Carcinoma of the Uterine Cervix

PathologyEtiologyNatural HistoryScreening and DiagnosisStagingPrognosisTreatmentConclusionReferences

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 high-risk 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.

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.

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 squamous-cell 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 cone-shaped section of the cervix, to rule out invasive carcinoma. This is done using either cold knife, electrosurgical, or laser techniques. Indications for conization include:

• 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.

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 para-aortic 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, lymph-node 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].

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 cm³ to 48% for patients with tumors larger than 50 cm³. 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/µL)[69] have been associated with decreased survival rates. A lower survival rate was also reported for patients whose oral temperatures were greater than 100ºF. 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.

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 progression-free 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 (Platinol) and ifosfamide (Ifex)[79].

Cisplatin has been the most extensively evaluated single agent for cervical carcinoma. A dose of 100 mg/m² has been shown to have a higher response rate (31%) than a dose of 50 mg/m² (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/m² 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 (CPT-11), 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 (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 (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.

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 [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.

References:

References

1. Devesa SS, Silverman DT, Young JL, et al: Cancer incidence and mortality trends among whites in the United States, 1947–84. J Natl Cancer Inst 79:701-770, 1987.

2. Guzick DS: Efficacy of screening for cervical cancer: A review. Am J Public Health 68:125–134, 1978.

3. Wingo PA, Tong T, Bolden S: Cancer Statistics, 1995. CA Cancer J Clin 45:8–30, 1995.

4. Parkin DM, Muir CS, Whelan SL, et al (eds): Cancer Incidence in Five Continents, Volume VI. Lyon, International Agency for Research on Cancer, 1992.

5. Zaino RJ, Ward S, Delgado G, et al: Histopathologic predictors of the behaviour of surgically treated stage IB squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Cancer 69:1750–1758, 1992.

6. Goellner JR: Carcinoma of the cervix: Clinical pathologic correlation of 196 cases. Am J Clin Pathol 66:775–785, 1976.

7. Greer BE, Figge DC, Tamimi HK, et al: Stage IB adenocarcinoma of the cervix treated by radical hysterectomy and pelvic lymph node dissection. Am J Obstet Gynecol 160: 1509–1514, 1989.

8. Young RH, Scully RE: Invasive adenocarcinoma and related tumors of the uterine cervix. Semin Diagn Pathol 7:205–227, 1990.

9. Eifel PJ, Morris M, Oswald J, et al: Adenocarcinoma of the uterine cervix. Cancer 65:2507–2514, 1990.

10. Hale RJ, Wilcox FL, Buckley CH, et al: Prognostic factors in uterine cervical carcinoma: A clinicopathological analysis. Int J Gynecol Cancer 1:19–23, 1991.

11. Anton-Culver H, Bloss JD, Bringman D, et al: Comparison of adenocarcinoma and squamous cell carcinoma of the uterine cervix: A population based epidemiologic study. Am J Obstet Gynecol 186:1507–1514, 1992.

12. Kurman RJ, Norris HJ, Wilkinson E: Atlas of Tumor Pathology, series 3: Vol 4. Tumors of the cervix, vagina, and vulva. Washington, DC, Armed Forces Institute of Pathology, 1992.

13. Shingleton HM, Gor H, Bradley DH, et al: Adenocarcinoma of the cervix: I. Clinical evaluation and pathologic features. Am J Obstet Gynecol 139:799–814, 1981.

14. Yazigi R, Sandstad J, Munoz AK, et al: Adenosquamous carcinoma of the cervix: Prognosis in stage IB. Obstet Gynecol 75:1012–1015, 1990.

15. Maier RC, Norris HJ: Glassy cell carcinoma of the cervix. Obstet Gynecol 60:219–224, 1982.

16. Van Nagell JR, Powell DE, Gallion HH, et al: Small cell carcinoma of the uterine cervix. Cancer 62:1586–1593, 1988.

17. Harris RWC, Brinton LA, Cowdell RH, et al: Characteristics of women with dysplasia or carcinoma in situ of the cervix uteri. Br J Cancer 42:359–369, 1980.

18. Rotkin ID: Epidemiology of cancer of the cervix: III. Sexual characteristics of a cervical cancer population. Am J Public Health 57:815–829, 1967.

19. Schiffman MH, Bauer HM, Hoover RN, et al: Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 85:958–964, 1993.

20. Lorincz AT, Reid R, Jenson AB, et al: Human papillomavirus infection of the cervix: Relative risk associations of 15 common anogenital types. Obstet Gynecol 79:328–337, 1992.

21. Reid R, Greenberg M, Jenson AB, et al: Sexually transmitted papillomaviral infections: I. The anatomic distribution and pathologic grade of neoplastic lesions associated with different viral types. Am J Obstet Gynecol 156:212–222, 1987.

22. Cullen AP, Reid R, Campion MJ, et al: Analysis of the physical state of different human papillomavirus DNAs in intraepithelial and invasive cervical neoplasms. J Virol 65:606–612, 1991.

23. Scheffner M, Werness BA, Hulbregtse JM, et al: The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:1129–1136, 1990.

24. Hoppe-Seyler F, Butz K: Repression of endogenous p53 transactivation function in HeLa cervical carcinoma cells by human papillomavirus type 16 E6, human mdm-2, and mutant p53. J Virol 67:3111–3117, 1993.

25. Dyson N, Howley P, Münger K, et al: The human papillomavirus 16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243:934–937, 1989.

26. Hartwell LH, Kastan MB: Cell cycle control and cancer. Science 266:1821–1828, 1994.

27. Kessis TD, Slebos RJ, Nelson WG, et al: Human papillomavirus 16 E6 expression disrupts the p53-mediated cellular response to DNA damage. Proc Natl Acad Sci USA 90:3988–3992, 1993.

28. Demers GW, Foster SA, Halbert CL, et al: Growth arrest by induction of p53 in DNA damaged keratinocytes is bypassed by human papillomavirus 16 E7. Proc Natl Acad Sci USA 91:4382–4386, 1994.

29. Paquette RL, Lee YY, Wilczynski SP, et al: Mutations of p53 and human papillomavirus infection in cervical carcinoma. Cancer 72:1272–1280, 1993.

30. Schneider V, Kay S, Lee HM: Immunosuppression as a high-risk factor in the development of condyloma acuminatum and squamous neoplasia of the cervix. Acta Cytol 27:220–224, 1983.

31. Sillman F, Stanek A, Sedis A, et al: The relationship between human papillomavirus and lower genital intraepithelial neoplasia in immunosuppressed women. Am J Obstet Gynecol 150:300–308, 1984.

32. Halpert R, Fruchter RG, Sedlis A: Human papillomavirus and lower genital neoplasia in renal transplant patients. Obstet Gynecol 68:251, 1986.

33. Vermund SH, Kelley KF, Klein RS, et al: High risk of human papillomavirus infection and cervical squamous intraepithelial lesions among women with symptomatic human immunodeficiency virus infection. Am J Obstet Gynecol 165:392–400, 1991.

34. Schafer A, Friedmann W, Mielke M, et al: The increased frequency of cervical dysplasia-neoplasia in women infected with the human immunodeficiency virus is related to the degree of immunosuppression. Am J Obstet Gynecol 164:593–599, 1991.

35. Maiman M, Fruchter RG, Serur E, et al: Recurrent cervical intraepithelial neoplasia in human immunodeficiency virus–seropositive women. Obstet Gynecol 82:170–174, 1993.

36. Maiman M, Fruchter RG, Guy L, et al: Human immunodeficiency virus infection and invasive cervical carcinoma. Cancer 71:402–406, 1993.

37. Verson SD, Hart CE, Reeves WC, et al: The HIV-1 tat protein enhances E2-dependent human papillomavirus 16 transcription. Virus Res 27:133–145, 1993.

38. Burger MPM, Hollema H, Gouw ASH, et al: Cigarette smoking and human papillomavirus in patients with reported cervical cytological abnormality. Br Med J 306:749–752, 1993.

39. Richart RM: Cervical intraepithelial neoplasia, in Somers S (ed): Pathology Annual, pp 301-329. East Norwalk, Connecticut, Appleton-Century-Crofts, 1973.

40. Richart RM: A modified terminology for cervical intraepithelial neoplasia. Obstet Gynecol 75:131–133, 1990.

41. Richart RM, Wright TC: Controversies in the management of low-grade cervical intraepithelial neoplasia. Cancer 71:1413–1421, 1993.

42. Nasiell K, Roger V, Nasiell M: Behaviour of mild cervical dysplasia during long-term follow-up. Obstet Gynecol 67:665–669, 1986.

43. Nasiell K, Nasiell M, Vaclavinková V: Behaviour of moderate cervical dysplasia during long-term follow-up. Obstet Gynecol 61:609–614, 1983.

44. Barron BA, Cahill MC, Richart RM: A statistical model of the natural history of cervical neoplastic disease: The duration of carcinoma in situ. Gynecol Oncol 6:196–205, 1978.

45. Carlson V, Delclos L, Fletcher GH, et al: Distant metastasis in squamous-cell carcinoma of the uterine cervix. Radiology 88: 961–966, 1967.

46. Fink DJ: Change in the American Cancer Society checkup guidelines for detection of cervical cancer. Cancer 38:127, 1988.

47. Gay JD, Donaldson LD, Goellner JR: False-negative results in cervical cytologic studies. Acta Cytol 29:1043–1046, 1985.

48. Wilkinson EJ: Pap smears and screening for cervical neoplasia. Clin Obstet Gynecol 33:817–825, 1990.

49. Papanicolaou GN, Trout HF: Diagnosis of uterine cancer by the vaginal smear. New York, The Commonwealth Fund, 1943.

50. National Cancer Institute Workshop: The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. JAMA 262:931–934, 1989.

51. Ismail SM, Colclough AB, Dinnen JS, et al: Reporting cervical intraepithelial neoplasia (CIN): Intra- and interpathologist variation and factors associated with disagreement. Histopathology 16:371–376, 1990.

52. Sherman ME, Schiffman MH, Erozan YS, et al: The Bethesda System: A proposal for reporting abnormal cervical smears based on the reproducibility of cytopathologic diagnoses. Arch Pathol Lab Med 116:1155–1158, 1992.

53. Cox JT, Schiffman MH, Winzelberg AJ, et al: An evaluation of human papillomavirus testing as part of referral to colposcopy clinics. Obstet Gynecol 80:389–395, 1992.

54. Wright TC, Gagnon S, Richart RM, et al: Treatment of cervical intraepithelial neoplasia using the loop electrosurgical excision procedure. Obstet Gynecol 79:173–178, 1991.

55. DePriest PD, van Nagell JR, Powell DE: Microinvasive cervical carcinoma. Clin Obstet Gynecol 33:846–851, 1990.

56. Creasman WF, Fetter BF, Clarke–Pearson DL, et al: Management of stage IA carcinoma of the cervix. Am J Obstet Gynecol 153:164–172, 1985.

57. Fagundes H, Perez CA, Grigsby PW, et al: Distant metastases after irradiation alone in carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 24:197–204, 1992.

58. Stehman FB, Bundy BN, DiSaia PJ, et al: Carcinoma of the cervix treated with radiation therapy: I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group. Cancer 67:2776–2785, 1991.

59. Burghardt E, Baltzer J, Tulusan AH, et al: Results of surgical treatment of 1028 cervical cancers studied with volumetry. Cancer 70:648–655, 1992.

60. Grimard L, Genest P, Girard A, et al: Prognostic significance of endometrial extension in carcinoma of the cervix. Gynecol Oncol 31:301–309, 1988.

61. Coia L, Won M, Lanciano R, et al: The patterns of care outcome study for cancer of the uterine cervix: Results of the second national practice survey. Cancer 66:2451–2456. 1990.

62. Delgado G, Bundy B, Zaino R, et al: Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Gynecol Oncol 38:352–357, 1990.

63. Zaino RJ, Ward S, Delgado G, et al: Histopathologic predictors of the behavior of surgically treated stage IB squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Cancer 69:1750–1758, 1992.

64. Tanaka Y, Sawada S, Murata T: Relationship between lymph node metastases and prognosis in patients irradiated postoperatively for carcinoma of the uterine cervix. Acta Radiol Oncol 23:455–459, 1984.

65. Strang P, Eklund G, Stendahl B, et al: S-phase rate as a predictor of early recurrence in carcinoma of the uterine cervix. Anticancer Res 7:807–810, 1987.

66. Berchuck A, Rodriguez G, Kamel A, et al: Expression of epidermal growth factor receptor and HER-2/neu in normal and neoplastic cervix, vulva, and vagina. Obstet Gynecol 76:381–387, 1990.

67. Bourhis J, Le MG, Barrios M, et al: Prognostic value of c-myc proto-oncogene overexpression in early invasive carcinoma of the cervix. J Clin Oncol 8:1789–1796, 1990.

68. Bush RS, Jenkin RDT, Allt WEC, et al: Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br J Cancer 37 (suppl 3):302–306, 1978.

69. Hernandez E, Lavine M, Dunton CJ, et al: Poor prognosis associated with thrombocytosis in patients with cervical cancer. Cancer 69:2975–2977, 1992.

70. Van Herik M: Fever as a complication of radiation therapy for carcinoma of the cervix. Am J Roentgenol Radium Ther Nucl Med 43:104–109, 1965.

71. Grisby PW, Perez CA: Radiotherapy alone for medically inoperable carcinoma of the cervix: Stage IA and carcinoma in situ. Int J Radiat Oncol Biol Phys 21:375–378, 1991.

72. Pilleron JP, Durand JC, Lenoble JC: Carcinoma of the uterine cervix, stages I and II, treated by radiation therapy and extensive surgery (1,000 cases). Cancer 29:593–596, 1972.

73. Eifel PJ, Burke TW, Delclos L, et al: Early stage I adenocarcinoma of the uterine cervix: Treatment results in patients with tumors less than or equal to 4 cm in diameter. Gynecol Oncol 41:199–205, 1991.

74. Hreshchyshyn MM, Aron BS, Boronow RC, et al: Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV cervical cancer confined to the pelvis. Int J Radiat Oncol Biol Phys 5:317–322, 1979.

75. Stehman FR, Bundy RN, Keys H, et al: A randomized trial of hydroxyurea versus misonidazole adjunct to radiation therapy in carcinoma of the cervix: A preliminary report. A Gynecologic Oncology Group study. Am J Obstet Gynecol 159:87–94, 1988.

76. Krebs HB, Helmkamp BF, Sevin BU, et al: Recurrent cancer of the cervix following radical hysterectomy and pelvic node dissection. Obstet Gynecol 59:422–427, 1982.

77. Shingleton HM, Soong SJ, Gelder MS, et al: Clinical and histopathological factors predicting recurrence and survival after pelvic exenteration for cancer of the cervix. Obstet Gynecol 73:1027–1034, 1989.

78. Duggan B, Muderspach LI, Roman LD, et al: Cervical cancer in pregnancy: Reporting on planned delay in therapy. Obstet Gynecol 82:598–602, 1993.

79. Thigpen T, Vance RB, Khansur T: Carcinoma of the uterine cervix: Current status and future directions. Semin Oncol 21 (suppl 2):43–54, 1994.

80. Bonomi P, Blessing J, Stehman F, et al: Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol 3:1079–1085, 1985.

81. Thigpen T, Blessing JA, DiSaia PJ, et al: A randomized comparison of a rapid versus prolonged (24 hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: A Gynecologic Oncology Group study. Gynecol Oncol 32:198–202, 1989.

82. Coleman R, Jarper P, Gallagher C, et al: A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix. Cancer Chemother Pharmacol 18:280–283, 1986.

83. Takeuchi S, Noda K, Yakushiji M, et al: Late phase II study of CPT-11, topoisomerase I inhibitor, in advanced cervical carcinoma (abstract). Proc Am Soc Clin Oncol 11:224, 1992.

84. Kavanagh JJ, Kudelka AP, Edwards CE, et al: CPT-11 (Irinotecan): Phase II study in refractory squamous cell carcinoma of the cervix (abstract). Proc Am Assoc Cancer Res 35:234, 1994.

85. Buxton EJ, Meanwell CA, Hilton C, et al: Combination bleomycin, ifosfamide and cisplatin chemotherapy in cervical cancer. J Natl Cancer Inst 81: 359–361, 1989.

86. Murad AM, Triginelli SA, Ribalta JCL: Phase II trial of bleomycin, ifosfamide, and carboplatin in metastatic cervical cancer. J Clin Oncol 12:55–59, 1994.

87. Friedlander M, Kaye SB, Sullivan A, et al: Cervical carcinoma: A drug-responsive tumor-experience with combined cisplatin, vinblastine, and bleomycin therapy. Gynecol Oncol 16:275–281, 1983.

88. Chan WK, Aroney RS, Levi JA, et al: Four-drug combination chemotherapy for advanced cervical carcinoma. Cancer 49:2437–2440, 1982.

89. Souhami L, Gil RA, Allan SE, et al: A randomized trial of chemotherapy followed by pelvic radiation therapy in stage IIIB carcinoma of the cervix. J Clin Oncol 9:970–977, 1991.

90. Chauvergne J, Rohart J, Heron JF, et al: Essai randomise de chimiotherapie initiale dans 151 carcinomes du col uterin localement etendus. Bull Cancer (Paris) 77:1007–1024, 1990.

91. Tattersall MHN, Ramirez C, Coppelson M: A randomized trial comparing platinum-based chemotherapy followed by radiotherapy vs radiotherapy alone in patients with locally advanced cervical cancer. Int J Gynecol Cancer 2:244–351, 1992.

92. Tattersall MHN, Lorvidhaya V, Vootiprux V, et al: Randomized trial of epirubicin and cisplatin chemotherapy followed by pelvic irradiation in locally advanced cervical cancer. J Clin Oncol 13:444–451, 1995.

93. Sardi J, Sananes C, Giaroli A, et al: The results of a prospective randomized trial with neoadjuvant chemotherapy in stage IB bulky squamous cell carcinoma of the cervix. Gynecol Oncol 49:156–165, 1993.

94. Tattersall MHN, Ramirez C, Coppelson M: A randomized trial of adjuvant chemotherapy after radical hysterectomy in stage IB-IIA cervical cancer patients with pelvic lymph node metastases. Gynecol Oncol 46:175–181, 1992.

95. Swenerton KD, Evers JA, White GW, et al: Intermittent pelvic infusion with vincristine, bleomycin and mitomycin C for advanced recurrent carcinoma of the cervix. Cancer Treat Rep 63:1379–1381, 1979.

96. Chen HSG, Gross GF: Intra-arterial infusion of anticancer drugs: Theoretical aspects of drug delivery and review of response. Cancer Treat Rep 64:31–40, 1980.

97. Kavanagh J, Wallace S, Delclos L, et al: Update of the results of intra-arterial (IA) chemotherapy for advanced squamous cell carcinoma of the cervix. Proc Am Assoc Cancer Res 3:172, 1984.

98. Lippman SM, Kavanagh JJ, Paredes-Espinoza M, et al: 13-cis-retinoic acid plus interferon alpha-2a: Highly active systemic therapy for squamous cell carcinoma of the cervix. J Natl Cancer Inst 84:241–245, 1992.

99. Lippman SM, Kavanagh JJ, Paredes-Espinoza M, et al: 13-cis-retinoic acid plus interferon-alpha 2a in locally advanced squamous cell carcinoma of the cervix. J Natl Cancer Inst 85:499–500, 1993.

100. Ahn WS, Lippman SM, Kavanagh JJ, et al: Biological basis of response of cervical squamous cell carcinoma to alpha interferon and 13-cis-retinoic acid (abstract 446). Proc Am Assoc Cancer Res 34:75, 1993.

101. Kavanagh JJ, Lippman SM, Paredes M, et al: 13-cis-retinoic acid (13cRA), interferon-alpha 2a (IFN-alpha 2a) with and without radiotherapy for carcinoma of the cervix (abstract). Int J Gynecol Cancer 3(suppl 1):6, 1993.

102. Kurman RJ (ed): Blaustein's Pathology of the Female Genital Tract, 4th ed. New York, Springer-Verlag, 1994.

103. Hatch, KD: Preinvasive cervical neoplasia. Semin Oncol 21:12–16, 1994.

104. Marcial VA, Marcial LV: Radiation therapy of cervical cancer. Cancer 71 (suppl):1438–1445, 1993.