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Draft 1
CERVICAL CARCINOMA
Index
1.
Screening
2.
2.1
2.2
2.3
Referral pathway
For GP
For non-oncological consultants/ firms
For referral from unit to centre
3.
3.1
3.2
Diagnosis
Early invasion
Clinical invasive disease
4.
4.1
4.2
4.3
4.4
Investigations
Examination under anaesthesia
MR and CT imaging
Other investigations
Relative benefit over other management options and resource implications
5.
5.1
Gynaecological cancer multidisciplinary team
Information
6.
6.1
Pathology
Modified WHO histological classification
7.
Staging
8.
Histopathology minimum dataset
9.
9.1
9.1.1
9.1.2
9.1.3
9.1.4
9.1.5
9.1.6
9.1.7
9.1.8
9.2
9.2.1
9.2.2
9.3
9.4
Treatment
Surgery
Loop/ cone
Radical trachelectomy
Wertheim hysterectomy
Shauta hysterectomy
Laparoscopic node dissection
Cancer complicating pregnancy
Cervical stump carcinoma/ management of unsuspected carcinoma after simple hysterectomy
Management of stage Ib2 carcinoma
Radiotherapy and chemoradiation
Radical treatment
Adjuvant treatment
Chemotherapy
Management of advanced disease
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10.
10.1
10.2
10.3
10.4
10.5
Dealing with recurrent disease
Imaging
Chemotherapy
Pelvic exenteration
Palliative care
Obstructive uropathy
11.
11.1
Survival
Cancer dataset/ inventory of active trials
12.
12.1
Follow up
Identification and management of late effects of treatment
13.
Contact names/ numbers
14.
Algorithm
15.
Summary
16.
References
Appendix 1: Relative benefit over other management options and resource implications for imaging
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Introduction
Cervical carcinoma is the second commonest cause of female cancer worldwide but accounts for about 2%
of all cancers in women in the UK. 3400 new cases are diagnosed each year in England and Wales of which
about 1200 women die of their disease (NHS Executive, 1999).
The incidence and death rate for cervical carcinoma has been declining since records began in the early part
of this century. However, the incidence of adenocarcinoma in 2001 had increased by 45% from 1971
(1.6/100,000 in 2001). The incidence of squamous carcinoma declined by 54% since 1971 (8.6/100,000 in
2001). Indeed the incidence has fallen by 42% between 1988 and 1997 in England and Wales. Incidence is
declining in all age groups but over 25% of women are diagnosed over 65 years of age.
Mortality for all cases has declined by 67% from 1971-2001 (2.7/100,000 in 2001; Quinn et al, 2001).
This appears to be despite the increasing incidence of CIN and may reflect the apparent success of the
national cervical screening programme which has been estimated to save 4500 lives/ year in England.
Carcinoma of the cervix is most prevalent in Wales and the North of England and in the unskilled.
The patient may be asymptomatic and detected up by cervical cytology. Fifty percent of women present at
an early stage appropriate for a surgical cure.
1.
Screening
Following the introduction of computerised recall in 1988 the incidence of cervical cancer has declined by
7% per annum and has been the major contribution to the decline in mortality from this disease. Presently 3
yearly screening is from 20–65 years of age in Wales. There are slight variations throughout the rest of the
UK. HPV testing and HPV vaccination are currently undergoing evaluation.
2.
Referral pathway (see 13. Contact names/ numbers)
2.1
For GP
If cervical cancer is suspected then referral should be to a general gynaecologist, the lead in the cancer unit
or gynaecological oncologist in the cancer centre.
Standards
Rapid access to the specialist should be available with the patient seen within 2
weeks of date of receipt of the referral letter/ fax.
Definitive treatment should be commenced no later than 62 days after receipt of the
referral letter/ fax.
Definitive treatment should be commenced no later than 31 days after diagnosis for
non urgent suspect cancer referrals.
2.2
For non-oncological consultants/ firms
If the diagnosis is suspected or confirmed referral to the local unit lead or gynaecological cancer centre
should be made.
2.3
For referral from unit to centre
This is appropriate for all cancer cases FIGO substage Ia2 or greater.
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3.
Diagnosis
This usually depends upon colposcopic examination where features of high grade CIN (large lesion,
mosaic, punctation) or invasion (abnormal vasculature, ulceration) may be present. Diagnosis depends on a
suitable sized biopsy (loop or cone). Punch biopsy may not be satisfactory as a means of colposcopic
diagnosis (ie for lesions that are not macroscopically visible).
3.1
Early invasion (see 9.1. Surgery)
The diagnosis of Ia disease requires a loop or cone biopsy.
The term microinvasive is used in different senses by different authors and is probably best dropped from
common usage. Stage Ia1 and Ia2 squamous carcinoma is defined by the FIGO staging system (see 7).
Debate surrounds the prognostic value of lymphovascular space involvement in stage Ia tumours. In the
United States prevailing opinion is that if a tumour shows lymphovascular space invasion it cannot be
included in the stage Ia category but others feel that evidence of the value of lymphovascular space
invasion prognostically is still unclear or that it is probably only of value in the 3-5mm deep early invasive
group. A diagnosis of stage Ia disease cannot be made in a biopsy where excision of tumour is incomplete.
Whilst the FIGO classification does not specifically exclude the application of stage Ia1 and 2 categories to
invasive adenocarcinoma it has in the past been felt that there is insufficient data to define stage Ia1 and Ia2
adenocarcinoma in prognostic terms. What data is accumulating suggests that for tumours less than 2-3mm
deep outcome in invasive adenocarcinomas is probably very good and similar to that for stage Ia squamous
carcinoma.
Management of multifocal < 3mm depth of penetration disease must be discussed with the cancer centre
MDT team.
3.2
Clinical invasive disease
More advanced lesions may present with a mass detectable at digital examination and diagnosed with a
wedge, loop biopsy or punch biopsy.
4.
Investigations
The patient with a bulky stage Ib or more advanced tumour may require an examination under anaesthesia
to determine suitability for operative treatment.
4.1
Examination under anaesthesia
Examination under anaesthesia requires a vaginal examination to determine the degree of encroachment of
tumour into the vagina, to the pelvic side wall and the mobility of any mass. A biopsy is then taken.
Cystoscopy and sigmoidoscopy may be helpful but cystoscopy and sigmoidoscopy should not be routinely
performed for staging purposes for all cancers (grade B recommendation).
Rectal examination allows assessment of parametrial involvement and spread of tumour toward the pelvic
sidewall. Simultaneous rectal and vaginal examination may provide improved assessment of the uterosacral
ligaments and pelvic sidewall compared to rectal examination. Clinical staging may underestimate the
extent of tumour due to difficulties in assessing parametrial, pelvic sidewall, rectal and bladder invasion as
well the presence or absence of metastatic disease.
4.2
MR and CT imaging
Primary tumour size (>1cm diameter; Fujiwara et al, 2000), vaginal invasion, presence of
lymphadenopathy (>1cm diameter) and ureteric involvement are ideally assessed with an MR scan of the
pelvis and abdomen (NHS Executive, 1999; grade B recommendation). MR imaging is therefore
appropriate for all patients with biopsy proven invasive cervical cancer that is colposcopically visible
ie. > 7mm diameter or > stage Ia2. Exceptions are those patients with clinically advanced stage IV disease
or contraindications to MR scanning when post contrast CT scanning will suffice.
MR technique is identified as being important in correct staging. Thin section T2 sequences including
those perpendicular to the long axis of the cervix, are of most value in primary tumour assessment (Sironi
et al, 2002; Shiraiwa et al, 1999) Intravenous contrast in MR is non contributory in primary tumour staging
(Sheu et al, 2001; Choi et al, 2004; Sironi et al, 2002).
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There are variable results of accuracy of parametrial staging of MR and CT (Bipat et al 2003; MSAC 2001,
Hricak et al. 2005a), but MR is generally superior, with specificity of approximately 85% and sensitivity of
approximately 55-70%. The greatest value of MR in influencing correct management options lies in the
high negative predictive value (85%) for parametrial invasion (Hricak et al, 2005b), thus conferring
operable versus inoperable status.
Absence of bladder and rectal invasion can be assessed reliably by MR (Rockall et al, 2006; evidence level
IIb, grade B recommendation) and if combined by vaginal examination in clinic can accurately stage
cervical cancer in the majority of cases. Sensitivities to bladder (75%) and rectal involvement (71%) are
better with MR than CT (60% and 42% respectively), but MR has a considerably higher specificity than CT
in determining bladder invasion (91% versus 71%). Specificities are similar (80%) for determining rectal
involvement (Bipat et al, 2003). MR therefore provides a high negative predictive value for bladder or
rectal invasion.
Post contrast spiral CT is a good alternative in patients who may not be MR compatible (good practice
point). CT imaging of the abdomen and pelvis is a useful alternative for advanced (stage IV) disease,
assessing lymph nodes, mapping for radiotherapy and guidance for directed biopsies.
4.3
Other investigations
Limited recent data is available on the use of chest X rays in staging, but as the yield of metastases in
patients with clinical stage IIb or greater is reported as 4%, this is likely to be an accepted, widely
available, non controversial and inexpensive imaging addition to determining FIGO stage in these patients.
CT scans are more accurate in identifying pleural effusions, thoracic nodal status and parenchymal
metastases (ACR Appropriateness Criteria, 2005).
Intravenous urography has been superceded as a stand alone investigation, as CT or MR (or ultrasound) are
as accurate in determining ureteric obstruction secondary to parametrial invasion and give additional
information.
Barium enemas are not routinely indicated (ACR appropriateness criteria, 2005). Ultrasound is not reliable
in either assessment of primary tumour size or nodal status (Hricak and Yu, 1996).
Despite lack of inclusion in FIGO staging criteria, it is generally agreed that the involvement of pelvic or
para-aortic lymph nodes in most histological types of cervical cancer, is the greatest single predictor of long
term survival. Lymphangiography is an invasive test, not now routinely available in many radiology
departments and positive predictive values in cervical carcinoma values are variable, but probably
comparable to MR and CT for the detection of involved pelvic and para-aortic nodes. There is consistent
evidence that both CT and MR have poor sensitivity for detection of nodal metastases, based on size
criteria.
PET/CT is likely to become a standard investigation tool over the next 5 years. In particular PET may
provide precise restaging information for patients with recurrent or locally advanced cervical cancer being
evaluated for salvage therapy (Nakamoto et al, 2005). Patient numbers in PET studies tend to be small,
(due to the more recent introduction of this imaging technique) but results appear consistent that PET is
superior to MR and CT in the detection of metastatic pelvic and para-aortic nodes, with higher sensitivities
and specificities (Rose et al, 1999a). However, sensitivities remain suboptimal, and perhaps technique
dependent, in <10mm sized nodes. PET shows improved accuracies over CT or MR in the detection of
metastatic lymphadenopathy and therefore the potential to significantly change patient management.
Patients with inoperable tumour (stage IIb+; or bulky Ib2 tumours, if node negative on MR or CT cross
sectional imaging), should be considered for PET/CT imaging to determine optimal radiotherapy fields as
more than 30% of these patients will have nodal metastases.
4.4
Relative benefit over other management options and resource implications (see appendix 1)
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5.
Gynaecological cancer multidisciplinary team
Core team
Named team member
Gynae oncologist
Gynae lead cancer surgeon
Medical oncologist
Clinical Oncologist
Pathologist/ Cytopathologist
Palliative care team
Radiologist
MDT co-ordinator
CNS
Extended team
Mr Leeson / Mr Toon
Mr Bickerton/ tba
Prof Stuart
Dr Al-Sammarie
Dr Lord
Dr Williams
Dr Barwick
Ms Jones
Ms Hall
Ultrasonographer
tba
Junior doctors
Psychologist
Geneticist
Ms Grier
Social worker
tba
Ward Sister
Sr Williams
Research nurse
Colorectal/ urological/ plastics as required
5.1
Additional member or Cover
(core team only)
Dr Williams
tba
tba
tba
Dr Wenham
tba
Core/ extended teams to include
members from YGC/ NEWT
Information
Standards
All patients must have access to a gynaecological oncology clinical nurse specialist
within 24 hours of the patient being informed of her diagnosis (this should include a
daytime contact telephone number for the clinical nurse specialist). Preferably the
nurse specialist should be at the consultation when the patient is given her diagnosis.
All referring practitioners and/ or patients GP’s should be informed by letter or
secure fax within 24 hours of the patient being informed of her diagnosis.
All patients must be given appropriate literature about the management, treatment
and outcome for cervical cancer such as a Cancerbackup leaflet or equivalent.
All these activities must be documented in the patient’s case record.
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6.
Pathology
Squamous carcinoma of the cervix makes up 60-90% of all carcinomas at this site, followed by
adenocarcinoma making up 10-34% of cases. There are significant problems with classification of
carcinomas of the cervix and dependent on the definition used adenosquamous carcinomas in some series
may make up to 30-40% of all cases. The known increased incidence of adeno- or adenosquamous
carcinoma may be real or apparent due to increased awareness and reporting of these histological types.
Other variants such as adenoid cystic and adenoid basal carcinoma are much less frequent as well as the socalled as are adenoma malignum (minimum deviation carcinoma), the small and large cell neuroendocrine
type carcinomas and other tumours such as malignant melanoma. A histological classification of invasive
carcinomas of the uterine cervix (as modified by Wright et al, 2002) is given below.
6.1
Modified WHO histological classification
Squamous cell carcinoma
Invasive squamous cell carcinoma
Keratinizing
Large cell
Small cell
Non keratinizing
Large cell
Small cell
Verrucous carcinoma
Warty (condylomatous) carcinoma
Papillary squamo-transitional carcinoma
Lymphoepithelioma-like carcinoma
Adenocarcinoma
Mucinous adenocarcinoma
Endocervical type
Intestinal type
Signet-ring type
Endometrioid adenocarcinoma
Endometrioid adenocarcinoma with squamous metaplasia
Clear cell carcinoma
Minimal deviation carcinoma
Endocervical type (adenoma malignum)
Endometrioid type
Well-differentiated villoglandular adenocarcinoma
Serous adenocarcinoma
Mesonephric adenocarcinoma
Other epithelial tumours
Adenosquamous carcinoma
Glassy cell carcinoma
Clear cell adenosquamous carcinoma
Mucoepidermoid carcinoma
Adenoid cystic carcinoma
Adenoid basal carcinoma
Typical carcinoid tumour
Atypical carcinoid tumour
Small and large cell neuroendocrine carcinoma
Undifferentiated carcinoma.
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Within an individual stage the known significant pathological prognostic factors for surgically treated stage
Ib and 2a squamous carcinoma are tumour size, depth of invasion, parametrial involvement and nodal
status. Presence or absence of lymphovascular space involvement also appears important. All histological
reports should include all of the information laid out in the minimum dataset of the Royal College of
Pathologists, or the tumours should be reported using minimum data set proformas.
Variants of squamous carcinoma of the cervix include true verrucous carcinomas, which produce
extensive, large, local tumours without nodal metastases, so-called warty or condylomatous carcinomas
and papillary squamo-transitional carcinomas that resemble transitional cell carcinomas of the bladder.
Lympho-epithelioma-like carcinomas, with a dramatic stromal inflammatory infiltrate, are rare but
appear to be more frequent in Asia than in the West and appear to have a better prognosis than usual
squamous carcinoma.
Most adenocarcinomas of the cervix are of endocervical type though there has been great variability in the
literature as to what proportion is better considered endometrioid in type. Intestinal type mucinous
carcinomas and signet ring carcinomas are well described and clear cell carcinomas make up around 4%
of adenocarcinomas of the cervix. Those in women exposed to DES tend to occur at a much younger age
than those without DES exposure. So-called minimal deviation or adenoma malignum type
adenocarcinoma is rare but probably has the same prognosis as other adenocarcinomas. Well
differentiated villoglandular adenocarcinoma is an important tumour to separate from other types. This
is a tumour with a papillary pattern and only mild cytological atypia. It tends to occur in women between
the age of approximately 25 and 55 and in the majority of cases is only superficially invasive. Clinical
outcome for such carcinomas, in cases published to date, has been excellent and those treated by a simple
excisional biopsy or cone biopsy were alive and well with no evidence of recurrent disease on follow up.
There is however some recent evidence that if there is lymphovascular space involvement, invasion >3mm
or admixture with any other tumour type, then prognosis worsens considerably and so local excision is not
always appropriate.
There has been considerable debate as to whether adenosquamous carcinomas have a poorer prognosis
than other types but at the moment there is no clear evidence of this. Some evidence exists that its
incidence is higher in younger women and that metastases to pelvic lymph nodes may be more frequent
than in squamous carcinoma or adenocarcinoma but there is no clear evidence that prognosis differs. Socalled glassy carcinomas are best considered a variant of adenosquamous carcinoma and these have been
reported to have an aggressive clinical course. Adenoid cystic carcinomas account for less than 1% of
adenocarcinomas. It is debatable whether they exist as a true entity in the cervix comparable to those seen,
for example, in salivary glands. These tumours commonly show lymphatic involvement, have an
aggressive local course but may also metastasise. They should be differentiated from adenoid basal
carcinomas which are commonly a coincidental finding in the elderly or found in older women being
investigated for CIN. These tumours are much less aggressive than adenoid cystic carcinomas and because
they have a very indolent course it has recently been suggested they are reclassified as adenoid basal
epitheliomas.
Neuroendocrine tumours of the cervix include classical carcinoid tumours which are very rare, small cell
and large cell neuroendocrine carcinoma. Some also recognise an atypical carcinoid tumour in the
cervix. It is important to identify small and large cell neuroendocrine carcinomas as these appear to be
aggressive tumours and in the literature some series have shown a median survival of only twelve months.
Only around 40% of small cell carcinomas of neuroendocrine type are actually positive with
neuroendocrine markers and differentiation of small cell squamous and small cell neuroendocrine
carcinoma can be difficult.
Spread of cervical carcinoma is by direct extension of the primary tumour into adjacent structures,
permeating lymphatics and at a late stage to blood vessels. Direct is spread to the vaginal, cardinal
ligaments and to the pelvic sidewall, involving the ureters, bladder or rectum at a late stage. Lymph nodes
are initially involved close to the parametrium, then to pelvic nodes around the obturator, internal iliac,
external iliac and common iliac vessels. Para-aortic lymphadenopathy and blood borne distant metastases
are generally believed to be late developments.
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7.
Staging
Stage I
Ia
Ia1
Ia2
Ib1
Ib2
Stage II
a
b
Stage III
a
b
Stage IV
a
b
Carcinoma confined to the cervix.
Invasive carcinoma diagnosed only by microscopy; all macroscopically
visible lesions, even with superficial invasion, are stage Ib.
Invasion < 3mm depth of invasion from parent epithelial base, horizontal
spread < 7mm
Invasion > 3mm depth of invasion not greater than 5mm from parent epithelial
base, the horizontal spread < 7mm
Carcinoma confined to cervix > 7mm wide or 5mm deep but < 4cm in size
Carcinoma > 4cm diameter
Carcinoma extending beyond the cervix but not extending to the pelvic
sidewall or involving the lower third of vagina.
No parametrial involvement
Parametrial involvement
Tumour extends to the pelvic sidewall, or involves the lower third of vagina.
On rectal examination there is no tumour free space between the tumour
and pelvic sidewall. All cases of hydronephrosis with non functioning
kidney should be included unless it is known to be from another cause.
No extension to pelvic sidewall
Extension to sidewall or non functioning kidney
Extension beyond the true pelvis or to mucosa of the bladder or rectum.
Adjacent organ involvement*
Distant organ involvement
* the presence of bullous oedema is not sufficient to classify tumour as stage IV.
FIGO, 1995
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8.
Histopathology minimum dataset
National Minimum Dataset – Cervical Cancer Histopathology Report
Gross description
Dimensions of uterus:
Length ..........mm
Vaginal cuff:
Present 
Transverse .......mm
Absent 
Antero-posterior........mm
Length .......mm
Maximum dimensions of tumour: .…......mm
Histology
Type:
squamous carcinoma 
adenocarcinoma 
adenosquamous 
other (please specify) …………………………………………………………….
Well 
Histological differentiation:
Tumour size:
Moderate 
Poor 
maximum horizontal dimension .......mm depth of invasion .......mm
distance from closest resection margin (minimum tumour-free rim) .......mm position of
this ……………………….
Paracervical involvement:
Yes 
No 
Parametrical involvement:
Yes 
No 
Vaginal involvement:
Yes 
Distance from vaginal margin .......mm No 
Lymphovascular invasion:
Present 
CIN:
Present  Grade (please circle) 1
CGIN:
Present  Grade (please circle) High
Pelvic nodes
Right
left
……..
……..
……..
Yes 
……..
No 
Absent 
2
Common iliac nodes
3 Absent 
Low Absent 
right
left
……..
……..
(including obturator, internal
and external iliac)
Total number of nodes
retrieved
lymph nodes with
tumour deposits
Extranodal spread
Para-aortic nodes:
not sampled 
Extranodal spread:
Yes 
total number of nodes
retrieved
lymph nodes with
tumour deposits
positive 
……..
Yes 
……..
No 
negative 
No 
Endometrium:
Normal 
Abnormal (please state) ……………………….
Myometrium:
Normal 
Abnormal (please state) ……………………….
Right ovary/tube:
Normal 
Abnormal (please state) ……………………….
Left ovary/tube:
Normal 
Abnormal (please state) ……………………….
Comments
SNOMED codes
T83000 (Cervix)
M80703 (Squamous cell carcinoma)
M81403
T08000 (Lymph node)
M85603 (Adenosquamous carcinoma)
M80706 (Metastatic squamous carcinoma) M81406 (Metastatic Adenocarcinoma)
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9.
Treatment
9.1
Surgery (see 14. Algorithm and 15. Summary)
Generally less than 1% of patients with Ia1 disease has pelvic lymph node involvement and do not need
nodal assessment. 6% of patients have pelvic lymph node metastases in lesions extending deeper than 3mm
(Duncan, 1986) and for these tumours radical surgery/ radiotherapy or chemoradiation is usually required
(Robertson and Grant, 1998; grade C recommendation). With a Ia2 lesion, a 2cm deep loop or cone may be
suitable if the invasive component or any CIN is completely excised. However, it will be necessary to
examine the lymph nodes and this can be performed laparoscopically. Retrospective case series suggest that
a simple hysterectomy and pelvic lymphadenectomy is adequate for Ia2 disease (Selman et al, 2005; Steed
et al, 2006). An alternative would be to offer a radical hysterectomy and pelvic lymphadenectomy.
Lymphovascular space involvement may be a marker for more aggressive disease (Van Nagell et al, 1983).
Incompletely excised early invasive disease at loop excision or cone biopsy requires radical treatment.
Stage for stage survival for adenocarcinoma of the cervix appears similar to squamous cell carcinoma and it
is treated in a similar manner.
9.1.1
Loop/ cone (suitable for FIGO stage Ia1- Ia2)
For stage Ia1 disease, the pathology should be reviewed by the local cancer MDT and involve review by a
pathologist with an interest in gynaecological oncology (good practice point). However assessment of the
depth of infiltration is dependant on the quality of local preparation of the histological sections.
Lymphovascular space involvement and multifocal disease may require lymph node dissection. Completely
excised stage Ia1 disease can be treated in a cancer unit.
9.1.2
Radical trachelectomy (suitable for FIGO stage Ib1 - IIa)
Radical trachelectomy combined with pelvic lymphadenectomy appears a suitable alternative to Wertheim
hysterectomy for women wishing to preserve their fertility with tumours under 2cm in size. Recurrence
rates appear acceptable (Shepherd et al, 1998; grade B recommendation). Experience of this in the UK is
limited and should still be considered as experimental with radical hysterectomy being the gold standard
treatment. Completion treatment may be necessary in 10% of patients because of either positive pelvic
lymph nodes or close/ incomplete excision margins.
9.1.3
Wertheim hysterectomy (suitable for FIGO stage Ib1 - IIa)
This procedure involves a radical hysterectomy, removing parametrium, the upper third of vagina and a
formal bilateral lymphadenectomy, removing the common iliac, internal and external iliac and obturator
lymph nodes. The para-aortic nodes may be selectively sampled at the start of the procedure and suspicious
nodes sent for frozen section. If they are involved then surgery should be abandoned as disease will be
widely disseminated. Para-aortic nodal involvement is seen in up to 6% of stage I disease and 11-29% of
stage II disease. Para-aortic sampling appears difficult to justify in stage Ia2 disease in the absence of
histologically involved pelvic nodes (Monaghan and Burghardt, 1993; grade C recommendation). The
fallopian tubes should be removed and if the ovaries are conserved then they are lifted out of the pelvis
away from any intended radiotherapy. The ovaries are only removed if there is coincident ovarian
pathology or if the patient is approaching or beyond her menopause.
Patients wishing future fertility by surrogacy may wish cryopreservation of eggs and should
contact the Hewitt Fertility Centre at Liverpool Womens Hospital.
9.1.4
Shauta hysterectomy
This is not part of the management algorithm for North Wales patients.
9.1.5
Laparoscopic node dissection
Patients are to be referred to the Liverpool Womens Hospital as part of management of FIGO
stage Ia2 disease treated by cone biopsy and wishing preservation of fertility.
9.1.6
Cancer complicating pregnancy
Pregnancy itself does not appear to alter the biological behaviour of cervical carcinoma but a difficult
decision is almost always encountered as to whether preterm delivery or termination of pregnancy is to be
considered in a trade off between the survival of the fetus versus the mother. Vaginal delivery is
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contraindicated as disease can disseminate through the large cervical venous sinuses and be implanted into
the vagina or perineum during the course of delivery. These tumours should be managed as in the nonpregnant patient stage for stage.
9.1.7
Cervical stump carcinoma/ management of unsuspected carcinoma after simple hysterectomy
Stump carcinoma is a rare problem where cervical carcinoma occurs after a subtotal hysterectomy. A
radical trachelectomy would be ideal and could be combined with post operative radiotherapy. Radical
radiotherapy is an alternative but there can be difficulty with the intrauterine applicators.
Following simple hysterectomy after excision of an unsuspected stage Ib+ carcinoma a radical
parametrectomy with excision of a cuff of vagina is possible but can be difficult. Again radical pelvic
radiotherapy is an option.
Patients are to be referred to Liverpool Womens Hospital or to the Royal Marsden if radical
Parametrectomy to be considered. Generally radiotherapy preferred but all cases must be
discussed at the gynae cancer MDT to decide further treatment.
9.1.8
Management of stage Ib2 carcinoma (also see 9.2.1 Radical treatment)
To refer for radical radiotherapy or chemoradiotherapy at YGC.
9.2
Radiotherapy and chemoradiation
Standards
Radiotherapy should start 14 days after referral for radical treatment (good practice)
although 28 days is acceptable (minimum standard).
Radiotherapy should start 28 days after referral for adjuvant treatment (minimum
standard).
JCCO/RCR guidance
9.2.1
Radical treatment
Radiotherapy is preferred for more advanced disease (stage IIb and beyond) and for surgically unfit women
with early stage disease. This can provide radical or palliative treatment. It is administered by external
beam radiation to deal with the central tumour, pelvic sidewall extension and the pelvic lymph nodes. This
is then supplemented by a remote after loading brachytherapy technique whereby intra-uterine and vaginal
radioactive sources are inserted. After treatment, rectovaginal or vesicovaginal fistulae can rarely occur;
more frequent are troublesome proctitis and cystitis.
Current practice in UK would be to give external beam radiotherapy (EBRT) to a dose of between 45-50
Gy with daily fractions of 1.8-2 Gy with minimal interruptions or gaps in treatment. Some centres use a
parametrial/ sidewall boost with EBRT. This would be followed by a brachytherapy boost with MDR
intracavity doses of 24-28 Gy to the “A” point whereas for HDR the dose would be 28-30 Gy in 4 or 5
insertions. An interstitial boost sometimes may be delivered for bulky residual disease. Planning of the
radiation therapy should optimally be performed using CT simulator (or MRI) to determine the fields and
organs at risk.
Recent studies have shown statistically highly significant improved survival after chemoradiotherapy
(relative risks between 0.61-0.52; Keys et al, 1999; Morris et al, 1999; Rose et al, 1999b) with low dose
weekly cisplatin or combination cisplatin regimens given during radiotherapy. Newer schedules including
cisplatin and gemcitabine, vinorelbine, paclitaxel are under investigation and induction therapy with
carboplatin and paclitaxel is in trial. The Italian SNAP 01 study showed paclitaxel, ifosfamide and cisplatin
to be significantly better than ifosfamide and cisplatin (Buda et al, 2005; evidence level Ib).
Chemoradiation is now recommended as standard treatment for patients having primary non-surgical
treatment (grade A recommendation; evidence level Ia) and are fit enough to tolerate the additional
morbidity (particularly neutropaenia and emesis).
9.2.2
Adjuvant treatment
Radiotherapy is also offered to patients with histologically involved nodes after hysterectomy/
lymphadenectomy or for undifferentiated tumours as their chance of recurrent disease is increased (grade A
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recommendation; evidence level Ib). A close vaginal surgical margin is an indication for radiotherapy but
there is no agreed measurement (<3 and <5mm are examples).
The effect of adjuvant radiotherapy upon patient survival is not clinically proven (Baltzer et al, 1984) but
this may have been due to small trial size (Thomas and Dembo, 1991). However a recent GOG randomised
controlled study of 277 women found a 47% reduction in the risk of recurrence (from 28% to 15%) in
women given adjuvant radiotherapy. Patients were all node negative but had other high risk features (Sedlis
et al, 1999). A single study suggests a survival advantage for chemoradiation in the adjuvant setting for 268
women following treatment for stage Ia2, Ib or IIa disease (Peters et al, 2000).
Patients with bulky nodal disease (larger than 2cm diameter) may gain a 1-4% survival benefit (from stage
Ib-III respectively) with surgical cytoreduction prior to chemoradiotherapy (Kinney et al, 1995; Kupets et
al, 2002) and therapeutic adenectomy may be considered in selected cases (grade B recommendation).
Furthermore previously unsuspected nodal involvement detected at frozen section during surgery could
have a bilateral pelvic lymphadenectomy and para-aortic nodal dissection but the uterus and cervix
conserved in order to assist brachytherapy dosing. This must be discussed with local clinical oncologists
before implementing as a local policy.
All cases must be discussed at the gynae cancer MDT to decide further treatment.
Patients wishing future fertility by surrogacy may wish cryopreservation of eggs and should
contact the Hewitt Fertility Centre at Liverpool Womens Hospital.
9.3
Chemotherapy
Chemotherapy followed by radical radiotherapy may be considered for small cell neuroendocrine tumours.
Four cycles of etoposide and cisplatin (with or without additional paclitaxel) in combination with
radiotherapy may significantly reduce local failure in comparison to radical hysterectomy with an
acceptable overall and progression free survival (Randall et al, 2005).
All cases must be discussed at the gynae cancer MDT to decide further treatment.
9.4
Management of advanced disease
(see 10.3-5 Pelvic exenteration, Palliative care, Obstructive uropathy)
All cases must be discussed at the gynae cancer MDT to decide further treatment.
10.
Dealing with recurrent disease
Recurrent disease is seen in 20-25% of women after primary therapy and may be amenable to radiotherapy
if this has not been given before. EUA, biopsy, colposcopy, MR/CT scanning, contrast studies and PET/CT
(if available) all need to be considered.
10.1
Imaging
MR, CT and isotope bone scans have an important role in the assessment of potential recurrence with
pelvic pain and the diagnosis of insufficiency fractures post radiotherapy.
MR and/or CT scans should be performed prior to exenterative surgery to allow consideration of resection
margins.
If performed prior to pelvic exenteration a whole body PET or PET/CT scan may improve selection of
patients and therefore improve survival and reduce morbidity. If performed prior to radiotherapy a whole
body PET or PET/CT scan may change planned radiotherapy fields.
False positives for detection of recurrence with PET/CT include inflammatory change, post radiotherapy
change initially and uptake related to the urinary tract. There is limited sensitivity of PET in the detection
of positive lymph nodes less than 10mm size.
MR or CT may be more appropriate to assess potential clinical recurrence initially.
10.2
Chemotherapy
Chemotherapy can be considered for patients with advanced disease who are otherwise fit and capable of
withstanding treatment. Single agent cisplatin at modest doses (50mg/m2) gives the best balance of
response and toxicity and is standard treatment. Responses are said to be less frequent when the disease is
within the irradiated fields. Prior cisplatin therapy also lowers the response rate and since most relapsing
patients have received this as first line and so may create problems for treatment of relapse. New drugs and
combinations are needed urgently. Combination chemotherapy gives a higher response rate but also a
substantial increase in toxicity. The GOG 179 study of 294 women has shown a statistically significant
overall survival benefit with cisplatin and topotecan vs cisplatin alone with median overall survivals of 9.4
vs 2.9 months and response rates of 27% and 13% (Long et al, 2005; grade A recommendation; evidence
North Wales Cancer Guidelines, Cervical Cancer (June, 2008)
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level Ib). There was a higher incidence of febrile neutropaenia in the combination arm. Newer studies are
looking at molecular targeted agents.
All cases must be discussed at the gynae cancer MDT to decide further treatment.
10.3
Pelvic exenteration
Pelvic exenteration is an option where there is no evidence of extra-pelvic disease and the pelvic recurrence
is central. This usually involves concomitant removal of the bladder or rectum or both. Careful preoperative counselling with a multi-specialist team is essential. Five year survival may approach 50% but
survival at 5 years is rare in node positive patients.
Patients are to be referred to Liverpool Womens Hospital if exenteration to be considered and all
cases must be discussed at the gynae cancer MDT to decide further treatment.
10.4
Palliative care (see palliative care file)
The provision of palliative and supportive care for patients with gynaecological malignancies should be an
integral part of service provision. The NICE guidance Improving Supportive and Palliative Care for Adults
with Cancer was published in March 2004 and provides detailed recommendations which complement and
inform this guidance (NICE, 2004).
There is little robust evidence from the palliative care literature that is specific to patients with advanced
gynaecological malignancies, therefore this guidance is based on evidence from studies looking at patients
with a broad range of advanced malignancies.
10.5
Obstructive uropathy
Anuria due to bilateral ureteric compression is usually a feature of locally advanced disease and placement
of bilateral ureteric stents is not usually in the best interests of the patient. This must be sensitively
discussed with the patient and her family and the informed wishes of the patient respected where possible.
Any discussion must involve the Palliative Care team.
11.
Survival
5 year survival:
76-87% for stage Ib disease
85-90% for node negative patients
60-70% if 1-2 nodes are involved
30-40% if 3 or more nodes are involved
If common iliac nodes are involved then survival only 25%.
Well differentiated tumour 84% versus poorly differentiated tumour 45%.
11.1
Cancer dataset/ inventory of active trials
CaNISC data items to be developed.
Active trials – nil.
12.
Follow up
Careful inspection and palpation of the vaginal vault and palpation for any pelvic masses should be
performed 3 monthly for 2 years, 6 monthly for 1 year and then annually.
Hospital follow up should be for 5 years. Vault cytology is not helpful if the patient has had radiotherapy.
Cervical cytology is necessary if the cervix has been conserved for early disease or after trachelectomy.
All patients must be encouraged to report any symptoms suggestive of recurrent disease immediately by
contacting their CNS rather than wait until their next outpatient appointment.
12.1
Identification and management of late effects of treatment
Pyschosexual, emotional, bowel, genitourinary, neuropraxia other problems may need detailed discussion
with the clinical nurse specialist and psychological, lymphoedema, pain, spiritual and other support
services.
13.
Contact names/ numbers
Simon Leeson Obstetrician and Gynaecologist YG (t 01248 384954); CNS Sr Liz Hall (t 01248 385003)
Philip Toon
Obstetrician and Gynaecologist NEWT (t 01978 725834)
Nigel Bickerton Obstetrician and Gynaecologist YGC (t 01745 534655)
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14.
Algorithm
Algorithm for management of patients with cervical cancer
Stage Ia1
Excisional local treatment (loop/ cone)
@
complete
incomplete (CIN/cGIN or
carcinoma)
Cytological/ colposcopic
follow up
Further excision
Stage Ia2
Fertility requested
Family complete
Radical trachelectomy or
@
loop/ cone and pelvic
lymphadenectomy
ERT if node positive
Close margins, poor differentiation
(consider adjuvant chemoradiation)
Radical hysterectomy (or
simple hysterectomy) and
pelvic lymphadenectomy
or
ERT + Brachytherapy
for surgically unfit
Stage Ib1/IIa
Radical trachelectomy (for Ib1 only) / radical hysterectomy and pelvic
lymphadenectomy
Stage Ib2*/IIb/III/IV
Chemoradiotherapy/ ERT + Brachytherapy depending upon patients fitness
Post Radiotherapy Recurrence
Exenteration for solitary central pelvic disease/ or chemotherapy/ palliative care
Chemotherapy/ palliative care for multiple metastases
ERT = external beam radiotherapy
if no lymphovascular space involvement, not multifocal disease, clear margins
*management of Ib2 tumours to be according to local policy
@
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15.
Summary
Pre-op assessment
 cervical biopsy/ loop excision/ cone biopsy
Cone biopsy/ loop excision is suitable treatment for Ia1 disease <3mm depth
of invasion, no lymphovascular space involvement and excision carcinoma/
CIN is complete. Ia2 may also be treated with a cone/ loop with pelvic
lymphadenectomy if satisfies above criteria.
 For palpable disease – EUA/ cystoscopy/ biopsy/ sigmoidoscopy or
VE/PR in clinic.
 MR scan abdomen/ pelvis (> Ia2). Consider CT abdomen/ pelvis (IV).
 chest X-ray (> Ia2).
 consider PET/CT (>IIb / Ib2 and node negative on imaging).
Surgery
 Cone biopsy/ loop excision (as above).
 Simple hysterectomy - this is suitable for remaining Ia2 disease.
 Wertheim hysterectomy - this is suitable for remaining Ia2 disease; 35mm depth of penetration, lymphovascular space involvement or
incomplete excision of carcinoma; Ib and IIa disease. If following cone/
loop then should ideally be performed <2 weeks later or at 6 weeks.
Oophorectomy if peri-/ post menopausal.
 Radical Trachelectomy – tumours under 2cm if fertility desired.
 Post radiation isolated central pelvic recurrence - anterior/ posterior
exenteration.
Radiotherapy/ chemotherapy
 ERT – as adjuvant treatment for poorly differentiated and node positive
surgical patients or those with narrow/ incomplete margins of excision or
extensive lymphovascular space invasion; surgically unfit; recurrent
disease if initially received surgery alone. Consider chemoradiation.
 Chemoradiation + HDR Brachytherapy – consider for fit patients with
Ib2, bulky IIa, IIb-IVa disease; recurrent disease if initially received
surgery alone.
 ERT + HDR Brachytherapy – if unfit for surgery/ chemoradiation.
 Chemotherapy - consider platinum based chemotherapy if unsuitable for
exenteration or for multiple metastases.
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16.
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ACR Appropriateness Criteria. (2005)
http://www.acr.org/s_acr/bin.asp?CID=1201&DID=11860&DOC=file.PDF. Accessed 09 September
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Buda A, Fossati R, Colombo N et al. (2005) Randomised trial of neoadjuvant chemotherapy
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surgery in patients with locally advanced squamous cell cervical carcinoma: the SNAP01 (Studio NeoAdjuvante Portio) Italian Collaboration Study. J Clin Oncol, 23, 4137-45.
Choi SH, Kim SH, Choi HJ, et al. (2004) Preoperative magnetic resonance imaging staging of uterine
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Hricak H, Yu KK. (1996) Radiology in invasive cervical cancer. Am J Roentgenol; 167, 1101-8.
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Hricak H, Gatsonis C, Chi DS et al. (2005) Role of imaging in pretreatment evaluation of early
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Keys HM, Bundy BN, Stehman FB et al. (1999) Cisplatin, radiation, and adjuvant hysterectomy
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Long HJ, Bundy BN, Grendys Jr. EC et al. (2005) Randomised phase III trial of Cisplatin with or
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Medical Services Advisory Committee. (2001) Magnetic resonance imaging for staging cervical and
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Shepherd JH, Crawford RAF, Oram DH. (1998) Radical trachelectomy: a way to preserve fertility in
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Classification of evidence levels
Ia
Evidence obtained from meta-analysis of randomised controlled trials
Ib
Evidence obtained from at least one randomised controlled trial
IIa
Evidence obtained from at least one well designed controlled study
without randomisation
IIb
Evidence obtained from at least one other type of well designed quasiexperimental study
III
Evidence obtained from well designed non-experimental descriptive
studies, such as comparative studies, correlation studies and case studies
IV
Evidence obtained from expert committee reports or opinions and/or
clinical experience of respected authorities
Lower limit of acceptable evidence base is level IIa.
Grades of recommendation
A
Requires at least 1 randomised controlled trial as part of a body of
literature of overall good quality and consistency addressing the specific
recommendation
B
Requires the availability of well controlled clinical studies but no
randomised clinical trials on the topic of recommendation
C
Requires evidence obtained from expert committee reports or opinions
and/or clinical experiences of respected authorities. Indicates an absence
of directly applicable clinical studies of good quality
Lower limit of acceptable grade of recommendation is B.
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Appendix 1: Relative benefit over other management options and resource
implications for imaging
Use of MR or CT in pre treatment assessment is less invasive and more accurate, as well as conferring
cost/time benefits in the staging schedule of patients (Hricak et al, 1996; Hricak et al, 2005; Rockall et al,
2005) compared to conventional ‘approved’ FIGO investigations of IVU, cystoscopy, sigmoidoscopy and
barium enema.
Cystoscopy and sigmoidoscopy should be reserved for those patients with > stage Ib1 tumour on clinical
exam or imaging (Liang et al, 2000; Chung et al, 2001; Hricak and Yu, 1996).
Lymphangiography is unreliable for preoperative assessment and may interfere with the specificity and
interpretation of PET scans (Reinhardt et al, 2001).
Assessment of pelvic and para-aortic nodal disease is most accurately determined by laparotomy or
laparoscopic surgery. This is an invasive procedure not routinely practised as part of pre treatment staging
and thus the contribution of pre operative or pre radiotherapy imaging determination of nodal status is still
worthwhile, despite the limitations in sensitivity of current techniques of MR, CT and PET.
The use of accurate cross sectional imaging in staging cervical cancer is more cost effective and less
invasive than routine use of FIGO recognised investigations of IVU, barium enema, cystoscopy and
examination under anaesthesia, with cost savings estimated at approximately £1100/ patient (£2.76 million
across the UK, based on UK wide incidence of 2990 cervical cancer patients annually and that some early
stage cancers do not require staging investigations – Rockall et al, 2005; Hricak et al, 2005, Hricak et al,
1996).
It is also a more effective use of the pre treatment investigative period, without use of day or inpatient beds
for anaesthetic/ investigative purposes. This strategy should also allow more compliance with government
waiting time referral targets.
PET/CT scanning has very limited availability at present. It is likely that the greatest impact of PET in
initial staging will be for inoperable patients with stage IIb and III disease, in the detection of possible paraaortic nodal metastases, and unexpected distant metastases, with subsequent change in planned
radiotherapy fields.
Whilst reported sensitivities are variable for detection of metastatic para-aortic nodes with PET, the
alternative gold standard of laparoscopic staging carries significant risk of morbidity and has estimated
costs of £1,628 -£4,646 compared to NHS costs for PET of approximately £750. (ISD data 2004/5 and
Scottish Executive Health Dept). The general reported sensitivity and specificity of PET/CT still make PET
imaging a cost effective alternative to inadequate radiotherapy fields, or inappropriate treatment options.
References:
Chung H, Ahn HS, Kim YS et al.(2001) The value of cystoscopy and intravenous urography after
magnetic resonance imaging or computed tomography in the staging of cervical carcinoma. Yonsei
Medical
Journal; 42: 527-31.
Hricak H, Yu KK. (1996) Radiology in invasive cervical cancer. Am J Roentgenol; 167: 1101-8.
Hricak H, Powell CB, Yu KK et al. (1996) Invasive cervical carcinoma: role of MR imaging in
pretreatment work up – cost minimization and diagnostic efficiency analysis. Radiology; 198: 403-9.
Hricak H, Gatsonis C, Chi DS et al. (2005) Role of imaging in pretreatment evaluation of early
invasive cervical cancer: results of the intergroup study American College of Radiology
Imaging Network 6651-Gynecologic Oncology Group 183. J Clin Oncol: 23: 9329-37.
Liang CC, Tseng CJ, Soong YK. (2000) The usefulness of cystoscopy in the staging of cervical cancer.
Gynecol Oncol; 76:200-3.
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Reinhardt MJ, Ehritt-Braun C, Vogelgesang D et al. (2001) Metastatic lymph nodes in patients with
cervical cancer: detection with MR imaging and FDG PET. Radiology; 218: 776-82.
Rockall AG, Sohaib SA, Harisinghani MG, et al. (2005) Diagnostic performance of nanoparticleenhanced magnetic resonance imaging in the diagnosis of lymph node metastases in patients with
endometrial and cervical cancer. J Clin Oncol; 23: 2813-21.
This guideline has been developed from the Guideline Group of the British Gynaecological Cancer Society
Simon Leeson
Rachel Connor
Richard Edmondson
Mark Heatley
Nick Johnson
Sean Kehoe
Tracy Miles
Alison Mitchell
Nick Reed
Karina Reynolds
Terry Rollason
Obstetrician and Gynaecologist (chair)
Consultant Radiologist
Gynaecological Oncologist
Gynaecological Pathologist
Gynaecological Oncologist
Gynaecological Oncologist
Nurse Specialist Gynaecological Oncology
Palliative Care Specialist
Clinical Oncologist
Gynaecological Oncologist
Gynaecological Pathologist
North Wales Cancer Centre Guideline Group
Simon Leeson
Philip Toon
Nigel Bickerton
Obstetrician and Gynaecologist (chair)
Obstetrician and Gynaecologist
Obstetrician and Gynaecologist
North Wales Cancer Guidelines, Cervical Cancer (June, 2008)
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