CERVICAL CANCER

CERVICAL CANCER

Cervical cancer is an important worldwide health problem, often affecting younger women in the prime of life. Newly diagnosed cervical cancer will affect over 500,000 women annually and will lead to over 250,000 deaths, making it the third most common cancer in women around the world. Because of the long natural history of premalignant and early cervical cancer, annual cytologic screening (Pap smear) has dramatically reduced the incidence of advanced cervical cancer in the developed world and areas with good medical infrastructure. Cervical cancer remains an important cause of cancer death in the developing world, often striking young women in their most productive years. It is primarily a disease afflicting patients of lower socioeconomic status whose access to advanced medical care is limited. The overall 5-year survival rate for cervical cancer is approximately 67% in the United States (~12,000 new cases and roughly 4000 deaths in 2014) but depends on the group prevalence of annual screening to detect early-stage disease. Younger women and white women have better outcomes than older women and black and Hispanic women based on many factors, including early diagnosis of localized cancers. Other factors linked to higher incidence of cervical cancer include age of first intercourse, parity (more live births linked to higher risk), current cigarette smoking, and male human papillomavirus (HPV)-related factors. Regions with a higher frequency of penile cancer and lower rates of male circumcision have a higher incidence of cervical cancer diagnoses. High prevalence of other sexually transmitted diseases is also a known risk factor, including Chlamydia trachomatis and herpes simplex virus infections. Finally, host immunity appears to play a major role. Both human immunodeficiency virus (HIV) infection and immune suppression related to transplantation are associated with dramatic increases in the incidence of cervical cancer.

Infection with specific, carcinogenic strains of HPV has been established as the necessary causal event for nearly all cervical cancer. This includes both the most common squamous cell cancers (85%) and the less common, more difficult to detect, adenocarcinomas. Not all HPV strains are linked to cervical cancer, and the most common cancer-related subtypes include 16, 18, 32, 33, 35, 45, 52, and 58. Although the prevalence of the genotype will show substantial regional variation, over 70% of all cervical cancers can be linked to HPV 16, 18, and 45. Many other HPV strains can cause infection but will not lead to cervical cancer. HPV infection tends to occur soon after sexual initiation, and in most women will be cleared by the immune system within 24 months. In some cases the HPV DNA is incorporated into the host DNA and can continue to produce viral proteins (persistence). Often the HPV DNA is silenced and will go through a period of latency but can be reactivated later. The HPV protein E7 mediates immortalization through abrogation of the G1/S transition through interaction with the Rb protein. Other targets of E7 include a variety of cyclin-dependent kinases and cyclins that are critical for cell cycle regulation. The E6 protein binds to p53 and promotes its degradation, leading to decreased capacity for DNA damage repair. E6 also upregulates the cellular telomerase complex and contributes to immortalization of HPV-infected epithelial cells. As a consequence of inactivation of Rb and p53, there is loss of cell cycle regulation and a variety of subsequent mutations appear to accumulate. Mutational load appears to play a dominant role in the eventual development and progression of cervical cancer.

HPV infection of cervical epithelial cells leads to a failure of cellular differentiation and to cytologic abnormalities of the cervical epithelium referred to as cervical intraepithelial neoplasia (CIN). Whereas early, or low-grade, CIN often resolves, higher grades of CIN (CIN 2/3) appear to be linked to viral integration into host DNA and a failure to clear the infection. Persistent CIN can be detected by Pap cytologic testing during its long preinvasive phase, and this fact has led to the success of screening strategies in developed countries. Current recommendations mandate initiation of cytologic (Pap) testing at age 21 and every 2 years until age 30, when women with persistently negative screening tests can be screened every 3 years until age 65. For women in the 30- to 65-year age group, a combined screening strategy of cytologic and HPV testing is preferred. The combination of HPV testing and liquid-based cytology has a sensitivity of 96.7%; patients testing positive for HPV 16/18 should all be referred for colposcopy, regardless of their cytologic result. At age 65, women with multiple negative cytologic screening tests may discontinue screening. Any woman with a cytologic screen revealing CIN 2 or other abnormalities should be referred to a gynaecologist for colposcopy and appropriate subsequent management. CIN 2/3 implies probable viral integration, so a woman with a history of CIN 2/3 should undergo more frequent and extended screening.

Early cervical cancer is generally asymptomatic, and thus detection is highly dependent on screening and routine gynaecologic care. In advanced stages, patients may present with vaginal discharge or bleeding, pelvic pain, or abnormalities of bowel, bladder, or sexual function. The diagnosis of cervical cancer is usually based on positive cytologic status and direct inspection by vaginal speculum examination. Early cervical cancers are detected primarily by colposcopy and direct biopsy. The staging of cervical cancer is based on both expert clinical evaluation of resectability and imaging studies of both the pelvis and potential sites of distant metastases (lymph nodes, lungs, and abdominal sites).

The primary treatment of localized cervical cancer is stage dependent. Staging of cervical cancer depends on the clinical evaluation of a skilled gynaecologic oncologist. In general, treatment of early-stage cervical cancer is exclusively surgical. The appropriate procedure will depend on patient age, comorbidities, stage, and tumour size. Radical hysterectomy with nodal dissection is the most common procedure, although younger patients with low risk for metastatic disease may undergo simple hysterectomy or even radical trachelectomy for highly selected patients who desire preservation of fertility. Patients with low-stage cervical cancer who have certain high-risk pathologic findings after surgery may benefit from radiation or chemotherapy.

APPROACH TO CERVIX CANCER BY STAGE*

STAGE BRIEF DEFINITION USUAL TREATMENT
0 Carcinoma in situ Conization, hysterectomy
IA1 Microscopic stromal invasion < 3 mm Conization, hysterectomy
IA2 Microscopic stromal invasion 3 to 5 mm Radical hysterectomy
IB1 Visible lesion < 4 cm in greatest dimension Radical hysterectomy
IB2 Visible lesion > 4 cm in greatest dimension Chemoradiation
IIA Tumour beyond the uterus, no parametrial involvement Radical hysterectomy (selected)
IIB Tumour beyond the uterus with parametrial extension Chemoradiation
IIIA Tumour involves lower third vagina but no pelvic wall extension Chemoradiation
IIIB Tumour extends to pelvic wall or hydronephrosis or regional lymph nodes Chemoradiation
IVA Involvement of mucosa of bowel or bladder Chemo-radiation
IVB Distant metastatic disease Chemotherapy only

* Cervical cancer is staged clinically and not by either radiographic or pathologic findings. Chemoradiation generally includes weekly cisplatin treatment. Metastatic disease chemotherapy is generally based on cisplatin doublet treatment.

There is some variability in treatment recommendations for patients with FIGO stage IB to IIA. Younger women with smaller tumours may be offered radical hysterectomy, whereas bulkier tumours and older patients may be better served by definitive chemoradiation. Patients with FIGO stage IIB to IV should all be treated with combinations of cisplatin and external beam radiation. It is important to note that the combination of cisplatin and external beam radiation can provide an opportunity for cure and long-term survival, even in stage IV cancer of the cervix.

Patients with recurrent cancer of the cervix or patients with distant metastases at diagnosis are very rarely curable. Death is usually related to local recurrence, but distant metastatic spread to the lung, peritoneum, or bone is also common in cervical cancer. Platinum-based chemotherapy remains the mainstay of palliative treatment. The addition of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer has been associated with an improvement of 3.7 months in median overall survival. Recurrent or persistent tumours within the prior radiation field are particularly difficult to manage with chemotherapy. Local problems such as pain, bleeding, and fistulas between the bladder, vagina, and bowel are common in the advanced stages of this disease.

Patients with a history of CIN 2/3 or other noninvasive disease require regular cytologic examinations, because the onset of cancer in patients with HPV 16/18 infection can occur years after primary infection. Early-stage cancer of the cervix is highly curable. Although perioperative complications can occur for any major operation, late complications of radical hysterectomy are not common but may include lymphedema and persistent bladder or rectal dysfunction. Patients with more advanced stage disease appropriately treated with chemoradiation combinations have long-term survival rates from 30 to over 80% percent, based on stage and underlying health. The late complications of chemoradiation are similar but probably more common, affecting 5 to 10% of survivors. Fistulas can occur between pelvic organs, including bladder, vagina, small bowel, and rectum. Other bladder problems may include urgency, incontinence, and chronic cystitis with loss of bladder capacity. Rectal problems include pain, diarrhoea or constipation, urgency, and incontinence. Skeletal complications can include pelvic insufficiency fractures, associated with pain in as many as 10% of patients after radiation. Vaginal stenosis, dryness, and dyspareunia are common but usually can be managed with vaginal dilators and appropriate lubricants. Late complications of cisplatin-based chemotherapy include neuropathy, as well as renal insufficiency with chronic wasting of potassium and magnesium. Multimodality therapy regimens including radiation, surgery, and chemotherapy pose a higher risk for late complications and impaired patient quality of life decades after primary curative treatment.

Our understanding of the pathobiology of HPV-derived cervical cancer supported the development of vaccines for the prevention of the most common oncogenic subtypes of HPV infection. There are now licensed vaccines that immunize against HPV 16, 18, and selected other high-risk types. They are both safe and effective in substantially reducing the risk for cervical dysplasia and carcinoma. HPV vaccines require administration before sexual activity and can be highly effective in reducing the risk for cervical cancer Both the approval trials and subsequent follow-up trials reveal a high level of safety and durable type-specific immunity that seems to persist for more than 5 years after a series of three initial vaccinations. Additional HPV type coverage may eventually be available, but it is already clear from population-based studies that the vaccine can reduce the incidence of precursor lesions such as cervical dysplasia. Beyond immunization, prevention is absolutely linked to regular screening for early HPV-related lesions and appropriate management during the premalignant phase of the disease.

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