Link H, Maschmeyer G, Meyer P, Hiddemann W, Stille W, Helmerking M, Adam D
Department of Hematology and Oncology, Medizinische Hochschule Hannover, Germany.
Ann Hematol. 1994 Nov;69(5):231-43. doi: 10.1007/BF01700277.
In this prospective multicenter trial, treatment strategies for 1573 patients with neutropenia < 1000/microliters and fever > or = 38.5 degrees C after cytotoxic chemotherapy were compared. Patients with unexplained fever were randomized to a three-phase sequential study for different established drug regimens. If an infection could be defined microbiologically or clinically, treatment modifications were determined. In phase I, treatment for all patients consisted of acylaminopenicillin (PEN) plus aminoglycoside (AMG); or third-generation cephalosporin (CEPH) plus AMG; or PEN plus CEPH. In 800 patients with unexplained fever the response rates were: PEN/AMG (n = 258): 74.4%, CEPH/AMG (n = 252): 73.4%; PEN/CEPH (n = 290): 70.0%. Total response rate was 72.5%. In phase II, patients not responding after 3 days received PEN/CEPH/vancomycin (n = 70) or PEN/CEPH/AMG (n = 74). The respective response rates were 52.9% and 55.4%, total 54.2%. If fever did not resolve, the patients received either PEN/CEPH (n = 40) or imipenem/cilastatin (n = 59) both in combination with amphotericin-B/5-flucytosin/rifampin. The response rates were 62.5% and 79.7%, respectively (p = 0.07), total 72.7%. No significant differences between the treatment modalities compared were found. Analyzing all three phases together, 91.3% of patients with unexplained fever were cured. The response rate was also analyzed according to patients with gram-positive bacteremia (n = 183), response rate = 82.5%; gram-negative organisms (n = 145) 78.6%; fungemia (n = 51) 43.1% (p < 0.001); lung infiltrates (n = 269) 61.3% (p < 0.001); clinically documented infections (n = 198) 84.4%; and clinically and microbiologically documented infections (n = 84) 82.1%. If infections were diagnosed after at least 5 febrile days, more lung infiltrates and fungal infections occurred (p < 0.001). Leukocytes rising above 500/mu during the infection predicted better response rates (p < 0.001): in unexplained fever 97.8% vs 86.5% and lower death rates 1.5% vs 8.5%. In documented infections the response rates were then 89.9% vs 62.3% and the death rates 7.0% vs 20.5%. Therapy of neutropenic fever and infections must be adapted according to risk factors and should include early empiric antifungal therapy. The therapeutic and prophylactic use of hematopoietic growth factors to overcome neutropenia should be evaluated.
在这项前瞻性多中心试验中，比较了1573例细胞毒性化疗后中性粒细胞减少<1000/微升且发热≥38.5℃患者的治疗策略。不明原因发热患者被随机分为针对不同既定药物方案的三阶段序贯研究。如果能从微生物学或临床上明确感染，则确定治疗调整方案。在第一阶段，所有患者的治疗方案包括酰氨基青霉素（PEN）加氨基糖苷类（AMG）；或第三代头孢菌素（CEPH）加AMG；或PEN加CEPH。在800例不明原因发热患者中，有效率分别为：PEN/AMG（n = 258）：74.4%，CEPH/AMG（n = 252）：73.4%；PEN/CEPH（n = 290）：70.0%。总有效率为72.5%。在第二阶段，3天后无反应的患者接受PEN/CEPH/万古霉素（n = 70）或PEN/CEPH/AMG（n = 74）治疗。各自的有效率分别为52.9%和55.4%，总计54.2%。如果发热未消退，患者接受PEN/CEPH（n = 40）或亚胺培南/西司他丁（n = 59）治疗，两者均与两性霉素B/5-氟胞嘧啶/利福平联合使用。有效率分别为62.5%和79.7%（p = 0.07），总计72.7%。所比较的治疗方式之间未发现显著差异。综合分析所有三个阶段，91.3%的不明原因发热患者治愈。还根据革兰氏阳性菌血症患者（n = 183）分析了有效率，有效率 = 82.5%；革兰氏阴性菌（n = 145）78.6%；真菌血症（n = 51）43.1%（p < 0.001）；肺部浸润（n = 269）61.3%（p < 0.001）；临床记录的感染（n = 198）84.4%；以及临床和微生物学记录的感染（n = 84）82.1%。如果在至少5个发热日后诊断出感染，则肺部浸润和真菌感染更多见（p < 0.001）。感染期间白细胞升至500/μ以上预示着更好的有效率（p < 0.001）：在不明原因发热中为97.8%对86.5%，死亡率更低，为1.5%对8.5%。在有记录的感染中，有效率分别为89.9%对62.3%，死亡率为7.0%对20.5%。中性粒细胞减少性发热和感染的治疗必须根据危险因素进行调整，且应包括早期经验性抗真菌治疗。应评估造血生长因子在克服中性粒细胞减少方面的治疗和预防用途。
