Cervical cancer

case presentation
Radosław Mądry, 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

0 20 40 60 80 100

Globocan 2002
 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 2 4 6 8 10 12

Globocan 2002
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
11,9
regions
10 22,4

9.5 23,8
developing
42.9
26,3
regions
0
51.8
41.9
15-44 years
45-54 years
55-64 years
>65 years
 Cervical cancer stages

Staging is the process physicians use to assess the size and

location of a patient’s 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
patient’s 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

0 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

0 10 20 30 40 50 60 70 80 90 100
Grading of tumor differentiation – risk of
metastasis

G3 30%

G2 21%

G1 15%

0 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

40%
tumor diameter>4 cm

90%
tumor diameter<4 cm

0 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. IB2 Radiotherapy Radiotherapy +

(GOG 123) Weekly Cisplatin
IIB-IVA Radiotherapy + Radiotherapy +
Hydroxyurea Weekly Cisplatin
ROSE, BUNDY, Or
WATKINS et al.
Radiotherapy +
(GOG 120)
Cisplatin, 5-FU,
Hydroxyurea
MORRIS et al IB2-IVA Extended field Radiotherapy +
(RTOG 9001) Radiotherapy Cisplatin and 5-FU
IIB-IVA Radiotherapy + Radiotherapy +
WHITNEY et al. Hydroxyurea Cisplatin and 5-FU
(GOG 85)

PETERS et al. IB or IIA(selected Radiotherapy Radiotherapy +

(SWOG-8797) Postoperatively) Cisplatin and 5-FU
 268 SWOG -8797 trial (Adjuv)
patients

PFS OS

p= 0,03 p= 0,07

• “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
 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 GOG 120 trial (Exclusive)
patients 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 IB2–IIA/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 IB–IIA, 7% for women with
stage IIB and 3% for women with stage IIIB–IVA.

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 standard
•  Neoadjuvant (NACT)
•  Adjuvant 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…

NACTSurgery
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 CRT

686 patients
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 standard
•  Neoadjuvant (NACT)
•  Adjuvant standard

• Metastatic Disease
 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

Cisplatin (50 mg/m2)

Day 1 of a 21-day cycle
Patients with stage 6 cycles total
IVB, recurrent, or N = 134
persistent
squamous cell Cisplatin (50 mg/m2)/Paclitaxel (135 mg/m2) **
cervical cancer Day 1 on a Q3W schedule
(N = 264*) 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 Cisplatin/ Paclitaxel P Value

(n = 134) (n = 130)
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

 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

Topotecan 0.75 mg/m2 Days 1-3

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

advanced
(stage IVB) Cisplatin 50 mg/m2 Day 1
Maximum of 6
recurrent or every 3 weeks
cycles for
(n = 146)
persistent nonresponders†
cervical
MVAC*
carcinoma Methotrexate 30 mg/m2 Days 1, 15, and 22
(N = 356) + 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 Cisplatin
(n = 135), n (%) (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 exophitical tumor including almost the

examination whole cervix, but not the fornix of vagina
normal uterus and adnexa
per rectum right parametrium normal, not involved, left
examination 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