Download Cervical cancer case presentation

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
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
2
4
6
Globocan 2002
8
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
0
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 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
tumor diameter>4 cm
40%
tumor diameter<4 cm
90%
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.
(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 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
•  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…
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
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), %
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
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