Final Results of a Placebo-Controlled Study of Filgrastim in Small-Cell Lung Cancer: Exploration of Risk Factors for Febrile Neutropenia

Supportive Cancer Therapy

original contribution

Key words: Chemotherapy, Clinical trials, Hematopoietic growth factor, Tumor response

Final Results of a Placebo-Controlled Study of Filgrastim in Small-Cell Lung Cancer: Exploration of Risk Factors for Febrile Neutropenia Jeffrey Crawford,1 John A. Glaspy,2 Ronald G. Stoller,3 Dianne K. Tomita,4 Martha E. Vincent,5 Brian W. McGuire,6 Howard Ozer7

Abstract Background: A phase III study of filgrastim as an adjunct to combination chemotherapy in previously untreated patients with limited- or extensive-stage small-cell lung cancer was conducted. This final analysis explores baseline factors that might predict febrile neutropenia and also reports the results of 463 open-label filgrastim cycles that were delivered after patients’ initial episode of the primary endpoint, ie, febrile neutropenia. Patients and Methods: A total of 244 patients were randomized to receive placebo or filgrastim in ≤ 6 cycles of chemotherapy (cyclophosphamide/doxorubicin/etoposide). Results: The cumulative percent of patients receiving filgrastim who experienced febrile neutropenia was approximately 50% lower than those given placebo (38% vs. 74%, respectively; P < 0.0001). Significant treatment-related reductions were also seen in the incidence and duration of grade 4 neutropenia. Cycle 1 displayed the highest incidence of neutropenia with or without fever and the longest duration of neutropenia relative to later cycles. Patients crossing over to open-label filgrastim from their blinded treatment assignment displayed event rates similar to those in the blinded filgrastim group. Patients who experienced febrile neutropenia in cycle 1 were at a significantly higher risk for subsequent events compared with those who were event-free in cycle 1. Women displayed a higher risk for febrile neutropenia than men, but no other baseline risk factors were detected. Conclusion: Given the high rate of febrile neutropenia in cycle 1 and the higher risk for subsequent events in patients with a cycle 1 event, we conclude that growth factor administration starting in cycle 1 should be considered for patients receiving moderately to highly myelosuppressive chemotherapy regimens.

Introduction

the function of mature neutrophils. A recombinant version of G-CSF is currently in wide use for decreasing the incidence of infection as manifested by fever and neutropenia consequential to myelosuppressive chemotherapy. In the

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor that preferentially stimulates the growth and differentiation of neutrophil precursors and

1Duke University Medical Center, Durham, NC 2University of California School of Medicine, Los Angeles 3University of Pittsburgh Medical Center, PA

Address for correspondence: Jeffrey Crawford, MD, Thoracic Oncology Program, Duke University Medical Center, PO Box 3476, Durham, NC 27710 Fax: 919-681-9599; e-mail: [email protected]

4Amgen Inc., Thousand Oaks, CA 5Agensys Inc., Santa Monica, CA

Submitted: Feb 7, 2005; Revised: Jul 13, 2005; Accepted: Jul 14, 2005 Supportive Cancer Therapy, Vol 3, No 1, 36-46, 2005

6Camarillo, CA 7Oklahoma University Cancer Center, Oklahoma City

Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1543-2912, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.

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Volume 3, Number 1 • October 2005

Figure 1

Table 1

Study Design and Treatment Cycle Structure

Patient Demographics and Disease Characteristics

A S C R E E N

R A N D O M I Z E

CAE + DoubleBlinded Placebo

Cycles 1-6

Characteristic

CAE+ DoubleBlinded Placebo

*

Mean Age, Years (Range ± SD)

CAE + Open-Label Filgrastim

*

CAE + Double-Blinded Filgrastim Cycles 1-6

Placebo (n = 120)

Filgrastim (n = 111)

62 (33-80 ± 8.6) 61.2 (31-78 ± 9.7)

CAE + Open-Label Filgrastim

< 65

66 (55)

71 (64)

CAE + Double-Blinded Filgrastim

≥ 65

55 (45)

40 (36)

Male

79 (66)

70 (63)

Female

41 (34)

41 (37)

73.2 ± 16.8

72.2 ± 15.7

0

27 (22)

18 (16)

1

69 (58)

76 (68)

2/3

24 (20)

17 (15)

Limited

29 (24)

27 (24)

Extensive

91 (76)

84 (76)

No

98 (82)

93 (84)

Yes

22 (18)

18 (16)

Sex *Febrile neutropenia. Randomize based on ECOG PS and marrow involvement.

B 1 2 3

4 5 6 7 8

Mean Body Weight (kg ± SD)

9 10 11 12 13 14 15 16 17 18 19 20 21 22

Baseline ECOG PS C A E E E

Study Drug

C A E

(A) Illustrates randomization to blinded filgrastim or placebo with a crossover feature to open-label filgrastim after the first episode of febrile neutropenia (ANC < 1000/mL) concurrent with fever ³ 38.2°C. (B) Shows structure of a cycle of chemotherapy and study drug. Doses of CAE (cyclophosphamide/doxorubicin/etoposide) were 1000 mg/m2, 50 mg/m2, and 120 mg/m2, respectively. Study drug started on day 4 and continued through day 12 to an ANC ³ 10,000/mL on day 17.

Disease Stage

Marrow Involvement

original phase III trials in patients with previously untreated limited- or extensive-stage small-cell lung cancer (SCLC),1,2 filgrastim, given once daily starting 24 hours after delivery of chemotherapy, significantly reduced the incidence of grade 4 neutropenia (absolute neutrophil count [ANC] < 500/μL), shortened the duration of neutropenia, and decreased the incidence of febrile neutropenia by approximately 50%, with similar reductions in hospitalization, intravenous antibiotic use, and culture-confirmed infections. We report the results of an expanded analysis of a phase III filgrastim study conducted in the United States.1 The previous report of this study included 199 patients evaluable for efficacy and focused on double-blinded cycles (N = 600), ie, through the first event of febrile neutropenia of each patient. The present analysis includes not only data from 32 additional patients but also nearly doubles the number of patientcycle data by incorporating the open-label filgrastim cycles that were not presented in the original publication. Despite the broad experience that has been gained with filgrastim over the past decade, clinical practice varies with regard to the application of this growth factor in ways such as

Values in parentheses are percentages unless otherwise specified.

whether it is used in all cycles versus only for treatment or rescue, primary versus secondary prophylaxis, when dosing is initiated within a cycle, and the duration of dosing within a cycle. The identification of specific risk factors for febrile neutropenia in patients receiving myelosuppressive chemotherapy could offer guidance for the appropriate use of this agent. However, given the current wide use of adjunctive growth factors, performing a prospective placebo-controlled trial in this setting would be problematic. The availability of a large homogeneous database containing placebo- and filgrastimtreated patients offers an opportunity to explore these possible risk factors and to identify subpopulations of interest.

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Supportive Cancer Therapy

Filgrastim for Chemotherapy-Induced Neutropenia

Table 2

Table 3

Summary of Cycles by Treatment

Filgrastim Dosing Duration by Cycle

Patient Cycles by Randomization Group Treatment

Placebo (n = 120)

Filgrastim (n = 111)

Total Patient Cycles

605

565

Blinded placebo

290

0

Blinded filgrastim

0

417

315

148

Open-label filgrastim

Cycle Number

Patients and Methods Study Design and Patient Population This was a multicenter, double-blinded, placebo-controlled phase III trial of filgrastim as an adjunct to combination chemotherapy for the treatment of patients with newly diagnosed, limited- or extensive-stage SCLC who had received no previous radiation therapy or chemotherapy. Institutional review boards for each participating center approved the study before initiation, and each patient granted written informed consent before his/her participation commenced. Randomization to double-blinded placebo or filgrastim was stratified by baseline Eastern Cooperative Oncology Group (ECOG) score and by bone marrow involvement. Cyclophosphamide (1000 mg/m2 on day 1), doxorubicin (50 mg/m2 on day 1), and etoposide (120 mg/m2 on days 1-3) were given in as many as six 21-day cycles (Figure 1). The blinded study drug, ie, filgrastim 230 mg/m2 (approximately 5 μg/kg per day) or the equivalent volume of placebo, was given subcutaneously starting 24 hours after the last dose of chemotherapy (day 4) through a postnadir ANC ≥ 10,000/μL or a maximum of 14 doses per cycle. In addition to routine monitoring for this patient population, complete blood counts with manual differential were performed 3 times per week with daily oral temperature readings to assess incidence of the primary endpoint, febrile neutropenia (temperature ≥ 38.2°C concurrent with ANC < 1000/μL). At the first incidence of febrile neutropenia, the patient’s treatment assignment was unblinded at the end of the cycle in which febrile neutropenia was documented, and, if originally assigned to the filgrastim arm, the patient continued subsequent cycles with open-label filgrastim. If febrile neutropenia occurred in patients assigned to the placebo arm, the patient was crossed over to open-label filgrastim for subsequent cycles. In the absence of an event of febrile neutropenia, patients continued the blinded study

Number of Patients

Days of Filgrastim Treatment* Mean ± SD

Median

Cycle 1

109

11.7 ± 1.9

12

Cycle 2

170

11.1 ± 1.9

11

Cycle 3

159

11.3 ± 2

11

Cycle 4

154

11.6 ± 2.2

11

Cycle 5

150

11.5 ± 2.3

11

Cycle 6

138

11.5 ± 2.4

11

All Cycles

880

11.4 ± 2.1

11

*Blinded plus open-label filgrastim cycles.

drug for a maximum of 6 cycles unless disease progression or unacceptable toxicity supervened. Dose reductions during double-blinded treatment were permitted for grade 4 nonhematologic toxicity but not for nadir ANCs. Additionally, patients initially on blinded filgrastim who experienced their first episode of febrile neutropenia could receive a chemotherapy dose reduction in the next cycle with open-label filgrastim; instead, patients initially on placebo would receive open-label filgrastim but at the full chemotherapy dose. In all cases, cycle delays for hematologic recovery were permitted. Study Drug Filgrastim, a sterile, clear, and colorless solution (0.3 mg protein/mL), was supplied in single-use vials of 2-mL fills. Placebo consisted of a sterile buffered solution in matching vials. Endpoints The primary endpoint was the cumulative proportion of patients experiencing febrile neutropenia. Additional laboratory-based endpoints included incidence and duration of grade 3/4 neutropenia (ANC < 1000/μL and < 500/μL, respectively). Febrile neutropenia was originally defined in the protocol as having an oral temperature ≥ 38.2°C concurrent with grade 3 neutropenia. During the previous analysis, it was ascertained that fever was most typically associated with grade 4 neutropenia and that the rates of febrile neutropenia were similar irrespective of the grade of neutropenia used; hence, in the initial report, febrile neutropenia was based on grade 4 neutropenia, as it was in this analysis.1

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Jeffrey Crawford et al

Table 4

Incidence of Grade 4 Neutropenia by Cycle Blinded Placebo Cycle Number

Placebo to OpenLabel Filgrastim

Blinded Filgrastim

Blinded to OpenLabel Filgrastim

All Filgrastim*

N

Percent (95% CI)

N

Percent (95% CI)

N

Percent (95% CI)

N

Percent (95% CI)

N

Percent (95% CI)

Cycle 1

117

97 (95-100)

–

–

108

82 (75-90)

–

–

108

82 (75-90)

Cycle 2

48

88 (78-97)

66

79 (69-89)

75

49 (38-61)

29

69 (52-86)

170

64 (57-71)

Cycle 3

38

82 (69-94)

63

68 (57-80)

67

46 (34-58)

28

61 (43-79)

158

58 (50-65)

Cycle 4

33

82 (69-95)

64

63 (51-74)

59

49 (36-62)

30

53 (35-71)

153

56 (48-63)

Cycle 5

27

78 (62-93)

63

60 (48-72)

55

38 (25-51)

32

50 (33-67)

150

50 (42-58)

Cycle 6

21

86 (71-100)

60

62 (49-74)

50

46 (32-60)

29

55 (37-73)

139

55 (46-63)

All Cycles

284

89 (85-93)†

316

66 (61-72)

414

56 (51-60)†

148

57 (49-65)

878

60 (57-63)

*Blinded

and open-label filgrastim cycles.

†P < 0.0001 for comparison of incidence of grade 4 neutropenia between placebo and filgrastim across cycles using a generalized estimating equations model.

described by Longo et al.3,4 Baseline characteristics that were tested as possible risk factors for febrile neutropenia included age, body weight, body surface area, sex, ECOG performance status (PS), disease stage (limited vs. extensive), and neoplastic disease involvement in the marrow (yes vs. no). Analyses for individual risk factors for febrile neutropenia were performed using the Cochran-Mantel-Haenszel test with adjustment for center. Logistic regression for continuous variables used treatment, facility, and the risk factor as independent variables. All analyses were performed using SAS® software. For the analyses of thrombocytopenia and anemia, only blinded cycles were considered in order to avoid confounding effects of patients changing treatment. For the bone pain analysis, all types of skeletal pain in areas containing significant bone marrow were included; joint pain and nonspecific types of pain (such as flank pain) were excluded. Onset day was tallied for every event of medullary bone pain in every cycle in which blinded or open-label filgrastim was administered, and a frequency distribution was constructed.

Statistical Analysis The crossover design of the study (unblinding patients who experienced febrile neutropenia and giving them openlabel filgrastim in subsequent cycles) created 4 distinct patient-cycle datasets: blinded placebo cycles, blinded filgrastim cycles, open-label filgrastim cycles after blinded placebo, and open-label filgrastim cycles after blinded filgrastim. For most variables, results for all 4 datasets were calculated, and, where appropriate, all filgrastim cycles were combined. For tumor response and chemotherapy dose intensity, an as-randomized approach was used. For cases in which the inclusion of open-label cycles was considered to create possible bias in the data, these cycles were excluded. Safety variables were assessed on an as-treated basis except where otherwise noted. Statistical methods were similar to those reported previously. Categoric variables were analyzed by incidence (by patient and cycle) and percentages. Continuous variables were analyzed using mean and standard deviation as well as median where appropriate. Incidence outcomes were expressed as percentages with 95% confidence intervals (CIs). Survival analyses used the Kaplan-Meier method, with cycle as the time variable and censoring patients who were lost to follow-up. P values were 2-sided except in χ2 tests. Comparisons based on a generalized estimating equations approach to account for multiple cycle data for a given patient assumed compound symmetry. The calculation of chemotherapy dose intensity (expressed in mg/m2 per week) followed the methodology of Hryniuk and Goodyear as

Results Patient Characteristics A total of 244 patients were randomized into the study. Five were withdrawn before treatment commenced; therefore, 239 patients received study drug and were evaluable for safety, and 231 patients were evaluable for efficacy. Of the patients evaluable for efficacy, 120 were randomized to receive

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Filgrastim for Chemotherapy-Induced Neutropenia

Figure 2

Mean (SD) Days of Grade 4 Neutropenia

CI, 51%-60%; P < 0.0001). With regard to open-label cycles, patients crossing from placeMean Duration of Grade 4 Neutropenia by Cycle bo to filgrastim displayed a lower incidence of neutropenia relative to placebo, but the rates 12 Placebo to OL Blinded Filgrastim Filgrastim to OL Blinded Placebo were higher than those for blinded filgrastim. Patients crossing from blinded to open-label fil10 P = 0.0001 grastim also displayed a neutropenia incidence 8 slightly higher than those for blinded filgrastim. This is suggestive of a segregation effect: 6 patients who quit blinded therapy (experienced 4 febrile neutropenia) were less robust than those who remained event-free in blinded treatment. 2 These differences appear to be reflected in the 0 incidence of grade 4 neutropenia. 1 2 3 4 5 6 All Similarly, duration of grade 4 neutropenia was Cycle longer in cycle 1 than in later cycles, with a mean n= 115 107 48 66 73 29 38 63 67 28 32 64 59 30 27 63 55 32 21 60 50 29 281 316 411 148 of 5.7 ± 2.2 days for placebo versus 2.4 ± 1.9 days Mean duration of grade 4 neutropenia by cycle for patients given blinded placebo (purple bars), patients crossing from for filgrastim (Figure 2). Although duration placebo to open-label filgrastim (blue bars), and patients randomized to filgrastim, including blinded (green bars) plus open-label cycles (red bars). Error bars denote standard deviation. P value of 0.0001 denotes comparison of blinded remained high in subsequent placebo cycles, in filgrastim versus blinded placebo across all cycles using a generalized estimating equations model. blinded filgrastim cycles, the mean duration continued to decrease to between 1 and 1.2 days after placebo, and 111 were randomized to receive filgrastim. Age, cycle 1. For placebo patients crossing over to open-label filgrasbody weight, and other baseline characteristics were compatim, duration of neutropenia decreased but not to values as low rable between groups (Table 1) and were also similar to those as with blinded filgrastim. Interestingly, mean duration of neuof the 199 patients in the original report.1 Approximately tropenia in cycle 2 for placebo patients who crossed over to filtwo-thirds of patients were male. Most patients in both treatgrastim after cycle 1 (representing their first exposure to filment groups displayed an ECOG PS of 1 and had extensivegrastim) was similar to cycle 1 for blinded filgrastim patients stage disease without marrow involvement. (2.3 days vs. 2.4 days, respectively). Filgrastim Dosing A total of 1170 double-blinded or open-label treatment cycles were delivered (Table 2). Because of the high incidence of febrile neutropenia among patients who received placebo and their consequent migration to open-label filgrastim, the majority of cycles (880) were filgrastim cycles. Across these 880 cycles, the mean number of days of filgrastim that were administered per cycle was 11.4 ± 2.1 days, with little variation between cycles (Table 3). The median number of days of filgrastim by cycle was 11-12 days. The median individual dose of the population was 375 μg (range, 250-540 μg).

Incidence of Febrile Neutropenia Substantial treatment-related differences were observed in the incidence of febrile neutropenia (Table 5). In every cycle of blinded therapy, the percentages of patients with febrile neutropenia were lower with filgrastim relative to placebo. The cumulative percent of patients who experienced ≥ 1 event throughout the study was 74% (95% CI, 66%-82%) with placebo compared with 38% (95% CI, 29%-47%) with filgrastim, a decrease of approximately 50% (P < 0.0001). These values compare closely with those in the original report: 77% versus 40%, respectively (P < 0.001).1 Over one-half of the patients assigned to placebo (56%; 95% CI, 47%-65%) experienced their first event of febrile neutropenia in cycle 1 (Figure 3); these patients then crossed to open-label filgrastim. In cycles 2-6, for patients who continued with blinded placebo (the minority of that population), event rates decreased successively from 17% in cycle 2 to 5% in cycle 6. Only 17% of patients who were randomized to receive placebo remained blinded and event-free throughout all 6 cycles of treatment. In the patients randomized to receive placebo who experienced febrile neutropenia and crossed over to open-label filgrastim, subsquent event rates ranged between 6% and 21% for cycles 2-6 and was 14% across all open-label cycles.

Incidence and Duration of Neutropenia Cycle 1 displayed the highest incidence of grade 4 neutropenia compared with later cycles (Table 4): 97% of patients receiving placebo (95% CI, 95%-100%) and 82% of patients receiving filgrastim (95% CI, 75%-90%). Although in subsequent cycles, incidence remained high for placebo patients (between 78% and 88%), incidence decreased to < 50% for blinded filgrastim patients. Across all blinded cycles, the incidence of grade 4 neutropenia was 89% for placebo (95% CI, 85%-93%) versus 56% for filgrastim (95%

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Volume 3, Number 1 • October 2005

Jeffrey Crawford et al

Table 5

Patients with Febrile Neutropenia by Cycle Cycle Number

Blinded Placebo

Placebo to OpenLabel Filgrastim

Blinded Filgrastim

Blinded to OpenLabel Filgrastim

All Filgrastim*

N

Percent (95% CI)

N

Percent (95% CI)

N

Percent (95% CI)

N

Percent (95% CI)

N

Percent (95% CI)

Cycle 1

117

56 (47-65)

–

–

107

29 (20-38)

–

–

107

29 (20-38)

Cycle 2

46

17 (6-28)

66

21 (11-31)

75

1 (0-4)

29

17 (3-31)

170

12 (7-17)

Cycle 3

38

16 (4-27)

63

21 (11-31)

67

6 (0-12)

28

18 (4-32)

158

14 (9-19)

Cycle 4

33

15 (3-27)

64

16 (7-25)

59

10 (2-18)

30

10 (0-21)

153

12 (7-18)

Cycle 5

27

15 (1-28)

63

6 (0-12)

55

4 (0-9)

32

19 (5-32)

150

8 (4-12)

Cycle 6

21

5 (0-14)

60

7 (0-13)

50

4 (0-9)

29

7 (0-16)

139

6 (2-10)

All Cycles

282

32 (26-37)

316

14 (10-18)

413

11 (8-14)

148

14 (9-20)

877

13 (11-15)

Cumulative

119

74 (66-82)†

–

–

110

38 (29-47)†

–

–

–

–

*Blinded

and open-label filgrastim cycles.

†P < 0.0001 for comparison of cumulative incidence of febrile neutropenia between placebo and filgrastim.

For patients randomized to receive blinded filgrastim, cycle 1 also displayed the highest incidence of febrile neutropenia (29%; 95% CI, 20%-38%). Event rates for patients remaining on blinded filgrastim in cycles 2-6 ranged from 1% to 10%. The proportions of patients who experienced subsequent events of febrile neutropenia on open-label filgrastim after their initial event on blinded filgrastim ranged from 7% to 19% by cycle. These were higher than the rates observed in the blinded cycles, perhaps because of the nature of these patients, which poses the question of whether patients who experienced febrile neutropenia early in the study appeared more likely to experience subsequent events. Overall, 13% of blinded plus open-label filgrastim cycles were complicated by febrile neutropenia, compared with 32% for placebo, a decrease of approximately 60%. Of the 31 patients randomized to receive filgrastim who had febrile neutropenia in cycle 1, 36% had ≥ 1 additional episode in cycles 2-6, compared with only 15% who were event-free in cycle 1 (P = 0.04). This analysis could not be applied to patients randomized to receive placebo because they crossed over to the alternate treatment after their first episode of febrile neutropenia and thus would not be assessable for subsequent placebo-associate events.

stantive differences in baseline characteristics between men and women were in body weight (mean, 78 ± 15.1 kg vs. 62.9 ± 13.8 kg, respectively) and in body surface area (1.9 ± 0.2 m2 vs. 1.6 ± 0.2 m2, respectively). However, regression analysis of these variables alone did not show either to be predictive of experiencing febrile neutropenia. Age, body weight class, PS, disease stage, and marrow involvement were not predictive of experiencing ≥ 1 episode of febrile neutropenia. Because of the eligibility criteria of the protocol, which required a pretreatment ANC of ≥ 2000/μL), there was insufficient variability to test for an effect on febrile neutropenia. Similar analytical approaches were used to identify risk factors for multiple events of febrile neutropenia. No consistent trends could be identified (data not shown). Chemotherapy Dose Delivery and Tumor Response Dose intensity for each of the chemotherapeutic agents in mg/m2 of body surface area per week was calculated for the 2 treatment groups as randomized, across the entire treatment course (Figure 4). Median dose intensities in patients randomized to the filgrastim group were 97.2%, 96.4%, and 92.2% of planned intensity for cyclophosphamide, doxorubicin, and etoposide, respectively, versus 92.3%, 91.6%, and 91.2% in patients randomized to receive placebo. As expected, these values are similar between treatment groups because more than half of patients randomized to receive placebo were receiving filgrastim after cycle 1.

Risk Factors for Febrile Neutropenia Various baseline patient characteristics were assessed as possible risk factors for ≥ 1 event of febrile neutropenia (Table 6). Only sex was marginally predictive (P = 0.05). The only sub-

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Filgrastim for Chemotherapy-Induced Neutropenia

Table 6

Figure 3

Analysis of Risk Factors for Febrile Neutropenia

Kaplan-Meier Plot of Cumulative Proportion of Patients Free from Febrile Neutropenia

Risk Factor Cumulative Proportion Free of Febrile Neutropenia

100

Placebo Filgrastim

Number of Patients with Febrile Neutropenia (%)

P Value

Placebo Filgrastim

All

CMH* LR†

< 60 kg

24 (79) 29 (45)

53 (60)

0.56 0.54

60-90 kg

79 (72) 71 (38) 150 (56)

> 90 kg

18 (78) 11 (27)

Body Weight Class

80 60 40 20

Sex

P < 0.0001 0

1

29 (59)

2

3

4

5

6

Male

80 (70) 70 (33) 150 (53) 0.05 0.05

Female

41 (83) 41 (49)

7

Cycle

82 (66)

Age Bar signifies 1 standard error. P value from log-rank test.

Excluding cycle 1, which by definition was delivered on schedule, 89% of blinded filgrastim cycles were delivered on schedule (no more than 3 days from planned dose), compared with 82% of blinded placebo cycles. Dose delays tended to increase with time, with the most delays occurring at cycle 6 for filgrastim (16% of cycles) and at cycle 5 for placebo (29% of cycles). The percentages of cycles delayed in the open-label filgrastim groups were higher than for blinded filgrastim groups. Cycle 2 (following patients’ initial episode of febrile neutropenia) was the most frequently delayed: 32% of cycles following crossover from blinded filgrastim and 43% of cycles following crossover from blinded placebo. For the tumor response assessment, patients were analyzed as originally randomized. Although more complete responses were observed in the filgrastim group relative to the placebo group (27% vs. 17%, respectively), the overall response rates (complete plus partial response) were similar: 68% for filgrastim versus 72% for placebo, which is comparable to those originally reported.1

< 65 Years

66 (77) 71 (37) 137 (56) 0.60 0.59

≥ 65 Years

55 (71) 40 (43)

95 (59)

0

27 (78) 18 (39)

45 (62)

1

70 (76) 76 (37) 146 (55)

2-3

24 (67) 17 (47)

41 (59)

Limited

29 (76) 27 (41)

56 (59)

Extensive

92 (74) 84 (38) 176 (57)

ECOG PS

0.91 0.91

Disease Stage

0.79 0.78

Marrow Involvement No

99 (73) 93 (42) 192 (58) 0.92 0.92

Yes

22 (82) 18 (22)

40 (55)

*Cochran-Mantel-Haenszel test of incidence of febrile neutropenia and risk factor adjusting for center. †Logistic

regression of incidence of febrile neutropenia on risk factor with treatment and center as covariates. Abbreviations: CMH = Cochran-Mantel-Haenszel test; LR = logistic regression test

Safety Considerations The safety profile of filgrastim was consistent with that in the original report. Skeletal pain was the most commonly reported adverse event that was attributable to filgrastim. Treatmentrelated laboratory trends consisted of reversible elevations in alkaline phosphatase, lactate dehydrogenase, and uric acid. The skeletal pain reported in patients receiving blinded or open-label filgrastim typically involved marrow-containing bone and included, in decreasing order of incidence, back pain (7% of cycles), unspecified bone pain (7%), limb

pain (4%), and hip pain (1%). The onset time was summarized as a frequency distribution of each episode of medullary bone pain versus day of cycle (Figure 5) in order to look for temporal patterns. The peak onset time of bone pain occurred on day 11 of the cycle, which was interestingly 3-4 days before ANC recovery, as evidenced by the superimposed ANC plot.

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Figure 4

Cyclophosphamide/Doxorubicin/Etoposide Median Dose Intensity A

Cyclophosphamide

B 20

300 200

100

15 10

5

Placebo

Filgrastim

Planned

125 100 75 50 25 0

0

0

Etoposide 150

Median Dose Intensity (mg/m2 per week)

Median Dose Intensity (mg/m2 per week)

400

Median Dose Intensity (mg/m2 per Week)

C

Doxorubicin

Placebo

Filgrastim

Planned

Placebo

Filgrastim

Planned

(A) Actual median dose intensity delivered for cyclophosphamide, (B) doxorubicin, and (C) etoposide compared with planned dose intensity. The analysis used an intent-to-treat approach. Error bars indicate interquartile ranges.

not shown to be predictive. Because this study enrolled only newly diagnosed patients who had received no previous chemotherapy or radiation therapy, we were unable to test whether previous treatment would predispose a patient to neutropenia and other chemotherapy-related toxicities. Likewise, detecting an effect from other baseline characteristics, such as pretreatment ANC, concurrent illnesses, and extremes in PS, was not possible because of the relative homogeneity of this patient population. The marginally significant sex differences seen in the incidence of febrile neutropenia may be secondary to some other yet-to-be-identified factor. With regard to baseline differences between men and women, mean body weight and body surface area emerged, as expected. However, neither of these variables alone appeared to predict which patients would experience febrile neutropenia. Differences in total bone mass might explain the lower incidence of febrile neutropenia seen in men, because greater marrow volume (as would be expected with men) might provide an individual with the ability to better tolerate chemotherapy and/or respond to an exogenous myeloid growth factor. However, we were unable to quantify bone mass directly to test for such an effect. A recent report on risk factors for febrile neutropenia in patients with intermediate-grade non-Hodgkin’s lymphoma who were receiving CHOP (cyclophosphamide/doxorubicin/ vincristine/prednisone) chemotherapy has been published.5 In a retrospective survey of 577 patients, the following risk factors were identified: aged ≥ 65 years, renal disease, cardiovascular disease, baseline hemoglobin < 12 g/dL, receipt of ≥ 80% of a standard dose intensity of CHOP therapy, and no prophylactic growth factor. Our study excluded clinically

Cycle by cycle, the incidence of grade 4 thrombocytopenia (platelets < 25,000/μL) and transfusion-requiring anemia (hemoglobin < 8 g/dL) were not dissimilar between the placebo and filgrastim groups (Table 7). Generally, thrombocytopenia and anemia were progressive, with the highest incidences seen in later cycles. The cumulative percent of patients on placebo who experienced grade 4 thrombocytopenia at least once was 24%, compared with 34% on blinded filgrastim. For anemia, the percentages were 28% and 45%, respectively. These differences may be a result of the higher rate of attrition from the placebo group, with fewer patients relative to filgrastim remaining in the later cycles when these toxicities are most likely to manifest.

Discussion This final analysis of a placebo-controlled phase III trial of filgrastim for chemotherapy-induced neutropenia in 231 patients with SCLC was consistent with the original report (N = 199) in demonstrating highly statistically significant reductions in the cumulative incidence of febrile neutropenia and in the incidence and duration of grade 4 neutropenia. The previously unreported open-label treatment with filgrastim (representing a large dataset of 463 cycles for patients randomized to receive placebo or blinded filgrastim after their initial event of febrile neutropenia) demonstrated similar treatment benefits of filgrastim. With the exception of sex, no baseline risk factors for experiencing ≥ 1 episode of febrile neutropenia could be identified. Age, body weight, ECOG PS, disease stage (limited vs. extensive), and marrow involvement by tumor were

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Filgrastim for Chemotherapy-Induced Neutropenia

fever in later cycles have been attributed to expansion of myeloid precursors.10 These observations support the initiation of growth factor from the first cycle of myelosuppressive chemotherapy regimens. Dose intensity was analyzed using an as-randomized approach. Two factors confounded the interpretation of this analysis. Firstly, over one-half of the cycles in patients originally randomized to receive placebo were delivered with open-label filgrastim (315 of 605 cycles) because of the crossover feature of the study design. Secondly, patients randomized to receive filgrastim were eligible for a chemotherapy dose reduction earlier than those randomized to receive placebo. At the first event of febrile neutropenia, patients randomized to receive filgrastim continued receiving filgrastim in the cycle following their event but were permitted to receive a chemotherapy dose reduction, whereas patients randomized to receive placebo were to continue at full chemotherapy dose with open-label filgrastim in the next cycle. Despite these study design features that tend to bias the analysis in favor of the placebo group, the trend was for higher relative dose intensities in the filgrastim group. Most of this was a result of a lower incidence of dose delays in the filgrastim group (data not shown), because a prompt ANC recovery allowed a higher proportion of subsequent cycles to be initiated on time. Nevertheless, the number of dose delays was higher in later cycles in both treatment groups (16% for cycle 6 in blinded filgrastim patients vs. 27% in blinded placebo), presumably for toxicities of a more progressive or cumulative nature such as thrombocytopenia. Overall, a high proportion of cycles in this study were delivered on time and at the planned doses. The analysis of hematologic toxicities that tend to be progressive in nature, namely, thrombocytopenia and anemia, is also complicated by the crossover feature of this study. For this reason, we used only the blinded cycles in these analyses. An as-treated data analysis would contain bias by enriching the filgrastim treatment group with what might be considered the poorer-prognosis patients (ie, those who experienced febrile neutropenia and were presumably more prone to hematologic toxicity). Cycle by cycle, the incidence of transfusion-requiring thrombocytopenia and anemia varied little between treatment groups; however, the cumulative percent of patients experiencing these toxicities was higher in the filgrastim group. Because of attrition out of the placebo group, only 22 of 120 patients remained on blinded placebo for 6 cycles, compared with 50 of 111 patients randomized to receive filgrastim. The bias towards fewer placebo cycles later in the study might be creating the appearance of a lower cumulative proportion of thrombocytopenia and anemia in the placebo group. In general, the onset time of bone pain did not correlate with the initiation of filgrastim dosing (day 4) but occurred approximately 1 week later in the cycle, anticipating the rapid rise in

Figure 5

40

Bone Pain Onset (Cycles 1-6) Median ANC (Cycle 1)

30

30 25 20 15

20

m

10

ANC (10,000/ L)

Number of Events of Bone Pain

Bone Pain Onset by Cycle Day

10

5 0 0

1

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Cycle Day Onset of medullary bone pain by cycle day (bars) for all blinded and open-label filgrastim cycles combined. Median ANC profile for cycle 1 blinded filgrastim (line) is superimposed for comparison.

significant organ disease and required hematologic values within normal range. Age was not found to be a risk factor for febrile neutropenia in our study, perhaps because, in a selected healthy population of previously untreated patients without comorbidities other than the primary tumor, elderly patients tolerate chemotherapy as well as younger ones. A risk factor model based on ANC, chemotherapy dose reductions, and dose delays was developed by means of retrospective chart review of patients receiving adjuvant chemotherapy for early-stage breast cancer.6 Pretreatment variables and cycle 1 events were examined as possible predictors of ANC of ≤ 25,000/μL, chemotherapy dose reduction > 15%, and/or delays of ≥ 7 days. Similar to our findings, no pretreatment prognostic variables emerged; however, the authors found that use of concurrent chemotherapy and radiation therapy, cycle 1 nadir, and declines in hemoglobin during cycle 1 predicted later events. Using firstcycle events to predict subsequent events presents something of a practical treatment dilemma. The majority of first episodes of febrile neutropenia in this study occurred in cycle 1. Other reports have made reference to this effect.1,2,5,7,8 Additionally, we have demonstrated that patients who experienced febrile neutropenia in cycle 1 were more likely to have febrile neutropenia in subsequent cycles than those who were event-free in cycle 1. These findings do not support the practice of withholding growth factor therapy until a patient experiences febrile neutropenia and then instituting growth factor in subsequent cycles. Administration of filgrastim in the previous cycle appears to have a beneficial carry-over or priming effect in subsequent cycles.9 The lower rates of neutropenia with and without

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Volume 3, Number 1 • October 2005

Jeffrey Crawford et al

Table 7

Thrombocytopenia and Anemia by Cycle Incidence of Platelet Count < 25,000/mL Cycle Number

Placebo*

Incidence of Hemoglobin < 8 g/dL

Filgrastim*

Placebo*

Filgrastim*

N

Percent (95% CI)

N

Percent (95% CI)

N

Percent (95% CI)

N

Cycle 1

118

14 (7-20)

109

12 (6-18)

118

7 (2-11)

109

6 (2-11)

Cycle 2

49

4 (0-10)

75

5 (0-10)

49

22 (11-34)

75

17 (9-26)

Cycle 3

39

5 (0-12)

68

10 (3-18)

39

33 (19-48)

68

37 (25-48)

Cycle 4

34

12 (1-23)

60

18 (9-28)

34

41 (25-58)

60

53 (41-66)

Cycle 5

28

18 (4-32)

55

16 (7-26)

28

46 (28-65)

55

42 (29-55)

Cycle 6

22

23 (5-40)

51

27 (15-40)

22

32 (12-51)

51

35 (22-48)

All Cycles

290

12 (8-15)

418

14 (11-17)

290

23 (18-28)

418

28 (24-33)

Cumulative

119

24 (16-31)

110

34 (25-42)

119

28 (20-36)

110

45 (35-54)

Percent (95% CI)

*Blinded cycles only.

Conclusion

peripheral neutrophils. This suggests that bone pain is an indirect consequence of the biologic effects of filgrastim on the bone marrow, occurring at a time during which the marrow would be most metabolically active and hypercellular. The approximately 50% reduction in the cumulative proportion of patients experiencing febrile neutropenia occurred in the context of a high event incidence overall (74% for placebo and 38% for filgrastim) and is a reflection of the highly aggressive chemotherapy dosages used in this study. The 2000 American Society of Clinical Oncology guidelines on the use of colony-stimulating factors espouse the use of primary prophylaxis in such situations in which the incidence of febrile neutropenia is > 40%.11 A randomized placebo-controlled trial of first- and subsequent-cycle pegfilgrastim that evaluated febrile neutropenia from moderately myelosuppressive chemotherapy (100 mg/m2 docetaxel every 3 weeks) in patients with breast cancer was recently reported.8 The cumulative percent of patients experiencing febrile neutropenia was significantly reduced from 17% in the placebo group to 1% in the pegfilgrastim group (P < 0.0001), with approximately two-thirds of the events occurring in the first cycle. These results together with ours indicate that patients receiving chemotherapy regimens with moderate to high potential for febrile neutropenia can benefit from first-cycle use of growth factor. Based on these results and others, the 2005 National Comprehensive Cancer Network guidelines have suggested that primary prophylaxis should be considered for patients at a > 20% risk for febrile neutropenia.

This randomized study in newly diagnosed patients with previously untreated SCLC, although confirming the ability of filgrastim to significantly decrease the incidence of febrile neutropenia, did not reveal baseline risk factors for febrile neutropenia that might be useful in selecting which patients should receive first-cycle growth factor therapy. Instead, given the very high incidence of first events in cycle 1, these data indicate that patients receiving moderately or highly myelosuppressive chemotherapy should be considered for growth factor support from the outset of treatment.

Acknowledgements The authors thank the principal investigators, study coordinators, and patients at each of the participating institutions. This study was supported by Amgen Inc., Thousand Oaks, CA.

References 1. Crawford J, Ozer H, Stoller R, et al. Reduction by granulocyte colonystimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991; 325:164-170. 2. Trillet-Lenoir V, Green J, Manegold C, et al. Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 1993; 29A:319-324. 3. Hryniuk WM, Goodyear M. The calculation of received dose intensity. J Clin Oncol 1990; 8:1935-1937. 4. Longo DL, Duffey PL, DeVita VT, et al. The calculation of actual or

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Filgrastim for Chemotherapy-Induced Neutropenia

received dose intensity: a comparison of published methods. J Clin Oncol 1991; 9:2042-2051. 5. Lyman GH, Morrison VA, Dale DC, et al. Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin’s lymphoma receiving CHOP chemotherapy. Leuk Lymph 2003; 44:2069-2076. 6. Silber JH, Fridman M, DiPaola RS, et al. First-cycle blood counts and subsequent neutropenia, dose reduction, or delay in early-stage breast cancer therapy. J Clin Oncol 1998; 16:2392-2400. 7. Donnelly S, Epstein J, Al-Bussam N, et al. Filgrastim experience in diverse nonmyeloid malignancies: a prospective study in community oncology practice. Proc Am Soc Clin Oncol 2003; 22:182 (Abstract #728). 8. 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 3 study. J Clin Oncol 2005; 23:1178-1184. 9. Crawford J, Kriesman H, Garewal H, et al. The impact of filgrastim schedule variation on hematopoietic recovery post-chemotherapy. Ann Oncol 1997; 9:1117-1124. 10. Molineux G, Dexter M. Biology of G-CSF. In: Morstyn G, Dexter TM, eds. Filgrastim (r-metHuG-CSF) in Clinical Practice. New York, NY: Marcel Dekker, Inc; 1994:1-21. 11. Ozer H, Armitage J, Bennett C, et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidencebased, clinical practice guidelines. J Clin Oncol 2000; 19:3558-3585.

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