Cervical Cancer

Introduction

Worldwide, cervical cancer is the second most common malignancy in women and is a major cause of morbidity and mortality. Three out of four cases occur in developing countries. The elderly, the economically disadvantaged, and those with poor healthcare access are all disproportionately represented among women who develop and die from this disease. Approximately 80% of cervical cancers are squamous cell carcinomas, and 15% are adenocarcinomas. Because of its association with human papilloma virus (HPV) infection, as well as our improved ability to screen for premalignant stages of disease, cervical cancer is now a largely preventable disease.

Epidemiology and Etiology

• Incidence 11,150 new cases in the US estimated for 2007 [1]
• Mortality rate of 3,670 estimated in the US for 2007, with most cases occurring in unscreened and suboptimally screened women [1, 2]
• Etiology of cervical cancer linked with human papilloma virus (HPV), a double-stranded DNA virus that is sexually transmitted. HPV-16 and HPV-18 are the most commonly subtypes linked to cervical cancers and high-grade CINs.
• Risk factors include young age at first intercourse, high number of sexual partners, high parity, cigarette smoking, race (African American women have 72% excess in incidence than Caucasian women[3]), low socioeconomic class, and immunosuppression

Screening Recommendations for Average-Risk Patients

• The American Cancer Society recommends cervical cancer screening with Papanicolaou (PAP) tests starting approximately three years after the onset of vaginal intercourse and/or no later than twenty-one years of age [3].
• Once cervical cancer screening has been initiated, it should be performed annually with conventional cytology or every two years with liquid-based cytology. When women reach 30 years of age and have had three consecutive, technically satisfactory tests with normal or negative results, they may be screened every two to three years unless they have additional risk factors.
• • Liquid-based cytology have decreased artifact, improved specimen adequacy, improved cellular sampling, and allow residual material for ancillary HPV DNA testing compared to conventional cytology.
• Women over 70 years who are not at high risk may safely stop screening if they have had 3 or more documented normal results from technically satisfactory PAP smears, with no abnormal results within the past 10 years.[4]

Clinical Presentation

• History: Cervical cancer is generally asymptomatic with effective screening. Occasionally, patients may complain of a heavier menstrual flow (menorrhagia), bleeding in between normal periods (metrorrhagia), post-coital bleeding, foul-smelling vaginal discharge, or pelvic pain. Anemia and its associated symptoms are frequently present. Less frequently, patients present with signs of advanced disease such as bowel obstruction and renal failure due to urinary tract obstruction.
• Physical exam: Cervical lesions can be superficial ulcerations, exophytic tumors in the exocervix, or infiltration of the endocervix. The cervix and entire vagina should be carefully inspected and palpated to identify overt tumor or subepithelial vaginal extension. Rectovaginal examination permits the best assessment of tumor size and parametrial involvement. Palpation of the liver and inguinal and supraclavicular lymph nodes is important to screen for metastatic disease. Examination under anesthesia is often performed.
• Lab studies: CBC, LFT/renal function studies, HIV testing
• Radiologic studies: Chest x-ray, CT/MRI, PET scan, intravenous pyelogram
• Diagnostic studies: Cystoscopy, proctoscopy, colposcopy, and hysteroscopy can be used to assess adjacent areas. Suspicious lesions should be confirmed by biopsy. IVP and chest x-ray are useful to evaluate for metastatic disease. Optional procedures including CT, MRI, PET, lymphangiography, and ultrasonography can be valuable for treatment planning for radiation or surgery, but cannot be used to assign disease stage in the FIGO classification (see below).

Natural Course and Pathology

• Staging The International Federation of Gynecology and Obstetrics (FIGO) or the American Joint Commission (AJC) use primarily clinical staging systems based on histology for the early-stage cancers. For more advanced tumors, staging is based on extension of the disease in the pelvis.
• • Stage IA - microscopic cancer confined to the uterus
  • Stage IB - cancer visible by the naked eye confined to the uterus
  • Stage II - cervical cancer invading beyond the uterus but not to the pelvic wall or lower 1/3 of the vagina
  • Stage III - cervical cancer invading to the pelvic wall and/or lower 1/3 of the vagina and/or causing a non-functioning kidney
  • Stage IVA - cervical cancer that invades the bladder or rectum, or extends beyond the pelvis
  • Stage IVB - distant metastases
• Radiographic examination allowed under the FIGO staging includes chest x-ray and barium enema, as well as IV pyelography. However, where available, CT scanning or MRI is the preferred diagnostic study.
• Surgical staging may reveal patients with microscopic disease in lymph nodes that can be treated with chemotherapy and potentially benefit in terms of long-term survival. However, the majority of patients who undergo it will be found not to have metastatic disease and will receive the same treatment as planned prior to surgical staging. The Gynecology Oncology Group (GOG) considers surgical staging to be optional for patients with advanced-stage cervical cancer.
• Pathology 80% of cervical cancers are squamous cell, and 15% are adenocarcinomas [5]. Although patients with adenocarcinomas may have a worse prognosis due to a relatively higher frequency of late-stage diagnoses, outcomes appeared to be similar to that of squamous lesions when controlled for stage and tumor size.
• Prognostic factors The most important prognostic factor remains clinical stage, defined by tumor volume and extent of disease spread. The overall 5-year survival rate ranges from 95% to 100% for patients with earliest stage cervical cancer, whereas patients with metastatic disease have a 5-year survival rate of less than 5 years after diagnosis [6]. Good prognostic factors include lesions less than 2 cm in diameter, superficially invasive, well-differentiated with no lymphovascular space involvement, positive surgical margins, and good general medical/nutritional status.

Treatment

• Early stage (Stage I-IIA)
• • Surgery - simple or radical hysterectomy depending on extent of disease.
  • • Most retrospective studies suggest that radical hysterectomy and definitive pelvic radiation therapy are equally effective in the treatment of early stage cervical cancer [7, 8].
    • • Surgery allows preservation of ovarian function and typically results in fewer detrimental effects on vaginal function compared to radiation therapy.
      • Alternative procedures: cervical conization (preserves future fertility)
      • Lymphadenectomy should be added for stage IA2 or above.
  • Radiation therapy - external beam or Intracavitary brachytherapy
  • • Indications for radiation therapy after radical hysterectomy include positive or close surgical margins, disease extension into the parametria, and lymph node metastasis.
    • GOG 92 study (phase III trial) showed that patients with high-risk factors (large tumor size, deep stromal involvement, lymphovascular space involvement) in hysterectomy specimen had a significantly reduced risk of recurrence by 47% after pelvic radiation therapy. However, 1 in 15 pts experienced life-threatening radiation-related toxicities [9]
    • Intracavitary brachytherapy - Radioactive isotopes can be introduced directly into the uterine cavity and vaginal fornices with special applicators. In low-dose-rate (LDR) brachytherapy, the applicator is placed into the uterus while the patient is under anesthesia in the operating room, and the patient must stay in the hospital for 2-3 days during the procedure. High-dose-rate procedures can be performed on an outpatient basis. Several studies have cited comparable disease control and complication rates with either technique[6]. Used in Stage IIA or above.
    • External beam radiation therapy can be used in conjunction with intracavitary radiotherapy for patients with significant risk of pelvic lymph node involvement.
  • Chemotherapy alone does not produce a cure but has a role as adjuvant treatment for select patients. Due to the inability of many commonly used chemotherapeutic agents to effectively cross the blood-brain barrier, alternative agents and administration techniques must be employed for patients with brain tumors.
  • • GOG phase III trial showed that concurrent chemo-RT patients who received cisplatin had higher rates of progression-free survival and overall survival than patients who received radiotherapy alone. Both groups had subsequent extrafascial hysterectomies 3-6 weeks after treatment [10]
• Locally advanced disease (stage IIB- IVA)
• • Radiation
  • • Advanced tumors require more external irradiation due to the inability of central radioisotope sources to effectively irradiate disease in the lateral parametrium.
    • Treatment aimed at pelvic control in advanced disease usually consists of radical chemoradiation (see below)
  • Chemotherapy
  • • Cisplatin chemotherapy is the standard treatment of locally advanced cervical cancer.
    • The superiority of concurrent platinum-based chemoradiation compared with radiation therapy alone has been confirmed in five phase III clinical trials, reducing the relative risk of death by 30-50% [10-14]

References

1. Jemal et al. Cancer statistics, 2007. CA Cancer J Clin 2007; 57(1): 43-66.
2. Bundrick, Screening for cervical cancer and initial treatment of patients with abnormal results from papanicolaou testing. Mayo Clinic Proceedings 2005;80(8): 1063-1068
3. Janicek, Cervical Cancer: Prevention, Diagnostics, and Therapeutics. CA Cancer J Clin 2001; 51: 92-114.
4. Schroeder. ACS Updates Guidelines for the Early Detection of Cervical Neoplasia and Cancer. American Family Physician 2003; 67(9)2011, 2015-2016.
5. Moore. Cervical cancer. Obstetrics Gynecol 2006; 107(5): 1152-61.
6. Chi, Perez, Lanciano, et al. Cervical cancer. Cancer Management: A Multidisciplinary Approach. New York, 1999, pp. 445-475.
7. Morley, Seski. Radical pelvic surgery versus radiation therapy for stage I carcinoma of the cervix. Am J Obstet Gynecol 1976; 126:785-798.
8. Landoni et al. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 1997; 350: 535-540.
9. Sedlis et al. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group study. Gynecol Oncol 1999;73:177-183.
10. Keys et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154-1161.
11. Whitney et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stages IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: A Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999; 17:1339-1348.
12. Morris et al. Pelvic radiation with concurrent chemotherapy versus pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137-1143.
13. Rose et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally-advanced cervical cancer. N Engl J Med 1999; 340:1144-1153.
14. Peters et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000; 18:1606-1613.