NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN GUIDELINES®: Cervical Cancer, Version 3.2019
Version 3.2019 12/17/18 © National Comprehensive Cancer Network, Inc. 2019 All rights reserved.
The NCCN 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 17, 1; 10.6004/jnccn.2019.0001
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.1–5
The earliest stages of cervical carcinoma may be asymptomatic or associated with a watery vaginal discharge and postcoital bleeding or intermittent spotting. Often these early symptoms are not recognized 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. Cone biopsy (ie, 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 (ie, endocervical canal).6,7 The College of American Pathologists (CAP) protocol for cervical carcinoma is a useful guide (available at http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2012/Cervix_12protocol.pdf). This CAP protocol was revised in June 2012 and reflects recent updates in the AJCC/FIGO staging (ie, AJCC Cancer Staging Manual, 8th edition).
Workup for these patients with suspicious symptoms includes history and physical examination, complete blood count (CBC; including platelets), and liver and renal function tests. Recommended radiologic imaging includes chest radiograph, CT, or combined PET/CT, and MRI as indicated (eg, to rule out disease high in the endocervix).2,8 For detailed imaging recommendations by stage and planned treatment approach, see “Principles of Imaging” in the NCCN Guidelines for Cervical Cancer, available online at NCCN.org). Smoking cessation and counseling, as well as HIV testing (especially in younger patients), are recommended. Cystoscopy and proctoscopy are only recommended if bladder or rectal extension is suspected. Options for fertility sparing should be considered.
NCCN GUIDELINES®: Cervical Cancer, Version 3.2019
Version 3.2019 12/17/18 © National Comprehensive Cancer Network, Inc. 2019 All rights reserved.
The NCCN 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 17, 1; 10.6004/jnccn.2019.0001
Principles of Staging and Surgery
Clinical Staging
Because noninvasive radiographic imaging may not be routinely available in low-resource countries, the FIGO system limits the imaging to chest radiography, intravenous pyelography, and barium enema. The staging of carcinoma of the cervix is largely a clinical evaluation. Although surgical staging is more accurate than clinical staging, surgical staging often cannot be performed in low-resource countries.4,9,10
The panel currently uses the 2009 FIGO definitions and staging system, which takes into account primary tumor characteristics (diameter in greatest dimension, cervical stromal invasion, locoregional spread) and distant metastasis.9,11 Regional nodal metastasis is not included in the FIGO staging criteria. With the 2009 FIGO staging, stage IIA is now subdivided into stage IIA1 (tumor size ɤ4 cm) and stage IIA2 (tumor size >4 cm), which is the only change from the previous 1994 FIGO staging system. FIGO directly aligns with AJCC staging with the exception of stage 0, which does not exist in the FIGO system.12,13 Importantly, lymphovascular space invasion (LVSI) does not alter the FIGO classification.9 FIGO did not include LVSI because pathologists do not always agree on whether LVSI is present in tissue samples. Some panel members believe that patients with stage IA1 who have extensive LVSI should be treated using stage IB1 guidelines.
The use of MRI, CT, or combined PET/CT scans may aid in treatment planning, but it is not accepted for formal staging purposes.8,10,14 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 (ie, CT, MRI, PET/CT) are used to guide treatment options and design. MRI is useful to delineate disease extent and to guide decisions regarding fertility-sparing versus non–fertility-sparing treatment approaches,15–21 whereas PET/CT may be useful to detect and/or rule out metastasis.22–26
Surgical Staging
Pathologic Assessment
Surgicopathologic factors may be used to guide the extent of surgical staging and treatment decisions. Findings from pathologic assessment of the surgical specimen should be carefully documented. Important elements
NCCN GUIDELINES®: Cervical Cancer, Version 3.2019
Version 3.2019 12/17/18 © National Comprehensive Cancer Network, Inc. 2019 All rights reserved.
The NCCN 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 17, 1; 10.6004/jnccn.2019.0001
The “Sedlis criteria,” which are intermediate risk factors used to guide adjuvant treatment decisions, include: (1) greater than one-third stromal invasion; (2) capillary lymphatic space involvement; or (3) cervical tumor diameters greater than 4 cm.27 However, potentially important risk factors for recurrence may not be limited to the Sedlis criteria. Additional risk factors for consideration include tumor histology (eg, adenocarcinoma component)28,29 and close or positive surgical margins.30,31
Recent findings suggest that predictive factors for lymph node metastasis in endocervical adenocarcinoma may differ from squamous cell carcinoma. Data from retrospective studies suggest that the pattern of cervical stromal invasion and presence of LVSI, but not primary tumor size, predict risk of nodal metastasis. Alternative classification systems incorporating stromal invasion pattern have been proposed for adenocarcinoma.32–34 These systems remain to be validated for clinical use.
Conservative/Fertility-Sparing Approaches
Fertility-sparing approaches may be considered in highly selected patients who have been thoroughly counseled regarding disease risk as well as prenatal and perinatal issues.35 Consultation with reproductive endocrinology fertility experts is suggested.
Microinvasive disease (FIGO stage IA1 with no LVSI) is associated with an extremely low incidence of lymphatic metastasis,36–39 and conservative treatment with conization is an option (category 2A) for individuals with no evidence of LVSI. In stage IA1 individuals with evidence of LVSI, a reasonable conservative approach is conization (with negative margins) in addition to SLN mapping algorithm or pelvic lymphadenectomy.
The goal of conization is en bloc removal of the ectocervix and endocervical canal; the shape of the cone can be tailored to the size, type, and location of the lesion
NCCN GUIDELINES®: Cervical Cancer, Version 3.2019
Version 3.2019 12/17/18 © National Comprehensive Cancer Network, Inc. 2019 All rights reserved.
The NCCN 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 17, 1; 10.6004/jnccn.2019.0001
Select patients with stage IA2 or IB1 cervical cancer, especially for those with tumors of less than 2 cm in diameter, may be eligible for conservative surgery.46,47 Radical trachelectomy may offer a reasonable fertility-sparing treatment option for patients with stage IA2 or IB1 cervical cancer with lesions that are less than or equal to 2 cm in diameter.48–50 In a radical trachelectomy, the cervix, vaginal margins, and supporting ligaments are removed while leaving the main body and fundus of the uterus intact.51 Laparoscopic pelvic lymphadenectomy accompanies the procedure and can be performed with or without SLN mapping (see “Lymph Node Mapping and Dissection” on page 69). Due to their aggressive nature, tumors of small cell neuroendocrine histology are considered inappropriate for radical trachelectomy.52 Trachelectomy is also inappropriate for treating gastric type cervical adenocarcinoma and adenoma malignum (minimal deviation adenocarcinoma) due to their diagnostic challenges and potentially aggressive nature.53
Vaginal radical trachelectomy (VRT) may be used for carefully selected patients with lesions of 2 cm diameter or less.54–56 Abdominal radical trachelectomy (ART) provides a broader resection of the parametria48,56 than the vaginal approach and is commonly used in stage IB1 lesions. Multiple case series have evaluated safety and outcomes with vaginal versus abdominal approaches to radical trachelectomy,54,57–59 including systematic reviews on VRT60 and ART.61 A limited number of studies have specifically examined this approach in patients with larger stage IB1 tumors between 2 cm and 4 cm in diameter and reported safe oncologic outcomes; however, as expected, more patients in this subgroup will require adjuvant therapy that may reduce fertility.62–64
Studies that examined pregnancy in women who underwent radical trachelectomy have provided differing success rates. One case series of 125 patients with cervical cancer who underwent VRT reported 106 pregnancies among 58 women.55 In a systematic review of 413 women who underwent ART, 113 women attempted pregnancy and 67 (59%) successfully conceived.58 However, miscarriage and preterm labor rates were elevated among women who underwent radical trachelectomy.55,65–67
NCCN GUIDELINES®: Cervical Cancer, Version 3.2019
Version 3.2019 12/17/18 © National Comprehensive Cancer Network, Inc. 2019 All rights reserved.
The NCCN 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 17, 1; 10.6004/jnccn.2019.0001
Non–Fertility-Sparing Approaches
The Querleu and Morrow surgical classification system68,69 describes the degree of resection and nerve preservation for radical hysterectomy in 3D planes and updates the previously used Piver-Rutledge classifications.70 Approaches to hysterectomy include simple/extrafascial hysterectomy (type A), modified radical hysterectomy (type B), and radical hysterectomy (type C).71,72
For patients with IA1 disease, cone excision, simple/extrafascial hysterectomy, and modified radical hysterectomy are options. Radical hysterectomy with bilateral pelvic lymph node dissection (with or without SLN mapping) is the preferred treatment approach for patients with FIGO stage IA2 through IIA1 cervical cancers. Radical hysterectomy is preferred over simple hysterectomy due to its wider paracervix margin of resection that also includes aspects of the cardinal and uterosacral ligaments, upper vagina, pelvic nodes, and at times, para-aortic nodes. In the United States, definitive chemoradiation is typically preferred over radical surgery for select patients with bulky FIGO IB2 lesions and the vast majority of FIGO stage IIA2 or greater cervical cancers. Abroad, select FIGO IB2 to IIB cases may be treated with radical hysterectomy or neoadjuvant chemotherapy followed by radical hysterectomy.
For recurrent or persistent cervical cancers that are confined to the central pelvis (ie, no distant metastasis), pelvic exenteration may be a potentially curative surgical option.73,74 Discussion of the various approaches to pelvic exenteration are offered by Chi and colleagues,71 and in the GOG Surgical Manual.72
Lymph Node Mapping and Dissection
Sentinel Lymph Node Mapping
Recent data suggest that SLN biopsy may be useful for decreasing the need for pelvic lymphadenectomy in patients with early-stage cervical cancer.75,76
Prospective studies generally support the feasibility of SLN detection in patients with early-stage cervical cancer and suggest that extensive pelvic lymph node dissection may be safely avoided in a significant proportion of early-stage cases.75–86
Meta-analyses of pooled data from SLN mapping studies have generated SLN detection rates of 89% to 92% and sensitivity of 89% to 90%.87,88 Factors determined to be important for detection included laparoscopy, dual blue dye/radiocolloid tracer approaches, and pathologic assessment using immunohistochemistry. However, based on a recent metaanalysis, indocyanine
NCCN GUIDELINES®: Cervical Cancer, Version 3.2019
Version 3.2019 12/17/18 © National Comprehensive Cancer Network, Inc. 2019 All rights reserved.
The NCCN 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 17, 1; 10.6004/jnccn.2019.0001
Study data also highlight the limited sensitivity of this approach and potential to miss SLN micrometastases and isolated tumor cells using intraoperative assessment (ie, frozen section or imprint cytology).78,82,84 The sensitivity of this approach appears to be better in patients with tumors ≤2 cm in diameter.75,77,79,91 Ultrastaging of detected SLNs has been shown to provide enhanced detection of micrometastases.80,81
The SENTICOL longitudinal study demonstrated the utility of SLN mapping to uncover unusual lymph drainage patterns.79,92 It also highlighted limited agreement between lymphoscintigraphy and intraoperative SLN mapping.92 Additionally, this study revealed that bilateral SLN detection and biopsy provided a more reliable assessment of sentinel nodal metastases and led to fewer false negatives than unilateral SLN biopsy.76 Generally, research supports ipsilateral lymphadenectomy if no sentinel nodes are detected on a given side of the pelvis as outlined in the SLN mapping algorithm.75,76,93
Based on these collective data, the panel recommends consideration of the SLN mapping algorithm and emphasizes that best detection and mapping results are in tumors of less than 2 cm diameter. Adherence to the SLN mapping algorithm is important; surgeons should perform side-specific nodal dissection in any cases of failed mapping and remove all suspicious or grossly enlarged nodes regardless of SLN mapping.75
Para-Aortic Lymph Node Assessment
Studies of the incidence and distribution of lymph node metastases in women with stage IB to IIB cervical cancers suggest that para-aortic lymph node involvement is closely tied to the presence of pelvic lymph node metastases, larger primary tumor size (>2 cm), and metastasis to the common iliac nodes.94,95
Analysis of outcomes data from 555 women who participated in GOG trials (GOG 85, GOG 120, and GOG 165) revealed a more positive prognosis for patients who underwent surgical exclusion of para-aortic lymph node involvement versus those who underwent radiographic determination of para-aortic node involvement.4 One study examined the efficacy of extending the radiation therapy (RT) field to the para-aortic region in patients with para-aortic lymph node involvement, and showed therapeutic benefit especially in patients with small-volume
NCCN GUIDELINES®: Cervical Cancer, Version 3.2019
Version 3.2019 12/17/18 © National Comprehensive Cancer Network, Inc. 2019 All rights reserved.
The NCCN 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 17, 1; 10.6004/jnccn.2019.0001
The panel recommends para-aortic lymph node dissection for patients with stage IB1 or greater disease.
Minimally Invasive Surgical Approaches
The standard and historical approach for radical hysterectomy is with an open abdominal approach.
Previous iterations of the guidelines had indicated that radical hysterectomy could be performed via either open laparotomy or minimally invasive surgery (MIS) laparoscopic approaches, using either conventional or robotic techniques. Data from previous retrospective reviews and prospective observational studies demonstrated oncologic outcomes after conventional laparoscopic radical hysterectomy that were comparable to open abdominal approaches after 3 to 6 years of follow-up.98–101 Similarly, multicenter retrospective reviews and matched cohort studies showed comparable oncologic outcomes (disease recurrence and survival rates) for open abdominal and robotic radical hysterectomy after 3 to 5 years of follow-up.101–104 Additionally, a systematic review and meta-analysis of data from 26 studies found that laparoscopic and robotic radical hysterectomy approaches appeared to provide equivalent intraoperative and short-term postoperative outcomes.105
However, several key contemporary reports have questioned the presumed therapeutic equivalency of open versus MIS approaches. A recently published prospective randomized trial demonstrated that minimally invasive radical hysterectomy was associated with lower rates of disease-free survival (DFS) and overall survival (OS) than open abdominal radical hysterectomy.106 This phase III LACC trial (Clinicaltrials.gov Identifier: NCT00614211) was designed to provide a definitive comparison of outcomes data in patients with early-stage cervical cancer undergoing total abdominal radical hysterectomy or total laparoscopic radical hysterectomy/total robotic radical hysterectomy. At closure, 319 patients had received MIS (84% laparoscopy, 16% robotic) and 312 patients underwent a total abdominal radical hysterectomy. Ninety-two percent of participants in both surgical arms had stage IB1 disease. MIS was associated with lower rate of DFS than open surgery (3-year DFS, 91.2% vs 97.1%; hazard ratio [HR], 3.74; 95% CI, 1.63 to 8.58), as well as a decrease in OS (3-year OS, 93.8% vs 99.0%; HR, 6.00; 95% CI, 1.77 to 20.30).106 MIS did not meet predetermined noninferiority criteria compared with standard-of-care laparotomy (P=.88).
NCCN GUIDELINES®: Cervical Cancer, Version 3.2019
Version 3.2019 12/17/18 © National Comprehensive Cancer Network, Inc. 2019 All rights reserved.
The NCCN 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 17, 1; 10.6004/jnccn.2019.0001
Two other recent epidemiologic studies also showed that minimally invasive radical hysterectomy was associated with shorter OS than open surgery among women with stage IA2 to IB1 cervical cancer.107,108 Melamed et al107 reported on a SEER-based cohort study that compared women with stage IA2 or IB1 cervical cancer who underwent laparotomy (n=1,236) or MIS (n=1,225). Four-year mortality was higher among patients undergoing MIS versus laparotomy (9.1% vs 5.3%; P=.002). Relative survival rates were stable before the adoption of MIS techniques (2000–2006), but a significant decline was noted in the years after adoption. Margul et al108 examined National Cancer Database data from 2010 to 2013 to compare outcomes of patients with stage IB1 cervical cancer who underwent radical hysterectomy performed by open abdominal versus MIS approaches. Although MIS was associated with decreased surgical morbidity and costs, patients with tumor sizes ≥2 cm who underwent MIS had decreased 5-year survival compared with those undergoing open radical hysterectomy (81.3% vs 90.8%; P<.001).108
These most recent findings stand in contradiction to the earlier referenced series that had suggested therapeutic equivalency of MIS compared with open approaches along with the MIS-associated potential advantages of decreased hospital stay and more rapid patient recovery.101,102,104,105,109–112
Given the recently presented findings of poorer oncologic outcomes and survival with the MIS techniques compared with open laparotomy, women should be carefully counseled about the oncologic risks and potential short-term benefits of the different surgical approaches.
Primary Treatment
The primary treatment of early-stage cervical cancer is either surgery or RT. Surgery is typically reserved for early-stage disease, fertility-preservation, and smaller lesions, such as stage IA, IB1, and selected IIA1 cases.3 The panel agrees that concurrent chemoradiation is generally the primary treatment of choice for stages IB2 to IVA disease based on the results of 5 randomized clinical trials (see Table 1, available online, in these guidelines, at NCCN.org).113,114 Chemoradiation can also be used for patients who are not candidates for hysterectomy. Although few studies have assessed treatment specifically for adenocarcinomas, they are typically treated in a similar manner to squamous cell carcinomas.115–117
Pelvic RT or chemoradiation will invariably lead to ovarian failure in premenopausal women.118 To preserve
NCCN GUIDELINES®: Cervical Cancer, Version 3.2019
Version 3.2019 12/17/18 © National Comprehensive Cancer Network, Inc. 2019 All rights reserved.
The NCCN 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 17, 1; 10.6004/jnccn.2019.0001
Important Phase III Clinical Trials Underpinning Treatment Recommendations
A randomized Italian study compared RT alone versus radical hysterectomy and lymph node dissection in patients with clinical early-stage disease (stage IB–IIA).121 Adjuvant RT was given to those with parametrial extension, less than 3 cm of uninvolved cervical stroma, positive margins, 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.
Concurrent chemoradiation, using platinum-containing chemotherapy (cisplatin alone [preferred] or cisplatin/fluorouracil), is the treatment of choice for stages IB2, II, III, and IVA disease based on the results of randomized clinical trials.122–127 These 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 trials clearly established a role for concurrent cisplatin-containing chemoradiation. Based on these data, the NCI issued an alert stating that strong consideration should be given to using chemoradiation instead of RT alone for invasive cervical cancer.127 Long-term follow-up of 3 of these trials has confirmed that concurrent cisplatin-containing chemoradiation improves progression-free survival (PFS) and OS when compared with RT with (or without) hydroxyurea.128–130 A recent meta-analysis reported that chemoradiotherapy leads to a 6% improvement in 5-year survival (HR, 0.81; P<.001).131 A large, population-based registry analysis in Canada (n=4,069) confirmed that chemoradiotherapy improved outcomes when compared with RT alone.132
Although chemoradiation is tolerated, acute and long-term side effects have been reported.131,133,134 Concurrent single-agent cisplatin chemoradiation may be preferred over cisplatin/fluorouracil chemoradiation due to lesser toxicity.114,135 Concurrent carboplatin (preferred if cisplatin intolerant) or non-platinum chemoradiation regimens are options for patients who may not tolerate cisplatin-containing chemoradiation.131,136–141 Carboplatin has been added to the guidelines as a preferred radiosensitizing agent for patients who are cisplatin intolerant.
Note that when concurrent chemoradiation is used, the chemotherapy is typically given when the external-beam
NCCN GUIDELINES®: Cervical Cancer, Version 3.2019
Version 3.2019 12/17/18 © National Comprehensive Cancer Network, Inc. 2019 All rights reserved.
The NCCN 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 17, 1; 10.6004/jnccn.2019.0001
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 NCCN.org). A new fertility-sparing algorithm was added in 2012 for select patients with stage IA and IB1 disease [see “Primary Treatment (Fertility Sparing)” on page 66]. Fertility-sparing surgery is generally not recommended for patients with small cell neuroendocrine tumors, gastric type adenocarcinoma, or adenoma malignum (minimal deviation adenocarcinoma) because of its high-risk nature and a paucity of data.
Stage IA1 Disease
Recommended options for stage IA1 disease depend on the results of cone biopsy and whether patients (1) want to preserve their fertility; (2) are medically operable; or (3) have LVSI [see “Primary Treatment (Fertility Sparing)” and “Primary Treatment (Non–Fertility Sparing)” in the algorithm, pages 66–68]. The extent of the lymph node dissection depends on whether pelvic nodal disease and/or LVSI are present and the size of the tumors. SLN mapping can be considered.
Fertility-Sparing
For patients who desire fertility preservation, cone biopsy with or without pelvic lymph node dissection is recommended.86,143,144
The goal of cone biopsy is margins that are negative for invasive disease and high-grade squamous intraepithelial lesion. For patients with negative margins after cone biopsy and no findings of LVSI, observation may be an option if fertility preservation is desired. For patients with positive margins after cone biopsy, options include repeat cone biopsy to better evaluate depth of invasion (to rule out stage IA2/IB1 disease) or a radical trachelectomy. In studies of patients who had positive margins after conization, predictors of residual disease included positive endocervical curettage, combined endocervical margin and endocervical curettage, and volume of disease.30,145,146
For patients with stage IA1 disease with LVSI, conization (with negative margins) plus laparoscopic pelvic
NCCN GUIDELINES®: Cervical Cancer, Version 3.2019
Version 3.2019 12/17/18 © National Comprehensive Cancer Network, Inc. 2019 All rights reserved.
The NCCN 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 17, 1; 10.6004/jnccn.2019.0001
After childbearing is complete, hysterectomy can be considered for patients who have had either radical trachelectomy or a cone biopsy for early-stage disease if they have chronic, persistent HPV infection, they have persistent abnormal Pap tests, or they desire this surgery.
For young (<45 years) premenopausal women with early-stage squamous cell carcinoma who opt for ovarian preservation (ie, hysterectomy only), the rate of ovarian metastases is low.151,152
Non–Fertility-Sparing
For medically and technically operable patients with stage IA1 disease who do not desire fertility preservation, extrafascial (ie, simple) hysterectomy is commonly recommended for patients without LVSI and with either negative margins after cone biopsy or with positive margins for dysplasia. For patients with positive margins for carcinoma, modified radical hysterectomy is recommended with SLN mapping/pelvic lymph node dissection (category 2B for node dissection). SLN mapping can be considered. Physicians can also consider repeat cone biopsy to better evaluate depth of invasion. If LVSI is present, then modified radical hysterectomy with SLN mapping/pelvic lymph node dissection is recommended. For patients with negative margins after cone biopsy, observation is recommended for those who are medically inoperable or those who refuse surgery.
Stage IA2 Disease
Recommendations for stage IA2 depend on whether a patient wishes to preserve her fertility and if the disease is medically operable.
Fertility-Sparing
For patients who wish to preserve their fertility, radical trachelectomy and pelvic lymph node dissection is recommended. SLN mapping can also be considered. Cone biopsy followed by observation is another option if the margins are negative and pelvic lymph node dissection is negative.
Non–Fertility-Sparing
For medically operable patients who do not desire fertility preservation, recommended treatment includes either surgery or RT [see “Primary Treatment (Non–Fertility Sparing),” page 67].
NCCN GUIDELINES®: Cervical Cancer, Version 3.2019
Version 3.2019 12/17/18 © National Comprehensive Cancer Network, Inc. 2019 All rights reserved.
The NCCN 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 17, 1; 10.6004/jnccn.2019.0001
Pelvic external beam RT (EBRT) with brachytherapy (traditionally 70–80 Gy to total point A dose) is a treatment option for patients who are medically inoperable or who refuse surgery.154 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, fractionation, and size of target volume or on biologic equivalence calculations when using high dose-rate brachytherapy.
Stage IB and IIA Disease
Depending on stage and disease bulk, patients with stage IB or IIA tumors can be treated with surgery, RT, or concurrent chemoradiation. Fertility-sparing surgery is only recommended for select patients with stage IB1 disease (see subsequent section). A combined PET/CT scan can be performed to rule out extrapelvic disease before deciding how to treat these patients. The GOG considers that surgical staging is an option for patients with advanced cervical cancer. Radiologic imaging is recommended for assessing stage IB2 and IIA2 tumors (see “Principles of Imaging,” available online, in these guidelines, at NCCN.org).
Stage IB1: Fertility-Sparing
For patients who desire fertility preservation, radical trachelectomy and pelvic lymph node dissection with (or without) para-aortic lymph node dissection is an option for stage IB1 disease, but typically only for tumors 2 cm or less [see “Primary Treatment (Fertility Sparing),” page 66].48,147–150,155 SLN mapping can also be considered. Tumors that are 2 to 4 cm have to be carefully selected for a fertility-sparing approach because many of these patients may require postoperative adjuvant therapy due to pathologic risk factors (eg, Sedlis criteria or positive nodes). However, some surgeons suggest that a 2-cm cutoff may be used for vaginal trachelectomy, whereas a 4-cm cutoff may be used for abdominal trachelectomy.156 In one study, oncologic outcomes were similar after 4 years when comparing radical trachelectomy with radical hysterectomy for patients with stage IB1 cervical carcinoma.48
NCCN GUIDELINES®: Cervical Cancer, Version 3.2019
Version 3.2019 12/17/18 © National Comprehensive Cancer Network, Inc. 2019 All rights reserved.
The NCCN 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 17, 1; 10.6004/jnccn.2019.0001
Stage IB and IIA: Non–Fertility-Sparing
For stage IB1 and IIA1 disease, primary surgery consists of radical hysterectomy plus bilateral pelvic lymph node dissection (category 1), with (or without) para-aortic lymph node dissection (category 2B for para-aortic lymph node dissection).122,157 SLN mapping can also be considered for stages IB1 and IIA1. Panel members feel that surgery is the most appropriate option for patients with stage IB1 or IIA1 disease, whereas concurrent chemoradiation is the most appropriate option for those with stage IB2 or IIA2 disease based on randomized trials.121–123,125,126 Thus, the primary surgical option is a category 1 recommendation for patients with stage IB1 or IIA1 disease; however, primary chemoradiation is the category 1 recommendation for those with stage IB2 or IIA2 disease. Para-aortic node dissection may be performed 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 with stage IB or IIA tumors (including those who are not candidates for hysterectomy), another option is combined pelvic EBRT and brachytherapy with (or without) concurrent platinum-containing chemotherapy [see “Primary Treatment (Non–Fertility Sparing),” page 68]. Preferred radiosensitizing regimens include cisplatin or carboplatin for patients who are cisplatin intolerant. Other recommended regimens include cisplatin/fluorouracil. 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. The panel recommends definitive EBRT with concurrent platinum-containing chemotherapy and brachytherapy (traditionally 75–80 Gy to total point A dose). Again, treatment should be modified based on normal tissue tolerance, fractionation, and size of target volume. Primary chemoradiation has a category 1 recommendation [see “Primary Treatment (Non–Fertility Sparing),” page 68].122,123
For stage IB2 or IIA2 tumors, the panel had a major disagreement about recommending adjuvant hysterectomy (category 3) (also known as completion surgery) after primary chemoradiation.122 Adjuvant hysterectomy after RT has been shown to improve pelvic control, but not overall survival, and is associated with increased morbidity.158 A recent Cochrane review examined whether the addition of hysterectomy to standard nonsurgical treatments benefitted women with locally advanced cervical cancer, finding insufficient data to demonstrate a survival benefit associated with surgery.159 The morbidity is higher after completion surgery but this may be reduced using a laparoscopic technique.160–163 Although routine completion hysterectomy is not typically performed, this approach may be considered in patients whose extent of disease or uterine anatomy precludes adequate coverage by brachytherapy.
Advanced Disease
This category has traditionally included patients with stage IIB to IVA disease (ie, 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, especially for evaluation of nodal or extrapelvic tumor (see “Principles of Imaging,” avialable online, in these guidelines, at NCCN.org). MRI is useful to describe local disease extent and assist in radiation treatment planning. However, needle biopsy of extrauterine abnormality can be considered for questionable imaging findings. Surgical staging (ie, extraperitoneal or laparoscopic lymph node dissection) is also an option (category 2B) for these patients.164 Surgical staging may also detect microscopic nodal disease that is not discernable with radiologic imaging.165
For patients without nodal disease or with disease limited to the pelvis only through surgical staging, treatment consists of pelvic EBRT with concurrent platinum-containing chemotherapy and brachytherapy (category 1).113,114,123,125–127,166 Currently, acceptable concurrent platinum-containing regimens include either weekly cisplatin (preferred), carboplatin (preferred if cisplatin intolerant), or cisplatin/fluorouracil, given every 3 to 4 weeks during RT. An international phase III randomized trial reported that concurrent cisplatin/gemcitabine and EBRT followed by 2 additional cycles of cisplatin/gemcitabine after RT improved PFS and OS when compared with a standard regimen of concurrent cisplatin with pelvic EBRT.167 However, this trial is controversial because of changes in its statistical design and because the reported superior regimen of concurrent cisplatin/gemcitabine and EBRT has unresolved toxicity issues.167–170
However, for patients with positive para-aortic and pelvic lymph nodes by imaging, imaging workup for metastatic disease is recommended. Extended-field EBRT, concurrent platinum-containing chemotherapy, and brachytherapy is recommended (see “Primary Treatment” in the algorithm). Patients with positive para-aortic lymph nodes who are positive for distant metastases are treated with systemic chemotherapy (see “Systemic Therapy Regimens for Cervical Cancer,” page 76) with (or without) individualized EBRT.171
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, negative margins, negative parametria, and no cervical risk factors after radical hysterectomy (Sedlis criteria). However, adjuvant treatment is indicated after radical hysterectomy if pathologic risk factors are discovered.
Pelvic EBRT is recommended (category 1) with (or without) concurrent platinum-containing chemotherapy (category 2B for chemotherapy) for patients with stage IA2, IB1, or IIA1 disease who have negative lymph nodes after surgery but have large primary tumors, deep stromal invasion, and/or LVSI).27,172–175 Recommended radiosensitizing regimens include cisplatin (preferred), carboplatin (preferred if cisplatin intolerant), or cisplatin/fluorouracil.
Adjuvant pelvic RT alone versus no further therapy was tested in a randomized trial (GOG 92) of selected patients with node-negative stage IB carcinoma of the cervix after hysterectomy and pelvic lymphadenectomy.27 Patients were considered to have “intermediate-risk” disease and were eligible for this trial if they had at least 2 of the following risk factors (commonly referred to as Sedlis criteria): (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 adjuvant RT versus 79% for the no-adjuvant-treatment group. After long-term follow-up (12 years), an updated analysis confirmed that adjuvant pelvic RT increased PFS; a clear trend towards improved OS was noted (P=.07).172 The role of concurrent cisplatin/RT in patients with intermediate-risk disease is currently being evaluated in an international phase III randomized trial (GOG 263, Clinicaltrials.gov Identifier: NCT01101451).
Potentially important risk factors for recurrence may not be limited to the Sedlis criteria (ie, stromal invasion, LVSI, primary tumor size). Additional risk factors for consideration include tumor histology (eg, adenocarcinoma component)28,29 and close or positive surgical margins.30,31
Postoperative pelvic EBRT with concurrent platinum-containing chemotherapy (category 1)124 with (or without) vaginal brachytherapy is recommended for patients with positive pelvic nodes, positive surgical margin, and/or positive parametrium; these patients are considered to have “high-risk” disease. Vaginal brachytherapy may be a useful boost for those with positive vaginal mucosal margins. Adjuvant concurrent chemoradiation significantly improves OS for patients with high-risk, early-stage disease (those with positive pelvic nodes, parametrial extension, and/or positive margins) who undergo radical hysterectomy and pelvic lymphadenectomy.124 The Intergroup trial 0107/GOG 109 showed a statistically significant benefit of adjuvant pelvic radiation with concurrent cisplatin and fluorouracil 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.124 A recent study re-evaluated these findings from GOG 109 in a population-based cohort (n=3,053) in the National Cancer Database, confirming the survival benefit of adjuvant chemoradiation but suggesting that this benefit may be best realized in patients with lymph node involvement.176
Depending on the results of primary surgery, imaging may be recommended to determine whether distant metastases are present. In women who are positive for distant metastases, perform biopsy of suspicious areas as indicated. For patients without distant metastases, recommended treatment is extended-field EBRT (including pelvic and para-aortic lymph nodes) with concurrent platinum-containing chemotherapy and with (or without) brachytherapy. Recommended radiosensitizing regimens include cisplatin (preferred), carboplatin (preferred if cisplatin intolerant), or cisplatin/fluorouracil. For patients with distant metastases, recommended treatment is systemic chemotherapy (see ”Systemic Therapy Regimens for Cervical Cancer,” page 76) with (or without) individualized EBRT.171
Although neoadjuvant chemotherapy followed by surgery has been used in areas where RT is not available, data suggest no improvement in survival when compared with surgery alone for early-stage cervical cancer177–179 or locally advanced cervical cancer.180,181 A meta-analysis of data on patients with stage IB1 to IIA cervical cancer found that neoadjuvant chemotherapy may reduce the need for adjuvant RT by decreasing tumor size and metastases, but indicated no OS benefit.181 However, data from a second meta-analysis suggested that response to neoadjuvant chemotherapy was a strong prognostic factor for PFS and OS.182,183 Outside of the clinical trial, the panel does not recommend the use of neoadjuvant chemotherapy.
Recurrent or Metastatic Disease
For recommendations regarding recurrent or metastatic disease, please see the full guidelines at NCCN.org.
Summary
Cervical cancer is decreasing in the United States because of the wide use of screening; however, it is increasing in developing countries (approximately 275,000 deaths/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 vaccines) will prevent persistent infection with the types of HPV against which the vaccine is designed, and will therefore prevent specific HPV cancer in women.184–186
Individual Disclosures for Cervical Cancer Panel
References
- 1.↑
Amit A, Schink J, Reiss A, Lowenstein L. PET/CT in gynecologic cancer: present applications and future prospects--a clinician's perspective. Obstet Gynecol Clin North Am 2011;38:1–21, vii.
- 2.↑
Patel S, Liyanage SH, Sahdev A et al.. Imaging of endometrial and cervical cancer. Insights Imaging 2010;1:309–328.
- 3.↑
ACOG practice bulletin. Diagnosis and treatment of cervical carcinomas. Number 35, May 2002. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 2002;78:79–91.
- 4.↑
Gold MA, Tian C, Whitney CW et al.. Surgical versus radiographic determination of para-aortic lymph node metastases before chemoradiation for locally advanced cervical carcinoma: a Gynecologic Oncology Group Study. Cancer 2008;112:1954–1963.
- 5.↑
Monk BJ, Tian C, Rose PG, Lanciano R. Which clinical/pathologic factors matter in the era of chemoradiation as treatment for locally advanced cervical carcinoma? Analysis of two Gynecologic Oncology Group (GOG) trials. Gynecol Oncol 2007;105:427–433.
- 6.↑
Sherman ME, Wang SS, Carreon J, Devesa SS. Mortality trends for cervical squamous and adenocarcinoma in the United States. Relation to incidence and survival. Cancer 2005;103:1258–1264.
- 7.↑
Sasieni P, Castanon A, Cuzick J. Screening and adenocarcinoma of the cervix. Int J Cancer 2009;125:525–529.
- 8.↑
Siegel CL, Andreotti RF, Cardenes HR et al.. ACR Appropriateness Criteria(R) pretreatment planning of invasive cancer of the cervix. J Am Coll Radiol 2012;9:395–402.
- 9.↑
Pecorelli S, Zigliani L, Odicino F. Revised FIGO staging for carcinoma of the cervix. Int J Gynaecol Obstet 2009;105:107–108.
- 10.↑
Moore DH. Surgical staging and cervical cancer: after 30 years, have we reached a conclusion? Cancer 2008;112:1874–1876.
- 11.↑
Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009;105:103–104.
- 12.↑
Cervix Uteri Cancer Staging. American Joint Committee on Cancer; Available at: http://cancerstaging.org/references-tools/quickreferences/Documents/CervixMedium.pdf. Accessed July 3, 2014.
- 13.↑
How is cervical cancer staged? American Cancer Society; 2014. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003094-pdf.pdf. Accessed July 3, 2014.
- 14.↑
Hricak H, Gatsonis C, Coakley FV et al.. Early invasive cervical cancer: CT and MR imaging in preoperative evaluation—ACRIN/GOG comparative study of diagnostic performance and interobserver variability. Radiology 2007;245:491–498.
- 15.↑
Woo S, Kim HS, Chung HH et al.. Early stage cervical cancer: role of magnetic resonance imaging after conization in determining residual tumor. Acta Radiol 2016;57:1268–1276.
- 16.
Mitchell DG, Snyder B, Coakley F et al.. Early invasive cervical cancer: tumor delineation by magnetic resonance imaging, computed tomography, and clinical examination, verified by pathologic results, in the ACRIN 6651/GOG 183 Intergroup Study. J Clin Oncol 2006;24:5687–5694.
- 17.
Downey K, Jafar M, Attygalle AD et al.. Influencing surgical management in patients with carcinoma of the cervix using a T2- and ZOOM-diffusion-weighted endovaginal MRI technique. Br J Cancer 2013;109:615–622.
- 18.
Lakhman Y, Akin O, Park KJ et al.. Stage IB1 cervical cancer: role of preoperative MR imaging in selection of patients for fertility-sparing radical trachelectomy. Radiology 2013;269:149–158.
- 19.
Downey K, Shepherd JH, Attygalle AD et al.. Preoperative imaging in patients undergoing trachelectomy for cervical cancer: validation of a combined T2- and diffusion-weighted endovaginal MRI technique at 3.0 T. Gynecol Oncol 2014;133:326–332.
- 20.
de Boer P, Adam JA, Buist MR et al.. Role of MRI in detecting involvement of the uterine internal os in uterine cervical cancer: systematic review of diagnostic test accuracy. Eur J Radiol 2013;82:e422–428.
- 21.↑
Thomeer MG, Gerestein C, Spronk S et al.. Clinical examination versus magnetic resonance imaging in the pretreatment staging of cervical carcinoma: systematic review and meta-analysis. Eur Radiol 2013;23:2005–2018.
- 22.↑
Park JY, Kim EN, Kim DY et al.. Comparison of the validity of magnetic resonance imaging and positron emission tomography/computed tomography in the preoperative evaluation of patients with uterine corpus cancer. Gynecol Oncol 2008;108:486–492.
- 23.
Lin SY, Tsai CS, Chang YC et al.. The role of pretreatment FDG-PET in treating cervical cancer patients with enlarged pelvic lymph node(s) shown on MRI: a phase 3 randomized trial with long-term follow-up. Int J Radiat Oncol Biol Phys 2015;92:577–585.
- 24.
Boughanim M, Leboulleux S, Rey A et al.. Histologic results of para-aortic lymphadenectomy in patients treated for stage IB2/II cervical cancer with negative [18F]fluorodeoxyglucose positron emission tomography scans in the para-aortic area. J Clin Oncol 2008;26:2558–2561.
- 25.
Zhao Q, Feng Y, Mao X, Qie M. Prognostic value of fluorine-18-fluorodeoxyglucose positron emission tomography or PET-computed tomography in cervical cancer: a meta-analysis. Int J Gynecol Cancer 2013;23:1184–1190.
- 26.↑
Gee MS, Atri M, Bandos AI et al.. Identification of distant metastatic disease in uterine cervical and endometrial cancers with FDG PET/CT: analysis from the ACRIN 6671/GOG 0233 Multicenter Trial. Radiology 2018;287:176–184.
- 27.↑
Sedlis A, Bundy BN, Rotman MZ et al.. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study. Gynecol Oncol 1999;73:177–183.
- 28.↑
Ryu SY, Kim MH, Nam BH et al.. Intermediate-risk grouping of cervical cancer patients treated with radical hysterectomy: a Korean Gynecologic Oncology Group study. Br J Cancer 2014;110:278–285.
- 29.↑
Noh JM, Park W, Kim YS et al.. Comparison of clinical outcomes of adenocarcinoma and adenosquamous carcinoma in uterine cervical cancer patients receiving surgical resection followed by radiotherapy: a multicenter retrospective study (KROG 13–10). Gynecol Oncol 2014;132:618–623.
- 30.↑
Diaz ES, Aoyama C, Baquing MA et al.. Predictors of residual carcinoma or carcinoma-in-situ at hysterectomy following cervical conization with positive margins. Gynecol Oncol 2014;132:76–80.
- 31.↑
Estape RE, Angioli R, Madrigal M et al.. Close vaginal margins as a prognostic factor after radical hysterectomy. Gynecol Oncol 1998;68:229–232.
- 32.↑
Parra-Herran C, Taljaard M, Djordjevic B et al.. Pattern-based classification of invasive endocervical adenocarcinoma, depth of invasion measurement and distinction from adenocarcinoma in situ: interobserver variation among gynecologic pathologists. Mod Pathol 2016;29:879–892.
- 33.
Roma AA, Mistretta TA, Diaz De Vivar A et al.. New pattern-based personalized risk stratification system for endocervical adenocarcinoma with important clinical implications and surgical outcome. Gynecol Oncol 2016;141:36–42.
- 34.↑
Rutgers JK, Roma AA, Park KJ et al.. Pattern classification of endocervical adenocarcinoma: reproducibility and review of criteria. Mod Pathol 2016;29:1083–1094.
- 35.↑
Bentivegna E, Gouy S, Maulard A et al.. Oncological outcomes after fertility-sparing surgery for cervical cancer: a systematic review. Lancet Oncol 2016;17:e240–253.
- 36.↑
Ueki M, Okamoto Y, Misaki O et al.. Conservative therapy for microinvasive carcinoma of the uterine cervix. Gynecol Oncol 1994;53:109–113.
- 37.
Al-Kalbani M, McVeigh G, Nagar H, McCluggage WG. Do FIGO stage IA and small (</=2 cm) IB1 cervical adenocarcinomas have a good prognosis and warrant less radical surgery? Int J Gynecol Cancer 2012;22:291–295.
- 38.
Webb JC, Key CR, Qualls CR, Smith HO. Population-based study of microinvasive adenocarcinoma of the uterine cervix. Obstet Gynecol 2001;97:701–706.
- 39.↑
Sevin BU, Nadji M, Averette HE et al.. Microinvasive carcinoma of the cervix. Cancer 1992;70:2121–2128.
- 40.↑
Huang LW, Hwang JL. A comparison between loop electrosurgical excision procedure and cold knife conization for treatment of cervical dysplasia: residual disease in a subsequent hysterectomy specimen. Gynecol Oncol 1999;73:12–15.
- 41.
Miroshnichenko GG, Parva M, Holtz DO et al.. Interpretability of excisional biopsies of the cervix: cone biopsy and loop excision. J Low Genit Tract Dis 2009;13:10–12.
- 42.
Greenspan DL, Faubion M, Coonrod DV et al.. Compliance after loop electrosurgical excision procedure or cold knife cone biopsy. Obstet Gynecol 2007;110:675–680.
- 43.
Fanning J, Padratzik J. Cold knife conization vs. LEEP. Are they the same procedure? J Reprod Med 2002;47:33–35.
- 44.
Simmons JR, Anderson L, Hernandez E, Heller PB. Evaluating cervical neoplasia. LEEP as an alternative to cold knife conization. J Reprod Med 1998;43:1007–1013.
- 45.↑
Kim MK, Kim MA, Kim JW et al.. Loop electrosurgical excision procedure findings for identification of patients with early-stage cervical cancer suitable for less radical surgery. Int J Gynecol Cancer 2012;22:1214–1219.
- 46.↑
Bouchard-Fortier G, Reade CJ, Covens A. Non-radical surgery for small early-stage cervical cancer. Is it time? Gynecol Oncol 2014;132:624–627.
- 47.↑
Kato T, Takashima A, Kasamatsu T et al.. Clinical tumor diameter and prognosis of patients with FIGO stage IB1 cervical cancer (JCOG0806-A). Gynecol Oncol 2015;137:34–39.
- 48.↑
Diaz JP, Sonoda Y, Leitao MM et al.. Oncologic outcome of fertility-sparing radical trachelectomy versus radical hysterectomy for stage IB1 cervical carcinoma. Gynecol Oncol 2008;111:255–260.
- 49.
Abu-Rustum NR, Tal MN, DeLair D et al.. Radical abdominal trachelectomy for stage IB1 cervical cancer at 15-week gestation. Gynecol Oncol 2010;116:151–152.
- 50.↑
Ramirez PT, Pareja R, Rendon GJ et al.. Management of low-risk early-stage cervical cancer: should conization, simple trachelectomy, or simple hysterectomy replace radical surgery as the new standard of care? Gynecol Oncol 2014;132:254–259.
- 51.↑
Dargent D, Martin X, Sacchetoni A, Mathevet P. Laparoscopic vaginal radical trachelectomy: a treatment to preserve the fertility of cervical carcinoma patients. Cancer 2000;88:1877–1882.
- 52.↑
Viswanathan AN, Deavers MT, Jhingran A et al.. Small cell neuroendocrine carcinoma of the cervix: outcome and patterns of recurrence. Gynecol Oncol 2004;93:27–33.
- 53.↑
Young RH, Clement PB. Endocervical adenocarcinoma and its variants: their morphology and differential diagnosis. Histopathology 2002;41:185–207.
- 54.↑
Cao DY, Yang JX, Wu XH et al.. Comparisons of vaginal and abdominal radical trachelectomy for early-stage cervical cancer: preliminary results of a multi-center research in China. Br J Cancer 2013;109:2778–2782.
- 55.↑
Plante M, Gregoire J, Renaud MC, Roy M. The vaginal radical trachelectomy: an update of a series of 125 cases and 106 pregnancies. Gynecol Oncol 2011;121:290–297.
- 56.↑
Abu-Rustum NR, Sonoda Y, Black D et al.. Fertility-sparing radical abdominal trachelectomy for cervical carcinoma: technique and review of the literature. Gynecol Oncol 2006;103:807–813.
- 57.↑
Einstein MH, Park KJ, Sonoda Y et al.. Radical vaginal versus abdominal trachelectomy for stage IB1 cervical cancer: a comparison of surgical and pathologic outcomes. Gynecol Oncol 2009;112:73–77.
- 58.↑
Wethington SL, Cibula D, Duska LR et al.. An international series on abdominal radical trachelectomy: 101 patients and 28 pregnancies. Int J Gynecol Cancer 2012;22:1251–1257.
- 59.↑
Abu-Rustum NR, Sonoda Y. Fertility-sparing surgery in early-stage cervical cancer: indications and applications. J Natl Compr Canc Netw 2010;8:1435–1438.
- 60.↑
Beiner ME, Covens A. Surgery insight: radical vaginal trachelectomy as a method of fertility preservation for cervical cancer. Nat Clin Pract Oncol 2007;4:353–361.
- 61.↑
Pareja R, Rendon GJ, Sanz-Lomana CM et al.. Surgical, oncological, and obstetrical outcomes after abdominal radical trachelectomy—a systematic literature review. Gynecol Oncol 2013;131:77–82.
- 62.↑
Lintner B, Saso S, Tarnai L et al.. Use of abdominal radical trachelectomy to treat cervical cancer greater than 2 cm in diameter. Int J Gynecol Cancer 2013;23:1065–1070.
- 63.
Wethington SL, Sonoda Y, Park KJ et al.. Expanding the indications for radical trachelectomy: a report on 29 patients with stage IB1 tumors measuring 2 to 4 centimeters. Int J Gynecol Cancer 2013;23:1092–1098.
- 64.↑
Lanowska M, Mangler M, Speiser D et al.. Radical vaginal trachelectomy after laparoscopic staging and neoadjuvant chemotherapy in women with early-stage cervical cancer over 2 cm: oncologic, fertility, and neonatal outcome in a series of 20 patients. Int J Gynecol Cancer 2014;24:586–593.
- 65.↑
Shepherd JH, Spencer C, Herod J, Ind TEJ. Radical vaginal trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer-cumulative pregnancy rate in a series of 123 women. BJOG 2006;113:719–724.
- 66.
Park JY, Kim DY, Suh DS et al.. Reproductive outcomes after laparoscopic radical trachelectomy for early-stage cervical cancer. J Gynecol Oncol 2014;25:9–13.
- 67.↑
Gizzo S, Ancona E, Saccardi C et al.. Radical trachelectomy: the first step of fertility preservation in young women with cervical cancer (review). Oncol Rep 2013;30:2545–2554.
- 68.↑
Cibula D, Abu-Rustum NR, Benedetti-Panici P et al.. New classification system of radical hysterectomy: emphasis on a three-dimensional anatomic template for parametrial resection. Gynecol Oncol 2011;122:264–268.
- 70.↑
Piver MS, Rutledge F, Smith JP. Five classes of extended hysterectomy for women with cervical cancer. Obstet Gynecol 1974;44:265–272.
- 71.↑
Chi DS, Abu-Rustum NR, Plante M, Roy M. Cancer of the cervix. In: Rock JA, Jones HW, eds, eds. TeLinde's Operative Gynecology, 10th ed. Philadelphia: Lippincott Williams and Wilkins; 2008:1227.
- 72.↑
Whitney CW, Spirtos NM. Gynecologic Oncology Group Surgical Procedures Manual. Philadelphia: Gynecologic Oncology Group; 2009. Available at: https://gogmember.gog.org/manuals/pdf/surgman.pdf. Accessed April 18, 2014.
- 73.↑
Sardain H, Lavoue V, Redpath M et al.. Curative pelvic exenteration for recurrent cervical carcinoma in the era of concurrent chemotherapy and radiation therapy. A systematic review. Eur J Surg Oncol 2015;41:975–985.
- 74.↑
Chiantera V, Rossi M, De Iaco P et al.. Morbidity after pelvic exenteration for gynecological malignancies: a retrospective multicentric study of 230 patients. Int J Gynecol Cancer 2014;24:156–164.
- 75.↑
Cormier B, Diaz JP, Shih K et al.. Establishing a sentinel lymph node mapping algorithm for the treatment of early cervical cancer. Gynecol Oncol 2011;122:275–280.
- 76.↑
Lecuru F, Mathevet P, Querleu D et al.. Bilateral negative sentinel nodes accurately predict absence of lymph node metastasis in early cervical cancer: results of the SENTICOL study. J Clin Oncol 2011;29:1686–1691.
- 77.↑
Altgassen C, Hertel H, Brandstadt A et al.. Multicenter validation study of the sentinel lymph node concept in cervical cancer: AGO Study Group. J Clin Oncol 2008;26:2943–2951.
- 78.↑
Bats AS, Buenerd A, Querleu D et al.. Diagnostic value of intraoperative examination of sentinel lymph node in early cervical cancer: a prospective, multicenter study. Gynecol Oncol 2011;123:230–235.
- 79.↑
Bats AS, Mathevet P, Buenerd A et al.. The sentinel node technique detects unexpected drainage pathways and allows nodal ultrastaging in early cervical cancer: insights from the multicenter prospective SENTICOL study. Ann Surg Oncol 2013;20:413–422.
- 80.↑
Cibula D, Abu-Rustum NR, Dusek L et al.. Bilateral ultrastaging of sentinel lymph node in cervical cancer: Lowering the false-negative rate and improving the detection of micrometastasis. Gynecol Oncol 2012;127:462–466.
- 81.↑
Cibula D, Abu-Rustum NR, Dusek L et al.. Prognostic significance of low volume sentinel lymph node disease in early-stage cervical cancer. Gynecol Oncol 2012;124:496–501.
- 82.↑
Fader AN, Edwards RP, Cost M et al.. Sentinel lymph node biopsy in early-stage cervical cancer: utility of intraoperative versus postoperative assessment. Gynecol Oncol 2008;111:13–17.
- 83.
Lecuru F, Bats A, Mathevet P et al.. Impact of sentinel lymph node biopsy on staging of early cervical cancer: Results of a prospective, multicenter study [abstract]. J Clin Oncol 2009;27(Suppl 18):Abstract CRA5506.
- 84.↑
Slama J, Dundr P, Dusek L, Cibula D. High false negative rate of frozen section examination of sentinel lymph nodes in patients with cervical cancer. Gynecol Oncol 2013;129:384–388.
- 85.
van de Lande J, Torrenga B, Raijmakers PGHM et al.. Sentinel lymph node detection in early stage uterine cervix carcinoma: a systematic review. Gynecol Oncol 2007;106:604–613.
- 86.↑
Andikyan V, Khoury-Collado F, Denesopolis J et al.. Cervical conization and sentinel lymph node mapping in the treatment of stage I cervical cancer: is less enough? Int J Gynecol Cancer 2014;24:113–117.
- 87.↑
Wu Y, Li Z, Wu H, Yu J. Sentinel lymph node biopsy in cervical cancer: a meta-analysis. Mol Clin Oncol 2013;1:1025–1030.
- 88.↑
Kadkhodayan S, Hasanzadeh M, Treglia G et al.. Sentinel node biopsy for lymph nodal staging of uterine cervix cancer: a systematic review and meta-analysis of the pertinent literature. Eur J Surg Oncol 2015;41:1–20.
- 89.↑
Ruscito I, Gasparri ML, Braicu EI et al.. Sentinel node mapping in cervical and endometrial cancer: indocyanine green versus other conventional dyes—a meta-analysis. Ann Surg Oncol 2016;23:3749–3756.
- 90.↑
Frumovitz M, Plante M, Lee PS et al.. The FILM Trial: a randomized phase III multicenter study assessing near infrared fluorescence in the identification of sentinel lymph nodes (SLN) [Abstract]. Gynecologic Oncology 2018;149:7.
- 91.↑
Eiriksson LR, Covens A. Sentinel lymph node mapping in cervical cancer: the future? BJOG 2012;119:129–133.
- 92.↑
Bats AS, Frati A, Mathevet P et al.. Contribution of lymphoscintigraphy to intraoperative sentinel lymph node detection in early cervical cancer: analysis of the prospective multicenter SENTICOL cohort. Gynecol Oncol 2015;137:264–269.
- 93.↑
Darlin L, Persson J, Bossmar T et al.. The sentinel node concept in early cervical cancer performs well in tumors smaller than 2 cm. Gynecol Oncol 2010;117:266–269.
- 94.↑
Sakuragi N, Satoh C, Takeda N et al.. Incidence and distribution pattern of pelvic and paraaortic lymph node metastasis in patients with stages IB, IIA, and IIB cervical carcinoma treated with radical hysterectomy. Cancer 1999;85:1547–1554.
- 95.↑
Huang H, Liu J, Li Y et al.. Metastasis to deep obturator and para-aortic lymph nodes in 649 patients with cervical carcinoma. Eur J Surg Oncol 2011;37:978–983.
- 96.↑
Gouy S, Morice P, Narducci F et al.. Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging. J Clin Oncol 2013;31:3026–3033.
- 97.↑
Frumovitz M, Querleu D, Gil-Moreno A et al.. Lymphadenectomy in locally advanced cervical cancer study (LiLACS): Phase III clinical trial comparing surgical with radiologic staging in patients with stages IB2IVA cervical cancer. J Minim Invasive Gynecol 2014;21:3–8.
- 98.↑
Chen Y, Xu H, Li Y et al.. The outcome of laparoscopic radical hysterectomy and lymphadenectomy for cervical cancer: a prospective analysis of 295 patients. Ann Surg Oncol 2008;15:2847–2855.
- 99.
Puntambekar SP, Palep RJ, Puntambekar SS et al.. Laparoscopic total radical hysterectomy by the Pune technique: our experience of 248 cases. J Minim Invasive Gynecol 2007;14:682–689.
- 100.
Nam JH, Park JY, Kim DY et al.. Laparoscopic versus open radical hysterectomy in early-stage cervical cancer: long-term survival outcomes in a matched cohort study. Ann Oncol 2012;23:903–911.
- 101.↑
Wang YZ, Deng L, Xu HC et al.. Laparoscopy versus laparotomy for the management of early stage cervical cancer. BMC Cancer 2015;15:928.
- 102.↑
Sert BM, Boggess JF, Ahmad S et al.. Robot-assisted versus open radical hysterectomy: a multi-institutional experience for early-stage cervical cancer. Eur J Surg Oncol 2016;42:513–522.
- 103.
Mendivil AA, Rettenmaier MA, Abaid LN et al.. Survival rate comparisons amongst cervical cancer patients treated with an open, robotic-assisted or laparoscopic radical hysterectomy: a five year experience. Surg Oncol 2016;25:66–71.
- 104.↑
Park DA, Yun JE, Kim SW, Lee SH. Surgical and clinical safety and effectiveness of robot-assisted laparoscopic hysterectomy compared to conventional laparoscopy and laparotomy for cervical cancer: a systematic review and meta-analysis. Eur J Surg Oncol 2017;43:994–1002.
- 105.↑
Shazly SA, Murad MH, Dowdy SC et al.. Robotic radical hysterectomy in early stage cervical cancer: a systematic review and meta-analysis. Gynecol Oncol 2015;138:457–471.
- 106.↑
Ramirez PT, Frumovitz M, Pareja R et al.. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med 2018;379:1895–1904.
- 107.↑
Melamed A, Margul DJ, Chen L et al.. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med 2018;379:1905–1914.
- 108.↑
Margul DJ, Yang J, Seagle BL et al.. Outcomes and costs of open, robotic, and laparoscopic radical hysterectomy for stage IB1 cervical cancer. J Clin Oncol 2018;36:5502.
- 109.↑
Nevis IF, Vali B, Higgins C et al.. Robot-assisted hysterectomy for endometrial and cervical cancers: a systematic review. J Robot Surg 2016.
- 110.
Lowe MP, Chamberlain DH, Kamelle SA et al.. A multi-institutional experience with robotic-assisted radical hysterectomy for early stage cervical cancer. Gynecol Oncol 2009;113:191–194.
- 111.
Nezhat FR, Datta MS, Liu C et al.. Robotic radical hysterectomy versus total laparoscopic radical hysterectomy with pelvic lymphadenectomy for treatment of early cervical cancer. JSLS 2008;12:227–237.
- 112.↑
Cantrell LA, Mendivil A, Gehrig PA, Boggess JF. Survival outcomes for women undergoing type III robotic radical hysterectomy for cervical cancer: a 3-year experience. Gynecol Oncol 2010;117:260–265.
- 113.↑
Gaffney DK, Erickson-Wittmann BA, Jhingran A et al.. ACR Appropriateness Criteria(R) on advanced cervical cancer expert panel on radiation oncology-gynecology. Int J Radiat Oncol Biol Phys 2011;81:609–614.
- 114.↑
Monk BJ, Tewari KS, Koh W-J. Multimodality therapy for locally advanced cervical carcinoma: state of the art and future directions. J Clin Oncol 2007;25:2952–2965.
- 115.↑
Gien LT, Beauchemin MC, Thomas G. Adenocarcinoma: a unique cervical cancer. Gynecol Oncol 2010;116:140–146.
- 116.
Baalbergen A, Veenstra Y, Stalpers LL, Ansink AC. Primary surgery versus primary radiation therapy with or without chemotherapy for early adenocarcinoma of the uterine cervix. Cochrane Database Syst Rev 2010:CD006248.
- 117.↑
Park JY, Kim DY, Kim JH et al.. Outcomes after radical hysterectomy in patients with early-stage adenocarcinoma of uterine cervix. Br J Cancer 2010;102:1692–1698.
- 118.↑
Wo JY, Viswanathan AN. Impact of radiotherapy on fertility, pregnancy, and neonatal outcomes in female cancer patients. Int J Radiat Oncol Biol Phys 2009;73:1304–1312.
- 119.↑
Pahisa J, Martinez-Roman S, Martinez-Zamora MA et al.. Laparoscopic ovarian transposition in patients with early cervical cancer. Int J Gynecol Cancer 2008;18:584–589.
- 120.↑
Morice P, Juncker L, Rey A et al.. Ovarian transposition for patients with cervical carcinoma treated by radiosurgical combination. Fertil Steril 2000;74:743–748.
- 121.↑
Landoni F, Maneo A, Colombo A et al.. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 1997;350:535–540.
- 122.↑
Keys HM, Bundy BN, Stehman FB et al.. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154–1161.
- 123.↑
Morris M, Eifel PJ, Lu J et al.. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137–1143.
- 124.↑
Peters WA, Liu PY, Barrett RJ et al.. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18:1606–1613.
- 125.↑
Whitney CW, Sause W, Bundy BN et al.. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999;17:1339–1348.
- 126.↑
Rose PG, Bundy BN, Watkins EB et al.. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–1153.
- 127.↑
Thomas GM. Improved treatment for cervical cancer—concurrent chemotherapy and radiotherapy. N Engl J Med 1999;340:1198–1200.
- 128.↑
Rose PG, Ali S, Watkins E et al.. Long-term follow-up of a randomized trial comparing concurrent single agent cisplatin, cisplatin-based combination chemotherapy, or hydroxyurea during pelvic irradiation for locally advanced cervical cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2007;25:2804–2810.
- 129.
Eifel PJ, Winter K, Morris M et al.. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of radiation therapy oncology group trial (RTOG) 90-01. J Clin Oncol 2004;22:872–880.
- 130.↑
Stehman FB, Ali S, Keys HM et al.. Radiation therapy with or without weekly cisplatin for bulky stage 1B cervical carcinoma: follow-up of a Gynecologic Oncology Group trial. Am J Obstet Gynecol 2007;197:1–6.
- 131.↑
Chemoradiotherapy for Cervical Cancer Meta-Analysis C. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 2008;26:5802–5812.
- 132.↑
Pearcey R, Miao Q, Kong W et al.. Impact of adoption of chemoradiotherapy on the outcome of cervical cancer in Ontario: results of a population-based cohort study. J Clin Oncol 2007;25:2383–2388.
- 133.↑
King M, McConkey C, Latief TN et al.. Improved survival after concurrent weekly cisplatin and radiotherapy for cervical carcinoma with assessment of acute and late side-effects. Clin Oncol (R Coll Radiol) 2006;18:38–45.
- 134.↑
Tan LT, Zahra M. Long-term survival and late toxicity after chemoradiotherapy for cervical cancer—the Addenbrooke's experience. Clin Oncol (R Coll Radiol) 2008;20:358–364.
- 135.↑
Gaffney DK, Du Bois A, Narayan K et al.. Practice patterns of radiotherapy in cervical cancer among member groups of the Gynecologic Cancer Intergroup (GCIG). Int J Radiat Oncol Biol Phys 2007;68:485–490.
- 136.↑
Cetina L, Garcia-Arias A, Uribe MdJ et al.. Concurrent chemoradiation with carboplatin for elderly, diabetic and hypertensive patients with locally advanced cervical cancer. Eur J Gynaecol Oncol 2008;29:608–612.
- 137.
Dubay RA, Rose PG, O'Malley DM et al.. Evaluation of concurrent and adjuvant carboplatin with radiation therapy for locally advanced cervical cancer. Gynecol Oncol 2004;94:121–124.
- 138.
Higgins RV, Naumann WR, Hall JB, Haake M. Concurrent carboplatin with pelvic radiation therapy in the primary treatment of cervix cancer. Gynecol Oncol 2003;89:499–503.
- 139.
Lorvidhaya V, Chitapanarux I, Sangruchi S et al.. Concurrent mitomycin C, 5-fluorouracil, and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial. Int J Radiat Oncol Biol Phys 2003;55:1226–1232.
- 140.
Wong LC, Ngan HY, Cheung AN et al.. Chemoradiation and adjuvant chemotherapy in cervical cancer. J Clin Oncol 1999;17:2055–2060.
- 141.↑
Tharavichitkul E, Lorvidhaya V, Kamnerdsupaphon P et al.. Combined chemoradiation of cisplatin versus carboplatin in cervical carcinoma: a single institution experience from Thailand. BMC Cancer 2016;16:501.
- 142.↑
Mileshkin LR, Narayan K, Moore KN et al.. A phase III trial of adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: Outback (ANZGOG0902/GOG0274/RTOG1174) [abstract]. J Clin Oncol 2014 32:abstract TPS5632.
- 143.↑
Koliopoulos G, Sotiriadis A, Kyrgiou M et al.. Conservative surgical methods for FIGO stage IA2 squamous cervical carcinoma and their role in preserving women's fertility. Gynecol Oncol 2004;93:469–473.
- 144.↑
Wright JD, NathavithArana R, Lewin SN et al.. Fertility-conserving surgery for young women with stage IA1 cervical cancer: safety and access. Obstet Gynecol 2010;115:585–590.
- 145.↑
Tierney KE, Lin PS, Amezcua C et al.. Cervical conization of adenocarcinoma in situ: a predicting model of residual disease. Am J Obstet Gynecol 2014;210:366 e361–365.
- 146.↑
Yoneda JY, Braganca JF, Sarian LO et al.. Surgical treatment of microinvasive cervical cancer: analysis of pathologic features with implications on radicality. Int J Gynecol Cancer 2015;25:694–698.
- 147.↑
Bernardini M, Barrett J, Seaward G, Covens A. Pregnancy outcomes in patients after radical trachelectomy. Am J Obstet Gynecol 2003;189:1378–1382.
- 148.
Boss EA, van Golde RJT, Beerendonk CCM, Massuger LFAG. Pregnancy after radical trachelectomy: a real option? Gynecol Oncol 2005;99:152–156.
- 149.
Plante M, Renaud M-C, Hoskins IA, Roy M. Vaginal radical trachelectomy: a valuable fertility-preserving option in the management of early-stage cervical cancer. A series of 50 pregnancies and review of the literature. Gynecol Oncol 2005;98:3–10.
- 150.↑
Marchiole P, Benchaib M, Buenerd A et al.. Oncological safety of laparoscopic-assisted vaginal radical trachelectomy (LARVT or Dargent's operation): a comparative study with laparoscopic-assisted vaginal radical hysterectomy (LARVH). Gynecol Oncol 2007;106:132–141.
- 151.↑
Landoni F, Zanagnolo V, Lovato-Diaz L et al.. Ovarian metastases in early-stage cervical cancer (IA2-IIA): a multicenter retrospective study of 1965 patients (a Cooperative Task Force study). Int J Gynecol Cancer 2007;17:623–628.
- 152.↑
Shimada M, Kigawa J, Nishimura R et al.. Ovarian metastasis in carcinoma of the uterine cervix. Gynecol Oncol 2006;101:234–237.
- 153.↑
Kokka F, Bryant A, Brockbank E, Jeyarajah A. Surgical treatment of stage IA2 cervical cancer. Cochrane Database Syst Rev 2014:CD010870.
- 154.↑
Small W Jr., Strauss JB, Jhingran A et al.. ACR Appropriateness Criteria(R) definitive therapy for early-stage cervical cancer. Am J Clin Oncol 2012;35:399–405.
- 155.↑
Raju SK, Papadopoulos AJ, Montalto SA et al.. Fertility-sparing surgery for early cervical cancer-approach to less radical surgery. Int J Gynecol Cancer 2012;22:311–317.
- 156.↑
Li J, Wu X, Li X, Ju X. Abdominal radical trachelectomy: Is it safe for IB1 cervical cancer with tumors ≥ 2 cm? Gynecol Oncol 2013;131:87–92.
- 157.↑
Landoni F, Maneo A, Cormio G et al.. Class II versus class III radical hysterectomy in stage IB-IIA cervical cancer: a prospective randomized study. Gynecol Oncol 2001;80:3–12.
- 158.↑
Keys HM, Bundy BN, Stehman FB et al.. Radiation therapy with and without extrafascial hysterectomy for bulky stage IB cervical carcinoma: a randomized trial of the Gynecologic Oncology Group. Gynecol Oncol 2003;89:343–353.
- 159.↑
Kokka F, Bryant A, Brockbank E et al.. Hysterectomy with radiotherapy or chemotherapy or both for women with locally advanced cervical cancer. Cochrane Database Syst Rev 2015;4:CD010260.
- 160.↑
Colombo PE, Bertrand MM, Gutowski M et al.. Total laparoscopic radical hysterectomy for locally advanced cervical carcinoma (stages IIB, IIA and bulky stages IB) after concurrent chemoradiation therapy: surgical morbidity and oncological results. Gynecol Oncol 2009;114:404–409.
- 161.
Touboul C, Uzan C, Mauguen A et al.. Prognostic factors and morbidities after completion surgery in patients undergoing initial chemoradiation therapy for locally advanced cervical cancer. Oncologist 2010;15:405–415.
- 162.
Huguet F, Cojocariu OM, Levy P et al.. Preoperative concurrent radiation therapy and chemotherapy for bulky stage IB2, IIA, and IIB carcinoma of the uterine cervix with proximal parametrial invasion. Int J Radiat Oncol Biol Phys 2008;72:1508–1515.
- 163.↑
Cetina L, Gonzalez-Enciso A, Cantu D et al.. Brachytherapy versus radical hysterectomy after external beam chemoradiation with gemcitabine plus cisplatin: a randomized, phase III study in IB2-IIB cervical cancer patients. Ann Oncol 2013;24:2043–2047.
- 164.↑
Kohler C, Mustea A, Marnitz S et al.. Perioperative morbidity and rate of upstaging after laparoscopic staging for patients with locally advanced cervical cancer: results of a prospective randomized trial. Am J Obstet Gynecol 2015;213:503 e501–507.
- 165.↑
Goff BA, Muntz HG, Paley PJ et al.. Impact of surgical staging in women with locally advanced cervical cancer. Gynecol Oncol 1999;74:436–442.
- 166.↑
Rose PG. Combination therapy: New treatment paradigm for locally advanced cervical cancer? Nat Rev Clin Oncol 2011;8:388–390.
- 167.↑
Duenas-Gonzalez A, Zarba JJ, Patel F et al.. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 2011;29:1678–1685.
- 168.
Thomas G. Are we making progress in curing advanced cervical cancer? J Clin Oncol 2011;29:1654–1656.
- 169.
Swisher EM, Swensen RE, Greer B et al.. Weekly gemcitabine and cisplatin in combination with pelvic radiation in the primary therapy of cervical cancer: a phase I trial of the Puget Sound Oncology Consortium. Gynecol Oncol 2006;101:429–435.
- 170.↑
Rose PG, Degeest K, McMeekin S, Fusco N. A phase I study of gemcitabine followed by cisplatin concurrent with whole pelvic radiation therapy in locally advanced cervical cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2007;107:274–279.
- 171.↑
Lutz ST, Chow EL, Hartsell WF, Konski AA. A review of hypofractionated palliative radiotherapy. Cancer 2007;109:1462–1470.
- 172.↑
Rotman M, Sedlis A, Piedmonte MR et al.. A phase III randomized trial of postoperative pelvic irradiation in stage IB cervical carcinoma with poor prognostic features: follow-up of a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 2006;65:169–176.
- 173.
Monk BJ, Wang J, Im S et al.. Rethinking the use of radiation and chemotherapy after radical hysterectomy: a clinical-pathologic analysis of a Gynecologic Oncology Group/Southwest Oncology Group/Radiation Therapy Oncology Group trial. Gynecol Oncol 2005;96:721–728.
- 174.
Chernofsky MR, Felix JC, Muderspach LI et al.. Influence of quantity of lymph vascular space invasion on time to recurrence in women with early-stage squamous cancer of the cervix. Gynecol Oncol 2006;100:288–293.
- 175.↑
Marchiole P, Buenerd A, Benchaib M et al.. Clinical significance of lympho vascular space involvement and lymph node micrometastases in early-stage cervical cancer: a retrospective case-control surgico-pathological study. Gynecol Oncol 2005;97:727–732.
- 176.↑
Trifiletti DM, Swisher-McClure S, Showalter TN et al.. Postoperative chemoradiation therapy in high-risk cervical cancer: re-evaluating the findings of Gynecologic Oncology Group study 109 in a large, population-based cohort. Int J Radiat Oncol Biol Phys 2015;93:1032–1044.
- 177.↑
Gong L, Lou JY, Wang P et al.. Clinical evaluation of neoadjuvant chemotherapy followed by radical surgery in the management of stage IB2-IIB cervical cancer. Int J Gynaecol Obstet 2012;117:23–26.
- 178.
Eddy GL, Bundy BN, Creasman WT et al.. Treatment of (“bulky”) stage IB cervical cancer with or without neoadjuvant vincristine and cisplatin prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy: a phase III trial of the gynecologic oncology group. Gynecol Oncol 2007;106:362–369.
- 179.↑
Rydzewska L, Tierney J, Vale CL, Symonds PR. Neoadjuvant chemotherapy plus surgery versus surgery for cervical cancer. Cochrane Database Syst Rev 2010:CD007406.
- 180.↑
Katsumata N, Yoshikawa H, Kobayashi H et al.. Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102). Br J Cancer 2013;108:1957–1963.
- 181.↑
Kim HS, Sardi JE, Katsumata N et al.. Efficacy of neoadjuvant chemotherapy in patients with FIGO stage IB1 to IIA cervical cancer: an international collaborative meta-analysis. Eur J Surg Oncol 2013;39:115–124.
- 182.↑
Landoni F, Sartori E, Maggino T et al.. Is there a role for postoperative treatment in patients with stage Ib2-IIb cervical cancer treated with neo-adjuvant chemotherapy and radical surgery? An Italian multicenter retrospective study. Gynecol Oncol 2014;132:611–617.
- 183.↑
Ye Q, Yuan HX, Chen HL. Responsiveness of neoadjuvant chemotherapy before surgery predicts favorable prognosis for cervical cancer patients: a meta-analysis. J Cancer Res Clin Oncol 2013;139:1887–1898.
- 184.↑
Arbyn M, Dillner J. Review of current knowledge on HPV vaccination: an appendix to the European Guidelines for Quality Assurance in Cervical Cancer Screening. J Clin Virol 2007;38:189–197.
- 185.
Rambout L, Hopkins L, Hutton B, Fergusson D. Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials. CMAJ 2007;177:469–479.
- 186.↑
Chan JK, Berek JS. Impact of the human papilloma vaccine on cervical cancer. J Clin Oncol 2007;25:2975–2982.
