Management of carcinoma cervix

Management of Carcinoma
Cervix
Dr. Varshu Goel
Second Year Post-Graduate Resident
Department of Radiation Oncology
Maulana Azad Medical College, Delhi

FIGO 2018 Staging
2
FIGO 2018
FIGO
stage
Definition
I Cervical carcinoma confined to uterus (extension to corpus should
be disregarded)
IA Invasive carcinoma diagnosed only by microscopy, with maximum
depth of invasion < 5 mm
IA1 Stromal invasion < 3.0 mm in depth (measured from the base of
the epithelium)
IA2 Stromal invasion  3.0 mm and < 5.0 mm in depth
IB Clinically visible lesion confined to cervix or microscopic lesion
with deepest invasion  5.0 mm (greater than Stage IA)
IB1 Invasive carcinoma  5.0 mm in depth of stromal invasion and <
2.0 cm in greatest dimension
IB2 Invasive carcinoma  2.0 cm and < 4.0 cm in greatest dimension
IB3 Invasive carcinoma  4.0 cm in greatest dimension

3
FIGO
stage
Definition
II Cervical carcinoma invades beyond uterus, but has not extended
onto the lower third of vagina or to the pelvic wall
IIA Involvement limited to the upper two-thirds of vagina without
parametrial involvement
IIA1 Invasive carcinoma < 4.0 cm in greatest dimension
IIA2 Invasive carcinoma  4.0 cm in greatest dimension
IIB Tumor with parametrial involvement but not to the pelvic wall
III The carcinoma involves the lower third of the vagina and/or
extends to the pelvic wall and/or causes hydronephrosis or
nonfunctioning kidney and/or involves pelvic and/or para-aortic
lymph nodes
IIIA Tumor involves lower third of vagina, no extension to pelvic wall
FIGO 2018 Staging
FIGO 2018

4
FIGO
stage
Definition
IIIB Tumor extends to pelvic sidewall and/or causes hydronephrosis or
nonfunctioning kidney
IIIC Involvement of pelvic and/or para-aortic lymph nodes,
irrespective of tumor size and extent
IIIC1 Pelvic lymph node metastasis only
IIIC2 Para-aortic lymph node metastasis
IV The carcinoma has extended beyond the true pelvis or has
involved (biopsy proven) the mucosa of the bladder or rectum
IVA Spread to adjacent organs
IVB Spread to distant organs
FIGO 2018 Staging
FIGO 2018

• Direct Invasion
• Lymphatic spread
• Blood-borne metastasis
Corpus 10-30% Urinary Bladder
Cervical Epithelium Cervical Stroma Parametrium
Vagina Rectum
Spreadof tumor
LN Involvement (%) Pelvic Stage Para-Aortic
0.5 IA1 0
5 IA2 < 1
16 IB 2.0
30 II 15
44 III 30
50 IV 40

Preinvasive disease
FIGO
stage
Management
Preinvasiv
e
Conization or loop electrosurgical excisional procedure (LEEP) or laser
or cryotherapy ablation or simple hysterectomy
Handbook of Evidence Based Radiation Oncology, 3rd edition

PreinvasiveDisease
Shaw’s Textbook of Gynecology, 16th edition and DC Dutta’s Textbook of Gynecology, 6th edition

8
Shaw’s Textbook of
Gynecology, 16th
edition

9
Shaw’s Textbook of Gynecology, 16th edition

• CIN1-2 has a spontaneous regression rate in 1 to 3 years of >50%
and therefore observation may be an appropriate course
• Patients with no visible lesion undergo frequent serial exams
• Cold knife conization (CKC) may be used for diagnostic and
therapeutic intent
• Loop electrosurgical excision procedure (LEEP) has become
popular, although bleeding and stenosis may occur; pregnancy
outcomes may be better with LEEP than with CKC
PreinvasiveDisease
Perez & Brady's Principles and Practice of Radiation Oncology, 7th edition

• Persistent high-grade CIS = TAH with or without a small portion of
the upper vagina removed.
• To preserve fertility : therapeutic conization, laser therapy, or
cryotherapy.
• If surgery contraindicated or patient refuses it: intracavitary
brachytherapy alone
Carcinomain situ

• Total abdominal or modified radical hysterectomy with pelvic
lymphadenectomy (or in some cases with simple conization or
radical trachelectomy)
• Preserve fertility : Vaginal trachelectomy (removal of the cervix)
and laparoscopic lymphadenectomy
• Inoperable patients may be treated with intracavitary radioactive
sources alone : LDR 65–75 Gy or HDR 7 Gy/# x 5–6 #.
• If HR pathologic features, treat as IB
StageIA
13

14

Stage IB1, IB2, IIA1
FIGO
stage
Management
IB1, IB2,
IIA1
• Radical hysterectomy with bilateral pelvic LN dissection OR
• Definitive RT: External beam radiation therapy (EBRT) to WP (45 Gy)
and brachy (HDR 6 Gy/# x 5 #, 7 Gy/# x 4 # or LDR 15–20 Gy/# x 2 #)

17
Lancet 1997
343 patients with stage Ib and IIa cervical carcinoma 1986-91
172 : surgery (class III radical abdominal
hysterectomy)
171 : radical RT (XRT+BT)
Total Point A dose 70-90 Gy
adjuvant RT for surgical stage  pT2b, < 3 mm
of safe cervical stroma, cut-through, or
positive nodes
5-year overall and DFS were identical in surgery and RT groups (83%
and 74%, respectively, for both groups)
17

• Surgery vs RT :
• Outcome between radiation alone versus surgery is comparable
StageIB1, IB2 < 4 cm or IIA1
18

• Post op RT or CTRT after radical hysterectomy:
StageIB1, IB2 or IIA1
Peters et al.
Any one of these factors :
• microscopic involvement
of the parametrium
• positive pelvic lymph
nodes
• positive surgical margins
Sedlis et al.
2 or more of these factors:
• LVSI involvement
• Deep stromal invasion
(middle or deep third)
• Size > 4 cm
19

20
277 patients with stage IB after radical hysterectomy and pelvic
lymphadenectomy with negative LNs
137 patients : pelvic RT
46 Gy/23# to 50.4 Gy/28#,
no brachy
140 patients : no further
treatment
46% reduction in risk of recurrence favoring RT arm
GOG
92

22
277 patients with stage IB after radical hysterectomy and pelvic
lymphadenectomy with negative LNs but with 2 or more of the
following features: more than one third (deep) stromal invasion,
capillary lymphatic space involvement, and tumor diameter of 4
cm or more
137 : pelvic RT 140 : no further treatment
RT is particularly beneficial in adenosquamous or adenocarcinoma: 9%
recurrence with RT versus 44% recurrence without RT 22

23
243 patients with clinical stage IA2, IB, and IIA carcinoma of the
cervix, initially treated with radical hysterectomy and pelvic
lymphadenectomy, and who had positive pelvic LNs and/or
positive margins and/or microscopic involvement of the
parametrium
116 patients : pelvic RT
49.3 Gy/29#, no brachy
127 patients : same pelvic RT with
bolus Cisplatin 70 mg/m2 and 5FU
1000 mg/m2/d as 96 hour infusion q
3wk x 4
SWOG
8797

25
Overall survival at 4 years was 71% with RT and 81% with RT and chemo
(Only 60% of patients received all 4 chemotherapy cycles)

26
smaller absolute benefit when only one node is positive or when the
tumor size is < 2 cm

• Post op EBRT dose :
• metastatic pelvic lymph nodes = 45 Gy to the whole pelvis
delivered with a four-field technique with concurrent weekly
cisplatin
• Gross residual disease = dose escalation to 54 to 65 Gy, depending
on small-bowel dose limits (D5cc < 55 Gy)
• Common iliac or para-aortic node metastases = 45 Gy to the entire
para-aortic region
• Gross residual nodal disease = nodal boost up to 65 Gy with IMRT

• Post op Brachytherapy dose : Based on the ABS guidelines,
vaginal cuff boost should be considered in patients with
• less-than-radical hysterectomy
• close or positive margins
• large or deeply invasive tumors
• parametrial or vaginal involvement
• extensive lymphovascular invasion

Stage IB3, IIA2 to IVA
FIGO
stage
Management
IB3, IIA2 • Concurrent chemo-RT with cisplatin. WP RT (45 Gy).
• Brachy = HDR 6 Gy/# x 5 #, 7 Gy/# x 4# or LDR 15–20 Gy/# x 2#
IIB • Concurrent chemo-RT with cisplatin. WP RT (45, nodal boost 50–50.4
Gy).
• Brachy = HDR 6 Gy/# x 5 #, 7 Gy/# x 4# or LDR 15–20 Gy/# x 2 #
IIIA • Concurrent chemo-RT with cisplatin. RT to WP, vagina, and inguinal
LN (45, nodal boost 50–50.4 Gy).
• Brachy = HDR 6 Gy/# x 5 #, 7 Gy/# x 4 # or LDR 17–20 Gy/# x 2 #
IIIB, IVA • Concurrent chemo-RT with cisplatin. WP RT (45, nodal boost 50–60
Gy).
• Brachy = HDR 6 Gy/# x 5#, 7 Gy/# 4 # or LDR 20 Gy/# x 2 #.
• If para-aortic LN+, add paraaortic LN IMRT (45–60 Gy)

• NCI Alert : In 1999, the National Cancer Institute (NCI) issued an
alert recommending that concomitant (cisplatin-based)
chemoradiotherapy should be considered instead of radiotherapy
alone in women with cervical cancer
• Concurrent chemoradiation : 12% absolute survival benefit
StageIB3, IIA2 to IVA
Gunderson Clinical Radiation Oncology, 4th edition
30

31
368 patients with stage IIB, III, or IVA (1986-1990), negative LN
177 patients : standard whole pelvic RT
with concurrent 5-FU infusion and bolus
Cisplatin
stage IIB: 40.8/1.7 Gy/d;
stage III–IVA: 51 Gy/1.7 Gy/d.
40 Gy (Point A) LDR BT,
total Point A: 80–81 Gy; parametrial
boost to 55–60 Gy
P 50 mg/m2, days 1 , 21;
F 100 mg/m2/day x 4 days
191 patients : same RT plus
oral HU 80 mg/kg 2 x per
week
GOG
85

32
significant changes in 5-year PFS 57% with PF versus 47%
OS 62% with PF versus 50%
less hematologic toxicity with PF
no change in 3-year late complication rate
Conclusion: P-based regimen superior to HU
SWOG
8695

33
526 patients : Randomized weekly P versus P F HU versus HU (1992–
1997)
Eligibility: IIB–IVA, negative LN by surgical staging
weekly P
40 mg/m2 GOG
120
P 50 mg/m2 D1 and D29
F 4 g/m2 as 96 hr infusion D1 & D29,
Oral HU 2 g/m2 x twice weekly x 6
weeks
HU 3 g/m2 x
twice weekly x
6 weeks
RT: stage IIB: 40.8/1.7 Gy/day EBRT; stage III–IVA: 51 Gy/1.7 Gy/d
40 Gy (Point A) LDR BT, total Point A: 80–81 Gy; parametrial boost to
55–60 Gy

34
GOG
120
P-based arms superior to HU, weekly P less toxic
significant change in 3-year OS, 65% in P-based arms versus 47%;
significant change in pelvic recurrence (20 versus 30%);
less acute toxicity for weekly P

35
IB2 (>4 cm), negative LN by CT, lymphangiogram, or surgical staging;
1992-1997
weekly P 40 mg/m2 upto 6 cycles during
EBRT or last dose during BT
GOG
123
EBRT: 45 Gy/1.8 Gy/day; LDR BT, total Point A: 75 Gy
Randomized concurrent weekly P versus RT alone followed by
extrafascial hysterectomy

36
36
weekly P superior to RT alone in bulky stage IB2
significant change in 3-year PFS, 79% with P versus 67%;
OS 83 versus 74%; pelvic control 91 versus 79%,
Complete pathologic response 52 versus 41%

37
386 patients : stages IIB-IVA or stage IB-IIA (> 5 cm or involvement
of pelvic lymph nodes); 1990-1997
193 patients : 45 Gy
of radiation to
the pelvis and para-
aortic lymph nodes;
45 Gy/1.8 Gy/day,
≥40 Gy LDR BT,
total Point A: ≥85 Gy;
parametrial boost to 55–60
Gy
RTOG
90-01
193 patients : 45 Gy of radiation to
the pelvis and para-aortic lymph nodes
with two cycles of 5FU 1,000 mg/m2
and cisplatin 75 mg/m2 (days 1
through 5 and days 22 through 26
of radiation)

38
significant change in 8-year DFS, 61% with PF versus 46%;
OS 67 versus 41%;
reduction of locoregional failure 85 versus 35%;
distant failure 20 versus 35%;
no change in PA failure without PA RT;
no change in complication rates
38
concurrent chemotherapy superior to pelvic/PA RT
Patients were then to receive one or two applications of low-dose-
rate intracavitary radiation, with a third cycle
of chemotherapy planned for the second intracavitary procedure in
the combined-therapy group

42
42
• On the basis of 13 trials that compared chemoradiotherapy versus the same
radiotherapy, there was a 6% improvement in 5-year survival with
chemoradiotherapy
• Chemoradiotherapy also reduced local and distant recurrence and
progression and improved disease-free survival
• Endorsed the recommendations of NCI alert, but also demonstrate their
applicability to all women and a benefit of non-platinum-based
chemoradiotherapy

43
• Twenty four trials (21 published, 3 unpublished) and 4921 patients
• Chemoradiation improves overall survival and progression free
survival, whether or not platinum was used with absolute benefits of
10% and 13% respectively
• Chemoradiation also showed significant benefit for local recurrence
and a suggestion of a benefit for distant recurrence.
• Acute hematological and gastrointestinal toxicity was significantly
greater in the concomitant chemoradiation group

Trial Description
NCI/Canada,
Pearcey et al
• Randomized (1991–1996)
• Eligibility: IB,IIA (>5 cm or histologically + LN), IIB–IVA
• RT: EBRT: 45 Gy/1.8 Gy/day, BT (LDR or HDR) equivalent Point
• A dose of 35 Gy(LDR), total Point A: 80 Gy; RT to be completed
• within 7 weeks
• CT: weekly P 50 mg/m2 x 5 cycles during EBRT
 Outcome: no change in 5-year PSF and OS, 62 versus 58%
• Conclusion: no benefit of concurrent weekly P. Possible reasons:
• shorter treatment duration, only imaging-based staging, more
• anemia in the chemotherapy arm, smaller sample size

• Carboplatin AUC 2
• Gemcitabine : 75-150 mg/m2 with Cisplatin-RT
• Paclitaxel : 40 mg/m2 with Cisplatin-RT
• Bevacizumab : 10 mg/kg q 2 weeks with Cisplatin-RT
Alternativeto Concurrent Cisplatin:
46

• GOG 165 : PVI 5FU : 35% failure rate
• Mitomycin C and oral 5FU
• Cisplatin, VCR and BLM
• Misonidazole : failed
• Hydroxyurea : failed
• Bevacizumab : Phase I study
• Intra-arterial Cisplatin
Alternativeto Concurrent Cisplatin

• BLM, VCR, mitomycin and Cisplatin
• BLM, Ifosfamide-mesna, Cisplatin
• Cisplatin and 5-FU
• CXII trial (Phase 2)
• INTERLACE trial (Phase 3)
Neoadjuvantchemotherapy
48

• MD thesis protocol at MAMC :
Neoadjuvantchemotherapy
N (%) where N is out of 22
Complete Response 9 (40.9)
Partial Response 11 (50)
Stable Disease 1 (4.5)
Progressive Disease -
Assessment not done 1 (4.5)
49

• Gemcitabine + Cisplatin
• Intensification CRT (Gem/Cisplatin) & adjuvant chemo ( GC x 2)
• 9% improvement PFS at 3 years
• OUTBACK trial
• CRT v CRT + 4 cycles adjuvant Carbo/Paclitaxel
Adjuvantchemotherapy
50

• Bulky endocervical tumors and the barrel-shaped cervix have
higher incidence of central recurrence, pelvic and PALN
metastases, and distant dissemination
• Patients should receive definitive doses of chemoradiation, with
hysterectomy reserved for salvage in patients with either gross
residual disease or PET-positive disease that is biopsy proven at 3
months after completion of radiation
• Morice et al, 2012 : routine adjuvant hysterectomy is no longer
practiced for patients who have no residual disease at 6 weeks
after chemoradiation
Need for salvagesurgeryafterCTRT
51

• independent factors associated with PALN relapse
• SCC-Ag level of >40 ng/mL
• advanced parametrial involvement
• presence of pelvic lymphadenopathy
• pretreatment CEA of ≥10 ng/mL (for pretreatment SCC-Ag
levels of <10 ng/mL)
• Role of prophylactic para-aortic radiation must be carefully
weighed against the potential toxicities of para-aortic radiation
ElectivePara-AorticLN Irradiation

• Average 5-year survival = 40%
• Toxicity to the small bowel (D5cc < 55 Gy) is important to consider
when treating para-aortic nodes
Para-AorticLN Irradiation
54

Stage IVB
FIGO
stage
Management
IVB Combination chemotherapy

• Medial survival = 7 months
• Platinum doublets
• Paclitaxel and Cisplatin
• Paclitaxel and Carboplatin
• Ifosfamide, Paclitaxel and Carboplatin
• Vinorelbine
• Topotecan and Irinotecan
• Gemcitabine
• Cetuximab
• Pazopanib and Lapatinib
• Bevacizumab : GOG 240
StageIVB
57

Stage Local Control (%) Disease Free Survival (%)
IA 95-100 95-100
IB1 90-95 85-90
IB2
IB3 60-80 60-70
IIA 80-85 75
IIB 60-80 60-65
IIIC1 Depends on T stage
IIIA 60 25-50
IIIB 50-60 25-50
IVA 30 15-30
IVB <10
LC and DFS
58

• Median time to recurrence ranged from 7 to 36 months after primary
treatment
• After previous surgery :
• Radiation may salvage 50% with localized pelvic recurrence
• Recommended : whole-pelvis external irradiation (45 to 50 Gy) with
concurrent chemotherapy followed by interstitial brachytherapy
• After Definitive Irradiation :
• Reirradiation with caution
• Consider : beam energy, volume, doses delivered with external or
intracavitary irradiation, time between two treatments
• external irradiation for recurrent tumor is given to limited volumes
(40 to 45 Gy, 1.8-Gy tumor dose per fraction, preferentially using
lateral portals
• Selected patients : Radical hysterectomy or pelvic exenteration
• Option : Gemcitabine and Cisplatin
RecurrentCarcinomaCervix
59

• Isolated PALN recurrence = 3%
• 5 year survival = 25%
• Concurrent chemoradiation
Para-AorticLN recurrence

• Recurrent or stage IVB
• 20 Gy in five fractions over 1 week
• 30 Gy in 10 fractions over 2 weeks
• 10 - Gy per fraction given at 3- to 4-week intervals for a total of
three fractions
• New diagnosis
• 3 to 4 Gy for two or three fractions, followed by standard 1.8
Gy to approximately 39.6 Gy and then brachytherapy.
• 1 to 2 days of 1.8 Gy twice a day, switching to once-a-day
treatment with 1.8 Gy per fraction after bleeding has stopped
on day 2 or 3, completing treatment after 45 Gy and then
commencing routine brachytherapy
UrgentBleedingand PalliativeIrradiation
61

• H&P every 3–6 mo for 2 yrs, then every 6–12 mo for 3–5 yrs, then
annually based on the risk of disease recurrence.
• Cervical/vaginal cytology annually as indicated for detection of
lower genital tract lesions.
• Imaging (chest X-ray, CT, PET-CT, and MRI) and labs as indicated
based on exam, symptoms and risk of recurrence.
• Patient education on sexual health, vaginal dilator use, and vaginal
lubricants
Followup
62

Gunderson’s Clinical Radiation Oncology, 4th edition
Conclusion
63

CarcinomaCervixin pregnancy
64
Shaw’s Textbook of Gynecology, 16th edition

• True : first symptom occurs 3 or more years after subtotal
hysterectomy (better prognosis)
• Coincidental : symptoms are noticed before the third
postoperative year
• Aim is to bring the tumor dose to approximately 80 to 90 Gy for
brachytherapy after completing a standard dose of 45 Gy to the
whole pelvis
CarcinomaCervicalStump
65

• Lesions with deep stromal invasion = one or two vaginal
intracavitary insertions to deliver a 65-Gy LDR mucosal dose to the
vault
• Fully invasive tumor = 40 to 45 Gy to whole pelvis with cylinder
brachytherapy to vaginal vault for an approx. 60-Gy mucosal dose
• Gross tumor in the vaginal vault or parametrium = 45 Gy dose to
whole pelvis with concurrent weekly cisplatin chemotherapy,
followed by an additional parametrial dose of 10 to 20 Gy.
• intracavitary insertion performed
• gross residual tumor = interstitial implant
CarcinomaCervixaccidentallytreatedwith
a Simple Hysterectomy

Thank You
67
In medical research, the most famous cell line known as HeLa was developed from cervical cancer cells of Henrietta Lacks in 1951

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