OverviewAn estimated 12,200 new cases of cervical cancer will be diagnosed in the United States in 2010, and 4200 people will die of the disease.1 Cervical cancer rates are decreasing among women in the United States, although incidence remains high among Hispanic/Latino, black, and Asian women.2–5 However, cervical cancer is a major world health problem for women. The global yearly incidence of cervical cancer for 2002 was 493,200; the annual death rate was 273,500. It is the third most common cancer in women worldwide,6,7 with 78% of cases occurring in developing countries, where cervical cancer is the second most frequent cause of cancer death in women.Persistent human papillomavirus (HPV) infection is regarded as the most important factor contributing to the development of cervical cancer. A relationship seems to exist between the incidence of cervical cancer and the prevalence of HPV in the population. The prevalence of chronic HPV in countries with a high incidence of cervical cancer is 10% to 20%, whereas its prevalence in low-incidence countries is 5% to 10%.6 Immunization against HPV prevents infection with certain types of HPV and, thus, is expected to prevent specific HPV cancer in women (see NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines] for Cervical Cancer Screening, in this issue; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).8–12 Other epidemiologic risk factors associated with cervical cancer are a history of smoking, parity, contraceptive use, early age at onset of coitus, larger number...

Overview

An estimated 12,200 new cases of cervical cancer will be diagnosed in the United States in 2010, and 4200 people will die of the disease.1 Cervical cancer rates are decreasing among women in the United States, although incidence remains high among Hispanic/Latino, black, and Asian women.25 However, cervical cancer is a major world health problem for women. The global yearly incidence of cervical cancer for 2002 was 493,200; the annual death rate was 273,500. It is the third most common cancer in women worldwide,6,7 with 78% of cases occurring in developing countries, where cervical cancer is the second most frequent cause of cancer death in women.

Persistent human papillomavirus (HPV) infection is regarded as the most important factor contributing to the development of cervical cancer. A relationship seems to exist between the incidence of cervical cancer and the prevalence of HPV in the population. The prevalence of chronic HPV in countries with a high incidence of cervical cancer is 10% to 20%, whereas its prevalence in low-incidence countries is 5% to 10%.6 Immunization against HPV prevents infection with certain types of HPV and, thus, is expected to prevent specific HPV cancer in women (see NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines] for Cervical Cancer Screening, in this issue; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).812 Other epidemiologic risk factors associated with cervical cancer are a history of smoking, parity, contraceptive use, early age at onset of coitus, larger number of sexual partners, history of sexually transmitted disease, and chronic immunosuppression.13

Squamous cell carcinomas account for approximately 80% of all cervical cancers, and adenocarcinoma for approximately 20%. In developed countries, the substantial decline in incidence and mortality of squamous cell carcinoma of the cervix is thought to be a result of effective screening, although racial, ethnic, and geographic disparities exist.2,3,14,15 However, adenocarcinoma of the cervix has increased over the past 3 decades, probably because cervical cytologic screening methods are less effective for adenocarcinoma.1619 Screening methods using HPV testing may increase detection of adenocarcinoma. Vaccination with HPV vaccines may also decrease the incidence of both squamous cell carcinoma and adenocarcinoma.18,20

F1NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer Version

Version 1.2011, 10-06-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0104

F2NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer Version

Version 1.2011, 10-06-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0104

F3NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer Version

Version 1.2011, 10-06-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0104

F4NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer Version

Version 1.2011, 10-06-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0104

F5NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer Version

Version 1.2011, 10-06-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0104

F6NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer Version

Version 1.2011, 10-06-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0104

By definition, the NCCN Guidelines cannot incorporate all possible clinical variations and are not intended to replace good clinical judgment or individualization of treatments. “Many exceptions to the rule” were discussed among the members of the cervical cancer panel during the process of developing these guidelines.

Diagnosis and Workup

These NCCN Guidelines discuss squamous cell carcinoma, adenosquamous carcinoma, and adenocarcinoma of the cervix. Neuroendocrine carcinoma, small cell tumors, glassy-cell carcinomas, sarcomas, and other histologic types are not within the scope of these guidelines.

Currently, the International Federation of Gynecology and Obstetrics (FIGO) evaluation procedures for staging are limited to colposcopy, biopsy, conization of the cervix, cystoscopy, and proctosigmoidoscopy. More complex radiologic and surgical staging procedures are not addressed in the FIGO classification. In the United States, however, CT, MRI, combined PET-CT, and surgical staging are often used to guide treatment options and design.2123

The earliest stages of cervical carcinoma may be asymptomatic or associated with a watery vaginal discharge and postcoital bleeding or intermittent spotting. These early symptoms frequently are unrecognized by the patient. Because of the accessibility of the uterine cervix, cervical cytology or Papanicolaou (Pap) smears and cervical biopsies can usually result in an accurate diagnosis (see NCCN Guidelines for Cervical Cancer Screening [in this issue and at www.NCCN.org]). Cone biopsy (i.e., conization) is recommended if the cervical biopsy is inadequate to define invasiveness or if accurate assessment of microinvasive disease is required. However, cervical cytologic screening methods are less useful for diagnosing adenocarcinoma, because adenocarcinoma in situ affects areas of the cervix that are harder to sample (i.e., endocervical canal).5,19

Workup for these patients with suspicious symptoms includes history and physical examination, complete blood cell count (including platelets), and liver and renal function tests. Radiologic imaging includes chest radiograph, CT or combined PET-CT, and MRI as indicated (e.g., to rule out disease high in the endocervix); however, imaging is optional for patients with stage IB1 or smaller tumors (see page 1390). Cystoscopy and proctoscopy should be reserved for patients in whom clinical concern exists for bladder or rectal extension.

Panel members discussed whether laparoscopic and robotic approaches should be included as part of these NCCN Guidelines in both staging and treatment. These techniques are being used more frequently, but long-term outcome data are not yet available. Laparoscopic staging, lymphadenectomies, and radical hysterectomies can be performed satisfactorily and are used routinely in selected patients in several NCCN Member Institutions.2426 Data from studies overseas suggest that recurrence rates are low for laparoscopic radical hysterectomy after 3 to 6 years of follow-up.27,28 Robotic radical hysterectomy (which is another minimally invasive surgical technique) is currently being performed in patients with early-stage cervical cancer. Potential advantages associated with laparoscopic and robotic approaches include decreased hospital stay and more rapid patient recovery.2931

Staging

Because of the variability of the availability and worldwide use of noninvasive radiographic imaging, the FIGO system limits imaging procedures to chest radiography, intravenous pyelography, and barium enema. The staging of carcinoma of the cervix remains largely a clinical evaluation. Although surgical staging is more accurate than clinical staging, surgical staging often cannot be used in low resource countries.22,32,33 The panel currently uses the 2009 FIGO definitions and staging system (see Table 1, available online, in these guidelines, at www.NCCN.org [ST-1]).32,34 This staging system from FIGO has been approved by the American Joint Committee on Cancer (AJCC).35 With the new staging, stage IIA is now subdivided into stage IIA1 (tumor size ≤ 4 cm) and stage IIA2 (tumor size > 4 cm), which is the only change from the previous 1994 FIGO staging system.

Importantly, lymphatic vascular space involvement (LVSI) does not alter the FIGO classification.32 FIGO did not include vascular space involvement, because pathologists do not always agree on whether LVSI is present in tissue samples. Some panel members believe that the presence of frank LVSI should exclude the lesion from the treatment schema for stage IA1 and that these patients should be treated using stage IB1 guidelines.

The use of MRI, CT, or combined PET-CT scans may aid in treatment planning but is not accepted for formalized staging purposes.22,33,36,37 In addition, FIGO has always maintained that staging is intended for comparison purposes only and not as a guide for therapy. As a result, the panel uses the FIGO definitions as the stratification system for these guidelines, although the findings on imaging studies (i.e., CT and MRI) are used to guide treatment options and design. MRI is useful to rule out disease high in the endocervix.

Primary Treatment

The primary treatment of early-stage cervical cancer is either surgery or radiation therapy (RT). Surgery is typically reserved for lower-stage disease and smaller lesions, such as stage IA, IB1, and selected IIA1. The panel agrees that concurrent chemoradiation is the primary treatment of choice for stages IB2 to IVA disease based on the results of 5 randomized clinical trials (see Table 2, available online, in these guidelines, at www.NCCN.org [MS-13]). Chemoradiation can also be used for patients who are not candidates for hysterectomy. Although few studies have assessed treatment specifically for adenocarcinoma, a recent analysis suggests that they can be treated effectively in a similar manner to squamous cell carcinomas.38,39

Clinical Trials and Basis for Treatment Selection

A randomized Italian study compared RT alone with radical hysterectomy and lymph node dissection.40 This study used adjuvant RT after surgery for women with surgical stage pT2b (which corresponds to FIGO stage IIB) or more extensive disease, less than 3 mm of uninvolved cervical stroma, and cut-through or positive nodes. Identical outcomes were noted for patients treated with radiation versus surgery, with (or without) postoperative radiation, but higher complication rates were noted for the combined modality approach. This study has been criticized by surgeons for its broad use of postoperative RT in the surgery arm and the high complication rate.

Concurrent chemoradiation, using cisplatin-based chemotherapy (either cisplatin alone or cisplatin/5-fluorouracil [5-FU]), is the treatment of choice for stages IB2, II, III, and IVA disease based on the results of 5 randomized clinical trials (see Table 2, available in these guidelines at www.NCCN.org [MS-13]).4146 These 5 trials have shown that the use of concurrent chemoradiation results in a 30% to 50% decrease in the risk of death compared with RT alone. Although the optimal concurrent chemotherapy regimen to use with RT requires further investigation, these 5 trials clearly established a role for concurrent cisplatin-based chemoradiation. Based on this data, the NCI issued an alert stating that strong consideration should be given to using chemoradiation instead of RT alone for invasive cervical cancer (http://www.nih.gov/news/pr/feb99/nci-22.htm). Long-term follow-up of 3 of these trials has confirmed that concurrent cisplatin-based chemoradiation improves progression-free and overall survival when compared with RT with or without hydroxyurea.4749 A recent meta-analysis reported that chemoradiotherapy leads to a 6% improvement in 5-year survival (hazard ratio, 0.81; P < .001).50 A large population-based registry analysis in Canada (n = 4069) confirmed that chemoradiotherapy improved outcomes when compared with radiotherapy alone.51

Although chemoradiation is tolerated, acute and long-term side effects have been reported.50,52,53 Some oncologists prefer concurrent single-agent cisplatin chemoradiation over cisplatin plus 5-FU chemoradiation, because the latter may be more toxic.54 Concurrent carboplatin or nonplatinum chemoradiation regimens are options for patients who may not tolerate cisplatin-containing chemoradiation.50,5559 Note that when concurrent chemoradiation is used, the chemotherapy is typically given when the external-beam pelvic radiation is administered.54 The panel believes that using “systemic consolidation” (i.e., adding chemotherapy after chemoradiation) should only be used in clinical trials (e.g., RTOG 0724).50,60,61

Early-Stage Disease

After careful clinical evaluation and staging, the primary treatment of early-stage cervical cancer is either surgery or RT. The treatment schema is stratified using the FIGO staging system (see Table 1, available online, in these guidelines, at www.NCCN.org [ST-1]).

Stage IA1 Disease: Extrafascial (i.e., simple) hysterectomy is commonly recommended for patients with clinical stage IA1 disease. Another option is modified radical hysterectomy with pelvic lymph node dissection if lymphovascular space invasion is present (category 2B for node dissection only). However, if the patient is medically inoperable or if fertility is desired, patients with negative margins from cone biopsy could undergo observation.62,63 For patients who desire fertility preservation, trachelectomy and pelvic lymph node dissection can be considered with (or without) para-aortic lymph node sampling for stage IA cervical cancer (see page 1391).6467

Stage IA2 Disease: Stage IA2 tumors can be treated with radical hysterectomy or radical trachelectomy and pelvic lymph node dissection with (or without) para-aortic lymph node sampling. Para-aortic node dissection is indicated for patients with known or suspected pelvic nodal disease.

Brachytherapy with (or without) pelvic radiation (total point A dose, 75–80 Gy) is another treatment option for stage IA2 disease. These doses are recommended for most patients based on summation of conventional external-beam fractionation and low–dose-rate (40–70 cGy/h) brachytherapy equivalents. Treatment should be modified based on normal tissue tolerance or on biologic equivalence calculations when using high–dose-rate brachytherapy (see Radiation Therapy, page 1409).

Stage IB and IIA Disease: Depending on their stage and disease bulk, patients with stage IB or IIA tumors can be treated with surgery, RT, or concurrent chemoradiation. A combined PET-CT scan can be performed to rule out extrapelvic disease before deciding how to treat these patients. The surgical option includes radical hysterectomy plus bilateral pelvic lymph node dissection with or without para-aortic lymph node sampling.40 Para-aortic node dissection is indicated for patients with larger tumors and suspected or known pelvic nodal disease. Some panel members feel that a pelvic lymph node dissection should be performed first and if negative, then the radical hysterectomy should be performed. If the lymph nodes are positive, then the hysterectomy should be abandoned; these patients should undergo chemoradiation.

For patients who desire fertility preservation, radical trachelectomy and pelvic lymph node dissection with (or without) para-aortic lymph node sampling can be considered for stage IB1 tumors 2 cm or less (see page 1391).6468 In one study, oncologic outcomes were similar after 4 years when comparing radical trachelectomy with radical hysterectomy for patients with stage IB1 cervical carcinoma.68 A study found that among women attempting to conceive after radical trachelectomy for early-stage cervical cancer, the 5-year cumulative pregnancy rate was 52.8%; the cancer recurrence rate was low, but the miscarriage rate is higher.69 For young (< 45 years) premenopausal women with early-stage squamous cell carcinoma who opt for ovarian preservation (i.e., hysterectomy only), the rate of ovarian metastases is low.70,71

Recent data suggest that sentinel lymph node biopsy may be useful for decreasing the need for pelvic lymphadenectomy in patients with early-stage cervical cancer, but panel members believe the technique is not yet sufficiently validated.7274 However, this is an interesting area for further research.7578

For patients with stage IB or IIA tumors (including those who are not candidates for hysterectomy), another option is combined pelvic radiotherapy and brachytherapy with or without concurrent cisplatin-containing chemotherapy (see page 1391). Although concurrent chemoradiation has been proven effective in the definitive treatment of more advanced-stage disease, this approach has not been specifically studied in patients with stage IB1 or IIA1 disease. Careful consideration of the risk/benefit ratio should be undertaken in these patients with smaller tumors.

For patients with clinical stage IB2 or IIA2 tumors who are treated with definitive radiation, concurrent cisplatin-containing chemotherapy has been shown to significantly improve patient survival.41,42 For stage IB2 or IIA2 tumors, the panel disagreed (category 3) about recommending adjuvant hysterectomy for patients undergoing primary chemoradiation.41

Advanced Disease

This category has traditionally included patients with stage IIB to IVA disease (i.e., locally advanced disease). However, many oncologists now include patients with IB2 and IIA2 disease in the advanced disease category. For patients with more advanced tumors who are undergoing primary chemoradiation, the volume of RT is critical and guided by assessment of nodal involvement in the pelvic and para-aortic nodes. Radiologic imaging studies (including PET-CT) are recommended for stage IB2 or greater disease. MRI is useful to rule out disease high in the endocervix. However, needle biopsy can be considered for questionable imaging findings. Surgical staging (i.e., extraperitoneal or laparoscopic lymph node dissection) is also an option (category 2B) for these patients. Surgical staging may also detect microscopic nodal disease that is not discernable with radiologic imaging.79

For patients without nodal disease or with disease limited to the pelvis only through surgical staging, treatment consists of pelvic RT with concurrent cisplatin-based chemotherapy and brachytherapy (category 1).42,4446,54 However, for patients with positive para-aortic and pelvic lymph nodes by imaging, extraperitoneal lymph node dissection should be considered followed by extended-field RT, concurrent cisplatin-containing chemotherapy, and brachytherapy (see page 1395). Patients with positive para-aortic lymph nodes who are positive for distant metastases are treated with systemic chemotherapy (see page 1401) and individualized RT.

Metastatic Disease

For patients who present with distant metastatic disease (i.e., stage IVB), primary treatment is often cisplatin-based chemotherapy (see Systemic Therapy for Metastatic Disease, page 1406). In these situations, individualized RT may be considered for control of pelvic disease and all other symptoms.

Adjuvant Treatment

Adjuvant treatment is indicated after radical hysterectomy, depending on surgical findings and disease stage. Observation is appropriate for patients with stage IA2, IB1, or IIA1 disease who have negative nodes and no risk factors after radical hysterectomy. However, adjuvant treatment is indicated after radical hysterectomy if pathologic risk factors are discovered. For patients with stage IA2, IB1, or IIA1 disease who have negative lymph nodes after surgery but have large primary tumor size, deep stromal invasion, and/or LVSI, pelvic radiation is recommended (category 1) with (or without) concurrent cisplatin-based chemotherapy (category 2B for chemotherapy).8083

Adjuvant pelvic RT alone versus no further therapy was tested in a randomized trial (Gynecologic Oncology Group [GOG] 92) of selected patients with node-negative stage IB carcinoma of the cervix after hysterectomy and pelvic lymphadenectomy.83 Patients were eligible for this trial after radical hysterectomy and pelvic lymphadenectomy if they had at least 2 of the following risk factors: 1) greater than one third stromal invasion; 2) capillary lymphatic space involvement; or 3) cervical tumor diameters more than 4 cm. Patients with positive lymph nodes or involved surgical margins were excluded. At 2 years, the recurrence-free rates were 88% for the RT group versus 79% for the no-further-treatment group. After long-term follow-up (12 years), an updated analysis confirmed that pelvic RT increased progression-free survival; there was also a clear trend towards improved overall survival (P = .07).84

Patients with positive pelvic nodes, positive surgical margin, and/or positive parametrium should be treated with postoperative pelvic radiation with concurrent cisplatin-containing chemotherapy (category 1)43 with (or without) vaginal brachytherapy (see page 1392). Vaginal brachytherapy may be a useful boost for patients with positive vaginal mucosal margins. The addition of concurrent chemoradiation significantly improves overall survival for high-risk patients with early-stage disease (those with positive lymph nodes, parametrial extension, and/or positive margins) who undergo radical hysterectomy and pelvic lymphadenectomy.43 The Intergroup trial 0107 showed a statistically significant benefit of adjuvant pelvic radiation with concurrent cisplatin and 5-FU in the treatment of patients with stage IA2, IB, or IIA disease who had positive lymph nodes, positive margins, and/or microscopic parametrial involvement found at surgery.43

If para-aortic lymph nodes are found to be positive during surgical staging, patients must undergo further screening with chest CT or combined PET-CT scan. In women who are positive for distant metastases, biopsy of suspicious areas should be considered as indicated (see page 1392). For patients without distant metastases, recommended treatment is extended-field RT (including pelvis and para-aortic lymph nodes) with concurrent cisplatin-based chemotherapy with (or without) brachytherapy. For patients with distant metastases, recommended treatment is systemic chemotherapy (see page 1401) and individualized radiotherapy.

Surveillance

Because no definitive study or uniform agreement exists on the best method for posttreatment surveillance for cervical cancer, the panel combined the practice patterns of NCCN Member Institutions and issued consensus recommendations. Patient follow-up includes interval history and physical examination, with cervical/vaginal cytology every 3 to 6 months for 2 years, every 6 months for another 3 to 5 years, and then annually (see page 1397). Some clinicians have suggested that rigorous cytology follow-up is not warranted because of studies stating that Pap smears did not detect recurrences in patients with stage I or II cervical cancer who were asymptomatic after treatment.85,86 It is important to emphasize good clinical evaluation and a high index of suspicion, because the detection rate of recurrent cervical cancer is low using cervical and vaginal cytology alone.87 Patient education regarding symptoms suggestive of recurrence is appropriate.

In patients at high risk for locoregional (central or para-aortic) failure, a combined PET-CT scan may be useful for detecting asymptomatic disease that is potentially curable.8890 Annual chest radiographs are optional.87,91 Many other tests remain optional based on clinical indications, such as semiannual complete blood counts, blood urea nitrogen, and serum creatinine determinations (see page 1397). Patients with persistent or recurrent disease must be evaluated using additional imaging studies as clinically indicated, and surgical exploration in selected cases, followed by therapy for relapse (see next section).92

Vaginal dilators are recommended after pelvic RT, because patients who receive RT are prone to vaginal stenosis, which can impair sexual function. Women can use vaginal dilators to prevent or treat vaginal stenosis. Dilator use can start 2 to 4 weeks after RT is completed and can be used indefinitely (http://www.ukons.org/storage/dilators_guidelines.pdf).

Cervical cancer survivors are at risk for second cancers.93 Data suggest that patients who undergo radiation therapy for pelvic cancers are at risk for radiation-induced second cancers, especially at radiated sites near the cervix (e.g., colon, rectum/anus, urinary bladder); therefore, careful surveillance is appropriate for these patients.94,95

Therapy for Relapse

Locoregional Therapy

Patients with a localized recurrence of cervical cancer after initial treatment should be evaluated to determine whether radiotherapy or surgery can be used for relapse. Long-term disease-free survival rates of approximately 40% have been reported in some situations.96

For patients who experience locoregional recurrences who have not undergone previous RT or who experience recurrences outside of the previously treated RT field, therapy for relapse includes tumor-directed RT and platinum-based chemotherapy with (or without) brachytherapy; surgical resection can be considered if feasible (see page 1398). Typically, the chemoradiation for recurrence uses cisplatin as a single agent or cisplatin plus 5-FU.97,98

Patients with central pelvic recurrent disease after RT should be evaluated for pelvic exenteration, with (or without) intraoperative RT (IORT).99105 Surgical mortality is generally 5% or lower, with survival rates approaching 50%.101 Concomitant measures with these radical procedures include adequate rehabilitation programs dealing with the psychosocial and psychosexual consequences of the operation and reconstructive procedures.100,106108 Although exenteration is the common surgical approach in postradiation patients, radical hysterectomy or brachytherapy may be an option in carefully selected patients with small central lesions (< 2 cm).

For patients with noncentral recurrent disease, options include resection with IORT for close or positive margins, tumor-directed RT with (or without) chemotherapy, chemotherapy, best supportive care (see NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines] for Palliative Care; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org), or participation in a clinical trial. Patients who experience recurrence after second-line definitive therapy, either surgery or RT, have a poor prognosis. They can be treated with chemotherapy or best supportive care, or be enrolled in a clinical trial.

Systemic Therapy for Metastatic Disease

Patients who develop distant metastases, either at initial presentation or at relapse, are rarely curable. For highly selected patients with isolated distant metastases, occasional long-term survival has been reported with 1) surgical resection with (or without) IORT; 2) RT with (or without) concurrent chemotherapy; or 3) chemotherapy (see page 1398). For most other patients with distant metastases, appropriate treatment is either chemotherapy (see page 1401) or best supportive care.

The palliation of pelvic recurrences in heavily irradiated sites that are not amenable to local pain control techniques or surgical resection is an unresolved clinical issue. These sites are generally not responsive to chemotherapy. Adequately palliating the complications of pain and fistulae from these recurrences is clinically challenging (http://emedicine.medscape.com/article/270646-overview). However, short courses of RT may provide symptomatic relief to patients with bone metastases, painful para-aortic nodes, or supraclavicular adenopathy.109,110

Chemotherapy has a limited role in prolonging survival or improving quality of life, and is recommended for patients with extrapelvic metastases or recurrent disease who are not candidates for RT or exenterative surgery. Patients who experience response to chemotherapy may have pain relief of a transient nature. If cisplatin was previously used as a radiosensitizer, combination platinum-based regimens are preferred over single agents in the metastatic disease setting based on several randomized phase III trials (see next section).111,112

First-Line Combination Chemotherapy: Cisplatin has been considered the most effective agent for treating metastatic cervical cancer.113 However, most patients who develop metastatic disease have received concurrent cisplatin/RT as primary treatment and may no longer be sensitive to single-agent platinum therapy.111,112 Cisplatin-based combination chemotherapy regimens, such as cisplatin/paclitaxel and cisplatin/topotecan, have been extensively investigated in clinical studies.111,112,114116

A randomized phase III study (GOG 169) in 264 eligible patients comparing paclitaxel and cisplatin with cisplatin alone showed that patients treated with the 2-drug combination had a higher response rate (36% vs. 19%) and improved progression-free survival (4.8 vs. 2.8 months; P > .001), although no improvement was seen in median survival.111 Patients who experienced response to cisplatin/paclitaxel experienced a significant improvement in quality of life. Although carboplatin/paclitaxel has not been studied in a prospective randomized setting, many physicians use carboplatin/paclitaxel because of ease of administration and tolerability.

Another randomized phase III GOG study (GOG 179) investigated the combination of cisplatin and topotecan versus cisplatin alone in recurrent or persistent cervical cancer. In this study of 294 eligible patients, the topotecan combination regimen was shown to be superior to single-agent cisplatin in overall response rate (27% vs. 13%; P = .004), progression-free survival (4.6 vs. 2.9 months; P = .014), and median survival (9.4 vs. 6.5 months; P = .017).112 The FDA has approved cisplatin/topotecan for advanced cervical cancer. However, the cisplatin/paclitaxel or carboplatin/paclitaxel regimens are less toxic and easier to administer than cisplatin/topotecan.

A recent phase III trial (GOG 204) in 513 patients with advanced metastatic or recurrent cancer assessed 4 cisplatin-doublet regimens (cisplatin/paclitaxel, cisplatin/topotecan, cisplatin/gemcitabine, and cisplatin/vinorelbine).116 The trial was closed early, because it was apparent that cisplatin/topotecan, cisplatin/gemcitabine, and cisplatin/vinorelbine were not superior to cisplatin/paclitaxel. No significant differences in overall survival were seen; however, the trends for response rate, progression-free survival, and overall survival (12.9 vs. 10 months) suggest that cisplatin/paclitaxel is superior to the other regimens. Cisplatin/paclitaxel was associated with less thrombocytopenia and anemia (but with more nausea, vomiting, infection, and alopecia) than the other regimens. Although cisplatin/gemcitabine was not shown to be a superior regimen in GOG 204, it was tolerable. Based on a phase III randomized trial for locally advanced cervical cancer, the guidelines include cisplatin/gemcitabine as an option.61 Cisplatin/gemcitabine may be a useful regimen for patients with neuropathy who cannot tolerate other regimens.

Many clinicians prefer using carboplatin rather than cisplatin because of ease of administration, tolerability, and preservation of renal function. A retrospective trial assessing cisplatin/paclitaxel versus carboplatin/paclitaxel confirmed these opinions.117 Paclitaxel and carboplatin have been assessed for recurrent or persistent cancer of the cervix. In a study using paclitaxel and carboplatin in 25 women, the median overall survival was 21 months.118 Recently, a study using paclitaxel and carboplatin in 51 women had a median overall survival of 13 months.119 A phase III trial is currently assessing carboplatin/paclitaxel versus cisplatin/paclitaxel.120 Nonplatinum doublets are also being studied.121

Single Agents: Cisplatin is generally regarded as the most active agent and is recommended as a possible first-line single-agent chemotherapy in recurrent or metastatic cervical cancer; reported response rates are approximately 20% to 30%, with an occasional complete response.111,113,122,123 Overall survival with cisplatin is approximately 6 to 9 months. Carboplatin and paclitaxel each have been reported to be tolerable and efficacious and are also possible first-line single-agent chemotherapies.124127 Therefore, palliation with single agents—cisplatin, carboplatin, or paclitaxel— is a reasonable approach in patients with recurrent disease not amenable to surgical or radiotherapeutic approaches. Complete responses were also observed with topotecan and paclitaxel; however, topotecan is associated with more toxicity than carboplatin and paclitaxel.

Other agents (which are category 2B unless otherwise indicated) that have shown responses or prolongation of progression-free survival and may be useful as second-line therapy include bevacizumab,128 docetaxel,129 5-FU,130 gemcitabine,131 ifosfamide,132,133 irinotecan,134 mitomycin,135 topotecan,136,137 pemetrexed (category 3),138 and vinorelbine (category 3).139

Drug Reactions: Virtually all drugs have the potential to cause adverse reactions, either during or after infusion.140 In cervical cancer treatment, drugs that more commonly cause adverse reactions include carboplatin, cisplatin, docetaxel, liposomal doxorubicin, and paclitaxel. Most of these drug reactions are mild infusion reactions (e.g., skin reactions, cardiovascular reactions, respiratory or throat tightness), but more severe allergic reactions (e.g., life-threatening anaphylaxis) can occur.141,142 In addition, patients can have severe infusion reactions and mild allergic reactions. Infusion reactions are more common with paclitaxel.143 Allergic reactions (i.e., true drug allergies) are more common with platinum agents (e.g., carboplatin, cisplatin).143,144

Management of drug reactions is discussed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Ovarian Cancer (see page OV-C, available online, in these guidelines, at www.NCCN.org).143 Importantly, patients who have experienced severe life-threatening reactions should not receive the implicated agent again. If a mild allergic reaction previously occurred and it is appropriate to administer the drug again, a desensitization regimen should be used even if the symptoms have resolved. Various desensitization regimens have been published and should be followed.144146 Patients must be desensitized with each infusion if they experienced a previous reaction. Almost all patients can be desensitized.140 To maximize safety, patients should be desensitized in the intensive care unit.140

Other Agents: Vaccine therapies currently have no established role in the treatment of cervical cancer, except in the setting of a clinical trial.147149 Targeted therapy (using small molecules or monoclonal antibodies) is currently utilized in clinical trials.60,128,150,151

Best Supportive Care: Patients with refractory systemic cancer warrant a comprehensive coordinated approach involving hospice care, pain consultants, and emotional and spiritual support, individualized to the situation (see NCCN Guidelines for Palliative Care; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).

Incidental Cervical Cancer

Invasive cervical carcinoma is sometimes found incidentally after extrafascial hysterectomy. Workup for these patients includes history and physical examination, complete blood cell count (including platelets), and liver and renal function tests. Radiologic imaging includes chest radiography, CT or combined PET-CT, or MRI as indicated (e.g., to rule out disease high in the endocervix), although imaging is optional for patients with stage IB1 or smaller tumors (see page 1396).

No definitive data exist regarding the appropriate primary treatment of these patients. The panel believes that a reasonable treatment schema for patients with either stage IA1 with LVSI or with stage IA2 or higher tumors (pathologic findings) should be based on the status of the surgical margins. If margins are positive and imaging is negative for nodal disease, then pelvic RT with concurrent cisplatin-containing chemotherapy with or without individualized brachytherapy should be recommended (see page 1396). Patients with stage IA1 disease with no LVSI should undergo surveillance.

If margins or imaging is negative in stage IA2 or greater tumors, options include pelvic RT with (or without) concurrent cisplatin-containing chemotherapy and brachytherapy; or a complete parametrectomy, upper vaginectomy, and pelvic lymph node dissection with (or without) para-aortic lymph node sampling. Patients with negative lymph nodes should be observed or treated with optional pelvic radiation with (or without) vaginal brachytherapy if they have high-risk factors (i.e., large primary tumor, deep stromal invasion, and/or LVSI; see page 1396).83 Concurrent cisplatin-based chemoradiation is recommended for gross residual disease, positive imaging, disease in the lymph nodes and/or parametrium, and/or a positive surgical margin; individualized brachytherapy is clearly indicated for a positive vaginal margin.

Radiation Therapy

RT is often used in the management of patients with cervical cancer, either for those with intact cervical cancer who are not amenable to surgery (e.g., definitive therapy for those with locally advanced disease or those who are poor operative candidates) or after radical hysterectomy (i.e., adjuvant RT) in those who have one or more pathologic risk factors (e.g., positive lymph nodes, parametrial infiltration, positive surgical margins, large tumor size, deep stromal invasion, lymphovascular space invasion).

The algorithm provides general RT dosage recommendations, which are expanded in the Principles of Radiation Therapy section (see pages 1399 and 1400). These RT dosages should not be interpreted as standalone recommendations, because RT techniques and clinical judgment are essential parts in developing an appropriate treatment regimen.

Optimum staging of patients to precisely delineate the primary tumor volume and draining lymph nodes, including abdominopelvic radiologic studies (CT, MRI, or combined PET-CT scans), is recommended in patients with stage IB2, IIA2, or advanced-stage tumors. Contemporary imaging studies must be correlated with careful assessment of clinical findings to define tumor extent, especially regarding vaginal or parametrial extension.

Radiation Treatment Planning

Technologic advances in imaging, computer treatment planning systems, and linear accelerator technology have enabled the more precise delivery of radiation dose to the pelvis. However, physical accuracy of dose delivery must be matched to a clear understanding of tumor extent, potential pathways of spread, and historical patterns of locoregional recurrence to avoid geographic misses.

CT-based treatment planning with conformal blocking and dosimetry is considered standard care for external-beam radiotherapy. Brachytherapy is a critical component of therapy in patients with intact cervical cancer and is typically combined with external-beam radiation in an integrated treatment plan.

For patients with locally advanced cancers, initial radiation treatment of 40 to 45 Gy to the whole pelvis is often necessary to obtain tumor shrinkage to permit optimal intracavitary placements. With low–dose-rate intracavitary systems, total doses from brachytherapy and external-beam radiation to point A of at least 80 Gy are currently recommended for small tumors, with doses of 85 Gy or higher recommended for larger tumors.

For lesions in the lower one third of the vagina, the inguinal lymph nodes must be treated. The use of extended-field radiation to treat occult or macroscopic para-aortic lymph node disease must be carefully planned to ensure an adequate dose is delivered (45 Gy for microscopic disease) without exceeding bowel, spinal cord, or renal tolerances.152 General recommendations for radiation volumes and doses are discussed in the algorithm (see pages 1399 and 1400).

Intensity-modulated radiotherapy (IMRT) is becoming more widely available; however, issues regarding target definition, patient and target immobilization, tissue deformation, and reproducibility remain to be validated.153157 The role of IMRT in cervical cancer continues to be evaluated in several prospective multicenter clinical trials.

Several retrospective analyses suggest that prolonged treatment duration has an adverse effect on outcome.158162 Extending the overall treatment beyond 6 to 8 weeks can result in approximately a 0.5% to 1% decrease in pelvic control and cause-specific survival for each extra day of overall treatment time. Thus, although no prospective randomized trials have been performed, it is generally accepted that the entire RT course (including both external-beam and brachytherapy components) should be completed in a timely fashion (within 8 weeks); delays or splits in the treatment should be avoided whenever possible.

Normal Tissue Considerations

Planning for RT in cervical cancer must take into account the potential impact on surrounding critical structures, such as rectum, bladder, sigmoid, small bowel, and bone. Acute effects (i.e., diarrhea, bladder irritation, fatigue) occur to some degree in most patients undergoing radiation and are typically magnified by concurrent chemotherapy. However, acute effects can often be managed with medications and supportive care, and they generally resolve soon after completion of radiation.

The risk of more significant late effects (e.g., obstruction, fibrosis/necrosis, fistula) is related to the volume, total dose, dose per fraction, and specific intrinsic radiosensitivity of the normal tissue irradiated.152 Careful blocking to minimize normal tissue exposure while not compromising tumor coverage is critical to achieving optimal outcomes. In addition, patient-related conditions (e.g., inflammatory bowel disease, collagen-vascular disease, multiple abdominal/pelvic surgeries, history of pelvic inflammatory disease, diabetes) influence determination of radiation dose and volumes.

For most patients, it is generally accepted that the whole pelvis can tolerate an external-beam radiation dose of 40 to 50 Gy. Gross disease in the parametria or unresected nodes may undergo tightly contoured external beam boosts to 60 to 65 Gy. Intracavitary brachytherapy boosts require attention to proper placement of the applicators within the uterus and against the cervix and vaginal apex, and appropriate packing to maximally displace the bladder and rectum.

Pregnancy and Cervical Cancer

In pregnant women, cervical cancer is the most frequently diagnosed type of cancer; however, most pregnant women with cervical cancer have stage I disease.163 Invasive cervical cancer during pregnancy creates a clinical dilemma. Women must make the difficult decision to either delay treatment until documented fetal maturity or undergo immediate treatment based on their stage of disease. Women who delay treatment until fetal maturity should have their children delivered by cesarean section. For women diagnosed with cervical cancer during pregnancy who wish to continue their pregnancies, delaying cancer treatment until the fetus has matured has been reported.163

Patients with early-stage disease may prefer to have radical hysterectomy and node dissection instead of RT to avoid radiation fibrosis and preserve their ovaries. Patients with early-stage disease who delay treatment until fetal maturity can undergo cesarean section with radical hysterectomy and pelvic node dissection. For those choosing RT, traditional RT with (or without) chemotherapy protocols (described previously) may need to be modified.163 Vaginal radical trachelectomy has been successfully performed in a few pregnant patients with early-stage cervical cancer.164167

Summary

Cervical cancer is decreasing in the United States because of the wide use of screening; however, it is increasing in developing countries (∼ 270,000 deaths per year), because screening is not available to many women. Effective treatment for cervical cancer (including surgery and concurrent chemoradiation) can yield cures in 80% of women with early-stage disease (stages I–II) and in 60% of women with stage III disease. The hope is that immunization against HPV (using the new vaccines) will prevent persistent infection with certain types of the virus, and will therefore prevent specific HPV cancer in women.11,12,168

Individual Disclosures for the NCCN Cervical Cancer Panel

T1

NCCN Clinical Practice Guidelines in Oncology for Cervical Cancer

NCCN Categories of Evidence and Consensus

Category 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus.

Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus.

Category 2B: The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement).

Category 3: The recommendation is based on any level of evidence but reflects major disagreement.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Please Note

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines™ is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representation or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their applications or use in any way.

© National Comprehensive Cancer Network, Inc. 2010, All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

Disclosures for the NCCN Guidelines Panel for Cervical Cancer

At the beginning of each NCCN Guidelines panel meeting, panel members disclosed any financial support they have received from industry. Through 2008, this information was published in an aggregate statement in JNCCN and online. Furthering NCCN's commitment to public transparency, this disclosure process has now been expanded by listing all potential conflicts of interest respective to each individual expert panel member.

Individual disclosures for the NCCN Guidelines for Cervical Cancer panel members can be found on page 1416. (The most recent version of these guidelines and accompanying disclosures, including levels of compensation, are available on the NCCN Web site at www.NCCN.org.)

These guidelines are also available on the Internet. For the latest update, please visit www.NCCN.org.

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    NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer Version

    Version 1.2011, 10-06-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

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    Version 1.2011, 10-06-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

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    NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer Version

    Version 1.2011, 10-06-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

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    NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer Version

    Version 1.2011, 10-06-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer Version

    Version 1.2011, 10-06-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer Version

    Version 1.2011, 10-06-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

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