Preventing Neutropenic Complications Michael Rader, MD Clinical Assistant Professor of Medicine, Columbia University College of Physicians and Surgeons Director, Union State Bank Cancer Center at Nyack Hospital Instructions While viewing this presentation, you can control the slides by using the next and previous controls. When using the audio format, a play/pause button is also available. You can also jump to a specific slide using the thumbnail. You can zoom into the slides by clicking the enlarge slide button. Then, click the slide to return it to its normal size.
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Educational Objectives Discuss the incidence of febrile neutropenia to have a better understanding of its frequency. Verify the importance of administering GSF in the first cycle of chemotherapy to reduce the risk of febrile neutropenia. According to NCCN Guidelines, outline the appropriate utilization of GSF in febrile neutropenia. Risk of Chemotherapy Induced Neutropenia Increases risk of febrile neutropenia Life threatening infections Hospitalization Increased Cost Suboptimal chemotherapy dosing Leading cause of dose reductions May impair quality of life Significance and incidence not always appreciated
Case 1 Patient is a 66 year old female who presents with a mass in her right neck which she has noted over the past month Patient was seen by her primary care physician who prescribed an antibiotic for ten days When the lymph node failed to shrink, she was sent for surgical evaluation Patient denies fever, chills sweats or weight loss Patients appetite is good Case 1 (continued) Patient s past medical history is positive for hypertension for the last five years Patient has type II diabetes for which she takes metformin Patient smokes 2 packs per day for the last 29 years and has been diagnosed with COPD Patients family history is noncontributory Patient does clerical work Review of systems is significant for a persistent cough which has been present for several years and she has associated with smoking
Case 1 Physical Examination and Laboratory Evaluation Physical Examination revealed a well nourished, well developed female in no acute distress Examination of the head, eyes, ears nose and throat is unremarkable. Patient has a 2 by 3 cm left cervical node Patient has several 1 x 1 cm axillary lymph nodes and a 2 x 3 cm left inguinal node Chest show occasional rhonchi The heart is regular with no murmurs, gallops or rubs Abdomen reveals no organomegaly Case 1 Physical Examination and Laboratory Evaluation (continued) Rectal and genital examination is unremarkable Breasts are normal and patient is neurologically intact Skin and extremities are unremarkable Patients WBC is 5400, Hb 10.3, Hct 31.2% and platelet count is 234,000 A complete metabolic profile reveals an LDH of 600 Albumin and total protein is normal Patient is sent for lymph node biopsy
Case 1 Workup Biopsy reveals a diffuse large cell lymphoma Staging is done PET CTT scan reveals FDG uptake in the cervical, axillary, paraortic and inguinal regions, Spleen and liver are normal No other abnormalities are noted Patient is felt to have Stage III A large cell lymphoma Patient is begun on rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone every 21 days Question 1 When is this patient at greatest risk of developing febrile neutropenia? a. Cycle 2 b. This patient is not at risk for febrile neutropenia c. Cycle 1 d. Risk increases each cycle and is higher in the last cycle
Answer 1 When is this patient at greatest risk of developing febrile neutropenia? a. Cycle 2 b. This patient is not at risk for febrile neutropenia c. Cycle 1 d. Risk increases each cycle and is higher in the last cycle Severe Neutropenic Events Occur in Many Types of Tumors 60 Patients (%) 50 40 30 20 48% 43% 42% 30% N = 2719 20% 10 0 Breast Lymphoma Ovarian Lung Colon ANC < 0.5 x 10 9 /L and neutropenic complications such as fever, infection, etc Crawford J, et al. Poster presented at: 16 th MASCC/ISOO International Symposium; June 24-27, 2004; Miami Beach, Fla.
Most Neutropenic Events Occur in the First Cycle of Therapy Cycle 1 Cycle 2 Cycle 3 Cycle 4 Patients with initial neutropenia (%) 70 60 50 40 30 20 10 N = 2303 0 Crawford J, et al. Blood. 2004;104:11. Abstract 2210. Chemotherapy Induced Neutropenia is the Major Cause of Dose Delays and Reductions Reason for Dose reduction 46% 44% 54% 56% Neutropenia Related Other Causes Reason for dose delay 42% 58% 41% 59% Early Stage Breast Cancer (n=436) Link BK, et al. Cancer. 2001;92:1354-1367. Picozzi VJ, et al. Oncology. 2001;15:1296-1305. Non-Hodgkin's Lymphoma (n=235)
Question 2 According to current NCCN guidelines R- CHOP has an incidence of febrile neutropenia between 10 and 20%? a. True b. False Answer 2 According to current NCCN guidelines R- CHOP has an incidence of febrile neutropenia between 10 and 20%? a. True b. False The NCCN guidelines state that RCHOP has a febrile neutropenia rate between 10 and 20% NCCN Guidelines V. 2006
Predicted Probability of Infection vs. Duration of Febrile Neutropenia (ANC< 500), Cycle 1 Predicted probability of Febrile neutropenia 1.0 0.8 0.6 0.4 0.2 Predicted probability 0.0 0 1 2 3 4 5 6 7 8 9 Days of Neutropenia Adapted from Blackwell S, Crawford J. In: Morstyn G, Dexter TM, eds. Filgrastim (r-met HuG-CSF) in Clinical Practice. New York, NY: Marcel Dekker; 1994:103-116; Crawford J, et al. N Engl J Med. 1991;325:164-170. Benefit of CSF at a 20% Febrile Neutropenia Rate Objective was to show that first and subsequent cycle pegfilgrastim reduced FN in a regimen associated with an expected FN incidence of ~ 20% Docetaxel 100mg/m2 IV every 3 weeks in patients with breast cancer was chosen as a representative clinical setting Double blind, randomized placebo control, multicenter First cycle pegfilgrastim or placebo day 2 Stratification by disease state Chemotherapy planned for 4 cycles Vogel et al. J Clin Oncol. 2005;23:1178-1184.
Incidence of Febrile Neutropenia 20 N = 928 17 94% Reduction P <.0001 Odds Ratio: 15.02* FN rate (%) 15 10 5 0 n = 465 Placebo 1 n = 463 Pegfilgrastim *95% CL, 6.51, 34.60 Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. FNH rate (%) 20 15 10 5 0 Febrile Neutropenia Related Hospitalizations N = 928 14 Placebo * 95% CL, 5.17, 28.78 93% Reduction 1 n = 465 n = 463 P <.0001 Odds Ratio: 11.99* Pegfilgrastim Vogel C, et al. J Clin Oncol. 2005;23:1178-1184.
Febrile Neutropenia Related IV Antiinfective Use IV anti-infective use (%) 20 15 10 5 0 N = 928 10 2 n = 465 n = 463 Placebo 80% Reduction P <.0001 Odds Ratio: 7.47* Pegfilgrastim * 95% CL, 3.35, 16.67 Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. Incidence of Neutropenia, by Cycle The incidence of grade 3 (hatched bars) and grade 4 (solid bars) neutropenia was markedly reduced for patients receiving pegfilgrastim across all cycles. Incidence (%) 100 80 60 40 20 0 Placebo Pegfilgrastim n = 465 n = 454 n = 438 n = 413 n = 463 n = 458 n = 445 n = 427 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Vogel C, et al. J Clin Oncol. 2005;23:1178-1184.
Febrile Neutropenia, by Cycle In the placebo group, 65% of febrile neutropenic events occurred in the first cycle. Patients With Febrile Neutropenia (%) 18 16 14 12 10 8 6 4 2 0 Placebo, n = 465 Pegfilgrastim, n = 463 11% 6% <1% <1% Cycle 1 Cycles 2 to 4 Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. Colony-Stimulating Factor Prophylaxis: Updated NCCN Guidelines Febrile Neutropenia Risk High (>20%) Intermediat e (10%-20%) Low (<10%) Curative/ Adjuvant Use CSF Consider CSF CSF not recommended Treatment Intent Prolong Survival/QOL Use CSF Consider CSF CSF not recommended Symptom Management/QOL Use CSF Consider CSF CSF not recommended QOL = quality of life; CSF = colony-stimulating factor. NCCN. Myeloid Growth Factors in Cancer Treatment. Version 1.2006.
Question 3 What are this patients risk factors for developing febrile neutropenia? a. Female Gender b. Diabetes Mellitus c. Age d. COPD e. All of the above f. a, b, d NCCN. Myeloid Growth Factors in Cancer Treatment. Version 1.2006 Answer 3 What are this patients risk factors for developing febrile neutropenia? a. Female Gender b. Diabetes Mellitus c. Age d. COPD e. All of the above f. a, b, d NCCN. Myeloid Growth Factors in Cancer Treatment. Version 1.2006
Explanation Question 3 The NCCN guidelines have identified risk factors which influence the risk of febrile neutropenia These risk factors are Treatment related :Drugs (esp. anthracyclines), treatment intent (rdi>80%), regimen, prior neutropenia or lymphocytopenia, prior chemotherapy, prior RT Patient related: Age >65, female gender, poor performance status, poor nutrition decreased immune function Comorbidities: COPD, Cardiovascular disease, liver disease,, diabetes mellitus anemia Cancer related: Bone Marrow involvement, uncontrolled cancer, elevated LDH, leukemia, lymphoma. Lung cancer Growth Factor Support Evaluate Assess risk Intervene Disease Regimen Patient Risk Factors Treatment Intent High >20% risk Intermediate 10-20% risk Low <10% risk Use G-CSF Consider G-CSF No routine G-CSF
Case 3 56 year old female presents with a 3cm mass in her left breast Patient is in otherwise good health except for hypertension Physical examination reveals a 3cm mass in the right breast Axiliary examination is normal Patient underwent a left segmental mastectomy An infiltrating ductal carcinoma was diagnosed Case 3 (continued) The tumor was noted to be estrogen receptor, progesterone receptor and Her-2 negative Axillary node dissection reveals 4 of 10 positive lymph nodes Patient elected to receive dose dense chemotherapy with cyclophosphamide 600mg/m2, doxorubicin 60mg/m2 every two weeks for four cycles followed by paclitaxel 175 mg/m2 every 2 weeks for four cycles This is to be followed by radiation therapy
Question 1 Which of the following statements are correct? a. Patient does not need growth factors for this regimen b. CSF should be administered for five days post each cycle of chemotherapy c. You cannot use pegfilgrastim in this regimen since the intervals between cycles is to short d. None of the above e. All of the above Question 1 Which of the following statements are correct? a. Patient does not need growth factors for this regimen b. CSF should be administered for five days post each cycle of chemotherapy c. You cannot use pegfilgrastim in this regimen since the intervals between cycles is to short d. None of the above e. All of the above
Explanation Question 3 Dose dense chemotherapy cannot be given without growth factor support. Indeed, the NCCN guidelines call for CSF beginning with the first cycle of chemotherapy when the intent of treatment is to provide a relative dose intensity of 80% or greater. Hudis et al have shown that figuratum 5 micrograms per kilogram on days 3-10 following dose dense chemotherapy reduced febrile neutropenia to 2-3%. Hudis et al. Journal of Clinical Oncology, Vol 17, Issue 1 (January), 1999: 93 Burstein et al. San Antonio Breast Conference 2004 Abstract1055 Yang et al. ASH 2003 Abstract 1918 Explanation Question 3 (continued) Burstein et al. showed that of 135 patients receiving this regimen treated with pegfilgrastim 6mg on day 2 only two developed febrile neutropenia. The rate was 1.5% with dose on time being 88.4%. The concentration of pegfilgrastim in the serum is mediated by neutrophil clearance. At a post nadir ANC greater > t 1000, pegfilgrastim serum concentration is <2ng/ml, allowing for the next cycle of chemotherapy.
Case 2 45 year old female has Stage II breast cancer. This was found on routine mammography. Tumor was an intraductal carcinoma, grade 3, 2 out of 12 lymph nodes positive. Estrogen and progesterone receptors are both positive (95% each) and her-2 is negative. Patient undergoes lumpectomy and axillary node dissection after having a positive sentinal node. Case 2 (continued) Physical examination is remarkable for a scar at the site of her surgery. The remainder of the examination is normal. Laboratory examination reveals a normal CBC and normal liver function studies. Following surgery, the patient opts for chemotherapy with TAC. (Taxotere 75 mg/m2, Adriamycin and Cytoxan) followed by radiation therapy and hormonal therapy.
Question 1 The appropriate method to lower the risk of febrile neutropenia would be: a. Pegfilgrastim 6 mg 24 hours post chemotherapy b. Antibiotic prophylaxis with a quinolone antibiotic c. Filgrastim or Sargramostim beginning 24 hours after chemotherapy given until after nadir d. Filgrastim for 5 days beginning day 5 e. a and c Question 1 The appropriate method to lower the risk of febrile neutropenia would be: a. Pegfilgrastim 6 mg 24 hours post chemotherapy b. Antibiotic prophylaxis with a quinolone antibiotic c. Filgrastim or Sargramostim beginning 24 hours after chemotherapy given until after nadir d. Filgrastim for 5 days beginning day 5 e. a and c
GEICAM 9805 Safety Analysis Confirms Benefit of First Cycle Use of G-CSF Patients (%) 100 80 60 40 20 0 93.6 % Gr 3-4 Neutropenia 40.9% Pre-amendment TAC (no first-cycle G-CSF; n=109) Post-amendment TAC (first- and subsequent cycle G-CSF; n=115) 23.9% P<.0001 3.5% Febrile Neutropenia* *Grade 2 fever ( 38.5 o C) with grade 4 neutropenia and requiring IV antibiotics and/or hospitalization in the same cycle. *TAC: docetaxel, doxorubicin, cyclophosphamide Martin M, et al. Proc. Am. Soc. Clin. Oncol. 2004:22-23 Abstract and Poster Primary Prophylaxis with Pegfilgrastim and Ciprofloxacin - Schema Supportive Care Management Filgrastim 150 µg/m 2 Days 5-10 (n=390) Breast cancer patients (n=1201) TAC Treatment (6-8 cycles) Docetaxel 75 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 Day 1 every 3 weeks Ciprofloxacin 500 mg bid Days 5-10 (n=252) Pegfilgrastim 6 mg Day 2 (n=323) Analysis of neutropenia, infection Pegfilgrastim 6 mg Day 2 + Ciprofloxacin 500 mg bid Day 5-10 (n=236) von Minckwitz, et al. ASCO 2005. Abstract 8008
Primary Prophylaxis with Pegfilgrastim and Ciprofloxacin - Results Filgrastim Ciprofloxacin Pegfilgrastim Pegfilgrastim/Ciprofloxacin Incidence Per Patient, % 100 80 60 40 20 0 18 P <.05 22 7 5 Febrile Neutropenia P <.001 67 70 45 43 Grade 3/4 Neutropenia 5 7 P <.001 4 1 Severe Infection Von Minckwitz et al. ASCO 2005. Abstract 8008 Growth Factor Administration Pegfilgrastim 6 mg subcutaneous 1-3 days post chemotherapy Filgrastim 5mgm/kg beginning 1-3 days post chemotherapy continuing past nadir Sargramostim 250mgm/m2/day beginning 1-3 days post chemotherapy continuing post nadir NCCN Guidelines v1.2006
Question 2 The patient lives 30 miles from the treatment center and requests that she receive her pegfilgrastim on the same day as her chemotherapy: a. Giving chemotherapy and pegfilgrastim on the same day are of no consequence b. Pegfilgrastim should be given on day 2 following chemotherapy c. Patients should not be given any CSF since it is inconvenient Question 2 The patient lives 30 miles from the treatment center and requests that she receive her pegfilgrastim on the same day as her chemotherapy: a. Giving chemotherapy and pegfilgrastim on the same day are of no consequence b. Pegfilgrastim should be given on day 2 following chemotherapy c. Patients should not be given any CSF since it is inconvenient
Explanation Question 2 Arrangements should be made to give the pegfilgrastim on the day following chemotherapy. Kaufman et al. randomized patients to receive pegfilgrastim 6mg within 4 hours of their chemotherapy or approximately 24 hours after chemotherapy in patients with breast cancer receiving TAC chemotherapy. The duration of grade 4 neutropenia in cycle 1 was 2.6 days in patients receiving same day pegfilgrastim vs 1.4 days in patients whose pegfilgrastim was delayed 24 hours during cycle one. In cycle 3 it was 2.1 days vs 1.2 days. Febrile neutropenia rates were 33% in the same day group vs 11% in the 24 hour group across all cycles. Kaufman et al. San Antonio Breast Cancer Symposium 2003. Saven et al. ASCO 2006 Abstract 7570. Explanation Question 2 (continued) Saven et al. in a similar study in NHL found the mean duration of grade 4 neutropenia was.9 days longer in the same day group and FN rates were 3 vs 11%. In cycle 4 the mean duration of grade of grade 4 neutropenia was.7 days more.
Summary Febrile neutropenia is associated with increased morbidity and mortality Appropriate use of GSF beginning in the first cycle of chemotherapy can significantly reduce this risk Guidelines have been developed identifying appropriate utilization of GSF Future needs to directed to identifying risk factors for the development of febrile neutropenia Thank you for participating in this program. Click Claim Credit to continue to Post-test.