犬淋巴瘤之治療反應、預後因子及治療策略的評估

Abstract

淋巴瘤是犬常見的腫瘤之一，而CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)是目前最常用於治療犬淋巴瘤的化學治療療程；為提供淋巴瘤患犬更好的醫療品質及更久的存活時間，本文中陸續探討評估治療的預後因子、設計新的化學治療療程、探討傳統化學治療療程失敗的可能原因，以及評估研發中化療藥物之療效。 在預後因子的部份，以往大多都是採用在診斷時及治療前的評估，作為淋巴瘤治療的預後因子，針對治療後的研究則很少，我們挑選「化療後嗜中性球低下」的現象，評估能否作為新的預後因子。結果顯示，患犬的初次中位疾病消退期在化療後有嗜中性球低下和無嗜中性球低下的組別間，分別為812和219天（P < 0.01），而平均存活時間則分別為952和282天（P < 0.01），均有顯著差異，顯示患犬在化療後若出現嗜中性球低下的情形，會有顯著較長的消退期和存活時間；因此，「化療後嗜中性球低下」應可作為正向的預後因子。 CHOP 療程中使用的doxorubicin副作用通常十分嚴重，因此我們以mitoxantrone取代doxorubicin重新設計CMOP療程；在針對44隻患犬進行兩個誘導化學治療療程的比較研究中顯示，CHOP和CMOP組的中位疾病消退期分別為222和162天（P = 0.75），而中位存活時間則分別為318和242天（P = 0.63）；治療過程中，厭食及腹瀉等副作用在CHOP組都比CMOP組顯著較高（P = 0.02和P = 0.01）；結果顯示，CMOP的化療療程可以是犬淋巴瘤的另一種治療選擇。 最後為探討CHOP療程中，最常造成復發的時間點，我們在治療68隻患犬的過程中，同時分析41隻在治療期間就復發的患犬資料；結果發現，患犬在接受cyclophosphamide治療後的復發率顯著地高於其它藥物(P < 0.01)。因此若將CHOP療程中的cyclophosphamide替換成其它化療藥物，應該可以增進治療的效果，我們也以細胞學試驗評估新的烷基化藥物BO-2094和cyclophosphamide對淋巴瘤細胞的毒殺能力；結果顯示，BO-2094毒殺犬淋巴腫瘤細胞的能力，顯著地高於cyclophosphamide，當然未來仍需要更多的研究來證明其臨床治療的價值。

Lymphoma is one of the common neoplasms in dogs. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) is the most used chemotherapy for treating canine lymphoma. In order to provide better therapeutic quality and longer survival time in lymphoma patients, this study discussed the prognostic factor for therapeutic evaluation, design of new chemotherapy protocol, possible reasons for the failure of conventional chemotherapy, and the efficacy of new chemotherapy drugs. Most prognostic factors of lymphoma were evaluated at diagnosis and before treatment. Prognostic factors after chemotherapy have not been widely reported for lymphoma treatment. We chose “chemotherapy-induced neutropenia” for prognostic factor evaluation. The result revealed that median first remission times in the neutropenia and no neutropenia groups were 812 and 219 days, respectively (P < 0.01). The median survival times were 952 and 282 days, respectively (P < 0.01). Dogs with lymphoma that had chemotherapy-induced neutropenia exhibited significantly increased remission and survival times. Therefore, “chemotherapy-induced neutropenia” can be a positive prognostic factor. The side effects of doxorubicin used in CHOP protocol are usually very severe. We used mitoxantrone instead of doxorubicin to design a new CMOP induction protocol. Forty-four multicentric lymphoma dogs were treated with CHOP or CMOP induction protocol. The median progression-free survival in the CHOP and CMOP groups were 222 and 162 days, respectively (P = 0.75). The median survival time were 318 and 242 days, respectively (P = 0.63). Anorexia and diarrhea episodes were significantly higher in the CHOP group than in the CMOP group (P = 0.02 and P = 0.01, respectively). Our results suggest that CMOP protocol may be another treatment choice for canine lymphoma. Finally, we discussed the most relapsed time point in CHOP protocol. When we treated sixty-eight lymphoma dogs, we analysed the data of forty-one relapsed patients. Our result showed that relapse occurred more frequently after administration of cyclophosphamide compared with vincristine or doxorubicin (P < 0.01). Therefore, the therapeutic outcome of traditional CHOP-based chemotherapy may be improved by replacing cyclophosphamide with other cytotoxic drugs. We also compared the cytotoxic effect of new alkylating agent BO-2094 and cyclophosphamide to canine lymphoma cells by cellular assay. The results showed that BO-2094 has significant cytotoxic ability than cyclophosphamide to lymphoma cells in vitro. Further studies may be needed to approve its clinical value.