犬内脏血管肉瘤单独手术治疗或手术加多柔比星治疗：37例（2005-2014年）

原文：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091137/ https://pubmed.ncbi.nlm.nih.gov/30197439/

Published: 2018 Sep

1 Abstract

这项回顾性研究的目的是确定仅接受手术或手术和多柔比星治疗的内脏血管肉瘤（HSA）狗的生存时间和预后因素。从 2005 年到 2014 年，从 2 家医院的医疗记录中检索了经组织病理学证实患有内脏 HSA 的狗。提取了与患者人口统计学、肿瘤特征和结局相关的数据。最常见的原发性器官是脾脏;然而，原发肿瘤位置对预后没有影响。23 只狗单独接受手术治疗，而 14 只狗接受手术和多柔比星治疗。单独接受手术治疗的狗和手术后接受阿霉素治疗的狗的生存时间存在显着差异（66 天对 274 天）。患有 I 期肿瘤（196 天）的狗比患有 II 期（117 天）和 III 期（23 天）疾病的狗具有更长的中位生存时间（MST）。总MST为179天，1年生存率为29.2%。

The purpose of this retrospective study was to determine survival times and prognostic factors of dogs with visceral hemangiosarcoma (HSA) treated with surgery alone or surgery and doxorubicin. Medical records from 2 hospitals from 2005 to 2014 were searched for dogs with histopathologically confirmed visceral HSA. Data relevant to patient demographics, tumor characteristics, and outcomes were abstracted. The most common primary organ affected was the spleen; however, primary tumor location had no influence on prognosis. Twenty-three dogs were treated with surgery alone, while 14 dogs were treated with surgery and doxorubicin. There was a significant difference in survival times between dogs treated with surgery alone and with surgery followed by doxorubicin (66 days versus 274 days). Dogs with stage I tumors (196 days) had a longer median survival time (MST) than dogs with stage II (117 days) and stage III (23 days) disease. The overall MST was 179 days with a 1-year survival rate of 29.2%.

2 Introduction

血管肉瘤（HSA）是一种侵袭性肿瘤，通常影响体型较大的中老年犬（1,2）。某些品种，如拉布拉多猎犬、金毛猎犬和德国牧羊犬的比例过高（1,2）。由恶性内皮细胞引起，最常见的原发性器官是脾脏，尽管这种类型的癌症可能发生在许多部位，包括右心房、肝脏、肾脏、腹膜后间隙、皮下和真皮（3,4）。在狗中，内脏 HSA 比皮肤 HSA 更常见，并且与较差的预后相关（5）。除真皮 HSA 外，局部浸润和器官转移（如肺、肝、肠系膜和网膜）通常在病程早期可见（1,3,4,6）。许多患者初次就诊时，由于肿瘤破裂或弥散性血管内凝血而出现内出血（7–9）。

虽然真皮 HSA 通常仅通过肿瘤切除即可治愈，但内脏肿瘤很少可治愈，因为它们原发性肿瘤生长迅速，转移广泛（4–6,10）。脾脏HSA的中位生存时间为19-86 d，手术是唯一治疗（8,11,12）。由于转移风险高，因此需要辅助化疗，手术后加用基于多柔比星的化疗方案可将 MST 改善至 5-6 个月，据报道 1 年生存率低于 16% （1,13–16）。在最近的一项研究中，将达卡巴嗪添加到基于多柔比星的常规方案中显示出诊断患有内脏 HSA 的狗的预后的潜在改善（17）。在这项研究中，所分析的狗组的 MST 和转移的中位时间都超过 550 天（17）。常规化疗方案的替代方法，包括节拍疗法、酪氨酸激酶抑制剂的使用、自体疫苗以及基于免疫和抗血管生成的疗法，在患有这种致命疾病的狗的预后中没有提供一致的显着益处（13,18–21）。Finotello 等人（22）的一项研究表明，在转移控制和生存率方面，与单独使用最大耐受性化疗（基于多柔比星的方案）相比，增加由低剂量口服环磷酰胺组成的维持性节拍化疗具有优势。在术后接受最大耐受化疗后接受节拍治疗的狗的转移中位时间（未达到 vs 150 天）和 MST（未达到 vs 168 天）显着延长（22）。化疗也已在患有大体 HSA 肿瘤的狗中进行了评估，包括患有转移的狗。Dervisis 等人（23）评估了由多柔比星、达卡巴嗪和长春新碱组成的联合化疗方案治疗被诊断患有晚期和不可切除 HSA 的狗的疗效。缓解率为 47.4%，肿瘤进展的中位时间为 101 d，MST 为 125 d。

Hemangiosarcoma (HSA) is an aggressive neoplasm that typically affects larger, middle-aged to geriatric dogs (1,2). Certain breeds, such as Labrador retrievers, golden retrievers, and German shepherds are overrepresented (1,2). Arising from malignant endothelial cells, the most common primary organ affected is the spleen, although this type of cancer can occur in many sites including the right atrium, liver, kidneys, retroperitoneal space, subcutis, and dermis (3,4). In the dog, visceral HSA is more common than cutaneous HSA, and is associated with a poorer prognosis (5). With the exception of dermal HSA, local infiltration and metastases to organs, such as lungs, liver, mesentery, and omentum, are typically seen early in the course of the disease (1,3,4,6). Many patients on initial presentation have internal bleeding due to rupture of the tumor or disseminated intravascular coagulation (7–9).

While dermal HSAs are often cured by tumor excision alone, visceral tumors are rarely curable since they have a rapid primary tumor growth with widespread metastases (4–6,10). Median survival times for splenic HSA range from 19 to 86 d with surgery as sole therapy (8,11,12). Adjuvant chemotherapy is indicated due to the high risk of metastases and the addition of doxorubicin-based chemotherapy protocols following surgery improves MST to 5 to 6 mo, with a reported 1-year survival rate of less than 16% (1,13–16). In a recent study, the addition of dacarbazine to conventional doxorubicin-based protocols showed a potential improvement in the prognosis of dogs diagnosed with visceral HSA (17). In this study, the MST and median time to metastasis were both more than 550 days for the group of dogs analyzed (17). Alternative approaches to conventional chemotherapy regimens, including metronomic therapies, the use of tyrosine kinase inhibitors, autologous vaccines, and immunebased and antiangiogenic therapies have not provided a consistent significant benefit in the prognosis of dogs with this fatal disease (13,18–21). A study by Finotello et al (22), suggested an advantage of the addition of maintenance metronomic chemotherapy consisting of low-dose oral cyclophosphamide over maximum tolerated chemotherapy alone (doxorubicin-based protocol) in terms of metastatic control and survival. Median time to metastasis (not reached versus 150 d) and MST (not reached versus 168 d) were significantly longer for dogs receiving maximum tolerated chemotherapy followed by metronomic therapy in the post-surgical setting (22). Chemotherapy has also been evaluated in dogs with gross HSA tumors, including dogs with metastases. Dervisis et al (23) evaluated the efficacy of a combination chemotherapy protocol comprised of doxorubicin, dacarbazine, and vincristine for the treatment of dogs diagnosed with advanced-stage and non-resectable HSA. The response rate was 47.4% with a median time to tumor progression of 101 d and an MST of 125 d.

在预后方面，原发性内脏HSA部位（包括右心房和肝脏）的预后与脾脏HSA相当[24]。据报道，在其他原发部位，肾脏 HSA 的预后略优于 HSA，MST 为 278 天（25）。然而，大约 90% 的腹膜后 HSA 狗在诊断时有远处转移（26）。与生存时间始终相关的预后因素之一是疾病的临床分期（1,11,27）。在 I 期，HSA 局限于原发性器官，在 II 期，原发性 HSA 破裂或扩散到区域淋巴结，在 III 期有远处转移（28）。研究表明，被诊断患有 I 期 HSA 的狗比患有 II 期或 III 期疾病的狗有更好的结果（1,11,27,28）。

这项回顾性研究的目的是扩大文献中的可用数据，包括被诊断患有内脏 HSA 的狗的结果和潜在预后因素的信息，这些狗患有任何阶段的疾病，仅接受手术治疗，或手术后使用多柔比星。

With regard to prognosis, primary visceral HSA sites, including right atrium and liver, have a comparable prognosis to splenic HSA (24). Renal HSA has been reported to have a slightly more favorable prognosis than HSA at other primary sites, with an MST of 278 d (25). Approximately 90% of dogs with retroperitoneal HSA, however, have distant metastases at diagnosis (26). One of the prognostic factors that has been consistently correlated to survival time is the clinical stage of the disease (1,11,27). In stage I HSA is confined to the primary organ, in stage II a primary HSA has ruptured or spread to the regional lymph node, and in stage III there are distant metastases (28). Studies show that dogs diagnosed with stage I HSA have a better outcome than dogs with stage II or III disease (1,11,27,28).

The goals of this retrospective study were to expand the available data in the literature with information on outcome and potential prognostic factors of dogs diagnosed with visceral HSA with any stage of the disease treated with surgery alone, or with surgery followed by doxorubicin.

NOTES:

I 期：HSA 局限于原发性器官
II 期：原发性 HSA 破裂或扩散到区域淋巴结
III 期：有远处转移

3 素材和方法 (Materials and methods)

回顾性回顾了 2005 年至 2014 年间在 Provet 兽医诊断和专科中心以及宠物护理动物医院被诊断患有内脏 HSA 的狗的医疗记录。该研究是根据巴西圣保罗大学兽医学院的机构动物护理和使用委员会指南进行的，该指南使用动物的医疗记录数据。如果狗在任何解剖位置都有内脏 HSA 的组织病理学诊断，则它们有资格被纳入研究。排除标准包括被诊断患有皮肤、皮下或肌肉注射 HSA 的狗;病历中随访不足的患者;以及接受阿霉素以外的化疗药物治疗的狗。

收集的患者数据包括：信号、体重、疾病的临床分期、原发肿瘤位置、进行的手术类型、化疗方案和生存时间。由于病历数据中的信息不足，未计算无进展生存期。

所有狗在诊断 HSA 时的初始诊断检查和临床分期包括全血（细胞）计数（CBC）、血清生化、腹部超声、超声心动图和 3 视图胸部 X 光片。HSA的组织病理学诊断是通过切除活检获得的。临床分期在初次就诊时确定，并根据世界卫生组织方案的修改进行分配（表1）（28）。

表 1：

基于世界卫生组织方案修改的犬血管肉瘤临床分期系统（28）

原发性肿瘤 Primary tumor（T）
 T0 — 无肿瘤证据
 T1 — 肿瘤直径小于 5 cm 且局限于原发部位
 T2 — 肿瘤 5 cm 或更大或破裂：侵犯皮下组织 (Tumor 5 cm or greater or ruptured: invading subcutaneous tissues)
 T3 — 肿瘤侵犯邻近结构，包括肌肉

区域淋巴结 Regional lymph nodes（N）
 N0 — 无区域淋巴结受累
 N1 — 区域淋巴结受累
 N2 — 远处淋巴结受累 (Distant lymph node involvement)

远处转移 Distant metastasis（M）
 M0 — 无远处转移的证据
 M1 — 远处转移

阶段
 I — T0 或 T1， N0， M0
 II — T1 或 T2、N0 或 N1、M0
 III — T2 或 T3、N0、N1 或 N2、M1

The medical records of dogs diagnosed with visceral HSA at Provet Veterinary Diagnostic and Specialty Center and Petcare Animal Hospital between 2005 and 2014 were retrospectively reviewed. The study was performed in compliance with the Institutional Animal Care and Use Committee guidelines of the College of Veterinary Medicine of the University of São Paulo, Brazil, for using medical record data of animals. Dogs were eligible for inclusion in the study if they had a histopathological diagnosis of visceral HSA at any anatomic location. Exclusion criteria included dogs diagnosed with dermal, subcutaneous, or intramuscular HSA; patients with insufficient follow-up in the medical record; and dogs treated with chemotherapy agents other than doxorubicin.

Patient data collected included: signalment, body weight, clinical stage of the disease, primary tumor location, type of surgery performed, chemotherapy protocol, and survival time. Progression-free survival was not calculated due to insufficient information in the medical record data.

Initial diagnostic work-up and clinical staging at the time of diagnosis of HSA of all dogs included complete blood (cell) count (CBC), serum biochemistry, abdominal ultrasound, echocardiogram, and 3-view thoracic radiographs. The histopathological diagnosis of HSA was obtained by excisional biopsy. Clinical stage was determined at the time of initial presentation and was assigned on the basis of a modification of the World Health Organization scheme (Table 1) (28).

总体而言，MST 定义为从手术日期到死亡日期的时间。对于生存计算，与肿瘤相关的死亡的狗被认为是已完成的事件，并且在数据累积终止或因随访而失去数据时存活的狗被审查。通过使用Kaplan-Meier产品限制法确定结局。对潜在危险因素分别采用log-rank检验和Cox回归进行单因素和多因素分析。分析的危险因素包括性别、中性状态、年龄、品种、基线体重（< 或 15 公斤>）、原发肿瘤位置、疾病分期和治疗类型（单独手术或手术后辅助化疗）。根据用于治疗小型（< 15 kg）和大型（> 15 kg）犬的多柔比星剂量，体重（BW）的临界值为 15 kg。对于Cox回归，如果P<0.05，则在回归模型中以正向方式输入潜在风险因素，如果P>0.1，则将其删除。P 值< 0.05 被认为具有统计学意义。市售软件（适用于 Mac 的 STATA 13.1;Stata Corp.， College Station， Texas， USA）用于所有统计计算。

Overall MST was defined as the time from the date of surgery to the date of death. For survival calculations, dogs that had neoplasia-related death were considered completed events, and dogs alive at the time of termination of data accrual or lost to follow-up were censored. Outcomes were determined by the use of the Kaplan-Meier product-limit method. Log-rank test and Cox regression were used for univariate and multivariate analysis of potential risk factors, respectively. The risk factors analyzed included gender, neuter status, age, breed, baseline weight (< or > 15 kg), primary tumor location, stage of disease, and treatment type (surgery alone or surgery followed by adjuvant chemotherapy). The cutoff value for body weight (BW) was 15 kg based on the dose of doxorubicin used for treating small (< 15 kg) and large (> 15 kg) dogs. For the Cox regression, the potential risk factors were entered in the regression model in a forward fashion if P < 0.05 and removed if P > 0.1. A P-value < 0.05 was considered to be statistically significant. Commercially available software (STATA 13.1 for Mac; Stata Corp., College Station, Texas, USA) was used for all statistical calculations.

4 Results

4.1 患者 (Patients)

本研究共纳入 37 只狗。代表的品种包括：混合品种（n = 8）、拉布拉多猎犬（n = 6）、美国斗牛犬（n = 3）、微型雪纳瑞犬（n = 4）和金毛猎犬、德国牧羊犬、微型贵宾犬、罗威纳犬和拳击手各 2 只。其余 6 只狗由以下品种各 1 只组成：拉萨阿普索犬、比熊犬、比格犬、西高地白梗犬、美国狐狸梗犬和英国可卡犬。诊断时的中位年龄为 10.5 岁（范围：3 至 15 岁），中位体重为 26 公斤（范围：6 至 43 公斤）。13 只狗的体重不到 15 公斤。14只狗为绝育雌性，1只为完整雌性，9只为绝育雄性，13只为完整雄性。统计分析显示，在存活时间方面没有与年龄、基线体重、性别、绝育状态或品种相关的显著发现。

A total of 37 dogs were included in this study. The breeds that were represented included: mixed breed (n = 8), Labrador retriever (n = 6), American pit bull terrier (n = 3), miniature schnauzer (n = 4), and 2 each of golden retriever, German shepherd, miniature poodle, Rottweiler, and boxer. The remaining 6 dogs consisted of 1 of each of the following breeds: lhasa apso, bichon frise, beagle, West Highland white terrier, American fox terrier, and English cocker spaniel. The median age at the time of diagnosis was 10.5 y (range: 3 to 15 y) and the median weight was 26 kg (range: 6 to 43 kg). Thirteen dogs weighed less than 15 kg. Fourteen dogs were spayed females, 1 was an intact female, 9 were neutered males, and 13 were intact males. Statistical analysis revealed no significant findings in survival time relating to age, baseline weight, gender, neuter status, or breed.

4.2 原发肿瘤位置和临床分期 (Primary tumor location and clinical stage)

HSA的组织病理学诊断是通过切除活检对所有狗进行的。在诊断时，由于肿瘤破裂和继发性腹腔血，有转移的狗的原发肿瘤被手术切除。

在初步诊断时，30 只狗的原发肿瘤位于脾脏。其他部位包括肝脏（2 只狗）、肾脏（2 只狗）和肠道、膀胱和淋巴结，每个部位供 1 只狗使用。被诊断患有 HSA 局限于淋巴结的狗被归类为患有原发性 HSA 而不是转移性疾病，因为临床分期（腹部超声和 3 视图胸部 X 光片）未显示其他肿瘤。在这项研究中，原发肿瘤位置与生存时间的显着差异无关（P = 0.6956）。

六只狗在就诊时有转移性 HSA 的证据，转移部位包括：肝脏（3/6）、肺（2/6）和肠系膜（1/6）。一只狗有 1 个以上的并发转移部位。所有在诊断时有转移的狗的原发肿瘤都位于脾脏。

临床分期患者分类如下：I期25只（67.6%），II期6只（16.2%），III期6只（16.2%）。患有 I 期肿瘤的狗比患有更晚期疾病的狗寿命更长。I期HSA的狗的MST为196天（范围：1至>1747天），II期HSA的狗的MST为117天（范围：8至>844天），III期HSA的狗的MST为23天（范围：9至788天），（P = 0.0457）（图1）。

Primary tumor location and clinical stage The histopathological diagnosis of HSA was obtained by excisional biopsy in all dogs. Dogs with metastases had their primary tumors surgically removed due to tumor rupture and secondary hemoabdomen at the time of diagnosis.

At the time of initial diagnosis, 30 dogs had their primary tumors located in the spleen. Other locations included liver (2 dogs), kidneys (2 dogs), and intestines, urinary bladder, and lymph node, each for 1 dog. The dog diagnosed with HSA confined to the lymph node was categorized as having a primary HSA rather than metastatic disease as clinical staging (abdominal ultrasound and 3-view thoracic radiographs) did not reveal other tumors. In this study, primary tumor location was not associated with a significant difference in survival time (P = 0.6956).

Six dogs had evidence of metastatic HSA at presentation and metastatic sites included: liver (3/6), lungs (2/6), and mesentery (1/6). One dog had more than 1 concurrent metastatic site. All dogs with metastases at the time of diagnosis had their primary tumor located in the spleen.

Clinical staging classified patients as follows: 25 dogs were stage I (67.6%), 6 dogs were stage II (16.2%), and 6 dogs were stage III (16.2%). Dogs with stage I tumors lived longer than those with more advanced disease. The MST of dogs with stage I HSA was 196 d (range: 1 to > 1747 d), the MST of dogs with stage II HSA was 117 d (range: 8 to > 844 d), and the MST for dogs with III HSA was 23 d (range: 9 to 788 d), (P = 0.0457) (Figure 1).

4.3 治疗 (Treatment)

23 只狗单独接受手术治疗，14 只狗接受手术和多柔比星（Oncoprod;Avenida Ibirapuera， São Paulo， Brazil），30 mg/m2（狗> 15 公斤）或 1 mg/kg（狗≤ 15 公斤），每 21 天静脉注射一次，共 6 个周期。

为所有 23 只单独接受手术治疗的狗和接受手术和单药多柔比星治疗的狗创建了 Kaplan-Meier 曲线。单独接受手术治疗的狗与接受手术和辅助阿霉素治疗的狗之间的生存时间存在显着差异（P = 0.042）（图2）。单独接受手术治疗的狗的中位生存时间为 66 天（范围：7 至 1075 天），而手术治疗后接受多柔比星治疗的狗的 MST 为 274 天（范围：202 至 > 1747 天）。

Twenty-three dogs were treated with surgery alone and 14 dogs were treated with surgery and doxorubicin (Oncoprod; Avenida Ibirapuera, São Paulo, Brazil), 30 mg/m2 (dogs > 15 kg) or 1 mg/kg (dogs ≤ 15 kg) given IV every 21 d for a total of 6 cycles.

Kaplan-Meier curves were created for all 23 dogs treated with surgery alone and for dogs treated with surgery and single agent doxorubicin. There was a significant difference in survival times between dogs treated with surgery alone and dogs treated with surgery and adjuvant doxorubicin (P = 0.042) (Figure 2). Median survival time of dogs treated with surgery alone was 66 d (range: 7 to 1075 d), whereas the MST of dogs treated with surgery followed by doxorubicin was 274 d (range: 202 to > 1747 d).

4.4 存活时间 (Survival time)

在数据分析时，有26只狗死亡（13只被安乐死），11只狗还活着。没有一只狗进行尸检以确认它们死于HSA;然而，与HSA相关的死因是根据体格检查结果、胸片和/或腹部超声来推测的。

所有 37 只狗都被纳入总体生存分析，其中 13 只狗被审查。11只狗在数据分析时还活着，2只狗因丢失而失踪。被诊断患有内脏HSA的狗的总MST为179天（范围：1至>1747天），1年生存率估计为29.2%（图3）。

At the time of data analysis, 26 dogs had died (13 had been euthanized) and 11 dogs were alive. None of the dogs had postmortem examinations to confirm that they had died of HSA; however, the cause of death related to HSA was presumed on the basis of physical examination findings, thoracic radiographs, and/or abdominal ultrasounds.

All 37 dogs were included in the overall survival analysis, with 13 dogs censored. Eleven dogs were censored since they were alive at the time of data analysis and 2 dogs due to being lost to follow-up. The overall MST for dogs diagnosed with visceral HSA was 179 d (range: 1 to > 1747 d) and the 1-year survival rate was estimated to be 29.2% (Figure 3).

5 讨论 (Discussion)

犬内脏HSA的治疗在过去20年中没有发生重大变化，这可能是由于对肿瘤生物学的了解不足（21,29）。直到最近，涉及分子发病机制、细胞个体发育、肿瘤微环境和 HSA 异质性的基础研究才成为兽医学的重点领域（21,29）。与之前关于被诊断患有内脏 HSA 的狗的结果和预后因素的回顾性研究相比，我们的研究显示了类似的结果。

历史上，患有HSA晚期临床阶段的狗的生存时间比患有早期疾病的狗短（1,11,27,28）。与以前的研究一致，我们的研究发现诊断时的临床分期与生存时间相关。正如预期的那样，在初次就诊时被诊断为转移的狗的生存时间最短，这可能是由于不适合手术的转移性病变出血，并且经常与这种疾病相关的凝血异常加剧 （1,30）。患有 I 期肿瘤的狗比患有 II 期疾病的狗具有更长的生存时间，这可能是由于缺乏肿瘤出血和肿瘤细胞继发植入腹腔或胸腔（1,10,27,31）。

科学数据表明，HSA 的生物学行为可能因起源组织而异（4,5,10,24–26）。与在其他解剖位置患有 HSA 的狗相比，患有真皮 HSA 的狗可能会经历更长的生存期或手术切除后治愈（10）。相反，尽管进行了充分的局部和全身治疗，但患有内脏HSA的狗通常会在一年内死亡（1,13-16）。与位于脾脏、右心房和肝脏的 HSA 相比，原发性肾 HSA 与侵袭性较低的疾病相关，而腹膜后 HSA 与较差的临床结果相关，因为在诊断时出现转移的狗比例很高（25,26）。与以前的研究相比，我们的研究没有发现原发性肿瘤位置会影响预后。原发肿瘤位置和生存时间之间缺乏相关性的一种可能解释是我们研究中狗的异质性种群。最常见的原发性器官是脾脏，占病例的81.1%（30/37）。其他受累的原发部位代表性不足，包括肝脏（2/37,5.4%）、肾脏（2/37,5.4%）、肠道（1/37,2.7%）、膀胱（1/37,2.7%）和淋巴结（1/37,2.7%）。由于与研究的小样本量相关的 II 型错误，位于不同主要部位的被诊断患有 HSA 的狗在结果上没有显着差异可能代表假阴性结果（32）。因此，根据我们的研究，不可能就HSA原发肿瘤位置的重要性得出明确的结论。

Treatment for canine visceral HSA has not changed considerably in the past 20 y, probably due to a poor understanding of the tumor biology (21,29). It is only recently that basic research involving molecular pathogenesis, cellular ontogeny, tumor microenvironment, and heterogeneity of HSA has become an area of emphasis in veterinary medicine (21,29). Our study showed similar results compared to previous retrospective studies regarding outcome and prognostic factors for dogs diagnosed with visceral HSA.

Dogs with advanced clinical stage of HSA historically have had shorter survival times than dogs with early-stage disease (1,11,27,28). In agreement with previous studies, our study found that clinical stage at diagnosis was associated with survival time. As expected, dogs diagnosed with metastases at initial presentation had the shortest survival time, possibly due to hemorrhage from metastatic lesions that are not amenable to surgery and compounded by coagulation abnormalities that are frequently associated with this disease (1,30). Dogs with stage I tumors had longer survival times than dogs with stage II disease probably due to lack of tumor hemorrhage and secondary implantation of neoplastic cells into the abdominal or thoracic cavities (1,10,27,31).

Scientific data suggest that the biological behavior of HSA may vary according to the tissue of origin (4,5,10,24–26). Dogs with dermal HSA may experience prolonged survival or be cured after surgical excision compared with dogs with HSA in other anatomic locations (10). On the contrary, dogs with visceral HSA usually die within a year despite adequate local and systemic treatments (1,13–16). When compared to HSA located in the spleen, right atrium, and liver, primary renal HSA has been associated with a less aggressive disease while retroperitoneal HSA has been associated with a poor clinical outcome due to the high percentage of dogs presenting with metastases at the time of diagnosis (25,26). In contrast to previous studies, our study did not find that primary tumor location influenced prognosis. One possible explanation for this lack of correlation between primary tumor location and survival time is the heterogenous population of dogs in our study. The most common primary organ affected was the spleen, accounting for 81.1% (30/37) of cases. Other primary sites affected were underrepresented, including liver (2/37, 5.4%), kidneys (2/37, 5.4%), intestines (1/37, 2.7%), urinary bladder (1/37, 2.7%), and lymph node (1/37, 2.7%). The absence of significant difference in outcome among dogs diagnosed with HSA located at different primary sites may represent a false-negative result due to a type II error related to the small sample size of the study (32). Therefore, it is not possible to establish definitive conclusions on the importance of primary tumor location of HSA based on our study.

虽然很难将我们的研究对象与先前发表的被诊断患有内脏 HSA 的狗的研究进行直接比较，但我们的结果与先前报道的单独接受手术治疗和手术后全身治疗的狗的生存时间相似。根据大多数研究，基于多柔比星的辅助方案将脾脏 HSA 狗的存活时间从平均 3 个月提高到 9 个月 （1,3,16,25,33,34）。在这项研究中，患有内脏 HSA 的狗的总体 MST 为 179 天（~6 个月），1 年生存率为 29.2%。单独接受手术治疗的狗的 MST 为 2 个月，接受手术治疗的狗随后接受多柔比星治疗的狗的 MST 为 9 个月。鉴于总体预后不良，需要替代治疗方式来治疗这种疾病。Wendelburg等人（31）报告说，接受基于多柔比星和节拍化疗联合治疗的狗的存活时间主观上比单独接受基于多柔比星或节拍化疗的狗的存活时间长。在另一项研究（17）中，在单独的常规最大耐受剂量化疗的基础上增加节律化疗与更长的进展时间和生存时间相关。根据这些结果，有理由相信，使用节拍疗法可能在减缓 HSA 进展方面发挥作用，这可能是由于其抗血管生成作用和免疫调节（35）。犬 HSA 细胞系和肿瘤样本表达受体酪氨酸激酶干细胞因子受体（KIT）、血小板衍生生长因子受体（PDGFR）和血管内皮生长因子受体（VEGFR）。Toceranib 是一种多靶点小分子抑制剂，可阻断 KIT、PDGFR 和 VEGFR 信号转导（21,36）。Gardner等人（21）在基于多柔比星的化疗后使用托塞拉尼作为犬脾 HSA 的维持治疗时，未发现无病间隔期或总生存期的改善。有必要研究基于托塞拉尼布和多柔比星的方案的同时给药而不是顺序给药，以确定这种组合是否对生存时间有显著影响（21）。除了节拍器或靶向治疗与最大耐受剂量化疗的组合外，免疫疗法也在临床试验中进行了评估（27）。例如，在脾切除术后，用免疫调节剂脂质体封装的胞壁酰三肽磷脂酰乙醇胺（L-MTP-PE）联合多柔比星和环磷酰胺治疗的狗比接受手术和最大耐受剂量化疗的狗有更好的结果（27）。需要进一步的研究来确认在诊断患有内脏 HSA 的狗使用基于多柔比星的化疗方案后使用节律化疗、免疫疗法或靶向疗法作为维持疗法的潜在益处。

我们的报告存在回顾性研究固有的局限性、狗的异质性种群和少量患者。被诊断患有HSA的狗位于脾脏以外的主要部位，代表性不足。此外，几名患者接受了不同的治疗，这些治疗是根据临床医生的判断确定的。术后辅助化疗患者治疗或不治疗的决定在病历中并不明确。由于对预后不良、不依从性、经济拮据或难以治疗不合作的动物的误解，主人的偏见可能会影响患者的治疗决策和结果。最后，没有一只狗进行尸检以确认死因，并假设它们死于HSA。

总之，本手稿中报告的数据表明，使用当前标准护理方法（例如积极手术和化疗）或单独手术治疗的内脏 HSA 狗的总生存率仍然很差，大多数狗在一年内死于疾病。临床分期与预后相关，被诊断患有 I 期肿瘤的狗比患有更晚期 HSA 的狗有更好的结果。在这项回顾性研究中，术后加用单药阿霉素显示出生存获益，尽管效果不大。因此，应评估新的治疗方法，包括使用维持性节律化疗、免疫治疗或最大耐受剂量化疗后的靶向治疗。对犬 HSA 生物学的进一步研究可能会提高对这种疾病的理解，并有助于推进治疗。CVJ

Although it is difficult to make direct comparisons between our study population and previously published studies of dogs diagnosed with visceral HSA, our results were similar to previously reported survival times of dogs treated with surgery alone and surgery followed by systemic therapy. According to the majority of studies, adjuvant doxorubicin-based protocols improve survival times of dogs with splenic HSA from an average of 3 to 9 mo (1,3,16,25,33,34). The overall MST of dogs with visceral HSA in this study was 179 d (~6 mo), with a 1-year survival rate of 29.2%. The MST of dogs treated with surgery alone was 2 mo and the MST of dogs treated with surgery followed by doxorubicin was 9 mo. Given the overall poor prognosis, alternative therapeutic modalities are needed for treatment of this disease. Wendelburg et al (31) reported that survival time of dogs treated with the combination of doxorubicin-based and metronomic chemotherapy was subjectively longer than survival time of dogs receiving either doxorubicin-based or metronomic chemotherapy alone. In another study (17), the addition of metronomic chemotherapy to conventional maximum-tolerated dose chemotherapy alone was associated with a longer time to progression and survival time. According to these results, it is reasonable to believe that the use of metronomic therapy may play a role in slowing the progression of HSA possibly due to its anti-angiogenic effect and immune modulation (35). Canine HSA cell lines and tumor samples express the receptor tyrosine kinases stem cell factor receptor (KIT), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR). Toceranib is a multitargeted small molecule inhibitor that blocks signaling of KIT, PDGFR and VEGFR (21,36). No improvement in disease-free interval or overall survival was noted by Gardner et al (21) when toceranib was used as maintenance therapy after doxorubicin-based chemotherapy for canine splenic HSA. The investigation of concurrent rather than sequential administration of toceranib and doxorubicin-based protocols is warranted to determine if this combination has a significant impact on survival time (21). In addition to the combination of metronomic or targeted therapies with maximum-tolerated dose chemotherapy, immunotherapy has also been evaluated in clinical trials (27). For instance, dogs treated with the immunomodulator liposome encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) combined with doxorubicin and cyclophosphamide after splenectomy had a better outcome than dogs treated with surgery and maximum-tolerated dose chemotherapy (27). Further studies are needed to confirm the potential benefit of using metronomic chemotherapy, immunotherapy, or targeted therapies as maintenance therapies after a doxorubicin-based chemotherapy regimen for dogs diagnosed with visceral HSA.

Our report suffers from limitations that are inherent in retrospective studies, the heterogenous population of dogs and the small number of patients. Dogs diagnosed with HSA located in primary sites other than the spleen were underrepresented. Also, several patients had different therapies that were determined based on the clinician’s discretion. The decision to treat or not to treat patients with adjuvant chemotherapy after surgery was not clear in the medical records. It is possible that owner bias due to misunderstanding of the poor prognosis, non-compliance, financial constraints, or difficulty treating an uncooperative animal could have influenced the treatment decision and outcome for the patients. Lastly, none of the dogs had a necropsy carried out to confirm the cause of death, and it was assumed that they died of HSA.

In summary, the data reported in this manuscript demonstrate that the overall survival of dogs with visceral HSA treated with either the current standard-of-care-approach, such as aggressive surgery and chemotherapy, or surgery alone, remain poor with most dogs succumbing to their disease within a year. Clinical stage was associated with prognosis and dogs diagnosed with stage I tumors had better outcomes than dogs with more advanced HSA. In this retrospective study, the addition of single agent doxorubicin after surgery showed a survival benefit, albeit modest. Thus, novel treatment approaches, including the use of maintenance metronomic chemotherapy, immunotherapy, or targeted therapies after maximum-tolerated dose chemotherapy, should be evaluated. Additional investigation into the biology of canine HSA will likely improve the understanding of this disease and help with the advancement of therapies. CVJ

6 Reference

[27] Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine adjuvant immunotherapy for splenic hemangiosarcoma in the dog: A randomized multi-institutional clinical trial. Clin Cancer Res. 1995
[28] Thamm DH. Miscellaneous tumors: hemangiosarcoma. In: Withrow SJ, Vail DM, Page RL, editors. Withrow and MacEwen’s Small Animal Clinical Oncology. 5th ed. St. Louis, Missouri: Elsevier Saunders; 2013

Nutritional Management of Patients with Neoplasia 小动物肿瘤患者的营养管理

狗狗心包积液