2. Infections in cancer patients Cancer patients are prone to infections because of: Cancer itself Disturbance of the immune system Anatomical obstruction Functional impairment Poor nutritional status Cancer therapy Chemotherapy: myelosuppression Radiotherapy: local tissue breakdown Surgery: infection complicated Stem-cell transplantation: acute & chronic immune suppression

3. Outline  Introduction  Definitions  Assessment & work-up  Management  CSFs in Neutropenia

4. Introduction  Bone marrow suppression is the most common dose limiting toxicity associated with traditional chemotherapy.  Bone marrow responsible for manufacturing and maintaining the blood components including: WBC, Platelets and RBCs.  WBC: normal range is 4.8 – 10.8 x 10 3 any values below considered leukopenia.

5.  Platelets: normal range 140,000 – 440,000 cells/mm 3. with life span of 5 – 10 days.  RBCs: normal range 4.6 -6.2 x 10 6 /mm 3. with life span 120 days.  Chemotherapy effects are more profound on WBC being of short life span 6-12 hours.  ANC = WBC x % granulocytes or neutrophils (segmented plus band).

6. Definitions  Neutropenia is defined as ANC of 500 /mm 3 or less or a count of less than 1000/mm 3 with expected drop to below 500/mm 3 in the next 48 hours.  Febrile neutropenia: is defined as neutropenia and a single oral temperature of ≥38.3°C, or a sustained temperature of ≥38.0°C over 1 hour.  Risk of infections increased when WBC below 500 and becoming severe if reached below 100.

7. Definitions  Nadir: is the lowest value to which blood counts falls (WBC) after chemotherapy. Usually 10-14 days after chemotherapy and recovered by 3-4 weeks. Exceptions include drugs e.g. Mitomycin and Nitrosurias which have nadir on 28-42 days and delayed recovery by 6-8 weeks.  To administer chemotherapy; ANC should be above 1500, platelets above 100,000 and Hb above 10. However, certain protocols use lower values.  MASCC: Multinational Association for Supportive Care in Cancer MASCC scoring index is a validated tool to rapidly assess risk in febrile neutropenic patients Max score = 26 Scores <21  high risk of complications Scores ≥21  low risk

8. Definitions

9. Case presentation  A 40 YOF diagnosed with locally advanced breast Cancer presented to ER.  History of Treatment: Completed 3 cycles neoadjuvant FEC q3wk Received 2 nd cycle docetaxel q3wk Receiving peg-filgrastim dose Day 2 post docetaxel (primary prophylaxis)

10. Case presentation  Temp = 39.5  C and feeling “unwell”  WBC = 2.2 (4-11), Neutrophil = 0.42 (2-7.5)  Creat = 87 (50-100)  BP 170/60, RR 20, HR 110

11. Whom to treat (as febrile neutropenia patients)  Febrile + ANC <500/mm³…… what else?  Febrile + ANC <1000/mm³ falling rapidly  Afebrile + ANC <500/mm³ + suggestive symptoms (↑ HR, ↑ RR, ↓ BP, confusion, disorientation… etc)

12. Risk Assessment  Assess as an emergency (within 1H of presentation)  Risk assessment is fundamental to determine the: Type of empirical antibiotic therapy (mono- or combination therapy) Treatment setting (ICU/inpatient/outpatient)

13. Pts. Should be admitted for empirical IV ttt Risk Status Assessment Candidates for PO ttt

14. Management  Utmost emergency: shock, ARD, DIC, MOF Resuscitate (maintain good perfusion) even before ICU admission in severe sepsis  Always assume: Fever = of infectious origin start appropriate antibiotics  Discontinue potential causative drugs.  Should I start G-CSF? G-CSF should not be used routinely in the treatment of established febrile neutropenia, although they may be considered in patients at increased risk for serious complications including mortality, ANC ≤ 100, and or age ≥ 65 with comorbidities.

15. Management  Assess vital signs at least every 4h, and more frequently if vitally unstable  CBC daily  Serial CRPs  Repeat blood culture if fever persists as clinically indicated  Repeat CXR as clinically indicated [until afebrile + ANC >1000 mm 3 ]

16. How to Choose Antibiotic Therapy

18. Vancomycin indication Including Glycopeptide (Vancomycin 15 mg/kg IV Q12h) as first line only if:  Signs of infection around the IV catheter insertion point or along catheter track  MRSA or Penicillin-resistant pneumococci are likely  Gram+ve organisms in the blood culture  Severe mucositis (high dose Cytarabine, or CCRT)  Septic shock (hypotension) Administrated through the lumens of the involved IV catheter Must be stopped after 3-4 days if no more indicated

19. Oral dual therapy  Low-risk empirical duotherapy: Vigilant observation  Access to medical care 24/7  RTC if: l Positive cultures l Persistent/recurrent fever at 3-5 days l Unable to tolerate PO regimen Ciprofluxacin 500 mg PO Q8h + amoxicillin- clavulanate 500 mg PO Q8h Oral route may be substituted by IV when necessary

20. Continuation of antibiotic treatment

22. Colony Stimulating Factors (CSFs) in Neutropenia and F.N  Specific agents used to enhance the function of their target cells in the bone marrow (namely the granulocyte precursors).  Different types: G-CSF (Filgrastim) 5mcg/kg S.C daily GM- CSF (Sargramostim) 250μg/m2/day S.C Pegylated G-CSF (Pegfilgrastim) 6mg once per cycle.  G-CSF and GM-CSF are used interchangeably.  Peg GSCF is equal to 11 daily doses of GCSF.

23. Precautions  Do not use in patients receiving radiotherapy.  All are used as S.C route which is the preferred route.  Use from 24 to 72 hours after completion of chemotherapy.  Peg GCSF used as one injection preferably with long protocols.  Short acting forms stopped when ANC is 2000 – 3000.

24. Indications (Clinical Situations to Use GCSF)  Primary prophylaxis  Secondary prophylaxis  Therapy of patient with neutropenia  CSF to increase chemotherapy dose density and intensity  In older patients  Other situations

25. Primary Prophylaxis  It is recommended for the prevention of febrile neutropenia(FN) in patients who have a high risk of FN based on age, medical history, disease characteristics and myelotoxicity of chemotherapy regimen.  Special circumstances: relative non-mylelo-suppressive chemotherapy but who have potential risk factors for febrile neutropenia or infection because of bone marrow compromise or comorbidity.

26. Primary Prophylaxis Indications  Primary prophylaxis is recommended if the incidence of neutropenia per protocol is ≥20%.  Should be considered If the incidence is 10 -20% unless treatment is palliative.

27. Secondary Prophylaxis  Recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy, IN which a reduced dose may compromise disease-free or overall survival or treatment outcome (Curative Intent of chemotherapy).  Re-evaluate the goal of chemotherapy. Dose reduction or delay remains an appropriate strategy for the palliative treatment of cancer.

28. Patients With Neutropenia  Afebrile neutropenia: is not recommended.  Febrile neutropenia: Should NOT be routinely used as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia. Only if risk factors are high:  ANC is below 100  Age above 65  Hospitalized at fever onset  Pneumonia  Haemodynamic instability  Multi organ dysfunction  Documented fungal infection  Already on GCSF and nadir was not reached yet; to continue

29. CSF to increase chemotherapy dose density and intensity  In a few specific settings, use of dose-dense (but not dose-intese) regimetn with CSF support have survival benefit.  CSF allows a modest to moderate increase in dose-density and/or dose-intensity of chemotherapy regimens e.g.  Dose-dense chemotherapy with CSF support has better disease-free and overall survival in node positive breast cancer.  CHOP-14 better than CHOP-21 in NHL.

30. Impact on quality of life and health care costs  No difference in global quality of life between the study arms.  In a cost-benefit study in Netherland, G-CSF as primary prophylaxis has higher total hospital cost.  When available, alternative regimens offering equivalent efficacy, but not requiring CSF support, should be utilized

31. Case Study  A 45 years old female presented 10 days after her second cycle of adjuvant AC protocol with fatigue. Laboratory findings showed WBC 600/mm, neutrophil is 60%, band neutrophil is 10%, monocytes 12%, basophils 8%and eosinophil 10%. She is afebrile and hemodynamically stable.  Questions: What is her ANC? Would she need antibiotics? Would you recommend starting GCSF right now? For her next cycle would you start prophylactic GCSF or reduce the dose of her chemotherapy?

32. Case II  A patient received her fourth cycle of chemotherapy with paclitaxel- carboplatin for ovarian cancer 12 days ago. She reports to the clinic today with a temperature this morning of 103°F. Her CBC is WBC 5 × 10 2 cells/ mm3; segmented neutrophils 55%; band neutrophils 5%; basophils 15%; eosinophils 5%; monocytes 15%; and platelet count 99,000/mm3. She denies any signs and symptoms of infection. Her blood pressure (BP) is 115/60 mm Hg; heart rate is 80 beats/minute; and respiratory rate is 15 breaths/minute. Which best represents the patient’s absolute neutrophil count (ANC)? A. 275. B. 300. C. 25. D. 500.

33. Which is the best course of action for the patient in the previous question? A. Admit to the hospital for intravenous antibiotic drugs. B. Treat as an outpatient with antibiotic drugs. C. Initiate a colony-stimulating factor (CSF). D. Discontinue chemotherapy.

34. Which statement about the above patient is most accurate? A. Given her monocyte count, her neutropenia is expected to last for another week. B. This is a nadir neutrophil count, and neutrophils would be expected to start increasing soon. C. The elevated absolute eosinophil count indicates an allergic reaction to carboplatin. D. It is unusual for the ANC to be this low in the face of an elevated platelet count.

36. References  IDSA, 2010  NCCN, 2013