By Leslie M. Randall, MD, MAS; Mark Stoler, MD, FASCP; and Linda R. Duska, MD, MPH
Originally published in ASCO Daily News; adapted and republished with permission.
In December 2021, we commemorated the 50th anniversary of the National Cancer Act (1971). In his remarks at the signing, President Richard Nixon stated: “As a result of the action, which will come into being as a result of signing this bill, the Congress is totally committed to provide the funds that are necessary, whatever is necessary, for the conquest of cancer.”1 In the subsequent 50 years, we have greatly improved our ability to “conquer” cervical cancer, through such measures as the development of a vaccine against HPV (the primary etiology of the vast majority of cases of cervical cancer) and the addition of novel targeted therapeutics that have given new hope to women with advanced or recurrent disease. However, even in the presence of novel screening techniques and a very efficacious vaccine, cervical cancer took the lives of an estimated 4,290 women in 2021 in the United States2 and continues to be the second leading cause of cancer death in American women age 20 to 39 years.3 Although the overall incidence of cervical cancer has declined, advanced-stage disease and adenocarcinomas are increasing, underscoring the need for targeted efforts to increase HPV vaccination and guideline-based screening.
NCI-Funded Research Led to Significant Advances in Early Detection and Prevention
The elucidation of HPV's etiologic role in more than 95% of cervical cancers, other anogenital cancers, and head and neck cancer is directly attributable to the funding that flowed from the creation of the National Cancer Institute (NCI). This history is the classic paradigm of basic research leading directly to massive benefits for humanity.4 The basic tools of molecular biology—DNA extraction, cloning, restriction enzyme digestion patterns, and sequencing—all had to be available to allow Harald zur Hausen, MD, in late-1970s Germany, as well as others in France, Scandinavia, and the United States, to establish the link between HPV and cervical cancer that was first suggested by surgical pathologists and cytopathologists 2 decades earlier.5-7 The initial observations, based on analysis of tissue pathology, showed that there were two broad classes of HPVs: low-risk, associated with warts; and high-risk, associated with cancer. The ability to detect and genotype tissues with just four probes—HPV types 6 and 11 in 95% of genital warts and HPV types 16 and 18 in approximately 70% of cervical cancers—formed the basis for all eventual clinical HPV tests and elucidated the primary targets of HPV vaccines. Refinement of the same basic technology and the ability to amplify nucleic acids by polymerase chain reaction, together with the analysis of tens of thousands of samples carefully correlated with pathology, established the knowledge base that HPVs are ubiquitous in humans and vertebrates and that more than 200 genotypes are responsible for a substantial disease burden.6 These data also established the parameters for all HPV tests, which has led to the establishment of clinically valid HPV testing as the preferred primary screening test for cervical cancer in current guidelines.8,9
This same science, as well as other NCI-funded research, led to laboratory models for growing infectious papillomavirus, the demonstration that antibodies directed against viral capsid protein could neutralize those infections, and the ability to then synthesize type-specific pseudovirions to use as vaccine antigens. These developments produced the necessary intellectual property in the early 1990s for the development of superbly efficacious prophylactic HPV vaccines that then came on the market in 2006, and whose type spectrum and disease coverage spectrum have expanded, all based on the same fundamental technologies.10,11 Likewise, the early investigations correlating HPV-associated disease pathogenesis with viral gene expression, in particular the understanding of the critical role of the dysregulation of the proteins E6 and E7 of HPV 16 and other high-risk types in neoplastic development, has led to refinement in clinical HPV tests as well as to the development of therapeutic vaccines in active clinical trials.7,12
Advances in Treatment Urgently Needed
The significant advances in early detection and prevention led to a decline in cervical cancer incidence, but they have not eliminated deaths from high-risk invasive disease,2 where treatment advances remain a priority. This autumn also marks the 50th anniversary of NCI's funding of the cooperative Gynecologic Oncology Group (GOG), which would eventually discover predictors of prognosis, define indications for adjuvant therapy, and set standards of care in all disease settings for cervical cancer.13 In early-stage cases, clinicopathologic studies identified two risk groups in patients who had undergone radical hysterectomy: (1) intermediate risk for those with tumors larger than 2 cm, lymphovascular space invasion, and/or deep stromal invasion; and (2) high risk for positive lymph nodes, surgical margins, or parametria.14 GOG clinical trials reported a 47% reduction in risk of recurrence for patients with intermediate risk disease who were treated with adjuvant pelvic radiation15 and a 50% reduction for patients at high risk who were treated with chemoradiotherapy.16 In the locally advanced disease space, where tumors remained localized in the pelvis, GOG collaborated with two additional cooperative groups, the Radiation Oncology Therapy Group and the Southwest Oncology Group, to conduct four additional trials (GOG-85, RTOG-9001, GOG-120, GOG-123) that investigated the addition of weekly radiosensitizing chemotherapy with either cisplatin, 5-FU, hydroxyurea, or their combinations. These studies reported remarkably consistent survival benefits with radiosensitizing chemotherapy, with cisplatin being the best tolerated.17-20 The findings of these studies prompted a rare NCI Clinical Announcement in 1999 that urged the use of radiosensitizing cisplatin for women with locally advanced disease21 and changed the standard of care for the treatment of cervical cancer, a standard that has continued to 2021.
For metastatic and recurrent disease, GOG discovered that, contrary to prevalent opinion, cervical cancer was indeed a chemosensitive disease. Two active phase II queues, the 127-series for cytotoxic regimens and the 227-series for biologic and targeted therapies, revealed activity for platinum, taxanes, topotecan, gemcitabine, and bevacizumab. The GOG-204 protocol ultimately investigated multiple platinum-containing doublets for frontline treatment in the phase III setting, declaring cisplatin plus paclitaxel as the most active combination.22 In 2013, GOG-240 subsequently reported the first shift toward biologic-targeted therapy when an overall-survival advantage was seen with the addition of the antiangiogenic drug bevacizumab to the standard chemotherapy backbone.23 Despite further work with cytotoxic regimens, the standard of care has not changed since these pivotal trials were completed.
Cervical cancer drug development is currently focused on molecular targets and is dominated by immunotherapy. The NCI was the first to show proof of concept for cellular immunotherapy with complete tumor regression in two patients with recurrent cervical cancer after a single infusion of HPV-16-reactive tumor-infiltrating lymphocytes (TILs).24 These two responses brought the HPV-driven biology of cervical cancer back full circle and initiated an explosion of interest in immunotherapy. Cellular therapies, although exciting, are associated with challenges in delivery, including the need for a resectable tumor from which to extract TILs, time to expand the TIL population in vitro, and the need for lymphodepletion and administration of interleukin-2 at the time of TIL administration.25
There is also significant enthusiasm for the study of immune checkpoint inhibitors (ICIs) as single agents, in combination with standard therapy, or in combination with other immune active agents. Development of these agents has been rapid, requiring partnership with industry and with former U.S. clinical trial groups to expedite trials, and further driven by the U.S. Food and Drug Administration Safety Innovation Act (FDASIA) of 2012, which allows accelerated approvals based on surrogate endpoints.26 Pembrolizumab was the first and, to date, only ICI to receive an accelerated approval in 2018 for the second- and third-line treatment of PD-L1+ tumors,27 based on an objective response rate that was low (14.3%) but which was associated with a long duration of response, with the median duration of response not being reached in the cohort.28 Two subsequent, large, phase III trials of ICI therapy have reported, meeting their primary endpoints of OS at early interim analyses.29,30 KEYNOTE-826, the confirmatory trial for pembrolizumab, will likely move ICI into the first-line chemotherapy space. Additional U.S. Food and Drug Administration innovations, such as breakthrough and fast-track designations, are also driving this wave of development, now extended to cellular and noncellular immunotherapy combinations and even earlier lines of therapy.
The Road Ahead: Addressing HPV Vaccine Hesitancy and Racial Disparities in Care
Although the advances that began in 1971 have brought us far, we can and must do better, as evidenced by several sobering U.S. statistics. It is clear that cervical cancer disproportionately affects women of racial and ethnic minorities, socioeconomically disadvantaged groups, and those residing in rural or underserved areas31; Black women have the worst 5-year relative survival by race.31 Vaccine uptake was estimated at only 21.5% among adults age 18 to 26 years in 2018 and at 54.2% in adolescents age 13 to 17 years in 2019.32,33 Screening rates fell by 82% during the COVID-19 pandemic, but quickly rebounded by targeting high-risk women and implementing home self-testing in one health system34; yet the United States continues to not follow the science of implementing HPV primary screening.
Globally, cervical cancer is more prevalent in the developing world and in areas where HIV is endemic.35 In 2020, the World Health Organization launched the Cervical Cancer Elimination Initiative, targeting a global annual incidence rate of less than 4 per 100,000 women-years by reaching 90% HPV vaccination uptake, 70% high-performance HPV testing, and effective treatment of 90% of invasive and preinvasive cases by 2030. We have the tools to achieve this goal, but the promise of the conquest of cervical cancer will require us to fully, innovatively, and equitably commit to its eradication.
Dr. Randall is the Dianne Harris Wright Professor and Director of Gynecologic Oncology in the Department of Obstetrics and Gynecology and Massey Cancer Center at VCU Health. She is also the Cervical Cancer Clinical Trials Lead for the GOG Partners side of the GOG Foundation. Disclosure.
Dr. Stoler is a professor (emeritus) of pathology and clinical obstetrics and gynecology at the University of Virginia Health. Disclosure.
Dr. Duska is the Lawrence Penniston Family Endowed Professor of Women's Oncology Research in the Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, and the Vice-Chair for Research for the Department of Obstetrics and Gynecology, University of Virginia School of Medicine. She serves as editor-in-chief of ASCO Connection. Disclosure.
- National Cancer Institute. Why Commemorate 50 Years of the National Cancer Act?. Accessed September 17, 2021.
- National Cancer Institute. Cancer stat facts: cervical cancer. Surveillance, Epidemiology, and End Results Program, National Cancer Institute. Accessed September 7, 2021.
- Siegel RL, Miller KD, Fuchs HE, et al. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71:7-33
- Jenkins D, Bosch X, eds. Human Papillomavirus: Proving and Using a Viral Cause for Cancer. Academic Press; 2020.
- zur Hausen H. Human papillomaviruses and their possible role in squamous cell carcinomas. Curr Top Microbiol Immunol. 1977;78:1-30
- Meisels A, Fortin R, Roy M. Condylomatous lesions of the cervix. II. Cytologic, colposcopic and histopathologic study. Acta Cytol. 1977;21:379-390.
- Stoler MH, Jenkins D, Bergeron C. The pathology of cervical precancer and cancer and its importance in clinical practice. In: Jenkins D, Bosch X, eds. Human Papillomavirus: Proving and Using a Viral Cause for Cancer. Academic Press; 2020:85-110.
- Wheeler CM, Hunt WC, Joste NE, et al. Human papillomavirus genotype distributions: implications for vaccination and cancer screening in the United States. J Natl Cancer Inst. 2009;101:475-487
- Polman NJ, Oštrbenk A, Xu L, et al. Evaluation of the Clinical Performance of the HPV-Risk Assay Using the VALGENT-3 Panel. J Clin Microbiol. 2017;55:3544-3551
- Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012;62:147-172
- Stanley M. Immune responses to human papillomavirus and the development of human papillomavirus vaccines. In Jenkins D, Bosch X (eds). Human Papillomavirus: Proving and Using a Viral Cause for Cancer./Academic Press; 2020:283-298.
- Smalley Rumfield C, Roller N, Pellom ST, et al. Therapeutic Vaccines for HPV-Associated Malignancies. ImmunoTargets Ther. 2020;9:167-200
- DiSaia PJ. The Gynecologic Oncology Group: 43 Years of Success. Gynecologic Oncology Group; 2013. Accessed September 7, 2021.
- Delgado G, Bundy B, Zaino R, et al. Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1990;38:352-357
- Sedlis A, Bundy BN, Rotman MZ, 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
- Peters WA III, Liu PY, Barrett RJ II, 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
- Keys HM, Bundy BN, Stehman FB, 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
- Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage 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
- Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999;340:1144-11520
- Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999;340:1137-1143
- National Cancer Institute. Concurrent chemoradiation for cervical cancer. Clinical Announcement, February 1999. Accessed September 15, 2021.
- Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009;27:4649-4655
- Tewari KS, Sill MW, Long HJ III, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370:734-743
- Stevanović S, Draper LM, Langhan MM, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol. 2015;33:1543-1550
- T-cell transfer therapy. National Cancer Institute. Accessed September 7, 2021.
- Accelerated approval. U.S. Food and Drug Administration. Accessed September 7, 2021.
- FDA approves pembrolizumab for advanced cervical cancer with disease progression during or after chemotherapy. U.S. Food and Drug Administration. Accessed September 7, 2021.
- Chung HC, Ros W, Delord JP, et al. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2019;37:1470-1478
- Merck announces phase III KEYNOTE-826 trial met dual primary endpoints of overall survival (OS) and progression-free survival (PFS) in patients with persistent, recurrent or metastatic cervical cancer. Merck. Published June 22, 2021. Accessed September 15, 2021.
- Tewari KS, Monk BJ, Vergote I, et al. VP4-2021: EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9: Interim analysis of phase III trial of cemiplimab vs. investigator's choice (IC) chemotherapy (chemo) in recurrent/metastatic (R/M) cervical carcinoma. Ann Oncol. 2021;32:940-941.
- Leading cancer cases and deaths, all races and ethnicities, male and female, 2018. United States Cancer Statistics: Data Visualizations, Centers for Disease Control and Prevention. Accessed September 7, 2021.
- Human papillomavirus vaccination among adults aged 18-26, 2013-2018. NCHS Data Brief No. 354. National Center for Health Statistics, Centers for Disease Control and Prevention. Published January 2020. Accessed September 7, 2021.
- National, regional, state, and selected local area vaccination coverage among adolescents aged 13–17 years—United States, 2019. Morbidity and Mortality Weekly Report, Centers for Disease Control and Prevention. Published August 21, 2020. Accessed September 7, 2021.
- Miller MJ, Xu L, Qin J, et al. Impact of COVID-19 on Cervical Cancer Screening Rates Among Women Aged 21-65 Years in a Large Integrated Health Care System - Southern California, January 1-September 30, 2019, and January 1-September 30, 2020. MMWR Morb Mortal Wkly Rep. 2021;70:109-113.
- Arbyn M, Weiderpass E, Bruni L, et al. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Glob Health. 2020;8:e191-e203.