By Deborah Borfitz 

February 8, 2021 | The pandemic has had potentially far-reaching effects on the treatment of cancer patients and conduct of oncology clinical trials, according to panelists presenting at last week’s COVID-19 and Cancer virtual meeting of the American Association for Cancer Research. While the medical community seems to favor extending “interim” policies related to telehealth and study enrollment, it also worries about the unintended consequences of institutional safety precautions—notably, delays in patients getting needed care and the possibility that some at-risk individuals may never return for preventive screens. 

In some respects, organizations over-reacted a bit during the early days of the pandemic since they were dealing with an unknown and unpredictable viral threat, says Jason Luke, M.D., a medical oncologist, immunologist, and trialist at the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center. At UPMC, reserving hospital beds for anticipated COVID-19 patients and temperature-based screening were among the “slowdown measures” quickly put in place last spring. Patients with symptoms were sent home as fast as possible and, since it was not feasible to test everyone, initially it was required only for patients ahead of surgery. 

As elsewhere, COVID-19 admissions came in “waves and peaks” at UPMC, says Robert Ferris, M.D., Ph.D., director of the Hillman Cancer Center and moderator of the panel session. A concerning 180 admissions in April mushroomed to 1,300 cases in one recent month. 

Health systems responded unevenly to the pandemic’s arrival, says Worta McCaskill-Stevens, M.D., director of the Community Oncology and Prevention Trials Research Group (COPTRG) at the National Cancer Institute (NCI). “We saw a lot of testing variability.” 

Staff at the National Institutes of Health (NIH) were sent home in March unless it was “mission-critical” that they remain on campus to do their job, says Michael Kurilla, M.D., Ph.D., director of the division of clinical innovation at the National Center for Advancing Translational Sciences (NCATS), part of the NIH. Only a small proportion of staffers ended up testing positive for the virus, due primarily to community exposure. 

“It has been a slow return to laboratory life,” he adds, with most staff continuing to work from home for the foreseeable future. He personally works out of a non-federal building and shares an entire floor with one other NIH employee.

Year Of Tiers

Among sites in the COPTRG, variability in trial enrollment was first seen on the east coast, says McCaskill-Stevens. Significant capacity issues eventually developed, with sites in the middle of the country hard hit by the virus running out of beds. The NCI “relaxed” some of its trial enrollment policies and allowed investigators to conduct telehealth visits—a practice that advocates hope is sustainable.

Surprisingly, adds Luke, some payers were unwilling to cover televisits. The medical community clearly sees the value of the technology to patient care.

Likewise, physicians have seen how well eConsent works for clinical trials and want to continue using it post-pandemic, says Kurilla. It is a “significant advance,” given that eConsent solutions have been available for years now.

On the reimbursement front, Ferris notes that new payment codes for outpatient visits were released Jan. 1 that de-emphasize physical exams, “which telemedicine visits miss completely.” This could help make payment discrepancies with in-person visits a moot point. 

A bigger concern, in his mind, is that 2020 became the “year of tiers” for cancer populations and trials. Oncology trials are lifesaving for patients with cancer, who typically have exhausted all their standard-of-care options, says Ferris. Stopping trials involving new cancer treatments in favor of those focused on COVID-19 sent the message that they were not as important... [their] armamentarium of treatment options have been taken from [them].”

Oncology trials require an Investigational New Drug application to the Food and Drug Administration, Ferris continues, but not necessarily because the drugs under study are not known to be effective. Typically, the agents are already an approved treatment for a different disease. “I feel like I’m shouting in the wilderness when I bring it up at a group meeting.”

The need for “more resilient” cancer screening modalities is among the lessons learned during the pandemic, says McCaskill-Stevens, echoing another concern expressed by Ferris. The COVID-19 outbreak meant fewer screenings could be done per day, and more people were foregoing preventive tests. One pleasant surprise, she adds, is that many women were still willing to come in for mammograms. 

Scheduling of screens gets complicated with the periodic peaks in COVID-19 cases, McCaskill-Stevens continues. She imagines “things won’t be the same” until at least 2023.

The Last Mile 

Even after the pandemic ends, it could take a while for new technologies like eConsent and remote monitoring to fully take hold because of the “implementation aspect,” says Kurilla. “It takes training, including additional personnel who are facile with that to make it seamless.” 

The advantage of new technologies is that they expand trial opportunities to a broader population, including people in rural communities, he adds. Ensuring the geographic barriers come down for everyone will require accommodating individuals with limited online access. 

For the cancer population specifically, disparities also need to be addressed when it comes to vaccination and screenings, says McCaskill-Stevens. Some cancer patients are reluctant to get a COVID-19 vaccine and doing so could mean deviating from a drug study protocol. 

Many questions about the suitability and safety of available vaccines remain unanswered for oncology patients as well as pregnant women and children under the age of 16, she says. As with influenza shots, the COVID-19 vaccine will also need to stay up to date as viral variants emerge. The “last mile” of getting vaccines into people wo really need them will require deliberate effort and standardized approaches. 

It would be helpful if professional societies would endorse vaccinating people being treated for cancer, says Luke. After all, patients are routinely advised to get their annual flu shot. 

While the Moderna and Pfizer/BioNTech COVID-19 vaccines are new, “we’re not completely flying in the dark here,” he adds. Researchers have been working with messenger RNA vaccines for decades and melanoma patients have recently been treated with anti-PD-1 monoclonal antibodies which, like the new COVID-19 vaccines, seek to trigger an immune response. There is no reason to think vaccination is not a good idea, Luke says. 

Vaccine skeptics include people working in the health system, says Ferris. At UPMC, “up to 20%” of employees offered a COVID-19 shot in December opted out. He was asked to bare his newly vaccinated, bandaged arm to encourage others to follow his lead.

Churches in the African American community have previously been recruited to participate in clinical research and some are now trying to help spread the word about the importance of vaccination, says McCaskill-Stevens. But it is too early to gauge the effectiveness of the approach.

Improving Trial Design

It also remains to be seen if pandemic-inspired changes to trial design will stick. 

A phase 1 trial is all many cancer patients want because it is their last hope, says Luke, but accessing one during the pandemic has been difficult when hospital beds are being reserved for COVID-19 patients or protocols stipulate that they be monitored for six to eight hours at a stretch. Studies have been amended to shorten the usual observation periods, but it is unclear how long regulatory and ethical authorities will allow less aggressive monitoring during early-phase trials. 

Luke is the principal investigator for an international adjuvant trial for melanoma and many patients do not want to return to the hospital post-surgery, which has hurt accrual, he says. Research with adjuvants requires a lot of visits and the goal is to reduce the risk of melanoma returning rather than treating current disease. 

While patients are unlikely to contract COVID-19 at the hospital or doctor’s office, says Luke, the drive to and from a trial site could introduce risk if it involves stopping for gas or food.  Identifying and permanently eliminating the collection of unnecessary data points could reduce the burden of participation and perhaps eliminate some study visits entirely.

McCaskill-Stevens concurs, saying she is hopeful trials in the future will be limited to the data points that matter. Longitudinal COVID-19 studies have been asking for an inordinate number of labs as well as information on social determinants of health.

Investigators in the future will be able to use results coming out of the National COVID Cohort Collaborative (N3C) to improve trial design, says Kurilla. N3C is a partnership among the NCATS-supported Clinical and Translational Science Awards Program that he oversees and the National Center for Data to Health. Collaborators are contributing and using COVID-19 clinical data to answer critical research questions to address the pandemic.

The centralized dataset is being created by harmonizing and aggregating electronic health records, Kurilla says. “There are over half a million COVID patients in the database and the data gets refreshed every two weeks.” At that pace, the final tally will be over one million COVID patients. Over 100 research projects address COVID-19 in cancer patients.

Preventive Screens

The medical community has been thinking seriously about creating a tiered process for preventive cancer screens, and “taking advantage of newer technologies like liquid biopsies and at-home screening tests,” says McCaskill-Stevens. People at low risk for colon cancer could potentially be screened at home with Cologuard versus going under for a colonoscopy, for example. 

Kurilla says development of rapid COVID-19 tests will be particularly impactful. Traditional PCR assays have good sensitivity and specificity but the turnaround time on results is days rather than minutes. At some locations, COVID-19 screening procedures involves little more than checking for fever, which is of limited utility since many infected individuals never get one.

Patients could be better informed that they will not contract COVID-19 at the hospital, suggests Luke. He says he has seen a shift toward deferring skin cancer screening, a worrying trend given that a six-month wait could be deadly for anyone with undiagnosed melanoma. 

Part of the problem is that people may have other obligations, including care of children or parents, making it difficult to get to screenings, says Ferris. “We’re back to 95% volume, but there’s a subset of folks who do not access the system anymore.”

Many Unknowns

Patients with hematologic cancer appear to be at higher risk of poor outcomes if they contract COVID-19, says Luke, so “we don’t let them go anywhere.” They should probably also not be vaccinated if they are neutropenic, he adds.

Luke says he does not believe concerns about immunotherapies causing pneumonitis (a COVID-like manifestation) in patients with solid tumors is on par with the actual risk, based on available data. But he advocates for getting them vaccinated as soon as possible and, if that causes a study protocol deviation, so be it.  

Cancer patients need to be encouraged to get vaccinated, says McCaskill-Stevens. Organizations also need to be following up on patients who had a fever and were instructed not to come in. 

“We need to be prepared for a lot of the unknowns with COVID,” says Kurilla. “The consequences of natural immunity are largely unanswered,” as is the association of anti-interferon and prothrombotic antibodies with severe lung disease. “Does COVID predispose us to other things not anticipated? We need to be watchful.”

From the perspective of science, it is ideal to be “as homogenous as possible” to tease out findings from trials, Kurilla adds. “But we always deal with heterogenous populations. We can’t lament the fact we can’t get rid of that.”

Yet to be answered is a question posed by Ferris about what should happen when cancer patients in a clinical trial contract COVID-19: When do they get the “all clear” to re-enter the study?