CARCINOMA CERVIX-

EVIDENCE BASED

MANAGEMENT AND

RADIOTHERAPY

Dr. Rajan Paliwal

Assistant Professor

Department Of Radiation Oncology

M. D. M. Hospital

Epidemiology

• Carcinoma Cervix is the third most common

cancer in women worldwide and second most

frequent cause of cancer death in women

• Highly prevalent in developing countries

• Most common cancer in women in India

• India incidence rate is 23.5 per 1 lac population

• 50% are diagnosed between ages 35 and 55.

• 20% at the age of 65 or over.

• Rarely occurs in women younger than 20

Risk Factors

• Human papillomavirus infection (HPV) –Primary factor

– HPV 16, HPV 18, HPV 31, HPV 33, HPV 45

– 85% are caused by HPV 16 AND 18

• Multiple sexual partners

• Early age of first sexual intercourse

• Early childbearing and high parity

• Exposure to STDs (HSV II, genital

warts, vaginal infections)

• Cigarette Smoking

• Intrauterine exposure to DES is

associated with clear cell

adenocarcinoma

• Immunosuppression

• Penile cancer in partner

Risk Factors

Natural history

• Originates at the squamous columnar

junction

• Start as severs cervical dysplasia and CIS

progressing to invasive carcinoma over 10-

20 yrs

• Manifest as superficial ulceration,

exophytic tumour or as infiltrative growth

• Local spread– Directly to adjacent vaginal fornices, to the

paracervical and parametrium

– Direct invades to the bladder and rectum

• Lymphatic spread– Spread to obturator node (medial group of

external illac nodes) and to other external illacnodes and hypogastric nodes through paracervical nodes

– And then to para aortic and left supraclavicularL.N

Natural history

Risk of nodal spread

Stage Pelvic

nodes

Para

aortic

nodes

I 15% 5%

II 30% 20%

III 50% 30%

Natural history

• Hematogenous spread

– Through the venous plexsus and the para

cervical veins

– M.C organ-Lung, others liver

– Bones, commonly to lumbar and thoracic

spine

Natural history

Clinical Presentations

• Intra-epithelial or early lesion:-

– Asymptomatic

• Local Symptoms due to disease

– Post coital bleeding/spotting (1st manifestation)

– Metrorrhagia, Menorrhagia

– Serosangious or yellowish discharge

– Foul smelling discharge

• Pain

– Streching of ligaments-back ache/ lower

abdominal pain

– Due to para aortic nodes- lumbar pain

– Hydronephrosis

• Cachexia – anemia

• Hematuria, rectal bleeding, dysuria – locally

advanced disease

Clinical Presentations

• Triad: Sciatic pain

Lower extremity edema

Hydronephrosis

• Urinary and rectal symptoms (bowel and/or

urinary obstruction,

vesicovaginal/rectovaginal fistula)

Clinical Presentations

• Complete History

• General Physical Examination

– Anaemia

– Jaundice

– Supraclavicular, inguinal lymph nodes

• P/A

– Liver enlargement

– Abdominal mass

Diagnostic workup

• Local Physical examination

• P/V, P/R

• Pelvic examination under anesthesia

• Diagnostic Procedures

• Cytological Smear (Pap smear)

• Colposcopy

• Biopsy

• Endocervical Curettage

• Conization

Diagnostic workup

• Laboratory examination

– Routine- CBC, LFT, RFT

• Radiograhic imaging

– Chest X-ray

– IVP

– CT/MRI

– PET, PET-CT

– Cystoscopy & rectosigmoidoscopy

Diagnostic workup

FIGO Classification

Stage 0 Preinvasive carcinoma / carcinoma in situ

Stage I Tumour confined to cervix.

IA Preclinical invasive ca, diagnosed by microscopy only.

IA1 Measured Stromal Invasion 3mm or less in depth and 7 mm or less in horizontal spread.

IA2 Measured stromal invasion 3 to 5mm and 7 mm or less in horizontal spread.

IB Clinically visible lesion confined to the cervix or microscopic lesion greater than IA2.

IB1 4 cm or less in size.

IB2 >4 cm in size.

Stage II Tumour beyond uterus but not the lower 1/3 of vagina or up to the pelvic side walls.

IIA without Parametrial invasion.(IIA1:<4 cm; IIA2:>4 cm)

IIB with Parametrial invasion.

Stage III Tumour extending up to pelvic wall, lower 1/3 vagina, hydronephrosis or non-functioning kidney.

IIIA No extension to pelvic wall but involved lower 3rd vagina.

IIIB Extension to pelvic side wall, hydronephrosis or non- functioning kidney.

Stage IV

IVA Invasion of mucosa of bladder/rectum, and/or extends beyond true pelvis (bullous edema is not sufficient to classify a tumor as IVA).

IVB Distant Metastasis.

FIGO Classification

Pathologic Classification

• Carcinoma

– Squamous cell carcinoma -80-90%

• large cell, small cell. Non kaeratinizing

• Verrucous carcinama- variant

– Adenocarcinoma 8-10%

• Endometrioid carcinoma

– Adenosquamous

• Glassy cell carcinoma

– Clear cell carcinoma

– Adenocystic carcinoma

• Sarcoma

– Leiomyosarcoma

– Rhabdomyosarcoma

– Stromal sarcoma

– Carcinosarcoma

• Lymphomas

• Metastasis

– Breast, ovary and kidney

Pathologic Classification

Prognostic Factors

• Clinical stage

• Tumor size

• Depth of stromal invasion

• LVSI

• Pelvic and para aortic lymph node involvement

• Parametrial involvement

• Status of surgical margins

• Hemoglobin level before and during RT

Stage Wise Management

STAGE 0 (Carcinoma In Situ)

• If FERTILITY PRESERVATION DESIRED

– For Ectocervical Lesions:

• Loop electrosurgical excision procedure (LEEP).

• Laser therapy

• Cryotherapy

• Conization

– If Endocervical Canal Involved:

• Conization

• POST MENOPAUSAL PATIENTS &

FERTILITY PRESERVATION NOT DESIRED

– Total abdominal or vaginal hysterectomy

• MEDICALLY INOPERABLE

– Intracavitary Irradiation Alone - 45 to 50 Gy

to Point A

Stage Wise Management

STAGE I A 1 ( No LV Invasion)

• CONIZATION: Adequate if biopsy have neg. margin

and pt. desire fertility.

• TOTAL HYSTERECTOMY:( Abdominal or Vaginal) simple extrafascial hysterectomy

(also in cone margin positive patients )

• INTRACAVITARY BRACHYTHERAPY ALONE Patients unfit for surgery. Dose: 60 to 70 Gy to Point A

• LV Invasion- Treated Similar to IA2/IB1

Stage Wise Management

STAGE IA2

• Modified Radical Hysterectomy with Pelvic Node Dissection +/- Para aortic lymph node sampling

• Women not fit for surgery: Brachytherapy plus External Pelvic Irradiation( Point A dose: 75 to 80 Gy).

45 Gy EBRT + Brachytherapy

• If pt. desire fertility

Radical trachelectomy plus pelvic node dissection +/- para aortic lymph node sampling

Stage Wise Management

STAGE IB1 and IIA (<4 cm)

• Radical Hysterectomy plus Pelvic Node Dissection +/- para aortic lymph node sampling .

• Pelvic RT plus Brachytherapy (Point A Dose: up to 80 Gy)

45 Gy by EBRT rest by I/C brachytherapy

• IB1 and pt. desire fertility

Radical trachelectomy plus pelvic node dissection +/- para aortic lymph node sampling

Stage Wise Management

The ABS recommendation:

DEFINITIVE RT/RADICAL SURGERY

Results Equivalent. The ABS recommends

that primary therapy should avoid routine

use of both Radical Surgery and RT to

minimize morbidity related to multimodality

therapy.

Stage Wise Management

STAGE IB2 and Bulky IIA(>4cm)

• Pelvic RT + Concurrent Cisplatin

containing Chemotherapy+ Brachytherapy (

Point A Dose: 85 Gy or more)

• Radical Hysterectomy + Pelvic Node

dissection + para aortic lymph node

sampling (lower evidence)

Stage Wise Management

INDICATIONS OF ADJUVANT TREATMENT

(Post Operative)

• Node Negative Patients

Pelvic Irradiation in pts. with any 2 of the following:

> 1/3rd StromalInvasion

LV space Invasion

Large (>4 cm) tumor

• Positive Pelvic Nodes/Positive Surgical margin/Positive

Parametrium

Pelvic RT+ Concurrent Cisplatin based chemotherapy and

vaginal brachytherapy if positive vaginal margin.

Stage Wise Management

STAGES IIB/IIIA/IIIB

Pelvic RT + concurrent Cisplatin based chemotherapy + Brachytherapy ( Total Point A Dose 85 Gy or more)

STAGE IVA

Individualized Tx based on Extent of Bladder/Rectal involvement/ Renal function/ Parametrial involvement/ Performance status.

Stage Wise Management

• Surgical Exenteration: Pts with no/minimal parametrial invasion and good performance status( anterior/posterior or total).

• Concurrent RT/CT: Selected pts with good general and renal status and not suitable for surgical exenteration.

• Palliative RT: Majority have poor GC and extensive local disease – best treated with Palliative RT alone. A short regime of 30 Gy/10#/2 wks- few pts who respond well-followed by intracavitary appl.

Stage Wise Management

Stage IVB

• Palliative RT: Palliation of distant metastases in Brain/Bone etc. Palliation of symptoms like pain/bleeding/tenesmus etc.

• Palliative CT: No standard CT regimen available. Combinations like Cisplatin/Paclitaxel, Cisplatin/Topotecan, Cisplatin/Ifosfamide have been used with varying response rates.

Stage Wise Management

5 year DFS

• STAGE IA: >95%

(With LV Invasion) up to 90%

• STAGE IB 1 : 86-90%

• STAGE IIA( Non bulky) : 75%

• STAGE IB 2/IIA Bulky: 60-65%

• STAGE IIB: 60-65%

• STAGE III: 30-55%

• STAGE IVA:18-30%

Post Treatment Results

CONCURRENT CHEMORADIATION

ABS/NCI Recommend the addition of

Cisplatin based CT during the course of

definitive RT for stage IB2 onwards. 5

Randomized Trials- significant

improvement in local control+ survival (In

women from affluent countries with better

performance/nutritional status and renal

parameters).

NCI Alert

INVASIVE CANCER FOUND AFTER SIMPLE HYSTERECTOMY :

1. Immediate Resurgery- Radical Parametrectomy and Pelvic LND.

2. Post op RT:

a) No disease/microscopic only at margins: Whole Pelvis RT 45-50 Gy with Concurrent Cisplatin based Chemotherapy for Microscopic disease at margins, followed by ICRT to boost the dose at vaginal apex to 60-65 Gy (Total dose).

b) Gross Residual in vault: Whole Pelvis 40 Gy + parametrium additional 20 Gy, with Concurrent Cisplatin based Chemotherapy followed by ICRT up to 65 Gy mucosal dose.

Special Clinical Problems

Post RT:

• Central Disease Small lesions RadicalHysterectomy or Brachytherapy

• Largerlesions, good PS

Pelvic Exenteration

• Pelvic Side Wall Recurrence PalliativeCT/Symptomatic& supportive care.

Post Surgery:

• Definitive Pelvic RT+ Cisplatin based chemotherapy

Extrapelvic/Distant Mets: Palliative Intent

Recurrent Disease

Carcinoma cervix during

Pregnancy

• Incidence – 0.5% to 5%

• Pelvic examination and pap smear at first

antenatal visit for all pregnant patients

• Colposcopy and biopsy

• Conization c/I in first trimester performed

in second trimester

• Conization in first trimester associated with

an abortion rate of up to 33%

• Stage IA and carcinoma in situ patients definitive treatment may be delayed safely until fetus has matured.

• Less than 3mm invasion and no LVSI may be followed to term and delivered vaginally. Vaginal hysterectomy may be performed 6 weeks after childbirth if further childbearing not desired.

• 3 to 5mm invasion and LVSI also followed to term delivered by cesarean section followed immediately by modified radical hysterectomy and pelvic lymph node dissection.

Carcinoma cervix during

Pregnancy

• Stage IB1 tumors – classic C. S. followed by

radical hysteretomy with pelvic lymph node

dissection.(if fetus viable or pulmonary

maturity documented)

• Stage II – IV Radiotherapy

Fetus viable –classic c.s.-RT postoperatively

Frist trimester –start RT

Second trimester –delay therapy

Carcinoma cervix during

Pregnancy

RADIOTHERAPY

• EXTERNAL IRRADIATION- Treats Whole

Pelvis+ Parametria

• ICRT- primarily irradiates central disease(

cervix, vagina and medial parametria)

• EBRT delivered before ICRT If

– Bulky cervical lesions to improve the geometry

– Exophytic, easily bleeding tumors

– Tumors with necrosis or infection

– Parametrial involvement

• MODALITIES TO DELIVER EBRT

– CONVENTIONAL

• COBALT-60

– CONFORMAL

• 3D-CRT

• IMRT

• PET-CT BASED PLANNING

RADIOTHERAPY

Cobalt Machine

Co 60

t ½ = 5.26 years

Gamma emitter

Energy 1.25 MV

3D Conformal Radiotherapy

• Conformal RT improves the delineation of target

volume while sparing nearby normal tissues

• Conformal RT decrease bowel and bladder doses

in pelvic RT, to reduce acute grade 3 or higher

gastrointestinal toxicity, bone marrow dose, and

hematologic toxicity. However, Conformal RT is

more vulnerable to inter- and intrafractional

organ motion, and meticulous attention has to be

paid during planning.

• Patient position and immobilization

• Volumetric data acqusition

• Image transfer to the TPS

• Target volume delineation

• 3D modal generation

• Forward planning or innverse planning

• Dose distribution analysis

• Treatment QA

• Treatment delivery

Steps in 3D CRT Planning

Linear Accelerator3D Conformal Radiotherapy

CT Simulator

Treatment Planning

•

Beam

Placement

3D Conformal Radiotherapy

3D Conformal Radiotherapy

Multileaf Collimator (MLC)

Linear Accelerator

• X-rays

• Higher energy (4 - 18Mv)

– compared to Gamma rays (1.25 Mv)

• Higher energy means

– More penetrating beam

– Treat deeper tumors

– Enhanced skin sparing

Linear Accelerator

• Type of radiation treatment in which

radioactive sources are arranged in such a

fashion that radiation is delivered to the

tumor at a short distance by interstitial,

intracavity, or surface application

BRACHYTHERAPY

BRACHYTHERAPY

ABS strongly recommends that

1) Definitive Irradiation for cervical carcinoma must include brachytherapy as a component.

2) Precise applicator placement is essential for improved local control and reduced morbidity.

3) Interstitial brachytherapy should be considered for patients with disease that can’t be optimally encompassed by intracavitary brachytherapy.

4) Total treatment duration be less than 8 weeks when possible( exceeding beyond 8 wks can reduce local control and survival by about 1% per day of prolongation.

Treatments Classified with respect to

DoseRate:

LDR: 0.4 – 2 Gy/hr

MDR: 2- 12 Gy/hr

HDR: > 12 Gy/hr ( practically much higher

dose rate used)

BRACHYTHERAPY

• POINT A

• PARACERVICAL TRIANGLE where initial lesion of radiation necrosis occurs

• Area in the medial edge of broad ligament where the uterine vessel cross over the ureter

• The point A -fixed point 2cm lateral to the center of uterine canal and 2 cm from the mucosa of the lateral fornix

• POINT B

• Rate of dose fall-off laterally

• Imp. Calculating total dose-Combined with EBRT

• Proximity to important OBTURATOR LNs

• Same level as point A but 5 cm from midline

• Dose ~20-25 % of the dose at point A

BRACHYTHERAPY

Image-guided BT may further improve precision

and quality of treatment, as compared with

conventional plain film based BT planning.

commonly used imaging techniques include

ultrasound, CT, and MRI. A recent American

Brachytherapy Society (ABS) survey showed that

ultrasound, CT, and MRI are used routinely for

applicator placement in 56, 70, and 2% of cases,

respectively, and that contouring of bladder and

rectum is commonly performed

BRACHYTHERAPY

Intracavitary Brachytherapy

Fletcher-Suit applicator

SEQUELAE OF RADIATION

THERAPY

• Acute:

Diarrhea, abdominal cramping, rectal discomfort, Occasionally, rectal bleeding.

Dysuria, frequency, nocturia, rarely hematuria; UTIs .

Erythema, dry/moist desquamation in perineum or intergluteal fold.

Radiation vaginitis/superficial ulceration of vagina/ vaginal stenosis

• Late:

Rectovaginal/vesicovaginal fistula- 1to2%

Proctitis/cystitis(3-5% stage I-IIA, 10-15%

for stage IIB-III).

Vaginal stenosis,

Anal Incontinence

Femoral neck fractures/ lumbosacral

plexopathy (extremely rare)

SEQUELAE OF RADIATION

THERAPY

Follow-up

• Every month- For first 3 months.

• Every 3 months- For remaining of the first year.

• Every 4 months- The 2nd year.

• Every 6 months- During the 3rd through 5th year.

• And yearly thereafter.

• Patients undergo Complete physical+ pelvic/rectal examination with Pap smear taken from 3 months onwards.(+ chest X-ray annually; CBC, Urea/creat. 6 monthly)

• Other investigations( USG/CT) as clinically indicated.