Impact of Five Prophylactic Filgrastim Schedules on Hematologic Toxicity in Early Breast Cancer Patients Treated With Epirubicin and Cycloph
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《临床肿瘤学》
the Departments of Medical Oncology and Surgery, Regina Elena Cancer Institute
Division of Medical Oncology, S. Andrea Hospital
Division of Medical Oncology, University "La Sapienza"
Division of Medical Oncology, S. Eugenio Hospital
Division of Medical Oncology, Catholic University School of Medicine, Rome, Italy
ABSTRACT
PURPOSE: To evaluate the comparative efficacy of varying intensity schedules of recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim) support in preventing febrile neutropenia in early breast cancer patients treated with relatively high-dose epirubicin plus cyclophosphamide (EC).
PATIENTS AND METHODS: From October 1991 to April 1994, 506 stage I and II breast cancer patients were randomly assigned to receive, in a factorial 2 x 2 design, epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 intravenously on day 1 every 21 days for 4 cycles ± lonidamine ± G-CSF. The following five consecutive G-CSF schedules were tested every 100 randomly assigned patients: (1) 480 μg/d subcutaneously days 8 to 14; (2) 480 μg/d days 8, 10, 12, and 14; (3) 300 μg/d days 8 to 14; (4) 300 μg/d days 8, 10, 12, and 14; and (5) 300 μg/d days 8 and 12.
RESULTS: All of the G-CSF schedules covered the neutrophil nadir time. Schedule 5 was equivalent to the daily schedules (schedules 1 and 3) and to the alternate day schedules (schedules 2 and 4) with respect to incidence of grade 3 and 4 neutropenia (P = .79 and P = .89, respectively), rate of fever episodes (P = .84 and P = .77, respectively), incidence of neutropenic fever (P = .74 and P = .56, respectively), need of antibiotics (P = .77 and P = .88, respectively), and percentage of delayed cycles (P = .43 and P = .42, respectively). G-CSF had no significant impact on the delivered dose-intensity compared with the non–G-CSF arms.
CONCLUSION: In the adjuvant setting, the frequency of prophylactic G-CSF administration during EC could be curtailed to only two administrations (days 8 and 12) without altering outcome. This nonrandomized trial design provides support for evaluating alternative, less intense G-CSF schedules for women with early breast cancer.
INTRODUCTION
Adjuvant chemotherapy is widely used for operable breast cancer and has been shown to improve both disease-free survival (DFS) and overall survival (OS).1 The equivalence between four cycles of anthracycline/cyclophosphamide and six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) was demonstrated in the National Surgical Adjuvant Breast and Bowel Project B15 trial.2 Acute dose-limiting hematologic toxicity and cumulative dose-related cardiac toxicity are less severe after epirubicin than after doxorubicin administration.3 Although, in the vast majority of trials, increased dose-intensity has not been demonstrated to improve OS, some data are consistent with the hypothesis that there is a dose-response curve for epirubicin in breast cancer adjuvant therapy.4,5
Neutropenia is a major cause of morbidity and mortality after antineoplastic therapy. It causes a reduction in the dose of the cytotoxic agents and a delay in the interval between cycles, limiting the intensity of treatment. Recombinant human granulocyte colony-stimulating factor (G-CSF) induces proliferation and differentiation of neutrophil lineage cells, potentially reverses myelosuppression, and improves the efficacy of therapies, ensuring the dose-intensity. When cancer patients receive high-intensity chemotherapeutic regimens, G-CSF support is found to decrease the duration of neutropenia and reduce the incidence of febrile neutropenia (FN).6 In settings characterized by lower intensity chemotherapy regimens (ie, in the range of 20% rates or lower of FN), the American Society of Clinical Oncology (ASCO) guidelines7-9 raise concern that G-CSF support may not be necessary. Although a more appropriate use of colony-stimulating factors (CSFs), in accordance with the ASCO guideline recommendations, occurred between 1994 and 1997, many oncologists continue to support the use of CSFs in special clinical situations and with scheduling criteria that the guidelines and evidence do not support.9 Furthermore, the optimal schedule and dose are still debatable. The controversy includes studies not supporting G-CSF use10 or questioning the clinical and economic benefit of G-CSF in settings that are not associated with high-intensity chemotherapy regimens.11-13 Conversely, there is less controversy and uncertainty over alternative scheduling regimens in the setting of moderate- to high-intensity chemotherapy.14-16
With the aim of increasing the efficacy of current antineoplastic drugs, we added to chemotherapy the energolytic derivative of indazole-carboxylic acid known as lonidamine (LND), which has proven to be capable of reversing resistance to anthracyclines in vitro.17-22 In addition, in metastatic breast cancer patients, we reported that LND increased the fluorouracil, doxorubicin, and cyclophosphamide activity, with significantly better OS in postmenopausal patients.23 Given these findings, at the end of the 1980s, we planned a prospective, randomized, phase III trial with a 2 x 2 factorial design to evaluate whether the addition of LND or G-CSF could increase the efficacy of epirubicin/cyclophosphamide (EC) in the treatment of early breast cancer patients.24 To maintain the dose-intensity of chemotherapy, maximize the patients' chemotherapy doses, and evaluate standard versus lower doses and less frequent schedules of G-CSF support, we studied the effectiveness of five different schedules of G-CSF administration in countering neutropenia after relatively high-dose epirubicin-based adjuvant chemotherapy for patients with early breast cancer. At the time the study was initiated, there were no conclusive data supporting or discouraging the dose-intensity maintenance. The current study determined whether varying the dose and frequency of filgrastim administration resulted in different clinical and hematologic outcomes in women with early breast cancer who received chemotherapy. In particular, we investigated whether the efficacy and safety end points were similar with a short twice-per-cycle filgrastim schedule versus a prolonged schedule. At present, the analysis of these data could support a lower intensity of prophylactic G-CSF use for patients who might benefit from relatively myelosuppressive chemotherapy or need a planned dose of drugs to optimize the treatment efficacy but have potential risk of developing FN.
PATIENTS AND METHODS
This study was conducted in accordance with institutional ethical standards and approved by an independent ethical committee. Oral informed consent was obtained from all patients before random assignment. Eligibility criteria for entry were as previously published24 and are as follows: histologically confirmed diagnosis of breast cancer according to the typing criteria of WHO; age 18 to 65 years; stage I or II disease, with tumor more than 1 cm; adequate bone marrow function (WBC count 4.0 x 109/L, with neutrophil count > 2,000 x 109/L and platelets 100 x 109/L); normal hepatic, renal, and cardiac functions; no history of active infection; and no previous or concurrent malignancies of other sites. Within 40 days of surgery, patients were randomly assigned to receive one of the following regimens: four cycles of chemotherapy with relatively high-dose epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 (EC) by slow intravenous push on day 1 every 21 days; EC plus LND; EC plus G-CSF; or EC plus LND plus G-CSF. G-CSF (filgrastim) was prophylactically administered only in the G-CSF groups after each chemotherapy cycle; in the control arms (EC and EC with LND), dose reduction was performed as per protocol in case of toxicity. Data analysis and hematologic toxicity evaluation were performed every 6 months.
To assess the optimal G-CSF schedule, five different schedules were tested in five consecutive cohorts of patients: (1) 480 μg/d subcutaneous injection every day (qd) on days 8 to 14; (2) 480 μg/d subcutaneous every other day (qod) on days 8, 10, 12, and 14; (3) 300 μg/d subcutaneous qd on days 8 to 14; (4) 300 μg/d subcutaneous qod on days 8, 10, 12, and 14; and (5) 300 μg/d subcutaneous on days 8 and 12. G-CSF was administered from day 8 because the onset of myelosuppression by anthracyclines usually takes place 7 days after administration, with maximum effect seen at approximately days 10 to 14.25 Furthermore, within 24 hours of starting G-CSF injection, neutrophils are rapidly released from the marrow into the circulation.26 For this reason, we thought that it would be sufficient to administer G-CSF 24 to 48 hours before the expected nadir.
No statistical analysis plan was performed because no G-CSF schedule variation was originally planned in the study design. Although no power calculations were performed for the comparison of the five G-CSF schedules described in this study, it should be noted that, with approximately 50 individuals in each group, we would have a statistical power of 80% to be able to detect only large differences in proportions and in survival rates (eg, differences of 20 to 30 percentage points). The G-CSF dose was changed for every 100 patients randomly assigned in the study based on the analysis of neutrophil curves. The five different consecutive schedules and doses of filgrastim were primarily changed to eliminate the marked neutrophilia seen with G-CSF 480 μg (qd or qod) or 300 μg (qd or qod); the assessment of whether a short twice-per-cycle schedule would at least be equivalent to a prolonged (qd or qod) schedule was a secondary objective. Thus, the schedules were changed systematically, and clinicians were not blinded to which schedule the patient was on. However, because this was a multicenter study, several investigators assessed toxicity. This fact could have protected against biases in evaluating toxicity.
CBC count was performed at baseline and weekly on days 7, 14, and 21 in each group. Left ventricular ejection fraction was assessed before the first and third cycles, 21 days after the fourth cycle, and during the follow-up if indicated. In case of myelosuppression (neutrophil count < 2.0 x 109/L and platelet count < 100 x 109/L), the therapy was delayed weekly until recovery. If the patient did not recover the hematologic parameter after a 6-week interval, the treatment was stopped. A 25% reduction of the total dose was planned when neutropenic fever occurred, in the event of grade 4 neutropenia and/or thrombocytopenia lasting for more than 6 days, or in the event of an infectious episode (fever associated with confirmed or suspected infection, fever resulting in hospitalization, or oral/intravenous antibiotics administered for a documented infection). Use of G-CSF was not allowed out of protocol indications. The other recommended treatment modifications have previously been reported.24 Myalgia, gastric pain, and asthenia were graded as mild, moderate, or severe. All other toxicities were graded using the WHO scale.
Comparisons of treatment toxicity among the five G-CSF groups were performed by the 2 and Kruskal-Wallis tests. Total delivered dose (mg/m2) was calculated as the sum of single delivered doses. Total time on treatment (weeks) was calculated as the interval between day 1 of the first cycle up to day 21 of the fourth cycle. This means that nondelivered cycles were counted as being 3 weeks long and with zero doses of EC administered. Curves of neutrophils were calculated by means per week. SPSS for Windows packages (SPSS, Inc, Chicago, IL) were used for statistical computation. No correction was made for multiple comparisons. Administrative issues delayed the analysis and final reporting of this aspect of the study.
RESULTS
A total of 506 patients were enrolled between October 1991 and April 1994, and 497 were assessable for treatment efficacy. Toxicity data were considered inadequate for 17 patients in the G-CSF arms. Patient characteristics are listed in Table 1. Patients were consecutively assigned to one of the five filgrastim dose schedules administered, together with EC chemotherapy ± LND, for a maximum of four cycles. When this trial began, the guideline recommending a dose regimen of filgrastim 5 μg/kg/d to support standard-dose chemotherapy had not yet been approved. Filgrastim was initially available in prefilled syringes and vials containing 480 μg of the drug, and syringes and vials containing 300 μg of G-CSF were successively introduced. Thus, after identifying mean peak absolute neutrophil counts (ANCs) of 33,444 cells/μL with 480 μg and of 24,043 cells/μL with 300 μg of daily filgrastim and mean peak ANCs of 17,483 cells/μL with 480 μg and of 20,591 cells/μL with 300 μg of qod filgrastim (schedules 1 through 4, each schedule was used every 100 consecutive patients enrolled), it seemed reasonable to adopt a short schedule on days 8 and 12 (schedule 5). The G-CSF arms comprised 254 patients: 53 women were included in group 1 with G-CSF 480 μg/d for 7 days, 55 were in group 2 with G-CSF 480 μg/d qod for 4 days, 43 were in group 3 with G-CSF 300 μg/d for 7 days, 52 were in group 4 with G-CSF 300 μg/d qod for 4 days, and 51 were in group 5 with G-CSF 300 μg/d on days 8 and 12. The control arms comprised 243 patients. The patient features were comparable across each arm and G-CSF group. LND administration was well balanced between the control and G-CSF arms and among each G-CSF group.
Neutropenia
Neutropenia was significantly more severe in the control arms than in the G-CSF arms (P < .0001). In fact, the incidence of grade 3 to 4 neutropenia was 82% in the control arms compared with 29% in the G-CSF arms (Table 2). There were no statistically significant differences in neutropenia rates between any of the G-CSF groups (P = .96), in particular between the qd schedules (schedules 1 and 3) and schedule 5 (31% v 27%, respectively; P = .79) and between the qod schedules (schedules 2 and 4) and schedule 5 (28% v 27%, respectively; P = .89). The population-based mean ANCs for each group and cycle are presented in Figure 1. All five curves in the G-CSF arms showed early increases in ANC and had similar patterns of neutrophil overshoot on day 14, when the neutrophil nadir of the control arms occurred. The mean ANCs were different in the five G-CSF groups on day 14. Patients on schedules 1 through 4 experienced a marked response to G-CSF, with the mean peak ANC exceeding approximately 5x the upper normal limit (7.5 x 109/L). For patients on schedule 5 (300 μg on days 8 and 12), the mean ANC on day 14 was within the normal range (1.8 to 7.5 x 109/L), with a trend to increase after the G-CSF suspension, warranting a good protection from ANC nadir. In cycle 1, statistically significant differences were observed comparing the mean ANCs on day 14 of the qd schedules (schedules 1 and 3; range, 17.5 to 29.17 x 109/L) with the mean ANC on day 14 of schedule 5 (range, 3.86 to 4.20 x 109/L; P < .0001) and comparing the mean ANCs on day 14 of the qod schedules (schedules 2 and 4; range, 12.40 to 19.07 x 109/L) with the mean ANC of schedule 5 (P < .0001). In the subsequent cycles (2 through 4), the mean ANCs at nadir time in the control arms remained approximately the same, whereas the mean ANC for each G-CSF group decreased slightly, although not significantly. In cycles 2 through 4, the differences in mean ANCs at nadir time (day 14 of each cycle) between the qd schedules (schedules 1 and 3) and schedule 5 or between the qod schedules (schedules 2 and 4) and schedule 5 remained statistically significant, resembling the pattern observed for cycle 1 (P < .0001 for each comparison). Comparing the mean ANCs on day 1 or on day 7 of each course of chemotherapy (courses 1 through 4), no statistically significant differences were observed between the qd schedules (schedules 1 and 3) and schedule 5 or the qod schedules (schedules 2 and 4) and schedule 5 (all P > .2). The ANC curves showed that the time of G-CSF administration was correct because it covered the expected neutrophil nadir.
Clinical Aspects of Neutropenia
FN was defined as an oral or oral-equivalent temperature of more than 38.2°C concurrent with an ANC less than 0.5 x 103/μL. The FN rate was 1% in the G-CSF arms v 7% in the control arms (P = .004). The rate of FN by cycle was 0.3% in the G-CSF arms v 2% in the control arms (P = .0007). Only two patients receiving schedule 2 (4%) and one patient receiving schedule 5 (2%) developed FN during therapy, compared with 16 patients (7%) in the control arms. The rates of fever episodes per patient and per cycle were 8% and 2% in the G-CSF arms and 15% and 5% in the control arms, respectively (P = .03 and P = .002, respectively), with no statistically significant differences between the daily schedules (schedules 1 and 3) and schedule 5 (9% v 6%, respectively; P = .84) or between the qod schedules (schedules 2 and 4) and schedule 5 (9% v 6%, respectively; P = .77). The rates of intravenous antibiotic use per patient and per cycle were 7% and 2% in the G-CSF arms and 13% and 4% in the control arms, respectively (P = .02 and P = .003, respectively). Schedule 5 was equivalent to the qd schedules (schedules 1 and 3) and to the qod schedules (schedules 2 and 4) with respect to incidence of neutropenic fever (2% v 0%, P = .74; and 2% v 2%, P = .56, respectively), need of antibiotics (6% v 7%, P = .77; and 6% v 7%, P = .88, respectively), and percentage of delayed cycles (4% v 5%, P = .52; and 3% v 3%, P = .84, respectively).
Other Hematologic Variables
The rate of grade 2 anemia was higher in the G-CSF group (39%) than in the control group (26%; P = .005). Mean hemoglobin levels progressively decreased throughout the treatment compared with the initial values, which were 12.177 g/dL (standard deviation [SD] = 1.433 g/dL) in the G-CSF arms and 12.242 g/dL (SD = 0.988 g/dL) in the control arms (P = .70). The last mean hemoglobin values recorded (84 days after starting chemotherapy) were 10.547 g/dL (SD = 1.325 g/dL) and 10.960 g/dL (SD = 1.238 g/dL) for the G-CSF and control arms, respectively (P = .01). Five women were transfused with RBCs; two of these patients had been assigned to EC alone, two patients had been assigned to EC plus G-CSF, and one patient had been assigned to EC plus G-CSF (schedule 2) plus LND.
Thrombocytopenia was modest in both arms and in all five G-CSF groups. No statistically significant differences were found between the G-CSF and control arms in the incidences of grade 1 to 2 (11% and 7%, respectively; P = .12) and grade 3 to 4 thrombocytopenia (1% and 2%, respectively; P = .97).
Different Incidence in Nonhematologic Toxicity
The incidence of stomatitis (grade 1 to 3) per cycle was higher in the control arms (8%) than in the G-CSF arms (6%; P = .004). No difference in grade 1 to 3 stomatitis per cycle was observed between the qd schedules (schedules 1 and 3) and schedule 5 (7% v 9%, respectively; P = .39), whereas a higher incidence of stomatitis was seen with schedule 5 (9%) compared with the qod schedules (schedules 2 and 4, 4%; P = .03).
G-CSF–Related Toxicity
Filgrastim-related toxicity was mild and well controlled by nonsteroidal anti-inflammatory drugs. G-CSF administered as schedule 5 (G-CSF on days 8 and 12) was better tolerated (Table 3). The most frequently reported adverse events were skeletal pain, which occurred in 87 (46%) of 189 patients on schedules 1 through 4 and in 14 (29%) of 48 patients on schedule 5, and fever, which occurred in 35 (18%) of 189 women on schedules 1 through 4 and in four (8%) of 48 women on schedule 5. A statistically significant difference was observed between the qd schedules (schedules 1 and 3) and schedule 5 for grade 1 to 3 bone pain (53% v 29%, respectively; P = .01) and grade 1 to 2 fever (24% v 8%, respectively; P = .04). No differences were observed between the qod schedules (schedules 2 and 4) and schedule 5 for bone pain (40% v 29%, respectively; P = .28) and fever (13% v 8%, respectively; P = .55) Adverse events that led to withdrawal were reported in two patients in the EC plus G-CSF arm and in four patients in the EC plus G-CSF and LND arm (bone pain, grade 3).
Time Frame of Chemotherapy
The number of treatment cycles administered was 963 for the G-CSF arms and 961 for the control arms. The rate of delayed cycles was 4% in the G-CSF arms and 10% in the control arms (P < .0001), and the frequency of dose reduction was 1% and 4% in the G-CSF and control arms, respectively (P = .002). The EC dose-intensity was greater, although not significantly (P = .17), in the G-CSF arms than in the control arms (98% v 95% of the planned dose-intensity, respectively). With the addition of G-CSF, no advantage in 5-year DFS and OS was observed comparing the G-CSF arms and control arms. Results of the major outcomes have been reported in our previous article.24 Furthermore, no significant difference in terms of 5-year DFS was observed when comparing the qd schedules (schedules 1 and 3) with schedule 5 (67% v 77%, respectively; P = .25) or the qod schedules (schedules 2 and 4) with schedule 5 (64% v 77%, respectively; P = .18). These apparent differences of 10% and 13%, which some might consider to be clinically important, were not significant because, with a statistical power of 80%, we were able to detect only large differences in proportions and survival rates.
DISCUSSION
Several studies have demonstrated the possibility of achieving a modest to moderate increase in dose-intensity using CSFs as an adjunct to higher dose chemotherapy.27-36 Unfortunately, the number of randomized, multicenter, clinical trials in solid malignancies demonstrating a survival benefit for patients receiving higher dose therapy remains limited.8 It should be noted that, with respect to lymphomas, dose intensification may not be better.37,38 According to the most recent ASCO guidelines, there is no justification for the use of CSFs to increase chemotherapy dose-intensity outside of a clinical trial because conclusive trials showing an improvement in quality of life, DFS and OS, or toxicity are still lacking.8,9 However, some results provide evidence that a reduction in chemotherapy doses (below levels shown to improve the outcome in breast cancer patients) reduces the benefit of adjuvant therapy. In the study by Wood et al,39 postmenopausal women treated with higher doses of adjuvant chemotherapy had a significantly longer survival than women administered lower doses, but these data did not provide any evidence that an additional benefit would accrue from doses that are even higher than those used in this trial. On the basis of a dose-response relationship, several trials have demonstrated the importance of an adequate dose of epirubicin in metastatic and adjuvant settings. In women with metastatic breast cancer, epirubicin 120 mg/m2 via intravenous bolus administration every 3 weeks is the reference dose for the use of epirubicin as a single agent.40 In the adjuvant setting, because no randomized trial has yet compared fluorouracil plus EC with EC, we cannot assess whether EC for four cycles (epirubicin 120 mg/m2) is equivalent to fluorouracil plus EC for six cycles (epirubicin 100 mg/m2)4 or to EC for eight cycles (epirubicin 100 mg/m2).5 Thus, as yet, no conclusion can be drawn regarding the efficacy of an epirubicin dose of 120 mg/m2, even though the aforementioned studies confirm that escalating the dose to more than 90 mg/m2 might lead to an improved outcome. Furthermore, the results of a Canadian trial showed the superiority of cyclophosphamide plus EF (epirubicin 60 mg/m2 days 1 and 8) compared with CMF in terms of both DFS and OS in premenopausal women with axillary node–positive breast cancer.41
The ASCO Health Services Research Committee sought to assess patterns of use of CSFs by a 1994 survey42 before dissemination of its first-ever publication of ASCO guidelines.7 This survey found that 73% of physicians would use CSFs in conjunction with intravenous antimicrobial agents after the onset of fever and neutropenia, whereas 34% of the physicians would administer CSFs even to afebrile patients with neutropenia. Physicians at academic medical centers and in Health Maintenance Organization practices were more likely to prefer dose reduction over addition of CSFs, whereas fee-for-service physicians preferred the opposite strategy.42 Chemotherapy-induced neutropenia, with no growth factor support, is often associated with quality-of-life impairments that seem to persist after neutrophil recovery.43 FN is a common and sometimes fatal complication in patients with cancer who receive myelosuppressive chemotherapy and is accompanied by severe asthenia and stomatitis. The goal of therapeutic intervention with CSFs is to reduce the incidence of infectious episodes and infection-related morbidity and mortality. This improvement in supportive care could potentially enhance the patient's quality of life by reducing the incidence and duration of hospitalization and antibiotic use. Rivera et al44 demonstrated the possibility of identifying a subgroup of breast cancer patients at high risk of neutropenia who were being treated with adjuvant anthracycline/cyclophosphamide, CMF, or cyclophosphamide, doxorubicin, and fluorouracil; the fully planned dose was delivered on time, and the incidence of FN hospitalization was reduced by filgrastim support. However, the cost and toxicity of G-CSF therapy should be considered in each treatment decision. In the era of supportive care in cancer, physicians, to preserve an adequate quality of life for their patients, sometimes adapt their strategy to conflicting realities. Clinicians may occasionally be challenged by patients who might benefit from relatively myelosuppressive treatments but who have potential risk factors for FN or infections (elderly age, pre-existing neutropenia caused by disease, extensive prior chemotherapy, history of recurrent FN while receiving previous chemotherapy, poor performance status, decreased immune function, open wounds, and active tissue infections) or desire to lead a busy social life. In addition, clinicians may be faced with the consequent emotional distress related to chemotherapy delay. Thus, depending on the unique features of each clinical situation, there are instances in which G-CSF administration is appropriate outside of recommended uses.
In 1991, when this trial was started, one of the main goals was to evaluate whether increasing the dose-intensity of chemotherapy would be sufficient to improve its efficacy. The only way to study this was to prospectively analyze dose and timing of regimens administered with or without recombinant hematopoietic growth factor support. Unlike previous reports evaluating the impact of G-CSF on chemotherapy toxicities, this trial included five consecutive cohorts, who were evaluated in a large nonrandomized design, and explored both the doses and the schedules of filgrastim administered with prophylactic intent. The results reported herein reveal that relatively high-dose EC in the adjuvant setting is well tolerated and that the addition of G-CSF does not improve the 5-year DFS and OS. Filgrastim, regardless of the five tested schedules, significantly reduced the incidence of neutropenic fever (P = .0007) and stomatitis (P = .04), the need for antibiotics (P = .003), the number of delayed courses (P < .0001), and the number of cycles requiring dose reductions (P = .002). Unfortunately, at the time when the study began, quality-of-life assessment was not considered among the end points of the study. It is noteworthy that, as myelopoietic support to EC, no significant differences were found between the five different filgrastim schedules; the short schedule (filgrastim 300 μg/d on days 8 and 12) produced results similar compared with filgrastim 480 μg/d and 300 μg/d on days 8 through 14 in all the safety end points evaluated. However, the patients on the G-CSF arms complained of grade 1 to 3 bone pain and grade 1 to 2 fever. A significant reduction of G-CSF–related bone pain (P = .01) and fever (P = .04) was observed between the daily schedules (schedules 1 and 3) and schedule 5, even though no difference was registered between the qod schedules (schedules 2 and 4) and schedule 5. These findings are of particular interest because of the requirement of only two filgrastim injections per cycle of chemotherapy compared with seven injections per cycle. The goal of G-CSF should be to keep leukocyte values within the normal range without inducing leukocytosis. In our study, the short schedule, compared with the prolonged schedules, was able to achieve this goal, maintaining an ANC on day 14 (the nadir time as shown by the neutrophil curves in the non–G-CSF arms) within the normal range (1.8 to 7.5 x 109/L) and, thus, suggesting a more cost-effective prophylactic use of the drug. In this context, the use of filgrastim as daily administration necessitates a high degree of compliance, whereas two injections per cycle of cytokine would be of significant clinical value.
The package insert recommends that G-CSF be initiated no earlier than 24 hours after the administration of chemotherapy, that daily dosing with the drug be continued until the ANC has reached at least 10,000/μL after the neutrophil nadir, and that delaying the G-CSF administration until ANC nadir could result in minor efficacy.9 The reason for administering G-CSF from day 8 was based on the evidence that the onset of myelosuppression by anthracyclines usually takes place 7 days after administration, with maximum effect seen at approximately days 10 to 14.25 In 20 women with early-stage breast cancer receiving four courses of cyclophosphamide (600 mg/m2) and doxorubicin (60 mg/m2) chemotherapy, the mean time to neutrophil nadir was 14.8 ± 1.5 days.45 Moreover, between 24 and 48 hours from the G-CSF injection (5 to 10 μg/kg/d), there is a six-fold neutrophil increase, with reduction of neutrophil maturation time from 5 days to 1 day with a rapid elapse of neutrophils from the marrow into the circulation.26,46 Thus, in our opinion, it would not be convenient to start G-CSF 24 hours after completion of chemotherapy, and it would be sufficient to administer G-CSF 24 to 48 hours before the expected nadir.
It has been reported that G-CSF administered in a subcutaneous qod schedule did not significantly enhance neutrophil-related parameters, whereas G-CSF administered in a conventional qd schedule either alone or in combination with engineered interleukin-3 effectively enhanced neutrophil recovery in two similar models of radiation-induced myelosuppression.47-49 However, leridistim, which is a chimeric dual agonist that binds both G-CSF and interleukin-3 receptors, administered subcutaneously in an alternate-day schedule significantly enhanced neutrophil, platelet, and erythroid recovery, stimulating an early but transient recovery of CD3+CD8+ T lymphocytes in high-dose sublethally irradiated rhesus monkeys.50 In a nonhuman primate model, it has been demonstrated that the abbreviated qod subcutaneous leridistim schedule was as effective as the conventional qd or bid myelopoietin (SC-68420) schedules.51 Unfortunately, the exact mechanisms responsible for this phenomenon remain unknown.52-65 Filgrastim is freely filtered by the kidney, leading to rapid clearance of the molecule and a relatively short serum half-life of approximately 3 hours after subcutaneous dosing. Filgrastim is also cleared by neutrophils, presumably after the binding to cognate receptors on the cell surface. The mean blood neutrophil half-life of the circulating neutrophils (mean blood neutrophil half-disappearance time = approximately 10 hours) is not significantly changed with G-CSF use.26,46 These findings theoretically justify the necessity of daily G-CSF injections. However, it is common in clinical practice to administer drugs in a minimum number of injections for economic reasons, the patient's convenience, and ease of dosing. In our study, the patients treated with qod G-CSF schedules administered from days 8 through 14 (schedules 3 and 4) experienced a marked response to G-CSF, with elevated median ANCs that resembled ANCs obtained with qd schedules.
The results of our study clearly show that the rate of grade 2 anemia was higher in the G-CSF arms than in control arms (P = .005). The EC dose-intensity did not statistically differ between the G-CSF and control arms, although the rate of delayed cycles and the frequency of dose reduction were greater in the control arms than in the G-CSF arms. The higher incidence of grade 2 anemia in the G-CSF arms compared with the control arms implies that prolonged G-CSF treatment might cause erythroid suppression in the bone marrow, supporting the hypothesis that G-CSF administration would lead to a reduction of the stem-cell pool and be followed by a decline in erythropoietic progenitor numbers.66,67
We believe that our findings should be taken into account when designing a dose-dense chemotherapy study. The dose-dense schedule is accomplished by using G-CSF to permit a recycling of the drugs every 2 weeks, even though the use of G-CSF means added expense and may cause myalgias, arthralgias, the inconvenience of a certain number of injections per course, and leukocytosis. In node-positive early breast cancer patients, Citron et al68 have shown that dose-dense chemotherapy with filgrastim support significantly improves the clinical outcome and that severe neutropenia is less frequent in patients who receive the dose-dense regimens compared with conventional regimens (33% v 6%, respectively; P < .0001), even though patients on the dose-dense regimen had a higher need of RBC transfusions. Because the goal of using G-CSF in dose-dense schedules is recycling every 2 weeks without reaching leukocyte values much higher than normal, it is also plausible that four qod G-CSF injections would be sufficient to achieve this goal, as reported in our experience in advanced gastric cancer,69 with a cost reduction and fewer adverse effects. In fact, no statistically significant differences in G-CSF–related adverse effects were observed between the qod schedules (schedules 2 and 4) and schedule 5.
In clinical studies, filgrastim has been administered at different times (1 to 9 days or more) after initiating chemotherapy or at neutrophil nadir depending on the protocol, patient population, and expected outcomes, and filgrastim is most effective if initiated before neutropenia appears.70 As reported by several authors, optimal clinical benefits of filgrastim are achieved with approximately 11 daily injections of filgrastim.6,71 Guidelines on the use of CSFs, such as pegfilgrastim, recommend that they be used in the first chemotherapy cycle only with highly myelosuppressive regimens associated with a clinically significant incidence of FN (approximately 40%).9 Vogel et al72 recently evaluated the utility of using pegfilgrastim in a setting with a risk of developing FN in the range of 10% to 20%. Vogel et al72 reported that, in breast cancer patients randomly assigned to either placebo or pegfilgrastim on day 2 of each 21-day chemotherapy cycle of docetaxel 100 mg/m2, first and subsequent cycle use of pegfilgrastim significantly reduced FN, FN-related hospitalizations, and intravenous anti-infective use. In three recent trials73-75 comparing pegfilgrastim with filgrastim in high-risk, stage II or III/IV breast cancer patients treated with doxorubicin-docetaxel, patients randomly assigned to filgrastim received daily subcutaneous injections of filgrastim 5 μg/kg/d beginning on day 2 of each cycle and continuing until a documented ANC of 10 x 109/L after the expected nadir or for up to 14 days, whichever occurred first. In these studies, both pegfilgrastim and filgrastim showed similar ANC values through the nadir, and the duration of grade 4 neutropenia with pegfilgrastim was clinically and statistically similar to that observed after a mean of 11 daily injections of filgrastim. In the study by Holmes et al,73 filgrastim patients, who could continue to receive this drug through day 14, exhibited a consistent overshoot during the ANC recovery (approximately 30 x 109/L), whereas pegfilgrastim patients displayed a plateau profile, with limited overshoot of neutrophils (approximately 7 x 109/L) after the nadir. In our trial, using prophylactic filgrastim at nonconventional timing for a maximum of 7 consecutive days, we observed that the mean peak of ANCs exceeded approximately 5x the upper normal limit, which indicated that, as prophylaxis, the conventional administration of filgrastim and, as a consequence, the use of pegfilgrastim would probably be not necessary during EC or moderately intensive chemotherapy.
The results of this portion (which could be viewed as a phase II trial) of our original study24 comparing different G-CSF schedules suggest that, during relatively high-dose adjuvant EC, the daily filgrastim schedule can be shortened using only two filgrastim injections (on day 8 before the expected neutrophil nadir time and on day 12 during neutrophil nadir time) without any change in toxicity (chemotherapy-induced grade 3 to 4 neutropenia, neutropenic fever, need of antibiotics, and cycle delays) but with a substantial savings in pharmaceutical costs in the range of 70% compared with daily filgrastim and a significant reduction in the G-CSF–related toxicity. As a consequence, the use of a short schedule of filgrastim as four qod injections during moderately intensive chemotherapy (ie, dose-dense schedules every 14 days, cisplatin-etoposide-bleomycin, cisplatin-epirubicin-folinic acid-fluorouracil, cisplatin-etoposide, paclitaxel-ifosfamide-cisplatin, and epirubicin-ifosfamide)76-80 for responsive malignancies would provide lower financial costs to patients and caregivers, given this schedule's comparable efficacy to daily injections of filgrastim. However, because we did not compare the results with a more conventional G-CSF schedule in our trial, it is not possible to draw definitive conclusions between the qd schedules (schedules 1 and 3) and the other schedules (schedules 2, 4, and 5). Nevertheless, the low rates of grade 3 to 4 neutropenia, fever, FN, antibiotics use, and number of cycles requiring dose reductions certainly confirm that the qod schedules (schedules 2 and 4) and the short schedule were active.
Despite the small sample size of our schedules (only 50 women received the twice-per-cycle schedule), the potential cost savings of a shortened G-CSF administration is a strong justification for conducting a formal phase III trial comparing conventional G-CSF dosing with G-CSF dosing on days 8 and 12 to assess when and how much G-CSF use can improve the quality of life of these patients compared with patients who do not receive G-CSF. Clinical prediction models clearly represent tools for improving patient selection for G-CSF treatment and targeting filgrastim use at high-risk patients,81 but they are based on saving costs rather than on obtaining clinical benefit. The administration of two doses of prophylactic filgrastim on days 8 and 12 during moderately intensive chemotherapy, based on accurate comparisons between standard and novel schedules, could lead to a more cost-effective use of hematopoietic growth factors.
Appendix
The following persons contributed to the study: Federico Calabresi had the original idea; Paola Papaldo, MD, Massimo Lopez, MD, and Paolo Marolla, MD, designed and coordinated the study; Gianluigi Ferretti, MD, and Serena Di Cosimo, MD, prepared the first draft of the report, to which Paola Papaldo, MD, subsequently contributed; Diana Giannarelli, PhD, was responsible for the database and the statistical analysis and managed the data; all other authors took care of the patients enrolled onto this study.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank the nurse staff of the Department of Medical Oncology for their technical support and the Italian women who took part in this study.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Division of Medical Oncology, S. Andrea Hospital
Division of Medical Oncology, University "La Sapienza"
Division of Medical Oncology, S. Eugenio Hospital
Division of Medical Oncology, Catholic University School of Medicine, Rome, Italy
ABSTRACT
PURPOSE: To evaluate the comparative efficacy of varying intensity schedules of recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim) support in preventing febrile neutropenia in early breast cancer patients treated with relatively high-dose epirubicin plus cyclophosphamide (EC).
PATIENTS AND METHODS: From October 1991 to April 1994, 506 stage I and II breast cancer patients were randomly assigned to receive, in a factorial 2 x 2 design, epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 intravenously on day 1 every 21 days for 4 cycles ± lonidamine ± G-CSF. The following five consecutive G-CSF schedules were tested every 100 randomly assigned patients: (1) 480 μg/d subcutaneously days 8 to 14; (2) 480 μg/d days 8, 10, 12, and 14; (3) 300 μg/d days 8 to 14; (4) 300 μg/d days 8, 10, 12, and 14; and (5) 300 μg/d days 8 and 12.
RESULTS: All of the G-CSF schedules covered the neutrophil nadir time. Schedule 5 was equivalent to the daily schedules (schedules 1 and 3) and to the alternate day schedules (schedules 2 and 4) with respect to incidence of grade 3 and 4 neutropenia (P = .79 and P = .89, respectively), rate of fever episodes (P = .84 and P = .77, respectively), incidence of neutropenic fever (P = .74 and P = .56, respectively), need of antibiotics (P = .77 and P = .88, respectively), and percentage of delayed cycles (P = .43 and P = .42, respectively). G-CSF had no significant impact on the delivered dose-intensity compared with the non–G-CSF arms.
CONCLUSION: In the adjuvant setting, the frequency of prophylactic G-CSF administration during EC could be curtailed to only two administrations (days 8 and 12) without altering outcome. This nonrandomized trial design provides support for evaluating alternative, less intense G-CSF schedules for women with early breast cancer.
INTRODUCTION
Adjuvant chemotherapy is widely used for operable breast cancer and has been shown to improve both disease-free survival (DFS) and overall survival (OS).1 The equivalence between four cycles of anthracycline/cyclophosphamide and six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) was demonstrated in the National Surgical Adjuvant Breast and Bowel Project B15 trial.2 Acute dose-limiting hematologic toxicity and cumulative dose-related cardiac toxicity are less severe after epirubicin than after doxorubicin administration.3 Although, in the vast majority of trials, increased dose-intensity has not been demonstrated to improve OS, some data are consistent with the hypothesis that there is a dose-response curve for epirubicin in breast cancer adjuvant therapy.4,5
Neutropenia is a major cause of morbidity and mortality after antineoplastic therapy. It causes a reduction in the dose of the cytotoxic agents and a delay in the interval between cycles, limiting the intensity of treatment. Recombinant human granulocyte colony-stimulating factor (G-CSF) induces proliferation and differentiation of neutrophil lineage cells, potentially reverses myelosuppression, and improves the efficacy of therapies, ensuring the dose-intensity. When cancer patients receive high-intensity chemotherapeutic regimens, G-CSF support is found to decrease the duration of neutropenia and reduce the incidence of febrile neutropenia (FN).6 In settings characterized by lower intensity chemotherapy regimens (ie, in the range of 20% rates or lower of FN), the American Society of Clinical Oncology (ASCO) guidelines7-9 raise concern that G-CSF support may not be necessary. Although a more appropriate use of colony-stimulating factors (CSFs), in accordance with the ASCO guideline recommendations, occurred between 1994 and 1997, many oncologists continue to support the use of CSFs in special clinical situations and with scheduling criteria that the guidelines and evidence do not support.9 Furthermore, the optimal schedule and dose are still debatable. The controversy includes studies not supporting G-CSF use10 or questioning the clinical and economic benefit of G-CSF in settings that are not associated with high-intensity chemotherapy regimens.11-13 Conversely, there is less controversy and uncertainty over alternative scheduling regimens in the setting of moderate- to high-intensity chemotherapy.14-16
With the aim of increasing the efficacy of current antineoplastic drugs, we added to chemotherapy the energolytic derivative of indazole-carboxylic acid known as lonidamine (LND), which has proven to be capable of reversing resistance to anthracyclines in vitro.17-22 In addition, in metastatic breast cancer patients, we reported that LND increased the fluorouracil, doxorubicin, and cyclophosphamide activity, with significantly better OS in postmenopausal patients.23 Given these findings, at the end of the 1980s, we planned a prospective, randomized, phase III trial with a 2 x 2 factorial design to evaluate whether the addition of LND or G-CSF could increase the efficacy of epirubicin/cyclophosphamide (EC) in the treatment of early breast cancer patients.24 To maintain the dose-intensity of chemotherapy, maximize the patients' chemotherapy doses, and evaluate standard versus lower doses and less frequent schedules of G-CSF support, we studied the effectiveness of five different schedules of G-CSF administration in countering neutropenia after relatively high-dose epirubicin-based adjuvant chemotherapy for patients with early breast cancer. At the time the study was initiated, there were no conclusive data supporting or discouraging the dose-intensity maintenance. The current study determined whether varying the dose and frequency of filgrastim administration resulted in different clinical and hematologic outcomes in women with early breast cancer who received chemotherapy. In particular, we investigated whether the efficacy and safety end points were similar with a short twice-per-cycle filgrastim schedule versus a prolonged schedule. At present, the analysis of these data could support a lower intensity of prophylactic G-CSF use for patients who might benefit from relatively myelosuppressive chemotherapy or need a planned dose of drugs to optimize the treatment efficacy but have potential risk of developing FN.
PATIENTS AND METHODS
This study was conducted in accordance with institutional ethical standards and approved by an independent ethical committee. Oral informed consent was obtained from all patients before random assignment. Eligibility criteria for entry were as previously published24 and are as follows: histologically confirmed diagnosis of breast cancer according to the typing criteria of WHO; age 18 to 65 years; stage I or II disease, with tumor more than 1 cm; adequate bone marrow function (WBC count 4.0 x 109/L, with neutrophil count > 2,000 x 109/L and platelets 100 x 109/L); normal hepatic, renal, and cardiac functions; no history of active infection; and no previous or concurrent malignancies of other sites. Within 40 days of surgery, patients were randomly assigned to receive one of the following regimens: four cycles of chemotherapy with relatively high-dose epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 (EC) by slow intravenous push on day 1 every 21 days; EC plus LND; EC plus G-CSF; or EC plus LND plus G-CSF. G-CSF (filgrastim) was prophylactically administered only in the G-CSF groups after each chemotherapy cycle; in the control arms (EC and EC with LND), dose reduction was performed as per protocol in case of toxicity. Data analysis and hematologic toxicity evaluation were performed every 6 months.
To assess the optimal G-CSF schedule, five different schedules were tested in five consecutive cohorts of patients: (1) 480 μg/d subcutaneous injection every day (qd) on days 8 to 14; (2) 480 μg/d subcutaneous every other day (qod) on days 8, 10, 12, and 14; (3) 300 μg/d subcutaneous qd on days 8 to 14; (4) 300 μg/d subcutaneous qod on days 8, 10, 12, and 14; and (5) 300 μg/d subcutaneous on days 8 and 12. G-CSF was administered from day 8 because the onset of myelosuppression by anthracyclines usually takes place 7 days after administration, with maximum effect seen at approximately days 10 to 14.25 Furthermore, within 24 hours of starting G-CSF injection, neutrophils are rapidly released from the marrow into the circulation.26 For this reason, we thought that it would be sufficient to administer G-CSF 24 to 48 hours before the expected nadir.
No statistical analysis plan was performed because no G-CSF schedule variation was originally planned in the study design. Although no power calculations were performed for the comparison of the five G-CSF schedules described in this study, it should be noted that, with approximately 50 individuals in each group, we would have a statistical power of 80% to be able to detect only large differences in proportions and in survival rates (eg, differences of 20 to 30 percentage points). The G-CSF dose was changed for every 100 patients randomly assigned in the study based on the analysis of neutrophil curves. The five different consecutive schedules and doses of filgrastim were primarily changed to eliminate the marked neutrophilia seen with G-CSF 480 μg (qd or qod) or 300 μg (qd or qod); the assessment of whether a short twice-per-cycle schedule would at least be equivalent to a prolonged (qd or qod) schedule was a secondary objective. Thus, the schedules were changed systematically, and clinicians were not blinded to which schedule the patient was on. However, because this was a multicenter study, several investigators assessed toxicity. This fact could have protected against biases in evaluating toxicity.
CBC count was performed at baseline and weekly on days 7, 14, and 21 in each group. Left ventricular ejection fraction was assessed before the first and third cycles, 21 days after the fourth cycle, and during the follow-up if indicated. In case of myelosuppression (neutrophil count < 2.0 x 109/L and platelet count < 100 x 109/L), the therapy was delayed weekly until recovery. If the patient did not recover the hematologic parameter after a 6-week interval, the treatment was stopped. A 25% reduction of the total dose was planned when neutropenic fever occurred, in the event of grade 4 neutropenia and/or thrombocytopenia lasting for more than 6 days, or in the event of an infectious episode (fever associated with confirmed or suspected infection, fever resulting in hospitalization, or oral/intravenous antibiotics administered for a documented infection). Use of G-CSF was not allowed out of protocol indications. The other recommended treatment modifications have previously been reported.24 Myalgia, gastric pain, and asthenia were graded as mild, moderate, or severe. All other toxicities were graded using the WHO scale.
Comparisons of treatment toxicity among the five G-CSF groups were performed by the 2 and Kruskal-Wallis tests. Total delivered dose (mg/m2) was calculated as the sum of single delivered doses. Total time on treatment (weeks) was calculated as the interval between day 1 of the first cycle up to day 21 of the fourth cycle. This means that nondelivered cycles were counted as being 3 weeks long and with zero doses of EC administered. Curves of neutrophils were calculated by means per week. SPSS for Windows packages (SPSS, Inc, Chicago, IL) were used for statistical computation. No correction was made for multiple comparisons. Administrative issues delayed the analysis and final reporting of this aspect of the study.
RESULTS
A total of 506 patients were enrolled between October 1991 and April 1994, and 497 were assessable for treatment efficacy. Toxicity data were considered inadequate for 17 patients in the G-CSF arms. Patient characteristics are listed in Table 1. Patients were consecutively assigned to one of the five filgrastim dose schedules administered, together with EC chemotherapy ± LND, for a maximum of four cycles. When this trial began, the guideline recommending a dose regimen of filgrastim 5 μg/kg/d to support standard-dose chemotherapy had not yet been approved. Filgrastim was initially available in prefilled syringes and vials containing 480 μg of the drug, and syringes and vials containing 300 μg of G-CSF were successively introduced. Thus, after identifying mean peak absolute neutrophil counts (ANCs) of 33,444 cells/μL with 480 μg and of 24,043 cells/μL with 300 μg of daily filgrastim and mean peak ANCs of 17,483 cells/μL with 480 μg and of 20,591 cells/μL with 300 μg of qod filgrastim (schedules 1 through 4, each schedule was used every 100 consecutive patients enrolled), it seemed reasonable to adopt a short schedule on days 8 and 12 (schedule 5). The G-CSF arms comprised 254 patients: 53 women were included in group 1 with G-CSF 480 μg/d for 7 days, 55 were in group 2 with G-CSF 480 μg/d qod for 4 days, 43 were in group 3 with G-CSF 300 μg/d for 7 days, 52 were in group 4 with G-CSF 300 μg/d qod for 4 days, and 51 were in group 5 with G-CSF 300 μg/d on days 8 and 12. The control arms comprised 243 patients. The patient features were comparable across each arm and G-CSF group. LND administration was well balanced between the control and G-CSF arms and among each G-CSF group.
Neutropenia
Neutropenia was significantly more severe in the control arms than in the G-CSF arms (P < .0001). In fact, the incidence of grade 3 to 4 neutropenia was 82% in the control arms compared with 29% in the G-CSF arms (Table 2). There were no statistically significant differences in neutropenia rates between any of the G-CSF groups (P = .96), in particular between the qd schedules (schedules 1 and 3) and schedule 5 (31% v 27%, respectively; P = .79) and between the qod schedules (schedules 2 and 4) and schedule 5 (28% v 27%, respectively; P = .89). The population-based mean ANCs for each group and cycle are presented in Figure 1. All five curves in the G-CSF arms showed early increases in ANC and had similar patterns of neutrophil overshoot on day 14, when the neutrophil nadir of the control arms occurred. The mean ANCs were different in the five G-CSF groups on day 14. Patients on schedules 1 through 4 experienced a marked response to G-CSF, with the mean peak ANC exceeding approximately 5x the upper normal limit (7.5 x 109/L). For patients on schedule 5 (300 μg on days 8 and 12), the mean ANC on day 14 was within the normal range (1.8 to 7.5 x 109/L), with a trend to increase after the G-CSF suspension, warranting a good protection from ANC nadir. In cycle 1, statistically significant differences were observed comparing the mean ANCs on day 14 of the qd schedules (schedules 1 and 3; range, 17.5 to 29.17 x 109/L) with the mean ANC on day 14 of schedule 5 (range, 3.86 to 4.20 x 109/L; P < .0001) and comparing the mean ANCs on day 14 of the qod schedules (schedules 2 and 4; range, 12.40 to 19.07 x 109/L) with the mean ANC of schedule 5 (P < .0001). In the subsequent cycles (2 through 4), the mean ANCs at nadir time in the control arms remained approximately the same, whereas the mean ANC for each G-CSF group decreased slightly, although not significantly. In cycles 2 through 4, the differences in mean ANCs at nadir time (day 14 of each cycle) between the qd schedules (schedules 1 and 3) and schedule 5 or between the qod schedules (schedules 2 and 4) and schedule 5 remained statistically significant, resembling the pattern observed for cycle 1 (P < .0001 for each comparison). Comparing the mean ANCs on day 1 or on day 7 of each course of chemotherapy (courses 1 through 4), no statistically significant differences were observed between the qd schedules (schedules 1 and 3) and schedule 5 or the qod schedules (schedules 2 and 4) and schedule 5 (all P > .2). The ANC curves showed that the time of G-CSF administration was correct because it covered the expected neutrophil nadir.
Clinical Aspects of Neutropenia
FN was defined as an oral or oral-equivalent temperature of more than 38.2°C concurrent with an ANC less than 0.5 x 103/μL. The FN rate was 1% in the G-CSF arms v 7% in the control arms (P = .004). The rate of FN by cycle was 0.3% in the G-CSF arms v 2% in the control arms (P = .0007). Only two patients receiving schedule 2 (4%) and one patient receiving schedule 5 (2%) developed FN during therapy, compared with 16 patients (7%) in the control arms. The rates of fever episodes per patient and per cycle were 8% and 2% in the G-CSF arms and 15% and 5% in the control arms, respectively (P = .03 and P = .002, respectively), with no statistically significant differences between the daily schedules (schedules 1 and 3) and schedule 5 (9% v 6%, respectively; P = .84) or between the qod schedules (schedules 2 and 4) and schedule 5 (9% v 6%, respectively; P = .77). The rates of intravenous antibiotic use per patient and per cycle were 7% and 2% in the G-CSF arms and 13% and 4% in the control arms, respectively (P = .02 and P = .003, respectively). Schedule 5 was equivalent to the qd schedules (schedules 1 and 3) and to the qod schedules (schedules 2 and 4) with respect to incidence of neutropenic fever (2% v 0%, P = .74; and 2% v 2%, P = .56, respectively), need of antibiotics (6% v 7%, P = .77; and 6% v 7%, P = .88, respectively), and percentage of delayed cycles (4% v 5%, P = .52; and 3% v 3%, P = .84, respectively).
Other Hematologic Variables
The rate of grade 2 anemia was higher in the G-CSF group (39%) than in the control group (26%; P = .005). Mean hemoglobin levels progressively decreased throughout the treatment compared with the initial values, which were 12.177 g/dL (standard deviation [SD] = 1.433 g/dL) in the G-CSF arms and 12.242 g/dL (SD = 0.988 g/dL) in the control arms (P = .70). The last mean hemoglobin values recorded (84 days after starting chemotherapy) were 10.547 g/dL (SD = 1.325 g/dL) and 10.960 g/dL (SD = 1.238 g/dL) for the G-CSF and control arms, respectively (P = .01). Five women were transfused with RBCs; two of these patients had been assigned to EC alone, two patients had been assigned to EC plus G-CSF, and one patient had been assigned to EC plus G-CSF (schedule 2) plus LND.
Thrombocytopenia was modest in both arms and in all five G-CSF groups. No statistically significant differences were found between the G-CSF and control arms in the incidences of grade 1 to 2 (11% and 7%, respectively; P = .12) and grade 3 to 4 thrombocytopenia (1% and 2%, respectively; P = .97).
Different Incidence in Nonhematologic Toxicity
The incidence of stomatitis (grade 1 to 3) per cycle was higher in the control arms (8%) than in the G-CSF arms (6%; P = .004). No difference in grade 1 to 3 stomatitis per cycle was observed between the qd schedules (schedules 1 and 3) and schedule 5 (7% v 9%, respectively; P = .39), whereas a higher incidence of stomatitis was seen with schedule 5 (9%) compared with the qod schedules (schedules 2 and 4, 4%; P = .03).
G-CSF–Related Toxicity
Filgrastim-related toxicity was mild and well controlled by nonsteroidal anti-inflammatory drugs. G-CSF administered as schedule 5 (G-CSF on days 8 and 12) was better tolerated (Table 3). The most frequently reported adverse events were skeletal pain, which occurred in 87 (46%) of 189 patients on schedules 1 through 4 and in 14 (29%) of 48 patients on schedule 5, and fever, which occurred in 35 (18%) of 189 women on schedules 1 through 4 and in four (8%) of 48 women on schedule 5. A statistically significant difference was observed between the qd schedules (schedules 1 and 3) and schedule 5 for grade 1 to 3 bone pain (53% v 29%, respectively; P = .01) and grade 1 to 2 fever (24% v 8%, respectively; P = .04). No differences were observed between the qod schedules (schedules 2 and 4) and schedule 5 for bone pain (40% v 29%, respectively; P = .28) and fever (13% v 8%, respectively; P = .55) Adverse events that led to withdrawal were reported in two patients in the EC plus G-CSF arm and in four patients in the EC plus G-CSF and LND arm (bone pain, grade 3).
Time Frame of Chemotherapy
The number of treatment cycles administered was 963 for the G-CSF arms and 961 for the control arms. The rate of delayed cycles was 4% in the G-CSF arms and 10% in the control arms (P < .0001), and the frequency of dose reduction was 1% and 4% in the G-CSF and control arms, respectively (P = .002). The EC dose-intensity was greater, although not significantly (P = .17), in the G-CSF arms than in the control arms (98% v 95% of the planned dose-intensity, respectively). With the addition of G-CSF, no advantage in 5-year DFS and OS was observed comparing the G-CSF arms and control arms. Results of the major outcomes have been reported in our previous article.24 Furthermore, no significant difference in terms of 5-year DFS was observed when comparing the qd schedules (schedules 1 and 3) with schedule 5 (67% v 77%, respectively; P = .25) or the qod schedules (schedules 2 and 4) with schedule 5 (64% v 77%, respectively; P = .18). These apparent differences of 10% and 13%, which some might consider to be clinically important, were not significant because, with a statistical power of 80%, we were able to detect only large differences in proportions and survival rates.
DISCUSSION
Several studies have demonstrated the possibility of achieving a modest to moderate increase in dose-intensity using CSFs as an adjunct to higher dose chemotherapy.27-36 Unfortunately, the number of randomized, multicenter, clinical trials in solid malignancies demonstrating a survival benefit for patients receiving higher dose therapy remains limited.8 It should be noted that, with respect to lymphomas, dose intensification may not be better.37,38 According to the most recent ASCO guidelines, there is no justification for the use of CSFs to increase chemotherapy dose-intensity outside of a clinical trial because conclusive trials showing an improvement in quality of life, DFS and OS, or toxicity are still lacking.8,9 However, some results provide evidence that a reduction in chemotherapy doses (below levels shown to improve the outcome in breast cancer patients) reduces the benefit of adjuvant therapy. In the study by Wood et al,39 postmenopausal women treated with higher doses of adjuvant chemotherapy had a significantly longer survival than women administered lower doses, but these data did not provide any evidence that an additional benefit would accrue from doses that are even higher than those used in this trial. On the basis of a dose-response relationship, several trials have demonstrated the importance of an adequate dose of epirubicin in metastatic and adjuvant settings. In women with metastatic breast cancer, epirubicin 120 mg/m2 via intravenous bolus administration every 3 weeks is the reference dose for the use of epirubicin as a single agent.40 In the adjuvant setting, because no randomized trial has yet compared fluorouracil plus EC with EC, we cannot assess whether EC for four cycles (epirubicin 120 mg/m2) is equivalent to fluorouracil plus EC for six cycles (epirubicin 100 mg/m2)4 or to EC for eight cycles (epirubicin 100 mg/m2).5 Thus, as yet, no conclusion can be drawn regarding the efficacy of an epirubicin dose of 120 mg/m2, even though the aforementioned studies confirm that escalating the dose to more than 90 mg/m2 might lead to an improved outcome. Furthermore, the results of a Canadian trial showed the superiority of cyclophosphamide plus EF (epirubicin 60 mg/m2 days 1 and 8) compared with CMF in terms of both DFS and OS in premenopausal women with axillary node–positive breast cancer.41
The ASCO Health Services Research Committee sought to assess patterns of use of CSFs by a 1994 survey42 before dissemination of its first-ever publication of ASCO guidelines.7 This survey found that 73% of physicians would use CSFs in conjunction with intravenous antimicrobial agents after the onset of fever and neutropenia, whereas 34% of the physicians would administer CSFs even to afebrile patients with neutropenia. Physicians at academic medical centers and in Health Maintenance Organization practices were more likely to prefer dose reduction over addition of CSFs, whereas fee-for-service physicians preferred the opposite strategy.42 Chemotherapy-induced neutropenia, with no growth factor support, is often associated with quality-of-life impairments that seem to persist after neutrophil recovery.43 FN is a common and sometimes fatal complication in patients with cancer who receive myelosuppressive chemotherapy and is accompanied by severe asthenia and stomatitis. The goal of therapeutic intervention with CSFs is to reduce the incidence of infectious episodes and infection-related morbidity and mortality. This improvement in supportive care could potentially enhance the patient's quality of life by reducing the incidence and duration of hospitalization and antibiotic use. Rivera et al44 demonstrated the possibility of identifying a subgroup of breast cancer patients at high risk of neutropenia who were being treated with adjuvant anthracycline/cyclophosphamide, CMF, or cyclophosphamide, doxorubicin, and fluorouracil; the fully planned dose was delivered on time, and the incidence of FN hospitalization was reduced by filgrastim support. However, the cost and toxicity of G-CSF therapy should be considered in each treatment decision. In the era of supportive care in cancer, physicians, to preserve an adequate quality of life for their patients, sometimes adapt their strategy to conflicting realities. Clinicians may occasionally be challenged by patients who might benefit from relatively myelosuppressive treatments but who have potential risk factors for FN or infections (elderly age, pre-existing neutropenia caused by disease, extensive prior chemotherapy, history of recurrent FN while receiving previous chemotherapy, poor performance status, decreased immune function, open wounds, and active tissue infections) or desire to lead a busy social life. In addition, clinicians may be faced with the consequent emotional distress related to chemotherapy delay. Thus, depending on the unique features of each clinical situation, there are instances in which G-CSF administration is appropriate outside of recommended uses.
In 1991, when this trial was started, one of the main goals was to evaluate whether increasing the dose-intensity of chemotherapy would be sufficient to improve its efficacy. The only way to study this was to prospectively analyze dose and timing of regimens administered with or without recombinant hematopoietic growth factor support. Unlike previous reports evaluating the impact of G-CSF on chemotherapy toxicities, this trial included five consecutive cohorts, who were evaluated in a large nonrandomized design, and explored both the doses and the schedules of filgrastim administered with prophylactic intent. The results reported herein reveal that relatively high-dose EC in the adjuvant setting is well tolerated and that the addition of G-CSF does not improve the 5-year DFS and OS. Filgrastim, regardless of the five tested schedules, significantly reduced the incidence of neutropenic fever (P = .0007) and stomatitis (P = .04), the need for antibiotics (P = .003), the number of delayed courses (P < .0001), and the number of cycles requiring dose reductions (P = .002). Unfortunately, at the time when the study began, quality-of-life assessment was not considered among the end points of the study. It is noteworthy that, as myelopoietic support to EC, no significant differences were found between the five different filgrastim schedules; the short schedule (filgrastim 300 μg/d on days 8 and 12) produced results similar compared with filgrastim 480 μg/d and 300 μg/d on days 8 through 14 in all the safety end points evaluated. However, the patients on the G-CSF arms complained of grade 1 to 3 bone pain and grade 1 to 2 fever. A significant reduction of G-CSF–related bone pain (P = .01) and fever (P = .04) was observed between the daily schedules (schedules 1 and 3) and schedule 5, even though no difference was registered between the qod schedules (schedules 2 and 4) and schedule 5. These findings are of particular interest because of the requirement of only two filgrastim injections per cycle of chemotherapy compared with seven injections per cycle. The goal of G-CSF should be to keep leukocyte values within the normal range without inducing leukocytosis. In our study, the short schedule, compared with the prolonged schedules, was able to achieve this goal, maintaining an ANC on day 14 (the nadir time as shown by the neutrophil curves in the non–G-CSF arms) within the normal range (1.8 to 7.5 x 109/L) and, thus, suggesting a more cost-effective prophylactic use of the drug. In this context, the use of filgrastim as daily administration necessitates a high degree of compliance, whereas two injections per cycle of cytokine would be of significant clinical value.
The package insert recommends that G-CSF be initiated no earlier than 24 hours after the administration of chemotherapy, that daily dosing with the drug be continued until the ANC has reached at least 10,000/μL after the neutrophil nadir, and that delaying the G-CSF administration until ANC nadir could result in minor efficacy.9 The reason for administering G-CSF from day 8 was based on the evidence that the onset of myelosuppression by anthracyclines usually takes place 7 days after administration, with maximum effect seen at approximately days 10 to 14.25 In 20 women with early-stage breast cancer receiving four courses of cyclophosphamide (600 mg/m2) and doxorubicin (60 mg/m2) chemotherapy, the mean time to neutrophil nadir was 14.8 ± 1.5 days.45 Moreover, between 24 and 48 hours from the G-CSF injection (5 to 10 μg/kg/d), there is a six-fold neutrophil increase, with reduction of neutrophil maturation time from 5 days to 1 day with a rapid elapse of neutrophils from the marrow into the circulation.26,46 Thus, in our opinion, it would not be convenient to start G-CSF 24 hours after completion of chemotherapy, and it would be sufficient to administer G-CSF 24 to 48 hours before the expected nadir.
It has been reported that G-CSF administered in a subcutaneous qod schedule did not significantly enhance neutrophil-related parameters, whereas G-CSF administered in a conventional qd schedule either alone or in combination with engineered interleukin-3 effectively enhanced neutrophil recovery in two similar models of radiation-induced myelosuppression.47-49 However, leridistim, which is a chimeric dual agonist that binds both G-CSF and interleukin-3 receptors, administered subcutaneously in an alternate-day schedule significantly enhanced neutrophil, platelet, and erythroid recovery, stimulating an early but transient recovery of CD3+CD8+ T lymphocytes in high-dose sublethally irradiated rhesus monkeys.50 In a nonhuman primate model, it has been demonstrated that the abbreviated qod subcutaneous leridistim schedule was as effective as the conventional qd or bid myelopoietin (SC-68420) schedules.51 Unfortunately, the exact mechanisms responsible for this phenomenon remain unknown.52-65 Filgrastim is freely filtered by the kidney, leading to rapid clearance of the molecule and a relatively short serum half-life of approximately 3 hours after subcutaneous dosing. Filgrastim is also cleared by neutrophils, presumably after the binding to cognate receptors on the cell surface. The mean blood neutrophil half-life of the circulating neutrophils (mean blood neutrophil half-disappearance time = approximately 10 hours) is not significantly changed with G-CSF use.26,46 These findings theoretically justify the necessity of daily G-CSF injections. However, it is common in clinical practice to administer drugs in a minimum number of injections for economic reasons, the patient's convenience, and ease of dosing. In our study, the patients treated with qod G-CSF schedules administered from days 8 through 14 (schedules 3 and 4) experienced a marked response to G-CSF, with elevated median ANCs that resembled ANCs obtained with qd schedules.
The results of our study clearly show that the rate of grade 2 anemia was higher in the G-CSF arms than in control arms (P = .005). The EC dose-intensity did not statistically differ between the G-CSF and control arms, although the rate of delayed cycles and the frequency of dose reduction were greater in the control arms than in the G-CSF arms. The higher incidence of grade 2 anemia in the G-CSF arms compared with the control arms implies that prolonged G-CSF treatment might cause erythroid suppression in the bone marrow, supporting the hypothesis that G-CSF administration would lead to a reduction of the stem-cell pool and be followed by a decline in erythropoietic progenitor numbers.66,67
We believe that our findings should be taken into account when designing a dose-dense chemotherapy study. The dose-dense schedule is accomplished by using G-CSF to permit a recycling of the drugs every 2 weeks, even though the use of G-CSF means added expense and may cause myalgias, arthralgias, the inconvenience of a certain number of injections per course, and leukocytosis. In node-positive early breast cancer patients, Citron et al68 have shown that dose-dense chemotherapy with filgrastim support significantly improves the clinical outcome and that severe neutropenia is less frequent in patients who receive the dose-dense regimens compared with conventional regimens (33% v 6%, respectively; P < .0001), even though patients on the dose-dense regimen had a higher need of RBC transfusions. Because the goal of using G-CSF in dose-dense schedules is recycling every 2 weeks without reaching leukocyte values much higher than normal, it is also plausible that four qod G-CSF injections would be sufficient to achieve this goal, as reported in our experience in advanced gastric cancer,69 with a cost reduction and fewer adverse effects. In fact, no statistically significant differences in G-CSF–related adverse effects were observed between the qod schedules (schedules 2 and 4) and schedule 5.
In clinical studies, filgrastim has been administered at different times (1 to 9 days or more) after initiating chemotherapy or at neutrophil nadir depending on the protocol, patient population, and expected outcomes, and filgrastim is most effective if initiated before neutropenia appears.70 As reported by several authors, optimal clinical benefits of filgrastim are achieved with approximately 11 daily injections of filgrastim.6,71 Guidelines on the use of CSFs, such as pegfilgrastim, recommend that they be used in the first chemotherapy cycle only with highly myelosuppressive regimens associated with a clinically significant incidence of FN (approximately 40%).9 Vogel et al72 recently evaluated the utility of using pegfilgrastim in a setting with a risk of developing FN in the range of 10% to 20%. Vogel et al72 reported that, in breast cancer patients randomly assigned to either placebo or pegfilgrastim on day 2 of each 21-day chemotherapy cycle of docetaxel 100 mg/m2, first and subsequent cycle use of pegfilgrastim significantly reduced FN, FN-related hospitalizations, and intravenous anti-infective use. In three recent trials73-75 comparing pegfilgrastim with filgrastim in high-risk, stage II or III/IV breast cancer patients treated with doxorubicin-docetaxel, patients randomly assigned to filgrastim received daily subcutaneous injections of filgrastim 5 μg/kg/d beginning on day 2 of each cycle and continuing until a documented ANC of 10 x 109/L after the expected nadir or for up to 14 days, whichever occurred first. In these studies, both pegfilgrastim and filgrastim showed similar ANC values through the nadir, and the duration of grade 4 neutropenia with pegfilgrastim was clinically and statistically similar to that observed after a mean of 11 daily injections of filgrastim. In the study by Holmes et al,73 filgrastim patients, who could continue to receive this drug through day 14, exhibited a consistent overshoot during the ANC recovery (approximately 30 x 109/L), whereas pegfilgrastim patients displayed a plateau profile, with limited overshoot of neutrophils (approximately 7 x 109/L) after the nadir. In our trial, using prophylactic filgrastim at nonconventional timing for a maximum of 7 consecutive days, we observed that the mean peak of ANCs exceeded approximately 5x the upper normal limit, which indicated that, as prophylaxis, the conventional administration of filgrastim and, as a consequence, the use of pegfilgrastim would probably be not necessary during EC or moderately intensive chemotherapy.
The results of this portion (which could be viewed as a phase II trial) of our original study24 comparing different G-CSF schedules suggest that, during relatively high-dose adjuvant EC, the daily filgrastim schedule can be shortened using only two filgrastim injections (on day 8 before the expected neutrophil nadir time and on day 12 during neutrophil nadir time) without any change in toxicity (chemotherapy-induced grade 3 to 4 neutropenia, neutropenic fever, need of antibiotics, and cycle delays) but with a substantial savings in pharmaceutical costs in the range of 70% compared with daily filgrastim and a significant reduction in the G-CSF–related toxicity. As a consequence, the use of a short schedule of filgrastim as four qod injections during moderately intensive chemotherapy (ie, dose-dense schedules every 14 days, cisplatin-etoposide-bleomycin, cisplatin-epirubicin-folinic acid-fluorouracil, cisplatin-etoposide, paclitaxel-ifosfamide-cisplatin, and epirubicin-ifosfamide)76-80 for responsive malignancies would provide lower financial costs to patients and caregivers, given this schedule's comparable efficacy to daily injections of filgrastim. However, because we did not compare the results with a more conventional G-CSF schedule in our trial, it is not possible to draw definitive conclusions between the qd schedules (schedules 1 and 3) and the other schedules (schedules 2, 4, and 5). Nevertheless, the low rates of grade 3 to 4 neutropenia, fever, FN, antibiotics use, and number of cycles requiring dose reductions certainly confirm that the qod schedules (schedules 2 and 4) and the short schedule were active.
Despite the small sample size of our schedules (only 50 women received the twice-per-cycle schedule), the potential cost savings of a shortened G-CSF administration is a strong justification for conducting a formal phase III trial comparing conventional G-CSF dosing with G-CSF dosing on days 8 and 12 to assess when and how much G-CSF use can improve the quality of life of these patients compared with patients who do not receive G-CSF. Clinical prediction models clearly represent tools for improving patient selection for G-CSF treatment and targeting filgrastim use at high-risk patients,81 but they are based on saving costs rather than on obtaining clinical benefit. The administration of two doses of prophylactic filgrastim on days 8 and 12 during moderately intensive chemotherapy, based on accurate comparisons between standard and novel schedules, could lead to a more cost-effective use of hematopoietic growth factors.
Appendix
The following persons contributed to the study: Federico Calabresi had the original idea; Paola Papaldo, MD, Massimo Lopez, MD, and Paolo Marolla, MD, designed and coordinated the study; Gianluigi Ferretti, MD, and Serena Di Cosimo, MD, prepared the first draft of the report, to which Paola Papaldo, MD, subsequently contributed; Diana Giannarelli, PhD, was responsible for the database and the statistical analysis and managed the data; all other authors took care of the patients enrolled onto this study.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank the nurse staff of the Department of Medical Oncology for their technical support and the Italian women who took part in this study.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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