癌症患者静脉血栓栓塞风险评估NCCN2016v1

VTE Risk Assessment in Patients with Cancer 癌症患者静脉血栓栓塞风险评估

Many of the risk factors for development of VTE are common to patients with cancer. VTE risk factors in cancer patients can be grouped into 3 general categories: intrinsic and extrinsic patient-related factors, cancer-related factors, and treatment-related factors. The VTE risk factors in the individual cancer patient are likely to be represented by all 3 risk factor categories, and the VTE risk conferred by a single risk factor cannot be evaluated in isolation from the others. 山东省肿瘤医院呼吸肿瘤内科张品良
发生VTE的许多危险因素对于癌症患者是常见的。癌症患者中VTE的危险因素一般可分成3类内源性和外源性患者相关因素、肿瘤相关因素以及治疗相关因素。VTE危险因素在个别癌症患者中很可能表现为所有3个危险因素类别，并且不能根据从其他危险因素中分离出来的单一危险因素评估确认。

Patient-related Factors
患者相关因素

More advanced age, a common characteristic of many cancer patients, was shown to be associated with an increased risk for VTE in some clinical settings. In addition, obesity has been identified as a risk factor for VTE. There is also evidence that pre-chemotherapy thrombocytosis, leukocytosis, and hemoglobin level<10 g/dL are predictive of VTE in patients receiving chemotherapy, although the association of anemia with VTE may be complicated by use of erythropoietic stimulating agents (ESAs). Acquired risk factors for VTE include a history of VTE and certain hypercoagulable conditions, such as pregnancy. A history of prior VTE has been identified in a number of studies as an independent risk factor for developing a subsequent VTE. Moreover, recurrent VTE was found to be more common among patients with cancer; for example, 12-month cumulative incidences of recurrent VTE of 20.7% and 6.8% were reported for patients with and without cancer, respectively, undergoing anticoagulant treatment. Although factor V Leiden and prothrombin mutations were identified in 3.7% and 2.6%, respectively, of patients with breast or colon cancer receiving adjuvant chemotherapy in a recent prospective observational study, these inherited risk factors were not associated with an increased risk for VTE among cancer patients.
许多肿瘤患者普遍年龄更大，证明在一些临床环境下与静脉血栓栓塞风险增加有关。另外，肥胖症已确定为一个静脉血栓栓塞危险因素。还有数据证明在正在接受化疗的患者中化疗前血小板增多、白细胞增多以及血红蛋白水平＜10g/dL预报静脉血栓栓塞，但是贫血与静脉血栓栓塞的相关性由于红细胞生成刺激剂(ESAs)的应用变得复杂。静脉血栓栓塞获得性危险因素包括静脉血栓栓塞病史和某些高凝状态，比如妊娠。大量研究已确定既往静脉血栓栓塞病史为随后产生静脉血栓栓塞的一个独立的危险因素。此外，复发性VTE在癌症患者中更常见；例如，报道对于接受抗凝剂治疗有和没有恶性肿瘤患者复发性静脉血栓栓塞12个月的累计发生率分别是20.7%和6.8%。尽管在一项最新的前瞻性观察研究中发现正在接受辅助化疗的乳腺或结肠癌患者中莱登Ⅴ因子和凝血酶原突变分别为3.7%和2.6%，但是这些遗传性危险因素与肿瘤患者静脉血栓栓塞风险增加无关。

A number of other patient-related VTE risk factors, although not exclusive to cancer patients, are commonly found. These risk factors include hospitalization, other medical comorbidities, such as infection, poor performance status, and prolonged immobilization. In the latest report from the U.S. Centers for Disease Control and Prevention (CDC), VTE events were found to occur at a high rate among hospitalized patients. Among hospitalized adults, VTE was reported in more than 547,000 patients annually (annual rate of 239 per 100,000 persons hospitalized), with more than 28,700 deaths annually in these patients. The risk for VTE increased with age in hospitalized patients. This report confirms that hospitalization is an important risk factor for VTE, and emphasizes the need for greater awareness of VTE risks and appropriate implementation of preventive measures in this setting. Infection has also been identified as an important risk factor for VTE, including in patients with cancer. A recently published case- crossover study in individuals (≥51 years of age) hospitalized for VTE (n=399 among n=16,781 participating in the Health and Retirement Study) reported that infections, use of ESAs, blood transfusions, major surgeries, fractures, immobility, and chemotherapy were significant risk factors for VTE hospitalization. In the subgroup of patients with cancer from this study, the major predictors of VTE hospitalization were infections, blood transfusions, and insertion of a central catheter. In a recent population-based case-control study in patients with hospital- diagnosed VTE (n=15,009), the estimated incidence rate for VTE was increased by 3-fold among patients within the first 3 months after infection, compared with those without an infectious event during the year before VTE (incidence rate ratio=3.3 after adjustment for other VTE risk factors).
许多其他患者相关的静脉血栓栓塞危险因素，尽管不是肿瘤患者专有，却是司空见惯。这些危险因素包括住院、并存其它内科疾病比如感染、一般情况差以及长期制动。来自美国疾病控制和预防中心(CDC)最近的报告，发现静脉血栓栓塞事件在住院患者当中发生率高。在住院的成人当中，据报道每年静脉血栓栓塞患者超过547000(年率每10万住院人次239)，在这些患者中每年死亡超过28700。在住院患者中静脉血栓栓塞风险随着年龄增加而增加。该报告证实住院是静脉血栓栓塞一个重要的危险因素，并强调在此情形下需要更加意识到静脉血栓栓塞风险和预防措施的合理实施。此外已确定感染为一个重要的静脉血栓栓塞危险因素，包括在癌症患者中。一项最近发表的针对特殊(≥51岁)住院患者静脉血栓栓塞病例的交叉研究(在16781名参加健康与退休研究者当中n=399)报道感染、应用促红素、输血、重大手术、骨折、不活动以及化疗是静脉血栓栓塞需要住院的重要危险因素。在本研究的癌症患者亚组中，静脉血栓栓塞住院的主要预报因子是感染、输血和植入中心静脉导管。最近一项以人群为基础的病例对照研究中在医院确诊的静脉血栓栓塞患者中(n=15009)，与那些静脉血栓栓塞之前一年没有感染事件者相比在感染后最初3个月内估算的患者静脉血栓栓塞发病率增加3倍(校正其他静脉血栓栓塞危险因素后发生率比值=3.3)。

Cancer-related Factors
肿瘤相关因素

Several VTE risk factors are exclusive to cancer patients, including the presence of malignancy, chemotherapy, and extrinsic vascular compression due to cancer-associated regional bulky lymphadenopathy. Results from 2 population-based case-control studies showed that the presence of cancer increased the risk for VTE by 4- and 7-fold. An increased risk for VTE in patients with cancer has also been supported by the results of other studies. Furthermore, researchers have reported cancer as the cause of approximately 20% of the VTE cases seen in the community, and a recent cancer diagnosis and the occurrence of advanced malignancies and distant metastases also increase VTE risk. For example, Blom et al reported an adjusted odds ratio of 19.8 for VTE risk in solid tumor cancer patients with distant metastases compared with patients without. In addition, tumor histology has been shown to influence the risk for VTE in patients. Several studies have evaluated the association between different types of cancer and the risk for developing a VTE. For example, pancreatic cancer and brain tumors were associated with a high risk for VTE in a number of the studies. Adenocarcinomas appear to be associated with a higher risk than squamous cell cancers. Although differences in study designs make it difficult to compare VTE rates according to a specific type of malignancy, other cancers that have been associated with an increased risk for VTE include cancers of the stomach, kidney, uterus, lung, ovary, bladder, and testis. In addition, an increased risk for VTE has been observed in certain hematologic malignancies, such as lymphoma, acute leukemia, and multiple myeloma. Patients with high-grade lymphoma and acute promyelocytic leukemia appear to be at higher risk than patients with other forms of lymphoma or leukemia. In a study of patients with high-grade non-Hodgkin’s lymphoma, disease-related venous compression was shown to be the most common cause of VTE in that population.
一些静脉血栓栓塞危险因素是肿瘤患者独有的，包括存在恶性肿瘤、化疗和由于癌症局部巨大淋巴结转移所致的血管外压。来自2项以人群为基础的病例对照研究结果显示存在恶性肿瘤增加静脉血栓栓塞风险4倍和7倍。在癌症患者中静脉血栓栓塞风险增加已同样被其他研究的结果所证实。此外，研究者报道在该人群中观察到恶性肿瘤大约是20%静脉血栓栓塞病例的原因，而且新近诊断的恶性肿瘤和出现晚期恶性肿瘤以及远处转移同样增加静脉血栓栓塞风险。例如，Blom等报道在实体肿瘤患者中有远处转移与没有远处转移的患者相比静脉血栓栓塞风险校正后的优势比为19.8。另外，已证明肿瘤组织学影响患者静脉血栓栓塞风险。若干研究已经评估了不同类型恶性肿瘤与发生静脉血栓栓塞风险之间的相关性。例如，大量研究证明胰腺癌以及脑瘤与高危静脉血栓栓塞有关。似乎腺癌比鳞癌有更高风险。尽管在研究设计方面有差异造成难以比较某种特定类型恶性肿瘤的静脉血栓栓塞率，其他类型的恶性肿瘤包括胃、肾、子宫、肺、卵巢、膀胱以及睾丸癌与静脉血栓栓塞风险增加有关。另外，已观察到在某些恶性血液病如淋巴瘤、急性白血病和多发性骨髓瘤中静脉血栓栓塞风险增加。高度恶性淋巴瘤和急性早幼粒细胞白血病患者似乎比其他类型的淋巴瘤或白血病患者风险更高。在一项高分级非霍奇金淋巴瘤患者的研究中，证明疾病相关静脉压迫是该人群中最常见的静脉血栓栓塞原因。

Several factors associated with an increased risk for VTE in myeloma patients include the diagnosis of multiple myeloma itself, hyperviscosity, and treatment with thalidomide- or lenalidomide-based combination regimens (combined with high-dose dexamethasone, doxorubicin, or multiagent chemotherapy). Further validation of the influence of these risk factors on VTE rates in patients with myeloma is warranted. In contrast, breast cancer was associated with a relatively low VTE risk in some studies. Nevertheless, because of the relatively high prevalence of breast cancer, the occurrence of VTE in a patient with breast cancer is not uncommon. Furthermore, the risk for VTE was shown to increase by 6-fold when patients with metastatic breast cancer were compared with patients with localized disease.
骨髓瘤患者中几个与静脉血栓栓塞风险增加相关的因素包括多发性骨髓瘤诊断本身、高黏血症和用沙利度胺或来那度胺为基础的联合方案治疗(联合高剂量地塞米松、阿霉素或多药化疗)。已获批准进一步证实这些危险因素对骨髓瘤患者静脉血栓栓塞率的影响。相反，在一些研究中乳腺癌静脉血栓栓塞风险相对较低。虽然如此，由于乳腺癌的患病率比较高，在乳腺癌患者中发生静脉血栓栓塞不罕见。此外，与局限期疾病患者相比当患者出现乳腺癌转移时静脉血栓栓塞风险增加6倍。

Treatment-related Factors 治疗相关因素

Treatment-related risk factors include surgery, the presence of a central venous access device (CVAD, also known as a catheter), and administration of chemotherapy and other systemic treatments. For example, Heit et al reported nearly 22-fold and 8-fold increases in risks for the development of VTE in patients hospitalized or confined to a nursing home with and without recent surgery, respectively, compared with non-institutionalized patients who had not undergone recent surgery.
治疗相关危险因素包括手术、存在一种中心静脉通路装置(CVAD，即导管)和使用化疗及其他全身性治疗。例如，Heit等报道，与最近未曾接受手术的非机构内患者相比，在住院的患者或限于疗养院有和没有最近手术的患者中发生静脉血栓栓塞的风险几乎分别增加22倍和8倍。

A number of specific agents used in cancer treatment are associated with an increased risk for developing VTE. A detailed listing of these agents is not provided here; rather, the NCCN Guidelines describe some of the evidence for the association of 3 representative classes of cancer drugs (cytotoxic chemotherapy regimens, hormone therapy with estrogenic compounds, and antiangiogenic agents) with increased VTE risk.
许多专门用于治疗恶性肿瘤的药物与发生静脉血栓栓塞风险增加有关。这里未提供这些药物的详细列表；相反，NCCN指南描述一些3类代表性抗肿瘤药物(细胞毒药物化疗方案、雌激素化合物激素疗法和抗血管生成剂)与静脉血栓栓塞风险增加相关性的证据。

The association of cytotoxic chemotherapy with the development of VTE in cancer patients has been shown in several studies. For example, in one population-based case-control study, odds ratios of 6.5 and 4.1 for development of VTE were determined when cancer patients receiving chemotherapy and cancer patients not receiving chemotherapy, respectively, were compared with patients without a malignant neoplasm. In another retrospective study, the annual incidence of VTE was 15% in patients with colorectal cancer treated with chemotherapeutic regimens. Khorana et al have published a risk assessment model to estimate the risk for VTE in ambulatory cancer patients receiving chemotherapy. This risk assessment model has been recently validated and extended by Ay and colleagues, who identified D dimer and P selectin as additional discriminatory risk factors for VTE in ambulatory cancer patients. However, these laboratory tests are not routinely measured in cancer patients, so their inclusion in routine thrombotic risk assessment should be predicated upon their validation in future studies. The risk factors identified by Khorana et al, which formed the basis for the risk assessment models, set the stage for prospective, confirmatory randomized clinical trials evaluating the risks and benefits of risk-targeted VTE prophylaxis in ambulatory cancer patients receiving chemotherapy.
若干研究已证明在癌症患者中细胞毒药物化疗与发生静脉血栓栓塞的相关性。例如，在一项以人群为基础的病例对照研究中，与无恶性肿瘤的患者相比，当肿瘤患者接受化疗时与肿瘤患者不接受化疗时发生可确定的静脉血栓栓塞的比数比分别是6.5和4.1。在另一项回顾性调查中，在接受化疗的结直肠癌患者中静脉血栓栓塞年发病率是15%。Khorana等已公布了一个危险性评估模型用于评估正在接受化疗的不卧床的肿瘤患者中的静脉血栓栓塞风险。该危险性评估模型最近已被Ay和同事证实并推广，他们发现D二聚体和P选择蛋白为不卧床肿瘤患者静脉血栓栓塞另外能鉴别的危险因素。然而，这些实验室检查在癌症患者中不是常规测定，因此一旦在今后的研究中验证后就应将其包含在常规血栓形成危险性评估中。Khorana等发现的危险因素，建立了危险性评估模型的基础，为正在接受化疗的不卧床的肿瘤患者中开展前瞻性、验证性随机临床试验评估针对静脉血栓栓塞风险预防的风险与收益做好了准备。

Increased VTE risk was shown to be associated with the use of exogenous hormonal compounds, such as selective estrogen receptor modulators (eg, tamoxifen, raloxifene) for the prevention and treatment of certain estrogen-receptor positive cancers. Use of hormonal compounds, such as hormone replacement therapy or oral contraceptive agents, has also been associated with increased risk for developing VTE. Recent case-control studies and meta-analysis suggest that for combined oral contraceptives, VTE risks may be different between formulations, depending on the type of progestogen used. Diethylstilbestrol phosphate used in combination with doxorubicin for the treatment of hormone-refractory prostate cancer was reported to increase VTE risk when compared with use of doxorubicin alone. Evidence has been presented to support the association of immunomodulating agents that have antiangiogenic properties (eg, thalidomide in combination with doxorubicin and/or dexamethasone; lenalidomide in combination with dexamethasone) with an increased incidence of VTE when used in the treatment of multiple myeloma (see Guidelines section Outpatient Prophylactic Therapy in Ambulatory Cancer Patients). Other agents used in supportive cancer care, such as ESAs, have also been associated with the development of VTE. Concomitant use of erythropoietin with cancer therapies associated with the development of VTE, such as lenalidomide, may further increase VTE risk.
静脉血栓栓塞风险增加被证明与应用外原性激素化合物有关，如选择性雌激素受体调节剂(例如他莫昔芬、雷洛昔芬)用于防治某些雌激素受体阳性的癌症。应用激素化合物，如激素替代治疗或口服避孕药，也与发生静脉血栓栓塞风险增加有关。最新的病例对照研究和荟萃分析提示对于复方口服避孕药，在不同的配方之间静脉血栓栓塞风险可能不同，取决于使用的黄体酮类型。据报道己烯雌酚磷酸酯联合阿霉素用于治疗激素抵抗的前列腺癌时与仅应用阿霉素相比增加静脉血栓栓塞风险。已有证据支持具有抗血管生成功能的免疫调节剂(例如沙利度胺联合阿霉素和/或地塞米松；来那度胺联合地塞米松)用于治疗多发性骨髓瘤时与静脉血栓栓塞发生率增加相关(见不卧床门诊肿瘤患者预防性治疗指南部分)。其他用于癌症支持治疗的药物，如促红细胞生成素，也与静脉血栓栓塞的发生有关。癌症治疗的同期使用促红细胞生成素与静脉血栓栓塞的发生相关，如来那度胺，可能进一步增加静脉血栓栓塞风险。

Results from numerous studies have identified the presence of a CVAD as a risk factor for development of an upper-extremity DVT (UEDVT), although discrepancies exist concerning the incidence of catheter-related DVT. The association between catheter/device placement and the development of DVT may be the result of venous stasis and vessel injury after insertion of the CVAD or infections occurring as a result of catheter placement. Possible reasons for the reported discrepancies in the incidence of catheter-related DVT may include recent improvements in catheter materials and design and the different diagnostic strategies used in some of the studies (ie, clinical, which identifies symptomatic events, versus radiologic surveillance, which identifies symptomatic and asymptomatic events).
大量的研究结果已确定中心静脉导管的存在为发生上肢深静脉血栓形成(UEDVT)的一个危险因素，尽管有关导管相关深静脉血栓形成的发生率存在差异。导管/装置放置与深静脉血栓的发生之间的相关性可能是在插入中心静脉导管以后静脉淤滞和血管损伤或由于导管放置发生感染的结果。导管相关深静脉血栓形成的发生率报道的差异可能的原因也许包括最近在导管材料与设计方面的改善与在一些研究中应用的诊断策略各种各样(即，临床识别有症状的事件，而放射学检查确定有症状与无症状的事件)。