Neutropenia is the primary dose-limiting toxicity in patients treated with myelosuppressive chemotherapy, leading in some cases to substantial morbidity and early mortality, and disrupting treatment with potentially curative regimens. The use of granulocyte colony-stimulating factors (G-CSFs) such as filgrastim (Neupogen) and pegfilgrastim (Neulasta), as primary prophylaxis starting in the first cycle of chemotherapy, has been shown to reduce the rates of febrile neutropenia (FN) and of FN-related hospitalization, as well as the use of intravenous anti-infectives. A recent meta-analysis has shown significantly lower infection-related mortality with the first-cycle use of G-CSFs. Both filgrastim and pegfilgrastim were originally approved on the basis of their effectiveness in patients treated with chemotherapy regimens that are associated with a 40% or greater risk of FN. Pegfilgrastim, which is given once per cycle, has been shown to reduce the risk of FN by 94% in breast cancer patients treated with docetaxel (Taxotere). In addition, a recent cost-minimization analysis has shown that first-cycle use of pegfilgrastim may be cost-neutral in patients in whom the predicted risk of FN is less than 20%. These findings have important implications for clinical guidelines for preventing chemotherapy-induced neutropenia and FN.
Chemotherapy-induced neutropenia (CIN) is the primary dose-limiting toxicity in patients with cancer treated with systemic myelosuppressive agents. The most serious manifestation of neutropenia, febrile neutropenia (FN), which may be a sign of life-threatening infection, particularly in patients who are frail or elderly and in those with comorbidities. It frequently necessitates chemotherapy dose reductions and delays, which have been shown to compromise the efficacy of some chemotherapy regimens.[2-4] In addition, CIN and FN have negative effects on patients’ quality of life (QOL), an outcome that is getting more attention in the treatment of cancer.[5,6] Because the risk of CIN and FN is greatest in the first cycle of chemotherapy, appropriate supportive care should be initiated in the first cycle in patients who are at increased risk to minimize the effects of neutropenia and its complications.
The proactive use of the granulocyte colony-stimulating factors (G-CSFs) filgrastim (Neupogen) and pegfilgrastim (Neulasta) can reduce the incidence, severity, and duration of neutropenia and its complications. Filgrastim, which was approved by the US Food and Drug Administration (FDA) in 1991, is given daily in weight-based doses. Pegfilgrastim, a G-CSF that was bioengineered to have a sustained duration of action and was approved in 2002, is given once per cycle in a fixed dose.
Both filgrastim and pegfilgrastim were FDA approved on the basis of their efficacy in decreasing the risk of FN in patients with cancer who were treated with highly myelosuppressive chemotherapy regimens (rates of FN of ≥ 40%).[10-13] The results of more recent studies support the efficacy and cost-effectiveness of pegfilgrastim given in the first cycle with chemotherapy regimens with which the risk of FN is less than 20%. In this article, I review the clinical and economic benefits of initiating filgrastim and pegfilgrastim in the first cycle of chemotherapy.
Pivotal Trials of Filgrastim
Filgrastim was approved for managing CIN on the basis of the results in two multicenter trials in patients with small-cell lung cancer who were treated with cyclophosphamide (Cytoxan, Neosar), doxorubicin, and etoposide, a regimen associated with a risk of FN of about 60%.[10,11] Patients in both studies were randomized to filgrastim 4 to 8 µg/kg or to placebo on days 4 through 17 after the chemotherapy (the filgrastim could be discontinued if the postnadir absolute neutrophil count [ANC] exceeded 10 × 109/L after day 12). The primary end point was the incidence of FN, defined as a temperature ≥ 38.2°C and ANC < 1.0 × 109/L.
In both studies, the incidence of FN was lower by about 50% with filgrastim.[10,11] In one of them, the incidence was 77% in the placebo group and 40% in the filgrastim group (P < .001); in the other, it was 53% and 26% (P < .002), respectively. Furthermore, filgrastim also significantly reduced the incidence of culture-confirmed infections; the incidence and duration of grade 4 neutropenia (ANC < 0.5 × 109/L); the number of days of intravenous (IV) antibiotic use or the proportion of patients treated with IV antibiotics; and the number of days of hospitalization or the proportion of patients hospitalized. The only adverse event that was attributed to filgrastim was mild-to-moderate musculoskeletal pain, which was not dose-limiting.
Pivotal Trials of Pegfilgrastim
The approval by the FDA of pegfilgrastim for prevention of CIN was based on the results of two large randomized controlled trials in patients with breast cancer who were treated with doxorubicin and docetaxel (Taxotere),[12,13] a regimen that is associated with an FN rate of 38% in patients with breast cancer when it is used without growth factors.
The trials were similar in design and investigated whether pegfilgrastim was as effective as filgrastim in managing CIN. Patients were randomized to a single injection of pegfilgrastim per chemotherapy cycle followed by daily injections of placebo, or to daily injections of filgrastim 5 µg/kg. The pegfilgrastim was given as a weight-based dose (100 µg/kg) in one of the studies and as a fixed dose (6 mg) in the other. Treatment began on day 2 of each cycle, about 24 hours after the chemotherapy. The filgrastim or placebo injections were continued for 14 days or until the ANCwas at least 10 × 109/L after the nadir.
A single dose of pegfilgrastim was at least as effective as daily filgrastim in both trials. The incidence and duration of grade 4 neutropenia were similar with both agents in all cycles, and the agents were comparable in terms of the depth of the ANC nadir and the time to neutrophil recovery. There were no differences in safety. The trials were not designed to detect this effect, but in both, the incidence of FN (temperature ≥ 38.2°C and ANC < 0.5 × 109/L) was lower with pegfilgrastim (Figure 1), and in one of them, the difference was significant (P = .029). Retrospective analysis of pooled data from these studies showed that treatment with both filgrastim and pegfilgrastim helped make it possible to give the planned doses of chemotherapy on time. At least 90% of the patients in both groups were treated with an average relative dose intensity (RDI) of 85% or higher. Both studies also showed that the efficacy of the G-CSFs was greater in the later cycles, with the incidence of grade 4 neutropenia being lower in cycles 2 through 4 than in cycle 1 (Figure 2a).[12,13] One of the studies also reported that the duration of grade 4 neutropenia in cycles 2 through 4 was significantly shorter with pegfilgrastim than with filgrastim (Figure 2b).
A more recent pivotal trial has shown that pegfilgrastim as primary prophylaxis also has clinical benefits when it is given with a less toxic moderately myelosuppressive regimen. This randomized, multicenter, multinational, double-blinded study was conducted in 928 patients with breast cancer treated with single-agent docetaxel, 100 mg/m2 every 3 weeks, a regimen that has been associated with FN rates of 10% to 20% in the absence of CSFs.[17,18] The patients were randomized to pegfilgrastim 6 mg or placebo once per cycle, given approximately 24 hours after the chemotherapy. Patients in whom FN developed were treated with open-label pegfilgrastim in the following cycles. The primary end point was the incidence of FN, defined as in the other pivotal trials of pegfilgrastim.
The overall incidence of FN was 94% lower in patients randomized to pegfilgrastim than in those randomized to placebo, and the rates of FN-related hospitalization and use of IV anti-infectives were also significantly lower with pegfilgrastim (all P < .001) (Figure 3). Full-dose chemotherapy was given on schedule in similar proportions of patients (pegfilgrastim 80% and placebo 78%). This was expected, because the study design specified that patients in either group in whom FN developed be switched to open-label pegfilgrastim. It should also be noted that a greater proportion of patients in the placebo group were switched to open-label pegfilgrastim (19% vs 2%). There were two deaths due to infection-related complications in the placebo group but none in the pegfilgrastim group.
Dr Rader has received honoraria from Amgen.
1. Kuderer NM, Cosler L, Crawford J, et al: Cost and mortality associated with febrile neutropenia in adult cancer patients (abstract 998). Proc Am Soc Clin Oncol 21:250a, 2002.
2. Kwak LW, Halpern J, Olshen RA, et al: Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: Results of a tree-structured survival analysis. J Clin Oncol 8:963-977, 1990.
3. Ardizzoni A, Favaretto A, Boni L, et al: Platinum-etoposide chemotherapy in elderly patients with small-cell lung cancer: Results of a randomized multicenter phase II study assessing attenuated-dose or full-dose with lenograstim prophylaxis-a Forza Operativa Nazionale Italiana Carcinoma Polmonare and Gruppo Studio Tumori Polmonari Veneto (FONICAP-GSTPV) study. J Clin Oncol 23:569-575, 2005.
4. Bonadonna G, Moliterni A, Zambetti M, et al: 30 years’ follow up of randomised studies of adjuvant CMF in operable breast cancer: Cohort study. BMJ 330:217, 2005.
5. Lyman GH, Kuderer NM: Filgrastim in patients with neutropenia: Potential effects on quality of life. Drugs 62:65-78, 2002.
6. Fortner BV, Tauer KW, Okon T, et al: Experiencing neutropenia: Quality of life interviews with adult cancer patients. BMC Nurs 4:4, 2005.
7. Lyman GH: Guidelines of the National Comprehensive Cancer Network on the use of myeloid growth factors with cancer chemotherapy: A review of the evidence. J Natl Compr Canc Netw 3:557-571, 2005.
8. Neupogen (filgrastim) prescribing information. Thousand Oaks, Calif, Amgen Inc, 2004.
9. Neulasta (pegfilgrastim) prescribing information. Thousand Oaks, Calif, Amgen Inc, 2005.
10. Crawford J, Ozer H, Stoller R, et al: Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 325:164-170, 1991.
11. Trillet-Lenoir V, Green J, Manegold C, et al: Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 29A:319-324, 1993.
12. Holmes FA, O’Shaughnessy JA, Vukelja S, et al: Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol 20:727-731, 2002.
13. Green MD, Koelbl H, Baselga J, et al: A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 14:29-35, 2003.
14. Misset JL, Dieras V, Gruia G, et al: Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Ann Oncol 10:553-560, 1999.
15. Siena S, Piccart MJ, Holmes FA, et al: A combined analysis of two pivotal randomized trials of a single dose of pegfilgrastim per chemotherapy cycle and daily filgrastim in patients with stage II-IV breast cancer. Oncol Rep 10:715-724, 2003.
16. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al: First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: A multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol 23:1178-1184, 2005.
17. Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project protocol B-27. J Clin Oncol 21:4165-4174, 2003.
18. Chan S, Friedrichs K, Noel D, et al: Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 17:2341-2354, 1999.
19. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup trial C9741/Cancer and Leukemia Group B trial 9741. J Clin Oncol 21:1431-1439, 2003.
20. Hudis C, Citron M, Berry D, et al: Five-year follow-up of INT C9741: dose-dense chemotherapy is safe and effective. Presented at the 28th Annual San Antonio Breast Cancer Symposium, December 8-11, 2005; San Antonio, Tex.
21. Burstein HJ, Parker LM, Keshaviah A, et al: Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol 23:8340-8347, 2005.
22. Dang C, Smith K, Lake D, et al: Preliminary cardiac safety results of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab in HER2/neu overexpressed/amplified breast cancer. Presented at the 28th Annual San Antonio Breast Cancer Symposium, December 8-11, 2005; San Antonio, Tex.
23. Bentley M, Marlton P, Hovarth N, et al: Single dose per cycle pegfilgrastim successfully supports full dose intensity CHOP-14 in patients over 60 years with non-Hodgkin's lymphoma (NHL) and successfully mobilises peripheral blood progenitor cells (PBPC) (abstract 2348). Blood 102:636a, 2003.
24. Younes A, Fayad L, Romaguera J, et al: A single administration of a fixed dose pegfilgrastim (Neulasta) in inducing neutrophil count recovery after 170 consecutive doses of ABVD chemotherapy in patients with Hodgkin's lymphoma: Safety of pegfilgrastim with q14-day chemotherapy regimens (abstract 2352). Blood 102:637a, 2003.
25. Pirker R, Ulsperger E, Aigner K, et al: A phase II study of pegfilgrastim to support ACE 14 chemotherapy for the treatment of subjects with small cell lung cancer (SCLC; extensive disease) (abstract 7216). Proc Am Soc Clin Oncol 23:667, 2004.
26. Martin M, Pienkowski T, Mackey J, et al: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352:2302-2313, 2005.
27. Martin M, Lluch A, Segui MA, et al: Prophylactic growth factor (GF) support with adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) for node-negative breast cancer (BC): An interim safety analysis of the GEICAM 9805 study (abstract 620). Proc Am Soc Clin Oncol 23:32, 2004.
28. Martin M, Lluch A, Segui MA, et al: Toxicity and health-related quality of life (HQOL) in node-negative breast cancer (BC) patients (pts) receiving adjuvant treatment with TAC (docetaxel, doxorubicin, cyclophosphamide) or FAC (5-fluorouracil, doxorubicin, cyclophosphamide): impact of adding prophylactic growth factors (GF) to TAC. GEICAM study 9805 (abstract 604). J Clin Oncol 23(suppl):29s, 2005.
29. Lyman GH, Kuderer NM, Djulbegovic B: Prophylactic granulocyte colony-stimulating factor in patients receiving dose-intensive cancer chemotherapy: A meta-analysis. Am J Med 112:406-411, 2002.
30. Kuderer NM, Crawford J, Dale DC, et al: Meta-analysis of prophylactic granulocyte colony-stimulating factor (G-CSF) in cancer patients receiving chemotherapy. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005; Orlando, Fla.
31. Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4:1162-1170, 1986.
32. Hryniuk W, Frei E 3rd, Wright FA: A single scale for comparing dose-intensity of all chemotherapy regimens in breast cancer: summation dose-intensity. J Clin Oncol 16:3137-3147, 1998.
33. Budman DR, Berry DA, Cirrincione CT, et al: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst 90:1205-1211, 1998.
34. Ozer H, Mirtschling B, Rader M, et al: Impact of 1st and subsequent cycle pegfilgrastim on neutropenic events in patients receiving myelosuppressive chemotherapy: Preliminary results of FIRST, a prospective community-based study. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005; Orlando, Fla.
35. Kubista E, Glaspy J, Holmes FA, et al: Bone pain associated with once-per-cycle pegfilgrastim is similar to daily filgrastim in patients with breast cancer. Clin Breast Cancer 3:391-398, 2003.
36. Lyman GH, Lyman CG, Sanderson RA, et al: Decision analysis of hematopoietic growth factor use in patients receiving cancer chemotherapy. J Natl Cancer Inst 85:488-493, 1993.
37. Ozer H, Armitage JO, Bennett CL, et al: 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18:3558-3585, 2000.
38. Lyman GH, Kuderer N, Greene J, et al: The economics of febrile neutropenia: Implications for the use of colony-stimulating factors. Eur J Cancer 34:1857-1864, 1998.
39. Cosler LE, Calhoun EA, Agboola O, et al: Effects of indirect and additional direct costs on the risk threshold for prophylaxis with colony-stimulating factors in patients at risk for severe neutropenia from cancer chemotherapy. Pharmacotherapy 24:488-494, 2004.
40. Cosler LE, Edlar-Lissai A, Dale DC, et al: Economic analysis of pegfilgrastim in patients receiving cancer chemotherapy. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005; Orlando, Fla.