Cervical cancer

January 1, 2005
Dennis S. Chi, MD

Carlos A. Perez, MD

Rachelle M. Lanciano, MD

John J. Kavanagh, MD

The overall incidence of invasive cervical carcinoma has declined steadily sincethe mid-1940s. Of the predominant gynecologic cancers, cancer of the uterinecervix is the least common, with only 10,370 new cases anticipated in the UnitedStates in the year 2005. Nevertheless, approximately 3,710 women die of cancerof the uterine cervix annually in the United States.

The overall incidence of invasive cervical carcinoma has declined steadily sincethe mid-1940s. Of the predominant gynecologic cancers, cancer of the uterinecervix is the least common, with only 10,370 new cases anticipated in the UnitedStates in the year 2005. Nevertheless, approximately 3,710 women die of cancerof the uterine cervix annually in the United States.EpidemiologyAge The peak age of developing cervical cancer is 47 years. Approximately47% of women with invasive cervical cancer are < 35 years old atdiagnosis. Older women (> 65 years) account for another 10% of patientswith cervical cancer. Although these older patients represent only 10% ofall cases, they are more likely to die of the disease due to their more advanced stage at diagnosis.Socioeconomic class Carcinoma of the uterine cervix primarily affects womenfrom the lower socioeconomic class and those with poor access to routine medical care.Geography Although invasive cervical carcinoma is relatively uncommonin the United States compared with the more common cancers in women(breast, endometrial, and ovarian cancers), it remains a significant healthproblem for women worldwide. In many developing countries, not only iscervical carcinoma the most frequently occurring cancer among middleagedwomen, but also it is a leading cause of death. This is due, in part, topoor access to medical care and the unavailability of routine screening in many of these countries.Etiology and risk factorsSexual activity Invasive cervical carcinoma can be viewed as a sexually transmitteddisease. If a woman is never sexually active, it is extremely unlikely thatshe will ever develop this cancer. Conversely, any woman who has been sexuallyactive is at risk for invasive cervical carcinoma.Human papillomavirus Molecular and epidemiologic evidence clearly indicatesthat certain types of human papillomavirus (HPV), which is sexually transmit-ted, are the principal causes of invasive cervicalcancer and cervical intraepithelial neoplasia(CIN). More than 80 HPV types have beenidentified, and about 40 infect the genital tract.HPV-16 is the type most commonly linkedwith cancer, present in 50% of cervical cancersand high-grade CINs. A vaccine for HPV-16 is an area of ongoing research.Age of onset of sexual activity Population studiesof women with invasive cervical carcinomahave demonstrated that early age of onset ofsexual activity also plays a role in the later developmentof the cancer. It is postulated thatduring the time of menarche in early reproductivelife, the transformation zone of the cervixis more susceptible to oncogenic agents, suchas HPV. Women who begin sexual activitybefore 16 years of age or who are sexually activewithin 1 year of beginning menses are atparticularly high risk of developing invasive cervicalcarcinoma (Table 1).Other risk factors include multiple sexualpartners, a history of genital warts, and multiparity.Cigarette smoking has been identified as a significant risk factor for cervicalcarcinoma. The mechanism may be related to diminished immune functionsecondary to a systemic effect of cigarette smoke and its by-products or a localeffect of tobacco-specific carcinogens.Oral contraceptives may also play a role in the development of invasive cervicalcarcinoma, although this theory is controversial. Given that most womenwho use oral contraceptives are more sexually active than women who do notuse oral contraceptives, this may represent a confounding factor rather than atrue independent risk factor. The exception may be adenocarcinoma of thecervix. This relatively uncommon histologic subtype may be related to previous oral contraceptive use.Immune system alterations In recent years, alterations in the immune systemhave been associated with an increased risk of invasive cervical carcinoma,as exemplified by the fact that patients who are infected with the human immunodeficiencyvirus (HIV) have increased rates of both preinvasive and invasivecervical carcinoma. These patients also are at risk for other types of carcinoma,including Kaposi's sarcoma, lymphomas, and other squamous cell carcinomasof the head and neck and the anogenital region. (For further discussion of AIDSrelatedmalignancies, see chapter 27.)

Data suggest that patients who are immunocompromised due to immunosuppressivemedications also are at risk for both preinvasive and invasive cervicalcarcinoma. This association is probably due to the suppression of thenormal immune response to HPV, which makes patients more susceptible to malignant transformation.Signs and symptomsCommon symptoms A symptom of advanced cervical carcinoma is intermenstrualbleeding in a premenopausal patient. Other commonly reportedsymptoms include heavier menstrual flow, metrorrhagia, and/or postcoitalbleeding. With effective screening, cervical cancer is generally asymptomatic.Less common presentations Less frequently, patients with advanced cancerwill present with signs of advanced disease, such as bowel obstruction and renalfailure due to urinary tract obstruction. Only rarely are asymptomatic patientswith a normal screening Pap smear found to have a lesion on the cervixas their only sign or symptom of cervical cancer. Foul-smelling vaginal discharge,pelvic pain, or both are occasionally observed.Screening and diagnosisScreeningPap smear The paradigm for a cost-effective, easy-to-use, reliable screeningtest is the cervical cytology screen, or Pap smear. In every population studied,the introduction of the Pap smear has resulted in a significant reduction in theincidence of invasive cervical carcinoma, as well as a shift toward earlier stagedisease at the time of diagnosis. The success of cervical cytology, as measuredby the lowered incidence of cervical cancer, ironically has led to some controversyregarding the most effective application of this screening tool. With themarked reduction in the incidence of cervical carcinoma, more patients arescreened and greater costs incurred to detect each additional case of cervical carcinoma.Current screening recommendations The current recommendation of theAmerican College of Obstetricians and Gynecologists (ACOG) is that all womenwho are 18 years of age or older and are sexually active be screened. If thepatient has three consecutive annual cervical cytology smears that are normal,she may be safely screened at a less frequent interval of perhaps 2-3 years.There are no data to support screening patients on a less frequent basis. Anypatient who has a history of cervical dysplasia should be screened at least on a yearly basis.The current American Cancer Society (ACS) revised guidelines for cervicalcancer screening are as follows: Cervical cancer screening should begin~3 years after the onset of vaginal intercourse but no later than age 21. Cervicalscreening should be performed every year with conventional cervical cytologysmears, or every 2 years using liquid-based cytology until age 30. After age 30,as an alternative to annual routine cytology, HPV DNA testing may be addedto cervical cytology for screening. After this initial dual testing, women whoseresults are negative by both HPV DNA testing and cytology should not berescreened before 3 years. Women whose results are negative by cytology butwho are high-risk HPV DNA positive are at a relatively low risk of havinghigh-grade cervical neoplasia, and colposcopy should not be performed routinelyin this setting. Instead, HPV DNA testing along with cervical cytologyshould be repeated in these women at 6 or 12 months. If test results of eithermodality are positive, colposcopy should then be performed.Women who are > 70 years old with an intact cervix and who have had three ormore documented, consecutive, technically satisfactory normal cervical cytologytests and no abnormal cytology tests within the 10-year period prior to age70 may elect to cease cervical cancer screening. Women with a history of cervicalcancer, in utero exposure to diethylstilbestrol (DES), and/or who areimmunocompromised (including HIV+) should continue cervical cancer screeningfor as long as they are in reasonably good health and do not have a lifelimitingchronic condition. Women > 70 years old should discuss their need forcervical cancer screening with a health care professional and make an informeddecision about continuing screening based on its potential benefits, harms, andlimitations.Women who have had a subtotal hysterectomy should continue cervical cancerscreening as per current guidelines. Cervical cancer screening followingtotal hysterectomy (with removal of the cervix) for benign gynecologic diseaseis not indicated. Women with a history of CIN2/3 or for whom it is not possibleto document the absence of CIN2/3 prior to or as the indication for hysterectomyshould be screened until three documented, consecutive, technically satisfactorynormal cervical cytology tests and no abnormal cytology tests (withina 10-year period) are achieved. Women with a history of in utero DES exposureand a history of cervical carcinoma should continue screening after hysterectomyfor as long as they are in reasonably good health and do not have a lifelimitingchronic condition.Three new techniques designed to improve the sensitivity of the Pap smear(Thin Prep system, Autopap, and Papnet) have been approved by the FDA.However, no large, population-based, prospective studies have been completedto determine whether any of these techniques lowers the incidence ofinvasive cervical cancer or improves the survival rate. The improved sensitivityof liquid-based cytologies must be balanced against the increased cost.Diagnosis
The diagnosis of invasive cervical carcinoma can be suggested by either anabnormal Pap smear or an abnormal physical finding.Colposcopy In the patient who has an abnormal Pap smear but normalphysical findings, colposcopy is indicated. Colposcopic findings consistentwith invasive cervical carcinoma include dense white epithelium coveringthe ectocervix, punctation, mosaicism, and, especially, an atypical blood vessel pattern.Biopsy If the colposcopic findings are suggestive of invasion, biopsies areobtained from the ectocervix and endocervix. If these biopsies demonstrateonly precancerous changes but not an invasive carcinoma, the patientshould undergo an excisional biopsy of the cervix. In most currentclinical settings, the loop electrosurgical excision procedure (LEEP) is themost expedient method for performing an excisional biopsy. This can beeasily accomplished in the office with the patient under local anesthesiaand provides adequate tissue for diagnosis. Once the diagnosis of eithermicroinvasive or invasive carcinoma has been established, the patient canbe triaged accordingly.Patient with signs/symptoms of advanced disease The patient with signs/symptoms of advanced invasive cervical carcinoma requires a cervical biopsyfor diagnosis and treatment planning. In this setting, a Pap smear is superfluousand may be misleading.

PathologySquamous cell carcinoma The most common histology associated with invasivecervical carcinoma is squamous cell carcinoma, which accounts for approximately80% of all carcinomas of the uterine cervix. For the most part, thedecline in the annual incidence of invasive cervical carcinoma has been seenprimarily among patients with this subtype.Adenocarcinoma In the past, adenocarcinoma was relatively uncommon as aprimary histology of cervical cancer. As a result of the decrease in the overallincidence of invasive squamous cell cancer and, probably, an increase in thebaseline incidence of adenocarcinoma of the uterine cervix, this histology nowaccounts for approximately 20% of all cervical cancers.There is controversy over whether patients with adenocarcinoma of the cervixhave a worse prognosis than those with the more common squamous cell histology.The poorer prognosis associated with adenocarcinoma may be due tothe relatively higher frequency of late stage at the time of diagnosis amongpatients with this histologic type. In several series in which patients were stratifiedby stage and tumor size, the outcome of cervical adenocarcinoma appearedto be similar to that of squamous lesions of the cervix.Aggressive subtypes Among the various subtypes of adenocarcinoma, certain typesare particularly aggressive and are associated with a poor prognosis. Amongthem are the small cell or neuroendocrine tumors, which have a poor prognosiseven when diagnosed at an early stage.Rare tumor types More rare lesions of the cervix include lymphoma, sarcoma,and melanoma. These histologic subtypes account for < 1% of all cervicalcancers.Staging and prognosisClinical staging
The widely accepted schemas for staging of cervical carcinoma are outlined bythe International Federation of Gynecology and Obstetrics (FIGO) or theAmerican Joint Commission (AJC). They are primarily clinical staging systemsbased on histology for the earlier stage I cancers and tumor size (Table 2). Forthe more advanced tumors, staging is based on extension of the disease in thepelvis. Positron emission tomography with 18fluorodeoxyglucose (FDG-PET)is being used increasingly to evaluate lymphatic and distant metastasis.Radiographic examination allowed under the FIGO staging system includeschest x-ray and barium enema, as well as IV pyelography. However, whereavailable, CT scanning or MRI is the preferred diagnostic study. MRI is superiorto the CT scan in evaluating the extent of disease in the pelvis. The bariumenema and IV pyelography are usually not performed in patients with earlydisease. For advanced disease, cystoscopy and/or sigmoidoscopy may be indi-cated. Additional clinical information can begathered by pelvic examination with the patientunder anesthesia.A recent modification of the FIGO system hasclarified the description of patients withmicroinvasive cervical carcinoma. This betterdifferentiation between stages IA1 and IA2followed the lead established by the Societyof Gynecologic Oncologists (SGO) in its stagingof microinvasive carcinoma.In addition, the modified FIGO system nowstages patients with lesions that are clinicallyconfined to the cervix (stage IB) according tothe size of the primary tumor.Surgical staging
Clinical staging of cervical carcinoma, althoughwidely utilized, is not without controversy.When compared with surgical stagingperformed by large cooperative groups,clinical staging is frequently inaccurate in predicting locoregional spread. For many cooperative groups, including the GynecologicOncology Group (GOG), surgical staging may be required for patientswho are entering prospective, randomized clinical protocols. However,because of the controversy of risk and benefit, the GOG considers surgical staging optimal.The most common method used to stage patients with advanced disease isextraperitoneal sampling of the pelvic and aortic lymph nodes. This approachminimizes the risk of subsequent radiation injury to the small bowel due tosurgical adhesions and, in patients with advanced disease, allows for individualizedtreatment planning.Work-up for advanced disease The standard work-up of a patient with advancedcervical carcinoma who is not considered a candidate for radical surgeryincludes an abdominopelvic CT scan with both renal and GI contrast. Ifthere is evidence of aortic lymph node metastases, the patient should undergofine-needle aspiration (FNA) of these enlarged lymph nodes. If FNA confirmsthat there is aortic lymph node metastasis, treatment should be individualized,and extended-field irradiation should be considered as part of the primary treatment regimen.If the scalene lymph nodes are negative on clinical examination and the patientis known to have positive metastatic disease to the aortic lymph nodes, considerationcan be given to performing a scalene lymph node biopsy; the incidenceof positive scalene nodes when aortic lymph nodes are known to be positiveranges from 0% to 17%. The rationale for biopsying the scalene nodes is that if there is disease outside the radiation therapyfield, chemotherapy may be appropriate.If the result of FNA is negative, or if theabdominopelvic CT scan does not demonstrateenlarged aortic lymph nodes, the patientcan be considered for surgical staging.Recent data regarding the use of PET scan incervical cancer reveal that tumor volume canbe accurately measured by PET and can separatepatients into prognostic groups. In a seriesof 101 consecutive patients with advanced cervicalcancer, 67% had positive lymph nodeson PET, which correlated with decreased survivalfollowing chemoradiation therapy.Pros and cons of surgical staging The advantageof surgical staging is that patients withmicroscopic disease in the aortic lymph nodescan be treated with extended-field radiationtherapy and, possibly, chemotherapy and potentiallybenefit in terms of long-term survival.The controversy regarding surgical stagingstems from the fact that a small number of patientswill actually benefit from the procedure;the majority of patients who undergo it will befound not to have metastatic disease and willreceive the same treatment as planned prior tosurgical staging or if they are found to havemetastatic disease, they will be unlikely to benefitfrom extended-field radiation therapy. Becauseof this controversy, GOG considers surgical staging to be optional for patientswith advanced-stage cervical cancer.Laparoscopic surgery In more recent years, the introduction of minimalaccesssurgery has allowed surgeons to accurately stage patients via thelaparoscope prior to initiation of radiation therapy. However, the safetyand efficacy of laparoscopic surgical staging are areas of ongoing investigation.Work-up for early-stage disease For patients who have early-stage diseasefor which surgery is contemplated, only a minimal diagnostic work-up is indicatedprior to surgery. At most institutions, this would include a two-view chestx-ray. Patients who have stage IA cervical carcinoma (microinvasive carcinoma)do not require preoperative CT scanning prior to hysterectomy. For patientswith a small IB carcinoma of the cervix, a CT scan of the abdomen and pelvishas a low yield and is unlikely to change the treatment plan.Prognostic factorsClinical stage The most important determinant of prognosis remains clinicalstage, which is defined by tumor volume and extent of disease spread. Theoverall 5-year survival rate ranges from 95% to 100% for patients with stage IAcancer and from 75% to 90% for those with stage IB disease. Patients with stageIV disease have a ≤ 5% chance of surviving 5 years after diagnosis.Patients with early disease For patients with early invasive carcinoma (stageIB), the size of the lesion, percentage of cervical stromal invasion, histology,tumor grade, and lymphovascular space involvement are important local factorsthat predict prognosis. In general, good prognostic signs are lesions thatare ≤ 2 cm in diameter, superficially invasive, and well differentiated with nolymphovascular space involvement.For patients who have undergone radical hysterectomy for early cervical carcinoma,poor prognostic factors, in addition to the local factors previously mentioned,include positive vaginal or parametrial margins and metastasis tothe pelvic lymph nodes. For patients with stage IB disease and positive pelvicnodes, the 5-year survival rate drops from approximately 75%-85% to 50%.Patients with advanced disease
For patients with advanced-stage disease(stages II through IV), the primary determinants of prognosis are histology andsize of the primary lesion. Survival is significantly higher for patients withsmall stage IIB cervical carcinomas and minimal parametrial involvementthan for patients with large bulky tumors and bilateral parametrial involvement.Disease extension beyond the pelvis to the aortic nodes is associatedwith a significant decrease in overall survival rate. With regard to histology, abetter prognosis is associated with a large-cell nonkeratinizing squamous cellcancer of the cervix, as opposed to a poorly differentiated adenocarcinoma.Other prognostic factors Other factors that may predict outcome includethe patient's general medical and nutritional status. Patients who are anemicmay respond poorly to radiation therapy, as compared with those with normalhemoglobin levels. Patients with significant alterations in their immune systemmay not respond as well; this is becoming increasingly apparent with regard topatients who are HIV-seropositive.A retrospective review of 605 patients from seven institutions in Canada treatedwith irradiation for cervical cancer described average weekly nadir hemoglobinlevels as significant prognostic factors for survival, second only in importance totumor stage. Interestingly, Winter et al reported that hemoglobin levels duringtreatment were independent predictors of treatment outcome through a recentretrospective study of 494 patients from two consecutive prospective GOG trials.The pretreatment level was not a signficant predictor of outcome in the multivariateregression model. Levels in the last part of treatment were the most predictiveof disease recurrence and survival. However, erythropoietin should not be givenoutside a clinical trial as thrombosis is a significant complication and cause/effecthas not been proven.

The standard management of patients with early cervical carcinoma is surgicalremoval of the cervix. The extent of resection of surrounding tissue dependson the size of the lesion and the depth of tumor invasion.Stage IA1 diseaseSimple hysterectomy Patients who have a microinvasive squamous carcinomaof the cervix with ≤ 3 mm of tumor invasion, ≤ 7 mm of lateralextent, and no lymphovascular space involvement (stage IA1) can be treatedwith a simple hysterectomy. Vaginal and abdominal hysterectomies are equally effective.Cone biopsy Although simple hysterectomy is considered the standardtherapy for patients with microinvasive cervical carcinoma, there are somepatients in whom preservation of future fertility is a strong consideration. Acone biopsy entails removal of the cervical transformation zone. Providedthat the biopsy margins are free of dysplasia and microinvasive carcinoma,cone biopsy is probably a safe treatment for such patients who meet the criteriaof having superficial invasion < 3 mm, minimal lateral extension, and nolymphovascular space involvement.Since there is a small risk of recurrence among this population of patients treatedby cone biopsy alone, they should be followed closely. Follow-up includes aPap smear every 3 months for 2 years and then twice a year. An abnormal Papsmear is an indication for a repeat colposcopy. If such patients are successful inachieving pregnancy and have no evidence of recurrent squamous cell carcinoma,there is no need to proceed with hysterectomy at the completion of planned childbearing.Stages IA2, IB1, and nonbulky IIA diseaseRadical hysterectomy A standard treatment for patients with small cervicalcarcinomas (tumor ≤ 4 cm) confined to the uterine cervix or with minimalinvolvement of the vagina (stage IIA) is radical hysterectomy (removal of the uterus, cervix, and parametrial tissue), pelviclymphadenectomy, and aortic lymph nodesampling. The overall success of this treatmentis similar to that of radiation therapy,and for patients with early lesions, radical hysterectomymay provide an improved qualityof life. The benefits of surgical excision includerapid treatment, less time away from normalactivities, and preservation of normal ovarianand vaginal function.A recent randomized trial for patients withearly-stage cervical cancer reported no differencein survival between radical hysterectomyand definitive radiation therapy. Becausea significant percentage of patients followingradical hysterectomy required postoperativepelvic radiotherapy, the morbiditywas increased in the surgery arm. Therefore,patients selected for radical hysterectomyshould have small-volume disease soadjuvant pelvic radiation therapy is unnecessary.Currently, there are no specific contraindicationsto radical hysterectomy. Severalstudies have demonstrated that patients ≥ 65years old tolerate this procedure well, and agealone should not be considered a contraindication.Obesity also is not a contraindicationto radical hysterectomy.Alternatives to radical hysterectomy Reportshave described the use of laparoscopicallyassisted radical vaginal hysterectomy andlaparoscopic abdominal radical hysterectomyas less invasive alternatives to traditional radicalhysterectomy. Although these proceduresare not performed in all centers, the resultsfrom centers that have the surgical expertiseare promising. The use of fertility-preservingsurgery by means of pelvic lymphadenectomyfollowed by radical vaginal trachelectomy(removal of the uterine cervix) has alsobeen evaluated. Successful pregnancies afterthis procedure have been reported. However,further data are needed to assess the safetyand efficacy of fertility-preserving surgery.There is a lack of long-term follow-up dataand survival rates between conservative andradical treatment. These techniques shouldbe performed by fully trained surgeons. Therole of laparoscopic sentinel lymph node dissectionis an area of active investigation.Complications Due to improved surgical techniques,as well as the use of prophylactic antibiotics and prophylaxis againstdeep vein thrombosis, the morbidity and mortality associated with radical hysterectomyhave declined significantly over the past several decades. The currentlyaccepted complication rate for radical hysterectomy includes approximatelya 0.5%-1.0% incidence of urinary tract injury, a 0.5%-1.0% incidence ofdeep vein thrombosis, and an overall mortality of < 1.0%.The increased awareness of the risks associatedwith blood transfusion is reflected in thefact that, in many cases, no transfusions areadministered. The need for heterologousblood transfusion also can be decreased byencouraging autologous blood donation priorto radical hysterectomy or by using intraoperativehemodilution.The average hospital stay for patients undergoingradical hysterectomy is between 4 and7 days. Follow-up should include a vaginalPap smear every 3 months for 2 years, twicea year for 3 years, and yearly thereafter.Stages IB2 and bulky IIA disease
Numerous studies have demonstrated that patients with early-stage "bulky"lesions (tumor > 4 cm) have a worse prognosis than those with nonbulky tumors.Therefore, patients who have undergone radical hysterectomy and pelviclymphadenectomy for early-stage bulky cervical cancer have traditionallyreceived postoperative adjuvant pelvic radiation therapy. However, a randomizedtrial from Italy demonstrated that radical hysterectomy plus radiotherapydoes not improve overall or disease-free survival in patients with early-stagebulky tumors, as compared with radiation therapy alone, but does significantlyincrease morbidity.Furthermore, a recent GOG trial demonstrated the benefit of the addition ofcisplatin chemotherapy to pelvic radiation therapy followed by extrafascialhysterectomy in this group of patients (Figure 1). Therefore, many experts believethat patients with stage IB2 and bulky IIA cervical cancer should be treatedinitially with chemoradiation therapy instead of radical hysterectomy. The GOGattempted to compare chemoradiation therapy with radical hysterectomy followedby chemoradiation therapy for bulky stage IB2 cervical cancer, but unfortunately,the trial closed prematurely.RADIATION THERAPY FOR STAGES I-IV DISEASE
The role of curative surgery diminishes once cervical cancer has spread beyondthe confines of the cervix and vaginal fornices. Intracavitary irradiation forcentral pelvic disease and external-beam radiation therapy for lateral parametrialand pelvic nodal disease are typically combined to encompass the knownpatterns of disease spread with an appropriate radiation dose while sparing thebladder and rectum from receiving full doses. The addition of intracavitaryirradiation to external-beam irradiation is associated with improved pelvic controland survival over external irradiation alone, as the combination can achievehigh central doses of radiation.Radiation techniquesIntracavitary brachytherapyRadioactive isotopes, such as cesium-137, canbe introduced directly into the uterine cavity and vaginal fornices with specialapplicators. The most commonly used applicator is the Fletcher-Suit intrauterinetandem and vaginal ovoids.Calculating dose rates With the advent of computerized dosimetry, the dose rateto a number of points from a particular source arrangement can be calculated.Adjustments in the strength or positioning of the sources can then be made toyield a selected dose rate to one or more points.Quantification of acceptable implant geometry has been described by Katzand Eifel after review of 808 implants performed in 396 patients with cervicalcancer treated with irradiation at M. D. Anderson Cancer Center. These guidelinesset the standard for high-quality tandem and ovoid insertions.Points of interest usually include the maximal rectal and bladder dose, as wellas the dose to three standard pelvic points: A, B, and P (see Figure 2). Point A

is located 2 cm cephalad from the cervical os and 2 cm lateral to the uterinecanal. Anatomically, it represents the medial parametrium/lateral cervix, theapproximate point at which the ureter and uterine artery cross. Point B is 5 cmlateral to the center of the pelvis at the same level as point A and approximatesthe region of the obturator nodes or lateral parametrium. Point P is locatedalong the bony pelvic sidewall at its most lateral point and represents the minimaldose to the external iliac lymph nodes.LDR vs HDR brachytherapy Standard dose rates at point A are typically 50-70cGy/h; this level is considered low-dose-rate (LDR) brachytherapy. The applicatoris placed into the uterus while the patient is under anesthesia in the operatingroom, and the patient must stay in the hospital for 2-3 days during theprocedure. One or two implants are usually placed. Despite the fact that twoinsertions may allow time for regression of disease between placements, thereare no data indicating that two insertions improve pelvic control or survival rates over one insertion.Whereas LDR brachytherapy has been usedsuccessfully for decades in the treatment of carcinomaof the cervix, the use of high-dose-rate(HDR) brachytherapy has been increasing inthe United States over the past decade. Doserates are typically 200-300 cGy/min, with shorttreatment times allowing for stable position ofthe applicator.The major benefit of HDR brachytherapy isthat the procedure can be performed on anoutpatient basis with less radiation exposureto personnel. The major disadvantage is biologic:large single fractions of radiation (5-10Gy) are used with 3-10 insertions per patient,which may increase the rate of late complications.Several series have cited comparable diseasecontrol and complication rates with HDR andLDR brachytherapy. HDR brachytherapy isan alternative to LDR brachytherapy in currentGOG and Radiation Therapy Oncology Group(RTOG) advanced cervical cancer trials.Guidelines have been published for HDRbrachytherapy for cervical cancer by theAmerican Brachytherapy Society.External-beam pelvic radiation therapy
is used in conjunction with intracavitary radiotherapyfor stage IA2 disease and abovewhen the risk of pelvic lymph node involvementis significant. The amount of external-beam irradiation delivered and thetiming of its administration relative to intracavitary radiation are individualized.For example, the presence of a large exophytic cancer that distorts the cervixwould initially preclude successful placement of intracavitary brachytherapy.External-beam radiotherapy would be administered first, and after significantregression of disease, it could be followed by intracavitary radiotherapy.Various techniques have been developed to optimize external-beam irradiation,including CT simulation, conformal blocking, and, more recently, intensity-modulated radiation therapy (IMRT). These techniques reduce the volumeof normal tissue having full-dose irradiation while coverage of the target is not compromised.Recently, several preliminary reports have been published describing highlyconformal dose distributions for patients with carcinoma of the cervix in IMRT.Tumor control has been about 80% for various stages, and no patient has developed> grade 2 GI or genitourinary toxicity.

Advanced tumors require relatively more external irradiation due to the inabilityof central radioisotope sources to effectively irradiate disease in the lateralparametrium. Typically, external pelvic doses of 4,000-5,000 cGy are followed by4,000-5,000 cGy to point A with intracavitary LDR brachytherapy, for a totaldose of 8,000-9,000 cGy to point A. A parametrial boost completes treatment tothe lateral pelvis, for a total dose to point B or P of 6,000 cGy from external-beamirradiation and brachytherapy, depending on the extent of disease.With HDR brachytherapy, equivalent doses are prescribed using the linear quadraticequation. The HDR/LDR dose ratio ranges from .5 to .8 depending on the number of HDR fractions.External-beam para-aortic radiation therapy may be used in addition toexternal-beam pelvic irradiation when para-aortic disease is confirmed or suspected.An RTOG trial found that external-beam para-aortic irradiation conferreda survival benefit in patients with advanced cervical cancer (stage IB > 4cm, stage IIA, and stage IIB) over external-beam pelvic therapy alone. Althoughexternal-beam radiation therapy can successfully sterilize microscopic disease,its value in the treatment of gross para-aortic disease is limited, as the toleranceof surrounding organs (bowel, kidneys, spinal cord) precludes the delivery ofsufficiently high doses to the para-aortic region.In multivariate analysis, treatment factors associated with improved pelviccontrol for cervical cancer include the use of intracavitary brachytherapy,total point A dose > 8,500 cGy (stage III only), and overall treatment time < 8 weeks.Definitive radiation therapyCIS, stage IA disease Carcinoma in situ (CIS) and microinvasive cervicalcancer (stage IA) are not associated with lymph node metastases. Therefore,intracavitary LDR brachytherapy alone, delivering approximately 5,500 cGyto point A, can control 100% of CIS and stage IA disease and is an acceptable

alternative to surgery for patients who cannotundergo surgery due to their medicalcondition.Stage IB disease The most important prognosticfactor associated with pelvic tumor controland survival following radiation therapyfor stage IB cervical cancer is tumor size. Thecentral pelvic control rate with radiotherapyalone is excellent for tumors < 8 cm (97%),with total pelvic control and survival rates of93% and 82%, respectively. Therefore, manyexperts have argued that adjuvant hysterectomyfollowing chemoradiation therapy is unnecessaryfor cervical cancer < 8 cm. For bulky cervicalcancers ≥ 8 cm, pelvic control and survivalrates decrease to 57% and 40%, respectively,with irradiation alone, and adjuvanthysterectomy may potentially improve localcontrol and survival rates (Table 3).A recently updated RTOG trial (RTOG9001) for advanced cervical cancer (stageIB or IIA with tumor ≥ 5 cm or with biopsy-proven pelvic lymph node involvementand stages IIB-IVA) comparedexternal-beam pelvic irradiation plus concurrentexternal-beam pelvic irradiation plus concurrent fluorouracil (5-FU) andcisplatin with external-beam pelvic and para-aortic irradiation; in both arms,these therapies were followed by intracavitary irradiation. The addition ofchemotherapy to irradiation improved 5-year survival from 55% to 79% anddisease-free survival from 46% to 74% for stage IB/IIA disease by reducingrates of both local recurrence and distant metastases. For stage III/IVA disease,chemoradiotherapy improved 5-year survival from 45% to 59% and disease-free survival from 37% to 54% (Figures 1 and 3).A GOG trial (GOG 123) randomized similar patients to receive either localtreatment alone (external and intracavitary irradiation followed by hysterectomy)or local therapy plus weekly cisplatin. The combination of concurrentweekly cisplatin and irradiation significantly reduced the relapse rate and improvedsurvival by 50%. The 3-year survival rate was significantly improvedfrom 74% to 83% with the use of chemotherapy; this improvement was primarilydue to a reduced risk of local recurrence (21% vs 9%).On the other hand, an Australian gynecologic group randomized study with 76patients and a Canadian randomized study with 127 patients with stage IB to IIBcarcinoma of the cervix treated with chemotherapy and irradiation or irradiationalone showed no significant difference in tumor control or survival. A possibleexplanation for the discrepancy in the results between the five US trials and theNCI of Canada study has been analyzed by Lehman and Thomas.Current treatment recommendations Concurrentradiotherapy and chemotherapy (usuallycisplatin-based) with or without adjuvant hysterectomyare standard treatments for bulkyIB2 cervical cancer. An alternative approachis radical hysterectomy followed by tailoredpostoperative chemoradiation therapy.The use of adjuvant hysterectomy iscontroversial for small (< 8 cm) stage IB2 cervicalcancer, since dose-intense external pelvicand intracavitary irradiation plus chemotherapymay obviate the need for adjuvantsurgery. The GOG trial suggests that adjuvanthysterectomy reduces the recurrence rate butdoes not affect survival.The use of weekly cisplatin * six cycles or 5-FUand cisplatin every 3 weeks * two cycles concurrentwith radiotherapy is the standard treatmentapproach for bulky IB2 cervical cancer.Stages IIA-IVA disease The most important prognostic factor associated withpelvic tumor control and survival is the bulk of pelvic disease within each stage.For stage IIB, bulky disease is variously defined as bilateral or lateral parametrialinfiltration or central bulky disease > 5 cm in diameter. For stage IIIB,bulky disease is defined as bilateral sidewall involvement, lower-third vaginalinvolvement, or hydronephrosis.In the previous GOG experience, in which para-aortic lymph node staginghad been mandated, multivariate analysis testing revealed para-aortic lymphnode involvement to be the most powerful negative prognostic factor, followedby pelvic lymph node involvement, larger tumor diameter, young age, advancedstage, and lower performance status for patients with negative paraaorticlymph nodes. Five-year survival rates for radiotherapy alone vary from80% for stage I, 60% for stage II, and 45% for stage III disease, with correspondingpelvic control rates of 90%, 80%, and 50%, respectively.Chemoradiation therapy A GOG phase III trial (GOG 120) compared standardpelvic external-beam irradiation/intracavitary brachytherapy plus hydroxyurea(Hydrea) vs weekly cisplatin vs hydroxyurea, 5-FU, and cisplatin. Both theweekly cisplatin and the 5-FU-cisplatin-hydroxyurea arms produced significantlyimproved survival and relapse rates compared with hydroxyurea alone.Two-year disease progression-free survival rates were significantly improvedfrom 47% to 67% and 64% with weekly cisplatin-irradiation and 5-FU-cisplatin-hydroxyurea-irradiation compared with hydroxyurea and radiotherapy (Figure1). The improved outcome was due to reduced rates of pelvic failure andlung metastases. Because of an improved therapeutic ratio, weekly cisplatin is the favored regimen.A recently completed GOG trial (GOG 165) compared standard radiationtherapy plus concurrent weekly cisplatin vs concurrent protracted venous infusion5-FU (225 mg/m2/d over 5 weeks) as radiation sensitizers. In this study,the dose of radiation to point A (in Figure 2) had been increased by 500 cGy,and the pelvic fields were redefined to improve the dose intensity and accuracy of radiotherapy.Current treatment recommendations In view of the multiple randomized trialsdocumenting a survival benefit with concurrent chemoradiation therapy, theuse of concurrent weekly cisplatin or cisplatin-5-FU every 3 weeks with irradiationis standard therapy for stages IB2-IVA cervical cancer (Figure 1).Five large randomized clinical trials demonstrated a significant survival benefitfor patients treated with concurrent chemotherapy, using a cisplatin-based regimen,with a 28%-50% relative reduction in the risk of death. In addition, theresults of a meta-analysis of 19 randomized clinical trials of concurrent chemotherapyinvolving 4,580 patients showed that concurrent chemotherapy significantlyimproved overall survival (hazard ratio [HR] = 0.71; P < .001), aswell as disease progression-free survival (HR = 0.61; P < .0001). In line withthese results, concurrent chemotherapy is currently recommended as standardtherapy (Table 4).For patients without para-aortic lymph node metastases, pelvic external irradiation(4,000-5,000 cGy) should be used, followed by intracavitary LDRbrachytherapy (4,000-5,000 cGy) to point A, for a total dose of 8,000-9,000 cGy to point A.Adjuvant radiotherapy following radical hysterectomyNode-negative disease Local failure rates approach 20% following radical hysterectomyand pelvic lymphadenectomy when pelvic lymph nodes are not involvedbut the primary tumor has high-risk characteristics (primary tumor > 4cm, outer-third cervical stromal invasion, and capillary-lymphatic space invasion).A recently completed GOG trial randomized these intermediate-risk patients withnode-negative disease to receive pelvic external-beam radiation therapy (5,100cGy/30 fractions) or no further therapy following radical hysterectomy-pelviclymphadenectomy. Postoperative irradiation produced a significant 44% reductionin recurrence; the recurrence-free rate at 2 years was 88% with irradiation vs79% without it. Survival analysis awaits further follow-up.Node-positive disease For patients with positive pelvic lymph nodes followingradical hysterectomy-pelvic lymphadenectomy, pelvic radiotherapyreduces the pelvic failure rate from approximately 50% to 25% but does notaffect survival, since distant metastases are still seen in 30% of patients. Arecently reported GOG/Southwest Oncology Group (SWOG 8797) trial randomizedthese high-risk patients with node-positive disease (or patients withpositive surgical margins) to pelvic external-beam irradiation (4,930 cGy/29 fractions) vs pelvic external-beam irradiation plus concurrent 5-FU andcisplatin for four cycles following radical hysterectomy-pelvic lymphadenec-tomy. A significant improvement in disease progression-free and overall survivalwas seen for concurrent 5-FU-cisplatin and radiation therapy comparedwith radiation therapy alone (4-year survival, 81% vs 71%).Current treatment recommendations At present, the use of adjuvant pelvic radiotherapyshould be considered for patients with negative nodes who are at riskfor pelvic failure and remains the standard postoperative treatment for patientswith positive lymph nodes. Treatment consists of external pelvic irradiation(45-50 Gy), with specific sites boosted with further external-beam or intracavitary irradiation as needed.Since the combination of radical surgery and irradiation has greater morbiditythan either modality alone, complete preoperative assessment is crucial to minimizethe need for both.Since concurrent chemoradiation therapy following radical hysterectomy providesa significant benefit in node-positive high-risk cervical cancer, it shouldbe part of the postoperative treatment plan. Postoperative chemoradiationtherapy following radical hysterectomy should be strongly considered for patientswith negative nodes but positive margins or parametria, ≥ middle-thirdstromal invasion, and lymphovascular space invasion for tumors ≥ 5 cm.SURGICAL MANAGEMENT OF RECURRENTOR METASTATIC DISEASERecurrent advanced diseasePelvic exenteration For patients whose disease fails to respond to primaryradiation therapy or for those with early invasive cervical carcinoma whosedisease recurs after surgery or radiation therapy, pelvic exenteration offers thepossibility of cure. Patients should be considered for pelvic exenteration only ifthey have locoregional disease that can be completely removed by this radicalsurgical procedure. In most cases, patients will require surgical removal of the bladder, uterus, cervix, vagina, and rectum.Of all patients who are considered candidatesfor pelvic exenteration, only about half willbe found to have resectable disease at the timeof exploratory laparotomy. For patients whosuccessfully undergo pelvic exenteration, 5-year survival rates range from 25% to 50%.When the patient has central recurrence ofsquamous cell or adenocarcinoma of the cervix,the initial evaluation includes a completephysical examination, as well as anabdominopelvic CT or MRI scan and, usually,a chest CT scan.

Evidence of extrapelvic disease is a contraindication to pelvic exenteration. Ifno evidence of disease beyond the pelvis is found, the patient can be preparedfor pelvic exenteration.Preparation for exenteration includes complete bowel preparation, a visit with thestomal therapy nurse, and counseling regarding the radical nature of the surgeryand the anticipated changes in body image after the operation. In mostcases, we counsel the patient that vaginal reconstruction should be performedat the time of pelvic exenteration, both for maintenance of body image and improved healing.Surgical procedure During surgery, a careful exploration is carried out to confirmthat there is no evidence of unresectable disease beyond the pelvis. Thepelvic sidewall spaces are opened and resectability is determined. An en blocresection is usually performed; in some cases, especially when the recurrenttumor involves the lower vagina, a two-team approach can expedite the procedure.The actual exenterative portion of the procedure may take several hoursand is usually accompanied by significant blood loss. In cases where surgicalmargin status may be questionable, the use of intraoperative radiation therapy is considered.Reconstruction Following the exenterative procedure, the reconstructive portionof the procedure begins. We currently recommend to nearly all patientsthat they consider a continent urinary diversion. Although this step may addapproximately 30-60 minutes to the surgical procedure, the improvement in quality of life is significant.In patients who have undergone a supralevator pelvic exenteration, we frequentlyattempt a stapled reanastomosis of the colon. Unless there is excessive tensionon the anastomosis or other problems, a diverting colostomy is not routinely indicated.About one-third of these patients suffer anastomotic breakdown in the postoperativeperiod. At that time, a diverting colostomy can be performed. Unfortunately,Hatch et al found no benefit to the earlier use of colostomy.Lung metastasis
For the rare patient who presents with a single isolated lung metastasis aftertreatment of invasive cervical carcinoma, pulmonary resection may offer thepossibility of long-term disease-free survival or even cure in selected cases.For patients who have multiple lung metastases or unresectable pelvic disease,surgery offers little or no hope and produces significant morbidity and mortality.RADIATION THERAPY FOR RECURRENTOR METASTATIC DISEASELocal recurrence after radical hysterectomy
Local recurrence confined to the pelvis and para-aortic lymph nodes followingradical hysterectomy for cervical cancer can be treated with radiotherapy

with curative intent. An experience with 5-FU-based chemotherapy and concurrentpelvic external-beam irradiation resulted in a 58% complete responserate and a 45% no-evidence-of-disease rate, at a median follow-up of 57 months.The total pelvic external-beam dose was 5,280 cGy plus a boost to sites ofrecurrence with twice-daily 160-cGy fractions during the 5-FU infusion. Therefore,radiotherapy, with or without chemotherapy, can provide durable local control, with better results attainable for small, central recurrences, for whichbrachytherapy is possible.Local recurrence after definitive radiation therapy
Local recurrence confined to the pelvis following definitive radiation therapyrarely can be cured with exenteration. In a series of patients treated with definitiveradiotherapy, 21% of recurrences (80 of 376) were isolated to the pelvis.Only 29% of these localized pelvic recurrences (23 of 80) were explored forcurative exenteration, and for the 43% of patients (10 of 23) deemed operable,the 5-year survival rate was 16%.Palliation of metastatic disease
Palliative radiation therapy to sites of metastatic cervical cancer is effective.The most common sites of metastasis are distant lymph nodes, bone, and lungs.Reirradiation of the pelvis is possible in selected patients to control local symptoms,such as bleeding, but carries an increased risk of bowel complications.For previously unirradiated sites of metastatic disease, 3,000 cGy in 10 fractionsprovides palliation of symptoms in the majority of patients.CHEMOTHERAPY FOR ADVANCED/RECURRENT DISEASE
Chemotherapy has traditionally been used for the palliative management ofadvanced or recurrent disease that can no longer be managed by surgery orradiation therapy (see Table 4). Various factors complicate the use of chemotherapyin such patients, however. Prior radiation treatment can affect the bloodsupply to the involved field, which may result in decreased drug delivery to thetumor site. Pelvic irradiation also reduces bone marrow reserve, thus limitingthe tolerable doses of most chemotherapeutic agents. Moreover, irradiationmay produce its cytotoxic effect, in part, through a mechanism similar to thatof alkylating agents; thus, it is thought to be cross-resistant with some chemotherapeuticagents. A significant number of patients with advanced disease mayalso have impaired renal function, further limiting the use of certain chemotherapeutic regimens.Single agents
Among the chemotherapeutic agents used for cervical cancer, cisplatinand ifosfamide (Ifex) have shown the most consistent activity as single agents(Table 5). The duration of response with any single agent is brief, ranging from4 to 6 months, with survival ranging from 6 to 9 months.Cisplatin has been the most extensively evaluated single agent for cervicalcarcinoma. A dose of l00 mg/m2 was shown to have a higher response ratethan a dose of 50 mg/m2 (31% vs 21%), but the higher dose was associated withincreased toxicity, and overall survival did not differ significantly between thetwo groups. A 24-hour infusion of cisplatin was tolerated better than a 2-hourinfusion, with no difference in therapeutic efficacy.

Ifosfamide produces response rates ranging from 33% to 50% in various doseschedules. A dose of 1.5 g/m2 over 30 minutes for 5 days (with mesna [Mesnex])produced an overall response rate of 40% and a complete response rate of 20%.Lower response rates are generally seen in patients who have had prior chemotherapy.Responses also are decreased in previously irradiated sites.Taxanes Paclitaxel and docetaxel (Taxotere) have been reported to be active incervical cancer. A study of paclitaxel (170 mg/m2 over 24 hours) showed an objectiveresponse rate of 17%, and another study of paclitaxel (250 mg/m2 over 3hours) demonstrated an objective response rate of 27%. Docetaxel (100 mg/m2over 1 hour) has yielded a response rate of 19%.Camptothecins Irinotecan (CPT-11 [Camptosar]) and topotecan (Hycamtin),semisynthetic camptothecins, have shown activity in patients with cervical cancer,even in patients who did not respond to prior chemotherapy and priorradiation therapy. The reported objective response rates were 21% and 19%, respectively.

Combination regimens
Various combination chemotherapy regimens have been evaluated in phase IItrials, and high response rates (> 50%) were noted, even in patients who hadreceived prior radiation therapy. The results of some of these trials are summarizedin Tables 6 and 7. In one study, a subset analysis showed a response rateof 72% with the combination of bleomycin, ifosfamide, and cisplatin as treatmentfor tumors located in previously irradiated sites. Neoadjuvant regimensof cisplatin combined with gemcitabine (Gemzar) in patients with locally advancedcervical cancer demonstrated very high activity, with a clinical responserate of 95%. Neoadjuvant ifosfamide and cisplatin, with or without paclitaxel,reported 87% and 82% response rates, respectively, among 146 evaluable patientsin a randomized study. However, no adequate phase III trial has yetdetermined whether polychemotherapy regimens offer a survival benefit over single-agent cisplatin.Palliative care
Palliation of the dying cervical cancer patient is difficult. Pain due to recurrentpelvic disease can be extreme and requires skillful use of combinations ofnarcotics, sedatives, and anxiolytics. Fistula from the bladder or rectum demandsmeticulous local skin care and occasionally surgical diversion proceduresin patients with reasonable expected longevity. This patient populationoften has limited resources, with dependent children requiring careful socialservice planning. A small percentage has concurrent HIV infection, makingthe infectious disease specialist part of the palliative care team. The tripod ofcare in advanced cervical cancer is the judicious use of chemotherapy andradiation therapy, palliation of the symptoms of advancing disease, as well asemotional and social support for the patient and family members.


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