Erdafitinib gets Breakthrough Therapy designation for metastatic urothelial cancer

Drugs and Targets

Erdafitinib gets Breakthrough Therapy designation for metastatic urothelial cancer

FDA has granted Breakthrough Therapy Designation for erdafitinib in the treatment of urothelial cancer. 

The drug is sponsored by Janssen Pharmaceutical Companies of Johnson & Johnson.

The designation is based on data from a multicenter, open-label phase II clinical trial evaluating the efficacy and safety of erdafitinib in the treatment of adult patients with locally advanced or metastatic urothelial cancer, whose tumors have certain fibroblast growth factor receptor genetic alterations.

The phase II study BLC2001 presented at the 2018 ASCO Genitourinary Cancers Symposium showed an overall response rate of 42 percent in 59 patients with relapsed/refractory metastatic urothelial cancer whose tumors harbored actionable FGFR mutations (ASCO-GU abstract #411).

Erdafitinib is an oral pan-fibroblast growth factor receptor tyrosine kinase inhibitor being evaluated by Janssen in phase II and III clinical trials in patients with advanced urothelial cancer. In 2008, Janssen entered into an exclusive worldwide license and collaboration agreement with Astex Therapeutics Ltd. to develop and commercialize erdafitinib.


FDA grants priority review to Merck’s sBLA for Keytruda for advanced cervical cancer

FDA has accepted a supplemental New Drug Application  and granted priority review for Keytruda  (pembrolizumab), an anti-PD-1 therapy.

The drug is sponsored by Merck.

The application seeks approval for Keytruda as a treatment for patients with advanced cervical cancer with disease progression on or after chemotherapy. This is the first filing acceptance and priority review granted for an anti-PD-1 therapy in cervical cancer and the 14th regulatory submission accepted by the FDA for Keytruda. The FDA has set a target action date of June 28, 2018.

The application, which is seeking accelerated approval for this new indication, is based in part on data from the phase II KEYNOTE-158 trial. KEYNOTE-158 is an ongoing global, open-label, non-randomized, multi-cohort, multi-center study evaluating Keytruda in patients with multiple types of advanced solid tumors that have progressed on standard of care therapy.

Merck said it’s executing an extensive clinical development program in a broad range of cancers that affect women. To date, the program includes numerous studies evaluating Keytruda (pembrolizumab) as monotherapy or in combination with other anti-cancer treatments across various types of breast and gynecological cancers.

ASTRO issues updated clinical guideline for whole breast radiation therapy

Clinical Roundup

ASTRO issues updated clinical guideline for whole breast radiation therapy

The American Society for Radiation Oncology issued a clinical guideline for the use of whole breast radiation therapy for breast cancer that expands the population of patients recommended to receive accelerated treatment known as hypofractionated therapy.

With hypofractionated WBI, patients receive larger doses of radiation across fewer treatment sessions—typically completing treatment in three to four weeks, compared with five to seven weeks for conventional treatment.

Reflecting current evidence from clinical trials and large cohort studies, the new guideline recommends hypofractionated WBI for breast cancer patients regardless of age, tumor stage and whether they have received chemotherapy. It replaces the existing ASTRO WBI guideline published in 2011.

“Previously, accelerated treatment was recommended only for certain patients, including older patients and those with less advanced disease, but recent long-term results from several large trials strongly support the safety and efficacy of accelerated treatment for most breast cancer patients,” said Benjamin Smith, co-chair of the guideline task force and an associate professor of radiation oncology at the University of Texas MD Anderson Cancer Center in Houston. “Conventional therapy does not provide an incremental benefit in either tumor control or side effects compared to hypofractionated WBI.”

Despite the data supporting accelerated treatment, large numbers of eligible breast cancer patients are not receiving shorter courses of radiation therapy. A 2013 JAMA study found an adoption rate of approximately 30 percent, and a 2017 analysis for Kaiser Health News indicated that fewer than half of patients over age 50 with early-stage disease receive the accelerated treatment.

The guideline provides clinical guidance for dosing, planning and delivering WBI with or without an additional “boost” of radiation therapy to the tumor bed. Full recommendations and supporting evidence are provided in the guideline.

Delivery and Dosing of WBI

Treatment decisions, including decisions between hypofractionated and conventional approaches, should be individualized to each patient and shared between the patient and their physician(s).

For women with invasive breast cancer receiving WBI with or without inclusion of the low axilla, the preferred dose-fractionation scheme is hypofractionated WBI to a dose of 4000 Centigray (cGy) in 15 fractions or 4250 cGy in 16 fractions.

The decision to offer hypofractionated therapy should be independent of the following factors: tumor grade; whether the tumor is in the left or right breast; prior chemotherapy; prior or concurrent trastuzumab or endocrine therapy; and breast size, provided that homogenous dosing can be achieved.

It may be independent of the following factors: hormone receptor status; HER2 receptor status; margin status following surgical resection; and age.

For patients with DCIS, hypofractionated WBI may be used as an alternative to conventional fractionation.

Radiation Boost

All decisions related to use and dosing of the boost should be discussed between the patient and provider(s) and consider individual patient, tumor, and treatment factors. These decisions also should be independent of whether the patient received conventional or hypofractionated WBI.

For invasive cancer cases, a tumor bed boost is recommended for patients with a positive margin following surgical resection, patients age 50 and younger, and patients age 51 to 70 if they have a high-grade tumor. Omitting a tumor bed boost is suggested for patients with invasive cancer who are older than 70 and have low-to-intermediate-grade, hormone-positive tumors resected with widely negative margins.

For DCIS, a boost is recommended for patients age 50 and younger, patients with high-grade tumors and/or those with positive or close margins following resection. A boost may be omitted for patients with DCIS who are older than 50; have been screen detected; have smaller, low-to-intermediate grade tumors; and have widely negative margins following surgery.

Recommendations for boost dosing, sequencing and radiation delivery techniques are outlined in the guideline.

Preferred Techniques for Treatment Planning

Treatment plans should be individualized after consideration of many factors, including tumor characteristics, patient anatomy and comorbidities.

Three-dimensional conformal treatment planning with a forward planned, field-in-field technique is recommended to achieve homogenous radiation dosing and full coverage of the tumor bed.

Approaches that incorporate deep inspiration breath hold, target and organ-at-risk contouring and optimal patient positioning are recommended to minimize the radiation dose affecting nearby organs and normal tissue, including the heart, lungs and opposite breast.

The guideline was based on a systematic literature review of studies published from January 2009 through January 2016. A total of 528 abstracts were retrieved from PubMed, and the 100 articles that met inclusion criteria were evaluated by a 15-member task force of radiation oncologists who specialize in breast cancer, a medical physicist and a patient representative.

The guideline was approved by ASTRO’s board of directors following a period of public comment. The guideline has been endorsed by the Royal Australian and New Zealand College of Radiologists and the Society of Surgical Oncology.


Testicular cancer survivors need screening for long-term heart disease risk

A newly-published study shows many remain at risk for later complications from chemotherapy or other treatments. The study in the Journal of the National Comprehensive Cancer Network confirms testicular cancer survivors are more likely to develop high blood pressure, high cholesterol, and obesity, which can significantly increase their risk of heart disease.

The Platinum Study, which was funded by the National Cancer Institute, is the largest study to examine the rates of metabolic abnormalities among testicular cancer survivors who received prior platinum-based chemotherapy, and the only study using North American patients, rather than European. 

For the study, MetS was defined by the standard medical criteria of three or more of the following conditions: hypertension, abdominal obesity, hypertriglyceridemia, decreased levels of high-density lipoprotein, and diabetes.

The researchers evaluated 486 testicular cancer survivors, with a median age of 38.1 years, and found they were more likely to have hypertension than their cancer-free peers, (43.2% vs. 30.7%, P<.001), but were less likely to have lower levels of “good cholesterol” (23.7% vs. 34.8%, P<.001), or abdominal obesity (28.2% vs. 40.1%, P<.001).

As for other potential heart disease risk factors, testicular cancer survivors were significantly more likely to have higher amounts of low-density lipoprotein (17.7% vs. 9.3%, P<.001), higher overall cholesterol levels (26.3% vs 11.1%, P<.001), and be classified as overweight based on their body mass index (75.1% vs. 69.1%, P=.04).

“Testicular cancer survivors whose treatment included chemotherapy, radiation therapy, or both have an increased risk of dying from cardiovascular disease,” said Timothy Gilligan, vice chair for education & associate professor of medicine, Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute. “This study provides valuable information as we try to understand why. It also serves as an important reminder for appropriate long-term healthcare after completing cancer treatment, as detailed in the NCCN Guidelines for Survivorship.”

“The overarching goal of our study is to implement early interventions in order to reduce the risk of heart disease,” said Abu Zaid. “At this time, there are no criteria for determining what exactly causes metabolic syndrome in cancer survivors. Developing those criteria requires long-term follow up of cancer survivors, which is something we’ll be doing as part of this ongoing Platinum Study. This will help us understand which risk factors are more likely to lead to heart disease for this particular population.”

The researchers encourage providers to screen and adequately treat testicular cancer survivors for hypertension, dyslipidemia, and hypogonadism, and to advocate for the adoption of healthy lifestyle practices like regular exercise and tobacco avoidance.

They also recommend that young testicular cancer survivors discuss the risks and benefits of testosterone replacement therapy with their physicians. Testicular cancer survivors with abnormally low testosterone levels may experience fatigue, low energy, and decreased sexual desire. In addition, they can be at risk for metabolic syndrome, decreased muscle mass, fragile bones, and potentially heart disease.

“Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors” can be found here.

Rare Cancers, Common Need

Trials and Tribulations

Rare Cancers, Common Need

Sandip Patel

Sandip Patel

S1609 DART clinical study chair

Assistant professor of medicine, UC San Diego Cancer Center

Assistant director, Clinical Trials Office, Moores Cancer Center

Investigator, SWOG early therapeutics and rare cancers committee 


Young Kwang Chae

Young Kwang Chae

S1609 DART translational medicine study chair

Assistant professor, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine

Co-director, Developmental Therapeutics – Lurie Cancer Center

Vice chair, SWOG early therapeutics and rare cancers committee


Razelle Kurzrock1

Razelle Kurzrock

S1609 DART senior study chair,

Senior deputy center director, Moores Cancer Center

Chief, Division of Hematology and Oncology, UC San Diego

Chair, SWOG early therapeutics and rare cancers committee 


Cancer immunotherapy, and in particular immune checkpoint blockade, has transformed oncology with the potential for durable responses even in patients with metastatic disease. To date, regulatory approvals and clinical trials have focused on the study of these agents in relatively more common tumor types, such as melanoma, non-small cell lung cancer, bladder cancer, and kidney cancer, amongst others.

Efficacy for immune checkpoint blockade, in particular therapies that target the CTLA-4 and PD-1 axes, has also been demonstrated in some rarer tumors such as Merkel cell carcinoma and across microsatellite-unstable tumors.

However, the vast majority of rare cancer histologies, which collectively represent almost a quarter of all cancers diagnosed worldwide, are generally not included in clinical trials and the efficacy of immune checkpoint blockade in these patient populations is unknown.

Additionally, rare cancers present a disproportionate burden on younger patients, particularly patients 40 years old and younger. Finally, rare tumors segregate across organ systems and traditional tumor classification schema, and patients are often left searching for both expertise and clinical trials for their rare cancer, for which there exist few resources. Due to these factors, rare cancers are traditionally understudied from both a clinical and basic science standpoint, despite their substantial burden on society.

Given the profound potential of immunotherapy in other cancer types, the idea for a basket rare tumor immunotherapy study grew from a potential investigator-initiated trial collaboration across our institutions (UC San Diego, Northwestern) to a clinical trial managed by SWOG and supported by the National Cancer Institute and its Cancer Therapy Evaluation Program.

Known as S1609 or Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART), the SWOG trial is a basket immunotherapy study testing the effects of nivolumab and ipilimumab across a myriad of rare tumor histologic subtypes. Rare cancers, for the purposes of this study, are defined as diseases with an incidence of less than 6 in 100,000 per year.

DART in its current form is the only public basket rare tumor immunotherapy study available—currently featuring 37 rare tumor subtypes with the flexibility to add additional rare tumors. So far, we are seeing strong interest and accrual to the trial. To date, over 340 patients have enrolled on the study, which means DART has cleared the halfway point in its initial form, averaging two accruals a day.

Over 750 sites have opened DART, demonstrating the need for studies to address the burden of rare cancers with novel immunotherapeutics. The rapid accrual to DART proves false the notion that rare cancer studies are not feasible, and provides a framework by which future studies of rare tumors can be explored.

In addition to the central question of DART, evaluating the clinical efficacy of nivolumab and ipilimumab in rare tumors, the study has a number of important translational medicine objectives that use the NCI’s newly formed Cancer Immune Monitoring and Analysis Centers (CIMACs) to perform whole exome sequencing, transcriptomics, and immune cell profiling to interface with multimodal exploratory cfDNA, proteomic, and immunohistochemical approaches.

This constellation of translational medicine correlatives will provide unique insights into a number of rare tumor types, many of which have not been studied previously, with the goal of both deriving novel biomarker signatures for immunotherapeutic response across tumor types, but also to elucidate unique tumor biology for many of these previously uncharacterized rare tumor histologies.

While it’s early yet, the DART team is proving that the oncology community can successfully test new treatments for rare cancers, particularly through the NCI’s National Clinical Trials Network, with its national and international reach. The support of the oncology community for DART has been inspiring, with critical involvement of the NCI, CTEP, SWOG, ECOG-ACRIN, patient advocacy organizations, and most importantly, patients. Currently at the halfway mark, DART represents a promising clinical trial opportunity for patients with rare cancers who historically have had few options, particularly for cutting edge immunotherapies such as nivolumab and ipilimumab, and shatters the myth that rare tumor trials are not feasible.

Most importantly, we hope DART is an exemplar of the adage that the patients are not there for the trials, rather, the trials are there for the patients—regardless of how rare their disease.

Learn more about DART at and see the list of rare cancer cohorts involved here.

Read the SWOG press release on DART.

President’s Cancer Panel calls for urgent action on drug prices

In Brief

President’s Cancer Panel calls for urgent action on drug prices

Urgent action must be taken to address the dramatic rise of cancer drug prices and to better align prices with value, the President’s Cancer Panel urged in a recent report.

The report, “Promoting Value, Affordability, and Innovation in Cancer Drug Treatment,” finds that while some cancer drugs have indeed been transformative, and may warrant prices that reflect their value, many new drugs do not provide benefits commensurate with their prices.

The panel concludes that stakeholders across the cancer enterprise—including drug developers and manufacturers, policy makers, government and private payers, healthcare institutions and systems, providers, and patients—must work together to maximize the value and affordability of cancer drug treatment and to support investments in science and research that drive future innovations.

The report acknowledges that many factors influence a drug’s value, and that the relative importance of these factors depends on stakeholders’ perspectives. The panel concludes that when it comes to defining the value of cancer drugs, patients’ benefit must be the central focus.

The panel’s report concludes that rapidly rising spending on cancer drugs is unprecedented and cannot be ignored, and that public-private collaboration is critical to ensure that patients receive high-quality cancer treatment and experience the best possible health outcomes without financial toxicity.

The panel proposes three guiding principles:

  • Cancer drug prices should be aligned with their value to patients;

  • All patients should have affordable access to appropriate cancer drugs; and

  • Investments in science are essential to drive future innovation.

The panel identifies six critical action items:

  • Promote value-based pricing and use of cancer drugs;

  • Enable meaningful communication about treatment options, including cost information, to   support patients’ decision making;

  • Minimize the contributions of drug costs to financial toxicity for cancer patients and their families;

  • Stimulate and maintain competition in the generic and biosimilar cancer drug markets;

  • Ensure that the FDA has appropriate resources to assess cancer drug safety and efficacy efficiently; and

  • Invest in biomedical research to create a strong foundation for developing innovative, high-value cancer drugs.


AACR launches initiative focused on health disparities in African-Americans

The American Association for Cancer Research has launched a collaborative initiative that will perform genomic sequencing of both tumor and normal tissue from 2,020 consented African-American cancer patients, and aggregate it with clinical data from the patients. 

The task is expected to be completed by the year 2020. Hence, the initiative’s name: “2020 by 2020”.  

To conduct 2020 by 2020, AACR is partnering with:

  • Pelotonia through The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

  • M2Gen and the Oncology Research Information Exchange Network

The 2020 by 2020 partners will work to facilitate the development of an infrastructure for consenting African-American patients to the ORIEN Total Cancer Care Protocol at Morehouse School of Medicine in Atlanta.

MSM is a member of ORIEN; the support through the 2020 by 2020 initiative will substantially increase the number of patients that the center can accrue and will allow for the continued collection of material from cancer patients well beyond the year 2020. The data will be added to the AACR Project GENIE registry, which has already made public 39,600 de-identified genomic records.

AACR Project GENIE and ORIEN will subsequently provide the genomic data generated through the 2020 by 2020 initiative to publicly accessible cancer genome registries.


Aurora Health Care & UTHealth join  Strata Oncology

Aurora Health Care and University of Texas Health Sciences at Houston have joined the Strata Precision Oncology Network.

Formed in 2016 by Strata Oncology, the network provides advanced cancer patients access to tumor profiling and matching to a portfolio of biomarker-driven pharma-sponsored clinical trials, it has since expanded to 10 healthcare systems representing more than 85,000 new cancer patients annually.

Members are able leverage the StrataNGS test, an 87-gene assay that sequences both DNA and RNA, as the foundation of solution to deliver precision oncology system-wide. StrataNGS is available to all advanced solid tumor and lymphoma patients at no cost through the Strata Trial, a nationwide observational study providing tumor profiling and trial matching for 100,000 patients with advanced cancer.

The Network’s additional members include:

  • Christiana Care’s Helen F. Graham Cancer Center & Research Institute

  • Kaiser Permanente-Northern California

  • Kettering Health Network

  • Metro Minnesota Community Oncology Research Consortium

  • Ochsner Health System

  • UAB Comprehensive Cancer Center

  • UNC Lineberger Comprehensive Cancer Center

  • University of Wisconsin Carbone Cancer Center


PRIMO Lara named deputy chair of SWOG

Primo Lara was named deputy chair of SWOG.

Lara, professor in the department of internal medicine and acting director of the UC Davis Comprehensive Cancer Center, will begin his new role in March 2019, replacing Anne Schott, of the University of Michigan. As the deputy chair, Lara will also oversee SWOG’s National Clinical Trials Network portfolio of treatment trials.

Lara is chair of SWOG’s professional review committee and an active investigator, serving on the early therapeutics, lung and genitourinary committees. He also serves on the board of the Hope Foundation, SWOG’s public charity.


Fox Chase’s Engstrom receives lifetime achievement award for cancer prevention

Paul Engstrom, the Samuel M.V. Hamilton Chair in Cancer Prevention and special adviser to the president at Fox Chase Cancer Center, will receive the Prevent Cancer Foundation’s Laurels Award for Lifetime Achievement in Cancer Prevention.

Engstrom’s career in oncology spans 50 years, including more than 45 at Fox Chase. In 1979, at Fox Chase, he established the first cancer prevention and control program at an NCI-designated cancer center, and he has served as the principal investigator for several cancer prevention and screening research programs.

Engstrom’s projects include the Early Detection Research Network, which focused on breast and ovarian cancer screening and diagnosis. He is also a founding member of the National Comprehensive Cancer Network Patient Guideline Committee and is known globally as a spokesperson for the national guidelines on screening, diagnosis, management, and patient support.

Engstrom will receive the award at the Foundation’s 2018 Dialogue for Action Conference in Tysons, VA, on April 12.


Bellerjeau gets lifetime achievement award from blood and marrow transplant group

Margaret Bellerjeau, of the Fox Chase–Temple University Hospital Bone Marrow Transplant Program, received the 2018 Nursing Special Interest Group Lifetime Achievement Award from the American Society for Blood and Marrow Transplantation.

She has spent 20 years at Fox Chase – Temple and is a longtime member of the Oncology Nursing Society and the ASBMT, where she serves on the Nursing Special Interest Group steering committee.

The ASBMT Nursing SIG gives the award annually to a member who has made continuous, high quality contributions to the field, and who has been practicing in the field of bone and marrow transplant for ten or more years. To be considered for the award, one must be nominated by his or her peers. Nominees are evaluated based on their publications, presentations, mentoring experience, and volunteer and leadership experience in professional organizations.

Porter: I can’t tell you how the Trump administration gets its budget numbers

Conversation with the Cancer Letter

Porter: I can’t tell you how the Trump administration gets its budget numbers


John Edward Porter

Former House appropriator who oversaw the doubling of the NIH budget


John Edward Porter, a long-time key Congressional appropriator and advocate for biomedical research, received the Research!America Legacy Award at an advocacy awards dinner March 14.

Porter was U.S. Congressman from the 10th district in Illinois for 21 years, serving on the U.S. House Committee on Appropriations and chairing the House Appropriations Subcommittee on Labor, Health and Human Services, Education and Related Agencies.


Porter spoke with Paul Goldberg, editor and publisher of The Cancer Letter.


Paul Goldberg:

The administration tried to slash the NIH budget by about 20% a year ago and failed. Then they regrouped and tried to slash it by 27% this year. What are they trying to accomplish? What’s the message they are sending?

John Porter:

They are sending a message to their base that they’re into cutting down on government.



They don’t care about the fact that it’s life-saving research?





They just don’t care?


No. They are cutting all kinds of programs that are important to people. They just want to show that they’re working to cut the size of government, and also the deficit.



Well, Congress has rescued NIH twice now. How long can this go on, this attack-and-rescue cycle?


Remember, the President’s budget has no force or effect. It is merely the President’s suggestion as to which way he would like to see things go. Congress has the legislative power. And Congress sometimes pays very close attention to a President’s budget, and other times they ignore it completely.



Well, this is certainly a time when they are ignoring it completely.


Yes, and they control both houses of Congress.



Right. But do you fear that ultimately they might prevail?





Just no chance?





Congress is too sober?


No. Congress has a lot of supporters for medical research, including a lot of Republicans. The Republican chairs of the Labor, HHS Subcommittee in both the House and the Senate are strong supporters of medical research and NIH. I feel quite sanguine about the end result being a strong one for continuing increases for NIH. A lot depends upon the allocations.



Which are working in favor of NIH at this point.


Well, the allocations to the subcommittee are what they have to work with. We just don’t know how those are going to turn out.



What struck me as disturbing in the budget proposal was the lack of justification for the cut that was being proposed. This wasn’t really punishment. It just represented the level of spending that the administration considers appropriate. Can this be allowed to just stand without being confronted.


Well, we’ll confront it. You’ve got to remember that they’re not only cutting NIH; they’re cutting all kinds of support safety net programs that are in the Labor, HHS bill, for example. They would like to see them cut also.



But still, there should be just a very clear statement that this just won’t do. Because it might come back. Shouldn’t this be taken seriously?


Absolutely. Absolutely, it should be taken seriously. Research!America hopes every day to send a message to members of Congress, either directly or through their supporters or people back home, that this spending cannot be allowed to drop it, and in fact it should be increased.



How do they even get these numbers? 20%, 27%. Do they do astrology or …


With this administration, probably.



Got it.


I can’t tell you how they get their numbers. They look at the overall spending rate, and then they determine where they’re going to suggest cuts and the hopeful message is to the people who want to cut down on the size of government and its reach, that they are doing what they were elected to do.



What does a 27% cut do? Can you even imagine such a thing?


Oh God. It would devastate medical research. Definitely devastate it.



What would it do?


I don’t know the numbers that I suppose you have, but what are we at—$32 point something billion overall?

Take better than a quarter of that away. You are down to $24 billion, or $23 billion? When we doubled funding for NIH, when I was subcommittee chairman, and funded NIH, we were working were from a base of $13.5 billion and got it to $27 billion. So, $24 [Trump’s proposal] would be below that number. It would be a devastating cut. It would take us back to the Dark Ages.



When you were in charge of appropriations, one way to make you irritated was to try to use the appropriations process, in place of the Legislative process. I see this game is very much being played now, like with Planned Parenthood for example. Is there a way to make this stop?


The way it works in the House at least, if you’re going to try to put a legislative provision into an appropriations bill you’ve got to get the signoff of the authorizers who would have had jurisdiction. They would have to say, “Oh yeah, that’s something we would have done but you go ahead and do it in the appropriations bill.” I think that’s always problematic to whether that’s going to happen. But if they do sign off, then it does happen.



Now that NIH has some real money, should the argument for growing NIH change now? It’s really quite a target for other constituencies. What should advocates for NIH do differently?


Than they’ve been doing?








It’s all good?


As I said, we work every day with the appropriators on trying to ensure there’s a substantial increase for NIH and for other programs, like CDC and AHRQ, and I think we should continue to do that. It’s been successful.



It’s good strategy?


Yeah. You just have to keep working on it. And we have gotten the Republican chairmen in both the House and the Senate aboard of those kinds of increases.



What’s your guess how long it should go at about $2 billion a year clip for NIH?


It depends on the economy. It depends on the revenue that the government receives. You’ve got have the money in order to spend the money, so revenue is very important.



So there’s no hard ceiling? The doubling was a doubling. This is not a doubling, this is kind of in perpetuity, sustainable and measured.


The idea after the doubling was to go back to the historic rate of increase of NIH, at least, which was 3% real [above biomedical research inflation rate] per year. That ended, if you look back in the United States since about 1945, 47, 48 right in there, that every year was about the average rate of increase.

Let’s say it’s $36. One billion would satisfy 3% or so. Getting two was like gravy. You always work for the highest level we can get.



Is there anything we have missed? Any other points you’d like to make?


I think what’s happening out there in the election process is extremely important, and I think the people who support NIH should be out there going to the town hall meetings, going to the campaign meetings, and asking the questions. Do you support NIH funding and how strongly?

Put them on the spot. That seems to be extremely important. People who will support NIH and determine who the candidates that support NIH.

They have to make sure they get the polls and their friends get to the polls and their colleagues get to the polls, because being for something means nothing in an election unless you actually vote.

My message to anybody is get out there and participate in democracy, where everybody gets a chance to have input, and every vote counts.

I’ve been looking at the 18th Congressional District in Pennsylvania today, to see which candidate there is more likely to be supporting medical research, and I would say Conor Lamb, the Democrat, is much more likely than [Rick] Saccone, a Trump guy all the way, would be supporting the increase in funding.

That’s the kind of thing that the people have to figure out and then get to the polls and vote that way.



It’s a question you totally don’t need to answer if you don’t want to … are you still a Republican?


Am I still a Republican?





Well, let me put it this way. I never left the Republican Party. The Republican Party left me.



Thank you for answering the question.


If I was there, I wouldn’t be voting with the Trumpistas. Believe me.



Absolutely. It’s a scary time.


Yeah. Extremely scary time.


In addition to Porter’s Legacy awards, the following awards were presented:

Sen. Susan Collins (R-ME) received the Edwin C. Whitehead Award for Medical Research Advocacy. Collins is the chairman of the Senate Aging Committee and the founder and co-chair of the Senate Alzheimer’s Task Force. She is also the founder and co-chair of both the Senate Alzheimer’s Task Force and Senate Diabetes Caucus. Since the diabetes caucus was founded, funding for diabetes research has more than tripled from $319 million to more than $1 billion in 2017. 

Atul Gawande, surgeon, writer, and public health researcher and advocate, received the Isadore Rosenfeld Award for Impact on Public Opinion. Gawande practices general and endocrine surgery at Brigham and Women’s Hospital, and is a staff writer for The New Yorker magazine, publishing essays on the science and practice of medicine, from people’s individual experiences to the effects of national policy. He is professor in the Department of Health Policy and Management at the Harvard T.H. Chan School of Public Health and the Samuel O. Thier Professor of Surgery at Harvard Medical School. He is also Executive Director of Ariadne Labs, a joint center for health systems innovation through simple, scalable solutions that improve the delivery of care. Gawande is chairman of the non-profit organization Lifebox, which is bringing the Safe Surgery Checklist, shown to cut post-operative deaths in half, to low-income countries around the world.

Roger Glass, director of the Fogarty International Center and associate director for international research at the NIH, won the Geoffrey Beene Builders of Science Award. Glass oversees an extensive portfolio of grants and awards that support training of global health researchers and facilitates NIH’s research and training partnerships abroad. Glass’s research expertise is in the prevention of gastroenteritis from rotaviruses, noroviruses and cholera. He has maintained field studies in India, Bangladesh, Brazil, Mexico, Israel, Russia, Vietnam, China and elsewhere, and created a team of epidemiologists and virologists that spearheaded global efforts to research and introduce rotavirus vaccine worldwide.

Shari and Garen Staglin, founders of the Staglin Family Vineyard, received the Gordon and Llura Gund Leadership Award for their commitment to accelerating cures for brain disorders through scientific research. Their focus on brain health research is the result of their son Brandon’s diagnosis of schizophrenia in 1990. Brandon is now director of marketing and communications at One Mind Institute and his sister Shannon is president at the Staglin Family Vineyard. The Staglins founded One Mind, One Mind Institute and Bring Change2Mind to address brain disorders and stigma. For the last 23 years their annual Music Festival for Brain Health, along with their other advocacy efforts, have raised over $280 million for brain health research. 

The EveryLife Foundation for Rare Diseases has been selected to receive the Paul G. Rogers Distinguished Organization Advocacy Award. The EveryLife Foundation was founded in 2009 to improve the regulatory process for drug development, from clinical trials to approval, by working with patient organizations, industry, academic scientists, FDA, and NIH to spur insightful scientific analysis and dialogue, expand grassroots support, and ultimately bring about key policy changes.

Peter Hotez, received the Research!America Advocacy Award for Sustained National Leadership for his far-reaching work in the areas of neglected tropical disease research and vaccine development. Hotez is dean of the National School of Tropical Medicine at Baylor College of Medicine where he is also professor of pediatrics and molecular virology and microbiology. He serves as the director of the Texas Children’s Hospital Center for Vaccine Development, where he leads a product development partnership for developing new vaccines for hookworm infection, schistosomiasis, Chagas disease, leishmaniasis, and SARS/MERS, diseases that affect hundreds of millions of people worldwide. In 2006 at the Clinton Global Initiative, he co-founded a Global Network for NTDs to provide access to essential medicines for hundreds of millions of people. Hotez was among the first to predict Zika’s emergence in the U.S. and is recognized as an authority on vaccines.

Basch: Patient-reported outcomes data can make cancer drugs safer, more tolerable

Conversation with the Cancer Letter

Basch: Patient-reported outcomes data can make cancer drugs safer, more tolerable

Ethan Basch

Ethan Basch

Director of the Cancer Outcomes Research Program, professor of medicine and public health at the UNC Lineberger Comprehensive Cancer Center.


Fifteen years ago, when Ethan Basch started developing measures for aggregating patient-reported outcomes, many of his colleagues in oncology saw no promise in this enterprise.

“We conducted cooperative group studies and showed that the vast majority of patients were willing and able to self-report even when extremely ill or close to death or hospice,” said Basch, director of the Cancer Outcomes Research Program and professor of medicine and public health at the UNC Lineberger Comprehensive Cancer Center.

“These data were useful for responding to my skeptical colleagues who asserted, ‘We understand our patients well, so we don’t need them to provide their own information. We know what’s going on with them, we talk to them all the time. And patients probably aren’t willing or able to report their toxicities during trials, they have a lot going on.’ But our data showed those assertions were not true.”

Now, NCI plans to commit $3.25 million in fiscal year 2018 to fund three to five awards focused on studying patient adverse event data to better understand how patients are tolerating cancer treatments—as part of the institute’s PRO-CTCAE platform, also known as the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events. This tool was developed by Basch’s team under contracts from the NCI.

Last year, NCI issued the first Request for Applications on PROs based on the scientific recommendations of NCI’s Blue Ribbon Panel for Vice President Joe Biden’s 2016 Cancer Moonshot.

In a wide-ranging conversation, Basch outlines the development of the PRO-CTCAE, FDA and industry’s roles, and his thoughts about the next steps for NCI.

“With the caveat that I’m a researcher, not an NCI employee, in my opinion, the day-to-day oversight of the PRO-CTCAE tool at NCI is ready to be moved into the Cancer Therapy Evaluation Program along with the CTCAE, and be managed by the same or a similar clinical research team,” Basch said.

“Enough is known about this tool for it to be integrated with the CTCAE, as was its initial intention, and be implemented in trials, through partnership with industry, the NCTN, and regulators. Research on the PRO-CTCAE like the pending Moonshot project on this topic could remain in the Division of Cancer Prevention, but this would be focused on expanding understanding of the tool and its applications.”


Basch spoke with Matthew Ong, a reporter with The Cancer Letter.


Matthew Ong:

What was your role in the creation of the PRO-CTCAE? Did you design the framework? When did this work begin?

Ethan Basch:

My research collaborators and I developed the PRO-CTCAE, under contracts to the NCI between 2008-2015.

The foundational work for assessing patient-reported adverse symptoms goes back further than the PRO-CTCAE itself, though. About 15 years ago, I developed an interest in this area based on an observation that, in early phase trials we were conducting, many patients experienced debilitating symptomatic side effects that impact tolerability.

Yet, when we looked at the reported CTCAE data for trials, that information was missing. It was invisible in the trial documentation because we, not the patients, were reporting on the patient experience.

It occurred to me that this was a missed opportunity—there seemed to be an excess of risk to patients from toxicities that we weren’t aware of. So, my collaborator Dr. Deb Schrag and I conducted a series of studies where we started to collect symptom information from patients about their side effects during treatment. The first thing we found was that we as clinicians miss about half of our patients’ symptoms.

We became interested in developing standardized tools, because we thought, if we can capture this information from our patients, this is an opportunity both to improve management of patient symptoms and side effects, and to improve the integrity of clinical trial data.

If you think about the downstream consequences of missing many symptomatic adverse events our patients are experiencing, when an investigator or regulatory authority is reviewing data from a trial, they are going to have a substantial underestimation of the risk of the product. I felt that by improving the tools that we use, we could improve both the quality of data and patient management.

We began developing standardized tools and testing them in various ways, both locally and nationally. We conducted cooperative group studies in the old [Cancer and Leukemia Group B] (now the Alliance), where we inserted these early tools into clinical trials and showed that the vast majority of patients were willing and able to self-report even when extremely ill or close to death or hospice.

These data were useful for responding to my skeptical colleagues who asserted, “We understand our patients well, so we don’t need them to provide their own information. We know what’s going on with them, we talk to them all the time. And patients probably aren’t willing or able to report their toxicities during trials, they have a lot going on.” But our data showed those assertions were not true.



You probably ran into people saying, “Self-reports are by definition, variable, non-discrete data and it’s not easy to turn it into something useful,” right?


Absolutely, that was another area of skepticism where some clinicians asserted, “Well, you know, my patients don’t really understand their own symptoms. I as an oncologist understand symptoms well. I see patients across the whole spectrum of illness. I can normalize or calibrate how patients feel.”

But when we studied clinician reporting of CTCAE symptoms in trials, we found it to be unreliable. In inter-rater reliability studies, we found that investigator agreement on the grading of CTCAE symptoms was low. If you and I saw the same patient on the same day, and we used the CTCAE criteria, there’s a good chance we would not agree with each other. On the other hand, in our studies of patient self-reporting, we found that patients are highly reliable in reporting symptoms over time. So we pushed forward with these empiric data.

But you’re absolutely right. There was definitely an old-school bias out there that “I know better than my patients,” and that we can’t really trust patients to be reliable. But the data show that’s not true. What we find is that, in fact, when clinicians report on their patients’ symptoms, that’s where the real subjectivity comes in.

It happens as the clinician eyeballs the patient and makes assumptions about their health status that may not be true. We know from the psycho-behavioral literature that it is very hard for a person to understand another person’s feelings or symptoms.



And so, with the standardized criteria that you and your team developed, did CTCAE itself exist way before that?


The CTCAE already existed, and provided a framework on which to build the patient-reported tools. The CTCAE is an item library designed for clinician reporting of adverse events, with a lot of technical language. It includes about 800 discrete adverse events in it. Many of these are not appropriate for patient reporting, like retinal detachment. But items like nausea, dysphagia, taste disturbance, or sleep problems are appropriate for patient self-reporting—experiences that the patient knows best.



About 78 out of 800 items, right?


Yes, about 10 percent of the CTCAE is comprised of symptoms. In our early work, we created quite literal adaptations of CTCAE criteria into patient language, called the STAR (Symptom Tracking and Reporting) system, which predated the PRO-CTCAE.



So, NCI and FDA became interested in your work?


About 10 years ago or so the NCI became interested and I was invited down to present our early work.

Several people at the NCI were particularly enthusiastic and championed the concept—there was Dr. Bryce Reeve [then at the Outcomes Research Branch in the Division of Cancer Control and Population Sciences and now director of the Center for Health Measurement and professor of population health sciences and pediatrics at the Duke University School of Medicine] and Dr. Lori Minasian [deputy director of the NCI Division of Cancer Prevention], in two different divisions at the NCI.

They issued a series of contracts, to develop a formal patient version of the CTCAE called the PRO-CTCAE. As an aside, Bryce was also the one who hatched the idea of PROMIS (Patient-Reported Outcomes Measurement Information System) and named it. Jeff Abrams in CTEP was also an early advocate for this tool, and continues to valiantly support its implementation.

Bryce subsequently left the NCI and went into academia, but he was really responsible for the NCI’s initial push to develop patient-reported tools like PROMIS and PRO-CTCAE that are coming into their own now, more than a decade later. He was important, as was Lori, who’s still at the NCI, as well as Dr. Ann O’Mara who’s overseeing the new PRO-CTCAE NCI Moonshot announcement, and Dr. Sandy Mitchell who took over Bryce’s role when he left the NCI.

NCI leadership has also been highly supportive, including Dr. Bob Croyle at DCCPS, Dr. Barry Kramer in DCP, and leadership in [the Center for Biomedical Informatics and Information Technology] and [the Division of Cancer Treatment and Diagnosis]. So overall, this effort has had broad-based and interdisciplinary support at the NCI. I’m delighted that Dr. Ned Sharpless, our new NCI director, is also very committed to PROs and the PRO-CTCAE for bringing the patient voice into cancer trials.

FDA input has also been key, and FDA stakeholders were involved from the start, particularly Lori Burke, Gini Kwitkowski, and more recently Paul Kluetz, who is a major champion for PROs in oncology at the FDA. Rick Pazdur has also been a strong supporter, and the PRO-CTCAE has been seen as a vehicle for enhancing the patient-centeredness of cancer drug development. The FDA has had several panels on the use of the PRO-CTCAE in trials as it’s been rolled out.



In terms of timeline, how long has CTCAE been around?


The CTCAE is a longstanding tool that’s been developed and maintained by the NCI, with revisions every several years. It’s been widely used in oncology both in clinical trials and in routine care. But there was no patient reporting component to it, which is the innovation of the PRO-CTCAE.



So, the NCI supported a team of researchers you led to develop the PRO-CTCAE?


With NCI contract support, we assembled a national team to build and test the PRO-CTCAE, also with terrific input from many NCI and FDA stakeholders. The team included incredible collaborators—Dr. Deb Schrag [Dana-Farber Cancer institute], Dr. Amylou Dueck [Mayo], Dr. Amy Abernethy [then at Duke, now at Flatiron Health], Dr. Deb Bruner [Emory], Dr. Charlie Cleeland [MD Anderson], Dr. Jeff Sloan [Mayo], Diane Paul and Cindy Geoghegan [patient representatives]. It was a very exciting time and project—one of the highlights of my career. We felt we were doing something new that could make a real difference for patients and improve trial data.

The first thing we did was to systematically evaluate the CTCAE and identify items that are amenable to patient self-reporting, that’s the 78 items that you referred to. Then, we developed a structure for how patients would report this information, that is, how we would ask the questions. Next, we had to generate patient-friendly language for terms like dysphasia and dyspnea in the CTCAE, which are too technical for patient questions.

Then, we did a national interviewing study, led by Drs. Jennifer Hay and Tom Atkinson at MSKCC, what we call a cognitive interviewing study, among patients from different backgrounds and cancer types. This study made sure that patients understood the terminology and that the questions truly measured the concepts of interest. This is a requirement when creating rigorous PRO tools.

Next, we conducted a large national validation study led by Dr. Amylou Dueck at Mayo where we looked at what’s called the measurement properties of the tool, to make sure that the items are valid, reliable, and sensitive to changes over time. We tested what the recall period should be, which is how far back people’s memory can reasonably go to remember these AEs (led by Dr. Tito Mendoza at MD Anderson) and the optimal recall period for the tool, which turned out ideally to be over the past 7 days, but could reasonably be stretched out to a month (led by Dr. Antonia Bennett at UNC).

We created an electronic system for administering the questions, and tested that through usability testing, led by Dr. Amy Abernethy. The whole initiative was overseen by an incredible project manager, Lauren Rogak, who I still work with closely.

And then, we implemented the tool in big national trials.



When thinking of patient safety and tolerability, could you explain how the PRO component can provide a more complete picture of what’s going on, especially in terms of how tolerability is understood?


There’s a lot of interest now in developing a more patient-centered approach to tolerability.

The current standard definition of tolerability is a bit circular: how well a patient tolerates a treatment. But, a more patient-centered approach has to do with the ability of a patient to continue treatment based on how they feel and function during that treatment. So, it’s the extent to which the impact on their symptoms or their physical functioning affects their ability to continue taking the drug.

Friends of Cancer Research is supporting a current effort to refine understanding of tolerability from the patient perspective through an international, multidisciplinary working group. This effort reflects the broader championing of PROs and the PRO-CTCAE by Friends of Cancer Research, particularly by its founder Ellen Sigal, who is an incredible advocate for cancer research, and its director Jeff Allen.

In order to operationalize that kind of approach to considering tolerability you need to have the patients’ own report of their symptomatic adverse events, in addition to essential non-PRO information such as hospitalizations and clinician-reported information from the CTCAE.

But the key point here is that it’s essential to have the patient’s self-report, for example to know if there’s an excess of rash, or myalgias, or disabling nausea and vomiting etc. that we wouldn’t otherwise appreciate. You’re going to get that best from patients to understand how well people are tolerating a drug. Once you have that information, you can make better decisions about dosing of drugs, or the frequency of giving a drug, or the balance between risk and benefits. And avoid picking a dose that’s ultimately tough on patients or will impair compliance.

There are multiple examples of drugs that were released that were really not tolerable for patients, and we didn’t figure that out until they were out on the market, because we simply didn’t collect how patients felt when they were receiving the drug in early phase development.



Which brings us to, could you explain in laymen terms, step by step, how exactly you or an investigator would use PRO-CTCAE in a clinical trial?  So, sort of walk me through a case study if you would.


Sure. The PRO-CTCAE can be used in trials at any phase of development for a descriptive summary of adverse events, much like the CTCAE, or as a component of assessing tolerability—either for selecting dose in early phase work, or for comparing the tolerability of different treatments in later phase trials.

There are currently numerous NCI and industry clinical trials in which the PRO-CTCAE has been embedded. The generic way that it would be embedded would first involve selection of PRO-CTCAE items for administration in a trial. To do this, the investigators would anticipate the likely symptomatic side effects that would occur, based on what’s known about the properties of the drugs in all arms of the study, prior experience with the product, and if available some pre-trial questionnaires or interviews with patients who previously received the product(s).

Based on this information, they would create an electronic form to administer PRO-CTCAE items to patients corresponding to those pre-designated symptomatic side effects. An important point is that we don’t administer all PRO-CTCAE items in a given trial, only the salient ones, perhaps 10-15. I would also recommend including a mechanism to capture unsolicited symptoms from patients, for example through a free text box at the end of the PRO-CTCAE questionnaire. We have found this to be a rich source of supplemental information.

The PRO-CTCAE should be administered on a regular basis throughout active treatment, or at least during early cycles, either once a week, or every two weeks. Regular administration assures that we don’t miss important events during treatment. As I mentioned, this can be stretched out to as infrequently as every month, but that’s not ideal, because if a patient misses a report, they’ll have a long stretch between time points.

Reminding patients who miss self-reports is also very helpful for data completeness. For patients who don’t self-report on time, a PRO system can send an alert to an administrator, who can call the patient to capture the missing data and remind them to self-report next time. We have found that by doing this, we can boost completeness of our data by 15 percent, which is substantial.

After patients finish active treatment, you can space out PRO-CTCAE administration, for example, every six months for another one or two years depending on the context and the patient population.

In the analysis and reporting, there are a number of different ways to look at the data. We have quite a bit of active work in the area of how to analyze and visualize the data, and this is the topic of the planned NCI Moonshot project. I am particularly interested in how the data should look in drug labels.

There’s an industry PRO-CTCAE working group now with representatives from numerous companies working on this very question, which has been led by Alicyn Campbell and Sheetal Patel at Genentech, who have been important pioneers incorporating rigorous PROs in cancer trials.

The classic way to analyze adverse events in cancer trials it is to look at the proportion of patients with the worst level of each adverse event between arms, for example, the proportion of patients with any amount of nausea, and with grade 3 nausea throughout the trial.

An innovation in the PRO-CTCAE is that we can adjust for the baseline symptoms of a patient. Patients do a much better job reporting baseline symptomatology than clinicians. Baseline symptoms are common and are often misattributed to study drug. By adjusting for these in analyses, we remove noise in analyses, and improve the precision of adverse event assessment.

PRO-CTCAE information can be shown in a table form or in histograms displaying the distribution of scores overall or more granularly at each time point of measurement.



You also mentioned real-world use and how PRO-CTCAE is coming in handy in understanding the full range of symptomatic adverse events in drugs that weren’t apparent until those drugs went on the market.


So real-world use is a different application of PRO tools with some special considerations. But its value is predicated on the same early finding idea we talked about, that we as clinicians miss about half of our patients’ symptoms. This means that in clinical practice, many of our patients are quietly suffering at home without our knowledge.

If we don’t know how our patients are doing, we can’t intervene. Systematic collection of PROs can key us in and improve symptom management and clinical outcomes like quality of life and survival, as well as reduce ER visits and lengthen tolerability of chemotherapy, which we showed in a recent randomized trial presented at the last ASCO.

And, of course, a central part of our job as cancer care providers, of my job as an oncologist, is to address my patients’ symptoms. So, I need to know how my patients are doing. These kinds of tools can be inserted into clinical care and integrated into the electronic health record.

There are multiple reasons why it’s important to collect PRO information in the real world. One reason is to manage patient symptoms; the second reason is to collect population level data to understand problems that people have long-term that we simply can’t collect in very small, brief, clinical trials. Once PRO information becomes a standard part of the EHR, it can be combined with other clinical data for real world trials of drugs.



Is that done widely?


Not yet, but interest is rapidly growing. But it’s technically challenging. A major barrier is the difficulty of integrating PROs in electronic health record systems, and EHR vendors have been slow to develop PRO interfaces well, which has stalled the widespread collection of this information. There has been pressure on the big EHR vendors to improve their PRO functionality, but more is needed. That said, many health systems are implementing PRO collection, either using the limited native functionality of their EHR, building an interface to their EHR with a third-party PRO platform, or using a freestanding PRO system.



I guess it’s becoming even more relevant with immunotherapies and targeted therapies, and many of these more recent treatment modalities don’t have long-term outcomes data. Would this become a more central way of assessing those outcomes?


With newer therapies, we know that patterns of adverse events are different from cytotoxic chemotherapy. There are low-grade, chronic symptoms that people find bothersome and impair compliance. And there can be catastrophic adverse events that are preceded by milder symptoms that we could better pick up using PROs.



From what I heard at the NCAB meeting, the latest is about fully implementing ePRO, which is electronic version of this. How far have we come as a field, or rather, what is your sense of how well the cancer world understands the process, and are we as a field further along in PRO than other medical specialties?


There’s been tremendous progress in the ePRO area over the past 10 to 15 years, and much of this has been spearheaded in oncology. Stakeholders across institutions in our field are increasingly conscious of the importance of PROs, and PROs are incrementally making their way into trials and routine care as a result.

A lot of this started with oncology-specific quality of life tools developed by pioneers like Dr. Neil Aaronson and Dr. Dave Cella, which were initially administered by paper and pencil in trials. In oncology, patients have many symptoms, both from disease and treatment, so it makes sense that much of this worked stemmed from our field. More recently, it’s become more common to collect PROs electronically, and the NCI just licensed a downloadable app for collecting ePROs across cooperative group and other NCI-sponsored trials, which is an exciting development.

When I started this kind of work, very few of my clinical colleagues had heard of a patient-reported outcome, or given this much thought. I’d say there really is widespread consciousness now. The fact that we’re having this conversation reflects that. PROs and the importance of truly understanding the patient experience with disease and treatment have risen prominently in the discussion across the sector.

I attribute much of this to early advocacy by leaders in our field. I’ve done a lot of my work in the cooperative groups, particularly in the old CALGB and now in the Alliance. Strong support from leaders like Rich Schilsky who was CALGB Group Chair (now at ASCO), and now by his successor in the Alliance, Monica Bertagnolli, have been essential. And Cliff Hudis was an early collaborator and champion of this work.

I’d say the FDA and the EMA have also been central to raising the prominence of PROs in oncology and more widely. Both agencies have developed guidance documents to try to help drug developers figure out how to use PROs.

Many of the larger industry sponsors have PRO units that mostly operate on the post-marketing side, but are starting to migrate towards being involved in pre-approval trials. The inception of PCORI and PCORI’s emphasis on including the patient voice in research has also been important in raising consciousness and funding PRO research.

There are now a lot of commercial ePRO systems out there that are available. The big EHR vendors, Epic in particular, also have a rudimentary ability to collect patient reported outcomes—they could use a lot of improvement, but at least they’re out there, it’s a start.

And health systems are rapidly becoming interested in this. As accountable care organizations and bundled payment programs become more widespread, there is interest to catch symptoms early through PROs, before they lead to expensive downstream use of services. As I mentioned, some of our work showed that systematic PRO monitoring in routine care reduces ER visits.

No doubt there’s been tremendous progress in the methodology of developing questionnaires, the technology for collection of PRO data, the enthusiasm of patients for reporting it, and the consciousness of many stakeholders about the importance of this. But, we’re not quite there yet. We’re on the cusp on this coming into common use, but a number of barriers still exist.



Would you say that this movement to collect PROs did start in oncology, or was it a simultaneous effort spanning a couple of specialties?


Assessment of health status and quality of life through questionnaires goes back further and developed in a number of areas of healthcare, not just oncology. A number of generic PRO tools have been around for decades. But I would say that some of the leaps in PROs have happened in oncology over the years. And now especially, there is tremendous activity in the oncology space around PROs.



I see that FDA and CDRH have provided PRO guidances for medical devices, for instance.


Yes, as I mentioned earlier, the regulatory agencies have been key to the rise of PROs in oncology and more broadly. Both the FDA and EMA have issued guidance around methods for integrating PROs into drug development towards labeling claims. Some have criticized these as being too stringent, but they have nonetheless been very important for bringing PROs into the consciousness of drug developers. Key stakeholders at the FDA and EMA like Paul Kluetz and Dan Sherman, respectively, are pushing this field further now, particularly for thinking about how the PRO-CTCAE and other PROs fit into labeling.



Since PRO-CTCAE has been used in at least 20 NCI-sponsored trials and many industry trials, how is FDA formally engaging the framework? You said industry-sponsored trials will follow FDA guidances and that PRO-CTCAE is used to inform drug labels.


Stakeholders in the FDA and EMA have been enthusiastic about the PRO-CTCAE. They have hosted panels and published on the PRO-CTCAE specifically. There is a lot of ongoing work in the weeds between the regulators and sponsors to figure out clinical trial design and reporting standards for the PRO-CTCAE.

Some of this builds on prior guidance, and some on evaluating data from trials that already include the PRO-CTCAE. We are rapidly getting there. This FDA in particular has a mandate around patient-focused drug development, and PRO-CTCAE fits into this well.



So, beyond the challenges of the industry and getting EHR systems to incorporate this into their platforms, what else do you foresee as needing to do as a field over the next few years to really make it happen?


In my opinion, there are several things that need to happen to broadly implement the PRO-CTCAE—with the caveat that I’m simply a researcher who helped develop the tool, and an understanding that the PRO-CTCAE is a public product supported and maintained by the NCI.

At the NCI:

  • First, I think that the day-to-day oversight of the PRO-CTCAE tool at NCI should be moved into CTEP along with the CTCAE, and be managed by the same or a similar clinical research team. Enough is known about this tool for it to be integrated with the CTCAE and implemented in trials, through partnership with industry, the NCTN, and regulators. Research on the PRO-CTCAE like the pending Moonshot project could remain in DCP, but this would be to expand understanding of the tool and its applications.

  • Second, a standard operating manual for the PRO-CTCAE is greatly needed, and would ideally be developed by an interdisciplinary group of clinical investigators, PRO experts, and stakeholders from the NCI and FDA. This manual should be updated regularly as we learn more about the tool.

  • Third, the tool needs to be regularly updated with a standardized process, just like the CTCAE is, with new items and tweaks to existing items. We have known for several years that there are items that likely should be added, for example to better accommodate radiation oncology trials, but there has not been any visible activity to make this happen.

  • Fourth, the PRO-CTCAE should be fully integrated with the CTCAE in its next release.

  • Fifth, a mapping algorithm for converting PRO-CTCAE scores to summary grades has been developed and should be released.

  • Sixth, many more language translations of the PRO-CTCAE are needed. Most available languages for the PRO-CTCAE to date were actually funded by Genentech, which is wonderful, but it is unclear to me why NCI, which has already invested substantially in this tool, has not supported translations that are essential for international trials. NCI should support broader translations to make the tool optimally usable in my opinion.

  • Seventh, although the PRO-CTCAE can be downloaded for free from an NCI site, there is overly restrictive licensing language that appears on that site to preclude use of the PRO-CTCAE in real world settings like routine clinical care. I see no reason for this restrictiveness. This is a public tool created with public money, and should be available for improving care.

  • Finally, the NCI should not play a role in the interactions between the FDA and sponsors who are using this tool in drug development, unless consulted specifically.

For the FDA:

  • About PROs in general: Tremendous work has been done at the FDA thinking about methods and standards for integrating PROs into trials. But industry sponsors will not widely and rigorously do this until the FDA makes clear that this is an expectation of trials. In other words, that the characteristics of a product cannot be fully understood without direct reports by patients about how they feel and function during treatment.

  • Messaging from the FDA to sponsors currently is ‘if you decide to use PROs, here are the methods we would like to see’. But to me, the message should be ‘we need to understand the patient experience with your product, so show us your strategy for rigorously collecting that information’. I believe that until that happens, we’ll see inconsistent and sub-par PROs in cancer trials, yielding an inadequate understanding of benefit and risks.



Where is the PRO-CTCAE managed right now in NCI?


Right now, it’s managed between two population science research branches, the Division of Cancer Prevention and the Division of Cancer Control and Population Sciences.



So, it should go to CTEP.


Yes, I think so, for day-to-day maintenance, updates, SOPs, and dissemination efforts – particularly in partnership with FDA. But for research on the tool, I think the model of the Moonshot announcement makes sense, with that part living in DCP.

It is visionary that the NCI supported creation of this tool, which is truly a unique contribution for bringing the patient voice into clinical research. It is a model for other diseases. The challenge now is to move to the next step of dissemination so it can take on a life of its own and truly yield its potential value for patients.

Do patients know best? Industry, NCI committing dollars to studying patient-reported outcomes

Do patients know best? Industry, NCI committing dollars to studying patient-reported outcomes

By Matthew Bin Han Ong

Researchers are coming to the conclusion that cancer patients are the best authority on how therapies affect them.

Over the past few years, about 20 NCI trials and over 125 industry studies have incorporated direct reports of symptomatic adverse events by cancer patients through an NCI program.

Last year, building on Vice President Joe Biden’s 2016 Cancer Moonshot, NCI issued a Request for Applications to study application of patient-reported outcomes. The institute said it intends to commit $3.25 million in FY2018 to fund three to five awards.

Here is how such data can be used: (1) investigators predict a therapy’s side effects, (2) they list these side effects in an electronic questionnaire, (3) patients report on their experience, and (4) investigators refine their understanding of the way the drug is tolerated and, possibly, adjust the regimen.

Some studies have shown that reporting of symptomatic adverse events by patients is more reliable than such assessments by physicians. Two oncologists seeing the same patient minutes apart from each other tend to disagree quite frequently about the level and severity of symptoms.

Through patient-reported outcomes, clinicians would be able to improve the measurements of risk and benefits, said Ethan Basch, director of the Cancer Outcomes Research Program and professor of medicine and public health at the UNC Lineberger Comprehensive Cancer Center.

“There was previously a bias among some investigators that ‘I know better than my patients,’ or that we can’t really trust patients to be reliable, or that patients will be too ill to report their own toxicties, but empiric data show that none of that it true,” Basch said to The Cancer Letter. “What we find is that, in fact, when clinicians report patient symptoms, that’s where the real subjectivity comes in.

“Without patient-reported information about these experiences, we have an incomplete understanding of the characteristics of drug products. And that simple messaging, I hope, will really push the industry to bring their resources forward around the methods for doing this.”

A conversation with Basch appears here.

Recording patient-reported outcomes electronically in real time and allowing clinicians to review longitudinal reports can improve patients’ quality of life and lengthen survival, Basch wrote in an article published January 2017 in the New England Journal of Medicine.

More than a decade ago, many in the oncology field scoffed at efforts by Basch and his team to systematize these data by using an existing grading scale for adverse events.


“I faced a lot of skepticism from my colleagues, who, first of all, said, ‘We understand our patients well, so we don’t need them to provide their own information. We know what’s going on with them, we talk to them all the time,’” Basch said. “And the second [strand of] skepticism that I faced was that colleagues felt that it just wasn’t feasible to collect this information.

“We demonstrated conclusively that that just wasn’t the case. We found the vast majority of patients were willing and able to self-report even when they were extremely ill and even close to death or hospice.”

Now, at NCI and in the pharmaceutical industry, cancer research is moving beyond basic clinical metrics for drug safety, to including patient self-report measures—enabling investigators to assess patient outcomes over time.

These self-reports allow for real-time capture of symptomatic adverse events experienced by patients undergoing cancer treatment, giving researchers insight into the patient experience outside the clinic and providing additional data on the frequency and severity of the toxic effects of investigational drugs.

Enter NCI’s patient self-reporting platform, PRO-CTCAE, also known as the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events.

The program was built as a companion to the institute’s existing CTCAE library, which is a standardized set of criteria used to classify adverse events from drugs used to treat cancer. Before the PRO companion was developed, clinical investigators relied on the CTCAE to grade the severity of each adverse event, based on laboratory findings, clinical observations and other sources of data.

The PRO-CTCAE item library has been publicly available since April 2016, eight years after the start of its development.

Conceptually, the CTCAE bundles the frequency and severity of adverse events, whereas the PRO component serves to distinguish the frequency, severity, and interference associated with each of those toxicities.

The CTCAE provides a comprehensive list of adverse events—about 800, each graded on a five-point scale—its use generates safety data on patients at limited treatment cycles. On its own, the CTCAE doesn’t allow investigators to assess the onset, resolution, or trajectory of toxicities or symptomatic adverse events resulting from therapy over time.

“The routine collection of toxicities by clinicians didn’t fully capture the patient experience and often missed some of the problems that were of most importance to patients,” Barnett Kramer, director of NCI’s Division of Cancer Prevention, said to The Cancer Letter. “These occurred between study visits, or were chronic, and therefore not picked up in any specific clinical visit. So, it was known that on questioning, patients would very clearly state that they had either more frequent, more chronic, or more severe symptoms than were captured in the medical record.”

Self-reports are used not only to examine toxicity, which would enable investigators to address the need for action or management of particular adverse events.

The Moonshot RFA will focus on using PRO-CTCAE with CTCAE data and other clinical trial data to determine tolerability.

“The initiative started sometime around 2014 and the [Moonshot] RFA shows that it’s still an evolving process to refine it and make sure that it is fully implemented,” Kramer said.

The application period for the RFA closed on Jan. 17. At this time, the RFA was a one-time solicitation, but investigators are also free to submit investigator-initiated awards, NCI officials said.

“There’s a collaboration that has gone on with FDA, as far as I’m aware, from the beginning of the development of PRO-CTCAE, because the information clearly could be of real use to the FDA, not just the NCI research community and to clinical practitioners, but ultimately could be in the mix of how the FDA looks at drugs,” Kramer said.

“But the main thrust of the funding opportunity announcement was to enhance our understanding in the cancer institute of how it’s used, who uses it, the utility, and simple things like, how can the different domains of the PRO-CTCAE be combined and analyzed, and whether or not the same questions can be modified for children.”


Safety vs. tolerability

The primary goal for PRO-CTCAE is to improve researchers’ understanding of patient tolerability—how well patients can tolerate a treatment regimen or investigational agent.

“I think that safety and tolerability overlap, but there’s not a one-to-one correspondence,” Kramer said. “Very frequently, the clinically-obtained side effects are used directly in protocols to adjust doses and especially in early phase studies, phase one studies, to find the maximal tolerable dose for the patient.

“But, the goal of the PRO-CTCAE is to go beyond that and get at the full patient experience and their tolerability over time, and so not every patient can tolerate the maximally tolerated dose or one dose below that. Compliance may be much, much worse in the real world than would be suggested by simply delivering the maximally tolerated or safe dose.

“I think they’re complementary. The PRO-CTCAE provides information not obtained through CTCAE and vice versa, so I don’t see one eliminating the need for the other.”

These complementary measures will become increasingly important with the development and testing of immunotherapies and molecularly targeted agents.

“Our vision for PRO-CTCAE in NCI clinical trials is to capture patients’ perception of symptomatic adverse events in a manner that’s complementary to clinician-graded adverse events, the primary reason of which is really to improve our identification of tolerability for cancer treatment regimens and cancer prevention and control interventions,” Lori Minasian, deputy director of NCI’s Division of Cancer Prevention, said at a recent joint meeting of the NCI Board of Scientific Advisors and the National Cancer Advisory Board.

“Patients are receiving drugs on a chronic basis, with some of these toxicities developing into chronic toxicities and things that impair adherence over the long run,” Minasian said. “PRO-CTCAE data currently is analyzed like other PRO data—analyzed in aggregate, out of trial-level, to provide information about the trajectory over time, but really does not result in any dose modification for an individual patient at this time.

“There’s a huge opportunity here to use this brand-new tool to provide a signal for tolerability that will give us more information on how to use this and how to think about delivering therapy to patients.”

NCI’s ongoing work is focused on interpretability and utility, said Sandra Mitchell, a research scientist at the Outcomes Research Branch, Healthcare Delivery Research Program at NCI’s Division of Cancer Control and Population Sciences.

“Measuring safety and tolerability in cancer clinical trials is really fundamental to the kinds of conclusions we wish to draw about the effectiveness of cancer therapies,” Mitchell said at the meeting. “This is really the motivation for us to support the development of the Patient-Reported Outcomes version of the CTCAE, and it’s designed to allow for real-time ascertainment using PROs to improve the precision and reproducibility of our capture of symptomatic adverse events.

“We’ve built this tool, but we really need to understand better how best to interpret it and what is its clinical utility. This is still evolving. We have broad implementation in a number of early-phase studies and randomized studies, both NCI-sponsored trials but also, we’ve had very broad adoption of this through pharma, and this work has definitely been encouraged and supported through our interactions with the FDA.”

Patient-reported outcomes may one day become a factor in drug approval. Alongside other data, these reports may also be used as a basis for dose modifications or treatment discontinuation, said Paul Jacobsen, associate director of the Healthcare Delivery Research Program at the DCCPS.

“There is good reason to believe that the validity of symptom toxicity reporting could be strengthened by the inclusion of patient self-report measures,” Jacobsen said at the meeting.

“We’ve drawn from 78 symptomatic adverse events listed in CTCAE to develop an item library of questions and items, and it’s possible to create customized surveys so that not every patient sees every item, but only those items that are related to the potential toxicities from the treatments they might receive.

“Work on PRO-CTCAE has progressed to the point that has been publicly available since April 2016, along with related materials.”


Real-world implementation

Systematic collection of patient-reported outcomes outside the clinical trial setting is technically challenging, because electronic health record systems are evolving slowly, Basch said.

“There’s quite a bit of interest not just in oncology, but beyond to systematically collect patient reported outcomes during clinical care,” Basch said. “Electronic health record vendors have been slow to develop PRO interfaces well, which has stalled the widespread collection of this information. There has been a lot of pressure on the big EHR vendors to improve their PRO functionality.”

Real-world data is playing a rapidly expanding role in cancer research—by tracking drug use and effectiveness in the real world, in real-time, researchers and drug manufacturers are able to respond quickly to adverse events and also aggregate patient data to inform regulatory decisions.

“Well, there are multiple reasons why it’s important to collect this information in the real world,” Basch said. “One reason is to manage patient symptoms; the second reason is to collect population level data to understand problems that people have long-term that we simply can’t collect in very small, brief, clinical trials.

“And then the third is to do comparative effectiveness research, where we compare therapies to each other based on population-level data. And currently, we don’t have a living repository of patient-reported outcomes to do effectiveness research—this could be a future area for the NCI’s SEER registries to develop.”

A best practices white paper for the PRO-CTCAE is needed, and ideally would be developed in partnership with clinical investigators, PRO experts, as well as NCI and FDA, Basch said.

“It probably should come through a multidisciplinary meeting that is sponsored by the NCI that brings together outside investigators, regulatory authorities, patients, and other stakeholders in order to lay out how this tool should be used,” Basch said. “I laid out for you how I feel it should be used in a trial, but that needs to be codified with the imprimatur of multiple stakeholders.”

Roswell Park ovarian cancer registry data links ovarian and testicular cancer

Clinical Roundup

Roswell Park ovarian cancer registry data links ovarian and testicular cancer

Using data from a large ovarian cancer registry, a research team from Roswell Park Comprehensive Cancer Center uncovered a link between testicular cancer and familial ovarian cancer that may be attributable to genetic factors on the X chromosome.

The Familial Ovarian Cancer Registry at Roswell Park was established in 1981 and contains clinical and epidemiological information from 2,636 families with multiple cases of ovarian cancer. The overall goal of this registry is to identify all of the genes responsible for ovarian cancer development so that women who are genetically predisposed to the disease can be identified and monitored carefully.

Using Familial Ovarian Cancer Registry data, the Roswell Park investigators took a closer look at the family histories of 34 men with testicular cancer who were in the registry. These men with testicular cancer were more likely than men with other cancers to have a mother or sister with ovarian cancer.

None of the men with testicular cancer who were included in the registry had a paternal grandmother with ovarian cancer, lending support to the theory that the genes driving testicular cancer development may be X-linked.

Based on the results of this study, the Familial Ovarian Cancer Registry will now include all patients with at least one case of testicular cancer and re-contact existing families to update their information.

Although more studies are needed to further explore the link between testicular and ovarian cancers, this registry may provide new insight into the etiology and transmission of both cancers and identify gene targets for prevention and therapy.

The study, “Hereditary association between testicular cancer and familial ovarian cancer: A Familial Ovarian Cancer Registry study,” was published in Cancer Epidemiology and is available at