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MEDICAL PROTOCOL
ONCOLOGICAL MANAGEMENT OF CERVICAL
CANCER
These guidelines have been developed by members of the Gynaecological
Oncology Guidelines Group, for approval by the Merseyside and Cheshire
Gynaecological Cancer Network Group.
1. Background ........................................................................................................................................ 3
2. General Information .......................................................................................................................... 3
3. Prevention – Cervical Screening and Colposcopy .............................................................................. 4
4. Referral............................................................................................................................................... 5
Histological Types and Incidence ........................................................................................................ 5
5. Stage Information .............................................................................................................................. 6
6. Pre-Treatment Assessment ............................................................................................................... 6
Clinical Staging..................................................................................................................................... 6
Pre-operative imaging ......................................................................................................................... 7
7. Treatment overview .......................................................................................................................... 7
8. Management of Invasive Disease ...................................................................................................... 8
I. Superficially invasive cervical carcinoma (microinvasive carcinoma).............................................. 8
II. Stage IBI and stage 2A less than 4 cms ........................................................................................... 8
III. More advanced stage (1B2, bulky 2a and higher) and patients unsuitable for surgery
irrespective of stage ............................................................................................................................ 9
9.
Cervical adenocarcinomas ........................................................................................................... 9
10. Small cell cervical carcinomas (neurendocrine tumours, malignant carcinoids) ............................. 9
11. Incidental finding of invasive cancer of the cervix found after Simple Hysterectomy .................... 9
12. Radical Trachelectomy ................................................................................................................... 10
13. Relapse ........................................................................................................................................... 10
14. Adjuvant Surgery............................................................................................................................ 10
15. Radiotherapy or Surgery for Carcinoma of the Cervix ................................................................... 11
I. Stage 1a disease ............................................................................................................................. 11
II. Stage 1b1 and 2a disease (non bulky) ........................................................................................... 11
III. Bulky stage 1B and 2A disease and stages IIb – IVa ..................................................................... 12
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Squamous cell carcinoma (SCC) versus adenocarcinoma (ACC) ....................................................... 12
16. Chemotherapy and radiotherapy for cervical cancer ..................................................................... 12
I. Neoadjuvant chemotherapy .......................................................................................................... 12
II. Concurrent Chemoradiation ......................................................................................................... 12
III. Integrated chemotherapy ............................................................................................................ 13
17. Postoperative radiotherapy ........................................................................................................... 13
I. Patients with involved pelvic lymph nodes:................................................................................... 13
II. Postoperative radiotherapy for patients with involved resection margins after RH: .................. 13
III. Postoperative radiotherapy for high-risk node negative patients: ............................................. 14
IV. Postoperative radiotherapy for patients treated inadvertently with simple hysterectomy: ..... 14
Morbidity of combined treatment with RH and radiotherapy. ........................................................ 14
18. Extended field radiotherapy .......................................................................................................... 15
I. Prophylactic extended field radiotherapy: .................................................................................... 15
II. Irradiation of patients with known para-aortic nodal metastases: .............................................. 15
19. Radiotherapy for patients with isolated local failure in the pelvis after RH .................................. 16
20. Palliative radiotherapy ................................................................................................................... 16
21. Improving Effectiveness of Radiotherapy: Hb Levels .................................................................... 16
22. Chemotherapy for advanced or recurrent cervical cancer ............................................................ 17
23. Follow-Up ....................................................................................................................................... 20
24. Maintenance of Quality ................................................................................................................. 20
25.
Audit and Clinical Outcome ....................................................................................................... 20
26. Clinical Trials ................................................................................................................................... 20
27. Palliative Care and Nursing care ..................................................................................................... 21
Appendix I ............................................................................................................................................. 23
Appendix II ............................................................................................................................................ 25
References ............................................................................................................................................ 27
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1. Background
1897: Ernest Wertheim in Vienna embarked on a remarkable series of radical
hysterectomies and limited pelvic node resections – eventually performing
over 1300 procedures with no patient lost to follow-up. Operative mortality of
30% in the first hundred cases was later reduced to 10%.
1903: Margaret Cleaves, a New York physician first applied radium to carcinoma of
the cervix.
1911: the first “clinical cure” of cervical cancer by radium reported from the
Radiumhemmet at Stockholm which had been established in 1910.
1940s: Meigs of Boston revised and extended the Wertheim operation, claiming
75% survival among his first hundred cases and a survival of stage I of
81.8%.
1948: Brunschwig of New York published on adjacent pelvic organs with diversion of
urine and the faecal stream through conduits leading to the abdominal wall for
advanced and recurrent cervical cancer.
2. General Information
Carcinoma of the cervix is the third most common gynaecological malignancy in
women, accounting for 2740 new cases and 1,225 deaths in England and Wales in
1997(1). World-wide, cervical cancer is second only to breast cancer as the most
common malignancy in both incidence and mortality. More than 420,000 new cases
are diagnosed each year (2), predominantly among the lower socio-economic
classes in both developing and industrialised nations (3)
There is a very strong aetiological link with human papilloma virus (HPV) infection
and cervical cancer (4). Indeed HPV has recently been identified in 99.7% of all
cervical cancers tested by Walboomers et al (5). Apart from smoking all other risk
groups are merely co-factors for the risk of high risk HPV infection eg age at first
intercourse and number of sexual partners.
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The Health of the Nation set a target to reduce the incidence of cervical cancer by
20% before the year 2000 (6). This was achieved in 1993, in part as a consequence
of an effective cervical screening programme (5).
Among the major factors that influence prognosis are stage, tumour volume and
grade of tumour, histological type, lymphatic spread, and vascular invasion, depth of
stromal invasion with the latter being most important and reproducible. ( 7,8,9). A
multivariate analysis of prognostic variables in 626 patients with locally advanced
disease (II, III, and IV) studied by the GOG revealed that para-aortic and pelvic
lymph node status, tumour size, patient age, and performance status were
significant for progression-free interval and survival.
Adenocarcinoma of the cervix over recent years has increased both in proportion
and true incidence compared to squamous tumours ( 10). Immunocompromised
women have more aggressive and advanced disease and a poorer prognosis.
3. Prevention – Cervical Screening and Colposcopy
Compelling evidence exists that large numbers of cervical cancers can be prevented
by a well-organised cervical screening programme (11). These programmes combine
cervical cytology as a primary screen with colposcopy, and treatment where
appropriate, for those who are screen positive. In the United Kingdom, “Health of the
Nation” targets for the reduction of cervical carcinoma incidence have been reached
many years ahead of target. A consistent fall in incidence at all ages follows
improvements in the NHS Cervical Screening Programme (NHSCSP) and the
introduction of computerised “call and recall” systems in the late 1980’s. This
success reflects the huge rise in the percentage of the target population who are
now being screened (eg this rose from 44 – 83% between 1988 and 1993). The
NHSCSP has produced a number of publications which outline the standards that
are expected from those who participate in all aspects of the screening process ( 12).
The main role of the cervical screening programme is to lower the incidence and
mortality of cervical carcinoma. However, there will be occasional referrals where it
is felt that an invasive lesion may be present, and these patients should receive
urgent management on the grounds of clinical suspicion.
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The North West presently has the highest regional incidence and lowest screening
cover for cervical cancer in the country. The regional quality assurance team is coordinating initiatives to correct this.
4. Referral
Any woman with either post-coital or inter-menstrual bleeding, persistent vaginal
discharge or whose cervix looks abnormal should be referred by a rapid access
referral to a gynaecologist or colposcopy clinic. If the patient appears to have
superficial invasion a loop or cold knife cone biopsy should be performed by the lead
clinician locally. The specimens should be reported by a pathologist with special
interest in gynaecological malignancies and reviewed by the MDT. When the
disease is higher than stage IaI, and for all non-squamous invasive lesions, referral
of the patient to the specialist gynaecological team is indicated. All patients with
biopsy proven invasive disease should be considered for pathological review.
Our aim is to achieve clinical management of all patients within the target cancer
waiting times of the Dept of Health.
Histological Types and Incidence
As a result of screening, rates per 100,000 for all invasive cervical cancers
decreased by 36.9% over 24 years [12.35 (1973–1977) vs 7.79 (1993–1996)].
Similarly, the age-adjusted incidence rates for squamous cell carcinoma declined by
41.9%. In contrast, the age-adjusted incidence rates for adenocarcinoma increased
by 29.1%. The proportion of adenocarcinoma increased 95.2% relative to squamous
cell carcinoma. Observed survival rates for adenocarcinoma vs squamous cell
carcinoma were poorer for regional but not localized or distant disease (13).
Adenosquamous, small cell carcinomas and primary sarcomas of the cervix have
been described occasionally, and malignant lymphomas of the cervix, both primary
and secondary, have also been reported.
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5. Stage Information
The precursor lesion is dysplasia or cervical intraepithelial neoplasia [CIN], which
can subsequently become invasive cancer. This process can be quite slow.
Longitudinal studies have shown that in untreated patients with CIN 3, 18% will
develop invasive carcinoma over a period of 10 years (13). As it becomes invasive,
the tumour breaks through the basement membrane and invades the cervical
stroma. Extension of the tumour in the cervix may ultimately manifest as an
exophytic growth (70%), ulceration (20%) endocervical barrel shaped cervix or with
extensive infiltration of underlying tissue including bladder or rectum. In addition to
local invasion, carcinoma of the cervix can spread via the regional lymphatics or
blood stream. Tumour dissemination is generally a function of the extent and
invasiveness of the local lesion. While cancer of the cervix generally progresses in
an orderly manner, one occasionally sees a small tumour with distant metastasis.
For this reason, patients must be carefully evaluated for metastatic disease.
Treatment is very dependent on stage and can therefore affect management and
outcome (14).
FIGO Staging System (See Appendix I)
6. Pre-Treatment Assessment
Examination under anaesthetic, cystoscopy and biopsy of the cervix for histology
Sigmoidoscopy may be performed if clinically indicated
Other investigations should include:
 FBC, Biochemical Profile
 Chest X-Ray
 IVP or MRI
Clinical Staging
The staging should be performed by an experienced examiner under GA, including a
cystoscopy. There are occasions where outpatient clinical assessment and imaging
may be sufficient. The clinical staging should not be changed on the basis of
subsequent findings, thus allowing more accurate comparison to other treatment
regimes. There are however limitations to clinical staging.
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Pre-operative imaging
Magnetic Resonance Imaging (MRI) is accurate in evaluating cervical disease, early
parametrial extension and lymph node status which translates into prognosis and
survival predictions. MRI, in terms of determining extent of tumour, is generally
superior to CT (15) and ultrasound (16,17), but in many cases clinical examination will
be the overriding factor. MRI may be superfluous and delay treatment if clinical
examination confidently indicates a stage of 1b1 or less, when a traditional IVP may
be sufficient.
Ultrasound (US) is commonly used to predict hydroureter and hydronephrosis and
has replaced IVP in many centres. There is some evidence to suggest that the use
of internal coils for high resolution MRI of the cervix for greater detailed cervical
anatomy and pathology (18). Advances in radiology mean that cancer of the cervix
can be evaluated pre-operatively allowing for more informed discussion regarding
the optimum treatment, either radiotherapy or surgery. PET-CT scanning is being
evaluated and my prove to be useful for selected patients. It may help reduce
inappropriate surgery for women with parametrial extension.
7. Treatment overview
Radiotherapy and surgery are equally effective in terms of survival for the majority of
women with early cervical cancer. Surgical treatment should be offered to women
with early stage cancer for whom a cone biopsy is inadequate. This should be
carried out by a sub-specialist gynaecological oncologist working within a Cancer
Centre. Radical radiotherapy should be offered when surgery is unlikely to remove
the tumour completely. The effects of radiotherapy can cause long term damage to
other organs; bowel, bladder and ovary, and this is worst when combined with
surgery. Two meta-analyses have shown convincing evidence of survival benefit for
chemoradiation over radiotherapy alone in locally advanced disease, at a cost of
greater short term toxicity and an uncertain increase in late effects. The survival and
disease free benefit may be greater in Stage I and II disease. (2, 19)
During pregnancy, no therapy is warranted for lesions of the cervix which can be
confidently assessed colposcopically as being preinvasive. One third of these
lesions will regress during pregnancy so colposcopic assessment and treatment as
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required should be arranged at a suitable interval after delivery. Treatment of
invasive cervical cancer during pregnancy depends on the stage of the cancer and
gestational age at diagnosis. The traditional approach is to recommend immediate
therapy appropriate for the disease stage when the cancer is diagnosed before fetal
maturity, and to delay therapy only if the cancer is detected in the final trimester
(20,21). However, other reports suggest that deliberate delay to allow improved fetal
outcome may be a reasonable strategy. Published evidence regarding this problem
is largely anecdotal but there is no published work suggesting that such delay results
in a large reduction in survival.
8. Management of Invasive Disease
All patients with a diagnosis of invasive cervical cancer are referred for MDT opinion
and almost all will be subsequently managed by the specialist team at the
gynaecological oncology centre.
I. Superficially invasive cervical carcinoma (microinvasive carcinoma).
Early stromal invasion with unmeasurable invasive component is diagnosed and
treated by cone biopsy, normally at the referring unit. Stage IA2 disease within the
current staging definition is treated at the centre by modified radical hysterectomy
(Meigs 2), with pelvic node dissection up to the iliac bifurcation. Intermediate cases
of superficially invasive disease are reviewed on an individual basis at the central
diagnostic MDT meeting and the individual management thereby determined. In premenopausal patients, the ovaries are normally conserved.
II. Stage IBI and stage 2A less than 4 cms
Treatment of choice is Meigs 3 radical hysterectomy with pelvic lymphadenectomy
up to the aortic bifurcation. We usually aim to conserve the ovaries in patients under
the age of 45 (squamous) or age of 40 (adeno).
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III. More advanced stage (1B2, bulky 2a and higher) and patients unsuitable for
surgery irrespective of stage
Patients are normally referred for radiotherapy +/- chemotherapy. See sections 15.3
and 16.3.
9.
Cervical adenocarcinomas
They are treated the same as invasive squamous carcinomas stage for stage.
Microinvasive adenocarcinomas are more difficult to diagnose than their squamous
counterparts, but when diagnosed with confidence may be amenable to local
treatment. High grade glandular intraepithelial neoplasia (adenocarcinoma in-situ), is
diagnosed and treated by cone biopsy but radical treatment tends to be
recommended for most invasive lesions.
Villoglandular carcinomas should be treated similarly to other adenocarcinomas,
though following definitive histology a more favourable prognosis may be assigned
for true villoglandular lesions. (22)
10. Small cell cervical carcinomas (neurendocrine tumours,
malignant carcinoids)
Combined modality treatment is recommended with chemotherapy and radiotherapy
in patients with good performance status. The standard regimen in Clatterbridge
Centre for Oncology for small cell tumours is : Carboplatin AUC 6 and Etoposide
100mg/m2 daily X 4 cycles, followed by radiotherapy for localised disease.
11. Incidental finding of invasive cancer of the cervix found after
Simple Hysterectomy
Further management is based on the above principles. Treatment options will
therefore, lie between expectant management, node dissection (open or
laparoscopic) with or without radical parametrectomy, or chemoradiation.
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12. Radical Trachelectomy
Trachelectomy is becoming an accepted alternative approach to early cervical
cancers in women wishing to preserve the option of fertility (23). The procedure
involves removing the cervical together with the parametrial tissue whilst preserving
the uterine body. Publications have suggested an equivalent survival when
compared to a standard radical hysterectomy, for stage 1a2 or small (<2cm) stage
1b1 cervical tumours. Trachelectomy for 1b1 tumours of >2cm has been associated
with a higher recurrence rate. The procedure is carried out in conjunction with a
laparoscopic pelvic lymphadenectomy.
Preoperative evaluation prior to consideration of a trachelectomy includes an EUA
(and assessment of the cervical length), MRI and careful counselling regarding the
risks associated with the procedure. Published figures have stated a 60-70% chance
of pregnancy following trachelectomy, but a 25-75% risk of a preterm (potentially
extremely preterm) delivery. (24,25,26,27). In the Liverpool Womens Hospital, all
women who have undergone a radical trachelectomy have a prophylactic cervical
cerclage placed at the time of the original surgery, and are followed up during any
subsequent pregnancy by the recurrent miscarriage team.
13. Relapse
Local relapse after primary surgery is managed in most cases by radical
chemoradiation. Those patients who relapse after radiotherapy are carefully
assessed for surgery. However, pelvic exenteration is technically difficult, bladder
and bowel diversion are required with associated morbidity and in this centre it is
considered only in very selected patients. Metastatic disease is managed with
palliative chemotherapy +/- radiotherapy.
14. Adjuvant Surgery
In the recent GOG series, bulky stage IB patients were followed by hysterectomy
after chemoradiation.(28,29). No survival advantage ensued but pelvic control was
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improved. A second option may be surgery following neo-adjuvant chemotherapy for
Stage 1B-IIB patients, as in the proposed EORTC trial 55994. This is based on
studies in Argentina and more recently Italy (30). A meta-analysis has been published
in preliminary form and shows a highly significant survival benefit compared to
radiation alone (31). The place of hysterectomy as a routine adjunct to pelvic
radiotherapy is controversial. The increased risk of combined modality treatment is
not necessarily balanced by improved outcome (32). In this centre it is considered
only in exceptional cases, such as disruption of optimal dose fractionation, distortion
of normal pelvic anatomy (e.g. fibroids), coincidental gynaecological pathology, or in
selected cases of poor response to external beam radiotherapy.
15. Radiotherapy or Surgery for Carcinoma of the Cervix
I. Stage 1a disease
These patients are generally managed surgically but those unsuitable for surgery
can be treated with intracavitary brachytherapy alone. .
II. Stage 1b1 and 2a disease (non bulky)
There is agreement that for these patients either radical chemoradiation or radical
hysterectomy (RH) are equally effective treatments with approximately 85-90% of
patients being cured with either modality (33,34). RH and radiotherapy are associated
with different types of complications. The choice of treatment depends on the
general health of the patient. Surgery is generally recommended for pre-menopausal
women as preservation of ovarian function is possible and vaginal stenosis can be
avoided. The risk of late bladder and bowel toxicity is also less after surgery. For
less fit patients surgery with prolonged general anaesthesia is best avoided and
these patients are generally treated with radiotherapy or chemoradiation. As the risk
of pelvic lymph node involvement is estimated to be 15% our policy is to treat these
patients with a combination of external beam radiotherapy and intracavitary
treatment.
For less fit patients intracavitary treatment alone can be considered
accepting a higher risk for nodal failure.
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III. Bulky stage 1B and 2A disease and stages IIb – IVa
These patients are best treated with a radical course of chemoradiation. Less fit
patients may be treated with radiotherapy alone.
Squamous cell carcinoma (SCC) versus adenocarcinoma (ACC)
These are treated similarly with either radical surgery or radiotherapy. A large series
from the MDA hospital showed that with radiation therapy the control of disease in
the pelvis was similar for ACC as for SCC. The survival rates were lower for ACC
than for SCC due to a higher rate of distant metastases (13).
16. Chemotherapy and radiotherapy for cervical cancer
I. Neoadjuvant chemotherapy
This is not routinely recommended. Eight of nine randomised studies and a recent
literature based meta-analysis have not shown a benefit with this approach ( 35), but
a second individual patient meta-analysis is more optimistic for further development
of this (36). It is not standard treatment, but patients may be considered for
randomisation to EORTC 55994.
II. Concurrent Chemoradiation
This is now standard practice for patients with bulky or locally advanced disease who
are fit for the combined approach. There have been six North American based
randomised trials published since April 99, and there have been 2 meta-analyses,
one of 19 studies (2), the other comprising 8 English language publications using
only cisplatin based chemotherapy (19) . All except one of the US trials showed a
clear benefit for this approach in terms of improved disease control in the pelvis and
a 10 –15% improvement in overall survival (2,28,37,38,39,40). The overview
demonstrated both an improvement in overall survival but also improved local and
distant control rates (2). The acute toxicity is greater with concurrent chemotherapy
and potentially higher rate of late complications. This approach is considered in all
patients with locally advanced carcinoma of the cervix who have good performance
status and considered suitable for radical treatment (41).
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III. Integrated chemotherapy
This is a specialised approach piloted at Clatterbridge over the last 10 years and can
be considered in patients who have persistently bulky disease after external beam
XRT or disease extending to the pelvic side wall and brachytherapy is not
appropriate. These patients are given three cycles of chemotherapy and repeat EUA
is performed in view to proceed with brachytherapy.
Clatterbridge experience with
this approach has been good particularly for patients with stage II disease (32).
17. Postoperative radiotherapy
This is considered for patients at high risk for disease recurrence. These include the
following groups of patients.
I. Patients with involved pelvic lymph nodes:
There are no randomised trials looking at the benefit of postoperative XRT in this
situation. Retrospective studies show that pelvic radiotherapy reduces the risk of
local failure but does not impact on overall survival (42,43). One study showed that
for patients with a single positive node with small primary tumours the prognosis is
good without radiotherapy (29).
Our current policy is to consider adjuvant radiotherapy to patients with more than
one involved pelvic lymph node, or where there is extracapsular spread.
II. Postoperative radiotherapy for patients with involved resection margins
after RH:
Patients with close margins are discussed at the multidisciplinary meeting and
decisions regarding further treatment are made on an individual basis.
Our policy is to consider postoperative external beam  intracavitary treatment.
Patients with gross residual disease after RH do badly. To optimise local control
higher radiation doses may be used than for patients with residual microscopic
disease.
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III. Postoperative radiotherapy for high-risk node negative patients:
A recent GOG randomised study showed that for patients with negative pelvic nodes
and either large primary tumours, CLS invasion or deep stromal invasion, there was
an advantage for postoperative radiotherapy in terms of reducing the risk of
recurrence. No survival advantage was seen and the rate of major complications
was 6% in the combined treatment group vs 2% in the patients treated with RH (29).
Our current policy is not to offer radiotherapy to these patients.
IV. Postoperative radiotherapy for patients treated inadvertently with simple
hysterectomy:
These patients can subsequently have parametrectomy, pelvic lymphadenectomy
and upper vaginectomy. The complication rates with reoperation can be substantial
and there are several reports suggesting very good outcome with radiotherapy (44).
Our policy is to discuss the further management of these cases at our
multidisciplinary meeting.
For those patients treated with radiotherapy a combination of external beam and
intracavitary treatment is used in combination with chemotherapy.
Morbidity of combined treatment with RH and radiotherapy.
There is evidence that the major complication rate is increased with combined
treatment. One randomised study comparing surgery with radiotherapy described a
28% rate of major complications in the surgical arm vs 12% with radiotherapy (45).
However almost two thirds of the surgical arm had postoperative radiotherapy
because of bulky disease, tumour cut-through or involved pelvic lymph nodes For
this reason it is important to predict patients who are likely to need postoperative
radiotherapy if treated with RH, such as those with tumours >4cm. These patients
are best treated with radiotherapy
Our aim is to carefully select patients for surgery and to avoid postoperative
radiotherapy as it is associated with much greater morbidity.
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18. Extended field radiotherapy
Extended field radiotherapy, which includes para-aortic nodes, is associated with an
increased rate of acute and late toxicity.
I. Prophylactic extended field radiotherapy:
There is evidence from one randomised study that extended field radiotherapy offers
a survival advantage compared with pelvic radiotherapy for stage I and II patients
with a high risk of para-aortic nodal metastases i.e. those with either bulky disease
or involved pelvic lymph nodes (46). However one of the recent Chemoradiation trials
compared extended field radiotherapy with Chemoradiation and found the latter to
be better in terms of overall and disease free survival (47).
Prophylactic para-aortic radiotherapy can be considered for patients not fit for
primary chemoradiation.
II. Irradiation of patients with known para-aortic nodal metastases:
Five-year survival rates for patients with para-aortic node metastases treated with
extended field radiotherapy vary between 8-50% (48). The worst results are in
patients with stage III and IV disease as control of pelvic disease is also an issue for
these patients. The best results are seen in patients with small volume stage I and II
disease who are found to have microscopic nodal disease intraoperatively.
The management of patients with multiple grossly involved para-aortic nodes is
generally palliative.
A recently published single arm study using extended field
radiotherapy and concurrent chemotherapy reported a three year overall survival
rate of 39% for patients with para-aortic nodal metastases (49). Both acute and late
toxicity was substantial. In highly selected patients this approach would appear to
have a curative potential.
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19. Radiotherapy for patients with isolated local failure in the pelvis
after RH
Up to 50% of these patients can be salvaged with radiotherapy ( 50,51). The prognosis
is best for those with small volume central recurrences. Treatment includes both
external beam and intracavitary radiotherapy. Patients with bulky recurrences have a
poor
prognosis
and
may
be
considered
for
neoadjuvant
or
concurrent
chemotherapy. Decisions regarding the use of chemotherapy are made on an
individual basis.
20. Palliative radiotherapy
This is considered for patients with either advanced, recurrent, metastatic disease or
for unfit patients with any stage of disease.
Palliative local radiotherapy is
particularly effective for bleeding, discharge or pain. Depending on the performance
status of the patient external beam or intracavitary or combinations of both can be
used.
21. Improving Effectiveness of Radiotherapy: Hb Levels
The presence of oxygen has important implications in effectiveness of radiotherapy.
Hypoxia plays an important role in tumour resistance in most solid tumours including
carcinoma of the cervix. There is growing evidence in the literature that local control
by radiotherapy is closely related with haemoglobin levels and this reflects the
overall survival. Our policy at CCO is that all patients with cervical carcinoma
undergoing radical radiotherapy should have weekly blood test for FBC and would
require blood transfusion if Hb is <12g/dl. Selected patients may benefit from
prophylactic use of growth factors (Erythropoetin) where the Hb level prior to starting
chemoradiation is <12.0g/dl (52).
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22. Chemotherapy for advanced or recurrent cervical cancer
Cytotoxic chemotherapy with drugs including mitomycin C, cisplatin, 5FU and more
recently ifosfamide has been employed in the management of advanced disease for
several years, with response rates of the order of 30% and a duration of response of
6-9 months. The most active drug is cisplatin, which therefore restricts the eligible
patient group to those without renal impairment. There is little evidence in favour of
activity of carboplatin
Problems such as prior radiation treatment, extensive surgical procedures and often
poor general performance status in elderly patients have contributed to the low
expectation of efficacy of this modality in the past. A number of trials in the 1970’s
addressed first line chemotherapy (neoadjuvant) followed by radiation therapy, and
these were largely negative in terms of improvement in progression free or overall
survival, although response rates were higher than in the advanced disease patients
(35). Two more recent series have explored neoadjuvant chemotherapy followed by
surgical excision (NACT-S). (53,54), with more promising results, as a result of which
an EORTC trial is being proposed for this approach with cisplatin based
chemotherapy in Stage IIB patients.
The regimen employed in the CCO for many years has been bleomycin, mitomycin
C and cisplatin (BMC) based on the original MD Anderson publication (55) and there
is experience in both advanced disease and as adjuvant therapy after external beam
radiation therapy (32). A number of other regimens have been advocated including
Bleomycin, Ifosfamide and Cisplatin (BIP) as published by Buxton et al (56), which is
considered to be toxic, and cisplatin and 5FU regimens such as that proposed in the
CE04 study.
Topotecan is a topoisomerase I inhibitor. The response rates to single agent
Toptecan ranges from 13% to 28% depending on whether or not patients received
prior treatment. The GOG 179 confirmed significantly superior response rates, DFS
and OS in patients treated with combination Cisplatin and Topotecan as compared
to single agent Cisplatin (Long HJ 3rd, et al. Randomized phase III trial of cisplatin
with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology
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Group Study. J Clin Oncol. 2005 Jul 20;23(21):4626-33). In this study, patients had
a better outcome irrespective of previous cisplatin chemotherapy. However, on
multivariate analysis, the improvement in OS is statistically significant only in
patients with a long duration from time of diagnosis to time of starting study
treatment (16 months or more). There was a significant 17.7% rate of FN in the
combination arm and the protocol recommended secondary prophylactic G-CSF if
FN occurs after dose modification.
When Topotecan is licensed for the use in cervical cancer we recommend selecting
patients who have more chance of benefit from Topotecan and Cisplatin
combination to justify administration of this potentially myelotoxic regimen as follow:
Time from diagnosis to relapse >/= 12 months (Whether or not had prior radiosensitizing cisplatin)
No prior radio-sensitizing cisplatin (irrespective of time from diagnosis to relapse).
PS 0/1 (only 8% of patients in each arm had PS 2).
The regimen will be as follows:
TC
Topotecan 0.75 mg/m2 IV (over 30 min) D1,2,3
Cisplatin 50 mg/m2 IV infusion
D1
Body surface area capped at 2 m2
Repeated every 21 days for maximum of 6 cycles.
Attention to 20% and 40% Toptecan dose reduction for grades III and IV
myelotoxicity respecrively.
Option 2; Cisplatin and Paclitaxel (cisplatin 50 mg/m2 plus paclitaxel 135 mg/m2)
every 3 weeks for six cycles.
Moore DH. J Clin Oncol. 2004 Aug 1;22(15):3113-9. Phase III study of cisplatin with
or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma
of the cervix: a gynecologic oncology group study.
Rationale is: higher RRs and longer PFS for this combination as compared to single
agent Cisplatin.
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Adenocarcinoma and Adeno.squamous carcinoma.
Traditionally literature report similar or worse overall outcome for Adenocarcinoma
and Adeno.squamous carcinoma as compared to Sq C Ca. However, there is
substantial evidence that Adenocarcinoma and Adeno.squamous carcinoma are
equally chemosensitive and in some reports more sensitive to chemotherapy.
Ref
(n of pts)
Treatment
Histology
RR %
Fiorica J
(n=35)
(no prior
CTH)
Dimopoulo
s MA.
(n=60)
Routine
GCSF
Topotecan+
Cisplatin
Sq=21
Non Sq=11
33
27
(ORR=28)
Cisplatin+
Ifosfamide+Paclitax
el
Sq
=41 36*
Non Sq=19 67*
Kavanagh
JJ.
(n=24)
Cisplatin+
Doxorubicin+5FU
(76h infusion / 4w)
Curtin JP. Paclitaxel
(n=42) pts 175mg/m2.
130
failed
mg/m2 if prior RTH
standard
treatment)
(Ad.Ca &
Ad.Sq.Ca)
42
(25)
Ad. Ca 27 31
pts
(22)
Ad.Sq
15
pts
PFS
G3/4
neutrope
nia 26%
&
Thrombo
cytopenia
7%
DOR=7m
DOR
4.8 m
OS
(month)
Irradiation
% (CR)
All 10
In=33 (11)
Out=30 (10)
11.5 m*
24.7 m*
In=23%
Out=58%
GIII/IV
Neut 26%
NF 10/296
cycles
(OS=8.3
)
=
For Adeno Ca and Adeno.sq.ca
Option 1: Single agent paclitaxel (Curtin JP JCO 2001. 1,19 (5).1275 (GOG). (see
table)
Option 2: Cisplatin and Paclitaxel
Rational for option 2: (1) Curtin JP study showed RR of 31%. We know that Cisplatin
is tradionally the drug of choice. Combining them is likely to improve response rates.
(2) Cisplatine+ Ifosfamide+Paclitaxel yields high response RR of 67% in Non
Squamous histologies (Dimopoulos MA. Gynecol Oncol. 2002 Jun;85(3):476-82).
However myelotoxicity was high despite G-CSF). This toxicity is most likely to be due
to Ifosfamide rather than Cisplatin. It is sensible to omit Ifosfamide from this regimen
for treating these patients with an intent of palliation. (3) If we also chose Cisplatin
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and Paclitaxel for Sq C Ca as discussed above, then this treatment will be for all
histologies.
Other drugs
Carboplatin
AUC 5 unproven
Some centres employ methotrexate in place of mitomycin C
CPT 11 (ironitecan)
Gemcitabine
promising)
promising)
Taxanes
23. Follow-Up
Standard: Four monthly for years 1 and 2, six monthly to 3 years. Discharge with
open access to CNS in the event of new symptoms or concerns. CNS holistic
assessment is carried out 6 weeks after the completion of primary treatment.
24. Maintenance of Quality
These guidelines conform to:
Improving outcomes in Gynaecological Cancers NHS Executive 1999-10-21
RCOG recommendations on specialists in gynaecological oncology 1996
NIH Consensus Statement on Chemoradiation 1999
25.
Audit and Clinical Outcome
Gynaecological database is now in place which will facilitate clinical audit and
research.
26. Clinical Trials
1- EORTC 55994 – Stage Ia2- IIB Ca Cervix : Cisplatin based chemotherapy
followed by surgery compared to chemoradiation therapy
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27. Palliative Care and Nursing care
Palliative care input is appropriate to consider at all stages of the patient’s cancer
journey. Please refer to the separate palliative care guideline for detailed advice.
All women with a diagnosis of a Gynaecological Cancer should be offered the
support of, and have access to a Clinical Nurse Specialist (CNS), in order to
facilitate the woman’s needs throughout the Cancer Journey, including those of her
partner or carer.
The skills of the C.N.S. as a consultant, practitioner and educator can be drawn
upon at all stages throughout their illness, from the pre-diagnosis to the terminal
stage – incorporating the Specialist Palliative Care Services provided in the hospital
and the community setting. Bereavement Support will also be available, if
appropriate.
Important aspects of the role are to provide advice, support, information and to
effectively incorporate appropriate resources. The C.N.S. will be receptive to the
social, physical, psychological, cultural, sexual and spiritual needs of the patient.
The aim of the patient support is to assist with the improvement in the quality of their
lives, allowing them to become more empowered; to help take control and enhance
their self esteem.
The C.N.S. works closely with Surgeons, Oncologists, Radiotherapists, Consultants
in Palliative Medicine and others (Nurses & P.A.M.s).
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They will undertake a number of key responsibilities including:
Linking with other professionals who can help the patients throughout the
system
A resource for information and support to the patient carer and other H.C.P.s
Liaison point for other health care professionals in primary and secondary
care
Teacher and Educator
Researcher
Standards and Audit Co-ordinator
Co-ordinate Care Services
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Appendix I
FIGO Staging System
Stage I
IA
Clinical lesions strictly confined to cervix
Preclinical carcinomas of cervix diagnosed only by microscopy. All gross
lesions even with superficial invasion are stage IB cancers. Invasion is limited
to measured stromal invasion with maximum depth of 5.0 mm and no wider
than 7.0 mm (1)
IAI
Stromal invasion no greater than 3.0 mm and no wider than 7.00 mm
IA2
Maximum depth of invasion of stroma greater than 3 mm and no
greater than 5 mm taken from base of epithelium, either surface or glandular,
from which it originates; horizontal invasion not more than 7 mm
IB
Clinical lesions confined to the cervix or preclinical lesions greater than stage
IA
IBI
Clinical lesion no greater than 4.0 cm in size
IB2
Clinical lesion greater than 4.0 cm in size
Stage II
Extension beyond cervix but not to pelvic wall. Involves vagina, but not
the lower third
IIA
Involves vagina, but not lower third. No obvious extension to parametria
IIB
Obvious parametrial involvement but not extending to pelvic sidewall
Stage III
Extension to pelvic wall. On rectal examination, no cancer-free space
between tumour and pelvic wall. Involves lower third of vagina
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IIIA
Involves lower third of vagina
IIIB
Extension to pelvic side wall and/or hydronephrosis or non-functioning kidney
Stage IV
Extension beyond true pelvis or involvement of bladder or rectal
mucosa. Bullous oedema does not permit a case to be assigned to
Stage IV (IVa = local spread; IVb = distant mets)
Notes: Diagnosis of both Stages IA1 and IA2 is based on microscopic examination
of biopsy specimens, preferably a cone, which must include the entire lesion.
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Appendix II
Radiotherapy Details
External Beam radiotherapy:
Patient Position: Patient should be lying supine. Vaginal examination performed
and a vaginal marker is placed if required. These patients now have a planning CT
scan to outline the gross tumour clinical target volume.
Field Size: Upper Border: L4/L5 disc space ( half way through L-5 if increased risk
of morbidity)
Lower Border: Bottom of Obturator foramen. In case of vaginal
involvement, 2-3 Cm below the lower extent of disease.
Lateral Border: 1 Cm lateral to the pelvic brim
Posterior Border: Junction of S2 and S3 vertebrae or 2 Cm anterior to the
most concave part of anterior sacrum. Take into account the sagital view of
MRI scan films. Treat with parallel opposed field if Uterosacral ligament
involved.
Consider appropriate lead shielding.
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Dose Fractionation:
Stage I B1and non-bulky IIa:
XRT: 45 Gy in 25 fractions over 35 days
Brachytherapy: HDR: 7Gy x 2 to point “A”: 1 week apart
Stage I B2, IIB, III and IVA:
XRT: 50.4 Gy in 28 Fractions over 38 days
Brachytherapy:
HDR: 7Gy x 2 to point “A”
1 week apart.
Consider Parametrial Boost if the disease is extending to
Parametriem at the end of XRT 5.4 Gy in 3 fractions over 3 days
Palliative XRT:
30 Gy in 10 fractions over 14 days or
20 Gy in 5 Fractions over 7 days
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