Cervical Cancer: Awareness and Equity

CE / CME

Improving Provider Awareness About Healthcare Equity: Improving All Patients’ Access to Care in Cervical Cancer

Pharmacists: 0.75 contact hour (0.075 CEUs)

Nurses: 0.75 Nursing contact hour

Physicians: Maximum of 0.75 AMA PRA Category 1 Credit

Released: June 26, 2023

Expiration: June 25, 2024

Shannon N. Westin
Shannon N. Westin, MD, MPH, FASCO

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Introduction

Hello. My name is Shannon Westin, and I am a Professor in the Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, at the University of Texas MD Anderson Cancer Center in Houston, Texas. 

In this module, I will be talking about “Improving Provider Awareness About Healthcare Equity: Improving All Patients’ Access to Care in Cervical Cancer.”

Cervical Cancer: Overview

Cervical cancer is the third most common gynecologic malignancy in the United States and the most common worldwide.1 The primary cause of cervical cancer is human papillomavirus (HPV) infection, which is nearly 100% preventable with vaccination. Vaccination is our number one opportunity to improve on the incidence of this disease.2  

Other risk factors for the development of cervical cancer include smoking, unprotected sexual activity, and having a weakened immune system.

HPV infection can occur on the skin surface or the tissues lining the genitals, anus, mouth, and throat. HPV can be spread via skin-to-skin contact, including intercourse. HPV infection is common, and in most people, the body can clear the infection. However, if individuals have a weakened immune system, they may be at higher risk for chronic HPV infection, which potentially can lead to precancerous lesions and even cervical cancer.

Cervical Cancer: Challenges

Cervical cancer incidence and mortality have declined over time, but the decreases are disproportionate and reflect the lack of effective salvage treatments for patients with recurrent disease.

Cervical Cancer: US Incidence and Mortality Rates by Race

Prevention of cervical cancer is key, and we must address the inequities among racial and ethnic minority patients who have been diagnosed with the disease. In the United States, the overall incidence of cervical cancer is 7.5 per 100,000 women.4 However, the incidence is disproportionately higher in Black patients and Hispanic/Latin descent patients. Mortality also is disproportionately higher in Black patients. There is a significant unmet need to balance those disparities.

Cervical Cancer: Incidence per 100,000 Women by State

When we tease out the incidence of cervical cancer by location within the United States, the Southern states have a disproportionately higher incidence of cervical cancer.4 This may be somewhat related to low rates of vaccination.

Low Rates of Vaccination May Contribute to High Incidence Rates of Cervical Cancer

Here we can see that vaccination rates are lower in those Southern states with higher cervical cancer incidence.5 In general, we recommend HPV vaccination up to 26 years of age, although adults 27-45 years of age also can be considered for vaccination if they have not been vaccinated in the past.

Distrust and Limited Access to HCPs May Result in Lower HPV Vaccination Rates Among Underrepresented Racial/Ethnic Minority Patients

Why do we see lower rates of vaccination in the Southern states—specifically in underrepresented racial and ethnic minority patients? As with the other cancer types, this may be due to limited healthcare access, but it also could be due to distrust of the medical system.6 Distrust and lack of access can be associated with racial differences in communication, lack of medical insurance, and/or transportation challenges. Patients may be unable to take the time to go to their HCP to receive basic care. Of course, low availability of HCPs, pediatricians, or other specialty physicians also can contribute to the problem. Poor health literacy certainly can contribute to a distrust of the HPV vaccine. There is some distrust regarding all vaccines right now across the United States, and acceptance of the HPV vaccine may be affected by this.

Leveraging Community Pharmacies as Vaccines for Children Providers May Help Increase HPV Vaccination

There are opportunities to improve vaccination rates for children. Community pharmacies have been explored as a way to increase HPV vaccination among children to help overcome economic barriers, lack of access, and low awareness. In one study, a specific community pharmacy in Alabama was enlisted as a Vaccines for Children provider, which allowed pharmacists to give free vaccines to eligible adolescents.7 During the 8-month pilot period, there was an increase in the vaccines administered across the population, especially vaccine combinations. Vaccines administered in addition to the HPV vaccine included those for tetanus, pertussis, flu, and other important diseases. Thus, there is an opportunity for getting into the community, building trust, and providing the necessary care to young individuals.

ACS/USPSTF Guidelines on Cervical Cancer Screening Frequency

As previously mentioned, prevention of cervical cancer is key, and screening represents a large part of that. In general, HPV testing is the primary screening target for avoiding cervical cancer.8,9 Women 21-29 years of age should be screened every 3 years with cervical cytology alone. Women 30-65 years of age should be screened every 5 years with HPV testing or every 3 years with cervical cytology. The bottom line is making sure that patients are connecting with their HCPs and getting the appropriate screening as indicated based on their medical history and age.

Health Disparities in Screening for Cervical Cancer

There are some data regarding health disparities in cervical cancer screening. Within the table on the right, one can see a higher odds of Pap and HPV testing in White vs Black patients.10 The screening rates also are influenced by level of education, type of insurance, and household income among individuals. In summary, numerous factors seem to contribute to barriers to cervical cancer screening.

Barriers to Cervical Cancer Screening for White, Black, and Hispanic Women

This study specifically asked individuals why they were not getting cervical cancer screening.11 Black women, represented by the orange bars, and Hispanic/Latin descent women, represented by the green bars, noted fewer issues with cost but more issues with fear of finding cancer, anxiety about the procedure, anticipation of pain, lack of knowledge, and other health problems. Only lack of knowledge and other health problems were statistically significant (P = .002), but many of the issues were numerically higher in the Black and Hispanic populations.

Navigating the Healthcare Ecosystem: Expanding Access to Care for Underrepresented Racial/Ethnic Minority Patients

How can we improve access to care for underrepresented racial and ethnic minority patients? This randomized trial evaluated various interventions, including outreach by community health workers that included a patient brochure, individualized community health worker‒led education and navigation to a healthcare facility, and community health worker‒led education in tandem with HPV self-sampling by patients after they were taught how to do it.12 The patients who were educated and able to sample themselves had a much higher completion rate of cervical cancer screening. This supports the feasibility and effectiveness of mailed HPV self-screening tests, which improved overall access to screening. Of note, only a few patients—2 of 265—had to perform repeat sampling because of inadequate specimen collection. This illustrates the benefit of meeting people where they are to help improve access to care.

Cervical Cancer: Treatment Options

The schematic on the right illustrates the various available treatment options for patients with cervical cancer based on the stage of disease.13-15 Suffice to say, early-stage disease can receive treatment with surgery with or without radiotherapy and other treatments. Locally advanced disease requires chemoradiation therapy. Patients with metastatic disease can receive systemic treatments.

Cervical Cancer: Interactive Decision Support Tool for Advanced Gynecologic Cancers

To see recommendations from 5 experts for systemic therapy for advanced cervical cancer based on specific patient and disease characteristics, access this Interactive Decision Support Tool.

Black and White Women With Cervical Cancer Receive Different Treatments

When it comes to disparities, data suggest that Black and White patients with cervical cancer receive different treatments.16 In this study by Uppal and colleagues, Black patients received less surgery, more chemotherapy, more chemoradiation, and more pelvic radiotherapy without brachytherapy. They also were more likely to receive no treatment. When we look at the impact of brachytherapy, we see that lack brachytherapy was associated with worse overall outcomes, particularly among patients who were Black.

Uniformity of Treatment and Guideline-Concordant Care May Help Reduce Health Disparities in Cervical Cancer

The data on the right illustrate what we have seen many times before. When there is uniformity of treatment and guideline-concordant care, we see improvements in outcomes and the ability to overcome health disparities. These data also indicate receipt of guideline-based care by race, as well as the probability of receipt of guideline-based care according to hospital volume.17 Research shows that when appropriate guideline-based care for cervical cancer is provided, patient survival improves irrespective of race, ethnicity, cancer stage, and hospital volume. 

Black Patients With Cervical Cancer Who Receive Care Comparable With White Women Achieve Similar Survival Outcomes

When Black patients with cervical cancer receive care comparable to White patients, they achieve similar survival outcomes.18 This suggests there is an opportunity to improve disparities by ensuring all patients get appropriate care.

KEYNOTE-158 Phase II Basket Trial (Update): Pembrolizumab Monotherapy in Advanced CC

Let us talk about appropriate care in the second-line setting and beyond in patients with advanced cervical cancer. The KEYNOTE-158 study demonstrated that single-agent immunotherapy with pembrolizumab was an appropriate option for patients with advanced squamous cell carcinoma, yielding a 14% response rate in the overall population.19 Among patients with PD-L1‒positive disease, the response rate was slightly higher at 17%. This trial did lead to FDA approval of single-agent pembrolizumab for patients with cervical cancer that is PD-L1 positive or that has microsatellite instability‒high/mismatch repair deficient (dMMR) status. Of importance, the duration of response to pembrolizumab is remarkably high. An updated analysis of the trial showed that median overall survival (OS) was 9.3 months among this previously treated group of patients.20

Updated Efficacy Results

GARNET is another study that evaluated immunotherapy. This was a multicenter, open-label, single-arm phase I study in a group of patients who had dMMR disease. Based on the results from this study, which demonstrated an objective response rate of 38.7% and a disease control rate of 63.2%, dostarlimab received FDA approval for a tumor-agnostic indication in adult patients with recurrent or advanced solid tumors characterized by dMMR.

In fact, the ongoing phase II STAR trial is evaluating dostarlimab plus niraparib in patients with recurrent or progressive cervical cancer.

Pembrolizumab + CT ± Bevacizumab vs Placebo + CT ± Bevacizumab in CC (KEYNOTE-826): Study Design

KEYNOTE-158 led to KEYNOTE-826, in which pembrolizumab was added to the standard of care—that is, chemotherapy (platinum/paclitaxel) with or without bevacizumab—in patients with advanced or recurrent cervical cancer who had received no previous systemic therapy.21 Patients in this trial were randomly assigned to receive pembrolizumab or placebo in combination with chemotherapy with or without bevacizumab, and they received treatment until progression or unacceptable toxicity. Of importance, there was a dual primary endpoint of OS and progression-free survival (PFS).

KEYNOTE-826: Baseline Characteristics

The patient population in KEYNOTE-826 was representative of the patients we treat in real-world practice.21 The majority of patients (51%) did have high PD-L1 combined positive scores (≥10), and most had received previous chemoradiotherapy. The population was diverse compared with other studies in this setting. Regarding ethnicity, 40% of patients were non-Hispanic White, so this better represents the patients we see in clinic. 

KEYNOTE-826: PFS and OS

The Final OS results presented at ASCO 2023 showed an improvement across all patient groups with the addition of pembrolizumab to standard therapy, whether it was the all-comer population or subgroups broken out into different degrees of PD-L1 positivity.21, 22 The reduction in risk of death was approximately 40% (P = .001) for patients with PD-L1‒positive disease. Of importance, PFS also was improved. The risk of death in all-comers was reduced by approximately 37% (HR: 0.63) for patients with PD-L1‒positive disease when pembrolizumab was added to chemotherapy with or without bevacizumab.

KEYNOTE-826: PFS/OS Across Protocol-Specified Subgroups

Approximately 60% of patients in KEYNOTE-826 received bevacizumab because of numerous contraindications, which led to some concern about the results. However, the PFS and OS benefits persisted regardless of whether bevacizumab was used.21 Improvements with the additional of pembrolizumab also were seen across age, race, performance status, and metastatic disease. Thus, this 4-drug regimen seems to be the ideal option for our patients.

InnovaTV 204: International, Multicenter Phase II Study of Tisotumab Vedotin in Recurrent/Metastatic CC

What do we do for patients with disease recurrence? The innovaTV 204 study evaluated tisotumab vedotin, an antibody‒drug conjugate targeting tissue factor, which is highly overexpressed in cervical cancer.23 Patients who had received more than 1 previous line of therapy were treated with tisotumab vedotin 2 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by independent review committee. Tisotumab vedotin demonstrated a response rate of 24%, which met the prespecified response rate target of 21% to 25% and led to FDA approval for tisotumab vedotin in September 2021. Confirmatory trials are ongoing.

Phase II innovaTV 204: Prespecified AEs of Interest

Tisotumab vedotin is associated with ocular AEs.22 These are mostly mild to moderate in severity, but they can be frightening to a patient who does not know what to expect. For instance, a patient who starts to have vision changes is going to become nervous. This is where proactive patient education becomes so important. Patients need to be made aware of the possibility of these ocular AEs and that they will resolve, but they need to be managed appropriately. There is specific guidance to help mitigate ocular toxicities that potentially may be experienced with tisotumab vedotin. For example, patients should be seen by an eye care provider (ophthalmologist/optometrist) before treatment and then before every treatment cycle to assess for any new or worsening signs or symptoms of ocular AEs.15 In the innovaTV 204 study, the median time to onset for ocular AEs was 1.4 months, and 86% of events resolved in less than 1 month.

Other AEs that can occur with tisotumab vedotin include bleeding AEs, predominantly epistaxis, and neuropathy.23 These AEs are related to monomethyl auristatin E, the chemotherapy payload, which binds to tubulin and inhibits tubulin polymerization. Again, patients should be made aware of these AEs, especially patients who already have received taxanes and who may have preexisting neuropathy. Of importance, most peripheral neuropathy reported in the innovaTV 204 study was low grade and manageable with dose modifications. The median time to onset for peripheral neuropathy was 3.1 months, and 21% of events resolved. The median time to resolution was 0.6 months.

Addressing Potential Healthcare Disparities in Clinical Trial Enrollment

As HCPs, we need to ensure that we are effectively communicating with patients and understand their level of satisfaction with their treatment. How well are they tolerating therapy? What are their symptoms, and how severe are they? Do they feel supported? Are they able to get to and from their treatment appointments and clinic visits? Are they experiencing financial toxicity? Understanding all of these issues is necessary for fine-tuning treatment, helping patients navigate insurance claims or financial assistance programs, and trying to develop a unique care plan for each patient.

A useful patient resource with links to financial assistance programs can be downloaded here

  • A phase II study of atezolizumab and stereotactic body radiation therapy compared with atezolizumab alone in patients with recurrent, persistent, or metastatic cervical cancer (MCC-19662, NCT03614949)
  • A phase II study of niraparib and dostarlimab as a combination treatment in patients with recurrent or progressive cervical cancer (STAR, NCT04068753)
  • A randomized phase III study of the combination of platinum-based chemotherapy plus paclitaxel with bevacizumab and atezolizumab vs platinum-based chemotherapy plus paclitaxel and bevacizumab in metastatic, persistent, or recurrent cervical cancer (BEATcc, NCT03556839)
  • A phase III study of chemoradiotherapy with or without pembrolizumab for high-risk, locally advanced cervical cancer (KEYNOTE-A18, NCT04221945) 
  • A phase III study evaluating tisotumab vedotin vs investigator’s choice single-agent chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) in second- or third-line recurrent or metastatic cervical cancer (innovaTV 301, NCT04697628)

Visit ClinicalTrials.gov for enrolling clinical trials near you.

Navigating the Healthcare Ecosystem: Addressing Potential Disparities

We need to improve communication between patients and HCPs, acknowledge patients’ beliefs and values, minimize HCP bias, ensure that we are offering clinical trials to all patients, and work on having the medical care team be representative of the patients they see.24-25 Regarding costs, we must work on reducing treatment costs and provide support for costs unrelated to medications, such as transportation and missed wages. Regarding gaps in outcomes research, we need to increase the participation of underrepresented groups in clinical trials and understand not only the social differences, but also the genetic and potential molecular differences in tumor biology based on race. Oncology pharmacists, nurses, patient navigators, and other members of the healthcare team can help empower patients and ensure that they have adequate resources and education so they can make the right treatment choices for themselves. 

A useful handout to help inform patients about improving patient‒HCP communication and treatment choices for the management of cervical cancer can be downloaded here

Conclusions and Takeaways

To achieve health equity in cervical cancer, there are clear opportunities.

  • Low vaccination rates and lack of HPV screening are key contributors to the higher incidence of cervical cancer in Black and Hispanic patients vs White patients. There is a significant opportunity to get out into the community to provide education and leverage community pharmacies to get HPV vaccines to those groups of patients at higher risk for not receiving them. Moreover, we must ensure that all young women get the appropriate screening as indicated based on their medical history and age.
  • In a patient with a diagnosis of cervical cancer, we must ensure that they get appropriate guideline-concordant care, such as use of chemoradiotherapy with brachytherapy and use of novel agents (eg, immunotherapy, antibody‒drug conjugates) when appropriate.
  • We must help Black patients overcome disparities, provide them with appropriate education about the potential benefits of clinical trial participation, and ensure that they receive treatment at a high-volume center, which may potentially result in improved outcomes.

Go Online for More Coverage of Gynecologic Malignancies!

I invite you to visit the program page to access downloadable slides, on-demand webcasts, and other text modules on endometrial and ovarian cancer to update yourself and your healthcare team on providing equitable and evidence-based care to all patients with gynecologic cancers. In addition, download these helpful point-of-care resources to share with your patients.

I hope to see you at the next event.

Assessment 

Dorian is a 37-year-old patient with a history of advanced cervical cancer. She previously received treatment with surgery plus chemoradiation. She recently presented with liver recurrence and residual peripheral neuropathy from previous chemoradiation. IHC testing performed on her liver biopsy demonstrated a PD-L1 combined positive score of 2 (positive) and was found to have HER2 mutation by NGS.

Based on these presentation characteristics, which second-line treatment options would be most appropriate for her?

To which of the following specialists should you send your patients receiving tisotumab vedotin for recurrent cervical cancer to implement the recommended adverse event (AE) prevention and mitigation strategies for this agent?