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3 Questions on…

Answers straight from the experts on the latest news and topics in oncology

Monday, November 5, 2018

With Anna Dorothea Wagner, MD, of the Lausanne University Hospital in Switzerland

By Sarah DiGiulio

Precision medicine is a hot topic in oncology right now. Check any oncology meeting schedule and you'll likely find at least one session on the topic. It makes sense. It's the idea that treating different patients with the same therapeutic approach may not result in the same outcome—given their genetics, their previous health status, their psychosocial needs, and numerous other factors.

And one of those factors that deserves a lot more attention is gender, according to Anna Dorothea Wagner, MD, an oncologist at the Lausanne University Hospital in Switzerland. She recently co-authored a comment within the "Comments and Controversies" section of the Journal of Clinical Oncology to bring more awareness to the issue of identifying sex differences in clinical trials (2018;36:2680-2683).

"Sex may have an impact on the efficacy and toxicity of all kinds of drugs," she told Oncology Times. "We need to learn more about it."

For some drugs (like 5-fluorouracil [5-FU], for example), evidence clearly shows there's more toxicity when used in women compared with men, she noted. But for other drugs, it's unknown (JAMA Oncol 2018;4:1003-1006). "And we need to learn more about it."

Other data show that women are at higher risk of things like mucositis, nausea and emesis, and alopecia when they take certain cancer drugs for several types of cancer, Wagner and her coauthors noted in the study. For other drugs, there's evidence sex differences may change how well the drugs work in treating some cancers. And there's more evidence still that gender may affect tumor biology, which could mean that developing sex-specific strategies for treatment (in terms of dose and types of drug) might improve outcomes.

Wagner told Oncology Times why the issue warrants attention and what she suspects effective next steps will be.

1. Why did you decide to write this editorial with your coauthors and why now?

"I work as a gastrointestinal oncologist and see many patients. I had several women, especially women with pancreatic cancer who had been treated with FOLFIRINOX (but after other treatments, too), who had major side effects—not only nausea and vomiting, but fatigue, diarrhea, and hematological toxicities, too.

"It was those clinical observations, and the suspicion of greater toxicities in women. I wondered why this was the case. These were patients in their 50s, motivated and dynamic, and in many cases managing full-time jobs [and/or] kids, who became too weak to leave [their couches] for at least 1 week after the treatment, and even in the second week they were too tired to do anything.

"They had no other reasons to develop such major side effects. So I suspected finally that it might be their sex. I looked in the literature and found some—but overall little—data on sex differences in side effects from chemotherapy.

"We then did a [secondary] analysis of the PETACC-3 trial, which confirmed the observation of significant higher toxicities in women for both 5-FU and FOLFIRI (JAMA Oncol 2018;4:1003-1006). The more I learned about the topic, the more interesting it became."

2. In your opinion, what are some of the reasons that sex differences have not been well-investigated in cancer research, particularly in terms of treatment and treatment efficacy?

"The discipline which systematically analyzes sex differences is gender medicine. For example, in Berlin and Vienna, medical faculties have a chair for Gender Medicine. At Stanford University, there is the Gendered Innovations in Science, Health & Medicine, Engineering, and Environment (to 'harness the creative power of sex and gender analysis for innovation and discovery,' according to the department's website).

"I think oncology could benefit significantly from this approach.

"The pioneer in gender medicine, Marianne Legato, MD, PhD, was a cardiologist. Following her initiative, much has been learned in the field of cardiology. In oncology, this work needs to be done. We just have not yet had the pioneers in this field."

3. The FDA and NIH have made some efforts in defining guidelines for participation in clinical trials. Why have previous steps not been significant enough to push the needle when it comes to this issue?

"They have certainly made important steps, but more remains to be done. The founding of the U.S. Department of Health and Human Services Office on Women's Health is an important step.

"However, the focus on women's health is not enough. I am not sure if that office will consider the question: for a drug with higher efficacy and a higher, but still acceptable toxicity in women, the dose in men might need to be increased to achieve a similar level of efficacy.

"The point is that what is the optimal treatment for a man might not necessarily be the optimal treatment for a woman. Current medical research needs to take this into account.

"Large databases which analyze systematically the effect of a patient's sex on all types of outcomes—efficacy and toxicity—are needed. If such differences are detected, they need to be correlated with pharmacokinetic data. As a function of the results, dose modifications according to sex may need consideration."

Monday, October 22, 2018

With Todd Pickard, MMSc, PA-C, DFAAPA, Director of Physician Assistant Practice at MD Anderson Cancer Center and Chair of ASCO's Workforce Advisory Group

By Sarah DiGiulio

The numbers of advanced practice providers involved in oncology is quickly growing. The number of U.S. oncology practices who've reported employing advanced practice providers has jumped from 52 percent in 2014 to 81 percent in 2017, according to ASCO's annual Practice Census Survey (J Oncol Pract 2018;14:e412-e420).

To better understand the role and scope that these advanced practice providers—including nurse practitioners and physician assistants—play in cancer care, several major health groups collaboratively conducted and published a survey to identify such providers. The data was published in the Journal of Oncology Practice (2018;14:e518-e532).

"There has been a great deal of interest in the role of advanced practice providers in oncology, but a limited understanding of how many advanced practice providers practice in this area, what services they provide, what influences their practice, and how they are compensated," survey co-author Todd Pickard, MMSc, PA-C, DFAAPA, Director of Physician Assistant Practice at The University of Texas MD Anderson Cancer Center and Chair of ASCO's Workforce Advisory Group that worked on the survey, shared with Oncology Times.

The collaboration included ASCO, the American Academy of Physician Assistants (AAPA), the Association of Physician Assistants in Oncology (APAO), the Advanced Practitioner Society for Hematology and Oncology (APSHO), and the Oncology Nursing Society.

"There has been a well-published disconnect between demand for oncology services and the supply of providers available to meet this growing demand," Pickard said. "One of the solutions to close this gap between supply and demand is the addition of advanced practice providers as oncology providers and integration into the care team.

"Oncology practices have real-world needs to respond to their communities and advanced practice providers have been a valuable resource to meet these needs. It simply makes sense that this growth has occurred and will likely continue," he added.

The analysis identified 5,350 advanced practice providers currently working in oncology, though the paper notes there could be as many as 7,000. The data also includes information about the demographics of those providers, as well as the roles they play and challenges they face.

According to the paper, it is the first detailed examination of advanced practice providers in oncology. Pickard further explained what the new data revealed.

1. What findings stood out to you?

"Several items stand out: 1) It is still very difficult to get a true 'census' of advanced practice providers in oncology due to limitations in how they are accounted for in the health care system. Many times their contributions are hidden in co-managed work and billing data that is attributed to our physician colleagues.

"2) Advanced practice provider practice in oncology is heavily influenced by physician preferences rather than patient care demands or standardization of the advanced practice provider role.

"3) Advanced practice providers in oncology have unique educational needs to ensure that they are fully prepared to provide the complex care of the oncology patient. ASCO, APSHO, APAO, and AAPA have worked to create in-person meetings, web-based learning, and other medical knowledge tools to meet these needs.

"4) There has been a very rapid growth and wide acceptance of the advanced practice provider in oncology since 2014."

2. How is the increasing presence of advanced practice providers in oncology care changing how care is delivered?

"The growing presence of advanced practice providers in oncology has created several opportunities for increasing patient access to care, quality of care, coordination of care, new services for cancer survivors, and safer care. When you have a fully integrated care team of physicians, advanced practice providers, nurses, pharmacists, social workers, and business/office staff, the team is positioned and resourced to provide the entire spectrum of care for oncology patients.

"This care is incredibly complex and relies on the knowledge, skills, and engagement of the entire team. Advanced practice providers fit perfectly into the area of need.

"They are flexible providers that can move quickly to fill in needed coverage of clinical appointments, perform procedures, educate patients, supervise chemotherapy treatments, manage symptoms, coordinate care across the health care system, and provide survivorship care."

3. What are the implications of these findings and what's most important for practicing oncologists and all cancer care providers to know about this research?

"This is great news for oncology physicians. They have the opportunity to work with advanced practice providers who can become critically important and valuable members of the team that improve the care for patients with cancer. Advanced practice providers have a proven track record in oncology and this enables physicians to understand and embrace [their] role in oncology.

"Advanced practice providers have a critical role in the delivery of oncology care that brings value, quality, and safety to those we serve. Advanced practice providers are focused on team-based care that is perfectly suited to the complex care of the patient with cancer."

Friday, October 5, 2018

With Emily Largent, PhD, JD, RN, at the Perelman School of Medicine at University of Pennsylvania

By Sarah DiGiulio

In a recent JAMA Oncology Viewpoint article, two medical ethics experts from the University of Pennsylvania argue it's time to revise how we reimburse and incentivize cancer clinical trial participation (2018;4:913-914).

The authors—Emily Largent, PhD, JD, RN, Assistant Professor, and Holly Fernandez Lynch, JD, MBe, Assistant Professor and Assistant Faculty Director of Online Education, both in the Department of Medical Ethics and Health Policy at the Perelman School of Medicine at University of Pennsylvania—say reimbursement for clinical trial-related expenses will help make access to investigational drugs and treatments more equitable. In particular, access will be fairer for people of lower socioeconomic status (as trial participants often incur out-of-pocket expenses for supportive care that is not covered by the trial sponsor). Such expenses may be for travel and lodging for the purpose of participating in the trial, as well as copayments, co-insurance, and deductible payments associated with usual care received over the course of a trial.

FDA policy does not discourage reimbursement to patients for clinical trial-related expenses, and a recent policy update explicitly states it's not coercive or unduly influential to do so. Largent and Lynch suggest, however, that this stand is too narrow—and there are other permissible uses for payment including compensation for time and effort, as well as incentives to encourage patients to participate in clinical trials.

Some states have considered passing state-level laws that clarify that reimbursement of clinical trial-related expenses (such as travel and lodging) is not coercive, which, according to Largent and Lynch, is appropriate.

Oncologists and cancer care providers can (and should) be advocates for addressing these barriers to clinical trial participation, Largent explained. "People need to be aware that clinical trials are not 'free'—but the research is incredibly important."

Here's what else Largent told Oncology Times about the issue.

1. What prompted you to write this editorial and why is the issue so important now?

"This issue came to my attention because I live in a state (Pennsylvania) that is currently considering such an act [that would clarify that reimbursement for clinical trial-related expenses is not coercive]. I have been working on issues related to paying research participants for years—and most attention is focused on issues of payment at the federal level. So, this felt like a novel approach.

"A lot of cancer trials fail to enroll the target number of participants. In extreme cases, the trial may have to close prematurely; in other cases, there may be less statistical power to answer the questions of interest. If we could address financial barriers to trials, we might be able to recruit more people into trials.

"In addition, a common concern is that we want to distribute the burdens and benefits of clinical trial participation evenly over the population—and addressing financial barriers may help ensure that this distribution of burdens and benefits is more even."

2. What are the costs of participating in a clinical trial?

"There isn't typically an 'entry fee' to be enrolled in a clinical trial. And, in many cases, the investigational drug or experimental intervention will be paid for by a sponsor; and usual care will be covered by the insurer.

"However, individuals may still have to pay for travel and lodging or assume increased copayments and deductibles (on the usual care). These expenses may not be immediately obvious to trial participants but can be significant.

"People often talk about the 'financial toxicity' of cancer therapy—that is, treatment-related financial hardship. But there is increasing evidence that participating in cancer clinical trials can have additional financial toxicity, and that is not something that is discussed enough. Participating in clinical trials can require patients to assume out-of-pocket costs, such as travel and lodging for study visits or increased copayments and deductibles. This expense can be a barrier to trial participation for a lot of people."

3. Your editorial explains several options to incentivize clinical trial participation by offering payment from expense reimbursement to compensation. What do you think is the best option?

"I think that the default should be reimbursing people for out-of-pocket expenses and offering compensation for their time and effort. Although I think this is possible within existing regulations, institutional review boards may be hesitant to do this out of fear that offering payment will distort the patient's decision about whether or not to participate in research. So, it would help for the Office of Human Research Protections and the FDA to further clarify that offering payment is acceptable and even desirable. This might calm some anxiety around payment, which is an important first step."

Friday, September 21, 2018

With Lindor Qunaj, BSc, of the Warren Alpert Medical School of Brown University

By Sarah DiGiulio

If a clinical research trial showed that an oncology drug you were prescribing to your patients had a previously unrecognized adverse side effect, how soon would you want to know? Would you prefer to know as soon as the data was available—or 300 days later?

Oncologists and other members of the cancer care team would presumably want that information sooner rather than later to be able to more appropriately prescribe those drugs and take care of their patients. But new data that reviewed 100 pharmaceutical company-sponsored clinical trials shows that the median delay from when results are available to publication of complete data was 300 days, with negative findings taking longer to reach the public. The study was recently published online in JAMA Oncology (2018; doi:10.1001/jamaoncol.2018.0264).

"The complete and timely dissemination of clinical trial data is essential to all fields of medicine, with delayed or incomplete data release having potentially deleterious effects on both patient care and scientific inquiry," the researchers noted in the study. "Even for the most pressing study findings, median publication delays approach 1 year."

The median delay for trials reporting negative trial data was 407 days. Though previous studies have investigated delays in the publication of clinical trial data, this new study used novel criteria for selecting trials for the analysis. The researchers only looked at phase III industry-sponsored trials for which the drug company had issued a press release about the results.

"Industry-sponsored phase III trials examining novel therapeutics have some of the greatest potential to shape practice guidelines and research programs in oncology," explained study coauthor Lindor Qunaj, BSc, a medical student at the Warren Alpert Medical School of Brown University. "These studies also offer a clear proxy—in the form of a press release—for the time at which data is sufficiently processed to draw a directional conclusion."

The study measured the duration from when a press release announcing trial findings was issued until that data were posted on ClinicalTrials.gov or published in a medical journal.

The eight drug companies from which sponsorship of the clinical trials analyzed in this study come collectively accounted for 72 percent of all oncology drug sales in 2015, according to the study.

In an interview with Oncology Times, here's why Qunaj says these findings are so important.

1. What were the key findings from this new research and why are they so important now?

"Even for clinical trials expected to have an important effect on patient care and scientific innovation in the field of oncology, delays in meaningful data release are considerable. These delays are significantly longer for studies reporting negative (compared to positive) results.

"Delayed or incomplete release of clinical trial results forces providers to make treatment decisions based on limited information, potentially putting patients at risk of newly discovered toxicities—or not offering interventions that may prolong survival.

"It also causes companies and researchers to shape their research agendas with incomplete data, which can lead to duplicative studies and slow the overall pace of medical innovation. Our study sought to better characterize the magnitude of these delays."

2. Given the delays in the publication of clinical trial results that you've identified, what's the next step in moving the needle to actually improve the situation?

"Our research suggests the scientific community has a long way to go in improving the speed and completeness of clinical trial data releases. We recommend 1) placing a greater emphasis on prepublication, and 2) more strictly enforcing data posting requirements on databases, such as ClinicalTrials.gov, as two potential approaches for change. But we recognize that these suggestions are just a start.

"Any strategy designed to facilitate rapid and thorough data dissemination will need to secure buy-in from journals, regulatory agencies, conference organizers, and industry sponsors to be broadly effective. Because these varied stakeholders often have competing interests, creating integrated solutions may be difficult, but should be a priority—not just in oncology—but across the biomedical community. In the meantime, both patients and the pace of scientific innovation will continue to be negatively affected."

3. Do you plan to do any follow-up investigation in this area?

"A natural follow-up from our study would be to estimate the effect data delays have on patient outcomes. How many patients are being treated with incomplete information each day, and how would their management have differed if that information were available? While these calculations would be decidedly difficult to perform, the conclusions could serve as even more convincing arguments for systemic policy change."​

Wednesday, September 5, 2018

With Sheila Prindiville, MD, MPH, Director of the Coordinating Center for Clinical Trials at NCI

By Sarah DiGiulio

The NCI and the Department of Veterans Affairs (VA) recently announced an agreement that outlines specific ways the agencies will collaborate to boost veterans' access to cancer clinical trials.

The initiative is called NAVIGATE, which stands for the NCI and VA Interagency Group to Accelerate Trials Enrollment. And a key facet of the agreement is that NCI will provide more infrastructure to help the VA better participate in NCI-sponsored trials.

NAVIGATE will also allow for more VA investigators to be involved in clinical cancer research and provide more opportunities for these investigators to determine what research is needed, including ones of particular importance to veterans with cancer.

"This agreement will not only provide veterans greater access to NCI clinical trials, it will enhance accrual to NCTN [National Clinical Trials Network] and NCORP [NCI Community Oncology Research Program] trials, resulting in more timely completion of these studies. This interagency collaboration will also work to help veterans overcome barriers they've faced trying to access clinical trials as part of their cancer care," noted James H. Doroshow, MD, NCI's Deputy Director for Clinical and Translational Research, in a press release.

In the recent agreement, NCI and the VA agreed to jointly manage the new program for up to 3 years. The participating sites are expected to establish best practices and share insights as they go to help other VA sites nationwide initiate new research and increase veteran enrollment in cancer clinical trials.

In an interview with Oncology Times, Sheila Prindiville, MD, MPH, Director of the Coordinating Center for Clinical Trials at NCI, explained more about the goals and specifics of the program.

1. What is NAVIGATE and how will it change how NCI and the VA work together on cancer clinical trials?

"NAVIGATE is a partnership between NCI and the VA to make it easier for veterans to access state-of-the-art treatments through NCI-supported clinical trials directly at VA sites, rather than seeking treatment outside of the Veterans Health Administration.

"It's a 3-year collaboration between NCI and the VA to facilitate enrollment of veterans into NCI-funded clinical trials. It's also an opportunity for government agencies long committed to veterans' health to partner at the national level to make clinical trials more accessible. This strategic partnership was prompted by the observation that fewer veterans were participating in NCI-supported clinical trials than in the past. One of the reasons identified was the lack of infrastructure support for dedicated clinical research staff.

"NAVIGATE is a win–win initiative. It will make it easier for veterans with cancer to receive the newest treatments and increase their participation in NCI-supported clinical trials. The increased participation should allow the trials to be completed more quickly and new treatments to become available sooner."

2. But the VA had already been conducting clinical trials in cancer. Can you explain how the agency had been collaborating with NCI, if at all?

"The VA offers clinical trials in many disease sites, including cancer. Historically, the VA had a role in the establishment of multisite clinical trials for evidence-based practice starting in the 1940s. The [agency] conducts cancer clinical trials sponsored by the NCI, as well as [trials sponsored by] other organizations such as industry, academia, and other partners. The VA will continue to conduct trials with these partners, including NCI, as it has done in the past.

"What is new is that NCI is providing funding to the VA through NAVIGATE so that sites have support for dedicated research coordinators specifically for NCI-funded trials. Additionally, the program will utilize a centralized approach coordinated by the VA Cooperative Studies Program to address site-level and system-wide challenges to trial activation and enrollment."

3. Can you share any specifics about how NAVIGATE is being rolled out?

"Twelve VA sites are participating in the program and will receive funding for dedicated clinical research staff to assist with the conduct of clinical trials. At each site, a VA principal investigator will oversee the NAVIGATE activities.

"The VA Cooperative Studies Program, Office of Research & Development, and the NCI Coordinating Center for Clinical Trials will provide coordination and management for NAVIGATE.

"A steering committee consisting of VA and NCI staff will use a centralized approach to address system-wide and site-level challenges to trial activation and enrollment.

"An executive committee consisting of NCI, VA, and NCTN senior leadership will monitor the overall progress and direction towards meeting the NAVIGATE program goals."