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Oncology Emergencies

The cancer patient at times is quite prone to collapse and sudden death. When it occurs, it is usually on the basis of an arrhythmia. Not at all uncommonly, it is an independent event related to actual sclerotic disease and to the general disease of older people, or all of us, as we age. Nonetheless, it’s fair to say that many types of tumors, solid and hematologic, will involve the heart and its various substructures. A few examples in am going to amplify in a short while, involvement with the pericardium. But a few examples: for instance, it would amyloidosis in the context of, let’s say, of multiple myeloma. An important infiltrate of cardiomyopathy. Marantic endocarditis often seen and usually produce the adenocarcinomas. Abnormalities of the valve leaflets and an infiltration of the myocardium in hypereosinophilias syndromes. And in the acute carcinoid crisis there can be cardiac collapse in the context of massive serotonin release. A little more about that in a few moments.

Now various modalities that are utilized in treatment for patients with cancer and at times can be implicated in causes for severe acute cardiac morbidity. In this case we are going to focus on radiation therapy, an important modality. We know for example that radiation can cause an acute pericarditis with the classical symptoms of pericarditis and an acute onset of a pericardial effusion. Radiation used more commonly rather than acute will result in a chronic pericarditis and a chronic pericardial effusion. Frequently occurring many months - even a couple of years - after the onset of therapy. In fact, it’s not uncommon to find this as an asymptomatic finding in patients who have had prior radiation therapy, if you are investigating

We know too that chemotherapy, not just radiation and not just the patient’s underlying cancer, but chemotherapy is an important cause of cardiac events that can lead to collapse and death. For example, a number of drugs will cause acute cardiac toxicity. Probably the best known among them for an acute and very severe cardiac toxicity is on cyclophosphamide. Cyclophosphamide or Cytoxan is an ubiquitously used alkylating agent of great value in many many cancers. It has tremendous utility in a number of high dose chemotherapy programs as a precursor to either autologous or stem cell infusions. But cyclophosphamide is capable of causing acute cardiomyopathy with pericarditis and pericardial effusion and occasionally life threatening arrhythmias. Probably more common is the category of anthracycline antibiotics. Anthracyclenes as you know are among the most useful anticancer drugs that we have. Probably the best known is Adriamycin, but there are cousins, structural cousins antarubicin and idarubicin and daunomycin which medicinally are quite similar. They can each upon effusion cause acute arrhythmias, not uncommonly ventricular premature beat and runs of v tach. Occasionally these can be lethal. The arrhythmogenic effects of the anthracyclenes are not dose dependent. Conversely, on the cardiomyopathy that results in congestive heart failure and certainly can be a cause of death in the cancer patient, is a chronic and dose dependent phenomenon. Generally 450 mg per square meter is considered the maximum threshold dose above which the incidence for heart failure rises with the use of these.

Now lets talk about pericardial tamponade. Why? Because it is indeed the most common manifestation in the heart of an urgent medical problem related to an underlying neoplasty. It is often quite insidious in its onset. Patients may feel just fatigued and nothing more specific. It’s not uncommon that a patient with have abdominal complaints. Increased gaseousness, crampiness, thinking that they just have a persistent upset stomach. Some will have shortness of breath and others will have substernal chest pain. Although by no means is that a requirement. You will find the patient to be frequently tachycardic and have a variety of classical and telltales signs, such as the Kussmaul’s sign, which is venous neck vein distention upon deep inspiration as opposed to neck vein collapse, which is the usual. Tender cardiomegaly and a greater than 10 mm pulses paradoxus. Very often the tamponade syndrome appears acutely and suddenly but it really reflects a process that is quite chronic and insidious at its onset. The diseases that are most commonly associated with malignant pericardial involvement, pericardial effusions and tamponade, are listed here. Probably the most common is cancer of the lung. Why? Because it occurs in the mediastinum or in the lower thorax and it is probably the most common disease. Disproportionately represented are the leukemias and lymphomas, specifically Hodgkin’s and non-Hodgkin’s lymphomas also because of the

Pathophysiologically, as you know, there is on normal inspiration there is increased right heart filling, as depicted here, with enlargement of the right ventricle in particular as the intrapericardial pressure diminishes during inspiration. During the context of tamponade physiology, which is depicted in the left lower quadrant here, what you see is unlike the normal inspiration over here. You basically see a contracted ventricular space. The right

Now, what to do about this is fairly straightforward, however it requires skilled hands. I think it should not be left to the oncologist, or in fact the generalist who is not familiar with doing pericardiocenteisis unless the situation is absolutely urgent and a cardiologist is not around. At times it will present very acutely and formidably and there won’t be a diagnosis, and a diagnosis is key. It is absolutely essential to figure out if the patient has got tamponade related to prior therapy, as in XRT, or is the tamponade occurring as a manifestation of progression of the disease. The

Now cardiac defects, in addition to infiltration of the pericardium or even the myocardium and damage to the myocardium from cytotoxic agents. The heart itself is also prone to being victimized by some of the tumoral substances that tumors secrete. A telltale one is associated with 5HT serotonin production by the carcinoid tumor. Commonly carcinoid tumors produce metastasis to the liver in such a context: if the tumor is a heavy secretor of serotonin or 5HIA there will be right-sided heart lesions that are produced. What one sees typically and readily is intimal and valvula thickening on the right side of the heart leading to tricuspid regurgitation and pulmonic stenosis. Very very dramatic presentations at times. This will lead to intractable and irreversible right sided congestive heart failure. So the only way to deal with this is to recognize it, number one - which means looking for it with an endo in the proper clinical context - and secondly the therapy needs to be directed with interfering with the affective dismediator. That’s difficult. That’s more easily said than done. Somatistat is often used to oppose the effect of serotonin, but ultimately this is extremely dangerous and not uncommonly, a fatal complication causing cardiac death. I should point out that every once in awhile, quite rarely, there is a syndrome in which the carcinoid is in the bronchus, bronchial carcinoid and that it draining into the left side of the heart. So you are going to see comparable lesions on the left side of the heart.

The other cardiac abnormality that occurs in the context of cancer that needs to be thought about - because it can precipitate acute cardiac type illness or hemodynamic crises or even sudden catastrophe - is high output cardiac failure. We see this of course in patients who in the context of their neoplasm or its therapy, or are profoundly anemic, occasionally you will see it in hyperthyroidism unrelated to cancer, and sometimes in those illnesses, like hematologic cancers that are associated with very very nasty splenomegaly, you can get internal shunting within the spleen and that will produce high output state. How do you figure this out? Well, for one thing, one has to be prepared to just consider this as a possibility. And echocardiogram might be useful to demonstrate the high output state. Its therapy of course relates to basically reversing it. Those parameters that are indeed reversible that are contributing to this, it first has to be recognized.

Let’s move on a few millimeters from the heart to the lungs. Patients with malignant disease, as you know, have a plethora of pulmonary problems that can develop. Some of which will culminate or others of which will present with acute respiratory failure. When confronting such a patient a series of questions in virtually every case needs to be considered. Is the phenomenon you are observing related to the rest of the patient’s disease? That is fairly straightforward. Is there an opportunistic infection at work? We know that certain tumors paralyze the immune system, such as CLL for example. Multiple myelomas. When you add the impact of the therapy we apply to cancer which generally is quite damaging to T-cell function, most patients are ripe for opportunistic infection.

The therapies that we utilize, be it chemotherapy or radiation therapy, often will induce pulmonary damage as I will point out in a moment. Patients with cancer are particularly prone to thromboembolism, which of course is a source of possible acute respiratory collapse and even death. This slide depicts some treatment for related pulmonary complications that are worthy of your consideration in the context of patients who are presenting you with either chronic or acute respiratory problems. They come in several categories. The first is depicted as interstitial pneumonitis. Interstitial pneumonitis is absolutely drug related in some instances and it is related commonly to bleomycin. Probably the most fearsome side effect of this drug is interstitial pneumonitis. Other agents that will cause interstitial pneumonia are alkylating agents like BCNU, or busulfan also known as Myleran, which is a drug that has been commonly used for the treatment of chronic myelocytic leukemia. It is used less so now than it was before. Cyclophosphamide; we mentioned it a few moments ago as a potential for causing acute pericardial effusions and cardiomyopathy. It can also cause interstitial pneumonitis. These are patients who will present with a restrictive pulmonary defect on PIT’s. The DLCO is going to be diminished. The only way we can make this diagnosis is by lung biopsy. It is sometimes reversible and sometimes it is fatal no matter what we do.

Some patients in the context of cancer treatment will have a hypersensitivity reaction and this too can be related to either prior bleomycin or methotrexate exposure as well as carmustine, the drug that we commonly use in the treatment in Hodgkin’s disease. These patients however, unlike those with interstitial pneumonitis, will frequently have fever. Sometimes with eosinophilia. They benefit from steroids. A number of anti-cancer treatments are associated with non-cardiogenic pulmonary edema. A truly acute respiratory crisis. Probably the most common nowadays is the use of interleukin-2. High doses of interleukin-2, as you probably know, have found utility in the treatment of hypernephroma that is metastatic and malignant melanoma. It causes a vascular permeability syndrome with massive third spacing, including pulmonary edema. One can see similar things with Cytoxan and ara-AC although fortunately much less common. Occasionally leukoagglutinins that are contained within a unit of transfused blood will result in leukoagglutination within the lung and a vascular permeability syndrome that produces pulmonary edema. This is quite reversible. In fact, they are both quite reversible if the patient does support it.

Finally, pulmonary hemorrhage is a really acute catastrophe that the oncology patient finds him or herself in. Often associated with thrombocytopenia with a platelet count of less than 5,000. That usually is the considered cut-off at which the risk of serious hemorrhage of any type from any where is recognized - below 5,000. Or in the context of DIC which can either be a complication of sepsis or indeed can be secondary to an underlying, evolving neoplasm, like acute promyelocytic leukemia.

These are thromboembolic phenomenon that is in part indeed thromboembolic in origin and in part probably due to extrinsic impression of a great pain. Now the thing that is worth saying about this superior vena cava syndrome is that in all likelihood, in most cases I’d say, it’s not really a true medical emergency. I call it a matter of medical urgency, but not so much emergency. Meaning, most people don’t die because they have superior vena caval compression. But it does cry out for diagnosis for sure. And some patients with massive compression that has been acute, without much collateralization, indeed can have a facial suffusion here under the eyes, facial plethora and light-headedness and dizziness. In most patients this syndrome evolves rather insidiously before they come to the physician. The most frequent cause of this is primary lung cancer, pathogenic carcinoma. But malignant lymphomas, again, because they commonly involve mediastinal lymph nodes. Breast cancer because it commonly goes to the

Oncologic Emergencies 

Therapy Related Sudden Death: XRT

• Acute pericarditi

• Chronic pericarditis-usually months or a few years after treatment

• Pericardial effusion and tamponade

• Coronary artery endarteritis-can result in MI, sudden death within a few years to many years after the therapy

Sudden Cardiac Death: Chemotherapy

• Acute cardiotoxicity associated with a number of anti-neoplastic agents

• Anthracyclines: Adriamycin, epirubicin, idarubicin, daunomyein-acute dysrhythmias are rare, can be lethal, are not dose dependent; chronic cardiomyopathy is more common, is close dependent

• Cyclophosphamide: when used in high doses, as in BMT, associated with acute cardiomyopathy, arrhythmias, pericardial effusion

Pericardial Tamponade/Pericardial Effusion

Differential Diagnosis

• Primary Ca lung, Hodgkins Disease, NHL, leukemias

• Breast Cancer-commonly involve the pericardium

• Melanoma-most common tumor forming metastases in the heart

Malignant Pericardial Effusion/Tamponade: Clinical

• Most common manifestation of malignant involvement of pericardium

• Insidious: enlargement cardiac silhouette, ECG changes (low voltage), ECHO, CT

• Dyspnea, +/- pain, fatigue, abdominal complaints, edema, cough, diaphoresis

• Tachycardia, Kussmaul's sign, tender hepatomegaly, paradoxical pulse

Pericardial Tamponade: Dx

• History is key: specific cancer dx, prior rx

• Signs of sepsis vs not

• Hypotension/shock

• Kussmaul sign

• Paradoxical pulse

• ECHO-RV collapse

Pericardial Tamponade: Therapy

• Emergent therapy occasionally needed: pericardiocentesis (dx and therapeutic

• Prolonged drainage (overnight) may be therapeutic if used in conjunction with local (x-ray therapy) or systemic therapy

• Pericardial window: rx of choice (6 mo. Prognosis)

• Pericardial sclerosis: not used much

• Pericardial stripping: Constrictive lesions as in post x-ray therapy

Cardiac Effects of Mediators Derived form Tumors

• Carcinoid tumors with metastases to liver >right sided lesions; primary pulmonary carcinoid >left sided lesions

• Intimal and valvular thickening; TR, PS

• Culminates in irreversible right sided CHF

• Therapy directed at reduction of the secretory cell mass; irreversible

High Output Cardiac States

• Causes: anemia, hyperthyroidism, primary/secondary hyperaldosteronism, shunting through large tumors or organs (spleen)

• Dx: think of it, ECHO to demo high output

• RX: underlying cause, eg, anemia, thyroid status, hypoxia, etc

Pulmonary Complications

Sorting it out: the patient presents with cough, dyspnea, sometimes fever, and pulmonary infiltrates:

• Is it tumor progression?

• Is it opportunistic infection?

• Is it therapy related?

• Is it thromboembolic?

Pulmonary complications due to Therapeutic Modalities

• Interstitial pneumonitis: methotrexate, bleomycin, Cytoxan, Busuifan, BCNU: restrictive defects, DLCO down, need BX 

• Hypersensitivity Pneumonitis: Bleomycin, methotrexate, procarbzine: fever sometimes, need biopsy--rx with steroids 

• Non-cardiogenic pulmonary edema: Cytoxan, ara-C, IL-2, methrotrxate, transfusion with leukoagglutinins, most patients will recover with supportive care, some will require intubation

• Pulmonary hemorrhage: due to DIC, thrombocytopenia

Superior Vena Cava Syndrome

• Bronchogenic ca, Lymphoma, Breast Ca, Germ Cell tumors

• Extrinsic compression/thrombosis

• Venous distention, facial edema, telangiectasia, plethora, cyanosis

• CT/CT angiogram for diagnosis is best

• Surgery to make dx not contra-indicated

• Chemotherapy (SCLC, lymphoma) or CT/XRT

Neurological Emergencies

• Metastatic

• Intracranial

• Spinal

• Leptomeningeal

• Cranial/Peripheral nerves

• Non-metastatic rx related vascular disorders toxic/metabolic paraneoplastic

Brain Metastases: Clinical

• Most common neuro complication of cancer-infrequently is first manifestation (lung Ca)

• Usually symptoms are a combination of mass effect due to combined consequences of tumor mass and edema-indistinguishable from primary brain tumor

• Lung ca (#1), breast (#2), melanoma, renal cell ca

• May be multiple, or singular

Brain Metastasis: Dx

• Fifty percent are solitary

• Signs relate to area of the lesion, and may be generalized, eg, seizures, personality change, obtundation

• Must be verified histologically

• MRI-Gd best test; large areas of edema

• Differential Diagnosis: infectious masses, hemorrhage, with or w/o mass, primary brain tumor

Brain Metastasis: Therapy

• Surgery: reserved for a single metastasis in a patient with good performance status, and therapeutic options for systemic disease, stable systemic disease

• Surgery plus x-ray therapy for single met (up to 2 cm) yields best survival data for this subset (19 v 9 rues median)

• For multiple metastases: x-ray therapy to whole brain plus decadron Stereotactic x-ray therapy: for delivering boost to large tumor mass

• Systemic chemotherapy: usually of little value-blood brain barrier: new agents, eg, temazoiamide

• Prognosis: guarded, and varies with underlying disease

Spinal Metastasis

• Five percent all patients dying of cancer

• Breast, lung, prostate, lymphoma are most common

• Direct extension from a vertebral met

• Can be by direct extension

• T-spine most common location (T>LS>C)

Spinal Metastasis: pathophysiology

• Demyelination, lipid-laden macrophages, interstitial edema, focal axonal swelling

• Mechanical pressure causes impingement on venous flow in cord, producing conduction block and cord dysfunction

• Infarction occurs late if at all

Spinal Metastasis: Clinical

• Back pain 96%

• Progressive, ? Radicular, worse when supine (disc disease improves when supine)

• Exacerbated by coughing or flexing

• Weakness-next most common after pain (P>D)

• Bowel/bladder are late deficits

• Sensory level

• V. zoster eruption may occur at level of cord lesion

Spinal Metastasis: DX

• Back pain in a ca pt=SCC until disproven

• Myelopathy

• Local or radicular pain

• MRI best test (myelography as good)

• MRI assists treatment planning

Spinal Mets: Therapy

• Corticosteroids: oncolytic (lymphoma, breast ca, myeloma) reduce edema

• Decadron: 10mg IV stat, then 96mg over 4 doses/day, x 11 days (MSKCC)

• Radiation Therapy

• Surgery: appropriate if no dx, or if lesion is in previously irradiated site

Spinal Mets: DDX

• Epidural SCC

• Leptomeningeal disease

• Abscess

• Epidural subdural hemorrhage

• Lumbosacral plexopathy

• Unrelated to cancer: spinal stenosis, disc disease, osteoporotic fx

Leptomeningeal Disease

• Malignant cells enter subarachnoid space via bridging veins, or by direct extension

• Blood vessels ensheathed by tumor, encasing cranial nerves, peripheral nerves

• Pathophysiology: direct extension to nervous tissue, interfere with flow of CSF>hydrocephalus, vascular compromise, interfere with neuronal metabolism

Leptomeningeal Disease: Clinical

• Synchronous symptoms and signs at multiple levels

• Asymptomatic findings on exam

• Headache, especially in AM, without brain metastases

• Urinary incontinence may be an early sign, impotence

Leptomeningeal Disease: DX

• Malignant cells in CSF

• Head CT or MR (w/gad) prior to LP

• Almost always at least one abnormality on LP: pleocytosis, elev. protein, low glucose

• Tumor markers: CEA (>1% serum), B-HCG, AFP, CA-125, CA15-3: rarely helpful

Leptomeningeal Disease: Rx

• Often causes death within weeks to months

• Responsive tumors do better

• Radiation therapy: to symptomatic area

• Chemotherapy: methotrexate IT-12-15 mg/dose >therapeutic levels for 36-48hrs, biw x 5, then qw till clearing

• ara-C second line--depot formulations in study

Cerebrovascular Complications

• Second to metastases

• Cerebral hemorrhage: mets from melanoma, germ cell tumor, renal cell ca

• Hemorrhage due to AML, APML, DIC

• Venous thrombosis and infarction due to mass effect

• NBTE-marantic endocarditis

Tumor Lysis Syndrome

• Seen with tumors having high growth fraction, high cell turnover, large tumor cell mass, and responsive to therapy: Burkitts lymphoma, ALL, ANLL, CLL, CML,

• Acute hyperuricemia, and metabolic derangements: rapid rise in uric acid, potassium, phosphate, hypocalcemia, arrhythmias, sudden death

Tumor Lysis Syndrome

• Develops 1-2 days after cytotoxic therapy

• N/V, lethargy, oliguria, CHF, seizures, arrhythmia

• Uric acid crystals in urine

• Therapy: focus on prevention=avoid drugs that inhibit tubular reabsorption of urate (thiazides, salicylates, contrast material), maintain dilate, alk. urine, achieve pH=7 in urine pre-rx, allopurinol

• Ideally, hold therapy until uric acid normal, urine pH=7

Hypercalcemia of Malignancy

• PTHRH, OAF, IL-6, PTH

• Epithelial malignancies (PTHRH), myeloma (OAF, IL-6), Parathyroid Carcinoma

• Direct resorption of bone by tumor cells mediated through cytokines

• Often seen in absence of bone metastases

Hypercalcemia of Malignancy: Therapy

• Fluids-all hypercalcemic patients are dehydrated-replete fluids

• Commence furosemide only after fluid repletion