Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Clarity Still Awaited for Prostate Cancer Diagnosis

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Nelson N. Stone, MD, Professor of Urology and Radiation Oncology at The Icahn School of Medicine at Mount Sinai, NY, NY; CEO and Founder, 3DBiopsy, Inc., Aurora, CO. E. David Crawford, MD, Professor of Urology and Radiation Oncology at The University of Colorado, Anschutz Campus, Aurora, CO; Medical Advisor and Founder, 3DBiopsy, Inc., Aurora, CO

Q: Whether and how to decide to do a prostate biopsy when a patient is found to have a “high” PSA remains a debated issue. The Lancet published a large controlled UK study on 1/19/2017 evaluating multi-parametric MRI and TRUS (PROMIS) that some observers have found to be informative. Do you believe that these findings will affect clinical practice?
A: Yes and no: in a landmark study (PROMIS) Ahmed et al. found an 88% sensitivity and 45% specificity for mpMRI in biopsy naïve men for clinically significant prostate cancer. The authors proposed mpMRI as a screening test before biopsy (to eliminate 25%). The caveat here was the biopsies were performed both by a transperineal mapping (TPM) and a transrectal (TRUS) approach-with the latter being only 50% accurate. This would argue against doing TRUS biopsies and taking the men with a positive MRI to the operating room for a more aggressive mapping procedure. If TPM is known to perform better than TRUS (70% vs 30% cancer detection rate) why are only 5% of biopsies performed by TPM?
The TRUS needle takes a 17mm specimen and most lesions (regardless of aggressiveness) are invisible to ultrasound. This makes the TRUS procedure “semi-blind” at best. Trying to span the longer sagittal length of the gland (often > 50 mm) with the TRUS needle requires multiple in-line punctures resulting in more than 50 biopsies per procedure (as opposed to 12 for TRUS). Devices developed specifically for TPM could improve the diagnostic accuracy and shorten the time required. It could also offer the potential to treat patients with targeted focal therapy, an option for more than 1/3 of men with prostate cancer. A biopsy needle and actuator that takes one specimen across the length of the prostate (between 20 and 60 mm), a 3-D image guided tracking program that provides a digital map for focal therapy and a pathology device that preserves the integrity of the longer core allowing the pathologist to identify the location and of every lesion are currently under development. A system such as this will be able to accurately select patients for surgery or observation and open the door for accurate and safe focal ablation.
The initial step in evaluating prostate cancer risk is the PSA test, most of which are ordered by the patients’ family physician. The TRUS biopsy misses cancers in 30% of patients. In patients with prostate cancer, 75% have low to intermediate risk disease, but because prostate cancer is multifocal in 70% of patients, smaller potentially lethal cancers often coexist with the low risk cancers. Out of an abundance of caution, physicians recommend surgery (or radiation) knowing that as many as 50% could have avoided it. In those selecting observation, 40% switch to active treatment because aggressive cancer declares itself or because of worry. It is no wonder that the USPSTF has said that PSA testing does more harm than good.
Crawford et al. has recently published data that suggests if the PSA < 1.5 ng/ml the risk of prostate cancer is low. This argues for getting baseline testing in all men and in the 70% with low PSA’s reducing testing to every 5 years. For those with a slightly elevated PSA, a PHI score or a liquid marker such as SelectMDx (urine test) could help further reduce unnecessary biopsies by identifying men at risk for high grade cancers.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

AACR: Advances in Precision Medicine to Continue

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Srivani Ravoori, PhD, Associate Director, Science Communications; American Association for Cancer Research

Intro: The American Association for Cancer Research (AACR) publishes a forecast blog post at the start of each year to ask prominent cancer research leaders what they envision the new developments will be in areas like immunotherapy, precision medicine, cancer prevention, and health disparities.

In this excerpt from the 2017 post in Cancer Research Catalyst, we interviewed precision medicine expert George Demetri, MD, Professor of Medicine at Harvard Medical School, Director of the Ludwig Center at Dana-Farber/Harvard Cancer Center, and Director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute. Dr. DeMetri is a founding member of the CollabRx Editorial Advisory Board and Chief Editor for CollabRx Sarcoma. Here’s what he had to say about developments in precision medicine for treating cancer – as well as his thoughts on aspects of the 21st Century Cures Act, federal support for cancer research, and the value in supporting basic science.

Q: The American Association for Cancer Research (AACR) is arguably the World’s most important professional organization of volunteers in the cancer research field. As we enter 2017, what does AACR consider the field’s greatest challenges and opportunities?

A: “The good news is that we are still uncovering virtually monogenic diseases – diseases that are driven by single oncogenic fusions or mutations,” says Demetri, a board member of the AACR. Therapies targeting single mutations, such as NTRK fusions, lead to durable and dramatic responses, he notes.For the vast majority of common cancers, however, it is not a simple monogenic problem. We need more combination therapies and more research to find where the Achilles’ heel is, Demetri says. “This is where we, as professionals, need to be careful about overstating the value of precision targeting to the public without also getting too negative.”
“Cancer diagnostics are going to get better and better,” says Demetri, and predicts that we may be on the verge of putting together a composite set of predictive and prognostic biomarkers. “Our diagnostic tools are getting so sophisticated that we can put cancers into different bins at different times in a patient’s treatment course.” With treatment, cancers acquire new mutations to thrive, and with technological advances we can now, in many cases, track the different mutations that are likely driving the disease and match them with different drugs.
While Demetri notes that we have to be intellectually honest about the fact that most patients treated with targeted therapies develop resistance, he is not yet giving up on our aim of finding cures. It may appear as not achievable now, but we are getting there through combination therapies, he adds.
We really need to hone our ability to pick combinations that are not cross-resistant and truly synergistic or complementary, he notes. One of the many approaches is to tie targeted therapies with less-targeted, more multifunctional modalities such as immuno-oncology, which can trigger the immune system. “Even though checkpoint inhibitors are a multibillion dollar market, I would say they are still in their infancy as far as our extent of understanding goes,” notes Demetri.

 
We are likely to see more efforts in developing very potent epigenetic drugs, according to Demetri. Drugs that target EZH1, EZH2, and bromodomain inhibitors are an alternative way to addressing the bad wiring in cancer cells, notes Demetri, who expects to see more studies testing combinations of epigenetic therapies with targeted therapies and immunotherapies.
This year, Demetri predicts, we will gain further understanding into the smaller, molecularly defined subsets of cancer, and develop even better, more precisely targeted therapies.
A recent development is the work on protein degradation technologies, which make it possible to bring the ubiquitin-proteasome system to degrade a protein of interest in a very catalytic way, Demetri says. “This could be a real game changer,” he predicts. Researchers are still trying to understand how to use the protein degradation system appropriately to target undruggable proteins such as Myc and Ras. “I think this is an exciting area of research and this year we are likely to see some proof-of-concept studies. I feel it is just about to hit the mainstream,” Demetri notes.
Progress with cancer genomic medicine depends on a key element, data sharing—large genomic datasets made available to all so the significance of the genetic alterations present in patients’ tumors could be gleaned through collective evidence. However, data sharing comes with many challenges, such as protection of patients’ privacy and ownership of the data.
Progress with breaking the barriers of genomic data sharing will come from continued advocacy from the patients rather than the professionals, Demetri says. “It is vital to leverage our interactions with patients and patient advocates who want the same things that we do to push the kind of data sharing that will advance the field.”
In the event that the efforts from the federal government to further data-sharing initiatives are insufficient, we may see the private sector jumping in to build databases, he notes. “A lot of this will depend on the next heads of the NIH and the NCI,” he adds.
Regarding the provisions in the 21st Century Cures Act to roll back FDA regulations to accelerate drug development, “I like the idea that we can streamline and simplify and have more transparency in the rules for therapeutic development in cancer,” Demetri says. “I’m optimistic that we will keep the focus on both safety and efficacy.” Ultimately, if a drug does not work sufficiently well to justify its use or if it is prohibitively expensive compared to other equally effective options, Demetri says he would trust our community of professionals would have the integrity to not use it, and to explain these choices and options to our patients.
We are in the post-genomic era where we need to overlay other elements (such as epigenetic compensatory mechanisms, metabolic or anatomic resistance mechanisms, etc.) on top of simple genotyping and basic interpretation of the genotype, Demetri says. Adding this is more complicated and will take a lot of effort and money to fund the necessary research. “I feel that the advances against cancer are very powerful and will go forward no matter what, but the question is, how fast can we get there and at what scale and scope?” Demetri asks.
“Reading the tea leaves of the new administration, we may be facing less than optimal federal support for cancer research, but I’m hopeful that we will see more private sector-based and philanthropy-based partnerships that will step up to support cancer researchers at this important juncture,” Demetri says.
“What I’d like to see this year is some time for positive reflection to realize the importance of public funding of science, which is tied to the importance of funding investigators who can follow their instincts to make new discoveries,” says Demetri. He adds, “Fundamental, curiosity-driven research is the only way we are going to get to unthinkable breakthroughs – real paradigm shifters akin to kinase inhibitors in the late 90s and immuno-oncology drugs more recently.”
“We need to recognize that there is a social good to funding basic research: without fundamental scientific understanding, applied medical research is limited to moving already existing therapies around the chessboard. We need science-based novel agents and new approaches to change the therapeutic approach and help patients in ways we might not be able to conceive of today,” Demetri notes and adds, “We have not told that story well enough and I’d like 2017 to be the year where we make that a little clearer to the public so there’s more support for basic science. That is critical.”

Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Why the 21st Century Cures Act is a Good Thing

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Mary Woolley, President and CEO of Research!America

Q: You attended the December signing by President Obama of the 21st Century Cures Act and are recognized to be a strong supporter. Yet harsh criticism of it has quickly appeared in JAMA, BMJ, a variety of other venues, as well as on these pages. Please tell our readers why this is good legislation and how the public health will be protected from exploitation in this very different regulatory world.
A: The bi-partisan 21st Century Cures Act is grounded in a commitment to assuring that our nation’s research ecosystem has the capacity to accelerate the pace at which safe and effective medical advances reach patients. The Act will expand the efficiency, reach and impact of medical discovery in a manner that sustains crucial safeguards against unsafe or ineffective products. The law finances more research, helps to reduce the administrative cost surrounding basic research, and takes additional steps to overcome challenges the Food and Drug Administration (FDA) faces. Patient groups, health care professionals, academic leaders, industry leaders and the FDA and the National Institutes of Health (NIH) were frequently consulted regarding provisions of this bipartisan bill, and their insights were incorporated. We at Research!America were closely involved throughout development of the bill, and are pleased that it crossed the finish line last December.
After years of automatic spending cuts and flat-funding, researchers have been stressed as they work to find solutions to deadly and complex diseases. The 21st Century Cures provides some relief in that regard with an initial $352 million in FY17 to support the NIH Precision Medicine, BRAIN, and Cancer Moonshot initiatives. Congress recognizes that these dollars are targeted and temporary; they do not supplant the need to grow NIH’s annual budget. As reflected in surveys that Research!America commissions regularly, Americans recognize the importance of federally-funded research and support streamlining the pursuit of medical research and innovation.
The FDA, which has for years been underfunded, will also receive new funding with an initial $20 million in FY17 to improve efficiencies in the R&D pipeline. This new funding, in combination with other provisions of the law, is particularly meaningful as it will give the FDA more flexibility to recruit additional experts needed to assure that our regulatory system can properly evaluate rapidly evolving science in areas such as immunology and regenerative medicine.
One important example of rapidly evolving science is the potential to diversify the evidence base used to evaluate the safety and efficacy of medical advances by leveraging “real world evidence” (RWE). The Cures Act defines real world evidence as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.” While concerns have been raised that the RWE provisions would force the FDA to relax critical safety and efficacy standards, these provisions were developed with agency input. This section of the law is designed to empower, not require, the FDA to capitalize on real world data. Real world data will be used when — and only when — it is appropriate to do so.
Faster medical progress saves lives. The 21st Century Cures Act will fuel faster progress. It’s incumbent upon research advocates to engage elected officials to build on the Cures Act, and ensure that adequate funding is provided to make the promise of science and innovation a reality in our lifetime.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Best Uses of PM&R in Patients with Cancer

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Val Jones, MD, Medical Director of Admissions, Saint Luke’s Rehabilitation Institute, Spokane, WA

Q: Your principal practice in Spokane, Washington is Physical Medicine and Rehabilitation. What do you find to be the best uses of PM&R in patients with cancer at your facility?
A: Rehabilitation medicine is one of the best-kept secrets in healthcare. Although the specialty is as old as America’s Civil War, few people are familiar with its history and purpose. Born out of compassion for wounded soldiers in desperate need of societal re-entry and meaningful employment, “physical reconstruction” programs were developed to provide everything from adaptive equipment to family training, labor alternatives and psychological support for veterans.
Physical medicine and rehabilitation (PM&R) then expanded to meet the needs of those injured in World Wars I & II, followed closely by children disabled by the polio epidemic. In time, people recognized that a broad swath of diseases and traumatic injuries required focused medical and physical therapy to achieve optimal long term function. Today, cancer patients frequently benefit from comprehensive rehabilitation as they recover from the effects of chemo (neuropathy, weakness, and cognitive impairments), radiation (scarring and range of motion limitations), surgery (flaps, plastics procedures, tumor resection, amputations), and brain injuries (edema, debulking, gamma knife and neurosurgery).
Rehabilitation is a phase of recovery occurring after any major life-changing medical or surgical event. Our bodies are designed to regenerate and repair, though optimizing this process takes skilled guidance. PM&R physicians (also known as physiatrists) are trained to use physical modalities (stretching, strengthening, heat, cold, etc.) to mechanically enhance healing. They prescribe medications to manage pain, spasticity, nerve injury, and cognitive impairments, while also leveraging the power of physical therapy to increase cardiopulmonary fitness, muscle strength and flexibility. PM&R physicians are also experts in neurologic injury, and can adapt exercises to coax spinal cord, brain and peripheral nerve injuries to construct new pathways for movement and repair.
Inpatient rehab’s prime directive is to get patients back home. To succeed at home, patients need to be able to function as independently as possible, using trained assistants for managing the activities that cannot be performed without help. Admission to a rehab hospital or unit offers the patient home practice opportunities – with simulated challenges that can include everything from terrain parks, test kitchens, medication management trials, driving simulators, balance tests, electric wheelchairs and even exoskeletons that allow paralyzed patients to walk again. It is like a robotic Disney World, with endless aquatic and equipment possibilities for restoring movement and independence.
When I discuss admission to inpatient rehab with my cancer patients, I ask them about their goals, motivation, and energy levels. Timing of rehab is important, because it must dovetail with treatment, so that the physical exertion strengthens, not saps, the patient. Often times when a person is newly diagnosed with cancer, they want “everything done” – intensive chemo/radiation/surgery as well as rehab/exercise. But staggering these interventions can be more effective.
In other cases when care is palliative, learning new skills and being fitted with battery or electric-powered equipment can mean the difference between living at home or in an assisted environment. Some successful cancer patients come to inpatient rehab to practice managing their activities of daily living with varied amounts of assistance, preparing for increased needs as time goes on so they can enjoy being at home for as long as possible.
For the physiatrist, cancer is a cause of impairments that can be overcome with creativity and practice, no matter the long-term prognosis. Adaptive equipment, physical exercise, and cognitive retraining may be applied intensively (3 hours a day in the inpatient setting), or at a slower outpatient pace, depending on individual need. Rehab physicians desire to support and sustain patient function at the highest level, and “add life to years.” As such, rehabilitation should be considered an integral part of successful cancer care and management.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The Importance of Clinical Trial Matching

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Adrienne Craig-Kennard, MBA, VP Global Business Development & Strategic Alliances at CollabRx

Q: You have served as Vice President, Global Business Development and Strategic Alliances of CollabRx for more than one year. How do you rank the importance of the CollabRx Clinical Trial Matcher in the “big picture” of cancer care?
A: Thousands of people each day learn that their cancer is no longer treatable by approved therapies. It is devastating news for both the patient and their loved ones. For some of these patients, however, there are still therapeutic options. Finding the “right” clinical trial has the potential to give them a new lease on life. Indeed, all of us rely on clinical trials to deliver the next generation of life-improving and life-saving therapies.
Despite the large number of clinical trials seeking to provide patients with access to potentially promising cancer therapies, only 3% – 6% of cancer patients who are eligible to participate in a clinical trial do so. There are many reasons for this, but as former Vice President Biden stated, one reason for low clinical trial enrollment is “… because patients and doctors don’t know what trials are available.” Matching patients to clinical trials effectively is often a challenging, time-consuming endeavor, and one that can be difficult to scale to meet the needs of many patients.
Molecular characterization of patients’ cancers can also help expand treatment options, opening opportunities for patients to participate in one of the growing number of genomically driven trials. Fortunately, molecular characterization of patients’ cancers is becoming more common, not only in large academic medical centers, but also in community cancer centers, which treat the vast majority of cancer patients in the United States.
There is a pressing need for better tools to help match beyond standard of care patients with the most appropriate trials for their individual needs. Many individuals and organizations are working to address this problem and the growing number of clinical trial matching services reflects this. Approaches range from online tools that provide basic trial matching via mutation searches, to big data analytics solutions designed to integrate with hospital EMRs. Some patient-facing services have developed platforms that match molecularly characterized patients with trial recruiters. Others connect patients with a network of physicians and cancer researchers to help them find the best next-step options. Clinicaltrials.gov is a valuable resource, however critical information is often unstructured, and it can be difficult to find best-fit trials for molecularly characterized patients quickly. Many providers are still seeking the right tool for their practice’s needs.
The CollabRx Clinical Trial Matcher helps solve this problem quickly and effectively. It is a web-based service that enables oncology care teams to identify all potentially relevant investigational therapies in the context of a patient’s molecular tumor profile and diagnosis. The oncologist or clinician can then quickly sort, filter and prioritize trials to create a short list of preferred trials.
I see the CollabRx Clinical Trial Matcher as having an important role in the bigger picture of cancer care because it combines an effective and unique approach to trial matching for molecularly characterized patients with speed and ease of use at point of care. This makes it accessible to oncologists in both the broader community and academic cancer care settings.
It is heartening to see the increasing number of innovative approaches for matching cancer patients with appropriate trials. I am optimistic that with these advances, a far greater percentage of cancer patients will have that chance for a new lease on life.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The Autopsy is Essential in Proper Cancer Care

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David S. Priemer, M.D., Resident Physician in Anatomic Pathology and Neuropathology, Indiana University School of Medicine Department of Pathology and Laboratory Medicine, Indianapolis, IN; priemerd@iu.edu

Q: The numbers show that American physicians are ready to cast the medical/hospital autopsy into some relic or trash bin. Yet some physicians believe that the low tech autopsy still has much to contribute. Do you believe that the autopsy still can be useful in cancer deaths? And, if so, in what ways?

A: As an aspiring autopsy pathologist, it has been disappointing to learn of the decreasing role of autopsy in medicine. Many in pathology do not care for autopsies because they are dirty, time-consuming, and not reimbursed. Issues also exist amongst clinicians who trust that modern diagnostic modalities provide equivalent value, fear exposing mistakes, fear litigation, and are growing increasingly uncomfortable with approaching patient families. This medical environment which has largely forgotten the autopsy is also that in which trainees are developing habits as future practitioners. As a result, we may be facing further decline in the use of autopsies in the years to come.
Despite diminishing emphasis on the autopsy, data suggests that it has retained its value. This is as true for cancer patients as it is for any. Below I have highlighted what I think are the most important ways in which autopsies are useful for cancer patients:

  1. Establishing cause of death. This reason for performing autopsies does not change because an individual has cancer. According to recent studies, major discrepancies (missed major diagnoses relating to the death that would have had a positive or equivocal impact on survival) between pre-and post-mortem findings occur in approximately one quarter of critically ill cancer patients. This rate is within the range of those observed in recent studies that used generalized patients. Therefore, it does not appear that deaths in critically ill cancer patients are any less likely to involve discrepant diagnoses than deaths in other settings. In addition to confirming the events that led to a death from cancer, the autopsy may also be the only way to discover that a patient died independently of their cancer. In other words, autopsy may be the only way to truly confirm a cancer death at all.
  2. Assessing diagnostic accuracy. Autopsy is the gold-standard for assessing the accuracy of medical imaging. In the cancer setting, autopsy can confirm or deny imaging results and may discover lesions that were not clinically noted. In addition, autopsy allows for histopathologic confirmation of the malignancy; this may be particularly important in patients who had limited tissue sampling prior to death.
  3. Evaluating effectiveness and potential adverse effects of treatment. The autopsy allows access to the entirety of a patient’s tissues, and therefore can serve as the ultimate tool for the determination of treatment effect and harmful side effects in the sickest of cancer patients, those who die. This should be especially considered in patients undergoing chemotherapeutic trials, which is where these outcomes are being studied. However, it is not required that research protocols in the United States include autopsies for patients who die while on trial therapies.
  4. Research. Perhaps the most notable modern example of the use of autopsy in research is actually in cancer research. Tumor molecular biology has been of growing research interest as we move toward targeted cancer therapies. However, tumor harvested for these purposes from living patients is often suboptimal for the purposes of comprehensive molecular analysis. Because of this, autopsy has emerged as a method to collect large amounts of tumor from deceased patients, and the field of “rapid autopsy” has been born. Rapid autopsies, which are performed within 6 hours of death to sample viable tumor, are now being performed in a handful of American institutions. The number is expected to grow in the coming years.

Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The Future of Nursing Care for Advanced Cancer Patients

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Karen Donelan, ScD, EdM, Senior Scientist in Health Policy, Mongan Institute Health Policy Center, Massachusetts General Hospital; Associate Professor of Medicine, Harvard Medical School Boston, MA 02114; kdonelan@mgh.harvard.edu

Q: You have gained remarkable insights into the American nursing profession by performing and publishing survey research for many years. What do you envision as the major roles for nurses in caring for patients with advanced cancer?

A: As our nation grapples with the aging of our population, the care of people with cancer will cost an estimated $158 billion annually by 2020. That is a lot of health care. Some who hear the words “advanced cancer” think about living out their final days far from healthcare settings, perhaps at the beach sipping tropical beverages. Others head for cancer centers and death-defying new therapies: different “cocktails” of personalized plans, targeted therapies, clinical trials. Still others have few options—our national shame of rationing access by income and insurance status.
Nurses, especially oncology trained specialist nurses, have key roles to play for any of these patients. The Oncology Nursing Society has set standards for core competencies for several nurse roles: general care, patient navigation, research, advanced practice, leadership. Oncology nurses may lead infusion and intensive care units and cancer centers. In a community, they work in widely varied roles from ambulatory care to nursing homes, hospices, and home health agencies.
The role of the nurse in our society has its roots hundreds of years ago in the religious orders of Christian, Islamic and Buddhist faiths where the sick and dying were comforted in convents and monasteries around the world. The profession advanced in the 19th century from the battlefield in Crimea to the hospital bedsides of the 21st century. Specialized oncology nursing and advanced practice nursing were born in the 1970s as advanced specialized training, board certification and licensure evolved, much as they have in medicine. The National Academy of Medicine, in two major reports on the Future of Nursing in 2010 and 2015, recommended that all states allow nurses to practice to the full extent of their education and training, and encouraged the profession to seek advanced education at all levels so as to be full participants in interprofessional clinical teams. The meaning of the term “full extent of education and training” is evolving rapidly. The concepts of interdisciplinary and interprofessional teams have been visible in oncology for many years. Nurses are working in every aspect of advanced cancer care. It is unclear what the limits may be on their work and practice—or what price they will be willing to pay for that advanced skill, education and labor.
Perhaps the question we should be asking is: what is the role for physicians in the future care of patients with advanced cancer? In a future of team-based care in academic centers, will physician oncologists oversee care for the sick and dying or mostly focus their time on administration and research? Will palliative and hospice care be overseen by physician and nurse specialists or by community based primary care physicians and advanced practice nurses? How will care be organized, whom will we treat and for how long, and what will be the cost? These are issues we must understand to plan the future of the health professions in the care of advanced care patients.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

21st Century Cures Act, Societal Net Negative or Positive?

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Daniel R. Hoffman, Ph.D., Health Care Consultant in Glenmoore, PA.

Q: Many people are praising the recently passed 21st Century Cures Act. But there are also critics. What are some of the downsides that the American public might experience from this important piece of legislation?

A: On December 13 President Obama signed into law the 21st Century Cures Act, a piece of legislation that the blogosphere has called the “21st Century Giveaway Act” and “Obama’s Gift to Biopharma.” While such appellations suggest the windfall the new law represents for pharma and other health care manufacturers, they fail to hint at its likely harm to public health and safety.
As the price for continuing to fund the National Institutes of Health and various exotic programs such as the cancer “moonshot,” pharma extracted a major step at deregulation that sets back oversight of the nation’s approval and use of medications.
Even as a funding measure, the Cures Act is skewed in favor of pet projects such as Joe Biden’s cancer initiative, while it reduces support for less glamorous public health programs such as immunizations and tobacco prevention.
But the 21st Century Cures Act distinguishes itself by setting back the regulatory process that protects public safety. It does that by relaxing the standards the FDA currently uses for approving new drugs. The entire status of prospectively designed, placebo-controlled, double-blind studies as the gold standard for approving new drugs and devices is now weakened in favor of the deceptive euphemism, “real world evidence” (RWE) defined in the Cures Act as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.”
The concept and definition from the Cures Act is not yet precise. Several authors of an article in the December 8 New England Journal, including FDA Director Rob Califf, claim that the agency is currently “developing guidance” on what constitutes RWE and how it may be used. Until such definition and operational use are precisely defined, several writers in clinical studies, public health and pharmaceutical marketing have chimed in on how the practice of including RWE in regulatory approval is likely to play out. The Pharma Marketing Blog contends the 21st Century Cures Act will permit pharma companies to include “the experience of their KOLs with their patients” as evidence to support a submission.
Section 3022 of the Cures Act about RWE requires FDA to evaluate the use of real world evidence to help support the approval of a new indication for a previously approved drug and to help support or satisfy post-approval study requirements. Health care reporter Julia Belluz in Vox notes that researchers with whom she discussed RWE consider it as “just observations about things that are already happening, not experiments with placebo controls.” According to experienced clinicians, the practice opens the door to “data dredging” that makes it impossible to tell whether a drug is really safe or effective.
So unless the FDA’s eventual guidelines come out with requirements that appear entirely at odds with the relaxed standards that are at the core of the legislation, the practice of RWE will be open to a range of abuses.
The phrase “real world evidence” is one of those semantic sleights of hand typically used by corporate shills in support of egregious giveaways to multinationals and the wealthy. For example, instead of using the term “estate tax,” which most Americans support because it suggests a justifiable tax on the wealthy, they concocted the term, “death tax,” which people in surveys and focus groups considered a penalty on the children of every working person who passes away.
“Real world evidence” involves using observational studies that lack the rigor of current standards. Anyone who has ever done any clinical or survey research knows that crosstabs can be sliced and diced to yield correlations that appear impressive but, upon further analysis, result from intervening and confounding variables. Yet the Cures Act permits drug makers to present precisely such statistical damned lies as proof their products work. One point of reference is Merck’s Vioxx.
Snigdha Prakash studied the Vioxx situation and its ensuing litigation in her book, All the Justice Money Can Buy. She stated she was really “shocked” by “the extent of the scientific…and clinical trial data manipulation” routinely practiced by pharma companies. “I couldn’t believe,” she said, that “a company of Merck’s stature could be doing that.” The 21st Century Cures Act and its relaxed standards involving RWE make such manipulation more likely and potentially more dangerous to public health. FDA epidemiologist Dr. David Graham concluded that Vioxx was responsible for causing 30,000 to 55,000 deaths and 88,000 to 139,000 heart attacks, 30-40% of which were fatal. How many more products are likely to be approved and used with similar or worse adverse consequences?
Equally appalling, the new law will allow the FDA to rely upon “qualified data summaries” to support new indications for a drug, thereby allowing pharma companies to submit their own reviews as the basis for securing label modifications and expansions.
In return for pharma not reprising the infamous “George and Martha” ads in 2009-10 that helped sink Hillary Clinton’s health care initiative in 1993-94, Barack Obama has repaid the predatory pharmaceutical industry many times over. He beat down an initiative to permit drug re-importation, he appointed a pharma functionary as director of the FDA, and he championed the Trans Pacific Partnership, which would abrogate national sovereignty by using secret courts to overturn drug-pricing decisions made in signatory countries. The 21st Century Cures Act represents the final installment in the health care extortion of U.S. consumers that Obama and a compliant Congress engineered.
The previous Democratic administration under Bill Clinton dismantled many of the public safeguards that the New Deal enacted on the banking industry, thereby enabling the 2008 financial meltdown and the worst recession since the 1930s. Obama’s 21st Century Cures Act is motivated by the same neoliberal ideology and, for that reason, it sets U.S. public health on a destination that predates The Jungle and adulterates patent medicines.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The Role of the NCQA in Advancing Cancer Care

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Margaret E. O’Kane, MHA. Founder and President, National Committee for Quality Assurance (NCQA) Washington, DC.

Q: Under your visionary leadership, the National Committee for Quality Assurance (NCQA) has established and enforced quality standards for much of American medicine for >25 years. What is the current major role of NCQA in caring for patients with advanced cancer?

A: We at NCQA (National Committee for Quality Assurance) are proud of our role in helping drive better performance in health care. Since 1993, when HEDIS (Healthcare Effectiveness Data and Information Set) measures were first publicly reported, we have seen substantial improvement in colon cancer screening rates, diabetes and blood pressure control. This comes as a result of HEDIS measures driving pay for performance Medicare stars and a variety of rating and reward systems. These gains translate into better quality of life—and even longer life—for the people to whom the measures apply.
In NCQA’s Accreditation and Recognition programs, plans and practices are rated on whether they are organized for quality through structure and process measures. In patient-centered medical homes and specialty practices, we look at whether access is adequate, whether there are systems to follow up on abnormal test results and whether practices “talk to each other” to ensure that patients benefit from an unbroken chain of coordinated care. Study after study has shown that practices “organized for quality” do better on quality and patient experience and have lower rates of hospital and emergency department use.
We have been working on cancer care from a number of different angles. For me, this is personal: I lost my father to cancer and a number of my family members have struggled with it. NCQA is partnering with Dr. Ezekiel Emanuel and the Center for American Progress to focus on two issues: adherence to treatment guidelines and management of patient symptoms. There will be needless deaths unless life-saving knowledge is disseminated to patients as it is generated, so adherence to guidelines matters. If patients’ symptoms are managed carefully, suffering, needless emergency room visits and hospitalizations can be avoided—along with the attendant risk of infection and avoidable costs.
Parallel to those efforts, we have worked for a number of years with forward-looking oncology practices to certify that they are organized for quality. Dr. John Sprandio, for example, brought his oncology practice through our PCMH (Patient-Centered Medical Home) Recognition program before we had a specialty practice program. Work has continued on a project involving a number of oncology practices in Pennsylvania, with funding from the Patient-Centered Outcomes Research Institute. So far, 35 oncology practices have earned Patient-Centered Specialty Practice Recognition. And we are evolving that program to be more cancer-specific, with the collaboration of Dr. Barbara L. McAneny, who has made groundbreaking efforts on the organization of cancer practices.
In addition, we were recently awarded a grant by the Gordon and Betty Moore Foundation to focus on patients who are at the end of life from illnesses such as cancer. Watching a loved one suffer is never easy, and when there is unnecessary suffering due to defects in the system of care, it is particularly difficult. Cancer treatment is often very difficult, particularly in advanced stages, where the rigors of treatment can actually cause harm. We must learn to engage with patients more effectively—to give them information about a treatment’s potential risks and harms and, when treatment is futile, to give them emotional and personal support.
NCQA is proud of the course we have charted to improve the quality and outcomes of cancer care. Much remains to be done, and much good remains to be achieved.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Clinical Trial Matching for Patients with Molecularly Characterized Tumors

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Smruti Vidwans, PhD, Chief Science Officer at CollabRx

Q: Clinical Trials is such an important topic, but it is so broad. Is there a way to provide better matching for Clinical Trials involving cancer patients, especially those whose cancers may have the added diagnostic information of molecular profiling?

A: Clinical trials provide cancer patients, especially those whose cancer has progressed beyond standard of care, access to potentially promising investigational therapies or novel combinations of approved therapies. Yet only a small fraction (less than 5%) of the 1,700,000 Americans diagnosed annually with potentially lethal cancer participate in clinical trials. A growing number of cancer patients now have their tumors profiled molecularly and there is real opportunity to use that information in better matching them to clinical trials. Below I outline the CollabRx approach to this problem.
Most clinical trials for cancer seek patients based on criteria such as tissue of origin and/or histological characteristics of the tumors. But with hundreds of targeted therapies now approved or under development, there are a growing number of clinical trials looking for patients based on the molecular characteristics of their cancer. Of note are genomically-driven trials such as basket and umbrella trials that match patients to therapies based on the individual molecular profiles of their individual cancers.
While such trials are a natural fit for patients whose tumors have been molecularly characterized, they are not easy to identify in clinicaltrials.gov. For example, a search for the gene ‘BRAF’ identifies trials for patients with BRAF mutations as well as those without. This issue can be resolved only with careful annotation and structuring of trial inclusion and exclusion criteria from sources.
Some trials without explicit molecular criteria may ALSO be relevant to patients with certain molecular profiles. What are these trials and how can physicians and patients identify them?
A patient whose cancer has a certain molecular profile (defined as having a particular set of variants) may benefit from participating in a clinical trial if the trial therapy can be “associated” with one or more individual variants in the patient’s molecular profile. For example, if:

  • The therapy either directly mitigates the oncogenic effect of one or more variants in the patient’s tumor or a downstream component of a relevant biological pathway
  • There are published data suggesting that one or more variants are predictive of response to therapy
  • Clinical experience of oncologists/cancer centers call for use of therapy for a patient with a certain molecular profile

At CollabRx, we use ‘treatment strategies’ to match cancer patients with trials. Treatment strategies explicitly connect a drug or drug class to a variant or variant class and a diagnosis. For example, a treatment strategy for ‘BRAF activating mutations’ in thyroid cancer could include ‘BRAF inhibitors’ (drugs that directly target BRAF) and, say, ERK inhibitors (if published data were to suggest efficacy of ERK inhibitors in BRAF-mutated thyroid cancer). We then match any trials evaluating BRAF inhibitors or ERK inhibitors to patients with BRAF activating mutations, even if those trials don’t have “BRAF activating” molecular criteria.
We believe that matching patients to clinical trials using this two-pronged approach–using molecular inclusion criteria AND using strategically relevant therapies–could identify treatment options for patients that they may not have considered otherwise.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.