Chapter 33: Tumors of the Uterine Cervix

Demographics

Cancer of the cervix is the third most common gynecologic malignancy in the United States. In 2015, a total of 12,900 new cases of cervical cancer and 4,100 deaths are estimated (¹). The incidence of this disease has decreased steadily over the past several decades. However, cervical cancer remains one of the most common cancers in women worldwide with approximately 527,600 new cases diagnosed each year and 265,700 related deaths (²).

Squamous cell carcinoma (SCC) of the cervix may occur at any age from the second decade of life onward. The mean age at diagnosis is approximately 51.4 years, with the number of cases evenly divided between patients at 30 to 39 and 60 to 69 years of age (³). Adenocarcinoma makes up to 15% to 25% of all invasive cervical cancers.

Etiology and Risk Factors

Risk factors for cervical cancer are listed in Table 33-1.

Human Papillomavirus

To understand the current methods for cervical screening, a basic understanding of the nature of cervical abnormalities is essential. Human papillomavirus (HPV) is the critical factor for the development of preinvasive and invasive cervical lesions. More than 14 million incident cases are reported annually, the majority of which occur in persons age 15 to 24 years (^4,5,6). HPV is a small, nonenveloped, double-stranded DNA virus predominantly transmitted through sexual intercourse. The most consistent risk factors for acquiring HPV are number of sexual partners, age of first sexual intercourse, and a partner infected with HPV.

More than 40 genotypes of HPV infect the epithelial lining of the anogenital tract and other mucosal areas of the body (⁷). These subtypes are further classified into high-risk HPV (HR-HPV) and low-risk HPV (LR-HPV) depending on their oncogenic potential for cervical cancer and its precursors. Low-risk HPV genotypes include HPV-6 and -11 and typically cause benign anogenital warts, although they may occasionally be associated with neoplastic cervical changes (⁸). Invasive lesions, on the other hand, are much more commonly caused by HR-HPV including, in order of frequency, types 16, 18, 31, 45, 52, and 33 (⁹). Although the majority of premalignant and invasive disease can be directly attributed to types 16 or 18, HPV DNA from any genotype is detectable in greater than 99% of all cervical cancer specimens (⁸).

Immunodeficiency Status

Many studies have reported an increased risk of HPV infection and preinvasive and invasive cervical cancer in women who have low immunity, such as those with human immunodeficiency virus (HIV) infection (¹⁰). It was found that rare HR-HPV types are more common in cervical dysplasia of HIV-infected women. It is possible that these other HPV types (35, 45, 52, and 59) are not able to evade the immune system as efficiently as HPV types 16 and 18, except in HIV-infected individuals who are immunocompromised (¹¹).

Number of Sexual Partners

The number of sexual partners is an important risk factor for both preinvasive and invasive cervical cancer. Many studies have found an increased relative risk of cervical cancer in women who have had more than six sexual partners (¹²). This is related to a higher risk of acquiring HPV infection.

Age at First Intercourse

Women who have intercourse early in life (<16 years of age) are more prone to develop cervical cancer (¹³). This increase in risk has been proposed because the process of transformation of columnar epithelium to squamous epithelium is active and is vulnerable to carcinogenic agents during early adolescence. However, these women frequently have other associated risk factors, such as multiple sexual partners and HPV infection.

Contraception

Many studies have produced controversial results on the effect of oral contraception on cervical cancer risk. The relative risk of cervical cancer is increased in current users of oral contraceptives and declines after use ceases (¹⁴).

Smoking

Tobacco use is a well-established risk factor for cancer of the cervix. Cigarette smoking confers a 1.5- to 2.5-fold increase in cancers of the cervix. Overall, tobacco smoking is estimated to account for 21% of cancer deaths worldwide, of which 2% (2% in high-income countries and 11% in low- and middle-income countries) are due to cervical cancer. Therefore, it is the most preventable risk factor for smoking-related cancer deaths (¹⁵).

Male Factors

Women with cervical cancer frequently report a history of having a male partner who has multiple other female partners, a history of condyloma infection, a history of intercourse with prostitutes, or an ex-wife or former partner with cervical cancer (¹²).

Squamous Cell Tumors and Precursors

Squamous Intraepithelial Lesions

Cervical SCCs are believed to develop from precursor or preinvasive lesions, which have been classified in a variety of ways but are generally based on the degree of disruption of epithelial differentiation. The oldest such system is the dysplasia–carcinoma in situ (CIS) system, with mild dysplasia at one end and severe dysplasia/CIS at the other. Another is the cervical intraepithelial neoplasia (CIN) classification, with mild dysplasia termed CIN1 and CIS termed CIN3. The Bethesda System for reporting cervical/vaginal cytologic abnormalities categorizes squamous abnormalities as follows: low-grade squamous intraepithelial lesion (LSIL), encompassing HPV infection and CIN1; high-grade squamous intraepithelial lesion HSIL, encompassing CIN2 and CIN3; and SCC. These systems are compared in Table 33-2 (¹⁶).

Microinvasive Carcinoma

Microinvasion has been defined variably depending on the recommendations of the International Federation of Gynecology and Obstetrics (FIGO) (“preclinical invasive carcinoma diagnosed microscopically only”; depth of lesion, ≤5 mm; width, ≤7 mm) or Society of Gynecologic Oncology (depth of invasion, ≤3 mm with no lymphovascular space invasion [LVSI] or confluent pattern) (¹⁷). The depth of stromal invasion is measured from the base of the epithelium, either squamous or glandular, to the deepest point of invasion. Microinvasion can be diagnosed only with a conization specimen containing the entire lesion, having uninvolved margins, and having a sufficient number of sections examined by the pathologist.

The histology of invasive foci is usually better differentiated than that of the nearby squamous intraepithelial lesion (Figs. 33-1 and 33-2).

Invasive Squamous Cell Carcinoma

The histopathology of SCC is shown in Figs. 33-3 and 33-4.

Glandular Tumors and Precursors

The World Health Organization (WHO) has classified cervical adenocarcinoma into eight categories: (1) adenocarcinoma in situ, (2) early invasive adenocarcinoma, (3) adenocarcinoma not otherwise specified, (4) mucinous adenocarcinoma (including endocervical, intestinal, minimal deviation adenocarcinoma or adenoma malignum, signet ring cell, and villoglandular adenocarcinoma), (5) endometrioid adenocarcinoma, (6) clear cell adenocarcinoma, (7) serous adenocarcinoma, and (8) mesonephric adenocarcinoma.

Adenocarcinoma in Situ

Adenocarcinoma in situ (AIS) is an intraepithelial glandular neoplasm that occurs in women at a younger age than invasive adenocarcinoma (¹⁸). Adenocarcinoma in situ is typically located at the transformation zone, although it may be present high up in the endocervical canal (between 20 and 30 mm, measured from the maximum convexity of the portio vaginalis). The principal morphologic features are cytologic malignant glandular epithelium with stratification, atypia, mitotic activity, and frequent apoptosis without stromal invasion. The cellular changes may be found focally in the glands and may have features of endocervical, endometrial, intestinal, or mixed cell types. The distinction between AIS and nonneoplastic glandular epithelium may at times be difficult; some authors have coined terms such as glandular dysplasia and glandular atypia for these lesser changes.

Early Invasive or Microinvasive Adenocarcinoma

Although the concept of microinvasive adenocarcinoma has not been universally accepted, published literature suggests that patients with LVSI-negative cervical adenocarcinoma with depth of stromal invasion of <5 mm and a tumor volume of <500 μL can be treated with nonradical management (extrafascial hysterectomy with excision of the anterior leaf of the vesicouterine ligament, without lymph node dissection and oophorectomy) (¹⁹).

Adenocarcinoma

Various subtypes of adenocarcinoma have been noted due to their differentiation, as their respective names imply, such as mucinous adenocarcinoma, which can have endocervical or intestinal goblet cell features and the appearance of endometrioid, clear cell, serous, or mesonephric types. Adenoma malignum is usually an extremely benign-appearing cancer that is often diagnosed late and thus has a clinically poor prognosis. Clear cell adenocarcinomas may or may not be associated with diethylstilbestrol exposure in utero, but they have no known association with HPV (²⁰). Serous adenocarcinoma is rare, with histology identical to its ovarian counterpart, and it carries a similarly bad prognosis. Mesonephric carcinomas are rare and are found in embryonal remnants of wolffian ducts, such as the uterine cervix, broad ligament, mesosalpinx, and exceptionally in the uterine corpus. The primary histologic pattern is tubular glands that vary in size and are lined by one to several layers of columnar cells (²¹) (Fig. 33-5).

Pap Smear and Bethesda System

Pap Smear

Guidelines for screening have been put forth by American College of Obstetricians and Gynecologists (²²) and are summarized below:

• Cervical cancer screening should begin at age 21 years. Women younger than age 21 years should not be screened regardless of the age of sexual initiation or the presence of other behavior-related risk factors.

• Women age 21 to 29 years should be tested with cervical cytology alone, and screening should be performed every 3 years. Human papillomavirus testing should not be performed in women younger than 30 years.

• For women age 30 to 65 years, co-testing with cytology and HPV testing every 5 years is preferred.

• In women age 30 to 65 years, screening with cytology alone every 3 years is acceptable. Annual screening should not be performed.

• Women who have a history of cervical cancer, have HIV infection, are immunocompromised, or were exposed to diethylstilbestrol in utero should not follow routine screening guidelines.

• Both liquid-based and conventional methods of cervical cytology collection are acceptable for screening.

• In women who have had a hysterectomy with removal of the cervix (total hysterectomy) and have never had CIN2 or higher, routine cytology screening and HPV testing should be discontinued and not restarted for any reason.

• Screening by any modality should be discontinued after age 65 years in women with evidence of adequate negative prior screening results and no history of CIN2 or higher. Adequate negative prior screening results are defined as three consecutive negative cytology results or two consecutive negative co-test results within the previous 10 years, with the most recent test performed within the past 5 years.

Since the Pap smear was initially developed, there have been several changes in nomenclature and interpretation to make the results more clinically relevant. At present, the Bethesda System is being used worldwide for cytologic diagnosis (see Table 33-2).

Bethesda System

The Bethesda System is another procedure used for the cytologic diagnosis of cervical cancer. It was developed in 1988 and last updated in 2001 and is now used widely (²³). The Bethesda System report is divided into three sections:

1. Specimen adequacy

   Satisfactory for evaluation

   Unsatisfactory for evaluation

2. General categorization (optional)

   Negative for intraepithelial lesion or malignancy

   Epithelial cell abnormality

   Other

3. Interpretation/result

   Negative for intraepithelial lesion or malignancy

   • Organism

   • Other nonneoplastic findings (optional to report; list not comprehensive)

     • Reactive cellular changes associated with (descriptive findings)

     • Glandular cells status post hysterectomy

     • Atrophy

   Epithelial cell abnormalities

   Squamous cell

   • Atypical squamous cells (ASCs); ASC of undetermined significance (ASC-US) and ASC cannot exclude HSIL (ASC-H)

     • LSIL

     • HSIL

   • Glandular cell (specify endocervical, endometrial, or not otherwise specified)

     • Atypical glandular cells (AGCs)

     • AGCs, favor neoplastic

     • Endocervical AIS

   • Adenocarcinoma

     • Other (list not comprehensive)

     • Endometrial cells in a woman ≥40 years of age

     • Automated review and ancillary testing (include as appropriate)

   Educational notes and suggestions (optional)

Note the following:

1. ASC: Some cells were seen that cannot be called normal but do not meet the requirements to call them precancerous. The abnormal cells may be caused by an infection, irritation, or intercourse or may be precancerous.

   1. ASC-US

   2. ASC-H

2. Squamous intraepithelial lesion: Changes were seen in the cells that may show precancerous signs. Squamous intraepithelial lesion can be low or high grade.

   1. LSIL: Early, mild changes in the size or shape of cells were seen.

   2. HSIL: Moderate or severe cell changes are seen; HSIL changes on a Pap smear suggest an increased risk of “precancer” when compared with LSIL changes.

3. AGC: Cell changes were seen that represent an abnormality that must be evaluated more closely. The type of evaluation depends on patient age and other factors.

Example of cytologic features of HPV and CIN are shown in Fig. 33-6.

The natural history of growth of a cervical lesion is believed to progress through a state of microscopic invasion into the stroma and radial growth on the surface. Ultimately, a mass is formed, which, in general, grows locally to invade first the deeper stroma and later the paracervical and parametrial tissues. If left untreated, the disease will expand through these tissues to involve the lateral pelvic side wall and nearby viscera, such as the urinary bladder and rectum. Cancer arising from the cervix has been reported to involve the uterine corpus in 10% to 30% of cases. The incidence of ovarian metastasis in patients with cervical cancer is estimated at 0.22% for stage IB, 0.75% for stage IIA, and 2.2% for stage IIB with SCC, and 3.7%, 5.3%, and 9.9%, respectively, in adenocarcinoma (²⁴).

A retrospective review of 360 patients with carcinoma of the cervix with clinical stage IB and IIA who had undergone radical hysterectomy and pelvic node dissection showed that lymph node metastasis was present in 21.9% of patients. In patients with and without lymph node metastasis, lymphovascular space invasion positivity, full-thickness stromal invasion, involvement of the uterine isthmus, positive parametrium, positive vaginal margins, and involvement of uterine corpus were seen in 25.3% and 9.2% (P < .001), 63% and 32% (P < .001), 32.9% and 13.8% (P < .001), 15.2% and 5% (P < .004), 24% and 14.2% (P < .005), and 17.7% and 13.8% (P = .11) of patients, respectively. In patients with lymph node metastases, 79.7% had grade 3 tumor compared with 69.5% of patients without lymph node metastases (P = .19). Multiple logistic regression indicated that only LVSI and full-thickness stromal invasion were statistically significant (P < .001 and P < .002, respectively) for lymph node metastasis (²⁵). Distant metastasis to bones, lungs, breast, brain, and abdominal viscera often has a late presentation. Variant cell types, such as neuroendocrine and glassy cell carcinoma, may be associated with distant disease in the absence of local involvement.

Symptoms

The clinical signs and symptoms of patients with cervical cancer vary depending on the stage and characteristic features of their lesions. Patients with early-stage disease may not have any abnormal symptoms; rather, their lesions may be discovered incidentally on a Pap smear. In patients with gross lesions, the most common presenting symptom is vaginal bleeding, which may have a characteristic pattern of mucous bloody discharge, postcoital bleeding, and/or intermenstrual, intermittent, or continuous vaginal bloody discharge. Vaginal bleeding is often found with exophytic cervical lesions. Tumor necrosis with superimposed infection may cause a mucopurulent bloody discharge with a foul smell due to anaerobic organisms. The symptoms in patients with more advanced disease include leg swelling due to compression of the venous or lymphatic system, pain due to nerve or bone involvement, and other urinary or bowel symptoms due to cancer invasion, such as hematuria or hematochezia.

Cervical cancer is currently staged clinically using the FIGO system (¹⁷). Routine evaluation includes physical examination, pelvic and rectal examination, and pathologic review of cervical or cone biopsy specimens. Basic imaging studies such as chest x-ray, intravenous pyelography, cystoscopy, and proctoscopy are allowed in order to classify the disease into four stages, as shown in Table 33-3.

Imaging plays an important role in the pretreatment evaluation of patients with common gynecologic malignancies. Magnetic resonance imaging (MRI) is the best imaging technique for evaluation of extent of disease in patients with cervical cancer. Magnetic resonance imaging is also useful in the pretreatment evaluation of young women with small-volume disease who wish to preserve fertility. Computed tomography (CT) is able to identify extra-uterine spread of disease, including enlarged pelvic and/or retroperitoneal lymph nodes, extension to the pelvic sidewalls and hydronephrosis, fistulation into bladder or into rectum, and the presence of distant parenchymal metastases. Positron emission tomography (PET)/CT is useful in the detection of lymph node metastases, with sensitivities of 75% to 100% and specificities of 87% to 100%, demonstrating abnormal tracer uptake even in normal-size nodes (²⁶).

Stage IA

The depth of stromal invasion correlates with the risk of pelvic lymph node metastases and progression-free interval. In tumors with a depth of invasion <1, 1 to 3, and <3 mm, the risk of lymph node involvement (LNI) was 0% to 1.6%, 0% to 5.3%, and 1.3% to 13.8%, respectively; the risk of parametrial invasion was 0%, 0% to 2.3%, and 0% to 3.3%, respectively (²⁷). Positive LVSI status has significant adverse prognostic effects on relapse-free survival and overall survival in tumors with increasing depth of invasion (P < .001) (²⁸). In a study by Milam et al (²⁹), the authors aimed to determine the association between findings on review of preoperative biopsy specimens and the risk of LNI at radical hysterectomy in patients with early-stage (stage IA-IB1) cervical cancer. In that study, the authors found that 12 patients (14.8%) had LNI at radical hysterectomy. Stage, grade, and histologic subtype were not associated with LNI. Lymphovascular space invasion and depth of invasion >4 mm were both significantly associated with LNI (25.6% vs 4.8%, P = .01; and 25.0% vs 4.5%, P = .01, respectively). Patients with LVSI with >4 mm invasion were 6.6 times more likely to have LNI at the time of radical hysterectomy (relative risk, 6.6; 95% confidence interval [CI], 2.1-21.9). The authors concluded that patients with preoperative LVSI are at higher risk for LNI at radical hysterectomy and should be counseled regarding potential implications for management.

Stage IB-IIA

The incidence of lymph node metastasis in patients with stage IB1 and IB2 cervical cancer has been reported to be as high as 15% to 20% and 30% to 50%, respectively. Parametrial invasion is related to the grade of the tumor, depth of stromal invasion, and presence of LVSI. A study by Frumovitz et al (³⁰) evaluated the incidence of parametrial involvement and the factors associated with parametrial spread in women with early-stage cervical cancer. In that study, the authors sought to also identify a cohort of patients at low risk for parametrial spread who may benefit from less radical surgery. Three hundred fifty patients met the inclusion criteria. Overall, 27 women (7.7%) had parametrial involvement. The majority of specimens with parametrial involvement (52%) had tumor spread through direct microscopic extension. Patients with parametrial involvement were more likely to have a primary tumor size larger than 2 cm (>2 cm, 14%; <2 cm, 4%; P = .001), higher histologic grade (grade 3, 12%; grades 1 and 2, 3%; P = .01), LVSI (positive, 12%; negative, 3%; P = .002), and metastasis to the pelvic lymph nodes (positive, 31%; negative, 4%; P ≤ .001). One hundred twenty-five women (36%) had squamous, adenocarcinoma, or adenosquamous lesions, all grades, with primary tumor size ≤2 cm and no LVSI. In this group of patients, there was no pathologic evidence of parametrial involvement. Significant prognostic factors include tumor diameter, positive lymphangiography, and adenocarcinoma histology.

Preventive Setting

Koutsky et al (³¹) conducted a double-blinded randomized study in 2,392 women at risk for infection who received three doses of a placebo or HPV-16–like particle vaccine (40 mg/dose). After a median follow-up duration of 17.4 months from administration of the last dose, the incidence of HPV-16 infection was significantly lower in the study group (3.8% in the placebo group, 0.0% in the vaccinated group; P < .001).

The first HPV vaccine was licensed for use in the United States in June 2006. At present, there are two HPV vaccines available in the United States. Human papillomavirus quadrivalent, or HPV4 (types 6, 11, 16, 18), vaccine, recombinant (Gardasil) and HPV bivalent, or HPV2 (types 16 and 18), vaccine, recombinant (Cervarix). Both vaccines have greater than 95% efficacy in preventing HPV-16– and HPV-18–related cervical precancer lesions (³²).

The WHO has changed its previous recommendation of a three-dose schedule to a two-dose schedule, with increased flexibility in the interval between doses, which may facilitate vaccine uptake. For both the bivalent and quadrivalent HPV vaccines, a two-dose schedule with a 6-month interval between doses is recommended for females younger than 15 years. Those who are >15 years old at the time of the second dose are also adequately covered by two doses. There is no maximum recommended interval between doses. However, an interval no greater than 12 to 15 months is suggested in order to complete the schedule promptly and before becoming sexually active. If the interval between doses is shorter than 5 months, a third dose should be given at least 6 months after the first dose. A three-dose schedule (at 0, 1-2, and 6 months) is recommended for females age 15 years and older and for those known to be immunocompromised and/or infected with HIV (regardless of whether they are receiving antiretroviral therapy) (³³).

The data from the National Health and Nutrition Examination Surveys (NHANES) continue to show good efficacy for the HPV vaccines. Data comparing 2003 to 2006 with 2007 to 2010, the first 4 years of the HPV vaccination program in the United States, have shown that there was a 56% reduction in prevalence of HPV types 6, 11, 16, and 18 in girls age 14 to 19 years and 36% reduction in genital warts in US girls age 15 to 19 years from 2006 to 2010 (³²).

Apter et al (³⁴) conducted the double-blinded randomized PATRICIA trial on the immunogenicity and efficacy of the HPV-16/18 AS04-adjuvantedvaccine in young women age 15 to 25 years. The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n = 9,319; control, n = 9,325) at months 0, 1, and/or 6. The TVC-naïve group (vaccine, n = 5,822; control, n = 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. It was concluded that vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective.

Squamous Cell Carcinoma Antigen

A study was conducted to identify patient-, disease-, and treatment-related factors associated with unusual levels of SCC antigen (SCC-Ag) and to determine whether SCC-Ag is a useful tumor marker in patients. Among 129 patients with recurrence, 14 who showed a normal SCC-Ag level at diagnosis but an elevated level at recurrence were classified as group I; 22 patients with an elevated SCC-Ag level at diagnosis but not at recurrence were classified as group II; and 76 patients with an elevated SCC-Ag level at both diagnosis and recurrence were classified as group III. In univariate analysis, unusual SCC-Ag showed statistically significant relationships with pathology and biochemical response to treatment. However, in the multivariate analysis, none of the clinicopathologic factors showed a statistical relationship with unusual levels of SCC-Ag. The 5-year disease-free survival rates for groups I, II, and III were 7.1%, 9.1%, and 0% (P = .418), and the 5-year overall survival rates were 34.3%, 58.4%, and 33.3%, respectively (P = .142). It was found that patients with a high initial SCC-Ag and elevated SCC-Ag at relapse have poor prognosis due to high SCC-Ag level (³⁵).

Management of Abnormal Pap Smears

The current consensus guidelines from the American Society for Colposcopy and Cervical Pathology (ASCCP) for the management of abnormal Pap tests and treatment of cervical dysplasia are summarized below (³⁶).

Atypical Squamous Cells

Treatment of ASC depends on the subcategory based on the Pap smear: undetermined significance (ASC-US) or cannot exclude HSIL (ASC-H).

1. ASC-US: Atypical squamous cells of undetermined significance is the most common cytologic abnormality, but it carries the lowest risk of CIN3+, partly because one- to two-thirds of cases are not HPV associated. For women >25 years old with ASC-US cytology, HPV testing is recommended. If HPV-negative ASC-US is present, repeat co-testing (Pap and HPV testing) at 3 years is recommended. If HPV-positive ASC-US is present, colposcopy is recommended. For women age 21 to 24 years with ASC-US, repeat cytology in 12 months is recommended. Immediate colposcopy or repeat HPV testing is not recommended. Management of pregnant women with ASC-US is identical to that described for nonpregnant women, with the exception that deferring colposcopy until 6 weeks postpartum is acceptable. Endocervical curettage in pregnant women should not be performed.

2. ASC-H: For women with ASC-H cytology, colposcopy is recommended regardless of HPV result.

Low-Grade Squamous Intraepithelial Lesion

For women with LSIL who are 21 to 24 years old, follow-up with cytology at 12-month intervals is recommended. For women >25 years old, colposcopy is recommended. For pregnant women with LSIL, colposcopy is preferred and can be performed immediately or deferred until 6 weeks postpartum.

High-Grade Squamous Intraepithelial Lesion

For women >25 years old with HSIL cytology, colposcopy or immediate treatment with loop electrosurgical excision or colposcopy is recommended. For women age 21 to 24 years with HSIL, colposcopy is recommended. When CIN2+ is not identified histologically, observation for up to 24 months using both colposcopy and cytology at 6-month intervals is recommended, provided the colposcopic examination is adequate and endocervical assessment is negative or CIN1.

Atypical Glandular Cells, Adenocarcinoma In Situ, and Benign Glandular Changes

For women with AGC or AIS on Pap test, colposcopy with endocervical sampling is recommended regardless of HPV result. Endometrial sampling is recommended in conjunction with colposcopy and endocervical sampling in women 35 years of age and older with all subcategories of AGC and AIS. Endometrial sampling is also recommended for women younger than 35 years with risk factors for endometrial cancer (obesity, chronic anovulation, Lynch syndrome, or family history of endometrial and/or colorectal cancer). For women with atypical endometrial cells, initial evaluation limited to endometrial and endocervical sampling is preferred, with colposcopy acceptable either at the initial evaluation or deferred until the results of endometrial and endocervical sampling are known; if colposcopy is deferred and no endometrial pathology is identified, colposcopy is then recommended.

For women with AGC not otherwise specified cytology in whom CIN2+ is not identified, co-testing at 12 months and 24 months is recommended. If both co-tests are negative, return for repeat co-testing in 3 years is recommended.

For women with AGC “favor neoplasia” or AIS cytology, if invasive disease is not identified during the initial colposcopic workup, a diagnostic excisional procedure is recommended. It is recommended that the type of diagnostic excisional procedure used in this setting provide an intact specimen with interpretable margins. Endocervical sampling above the cone bed is recommended. The initial evaluation of AGC in pregnant women should be identical to that of nonpregnant women, except that endocervical curettage and endometrial biopsy are not performed.

For asymptomatic premenopausal women with Pap showing benign endometrial cells, endometrial stromal cells, or histiocytes, no further evaluation is recommended. For postmenopausal women with benign endometrial cells, endometrial biopsy is recommended.

Cervical Intraepithelial Neoplasia Grade 1

The recommended management of women with a histologic diagnosis of CIN1 preceded by an ASC-US, ASC-H, or LSIL cytology is follow-up with either HPV DNA testing every 12 months or repeat cervical cytology every 6 to 12 months. If the HPV DNA test is positive or if repeat cytology shows ASC-US or greater, colposcopy is recommended. If the HPV test is negative or two consecutive repeat cytology tests are negative, return to routine cytologic screening is recommended. If CIN1 persists for at least 2 years, either continued follow-up or treatment with excision or ablation can be performed. Hysterectomy as the primary and principal treatment for histologically diagnosed CIN1 is not recommended. For CIN1 preceded by HSIL or AGC not otherwise specified cytology, either a diagnostic excisional procedure or observation with colposcopy and cytology at 6-month intervals for 1 year is acceptable. If observation with cytology and colposcopy is elected, a diagnostic excisional procedure is recommended for women with repeat HSIL or AGC not otherwise specified cytologic results at either the 6- or 12-month visit. The recommended management of pregnant women with a histologic diagnosis of CIN1 is follow-up without treatment.

Cervical Intraepithelial Neoplasia Grades 2 and 3

Both excision and ablation are acceptable treatment modalities for women with a histologic diagnosis of CIN2/3 and satisfactory colposcopy. If the colposcopy is unsatisfactory or the lesion is large, excision should be performed with ablation not recommended.

For women <25 years of age with a histologic diagnosis of CIN2, either treatment or observation for up to 24 months using both colposcopy and cytology at 6-month intervals is acceptable, provided colposcopy is satisfactory. Treatment is recommended if CIN3 is subsequently identified or if CIN2/3 persists for 24 months.

In the absence of invasive disease, additional colposcopic and cytologic examinations are acceptable in pregnant women with a histologic diagnosis of CIN2/3 at intervals no more frequent than every 12 weeks. Repeat biopsy is recommended only if the appearance of the lesion worsens or if cytology suggests invasive cancer. Reevaluation with cytology and colposcopy is recommended 6 weeks postpartum.

Treatment of Adenocarcinoma In Situ

Hysterectomy is preferred for women who have completed childbearing and have a histologic diagnosis of AIS. Conservative management with cervical conization is acceptable if future fertility is desired. If the margins of the specimen are involved or endocervical sampling obtained above the cone bed contains CIN or AIS, reexcision to increase the likelihood of complete excision is recommended. Long-term follow-up is recommended for women who do not undergo hysterectomy.

Treatment of Invasive Cervical Carcinoma

Type of Treatment

Treatment of invasive cervical cancer depends on many factors, including disease stage, patient age, performance status, fertility of the patient, and skill and resources of the care providers. The treatment of cervical cancer is described by stage of disease in the following sections.

Hysterectomy Classification According to Piver et al

In 1974, Piver et al (³⁷) categorized hysterectomy into five classes according to the extent of tissue resection.

Class I

Simple hysterectomy is removal of the uterus along with the cervix in an extrafascial manner without incision into the cervical or uterine tissue.

Class II

Modified radical hysterectomy is removal of the uterus with part of the paracervical and parametrial tissue in the lateral aspect of the cervix after dissecting the ureters away. Half of the cardinal ligament (lateral aspect), the uterosacral ligament (posterior aspect), and one-third of the upper vagina are all removed. This is usually performed in cases of stage IA2 or persistent or local recurrent cervical cancer after radiation therapy.

Class III

Radical hysterectomy is removal of the uterus in a manner similar to that of class II hysterectomy, but the tissue structure is removed to a greater extent, generally close to the pelvic side wall laterally and sacrum posteriorly; the upper half of the vagina is also removed. Conventionally, this class of hysterectomy is done for cases of stage IB to IIA disease. However, it can be performed for persistent or recurrent cervical cancer after primary radiation therapy as an alternative procedure to exenteration in highly selected patients. These include patients with stage IB to IIA disease at primary diagnosis, no clinical parametrial involvement, and a tumor diameter of ≤4 cm at the time of recurrence.

Class IV

Extended radical hysterectomy is complete removal of the cervix, uterus, parametrial tissue, cardinal, and uterosacral ligaments. In addition, the ureter is completely dissected from the vesicouterine ligament, and the superior vesical artery is sacrificed. This is a possible procedure for central locoregional recurrence.

Class V

Partial exenteration is partial excision of the involved organs. In addition to the above procedures, this encompasses the removal of the distal ureter and urinary bladder. This procedure is performed in cases of central recurrence.

Hysterectomy Classification According to Cibula et al

A more recent classification has been introduced by Cibula et al (³⁸).

Type A: Minimum Resection of Paracervix

This resection is an extrafascial hysterectomy, in which the position of the ureters is determined by palpation or direct vision (after opening of the ureteral tunnels) without freeing the ureters from their beds. The paracervix is transected medial to the ureter but lateral to the cervix. The uterosacral and vesicouterine ligaments are not transected at a distance from the uterus. Vaginal resection is generally at a minimum, routinely less than 10 mm, without removal of the vaginal part of the paracervix (paracolpos).

Type B: Transection of Paracervix at the Ureter

Partial resection of the uterosacral and vesicouterine ligaments is a standard part of this category. The ureter is unroofed and rolled laterally, permitting transection of the paracervix at the level of the ureteral tunnel. The caudal (posterior, deep) neural component of the paracervix caudal to the deep uterine vein is not resected. At least 10 mm of the vagina from the cervix or tumor is resected.

Type C: Transection of Paracervix at Junction With Internal Iliac Vascular System

The Q–M classification system distinguishes between a type C1 procedure, which corresponds to the nerve-sparing modification, and the type C2 procedure, which aims for a complete parametrial resection. Type C1 requires separation of two parts of the dorsal parametria; the medial part, which entails rectouterine and rectovaginal ligaments, and the lateral laminar structure, also called mesoureter, which contains the hypogastric plexus. Furthermore, type C1 requires only a partial dissection of the ureter from the ventral parametria, which is usually asymmetric towards more extensive resection of the medial leaf of the cranial (above the ureter) part of the ventral parametria. In the C2 type, the ureter is completely dissected from the ventral parametria up to the urinary bladder wall. Defining the resection limits on the longitudinal (deep parametrial or vertical) plane is crucial for distinguishing between types C1 and C2.

Type D: Laterally Extended Resection

This type differs from type C2 only in the lateral extent of the lateral parametria resection. Ureteral dissection and resection of both dorsal and ventral parametria is identical to the type C2. Laterally, however, it requires ligation and removal of the internal iliac artery and vein, together with their branches, including the gluteal, internal pudendal, and obturator vessels.

Treatment by Stage of Disease

Stage IA1

Stage IA1 cervical cancer should be diagnosed using a conization specimen, because small tissue biopsy study may not be accurate enough to rule out other areas of a more extensive lesion. The treatment depends on the need for fertility preservation.

Conization

In a recent study, He et al (³⁹) evaluated the value of cold knife conization (CKC) as a conservative management in patients with microinvasive cervical SCC. A total of 108 patients with stage IA1 were enrolled. Eighty-three patients (76.9%) underwent further hysterectomy, out of which 48 (57.8%) underwent extrafascial hysterectomy, 30 (36.1%) underwent extensive hysterectomy, and 5 (6.1%) underwent radical hysterectomy. All patients were followed up for 1 year. The 18 patients with positive resection margins had greater likelihood of cervical residual lesions (CIN1-3) than the 65 patients with clear resection margins, but there were no significant differences (P = .917). Twenty-five patients who underwent CKC as final therapy were followed up for 1 year. Two patients with positive resection margins had a second CKC surgery; one patient was diagnosed with CIN1, and the other was diagnosed with cervicitis by pathology. Twenty-three patients had clear resection margins; two patients underwent a second CKC 3 months after the first CKC because of the abnormal ThinPrep Cytologic Test (TCT) result, and they were both diagnosed with microinvasive cervical SCC (stage IA1) by pathology with clear resection margins. No one enrolled in this study presented with metastasis or progression within 1 year of follow-up. This provided the clinical evidence for the possibility of fertility-sparing treatments, especially CKC, as conservative treatment for microinvasive cervical SCC.

Simple Hysterectomy

Simple hysterectomy may be performed in women with stage IA1 cervical cancer in whom preservation of fertility function is not required. However, in patients with LVSI, a modified radical hysterectomy may be the procedure of choice.

Stage IA2

The incidence of LNI in patients with this stage of cervical cancer is as high as 7% with a recurrence rate of 3% to 5%, and these patients should be treated with a radical hysterectomy with pelvic lymph node dissection. In women who want to conserve fertility, another approach that has been reported to have a successful outcome is radical trachelectomy with laparoscopic pelvic lymphadenectomy, in which the body of uterus is preserved for fertility function (⁴⁰). Individualization of therapy based on findings from extensive pathologic review of an adequate cone biopsy specimen is important for treatment planning.

Stage IB1

The standard surgical treatment for FIGO stage IB1 cervical cancer consists of a radical hysterectomy or trachelectomy and systematic pelvic lymphadenectomy.

Radical Hysterectomy

Traditionally, surgery for stage IB disease consists of radical hysterectomy performed in conjunction with pelvic lymphadenectomy. Lately, some have recommended class II hysterectomy rather than conventional class III hysterectomy in stages IB and IIA disease with a tumor size <2 cm due to fewer complications from the former and no difference in the 5-year survival (⁴¹) (Figs. 33-7 and 33-8).

Sentinel Lymph Node Mapping

The concept of the sentinel node (SN) was first clinically developed by Cabanas in association with penile carcinoma (⁴²). It is based on the principle that if the SN or the first node receiving drainage from tumor is negative, more extensive lymphadenectomy may be exempted to avoid the morbidity of the procedure.

Generally, the techniques used to map SNs involve identification of the lymphatic duct by injecting isosulfan blue dye or lymphoscintigraphy, using gamma probe detection of technetium 99m–labeled colloid, which is injected into the cervix. This can be done either before or during the operation. A number of studies of SN mapping for cervical cancer have been published; in these instances, the investigators used either blue dye, lymphoscintigraphy, or both with varying degrees of success. The introduction of indocyanine green (ICG) as another tool for SN mapping may be revolutionizing the field because it is now being used in patients undergoing minimally invasive surgery, both by the laparoscopic and robotics approach. Indocyanine green is a dye that fluoresces in the near-infrared (NIR) spectrum when illuminated with 806-nm light. When a laser emitted from the NIR imager excites ICG, it produces a wavelength that is converted to a fluorescent image. The emitted fluorescence is captured with a video camera device that allows for the ICG to be displayed in the visible light spectrum (⁴³).

Jewell et al (⁴⁴) assessed the detection rate of SNs using ICG in patients with uterine and cervical cancer. A total of 227 cases were performed. The median SN count was 3 (range, 1-23). An SN was identified in 216 cases (95%), with bilateral pelvic mapping in 179 cases (79%). The authors found that there was no difference in the detection rate when ICG alone was used versus the combination of both dyes (ICG and isosulfan blue). The authors concluded that combined use of ICG and blue dye appears unnecessary.

In the SENTICOL study by Lécuru et al (⁴⁵), the authors aimed to determine if bilateral negative SNs accurately predict absence of lymph node metastasis in early cervical cancer patients with stage IA1 disease with LVSI to stage IB1. One hundred forty-five patients were enrolled, and 139 were included in a modified intent-to-diagnose analysis. Intraoperative radioisotope-blue dye mapping detected at least one SN in 136 patients (97.8%; 95% CI, 93.8%-99.6%), 23 of whom had true-positive results and two of whom had false-negative results, yielding 92.0% sensitivity (23 of 25 patients; 95% CI, 74.0%-99.0%) and 98.2% negative predictive value (111 of 113 patients; 95% CI, 74.0%-99.0%) for node metastasis detection. No false-negative results were observed in the 104 patients (76.5%) in whom SNs were identified bilaterally. Therefore, the authors concluded that SN biopsy was fully reliable only when SNs were detected bilaterally.

Radical Trachelectomy

Radical trachelectomy (RT) is resection of the cervix together with paracervical and parametrial tissue, with retention of the corpus uteri. The procedure is indicated in reproductive-age women with disease stage IA1 (with LVSI), IA2, or IB1 (<2 cm) disease who wish to preserve fertility (⁴⁶).

Abu-Rustum and Sonoda (⁴⁰) analyzed a prospectively maintained database of all patients with FIGO stage IA1 to IB1 cervical cancer admitted to the operating room for planned fertility-sparing abdominal RT. Sentinel node mapping was performed through cervical injection. Between November 2001 and May 2010, 98 consecutive patients with FIGO stage IA1 to IB1 cervical cancer and a median age of 32 years (range, 6-45 years) underwent a fertility-sparing RT. The most common histology was adenocarcinoma in 54 patients (55%) and squamous carcinoma in 42 patients (43%). Lymphovascular invasion was seen in 38 patients (39%). The FIGO stages included IA1 (with lymphovascular invasion) in 10 patients (10%), IA2 in 9 patients (9%), and IB1 in 79 patients (81%). Only 15 patients (15%) needed immediate completion radical hysterectomy because of intraoperative findings. Median number of nodes evaluated was 22 (range, 3-54), and 16 patients (16%) had positive pelvic nodes on final pathology. Final trachelectomy pathology showed no residual disease in 44 patients (45%), dysplasia in 5 patients (5%), and AIS in 3 patients (3%). Overall, 27 patients (27%) needed hysterectomy or adjuvant pelvic radiation postoperatively. One documented recurrence (1%) was fatal at the time of this report. It was thus concluded that cervical adenocarcinoma and lymphovascular invasion are common features of patients selected for RT, and most patients can undergo the operation successfully, with approximately 65% having no residual invasive disease; however, nearly 27% of all selected cases will require hysterectomy or postoperative chemoradiation for oncologic reasons.

Diaz et al (⁴⁷) compared the oncologic outcomes of women who underwent a fertility-sparing RT to those who underwent a radical hysterectomy for stage IB1 cervical carcinoma. Forty stage IB1 patients underwent an RT, and 110 patients underwent a radical hysterectomy. There were no statistical differences between the two groups for the following prognostic variables: histology, median number of lymph nodes removed, node-positive rate, LVSI, or deep stromal invasion. The median follow-up time for the entire group was 44 months. The 5-year recurrence-free survival rate was 96% for the RT group compared with 86% for the radical hysterectomy group (P value not significant). On multivariate analysis in this group of stage IB1 lesions, tumor size <2 cm was not an independent predictor of outcome, but both LVSI and deep stromal invasion retained independent predictive value (P = .033 and P = .005, respectively). The authors concluded that for selected patients with stage IB1 cervical cancer, fertility-sparing RT appears to have a similar oncologic outcome to radical hysterectomy. Lymphovascular space invasion and deep stromal invasion appear to be more valuable predictors of outcome than tumor diameter in this subgroup of patients.

In 2013, Pareja et al (⁴⁸) published a systematic literature review of patients with early-stage cervical cancer who underwent abdominal RT. A total of 485 patients age 6 to 44 years were identified. The most common stage was IB1 (71%), and the most common histologic subtype was SCC (70%). Operative times ranged from 110 to 586 minutes. Blood loss ranged from 50 to 5568 mL. Forty-seven patients (10%) had conversion to radical hysterectomy. One hundred fifty-five patients (35%) had a postoperative complication. The most frequent postoperative complication was cervical stenosis (n = 42; 9.5%). The median follow-up time was 31.6 months (range, 1-124 months). Sixteen patients (3.8%) had disease recurrence. Two patients (0.4%) died of disease. A total of 413 patients (85%) were able to maintain their fertility. A total of 113 patients (38%) attempted to get pregnant, and 67 of these patients (59.3%) were able to conceive. Therefore, the authors concluded that abdominal RT is a safe treatment option in patients with early-stage cervical cancer interested in preserving fertility.

Conservative Treatment

The possibility of less radical surgery may be appropriate not only for patients desiring to preserve fertility but also for all patients with low-risk early-stage cervical cancer. Recently, a number of studies have explored less radical surgical options for early-stage cervical cancer, including simple hysterectomy, simple trachelectomy, and cervical conization with or without SN biopsy and pelvic lymph node dissection. Criteria that define this low-risk group include squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma, tumor size <2 cm, stromal invasion <10 mm, and no LVSI (⁴⁹).

The ConCerv study is one of the several prospective studies evaluating the role of conservative surgery in women with newly diagnosed, early-stage cervical cancer.

Retrospective data have shown that low-risk cervical cancer may not require radical hysterectomy because the risk for parametrial involvement is less than 1% in these patients. In this study, eligible women undergo CKC or simple hysterectomy and pelvic lymphadenectomy with SN based on their desire for future fertility. The primary outcome of this study is the safety and feasibility of a conservative approach (⁴⁹).

More recently, a Gynecologic Cancer Intergroup (GCIG) trial was led by the National Cancer Institute of Canada Clinical Trials Group, called the SHAPE trial. In this trial, patients with stage IA2 to IB1 cervical cancer with low-risk qualities (early-stage cervical cancer [IA2, IB1 <2 cm], limited stromal invasion <10 mm on loop electrosurgical excision procedure/cone biopsy, <50% stromal invasion on pelvic MRI) are randomized to either simple or radical hysterectomy. The study is currently ongoing and is aiming to accrue a total of 700 patients (⁵⁰).

Stage IB2-IVA

Concurrent Chemoradiation

In 1999, the US National Cancer Institute announced its support of concurrent cisplatin-based chemotherapy and radiation therapy in women who require radiation therapy for the management of cervical cancer. This was based on data from five randomized controlled trials that showed a significant benefit of concurrent chemoradiation either as postoperative adjuvant therapy in patients with high-risk factors or primary therapy in patients with locally advanced cervical cancer. All five trials sed concurrent cisplatin either alone or in combination with 5-fluorouracil (5-FU) or 5-FU and hydroxyurea. Peters et al (⁵¹) applied concurrent chemoradiation as postoperative adjuvant therapy in patients with risk factors found from radical hysterectomy in stage IA2 to IIA disease and indicated that it was superior to radiation therapy alone. Keys et al (⁵²) compared chemoradiation and radiation with adjuvant hysterectomy as the definitive treatment in patients with stage IB2 disease. Significant improvement of 3-year survival was found in the chemoradiation group (83% vs 74%). Pathologic examination of the hysterectomy specimens demonstrated a significant decrease in persistent disease with chemoradiation.

Three other studies comprised patients with more advanced disease (^53,54,55). The Radiation Therapy Oncology Group trial (RTOG) 9001 by Morris et al randomized stage IB-IVA patients to concurrent chemoradiation with cisplatin and 5-FU versus extended-field radiation (⁵³). Chemoradiation was superior, with an increase in overall survival of 73%, compared with 58% for radiation alone. Acute toxicity was more common with chemoradiation, but the rates of late complications (>60 days after treatment) were similar. A trial by Rose et al (⁵⁴) studied the optimal chemoradiation regimen by randomizing patients with stage IIB-IVA disease to receive radiation therapy concurrent with one of the following chemotherapy regimens: cisplatin alone; cisplatin, 5-FU, and hydroxyurea; or hydroxyurea alone. With a median follow-up time of 35 months, the results demonstrated superior survival rates for both concurrent cisplatin regimens (66% and 64%, respectively) compared with concurrent hydroxyurea alone (39%). The toxicity of treatment was least with the single-agent cisplatin regimen. Another Gynecologic Oncology Group trial in stage IIB to IVA cervical cancer by Whitney et al (⁵⁵) compared the efficacy of a chemotherapy regimen in the concurrent chemoradiation setting. The results showed superiority of cisplatin and 5-FU over hydroxyurea; survival rates at a median follow-up of 8.7 years were 55% and 43%, respectively. Leukopenia occurred less often in the group receiving cisplatin and 5-FU than in those receiving hydroxyurea.

A summary of these five trials is presented in Table 33-4.

Neoadjuvant Chemotherapy

A review by the Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer Meta-Analysis Collaboration group discovered seven randomized controlled trials available for analysis, comprising 872 patients (⁵⁶). The overall analysis and analysis of each individual trial showed significant improvement of all outcomes with neoadjuvant chemotherapy: hazard ratio of 0.65 for survival, with 14% absolute improvement in 5-year survival rate (50% to 64%); hazard ratio of 0.68 for disease-free survival, with 13% absolute improvement of disease-free survival (45% to 58%); and hazard ratio of 0.63 for metastasis-free survival, with 15% absolute improvement in metastasis-free survival (45% to 60%). However, many confounding factors were inherent and unavoidable in this systematic analysis: these factors were that a number of patients, ranging from 28% to 90% in each trial, also received postoperative adjuvant radiation therapy or triple-modality treatment compared with radiation therapy, the route of cisplatin administration differed (intra-arterial in one trial), and patients recruited to each trial had different stages of disease.

Eddy et al (⁵⁷) published a phase III trial from the Gynecologic Oncology Group to determine whether neoadjuvant chemotherapy (NACT) prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy (RHPPL) could improve progression-free survival and overall survival, as well as operability, with acceptable levels of toxicity. Two hundred eighty-eight eligible patients with bulky FIGO stage IB cervical cancer, tumor diameter ≥4 cm, adequate bone marrow, renal, and hepatic function, and performance status ≤2 were randomly allocated to RHPPL (n = 143) or NACT + RHPPL (n = 145). The NACT + RHPPL group had a similar recurrence rate (relative risk, 0.998) and death rate (relative risk, 1.008) compared with the RHPPL group. Seventy-nine percent of patients had surgery in the RHPPL group compared to 78% in the NACT + RHPPL group. Fifty-two percent of patients received postoperative RT in the RHPPL group compared to 45% in the NACT + RHPPL group (not statistically significant). The authors concluded that NACT offered no additional objective benefit to patients undergoing RHPPL for stage IB cervical cancer.

Another phase III trial was conducted by Katsumata et al (⁵⁸) to determine whether NACT before radical surgery improved overall survival. A total of 134 patients with stage IB2, IIA2, or IIB SCC of the uterine cervix were randomly assigned to receive either BOMP (bleomycin, vincristine, mitomycin, cisplatin) plus radical surgery (NACT group) or radical surgery alone (radical surgery group). Patients with pathologic high-risk factors received postoperative radiotherapy. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the radical surgery group. The 5-year overall survival was 70.0% in the NACT group and 74.4% in the radical surgery group (P = .85). Hence, it was concluded that NACT with BOMP regimen before radical surgery did not improve overall survival but reduced the number of patients who received postoperative radiotherapy.

Stage IVB

In patients with stage IVB cervical cancer, which implies systemic disease, treatment is palliative rather than curative. Radiation therapy has a role for local primary disease to alleviate symptoms such as bleeding and pain. In patients who have distant metastasis, symptoms such as bone pain can be relieved with high-dose radiation. Chemotherapy is also an option for patients with stage IVB disease, but the response is modest because of factors like poor vascular supply and bone marrow reserve.

The recommended surveillance is based on patients’ risk for recurrence and personal preferences. History and physical examination are recommended every 3 to 6 months for 2 years, every 6 to 12 months for another 3 to 5 years, and then annually. Patients with high-risk disease can be assessed more frequently (eg, every 3 months for the first 2 years). Annual cervical/vaginal cytology tests can be considered as indicated for detection of lower genital tract dysplasia. Patient education regarding symptoms suggestive of recurrence is recommended (eg, vaginal discharge; weight loss; anorexia; pain in the pelvis, hips, back, or legs; persistent coughing). Patients who have received RT for cervical cancer may experience vaginal stenosis and dryness and should receive education on important issues regarding sexual health and vaginal health. Cervical cancer survivors are at risk for second cancers; therefore, careful surveillance is appropriate for these patients (⁵⁹).

It is generally accepted that any lesions detected within 6 months after treatment should be considered persistent. The diagnosis of recurrence is usually made after 6 months. If a lesion is noted within 3 months after radiation therapy, no treatment is recommended due to the ongoing effects of irradiation at this time period.

Choosing the type of therapy for recurrent cervical cancer depends on many factors, including site of recurrence, previous therapy, and performance status of the patients.

Locoregional

Concurrent platinum-based chemotherapy reduces the risk of pelvic recurrence by approximately 50% and extends overall survival by an absolute 5% to 20% compared to radiation therapy alone; this includes tumor-directed radiation therapy and platinum-based chemotherapy with (or without) brachytherapy; surgical resection can be considered if feasible. Typically, the chemoradiation for recurrence uses cisplatin as a single agent or cisplatin plus 5-FU. Patients with central pelvic recurrent disease after radiotherapy should be evaluated for pelvic exenteration, with (or without) intraoperative radiotherapy. Surgical mortality is generally 5% or less, with survival rates approaching 50% in carefully selected patients. Although exenteration is the common surgical approach in postradiation patients with isolated central pelvic relapse, radical hysterectomy or brachytherapy may be an option in patients with small central lesions (<2 cm) (⁵⁹).

Westin et al (⁶⁰) conducted a study to determine the impact of clinical and pathologic factors on 5-year survival after pelvic exenteration for gynecologic malignancies. A total of 160 women who underwent pelvic exenteration were evaluated. Five-year recurrence-free survival was 33% (95% CI, 0.25-0.40). Factors that negatively impacted recurrence-free survival included shorter treatment-free interval (P = .050), vulvar primary (P = .032), positive margins (P < .001), LVSI (P < .001), positive lymph nodes (P < .001), and perineural invasion (P = .030). Factors that negatively impacted overall survival included vulvar primary (P =.04), positive margins (P < .001), LVSI (P < .001), positive lymph nodes (P < .001), and perineural invasion (P = .008). Hence, it was concluded that the 5-year overall survival after pelvic exenteration was 40%.

Distant

Distant recurrence with or without associated locoregional lesions denotes systemic disease and carries a poor prognosis and minimal chance of a cure. Monk et al (⁶¹) published the phase III trial from the Gynecologic Oncology Group evaluating the toxicity and efficacy of cisplatin doublet combinations in advanced and recurrent cervical carcinoma. Patients were randomly assigned to paclitaxel 135 mg/m² over 24 hours plus cisplatin 50 mg/m² on day 2 every 3 weeks (PC, reference arm); vinorelbine 30 mg/m² on days 1 and 8 plus cisplatin 50 mg/m² on day 1 every 3 weeks (VC); gemcitabine 1,000 mg/m² on days 1 and 8 plus cisplatin 50 mg/m² on day 1 every 3 weeks (GC); or topotecan 0.75 mg/m² on days 1, 2, and 3 plus cisplatin 50 mg/m² on day 1 every 3 weeks (TC). Survival was the primary end point, with a 33% improvement relative to PC considered important (85% power, α = 5%). Quality-of-life data were prospectively collected. A total of 513 patients were enrolled when a planned interim analysis recommended early closure for futility. The experimental-to-PC hazard ratios of death were 1.15 (95% CI, 0.79-1.67) for VC, 1.32 (95% CI, 0.91-1.92) for GC, and 1.26 (95% CI, 0.86-1.82) for TC. The hazard ratios for progression-free survival were 1.36 (95% CI, 0.97-1.90) for VC, 1.39 (95% CI, 0.99-1.96) for GC, and 1.27 (95% CI, 0.90-1.78) for TC. Response rates for PC, VC, GC, and TC were 29.1%, 25.9%, 22.3%, and 23.4%, respectively. The arms were comparable with respect to toxicity except for leukopenia, neutropenia, infection, and alopecia. The authors concluded that none of the regimens studied was superior to PC in terms of overall survival. However, the trends in response rate, progression-free survival, and overall survival favored PC.

Until recently, no chemotherapy combination or single agent had shown a survival advantage in phase III trials. Tewari et al (⁶²) evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. A total of 452 patients were randomly assigned to chemotherapy with or without bevacizumab at a dose of 15 mg/kg of body weight. Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. The addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 vs 13.3 months; hazard ratio for death, 0.71; 98% CI, 0.54-0.95; P = .004 in a one-sided test) and higher response rates (48% vs 36%, P = .008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs 2%), thromboembolic events of grade 3 or higher (8% vs 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs 0%). Therefore, it was concluded that the addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival.