查看2014.Doxorubicin.HSA的源代码

== 讨论 (Discussion) ==

本研究针对执业肿瘤学家经常遇到的临床情况，其中患者被推定为心脏 HSA。尽管通过手术干预获得组织学诊断被认为是大多数实体瘤的金标准方法，但对于这种肿瘤通常不可行，因此临床医生面临着在没有明确组织诊断的情况下治疗可测量肿瘤的挑战。本研究的设计纳入了一组同时未经治疗的 CTL，虽然不完美，但可以相对公平地评估 DOX 化疗为该患者群体提供的潜在生存益处。与未经治疗的 CTL 相比，接受 DOX 化疗治疗推定心脏 HSA 的狗的生存率显着提高。然而，中位PFS（66天）和MST（116天）仍然相对较短，只有14%的接受治疗的狗有可能存活超过6个月。

This study addresses a clinical situation commonly encountered by the practising oncologist, in which a patient presents with a presumptive diagnosis of cardiac HSA. Although obtaining a histologic diagnosis via surgical intervention is considered the gold standard approach for most solid tumours, it is often not feasible for this tumour, thus leaving the clinician with the challenge of treating a measureable tumour without a definitive tissue diagnosis. The design of this study, which incorporates a group of contemporaneous untreated CTLs, while imperfect, allows for a relatively evenhanded evaluation of the potential survival benefit offered by DOX chemotherapy for this patient population. Dogs undergoing DOX chemotherapy for presumptive cardiac HSA had significantly improved survival compared with untreated CTLs. However, the median PFS (66 days) and MST (116 days) still remain relatively short, with only 14% of treated dogs having a probability of surviving beyond 6 months.

在这项研究中，对治疗的反应对于确定生存时间很重要，与那些没有反应的狗相比，那些经历临床益处的狗享有显着更长的 PFS 和 MST。客观缓解率与先前报道的接受化疗的可测量非心脏 HSA 的缓解率相当.26， 27 生物反应率或临床获益为 68%，并且将 SD 作为阳性结果是评估具有挑战性的癌症（如心脏 HSA）治疗方案的重要考虑因素。对于这种肿瘤类型，一旦最初的紧急事件消退，大多数狗都会迅速恢复，无论是否进行心包穿刺术。因此，即使没有达到可测量的肿瘤反应，在没有进一步发生心包积液和心包填塞的情况下保持良好的生活质量，对于大多数患者群体来说仍然是一个积极的结果。重要的是，在这项研究中，所有被认为患有 SD 的狗都必须持续这种反应，直到第二次超声心动图反应评估（至少 6 周）时。七只狗持续超声检查确认的 SD >100 天。由于一些狗 （n = 6） 每 3 周而不是每 2 周进行一次 DOX，因此正在进行的反应评估超声心动图的时间并不完全标准化，并且代表了回顾性研究的固有缺陷。此外，在一剂化疗后进行初始反应评估的时间可能不是每个执业肿瘤学家的惯例，因为许多临床医生更喜欢在判断治疗效果之前进行两到三剂治疗。理想的反应评估方案可能包括在每次治疗就诊时进行超声心动图检查，以便对患者反应充满信心;然而，在临床实践中，这通常是一种成本过高的措施。此外，由于肿瘤测量可能存在一些差异，具体取决于存在的心包积液量，因此在未来的前瞻性研究中考虑将心脏门控 MRI 或 CT 扫描作为肿瘤测量工具可以提高反应评估的精确度，尽管这些方式所需的重复麻醉事件和增加的财务承诺在该患者群体中可能是不可取的。

In this study, response to therapy was important in determining the duration of survival, where those dogs that experienced clinical benefit enjoyed significantly longer PFS and MST compared with those dogs not experiencing a response. The objective response rate was comparable with those previously reported for measureable non-cardiac HSA treated with chemotherapy.26, 27 The biologic response rate, or clinical benefit, was 68%, and the inclusion of SD as a positive outcome is an important consideration in the evaluation of a treatment protocol for a challenging cancer such as cardiac HSA. With this tumour type, most dogs recover quickly once the initial emergent event subsides, with or without pericardiocentesis. Thus, maintenance of a good quality of life without further episodes of pericardial effusion and cardiac tamponade, even without achievement of a measureable tumour response, is still a positive outcome for the majority of this patient population. Importantly, all dogs deemed to have SD in this study must have sustained that response until the time of the second echocardiographic response assessment (minimum of 6 weeks). Seven dogs sustained ultrasonographically confirmed SD for >100 days. Because some dogs (n = 6) were administered DOX every 3 weeks instead of every 2 weeks, the timing of ongoing response assessment echocardiograms was not exactly standardized and represents an inherent shortcoming of a retrospective study. Furthermore, the timing of the initial response assessment just after one dose of chemotherapy may not be a convention for every practising oncologist, as many clinicians prefer to administer two or three doses of treatment before making a judgement on the efficacy of a therapy. An ideal response assessment protocol might include an echocardiogram at each treatment visit in order to be confident in patient response; however, this is typically a cost-prohibitive measure in clinical practice. Additionally, as there could be some variability in tumour measurement depending on how much pericardial fluid is present, the consideration of cardiac-gated MRI or CT scan as tumour measurement tools in a future prospective study could improve the precision of response assessments, although the repeated anaesthetic events and increased financial commitment required for these modalities may be undesirable in this patient population.


AE 通常为轻度，与先前报道的与 DOX 治疗相关的 AE 一致。没有狗经历过危及生命的AE。血小板减少症的存在与接受心脏 HSA DOX 化疗的狗的存活率降低有关。对这一发现的可能解释可能是，这些狗正在经历弥散性血管内凝血，这是 HSA31、32 的已知并发症，因此本质上处于更受损的临床位置。血小板减少症在直觉上也与肿瘤出血有关，可能代表更大、更脆弱的肿瘤;鉴于肿瘤大小较大也与生存率下降有关，这一推理似乎是合理的。然而，只有 67% 的狗进行了 CBC;因此，这些推论并非基于整个研究人群。此外，未进行手动血片评估以确认血小板减少症;因此，不能排除血小板聚集引起的人为血小板减少的可能性。因此，如果所有狗都接受全血细胞计数和手动血小板计数，血小板减少症是否仍将是阴性预后指标，可能存在一些问题。这项研究中的数字太小，无法使多变量分析具有统计学意义。

AEs were typically mild and consistent with previously reported AEs related to DOX therapy. There were no dogs that experienced life-threatening AEs. The presence of thrombocytopenia was associated with decreased survival for dogs undergoing DOX chemotherapy for cardiac HSA. A possible explanation for this finding may be that these dogs were experiencing disseminated intravascular coagulation, a known complication of HSA31, 32 and as such were inherently in a more compromised clinical position. Thrombocytopenia is also intuitively related to tumour haemorrhage and could possibly be representative of larger and more fragile tumours; in the light of the finding that larger tumour size was also associated with decreased survival, this reasoning seems plausible. However, only 67% of dogs had a CBC performed; thus, these inferences are not based on the entire study population. Furthermore, manual blood film evaluations were not performed to confirm thrombocytopenia; therefore, the possibility of artifactual thrombocytopenia due to platelet clumping cannot be ruled out. Therefore, there may be some question as to whether thrombocytopenia would remain a negative prognostic indicator had all dogs undergone a CBC with manual platelet count. Numbers in this study were too small to make multivariate analysis statistically meaningful.


这项研究的局限性源于其回顾性，它排除了分期的标准化和将狗随机分配到治疗组或非治疗组。具体来说，在进行的分期测试以及随后每组转移的狗的数量方面，各组之间存在显着差异。然而，DOX治疗组包含更多患有转移性疾病的狗，降低了治疗组中低阶段狗的选择偏倚机会，但并没有消除这种可能性，因为CTL组中完全分期的狗较少，而CTL狗明显更多根本没有分期。这种差异很可能反映了业主在已经有动力进行化疗时进行诊断的意愿，并说明了客户对治疗侵袭性癌症（如心脏HSA）的看法存在潜在偏差。具体来说，拒绝化疗的所有者，可能部分是因为整体预后，可能更倾向于更早地寻求安乐死，这种偏倚可能影响了OS中注意到的差异。 理想情况下，治疗组和CTL组都将接受类似的PFS随访和记录，以进一步消除这种偏倚。尽管一部分狗也同时或在 DOX 方案之后接受了节拍化疗，但这组狗的 PFS 或 OS 没有显着差异;因此，使用节拍化疗并没有给这组患者带来生存优势。此外，接受抢救治疗的狗（n = 23）的OS有缩短的趋势（74天 vs 139天），尽管这种差异并不显着（P = 0.1243），并且很可能代表DOX治疗的早期治疗失败和随后对救援治疗没有反应。

A limitation of this study stems from its retrospective nature, which precluded the standardization of staging and the randomization of dogs to treatment or non-treatment groups. Specifically, there was a significant difference between groups with respect to staging tests performed and subsequently the number of dogs with metastasis in each group. However, the DOX-treated group contained a larger number of dogs with metastatic disease, decreasing the chance of selection bias for lower stage dogs in the treated group but not eliminating this possibility, as fewer dogs in the CTL group were fully staged and significantly more CTL dogs underwent no staging at all. This difference most likely reflects a willingness of owners to perform diagnostics when already motivated to pursue chemotherapy and speaks to potential bias of client perspectives for treating an aggressive cancer such as cardiac HSA. Specifically, owners who declined chemotherapy, presumably in part because of overall prognosis, may be more inclined to seek euthanasia earlier, and this bias may have impacted differences noted in OS. Ideally, both treatment and CTL groups would have been subjected to similar follow-up and documentation of PFS in order to further eliminate such bias. Although a subset of dogs also received metronomic chemotherapy either concurrent or subsequent to the DOX protocol, there was no significant difference in PFS or OS for this group of dogs; thus, the use of metronomic chemotherapy did not confer a survival advantage to this group of patients. Additionally, dogs receiving rescue therapy (n = 23) had a trend towards shorter OS (74 versus 139 days), although this difference was not significant (P = 0.1243) and most likely represents an early treatment failure on DOX therapy and subsequent failure to respond to rescue therapy.


另一个局限性是本研究中缺乏对狗的组织学诊断，所有这些都是基于心脏 HSA 的推定诊断而包括的。患有其他肿瘤类型的狗，可能具有较少的攻击性生物学行为和优越的生存时间，可能已被纳入该患者群体。此外，根据影像学和超声学特征推测与转移一致的病变实际上可能代表良性变化。同样，一些推测的转移性病变可能是原发性肿瘤，并转移至心脏。无论如何，由于在该位置对肿瘤进行取样的固有困难，发现许多患者不适合进行全身麻醉和外科手术，以及与此类努力相关的费用，因此根据解剖位置、超声特征和临床病理特征确定心脏 HSA 的推定诊断应被视为接近这种常见的“现实生活”临床场景的合理方法。

Another limitation regards the lack of histologic diagnosis for dogs in this study, all of which were included based on a presumptive diagnosis of cardiac HSA. It is possible that dogs with other tumour types, potentially carrying less aggressive biologic behaviours and superior survival times, could have been included in this patient population. Furthermore, lesions that were presumed to be consistent with metastasis based on radiographic and ultrasonographic features could have actually represented benign changes. Similarly, some of the presumed metastatic lesions could have been primary tumours with metastasis to the heart. Regardless, because of the inherent difficultly in sampling tumours in this location, the finding that many patients are poor candidates for general anaesthetic and surgical procedures, and the expense associated with such endeavours, the determination of a presumptive diagnosis of cardiac HSA based on anatomic location, ultrasonographic characteristics and clinicopathologic features should be considered a reasonable method of approaching this common ‘real life’ clinical scenario.


在这项研究中，DOX 对 cHSA 的临床活性表现为客观和生物学反应率高、MST 具有统计学意义的延长以及与先前联合手术和化疗的报道相当的 OS。然而，这种疾病的生存期仍然很短，少数狗 （14%） 的生存期为 6 个月。因此，在本研究中观察到的单药 DOX 对宏观推测心脏 HSA 的任何活性都代表了结果的适度但渐进的改善。

In this study, clinical activity of DOX for cHSA is suggested by the high rate of objective and biological response, statistically significant prolongation of MST, and OS that is comparable with prior reports combining surgery and chemotherapy. However, the disease still carries a short temporal survival with a minority of dogs (14%) achieving 6-month survival. Therefore, any activity of single-agent DOX for macroscopic presumed cardiac HSA observed in this study represents a modest yet incremental improvement in outcome.


当然，手术切除肿瘤后进行辅助化疗，就像目前脾 HSA 的首选治疗方法一样，仍然是最有可能为这种肿瘤组织学的任何解剖学表现提供最长生存获益的方法。然而，可切除的心脏肿瘤的稀缺性、相关费用和尝试此类手术的固有困难可能会阻止手术切除肿瘤成为这种犬癌广泛适用的治疗方法。因此，使用基于 DOX 的方案进行全身治疗，并可能增加局部疗法，例如心包切除术甚至放射疗法，就像最近用于其他心脏基础肿瘤一样，33 可能仍然是治疗这种具有挑战性的癌症的最合理的治疗方法。一项随机前瞻性研究评估了 DOX 对心脏 HSA 联合和不联合心包切除术的施用可能是继续寻找针对这种具有挑战性的疾病表现的最佳治疗方法的一个有趣的未来方向。

Certainly, surgical tumour removal followed by adjuvant chemotherapy, as is the current treatment of choice for splenic HSA, remains the most likely approach to provide the longest survival benefit for any anatomic presentation of this tumour histology. However, the scarcity of resectable cardiac tumours, associated expense and inherent difficulty in attempting such a procedure will likely prevent surgical tumour removal from becoming a broadly applicable treatment approach for this canine cancer. Thus, systemic therapy with DOX-based protocols, with the possible addition of local therapies such as pericardiectomy or even radiation therapy, as has more recently been employed for other heart-base tumours,33 will likely remain the most rational treatment approach for this challenging cancer. A randomized prospective study evaluating the administration of DOX for cardiac HSA with and without pericardiectomy might be an interesting future direction in the continuing search for the best treatment for this challenging disease presentation.

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