What every physician needs to know:

Cervical cancer is the third leading cause of cancer among women worldwide, and the second leading cause of cancer death for women living in developing countries. The highest incidence of cervical cancer is seen in Central and South America, Africa and the Caribbean. Cervical cancer is highly preventable, and as a result it is an uncommon cancer in the US, representing only 2% of all cancer deaths.

Persistent HPV infection is thought to be responsible for the majority of cervical cancer cases and cervical cancer typically follows the development of pre-invasive cervical lesions. Cervical screening programs have resulted in the detection and treatment of pre-invasive lesions, which has led to a dramatic decrease in the incidence of invasive cervical cancer in countries where this screening is available and utilized.

In addition, new vaccinations against high-risk HPV strains are anticipated to lead to an even further reduction in the incidence of invasive cervical cancer. In the US, women who develop invasive cervical cancer tend to be those who have not had recent screening and are often elderly, uninsured, of lower socioeconomic status or members of minority groups.

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Cervical cancer generally has a favorable prognosis as it is often detected at an early stage and is effectively treated with surgery or chemo-radiation. Even advanced stage disease is highly treatable with chemo-radiation, resulting in a 5-year survival for about 50% in women with stage III disease.

Are you sure your patient has cervical cancer? What should you expect to find?

Cervical cancer is definitively diagnosed by cervical biopsy. Most women with early stage cervical cancer are asymptomatic and are typically diagnosed following an abnormal pap smear. Women with early stage cancer sometimes complain of watery vaginal discharge or more commonly post-coital spotting.

Patients with advanced cervical cancer almost always have some form of abnormal vaginal bleeding. Women with advanced stage disease may also present with symptoms related to the local spread of disease. This may include unilateral or bilateral ureteral obstruction and lower extremity swelling from deep venous thrombosis.

The “classic triad” of findings with advanced cervical cancer is sciatic pain, leg swelling and hydronephrosis. In addition these women sometimes present with malodorous vaginal discharge from large necrotic cervical tumors or fistulas.

Beware of other conditions that can mimic cervical cancer:

The key to diagnosis is biopsy. Since many cases in the US are preclinical and diagnosed by way of pap smear and biopsy, there is little chance of diagnostic confusion. One situation sometimes seen by clinicians performing pelvic exams for abnormal bleeding that can be confused with cervical cancer is a prolapsed uterine fibroid. In this situation a large mass is seen on pelvic exam coming from the cervix. Again a biopsy if the diagnosis is uncertain will provide clarity.

Which individuals are most at risk for developing cervical cancer:

Most cervical cancers are a result of persistent HPV infection, thus risk factors for the disease follow a pattern that is typical for sexually transmitted diseases. This includes first coitus at a young age, multiple sexual partners (self or partner), history of other sexually transmitted diseases, contraceptive use and high parity.

In addition smoking and chronic immunosuppression, especially as a result of HIV infection, are associated with cervical cancer. Women who are under-screened in the US are at an increased risk of cervical cancer – this includes underinsured women, ethnic minorities, poor women, those living in rural areas, immigrants and elderly women. In the US, about 60% of cervical cancer cases occur in women that have not had a pap smear in at least 5 years.

More recently, in addition to pap smear detection of pre-invasive lesions, several HPV vaccines have been developed mostly targeting HPV 16 and 18, the most carcinogenic serotypes. This vaccine is currently recommended for girls and women aged between 9-26. In the best circumstances administration of this vaccine prior to onset of sexual activity maximizes the prevention of HPV infection. Additional administration of this vaccine to women of any age with cervical dysplasia, who are previously unvaccinated, appears to decrease the rate of subsequent procedures to treat dysplasia and thus may prevent some cervical cancers.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, Ct/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Cervical cancer is staged (Table I) clinically according to the guidelines of the International Federation of Gynecology and Obstetrics (FIGO). This is mainly due to the fact that the majority of cases are diagnosed in resource limited countries; in these settings, advanced imaging may not be available. In addition, many women with cervical cancer are treated with primary radiation and thus surgical staging has not been adopted.

Procedures that may be used for FIGO staging are limited to the following:

  • Physical examination.

  • Colposcopy with biopsy (microscopic cervical exam with the aid of acetic acid or other agents that highlight cervical lesions).

  • Chest radiography.

  • Cone biopsy (excision of a large piece of the cervix) may be used if cervical biopsy is inadequate or for the accurate assessment of microinvasive disease.

In selected cases, cystoscopy, proctoscopy or barium enema, intravenous pyelography or alternative imaging to assess for ureteral obstruction and bone films may be indicated and may be used for FIGO staging. CT, MRI, positron emission tomography (PET), and surgical lymph node sampling are often used in the work-up of a cervical cancer when they are available, but do not change FIGO stage. These studies often provide additional prognostic information and influence clinical decision making.

Staging

See Table I. TNM and Figo staging tables for cervical cancer.

Stage I

Stage I cancers are confined to the cervix. Cancers that are not clinically visible are classified as stage IA and by definition are only detected microscopically by the use of colposcopy and/or cervical biopsy. Stage IA disease is further sub-classified, based on depth of invasion into stages 1A1 (“microinvasive disease”; 3mm or less) and 1A2 (>3mm and <5mm). Microscopic lesions are classified as 1B disease when the biopsy reveals a depth of invasion of 5mm or more, or the lesion is 7mm or more in diameter. Any tumor confined to the cervix that is clinically visible is considered stage IB; lesions that are 4cm or less are considered stage IB1 and those larger than 4cm are stage IB2.

Stage II

Lesions that extend beyond the cervix (excluding the uterus) but not to the pelvic sidewall or lower third of the vagina are considered stage II. Stage II tumors that do not involve the parametrium are considered stage IIA (sub-classified into IIA1 4cm or less, IIB2 >4cm). Tumors clinically involving the parametrium are considered stage IIB. Involvement of the parametrium is assessed by a thorough rectovaginal exam performed by a clinician with experience in the evaluation of cervical cancer. This exam may be intolerable in the office and an exam under anesthesia may be required.

Stage III

Tumors involving the lower third of the vagina without extension to the sidewall are considered stage IIIA. Tumors that extend to the pelvic sidewall or result in hydronephrosis or a non-functioning kidney are considered stage IIIB. Extension to the pelvic sidewall is determined by pelvic and rectovaginal exam by an experienced provider.

Stage IV

Tumor that extends beyond the pelvis into adjacent mucosa of the bowel or bladder is considered stage IVA disease. Biopsy by cystoscopy or proctoscopy is required for confirmation of diagnosis and should be performed whenever women have large lesions or there is any clinical suspicion of organ involvement (i.e. symptoms or hematuria). Disease spread to other distant organs is considered stage IVB.

Radiographic Studies

Women with stage IB2 or greater disease should be evaluated with additional imaging. Chest x-ray would be indicated in these patients and would result in upstaging if extra-pelvic disease is confirmed. Other imaging studies are routinely used when available but only change staging if hydronephrosis is identified. Though intravenous pyelography may be used, in settings where CT (or PET-CT) is available, this is generally preferred. A combined PET-CT is the most sensitive way of identifying suspicious lymph nodes. PET-CT is more sensitive for the detection of positive nodes and is preferred over CT alone if it is available. If PET-CT is not available CT is an acceptable alternative. MRI is indicated in certain cases and is specifically useful for tumors high in the endocervix. These lesions are often adenocarcinomas and MRI aids in the differentiation between uterine and cervical primary lesions, which may be managed differently.

Physical examination is the single most important tool for staging cervical cancer. If an aggressive exam is not tolerated by the patient in the office or advanced cancer is suspected and cystoscopy or proctoscopy is required, an exam under anesthesia is recommended.

What therapies should you initiate immediately i.e., emergently?

While prompt management of newly diagnosed cervical cancer is encouraged, emergent therapy is limited to management of complications such as hemorrhage or ureteral obstruction. Women who present with hemorrhage secondary to a cervical tumor can be managed with vaginal packing or the application of a topical hemostatic agent such as Monsel’s solution.

If these techniques fail to control the bleeding, embolization by interventional radiology or hyperfractionated external bean radiation therapy (EBRT) (for example, 1.5 to 1.8 Gy/fraction twice daily for 2 to 3 days) are more aggressive techniques that are occasionally required. Ureteral obstruction should be managed by ureteral stenting if possible, or percutaneous nephrostomy if stenting is not possible.

What should the initial definitive therapy for the cancer be?

Treatment recommendations for cervical cancer are primarily based on clinical stage and assessment of nodal involvement.

Surgery

Surgery is generally reserved for women with lower stage disease and smaller lesions (1A, IB1 and selected IIA1). Minimally invasive approaches including laparoscopy or robotic surgery are increasingly being used in these cases.

Radiation therapy with concurrent chemotherapy (radiosensitizing)

Chemoradiation is the preferred treatment for women with stage IB2-IVB disease. It is also acceptable treatment for women with early stage IA2-IB1 disease who are poor surgical candidates, although the data supporting the benefit of adding radiosensitizing chemotherapy is less strong in these early tumors that have high cure rates with radiation alone.

Radiation therapy may be administered as intracavitary brachytherapy, external beam radiation therapy (EBRT), or both. EBRT is often combined with chemotherapy, generally low dose weekly cisplatin (40 mg/m2). With intracavitary brachytherapy, radioactive isotopes are introduced directly into the uterine cavity and vaginal fornices with special applicators (e.g., Fletcher-Suit intrauterine tandem and vaginal ovoids). The applicator is placed while the patient is under anesthesia and the radiation is applied through the applicator. This can either be done using the high dose (HDR) or low dose (LDR) methods and depends on the resources available.

In the U.S. most treatment centers are using HDR as this can be performed as an outpatient and takes less than an hour, as opposed to LDR in which the radiation source remains in place for 2-3 days, during which time the patient remains hospitalized in a designated brachytherapy room.

For IA2 and higher stage disease the pelvic lymph nodal beds are often covered in the radiation treatment fields. If there is concern for para-aortic disease, para-aortic EBRT may be added as well. The radiation field is generally designed to cover the nodal areas at least one region above the level above any suspected or involved nodes.

A typical radiation plan may involve EBRT doses of 4000-5000 cGy and brachytherapy doses of 4000-5000 cGy to central tumor regions, with a total dose of 8000-9000 cGy. Sequencing of EBRT and brachytherapy depends on the lesion and may change depending on the initial response to therapy.

Chemotherapy

Systemic chemotherapy is used as primary treatment for women with stage IVB or recurrent disease. More recently systemic chemotherapy, generally a doublet involving cisplatin (with gemcitabine, topotecan or paclitaxel) is used for high-risk localized disease (especially stage III or higher). This may be administered before or after chemoradiation depending on the clinical situation.

Stage-specific treatment

Stage IA

Microinvasive (IA1) tumors can be treated with a standard (“extrafascial”) abdominal or vaginal hysterectomy unless lymphovascular space invasion (LVSI) is identified on biopsy, or the tumor is an adenocarcinoma. In the case of an adenocarcinoma, a radical hysterectomy is recommended by many, even for IA1 disease, although observational data suggests this may not be necessary. Oophorectomy is not routinely indicated unless there is an adenocarcinoma, in which case removal of the ovaries should be considered.

Women who desire fertility or who are poor surgical candidates could be treated with cone biopsy (surgical excision of the cervical transformation zone) and careful surveillance alone if margins are negative.

Women with stage IA2 or IA1 with LVSI should be managed by radical hysterectomy with bilateral pelvic lymph node dissection. Para-aortic node dissection is indicated if pelvic lymph nodes involvement is known or suspected. Any clinically or radiologically suspicious para-aortic nodes should also be removed. Ovaries can be left in place if there is no suspicion of involvement or adenocarcinoma.

Alternatively, primary radiation (generally with chemotherapy) may be used in the case of women with stage IA tumors who are not surgical candidates.

Stage IB-IIA

Stage IB1 and selected IIA1 lesions can be managed with surgery if nodal disease is not suspected. In these cases, radical hysterectomy with bilateral pelvic lymph node dissection can be performed. Some believe that the case should begin with a pelvic lymph node evaluation, and if the nodes are positive then the hysterectomy cannot be performed and the patient should be treated with primary chemoradiation. Para-aortic node dissection is indicated if pelvic lymph node involvement is known or suspected, even if the hysterectomy is abandoned. Any clinically or radiologically suspicious para-aortic nodes should also be removed.

Women with IB2-IVA disease who have radiologically detected pelvic or para-aortic lymph node involvement should have lymph node dissection considered. This nodal dissection can be performed using minimally invasive surgery or open technique, avoiding entry into the peritoneal cavity in the latter, if possible, to minimize adhesions and subsequent radiation complications (extra-peritoneal). Extra-peritoneal lymph node dissection for primary nodal evaluation is also used, especially where PET-CT is not available.

Chemoradiation regimens for locally advanced disease include EBRT to doses ranging 4000-6000 cGy, concurrent cisplatin or cisplatin-5FU chemotherapy, followed by intracavitary brachytherapy. Commonly used regimens include:

  • Cisplatin 40 mg/m2 weekly with concurrent RT 5500-7500 cGy (most common).

  • Cisplatin 70 mg/m2 day 1, plus 5-FU 1000 mg/m2/d days 1-4 every 3 weeks x 2 cycles with concurrent RT 4930 cGy, then Cisplatin 70 mg/m2 day 1, plus 5-FU 1000 mg/m2/d days 1-4 every 3 weeks x 2 cycles.

Following chemoradiation for stage IB2-IIA disease there are some circumstances where a simple hysterectomy (“completion hysterectomy”) may be performed, specifically for women whose initial tumors were large (>6cm) IB2 tumors or in some cases where the tumor response to chemoradiation is incomplete or a full dose of radiation was not able to be delivered.

Fertility preservation

Fertility preserving surgery is an option for certain patients with stage IA2-IB1 tumors. Tumors should be less than 2cm and have limited endocervical involvement. Surgical treatment with radical trachelectomy (cervical excision leaving in the uterus) and pelvic lymph node dissection with or without para-aortic lymph node sampling is recommended.

Adjuvant radiation therapy

Following primary surgery for early stage disease, adjuvant radiation therapy is recommended for patients with surgical pathologic factors that put them at an elevated risk of relapse. These factors include:

  • large and/or deeply invasive tumors.

  • positive margins.

  • parametrial or lymph nodal involvement.

In these cases adjuvant treatment most commonly consists of external beam radiation with radiosensitizing chemotherapy as described above. Vaginal cuff brachytherapy is infrequently used in these cases.

Stage IIB to IVA (“Locally advanced disease”)

In general, patients with stage IIB to IVA cervical cancer are considered to have locally advanced disease, and are not candidates for initial surgical resection due to tumor volume and/or disruption of appropriate surgical planes. Many practitioners would also include in this groups patients with stage IB2 or IIA2 cases, where the tumors have a largest clinical diameter exceeding 4 cm.

The standard of care for these patients with locally advanced disease is chemoradiation as described above, including EBRT and brachytherapy. Systemic chemotherapy (generally a platinum-based doublet as described below) following (or in some cases preceding) chemoradiation is increasingly being used in this population of patients and its role is being evaluated in numerous ongoing clinical trials.

Stage IVB or recurrent disease

Chemotherapy is used for the palliation of advanced or recurrent disease not amenable to treatment with surgery or radiation therapy. Commonly used regimens are listed below:

1. First-line combination chemotherapy (favored for primary treatment)

  • Cisplatin 50 mg/m2 plus paclitaxel 135-175 mg/m2 plus bevacizumab 15 mg/kg on day 1 every 3 weeks until progression or unacceptable toxicity (median of 6 cycles)

  • Cisplatin 50 mg/m2 plus paclitaxel 135 mg/m2 every 3 weeks x up to 6 cycles.

  • Paclitaxel 175 mg/m2 on day 1 plus topotecan 0.75 mg/m2/d days 1-3 plus bevacizumab 15 mg/kg on day 1 given every 3 weeks until progression or unacceptable toxicity (median of 6 cycles)

  • Cisplatin 50 mg/m2 day 1 plus topotecan 0.75 mg/m2/d days 1-3 every 3 weeks x up to 6 cycles.

  • Cisplatin 50 mg/m2 day 1 plus vinorelbine 30 mg/m2 day 1 and 8 every 3 weeks x up to 6 cycles.

  • Cisplatin 50 mg/m2 day 1 plus gemcitabine 1000 mg/m2 day 1 and 8 every 3 weeks x up to 6 cycles.

2. Single-agent therapy (more commonly considered for recurrent disease)

  • Cisplatin 50 mg/m2 every 3 weeks.

3. Second-line therapy.

  • Topotecan 1.5 mg/m2/d days 1-5 every 3-4 weeks.

  • Paclitaxel 110-200 mg/m2 every 3 weeks.

  • Vinorelbine 30 mg/m2 days 1 and 8 every 3 weeks.

  • Bevacizumab 15 mg/kg every 14 days.

Carboplatin and nanoparticle albumin-bound (Nab) paclitaxel (Abraxane) are emerging as agents with promising activity in this population and may have a more central role in the future. The anti-VEGF humanized monoclonal antibody bevacizumab has been shown to increase overall survival when added to combination chemotherapy consisting of paclitaxel with cisplatin or topotecan, and has been incorporated into standard first-line combination chemotherapy for recurrent or metastatic disease.

Radiation

In this group of patients, radiation therapy is generally reserved for women with isolated pelvic recurrences. If not previously radiated, pelvic recurrence is typically treated with chemoradiation as described above often including vaginal brachytherapy. Radiation to other sites of recurrence is considered on a case by case basis and is generally reserved for single site recurrence. Systemic chemotherapy using one of the regimens above is also generally added in these situations following radiation.

Surgery

Surgery for recurrent disease can be curative in highly selected cases. Radical pelvic excision, including removal of the vaginal, rectum and bladder (pelvic exenteration) with associated reconstruction can be considered for women with isolated pelvic recurrence when radiation has been previously used. Also excision of isolated recurrence such as solitary pulmonary metastasis can be associated with long disease free intervals or even more rarely cure.

What should you tell the patient and the family about prognosis?

Radiation and surgery yield comparable cure rates of 80-90% for patients with early-stage disease. Radiation therapy plus concurrent chemotherapy, which is the treatment of choice for patients with locally advanced disease, is curative in over 70% of patients with FIGO stage II disease and in about 50% of patients with FIGO stage III disease.

Recognized associated prognostic factors are stage, tumor size, lymph node metastasis and hemoglobin level. The presence of para-aortic lymph nodes is the most significant negative prognostic factor.

Stage specific 5-year survival:

  • IA1 >98%

  • IA2 > 95%

  • IB1/limited IIA1 ~90%

  • IB2/larger IIA1/ IIA2 80-85%

  • IIB 70-75%

  • III ~50%

  • IVA 15-25%

  • IVB ~0%

What if scenarios.

In this case management is based on the best assessment of disease stage, based on pathologic findings, surgical margin status, and imaging to assess for metastatic disease. Women with stage IA1, no LVSI and negative margins may be managed with surveillance. Women with apparent stage IA2 or greater disease, with negative margins and negative imaging may be managed by surgery or radiation (with or without chemotherapy). Surgery would include a radical trachelectomy (removal of the cervix without the uterus) and bilateral pelvic lymph node dissection. Para-aortic node dissection is indicated if pelvic or para-aortic lymph node involvement is known or suspected.

If cervical cancer is diagnosed when the patient is pregnant the situation becomes more difficult. Women need to decide if they wish to delay treatment until fetal maturity or be treated immediately.

Women who are treated before 20 weeks are generally treated with a radical hysterectomy and nodal dissection with the fetus in situ unless advanced disease is present precluding surgery. Women treated after 20 weeks can generally wait until fetal lung maturity is documented and then proceed with a cesarean radical hysterectomy unless advanced stage disease is present. Women should avoid vaginal delivery unless disease is limited to stage IA1. Radiation therapy is absolutely contraindicated during pregnancy.

Follow-up surveillance and therapy/management of recurrences.

Surveillance consists of follow-up exam every 3-6 months for 2 years, then every 6 months for another 3-5 years. While pap smears were traditionally recommended as part of surveillance, this has recently been called into question as most recurrences are detected clinically. Patients with higher stage disease or known nodal involvement may be follows up with periodical imaging including chest x-ray and CT. Recurrent pelvic disease is seen in about two-thirds of patients who relapse after treatment. While hematogenous metastases are rarely detectable at diagnosis, distant metastases are a common feature of disease relapse.

The management of recurrent disease is outlined in the treatment section above. Women with isolated centrally recurrent disease may be candidates for surgical treatment. Surgery in these cases consists of radical resection with wide margins with a pelvic exenteration. This procedure involves en bloc removal of the bladder, vagina and rectum and anus with construction of ostomies. For properly selected patients this procedure can result in long term cure for over half of the patients.

The best candidates for this procedure are women with central pelvic recurrence without evidence of disease outside of the pelvis. Patients must be healthy enough to tolerate a lengthy risky surgical procedure and psychologically able to deal with the ostomy care and disfigurement associated with this procedure. Women who have a longer interval between primary therapy and recurrence are more likely to have isolated recurrent disease.

Pathophysiology

Cervical cancer generally develops following the progression of pre-invasive lesions in the cervix which generally take many years to progress to invasive cancer. The average age of women with dysplasia is 16 years younger than that of women with invasive cancer. Pre-invasive lesions of the cervix generally follow HPV infection and the majority of these early lesions regress spontaneously and the HPV infection clears. However, in a minority of patients, persistent HPV infection can occur and cervical dysplasia can persist and progress.

HPV DNA is detected in nearly all cervical cancers of both squamous and adenocarcinoma histology. While there are hundreds of HPV strains, HPV-16 and HPV-18 have been most commonly associated with squamous cell carcinoma and adenocarcinoma, respectively. HPV carcinogenesis is mediated through its oncogenes E6 and E7. E6 leads to the degradation of p53 which is a key regulator of cellular growth, and its loss is implicated in many human malignancies. The E7 protein binds to, and functionally inactivates, the gene product of the retinoblastoma (rb) tumor-suppressor gene. This binding results in the uncontrolled release of active transcription factors (E2F) and unregulated progression through the cell cycle.

Histology of cervical cancer is 80-90% squamous; however, the incidence of adenocarcinoma appears to be increasing in developed countries. This may be related to the decreased ability of pap smears to detect adenocarcinomas and upper cervical lesions. Clear cell carcinoma, a rare form of cervical adenocarcinomas, has been clearly linked with prenatal exposure to diethylstilbestrol (DES), a drug that was used to prevent miscarriages in the 1940s and 1950s. Small cell cancers are rare and have histologic features that resemble small cell neuroendocrine neoplasms of the lung, and tend to have a particularly aggressive clinical course.

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