8 4 a Cervical Cancer

7/24/2019 8 4 a Cervical Cancer

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Cervical cancercase presentation

Uniwersytet Medyczny im.

K. Marcinkowskiego w Poznaniu2011

Radosaw Mdry, Janina Markowska


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Cervical cancer incidence (standarized

indices)

87,3

0 20 40 60 80 100

Israel

Bolivia

Zimbabwe

Haiti

8,3

55

52,1

4,6

Globocan 2002


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Cervical cancer incidence

(standarized indices for European countries)

0 2 4 6 8 10 12

Finland

Denmark

Sweden

Iceland

Norway

Austria

Netherlands

Latvia

Spain

UK8.3

7.6

9.5

6.6

108

9.8

8.5

7.7

10.5

4.3

Globocan 2002


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Cervical cancer Screening


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Age-specific incidence of cervical cancer 2003

15-44 years

45-54 years

55-64 years

>65 ears

0

10

20

30

40

50

60

70

world

developedregions

developingregions

9.5

42.9

51.8

41.9

11,9

22,4

23,826,3

9.0

53.665.0

53.8


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Cervical cancer stages

Staging is the process physicians use to assess the size andlocation of a patients cancer. Identifying the cancer stage is one

of the most important factors in selecting treatment options.

The FIGO (International Federation of Gynecology and

Obstetrics) system is used to stage cervical cancer.

The FIGO system involves assigning a numerical stage to a

patients cancer based on physical examination and other

diagnostic examinations, such as cystoscopy or proctoscopy.

The stage of a cancer describes its size and the extent to which it

has spread.

The staging system ranges from Stage I (early stage) through to

Stage IV (late stage).


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There is no stage 0 or cancer in situ

CIN3


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Stage IA:

This is the earliest form of Stage I cancer. Only a

small amount of cancer is visible upon

microscopic examination.

Stage IA1:

The area of invasion

< than 3 mm (approximately 1/8 inch) deep

< than 7 mm (approximately 1/3 inch) wide

Stage IA2:The area of invasion

between 3 mm and 5 mm (approximately 1/5

inch) deep

< than 7 mm (approximately 1/3 inch) wide.

Stage I

This stage describes cancer that has spread from the lining of the

cervix into the deeper connective tissue of the cervix. Stage I cancer isstill confined to the uterus.


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This stage includes cancers that can be

seen without a microscope. It alsoincludes cancers seen only with a

microscope that have spread deeper

than 5 mm (approximately 1/5 inch) into

connective tissue of the cervix or are

wider than 7 mm.

Stage IB1:

This is a stage IB cancer that is no larger

than 4 cm (approximately 1 and 3/5

inches).

Stage IB2:

This is a stage IB cancer that is larger

than 4 cm (approximately 1 and 3/5

inches).

Stage I


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Stage IIA:

This stage includes cancer that has

spread beyond the cervix to the upper

portion of the vagina.

However, the cancer does not involve

the lower third of the vagina.

FIGO 2009 II A1 and II A2 ( < 4 cm >)

Stage IIB:

This stage includes cancer that hasspread to the tissue next to the cervix (the

parametrial tissue).

This stage describes cancer that has spread beyond the cervix to

nearby area but is still inside the pelvic area.

Stage II


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Stage IIIA:


spread to the lower third of the

vagina but has not spread to the

pelvic wall.

Stage IIIB:

This stage includes cancer that

extends to the pelvic wall and/or

blocks urine flow to the bladder.

This stage describes cancer that has spread to the lower part of the

vagina or the pelvic wall. The cancer may be blocking the ureters.

Stage III


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Stage IVA:


spread to the bladder or rectum

organs close to the cervix.

Stage IVB:


spread to distant organs beyond

the pelvic area, such as the lungs.

This is the most advanced stage of cervical cancer. The cancer has

spread (metastasized) to other parts of the body.

Stage IV


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Prognostic factors

The established and generally recognized prognosticindices include:

stage of clinical advancement (size of the tumor and

depth of infiltration, involvement of parametria,vascular invasion)

histological type of the tumor grade of tumor differentiation condition of draining lymph nodes

extent of surgical procedure


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0 10 20 30 40 50 60 70 80 90 100

stage I

stage II

stage III

stage IV

Clinical staging five years survival

Stage of clinical advancement represents one of the most

significant prognostic factors

7%

30%

60%

80%


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Histological type five years survival

0 10 20 30 40 50 60 70 80 90 100

squamous cell ca

adenoca

squamous cell adenoca

50%

76%

84%

+


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Grading of tumor differentiation risk of

metastasis

0 10 20 30 40 50 60 70 80 90 100

G1

G2

G330%

21%

15%


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Treatment options

Surgery

External beam Radiotherapy (adjuvant or exclusive )

+/- Chemotherapy+/- Brachytherapy

Chemotherapy


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Treatment option


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Surgery


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Trachelectomy vs simply hysterectomy vs

radical hysterectomy


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Cervical cancer surgery


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Risk of lymph nods mets incresases with stage

(and size)

Stage %PLN (+) %PALN (+)

IB1 13,2-17,1 1,7

IB2 23,8-30,5 11,9

IIA 26,3-28,8 2,4-18,2

IIB 37,7-39 16,7-32,8

IIIA 48,3 33,3

IIIB 60,7 24,9-31,1

IVA 57,1 12,5-33


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Size of tumor and depth of infiltration

five years survival

Tumor diameter correlates with depth of invasion.

This is reflected by division of stage IB and IIA to IB1 /IIA1 with tumor diameter

below 4 cm and IB2/IIA2 with greater tumor diameter

0 10 20 30 40 50 60 70 80 90 100

tumor diameter4 cm 40%

90%


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Treatment option


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Treatment option


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Trachelectomy literature review

Treatment option


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Trachelectomy

Pregnancy can be achieved but

25% chance of miscarriage

30% + risk of premature labour

100% risk of Caesarean Section


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Treatment options

Surgery

External beam Radiotherapy (adjuvant or exclusive )

+/- Chemotherapy+/- Brachytherapy

Chemotherapy


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Strong consideration should be given to the incorporation

of concomitant cisplatin based chemotherapy in women

who require radiation therapy for treatment of cervical

cancer

1999 - Something changed...

The NCI Clinical Announcement


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Randomized Trials on CRT


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Five clinical Trials on concomitant CRT

STUDY FIGO stage Control Group Comparison Group

KEYS et al.

(GOG 123)IB2 Radiotherapy Radiotherapy +

Weekly Cisplatin

ROSE, BUNDY,WATKINS et al.

(GOG 120)

IIB-IVA Radiotherapy +

Hydroxyurea

Radiotherapy +

Weekly Cisplatin

OrRadiotherapy +

Cisplatin, 5-FU,

Hydroxyurea

MORRIS et al

(RTOG 9001)IB2-IVA Extended field

Radiotherapy

Radiotherapy +

Cisplatin and 5-FU

WHITNEY et al.

(GOG 85)

IIB-IVA Radiotherapy +

Hydroxyurea

Radiotherapy +

Cisplatin and 5-FU

PETERS et al.

(SWOG-8797)IB or IIA(selected

Postoperatively)

Radiotherapy Radiotherapy +

Cisplatin and 5-FU

SWOG 8797 t i l (Adj )


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SWOG -8797 trial (Adjuv)

The addition of concurrent cisplatin based CT to RT significantly

improves progression-free and overall survival for high-risk, early-

stage patients who undergo radical hysterectomy and pelvic

lymphadenectomy for carcinoma of the cervix. Peters JCO 2000

268

patients

p= 0,03 p= 0,07

PFS OS


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RTOG 9001 Trial (Exclusive)

The addition of chemotherapy with fluorouracil and cisplatin to

treatment with external-beam and intracavitary radiation significantly

improved survival among women with locally advanced cervical

cancer.Morris NEJM, 1999

430

patients

p= 0,04

OSp= < 0,01

PFS

Eifel JCO 2004


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GOG 123 trial (Neoadjuv)

Adding weekly infusions of cisplatin to pelvic radiotherapy followed

by hysterectomy significantly reduced the risk of disease recurrence

and death in women with bulky stage IB cervical cancers.

374

patients

Keys NEJM, 1999

p= 0,008

OS

p< 0,001

PFS

GOG 120 trial (Exclusive)

526


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Rose, P. G. JCO 2007

Overall survival by treatment and number

of patients at risk (for death) at 60 and 120months

GOG 120 trial (Exclusive)

Stage IIB

Stage III

OS

526

patients


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Green JA Survival and recurrence after concomitantchemotherapy and radiotherapy for cancer of the uterine cervix: a

systematic review and meta-analysis. Lancet 2001

Patients with advanced stage IB2IIA/B may

benefit more from chemoradiotherapy thanpatients with stage III and IVA,translating to a 5-year survival benefit of 10% forwomen with stage IBIIA, 7% for women with

stage IIB and 3% for women with stage IIIBIVA.

Non-platinum-based regimens for chemoradiationappear to be as efficient as platinum-basedchemotherapy. The most common regimen,however, is cisplatin monotherapy 40 mg/m2 on aweekly schedule.

Meta - analysis


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Synergy between RT and cytotoxic drugs

Direct effect of CHT on primary tumor and on distant

metastases

Activity on different cell populations

Rational of RT with concomitant CHT

Only CDDP ?


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Only CDDP ?


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What is the role of Chemotherapy?

In association with RT

Concomitant standard Neoadjuvant (NACT)

Adjuvant investigational


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Neoadjuvant chemotherapy:

a possible role

Tumor size reduction to facilitate local therapy

Inoperable tumors Radically resectable tumors

Increase of radiosensitivity and decrease of hypoxic cell

fraction

Action on micrometastases

Response to NACT can be considered as a prognostic

factor

Wh NACT i t d t d ?


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Why NACT is not so used today?

Meta - analysis did not support the administration of

NACT before RT alone

Meta-analysis suggested an advantage of NACT before

surgery, when compared with RT alone (but this control

arm is evidently inferior)

Radiotherapy was given only to a part of the population

analysed in comparison

No Phase III study to select the best drug to use in

Neoadjuvant setting

NACT is still considered investigational, new studies are

required

Gonzalez-Martin A. Gynecol Oncol. 2008


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EORTC 55995 trial is ongoing

Stage IB2-IIB

cervical cancer

NACTSurgery

CDDP total dose 225 mg/mq

Dose intensity at least of 25 mg/mq/week

For a maximum of 8 weeks

CRT

CDDP 40 mg/mq/week x 6 weeks+External beam RT 45-50 Gy

From 2002, planned accrual686 patients

Incusion criteria: age 18-75, stages IB2-IIB, PS


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What is the role of Chemotherapy?

In association with RT

Concomitant standard Neoadjuvant (NACT)

Adjuvant standard

Metastatic Disease


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Metastatic disease

Prognosis is poorfor patients with advanced cervicalcancer, who are no longer amenable for surgical

resection or radiotherapy 1 year survival is less than

20%

For several years cisplatin alone has been consideredthe most active drug in this setting

Single-agent cisplatin showed 20% to 30% ORR, 7

months of PFS; 7.1 months of OS.

A number of studies have been conducted to identifyother active agents to be used alone or in combination

with CDDP

Moore DH JCO 2004, Long HJ, JCO 2005


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Cisplatin Plus Paclitaxel Improves Response Rates and

Progression-Free Survival in Women With Stage IV B, Persistent,

or Recurrent SquamousCell Cervical Carcinoma Compared With

CisplatinAlone, PHASE III study

Phase 2 data showed an objective response rate (RR)

46% with paclitaxel/cisplatin vs 17% with cisplatin alone

Cisplatin + Paclitaxel vs Cisplatin Alone

Moore DH JCO 2004


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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 on a Q3W schedule

6 cycles totalN = 130

Patients with stageIVB, recurrent, or

persistent

squamous cell

cervical cancer

(N = 264*)

Quality of life (QoL) and tumormeasured after each cycle

*N = 264 for intent-to-treat analysis

* * Pacli taxel given as a 24-hour in fusion followed immediately by cisplatin.

Moore DH JCO 2004


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Clinical Outcomes Cisplatin

(n = 134)

Cisplatin/ Paclitaxel

(n = 130)

P Value

Complete response (CR), % 6 15

Partial response (PR), % 13 21

PR + CR (%) 19 36 .002

Median progression-free survival 2.8 4.8 < .001

Median overall survival 8.8 9.7 ns

Moore DH JCO 2004


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Cisplatin + Topotecan vs Cisplatin alone

Randomized phase III trial of cisplatin with or without

topotecan in carcinoma of the uterine cervix: a Gynecologic

Oncology Group

Long HJ JCO 2005

Topotecan/cisplatin and MVAC (methotrexate, vinblastine,

doxorubicin, cisplatin) both superior to cisplatin in phase 2 trials


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Patients

with

advanced

(stage IVB)recurrent or

persistent

cervical

carcinoma

(N = 356)

MVAC*

Methotrexate 30 mg/m2 Days 1, 15, and 22

+ Vinblastine 3 mg/m2 Days 2, 15, and 22

+ Doxorubicin 30 mg/m2 Day 2

+ Cisplatin 70 mg/m2 Day 2

every 4 weeks (n = 63)

Topotecan 0.75 mg/m2 Days 1-3

+ Cisplatin 50 mg/m2 Day 1

every 3 weeks

(n = 147)

Cisplatin 50 mg/m2 Day 1every 3 weeks

(n = 146)

Maximum of 6

cycles for

nonresponders

*MVAC arm closed early because of treatment-related deaths; trial continued as 2-arm study.Patients achieving partial response with acceptable toxicity could continuetreatment beyond 6 cycles.


Long HJ JCO 2005


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OS longer in topotecan/cisplatin vs cisplatin arm

9.4 vs 6.5 mos

HR, 0.76 (95% CI, 0.593-0.979); P= 0.017

PFS longer in topotecan/cisplatin vs cisplatin arm

4.6 vs 2.9 mos

HR, 0.76 (95% CI, 0.597-0.969); P= 0.014


Long HJ JCO 2005


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Cisplatin-naive vs cisplatin-experienced patients

Adding topotecan significantly extended PFS

PFS, 6.9 vs 3.2 mos; HR, 0.50 vs 0.87 (P= 0.03)

OS, 15.4 vs 8.8 mos; HR, 0.63 vs 0.78 (P

= 0.42)ORR significantly higher in topotecan/cisplatin arm

Outcome Topotecan + Cisplatin

(n = 135), n (%)

Cisplatin

(n = 139), n (%)

CR 14 (10) 4 (3)

PR 22 (16) 14 (10)

ORR (CR + PR) 36 (27) 18 (13)*

Stable disease 61 (45) 70 (50)

Progressive disease 38 (28) 51 (37)


Long HJ JCO 2005


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In patients with advanced cervical cancer,topotecan/cisplatin:

Prolonged OS vs cisplatin alone

Improved median survival by approximately 3 mos

Improved PFS

Increased ORR

This combination was active in both cisplatin-naive andcisplatin- treated patients

High incidence of grade 3/4 neutropenia w/topotecan

Manageable toxicity did not impact quality of life


Long HJ JCO 2005


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53 year old woman visited her gynecologist, because she had vaginal

bleeding after having sex since a year

after 2 deliveries

No gynecological examination performed since the 7 year!

An exophitical tumor of the cervix was diagnosed during the

examination

Biopsy and were performed: carcinoma planoepitheliale partim

keratodes G2

Case presentation


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Cervical cancer


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Clinical findings

gynecological

examination

exophitical tumor including almost the

whole cervix, but not the fornix of vagina

normal uterus and adnexa

per rectum

examination

right parametrium normal, not involved, left

abnormal

Urography normal

CT No evidnece of positive nodes

NMR Tumor in cervix 3 x 4,5 cm

Infiltration in both parametrium


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Stage ?

II B2


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What can we do ?

Trachelectomy

Simply hysterectomy

Radical hysterectomy

Radiochemotherapy


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Trachelectomy

Simply hysterectomy

Radical hysterectomy

Radiochemotherapy

8 4 a Cervical Cancer

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