Teaching pack: Cervical cancer

Cervical cancer is almost entirely caused by persistent infection with high-risk human papillomavirus, which makes it the one common cancer that could be eliminated: HPV vaccination prevents about 90% of cases, HPV screening finds the precancers that remain, and a minute of thermal ablation or a loop excision cures them. Around 660,000 women are diagnosed and 350,000 die each year, nine in ten of them in low- and middle-income countries where vaccination and screening have not reached. In Sweden, Scotland, and Australia, cohorts vaccinated at 12-13 show near-zero invasive cancer, and Australia expects to pass the WHO elimination threshold (4 per 100,000) around 2035.

For women who develop cancer, treatment depends on stage. Early disease is treated with open radical hysterectomy (minimally invasive surgery proved worse in the LACC trial) or, for the smallest tumours, fertility-sparing surgery, with sentinel node mapping under evaluation. Locally advanced disease is cured in roughly two-thirds by cisplatin chemoradiation with brachytherapy, and two 2023-24 trials improved on that standard for the first time since 1999: six weeks of induction carboplatin-paclitaxel (INTERLACE, 5-year OS 80% vs 72%) and pembrolizumab with chemoradiation (KEYNOTE-A18, 36-month OS 82.6% vs 74.8%). Metastatic or recurrent disease, once treated with chemotherapy alone, now has first-line chemotherapy plus a checkpoint inhibitor with or without bevacizumab (KEYNOTE-826, BEATcc, COMPASSION-16 in China), the tissue-factor ADC tisotumab vedotin in second line (innovaTV 301), and HER2-directed therapy for the minority with HER2-positive tumours.

• Near-elimination in vaccinated cohorts (Scotland, Sweden).
• IO in locally advanced and metastatic disease.
• Vaccinated cohorts in Sweden and Scotland show a ~90% to near-total reduction in invasive cervical cancer; single-dose schedules (97.5% efficacy in KEN SHE) make global coverage achievable.
• HPV primary screening with self-sampling has replaced the Pap smear as the recommended test and reaches women who never attended clinics.
• Two curative-intent advances in one year after 24 years of stasis: induction chemotherapy (INTERLACE, OS HR 0.60) and pembrolizumab with chemoradiation (KEYNOTE-A18, OS HR 0.67).
• First-line chemo-immunotherapy roughly doubles median survival in metastatic disease compared with the pre-2014 era (KEYNOTE-826 26.4 months; BEATcc 32.1 months).

1. 1943Pap smear introduced
2. 1943Papanicolaou smear introduced
3. 1983zur Hausen identifies HPV16 in cervical cancer
4. 1999NCI clinical alert: cisplatin with radiation
5. 2006HPV vaccine approved
6. 2006First HPV vaccine (Gardasil) approved
7. 2014Bevacizumab extends survival in advanced disease (GOG-0240); Gardasil 9 approved; HPV primary screening approved in the US
8. 2018LACC: minimally invasive radical hysterectomy is inferior
9. 2020WHO launches the Cervical Cancer Elimination Initiative (90-70-90 by 2030)
10. 2021Tisotumab vedotin approved

• Sacituzumab tirumotecan (product)
• Lifileucel (product)
• Cadonilimab (product)
• Trastuzumab deruxtecan (product)
• SENTICOL III (trial)
• HPV DNA testing and self-sampling (technology)
• Thermal ablation and cryotherapy for cervical precancer (technology)
• Single-dose HPV vaccination plus HPV self-sampling to reach WHO elimination in low-income countries (idea)
• HPV circulating tumour DNA to guide cervical cancer therapy (idea)
• Nonavalent HPV vaccine (product)
• MRD / molecular residual disease testing (technology)
• Proton therapy (technology)

• KEYNOTE-826 (phase 3, n=617): Overall survival (all comers): 26.4 months vs 16.8 months, HR 0.63
• KEYNOTE-A18 / ENGOT-cx11 / GOG-3047 (phase 3, n=1,060): Progression-free survival at 24 months: 68% vs 57%, HR 0.7
• INTERLACE (phase 3, n=500): Progression-free survival at 5 years: 72% vs 64%, HR 0.65
• KEN SHE (single-dose HPV vaccine) (phase 3, n=2,275): Vaccine efficacy against persistent HPV16/18 infection: 97.5%
• EMPOWER-Cervical 1 / GOG-3016 / ENGOT-cx9 (phase 3, n=608): Overall survival: 12 months vs 8.5 months, HR 0.69
• innovaTV 301 / ENGOT-cx12 / GOG-3057 (phase 3, n=502): Overall survival: 11.5 months vs 9.5 months, HR 0.7

• Vaccine and screening access in LMICs.
• Brachytherapy capacity.
• Global HPV vaccination coverage of girls is around 27%; the disease is preventable and 350,000 women still die each year.
• Screening reaches under 30% of women in most low- and middle-income countries; brachytherapy capacity is absent in much of Africa.
• Pembrolizumab with chemoradiation costs far more than induction chemotherapy; how to combine or choose between KEYNOTE-A18 and INTERLACE is untested.
• Recurrent disease after chemo-immunotherapy has few options; tisotumab adds two months of median survival.

1. What is brachytherapy and where is it essential?
   Answer

   Placing a radioactive source directly inside or next to the tumour; essential in cervical cancer, used in prostate (seeds or HDR), breast, skin, and eye melanoma.
2. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
3. Why does trastuzumab deruxtecan work in 'HER2-low' breast cancers that older HER2 drugs ignored?
   Answer

   Its cleavable linker releases a membrane-permeable topoisomerase-I payload (DXd) at high DAR, so a small amount of HER2 is enough to deliver drug and the payload diffuses to kill neighbouring cells (bystander effect); HER2-low is a delivery address, not a driver. DESTINY-Breast04 and -06 proved it.
4. In what setting did T-DXd move into early-stage HER2-positive breast cancer in 2026?
   Answer

   Neoadjuvant (DESTINY-Breast11, T-DXd followed by THP, pCR 67.3% vs 56.3%) and post-neoadjuvant residual disease (DESTINY-Breast05, beating T-DM1), both approved Q2 2026.
5. What was the first cancer drug approved on the basis of a blood test for leftover disease?
   Answer

   Atezolizumab for ctDNA-positive muscle-invasive bladder cancer after cystectomy (IMvigor011, using Signatera), approved Q2 2026; DFS HR 0.64, OS HR 0.59.
6. Can a blood test decide who needs chemotherapy after colon cancer surgery?
   Answer

   Yes in stage II: the DYNAMIC trial used ctDNA to guide adjuvant chemotherapy, halving its use (15% vs 28%) with non-inferior recurrence-free survival (93.5% vs 92.4% at two years).

• Wikipedia: https://en.wikipedia.org/wiki/Cervical_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1426
• Guideline: https://pmc.ncbi.nlm.nih.gov/articles/PMC11163648/
• Guideline: https://www.who.int/publications/i/item/9789240014107