2017.HSA.doxorubicin.AC.vs.ADTIC

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

Comparison of doxorubicin-cyclophosphamide with doxorubicin-dacarbazine for the adjuvant treatment of canine hemangiosarcoma

https://doi.org/10.1111/vco.12139

1 摘要

犬血管肉瘤 （HSA） 是一种血管内皮起源的肿瘤，具有侵袭性生物学行为，在诊断后 12 个月内存活的狗不到 10%。首选的治疗包括手术，然后以阿霉素为基础的辅助化疗。我们前瞻性地比较了阿霉素和达卡巴嗪（ADTIC）辅助治疗与传统的多柔比星和环磷酰胺（AC）治疗，旨在确定安全性并评估该方案是否能延长生存期和转移时间（TTM）。招募了 27 只狗;分期检查后，18 例接受 AC 治疗，9 例接受 ADTIC 治疗。与接受AC治疗的狗相比，接受ADTIC治疗的狗的中位TTM和生存时间更长（分别为>550天和112天，P=0.021和>550天和142天，P=0.011）。两种方案的耐受性都很好，不需要减少剂量或增加治疗间隔。由多柔比星和达卡巴嗪联合组成的方案在患有 HSA 的狗中是安全的，并延长了 TTM 和生存时间。

Canine hemangiosarcoma (HSA) is a neoplasm of vascular endothelial origin that has an aggressive biological behaviour, with less than 10% of dogs alive at 12-months postdiagnosis. Treatment of choice consists of surgery followed by adjuvant doxorubicin-based chemotherapy. We prospectively compared adjuvant doxorubicin and dacarbazine (ADTIC) to a traditional doxorubicin and cyclophosphamide (AC) treatment, aiming at determining safety and assessing whether this regimen prolongs survival and time to metastasis (TTM). Twenty-seven dogs were enrolled; following staging work-up, 18 were treated with AC and 9 with ADTIC. Median TTM and survival time were longer for dogs treated with ADTIC compared with those receiving AC (>550 versus 112 days, P = 0.021 and >550 versus 142 days, P = 0.011, respectively). Both protocols were well tolerated, without need for dose reduction or increased interval between treatments. A protocol consisting of combined doxorubicin and dacarbazine is safe in dogs with HSA and prolongs TTM and survival time.

3 材料与方法 (Materials and methods)

患者资格 (Patient eligibility)

前瞻性地招募了由任何腹部器官或皮下引起的具有手术切除、经组织学证实的 HSA 的客户拥有的狗。术前检查包括体格检查、血液学、血清生化、腹部超声和至少两次胸部 X 线片的侧视图。如果使用超声心动图确定的收缩期缩短分数为 <25%，则认为狗发生多柔比星相关心脏毒性的高风险。具有这种心脏功能的狗没有参加这项研究。患有与 HSA 不同的限制生命的疾病的狗和患有真皮 HSA 的狗也被排除在外。根据世界卫生组织 （WHO） 的家畜分期系统对狗进行分期.29.第1组包括提及一位作者（D.S.）机构的狗，而提及两位不同作者（L.M.和R.F.）机构的狗被列入第2组。

Client-owned dogs with a surgically removed, histologically confirmed HSA, arising from any abdominal organ or subcutis, were prospectively recruited. Presurgical investigations included physical examination, haematology, serum biochemistry, abdominal ultrasound and at least two lateral views thoracic radiographs. Dogs were considered to be at high risk of developing doxorubicin-related cardiotoxicity if systolic fractional shortening determined by using echocardiography was <25%. Dogs with such cardiac function were not enrolled in this study. Dogs with life-limiting diseases different than HSA and those with dermal HSA were also excluded. Dogs were staged according to the World Health Organization (WHO) staging system for domestic animals.29. Dogs referred to the institution of one author (D. S.) were included in group 1, whereas dogs referred to the institutions of two different authors (L. M. and R. F.) were included in group 2.

治疗方案 (Treatment protocol)

目的是在手术干预后 7-10 天内开始化疗。第 1 组的狗接受辅助多柔比星 （Doxorubicina， Ebewe Italia s.r.l.， Roma， Italy） 和环磷酰胺 [Endoxan®， Baxter s.r.l.， Lurago d'Erba， Como， Italy （AC）] 治疗，而第 2 组的狗接受辅助多柔比星和达卡巴嗪 [Deticene®， Aventis Pharma S.p.A， Milano， Italy （ADTIC）]。与AC相比，ADTIC更昂贵，并且由于该研究没有得到资助，因此无法随机分组。由于与传统的 AC 协议相比，ADTIC 在进行本研究时完全处于研究阶段，因此所有选择 ADTIC 的业主都被要求在注册前签署书面知情同意书。

The objective was to initiate chemotherapy within 7–10 days after surgical intervention. Dogs included in group 1 were treated with adjuvant doxorubicin (Doxorubicina, Ebewe Italia s.r.l., Roma, Italy) and cyclophosphamide [Endoxan®, Baxter s.r.l., Lurago d’Erba, Como, Italy (AC)], whereas dogs included in group 2 received adjuvant doxorubicin and dacarbazine [Deticene®, Aventis Pharma S.p.A, Milano, Italy (ADTIC)]. ADTIC was more expensive compared with AC, and as the study was not supported by a grant, groups could not be randomized. Because ADTIC was completely investigational at the time this study was carried out compared with the traditional AC protocol, all owners electing ADTIC were asked to sign a written informed consent prior to enrolment.

在任一治疗组中，阿霉素以 30 mg/m^2 的剂量静脉注射，每 3 周一次，持续四个周期。阿霉素在 20 分钟内以缓慢静脉推注给药。

In either treatment groups, doxorubicin was administered IV at the dose of 30 mg/m^2 every 3 weeks for four cycles. Doxorubicin was administered as a slow IV bolus within 20 min.

在第 1 组中，环磷酰胺以 75 mg/m^2 口服给药，连续 4 天，从每次阿霉素给药当天开始。在第 2 组中，达卡巴嗪以 200 mg/m^2 的剂量静脉注射（每天不超过 250 mg），每天一次，持续 5 天，从每次多柔比星给药之日开始。简言之，将达卡巴嗪与注射用水复溶，以获得10mg mL-1的浓度。然后通过先前放置的留置导管静脉输注 1 分钟以上给药复溶药物，以给予多柔比星。然后移除导管，并在接下来的四次给药中反复放置新导管。表1.30列出了两种方案的分数和总和剂量强度（SDI）

In group 1, cyclophosphamide was administered orally at 75 mg/m^2 for 4 consecutive days, starting on the day of every doxorubicin administration. In group 2, dacarbazine was administered IV at the dose of 200 mg/m^2 (without exceeding 250 mg total daily) once daily for 5 days, starting on the day of every doxorubicin administration. Briefly, dacarbazine was reconstituted with water for injection to obtain a concentration of 10 mg mL−1. Reconstituted drug was then given by intravenous infusion over 1 min via the indwelling catheter previously placed to administer doxorubicin. The catheter was then removed, and a new catheter was repeatedly placed for the following four administrations. Fractional and summation dose intensities (SDIs) for the two protocols are listed in Table 1.30

在任一组中，标准止吐治疗包括从化疗第一天开始连续 3 天以 2 mg kg-1 q24h 的剂量口服 maropitant（Cerenia®、Pfizer、Latina、Italy）。克拉维酸增强阿莫西林（Synulox®，辉瑞，拉丁，意大利）以 12.5-20 mg kg-1 q12h 的频率预防性口服给药，直到预期的中性粒细胞减少性最低点，此后如图所示。抗生素剂量取决于临床医生的偏好。

In either group, standard antiemetic therapy consisted in maropitant (Cerenia®, Pfizer, Latina, Italy) administered orally at the dose of 2 mg kg−1 q24h for 3 consecutive days starting on the first day of chemotherapy. Clavulanate-potentiated amoxicillin (Synulox®, Pfizer, Latina, Italy) was prophylactically administered orally at 12.5–20 mg kg−1 q12h until the time of the expected neutropenic nadir, and as indicated thereafter. Antibiotic dosage depended on clinician’s preference.

在两个周期的化疗后，进行了重复的临床分期检查，包括胸片和腹部超声检查。如果没有观察到局部复发和/或转移性疾病，则将相同的化疗方案继续两个周期。在疾病进展的情况下，提供了抢救方案。随访重新分期包括在方案结束后 1 个月和之后每 3 个月进行一次胸片和腹部超声检查，以确定对治疗的反应。

A repeated clinical staging work-up consisting of thoracic radiographs and abdominal ultrasoundo was performed after two cycles of chemotherapy. If no local recurrence and/or metastatic disease were observed, the same chemotherapy protocol was continued for two additional cycles. In case of disease progression, a rescue protocol was offered. Follow-up re-staging consisted of thoracic radiographs and abdominal ultrasound performed 1 month after the end of the protocol and every 3 months afterwards to define response to treatment.

毒性评估 (Assessment of toxicity)

根据第 7-10 天和每个周期开始前进行的狗的病史、体格检查和全血细胞计数 （CBC），在第 1 组中评估化疗产生的毒性，如兽医合作肿瘤学组所述.31 在第 2 组中，在每个化疗周期的第 1、4、5 和 10 天检查 CBC。第 1 天被认为是阿霉素给药的日子。

Toxicity resulting from chemotherapy was assessed in group 1 based on the dog’s history, physical examination and complete blood count (CBC) performed 7–10 days after doxorubicin and before the beginning of each cycle, as stated by the Veterinary Co-operative Oncology Group.31 In group 2, CBC was checked on days 1, 4, 5 and 10 of each chemotherapy cycle. Day 1 was considered as the day of doxorubicin administration.