Oncological Emergencies Dr. Gary Harding MD, FRCPC Medical Oncology Fellow
Oncological Emergencies Dr. Gary Harding MD, FRCPC Medical Oncology Fellow CancerCare Manitoba CASE 1… Mr. SV ID: 65 year old male with PMHx of CAD and emphysema EC: present to clinic with one week history of increasing SOB HPI: 3 month history of weight loss, decreased appetite, a change in his chronic cough, and intermittent hemoptysis On Physical Examination Inspection: Respiratory Examination Stridor Dullness to percussion on right lower lung fields Increased tactile fremitus to right lower lung fields Decreased fields A/E to right lower lung Chest X-Ray… right pleural effusion Thoracentesis Exudate Gram stain – Negative AFB stain – Negative Cytology – non-small cell lung cancer Large cell type T1-weighted axial MRI demonstrating paratracheal soft tissue mass that invades into the SVC Superior Vena Cava Syndrome Definition Obstruction of blood flow in the superior vena cava results in signs and symptoms of SVC syndrome Etiology Caused by either invasion or external compression of the SVC by contiguous pathologic process Right lung pathology, lymph nodes, other mediastinal structures, or thrombosis Etiology Before antibiotics the most common causes were from complications of untreated infection – Syphilitic thoracic aneurysms – fibrosing mediastinitis Malignancy is presently the most common cause Symptoms and Signs As the obstruction develops venous collaterals are formed Symptom onset depends on speed of SVC obstruction onset Malignant disease can arise in weeks to months – Not enough time to develop collaterals Fibrosing mediastinitis can take years to have symptoms Symptoms and Signs Central venous pressures remain high even in collaterals – High pressures cause the characteristic clinical picture Shortness of breath is the most common symptom1 1. Parish, JM, Marschke, RF Jr, Dines, DE, Lee, RE. Etiologic considerations in superior vena cava syndrome. Mayo Clin Proc 1981; 56:407. Signs and Symptoms Facial swelling or head fullness – exacerbated by bending forward or lying down Cough Arm edema Cyanosis Facial swelling associated with SVC Syndrome in a patient with malignancy Physical Findings Venous distension – neck – chest wall Pemberton’s Facial Sign Edema Patient who presented with progressively enlarging veins over the anterior chest wall. A diagnosis of a right-sided superior sulcus (Pancoast) tumor compressing the SVC was made. Etiology: Malignancy Lung cancer is the most common2 Lymphoma together is second most common represent 94% of cases 2. Escalante, CP. Causes and management of superior vena cava syndrome. Oncology (Huntingt) 1993; 7:61. NSCLC 2-4% of bronchogenic cancer patients develop SVC syndrome3 extrinsic invasion compression or direct – primary tumor or by enlarging mediastinal nodes 3. Armstrong, BA, Perez, CA, Simpson, JR, Hederman, MA. Role of irradiation in the management of superior vena cava syndrome. Int J Radiat Oncol Biol Phys 1987; 13:531. Small Cell Lung Cancer Greatest 20% more risk will develop SVC obstruction3 common because SCLC tends to occur centrally in contrast to other types Lymphoma 2-4% of patients predominantly non-Hodgkin’s lymphoma4 Hodgkin’s rarely causes SVC syndrome 4. Perez-Soler, R, McLaughlin, P, Velasquez, WS, et al. Clinical features and results of management of superior vena cava syndrome secondary to lymphoma. J Clin Oncol 1984; 2:260. Lymphoma Extrinsic compression caused by enlarging lymph nodes subtypes of large B cell can be intravascular and cause occlusion (angiotropic) diffuse large cell and lymphoblastic are most commonly associated with SVC syndrome Other cancers Thymoma primary mediastinal germ cell neoplasm solid tumors with mediastinal nodal metastases – breast cancer most common type Other causes Post radiation local vascular fibrosis can also be considered in oncology patients – Thoracic radiation treatment may predate syndrome by many years Other causes Thrombosis Indwelling central venous catheters Subcutaneous tunneled catheters have fewer thrombotic and infectious complications – Can also cause pulmonary embolism5 5. Sivaram, CA, Craven, P, Chandrasekaran, K. Transesophageal echocardiography during removal of central venous catheter associated with thrombus in superior vena cava. Am J Card Imaging 1996; 10:266. Diagnosis Timely identification of the cause is essential Radiographic studies are useful Up to 60% of patients with SVC syndrome related to neoplasm do not have a known diagnosis of cancer6 – Need a tissue biopsy for histologic studies 6. Schraufnagel, DE, Hill, R, Leech, JA, Pare, JA. Superior vena caval obstruction. Is it a medical emergency?. Am J Med 1981; 70:1169. Radiographic Studies Most patients have an abnormal chest x-ray at presentation Most common findings are – Mediastinal widening – Pleural effusion CT Chest Preferred IV choice contrast – defines the level of obstruction – Maps out collateral pathways – Can identify underlying cause of obstruction Venography Bilateral upper arm venograpy – superior to CT to define site of obstruction – Does not define cause unless thrombosis is solely responsible Helical CT With bilateral upper arm IV contrast injection Best visualization of level of obstruction and cause MRI Can be useful in patients with IV contrast allergies T1-weighted axial MRI demonstrating the primary tumor and the paratracheal soft tissue mass that invades into the SVC Same patient’s MRI with different technique to further define the intramural mass Histologic Diagnosis Essential Guides Aids treatment in defining prognosis Histologic Diagnosis Sputum cytology, pleural fluid cytology, biopsy of enlarged peripheral nodes Bone marrow biopsy for NHL Bronchoscopy, mediastinoscopy, or thoracotomy are more invasive but sometimes necessary Treatment of Oncologic Causes Treatment Aimed at underlying cause Evolution of thought has occurred in recent years Historically SVC syndrome was considered a potentially lifethreatening emergency Standard of care was immediate radiotherapy –Zap now –Ask questions later The emergent approach is not appropriate for most patients Newer strategies Emergent to Urgent Symptomatic obstruction is usually a prolonged process Most patients are not in immediate danger at presentation Most have time for a full diagnostic work up Emergent to Urgent Prebiopsy diagnosis Current radiation can obscure the strategies aim at accurate diagnosis of underlying etiology before therapy Exception to new rule Stridor – Central airway obstruction or laryngeal edema True medical emergency Immediate action needed – Possible intubation and ICU admission – Immediate therapy to target obstruction needed Prognosis… Linked to tumor histology and stage at presentation Treatment Sensitive Tumors NHLs, germ cells, and limited-stage small cell lung cancers usually respond to chemotherapy and or radiation Can achieve long term remission with tumor specific directed therapy Symptomatic improvement usually takes 1-2 weeks after start of therapy Note: Corticosteroids Controversial issue with regards to treatment benefit at presentation Non-small cell lung cancer SVC obstruction is a strong predictor of poor prognosis Median survival around 5 months7 Choice of therapy considers likelihood of response to each modality 7. Martins, SJ, Pereira, JR. Clinical factors and prognosis in non-small cell lung cancer. Am J Clin Oncol 1999; 22:453. Non-small cell lung cancer Goal usually directed to palliation rather than long term remission Palliative radiation and chemotherapy can be used Intraluminal Stents Endovascular fluoroscopy placement under Patients who have recurrent disease in previously irradiated fields Tumors Patient refractory chemotherapy too ill to tolerate radiation or chemotherapy Intraluminal Stents Some data suggests benefit from immediate stent placement in NSCLC at presentation8 Tends to provide more rapid relief of symptoms Issue of anticoagulation after is not resolved 8. Rowell, NP, Gleeson, FV. Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: a systematic review. Clin Oncol (R Coll Radiol) 2002; 14:338. CASE 2… Mr. EC ID: 56 year old man with history of HTN and osteoarthrtis EC: presents to family doctor with one month history of back pain that is not responding to Tylenol – Pain beginning to wake him at night – More pain with recumbancy – Some shooting pains down right leg ROS: negative On examination vitals stable, no fever CVS, Respiratory, GI, GU exams reported as normal Back exam – Inspection: normal – Palpation: some pain in L1 – ROM: normal – Some pain in right leg with straight leg raising Investigation in Clinic Lumbar Spine X-ray – Some age related degeneration Diagnosis Sciatica vs. Back strain Treatment: – NSAIDS – Few days of bed rest The story continues… Mr. EC’s pain does not resolve More trials of various forms of pain control fail One month later Mr. EC awakens in the morning and has difficulty supporting his weight – Subjective leg muscle weakness Goes to HSC Emergency room In ER Patient has objective leg weakness on physical exam A very keen medical student does a rectal exam and discovers a large nodular prostate PSA: 45.0 MRI Spine….. Spinal Cord Compression Malignant Epidural Spinal Cord Compression (ESCC) Neoplastic invasion of the space between vertebrae and spinal cord (epidural invasion) – Usually from bone metastases Compresses thecal sac of spinal cord Frequent complication of malignancy Can cause pain Can cause irreversible loss of neurologic function Definition Any radiological indentation of the thecal sac Tip of the spinal cord lies at the L1 vertebral level Lumbosacral nerve roots form the cauda equina Epidemiology Many cases of unrecognized ESCC Difficult to define incidence Autopsy review studies suggest around 5% of cancer patients die with ESCC9 9. Barron, KD, Hirano, A, Araki, S, Terry, RD. Experiences with metastatic neoplasms involving the spinal cord. Neurology 1959; 9:91. Causes Metastatic tumor from any primary site Tumors with predilection to metastasize to spinal column Prostate, breast, and lung carcinoma – 15-20% of cases Renal cell, non-Hodgkin’s lymphoma, or myeloma – 5-10% of cases Vertebral metastases are more common than ESCC Prostate cancer: 90% Breast Cancer: 74% Lung Cancer: 45% Lymphoma: 29% Renal cell: 29% GI: 25% 10. Posner, JB. Neurologic Complications of Cancer. FA Davis, Philadelphia, 1995 ESCC can be initial presentation of a malignancy – Around 20% of cases – In many cases diagnosis is made by biopsy of the spinal lesion Spinal Location10 Thoracic spine: 60% Lumbosacral spine: 30% Cervical spine: 10% Specific tumor predilection is difficult to define Clinical Features Important to recognize Early recognition leads to better outcomes Efficacy of treatment depends most on patient’s neurological function at presentation Median time from symptoms to diagnosis is around 2 months11 More than half of patients who present to hospital are nonambulatory 11. Husband, DJ. Malignant spinal cord compression: Prospective study of delays in referral and treatment. BMJ 1998; 317:18. RED FLAGS….. First Red Flag: Pain Usually first symptom12 – 80-90% of the time Usually precedes other neurologic symptoms by seven weeks – Increases in intensity Severe local back pain Aggravated by recumbency – Distension of venous plexus May become radicular 12. Bach, F, Larsen, BH, Rohde, K, et al. Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression. Acta Neurochir (Wien) 1990; 107:37. Second Red Flag: Motor Weakness: 60-85%13 At or above conus medularis – Extensors of the upper extremities Above the thoracic spine – Weakness from corticospinal dysfunction – Affects flexors in the lower extremities Patients may be hyperreflexic below the lesion and have extensor plantars 13. Greenberg, HS, Kim, JH, Posner, JB. Epidural spinal cord compression from metastatic tumor: Results with a new treatment protocol. Ann Neurol 1980; 8:361. Weakness tends to be symmetrical Progressive weakness is followed by lost of gait function then paralysis The severity of weakness is greatest with thoracic metastases Third Red Flag: Sensory Less Still common than motor findings present in majority of cases Ascending numbness and parathesias Fourth Red Flag: Bladder and Bowel Function Loss is late finding Autonomic neuropathy presents usually as urinary retension – Rarely sole finding Radiologic Investigation Diagnosis depends on ability to demonstrate a mass compressing the thecal sac Plain radiographs are not enough Historically this involved invasive procedures Advent of MRI has allowed noninvasive diagnosis Clinical examination is not reliable in determining level of lesion Entire imaging of spine is ideal – Focused CT imaging can miss clinically unapparent lesions Myelography and MRI are better than plain X-Rays, bone scans and CT for diagnosis Plain Spine Radiographs Easiest and cheapest Need large bony destruction or vertebral collapse to be diagnostic High Not false negative rate recommended to confirm diagnosis MRI vs. CT Myelography Both image thecal sac and display indentation and encircling CT myelography involves a lumbar puncture – Contraindicated in brain metastases, thrombocytopenia, or coagulopathy – Can diagnose leptomeningeal metastases – Available in Winnipeg in middle of the night MRI Images High whole spine detail Spares lumbar puncture Patients in pain must lie still Roughly equivalent in terms of sensitivity and specificity Presently no large comparative studies b/c MRI in the US has become so readily available MRI standard of care in centers that have access Bone Scan More sensitive than plain radiograph Visualizes Can entire skeleton miss neoplasms that do not have increased blood flow CT Scan alone Does not visualize spinal cord and epidural space clearly Intramedullary Metastases Less common Often present with hemicord symptoms – Unilateral weakness below lesion – Contralateral diminution of pain and temperature sensation – Can progress to bilateral dysfunction Radiation Myelopathy Can MR mimic ESCC imaging can make distinction MRI of epidural spinal cord compression in a women with past history of breast cancer. Treatment Treatment delays……. 2 month median delay in treatment from onset of back pain11 14 day delay in treatment from onset of neurological symptoms11 Why the delay? Patient factors General practitioner factors Hospital factors EDUCATION Treatment Objectives Pain control Avoidance Preserve function of complications or improve neurological Pain management Corticosteroids – Decrease edema Opiates – Needed to decrease pain for comfort and examination purposes Bed Rest No No No No Anticoagulation Cancer is a hypercoaguable state High burden of tumor in metastatic disease Possible value in prophylaxis against venous thromboembolism If patient not mobile subcutaneous heparin or compression devices is indicated Prevention of Constipation Factors – Autonomic dysfunction – Limited mobility – Opiate analgesic Risk of perforation – Masked by corticosteroids Bowel regimen needed Corticosteroids Part of standard regimen Limited effects data on benefit vs. side Many studies suggesting lower doses can be effective – No randomized trials Corticosteroid Recommendations High dose dexamethasone and half dose every three days Pain with minimal neurological dysfunction can have lower dose Small asymptomatic lesions can forgo steroids Radiation Therapy Definitive Portal choice 8 cm wide Centered on spine Extends one to two vertebral bodies above and below the epidural metastasis Relieves pain in most cases Post-neurological function usually determines response Response most associated with tumor type and radiosensitivity; eg. lymphoma Dosing 20 to 40 Gy in 5 to 20 fractions Popular – 30 Gy in 10 fractions Surgery Changing role Historically posterior vertebral decompression was done – No survival benefit with or without radiation15 15. Findlay, GF. Adverse effects of the management of malignant spinal cord compression. J Neurol Neurosurg Psychiatry 1984; 47:761. Better techniques today allow aggressive approach Gross spinal tumor resection with vertebral reconstruction now possible Experienced surgeon required Recent controlled trial comparing aggressive surgery followed by radiation vs. radiation alone16 Improvement in surgery+rads – Days remained ambulatory (126 vs. 35) – Percent that regained ambulation after therapy (56% vs. 19%) – Days remained continent (142 vs. 12) – Less steroid dose, less narcotics – Trend to increase survival 16. Patchell, R, Tibbs, PA, Regine, WF, et al. A randomized trial of direct decompressive surgical resection in the treatment of spinal cord compression caused by metastasis (abstract). proc Am Soc Clin Oncol 2003; 22:1. Chemotherapy Can be successful in chemosensitive tumors – Hodgkin’s lymphoma – Non-Hodgkin’s lymphoma – Neuroblastoma – Germ cell – Breast cancer (hormonal manipulation) – Prostate cancer (hormonal manipulation) Bisphosphonates Recommended Decrease pathologic fractures in bony disease – Multiple myeloma – Breast cancer Prognosis Median survival with ESCC is 6 months14 Ambulatory patients with radiosensitive tumors have the best prognosis 14. Sorensen, PS, Borgesen, SE, Rohde, K, et al. Metastatic epidural spinal cord compression. Results of treatment and survival. Cancer 1990; 65:1502. Treatment Delay Education EXPERIENCE Education EXPERIENCE Case 3: Mrs. HC ID: 75 year old female living alone with no significant past medical history EC: brought to ER by paramedics after neighbor called b/c she was found in her apartment unresponsive No collateral history Examination Fluctuating Vitals level of consciousness normal, no fever Dehydrated Coarse No upper airway sounds other pertinent findings Investigations CBC normal Mildly elevated BUN and Cr Normal LFTs Standard electrolytes normal Concern Chest of pneumonia x-ray ordered…… Multiple Pulmonary Metastasis Calcium – 4.5 checked Hypercalcemia Symptoms Usually nonspecific Many times patients present with very high calcium level Most research done in hyperparathyroidism Gastrointestinal Constipation is most common15 – Exacerbated or confused with narcotic effects – Related to autonomic dysfunction Anorexia Vague abdominal pain Rarely can lead to pancreatitis 15. Heath, H 3d. Clinical spectrum of primary hyperparathyroidism: Evolution with changes in medical practice and technology. J Bone Miner Res 1991; 6(Suppl 2):S63. Renal Dysfunction Nephrolithiasis – More common in hyperparathyroidism Nephrogenic diabetes insipidus – Defect in concentrating ability – Polyuria and polydipsia Chronic renal failure – Longstanding high calcium Calcifcation, tubules degeneration, and necrosis of Neuropsychiatirc Anxiety Depression Cognitive dysfunction – Delerium – Psychosis – Hallucinations – Somnolence – Coma Cardiovascular Short QT interval Supraventricualr Ventricular arrhythmias arrhythmias Physical Findings Usually not specific Dehydration secondary to diuresis caused by the hypercalcemia Corneal deposition of calcium – “band keratopathy” on slit lamp exam Epidemiology Occurs in about 10 to 20% of patients with cancer Both solid tumors and leukemias Most common – Breast – Lung – Multiple myeloma Pathogenesis Three mechanisms Osteolytic metastases with local cytokine release Tumor secretion of parathyroid hormone-related protein (PTHrP) Tumor production of calcitriol Osteolytic Metastases Breast cancer Non-small cell lung cancer Cytokines released – Tumor necrosis factor – Interleukin-1 – Stimulate osteoclast precursor differentiation into mature osteoclasts Leading to more bone breakdown and release of calcium PTH-Related Protein Most common in patients with nonmetastatic tumors Called humoral hypercalcemia of malignancy Secretion of PTH itself is a rare event PTHrP binds to same receptor as PTH and stimulates adeynylate cyclase activity – Increased bone resorption – Increases kidney calcium reabsorption and phosphate excretion Calcitriol Hodgkin’s majority) disease (mechanism in Non-Hodgkin’s Usually therapy (mechanism in 1/3) responds to glucocorticoid Diagnosis Clinical symptomology with – History of cancer – Risk factors for cancer – Suppressed PTH Some centers can test for PTHrP to confirm Dx of humoral hypercalcemia High PTHrP may predict response to pamidronate16 – Less of a response 16. Gurney, H, Grill, V, Martin, TJ. Parathyroid hormonerelated protein and response to pamidronate in tumourinduced hypercalcemia. Lancet 1993; 341:1611. Malignancy must be ruled out in patients that present with a very high calcium and no other obvious cause Treatment Aims Lower serum calcium concentration Treat complications if present Treat underlying disease Large Volume volume of normal Saline administration Expands intravascular volume Increases calcium excretion – Inhibition of proximal tubule and loop reabosrption – Reduces passive reabsorption of calicum Follow fluid status b/c of danger of fluid overload Inhibition of Bone Resorption Three therapies – Calcitonin – Bisphosphonates – Gallium nitrate Historical therapy – Antitumor antibiotic plicamycin (mithramycin) Multiple serious side effects No longer manufactured Calcitonin Salmon calcitonin Increases renal excretion of calcium Decreases bone reabsorption by interfering with osteoclast maturation Weak agent Works the fastest Bisphosphonates Adsorb to the surface of bone hyroxyapatite Interfere with osteoclast activity Cytotoxic to osteoclasts Inhibit calcium release from bone Three commonly used – Pamidronate – Zoledronic acid – Etidronate (1st generation, weaker) Bisphosphonates More potent than calcitonin Maxium effect occurs in 2 to 4 days Trend to use of IV zoledronic acid in the acute situation Both are can be renal toxic – More potent than pamidronate – Administered over a shorter period of time (15 minutes vs. 2 hours) Prophylactic Bisphosphonates Pamidronate use in patients with known lytic lesions17 – Less – Less – Less – Less – Less episodes of hypercalcemia pathologic fractures pain spinal cord compression need for radiation or surgery 17. Hortobagyi, GN, Theriault, RL, Porter, L, et al for the Protocol 19 Aredia Breast Cancer Study Group. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med 1996; 335:1785. Newly discovered side effect… Osteonecrosis of the jaw Recent case reports of jaw bone necrosis in patients on pamidronate EDUCATION needed Gallium Nitrate Effective More potential for nephrotoxicity Rarely used Dialysis Last resort Dialysis fluid with little or no calcium is effective Useful when patients can’t tolerate large volume resuscitation If calcium needs to be correct emergently Recommendations in symptomatic situation Volume expansion Salmon calcitonin IV zoledronic acid or pamidronate Close follow up of calcium level and symptoms Transitions in Treatment Chemotherapy Two roles Direct treatment of cancer Palliation of symptoms Palliative Chemotherapy Goal is not cure Goals – Control of tumor – Preservation of function – Help tumor symptoms Pain Dsypnea Pruritis Poor appetite Weight loss Fine Balance Chemotherapy can be very toxic Ratio: benefit vs. toxicity Host factors and tumor factors Delicate situation Want balance in palliative medications that affect tumor but do not heavily affect host Psychology of Cancer Psychological evolution during cancer treatment Many people have fought very hard with their disease Chemotherapy for “relief” not “cure” can be difficult concept for patients ART of medicine Evolution Chemotherapeutic protocols that have less side effects molecular targeted therapies – Attack tumor specifically – Less effect on host Breast Colon cancer Cancer Prostate Lung cancer cancer Breast Cancer Aromatase tumors inhibitors for ER positive – Anastrozole, Letrozole, Exemestane Trastuzumab (Herceptin) – Humanized monoclonal antibody targeting Her-2/neu protein on breast cancer cells – Inhibits growth factor signal transduction – Tolerated quite well Colon Cancer Capecitabine (Xeloda) Oral drug that is transformed into 5FU with three enzymatic reactions – Final enzyme is at higher levels in tumor cells – Contributes to drug’s less toxic side effect profile Less stomatitis, less myelosupression Targeted GI Therapies Bevacizumab – Monoclonal antibody to vascular endotheial growth factor receptor – Some cardiac toxicity Cetuximab – Monoclonal antibody to human epidermal growth factor receptor – Skin toxicity Prostate Cancer LHRH analogues Leuprolide Goserelin Stop (Lupron) (Zoladex) testosterone production with limited side effects Lung Cancer In stage IV disease patients who receive Cisplatin based doublet chemotherapy live longer and feel better than best supportive care Hard to balance side effects Gefitinib (Iressa) Targets epidermal growth factor receptor (tyrosine kinase small molecule inhibitor) May have a role in the palliation of advanced non small cell lung cancer patients Palliative Care Debate Do not accept any patient on “active” therapy This needs to be further elucidated Patients being palliated with chemotherapy or targeted therapies still have other palliative care issues and needs Should a patient still on Xeloda for breast or colon cancer not be admitted to St. Boniface 8A? Thank you Any questions?
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