CERVICAL CARCINOMA – Long journey of gyn&obs

CLINICAL PRESENTATION

Women with pre-cancerous lesions are usually asymptomatic.

PCB, IMB, PMB, Persistent/irregular vaginal bleeding
Abnormal & offensive vaginal discharge
May also be associated dyspareunia or pelvic pain
Cervix looks or feels abnormal (Barrel cervix)
Features of spread

➢ If symptoms are present, it is essential to do a speculum examination

➢ Pap smear is mandatory even if the cervix looks normal

However, in SL majority (70%) of cervical CAs are diagnosed at an advanced stage (Stage III & IV)

SPREAD

Direct spread into the cervical stroma, parametrium & beyond
Lymphatic metastasis into parametrial, pelvic sidewall & para-aortic LNs
Blood-borne spread is unusual.

PROGNOSTIC FACTORS

Stage of tumour
- Grade of tumour
- Histological type
- Volume
- Lymphatic spread
- Vascular invasion.

CLINICAL MANAGEMENT

Goals of the management
- To stage the disease
- To treat both the primary lesion and other sites of spread.
Factors predict the LN metastases (clinical disease confined to the cervix)
- Increasing tumour size
- Increasing depth of stromal invasion
- Capillary–lymphatic space involvement by tumour
Significant prognostic factors for a reduction in progression-free interval and survival in locally advanced disease
- Age
- Performance status
- Clinical stage
- Tumour size
- Lymph node status (para-aortic and pelvic)

INCIDENCE OF LYMPH NODE DISEASE ACCORDING TO STAGE

STAGING

MANAGEMENT

Specialised gynaecological oncology teams should determine the management.
Factors that influence the mode of treatment include stage, age & health status.
Radiation can be used for all stages
Surgery should only be considered an option for early-disease (stage – I & IIA)
Both surgery and radiotherapy are effective in early-stage disease
Locally advanced disease relies on treatment by radiation or chemoradiation
- Radiation = Radical hysterectomy (5 year overall & disease-free survival rates)
Morbidity ==== Surgery + adjuvant radiotherapy > Either surgery / radiation alone

Advantages to surgery

Permits conservation of ovarian function in pre-menopausal women
Reduces the risk associated with radiotherapy
- Chronic bladder dysfunction
- Chronic bowel dysfunction
- Sexual dysfunction
Also permits the assessment of risk factors, such as LN status >>> Influence prognosis

Complications of surgery

Complications in the hands of skilled surgeons are uncommon.
Possible complications
- Fistulae (<1 per cent)
- Primary haemorrhage
- Lymphocyst
- Bladder injury
Chronic bowel & bladder problems that require medical / surgical intervention occur in up to 8–13% of women due to parasympathetic denervation secondary to surgical clamping at the lateral excision margins.

STAGE	DESCRIPTION		LN Involvement			TREATMENT OPTIONS
			Pelvic		P.Aortic
1	Strictly confined to the cervix (Extension to the uterus does not affect the stage)
IA	Microscopic invasive cancer. Stromal invasion with a maximum depth of 5 mm and no wider than 7 mm					if fertility wish+ IA1 Local excision with clear margins. Cone biopsy or diathermy excision. If clear margin – No further excision or hysterectomy. If margins involved – further excision or hysterectomy (simple). Lymphadenectomy is not indicated. IA2 Like IA1 + Lymphadenectomy BUT standard Treatment TAH+BSO+ B/L pelvic lymphadenectomy
IA1 (<3 mm)	≤3 mm in depth & <7 mm diameter		0.6		0
IA2 (3–5 mm)	>3 mm but ≤5 mm in depth & <7 mm diameter		4.8		<1
IB	Clinical lesions		15.9		2.2	IB1 just > 7mm (selected cases) large-cone biopsy –for central control + Lymphadenectomy Small volume IB1, fertility wishes+ Trachelectomy, Lymphadenectomy & Abdominal isthmic cervical cerclage Other wise RH + PND + Para-aortic if suspicious nodes BUT standard Treatment TAH+BSO+ B/L pelvic lymphadenectomy
IB1	≤4 cm
IB2	>4cm
2	Extends beyond the cervix, but not extended on to the pelvic wall. Involves the vagina, but not as far as the lower third
IIA	Extends beyond the cervix. Not extended to the pelvic wall. Involves upper 2/3 of vagina.		24.5		11
IIA1	<4 cm					RH + PND
IIA2	>4 cm
IIB	Obvious parametrial involvement, but not on to the pelvic sidewall.		31.4		19	No surgery with curative intent. Radical radiotherapy and chemoradiation – potential for cure.
3	Extended on to the pelvic sidewall. Involves the lower 1/3 of the vagina. All cases of hydronephrosis / non-functioning kidney should be included, unless they are known to be due to other causes
IIIA	No extension on to the pelvic sidewall, but involvement of the lower 1/3 of the vagina	44.8		30
IIIB	Extension on to the pelvic sidewall or hydronephrosis or non-functioning kidney
4	Extended beyond the true pelvis/clinically Involved the mucosa of the bladder and/or rectum
IVA	Spread to adjacent pelvic organs	55		40
IVB	Spread to distant organs

– Confirmed paraortic lymph node mets is a contraindication to radical pelvic surgery

STAGE IA DISEASE

Can be treated with less aggressive and, importantly, fertility-sparing therapy.
Should be formally diagnosed by cone biopsy or diathermy excision.
Knife cone biopsy does not cause any thermal damage, and the extent of disease may be more accurately assessed than on a loop excision specimen.
- Stage IA1 disease is rarely associated with lymph node metastases
If removed with clear margins, no further treatment is necessary.
If disease is present at the margins, further excision or hysterectomy is required.
Simple TAH is sufficient, as there is no risk of parametrial involvement (very low risk of lymph node disease), lymphadenectomy is not indicated.
- Consider TAH + lymphadenectomy for IA2 as 5% chance of LN involvement, particularly if the tumour is poorly differentiated.

STAGE IB–IIA

Radical hysterectomy (excising parametrial tissue around the cervix & upper vagina, with removal of part or all of the cardinal and uterosacral ligaments, depending on the extent of the dissection) and pelvic lymphadenectomy (obturator, internal, external & common iliac nodes) with adequate disease-free margins.
More radical dissections > higher incidence of peri-operative morbidity and chronic bladder and bowel dysfunction with no survival advantage
selected cases of IB1 disease (just greater than 7 mm in horizontal spread) a large-cone biopsy may be adequate for central control, combined with lymphadenectomy
Some women with small volume IB tumours with fertility wishes might be suitable for trachelectomy (radical excision of the cervix) combined with either laparoscopic or open lymphadenectomy.
- Vaginal approach – Most common approach, 4%recurrence rate & 70% term delivery rate.
- Abdominal approach – Greater excision of the parametrium & some recommend the insertion of an abdominal isthmic cervical cerclage to reduce the risk of late miscarriage.
Bulky IB tumours have a higher risk of positive nodes & close surgical margins (better treated with chemoradiation as opposed to surgery or radiotherapy alone
Careful preoperative radiological imaging reduces the risk of encountering unexpected lymphadenopathy or unexpectedly large tumours.
The presence of suspicious LN on pre-operative MRI should dictate chemoradiation.
If any doubt à laparoscopic biopsy or PET imaging should be considered prior
If positive nodes are encountered unexpectedly,
- Abandoning surgery in favour of radical chemoradiation
- If suspicious nodes à confirmed at frozen section à remove resectable nodes & treat with chemoradiation (brachytherapy requires the uterus to be in situ)
- Radical surgery and adjuvant RT (associated with increased morbidity)

STAGE IIB AND ABOVE

No surgery with curative intent
Radical radiotherapy & chemoradiation are the only modalities of treatment for cure
Pre-operative chemotherapy to shrink disease followed by radical surgery may be superior to radical RT, but this has not been confirmed (young patient/IIB disease)
It is inevitable that pre-operative chemotherapy followed by surgery will still require some women to undergo adjuvant or non-adjuvant radiotherapy that is more likely to result in unacceptable toxicity.

Complication of lymphadenectomy

Lymphocyst formation (4-5%)

Lymphoedema (incidence increases with adjuvant radiotherapy)

Adjuvant radiotherapy

Positive pelvic nodes Close vaginal margins (<0.5 cm) (Can improve pelvic control, but there is no firm evidence of increased survival)

RADICAL RADIOTHERAPY

Indication

Unfit for surgery Bulky stage IB2 disease and more advanced disease

Goals

Treat primary disease Control metastatic pelvic lymph nodes

Types

The radical dose is delivered by

External-beam (teletherapy) – treat any pelvic spread.
Intracavitary treatment (brachytherapy) – high doses locally to the primary site
Challenge àachieving an optimal dose throughout the primary tumour & pelvic sidewall without causing high morbidity.
Peripheral field of ICR delivers an insufficient dose to treat the pelvic sidewalls.
The dose-limiting normal tissues within the pelvis are the rectum posteriorly, the bladder anteriorly and any loops of small bowel within the pelvic radiation fields.

Manchester system

The total dose is a product of the dose rate and treatment time.
The usual doses delivered are 70–80 Gy to point A and 60 Gy to point B, limiting the bladder and rectal dose to 60 Gy.
External-beam radiation is usually given two to three weeks after intracavitary treatment to allow for involution of the primary disease.
Fractionated over 20-30 days – to allows recovery of normal tissues between fractions
No additional benefit (including survival) from routine extended RT which includes para-aortic LN (severe GIT complications). But indicated if they are positive.

CHEMORADIATION

An overall survival advantage for cisplatin given concurrently with radiation therapy
Mortality from cervical cancer decreased by 30%
Higher rates of short & medium term complications
International acceptance that this is the treatment of choice for advanced disease & is superior to radiation alone
Indications
- IIb and beyond
- Ib bulky disease some consider to be treated by chemoradiation

NEOADJUVANT CHEMO + RADICAL SURGERY

No conclusive evidence

RADIOTHERAPY VS SURGERY

Same 5 year survival Both modalities more morbidity

RECURRENT CERVICAL CANCER

Treatment depends on the mode of primary therapy and the site of recurrence.
- Initial treatment by surgery / radiotherapy
- Initial treatment by radiotherapy
- exenterative surgery provided the recurrence is central & there is no evidence of distant recurrence.
Require very careful pre-operative assessment & counselling in order to understand the consequences of defunctioning surgery.
Exenterative surgery >5 year survival of 50 %
Poor prognostic factors
- Positive nodes at the time of attempted salvage surgery
- positive resection margins
- Relapse within two years of primary treatment
Anterior exenteration- excision of bladder, most of vagina en bloc with the recurrence
Posterior exenteration- excision of the sigmoid rectum with formation of a colostomy.
Cab be combination of the two
Presence of hydronephrosis and symptoms of pain

PALLIATION OF PROGRESSIVE CERVICAL DISEASE

Chemotherapy is palliative
Ureteric obstruction – subsequent pain, infection & ultimately impaired renal function – Mechanical diversion by nephrostomy or ureteric stenting.
Fistulae ( late-stage) cause intolerable symptoms
Palliative surgery in order to divert faeces or urine, if surviving >8 weeks
Pain due to infiltration of the lumbosacral nerve plexuses- pain control
Psychological and emotional support

Fertility sparing Treatment

20% of gynaecological cancers are diagnosed in young women (not have completed their family, with a rising age at first pregnancy)
Primary aim of cancer management remains the eradication of the disease
Currently less radical options in attempts to reduce morbidity, improve QOL & retain fertility.
Definitive treatment is usually offered once family is completed

CERVICAL CANCER

43% of cervical cancer cases are diagnosed in women under the age of 45 years.
Standard treatment RH, chemoradiation – invariably leading to loss of fertility.
Early stage disease, less radical fertility-sparing options has been described for those tumours smaller than 2 cm.
Fertility sparing surgery in adenocarcinoma is controversial due to multifocal nature. But increasingly, evidence suggests that early stage adenocarcinoma and squamous cell cancers have a similar prognosis.
Selection of surgery depends on ;
- Stage
- Grade
- Lymphovascular invasion.

STAGE 1A1

Simple cone Biopsy – curative
Incidence of metastatic nodal or parametrial disease is extremely small – LND is not required
Obstetric outcome:
- Excellent
- Increase preterm delivery – 11% – Depend on proportion of cx removed, no of Rx attempt
Clear histological excision margins are paramount.
In adenocarcinoma, it is recommended that the depth of excision should be at least 25 mm with a clear margin of 5 mm
Not recommend the use of LLETZ in stage IA disease – can make pathological assessment difficult because of the heat artifact
Also, to obtain 2.5 cm depth of cervical tissue, 2 loop specimens will frequently be provided, whereas with a knife/laser cone one can be readily obtained. Pathological assessment is vital to staging, which can be more accurately assessed with one intact specimen rather than with two

STAGE 1A2

If <1cm tumour volume has 0.6% chance of parametrial involvement – may need vaginal trachelectomy. But, nowadays more conservative approaches used to treat this stage
Cone biopsy & lymphadenectomy as LN spared is 5%

STAGE 1B1 – JUST ABOVE STAGE 1A2

Cone biopsy & lymphadenectomy with good survival outcome.

STAGE 1B1 – SMALL VOLUME DISEASE (<2CM)

Neoadjuvant chemotherapy & cone biopsy & pelvic lymhadenectomy (can treat tumour >2cm)
To reduce morbidity and the radicality of surgery,
Chemotherapy will have a damaging effect on ovarian function.
Effect depend on the woman’s pre-existing fertility status, type and dose of chemotherapy

Radical vaginal trachelectomy (RVT) + lymphadenectomy
Radically remove the cervix, upper vagina & para-cervical tissue vaginally, to remove regional LNs laparoscopically and to leave body & fundus of the uterus in order to allow conception.
A cerclage was placed in the neocervix (abdominal isthmic cervical circlage) – decrease the incidence of mid and late pregnancy loss.
5 year survival 97% = RH
- Obstetric outcome
  - Pregnancy rate 40- 80%T1 MC – 16 -20% ( similar to general population) T2 MC – increased 8 -10% Life birth rate – 68% Significant prematurity – 10% at 32weeks, 20% at 36weeks
  - Term delivery 70 – 75%
MOD – CS – classical
TOD – 34 – 37weeks after ANCS
Complications: (As RH)
- Need adjuvant Rx in 10 -12%( positive margin, positive LN, poor prognostic features) Recurrence – 5.8% ( RH – 4.4%)- A significantly raised recurrence rate has been observed with tumours over 2 cm
- Cervical stenois (15%) – dysmenorrhoea or infection.

SPECIALLY STAGE 1B (>2CM)

Radical abdominal trachelectomy (Laproscopic / laparotomy) + lymphadenectomy

STAGE ABOVE 1B2– IF RADIOTHERAPHY REQUIRED

Ovarian transposition

Ovaries can be hitched up and sutured to the mid abdominal sidewall- into the paracolic gutters at the level of the lower ribs.
Whilst their blood supply is preserved.
May prevent early menopause & ovaries used for oocyte retrieval, IVF & achieving pregnancy through surrogacy if appropriate still a high risk of ovarian failure (28 – 50%) and oocyte retrieval should therefore be considered prior to administration of radiotherapy.
Complications
- Ovarian cyst formation
- Ovarian torsion
- Presence of metastatic ovarian deposits in advanced tumours.
Transposition of the ovaries can be performed after egg retrieval, but may be complicated due to the increased size of the ovaries caused by the hormonal stimulation required.

EVIDENCES