Spugnini Enrico P, Buglioni Sabrina, Carocci Francesca, Francesco Menicagli, Vincenzi Bruno, Fanciulli Maurizio, Fais Stefano
Department of Drug Research and Medicine Evaluation, National Institute of Health (ISS), Anti-Tumor Drug Section, Rome, Italy.
J Transl Med. 2014 Aug 21;12:225. doi: 10.1186/s12967-014-0225-y.
The treatment of human cancer has been seriously hampered for decades by resistance to chemotherapeutic drugs. A very efficient mechanism of tumor resistance to drugs is the proton pumps-mediated acidification of tumor microenvironment. Metronomic chemotherapy has shown efficacy in adjuvant fashion as well as in the treatment of pets with advanced disease. Moreover, we have shown in veterinary clinical settings that pre-treatment with proton-pumps inhibitors (PPI) increases tumor responsiveness to chemotherapeutics. In this study pet with spontaneously occurring cancer have been recruited to be treated by a combination of metronomic chemotherapy and high dose PPIs and their responses have been matched to those of a historical control of ten patients treated with metronomic chemotherapy alone.
Single arm, non randomized phase II open study, with historical control group, evaluating safety and efficacy of the combination of metronomic chemotherapy and alkalization. Twenty-four companion animals (22 dogs and 2 cats) were treated adding to their metronomic chemotherapy protocol the pump inhibitor lansoprazole at high dose, and a water alkalizer. Their responses have been evaluated by clinical and instrumental evaluation and matched to those of the control group.
The protocol was overall well tolerated, with only two dogs experiencing side effects due to gastric hypochlorhydria consisting with vomiting and or diarrhea. In terms of overall response, in the alkalized cohort, 18 out of 24 had partial or complete responses (75%), two patients had a stable disease and the remaining patients experienced no response or progressive disease. On the other hand, only one patient in the control group experienced a complete response (10%) and three other experienced short lived responses. Median time to terminal event was 34 weeks for the experimental group versus 2 weeks in the controls (p= 0.042).
Patient alkalization has shown to be well tolerated and to increase tumor response to metronomic chemotherapy as well the quality of life in pets with advanced cancer. Further studies are warranted to assess the efficacy of this strategy in patients with advanced cancers in companion animals as well as in humans.
几十年来，对化疗药物的耐药性严重阻碍了人类癌症的治疗。肿瘤对药物产生耐药性的一种非常有效的机制是质子泵介导的肿瘤微环境酸化。节拍化疗已显示出在辅助治疗以及治疗患有晚期疾病的宠物方面的疗效。此外，我们在兽医临床环境中已经表明，用质子泵抑制剂（PPI）进行预处理可增加肿瘤对化疗药物的反应性。在本研究中，招募了患有自发性癌症的宠物，用节拍化疗和高剂量PPI联合治疗，并将它们的反应与仅接受节拍化疗的10例患者的历史对照组进行匹配。
单臂、非随机II期开放研究，设有历史对照组，评估节拍化疗和碱化联合治疗的安全性和有效性。24只伴侣动物（22只狗和2只猫）在其节拍化疗方案中添加高剂量的泵抑制剂兰索拉唑和水碱化剂进行治疗。通过临床和仪器评估来评估它们的反应，并与对照组的反应进行匹配。
该方案总体耐受性良好，只有两只狗因胃酸过少出现副作用，表现为呕吐和/或腹泻。就总体反应而言，在碱化队列中，24只中有18只出现部分或完全反应（75%），2只患者病情稳定，其余患者无反应或病情进展。另一方面，对照组中只有1例患者出现完全反应（10%），另外3例有短暂反应。实验组至终末事件的中位时间为34周，而对照组为2周（p = 0.042）。
患者碱化已显示出耐受性良好，并增加了晚期癌症宠物对节拍化疗的反应以及生活质量。有必要进一步研究评估该策略在伴侣动物以及人类晚期癌症患者中的疗效。
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