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

Serious Caveats in Screening for Pancreatic Cancer

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A Q&A with Rama Gullapalli, MD, PhD; a a physician-scientist in the departments of Pathology, Chemical and Biological Engineering at the University of New Mexico. His research lab focuses on the role of the environment in hepatobiliary cancers. He is also a practicing molecular pathologist with an interest in emerging molecular diagnostics, next generation sequencing and bioinformatics. Email: rgullapalli@salud.unm.edu 
Q: A recent New York Times op-ed piece from an NYU Langone Health professor urged an aggressive approach to screening for early-stage pancreatic cancer. Despite optimism, the history of cancer screening is rife with trouble, the harms often exceeding the benefits. What do you think is the best way to proceed?
A: Imagine a scenario.
A new cancer test hits the market with some impressive characteristics: a detection sensitivity of 95% and a specificity of an equally impressive 95%. If you were asked the question, “Given a positive test result, what are your chances of actually having cancer?” and you guessed a number of 80 or 90%, you would not be alone. But you’d be wrong.
The key missing information necessary to answer this question is the disease probability among the general population. The number of new cases of cancer detected every year in the U.S. is about 462 cases per 100,000 people. This means that the probability of a new cancer being detected in a member of the U.S. population annually is roughly 0.00462%. Incorporating this information leads to only an 8.1% chance of having cancer for a test that is positive! This is what is called an inverse probability problem.
Puzzled? Let me explain it in a different way. Statistics show that, in the U.S., about 462 people are newly diagnosed with cancer for every 100,000 people among the general population each year. The new test will correctly pick up 95% of these new cancer patients (i.e., about 439 patients). Of the remaining 99,538 people who do not have cancer, the test will incorrectly diagnose cancer in about 4,977 individuals! This is what pathologists would refer to as a “false-positive” diagnosis. The key point to remember is that cancer is a relatively rare disease. This basic fact enormously influences the value of any given cancer-screening test available in the market.
There has been much optimism and hype associated with cancer screening. Some cancer screening tests, such as tests for colorectal cancer or cervical cancer, have indeed made a dent in our ability to detect and treat the disease at an earlier stage. But in other cancers, such as breast cancer and prostate cancer, the results have been a mixed bag. For instance, screening for cancer in hard-to-access organs, such as ovarian cancer, led to an increase in complications due to surgery with no difference in the cancer outcomes.
A screening test with an increased false-positive rate (think of the 4,977 people in our imagined scenario who had a false-positive test result, but no real cancer), results in unnecessary and invasive testing that is ultimately of no clinical value. However, the societal costs of following up false-positive test results are enormous and include increased downstream testing and increased patient interventions. For patients, an enormous amount of anxiety and stress is expended in resolving false-positive screening test outcomes.
A recent New York Times op-ed piece discussed the issue of cancer screening in one such hard-to-treat disease: pancreatic cancer. In response to beloved TV host Alex Trebek’s diagnosis of stage 4 pancreatic cancer, author Diane Simeone, MD, suggests DNA testing as a first step to identify high-risk BRCA gene mutations in potential pancreatic cancer patients. BRCA gene mutations are associated with a higher risk of some types of cancer, including breast, ovarian, and pancreatic cancers. In her op-ed, Dr. Simeone reports that her clinic identified BRCA gene mutations in roughly 15% of the pancreatic cancer patients treated there. The key point is that these mutations were detected in patients who already had pancreatic cancer.
The op-ed piece correctly states the importance of identifying individuals at a higher risk for pancreatic cancer. While it is indeed optimal to screen for these high-risk pancreatic cancer patients, the means by which we can identify these patients beforehand is unresolved and very much a work in progress. One must be especially careful in the context of hard-to-diagnose and hard-to-treat diseases, such as pancreatic, liver, and ovarian cancers.
With the dramatically falling costs of DNA testing, one may be tempted to view it as the silver bullet for early cancer detection. However, the utility of DNA testing for screening purposes in different cancers is unproven currently and needs further research. Patients and physicians must be fully aware of the potential harms of unnecessary downstream testing due to the false positive outcomes of DNA testing. DNA testing may be cheap, but the consequences of DNA testing may prove to be very costly.
Caveat emptor!
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Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Encouraging and Paying for Clinical Trials, Right to Try, and Expanded Access: Part Three

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A Q&A with Mark Shapiro, PhD,Vice President of Clinical Development at xCures, Inc., Partner at Pharma Initiatives; mshapiro@xcures.com. This is the final installment in a three-part series in which Dr. Shapiro has shared his thoughts on the question below. Read part 1 and part 2.
Q: Treatment of Americans with advanced cancer is complex and challenging and can be very expensive. Many urge greater participation of such patients in clinical trials. In general, who pays the expenses of clinical trials? And, specifically, how are the costs for Right to Try and expanded-access approaches reimbursed?
A: In clinical research, agreements between the research sponsor and the treating institution define what aspects of a study protocol are charged as research or related administrative costs, and what items are considered standard-of-care; that is, eligible for billing to insurance. This is made by a coverage review at the institution. While the sponsors provide the study drug freely to the site and patients, they expect to receive valuable data in exchange. In expanded access, which is treatment rather than research—but stills follows a protocol approved by the U.S. Food and Drug Administration (FDA)— sponsors pay the required administrative costs and the free provision of the investigational drug. The drugs are expensive, and the sponsor incurs additional compliance costs when they make an investigational drug available. So, expanded access is largely a charitable act on behalf of the sponsor. While there are regulations allowing sponsors to recoup their costs under expanded access, these are rarely used. Most sponsors, especially larger companies, deliberately plan for expanded access when planning manufacturing campaigns during oncology drug development. In fact, large sponsors report that they approve about 95% of the expanded-access requests that they receive.
Recently, the FDA commissioned a study by McKinsey & Company on their processes for expanded access and has been busy implementing several recommendations to streamline the administrative barriers. In that report, it was estimated that it takes a physician and their support staff an average of 30 hours to prepare a single-patient expanded-access request, so the FDA introduced a plan to prepare the requisite forms for single-patient expanded-access requests for doctors who request it. The cost of expanded access then is partly borne by the patient’s doctor, who must invest significant extra time to request the drug and comply with the additional responsibilities associated with using it.
These programs are for the primary purpose of treatment, not research. Nonetheless, ethicists have made it clear that there is an ethical imperative to learn from treatment provided under expanded access. Therefore, at xCures we try to learn as much as we can in the least burdensome way possible while helping to meet regulatory requirements for reporting on safety and patient outcome by using real-world data to further reduce the administrative burden for sponsors and physicians participating in expanded-access programs.
Under the Right to Try Act, the patient does not have a “right to try,” but they do have a “right to ask.” Specifically, they can ask their doctor, who, if suitably licensed to practice medicine, can ask a sponsor to make an experimental drug available. That is no different than expanded access—there is a right to ask. In both cases, the sponsor is under no obligation to provide the drug. The difference is that with Right to Try, a health insurer is not required to pay for care associated with the treatment, which contrasts with the coverage determination for clinical trials, including expanded access, conducted under an Investigational New Drug authorization.
The law does provide clarification about liability, which is another aspect of medical costs. The physician, their institution, and manufacturer are explicitly shielded from liability related to a drug administered under Right to Try for anything other than reckless or willful misconduct, gross negligence, or an intentional tort. I think this may reduce barriers to access, but in my experience, expanded access is not typically inhibited by insurance coverage, and only rarely does language around indemnification in compassionate use agreements become a contentious point of negotiation between sponsors and hospitals. In clinical trials, the consent must disclose who is responsible for costs in the event of a trial-related injury. Often that risk is insurable since adverse experiences that occur during a clinical trial are treated and billed normally. Under Right to Try, the costs of treating any adverse drug effects are likely to be billed entirely to the patient.
So, under Right to Try, the patient will bear the costs of medical care, and unlike an insurer with market power to negotiate discounted rates, they will likely pay the chargemaster rates. They may end up paying for the cost of the drug as well, since the Right to Try Act waives the application of sections in 505 and 351 prohibiting commercialization of unapproved drugs. Only those who are wealthy enough to completely self-pay their healthcare could reasonably access treatments under Right to Try, which could easily run into the hundreds of thousands of dollars (perhaps more). With expanded access, the cost is spread across the sponsor, insurer, institution, and patient, making it more accessible for now.
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Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Encouraging and Paying for Clinical Trials, Right to Try, and Expanded Access: Part Two

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A Q&A with Mark Shapiro, PhD,Vice President of Clinical Development at xCures, Inc., Partner at Pharma Initiatives; mshapiro@xcures.com. Last week, Dr. Shapiro shared his initial thoughts on the question below. Today, he discusses issues of cost and equitable access to care.
Q: Treatment of Americans with advanced cancer is complex and challenging and can be very expensive. Many urge greater participation of such patients in clinical trials. In general, who pays the expenses of clinical trials? And, specifically, how are the costs for Right to Try and expanded-access approaches reimbursed?
A: In late-stage cancer care, treatment is very expensive. While there is a great deal of focus on the cost of the drugs, many other costs are involved, including the cost of care, the cost of the facility, and the cost of laboratory and other tests. When you add clinical research on top of care, there are additional tasks, but it is normally the research sponsor that pays for those administrative and research costs, which are incurred by physicians and the institutions conducting the clinical trial.
Insurance companies also pay for at least some of the associated costs of care. In fact, sponsors of cancer trials strive to design studies that follow existing standards of care to minimize the additional costs of non-standard procedures. The Affordable Care Act (ACA) specified that standard-of-care procedures delivered during a clinical trial could be charged to insurance for studies conducted under an Investigational New Drug application. Before the ACA, insurers in many states did not cover procedures performed when the patient was in a clinical trial, so the passage of the ACA can be credited with the increase of access to and enrollment in cancer clinical trials in the past few years. Patients also bear many of the costs of their cancer care, even when they are in clinical trials, because they are responsible for insurance copays and deductibles.
The new company xCures is working with Cancer Commons to help cancer patients who cannot participate in clinical trials—either because they are too sick, otherwise don’t qualify, or don’t live near enough to a center conducting a suitable trial. To help these patients gain access to medically logical therapy, we create a bridge between the research sponsor’s companies, physicians, and patients to facilitate expanded access. We are focused on reducing the administrative burdens and barriers that inhibit these stakeholders from providing expanded-access treatments.
Right to Try has a similar set of requirements as expanded access but removes some of the administrative time and cost involved, such as oversight from an institutional review board and the U.S. Food and Drug Administration (FDA) or following a formal treatment protocol that defines the safe use of the treatment. It also removes the need to notify the FDA of serious and unexpected adverse drug reactions altogether. That caused ethicists some concern since it is important to learn whether a patient was helped or harmed and share that information with other patients or doctors. It also makes assessing the effects of the law difficult for policymakers.
While the FDA has been clear that expanded access can help and rarely hurts research sponsors, some companies are reluctant to offer expanded access out of fear that they will learn something that might harm their chances for a drug approval. A review of hundreds of non-disclosure agreements and tens of thousands of patients treated under expanded access had laid this fear to rest. But, a clear advantage for sponsors is that under Right to Try, the law disallows the use of outcomes from Right to Try patients to adversely affect the review of the product by FDA. This type of clarification would certainly help encourage expanded access but risks creating a problem of unreported results even as new legal requirements for registration and reporting of clinical trials were implemented under 42 U.S.C. § 282(j)(5)(B).
So, Right to Try is a new tool in the toolkit for seriously ill patients, but the pathway for expanded access is better defined and may be less expensive to implement for most stakeholders, points I will discuss in part three of this series.
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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

Encouraging and Paying for Clinical Trials, Right to Try, and Expanded Access: Part One

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A Q&A with Mark Shapiro, PhD,Vice President of Clinical Development at xCures, Inc., Partner at Pharma Initiatives; mshapiro@xcures.com
Q: Treatment of Americans with advanced cancer is complex and challenging and can be very expensive. Many urge greater participation of such patients in clinical trials. In general, who pays the expenses of clinical trials? And, specifically, how are the costs for Right to Try and expanded-access approaches reimbursed?
A: Incorporating clinical research into the clinical care of cancer patients may provide more options, and better outcomes, but participation is quite low. In 2004, only about 3% of American cancer patients participated in clinical trials.
More recent data suggest that the number may now be about 5%, although it is lower for women, children, minorities, and patients in community settings. The low figure should be of concern for a couple of reasons. First, patients are the scarcest resource in cancer research. Low participation in clinical trials represents a lost opportunity to learn and improve care. If every patient were part of systematic research, we could greatly accelerate the pace of cancer research findings. Second, most cancer treatment guidelines recommend a clinical trial as the standard-of-care at some stage in the course of disease. So, with current levels of participation, as many as 95% of American cancer patients are NOT receiving standard-of-care treatment at some point in their care. This deficit is partially attributed to the presence of comorbidities or poor function. Recent research suggests that liberalizing inclusion and exclusion criteria in clinical trials could increase enrollment by about 45%. In the study of common cancers, enrollment of patients with solid tumors could be increased from about 7% to 11%.
In my work at xCures, in partnership with Cancer Commons, we recently had a patient who traveled out of state to be screened for enrollment into a targeted-therapy clinical trial at an academic center. At screening, the patient was deemed ineligible because the disease had not yet progressed. A few months later, that patient began to progress, made another trip out of state, was re-screened and found eligible for the trial, but developed an acute and disqualifying comorbid condition the night before starting treatment. This illustrates a common challenge to enrolling patients in cancer clinical trials: The need to thread the needle during a window where the patient is “sick enough but not too sick.” This period can be days or weeks in diseases like glioblastoma and pancreatic adenocarcinoma. We would like to see more use of the U.S. Food and Drug Administration (FDA)’s expanded access programs for the 90% to 95% of cancer patients who can’t participate in a trial. Of course, the results of such participation would have to be reported so as to increase shared knowledge. Expanded access is a mechanism for doctors to access investigational treatments outside of a clinical trial for patients who have serious or life-threatening conditions without satisfactory therapeutic options.
Recently, the national Right to Try Act became law in May of 2018 (Public Law 115-176) following the passage of right-to-try laws in 40 states. The first patient treated under the federal Right to Try Act was in California last year. The sponsor, ERC-USA, notified the FDA that it would make their brain cancer vaccine available in June, shortly after the passage of the law, and treated a patient in November. While the stated goal was to move quickly, the time to treatment was longer than what we typically see for glioma patients with expanded access. However, this is a new alternative for treatment of cancer patients with an investigational therapy and may supplement clinical trials and expanded access programs as options for those patients who lack other treatment options.
All three of these approaches to treatment—clinical trials, expanded access, and Right to Try—raise issues of both cost and equitable access to care, which I’ll discuss next week in part two of this Q&A.
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Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

At Diagnosis, What Do Cancer Patients Want?

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A Q&A with Laura Benson, RN, MS, ANP, president of Conversations in Care, LLC; LauraBensonRN@Gmail.com

Q: In our digital communication world of 2019, some patients may receive the initial message that YOU HAVE CANCER by cell phone, text, email, or even voice mail. When this happens, what do patients most want, and how can that best be accomplished?

A: When I first read your question, I was immediately brought back to a National Cancer Survivors Day around 1988. During the open microphone portion of the program, a patient bravely rose to address the audience. She proceeded to tell us she didn’t know she had cancer until she received the Survivors Day invitation, whereupon she turned to her attending physician and asked, “Well doctor, do I have cancer?” Since then, communication in today’s digital age has not seen a vast improvement. Indeed, a recent report out of California tells the tale of a patient and family learning he was dying via a video robot interaction.

What has not changed over the decades is the need for information that is easily understood, easily accessible, scientifically accurate, and delivered with compassion and connection. The dawn of the “Dr.Google” age has brought new and unique challenges.

There is no lack of information available. Patients and families still want to know cure rates, prognosis, treatment options, whether they will experience pain, where to find specialists, the costs involved, and what clinical trials are available.

Today’s challenge is guiding patients and families to use reliable information sources, and to avoid recommendations made for “cures” based on questionable science. The need for information remains present from the first day of diagnosis until the last day of the patient’s cancer journey. The focus of the information might change over time, but the need is there. For example, if an initial treatment fails to bring about a successful outcome, information needs shift to second opinions and clinical trials.

When searching for information, patients should first look to the source. Where is the information coming from? I recommend looking at websites that not only have vetting and validation behind them, but also are written at a level that is understandable, complete with a glossary and lots of illustrations, such as the National Cancer Institute’s website. Websites of patient advocacy groups are another good source of information. Many of these groups have full-time scientific personnel and top-notch medical boards providing input and comment to the available information. There are many well-known cancer advocacy groups, such as the American Cancer Society, that provide information on a wide variety of cancer types and treatment options. Other organizations focus on the psychosocial needs of patients and families, like CancerCare, which offers counselling, financial assistance, and support groups. Many disease-specific groups exist, as well.

One area of specific need is understanding and navigating the world of clinical trials. ClinicalTrials.gov offers a comprehensive searchable database, but patients need assistance in understanding the medical jargon associated with inclusion and exclusion criteria. Advocacy groups like Cancer Commons bridge the gap for patients, taking into consideration the nuances of an individual patient’s “case” and connecting them with the latest science and experts in relevant fields. This enables patients to learn which science-based treatment options might be best for them. These kinds of groups help assist the patient to their personalized and best next step.

We are moving from the age of personalized medicine to that of precision medicine, and oncology care is leading the way. It is imperative that we guide the patient along with us as the reason for the journey.

As author Chris Pirschel wrote earlier this month for ONS Voice, “Every cancer diagnosis is as individualized and unique as the person receiving it. From family history to societal and economic background to a patient’s genetic make-up and composition, cancer affects each person with cancer differently.”

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

Capturing Patients’ Real-World Experiences to Improve Cancer Research and Care

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A Q&A with Grace Castillo-Soyao, founder and CEO of Self Care Catalysts; grace@selfcarecatalysts.com
Q: You are well known as a visionary in the field of Real World Experience-Evidence (RWEE). As the founder and CEO of Self Care Catalysts, headquartered in Toronto, how do you see RWEE evolving to favorably impact the field of oncology?
A: I started Self Care Catalysts with some very basic questions. Why is the patient at the farthest end of the care line, treated as simply the recipient of care? It’s a very industrial mindset, a bit like an assembly line; the patient as something to be acted upon. But patients are often experts at their own conditions, including the many kinds of cancer. Why are they not invited to become participants in their own care, in contributing their own experiences? Why are patient experiences not considered to be scientifically valid?
As noted physician Sir William Osler famously said, “It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.”
About 90% of disease management happens at home, but very little information has been gathered about what happens in between clinical visits, and how self care might impact outcomes. This knowledge gap between caring for and living with cancer is wide, yet patients’ experiences—such as the burden of their cancer, their treatments, side effects, and the impact on their sleep, diet, relationships, and work—are barely acknowledged, documented, or discussed with their clinical care team. It’s not because nobody cares; it’s because of a time barrier and an economic barrier. Physicians traditionally get paid for services that happen inside the clinic, not beyond it.
Oncology is one of the disease states for which treatment technologies have undergone significant growth and evolution. Recently, the U.S. Food and Drug Administration has been employing new approaches to expedite the drug development and approval process. These include an emphasis on understanding the “real world,” or what happens with patients outside of clinics and clinical trials.
Because of these changes, and the complexity of cancer management by patients themselves, clinical trials will increasingly need to employ new measures that account for patients’ day-to-day experiences with their disease and treatments. And, as more promising cancer drugs enter the oncology market, the need to collect real world patient experience evidence (RWEE) will become a cornerstone in patient care and treatment decisions.
This shift in oncology will be enabled by the use of digital tools that collect data in a more rigorous way. Such tools can now address long-standing doubts and concerns regarding the validity and subjectivity of data reported by patients. The same tools can also be applied to disease management, which we at Self Care Catalysts believe will dramatically improve clinical outcomes. Indeed, Ethan Basch, MD, MSc, an oncologist at the University of North Carolina and one of our advisors, recently demonstrated that enabling patients to report their symptoms in clinical cancer care improved outcomes dramatically.
For the medical and scientific community, I’m sure it’s comforting to see that collecting patient-reported outcomes in cancer actually provides a dramatic improvement to care! We expect to see that digital engagement has a dramatic effect in how well a patient’s disease is managed and the quality of outcomes that can be gained, and we’ll see it in ever more rigorous studies.
At Self Care Catalysts, we design and build tools to capture the true patient experience. Patient experience data from approximately 3,500 cancer patients who use our Health Storylines Real World Experience Evidence platform reveal that their most common concerns are related to psychosocial, mood, quality-of-life, disease, and treatment experiences. These factors are hardly captured in clinical, lab, and medical reports at all, and not accurately represented in validated quality-of-life surveys.
RWEE combined with traditional clinical, medical, and even genomics data will bring quality of life realities to oncology, and it will advance many aspects of research and care, including drug development, clinical trials, and commercialization. Most importantly, RWEE will improve how cancer patients are involved in their own care, leading to big improvements in outcomes.
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Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The Crucial 90% Missed by Doctors on Computers

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A Q&A with Kevin B. Knopf MD, MPH, chairman of hematology and oncology at Highland Hospital in Oakland, California; kevinbknopf@gmail.com
Q: A successful patient-physician relationship depends upon effective bidirectional attention and mutual understanding. Many patients and physicians believe that common current versions of mandated electronic health records (EHRs) severely impede that interaction, especially eye contact. How can a competent and caring clinical oncologist overcome that problem?
A: For all my faults as a doctor, and I’m sure there are many, there is one thing I think I do correctly, and that is I am never on a computer in front of a patient.
I hear from many colleagues that they can be efficient and personable while going back and forth from the patient to their electronic health record (EHR)—and it is true there are various levels of skill here. However, none do as well, in my opinion, as a computer-free patient environment. I say this from my side as a patient having seen dozens of doctors myself—nothing compares to a doctor who spends all of their time looking you in the eye and interacting face to face. This human contact costs nothing, and yet is so vital.
I’m hardly a Luddite; from my side as a doctor the math is infallible here: approximately 90% of all human communication is nonverbal, so if I am typing on a computer I’m only processing 10% of what is going on and my clinical efficiency drops accordingly. I’m convinced that this 90% is important not just for healing the patient; the way questions are answered and interpreted subtly can allow me to order fewer unnecessary tests and be a more cost-effective doctor.
In oncology many of the discussions veer into existential and religious domains, and this can’t be done except on a very intimate level. My greatest enjoyment in clinic are my patient interactions; for my own wellbeing, I hate to poison these with the EHR.
Some days it seems that the patient note in the EHR deteriorates to a “set of lies agreed upon,” particularly the review of symptoms and the physical exam, which is often templated and describes some Faulknerian version of the truth of what is actually happening.
In today’s world of “high throughput healthcare” designed to maximize relative value units (RVUs) and document in the EHR to upcode, it is the patient who suffers. And yet, it is the patient for whom we all go into medicine. I have done my own time and motion studies on this topic, and my current habit of reviewing the EHR in a separate room before I see the patient and then returning to that room to write the encounter after is more efficient than trying to go back and forth between the patient and the computer.
As a third-year medical student, now 30 years ago, the attending asked me to perform a history and physical on an inpatient in front of the entire team (gulp). I’ll never forget that afterwards he said, “you did a good job, but I want you to pull up a chair next time and sit down when you are talking to the patient.” This echoes the saying of the great oncologist Dr. Jamie Von Roenn: “Don’t just do something, sit there.” Indeed, there is a pleasure in the slowness of the patient encounter that most of us went into medicine to experience—and the EHR continually interferes with that process.
I recently spent about 10 days as a patient in the hospital—in three different hospitals—and different health care providers spent more or less time on a computer in front of me. The best came in my room and were computer free. In the end only one pulled up a chair and sat down to ask how I was doing—my friend the breast surgeon, who is a generation younger than me. I notice in her clinic she is an “EHR-free doctor” as well. Consider this a start.
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Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The Promise of Plerixafor in Glioblastoma Treatment

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A Q&A with Adan Rios, MD; Professor in the Division of Oncology-Department of Internal Medicine of The University of Texas McGovern Medical School at Houston, Texas Medical Center; adan.rios@uth.tmc.edu
Q: Glioblastoma multiforme (GBM) remains a scourge with a typically rapid fatal course resistant to most therapy. All solid tumors must receive sufficient blood supply to grow. Plerixafor is an FDA-approved drug that may inhibit tumor angiogenesis. How might plerixafor be sensibly used off-label as an adjunctive therapy for GBM?
A: Glioblastoma multiforme (GBM) is a CNS (central nervous system) tumor with post-therapy median time to progression of 7 months and median overall survival of 15 months. I decided to use plerixafor for the prevention of recurrence of GBM in one patient treated with standard chemo-radiotherapy five years ago and since then have studied this patient and this subject in depth.
The decision to recommend plerixafor to this patient was borne out from the availability of a human xenograft mice model of GBM developed at Stanford University and in which a variety of experimental conditions clearly demonstrated clinical impact on survival by using plerixafor as an adjuvant to treatment of the experimental GBM with radiotherapy and temodar. An interesting aspect of this model was that plerixafor, on its own, did not have direct anti-tumor effect. This lack of plerixafor anti-tumor effect in the absence of effective established therapy may explain the failure of clinical Phase I-II trials of plerixafor alone in patients with relapsed GBM. In these trials plerixafor was administered intravenously in escalating doses and for periods of up to one month, undoubtedly reaching levels that would have demonstrated direct anti-tumor activity against GBM, should plerixafor have such activity.
It must also be pointed out that the mechanism invoked for the activity against GBM in the Stanford experimental model has less to do with the anti-angiogenic characteristics of plerixafor and expression of CXCR4 receptors by the tumor and endothelial cells and more to do with the active blocking of bone marrow-derived myeloid precursors (BMDCs, MMP-9 expressing CD11b+ myelomonocytes). In the presence of active chemo-radiotherapy against GBM, this active blocking rescues the tumor from the effects of treatment by a process known as vasculogenesis, in opposition to primary angiogenesis. Chemo-radiotherapy eliminates the endothelial cells of the tumor (responsible for primary angiogenesis) resulting in an increased production of hypoxia-dependent HIF-1 and an increased secretion of SDF-1 (CXCL12), the cognate ligand of the CXCR4 receptor, by the tumor and stromal tumor-bed cells. This causes a specific increase mobilization and retention in the tumor bed of BMDCs initiating the tumor recurrence through vasculogenesis. This SDF-1 effect (hypoxia-dependent) can be blocked by plerixafor, an inhibitor of SDF-1-CXCR4 interactions.
The first patient I treated with plerixafor had a relapse of GBM after being free of disease for five years and one month. The small area of relapse was treated with gamma knife and initiation of avastin combined with plerixafor, with no change in his performance status or quality of life. Three other patients of mine are on adjuvant plerixafor off label. One had an early relapse resected and is now back on temodar, an “electric cap,” and continuation of plerixafor. The other two are about to complete one year on adjuvant plerixafor, and while is too early to comment further, they have experienced no unexpected events.
Stanford University’s clinical trials with plerixafor as an adjuvant to chemo-radiotherapy have had ambiguous results that were not as dramatic as expected from the experimental model. I have attributed this to the plerixafor schedule used at Stanford; they administered plerixafor in high doses, but only for the duration of the initial chemo-radiotherapy, and then stopped it. In contrast, the approach I have used is to administer plerixafor on weekly doses until the patient overcomes two critical thresholds: the 7 months of median for progression and the 15 months of overall survival. Plerixafor is long-acting and thus intense daily administration for a relatively short period of time may not be the best strategy of administration for this purpose.
Finally, new data indicates that neural stem cells (NSCs) seem to originate from a very specific zone in the brain, anatomically identified as the sub-ventricular zone (SVZ), from where these cells migrate to different areas of the brain and become transformed into GBM. This raises the fascinating possibility that, regardless of the location of the diagnosed GBM, the prospective irradiation of this specific zone may be of great relevance in the treatment of GBM. This is important because most treatments of GBM with radiotherapy are circumscribed to only the tumor-involved fields.
In conclusion, I believe that there is sufficient experimental evidence to suggest that plerixafor can play a critical role in enhancing the outcomes of conventional therapy of GBM with chemo-radiotherapy. It must be used for a long-enough time to allow the chemo-radio-therapy to eliminate the tumor by a hypoxia-mediated mechanism (elimination of primary angiogenesis) and the blocking of BMDCs, CD11b+ mylomonocytes responsible for vasculogenesis. The outsourcing of GBM stem cells from a specific zone of the brain (the SVZ) is a new and critical observation, the study of which could play a significant role in further understanding the pathogenesis of this tumor and of important changes in our approaches to its therapy.
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

Might Cancer Be a Metabolic Disease?

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Thomas SeyfriedBiology Departmentscience

A Q&A with Thomas N. Seyfried, PhD, Professor of Biology, Boston College
Q: As a geneticist, you know that the genomic makeup of cancers recently has captivated much of the scientific community with new knowledge and new treatments. And yet, cancer outcomes remain dismal for many patients. You have written about cancer from a very different perspective. Why do you consider cancer to be a metabolic disease, and how might we look at different therapeutic options under that rubric?
A: Over 1,600 people die each day from cancer in the U.S., according to recent data from the American Cancer Society (Siegel et al., 2018). The failure to manage cancer has been due in large part to the dogmatic belief that cancer is a constellation of genetic diseases. Accumulating evidence, however, indicates that cancer is primarily a mitochondrial metabolic disease involving disturbances in energy production through respiration and fermentation (Seyfried et al., 2014).
The disturbances in tumor cell energy metabolism are linked to abnormalities in the structure and function of mitochondria that disrupt ATP synthesis through oxidative phosphorylation (OXPhos) (Seyfried, 2015; Seyfried & Shelton, 2010). Consequently, all cancer can be considered a single disease with a common pathophysiological mechanism involving dysfunction of mitochondrial OxPhos. As reactive oxygen species (ROS) arise from defects in mitochondrial OxPhos, the gene mutations observed in various cancers and all other recognized cancer hallmarks are considered downstream effects, and not causes, of the initial disturbance of cellular energy metabolism (Seyfried, 2012; Seyfried et al., 2014).
Arising from this metabolic basis of cancer, cancer growth and progression can be best managed following a whole-body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies (Seyfried et al., 2017). Normal cells transition to ketone bodies for energy under low glucose conditions. Ketone body metabolism thus protects the brain against hypoglycemia. Tumor cells, on the other hand, cannot effectively use ketone bodies for energy due to their dysfunction in OxPhos. Therapeutic fasting and calorie restricted ketogenic diets lower cancer-provoking glucose and insulin-like growth factor (IGF-1) levels, while elevating ketone bodies (Marsh et al., 2008; Mukherjee et al., 2004; Mukherjee et al., 2002). The metabolic transition from glucose to ketone bodies reduces tumor angiogenesis and inflammation while enhancing tumor cell apoptosis.
The Press-Pulse therapeutic paradigm used with the Glucose/Ketone Index will facilitate the non-toxic management and prevention of cancer (Meidenbauer et al., 2015; Seyfried et al., 2017). In addition to glucose, tumor cells can obtain significant energy from the fermentation of amino acids, especially glutamine. The simultaneous restriction of glucose and glutamine, while under therapeutic ketosis, offers an opportunity for long-term cancer management without toxicity. As each individual is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment and prevention strategy will require fine-tuning to match the therapy to an individual’s unique physiology.
The efficacy of metabolic therapy for management of malignant cancer is seen in preclinical models and in humans with various cancers (Elsakka et al., 2018; Iyikesici et al., 2017; Seyfried et al., 2014; Seyfried et al., 2017; Shelton et al., 2010; Toth & Clemens, 2016). It is anticipated that metabolic therapies targeting glucose and glutamine while increasing therapeutic ketosis will significantly improve quality of life and overall survival for most cancer patients.

Editor’s note: If you are curious to learn more about this unusual perspective on cancer, we invite you to follow these links or send us your questions via our ASK Cancer Commons service:

  1. Is Cancer a Metabolic Disease?
  2. Mitochondrial metabolism and cancer
  3. Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer

 
References:
Elsakka, A.M.A., Bary, M.A., Abdelzaher, E., Elnaggar, M., Kalamian, M., Mukherjee, P. & Seyfried, T.N. (2018). Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic Metabolic Therapy and Modified Standard of Care: A 24-Month Follow-Up.. Front Nutr, 5, 20.
Iyikesici, M.S., Slocum, A.K., Slocum, A., Berkarda, F.B., Kalamian, M. & Seyfried, T.N. (2017). Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer. Cureus, 9, e1445.
Marsh, J., Mukherjee, P. & Seyfried, T.N. (2008). Akt-dependent proapoptotic effects of dietary restriction on late-stage management of a phosphatase and tensin homologue/tuberous sclerosis complex 2-deficient mouse astrocytoma. Clin Cancer Res, 14, 7751-62.
Meidenbauer, J.J., Mukherjee, P. & Seyfried, T.N. (2015). The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of brain cancer. Nutr Metab (Lond), 12, 12.
Mukherjee, P., Abate, L.E. & Seyfried, T.N. (2004). Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors. Clin Cancer Res, 10, 5622-9.
Mukherjee, P., El-Abbadi, M.M., Kasperzyk, J.L., Ranes, M.K. & Seyfried, T.N. (2002). Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model. Br J Cancer, 86, 1615-21.
Seyfried, T.N. (2012). Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer. John Wiley & Sons: Hoboken.
Seyfried, T.N. (2015). Cancer as a mitochondrial metabolic disease. Front Cell Dev Biol, 3, 43.
Seyfried, T.N., Flores, R.E., Poff, A.M. & D’Agostino, D.P. (2014). Metabolic therapy: a new paradigm for managing malignant brain cancer. Carcinogenesis, 35, 515-27.
Seyfried, T.N. & Shelton, L.M. (2010). Cancer as a metabolic disease. Nutr Metab (Lond), 7, 7.
Seyfried, T.N., Yu, G., Maroon, J.C. & D’Agostino, D.P. (2017). Press-pulse: a novel therapeutic strategy for the metabolic management of cancer. Nutr Metab (Lond), 14, 19.
Shelton, L.M., Huysentruyt, L.C. & Seyfried, T.N. (2010). Glutamine targeting inhibits systemic metastasis in the VM-M3 murine tumor model. Inter. J. Cancer. , 127, 2478-85.
Siegel, R.L., Miller, K.D. & Jemal, A. (2018). Cancer statistics, 2018. CA Cancer J Clin, 68, 7-30. (https://doi.org/10.3322/caac.21387)
Toth, C. & Clemens, Z. (2016). Halted Progression of Soft Palate Cancer in a Patient Treated with the ..     . Paleolithic Ketogenic Diet Alone: A 20-months Follow-up. American Journal of Medical Case Reports, 4, 288-292. (doi: 10.12691/ajmcr-4-8-8).

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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A Q&A with Mary Woolley, President and CEO of Research!America
Q: You attended the December 2016 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. In FY18, Congress released another $496 million in 21st Century Cures funds for NIH. 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, is authorized to receive a total of $500 million under the 21st Century Cures law. In FY17 FDA received $20 million and in FY18 $60 million from this mandatory funding stream. 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.
An earlier version of this post was published Feb. 8, 2017.
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.