Various G-CSF Regimens to Prevent Infection During Chemotherapy

This study has been terminated.
(More cases of Febrile Neutropenia were observed in experimental group compared to standard treatment.)
Sponsor:
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by:
Academisch Ziekenhuis Maastricht
ClinicalTrials.gov Identifier:
NCT00536081
First received: September 25, 2007
Last updated: December 22, 2009
Last verified: December 2009
  Purpose

The purpose of this study is to prevent chemotherapy-related febrile neutropenia, prophylaxis with antibiotics and granulocyte colony-stimulating factor (G-CSF) have proven efficacious [1-3]. G-CSF has only few side effects, but is expensive. In 2006, updated G-CSF guidelines conclude that primary G-CSF prophylaxis has clinical benefits for and should be offered to patients at a more than 20% risk of febrile neutropenia.

Based on many positive and few negative trials, one can consider the use of taxanes as standard of care in the adjuvant setting in node-positive breast cancer. Taxanes (with or without anthracyclines) have an increased risk for febrile neutropenia.

The updated guidelines and changes in daily clinical practice will have a significant impact on the investigators health care resources. There is a higher risk of febrile neutropenia for the first chemotherapy cycle compared to subsequent cycles in small cell lung cancer patients. Also in advanced breast cancer the majority of first observed episodes of febrile neutropenia occur in the initial chemotherapy cycles Irrespective of tumour type or chemotherapy regimen, the risk of febrile neutropenia is highest during the first two cycles of chemotherapy. Thereafter, the risk rapidly declines, and the benefit of G-CSF largely seems to disappear.

So, in order to improve the cost-effective administration of primary G-CSF prophylaxis, it is justified to assess whether G-CSF prophylaxis can be limited to the first two chemotherapy cycles as compared to the current practice of continuous G-CSF prophylaxis.


Condition Intervention Phase
Breast Cancer
Chemotherapy
Febrile Neutropenia
Drug: pegfilgrastim
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Primary G-CSF Prophylaxis During the First Two Cycles Only or Throughout All Chemotherapy Cycles in Breast Cancer Patients at Risk of Febrile Neutropenia

Resource links provided by NLM:


Further study details as provided by Academisch Ziekenhuis Maastricht:

Primary Outcome Measures:
  • number of febrile neutropenia episodes costs per treatment arm [ Time Frame: 18 weeks (all chemotherapy cycles) ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Febrile neutropenia rates per cycle number. Other haematological and non-haematological toxicities. Number of chemotherapy cycles delivered. Dose and dose-intensity of chemotherapy. Disease progression. Number of toxic deaths per treatment arm. [ Time Frame: 18 weeks (all chemotherapy cycles) ] [ Designated as safety issue: Yes ]

Enrollment: 172
Study Start Date: January 2008
Estimated Study Completion Date: December 2010
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: A
Pegfilgrastim during all 6 cycles of chemotherapy
Drug: pegfilgrastim
6 mg s.c. 24-36 h post-chemotherapy
Other Name: Pegfilgrastim
Experimental: B
Pegfilgrastim during the first two cycles of chemotherapy
Drug: pegfilgrastim
6 mg s.c. 24-36 h post-chemotherapy
Other Name: Pegfilgrastim

  Hide Detailed Description

Detailed Description:

1. Febrile neutropenia Febrile neutropenia is a serious side effect of cancer treatment. Febrile neutropenia predisposes to serious and sometimes life-threatening infections. Given the seriousness, the majority of febrile neutropenia patients are admitted to hospital for treatment with intravenous antibiotics. Thus, chemotherapy-induced febrile neutropenia can result in death, increased hospitalisations and intravenous antibiotic use. In addition, it can lead to significant chemotherapy dose modifications, which may theoretically be of concern for treatments with curative intent. Clearly, prevention of chemotherapy-induced febrile neutropenia is a medical priority.

2 Prophylaxis of febrile neutropenia To prevent chemotherapy-related febrile neutropenia, prophylaxis with antibiotics and granulocyte colony-stimulating factor (G-CSF) have proven efficacious [1-3]. The use of the G-CSF was shown to shorten the duration of neutropenia, resulting in reduction of the incidence of febrile neutropenia, hospitalisation and use of intravenous therapeutic antibiotics by approximately 50%. .Antibiotics may, however, lead to emergence of microbial resistance. G-CSF has only few side effects, but is expensive. Previous guidelines recommended primary G-CSF prophylaxis to prevent febrile neutropenia, but only for patients at substantial risk of febrile neutropenia (more than 40%). In 2006, updated G-CSF guidelines conclude that primary G-CSF prophylaxis has clinical benefits for and should be offered to patients at a more than 20% risk of febrile neutropenia.

Most of the recent EORTC-reviewed evidence indicate that primary and secondary G-CSF prophylaxis had no significant impact on survival, despite the fact that G-CSF prophylaxis enabled to maintain chemotherapy dose and dose intensity. In the GEICAM 9805 study, primary G-CSF support did not lead to improved median dose intensity or cumulative dose when compared to secondary G-CSF prophylaxis, although the percentage of patients who completed six cycles of therapy increased significantly.

3. Developments in the adjuvant treatment of breast cancer After the introduction of taxanes in the treatment of advanced breast cancer in the late nineties, these agents have now also been introduced in the (neo) adjuvant setting. Many adjuvant trials with a positive outcome have recently been reported.

Based on the available data with many positive and few negative trials, one can consider the use of taxanes as standard of care in the adjuvant setting in node-positive breast cancer, although the preferred schedule, concurrent or sequential, with or without dose-densification, needs to be clarified from ongoing trials.

Martin et al. report on the results of a randomized adjuvant trial comparing TAC with FAC for high-risk N0 breast cancer patients, the GEICAM 9805 trial. Comparisons are reported for toxicity and quality of life. Only secondary G-CSF prophylaxis was allowed or even mandatory after an episode of febrile neutropenia. After a protocol amendment, patients in the TAC arm received primary G-CSF prophylaxis. So, in addition to the upfront planned comparison of TAC versus FAC, the unplanned comparison of TAC-pre versus TAC-post amendment is reported. This comparison is very interesting, as it is to our knowledge the first comparison of primary versus secondary G-CSF prophylaxis ever reported. The use of primary G-CSF prophylaxis significantly reduced the incidence of febrile neutropenia associated with TAC chemotherapy. The percentage of patients with febrile neutropenia in one or more cycles was 24.6% and 6.5% in TAC-pre and TAC-post, respectively. Of note, in the TAC-pre group 71.1% of patients had received secondary G-CSF prophylaxis during on average 4 cycles of treatment. In the FAC group, only 2.3% of patients had febrile neutropenia as per protocol definition.

So, the combined use of anthracyclines and taxanes come with considerable increased risk of febrile neutropenia. Perez concluded in an editorial in the New England Journal of Medicine that on the basis of the available data, one can consider TAC (docetaxel, adriamycin, cyclophosphamide) to be a standard of care, as is the dose-dense regimen of doxorubicin and cyclophosphamide followed by paclitaxel, for patients with node-positive breast cancer. With this regimen, prophylactic growth-factor support is necessary to ameliorate myelosuppression and febrile neutropenia.

4. Consequences for health care costs We have recently reported that, even for patients with a considerable risk of febrile neutropenia, primary G-CSF prophylaxis comes with considerable extra costs in the Netherlands: on average € 5,123 per patient who have a baseline risk of febrile neutropenia of 32%. The updated guidelines and changes in daily clinical practice will have a significant impact on our health care resources. In the Netherlands several thousands of patients with many tumour types will require primary G-CSF prophylaxis, leading to an cost increase of at least € 10-20 million per year.

5. Rationale for the present study It has been demonstrated that there is a higher risk of febrile neutropenia for the first chemotherapy cycle compared to subsequent cycles in small cell lung cancer patients. Also in advanced breast cancer the majority of first observed episodes of febrile neutropenia occur in the initial chemotherapy cycles. With primary G-CSF prophylaxis the absolute neutrophil count nadir is less deep and of shorter duration in later cycles compared to the first cycle. This may suggests that there may be a priming effect of G-CSF to subsequent cycles, emphasizing that administration of G-CSF early in the course of treatment might be important.

So, irrespective of tumour type or chemotherapy regimen, the risk of febrile neutropenia is highest during the first two cycles of chemotherapy. Thereafter, the risk rapidly declines, and the benefit of G-CSF largely seems to disappear.

So, in order to improve the cost-effective administration of primary G-CSF prophylaxis, it is justified to assess whether G-CSF prophylaxis can be limited to the first two chemotherapy cycles as compared to the current practice of continuous G-CSF prophylaxis.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Breast cancer patients ≥18 years.
  • Indication for 3-weekly chemotherapy.
  • Considered fit enough to receive chemotherapy, with adequate renal and hepatic function.
  • Planned a chemotherapy regime in adjuvant, neo-adjuvant, advanced setting with an increased risk of febrile neutropenia, i.e.:
  • Regimes with >20% risk of febrile neutropenia:

    • e.g. TAC (docetaxel, adriamycin, cyclophosphamide)
    • AT (adriamycin, docetaxel)
  • Regimes with 10-20% risk of febrile neutropenia (e.g. AC, doxorubicin and vinorelbine, or docetaxel monotherapy) in the presence of ≥1 patient risk factor (>65 yrs, extensive bone marrow involvement or prior extensive radiotherapy on bone tissue
  • Prior chemotherapy
  • ECOG performance status of 2 or more, grade 2 or higher liver function abnormalities).
  • That is, patients starting with docetaxel as second part of FEC-D are eligible for the last 3 docetaxel cycles, if there is an increased risk of febrile neutropenia, e.g. by elderly age.
  • Able to comply with the protocol.
  • Written informed consent obtained prior to any study specific screening.

Exclusion Criteria:

  • Active uncontrolled infection.
  • Inadequate renal or hepatic function.
  • Any evidence or history of hypersensitivity or other contraindications to G-CSF medication.
  • Not recovered from acute toxicities of prior therapies.
  • Absolute neutrophil count (ANC) <1.5 x 109/l, not caused by bone marrow involvement.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00536081

Locations
Netherlands
Ziekenhuis Rijnstate, Alysis
Arnhem, Netherlands
Wilhelmina Ziekenhuis
Assen, Netherlands
Jeroen Bosch Ziekenhuis
Den Bosch, Netherlands
Slingeland Ziekenhuis
Doetinchem, Netherlands
Catharina Ziekenhuis
Eindhoven, Netherlands
Maxima Medisch Centrum
Eindhoven, Netherlands
Groene Hart Ziekenhuis
Gouda, Netherlands
Martini Ziekenhuis
Groningen, Netherlands
Ziekenhuis St. Jansdal
Harderwijk, Netherlands
Elkerliek Ziekenhuis
Helmond, Netherlands
Diaconessenhuis Leiden
Leiden, Netherlands
Leids Universitair Medisch Centrum
Leiden, Netherlands
University Hospital Maastricht
Maastricht, Netherlands, 6202 AZ
Canisius Wilhelmina Ziekenhuis
Nijmegen, Netherlands
UMC St. Radboud
Nijmegen, Netherlands
Maasstad Ziekenhuis
Rotterdam, Netherlands
Erasmus MC - Daniel den Hoed
Rotterdam, Netherlands
Orbis Medisch Centrum
Sittard, Netherlands
Mesos Medisch Centrum
Utrecht, Netherlands
VieCuri Medisch Centrum
Venlo, Netherlands
Ziekenhuis Zevenaar, Alysis
Zevenaar, Netherlands
Sponsors and Collaborators
Academisch Ziekenhuis Maastricht
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
Principal Investigator: Vivianne CG Tjan-Heijnen, MD PhD Maastricht University Medical Center
  More Information

Additional Information:
No publications provided by Academisch Ziekenhuis Maastricht

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Prof. Dr. V. Tjan-Heijnen, Academisch Ziekenhuis Maastricht
ClinicalTrials.gov Identifier: NCT00536081     History of Changes
Other Study ID Numbers: 2-2-6 STUDY, ZonMw ID 80-82310-98-08006, EudraCT number 2007-005402-53
Study First Received: September 25, 2007
Last Updated: December 22, 2009
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Academisch Ziekenhuis Maastricht:
Breast cancer
Adjuvant
Advanced
Chemotherapy
G-CSF
Pegfilgrastim
Prevention
Febrile neutropenia

Additional relevant MeSH terms:
Breast Neoplasms
Febrile Neutropenia
Fever
Neutropenia
Agranulocytosis
Body Temperature Changes
Breast Diseases
Hematologic Diseases
Leukocyte Disorders
Leukopenia
Neoplasms
Neoplasms by Site
Signs and Symptoms
Skin Diseases

ClinicalTrials.gov processed this record on October 23, 2014