2024年6月24日 (一) 10:25的版本

Treatment of canine hemangiosarcoma: 2000 and beyond

https://doi.org/10.1892/0891-6640(2000)014%3C0479:tochab%3E2.3.co;2

1 摘要

犬血管肉瘤 （HSA） 是一种侵袭性恶性肿瘤，预后严重。手术和化疗在延长 HSA 狗狗的生存时间和提高生活质量方面的成功有限。肿瘤内科的进步正在提高兽医癌症患者的生存率和生活质量。对转移机制的理解导致了旨在延缓或抑制肿瘤扩散的新疗法的开发。有前途的新治疗选择包括新型给药系统（吸入或腔内化疗）;使用免疫调节剂，如脂质体封装的胞壁酰三肽-磷脂酰乙醇胺;抗转移药物，如血管生成抑制剂（干扰素、沙利度胺）、基质金属蛋白酶抑制剂和米诺环素;饮食调整;和基因治疗。血管生成抑制剂似乎是安全的，并且与传统化疗不同，不会引起耐药性。尽管许多较新的方法仍在开发和审查中，但使用结合创新治疗方式的多模式疗法可能为受 HSA 影响的狗提供最佳治疗选择。

Canine hemangiosarcoma (HSA) is an aggressive and malignant neoplasia with a grave prognosis. Surgery and chemotherapy have limited success in prolonging survival times and increasing quality of life in dogs with HSA. Advances in medical oncology are resulting in increased survival rates and a better quality of life for veterinary cancer patients. An understanding of mechanisms of metastasis has led to the development of new treatments designed to delay or inhibit tumor spread. Promising new treatment options include novel delivery systems (inhalation or intracavitary chemotherapy); use of immunomodulators such as liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine; antimetastatic agents such as inhibitors of angiogenesis (interferons, thalidomide), matrix metalloproteinase inhibitors, and minocycline; dietary modifications; and gene therapy. Inhibitors of angiogenesis seem to be safe and, unlike conventional chemotherapy, do not induce drug resistance. Although many of the newer approaches are still under development and review, the use of multimodality therapy incorporating innovative treatment modalities may offer the best therapeutic option for dogs affected with HSA.

2 概述

3 传统疗法 (Traditional Therapy)

从历史上看，手术一直是 HSA 的首选治疗方法，尽管它对改善总体生存时间几乎没有作用.4,18,19 三项对仅通过手术治疗的脾脏 HSA 狗的研究报告称，中位生存时间为 2-3 个月[4,18,19]。心脏 HSA 的手术切除也产生了不令人满意的结果，中位生存时间从 3 到 5 个月不等[20-22]。皮肤 HSA 通常与更长的生存时间有关[23]。由于手术的局限性[11]，据报道，基于多柔比星的各种方案，无论是否添加长春新碱和环磷酰胺，都具有最佳生存时间[2,3,24-27]。已发表的方案包括单药阿霉素（30 mg/m^2，静脉注射，每 3 周一次，最多 5 个周期）；多柔比星和环磷酰胺（阿霉素作为单药方案，在每 3 周周期的第 3-6 天静脉注射环磷酰胺 50-75 mg/m^2）；和长春新碱、多柔比星和环磷酰胺（多柔比星作为单药方案，环磷酰胺在每 3 周周期的第 1 天静脉注射 100 mg/m^2，长春新碱在每个周期的第 8 天和第 15 天静脉注射）[1-3,24-26]。据报道，各种基于多柔比星的方案的生存时间从 140 到 202 天不等， 虽然没有任何一个方案明显更好。

Historically, surgery has been the treatment of choice for HSA, although it does little to improve overall survival times.4,18,19 Three studies of dogs with splenic HSA treated by surgery alone reported median survival times of 2–3 months.4,18,19 Surgical excision for cardiac HSA also yields unsatisfactory results, with median survival times ranging from 3 to 5 months.20–22 Cutaneous HSA is generally associated with longer survival times.23 Because of the limitations of surgery, chemotherapy has evolved into a principal component of therapy.11 Various protocols based on doxorubicin with and without the addition of vincristine and cyclophosphamide have been reported to have the best survival times.2,3,24–27 Published protocols include single-agent doxorubicin (30 mg/m2 intravenously every 3 weeks for up to 5 cycles); doxorubicin and cyclophosphamide (doxorubicin as for single-agent protocol, with cyclophosphamide incorporated at 50–75 mg/m2 intravenously on days 3–6 of every 3-week cycle); and vincristine, doxorubicin, and cyclophosphamide (doxorubicin as for single-agent protocol, with cyclophosphamide incorporated at 100 mg/m2 intravenously on day 1 of every 3-week cycle, and vincristine at 0.75 mg/m2 intravenously on days 8 and 15 of each cycle).1–3,24–26 Survival times ranging from 140 to 202 days have been reported for the various doxorubicin-based protocols, although no protocol is clearly superior [3,24-27].

4 新型输送系统 (Novel Delivery Systems)

对 HSA 转移行为的理解促使设计了针对预防转移的方案。许多患有 HSA 的狗死于肺部和腹腔内转移性疾病。针对常见转移部位的额外局部化疗可能有可能延缓转移并延长生存期28。

An understanding of the metastatic behavior of HSA has prompted the design of protocols tailored to the prevention of metastases. Many dogs with HSA die of pulmonary and intra-abdominal metastatic disease. Additional locally delivered chemotherapy aimed at common metastatic sites may have the potential to retard metastasis and prolong survival.28

吸入化疗是旨在抑制肺部微转移的一种策略。吸入化疗的疗效和安全性研究已在几只患有脾脏 HSA 的狗中进行.28 脾切除术后，狗每 3 周接受 4 个周期的多柔比星和环磷酰胺以及吸入阿霉素。吸入式阿霉素是一种新开发的制剂，通过专门设计的气溶胶装置给药。在第 4 个周期完成后进行 X 光检查和腹部超声检查，此后每 2 个月进行一次。对数据的中期分析表明，该方案可能是有效的，并且没有注意到由于同时全身性多柔比星化疗而增加的毒性28。

Inhalation chemotherapy is 1 strategy aimed at inhibiting pulmonary micrometastasis. Efficacy and safety studies with inhalation chemotherapy have been performed in several dogs with splenic HSA.28 After splenectomy, dogs received 4 cycles of doxorubicin and cyclophosphamide every 3 weeks in conjunction with inhaled doxorubicin. The inhaled doxorubicin was a newly developed formulation that was administered via a specially designed aerosol device. Radiographs and abdominal ultrasound were performed after the completion of the 4th cycle and every 2 months thereafter. Interim analysis of data suggests that this protocol may be efficacious and no increase in toxicity due to concurrent systemic doxorubicin chemotherapy has been noted.28

空间稳定脂质体是含有一小部分膜糖脂或其他表面稳定剂的脂质体，可作为硬脂屏障外膜.29 该制剂导致单核细胞吞噬系统的摄取减少，从而延长了肿瘤对药物的暴露.29 聚乙二醇化脂质体包封的多柔比星是一种独特的多柔比星递送系统.29 Doxil 已在患有多种恶性肿瘤的狗中进行了评估， 包括HSA，与阿霉素相比，具有增强的杀瘤作用、降低的心脏毒性和持续的药物血液水平29,30。

Sterically stabilized liposomes are liposomes containing a small fraction of membrane glycolipid or other surface stabilizer that acts as a stearic barrier outer membrane.29 This formulation results in decreased uptake by the monocytic phagocytic system thereby prolonging tumor exposure to the drug.29 Pegylated liposomal-encapsulated doxorubicina is a unique doxorubicin delivery system.29 Doxil has been evaluated in dogs with a variety of malignancies, including HSA, and has enhanced tumoricidal effects, decreased cardiotoxicity, and sustained drug blood levels compared to doxorubicin.29,30

腹腔是 HSA 患者转移性肿瘤扩散的另一个常见部位.31 腹腔转移的一种方法是腔内给予化疗药物，如顺铂或卡铂。32 正在研究腹腔内卡铂对明显腹腔转移性 HSA 狗的疗效（后，个人交流）。然而，由于卡铂的组织扩散和渗透能力低于顺铂，因此卡铂不太可能提高对HSA的疗效33,34。

The abdominal cavity is another common site of metastatic tumor spread in HSA patients.31 One approach to abdominal metastases is the intracavitary administration of chemotherapeutic agents such as cisplatin or carboplatin. The use of intracavitary cisplatin has been described in dogs with various intra-abdominal tumors.32 The efficacy of intra-abdominal carboplatin in dogs with overt abdominal metastatic HSA is being investigated (Post, personal communication). However, because carboplatin has less tissue diffusion and penetration ability than cisplatin, carboplatin is unlikely to have improved efficacy against HSA.33,34

5 免疫调节剂 (Immunomodulators)

6 抗转移药物 (Antimetastatic Agents)

7 抑制血管生成 (Inhibition of Angiogenesis)

8 Matrix Metalloproteinase Inhibitors

9 四环素衍生物 (Tetracycline Derivatives)

10 饮食调整 (Dietary Modifications)

最近，兽医癌症患者的营养方面受到了很多关注.77-84许多代谢异常与肿瘤有关。用于描述这些异常的副肿瘤综合征是癌症恶病质，其特征是尽管摄入了足够的营养，但体重减轻。碳水化合物、脂质和蛋白质代谢都会对癌症患者产生不利影响。

Recently, a great deal of attention has been directed toward nutritional aspects of the veterinary cancer patient.77–84 Numerous metabolic abnormalities have been associated with neoplasia. The paraneoplastic syndrome used to describe these abnormalities is cancer cachexia, which is characterized by weight loss despite adequate nutritional intake. Carbohydrate, lipid, and protein metabolism are all adversely affected in cancer patients.

癌症相关代谢异常的临床影响导致使用饮食操纵来试图减轻癌症恶病质。简单碳水化合物含量低的饮食，适量的高生物利用度蛋白质来源，补充 omega-3 脂肪酸和特定氨基酸，如精氨酸、甘氨酸、谷氨酰胺和半胱氨酸，可能对一些癌症患者有益.77 癌症饮食管理的关键组成部分之一是利用脂肪来源作为主要的膳食能量成分， 注意脂肪酸的类型和比例与饮食.77,84 高脂肪饮食可能对癌症患者有 2 个主要的有益影响.77,78,80,84 首先，肿瘤似乎在使用脂肪作为能量来源方面效率低下，与正常体细胞相比，富含脂肪衍生卡路里的饮食可能会有效地“饿死”肿瘤细胞.77，80,84 其次，特别是 omega-3 脂肪酸已被证明具有抗血管生成特性，并在动物模型中抑制肿瘤发展.78 二十碳五烯酸是一种 omega-3 脂肪酸，在实验性肿瘤模型中具有杀瘤作用而不会损害正常细胞.78 最近的一项双盲随机研究评估了富含多不饱和 omega-3 脂肪酸和精氨酸的特殊饮食对代谢参数的影响， 77 在特殊饮食的患者中注意到乳酸水平降低，与对照动物相比，这些狗的无病间隔和生存时间明显更长.79 此后开发了一种可比较的商业饮食，旨在提高犬癌患者的生存时间和生活质量（希尔肿瘤饮食 [ND]）.b 虽然ND饮食是为患有淋巴瘤的狗设计的，它在其他肿瘤中的使用似乎是合理的.85因为患有HSA的动物已被证明会发展为癌症恶病质，因此饮食疗法可能是一种可行的治疗方式。目前，一项兽医研究正在检查饮食操纵对患有 HSA 的狗的影响（Ogilvie，个人交流）。

The clinical impact of cancer-associated metabolic abnormalities has led to the use of dietary manipulation in an attempt to lessen cancer cachexia. A diet low in simple carbohydrates with a moderate amount of a highly bioavailable protein source supplemented with omega-3 fatty acids and specific amino acids such as arginine, glycine, glutamine, and cysteine may be beneficial to some cancer patients.77 One of the key components to the dietary management of cancer is the utilization of a fat source as the major dietary energy component, with attention to the type and ratio of fatty acids with the diet.77,84 High-fat diets may have 2 major beneficial effects in cancer patients.77,78,80,84 First, tumors seem to be inefficient in using fat as an energy source, and a diet that is high in fat-derived calories may effectively ‘‘starve’’ neoplastic cells compared to normal body cells.77,80,84 Second, omega-3 fatty acids in particular have been shown to possess antiangiogenic properties, and inhibit tumor development in animal models.78 Eicosapentaenoic acid, an omega-3 fatty acid, has tumorcidal effects without damaging normal cells in experimental tumor models.78 A recent double-blind, randomized study evaluated the effect of a specialized diet high in polyunsaturated omega-3 fatty acids and arginine on metabolic parameters, chemical indices of inflammation, quality of life, and disease-free interval and survival time of dogs with lymphoma.77 Decreased levels of lactic acid were noted in patients on the special diet and these dogs had significantly longer disease-free interval and survival times compared to control animals.79 A comparable commercial diet has since been developed that is designed to enhance survival time and quality of life in canine cancer patients (Hill’s Neoplasia Diet [ND]).b Although the ND diet was designed for dogs with lymphoma, its use in other neoplasia seems plausible.85 Because animals with HSA have been shown to develop cancer cachexia, it stands to reason that dietary therapy may be a viable modality of treatment. Currently, a veterinary study is examining the effect of dietary manipulations on dogs with HSA (Ogilvie, personal communication).

11 Reference

• Doxorubicin chemotherapy for presumptive cardiac hemangiosarcoma in dogs 2014 阿霉素化疗治疗狗的推定性心脏血管肉瘤

• Comparison of doxorubicin-cyclophosphamide with doxorubicin-dacarbazine for HSA 2017 多柔比星-环磷酰胺与多柔比星-达卡巴肼辅助治疗犬血管肉瘤的比较