Cervical Cancer – Causes, Symptoms, Diagnosis, Treatment

Increasing age is the most important risk factor for most cancers. The primary risk factor for cervical cancer is human papillomavirus (HPV) infection.[rx–rx]

Other risk factors for cervical cancer include the following:

Human papillomavirus (HPV) infection

HPV infection is a necessary step in the development of virtually all precancerous and cancerous lesions. Epidemiologic studies convincingly demonstrate that the major risk factor for the development of preinvasive or invasive carcinoma of the cervix is HPV infection, far outweighing other known risk factors.

More than 6 million women in the United States are estimated to be infected with HPV. Transient HPV infection is common, particularly in young women,[rx] while cervical cancer is rare. The persistence of an HPV infection leads to an increased risk of developing precancerous and cancerous lesions.[rx,rx]

The strain of HPV infection is also important in conferring risk. There are multiple subtypes of HPV that infect humans; of these, subtypes 16 and 18 have been most closely associated with high-grade dysplasia and cancer. Studies suggest that acute infection with HPV types 16 and 18 conferred an 11-fold to 16.9-fold risk of rapid development of high-grade CIN.[rx–rx] Further studies have shown that infection with either HPV 16 or 18 is more predictive than cytologic screening of high-grade CIN or greater disease, and that the predictive ability is seen for up to 18 years after the initial test.[rx–rx]

There are two commercially available vaccines that target anogenital-related strains of HPV. The vaccines are directed towards HPV-naïve girls and young women, and although penetration of the vaccine has been moderate, significant decreases in HPV-related diseases have been documented.[rx]

HPV testing

Cervical cytology (Pap smear) has been the mainstay of cervical cancer screening since its introduction. However, molecular techniques for the identification of HPV DNA are highly sensitive and specific. Current screening options include the following:

HPV testing is suggested when it is likely to successfully triage patients into low- and high-risk groups for a high-grade dysplasia or greater lesion.

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.[rx] 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.[rx]

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.[rx–rx]

Other studies show that patients with low-risk cytology and high-risk HPV infection with types 16, 18, and 31 are more likely to have CIN or micro-invasive histopathology on biopsy.[rx,rx–rx] 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.[rx]

For women older than 30 years who are more likely to have persistent HPV infection, HPV typing can successfully triage women into high- and low-risk groups for CIN 3 or worse disease. In this age group, HPV DNA testing is more effective than cytology alone in predicting the risk of developing CIN 3 or worse.[rx] Other studies have shown the effectiveness of a primary HPV DNA–screening strategy with cytology triage over the previously used cytology-based screening algorithms.[rx,rx]

Clinical stage

Clinical stage as a prognostic factor is supplemented by several gross and microscopic pathologic findings in surgically treated patients.

Evidence (clinical stage and other findings):

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 most prominently predicted 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 the most important and reproducible.[rx,rx]

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 with clinical or histologic stage.[rx]

A multivariate analysis of prognostic variables in 626 patients with locally advanced disease (primarily stages II, III, and IV) studied by the GOG identified the following variables that were significant for progression-free interval and survival:[rx]

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.

It is controversial whether adenocarcinoma of the cervix carries a significantly worse prognosis than squamous cell carcinoma of the cervix.[rx] Several population-based and retrospective studies show a worse outcome for patients with adenocarcinoma, with an increase in distant metastasis noted, when compared with those with squamous histology.[rx–rx] Reports conflict about the effect of adenosquamous cell type on the outcome.[rx,rx] 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.[rx]

In a large series of cervical cancer patients treated by radiation therapy, the incidence of distant metastases (most frequently to the 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.[rx] A multivariate analysis of factors influencing the incidence of distant metastases showed stage, an endometrial extension of tumor, and pelvic tumor control to be significant indicators of distant dissemination.[rx]

GOG studies have indicated that prognostic factors vary depending on whether clinical or surgical staging are utilized and with different treatments. Delay in radiation delivery completion is associated with poorer progression-free survival when clinical staging is used. To-date, stage, tumor grade, race, and age are uncertain prognostic factors in studies utilizing chemoradiation.[rx]

Other prognostic factors

Other prognostic factors that may affect outcome include the following:

Conization

When the endocervical canal is involved, laser or cold-knife conization may be used for selected patients to preserve the uterus, avoid radiation therapy, and more extensive surgery.[rx]

In selected cases, the outpatient LEEP may be an acceptable alternative to cold-knife conization. This procedure requires only local anesthesia and obviates the risks associated with general anesthesia for cold-knife conization.[rx–rx] However, controversy exists about the adequacy of LEEP as a replacement for conization; LEEP is unlikely to be sufficient for patients with adenocarcinoma in situ.[rx]

Evidence (conization using LEEP):

Hysterectomy for postreproductive patients

Hysterectomy is standard therapy for women with cervical adenocarcinoma in situ, because of the location of the disease in the endocervical canal and the possibility for skip lesions in this region, making margin status a less reliable prognostic factor. However, the effect of hysterectomy compared with conservative surgical measures on mortality has not been studied. Hysterectomy may be performed for squamous cell carcinoma in situ if conization is not possible because of previous surgery, or if positive margins are noted after conization therapy. Hysterectomy is not an acceptable front-line therapy for squamous carcinoma in situ.[rx]

Internal radiation therapy for medically inoperable patients

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.[rx]

Conization

If the depth of invasion is less than 3 mm, no vascular or lymphatic channel invasion is noted, and the margins of the cone are negative, conization alone may be appropriate in patients who wish to preserve fertility.[rx]

Total hysterectomy

If the depth of invasion is less than 3 mm, which is proven by cone biopsy with clear margins,[rx] no vascular or lymphatic channel invasion is noted, and the frequency of lymph-node involvement is sufficiently low, lymph-node dissection at the time of hysterectomy is not required. Oophorectomy is optional and should be deferred for younger women.

Modified radical hysterectomy with lymphadenectomy

For patients with tumor invasion between 3 mm and 5 mm, modified radical hysterectomy with pelvic-node dissection has been recommended because of a reported risk of lymph-node metastasis of as much as 10%.[rx] Radical hysterectomy with node dissection may also be considered for patients for whom the depth of tumor invasion was uncertain because of invasive tumor at the cone margins.

Evidence (open abdominal surgery [open] versus minimally invasive surgery [MIS]):

Although questions remain regarding the use of MIS radical hysterectomy for some subpopulations of good-risk patients, the data from this trial suggest that open abdominal surgery should be considered the standard of care for patients with early-stage cervical cancer who are candidates for radical hysterectomy.

Radical trachelectomy

Patients with stages IA2 to IB disease who desire future fertility may be candidates for radical trachelectomy. In this procedure, the cervix and lateral parametrial tissues are removed, and the uterine body and ovaries are maintained. Most centers utilize the following criteria for patient selection:

Intraoperatively, the patient is assessed in a manner similar to a radical hysterectomy; the procedure is aborted if more advanced disease than expected is encountered. The margins of the specimen are also assessed at the time of surgery, and a radical hysterectomy is performed if inadequate margins are obtained.[rx–rx]

Intracavitary radiation therapy

Intracavitary radiation therapy is a treatment option when palliative treatment is appropriate because of other medical conditions and for women who are not surgical candidates.

If the depth of invasion is less than 3 mm and no capillary lymphatic space invasion is noted, and the frequency of lymph-node involvement is sufficiently low, external-beam radiation therapy is not required. One or two insertions with tandem and ovoids for 6,500 mg to 8,000 mg hours (100–125 Gy vaginal surface dose) are recommended.[rx]

Radiation therapy with concomitant chemotherapy

Concurrent, cisplatin-based chemotherapy with radiation therapy is the standard of care for women who require radiation therapy for the treatment of cervical cancer.[rx–rx] Radiation therapy protocols for patients with cervical cancer have historically used dosing at two anatomical points, termed point A and point B, to standardize the doses received. Point A is defined as 2 cm from the external os, and 2 cm lateral, relative to the endocervical canal. Point B is also 2 cm from the external os, and 5 cm lateral from the patient midline, relative to the bony pelvis. In general, for smaller tumors, the curative-intent dose for point A is around 70 Gy, whereas for larger tumors, the point A dose may approach 90 Gy.

Evidence (radiation with concomitant chemotherapy):

Radical hysterectomy and bilateral pelvic lymphadenectomy with or without total pelvic radiation therapy plus chemotherapy

Radical hysterectomy and bilateral pelvic lymphadenectomy may be considered for women with stages IB to IIA disease.

Evidence (radical hysterectomy and bilateral pelvic lymphadenectomy with or without total pelvic radiation therapy plus chemotherapy):

Evidence (open abdominal surgery [open] versus minimally invasive surgery [MIS]):

Although questions remain regarding the use of MIS radical hysterectomy for some subpopulations of good-risk patients, the data from this trial suggest that open abdominal surgery should be considered the standard of care for patients with early-stage cervical cancer who are candidates for radical hysterectomy.

Radical trachelectomy

Patients with presumed early-stage disease who desire future fertility may be candidates for radical trachelectomy. In this procedure, the cervix and lateral parametrial tissues are removed, and the uterine body and ovaries are maintained. The patient selection differs somewhat between groups; however, general criteria include the following:

Intraoperatively, the patient is assessed in a manner similar to a radical hysterectomy; the procedure is aborted if more advanced disease than expected is encountered. The margins of the specimen are also assessed at the time of surgery, and a radical hysterectomy is performed if inadequate margins are obtained.[rx–rx]

Neoadjuvant chemotherapy

Several groups have investigated the role of neoadjuvant chemotherapy to convert patients who are conventional candidates for chemoradiation into candidates for radical surgery.[rx–rxrx] Multiple regimens have been used; however, almost all utilize a platinum backbone. The largest randomized trial to date was reported in 2001, and its accrual was completed before the standard of care included the addition of cisplatin to radiation therapy.[rx] As a result, the control arm utilized radiation therapy alone. Although there was an improvement in OS for the experimental arm, the results are not reflective of current practice. This study accrued patients with stages IB through IVA disease, but improvement in the experimental arm was only noted for participants with early stage disease (stages IB, IIA, or IIB).

EORTC-55994 (NCT00039338) randomly assigned patients with stages IB2, IIA2, and IIB cervical cancer to standard chemoradiation or neoadjuvant chemotherapy (with a cisplatin backbone for three cycles) followed by evaluation for surgery. With OS as the primary endpoint, this trial may delineate whether there is a role for neoadjuvant chemotherapy for this patient population.

Radiation therapy alone

External-beam pelvic radiation therapy combined with two or more intracavitary brachytherapy applications is appropriate therapy for patients with stage IA2 and IB1 lesions. For patients with stage IB2 and larger lesions, radiosensitizing chemotherapy is indicated. The role of radiosensitizing chemotherapy in patients with stage IA2 and IB1 lesions is untested. However, it may prove beneficial in certain cases.

IMRT

IMRT is a radiation therapy technique that allows for conformal dosing of target anatomy while sparing neighboring tissue. Theoretically, this technique should decrease radiation therapy–related toxicity, but this could come at the cost of decreased efficacy if tissue is inappropriately excluded from the treatment field. Several institutions have reported their experience with IMRT for postoperative adjuvant therapy in patients with intermediate-risk and high-risk disease after radical surgery.[rx–rx] The Radiation Therapy Oncology Group (RTOG) has closed accrual for a phase II trial (RTOG-0418 [NCT00331760]) that is evaluating the use of IMRT in patients with both cervical and endometrial cancers who require adjuvant radiation therapy.

Radiation therapy with concomitant chemotherapy

Strong consideration should be given to the use of intracavitary radiation therapy and external-beam radiation therapy (EBRT) to the pelvis combined with cisplatin or cisplatin/fluorouracil (5-FU).[rx–rx]

Evidence (radiation therapy with concomitant chemotherapy):

Evidence (low-dose rate vs. high-dose rate intracavitary radiation therapy):

The addition of adjuvant chemotherapy following chemoradiation therapy is currently being evaluated as part of a large multinational clinical trial. The OUTBACK trial (NCT01414608) is randomly assigning women to receive cisplatin (40 mg/m2 weekly for 5 doses) with whole-pelvic radiation therapy (standard chemoradiation therapy) with or without standard chemoradiation therapy plus adjuvant carboplatin (AUC 5 + paclitaxel 155 mg/m2).

Interstitial brachytherapy

For patients who complete EBRT and have bulky cervical disease such that standard brachytherapy cannot be placed anatomically, interstitial brachytherapy has been used to deliver adequate tumoricidal doses with an acceptable toxicity profile.[28]

Neoadjuvant chemotherapy

Several groups have investigated the role of neoadjuvant chemotherapy to convert patients who are conventional candidates for chemoradiation into candidates for radical surgery.[rx–rx] Multiple regimens have been used; however, almost all utilize a platinum backbone. The largest randomized trial to date was reported in 2001, and its accrual was completed before the standard of care included the addition of cisplatin to radiation therapy.[rx] As a result, although there was an improvement in OS for the experimental arm, the results are not reflective of current practice. This study accrued patients with stages IB through IVA disease, but improvement in the experimental arm was only noted for participants with early stage disease (stages IB, IIA, or IIB).

EORTC-55994 (NCT00039338) randomly assigned patients with stages IB2, IIA2, and IIB cervical cancer to standard chemoradiation or neoadjuvant chemotherapy (with a cisplatin backbone for three cycles) followed by evaluation for surgery. With OS as the primary endpoint, this trial may delineate whether there is a role for neoadjuvant chemotherapy for this patient population.

Palliative radiation therapy

Radiation therapy may be used to palliate central disease or distant metastases.

Palliative chemotherapy and other systemic therapy

Multiple agents are associated with objective response rates; however, durable responses are rare.

Drugs used in stage IVB cervical cancer treatment are shown in Table 6.

Immunotherapy

Radiation therapy and chemotherapy

For recurrence in the pelvis after initial radical surgery, radiation therapy and chemotherapy (fluorouracil with or without mitomycin) may cure 40% to 50% of patients.[rx]

Palliative chemotherapy and other systemic therapy

Chemotherapy can be used for palliation. Drugs used for palliative chemotherapy are shown in Table 7.

Pelvic exenteration

No 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.[rx,rx] These patients are appropriate candidates for clinical trials testing drug combinations or new anticancer agents.