Cervical Cancer

Overview

The incidence of cervical cancer in the United States has significantly declined over the years as a result of the development of effective screening methods.

Nevertheless, in 2015 it is estimated that cervical cancer will be diagnosed in 12,900 women in the United States, and approximately 4,100 women will die of the disease. Currently, an estimated 249,496 women are living with cervical cancer in the United States.

Epidemiology

Age

The peak age of developing cervical cancer is 47 years. Approximately 47% of women with invasive cervical cancer are younger than 35 years of age at diagnosis. Older women (> 65 years) account for another 10% of patients with cervical cancer. Although these older patients represent only 10% of all cases, they are more likely to die of the disease because of their more advanced stage at diagnosis.

Socioeconomic Class

Carcinoma of the uterine cervix worldwide affects women from lower socioeconomic classes and those with poor access to routine medical care.

Geography

Although invasive cervical carcinoma is relatively uncommon in the United States compared with the more common cancers in women (breast, endometrial, and ovarian cancers), it is the second most common malignancy in women worldwide, accounting for 15% of all new cancers in females. Worldwide, there are an estimated 500,000 new cases of, and 240,000 deaths from, cervical cancer every year. It remains a significant health burden in developing countries, where more than 80% of women with cervical cancer receive the diagnosis at advanced stages. This is due, in part, to poor access to medical care and the lack of available routine screening in many of these countries.

Etiology and Risk Factors

Sexual Activity

Human papillomavirus

Molecular and epidemiologic evidence clearly indicates that certain types of human papillomavirus (HPV), which are sexually transmitted, are the principal causes of invasive cervical cancer and cervical intraepithelial neoplasia (CIN). More than 100 HPV types have been identified, and about 40 infect the genital tract. HPV-16 and HPV-18 are the types most commonly linked with cancer and are present in 70% of cervical cancers and high-grade CINs. Two vaccines to prevent cervical cancer were approved by the US Food and Drug Administration (FDA) and became available in 2006 and 2009, respectively.

Gardasil is a quadrivalent vaccine approved by the FDA in 2006 for prophylactic vaccination in girls and women aged 9 to 26 years. The vaccine is composed of the major capsid protein of HPV, which is the product of the L1 gene of HPV. The capsid protein assembles itself into virus-like particles, or VLPs. VLPs lack viral DNA and are therefore unable to induce cancer, but they are able to trigger an antibody response against the HPV types represented in the vaccine. Gardasil contains the recombinant VLPs assembled from the L1 proteins of HPV types 16 and 18, which cause approximately 70% of cervical cancers, as well as types 6 and 11, which cause more than 90% of genital wart cases. Cervarix is a bivalent vaccine also approved by the FDA to prevent cervical dysplasia and cervical cancer caused by HPV types 16 and 18. Prophylactic vaccination with these HPV VLP vaccines against HPV-16 and HPV-18 has transformed the prospects for reducing the incidence of this disease on a global scale, achieving more than 98% protection in randomized clinical trials against precursor lesions such as CIN grade 2/3 and adenocarcinoma in situ. Regrettably, according to a recent report of the National Health Interview Survey (2010 data), only 22.7% of eligible women received one or more doses and only 12.7% received the three required doses. Education, access, and cost were the main deterrents. Screening for cervical cancer will have to continue, because only 2 of the 15 oncogenic HPV types are in the vaccines, and for 2 to 3 decades at least, unvaccinated sexually active women will remain at risk for the disease. If both vaccination and screening are combined, the virtual elimination of cervical cancer and the other HPV-16– and HPV-18–associated cancers is possible. A novel nonavalent vaccine that covers five additional subtypes of HPV (31, 33, 45, 52, and 58) in addition to 6, 11, 16, and 18, has completed phase III testing and received FDA approval in December 2014 for use in females 9 through 26 years of age and males 9 through 15 years old.

Age of onset of sexual activity

Population studies of women with invasive cervical carcinoma have demonstrated that early age of onset of sexual activity also plays a role in the later development of the cancer. It is postulated that during the time of menarche in early reproductive life, the transformation zone of the cervix is more susceptible to oncogenic agents, such as HPV. Women who began sexual activity before 16 years of age or who are sexually active within 1 year of beginning menses are at particularly high risk for developing invasive cervical carcinoma.

Other risk factors

These risk factors include malnutrition (micronutrient deficiency), multiple sexual partners, a history of genital warts, and multiparity.

Cigarette Smoking

Cigarette smoking has been identified as a significant risk factor for cervical carcinoma. It is thought to increase the risk by twofold to fivefold. The mechanism may be related to diminished immune function secondary to a systemic effect of cigarette smoke and its by-products or a local effect of tobacco-specific carcinogens. Nicotine, when inhaled, becomes converted to cotinine, which becomes deposited in the cervix and adversely affects the function of cells of Langerhans, which are primarily involved in cell-mediated immunity.

Oral Contraceptives

Oral contraceptives may also play a role in the development of invasive cervical carcinoma. It can be postulated that most women who use oral contraceptives are more sexually active than women who do not, and this may represent a confounding factor rather than a true independent risk factor. However, estrogen and high parity maintains the transformation zone on the ectocervix, thus increasing exposure to the harsh acidic environment of the vagina and HPV. In addition, oral contraceptives also enhance HPV gene expression in the cervix, which can promote viral DNA integration into the host chromosome.

Immune System Alterations

In recent years, alterations in the immune system have been associated with an increased risk of invasive cervical carcinoma, as exemplified by the fact that patients who are infected with the human immunodeficiency virus (HIV) have increased rates of both preinvasive and invasive cervical carcinomas. These patients also are at risk for other types of carcinoma, including Kaposi sarcoma, lymphomas, and other squamous cell carcinomas of the head and neck and the anogenital region. (For further discussion see the “AIDS-Related Malignancies” chapter.)

Data suggest that patients who are immunocompromised as a result of immunosuppressive medications also are at risk for both preinvasive and invasive cervical carcinomas. This association is probably due to the suppression of the normal immune response to HPV, which makes patients more susceptible to malignant transformation. An exciting recent development in the prevention of carcinoma of the cervix is the increasing use of HPV vaccines; if used on a timely basis in young women (ideally before they are exposed to the HPV virus), they can decrease this infection and eventually the incidence of cervical cancer.

Signs and Symptoms

A symptom of advanced cervical carcinoma is intermenstrual bleeding in a premenopausal patient. Other commonly reported symptoms include heavier menstrual flow, menorrhagia, and/or postcoital bleeding. With effective screening, early cervical cancer is generally asymptomatic.

Less frequently, patients with advanced cancer will present with signs of advanced disease, such as back pain, bowel obstruction, and renal failure due to urinary tract obstruction. Only rarely are asymptomatic patients with a normal screening Pap smear found to have a lesion on the cervix as their only sign or symptom of cervical cancer. Foul-smelling vaginal discharge, pelvic pain, or both are occasionally observed.

Screening and Diagnosis

Screening

Pap smear

The paradigm for a cost-effective, easy-to-use, reliable screening test is the cervical cytology screen, or Pap smear. In the United States, the introduction of the Pap smear resulted in a 70% reduction in the incidence of invasive cervical carcinoma between 1955 and the mid-1980s, as well as a shift toward earlier stages at the time of diagnosis. Detection of atypical cells and cervical cancer and its precursor lesions was further improved by the introduction of liquid-based cytologic screening. ThinPrep and SurePath are two currently commercially available liquid-based techniques. Studies have demonstrated that liquid-based cytologic screening has an increased sensitivity in detecting high-grade lesions, a decreased false-negative rate, and a decreased incidence of inadequate samples compared with the conventional Pap test. The ThinPrep Pap Test was also given FDA approval for detection of glandular lesions and adenocarcinoma after studies demonstrated an improved sensitivity in detecting these lesions. The success of cervical cytology, as measured by the lowered incidence of cervical cancer, ironically has led to some controversy regarding the most effective application of this screening tool. With the marked reduction in the incidence of cervical carcinoma, more patients are screened and greater costs incurred to detect each additional case of cervical carcinoma. In a recent report of 176,464 women aged 20 to 64 years randomly assigned to HPV-based (experimental arm) or cytology-based (control arm) screening in Sweden (Swedescreen), the Netherlands (POBASCAM), England (ARTISTIC), and Italy (NTCC) with a median follow-up of 6.5years (1,214,415 person-years), 107 invasive cervical carcinomas were identified. It was found that HPV-based screening provides 60% to 70% greater protection against invasive cervical carcinomas compared with cytology-based screening. Data from large-scale randomized trials support initiation of HPV-based screening from age 30 years and extension of screening intervals to at least 5 years.

HPV DNA testing

The devleopment of molecular-based HPV DNA testing has enhanced cervical cancer screening by identifying women at risk for developing preinvasive cervical lesions and subsequent invasive cancer, thus compensating for the false-negative rates with Pap tests that occur with sampling and detection errors. HPV DNA testing has been shown to have greater sensitivity in detecting preinvasive high-grade cervical lesions. The persistence of high-risk HPV infection contributes to the development of CIN as well as the progression from CIN to cervical cancer. Currently FDA-approved HPV tests include Digene Hybrid Capture 2 (HC2), Cervista HPV HR, Cervista HPV 16/18, cobas HPV test, and the Aptima HPV assay. Recommended screening guidelines still advocate for co-testing with cytology and HPV DNA assays. However, several randomized trials have recently shown high-risk HPV DNA testing to be at least as effective as cytology for screening. In April 2014, the FDA approved the first HPV DNA test for use as a primary screening method for women 25 years of age and older.

Current screening recommendations

The American College of Obstetricians and Gynecologists recently changed its recommendations to start cervical cancer screening for women at the age of 21 regardless of the age of onset of sexual intercourse. For women between the ages of 21 and 29 years, cervical cytology screening is recommended every 3 years with either conventional or liquid-based cytology. Women aged 30 and older should have a Pap smear with HPV DNA testing every 5 years (preferred) or a Pap smear alone every 3 years. Screening can be discontinued in women older than 65 years who have had three or more negative cytology test results in a row and who have had no abnormal test results in the past 10 years. If screening is discontinued, risk factors should be assessed annually to determine whether reinitiating screening is appropriate. Routine cytologic testing should be discontinued in women who have had a total hysterectomy for benign indications and have no prior history of high-grade CIN. Adjunct HPV testing should not be performed in females younger than 21 years and should not influence management if the test was inadvertently performed. HPV DNA testing should only be used as a triage test to stratify risk to women 21 years and older with a cytology diagnosis of atypical squamous cells of undetermined significance (ASC-US) and postmenopausal women with a cytology diagnosis of low-grade squamous intraepithelial lesion (LSIL). It may be used as an adjunct to cytology for primary screening in women older than 30 years and as a follow-up test after CIN 1 or negative findings on colposcopy in women whose prior cytology diagnosis was ASC-US, ASC-H (atypical squamous cells, cannot rule out high-grade lesion), LSIL, or atypical glandular cells, and in follow-up after treatment for CIN 2 and CIN 3.

In March 2012, the American Cancer Society (ACS) and United States Preventive Services Task Force (USPSTF) also released new cervical screening guidelines that recommended against yearly screening. The ACS now recommends that all women start cervical cancer screening at 21 years of age. Women aged 21 to 29 should be screened with conventional cervical cytology smears using liquid-based cytology every 3 years. HPV DNA testing should not be performed in this age group unless necessary after an abnormal Pap smear. Women aged 30 to 65 should have a Pap smear and HPV testing every 5 years, although testing every 3 years with a Pap smear alone is also acceptable. Women older than 65 years who have had regular screening and normal results should no longer be screened for cervical cancer, while women who have had a diagnosis of cervical cancer or precancerous lesions should continue to be screened. Women who have had a complete hysterectomy (removal of uterus and cervix) and have no history of cervical cancer or precancer should not be screened. Women who received the HPV vaccine should still follow the screening recommendations for their age group. Women who are at high risk for cervical cancer (ie, those with HIV infection, those who have had an organ transplant, or those who were exposed to the drug diethylstilbestrol) may need to be screened more often. The USPSTF recommendation statement can be accessed at their website.

Diagnosis

The diagnosis of invasive cervical carcinoma can be suggested by either an abnormal Pap smear or an abnormal physical finding.

Colposcopy

In the patient who has an abnormal Pap smear but normal physical findings, colposcopy is indicated. Colposcopic findings consistent with invasive cervical carcinoma include dense white epithelium covering the ectocervix; punctation; mosaicism; and especially, an atypical blood vessel pattern.

Biopsy

If the colposcopic findings are suggestive of invasion, biopsies are obtained from the ectocervix and endocervix. If these biopsies demonstrate only precancerous changes but not an invasive carcinoma, the patient should undergo an excisional biopsy of the cervix. In most current clinical settings, the loop electrosurgical excision procedure is the most expedient method for performing an excisional biopsy. This can be easily accomplished in the office with the patient under local anesthesia and provides adequate tissue for diagnosis. Once the diagnosis of either microinvasive or invasive carcinoma has been established, the patient can be triaged accordingly.

Patient with signs/symptoms of advanced disease

The patient with signs/symptoms of advanced invasive cervical carcinoma requires a cervical biopsy for diagnosis and treatment planning. In this setting, a Pap smear is superfluous and may be misleading.

Pathology

Squamous Cell Carcinoma

The most common histology associated with invasive cervical carcinoma is squamous cell carcinoma, which accounts for approximately 80% of all carcinomas of the uterine cervix. For the most part, the decline in the annual incidence of invasive cervical carcinoma has been seen primarily among patients with this subtype.

Adenocarcinoma

In the past, adenocarcinoma was relatively uncommon as a primary histology of cervical cancer. As a result of the decrease in the overall incidence of invasive squamous cell cancer and, probably, an increase in the baseline incidence of adenocarcinoma of the uterine cervix, this histology now accounts for approximately 20% of all cervical cancers.

There is controversy over whether patients with adenocarcinoma of the cervix have a worse prognosis than those with the more common squamous cell histology. The poorer prognosis associated with adenocarcinoma may be due to the relatively higher frequency of late-stage disease at the time of diagnosis among patients with this histologic type. In several series in which patients were stratified by stage and tumor size, the outcome of cervical adenocarcinoma appeared to be similar to that of squamous lesions of the cervix.

Among the various subtypes of adenocarcinoma, certain types are particularly aggressive and are associated with a poor prognosis. Among them are the small-cell, or neuroendocrine, tumors, which have a poor prognosis even when diagnosed at an early stage.

Rare Tumor Types

More rare lesions of the cervix include lymphoma, sarcoma, and melanoma. These histologic subtypes account for less than 1% of all cervical cancers.

Staging and Prognosis

Clinical Staging

Suspected early disease

When a diagnosis of invasive cervical cancer has been established histologically, an evaluation of all pelvic organs should be performed to determine whether the tumor is confined to the cervix or has extended to the adjacent vagina, parametrium, endometrial cavity, bladder, ureters, or rectum. According to the International Federation of Gynecology and Obstetrics (FIGO) guidelines for clinical staging (Table 1), diagnostic studies may include intravenous urography; cystoscopic examination of the bladder and urethra; a proctosigmoidoscopic study; a barium enema; and in the case of early-stage disease, a colposcopic study of the vagina and the vaginal fornices. Colposcopic findings may be used for assigning a stage to the tumor (eg, FIGO stage IIA), but the results must be confirmed by biopsy.

A pelvic examination must be performed as part of the staging process, and the procedure is best done with the patient completely relaxed by general anesthesia. In up to 20% of patients, the initial clinical classification of the disease has proved to be incorrect at the time of pelvic examination. Such an examination can reveal a more advanced stage of the disease than was originally found; additional biopsies (if indicated) or fractional curettage can be performed as well as colposcopy, cystoscopy, and proctosigmoidoscopy.

TABLE 1

AJCC and FIGO staging for carcinoma of the uterine cervix

Suspected advanced disease

When studies detect ureteral obstruction, a tumor is classified as a stage IIIB lesion, regardless of the size of the primary lesion. Ureteral obstruction, either hydronephrosis or nonfunction of the kidneys, is well established as an indicator of poor prognosis, as recognized in the FIGO classification.

In women with bulky or advanced-stage tumors, the bladder mucosa also should be inspected cystoscopically for possible bullous edema, which indicates lymphatic obstruction within the bladder wall. Evidence of tumor in the bladder must be confirmed by biopsy before the lesion can be classified as stage IVA. Rectal mucosal lesions also require a biopsy via proctosigmoidoscopy, because they can be related to an inflammatory process rather than to the cervical tumor.

Surgical experience from pelvic lymphadenectomy has confirmed an error rate of 15% to 25% in the clinical staging of patients with stage IB or II lesions. In 10% to 30% of cases involving stage II/III tumors, in addition to positive findings of occult pelvic lymph nodes, other metastases may be found in the para-aortic nodes. Unfortunately, pelvic examinations and clinical staging as defined by FIGO cannot detect such metastases.

Consequently, there is a growing body of literature that shows the superiority of cross-sectional imaging (computed tomography [CT] and magnetic resonance imaging [MRI]) over clinical staging in delineating the extent of disease in patients with cervical cancer. As stated previously, official FIGO guidelines do not incorporate the use of either CT or MRI findings into the staging of cervical cancer. However, as knowledge of prognostic factors and the value of cross-sectional imaging has accumulated, its use in treatment planning has increased without changing the official FIGO clinical staging guidelines. Similarly, although the benefits of laparoscopic extraperitoneal surgical staging have also been reported in this setting, this approach has not been incorporated into the FIGO staging system.

In a study by Tsai et al, 129 patients with cervical cancer at stages IB to IV who had pretreatment MRI were randomized to an FDG-PET (18F-fluorodeoxyglucose positron emission tomography) scan (n = 66) or to no additional study (n = 63). Seven patients (11%) were found to have extrapelvic metastasis on PET scans (six para-aortic nodes and one omental). The 4-year overall survival was 79% and 85%, respectively (P = .65), and the disease-free survival was 75% and 77%, respectively (P = .64).

The value of CT scanning in the pretreatment evaluation of patients with cervical cancer is in the assessment of advanced disease (stage IIB and greater) and in the detection and biopsy of suspected lymph node metastasis. The treatment plan for patients with locally advanced disease must be modified if upper abdominal tumor masses and/or distant metastasis is discovered. The soft tissue contrast resolution of CT scanning does not allow for consistent tumor visualization at the primary cervical site and, therefore, neither tumor size nor early parametrial invasion can be evaluated reliably. However, T2-weighted MRI allows consistent tumor visualization and has been reported to be more than 90% accurate in determining tumor size to within 5 mm of measurements of surgical specimens. Nevertheless, a study by the American College of Radiology Imaging Network in 208 patients with invasive cervical cancer evaluated with CT or MRI before radical hysterectomy showed that MRI was superior to CT and clinical examination in evaluating uterine body involvement and in measuring tumor size, but neither method was accurate in evaluating the cervical stromal depth of tumor invasion.

Recent reports show the value of PET in the pretreatment evaluation, treatment planning, and post-therapy assessment of response in patients with higher-risk invasive carcinoma of the cervix. In a series of 120 patients with newly diagnosed cervical cancer, FIGO stage higher than IB, PET/CT scanning demonstrated a 94% positive predictive value (PPV) and 100% negative predictive value (NPV) in detecting positive para-aortic lymph nodes. There was 100% sensitivity and 99% specificity. When scanning for the presence of distant metastasis, PET/CT scanning had a 63% PPV and 100% NPV, with 100% sensitivity and 94% specificity. In a prospective study of 103 patients who were successfully treated initially with concurrent chemotherapy and radiation therapy, surveillance FDG-PET detected asymptomatic recurrent disease earlier, which may be potentially amenable to salvage therapy.

It is noteworthy that, in 60 patients with stages IA2–IIA cervical cancer up to 4 cm with MRI-negative nodes, preoperative FDG-PET scanning detected 1 para-aortic node metastasis but only 1 of 10 pelvic node metastases, which led to the conclusion that PET scanning is of little value in evaluating patients with stages IA2–IIA cervical cancer up to 4 cm. A second study showed that 3 of 38 patients with no para-aortic uptake on FDG-PET/CT imaging had histologically proven para-aortic node involvement.

Surgical Staging

Clinical staging of cervical carcinoma, although widely used, is not without controversy. When compared with surgical staging performed by large cooperative groups, clinical staging is frequently inaccurate in predicting locoregional tumor spread. For many cooperative groups, including the Gynecologic Oncology Group (GOG), surgical staging may be required for patients who are entering prospective randomized clinical protocols.

The most common method used to stage patients with advanced disease is extraperitoneal sampling of the pelvic and para-aortic lymph nodes. This approach minimizes the risk of subsequent radiation injury to the small bowel due to surgical adhesions and, in patients with advanced disease, allows for individualized treatment planning. Another approach is sentinel lymph node detection in the pelvis, which is still an active area of research.

Pros and cons of surgical staging

The advantage of surgical staging is that patients with microscopic disease in the para-aortic lymph nodes can be treated with extended-field radiation therapy (EFRT) and, possibly, chemotherapy, and potentially benefit in terms of long-term survival. The controversy regarding surgical staging stems from the fact that a small number of patients will actually benefit from the procedure; the majority of patients who undergo it will be found not to have metastatic disease and will receive the same treatment as planned before surgical staging; if they are found to have metastatic disease, they will be unlikely to benefit from EFRT. Because of this controversy, the GOG considers surgical staging to be optional for patients with advanced-stage cervical cancer.

Workup for advanced disease

The standard workup of a patient with advanced cervical carcinoma who is not considered a candidate for radical surgery includes an abdominopelvic CT scan with both intravenous and gastrointestinal oral contrast. If there is evidence of para-aortic lymph node metastases, the patient should undergo fine-needle aspiration (FNA) of these enlarged lymph nodes. If FNA confirms that there is para-aortic lymph node metastasis, treatment should be individualized, and EFRT should be considered part of the primary treatment regimen.

If the scalene lymph nodes are negative on clinical examination and the patient is known to have positive metastatic disease to the para-aortic lymph nodes, consideration can be given to performing a scalene lymph node biopsy; the incidence of positive scalene nodes when para-aortic lymph nodes are known to be positive ranges from 0% to 17%. The rationale for doing a biopsy of the scalene nodes is that if there is disease outside the radiation therapy field, chemotherapy may be appropriate.

If the result of FNA is negative, or if the abdominopelvic CT scan does not demonstrate enlarged para-aortic lymph nodes, the patient can be considered for surgical staging.

An American Society of Clinical Oncology (ASCO) 2007 report compared the accuracy of PET vs PET/CT for detecting lymph node metastasis in cervical cancer. In a series of 86 patients with stages IB–IVA cervical cancer, a total of 688 lymph node regions were evaluated. PET/CT was more sensitive than PET for detecting small (< 5 mm) lymph node metastases. Meta-analyses performed by Choi et al showed that PET or PET/CT had an overall higher diagnostic performance (82% sensitivity and 95% specificity) in detecting metastatic lymph nodes in patients with cervical cancer than CT (50% sensitivity and 92% specificity) and MRI (56% sensitivity and 91% specificity).

Laparoscopic surgery

The introduction of minimal-access surgery has allowed surgeons to accurately stage patients via the laparoscope before initiation of radiation therapy. Laparoscopic para-aortic lymph node dissection has been shown to be feasible in gynecologic malignancies and has been proposed as a diagnostic tool for determining the presence of lymph node metastasis. More recently, robotic surgery has also been used in surgical staging before radiation treatment. However, the safety and efficacy of both laparoscopic and robotic surgical staging are areas of ongoing investigation.

Workup for early-stage disease

For patients who have early-stage disease for which surgery is contemplated, only a minimal diagnostic workup is indicated before surgery. At most institutions, this would include two-view chest radiographs. Patients who have stage IA cervical carcinoma (microinvasive carcinoma) do not require preoperative CT scanning before hysterectomy. For patients with a small stage IB carcinoma of the cervix, a CT scan of the abdomen and pelvis has a low yield and is unlikely to change the treatment plan.

Prognostic Factors

Clinical stage

The most important determinant of prognosis remains clinical stage, which is defined by tumor volume and extent of disease spread. The overall 5-year survival rate ranges from 95% to 100% for patients with stage IA cancer and from 75% to 90% for those with stage IB disease. Patients with stage IV disease have a 5% or less chance of surviving 5 years after diagnosis.

Patients with early disease

For patients with early invasive carcinoma (stage IB), the size of the lesion, percentage of cervical stromal invasion, histology, tumor grade, and lymphovascular space involvement are important local factors that predict prognosis. In general, good prognostic signs are lesions that are 2 cm or less in diameter, superficially invasive, and well-differentiated with no lymphovascular space involvement. In a study of 1,067 patients treated with surgery, HPV-16 was detected in 63.8% and HPV-18, in 16.5% of samples. With a median follow-up of 77 months, HPV was not found to be a significant prognostic factor.

For patients who have undergone radical trachelectomy or hysterectomy for early cervical carcinoma, poor prognostic factors, in addition to the local factors previously mentioned, include positive vaginal or parametrial margins and metastasis to the pelvic lymph nodes. For patients with stage IB disease and positive pelvic nodes, the 5-year survival rate drops from approximately 75% to 85%, to 50%.

Patients with advanced disease

For patients with advanced-stage disease (stages IIB–IV), the primary determinants of prognosis are histology and size of the primary lesion. Survival is significantly longer for patients with small stage IIB cervical carcinomas and minimal parametrial involvement than for patients with large bulky tumors and bilateral parametrial involvement. Disease extension beyond the pelvis to the para-aortic nodes is associated with a significant decrease in overall survival rate. With regard to histology, a better prognosis is associated with a large-cell nonkeratinizing squamous cell cancer of the cervix, as opposed to a poorly differentiated adenocarcinoma. In patients with stage IIIB cervical cancer restricted to the pelvis, it was shown that the presence of hydronephrosis at presentation is a significant prognostic factor associated with a poor performance status and a worse survival. To better estimate prognosis in locally advanced cervical cancer limited to the pelvis, a nomogram was recently developed using the GOG database. Estimates of 2-year progression-free survival, 5-year overall survival, and pelvic recurrence rates can be determined via prognostic factors: race/ethnicity, performance status, tumor size, FIGO stage, tumor grade, pelvic node status, and treatment with concurrent cisplatin-based chemotherapy.

Other prognostic factors

Other factors that may predict outcome include the patient’s general medical and nutritional status. Whether anemia is related to response to radiation therapy has been debated. Patients with significant alterations in their immune system may not respond as well; this result is becoming increasingly apparent with regard to patients who are HIV-seropositive.

A retrospective review (Grogan et al: Cancer 1999) of 605 patients from seven institutions in Canada treated with irradiation for cervical cancer described average weekly nadir hemoglobin levels as significant prognostic factors for survival, second only in importance to tumor stage. Interestingly, Winter et al reported that hemoglobin levels during treatment were independent predictors of treatment outcome through a retrospective study of 494 patients from two consecutive prospective GOG trials. The pretreatment level was not a significant predictor of outcome in the multivariate regression model. Hemoglobin levels in the last part of treatment were the most predictive of disease recurrence and survival. However, erythropoietin should not be given outside a clinical trial, because thrombosis is a significant complication and cause/effect has not been proved. Most recently, a review of patients treated at The University of Texas MD Anderson Cancer Center showed hemoglobin levels had no impact on outcome.

PET scanning is being used to determine response and outcome after therapy. In 152 patients with cervical cancer treated with irradiation alone or in combination with chemotherapy, Grigsby et al reported cause-specific survival of 80% in 114 patients without post-therapy PET abnormalities, 32% in 20 patients with persistent abnormal scans, and no survivors in 18 patients who developed new sites of abnormal uptake.

Treatment

Surgical Treatment of Early-Stage Disease

The standard management of patients with early cervical carcinoma is surgical removal of the cervix. The extent of resection of surrounding tissue depends on the size of the lesion and the depth of tumor invasion.

Stage IA1 disease

Simple hysterectomy. Patients who have a microinvasive squamous cell carcinoma of the cervix with 3 mm or less of tumor invasion, 7 mm or less of lateral extent, and no lymphovascular space involvement (stage IA1) can be treated with a simple hysterectomy. Vaginal, abdominal, and laparoscopic hysterectomies are equally effective.

Cone biopsy. Although simple hysterectomy is considered the standard therapy for patients with microinvasive cervical carcinoma, preservation of future fertility is a strong consideration in some patients. A cone biopsy entails removal of the cervical transformation zone. Provided that the biopsy margins are free of dysplasia and microinvasive carcinoma, cone biopsy is probably a safe treatment for such patients who meet the criteria of having superficial invasion of less than 3 mm, minimal lateral extension, and no lymphovascular space involvement.

Since there is a small risk of recurrence among this population of patients treated by cone biopsy alone, they should be followed closely. Follow-up includes a Pap smear and pelvic examination every 3 months for 2 years, every 6 months for 4 years, and then yearly thereafter. An abnormal Pap smear is an indication for a repeated colposcopy. If such patients are successful in achieving pregnancy and have no evidence of recurrent squamous cell carcinoma, there is no need to proceed with hysterectomy at the completion of planned childbearing.

Stages IA2, IB1, and nonbulky IIA disease

Radical hysterectomy. A standard treatment for patients with small cervical carcinomas (≤ 4 cm) confined to the uterine cervix or with minimal involvement of the vagina (stage IIA) is radical hysterectomy (removal of the uterus, cervix, and parametrial tissue); pelvic lymphadenectomy; and para-aortic lymph node sampling, with the hope that patients selected for surgery will not require postoperative radiation therapy. The overall success of this treatment is similar to that of radiation therapy, although how it compares to the current standard of chemoradiation is not known. For patients with early lesions, radical hysterectomy may provide an improved quality of life. The benefits of surgical excision include rapid treatment, less time away from normal activities, and preservation of normal ovarian and vaginal function.

A randomized trial for patients with early-stage cervical cancer reported no difference in survival between radical hysterectomy and definitive radiation therapy. Because a significant percentage of patients required postoperative pelvic radiotherapy following radical hysterectomy, the morbidity was increased in the surgery arm. Therefore, patients selected for radical hysterectomy should have small-volume disease (< 2 cm) so adjuvant pelvic radiation therapy is unnecessary. In addition, the standard now is chemoradiation rather than radiation alone for cervical cancer patients at stages IB2 and higher, due to RTOG 90-01 trial results demonstrating improved survival with chemoradiation; it is not known how chemoradiation performs in comparison to radical hysterectomy. Studies addressing outcomes with fertility-sparing surgeries, such as radical abdominal trachelectomy versus radical vaginal trachelectomy, are ongoing. A prospective study by Einstein et al included 43 women with stage IB1 cervical cancer; the vaginal approach was performed on 28 patients and the abdominal approach was performed on 15 patients. There was no statistical difference between the two approaches in terms of average blood loss or the number of lymph nodes removed. There was the possibility that the abdominal approach would provide a wider margin of resection of the parametria, but overall, both the radical abdominal and vaginal approaches are potential fertility-sparing options for women with early-stage cervical cancer. A study by Diaz et al has compared outcomes associated with radical trachelectomy as a fertility-sparing option vs radical hysterectomy for stage IB1 cervical cancer. Radical trachelectomy was performed in 40 women, and radical hysterectomy was performed in 110 patients. After 5 years, the recurrence-free survival was 96% for those patients who underwent radical trachelectomy and 86% for those who underwent radical hysterectomy. Therefore, there are potential radical surgeries that can be used as fertility-sparing options for women with early-stage cervical cancer.

Currently, there are no specific contraindications to radical hysterectomy. Several studies have demonstrated that patients 65 years and older tolerate this procedure well, and age alone should not be considered a contraindication. Obesity also is not a contraindication to radical hysterectomy.

• Alternatives to radical hysterectomy-Reports have described laparoscopically assisted radical vaginal hysterectomy, laparoscopic abdominal radical hysterectomy, laparoscopic-assisted radical vaginal hysterectomy, and robotic-assisted surgery as less invasive alternatives to traditional radical hysterectomy. Robotic-assisted radical hysterectomy has become an area of particular interest. Multiple series have demonstrated the feasibility of performing surgeries on gynecologic malignancies using robotics. The largest case-control series to date by Boggess et al comparing robotic vs open type III radical hysterectomy reported statistically significant differences in operative time, blood loss, and node retrieval in favor of the robotic approach. However, more studies need to be conducted to evaluate intraoperative and postoperative complications with robotic-assisted surgery and to assess data regarding recurrence rates and overall survival in comparison to those with the traditional open and laparoscopic approaches. The use of fertility-preserving surgery by means of pelvic lymphadenectomy combined with radical vaginal trachelectomy (removal of the uterine cervix) has also been evaluated in select women with early cervical cancer. Successful pregnancies after this procedure have been reported. However, further data are needed to assess the safety and efficacy of fertility-preserving surgery. There is a lack of long-term follow-up data and comparative survival rates for conservative versus radical treatments. These techniques should be performed by fully trained surgeons. The role of laparoscopic sentinel lymph node dissection is an area of active investigation. Several studies addressing the utility of intraoperative lymphatic mapping utilizing blue dye and technetium are being conducted in patients with early-stage cervical cancer undergoing radical hysterectomy. Although studies are ongoing, the role of sentinel node detection appears promising.

• Complications-As a result of improved surgical techniques, as well as the use of prophylactic antibiotics and prophylaxis against deep venous thrombosis, the morbidity and mortality associated with radical hysterectomy have declined significantly over the past several decades. The currently accepted complication rate for radical hysterectomy includes approximately a 0.5% to 1% incidence of urinary tract injury, a 0.5% to 1% incidence of deep venous thrombosis, and an overall mortality of less than 1%.

The increased awareness of the risks associated with blood transfusion is reflected in the fact that in many cases, no transfusions are administered. The need for heterologous blood transfusion also can be decreased by encouraging autologous blood donation before radical hysterectomy or by using intraoperative hemodilution.

The average hospital stay for patients who undergo radical hysterectomy is between 4 and 7 days. Follow-up should include a vaginal Pap smear with pelvic examination every 3 months for 2 years, twice a year for 3 years, and yearly thereafter.

FIGURE 1

Relative risk estimate of survival derived from five phase III randomized controlled clinical trials of chemoradiation therapy in women with cervical cancer.

Stages IB2 and bulky IIA disease

Numerous studies have demonstrated that patients with early-stage “bulky” lesions (> 4 cm) have a worse prognosis than those with nonbulky tumors. Therefore, these patients are candidates for chemoradiation as reported in the RTOG 90-01 trial, to avoid the need for postoperative radiation based on pathologic risk factors. Based on results from a large trial from France in which the use of an adjuvant hysterectomy was standard in the past, the use of a post-radiation hysterectomy is no longer recommended in patients who have been treated with image-guided brachytherapy. Therefore, many experts believe that patients with stages IB2 and bulky IIA cervical cancer should be treated initially with chemoradiation therapy instead of radical hysterectomy. Others argue that treatment decisions should not be based on tumor size alone, because some studies have demonstrated that significant independent predictors of disease-free survival are lymphovascular space involvement and outer two-thirds depth of invasion. Overall, there are still conflicting data in terms of the efficacy of using chemoradiation therapy alone vs chemoradiation therapy followed by surgery for bulky stage 1B2 cervical disease for centers that do not have access to image-guided brachytherapy. The role of curative surgery diminishes once cervical cancer has spread beyond the confines of the cervix and vaginal fornices.

Intracavitary irradiation for central pelvic disease and EBRT for lateral parametrial and pelvic nodal disease are typically combined to encompass the known patterns of disease spread with an appropriate radiation dose while sparing the bladder and rectum from receiving full doses. The addition of intracavitary irradiation to EBRT is associated with improved pelvic tumor control and survival over external irradiation alone, because the combination can achieve high central doses of radiation. Recent studies show a decline in the use of brachytherapy in the United States and the use of external beam radiotherapy instead, with a concomitant decrease in survival; therefore, brachytherapy should be attempted in every feasible case.

Radiation Therapy

Intracavitary brachytherapy

Radioactive isotopes, such as cesium-137 or iridium-192 can be introduced directly into the uterine cavity and vaginal fornices with special applicators. The most commonly used applicator is the Fletcher-Suit intrauterine tandem and vaginal ovoids.

Calculating dose rates. With computerized dosimetry, the dose to a number of points from a particular source arrangement can be calculated. Adjustments in the strength or positioning of the sources can then be made to yield a selected dose to one or more points.

Quantification of acceptable implant geometry has been described in a review of 808 implants performed in 396 patients with cervical cancer treated with irradiation at MD Anderson Cancer Center (Katz et al: Int J Radiat Oncol Biol Phys 2000). These guidelines set the standard for high-quality tandem and ovoid insertions. A Radiation Therapy Oncology Group (RTOG) publication showed that implant geometry was related to disease-free survival. Numerous recent publications have described better dosimetric parameters (D90 CTV; D2cc rectum, bladder, sigmoid) and coverage of target volumes at risk (cervical tumor, parametrial extensions) with the use of MRI.

Points of interest usually include the maximal rectal and bladder dose as well as the dose to three standard pelvic points: A, B, and P (Figure 2). Point A is located 2 cm cephalad from the cervical os and 2 cm lateral to the uterine canal. Anatomically, it represents the medial parametrium/lateral cervix, the approximate point at which the ureter and uterine artery cross. Point B is 5 cm lateral to the center of the pelvis at the same level as point A and approximates the region of the obturator nodes or lateral parametrium. Point P is located along the bony pelvic sidewall at its most lateral point and represents the minimal dose to the external iliac lymph nodes. Publications have advocated the use of imaging (CT or MRI) to delineate tumor/target volumes and to specify more precisely the doses of brachytherapy administered to patients with carcinoma of the cervix (Potter et al).

LDR vs high-dose-rate (HDR) brachytherapy. Dose rates at point A are typically 50 to 70 cGy/hour; this level is considered LDR brachytherapy. The applicator is placed into the uterus while the patient is under anesthesia in the operating room, and the patient must stay in the hospital for 2 to 3 days during the procedure. One or two implants are usually placed. Despite the fact that two insertions may allow time for regression of disease between placements, there are no data indicating that two insertions improve pelvic tumor control or survival rates over one insertion.

FIGURE 2

GOG definitions of points A, B, and P.

Whereas LDR brachytherapy has been used successfully for decades in the treatment of carcinoma of the cervix, the use of HDR brachytherapy has increased in the United States over the past decade. Dose rates are typically 200 to 300 cGy/minute, with short treatment times allowing for stable position of the applicator.

The major benefit of HDR brachytherapy is that the procedure can be performed on an outpatient basis with less radiation exposure to personnel. The major potential disadvantage is biologic: large single fractions of radiation (5 to 8 Gy) are used with 3 to 5 insertions per patient, which may increase the rate of late complications.

Several series have cited comparable disease control and complication rates with HDR and LDR brachytherapy. A total of 237 patients with previously untreated invasive cervical cancer were enrolled in one randomized study to compare the clinical outcome between HDR and LDR intracavitary brachytherapy. The median follow-up for LDR and HDR groups was 40.2 and 37.2 months, respectively. The 3-year overall and relapse-free survival rates for all patients were 69.6% and 70%, respectively. There was no significant difference in the following clinical parameters between LDR and HDR groups: the 3-year overall survival rate was 70.9% and 68.4% (P = .75), the 3-year pelvic control rate was 89.1% and 86.4% (P = .51), and the 3-year relapse-free survival rate in both groups was 69.9% (P = .35). Considering patient convenience, the small number of medical personnel needed, and the decreased radiation exposure to health care workers, HDR intracavitary brachytherapy (5 to 6 Gy per fraction for five fractions) is an alternative to conventional LDR brachytherapy and is in current NRG advanced cervical cancer trials.

Guidelines have been published for HDR brachytherapy for cervical cancer treatment by the American Brachytherapy Society. Several studies have shown a benefit to the use of three-dimensional planning, with either CT or MRI, with the largest prospective study in CT-based planning showing a 20% reduction in toxicity with optimized brachytherapy planning.

Pelvic EBRT

Pelvic EBRT is used in conjunction with intracavitary radiotherapy for stage IA2 disease and above when the risk of pelvic lymph node involvement is significant. The amount of EBRT delivered and the timing of its administration relative to intracavitary radiation are individualized. For example, the presence of a large exophytic cancer that distorts the cervix would initially preclude successful placement of intracavitary brachytherapy. EBRT would be administered first, and after significant regression of disease, it could be followed by intracavitary radiotherapy.

Various techniques have been developed to optimize EBRT, including CT simulation, conformal blocking, and, more recently, intensity-modulated radiation therapy (IMRT). These techniques reduce the volume of normal tissue that receives full-dose irradiation while not compromising coverage of the target. MRI has been shown to enhance the accuracy of tumor delineation and design of treatment portals, to avoid geographic misses, particularly in the posterior margin of the lateral pelvic fields.

FDG-PET scanning has been used to more accurately identify the tumor volume in the cervix and optimize the radiation dose administered with intracavitary brachytherapy (to point A), without increasing the dose delivered to the bladder or the rectum.

Several preliminary reports describing highly conformal dose distributions with IMRT for patients with carcinoma of the cervix have been published. Tumor control has been about 80% for various stages, and no patient has developed higher than grade 2 gastrointestinal or genitourinary toxicity.

Advanced tumors require relatively more external irradiation because of the inability of central radioisotope sources to effectively irradiate disease in the lateral parametrium. Typically, external pelvic doses of 4,000 to 5,000 cGy are followed by 4,000 to 5,000 cGy to point A with intracavitary LDR brachytherapy, for a total dose of 8,000 to 9,000 cGy to point A. A parametrial boost completes treatment to the lateral pelvis, for a total dose to point B or P of 6,000 cGy from EBRT and brachytherapy, depending on the extent of disease.

With HDR brachytherapy, equivalent doses are prescribed using the linear quadratic equation converted to 2 Gy equivalents (EQD2 formula). The HDR/LDR dose ratio ranges from 0.5 to 0.8 depending on the number of HDR fractions. Deep hyperthermia (administered once weekly) has been combined with pelvic external beam and intracavitary brachytherapy to treat patients with bulky tumors of the cervix. In multivariate analysis, treatment factors associated with improved pelvic control for cervical cancer include the use of intracavitary brachytherapy, total point A dose greater than 8,500 cGy (stage III only), and overall treatment time of less than 8 weeks.

FIGURE 3

Top

–Kaplan–Meier estimates of overall survival for patients who received extended-field radiotherapy (EFRT) or concurrent chemotherapy and radiotherapy.

Bottom–

Kaplan-Meier estimates of overall survival for patients who received EFRT or CT-RT in subgroups stratified by International Federation of Gynecology and Obstetrics stage.

In 378 patients, overall complete tumor response was 77%; at 5 years, the tumor control rate was 53%, and the disease-free survival was 47%. Late toxicity was observed in 12% of the patients.

Para-aortic EBRT

Para-aortic EBRT (45 to 50 Gy in 1.8 Gy fractions, followed by a boost to 54 to 65 Gy in patients with gross nodal disease) may be used in addition to pelvic EBRT when para-aortic disease is confirmed or suspected. An RTOG trial found that para-aortic EBRT conferred a survival benefit in patients with advanced cervical cancer (stages IB > 4 cm, IIA, and IIB) over pelvic EBRT alone; however, a subsequent RTOG 90-01 trial showed that prophylactic para-aortic radiation was not indicated unless the para-aortic nodes were involved with disease. Since the advent of IMRT, dose escalation with sparing of the bowel is now feasible, with a recommended dose constraint to contoured loops of small bowel with contrast of 55 Gy to less than 5 cc, as well as constraints to the kidneys and spinal cord) precludes the delivery of sufficiently high doses to the para-aortic region. IMRT is very effective in irradiation of the para-aortic nodes.

IMRT

IMRT, a highly conformal technique to deliver radiation, has been used effectively in patients with postoperative cervical cancers and in patients for whom a nodal boost is indicated. In a prospective cohort study by Kidd et al, 452 patients with cervical cancer were treated with curative intent (135 with IMRT and 317 with non-IMRT external irradiation and brachytherapy); 85% of patients received concurrent chemotherapy. All IMRT patients underwent an FDG-PET/CT simulation. The mean follow-up for all patients alive at the time of the last follow-up was 52 months (72 months for non-IMRT patients and 22 months for IMRT patients). A recurrence developed in 178 patients (39 IMRT [28.9%], 139 non-IMRT [43.8%]). The difference in recurrence-free survival between the two groups did not reach statistical significance, although the IMRT group showed better overall and cause-specific survival. Grade 3 complications were seen in 8 IMRT patients (6%) and in 54 non-IMRT patients (17%).

Definitive radiation therapy

CIS, stage IA disease. Carcinoma in situ (CIS) and microinvasive cervical cancer (stage IA) are not associated with lymph node metastases. Therefore, intracavitary LDR brachytherapy alone, delivering approximately 5,500 cGy to point A, can control 100% of CIS and stage IA disease and is an acceptable alternative to surgery for patients who cannot undergo surgery because of their medical condition.

Stage IB disease. The most important prognostic factor associated with pelvic tumor control and survival following radiation therapy for stage IB cervical cancer is tumor size. The central tumor pelvic control rate with radiotherapy alone is excellent for tumors smaller than 8 cm (97%), with total pelvic tumor control and survival rates of 93% and 82%, respectively. Therefore, many experts have argued that adjuvant hysterectomy following chemoradiation therapy is unnecessary for cervical tumors smaller than 8 cm. For bulky cervical cancers 8 cm or larger, pelvic tumor control and survival rates decrease to 57% and 40%, respectively, with irradiation alone, and adjuvant hysterectomy may potentially improve local tumor control and survival rates (Table 2).

TABLE 2

Relationship between tumor size and outcome in patients with tumors ≥ 5 cm treated with irradiation alone

Stage III disease. Hyperthermia combined with pelvic irradiation was introduced into oncology practice several decades ago. A recent meta-analysis showed that 74% of patients treated with this combination had FIGO stage IIIB disease. Outcomes were better for patients who received the combined treatment, with a significantly higher complete response rate (RR = 0.56; 95% CI, 0.39–0.79; P < .001), a significantly reduced local recurrence rate (hazard ratio [HR] = 0.48; P < .001), and a significantly better overall survival (HR = 0.67; P = .05). No significant difference was observed in treatment-related acute (RR = 0.99; P = .99) or late grade 3/4 toxicity (RR = 1.01; P = .96) between both treatments. The authors stated that the limited number of patients available for analysis, methodologic flaws, and a significant overrepresentation of patients with FIGO stage IIIB disease prohibited drawing definitive conclusions regarding the impact of adding hyperthermia to standard radiotherapy in cervical cancer. However, the data did suggest that the addition of hyperthermia improves local tumor control and overall survival in patients with locally advanced cervical carcinoma, without affecting treatment-related grade 3 to 4 acute or late toxicity.

Chemoradiation Therapy for Locally Advanced Disease

An updated RTOG trial (RTOG 90-01) for advanced cervical cancer (stage IB or IIA with tumor ≥ 5 cm or with biopsy-proven pelvic lymph node involvement and stages IIB–IVA disease) compared EFRT vs pelvic radiotherapy with concomitant 5-FU and cisplatin in women with locoregionally advanced carcinomas of the uterine cervix. The addition of chemotherapy to irradiation improved 5-year survival from 55% to 79% and disease-free survival from 46% to 74% for stage IB/IIA disease by reducing the rates of both local recurrence and distant metastases. For stage III/IVA disease, chemoradiotherapy improved 5-year survival from 45% to 59% and disease-free survival from 37% to 54% (Figures 1 and 3). On the other hand, a small Australian gynecologic group randomized study with 76 patients and a Canadian randomized study of 127 patients with stages IB–IIB carcinoma of the cervix treated with chemotherapy and irradiation or irradiation alone showed no significant difference in tumor control or survival. A possible explanation for the discrepancy in the results between the five US trials and the National Cancer Institute of Canada study has been analyzed by Lehman and Thomas. A review of 4,069 patients with invasive carcinoma of the cervix treated in Ontario, Canada, between 1992 and 2001 documented a significant increase in 3-year survival in patients treated with concurrent chemotherapy-radiotherapy (CT-RT; 75.9%) compared with those treated with irradiation alone (71.1%).

Current treatment recommendations

Concurrent CT-RT (usually cisplatin-based) is standard treatment for bulky stage IB2 cervical cancer. The use of adjuvant hysterectomy is controversial for stage IB2 cervical cancer, since dose-intense external pelvic and intracavitary irradiation plus chemotherapy may obviate the need for adjuvant surgery. In the era of image-guided brachytherapy, adjuvant hysterectomy is reserved for patients with residual FDG uptake on PET scan at 3 months after definitive chemoradiation therapy.

The use of weekly cisplatin for six cycles or 5-FU and cisplatin every 3 weeks for two cycles concurrently with radiotherapy is the standard treatment approach for bulky stage IB2 cervical cancer.

Stages IIA–IVA disease

The most important prognostic factor associated with pelvic tumor control and survival is the bulk of pelvic disease within each stage. For stage IIB, bulky disease is variously defined as bilateral or lateral parametrial infiltration or central bulky disease greater than 4 cm. For stage IIIB, bulky disease is defined as bilateral sidewall involvement, lower-third vaginal involvement, or hydronephrosis.

In the previous GOG experience, in which para-aortic lymph node staging had been mandated, multivariate analysis testing revealed para-aortic lymph node involvement to be the most powerful negative prognostic factor, followed by pelvic lymph node involvement, larger tumor diameter, young age, advanced stage, and lower performance status for patients with negative para-aortic lymph nodes. Five-year survival rates for radiotherapy alone vary from 80% for stage I, 60% for stage II, and 45% for stage III disease, with corresponding pelvic tumor control rates of 90%, 80%, and 50%, respectively.

CT-RT. A GOG phase III trial (GOG 120) compared standard pelvic EBRT/intracavitary brachytherapy plus hydroxyurea vs weekly cisplatin vs hydroxyurea, 5-FU, and cisplatin. Both the weekly cisplatin and the 5-FU–cisplatin–hydroxyurea arms produced significantly improved survival and relapse rates compared with hydroxyurea alone. Two-year progression-free survival rates were significantly improved, from 47% with hydroxyurea and radiotherapy to 67% with weekly cisplatin–irradiation and 64% with 5-FU–cisplatin–hydroxyurea–irradiation (Figure 1). The improved outcome was due to the reduced rates of pelvic failure and lung metastases. Because of an improved therapeutic ratio, weekly cisplatin is the favored regimen. Updated results of this trial confirm the original observations.

GOG 165 compared standard radiation therapy plus concurrent weekly cisplatin vs concurrent protracted venous infusion of 5-FU (225 mg/m²/d over 5 weeks) as radiation sensitizers. In a randomized trial, 294 patients with advanced cervical cancer were enrolled to compare cisplatin and cisplatin plus topotecan (Hycamtin). Patients who received topotecan had outcomes that were statistically superior to those of patients who received cisplatin alone, with median overall survival time of 9.4 months and 6.5 months (P = .017), median progression-free survival time of 4.6 months and 2.9 months (P = .014), and response rates of 27% and 13%, respectively. This study confirms the efficacy of pelvic radiotherapy with weekly cisplatin. The study was closed prematurely when a planned interim analysis indicated that patients in the 5-FU arm had a 35% higher rate of treatment failure. An editorial published with the article highlighted the future difficulties with randomized trials for this population.

A randomized study of patients with stages IIIB–IVA cervical cancer was presented at ASCO 2009. The study had two arms: (1) a standard regimen of weekly cisplatin with pelvic radiation therapy and (2) concurrent radiation therapy and weekly cisplatin (40 mg/m²) plus weekly gemcitabine (Gemzar, 125 mg/m²), followed by two additional cycles of higher-dose cisplatin and gemcitabine after radiation therapy was completed. This study enrolled more than 500 patients worldwide, most notably in developing countries. There was a significant survival advantage with the addition of gemcitabine and post–radiation therapy chemotherapy (3-year progression-free survival rate, 65% vs 74%; overall survival HR = 0.68). Neutropenia and anemia rates were higher in the gemcitabine group. This study did not clarify whether the addition of gemcitabine or the post-radiation chemotherapy, or both, was the reason for the survival improvements.

Current treatment recommendations. In view of the multiple randomized trials documenting a survival benefit with concurrent CT-RT, the use of concurrent weekly cisplatin or cisplatin–5-FU every 3 weeks with irradiation is standard therapy for stages IB2–IVA cervical cancer (Figure 1). Further prospective studies should be explored to determine the role of gemcitabine and chemotherapy admininstered post radiation therapy.

Five of six large randomized clinical trials demonstrated a significant survival benefit for patients treated with concurrent CT-RT, using a cisplatin-based regimen, with a 28% to 50% relative reduction in the risk of death. In addition, the results of a meta-analysis of 19 randomized clinical trials of concurrent CT-RT involving 4,580 patients showed that concurrent CT-RT significantly improved overall survival (HR = 0.71; P < .001) as well as progression-free survival (HR = 0.61; P < .0001). In line with these results, concurrent CT-RT is currently recommended as standard therapy (Table 3).

TABLE 3

Large randomized studies of concurrent chemoradiotherapy in cervical cancer

A meta-analysis from all randomized trials reaffirms the benefits of concurrent CT-RT. On the basis of 13 trials that compared CT-RT with the same radiation therapy, there was a 6% improvement in 5-year survival with CT-RT (HR = 0.81; P < .001). A larger survival benefit was seen for the two trials in which chemotherapy was administered after CT-RT. There was a significant survival benefit for both the group of trials that used platinum-based (HR = 0.83; P < .017) and non–platinum-based (HR = 0.77; P < .009) CT-RT, but no evidence of a difference in the size of the benefit by radiation therapy or chemotherapy dose or scheduling was seen. CT-RT also reduced local and distant recurrence and disease progression and improved disease-free survival. There was a suggestion of a difference in the size of the survival benefit with tumor stage, but not across other patient subgroups. Acute hematologic and gastrointestinal toxicities were increased with CT-RT, but data were too sparse for an analysis of late toxicity. This meta-analysis clearly demonstrates the benefit of concurrent CT-RT and suggests further exploration should continue with additional adjuvant chemotherapy and non–platinum-based CT-RT.

The use of chemotherapy with cisplatin and gemcitabine after concurrent chemoradiation has been shown in one randomized trial to have a survival benefit. A currently accruing trial by the GOG (GOG 274; ClinicalTrials.gov identifier: NCT01414608) is evaluating whether a similar survival improvement is seen with carboplatin and taxol after concurrent chemoradiation for locally advanced cervical cancer.

For patients without para-aortic lymph node metastases, pelvic external irradiation (4,000 to 5,000 cGy) should be used, followed by intracavitary brachytherapy. Since 2005, the recommended prescription is a high-risk clinical target volume (HR-CTV) D90 > 87 Gy or in non–image-based brachytherapy, a total dose (both beam and brachytherapy) of 80 to 90 Gy to point A. It is noteworthy that, in a study at the Norwegian Radium Hospital by Vistad et al of 147 patients, the estimates of physician-assessed intestinal, bladder, and vaginal grade 3/4 morbidity were 15%, 13%, and 23%, respectively, whereas the prevalence of patient-reported severities of the same symptoms were 45%, 23%, and 58%, respectively. The study underscores the importance of incorporating patient assessment in the analysis of treatment morbidity.

The RTOG 90-01 trial showed no increase in toxicity with chemoradiation compared with radiation alone. Other studies, however, indicate possible higher risk. A study of 179 patients with cervical cancer treated with CT-RT and 195 treated with RT alone showed an incidence of vaginal sequeleae at 3 years of 35.1% and 20.2%, respectively. Toxicity was correlated with the compliance of using vaginal dilators after treatment. The incidence of skeletal severe sequelae was 7.5% in the CT-RT group and 1.6% in the RT alone group. Nevertheless, concomitant chemoradiation therapy was not associated with higher intestinal or urologic toxicity.

Adjuvant radiotherapy following radical hysterectomy

Node-negative disease. Local failure rates approach 20% following radical hysterectomy and pelvic lymphadenectomy when pelvic lymph nodes are not involved but the primary tumor has high-risk characteristics (primary tumor > 4 cm, outer-third cervical stromal invasion, and capillary-lymphatic space invasion). A GOG trial randomized these intermediate-risk patients with node-negative disease to receive pelvic EBRT (5,100 cGy in 30 fractions) or no further therapy following radical hysterectomy–pelvic lymphadenectomy. Postoperative irradiation produced a significant 44% reduction in recurrence; the recurrence-free rate at 2 years was 88% with irradiation vs 79% without it. A phase III trial is assessing whether there is a benefit to the addition of concurrent chemotherapy.

Node-positive disease. For patients with positive pelvic lymph nodes following radical hysterectomy–pelvic lymphadenectomy, pelvic radiotherapy reduces the pelvic failure rate from approximately 50% to 25% but does not affect survival, since distant metastases are still seen in 30% of patients. GOG/Southwest Oncology Group 8797 randomized these high-risk patients with node-positive disease (or patients with positive surgical margins) to undergo pelvic EBRT (4,930 cGy in 29 fractions) vs pelvic EBRT plus concurrent 5-FU and cisplatin for four cycles following radical hysterectomy–pelvic lymphadenectomy. A significant improvement in disease progression–free and overall survival was seen for concurrent 5-FU–cisplatin and radiation therapy compared with radiation therapy alone (4-year survival, 81% vs 71%).

• Current treatment recommendations-At present, adjuvant pelvic radiotherapy should be considered for patients with negative nodes who are at risk for pelvic failure and remains the standard postoperative treatment for patients with positive lymph nodes. Treatment consists of external pelvic irradiation (45 to 50 Gy), with specific sites boosted with further external beam or intracavitary irradiation as needed.

Since the combination of radical surgery and irradiation has greater morbidity than either modality alone, complete preoperative assessment is crucial to minimize the need for both.

Since concurrent CT-RT following radical hysterectomy provides a significant benefit in node-positive, high-risk cervical cancer, it should be part of the postoperative treatment plan. Postoperative CT-RT following radical hysterectomy should be strongly considered for patients with negative nodes but positive margins or parametrial invasion, middle-third or greater stromal invasion, and lymphovascular space invasion for tumors 5 cm or larger.

Surgical Management of Recurrent or Metastatic Disease

Recurrent advanced disease

Pelvic exenteration. For patients whose disease fails to respond to primary radiation therapy or for those with early invasive cervical carcinoma whose disease recurs after surgery or radiation therapy, pelvic exenteration offers the possibility of cure. Patients should be considered for pelvic exenteration only if they have locoregional disease that can be completely removed by this radical surgical procedure. In most cases, patients will require surgical removal of the bladder, uterus, cervix, vagina, and rectum.

Of all patients who are considered candidates for pelvic exenteration, only about half will be found to have resectable disease at the time of exploratory laparotomy. For patients who successfully undergo pelvic exenteration, 5-year survival rates range from 25% to 50%.

When the patient has central recurrence of squamous cell or adenocarcinoma of the cervix, the initial evaluation includes a complete physical examination, as well as a CT, MRI, or PET/CT scan.

Evidence of extrapelvic disease is a contraindication to pelvic exenteration. If no evidence of disease beyond the pelvis is found, the patient can be prepared for pelvic exenteration.

• Preparation for exenteration-includes complete bowel preparation, a visit with the stomal therapy nurse, and counseling regarding the radical nature of the surgery and the anticipated changes in body image after the operation. In most cases, we counsel the patient that vaginal reconstruction should be performed at the time of pelvic exenteration, both for maintenance of body image and improved healing.

• Surgical procedure-During surgery, a careful exploration is carried out to confirm that there is no evidence of unresectable disease beyond the pelvis. Explorative laparoscopy before pelvic exenteration has been used in this regard to localize the tumor and evaluate the presence of adjacent organ involvement. The pelvic sidewall spaces are opened and resectability is determined. If there is no evidence of adjacent organ involvement, an en bloc resection is usually performed; in some cases, especially when the recurrent tumor involves the lower vagina, a two-team approach can expedite the procedure. The actual exenterative portion of the procedure may take several hours and is usually accompanied by significant blood loss. In cases of questionable surgical margin status, the use of intraoperative radiation therapy is considered.

• Reconstruction-Following the exenterative procedure, the reconstructive portion of the procedure begins. We currently recommend a continent urinary diversion to nearly all patients. Although this step may add approximately 30 to 60 minutes to the surgical procedure, the improvement in quality of life is significant.

In patients who have undergone a supralevator pelvic exenteration, we frequently attempt a stapled reanastomosis of the colon. Unless there is excessive tension on the anastomosis or other problems, a diverting colostomy is not routinely indicated. About one-third of these patients suffer anastomotic breakdown in the postoperative period. At that time, a diverting colostomy can be performed. Unfortunately, Hatch et al (Gynecol Oncol 1990) found no benefit to the earlier use of colostomy.

Lung metastasis

For the rare patient who presents with a single isolated lung metastasis after treatment of invasive cervical carcinoma, pulmonary resection may offer the possibility of long-term disease-free survival or even cure in select cases. For patients who have multiple lung metastases or unresectable pelvic disease, surgery offers little or no hope and produces significant morbidity and mortality.

Therapy for Recurrent or Metastatic Disease

Local recurrence after radical hysterectomy

Local recurrence confined to the pelvis following radical hysterectomy for cervical cancer can be treated with radiotherapy with curative intent. An experience with 5-FU–based chemotherapy and concurrent pelvic EBRT resulted in a 58% complete response rate and a 45% no-evidence-of-disease rate at a median follow-up of 57 months. The total pelvic EBRT dose was 5,280 cGy plus a boost to sites of recurrence with twice-daily 160-cGy fractions during the 5-FU infusion. Therefore, radiotherapy, with or without chemotherapy, can provide durable local tumor control, with better results attainable for small, central recurrences, for which brachytherapy is possible.

Local recurrence after definitive radiation therapy

Local recurrence confined to the pelvis following definitive radiation therapy rarely can be cured with exenteration. In a series of patients treated with definitive radiotherapy, 21% of recurrences (80 of 376) were isolated to the pelvis. Only 29% of these localized pelvic recurrences (23 of 80) were explored for curative exenteration, and for the 43% of patients (10 of 23) deemed operable, the 5-year survival rate was 16%. Para-aortic lymph node recurrences are also observed in some of these patients, and some are successfully treated with aggressive irradiation and chemotherapy. Of 758 patients, 42 (6%) had isolated and nonisolated para-aortic lymph node failures. The 5-year survival in the above group was 28%. Careful follow-up, early detection, and aggressive treatment of para-aortic lymph node recurrences may increase the probability of salvage for some of these patients.

Palliation of metastatic disease

Palliative radiation therapy to sites of metastatic cervical cancer is effective. The most common sites of metastasis are distant lymph nodes, bone, and lungs. Reirradiation of the pelvis is possible in select patients to control local symptoms, such as bleeding, but carries an increased risk of bowel complications. For previously unirradiated sites of metastatic disease, 3,000 cGy in 10 fractions provides symptom palliation in the majority of patients.

Chemotherapy for Advanced/Recurrent Disease

Chemotherapy has traditionally been used for the palliative management of advanced or recurrent disease that can no longer be managed by surgery or radiation therapy. Various factors complicate the use of chemotherapy in such patients, however. 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 reserve, thus limiting the tolerable doses of most chemotherapeutic agents. Moreover, irradiation may produce its cytotoxic effect, in part, through a mechanism similar to that of alkylating agents; thus, it is thought to be cross-resistant 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.

TABLE 4

Active agents as defined by a response rate of at least 15%

Single agents

Among the chemotherapeutic agents used for cervical cancer, cisplatin, paclitaxel, and ifosfamide have shown the most consistent activity as single agents (Table 4). The duration of response with any single agent is brief, ranging from 4 to 6 months, with survival ranging from 6 to 9 months.

Cisplatin. Cisplatin has been the most extensively evaluated single agent for cervical carcinoma. A dose of 100 mg/m² was shown to have a higher response rate than a dose of 50 mg/m² (31% vs 21%), but the higher dose was associated with increased toxicity; overall survival did not differ significantly between the two groups. A 24-hour infusion of cisplatin was tolerated better than a 2-hour infusion, with no difference in therapeutic efficacy.

TABLE 5

Combination chemotherapy for advanced or recurrent cervical carcinoma

Ifosfamide. Ifosfamide produces response rates ranging from 33% to 50% in various dose schedules. A dosage of 1.5 g/m² over 30 minutes for 5 days (with mesna [Mesnex]) produced an overall response rate of 40% and a complete response rate of 20%.

Lower response rates are generally seen in patients who have had prior chemotherapy. Responses also are decreased in previously irradiated sites.

Taxanes. Paclitaxel and docetaxel (Taxotere) have been reported to be active in cervical cancer. A study of paclitaxel (170 mg/m² over 24 hours) showed an objective response rate of 17%, and another study of paclitaxel (250 mg/m² over 3 hours) demonstrated an objective response rate of 27%. Docetaxel (100 mg/m² over 1 hour) has yielded a response rate of 19%.

Camptothecins. Irinotecan and topotecan, semisynthetic camptothecins, have shown activity in patients with cervical cancer, even in patients who did not respond to prior chemotherapy and prior radiation therapy. The reported objective response rates were 21% and 19%, respectively.

Targeted therapies. Newer biologic agents are being actively studied. Two important receptors in cervical cancer include vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). VEGF is a key promoter of tumor progression in cervical cancer. A GOG phase II study of 46 patients with metastatic cervical cancer explored the role of bevacizumab (Avastin), a recombinant humanized anti-VEGF monoclonal antibody. Eleven patients (24%) survived progression-free for at least 6 months, and five patients (11%) had objective radiographic responses. This finding compared favorably with results of historic phase II studies in this population. Results of another GOG phase II study testing cetuximab (Erbitux), a monoclonal antibody to the EGFR, in patients with persistent or recurrent disease did not show any significant clinical response. The 5 patients out of 38 who showed progression-free survival for 6 months had tumors with squamous cell histology, thus suggesting cetuximab activity may be limited to cervical cancer patients with squamous cell histology.

Combination regimens

Various combination chemotherapy regimens have been evaluated in phase II trials, and high response rates (> 50%) were noted, even in patients who had received prior radiation therapy. The results of some of these trials are summarized in Tables 5 and 6. In one study, a subset analysis showed a response rate of 72% with the combination of bleomycin, ifosfamide, and cisplatin as treatment for tumors located in previously irradiated sites. Neoadjuvant regimens of cisplatin combined with gemcitabine in patients with locally advanced cervical cancer demonstrated very high activity, with a clinical response rate of 95%. Neoadjuvant ifosfamide and cisplatin, with or without paclitaxel, produced 87% and 82% response rates, respectively, among 146 evaluable patients in a randomized study.

A randomized trial was reported by Long et al. A total of 146 patients with advanced persistent or recurrent cervical cancer were treated with cisplatin (50 mg/m² IV every 21 days), and 147 patients were treated with topotecan (0.75 mg/m² IV during a 30-minute infusion period on days 1, 2, and 3 followed by cisplatin (50 mg/m² on day 1) repeated every 21 days. All regimens were administered for a maximum of six cycles for nonresponders or until disease progression or unacceptable toxicity prohibited additional chemotherapy. The complete response rate was 3% for cisplatin and 10% for the cisplatin-topotecan combination, and the complete and partial remission rates were 13% and 27%, respectively; the median progression-free survival was 2.9 months and 4.6 months, respectively. Chemotherapy remains palliative, with no longevity prolongation of survival in recurrent or metastatic disease.

A phase III GOG randomized trial explored four cisplatin-containing doublet combinations in stage IVB, recurrent or persistent cervical carcinoma. A total of 434 evaluable patients received cisplatin (50 mg/m² on day 1), combined with either paclitaxel (135 mg/m²) or vinorelbine (30 mg/m² on days 1 and 8) or gemcitabine (1,000 mg/m² on days 1 and 8) or topotecan (0.75 mg/m² on days 1, 2, and 3). Each cycle was repeated every 21 days. In the analysis, the cisplatin and paclitaxel regimen was considered the standard arm, and a 33% death reduction was considered to be a significant endpoint. In the final results, there was no survival difference seen among the four groups. Cisplatin-paclitaxel had the highest radiographic response rate (29.1%) and slightly higher survival rates (2.6 months longer), but still these results were not statistically better than those of the other treatment groups.

A phase III trial conducted by the Japanese Clinical Oncology Group compared palliative chemotherapy containing paclitaxel and carboplatin (TC) with paclitaxel and cisplatin (TP) as a standard treatment for patients with newly diagnosed stage IVB persistent or recurrent cervical cancer. The study was designed to demonstrate the non-inferiority of the TC regimen; the primary endpoint was overall survival. The median overall survival for TP was 18.3 months, and for TC, 17.5 months. The authors suggested that “the more feasible and less toxic TC can be recommended as the new standard treatment for stage IVB or recurrent cervical caner.”

Most recently, a phase III GOG randomized trial exploring the role of bevacizumab in platinum and non-platinum doublets for women with stage IVB recurrent or persistent cervical carcinoma was presented at ASCO 2013. Four regimens were cisplatin and paclitaxel (with or without bevacizumab), and topotecan and paclitaxel (with or without bevacizumab). The primary endpoint was overall survival. At completion, 452 women were enrolled. The addition of bevacizumab statistically improved overall survival and response. Median overall survival was 17 months with bevacizumab and 13.3 months without it (HR = 0.71; CI, 0.54–0.94; P = .0035). Response rate was 48% with bevacizumab and 36% without it (P = .008). The non-platinum regimens were considered inferior at the interim analysis, and accrual halted in those two arms. Toxicity was higher with bevacizumab: thromboembolism (8% vs 1%); gastrointestinal fistula, grade 3 or higher (3% vs 0%); genitourinary fistula, grade 3 or higher (2% vs 0%); hypertension, grade 2 or higher (25% vs 2%); and neutropenia, grade 4 or higher (35% vs 26%). With these promising results, the addition of bevacizumab to cisplatin and paclitaxel is a reasonable first-line treatment option.

TABLE 6

Phase III clinical trials in advanced or recurrent cervical cancer

Palliative care

Palliation of the dying cervical cancer patient is difficult. Pain due to recurrent pelvic disease can be extreme and requires skillful use of combinations of narcotics, sedatives, and anxiolytics. Fistula from the bladder or rectum demands meticulous local skin care and occasionally surgical diversion procedures in patients with reasonable expected longevity. This patient population often has limited resources, with dependent children requiring careful social service planning. A small percentage has concurrent HIV infection, making the infectious disease specialist part of the palliative care team. The tripod of care in advanced cervical cancer is the judicious use of chemotherapy and radiation therapy, palliation of the symptoms of advancing disease, and emotional and social support for the patient and family members.

In the follow-up of patients treated for carcinoma of the cervix, it is important to keep in mind that they are at risk for the development of secondary malignant tumors. In a study of more than 85,000 patients with squamous cell carcinoma and 10,280 with adenocarcinoma treated in Scandinavian countries and the United States, there were 10,559 second cancers (standardized incidence ratio [SIR] = 1.31) in the squamous cell carcinoma and 920 (SIR = 1.29) in the adenocarcinoma patients. Risk of lung cancer was increased in both groups of patients. SIRs for second cancers of the colon and soft tissues, melanoma, and non-Hodgkin lymphoma were significantly higher among the adenocarcinoma survivors than the squamous cell carcinoma survivors.

Carcinoma of the cervix and pregnancy. About 1% of patients with cervical cancer are pregnant at diagnosis. Most patients present with an abnormal cytology or vaginal bleeding. Colposcopy during pregnancy is used to rule out invasive carcinoma. This procedure and biopsies of suspicious lesions are safe for these patients. In patients with high-grade dysplasia, a conservative approach is reasonable. Conization during pregnancy was associated with fetal loss of 10% to 20% in some series.

More than 70% of cervical cancer cases diagnosed during pregnancy are stage I disease. Management requires a multidisciplinary approach, involving a gynecologist, radiation oncologist, perinatologist, and psychological counselor. Important elements in the therapeutic decision involve tumor size, tumor stage, gestational status, and the patient’s desire to continue the pregnancy.

Invasive cancer in a pregnant woman (< 20 weeks) generally is managed immediately, with loss of the fetus, although there have been reports of delayed treatment in select patients with small tumors. The majority of patients are treated with a total or radical hysterectomy, which can be performed after a cesarean section and fetal delivery in women with pregnancy in the second or third trimester. An alternative is radiation therapy alone, for stage I/II disease, or combined with chemotherapy, for locally advanced disease. Spontaneous abortion usually occurs at about 4 weeks after initiation of pelvic irradiation (40 Gy). In patients whose cancer is diagnosed during the third trimester, fetal delivery is accomplished with a cesarean section or vaginal delivery, after which definitive treatment with radical surgery or irradiation is instituted. Several reports show comparable results with either therapeutic approach.

Acknowledgments: The authors would like to thank Dr. Xipeng Wang, Dr. Hye-Sook Chon, Dr. Xi Cheng, and Lora Lothringer for their assistance.

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