骨髓生长因子的获益与风险NCCN指南2016V2

Myeloid Growth Factors骨髓生长因子

NCCN Guidelines Version 2.2016
NCCN指南2016第2版山东省肿瘤医院呼吸肿瘤内科张品良

Discussion 讨论

Benefits and Risks of MGFs 骨髓生长因子的获益与风险

There are several circumstances in which MGFs are incorporated into cancer regimens to improve the care of patients. MGFs are used in the prophylactic and therapeutic treatment of FN as well as in the hematopoietic cell transplant setting for mobilization and supportive care. MGFs may also be used for the treatment of severe chronic neutropenia.
为改善患者的治疗，在几种情况下，将骨髓生长因子加入到癌症方案中。骨髓生长因子用于中性粒细胞减少性发热的预防和治疗以及用于造血细胞移植情况下的动员和支持治疗。骨髓生长因子也可用于重度慢性中性粒细胞减少症的治疗。

Studies showed that the prophylactic use of MGFs reduced the incidence, length, and severity of chemotherapy-related neutropenia in small cell lung cancer, breast cancer, sarcoma, solid tumors, non-small cell lung cancer, and NHL. Additionally, the benefit of GM-CSF therapy was seen in the treatment of myeloid malignancies. MGFs improved the delivery of full dose-intensity chemotherapy on schedule, although this has not been shown to lead to better response or higher overall survival (OS) in most studies. However, in node-positive breast cancer and aggressive lymphoma, dose-dense regimens supported by MGFs improved disease-free survival and/or OS compared to conventional chemotherapy.
研究显示，在小细胞肺癌、乳腺癌、肉瘤、实体瘤、非小细胞肺癌以及非霍奇金淋巴瘤中，预防性应用骨髓生长因子降低与化疗有关的中性粒细胞减少症的发生率、持续时间和严重程度。此外，在髓系恶性血液病的治疗中见到GM-CSF治疗获益。骨髓生长因子提高按照预定时间给予全剂量强度化疗，虽然大多数研究尚未证明可取得更好的疗效或更高的总生存（OS）。然而，在淋巴结阳性乳腺癌和侵袭性淋巴瘤中，与传统化疗相比，骨髓生长因子支持的剂量密集方案延长无病生存期和/或总生存期。

Meta-analyses confirmed the efficacy of prophylactic MGFs in decreasing rates of infection and risk of neutropenia. The meta-analysis from Clark et al included 13 studies, in which 6 studies involved treatment of patients with G-CSF; 6 studies involved treatment of patients with GM-CSF; and one 3-arm study included G-CSF, GM-CSF, or a placebo in the treatment. In total, 1518 patients were evaluated for overall mortality, infection-related mortality, length of hospitalization, and time to neutrophil recovery. While overall mortality did not appear to reach statistical significance (odds ratio [OR], 0.68; 95% CI, 0.43–1.08; P = .10), the infection-related mortality had a borderline significant benefit with the use of MGFs (OR, 0.51; 95% CI, 0.26–1.00; P = .05). A clear reduction in the length of hospitalization (hazard ratio [HR] = 0.63; 95% CI, 0.49–0.82; P = .0006) and time to neutrophil recovery (HR = 0.32; 95% CI, 0.23–0.46; P < .0001) was observed with the addition of MGFs.
Meta分析证实了预防性骨髓生长因子在降低感染率和中性粒细胞减少症风险方面的疗效。克拉克等的meta分析包括13项研究，其中6项研究包括G-CSF治疗的患者；6项研究包括GM-CSF治疗的患者；和一项3组研究包括G-CSF、GM-CSF或安慰剂治疗。总计1518例患者可评价总死亡率、感染相关死亡率、住院时间和至中性粒细胞恢复的时间。而总死亡率似乎没有达到统计学意义（比值比[OR]，0.68；95% CI，0.77–0.92；P = 0.10），感染相关死亡率使用骨髓生长因子具有边缘显著受益（OR，0.51；95% CI，0.26–1.00；P =0.05）。外加骨髓生长因子观察到明显减少住院天数（危险比[HR]= 0.63；95% CI，0.49–0.82；P =0.0006）和中性粒细胞恢复时间（HR = 0.32；95% CI，0.23–0.46；P<0.0001）。

In a systematic review of 17 randomized trials of prophylactic G-CSFs, including 3493 adult patients with solid tumors and lymphoma, G-CSF as primary prophylaxis reduced the risk of FN (relative risk [RR], 0.54; 95% CI, 0.43–0.67; P < .001) and improved the relative dose intensity of the chemotherapy delivered with an average difference between study arms of 8.4% (P = .001). For the first time, this analysis also reported a substantial reduction in risk of infection-related mortality (RR, 0.55; 95% CI, 0.33–0.90; P = .018) and of early death during chemotherapy (RR, 0.60; 95% CI, 0.43–0.83; P = .002). The survival advantage was confirmed in a systematic review by Lyman et al of 25 randomized controlled trials that involved more than 12,000 patients undergoing chemotherapy with or without G-CSF support. With an average follow-up of 5 years, G-CSF was associated with a 3.40% and 0.90 reduction in absolute risk and RR for all-cause mortality, respectively, although an increased risk for AML and myelodysplastic syndromes (MDS) was observed (see later discussion). The degree of benefit correlated with the chemotherapy dose intensity.
在17个预防性G-CSF随机试验的一项系统评价中，包括3493例成年实体瘤和淋巴瘤患者，G-CSF作为主要预防措施降低中性粒细胞减少性发热风险（相对危险[RR]，0.54；95% CI，0.43–0.67；P<0.001）和提高化疗实施的相对剂量强度，研究组之间平均差异8.4%（P = 0.001）。首次分析也报告大幅度降低感染相关死亡率风险（RR，0.55；95% CI，0.33–0.90；P = 0.018）和化疗期间的早期死亡（RR，0.60；95% CI，0.43–0.83；P =0.002)。莱曼等对25项随机对照试验包括超过12000例接受化疗加或不加G-CSF支持的患者进行的一项系统评价确认了生存优势。平均随访5年，G-CSF与分别降低全因死亡绝对风险和相对危险度3.40%和0.90相关，虽然观察到对于AML和骨髓增生异常综合征（MDS）风险增加（稍后讨论）。受益程度与化疗剂量强度相关。

Several randomized trials have also demonstrated improved outcomes with the prophylactic use of tbo-filgrastim for the prevention of FN. One trial randomized 348 patients with breast cancer receiving docetaxel/doxorubicin therapy to tbo-filgrastim, filgrastim, or placebo. Tbo-filgrastim was equivalent to filgrastim and superior to placebo in reducing the duration of severe neutropenia and incidence of FN. Two other randomized studies of patients with lung cancer and NHL receiving chemotherapy also reported similar efficacy of tbo-filgrastim and filgrastim. Toxicities were similar between the 2 agents. A meta-analysis of the 3 trials concluded tbo-filgrastim to be non-inferior to filgrastim for the reduced incidence of FN, irrespective of the myelotoxicity of the chemotherapy regimen. Studies in healthy subjects demonstrated similar pharmacokinetic and pharmacodynamic profiles.
若干随机试验也显示预防性应用梯瓦-非格司亭预防中性粒细胞减少性发热改善结局。一项试验将348例乳腺癌患者随机分入接受多西他赛/阿霉素加梯瓦-非格司亭、非格司亭或安慰剂治疗。在降低严重的中性粒细胞减少症持续时间和中性粒细胞减少性发热的发生方面，梯瓦-非格司亭等于非格司亭优于安慰剂。接受化疗的肺癌和非霍奇金淋巴瘤患者的两项其他随机研究也报告梯瓦-非格司亭和非格司亭疗效相似。两药间的毒性相似。一项3个试验的meta分析推断，对于降低中性粒细胞减少性发热的发生率，不管化疗方案的骨髓毒性如何，梯瓦-非格司亭均不劣于非格司亭。健康受试者的研究表明药动学和药效学特征相似。

In addition to improved outcome, MGFs have associated toxicity risks that have been reported (see Toxicity Risks with Myeloid Growth Factors in the algorithm). Similar toxicities to filgrastim are expected for pegfilgrastim and filgrastim biosimilars, although not all toxicities have been reported with each preparation. To date, the main consistently observed toxicity associated with G-CSF therapy is mild to moderate bone pain in 10% to 30% of patients. This is usually effectively controlled by non-narcotic analgesics. The meta-analysis by Kuderer et al confirmed a heightened risk of musculoskeletal pain associated with MGFs (RR, 4.03; 95% CI, 2.15–7.52; P < .001).
已报道，骨髓生长因子除了改善预后外，也与毒性风险相关（见工作步骤中的骨髓生长因子毒性风险）。预期非格司亭与培非格司亭和非格司亭生物类似物的毒性相似，虽然已报道每个制剂并无所有的毒性。迄今为止，G-CSF治疗一致观察到的主要毒性是10%-30%的患者轻中度骨痛。非麻醉镇痛药通常可有效控制。Kuderer等的meta分析证实，与骨髓生长因子相关的肌肉骨骼痛的风险更高(RR，4.03；95% CI，2.15–7.52；P<0.001).

There have also been reports of rare cases of splenic rupture with G-CSF usage, some of which were fatal. These cases occurred in patients and healthy donors in the hematopoietic cell transplantation setting. Some patients develop allergic reactions involving the skin, the respiratory system, or the cardiovascular system (filgrastim only). Other warnings from the prescribing information include acute respiratory distress syndrome, alveolar hemorrhage, and hemoptysis. Sickle cell crisis, sometimes fatal, has been reported in patients with sickle cell disease, but not for patients with sickle cell trait. Worsening of amyloidosis following G-CSF administration has been reported; however, this is based on two case reports in patients who were already prone to life-threatening complications.
也有使用G-CSF罕见的脾破裂病例报道，其中一些是致命的。这些病例发生在患者和造血细胞移植健康供体情况下。某些患者出现过敏反应包括皮肤、呼吸系统或心血管系统（仅非格司亭）。处方信息的其他警告包括急性呼吸窘迫综合症、肺泡出血和咯血。在镰状细胞病患者而非镰状细胞特质患者中已报道镰状细胞危象，有时是致命的。已报道在给予G-CSF后淀粉样变性恶化；不过，这基于两例已有危及生命的并发症倾向患者的报告。

Pulmonary toxicity has been reported following the use of G-CSFs for patients with Hodgkin lymphoma undergoing bleomycin-containing chemotherapy, especially ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). An increased risk of bleomycin pulmonary toxicity has been reported with G-CSF use for this disease in a retrospective study of 141 patients. In a systematic review of case reports by Azoulay and colleagues, 70 cases of G-CSF–related pulmonary toxicity were identified in neutropenic patients with cancer. Thirty-six patients had received bleomycin, but the majority of patients with NHL had also received drugs known to induce pulmonary toxicity (cyclophosphamide and/or methotrexate). The toxicity potential for patients following the BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen is more unclear, although bleomycin is given every 3 weeks in this regimen as opposed to every 2 weeks in ABVD. Conversely, an increase in bleomycin pulmonary toxicity has not been reported with G-CSF use in bleomycin-containing testicular cancer chemotherapy regimens. Due to the controversy of G-CSF use during bleomycin-containing chemotherapy, clinicians should be highly alert to signs and symptoms of this complication. The routine use of G-CSF is not recommended in conjunction with the most common chemotherapy regimens for classical Hodgkin lymphoma (ABVD and Stanford V). Furthermore, two studies have shown that ABVD can be safely administered at full dose without G-CSF support. However, due to the high incidence of toxicity and treatment delays, G-CSF support is recommended for patients with Hodgkin lymphoma treated with the escalated BEACOPP regimen.
已报道在接受含博莱霉素尤其是ABVD（阿霉素、博莱霉素、长春花碱和达卡巴嗪）化疗的霍奇金淋巴瘤患者使用G-CSF后发生肺毒性。一项141例患者的回顾性研究已报道G-CSF用于该疾患博莱霉素肺毒性风险增加。阿祖莱及其同事进行的一项病例报告系统回顾，在粒细胞缺乏的癌症患者中确定70例G-CSF相关肺毒性。36例患者接受了博莱霉素，但是大多数NHL患者同时还接受了已知引起肺毒性的药物（环磷酰胺和/或氨甲蝶呤）。在BEACOPP（博莱霉素、依托泊苷、多柔比星、环磷酰胺、长春新碱、丙卡巴肼和泼尼松）方案后患者的潜在肺毒性更不清楚，尽管与ABVD中的每2周1次完全不同，该方案中博莱霉素每3周给予1次。相反，尚无报告在含博莱霉素的睾丸癌化疗方案中G-CSF的使用增加博莱霉素肺毒性。由于在含博莱霉素化疗期间G-CSF的使用存在争议，临床医生应高度警惕该并发症的症状与体征。对于经典霍奇金淋巴瘤，不推荐常规使用G-CSF联合最常见的化疗方案（ABVD和Stanford V）。此外，两项研究均证明在没有G-CSF支持的情况下可安全足量给予ABVD。不过，对于接受剂量递增BEACOPP方案治疗的霍奇金淋巴瘤患者，由于毒性反应发生率高和治疗延迟，推荐G-CSF支持。

Adverse events have also been reported with GM-CSF. An early study of patients with advanced malignancy evaluated side effects following administration of GM-CSF. Adverse reactions were seen in 65% of these patients, though they were not severe and were reversible. These reactions included mild myalgias, facial flushing, low-grade fever, headache, bone discomfort, nausea, and dyspnea. A side-effect profile of GM-CSF, completed several years later, reported a lower rate of 20% to 30% mild-to-moderate adverse events, and attributed this decline to improved dosing and delivery.
也报道了GM-CSF的不良事件。晚期恶性肿瘤患者的一项早期研究评估了给予GM-CSF后的副作用。这些患者中65%见到不良反应，不过不严重且可逆。这些反应包括轻微的肌痛、面部潮红、低热、头痛、骨骼不适、恶心和呼吸困难。GM-CSF结束数年后的副作用概况，报告轻中度不良事件的发生率较低，为20%-30%，这种下降归因于剂量和给药的改进。

Though uncommon, significant side effects have been reported for GM-CSF. Less than 1% of patients will develop blood clots. Though blood clots rarely lead to pulmonary embolism or stroke, these life-threating conditions are possible. There have been reports in clinical trials of capillary leak syndrome, a condition in which fluids move from the vascular system into the interstitial space resulting in hypotension and reduced blood flow to internal organs. While this is more common with GM-CSF, it has also been reported to occur with G-CSF therapy.
虽然不常见，但已报道GM-CSF显著的副作用。不到1%的患者发生血栓。虽然血栓罕见引起肺栓塞或中风，但是有可能出现这些威胁生命的情况。已有临床试验报道毛细血管渗漏综合征，液体从脉管系统进入组织间隙导致低血压和内脏血流量降低的一种状态。尽管GM-CSF更常见，但也有报道G-CSF治疗会发生。

Although there have been suggestions of a potentially increased risk for AML/MDS with MGF administration from epidemiologic studies, this was not observed in individual randomized trials. The meta-analysis by Lyman et al reported an increase in absolute risk and RR for AML/MDS of 0.41% and 1.92, respectively, related to G-CSF. It is not possible from this meta-analysis to determine whether the risk for AML/MDS is secondary to G-CSF or related to the higher total doses of chemotherapy. As discussed above, overall mortality was nevertheless decreased. These data mirror an earlier report based on the SEER database that showed an elevated risk of developing AML/MDS in patients with either G-CSF or GM-CSF therapy. One caveat of the study was that it could not exclude the possibility that the increase was due to the use of growth factors in cases that were more likely to progress into AML/MDS, regardless of the presence or absence of adjuvant therapy.
虽然流行病学研究已提示给予骨髓生长因子可能增加AML/MDS风险，但在具体的随机试验中未观察到。莱曼等的meta分析报告，与G-CSF相关的AML/MDS绝对风险和相对危险度分别增加0.41%和1.92。对于AML/MDS，从该meta分析中不可能确定风险是继发于G-CSF还是与更高总剂量的化疗相关。正如上述讨论的，仍然降低了总死亡率。这些数据反映出一项基于SEER数据库的早期报告显示，在G-CSF或GM-CSF治疗的患者中，发生AML/MDS的风险升高。该研究的一个警告是，可能不排除生长因子的使用增加患者更可能发展成AML/MDS的可能性，不管有无辅助治疗。

The recommendations in the NCCN Myeloid Growth Factors Guidelines are based on therapeutic efficacy and clinical benefit of treatment. However, in addition to evaluating the clinical benefits and risks of MGF therapy, an increasing number of studies have assessed the financial implications of its use. Over the last decade, the costs of inpatient hospitalization have escalated, changing the risk threshold on a pure cost basis from 40% to approximately 20%. Economic analyses of MGFs have yielded mixed results, depending on the context of usage. While the addition of MGFs to treatment regimens inevitably raises the drug cost, it may actually equate to substantial savings in comparison to the cost of hospitalization and subsequent treatment of neutropenia.
NCCN骨髓生长因子指南的推荐是基于治疗效果和治疗的临床获益。然而，除了评估骨髓生长因子治疗的临床受益与风险外，越来越多的研究还评估其使用的资金问题。在过去的十年里，住院患者的住院花费逐渐增加，纯粹成本风险阈值从40%降至大约20%。骨髓生长因子的经济学分析得到的结果好坏参半，取决于使用的背景。当治疗方案增加骨髓生长因子时，不可避免地增加药费，但这部分费用可能实际上等于节省了在中性粒细胞减少症住院和后续治疗中的大量费用。