比較犬多中心型淋巴瘤15週與25週化療療程之成效與副作用

Abstract

犬多中心型淋巴瘤為犬隻最常見之淋巴增生性疾病。多種藥物組合之化學治療因有機會達到高治療反應率、持續之疾病消退期、相對較長之存活時間，故成為主流治療方式。其中，改良之威斯康辛麥迪遜大學無維持期療程（即25週療程）已被廣泛使用，搭配藥物包含vincristine、cyclophosphamide、doxorubicin和類固醇（簡稱CHOP）。雖然多數病患對治療反應良好，但最終仍會因疾病復發而死亡。為了增進治療效果、縮短療程長度和花費，將劑量更加密集給予以改良療程的方式開始被提出，包括化療藥物的同時給予、縮短藥物給予間隔或增加藥物劑量等。15週CHOP療程即因此被提出，初步研究顯示效果和過往相當且毒性可耐受 [1]。本研究的目的為更深入地針對此15週CHOP療程和上述25週療程進行成效與毒性比較，而此兩種療程也是國立臺灣大學生物資源暨農學院附設動物醫院最常使用之兩種療程。本研究以回溯性方法收集自西元2010年一月至西元2018年二月於國立臺灣大學生物資源暨農學院附設動物醫院內，透過細胞學或病理學診斷為多中心型淋巴瘤之犬隻病歷資料進行分析，最終共計62隻犬隻符合收案條件而納入研究。根據使用之療程類型，42隻犬隻被分配至25週療程組；22隻犬隻被分配至15週療程組。兩組在病患特徵和疾病臨床特性（包括臨床分期、次分期、可能與較差預後有關的指標如診斷時出現血小板低下、T細胞免疫分型、、高血鈣）分佈上並無顯著差異。反應率方面，25週療程與15週療程之整體反應率分別為97.6%和100%。其中，25週療程組及15週療程組中分別有83.3%及95.5%的犬隻反應達到完全消退。無論整體反應率或各類反應分佈，在兩組之間並無統計顯著差異。25週療程之中位疾病進展時間（Time to progression）為242天，而15週療程為217天，兩者之間無顯著差異（P=0.503）。中位存活時間（Overall survival time）方面，25週和15週療程分別為354及326天，兩者同樣無顯著差異（P=0.999）。毒性評估部分，全部的副作用發生事件中有67.8%源自腸胃道，又以厭食、嘔吐出現的頻率相當且均高於下痢。其餘事件屬於血液方面毒性，以嗜中性球低下為主。不論何種類型副作用，均有超過50%以上事件之毒性強度被歸類為第一至二級。各類副作用之發生率在兩組之間無顯著差異。預後因子部分，體重高於中位數之犬隻、黃金獵犬、出現異常胸腔影像者，被發現能達到完全消退的比率較低。能在治療時達到完全消退的犬隻，在單變數和多變數分析中顯示均有顯著較長的疾病進展時間。經歷過嗜中性球低下的犬隻，僅在單變數分析中顯示有顯著較長的存活時間。總體而言，15週療程大致與改良之威斯康辛麥迪遜大學25週療程，兩者之療效和毒性相當。因此，療效不受影響且無副作用增加的情況下，使用較短且劑量密集的療程預期能夠為病患及飼主帶來更多臨床益處及便利性。

Canine multicentric lymphoma is the most common lymphoproliferative disease in dogs. Multi-agent chemotherapy has been as the mainstay of treatment due to high response rate, durable remission and relatively long survival time. Among them, the modified University of Wisconsin-Madison (UW-Madison) protocol without maintenance (i.e. the 25-week protocol), which included vincristine, cyclophosphamide, doxorubicin and prednisolone (known as CHOP), has been extensively used. Although most patients generally respond well to the treatment, however, progressive diseases developed and the patients inevitably succumb to the disease. To improve the treatment efficacy and shorten the lengthy and costly treatment, modification of protocol in a more dose-intense fashion has been proposed, such as co-administration of chemotherapeutic agents, decreased interval of drug administration or dose escalation. A 15-week CHOP protocol was therefore reported, and comparable efficacy and well-tolerated toxicity were showed initially [1]. The purpose of this study is to further compare two protocols most commonly used in National Taiwan University Veterinary Hospital Animal Cancer Treatment Center (NTUVHACTC) the 15-week CHOP protocol and the 25-week CHOP protocol, regarding their efficacy and possibility of adverse events. Potential prognostic impact was also evaluated. Medical records of dogs diagnosed with multicentric lymphoma by either cytology or histopathology evaluation in NTUVHACTC from January 2010 to February 2018 were included for comparison. A total of sixty-four dogs met the inclusion criteria and were enrolled. According to the treatment protocol each patient received, forty-two dogs are assigned to 25-week and twenty-two dogs were assigned to the 15-week protocol, respectively. There was no significant difference in distribution of patient demographics and clinical characteristics including stage, substage and parameters possibly associated with poor prognosis (e.g. thrombocytopenia, T-cell immunophenotype and hypercalcemia). Overall response rate of 25-week and 15-week protocol was 97.6% and 100% respectively. Among them, 83.3% of dogs in 25-week group and 95.5% of dogs in 15-week group attained complete remission. No statistically significance was noted for either overall response rate or distribution of each response between two groups. Median time to progression was 242 days in 25-week group and 217 days in 15-week group, which was showed no significantly difference (P=0.503). Median overall survival time was 354 days in 25-week group and 326 days in 15-week group, without statistical significance presented (P=0.999). For adverse events, 67.8% of episodes were gastrointestinal in nature, with anorexia and vomiting equally and both more frequently presented than diarrhea. Rest of episodes were hematological in nature, majorly consisting of neutropenia. More than 50% of episodes were grade 1 to 2 toxicity, regardless of type of adverse events. No significant differences for the adverse event were noted between two groups. In the aspect of prognostic factors, dogs with body weight higher than median value, Golden retrievers and presence of abnormal thoracic image had significantly lower rate of complete remission. Dogs attaining complete remission has shown to have significantly longer time to progression in univariate and multivariate analysis. Dogs experiencing neutropenia are associated with significantly longer overall survival time only in univariate analysis. In conclusion, the 15-week protocol was generally comparable to the modified UW-Madison 25-week protocol in both efficacy and adverse events. Therefore, a shorter, dose-intense protocol with similar efficacy and toxicity profile can bring more clinical benefits and convenience for both patients and their owners.