2024年6月23日 (日) 14:56的版本

阿霉素（多柔比星）化疗治疗狗的推定性心脏血管肉瘤

Doxorubicin chemotherapy for presumptive cardiac hemangiosarcoma in dogs

1 摘要

64 只狗接受单药多柔比星 （DOX） 治疗推定性心脏血管肉瘤 （cHSA）。客观缓解率（CR + PR）为41%，生物缓解率（CR + PR + SD）或临床获益为68%。接受治疗的狗的中位无进展生存期 （PFS） 为 66 天。该组的中位生存时间 （MST） 为 116 天，与未经治疗的对照犬的 12 天的 MST 相比显着改善 （P = 0.0001）。生物反应与PFS（P < 0.0001）和OS（P < 0.0001）的改善显著相关。单因素分析发现较大的肿瘤大小是与PFS呈负相关的变量。较高的临床获益率和改进的 MST 表明 DOX 在犬 cHSA 中具有活性。

Sixty-four dogs were treated with single-agent doxorubicin (DOX) for presumptive cardiac hemangiosarcoma (cHSA). The objective response rate (CR + PR) was 41%, and the biologic response rate (CR + PR + SD), or clinical benefit, was 68%. The median progression-free survival (PFS) for treated dogs was 66 days. The median survival time (MST) for this group was 116 days and was significantly improved compared to a MST of 12 days for untreated control dogs (P = 0.0001). Biologic response was significantly associated with improved PFS (P < 0.0001) and OS (P < 0.0001). Univariate analysis identified larger tumour size as a variable negatively associated with PFS. The high rate of clinical benefit and improved MST suggest that DOX has activity in canine cHSA.

2 介绍

血管肉瘤 （HSA） 是一种高度侵袭性的恶性内皮细胞及其前体肿瘤，是狗中最常见的心脏肿瘤，心脏是该肿瘤仅次于脾脏的第二大常见解剖位置。在一项针对犬类心脏肿瘤的大型回顾性研究中[1]，HSA 的报告频率是任何其他心脏肿瘤类型的 10 倍。心脏HSA（cHSA）最常位于右心房或耳廓，在心脏其他部位很少见[2]。与脾脏表现一样，金毛猎犬、拉布拉多猎犬和德国牧羊犬的 cHSA 报告常见[3-6]。

Hemangiosarcoma (HSA), a highly aggressive tumour of malignant endothelial cells and their precursors, is the most common cardiac tumour in the dog, and the heart represents the second most common anatomic location for this tumour after the spleen. In a large retrospective study of canine cardiac tumours,1 HSA was reported 10 times more frequently than any other cardiac tumour type. Cardiac HSA (cHSA) is most often located in the right atrium or auricle, although can be infrequently found in other cardiac locations.2 Like the splenic presentation, golden retrievers, Labrador retrievers and German shepherds are often over-represented in reports of cHSA.3-6

HSA 的生物学行为包括侵袭性原发性肿瘤生长和病程早期的广泛转移，肿瘤破裂和不受控制的出血是这些患者最常见的死亡原因[3-6]。患有 cHSA 的狗最常见的表现包括与急性出血相关的临床体征，导致心包积液和随后的心包填塞。最近的一项研究[2] 记录了 75% 的犬 cHSA 患者存在远处转移。不常见的是，狗同时出现脾脏和心脏受累[7]。在这些病例中，很难确定这些发现是否代表同步独立的原发性肿瘤或从一个部位转移到另一个部位。

The biologic behaviour of HSA consists of invasive primary tumour growth and widespread metastasis early in the course of disease, with tumour rupture and uncontrolled haemorrhage being the most common cause of death in these patients.3-6 The most frequent presentation for dogs with cHSA consists of clinical signs related to acute haemorrhage resulting in pericardial effusion and subsequent cardiac tamponade. A recent study2 documented the presence of distant metastasis in 75% of canine patients with cHSA. Uncommonly, dogs present with concurrent involvement of both the spleen and heart;7 in these cases, it is difficult to determine whether these findings represent synchronous independent primary tumours or metastasis from one site to the other.

很少有大规模研究批判性地评估患有 cHSA 的狗的手术和药物治疗。相反，对于更常见的脾脏表现，脾切除术后辅助多柔比星 （DOX） 化疗是迄今为止最有效的方法，一致证明为没有可测量转移性疾病的狗提供 5 至 8 个月的生存获益[8-15]。 患有 cHSA 的狗的中位生存时间 （MST） 仍然明显低于脾表现， 可能是由于与脾脏或肝脏肿块相比，难以获得心脏肿瘤的局部控制。cHSA 原发性肿瘤切除术的可行性取决于许多因素，包括肿瘤体积小、肿瘤局限于右心耳/耳廓或心房游离壁、冠状动脉和心脏瓣膜不受累，以及如果进行心房游离壁切除术，能否构建心包补片移植物以替换切除的组织[16-18] 直观地说， 这些规范将手术切除肿瘤的适用性限制在有限的狗群中。一些病例报告连续记录了通过不同方法接受手术切除肿瘤的个别患者的令人鼓舞的结果[16-22]。然而，尚未进行大规模研究评估手术治疗对该肿瘤的益处。因此，cHSA的手术干预通常包括包括心包切除术的姑息性方法。尽管该手术可以为患有非血管性心底肿瘤的狗提供长期生存，但对于那些患有 cHSA 仅接受心包切除术的狗来说[23]， 的生存时间历来不足[24]。

Few large-scale studies exist which critically evaluate the surgical and medical treatment of dogs with cHSA. Conversely, for the more common splenic presentation, splenectomy followed by adjuvant doxorubicin (DOX)-based chemotherapy has been the most efficacious approach to date, consistently documented to provide a survival benefit in the 5- to 8-month range for dogs presenting without measureable metastatic disease.8-15 The median survival times (MSTs) for dogs with cHSA remain notably lower than those achieved for the splenic presentation, likely due to the difficultly in obtaining local control for a cardiac tumour as compared with a splenic or hepatic mass. The feasibility of primary tumour resection for cHSA depends on numerous factors, including small tumour size, restriction of the tumour to the right atrial appendage/auricle or atrial free wall, lack of involvement of coronary arteries and heart valves, and the ability to construct a pericardial patch graft to replace resected tissue if atrial free wall resection is performed.16-18 Intuitively, these specifications restrict the applicability of surgical tumour removal to a limited group of dogs. A few case reports and series document encouraging results of individual patients undergoing surgical tumour removal through varying methods;16-22 however, no large-scale studies evaluating the benefit of surgical therapy for this tumour have been conducted. Thus, surgical intervention for cHSA typically encompasses a palliative approach involving pericardiectomy. Although this procedure can provide long-term survival for dogs with non-vascular heart-base tumours,23 survival times have historically fallen short for those dogs with cHSA undergoing pericardiectomy alone.24

即使手术切除肿瘤是可行的，如果不与辅助全身治疗联合使用，从历史上看也只能带来短期益处，因为患者总是会死于转移性疾病。脾切除术后接受辅助化疗的脾 HSA 狗的 MST 是单独脾切除术的两倍多[3]。这支持了对这种肿瘤的其他表现（包括心脏表现）采用类似方法的基本原理。最近，一项针对 51 只犬 cHSA 的流行病学研究[2] 报告称，与未接受 DOX 辅助化疗的 5 只狗相比，5 只在肿瘤切除后接受 DOX 辅助化疗的狗的 MST 明显更长（189 天）。同样，一项评估 23 只患有孤立性右心房 HSA 的狗的回顾性研究表明，与未接受化疗的狗相比，接受心包切除术、肿瘤切除术和 DOX 化疗的 8 只狗的生存时间明显更长（中位数，175 天）[22]。另外两份接受右心房肿块切除术然后化疗的狗的病例报告与这些发现一致， 报告的生存时间为 260 天和 177 天[19][21]。 尽管病例数量历来有限，但上述研究的结果令人鼓舞。

Even if surgical tumour removal is feasible, it is historically of only short-term benefit if not combined with adjuvant systemic therapy, as patients invariably succumb to metastatic disease. Dogs with splenic HSA undergoing adjuvant chemotherapy after splenectomy enjoy MSTs more than double of those achieved with splenectomy alone.3 This supports the rationale for a similar approach for other presentations of this tumour, including the cardiac manifestation. Recently, an epidemiological study2 of 51 canine cHSA reported a significantly longer MST (189 days) for 5 dogs that received adjuvant chemotherapy with DOX after tumour resection compared with 12 dogs that did not. Similarly, a retrospective study evaluating 23 dogs with solitary right atrial HSA showed that the subset of 8 dogs undergoing a combination of pericardiectomy, tumour resection and DOX chemotherapy experienced significantly longer survival times (median, 175 days) compared with those dogs that did not receive chemotherapy (median, 42 days).22 Two other case reports of dogs undergoing right atrial mass resection followed by chemotherapy concurred with these findings, with reported survival times of 260 and 177 days.19, 21 Although the number of cases has been historically limited, the results of the aforementioned studies are encouraging.

将原发肿瘤手术切除和辅助化疗相结合的积极和多模式治疗方法明确适用于犬心脏 HSA。然而，对于无法手术的心脏肿瘤，或手术是不利选择的患者，有必要考虑单独将全身治疗作为合理的第二选择。两项研究评估了基于 DOX 的化疗方案对患有宏观非心脏 HSA 的狗的效用，报告了 38 和 47% 的令人鼓舞的反应率[25][26]。最近，据报道，用各种基于 DOX 的方案治疗可测量右心房肿瘤的狗的 MST 为 140 天[27]。然而，本研究中的数量有限 （n = 16），并且治疗和反应评估没有标准化。最后，最近的一项研究评估了 VAC（长春新碱/DOX/环磷酰胺）化疗对患有 I 期（孤立性原发性肿瘤）、II 期（孤立性原发性肿瘤，>5 厘米；破裂的孤立性原发性肿瘤；或具有区域淋巴结转移的孤立性原发性肿瘤）和 III 期（具有转移性或多中心疾病的原发性肿瘤）HSA 的效用，来自不同解剖位置的 HSA 报告了 86% 的反应率患有可测量疾病的狗。 只有不到 50% 的狗接受了正式的反应评估，只有 5 只狗有心脏表现。

An aggressive and multimodal therapeutic approach combining surgical removal of the primary tumour and adjuvant chemotherapy is clearly indicated for canine cardiac HSA. However, in the cases of inoperable cardiac tumours, or those patients for which surgery is an unfavourable option, the consideration of systemic therapy alone as a reasonable secondary option is warranted. Two studies evaluating the utility of DOX-based chemotherapy protocols for dogs with macroscopic non-cardiac HSA reported encouraging response rates of 38 and 47%.25, 26 More recently, an MST of 140 days was reported for dogs treated with various DOX-based protocols for measureable right atrial tumours.27 However, numbers in this study were limited (n = 16), and treatment and response assessments were not standardized. Finally, a recent study evaluating the utility of VAC (vincristine/DOX/cyclophosphamide) chemotherapy for dogs with stage I (solitary primary tumour), stage II (solitary primary tumour, >5 cm; ruptured solitary primary tumour; or solitary primary tumour with regional lymph node metastasis), and stage III (primary tumour with metastasis or multicentric disease) HSA arising from various anatomic locations reported an 86% response rate for dogs with measureable disease.28 However, fewer than 50% of dogs underwent formal response assessment and only five dogs had a cardiac presentation.

由于肿瘤的位置和性质，手术活检通常是这些患者的不利选择，临床医生必须整合对患者信号和品种风险、临床表现和超声心动图结果的了解，以推断心脏 HSA 的“推定诊断”，而不是组织病理学。显然，本研究中涉及的场景代表了临床兽医肿瘤学中常见的诊断和治疗困境，尽管没有纳入组织病理学诊断的黄金标准，但必须进行评估，以便为临床医生提供合理的治疗选择这种具有挑战性的癌症。本研究的目的是描述接受 DOX 化疗的狗对可测量的推定心脏 HSA 的反应率和无进展生存期 （PFS），确定影响结果的预后因素，并将接受治疗的狗的结果与大量未经治疗的当代对照 （CTL） 的结果进行比较。假设是接受化疗的狗比不接受治疗的狗经历了更长的生存时间。

Since surgical biopsy is usually an unfavourable option in these patients owing to location and nature of the tumour, clinicians must integrate knowledge of the patient's signalment and breed risk, clinical presentation and echocardiographic findings to deduce a ‘presumptive diagnosis’ of cardiac HSA in lieu of histopathology. Clearly, the scenario addressed in this study represents a common diagnostic and therapeutic dilemma in clinical veterinary oncology, and one that although not incorporating the gold standard of histopathologic diagnosis, must be evaluated in order to provide clinicians with reasonable therapeutic options for this challenging cancer. The purposes of this study were to describe the response rate and progression-free survival (PFS) of dogs receiving DOX chemotherapy for measureable presumptive cardiac HSA, identify prognostic factors influencing outcome and compare outcomes of treated dogs with those of a large cohort of untreated contemporary controls (CTLs). The hypothesis was that dogs receiving chemotherapy experienced longer survival times than dogs not receiving treatment.

3 材料与方法 (Materials and methods)

3.1 治疗剂量和时间表 (Treatment dosing and schedule)

接受治疗的狗接受单药化疗方案，包括 DOX（狗 1 mg/kg <10 kg，狗 30 mg/m^2 >10 kg），每 2-3 周静脉输注一次。狗继续接受治疗，直到检测到疾病进展或完成计划的方案，通常包括至少五次总治疗。如果主治临床医生认为合适，狗可以接受超出计划方案的额外剂量的 DOX。一组未接受化疗的当代狗（提交给同一机构）被用作 CTL 人群。接受DOX的狗的主人被提供口服抗恶心药物（maropitant，2mg/kg PO，每天一次），以备不时之需。

Dogs undergoing treatment received a single-agent chemotherapy protocol consisting of DOX (1 mg kg−1 for dogs <10 kg, 30 mg m−2 for dogs >10 kg) given once every 2–3 weeks by intravenous infusion. Dogs continued to receive treatments until disease progression was detected or the planned protocol, typically consisting of a minimum of five total treatments, was completed. Dogs could receive additional doses of DOX beyond the planned protocol if deemed appropriate by the attending clinician. A contemporary group of dogs (presented to the same institution) not undergoing chemotherapy was used as a CTL population. Owners of dogs receiving DOX were provided oral anti-nausea medication (maropitant, 2 mg kg−1 PO once daily) for use as needed.

3.2 其他治疗 (Other treatments)

在计划的 DOX 方案完成后或在疾病进展的情况下，狗可以继续使用替代或抢救性化疗方案。一些狗接受了节律化疗的维持治疗，其中一部分在 DOX 方案期间启动了这种治疗。如果适用，记录了对非心脏疾病部位进行的治疗。

Following the completion of the planned DOX protocol or in the event of disease progression, dogs could continue with alternative or rescue chemotherapeutic protocols. Some dogs received maintenance therapy with metronomic chemotherapy, with a subset initiating this therapy during the DOX protocol. Treatments administered for non-cardiac sites of disease were recorded, if applicable.

3.3 AE 的评估、反应和结果 (Evaluation of AEs, response and outcome)

业主在每次就诊时完成书面问卷（图 1），以报告胃肠道和其他 AE。所有接受治疗的狗在每次使用 DOX 治疗之前都进行了 CBC，偶尔在治疗后 7 天进行。根据 VCOG-CTCAE 1.1.29 对与治疗相关的 AE 进行分级，在每个治疗日和随访中对狗进行体格检查。所有接受 DOX 治疗的狗在第二次预定剂量的 DOX 之前立即接受了超声心动图的初步反应评估。根据 RECIST 1.1 指南30 进行反应评估，其中完全反应 （CR） 包括肿瘤完全消失;部分缓解 （PR） 包括最长肿瘤直径至少减少 30%;进行性疾病 （PD） 包括最长肿瘤直径至少增加 20%、出现转移性病变或提示疾病进展的临床体征（心包积液、腹腔积血和相关后遗症）;稳定疾病 （SD） 既没有充分的消退来符合 PR 的条件，也没有足够的进展来符合 PD 的条件。 建议在初始反应评估后每隔一次治疗就诊时进行超声心动图检查，以确认持续的反应并检测肿瘤进展。在第一次反应评估（第二次 DOX 剂量之前）检测到的 SD 必须至少持续到第二次反应评估时（每 2 次接受 DOX 的狗从治疗开始之日起 6 周，每 3 周接受一次 DOX 的狗从治疗开始之日起 9 周）才能被认为是真正的 SD。主要结局终点是PFS和总生存期（OS）。对所有接受至少一次 DOX 治疗的狗进行 PFS 评估，并计算从治疗开始到疾病进展或任何原因死亡的时间。如果狗在随访中丢失或在数据收集时没有疾病进展仍然活着，则从PFS分析中删失。对两个人群的OS进行了评估，并计算为从诊断到疾病进展死亡的时间。如果狗在随访中丢失，死于与肿瘤无关的原因，或者在数据收集时还活着，则从OS分析中剔除。

Owners completed written questionnaires (Fig. 1) at each visit to report gastrointestinal and other AEs. All treated dogs had a CBC performed before each treatment with DOX and occasionally at the 7-day mark after treatment. Treatment-related AEs were graded according to the VCOG-CTCAE 1.1.29 Dogs were assessed with physical examinations on every treatment day and follow-up visit. All dogs receiving treatment with DOX underwent an initial response assessment with echocardiogram immediately before their second scheduled dose of DOX. Response assessment was made based on RECIST 1.1 guidelines,30 where complete response (CR) consisted of complete disappearance of the tumour; partial response (PR) consisted of at least a 30% reduction in longest tumour diameter; progressive disease (PD) consisted of at least a 20% increase in longest tumour diameter, the appearance of metastatic lesions, or clinical signs suggestive of disease progression (pericardial effusion, hemoperitoneum and related sequelae); and stable disease (SD) consisted of neither sufficient regression to qualify for PR nor sufficient progression to qualify for PD. Echocardiograms were recommended to be performed at every other treatment visit after the initial response assessment to confirm ongoing response and to detect tumour progression. SD detected at the first response assessment (before the second dose of DOX) had to be sustained at least until the time of the second response assessment (6 weeks from the time of treatment initiation in dogs receiving DOX every 2 and 9 weeks from treatment initiation for dogs receiving DOX every 3 weeks) in order to be considered true SD. The primary outcome endpoints were PFS and overall survival (OS). PFS was assessed for all dogs receiving at least one DOX treatment session and was calculated as the time from treatment initiation to disease progression or death from any cause. Dogs were censored from PFS analysis if they were lost to follow-up or still alive without disease progression at the time of data collection. OS was assessed for both populations and was calculated as the time from diagnosis to death from disease progression. Dogs were censored from OS analysis if they were lost to follow-up, died from causes unrelated to the tumour, or were still alive at the time of data collection.

3.4 统计分析 (Statistical analysis)

使用分类变量（例如品种、性别、转移的存在和分期程序）的 Fischer 精确检验和连续变量（例如体重、年龄）的不配对 t 检验进行组比较（DOX 治疗组与未治疗组）。

PFS 和 MST 使用 Kaplan-Meier 乘积极限法计算。在DOX治疗组中，检查与狗的PFS和OS预后因素相关的变量包括体重，诊断时是否存在转移，诊断时贫血，诊断时血小板减少症，诊断时心电图异常，诊断时填塞，肿瘤位置，肿瘤大小（平均值和中位数），进行心包穿刺术的次数，DOX剂量（30mg m-2 vs 1 mg kg-1）， DOX 时间表（每 2 周一次与每 3 周一次）、同时使用节律化疗、使用抢救疗法（仅适用于 OS）和对治疗的反应。使用两个数据集的对数秩 （Mantel-Cox） 检验和趋势的对数秩检验（当输入两个以上数据集时）比较生成的生存曲线，并报告双尾 P 值。P 值为 ≤0.05 被认为是显著的。所有统计分析均使用商业软件包（Prism v5.0，GraphPad Software，LaJolla，CA，USA）进行。

Group comparisons (DOX-treated versus untreated groups) were made using Fischer’s exact test for categorical variables (e.g. breed, sex, presence of metastasis and staging procedures) and the unpaired t-test for continuous variables (e.g. weight, age).

The PFS and MST were calculated using the Kaplan–Meier product-limit method. Variables examined for association as prognostic factors for PFS and OS for dogs in the DOX-treated group included body weight, presence of metastasis at diagnosis, anaemia at diagnosis, thrombocytopenia at diagnosis, ECG abnormalities at diagnosis, tamponade at diagnosis, tumour location, tumour size (mean and median), number of pericardiocenteses performed, DOX dose (30 mg m−2 versus 1 mg kg−1), DOX schedule (every 2 weeks versus every 3 weeks), concurrent use of metronomic chemotherapy, use of rescue therapy (for OS only) and response to treatment. Generated survival curves were compared using the log-rank (Mantel–Cox) test for two data sets and the log-rank test for trend (when more than two datasets were entered) with two-tailed P values reported. A P value of ≤0.05 was considered significant. All statistical analyses were performed using a commercial software package (Prism v5.0, GraphPad Software, LaJolla, CA, USA).

4 Reference

• 狗狗心包积液