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Granulocyte-Macrophage Colony-Stimulating Factor in Established Febrile Neutropenia

Austin & Repatriation Medical Centre, Melbourne, Australia
Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom

To the Editor: In the September 1998 issue of the Journal of Clinical Oncology, Ravaud et al reported on a randomized study of granulocyte-macrophage (GM) colony-stimulating factor (CSF) used after chemotherapy in patients with established febrile neutropenia.¹ A total of 68 patients were included in this unblinded study. Patients given GM-CSF had more rapid neutrophil recovery, but there was no difference in the duration of fever or febrile neutropenia. No justification for the study sample size was given, and the study would seem inadequately powered to detect a difference in the duration of febrile neutropenia, which was the primary end point. These results highlight the problem of defining clinically relevant end points for CSF trials in established febrile neutropenia. Neutrophil recovery is a relatively meaningless end point in itself, if it is not reflected in benefits for patient morbidity, requirement for hospitalization, or cost.

It was stated that for patients randomized to receive GM-CSF there was a significant reduction in median time in hospital on study (from 6.5 days to 5 days, P = .018). However, after going off study, 11 patients in the GM-CSF arm then remained in hospital for a further 1 to 3 days to complete antibiotic or GM-CSF therapy. The report does not explain why these patients were considered to have gone off study but were still receiving inpatient treatment for infection and neutropenia. This is of considerable importance because, although there was a significant reduction in the time in hospital "on study," the total length of hospitalization was not different between the two arms.

The authors should be commended for the prospective stratification of patients according to intensity of chemotherapy (low risk for febrile neutropenia v high risk). The benefits of GM-CSF were seen only in the low-risk subgroup, but the results should be viewed with caution because numbers were small (18 patients in the GM-CSF arm and 16 in the control). However, this finding is supported by our much larger double-blinded randomized study of 186 episodes of febrile neutropenia in pediatric patients, in which patients were randomized to receive granulocyte CSF (filgrastim) or placebo. We similarly found that patients receiving less intensive chemotherapy had a significant reduction in hospitalization when randomized to receive granulocyte CSF (7 days v 5 days, P < .005), whereas no benefit for hospitalization was seen for those receiving more intensive chemotherapy.²

It is reasonable to speculate that some patients in these studies with febrile neutropenia following less intensive chemotherapy regimens might have been managed using other strategies, such as administration of antibiotics in the outpatient setting. An alternative strategy would be an initial short hospital admission, then early discharge to antibiotic therapy at home if the patient rapidly becomes afebrile and cultures are negative. Further studies are needed to define the optimum approach in both adult and pediatric populations.

REFERENCES

1. Ravaud A, Chevreau C, Cany L, et al: Granulocyte-macrophage colony-stimulating factor in patients with neutropenic fever is potent after low-risk but not after high-risk neutropenic chemotherapy regimens: Results of a randomized phase III trial. J Clin Oncol 16:2930-2936, 1998[Abstract/Free Full Text]

2. Mitchell PLR, Morland B, Stevens MCG, et al: Clinical benefits of granulocyte colony-stimulating factor used in established febrile neutropenia: A randomised study of paediatric patients. J Clin Oncol 15:1163-1170, 1997[Abstract/Free Full Text]

Granulocyte-Macrophage Colony-Stimulating Factor in Established Febrile Neutropenia

Institut Bergonié, Regional Cancer Center, Bordeaux, France

In Reply: We agree with the comments made by Drs Mitchell and Pinkerton. The study and the sample size were based on a previous retrospective study done in patients hospitalized for febrile neutropenia following chemotherapy. The mean duration of fever was 2.9 days, the mean duration of neutropenia (absolute neutrophil count [ANC] < 1 x 10⁹/L) was 7.4 days (SD, 5.7 days), and the length of hospitalization was 10 days. The sample size was calculated to detect a 50% reduction of neutropenia period and a reduction of hospitalization duration from 10 to 7 days using a one-sided Student's test, with a 5% alpha risk and a 90% power rate. Forty-two patients per group were necessary. Due to a slow inclusion rate, this trial had to be stopped earlier. Nevertheless, despite the smaller number of patients analyzed, the lack of any difference in febrile neutropenia and hospitalization duration between the two arms led us to consider that a meaningful difference in febrile neutropenia or hospitalization duration would be unlikely even with an increase of patient inclusion to the initially expected level, as in regard to the significant difference in neutropenia duration at this time.

As mentioned in the article,¹ patients were considered to be off study when axillary temperature was less than 38°C and ANC 1 x 10⁹/L.

The stratification of patients according to intensity of chemotherapy was based on a retrospective study conducted in our institution, where 65% of the hospitalizations for patients with febrile neutropenia were the consequence of four chemotherapy protocols (mesna, doxorubicin, interleukin-3, dacarbazine; DVCP, vincristine, infusfamide, and cisplatin; VPH).¹

We fully agree that although GM-CSF showed a significant advantage in moderate-risk chemotherapy regimens, other strategies should be considered, such as short initial hospitalization, oral antibiotics, and early discharge after the ANC rises above 0.5 x 10⁹/L.

REFERENCES

1. Ravaud A, Chevreau C, Cany L, et al: Granulocyte-macrophage colony-stimulating factor in patients with neutropenic fever is potent after low-risk but not after high-risk neutropenic chemotherapy regimens: Results of a randomized phase III trial. J Clin Oncol 16:2930-2936, 1998

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This Article Full Text (PDF) Erratum (v17,p3860) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mitchell, R. Articles by Bui, B. N. Search for Related Content PubMed PubMed Citation Articles by Mitchell, R. Articles by Bui, B. N. Social Bookmarking                            What's this?