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.

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

The Value of Molecular Disease Models for Cancer Treatment Planning

/in

Smruti Vidwans, PhD, Chief Science Officer at CollabRx

Q: You have been notified that your article entitled “A Melanoma Molecular Disease Model” is among the top 10% of most cited articles in 10 years at PLOS ONE. Congratulations. What is the essence of that paper, why it is important, and what has changed in the past 6 years?

A: Molecular testing of cancer, especially late stage, is increasing in a clinical setting. For it to be relevant, molecular profiles have to be linked with potential treatment options (approved or investigational drugs) and clinical trials. In the paper alluded to above, we 1) defined “actionable” molecular subtypes of melanoma and 2) linked them to clinical trials and drug/ drug classes on the basis of published literature.
Subtypes were defined at the level of pathways and biomarkers/genes rather than individual variants. For example, subtype 1 was defined as having an aberrant MAPK pathway, either by itself or in combination with the AKT/PI3K or CDK pathways. Subtype 1.1 provided more granularity and was characterized as having a mutation in a specific component of the MAPK pathway – BRAF.
The field of precision oncology has evolved much since this paper was published 6 years ago. For example, with next generation sequencing (NGS), non-canonical and uncommon variants can now be identified. Before NGS, patients may have learned only that their cancer did *not* have the common, activating BRAF mutation – V600E. With NGS, they may now learn that their cancer, instead, has another activating BRAF variant – R462I. A classification scheme today must support a more nuanced molecular profile.
Over the last few years, there has been an explosion of clinical and preclinical data around the therapeutic impact of molecular biomarkers and specific variants. For the BRAF R462I variant, there may, in fact, be studies that suggest therapeutic relevance. But if not, is this variant inactionable? Not necessarily. There might be learning points from “related” variants that could be applicable. “Related” variants could include those that 1) have the same functional effect on a biomarker (activation of BRAF), 2) reside in the same protein domain (BRAF kinase domain) or 3) lie in the part of the gene shown to have functional impact (EGFR exon 19).
Therapeutically relevant data may be in a cancer different than the patient’s diagnosis. Should data from another cancer be used in making treatment decisions? If so, under what circumstances? In another publication (Genomically Driven Tumors and Actionability across Histologies: BRAF-Mutant Cancers as a Paradigm), we used BRAF as an example to posit that data from one cancer could inform choice of therapies in another cancer, perhaps as part of combinations.
If predictive data is available for a specific drug (say vemurafenib for BRAF V600E), should that be the only drug under consideration? What if the patient has already been treated with that drug and is resistant or that drug is not available to that patient? Could “similar” drugs (say, other BRAF inhibitors) be used? If so, what is the heuristic?
Today NGS provides physicians with a wealth of molecular data that could inform treatment for their patients’ cancer. However, in many cases, this may depend on leveraging data about “related” variants, data from other cancers, and data about “related” drugs. Risk tolerance of individual physicians toward using these types of data may vary. User-friendly reporting tools that map the variant/cancer/drug relationships leveraged in formulating potential treatment options may help physicians quickly evaluate whether to use a particular variant to inform the choice of treatments.

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

How to Initiate Treatment for Chronic Myelogenous Leukemia March 2016 vs July 2017

/in

Jerald P. Radich, MD, Director of the Molecular Oncology Lab at the Fred Hutchinson Cancer Research Center, and Professor of Medicine at the University of Washington School of Medicine

Q: In March 2016, we published your blog about how to initiate therapy for an adult patient newly diagnosed with chronic myeloid leukemia (CML). As of July 2017, what, if anything, has changed?
A: Two words: Generic imatinib.
The National Comprehensive Cancer Network (NCCN) and its European counterpart, the European Leukemia Network (ELN) are both agnostic in regards to the initial tyrosine kinase inhibitor (TKI) treatment of choice for chronic phase CML.  To review, the more potent “second generation” TKIs (dasatinib and nilotinib) have, compared to the “first generation” TKI imatinib, more efficacy in regards to a lower rate of progression to blast crisis, and deeper molecular responses. Imatinib appears to have a safer long-term toxicity profile, especially in regards to cardiovascular issues. TKI therapy has allowed CML patients to have a near normal life expectancy, and randomized trials show no survival advantage of one TKI over another.  When the second generation TKIs were approved, they were considerably more expensive than imatinib, but by way of some imaginative marketing feats, branded imatinib prescription costs rose to similar levels as the newer TKIs (~$140.000/year). Thus, there is no obvious cost advantage for prescribing the old, reliable imatinib. (Imagine this happening in the auto industry. The 2018 models come out, and last year’s price for the 2017 model suddenly rises to the 2018 version level. Who would buy the outdated model?)
However, in 2016 a generic version of imatinib became available. Costs of this generic were initially very similar to the branded drug, but a second generic was introduced, and costs have predictably begun to fall. A quick internet search finds that branded imatinib will cost roughly $11,000/month, whereas generic imatinib runs from $6-10,000/month. Experience with other generics suggest that these costs should further plummet with the introduction of more generics. In the meantime, you can send your patient to Canada ($9,000/year) or, if more adventuresome, India ($400/year). The extra savings should cover business class flight and a number of fine hotel stays.
The goals of CML treatment are

  1. prevent progression to blast phase (since therapy efficacy has not progressed in decades)
  2. minimize toxicity
  3. in the appropriate patients, get a deep molecular response, as some patients with a deep and lasting molecular response can have their TKI discontinued, and not relapse

Considerations in this latter group are younger patients (especially if they wish to have children), and those patients who actually will consider discontinuation (some don’t if they have had a great response to therapy). Thus, in patients with high-risk chronic phase CML (by Sokal, Hasford, or EUTOS clinical score), or young patients wishing the option of possible discontinuation, the second generation TKIs are a fine choice. For patients with low-risk disease, older, and/or adverse co-morbidities (particularly cardiovascular) imatinib is a solid pick. The availability of generic imatinib makes this an even more attractive option for the majority of newly diagnosed cases.
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

How to Initiate Treatment for Chronic Myelogenous Leukemia March 2016 vs July 2017

/in

Jerald P. Radich, MD, Director of the Molecular Oncology Lab at the Fred Hutchinson Cancer Research Center, and Professor of Medicine at the University of Washington School of Medicine

Q: In March 2016, we published your blog about how to initiate therapy for an adult patient newly diagnosed with chronic myeloid leukemia (CML). As of July 2017, what, if anything, has changed?
A: Two words: Generic imatinib.
The National Comprehensive Cancer Network (NCCN) and its European counterpart, the European Leukemia Network (ELN) are both agnostic in regards to the initial tyrosine kinase inhibitor (TKI) treatment of choice for chronic phase CML.  To review, the more potent “second generation” TKIs (dasatinib and nilotinib) have, compared to the “first generation” TKI imatinib, more efficacy in regards to a lower rate of progression to blast crisis, and deeper molecular responses. Imatinib appears to have a safer long-term toxicity profile, especially in regards to cardiovascular issues. TKI therapy has allowed CML patients to have a near normal life expectancy, and randomized trials show no survival advantage of one TKI over another.  When the second generation TKIs were approved, they were considerably more expensive than imatinib, but by way of some imaginative marketing feats, branded imatinib prescription costs rose to similar levels as the newer TKIs (~$140.000/year). Thus, there is no obvious cost advantage for prescribing the old, reliable imatinib. (Imagine this happening in the auto industry. The 2018 models come out, and last year’s price for the 2017 model suddenly rises to the 2018 version level. Who would buy the outdated model?)
However, in 2016 a generic version of imatinib became available. Costs of this generic were initially very similar to the branded drug, but a second generic was introduced, and costs have predictably begun to fall. A quick internet search finds that branded imatinib will cost roughly $11,000/month, whereas generic imatinib runs from $6-10,000/month. Experience with other generics suggest that these costs should further plummet with the introduction of more generics. In the meantime, you can send your patient to Canada ($9,000/year) or, if more adventuresome, India ($400/year). The extra savings should cover business class flight and a number of fine hotel stays.
The goals of CML treatment are

  1. prevent progression to blast phase (since therapy efficacy has not progressed in decades)
  2. minimize toxicity
  3. in the appropriate patients, get a deep molecular response, as some patients with a deep and lasting molecular response can have their TKI discontinued, and not relapse

Considerations in this latter group are younger patients (especially if they wish to have children), and those patients who actually will consider discontinuation (some don’t if they have had a great response to therapy). Thus, in patients with high-risk chronic phase CML (by Sokal, Hasford, or EUTOS clinical score), or young patients wishing the option of possible discontinuation, the second generation TKIs are a fine choice. For patients with low-risk disease, older, and/or adverse co-morbidities (particularly cardiovascular) imatinib is a solid pick. The availability of generic imatinib makes this an even more attractive option for the majority of newly diagnosed cases.
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

How to Treat Metastatic Colorectal Cancer

/in

Bassel El-Rayes, MD, Professor and Vice Chair for Clinical Research, Department of Hematology and Medical Oncology, Associate Director for Clinical Research, and Director of the Gastrointestinal Oncology Program Winship Cancer Institute of Emory University

Q: You have just received a new patient, referred to you from Macon, GA. She is a 52-year-old white woman in good general health who is 3 months post op from a left hemicolectomy for a grade 3 adenocarcinoma with extension through muscle but not through the serosa. Three of 15 lymph nodes were positive for cancer. She did not receive post-op radiation or chemotherapy. No molecular testing of the tumor was performed. She now presents with a single 3 cm mass in the liver discovered by CT scan. How will you manage her care?

A: (2016) This 52-year-old patient presents with a solitary liver lesion 3 months after resection of a stage III colon primary. If all her other staging is negative, my first question is do we proceed directly to surgery or should we try chemotherapy first? The short interval between the original cancer and the recurrence makes the case for using chemotherapy upfront followed by surgery. FOLFOX would be the chemotherapy of choice. The biologic agent may be influenced by the molecular profile of the tumor specifically RAS mutational status and MSI. Furthermore, knowing the BRAF mutational status may provide valuable information regarding prognosis. For these reasons, I would obtain a genomic profiling of the tumor. I would administer 2 to 3 months of chemotherapy and then obtain re-staging scans. My overall objective would be to complete roughly 6 months of therapy and follow that by surgical resection or ablation of the liver lesion.
A: (2017) The starting point for the management of this patient is to decide whether to do surgical resection only or to use surgery plus systemic therapy. Given she had initially stage III disease and did not receive adjuvant therapy and the short time interval between resection and recurrence, my preference would be to consider systemic therapy. The second question is about the sequencing of therapies. My preference is to do the chemotherapy first since this will allow for evaluation of responsiveness to therapy. The third question: what type of systemic therapy? This decision is driven by the clinical presentation (left versus right side), molecular profile specifically MSI, extended RAS and BRAF, as well as overall health of the patient. For the right-sided tumors, there is now sufficient data to recommend using bevacizumab in combination with chemotherapy as front-line agent. In the left-sided tumors, there are more options for the biologic agent including bevacizumab or an EGFR inhibitor in the extended RAS wild type. In the mutated RAS, the main option is still bevacizumab. In the MSI-high tumors, consideration of PD-1 antibody without chemotherapy is warranted although data for use of a checkpoint inhibitor in the frontline setting is still limited. The last question is related to the duration of therapy. With the recently presented data in the adjuvant setting showing the relatively small benefit for 6 months over 3 months, I would lean towards giving only 3 months of therapy in this case prior to proceeding to surgery.
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

You, Me, and 23: DTC Gene Tests

/in

Melinda Roberts, Web and Product Development Lead Globiana Inc.

Q: Many people are interested in their own genes and wonder whether they are predisposed to cancer or other maladies.  You recently participated in the “23 and me” testing process. As a well-educated and informed consumer, did you find that service useful? Were the explanations given sufficient? Was it worth the cost and trouble? Have the results changed anything about your life?

A: Last December, my septuagenarian uncle left an urgent voice message for me, setting off several days of phone tag. When we finally connected he asked, “Have you heard of those DNA-based ancestry services? I know you’ve been researching our family tree, so I thought, why not? I did one and found out that we aren’t even Scottish! We’re Irish! My whole life has been a lie!”
The Pulpit Rock
Grandpa Tam
I thought of all the time I spent tracing some ancestors to the year 1639 and being frustrated that I couldn’t get more than a hundred years on the paternal side. At least we had documents! I looked at the ship’s manifest marking my grandparents’ emigration from Scotland, our family coat of arms that inspired one son’s semester art project, a photo of my Glaswegian grandfather posing proudly in the Shotts and Dykehead Caledonia Pipe Band in East Calder, and thought, “Well, shoot. I’m going to have to spit in a tube.”

Off to 23andMe.com. I had, of course, heard of these services but thought them cost-prohibitive in light of our richly documented heritage, but now I was a little peeved and suddenly $99 was just fine. In fact, I would go one further and spring for the $199 “Health and Ancestry Service” that promised a comprehensive understanding of my ancestry, traits, and health. What a steal.
Just this month my reports were ready, and they were voluminous. Ancestry: 5 reports. Carrier Status: 42 reports. Genetic Health Risk: 4 reports. Traits: 19 reports (What??). Wellness: 8 Reports, plus an invitation to participate in their “DNA Relatives” program and to continue to share and compare information. They even worked in a little gamification, awarding “insights” for each set of research questions answered. 77 reports worked out to $2.58 a report. This was more than a steal.
What I learned:

  • No variant detected for any of the 42 carrier status listed
  • No variants detected for Late-onset Alzheimer’s Disease (you’re welcome, kids), Parkinson’s disease, or Hereditary Thrombophilia
  • Variant detected for Alpha-1 Anti…Antitryp…Antitrypsin Deficiency, but not likely at risk
  • I can detect Asparagus in urine
  • I probably don’t have dimples (I do), or a cleft chin
  • I probably DO have detached earlobes (check), light freckling (check), wet earwax (I have nothing to compare it to, so likely check), lighter eyes (check) had little baby hair (check), a longer second toe (check), no widow’s peak (check), little or no unibrow (check, thanks to tweezing), and prefer sweet taste over bitter (check), am predisposed to weigh more than average (thanks), unlikely to flush with alcohol (how can I tell? I’m probably drunk), likely to be a deep sleeper (check, until firstborn arrived), and don’t move around much in sleep (if I did, my husband and I would have to sleep in the Coliseum)
  • I have 1,258 relatives already in the 23andMe DNA Family! (Good upsell)

The service provides lots of fun graphics, such as the locations of my DNA relatives and migrations of my maternal line (presumably because the guys never asked for directions). Mom, you swung way east before heading north (the shortest route). Good job.

I can’t say I’ve changed anything in my life as a result of these findings, but I am very pleased to be able to tell my children that we are unlikely to face several very traumatic future ailments, and am newly motivated to contribute to their research.
By the way, I am 63% British and Irish. And as I was warned, nothing about Scotland, but of course that is because “Scottish” falls under British. I won’t tell Uncle Dougal.

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

Leading Retractions in the Cancer Research Literature

/in



Ivan Oransky, MD, is co-founder of Retraction Watch. Oransky is Distinguished Writer In Residence at New York University’s Arthur Carter Journalism Institute, and editor at large of MedPage Today. Adam Marcus is also co-founder of Retraction Watch. Oransky is Distinguished Writer In Residence at New York University’s Arthur Carter Journalism Institute, and managing editor of Gastroenterology & Endoscopy News.

Q: You founded “Retraction Watch” in 2010. It has flourished and filled a substantial niche. In your view, what are the most important retractions or corrections in the cancer literature to date?

A: Without passing judgment on the integrity of cancer research broadly speaking, we have indeed seen several significant cases involving retractions in this field.
Topping the list almost certainly is Anil Potti, formerly of Duke University, whose promising work in oncogenomics – using genetic information to fine-tune chemotherapy – proved to be largely fabricated. Potti’s misconduct helped trigger at least a dozen now-settled lawsuits brought by patients against Duke, and lead to the retraction of 11 papers on which he was a co-author.
Although Duke cut ties with Potti in 2010, the same cannot be said for The Ohio State University and one of its star oncology researchers, Carlo Croce. Croce, chair of the department of cancer biology and genetics at Ohio State, has been under a cloud of suspicion at the institution at various times since the 1990s, but never sanctioned. Although he has at least six retractions to his name, and more than 20 publications with corrections, expressions of concern and other red flags, he has managed to survive several misconduct investigations. He even won a major award this year. One of Croce’s frequent co-authors, Alfredo Fusco, of Naples, Italy, is also on shaky ground. Fusco has lost nine papers to retraction and was under criminal investigation in 2012 for manipulating images in articles and grant applications. According to Nature, Fusco is believed to have employed the services of a professional photography firm to help him prepare his figures.
Even some of the world’s leading oncology researchers have been caught up in misconduct scandals, although not always of their own making. Robert Weinberg of MIT, for example, has had four articles retracted because a former student of his, Scott Valastyan, appears to have improperly reported the data in the studies. (Weinberg has a fifth retraction, of a 2003 paper in Cancer Cell, that did not include Valastyan.)
And Bharat Aggarwal, another highly cited cancer researcher, formerly of the MD Anderson Cancer Center in Houston, has 18 retractions, earning him a spot, at the time of this writing, on our leaderboard.
For sheer volume, we have to single out the recent misfortune at Tumor Biology. The journal was forced to retract 107 papers at a single go after editors learned that they had been victimized in a peer-review scam. (The journal purged 25 articles last year for related reasons.) The authors of the tainted studies all appeared to be based in China. Many of them provided the journal with the names of real scientists but used bogus email addresses that they controlled. Others are believed to have worked with third parties in China that facilitate the publishing of scientific papers.
To anticipate a typical query: Whether cancer research has a higher rate of retraction than other fields is unclear, partly because much research into basic cancer biology is categorized into various areas so the denominator is vague. But we hope our retraction database — still in formation at the time of this writing — will help answer questions like these.
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.