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3 CATEGORIES • Structural/ obstructive - spinal cord compression - SVC obstruction - raised intra-cranial pressure - pericardial tamponade, urinary obstruction, massive hemoptysis ONCOLOGICAL EMERGENCIES Dr Linda Mileshkin Medical Oncologist Peter MacCallum Cancer Centre • Metabolic – Hypercalcemia – Hyponatremia: SIADH, volume depletion, adrenal insufficiency • Treatment-related - febrile neutropenia - tumour lysis syndrome - anaphylaxis SPINAL CORD COMPRESSION • Can occur with any cancer that goes to bone Eg. Breast, lung, prostate, lymphoma, myeloma • Affects 5-15% of cancer patients - 30% of patients alive at 1 year - Converts ambulatory patients into bed ridden, & in pain - early treatment effective in 80% if early diagnosis when patient can still walk • Early detection is best prevention • Pretreatment mobility is best predictor of outcome SPINAL CORD COMPRESSION Compression of the thecal sac by tumour in the epidural space: at level of spinal cord or cauda equina DDx – osteoporotic fracture, abscess, paraneoplastic, haematoma SYMPTOMS AND SIGNS PAIN and TENDERNESS • >90% of patients with spinal cord compression have back pain: usually the first symptom • Usually constant, dull pain which maybe worse at night • Worse with movement, being supine, sneezing • Radicular pain is very suspicious (i.e. band like thoracic pain or shooting pains in limbs) • Tender to spinal percussion • 90% will have prior diagnosis of malignancy SYMPTOMS AND SIGNS WEAKNESS and LOSS of POWER • Difficulty walking • Need full neuro exam: usually LMN signs if happens acutely, later UMN • Need PR examination for reduced anal tone • Acute or slowly evolving changes in bowel/bladder function SENSORY LOSS • Numbness or paraesthesia • Look for sensory level 1 INVESTIGATIONS • Plain x-rays: only show lesion once 50% bone destroyed, cannot see paraspinal masses • MRI (CT myelogram if no access or patient can’t have one) Indications for urgent MRI: • Focal weakness /Abnormal neurological examination • Unexplained bladder/bowel dysfunction (in a cancer patient with back pain) TREATMENT • Dexamethasone (i.e. 16 mg bolus, then 4 mg qid) • Radiotherapy alone is main primary treatment Indications for surgery :Spinal instability : No tissue diagnosis :Previous radiotherapy to the area or progression despite radiotherapy :Radioresistant ca (i.e. RCC) Two arms • Radiation arm – 30 Gray – To start within 24 hours • Surgery arm – Within 24 hours of presentation – Removal of as much of tumour bulk as possible – Stabilisation of spine if necessary – Radiotherapy within 2 weeks (30Gy) 2 RESULTS Stats • 1 planned interim analysis at 50% accrual (100 patients) • At planned analysis, trial was stopped with a p value of 0.0045 • 7 institutions in US participated, however 70% came from one site 3 4 SVC OBSTRUCTION Conclusions of Patchell et al. • Surgery + XRT is superior to XRT alone arm in treatment in the treatment of spinal cord compression by metastases • Surgery seems to works best when given up front treatment • Pros of surgery • Immediate stabilisation tumour – better pain control • Immediate decompression Mechanical obstruction occluding the SVC -at risk due to thin walled vessel in a limited compartment AETIOLOGY • Lung cancer (75%)– small cell and non-small cell • NHL • Mediastinal tumour: Primary eg thymoma : Secondary eg. Germ, mesothelioma DDx • Goitre, heart failure, SVC/subclavian thrombosis, TB, aortic aneurysm Most commonly occurs in men aged 50-70 with cancer) • Cons of surgery • Major operation, with morbidity/mortality- anterior approach • Need to pick patients who will benefit – Younger, better ECOG, controlled other disease • Need experienced neuro-surgeons SYMPTOMS • • • • • • • Dyspnoea +/- orthopnoea Facial ± arm swelling Head ‘fullness’, change in colour Dizziness : worse with bending over or supine Difficulty buttoning shirt Dysphagia, hoarseness Prominence of chest wall veins SIGNS • • • • • • Neck/chest wall venous distension Loss of pulsation in neck veins Facial/periorbital/arm or finger oedema Cyanosis / plethora Pembertons sign Pleural effusion • If more rapid onset, may have respiratory distress and mental state changes due to cerebral oedema, altered cardiac output and laryngeal oedema (all rare) INVESTIGATIONS · CXR – almost always shows mediastinal widening/mass · CT chest · Basic bloods and tumour markers · Doppler venous U/S if thrombosis possible · Histological diagnosis if possible in newly diagnosed pt – sputum cytology - biopsy of node - bronchoscopy/mediastinoscopy - bone marrow if suspect NHL 5 Safety of Investigations • May have risk of anaesthetic complications or bleeding complications • Ahmann et al 1984 : review of literature since 1934 : 90 publications with 1986 cases : 4 confirmed deaths from syndrome : few reports of complications from diagnostic Ix MANAGEMENT Depending on histology: • RT for most patients: may improve symptoms without increasing blood flow • Chemo if v. chemosensitive eg NHL, germ • Stenting sometimes used • Removal of catheter and anti-coagulation +/thrombolysis if catheter associated thrombosis • Steroids help acutely plus sit up / give O2 FEBRILE NEUTROPENIA • Temperature is > 38.3 once or > 38 twice in an hour with neutrophils <1.0 x 109/L • Risk increases with depth and duration of neutropenia • Highest risk with NØ <0.1 • Neutrophil nadir usually 5-10 days after chemo 6 ACTION ASSESSMENT • Vital signs - blood pressure, pulse, urine output, conscious level • Sites of infection – mouth, throat, sinuses, chest, abdomen, perineum, skin and central venous access sites • Full Septic Work Up 3 sets of blood cultures within the first 24 hours :peripheral and venous access device (if present) Full blood count and diff, CRP, U&E Chest X-ray MSU for m/c/s Stool specimen if diarrhoea present Sputum specimen if productive cough Swab any wound sites, skin lesions, mouth, throat, perianal area and Central venous access sites EMPIRIC TREATMENT • Any oncology patient receiving chemotherapy who presents with a fever >38 C should be assumed to have febrile neutropenia until proven otherwise. This includes a patient who measures a temperature >38 C at home, and then presents at the hospital afebrile after taking recent paracetamol. Intravenous antibiotics must be commenced immediately after taking the first set of blood cultures without waiting for the results of an FBE. Causative Organisms • Frequently culture negative • 70% gram positive organisms - S.aureus, coag neg staph, strep, enterococci • 30% gram negatives - E.Coli, Klebsiella, Enterococci - Pseudomonas now less common - Rarer types: Stenotrophomonas, Citrobacter Patients without significant sepsis or septic shock Single agent 4th generation cephalosporin OR combination therapy to cover gram negs and some positives including Pseudomonas Eg. Cefepime, Piperacillin/tazobactam • Consider adding stat gentamicin if moderately unwell and/or patient admitted after hours or on weekends • Add metronidazole if severe diarrhoea • If signs of indwelling catheter infection, known MRSA colonized or septic shock add vancomycin • Ciprofloxacin if beta-lactam allergy • Cover any prior known organism present now or in past • Work with ID physician ONGOING TREATMENT • Continue antibiotics until NØ >0.5 and patient afebrile if culture negative • Treat for 10-14 days for bacteremia depending on organism • May need longer treatment if deep-seated S.aureus infection • Consider TOE once neutrophils recovered if persistently positive blood cultures > 3 days on appropriate treatment • Continue monotherapy if blood culture negative, stable and asymptomatic • Add new antibiotics for new symptoms / signs or positive cultures • Stop Vancomycin after 72 hours if no there is no indication (to reduce rates of VRE) • Consider anti-fungals if patient unwell with ongoing fever and at-risk patient eg induction for acute leukemia: further investigation with HRCT ONGOING FEVER 7 G-CSF • Primary prophylaxis : only reduces the risk of febrile neutropenia if regimen associated with >40% risk of this • Secondary prophylaxis: of benefit to use with next cycle following an episode if maintenance of dose intensity important eg. Rx of aggressive lymphoma or adjuvant breast • For most metastatic solid tumour no evidence that prophylactic G-CSF superior to dose reduction • Pegylated form now available (pegfilgrastim): one dose per cycle Use of G-CSF in established febrile neutropenia • Some trials suggest a small decrease in length of hospital stay or neutropenia duration • Meta-analysis shows no decline in overall mortality • Possible reduction in ‘infection-related mortality’ but results heavily influenced by one trial OUTPATIENT TREATMENT • Shown to be safe in low-risk patients : solid tumour pts given usual dose chemo : expected short duration neutropenia (<7D) : no comorbidities and compliant : clinically stable with fever alone/ simple infection eg UTI • Patients need appropriate social supports and hospital need infrastructure • Augmentin plus ciprofloxacin HYPERCALCAEMIA Serum calcium > 3.0 mmol/L Affects 10-20% cancer pts : usually late in illness Main culprits: • Myeloma • Breast cancer • NSCLC • Lymphoma • Any tumour with extensive bony mets -rare in prostate cancer, small cell lung 8 Mechanism maybe: HUMORAL (main mechanism) OSTEOLYTIC (any cancer with bone mets) with local cytokine release TUMOUR PRODUCTION of CALCITRIOL (lymphomas) PTHrP acts like PTH – increases bone resorption and distal tubular calcium reabsorption Symptoms and Signs • Dehydration, lethargy, renal failure • Anorexia, nausea and confusion • Constipation • Polyuria and polydipsia DIAGNOSIS • Always check Ca++ on admission in oncology patients Check that value is corrected for albumin If not : Add (40-Alb) X 0.02 HCM severity Mild Moderate Severe 3.0* >3.2 >3.4 Symptoms Mild anorexia, nausea, weight loss, weakness, constipation, and altered mental status Similar to mild HCM, with renal insufficiency and deposition of calcium in organs and tissues Severe nausea and vomiting, dehydration, renal insufficiency, and clouding and loss of consciousness Coma and cardiac arrest Lifethreatening >3.7 •Normal serum calcium (corrected for albumin) is 2.0 to 2.7 mmol/l •ECG changes: bradycardia, prolonged PR, short QT, widened T waves, arrythmia TREATMENT • Hydration (may need many litres of N Saline) • IV bisphosphonate :pamidronate (APD, Aredia) or zoledronate • Can use small dose of frusemide once rehydrated as calciuric • Corticosteroids helpful if steroid responsive tumour eg NHL • Avoid other meds which inhibit urinary calcium excretion or reduce renal blood flow (NSAIDs, thiazides) • Rarely require other measures eg. calcitonin • Of underlying tumour as hypercalcaemia usually means it has progressed BISPHOSPHONATES -bind to hydroxyapatite and then internalised by osteoclasts -inhibit osteoclast activity and survival -second generation nitrogen containing bisphosphonates more potent -zoledronic acid the most potent available : more rapid and sustained fall in calcium than APD : shorter infusion (15 vs 90 mins) : 8mg no better than 4mg and some renal toxicity : don’t give if GFR < 30 ml/min 9 CLINICAL FEATURES TUMOUR LYSIS SYNDROME • Due to spontaneous or treatment-induced rapid lysis of malignant cells - chemotherapy(<5days), steroids, rituximab • High mortality if occurs • Results in release of intracellular products (DNA) and ions into the circulation which exceeds the excretory capacity of the kidney • Hyperkalemia: 6-72 hrs • Hyperphosphatemia: 24-48 hrs • Hypocalcemia: 24-48 hrs -secondary due to precipitation in tissues, plus inadequate production of calcitriol • Hyperuricemia: 24-48 hrs -due to break down of purine nucleotides • Renal failure: 48-72 hrs -due to nephocalcinosis and uric acid crystallization in renal tubules • Seizures / arrythmias ASSOCIATED CONDITIONS • Haematological with high proliferation rate - Burkitts - Lymphoblastic lymphoma - ALL, AML, CLL • Solid tumours rare - small cell lung, breast, germ cell - neuroblastoma PATIENT RISK FEATURES • Large tumour burden-advanced intra-abdo mass or high blast counts in a chemosensitive disease • Increased LDH • Pre-existing volume depletion • Pre-exisiting renal failure • Acidic urine • Male • Young age (<25 yrs) PURINE XANTHINE HYPOXANTHINE Xanthine Oxidase Best treatment is prevention • • • • Urate Oxidase URIC ACID ALLANTOIN (other mammals) Hydration, monitor electrolytes Alkalinize the urine – increases solubility of uric acid Allopurinol Urate oxidase (Rasburicase) - recombinant DNA version - more rapid onset of action - lowers preexisting uric acid levels - contraindicated in G-6PD deficiency - no effect on electrolyte/acid base disturbance 10 OTHER TREATMENT • Correct electrolyte disturbances -hypocalcemia only if symptomatic as may cause precipitation • Dialysis maybe required for renal failure or uncontrolled electrolyte disturbance Good reference articles Cervantes A, Chirivella I. Oncological emergencies. Annals of Oncology 2004, 15 (Suppl 4): 299-306 Halfdanarson TR, Hogan WJ, Moynihan TJ. Oncologic Emergencies: Diagnosis and Treatment. Mayo Clin Proc 2006, 81(6): 835-848 Spinazze S, Schrijvers D. Metabolic emergencies. Crit Reviews in Onc/Hematol 2006, 58: 79-89 11