טיפול בגורמי צמיחה של השורה הלבנה: קווים מנחים בספרות ונתונים לביסוסם

1. טיפול בגורמי צמיחה של השורה הלבנה: קווים מנחים בספרות ונתונים לביסוסם - מפגש החוג לכימותרפיה/האיגוד הישראלי לרדיותרפיה ואונקולוגיה קליני- שרתון סיטי טאור19.5.06 (עודכן- אוגוסט 2008) פרופ'נסים חיים - מכון אונקולוגי-מ.ר. רמב"ם

2. CSFs • Therapeutic benefits…. • Side effects…. • Guidelines….

3. Therapeutic benefits of CSFs Reduces the risk of febrile neutropenia?

4. Reduced risk of febrile neutropenia “Administration of CSFs result in a 50% risk reduction of developing febrile neutropenia”(NCCN Practice Guidelines in Oncology – v.2.2005 (Overview).

5. 1.0 0.8 G-CSF 0.6 Proportion Free of Fever with Neutropenia 0.4 Placebo 0.2 0.0 0 1 2 3 4 5 6 Cycles of Chemotherapy Chemotherapy Induced Neutropenia Planned DI + G-CSF Primary prophylaxis Crawford J. et al. N Engl J Med 1991;325:164-170. Purpose: Testing the hypothesis and clinical implications of chemotherapy-related neutropenia reduction in patients with cancer. Patients and methods: 211 SCLC patients participated a double-blind, randomized, placebo-controlled trial of G-CSF support to 6 cycles of Cyclophosphamide, Doxorubicin, and Etoposide. P < 0.001

6. 39.5% 22.4% GCSF Control Risk of febrile neutropenia with and without GCSF-results of a meta-analysis Kuderer NM et al. J Clin Oncol 25: 3158-67, 2007(a meta-analysis of 15 controlled trials (n=3182 pts) using GCSF before the onset of fever or neutropenia following systemic chemotherapy for solid tumors or lymphomas): Mean risk for FN RR=0.54---P<,0001

7. Therapeutic benefit of CSFs Shortens the length of neutropenia and febrile neutropenic episode, and reduces the period of hospitalization and IV antibiotics?

8. 100 10 Placebo 1 Neutrophils X 109/L G-CSF 0.1 0.01 0 3 6 9 12 15 18 21 Day of Treatment (CDE – Cyclophosphamide, Doxorubicin, Etoposide) Trillet-Lenoir V. et al. Eur J Cancer 1993;29A(3):319-324.

9. Neupogen reduces the duration of hospitalizationand i.v. antibiotic use in patients with AML p=0.0001 30 20 10 0 p=0.0001 Median duration (days) Hospitalisation i.v. antibiotics Neupogen Placebo Adapted from Heil G et al. Blood 1997

10. Therapeutic benefit of CSFs Reduces the risk of documented infection?

11. mean risk of documented infection Risk of documented infection-results of a meta-analysis Lyman GH et al. Am J Med 112: 406-11, 2002(a meta-analysis of 8 controlled trials (n=1144 pts)…7 trials reported information on the documented infection… Odds ratio= 0.51 (p= 0.001)

12. Therapeutic benefit of CSFs Reduces the risk of documented infection-related mortality?

13. 2.8% 1.5% Control GCSF Risk of documented infection-related mortality- results of a meta-analysis Kuderer NM et al. J Clin Oncol 25: 3158-67, 2007(a meta-analysis of 12 controlled trials (n=3122 pts) using GCSF before the onset of fever or neutropenia following systemic chemotherapy for solid tumors or lymphomas): (RR=0.55; P=0.018) *reduction in infection-related mortality was significant among studies of filgrastim but did not reach statistical significance with lenograstim or pegfilgrastim.

14. Therapeutic benefit of CSFs Reduces the need for dose reductions and treatment delays (& reduced dose-intensity)?

15. Mean RDI 95.1% 86.7% Controls GCSF Relative Dose Intensity (RDI) Kuderer NM et al. J Clin Oncol 25: 3158-67, 2007(a meta-analysis of 10 controlled trials using GCSF before the onset of fever or neutropenia following systemic chemotherapy for solid tumors or lymphomas): P = 0.001

16. Therapeutic benefit of CSFs Enables full-dose following a prior cycle with febrile neutropenia?

17. Full-dose chemotherapy following a prior cycle with febrile neutropenia • Metastatic small cell lung cancer treated with a combination of cyclophosphamide, doxorubicin, and etoposide • Patients who developed neutropenic fever during the first cycle received the second cycle with full dose+ G-CSF • Only 23% of these patients developed neutropenic fever during the second cycle. (Crawford J et al. N Engl J Med 1991; 325: 164-170)

18. Full-dose chemotherapy with GCS-F support* following a prior cycle with febrile neutropenia- Dept Oncology, Rambam Medical Center experience • Since September 1995, a standard policy in patients treated with an intent for cure or for durable complete remission. * filgrastim (neupogen)300 or 480 mcg/day for ~10 days

19. Eligibility Criteria • Neutropenic fever was not associated with life-threatening infection. • There were no other dose-limiting toxicities. • Age 75 or less; performance status (WHO) 0-2

20. Diagnosis in 51 patients who developed neutropenic fever (without GCSF)—(age:22-75,median: 47)

21. Chemotherapy protocols (n=51)

22. Next cycle (n+1) (full dose with GCSF support in all pts) • Number of pts…………………………………………51 • Neutropenic fever:……………………..8/51(16%) • Days of IV antibiotics:…..4.5 (median),(3-7) • Evidence of bacterial infection:…………none

23. Next cycle (n+2) (full dose with GCSF support in all pts) • Number of pts…………………………………………41 • Neutropenic fever:……………………..4/41 (10%) • There was no drug-related death associated with either cycle.

24. A policy of full-dose chemotherapy with secondary G-CSF support in pts who develop febrile neutropenia following moderately myelotoxic chemotherapy is relatively safe and feasible. Haim N, Shulman K, Goldberg H, Tsalic M. Med Oncol 22: 229-32, 2005

25. Therapeutic benefit of CSFs Enables administration of dose-dense therapy?

26. Dose-intensity & Dose-density 90 mg/m2 every 3 wks vs. 30 mg/m2/week: • Both regimens have the same dose intensity. • 30 mg/m2/week gives a greater dose density than the 3-weekly administration.

27. Tolerability of dose-dense chemotherapy with GCSF-breast cancer Citron ML et al. J Clin Oncol 21: 1431-39, 2003 • AC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2) q 3 wks or q 2 weeks +filgrastim days 3-10 at 5 mcg/kg rounded to either 300 or 480 mcg. • Treatment was well tolerated. Severe neutropeniawas less frequent in patients who received the dose-dense regimens (6% vs. 33%).

28. Dose-dense CHOP (CHOP-14) • Cyclophosphamide 750 mg/m2 IV, day 1 • Adriamycin 50 mg/m2 IV , day 1 • Vincristine 1.4 mg/ m2 IV , day 1 • Dexamethasone 20 mg IV, day 1 • Prednisone 100 mg PO, days 2-5 • Cycles are repeated every 2 weeks. • GCSF is given on days 4-13. • Pfreundschuh M et al. Blood 104: 626-33, 2004 (young pts) • Pfreundschuh M et al. Blood 104: 634-41, 2004 (elderly pts)

29. Therapeutic benefit of CSFs Enables administration of “high-dose” chemotherapy (without peripheral blood stem cell support)?

30. CHOP & Mega CHOP in aggressive non Hodgkin`s lymphomas CHOP: • Cyclophosphamide750 mg/m2 IV, day 1 • Adriamycin 50 mg/m2 IV , day 1 • Vincristine 1.4 mg/ m2 IV , day 1 • Prednisone 100 mg PO, days 1-5 (cycles repeated every 3 weeks) “Mega” CHOP: • Cyclophosphamide1500mg/m2 IV (1hr), days • 1 and 2 • Mesna 200 mg/m2 X 4, IV, day 1; 200 mg/m2 X 8,IV day 2 • Adriamycin 50 mg/m2 IV , day 1 • Vincristine 1.4mg/m2 (max. 2mg) IV, day 1 • Prednisone 100 mg PO , days 1-5 (cycles repeated every 3 weeks)

31. Therapeutic benefit of CSFs Improves the outcome of febrile neutropenia when started at the time of established neutropenia?

32. ASCO 2000 Guidelines for GCSF Therapy- Febrile Patients with neutropenia (2000) • “The results of 8 randomized trials provide strong and consistent support for the recommendation that G-CSFs should not be routinely used as adjunct therapy for the treatment of uncomplicated fever and neutropenia…”. • GCSF should be considered in pts with complicated neutropenia and fever”.

33. CSFs for chemotherapy-induced febrile neutropenia: a meta-analysis (Clark OAC et al. J Clin Oncol 23: 4198-4214, 2005)(13 trials with a total of 1,518 pts) • Significantly reduces the length of hospitalization(HR=0.63;P=0.006) • Significantly reduces the time to neutrophil recovery(HR=0.32;P<0.0001). • A marginally significant result was obtained for the use of CSF in reducing infection-related mortality(3.1% VS. 5.7%; HR=0.51; p=0.05).

34. Therapeutic benefit of CSFs Improves treatment outcome?

35. ESMO recommendations for the application of haematopoietic growth factors (hGFs). Ann Oncol 12: 1219-20, 2001: No high level evidence for increase in survival

36. CSFs in lymphoma-meta-analysis Bohlius J et al. Cochrane Database Syst Rev. 3: CD003189, 2004 (12 eligible randomized controlled trials with 1823 pts) • -----reduced the risk of neutropenia, febrile neutropenia and infection. • However, there is no evidence that CSFs provide a significant advantage in terms of CR, freedom from treatment failure or overall survival.

37. Therapeutic benefit of CSFs Enables stem cell mobilization ?

38. Side effects

39. Adverse Events –“Bone pain” • In bone marrow bearing locations • Usually of mild/moderate severity ~(15%)* • Transient - controlled with oral analgesics *Med Oncol 22: 229-32, 2005: 20/51(=39%);severe in 8 (=16%)

40. Adverse Events – Transient elevations in LDH, uric acid, and alkaline phosphatase • InLDH, and uric acid: attributed to the proliferative effects of G-CSF on neutrophil precursors in the bone marrow, with increased cell turnover • In alkaline phosphatase: potentially secondary effects on bone.

41. GCSF and lung toxicity Pulmonary complications of GCSF are very rare and include cough, dyspnea, and interstitial or alveolar pulmonary edema. Few cases of acute respiratory distress syndrome have been reported.

42. A possible interaction between bleomycin and GCSF Martin WG et al. J Clin Oncol 23: 7614-20, 2005 : GCSF was associated with increased lung toxicity in Hodgkin`s disease patients treated with bleomycin containing drug combinations). (GCSF may enhance bleomycin-induced lung toxicity by a mechanism that probably involved neutrophils). On the other hand: Saxman SB et al. Chest 111: 657-60, 1997: There is no increase in pulmonary toxicity with co-administration of G-CSF and bleomycin compared to bleomycin alone in pts with advanced germ cell tumors.

43. GCSF: effect on spleen • Spleen enlargement (Picardi M et al. Haematologica 88: 794, 2003), • Splenic rupture (Falzetti F et al. Lancet 353: 555, 1999; Dincer AP et al. J Pediatr Hematol Oncol 26: 761, 2004).

44. GCSF & leukemia/MDS • “The associated risk of leukemia and MDS has been suggested by epidemiologic studies, but has not been observed in the available prospective studies” (NCCN Guidelines: Myeloid Growth Factors V.1. 2008)

45. Guidelines for the use of CSFs* * “…guidelines cannot always account for individual variations among patients. They are not intended to supplant physician judgement with respect to to particular patients or special clinical situations….”(ASCO guidelines-2006)

46. ASCO(American Society for Clinical Oncology)Guidelines 2006 Update of recommendations for the use of white blood cell growth factors: an evidence-based, clinical practice guidelines. Smith TJ et al. for the American Society of Clinical Oncology Growth Factor Expert Panel.Published ahead of print on J Clin Oncol May 8, 2006

47. Clinical Practice Guidelines in Oncology: Myeloid Growth Factors Version 1. 2008 http://www.nccn.org

48. EORTC (European Organization for Research and Treatment of Cancer) Guidelines EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia adult patients with lymphomas and solid tumors.Aapro MS et al. Published ahead of print, Europ J Cancer , 2006

49. Types of CSFs, Dosage & Administration

50. Dosage and administration • Filgrastim (Neupogen) (category 1)*: • Daily dose of 5mcg/kg (rounding to the nearest vial size)(300 mcg/day for pts < 78 kg and 480 mcr/day for pts > 78 kg) • Pegfilgrastim (Neulasta = Neulastim) (category 1)*: • One dose of 6mg per cycle of treatment • (There is evidence to support use for chemotherapy regimens given every 3weeks/2 weeks) *Category 1: There is uniform NCCN consensus, based on high-level evidence, that the recommendation is appropriate.