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

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Unit 10：临床实践指南主讲教师：王小钦助理教师：陈波斌授课时间：2010 年 4 月 27 日（1 班）；2010 年 4 月 30 日（2 班）一、教学目的：掌握和熟悉临床实践指南的应用原则和方法二、教学内容： 1. 掌握临床实践指南的基本概念、推荐意见的证据级别、评价原则和应用原则 2. 熟悉临床实践指南的检索方法 3. 了解临床实践指南的制定步骤三、教学重点：实践指南的推荐意见的证据级别四、教学难点：实践指南的评价原则五、中文和英文关键词临床实践指南 Clinical Practice Guidelines 推荐意见 Recommendations 证据等级 Levels of evidence 六、阅读文献：请上网查询 2 个指南，并阅读 1、American Society of Clinical Oncology 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline (http://www.asco.org) 2、Prevention and treatment of cancer-related infections (http://www.nccn.org) 七、讨论思考题：（一）临床病例：肿瘤化疗后白细胞减少，发热感染的病史资料。 1. 患者，女性，31 岁，公司职员 2. 系发现皮肤瘀点、瘀斑一周而入院。患者 2009 年 1 月 8 日无意中发现双下肢瘀点、瘀斑，2 天后发展至足背，伴有牙龈出血，就诊我科门诊，查血常规：WBC：243.13×109 /L，中性粒细胞 6%，淋巴细胞 5%，单核细胞 1%，异常细胞 88%，Hb 98g/L，Plt 32×109 /L，为进一步诊治而入院。患者在半年前体检血常规正常。 3. 入院体检：消瘦，贫血貌，四肢、躯干部可见多处瘀点、瘀斑，以双下肢明显，胸骨中下端有明显触痛，双侧颈部、左侧腋下可及多枚黄豆大小淋巴结，活动度可，余浅表淋巴结未扪及肿大，颈软，两肺呼吸音清，未闻及啰音， HR 90 次/分，各瓣膜区未闻及杂音，肝脏肋缘下平脐，脾脏肋缘下 3 指，质地中等，无压痛，双下肢无水肿。第 216 页

VOLUME 24 NUMBER 19 JULY 1 2006 JOURNAL OF CLINICAL ONCOLOGY A SCO SPECIAL ARTICLE 2006 Update of Recommendations for the use of white Blood Cell growth Factors: An Evidence-Based Clinical Practice guideline Thomas/ Smith( Chair), James Khatcheressian, Gary H. Lyman, Howard Ozer, James O. Armitage Lodovico Balducci, Charles L. Bennett, Scott B. Cantor, Jeffrey Crawford, Scott /. Cross, George Demetri, Christopher E. Desch, Philip A. Pizzo, Charles A. Schiffer, Lee Schwartzberg, Mark R. Somerfield, George Somlo James C. Wade, James L. Wade, Rodger /. Winn, Antoinette J. Wozniak, and Antonio C. Wolf From the American Society of Cinical A B S TRA C T Submitted March 14, 2006; accepted March 24. 2006 To update the 2000 American Society of Clinical Oncology guideline on the use of hematopoietic Authors disclosures of potential con- colony-stimulating factors (CSF) cts of interest and author contribu- ions are found at the end of this The Update Committee completed a review and analysis of pertinent data published from 1999 through September 2005. Guided by the 1996 ASco clinical outcomes criteria, the Update ociety of Clinical Oncology, Cancer Committee formulated recommendations based on improvements in survival, quality of life, toxicity reduction and cost-effectiveness Street. Suite 200. Alexandria, VA Recommendations 22314: e-mail: guidelines@asco.org The 2005 Update Committee agreed unanimously that reduction in febrile neutropenia(FN) is an 0 2006 by American Society of Clinical important clinical outcome that justifies the use of CSFs, regardless of impact on other factors, when the risk of fN is approximately 20% and no other equally effective regimen that does not 0732-183X06/24193187/2000 require CSFs is available. Primary prophylaxis is recommended for the prevention of FN in patients who are at high risk based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. CSF use allows a modest to moderate increase in dose-density and/or dose- intensity of chemotherapy regimens. Dose-dense regimens should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Prophylactic CSF for patients with diffuse aggressive lymphoma aged 65 years and older treated with curative chemotherapy (CHOP or more aggressive regimens) should be given to reduce the incidence of FN and infections. 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 J Clin Oncol 24: 3187-3205 2006 by American Society of Clinical Oncology INTRODUCTION The Update Committee had four face-to-face neetings to consider the evidence for each of the The American Society of Clinical Oncology 2005 Recommendations. The guideline was circu- (ASCO) published its first evidence-based clinical lated in draft form to the Update Committee for practice guideline in 1994 on the use of hemato- review and approval. ASCOs Health Services Com poietic colony-stimulating factors(CSF). An Up- mittee and the ASCO Board of Directors also re date Committee of the original Expert Panel viewed the final document. updated this guideline in 1996, 1997, and 2000 (It is important to emphasize that guidelines For the 2005 update, an Update Committee com- and technology assessments cannot always account posed of members from the full Panel and selected for individual variation among patients. They are ad hoc members was formed to complete the re- not intended to supplant physician judgment with view and analysis of data published since the 2000 respect to particular patients or special clinical situ Update. A series of computerized literature ations, and cannot be considered inclusive of all searches of MEDLINE and the Cochrane Library proper methods of care or exclusive of other treat- was performed. Details of the searches are re- ments reasonably directed at obtaining the same ported in Appendix A result. Accordingly, ASCO considers adherence to

2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline Thomas J. Smith (Chair), James Khatcheressian, Gary H. Lyman, Howard Ozer, James O. Armitage, Lodovico Balducci, Charles L. Bennett, Scott B. Cantor, Jeffrey Crawford, Scott J. Cross, George Demetri, Christopher E. Desch, Philip A. Pizzo, Charles A. Schiffer, Lee Schwartzberg, Mark R. Somerfield, George Somlo, James C. Wade, James L. Wade, Rodger J. Winn, Antoinette J. Wozniak, and Antonio C. Wolff ABSTRACT Purpose To update the 2000 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors (CSF). Update Methodology The Update Committee completed a review and analysis of pertinent data published from 1999 through September 2005. Guided by the 1996 ASCO clinical outcomes criteria, the Update Committee formulated recommendations based on improvements in survival, quality of life, toxicity reduction and cost-effectiveness. Recommendations The 2005 Update Committee agreed unanimously that reduction in febrile neutropenia (FN) is an important clinical outcome that justifies the use of CSFs, regardless of impact on other factors, when the risk of FN is approximately 20% and no other equally effective regimen that does not require CSFs is available. Primary prophylaxis is recommended for the prevention of FN in patients who are at high risk based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. CSF use allows a modest to moderate increase in dose-density and/or dose-intensity of chemotherapy regimens. Dose-dense regimens should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Prophylactic CSF for patients with diffuse aggressive lymphoma aged 65 years and older treated with curative chemotherapy (CHOP or more aggressive regimens) should be given to reduce the incidence of FN and infections. 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. J Clin Oncol 24:3187-3205. © 2006 by American Society of Clinical Oncology INTRODUCTION The American Society of Clinical Oncology (ASCO) published its first evidence-based clinical practice guideline in 1994 on the use of hematopoietic colony-stimulating factors (CSF). An Update Committee of the original Expert Panel updated this guideline in 1996, 1997, and 2000. For the 2005 update, an Update Committee composed of members from the full Panel and selected ad hoc members was formed to complete the review and analysis of data published since the 2000 Update. A series of computerized literature searches of MEDLINE and the Cochrane Library was performed. Details of the searches are reported in Appendix A. The Update Committee had four face-to-face meetings to consider the evidence for each of the 2005 Recommendations. The guideline was circulated in draft form to the Update Committee for review and approval. ASCO’s Health Services Committee and the ASCO Board of Directors also reviewed the final document.* (*It is important to emphasize that guidelines and technology assessments cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments reasonably directed at obtaining the same result. Accordingly, ASCO considers adherence to From the American Society of Clinical Oncology, Alexandria, VA. Submitted March 14, 2006; accepted March 24, 2006. Authors’ disclosures of potential con- flicts of interest and author contributions are found at the end of this article. Address reprint requests to American Society of Clinical Oncology, Cancer Policy and Clinical Affairs, 1900 Duke Street, Suite 200, Alexandria, VA 22314; e-mail: guidelines@asco.org. © 2006 by American Society of Clinical Oncology 0732-183X/06/2419-3187/$20.00 DOI: 10.1200/JCO.2006.06.4451 JOURNAL OF CLINICAL ONCOLOGY ASCO SPECIAL ARTICLE VOLUME 24 NUMBER 19 JULY 1 2006 3187 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 218 页

this technology assessment to be voluntary, with the ultimate deter- the chemotherapy regimen. For"dose dense"regimens, CSEs are mination regarding its application to be made by the physician in light required and recommended New clinical trial data support the use of of each patients individual circumstances. In addition, this technol- CSF when the risk of FN is in the range of approximately 20%or ogy assessment describes the use of procedures and therapies in clini- higher. The use of regimens, if available, that do not require CSFs cal practice; it cannot be assumed to apply to the use of these because of equal efficacy and lower risk of FN remains standard med interventions performed in the context of clinical trials, given that ical practice. In the absence of special circumstances, most commonly clinical studies are designed to evaluate or validate innovative ap- used regimens have risks of fN of less than 20%(Table 1). In making proaches in a disease for which improved staging and treatment is the decision to use prophylactic CSF or not, oncologists should con needed. In that guideline and technology assessment development sider not only the optimal chemotherapy regimen, but also the indi involve a review and synthesis of the latest literature, a practice guide- vidual patient risk factors and the intention of treatment; that is, line or technology assessment also serves to identify important ques- curative, prolongation of life, or symptom control and palliation. tions and settings for further research. Examples of appropriate use in the curative setting include adjuvant In this review, the Update Committee was guided by the 1996 treatment of early-stage breast cancer with more intensive regimens ASCO outcomes criteria that justify the use of a drug or technology, such as TAC or FEC100 or the use of CHOP or CHOP-like regimens and recommended therapy when compelling positive effects to those in older patients with aggressive non-Hodgkins lymphoma. utcomes was demonstrated. The 2005 Update Committee agreed Special circumstances. Clinicians may occasionally be faced with unanimously that reduction in febrile neutropenia was an important cinical patients who might benefit from relatively nonmyelosuppressive outcome that justified useof CSFs, regardless of impact on other factors, when chemotherapy but who have potential risk factors for febrile neut- the risk of febrile neutropenia(FN)was approximately 20% and no other ropenia or infection because of bone marrow compromise or equally effective regimen that did not require CSFs was available. comorbidity. It is possible that primary CSF administration may be exceptionally warranted in patients at higher risk for chemotherapy- SUMMARY OF RELEVANT BACKGROUND DATA induced infectious complications, even though the data supporting such use are not conclusive Certa in clinical factors predispose to increased complicat Myelotoxicity of Standard Chemotherapy Regimens from prolonged neutropenia, including: patient age greater than 65 benefits and risks. In 1996, the American Society of Clinical On- years: poor performance status; previous episodes of FN; extensive prior treatment including large radiation ports; administration of cology published a list of important clinical outcomes that justify combined chemoradiotherapy; cytopenias due to bone marrow in- the use of a technology or drug in the guideline development volvement by tumor; poor nutritional status; the presence of open process. The clinical outcomes include the following improve- wounds or active infections;, more advanced cancer, as well as other ments in overall or disease-free survival:; improvement in quality of serious comorbidities. In such situations, primary prophylaxis with life; reduced toxicity; and improved cost-effectiveness. Table 1 lists many common chemotherapeutic regimens cur CSF is often appropriate even with regimens with FN rates less than rently in use. Of note, unless these regimens meet or exceed the FN high-risk patients are most often excluded from clinical trials, and this risk threshold suggested in the specific guideline recommendations is not a situation likely to have additional clinical data. that follow, the regimens are usually administered without growth The special circumstances have always been part of ASCOs CSF factor support. Whenever possible, large clinical trials performed guidelines, in recognition that there are patient factors that predict for since the 2000 update are referenced. While this listing is not the rate and severity of febrile neutropenia. These special circum- all-inclusive, it incorporates some new treatment trends such as stances have been maintained from previous versions of the guideline dose-dense therapy Studies dealing with older patients have been There are no additional new data on patients with special circum- included to illustrate a growing interest in the treatment of older stances that predispose to high FN risk. The rate at which the use of cancer patients and concern regarding their tolerance for chemo- CSFs should be considered has changed from 40%to 20%,consis Table 1 documents the febrile neutropenia rates for common usual risk patient, 34. hat demonstrates efficacy in reducing therapy, and a special recommendation has been added for those tent with the new evidence t regimens in everyday use. It is not intended to be a definitive guide to therapy, but as a guide to FN rates. Healthcare providers may 2005 update wish to check the FN rate before prescribing CSFs. Clinical efficacy data. In some situations, primary prophylaxis with CSFs is essential and recommended to alleviate the toxicity of SPECIFIC RECOMMENDATIONS certain"dose dense"chemotherapy regimens. Dose dense regimens have demonstrated efficacy in the adjuvant treatment of breast cancer 1. Recommendations for Primary Prophylactic CSF and possible efficacy in the treatment of elderly patients with aggres Administration ( First and Subsequent-Cycle Use) sive lymphoma, based on one large trial. Two large randomized clinical trials have documented that the 2005 recommendations risk of FN may be reduced substantially by primary prophylaxis with General circumstances. Primary prophylaxis is recommended CSFs, when the risk of FN without CSFs is approximately 20%. Vogel for the prevention of FN in patients who have a high risk of fN based et al randomized 928 patients with metastatic breast cancer( 62%)or on age, medical history, disease characteristics, and myelotoxicity of in the adjuvant setting(38%)to receive or not to receive pegfilgrastim OURNAL OF CLINICAL ONCOLOGY Information downloaded from jco. ascopubs org and 33,阻 arlesworth on August 12, 2009 from 202. 120.79.222 Copyright 2006 by the American Society of Clinical Oncology. All rights reserved

this technology assessment to be voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient’s individual circumstances. In addition, this technology assessment describes the use of procedures and therapies in clinical practice; it cannot be assumed to apply to the use of these interventions performed in the context of clinical trials, given that clinical studies are designed to evaluate or validate innovative approaches in a disease for which improved staging and treatment is needed. In that guideline and technology assessment development involve a review and synthesis of the latest literature, a practice guideline or technology assessment also serves to identify important questions and settings for further research.) In this review, the Update Committee was guided by the 1996 ASCO outcomes criteria that justify the use of a drug or technology, and recommended therapy when compelling positive effects to those outcomes was demonstrated. The 2005 Update Committee agreed unanimouslythat reductioninfebrile neutropeniawas animportant clinical outcomethatjustified use ofCSFs, regardless ofimpact on otherfactors,when the risk of febrile neutropenia (FN) was approximately 20% and no other equally effective regimen that did not require CSFs was available. SUMMARY OF RELEVANT BACKGROUND DATA Myelotoxicity of Standard Chemotherapy Regimens The use of any technology or drug requires a balance of the benefits and risks. In 1996, the American Society of Clinical Oncology published a list of important clinical outcomes that justify the use of a technology or drug in the guideline development process.1 The clinical outcomes include the following: improvements in overall or disease-free survival; improvement in quality of life; reduced toxicity; and improved cost-effectiveness. Table 1 lists many common chemotherapeutic regimens currently in use. Of note, unless these regimens meet or exceed the FN risk threshold suggested in the specific guideline recommendations that follow, the regimens are usually administered without growth factor support. Whenever possible, large clinical trials performed since the 2000 update are referenced. While this listing is not all-inclusive, it incorporates some new treatment trends such as dose-dense therapy. Studies dealing with older patients have been included to illustrate a growing interest in the treatment of older cancer patients and concern regarding their tolerance for chemotherapy, and a special recommendation has been added for those over 65 years of age. Table 1 documents the febrile neutropenia rates for common regimens in everyday use. It is not intended to be a definitive guide to therapy, but as a guide to FN rates. Healthcare providers may wish to check the FN rate before prescribing CSFs. SPECIFIC RECOMMENDATIONS 1. Recommendations for Primary Prophylactic CSF Administration (First and Subsequent-Cycle Use) 2005 recommendations General circumstances. Primary prophylaxis is recommended for the prevention of FN in patients who have a high risk of FN based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. For “dose dense” regimens, CSFs are required and recommended. New clinical trial data support the use of CSF when the risk of FN is in the range of approximately 20% or higher.2,3 The use of regimens, if available, that do not require CSFs because of equal efficacy and lower risk of FN remains standard medical practice. In the absence of special circumstances, most commonly used regimens have risks of FN of less than 20% (Table 1). In making the decision to use prophylactic CSF or not, oncologists should consider not only the optimal chemotherapy regimen, but also the individual patient risk factors and the intention of treatment; that is, curative, prolongation of life, or symptom control and palliation. Examples of appropriate use in the curative setting include adjuvant treatment of early-stage breast cancer with more intensive regimens such as TAC or FEC100 or the use of CHOP or CHOP-like regimens in older patients with aggressive non-Hodgkin’s lymphoma. Special circumstances. Clinicians may occasionally be faced with patients who might benefit from relatively nonmyelosuppressive chemotherapy but who have potential risk factors for febrile neutropenia or infection because of bone marrow compromise or comorbidity. It is possible that primary CSF administration may be exceptionally warranted in patients at higher risk for chemotherapyinduced infectious complications, even though the data supporting such use are not conclusive. Certain clinical factors predispose to increased complications from prolonged neutropenia, including: patient age greater than 65 years; poor performance status; previous episodes of FN; extensive prior treatment including large radiation ports; administration of combined chemoradiotherapy; cytopenias due to bone marrow involvement by tumor; poor nutritional status; the presence of open wounds or active infections; more advanced cancer, as well as other serious comorbidities. In such situations, primary prophylaxis with CSF is often appropriate even with regimens with FN rates less than 20%. This was the consensus opinion of the expert committee. Such high-risk patients are most often excluded from clinical trials, and this is not a situation likely to have additional clinical data. The special circumstances have always been part of ASCO’s CSF guidelines, in recognition that there are patient factors that predict for the rate and severity of febrile neutropenia. These special circumstances have been maintainedfrom previous versions of the guideline. There are no additional new data on patients with special circumstances that predispose to high FN risk. The rate at which the use of CSFs should be considered has changed from 40% to 20%, consistent with the new evidence that demonstrates efficacy in reducing FN rates when the risk is approximately 20%, as noted above for usual risk patients.2,3 2005 update Clinical efficacy data. In some situations, primary prophylaxis with CSFs is essential and recommended to alleviate the toxicity of certain “dose dense” chemotherapy regimens. Dose dense regimens have demonstrated efficacy in the adjuvant treatment of breast cancer and possible efficacy in the treatment of elderly patients with aggressive lymphoma, based on one large trial.4 Two large randomized clinical trials have documented that the risk of FN may be reduced substantially by primary prophylaxis with CSFs, when the risk of FN without CSFs is approximately 20%. Vogel et al randomized 928 patients with metastatic breast cancer (62%) or in the adjuvant setting (38%) to receive or not to receive pegfilgrastim Smith et al 3188 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 219 页

Table 1. Incidence of Hematologic and Infectious Toxicities Associated With Selected Chemotherapy Regimens Cancer Histology Stage and Prior Therapy Regimen No. of Patients Leukopenia (grade 4; %) Neutropenia (grade 4; %) Febrile Neutropenia (%) Fever (grade 2; %)‡ Infection (grade 3; %)§ Infectious Death (%) Adult AML84 Newly diagnosed Ara-C/DNR 163 93 — — 37 (no infection) 64 12 AIDS-related85-87 Advanced/1st and 2nd line Lipo Dox G(M)-CSF 133 36 (3 4) 6 — 1 0 Kaposi’s Sarcoma VP-16 (oral); 36; — 19.4; —— 8 — — — — — Paclitaxel 56 — 35 AIDS-related†88 Intermediate CHOP (modified) 40 — 25 (3 4) 2.5 — — 10 NHL High-grade, untreated CHOP G-CSF 25 — 13 (3 4) 0 — — Bladder89,90 Advanced, no prior systemic therapy GC 203 — 29.9 2 0 2.5 1 MVAC 202 — 65.2 14 3.1 15.1 2.5 Prior adjuvant allowed CBDCA/Pac G-CSF 33 — 21 21 — 1 patient, sepsis 0 Breast18,91-97 Adjuvant CA(60 mg/m2 ) 1060 — 62 10 (hospitalized) — 17 0 CA3T(all dose levels) 1590 — 16 3 — 11 0 CEF 351 49.9 89.7 8.5 — — 0 TAC 109 — — 23.8 — — — A3T3C 484 1 24 3 — 3 0 Adjuvant (dose dense) A3T3C G-CSF 493 — 3 2 — 4 0 AC3T 501 11 43 6 — 5 0 AC3T G-CSF 495 6 9 2 — 3 0 Metastatic (1st line) A (75) 165 — 77.8 12.3 — 4.3 1 death Doc (100) 161 — 78.6 5.7 — 2.5 1 death AC 215 — 88 (3 4) 10 — 2 0.5 AT 214 — 97 (3 4) 33 — 8 0 TAC 54 — 100 (3 4) 34 — 2 0 Metastatic (2nd line) CapDoc 255 — 11 16 — — 1 Doc 256 — 12 21 — — 0 Colorectal98-103 Adjuvant 5-FU/LV/L 449 2 — — — — 1 5-FU/LV 116 15 (high LV) — — — — 1.7 22 (low LV) Advanced IFL 189 — 24 7.1 — 1.8 1 FL 226 — 42.5 14.6 — 0 1.4 I 226 — 12.1 5.8 — 2.2 1 FOLFOX4 152 — 17 6 — — 0 FOLFIRI 145 20.4 (3 4) 28.8 (3 4) 9.3 — 1.9 1 Advanced (one prior chemo allowed) CPT-11 (350 mg/m2 Q3wk) 213 36 (3 4) 48 (3 4) 14 — 1 3 deaths Gastric104 Advanced ECF (infusion) 289 13 32 — 1 6 1 Germ cell105,106 Advanced BEP 141 — 34 — — —2 VIP 145 — 60 — — — 2.8 Relapsed VeIP 135 — — 71 — — 2.1 (all deaths) Head/neck107-109 Recurrent; metastatic 5-FU/CBDCA 86 2.3 1.2 — — — 1.2 CBDCA/Pac 41 4.9 9.8 — — — 2.4 Cis/Doc 36 — 71 6 — 11 0 Induction Cis/Doc/5-FU 43 — 95 (3 4) 19 — 2 0 Lung110-117 Extensive SCLC Cis/VP-16 159 14 38 — — 8 6 (all toxic deaths) No prior treatment CAV 156 28 52 — — 16 4 (all toxic deaths) CBDCA/VP-16 74 5 — — — — 2.6 Cis/CPT-11 77 4 25.3 — 1.3 5.3 3.7 Recurrent Topo 107 31.7 70.2 28 — 4.7 CAV 104 43.6 71.7 26 — 4.8 1 Advanced NSCLC Cis/VNR 206 — 59 10 — — 2 No prior treatment 1 Cis/Pac (24hr) 288 — 57 16 — 10 2 Cis/Gem 288 — 39 4 — 7 1 Cis/Doc 289 — 48 11 — 9 CBDCA/Pac 290 — 43 4 — 6 — CBDCA/Doc 406 49.5 (3 4) 74.4 (3 4) 3.7 — 11 — Recurrent (2nd line) Doc (75 mg/m2 ) 276 40.2 (3 4) — 12.7 — 3.3 Pemetrexed 265 5.3 (3 4) 1.9 — 0 (continued on following page) 2006 Recommendations for WBC Growth Factors www.jco.org 3189 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 220 页

Smith et al Table 1. Incidence of Hematologic and Infectious Toxicities Associated With Selected Chemotherapy Regimens (continued) stage arad prior eukopenia Neutropenia Regimen Patients lgrade 4: %).(gr Neutropenia(%) (grade 22: %)t 3 (no infection) 2 NHL: no prior grade 4) treatment -R 1 18 6 Relapse NHL APEC-B 2 deaths ESHAP DHAP 48 Recurrent/refractory VAD + Inf 654 7.7 78 32.7 Few instances CBDCA/Pac 72 Salvage 82.4 Sarcoma 27,128 Advanced 32 0 5.3 (all study arms) 11 (all study 32 lations-NHL, untreated 5g+4) 16 patents CHOP-R oxaliplatin, fluorouracil, leucovorin; FOL FIRL, irinotecan, fluorouracil (infusion), leucovorin: CPT-11 levamisole: Flde: A,doxorubicin;T,paclitaxel;Doc,docetaxel oxorubic OX4 elP. vin etoposide; Cis/CPT-11, cisplatin, irinotecan: Topo, topotecan; CDDPN, oposide: CAV, cyclophosphamide, doxorubicin, vincristine: CBDCAWP-16 ab: VAPEC-B, vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide methasone carbazine: MAl lophosphamide, vincristine, doxorubicin, dacarbazine: CMF, cyo iNfection 2 grade 3: systemic infection requiring hospitalization. l Includes all grade 4 hematologic malignancies 6 mg after 100 mg/m- docetaxol every 3 weeks for four cycles. The platinum-containing regimens for small-cell lung cancer, with equal incidence of FN(1% versus 17%)and hospitalization for FN (1%v efficacy and less risk of FN and need for prophylactic CSF, has made 14%)was reduced by more than 90%(P<. 001). Atrial of intensified them a standard of care in the US. herapy in 171 patients with small-cell lung cancer, with companion The ASCO CSF Update Committee does not recommend for or randomizations to prophylactic CSF and/or antibiotics showed that against any specific chemotherapy regimen, but the evidence is clear the rate of FN in the first cycle was reduced from 23% with antibiotics that CSFs reduce the incidence of fN when the rate is approximately alone to 10% with antibiotics and CSF; the rate of FN overall was 20%. When available, alternative regimens offering equivalent effi similarly reduced from 32% to 18%(P<. 01). The use of CSF to cacy, but not requiring CSF support, should be utilized. However, reduce the risk of fN is justified to reduce the risk of fN when that risk when regimens are used that have a FN incidence of greater than 20%, is approximately 20%, as with both of these treatment regimens. CSFs have been proven to be effective and are recommended. A new However, if alternative but equal treatment that does not require CSF meta-analysis of prophylactic CSFs in patients with solid tumor or is available, it should be used. Results of efficacy from docetaxol 100 malignant lymphoma was presented at ASCO 2005 and reviewed by mg/m in the first trial have not been reported yet. The efficacy of the Update Committee. The study reports significant reductions in the hm3m:120会m

6 mg after 100 mg/m2 docetaxol every 3 weeks for four cycles. The incidence of FN (1% versus 17%) and hospitalization for FN (1% v 14%)was reduced bymore than 90% (P.001).3A trial of intensified therapy in 171 patients with small-cell lung cancer, with companion randomizations to prophylactic CSF and/or antibiotics showed that the rate of FN in the first cycle was reduced from 23% with antibiotics alone to 10% with antibiotics and CSF; the rate of FN overall was similarly reduced from 32% to 18% (P .01).2 The use of CSF to reduce the risk of FN is justified to reduce the risk of FN when that risk is approximately 20%, as with both of these treatment regimens. However, if alternative but equal treatment that does not require CSF is available, it should be used. Results of efficacy from docetaxol 100 mg/m2 in the first trial have not been reported yet. The efficacy of platinum-containing regimens for small-cell lung cancer, with equal efficacy and less risk of FN and need for prophylactic CSF, has made them a standard of care in the US. The ASCO CSF Update Committee does not recommend for or against any specific chemotherapy regimen, but the evidence is clear that CSFs reduce the incidence of FN when the rate is approximately 20%. When available, alternative regimens offering equivalent effi- cacy, but not requiring CSF support, should be utilized. However, when regimens are used that have a FN incidence of greater than 20%, CSFs have been proven to be effective and are recommended. A new meta-analysis of prophylactic CSFs in patients with solid tumor or malignant lymphoma was presented at ASCO 2005 and reviewed by the UpdateCommittee. The study reports significant reductionsin the Table 1. Incidence of Hematologic and Infectious Toxicities Associated With Selected Chemotherapy Regimens (continued) Cancer Histology Stage and Prior Therapy Regimen No. of Patients Leukopenia (grade 4; %) Neutropenia (grade 4; %) Febrile Neutropenia (%) Fever (grade 2; %)‡ Infection (grade 3; %)§ Infectious Death (%) Lymphoma63,118-122 Relapsed HD; prior RT only MOPP 123 — 22 — 3 (no infection) 13 1 ABVD 115 — 3 — 5 (no infection) 2 0 Intermediate to high grade 6 NHL; no prior treatment CHOP 216 25 22 — 5 ( grade 4) 1 CHOP-R 33 1.2 58 18 — 6 0 Relapse NHL VAPEC-B 39 — 72 44 — 5 pt 2 deaths ESHAP 122 — 500/L median 30 — — 4.1 DHAP 90 — 53 48 31 11 Multiple myeloma123,124 Untreated VAD Inf 169 — — — — — 1.2 Recurrent/refractory VAD Inf 52 65.4 — — — 32.7 7.7 Ovary125,126 Resected, minimal residual Cis/Pac (24 hours) 400 12 78 Few instances — — — CBDCA/Pac 392 6 72 — — — Salvage Topo 139 30.1 82.4 18 — — 0 Sarcoma127,128 Advanced, untreated AD 186 32 38 — — — 0 MAID 188 86 79 — — — 3.5 A 263 13 — — 5.3 (all study arms) 11 (all study arms) — AI 258 32 — — CYVADIC 142 15 — — Special populations34,45 (elderly) NHL, untreated CHOP 197 — — — 5 (3 4) 20 16 patients (both arms) CHOP-R 202 — — — 2 12 Breast, adjuvant CMF 76 4 (grade 3) — — — — NOTE. See cited publications for information regarding chemotherapy agents, doses, and schedules, and the use of CSFs and prophylactic antibiotics. “—” indicates no information. Abbreviations: Ara-C, cytarabine; DNR, daunorubicin; Lipo Dox, liposomal doxorubicin; VP-16, etoposide; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; GC, gemcitabine, cisplatin; M-VAC, methotrexate, vinblastine, doxorubicin, cisplatin; CBDCA/Pac, carboplatin, paclitaxel; CA or AC, doxorubicin, cyclophosphamide; CEF, cyclophosphamide, epirubicin, fluorouracil; TAC, docetaxel, doxorubicin, cyclophosphamide; A, doxorubicin; T, paclitaxel; Doc, docetaxel; AT, doxorubicin, docetaxel; CapDoc, capecitabine, docetaxel; 5-FU/LV/L, fluorouracil, leucovorin, levamisole; IFL, irinotecan, fluorouracil, leucovorin; FOLFOX4, oxaliplatin, fluorouracil, leucovorin; FOLFIRI, irinotecan, fluorouracil (infusion), leucovorin; CPT-11, irinotecan; ECF, epirubicin, cisplatin, fluorouracil (infusion); BEP, bleomycin, etoposide, cisplatin; VIP, etoposide, ifosfamide, cisplatin; VeIP, vinblastine, ifosfamide, cisplatin; 5-FU/CBDCA, fluorouracil, carboplatin; 5-FU/Cis, fluorouracil, cisplatin; Cis/Doc, cisplatin, docetaxel; Cis/VP-16, cisplatin, etoposide; CAV, cyclophosphamide, doxorubicin, vincristine; CBDCA/VP-16, carboplatin, etoposide; Cis/CPT-11, cisplatin, irinotecan; Topo, topotecan; CDDP/VNR, cisplatin, vinorelbine; Cis/Pac, cisplatin, paclitaxel; Cis/Gem, cisplatin, gemcitabine; CBDCA/doc, carboplatin, docetaxel; MOPP, mechlorethamine, vincristine, procarbazine, prednisone; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; CHOP-R, cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab; VAPEC-B, vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide, bleomycin; ESHAP, etoposide, methylprednisolone, Ara-C, cisplatin; DHAP, dexamethasone, cisplatin, cytarabine; VAD, vincristine, doxorubicin, dexamethasone; inf, alpha interferon; AD, doxorubicin, dacarbazine; MAID, mesna, doxorubicin, ifosfamide, dacarbazine; A, doxorubicin; AI, doxorubicin, ifosfamide; CYVADIC, cyclophosphamide, vincristine, doxorubicin, dacarbazine; CMF, cyclophosphamide, methotrexate, fluorouracil. Grade 4 leukopenia: WBC count 1.0 109 /L; grade 4 neutropenia: ANC 0.5 109 /L. †Most patients received antiretroviral therapy and data do not include opportunistic infections. ‡Common Toxicity Criteria Fever grade 2; 38.1°C ( 100.5°F). §Infection grade 3: systemic infection requiring hospitalization. Includes all grade 4 hematologic malignancies. Smith et al 3190 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 221 页

2006 Recommendations for wBC Growth Factors risk of FN from 37% to 20%(14 studies, n=3,091, relative risk support, but none of the other significant clinical outcomes(sur reduction 46%, P 10 days) and profound(<0.1 X 10/L)neutro hat basis penia, age greater than 65 years, uncontrolled primary disease. A valid model to predict who will develop FN, so that CSF use pneumonia, hypotension and multiorgan dysfunction (sepsis syn could be restricted to that group, would represent a major advance in drome), invasive fungal infection, or being hospitalized at the time of patient management. A systematic review of previously report the development of fever. This was the consensus opinion of the models has identified a number of risk factors for either en occur. update committee, as there are no new data. Prior Infectious Disease rence or for adverse outcome of established FN&9 While current Society of America guidelines have supported the use of CSFs models are promising, they are based on retrospective data sets and sImilar nces,referring to the ASCO guidelines 2005 update. Several relevant studies have been reported since tential to improve the efficacy and cost-effectiveness of growth factor 2000. In a multicenter trial conducted in Spain, adult patients with prophylaxis and therapy. solid tumors or lymphoma who developed FN and had at least one high-risk factor, were treated with intravenous antibiotics and ran 2. Recommendations for Secondary Prophylactic domly assigned to receive G-CSF(5 ug/kg per day)until neutrophil CsF Administration recovery. CSF recipients had a shorter period of grade 4 neutropenia (median 2 versus 3 days, P=0004), antibiotic therapy(median 5 2005 recommendation versus 6 days, P=.013), and hospital stay (median 5 versus 7 days, Secondary prophylaxis with CSFs is recommended for pa- P=.015). Survival between groups was similar tients who experienced a neutropenic complication from a prior Two meta-analyses of trials of adjunctive CSF therapy for cancer cycle of chemotherapy (for which primary prophylaxis was not patients with FN have now been reported. These analyses included received),in which a reduced dose may compromise disease-free different patient numbers as a consequence of different search strate- or overall survival or treatment outcome. In many clinical situa- gies and the inclusion by one analysis of data that was not published ir tions, dose reduction or delay may be a reasonable alternative English. Berghmans analysis, which incorporated 962 patients, de- tected no advantage for the use of CSF in terms of mortality from FN, 2005 update with a relative risk of 0.71(95%CI 0.44 to 1.15). No other analysis of Since the 2000 update, no prospective studies of secondary clinical benefit was reported. In a Cochrane systematic review and CSF prophylaxis have been reported. Dose reduction or delay meta-analysis, which included 1518 patients from 13 trials, patients remains an appropriate strategy for the palliative treatment of randomized to receive CSF experienced less prolonged neutropenia cancer, as there is no evidence that dose maintenance or escalation (25% versus 45%%; OR=0.32[0.23-0.46]; P<. 00001), less prolonged improves clinically important outcomes in this setting hospitalization(23% versus 32%%; OR=0.63 [0.49-0.82];P=0006), For adjuvant therapy, conditional models have been devel arginally less infection-related mortality (3. 1% versus 5.7% oped based on the nadir neutrophil count during cycle 1. Rivera et OR=0.51 [0.26-1.00; P=.05)and no significant difference in al conducted a prospective clinical trial that assigned women re- overall mortality(5.1% versus 7. 1%; r=0.68[0.43-1.06];P= 10). eiving adjuvant breast cancer chemotherapy who experience and arthralgias were more common in CSF treated neutropenia of less than 500/mmin cycle 1 to granulocyte colony patients(P=.007) stimulating factor(G-CSF) in subsequent cycles. The G-CSF Clinical prediction models have been developed to help prospec- recipients experienced fewer episodes of hospitalization for FN and tively identify patients with cancer who are at higher risk of complica- reater dose-intensity compared to historical controls without CSF tions as a result of fever and neutropenia. Reported risk factors for co.org

risk of FN from 37% to 20% (14 studies, n 3,091, relative risk reduction 46%, P .0001) and the risk of infection-related mortality from 3.3% to 1.7% (10 studies, n 2,468, relative risk reduction 48%, P .01).5 Impact on overall mortality has not been reported. If this result is confirmed in the final publication, it will provide more support for the use of prophylactic CSFs in regimens with sufficient risk. There are new datafor specific clinical situations.Ameta-analysis of 12 randomized trials from 1992 to 2003 with 1,823 non-Hodgkin’s lymphoma (NHL) and Hodgkin’s disease (HD) patients found that, compared with no prophylaxis, prophylactic CSFs significantly reduced the relative risk (RR) of severe neutropenia (RR 0.67; 95% CI 0.60 to 0.73), febrile neutropenia (RR 0.74; 95% CI 0.62 to 0.89), and infection (RR 0.74; 95% CI 0.64 to 0.85). However, there was no evidence that CSFs reduced the number of patients requiring intravenous antibiotics (RR 0.82; 95% CI 0.57 to 1.18), lowered infectionrelated mortality (RR 1.37; 95% CI 0.66 to 2.82); or improved complete tumor response (RR 1.02; 95% CI 0.94 to 1.11), freedom from treatment failure (hazard ratio 1.11; 95% CI 0.91 to 1.35), or overall survival (hazard ratio 1.00, 95% CI 0.86 to 1.16).6 One study evaluated quality of life and found no differences with CSFs.7 Overall, the impact of CSFs on the disease has been small and does not routinely warrant use to improve survival. CSFs do reduce the risk of FN significantly, and were recommended by the update committee on that basis. A valid model to predict who will develop FN, so that CSF use could be restricted to that group, would represent a major advance in patient management. A systematic review of previously reported models has identified a number of risk factors for either FN occurrence or for adverse outcome of established FN.8,9 While current models are promising, they are based on retrospective data sets and need prospective validation. Future prospective models have the potential to improve the efficacy and cost-effectiveness of growth factor prophylaxis and therapy. 2. Recommendations for Secondary Prophylactic CSF Administration 2005 recommendation Secondary prophylaxis with CSFs is recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose may compromise disease-free or overall survival or treatment outcome. In many clinical situations, dose reduction or delay may be a reasonable alternative. 2005 update Since the 2000 update, no prospective studies of secondary CSF prophylaxis have been reported. Dose reduction or delay remains an appropriate strategy for the palliative treatment of cancer, as there is no evidence that dose maintenance or escalation improves clinically important outcomes in this setting. For adjuvant therapy, conditional models have been developed based on the nadir neutrophil count during cycle 1. Rivera et al conducted a prospective clinical trial that assigned women receiving adjuvant breast cancer chemotherapy who experienced neutropenia of less than 500/mm3 in cycle 1 to granulocyte colony stimulating factor (G-CSF) in subsequent cycles.10 The G-CSF recipients experienced fewer episodes of hospitalization for FN and greater dose-intensity compared to historical controls without CSF support, but none of the other significant clinical outcomes (survival, quality of life, toxicity, or cost) were reported. Based on the available data, no definitive conclusions can be drawn regarding the benefits of secondary prophylaxis on survival, quality of life, or cost. Randomized trials to properly test the hypothesis are required. 3. Recommendations for Therapeutic Use of CSF A. Therapy of patients with afebrile neutropenia 2005 recommendation. CSFs should not be routinely used for patients with neutropenia who are afebrile. 2005 update. There are no new published data since the 2000 ASCO guideline that pertain to the use of CSF in patients who are afebrile and neutropenic. B. Therapy of febrile patients with neutropenia 2005 recommendation. CSFs should not be routinely used as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia. However, CSFs should be considered in patients with fever and neutropenia who are at high-risk for infectionassociated complications, or who have prognostic factors that are predictive of poor clinical outcomes. High-risk features include expected prolonged ( 10 days) and profound ( 0.1 109 /L) neutropenia, age greater than 65 years, uncontrolled primary disease, pneumonia, hypotension and multiorgan dysfunction (sepsis syndrome), invasive fungal infection, or being hospitalized at the time of the development of fever. This was the consensus opinion of the update committee, as there are no new data. Prior Infectious Disease Society of America guidelines have supported the use of CSFs in similar circumstances, referring to the ASCO guidelines. 2005 update. Several relevant studies have been reported since 2000. In a multicenter trial conducted in Spain, adult patients with solid tumors or lymphoma who developed FN and had at least one high-risk factor, were treated with intravenous antibiotics and randomly assigned to receive G-CSF (5 g/kg per day) until neutrophil recovery. CSF recipients had a shorter period of grade 4 neutropenia (median 2 versus 3 days, P .0004), antibiotic therapy (median 5 versus 6 days, P .013), and hospital stay (median 5 versus 7 days, P .015).11 Survival between groups was similar. Two meta-analyses of trials of adjunctive CSF therapy for cancer patients with FN have now been reported. These analyses included different patient numbers as a consequence of different search strategies and the inclusion by one analysis of data that was not published in English. Berghmans’ analysis, which incorporated 962 patients, detected no advantage for the use of CSF in terms of mortality from FN, with a relative risk of 0.71 (95% CI 0.44 to 1.15). No other analysis of clinical benefit was reported.12 In a Cochrane systematic review and meta-analysis, which included 1518 patients from 13 trials, patients randomized to receive CSF experienced less prolonged neutropenia (25% versus 45%; OR 0.32 [0.23-0.46]; P .00001), less prolonged hospitalization (23% versus 32%; OR 0.63 [0.49-0.82]; P .0006), marginally less infection-related mortality (3.1% versus 5.7%; OR 0.51 [0.26-1.00]; P .05) and no significant difference in overall mortality (5.1% versus 7.1%; r 0.68 [0.43-1.06]; P .10).13 Bone, joint pain, and arthralgias were more common in CSF treated patients (P .007). Clinical prediction models have been developed to help prospectively identify patients with cancer who are at higher risk of complications as a result of fever and neutropenia.14,15Reported risk factors for 2006 Recommendations for WBC Growth Factors www.jco.org 3191 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 222 页

Smith et al serious medical complications, including death, in patients with estab- therapy with filgrastim and blood progenitor cell support. lished FN include the development of FN as an inpatient; hypoten- Treatment time was reduced, and the rate of FN was reduced by 4% sion;sepsis; various comorbidities, including cardiovascular and in the dose-dense group(11% versus 15%), but there was no pulmonary disease; leukemiaorlymphoma diagnosis; age greater than clinical advantage. Overall response rates, median survival, 1-and 65 years, prior fungal infection; visceral organ involvement; organ 2-year survival, and overall survival were unchanged. dysfunction; uncontrolled malignancy, and the severity and duration There are two recent trials of dose-intense therapy in small- of neutropenia. cell lung cancer. A recent randomized trial of chemotherapy for Two recent studies have reported that hypotension and bacter- small-cell lung cancer with cyclophosphamide, adriamycin, and mia in the setting of neutropenia are significant risk factors for pro- etoposide attempted to increase relative dose-intensity and prevent longed hospitalization(> 7 days)and high mortality. Malik et al infections by the use of G-CSF at standard doses, and/or prophy- reported a mortality rate associated with FN in patients presenting lactic antibiotics. Increasing the dose-intensity by 70% was associ- with shock of 82%, and a study from France reported that patients ated with more grade 4 leukopenia(79% versus 50%); grade 4 admitted to an ICU with FN experienced a 54% 30-day mortality. thrombocytopenia(44% versus 11%); anorexia, nausea, and mu- While a number of clinical characteristics may provide prognostic cositis; but not deaths. Response rates, median survival, and 2-year information regarding the outcomes of hospitalized patients with FN, survival rates were not different between the experimental and predictive models are needed to better identify high-risk patients who control arms. Timmer-Bonte et al intensified therapy for 171 may benefit from the addition of adjunctive CSFs. a risk model for patients with small cell lung cancer. As noted above, the rate of fN mortality in hospitalized cancer patients with FN has recently been in the first cycle was reduced from 23% with antibiotics alone to reported In a multivariate model, several independent risk factors for 10% with antibiotics and CSF; the rate of FN overall was similarly npatient mortality among hospitalized patients with FN have been reduced from 32% to 18%. There was no major effect on the identified including: age 2 65, cancer type(leukemia, lung cancer), disease itself. As noted by the authors, this therapy is used in comorbidities( CHE, PE, lung, renal, liver, and cerebrovascular dis- Europe but not the US where platinum-containing regimens ease), and infectious complications(hypotension, pneumonia, bacte- are used with equal efficacy, and less need for routine CSF support. rema, a Berghmans et al performed a meta-analysis of 12 studies since 4. Recommendations for use of csfs to ncrease 1991, including a total of 2, 107 randomized patients. The authors Chemotherapy Dose-Intensity and Dose-Density concluded that there was no significant impact of CSFs survival from dose-maintenance or dose-intensification 05 A recent study of young patients with diffuse aggressiv Use of CSEs allows a modest to moderate increase in dose- NHL compared CHOP every 21 days( CHOP-21)to CHOP every density and/or dose-intensity of chemotherapy regimens. Avail- 14 days with CSF support(CHOP-14), with or without etoposide able data would suggest a survival benefit from the use of dose- CHOEP-21, CHOEP-14)in 2 X 2 factorial design; the primary dense(but not dose-intense)regimens with CSF support in a few end point of the study was event-free survival(EFS). The addition specific settings (eg, node-positive breast cancer; and possibly of CSF to CHOP (CHOP-14 versus CHOP-21)displayed a statis- NHL pending confirmation of results of individual trials). How- tically significant improvement to EFS(RR=0.61: CI 0.38 to 0.99, ever, additional data in these settings are needed and these results P=.048), while the addition of CSF to the etoposide arm cannot be generalized to other disease settings and regimens. Dose- (CHOEP-14 versus CHOEP-21)showed no difference in EFS(P dense regimens should only be used within an appropriately de-. 842)or overall survival(P=472). In elderly diffuse aggressive igned clinical trial or if supported by convincing efficacy data. lymphoma patients on another study of similar design, there ap peared to be a greater benefit with the reduction in cycle length to 2005 update: Dose density two weeks, facilitated by the addition of CSF(CHOP-14),com There has been increasing interest in the development of pared to standard CHOP(CHOP-21), with improvements in EFS dose-dense chemotherapy schedules for a variety of tumor types. (RR=0.66, P=.003)and overall survival(rR=0.58, P<.001). We have summarized the evidence from randomized studies of the most common tumor types treated in a dose-dense fashion. 5. Recommendation for the Use of CSFs As Adjuncts Citron et al demonstrated a disease-free and overall survival to Progenitor-Cell Transplantation benefit to dose-dense chemotherapy with CSF versus standard 2005 recommendation chemotherapy scheduling in node-positive breast cancer Administration of CSFs to mobilize peripheral-blood progen The use of CSFs to intensify therapy for small-cell lung cancer itor cell(PBPC)often in conjunction with chemotherapy and their has reduced the risk of N but had mixed results in treatment of the administration after autologous, but not allogeneic, PBPC trans- disease. There are two recent trials of dose-dense therapy. Thatcher plantation is the current standard et al used every 2 week dose-dense therapy(doxorubicin, cyclo- phosphamide and etoposide) versus conventional every 3 week 2005 update therapy in 403 patients with small-cell lung cancer; survival at 12 The major complications of high-dose chemothera months was increased to 47% from 39%and to 13% from 8% at 24 ported by autologous bone marrow transplantation(BMT)or months(HR=0.80; 95%CI 0.65 to 0.99 P=.04). Quality of life PBPC transplantation are disease recurrence, infection, the need and toxicities were similar in the two groups. More recently, for RBC and platelet transfusions, delayed or incomplete engraft morrigan et al randomized 318 patients with good-prognosis small- ment, and organ damage from the ablative regimen. Prolonged lI lung cancer to standard chemotherapy or dose-dense chemo- hospitalization and the high cost of treatment are also associated OURNAL OF CLINICAL ONCOLOGY Information downloaded from jco. ascopubs org and 33y阻 arlesworth on August 12, 2009 from 202. 120.79.222 Copyright 2006 by the American Society of Clinical Oncology. All rights reserved

seriousmedical complications,including death,in patientswith established FN include the development of FN as an inpatient; hypotension; sepsis; various comorbidities, including cardiovascular and pulmonary disease;leukemia orlymphoma diagnosis; age greater than 65 years, prior fungal infection; visceral organ involvement; organ dysfunction; uncontrolled malignancy; and the severity and duration of neutropenia. Two recent studies have reported that hypotension and bacteremia in the setting of neutropenia are significant risk factors for prolonged hospitalization ( 7 days) and high mortality. Malik et al reported a mortality rate associated with FN in patients presenting with shock of 82%,16 and a study from France reported that patients admitted to an ICU with FN experienced a 54% 30-day mortality.17 While a number of clinical characteristics may provide prognostic information regarding the outcomes of hospitalized patients with FN, predictive models are needed to better identify high-risk patients who may benefit from the addition of adjunctive CSFs. A risk model for mortality in hospitalized cancer patients with FN has recently been reported. In a multivariate model, several independent risk factors for inpatient mortality among hospitalized patients with FN have been identified including: age 65, cancer type (leukemia, lung cancer), comorbidities (CHF, PE, lung, renal, liver, and cerebrovascular disease), and infectious complications (hypotension, pneumonia, bacteremia, and fungal infection).5 4. Recommendations for Use of CSFs to Increase Chemotherapy Dose-Intensity and Dose-Density 2005 recommendation Use of CSFs allows a modest to moderate increase in dosedensity and/or dose-intensity of chemotherapy regimens. Available data would suggest a survival benefit from the use of dosedense (but not dose-intense) regimens with CSF support in a few specific settings (eg, node-positive breast cancer; and possibly NHL pending confirmation of results of individual trials). However, additional data in these settings are needed and these results cannot be generalized to other disease settings and regimens. Dosedense regimens should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. 2005 update: Dose density There has been increasing interest in the development of dose-dense chemotherapy schedules for a variety of tumor types. We have summarized the evidence from randomized studies of the most common tumor types treated in a dose-dense fashion. Citron et al demonstrated a disease-free and overall survival benefit to dose-dense chemotherapy with CSF versus standard chemotherapy scheduling in node-positive breast cancer.18 The use of CSFs to intensify therapy for small-cell lung cancer has reduced the risk of FN but had mixed results in treatment of the disease. There are two recent trials of dose-dense therapy. Thatcher et al used every 2 week dose-dense therapy (doxorubicin, cyclophosphamide and etoposide) versus conventional every 3 week therapy in 403 patients with small-cell lung cancer; survival at 12 months was increased to 47% from 39% and to 13% from 8% at 24 months (HR 0.80; 95% CI 0.65 to 0.99; P .04). Quality of life and toxicities were similar in the two groups.7 More recently, Lorrigan et al randomized 318 patients with good-prognosis smallcell lung cancer to standard chemotherapy or dose-dense chemotherapy with filgrastim and blood progenitor cell support. Treatment time was reduced, and the rate of FN was reduced by 4% in the dose-dense group (11% versus 15%), but there was no clinical advantage. Overall response rates, median survival, 1- and 2-year survival, and overall survival were unchanged.19 There are two recent trials of dose-intense therapy in smallcell lung cancer. A recent randomized trial of chemotherapy for small-cell lung cancer with cyclophosphamide, adriamycin, and etoposide attempted to increase relative dose-intensity and prevent infections by the use of G-CSF at standard doses, and/or prophylactic antibiotics. Increasing the dose-intensity by 70% was associated with more grade 4 leukopenia (79% versus 50%); grade 4 thrombocytopenia (44% versus 11%); anorexia, nausea, and mucositis; but not deaths. Response rates, median survival, and 2-year survival rates were not different between the experimental and control arms.20 Timmer-Bonte et al intensified therapy for 171 patients with small cell lung cancer. As noted above, the rate of FN in the first cycle was reduced from 23% with antibiotics alone to 10% with antibiotics and CSF; the rate of FN overall was similarly reduced from 32% to 18%.2 There was no major effect on the disease itself. As noted by the authors, this therapy is used in Europe but not the US where platinum-containing regimens are used with equal efficacy, and less need for routine CSF support. Berghmans et al performed a meta-analysis of 12 studies since 1991, including a total of 2,107 randomized patients.21The authors concluded that there was no significant impact of CSFs survival from dose-maintenance or dose-intensification. A recent study22 of young patients with diffuse aggressive NHL compared CHOP every 21 days (CHOP-21) to CHOP every 14 days with CSF support (CHOP-14), with or without etoposide (CHOEP-21, CHOEP-14) in 2 2 factorial design; the primary end point of the study was event-free survival (EFS). The addition of CSF to CHOP (CHOP-14 versus CHOP-21) displayed a statistically significant improvement to EFS (RR 0.61; CI 0.38 to 0.99, P .048), while the addition of CSF to the etoposide arm (CHOEP-14 versus CHOEP-21) showed no difference in EFS (P .842) or overall survival (P .472). In elderly diffuse aggressive lymphoma patients on another study of similar design, there appeared to be a greater benefit with the reduction in cycle length to two weeks, facilitated by the addition of CSF (CHOP-14), compared to standard CHOP (CHOP-21), with improvements in EFS (RR 0.66, P .003) and overall survival (RR 0.58, P .001).4 5. Recommendation for the Use of CSFs As Adjuncts to Progenitor-Cell Transplantation 2005 recommendation Administration of CSFs to mobilize peripheral-blood progenitor cell (PBPC) often in conjunction with chemotherapy and their administration after autologous, but not allogeneic, PBPC transplantation is the current standard of care. 2005 update The major complications of high-dose chemotherapy supported by autologous bone marrow transplantation (BMT) or PBPC transplantation are disease recurrence, infection, the need for RBC and platelet transfusions, delayed or incomplete engraftment, and organ damage from the ablative regimen. Prolonged hospitalization and the high cost of treatment are also associated Smith et al 3192 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 223 页

2006 Recommendations for wBC Growth Factors with autologous transplant. The same problems, plus graft-versus- 2005 update: CSF priming of leukemia cells in patients with AML. host disease(GvHD) and graft rejection, are also present in pa- A randomized trial published in 2003 evaluated priming with tients undergoing allogeneic BMT or allogeneic PBPC G-CSF in younger adults(aged 18 to 60 years)receiving initial transplantation. Among autologous PBPC patients, post- induction therapy, and demonstrated a higher rate of disease-free transplant G-CSF use has been associated with savings in the du- survival in the G-CSF recipients, though there was no effect on Cr ration of hospitalization and overall medical costs. In contrast, rate or overall survival. The effect was most prominent in the G-CSF use following allogeneic blood SCT has been shown to subgroup of patients with"standard risk"cytogenetics, with no decrease the duration of absolute neutropenia, but did not lead to benefit for those in better or unfavorable risk groups. There is no shorter hospitalizations, cost savings, or less frequent antibiotic standard definition of this biologically and clinically heteroge- use neous group of standard risk" patients, and it is not clear how to However, CSFs used after allogeneic transplantation have apply this finding in clinical practice. A large European trial been reported to increase the incidence of severe GvHD and mized patients older than 60 years of age who had AML reduce survival. A 2004 European study of 1,789 patients with receive either no growth factor or G-CSF given during, during and acute leukemia who received BMT found a higher rate of GvHD after, or after the completion of therapy. Although the complete of grades 2 to 4 among patients receiving G-CSF than among remission rate was higher in the two groups of patients who re controls(50% versus 39%). The G-CSF group also had a higher ceived the G-CSF simultaneous with the chemotherapy(60%ver sk of transplantation-related mortality(RR 1.73, P=.00016). sus 50%, P=.01), there was no difference in event-free or overall Patients who received G-CSF also had a lower overall survival(rr survival, and the authors concluded that the"quality" of these 0.59, P<0001)and lower leukemia-free survival(RR 0.645, P= remissions was poor. 0003). An adverse effect on survival was not noted in recipients of Consolidation therapy for patients with AML in peripheral blood stem cell The use of CSFs to mobilize peripheral blood progenitor cells complete remission 2005 recommendation for consolidation chemotherapy in AML. (PBPC)and to shorten the period of neutropenia after cytoreduc- CsF use can be recommended after the completion of consolidation reports of splenic rupture and severe thrombocytopenia have been chemotherapy because of the potential to decrease the incidence of tion and PBPC transplantation, is well established. Although rare, documented after use of filgrastim, lenograstim, and sargramostim patients receiving intensive postremission chemotherapy. There for PBPC mobilization. Individuals receiving CSFs for mobiliza- seems to be more profound shortening of the duration of neutro- tion should have their platelet counts monitored. Filgrastim is indicated for the mobilization of hematopoietic progenitor cells penia after consolidation chemotherapy for patients with AML in into the peripheral blood for collection by leukapheresis. . The There is no effect on the duration of complete response duration or tion ar Itly being investigated in phase I/II studies There is, as yet, no information about the effect of longer acting, 6. Recommendations for Use of CSes in Patients With pegylated CSFs in patients with myeloid leukemias, and they should Acute Leukemia and Myelodysplastic Syndromes not be used in such patients outside of clinical trials. 2005 update: Consolidation therapy for patients with AMl in con Because considerations are different for acute myeloid leuke- plete remission. Postremission chemotherapy is routinely adminis- mia(AML), acute lymphocytic leukemia(ALL), and myelodys- tered to patients with AML in an attempt to increase the probability of plastic syndrome(MDS), evidence and recommendations for each long-term, disease-free survival in younger patients. In most cen re discussed separately ters, this chemotherapy is administered either in the outpatient AML setting or during a brief hospital admission after which the patient 2005 recommendation for initialinduction chemotherapy. Several is discharged to home. Two large randomized trials evaluated the studies have shown that CSF administration can produce modest role of G-CSF given after completion of relatively standard consol decreases in the duration of neutropenia when begun shortly after idation therapy to such patients. 30. 3 Both demonstrated marked completion of the initial induction chemotherapy. Beneficial effects decreases in the duration of severe neutropenia, with elimination on end points such as duration of hospitalization and incidence of severe neutropenia in a fraction of patients. This was associated severe infections have been variable and modest. CSF use following with a decreased rate of infection requiring antibiotic therapy initial induction therapy is reasonable, although there has been no cre was no effect on complete response duration or overall favorable impact on remission rate, remission duration or survival. patient survival Patients older than 55 years of age may be most likely to benefit from MDs 2005 recommendation. No change from 2000 update. CSFs can 2005 update: Primary CSF administration after initial increase the absolute neutrophil count in neutropenic patients with induction chemotherapy for AML myelodysplastic syndromes(MDS). Data supporting the rout There have been no major studies published since the 2000 update. long-term continuous use of CSFs in these patients are lacking. Inter mittent administration of CSFs may be considered in a subset of CSF priming of leukemia cells in patients with AML patients with severe neutropenia and recurrent infection. 2005 recommendation for CSFs for priming effects. Use of CSFs 2005 update. There have been no studies with results that for priming effects is not recommended change the recommendation. co.org 3193 Information downloaded from jco. ascopubs org and 3刮 halesworth on august 12, 2009 from 202. 120.79.222 Copyright 2006 by the American Society of Clinical Oncology. All rights reserved

with autologous transplant. The same problems, plus graft-versushost disease (GvHD) and graft rejection, are also present in patients undergoing allogeneic BMT or allogeneic PBPC transplantation. Among autologous PBPC patients, posttransplant G-CSF use has been associated with savings in the duration of hospitalization and overall medical costs.23 In contrast, G-CSF use following allogeneic blood SCT has been shown to decrease the duration of absolute neutropenia, but did not lead to shorter hospitalizations, cost savings, or less frequent antibiotic use.24 However, CSFs used after allogeneic transplantation have been reported to increase the incidence of severe GvHD and to reduce survival. A 2004 European study of 1,789 patients with acute leukemia who received BMT25 found a higher rate of GvHD of grades 2 to 4 among patients receiving G-CSF than among controls (50% versus 39%). The G-CSF group also had a higher risk of transplantation-related mortality (RR 1.73, P .00016). Patients who received G-CSF also had a lower overall survival (RR 0.59, P .0001) and lower leukemia-free survival (RR 0.645, P .0003). An adverse effect on survival was not noted in recipients of peripheral blood stem cells. The use of CSFs to mobilize peripheral blood progenitor cells (PBPC) and to shorten the period of neutropenia after cytoreduction and PBPC transplantation, is well established. Although rare, reports of splenic rupture and severe thrombocytopenia have been documented after use of filgrastim, lenograstim, and sargramostim for PBPC mobilization. Individuals receiving CSFs for mobilization should have their platelet counts monitored. Filgrastim is indicated for the mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.26,27 The efficacy and safety of newer CSFs in the setting of PBPC mobilization are currently being investigated in phase I/II studies. 6. Recommendations for Use of CSFs in Patients With Acute Leukemia and Myelodysplastic Syndromes Because considerations are different for acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS), evidence and recommendations for each are discussed separately. AML 2005 recommendationforinitialinduction chemotherapy. Several studies have shown that CSF administration can produce modest decreases in the duration of neutropenia when begun shortly after completion of the initial induction chemotherapy. Beneficial effects on end points such as duration of hospitalization and incidence of severe infections have been variable and modest. CSF use following initial induction therapy is reasonable, although there has been no favorable impact on remission rate, remission duration or survival. Patients older than 55 years of age may be most likely to benefit from CSF use. 2005 update: Primary CSF administration after initial induction chemotherapy for AML There have been no major studies published since the 2000 update. CSF priming of leukemia cells in patients with AML 2005 recommendation for CSFs for priming effects. Use of CSFs for priming effects is not recommended. 2005 update: CSF priming of leukemia cells in patients with AML. A randomized trial published in 2003 evaluated priming with G-CSF in younger adults (aged 18 to 60 years) receiving initial induction therapy, and demonstrated a higher rate of disease-free survival in the G-CSF recipients, though there was no effect on CR rate or overall survival. The effect was most prominent in the subgroup of patients with “standard risk” cytogenetics, with no benefit for those in better or unfavorable risk groups. There is no standard definition of this biologically and clinically heterogeneous group of “standard risk” patients, and it is not clear how to apply this finding in clinical practice.28 A large European trial randomized patients older than 60 years of age who had AML to receive either no growth factor or G-CSF given during, during and after, or after the completion of therapy. Although the complete remission rate was higher in the two groups of patients who received the G-CSF simultaneous with the chemotherapy (60% versus 50%, P .01), there was no difference in event-free or overall survival, and the authors concluded that the “quality” of these remissions was poor.29 Consolidation therapy for patients with AML in complete remission 2005 recommendation for consolidation chemotherapy in AML. CSF use can be recommended after the completion of consolidation chemotherapy because of the potential to decrease the incidence of infection and eliminate the likelihood of hospitalization in some patients receiving intensive postremission chemotherapy. There seems to be more profound shortening of the duration of neutropenia after consolidation chemotherapy for patients with AML in remission than for patients receiving initial induction therapy. There is no effect on the duration of complete response duration or overall survival. There is, as yet, no information about the effect of longer acting, pegylated CSFs in patients with myeloid leukemias, and they should not be used in such patients outside of clinical trials. 2005 update: Consolidation therapy for patients with AML in complete remission. Postremission chemotherapy is routinely administered to patients with AML in an attempt to increase the probability of long-term, disease-free survival in younger patients. In most centers, this chemotherapy is administered either in the outpatient setting or during a brief hospital admission after which the patient is discharged to home. Two large randomized trials evaluated the role of G-CSF given after completion of relatively standard consolidation therapy to such patients.30,31 Both demonstrated marked decreases in the duration of severe neutropenia, with elimination of severe neutropenia in a fraction of patients. This was associated with a decreased rate of infection requiring antibiotic therapy. There was no effect on complete response duration or overall patient survival. MDS 2005 recommendation. No change from 2000 update. CSFs can increase the absolute neutrophil count in neutropenic patients with myelodysplastic syndromes (MDS). Data supporting the routine long-term continuous use of CSFs in these patients are lacking. Intermittent administration of CSFs may be considered in a subset of patients with severe neutropenia and recurrent infection. 2005 update. There have been no studies with results that change the recommendation. 2006 Recommendations for WBC Growth Factors www.jco.org 3193 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 224 页

ALL 8. Recommendations for use of csfs in older 2005 recommendation. CSFs are recommended after the com- Patients(Note: This Topic is New to the Guideline) pletion of the initial first few days of chemotherapy of the initial induction or first postremission course, thus shortening the duration 2005 recommendation of neutropenia of less than 1,000/mm by approximately 1 week. Prophylactic CSF for patients with diffuse aggressive lym There are less consistent effects on the incidence and duration of phoma aged 65 and older treated with curative chemotherapy hospitalization and the acquisition of serious infections. Although (CHOP or more aggressive regimens)should be given to reduce there was a trend for improved CR rates in one large study, particu larly in older adults, there was no prolongation of disease-free or Definition of the problem overall survival in any of the trials. G-CSF can be given together with Age and risk of chemotherapy-induced neutropenia. Aging is one the continued corticosteroid/antimetabolite therapy, which is a of the conditions for which prophylactic use of growth factors may be feature of many ALL regimens, without evidence that such concurrent indicated irrespective of the threshold risk of neutropenia. Multiple herapy prolongs the myelosuppressive effects of the chemotherapy. studies, primarily in breast cancer patients, have found that the risk of As in AML, it is unknown from the published data whether the CSFs neutropenia following chemotherapy increases with age. 34-37The significantly accelerate recovery to neutrophil counts of 100 to 200/ threshold for this effect varies with different studies, and has beer mm. In most patients, regenerating counts of this level are sufficient associated with ages over 60, 65, and 70 5-37 Mortality resulting to protect against infection so as to permit safe discharge of patients from neutropenic infections is also increased for older patients from the hospital. The use of G-CSF for children with ALL was asso with lymphoma. ciated with small benefits in days of antibiotics or in-hospital days, The most persuasive documentation of the association of aging although a small amount of additional costs was incurred, after taking and chemotherapy-induced myelosuppression(sometimes with in fection)comes from the studies of older patients with NHL. In a adults with ALL have not been reported. retrospective study of community practice, the incidence of neutro- update. A large randomized study of cha s published since the 2000 penic fever was 34% in patients over 65 years and 21% for those 2005 update. Only one new study w dren with high risk ALL younger, and most of the episodes of FN occurred after the first receiving intensive induction and consolidation therapy failed to show course of treatment. 2 The average hospital duration for FN was also incidence of severe infection in G-CSF recipients despite an improve- 8.2 days for those younger ment in time to neutrophil recovery of 2.5 days. Prospective studies of CHOP-like combinations of chemother Acute leukemia in relapse apy for individuals aged 60 and older have reported an incidence of 2005 recommendation. CSFs should be used judiciously, or not neutropenic infections between 27% and 47%. 0,43-30There is asingle at all, in patients with refractory or relapsed myeloid leukemia since exception, a 2003 study reporting a cumulative incidence of infections the expected benefit is only a few days of shortened neutropenia. (WHO grade 2-4)of 11% to 15%. The incidence of infection was Because of the relatively low response rate in AML patients with 32% during the first course of treatment and declined as the doses of relapsed or refractory disease, clinicians may be faced with the difficult chemotherapy were reduced and the treatment was administered at dilemma of whether the persistence ofleukemia after chemotherapy is wider time intervals. In this study, FN (reported separately from infec a consequence of drug resistance or a stimulatory effect of the CSE. tion)was observed in 36% to 45% of pat Although drug resistance is the most likely cause of treatment failure, otherapy, and patients older than 80 years completed significantly it is sometimes necessary to stop the CSF and observe the patient for a few fewer treatments than younger patients(43%versus 80%,P<.001)as days to be certain. No significant change from 2000 recommendation. a result of toxicity, refusal of treatment, or death. 2005 update.No additional studies have been published that Alternative strategies ould change the recommendation. 7 Recommendations for use of csfs in patient with reduced respo. 52-54 of lymphoma patients undergoing curative se rate and survival in several randomized con- Receiving Radiotherapy With or Without trolled studies6,48 Concurrent Chemotherapy therapy, and is therefore not recommended in this patient population. The data in other tumor types is lacking. Thus, dose reduction may be 2005 recommendation a reasonable approach in certain patient populations, but the available CSFs should be avoided in patients receiving concomitant clinical data do not allow for a definit tive conclu chemotherapy and radiation therapy, particularly involving the Patient selection. Among patients aged 65 years and older, those diastinum. In the absence of chemotherapy, therapeutic use of with a poor performance status(2 or higher)are at increased risk of CSes may be considered in patients receiving radiation therapy FN. The use of performance status to select patients has significar alone if prolonged delays secondary to neutropenia are expected drawbacks, however, including the subjectivity of assessment and its limited reliability as a predictor of FN. For patient selection to be a 2005 update useful alternative to cSf use additional risk factors must be consid CSF use with chemoradiotherapy. No additional studies have ered to identify older patients at risk of FN. Aside from data available been published that would change the recommendation. in patients with lymphoma, there is insufficient evidence to support CSEs with radiotherapy. No additional studies have been pub- the use of prophylactic CSFs in patients solely based on age. Further lished that would change the recommendation. clinical trials are warranted to address this issue OURNAL OF CLINICAL ONCOLOGY Information downloaded from jco. ascopubs org and 33,阻 arlesworth on August 12, 2009 from 202. 120.79.222 Copyright 2006 by the American Society of Clinical Oncology. All rights reserved

ALL 2005 recommendation. CSFs are recommended after the completion of the initial first few days of chemotherapy of the initial induction or first postremission course, thus shortening the duration of neutropenia of less than 1,000/mm3 by approximately 1 week. There are less consistent effects on the incidence and duration of hospitalization and the acquisition of serious infections. Although there was a trend for improved CR rates in one large study,32 particularly in older adults, there was no prolongation of disease-free or overall survival in any of the trials. G-CSF can be given together with the continued corticosteroid/antimetabolite therapy, which is a feature ofmany ALL regimens,without evidence that such concurrent therapy prolongs the myelosuppressive effects of the chemotherapy. As in AML, it is unknown from the published data whether the CSFs significantly accelerate recovery to neutrophil counts of 100 to 200/ mm3 . In most patients, regenerating counts of this level are sufficient to protect against infection so as to permit safe discharge of patients from the hospital. The use of G-CSF for children with ALL was associated with small benefits in days of antibiotics or in-hospital days, although a small amount of additional costs was incurred, after taking into consideration the costs of the CSFs. Cost estimates of CSFs for adults with ALL have not been reported. 2005 update. Only one new study was published since the 2000 update. A large randomized study of children with high risk ALL receivingintensiveinduction and consolidation therapyfailed to show any differences in the duration of hospitalization, incidence of FN, or incidence of severe infection in G-CSF recipients despite an improvement in time to neutrophil recovery of 2.5 days.33 Acute leukemia in relapse 2005 recommendation. CSFs should be used judiciously, or not at all, in patients with refractory or relapsed myeloid leukemia since the expected benefit is only a few days of shortened neutropenia. Because of the relatively low response rate in AML patients with relapsed or refractory disease, clinicians may befaced with the difficult dilemma of whether the persistence of leukemia after chemotherapy is a consequence of drug resistance or a stimulatory effect of the CSF. Although drug resistance is the most likely cause of treatment failure, itis sometimes necessary to stop theCSF and observe the patientfor afew days to be certain. No significant change from 2000 recommendation. 2005 update. No additional studies have been published that would change the recommendation. 7. Recommendations for Use of CSFs in Patients Receiving Radiotherapy With or Without Concurrent Chemotherapy 2005 recommendation CSFs should be avoided in patients receiving concomitant chemotherapy and radiation therapy, particularly involving the mediastinum. In the absence of chemotherapy, therapeutic use of CSFs may be considered in patients receiving radiation therapy alone if prolonged delays secondary to neutropenia are expected. 2005 update CSF use with chemoradiotherapy. No additional studies have been published that would change the recommendation. CSFs with radiotherapy. No additional studies have been published that would change the recommendation. 8. Recommendations for Use of CSFs in Older Patients (Note: This Topic is New to the Guideline) 2005 recommendation Prophylactic CSF for patients with diffuse aggressive lymphoma aged 65 and older treated with curative chemotherapy (CHOP or more aggressive regimens) should be given to reduce the incidence of FN and infections. Definition of the problem Age and risk of chemotherapy-induced neutropenia. Aging is one of the conditions for which prophylactic use of growth factors may be indicated irrespective of the threshold risk of neutropenia. Multiple studies, primarily in breast cancer patients, have found that the risk of neutropenia following chemotherapy increases with age.34-37 The threshold for this effect varies with different studies, and has been associated with ages over 60, 65, and 70.35-37 Mortality resulting from neutropenic infections is also increased for older patients with lymphoma.38-40 The most persuasive documentation of the association of aging and chemotherapy-induced myelosuppression (sometimes with infection) comes from the studies of older patients with NHL. In a retrospective study of community practice, the incidence of neutropenic fever was 34% in patients over 65 years and 21% for those younger,41 and most of the episodes of FN occurred after the first course of treatment.42 The average hospital duration for FN was also longer for older patients: 12.1 days for patients 65 years and older and 8.2 days for those younger. Prospective studies of CHOP-like combinations of chemotherapy for individuals aged 60 and older have reported an incidence of neutropenic infections between 27% and 47%.40,43-50There is a single exception, a 2003 study reporting a cumulative incidence of infections (WHO grade 2-4) of 11% to 15%.51 The incidence of infection was 32% during the first course of treatment and declined as the doses of chemotherapy were reduced and the treatment was administered at wider time intervals. In this study, FN (reported separatelyfrom infection) was observed in 36% to 45% of patients receiving CHOP chemotherapy, and patients older than 80 years completed significantly fewer treatments than younger patients (43% versus 80%,P.001) as a result of toxicity, refusal of treatment, or death.51 Alternative strategies Dose reduction. A strategy of dose reduction has been associated with reduced response rate and survival in several randomized controlled studies46,48,49,52-54 of lymphoma patients undergoing curative therapy, andis therefore not recommendedin this patient population. The data in other tumor types is lacking. Thus, dose reduction may be a reasonable approach in certain patient populations, but the available clinical data do not allow for a definitive conclusion. Patient selection. Among patients aged 65 years and older, those with a poor performance status (2 or higher) are at increased risk of FN.55 The use of performance status to select patients has significant drawbacks, however, including the subjectivity of assessment and its limited reliability as a predictor of FN. For patient selection to be a useful alternative to CSF use, additional risk factors must be considered to identify older patients at risk of FN. Aside from data available in patients with lymphoma, there is insufficient evidence to support the use of prophylactic CSFs in patients solely based on age. Further clinical trials are warranted to address this issue. Smith et al 3194 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 225 页

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