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Cervical Cancer

The Society of Gynecologic Oncologist of the Philippines


(Foundation), Inc.
Unit 414 Manila Astral Tower
1330 Taft Avenue corner P. Faura Street
Ermita Manila
Telefax No: 526-47-87
Website: http://www.sgop.org

Officers 2008-2010
President
Vice-President
Secretary
Treasurer
PRO
Immediate Past President
Board of Directors

Rey H. Delos Reyes, MD, MHSA


Gil S. Gonzalez, MD
Ma. Cynthia F. Tan, MD
Ma. Lilibeth L. Sia Su, MD
Mary Christine F. Palma, MD
Efren J. Domingo,MD, PhD
Teresita B. Cardenas, MD
Benjamin D. Cuenca, MD
Aris Luke I. Dungo, MD
Cecilia L. Llave, MD, PHD
Jericho Thaddeus P. Luna, MD
Manuel S. Manabat, MD,
Concepcion D. Rayel, MD
Rafael S. Tomacruz, MD

Philippine Board of Gynecologic Oncology


Chairman
Members

Gil S. Gonzalez, MD
Cecilia L. Llave, MD, PhD
Virgilio R. Oblepias, MD

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25

II. Malignant Disease

Cervical Cancer
GENERAL GUIDELINES
1. Cervical cancer is diagnosed by biopsy1(Benedet 2006).
2. Cervical cancer is staged clinically (Appendix C.I)1
3. If clinically indicated, proctosigmoidoscopy and cystoscopy should be done to rule out invasion. Metastatic
work-ups include renal imaging studies (IVP), liver
function tests, chest x-ray, and skeletal survey1.
4. Special diagnostic imaging studies may be done to
guide treatment planning: ultrasound, magnetic resonance imaging (MRI), computed tomography scan (CT
scan), positron emission tomography scan (PET scan),
PET CT Scan and bone scintigraphy1. These imaging
studies will not be part of the staging
a. MRI is more accurate than CT scan in determining
the following2
i. Primary tumor volume
ii. Vaginal invasion
iii. Parametrial involvement
iv. Bladder and rectal involvement
b. PET CT scan is more accurate in determining
lymph node involvement3
c. KUB IVP and barium enema not routinely indicated
anymore as MRI and CT scan are more accurate2
d. Cystoscopy and protosigmoidoscopy should be
reserved for women in whom a normal bladder or
rectum cannot be confirmed on clinical or radiological assessment2
5. Concurrent chemotherapy and complete radiotherapy
(chemoradiation) is the standard of treatment.4-9
6. For patients who are unable to receive chemotherapy,
radiation treatment alone may be given10.
7. Adenocarcinomas have shown no significant difference in clinical behavior from squamous cell carcinomas9,10.
MANAGEMENT
I. Biopsy Proven Premalignant Lesions11(ASCCP 2006 Guidelines)
LESION

Cervical Cancer

TREATMENT

SATISFACTORY
COLPOSCOPY

UNSATISFACTORY
COLPOSCOPY


1. Preceded by
Diagnostic Excisional
CIN 1

ASCUS, ASC-H, Procedures:
LSIL: Follow up
LEEP/CONE11
every 6-12 months [Level 3a]
11,12(ALTS Follow up study 2003)
[Level 2b]

2. Preceded by HSIL,
AGC: Follow up
every 6 months
OR Diagnostic exci sional Procedure11,12
[Level 3b]

CIN 2,3 1. Cryotherapy11
[Level 1a]


2. Conization: Cold-
Knife Cone Biopsy
or LEEP/LLETZ11,13,14
[Level 1a]

Diagnostic Excisional
Procedures:
LEEP/CONE11,13,14
(Massad 2001/Dunn 2003)

[Level 2a]

STAGE
STATUS
TREATMENT


1. Desirous of pregnancy,
no lymphovascular space
invasion(LVSI)
a. Negative margins
observe1,15-19 (Benedetti Panici

2007 review)
[Level 1b]
b. Positive margins - repeat
cone biopsy1,15-19
[Level 1b]
Stage 0a Good
2. Not desirous of pregnancy
Stage I A 1a surgical a. Extrafascial hyste
risk rectomy (EH) with
or without bilateral sal-
pingo- oophorectomy
( BSO)1,15-19
[Level 1b]
b. Vaginal extrafascial
hysterectomy ( BSO)15
[Level 1b]
c. If positive for lympho vascular space invasion



(LVSI): modified radical
hysterectomy( BSO)
with bilateral pelvic
lymph node dissection
1,15,21(Benedetti Panici 2007 Review,

Koliopoulous 2007 review

[Level2b]


1. Negative margins observe1,15-19 (Benedetti Panici

2007 review)
[Level 1b]

2. Positive margins
Poor a. Repeat Cone/LEEP 1,15-19

surgical (Benedetti Panici 2007 review)

risk b. Intracavitary Radio therapy (Brachytherapy):
High Dose Rate (HDR)
or Low Dose Rate (LDR)
3. Positive LVSI pelvic
EBRT + brachytherapy
[Level 3c]

1. Desirous of pregnancy,
no LVSI
Radical trachelectomyc
and extra-peritoneal or
Laparoscopic pelvic
lymphadenectomy22-24,

Good
[Level 2b]

surgical
2. Not desirous of pregnancy


risk
Modified radical hyste rectomy (MRH), bilateral
pelvic lymph node dis section (BLND) BSO16,24
[Level 1b]
Stage IA2

Pelvic External Beam

Poor Radiotherapy (EBRT)b

surgical + Brachytherapy

risk [Complete RT] 21 (Koliopoulous 2007)
[Level2b]

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27

Cervical Cancer
Notes:
a. Stages 0, IA1 and IA2 are diagnosed by cone biopsy
(cold-knife or LEEP/LLETZ).1
b. Pelvic EBRT includes the upper half of the vagina.
c. Radical vaginal trachelectomy and laparoscopic
extraperitoneal pelvic lymphadenectomy23 inclusion
criteria:
1. Desire to preserve fertility
2. No clinical evidence of impaired fertility
3. FIGO Stage 1a2-1B1
4. Lesion size less than 2 cms
5. No evidence of pelvic lymph node metastasis
6. No LVSI
7. Informed consent
STAGE STATUS
TREATMENT


1. Radical hysterectomy
(RH), BLND Para aortic lymph node
sampling BSO25-26
[Level 1a]

2. Concurrent chemotherapya
and pelvic EBRT + Brachy
Stage therapy (Chemoradia IB1 , IIA Good tion)27,28 [Level 1a]
(tumor surgical
3. Radical Vaginal Hyste diameter risk rectomy BSO and extra
<4 cms.) peritoneal or laparoscopy
assisted pelvic lympha denectomyb 29,30[Level IC]

4. Radical trachelectomyc
and extra-peritoneal or
Laparoscopic pelvic
lymphadenectomy21-24,
[Level 2b]



Poor

surgical

risk

Concurrent chemotherapya
and pelvic EBRT +
Brachytherapy
(Chemoradiation)27,28
[Level 1a]

Notes:
a. Standard Chemotherapy drug to use for concurrent treatment with radiotherapy:
Cisplatin 40 mg/ m2 given weekly for 6 courses during
pelvic EBRT1,4-9 [Level 1a]
b. PGH Section of Gynecologic Oncology Eligibility
Criteria for Radical Vaginal Hysterectomy:
1. Selected Stage 1B1 IIA (low risk for parametrial or nodal metastasis, tumor size less than 2 cm, no evidence
of metastasis by imaging and metastatic work-up)
2. Pelvic organ prolapse
c. Radical vaginal trachelectomy and laparoscopic/
extraperitoneal pelvic lymphadenectomy23 inclusion criteria:
1. Desire to preserve fertility
2. No clinical evidence of impaired fertility
3. FIGO Stage 1a2-1B1
4. Lesion size less than 2 cms
5. No evidence of pelvic lymph node metastasis
6. No LVSI
7. Informed consent
d. May proceed with RHBSO + lymphadenectomy
even with the presence of resectable lymph node
metastasis with uninvolved parametria.31,32

28



STAGE

TREATMENT


1. Concurrent chemotherapya and
pelvic EBRT + Brachytherapy
(Chemoradiation)b 6,33-35
[Level 1b]

2. Neoadjuvant chemotherapy
(three rapidly delivered courses
of platinum-based chemotherapy),
followed by RHBLND BSO +

adjuvant postoperative radiation
or chemoradiation36,37[Level 1b].
Chemotherapeutic options
include:
a. Cisplatin-Paclitaxel
Stage IB 2 , II A b. Cisplatin Vinblastine
(tumor diameter Bleomycin (PVB)
>4 cms) c. Cisplatin Ifosfamide

3. Pelvic EBRT concurrent with
chemotherapya followed by

RHBSO with selective lympha denectomy (Level 2b)38 (Toral 2005)

4. Primary RHBSO and bilateral
pelvic lymphadenectomy, with
adjuvant chemoradiation1,39,40
(type of radiotherapy will be
dependent on the surgico-patho
logic factors) [Level 2B]

Notes
a. Standard chemotherapy drug to use for concurrent
treatment with radiotherapy:
Cisplatin 40 mg/ m2 given weekly for 6 courses during
pelvic EBRT1,4-9 [Level 1a]
b. Surgical intervention (EHBSO or Type II RHBSO)
is an option for the following cases:
1. After protracted chemoradiation (>8 weeks)38,41
(Level 2b)
2. Bulky residual disease (>2 cm) at the end of radiation therapy42,43
c. Pelvic EBRT (with no midline shield) concurrent with
chemotherapy followed by RHBSO with selective
lymphadenectomy is an option especially for areas
with no brachytherapy facilities (consensus-based)
d. Ongoing trial EORTC 55994 : Randomized phase
III study of neoadjuvant chemotherapy (3 courses
cisplatin based) followed by surgery vs. concomitant radiotherapy and chemotherapy in FIGO Ib2,
IIa >4 cm or IIb cervical cancer

STAGE

TREATMENT

Concurrent chemotherapya,b and


pelvic EBRT + Brachytherapy
Chemoradiation4-7,9,39,40 [Level 1a]



Stage IIB - IV



Paraaortic lymphadenopathy (size


>1.0 cm) by MRI, CT scan or PET
scan confirmed by FNA or extraperitoneal or laparoscopic lymphadenectomy: extended field radiotherapy (EFRT)+ brachytherapy
+ concurrent cisplatin chemo-

Cervical Cancer

therapy44-46 [Level 2A]

EBRT52[Level 1B]

If with evidence of distant metas-


tases on imaging and/or biopsy:
Systemic combination chemotherapy and individualized radiotherapy 1[Level 2A]

Concurrent chemotherapy, pelvic EBRT


and brachytherapy
[consensus-based]

Notes:
a. Standard chemotherapy drug to use for concurrent
treatment with radiotherapy:
Cisplatin 40 mg/ m2 given weekly for 6 courses during
pelvic EBRT1,4-8 [Level 1a]
b. Other chemotherapy regimens used for concurrent
treatment with radiotherapy (For locally advanced
cervical cancer)
1. Carboplatin 300 mg/m2 (AUC 3.9) every 3 weeks
or 60-90mg/m2 (AUC 2) weekly47,48
2. Cisplatin 40 mg/m2 and Paclitaxel 40 mg/m2 weekly
for 6 cycles49
c. Ongoing trial GOG 219:A Phase III, Randomized
Trial of Weekly Cisplatin and Radiation Versus
Cisplatin and Tirapazamine and Radiation in Stage
IB2, IIA, IIB, IIIB and IVA Cervical Carcinoma Limited to the Pelvis
FINAL HISTOPATHOLOGY REPORT OF CERVICAL
CANCER SPECIMENS:
1. Histologic type
2. Histologic grade
3. Lymphovascular space involvement (LVSI)
4. Parametria
5. Vaginal cuff to include distance from tumor to margin
6. Stromal invasion divided into thirds
7. Endomyometrial invasion
8. Lymph nodes, to include number and location,
and/or Perinodal fat involvement
9. Adnexa, if BSO performed
10. For MICA, vertical and horizontal invasion in mm
11. For CIN/CIS post-conization (cold-knife or LEEP/
LLETZ), status of margins and +/- LVSI
12. Mark a cone specimen at the 12 oclock position
13. No mention of stage of disease in histopathologic
reports
SURGICO-PATHOLOGIC PROGNOSTIC FACTORS
PROGNOSTIC
FACTORS
1. Tumor
size >2 cm**

ADJUVANT
TREATMENT
Concurrent chemotherapy and
pelvic EBRT50,51 [Level Ib: 4 cms]
Consensus based

2. Greater than Concurrent chemotherapy and


1/3 stromal pelvic EBRT30,50,52 Delgado1990, Sedlis 1999,
Rotman2006)
invasion
[Level IB]

3. Positive
Parametrium
lines of
resection

Concurrent chemotherapy and pelvic


EBRT52Delgado 1990
[Level 1B]

Concurrent chemotherapy and pelvic

Surgical
margins

Vaginal cuff
or <2 cm
tumor free
margin

4. Lymph node Pelvic


metastasis

Concurrent chemo-
therapy and pelvic
EBRT8,50,52-53 [Level 1B]

Note: If para-aortic
sampling not performed, may do EFRT
if MRI or CT Scan
confirms periaortic
lymphadenopathy.

Para-aortic Concurrent chemoand Common therapyandEFRT29,52-55


iliac
[Level 2A]

5. Lymphovascu- Concurrent chemotherapy and


cular space pelvic EBRT30,48,51,52 Delgado1990,

invasion (LVSI) Sedlis 1999, Rotman2006) [Level IB]
6. Endomyome- Concurrent chemotherapy and
trial invasion pelvic EBRT52[Level C]
7. Biopsy proven Systemic chemotherapy and Indivi abdominal
dualized radiotherapy52,53

metastasis
[Level 2A]
CLINICAL SITUATIONS
A. INCIDENTAL FINDING OF INVASIVE CANCER
AFTER SIMPLE HYSTERECTOMY
1. Pathologic review
2. Chest x-ray
3. CTScan, MRI or PET Scan
4. Liver function tests
5. Renal function tests
6. If tumor size is more than 4 cms: cystoscopy/proctosigmoidoscopy

Pathologic Review
Result

Treatment

Stage 1A1, no LVSI

Observation 1 [ Level 2A]

Stage 1A1 with LVSI,


Stage 1A2 and IB1
Negative margins,
negative imaging studies

Concurrent chemotherapy
and pelvic EBRT +
Brachytherapy Chemoradiation54 [Level 2A]

Complete parametrectomy
with upper vaginectomy
with pelvic lymphadenec-
tomy +/-paraaortic lymph
node sampling54 [Level 2A]

Stage 1A1 with LVSI,


Stage 1A2 and above
Positive margins, gross
residual disease, positive
imaging studies

Concurrent chemotherapy
and pelvic EBRT + Brachytherapy chemoradiation55
[Level 2A]
If paraaortic lymphadenopathy: give EFRT55 [Level 2A]

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29

Cervical Cancer
B. In Association with Pregnancy
MRI may be done to assess extent of disease 10

Age of
Gestation

Early Stage
(Stage I II A)

Late Stage
(Stage II B IV)


Early
Good surgical risk
Pregnancy RHBLND BSO10

up to
Chemoradiation10
20 weeks
Poor surgical risk

AOG
Chemoradiation10


May delay treatment

till after delivery1
20-28 weeks
Antepartal
Chemoradiation

AOG
chemotherapy

(Cisplatin based)

then CS1

Late
Good surgical risk
Pregnancy

After
CS RHBLND
28 weeks
BSO1,10

*CS followed by
Chemoradiation10

* Perform Poor surgical risk


Antepartal
Cesarean
CS followed by
chemotherapy
Section (CS)10 Chemoradiation56 (Cisplatin based )
at best time
then CS56

of fetal

survival

Notes:
1. There is no standard definition on what constitutes
significant treatment delay.1
2. The duration of the treatment delay should be influenced by clinical stage and histopathologic findings
of the tumor, gestational age at diagnosis, and the
parents desire regarding their unborn child. Close
clinical surveillance is mandatory.1
3. No long term studies have looked into giving neoadjuvant chemotherapy in an attempt to prevent disease
progression
4. Delivery should be performed not later than 34 weeks
of gestation.1
OTHER CLINICAL SITUATIONS
Ovarian
1. Age 45years old57
conservation [Level 2B]
during radical
2. Early stage disease
surgery in young (up to IIA)57,58 [Level 2B]
patients57
3. Squamous large cell histo logy57-58,61-64 [Level 2B]

4. Cervical stromal involve ment inner 1/357 [Level 2B]

5. No family history of ovarian
or breast cancer1,58

6. Tumor size 2 cm60,62

7. No lymph node metastasis
or LVSI60-64

8. Absence of extracervical/
corpus spread62,63

9. No gross abnormalities in
the ovaries62,63

10. No need for post operative radiation57,58,62,63

30

Non-metastatic
adnexal masses



Exploratory laparotomy
(EL), BSO and appropriate
surgical procedures as
indicated, before chemoradiation
Option: Laparoscopy

Primary cases
with urinary
obstruction

Urinary diversion and/or


stenting followed by primary
treatment10

Primary cases
with gut
obstruction

Medical or surgical decompression followed by


primary treatment

Hemato-/hydro-/
pyometra
(post RT)

Connective
tissue disease
(All stages
requiring RT)


Drainage by cervical
dilatation or EHBSO
Patients should be seen by the
Multidisciplinary Team, which
should ideally include a
rheumatologist.
Ideally, patients disease
should not be active at the
time of radiotherapy.

PERSISTENT OR RECURRENT DISEASE


PELVIC
With prior surgery, no
prior radiotherapy

Chemoradiation1,65
[Level 2A]

With prior radio-


therapy, central
disease with
tumor size 2 cm



Appropriate surgery (Type I


(Type I or II extended
hysterectomy) may be
performed1,66 [Level C] (if
adverse surgico-prognostic
factors are present, adjuvant
chemotherapy should be
instituted)

With prior radiotherapy, Platinum-based chemo central disease with


therapy or best support tumor size > 2 cm and ive care1,44
noncentral disease

With prior chemo-
Nonplatinum-based
radiation, central
chemotherapy or best
disease with tumor
supportive care1,44
size >2 cm and non central disease


EXTRAPELVIC OR PARAAORTIC
Multiple sites,
unresectable

Isolated site

Systemic chemotherapy or
best supportive care1,44,67
[Level 2A]
Tumor resection44[ Level 2A]
Tumor directed radiotherapy44
[Level 2A]
Systemic chemotherapy or
best supportive care 1,44,67
[Level 2A]

Cervical Cancer
Notes:
1. Chemotherapy may be given for palliative intent or
symptomatic care. Chemotherapeutic options include:
SINGLE AGENT1,44,68,69
a. Cisplatin [Level 1B] 50mg/m2 every 3weeks
b. Carboplatin [Level 1B]-50 mg/m2 every 3 weeks or
400mg/m2 every 3 weeks
c. Topotecan [Level 1B]-1.5mg/m2 days 1-5 every 4
weeks
d. Paclitaxel [Level 1B]- 170 mg/m2 for 24 hours every
3 weeks
COMBINATION CHEMOTHERAPY1,44,68,69
a. Cisplatin Topotecan [Level 1B]- GOG 179 Cis 50
mg/m2 day 1, Topo 0.75 mg/m2 days 1-3 every 3
weeks
b. Cisplatin Paclitaxel [Level 1B]- GOG 169 Cis 50 mg/m2
day 1, Pacli 135 mg/m2 24 hours 3 weeks
c. Cisplatin-Ifosfamide [Level 1B] GOG 110 Cis 50 mg/m2
day 1, Ifos: 5 gm/m2/24 hours every 3 weeks
d. Cisplatin Gemcitabine [Level 2b] Cis 70 mg/m2
day 1, Gemcitabine 1.25 mg/m2 day 1, 8 every 3
weeks
e. Cisplatin- Irinotecan [Level 2b] Cis 50mg/m2, CPT11 100mg/m2 every 3 weeks
f. Cisplatin Vinoralbine [Level 2b] Cis 75 mg/m2 Vin
30 mg/m2 every 4 weeks
g. Carboplatin-Paclitaxel [Level 2b] Carbo AUC 5-6
day pacli 155-175mg /m2 every 4 weeks
h. Topotecan-Paclitaxel [Level 2b] Pacli 175 mg/m2
day 1, topo 1 mg/m2 days 1-5 every 3 weeks
2. Combination regimens are preferred and are first line
therapy if Cisplatin was previously used as a radiosensitizer
3. Ongoing Trial GOG204-A Randomized Phase III Study
of Paclitaxel plus Cisplatin Versus Vinorelbine Plus
Cisplatin Versus Gemcitabine Plus Cisplatin Versus
Topotecan Plus Cisplatin in Stage IVB, Recurrent or
Persistent Carcinoma of the Cervix

HORMONAL REPLACEMENT THERAPY (HRT) AFTER


TREATMENT OF CERVICAL CANCER
Hormone therapy may be given to symptomatic women
who have been treated for cervical cancer.
1. HRT significantly reduced long term post radiation
rectal, bladder and vaginal complications71
2. There is no evidence that HRT increases risk of squamous cell carcinoma. For adenocarcinoma, a risk
of recurrence is noted in a descriptive study72.
REFERENCES
1. Benedet JL, Pecorelli, S, Hacker NF, Ngan HYS. Staging Classifications
and Clinical Practice Guidelines of Gynecologic Cancers by FIGO
Committee on Gynecologic Oncology and IGCS Guidelines Committee,
3rd edition, November 2006.
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4. Whitney CW, Sause W, Bundy BN, et al. Randomized comparison
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FOLLOW UP
1. Weekly while on concurrent chemotherapy and radiotherapy.
2. Two (2) weeks post-completion of brachytherapy.
3. After completion of treatment, recommended follow-up
is as follows:
a. Physical and pelvic exams every 3 months for the
first 2 years, every 6 months from years 3-5, then
yearly thereafter.70
b. Pap smear every three months for the first 2 years,
followed by pap smear every six months for the 3rd
5th year, then annual pap smear thereafter.
NOTE: Perform colposcopy with appropriately
guided biopsy and/or ECC, as warranted.
c. Chest x-ray annually or as indicated70.
d. An annual CT scan, MRI or PET scan for the first
3 years post-treatment is recommended, or when
warranted.
4. Use of a vaginal dilator is suggested after radiotherapy
for women who are sexually active70 Denton 2003 systematic review.

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Cervical Cancer
Available Drugs in the Philippines
Antineoplastics
Alkaylating Agents
Cisplatin
Docistin
Kemoplat
Nippon Kayaku Cisplatin
Platamine
Platinol
Pyrimidine analogs
(Pyrimidine antagonists)
Gemcitabine
Gemita
Gemzar
Other cytotoxic antibiotics
Bleomycin sulfate
Blenoxane
Mitotic Inhibitors
Vinca Alkaloids
Vinorelbine
Vinotel
Camptothecins
Topotecan HCl
Topotel
Taxanes
Paclitaxel
Biomedis Paclitaxel
Intaxel
Paclitaxin
Paxus
Sandoz Paclitaxel
Taxol
Irinotecan
Biomedis Irinotecan
Campto
Irican

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