Carcinoma of the Uterine Cervix Medical Oncology: A Comprehensive Review 9th Edition Coming Soon By Arsenio Lopez, MD Andrzej

P. Kudelka, MD Creighton L. Edwards, MD John J Kavanagh, MD M.D. Anderson Cancer Center, Houston, Texas | April 1, 2005

Pathology Etiology Natural History Screening and Diagnosis Staging Prognosis Treatment Conclusion References Over the past four decades, the incidence and mortality rates for uterine cervical carcinoma have decreased in the United States by as much as 70% to 75% [1]. This improvement is among the largest seen for any cancer site and has been attributed to the use of cervical cytologic screening [2]. The Papanicolaou smear allows detection of the disease at a preinvasive stage, and about 65,000 cases of carcinoma in situ are found this way annually [3]. However, cervical cancer remains a significant problem, and it is the most common female cancer in some developing countries [4]. In the United States, it is the seventh most common cancer in females. It is estimated that, in 1995, 15,800 new cases will be found and 4,800 deaths will be caused by cervical cancer [3].

Pathology The majority of cervical cancers are squamous-cell carcinomas. These lesions arise from the squamocolumnar junction and may be keratinizing or nonkeratinizing. Various methods of histologic grading have been used for cervical squamous-cell carcinoma, but these have no significant impact on prognosis [5,6]. Adenocarcinomas of the uterine cervix arise from the endocervical columnar cells and account for about 14% of cervical carcinomas [7]. Over the past few decades, the percentage of adenocarcinomas has increased because, compared with squamous-cell carcinomas, they are more difficult to detect at a preinvasive stage [8]. Although most clinical studies on cervical neoplasia have involved patients with squamous-cell carcinomas, patients with adenocarcinomas are generally treated similarly. It was reported that adenocarcinoma has a worse prognosis than squamous-cell carcinoma [9]. However, several recent

investigations showed that long-term survival rates for these two histologic types of disease are not significantly different [10,11]. Other types of epithelial carcinomas of the cervix are less common but have important clinical implications [12]. Adenosquamous carcinomas contain malignant squamous and glandular components in the same tumor. These tumors are associated with a higher risk of pelvic lymph-node metastasis than squamous-cell carcinomas or adenocarcinomas, but this finding has not had any significant effect on survival rates [10,13,14]. Glassy-cell carcinoma is a poorly differentiated form of adenosquamous carcinoma that responds poorly to surgery and radiation therapy [15]. Verrucous carcinoma is an extremely well-differentiated variant of squamous-cell carcinoma. This tumor may invade the vagina or endometrium but usually does not metastasize to the lymph nodes. Small-cell carcinomas are distinctive and, collectively, have a very poor prognosis; the most aggressive tumors are those with neuroendocrine differentiation [16]. This group should be distinguished from the poorly differentiated squamous-cell carcinomas with small cells and the adenocarcinomas with carcinoid features. Other cervical malignancies include sarcomas, malignant melanomas, lymphomas, mixed mllerian tumors, germ-cell tumors, and trophoblastic tumors.

Etiology The association between cervical neoplasia and sexual activity is well established [17,18], and current studies have identified the human papillomavirus (HPV) as the most important factor responsible for this association. HPV, therefore, may be a causal agent in cervical neoplasia. An epidemiologic study by Schiffman et al [19] showed that the increased risk of cervical intraepithelial neoplasia (CIN) previously associated with other factors, such as increased lifetime number of sex partners, earlier age at first intercourse, lower level of education, lower income, and smoking, is actually a result of HPV infection. The only risk factor studied that was noted to be independent of HPV status was increased parity. Schiffman et al concluded that HPV satisfied all the requirements that designate a cause of cervical neoplasia. Many types of HPV have been isolated in the human genital tract; infection with HPV types 16, 18, 45, or 56 has a high correlation with cervical cancer. In a retrospective study by Lorincz et al [20], these highrisk types of HPV were present in 74% of cases of invasive cervical cancer and in 53% of cases of moderate to severe dysplasia. HPV-16 is the most prevalent among these types. HPV types 31, 33, 35, 51, 52, and 58 were deemed intermediate-risk viruses and were present in 10% of cases of invasive carcinoma and in 24% of cases of moderate to severe dysplasia. Types 6, 11, 42, 43, and 44 were designated low-risk viral types; they were present in only 4% of cases with moderate to severe dysplasia and not at all in invasive cancer. HPV types 6 and 11 were previously shown to be responsible for 95% of vulvar, vaginal, and anal exophytic condylomas [21]. The multistep process from HPV infection to carcinogenesis is not yet completely understood. HPV genetic sequences have been observed to be integrated into the host genome just as the cell develops invasive properties [22]. It is known that the E6 protein produced by high-risk HPV types 16 and 18 can combine with the p53 protein and cause the same functional consequence as a p53 gene mutation [23,24].

In contrast, E6 protein expression from the low-risk HPV-6 does not produce any such effect. The E7 protein of HPV-16 was also shown to bind to the p105-RB protein encoded by the retinoblastoma gene (RB1)[25]. The p53 and pRb proteins participate in the activity at the G1-S cell-cycle checkpoint that normally causes cells with DNA damage to undergo either cellular arrest at G1 or apoptosis [26]. The E6 and E7 oncoproteins produced by HPV-16 cause decreases in p53 and pRb proteins, respectively, undermining this cell-cycle checkpoint [27,28]. The alteration of the G1-S checkpoint leads to the inappropriate survival of genetically damaged cells and, thus, may be a step in the development of a malignancy. Various cofactors are probably necessary for carcinogenesis to progress completely. Somatic mutations of the p53 gene may also be present in cervical carcinoma, but they are uncommon [29]. An increased risk of cervical neoplasia also results from immunosuppression [30]. Immunosuppression was associated with an increased rate of HPV infection in several studies [31-33] and allows neoplastic proliferation due to deficient host-regulatory mechanisms. Women who have the human immunodeficiency virus (HIV) have increased incidence and recurrence rates of CIN that correlate with their degree of immunosuppression [34]. Furthermore, women who were HIV positive and who developed invasive cervical carcinoma were noted to have more advanced disease at presentation, poorer response to therapy, and higher recurrence and death rates [35,36]. A direct molecular interaction between HIV and HPV has also been described, with HIV gene products causing transactivation of HPV proteins [37]. Smoking has been reported to increase HPV infection rates [38], and this may explain the previously noted association between smoking and cervical neoplasia. Conflicting data have been reported for other postulated risk factors for cervical neoplasia, including herpes simplex virus type 2 infection, vitamin A and vitamin C deficiencies, use of oral contraceptives, and prenatal exposure to diethylstilbestrol(Drug information on diethylstilbestrol).

Natural History Cervical Intraepithelial Neoplasia The development of invasive cervical carcinoma traditionally has been viewed as a continuum that begins with mild dysplasia. The terminology used to classify the precursor lesions of cervical cancer reflected this view; mild dysplasia was designated as CIN-1 and moderate dysplasia as CIN-2. Severe dysplasia and carcinoma in situ were grouped together as CIN-3, based on data suggesting that both types of lesions should be managed similarly [39]. Cervical lesions with histologic features of HPV infection were usually referred to as flat condylomas. With the current understanding of the pathogenesis of cervical squamous-cell neoplasia, Richart has suggested modified terminology for the histologic classification of CIN [40,41]. CIN-2 and CIN-3 lesions, generally associated with aneuploidy and infection from just one of the high-risk HPV types, are grouped together as high-grade CIN and have a high probability of transformation to invasive carcinoma if left untreated. Flat condylomas and CIN-1 lesions are both associated with multiple infections from a heterogeneous group of HPV types and are grouped as low-grade CIN. This group has uncertain

oncogenic potential, because no histologic features distinguish the low-grade lesions that will progress to carcinoma from those that will remain stable or regress. This modified histologic classification conforms with the Bethesda system for reporting cervical cytologic diagnosis, which is discussed later in this chapter. Richart's classifiction also recognizes that these lesions may involve two separate disease processes instead of the continuum they were previously thought to represent. CIN-1 lesions have a high spontaneous remission rate. Nasiell et al [42] reported a 62% regression rate for CIN-1 lesions over the course of a large prospective study. Progression to either CIN-3 or invasive carcinoma occurred in 16% of the cases, with an average time to progression of 48 months. In an earlier study of CIN-2 lesions, the subgroup of patients that did not undergo a biopsy for diagnosis had a 50% regression rate and a 35% progression rate (average time to progression was 51 months)[43]. A biopsy can eradicate a lesion; therefore, studies on the natural history of CIN should not include patients who have undergone this procedure. It is generally agreed that most patients with CIN-3 will eventually develop invasive cancer. Varied estimates have been made regarding the length of time it takes carcinoma in situ to progress to invasive carcinoma. A range of 3 to 10 years was reported by Barron et al [44]. Preinvasive lesions are usually confined to the transformation zone of the cervix. This is a region in the cervical mucosa that was originally composed of columnar epithelial cells that are being replaced by squamous epithelium through the normal physiologic process of metaplasia. The change occurs most actively during fetal development, during adolescence, and at the time of a first pregnancy.

Invasive Cervical Carcinoma Invasive carcinoma develops when malignant epithelial cells break through the basement membrane and spread to the cervical stroma. As the malignancy grows, it may produce a visible ulceration or an exophytic mass, or it may extensively infiltrate the endocervix, causing the cervix to expand and harden. The tumor usually presents as vaginal bleeding, frequently postcoital; with further progression, a malodorous vaginal discharge becomes more pronounced. The tumor then extends into the paracervical tissue, vagina, and endometrium. Inflammatory changes or tumor necrosis may produce a dull pain in the pelvic region. Lateral extension of disease to the pelvic wall results in severe discomfort, and lumbosacral nerve or nerve root involvement causes pain resembling sciatica. Anterior tumor growth results in bladder involvement manifested by urinary frequency, hematuria, a vescicovaginal fistula, or obstructive uropathy. Posterior tumor growth causes rectal extension, which leads to tenesmus, rectal bleeding, or a rectovaginal fistula. Lymphatic spread of the carcinoma occurs with sequential involvement of pelvic, para-aortic, mediastinal, and supraclavicular lymph nodes. Hematogenous dissemination usually occurs late in the course of the disease and most commonly involves the lungs, bones, and liver [45].

Screening and Diagnosis Cervical Cytologic Screening The use of the Pap smear as a screening tool for cervical cancer was first endorsed by the American Cancer Society in 1945. Its efficacy has resulted in reductions in both incidence rates and mortality rates for invasive cervical cancer in areas where the test is widely used [2]. Currently, both the American Cancer Society and the American College of Obstetricians and Gynecologists recommend that all women who are or have been sexually active or who have reached the age of 18 years should have an annual Pap smear and pelvic examination. After a woman has had three or more consecutive satisfactory normal annual examinations, the Pap smear may be performed less frequently at the discretion of her physician. [46] The Pap smear has a reported false-negative rate of 20% [47], and factors that may contribute to underdiagnosis include inadequate sampling by the physician as well as laboratory errors. Samples must be obtained from the cervical surface with an Ayre spatula and from the endocervical canal using a cytobrush, and the collected cells must undergo rapid fixation [48]. It is important to realize that a cervical cytology study is a screening tool and not a diagnostic test; therefore, a biopsy should be done on any visible lesion. The cytologic classification system originally proposed by Dr. George Papanicolaou [49] had five groups (class I to class V). However, these groups were difficult to correlate with biopsy results, so other methods of reporting cervical cytologic findings were created, such as the World Health Organization (WHO) classification and CIN-based terminology. Because no uniform reporting system existed for cervical cytology, the Bethesda system was developed in a workshop convened by the National Cancer Institute (NCI) [50]. Table 1 correlates the various terminologies used in reporting Pap smear results with histologic (ie, CIN-based) terminology. Cytologic Papanicolaou system Class I Class II Histologic

WHO system Normal Atypical

Bethesda system

CIN classification

Within normal limits Reactive or reparative changes: ASCUS Low-grade SIL High-grade SIL High-grade SIL High-grade SIL CIN-1 CIN-2 CIN-3 CIN-3 Squamous-cell

Class III Class III Class II Class IV Class V

Mild dysplasia Moderate dysplasia Severe dysplasia Carcinoma in situ Invasive

squamous-Squamous-cell

cell carcinoma Class V Adenocarcinoma

carcinoma Adenocarcinoma

carcinoma Adenocarcinoma

Includes changes assoicated with human papillomavirus (HPV) infection. ASCUS = atypical squamous cells of undetermined significance, CIN = cervical intraepithelial neoplasia, SIL = squamous intraepithelial lesion, WHO = World Health Organization The Bethesda system introduces several changes in the way the results of Pap smears are reported. The term squamous intraepithelial lesion (SIL) is used to refer to the precursor lesions of invasive squamouscell carcinoma. Low-grade SIL includes CIN-1 and cellular changes associated with HPV. High-grade SIL combines CIN-2 and CIN-3. This categorization is based on the similarity in etiology, behavior, and treatment of the lesions within each group. Among cytologists, the lack of reproducibility encountered using the dysplasia-CIN terminology [51] may be corrected with the use of only two categories [52]. Atypical squamous cells of undetermined significance (ASCUS) is a term used strictly for changes that truly are of unknown significance. This term should not be used for inflammatory or atrophic changes that were also referred to as atypical in the previous terminology. Under the Bethesda system, the cytology report is regarded as a medical consultation, and recommendations for further patient evaluation are given when appropriate. A statement about the adequacy of the specimen is also part of the cytology report.

Management of Abnormal Smears/Preinvasive Lesions The main objectives in the evaluation of abnormal Pap smears are to rule out invasive carcinoma and to determine the extent of noninvasive lesions. A colposcopy is usually performed first when further evaluation is required. The colposcopy involves the use of a stereoscopic microscope to examine the cervix. A 3% acetic acid solution applied to the cervix prior to the examination will cause epithelial lesions to turn white. The subepithelial vascular distribution is also closely examined because it may be abnormal in the presence of CIN. The examination is considered adequate only if the transformation zone and any lesions that may be present are seen in their entirety. Otherwise, the presence of invasive cancer cannot be ruled out. Punch biopsies are done on areas with significant colposcopic abnormalities, and an endocervical curettage (ECC) is performed to evaluate the endocervical canal. Certain patients may require a cervical cone biopsy (conization), which involves the removal of a coneshaped section of the cervix, to rule out invasive carcinoma. This is done using either cold knife, electrosurgical, or laser techniques. Indications for conization include: 1. 2. 3. 4. an inadequate colposcopic examination, a positive ECC, biopsy results showing microinvasive carcinoma or indicating possible invasive carcinoma, and findings of a lesion in the Pap smear with a higher grade than that found with colposcopically directed biopsy.

Complications associated with the procedure include hemorrhage, cervical stenosis, or cervical incontinence. Laser conization is a technically more difficult procedure, but it may result in fewer complications than cold knife conization. However, laser conization may cause thermal damage to the margins of the specimen, making it difficult to determine whether the margins are involved with tumor. In such cases, subsequent cold knife conization may be necessary. Because fewer than 5% of patients with ASCUS have high-grade SIL on colposcopy [53], it is reasonable to defer this procedure initially and repeat a Pap smear in 4 to 6 months. However, a colposcopy is needed if malignancy is suspected or if the atypical findings persist. Patients with a Pap smear showing low-grade SIL usually undergo an immediate colposcopy for further evaluation. However, some physicians may elect to manage these patients by repeating Pap smears in 4 months because most of these lesions spontaneously regress. Colposcopy can be reserved for persistent lesions. If a biopsy done with an adequate colposcopy confirms the finding of low-grade SIL, the lesion can be treated immediately or can be followed via repeat colposcopy every 6 months. Treatment is indicated for any lesion that progresses and for those that persist after 2 years of follow-up. Patients whose cervical cytology reveals high-grade SIL require a colposcopy. If the colposcopy is adequate and a biopsy confirms the presence of a high-grade lesion, immediate treatment is indicated. SIL can be treated with either ablative therapy (ie, laser ablation or cryosurgery) or by excisional methods (ie, shallow laser conization or a loop electrosurgical excision procedure [LEEP]). Although ablative therapy results in many fewer complications, excisional methods offer the advantage of obtaining tissue for further histologic evaluation. LEEP uses thin wire loop electrodes to excise the entire transformation zone and any lesions it may contain [54]. This procedure requires less expensive equipment and causes less morbidity than laser conization.

Staging When a diagnosis of invasive cervical carcinoma is histogically confirmed, the disease should be staged prior to initiating treatment. The most widely used staging system is the one developed by the International Federation of Gynecology and Obstetrics (FIGO; see Table 2). The FIGO system uses the findings from the physical examination, colposcopy, biopsies, ECC, x-ray examination of the lungs and skeleton, intravenous pyelography (IVP), cystoscopy, and proctosigmoidoscopy to determine the clinical stage. TABLE 2: FIGO Staging of Carcinoma of the Cervix Uteri Preinvasive carcinoma Stage 0 Carcinoma in situ, intraepithelial carcinoma (cases of stage 0 tumors should not be included in any therapeutic statistics)

Invasive carcinoma

Stage I

Carcinoma is stricutly confined to the cervix (extension to the corpus should be disregarded) Invasive cancer identified only microscopically; all gross lesions, even with superficial invasia, are stage Ib cancers; invasion is limited to measured stromal invasion with a maxium depth of 5 mm and no wider than 7 mm Measured invasion of stroma no greater than 3 mm in depth and no wider than 7 mm Measured invasion of stroma greater than 3 mm and no greater than 5 mm in depth and no wider than 7 mm Clinical lesions confined to the cervix or preclinical lesions greater than Ia Clinical lesions no greater than 4 cm in size Clinical lesions greater than 4 cm in size Carcinoma extends beyond the cervix but has not extended on the pelvic wall; the carcinoma involves the vagina, but not as far as the lower third No obvious parametrial involvement Obvious parametrial involvement Carcinoma has extended to the pelvic wall; on rectal examination, there is no cancerfree space between the tumor and pelvic wall; the tumor involves the lower third of the vagina; all cases with a hydronephrosis or nonfunctioning kidney should be included, unless they are known to be due to other cause No extension onto the pelvic wall, but involvement of the lower third of the vagina Extension onto the pelvic wall or hydronephrosis or nonfunctioning kidney Carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum Spread of the growth to adjacent organs Spread to distant organs

Ia

Ia1 Ia2

Ib Ib1 Ib2 Stage II

IIa IIb Stage III

IIIa IIIb Stage IV

IVa IVb

FIGO = International Federation of Gynecologists and Oncologists The depth of invasion should not be more than 5 mm taken from the base of the epithelium, either surface or glandular, from which it originates. Vascular space involvement, either venous or lymphatic, should not alter the staging. Adapted from Shepherd JH: Staging announcementFIGO staging of gynecologic cancers; cervical and vulva. Int J Gyn Cancer 5:319, 1995.

In difficult cases, the pelvic examination ideally should be performed by several examiners while the patient is under general anesthesia. An IVP is recommended for all patients to rule out ureteral obstruction. Cystoscopy should be performed for disease stage IB or higher, and proctosigmoidoscopy can be limited to cases of clinically suspected rectal involvement or a history of diverticulitis. Involvement by a tumor should be confirmed by a biopsy. When qualified examiners disagree on the stage of the disease, the lower stage should be assigned. The results of other diagnostic examinations, together with the operative findings, may be used to plan treatment; however, they should not be used to assign the clinical stage. These diagnostic examinations include computerized tomography (CT) scanning, magnetic resonance imaging (MRI), lymphangiography, and laparoscopy. A CT scan is sometimes used in place of an IVP to evaluate whether obstructive uropathy is present. The technique is helpful in determining para-aortic node involvement and is sometimes used to guide needle biopsies of these nodes. An MRI provides more accurate information about stromal and parametrial infiltration. A lymphangiogram may help to assess whether pelvic or paraaortic lymph-node metastasis has taken place. Stage IA tumors, as defined by FIGO, are sometimes referred to as microinvasive carcinoma. Nevertheless, this definition includes cases of stromal invasion ranging from 3.1 to 5.0 mm deep, with a significant risk of lymph-node metastasis (6.2%)[55]. Prior to the introduction of the FIGO system, the Society of Gynecological Oncologists (SGO) proposed a more restrictive definition, stating that a microinvasive lesion is one that invades the stroma to a maximum depth of 3 mm beneath the basement membrane, with no lymphatic or vascular involvement [56]. The SGO definition is more widely used because it identifies tumors with a very low potential for metastasis (0.2%) [55]. In such cases, lymphnode dissection is not required. A recent revision of the FIGO staging divides stage 1b disease into 1b1 and 1b2 based on the size of the tumor. This change reflects the significance of tumor size in the management and prognosis of early-stage disease.

Prognosis The disease stage is an important factor that affects long-term survival (see Table 3). Clinical stage correlates with tumor burden as well as with the risk for lymph node and distant metastases [57]. Other gross tumor characteristics that have been shown to affect survival include tumor size and volume [58,59], endometrial extension [60], and bilateral parametrial involvement [58]. TABLE 3: Worldwide 5-Year Actuarial Survival Rates for Cervical Carcinoma by FIGO Stage Stage I II Number of patients 12,143 10,285 5-Year Survival (%) 81.6 61.3

III IV

8,206 1,378

36.7 12.1

FIGO = International Federation of Gynecologists and Oncologists Adapted from Petterson F (ed): Annual report on the results of treatment in gynecological cancer. Int J Obstet 36 (suppl):35, 1991. In surgically treated patients, Burghardt et al [59] reported that tumor volume, determined by MRI, was a better prognostic indicator than the FIGO disease stage. Five-year survival ranged from 91% in patients with tumors smaller than 2.5 cm to 48% for patients with tumors larger than 50 cm. Grimard et al [60] reported that the decreased survival rate associated with endometrial extension of the tumor was seen only in patients with stage IB disease. Decreased survival rate for patients having bilateral parametrial extension, compared with patients having only unilateral involvement, was reported for stage IIB disease [61]. The effect of histologic cell type on prognosis is discussed at the beginning of this chapter in the section on pathology. Other histologic features that have been correlated with a decrease in the disease-free interval in patients with stage IB disease include increasing depth of tumor invasion and lymph-vascular space involvement [62,63]. The presence of periaortic and pelvic lymph-node metastases results in lower survival rates. Tanaka et al [64] reported a 10% 5-year survival for surgically treated patients with periaortic lymph-node metastasis, 49% for those with involved pelvic lymph nodes, and 92% for patients with negative lymph-node involvement. This study also revealed a correlation between the number of disease-positive pelvic nodes and survival. The 5-year survival rate was 62% for those with one node positive for tumor, 36% for two positive nodes, 20% for three or four positive nodes, and 0% for those with five or more positive nodes. A higher rate of recurrence was seen in patients with an S-phase fraction greater than or equal to 20% [65]. The overexpression of the HER-2/neu [66] and c-myc [67] oncogenes has been found to be associated with a poor prognosis. The effect of various patient factors on prognosis has also been investigated. The results of studies on the effect of age were variable. In patients treated with radiation therapy, both anemia (Hb < 12 g/dL)[68] and thrombocytosis (> 400,000/L)[69] have been associated with decreased survival rates. A lower survival rate was also reported for patients whose oral temperatures were greater than 100F. In this study, the etiology of the fever remained uncertain for the majority of patients [70].

Treatment General Principles

The primary therapy for most cases of cervical carcinoma consists of surgery and/or radiation therapy. Treatment should be individualized based on the extent of disease and patient characteristics. Surgery: Primary surgical management for invasive cervical cancer can be curative for patients with stage I through stage IIA disease. Which procedure is appropriate depends on the extent of disease and can range from a cervical conization to a radical hysterectomy with bilateral lymphadenectomy. Cervical conization is usually used for diagnostic purposes but may occasionally be adequate therapy for patients with microinvasive carcinoma. A total extrafascial hysterectomy entails the excision of the uterus and cervix plus a small vaginal cuff. A radical hysterectomy with pelvic lymphadenectomy requires a more extensive dissection, with the en bloc removal of the uterus, cervix, parametrium, pelvic lymph nodes, and the upper portion of the vagina. Pelvic exenteration is an option in some patients who develop central disease recurrence following primary radiation therapy. A total exenteration is usually required, and this involves the removal of the vagina, cervix, uterus, fallopian tubes, ovaries, bladder, and rectum. An anterior exenteration spares the rectum and may be used when disease recurrence is confined to the anterior vagina, cervix, or bladder. A posterior exenteration spares the bladder and is indicated for recurrent disease to the posterior fornix and rectovaginal septum. Radiotherapy: Radiation therapy may be used as primary treatment for all stages of cervical cancer. Careful planning of treatment is necessary to maximize the radiation dose to the tumor while minimizing the risk of complications to the surrounding tissues. A combination of external and intracavitary irradiation is used for most stages of disease, with the exception of stage IA, in which intracavitary treatment alone is adequate. The dose of radiation is reported using two reference points, with both external and intracavitary sources contributing to each point. Point A is located 2 cm lateral and superior to the external os of the cervix. This point is used to express the dose delivered to the paracervical tissues. Point B is located 3 cm lateral to point A and corresponds to the pelvic sidewall. External pelvic irradiation (teletherapy) should be delivered by a linear accelerator using portals encompassing the whole pelvis with additional boosts to the parametrium. Daily doses range from 150 to 200 cGy. External irradiation will result in a decrease in the anatomic distortion resulting from the tumor, thus allowing a more effective dose delivery with subsequent intracavitary irradiation. Brachytherapy is most often given through intracavitary irradiation. This is delivered using applicators consisting of an intrauterine tandem, together with vaginal ovoids placed beside the cervix. The positions of the applicators are verified by radiographs. The applicators are then loaded with the radioactive isotope (usually cesium 137). This afterloading is performed either manually or by remote control. Most patients require two separate brachytherapy insertions, which are given 1 to 3 weeks apart. Occasionally, interstitial implants are also used for brachytherapy.

Carcinoma In Situ: Patients with only ectocervical lesions can be treated with cryotherapy, LEEP, laser therapy, or conization. Patients with endocervical involvement are treated with cervical conization if preservation of fertility is desired. A total abdominal or vaginal hysterectomy is the treatment of choice for women past reproductive age, especially if the lesion involves the inner cone margin. If surgery is

contraindicated, a single intracavitary radiation treatment delivering an average dose of 4,612 cGy to point A has been shown to be adequate therapy [71].

Stage IA: The preferred treatment for stage IA cancer of the uterine cervix is surgery. In cases where tumor invasion is less than or equal to 3.0 mm without lymph-vascular space involvement (microinvasive carcinoma), a total extrafascial hysterectomy is recommended. Conization alone may be adequate treatment for these patients (to preserve fertility), but they must be closely followed up. The risk of lymphatic involvement in microinvasive carcinoma is less than 1%; therefore, a lymph-node dissection is not required. If the tumor invasion is greater than 3.0 mm or if the tumor extends beyond the cone margins, then a radical hysterectomy with pelvic node dissection is recommended. Patients with stage IA disease who are not surgical candidates can be treated with intracavitary radiation therapy alone [71], receiving a dose to point A of 6,000 to 7,500 cGy.

Stages IB and IIA: Selected small-volume stage IB and early-stage IIA disease can both be managed by radical hysterectomy or radiation therapy. Patient survival rates for these stages have been equivalent with either modality [72]. Treatment choice can be affected by various factors. In premenopausal or sexually active patients, surgery may be preferred because ovarian function and vaginal pliability can be preserved. Patients with medical contraindications to extensive surgery can usually tolerate radiation therapy. Table 4 summarizes the sequelae from both modalities. TABLE 4: Comparison of Surgery vs Radiation Therapy for Stage IB/IIA Cancer of the Cervix Criterion Survival Serious complications Vagina Surgery 85% Radiation therapy 85%

Urologic fistulae in 1%-2% Intestinal and urinary strictures and fistulae in 1.4%-5.3% Initially shortened, but may Fibrosis and possible stenosis, lengthen with regular particularly in postmenopausal intercourse patients Can be conserved Destroyed Radiation fibrosis of bowel and bladder in 6%-8% patients are potential

Ovaries

Chronic effects Bladder atony in 3%

Applicability

Best candidates are < 65 All years old, < 200 lb, and in

good health Surgical mortality 1%

candidates < 1% (arising from pulmonary embolism during intracavitary therapy)

Adapted from Hatch KD: Cervix cancer, in Berek JS, Hacker NF (eds): Practical Gynecologic Oncology, 2nd Ed, pp 243-283, Baltimore, Williams & Wilkins, 1994 Patients with stage IB disease and a tumor size greater than 3.0 cm have been reported to have lower recurrence rates and fewer complications when treated with radiation therapy instead of surgery [73]. Patients with para-aortic node involvement and patients with stage IIA disease and extensive extracervical involvement should be treated with radiation therapy. Radiation therapy usually consists of both external beam and intracavitary irradiation with a dose of 6,500 to 8,500 cGy to point A, but higher doses may be required for those with bulky endocervical carcinoma (at least 6-cm-diameter barrel-shaped cervix). In patients found to have disease-positive lymph nodes after a radical hysterectomy, total pelvic irradiation is recommended.

Stages IIB, III, and IV: The treatment for stages IIB, III, and IVA disease is radiation therapy. The usual regimen consists of external beam irradiation to the whole pelvis with two or more intracavitary applications delivering a dose of 7,000 to 9,000 cGy to point A. Studies by the Gynecologic Oncology Group (GOG) have indicated that the concomitant use of hydroxyurea as a radiosensitizer resulted in an improved complete response rate, a longer progressionfree interval, and a better survival rate in patients with stage IIIB and IVA disease [74,75]. Hydroxyurea was given at a dose of 80 mg/kg twice weekly during radiation. Patients with stage IVB disease are treated palliatively with radiation therapy or chemotherapy.

Recurrent Disease: The treatment of recurrent cervical cancer will depend on the previous primary therapy and the site of tumor recurrence. Local disease recurrence after radical surgery can be managed with a combination of external and intracavitary irradiation. Additional interstitial irradiation may also be required. A 25% 5-year survival rate has been reported for these patients treated with salvage radiotherapy [76]. Patients who develop locally recurrent disease after primary radiotherapy are candidates for pelvic exenteration if the tumor does not extend to the pelvic wall. A 6.3% operative mortality rate has been reported for this procedure with a 5-year survival rate of 50% [77]. Chemotherapy may also be used for palliation.

Management During Pregnancy: The treatment of cervical cancer diagnosed during pregnancy depends on the stage of the disease and the age of gestation. When cervical carcinoma is diagnosed during the first

trimester, immediate treatment appropriate for the stage of disease is recommended, and this will result in the termination of the pregnancy. Patients in the second trimester who have stage I disease may delay treatment until fetal maturity is reached without compromising treatment outcome [78]. Women who have more advanced disease should undergo immediate treatment. Delayed treatment is an option for all stages of the disease if the diagnosis is made during the third trimester.

Invasive Carcinoma Found at Simple Hysterectomy: Cervical carcinoma diagnosed in patients after a simple hysterectomy requires further therapy if found at a stage beyond microinvasive disease. Treatment options include radiotherapy or a second operation, depending on the extent of the tumor. Surgery would involve radical excision of parametrial tissue, cardinal ligaments, and vaginal cuff and a pelvic node dissection. Ureteral Obstruction: If an untreated patient presents with ureteral obstruction and has no evidence of distant disease, ureteral catheters should be placed and radiotherapy with curative intent should be started. In patients with metastatic disease, treatment options include ureteral stents, palliative radiotherapy, chemotherapy, or supportive care only.

The Role of Chemotherapy Because surgery and radiation therapy have been highly effective in treating most cases of early cervical carcinoma, chemotherapy has traditionally been used for the palliative management of advanced or recurrent disease that can no longer be managed by the other two modalities. However, various factors complicate the use of chemotherapy in patients with such disease. Prior radiation treatment can affect the blood supply to the involved field, which may result in decreased drug delivery to the tumor site. Pelvic irradiation also reduces bone marrow reserves, thus limiting the tolerable dose of most chemotherapeutic agents. Radiation may produce some of its cytotoxic effects through the same mechanism as alkylating agents, and it is thus thought to result in cross-resistance with some chemotherapeutic agents. A significant number of patients with advanced disease may also have impaired renal function, further limiting the use of certain chemotherapeutic regimens. Among the chemotherapeutic agents used for cervical cancer (see Table 5), the ones that have demonstrated the most consistent activity as single agents are cisplatin(Drug information on cisplatin) (Platinol) and ifosfamide(Drug information on ifosfamide) (Ifex)[79]. TABLE 5: Single-Agent Chemotherapy for Cervical Carcinoma Response % Alkylating agents Cyclophosphamide Chlorambucil 38/251 (15) 11/44 (25)

Melphalan Ifosfamide Mitolactol Heavy metal complexes Cisplatin Carboplatin Antitumor antibiotics Doxorubicin Bleomycin Mitomycin Antimetabolites Fluorouracil Methotrexate Hydroxyurea Plant alkaloids Vincristine Vinblastine Etoposide Miscellaneous agents Altretamine Irinotecan (CPT-11) Paclitaxel CCOP GOG* Docetaxel

4/20 (20) 25/84 (29) 16/55 (29)

182/785 (23) 271/175 (15)

33/205 (16) 19/176 (11) 5/23 (22)

29/142 (20) 17/96 (18) 0/14 (0)

10/55 (18) 2/20 (10) 0/31 (0)

12/64 (19) 13/55 (24)

3/21 (14) 9/52 (17) 1/13 (8)

 Personal communication: A.P. Kudelka, Gynecologic Medical Oncology, M.D. Anderson Cancer Center, Houston, Texas, 1995. * Personal communication: W. McGuire, Medical Oncology, Emory University, Atlanta, Georgia, 1995. CCOP = Community Clinical Oncology Program, GOG = Gynecologic Oncology Group Adapted from Thigpen T, Vance RB, Khansur T: Carcinoma of the uterine cervix: Current status and future directions. Semin Oncology 21 (suppl 2):45, 1994, and from Vermorken JB: The role of chemotherapy in squamous cell carcinoma of the uterine cervix: A review. Int J Gynecol Cancer 3:130, 1993. Cisplatin has been the most extensively evaluated single agent for cervical carcinoma. A dose of 100 mg/m has been shown to have a higher response rate (31%) than a dose of 50 mg/m (21%), but the higher dose was associated with increased toxicity, and the overall survival rates for the two dose groups did not differ significantly [80]. A cisplatin infusion over 24 hours is better tolerated than a 2-hour infusion, with no significant change in efficacy [81]. Ifosfamide has been reported to produce response rates ranging from 33% to 50% in various dose schedules [82]. A dose of 1.5 g/m over 30 minutes for 5 days (administered with mesna [Mesnex]) produced a 40% overall response rate and a 20% complete response rate. One of the more promising new agents is irinotecan(Drug information on irinotecan) (CPT11), a semisynthetic camptothecin analog that causes inhibition of topoisomerase I. Takeuchi et al [83] reported a response rate of 24% for cervical cancer. Preliminary data from a phase II trial at The University of Texas M.D. Anderson Cancer Center showed a 27% response rate [84]. Paclitaxel(Drug information on paclitaxel) (Taxol) has shown some activity in squamous-cell cancer of the cervix, producing response rates of 14% to 17% (personal communication, McGuire W and Kudelka AP, 1995). Lower response rates are generally seen in patients who have had prior chemotherapy. Responses are also decreased in previously irradiated sites. The duration of response with single agents is brief, usually ranging from 4 to 6 months with survival durations ranging from 6 to 9 months. Various combination chemotherapy regimens have been evaluated in phase II trials, and high response rates (greater than 50%) were seen even in patients who had prior radiation therapy. The results of some of these trials are listed in Table 6 [85-88]. In the study of Buxton et al [85], a subset analysis showed a response rate of 72% for the combination of bleomycin(Drug information on bleomycin) (Blenoxane)/ifosfamide/cisplatin in patients with tumors located in previously irradiated sites. However, there has not been an adequate phase III trial to determine whether any of the combination regimens offer a significant survival benefit over single-agent cisplatin. TABLE 6: Combination Chemotherapy for Advanced or Recurrent Cervical Carcinoma Prior Number radiation Complete Overall of therapy response response patients (%) rate (%) rate (%) 49 86 20 69

Chemotherapy regimen Bleomycin/ifosfamide/cisplatin [85]

Bleomycin/ifosfamide/carboplatin [86] Vinblastine/bleomycin/cisplatin [87]

21 33

49 66 87

23 18 9

60 67 58

Fluorouracil/doxorubicin/vincristine/cyclophosphamide 31 [88]

The use of chemotherapy in the neoadjuvant (primary) setting for cervical carcinoma has also been investigated. Four randomized trials, wherein cisplatin-based combination chemotherapy followed by radiation therapy was compared with radiation therapy alone for disease stages ranging from IIB to IVA, failed to show any survival benefit from chemotherapy [89-92]. The study by Souhami et al [89] even showed increased toxicity and decreased survival rate in the neoadjuvant arm. The trial by Tattersall et al [92] also reported significantly inferior local disease control and survival rates in the patients randomized to receive primary chemotherapy, compared with those who received radiotherapy alone [92]. Theoretically, toxic effects from neoadjuvant chemotherapy may prevent the delivery of adequate doses of radiation, and the issue of cross-resistance between these two modalities was mentioned earlier. Neoadjuvant chemotherapy may be more suitable when it is combined with surgery. Such therapy has been noted to result in a decrease in lymph-node involvement, compared with the rate seen in historical controls. However, a randomized trial by Sardi et al [93] of patients with stage IB bulky disease failed to show any benefit in overall survival for patients who received neoadjuvant cisplatin/vincristine (Oncovin)/bleomycin prior to surgery and radiation therapy, compared with patients who had surgery and/or postoperative radiation therapy only. Adjuvant chemotherapy has not been proven to benefit patients found to have pelvic lymph-node involvement after a radical hysterectomy. A randomized trial by Tattersal et al [94] failed to show any improvement in survival and relapse rates when adjuvant cisplatin/vinblastine/bleomycin was given to this group of patients. The use of intra-arterial chemotherapy theoretically offers the advantage of increased drug concentration at the tumor site as well as decreased systemic delivery of the drug if a first-pass effect is present. Most response rates obtained with various regimens have not been superior to systemic chemotherapy [95-97]. Furthermore, catheter-related complications have been encountered and drug-related toxicity is still significant with intra-arterial chemotherapy. Biologic agents have recently been found to have activity in cervical cancer. Lippman et al [98,99] reported an overall response rate of 50%, with a 12% complete response rate, in 32 previously untreated patients who had locally advanced cervical squamous-cell carcinoma and were treated with a combination of 13-cis-retinoic acid, 1 mg/kg orally, and alpha interferon (IFN-alfa), 6 million units subcutaneously, administered daily for at least 2 months. Of the 16 patients who responded, 9 eventually had disease progression, after a median response duration of 3 months. It is notable that only minimal toxicity was noted with this regimen. Interferons and retinoids both have antiviral as well as immunoregulatory properties and are known to modulate malignant cell differentiation and proliferation. Furthermore, they are known to inhibit angiogenesis. Results from serial biopsies of the responders in the Lippman study showed a significant reduction in the amount of blood vessels [100]. Preliminary data from an ongoing trial using an induction regimen consisting of 13-cis-retinoic acid and IFN-alfa followed by concomitant

radiotherapy, compared with radiotherapy alone, show a 42% response rate after the induction regimen, thus confirming the results of the previous trial [101]. The use of these biologic agents together with cisplatin is also being investigated.

Posttherapy Surveillance Tumor regression may continue for up to 3 months after a patient completes radiation therapy, so response must be confirmed by monthly examinations during this period. Because the majority of recurrences appear within the first 2 years after treatment, patients should be evaluated every 3 months during that interval and less frequently thereafter. The physical examination should include palpation of the supraclavicular and inguinal lymph nodes, a breast examination, and a rectovaginal examination. An annual Pap smear and chest x-ray are also recommended. If there are no contraindications, low-dose estrogen (eg, Premarin, 0.3 or 0.625 mg/d) and a progestational agent (eg,medroxyprogesterone(Drug information on medroxyprogesterone) [Provera], 2.5 or 5.0 mg/d) should be used indefinitely. The progestational agent is omitted in patients who have had a hysterectomy. An estrogen-containing vaginal cream (eg, Premarin) may be helpful for patients who still have dryness and dyspareunia. Sexual activity may be resumed after the completion of radiation therapy. For sexually inactive patients, use of a vaginal dilator may help maintain vaginal patency and allow better posttherapy surveillance.

Conclusion The detection of HPV as an etiologic agent in cervical neoplasia has greatly advanced the understanding of this disease process. Interventions such as immunizations aimed against high-risk HPV types may have a future role in the prevention of cervical neoplasia. HPV screening may also have a role in the management of CIN and is under investigation. Although surgery and radiation therapy have been very successful in the treatment of early-stage cervical carcinoma, the prognosis for advanced and recurrent disease remains poor, mainly because there is no effective systemic therapy. Cervical cytologic screening should be promoted. Other priorities should include the evaluation of new therapeutic agents through phase II trials and comparisons of combination chemotherapy regimens to single agents in adequate phase III trials. The use of neoadjuvant systemic therapy, including the biologic agents, should be explored further.