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PRACTICE
BULLETIN
CLINICAL MANAGEMENT GUIDELINES FOR
OBSTETRICIANGYNECOLOGISTS
NUMBER 35, MAY 2002
(Replaces Committee Opinion Number 242, October 2000)
Background
Prevalence
The American Cancer Society estimated that 12,900 new cases of cervical cancer would be diagnosed in the United States in 2001 and that 4,400 deaths from
cervical cancer would result (2). Cervical cancer comprises approximately 16%
of the estimated 80,300 cases of reproductive-tract cancers among women in
the United States. Seventy-eight percent of cases occur in developing countries
where cervical cancer is the second most frequent cause of cancer-related death
in women. The substantial decrease in incidence and mortality in developed
countries is thought to be a result of effective screening.
Risk Factors
Human papillomavirus is considered the most important factor contributing to the
development of cervical intraepithelial neoplasia and cervical cancer. Countries with
a high incidence of cervical cancer also have a high prevalence of human papillomavirus (1). Other epidemiologic risk factors associated with cervical intraepithelial
neoplasia and cervical cancer include history of sexual intercourse at an early age, multiple sexual partners, sexually
transmitted diseases (including chlamydia), and smoking (3).
Additional risk factors include a male partner or partners
who have had multiple sexual partners; previous history of
squamous dysplasias of the cervix, vagina, or vulva; and
immunosuppression, such as after organ transplantation or
patients with acquired immunodeficiency syndrome.
Diagnosis
The signs and symptoms of early cervical carcinoma
include watery vaginal discharge, intermittent spotting, and
postcoital bleeding. Often the symptoms go unrecognized
by the patient. Because of the accessibility of the cervix,
accurate diagnosis often can be made with cytologic screening, colposcopically directed biopsy, or biopsy of a gross or
palpable lesion (4). In cases of suspected microinvasion and
early-stage cervical carcinoma, cone biopsy of the cervix is
indicated to evaluate the possibility of invasion or to define
the depth and extent of microinvasion. Cold knife cone biopsy provides the most accurate evaluation of the margins.
Histology
The two major histologic types of invasive cervical carcinomas are squamous cell carcinomas and adenocarcinomas. Squamous cell carcinomas comprise 80% of cases,
and adenocarcinoma or adenosquamous carcinoma comprise approximately 15%. The remaining cases are made
up of various rare histologies, which may have very different biologic behavior.
Management
Early carcinomas of the cervix usually can be managed by
surgical techniques or radiation therapy. The more
advanced carcinomas require primary treatment with radiation therapy. Many changes in radiation therapy techniques have occurred in the past decade. These include
incorporation of higher energy external beam equipment,
improved field design to cover anatomic regions at risk,
increased use of tomographic imaging, recognition of the
adverse impact of prolonged treatment, increased familiarity with high-dose-rate brachytherapy, and, more recently,
the use of chemotherapy concurrent with radiation therapy.
tific comparison of treatment results from different centers or protocols. The three major staging systems are
those of FIGO, the American Joint Committee on Cancer,
and the International Union Against Cancer. Cancer registries approved by the American College of Surgeons
use the American Joint Committee on Cancers TNM
(tumor, nodes, metastasis) staging system. However, the
scientific literature reports gynecologic oncology statistics using the FIGO system. It is recommended that the
FIGO system be used to facilitate comparisons of international data.
Staging of invasive cervical cancer with the FIGO
system is achieved by clinical evaluation. Other gynecologic cancers are staged surgically. The current FIGO
nomenclature for cancer of the cervix was first adopted in
1994 (5) (see box, Carcinoma of the Cervix Uteri: FIGO
Nomenclature).
Careful clinical examination should be performed on
all patients. Examinations should be conducted by experienced examiners and may be performed under anesthesia.
Pretreatment evaluation of women with cervical carcinoma
often can be helpful if provided by an obstetriciangynecologist with advanced surgical training, experience, and
demonstrated competence, such as a gynecologic oncologist. The procedure may be scheduled to occur at the same
time the patient is undergoing another procedure requiring
anesthesia. Once established, the clinical stage must not be
revised because of subsequent findings, even if the cancer
recurs. The box, Guidelines for Clinical Staging of
Invasive Cervical Carcinoma, identifies key points in staging disease. These guidelines are made up of examinations
generally available throughout the world. Strict adherence
to the rules for staging provides the framework for making
valid scientific comparison of results.
Various optional examinations, such as ultrasonography, computed tomography (CT), magnetic resonance
imaging (MRI), lymphangiography, laparoscopy, and fineneedle aspiration, are valuable for treatment planning.
Surgical findings provide extremely accurate information
about the extent of disease and will guide treatment plans
but will not change the results of clinical staging. The
occasional hysterectomy specimen with unsuspected
extensive invasive cervical carcinoma cannot change the
previously documented clinical stage.
While not required as part of FIGO staging procedures, in the United States, various radiologic tests are
frequently undertaken to help define the extent of tumor
growth and guide therapy decisions, especially in
patients with locally advanced disease (ie, stage IIb or
more advanced). Computed tomography of the abdomen
and pelvis is the most widely used imaging study. Early
evaluation of the efficacy of CT scans in detecting
paraaortic adenopathy noted a very high specificity
(96%) but low sensitivity (34%) (6). However, with technologic advancements leading to increased imaging resolution, accuracy of CT scanning has improved (7).
Recent experience has suggested MRI is as accurate as
CT in assessing nodal involvement and provides better
definition of the extent of local tumors within the pelvis
(7). Some investigators have advocated the use of lymphangiography as the standard for noninvasive assessment of retroperitoneal adenopathy, but a recent review
has shown that contemporary CT and MRI results are as
accurate as lymphangiography and are preferable given
that more information is provided on local tumor
infiltration (7). Early experience with a new imaging
modality, positron emission tomography (PET), shows
considerable promise in further increasing the accuracy
of noninvasive radiologic staging. The sensitivity of
PET has been reported to be 75%, and the specificity
92% (8).
surgical evaluation of cervical cancer remains controversial, it is the best method of assessing nodal involvement.
Retroperitoneal surgical lymph node dissection of the
pelvic and paraaortic lymph nodes provides important
information about treatment planning and prognosis.
Patients with positive lymph nodes can have radiation
fields modified appropriately to cover areas at risk.
Resection of positive lymph nodes is thought to provide
therapeutic benefit (15, 16). Therefore, surgical evaluation allows individualization of therapy and may result in
better clinical outcomes.
with inconsistent results. More careful analysis of patterns of failure following radical hysterectomy has led to
better stratification of patients into risk groups and incorporated testing of systemic chemotherapy agents in those
considered at high risk of distant failure (28).
Two randomized clinical trials have greatly
advanced our understanding of the role of postoperative
therapy in cervical cancer (29, 30). Patients with histologically documented extracervical diseasespecifically
those with pelvic nodal involvement, positive margins, or
parametrial extensionare treated with concurrent
pelvic radiation therapy and cisplatin-based chemotherapy. The use of combined adjuvant chemotherapy
and radiation therapy in these high-risk patients following primary surgery significantly improves relapse-free
survival and overall survival rates when compared with
radiation therapy alone (29).
Following radical hysterectomy, a subset of nodenegative patients who have a constellation of primary risk
factors (large tumors, depth of stromal infiltration, and
lymphovascular space involvement) may be defined as
having intermediate risk for relapse. For these patients,
adjuvant pelvic radiation therapy provides clear therapeutic benefit, with significantly improved relapse-free
survival rates when compared with those who had no further therapy. However, observation of improvement in
overall survival favoring patients who had radiation therapy awaits further statistical confirmation following maturation of the data (30).
Until recently, there have been no prospective randomized studies comparing surgery and radiation therapy. An Italian randomized trial provides information
about primary surgery and radiation therapy but does not
include the addition of concurrent or neoadjuvant
chemotherapy (27). This study compared radical hysterectomy and primary radiotherapy with adjuvant radiation therapy in high-risk surgically treated patients.
Stratification for stage Ib and Ib2 was included.
Pathologic findings indicated identical 5-year overall and
disease-free survival rates in the radiation therapy group
and the surgical group with tailored postoperative radiation therapy. Severe morbidity occurred in 28% of patients
in the surgery and postoperative radiation therapy group
and in 12% of patients in the radiation therapyonly
group (P = 0.0004). In this study, adjuvant radiation therapy after primary surgery was used in 54% of patients
with tumors measuring 4 cm or less and in 84% of
patients with tumor diameters greater than 4 cm.
Significant prognostic factors included tumor diameter,
positive lymphangiography, and adenocarcinoma histology as identified on univariate and multivariate analyses.
Although the two modalities were found to be similarly effective in the randomized trials, the rate and types
of complications differ. The preference of treatment
depends on the situation, the physicians input, and the
patients age, health, and tumor characteristics.
Those who favor radical surgery point out that it
leaves the vagina in more functional condition, while
radiation therapy results in a reduction in length, caliber,
and lubrication of the vagina. In premenopausal women,
ovarian function can be preserved with surgery. The surgical approach also provides the opportunity for pelvic
and abdominal exploration and provides better clinical
and pathologic information with which to individualize
treatment. Surgery may be preferred over radiation therapy in women who have diverticular disease, tuboovarian
abscess, or appendiceal abscess; have had prior radiation
therapy; have congenital pelvic located kidney; or are
psychotic or noncompliant. Proponents of radiation therapy advocate primary radiation to avoid surgical morbidity or mortality, risk of blood loss and transfusion, and
excessive anesthesia time.
Underlying this question is the continuing debate regarding the independent prognostic implications of adenocarcinoma versus squamous cell histologies in cervical
cancer, especially in early-stage disease. Two large
reviews reflect the ongoing controversy. In an analysis of
813 patients with stage Ib cervical cancer entered into a
Gynecologic Oncology Group surgicalpathologic
study, excluding patients with positive paraaortic nodes
or gross extracervical disease, three specific cell types
were identified (645 squamous cell, 104 adenocarcinoma, and 64 adenosquamous). No significant differences
were found among the cell types with regard to the
Surveillance after primary therapy for invasive carcinoma of the cervix is universally recommended.
Approximately 35% of patients will have persistent or
recurrent disease. The main goal of surveillance is early
detection of recurrent disease so that patients can be
offered potentially curative salvage therapy. The average
1-year survival for patients with recurrent cervical cancer is 1020% (39, 40). Surveillance schedules should
take into account the risk of recurrence, which is highest
in the first 2 years following treatment (41). The potential benefit of salvage therapy depends on the stage of
disease, type of treatment, and location of recurrence (ie,
local, regional, or distant). In general, radical radiation
therapy is used for recurrent cervical cancer after primary hysterectomy, while salvage surgery is required for
those who relapse after primary radiation therapy. In
selected patients with centralized pelvic recurrences, salvage may be achieved in about 50% of cases (42).
Few studies have specifically addressed the efficacy
of routine surveillance follow-up after definitive cervical
cancer therapy in asymptomatic and disease-free
patients, as opposed to symptom-based reassessment.
Schedules for posttherapy surveillance vary by practitioner and institution, although a common approach
includes examinations and Pap tests every 34 months
for the first 3 years, decreasing to twice yearly in the
fourth and fifth years (4).
Investigators recently attempted to develop an optimal surveillance program based on outcome analysis
following primary therapy for stage-Ib cervical cancer
(43). Detection of asymptomatic recurrences, whether
locally in the pelvis or with isolated pulmonary metastases, led to significantly better salvage options and survival when compared with detection only in patients
presenting with symptomatic recurrences. The authors
concluded this subset of patients may benefit from careful posttherapy surveillance and proposed a schedule
involving thrice-yearly follow-up visits for the first 2
years, and twice-yearly visits subsequently to year 5,
with Pap tests and chest X-rays on a yearly basis.
Posttreatment follow-up also is beneficial for reasons other than the diagnosis of recurrence. The psychologic support and reassurance of continued contact with
the treating team is vitally important. Annual health
maintenance visits for mammography, blood pressure,
and evaluation of other medical problems are important.
Many of these patients undergo bilateral salpingooophorectomy or radiation therapy, and hormone
replacement therapy should be considered in such
patients. Cervical adenocarcinoma is not a contraindication to hormone replacement therapy.
Microinvasive
squamous
carcinoma
Invasive carcinoma
Malignant
cytology
suggesting
invasion
Diagnostic
conization or
wedge biopsy
of cervix
Appropriate
therapy
Abnormal
cytology
without
suggesting
invasion
Papanicolaou test
and colposcopy
every 8 weeks
Microinvasion
3 mm
Invasive
carcinoma
Appropriate
therapy
rates, and an opportunity for preservation of ovarian function (49). Gestational edema and more pronounced cleavage planes facilitate the dissection.
When radical cesarean hysterectomy is performed, a
classical uterine incision is preferred. Bilateral ovariopexy is a reasonable consideration at the time of surgery
in the event that adjuvant radiation might be indicated
for patients with high-risk histopathologic features.
Results of a casecontrol study comparing radical surgery outcomes in pregnant and nonpregnant patients
demonstrated a higher blood loss in pregnant patients,
but this did not translate into a significant increase in
blood transfusion, operative morbidity, or major complication rates (58). Survival was 97% in the pregnant
patients and 90% in the controls, with mean follow-up
over 140 months.
Most pregnant patients who are candidates for radical surgery will benefit from surgery rather than radiation therapy, given the advantage of ovarian preservation
and the avoidance of radiation-associated vaginal fibrosis. Pregnant patients with stage IIb or more advanced
invasive cervical cancer and patients either not medically fit or not interested in primary surgical treatment
should undergo definitive radiation therapy. Patients
with advanced disease who elect to delay treatment
should have documented fetal pulmonary maturity prior
to classic cesarean delivery and should start their radia-
Stage IIb and greater should be treated with external-beam and brachytherapy radiation and concurrent cisplatin-based chemotherapy.
The following recommendations are based on limited or inconsistent scientific evidence (Level B):
10
Summary
The following recommendations are based primarily on expert opinion and consensus (Level C):
Treatment for pregnant patients with invasive carcinoma of the cervix should be individualized on the
basis of evaluation of maternal and fetal risks.
References
1. Parkin DM, Pisani P, Ferlay J. Global cancer statistics.
CA Cancer J Clin 1999;49:3364,1 (Level II-3)
2. Greenlee RT, Hill-Harmon MB, Murray T, Thun M.
Cancer statistics, 2001. CA Cancer J Clin 2001;51:1536
(Level II-3)
3. Anttila T, Saikku P, Koskela P, Bloigu A, Dillner J,
Ikaneimo I, et al. Serotypes of Chlamydia trachomatis and
risk for development of cervical squamous cell carcinoma. JAMA 2001;285:4751 (Level II-2)
4. National Comprehensive Cancer Network. NCCN
practice guidelines for cervical cancer. In: The complete
library of NCCN oncology practice guidelines
(CD-ROM), Version 2000, Revision date: June 1, 2000
(Level III)
5. Benedet JL, Odicino F, Maisonneuve P, Beller U,
Creasman WT, Heintz AP, et al. Carcinoma of the cervix
uteri. J Epidemiol Biostat 2001;6:743 (Level II-3)
6. Heller PB, Maletano JH, Bundy BN, Barnhill DR,
Okagaki T. Clinical-pathologic study of stage IIB, III and
IVA carcinoma of the cervix: extended diagnostic evaluation for paraaortic node metastasisa Gynecologic
Oncology Group study. Gynecol Oncol 1990;38:425430
(Level II-3)
7. Scheidler J, Hricak H, Yu KK, Subak L, Segal MR.
Radiological evaluation of lymph node metastases in
patients with cervical cancer. A meta-analysis. JAMA
1997;278:10961101 (Meta-analysis)
8. Rose PG, Adler LP, Rodriguez M, Faulhaber PF, AbdulKarim FW, Miraldi F. Positron emission tomography for
evaluating para-aortic nodal metastasis in locally
advanced cervical cancer before surgical staging: a surgicopathologic study. J Clin Oncol 1999;17:4145 (Level
III)
9. Alvarez RD, Soong SJ, Kinney WK, Reid GC, Schray
MF, Podratz KC, et al. Identification of prognostic factors
and risk groups in patients found to have nodal metastasis
at the time of radical hysterectomy for early-stage squamous carcinoma of the cervix. Gynecol Oncol 1989;35:
130135 (Level II-2)
10. Fuller AF Jr, Elliott N, Kosloff C, Hoskins WJ, Lewis JL
Jr. Determinants of increased risk for recurrence in
11
47. Monk BJ, Montz FJ. Invasive cervical cancer complicating intrauterine pregnancy: treatment with radical hysterectomy. Obstet Gynecol 1992;80:199203 (Level III)
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Diagnosis and treatment of cervical carcinomas. ACOG Practice
Bulletin No. 35. American College of Obstetricians and Gynecologists.
Obstet Gynecol 2002;99:855-867
Evidence obtained from at least one properly designed randomized controlled trial.
II-1 Evidence obtained from well-designed controlled
trials without randomization.
II-2 Evidence obtained from well-designed cohort or
casecontrol analytic studies, preferably from more
than one center or research group.
II-3 Evidence obtained from multiple time series with or
without the intervention. Dramatic results in uncontrolled experiments also could be regarded as this
type of evidence.
III Opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert
committees.
Based on the highest level of evidence found in the data,
recommendations are provided and graded according to the
following categories:
Level ARecommendations are based on good and consistent scientific evidence.
Level BRecommendations are based on limited or inconsistent scientific evidence.
Level CRecommendations are based primarily on consensus and expert opinion.
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