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 majorityof 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 Infectionin 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 transientGradual 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 regression61% 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

Cervical Intraepithelial Neoplasia

Normal LSIL HSIL Invasion

Metastasis

CIN1 CIN2 CIN3

0–1 Year 0–5 Years 1–20 Years

子宮頸癌

HPV 感染清除YU2009

持續感染

人類乳突病毒與子宮頸癌

CIN1

CIN2/3

HPV

子宮頸癌

篩檢-1 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。

篩檢-2a 首次抹片結果為4(ASCUS)者，於6個月內已追蹤的比率。

篩檢-2b 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 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。

篩檢-3a2 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。

篩檢-3b1 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。

篩檢3-b2 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

低危險病變CIN1

高危險病變CIN2/3

治療-a 切片結果為04，05，07-10，12者，於2個月內接受治療的比率。

前驅病灶-1 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。

前驅病灶-2 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。

前驅病灶-3 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。

前驅病灶-4 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。

前驅病灶-5 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。

前驅病灶-6 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。

前驅病灶-7 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。

前驅病灶-8 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。

0–1 Year 0–5 Years 1–20 Years

子宮頸癌

HPV 感染清除YU2009

持續感染

子宮頸癌疫苗預防癌前病變

CIN1

CIN2/3

HPV

子宮頸癌

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 dissatisfactionReduced sexual interest, and diminished arousal

Surgical Endpoints1900-2000

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 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。

診療-2 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。

診療-3 子宮頸癌病人治療後1年內充分追蹤的比率。

診療-4 非第 IV B期（FIGO期別）之子宮頸癌病人3個月內死亡的比率。

診療-5 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

EBRT(external bean)

Interstitial implant

Brachytherapy

CCRT in recurrent disease

IORT(intraoperative)

Salvage Treatment after Previous

Surgery: RT or CCRT

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

Bonomi F et al, JCO 1985

Thigpen JT et al, Gynecol Oncol 1989

McGure III WP et al, JCO 1989

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/m2 became the best choice

GOG 169

Cisplatin (50 mg/m2)

Day 1 of a 21-day cycle

6 cycles total

N = 134

Cisplatin (50 mg/m2)/Paclitaxel (135 mg/m2) **

Day 1 of a 21-day cycle

6 cycles total

N = 130

Patients with stage IVB,

recurrent, or persistent

squamous cell cervical

cancer

(N = 264*)

Quality of life (QoL) and tumor

measured after each cycle

*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.

293 patients

Cervical cancer

Stage IV

Recurrent

Persistent

R

A

N

D

O

M

I

Z

E

GOG 179

•1º endpoint : Survival

•2º endpoints: PFS,ORR, QOL, toxicity

Cisplatin 50 mg/m2. Day 1, q21d

Topotecan 0.75 mg/m2/d1-3 plus

Cisplatin 50 mg/m2 d1

Long HJ III et al, JCO 2005

Adverse Events

GOG 204: Schema

Regimen II

Topotecan/Cisplatintopotecan 0.75 mg/m2 days 1, 2,

and 3 + CIS 50 mg/m2 day 1,Q3W

Regimen III

Navelbine/Cisplatinvinorelbine 30 mg/m2 day 1 and 8 +

CIS 50 mg/m2 day 1 every 3 wks

Regimen I

Paclitaxel/Cisplatinpaclitaxel 135 mg/m2 over 24 hrs +

CIS 50 mg/m2 day 2 every 3 wks

Regimen IV

Gemcitabine/Cisplatingemcitabine 1,000mg/m2 day 1 and

8 + CIS 50 mg/m2 day 1 Q 3 wks

R

• 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

1. Cisplatin/Paclitaxel was reference arm

2. Primary endpoint: Overall survival

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

Modified from Folkman J. N Engl J Med 1971;285:11826

TAF(Tumour

angiogenic factor)

(擴散)

(佈滿;灌注)

腫瘤血管生成因子（Tumor angiogenesis factors,TAFs）

http://www.businessweek.com/magazine/content/03_40/b3852088.htm

OCTOBER 6, 2003SCIENCE & TECHNOLOGY

GOG 204-R: 2x2 Factorial Design

Cervical cancer stage IVB, recurrent, persistent

RA

ND

OM

IZA

TIO

N

• 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

RA

ND

OM

IZA

TIO

NR

AN

DO

MIZ

AT

ION

Bevacizumab

Bevacizumab

Placebo

Placebo

GOG; on-going study

GOG 204 Replacement Protocol

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 cisplatin-

containing 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 子宮頸癌病患(FIGO)II期，1年存活率。

存活分析-2b 子宮頸癌病患(FIGO)II期，3年存活率。

存活分析-2c 子宮頸癌病患(FIGO)II期，5年存活率。

存活分析-3a 子宮頸癌病患(FIGO)III 期，1年存活率。

存活分析-3b 子宮頸癌病患(FIGO)III 期，3年存活率。

存活分析-3c 子宮頸癌病患(FIGO)III 期，5年存活率。

存活分析-4a 子宮頸癌病患(FIGO)IV期，1年存活率。

存活分析-4b 子宮頸癌病患(FIGO)IV期，3年存活率。

存活分析-4c 子宮頸癌病患(FIGO)IV期，5年存活率。

敬 請 指 教

謝 謝 聆 聽