It s not the first time.. History and epidemiology 一切從這兒開始. History and Epidemiology 2012/8/27 請注意! 因為醫學資訊更新快速, 本文僅有 2-3 年的參考價值!

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1 國立臺灣大學臨床動物醫學研究所臺灣獸醫外科專科醫學會葉力森 請注意! 因為醫學資訊更新快速, 本文僅有 2-3 年的參考價值! It s not the first time.. History and epidemiology 2004/4 2010/ 一切從這兒開始. Do injection site reactions induce fibrosarcomas in cats? History and Epidemiology 美國賓州大學獸醫學院病理實驗室, 自 1970 年代開始提供外科病理學診斷, 最多每年可收到 個病例, 其中 20-30% 為貓 (Hendrick MJ, 1991, 1992) (JAVMA, Vol 199, No. 8, October 15, 1991) 5 6 1

2 History and Epidemiology History and Epidemiology 1987 年起, 發現過去很罕見的, 在皮下注射部位引起炎症反應之貓病例突然逐年增加 年間, 貓病例診斷為 fibrosarcoma 的數量大幅增加, 上升幅度為 61% 之多 (Hendrick MJ, 1991, 1992) (Hendrick MJ, 1991, 1992) 7 8 History and Epidemiology Coincidently 1985 年, 以鋁為佐劑的狂犬病不活化疫苗及貓白血病疫苗 (FeLV) 問世 (Macy DW, 1996) 1987 年, 賓州正式頒佈貓需接受狂犬病疫苗注射之法令 9 10 History and Epidemiology 因為以上的原因,1991 年,Hendrick 等人投稿, 懷疑不活化疫苗引起注射部位肉芽腫性病變, 甚至是惡性纖維肉瘤! History and Epidemiology 1991 年後, 陸續有研究以流病學角度確立 killed vaccine (rabies and FeLV) 及疫苗注射部位軟組織肉瘤 (soft tissue sarcomas) 間之關聯 (Hendrick MJ, 1992) 1993 年 Kass 等人的統計指出, 在最常施打疫苗的肩頸部, 施打單次疫苗較未施打過疫苗的貓之腫瘤發生率, 約高出 50%, 施打兩次則為 127% 大於三次則為 175% (Kass PH, 1993)

3 History and Epidemiology History and Epidemiology It was then named: Vaccine Associated Sarcoma (VAS) 疫苗相關肉瘤 Later also known as: Feline injection site sarcoma (FISS) 注射部位肉瘤, or FISAS: Feline injection site-associated sarcoma 確切的發生率仍不明 Incidence of VAS was ranging from 1 case/10,000-30,000 vaccination(coyne MJ,1997; Gobar GM, 2002) Tumor may develop 2 months to 11 years after vaccination (McEntee MC, 2001; Martin M, 2003) 來自 JAVMA 的一篇回朔性研究結果 *: 複合施打疫苗項目 疫苗不良反應率 ( 注射部位腫漲 ) 疫苗實施後 1-3 年觀察期整體 FISAS 發生率 含三 / 四合一 (FVR/C/P/ Chlamydia) 含貓白血病 (FeLV) 含狂犬病 (Rabies) 0.10/ / / ~0.006/100 *Ref: Glenna M. G., Philip H. K. World Wide Web-based survey of vaccination practices, and vaccine site-associated sarcomas in cats. JAVMA, 220(10), May Retrospective survey of surgical excision of feline vaccineassociated sarcoma: 57 cases ( ). Chou TH, Chiou HY, Cheng CH, Yeh LS. Taiwan Vet J: 37(1): 53-62, Cases collection Cats with histologically confirmed VAS from pathology department of School of Veterinary Medicine National Taiwan University and Division of Animal Medicine of Animal Technology Institute Taiwan Exclusion criteria: tumors not at typical region of injection site (head, distal limbs or ventral aspect) Medical record review (cont.) Clinical staging Modified staging system of canine soft tissue sarcoma (Dillon, 2005) Treatment Surgery alone or surgery + radiotherapy(rt) Wide margin/ non-wide margin Complications (healing problem/ post-rt) Outcome Disease free interval (DFI) Overall survival time (OST) Others (pelvic paralysis)

4 Results: signalment 57 cats with VAS met the inclusion criteria. Sex: 35% were castrated males, 27% were spayed females, 24% were intact males, and 14% were intact females. 29 例 (51%) 為短毛家貓 20 例 (35%) 為波斯血統長毛貓 5 例 (9%) 為美國短毛貓, 另 3 例 (5%) 分別為英國短毛貓 蘇格蘭折耳貓 緬因貓 The percentage of Persians breed in other studies was between 1-3% (Martano, 2005; Romanelli, 2008) Signalment (cont.) Age Median age was 7.5 years old (range: 2-16years old) 6 (10%) cats were younger than 4 years old The median age of other retrospective studies was 8-10 years old. The youngest patients of the studies were 1, 1.5, 3 and 4 years old. (Eckstein,2009; Martano, 2005; Hahn, 2007; Romanelli, 2008) Vaccination history Clinical appearance Vaccine: 74% were vaccinated, 2% was not (since the client adopted it) and 24% unknown 71% accepted at least one injection of 5 in 1(including FeLV) or rabies vaccines in their life 1 cat only accepted 3 in 1 (FPV, FHV-1 and FCV) vaccine before 1 cat accepted 3 in 1 and rabies vaccine after 1st excision, and new tumor recurred in 2 months 21 Primary tumor location Back: 24 (42%) Scapular region: 19 (33%) Neck: 7 (12%) Flank: 4 (7%) Thigh: 3 (5%) 最大直徑之中位數為 5 公分 ( 範圍從 1-15 公分 ), 其中僅 5 例之腫塊直徑小於等於 2 公分 22 Histopathologic findings Follow-up (cont.) Histopathologic diagnosis Diagnosis Case number Fibrosarcoma 25 (44%) Sarcoma 18 (32%) Rhabdomyosarcoma 3 (5%) Leiomyosarcoma 3 (5%) Spindle cell tumor 3 (5%) Median disease free interval: 120 days Median survival time: days Adjuvant radiotherapy (DFI 300 days; OST 720 days) Myxomatoid sarcoma 2 (3.5%) Giant cell sarcoma 2 (3.5%) Chondrosarcoma 1 (2%)

5 Sarcoma Task Force (VAFSTF) How did it happen? Etiopathogenesis 由於 FISS/ VAS 的問題嚴重威脅到貓族群的健康, 於 1996 年 11 月 1 號, 由美國的 AVMA AAHA AAFP(feline practitioners) 等組織共同組成專案小組 目的為對此問題加以研究及教育, 並預計三年內將階段性任務完成 2005 年該會解散 Etiopathogenesis 多步驟 (multi-step) 的致腫瘤模式, 包括局部因子 (inflammation) 基因, 及醫源性為貓疫苗相關肉瘤之較可信的致病原因 (Kirpensteijn J, 2006) Inflammation tumor 貓白血病及狂犬病疫苗當時為研究的主要對象, 因為此二種疫苗含有鋁佐劑 (Aluminum adjuvant), 被認為最可能引發局部炎症反應, 繼而導致腫瘤生成 (Hendrick, 1992) Etiopathogenesis (cont.) Genetic and growth factors Abnormal expression of p53 gene, plateletderived growth factor (PDGF), cytoplasmic basic fibroblast growth factor (FGF-b), transforming growth factor-α(tgf-α), and c- jun gene. (Nieto, 2003) Etiopathogenesis (cont.) Activation of Akt/mTOR/S6K pathway proteins in feline injection-site sarcomas Shih-Chieh Chang et al. strong immune-staining intensity of p-mtor correlated with grade III FISS. It indicated that Akt/mTOR/S6K pathway proteins play an important role and can be promising as a target in FISS therapy 貓白血病 (FeLV) 疫苗與貓注射部位相關肉瘤 (FISAS) 世界分析 根據來自 2006 年一份回顧性論文 (J.Kirpensteijn. Veterinary Microbiology 117 (2006) ) 綜觀過去 10 年來所有的大規模的流行病學研究調查看來, 對於 FISS 的發生, 有以下結論 : 1. 是否與注射刺激性產品有關至今仍是問號 2. 沒有疫苗品牌 / 製造者之相關特異性 3. 沒有疫苗施予方式上之相關特異性 貓之疫苗注射應該以個體的損益平衡為考量 30 5

6 Categories GUIDELINES OF FELINE VACCINATION Core vaccines 核心疫苗 : are recommended for all cats Noncore vaccines 非核心疫苗 : should be administrated to cats in specific risks Not generally recommended vaccines: have little or no indication - adjusted by areas according to disease risks 32 AAFP American Association of Feline Practitioners Feline Vaccine Advisory Panel Report (JAVMA, November 2006, 229(9), ) WSAVA World Small Animal Association Vaccine Guidelines Group (WSAVA VGG) WSAVA guidelines for the vaccination of dogs and cats (J Small Anim Pract. June 2010;51(6): ) ABCD European Advisory Board on Cat Diseases (ABCD) Core vaccines 核心疫苗 Vaccines against FPV (Feline parvovirus) 貓小病毒 FHV-1 (Feline herpesvirus-1) 貓疱疹病毒 FCV (Feline calicivirus) 貓卡里西 Rabies virus 狂犬病 ( 歐洲貓流行 )

7 Noncore vaccines 非核心疫苗 Vaccines against FeLV (Feline leukemia virus) 貓白血病 Chlamydophila felis 貓披衣菌 Bordetella bronchiseptic 包氏桿菌 FIV (Feline immunodeficiency virus) 貓愛滋病毒 (AAFP) FIP (Feline coronavirus) 貓傳染性胸腹膜炎 (ABCD) Not generally recommended vaccines Vaccines against Giardia spp 梨形鞭毛蟲 FIP 貓傳染性胸腹膜炎 (AAFP, WASAVA) 因 mutation 太快 FIV (Feline immunodeficiency virus) 貓愛滋病毒 (WASAVA, ABCD) 因 mutation 太快 Feline vaccine in Taiwan Vaccine against FPV, FHV-1 and FCV 三合一 ( 多為活毒減毒, 亦有死毒含佐劑疫苗, 須辨認 ) FPV, FHV-1, FCV, C felis and FeLV 五合一 ( 其中 FeLV 為死毒含佐劑 ) Rabies ( 死毒, 含佐劑 )( 台灣尚無重組且無佐劑之狂犬病疫苗 ) 單價 FeLV ( 基因重組, 也含佐劑 ) FIP ( 活毒減毒, 點鼻 ) 打疫苗前 Make plan of vaccination depends on EVERY INDIVIDUAL Do routine physical examination and history taking prior to administration of vaccine Do FeLV/FIV screen if needed 選擇疫苗種類 單價比多價疫苗好 無佐劑比有佐劑疫苗好 Low-risk: 完全室內貓 Moderate: 常進出醫院 美容院 寄宿 多貓家庭 High-risk: 自由進出 可能與浪貓接觸 Special consideration: age, breed, breeding, lactating, preexisting illness, retrovirus-infected cats, concurrent use of corticosteroids, prior vaccine-associated adverse events 建議的給予方式 -AAFP 1. 皮下注射, 不肌肉注射 2. 四肢, 越遠越好 3. 避免注射同一部位肘部以下膝蓋以下 41 (VAFSTF at 1996) 42 7

8 Changes of proportion of VAS site Temporal changes in characteristics of injection-site sarcomas in cats: 392 cases ( ) Shaw SC, JAVMA, 234(3), , 2009 Standardize vaccination site by VAFSTF at 1996 From before to after publication of the vaccination recommendations, proportions of VAS significant changed Interscapular VAS 53.4% 39.5% Rt. Pelvic limb with Rt. Lateral abdomen VAS 12.5% 25.0% (Shaw SC, 2009) 側腹注射 根據 2009 年 Shaw SC 等人之研究結果, 顯示可能因肢體遠端注射疫苗不易, 反而使 VAS 長於肢體近端而更難治療 注射於側腹皮下 :WSAVA 2010 年提出 較易施行 若發生 VAS, 可實現 wide margin/ radical excision 而不需犧牲肢體 較易有效包紮 (J Small Anim Pract. June 2010;51(6): ) 頻率 FPV, FHV-1, FCV vaccine: 基礎疫苗 : 小於 16 週齡貓,6 週齡可開始施打, 間隔 3-4 週注射一次, 直到 16 週齡 大於 16 週齡貓, 注射兩劑, 間隔 3-4 週 基礎疫苗注射後一年補強, 之後三年一次 減毒活毒之 FPV 疫苗不用於 FeLV/FIV 陽性貓 Rabies vaccine 基礎疫苗 :8 週齡可注射第一劑, 一年後第二劑 補強 : 一年一劑 若為三年期之狂犬病疫苗, 基礎疫苗於 12 週齡注射一次, 一年後再補強, 之後 3 年一次 / 成貓才開始預防, 則頭兩劑相隔一年, 之後 3 年一次 FeLV vaccine 基礎疫苗 :8 週齡第一劑,3-4 週後第二劑 ; 若成貓開始施打, 則頭兩劑間隔 3-4 週 補強 : 有風險者才需每年補強 FeLV 陽性者不建議施打

9 Chlamydophila felis 基礎 :9 週齡第一劑, 間隔 3-4 週第二劑 / 成貓開始施打, 兩劑間隔 3-4 週 補強 : 有風險者才需每年補強 FIP ( 點鼻 ) 基礎 :16 週齡第一劑,3-4 週後第二劑 / 成貓兩劑間隔 3-4 週 製造商建議每年補強 因研究仍有限, 被認為給予 FCoV 抗體陰性之貓, 可能有些許保護力 家中有其他貓罹患 FIP 或 FCoV 抗體陽性者不宜給予 病歷紀錄 詳實紀錄病歷 施打疫苗 / 藥物之廠牌種類 施打之部位 注射後有無特殊反應 台灣地區貓疫苗建議 8 週齡 : 五合一 or 三合一 +FeLV 12 週齡 : 五合一 or 三合一 +FeLV 16 週齡 : 五合一 or 三合一 +FeLV 1 歲 4 個月 : 五合一 or 三合一 +FeLV 之後每三年追加三合一 有風險者才需每年追加 FeLV 疫苗 狂犬病疫苗依政府規定施打 台灣市場貓 FelV 相關疫苗 Pfizer 五合一 MSD 五合一 Virbac 三合一 +FeLV 抗原製作 死毒疫苗單支疫苗 FeLV 為死毒疫苗其餘為減毒活毒疫苗雙支疫苗混合使用 減毒活毒疫苗建議與 FeLV ( 基因工程蛋白質疫苗, 以 Quil A Aluminum hydroxide 為佐劑 ) 混合使用 內含佐劑 Break 9

10 Clinical Signs and Diagnosis/Treatment Clinical signs and diagnosis 通常發生於中老年貓, 平均發病年齡為 8.1 歲, 較非疫苗引起的自發性肉瘤為年輕 無任何性別與品種好發 最常發生的部位為肩胛間 ( 84%), 其次為大腿 (6%) 腹脅部 (5%) 腰椎處 (3%) 及臀部 (2%) 腫塊本身通常為實質 無痛的突起腫塊, 通常與其下組織緊連, 偶爾可見囊狀結構 [3-2-1 guideline] 如果貓在注射部位出現腫塊, 並且符合以下三點中的至少一點, 就應儘快進行積極的診斷與治療 持續存在三個月以上 (Persists >3 months after injection) 立體直徑在 2 公分以上 (Is >2 cm in diameter (by caliper in 3D ) 在注射後一個月仍增加大小 (Is increasing in size 1 month after injection) (Morrison WB, 2001) Detecting possible metastasis before anesthesia 3 direction thoracic X-ray Chest CT Treatment (Retrospective survey of surgical excision of feline vaccine-associated sarcoma: 57 cases ( ). Margin of surgical excision Margin Case number Non-wide margin 29 (52%) Wide margin 14 (25%) Unknown 12 (21%) Amputation 1 (2%) Spinous process removal at 7 cats / 2 cases combined with RT Margin of the first excision of VAS was proved to be a crucial prognostic factor 切除範圍的問題 Too big to do wide margin excision Don t know the importance of wide margin Worry about the skin defect after wide margin excision

11 Healing problem in 15 cases Pocket like capsule at the 3 cases, and pathologic diagnosis of the capsule was fibrosarcoma of 1 case. All 15 cases healed well after surgical or medical treatment. 2 of them recoverred well, DFI and OST were longer than 388 and 1440 days. 大範圍切除 傷口癒合的問題 ( 不癒合總比有腫瘤好 ) Healing problem of 15 cases 8 cases accepted wide margin excision Re-excision and closure of the wound in 3 of 15 cases Pocket like capsule lining of the dead space of the surgical region was noted at the 3 cases, and pathologic diagnosis of the capsule was fibrosarcoma of 1 case. All 15 cases healed well after surgical or medical treatment. 2 of them recoverred well, DFI and OST were longer than 388 and 1440 days. Hypothesis 第一次大範圍切除可有較好預後 大範圍切除時腫瘤愈小預後愈佳 大型腫瘤進行大範圍切除仍有機會存活 Follow-up (cont.) 4 cases of pelvic paralysis of VAS N 年齡位置大小 (cm) 手術次數病理診斷癱瘓原因 DFI OST 1 6y/o 左肩胛 10x8x5 1 平滑肌肉瘤不明 y/o 背中央 15x10x10 4 黏液性 / 纖維肉瘤 以電腦斷層確認為腫瘤侵犯 y/o 背中央 8x8 1 纖維肉瘤不明 y/o 背部 5x4x3 2 巨細胞肉瘤 以屍體解剖確認為腫瘤侵犯 Conclusion 預防及早期偵測 良好的飼主教育 良好的預防注射計畫 積極診斷 積極治療 首次即大範圍切除 合併放射線治療

12 以根治為目的的腫瘤治療 Tumor is like a crab 腫瘤的 身體 常常較為靜止, 含氧量也較低 Management of tumors 但腫瘤的 觸角 卻較多血液循環, 侵犯性高 Treatment 由於 VAS 具有高侵略性及局部侵犯性, 手術後比非注射引起的肉瘤更容易復發, 因此治療貓疫苗相關肉瘤比治療其他肉瘤更具挑戰性, 目前尚無治療此病之黃金準則 VAS=VERY AGGRESSIVE SARCOMA Local invasive Recurrence Metastasis Treatment 不論組織病理學的分級為何, 有效的治療通常需配合術後的放射線治療或化療, 或是兩者皆進行 多元治療 Multi-modality therapy (McEntee MC, 2001) Surgery Radiotherapy Chemotherapy Tumor imaging Tumor size depending by palpation is CT scan may be done before surgery or radiotherapy What is a Safe margin for surgical excision? Marginal: 團塊外切除 Extracapsular dissection, 會進入腫瘤的 反應區 reactive zone 將團塊鈍剝出來 shell-outs and peeling mass out from this tissue bed and off local attachments. High-grade 病灶會有殘瘤癌細胞問題 Extracapsular microextensions of disease and skip metastases of high-grade lesions usually still exist

13 Safe margin for surgical excision Marginal excision of VAS is seldom curative and ultimately leads to local recurrence and a more difficult 2nd surgery. (Recurrence rate: 30-70%) (McEntee, 2001) Wide margin: 將團塊及四周的反應區一併整塊拿掉, 切割都在正常區域進行 En bloc removal of lesion and reactive zone, always working in normal uncontaminated tissue. Normal tissue is left at the margin 跳脫轉移仍有可能, 但可能性較小 skip metastases still possible, but not that likely Safe margin 如何取得安全邊緣 : 數字法 metric approach: e.g. 3-5 cm for VAS 組織界線法 barrier approach: anatomical boundaries and dissecting up to an uninvolved barrier, or barrier with great functional significance. WRONG RIGHT Safe margin 混合法 Metric/barrier hybrid: 切除四周以長度定義, 深度由組織界線定義 (fascial plane) often leads to a histopathological report of several cms clearance laterally, but only 1-2 mm clearance deep

14 Safe margin for surgical excision 極端及大區塊切除 Radical margin and Large body portion excisions 移除大部身體結構 例如截肢 半骨盆切除術 上下顎切除術, 全耳道切除術等 e.g. amputation, hemipelvectomy, mandibulectomy, maxillectomy. 殘餘腫瘤細胞機會較少 Safe margin 再切除 Re-excision (AKA scar revision) 原切除區往外 1-3 cm, 往下一個肌膜界線 1 fascial plane 確認上回切除仍有癌細胞殘留 合併放射輔助治療之外的另一選擇 但是在 VAS 很少有效!!! Safe margin 再切除 Re-excision (AKA scar revision) 重覆進行對於延長生命或改善生活品質是可行的 在肉瘤, 局部復發只是預後不良的訊號, 但通常不是造成死亡的原因 ( 是否 apply VAS 存疑 ) 預防手術造成的污染及腫瘤細胞散播 預防手術造成的污染及腫瘤細胞散播 無論如何剃毛區域要夠大! 阻隔完整! 窗巾要大! OP Site, 窗巾區域固定法 不要捏壓腫瘤 Don t pinch or squeeze tumor! 先結紮血管, 並且不要太靠近腫塊 Ligate vessels first (V A), avoid too close to the margin 使用手術刀銳利切割 使用單股縫線 Monofilament sutures 小心沖洗的動作 Lavage carefully! (tumor cells are not bacteria! ) 關閉或重建時使用新的一組器械 手套及窗巾

15 切除組織之處理 General Guidelines for excised samples 病理切片並非供主人選擇的治療項目! 最好不要使用電刀或雷射 (tends to deform the cellular architecture) 不要以器械使樣本損壞或變形 with forceps, suction or other methods prior to fixation. 移除所有的皮釘或止血夾 Removed all stainless steel staples / hemoclips 切除組織之處理 General Guidelines for excised samples 標示邊界 Marking margins 線材 Suture materials 染劑 Ink / dye Alcian Blue India ink Commercial kits 同時送檢切除區四周一圈組織 術後 Postoperative and wound care 疼痛控制 內分泌 / 營養支持 傷口相關併發症 感染 血清腫 / 血腫 Seroma/hematoma (due to large dead space and possibly remaining tumor cells) 傷口癒合不良 Delay union / dehescience 肢體水腫 Wound care

16 Surgery alone 不清爽的邊界 Unclean margin: disease free interval (DFI) was days; median survival time (MST) was 270 days 清爽的邊界 (wide margin): DFI was 325 days; ST was >480 (576) days (Davison, 1997; Hershey, 2000) 極端切除 Radical excision: MST 901 days (still depends on original sizes) (Phelps HA et al, 2011) 94 手術合併輔助治療 Surgery with adjuvant treatments (Chemotherapy / irradiation/ immune therapy) 已經愈來愈常見 VAS Tumor likes a crab 存活率 of VAS: wide margin + irradiation> wide margin > marginal 手術後 7 to 10 days 等待傷口癒合再開始 chemotherapy and/or irradiation

17 Adjuvant radiotherapy (RT) Therapeutic: 3-6 weeks of therapy using daily doses of Gy fractions to a total dose of Gy (Ogilvie, 2001) Palliative: 3-5 times, 1 week interval, 8 Gy a time (Eckstein, 2009) Side effects: hair loss, skin color change, and altered hair color regrowth as well as moist or day desquamation (Ogilvie, 2001) Postoperative RT The disease free interval (DFI) and median survival time (MST) of the cases with unclean surgical margin combined with radiotherapy can be prolong to 300 and 720 days Wide margin excision combined with radiotherapy: DFI days; MST >1200 days (Eckstein, 2009) Chemotherapy Chemotherapy alone may be attempted in the palliative setting. Doxorubicin was the most effective chemotherapy of VAS. The DFI of the cases was longer than control. But no significant difference of MST Gene therapy One study evaluated the role of xenogeneic cells that secrete human interleukin-2 to treat VAS. The median DFI and OST of treated cases were longer than control (Quintin- Colonna, 1996) Immunomodulation Acemannan 101 Prognosis 與預後相關之因子備註參考文獻 原發腫塊位置腫塊位於肢端者, 截肢預後較佳 Hershey AE, 2000 手術切除範圍 大範圍切除預後較佳 Croin K, 1998 Hershey AE, 2000 手術合併放射線治療 合併放療預後較佳 Kobayashi T, 2002 Eckstein C, 2009 局部復發 / 轉移 局部復發 / 轉移者預後較差 Cohen M, 2001 Romanelli G, 2008 Phelps HA, 2011 未證實與預後相關備註參考文獻 原發腫塊大小 不同研究之結果不同, Cohen M, 2001 Romanelli G, 2008 手術及放療合併化學治療 首次切除或復發後切除 化療可能可延長無病時間, 但不影響存活時間 Bregazzi VS, 2001 Martano M, 2005 Hahn KA, 2007 兩者間無差異 Romanelli G, 2008 組織病理學分級 較低級數者預後不一定較佳 Nieto A, 2003 Romanelli G,

18 減容及緩解手術 Debulking / Cytoreductive/ palliative surgery VAS: will usually recur if > 3cm Indications 在輔助治療前減少腫瘤組織量 (cryosurgery or irradiation), aim to decrease the size of tumor. 減少巨大腫瘤所致之全身效應 緩解效應 : 提供較好的生活品質, 但不一定能延長壽命 Thank you, for your attention