2024年6月26日 (三) 21:38的版本

原文：https://pubmed.ncbi.nlm.nih.gov/24697499/

Published: 2014 May

© 2014年英国小动物兽医协会

1 Abstract

目的：报告以多柔比星为基础的化疗作为超声心动图识别为右心房肿块和心包积液的狗的唯一治疗方法的结果。

方法：对接受多柔比星治疗的右心房肿块狗的病例记录进行回顾性研究。如果狗进行了任何类型的手术，例如心包切除术或右心房肿块切除术，或者它们的化疗方案不包括多柔比星，则它们被排除在研究之外。收集的数据包括信号、病史、体格检查结果、诊断测试结果和长期生存率。

结果：仅接受多柔比星化疗的右心房肿块和心包积液的狗的中位生存期为 139.5 天（范围 2 到 302 天）。化疗副作用频繁但轻微。

临床意义：单独使用基于多柔比星的化疗似乎是超声心动图识别为右心房肿块和心包积液的狗的可行治疗选择。

Objective: To report the outcome of doxorubicin-based chemotherapy as the sole treatment for dogs with echocardiographically identified right atrial masses and pericardial effusion.

Methods: A retrospective study of case records of dogs with right atrial masses treated with doxorubicin. Dogs were excluded from the study if they had any type of surgery performed such as pericardiectomy or right atrial mass resection, or if their chemotherapy protocol did not include doxorubicin. The data collected included signalment, history, physical examination findings, diagnostic test results and long-term survival.

Results: Dogs with right atrial masses and pericardial effusion that received doxorubicin-based chemotherapy alone had a median survival of 139 · 5 days (range 2 to 302 days). Chemotherapy side effects were frequent but mild.

Clinical significance: Doxorubicin-based chemotherapy alone appears to be a viable treatment option for dogs with echocardiographically identified right atrial masses and pericardial effusion.

2 Introduction

狗心包积液 （PE） 最常见的原因是肿瘤或特发性疾病（Kersetetter 等人，1997 年，Dunning 等人，1998 年，Ware & Hopper 1999 年，Stafford Johnson 等人，2004 年，Weisse 等人，2005 年，MacDonald 等人，2009 年，Rajagopalan 等人，2013 年）。右心房和心脏底部是 PE 狗发现肿瘤的两个最常见位置。当发现源自右心房的肿块时，血管肉瘤 （HSA） 是迄今为止最常见的组织病理学诊断，尽管偶尔会发现其他肿瘤，包括神经内分泌肿瘤、甲状腺腺癌、间皮瘤和淋巴瘤（Ware & Hopper 1999， MacDonald et al. 2009， Rajagopalan et al. 2013）。虽然心包穿刺术可以缓解体征，但 PE 经常在存在右心房 （RA） 肿块的情况下迅速复发，并且长期预后较差，大多数狗在诊断后 30 天内死亡或被安乐死（Kersetetter 等人，1997 年，Dunning 等人，1998 年，Stafford Johnson 等人，2004 年，Weisse 等人，2005 年，MacDonald 等人，2009 年）。因此，已经评估了进一步的治疗方案，包括心包切除术（Kersetetter 等人，1997 年）和手术切除 RA 肿块，联合或不联合辅助化疗（Weisse 等人，2005 年）。与单独手术相比，手术切除 RA 肿块后给予基于多柔比星的化疗显着缩短了生存时间（Weisse 等人，2005 年）。然而，手术通常昂贵、侵入性强，并且经常与并发症有关（Weisse 等人，2005 年）。因此，本研究旨在评估基于多柔比星的化疗作为超声心动图检查中发现 RA 肿块和 PE 的狗的唯一治疗方法。

The most common cause of pericardial effusion (PE) in dogs is neoplasia or idiopathic disease (Kersetetter et al. 1997, Dunning et al. 1998, Ware & Hopper 1999, Stafford Johnson et al. 2004, Weisse et al. 2005, MacDonald et al. 2009, Rajagopalan et al. 2013). The right atrium and the heart base are the two most common locations where neoplasia is identified in dogs with PE. When a mass is identified originating from the right atrium, haemangiosarcoma (HSA) is by far the most common histopathological diagnosis although other neoplasms are occasionally identified including neuroendocrine tumours, thyroid gland adenocarcinoma, mesothelioma and lymphoma (Ware & Hopper 1999, MacDonald et al. 2009, Rajagopalan et al. 2013). While pericardiocentesis can relieve the signs, PE frequently rapidly recurs in the presence of a right atrial (RA) mass and the long-term prognosis is poor with most dogs dying or being euthanased within 30 days of diagnosis (Kersetetter et al. 1997, Dunning et al. 1998, Stafford Johnson et al. 2004, Weisse et al. 2005, MacDonald et al. 2009). Consequently, further treatment options have been evaluated including pericardiectomy (Kersetetter et al. 1997) and surgical resection of the RA mass with or without adjuvant chemotherapy (Weisse et al. 2005). The administration of doxorubicin-based chemotherapy after surgical resection of the RA mass significantly improved survival time compared with surgery alone (Weisse et al. 2005). However, surgery is typically expensive, invasive and frequently associated with complications (Weisse et al. 2005). As such, this study was designed to evaluate the administration of doxorubicin-based chemotherapy as the only treatment for dogs identified with a RA mass and PE on echocardiographic examination.

3 材料与方法 (MATERIALS AND METHODS)

3.1 Case selection

对美国洛杉矶周边四家小动物专科医院（高级兽医护理中心、VCA 西洛杉矶动物医院、洛杉矶高级重症监护和奥兰治县兽医癌症小组）的病历数据库进行了审查，以寻找超声心动图识别出 RA 肿块和 PE 的狗。必须通过超声心动图识别源自右心房、RA 附属物或右房室 （AV） 沟的肿块才能纳入研究。超声心动图必须由董事会认证的心脏病专家或心脏病学住院医师在董事会认证的心脏病专家的监督下进行。由于对生存的潜在影响，对 RA 肿块进行任何手术（包括心包切除术或肿块切除术）的狗被排除在外（Kersetetter 等人，1997 年，Weisse 等人，2005 年）。未接受多柔比星作为化疗方案一部分的狗也被排除在研究之外。从病历中收集的数据包括信号、临床体征、体格检查结果、诊断测试结果和长期生存率。当病历中没有长期存活记录时，会向转诊兽医或狗的主人拨打后续电话。生存数据从超声心动图确定 RA 肿块后出院之日开始计算。

The medical record database from four small animal specialty hospitals (Advanced Veterinary Care Center, VCA West Los Angeles Animal Hospital, Advanced Critical Care of Los Angeles and Veterinary Cancer Group of Orange County) around Los Angeles in the USA was reviewed for dogs that had echocardiographically identified RA masses and PE. A mass originating from the right atrium, RA appendage or right atrioventricular (AV) groove had to be identified echocardiographically for inclusion in the study. The echocardiogram had to have been performed by a board-certified cardiologist or a cardiology resident under supervision of a board-certified cardiologist. Dogs that had any surgery for the RA mass including pericardiectomy or mass resection were excluded owing to the potential effect on survival (Kersetetter et al. 1997, Weisse et al. 2005). Dogs that did not receive doxorubicin as part of their chemotherapy protocol were also excluded from the study. Data collected from the medical record included signalment, clinical signs, physical examination findings, diagnostic test results and long-term survival. When long-term survival was not available in the medical record, follow-up phone calls were made to the referring veterinarian or to the owner of the dog. Survival data were calculated from the date of discharge from the hospital after identification of the RA mass on echocardiography.

3.2 Statistical analysis

使用标准统计软件包（SPSS 14.0 for Windows，Microsoft）进行统计分析。计算了从诊断到死亡的分布的Kaplan-Meier估计值。除非另有说明，否则结果以中位数和范围表示。

Statistical analyses were performed using a standard statistical software package (SPSS 14.0 for Windows, Microsoft). The Kaplan–Meier estimates of the distribution from diagnosis to death were computed. Results are presented as median and range unless indicated otherwise.

4 Results

16只狗符合该研究的纳入标准。代表的品种包括金毛猎犬（n = 4）、杂交品种（n = 2）和以下品种各一只狗：挪威麋鹿猎犬、罗威纳犬、拳击手、比格犬、德国短毛指针犬、澳大利亚牧羊犬、西伯利亚雪橇犬、澳大利亚牧牛犬、莱昂伯格犬和红色法老猎犬。信号、主诉和体格检查结果见表 1-3。

Sixteen dogs met the inclusion criteria for the study. Breeds represented included golden retriever (n = 4), crossbreed (n = 2) and one dog each of the following breeds: Norwegian elkhound, Rottweiler, boxer, beagle, German shorthaired pointer, Australian shepherd, Siberian husky, Australian cattle dog, Leonberger and red Pharaoh hound. Signalment, presenting complaints and physical examination findings are shown in Tables 1-3.

对所有 16 只狗进行了胸片检查，对 14 只狗进行了心电图检查，对 12 只狗进行了腹部超声检查。胸片、心电图和腹部超声检查发现的异常频率见表 4。八只狗的心脏肿块来自右心房，四只狗的 RA 附属物和四只狗的右房室沟。中位质量大小为 2.8 厘米 × 3.8 厘米（范围 1.8 厘米×2.2 厘米至 6.97 厘米×4.86 厘米）。提交了 14 只狗的 PE 样本进行分析，所有 14 只狗的出血性积液一致。在接受化疗的 16 只狗中，10 只狗接受多柔比星和环磷酰胺，4 只狗单独接受多柔比星，1 只狗接受多柔比星和异环磷酰胺，最后一只狗接受多柔比星和达卡巴嗪。化疗的副作用很常见，但通常被描述为轻度和自限性。

Thoracic radiographs were performed in all 16 dogs, while electrocardiography was performed in 14 dogs and abdominal ultrasonography was performed in 12 dogs. The frequency of abnormalities identified on thoracic radiographs, electrocardiography and abdominal ultrasound is shown in Table 4. The cardiac mass was identified originating from the right atrium in eight dogs, RA appendage in four dogs and in the right AV groove in four dogs. The median mass size was 2 · 8 cm×3 · 8 cm (range 1 · 8 cm×2 · 2 cm to 6 · 97 cm×4 · 86 cm). A sample of PE was submitted for analysis in 14 dogs and was consistent with a haemorrhagic effusion in all 14 dogs. Of the 16 dogs that received chemotherapy, 10 dogs received doxorubicin with cyclophosphamide, 4 dogs received doxorubicin alone, 1 dog received doxorubicin and ifosfamide and the last dog received doxorubicin and dacarbazine. Side effects attributed to chemotherapy were common but were typically described as mild and self-limiting.

在研究期结束时，所有狗都已死亡。死因是复发性肺栓塞 （n = 4）、未记录 （n = 3）、腹腔出血 （n = 2）、安乐死、未记录原因 （n = 2） 和以下各一项：在家中猝死、心包穿刺时心室颤动、血胸、肺炎和急性神经系统症状，包括癫痫发作伴前庭体征。一只狗在尸检中被组织学证实患有 RA HSA，并且是病例系列中所有狗中存活时间最长的狗之一（298 天）。接受基于多柔比星的化疗的狗的中位生存时间为 139.5 天（范围 2 至 302 天）（图 1）。

All dogs had died by the conclusion of the study period. Cause of death was recurrent PE (n = 4), not recorded (n = 3), haemoabdomen (n = 2), euthanasia, cause not recorded (n = 2) and one each of the following: sudden death at home, ventricular fibrillation during pericardiocentesis, haemothorax, pneumonia, and acute neurological symptoms consisting of seizures with vestibular signs. One dog was histologically confirmed to have a RA HSA on post-mortem examination and had one of the longest survival times of all dogs in the case series (298 days). Dogs that received doxorubicin-based chemotherapy had a median survival time of 139 · 5 days (range 2 to 302 days) (Fig 1).

5 Discussion

这项研究的主要发现是，单独接受基于多柔比星的化疗方案的狗的中位生存时间为 139 ·5天。与单独接受心周穿刺术（少于 30 天）或单独接受 RA 肿块切除术（中位数 42 天）治疗的狗相比，生存时间更长（Kersetetter 等人，1997 年，Dunning 等人，1998 年，Stafford Johnson 等人，2004 年，Weisse 等人，2005 年，MacDonald 等人，2009 年）。它与接受 RA 肿块切除和辅助化疗的狗报告的 175 天的中位生存时间相当（Weisse 等人，2005 年）。因此，对于不希望进行手术干预的主人或RA肿块无法手术切除的狗来说，单独使用基于多柔比星的化疗似乎是一种可行的选择。

本研究中最常用的化疗方案是多柔比星和环磷酰胺，之前有报道称，多柔比星和环磷酰胺可提高早期 HSA 犬患者的生存率和可接受的发病率（Sorenmo 等人，1993 年）。兽医文献中已经报道了 HSA 的其他化疗方案，但只要包含多柔比星，就没有方案被认为优于另一种方案（Hammer 等人，1991 年，Sorenmo 等人，1993 年，Ogilvie 等人，1996 年，Clifford 等人，2000 年）。有必要进行具有标准化化疗方案和对照组的进一步前瞻性研究，以更好地评估对治疗的反应。

初步研究报告称，超声心动图检测心脏肿块的敏感性相对较差（Kersetetter 等人，1997 年，Weisse 等人，2005 年）。然而，最近的一项研究报告称，识别狗的心脏肿块，尤其是 RA 肿块具有很高的敏感性和特异性（MacDonald 等人，2009 年）。最近的另一项研究发现，基于超声心动图肿瘤位置的推定诊断与组织病理学诊断之间只有中等程度的一致性（Rajagopalan 等人，2013 年）。后两项研究在超声心动图诊断的敏感性和特异性方面的差异可能与评估的人群有关，因为前一项研究仅包括患有 PE 的狗，而后一项研究中只有不到一半的病例出现 PE。根据作者的经验，由于无声心包液的对比作用，PE 的存在通常能够更准确地定位心脏肿瘤。此外，Rajagopalan等人（2013）进行的研究是一项基于病理学的研究，因此可能反映了由于异常的超声心动图发现或无法定位肿块的起源而更有可能在尸检中评估的狗的选择偏倚。超声心动图识别 PE 狗心脏肿瘤位置的敏感性和特异性需要进一步评估。

本研究中的狗在随后的重新评估中重复进行了超声心动图检查，以确定 RA 质量尺寸是保持不变还是正在变化。在大多数情况下，质量尺寸似乎是静态的，尽管由于没有PE，很难确定质量是否一致。此外，进行复查评估的心脏病专家或心脏病学住院医师并不总是最初确定 RA 肿块的同一个人，因此可能存在一定程度的观察者间差异，可能会影响测量的一致性。

本研究的进一步局限性在于其回顾性设计和缺乏对照组所固有的。没有报告临床症状的严重程度，因此临床症状不太明显的动物可能会接受化疗，而临床症状更严重的狗则没有，这进一步影响了本研究的结果。治疗组中只有一只狗经组织学证实为 RA HSA。研究报告称，多达 88% 的具有超声心动图识别的 RA 肿块的狗随后被诊断为 HSA，但其他确定的肿瘤包括甲状腺癌、间皮瘤、淋巴瘤和神经内分泌肿瘤（Ware & Hopper 1999， MacDonald et al. 2009， Rajagopalan et al. 2013）。因此，虽然本研究中包含的大多数狗确实患有 RA HSA，但一小部分人没有，这将影响此处报告的狗的存活时间，具体取决于个体肿瘤对基于多柔比星的化疗方案的反应性。此外，大多数狗的分期很少，因此很难准确评估疑似心脏HSA的分期及其对生存的影响。最后一个限制是本研究中包含的狗数量相对较少，因此需要大量具有组织学证实的 HSA 的 RA 肿块的狗接受标准化化疗方案来验证此处报告的结果。

The primary finding of this study was that dogs receiving a doxorubicin-based chemotherapy protocol alone had a median survival time of 139 · 5 days. This is a longer survival time compared to dogs treated with periocardiocentesis alone (less than 30 days) or with RA mass resection alone (median of 42 days) (Kersetetter et al. 1997, Dunning et al. 1998, Stafford Johnson et al. 2004, Weisse et al. 2005, MacDonald et al. 2009). It is comparable to the median survival time of 175 days reported for dogs with RA mass resection and adjuvant chemotherapy (Weisse et al. 2005). Consequently, doxorubicin-based chemotherapy alone appears to be a viable alternative for owners who do not wish to pursue surgical intervention or for dogs whose RA mass is not surgically resectable.

The most commonly used chemotherapy protocol in this study was doxorubicin and cyclophosphamide, which has been reported previously to improve survival with acceptable morbidity in canine patients with early-stage HSA (Sorenmo et al. 1993). Other chemotherapy protocols for HSA have been reported in the veterinary literature although no protocol is considered superior to another as long as doxorubicin is included (Hammer et al. 1991, Sorenmo et al. 1993, Ogilvie et al. 1996, Clifford et al. 2000). Further prospective studies with a standardised chemotherapy protocol and a control group are warranted to better evaluate response to therapy.

Initial studies reported a relatively poor sensitivity for echocardiography at detecting cardiac masses (Kersetetter et al. 1997, Weisse et al. 2005). However, a more recent study reported a high sensitivity and specificity for identification of cardiac masses in dogs and RA masses in particular (MacDonald et al. 2009). Another recent study found only moderate agreement between presumptive diagnosis based on echocardiographic tumour location and histopathological diagnosis (Rajagopalan et al. 2013). The discrepancy in the sensitivity and specificity of echocardiographic diagnosis between these latter two studies is likely related to the population evaluated as the former study included only dogs with PE whereas less than half the cases in the latter study presented with PE. In the authors’ experience, the presence of PE typically enables more accurate anatomic localisation of the cardiac tumour owing to the contrasting effect of anechoic pericardial fluid. Furthermore, the study performed by Rajagopalan et al. (2013) was a pathology-based study and therefore likely to reflect a selection bias for dogs that were more likely to be evaluated at necropsy owing to unusual echocardiographic findings or inability to localise the origin of the mass. The sensitivity and specificity of echocardiography for identifying cardiac tumour location in dogs with PE requires further evaluation.

The dogs in this study had repeat echocardiograms performed in subsequent re-evaluations to determine if the RA mass dimensions remained static or were changing. In most instances, the mass dimensions appeared static although it was difficult to determine if the masses were measured consistently because of the absence of PE. Furthermore, the cardiologist or cardiology resident performing the recheck evaluation was not always the same person who had identified the RA mass initially, and therefore there was likely some degree of interobserver variation that could affect the consistency of the measurements.

Further limitations to this study are inherent to its retrospective design and lack of a control group. Severity of clinical signs was not reported, and therefore it is possible that animals with less significant clinical signs pursued chemotherapy while dogs with more severe clinical signs did not, further affecting the results of this study. Only one of the dogs in the treatment group had histologically confirmed RA HSA. Studies have reported that as many as 88% of dogs with echocardiographically identified RA masses are subsequently diagnosed as HSA, but other tumours identified include thyroid carcinomas, mesothelioma, lymphoma and neuroendocrine tumours (Ware & Hopper 1999, MacDonald et al. 2009, Rajagopalan et al. 2013). As such it is likely that while the majority of dogs included in this study did have RA HSA, a small population did not, which would affect the survival times of the dogs reported here depending on the responsiveness of the individual tumour to a doxorubicin-based chemotherapy protocol. In addition, most dogs had minimal staging performed and therefore it is difficult to accurately assess the stage of the suspected cardiac HSA and its impact on survival. A final limitation was the relatively small number of dogs included in this study, and therefore larger populations of dogs with RA masses with histologically confirmed HSA receiving a standardised chemotherapy protocol are required to validate the results reported here.

总之，与之前仅进行心包穿刺或手术的报道相比，对患有 RA 肿块和 PE 的狗进行基于多柔比星的化疗可缩短生存时间，这与接受 RA 肿块切除术和辅助化疗的狗相当。有必要进行更大规模的前瞻性研究，包括标准化化疗方案和对照组的疾病组织病理学确认，以调查和验证这些初步结果。

In conclusion, doxorubicin-based chemotherapy for dogs with RA masses and PE resulted in an improved survival time compared with previous reports for pericardiocentesis or surgery alone, and that was comparable to dogs treated with RA mass resection and adjuvant chemotherapy. Larger prospective studies with standardised chemotherapy protocols and histopathological confirmation of disease with a control group are warranted to investigate and validate these initial results.

6 Reference

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