子宮頸癌 Cervical Cancer 三軍總醫院 余慕賢
96 台灣女性 10 大癌症 ( 發生率排序 ) 乳癌 7,502 66.10 結腸癌 4,471 39.39 肺癌 3,161 27.85 肝癌 2,900 25.55 子宮頸癌 1,749 15.41 甲狀腺癌 1,407 12.40 胃癌 1,301 11.46 子宮體癌 1,165 10.26 皮膚癌 1,113 9.81 卵巢癌 1,047 9.23
87/98 台灣女性主要癌症死亡原因 肺癌 1708/2615 16.06/22.8 肝癌 1377/2292 12.95/20.0 直腸結腸癌 1227/1969 11.54/17.2 乳癌 995/1588 9.4/13.9 胃癌 812/825 7.6/7.2 子宮頸癌 1017/657 9.6/5.7 卵巢癌 273/435 2.6/3.8
Human Papillomavirus >200 types identified 30-40 anogenital 15-20 oncogenic types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 58 -HPV 16 (54%) and HPV 18 (13%) account for the majority of worldwide cervical cancers Nononcogenic types include: 6, 11, 40, 42, 43, 44, 54 -HPV 6 and 11 are most often associated with external genital warts
Risk Factors for HPV Infection Women Young age(peak age group 20-24 y/o) Lifetime number of sex partners Early age of first sexual intercourse Male partner sexual behavior Smoking Oral contraceptive use Uncircumcised male partners Men Young age(peak age group 25-29 y/o) Lifetime unmber of sex partners Being uncircumcised
Natural History of HPV Infection in Young Women Rotgers University, New Jersey Study The cumulative 24/36-month incidence: 34/43% The median duration of HPV infection: 8 months Only 9% remained infected by 24 months after the incident infection Probability of acquiring a subsequent infection with a different HPV type within 24 months of the initial infection: 70% Ho et al., 1998 (N Engl J Med 338:423-428) Ho et al., 2002 (J Infect Dis 186:737-742)
HPV Clearance In women 15-25 years of age, ~80% of HPV infections are transient Gradual development of cell-mediated immune response presumed mechanism In a study of 608 college women, 70% of new HPV infection cleared within 1 year and 91 % within 2 years Median duation of infection = 8 months Certain HPV types are more likely to persist (eg, HPV 16 and HPV 18)
HPV Persistence Persistent infection: Detection of same HPV type two or more times over several months to 1 year Widely accepted that persistence of high-risk types of HPV is crucial for development of cervical precancer and cancer Infection with multiple HPV types Immune suppression Currently, there are no antiviral available to treat the underlying HPV infection
HPV Disease Progression In a study of women(n=899) 13-22 years of age positive for HPV DNA 260(29%) were diagnosed with LSIL by cytology Probability of LSIL regression 61% at 12 months follow up 91% at 36 months follow up Probability of progression to HSIL = 3% Moscicki 2004
人類乳突病毒 ( HPV) 超過 200 型的 HPV,96 種確定會感染人類 HPV 可分為高危險性及低危險性兩大類型 性行為是 HPV 感染主要的傳染途徑 61% 於一年內清除 ; 91% 三年內清除 80% 的感染是短暫的 平均感染期間為 8 個月 HPV 16,18 較易持續感染
Normal LSIL HSIL Invasion CIN1 CIN2 CIN3 Cervical Intraepithelial Neoplasia Metastasis
人類乳突病毒與子宮頸癌 0 1 Year 0 5 Years 1 20 Years HPV 持續感染 子宮頸癌 CIN1 CIN2/3 子宮頸癌 HPV 感染清除 YU2009
篩檢 -1 篩檢 -2a 篩檢 -2b 首次抹片結果為難以判讀者, 於 6 個月內再次接受抹片檢查的比率 首次抹片結果為 4(ASCUS) 者, 於 6 個月內已追蹤的比率 首次抹片結果為 6,7(CIN 1) 者, 於 6 個月內已追蹤的比率 篩檢 -3a1 篩檢 -3a2 篩檢 -3b1 篩檢 3-b2 首次抹片檢查結果為 8-11(CIN2,3),16(ASC-HSIL),17(HSIL) 者, 於 2 個月內接受陰道鏡檢查的比率 首次抹片檢查結果為 8-11(CIN2,3),16(ASC-HSIL),17(HSIL) 者, 於 2 個月內接受切片檢查的比率 首次抹片檢查結果為 5(AGCUS),15AGC-N),18(AIS) 者, 於 2 個月內接受陰道鏡檢查的比率 首次抹片檢查結果為 5(AGCUS),15AGC-N),18(AIS) 者, 於 2 個月內接受切片檢查的比率 篩檢 -4a 首次抹片結果為 16(ASC-HSIL) 者, 於 2 個月內其組織病理檢查結果亦為 03,04, 05,07-10,12 的比率 篩檢 -4b 首次抹片結果為 8-11(CIN2,3) 者, 於 2 個月內其組織病理檢查結果亦為 03,04, 05,07-10,12 的比率 篩檢 -5 首次抹片結果為首次 8-13 及 5 者, 於 6 個月內於陰道鏡下實施切片的比率
子宮頸癌前病變 正 常 高危險病變 CIN2/3 低危險病變 CIN1
治療 -a 前驅病灶 -1 前驅病灶 -2 前驅病灶 -3 前驅病灶 -4 前驅病灶 -5 前驅病灶 -6 前驅病灶 -7 前驅病灶 -8 切片結果為 04,05,07-10,12 者, 於 2 個月內接受治療的比率 子宮頸手術標本之組織病理檢查結果為 HSIL 的個案, 在確定診斷時曾接受陰道鏡檢查的比率 診斷性子宮頸手術標本之組織病理檢查結果為 HSIL 之個案, 於 6 個月內已接受適當處置的比率 診斷性子宮頸手術標本之組織病理檢查結果為 HSIL 之個案, 於 1 年內未接受適當處置的比率 診斷性子宮頸手術標本之組織病理檢查結果為 HSIL 且接受治療之個案中, 接受子宮全切除手術所占的比率 診斷性子宮頸手術標本之組織病理檢查結果為 HSIL 之 50 歲 ( 含 ) 以上個案, 進行子宮頸錐狀手術時, 同時接受子宮內頸搔刮取樣 (ECC) 人數的比率 診斷性子宮頸手術標本之組織病理檢查結果為 HSIL 之個案, 以子宮頸錐狀手術為完整治療後,6 個月內抹片追蹤的比率 診斷性子宮頸手術標本之組織病理檢查結果為 HSIL 之個案, 以子宮全切除手術為完整治療後,6 個月內抹片追蹤的比率 診斷性子宮頸手術標本之組織病理檢查結果為 HSIL, 且接受子宮全切除手術之個案中, 術前曾接受子宮頸錐狀手術所占的比率
子宮頸癌疫苗預防癌前病變 0 1 Year 0 5 Years 1 20 Years HPV 持續感染 子宮頸癌 CIN1 CIN2/3 子宮頸癌 HPV 感染清除 YU2009
子宮頸癌疫苗 誘出體內抗體以保護身體免於病毒感染 能夠在接種者體內, 有效產生疫苗所涵蓋之 HPV 病毒型的抗體 對持續感染的預防效益可以達到 100% 對由 HPV 病毒型所引起的子宮頸癌前病變產生 100% 的預防效果 後續追蹤已經確定效益至少可維持 8 年以上 治療性疫苗還處於人體試驗及前臨床試驗中
Cervical cancer Early age at first intercourse Intercourse with multiple sexual partners HPV types: low risk(6, 11) vs high risk(16, 18, 45, 56 in 84% cervical cancer tissue; 31, 33, 35, 51, 52, 58 in 10% cervical cancer tissue)
子宮頸侵襲癌
Radical hysterectomy Bladder dysfunctions Sensory loss, storing and voiding dysfunctions, urinary incontinence, and detrusor instability Anorectal mobidity dysorders Constipation and related symptoms including dyschezia, tenesmus, and the sensation of incomplete evacuation Sexual dissatisfaction Reduced sexual interest, and diminished arousal
Surgical Endpoints 1900-2000 Removal of tumor and the area of possible extension (en bloc resection) Reduce the operative mortality >2000 Reduce mortality Balancing prognosis and morbidity Improve therapeutic efficacy The shortest survival is operative death
Reducing surgery-related pelvic nerve damage Less radical surgery by reducing the extent of the resected parametrial tissues. Preserving the nerves without reducing the radicality of surgery.
Radical Hysterectomy
RH after Neoadjuvant C/T
診療 -1 診療 -2 診療 -3 診療 -4 診療 -5 原發子宮頸癌病人以同步化放療 (CCRT) 為主要治療時, 病患有接受化療次數至少 2 次以上的比率 子宮頸癌病人接受體外放射治療, 於治療期間有再度確認放療位置的比率 子宮頸癌病人治療後 1 年內充分追蹤的比率 非第 IV B 期 (FIGO 期別 ) 之子宮頸癌病人 3 個月內死亡的比率 子宮頸鱗狀上皮細胞癌, 接受子宮切除手術 ( 包括任一型的子宮切除手術及次全子宮切除手術 ), 於 365 天內再接受骨盆放射線治療的比率
Treatment of Recurrent Cervical Cancer Extent of disease Site of recurrence Disease free interval Performance status Comorbidities
Salvage Treatment after Previous Surgery: RT or CCRT EBRT(external bean) Interstitial implant Brachytherapy CCRT in recurrent disease IORT(intraoperative) Monk BJ, et al Gyneco Oncol, 1994 Ijaz T, et al Gynecol Oncol 1998 Grigsby PW, et al IJGO 2004
Salvage Treatment after Definitive Radiation Therapy: Radical Surgery Radical hysterectomy Pelvic exenteration High acute and late complications Recurrent central pelvic disease Pelvic reconstruction Berek JS, et al Gynecol Oncol 2005 Marnitz S, et al Gynecol Oncol 2006
Chemotherapy in advanced & recurrent cervical cancer 5 randomized trials in 1980 and 1990s Platinum-based therapies most effective Cisplatin more active than carboplatin 3 ways to increase response without prolonging survival Increase platinum dose Add ifosfamide to cisplatin Add paclitaxel to cisplatin Single agent cisplatin 50 mg/m 2 became the best choice Bonomi F et al, JCO 1985 Thigpen JT et al, Gynecol Oncol 1989 McGure III WP et al, JCO 1989
GOG 169 Quality of life (QoL) and tumor measured after each cycle Patients with stage IVB, recurrent, or persistent squamous cell cervical cancer (N = 264*) Cisplatin (50 mg/m 2 ) Day 1 of a 21-day cycle 6 cycles total N = 134 Cisplatin (50 mg/m 2 )/Paclitaxel (135 mg/m 2 ) ** Day 1 of a 21-day cycle 6 cycles total N = 130 *280 patients enrolled; 16 ineligible (8 from each arm) N = 264 for intent-to-treat analysis **Paclitaxel given as a 24-hour infusion followed immediately by cisplatin. Moore DH, et al. J Clin Oncol. 2004;22:3113-3119.
GOG 179 293 patients Cervical cancer Stage IV Recurrent Persistent R A N D O M I Z E Cisplatin 50 mg/m2. Day 1, q21d Topotecan 0.75 mg/m2/d1-3 plus Cisplatin 50 mg/m2 d1 1º endpoint : Survival 2º endpoints: PFS,ORR, QOL, toxicity Long HJ III et al, JCO 2005
Adverse Events
GOG 204: Schema Patients with stage IVB, recurrent or persistent cancer not amenable to cure GOG PS 0,1 No CNS meta Measurable disease Planned: max 600 patients Between May 2003 and April 2007, 513 patients were enrolled R 1. Cisplatin/Paclitaxel was reference arm 2. Primary endpoint: Overall survival Regimen I Paclitaxel/Cisplatin paclitaxel 135 mg/m2 over 24 hrs + CIS 50 mg/m2 day 2 every 3 wks Regimen II Topotecan/Cisplatin topotecan 0.75 mg/m2 days 1, 2, and 3 + CIS 50 mg/m2 day 1,Q3W Regimen III Navelbine/Cisplatin vinorelbine 30 mg/m2 day 1 and 8 + CIS 50 mg/m2 day 1 every 3 wks Regimen IV Gemcitabine/Cisplatin gemcitabine 1,000mg/m2 day 1 and 8 + CIS 50 mg/m2 day 1 Q 3 wks
癌細胞餓死理論 Folkman 博士認為 無血液供應則癌不能生長 腫瘤細胞增長分裂至 0.1-0.2 公分左右會誘導血管的新生, 以提供其養分和氧氣 癌細胞的成長和轉移都和血管新生有密切的關係 腫瘤血管新生的程度 惡性度和臨床的預後息息相關 新生的血管會幫助癌細胞的轉移
腫瘤生長需要血管新生 ( 擴散 ) ( 佈滿 ; 灌注 ) TAF (Tumour angiogenic factor) 腫瘤血管生成因子 (Tumor angiogenesis factors,tafs) Modified from Folkman J. N Engl J Med 1971;285:1182 6
http://www.businessweek.com/magazine/content/03_40/b3852088.htm OCTOBER 6, 2003 SCIENCE & TECHNOLOGY
GOG 204-R: 2x2 Factorial Design GOG 204 Replacement Protocol Cervical cancer stage IVB, recurrent, persistent RANDOMIZATION Paclitaxel 175mg/m2 for 3 hrs day 1 Cisplatin 50mg/m2 day 2, q3wks x 6 Paclitaxel 175mg/m2 for 3 hrs day 1 Topotecan 0.75mg/m2 day 1-3, q3wks x 6 RANDOMIZATION RANDOMIZATION Bevacizumab Placebo Bevacizumab Placebo GOG; on-going study
Chemotherapy for advanced, recurrent, and metastatic cervical cancer. Moore DH. Journal of the National Comprehensive Cancer Network. 6(1):53-7, 2008 Jan. When cervical cancer is beyond curative treatment with surgery or radiation therapy, the prognosis is poor and palliation is the primary objective. Early prospective studies identified cisplatin as an active drug for advanced, metastatic, or recurrent cervical cancer, and results with other platinum analogs seemed inferior to cisplatin.
Chemotherapy for advanced, recurrent, and metastatic cervical cancer. (2) Moore DH. Journal of the National Comprehensive Cancer Network. 6(1):53-7, 2008 Jan. Several phase III trials have established the combination of cisplatin plus paclitaxel as standard therapy for comparison. Using pooled data from 3 Gynecologic Oncology Group (GOG) phase III studies, a predictive model was developed to better identify patients who are unlikely to respond to cisplatincontaining chemotherapy. The GOG is currently developing a phase III trial to investigate the impact of bevacizumab and a regimen containing topotecan instead of cisplatin in combination with paclitaxel chemotherapy This study has the potential to radically change standard care for cervical cancer chemotherapy.
存活分析 -2a 存活分析 -2b 存活分析 -2c 存活分析 -3a 存活分析 -3b 存活分析 -3c 存活分析 -4a 存活分析 -4b 存活分析 -4c 子宮頸癌病患 (FIGO)II 期,1 年存活率 子宮頸癌病患 (FIGO)II 期,3 年存活率 子宮頸癌病患 (FIGO)II 期,5 年存活率 子宮頸癌病患 (FIGO)III 期,1 年存活率 子宮頸癌病患 (FIGO)III 期,3 年存活率 子宮頸癌病患 (FIGO)III 期,5 年存活率 子宮頸癌病患 (FIGO)IV 期,1 年存活率 子宮頸癌病患 (FIGO)IV 期,3 年存活率 子宮頸癌病患 (FIGO)IV 期,5 年存活率
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