ONCOLOGY EMERGENCIES

1. ONCOLOGY EMERGENCIES • AHD “A” • Dr Joseph Kozar, CCFP (EM) • Mar 28, 2013

2. Oncology Emergencies - Categories • Local Tumour Effect -Compressions and Obstructions • Metabolic Crises • Hematologic Crises • Treatment Related Adverse Effects • Pain Crisis

3. Oncology Emergencies • Local Tumour Effect – Compressions & Obstructions • Superior Vena Cava Syndrome • Malignant Spinal Cord Compression • Malignant Pericardial Effusion • Ureteral Obstruction • Upper Airway Obstruction • Massive Hemoptysis • Pathologic Fractures • CNS • Increased ICP effects • Seizures • GI • Obstruction • Perforation • Bleeding

4. Oncology Emergencies • Metabolic Crises • Hypercalcemia • Hyponatremia and SIADH • Tumour Lysis Syndrome • Hyperuricemia • Tumour-associated hypokalemia • Hypoglycemia

5. Oncology Emergencies • Hematologic Crises • Febrile Neutropenia • Hyperviscosity Syndrome • Thromboembolic disease • Acute hemolytic anemia • Thrombocytopenic bleeding

6. Oncology Emergencies • Treatment Related Adverse Effects • Chemotherapy induced nausea and vomiting • Constipation/Obstipation • Diarrhea • Radiation induced pneumonitis, proctitis

9. CASE • 55 yr old male with colon CA, chemo 9 days ago with 5-Fluorouracil and has T38.5 • No other infectious symptoms

11. FEVER in the Cancer Patient • Fever occurs in chemo-induced neutropenia • 10-50% pts with solid tumours • >80% pts with hematologic malignancies • Documented infection in only 20-30% of febrile episodes 5 • Common sites of tissue based infection: GI tract, Lungs, Skin • Bacteremia in 10-25%, esp in prolonged or profound neutropenia • Non-infectious causes of fever: • Antineoplastics • Antimicrobials • Tumour necrosis • Inflammation

12. Febrile Neutropenia - Definition • Fever • Single oral temp > 38.3 C • OR • Sustained oral temp > 38 C for > 1 hour • avoid axillary temp (inaccurate) and rectal temp (risk of infection) • Caveats 3: Elderly, steroids, sepsis presenting as hypothermia

13. Febrile Neutropenia - Definition • Neutropenia • Absolute Neutrophil Count (ANC) < 0.5 X 109/L • OR • ANC predicted nadir < 0.5 X 109/L in next 48 hrs • Profound neutropenia = ANC < 0.1 X 109/L • Functional neutropenia = Hematologic malignancies with a qualitative defect (impaired phagocytosis and killing of pathogens) of circulating neutrophils despite normal neutrophil counts

14. Neutropenia Typical nadir 5-10 days after last dose Recovery within 5 days of nadir Regimens for leukemias and lymphomas produce longer lasting and more profound neutropenia 4

15. Febrile Neutropenia • Risk of infection varies • Directly with duration of neutropenia • Directly with rate of decline • Inversely with ANC • > 20% with ANC <0.1 are bacteremic

16. Febrile Neutropenia • Primary anatomic sites of infection often include 1: • GI tract • Chemo –induced mucosal damage allows invasion of opportunistic organisms • Skin • Invasive procedures (vascular access devices) provide portals of entry

17. Febrile Neutropenia - Microbiology • 1960 and 1970’s gram negatives predominate • 1980 and 1990’s gram positives become more common with indwelling venous catheters • allow skin flora entry • Fungal : Candida & Asperigillus • consider in fevers unresponsive to antibacterials

18. Febrile Neutropenia - Current Microbiology • Coagulase-negative staph most common blood isolate in most centres • Enterobacteriaciae (Enterobacter, E coli, Klebsiella) as well as Pseudomonas and Stenotrophomonas less common • Recently, drug resistant Gram Negatives on the rise in some centres • Gram Negative resistance • ESBL (Klebsiella and E coli) • Carbapenamase resistance (Klebsiella and Pseudomonas -KPC) • Gram Positive resistance • MRSA • VRE • penicillin resistant Strep pneumoniae & viridans

19. Febrile Neutropenia • Diagnosis of infection is difficult because signs & symptoms of inflammation often attenuated or absent • skin and soft tissue infections may lack erythema, warmth, induration, pus • chest infection may have no infiltrate on CXR • UTI may have little pyuria • Fever often only sign of serious infection • Rigors or toxic appearance highly associated with infection and possible bacteremia

20. Febrile Neutropenia - Historical Features • Underlying malignancy • Timing and type of chemo • Nadir usually 5-10 days after chemo • Site specific infectious symptoms • Presence of central venous catheters (CVC) • Anti-microbial prophylaxis • Prior documented infections or pathogen colonization • Underlying comorbid conditions eg DM, COPD, CKD, recent surgical procedures

21. Febrile Neutropenia - Physical Exam • Vitals • Most common infection sites • Chest • Skin esp current or past catheter sites, marrow aspiration sites, periungal area • Oropharynx including gums • Abdomen • Perineum • no rectal exam

22. Febrile Neutropenia - Investigations • Cultures • Blood Cultures • > 2 sets ( a set = 20 mL divided in aerobic and anaerobic bottles) • if CVC present, culture from each lumen plus a peripheral source • Urine C&S • If S&S of UTI, urinalysis abnormal or catheter present • Sputum C&S if productive cough • Stool for C diff toxin assay only if diarrhea • No bacterial C&S or O&P unless travel history • CSF if meningitis clinically suspected • Skin :aspiration of clinically suspected infection

23. Febrile Neutropenia - Investigations • CBC and differential • Creatinine, Urea, LFTs, electrolytes • CXR if respiratory symptoms • CT as clinically indicated (eg Head, sinuses, chest, abdomen/pelvis) • Interestingly, CT chest will reveal evidence of pneumonia in >50% of febrile neutropenics with normal CXR

25. CASE • 55 yr old male with colon CA, chemo 9 days ago with 5-Fluorouracil and has T38.5 • No other infectious symptoms • No significant past medical history • Looks well • Vitals normal • Porta-cath • No evidence infection • Exam: no abnormalities • ANC = 0.2 X109/L

26. Question • Which antibiotics will you give him? • A] Cipro po & Clavulin po • B] Piperacillin/Tazobactam IV & Vancomycin IV • C] Meropenem IV • D] Ceftazidime IV & Gentamicin IV • E] Piperacillin/Tazobactam IV

27. Febrile Neutropenia - Therapy • Febrile Neutropenia is a medical emergency • Start Empiric broad spectrum antibiotics promptly (< 2 hrs) as untreated infections have 25-50% mortality at 48hrs • No specific drug or combination can be unequivocally recommended for all pts • Guidelines applicable in most situations, but require modification based on local circumstances and epidemiologic data • Change from previous guidelines: More structured assessment of individual febrile neutropenic patient as high or low risk for serious infectious complications • Affects therapy and venue of therapy

28. Febrile Neutropenia - Risk Assessment • Can divide patients into high risk or low risk for infectious complications • High Risk patients: IV antibiotics as inpatients • Low Risk patients: Carefully selected Low Risk patients may be eligible for Oral and / or Outpatient antibiotic therapy (?early discharge) • 2 risk assessment tools: • Clinical • Formal classification with MASCC scoring system

29. Febrile Neutropenia - Risk Assessment • Clinical Criteria for High Risk • Profound neutropenia (ANC < 0.1) and anticipated to last > 7 days • Hepatic insufficiency (aminotransferases >5X normal) • Renal insufficiency (Creat clearance <30 mL/min) • Presence of any co-morbid medical problems including but not limited to: • Hemodynamic instability • Oral or GI mucositis that interferes with swallowing or causes severe diarrhea • Neurologic or mental status changes of new onset • Intravascular catheter infection, esp catheter tunnel infection • New pulmonary infiltrate or hypoxemia, or underlying chronic lung disease • Uncontrolled pain • Uncontrolled Cancer • Advanced Age • Poor functional status

30. Febrile Neutropenia - Risk Assessment • Clinical Criteria for Low Risk • Anticipated neutropenia < 7days • No or few co-morbidities • Stable and adequate hepatic and renal function • More often in solid tumours

31. Febrile Neutropenia - Risk Assessment High risk <21 Low risk >21 Fundamental problem is nebulous nature of “Burden of febrile neutropenia and symptoms associated with that burden”

32. Febrile Neutropenia - Treatment • Goal of initial empiric antibiotics: Prevent serious morbidity and mortality until results of cultures available to guide more precise antibiotic choices • However recent prospective observational study of > 2000 pts revealed only 23% with documented bacteremia • gram positives: 57% • gram negatives: 34% • polymicrobial: 9% • But mortality: Gram Negatives 18% > Gram Positives 5% • Even if blood cultures negative, empiric antibiotics considered vital to cover occult infections

33. Febrile Neutropenia - Treatment • despite decades of well performed clinical trials, no single empiric regimen proved superior • all effective regimens share certain features: • bactericidal in the absence of WBCs • anti-pseudomonal activity • minimal toxicity • Recently, increasing array and incidence of resistant pathogens causing challenges in the treatment of febrile neutropenics

34. Febrile Neutropenia - IDSA 2010

35. Febrile Neutropenia - Treatment • Initial IV antibiotics: Monotherapy with anti-pseudomonal Beta-lactam • Piperacillin-Tazobactam: 3.375 IV q6h • Carbapenem : eg Meropenem 1g IV q8h • Cefipime: (4th generation cephalosporin) 2g IV q12h • Ceftazidime: (3rd gen cephalosporin) 1g IV q8h • Many centres find has decreased potency gram negatives & poor activity against many gram positives eg streptococci so has fallen out of favour

36. Febrile Neutropenia - Treatment • Vancomycin (or other gram positive agent) not part of empiric initial therapy • Randomized studies show no difference with or without Vancomycin for empiric initial therapy despite predominance of cultures being gram positive (most common coagulase negative staph) • Add Vancomycin for specific indications -Table 4

38. Febrile Neutropenia - Treatment • Modifications to initial empiric antibiotic therapy for pts at risk for with antibiotic resistant organisms esp • if unstable • positive blood cultures suspicious for resistant bacteria

39. Febrile Neutropenia - Treatment • Penicillin allergic patients with immediate type hypersensitivity • Ciprofloxacin + Clindamycin • Aztreonam + Vancomycin • AFEBRILE NEUTROPENIC pts with signs and symptoms of infection should be evaluated and treated as high risk patients

40. Febrile Neutropenia - IDSA 2010

41. Febrile Neutropenia - Treatment • Low Risk Pts should receive initial Oral or IV empiric antibiotics in hospital or clinic setting • Recommended empiric Oral Rx: Ciprofloxacin + Clavulin • Alternatives are less well studied: • Levofloxacin monotherapy • Better gram positive coverage than cipro but less potent anti-pseudomonal coverage so should use 750mg daily dose for higher bacericidal drug concentrations • Ciprofloxacin + Clindamycin

42. Febrile Neutropenia - Treatment • 2 large placebo controlled studies of low risk patients showed Oral cipro & clavulin comparable to empiric IV therapy, However, both groups were inpts • few studies have assessed feasibility of treating low risk patients solely in outpatient settings • most studies have observed pts in hospital for 24hrs of empiric therapy, although a few have discharged patients 6 hrs after antibiotics initiated • outpt oral or IV therapy can be considered after brief inpt stay, with IV antibiotics initiated, fulminant infection excluded, patient deemed low risk and stable, outpatient supports in place, status of initial cultures ascertained, prompt access (< 1hr from medical facility) to medical care 24/7

43. Outpatient management of febrile neutropenia • At TOH, decision made by oncology • “Outpt strategy should not be viewed as the current standard of care for febrile neutropenic patients” 3

44. CASE • 55 yr old male with colon CA, chemo 9 days ago with 5-Fluorouracil and has T38.5 • No other infectious symptoms • No significant past medical history • Looks well • Vitals normal • Porta-cath • No evidence infection • Exam: no abnormalities • ANC = 0.2 X109/L

45. Question • Which antibiotics will you give him? • A] Cipro po & Clavulin po • B] Piperacillin/Tazobactam IV & Vancomycin IV • C] Meropenem IV • D] Ceftazidime IV & Gentamicin IV • E] Piperacillin/Tazobactam IV

48. Summary • Febrile Neutropenia • IDSA 2010 guidelines • ANC < 0.5 • Early antibiotics • Pip/Tazo +/- Vancomycin

49. References – Febrile Neutropenia • 1. Hughes et al. 2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer. Clinical Infectious Diseases 2002; 34: 730-51. • 2. Bal, Gould. Empirical Antimicrobial Treatment for Chemotherapy-induced Febrile Neutropenia. International Journal of Antimicrobial Agents 2007; 29: 501-509. • 3. Adelberg DE, Bishop MR. Emergencies related to cancer chemotherapy and hematopoietic stem cell transplantation. Emergency Med Clin N Am 2009; 27: 311-331. • 4. Halfdanarson TR et al. Oncologic Emergencies: Diagnosis and Treatment. Mayo Clin Proc 2006; 81:835-848. • 5. Freifeld AG et al. Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Disease Society of America. Clinical Infectious Diseases 2011; 52(4): e56-e93.