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== 材料与方法 (Materials and methods) ==

=== 患者群体 (Patient population) ===
评估了 8 年（2005-2013 年）在单个兽医转诊中心（红岸兽医医院）就诊的推定心脏 HSA 的狗的医疗记录，以确定符合条件的患者。纳入本研究的标准如下：根据位置（右心房、右耳廓、房室沟、房室或三尖瓣、无心室壁）和/或异质性或空腔超声外观，强烈怀疑为 HSA 的原发性心脏肿瘤;至少进行一次完整的超声心动图检查;以及充分的随访信息，以便进行结果分析。排除显示回声特征或更提示化疗瘤或其他非血管性心脏肿瘤的解剖位置的肿瘤。如果狗因心脏肿瘤而接受手术干预（切除或心包切除术），则不包括在内。诊断时有转移的影像学或超声学证据的患者符合纳入条件。根据业主的意愿决定使用DOX进行全身治疗;然而，所有纳入的患者都接受了肿瘤科医生的会诊。

Medical records of dogs presenting for presumed cardiac HSA at a single veterinary referral centre (Red Bank Veterinary Hospital) over an 8-year period (2005–2013) were evaluated to identify eligible patients. Criteria for inclusion in this study were as follows: a primary cardiac tumour strongly suspected to be HSA based on the location (right atrium, right auricle, AV groove, AV or tricuspid valve, ventricular-free wall) and/or heterogeneous or cavitated ultrasonographic appearance; at least one full echocardiogram performed; and adequate follow-up information to allow for outcome analysis. Tumours displaying echogenic characteristics or an anatomic location more suggestive of a chemodectoma or other non-vascular cardiac tumour were excluded. Dogs were not included if they underwent surgical intervention (either resection or pericardiectomy) for their cardiac tumour. Patients with radiographic or ultrasonographic evidence of metastasis at diagnosis were eligible for inclusion. The decision to pursue systemic treatment with DOX was made according to owner preference; however, all included patients underwent consultation with an oncologist.

从病历中获得的信息包括品种;年龄;性;重量;初次就诊和诊断的日期;提出投诉;分期试验的结果;超声心动图结果包括肿瘤大小、是否存在心包填塞、进行的心包穿刺次数、是否进行治疗、化疗方案、治疗反应、治疗相关不良事件 （AE）、死亡日期和尸检结果（如果进行）。病历中没有的随访信息是通过与主人和/或转诊兽医的电话联系获得的。使用上述方法跟踪所有狗，直到死亡或失去联系。

Information obtained from the medical records included breed; age; sex; weight; date of initial presentation and diagnosis; presenting complaint; results of staging tests; echocardiogram findings including size of tumour, the presence of tamponade, the number of pericardiocenteses performed, whether treatment was pursued, chemotherapy protocol, treatment response, treatment-related adverse events (AEs), date of death and necropsy results if performed. Follow-up information not available in the medical record was obtained over telephone contact with owners and/or referring veterinarians. All dogs were followed until the time of death or loss of contact using the above methods.

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=== 诊断性检查 (Diagnostic workup) ===

记录诊断时进行的分期检查结果，包括自动全血细胞计数 （CBC）、血清生化特征、胸部 X 线摄影和腹部超声检查。仅接受腹部超声或胸部 X 光检查的狗被认为是部分分期的，而同时接受腹部超声和胸部 X 光检查的狗被认为是完全分期的。记录了提示转移性肿瘤（充满液体或空洞的结节/肿块）的影像学和超声变化。还记录了心电图和超声心动图的结果。使用超声心动图测量基线原发性肿瘤大小。所有超声心动图均使用单板认证的心脏病专家 （CDS） 进行评估。

Results of staging tests performed at diagnosis were recorded, including automated complete blood count (CBC), serum biochemical profile, thoracic radiography and abdominal ultrasonography. Dogs undergoing only an abdominal ultrasound or thoracic radiographs were considered partially staged, while dogs that had both an abdominal ultrasound and thoracic radiographs were considered fully staged. Radiographic and ultrasonographic changes suggestive of metastatic neoplasia (fluid-filled or cavitated nodules/masses) were documented. Findings from electrocardiography and echocardiography were also recorded. Baseline primary tumour size was measured using echocardiography. All echocardiograms were evaluated using a single board-certified cardiologist (CDS).

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=== 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 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.

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=== 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.

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=== 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不良事件。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 对治疗相关的 AE 进行分级

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


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。

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.


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。

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.

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=== 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).

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