Differences in Clinical Trial Availability vs Distribution of Disease Among Gynecological Cancers

Introduction

Clinical trials allow for the discovery and translation of new and more effective methods of prevention, diagnosis, and treatment, and are an essential part of advancing quality cancer care.¹ National Cancer Institute (NCI)–supported clinical trials have provided much of the evidence behind clinical guidelines for the treatment of patients with ovarian, uterine, and cervical cancers.² Aside from providing access to the latest innovations and increasing treatment options, clinical trial participation has also been associated with improved survival for patients.³ Accruing representative populations on clinical trials is critical, as it ensures generalizability of results and is an important part of bridging the gap in cancer health disparities. Toward this end, NCI Comprehensive Cancer Centers are expected to enroll women and racial and ethnic minority groups to clinical trials in approximate proportion to the population of patients with cancer in their reported catchment area.⁴ Despite this requirement, the ethnic composition of cancer trial participants does not optimally reflect the communities being served.⁵ This remains a major challenge, and in both gynecologic oncology and the larger field of cancer research, minority enrollment has worsened rather than improved over the past 15 years.⁶

In gynecologic oncology, racial and ethnic disparities exist across a broad range of health measures, including screening rates, incidence, stage at diagnosis, and mortality. Of the widest Black-White mortality gaps among all cancer diagnoses in the US, 2 of the top 5 are seen in gynecologic malignancies: cervical cancer and endometrial cancer.⁷ Cervical cancer incidence and mortality rates are twice as high in Black, Hispanic, and American Indian/Alaska Native women compared with White women.⁸ Uterine cancer incidence and mortality are higher among Black women than White women, and although uterine cancer incidence is rising among all groups, it is rising at higher rates in Black, Hispanic, American Indian/Alaska Native, and Asian/Pacific Islander women than in White women. Worse patient outcomes in uterine and cervical cancer have been associated with low socioeconomic status.^8,9 In contrast, ovarian cancer incidence and mortality are highest among White women, intermediate for Hispanic women, and lowest among Black and Asian women.¹⁰ The most notable disparity related to ovarian cancer is access to receiving high-quality care after diagnosis, as this has a major impact on survival; in addition, Black race and low socioeconomic status have been associated with non–guideline-
adherent care.⁸

Given these differences, with cervical and uterine cancer disproportionately impacting racial and ethnic minority populations, and ovarian cancer more commonly impacting White women, gynecological cancers are a unique opportunity to study disparities in clinical trials. All 3 disease types fall under the purview of gynecologic oncologists, often rely on the same cooperative group networks, and use the same institutional research infrastructures. However, we hypothesized that the availability of clinical trials would not be equitably distributed by the ethnic and racial makeup of the surrounding community.

The UCLA Jonsson Comprehensive Cancer Center (JCCC) is a large academic center in Los Angeles County, California, which serves as its catchment area. Los Angeles County is the most populous county in the US and has highly diverse demographics.¹¹ The purpose of this study was to evaluate whether the availability of clinical trials for cervical, uterine, and ovarian cancer reflects the clinical volume of each cancer at the JCCC, an NCI Comprehensive Cancer Center serving a large, diverse patient population. We also examined whether the number of patients who consented reflects the racial and ethnic distribution of each cancer type in the catchment area. Lastly, we assessed for differences in industry sponsorship among the clinical trials for each cancer type, as industry-sponsored studies are more frequently associated with positive studies and novel agents.¹²

Methods

Data Sources

After receiving Institutional Review Board approval for this retrospective cohort study, we obtained data from a database of all patients who signed consent to interventional trials open at the JCCC from January 1, 2013, through December 31, 2018.¹³ This period represents one of the most recent competitive renewal periods for NCI Cancer Center Support Grants, during which cancer centers must provide an overview of accrual to interventional clinical trials over the current project period.⁴ Information on cancer incidence in Los Angeles County was obtained from the statewide, population-based California Cancer Registry.¹⁴

Study Population

All patients who consented to clinical trials for cervical, uterine, or ovarian cancer at the JCCC from January 1, 2013, through December 31, 2018, were included. This included patients who gave consent at Olive View-UCLA Medical Center (OVMC), a Los Angeles County safety-net hospital with an established collaboration with the JCCC, which ensures that patients receiving cancer care at OVMC have access to available clinical trials. Clinical trials specific to cervical, uterine, or ovarian cancer were identified from a database of all JCCC interventional trials using the keywords cervical, cervix, uterine, uterus, ovarian, fallopian tube, and primary peritoneal to search study titles, subject disease sites, and clinical trial disease sites. Clinical trials that included but were not specific to cervical, uterine, or ovarian cancers (ie, basket trials) were excluded. One clinical trial was open to patients with either uterine or cervical cancer and was counted for both at the trial level; at the patient level, those who consented to this trial were sorted according to their histology. Because the database consists of patient-level data, data were only available for clinical trials that enrolled at least 1 patient for the trial. Clinical trials identified were reviewed by study authors to ensure that they were appropriate for participation based on reported inclusion and exclusion criteria. Cancer center records for included trials were reviewed for study sponsor, race, and ethnicity of patients who consented for each study, and the patient-consenting site. Missing patient information was collected from the patient’s electronic medical records. Patient demographic data on race and ethnicity were self-reported and recorded so that they aligned with available California Cancer Registry data on race and ethnicity, where Hispanic is mutually exclusive from Asian/Pacific Islander, non-Hispanic Black, and non-Hispanic White designations during the same period, from January 1, 2013, through December 31, 2018.

Analysis

Using county-level data on the incidence of each cancer type during the same period, the expected number of patients who consented for each cancer type was calculated. Expected rates were then compared with observed rates for each cancer type. Similarly, using county-level data on the racial and ethnic distribution of cancer, the expected proportions of different racial and ethnic minority groups consented for clinical trials were calculated. The expected ratios based on county-level data were then compared with the observed ratios for each cancer type. To account for the fact that patients with advanced disease are more likely to need a clinical trial, the expected proportion was also calculated using the reported percentage of incident cases with distant disease in the county. The proportion of industry-sponsored vs cooperative group-sponsored trials was compared across cancer types. χ-Square and Fisher exact tests were used to compare proportions as appropriate.

Results

The average gynecologic cancer incidence rates per 100,000 in the catchment area from January 1, 2013, through December 31, 2018, were 11.7 for ovarian cancer, 27.0 for uterine cancer, and 7.8 for cervical cancer.¹⁵ This was similar to reported national rates for the same time period according to the Surveillance, Epidemiology, and End Results (SEER) Program data.^16-18 The average number of incident cases per year in the catchment area and the distribution across different racial/ethnic groups are reported in Table.

A total of 24 gynecologic oncology clinical trials were identified: 16 (67%) ovarian, 5 (21%) uterine, and 3 (12%) cervical cancer trials. Although there were 23 total studies, 1 trial was counted twice as it was classified as both uterine and cervical due to the eligibility criteria. A total of 190 patients consented for trials: 155 with ovarian cancer (82%), 18 with uterine cancer (9%), and 17 with cervical cancer (9%) (Figure 1).

Compared with corresponding county incidence rates, respectively, the proportion of patients with ovarian (82% vs 25%), uterine (9% vs 59%), or cervical (9% vs 6%) cancer who consented for clinical trials differed significantly (P < .001). These findings suggested an overrepresentation of patients with ovarian cancer and an underrepresentation of those with uterine cancer in clinical trial enrollment relative to the local disease burden. Even when adjusting the expected proportion using the reported percentage of incident cases with distant disease in the county (61% ovarian, 28% uterine, 11% cervical), the proportions were still significantly different (P < .001). Trial participation also varied significantly by race and ethnicity, with enrollment patterns diverging from expectations based on county-level cancer incidence by racial group for ovarian (P < .001) and cervical (P = .002) cancers, but not for uterine cancer. Patients who were non-Hispanic White were overrepresented in ovarian cancer trials, whereas patients who were Asian/Pacific Islander, Black, or Hispanic were underrepresented. In contrast, patients who were Hispanic were overrepresented in cervical cancer trials. Specifically, those who were Hispanic comprised 94% (n = 16/17) of cervical cancer trial participants, but only 8% (n = 12/155) and 3% (n = 5/155) of participants in ovarian and uterine cancer trials, respectively. Patients who were non-Hispanic White represented 79% (n = 122/155) of ovarian cancer trial participants, compared with only 6% (n = 1/17) in cervical cancer trials (Figure 2).

Ninety-three percent (n = 15/16) of ovarian cancer trials were industry-sponsored compared with 40% (n=2/5) of uterine cancer trials. No cervical cancer trials were industry-sponsored. There was a significant association between ovarian cancer and industry sponsorship, and uterine and cervical cancers and cooperative group sponsorship (P < .001). Of note, 9 of 155 (6%) patients with ovarian cancer, 4 of 18 (22%) patients with uterine cancer, and 17 of 17 (100%) patients with cervical cancer consented for trials through the JCCC’s partnership with OVMC.

Of the uterine cancer trials, 1 was an interventional trial on lymphedema, 3 were interventional trials with investigational drugs, and 2 were interventional trials with no investigational drugs. Of the ovarian cancer trials, 1 was an interventional trial on diet and physical activity, and 15 were interventional trials with investigational drugs. Of the cervical cancer trials, one was an interventional trial on lymphedema, and 2 were interventional trials with no investigational drugs.

Discussion

This study identified significant disparities in the representation, sponsorship, and site of enrollment of patients with gynecologic malignancies in clinical trials. Ovarian cancer was overrepresented in participant enrollment relative to county incidence and was primarily supported by industry-sponsored trials. In contrast, uterine cancer had the highest county incidence but accounted for a small proportion of trial enrollment; both uterine and cervical cancer trials were primarily sponsored by cooperative groups. Trial access also varied by site, with participants with cervical cancer mostly enrolled at OVMC. Racial and ethnic disparities were evident, with Hispanic patients overrepresented in cervical cancer trials but underrepresented in ovarian cancer trials, whereas non-Hispanic White patients were overrepresented in ovarian cancer trials.

According to the theoretical model developed by Ford et al to examine barriers/promoters to clinical trials, recruitment barriers occur at 3 junctures: awareness of clinical trials, opportunity to participate, and acceptance or refusal of enrollment.¹⁹ Because opportunity barriers largely reflect protocol design and the process of study implementations, investigators play a major role in determining the extent to which trials are accessible to underrepresented groups. Although eligibility criteria have been studied as an opportunity barrier to clinical trial enrollment, this does not capture how the availability of trials across disease sites impacts participation.²⁰ Given the disparities in incidence among different racial and ethnic groups and differences in patient characteristics among the 3 main types of gynecological cancers, there is a unique opportunity to study disparities in clinical trial availability. In this study, we found that among the 3 main gynecologic cancers (ovarian, uterine, and cervical), the number of clinical trials available at a large cancer center in Los Angeles was not proportional to the incidence of each cancer in the center’s catchment area. Ovarian cancer, which is more common in White women, had the most available clinical trials, and most patients consented. Cervical cancer, which has greater racial and ethnic diversity, had the fewest available clinical trials, and all patients consented at the affiliated county hospital. None of the cervical cancer studies were industry-sponsored, and patients who were Hispanic were overrepresented.

These findings are consistent with results recently reported in a review of 357 articles of gynecologic oncology phase 1 trials from 1985 to 2018, which found that ovarian cancer trials were the most common, accounting for 60% of publications reviewed, followed by cervical cancer (25%), endometrial cancer (3%), and multiple cancers (12%).²¹ This trend is also seen in a review of NCI-sponsored gynecological cancer treatment trials from 2003 to 2012; out of 18,913 accruals, 55.6% of patients enrolled in 70 ovarian cancer trials, 32% of patients enrolled in 51 uterine cancer trials, and 12.3% enrolled in 35 cervical cancer trials.²

It is important to note that there are differences in the presentation and prognosis of these cancers. Ovarian cancer most often presents at an advanced stage, with a 5-year survival of approximately 48%, whereas uterine cancer often presents at an early stage, with a 5-year survival of 81%.^17,18 Cervical cancer presents as localized disease approximately 43% of the time and has a 5-year survival of 67%.¹⁶ Cervical cancer also has effective screening and a vaccine that substantially reduces its risk.²² These disease characteristics certainly play a role in the availability of clinical trials for each cancer, and the greater lethality and lack of effective screening for ovarian cancer likely contribute to its greater proportion of available clinical trials. However, even when accounting for the county-reported average proportion of patients with distant disease for each cancer (54% ovarian, 11% uterine, 15% cervical) for the time period, there were still more patients with ovarian cancer and fewer with uterine cancer who consented for trials than expected. It should also be noted that uterine and cervical cancer have higher mortality rates among those with distant disease, with a 5-year survival of 18.0% for uterine and cervical cancer compared with 31.5% for ovarian cancer. Ovarian cancer mortality is decreasing, likely due to decreasing incidence, effective risk-reducing surgery, and improved survival of patients with the introduction of new treatments.^23,24 Uterine cancer mortality is rising, and cervical cancer mortality is decreasing, but this decrease is disparate among the most vulnerable populations.^25,26 These cancers would likely benefit from the same level of research interest and clinical trial availability seen in ovarian cancer.

A particular challenge for studies in gynecologic cancers is funding. Results of a recent study of National Institutes of Health (NIH) funding in 2019 showed that NIH applies a disproportionate share of its resources to diseases that affect primarily men, at the expense of those that affect primarily women.²⁷ Given these challenges, industry sponsorship of clinical trials can be of particular importance; additionally, industry-sponsored studies are more frequently associated with positive studies and novel agents. In this study, all but 1 of the ovarian cancer trials were industry-sponsored, whereas none of the cervical cancer trials were industry-sponsored. Of note, no industry-sponsored studies had patients at the affiliated county hospital who consented. The role of study sponsorship as it relates to the disparities in clinical trials should be explored further, particularly as more industry partners commit to improving diversity, equity, and inclusion in their work.

An unexpected but notable finding in this study was that all patients enrolled in cervical cancer clinical trials consented at OVMC, a Los Angeles County safety-net hospital that serves the San Fernando and Antelope valleys. Investigators in a recent study found that community sites affiliated with an NCI-designated cancer center accrued patients to a wide selection of solid tumor trials, which may represent a unique opportunity to expand clinical trial access to underserved and underrepresented populations.²⁸ Similarly, safety-net hospitals provide a disproportionate share of care to low-income and uninsured populations, which represents an opportunity to improve accrual of diverse patient populations, as exemplified by the consent of patients to cervical cancer trials in this study at OVMC.

The strengths of this study include the evaluation of trial consents over 6 years at a large, high-enrolling NCI-designated Comprehensive Cancer Center from the most recent reporting period. The availability of county-level data on cancer incidence, including race and ethnicity data, available through the California Cancer Registry, also made it possible to compare clinical trial enrollment at the JCCC with the center’s reported catchment area. Incidence rates in Los Angeles County are consistent with national rates. A significant limitation of this study is that our database does not include any clinical trials that may have been open but failed to have at least 1 patient sign a consent form. Understanding why open clinical trials fail to accrue patients is important for understanding institution-level barriers and is an important area of study for addressing disparities in clinical trials. A weakness of this study is that it is from a single institution, and there are multiple institutions in the area that also enroll patients in clinical trials. However, the general consistency of greater availability of ovarian cancer trials compared with uterine and cervical trials is evidenced by the aforementioned retrospective studies and supports that this is a widespread issue. Another limitation is our inability to compare the number of industry vs cooperative group trials available in gynecologic cancers to other cancers, such as head and neck cancer, as there were no other oncology trials with accruals at OVMC. Given that our database includes only patients who signed consent forms, we cannot comment on the number of patients who were not enrolled in trials, which is an important area of ongoing research in gynecologic oncology. This study also does not include basket trials that might have been available to patients with gynecologic cancers, which might underrepresent another source of clinical trial availability for these patients.

This study highlights the important role the cancer center plays in selecting clinical trials that fit the patients in its catchment area. Given the limited funding for clinical trials in gynecologic cancers, greater intentionality in the selection of clinical trials is needed to ensure that the selected trials fit the needs of their patient population. This requires regular assessment and understanding of the disease burden and community needs in the catchment area. The same level of careful consideration must come at the national level, as NCI-sponsored cooperative groups such as NRG Oncology also impact clinical trial availability among gynecologic cancers. Deliberate attention should be paid to ensuring that patients with uterine and cervical cancers can benefit from clinical trials, while continuing the progress seen in ovarian cancer trials. This requires not only advocating for greater government funding of gynecologic cancer research but also identifying ways of bringing greater industry investment in these relatively rare cancers that are often seen in patients who are uninsured or underinsured rather than privately insured.

True equity in clinical trials should include not only adequate availability of trials for patients from different racial and ethnic groups, but also availability of trials with similar characteristics and sponsorship. The role of study sponsor and partnership with safety-net hospitals presents promising areas for investigation to bring greater equity to clinical trial disease sites and enrollment. Addressing these system-level barriers must be a focus in the effort to accrue diverse and representative patient populations in clinical trials.

Disclosures

Dr Garon reports the following disclosures: Consultant and/or adviser: AbbVie, Arcus, AstraZeneca, Atreca, BridgeBio, Bristol Myers Squibb, Eli Lilly, EMD Serono, Gilead, GSK, Hookipa, Merck, Merus, Novartis, Nuvalent, Regeneron, Sanofi, Seagen, Sumitomo, Summit, Synthekine. Grant/research support: ABL-Bio, ArriVent BioPharma, AstraZeneca, Bristol Myers Squibb, Daiichi Sanko, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, Novartis, Regeneron, Synthekine.

Corresponding Author

Andrea I. Nañez, MD

Address: UCSF, Box 0132, 490 Illinois St, 10th Floor, San Francisco, CA 94143

Telephone: (415) 885-7561

Email: Andrea.Nanez@ucsf.edu

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