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Guidelines for the Treatment of Recurrentand 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

ABSTRACT

Although there have been important advances inthe 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 manage-

ment of patients who relapse after primary treatment

for cervical cancer. Patients who are still potentiallycurable 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

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

Correspondence: Michael Friedlander, M.D., Department of Medical Oncology, Prince of Wales Hospital, High StreetRandwick NSW 2031, Australia. Telephone: 612-9382-2606; Fax: 612-9382-2588; e-mail: [email protected] February 27, 2002; accepted for publication June 17, 2002 AlphaMed Press 1083-7159/2002/$5.00/0

BACKGROUND

Patients with cervical cancer may develop pelvic recur-

rence, 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 dis-

ease 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

TheOncologist

LEARNING OBJECTIVES

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.

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


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Friedlander, Grogan 343

(7%) [6]. Bone metastases occurred in 16% of patients, pre-

dominantly 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 diag-

nosis, 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 cer-

vical 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 pal-

liative 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 exclu-sion 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 psycholo-

gists, 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 treat-

ment 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:

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-con-

trolled 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 radiother-

apy 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 histopatho-

logical 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 prog-

nostic 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 dis-

ease-free interval greater than 6 months, recurrence


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344 Treatment of Recurrent and Metastatic Cervical Cancer

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 long-

term 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-freeinterval, 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 recur-

rences. 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 con-

current chemotherapy and radiotherapy, which appears to be

associated with superior results compared with thoseachieved with radiotherapy alone, but there have not been

any randomized trials of combined chemoirradiation com-

pared 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 incor-

porate concurrent cisplatin-based chemotherapy with radia-

tion 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 can-

cer [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

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

The response rate of other platinum compounds, such as car-

boplatin, 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 sup-

portive 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 cis-

platin and methotrexate was associated with a significant

increase in survival compared with a single inactive agent,

hydroxyurea [39]. In another relatively small study of cis-platin-based chemotherapy, it was demonstrated that, while

Table 2.

Guidelinelocal recurrence of cervical Level of evidencecancer following surgery

Radiation therapy is indicated in patients IIIwith locally recurrent cervical cancer

following radical surgery.Concurrent chemotherapy with either IIIfluorouracil and/or cisplatin with radiationshould be considered and may improveoutcome.

Pelvic exenteration may be an alternative III(particularly if a fistula is present) to radicalradiotherapy and concurrent chemotherapyin selected patients without pelvic side wallinvolvement.

Table 3.

Guidelinesystemic chemotherapy in Level of evidencemetastatic cervical cancer

Cisplatin is the single most active agent IIto treat cervical cancer.

The response rate (31%) with 100 mg/m2 IIcisplatin is higher than that with 50 mg/m2

(21%), but is not associated with any

improvement in progression-free or overallsurvival.

Cisplatin-based combination therapy is IIassociated with a higher response rate andlonger progression-free survival thansingle-agent cisplatin therapy, but there isno difference in overall survival.

Response rates to chemotherapy are IIIconsistently higher in patients with goodperformance status and extrapelvic disease,and low in previously irradicated sites.

The impact of chemotherapy on palliation IIIand survival is unclear.


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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 progression-

free 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 cis-

platin in phase II studies in patients with either locallyadvanced and/or recurrent cervical cancer [49-54]. High

response rates have been observed (40%-66%), particu-

larly among patients with locally advanced disease at pre-

sentation [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% ver-

sus 18%). These higher response rates translated into a sig-

nificantly 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 com-

bination also improved various health-related quality-of-

life 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 symp-

tomatic 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 cere-

bral 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 rad-

ical 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 wellunderstood, 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 Level of evidencemetastatic disease

Short courses of radiotherapy are as Ieffective as longer courses for painfulbone metastases.

Short courses of radiotherapy are as IIeffective as longer courses for cerebralmetastases.

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 6%-77%: 5-year survival

Distant metastases Cisplatin-based chemotherapy 17%-50% response: 4-9 months median survival


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346 Treatment of Recurrent and Metastatic Cervical Cancer

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The Oncologist 2002 Friedlander 342 7