Is the PBM Now Your Doctor?
June 21, 2017
Q: Prescription drugs are a big ticket item in American Money Driven Medicine. Since the initiation of pharmacy benefits management (PBM) in 1968, the growth and proliferation of functions of this “middle-man managed care ” concept has been so successful that PBMs now control not only pricing, discounts, and drug selection for >250 million Americans, they threaten to become “the prescriber”. Is this a good thing?
A: You and I naively imagine that medical care responsibility logically devolves to the doctor who cares for the patient, diagnoses their condition, and provides accountability for management, treatment, and outcomes. Guess again. Since medicines have grown in cost and costs continue to skyrocket, profit-oriented businesses have muscled the patient and the doctor out of the way. Pharmacy Benefit Manager (PBM)’s plans now replace physician choice in many settings, and if the physician’s choice is expensive, they replace it with less expensive alternatives. These PBMs then profit from the resultant savings…
Treating Metastatic Malignant Melanoma, March 2016 vs April 2017
June 14, 2017
Q: A lot has happened in the field of Metastatic Melanoma since March, 2016. In April of 2017, would your reply be any different? If so, in what way, and why?
A: The only change from 2016 to 2017 in terms of treatment options for a young patient with metastatic disease is that the 2016 leaning toward combination CTLA-4/PD1 immunotherapy has come back to PD1 monotherapy versus BRAF/MEK combination therapy. With two-year follow-up data from the BMS 067 trial, there was very little difference in survival (5%) versus the very large difference in risk of severe toxicity. But, PD1 antibody therapy with CTLA-4 antibody therapy as a backup remains a very compelling option for BRAF wild-type patients and BRAF/MEK combination therapy as a first-line or second line therapy for those with a BRAF mutation remains on the menu…
Preventing Breast Cancer: Research Worth Watching
June 7, 2017
Q: The goal of the Dr. Susan Love Research Foundation is “…..to find the cause of breast cancer and prevent it now – before it starts”. What are some of the ongoing research studies that are worth watching?
A: Challenging the status quo is part of Dr. Susan Love Research Foundation’s DNA. We are a small nonprofit that seeks to work with the public to conduct, facilitate, and explain research about breast cancer. Working with diverse collaborators such as NASA’s Jet Propulsion Lab and the John Wayne Cancer Center, we extend our ability to focus on innovative research. Our research program is focused on better understanding the human breast to discover why women and some men get cancer. For example, we are working to develop a map of the human breast ducts to facilitate surgery for breast cancer as well as lay the basis for direct delivery of therapy for intraductal disease. Our work on the physiology of the non-lactating ducts suggests that the unit of study is the duct and not the breast, as hormones levels vary…
2017 USPSTF on PSA: A Bad Idea
May 31, 2017
Q: The new draft USPSTF recommendations for rapid comment on use of PSA for screening represent a big change from 2012. They now read: “The decision about whether to be screened for prostate cancer should be an individual one. The USPSTF recommends that clinicians inform men ages 55 to 69 years about the potential benefits and harms of prostate-specific antigen (PSA)–based screening for prostate cancer” and much more. Shared patient-physician decision making. What do you think? (For last week’s answer to the same question see here)
A: In a troubling reversal of its previous Recommendation against the use of prostate-specific antigen (PSA) screening, the US Preventive Services Task Force has issued a Draft Recommendation that doctors should have a meaningful conversation with male patients between the ages of 55 and 69 about the risks and benefits of undergoing PSA screening. This is a bad public health decision that will only increase the use of an intrinsically flawed test that—as formally noted by the Task Force—does far more harm than good…
Big 2017 Change on PSA by USPSTF
May 24, 2017
Q: The new draft USPSTF recommendations for rapid comment on use of PSA for screening represent a big change from 2012. They now read: “The decision about whether to be screened for prostate cancer should be an individual one. The USPSTF recommends that clinicians inform men ages 55 to 69 years about the potential benefits and harms of prostate-specific antigen (PSA)–based screening for prostate cancer” and much more. Shared patient-physician decision making. What do you think?
A: The long awaited updated recommendations from the United States Preventive Services Task Force, issued at their traditional 5-year interval, got it right–Again!! While the 2012 “D” recommendation from the Task Force was met with great skepticism and animosity from several groups, the change in the 2017 recommendation now emphasizes the importance of the Task Force’s continuing evaluations of new and more mature data.
In a series of four detailed, analytic and erudite publications that provide the underpinnings for their new recommendations, even the most serious students of prostate cancer and prostate cancer screening–ourselves included–can appreciate the enormous task that members of the Task Force and its sub-sections undertook. The result not only justifies the correct C recommendation for those men between ages of 55 and 69 and the unchanged D recommendation for those above 70. Moreover, the recommendation calling for the serious need for more study about the complexities facing men who are at increased risk for prostate cancer– African-American and those with a significant family history–should serve as a call to action for research agencies whose worldwide populations are affected…
Forget Moonshots: Biomedicine Needs an Air Traffic Control System
May 17, 2017
Q: There never seem to be enough patients matched to cancer clinical trials to quickly test new cancer treatments. Might there be a better way, using new communication technology?
A: Among the few things that everyone can agree upon, one is surely that biomedicine is not an efficient engineering system — that is, a system that efficiently (in time, cost, lives, or whatever else you’d like to measure) reaches its goals to alleviate suffering, etc. When we think of efficient engineering systems, companies such as Apple, Boeing, Google, Tesla, NASA, GE, and Toyota come to mind. Perhaps Big Pharma and parts of the VA and military are efficient engineering systems but surely biomedicine, as a whole, is not.
Granted, biomedicine faces the highly complex problem of matching patients to treatments while at the same time creating and ethically testing novel treatments with budgets that are under constant pressure. But this problem is faced by a huge number of extremely smart people. What is the difficulty? I contend that the difficulty is, in large part, lack of coordination.
When I think of highly efficient coordination, I think of the Air Traffic Control system. The notable pain of air travel notwithstanding, one has to admit that the flight coordination is nearly magical! You can fly from New York to London in 5hrs for $500 while strapped into a 20x200ft aluminum tube (full of explosive fuel) traveling at 500mph, 50,000ft high in an airspace shared with 100,000 other flights doing the same thing in every direction all over the world. And you never think about dying! Well, you may think about it, but realistically you shouldn’t because air travel is spectacularly safe. Instead, worry about escalators and bicycles!
I contend that we can learn from the spectacular success of Air Traffic Control …
Proposed FDA “Conditional Approval”- More Details
May 10, 2017
Q: Your April 5, 2017 blog post that proposed a new “Conditional” category for FDA drug approval elicited a number of positive and negative responses. Please explain the proposal in more detail to enable better reader understanding.
A: ￼In Response to “Conditional Approval: Right Solution for the Wrong Problem” by
We appreciate Ms. Brownlee’s comments on our recent blog post, but think she missed our key points—perhaps we weren’t clear enough:
- Conditional approval isn’t intended for cancers that have other options—like ￼some types of breast cancer—but rather for the invariably fatal cancers like ￼glioblastoma multiforme (GBM), for which there aren’t any good FDA-approved options.
- TConditional approval requires not just evidence of safety, but evidence that the drug has promise, at least in some patients.
- Using the registry is just a different way of collecting the data that traditionally is collected in clinical trials. Instead of a traditional trial in which only highly selected patients participate and relatively few doctors collect the data, we will be collecting data on the entire range of patients from many doctors.
Having many doctors and patients participate removes a lot of the bias inherent in clinical trials. For example, consider a doctor using an experimental treatment on “thousands” of brain tumor patients in 100 clinical trials in which only a handful of doctors are collecting all of the data. All of the doctors involved have a major financial interest in the outcome. We still have no idea if this treatment helps or hurts—and it has been going on for 40 years. With our system, we would know in a year if it helps or hurts.
￼Moreover, Ms. Brownlee’s arguments extolling the virtues of randomized clinical trials ￼(RCTs) may reflect an unfamiliarity with the cost-effectiveness of “registry trials,” especially when coupled with modern Bayesian designs.
With the traditional approach, we have been lucky to get 3 or 4 treatments approved in the last 40 years. With our approach, we can expect at least 3–6 new treatments conditionally approved…
Next steps for improving clinical evidence and consistency of payment for precision oncology
May 3, 2017
Q: Adoption and insurer coverage for precision oncology may require evidence that it can improve patient outcomes. The current situation is confusing for many. What are some practical next steps that workers in the field can take to improve clinical evidence and consistency of payment?
A: It’s been said that the greatest challenges facing genomic medicine are not scientific, but economic. Much has been written about the need for improved clinical evidence and consistent reimbursement policies, but there have been relatively few studies that illuminate what steps can be taken to address them. Two new studies from the University of California San Francisco Center for Translational and Policy Research on Personalized Medicine (TRANSPERS) address these questions.
A newly published study in Genetics in Medicine combines insights from TRANSPERS collaborators and leading genomic medicine experts to identify evidence gaps in genomic medicine that comparative effectiveness research can address, with direct relevance to precision oncology. For genomic/precision medicine to fulfill its potential, it must be (1) evidence-based and (2) consider a full range of patient outcomes. Does the literature to date suggest that these objectives have been met? TRANSPERS and experts from multiple institutions addressed this question. This is the first study that uses a systematic structured literature review (combined with expert input) to provide an overarching assessment of comparative effectiveness research for genomic medicine. We found that all included reviews (N=21) identified potentially important clinical applications of the genomic medicine interventions. Most had significant methodological weaknesses and there were few studies of conditions other than cancer. There were only a few analyses examining a broad range of patient-centered outcomes. Our findings provide next steps about where to focus future research activities and policy initiatives by identifying conditions, tests, and interventions where comparative effectiveness questions may be appropriate for study. We also discuss the limitations of prior research and how they could be addressed.
Specifically for precision oncology, we found that studies are needed to measure whether tumor sequencing tests lead to better clinical outcomes than alternative prognostic methods in different stages of common cancers. Additionally, studies are needed for…
Conditional Approval: Right Solution for the Wrong Problem
April 26, 2017
Q: Q: Musella and Tenenbaum recently proposed a new way, called conditional approval, for the American FDA to move potentially useful drugs to a patient market. They wrote that safety would be covered and efficacy assessed by a registry. What do you think of that idea?
They have proposed giving new cancer drugs conditional approval, allowing them on the market after Phase I (safety) trials in as few as 50 patients. Patients and their doctors would be free to use the new, and unproven products, provided all patients enroll in a registry. The patient’s (de-identified) clinical information (pathology reports and biomarkers, for example) would be included in the registry. This would allow the FDA and researchers to determine, by the end of a pre-set conditional period, whether or not the drug is safe and effective when used on a larger population.
Sounds like a great idea, doesn’t it? It eliminates Phase III efficacy trials, which are slow to complete, expensive to conduct, and drive up drug prices. Musella and Tenenbaum’s plan would give patients ready access to potentially life-saving treatments, speed up approval, reduce the burden on the FDA, bring down the cost of drug development, and create a registry for cancer patients that would open up research avenues. What’s more, Japan, Canada, and South Korea have conditional pathways for new cancer treatments. Why not us?
Because it’s a bad idea that will waste a lot of money and hurt patients. Have we all forgotten the recent history of ineffective and harmful cancer treatments? Autologous bone marrow transplant, or ABMT, and Avastin (bevacizumab) are two that come to mind.
ABMT was developed in the 1980s and was used on at least 41,000 women with metastatic breast cancer. Oncologists, transplanters, and the press embraced the treatment enthusiastically on the basis of a single study comparing it to historical controls. It took more than a decade to accumulate enough patients in randomized controlled trials (RCTs), which showed in 1999 that ABMT was worse than standard chemotherapy—it killed about 10 percent of patients. Insurers paid more than $3.4 billion over the course of the decade for a treatment that actively harmed patients.
A decade after that, Avastin was approved for breast cancer on a fast track in 2008, based on “time to progression.” While there wasn’t any proof that time that progression directly affects how long patients live or their quality of life, Genentech, the manufacturer, argued that it was a good marker of improved patient outcomes. By 2010, worldwide sales of Avastin had hit $6.8 billion…
In Memorium: Richard E. Horowitz, M.D.
April 19, 2017
by Dr. George Lundberg
Searching for Truth in Cancer Clinical Trials
Q: Who has been among the strongest supporters and most constructive critics of CollabRx (since 2010) and Curious Dr. George (since 2016)?
A: American pathology lost one of its greatest leaders (and I lost one of my best friends) when Richard Horowitz died on March 15, 2017 in Los Angeles, California. Still of sharp mind and keen humor, he died with dignity and grace, in a manner of his own choice during home hospice care, of metastatic non-small-cell adenocarcinoma of the lung.
Richard and I met across an autopsy table at the old LA County General Hospital in summer 1967. We bonded and remained colleagues and friends who shared many professional beliefs based on personal experiences for 50 years.
Richard was born in Vienna, Austria on May 17, 1931. He left Austria with his parents to flee Hitler’s scourge in 1939.
His college was UCLA, medical school UCSF, internship at Los Angeles County General Hospital, and pathology training (after 2 years in the US Army at Walter Reed doing germfree research) at Mount Sinai in New York. Richard was one of those rare individuals who could keep one foot in academia and one foot in private practice in perpetuity and perform brilliantly in both.
Richard’s “real world” pathology practice management writings and teachings exerted wide influence. But his “tour de force” was always the irreplaceable medical learning uniquely gleaned from his legendary “Organ Recitals” at USC, UCLA, and especially the Wadsworth Veterans Administration Hospital…
Fibrolamellar Hepatocellular Carcinoma: Still Rare but Deadly
April 12, 2017
Q: You were the lead author in a 1980 paper in Cancer that clearly delineated an unusual form of Hepatocellular Carcinoma that you termed “Fibrolamellar Carcinoma”. Now, 37 years later, what insights of importance can you share about this unique malignancy?
A: CRISPR/Cas 9 technology, fruit flies, mice and zebrafish are among the tools being used in numerous academic laboratories, encouraged by the Fibrolamellar Foundation, to determine whether the 400kb deletion found on Chromosome 19 in 90% of patients with Fibrolamellar Hepatocellular Carcinoma (S. Simon PhD, Rockefeller University) is a driver mutation.
In 1980, with renowned liver pathologist co-authors Hugh Edmondson and Robert Peters, I compiled and published the first large series of Fibrolamellar Hepatocellular Carcinoma (FL-HCC) cases in the journal Cancer.
This rare cancer has an annual detection rate of approximately 100-200 patients in the USA and occurs primarily in young adults 15-30 years of age.
After our publication, we received many consultations by pathologists who were eager to share patient information and observation. Over the next 25 years, additional publications introduced unusual findings such as increased serum vitamin B12 binding globulin and other tumor markers, such as des-carboxy prothrombin, and plasma neurotensin. Unfortunately, none of these observations advanced either the detection of the tumor or improved treatment.
Some patients are cared for at academic medical centers, but neither chemotherapy nor radiation treatment has been found to be useful. Complete surgical resection offers the best hope but is usually performed late in the course of the disease since the young patients are often thought to be in good health and have few symptoms.
In recent years, these young patients often connect by social media and have developed Facebook pages. They communicate about their disease, their suffering, treatment options, and acceptance of their disease. There is an annual fall meeting of patients and families to share their experiences.
The family of one young patient (Tucker Davis) answered the plea of their son, and in his honor, in 2008, established the Fibrolamellar Foundation with the goal of finding a cure.
The mutation described above is the result of a fusion of the first exon of DNAJB1 with exons 2-10 of PRKACA. This mutation results in a functional…
A Proposed New FDA Drug Approval Pathway: “Conditional”
April 5, 2017
Q: The delay time from discovery/observation, through validation to approval and distribution/use of new cancer treatments remains excessive. With promising experimental treatments, advanced computer technology and biostatistics, creative alternatives to traditional randomized clinical trials, and a government seeking efficiencies, might it now be time for the FDA to issue: “Conditional Approvals”?
A: The first advances in oncology occurred at a time when there were no regulations. Doctors had ideas, and put them to work immediately. They adjusted and combined treatments as needed until they were optimized and became standard treatments. Many types of cancer were cured by this work.
Unfortunately, for patients, with glioblastoma, pancreatic cancer and other rarer cancers, the prognosis remains dire: average survival with currently approved treatments is less than 2 years. These patients can’t afford to wait a decade or more for new drugs to be approved.
The good news is that the oncology drug development pipeline is full of promising targeted- and immuno-therapies that have already demonstrated safety and at least some evidence of effectiveness. However, under current regulations, it will take years before the average patient can get access to these potentially life-saving treatments. Moreover, it is likely that a cure will involve intelligent combinations of treatments. Under current regulations, combination testing cannot even begin until these drugs are approved. And what if a new treatment was not effective as a monotherapy, but could be an essential component of a multi-drug cocktail, say to block a resistance pathway. Catch 22. Under current regulations, many good ideas will never get to patients, and those that do get approved have to be priced so high that many patients cannot afford them.
We would like to propose a new pathway to FDA approval – the “Conditional Approval” – that addresses these issues. It would allow the FDA to approve a treatment that shows safety and a biological effect…
AACR: Advances in Immunotherapy to Continue
March 29, 2017
Intro: The American Association for Cancer Research (AACR) publishes a forecast blog post at the start of each year to ask prominent cancer research leaders what they envision the new developments will be in areas like immunotherapy, precision medicine, cancer prevention, and health disparities.
|In this excerpt from the 2017 post in Cancer Research Catalyst, we interviewed immunotherapy expert Elizabeth Jaffee, MD, on her views on what might develop in immunotherapy this year. Dr. Jaffee is the Dana and Albert “Cubby” Broccoli Professor of Oncology and Professor of Pathology at Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. She is also the Associate Director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins. Dr. Jaffe was recently named the President-Elect of AACR for 2017-2018.|
Q: The American Association for Cancer Research (AACR) is arguably the World’s most important professional organization of volunteers in the cancer field. As we enter 2017, what does AACR consider the field’s greatest challenges and opportunities?
We have already turned this knowledge into therapeutics that inhibit some of these signals (checkpoint inhibitors) so the T cells can be effective in attacking the cancer cells, and developing therapeutics that can activate certain other cells within the tumor microenvironment (checkpoint agonists) to help further activate the T cells, she says.
With these approaches, we have been able to convert some metastatic cancer patients with weeks to live into those with chronic disease living a better quality of life, Jaffee adds. In 2017, we are going to see checkpoint inhibitors being approved for more cancer types and as first-line treatment for some cancers, she notes.
The bad news, however, is that these drugs only work for about 20 to 25 percent of all cancers. Further, these drugs can unleash…
A Fully Integrated Histo-Molecular Pathology Report
March 22, 2017
Q: The CAP, ASCO, ASCP and AMP have developed guidelines for interpretation and reporting of NGS variants in cancers. These analyses are performed in a wide range of types of labs and involve professionals from many disciplines. The reports should take into consideration the bioinformatics, molecular data, source of specimen, age, gender, and location of patient, treatment background, morphologic diagnosis, immunohistochemical tumor profile, and special stains. Who is the best qualified and positioned person to consolidate all of this information and produce a final integrated pathology report and how should this be accomplished?
A: Pathologists are the best professionals to synthesize data from all the tests done on a given tumor specimen via an integrated report that is actionable for downstream medical decision-making.
Hematopathologists enthusiastically embrace new technologies and they are the role models for data integration and analysis of microscopy, flow cytometry, histochemistry (IHC, ISH, FISH), karyotype, PCR, or sequencing.
College of American Pathologists guidance for reporting molecular test results suggests that all results on a given tissue be synthesized by one pathologist, typically the histopathologist although increasingly the molecular pathologist who performs ancillary genomic testing. Since molecular results are best interpreted in the context of histomorphology of input tissue (e.g. percent malignant cells), and in the context of the clinical dilemma to be solved by the test, good communication is essential to assuring that professionals selecting the tissue block, doing the test, and interpreting results provide answers to pertinent medical questions. Access to patient medical records promotes high quality interpretation of histo-molecular findings.
Pathologists are in the best position to allocate precious (often small) specimens and to prioritize which ancillary tests are most critical in a given clinical scenario. Certain tests are feasible only on selected specimen preparations (e.g. karyotype requires fresh tissue), and the pathologist is vital to assuring that…
Paying for Precision Oncology – Who Decides?
March 15, 2017
Q: Paying for Precision Oncology – Who Decides?
A: There is tremendous enthusiasm for the scientific rationale and clinical promise of precision oncology amongst researchers, oncologists, industry and subgroups of cancer patients. Nearly three-quarters of the compounds in the oncology pipeline have the potential to become personalized medicines and over 90% of the $25 billion personalized medicine market in 2015 came from the sale of oncology drugs that required use of a companion diagnostic, such as Herceptin and Her2 testing. The typical companion diagnostic analyzes single gene mutations or abnormal gene expression profiles, in contrast to next generation tumor sequencing (NGTS), which assays genomic alterations in tens to hundreds of genes simultaneously. Tumor profiling using NGTS now occurs frequently at major cancer centers across the U.S., however reimbursement for both the test and the off-label use of targeted therapies is unpredictable and challenging for most molecular tumor board staff, oncologists and their patients. Without coverage by either private or public insurers, most patients will not have access to NGTS tests and targeted therapies.
Payers typically use a stepwise approach for coverage decision-making when evaluating the evidence supporting the technical and clinical aspects of new molecular diagnostic tests. Based on published studies, technology assessments and professional guidelines, payers assess:
1) analytic validity – whether a new test is accurate and reliable,
2) clinical validity – if the result is medically meaningful, and
3) clinical utility of the test – whether results affect clinical decisions and improve health outcomes.
Payers are one of key stakeholder groups that require evidence of clinical utility for decision-making, however clinical utility cannot be demonstrated until analytic and clinical validity are established. As compared to “ single test/single result” assays, each of the two validation steps are inherently more difficult for…
A Plea for Gold Standards in Precision Oncology
March 8, 2017
Q: Is Precision Oncology Accurate?
A: Precision oncology in 2017 is neither accurate nor precise.
From my clinical pathology background, accurate means correct, as close to a “Gold Standard” as you can get, regarding sensitivity and specificity. Precise means reproducible. Prasad and Gale have recently demonstrated that not even the use of the term “precision oncology” is precise. It has changed often and dramatically.
We need to determine current (they would float with new information) “Gold Standards” for every step (and many sub-steps) in the Brain to Brain loop of molecular testing and clinical actions in oncology.
WHICH cancers should be subjected to some sort of molecular analysis? All, or all except non-melanoma skin cancers? Only those cancers for which there are FDA approved therapies matched by molecular definition? Cancers for which there are open relevant clinical trials?
WHEN should NGS be performed on a cancer? At initial diagnosis, or not until after spread, or both, or after other treatment failures, or depends on histopathologic diagnosis?
WHERE to sample the tumor? Primary, and/or one or many metastatic sites, or depends on tumor diagnosis?
Precision Oncology: Requirements for the Next Leap Forward
March 1, 2017
Q: Some workers in the field of precision oncology are growing despondent because of observed limitations of therapeutic effectiveness. What do you believe are now the best approaches to consider in order to move towards potential cures?
A: The pillars of precision oncology are genomically-targeted and immune-targeted therapies. Of interest, the fields of immunotherapy and genomics, often considered to be separate, are actually married to each other. Inhibiting checkpoints exploited by the tumor to shield itself from the immune machinery can reactivate the immune system. But, once reactivated, the immune system must be able to differentiate tumor cells from normal elements. The mutanome produces neo-antigens that permit this differentiation—and the more genomically aberrant the cancer, the more likely that the reactivated immune system will eradicate it. In contrast, with genomically-targeted therapies, the fewer the aberrations, the less likely that resistance will occur.
Yet, in treating patients, we are using old clinical trial paradigms rather than adjusting to the realities unveiled by genomic interrogation.
For instance, we administer genomically targeted therapies, mainly as monotherapy, to patients with heavily-pretreated, advanced metastatic disease—ie., the equivalent of heavily-pretreated chronic myelogenous leukemia (CML) blast crisis (where the response rate to imatinib is vanishingly low) (see Table). These patients have highly complex molecular portfolios and we should not expect that genomically targeted monotherapies will be curative.
We should not be then wringing our hands and talking about the limitations of our therapy–but rather the limitations of our approach.
The real eye opener is that so many patients with such late-stage…
Clarity Still Awaited for Prostate Cancer Diagnosis
February 22, 2017
Q: Whether and how to decide to do a prostate biopsy when a patient is found to have a “high” PSA remains a debated issue. The Lancet published a large controlled UK study on 1/19/2017 evaluating multi-parametric MRI and TRUS (PROMIS) that some observers have found to be informative. Do you believe that these findings will affect clinical practice?
A: Yes and no: in a landmark study (PROMIS) Ahmed et al. found an 88% sensitivity and 45% specificity for mpMRI in biopsy naïve men for clinically significant prostate cancer. The authors proposed mpMRI as a screening test before biopsy (to eliminate 25%). The caveat here was the biopsies were performed both by a transperineal mapping (TPM) and a transrectal (TRUS) approach-with the latter being only 50% accurate. This would argue against doing TRUS biopsies and taking the men with a positive MRI to the operating room for a more aggressive mapping procedure. If TPM is known to perform better than TRUS (70% vs 30% cancer detection rate) why are only 5% of biopsies performed by TPM?
The TRUS needle takes a 17mm specimen and most lesions (regardless of aggressiveness) are invisible to ultrasound. This makes the TRUS procedure “semi-blind” at best. Trying to span the longer sagittal length of the gland (often > 50 mm) with the TRUS needle requires multiple in-line punctures resulting in more than 50 biopsies per procedure (as opposed to 12 for TRUS). Devices developed specifically for TPM could improve the diagnostic accuracy and shorten the time required. It could also offer the potential to treat patients with targeted focal therapy, an option for more than 1/3 of men with prostate cancer. A biopsy needle and actuator that takes one specimen across the length of the prostate (between 20 and 60 mm), a 3-D image guided tracking program that provides a digital map for focal therapy and a pathology device that preserves the integrity of the longer core allowing the pathologist to identify the location and of every lesion are currently under development. A system such as this will be able to accurately select patients for surgery or observation and open the door for accurate and safe focal ablation.
The initial step in evaluating prostate cancer risk is the PSA test, most of which are ordered by the patients’ family physician. The TRUS biopsy misses cancers in 30% of patients. In patients with prostate cancer, 75% have…
AACR: Advances in Precision Medicine to Continue
February 15, 2017
Intro: The American Association for Cancer Research (AACR) publishes a forecast blog post at the start of each year to ask prominent cancer research leaders what they envision the new developments will be in areas like immunotherapy, precision medicine, cancer prevention, and health disparities.
|In this excerpt from the 2017 post in Cancer Research Catalyst, we interviewed precision medicine expert George Demetri, MD, Professor of Medicine at Harvard Medical School, Director of the Ludwig Center at Dana-Farber/Harvard Cancer Center, and Director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute. Dr. DeMetri is a founding member of the CollabRx Editorial Advisory Board and Chief Editor for CollabRx Sarcoma. Here’s what he had to say about developments in precision medicine for treating cancer – as well as his thoughts on aspects of the 21st Century Cures Act, federal support for cancer research, and the value in supporting basic science.|
Q: The American Association for Cancer Research (AACR) is arguably the World’s most important professional organization of volunteers in the cancer research field. As we enter 2017, what does AACR consider the field’s greatest challenges and opportunities?
For the vast majority of common cancers, however, it is not a simple monogenic problem. We need more combination therapies and more research to find where the Achilles’ heel is, Demetri says. “This is where we, as professionals, need to be careful about overstating the value of precision targeting to the public without also getting too negative.”
“Cancer diagnostics are going to get better and better,” says Demetri, and predicts that we may be on the verge of putting together a composite set of predictive and prognostic biomarkers. “Our diagnostic tools are getting so sophisticated that we can put cancers into different bins at different times in a patient’s treatment course.” With treatment, cancers acquire new mutations to thrive, and with technological advances we can now, in many cases, track the different mutations that are likely driving the disease and match them with different drugs.
While Demetri notes that we have to be intellectually honest about the fact that most patients treated with targeted therapies develop resistance, he is not yet giving up on our aim of finding cures. It may appear as not achievable now, but we are getting there through combination therapies, he adds…
Why the 21st Century Cures Act is a Good Thing
February 8, 2017
Q: You attended the December signing by President Obama of the 21st Century Cures Act and are recognized to be a strong supporter. Yet harsh criticism of it has quickly appeared in JAMA, BMJ, a variety of other venues, as well as on these pages. Please tell our readers why this is good legislation and how the public health will be protected from exploitation in this very different regulatory world.
A: The bi-partisan 21st Century Cures Act is grounded in a commitment to assuring that our nation’s research ecosystem has the capacity to accelerate the pace at which safe and effective medical advances reach patients. The Act will expand the efficiency, reach and impact of medical discovery in a manner that sustains crucial safeguards against unsafe or ineffective products. The law finances more research, helps to reduce the administrative cost surrounding basic research, and takes additional steps to overcome challenges the Food and Drug Administration (FDA) faces. Patient groups, health care professionals, academic leaders, industry leaders and the FDA and the National Institutes of Health (NIH) were frequently consulted regarding provisions of this bipartisan bill, and their insights were incorporated. We at Research!America were closely involved throughout development of the bill, and are pleased that it crossed the finish line last December.
After years of automatic spending cuts and flat-funding, researchers have been stressed as they work to find solutions to deadly and complex diseases. The 21st Century Cures provides some relief in that regard with an initial $352 million in FY17 to support the NIH Precision Medicine, BRAIN, and Cancer Moonshot initiatives. Congress recognizes that these dollars are targeted and temporary; they do not supplant the need to grow NIH’s annual budget. As reflected in surveys that Research!America commissions regularly, Americans recognize the importance of federally-funded research and support streamlining the pursuit of medical research and innovation.
The FDA, which has for years been underfunded, will also receive new funding with an initial $20 million in FY17 to improve efficiencies in the R&D pipeline. This new funding, in combination with other provisions of the law, is particularly meaningful as it will give…
Best Uses of PM&R in Patients with Cancer
February 1, 2017
Q: Your principal practice in Spokane, Washington is Physical Medicine and Rehabilitation. What do you find to be the best uses of PM&R in patients with cancer at your facility?
A: Rehabilitation medicine is one of the best-kept secrets in healthcare. Although the specialty is as old as America’s Civil War, few people are familiar with its history and purpose. Born out of compassion for wounded soldiers in desperate need of societal re-entry and meaningful employment, “physical reconstruction” programs were developed to provide everything from adaptive equipment to family training, labor alternatives and psychological support for veterans.
Physical medicine and rehabilitation (PM&R) then expanded to meet the needs of those injured in World Wars I & II, followed closely by children disabled by the polio epidemic. In time, people recognized that a broad swath of diseases and traumatic injuries required focused medical and physical therapy to achieve optimal long term function. Today, cancer patients frequently benefit from comprehensive rehabilitation as they recover from the effects of chemo (neuropathy, weakness, and cognitive impairments), radiation (scarring and range of motion limitations), surgery (flaps, plastics procedures, tumor resection, amputations), and brain injuries (edema, debulking, gamma knife and neurosurgery).
Rehabilitation is a phase of recovery occurring after any major life-changing medical or surgical event. Our bodies are designed to regenerate and repair, though optimizing this process takes skilled guidance. PM&R physicians (also known as physiatrists) are trained to use physical modalities (stretching, strengthening, heat, cold, etc.) to mechanically enhance healing. They prescribe medications to manage pain, spasticity, nerve injury, and cognitive impairments, while also leveraging the power of physical therapy to increase cardiopulmonary fitness, muscle strength and flexibility. PM&R physicians are also experts in neurologic injury, and can adapt exercises to…
The Importance of Clinical Trial Matching
January 25, 2017
Q: You have served as Vice President, Global Business Development and Strategic Alliances of CollabRx for more than one year. How do you rank the importance of the CollabRx Clinical Trial Matcher in the “big picture” of cancer care?
A: Thousands of people each day learn that their cancer is no longer treatable by approved therapies. It is devastating news for both the patient and their loved ones. For some of these patients, however, there are still therapeutic options. Finding the “right” clinical trial has the potential to give them a new lease on life. Indeed, all of us rely on clinical trials to deliver the next generation of life-improving and life-saving therapies.
Despite the large number of clinical trials seeking to provide patients with access to potentially promising cancer therapies, only 3% – 6% of cancer patients who are eligible to participate in a clinical trial do so. There are many reasons for this, but as former Vice President Biden stated, one reason for low clinical trial enrollment is “… because patients and doctors don’t know what trials are available.” Matching patients to clinical trials effectively is often a challenging, time-consuming endeavor, and one that can be difficult to scale to meet the needs of many patients.
Molecular characterization of patients’ cancers can also help expand treatment options, opening opportunities for patients to participate in one of the growing number of genomically driven trials. Fortunately, molecular characterization of patients’ cancers is becoming more common, not only in large academic medical centers, but also in community cancer centers, which treat the vast majority of cancer patients in the United States.
There is a pressing need for better tools to help match beyond standard of care patients with the most appropriate trials for their individual needs. Many individuals and organizations are working to address this problem and the growing number of clinical trial matching services reflects this. Approaches range from…
The Autopsy is Essential in Proper Cancer Care
January 18, 2017
Q: The numbers show that American physicians are ready to cast the medical/hospital autopsy into some relic or trash bin. Yet some physicians believe that the low tech autopsy still has much to contribute. Do you believe that the autopsy still can be useful in cancer deaths? And, if so, in what ways?
A: As an aspiring autopsy pathologist, it has been disappointing to learn of the decreasing role of autopsy in medicine. Many in pathology do not care for autopsies because they are dirty, time-consuming, and not reimbursed. Issues also exist amongst clinicians who trust that modern diagnostic modalities provide equivalent value, fear exposing mistakes, fear litigation, and are growing increasingly uncomfortable with approaching patient families. This medical environment which has largely forgotten the autopsy is also that in which trainees are developing habits as future practitioners. As a result, we may be facing further decline in the use of autopsies in the years to come.
Despite diminishing emphasis on the autopsy, data suggests that it has retained its value. This is as true for cancer patients as it is for any. Below I have highlighted what I think are the most important ways in which autopsies are useful for cancer patients:
- Establishing cause of death. This reason for performing autopsies does not change because an individual has cancer. According to recent studies, major discrepancies (missed major diagnoses relating to the death that would have had a positive or equivocal impact on survival) between pre-and post-mortem findings occur in approximately…
The Future of Nursing Care for Advanced Cancer Patients
January 11, 2016
Q: You have gained remarkable insights into the American nursing profession by performing and publishing survey research for many years. What do you envision as the major roles for nurses in caring for patients with advanced cancer?
A: As our nation grapples with the aging of our population, the care of people with cancer will cost an estimated $158 billion annually by 2020. That is a lot of health care. Some who hear the words “advanced cancer” think about living out their final days far from healthcare settings, perhaps at the beach sipping tropical beverages. Others head for cancer centers and death-defying new therapies: different “cocktails” of personalized plans, targeted therapies, clinical trials. Still others have few options—our national shame of rationing access by income and insurance status.
Nurses, especially oncology trained specialist nurses, have key roles to play for any of these patients. The Oncology Nursing Society has set standards for core competencies for several nurse roles: general care, patient navigation, research, advanced practice, leadership. Oncology nurses may lead infusion and intensive care units and cancer centers. In a community, they work in widely varied roles from ambulatory care to nursing homes, hospices, and home health agencies.
The role of the nurse in our society has its roots hundreds of years ago in the religious orders of Christian, Islamic and Buddhist faiths where the sick and dying were comforted in convents and monasteries around the world. The profession advanced in the 19th century from the battlefield in Crimea to the hospital bedsides of the 21st century. Specialized oncology nursing and advanced practice nursing were born in the 1970s as advanced specialized training, board certification and licensure evolved, much as they have in medicine. The National Academy of Medicine, in two major reports on the Future of Nursing in 2010 and 2015, recommended that all states allow nurses to practice to the full extent of their education and training, and…
21st Century Cures Act, Societal Net Negative or Positive?
January 4, 2016
Q: Many people are praising the recently passed 21st Century Cures Act. But there are also critics. What are some of the downsides that the American public might experience from this important piece of legislation?
A: On December 13 President Obama signed into law the 21st Century Cures Act, a piece of legislation that the blogosphere has called the “21st Century Giveaway Act” and “Obama’s Gift to Biopharma.” While such appellations suggest the windfall the new law represents for pharma and other health care manufacturers, they fail to hint at its likely harm to public health and safety.
As the price for continuing to fund the National Institutes of Health and various exotic programs such as the cancer “moonshot,” pharma extracted a major step at deregulation that sets back oversight of the nation’s approval and use of medications.
Even as a funding measure, the Cures Act is skewed in favor of pet projects such as Joe Biden’s cancer initiative, while it reduces support for less glamorous public health programs such as immunizations and tobacco prevention.
But the 21st Century Cures Act distinguishes itself by setting back the regulatory process that protects public safety. It does that by relaxing the standards the FDA currently uses for approving new drugs. The entire status of prospectively designed, placebo-controlled, double-blind studies as the gold standard for approving new drugs and devices is now weakened in favor of the deceptive euphemism, “real world evidence” (RWE) defined in the Cures Act as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.”
The concept and definition from the Cures Act is not yet precise. Several authors of an article in the December 8 New England Journal, including FDA Director Rob Califf, claim that the agency is currently “developing guidance” on what constitutes RWE and how it may be used. Until such definition and operational use are precisely defined, several writers in clinical studies, public health and pharmaceutical marketing have chimed in on how the practice of including RWE in regulatory approval is likely to play out. The Pharma Marketing Blog contends the 21st Century Cures Act will permit pharma companies to include “the experience of their KOLs with their patients” as evidence to support a submission…
The Role of the NCQA in Advancing Cancer Care
December 28, 2016
Q: Under your visionary leadership, the National Committee for Quality Assurance (NCQA) has established and enforced quality standards for much of American medicine for >25 years. What is the current major role of NCQA in caring for patients with advanced cancer?
A: We at NCQA (National Committee for Quality Assurance) are proud of our role in helping drive better performance in health care. Since 1993, when HEDIS (Healthcare Effectiveness Data and Information Set) measures were first publicly reported, we have seen substantial improvement in colon cancer screening rates, diabetes and blood pressure control. This comes as a result of HEDIS measures driving pay for performance Medicare stars and a variety of rating and reward systems. These gains translate into better quality of life—and even longer life—for the people to whom the measures apply.
In NCQA’s Accreditation and Recognition programs, plans and practices are rated on whether they are organized for quality through structure and process measures. In patient-centered medical homes and specialty practices, we look at whether access is adequate, whether there are systems to follow up on abnormal test results and whether practices “talk to each other” to ensure that patients benefit from an unbroken chain of coordinated care. Study after study has shown that practices “organized for quality” do better on quality and patient experience and have lower rates of hospital and emergency department use.
We have been working on cancer care from a number of different angles. For me, this is personal…
Clinical Trial Matching for Patients with Molecularly Characterized Tumors
December 21, 2016
Q: Clinical Trials is such an important topic, but it is so broad. Is there a way to provide better matching for Clinical Trials involving cancer patients, especially those whose cancers may have the added diagnostic information of molecular profiling?
A: Clinical trials provide cancer patients, especially those whose cancer has progressed beyond standard of care, access to potentially promising investigational therapies or novel combinations of approved therapies. Yet only a small fraction (less than 5%) of the 1,700,000 Americans diagnosed annually with potentially lethal cancer participate in clinical trials. A growing number of cancer patients now have their tumors profiled molecularly and there is real opportunity to use that information in better matching them to clinical trials. Below I outline the CollabRx approach to this problem.
Most clinical trials for cancer seek patients based on criteria such as tissue of origin and/or histological characteristics of the tumors. But with hundreds of targeted therapies now approved or under development, there are a growing number of clinical trials looking for patients based on the molecular characteristics of their cancer. Of note are genomically-driven trials such as basket and umbrella trials that match patients to therapies based on the individual molecular profiles of their individual cancers.
While such trials are a natural fit for patients whose tumors have been molecularly characterized, they are not easy to identify in clinicaltrials.gov. For example, a search for the gene ‘BRAF’ identifies trials for patients with BRAF mutations as well as those without. This issue can be resolved only with careful annotation and structuring of trial inclusion and exclusion criteria from sources.
Some trials without explicit molecular criteria may ALSO be relevant to patients with certain molecular profiles. What are these trials and how can physicians and patients identify them?
Complementary/Alternative Approaches in Advanced Cancer
December 14, 2016
Q: Many, even millions, of Americans are living with advanced cancer. You are the author of the definitive text “Fundamentals of Complementary and Alternative Medicine,” now in its 5th edition. What forms of complementary and alternative medicine might be most useful for patients with advanced cancer?
A: In cancer treatment trials, both treatment and control groups receive treatment. Likewise, standard oncological treatments are not directly compared to various complementary/alternative (CAM) therapies. Rather CAM treatments are added, or not, to the standard oncological protocol. Thus, in research conducted, they are truly “complementary” as adjuncts to cancer treatment. Some trials on commonly occurring cancers have allowed observations of improvements in both survival times and quality of life in patients with advanced cancer. The most direct analogies to mainstream cancer treatments for research trials are dietary supplements (vitamin and mineral micronutrients, and botanicals) since they can be administered the same way as drug treatments.
Vitamin D shows strong clinical evidence of anti-cancer activity. In a recent study by Garland et al, people in the highest quantile of serum vitamin D had 17% less risk of developing advanced lung cancer compared with the lowest quantile. Men with blood serum vitamin D levels less than 30 ng/ml had 2.6 times greater likelihood of having an advanced form prostate cancer at time of diagnosis. People with lower vitamin D were four times more likely to develop aggressive melanoma. Women with malignant melanoma took in only 311 IU Vitamin D per day, about half the RDA of 600 IU/day. (Garland recommends 4000 IU daily; very few foods contain Vitamin D). In several clinical trials, women with advanced breast cancer administered Vitamin D dietary supplements showed significant improvements in quality of life and prolongation of survival time.
For Vitamin C, a key observation is that intravenous infusions are necessary to achieve the higher, steady state blood levels observed to benefit cancer patients. Clinical data suggest that high-dose Vitamin C infusions improve survival in advanced cancer patients. A study on IV vitamin C for cancer, conducted in 2012, focused on the inflammatory component of cancer. When cancer tumors are growing, there’s typically an inflammatory response in the local area. Elevated inflammation can worsen prognosis and shorten survival times…
Best Use of Palliative Care in Cancer Patients
December 7, 2016
Q: Many, even millions, of Americans are living with advanced cancer. You are a board certified Emergency Physician and also boarded in Palliative Care. Please explain the fundamental premises, promises, and practices of palliative care for cancer patients.
A: “Quality of life” defies a singular, concise definition and thwarts researchers’ attempts to be measured. It is easier to express a personal definition of what isn’t quality of life i.e. “Don’t ever put me in a nursing home,” or “I never want to be kept alive by machines.” A cancer diagnosis changes everything and ever after. In best-case scenarios involving serious illness, “quality of life” becomes less about negatives and more about individualized, ongoing, informed conversations. Such communication happens when a Palliative Medicine (PM) specialist is invited to collaborate in cancer care.
When a cancer outpaces a prescribed oncology regimen, it is not uncommon for the patient to feel hopeless. The oncologist, “battling” cancer, may be reluctant to transition to a treatment plan focusing on quality rather than quantity. This is fertile ground for PM; it’s our wheelhouse in any disease that is life limiting. A patient should never hear: “There’s nothing more we can do.” Such words are the greatest disservice and opinion any physician can deliver. When cure is no longer possible, PM replaces despair with a new road map—“Let’s get you where you want to be.”
Scrupulous symptom management is a primary focus of PM. Pain, dyspnea, nausea, even constipation can be bothersome but depression, anxiety, grief, and spiritual distress are under-recognized comorbidities…
Will Advanced Computing Help Eradicate Cancer?
November 30, 2016
Q: Computers and artificial intelligence show both great progress and great promise in many fields. Can “Big Data”, A.I., and the Watson ilk devise a way to end cancer?
A: In 2011, a young and emotionless Watson grabbed the tech industry’s attention by dominating Jeopardy’s two greatest champions. That night, the show was not at all about the $1 million prize. Instead all eyes were on the one-of-a kind contestant: Watson, IBM’s supercomputer. Watson had just proved that intelligent machines can understand, process, and respond to questions posed in human language.
A few years later, artificial intelligence (AI) exploded into many information-intensive industries with its market expected to reach $47 billion by 2020. But young Watson had one main career in mind since its inception: healthcare. It entered medical school in 2011 and graduated in 2 years.
So how can AI change the oncology field? According to a paper published by Michael Schatz in the journal PLoS Biology, genomic data is likely to generate the most raw data in the next ten years–data which holds answers to many health questions. While understanding and finding patterns in this enormous amount of data might seem impossible for the human brain, cognitive computing capable of ingesting data that analyzes and self-learns without forgetting might hold the key to uncovering the answers.
AI can therefore revolutionize oncology care, save doctors time, and save patients’ lives. Because supercomputers store millions of oncological records which they can rapidly analyze and cross-reference, their deep learning ability has the potential to…
The Essential Value of ICMJE
(International Committee of Medical Journal Editors)
November 23, 2016
Q: The internet has produced mass democratization of information provision and access with little quality control. You represented JAMA at the International Committee of Medical Journal Editors (ICMJE) for over 10 years. How important is the ICMJE in protecting quality and ethics?
A: Since 1978, when a group of high impact medical journal editors representing several countries first met, the ICMJE has played a major role in setting standards for the ethics, preparation, and formatting of biomedical manuscripts. The current membership consists of thirteen medical journal editors and representatives of selected related organizations including the National Library of Science and the World Association of Medical Editors (WAME). These individuals work together to improve the quality of medical science and the reporting of such science.
The ICMJE publishes recommendations for the conduct, reporting, editing and publication of scholarly work in medical journals. These guidelines, primarily for authors, reviewers and editors, are available on line for anyone. ICMJE developed these recommendations to review best practices and ethical standards for the conduct and reporting of research and other material published in medical journals. The recommendations also help authors, editors, and others involved in peer review and biomedical publishing create and distribute accurate, clear, reproducible, and unbiased medical journal articles. These guidelines have also provided useful insights into the medical editing and publishing process for the media, patients and their families, and general readers.
One example of the important role the ICMJE has played in helping to assure the ethical publication of sound research occurred in September 2004 when the editors published a joint editorial regarding the registration of randomized clinical trials. At that time the law in the United States required that all clinical trials be registered in clinicaltrials.gov as soon as the first patient was enrolled. Very few such trials were registered because no one enforced the law. This put editors in a quandary because they had no idea if the submission of a manuscript that described a trial accounted for…
Making Cancer Care Great Again
November 16, 2016
Q: Donald Trump’s campaign for the presidency included a promise to repeal “Obamacare” in its entirety. If he succeeds in fulfilling that promise, what impact can we expect on American cancer prevention and cancer treatment?
A: Donald Trump, emboldened by eliminating ISIS, ending illegal immigration and energizing the economy, will eradicate cancer. Or at the very least, I predict, he will append it to his list of promised achievements as president.
Our current chief executive, dubbed “No Drama Obama” by his staff during the 2008 campaign, couldn’t resist the heady promise of a cancer “moonshot.” Trump, who’s declared, “I will take care of ISIS,” “close up those borders” and “jump-start America,” will likely rev up the rhetoric back to Nixonian “War on Cancer” levels.
A candidate whose campaign centered on his personal pledge to “make America great again” will surely be galvanized by the chance to make cancer care “great,” too.
The current Cancer Moonshot initiative, featured in President Barack Obama’s last State of the Union Address, is codified in a presidential memorandum of Jan. 28, 2016 and placed within the Office of the Vice President. While fighting cancer was of deep personal interest to Vice President Joe Biden, Vice President-elect Mike Pence was governor of Indiana, where pharmaceutical giant Eli Lilly has a major portfolio of oncology products…
How to Control American Drug Costs
November 9, 2016
Q: Many newer (as well as many older) drugs are of great value in treating many diseases. But the prices charged seem very high and rising, causing serious concern for many. Is there anything the United States can do to control these costs?
A: We can do a lot to control drug costs, but success will take the cooperation of Congress and the legislatures, which are fundamentally in the drug industry’s pocket.
The industry lavishes money on Congress to buy that favor. Open Secrets data show that the pharmaceutical/health products sector, the most politically influential industry, gave Congress $3.3 billion in campaign contributions between 1997-2015. That largess averages out to $183 million annually over that 18-year period, or a stunning $343,000 per legislator per year. Within these dynamics, every relevant law and rule is spun to favor the interests of the drug industry over those of the American people.
In an excellent recent JAMA article on the sources of US drug pricing, Kesselheim et al. point out that influence over policy has translated into two core problems: “granting government-protected monopolies to drug manufacturers, combined with coverage requirements imposed on government-funded drug benefits.”
Consider Congress’ prohibition against Medicare negotiating drug prices. Millions of patients’ medications are subsidized by Medicare, which pays whatever price is demanded. It’s hard to imagine a better deal than the purchaser allowing the manufacturer to set any price, with the guarantee that the bill will be paid.
These dynamics translate to harsh realities…
Expanded-Compassionate Use of an Investigational Drug
November 2, 2016
Q: You have exhausted surgical, radiation, and standard chemotherapy options for a patient with an advanced epithelial malignancy. Yet the patient has a strong will to live and to advance science during palliative care. No active clinical trial is available. How would you evaluate pre-clinical data to try to identify an investigational drug for “expanded-compassionate” use?
A: Thank you for the question. This is a challenging situation. It is subjective and complex.
My answer – “it depends”. Let me give you 2 scenarios.
Scenario A: A 30-year-old surgeon, recently married with the love of his life who has just graduated from a neurosurgery residency, is expecting his first child and diagnosed with Stage IV non-small cell lung cancer. Has exhausted radiation, surgery, and standard chemotherapy. Has a strong will to live.
Scenario B: An 85-year-old man, who has a wife in the nursing home and a son in California and another son in Australia has been diagnosed with Stage IV non-small lung cancer. Has exhausted radiation, surgery, and standard chemotherapy. He lives alone and has a declining PS with multiple co-morbid conditions.
In the first case, yes, as an experimental investigator I would go to any lengths to try to provide investigational drug for expanded-compassionate use.
In the second case, I would likely arrange a family meeting to discuss the reality and lean towards providing best supportive palliative care.
Breakthroughs in oncology or any other field infers that successful outcome in the face of what was considered impossible. We all live in the future. If we do not take risky experiments, breakthroughs cannot be made. It could be argued…
The “Hutch” and Improving Baseball: World Series Edition
October 26, 2016
Q: You are known to be good at clever solutions to daunting problems, and a baseball fan to boot. What should we do about the conflicted designated hitter (DH)?
A: The last six months have been contentious across our land, with anger and hostility replacing civility and tolerance. Families and friends are pitted against each other. Religions and cultures are torn apart.
Can we save our nation from the additional conflict at World Series time, the designator hitter (DH) divide?
As the World Series is upon us, the wound will continue to fester.
Here is a solution that will both satisfy baseball “purists” (National League) and “progressives.” There are four easy steps.
- Make the DH available and optional for all games, all season long, in both leagues.
- Before each game, a designated specific team decides whether or not the DH will be used in that game.
- Which team gets to choose will always be the same, but is based on an anticipated upcoming decision by Major League Baseball (MLB). If MLB wants to soften home field advantage…
- Panobinostat with bortezomib and dexamethasone
- Carfilzomib with lenalidomide and dexamethasone
- Ixazomib with lenalidomide and dexamethasone and these were complemented by a pair of antibodies:
- –Elotuzumab with lenalidomide and dexamethasone.
- Brain MRI
- Serum LDH
- V600 BRAF mutation status (younger patients are significantly more likely than older patients to have a V600 BRAF mutation), so it’s likely that this patient has one
- Presence or absence of disease-related symptoms
- Prior scans that might allow the pace of disease progression to be ascertained (not always possible in a very recently diagnosed patient; but even if 4-6 weeks have passed since the first assessment prior to me seeing the patient, I’ll consider repeating imaging of the lungs and liver to glean the pace of progression…
How to Decide to Offer a New Lab Test
October 19, 2016
Q: Pathologists are faced with the need to set up additional lab tests routinely. Immunotherapy for cancer is the current rage. How does a pathologist decide whether and how to offer a new test such as PD-L1 Expression Testing?
A: The decision to introduce a new test or remove an old test is not as easy as one would think. There are many variables that must be taken into consideration. Concerning your question i.e. when to introduce a “new” test that may be used to direct therapy in a patient with cancer is an especially important task for the pathologist.
In my own experience using your example the subject would probably arise at a tumor board or multidisciplinary conference. This is setting where pathologists, oncologists, radiologists, surgeons and other medical specialists discuss possible or already identified cancer patients for input and recommendations on evaluation, more specific diagnostic information, treatment options and follow-up plans.
Today with the rapidly expanding complexities resulting from the introduction and availability of new biomarkers be they genomic, proteomic etc. that aid in diagnostic, prognostic and/or therapeutic decisions the burden of proof to introduce a test into your lab is very high. The more so if the “claims” being made are the specific biomarker results which are important and maybe critical in enhancing patient outcomes. The point is that the initial but critical decision of whether a new test should be available and introduced into your lab will be a team effort with input from users of test (the utility) and those responsible for ensuring the test can in fact be performed accurately in your specific lab environment (your validation).
The FDA has already approved PD-LD1. Its value is backed up by…
Preventing Hair Loss from Cancer Chemotherapy
October 12, 2016
Q: Loss of hair is a predictable adverse effect of much chemotherapy. Although “only cosmetic” this can be a troubling event for some patients. What is your opinion about the new devices or methods available to diminish chemotherapy-induced alopecia?
A: Scalp cooling to reduce chemotherapy-induced alopecia has been available for many years. This approach is effective for taxane-based chemotherapy regimens and, in my experience, can have benefit even with anthracycline-based regimens. There is good safety data for acute toxicity (for example frostbite hasn’t been an issue) but there is no good data on how exclusion of chemotherapy from the scalp might affect the risk of recurrence in this area of the body. Fortunately scalp recurrences are extremely rare, which is the major reason why data on scalp recurrence risk with cooling is not likely to ever be available. Regardless, I always educate my patients about this hypothetical risk. Given that the benefit of adjuvant chemotherapy for some breast cancer patients can be modest, this approach to reduce toxicity is quite reasonable.
In the past Penguin Cold Caps were used by some of my patients, under their own arrangements. This approach is quite burdensome requiring patients to bring in caps on dry ice and have an assistant with them to exchange these caps frequently during the infusion, and for some hours after as well. The total duration of recommended use varies with chemotherapy regimen but is about 5-6 hours per treatment. More recently Dignitana has obtained FDA approval for their system. The advantage of their system is that cap exchanges are not needed. A disadvantage is that centers offering this system need to lease a machine and thereby become involved in the business of scalp cooling. Given that insurance rarely reimburses any costs associated with the treatment of chemotherapy-induced alopecia this is a significant issue. Patients can expect to pay approximate $500 per treatment so a typical course of chemotherapy, with 4 treatments, scalp cooling will cost an additional…
Mutational Oncology: The Basics
October 5, 2016
Q: Many mature clinicians find “Mutational Oncology” to be a bit mysterious. Please help them understand. As they pertain to cancer, what are somatic (as opposed to germ line) mutations, transitions, transversions, “point”, “missense”, “nonsense”, insertion, deletion, and copy numbers and why does it matter?
A: With the plethora of molecular alterations that commonly occur in cancer, it can be confusing to understand what causes them and how these alterations affect the proteins that these genes encode. To begin, in cancer a somatic alteration refers to a non-inherited molecular alteration, which can occur spontaneously during replication or may be due to DNA damage or mistakes during DNA damage repair, and is only detectable in the tumor. These mutations are not passed to offspring. In contrast, a germ line mutation is heritable and detectable in nearly all tissues.
Many types of alterations occur in cancer. For example, a point mutation is the modification of a single base in a DNA coding sequence. A point mutation may be a transversion (replacement of a purine base with a pyrimidine and vice versa) or more commonly, a transition (replacement of a purine with a purine or pyrimidine with a pyrimidine). These single-base modifications can have several different effects. One common type of mutation is a missense mutation, in which the resulting base substitution changes the coding sequence for one amino acid to another. Another type of single base substitution may lead to a change from a coding amino acid to a termination codon, resulting in premature truncation of the protein. A point mutation may also result in the insertion or deletion of a base resulting in a change of the reading frame (a frameshift mutation) during protein translation. Finally, a single base substitution may not have an effect and will code for the same amino acid; this effect is known as a silent mutation…
The Most Relied Upon Journals in Precision Oncology
September 28, 2016
Q: The medical world is running amuck with new information, some credible, some not. What are the most reliable sources of information in Precision Oncology?
A: “Half of knowledge is knowing where to find knowledge”.
No one knows how many medical journals/periodicals there are in the world. Estimates range from 20,000 to 40,000.
Many are general medical journals; many more are specialty or sub-specialty journals. Their foci may be scientific, clinical, or even marketing. A few are strictly on paper; most also have an internet version, either a replicate of the print version, or a hybrid; some are exclusively electronic.
There are many parameters used to evaluate medical journals: exclusionary indexing systems, circulation, readership, revenue, advertising, paid subscription or open access, author fees, profitability, volume of information, frequency of publication, speed to publication, reference citation scores and indices, open and click through rates, page views, library catalogs, public media attention, owner/publisher status, primary language, location, tradition, brand name recognition, and others.
Of course the internet “changed everything “ so now there are “legitimate” as well as “predatory” online-only, open access journals.
CollabRx works in the field of Precision Oncology. We rely heavily on availability and veracity of the published literature. CollabRx enjoys the voluntary contributions of scores of unpaid editorial board members.
So, in 2016, I made the following request of sixty-six (66) of our editorial board members, paid staff and a few other esteemed experts:
“PLEASE PROVIDE FOR ME A LIST OF THE TOP 10 (OR SO) JOURNALS THAT YOU MOST RELY UPON TO INFORM PRECISION ONCOLOGY. NO PARTICULAR ORDER.
Twenty nine individuals (44%) responded. A total of 70 journals were named. ONLY 10 journals had 10 or more advocates…
Length and Quality of Life in Cancer Patient Treatment
September 21, 2016
Q: Although you have practiced as a surgeon in the British National Health Service (NHS) for most of your career, how is it that you’ve been such an outspoken critic of the “21st C cures act” that was passed through congress last year? What possible relevance might this have for your NHS?
A: All first year medical students should be taught the raison d’être for the practice of their chosen profession. Simply stated this distills down to three principles: the maintenance of health (well-being) for those who are free of disease and, for those with life threatening disease, the improvement of quality of life (QoL) and length of life (LoL). Therefore for patients diagnosed with cancer, QoL and LoL should be the primary outcome measures for all randomized clinical trials (RCTs) of innovative treatment. All other outcome measures have to be considered surrogates that may or may not translate into improvements in the primary outcomes. These may be used for legitimate reasons, such as aborting a trial early if surrogates all point in the wrong direction, but more often than not these surrogates are used to replace the primary outcome measures in order to fast track the adoption of what look like “promising” new interventions.
At its best, even significant improvements in cancer specific mortality might be abrogated by deaths directly related to the toxicities of treatment. At its worst is the assumption that some third or fourth level indices of “activity” of the novel treatment are accepted as evidence sufficiently compelling to bring the treatment to market.
In a recent JAMA Internal Medicine study, Prasad et al used meta-analysis to study the association of surrogate end points and overall survival in oncology. In 52% of examined studies the correlation was low; 25% showed medium correlation: only 23% showed a high level. Well over half the time surrogate end points failed to…
September 14, 2016
Q: As a journalist, you are a savvy native Canadian consumer/patient who also knows a lot about the United States. What do you see as the main similarities and differences between cancer prevention and care in the US and Canada?
A: Writing a 500-word answer to this is like trying to boil down 40 gallons of sap collected amid a chilly stand of trees to make 1 gallon of maple syrup. If all goes well, you get a dreamy confection where waffles are merely a delivery system. If not, you get a soggy gooey mess leaving you with sticky pails and spouts, a burnt-out fire, cranky people who remind you they could have spent the day elsewhere, an awful friggin’ lot of cleaning up and a spike in wine sales at my closest store.
I started in healthcare in 1985; written and ghosted a whack of health material including on cancer, volunteered and taken care of friends including my best friend who died partially from sheer weariness and partially because a doctor missed his calling as a government clerk. I read, I nod, I empathize, I sympathize and I get mad. Then I forget until a fresh sad story comes along; so I’ll first address the main difference. With the US a market-driven system – which is very bad for healthcare – your cancer services are slick and self-serving, like a smarmy blind date who shows up perfectly groomed with an IQ of 49 who mowed down the uninsured and underinsured to get to me. Under that difference is that Canadian parents don’t have to mortgage houses to pay for a child’s cancer care, Canada doesn’t have the many hundreds of insurance companies as in the US; with overhead and administrative costs dramatically reduced if rolled into a single-payer system the US would see enough savings to cover every citizen.
Turning to similarities between the two countries, my overarching thought is we should all be ashamed. Ashamed, as Brian Klepper wrote on this blog, “Cancer care is such lucrative business that more than one in four health systems is now building a cancer center.” Ashamed, that since Richard Nixon declared a war on cancer in 1971, cancer became the disease dominating…
Conflict of Interest in Cancer Clinical Trials
September 7, 2016
Q: Clinical trials are the lifeblood of continuing drug development in the US. Yet they are often undersubscribed. What do you see as key conflicts of interest in recruiting for patients in the academic medical center, the hospital, and the private oncologists’ practice?
A: Recently readers of this blog engaged in a spirited debate about conflict of interest in cancer clinical trials. The issue was divided as to whether or not the treating oncologist was the best person to offer a patient a clinical trial. I might suggest that the question can not be reduced to an “either or” answer – but is best understood as an asset allocation problem – the result of increasing financial pressures on cancer care due to trends over the past several decades.
The patient’s interest is in finding the best possible treatment for their cancer – on or off a clinical trial. The provider wants the patient to achieve the best possible outcome for their cancer and has an altruistic motivation to find better treatments for other patients. At the same time any provider stands to gain financially or secondarily (publication, promotion) from their involvement with a clinical trial. PHARMA has vested interests in finding new drugs that will provide return on investment and wisely invests heavily in clinical trials.
The American oncology enterprise is adopting to thinner profit margins. There is less profit from chemotherapy and radiotherapy reimbursement, and funding by the NCI for research is at a 20 year low. Thus the necessity of running clinical trials as a “revenue surplus” has risen – particularly in academic medical centers. At the same time clinical trials are the main engine that drives progress in cancer care…
Can Preclinical Data Guide Clinical Cancer Therapy?
August 31, 2016
Q: Under what circumstances and to what extent are you willing to take clinical actions on a cancer patient based primarily on preclinical data?
A: There are two scenarios that come to mind when thinking about reliance on preclinical data for treatment decision-making: (1) use of an agent that is an established treatment for a noncancer indication and (2) use of an established cancer therapy outside of the context(s) for which there is known clinical efficacy.
In the first scenario, I am essentially NEVER willing to accept a preclinical finding that suggests efficacy as a basis for prescribing use of such an agent. This perspective comes from a career focused on performing early phase clinical trials with agents that demonstrated promising in vitro and in vivo effects that failed to exert any discernible effect in cancer patients.
The explanations for these failures are numerous, but the most common explanations are inability to achieve the drug concentrations/exposures needed to match those used in preclinical experiments and lack of fidelity of the preclinical model systems for predicting outcomes in patients.
This second category remains a major challenge for many cancer therapeutics in that we simply do not have a repertoire of ex vivo or in vivo model systems that fully recapitulate the complexity of human cancer with regard to the molecular features of the cancer cells themselves, the tumor microenvironment, and an intact immune system. This is a greater or lesser liability…
Circadian Cancer Therapy
August 24, 2016
Q: Are there meaningful advantages to show for optimizing and specifying time of day treatments for cancer?
A: Everyone knows: GEICO can save you 15%. Everyone knows “Timing is everything”. Almost no one knows: the time of day cancer therapy is given determines the severity of its toxicities, its anti-cancer efficacy and the likelihood of five year advanced cancer patient survival (four fold).
Some 25 years ago, a physicist and engineer, since friend and research collaborator, read of our circadian cancer therapy work in “Science” and came to visit me.
He had just had a colon cancer resected. This cancer was very mean and aggressive under the microscope and involved many lymph nodes. He had been told that he should undergo multi-agent chemotherapy. He was also told his cancer would probably recur and kill him within a few months or years, despite this highly toxic chemotherapy. Mike is a compulsive bike rider & athlete and had read about our work, creating, programmable continuous infusion pump based regimens with little or no toxicity and greater efficacy in metastatic colorectal cancer when given by continuous infusion, mostly at the right time of each day. I told him that such data were solid but that we had not done post surgical adjuvant (after surgery to increase cure) studies.
He and I created an adjuvant regimen which provided the vast majority of each day’s continuous 24 hour infusion in the night time hours, when in the day our clinical studies demonstrated unequivocally the patient would be spared the most damaging ill effects. Within six months this 24 hour continuous personalized timed chemotherapy regimen devolved…
Generic Drugs vs. Biosimilar Biologics
August 17, 2016
Q: Are biosimilars the same as generic versions of biologics? Will they be approved by the FDA? Are they safe? Are they cheaper? What about the intellectual property rights of the manufacturer of the reference biologics? If they are only slightly less expensive than the reference biologics, why would anyone prescribe them- particularly if we are not certain that they are as safe as the reference biologic?
A: Biosimilars are NOT generic versions of biologics. Biosimilars are HIGHLY SIMILAR to the reference product they were compared to, but have allowable non-clinical differences. Differently, generic drugs are copies of brand-name drugs, have the identical active ingredient, and are the same as those brand name drugs in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. Biosimilars are produced from a living organism; therefore, it is impossible to produce an exact copy of the reference biologic. Two biosimilars are approved in the U.S. as of July 2016: one is marketed (Zarxio, a Neupogen biosimilar) and the other is involved with patent litigation (a Remicaide biosimilar approved in April). A third and fourth biosimilar received unanimous votes in July of support from FDA’s Arthritis Advisory Committee (a Humira and an Enbrel biosimilar) although patent litigation may occur before marketing is allowed to begin.
For years, biosimilars have been approved and safely used by patients in Europe, Japan, Australia and other countries. While the regulations for approval are similar internationally, Europe has been way out in front on approving biosimilars and the U.S. is just entering this market. The biosimilar approval in developed countries relies on each country’s regulatory agency’s previous findings that the agency-approved reference biologic is safe and effective.
Although biosimilars in the U.S. are not expected to provide the 70-80 percent savings we have seen with traditional generics, biosimilars have historically cost at least 20-30 percent less than the reference product, which can cost over…
Driver and Passenger Mutations in Cancer Cell Genes
August 10, 2016
Q: What are the similarities and differences between “driver” mutations and “passenger” mutations and in what common malignancies is that distinction most important?
A: The commonly accepted definition of a driver mutation is a mutation within a gene that confers a selective growth advantage (thus promoting cancer development), while passenger mutations are those that do not provide a growth advantage. Independent of context, the type of mutation observed is not a factor in differentiating between a driver versus a passenger mutation. However depending upon whether the driver gene is classified as an oncogene or tumor suppressor, the type of mutation observed can play a role in determining whether it is a driver or passenger. For instance, driver mutations in oncogenes tend to be missense mutations at specific codons or focal amplifications, while nonsense or frameshift mutations or focal deletions are often the hallmark driver mutation type in tumor suppressors. Driver mutations have a tendency to occur in protein-coding regions of genes and within important functional domains of the protein, although it’s increasingly being recognized that non-coding mutations, like splice-site or promoter mutations, can also be driver mutations. Thus, using mutation location as a discriminatory factor may be becoming a less reliable indicator of whether a mutation is a driver or passenger. Additionally, driver mutations are often somatic in origin, with germline mutations often fast-tracked to the passenger bucket; however, a cautionary note should be inserted here as there are very clear examples of where germline mutations are driver mutations (e.g. BRCA1/2 in familial breast and ovarian cancer or TP53 mutations in Li-Fraumeni syndrome).
In terms of the ‘how’, there are generally two methods or approaches to classifying a mutation as a driver or passenger: 1) by frequency (driver mutations should be mutated in a greater proportion of cancer samples than would be expected from the background mutation rate) and/or 2) by prediction of functional impact (either via in-silico algorithms or cell/model-based assays). Each method is fraught with caveats and disadvantages or challenges, however the gold standard of evidence that a mutation is a driver is experimental evidence demonstrating that the mutation produces a cellular phenotype that provides…
Patients and Physicians Should Share Decisions in Oncology
August 3, 2016
Q: Many of us have been touched by the publication of your sensitive but serious criticism of your wife’s care once her ultimately lethal peritoneal cancer had spread. How do you propose that oncologists, patients and their families should best practice “shared decision making”?
A: Sad but true, most cancer patients today unknowingly enter highly conflicted treatment environments where, as a practical matter, the ideal of shared decision making may run counter to the provider organization’s interests. Cancer care is such lucrative business that more than one in four health systems is now building a cancer center. Physicians or the health systems they work for typically profit from the drugs they prescribe, which often lack evidence of efficacy. These vectors often result in care decisions that accrue more to the health system’s than the patient’s benefit.
Patients should assume that their physicians have their best interests at heart but, in complicated, unfamiliar territory, insist on asking hard questions. Doctors are increasingly aware that their role includes making patients aware of their options, but they, like all of us, may also have inherent biases that manifest in what treatments they urge for their patients.
Physicians can be optimistic about outcomes and patients may be unreasonably hopeful, so an honest evidence-based assessment of current realities is critical. What benefits will the treatment realistically buy the patient and how much of an ordeal will it induce? What are the odds of success and what, exactly, is the definition of success in each case. The goal is to arrive at care decisions based not just on abstract notions of what works better, but on results that will be meaningful to the patient’s and family’s lives.
Treatments that buy a few extra days or months may not be worth…
Targeted Therapy for Waldenstrom’s Macroglobulinemia
July 27, 2016
Q: A 76-year-old male is referred to you. His labs at presentation showed anemia and elevated immunoglobulin M. A bone marrow biopsy showed lymphoplasmacytic lymphoma with MYD88 gene mutation. He received a rituximab-based chemotherapy regimen frontline although his disease relapsed with worsening anemia and increased Ig M levels. The patient has no siblings. How do you manage his care?
A: My recommendation at this point would be to prescribe the Bruton tyrosine inhibitor (BTK) ibrutinib. The U.S. Food and Drug Administration granted accelerated approval to ibrutinib (420 mg daily) for patients with lymphoplasmacytic lymphoma in 2015. Clinical response correlates with the presence of mutations in the MYD88 and CXCR4 genes which are commonly seen in this hematologic condition.
What is the difference between Waldenström’s macroglobulinemia (WM) and lymphoplasmacytic lymphoma?
There are some differences even though the terms are used interchangeably by some. Lymphoplasmacytic lymphoma is a neoplasm of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells that usually involve the bone marrow. Waldenström’s macroglobulinemia is a lymphoplasmacytic lymphoma with bone marrow involvement and monoclonal immunoglobulin M of any concentration. This particular case is better defined as WM.
What is the molecular basis for using ibrutinib in WM?
Whole genome sequencing has revealed highly prevalent somatic mutations in WM. MYD88 L265P is highly present in patients with WM and supports malignant growth via signaling involving BTK. Ibrutinib inhibits…
How Are Cancer Mutations Like Palm Trees?
July 20, 2016
Q: How might current thinking on tumor evolution/heterogeneity and sequential mutational profiling inform optimal therapy selection?
A: I’d like to share some learnings from ASCO, 2016:
To help think about tumor evolution over the course of time and treatment of cancer, I’m a fan of the palm tree analogy (made by Charles Swanton, ASCO 2016). Early genetic alterations that occur in the developing tumor are “trunk” genetic events that are present in every cancer cell in the tumor. Trunk driver mutations may be predictive of drug sensitivity or intrinsic resistance. As the tumor continues to grow some cells will develop additional mutations that will be shared by their progeny cells within the tumor. To continue the palm tree analogy, this results in a branching effect, with each branch representing a sub-clonal population of tumor cells that have new acquired mutations not shared with the original trunk cells or cells in branches that evolved earlier. Swanton cites an earlier study (Landau et al, Cell, 2013) that demonstrated that acquisition of subclonal driver mutations (occurring in the tree branches) results in significantly reduced survival over time as compared to patients whose tumors lack…
Using Patient Navigators to Improve Cancer Care
July 13, 2016
Q: What are Patient Navigators and why are they sometimes necessary for some cancer patients? How do the best programs work?
A: As precision medicine, information technology and an increasingly savvy internet society merge, there will be a greater expectation that patients be involved, informed and engaged with their healthcare team. Navigators will be pivotal in this process, both those that are within the healthcare system and increasingly those that are lay navigators outside of the system. Lay navigators are often resourceful survivors or caregivers themselves, experienced in research and the health care process, with critical skills, resources and most importantly the “heart connection” that patients will need throughout their cancer experience.
Accessing resources and seeking quality care for those diagnosed with cancer is a demanding and complicated process. A patient’s survival can be impacted by critical decisions, so there’s the pressure to get it right. The reality of receiving a cancer diagnosis begins with an avalanche of emotion, anxiety and uncertainty both for the patient and their family. Many patients will inevitably encounter barriers along the way and face important crossroads critical to their care. Often they will feel buried and paralyzed under the weight of a system focused on time and process and may feel uncomfortable with their ability to question or evaluate the process. With multiple experts and treatments involved, it is often difficult to transition levels of care. Many also experience long term side effects following treatment, impacting their transition from patient to survivor.
Patient navigators are resourceful problem solvers there to guide patients through a difficult experience often never encountered before. They help to prevent and eliminate barriers to quality care and treatment, locate resources and often act as a communication liaison between the patient and the care team. A navigator can help support patient satisfaction through their compassionate guidance, often having first hand experience as a cancer patient themselves, resulting in improved quality of care and overall outcomes. Navigators are also…
CollabRx and the 2016 Cancer Moonshot
July 6, 2016
Q: Did the CollabRx vision of 2008-2010 foretell the 2016 Cancer Moonshot?
A: True history is difficult to confirm. Its representation depends in large part on who recorded “his-story.” Even Socrates, who, amazingly, did not himself write, is known mostly because of the extensive writings by his students.
Did Richard Nixon, in declaring “War on Cancer” in 1972, calling for vast research to find a cancer cure foretell the Obama-Biden 2016 “Moonshot”? Perhaps, since it also was a presidential decree.
It takes many threads to weave a tapestry.
Jay Martin (Marty) Tenenbaum PhD, himself both a former Stanford professor and pioneering internet entrepreneur as well as a metastatic melanoma survivor, founded CollabRx as a privately held, for profit company in 2008.
When Marty conceived CollabRx, he envisioned breaking down the silos…
Sun Exposure and Skin Cancer Risk
June 29, 2016
Q: Summer sun season is upon us. What role, if any, does sun exposure have in the causation of cutaneous: 1) Actinic keratosis? 2) Squamous cell carcinoma? 3) Basal cell carcinoma? 4) Malignant melanoma? How completely should humans try to eliminate sun exposure lifelong?
A: The potential health effects (both benefits and harms) of sun exposure have been the subject of much controversy over the last 100 years. In the early 20th century when dietary sources of vitamin D were more limited, sun exposure was thought to promote both bone health and optimal health overall. Early epidemiologic studies, and later laboratory investigations demonstrated a definitive causal link between ultraviolet light exposure (i.e. the damaging wavelengths from sunlight) and skin tumors. Unfortunately, the genie was out of the bottle, and everybody wanted to be tan due to the mistaken belief that it was a sign of good health.
Interestingly, the contribution of sun exposure in different skin cancers varies.
Actinic keratosis: These extremely common skin growths are potentially pre-cancerous pre-cursors of squamous cell carcinoma. They occur on the same skin sites as squamous cell carcinoma (described below) and have a high rate of ultraviolet light-induced mutations.
Squamous cell carcinoma: This malignant tumor has the most direct relationship between sunlight and cancer. These growths occur on the face, arms and hands; skin sites that have received high cumulative levels of sun exposure. In addition, epidemiologic studies found a strong association of squamous cell carcinoma and outdoor occupations. Ultraviolet light-induced mutations are seen in more than 80% to 90% of these growths…
Is there a Better Descriptive Name than Personalized Medicine?
June 22, 2016
Q: What’s in a name? Should “it” be “Personalized Medicine,” “Precision Medicine,” or perhaps, “Accurate Medicine”?
A: Much of what we do in my laboratory at the Fred Hutchinson Cancer Research Center revolves around the genetics of response and relapse in leukemia. I often describe this as the biology of luck. Why do some good risk patients fail to respond to therapy, while some patients with characteristics of very poor risk nevertheless respond well? This phenomenon is often ascribed to deity, diet, or luck.
One must hope that there is some biology behind the differential response we see in patients. This then is the heart of “personalized” or “precision” medicine. Words matter, however, and in this case, neither of these trendy phrases passes muster. The term “personalized medicine” suggests…
Multiple Sequential Biopsies now Standard of Care in NSCLC
June 15, 2016
Q: How has the introduction of molecular testing of non small cell lung cancer (NSCLC) altered therapy and outcomes?
A: The understanding of lung cancer as a genetic disease has been developing over at least 30 years. The technology (and cost of this technology) to utilize this understanding has only been developed over the last 10 years, and importantly, along with the technical ability to test for molecular/genetic abnormalities has been the development of a new generation of targeted agents that can specifically target these abnormalities.
In 2004, several groups described mutations with the epidermal growth factor receptor (EGFR) in patients who had sustained substantial responses to EGFR targeted tyrosine kinase inhibitors (TKIs). At this time, a number of TKIs had been approved for treatment of non-small cell lung cancer without respect to mutations. Over the next months and years, clinicians started to understand the frequency and clinical characteristics of these mutations – seen in adenocarcinomas from patients with a light or never smoking history, and especially those from East Asia. The concept of “clinical selection” of patients most likely to benefit from these agents developed between 2004 and 2009. This strategy changed forever however in 2009 with the publication of the IPASS (Iressa Pan Asia Study) which compared gefitinib (Iressa®) to standard platinum based chemotherapy in patients with a light or never smoking lung adenocarcinoma. This study demonstrated conclusively that clinical selection was inadequate – patients with the sensitizing EGFR mutations had profound benefit from the TKI, while those with the same clinical features, but lacking the mutation, had essentially no benefit from the TKI. Multiple subsequent studies have confirmed the benefit from EGFR TKI treatment in patients with molecular selection.
More recently, the development of additional TKIs against the anaplastic lymphoma kinase (ALK) and ROS1 genes have been developed SOLELY in patients who express the molecular abnormality – i.e. the drug and the molecular test have been developed concurrently…
Use CUREUS to Build Rapid Learning Communities
June 8, 2016
Q: CollabRx, and its “sister” not for profit organization “Cancer Commons,” are dedicated to rapid dissemination and implementation of the best evidence to improve cancer care. The National Academy of Medicine has called for the building of rapid learning communities. How can your company and journal “CUREUS” help facilitate these efforts?
A: CollabRx is dedicated to rapid dissemination and implementation of the best evidence to improve cancer care. But where does one find such evidence? Meanwhile, the National Academy of Medicine has called for the building of rapid learning communities. Yet what is the vehicle for such physician interaction? The answer to both of the above questions is peer-reviewed journals, which are the foundation for most scientific communication. Unfortunately the processes inherent to traditional medical journals undermine these very objectives, i.e. the “rapid” dissemination and “rapid” learning of critical knowledge. I would like to argue here that our reflexive reverence for conventional processes for curating peer reviewed knowledge can and is holding back better cancer treatment…
Should All Potentially Lethal Tumors Be Sequenced?
June 1, 2016
Q: Is there enough benefit to justify sequencing all patients’ tumors? – Perspective from a scientific knowledge engineer.
A: As a scientist working as a scientific knowledge engineer in molecular oncology, part of my job is to collect, organize, and deliver data that correspond to aberrations present in cancer that could inform clinical decision making.
I recently read with great interest, the opposing viewpoints on “Is there enough benefit to justify sequencing all patients tumors?”, published in JAMA Oncology (April 14, 2016). From the Yes side: sequencing technology provides invaluable intelligence to diagnose, treat, and defeat cancer (Universal Genomic Testing Needed to Win the War Against Cancer by Razelle Kurzrock, MD, and Vivek Subbiah, MD). From the No side: rigorously tested superiority and outcome data are lacking and the cost to patients is still prohibitive (No Solid Evidence, Only Hollow Argument for Universal Tumor Sequencing by Howard Jack West, MD). Both of these are compelling arguments, in spite of their contradictory nature, that deserve ongoing consideration in the oncology community. What we are increasingly coming to understand is that beyond a relatively small set of driver aberrations, whose testing and treatment are specified in standard treatment guidelines, there are a wealth of other molecular abnormalities in cancer that may be highly useful in informing clinical decision making. A few examples to illustrate the point:
1) Biomarker overexpression suggests selection of one targeted therapy drug may be superior to the other targeted drugs recommended for the diagnosis in treatment guidelines (example: high AXL expression in EGFR-mutated NSCLC is associated with acquired and de novo resistance to first generation EGFR inhibitors)…
Use of Circulating Tumor Cells (CTCs) in Detection and Management of Lung Cancer
May 25, 2016
Q: Liquid biopsy is “all the rage” in the cancer diagnostic space these days. You have worked with Circulating Tumor Cells (CTCs) for quite some time. Beyond R and D, is there a practical clinical usefulness for CTC at this time, what is it and how does one go about using it well?
A: Yes, I believe there are several important practical clinical applications for CTCs beyond R&D, including the early diagnosis of lethal cancers, such as lung cancer. If discovered at an early stage in the disease and treated appropriately with video-assisted transthoracic resection or stereotactic body radiation therapy (SBRT), the early diagnosis of lung cancer would result in a much improved survival rate. If there is a sensitive and specific CTC test for lung cancer, that can be performed as an adjunct to an indeterminate nodule on spiral CT scan or as a primary screening test in high risk individuals and that can be validated and replicated in laboratories worldwide, it would have a major impact on the devastating morbidity and mortality that lung cancer currently wreaks…
Can Precision Oncology Develop Despite Pharmaphobia?
May 18, 2016
Q: Your recent book “Pharmaphobia:—–” about conflict of interest “Myths” drew great attention to what you and David Shaywitz earlier called the “Pharmascolds” hazard. How do you see that phenomenon impacting the current national movement toward “Precision Oncology”?
A: The public’s dread of cancer engenders electric excitement every time something new comes along to combat the disease. The latest example of such a development is “precision oncology:” using the specific genetic makeup of a patient’s malignancy to target therapy against it or else engineering a subject’s immune system to recognize and destroy tumors based on their unique composition…
How do Phase 1 Clinical Trials for Cancer Drugs Work?
May 11, 2016
Q: How is it determined that an investigational cancer drug is ready for entrance into Phase 1 clinical trials. And, how is that transition accomplished?
A: Phase 1 oncology studies encompass clinical trials wherein a new drug or combination of drugs is given to patients for the first time. These studies may include: (i) new combinations of FDA-approved or investigational drugs; and (ii) a first-in-human drug.
For this commentary, I will concentrate on first-in-human phase 1 studies. The main objectives of first-in-human studies include elucidating: (i) safety/toxicity; (ii) pharmacokinetics; (iii) optimal dose; and (iv) response signals…
NextGenU.org and the Prevention of Cancer
May 4, 2016
Q: What is Next Gen U and how does it approach the prevention of cancer?
A: NextGenU.org is essentially the world’s first free university; uniquely global for credit, for free. Founded in 2001 with a focus in the health sciences, NextGenU’s accredited courses span from college-level pre-health sciences and community health worker training through medical and public health graduate training, residency programs, and continuing medical education. The courses are competency-based, and include online knowledge transfer, a web-based global peer community of practice, and local and remote skills-based mentorships. Our accredited partners, North American universities that are outstanding in each particular course topic, give individual learners credit for this training (or institutions can adopt them and use them with their students). We collaborate with leading universities, professional societies, and government organizations including the American College of Preventive Medicine, CDC, Grand Challenges, Harvard Institute for Lifestyle Medicine, NATO Science for Peace, and WHO…
Targeted Therapy and/or Immunotherapy for Cancer
April 27, 2016
Q: Surgery and radiation treatment for many cancers are now being followed by not only adjuvant chemotherapy but also a huge panoply of targeted therapies based on precision diagnostics. In your crystal ball, how do you see immunotherapy evolving in relation to targeted therapies based on cancer genomic findings? Exclusive or sequenced or blended?
A: For decades the interplay of the neoplastic process with the immune system has been described. There are several longstanding observations that are relevant:
First, in a variety of animal models of cancer, the adaptive (cellular or humoral) and innate immune systems (natural killer cells, proteins, etc)_can be primed or manipulated to limit or eradicate tumors, or delay their development in high risk settings…
A Full House for Myeloma Therapy: What’s Next in the Cards?
April 20, 2016
Q: Some writers have characterized 2015 as a year of great progress in the treatment of Multiple Myeloma. What advances in Myeloma treatment in 2015 do you consider to be the most important and why?
A: Five new drug approvals for patients with relapsed and/or refractory multiple myeloma mark 2015 as a year of great progress against this disease. Proteasome inhibitors were full with three new regimens:
All of these are exciting developments that will help further improve myeloma patient outcomes. Panobinostat, an oral deacetylase inhibitor, is the first agent in its class to be approved for myeloma…
Managing Metastatic Colorectal Cancer
April 13, 2016
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 hemi-colectomy 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: 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 to use chemotherapy upfront followed by surgery…
Compassionate Use of Investigational Drugs
April 6, 2016
Q: What is the ethical basis for compassionate use of investigational drugs; and what are some practical considerations in making such use reality?
A: In seeking relief from the burden of disease, some patients face a lack of satisfactory treatment options from the range of available, government regulatory authority approved medicines. In these circumstances, patients often turn to investigational medicines, or “preapproval access.” The main avenue for preapproval access is for patients to enter clinical trials…
Single Cell Biology in Cancer Research and Treatment
March 30, 2016
Q: What do you see as the best roll for single cell biology in cancer research and treatment in the near future?
A: Supporting immuno-oncology research and development.
Single cell biology refers to the analysis of individual cells isolated from complex tissues obtained from multi-cellular organisms and can be applied to many biologically relevant areas of study. For example, the identification and characterization of various cell compartments, the study of cell fate including lineage mapping and phenotypic plasticity, and understanding mechanisms of tumorigenesis…
How to Initiate Treatment for Chronic Myelogenous Leukemia
March 23, 2016
Q: What is your basic approach to handling a middle aged adult patient in good general health who is referred to you with a new diagnosis of Chronic Myelogenous Leukemia?
A: First off, the treatment of choice for chronic phase CML is a tyrosine kinase inhibitor (TKI). Currently there are three approved TKIs in the front line setting, imatinib and the second generation TKIs, nilotinib and dasatinib. There have been three randomized trials comparing imatinib to either nilotinib or dasatinib, and all three show remarkably similar results…
Making NGS Work for Oncologists
March 16, 2016
Q: Your group has recently described an Actionability Framework for designing treatment strategies for cancers that are characterized by mutations. What is the basis and rationale for such an approach?
A: As Next Generation Sequencing (NGS) is increasingly adopted into clinical practice, physicians are faced with the daunting task of identifying variants that are clinically actionable – those that can help them select potential treatment options. In oncology, NGS technologies are used to profile tumor or liquid biopsies and identify variants in cancer-related genes. Cancer gene panels range in size from a handful of genes to several hundred. Depending on the size of the panel, many variants may be observed in tumors…
Treating Metastatic Malignant Melanoma
March 9, 2016
Q: What is your basic approach to handling a new young adult patient in good general health who is referred to you with a diagnosis of Malignant Melanoma, metastatic to liver or lung? The primary cutaneous melanoma, 1.5 mm in thickness, was diagnosed in Maine 5 years ago and was of skin on the forearm; treated there by wide resection with clear margins and no lymph node dissection. There was no molecular/genomic testing of the primary.
A: In a case like this, there are a few additional elements of data that I always try to obtain:
Introducing a New CollabRx Blog
March 2, 2016
Q: Why are we starting The CollabRx Blog?
A: With our new blog, we intend to provide a vehicle to communicate timely information of importance about cancer to a broad audience. Our Editorial Board members come from hospitals, cancer research centers, government, academia, industry, and other organizations, invited guest experts, and the CollabRx staff.
Our goal is to teach about the use of genomic (and other -omic) data in cancer diagnosis, prognosis, therapy selection, and clinical trials, as well as payer attitudes, policies, ethics, and economics; and focus, filter, and distill pointed and clear understanding selected from an abundance of very complicated and often confusing source data.
The CollabRx Blog will be a regular recurring journalism column about cancer in blog format with a link on the home page of the corporate website www.collabrx.com. It begins today, Wednesday, March 2, 2016. Our primary audience will be physicians (especially oncologists, pathologists, radiologists and surgeons) plus basic and clinical scientists. We welcome the viewpoints of other health care professionals, students, foundations, pharmaceutical, biotech and device company workers, hospital employees, investors, NGOs, government, public media, payers, purchasers, cancer patients and their families
We will publish weekly at 12 noon PT each Wednesday. The posts will be about 500 words or less. Our blog will be in a Q&A format with specific questions from the CollabRx Editor in Chief to invited experts who respond with answers. Each posting will eventually have an open-ended discussion forum.
Our blog will abide by the Creative Commons rules for open access.
Our posts will be found on Social Media Platforms such as Twitter, LinkedIn, and Facebook in the near future.
Thank you for looking and for reading. We hope to provide regular information of value so as to merit your frequent return.