Understanding Cervical Cancer: Prevention, Screening, and Treatment Options

Table of Contents

• Global Impact and Epidemiology
• Risk Factors and Causes
• HPV Biology and Cancer Development
• Screening and Prevention Strategies
• Diagnosis and Staging
• Treatment for Early-Stage Disease
• Treatment for Locally Advanced Disease
• Special Considerations
• Clinical Implications for Patients
• Study Limitations
• Patient Recommendations
• Source Information

Global Impact and Epidemiology

Cervical cancer affects women worldwide with significant regional disparities. In 2020, there were an estimated 604,127 new cases globally and 341,831 deaths related to this disease. The burden falls disproportionately on low-resource regions including Latin America, sub-Saharan Africa, and Southeast Asia (particularly India), where healthcare access and screening programs may be limited.

There is a clear correlation between socioeconomic status and cervical cancer outcomes. As a country's Human Development Index increases, both incidence and mortality rates progressively decrease. In developed nations, the numbers are lower but still significant: the United States anticipated 13,820 new cases and 4,360 deaths in 2024, while the European Union expected 58,169 cases (with 56% coming from central and eastern Europe) and 22,989 deaths.

The median age at diagnosis is 50 years, meaning this primarily affects women in mid-life. However, the disease process begins much earlier, with HPV infections typically occurring in adolescence or young adulthood and taking years to develop into cancerous changes.

Risk Factors and Causes

Most risk factors for cervical cancer relate to sexual behavior and HPV exposure. These include:

• Early age at first sexual intercourse
• Multiple sexual partners
• Partners who have had multiple partners
• Lack of access to regular screening
• History of abnormal Pap smears
• Previous HPV infection
• Cervical dysplasia (precancerous changes)
• History of sexually transmitted infections

Additional factors that increase risk include tobacco use and long-term use of oral contraceptives. These factors appear to work in combination with HPV infection to increase cancer risk rather than causing cancer independently.

HPV Biology and Cancer Development

Human papillomavirus (HPV) is a double-stranded DNA virus that infects cervical cells. There are multiple subtypes with different risk levels:

Low-risk subtypes (most commonly types 6 and 11) may cause anogenital warts but rarely lead to cancer. High-risk subtypes (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) carry oncogenes that can trigger cancerous changes.

The cancer development process begins when the virus integrates into the host's cellular DNA. This integration disrupts the E2 regulatory protein, leading to increased production of E6 and E7 viral proteins. These proteins inactivate the body's natural tumor suppressors (p53 and pRb respectively), allowing uncontrolled cell growth and eventually leading to cancer.

Screening and Prevention Strategies

HPV is extremely common—most sexually active people will have a transient infection at some point. The critical factor is whether the infection clears or persists. In women with persistent high-risk HPV infections that haven't cleared by age 30, cervical intraepithelial neoplasia (CIN), or dysplasia, may develop. This precancerous condition can take 10-15 years to progress to invasive cancer, providing a long window for detection and intervention.

Prophylactic vaccination is highly effective when administered before HPV exposure. The CDC recommends:

• Ages 11-14: Two doses of HPV vaccine, with the second dose 6-12 months after the first
• Ages 15-26: Three doses of HPV vaccine (second dose 1-2 months after first, third dose 6 months after first)
• Ages 27-45: Vaccination may be considered if not fully vaccinated earlier

Three vaccines are available in the U.S.: bivalent (types 16, 18), quadrivalent (types 6, 11, 16, 18), and nine-valent (types 6, 11, 16, 18, 31, 33, 45, 52, 58). Vaccinating males also reduces transmission rates to females.

Screening performance varies by method:

• Papanicolaou (Pap) testing: 55.4% sensitivity and 96.8% specificity for detecting moderate-to-severe dysplasia
• High-risk HPV testing: 94.6% sensitivity and 94.1% specificity

A landmark study in rural India involving 34,126 healthy women showed that HPV testing reduced cervical cancer death rates by 48% compared to no screening (hazard ratio 0.52; 95% CI, 0.33 to 0.83).

The U.S. Preventive Services Task Force recommends:

• Under 21: No screening
• 21-29: Cytologic testing alone every 3 years
• 30-65: Either cytologic testing every 3 years, co-testing (HPV + Pap) every 5 years, or primary HPV testing every 5 years
• Over 65: No screening after adequate previous negative results

Diagnosis and Staging

When screening identifies abnormalities, colposcopy (magnified examination of the cervix with acetic acid staining) helps identify areas suspicious for dysplasia or early cancer. Biopsy then confirms the diagnosis.

Preinvasive disease is treated with:

• Ablative techniques: carbon dioxide laser or cryotherapy
• Excisional techniques: large loop excision of the transformation zone or conization

Visual inspection with acetic acid followed by immediate cryotherapy has been endorsed by the World Health Organization for low-resource settings after a trial in India showed a 30% reduction in cervical cancer mortality with this approach.

Spontaneous regression occurs in approximately 50-75% of patients with mild to moderate dysplasia (CIN 1 or CIN 2), allowing for conservative management with follow-up in some cases.

Staging follows International Federation of Gynecology and Obstetrics (FIGO) criteria updated in 2018 to include pathological or radiographic assessment of lymph nodes. Patients with early disease may have no symptoms, while those with more advanced disease may experience:

• Abnormal bleeding
• Pelvic pain and pressure
• Flank pain (if hydronephrosis present)
• Lower-extremity edema
• Deep vein thrombosis (DVT)
• Hematuria or rectal bleeding

Diagnostic workup includes physical examination, blood tests, urinalysis, and imaging studies. PET/CT scans increase sensitivity for detecting paraaortic nodal metastases larger than 1 cm, while MRI helps evaluate tissue planes between vagina, bladder, and rectum.

Treatment for Early-Stage Disease

For early-stage cervical cancer (stages IA through IB₂), treatment options include surgery or radiotherapy. Surgery offers the advantage of ovarian preservation for endogenous hormones and possible fertility preservation through oocyte retrieval for in vitro fertilization.

Radical hysterectomy with pelvic lymphadenectomy involves removing the uterus, upper vagina, parametria, and pelvic lymph nodes. This procedure carries a less than 5% risk of complications including hemorrhage, constipation, DVT, pulmonary embolism, lymphocyst formation, lymphedema, and ureteral injury.

The landmark LACC trial compared minimally invasive radical hysterectomy to open surgery and found significantly worse outcomes with minimally invasive approaches: higher recurrence rates and lower 3-year disease-free survival (91.2% vs. 97.1%; hazard ratio 3.74; 95% CI, 1.63 to 8.58). Consequently, the FDA and National Comprehensive Cancer Network recommend against minimally invasive radical hysterectomy for cervical cancer.

For women wishing to preserve fertility, radical trachelectomy (removal of the cervix, upper vagina, and parametria while preserving the uterus) emerged as an option. While successful pregnancy rates exceed 60% among those who attempt conception, about 30% deliver preterm. Newer research from the SHAPE trial suggests that less radical surgery may be sufficient for small tumors.

Sentinel lymph node biopsy techniques (using blue dye, technetium-99, or indocyanine green) show promise for reducing complications compared to full lymphadenectomy, though survival data from ongoing trials are pending.

Treatment for Locally Advanced Disease

For locally advanced cervical cancer (stages IB₃ through IVA), treatment typically involves chemoradiation therapy plus brachytherapy. The combination approach is based on five randomized trials showing that adding chemotherapy to radiation reduces disease recurrence by approximately 50%, despite increasing grade 3 or 4 hematologic and gastrointestinal side effects.

The standard protocol involves weekly cisplatin (40 mg/m²) with daily pelvic radiotherapy (1.8-2.0 Gy per day for 45.0-50.4 Gy total), followed by high-dose-rate intracavitary brachytherapy. Radiation planning has evolved from traditional bony landmarks to CT-guided conformal three-dimensional techniques that better spare healthy organs while targeting tumor tissue.

Intensity-modulated radiation therapy has shown significant benefits in a meta-analysis of over 1000 patients, reducing grade 3 or 4 gastrointestinal toxicity (odds ratio 0.55) and genitourinary toxicity (odds ratio 0.31) without compromising 3-year overall survival.

For selected patients with International Federation of Gynecology and Obstetrics (FIGO) stage III through IVA disease, incorporating immunotherapy provides a survival benefit. Patients with recurrent or metastatic disease may benefit from chemotherapy plus immunotherapy, with or without bevacizumab. For those with disease progression after these treatments, antibody-drug conjugates represent a new option.

Special Considerations

Pregnancy presents unique challenges for cervical cancer management. Dysplasia complicates approximately 1 in 1000 pregnancies. While cervical biopsy during first or early second trimester is safe to rule out invasive disease, endocervical sampling should be avoided. Surveillance each trimester by an experienced colposcopist is recommended, with definitive treatment postponed until after delivery.

Some data suggest vaginal delivery may induce regression of dysplasia. For pregnant patients with early-stage cancer (IA through IB₁) without significant bleeding, conservative monitoring may be possible. Cesarean section with extrafascial hysterectomy at approximately 34 weeks' gestation (after administering glucocorticoids to accelerate fetal lung maturation) avoids the risks of vaginal delivery, which include hemorrhage, obstructed labor, and tumor dissemination.

For locally advanced disease in early pregnancy, neoadjuvant chemotherapy after first-trimester organogenesis may permit gestational advancement while controlling cancer growth.

Clinical Implications for Patients

This comprehensive review underscores several critical points for patients. First, cervical cancer is largely preventable through HPV vaccination and regular screening. The vaccines are highly effective when administered before sexual debut, and screening methods have improved significantly with the advent of primary HPV testing.

For those diagnosed with precancerous changes, multiple effective treatment options exist, and many low-grade lesions will resolve spontaneously. For invasive cancer, treatment approaches have become more refined with better understanding of which patients need more aggressive therapy and which can benefit from fertility-sparing approaches.

The finding that minimally invasive surgery yields worse outcomes than open surgery for radical hysterectomy is particularly important for patients making treatment decisions. This unexpected result highlights how surgical technique can significantly impact cancer outcomes.

For advanced disease, the integration of immunotherapy represents a major advancement, offering new hope for patients who previously had limited options. The continued development of targeted therapies like antibody-drug conjugates suggests further improvements in outcomes are likely.

Study Limitations

While this review synthesizes current evidence on cervical cancer, several limitations should be noted. The recommendations are based on available clinical trial data, but real-world outcomes may differ from those observed in controlled research settings.

Geographic and socioeconomic disparities in cervical cancer burden highlight that access to prevention, screening, and treatment remains unequal worldwide. The strategies described may not be available in all healthcare settings.

Some recommendations, particularly regarding sentinel lymph node biopsy and newer surgical techniques, await additional survival data from ongoing clinical trials. As with all medical advice, treatment decisions should be individualized based on patient circumstances, preferences, and available resources.

The rapid pace of advancement in cervical cancer management means that new evidence continues to emerge that may modify current recommendations. Patients should maintain ongoing dialogue with their healthcare providers about the latest developments.

Patient Recommendations

Based on this comprehensive review, patients should consider the following actions:

1. Vaccination: Discuss HPV vaccination with your healthcare provider, ideally before becoming sexually active. Vaccination is recommended for both females and males ages 11-12, though it can be administered as early as age 9 and through age 45 in some circumstances.
2. Screening: Follow age-appropriate screening guidelines:
   • 21-29: Pap test every 3 years
   • 30-65: Either Pap test every 3 years, HPV test every 5 years, or co-testing (Pap + HPV) every 5 years
   • Over 65: Discuss with your doctor whether continued screening is necessary
3. Risk Reduction: Limit sexual risk factors including multiple partners and early sexual debut. Avoid tobacco use, which increases cervical cancer risk.
4. Symptom Awareness: Report any abnormal bleeding, pelvic pain, or other concerning symptoms to your healthcare provider promptly.
5. Treatment Discussions: If diagnosed with cervical cancer, discuss all treatment options including surgical approach (particularly the evidence against minimally invasive radical hysterectomy), fertility preservation possibilities, and newer approaches like immunotherapy for advanced disease.
6. Second Opinions: Consider seeking second opinions for cancer diagnosis and treatment planning, especially for complex cases or when fertility preservation is desired.

Source Information

Original Article Title: Cervical Cancer
Authors: Krishnansu S. Tewari, M.D.
Publication: The New England Journal of Medicine, 2025;392:56-71
DOI: 10.1056/NEJMra2404457
Note: This patient-friendly article is based on peer-reviewed research from the New England Journal of Medicine and represents comprehensive coverage of the original scientific content.