Correspondence
Granulocyte Colony-Stimulating Factor in Children with Acute Lymphoblastic Leukemia
N Engl J Med 1997; 337:1320-1321October 30, 1997
- Article
To the Editor:
The conclusion of Pui et al. (June 19 issue)1 that “whether the benefits of G-CSF [granulocyte colony-stimulating factor] therapy justify its use in individual cases is ultimately a matter of clinical judgment” is surprising. Their study showed that G-CSF use halved the median duration of hospital stays (from 10 days to 6 days, P = 0.011) and the incidence of documented infections (from 27 to 12, P = 0.009). Children receiving G-CSF had fewer episodes of bacteremia, disseminated fungal infections, cellulitis, central venous catheter–associated infections, otitis media, Clostridium difficile enterocolitis, and lymphadenitis. Nevertheless, the editorial in the same issue2 also concludes that “since there was no clear-cut clinical benefit of treatment with G-CSF and the median total costs of supportive care were similar in the G-CSF and placebo groups, the results of the study have to be considered negative.”
Formal quality-of-life evaluations in this and similar studies are lacking. But surely the instruments and criteria used to make a quality-of-life assessment in very young children would be purely conjectural, based on projections of our values as adults; for how could we ever look at the world through the eyes of an infant? Common sense suggests that if they could, infants would tell us that hospital stays and infections of the kind listed above are distressing and that they would be grateful if physicians could prevent such events. While event-free survival and cost–benefit analysis may be more important measures from a scientific and economic standpoint,3 let us remember that our primary role as physicians is to alleviate and prevent patients' suffering. When outcomes we consider important differ from those that our patients might consider important, let us defer to our patients. Compassionate clinical judgment suggests that G-CSF as used by Pui et al.1 does have clear-cut clinical benefit. Moreover, the price of G-CSF therapy was adequately offset by reductions in the cost of supportive care, so that the clinical benefit observed was achieved at no extra cost.
3 ReferencesPankaj Gupta, M.D.
Veterans Affairs Medical Center, Minneapolis, MN 554171
Pui C-H ,Boyett JM ,Hughes WT , et al. Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia. N Engl J Med 1997;336:1781-1787
Full Text | Web of Science | Medline2
Hoelzer D . Hematopoietic growth factors -- not whether, but when and where. N Engl J Med 1997;336:1822-1824
Full Text | Web of Science | Medline3
American Society of Clinical Oncology
Web of Science | Medline
To the Editor:
We were impressed with the clinical benefits of G-CSF given after induction chemotherapy in children with acute lymphoblastic leukemia reported by Pui et al. They reported a statistically significant reduction in the duration of grade 3 and 4 neutropenia, a reduction of the duration of hospital stays, and a reduction of more than 50 percent in documented infections. This study supports our results in children with high-risk acute lymphoblastic leukemia who received nine courses of intensive chemotherapy, with G-CSF administered between courses.1 We found additional clinical benefits, including reductions in the incidence and duration of febrile neutropenia and in the use of intravenous antibiotics. Similar benefit has been reported in adult patients with acute lymphoblastic leukemia when G-CSF was used concomitantly with chemotherapy.2
The benefits of G-CSF in pediatric acute lymphoblastic leukemia may be underestimated if the interpretation of the clinical results is based on only one chemotherapy cycle per patient as in the study by Pui et al. We achieved our results by using G-CSF after repeated cycles.1 In addition, Pui et al. chose to emphasize such clinical end points as the rate of hospitalization and disease-free survival, which not surprisingly did not show statistically significant differences. The elected study design might not have allowed a better result. In our study there were also only minor effects of G-CSF on the frequency of febrile neutropenic episodes after the first chemotherapy cycle. The real benefit of G-CSF treatment started at chemotherapy cycle 3 (7 percent febrile neutropenia episodes in the G-CSF arm vs. 53 percent in the control arm) and continued throughout cycle 9. This supports the hypothesis that the beneficial effects of G-CSF are more pronounced when the damage to hematopoietic progenitor cells is more severe (e.g., after repeated cycles of chemotherapy3) and explains the lack of reduction of febrile neutropenia in the study by Pui et al. Patients and their families may value these clinical benefits of G-CSF, especially when they are attained without an increase in costs.
3 ReferencesKarl Welte, M.D.
Hansjörg Riehm, M.D.
Medizinische Hochschule Hannover, D-30625 Hannover, Germany1
Welte K ,Reiter A ,Mempel K , et al. A randomized phase-III study of the efficacy of granulocyte colony-stimulating factor in children with high-risk acute lymphoblastic leukemia. Blood 1996;87:3143-3150
Web of Science | Medline2
Ottmann O ,Hoelzer D ,Gracien E , et al. Concomitant granulocyte colony-stimulating factor and induction chemoradiotherapy in adult acute lymphoblastic leukemia: a randomized phase III trial. Blood 1995;86:444-450
Web of Science | Medline3
Welte K ,Gabrilove J ,Bronchud MH ,Platzer E ,Morstyn G . Filgrastim (r-metHuG-CSF): the first 10 years. Blood 1996;88:1907-1929
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree with Dr. Gupta that quality-of-life considerations in the young children we studied are conjectural at best; hence, we focused on more objective end points in our study. In this regard, G-CSF therapy did not significantly reduce the frequency of hospitalization or severe infection in comparison with treatment with normal saline. Moreover, a third of the patients presumably did not derive any clinical benefit from G-CSF, since 32 percent of the placebo group did not require hospitalization. Although the median duration of hospitalization was reduced by four days among G-CSF–treated patients who had febrile neutropenia, it was shortened by only two days if the analysis included all the patients receiving G-CSF. Thus, whether a child would prefer daily injections of G-CSF for nine days, without any guarantee of benefit, over two extra days in the hospital is a matter of conjecture. These remarks notwithstanding, we believe that G-CSF treatment does produce modest clinical benefits for some children who receive intensive induction chemotherapy for acute lymphoblastic leukemia, but the magnitude of these effects does not appear to justify routine use of the growth factor in all patients. Clearly, elucidation of factors that would identify the patients at greatest risk of febrile neutropenia and prolonged hospitalization is needed to improve the cost:benefit ratio of G-CSF therapy. We also agree with Dr. Gupta that “our primary role . . . is to alleviate and prevent patients' suffering,” a role that involves the appropriate use of medications based on proper interpretation of well-designed clinical trials.
With regard to Drs. Welte and Riehm's comments, we did in fact cite the interim report of his study and suggested that G-CSF treatment might prove advantageous in the treatment of malignant diseases that require repeated courses of intensive chemotherapy (e.g., advanced-stage Burkitt's lymphoma and B-cell leukemia). However, administration of G-CSF has not yet been shown to improve leukemia-free survival in a randomized, placebo-controlled study.
Ching-Hon Pui, M.D.
William E. Evans, Pharm.D.
St. Jude Children's Research Hospital, Memphis, TN 38105- Citing Articles (3)
Citing Articles
1
Jean Delorme, Stéphanie Badin, Anne-Gaelle G. Le Corroller, Anne Aurtignon Auvrignon, Marie-Françoise Auclerc, Virginie Gandemer, Pierre Bordigoni, Jean-Pierre Lamagnere, François Demeocq, Yves Perel, Christian Berthou, François Bauduer, Brigitte Pautard, Jean-Pierre Vannier, Diane Braguer, Thierry Leblanc, Guy Leverger, André Baruchel, Gérard Michel. (2003) Economic Evaluation of Recombinant Human Granulocyte Colony-Stimulating Factor in Very High-Risk Childhood Acute Lymphoblastic Leukemia. Journal of Pediatric Hematology/Oncology 25:6, 441-447
CrossRef2
M.A. Little, B. Morland, J. Chisholm, A. Hole, A. Shankar, T. Devine, D. Easlea, L.C. Meyer, C.R. Pinkerton. (2002) A randomised study of prophylactic G-CSF following MRC UKALL XI intensification regimen in childhood ALL and T-NHL. Medical and Pediatric Oncology 38:2, 98-103
CrossRef3
Michael E. Trigg, Charles Peters, M. Bridget Zimmerman. (2000) Administration of recombinant human granulocyte-macrophage colony-stimulating factor to children undergoing allogeneic marrow transplantation: A prospective, randomized, double-masked,placebo-controlled trial. Pediatric Transplantation 4:2, 123-131
CrossRef
