复旦大学：《循证医学》课程教学资源（预习资料）临床实践指南预习

2006 Recommendations for wBC Growth Factors Review of relevant literature 10. Recommendations for CSF Initiation, Duration The prophylactic use of CSFs in older patients was explored in Dosing, and Administration several randomized studies of patients treated with CHOP or 2005 recommendation for CSF dosing CHOP-like chemotherapy In three cases, G-CSF reduced the risk of FN or infections by more than 50%. ,50, Similar results were and administration reported in two retrospective reviews of practice experiences CSF. CSF should be given 24 to 72 hours after the administra- tion of myelotoxic chemotherapy In the setting of high-dose therapy Osby et al randomized patients receiving CHOP or CNOP to and autologous stem-cell rescue, CSF can be given between 24 and 120 prophylactic G-CSF or not. CHOP patients randomized to receive hours after administration of high-dose therapy. CSF should be con G-CSF experienced significantly fewer episodes of severe(89% tinued until reaching an absolute neutrophil count (ANC)of at least 2 versus 55%)or febrile neutropenia (50% versus 34%; P <.001), to 3 x 10%/L. For PBPC mobilization, CSF should be started at least 4 ind significantly fewer deaths(62% versus 45%)with projected days before the first leukapheresis procedure and continued until the five-year survivals of 45% and 60% in the control and G-CSF arms last leukapheresis. espectively(P=.04) In adults, the recommended CSF doses are 5 ug/kg/d for G-CSF In the study by Doorduijn et al, elderly NHL patients receiving and 250 ug/m /d for granulocyte macrophage colony stimulating CHOP and randomized to receive a fixed dose of G-CSF of 300 ug factor(GM-CSF) for all clinical settings other than PBPC mobiliza- daily experienced significantly fewer episodes of severe neutrope- tion In the setting of PBPC mobilization, if G-CSF is used, a dose of 10 nia(P<.001), infection in cycle 1(P=.01)with modest increase ug/kg/d may be preferable. The preferred route of CSF administration in relative dose-intensity (P<.05)and no difference in projected is subcutaneous 5-year survival. Therefore, the evidence related to the impact of Pegylated G-CSF(pegfilgrastim). Pegfilgrastim 6 mg should be CSF support on survival remains inconclusive given once, 24 hours after completion of chemotherapy. Pegfilgrastim is not currently indicated for stem cell mobilization. The safety and 9. Recommendations for use of csfs in the efficacy of pegylated G-CSF has not yet been fully established in the Pediatric Population setting of dose-dense chemotherapy. The 6 mg formulation should not be used in infants, children, or small adolescents weighing less 2005 recommendation than 45 kg The use of CSFs in pediatric patients will almost always be guided by clinical protocols. As in adults, the use of CSFs is reason- 2005 update ble for the primary prophylaxis of pediatric patients with a likeli- G-CSF and GM-CSF. A recent study by Papaldo et al evalu- ated the role of alternative filgrastim dosing schedules for early stage hood of FN. Similarly, the use of CSFs for secondary prophylaxis or breast cancer patients receiving epirubicin and cyclophosphamide for therapy should be limited to high-risk patients. However, the potential risk for secondary myeloid leukemia chemotherapy. A total of 506 patients were assigned to five different treatment arms with or without CSF. The CSF schedules were as or myelodysplastic syndrome associated with CSFs represents a follows: (1)480 mcg/d subcutaneously days 8 to 14; (2)480 mcg/d concern in children with ALL whose prognosis is otherwise excel lent. For these reasons, the use of CSFs in children with ALL should days 8, 10, 12, and 14; (3)300 mcg/d day 8 to 14; (4)300 mcg/d day 8, be considered with 4 neutropenia was reduced from 41.6% in controls to 5.4% in G-CSF 2005 update arms. The more important parameter, febrile neutropenia, was ob. Since the 2000 review, several multicenter randomized clinical served in only 7% of non-CSF patients, So CSEs would not have been suggested under existing guidelines. Schedule 5 was equivalent to the trials have evaluated prophylactic CSFs in children, particularly daily or alternate day schedules of CSF with respect to grade 3 and 4 with acute leukemia. A meta-analysis has been presented of 16 RCTs of prophylactic CSFs in children receiving systemic chemo- neutropenia (P=.77 and P=. 89, respectively) and percentage of therapy reporting significant reductions in FN(RR=0.80,95%CI delayed cycles of chemotherapy(P= 43 and P= 42, respectively) 0.67 to 0.95;P=.01), documented infection(RR=0.78,95% CI Compared with daily CSF administration(schedules I and 3),sched- 0.62 to 0.97; P=.02), and a length of hospitalization(weighted ule 5 demonstrated less grade 1 to 3 bone pain(53% versus 29%6 mean difference=1.9, 95%CI 1. 1 to 2.7 days; P<.00001).57 For respectively; P=.01) and less grade I to 2 fever(24% versus 8%, respectively; P=.04). However, the small number of patients in each pediatric ALL patients, however, G-CSF use is unlikely to lead to arm(42 to 52)would have 80% power to detect only very large cost saving 58 The recent observationthat the administration of differences in FN incidence, eg, 20% to 30%. These findings from th G-CSF to children with ALL may increase the risk for developing a underpowered trial, for patients in whom CSEs are not routinely therapy-related myeloid leukemia or myelodysplastic syndrome indicated, are not definitive proof of the efficacy of less frequent CSF adds a further note of caution to its usage, especially in patients dosing, but suggest that alternative dose schedules warrant further receiving concurrent irradiation, topoisomerase II inhibitors, or study in larger randomized clinical trials to improve efficacy, reduce alkylating agents. side effects, and reduce cost. For treatment of febrile neutropenia, Ozkaynak et al random Pegylated G-CSF. The inconvenience associated with daily ad- ized pediatric patients with FN to receive antibiotics or antibiotics ministration of CSFs prompted development of a longer-acting and CSF. The group that received CSF had fewer days of neutro- form by pegylation of G-CSF. Following initial phase II assessment penia, but only 1 less day with fever, and their hospital stay was of safety and efficacy, two phase II studies evaluated variable, decreased by I day weight-adjusted, and fixed doses of pegylated G-CSF, given 24 co.org 3195

Review of relevant literature The prophylactic use of CSFs in older patients was explored in several randomized studies of patients treated with CHOP or CHOP-like chemotherapy. In three cases, G-CSF reduced the risk of FN or infections by more than 50%.44,50,52 Similar results were reported in two retrospective reviews of practice experiences.42,56 Osby et al randomized patients receiving CHOP or CNOP to prophylactic G-CSF or not. CHOP patients randomized to receive G-CSF experienced significantly fewer episodes of severe (89% versus 55%) or febrile neutropenia (50% versus 34%; P  .001), and significantly fewer deaths (62% versus 45%) with projected five-year survivals of 45% and 60% in the control and G-CSF arms respectively (P  .04).47 In the study by Doorduijn et al, elderly NHL patients receiving CHOP and randomized to receive a fixed dose of G-CSF of 300 g daily experienced significantly fewer episodes of severe neutrope￾nia (P  .001), infection in cycle 1 (P  .01) with modest increase in relative dose-intensity (P  .05) and no difference in projected 5-year survival.51 Therefore, the evidence related to the impact of CSF support on survival remains inconclusive. 9. Recommendations for Use of CSFs in the Pediatric Population 2005 recommendation The use of CSFs in pediatric patients will almost always be guided by clinical protocols. As in adults, the use of CSFs is reason￾able for the primary prophylaxis of pediatric patients with a likeli￾hood of FN. Similarly, the use of CSFs for secondary prophylaxis or for therapy should be limited to high-risk patients. However, the potential risk for secondary myeloid leukemia or myelodysplastic syndrome associated with CSFs represents a concern in children with ALL whose prognosis is otherwise excel￾lent. For these reasons, the use of CSFs in children with ALL should be considered with caution. 2005 update Since the 2000 review, several multicenter randomized clinical trials have evaluated prophylactic CSFs in children, particularly with acute leukemia. A meta-analysis has been presented of 16 RCTs of prophylactic CSFs in children receiving systemic chemo￾therapy reporting significant reductions in FN (RR  0.80, 95% CI 0.67 to 0.95; P  .01), documented infection (RR  0.78, 95% CI 0.62 to 0.97; P  .02), and a length of hospitalization (weighted mean difference  1.9, 95% CI 1.1 to 2.7 days; P  .00001).57 For pediatric ALL patients, however, G-CSF use is unlikely to lead to cost saving.58 The recent observation59 that the administration of G-CSF to children with ALL may increase the risk for developing a therapy-related myeloid leukemia or myelodysplastic syndrome adds a further note of caution to its usage, especially in patients receiving concurrent irradiation, topoisomerase II inhibitors, or alkylating agents. For treatment of febrile neutropenia, Ozkaynak et al random￾ized pediatric patients with FN to receive antibiotics or antibiotics and CSF. The group that received CSF had fewer days of neutro￾penia, but only 1 less day with fever, and their hospital stay was decreased by 1 day.60 10. Recommendations for CSF Initiation, Duration, Dosing, and Administration 2005 recommendation for CSF dosing and administration CSF. CSF should be given 24 to 72 hours after the administra￾tion of myelotoxic chemotherapy. In the setting of high-dose therapy and autologous stem-cell rescue,CSF can be given between 24 and 120 hours after administration of high-dose therapy. CSF should be con￾tinued until reaching an absolute neutrophil count (ANC) of at least 2 to 3  109 /L. For PBPC mobilization, CSF should be started at least 4 days before the first leukapheresis procedure and continued until the last leukapheresis. In adults, the recommended CSF doses are 5 g/kg/d for G-CSF and 250 g/m2 /d for granulocyte macrophage colony stimulating factor (GM-CSF) for all clinical settings other than PBPC mobiliza￾tion. In the setting of PBPCmobilization,if G-CSFis used, a dose of 10 g/kg/dmay be preferable. The preferred route of CSF administration is subcutaneous. Pegylated G-CSF (pegfilgrastim). Pegfilgrastim 6 mg should be given once, 24 hours after completion of chemotherapy. Pegfilgrastim is not currently indicated for stem cell mobilization. The safety and efficacy of pegylated G-CSF has not yet been fully established in the setting of dose-dense chemotherapy. The 6 mg formulation should not be used in infants, children, or small adolescents weighing less than 45 kg. 2005 update G-CSF and GM-CSF. A recent study by Papaldo et al61 evalu￾ated the role of alternative filgrastim dosing schedules for early stage breast cancer patients receiving epirubicin and cyclophosphamide chemotherapy. A total of 506 patients were assigned to five different treatment arms with or without CSF. The CSF schedules were as follows: (1) 480 mcg/d subcutaneously days 8 to 14; (2) 480 mcg/d days 8, 10, 12, and 14; (3) 300 mcg/d day 8 to 14; (4) 300 mcg/d day 8, 10, 12, and 14; and (5) 300mcg/d days 8 and 12. Theincidence of grade 4 neutropenia was reduced from 41.6% in controls to 5.4% in G-CSF arms. The more important parameter, febrile neutropenia, was ob￾served in only 7% of non-CSF patients, so CSFs would not have been suggested under existing guidelines. Schedule 5 was equivalent to the daily or alternate day schedules of CSF with respect to grade 3 and 4 neutropenia (P  .77 and P  .89, respectively) and percentage of delayed cycles of chemotherapy (P  .43 and P  .42, respectively). Compared with daily CSF administration (schedules 1 and 3), sched￾ule 5 demonstrated less grade 1 to 3 bone pain (53% versus 29%, respectively; P  .01) and less grade 1 to 2 fever (24% versus 8%, respectively; P  .04). However, the small number of patients in each arm (42 to 52) would have 80% power to detect only very large differences in FN incidence, eg, 20% to 30%. These findings from this underpowered trial, for patients in whom CSFs are not routinely indicated, are not definitive proof of the efficacy of less frequent CSF dosing, but suggest that alternative dose schedules warrant further study in larger randomized clinical trials to improve efficacy, reduce side effects, and reduce cost. Pegylated G-CSF. The inconvenience associated with daily ad￾ministration of CSFs prompted development of a longer-acting form by pegylation of G-CSF. Following initial phase II assessment of safety and efficacy, two phase II studies evaluated variable, weight-adjusted, and fixed doses of pegylated G-CSF, given 24 2006 Recommendations for WBC Growth Factors www.jco.org 3195 Copyright © 2006 by the American Society of Clinical Oncology. All rights reserved. Information downloaded from jco.ascopubs.org and provided by charlesworth on August 12, 2009 from 202.120.79.222. 第 226 页

Smith et al hours after chemotherapy. A recent combined, retrospective analy- transplant periods and a longer time to progression(61 months for sis compared once-per-chemotherapy-cycle pegfilgrastim with daily G-CSF-treated patients and 25 months for GM-CSF-treated pa G-CSF(filgrastim)in breast cancer patients undergoing myelosup- tients). After a median follow-up of 40 months, the overall survival pressive chemotherapy enrolled in two similarly designed, random- rate was 75% for patients who received G-CSF and 50% for pa ized, double-blind, pivotal trials. On day 2 of each chemotherapy tients who received GM-CSF. A phase Ill study in 156 patients with cycle, patients received a single subcutaneous(SC)injection of pegfil- breast cancer, myeloma, or lymphoma concluded that G-CSF was grastim(either 6mg [n=77]or 100 ug/kg [n= 149 ) or daily G-CSF superior to GM-CSF as demonstrated by a faster time to recovery SC injections(5 ug/kg/d; n=222). G-CSF injections were continued of granulocyte counts(11 versus 14 days, P=.0001) and fewer until either ANC 2 10 X 10/L after the expected nadir or for up to 14 patients with fever(18% versus 52%, P=001). The yield of CD days, whichever occurred first. Each of these trials demonstrated that a 34 cells was also found to be higher for G-CSF. Earlier mobiliza single pegfilgrastim injection per cycle is as effective at reducing the tion of CD 34- cells with G-CSF than with GM-CSF was also duration of severe neutropenia as daily injections of filgrastim Clini- demonstrated in another study after high-dose nonmyeloablative cal efficacy data from the two trials were combined for analysis therapy with cyclophosphamide, etoposide, and cisplatin (n=448). The risk of fn(ANC<0.5×10° with fever≥38.2°C) In addition to these studies comparing the single agents, three was significantly lower(11%versus 19%, respectively [RR, 0.56; 95% studies have examined a comparison of G-CSF with a combination CI 0.35 to 0.89))in patients receiving pegfilgrastim than for those of G-and GM-CSF. Utilizing a cross-over design, Koc et al found receiving filgrastim that G-CSF alone resulted in a mobilization of more cd 34 cells A smaller randomized phase-II study in patients with lymphoma and that the single agent was effective after failure of the combin treated with etoposide, methylprednisolone, cisplatin, and cytarabine tion to mobilize sufficient progenitors. Two other studies using a showed equivalent effects of daily administration of G-CSF and standard comparative design failed to demonstrate significant differ one-time administration of pegylated G-CSF.3 In a placebo- ences between the two regimens with respect to granulocyte func controlled phase Ill study of patients treated for breast cancer, peg- tion, though in the Recchia et al study, patients on the G-CSF- lated G-CSF reduced the incidence of FN, hospitalization, and alone arm had lower platelet counts one month after transplantation. intravenous anti-infective use in patients receiving a docetaxel-based regimen, with an incidence of FN in the control arm of approxi- 12. Special Comments on Growth Factors As a mately 17% versus 1% in the treatment group(P <.001); the Treatment for Radiation Injury (Note: This Topic Is incidence of hospitalization was also reduced from 14%in the New to the Guideline) control group to 1%(P <. 001) 2005 recommendation The long-term effects of long acting growth factors are unknown and the Update Committee expressed concern about potential leuko- Current recommendations for the management of patients exposed to lethal doses of total body radiotherapy, but not doses cytosis, late neutropenia after discontinuation of pegylated G-CSF, high enough to lead to certain death due to injury to other organs, and the need for long-term safety data. ncludes the prompt administration of SF or p 11. Special Comments on Comparative Clinical G-CSF 70,71 Activity of G-CSF and GM-CSF Accidental or intentional (eg, resulting from a terrorist attack or war)total body radiation leads to probable or certain death from 2005 recommendation bone marrow failure at doses of 3 to 10 Grays(Gy) without sup- No change. No guideline recommendation can be made regard- portive care, CSFs, and/or a bone marrow transplant. - Doses ing the equivalency of the two colony-stimulating agents. As in 2000, below that level are almost always survivable with excellent nursing further trials are recommended to study the comparative clinical ac- care, and higher doses are lethal because of injury to other organs tivity,toxicity, and cost-effectiveness of G-CSF and GM-CSe. such as the gastrointestinal tract. The chance for mortality from any radiation dose rises with combined injuries to the skin, lungs, 2005 update In a recent meta-analysis of effectiveness of the colony and so or Hematopoietic growth factors can increase the survival, pro- stimulating factors, the issue of equivalency was not addressed. A liferation, amplification, and differentiation of granulocyte pro recent systematic review of the subject concluded that head-to- genitors to produce neutrophils. Although no prospective head trials ofG-CSF and GM-CSF demonstrate higher incidence of randomized trials have been carried out to determine the benefit of fever in the GM-CSF arms but data on the comparative ability to hematopoietic growth factors in humans exposed to accidental reduce chemotherapy-induced complications are lacking intentional radiation injury, they have been utilized in radiation acci A variety of studies continue to investigate differences be- dent victims, and neutrophil recovery appears to have been hastened tween the two agents as enhancers of progenitor cells following in 25 of 28 cases(REACT/TS registry). In animal models, prompt growth factor administration. Three of these studies compared administration of hematopoietic growth factors after otherwise letha domized study in 71 breast and ovarian cancer patients treated total body radiation exposure dramatically increases survival. 76-81 with carboplatin, etoposide, and melphalan, no difference in he- 13. Impact of CSFs on Quality of Life and Health matopoietic recovery was noted between G-CSF or GM-CSF pa- Care Costs tients, all treated at a dosed of5 ug/kg of the designated agent until The Update Committee had much discussion about the cost ompletion of stem cell harvest. Patients treated with G-CSF had of CSFs, their impact on the health system and patients, and their ignificantly higher T-cell levels in the early and late post- impact on global quality of life. The Update Committee made the hm0:1200会m

hours after chemotherapy. A recent combined, retrospective analy￾sis62 compared once-per-chemotherapy-cycle pegfilgrastimwith daily G-CSF (filgrastim) in breast cancer patients undergoing myelosup￾pressive chemotherapy enrolled in two similarly designed, random￾ized, double-blind, pivotal trials. On day 2 of each chemotherapy cycle, patients received a single subcutaneous (SC) injection of pegfil￾grastim (either 6 mg [n  77] or 100g/kg [n  149]) or daily G-CSF SC injections (5 g/kg/d; n  222). G-CSF injections were continued until either ANC
10  109 /L after the expected nadir or for up to 14 days,whichever occurred first. Each of these trials demonstrated that a single pegfilgrastim injection per cycle is as effective at reducing the duration of severe neutropenia as daily injections of filgrastim. Clini￾cal efficacy data from the two trials were combined for analysis (n  448). The risk of FN (ANC  0.5  109 /L with fever
38.2°C) was significantly lower (11% versus 19%, respectively [RR, 0.56; 95% CI 0.35 to 0.89]) in patients receiving pegfilgrastim than for those receiving filgrastim. A smaller randomized phase-II study in patients with lymphoma treated with etoposide, methylprednisolone, cisplatin, and cytarabine showed equivalent effects of daily administration of G-CSF and one-time administration of pegylated G-CSF.63 In a placebo￾controlled phase III study of patients treated for breast cancer, pegy￾lated G-CSF reduced the incidence of FN, hospitalization, and intravenous anti-infective use in patients receiving a docetaxel-based regimen, with an incidence of FN in the control arm of approxi￾mately 17% versus 1% in the treatment group (P  .001); the incidence of hospitalization was also reduced from 14% in the control group to 1% (P  .001).3 The long-term effects of long acting growthfactors are unknown, and the Update Committee expressed concern about potential leuko￾cytosis, late neutropenia after discontinuation of pegylated G-CSF, and the need for long-term safety data. 11. Special Comments on Comparative Clinical Activity of G-CSF and GM-CSF 2005 recommendation No change. No guideline recommendation can be made regard￾ing the equivalency of the two colony-stimulating agents. As in 2000, further trials are recommended to study the comparative clinical ac￾tivity, toxicity, and cost-effectiveness of G-CSF and GM-CSF. 2005 update In a recent meta-analysis of effectiveness of the colony￾stimulating factors, the issue of equivalency was not addressed.12 A recent systematic review of the subject concluded that head-to￾head trials of G-CSF and GM-CSF demonstrate higher incidence of fever in the GM-CSF arms but data on the comparative ability to reduce chemotherapy-induced complications are lacking.64 A variety of studies continue to investigate differences be￾tween the two agents as enhancers of progenitor cells following growth factor administration. Three of these studies compared G-CSF to GM-CSF as single agents in different settings. In a ran￾domized study in 71 breast and ovarian cancer patients treated with carboplatin, etoposide, and melphalan, no difference in he￾matopoietic recovery was noted between G-CSF or GM-CSF pa￾tients, all treated at a dosed of 5 g/kg of the designated agent until completion of stem cell harvest.65 Patients treated with G-CSF had significantly higher T-cell levels in the early and late post￾transplant periods and a longer time to progression (61 months for G-CSF-treated patients and 25 months for GM-CSF–treated pa￾tients). After a median follow-up of 40 months, the overall survival rate was 75% for patients who received G-CSF and 50% for pa￾tients who received GM-CSF. A phase III study in 156 patients with breast cancer, myeloma, or lymphoma concluded that G-CSF was superior to GM-CSF as demonstrated by a faster time to recovery of granulocyte counts (11 versus 14 days, P  .0001) and fewer patients with fever (18% versus 52%, P  .001).66 The yield of CD 34 cells was also found to be higher for G-CSF. Earlier mobiliza￾tion of CD 34 cells with G-CSF than with GM-CSF was also demonstrated in another study after high-dose nonmyeloablative therapy with cyclophosphamide, etoposide, and cisplatin.67 In addition to these studies comparing the single agents, three studies have examined a comparison of G-CSF with a combination of G- and GM-CSF. Utilizing a cross-over design, Koc et al found that G-CSF alone resulted in a mobilization of more CD 34 cells, and that the single agent was effective after failure of the combina￾tion to mobilize sufficient progenitors.67 Two other studies using a standard comparative design failed to demonstrate significant differ￾ences between the two regimens with respect to granulocyte func￾tion,68,69 though in the Recchia et al study,69 patients on the G-CSF– alone arm had lower platelet counts one month after transplantation. 12. Special Comments on Growth Factors As a Treatment for Radiation Injury (Note: This Topic Is New to the Guideline) 2005 recommendation Current recommendations for the management of patients exposed to lethal doses of total body radiotherapy, but not doses high enough to lead to certain death due to injury to other organs, includes the prompt administration of CSF or pegylated G-CSF.70,71 Accidental or intentional (eg, resulting from a terrorist attack or war) total body radiation leads to probable or certain death from bone marrow failure at doses of 3 to 10 Grays (Gy) without sup￾portive care, CSFs, and/or a bone marrow transplant.72-74 Doses below that level are almost always survivable with excellent nursing care, and higher doses are lethal because of injury to other organs such as the gastrointestinal tract. The chance for mortality from any radiation dose rises with combined injuries to the skin, lungs, and so on.75 Hematopoietic growth factors can increase the survival, pro￾liferation, amplification, and differentiation of granulocyte pro￾genitors to produce neutrophils. Although no prospective, randomized trials have been carried out to determine the benefit of hematopoietic growth factors in humans exposed to accidental or intentional radiation injury, they have been utilized in radiation acci￾dent victims, and neutrophil recovery appears to have been hastened in 25 of 28 cases (REACT/TS registry). In animal models, prompt administration of hematopoietic growth factors after otherwise lethal total body radiation exposure dramatically increases survival.76-81 13. Impact of CSFs on Quality of Life and Health Care Costs The Update Committee had much discussion about the cost of CSFs, their impact on the health system and patients, and their impact on global quality of life. The Update Committee made the Smith et al 3196 JOURNAL OF CLINICAL ONCOLOGY Copyright © 2006 by the American Society of Clinical Oncology. All rights reserved. Information downloaded from jco.ascopubs.org and provided by charlesworth on August 12, 2009 from 202.120.79.222. 第 227 页

2006 Recommendations for wBC Growth Factors recommendations for CSF use when the FN rate was approxi- The CSF Update Committee recognized that these are expensive mately 20% based on clinical impact alone, due to the consensus agents. As stated explicitly above, when available, alternative regi that reduction in febrile neutropenia itself was an important clin- mens offering equivalent efficacy, but not requiring CSF support, ical outcome. Evidence from meta-analysis that CSFs reduced should be utilized. infection-related mortality added to the clinical evidence that use Recently published data by Papaldo et al suggest that, when of CSFs was important, and further emphasized that the primary compared with standard CSF dosing, less frequent CSF dosing decisions were clinical and not economic schedules may equally prevent neutropenia and chemotherapy In the original CSF guideline and subsequent updates, the use dose delay and cause less bone pain and fever. This trial was a of CSFs could be justified on economic grounds if the rate of fn nonrandomized, observational study its results should be consid approached 40%6, which was coincidentally the same as the clinical ered hypothesis generating. As stated by Djulbegovic, because the threshold for use of CSFs. With the new clinical threshold of uncertainty of benefits/harms of alternative treatment options is benefit at a FN rate of 20%, and evidence of reduction in infection- high and the benefit-harm ratio is unclear, a high level of eviden- related mortality, the Update Committee noted that CSFs should tiary standards, such as a randomized clinical trial be used when indicated for clinical reasons, not economic ones. standard versus alternative CSF dosing schedules, is needed.83If There was substantial discussion on the role of the Update Com mittee in limiting access to expensive but important drugs, the proven to be equally efficacious, less frequent CSF dosing could current threshold at which CSFs would be cost saving, and the im- have a significant impact on the cost of treatment. The quality-of-life impact of the CSFs has been less well stud- efficacy and cost of prophylactic CSF in elderly patients with ag- ied, but the available data show no difference in formal quality of ressive lymphoma treated with CHOP chemotherapy. 2 While life between placebo and CSF. A recent study directly addressed esponse rates, overall survival, and event-free survival were no quality of life in a subgroup of patients using a standardized instru different between the CHOP and CHOP-CSF arms, total hospi ment in patients receiving primary prophylactic CSF versus stan- costs were higher for patients treated with CHOP-CSF (E 18,356 dard therapy alone. Although underpowered for this outcome,the 12, 178:95%CI E 10, 297 to E14,059). Even a low, fixed dose of CSF the study arms, even though fewer patients were hospitalized in the reduced febrile neutropenia rates. Given the low cost of a hospital CSF group. Thatcher et al noted that palliation of symptoms and day in the Netherlands(a few hundred dollars, not $2, 500 as in the quality of life was the same for small-cell lung cancer patients US, their conclusions hold for there alone. a better trial would have treated with a conventional every-3-week regimen, or a dose used enough CSF to allow dose-dense therapy and collected re- intense every-2-week regimen with CSF. Further research into this urce utilization to allow other countries to plug in their numbers. important area of patient experience is warranted before any con Further research into the cost implications of CSF use is warranted. clusions can be drawn. 2002]. Cochrane Database of Systematic Reviews 13. Clark OA, Lyman GH, Castro AA, et al REFERENCES 7. Thatcher N, Girling DJ, Hopwood P, et al: induced febrile neutropenia: A meta-analysis of ran- 1. American Society of Clinical Oncology. Out. Improving survival without reducing quality of life domized controlled trials. 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Darmon M, Azoulay E, Alberti C, et al: Impact without etoposide for the treatment of elderly breast carcinoma: Toward the implementation of a of neutropenia duration on short-term mortality in nts with aggressive lymphomas: Results of the NHL- B2 trial of the dshnhl. blood 104: 634-64 11. Garcia-Carbonero R, Mayordomo JI, Tomamira Care Med 28: 1775-1780, 2002 MV, et at Granulocyte colony-stimulating factor in the 18. Citron ML, Berry DA, Cirrincione C, et al sent of high-risk febrile neutropenia: A mult- Randomized trial of dose-dense versus convention. 5. Kuderer NM. Crawford J. Dale DC. et al. er randomized trial. J Natl Cancer Inst 93: 31-38 ally scheduled and sequential versus concurren omplications and costs associated with febnile combination chemotherapy as postoperative adj neutropenia in hospitalized adult cancer patients. 12. Berghmans T, Paesmans M, Lafitte JJ, et al: vant treatment of node-positiy east ca J Clin Oncol 22, 2004 (abstr 6049) erapeutic use of granulocyte and granulocyte. cer. First report of Intergroup Trial C9741/Cancer 6. Bohlius J, Reiser M, Schwarzer G, et al: macrophage colony-stimulating factors in febrile and Leukemia Group B Trial 9741. J Clin Oncol Granulopoiesis-stimulating factors to prevent ad- neu 1431-1439,2003 verse effects in the treatment of malignant lyn the literature with meta-analysis Support Care Can- 19. Longan P. Woll PJ. O'Brien ME, et al: Ran- homa [Update of Cochrane Database Syst Rev. cer 10: 181-188, 2002 domized phase Ill trial of dose-dense chemotherapy 3197 Information downloaded from jco. ascopubs org and arlesworth on August 12, 2009 from 202. 120.79.222 Copyright 2006 by the American Society of Clinical Oncology. All rights reserved

recommendations for CSF use when the FN rate was approxi￾mately 20% based on clinical impact alone, due to the consensus that reduction in febrile neutropenia itself was an important clin￾ical outcome. Evidence from meta-analysis that CSFs reduced infection-related mortality added to the clinical evidence that use of CSFs was important,5 and further emphasized that the primary decisions were clinical and not economic. In the original CSF guideline and subsequent updates, the use of CSFs could be justified on economic grounds if the rate of FN approached 40%, which was coincidentally the same as the clinical threshold for use of CSFs. With the new clinical threshold of benefit at a FN rate of 20%, and evidence of reduction in infection￾related mortality, the Update Committee noted that CSFs should be used when indicated for clinical reasons, not economic ones. There was substantial discussion on the role of the Update Com￾mittee in limiting access to expensive but important drugs, the current threshold at which CSFs would be cost saving, and the im￾pact of CSFs on health care costs. Doorduijn et al evaluated the efficacy and cost of prophylactic CSF in elderly patients with ag￾gressive lymphoma treated with CHOP chemotherapy.82 While response rates, overall survival, and event-free survival were no different between the CHOP and CHOP-CSF arms, total hospital costs were higher for patients treated with CHOP-CSF (€ 18,356; 95% CI € 15,807 to € 20,906) compared with CHOP alone (€ 12,178; 95% CI € 10,297 to €14,059). Even a low, fixed dose of CSF reduced febrile neutropenia rates. Given the low cost of a hospital day in the Netherlands (a few hundred dollars, not $2,500 as in the US, their conclusions hold for there alone. A better trial would have used enough CSF to allow dose-dense therapy and collected re￾source utilization to allow other countries to plug in their numbers. Further research into the cost implications of CSF use is warranted. The CSF Update Committee recognized that these are expensive agents. As stated explicitly above, when available, alternative regi￾mens offering equivalent efficacy, but not requiring CSF support, should be utilized. Recently published data by Papaldo et al suggest that, when compared with standard CSF dosing, less frequent CSF dosing schedules may equally prevent neutropenia and chemotherapy dose delay and cause less bone pain and fever.61 This trial was a nonrandomized, observational study; its results should be consid￾ered hypothesis generating. As stated by Djulbegovic, because the uncertainty of benefits/harms of alternative treatment options is high and the benefit-harm ratio is unclear, a high level of eviden￾tiary standards, such as a randomized clinical trial comparing standard versus alternative CSF dosing schedules, is needed.83 If proven to be equally efficacious, less frequent CSF dosing could have a significant impact on the cost of treatment. The quality-of-life impact of the CSFs has been less well stud￾ied, but the available data show no difference in formal quality of life between placebo and CSF. A recent study directly addressed quality of life in a subgroup of patients using a standardized instru￾ment in patients receiving primary prophylactic CSF versus stan￾dard therapy alone. Although underpowered for this outcome, the authors found no difference in global quality of life between the study arms, even though fewer patients were hospitalized in the CSF group.51 Thatcher et al noted that palliation of symptoms and quality of life was the same for small-cell lung cancer patients treated with a conventional every-3-week regimen, or a dose￾intense every-2-week regimen with CSF.7 Further research into this important area of patient experience is warranted before any con￾clusions can be drawn. REFERENCES 1. American Society of Clinical Oncology: Out￾comes of cancer treatment for technology assess￾ment and cancer treatment guidelines. J Clin Oncol 14:671-679, 1996 2. Timmer-Bonte JN, de Boo TM, Smith HL, et al: Cost-effectiveness of adding granulocyte colony￾stimulatng factor to primary prophylaxis with anti￾bodies in small-cell lung cancer. J Clin Oncol 24: 2991-2997, 2006 3. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al: First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: A multicenter, double-blind, placebo￾controlled phase III study. J Clin Oncol 23:1178- 1184, 2005 4. Pfeundschuh M, Truemper L, Kloess M, et al: 2-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: Results of the NHL-B2 trial of the DSHNHL. Blood 104:634-641, 2004 5. Kuderer NM, Crawford J, Dale DC, et al: Complications and costs associated with febrile neutropenia in hospitalized adult cancer patients. J Clin Oncol 22, 2004 (abstr 6049) 6. Bohlius J, Reiser M, Schwarzer G, et al: Granulopoiesis-stimulating factors to prevent ad￾verse effects in the treatment of malignant lym￾phoma [Update of Cochrane Database Syst Rev. 2002]. Cochrane Database of Systematic Reviews CD003189, 2004 7. Thatcher N, Girling DJ, Hopwood P, et al: Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor support: Results of a British Medical Research Council Multicenter Ran￾domized Trial—Medical Research Council Lung Cancer Working Party. J Clin Oncol 18:395-404, 2000 8. Lyman GH, Kuderer NM: Epidemilogy of febrile neurtopenia. Supportive Cancer Therapy 1:23-35, 2003 9. Lyman GH, Kuderer NM, Balducci L: Cost￾benefit analysis of granulocyte colony-stimulating factor in the management of elderly cancer patients. Curr Opin Hematol 9:207-214, 2002 10. Rivera E, Erder MH, Moore TD, et al: Tar￾geted filgrastim support in patients with early-stage breast carcinoma: Toward the implementation of a risk model. Cancer 98:222-228, 2003 11. Garcia-Carbonero R, Mayordomo JI, Tornamira MV, et al: Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: A multi￾center randomized trial. J Natl Cancer Inst 93:31-38, 2001 12. Berghmans T, Paesmans M, Lafitte JJ, et al: Therapeutic use of granulocyte and granulocyte￾macrophage colony-stimulating factors in febrile neutropenic cancer patients: A systematic review of the literature with meta-analysis. Support Care Can￾cer 10:181-188, 2002 13. Clark OA, Lyman GH, Castro AA, et al: Colony-stimulating factors for chemotherapy￾induced febrile neutropenia: A meta-analysis of ran￾domized controlled trials. J Clin Oncol 23:4198- 4214, 2005 14. Klastersky J, Paesmans M, Rubenstein EB, et al: The Multinational Association for Sup￾portive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neu￾tropenic cancer patients. J Clin Oncol 18:3038- 3051, 2000 15. Talcott JA, Siegel RD, Finberg R, et al: Risk assessment in cancer patients with fever and neu￾tropenia: A prospective, two-center validation of a prediction rule. J Clin Oncol 10:316-322, 1992 16. Malik I, Hussain M, Yousuf H: Clinical char￾acteristics and therapeutic outcome of patients with febrile neutropenia who present in shock: Need for better strategies. J Infect 42:120-125, 2001 17. Darmon M, Azoulay E, Alberti C, et al: Impact of neutropenia duration on short-term mortality in neutropenic critically ill cancer patients. Intensive Care Med 28:1775-1780, 2002 18. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus convention￾ally scheduled and sequential versus concurrent combination chemotherapy as postoperative adju￾vant treatment of node-positive primary breast can￾cer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003 19. 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Smith et al upported by whole-blood hematopoietic progen- acute myeloid leukemia-The International Acute alone in ith diffuse large-B-cell in better-prognosis small-cell lung cancer. J Natl Myeloid Leukemia Study Group. Blood 90: 4710- lymphoma. N Engl J Med 346: 235-242, 2002 4718,1997 46. Gisselbrecht C, Haioun C, Lepage e, 20. Ardizzoni A, Tjan-Heijnen VC, Postmus PE,et 2. Larson RA, Dodge RK, Linker CA, et al: Placebo-controlled phase Ill study of lenograstim erapy for adults with acute lymphoblastic lymphoma: Factors infiuencing chemotherapy ad- inization for Research and Treatment of cancer. 556- ministration: Groupe d'Etude des Lymphomas d ung Cancer Group Phase Ill Trial-08923. J Clin 1564, 1998 r'Adulte. Leuk Lymphoma 25: 289-300., 1997 Oncol20:39473955,2002 33. Heath JA, Steinherz PG, Altman A, et al: 47. Osby E, Hagberg H, Kvaloy S, et al: CHOP 21. 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Blood 104:626-633, 2004 23. McQuaker IG, Hunter AE, Pacey S, et al: Low-dose filgrastim significantly enhances neutro￾phil recovery following autologous peripheral￾blood stem-cell transplantation in patients with lymphoproliferative disorders: Evidence for clini￾cal and economic benefit. J Clin Oncol 15:451- 457, 1997 24. Stinson TJ, Adams JR, Bishop MR, et al: Economic analysis of a phase III study of G-CSF versus placebo following allogeneic blood stem cell transplantation. Bone Marrow Transplant 26:633- 666, 2000 25. Ringden O, Labopin M, Gorin NC, et al: Treatment with granulocyte colony-stimulating fac￾tor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus￾host disease and death: A study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 22:416-423, 2004 26. Kloess M, Zeynalova S, Truemper L, et al: Effects of G-CSF schedule on leukocyte recovery and infection rate in the CHOP-14 regimen for elderly patients with aggressive lymphoma. Proc Am Soc Clin Oncol 22, 2003 (abstr 2403) 27. Kroger N, Zander AR: Dose and schedule effect of G-GSF for stem cell mobilization in healthy donors for allogeneic transplantation. Leuk Lym￾phoma 43:1391-1394, 2002 28. Lowenberg B, van Putten W, Theobald M, et al: Effect of priming with granulocyte colony￾stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med 349:743- 752, 2003 29. Amadori S, Suciu S, Jehn U, et al: Use of glycosylated recombinant human G-CSF during and/or after induction chemotherapy in elderly pa￾tients with acute myeloid leukemia: Final results of AML-13, a randomized phase III study of the EORTC and GIMEMA Leukemia Groups. Blood 106:27-34, 2005 30. Harousseau JL, Witz B, Lioure B, et al: Granulocyte colony-stimulating factor after intensive consolidation chemotherapy in acute myeloid leuke￾mia: Results of a randomized trial of the Groupe Ouest-Est Leucemies Aigues Myeloblastiques. J Clin Oncol 18:780-787, 2000 31. Heil G, Hoelzer D, Sanz MA, et al: The International Acute Myeloid Leukemia Study Group: A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia—The International Acute Myeloid Leukemia Study Group. Blood 90:4710- 4718, 1997 32. Larson RA, Dodge RK, Linker CA, et al: A randomized controlled trial of filgrastim dur￾ing remission induction and consolidation chemo￾therapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 92:1556- 1564, 1998 33. 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