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== 讨论 (Discussion) == HSA 的治疗在兽医肿瘤学中仍然极具挑战性,并且由于侵袭性疾病,患有 HSA 的狗的预后很差,导致附近器官和血管的侵袭、早期转移和有限的治疗选择,从而提供持久的疾病控制。手术旨在切除所有肉眼肿瘤并防止进一步的急性出血风险,但被认为是纯粹的姑息治疗。据记载,在治疗微观疾病的过程中增加化疗可适度改善结果,据报道,中位生存时间在 6-8 个月之间,不到 10% 的狗在 12 个月时存活。 在这项研究中,我们使用多柔比星和达卡巴嗪的组合作为辅助化疗,以确定这种治疗在生物侵袭性犬 HSA 中的安全性和有效性。 这项研究表明,ADTIC 组合是可行的,并且可以在患有 HSA 的狗中每 21 天安全地给药一次,从而允许遵守预计的药物剂量和周期之间的预定间隔。所有狗都在门诊接受治疗,强调了目前描述的 ADTIC 方案的可行性。副作用是可逆的和可控的,中性粒细胞减少是主要毒性。一只狗在第二个周期后出现发热性 2 级中性粒细胞减少症,一只狗在第三个周期后出现无症状的 4 级中性粒细胞减少症;然而,他们都在支持性治疗下康复,随后的剂量减少被认为是没有必要的。值得注意的是,没有一只狗因中性粒细胞减少而患上败血症。 尽管在接受联合化疗的狗中预防性使用抗生素仍存在争议,但给予克拉维酸增强阿莫西林可能有效减少中性粒细胞减少发作和相关不良反应。 总体而言,胃肠道毒性(呕吐和食欲不振)的发生率较低,第 1 组和第 2 组之间没有观察到显著差异。我们假设标准止吐药物加 maropitant 可预防 3-4 级呕吐的发生。更长的 maropitant 给药时间(连续超过 5 天)可能会进一步减少呕吐的发生。 抗肿瘤药物剂量调整的具体指南在兽医肿瘤学中尚未标准化;然而,对于经历中度至重度剂量限制性毒性(即 3-4 级毒性)的患者,通常建议将后续剂量减少 20-25%,例如中性粒细胞减少或呕吐[32] 过度毒性也更有可能增加治疗相关成本,有可能失去所有者的依从性,并且至少但不是最后一次,对患者的生存产生负面影响。另一方面,抗癌细胞毒性治疗可实现的最大益处需要对剂量强度的承诺。缺乏或降低剂量密度有可能对癌症治疗有害,特别是在已知具有高生长分数潜力的肿瘤疾病中[33,34] 当然,最佳剂量强度需要治疗监测,以便根据患者在有效治疗期间维持高质量生活 (QoL) 的能力减少或增加剂量。在上述案例中,临床医生密切监测临床体征和详细的所有者信息,结果没有缺乏依从性。狗完全康复,血液学异常得到解决,无需住院治疗,主人也没有感觉到生活质量持续下降。因此,我们选择在下一个周期时不减少化疗剂量,从而对化疗方案的预期 SDI 没有影响。这种毒性在治疗期间没有复发,可归因于可能增强化疗毒性的短暂性和未确诊的合并症、个体对化疗的一定程度的耐受性、所有者对胃肠道体征的适应或这些的组合。我们的方法基于这样一种思想,即剂量减少不应仅基于毒性程度,而应根据更广泛的变异来决定,例如癌症进展的风险、临床症状和所有者的依从性。此外,在我们的研究中也没有观察到累积毒性;事实上,血液学异常是可逆的,并且在接下来的治疗周期中毒性程度(胃肠道血液学)没有增加。 这些结果与最近的出版物不同,该出版物报道了使用由DAV[15]组成的联合化疗方案,在该研究中,与化疗相关的副作用是显着的,包括一些高级别的血液学和胃肠道毒性事件。此外,由于化疗相关的毒性,近 20% 的狗的方案被终止。然而,没有发生与治疗相关的死亡[15]。 The treatment of HSA continues to be extremely challenging in veterinary oncology, and prognosis for dogs with HSA is poor as a result of aggressive disease, leading to invasion of nearby organs and vessels, early metastasis and limited treatment options providing durable disease control. Surgery is designed to remove all macroscopic tumours and prevent further risk of acute haemorrhage, but is considered purely palliative. The addition of chemotherapy in an effort to treat microscopic disease has been documented to provide a modest improvement in outcome, with reported median survival times in the range of 6–8 months and less than 10% of dogs being alive at 12 months.1,2 In this study, we used a combination of doxorubicin and dacarbazine as adjuvant chemotherapy to determine the safety and efficacy of this treatment in biologically aggressive canine HSA. This study showed that the ADTIC combination is feasible and can be safely administered every 21 days in dogs with HSA, thereby allowing compliance with projected drug doses and scheduled intervals between cycles. All dogs were treated on an outpatient basis, stressing the feasibility of the presently described ADTIC regimen. Side effects were reversible and manageable, with neutropenia being the primary toxicity. One dog experienced febrile grade 2 neutropenia after the second cycle and one asymptomatic grade 4 neutropenia after the third cycle; however, they both recovered with supportive care, and subsequent dose reductions were not considered necessary. Notably, none of the dogs developed sepsis due to neutropenia. Although the prophylactic use of antibiotics in dogs receiving combination chemotherapy is still controversial, it is possible that the administration of clavulanate-potentiated amoxicillin was effective in reducing the neutropenic episodes and the related adverse effects. Overall, the incidence of gastrointestinal toxicity (vomiting and loss of appetite) was low, and no significant differences were observed between groups 1 and 2. We assume that the standard antiemetic medication with maropitant prevented the onset of grades 3–4 emesis. It is possible that a longer maropitant administration (over 5 consecutive days) might have reduced the occurrence of vomiting further. Specific guidelines for dose adjustments of antineoplastic agents are not standardized in veterinary oncology; however, a 20–25% reduction is commonly recommended for the subsequent dose in patients experiencing moderate–severe dose-limiting toxicity (i.e. grade 3–4 toxicities), such as neutropenia or emesis.32 Excessive toxicity is also more likely to increase treatment-associated costs, has chances of losing owners’ compliance and, least but not last, to negatively affect patients’ survival. On the other hand, the greatest benefit achievable with anticancer cytotoxic therapy requires a commitment to dose intensity; lack of or reduced dose density has the potential to be detrimental in cancer treatment, especially in neoplastic diseases known to have the potential of high growth fractions.33,34 Of course, optimal dose intensity demands therapeutic monitoring in order to either reduce or increase doses based on the patient’s capacity to maintain a high quality of life (QoL) during effective therapy. In the mentioned cases, a close monitoring of clinical signs by the clinicians and detailed owners’ information resulted in no lack of compliance. Dogs recovered completely and haematological abnormalities resolved without requiring hospitalization and with no perception of durable decline in QoL by the owner. We therefore elected not to reduce chemotherapy doses at the time of the following cycle, resulting in no effect on the intended SDIs of the chemotherapy protocol. Such toxicities did not recur during treatment, being attributable to transient and undiagnosed comorbidities that might have enhanced chemotherapy toxicities, a degree of individual tolerance to chemotherapy, adaption of the owner to gastrointestinal signs or a combination of these. Our approach was based on the thought that dose reductions should not be solely based on the degree of toxicity, but decided on a broader spectrum of variants such as risk of cancer progression, presenting clinical signs and owner compliance. Moreover, cumulative toxicity was also not observed in our study; in fact, haematological abnormalities were reversible and the degree of toxicity (either hematological of gastrointestinal) did not increase in the following treatment cycles. These results differ from a recent publication that reported the use of combined chemotherapy protocol consisting of DAV.15 In that study, chemotherapy-related side effects were notable, including several high-grade hematologic and gastrointestinal toxic events. Moreover, almost 20% of the dogs had their protocol discontinued as a result of chemotherapy-related toxicities; however, no treatment-related deaths occurred.15 这可能有多种解释。在这项研究中,达卡巴肼的总预期剂量分为每天五次推注,而在 DAV 研究中,这是在 8 小时内作为单剂量给药;事实上,有人认为,与缓慢的静脉输注相比,每日达卡巴嗪静脉推注可能会降低胃肠道毒性,而不会产生负面影响.16,28 此外,长春新碱未在 ADTIC 狗中给药,可能降低胃肠道毒性的风险。还应该注意的是,第 2 组中的大多数狗没有临床晚期,而在 DAV 研究中,狗最有可能患有 III 期疾病;患有晚期疾病的狗很容易出现体能状态下降,可能导致对化疗毒性的易感性增加35。 在我们的研究中没有发现临床心脏毒性的证据。这一发现可归因于有关心脏功能的入组标准、研究中的狗数量有限和/或施用的多柔比星治疗数量少,未达到心脏毒性的累积剂量。 尽管这项研究的规模很小,但我们的结果表明,在转移控制和生存方面,特别是对于II期HSA,使用ADTIC治疗生物侵袭性犬HSA比AC更具优势。在第 1 组中,83% 的狗(AC 方案)因 HSA 进展而被安乐死,MST 为 142 天,而在第 2 组(ADTIC 方案)中,44.4% 的狗因肿瘤相关原因死亡,MST 为 >550 天 (P =0.011)。此外,在第 2 组中,分别有 66.8% 和 55.8% 的患者实现了 1 年和一年半的生存率,而第 1 组没有患者达到一年生存率。从我们的角度来看,这些数据可能是支持ADTIC对患者生存率进一步获益的最相关数据,并且还可能表明,如果在没有宏观转移性疾病的情况下开始化疗,相当一部分患有生物侵袭性HSA的狗可能仍然有良好的结果。然而,这些数据应谨慎解释,因为它可能因第 2 组中登记的狗数量较少而存在偏差,尽管存在争议,但与其他内脏位置相比,肾脏和皮下 HSA 的侵袭性生物学行为可能较小[4,36] 话虽如此,必须承认直径最长 >6 cm 的皮下 HSA 与肿瘤进展时间和生存时间较短显着相关[4] 在这项研究中,三个皮下 HSA 分别测量了 8、6.5 和 12 cm,支持攻击性行为和发生转移性疾病的可能性增加。此外,其中一只狗在区域淋巴结中患有转移性疾病,进一步支持了攻击性生物学行为。 关于TTM,在研究期间,接受 AC 治疗的狗中有 66.6% 发生远处转移,而接受 ADTIC 治疗的狗中有 44% 发生远处转移。与生存期一样,如果将 ADTIC 用作辅助一线治疗策略,则 TTM 显著延长(P=0.021)。这一发现可能是由于几个原因造成的。虽然环磷酰胺和达卡巴嗪都是烷化剂,但由于不同的药代动力学特征、脂质溶解度、膜转运特性和能够修复 DNA 上烷基化位点的特异性酶促反应,它们的抗肿瘤活性差异很大[16,37] 环磷酰胺干扰 RNA 的 DNA 复制和转录,从而导致核酸功能的破坏[37] 达卡巴嗪通过烷基化起作用[16],由于优化治疗策略以最大限度地提高疗效同时限制毒性的问题具有临床意义,因此我们通过直接比较环磷酰胺和达卡巴嗪进一步研究了两种采用方案的剂量强度。与环磷酰胺相比,达卡巴嗪具有更大的个体分数剂量强度,最终导致与多柔比星联合使用时更高的 SDI。研究中包括的所有狗都接受了预定剂量,无需减少剂量。因此,接受 ADTIC 治疗的狗接受了更强烈的化疗,可能导致更长的 TTM 和生存期。 此外,除了其细胞毒性活性外,达卡巴嗪已被证明在小鼠中具有抗转移特性,其潜在机制与其增强肿瘤免疫原性的能力有关[38,39]。在这项研究中,用 ADTIC 治疗的狗具有更长的 TTM,这可能反映了达卡巴嗪抑制转移扩散的能力,或者是因为研究的样本量小。 This could have multiple explanations. In this study, the total intended dose of dacarbazine was divided into five daily boluses, whereas in the DAV study this was administered as a single dose over 8-h infusion; in fact, it has been suggested that daily dacarbazine IV boluses may cause reduced gastrointestinal toxicity than slow IV infusions, without negatively affecting antitumour activity.16,28 Moreover, vincristine was not administered in ADTIC dogs, possibly reducing the risk of gastrointestinal toxicity. It should also be noted that the majority of dogs included in group 2 presented with no advanced clinical stage, whereas in the DAV study dogs were most likely to have stage III disease; dogs with advanced disease could easily have reduced performance status, potentially leading to enhanced susceptibility to chemotherapy toxicity.35 No evidence of clinical cardiotoxicity was noted in our study. This finding could be attributed to the entry criteria with regard to cardiac function, the limited number of dogs in the study and/or the low number of doxorubicin treatments administered not reaching the cumulative dose for cardiotoxicity. Despite the small size of this study, our results document an advantage in the use of ADTIC over AC for the treatment of biologically aggressive canine HSA in terms of metastatic control and survival, particularly for stage II HSA. In group 1, 83% of dogs (AC protocol) were euthanized because of HSA progression with an MST of 142 days, whereas in group 2 (ADTIC protocol) 44.4% of dogs died because of tumour-related causes with an MST >550 days (P =0.011); moreover, in group 2, the one and one-and-a half-year survival was achieved in 66.8 and 55.8%, respectively, whereas none of the patient reached one-year survival in group 1. From our perspective, these data are probably the most relevant supporting the benefit of ADTIC on patients’ survival further, and may also suggest that a notable proportion of dogs with biologically aggressive HSA may still have a good outcome, if chemotherapy is started in the absence of macroscopic metastatic disease. However, these data should be interpreted carefully as it may be biased by the small number of dogs enrolled in group 2 and, although debated, to the potentially less aggressive biological behaviour of renal and subcutaneous HSA compared with other visceral locations.4,36 This being said, it must be acknowledged that subcutaneous HSA with the longest diameter >6 cm has significantly been associated with a shorter time to tumour progression and survival time than smaller tumours.4 In this study, the three subcutaneous HSA measured 8, 6.5 and 12 cm, respectively, supporting the aggressive behaviour and the increased likelihood of developing metastatic disease. Also, one of these dogs had metastatic disease in the regional lymph node, further supporting the aggressive biological behaviour. Concerning TTM, 66.6% of the dogs treated with AC developed distant metastasis during the study compared with 44% of the dogs treated with ADTIC. Like survival, TTM was significantly longer (P =0.021) if ADTIC was used as adjuvant first-line treatment strategy. This finding may be due to several reasons. Although both cyclophosphamide and dacarbazine are alkylating agents, their antitumour activity differs considerably because of different pharmacokinetic features, lipid solubility, membrane transport properties and specific enzymatic reactions capable of repairing alkylation sites on DNA.16,37 Cyclophosphamide interferes with DNA replication and transcription of RNA, thereby resulting in the disruption of nucleic acid function.37 Dacarbazine acts by means of alkylation, antimetabolite activity as a purine precursor, and interaction with sulfhydryl groups in proteins.16 Because the issue of optimizing the treatment strategy to maximize efficacy while limiting toxicity has clinical implications, here we further investigated dose intensity of both adopted protocols by directly comparing cyclophosphamide and dacarbazine. Dacarbazine has greater individual fractional dose intensity when compared with cyclophosphamide, ultimately leading to a greater SDI in combination with doxorubicin. All dogs included in the study received the scheduled doses without any need for dose reduction; therefore, ADTIC-treated dogs received a more intense chemotherapy, possibly leading to longer TTM and survival. Furthermore, besides its cytotoxic activity, dacarbazine has been demonstrated to have antimetastatic property in mice, the underlying mechanism being related to its capacity to enhance tumour immunogenicity.38,39 In this study, dogs treated with ADTIC had a longer TTM, which may either reflect the capacity of dacarbazine to inhibit metastatic spread or be because of the small sample size of the study. 这项研究的局限性包括缺乏随机化、病例数少、肿瘤部位起源不同和缺乏尸检。尽管皮下和内脏 HSA 已被描述为具有侵袭性生物学行为,1,3,4 对肠系膜 HSA 知之甚少.2 患有肠系膜 HSA 的狗被纳入本研究。此外,第 2 组中的两只狗在发生远处转移后接受了抢救方案,可能有助于提高存活率。 此外,两种治疗方案(AC 与 ADTIC)在不同的诊所提供,而不是在每个地点提供任何一种治疗,这可能导致选择偏倚。然而,对各组的分析证实,除了入组的患者数量外,这些组没有显着差异,这表明样本是同质的。 总而言之,ADTIC组合耐受性良好,可以延长具有生物侵袭性HSA的狗的TTM和生存时间,尤其是在就诊时没有转移的情况下。 Limitations of this study include lack of randomization, low number of cases, different tumour site origin and lack of necropsy. Although subcutaneous and visceral HSA have been described to have an aggressive biological behaviour,1,3,4 little is known about mesenteric HSA.2 A dog with mesenteric HSA was included in this study. In addition, two dogs included in group 2 received a rescue protocol after having developed distant metastases, possibly contributing to increased survival. Also, the two treatment options (AC versus ADTIC) were offered at different clinics, instead of offering either treatment at each location, possibly leading to selection bias. However, the analysis of the groups confirmed that these did not have significant differences, except for the number of patients enrolled, suggesting that the samples were homogeneous. To conclude, the combination ADTIC was well tolerated and may prolong TTM and survival time in dogs with biologically aggressive HSA, especially if not metastatic at presentation. <br> <br>
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