2024年7月8日 (一) 12:00的版本

原文：https://pubmed.ncbi.nlm.nih.gov/8947871/

发表于：1996

1 摘要

在一项前瞻性研究中，使用了 46 只经组织学证实的除皮肤以外的不同部位血管肉瘤的狗，以确定辅助阿霉素（30 mg/m2，静脉注射，每 3 周，5 次治疗）在肿瘤部分或完全切除后 10 至 14 天的疗效。数据分析包括假设影响治疗反应、无病间隔 （DFI） 或生存时间 （ST） 的变量信息。收集的其他信息包括年龄、性别、品种、体重、既往治疗、手术类型、原发肿瘤位置、转移的存在、阿霉素的剂量数、对阿霉素治疗的反应（完全或部分反应）以及以下组织学标准：总体分化、核多形性、坏死百分比、有丝分裂评分、组织学总分和分级。手术结果（完全手术切除与不完全手术切除）显着影响生存时间（P < .001）。20% 的无病狗在 1 岁时存活，而手术后有残留肿瘤的狗在 1 年时都没有存活。大多数组织学标准（核多形性、有丝分裂评分、分级、总体分化）对于完全切除肿瘤的狗，具有显著的 （P < .05） 或接近显著的与 ST 的独立关联。DFI 的分析结果在完全切除肿瘤的狗中通常与 ST 相似。46 只狗中有 27 只 （58.7%） 成功切除了肿瘤的所有临床证据。手术结果（切除所有可见肿瘤的能力）的Logistic回归分析表明，受试者的年龄是显着影响手术结果的唯一因素（P = .017）。随着年龄的增长，成功的可能性增加。那些以前接受过血管肉瘤治疗的狗往往 （P = .08） 具有较短的 DFI 和 ST。因此，完全去除所有肿瘤证据，然后服用 5 剂阿霉素可能是患有血管肉瘤的狗的有效治疗方法。成功切除所有肿瘤的狗的平均 ST 和中位 ST 分别为 267 天和 172 天。肿瘤切除不完全的狗的平均 ST 和中位 ST 分别为 172 天和 60 天。同样，预后变量（例如完全切除所有肿瘤证据的能力、组织学标准和患者年龄）是预测结果的潜在重要预后变量。

Forty-six dogs with histologically confirmed hemangiosarcoma of various locations other than skin were used in a prospective study to determine the efficacy of adjuvant doxorubicin (30 mg/m2 IV q 3 weeks for 5 treatments) 10 to 14 days after the tumor was partially or completely excised. Analysis of the data included information on variables that were hypothesized to influence response to therapy, disease-free interval (DFI), or survival time (ST). Other information collected included age, gender, breed, weight, prior therapy, type of surgery, location of the primary tumor, presence of metastases, number of doses of doxorubicin, response to doxorubicin therapy (complete or partial response), and the following histological criteria: overall differentiation, nuclear pleomorphism, percent necrosis, mitotic score, total histological score, and grade. Surgery outcome (complete versus incomplete surgical excision) markedly influenced survival times (P < .001). Twenty percent of the dogs rendered free of disease were alive at 1 year, whereas none of the dogs that had residual tumor after surgery were alive at 1 year. Most of the histological criteria (nuclear pleomorphism, mitotic score, grade, overall differentiation) had marked (P < .05), or close to marked, independent associations with ST for dogs that had complete tumor removal. Results from analysis of DFI were generally similar to those of ST in dogs with complete excision of the tumor. Twenty-seven of the 46 dogs (58.7%) had all clinical evidence of tumour successfully removed. Logistic regression analysis of surgical outcome (ability to remove all visible tumor) suggested that age of the subject was the only factor markedly influencing surgical outcome (P = .017). As age increased, the probability of success increased. Those dogs that had previous treatment for their hemangiosarcoma tended (P = .08) to have a shorter DFI and ST. Therefore, complete removal of all evidence of tumor followed by 5 doses of doxorubicin may be an effective treatment for dogs with hemangiosarcoma. Dogs that had all tumor successfully removed had a mean and median ST of 267 and 172 days, respectively. Dogs with incomplete tumor removal had a mean and median ST of 172 and 60 days, respectively. Similarly, prognostic variables such as the ability to completely excise all evidence of tumor, histological criteria, and age of the patient are potentially important prognostic variables for predicting outcome.

2 概述

手术是血管肉瘤的初始治疗选择[1-4] 然而，由于这种肿瘤的快速生长和转移，手术对延长除皮肤血管肉瘤外的所有疾病的狗的生存期几乎没有作用。单独手术治疗脾脏和右心房血管肉瘤的结果 中位生存时间 （STs） 范围为 19 至 83 天。[1-4] 只有疾病分期被证明是一个重要的预后变量。由于对手术的反应不佳，化疗已被评估为延长无病间隔 （DFI） 和受影响患者生存期的一种手段。[6,7] 使用长春新碱、多柔比星和环磷酰胺联合治疗的脾脏血管肉瘤犬的中位 ST 为 164 天。[6] 在另一组接受多柔比星和环磷酰胺的狗中，中位 ST 为 179 天 [7] 尽管这些报告表明联合化疗可能有效，但这些方案导致了一些毒性。两项研究的毒性包括中性粒细胞减少症和胃肠道体征，严重到足以导致15只狗中有7只（46.7%）和16只狗中有3只（18.8%）需要住院治疗。[6,7] 每项研究中都有一只狗死于败血症，这是化疗引起的中性粒细胞减少症的结果。

联合化疗的基本原则之一是每种药物在单独使用时都应该有效。关于阿霉素作为单一药物治疗血管肉瘤的疗效的数据很少。因此，本研究的目的是前瞻性地确定患有血管肉瘤的狗的 DFI 和 ST，其中肿瘤被部分或全部切除，然后用阿霉素治疗。此外，还分析了各种因素（协变量），以确定它们是否有助于预测 DFI 和 ST。

surgery is the initial treatment of choice for hemangiosarcoma [1-4] However, because of the rapid growth and metastases of this tumor, surgery does little to prolong survival of dogs with all but cutaneous hemangiosarcomas. Surgery alone for splenic and right atrial hemangiosarcomas results in median survival times (STs) ranging from 19 to 83 days. [1-4] Only stage of disease has been shown to be an important prognostic variable.' Because of the poor response to surgery, chemotherapy has been evaluated as a means to prolong disease-free interval (DFI) and survival of affected patients. [6,7] The median STs of dogs with splenic hemangiosarcoma treated with a combination of vincristine, doxorubicin, and cyclophosphamide, followed by chlorarnbucil and methotrexate, was 164 days. [6] In another group of dogs that received doxorubicin and cyclophosphamide, the median ST was 179 days [7] Although these reports suggest that combination chemotherapy may be effective, these protocols resulted in some toxicity. Toxicities in both studies included neutropenia and gastrointestinal signs severe enough to necessitate hospitalization in 7 of 15 (46.7%) and 3 of 16 (18.8%) dogs, respectively. [6,7] One dog in each study died of sepsis as a result of chemotherapy-induced neutropenia.

One of the basic tenents of combination chemotherapy is that each drug should be effective when used alone. Few data exist concerning the efficacy of doxorubicin as a single agent for the treatment of hemangiosarcoma. Therefore, the objectives of this study were to prospectively determine the DFI and ST of dogs with hemangiosarcoma in which the tumor was partially or totally excised, and were then treated with doxorubicin. In addition, various factors (covariates) were analyzed to determine if they can help predict DFI and ST.

3 材料和方法

1989 年 7 月 1 日至 1994 年 8 月 1 日期间，所有进入方案的带瘤犬都在科罗拉多州立大学的比较肿瘤学部门接受了治疗和评估。所有狗均根据美国国立卫生研究院《实验动物护理和使用指南》中概述的原则进行护理，实验设计得到了该机构动物护理和使用委员会的批准。46只狗的平均年龄和中位年龄和体重分别为9岁和9.3岁，体重分别为15岁和14.9公斤。每只狗的肿瘤都是根据世界卫生组织的分类方案进行分期的[7]。诊断方法取决于血管肉瘤的解剖部位和狗的健康状况。最低限度的初始和后续分期方案至少包括胸部和腹部放射线片、全血细胞计数、生化特征和尿液分析。在每种病例中，在确定原发肿瘤时，没有通过体格检查和射线图评估或在适当时进行超声检查检测到转移性疾病的临床证据。在手术时为每只狗获得了组织学诊断证明。46只患有血管肉瘤的狗（脾脏，n = 14;心脏，n = 5;有或没有肌肉受累的 SC 组织，n = 9;舌头、眼睛、肾脏、肋骨、肋骨、下颌骨、肺叶等皮肤以外的部位，n = 18） 有原发肿瘤，并且在可能的情况下，

All tumor-bearing dogs entered into the protocol were treatedand evaluated at the Comparative Oncology Unit at Colorado State University between July 1, 1989 and August 1, 1994. All dogs were cared for according to the principles outlined in the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and the experimental design was approved by the institution alanimal care and use committee. The mean and median ages and weights of the 46 dogs were 9 and 9.3 years, and 15 and 14.9kg, respectively. Each dog's tumor was staged according to the classification scheme of the World Health Organization[7]. Diagnostic methods depended on the anatomic site of the hemangiosarcoma and the health status of the dog. Minimum initial and follow-upstaging schemes included at least thoracic and abdominal radio graphs, CBC, biochemical profile, and urinalysis. In each case, at the time the primary tumor was identified, there was no clinical evidence of metastatic disease detected by physical examination and evaluation of roentgenograms, or when appropriate, ultrasonograms.Histological proof of diagnosis was obtained at surgery for eachdog. Forty-six dogs with hemangiosarcoma (spleen, n = 14; heart,n = 5; SC tissue with or without muscle involvement, n = 9; sitesother than skin such as tongue, eye, kidney, rib, ornentum, mandible, lung lobe, n = 18) had the primary tumor, and when possible,