1. La Neutropenia Marco Danova Oncologia Medica Universita e IRCCS San Matteo Pavia

2. Grading of Chemotherapy-Induced Neutropenia  LLN** Grade 1  1.5 Grade 2  1.0 Grade 3 MildModerateSevere Severe/life- threatening  0.5 Grade 4 *Absolute neutrophil count; **Lower limit of normal ANC* x 10 9 /L Common Toxicity Criteria for Adverse Effects Version 3.0 [electronic document]. Bethesda, Md: National Cancer Institute; 1999 Available at: http://ctep.info.nih.gov/reporting/ctc.html. Accessed January 4 2005

3. Neutropenia A Devastating Side Effect of Chemotherapy Boxer L, et al. Semin Hematol 2002;39:75-81. Crawford J, et al. Cancer. 2004;100:228-237 Neutropenia = Deficiency of neutrophils A common side effect in patients receiving chemotherapy treatment Predisposes to life-threatening infections Neutropenic complications after myelosuppressive chemotherapy can lead to –Morbidity –Mortality

4. High-dose chemotherapy Neutropenia Febrile Neutropenia Risk Factors for Neutropenia *Non-Hodgkin's lymphoma; **Breast cancer Silber JH, et al. J Clin Oncol 1998;16:2392-400 Scott S, Am. J Health Syst Pharm 2002; 59 (15 suppl 4):S16-S19 Ozer H, et al. J. Clin. Oncol. 2000;18:3558-3585 Crivellari D, et al. J Clin Oncol 2000;18:1412-1422 Advanced age > 65 years Advanced cancer Performance status (ECOG II-IV) Bone marrow involvement Infection, open wounds Renal disease* Above normal LDH* Serum albumin > 3.5 g/dL* Independent and disease- related risk factors Prior therapy-related risk factors Low cycle 1 nadir ANC** History of recurrent chemotherapy-induced neutropenia Pre-existing neutropenia due to: - Extensive myelosuppressive therapy - Radiation therapy to pelvis or other large regions of bone marrow

8. Why Guidelines? To assist clinicians in evidence-based treatment decisions To ensure optimal resource allocation To standardise high quality of care Guidelines are created and updated when –Issues of significant clinical or economic importance arise –There are variations in treatment/access to care –There are new data –There are ethical considerations

9. Why Guidelines to Prevent Neutropenia? Neutropenia is a common side effect in patients receiving chemotherapy treatment and predisposes patients to life-threatening infections Neutropenic complications after myelosuppressive chemotherapy can lead to morbidity and mortality Neutropenic events often result in dose-reductions or treatment delays and therefore may compromise clinical outcome ‘Neutropenia is the major dose-limiting toxicity of conventional chemotherapy’ Crawford J, et al. Cancer 2004;100:228-237 Johnston EM and Crawford J. Semin Oncol 1998;25:552-561

10. What are the Potential Short- and Long-Term Consequences of neutropenia? Short-term impact 1 Long-term impact 2 Infections CT dose delay/reduction Hospitalisation Reduced efficacy of treatment 3 1 Kuderer NM, et al. Proc Am Soc Clin Oncol 2004;22: Abstract 6049 2 Leonard RCF, et al. Br J Cancer 2003;89:2062-2068 3 Bonadonna G, et al. N Engl J Med 1995;332:901-906

11. G-CSF Decreases the Depth and Duration of Neutropenia Median ANC during cycle 1, CAE chemotherapy in small-cell lung cancer Study day 0.01 0.1 0.5 1.0 10.0 100.0 04812162024 Start G-CSF/placebo Placebo (n = 110) G-CSF (n = 101) Severe neutropenia (ANC  500) ANC (  10 9 /L) Crawford J, et al. N Engl J Med 1991;325:164-170

12. A History of Growth Factor Guidelines: ASCO 1994-2000 CSFs are recommended as primary preventive care for patients: –At > 40% risk of FN –At high risk of CT-induced infectious complications Intervention for subsequent cycles: –Physicians should consider dose reduction as a primary therapeutic option List of FN risk factors: –Pre-existing neutropenia due to disease –Extensive prior chemotherapy –Previous radiation to the pelvis or other areas with large amounts of bone-marrow –A history of recurrent FN while receiving earlier chemotherapy of similar or lesser dose intensity –Conditions potentially enhancing the risk of serious infection (e.g. poor performance status, more advanced cancer, decreased immune function, open wounds, already-active tissue infections) American Society of Clinical Oncology. J Clin Oncol 1994;12:2471-2508 Ozer H, et al. J Clin Oncol 2000;18:3558-3585

13. Implementation of CSF Guidelines can reduce the impact of neutropenia Data from the West Michigan Cancer Centre White N et al. Cancer Nurs 2005;28:62-69

14. G-CSF Therapy at > 20% FN Risk Provides Clinical Benefits Recent publications have demonstrated efficacy of G-CSF for patients at a moderate risk of FN Use of G-CSF significantly reduced the incidence of –FN 1,2 –FN-related hospitalisation 2 –use of IV anti-infectives 2 1 Timmer-Bonte J, et al. Proc Am Soc Clin Oncol 2004;22:726. Abstract 8002 2 Vogel CL, et al. J Clin Oncol 2005;23:1178-1184

15. Patient-Related FN Risk Factors Advanced age Female gender Poor nutrition Low PS Low pre-treatment blood count Low lymphocyte count Low haemoglobin High LDH Bone marrow involvement Patient comorbidities –Chronic lung disease –Diabetes Komrokji RS and Lyman GH. Expert Opin Biol Ther 2004;4:1897-1910

16. NCCN 2005 Guidelines The NCCN guidelines take into account new data that was not available to ASCO in 2000 NCCN 2005 G-CSF guidelines focus on risk assessment of chemotherapy regimen and patients Taking new data into account, NCCN recommend routine use of G-CSF for patients at > 20% risk of FN NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors in Cancer Treatment. Available at http://www.nccn.org. Accessed July 2005.

20. Comparison of NCCN 2005 & ASCO 2000 Guidelines for G-CSF NCCN 2005ASCO 2000 Recommend first cycle G- CSF use Consider G-CSF risk of FN > 20% 10–20% FN risk risk of FN > 40% - Patient risk factorsExtensive listLimited list Recommendations for dose-dense regimens Include dose in risk assessmentCSF not justified to increase dose intensity Intervention for subsequent cycles Review FN risk and use of G-CSF at each cycle. Provide G-CSF support if there has been a dose-limiting neutropenic event or episode of FN in the previous cycle and the same schedule is planned for the next cycle In the setting of many tumours exclusive of curable tumours (e.g. germ cell tumours), dose reduction after an episode of severe neutropenia should be considered as a primary therapeutic option Recommended productsCategory 1 evidence for filgrastim and pegfilgrastim* None *Filgrastim (daily dose 5 mcg/kg s.c. administered from 1-3 days after chemotherapy until neutrophils reach normal level) Pegfilgrastim (single dose per chemotherapy cycle starting 24 hr after initiation of chemotherapy)

21. Implementing New Guidelines in Clinical Practice Case-Study Examples

22. Algorithm for Primary Preventive Growth Factor Support Disease Intermediate 10 – 20% FN Risk Consider G-CSF Use G-CSF No G-CSF 1. Patient2. Risk3. Protect Chemotherapy Regimen Patient Risk Factors Treatment Intent High > 20% FN Risk Low < 10% FN Risk Adapted from: Lyman GH. JNCCN 2005;3:557-571

23. Case 1 37-year-old female with relapsed high grade NHL First-line treatment was R-CHOP 21 Did not experience neutropenic complications with first-line chemotherapy Now receives ESHAP second-line chemotherapy Average risk of FN for relapsed patients with this treatment is over 30% 1-3 Q: Is G-CSF support appropriate for primary preventive care in this case? 1 Velasquez WS, et al. J Clin Oncol 1994;12:1169-1176 2 Johnson PW, et al. Ann Oncol 1993;4:63-67 3 Ozturk MA, et al. Chemotherapy 2002;48:252-258

24. Case 1: Additional Patient Notes Age - 37 Histology - High; diffuse large B-cell lymphoma Stage - IIA No. extranodal sites - 0 ECOG PS - 1 LDH - Normal IPI- 0 No other co-morbidities

25. Case 1: Algorithm for Primary Preventive Growth Factor Support Disease Intermediate 10–20% FN Risk Consider G-CSF Use G-CSF No G-CSF 1. Patient2. Risk3. Protect Chemotherapy Regimen Patient Risk Factors Treatment Intent High > 20% FN Risk Low < 10% FN Risk ESHAP = 30% Female gender Prior chemotherapy Lymphoma Curative Adapted from: Lyman GH. JNCCN 2005;3:557-571

26. Examples of NHL Regimens with High (> 20%) FN Risk –ESHAP 1 –DHAP 2 –VAPEC-B 3 –A(N)CVB 4 Note that these regimens carry a > 20% risk of FN, independent of other risk factors 1 Velasquez WS, et al. J Clin Oncol 1994;12:1169-1176 2 Velasquez WS, et al. Blood 1988;71:117-122 3 Pettengell R, et al. Blood 1992;80:1430-1436 4 Gisselbrecht C, et al. Leuk Lymphoma 1997;25:289-300

27. Case 2 50-year-old male Newly diagnosed with small cell lung cancer (SCLC) Naive to chemotherapy Prescribed etoposide and carboplatin (EP) chemotherapy and concomitant radiotherapy The treatment carries an average FN risk of 10% to 20% 1 Q: Is G-CSF support appropriate for primary preventive care in this case? 1 NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors in Cancer Treatment. Accessed from the following website 07/2005: http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf

28. Case 2: Additional Patient Notes Age - 50 Gender - male Histology - small cell lung cancer Stage – limited stage ECOG PS - 2 Comments – overweight, coronary artery disease

29. Case 2: Algorithm for Primary Preventive Growth Factor Support Disease Intermediate 10–20% FN Risk Consider G-CSF Use G-CSF No G-CSF 1. Patient2. Risk3. Protect Chemotherapy Regimen Patient Risk Factors Treatment Intent High > 20% FN Risk Low < 10% FN Risk EP ECOG = 2 CAD obese SCLC (limited stage) Palliative ? Adapted from: Lyman GH. JNCCN 2005;3:557-571

30. Examples of SCLC Regimens High (> 20%) FN risk: – CAE 1-3 –Topotecan 1,4 –Topotecan/paclitaxel 1 Intermediate (10 – 20%) FN risk: – Etoposide/carboplatin 1 – Topotecan/cisplatin 1,5 1 NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors in Cancer Treatment. Accessed from the following website 07/2005: http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf 2 Crawford J, et al. Ann Oncol 1997;8:1117-1124 3 Crawford J, et al. N Engl J Med 1991;325:164-170 4 Von Pawel J, et al. J Clin Oncol 1999;17:658-667 5 Ardizzoni A, et al. Clin Cancer Res 2003;9:143-150

31. Case 3 55-year-old male Presents with localised lymphadenopathy Diagnosed with NHL Receives R-CHOP 21 chemotherapy The average FN risk with this regimen is approximately 20% 1 Q: Is G-CSF support appropriate for primary preventive care in this case? 1 Calculated from data in Lyman GH and Delgado DJ. Cancer 2003;98:2402-2409

32. Case 3: Additional Patient Notes Age - 55 Gender - male Histology - Intermediate; follicular, predominantly large cell Stage - I No. extranodal sites - 0 ECOG PS - 1 LDH - Elevated IPI- 1 Comments - no major co-morbidities, chemotherapy na ï ve

33. Case 3: Algorithm for Primary Preventive Growth Factor Support Disease 1. Patient2. Risk3. Protect Chemotherapy Regimen Patient Risk Factors Treatment Intent R-CHOP 21 Planned RDI > 80% Anthracycline chemotherapy Low grade NHL Elevated LDH Curative Intermediate 10–20% FN Risk Consider G-CSF Use G-CSF No G-CSF High > 20% FN Risk Low < 10% FN Risk ? Adapted from: Lyman GH. JNCCN 2005;3:557-571

34. Examples of NHL Regimens with Intermediate (10 - 20%) FN risk –R-CHOP 1,2 –Fludarabine/mitoxantrone 1,3 –ACOD 1,4 Note that these regimens carry an FN risk of 10- 20%, independent of other risk factors 1 NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors in Cancer Treatment. Accessed from the following website 07/2005: http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf 2 Lyman GH and Delgado DJ. Cancer 2003;98:2402-2409 3 Dimopoulos MA, et al. Leuk Lymphoma 2002;43:111-114 4 Martinelli G, et al. Leuk Lymphoma 2003;44:801-806

35. Case 3: Continued This patient did not receive G-CSF primary prophylaxis and experienced FN during cycle 1, starting day 10 This patient required hospitalisation and i.v. antibiotics This patient has now recovered and has returned for his second cycle of chemotherapy Q: Is G-CSF support appropriate for intervention for subsequent cycles in this case?

36. Case 4 32-year-old female presents with lymphadenopathy Diagnosed with Hodgkin’s lymphoma Patient is chemotherapy-naive AVBD given as first-line chemotherapy The risk of neutropenia for this treatment is less than 10% 1 Q: Is G-CSF support appropriate for primary preventive care in this case? 1 Silvestri F, et al. Tumori 1994;80:453-458

37. Case 4: Additional Patient Notes Age – 32 Gender - female Histology – nodular sclerosis Lymphadenopathy size – 1.5 cm No. nodal sites – 3 Stage – III 1 A Bone marrow biopsy results - negative WBC – 10 x 10 9 /L ECOG PS - 1

38. Case 4: Algorithm for Primary Preventive Growth Factor Support Disease 1. Patient2. Risk3. Protect Chemotherapy Regimen Patient Risk Factors Treatment Intent AVBD Planned RDI > 80% Anthracycline chemotherapy Hodgkin’s lymphoma Curative Intermediate 10–20% FN Risk Consider G-CSF Use G-CSF No G-CSF High > 20% FN Risk Low < 10% FN Risk Adapted from: Lyman GH. JNCCN 2005;3:557-571

39. Case 5 34-year-old woman, newly diagnosed with breast cancer 6 positive axillary lymph nodes She is prescribed 6 cycles of adjuvant TAC chemotherapy as first-line treatment This regimen carries an FN risk of approximately 24% 1 Q: Is G-CSF support appropriate for primary preventive care in this case? 1 Martin M, et al. Proc Am Soc Clin Oncol 2004;22:Abstract 620

40. Case 5: Additional Patient Notes Age - 34 Gender – female Histology – ductal cell carcinoma - HR negative, HER-2-new negative Stage – IIIA (T2, N2, M0) No. lymphatic nodes - 6 ECOG PS - 0 ANC – 4 x 10 9 /L Serum bilirubin – 1.2 mg/dL Serum creatine – 1.45 mg/dL

41. Case 5: Algorithm for Primary Preventive Growth Factor Support Disease Intermediate 10–20% FN Risk Consider G-CSF Use G-CSF No G-CSF 1. Patient2. Risk3. Protect Chemotherapy Regimen Patient Risk Factors Treatment Intent High > 20% FN Risk Low < 10% FN Risk TAC Female gender Planned RDI > 80% Breast cancer Curative Adapted from: Lyman GH. JNCCN 2005;3:557-571

42. Examples of Breast Cancer Regimens High (> 20%) FN risk: – AC→T 1 – Doxorubicin/paclitaxel 2,3 – Doxorubicin/docetaxel 4,5 – TAC 6 Intermediate (10 – 20%) FN risk: – Docetaxel 7,8 – Doxorubicin/vinorelbine 9 – AC 10 – 5-FU/docetaxel 7 1 Perez EA, et al. Ann Oncol 2002;13:1225-1235 2 Gianni L, et al. J Clin Oncol 1995;13:2688-2699 3 Biganzoli L, et al. J Clin Oncol 2002;20:3114-3121 4 Alba E, et al. J Clin Oncol 2004;22:2586-2593 5 Nabholtz JM, et al. J Clin Oncol 2003;21:968-975 10 NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors in Cancer Treatment. Accessed from the following website 07/2005: http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf 6 Martin M, et al. Proc Am Soc Clin Oncol 2004;22:Abstract 620 7 O’Shaughnessy J, et al. J Clin Oncol 2002;20:2812-2823 8 Vogel CL, et al. J Clin Oncol 2005;23:1178-1184 9 Norris B, et al. J Clin Oncol 2000;18:2385-2394