Cervical cancer

case presentation
Radosaw Mdry, Janina Markowska

Uniwersytet Medyczny im.

K. Marcinkowskiego w Poznaniu
2011

Cervical cancer incidence (standarized

indices)

8,3 87,3
Haiti

55
Zimbabwe

52,1
Bolivia

4,6
Israel

20

40

60

Globocan 2002

80

100

Cervical cancer incidence

(standarized indices for European countries)
8.3

UK

7.6

Spain

9.5

Latvia

6.6

Netherlands

108

Austria

9.8

Norway

8.5

Iceland

7.7

Sweden

10.5

Denmark
4.3

Finland
0

Globocan 2002

10

12

Cervical cancer Screening

Age-specific incidence of cervical cancer 2003

70
60

53.6

65.0
53.8

50
40
30

9.0

world

20

developed
regions

11,9

10

22,4
9.5

23,8

26,3

42.9

51.8
41.9

15-44 years
45-54 years
55-64 years

>65 years

developing
regions

Cervical cancer stages

Staging is the process physicians use to assess the size and
location 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).

There is no stage 0 or cancer in situ

CIN3

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 is
still confined to the uterus.
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 includes cancers that can be
seen without a microscope. It also
includes 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 II
This stage describes cancer that has spread beyond the cervix to
nearby area but is still inside the pelvic area.

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 has
spread to the tissue next to the cervix (the
parametrial tissue).

Stage III
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 IIIA:
This stage includes cancer that has
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.

Stage IV
This is the most advanced stage of cervical cancer. The cancer has
spread (metastasized) to other parts of the body.
Stage IVA:
This stage includes cancer that has
spread to the bladder or rectum
organs close to the cervix.

Stage IVB:
This stage includes cancer that has
spread to distant organs beyond
the pelvic area, such as the lungs.

Prognostic factors
The established and generally recognized prognostic
indices 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

Clinical staging five years survival

7%

stage IV

30%

stage III

60%

stage II

80%

stage I

10

20

30

40

50

60

70

80

90

100

Stage of clinical advancement represents one of the most

significant prognostic factors

Histological type five years survival

50%
+
squamous cell
adenoca

76%

adenoca

84%

squamous cell ca

10

20

30

40

50

60

70

80

90

100

Grading of tumor differentiation risk of

metastasis

G3

30%

G2

21%

G1

15%

10

20

30

40

50

60

70

80

90

100

Treatment options
Surgery
External beam Radiotherapy (adjuvant or exclusive )
+/- Chemotherapy
+/- Brachytherapy

Chemotherapy

Treatment option

Surgery

Trachelectomy vs simply hysterectomy vs

radical hysterectomy

Cervical cancer surgery

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

Size of tumor and depth of infiltration

five years survival

tumor diameter>4 cm

40%

tumor diameter<4 cm

90%

10

20

30

40

50

60

70

80

90

100

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

Treatment option

Treatment option

Treatment option
Trachelectomy literature review

Trachelectomy
Pregnancy can be achieved but
25% chance of miscarriage
30% + risk of premature labour
100% risk of Caesarean Section

Treatment options
Surgery
External beam Radiotherapy (adjuvant or exclusive )
+/- Chemotherapy
+/- Brachytherapy

Chemotherapy

1999 - Something changed...

The NCI Clinical Announcement

Strong consideration should be given to the incorporation

of concomitant cisplatin based chemotherapy in women

who require radiation therapy for treatment of cervical

cancer

Randomized Trials on CRT

Five clinical Trials on concomitant CRT

STUDY

FIGO stage

Control Group

Comparison Group

KEYS et al.
(GOG 123)

IB2

Radiotherapy

Radiotherapy +
Weekly Cisplatin

IIB-IVA

Radiotherapy +
Hydroxyurea

Radiotherapy +
Weekly Cisplatin
Or
Radiotherapy +
Cisplatin, 5-FU,
Hydroxyurea

IB2-IVA

Extended field
Radiotherapy

Radiotherapy +
Cisplatin and 5-FU

IIB-IVA

Radiotherapy +
Hydroxyurea

Radiotherapy +
Cisplatin and 5-FU

IB or IIA(selected
Postoperatively)

Radiotherapy

Radiotherapy +
Cisplatin and 5-FU

ROSE, BUNDY,
WATKINS et al.
(GOG 120)

MORRIS et al
(RTOG 9001)
WHITNEY et al.
(GOG 85)
PETERS et al.
(SWOG-8797)

268
patients

SWOG -8797 trial (Adjuv)

PFS

p= 0,03

OS

p= 0,07

The addition of concurrent cisplatin based CT to RT significantly

improves progression-free and overall survival for high-risk, earlystage patients who undergo radical hysterectomy and pelvic
lymphadenectomy for carcinoma of the cervix.
Peters JCO 2000

430
patients

RTOG 9001 Trial (Exclusive)

PFS

p= 0,04
p= < 0,01
OS

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
Eifel JCO 2004

374
patients

GOG 123 trial (Neoadjuv)

PFS

p< 0,001

p= 0,008

OS

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.
Keys NEJM, 1999

526
patients

GOG 120 trial (Exclusive)

OS

Stage IIB

Stage III

Overall survival by treatment and number

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

Rose, P. G. JCO 2007

Meta - analysis
Patients with advanced stage IB2IIA/B may
benefit more from chemoradiotherapy than
patients with stage III and IVA,
translating to a 5-year survival benefit of 10% for
women with stage IBIIA, 7% for women with
stage IIB and 3% for women with stage IIIBIVA.
Non-platinum-based regimens for chemoradiation
appear to be as efficient as platinum-based
chemotherapy. The most common regimen,
however, is cisplatin monotherapy 40 mg/m2 on a
weekly schedule.
Green JA Survival and recurrence after concomitant
chemotherapy and radiotherapy for cancer of the uterine cervix: a
systematic review and meta-analysis. Lancet 2001

Rational of RT with concomitant CHT

Synergy between RT and cytotoxic drugs
Direct effect of CHT on primary tumor and on distant
metastases

Activity on different cell populations

Only CDDP ?

What is the role of Chemotherapy?

In association with RT
Concomitant
Neoadjuvant (NACT)
Adjuvant

standard
investigational

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

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

EORTC 55995 trial is ongoing

NACTSurgery
CDDP total dose 225 mg/mq
Dose intensity at least of 25 mg/mq/week
For a maximum of 8 weeks
Stage IB2-IIB
cervical cancer
From 2002, planned accrual
686 patients

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

Incusion criteria: age 18-75, stages IB2-IIB, PS<2

Waiting for the results

What is the role of Chemotherapy?

In association with RT
Concomitant
Neoadjuvant (NACT)
Adjuvant

Metastatic Disease

standard
standard

Metastatic disease
Prognosis is poor for patients with advanced cervical
cancer, who are no longer amenable for surgical
resection or radiotherapy 1 year survival is less than
20%
For several years cisplatin alone has been considered
the 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 identify
other active agents to be used alone or in combination
with CDDP

Moore DH JCO 2004, Long HJ, JCO 2005

Cisplatin + Paclitaxel vs Cisplatin Alone

Cisplatin Plus Paclitaxel Improves Response Rates and
Progression-Free Survival in Women With Stage IV B, Persistent,
or Recurrent SquamousCell Cervical Carcinoma Compared With
Cisplatin Alone, PHASE III study

Phase 2 data showed an objective response rate (RR)

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

Moore DH JCO 2004

Cisplatin + Paclitaxel vs Cisplatin Alone

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/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 total
N = 130

*N = 264 for intent-to-treat analysis

**Paclitaxel given as a 24-hour infusion followed immediately by cisplatin.
Moore DH JCO 2004

Cisplatin + Paclitaxel vs Cisplatin Alone

Clinical Outcomes

Cisplatin
(n = 134)

Cisplatin/ Paclitaxel
(n = 130)

P Value

Complete response (CR), %

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

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

Topotecan/cisplatin and MVAC (methotrexate, vinblastine,

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

Long HJ JCO 2005

Cisplatin + Topotecan vs Cisplatin alone

Patients
with
advanced
(stage IVB)
recurrent or
persistent
cervical
carcinoma
(N = 356)

Topotecan 0.75 mg/m2 Days 1-3

+ Cisplatin 50 mg/m2 Day 1
every 3 weeks
(n = 147)

Cisplatin 50 mg/m2 Day 1

every 3 weeks
(n = 146)

Maximum of 6
cycles for
nonresponders

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)

*MVAC arm closed early because of treatment-related deaths; trial continued as 2-arm study.
Patients achieving partial response with acceptable toxicity could continue
treatment beyond 6 cycles.
Long HJ JCO 2005

Cisplatin + Topotecan vs Cisplatin alone

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

Cisplatin + Topotecan vs Cisplatin alone

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

Cisplatin + Topotecan vs Cisplatin alone

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 and
cisplatin- treated patients
High incidence of grade 3/4 neutropenia w/topotecan
Manageable toxicity did not impact quality of life
Long HJ JCO 2005

Case presentation
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

Cervical cancer

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

Stage ?
II B2

What can we do ?

Trachelectomy
Simply hysterectomy

Radical hysterectomy
Radiochemotherapy

Trachelectomy
Simply hysterectomy

Radical hysterectomy
Radiochemotherapy