What are the latest treatment options for a patient with cervical (ca cervix) cancer?

Latest Landmark Studies and Treatment Advances in Cervical Cancer

Breakthrough Immunotherapy Approval for Advanced Disease

Pembrolizumab combined with chemoradiotherapy (CRT) is now FDA-approved for FIGO 2014 Stage III-IVA cervical cancer, representing the most significant recent advance in cervical cancer treatment. 1

The landmark KEYNOTE-A18 trial (2024) demonstrated that pembrolizumab 200 mg IV every 3 weeks (5 cycles) concurrent with cisplatin 40 mg/m² weekly and radiation therapy, followed by pembrolizumab 400 mg IV every 6 weeks (15 cycles), significantly improved progression-free survival in patients with Stage III-IVA disease (HR 0.59,95% CI: 0.43-0.81). 1 This represents the first major breakthrough in locally advanced cervical cancer treatment in over two decades.

Key findings from KEYNOTE-A18:

• The 12-month PFS rate was 81% in the pembrolizumab arm versus 70% in the placebo arm 1
• The benefit was primarily seen in Stage III-IVA disease, not in earlier stages (IB2-IIB showed HR 0.91, indicating minimal benefit) 1
• 93% of enrolled patients had PD-L1 CPS ≥1 tumors 1

Immunotherapy in Recurrent/Metastatic Disease

For recurrent or metastatic cervical cancer, pembrolizumab combined with chemotherapy (with or without bevacizumab) is now standard first-line treatment for PD-L1 CPS ≥1 tumors. 1

The FDA approval extends to three clinical scenarios:

• First-line combination therapy: Pembrolizumab with chemotherapy ± bevacizumab for persistent, recurrent, or metastatic disease with PD-L1 CPS ≥1 1
• Second-line monotherapy: Pembrolizumab as single agent after chemotherapy progression for PD-L1 CPS ≥1 tumors 1
• Squamous cell carcinoma: KEYNOTE-181 showed improved OS in ESCC with PD-L1 CPS ≥10 (median OS 10.3 vs 6.7 months, HR 0.64) 1

Current Standard Treatment by Stage

Early Stage Disease (IA1-IB1, IIA1)

Radical hysterectomy with pelvic lymphadenectomy remains the preferred surgical approach for stages IA2 through IIA1. 2, 3

• Stage IA1 without LVSI: Cone biopsy or simple hysterectomy 3, 4
• Stage IA1 with LVSI: Add pelvic lymph node dissection 3, 4
• Stage IB1-IIA1: Radical hysterectomy with bilateral pelvic lymphadenectomy is equivalent to radiation therapy in efficacy (5-year OS 83% vs 74%), but differs in morbidity profile (28% severe morbidity with surgery vs 12% with radiation) 2

Critical caveat: Fertility-sparing radical trachelectomy can be offered to young patients with tumors <20 mm, no LVSI, and negative lymph nodes, with recurrence rates of 5% and pregnancy rates of 41-78%. 2

Locally Advanced Disease (IB2-IVA)

Concurrent chemoradiation with weekly cisplatin 40 mg/m² is the established standard for stages IB2-IVA, now enhanced with pembrolizumab for Stage III-IVA disease. 2, 3, 4

The meta-analysis of 18 randomized trials demonstrated:

• Absolute 5-year survival benefit of 8% for overall survival 2
• 9% improvement in locoregional disease-free survival 2
• Greatest benefit in Stage IB2-IIA (10% improvement), moderate in Stage IIB (7%), and minimal in Stage IIIB-IVA (3%) 2

Radiation therapy specifications:

• High doses of 80-90 Gy to target delivered in <50-55 days 2, 4
• External beam radiation therapy (EBRT) plus intracavitary brachytherapy 2, 3
• Treatment completion within 55 days is critical for optimal outcomes 3

Adjuvant Treatment After Surgery

Postoperative concurrent chemoradiation is category 1 recommendation for high-risk features: positive pelvic nodes, positive surgical margins, or parametrial involvement. 2, 3

The Intergroup trial 0107/GOG 109 established this standard, showing significant OS benefit, with recent population-based data (n=3,053) confirming the benefit is primarily realized in patients with lymph node involvement. 2

Additional risk factors beyond Sedlis criteria that warrant adjuvant therapy:

• Adenocarcinoma histology 2
• Close surgical margins 2
• Deep stromal invasion, LVSI, and large tumor size 2, 3

Emerging Immunotherapy Approaches

Multiple novel immunotherapy modalities are in active clinical development beyond checkpoint inhibitors. 5, 6, 7

Current investigational approaches include:

• Therapeutic HPV vaccines: Targeting E6/E7 oncoproteins to stimulate tumor-specific immunity 6, 8, 9
• CAR-T cell therapy: Engineered T cells targeting tumor antigens 7, 9
• Tumor-infiltrating lymphocytes (TILs): Adoptive cell transfer showing promise in early trials 5, 9
• Antibody-drug conjugates: Combining targeted antibody delivery with cytotoxic payloads 5, 6

Cemiplimab, another PD-1 inhibitor, demonstrated significant prognosis improvement in phase 3 trials for advanced/metastatic disease, with ongoing combination therapy trials. 9

Critical Treatment Pitfalls to Avoid

Combined modality treatment (surgery followed by radiation) has significantly higher complication rates than either modality alone and should be avoided when possible. 3

• The NCCN guidelines do not recommend neoadjuvant chemotherapy outside clinical trials, as meta-analyses show no OS benefit despite reducing tumor size 2
• For patients intolerant to cisplatin, carboplatin or non-platinum chemoradiation regimens are acceptable alternatives 2
• Sentinel lymph node mapping shows 89-92% detection rates and 89-90% sensitivity, potentially reducing the need for complete pelvic lymphadenectomy in early-stage disease 2

Synergy Between Immunotherapy and Radiation

Radiation therapy may enhance immunotherapy efficacy through immunogenic cell death and increased tumor antigen presentation. 6

This synergy is being actively explored in clinical trials combining checkpoint inhibitors with definitive chemoradiation, as evidenced by the KEYNOTE-A18 trial design. 1, 6

Human papillomavirus-driven cervical cancers use multiple mechanisms to evade immune surveillance, making the combination of radiation-induced immune activation and checkpoint blockade particularly rational. 6, 7