- There are many screening questions that can be addressed through clinical trials.
- One size doesn’t fit all: There is a trend for increasingly personalized screening, where cancer screening recommendations are guided by detailed risk assessments, including models.
- Promising biomarkers, especially circulating free tumor DNA from plasma, are in development for many cancers.
- Compliance and implementation of screening guidelines can be issues.
- While there may be benefits to a cancer screening trial network, the ideal mechanism for funding screening trial sites remains an open question.
The Division of Cancer Prevention (DCP) of the National Cancer Institute (NCI) hosted a virtual workshop to obtain information relevant to the potential creation of a new NCI-funded cancer screening clinical trials network focused on small-to-mid range trials.
Possible advantages of such a network are that it would be purposefully designed to recruit asymptomatic, average or high-risk subjects without cancer and involve non-oncology practitioners. Potential disadvantages are high start-up costs, possible redundances with the NCI Community Oncology Research Program (NCORP) and a potential shortage of high-valued trial proposals.
The goals for the two-day workshop were to:
- Explore the logistical issues involved with performing and funding multi-center cancer screening trials currently and hear from potential stakeholders
- Assess the need for a new cancer screening trial network and discuss how such a network could be optimally set up and managed
- Understand what the scientific community thinks are the highest priority potential technologies/biomarkers that could be moved into trials across a broad range of organ sites
General Screening Trial Challenges
One challenge is deciding the study population. As there is a balance between harms and benefits, it may be advantageous to focus on high-risk individuals for cancer prevention trials. This population has a greater clinical need, shorter duration of time to events and greater motivation to participate. Specialists may provide access to moderate- or high-risk patients; primary care providers may be a source for average-risk trial participants.
Relatedly, because not everyone is equally at risk for different cancers, people need different levels of screening. Adapting screening to risk can improve efficacy and save costs. One approach is to use risk models, like the Tyrer-Cuzick model for breast cancer risk assessment. There are implementation issues with these models, however, like acceptance and infrastructure to collect and use risk information.
Another challenge is determining trial endpoints, which can include biological outcomes and patient-reported outcomes. Cancer is rarely singular in its molecular pathogenesis, which may affect timelines and endpoints.
Recruitment and retention are also challenging. There can be barriers related to targeted communities, health care providers and study design. It is important to approach the recruitment and retention of participants through theoretical perspectives, like the Health Belief Model and social marketing. PLCO successfully recruited participants from minority communities through outreach and educational services. Participants were retained through activities to keep them engaged and frequent contacts.
Another challenge is determining whether a biomarker is ready to move to a clinical utility study. As a first step, it is crucial that the biomarker assay meets appropriate analytic standards. Additionally, the biomarkers must provide diagnostic accuracy and clinical validity — this can be ensured by following the five phases of biomarker development. Finally, data must support the biomarker’s proposed role in the clinical utility trial. Additional details can be found in a 2019 article by Lord et al.
Pragmatic clinical trials offer an opportunity to overcome some of the challenges of cancer screening clinical trials. They take place in real-world settings and can be embedded within a system of healthcare delivery, where evidence feeds back into clinical care. Pragmatic trials can resolve difficulties with accrual experienced in prospective randomized trials and reach large, diverse, longitudinal patient populations. A system at Rush University Medical Center uses risk assessment to guide breast cancer screening, demonstrating the feasibility of this approach for evidence generation and dissemination.
GI Cancer Screening
Colorectal cancer is a significant public health problem. There have been substantial decreases in incidence and mortality in the last 2 to 3 decades, because screening has been effective. There are many recommended screening strategies. While technology for colorectal cancer screening is mature and accepted, there are still opportunities for further clarification. Potential screening intervention trial models are special populations (young, minorities, genetic high risk) and risk-based/personalized screening, like using polygenic risk scores.
Liver cancer is one of the most promising cancers for breakthroughs in screening. Existing screening tests (abdominal ultrasound and serum alpha fetoprotein) have low sensitivity and specificity for early cancers. But since most liver cancers arise in patients with cirrhosis or HBV infection, risk stratification may be possible. Curative treatments are also available. That said, patients with cirrhosis have high cirrhosis-related mortality and can also develop cancer again. Still, new biomarkers are in development, including circulating free tumor DNA. Ongoing studies are also evaluating abbreviated MRI, which is currently expensive but may be cost-effective in high-risk patients.
Esophageal adenocarcinoma is one of the fastest growing cancers of the past four decades. People with Barrett’s esophagus have an increased risk of esophageal cancer. Current screening relies on endoscopy, which is expensive, invasive and reserved for high-risk populations. Alternative noninvasive screening methods amenable to larger studies include the Cytosponge, methylated DNA markers (like EsoCheck/EsoGuard) and liquid biopsy. It would also be beneficial to incorporate multifactorial risk prediction models in studies. Esophageal squamous cell carcinoma occurs less often in the U.S. and there is a lack of effective screening tools, though there are promising targets early in development.
There are over 20,000 cases of gastric cancer each year in the U.S. Endoscopic screening is reserved for high-risk groups. A 2016 modeling analysis found that screening of smokers over 50 years old via serum pepsinogen levels and endoscopy could be cost-effective. Those results need to be validated, however, with a large prospective study.
The goal for pancreatic cancer screening should be detecting stage I pancreatic ductal adenocarcinoma (PDAC), the earliest stages of disease. However, diagnostic imaging is suboptimal and there are issues with screening compliance. Blood biomarkers, including MCED assays and tumor marker (CA19-9, CA125) genotype tests, could help. But current blood tests have low sensitivity for detecting stage I PDAC. Future trials that evaluate alternative screening methods may benefit from studying risk-stratified groups, as well as the Cancer of the Pancreas Screening Study (CAPS) high-risk population being followed at Johns Hopkins.
Prostate cancer screening has been a controversial topic for decades and there are multiple sets of guidelines. To avoid unnecessary (and repeated) biopsies, it is necessary to better identify men at higher risk for clinically significant prostate cancer (Gleason Grade Group 2 or higher), based on family history, race, age and PROMPT genetic score. Also, abnormal PSA should not result in automatic biopsy; instead, it should lead to an MRI or additional biomarker testing. If needed, a “quality” image-guided MRI or micro-ultrasound biopsy should be performed. If cancer is detected, patient and tumor factors should be considered before treatment.
Bladder cancer is the fourth most common cancer in men, but currently has no screening. One sign is hematuria, the presence of blood in the urine. Microhematuria can indicate earlier cancers but it is not evaluated consistently and has low specificity. New trials could incorporate microhematuria plus other biomarkers in an adaptive design focusing on persons with a substantial smoking history.
Breast and Gynecological Screening
Screening for breast cancer has led to the increased detection of localized cancers, but there has also been unnecessary treatment of indolent cancers and little progress toward identifying/screening those at high risk for aggressive breast cancers. Risk-based screening could address these shortcomings. The WISDOM study is comparing annual mammograms to screening frequencies determined by personalized risk profiles and investigating whether risk assessment can guide breast cancer screening and prevention.
Despite improved treatment, there’s still a need for ovarian cancer screening: current 5-year survival is below 50%. In an average-risk population, screening is not recommended, based on the PLCO and UKCTOCS trials. There are exciting biomarkers in the pipeline, including uterine sampling/lavage and circulating free tumor DNA in blood (including MCED tests). Ovarian cancer screening trials are actively evaluating these technologies in mainly average-risk women. There have also been screening trials in very high-risk women, for whom the recommendation is risk-reducing surgery. Future studies should incorporate risk stratification, early detection interventions and treatment. A phased approach could involve validation of new biomarkers for trial inclusion, then a multi-stage, multi-arm randomized controlled trial.
The need for regular screening for endometrial cancer is not yet there in the average population; women with Lynch syndrome are at highest risk. The immediate need for this group is implementation studies of recommended screening. There are no new tests ready for a prospective trial. PapSEEK, a liquid biopsy that identifies cancer-related alterations in DNA in Pap test samples, is promising.
Lung and Oral Cancer Screening
Lung cancer screening with low-dose CT is recommended by the U.S. Preventive Services Task Force for high-risk individuals with a smoking history. However, uptake has been slow. Most unmet needs primarily relate to implementation, but novel approaches to estimate risk and evaluate positive findings are also needed. Trials of existing interventions for evaluation of small and larger nodules are low-hanging fruit to improve screening outcomes. There are also a handful of promising biomarkers to aid in selection of candidates for screening.
Most have completed clinical validation but have not demonstrated clinical utility. Oropharyngeal (OP) cancer is a rare cancer overall. As such, there is no current recommendation for regular screening. Oral human papillomavirus (HPV) 16 is strongly associated with diagnoses of OP cancer. Antibodies to viral protein E6 may be a good biomarker for OP cancer in screening, since it has been associated with diagnosis of OP cancer in several studies. A challenge is that studies would need very large sample sizes, even if just considering the highest risk population.
Prior Network Experience
The PLCO and NLST trials were designed and run by NCI. They were initiated through a contract mechanism and all sites were focused on screening and prevention. Each site had a group of investigators that represented organ sites, as well as clinical epidemiologists and primary care providers. A challenge was that they were long trials, especially PLCO which was over 15 years. The trials worked well and PLCO and NLST could be models of trial organization and management.
NCORP is an academic community partnership that provides access to NCI trials in community settings, to adults and children. The network engages organizations to help reduce potential widening of cancer disparities and presents an opportunity to transition the services-oriented relationship between oncologists and screening disciplines to a research-oriented relationship.
ECOG-ACRIN is an NCORP Research Base and one of the cooperative groups in the NCI’s National Clinical Trials Network (NCTN). The workshop representative from ECOG-ACRIN suggested that a standing network may not be necessary for screening trials. Instead, it may be preferable to get sites on board through a contract mechanism and provide funding for each individual trial, which allows for more flexibility. Others disagreed, stating that writing contracts for each new trial is difficult and slow.