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Haemopoietic Growth Factors

The role of granulocyte colony-stimulating factor (G-CSF) in the post-transplant period

Abstract

The administration of G-CSF post transplant has been shown to accelerate the time to neutrophil engraftment. However, this does not necessarily translate into a meaningful clinical benefit to the patient. This randomized study was designed to determine the role of G-CSF following transplantation in patients with breast cancer (BC). A total of 241 evaluable patients with BC were included. There were 200 patients with high-risk BC, and 41 had disseminated BC in complete remission. All patients received conventional dose chemotherapy prior to transplantation. Patients were mobilized with G-CSF, received the STAMP V regimen, were transplanted with 2.5 × 106 of CD34+ cells/kg and were then randomized to receive 5 μg/kg of G-CSF starting on the day of infusion (arm A), five days later (arm B), or no G-CSF (arm C). The need for transfusion support, infectious complications and length of hospitalization were the variables chosen to demonstrate clinical benefit. Patients receiving G-CSF reached 500 and 1000 neutrophils significantly faster (P = 0.001) than patients with no G-CSF. This translated into a significantly (P < 0.05) shorter hospitalization time for patients receiving G-CSF. Arm C was closed and, after recruiting 110 patients in arm A, and 106 in arm B, the significant difference in neutrophil recovery persisted with no difference in the time of hospitalization between arms A and B. Therefore, G-CSF significantly accelerates the time to neutrophil engraftment. This translates into a shorter time of hospitalization. There is no difference in this variable regarding the time of administering the G-CSF: day 0 vs day +5. Therefore, G-CSF on day +5 should be the standard in this setting.

Transplantation with previously mobilized peripheral blood stem cells (PBSC) has resulted in a faster time to hematological recovery following administration of high-dose chemotherapy, compared to bone marrow transplantation.1,2 In addition, engraftment appears to be complete, and sustained.3 This advantage has resulted in fewer complications derived from the profound aplasia that follows administration of intensive chemotherapy, making the procedure itself safer and less costly than bone marrow transplantation.4,5,6 In fact, these advantages have facilitated the development of multiple studies in solid tumors in general, and in breast cancer in particular, designed to test the hypothesis that the resistance to conventional doses of chemotherapy is overcome by administering very high doses of chemotherapy.7

Granulocyte colony-stimulating factor (G-CSF), has been shown to significantly shorten the duration of febrile neutropenia that follows the administration of chemotherapy.8 Treatment with G-CSF after autologous transplantation with both bone marrow9,10 and PBSC11,12,13 has been shown in some studies to further accelerate the time to neutrophil recovery. However, it is unclear if this reduction of a few days of the absolute neutropenic period necessarily translates into a clinical benefit.14,15,16

When G-CSF is employed following transplantation, it is usually started the same day or the day following infusion. However, the same effect in neutrophil recovery can be expected by commencing the G-CSF a few days after transplantation,17,18 and this issue, with important economical indications, has not being sufficiently investigated.

In order to address these questions we performed a prospective, multicenter, randomized study in patients with breast cancer undergoing high-dose chemotherapy treatment and autologous transplantation with G-CSF mobilized PBSC. The trial was designed as a three-arm study in which patients were randomized to receive G-CSF on the day of transplantation (day 0), or day +5 following transplantation, or no G-CSF.

Materials and methods

Patient characteristics and treatments

Two hundred and forty-six patients with breast cancer were included in the study. The treatment program was approved by each hospital review committee. Patients gave written informed consent. All patients were 18 years and 60 years old, and had histologically proven infiltrating breast cancer. All patients were participating in a national program studying the role of high-dose chemotherapy in solid tumors (SOLTI group).

One hundred and thirty-nine evaluable patients were included in the protocol SOLTI 9301. These patients had >9 metastatic axillary lymph nodes at the time of initial surgery. The patients started adjuvant conventional dose chemotherapy, with the FEC regimen within 6 weeks of surgery. In mg/m2: 5-fluorouracil: 600; 4-epirubicin: 75, and cyclophosphamide: 600. Courses were administered every 21 days for a total of six cycles.

Patients with inflammatory breast cancer, and those with locally advanced breast cancer (stages, IIIA and IIIB, non-inflammatory, and inflammatory breast cancer), or patients with stage II treated with preoperative chemotherapy, that at the time of surgery were found to have >3 involved axillary lymph nodes, were registered in the SOLTI 9302. Sixty-one evaluable patients were included and received between four and six courses of neoadjuvant chemotherapy with the same FEC regimen, followed by surgery. All patients completed a total of six FEC chemotherapy courses.

Forty-one evaluable patients with disseminated breast cancer in complete response entered the SOLTI 9303 protocol. Of these patients, 28 achieved a complete response after six cycles of an anthracycline-containing regimen, and six with chemotherapy other than FEC. Seven patients with a single metastatic site, surgically removed, were also included. These patients classified as stage IV, with no evidence of disease (stage IV NED), received only three cycles of FEC chemotherapy prior to high-dose chemotherapy.

Mobilization and apheresis

Mobilization was started >4 weeks after completion of the last course of chemotherapy. G-CSF (Amgen, Thousand Oaks, CA, USA), in a single, subcutaneous daily dose of 10 μg/kg, was used for mobilization.

Aphereses were started on day 5 of mobilization and continued until a minimum of 2.5 × 106 CD34+ cells/kg was obtained. The number of CFU × 104kg was determined by various participating institutions but was not mandatory. The total blood volume was processed at least 2.5 times with a continuous flow blood cell separator.

If after four consecutive apheresis procedures the minimum of CD34+ cells/kg was not reached, patients were re-mobilized with 4000 mg/m2 i.v. of cyclophosphamide, plus G-CSF 10 μg/kg/day, subcutaneously. Aphereses were started when more than 3000 leukocytes were present in the peripheral blood following the chemotherapy-induced aplasia.

If with this second mobilization procedure the patient did not reach the minimum required, bone marrow was obtained and the patient was transplanted with the marrow and the PBSC.

High-dose chemotherapy and randomization

Patients were admitted to the hospital and, after venous hydration, received high-dose chemotherapy with the STAMP V regimen: cyclophosphamide: 6000 mg/m2; carboplatin: 800 mg/m2, and thiotepa: 500 mg/m2, days −7 to −4, administered as a continuous i.v. infusion. Transplantation was on day 0.19

Patients were randomized to receive G-CSF starting on the day of transplantation: day 0 (arm A); or day +5, following transplantation (arm B), or no G-CSF (arm C). G-CSF was administered at the dose of 5 μg/kg/day subcutaneously, until a total of 1000 neutrophils/μl were present in the peripheral blood.

Variables analyzed, transfusions requirements, management of fever and neutropenia, variables with clinical benefit

The variables included in the analysis were: age, weight, and the total numbers of CD34+ cells × 106/kg. The hematological recovery parameters analyzed were: days to reach 500, and 1000 neutrophils; day of 20 000 and of 50 000 platelets, independent of transfusion; number of platelet transfusions and day of the last platelet transfusion; number of packed red blood cells transfused.

Patients were transfused with either random, or single donor platelet transfusions to maintain a platelet count over 15 000–20 000/μl. Packed red blood cells were transfused in order to maintain a hemoglobin level 8g/dl. All blood products were irradiated.

Regarding the transfusion requirements, both the number of platelet and packed red blood cell transfusions were considered in association with a clinical benefit.

The difference in time to reach 500 and 1000 neutrophils following transplantation was analyzed but did not consider variables with clinical benefit per se. The purpose of the study, beyond any numerical difference, was to establish if the effect of use of G-CSF following transplantation of PBSC was clinically significant. The number of days with fever and neutropenia of less than 500, total number of days with fever, number of days with broad spectrum i.v. antibiotics, number of positive blood cultures and use of amphotericin B were all considered parameters with significant clinical benefit. The number of days from transplantation to hospital discharge was also analyzed as a variable with strong clinical benefit.

Blood counts were monitored daily while in the hospital. Once the patient was discharged blood counts were performed as needed, according to the physician responsible. Therefore the exact day of a platelet count of 50 000/μl is not accurate.

The treatment of fever with neutropenia was managed following the criteria of each participating institution. The study protocol did not include specific guidelines for prophylactic oral antibiotic use or a particular combination of empiric broad-spectrum antibiotics. The initiation of amphotericin B was based on clinical grounds and microbiological information. The day of discharge was not strictly predefined. In general, patients were discharged when more than 1000 neutrophils were present in the peripheral blood, had no fever and were capable of ensuring an adequate oral intake of fluids and alimentation.

Eight variables were considered to have clinical benefit: number of platelet transfusions, number of packed red cell transfusions, number of days with fever, number of days with fever and lesss than 500 neutrophils, number of days with broad-spectrum antibiotics, number of positive blood cultures, use of amphotericin B and day from infusion to hospital discharge.

Study design and sample size

The sample size was not predetermined. There were eight different variables chosen that were considered to reflect a clinical benefit. After randomizing 80 patients (29 in arm A, 31 in arm B, and 20 in arm C) a statistically significant difference in favor of the arms with G-CSF (A and B) was demonstrated in two of the variables defined as having clinical benefit: length of hospitalization and number of days with <500 neutrophils and fever and arm C, with no G-CSF, was closed. Considering that a reduction of 2 days hospitalization (15% reduction in the duration of hospitalization) will be an important significant difference, we estimated that an additional 80 patients in each arm (A and B) should be included to detect this difference, with an α value of 0.05 and a statistical power of 80% (β = 0.2).

Statistical analysis

In order to compare variables, different statistical techniques were employed depending upon whether they were parametric or non-parametric variables. The variables with a normal distribution and with a homogeneous variance (parametric) were compared with the Student's t-test and variance analysis. If the variables had an non-normal distribution or their variances were not homogeneous, non-parametric techniques were employed like Mann–Whitney's U test, or the Kruskal–Wallis test.

To compare the frequency of different variables, the chi-square, with the Yates correction was employed or the Fisher's exact probability test if the expected frequencies were small.

The P value is given with the standard deviation expressed as a +/− value.

Results

A total of 246 patients were enrolled in the study. They were all females with infiltrating breast cancer. Of these patients, five were excluded from the analysis. One, because of refusal to accept arm C (no G-CSF) following randomization. Another patient randomized to arm C was started with G-CSF in the presence of persistent fever and neutropenia. The remaining three patients did not receive the treatment to which they were allocated due to different protocol violations. The total number of evaluable patients was 241. Median age for the entire group was 44.4 years. Patient characteristics and treatment prior to mobilization are shown in Table 1.

Table 1 Patient characteristics and chemotherapy treatment prior to mobilization

The number of peripheral blood stem cells (PBSC) infused, determined by the total number of CD34+ cells, age and weight of the patients per arm is shown in Table 2. The distribution of patients from each of the treatment protocols (SOLTI: 9301, 9302 and 9303), is also shown in Table 2.

Table 2 Distribution and characteristics of patients in each arm

There were no significant statistical differences in any of these parameters. Specifically, the median number of CD34+ cells is similar in each arm.

An interim analysis was performed when a total of 80 patients were included. Significant results are shown in Table 3. There were 29 patients in arm A (G-CSF day 0), 31 patients randomized to arm B (G-CSF, day +5), and 20 patients in arm C (no G-CSF). At that time there was a significant statistical difference (P < 0.001) in the days to reach 500 and 1000 neutrophils. For arm A the mean was 9.9 ± 1.1, 10.6 ± 6.6, in arm B, and 12.6 ± 1.9 for arm C, for 500 neutrophils. Mean days to reach 1000 neutrophils were 9.9 ± 1.2, 11.4 ± 6.6 and 15.3 ± 4.6 (P < 0.001), respectively. No difference was detected in the time to platelet engraftment. The mean numbers of platelet transfusions and packed red cell transfusions were similar in each arm.

Table 3 Variables with statistical difference

There were differences in two variables considered to have clinical benefit. There was a significant statistical difference in the number of days with fever and neutropenia of less than 500 neutrophils between arms A and C: median of 1.5 vs 3.4 days (P < 0.05). No statistically significant differences were observed between arms A, B and C in antibiotic usage (P = 0.15), blood culture positivity (P = 0.63) or amphotericin usage (P = 0.18).

The variable day of discharge following infusion, showed statistically significant differences in favor of G-CSF. There was no difference between arms A and B (both with G-CSF), but there was a mean of 14.7 ± 8.1 days in arm B, compared to 15.4 ± 3.4 in arm C; P < 0.05) and of 13.3 ± 3.3 days in arm A vs 15.4 ± 3.4 in arm C (P < 0.05).20

When these results became available, arm C was closed. We estimated that in order to detect a 2 day difference in the number of days from transplantation to discharge from the hospital, considering this variable the one with an important clinical benefit difference, an additional 80 patients should be included in each arm with G-CSF (A and B).

After including a total of 82 patients in arm A (total 110), 81 in arm B (total 116), and five additional patients in arm C (total 25) that were included while the analysis was being performed, the difference in time to neutrophil recovery persisted. The mean time to reach 500 neutrophils was significantly faster for patients starting G-CSF on day 0: 9.33 ± 0.96, than for patients randomized to receive G-CSF on day +5: 10.25 ± 0.89; P < 0.001. The mean day of 1000 neutrophils was 9.87 ± 1.01, and 10.67 ± 1.77; P < 0.001, for patients randomized to arms A and B, respectively (Table 4) and (Figure 1).

Table 4 Neutrophil recovery, infectious parameters and time to discharge
Figure 1
figure1

Days to engraftment following transplant according to the use of G-CSF (day 0 or day +5) or no G-CSF.

No difference was detected in other variables. Specifically, there was no statistical difference in the number of days with fever and neutropenia of less than 500 neutrophils, number of days with fever, use of amphotericin B or number of positive blood cultures (Table 5).

Table 5 Transfusion requirements and platelet engraftment

Regarding the time to discharge, there was no statistically significant difference between arms A (G-CSF day 0) and B (G-CSF day +5); P = 0.4. (Table 4).

It was considered that arm B should be the standard, since the difference in the time to discharge persisted, but there was not a significant difference for G-CSF on day 0, and there is a 5 day reduction in the use of G-CSF in this arm.

Two patients died during transplantation (mortality rate of 0.82%). One was randomized to arm A and the other to arm B.

Discussion

Autologous transplantation with PBSC following myeloablative doses of chemotherapy accelerates the time to hematological recovery compared to autologous bone marrow transplantation.1,2 Specifically, the rate of platelet recovery is improved by transplanting with PBSC.21 A faster time to hematopoietic reconstitution determines a safer and less costly procedure compared to bone marrow transplantation.3,4,5 In fact, in the last few years the number of autologous transplants with PBSC compared to bone marrow in breast cancer have increased significantly from 19% to 90% (P < 0.00001). In addition, the mortality rate has dropped from 22% to 5% (P < 0.00001),22 and the initial doubts regarding durable long-term engraftment with PBSC are no longer a concern.3,23

It is clear therefore that a short time to hematological recovery is associated with less morbidity and mortality and in this regard the PBSC are at the present time the preferred source of hematopoietic precursors to restore marrow function after administering high doses of chemotherapy. However, there is threshold of around 7 to 8 days to reach 500 neutrophils, and an unsupported platelet count of >20 000 × 109/l, that is independent of the number of progenitors infused above the minimum.11

G-CSF has been shown to accelerate neutrophil engraftment following bone marrow transplantation,9,10,24 and neutrophil recovery is further accelerated after PBSC transplantation.11,12,13,14 However, as happens in different settings, the fact that the neutrophil recovery is shortened after administration of conventional doses of chemotherapy does not necessarily translate into a clinical benefit.25

Some of the randomized studies performed to address the issue of the role of hematopoietic growth factors (G and GM-CSF) in the transplantation setting have shown that the faster time to neutrophil recovery correlates with a shorter hospitalization time,11,12,13,24,26,27,28 and fewer infectious complications or less antibiotic use.24,26,28 However, others have demonstrated only a modest clinical benefit14 and yet other studies have found no clinical benefit of administering growth factors following transplantation.15,16,29,30 Furthermore, one of them did not even find a faster time to neutrophil recovery.16 However, the vast majority of these trials was performed in patients with lymphoproliferative malignancies, with a significant heterogeneity regarding amount of prior therapies and number of CD34+ cells infused.13,15,24,27,28,29,30 In other studies there was a marked patient population heterogeneity including lymphoma and solid tumors.11,12,14,26 In our study, by contrast, there is large number of patients, all of them with breast cancer. The majority (92%), received six cycles of conventional dose FEC chemotherapy, prior to mobilization and transplant, and all of them were mobilized with 10 μg/kg of G-CSF.

In the present study the administration of G-CSF was followed by a shorter time to reach 500 and 1000 neutrophils, compared to no G-CSF (Table 3). Regarding day 0 vs day +5 administration of G-CSF, there is a significant reduction in neutrophils when G-CSF is given from day 0. This advantage does translate into clinical benefit in terms of days of hospitalization (from transplantation to discharge) when comparison is made between G-CSF administration, either day 0, or day +5, vs no G-CSF (Table 3).

Regarding this variable with a strong clinical benefit impact there were no strict predefined criteria for discharging patients. Platelet transfusion dependence was not necessarily a reason for retaining the patient in hospital. On the other hand, there is a number of non-medical reasons to keep a patient in hospital, due to social, psychological or economical situations. Patients were discharged in general, when they had more than 1000 neutrophils and had no fever, also when they were capable of oral intake of fluids and alimentation. In a recent European survey that included information from 200 centers treating breast cancer with high-dose chemotherapy, there were up to 40 different sets of criteria for discharging patients.31 In most of them, hematopoietic recovery, absence of fever and adequate nutritional and ambulatory status were requirements for discharge. Some of the centers responded that discharge was a ‘clinical decision’, or that discharge was done with ‘clinical recovery’.

The fact that in a multicenter trial, like the present one with a very homogeneous patient population, hospitalization was shortened by the administration of G-CSF following transplantation is in accordance with similar results found in lymphoma patients in a more heterogeneous situation regarding previous treatment and source and quantity of hematopoietic precursors.13,15,24,27,28,29 Shortening of hospitalization has the greatest impact in terms not only of clinical benefit, but also in financial terms, in this very expensive treatment strategy. Therefore arm C, with no G-CSF, was closed when the an interim analysis showed this advantage.

The number of days with fever and profound neutropenia (less than 500 neutrophils) showed a significant difference (P < 0.05) between arms A and C, but no difference between the arms including G-CSF. This difference, however, was not maintained when the study continued including a larger number of patients.

The shortening of hospitalization was maintained after including a total of 116 patients in arm A and 110 in arm B. There was a statistically significant difference between arms with G-CSF vs arm C (no G-CSF). However, there was no difference between arm A and arm B: 13.5 ± 4.3 vs 13.9 ± 5.4; P = 0.4. (Table 4). It can be assumed that the faster time to neutrophil engraftment favored by G-CSF translated into an earlier discharge from the hospital of about 2 days (Table 3). Therefore, since there is less hematopoietic growth factor administration in arm B, this was chosen as the standard.

No difference was detected in variables like antibiotic usage, number of positive blood cultures and use of amphotericin B (Table 4). Despite the fact that these support measures were not protocolized, and that each participating institution followed their own policies, the rather small differences in days of profound neutropenia between the arms were probably not of sufficient magnitude to detect significant differences in these variables.

Not surprisingly, no differences were observed regarding transfusional support (Table 5). The number of packed red cell transfusions, the day of the last platelet transfusion, the number of platelet transfusions, the day to reach platelet transfusion independence and the day of an unsupported platelet count of 50 000 were all variables not affected by the administration of G-CSF. None of the studies discussed above11,12,13,14,15,24,27,28,29,30 have shown any significant difference between the use of G, or GM-CSF and the engraftment kinetics of platelets and red blood cells.

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Acknowledgements

We acknowledge the statistical assistance of JJ Sánchez and JF Casanovas from the Department of Biostatistics, Autonomous University of Madrid, School of Medicine and A Sanchez from ASD, SL, data manager of the SOLTI group.

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Correspondence to J Hornedo.

Appendix: Investigators and institutions of the SOLTI Group who participated in this study:

Appendix: Investigators and institutions of the SOLTI Group who participated in this study:

JR Germá, MD and A Montes MD

Instituto Catalán de Oncologia, Barcelona, Spain

JM Baselga, MD and R Vera, MD

Hospital General Vall D'Hebrón, Barcelona, Spain

V Guillem, MD and MA Climent, MD

Instituto Valenciano de Oncologa, Valencia, Spain

M Benavides, MD and M Cobo, MD

Hospital Carlos Haya, Málaga, Spain

JM Piera, MD and I Alvarez, MD

Hospital Na Sra. de Aránzazu, San Sebastian, Spain

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Hornedo, J., Solá, C., Solano, C. et al. The role of granulocyte colony-stimulating factor (G-CSF) in the post-transplant period. Bone Marrow Transplant 29, 737–743 (2002). https://doi.org/10.1038/sj.bmt.1703539

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Keywords

  • breast cancer
  • duration of hospitalization
  • granulocyte colony-stimulating factor (G-CSF)
  • high-dose chemotherapy
  • neutrophil engraftment
  • peripheral blood stem cell (PBSC) transplantation

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