SEMINAR

Seminar

Cervical cancer

Steven E Waggoner

Cervical cancer is a serious health problem, with nearly 500 000 women developing the disease each year worldwide.
Most cases occur in less developed countries where no effective screening systems are available. Risk factors include
exposure to human papillomavirus, smoking, and immune-system dysfunction. Most women with early-stage tumours
can be cured, although long-term morbidity from treatment is common. Results of randomised clinical trials have
shown that for women with locally advanced cancers, chemoradiotherapy should be regarded as the standard of care;
however, the applicability of this treatment to women in less developed countries remains largely untested. Many
women with localised (stage IB) tumours even now receive various combinations of surgery and radiotherapy, despite
unresolved concern about the morbidity of this approach compared with definitive radiotherapy or radical surgery.
Treatment of recurrent cervical cancer remains largely ineffective. Quality of life should be taken into account in
treatment of women with primary and recurrent cervical cancer.

Cervical cancer will develop in about 500 000 women this
year worldwide. In many less developed countries it is the
most common cause of cancer death and years of life lost
owing to cancer. The disease is most commonly
diagnosed in the fifth decade of life—several years earlier
than the median age at diagnosis of breast, lung, and
ovarian cancers. Here, I review current concepts about
the causes, natural history, diagnosis, and treatment of
cervical cancer. Although this cancer poses a far
greater health concern in less developed than in more
developed countries, by necessity most of the information
discussed here reflects work that has been done in more
developed countries. Much of this work has been the
result of studies or clinical trials under the direction of the
European Organisation for Research and Treatment of
Cancer (EORTC) and the Gynecologic Oncology
Group (GOG). Members of these multidisciplinary
organisations include gynaecological oncologists, radiation
oncologists, medical oncologists, immunologists, and
pathologists.
Epidemiology and risk factors
Worldwide, cervical cancer is the second most common
malignant disease among women, with nearly 80% of
cases arising in less developed countries (table 1).1 The
American Cancer Society estimates that during 2002,
13 000 cases of cervical cancer were diagnosed in women
living in the USA, and that 4100 women will die as a
result of this disease.2 In North America, the median age
at diagnosis is 47 years, and nearly half of cases are
diagnosed before the age of 35. However, women older
than 55 years contribute disproportionately to cervical-
cancer mortality, primarily as a result of more advanced
disease at diagnosis.3 The primary cause in development
of cervical cancer is human papillomavirus (HPV). More
than 90% of squamous cervical cancers contain HPV
DNA. The virus is acquired mainly through sexual
activity.4–6
Lancet 2003; 361: 2217–25
Section of Gynecologic Oncology, University Hospitals of
Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106, USA
(S E Waggoner MD)
(e-mail: steven.waggoner@uhhs.com)
Although many HPV types have been associated with
anogenital neoplasia, types 16, 18, 31, 35, 39, 45, 51, 52,
56, and 58 cause most invasive cancers.7 HPV 16 and 18
have two transcriptional units, E6 and E7, that encode
proteins essential for viral replication. The E6
oncoprotein exerts its effect by binding to and inactivating
the tumour-suppressor gene TP53 through ubiquitin
degradation, which disrupts an inherent cell-cycle
checkpoint.8–10 The E7 oncoprotein binds to and
inactivates products of the retinoblastoma gene, pRb,
which ultimately allows unchecked cell-cycle progression
in cells infected with HPV 16 or 18.11,12 Genomic variants
of HPV 16 have been identified, which differ in their
abilities to bind to and degrade TP53 in vitro.13 These
variants differ in their geographical distribution and
probably differ in their oncogenic potential. The Asian-
American variant, for example, has been associated with
more aggressive invasive cancer and a tendency to occur
in younger women.14 Other factors associated with
development of cervical cancer include sexual activity
starting at a young age (<16 years), a high total number of
sexual partners (more than four), and history of genital
warts. Patients receiving immunosuppressive agents and
those who are HIV positive are also at increased risk
of development of cervical cancer. Cigarette smoking
(and perhaps even exposure to environmental tobacco
Search strategy and selection criteria
I searched Medline (1990–2001) using the terms "cervical
cancer" and "cervical neoplasia". Initial search results were
selected from papers published in English on human beings,
then limited by use of the terms "epidemiology", "natural
history", "treatment", "radiation therapy", "chemotherapy",
"chemoradiation therapy", and "surgery". Reference lists of
articles identified by this strategy were searched, and
additional relevant publications were selected. Preference for
inclusion was given to publications reporting randomised
phase-3 trials and clinical trials describing data collected
prospectively. Material was also obtained from the most
recent (1998) annual report of the International Federation of
Obstetrics and Gynecology (FIGO) on the results of treatment
of cervical cancer, and from the American Cancer Society
Cancer Statistics 2001. The reference list was subsequently
modified during the peer-review process in response to
comments from reviewers.

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SEMINAR

Registry Recording Cases Rate per 100 000 diethylstilbestrol exposure, clear-cell carcinomas most
period woman-years commonly occur in women who are postmenopausal.
Ten highest rates Other uncommon subtypes include adenosquamous
Zimbabwe, Harare 1990–92 295 67·21 cancers and small-cell (neuroendocrine) carcinomas.
(African women)
Brazil, Belem 1989–91 931 64·78 Staging and prognosis
Peru, Trujillo 1988–90 288 53·48 Once a tissue diagnosis of invasive carcinoma has been
Uganda, Kyadondo 1991–93 248 40·76
India, Madras 1988–92 2540 38·91
established, the patient is staged (table 2). Stage is
Brazil, Goiania 1990–93 506 37·13 determined at the time of primary diagnosis and should
Colombia, Cali 1987–91 1061 34·41 never be changed, even after recurrence or on discovery of
New Zealand 1988–92 193 32·21 more extensive disease during surgery. Stage is
(Maori women) determined clinically, on the basis mainly of the size of the
Argentina, Concordia 1990–94 108 32·05
Ecuador, Quito 1988–92 697 31·66
tumour in the cervix or its extension into the pelvis.
Modifications to the FIGO staging system were made in
Ten lowest rates 1994 to clarify the description of microinvasive cervical
Spain, Navarra 1987–91 82 4·68
USA, Hawaii 1988–92 10 4·55 cancer (stage IA1 and IA2) and to subdivide stage IB into
(Chinese women) IB1 (tumour <4 cm) and IB2 (tumour >4 cm) tumours.
China, Tianjin 1988–92 454 4·39 In North America, roughly 60% of patients are diagnosed
Israel (Jewish women 1988–92 187 4·07 at stage I, 25% at stage II, 10% at stage III, and 5% at
born in USA or Europe) stage IV. In many less developed countries, most cervical
USA, Los Angeles 1988–92 20 4·05
(Japanese women)
cancers are diagnosed in the third or fourth stage. For
Finland 1987–92 893 3·62 smaller lesions (stage IA and IB1), stage
China, Shanghai 1988–92 860 3·26 is assigned after measurement of the depth of tumour
Israel (non–Jewish 1988–92 40 2·99 invasion (on cone biopsy), pelvic examination to assess
women) tumour size clinically, or both. For more advanced
Italy, Macerata 1991–92 12 2·77
China, Qidong 1988–92 97 2·64
tumours, pelvic examination under anaesthesia is
occasionally necessary to allow thorough assessment of
Table 1: Registries with highest and lowest incidence rates of the parametrial tissues adjacent to the cervix and uterus.
cervical cancer1 Additional tests permitted for clinical staging are outlined
in panel 1 and are restricted to modalities available in
smoke) is an independent risk factor for significant most countries. Although the results of CT, MRI, or
cervical dysplasia and invasive cervical cancer.15–17 positron-emission tomography (PET) cannot be used for
Tobacco-specific carcinogens and polycyclic aromatic
hydrocarbons have been identified in the cervical mucus
or epithelium of smokers.18,19 These compounds can bind Stage Description
to and damage cellular DNA and might cooperate with
Stage 0 Carcinoma-in-situ, intraepithelial carcinoma
HPV to produce malignant transformation.
Stage I Invasive carcinoma strictly confined to cervix
Stage IA Invasive carcinoma identified microscopically
Diagnosis and pathology (all gross lesions, even with superficial invasion,
Cervical cancer may be suspected on analysis of a Pap should be assigned to stage IB)
smear or visualisation of a lesion on the cervix. A biopsy Stage IA1 Measured invasion of stroma 3·0 mm or less in
sample must be taken from any suspicious lesion, depth and no wider than 7·0 mm
because many Pap smears are non-diagnostic or falsely Stage IA2 Measured invasion of stroma more than 3·0 mm
but no greater than 5·0 mm in depth and no wider
negative in the presence of invasive cancer. If a biopsy than 7·0 mm
sample shows cells suggesting microinvasion, and if the Stage IB Preclinical lesions greater than stage IA or clinical
patient does not have a grossly apparent invasive cancer, lesions confined to cervix
a cone biopsy should be done. For accurate staging of Stage IB1 Clinical lesions of 4·0 cm or less in size
clinically occult lesions, sufficient underlying stroma Stage IB2 Clinical lesions more than 4·0 cm in size
must be obtained to allow for adequate assessment of the Stage II Carcinoma extending beyond cervix but not to
depth and width of invasion below the basement pelvic sidewall; carcinoma involves vagina but not
its lower third
membrane. Stage IIA Involvement of upper two-thirds of vagina, no
About 80% of primary cervical cancers arise from pre- parametrial involvement
existing squamous dysplasia. Adenocarcinoma of the Stage IIB Obvious parametrial involvement
cervix accounts for about 20% of invasive cervical Stage III Carcinoma extending onto pelvic wall; on rectal
cancers; in more developed countries, the incidence of examination, there is no cancer-free space between
adenocarcinoma is rising in relation to that of squamous tumour and pelvic sidewall. The tumour involves
carcinoma. Although oncogenic HPV DNA has been lower third of the vagina. All patients with
hydronephrosis or non-functioning kidney are
identified in adenocarcinomas,20,21 smoking does not seem included unless known to be the result of other
to be a risk factor for this histological subtype. In most causes.
cases, adenocarcinoma-in-situ is probably the precursor Stage IIIA Involvement of lower third of the vagina; no
lesion, but it is detected much less efficiently by Pap- extension to pelvic sidewall
smear screening than are preinvasive squamous lesions. Stage IIIB Extension to pelvic sidewall and/or hydronephrosis
or non-functioning kidney
Clear-cell carcinoma is a rare adenocarcinoma subtype,
which accounts for fewer than 5% of adenocarcinomas. Stage IV Carcinoma extends beyond true pelvis or clinically
involves mucosa of bladder or rectum. Bullous
Previously, many cases developing in young women were oedema does not allow a case to be designated as
associated with in-utero exposure to diethylstilbestrol.22 stage IV.
Since use of diethylstilbestrol in pregnancy has been Stage IVA Spread of growth to adjacent organs
prohibited since 1971, the number of cases associated Stage IVB Spread to distant organs
with this drug has diminished. In the absence of Table 2: FIGO staging for cervical cancers

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Panel 1: Staging procedures for cervical cancer
Physical examination
Palpation of lymph nodes (ie, supraclavicular, inguinal)
Vaginal examination
Rectovaginal examination with or without anaesthesia
Radiographic studies
Chest radiograph
Skeletal radiograph
Intravenous pyelogram
Barium enema
Procedures
Cervical biopsy
Cervical conisation
Hysteroscopy
Colposcopy
Endocervical curettage
Cystoscopy
Proctoscopy
Other studies (not allowed for assignment of clinical staging)
Computed tomography
Magnetic resonance imaging
Positron emission tomography with fluorodeoxyglucose
Ultrasonography
Bone scanning (radionucleide)
Lymphangiography
Laparoscopy
FIGO staging, the information obtained from such studies
has been used to assess more accurately the extent of
pelvic disease and lymph-node metastasis, which might
affect treatment recommendations.23,24 Use of these
imaging modalities has not been proven, in a randomised
clinical trial, to lead to better survival for women with
cervical cancer. The American College of Radiology
Imaging Network has recently completed a multicentre
trial to assess the diagnostic performance of MRI and CT
compared with clinical staging, and to investigate whether
factors indicating high risk discovered by these imaging
techniques predict tumour recurrence in women
undergoing radical hysterectomy. Although metastasis to
pelvic and para-aortic lymph nodes does not change
clinical stage, adenopathy should be investigated by fine-
needle aspiration or retroperitoneal node dissection,
because nodal metastases could affect treatment
decisions. Transperitoneal node dissection should be
avoided, if possible, because of a higher risk of subsequent
radiation-related bowel complications. If positive nodes
are found, treatment should be individually designed,
because patients with large metastases have poorer
survival with surgery or radiotherapy than those without
such secondary tumours. Resection of enlarged pelvic
lymph nodes is possible in some cases and may improve
subsequent radiotherapy efficacy, although only a few
studies have reported benefit, and none as part of a
randomised clinical trial.25,26 The benefit of this approach
has not been proven with grossly involved para-aortic
nodal metastases.27
Surgical staging of patients with larger tumours, which
includes mainly retroperitoneal assessment of pelvic and
para-aortic lymph nodes, has the theoretical advantage
of identifying microscopic disease that can be treated
with extended-field radiotherapy to the para-aortic
lymph nodes. A surgical staging system has been
advocated by some clinicians, but clinical staging more
easily permits comparison of treatment results by
differing modes of therapy and different treatment
facilities. This issue is important because most cases of
cervical cancer occur in less developed countries where
access to surgical therapy may be restricted.
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SEMINAR
Clinical stage is a reliable prognostic indicator for
patients with cervical carcinoma. 5-year survival
approaches 100% for patients with tumours of stage IA
and averages 70–85% for those with stage IB1 and smaller
IIA lesions. Survival for more locally advanced tumours
(stages IB2 to IV) varies and is influenced significantly by
the volume of disease, the patient’s age, and
comorbidities. Overall, 5-year disease-free survival is
50–70% for stages IB2 and IIB, 30–50% for stage III, and
5–15% for stage IV.
Metastases to pelvic, and especially para-aortic, lymph
nodes are associated with poorer survival. Among patients
who have undergone surgical staging or lympha-
denectomy, 5-year survival has been correlated with the
number of positive lymph nodes: 62% for one positive
lymph node, 36% for two nodes, 20% for three or four,
and zero for five or more.28 For patients with early-stage
tumours treated with radical surgery, adverse pathological
factors in addition to nodal metastases include larger
tumour size, deep cervical-stromal invasion, involvement
of the lymphovascular space, or extension of cancer to the
vaginal or parametrial margins.29,30 Increasing tumour
volume is related to the risk of extrapelvic disease as well as
the risk of central recurrence after treatment. Delivery of
sufficient radiation to eradicate tumours greater than
5 cm in diameter is commonly hampered by concerns
about exceeding the radiation tolerance of surrounding
normal tissue. Pelvic failure rates can exceed 35% after
radiotherapy for larger tumours.31 Other important
prognostic factors include histological subtype, the
patient’s age, and medical comorbidities, including
anaemia.32,33 Although they comprise less than 5% of
cervical carcinomas, adenosquamous tumours and small-
cell carcinomas with neuroendocrine features have a
particularly poor prognosis.34 For HIV-seropositive women
with low counts of CD4-positive T cells, prognosis is also
poor, even for those with apparent early-stage disease.35
Treatment options (table 3)
Stage IA
In many more developed countries with established Pap-
smear screening systems, microinvasive or stage IA
cervical cancers are commonly detected in women who
are symptom free with cervices that seem normal on gross
examination. The diagnosis is usually made after a
cervical conisation, although many cases of superficially
invasive cervical cancer are incidentally discovered after
hysterectomy. If the focus of invasion extends no deeper
than 3 mm below the basement membrane (stage IA1),
the risk of pelvic nodal involvement is less than 1%.
Cervical conisation is a reasonable treatment option for
patients who want to preserve fertility.36 According to
FIGO, the presence of invasion of the lymphatic or
vascular space should not change the stage, but should be
noted by the pathologist, because it may affect treatment
recommendations owing to concerns about risk of nodal
involvement (see later). If the patient has completed
childbearing, the treatment of choice remains extrafascial
hysterectomy, by the abdominal or vaginal approach
(table 3).
For microinvasive squamous cancers invading 3–5 mm
in depth and with less than 7 mm of horizontal extension
(stage IA2), the risk of lymph-node metastasis is 2–8%.
Most gynaecological oncologists would advise radical
hysterectomy or radiotherapy as treatment. The extent of
the surgery is open to debate.37,38 In view of the low risk of
parametrial tumour extension with microinvasive
carcinomas, a modified radical hysterectomy in which less
parametrial tissue and vagina are removed is judged
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Stage Clinical features
IA1 Invasion 3·0 mm or less
With lymphovascular space invasion
IA2 3·0–5·0 mm invasion, <7·0 mm lateral spread
IB1 Tumour 4 cm or less
IB2 Tumour bigger than 4 cm
IIA Upper-two-thirds vaginal involvement
IIB With parametrial extension
IIIA Lower-third vaginal involvement
IVA Local extension within pelvis
IVB Distant metastases
*Pelvic lymph-node metastases; large tumour; deep cervical stromal invasion; lymphovascular space invasion; positive vaginal or parametrial margins.
Table 3: Treatment algorithm for cervical cancer
appropriate and may restrict associated complications
such as bladder dysfunction.39 Pelvic lymphadenectomy
includes removal of lymph nodes from the common iliac,
external iliac, internal iliac, and obturator regions. Para-
aortic lymph-node dissection is not necessary unless
suspicious pelvic lymph nodes are encountered.
A current topic of interest is the use of more
conservative surgery for patients with early cervical cancer
who wish to retain their fertility. In a selected group of
young patients with small cervical lesions, a laparoscopic
lymph-node dissection has been followed by a radical
vaginal trachelectomy to remove the cervix. Pregnancies
have occurred after this procedure, albeit with a 25% rate
of late miscarriage, and a disease-recurrence rate that has
ranged from zero to 4%.40–42
The best treatment for a microinvasive squamous-cell
cancer when there is invasion of the lymphatic or vascular
space remains ill defined. Invasion of the lymphatic
or vascular space has been associated with risk of
pelvic lymph-node metastases.43–45 Therefore, most
gynaecological oncologists advise a radical hysterectomy
with pelvic lymphadenectomy or radiotherapy.
There is no well-established classification of
microinvasive adenocarcinoma, mainly because of the
difficulty in identifying the basement membrane in the
endocervical region and the tendency for “skip lesions” to
be found in hysterectomy specimens removed after a
conisation. Nevertheless, accumulating evidence suggests
that when accurate tumour measurements are possible,
pelvic lymph-node metastasis is very rare for
adenocarcinomas invading less than 3 mm.46
Hysterectomy is still deemed standard treatment, but
studies comparing the route (vaginal or abdominal) or
type (radical or extrafascial) of hysterectomy are few. For
patients who want to retain fertility and who have little
stromal invasion on a conisation specimen and negative
margins for invasive or in-situ lesions, conservative
management with close follow-up has been used.47 The
patient must be aware of the limitations of this treatment
option, including recurrence of cancer.
Stage IB
Treatment for stage IB cervical cancer should take into
account tumour size, the patient’s age, the presence of
comorbidity, and the resources available at the treating
2220
For personal use. Only reproduce with permission from The Lancet
Treatment
If patient desires fertility, conisation of cervix
If she does not, simple hysterectomy (abdominal or vaginal)
Hysterectomy with or without pelvic lymphadenectomy
Radical hysterectomy with pelvic lymphadenectomy
Radiotherapy
Radical hysterectomy with pelvic lymphadenectomy plus
chemoradiotherapy for poor
prognostic surgical-pathological factors*
Radiotherapy
Radical hysterectomy with pelvic lymphadenectomy plus
chemoradiotherapy for poor
prognostic surgical and pathological factors*
Chemoradiotherapy
Chemoradiotherapy plus adjuvant hysterectomy
Radical hysterectomy with pelvic lymphadenectomy
Chemoradiotherapy
Chemoradiotherapy
Chemoradiotherapy
Chemoradiotherapy
Primary pelvic exenteration
Palliative chemotherapy
Chemoradiotherapy
facility. In 1994, FIGO substratified stage IB tumours
into those less than and more than 4 cm in diameter
(stages IB1 and IB2) to reflect the higher recurrence
rate and risk of nodal spread by the larger tumours. In
general, stage IB1 tumours can be treated effectively
by either radical hysterectomy with pelvic and para-
aortic lymphadenectomy or by primary radiotherapy.
Advantages of radical hysterectomy over radiotherapy
include a shorter duration of treatment, preservation of
ovarian function in younger patients, avoidance of vaginal
stenosis, and reassurance that there will be no future
recurrence in the uterus or cervix. The information
obtained at laparotomy, including lymph-node status or
the presence of gross disease beyond the cervix, provides
the opportunity for adjunctive therapy. Morbidities
associated with radical hysterectomy include chronic
bladder dysfunction (3%), ureterovaginal or vesicovaginal
fistula (1–2%), pulmonary embolism (1–2%), small-
bowel obstruction (1%), lymphocoele formation (5%),
nerve (obturator, genitofemoral) injury, and the risks
associated with blood loss requiring transfusion.48,49 Some
researchers have advocated use of a modified radical
hysterectomy for treatment of small cervical lesions to
limit some of the morbidity associated with a more radical
procedure (ie, urinary retention).50–52
A prospective, surgical pathological study of patients
with stage IB cervical cancer treated by radical
hysterectomy identified several risk factors for recurrence:
large tumour diameter, deep cervical stromal invasion, and
presence of tumour in the capillary or lymphatic spaces.
An estimate of recurrence risk was possible from
consideration of these factors after surgery.53 On the basis
of these pathological variables, GOG undertook a
prospective trial that randomly assigned patients with
different combinations of these risk factors adjuvant pelvic
radiation or no further treatment. Most patients had
tumours greater than 3 cm in diameter with either
capillary-lymphatic space involvement or deep invasion
into the cervical stroma. Patients were ineligible for the
trial if they had positive lymph nodes or involved vaginal or
parametrial margins. Use of radiotherapy was associated
with a 47% lower recurrence rate (27·9% in the no further
therapy group vs 15·3% in the radiotherapy group,
p<0·008).54 Although the survival data are not yet mature,
other studies have not shown improvement in survival with
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the use of adjuvant pelvic radiotherapy.55,56 For patients
with more serious poor prognostic pathological risk
factors, a prospective randomised trial by the Southwest
Oncology Group, the GOG, and the Radiation Therapy
Oncology Group (RTOG) showed that concomitant
chemotherapy was a significant factor in improving
survival in patients with early-stage disease after radical
hysterectomy and lymphadenectomy. In that study,
patients with pelvic nodal metastasis, parametrial
extension of tumour, or positive surgical margins were
randomly assigned to groups receiving external-beam
radiotherapy alone or radiotherapy with concurrent
cisplatin (70 mg/m2) and a 4-day infusion of fluorouracil
(1000 mg/m2 daily) every 3 weeks for four courses. Use of
chemoradiotherapy was associated with significantly better
progression-free and overall survival than radiotherapy
alone (80% vs 63% and 81% vs 71%, respectively, at
4 years). The group assigned chemoradiotherapy had more
grade 3 and 4 haematological toxic effects, which were
typically reversible.57
Primary radiotherapy for stage I cervical cancer offers
cure rates equivalent to those with radical hysterectomy.
Conventional radiotherapy includes a combination of
external irradiation and intracavitary brachytherapy. Whole-
pelvis radiotherapy, typically 40–50 Gy, is administered
over 4–5 weeks in daily fractions and is used mainly to treat
the parametrial tissue and lateral pelvic walls, including the
pelvic lymph nodes. External irradiation generally precedes
brachytherapy, because the former leads to reduction in
central tumour bulk and permits more effective dosimetry
in brachytherapy application. Low-dose-rate or high-dose-
rate brachytherapy can be used, with equivalent results.58
Low-dose-rate therapy (4–20 Gy/h) necessitates placement
of the brachytherapy implant device under anaesthesia and
in most cases a 2–3-day hospital stay. High-dose-rate
therapy (2 Gy/min) is given on an outpatient basis, typically
with three to five insertions with weekly intervals.59
The advantage of radiotherapy over surgery is its
applicability to nearly all patients irrespective of weight,
age, or medical condition. Long-term complications
involving the gastrointestinal tract or urinary tract are
related to increasing doses of radiation. The frequency of
severe complications can exceed 10% among patients who
receive more than 80 Gy.60 Duration of treatment time
should not exceed 7 weeks; extension beyond 7 weeks has
been associated with a significant negative effect on pelvic
tumour control and survival. These results are most notable
for patients whose tumours are greater than 3 cm in
diameter.61
Stage IB2 cancers, often referred to as bulky or barrel-
shaped tumours, pose a particular challenge. Survival is
substantially worse for women with these larger tumours
than for those with smaller primary tumours. Whereas
overall survival for patients whose lesions are less than
3–4 cm averages 90%, that for women with tumours above
this size is 65–75%.62,63 Stage IB2 tumours are associated
with a higher frequency of pelvic and para-aortic lymph-
node metastasis than stage IB1 tumours, and the lateral
extent of the tumour extends beyond the tumoricidal
isodose curve of the brachytherapy application in many
cases. These larger tumours probably contain areas of
hypoxia, which also renders radiotherapy less effective.
Both central and distant failures are more common than
with stage IB1 lesions. For this reason, at least three
treatment regimens have been advocated: radical
hysterectomy with pelvic and para-aortic lymphadenectomy
followed by adjuvant radiotherapy; a combination of
preoperative whole-pelvis radiotherapy and brachytherapy
followed by an extrafascial hysterectomy; and primary
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SEMINAR
radiotherapy with radiosensitising chemotherapy.
Radical hysterectomy with lymphadenectomy has
been routinely used as treatment for patients with stage
IB2 cervical cancer, with adjunctive radiotherapy given
for poor prognostic pathological factors. On the basis of
previously identified postsurgical risk factors, about
80% of patients with stage IB2 tumours would be
appropriate candidates for adjuvant radiotherapy. A
particular area of controversy has been the morbidity
associated with combined radical hysterectomy and
pelvic radiotherapy. Some investigators have shown
acceptable morbidity with combined therapies, but
others have shown a significant risk of complications,
especially urological, when radical hysterectomy is
followed by adjuvant radiotherapy.64–66 Concern about
this issue has led some clinicians to advocate
chemoradiotherapy alone or followed by a simple, not
radical, hysterectomy.
In the hope of decreasing the high pelvic-recurrence
rate with the bulky IB2 lesions, some gynaecological
oncologists have advocated treatment with pelvic
irradiation and brachytherapy followed by an adjuvant
extrafascial hysterectomy.67,68 The benefit of adjuvant
hysterectomy has remained controversial, but the benefit
of concurrent chemotherapy with radiotherapy has,
again, been shown.69,70 In a prospective trial by the
GOG, patients with stage IB2 squamous-cell cancers,
adenocarcinomas, and adenosquamous tumours were
randomly assigned pelvic radiotherapy and brachytherapy
with or without concurrent cisplatin 40 mg/m2 (up to 70
mg) once a week for a maximum of six doses. Patients in
both treatment groups underwent adjuvant hysterectomy.
Although 35% of patients in the combined-therapy
group had grade 3 or 4 adverse haematological or
gastrointestinal effects, the relative risks of disease
progression and death in the combined therapy group
were 0·51 (95% CI 0·34–0·75) and 0·54 (0·34–0·86),
respectively. 3-year survival was 74% in the radiotherapy
group and 83% in the combined-therapy group.71
Although another randomised GOG study has shown
that central recurrence rates are lower with adjuvant
hysterectomy, that study did not identify a survival
advantage for radiotherapy followed by extrafascial
hysterectomy over radiotherapy alone.72 Therefore, the
third treatment option used for stage IB2 tumours is to
forego surgery and primarily use chemoradiotherapy.
Further evidence on the best treatment option for
stage IB2 tumours may eventually come after completion
of a recently started multicentre randomised comparison
of radical hysterectomy and tailored chemoradiotherapy
versus primary chemoradiotherapy.
Neoadjuvant chemotherapy, followed by surgery or
radiotherapy, has been used with limited, but inconsistent,
success for locally advanced cervical cancer. A major
concern with this approach is the delay or prolongation of
potentially curative chemoradiotherapy for patients who
have been receiving several weeks of neoadjuvant
chemotherapy. This approach is not favoured as initial
treatment of locally advanced cervical carcinoma.73
Stage IIA
Treatment for these patients should be individually
planned and based on the extent of cervical and vaginal
involvement. Most patients with stage IIA tumours should
be given chemoradiotherapy. In rare cases, the amount
of cancer extension into the vaginal fornix is small
enough that the cancer can be treated effectively with
radical hysterectomy, lymphadenectomy, and upper
vaginectomy.
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Stages IIB, III, and IVA
Once cervical cancer has extended beyond the cervix,
cure with radical surgery alone is unlikely. After reports
from several randomised clinical trials showing an
improvement in time to progression and survival for
patients given chemoradiotherapy compared with
radiotherapy alone,57,71,74–76 the National Cancer Institute
advised that concomitant chemotherapy and radiotherapy
should be considered as standard care for locally
advanced (stage IIB–IVA) or high-risk early-stage cervical
carcinoma. Each of these clinical trials used cisplatin as
a component of the treatment regimen, in several cases
with fluorouracil. One GOG study,75 however, found that
weekly cisplatin alone was as effective as and less toxic
than the regimen combining cisplatin, fluorouracil, and
hydroxyurea. Given the ease of use of weekly cisplatin,
this regimen has generally been accepted as the
chemotherapy of choice. A systematic review and meta-
analysis of reports on the use of chemoradiotherapy
generally supported the use of chemoradiotherapy over
radiotherapy alone, or neoadjuvant chemotherapy
followed by radiotherapy.77 In that review,
chemoradiotherapy improved overall survival by about
30% and reduced the risk of both local and distant
recurrence. Absolute survival benefit was estimated as
12%, though several studies have reported higher survival
benefits.
Important questions remain unanswered, and
chemotherapy has by no means been established as a
necessary adjunct to all patients receiving primary or
adjuvant radiotherapy. For example, the benefit of
chemoradiotherapy has not been established for women
with metastasis to para-aortic lymph nodes. Likewise,
many women with stage IB tumours who have
intermediate risk factors for recurrence after radical
hysterectomy are being offered chemoradiotherapy despite
the absence of proven benefit in a randomised clinical trial.
Such a trial would require substantial resources and could
take a decade or longer to complete. Patients receiving
chemoradiotherapy commonly experience more severe
haematological and gastrointestinal toxic effects, which
may stress resources in less developed countries. Although
cisplatin is the drug of choice, its use during radiotherapy
in women with moderately impaired renal function has not
been adequately studied. Whether other, less nephrotoxic,
agents will lead to improvement in survival in this
subgroup of patients is unknown.
Radiation fields should be individualised on the basis of
the volume of tumour and degree of extension, if any, into
the vagina. Extended-field radiotherapy encompassing the
para-aortic nodes can be used unless surgical staging or
radiological studies have shown that this region is free of
disease. A study by RTOG analysed the role of extended-
field radiotherapy in women with stage IIB and bulky IB
and IIA cervical cancers. It showed a significant survival
benefit with prophylactic para-aortic irradiation, with
overall survival at 10 years of 44% in the group assigned
pelvic irradiation only compared with 55% in the group
assigned pelvic plus para-aortic irradiation (p=0·02). An
important feature was that women in this study were not
given concomitant chemotherapy. As expected, extended-
field irradiation was associated with higher rates of grade 4
and 5 adverse effects on bowel and bladder, especially in
the group that had previously undergone surgery.78 By
contrast, an EORTC randomised clinical trial on the role
of extended radiotherapy showed no difference in survival
with the use of prophylactic para-aortic irradiation in
women with advanced cervical carcinoma.79 Intensity-
modulated radiotherapy is thought by many radiation
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oncologists to represent an important technological
advance compared with conventional static external-beam
irradiation. This newer approach uses beams of variable
intensity, and the target volumes are contoured by means
of axial CT slices. Preliminary studies have shown that
intensity-modulated radiotherapy is feasible for treatment
of cervical cancer and have suggested a more favourable
toxicity profile than with conventional external-beam
irradiation. The technique, which is presently more
expensive and time consuming than conventional
irradiation, may also facilitate safer and more effective
concomitant chemotherapy by sparing a greater volume of
bone marrow.80,81
Stage IVB, recurrent, or refractory disease
Patients diagnosed with stage IVB disease who have a
satisfactory performance status should be offered
chemoradiotherapy as a means of helping to control
central disease. Although few of these patients will survive
12 months from diagnosis, about 20% of women with
stage IVB tumours survive for longer than 2 years.
Patients with recurrent or refractory disease after
irradiation can be offered chemotherapy or, occasionally,
surgery. 90% of recurrences are identified within 3 years
of initial diagnosis, and less than 5% of these patients
survive 5 years. Rare patients with potentially curable
recurrent disease include those with an isolated
pulmonary metastasis or isolated central recurrence.
Solitary lung metastases, although unusual, can be treated
with resection, and nearly 25% of these patients survive at
least 5 years. Pelvic recurrence after radical hysterectomy
can be treated with radiotherapy, provided it was
not given previously. Such treatment has resulted in
33% 5-year survival.82 Generally, only small recurrent
tumours (under 2–3 cm) are deemed potentially
curable. Improvements in radiotherapy and use of
chemoradiotherapy have led to better control of central
disease and, accordingly, fewer patients are developing
isolated pelvic recurrence. Some patients with a central
recurrence after radiotherapy can be cured with a total
pelvic exenteration. This procedure, which normally
encompasses removal of the uterus and cervix,
cystectomy, and resection of most of the rectum and
vagina, is generally done only in tertiary medical centres
and is not likely to be available to women in less
developed countries. Some patients can be managed with
a less extensive procedure (anterior pelvic exenteration or,
rarely, radical hysterectomy).83 Advances in reconstructive
surgical procedures have led to improvement in the
quality of life for many patients requiring urinary
diversion or vaginal reconstruction.84 Nevertheless, only
about 50% of patients with negative pelvic and para-aortic
lymph nodes and free surgical margins treated with pelvic
exenteration are alive 5 years later.85 Radiotherapy is an
effective modality for palliation of metastatic disease to
distant sites, including lymph nodes, bone, and brain.
Most lesions respond to about 30 Gy given in ten
fractions.
Chemotherapy
Chemotherapy for advanced or recurrent disease has been
and continues to be considered palliative. Many agents
have been investigated, as single or combined regimens.86
Response rates in multicentre phase-2 trials average
10–40%, with complete responses seen only rarely and for
short duration. Cisplatin is at present deemed the most
active single agent in recurrent disease. When it was
combined with paclitaxel in a phase-2 study, an overall
response rate of 46·3% was recorded (12·2% with
THE LANCET • Vol 361 • June 28, 2003 • www.thelancet.com

Panel 2: Areas of controversy and current research
What are the best chemotherapy drugs, doses, and schedules
to be used in conjunction with radiotherapy?
How can the efficacy of treatment for recurrent cervical cancer
be improved?
How should women with metastasis to para-aortic nodes be
managed?
What effect does anaemia have on the effectiveness of
chemoradiotherapy and what is the best way to correct
anaemia during treatment?
What is the optimum management of stage IB2 carcinoma?
Does cigarette smoking influence the efficacy of treatment of
cervical cancer?
Will wider use of advanced imaging techniques (MRI, CT, PET)
in planning therapy for cervical cancer lead to improvements in
survival?
How can clinicians keep treatment-related morbidity to a
minimum without significantly compromising cancer survival?
What are the most practicable and reliable ways of assessing
quality of life in women with cervical cancer?
Will vaccines directed against oncogenic HPV ultimately lead to
fewer cases of invasive cervical cancer?
complete responses and 34·1% with partial responses).87
As a single agent, cisplatin has been compared with the
combination of cisplatin and paclitaxel in a randomised,
phase-3 study. The combined regimen was superior to
single-agent cisplatin in terms of response rate and
survival, at a cost of reversible bone-marrow toxic
effects.88 The survival benefit is modest (a few weeks),
and quality-of-life assessments for the two treatment
groups have not yet been reported. A factor that seems
to affect chemotherapy effectiveness adversely is
whether a recurrence occurs within a previously
irradiated field. About 25% of patients with recurrence
outside the irradiated field respond to chemotherapy,
compared with 5% if the recurrence is within the
irradiated field.89
Issues requiring further study (panel 2) include
identification of the best chemotherapy regimen to be
used in combination with primary radiotherapy and
whether combination chemotherapy as a radiation
sensitiser can produce long-term improvement in distant
control. The potential benefit of aggressive correction of
anaemia during radiotherapy is being tested in a phase-3
trial.
Phase-1 investigational vaccine protocols with HPV 16
E7 peptides as an antigenic determinant are being studied
for patients with recurrent or persistent cervical cancers.
The effectiveness of a vaccine developed to prevent
infection with HPV 16 has recently been shown.90 If long-
term immunity is confirmed in future studies, prevention
of a substantial proportion of cervical cancers may be
possible. Advanced imaging modalities, including MRI,
should be incorporated into multi-institutional clinical
trials to investigate whether purported advantages in
assessing extent of tumour can be translated to
improvements in survival or quality of life over traditional
staging systems.
Other areas of investigation are directed at
improvement in both surgical and radiotherapy
techniques to limit morbidity and improve quality of
life. Radiotherapy and radical surgery, when given
alone, and particularly in combination, are associated
with distressing, long-term morbidity in many women
treated for cervical cancer. Side-effects, including
infertility, premature menopause, lymphoedema, sexual
THE LANCET • Vol 361 • June 28, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet
SEMINAR
dysfunction, and chronic bowel and bladder dysfunction,
have been viewed by clinicians as common and
unavoidable. Treatment of these conditions is
unsatisfactory in many cases, and more emphasis should
be given to preventing them. Fortunately, these and other
quality-of-life issues are being considered more frequently
during the design of clinical trials. Assessment of quality
of life will be a particularly important part of clinical trials
that compare radiotherapy with surgery alone or
combined surgery and radiotherapy.91,92
Conclusion
Over the past decade, women with cervical cancer of all
stages have benefited from tremendous improvements
in the treatment of this disease. These advances,
unfortunately, have not been extended to the vast majority
of women affected by the disease, who live in
impoverished countries with limited resources and no
screening programmes. Gynaecological and radiation
oncologists practising in more affluent countries are aware
of the substantial discrepancy in treatment options
available for women in more versus less developed
countries. Better efforts to expand eligibility for
cooperative clinical trials to women in less developed
countries are needed. In theory, hundreds of thousands of
women worldwide could benefit, each year, from the
advances in treatment of cervical cancer identified over
the past few years.
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