Cervical Health Awareness Month - Cervical Cancer: Prevention, Detection, Development

Cervical Health Awareness Month is a good time to review the state of cervical cancer, what you can do personally, and what is happening in drug development. Cervical cancer is most often caused by the human papillomavirus (HPV) and generally develops slowly with abnormal cells eventually becoming malignant in the tissue of the cervix. This transformation from healthy to abnormal to malignant cells takes time to develop^1,2.

In the United States, the National Cancer Institute (NCI) estimated there would be 14,480 new cervical cancer cases and 4290 deaths in 2021³ Prevention of cervical cancer is ideal. From 2006-2015, new cases of cervical cancer had stabilized, and death rates were declining at 0.7% annually³. Much of this is due to the availability of HPV vaccines. There are seven types out of the more than 200 kinds of HPV that are responsible for the majority of cervical cancers as well as two indicated in genital warts.⁴ In 2006, the FDA approved the HPV vaccine, Gardasil®, to prevent four of the nine types damaging to cervical health.

The vaccine was available to females 9 – 26 years old and according to the CDC cut rates of infection by 64% in American teenagers and 34% in women in their early 20s⁷. In December 2014, Gardasil-9®, a vaccine against 9 types of HPV was approved to provide further protection. According to the NCI, the age group most commonly diagnosed with cervical cancer are women 35-44 (22.8%) years old³. In October of 2018, the FDA expanded the ages approved for the HPV vaccine to include ages 27 – 45 years. While it is too soon to determine the effect of extending vaccine protection to the most often diagnosed age group, it provides another route to continue the decline of cervical cancer incidence. Unfortunately, the HPV vaccine is not 100% effective, therefore, early detection remains important.

Regular testing by a pap test (or pap smear), can identify abnormal changes in cervical cells indicating follow-up testing. Follow-ups may include another pap smear, an HPV test or a cervical biopsy. Due to the slow development, pap smears are recommended every three years for women between the ages of 21 and 65 years with a healthy cervical history⁵. Women 30 years and older may select a pap smear every five years in combination with HPV testing⁶. When identified early there are often positive outcomes, 5-year relative survival rates are 91.9% in women diagnosed with localized cervical cancer³.

Even with positive outcomes in localized cases, the 5-year survival rate is 66.3% leaving a need for continued improvement in late-stage and recurrent cancer treatments³. In addition to chemotherapy, early treatments included single-agent immunotherapy drugs intended to remove the barrier that cancer cells build to block immune response. Alone, these drugs have shown activity in 15% to 25% of patients, leaving ample space for improvement⁸. The first immunotherapy treatment for cervical cancer, Pembrolizumab (Keytruda, Merck) was approved on 13 October 2021, in combination with chemotherapy, with or without bevacizumab, for individuals with persistent, recurrent or metastatic cervical cancer.

It was also approved as a single agent in recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. To be eligible for treatment with pembrolizumab, the cervical cancer tumors must express PD-L1 per an FDA approved test. Investigations for pembrolizumab in combination with other targeted therapies continue.¹¹ Currently, combined therapies are being investigated, including two studies in advanced, recurrent cervical cancer. One pairs an immunotherapy drug (atezolizumab) with bevacizumab (a targeted antiangiogenic agent). Preclinical data suggest the use of the antiangiogenic agent may improve immunotherapy efficacy⁹.

The other combines two immunotherapy drugs (durvalumab and tremelimumab) with radiotherapy. Researchers are investigating the potential for radiation to improve the immune response¹⁰. Both studies have anticipated completion dates in 2022. Additional targeted therapies continue to be researched and developed. These agents are developed to specifically target changes in genes that can cause cancer. Kinase inhibitors, cediranib¹² and nintedanib¹³, who work by blocking certain growth factors that aid cancer cells in growing, have demonstrated a potential to be helpful in early studies of patients with advanced cervical cancer ¹⁴.

Both drugs have additional studies expected to be completed by 2023. Progress for improving cervical cancer outcomes has increased through prevention opportunities with vaccine availability and with continued diligence in regular appointments allowing early detection and treatment. Today efforts continue in drug development studies for late-stage and recurrent treatments to continue to discover more efficient and effective pathways to improve outcomes as we move forward with those still fighting. References

1. Cervical Cancer Treatment (PDQ®)-Patient Version. National Cancer Institute Website. Available at: https://www.cancer.gov/types/cervical/patient/cervical-treatment-pdq#link/_117 . Accessed 17 January 2019.
2. Improving Your Odds for Cervical Health. U.S> food & Drug Administration website. Available at: https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm383757.htm . Accessed 21 January 2019.
3. Cancer Stat Facts: Cervical Cancer. National Cancer Institute, Surveillance, Epidemiology and End Results Program. Available at: https://seer.cancer.gov/statfacts/html/cervix.html . Accessed 22 December 2021.
4. Chapter 11: Human Papillomavirus; Epidemiology and Prevention of Vaccine-Preventable Diseases 14TH Edition. Available at: https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/hpv.pdf
5. Cervical Cancer Screening Guidelines for Average-Risk women. Available at: https://www.cdc.gov/ . Accessed 21 January 2019.
6. Pap Smear. Mayo Clinic website. Available at: https://www.mayoclinic.org/tests-procedures/pap-smear/about/pac-20394841. Accessed 21 January 2019.
7. Markowitz LE, Liu G, Hariri S, Steinau M, Dunne EF, Unger ER. Prevalence of HPV After Introduction of the Vaccination Program in the United States. American academy of Pediatrics. 2016. Available at: https://publications.aap.org/pediatrics/article-abstract/137/3/e20151968/81400/Prevalence-of-HPV-After-Introduction-of-the?redirectedFrom=fulltext . Accessed 21 January 2019.
8. New Clinical Trials Test Immunotherapy for Cervical Cancer. Insight from Dana Farber Cancer Institute. Available at: https://blog.dana-farber.org/insight/2018/03/new-clinical-trials-test-immunotherapy-cervical-cancer/ . Accessed 22 January 2019.
9. Phase 1 / 2 Study of AGEN2034 in Advanced Tumors and Cervical Cancer. ClinicalTrials.gov website. Available at: https://clinicaltrials.gov/ct2/show/study/NCT03104699#contacts . Accessed 22 January 2019.
10. Durvalumab, Tremelimumab + Radiotherapy in Gynecologic Cancer. ClinicalTrials.gov website. Available at: https://clinicaltrials.gov/ct2/show/NCT03277482. Accessed 22 January 2019.
11. FDA approves pembrolizumab combination for the first-line treatment of cervical cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-combination-first-line-treatment-cervical-cancer. Accessed 28 December 2021
12. National Library of Medicine (U.S.). (2018, October 9 – ). A phase II clinical trial of cediranib and olaparib maintenance in advanced recurrent cervical cancer (COMICE). Identifier NCT04487587. https://clinicaltrials.gov/ct2/show/NCT04487587
13. National Library of Medicine (U.S.). (2014 March – ). ENGOT-cx1/BGOG-cx1: 3 weekly carboplatin/paclitaxel with or without nintedanib in cervix cancer. Identifier NCT02009579. https://clinicaltrials.gov/ct2/show/NCT02009579
14. What's New in Cervical Cancer Research? American cancer society website. Available at: https://www.cancer.org/cancer/cervical-cancer/about/new-research.html. Accessed 28 December 2021