The

Oncologist

Guidelines for the Treatment of Recurrent

and Metastatic Cervical Cancer
MICHAEL FRIEDLANDER, MICHELLE GROGAN
Department of Medical Oncology, Prince of Wales Hospital, Randwick, New South Wales, Australia
Key Words. Recurrent Metastatic Cervical cancer Treatment

L EARNING O BJECTIVES
After completing this course, the reader will be able to:
1. Describe the natural history and prognosis of patients with recurrent and/or metastatic cervical cancer.
2. Be able to select appropriate treatment options for patients with recurrent cervical cancer.
3. Be able to identify which patients with locally recurrent cervical cancer are potentially curable with pelvic exenterative
surgery.
4. Describe the role and limitations of chemotherapy in the treatment of patients with metastatic cervical cancer.
CME

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

A BSTRACT
Although there have been important advances in
the management of women with cervical cancer, the
optimal treatment for patients with locally recurrent
and metastatic disease is still problematic, and there
are relatively few randomized trials to guide treatment
decisions. This paper reviews the approach to management of patients who relapse after primary treatment

for cervical cancer. Patients who are still potentially

curable with radical treatment are identified, and the
various treatment strategies are discussed. However,
most women are treated with palliative intent, and the
literature on palliative management is reviewed
together with the levels of evidence. The Oncologist
2002;7:342-347

BACKGROUND
Patients with cervical cancer may develop pelvic recurrence, distant metastases, or a combination of both. A 10%20% recurrence rate has been reported following primary
surgery or radiotherapy in women with stage IB-IIA cervical
tumors with no evidence of lymph node involvement, while
up to 70% of patients with nodal metastases and/or more
locally advanced tumors will relapse [1-4]. As the bulk of a
pelvic tumor increases, the proportion of patients with disease recurrent or persistent in the pelvis as the only site of

failure is greater than the proportion developing distant

metastases. Perez et al. reported a total pelvic failure rate of
10% in stage IB, 17% in stage IIA, 23% in stage IIB, 42% in
stage III, and 74% in stage IVA after radiotherapy alone [5].
The 10-year actuarial incidence of distant metastases was 3%
in stage IA, 16% in stage IB, 31% in stage IIA, 26% in stage
IIB, 39% in stage III, and 75% in stage IVA [6]. In patients
who develop distant metastases, the most frequently
observed metastatic sites were lung (21%), para-aortic nodes
(11%), abdominal cavity (8%), and supraclavicular nodes

Correspondence: Michael Friedlander, M.D., Department of Medical Oncology, Prince of Wales Hospital, High Street
Randwick NSW 2031, Australia. Telephone: 612-9382-2606; Fax: 612-9382-2588; e-mail: m.friedlander@unsw.edu.au
Received February 27, 2002; accepted for publication June 17, 2002 AlphaMed Press 1083-7159/2002/$5.00/0

The Oncologist 2002;7:342-347 www.TheOncologist.com

Friedlander, Grogan
(7%) [6]. Bone metastases occurred in 16% of patients, predominantly involving the lumbar and thoracic spine. Patients
who relapsed in lymph nodes had a median survival of 24
weeks, while those who relapsed in other organs had a
median survival of only 12 weeks [6]. While these figures
relate to only one series, they serve to illustrate the generally
poor outcomes of patients with metastatic cervical cancer.
The majority of recurrences occur within 2 years of diagnosis, and the prognosis is poor, with most patients dying as a
result of uncontrolled disease. In a retrospective review of over
500 patients treated at the University of Kentucky, 31% of
patients developed tumor recurrence, 58% of these recurred
within 1 year and 76% within 2 years [7]. In this series, only
6% of patients with recurrent tumor survived 3 years. While it
is possible to identify subgroups of patients with recurrent cervical cancer who have a substantially better prognosis than this
and in whom the objective of treatment is cure, 50%-60% of
patients have disease situated beyond the pelvis, which, with
few exceptions, is incurable, and treatment is given with palliative intent, as is the case for most patients with pelvic side
wall involvement by recurrent cervical cancer.
Treatment decisions should be based on the performance
status of the patient, the site of recurrence and/or metastases,
the extent of metastatic disease, and prior treatment.
Patients with recurrent/metastatic cervical cancer may
experience a variety of symptoms including pain, anorexia,
vaginal bleeding, cachexia, and psychological problems,
among others. The specific management of these symptoms
will not be described further in these guidelines. This exclusion in no way underestimates the crucial importance of
control of these symptoms to the well-being of the patient.
Management of these symptoms is the first priority for the
physician treating patients with recurrent cervical cancer.
The coordinated efforts of a team of professionals is
required. The membership of the team will depend on the
patient, the goals of management, and the particular problems
faced by the individual. The team should include gynecologic
oncologists, radiation and medical oncologists, palliative
care physicians, specialized nursing staff, and psychologists, but may also require the services of stomatherapists
and a specialized pain team.
These guidelines relate to the management of patients
who relapse after primary treatment for cervical cancer.
Patients who are still potentially curable with radical treatment are identified, and the approach to management for the
majority of patients not amenable for curative treatment is
discussed in detail. The level of evidence for the most part is
level III or IV, due to the paucity of randomized controlled
trials of treatment for patients with recurrent cervical cancer.
The evidence rating system is based on a rating system
developed by the U.S. Preventative Services Task Force:

343

level I is evidence obtained from a systematic review of all

relevant randomized trials; level II is evidence from at least
one randomized trial; level III is evidence from well-controlled case studies; and level IV is evidence based on
expert opinion. These guidelines have been drawn up after
a review of the literature and are intended to provide an
evidence-based approach to treatment decision-making.
Local Recurrence Following Radiation
Most patients who relapse locally after primary radiotherapy are not candidates for further radiotherapy, and pelvic
exenterative surgery is the only potentially curative approach
for these patients (Table 1). The 5-year survival rate for
patients who undergo total pelvic exenteration ranges from
30%-60% [8-13]. Identification of the clinical and histopathological factors that predict recurrence and survival after pelvic
exenteration may improve our ability to better select patients
who are potentially curable with radical surgery. The prognostic factors that have been identified include disease-free
interval, size of recurrence, and preoperative lateral side wall
fixation [8-13]. The prognosis is better for patients with a disease-free interval greater than 6 months, recurrence <3 cm in
diameter, and no side wall fixation [8-13]. Older age is not a
contraindication to exenterative surgery. Tumor involvement
of the pelvic side wall may be difficult to assess if there is
extensive postradiation fibrosis. The triad of unilateral leg
edema, sciatic pain, and ureteral obstruction almost always
indicates unresectable disease involving the pelvic side wall,
and palliative measures are indicated.
All women who are candidates for pelvic exenterative
surgery require extensive preoperative counseling regarding
what the surgery involves and what the postoperative expectations are [14]. Despite a careful preoperative work-up to
exclude distant metastases, about one-third of cases are found
to be unsuitable for exenteration at the time of laparotomy
due to peritoneal spread, para-aortic node involvement, or
pelvic side wall involvement [13].
Patients with resectable central recurrences that involve
the bladder and/or rectum, without evidence of intraperitoneal or extra-pelvic spread, and who have a dissectable
tumor-free space along the pelvic side wall are potentially
suitable for exenteration. With appropriate selection, better
pre- and postoperative care, as well as improved techniques

Table 1.
Guidelinelocal recurrence following
prior radiotherapy
Selected patients with resectable central
recurrences should be considered for
pelvic exenteration

Level of evidence
III

Treatment of Recurrent and Metastatic Cervical Cancer

344

for urinary diversion, the 5-year survival of patients treated

with pelvic exenteration is on the order of 30%-60%, and
the operative mortality should be less than 10%.
Local Recurrence of Cervical Cancer Following Radical Surgery
The therapeutic options open for those patients who
relapse in the pelvis following primary surgery are either
radical radiation or pelvic exenteration (Table 2). The
reported survival rates range from 6%-77%; patients with
central recurrences having better prognoses than those with
pelvic side wall recurrence [15-19]. Patients with central
recurrences had a 77% 10-year survival rate, for those with
no palpable tumor, and a 48% 10-year survival rate if the
recurrence was less than 3 cm, while there were no longterm survivors among patients with bulky (>3 cm) central
recurrence in one series [19]. The major prognostic factors
associated with survival following salvage radiation in
patients with recurrent pelvic disease include disease-free
interval, site of recurrence (i.e., central versus pelvic side
wall), and size [15-19]. Higher doses of radiation can be
delivered with brachytherapy and increase the likelihood of
local control for patients with small volume central recurrences. Patients with large volume central or pelvic side
wall recurrences have poor prognoses, and efforts should be
made to detect pelvic recurrences early to enhance the
chance for long-term survival.
There have been a number of phase II studies using concurrent chemotherapy and radiotherapy, which appears to be
associated with superior results compared with those
achieved with radiotherapy alone, but there have not been
any randomized trials of combined chemoirradiation compared with radiation alone [20, 21]. However, in light of the
recently published randomized trials that have shown an
overall survival advantage for cisplatin-based therapy given
concurrently with radiation therapy in women with
International Federation of Gynecology and Obstetrics stages
IB2 to IVA [22-25], consideration should be given to incorporate concurrent cisplatin-based chemotherapy with radiation therapy in patients with locoregional recurrence
following prior radical surgery.
The Role of Systemic Chemotherapy in Metastatic Cervical
Cancer
There are a large number of chemotherapeutic agents
with activity in metastatic cervical cancer [28-38] (Table 3).
Cisplatin is the single most active agent to treat cervical cancer [25-27]. In the Gynecologic Oncology Group (GOG)
studies, involving approximately 800 patients, cisplatin was
associated with a response rate of 29% [26-28]. The response
rate was greater at 31% with 100 mg/m2 compared with 21%
at 50 mg/m2, but this was not associated with any significant

Table 2.
Guidelinelocal recurrence of cervical
cancer following surgery

Level of evidence

Radiation therapy is indicated in patients

with locally recurrent cervical cancer
following radical surgery.

III

Concurrent chemotherapy with either

fluorouracil and/or cisplatin with radiation
should be considered and may improve
outcome.

III

Pelvic exenteration may be an alternative

(particularly if a fistula is present) to radical
radiotherapy and concurrent chemotherapy
in selected patients without pelvic side wall
involvement.

III

improvement in progression-free or overall survival [27].

The response rate of other platinum compounds, such as carboplatin, is possibly lower (15%), but the two agents have
not been compared in a randomized trial [29, 30]. Cisplatin
is associated with response rates of 20%-30% and a median
survival of about 7 months. The impact of chemotherapy on
palliation and survival is unclear. There have not been any
randomized studies comparing chemotherapy with best supportive care or studies that have specifically investigated the
impact of chemotherapy on symptom control and quality of
life. One study demonstrated that the combination of cisplatin and methotrexate was associated with a significant
increase in survival compared with a single inactive agent,
hydroxyurea [39]. In another relatively small study of cisplatin-based chemotherapy, it was demonstrated that, while

Table 3.
Guidelinesystemic chemotherapy in
metastatic cervical cancer

Level of evidence

Cisplatin is the single most active agent

to treat cervical cancer.

II

The response rate (31%) with 100 mg/m2

cisplatin is higher than that with 50 mg/m2
(21%), but is not associated with any
improvement in progression-free or overall
survival.

II

Cisplatin-based combination therapy is

associated with a higher response rate and
longer progression-free survival than
single-agent cisplatin therapy, but there is
no difference in overall survival.

II

Response rates to chemotherapy are

consistently higher in patients with good
performance status and extrapelvic disease,
and low in previously irradicated sites.

III

The impact of chemotherapy on palliation

and survival is unclear.

III

Friedlander, Grogan

345

only 30% of patients had an objective response to treatment,

67% had palliation of their pain [40].
The wide range of reported response rates to the same
agent suggests that patient characteristics and selection bias
exert major impacts on response rates. Even within the
GOG studies of cisplatin, the response rates varied from
17%-50% [26-28]. The finding of a significantly lower
response in previously irradiated sites is a consistent finding
in most studies [41, 42].
Cisplatin-based combinations have been reported to be
associated with response rates in excess of 50% in some
studies, but the decision as to whether one should treat
patients with single agents or combination chemotherapy is
unclear [43-47]. The GOG randomized 454 patients with
metastatic cervical cancer to receive either cisplatin alone,
cisplatin plus mitolactol, or cisplatin plus ifosfamide [48].
The cisplatin/ifosfamide combination was associated with a
higher response (31% versus 17%) and longer progressionfree survival compared with cisplatin alone [49]. However,
the median times to progression or death were only 4.6 and
3.2 months, respectively. Survival was better among those
patients with initial good performance status and greater
age. Although combination chemotherapy with cisplatin and
ifosfamide was associated with an improved response rate
and progression-free survival, this was at the cost of greater
toxicity and no improvement in overall survival [48].
A number of new agents (e.g., paclitaxel, vinorelbine,
irinotecan, and gemcitabine) have been combined with cisplatin in phase II studies in patients with either locally
advanced and/or recurrent cervical cancer [49-54]. High
response rates have been observed (40%-66%), particularly among patients with locally advanced disease at presentation [49-54]. Similar findings have been observed
with older cisplatin-based combinations, and randomized
trials are essential before adopting such combinations for
routine use outside clinical trials. The preliminary results
of a large GOG study comparing cisplatin alone (50
mg/m2) with cisplatin (50 mg/m2) plus paclitaxel (135
mg/m2 over 24 hours) in 280 patients with recurrent or
stage IV B squamous cell carcinoma of the cervix were
presented at the American Society of Clinical Oncology
meeting in May 2001 [55].The combination produced a
significantly higher response rate compared with cisplatin

alone (36.2% versus 19.4%, p = 0.002). The combination

regimen also was associated with higher rates of complete
response (20% versus 8%) and partial response (27% versus 18%). These higher response rates translated into a significantly longer progression-free survival (p = 0.001) but
no significant difference in overall survival (median 9.7
versus 8.8 months). Interim results suggested that the combination also improved various health-related quality-oflife parameters, but the quality-of-life data were incomplete
at the time of presentation.
Radiotherapy for Metastatic Cervical Cancer
Local treatment with radiation therapy to sites of symptomatic involvement in patients with metastatic disease has
an important role to play in the alleviation of pain arising
from skeletal metastases and symptoms associated with cerebral metastases [56]. Meta-analyses have shown that short
courses of radiotherapy are as effective as long courses in the
relief of bone pain, and similar results were found in the
treatment of cerebral metastases (Table 4). In view of the
shortened life expectancy of patients with metastatic cervical
cancer, palliative radiotherapy should be given via larger
fractions over shorter periods of time than conventional radical courses of treatment [57].
CONCLUSIONS
Cervical cancer, despite being potentially preventable,
remains an important cause of morbidity and gynecological
cancer deaths throughout the world. The natural history is well
understood, and randomized trials have established the optimal
treatment strategies for patients with potentially curable
disease at initial diagnosis. The management of patients with
recurrent or metastatic disease has not been subjected to the
Table 4.
Guidelinesradiotherapy for
metastatic disease

Level of evidence

Short courses of radiotherapy are as

effective as longer courses for painful
bone metastases.

Short courses of radiotherapy are as

effective as longer courses for cerebral
metastases.

II

Table 5. Summary of outcomes for patients with recurrent cervical cancer

Recurrence

Treatment

Outcome

Central

Pelvic exenteration

30%-60%: 5-year survival

Local recurrence following surgery

Chemotherapy and radiotherapy

Distant metastases

Cisplatin-based chemotherapy

6%-77%: 5-year survival

17%-50% response: 4-9 months median survival

346

same degree of investigation, and there are relatively few randomized trials to guide treatment decision-making (Table 5).
The aim of this paper is to highlight the gaps in our knowledge

Treatment of Recurrent and Metastatic Cervical Cancer

and stimulate more rigorous investigation, while at the same
time providing an evidence-based foundation for treating
women with recurrent and metastatic cervical cancer.

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