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Estimated new cases and deaths from cervical (uterine cervix) cancer in the United States in 2014:[1]
The prognosis for patients with cervical cancer is markedly affected by the extent of disease at the time of diagnosis. A vast majority (>90%) of these cases can and should be detected early through the use of the Pap test and human papillomavirus (HPV) testing; however,[2] the current death rate is far higher than it should be, which reflects that, even today, the Pap test and HPV testing are not done on approximately 33% of eligible women. Clinical stage, however, as a prognostic factor must be supplemented by several gross and microscopic pathologic findings in surgically treated patients. These include: volume and grade of tumor, histologic type, lymphatic spread, and vascular invasion.
In a large, surgicopathologic staging study of patients with clinical stage IB disease reported by the Gynecologic Oncology Group (GOG) (GOG-49), the factors that predicted most prominently for lymph node metastases and a decrease in disease-free survival were capillary-lymphatic space involvement by tumor, increasing tumor size, and increasing depth of stromal invasion, with the latter being most important and reproducible.[3,4] In a study of 1,028 patients treated with radical surgery, survival rates correlated more consistently with tumor volume (as determined by precise volumetry of the tumor) than clinical or histologic stage.[5]
A multivariate analysis of prognostic variables in 626 patients with locally advanced disease (primarily stages II, III, and IV) studied by the GOG identified several variables that were significant for progression-free interval and survival:[6]
The study confirmed the overriding importance of positive periaortic nodes and suggested further evaluation of these nodes in locally advanced cervical cancer. The status of the pelvic nodes was important only if the periaortic nodes were negative. This was also true for tumor size.
In a large series of cervical cancer patients treated by radiation therapy, the incidence of distant metastases (most frequently to lung, abdominal cavity, liver, and gastrointestinal tract) was shown to increase as the stage of disease increased, from 3% in stage IA to 75% in stage IVA.[7] A multivariate analysis of factors influencing the incidence of distant metastases showed stage, endometrial extension of tumor, and pelvic tumor control to be significant indicators of distant dissemination.[7]
GOG studies have indicated that prognostic factors vary whether clinical or surgical staging are utilized, and with treatment. Delay in radiation delivery completion is associated with poorer progression-free survival when clinical staging is used. It is unclear whether stage, tumor grade, race, and age hold up as prognostic factors in studies utilizing chemoradiation.[8]
Invasive Carcinomas of the Uterine CervixWhether adenocarcinoma of the cervix carries a significantly worse prognosis than squamous cell carcinoma of the cervix remains controversial.[9] Reports conflict about the effect of adenosquamous cell type on outcome.[10,11] One report showed that approximately 25% of apparent squamous tumors have demonstrable mucin production and behave more aggressively than their pure squamous counterparts, suggesting that any adenomatous differentiation may confer a negative prognosis.[12] The decreased survival is mainly the result of more advanced stage and nodal involvement rather than cell type as an independent variable. Women with human immunodeficiency virus have more aggressive and advanced disease and a poorer prognosis.[13] A study of patients with known invasive squamous carcinoma of the cervix found that overexpression of the C-myc oncogene was associated with a poorer prognosis.[14] The number of cells in S phase may also have prognostic significance in early cervical carcinoma.[15] HPV type 18 DNA has been found to be an independent adverse molecular prognostic factor. Two studies have shown a worse outcome when identified in cervical cancers of patients undergoing radical hysterectomy and pelvic lymphadenectomy.[16,17]
Human Papillomavirus Infection and Cervical CancerMolecular techniques for the identification of HPV DNA are highly sensitive and specific. More than 6 million women in the United States are estimated to have HPV infection, and proper interpretation of these data is important. Epidemiologic studies convincingly demonstrate that the major risk factor for development of preinvasive or invasive carcinoma of the cervix is HPV infection, which far outweighs other known risk factors such as high parity, increasing number of sexual partners, young age at first intercourse, low socioeconomic status, and positive smoking history.[18,19] Some patients with HPV infection appear to be at minimal increased risk for development of cervical preinvasive and invasive malignancies, while others appear to be at significant risk and are candidates for intensive screening programs and/or early intervention.
HPV DNA tests are unlikely to separate patients with low-grade squamous intraepithelial lesions into those who do and those who do not need further evaluation. A study of 642 women found that 83% had one or more tumorigenic HPV types when cervical cytologic specimens were assayed by a sensitive (hybrid capture) technique.[20] The authors of the study and of an accompanying editorial concluded that using HPV DNA testing in this setting does not add sufficient information to justify its cost.[20] HPV DNA testing has proven useful in triaging patients with atypical squamous cells of undetermined significance to colposcopy and has been integrated into current screening guidelines.[20-22] Patients with an abnormal cytology of a high-risk type (Bethesda classification) should be thoroughly evaluated with colposcopy and biopsy.
Other studies show patients with low-risk cytology and high-risk HPV infection with types 16, 18, and 31 are more likely to have cervical intraepithelial neoplasia (CIN) or microinvasive histopathology on biopsy.[19,23-25] One method has also shown that integration of HPV types 16 and 18 into the genome, leading to transcription of viral and cellular messages, may predict patients who are at greater risk for high-grade dysplasia and invasive cancer.[26] Studies suggest that acute infection with HPV types 16 and 18 conferred an 11- to 16.9-fold risk of rapid development of high-grade CIN,[19,27] but there are conflicting data requiring further evaluation before any recommendations may be made. Patients with low-risk cytology and low-risk HPV types have not been followed long enough to ascertain their risk. At present, studies are ongoing to determine how HPV typing can be used to help stratify women into follow-up and treatment groups. HPV typing may prove useful, particularly in patients with low-grade cytology or cytology of unclear abnormality. At present, how therapy and follow-up should be altered with low- versus high-risk HPV type has not been established.
Related SummariesOther PDQ summaries containing information related to cervical cancer include the following:
Squamous cell (epidermoid) carcinoma comprises approximately 90%, and adenocarcinoma comprises approximately 10% of cervical cancers. Adenosquamous and small cell carcinomas are relatively rare. Primary sarcomas of the cervix have been described occasionally, and malignant lymphomas of the cervix, primary and secondary, have also been reported.
Cervical carcinoma has its origins at the squamous-columnar junction whether in the endocervical canal or on the portion of the cervix. The precursor lesion is dysplasia or carcinoma in situ (cervical intraepithelial neoplasia [CIN]), which can subsequently become invasive cancer. This process can be quite slow. Longitudinal studies have shown that in untreated patients with in situ cervical cancer, 30% to 70% will develop invasive carcinoma over a period of 10 to 12 years. However, in about 10% of patients, lesions can progress from in situ to invasive in a period of less than 1 year. As it becomes invasive, the tumor breaks through the basement membrane and invades the cervical stroma. Extension of the tumor in the cervix may ultimately manifest as ulceration, exophytic tumor, or extensive infiltration of underlying tissue including bladder or rectum.
In addition to local invasion, carcinoma of the cervix can spread via the regional lymphatics or bloodstream. Tumor dissemination is generally a function of the extent and invasiveness of the local lesion. While cancer of the cervix generally progresses in an orderly manner, occasionally a small tumor with distant metastasis is seen. For this reason, patients must be carefully evaluated for metastatic disease.
Pretreatment surgical staging is the most accurate method to determine the extent of disease.[1] Because there is little evidence to demonstrate overall improved survival with routine surgical staging, the staging usually should be performed only as part of a clinical trial. Pretreatment surgical staging in bulky but locally curable disease may be indicated in select cases when a nonsurgical search for metastatic disease is negative. If abnormal nodes are detected by computed tomography scan or lymphangiography, fine-needle aspiration should be negative before a surgical staging procedure is performed.
Definitions: FIGOThe Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging to define cervical cancer; the FIGO system is most commonly used.[2,3]
Table 1. Carcinoma of the Cervix Uteria| Stage | |
| I | The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded). |
| IA | Invasive carcinoma, which can be diagnosed only by microscopy with deepest invasion ≤5 mm and largest extension ≥7 mm. |
| IA1 | Measured stromal invasion of ≤3.0 mm in depth and extension of ≤7.0 mm. |
| IA2 | Measured stromal invasion of >3.0 mm and not >5.0 mm with an extension of not >7.0 mm. |
| IB | Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than stage IA.b |
| IB1 | Clinically visible lesion ≤4.0 cm in greatest dimension. |
| IB2 | Clinically visible lesion >4.0 cm in greatest dimension. |
| II | Cervical carcinoma invades beyond the uterus but not to the pelvic wall or to the lower third of the vagina. |
| IIA | Without parametrial invasion. |
| IIA1 | Clinically visible lesion ≤4.0 cm in greatest dimension. |
| IIA2 | Clinically visible lesion >4.0 cm in greatest dimension. |
| IIB | With obvious parametrial invasion. |
| III | The tumor extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or nonfunctioning kidney.c |
| IIIA | Tumor involves lower third of the vagina with no extension to the pelvic wall. |
| IIIB | Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney. |
| IV | The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV. |
| IVA | Spread of the growth to adjacent organs. |
| IVB | Spread to distant organs. |
| aAdapted from FIGO Committee on Gynecologic Oncology.[2] | |
| bAll macroscopically visible lesions—even with superficial invasion—are allotted to stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.00 mm and a horizontal extension of not >7.00 mm. Depth of invasion should not be >5.00 mm taken from the base of the epithelium of the original tissue—superficial or glandular. The depth of invasion should always be reported in mm, even in those cases with "early (minimal) stromal invasion" (~1 mm). | |
| The involvement of vascular/lymphatic spaces should not change the stage allotment. | |
| cOn rectal examination, there is no cancer-free space between the tumor and the pelvic wall. All cases with hydronephrosis or nonfunctioning kidney are included, unless they are known to be the result of another cause. |
Standard treatments for patients with cervical cancer include:
Five randomized, phase III trials (GOG-85, RTOG-9001, GOG-120, GOG-123, and SWOG-8797) have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy,[1-6] while one trial examining this regimen demonstrated no benefit.[7] The patient populations in these studies included women with Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) stages IB2 to IVA cervical cancer treated with primary radiation therapy and women with FIGO stages I to IIA disease found to have poor prognostic factors (metastatic disease in pelvic lymph nodes, parametrial disease, or positive surgical margins) at the time of primary surgery. Although the positive trials vary in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy. Based on these results, strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.[1-9]
Surgery and radiation therapy are equally effective for early-stage small-volume disease.[10] Younger patients may benefit from surgery in regard to ovarian preservation and avoidance of vaginal atrophy and stenosis.
Patterns of care studies clearly demonstrate the negative prognostic effect of increasing tumor volume. Treatment, therefore, may vary within each stage as currently defined by FIGO and will depend on tumor bulk and spread pattern.[11]
Therapy of patients with cancer of the cervical stump is effective, yielding results comparable to those seen in patients with an intact uterus.[12]
Treatments under clinical evaluation for patients with cervical cancer include:
Cervical cancer during pregnancy
During pregnancy, no therapy is warranted for preinvasive lesions of the cervix, including carcinoma in situ, though expert colposcopy is recommended to exclude invasive cancer. Treatment of invasive cervical cancer during pregnancy depends on the stage of the cancer and gestational age at diagnosis. The traditional approach is to recommend immediate therapy appropriate for the disease stage when the cancer is diagnosed before fetal maturity and to delay therapy only if the cancer is detected in the final trimester.[13,14] However, other reports suggest that deliberate delay of treatment to allow improved fetal outcome may be a reasonable option for patients with stage IA and early IB cervical cancer.[15]
ReferencesConsensus guidelines have been issued for managing women with cervical intraepithelial neoplasia or adenocarcinoma in situ.[1] Properly treated, tumor control of in situ cervical carcinoma should be nearly 100%. Either expert colposcopic-directed biopsy or cone biopsy is required to exclude invasive disease before therapy is undertaken. A correlation between cytology and colposcopic-directed biopsy is also necessary before local ablative therapy is done. Even so, unrecognized invasive disease treated with inadequate ablative therapy may be the most common cause of failure.[2] Failure to identify the disease, lack of correlation between the Pap smear and colposcopic findings, adenocarcinoma in situ, or extension of disease into the endocervical canal makes a laser, loop, or cold-knife conization mandatory. The choice of treatment will also depend on several patient factors including age, desire to preserve fertility, and medical condition. Most importantly, the extent of disease must be known. The World Health Organization has made recommendations about the use of cryotherapy for providers in low-resource settings and has recognized the need to consider the availability of cryotherapy in relation to the availability of other treatment options.[3]
In selected cases, the outpatient loop electrosurgical excision procedure (LEEP) may be an acceptable alternative to cold-knife conization. This quickly performed in-office procedure requires only local anesthesia and obviates the risks associated with general anesthesia for cold-knife conization.[4,5] However, controversy exists as to the adequacy of LEEP as a replacement for conization.[6] A trial comparing LEEP with cold-knife cone biopsy showed no difference in the likelihood of complete excision of dysplasia.[7] However, two case reports suggested that the use of LEEP in patients with occult invasive cancer led to an inability to accurately determine depth of invasion when a focus of the cancer was transected.[8]
In a randomized, double-blind, placebo-controlled, phase II trial of 59 patients, a vaginal preparation of imiquimod, an immune-modulating agent, showed improved clearance rates for cervical intraepithelial neoplasia (CIN), or CIN 2/3, and high-risk human papillomavirus.[9] This is the first proven medical treatment for preinvasive cervical disease; however, the vaginal preparation is not yet commercially available.
Standard treatment options:
Methods to treat ectocervical lesions include the following:
When the endocervical canal is involved, laser or cold-knife conization may be used for selected patients to preserve the uterus and avoid radiation therapy and/or more extensive surgery.
Total abdominal or vaginal hysterectomy is an accepted therapy for the postreproductive age group and is particularly indicated when the neoplastic process extends to the inner cone margin. For medically inoperable patients, a single intracavitary insertion with tandem and ovoids for 5,000 mg hours (80 Gy vaginal surface dose) may be used.[14]
After treatment for CIN, women remain at a higher risk of developing cervical cancer, even if they follow accepted posttreatment screening guidelines.[15]
Current Clinical TrialsCheck for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
ReferencesEquivalent treatment options:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IA cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
ReferencesEither radiation therapy or radical hysterectomy and bilateral lymph node dissection results in cure rates of 85% to 90% for women with Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) stages IA2 and IB1 small-volume disease. The choice of either treatment depends on patient factors and available local expertise. A randomized trial reported identical 5-year overall survival (OS) and disease-free survival rates when comparing radiation therapy to radical hysterectomy.[1] The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[2] For adenocarcinomas that expand the cervix more than 4 cm, the primary treatment should be concomitant chemotherapy and radiation therapy.[3]
After surgical staging, patients found to have small volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic radiation therapy and concomitant chemotherapy.[4] The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative chemotherapy and radiation therapy.[5] Treatment of patients with unresected periaortic nodes with extended-field radiation therapy and chemotherapy leads to long-term disease control in those patients with low volume (<2 cm) nodal disease below L3.[6] A single study (RTOG-7920) showed a survival advantage in patients with tumors larger than 4 cm who received radiation therapy to para-aortic nodes without histologic evidence of disease.[7] Toxic effects were greater with para-aortic radiation therapy than with pelvic radiation therapy alone but were mostly confined to patients with prior abdominopelvic surgery.[7] Patients who underwent extraperitoneal lymph node sampling had fewer bowel complications than those who had transperitoneal lymph node sampling.[6,8,9] Patients with close vaginal margins (<0.5 cm) may also benefit from pelvic radiation therapy.[10]
Five randomized, phase III trials have shown an OS advantage for cisplatin-based therapy given concurrently with radiation therapy,[11-16] while one trial examining this regimen demonstrated no benefit.[17] The patient populations in these studies included women with FIGO stages IB2 to IVA cervical cancer treated with primary radiation therapy, and women with FIGO stages I to IIA disease who, at the time of primary surgery, were found to have poor prognostic factors, which included the following:
Although the positive trials vary somewhat in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy. Based on these results, strong consideration should be given to the incorporation of concurrent, cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.[11-19]
Standard treatment options:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IB cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
ReferencesEither radiation therapy or radical hysterectomy results in cure rates of 75% to 80%. The selection of either option depends on patient factors and local expertise. A randomized trial reported identical 5-year overall survival (OS) and disease-free survival rates when radiation therapy was compared with radical hysterectomy.[1] The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[2] For patients with bulky (>6 cm) endocervical squamous cell carcinomas or adenocarcinomas, treatment with high-dose radiation therapy will achieve local control and survival rates comparable to treatment with radiation therapy plus hysterectomy. Surgery after radiation therapy may be indicated for some patients with tumors confined to the cervix that respond incompletely to radiation therapy or in whom vaginal anatomy precludes optimal brachytherapy.[3]
After surgical staging, patients found to have small volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic radiation therapy.[4] The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[5] Treatment of patients with unresected periaortic nodes with extended-field radiation therapy leads to long-term disease control in those patients with low volume (<2 cm) nodal disease below L3.[6] A single study (RTOG-7920) showed a survival advantage in patients who received radiation therapy to para-aortic nodes without histologic evidence of disease.[7] Toxic effects were greater with para-aortic radiation than with pelvic radiation alone but were mostly confined to patients with prior abdominopelvic surgery.[7] Patients who underwent extraperitoneal lymph node sampling had fewer bowel complications than those who had transperitoneal lymph node sampling.[6,8,9] Patients with close vaginal margins (<0.5 cm) after radical surgery may also benefit from pelvic radiation therapy.[10]
Five randomized, phase III trials have shown an OS advantage for cisplatin-based therapy given concurrently with radiation therapy,[11-17] while one trial examining this regimen demonstrated no benefit.[18] The patient populations in these studies included women with Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) stages IB2 to IVA cervical cancer treated with primary radiation therapy and women with FIGO stages I to IIA disease who, at the time of primary surgery, were found to have poor prognostic factors, which included the following:
Although the positive trials vary somewhat in terms of stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy. Based on these results, strong consideration should be given to the incorporation of concurrent, cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.[11-19]
Standard treatment options:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIA cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
ReferencesThe size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[1] Survival and local control are better with unilateral rather than bilateral parametrial involvement.[2] Patients who are surgically staged as part of a clinical trial and are found to have small volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic radiation therapy.[3] If postoperative external-beam radiation therapy (EBRT) is planned following surgery, extraperitoneal lymph node sampling is associated with fewer radiation-induced complications than a transperitoneal approach.[4] The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[5] Treatment of patients with unresected periaortic nodes with extended-field radiation therapy leads to long-term disease control in those patients with low volume (<2 cm) nodal disease below L3.[6] A single study (RTOG-7920) showed a survival advantage in patients who received radiation therapy to para-aortic nodes without histologic evidence of disease.[7] Toxic effects are greater with para-aortic radiation than with pelvic radiation alone but were mostly confined to patients with prior abdominopelvic surgery.[7] Patients who underwent extraperitoneal lymph node sampling had fewer bowel complications than those who had transperitoneal lymph node sampling.[4,6,8]
Five randomized, phase III trials have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy, [9-15] while one trial examining this regimen demonstrated no benefit.[16] The patient populations in these studies included women with Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) stages IB2 to IVA cervical cancer treated with primary radiation therapy, and women with FIGO stages I to IIA disease who, at the time of primary surgery, were found to have poor prognostic factors, which included the following:
Although the positive trials vary somewhat in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrated significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy. Based on these results, strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.[9-17]
In an attempt to improve on standard chemoradiation, a phase III randomized trial compared concurrent gemcitabine plus cisplatin and radiation therapy followed by adjuvant gemcitabine and cisplatin (experimental arm) with concurrent cisplatin plus radiation (standard chemoradiation) in patients with stage IIB to IVA cervical cancer.[18][Level of evidence: 1iiA] A total of 515 patients from 9 countries were enrolled. The schedule for the experimental arm was cisplatin (40 mg/m2) and gemcitabine (125 mg/m2) weekly for 6 weeks with concurrent external-beam radiation therapy (50.4 Gy in 28 fractions) followed by brachytherapy (30–35 Gy in 96 hours) and then two adjuvant 21-day cycles of cisplatin (50 mg/m2) on day 1 plus gemcitabine (1,000 mg/m2) on days 1 and 8. The standard arm was cisplatin (40 mg/m2) weekly for 6 weeks with concurrent external-beam radiation therapy and brachytherapy as described for the experimental arm.
The primary endpoint was PFS at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years (74.4% [95% CI, 68%–79.8%] vs. 65.0% [95% CI, 58.5%–70.7%]; overall PFS [HR, 0.68; 95% CI, 0.49–0.95]; and OS [HR, 0.68; 95% CI, 0.49–0.95]). Patients in the experimental arm had increased hematologic and nonhematologic grade 3 and 4 toxic effects, and two deaths in the experimental arm were possibly related to treatment. A subgroup analysis showed an increased benefit in patients with a higher stage of disease (stage III–IVA vs. stage IIB), and suggests that the increased toxic effects of the experimental protocol may be justified for these patients.[19] Additional investigation is needed to determine which aspect of the experimental arm led to improved survival (i.e., the addition of the weekly gemcitabine, the adjuvant chemotherapy, or both) and quality of life during and after treatment, the data for which were omitted from the protocol.
Standard treatment options:
Although low-dose rate (LDR) brachytherapy, typically with cesium Cs 137, has been the traditional approach, the use of high-dose rate (HDR) therapy, typically with iridium Ir 192, is rapidly increasing. HDR brachytherapy provides the advantage of eliminating radiation exposure to medical personnel, a shorter treatment time, patient convenience, and outpatient management. In three randomized trials, HDR brachytherapy was comparable with LDR brachytherapy in terms of local-regional control and complication rates.[21-23][Level of evidence: 1iiDii] The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as a component of cervical cancer treatment.[24,25]
Current Clinical TrialsCheck for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIB cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
ReferencesThe size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[1] Patterns-of-care studies in stage IIIA/IIIB patients indicate that survival is dependent on the extent of the disease, with unilateral pelvic wall involvement predicting a better outcome than bilateral involvement, which in turn predicts a better outcome than involvement of the lower third of the vaginal wall.[2] These studies also reveal a progressive increase in local control and survival paralleling a progressive increase in paracentral (point A) dose and use of intracavitary treatment. The highest rate of central control was seen with paracentral (point A) doses of more than 85 Gy.[3]
Patients who are surgically staged as part of a clinical trial and are found to have small volume para-aortic nodal disease and controllable pelvic disease may be cured with external-beam pelvic and para-aortic radiation therapy. If postoperative external-beam radiation therapy (EBRT) is planned following surgery, extraperitoneal lymph node sampling is associated with fewer radiation-induced complications than a transperitoneal approach.[4] The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[5] Treatment of patients with unresected periaortic nodes with extended-field radiation therapy leads to long-term disease control in those patients with low volume (<2 cm) nodal disease below L3. Patients who underwent extraperitoneal lymph node sampling had fewer bowel complications than those who had transperitoneal lymph node sampling.[6]
Five randomized, phase III trials have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy,[7-13] while one trial examining this regimen demonstrated no benefit.[14] The patient populations in these studies included women with Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) stages IB2 to IVA cervical cancer treated with primary radiation therapy and women with FIGO stages I to IIA disease who, at the time of primary surgery, were found to have poor prognostic factors, which included the following:
Although the positive trials vary somewhat in terms of stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy. Based on these results, strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.[7-15]
In an attempt to improve on standard chemoradiation, a phase III randomized trial compared concurrent gemcitabine plus cisplatin and radiation therapy followed by adjuvant gemcitabine and cisplatin (experimental arm) with concurrent cisplatin plus radiation (standard chemoradiation) in patients with stage IIB to IVA cervical cancer.[16][Level of evidence: 1iiA] A total of 515 patients from 9 countries were enrolled. The schedule for the experimental arm was cisplatin (40 mg/m2) and gemcitabine (125 mg/m2) weekly for 6 weeks with concurrent external-beam radiation (50.4 Gy in 28 fractions) followed by brachytherapy (30–35 Gy in 96 hours) and then two adjuvant 21-day cycles of cisplatin (50 mg/m2) on day 1 plus gemcitabine (1,000 mg/m2) on days 1 and 8. The standard arm was cisplatin (40 mg/m2) weekly for 6 weeks with concurrent external-beam radiation and brachytherapy as described for the experimental arm.
The primary endpoint was PFS at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years (74.4% [95% CI, 68%–79.8%]) vs. 65.0% [95% CI, 58.5%–70.7%]; overall PFS [HR, 0.68; 95% CI, 0.49– 0.95]; and OS [HR, 0.68; 95% CI, 0.49–0.95]). Patients in the experimental arm had increased hematologic and nonhematologic grade 3 and 4 toxic effects, and two deaths in the experimental arm were possibly related to treatment. A subgroup analysis showed an increased benefit in patients with higher stage of disease (stage III–IVA vs. stage IIB), suggesting that the increased toxic effects of the experimental protocol may be justified for these patients.[17] Additional investigation is needed to determine which aspect of the experimental arm led to improved survival (i.e., the addition of the weekly gemcitabine, the adjuvant chemotherapy, or both) and quality of life during and after treatment, which was omitted from the protocol.
Standard treatment options:
Although low-dose rate (LDR) brachytherapy, typically with cesium Cs 137, has been the traditional approach, the use of high-dose rate (HDR) therapy, typically with iridium Ir 192, is rapidly increasing. HDR brachytherapy provides the advantages of eliminating radiation exposure to medical personnel, a shorter treatment time, patient convenience, and outpatient management. In three randomized trials, HDR brachytherapy was comparable with LDR brachytherapy in terms of local-regional control and complication rates.[19-21][Level of evidence: 1iiDii] The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as a component of cervical cancer treatment.[22,23]
Current Clinical TrialsCheck for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
ReferencesThe size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[1] After surgical staging, patients found to have small volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic radiation therapy.
Five randomized, phase III trials have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy,[2-8] while one trial examining this regimen demonstrated no benefit.[9] The patient populations in these studies included women with Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) stages IB2 to IVA cervical cancer treated with primary radiation therapy and women with FIGO stages I to IIA disease who, at the time of primary surgery, were found to have poor prognostic factors, which include the following:
Although the positive trials vary somewhat in terms of stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy. Based on these results, strong consideration should be given to the incorporation of concurrent, cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.[2-10]
In an attempt to improve on standard chemoradiation, a phase III randomized trial compared concurrent gemcitabine plus cisplatin and radiation therapy followed by adjuvant gemcitabine and cisplatin (experimental arm) with concurrent cisplatin plus radiation (standard chemoradiation) in patients with stage IIB to IVA cervical cancer.[11][Level of evidence: 1iiA] A total of 515 patients from 9 countries were enrolled. The schedule for the experimental arm was cisplatin (40 mg/m2) and gemcitabine (125 mg/m2) weekly for 6 weeks with concurrent external-beam radiation (50.4 Gy in 28 fractions) followed by brachytherapy (30–35 Gy in 96 hours) and then two adjuvant 21-day cycles of cisplatin (50 mg/m2) on day 1 plus gemcitabine (1,000 mg/m2) on days 1 and 8. The standard arm was cisplatin (40 mg/m2) weekly for 6 weeks with concurrent external-beam radiation and brachytherapy as described for the experimental arm.
The primary endpoint was PFS at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years (74.4% [95% CI, 68%–79.8%]) vs. 65.0% [95% CI, 58.5%–70.7%]; overall PFS [HR, 0.68; 95% CI, 0.49–0.95]; and OS [HR 0.68; 95% CI, 0.49–0.95]). Patients in the experimental arm had increased hematologic and nonhematologic grade 3 and 4 toxic effects, and two deaths in the experimental arm were possibly related to treatment. A subgroup analysis showed an increased benefit in patients with higher stage of disease (stage III–IVA vs. stage IIB), suggesting that the increased toxic effects of the experimental protocol may be justified for these patients.[12] Additional investigation is needed to determine which aspect of the experimental arm led to improved survival (i.e., the addition of the weekly gemcitabine, the adjuvant chemotherapy, or both) and quality of life during and after treatment, which was omitted from the protocol.
Standard treatment options:
Although low-dose rate (LDR) brachytherapy, typically with cesium Cs 137, has been the traditional approach, the use of high-dose rate (HDR) therapy, typically with iridium Ir 192, is rapidly increasing. HDR brachytherapy provides the advantage of eliminating radiation exposure to medical personnel, a shorter treatment time, patient convenience, and outpatient management. In three randomized trials, HDR brachytherapy was comparable with LDR brachytherapy in terms of local-regional control and complication rates.[14-16][Level of evidence: 1iiDii] The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as a component of cervical cancer treatment.[13,17,18]
Current Clinical TrialsCheck for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IVA cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
ReferencesNo standard chemotherapy treatment that provides substantial palliation is available for patients with stage IVB cervical cancer. These patients are appropriate candidates for clinical trials testing single agents or combination chemotherapy employing agents listed below or new anticancer treatments in phase I and II clinical trials.[1]
Standard treatment options:
Treatment options under clinical evaluation:
Information about ongoing clinical trials is available from the NCI Web site.
Current Clinical TrialsCheck for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IVB cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
ReferencesNo standard treatment is available for patients with recurrent cervical cancer that has spread beyond the confines of a radiation or surgical field. For locally recurrent disease, pelvic exenteration can lead to a 5-year survival rate of 32% to 62% in selected patients.[1-3] These patients are appropriate candidates for clinical trials testing drug combinations or new anticancer agents.
The Gynecologic Oncology Group (GOG) has reported on several randomized phase III trials, (GOG-0179 [NCT00003945], GOG-0240 [NCT00803062]) in this setting. Single-agent cisplatin administered intravenously at 50 mg/m² every 3 weeks was the most-used regimen to treat recurrent cervical cancer since it was initially introduced in the 1970s.[4,5]
Various combinations containing cisplatin [4,5] failed to reach their primary endpoint of improving survival, however, a doubling of the cisplatin dose-rate did improve survival. Combinations with paclitaxel and with ifosfamide improved response rates (RR), but they did so at a cost of much greater toxicity, especially with the latter drug. A survival advantage over cisplatin was obtained with the cisplatin + topotecan (CT) doublet [5] leading to approval of this indication for topotecan by the U.S. Food and Drug Administration. However, in this study, cisplatin underperformed because many patients had received this drug earlier as a radiosensitizer. (Refer to Stages IIA, IIB, III, and IVA for more information on chemoradiation and the drug cisplatin, in particular.) Therefore, cisplatin plus paclitaxel (CP) was the reference arm in GOG-0204 (NCT00064077).
The GOG has reported on sequential randomized trials dealing with chemotherapy for stage IVB, recurrent, or persistent cervical cancer.[5-9] In the initial trial, the primary endpoint of exceeding the survival observed with cisplatin alone was not reached. However, in these trials:
GOG-0204 enrolled 513 patients, leading to an early closure because no one experimental arm was likely to significantly lower the hazard ratio of death (HRdeath) relative to PC:1.15 (95% confidence interval [CI], 0.79–1.67) for vinorelbine + cisplatin (VC), 1.32 (95% CI, 0.91–1.92) for gemcitabine plus cisplatin (GC), and 1.27 (95% CI, 0.90–1.78) for CT. Trend in RR, PFS, and OS favored CT.[10][Level of evidence: 1iiA] The patients in the various arms of the study differed in the extent of neutropenia, infection, and alopecia that they experienced,[10] but none of the patients in the study arms differed in health-related quality of life during treatment.[11] However, there were more neurologic side effects for PC.
Interim results for GOG-0240 (NCT00803062) were presented in abstract form and showed that 452 patients with stage IVB, recurrent, or persistent cervical cancer were randomly assigned to chemotherapy versus chemotherapy plus bevacizumab-containing regimens.[12] The chemotherapy regimens were cisplatin (50 mg/m2) plus paclitaxel (135–175 mg/m2) and topotecan (0.75 mg/m2 d1–d3) plus paclitaxel (175 mg/m2 d1). The bevacizumab dose was 15 mg/kg, and cycles were every 21 days unless toxicity, progression, or complete response were noted.
Preliminary results showed the topotecan-paclitaxel combination was not superior to the cisplatin-paclitaxel combination. The addition of bevacizumab led to improved median OS when compared with chemotherapy alone (17 months versus 13.3 months, respectively). The HRdeath was 0.71 when regimens were compared with and without bevacizumab [97.6% CI, 0.54–0.95; 1-sided P = .0035]. The bevacizumab-containing regimens were associated with more grade 3 or 4 bleeding, thrombosis and embolism, and gastrointestinal fistula.[12][Level of evidence: 1iiA]
Standard treatment options:
Treatment options under clinical evaluation:
Information about ongoing clinical trials is available from the NCI Web site.
Current Clinical TrialsCheck for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
ReferencesThe PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Cervical Cancer
Updated statistics with estimated new cases and deaths for 2014 (cited American Cancer Society as reference 1).
Added text to state that the World Health Organization has made recommendations about the use of cryotherapy for providers in low-resource settings and has recognized the need to consider the availability of cryotherapy in relation to the availability of other treatment options (cited Santesso et al. as reference 3).
Added text to state that in a randomized, double-blind, placebo-controlled, phase II trial of 59 patients, a vaginal preparation of imiquimod, an immune-modulating agent, showed improved clearance rates for cervical intraepithelial neoplasia (CIN), or CIN 2/3, and high-risk human papillomavirus (cited Grimm et al. as reference 9).
Revised text to add only if excisional biopsy is not feasible to the total abdominal or vaginal hysterectomy for postreproductive patients treatment option.
Added text to state that after treatment for CIN, women remain at a higher risk of developing cervical cancer, even if they follow accepted posttreatment screening guidelines (cited Rebolj et al. as reference 15).
Added text to state that a meta-analysis, which is evaluating the role of radiosensitizing chemotherapy in IA2 and IB1 lesions, suggests a likely benefit from the addition of platinum-based radiosensitizing chemotherapy, although numbers are small in this patient population (cited Rosa et al. as reference 26).
Added text about a phase III randomized trial that compared concurrent gemcitabine plus cisplatin and radiation therapy followed by adjuvant gemcitabine and cisplatin with concurrent cisplatin plus radiation in patients with stage IIB to IVA cervical cancer (cited 2011 Dueñas-González et al. as reference 18).
Added text to state that the primary endpoint was progression-free survival (PFS) at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years. Added that patients in the experimental arm had increased hematologic and nonhematologic grade 3 and 4 toxic effects, and two deaths in the experimental arm were possibly related to treatment. Also added that a subgroup analysis showed an increased benefit in patients with a higher stage of disease and suggests that the increased toxic effects of the experimental protocol may be justified for these patients (cited 2012 Dueňas-González et al. as reference 19).
Added text about a phase III randomized trial that compared concurrent gemcitabine plus cisplatin and radiation therapy followed by adjuvant gemcitabine and cisplatin with concurrent cisplatin plus radiation in patients with stage IIB to IVA cervical cancer (cited 2011 Dueñas-González et al. as reference 16).
Added text to state that the primary endpoint was PFS at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years. Added that patients in the experimental arm had increased hematologic and nonhematologic grade 3 and 4 toxic effects, and two deaths in the experimental arm were possibly related to treatment. Also added that a subgroup analysis showed an increased benefit in patients with a higher stage of disease and suggests that the increased toxic effects of the experimental protocol may be justified for these patients (cited 2012 Dueňas-González et al. as reference 17).
Added text about a phase III randomized trial that compared concurrent gemcitabine plus cisplatin and radiation therapy followed by adjuvant gemcitabine and cisplatin with concurrent cisplatin plus radiation in patients with stage IIB to IVA cervical cancer (cited 2011 Dueñas-González et al. as reference 11).
Added text to state that the primary endpoint was PFS at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years. Added that patients in the experimental arm had increased hematologic and nonhematologic grade 3 and 4 toxic effects, and two deaths in the experimental arm were possibly related to treatment. Also added that a subgroup analysis showed an increased benefit in patients with a higher stage of disease, and suggests that the increased toxic effects of the experimental protocol may be justified for these patients (cited 2012 Dueňas-González et al. as reference 12).
Added Schmidt et al. as reference 3.
Added text about interim results for GOG-0240 presented in abstract form that showed 452 patients with stage IVB, recurrent, or persistent cervical cancer were randomly assigned to chemotherapy versus chemotherapy plus bevacizumab-containing regimens (cited Tewari et al. as reference 12).
Added text to state that preliminary results for GOG-0240 showed the topotecan-paclitaxel combination was not superior to the cisplatin-paclitaxel combination. The addition of bevacizumab led to improved median overall survival when compared with chemotherapy alone. The hazard ratio for death was 0.71 when regimens were compared with and without bevacizumab. The bevacizumab-containing regimens were associated with more grade 3 or 4 bleeding, thrombosis and embolism, and gastrointestinal fistula (level of evidence 1iiA).
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of cervical cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and UpdatesThis summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Cervical Cancer Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of EvidenceSome of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This SummaryPDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Cervical Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/cervical/HealthProfessional. Accessed <MM/DD/YYYY>.
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