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

Public Health Personalized Medicine

/in

Gualberto Ruaño, MD, PhD, President, Genomas Inc.; Medical Director, Laboratory of Personalized Health; Hartford, CT;
Email: g.ruano@genomas.net

Q: Public participation by contributing specimens to assess personal genomic information is rapidly increasing. How might this expansion of testing become actually useful for the health of the public?

A: The fields of public health and medicine share a common objective of maintaining the well- being of people, but with very different modes of operation. Medicine has historically focused on interventions to treat illness and restore health, while public health seeks to prevent disease. Hence, medicine generally focuses on the needs of the individual, while public health focuses on the population. Because of this division, policies that serve the common good are limited by the individuals who do not realize the intended benefit. Could prevention become personalized with genomic information so that public health is synonymous with personal health?
The two perspectives can be illustrated by the approaches for dealing with nutrition. Various food pyramids purporting to guide the amount of milk products, fruits and vegetables, grains and legumes, meat, and water have been proposed amid controversy. A school system that adopts a public health approach to the problem might implement a food pyramid based menu, thus increasing its compliance but at the risk of variable responses among its students. Some individuals may have a gene or a lifestyle that makes them benefit from one kind of nutrient while others may have undesired weight gain. If it were possible to identify those individuals who would benefit most from a particular nutrient, then it may be possible to optimize the program as a whole, by avoiding side effects and increasing efficiency. In effect, this effort would bring together aspects of the medical and the public health perspectives by personalizing the public health strategies, thus providing a method by which individuals can optimize their own health, and in the process, benefit the population at large.
I believe the current consumer genomic products offer a path to personal health. Many citizens are purchasing these services and depositing their genomes with companies that will offer various interpretations of the genomic data, as the consumer requires. So far, the leading interest has been ancestry, but business models are evolving to offer consumers a variety of windows on their genome to guide diet and exercise and even expose disease susceptibility (information that can be “opened” by purchasing different products and applications). The genome is sequenced or genotyped once, the information is stored and queried repeatedly depending on the need or interest.
In this scenario, most of the algorithms leading to an interpretation will not be results of causative inference. Knowledge that a particular genetic polymorphism will produce a given effect on the outcome is really limited to genetic diseases, some pharmacokinetic polymorphisms and various cancers. A practical standard would be to determine whether ensembles of particular polymorphisms are associated with the outcome, a relationship that most likely is not causative.
We must be alert to this developing model. This is not science, which has the ultimate goal of understanding mechanisms of pathophysiology. This is modeling for predicting outcomes based on associations that exist between individual genomic characteristics and the outcome of interest. This would allow us to improve our prediction of the response by incorporating information that is related to the outcome, but when we cannot be certain that the associations are causal, we must maintain a level of caution in using the predictions.
There are various technical and medical problems with this model. The first is the quality of the genomic data. In the laboratory profession we strive to maintain a given level of quality and reproducibility so the test results are clinical grade and support medical interventions. But in the genome storage model, there is likely none because the algorithms are sampling multiple polymorphisms, and some redundant ones because of linkage disequilibrium may become the actual quality control. The second limitation is the relative contribution of phenotypic characteristics versus genetic markers to a prediction. It may be that for some predictions, the bulk of the prediction is carried by the phenotype, and the genotype is a small percentage of the predictive power. But will this matter to the consumer?
I believe the genie is out of the bottle concerning consumer genomics, and that an antagonistic view of the field by the medical profession is not in the best interest of the consumer or our profession. In the evolving genome storage model, a number of vendors could provide the initial sampling of the personal genome, and yet other vendors could support a marketplace of algorithms to interpret the genome and provide guidance. Competing algorithms will probably exist so that the consumer can select or compare for the same prediction. The models become fluid and there will be various versions released to the market, each claiming to be more precise. If a vendor persuades the consumer to give feedback information on individual response, the models could become self-improving. I predict that this world of genome data obtained once coupled to a diversity of algorithms for querying will allow public health to become personalized. I further suspect that the interest in ancestry will propel much demand for algorithms related to longevity, wellness, nutrition and fitness. These are indeed the historically desired outcomes of sound public health policy, but enabled by the interpretations of the personal genome of each individual.

RELATED BLOGS AND COMMENTARIES OF INTEREST

Gualberto Ruaño’s contact info is included in the author affiliations at the top of this page.
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.

CDG at TLI

Psychiatric Drug Use by Medical Students and Residents

/in

Pamela Wible, MD, Founder of the Ideal Medical Care movement; Author of Physician Suicide Letters—Answered; Family medicine practitioner in Oregon;

Q: Medical students and residents are among the most important human resources in the United States. Yet we lose many during training due to suicide. Have you information you can share with our readers about the mental health and psychiatric drug use of medical students?

A: I asked 220 doctors: “Have you ever been depressed as a physician?” Ninety percent stated yes. Yet few seek professional help. Here’s what depressed doctors do (when nobody’s looking). Some drink alcohol, exercise obsessively, even steal psychiatric meds. Still more shocking—I discovered that 75% of med students (and new doctors) are now on psychiatric medications.
“I was told by the psychologist at my med school’s campus assistance program, that 75% of the class of 175 people were on antidepressants,” shares psychiatrist Dr. Jaya V. Nair. “He wasn’t joking. How broken is the system, that doctors have to be pushed into illness in order to be trained to do their job?”
How many docs do we lose per year to suicide? The equivalent of one medical school full of students wiped out annually. In my 2016 TEDMED talk, I explain why doctors kill themselves. Personally, I lost both doctors I dated in med school to suicide and 8 physicians in my small town. In 2012 I decided to run a suicide hotline for doctors. I’ve heard from so many suicidal doctors that I published a book of their suicide letters.
In 1990, even I was severely depressed as a first-year med student. So my mom (a psychiatrist) mailed me a bottle of Trazodone. I thought I was the only one. Turns out occupationally-induced depression is rampant in medical training. Now schools dole out antidepressants like candy. Stimulants are used by med students like steroids in athletes. So where do we go from here? Should med schools distribute samples of Zoloft and Adderall during orientation?
The problem is physicians must answer mental health questions (right next to questions on felonies and DUIs) to secure a medical license, hospital privileges, and participate with insurance plans. Check the YES box and be forced to disclose your “confidential” medical history and defend yourself—again and again–for your entire career. You get treated like a criminal for taking meds to cope with the torment of medical training (and practice).
Maybe that’s why so many future (and current) physicians sneak drugs and go off-the-grid for mental health care.
“I’ve been in practice 20 years and have been on antidepressants and anxiolytics for all of that time,” says Jason. “I drive 300 miles to seek care and always pay in cash. I am forced to lie on my state relicensing every year. There is no way in hell I would ever disclose this to the medical board—they are not our friends.”
What if we stop the mental health witch hunt on our doctors? Why not replace threats and punishment with safe confidential care? What if we address the root of the problem—the great sickness in medical education—rather than shifting blame to 75% of medical students for not having enough serotonin or dopamine or norepinephrine in their brains?
As scientists, we can’t continue to approach medical education reform as a neurotransmitter deficiency in medical students. Can we?

Free Audio Book Download
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 Worst Phony Cancer Cures

/in
Stephen Barrett, MD, Retired Psychiatrist; Medical Editor for Quackwatch.org and 24 other consumer-protection Web sites; Publisher for Consumer Health Digest; Chapel Hill, NC;
Email: sbinfo@quackwatch.org

Q: Who tops your list as the most brazen promoters of phony cancer cures in the past 25 years?

A: Three people come to mind: Gregory Caplinger, Hulda Clark, and Dr. Lorraine Day.
Gregory Earl Caplinger died in 2009 while serving a 12-year prison sentence for fraud. For many years he claimed to be a distinguished and widely published medical doctor, professor, and researcher. However, he did not have a bona fide medical degree and accumulated more questionable “credentials” than any other impostor I have ever investigated or heard of. His bio listed more than 75 of them. A habitual con man, he got into legal trouble at least six times for defrauding people. During the mid-1990s, he began operating a clinic in the Dominican Republic that offered treatment to desperate cancer patients. In 2000, after a six-day trial, a North Carolina jury convicted him of wire fraud and money laundering related to “investments” in his phony remedy “ImmuStim.” In 2001, he was sentenced to federal prison and ordered to pay more than $1 million restitution to several victims.
Hulda Regehr Clark (1928-2009) falsely claimed to cure cancer, AIDS, and many other serious diseases with herbs and low-voltage electrical devices. She earned an accredited Ph.D. in zoology but practiced “naturopathy” based on a correspondence course obtained from a non-accredited correspondence school. She was best known for her book, Cure for All Cancers, which claimed that all cancers and many other diseases are caused by “parasites, toxins, and pollutants” and can be cured by killing the parasites and ridding the body of environmental chemicals. Clark used and promoted two medically worthless galvanometric devices. Her “Synchometer” allegedly identified diseased organs and detected toxic substances by noting whether the device made various sounds when “test substances” were placed on a plate. Her “Zapper” allegedly killed microorganisms with electrical energy without harming human tissue. Its use was based on the notion that all living things broadcast characteristic radio frequencies and that the device would issue counter-frequencies that killed unwanted organisms. Clark said she could tell when cancer and AIDS patients were cured within days or even a few hours after her treatment was begun. She died of complications of multiple myeloma under circumstances which suggest that her life was shortened by failure to seek timely medical care.
Lorraine Jeanette Day, M.D. (1937- ), would like people to believe that personal experiences have enabled her to discover the answer to cancer. Unlike Caplinger and Clark, Day has excellent credentials (as an orthopedic surgeon), but in 1989, she suddenly withdrew from medical practice. A few years later, she underwent diagnostic and incisional biopsies for breast cancer. About 20 years ago, she began marketing educational videotapes which claim that her cancer ultimately caused her to become deathly ill and bedridden for many months, but cured herself with a combination of diet and prayer. However, portions of medical records suggest that she had an early-stage intraductal carcinoma that was completely removed during her second biopsy. (She could easily address this issue but has refused repeated requests for the relevant medical records.) Day advises people not to trust the medical profession and claims that standard cancer treatment has never cured anyone. Instead, she recommends strengthening the immune system by dietary means and other methods recommended in her educational materials. Day’s medical credentials and apparent sincerity make her particularly dangerous. A few people have told me about relatives with treatable cancers who shortened their life by relying on Day’s advice instead of standard care.

For Additional Details (Links in-text as well)

Stephen Barrett’s contact info is included in the author affiliations at the top of this page.
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

Nordic Country Tobacco Control

/in

Astrid Nylenna, MD, Acting Head of Department, Department of Global Health, Norwegian Directorate of Health, Oslo, Norway;
Email: Astrid.Nylenna@helsedir.no

Q: Norway has been very active in tobacco control and prevention with some success. To what do you attribute the success Norway has had and are there any lessons from other Scandinavian countries that might be useful, potential approaches for other developed countries?

A: The success in the reduction of cigarette smoking is hard to assign to one single act of regulation or a specific campaign because it is the combination of many simultaneous efforts over the years. The prevalence of daily smoking in Norway declined by more than half in the past 10 years and has reached 12% in 2016 for people 16-74 years old. For young people between 16-24 years of age, the reduction has been even steeper and only 3% were daily smokers in 2016. The mean age of daily smokers has increased, showing that the main reason for the reduction in daily smoking is a decline in recruitment. The use of smokeless tobacco, snus, has risen in the past decade, especially among young people.
The Norwegian tobacco control policy includes a national tobacco control strategy, high taxes, a ban on advertising, age limits (18 years), comprehensive smoking bans, ban on the display of tobacco products, pictorial warnings, ban of packs < 20, normative provision on children’s rights to a smoke-free environment, and tobacco-free schools. Tobacco advertising was banned already in 1973. Norway was the first country in the world to ratify the WHO Framework Convention on Tobacco Control (FCTC) in 2003. In July 2017 Norway introduced plain packaging and became the first country in the world to introduce standardized snus boxes without logo and colors. (For more information: Helsedirektoratet, Folkehelseinstituttet (FHI, which translates to Norwegian Institute of Public Health), Tobacco Control Laws – Norway Summary)
Mass media campaigning is a key element in the present tobacco control strategy. Campaigns are informed by research literature, trends in tobacco use prevalence, dialogue with tobacco users, and trends in media use (especially social media). The decline in recruitment among young people indicates the need for emphasis on smoking cessation. The majority of daily smokers have a desire to quit, demonstrating a huge potential for helping people to quit smoking by promoting cessation tools and assistance. In the past five years, there have been mass media campaigns on a regular basis–including social media–offering cessation information.
One of the cessation tools being promoted is the free smart phone app “Slutta” (“Quit”) developed by the Norwegian Directorate of Health. It has been a huge success, downloaded 550,000 times since its launch in 2013. In a country of 5.5 million inhabitants and about 1 million tobacco users (both daily and occasional use of cigarettes and snus/snuff) the number of downloads is quite remarkable.
The Nordic countries collaborate and discuss tobacco issues. All the Nordic countries have strict tobacco laws and have seen a decline in daily smoking. One example is Finland, which has set a goal of becoming smoke free by 2040 (For more information: Valvira). Finland has also introduced rules on neighbor smoking. These rules include a ban on smoking on all common areas of housing cooperatives and also the possibility of these cooperatives to apply to the municipality to ban smoking on all separate balconies of private apartments, outdoor areas, and even inside the apartments.
Astrid Nylenna’s contact info is included in the author affiliations at the top of this page.
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

Surprise: Vitamin K2 and Cancer

/in

Micki Jacobs, Independent Researcher, Dayton, OH;
Email: mickijacobs@yahoo.com

Q: You know a great deal about Vitamin K2 and its precursors in human health and disease. What is the best evidence of any value of Vitamin K2, Menadione, Menaquinone-4, and Menaquinone-7 in the prevention or treatment of any forms of cancer?

A: Evidence and interest for benefits of vitamin K2 (K2) in cancer etiology and treatment are increasing. Menadione, vitamin K3, has been added to traditional treatments in response to findings that K3>K2>K1 in antitumor effects on various cancer cell lines, but K2 is garnering attention because it is not toxic at any dose, unlike known K3 toxicity. K2 in conjunction with traditional chemotherapy has shown benefits in vitro such as in Hepatocellular Carcinoma (HCC), pancreatic cancer, lung cancer, leukemia, prostate cancer, breast cancer and in a variety of animal models such as the rat model of HCC. Certain human patients have shown benefits with K2 supplements in terms of prevention and treatment; data show that more K intake reduces risk of all-cause mortality.
These forms of vitamin K–menadione (K3), MK-4, and MK-7 (the two most studied forms of vitamin K2 of about 14 identified K2 forms) are part of the larger vitamin K family which also includes vitamin K1, the K form found in plants. Whereas K1 and K2 can be found in food, K3 is not, yet newer findings show that the human body makes menadione from consumed vitamin K in a complex process leading to body-wide endogenously created MK-4, with possible interesting connections to cancer suppression involving the enzyme UBIAD1, dubbed a ‘tumor suppressor,’ essential in this conversion of K3 into K2 and which also controls cellular cholesterol and calcium metabolism.
Vitamin K has been postulated as among the various micronutrients whose subclinical insufficiency may lead to “diseases of aging” which includes cancer. In the Triage Theory, short-term essential processes utilize micronutrients to ensure immediate survival while long-term subclinical insufficiency leads to insidious diseases of aging. Seventeen vitamin K-dependent proteins (VKDP) require K sufficiency to be optimally activated, with coagulation as short-term essential, while VKDPs beyond the coagulation cascade may remain inactivate over time, leading to disease. It appears that subclinical vitamin K insufficiency is common and there is currently no clinical test for this. One of the many VKDPs that require K sufficiency to be activated is TGFBI – mice with this protein knocked out spontaneously manifest cancer and its expression is disrupted in various cancers as either over- or under-expressed. The various VKDPs appear to have multiple roles in cancer etiology, where K may offer disease preventative effects or disease promoting effects, depending on whether cancer has initiated or the stage in which the cancer has advanced.
K2 has become more of a consideration in cancer treatment after the success in turning melodysplastic syndrome (MDS) cells into healthy cells and preventing cancer. MDS is dominated by elderly (who often do not tolerate chemotherapy well) so higher dose MK-4 was used in a 65-year-old Japanese patient whose peripheral blood blast cells had increased to show progression to acute leukemic phase. Treatment with MK-4 offered benefits of reduced blast cell count and increased platelet count with no side effects leading to speculation that “suggests the clinical benefit of using non-toxic VK2 for the treatment of MDS, especially in elderly patients.” K2, sometimes in conjunction with vitamin D, was explored with other types of cancer cell lines. In 2002, K2 intervention was expanded to more MDS patients with various forms of refractory anemia where some were given menetetrenone v none. The benefits of intervention v none were mixed, but the fact that there were significant benefits of K2 with no toxicity led to further consideration of many cancer lines.
In the case of HCC, MK-4 inhibits cancer cell lines growth. K2 showed preventative effects in women with cirrhosis at high risk of HCC in a small randomized controlled trial (RCT). HCC is plagued with recurrence, and in a double-blind RCT of ‘cured’ HCC patients comparing placebo/45 mg/90mg/d MK-4, treatment did not offer benefits at any dose. The mechanism of HCC growthappears to involve PIVKA II, produced by HCC cells in the absence of vitamin K, and suppression appears to inhibit HCC. Unfortunately, administration of MK-4 increases PIVKA II and because HCC tumors are low in vitamin K, a newer way to directly administer K2 to cancer cells was tested and found to overcome their low menaquinone uptake and offer a potentially long-term, safe anti-tumor agent, a prodrug of menahydroquinone-4, a ‘pre-form’ of MK-4. This prodrug showed benefits in HCC mice models with significant tumor inhibition and substantial decrease in PIVKA II.
Micki Jacobs’s contact info is included in the author affiliations at the top of this page.
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

Precision Medicine in the Universal Healthcare System in the Netherlands

/in

Jack A. Schalken, PhD, Professor of Experimental Urology, Radboud University Medical Center, Nijmegen, NL
Email: Jack.Schalken@radboudumc.nl

Q: Science is universal but the practice of medicine varies widely by geography, economics, and culture. The Netherlands is an advanced developed country with universal healthcare. How does your country approach the issue of precision or molecular oncology?

A: The Netherlands, a country with approximately 17 million people, has a typical socialized healthcare system, i.e. equal access to state-of-the-art medical care for all Dutch citizens, including but not limited to oncological care. This healthcare system was the basis for a rather unique effort towards precision molecular oncology. While molecular tumor boards were being established, a Nationwide initiative started in 2014, named Centre for Personalized Cancer Treatment (CPCT). Physicians can enroll patients in CPCT in 50 medical centers in The Netherlands, including all academic cancer centers. Cancer biopsies, preferably from metastatic sites are snap frozen and sent to a centralized state-of-the-art sequencing facility that was made possible via a donation of the Hartwig Medical Foundation. In case actionable mutation(s) are identified, targeted treatments can be prescribed, which is enabled/specified in the Drug Rediscovery Protocol (DRUP). Methodological concerns around Next Generation Sequencing (NGS) such as, quality of tumor specimen, standardized operating procedures (CLIA/ ISO certified laboratory), bioinformatics’ pipelines for mutation calling, and physician reporting are all addressed. Around 2,000 patients have been enrolled, and we are awaiting results from this unique effort to systematically introduce NGS-based DNA analysis into clinical practice. I believe the CPCT approach is the way forward. However, we should realize that this is only the first step towards precision medicine. One improvement is straight forward: molecularly characterize the cancer as early as possible since clonal heterogeneity is a well-described complicating factor in the treatment of this disease. We should not ignore it in our treatment concepts (i.e. combination treatment). In addition to epigenetic changes, changes in gene and protein expression harbor the key to molecular classification of cancers as basis for rationalized treatment. I will keep you informed on CPCT’s progress at CollabRx.com.

Jack Schalken’s contact info is included in the author affiliations at the top of this page.
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 “Rapid Science” in Facilitating and Rewarding Collaboration in Biomedical Research

/in

Sarah Greene, MS, Chief Executive Officer, Rapid Science, Brooklyn, NY;
Email sg@rapidscience.org

Q: You are the leader of Rapid Science, an innovative initiative intended to speed up the process of research and validation of new information, and its use in practice, especially in Cancer. Can you explain this effort briefly for our readers, particularly that focused on sarcoma?

A: It is now a truism that significant advances in this hypercompetitive era of personalized medicine require shared resources such as massive datasets and specialized expertise. This understanding has resulted in many more research grants for multi-institutional and interdisciplinary projects. Indeed, the term collaboration is so fashionable in the scientific literature and RFPs that it has become practically invisible, like echoes of “incentivizing” and “leveraging” on the SF-to-Palo Alto Caltrain. Consider Joe Biden’s “Make it a team sport. Collaborate… rapidly change a million lives” and Sean Parker’s goal to speed immunotherapy cures by forging collaborations.A few years ago, I participated on two funded, multi-institutional research projects as executive director of Cancer Commons (attempting to fill the very large shoes of Dr. Lundberg). From this experience, and many others from the base of my nonprofit startup Rapid Science, it became clear that massive funding, online platforms, and shared datasets do not engender true collaboration or its expected improved outcomes.
There is an abundance of literature pointing out that the current incentive system of ‘publish or perish’ has resulted in dysfunction in the research establishment. The pressure on scientists to publish in high-impact, elite journals often creates competition on research teams that have been funded to collaborate. Lacking a means of tracking, assigning provenance, and rewarding the varied contributions of individual researchers, there is little incentive to share early findings and insights that will further project goals and is largely responsible for today’s reproducibility crisis.

In science… what gets measured is what gets rewarded, and what gets rewarded is what gets done. (Michael Nielsen)

The Rapid Science team of scientific and medical advisors, and a strong board of directors led by Drs. Bruce Alberts and Larry Marton, has conceptualized the C-Score to track and reward collaborative research. We intend this to serve as an antidote to publishing as the sole means of measuring the impact of scientists’ labors and as the primary arbiter of their careers.
Requirements for the design and implementation of this algorithm include a collaboration platform suitable for researchers to selectively share, discuss, and publish findings on a funded project (with software to track these activities). And secondly, editorial expertise is required to facilitate interaction among subgroups of the project and to reduce the burden collaboration places on scientists’ time and attention.
The Rapid Science platform for multi-institutional research teams was launched this month. The system enables posting and discussing findings in a continuum from closed to open access, with each participant controlling when and how widely to share their findings. The members of our first pilot group, Sarcoma Central, are sharing patient data from their institutions with the goal of advancing early detection and new therapies for this rare disease involving dozens of subtypes.
Strong editorial oversight is critical for facilitating meaningful discussion and assisting in coauthoring/disseminating early findings as preprints and publications (e.g., null results, datasets, unfinished experiments, case reports, and posters that are not generally accepted in high-impact journals). In this scenario, subject experts – those PhDs who have traditionally served as gatekeepers for scholarly publications — work alongside the research team to ensure optimal trafficking of ideas and to orchestrate an internal process of “organic” peer review as findings are discussed and iterated in the closed environment. We believe this scrutiny results in far more reliable output to an open audience than traditional peer review that occurs when the project has been terminated.
Working with pilot groups, we will continue refining our tools and methods to test the hypothesis that realigned incentives will result in authentic collaboration, more reliable/valuable outcomes, and earlier open dissemination of research results. We are seeking additional funded research teams to participate; and most crucially, alliance with funders, administrators, and other stakeholders who currently adjudicate scientists’ careers.

Sarah Greene’s contact info is included in the author affiliations at the top of this page.
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

Q&A: Air Traffic Control for Cancer

/in


David K. Cundiff, MD, Retired internist and palliative care physician from LA County + USC Medical Center; Email: dkcundiff@whistleblowerdoctor.org. Jeff Shrager, PhD, Director of Research, Cancer Commons; Adjunct Professor, Symbolic Systems Program, Stanford University; Email: jshrager@gmail.com.

Q: After May 17, 2017, you and Jeff Shrager engaged in a robust discussion about the place, if any, for an “Air Traffic Control system” called “Global Cumulative Treatment Analysis” (GCTA) for Cancer. Will you share excerpts with our readers?

DC: I see some major ethical and financial problems with GCTA:

  1. Who is going to authorize and pay for all treatment regimens (TRs) to be available to all patients at all times? USA health care costs are already out of control. An estimated one-third of all medical interventions do not benefit patients according to many evidence-based medical experts.
  2. How will vulnerable, terminally ill cancer patients and their loved ones be protected from ineffective, toxic, and expensive cancer treatments in the guise of advancing medical science?
  3. How will society be protected from the costs of ineffective cancer treatments with GCTA given that patient self-selection for experimental treatments generally means inconclusive results?

JS: There is no patient self-selection for experimental treatments in GCTA — or at least no more than there is now, and probably significantly less so. Under GCTA the patient, via their care team, is offered a set of options, along with rationales and data needed to make a rational choice about these options. This is just as it is today. The only difference is that under GCTA the set of options (rather than what your doctor happens to like) is guided by the GCTA process, which is running a global PROSPECTIVE adaptive trial over the whole equipoise set. Note that this is NOT “every damned thing” – just the things that we don’t know are better or worse.
DC: Very likely, the experimental cancer treatments that we don’t know are better or worse will be too expensive for all but the rich in the world. Rich people tend to do better in health outcomes. If all the drug companies and others with cancer interventions give their experimental treatments free, that problem might be mitigated. However, if those with cutting edge treatment already have FDA or other medical product licensing agency approval and are already getting $10k/month for their products, they may be reluctant to give the treatment away for free.
JS: It’s clearer to think of this in terms of cocktails, not individual drugs (although GCTA applies to both). There are many cocktails that we now use (PCV, CHOP, etc), and those have been empirically tested through trials, but the cocktails are often personalized, commonly to mitigate adverse reactions, and less commonly through physician experience or taste. But why are we stuck with those cocktails rather than some other plausible set (including different ratios and regimens)? Largely because we aren’t tracking and making global sense of the variations that commonly occur; also, because even if we were, we wouldn’t have enough patients to run RCTs on every plausible micro-modification. GCTA solves this problem–or, at least addresses it in an ethical and statistically strong manner.
DC: This might make some sense for comparing different first line chemotherapies for potentially curable cancers—e.g., acute granulocytic leukemia, Hodgkin’s Disease (stage IV), metastatic testicular cancer, etc. Insurers will pay for some combination chemo, so they might not mind which up front combination is chosen. However, for medically incurable cancers (e.g., metastatic non-small cell lung cancer or pancreatic cancer) or second line salvage chemo after recurrent disease following first-line chemo fails, insurers will be logically hesitant to fund expensive experimental drug treatment and drug companies are not likely to fund it. Again, the rich will be the ones more likely to get the experimental treatment.
JS: Physicians will initially balk at the idea of “positive control” — of being “controlled” – or told what options to offer their patients by a nameless algorithm in the sky. There are many aspects of the GCTA process that should put their minds at ease. First off, pilots don’t feel like the air traffic controllers are trying to … um … “control” them. Actually “air traffic controller” is a misnomer. It should be called something like “Air Traffic Collaborator”. The pilots rely on ATC to be able to see the whole system exactly so that they can guide the pilot around thunderstorms and other obstacles. Moreover, just as in flying, the patient and physician in GCTA have the final say; if they don’t like the options offered, they are more than welcome to make a different choice. The only thing that GCTA asks is for an EXPLANATION (i.e. a rationale). Again, take air traffic control: When a pilot decides to deviate from the flight plan, or the controller’s guidance — which they are 100% permitted, nay encouraged (!) to do if they have GOOD REASON–they actually have to give reason. The reason isn’t just there for show.
DC: Some good reasons for not following the GCTA direction may include (1) that the patient can’t afford the treatment, (2) the treatment is too toxic, (3) the patient is too old to undergo such rigorous treatment, (4) non-toxic alternative treatments sound more appealing, or (5) reason for not following GCTA direction is not stated. It would be a statistical nightmare to categorize all the reasons for not following GCTA direction and to compare outcomes of all those groups and individual patients not offered GCTA direction with the group that followed GCTA direction.
JS: The reason is used by the air traffic controller to redirect other flights. A very common example is if there is turbulence. Pilots will very commonly be redirected up down or around areas of turbulence. They mostly get these reports of turbulence from other pilots who have flown through it and deviated to get around it, either successfully or not. So not only is deviation for good reason encouraged, it is the way the system learns! The exact same thing goes for GCTA: natural deviations are how the system learns. In fact, when there’s no natural deviation, what GCTA does is insert deviation (within equipoise, of course) in order to explore the space.
JS: It’s important not to think of GCTA as a free-for-all. In fact, the whole idea is to avoid the free-for-all that medicine may become if, as Al says, we end up with the equivalent of an open carry law for medicine. Only in the classical sense is this a statistical nightmare. Moreover, it is what it is. We don’t want to drop data on the floor just because they scare statisticians! The whole challenge of GCTA — the thing that makes it, in a sort of statistical geek sense, “fun”, is exactly to confront the data as it is, and to design prospective ways of moving things forward, only dropping things on the floor when we have good Bayesian reasons to do so.
DC: The only way that I can see GCTA working is to have hundreds of millions of people covered by thousands of different healthcare organizations worldwide and to offer the experimental treatments randomly to some organizations providing healthcare for their patients and not to others. Then you follow outcomes in all the organizations before the intervention and after the intervention. Patients that agreed to the experimental intervention would also be compared with those who did not agree to it or for whom the personal physicians did not offer it. It would also be necessary for the experimental intervention provider to fund the trials of experimental therapies in hopes that they be shown effective and to later become the standards of care.
JS: Yes, that’s approximately right. And if you’re willing to narrow “randomly” to “based upon Bayesian information criteria”, or some such more specific process than “randomly”, then we are in complete agreement.

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

Options to Treat a Glioblastoma

/in

Al Musella, DPM, President, Musella Foundation For Brain Tumor Research & Information, Inc., Hewlett, NY;
Email: musella@virtualtrials.com Phone: 888-295-4740

Q: You direct an established foundation that supports research and information about brain tumors. What would you do if you yourself were diagnosed with a glioblastoma multiforme (GBM)?

A: Now that GBMs are in the news again, I would like to discuss what I would do if it happened to me — an adult in otherwise good shape. There are several choices.

  1. Standard of care: Surgery, radiation, Temozolomide. Chance of 5 year survival is about 5%.
  2. Standard of care PLUS Optune. Bumps my chance of 5 year survival up to 13% with no added toxicity.
  3. Phase 3 Clinical trials: There are only two phase 3 clinical trials for newly diagnosed GBM in the USA. The first, intraoperative radiotherapy may be worth trying, as it is a single application. However, there is only a 50-50 chance of getting the radiation, versus serving as a control. The other is using an off label immunotherapy drug, Nivolumab, which has previously failed as monotherapy, tested against Temozolomide in cases where Temozolomide is known to have little effect (unmethylated MGMT). Half of the patients will get Temozolomide in a situation where it is set up to fail. That is not acceptable to me especially since the Nivolumab is readily available off label outside of the trial without the risk of using an ineffective drug. (And using it off label opens up the possibility of combining with other treatments which may wind up working)
  4. Phase 1 or 2 trials: There are about 100 of these trials in the USA. There are many interesting choices here, but we do not have enough data to make an informed decision on which one to try. We do have early results from some phase 1 trials which show results much better than the standard therapies, but it is not likely that any one of these alone will make a big difference in survival for most patients. We do not have the ongoing results of these trials – we only get the results a few months after the trial is over. And while inside the trial, we cannot combine them with other treatments. Many of these trials will exclude you if you use Optune.
  5. Off label use of drugs approved for other diseases. There are many choices here and a rational approach might be to select a “cocktail of drugs” based on a genomic analysis of my tumor.
  6. Cocktail approach involving experimental and approved treatments. Right now this is impossible or very difficult to obtain. However, if it were possible, this would be my approach. Especially if we had a registry of all of the patients, the treatments they tried and the outcome so we can learn from every patient. A Proposed New FDA Drug Approval Pathway: “Conditional” April 5, 2017 and More Details May 10, 2017

Getting Access to Experimental Therapies
There are a few pathways to getting experimental therapies. Currently, none are really practical on a large scale. I have tried to get expanded access/ compassionate use / right to try access on the most promising experimental treatments and it is very hard. Last year, fewer than 1000 patients were able to get FDA approval to try experimental drugs under the FDA’s expanded access program. Getting multiple drugs this way for a cocktail is just about impossible. If the Trickett Wendler Right to Try Act of 2016 passes into law, it would make it easier to get these drugs. However, even if we could get them, without tracking the results, we are not learning and are doomed to repeating same failures.
Marty Tenenbaum and I previously wrote about our ideas for solving this problem. See https://virtualtrials.com/fda2017.cfm
So – bottom line: What would I do?

  1. Surgery – trying for maximal safe resection, possibly using Gliolan (a dye that helps surgeons see small clusters of GBM cells) to increase chances of maximal resection, and insertion of Gliadel wafer (intraoperative chemo therapy) if the resection cavity is not up against the ventricles (and we are not planning on entering a trial that excludes prior use of Gliadel).
  2. Radiation – standard radiation or possibly proton beam radiation. Possibly followed by some type of boost. Possibly try adding a radiation enhancer like Trans Sodium Crocetinate – especially if there is residual tumor.
  3. Temozolomide – during and after radiation. Only if the tumor sample has methylated MGMT. If the tumor is unmethylated, I would try to get Val-083 either in a trial or on compassionate use / right to try.
  4. Optune. We are put into a very tricky situation here. Many trials will disqualify you if you use Optune, but Optune has the highest survival rates in large trials. So you are being asked to gamble a known doubling of chances of 5 year survival for an unknown experimental treatment that might or might not help, and you might even be assigned to a control group. I would use Optune.
  5. There are a few immunotherapies that have shown remarkable results in a minority of patients. A few of the early vaccine trials and the MDNA55 trial have tails of 20% or more of patients living over 5 years and with minimal or no side effects. The early Tocagen trials showed some impressive results. I would try to get one (or maybe 2) of these, and consider adding a checkpoint inhibitor. The polio vaccine trial (PVSRIPO) is getting a lot of hype on “60 minutes” with some very impressive results – but on a small number of patients, and a few serious side effects. I know the first patient in the trial, and she is doing great and tumor free 5 years after the treatment. It is hard to get into, but I would try. [Disclaimer: I am on the patient advisory board of the brain tumor center at Duke, and helped fund the PVSRIPO Trial].

What would you do?
Al Musella’s contact info is included in the author affiliations at the top of this page.
Sign up below to participate in the group discussion for this blog post.
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

Lung Cancer Screening…The Clock is Ticking

/in

Paul R Billings MD, PhD, CEO and Chairman of Synergenz LTD

Q: Lung cancer screening of smokers (spiral CT over 3 years) is paid for by CMS (reimbursement), has a B endorsement from USPTF (method endorsement), and lots of NEJM papers (academic evidence). As many as 8M eligibles noted since 2012. No more than 400K screened to date. There are now realistic treatments for many of these patients. What is the disconnect and how can it be corrected?

A: The practice of medicine can change. Primum non nocere happily persists but the ever-burdensome realization that patients have a plethora of unmet needs, ailments, diseases and illnesses which cannot be specifically diagnosed or effectively treated demands innovation and practice evolution–new knowledge acquired, proven in care, applied and recurrently assessed with alacrity.
For me, the situation in smokers with risk for Non-Small Cell Lung Cancer (NSCLC) is notably galling. The facts are clear and unusually well established. Lung cancer is a deadly disease in most manifestations throughout the world. While lung lesions can be indolent and small cancers may regress, most detected tumors lead to morbid outcomes. NSCLC (a common pathological type) risk is influenced by genes and by environmental factors (cigarette smoke). The risk and disease burden can be reduced by prolonged removal of the environmental trigger (smoking cessation) and the illness successfully treated by surgery after very early stage diagnosis. In a small percent of more advanced cases, with immunotherapies and/or targeted agents (possibly with additional conventional chemotherapies), prolonged remissions and cures appear possible at substantial costs.
In the USA, several years ago, over 50,000 participants were studied in a randomized prospective clinical trial (RPCT) with a 6 year follow up (National Lung Screening Trial; NLST). The study showed that in heavy smokers in their 5th decade or older, lung cancer screening with 3 years of annual spiral CT (better than plain chest xray) reduced lung cancer deaths by 20% and all cause of death by 7%. This study and various others follow on improvements/observations that were published in the NEJM (NEJM 2011;365(5):395-409), favorably reviewed and graded by the USPTF (with recommendations) and the screening was deemed reimbursable (again with recommendations) by the Center for Medicare and Medicaid Services (CMS). It is unusual to have in a brief period a very large study, great data and a slew of high profile publications, national review body endorsement, and payment for important aspects of the test’s delivery in place.
Both USPTF and CMS noted that many of the findings in this study’s cohort were not cancer, that smoking cessation was a prudent medical course in essentially all study participants, and that screening program enrollees needed to be properly informed, consented and counseled to derive optimal benefits from this screening intervention. While not a simple test and cure scheme, these requirements and others illustrated in a recent report of the VA’s experience with a lung cancer prevention and early detection effort, indicate that a widely adopted program built on this type of testing could save many lives (JAMA Intern Med. 2017;177(3):399-406. doi:10.1001/jamainternmed.2016.9022).
Work is ongoing to better identify smokers that would benefit from screening (the NLST detection rate was about 1 case detected for about 375 screened) and if other smokers (younger, fewer pack/yrs) could be successfully screened. Many lung cancers occur in younger smokers than represented in the NLST cohort. There may be as many as 35,000,000 people who should be screened in this country alone. In addition, some presenting for screening have important comorbid illnesses (COPD and/or ASCVD) which might modify a recommendation for 3 years of annual CT screening to detect early stage NSCLC.
But a key disturbing fact is that despite great clinical science, national review and discussion, attention by institutions and patient groups, and reasonable payer reimbursement, less than 10 percent of the approximately 6 million Americans who fit the original NLST inclusion criteria have been engaged and complied with the endorsed protocol. Given the difficulty in conducting large RPCTs in non-overt disease cohorts, in proving screening benefits (data is not likely to improve), and in coping with the worldwide burden of cancers with risks linked to smoking and environmental inhalants, a better understanding of why we have failed smokers so dismally deserves prompt insight.
Cancer can be a terrible and frightening disease as Susan Sontag and many others have taught us. Smokers and those chronically exposed secondhand can be addicted. They may know they are harming their health and enhancing their disease risks but may be uniquely UNABLE to save their lives. Others may want to exercise the “right to be let alone” or think they have those surely rare protective genetic elements that can favorably modify induced oncogenesis.
No matter. We ought to quickly understand this situation better, modify our approach (sharpened targeted screening yielding higher actionable tumor findings; universal stop smoking programs; improved screening effectiveness in ethnic/genetic subgroups; sensitive environmental analysis for carcinogens; etc.) and then act. The carcinogen producers appear more sophisticated at concerted action than the caring medical establishment.

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.