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

Tuesday, January 10, 2017

With Carol Weil, JD, in the NCI Cancer Diagnosis Program

By Sarah DiGiulio

The NCI started enrolling patients in the NCI-MATCH trial in August 2015 with the goal of finding better treatments for patients with cancer based on the molecular profiles of their tumors rather than their tumor types. The trial marks a big step for advancing the science of targeted therapies and personalized medicine. But researchers, physicians, and patient advocates all say there is still much work needed to better educate patients about the delivery of such medicine.

"We need to develop best practices around how to communicate suspected germline information to patients who undergo tumor testing—what information patients want and need to know to determine whether to undergo confirmatory germline testing and what patient characteristics are associated with lower or higher levels of stress, anxiety, or depression around the receipt of this information," explained Carol Weil, JD, Program Director of Ethical and Regulatory Affairs in the Cancer Diagnosis Program in the Division of Cancer Treatment & Diagnosis at NCI.

In February 2015, Weil and a committee of oncologists, geneticists, bioethicists, and patient advocates convened to discuss ethical controversies of the trials that would be part of NCI-MATCH. The attendees realized they needed to find better ways to help patients better understand the results of their genetic data that was part of the trial.

"More empirical data were needed to understand both patient and physician attitudes and preferences about the receipt of genetic findings," Weil said. "We need better understanding of the relative benefits and risks of conveying tumor profiling information to patients."

And that is why the COMmunication and Education in Tumor profiling study (COMET) was created, she said. Weil told Oncology Times more about the specific questions COMET seeks to answer and how it works.

1. What is COMET?

"COMET tests the hypothesis that the knowledge patients gain by completing a self-guided, mobile-friendly, and tiered online genetic education program before getting their tumor test results will be associated with lower levels of testable distress, including anxiety, depression, and cancer worry.

"COMET Step 1 is a randomized controlled trial of a web-based genetic education intervention that will be administered to [one arm of] NCI-MATCH patients prior to receiving their genetic test results from the tumor sequencing required in NCI-MATCH. The other arm will receive 'usual care' (i.e., whatever the treatment center normally discusses with patients undergoing tumor profile testing). COMET Step 1 allows us to address the lack of empirical data regarding patients' experience with genetic testing, and learn how to mitigate the distress many patients carry through the tumor profiling process.

"COMET [also] includes a small pilot remote genetic counseling study known as COMET Step 2. As we continue to incorporate whole genome and whole exome sequencing technologies into oncology clinical trials to match patients with treatments that can potentially target their particular tumor mutations, it will be more and more imperative to ensure the availability of genetic counseling services for those with incidental findings. Particularly in the rural and community hospital setting, sites often do not have sufficient numbers of genetic counselors.

"[This] COMET remote genetic counseling pilot explores the feasibility and preliminary outcomes of providing genetic counseling by telephone to advanced cancer patients in whom a potential or suspected germline mutation is found upon tumor profiling in NCI-MATCH."

2. Is there a current standard of care in terms of educating patients about the results of the genetic tests they receive?

"In terms of a standard for genetic counseling when undergoing tumor profiling—there is not really a standard of care.

"[ASCO] has recommended that patients be counseled in advance of gene panel testing about the possibility of suspected germline findings, but there are not really any developed models for engaging in this complex, and often emotionally charged, communication when there is so much uncertainty about the significance of potential findings."​

3. Why would you say COMET is an important part of the MATCH trial?

"Most NCI-MATCH patients won't actually 'match.' They will undergo tumor testing only to discover there is no actionable mutation in their genomic profile for which there is an investigational therapy available in the NCI-MATCH trial.

"As NCI-MATCH patients typically have advanced and/or recurrent cancer, this news could be devastating. It is our hope that participating in COMET will provide some measure of comfort and empowerment for these cancer patients in that they may have better understanding of their personal and family genetics, and can facilitate communication with family members who could medically benefit from this information.

"Also, COMET will give patient reported outcomes on managing potential germline mutations when cancer patients undergo tumor testing. The results will help us design better policies for communicating individual genetic findings in future clinical trials that address the very real emotions and needs of advanced cancer patients."


Monday, January 2, 2017

​With Paul Mischel, MD, of the Ludwig Institute for Cancer Research San Diego Branch and the University of California, San Diego

In a study published in Cancer Cell, Paul Mischel, MD, and his team worked with colleagues at The Scripps Research Institute to identify a metabolic vulnerability in the incurable brain cancer glioblastoma (GBM) and show how it might be exploited for therapy (2016;30(5):683-93). They found that the cholesterol GBM tumors consume in large amounts is almost exclusively produced by astrocytes and imported by the cancer cells. The researchers described how GBM cells re-engineer existing metabolic pathways to ramp up cholesterol import and retention, and demonstrated that these mechanisms can be undermined by an experimental drug for metabolic disease named LXR-623. This drug accumulates in the mouse brain, and the researchers showed it causes dramatic GBM cell death while sparing non-cancerous cells, including astrocytes. They also report the drug dramatically shrank GBM tumors from human patients that were implanted in mice, significantly prolonging their survival. Mischel told Oncology Times more about the research and how it might suggest a new approach to the development of cancer therapies.

1. What turned your attention to cholesterol import and metabolism as a potential vulnerability of GBM?

"Glioblastoma is one of the most sequenced of human cancers. We know more about the mutations that cause the disease than those, perhaps, of any other cancer, since GBM was the first tumor analyzed by The Cancer Genome Atlas. But, so far, we haven't been able to use that information for the benefit of patients. One reason is that the drugs that target those mutations have a difficult time crossing the blood-brain barrier and hardly make it into the tumor.

"We'd been thinking about this problem and wanted to essentially flip it on its head, approaching it by looking not at the oncogenes themselves but at how oncogenes change the way normal, unmutated enzymes are used by the cell. Cancer cells rely heavily on some of those changes for survival, which is why they're referred to as oncogene-induced co-dependencies. Based on previous observations, we suspected that GBM oncogenes radically alter the way GBM cells take up and use lipids like cholesterol. Further, the tumor's location in the brain would also influence how they process cholesterol. We hypothesized that the GBM cell's metabolic co-dependencies and the tumor's location would together create vulnerabilities very specific to GBM cells and targetable with drugs, or experimental drugs, that can get into the brain."

2. Are there additional oncogene-induced co-dependencies or metabolic vulnerabilities in GBM and other cancers that might be ripe for targeting?

"Yes, I think so. We already have evidence that some transcription factors, though they aren't themselves mutated in any way, are used very differently by tumor cells than by normal cells, creating targetable co-dependencies. Tumor cells also process nutrients for glucose metabolism, lipid metabolism, and protein metabolism in very different ways, and these co-dependencies too may create vulnerabilities. This is probably true for cancers in general.

"Currently, the field tends to focus on targeting oncogene products themselves, and most of them are kinases whose enzymatic activity is blocked by the drugs. But many such drugs have trouble accessing their targets, especially in the brain. Yet there are many other drugs that target other critical enzymes and some are highly brain-penetrant. These could be used to treat cancers that either start in the brain or metastasize to the organ. So this whole idea of targeting those enzymes with drugs that aren't from cancer portfolios or pipelines may represent a very viable strategy, because co-dependencies stem from both the tumor itself and from the micro-environment in which the tumor sits."

3. What are the prospects that this strategy or others like it might be evaluated in clinical trials for GBM?

"There are really two aspects to that. One is access to the drugs themselves for testing, and the other is the design of the clinical trial. As to the first point, part of the message of this paper is that drugs that come from outside the cancer therapy pipeline and even drugs that might have failed in the clinic could turn out to be very useful for cancer patients, including brain cancer patients. As we've shown in this paper, the CNS side effects of an experimental cardiovascular disease drug may actually turn out to be a benefit in brain cancer therapy because it suggests the drug is actually getting in there. This would mean really re-examining and repurposing drugs that have failed in trials for other indications.

"The other aspect is that it's very difficult to design clinical trials for cancers of the brain, since they stratify into a whole bunch of different diseases based on their molecular profiles. One of the fascinating aspects of our recent work is that the metabolic co-dependency we identify seems to be there in the vast majority of GBMs, as well as in cancers that have metastasized to the brain. So this raises the possibility of doing really interesting types of clinical trials—for example, global adaptive clinical trials like the recently announced GBM AGILE trial. In such trials, different therapies and strategies can be tested on patients, and the treatments themselves altered, based on the molecular profiles of tumors and new information. Such approaches, which are also being taken for other cancers, will accelerate the development of innovative therapies like the targeting of cancer cell metabolism and other co-dependencies."


Monday, December 12, 2016

With Yair Lotan, MD, at UT Southwestern Medical Center, Dallas

By Sarah DiGiulio

In May 2012, the U.S. Preventive Services Task Force (USPSTF) issued a grade D recommendation against the use of PSA-based screening for prostate cancer in men of all ages based on data showing that PSA-based screening contributes to overtreatment and over diagnosis of prostate cancer (Ann Intern Med 2012;157:120-134).

That recommendation has sparked controversy since it was first issued. A new study analyzed the real-world data on PSA ordering and referral practices in the years surrounding that recommendation (at UT Southwestern Medical Center) to help understand its effect on practice (Cancer DOI: 10.1002/cncr.30330).

"The United States Preventive Services Task Force recommendation against PSA screening generated significant controversy," noted study author Yair Lotan, MD, Chief of Urologic Oncology and the Helen J. and Robert S. Strauss Professor in Urology at UT Southwestern Medical Center. "We examined a large, whole-institution dataset in the years before and after the USPSTF recommendations reflecting actual practice and found that the changes in PSA use at our institution, if any, were small," he explained. "This is more consistent with behavior seen after the vast majority of practice recommendations."

The researchers included 275,758 male ambulatory care visits between 2010 and 2015 at UT Southwestern Medical Center. The data did not reveal a significant change in the use of PSA-based screening as measured by the total number of PSA exams per ambulatory care visit.

Here's why Lotan said this data matters—and has implications for providers outside of UT Southwestern.

1. Why did you decide to conduct this research—and were you surprised by what you found?

"Policy regarding prostate cancer screening has important implications for men, as this is the most common cancer in men. We felt it was important to understand how the USPSTF recommendations impacted use of PSA at our large tertiary referral institution since we care for a large population of men.

"In many ways, I found the results reassuring since use of PSA did not change dramatically. I was not very surprised since I have two brothers who are internists and I am aware of how many guidelines they need to keep track of in any given year. It is difficult to change their practice with each new recommendation."

2. The actor Ben Stiller recently wrote an essay on how a PSA test "saved his life." His PSA test appears not to be in line with the current USPSTF recommendations. If his cancer had been discovered later, does the evidence suggest he still would have responded to treatment? Would you say that Stiller's claims are warranted?

"Ben Stiller's article provides important insight from a patient's perspective. He is correct that based on the USPSTF recommendation he may never have had screening.

"We know that prior to PSA screening many men were diagnosed only after they experienced metastatic disease. It is hard to know the impact of delayed diagnosis in any individual patient's case—but for a young man with intermediate-risk prostate cancer, there is no question that earlier diagnosis is preferable.

"In regards to current recommendations, the American Urological Association advocates for discussing the pros and cons of PSA screening with patients, which I think is a good policy so patients can make their own informed choices."

3. What should practicing oncologists and oncology care providers outside of UT Southwestern know about this research?

"Our institution's findings may not represent the nation as a whole; however, at least one survey dataset pointed to Texas as one of the states with the largest drop in PSA use, which we did not observe. With recent revelations about the flaws in studies used in the USPSTF recommendation, we hope the USPSTF will be diligent in considering the wisdom of their initial recommendation against PSA since this can have a significant impact on health of men.

"Future research directions are many, including looking at provider factors that may influence PSA use and finding new ways to appropriately treat men with prostate cancer and avoid treatment in men unlikely to benefit from further treatment. There is also need to optimize recommendations regarding screening for prostate cancer and developing more accurate tests."​


Monday, November 28, 2016

With Jonas de Souza, MD, MBA, of The University of Chicago Medicine

By Sarah DiGiulio

Research has established (along with countless personal anecdotes from cancer patients across the U.S.) that financial toxicity is a growing problem in cancer care—and one that will limit the quality of care that U.S. oncologists can provide. One barrier standing in the way of addressing the problem is the fact that there's no good standardized way to measure just how burdened cancer patients actually are, explained Jonas de Souza, MD, MBA, a medical oncologist at the University of Chicago Medicine.

That's why he and his colleagues developed and tested a new tool—the COmprehensive Score for financial Toxicity (COST) measure. The results validating that the tool reliably measured patients' financial burden were recently published online ahead of print in Cancer (DOI: 10.1002/cncr.30369).

"We wanted to show that the tool we developed actually performs well in practice. For example, by using the tool, were we measuring quality of life, wealth, depression—or were we actually measuring financial concerns?" de Souza explained.

The researchers tested the tool on 236 patients from either the University of Chicago Medicine or the NorthShore UniversityHealth System who had been diagnosed with stage IV cancer. They compared the patients' COST scores to other health-related quality-of-life scores, which showed that

the COST tool measured financial distress independently of income or psycho-social distress. They also found the tool to be reliable and consistent.

Here's more from de Souza about how the tool works and what he believes oncologists everywhere should know about using it in their own practices.

1. How does the COST tool work and what makes it different from other financial toxicity measures?

"It is the result of the work of 4 years with cancer patients. The questions were elicited and ranked by cancer patients. For example, when asking about finances in general, one can ask whether patients 'decreased going out for dinner due to out-of-pocket costs.' For the cancer patients we interviewed, this type of question was just not that important. (Maybe because cancer patients develop other priorities or concerns related to their finances, such as the sense of losing control over their finances—e.g. 'I feel I have no choice about the amount of money I spend on care.')

"One difference [compared with other financial toxicity measures] is related to the validation process. In order to be sure we were not actually measuring something else—such as quality of life, income, or psychological distress—but likely a combination of all of those on the finances, we have to go directly to the patients and actually measure all of [those variables] at the same time.

"Finally, when doing this type of research, we are always worried about the type of population we are interviewing. For example, are we only interviewing well-off patients? Or are we only interviewing patients on clinical trials who actually may have fewer out-of-pocket costs than other patients? Are we only interviewing patients who are willing to discuss costs with their physicians and may be having financial issues?

"In validating the COST tool, we were careful to document and account in the analyses for patients who were on clinical trials, [as well as] patients who want and those who did not want to discuss costs. And we also reported on the patients who did not want to participate in the research, showing that we did not have any type of selection bias.

"For these reasons, I would say that the COST is a validated patient-reported outcome that actually measures financial concerns."

2. Is it feasible for this tool to be used widely across other institutions and by other oncologists?

"The main challenge is related to what to do after a patient is 'diagnosed' with financial toxicity. One must have systems in place and available ways to intervene.

"We have made the tool available for any provider at www.costofcancercare.org. The results of the tool will come out automatically, placing the patient in contact with others who also filled out the tool. This is available and free for patients and their providers.

"But, I would say that providers must have systems in place to help the cancer patients when using such a tool. Just telling the patient 'you have financial issues' is simply not acceptable and not enough. We have to help them."​

3. What should oncologists and oncology care providers know about financial toxicity and using this tool themselves?

"Financial toxicity is a side effect like any other. Providers should diagnose what is causing it and treat it accordingly.

"And [to those who] think that providers are not educated to talk about costs: [Providers] are educated to talk about side effects. Therefore, by considering [financial toxicity] a side effect, we can start a conversation with our patients about it.

"What would one do if a patient has pain? Find out the reason and prescribe something to ameliorate the pain. It is not different with financial toxicity. At times, it may be the out-of-pocket costs related to a treatment [that is problematic], while other times the loss of income related to a particular condition. These different causes will then trigger different interventions. For one patient, it may be help paying the medical bills, while for others, filling out social security papers or helping them return to work."



Thursday, November 10, 2016

With Antonella Surbone, MD, PhD, FACP, of New York University Medical School; and Paolo Tralongo, MD, of RAO Umberto I Hospital

By Sarah DiGiulo

Physician and cancer patient Fitzhugh Mullan is credited as being the first to use the term cancer "survivor" in a 1985 New England Journal of Medicine article, "Seasons of Survival: Reflections of a Physician with Cancer". The following year, the National Coalition for Cancer Survivorship (NCCS) extended that definition to include any patient who is alive who has ever been diagnosed with cancer. In a new article published in the Journal of Clinical Oncology, two oncologists argue that definition is outdated (2016;34: 3372-3374). "An additional gap in survivorship care and research remains unaddressed—identification of categories of cancer survivors on the basis of clinical and epidemiologic data to provide better tailored care to people who are now lumped together under the umbrella of cancer survivors," noted the paper's coauthors—Antonella Surbone, MD, PhD, FACP, Professor in the Division of Hematology and Medical Oncology at New York University Medical School; and Paolo Tralongo, MD, Chief of the Medical Oncology Division at RAO Umberto I Hospital.

1. What are the new categories of cancer survivors you propose?

SURBONE: "A.) Acute: Patients/survivors at first diagnosis or relapse, requiring acute intervention; B.) Chronic: Patients/survivors with cancer that slowly progresses or alternates phases of remission and relapse, often accompanied by acceptable quality of life; C.) Long-Term: Patients/survivors in clinical remission for long periods of time or for their entire life, remaining at risk for distant relapse or second tumors, and potentially carrying late treatment-related medical and psychosocial sequels; and D.) Cured: Patients/survivors, such as many patients with early stage (thyroid, cervical, testicular, or colon cancer) when their cancer-specific mortality and life expectancy after several years from diagnosis equals that of gender- and age-matched members of the general population.

"Such categorization, based on clinical, epidemiological, and risk-assessment data is not necessarily in antagonism with the inclusive definition of 'survivor' coined in 1985 by oncologist and patient Mullan to describe the multiple medical and psychosocial needs and concerns, as well as the shifts in interpersonal roles and dynamics, that accompany cancer patients from the time of diagnosis and later extended by the NCCS. Rather, it complements [the current definition] by allowing tailored survivorship care to be effectively and sensitively delivered to different survivors belonging to different categories by way of their actual disease and risk status."

2. Why is it so important to talk about renaming these categories now?

SURBONE: "A too broad and inclusive use of the term 'survivor' with no further categorization prevents us from tailoring survivorship care to the actual clinical situation of different survivors by grouping together a too-heterogeneous population of millions of people who have had a cancer diagnosis in their life. In the era of personalized, precision oncology, categorization provides support for risk-based care, which is increasingly possible due to the intense research novel risk assessment tools in many types of cancer.

"We propose a novel categorization of persons now broadly defined as 'cancer survivors' that can provide support to risk-based survivorship care, new clinical and organizational approaches, and improved follow-up and surveillance recommendations and guidelines."

TRALONGO: "The distinction that characterizes patients alive after a diagnosis of cancer is their heterogeneity of perspective and needs in relation to their clinical status. At the same time, this clinical heterogeneity corresponds to existential and experiential differences among survivors, which require new approaches to communication and education, to optimize both physical and psychosocial rehabilitation for each individual survivor.

"As different medical, rehabilitation, and psychosocial needs often remain unmet (particularly during long-term survivorship), the science and art of survivorship care requires a complex and articulated management, which is not helped—but rather hindered—by insisting on a generic definition of cancer 'survivors.'"

3. What would you want oncologists to know about these new categories and why they are needed?

SURBONE: "We wrote about something to which most practicing oncologists are already acquainted. They all apply some form of categorization to communicate effectively with their patients/survivors and their families, and to plan adequate follow-up, surveillance, and general health maintenance. What we did is break a taboo surrounding the term 'survivor' by making a concise case for the need to define and apply categories of cancer survivors based on clinical, epidemiological, and risk-assessment data.

"[These categories] allow us to provide better care to our patients/survivors as they actually go, not only through the different 'seasons of survival,' but [as they] are in different positions with respect to their disease status, risk of recurrence, late sequels, etc.

"Finding the right balance between making our patients/survivors aware of the implications of their category of cancer survivorship, through communication and clinical recommendations, and acknowledging the desire of many to feel cancer-free—or at least not over-medicalized—will remain a difficult task. Here the wisdom of practicing oncologists—who are skilled in the science, as well as in the human side of cancer care, and are aware of the importance of a good, ongoing relationship patient-doctor relationship—is key."