Oncologic Emergencies (Including Hypercalcemia)

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ONCOLOGIC EMERGENCIES (INCLUDING HYPERCALCEMIA) Marie E. Wood, MD 1. Define oncologic emergency. A unique set of complications associated with patients with cancer requiring emergent evaluation and treatment. 2. List the four types of oncologic emergencies, and give examples of each. n Metabolic: Tumor lysis syndrome, hypercalcemia, syndrome of inappropriate antidiuretic hormone, lactic acidosis n Structural or mechanical: Spinal cord compression, superior vena cava (SVC) syndrome, malignant pericardial effusion n Hematologic: Neutropenic fever, leukostasis, disseminated intravascular coagulation, thrombosis, hyperviscosity n Side effects of chemotherapy: Extravasation, hemorrhagic cystitis, typhlitis

METABOLIC EMERGENCIES 3. What are the symptoms of hypercalcemia? Symptoms can be vague but most classically include lethargy, confusion, anorexia, nausea, constipation, polyuria, and polydipsia. Hypercalcemia occurs in 10% to 30% of individuals with advanced or metastatic cancer. 4. What are the important treatments for hypercalcemia? n Hydration: Use normal saline solution, watching for congestive heart failure. n Bisphosphonate therapy: The most common choices of therapy include either pamidronate 60 to 90 mg intravenously (IV) over a 2- to 4-hour period or zoledronic acid 4 mg IV over a 15-minute period (the latter must be adjusted for renal insufficiency). n Stop medications that contribute to hypercalcemia: calcium, vitamin D, thiazide diuretics. 5. Discuss reasons for not using furosemide (Lasix), calcitonin glucocorticoids, and other older therapies. The easy answer is that bisphosphonates work much better. However, furosemide can be helpful but only if the patient is hydrated. Calcitonin works but only for a short time. Glucocorticoids are really only a temporizing measure. 6. Which patients with cancer are at risk for lactic acidosis? Lactic acidosis is a rare complication of malignancy and is seen in patients who have cancer with a high proliferative rate such as lymphoma, leukemia, and small cell carcinoma. 7. How does lactic acidosis present, and how should it be treated? Common symptoms include tachypnea, tachycardia, abdominal pain, and hepatomegaly. Mortality is very high and institution of chemotherapy the most effective treatment.

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CHAPTER 57 ONCOLOGIC EMERGENCIES (INCLUDING HYPERCALCEMIA) 405 8. Can tumor lysis syndrome be prevented? Absolutely yes, with early initiation of allopurinol or rasburicase, close monitoring of laboratory values, and aggressive hydration. 9. Which patients are at risk for tumor lysis syndrome? Patients with large tumor burden and tumors with a high proliferative rate that are highly sensitive to chemotherapy (acute myelogenous leukemia, acute lymphocytic leukemia, Burkitt lymphoma, multiple myeloma, small cell carcinoma) are at risk for tumor lysis. Dehydration, renal insufficiency or obstruction, or elevated lactate dehydrogenase (LDH) or uric acid level before initiation of chemotherapy may increase the risk for complications from tumor lysis. 10. Can tumor lysis happen before administering therapy? Yes, tumor lysis can be seen in very actively growing tumors with a high proliferative rate. 11. Discuss the features of tumor lysis syndrome. Tumor lysis is caused by release of cell contents into the bloodstream. Therefore patients have elevated levels of LDH, uric acid, potassium, urea nitrogen, creatinine, and phosphate, and low calcium. 12. How should tumor lysis be treated? Patients at risk should start taking allopurinol (300-600 mg/day for 2 days) and be aggressively hydrated before initiation of chemotherapy. If tumor lysis develops despite these measures patients should have alkalinization of urine with forced diuresis with furosemide and frequent monitoring of urine volume, cardiac and volume status, and laboratory values (blood urea nitrogen, creatinine, uric acid, calcium, phosphate, and potassium levels). 13. When should rasburicase be used? Rasburicase promotes the degradation of uric acid whereas allopurinol decreases the formation of uric acid. One study shows improved control of uric acid compared with allopurinol. Rasburicase can be considered in patients with very high uric acid level in need of urgent treatment.

STRUCTURAL EMERGENCIES 14. What is the single most important predictor of functional status for a patient with cord compression? The neurologic status at presentation predicts functional status after treatment. Patients presenting with pain only are far more likely to be ambulatory after treatment than patients presenting with neurologic dysfunction. 15. Because back pain is common, how can you distinguish pain due to cord compression from other back pain? The cardinal features of cord compression include pain that worsens when supine and that can be reproduced with vertebral percussion. Additional findings of cord compression include constipation and incontinence (usually due to overflow incontinence) and sensory loss. 16. Should a patient with suspected cord compression receive steroids before imaging studies? Therapy for cord compression should be initiated as soon as possible after imaging studies have been done. However, it is not wrong to give steroids (dexamethasone 10-20 mg IV) before imaging for a patient with symptoms.

406 CHAPTER 57 ONCOLOGIC EMERGENCIES (INCLUDING HYPERCALCEMIA) 17. How important is a tissue biopsy in a patient with cord compression? A tissue biopsy is critical for a patient without a cancer diagnosis or with cancer that uncommonly metastasized to bone (as a second malignancy may exist). Biopsy is less important for patients with known metastatic malignancy. 18. Should patients with cord compromise be evaluated for surgery? Absolutely, yes. Although the mainstay of treatment had been steroids and radiation therapy a seminal paper published in 2005 demonstrated that patients treated with surgery (compared with radiation) were more likely to walk after treatment (84% vs. 57%), retained the ability to walk significantly longer, and required fewer steroids and less narcotic analgesia. 19. Are there any patients with cord compression who should receive chemotherapy? Chemotherapy should be considered for patients with very chemosensitive tumors such as myeloma, small cell carcinoma, and lymphoma. 20. How do patients with brain metastasis commonly present? Patients may present with headache, and classically this is a headache that worsens at night, may wake the patient from sleep, and may be associated with nausea and/or vomiting. Patients may have seizures or isolated neurologic findings. A careful neurologic examination in a patient with cancer is required to determine whether the lesion is central or in the spinal cord. The most common primary tumors with metastasis to the brain include lung cancer, breast cancer, and melanoma, although any cancer can metastasize to the brain. 21. What is the best test for identifying central nervous system (CNS) metastasis? The gold standard is magnetic resonance imaging with gadolinium. Computed tomography scanning is less sensitive and may miss multiple small metastases. 22. How should a patient with brain metastasis be treated? Patients with symptomatic brain metastasis should be given steroids. Resection can be considered for a solitary lesion in an accessible area. This should be followed by whole brain radiation. Stereotactic radiosurgery may be an option for individuals with one to three lesions and lesions less than 2 to 3 cm. Whole brain radiation would be the treatment of choice for individuals with multiple lesions. Chemotherapy is almost never used for control of brain metastasis. 23. What about anticonvulsant therapy? Anticonvulsant therapy should not be started empirically. 24. Patients with what tumor types are most likely to present with SVC syndrome? SVC syndrome is caused by invasion or compression of the SVC. Invasion of the SVC is seen in thrombosis, which can develop in any patient with cancer and a central line. Compression of the SVC is most commonly associated with lung cancer (both small and non–small cell types), lymphoma, and germ cell tumors. SVC syndrome can also occur as a result of radiation-induced fibrosis. 25. Discuss the signs and symptoms of SVC syndrome. The most common symptom is dyspnea. Patients may also complain of facial and/or arm swelling, head fullness, and/or headache. Symptoms may worsen with bending over or lying down. Rarely patients may present with confusion and coma related to SVC compression or invasion.

CHAPTER 57 ONCOLOGIC EMERGENCIES (INCLUDING HYPERCALCEMIA) 407 26. How should SVC syndrome be treated? The urgency of treatment should be guided by symptoms. Occasionally patients will present with stridor (due to airway obstruction or laryngeal edema), respiratory distress, or even coma. In this case stent placement and/or radiation should be considered. In less urgent situations care should be directed at obtaining a diagnosis as this may direct therapy. Options may include the following: n Stent placement: Percutaneous endovascular stents have been shown to provide effective symptom relief. n Steroids: Steroids are used to reduce edema or treat lymphoma. n Chemotherapy: Chemotherapy should be considered for very chemosensitive tumors such as germ cell, lymphoma, and small cell carcinomas. n Radiation: Radiation is used less commonly now but is still an important palliative modality. n Anticoagulation and/or thrombolytics: These can be helpful and considered for patients with thrombosis. n Support: Elevation of the head and/or diuretics can provide relief of symptoms. 27. Who is at risk for a malignant pericardial effusion? Any and all cancers have been associated with pericardial effusions. Effusions are most commonly seen in association with lung cancer and less commonly seen with breast and esophageal cancer, melanoma, lymphoma, and leukemia. Rarely pericardial effusions have been seen with radiation fibrosis. 28. How should a malignant pericardial effusion be treated? The fluid should be drained and sent for cytologic analysis. This is important for patients without a diagnosed malignancy. The effusion can recur, and a pericardial window may be necessary.

HEMATOLOGIC EMERGENCIES 29. What is leukostasis, and who gets it? Leukostasis is seen in patients with elevated blast counts (usually over 30,000). Although hyperleukocytosis (white blood cell count over 50,000) is commonly seen with acute and chronic leukemia, leukostasis is seen with acute myeloid and lymphoid leukemia and chronic myeloid leukemia in blast crisis. Symptoms relate to decreased tissue perfusion due to microvascular changes. The most common symptoms are dyspnea, hypoxia, and those affecting the central nervous system (CNS): visual changes, headache, dizziness, tinnitus, gait instability, confusion, somnolence, and, occasionally, coma. 30. How is leukostasis treated? The goal of treatment is to reduce the blast count. This can be done quickly with hydroxyurea (50100 mg/kg) and leukapheresis. These are temporizing measures, and definitive treatment should be initiated as soon as possible. 31. Should a blood transfusion be avoided in patients with leukostasis? Yes, as transfusion can increase blood viscosity and potentially worsen symptoms. 32. Define neutropenic fever. A neutropenic fever is defined as a single temperature over 38.3 C (101 F) or sustained temperature (over a 1-hour period) of 38 C (100.5 F) in a patient with an absolute neutrophil count of less than 500 cells/mm3. 33. Is a neutropenic fever ever fatal? Yes, but prompt evaluation and treatment essentially eliminate this risk.

408 CHAPTER 57 ONCOLOGIC EMERGENCIES (INCLUDING HYPERCALCEMIA) 34. What should be included in the evaluation of a patient with neutropenia? Patients suspected of having a neutropenic fever should have a thorough examination looking for potential sources of infection. A laboratory evaluation, including a complete blood cell count and differential, at least two blood cultures (one being from central venous access if present), chest radiograph, and culture of appropriate sites, is indicated. 35. Should the preceding evaluation be complete before the institution of antibiotics? Absolutely not; antibiotics should be started immediately after the blood cultures are obtained. 36. What would be considered appropriate antibiotic coverage for a neutropenic fever? Broad-spectrum IV therapy covering serious gram-negative bacteria and Pseudomonas aeruginosa is appropriate. Monotherapy with cefepime, ceftazidime, carbapenem, or piperacillintazobactam are all appropriate choices. 37. Does empirical vancomycin improve survival for neutropenic fever? No, but vancomycin should be started if concern exists for a catheter-related skin or soft tissue infection, pneumonia, or hemodynamic instability. 38. How long should a neutropenic fever be treated? The short answer is until both the neutropenia and fever resolve. Antibiotic coverage appropriate for the identified organism may be continued for the appropriate duration (i.e., for fungal sepsis). Coverage may be modified on the basis of cultures and sensitivities; however, a broad spectrum of coverage should be maintained until the neutropenia resolves. 39. Venous thromboembolism is common in patients with cancer; when is it considered an emergency? Patients with massive clot burden and/or limb-threatening disease (i.e., phlegmasia cerulea dolens) would be considered in need of emergent interventions. These patients may be considered for thrombectomy or thrombolysis.

SIDE EFFECTS OF CHEMOTHERAPY 40. What is typhlitis? Typhlitis or neutropenic enterocolitis is often a diagnosis of exclusion. The pathophysiology is not well understood but seems to be a combination of mucosal injury and neutropenia. The cecum is almost always involved, commonly with extension to the ascending colon and terminal ileum. Typhlitis is seen more commonly in patients with hematologic malignancy although it can be seen in any patients with severe mucosal injury from chemotherapy (such as capecitabine). 41. How should typhlitis be managed? Patients should initially be evaluated by a surgeon because typhlitis is often a diagnosis of exclusion, and other abdominal catastrophes should be excluded. Patients with perforation, peritonitis, or bleeding should be taken to the operating room. If not going to the operating room, patients’ conditions should be conservatively managed with the following: n Bowel rest with nasogastric suction. n Hydration and nutritional support. n Blood product (packed red blood cells and platelets) support as needed. n Antibiotic coverage is reasonable, and antifungal coverage may be considered for patients with persistent fever.

CHAPTER 57 ONCOLOGIC EMERGENCIES (INCLUDING HYPERCALCEMIA) 409 Avoid anticholinergic, antidiarrheal, or opioid agents as their use may create or aggravate ileus. Granulocyte colony-stimulating factor may be considered for patients expected to have a prolonged and/or profound neutropenia.

KEY POINTS: CHARACTERISTICS OF TUMOR LYSIS 1. Increased LDH level 2. Increased uric acid level 3. Increased phosphorus level 4. Increased potassium level 5. Increased blood urea nitrogen and creatinine levels 6. Decreased calcium level

BIBLIOGRAPHY 1. Cairo M, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127:3-11, 2004. 2. Cortes J, Moore JO, Maziarz RT, et al: Control of plasma uric acid in adults at risk for tumor lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone—results of a multicenter phase III study. J Clin Oncol 28:4207-4213, 2010. 3. Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 52: e56-e93, 2011. 4. Jabr FI: Lactic acidosis in patients with neoplasms: an oncologic emergency. Mayo Clin Proc 81:1505-1506, author reply 1506, 2006. 5. Jenkinson MD, Haylock B, Shenoy A, et al: Management of cerebral metastasis: evidence-based approach for surgery, stereotactic radiosurgery and radiotherapy. Eur J Cancer 47:649-655, 2011. 6. Lepper PM, Ott SR, Hoppe H, et al: Superior vena cava syndrome in thoracic malignancies. Respir Care 56:653-666, 2011. 7. Lewis MA, Hendrickson AW, Moynihan TJ: Oncologic emergencies: pathophysiology, presentation, diagnosis, and treatment. CA Cancer J Clin 61:287-314, 2011. 8. Patchell RA, Tibbs PA, Regine WF, et al: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 366:643-648, 2005.