INFORMATION ON DIAGNOSIS AND TREATMENT

In the United States (US) in 2008, there were estimated to be 11,070 new cases of invasive cervical cancer, with 3870 cancer-related deaths expected; this represents approximately 1 percent of cancer deaths in women. The occurrence of invasive cervical cancer is related to age, with a mean age at diagnosis of 47 years in the United States. From 1995 to 1999, the US incidence of cervical cancer in girls under age 20 is reported to be 0/100,000/year, rising to 1.7/100,000/year in women aged 20 to 24 years, and peaking at 16.5/100,000/year in women aged 45 to 49 years. Only 10 percent of cases occur in women age 75 or older. The probability of developing cervical cancer by age is: 1 in 638 for women age 39 years and younger; 1 in 359 for women age 40 to 59 years; 1 in 750 for women 60 to 69 years; and 1 in 523 for women age 70 years and older; with a lifetime probability of 1 in 142.

Epidemiology -  Risk factors for  cervical cancer include early onset of sexual activity, multiple sexual partners, a high-risk sexual partner (eg, promiscuous sexual activity, sexual exposure to a partner with human papillomavirus infection), history of sexually transmitted diseases (eg, Chlamydia trachomatis, herpes simplex virus), smoking, high parity, immunosuppression, low socioeconomic status, prolonged use of oral contraceptives, and previous history of vulvar or vaginal squamous dysplasia.

Role of human papiloma virus - The human papilloma virus (HPV) is central to the development of cervical neoplasia and can be detected in 99.7 percent of cervical cancers  (squamous cell and adenocarcinoma). Among the more than 40 genital mucosal HPV types identified, approximately 15 are known to be oncogenic. The two most common ones, HPV 16 and 18, are found in over 70 percent of all cervical cancers. Most HPV infections are transient and the virus alone is not sufficient to cause cervical neoplasia. When HPV infection persists, the time from initial infection to development of CIN 3 and finally invasive cancer takes an average of 15 years, although more rapid courses have been reported.
Histopathology – In the United States, the majority of cervical carcinomas are squamous cell type (70%), followed by adenocarcinomas (25%) and adenosquamous types (3 to 5%). Neuroendocrine or small cell carcinomas can also originate from the cervix, but are rare.

Clinical manifestations and diagnosis – Early cervical cancer is asymptomatic, so screening is extremely important. The most common signs at diagnosis are vaginal bleeding, bleeding after intercourse and vaginal discharge. The later can be mistaken for infection. Pevic and low back pain radiation to the back of the legs, in addition to bladder and bowel symptoms can occur in advanced disease. The diagnosis is established by pelvic examination and biopsy of any abnormal areas.

Routes of spread - Cervical cancer can spread by direct extension into the uterine corpus, vagina, parametria, peritoneal cavity, bladder, or rectum, and by lymphatic or hematogenous (blood stream) dissemination. The risk of lymph node metastasis increases with increasing depth of invasion. The most common sites for hematogenous spread are the lungs, liver, and bone; the bowel, adrenal glands, spleen, and brain are less frequent sites.
Staging - After histologic confirmation of invasive cervical cancer, the extent of disease needs to be determined. Two staging systems are available, both of which use clinical criteria to assign disease stage. By comparison, the staging criteria used for most other gynecological tumors are based primarily upon surgical/pathological results. As with all gynecologic cancers, tumor stage is determined at the time of primary diagnosis and is not altered, even if disease recurs.

The FIGO system is largely based on the physical examination, while the AJCC system uses surgical/pathological data. The pelvic examination should be performed by an experienced examiner and, under certain circumstances, may be performed under anesthesia. Since cervical cancer spreads locally by extension to the corpus, parametria, and vagina, the cervix and entire vagina should be both inspected and palpated to identify overt tumors and subepithelial vaginal extension. Tumor size and parametrial involvement is best assessed by rectovaginal examination. Colposcopy, hysteroscopy, cystoscopy, and proctoscopy can be used to assess adjacent areas. Suspicious lesions should be confirmed by biopsy. Palpation of the right upper quadrant and inguinal and supraclavicular lymph nodes, intravenous pyelogram, chest x-ray, and liver and renal function tests are important for evaluating for metastatic disease.
Optional procedures, including computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), lymphangiography, ultrasonography, and surgical staging, can be of value for planning treatment, particularly the extent of the radiation therapy field or scope of therapeutic surgery. As discussed above, these modalities cannot be used to assign disease stage in the FIGO classification.
Listed below are the two staging systems:
FIGO system

Management of early stage disease (FIGO IA, IB1, nonbulky IIa)
There are several options for treatment of early stage (stage IA, IB, and some small IIA tumors) cervical cancer. The optimal treatment depends upon the woman's age and her childbearing plans, the stage of the cancer, whether underlying medical conditions are present, and the physician's and patient's preferences.

The most common treatment for early stage cervical cancers is radical hysterectomy (surgical removal of the cervix and uterus). The alternative is radiation therapy, which is usually given in combination with chemotherapy. Patients with the earliest stage cervical cancers (stage IA1) may also be treated by cervical conization or simple hysterectomy alone.
Radical hysterectomy is a surgical procedure that removes the uterus and cervix with adjacent tissues and a portion of the vagina. Removal of the pelvic lymph nodes is also done at that time. If abnormal or cancerous cells are found at the margins (edges) of the tissue or in the lymph nodes that are removed, or if the tumor has other features that increase the risk that the cancer will recur, further (adjuvant) treatment is recommended. This generally includes both radiation therapy and chemotherapy.

Radiation therapy— Radiation therapy (RT) refers to the exposure of a tumor to high-energy x-rays in order to slow or stop its growth. There are two ways to deliver RT for cervical cancer: brachytherapy or external beam radiation therapy (EBRT).

Brachytherapy — Brachytherapy is a form of localized RT in which the source of the radiation is within the patient (internal irradiation). This allows the delivery of high doses of radiation to the area where cancer cells are most likely to be found, hopefully minimizing the effects of radiation on healthy tissues.
In most cases, a radiation applicator is temporarily inserted through the vagina into the cervix and uterus. Then, the radiation source is placed (or "afterloaded") into the applicator and left in place internally for a period of time. The treatment is traditionally accomplished using a radiation source that delivers the radiation at a low dose rate (LDR), which requires that the woman remain in the hospital for two to three nights. A newer technique delivers the radiation at a high dose rate (HDR). The main advantage of HDR is that it is completed within several minutes, and can be performed as an outpatient. Studies that compare HDR to LDR therapy are ongoing.

External beam radiation therapy (EBRT) — During EBRT, the radiation beam is generated by a machine that is outside the patient. The radiation is delivered to the patient, who is usually lying on a table underneath or in front of the machine. The high energy beams are targeted to the pelvic area.
Exposure to the beam typically takes only a few seconds (similar to having an x-ray). In general, treatment is repeated five days per week for approximately five to six weeks. Treatment cannot be given over a shorter period because the higher daily doses would cause too many side effects. Unless medically indicated, treatment should not be interrupted or extended beyond the projected time frame because changing the schedule or stopping temporarily could reduce the chance of curing the cancer.

Brachytherapy alone is adequate treatment for the earliest stage IA tumors, but EBRT is generally added to brachytherapy to improve the outcomes in women who have with more advanced disease.
Chemotherapy — Most women who undergo EBRT for cervical cancer also receive chemotherapy during the radiation therapy. Chemotherapy drugs are medicines that stop or slow the growth of cancer cells. In general, these drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or multiply.

Chemotherapy also has the ability to enhance the damaging effect of radiation therapy on cervical cancer cells; when chemotherapy drugs are used in this manner, they are referred to as "radiation sensitizers". The chemotherapy is usually given once per week through a vein during the course of EBRT.
It is not clear if there is a benefit of chemoradiotherapy (compared to radiotherapy alone) for all women with early stage cervical cancer. Studies of women with predominantly locally advanced cervical cancer have demonstrated that there is a lower risk of recurrence and a better survival when RT is given along with chemotherapy compared to when RT is given alone. The benefit was greater in trials that included a higher proportion of patients with stage I and II disease. These results may not apply to women with smaller early stage cervical cancers, although most gynecologic oncologists recommend that chemotherapy be administered when EBRT is used, regardless of the stage.

Management of advanced stage (bulky IIA, IIB, III, IVA) disease – Women with advanced stage disease are best treated with a combination of radiation therapy and concomitant chemotherapy. The extent of the radiation field depends on the presence of cancer in the pelvic or paraaortic lymph nodes.
Cancer surveillance — After cervical cancer treatment, periodic follow-up testing and examination are recommended. Guidelines from the National Comprehensive Cancer Network (NCCN) suggest the following:

• Physical examination every three months for one year, every four months for one year, every six months for three years, and then annually. This usually involves a physical examination and Pap test (cervical cytology).
• Annual chest x-ray; there are few data to support the benefit of annual chest x-rays and many doctors do not recommend them.
• Other radiographic studies, including CT or PET scan, are recommended if needed.

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two people are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
American Society of Clinical Oncology
      (www.cancer.net/portal/site/patient)
The Gynecologic Cancer Foundation
       (www.thegcf.org)
National Comprehensive Cancer Network
      (www.nccn.com)
Gynecologic Oncology Group
      (www.gog.org/gynecologiccancerinformation.html)
National Cancer Institute
       1-800-4-CANCER
       (www.cancer.gov)
American Cancer Society
       1-800-ACS-2345
      (www.cancer.org)
The National Cervical Cancer Coalition
      (www.ncc-online.org)
Patient Support — There are a number of online forums where patients can find information and support from other people with similar conditions.
About.com Cancer Forum
      (http://cancer.about.com/forum)