinic Journal of Medicine25-vitamin D to 1,25-vitamin D appears to beresponsible for some of the hypercalcemia ofmalignancy seen in both Hodgkin lymphomaand non-Hodgkin lymphoma. 14,15 Thus, it issimilar to the hypercalcemia associated withsarcoidosis and other granulomatous diseases.Direct tumor invasion into bony structures.Individual tumor cells secrete a varietyof mediators, including interleukin-1, interleukin-6,and tumor necrosis factor, that upregulatelocal osteoclastic activity, causingcalcium to be released into the serum. 16Treatment of hypercalcemia of malignancyTreatment must address these various mechanismsto be effective; ideally, the best way is byreducing or eliminating the causative malignancy.Hydration. Patients with hypercalcemiaof malignancy invariably present with somedehydration caused by calcium’s effect on thekidney. Thus, appropriate managementshould begin with giving intravenous fluids toimprove symptoms and to induce excretion ofcalcium. However, even with adequatehydration, most patients do not achieve anacceptable calcium level, and thus additionaltherapies are used to control the renal andskeletal mechanisms of hypercalcemia ofmalignancy.Diuresis with furosemide increases renalexcretion of calcium, but should be startedonly when the patient has been adequatelyhydrated—otherwise it will exacerbate thefree water loss relative to the loss of sodiumand calcium.Bisphosphonates. Most experts recommendusing bisphosphonates, most oftenpamidronate, to produce a sustained decreasein the calcium level by inhibiting osteoclasticactivity and calcium resorption from bone. 17Pamidronate is given intravenously in either aHypercalcemicpatientsinvariably aredehydratedCLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 3 MARCH 2002 213

ONCOLOGIC EMERGENCIESKRIMSKY AND COLLEAGUESExpertsrecommendpursuing atissue diagnosisin superior venacava syndrome60-mg or a 90-mg dose over at least 2 hours. 18Approximately 60% of patients respond to a60-mg dose and nearly 100% to a 90-mgdose. 19 Pamidronate usually takes approximately12 to 48 hours to produce an initialresponse, and the response is sustained for anaverage of about 2 weeks. 20Calcitonin is frequently used in additionto bisphosphonates because it has a rapidonset of effect: within 2 to 4 hours of administration.21 Its main drawbacks are hypersensitivityreactions and tachyphylaxis; the latterusually develops within 3 days.Gallium nitrate and plicamycin are usedinfrequently because of their toxicity.Steroids are frequently helpful in theshort term, especially in sensitive tumors suchas lymphoma and myeloma.Dialysis remains an option for those whocannot tolerate a saline load.■ SUPERIOR VENA CAVA SYNDROMESuperior vena cava syndrome is relatively rare,affecting 2.4% to 4.2% of lung cancerpatients, who account for 65% of all cases. 22Small cell lung cancer is the most frequentcause of the syndrome because it has apredilection for the central region of thelungs. 23 Lymphoma accounts for 8% of cases,and breast cancer and other mediastinalmetastatic lesions account for 10%. 22Of note: several nonmalignant diseasessuch as granulomatous and fibrosing mediastinitis,goiters, and aortic aneurysms can alsocause superior vena cava syndrome.Features of superior vena cava syndromeSuperior vena cava syndrome results from anincrease in central venous pressure caused byvena caval obstruction. Typically this producescough, dyspnea, and dysphagia combinedwith swelling and discoloration of theneck, face, or upper extremities. Dependingon the site of the disease, both vocal cordparalysis and Horner syndrome (sinking in ofthe eyeball, ptosis of the upper eyelid, elevationof the lower lid, constriction of the pupil,narrowing of the palpebral fissure, andanhidrosis and flushing of the affected side ofthe face; caused by compression of sympatheticnerves) can occur.Treatment of superior vena cava syndromeInitial treatment consists of elevating thehead of the bed and giving diuretics and corticosteroids.However, corticosteroids are moreuseful when the cause of the obstruction islymphoma rather than lung cancer.Chemotherapy and radiation therapy.Unless tracheal obstruction is present orimpending, superior vena cava syndrome isnot immediately life-threatening, and mostexperts recommend pursuing a tissue diagnosisso that specific treatment can be given for theprimary tumor alongside treatment for thesymptoms. 22Both primary chemotherapy and radiationare important components of therapy. In smallcell lung cancer, Chan et al 24 found no differencein the response rate in patients whoreceived chemotherapy compared with radiationtherapy. The recurrence rate of superiorvena cava syndrome depends on the type oftumor causing the obstruction. In large celllymphoma the high risk of recurrence withchemotherapy resulted in a recommendationto use radiation therapy. 25Intravenous stenting can relieve symptoms,particularly dyspnea, for most patients.Anticoagulation. Thrombus formationoccurs in up to 50% of patients with superiorvena cava syndrome. In a small study,Adelstein et al 26 attempted prophylaxis withfull doses of heparin and warfarin but found itconferred no survival advantage when treatedpatients were compared with 10 historicalcontrols. However, anticoagulation is stillused for symptom relief regardless of effect onsurvival.■ SPINAL CORD COMPRESSIONSpinal cord compression is not immediatelylife-threatening unless it involves level C3 orabove, but it may lead to profound, permanentmorbidity. Paraplegia or loss of sphincter controlor both not only diminishes a patient’squality of life but also predisposes to furthercomplications such as venous thrombosis,decubitus ulcers, and urinary obstruction.Spinal cord compression occurs at sometime in approximately 5% of all cancerpatients, 27 most often in carcinomas of theprostate, lung, and breast.214 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 3 MARCH 2002

ONCOLOGIC EMERGENCIESKRIMSKY AND COLLEAGUESMRI withoutcontrast is thebest test forspinal cordcompressionFeatures of spinal cord compressionPain is the primary symptom and iseventually reported in 96% of patients withspinal cord compression. 28 The pain may beacute or may gradually increase over weeks.Although the pain is similar to that of discdisease, one potential difference is that thepain of spinal cord compression can beincreased in the supine position anddecreased when upright.Other signs and symptoms are weakness,sensory deficits, and autonomic dysfunction.Diagnosis of spinal cord compressionIt is often difficult to decide whether a patientwith back pain should be thoroughly evaluatedto exclude spinal cord compression, but apatient with known or suspected metastaticdisease (especially tumor types with a tropismfor bone) presenting with a new pain patternor a neurologic deficit deserves meticulousevaluation.Magnetic resonance imaging (MRI)without contrast is the best and most costeffectivetest. 29Several nonmalignant conditions, suchas osteoporotic compression fractures andspinal abscesses, may also cause spinal cordcompression and must be diagnosed accurately,as their treatment and prognosis aremarkedly different.Treatment of spinal cord compressionNeurologic compromise can be rapid; therefore,treatment must begin quickly after diagnosis.Corticosteroids are a critical part of theinitial management because they decreaseedema that may compress vasculature or thenerves directly and lead to permanent injury.Although dosages are debated, the minimumis dexamethasone 10 mg (or an equivalent) byintravenous bolus followed by 4 mg intravenouslyevery 6 hours.Radiation therapy. Carcinomas of theprostate, lung, and breast are more predictablyresponsive to radiotherapy than are othertypes of tumors. However, a patient presentingwith any type of malignant spinal cord compressionshould also seen urgently by a radiationoncologist.Chemotherapy may be an option forextremely chemosensitive tumors such aspediatric neuroblastomas.Surgery is the remaining option if a tissuediagnosis is needed, the area has previouslyreceived maximal irradiation, spinal stabilizationis needed, or other treatments are notworking.■ STROKES AND SEIZURESStrokes and seizures are common in cancerpatients. Strokes occur in 7% of all cancerpatients 30 and are equally split between hemorrhagicand thrombotic subtypes. Seizuresoccur in 2.7% of patients with cerebral metastasesand in 1.8% of cancer patients withoutbrain metastases. 31Initial treatment of strokes and seizures incancer patients is the same as in patients withoutcancer. After initial stabilization, specifictreatment of the tumor such as radiotherapyor steroids should be started. In addition,patients with thrombotic strokes might beconsidered candidates for antiplatelet, anticoagulation,or thrombolytic therapy.Patients with cerebral metastasis withouta history of seizure should be advised not todrive or engage in activities in which an unexpectedseizure could harm them or others.Randomized studies have shown no benefitfrom prophylactic anticonvulsants, 32 withpossible exceptions for melanoma brainmetastases or leptomeningeal metastases.■ TREATMENT-RELATED EMERGENCIESExtravasation of chemotherapeutic drugsExtravasation—leakage of chemotherapeuticdrugs into the skin— results in pain, redness,swelling, and even necrosis. Its reported incidenceranges from 0.1% to 6.5% ofchemotherapy infusions. 33 Although thesereactions are usually seen in an oncologic setting,they are increasingly being seen in theprimary care physician’s office as morepatients undergo home infusion therapy.Occasionally, symptoms may develophours or days after the initial insult. The delaycan be caused by endocytolysis, in which asmall amount of drug kills and lyses cells atthe injection site and then moves on repeat-216 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 3 MARCH 2002

Not available for online publication.See print version of theCleveland Clinic Journal of Medicineedly to damage the surrounding tissues.Extravasation is important because largeareas of skin may break down, leading to poorcosmetic results, secondary infection, andcontractures if the injury is over a joint.The most common culprits are vesicants,which cause blisters when they contact skin.Anthracyclines (eg, doxorubicin and idarubicin)and vinca alkaloids (eg, vincristine andvinorelbine) are the most common vesicantsused in clinical practice.If the patient is complaining of pain orproblems during vesicant infusion, the infusionshould be stopped, the line aspirated toremove residual drug, and an antidote (ifavailable) instilled through the line (TABLE 3). 33If using a port, disconnect the infusion line; ifusing a temporary intravenous line, discontinueit. Compression of the site should be avoidedas this may spread the remaining drug furtherout from the injection site. The use ofheat, ice, and antidotes depends on the specificchemotherapeutic drug.If a patient presents to an internist withpain at an injection site, with or without redness,shortly after a chemotherapy infusion, heor she should be referred to his or her treatingoncologist urgently.Neutropenic feverNeutropenic fever is common, and if it is leftuntreated the mortality rate is 50%. 34Neutropenia is defined as a neutrophilcount lower than 0.5 ×10 9 /L (500/mm 3 ), orless than 1.0 × 10 9 /L and expected to declinebelow 0.5 soon. A fever is defined as a singletemperature of 38.3˚C (101.0˚F) or higher, ora temperature of 38.0˚C (100.4˚F) or higherlasting over 1 hour.A complete fever workup should be completed,and then antibiotics should be startedpromptly. All patients should receive a broadspectrumantipseudomonal drug such as ceftazidime.They also should receive vancomycinto cover resistant gram-positiveorganisms if any of the following is present:severe mucositis, catheter infection, currentquinolone prophylaxis, hypotension, orknown colonization with resistant gram-positiveorganisms. Often, despite a comprehensivesearch, the cause is never found; however,it is essential to start antibiotics immediatelyupon noting a neutropenic fever. Antibioticsshould be continued until the absolute neutrophilcount exceeds 0.5 × 10 9 /L and thepatient is afebrile.It is important for the patient and all ofhis or her contacts to routinely wash theirhands.DehydrationOften overlooked, dehydration is a serious riskand is very common in cancer patients becauseof cachexia caused by the disease or its treat-Stop theinfusion if thepatientcomplains ofpain duringvesicantinfusionCLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 3 MARCH 2002 217

ONCOLOGIC EMERGENCIESKRIMSKY AND COLLEAGUESment. Dehydration is associated with deliriumin 30% of cancer patients and is linked toshorter survival. 35 Common treatment-relatedcauses include emesis, diarrhea, and mucositis.For example, in some series of colon cancerpatients, 36 approximately 50% required achange in treatment because of dehydrationand 20% required intravenous fluids.An internist can improve a patient’s qualityof life by providing supportive care withfluids, antiemetics, and antidiarrheal drugsand by communicating with the oncologist todiscuss adverse effects that may require achange in treatment.■ REFERENCES1. Hande KR, Garrow GC. Acute tumor lysis syndrome inpatients with high grade non-Hodgkin’s lymphoma. Am JMed 1993; 94:133–139.2. Flombaum CD. Metabolic emergencies in the cancerpatient. Semin Oncol 2000; 27:322–334.3. Conger JD, Falk SA. Intrarenal dynamics in the pathogenesisand presentation of acute urate nephropathy. J ClinInvest 1977; 59:786–793.4. 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New York: Churchill Livingstone,2000:719–733.Anaphylaxis and capillary leakSome systemic treatments such as interleukin-2 (IL-2) may cause severe hypotension, especiallywhen given at high doses intravenously.The mechanism is decreased systemic vascularresistance and leakage out of vessels, leading tointravascular volume depletion. Somehypotension is seen in up to 70% of patientsreceiving IL-2 in high doses, and 3% experiencelife-threatening degrees of hypotension. 37Close monitoring in an intensive care unit iswise before starting such high-dose therapy.The treatment is to not give more IL-2until the patient recovers and to provide supportivecare with intravenous fluids andphenylephrine. IL-2 in low doses rarely causessuch hypotension.Hemorrhagic cystitisSome chemotherapeutic drugs have toxicmetabolites that are excreted by the kidneyand can cause severe bladder hemorrhage. 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KRIMSKY AND COLLEAGUESVisitOurWebsiteFor InformationonOnline CME&Upcoming Courses• Great Lakes Thrombosis Update, April 20, 2002• Contrast Echocardiographyand New Technologies, May 8, 2002• Update in Headache Management, May 15, 2002intravenous pamidronate in the treatment of tumorinducedhypercalcemia. Postgrad Med J 1992; 68:434–439.19. Nussbaum SR, Younger J, Vandepol CJ. Single-dose intravenoustherapy with pamidronate for the treatment ofhypercalcemia of malignancy: Comparison of 30-, 60-, and90-mg dosages. Am J Med 1993; 95:297–304.20. Wimalawansa SJ. Optimal frequency of administration ofpamidronate in patients with hypercalcemia of malignancy.Clin Endocrinol 1994; 41:591–595.21. Warrell RP Jr, Israel R, Frisone M, Snyder T, Gaynor JJ,Bockman RS. Gallium nitrate for acute treatment of cancer-relatedhypercalcemia. A randomized double-blindcomparison to calcitonin. Ann Intern Med 1988;108:669–674.22. Yahalom J. Superior vena cava syndrome. In: DeVita VT,Hellman S, Rosenberg SA, editors. Cancer: Principles andPractice of Oncology. Philadelphia: Lippincott Williams &Wilkins, 2001:2609–2653.23. Sculier JP, Evans WK, Feld R, et al. Superior vena cavaobstruction in small cell lung cancer. Cancer 1986;57:847–851.24. Chan RH, Dar AR, Yu E, et al. Superior vena cava obstructionin small cell lung cancer. Int J Radiat Oncol Biol Phys1997; 38:513–520.25. Perez-Soler R, McLaughlin P, Velasquez WS, et al. Clinicalfeatures and results of management of superior vena cavasyndrome secondary to lymphoma. J Clin Oncol 1984;2:260–266.26. Adelstein DL, Hines JD, Carter SG, et al. Thromboembolicevents on patients with malignant superior vena cava syndromeand the role of cardiac function. Cancer 1988;62:2258–2262.27. Byrne TN. Spinal cord compression from epidural metastases.N Engl J Med 1992; 327:614–619.28. Gilbert RW, Kim J-H, Posner JB. Epidural spinal cord compressionfrom metastatic tumor: diagnosis and treatment.Ann Neurol 1978; 3:40–51.29. Fuller BG, Heiss JD, Oldfield EH. Spinal cord compression.In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer:Principles and Practice of Oncology. Philadelphia:Lippincott Williams & Wilkins, 2001:2623–2624.30. Schiff D, Batchelor T, Wen PY. Neurologic emergencies incancer patients. Neurol Clin 1998; 16:449–483.31. Clouston PD, DeAngelis LM, Posner JB. The spectrum ofneurological disease in patients with systemic cancer. AnnNeurol 1992; 31:268–273.32. Schiff D, Batchelor T, Wen PY. Neurologic emergencies incancer patients. Neurol Clin 1998; 16:449–483.33. Albanell J, Baselga J. Systemic therapy emergencies. SeminOncol 2000; 27:347–361.34. Hughes WT, Armstrong D, Bodey GP, et al. 1997Guidelines for the use of antimicrobial agents in neutropenicpatients with unexplained fever. Clin Infect Dis1997; 25:551–573.35. Lawlor PG, Gagnon B, Mancini IL, et al. Occurrence, causes,and outcome of delirium in patients with advancedcancer. Arch Intern Med 2000; 160:786–794.36. Arbuckle RB, Huber SL, Zacker C. The consequences ofdiarrhea occurring during chemotherapy for colorectalcancer: a retrospective study. Oncologist 2000; 5:250–259.37. Physician’s Desk Reference in Micromedex; 1998.Druginfo.cc.nih.gov.38. Hensley ML, Schuchter LM, Lindley C, et al. AmericanSociety of Clinical Oncology clinical practice guidelines forthe use of chemotherapy and radiotherapy protectants. JClin Oncol 1999; 17:3333–3355.ADDRESS: Robert J. Behrens, MD, National Cancer Institute,Navy Building 8, Room 5101, Bethesda, MD 20892; e-mailbehrensr@mail.nih.gov.222 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 3 MARCH 2002