Various G-CSF Regimens to Prevent Infection During Chemotherapy
Various G-CSF Regimens to Prevent Infection During Chemotherapy
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.
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.
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.