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

How to Control American Drug Costs

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Brian Klepper PhD, Health Care Analyst, CEO of Health Value Direct and an advisor to The Lundberg Institute

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. Federal programs are required to cover most products – including those with sub-optimal performance – priced at whatever the market will bear. To a large degree, the commercial health plan sector follows suit. No rational market rules guide the way we currently buy drugs. We don’t require pricing to be tethered to what’s paid in other industrialized, international markets, or tied to the value delivered in care avoided or Quality-Adjusted Life Years gained.
For perspective, consider a 2015 JAMA Int Med study showing that between 2008-2012, 86 percent of the drugs approved with surrogate endpoints and 57 percent of cancer drugs approved by the FDA “have unknown effects on overall survival or fail to show gains in survival.” In other words, the authors write, “most cancer drug approvals have not been shown to, or do not, improve clinically relevant end points.” Realizations like this make clear the need to identify the measurable improvements that existing or new drugs represent. That would provide a rational way to value and price a drug.
Recently efforts have been afoot to tie pricing or purchasing decisions to known value. For example:

  • The American Society of Clinical Oncology recently unveiled its drug value framework, which evaluates new cancer therapies based on clinical benefit, side effects, and improvements in patient symptoms or quality of life in the context of cost.
  • The Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center is also focused on the price and value of drugs, under the belief that more rational pricing could increase patient access to important medications while driving innovation.
  • The Institute for Clinical and Economic Review (ICER) independently assesses the value of new drugs, guided by four questions:
    1. How well does the drug work?
    2. How much better is it than what we already have?
    3. How much could it save us?
    4. How much would it cost to treat everyone who needs it?

In other words, methodologies to achieve value-based drug pricing are well within reach, but the industry will resist with all its power and influence. Secretary Clinton is focused on this area, and believes that leadership can mobilize the agents of reform to make meaningful change achievable. That is what it will take.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

Expanded-Compassionate Use of an Investigational Drug

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Vivek Subbiah, MD, Assistant Professor, Department of Investigational Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

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 that there is a 1 in 100 chance that the investigational agent for expanded compassionate use works. I would say that the chance is ONE and not zero. For his mother, father, wife and future child it is HOPE. It is with this hope that we live in.
How do I evaluate the pre-clinical and/ or clinical data for justifying compassionate use?
I refer you to the webpage of Personalized Cancer Therapy at MD Anderson. Here there are quite a few resources to define actionability of a gene. I am highlighting the main aspects from that site as below:
Actionable Gene: A gene is deemed actionable if 1) there are clinically available drugs that directly or indirectly target tumors with genomic alterations in the gene of interest with minimally preclinical evidence of their use in tumors with alterations in the gene of interest, and/or 2) there are clinical trials specifically selecting for patients with tumors harboring genomic alterations in the gene of interest.
Actionable Variant: A variant is deemed actionable if all of the following criteria are met: 1) the variant occurs in a gene deemed actionable, 2) the alteration type (mutations, amplification, etc) for that gene is deemed actionable, and 3) there is either published literature or data from the MD Anderson Zayed al Nahyan Institute for Personalized Cancer Therapy (IPCT) functional genomics platform that the alteration is likely to be tumor promoting (e.g. activating mutation in an oncogene or inactivating mutation in a tumor suppressor), or there is evidence that the variant confers sensitivity or resistance to a clinically available therapy.

Table 1
Precision oncology decision support level of evidence classification: level of evidence for drug effectiveness in a specific tumor type harboring a specific biomarker*

Level 1
1A | Drug is FDA-approved for the same tumor type harboring a specific biomarker.
1B | An adequately powered, prospective study with biomarker selection/stratification, or a meta-analysis/overview demonstrates a biomarker, predicts tumor response to a drug or that the drug is clinically effective in a biomarker-selected cohort in the same tumor type.
Level 2
2A | Large-scale study demonstrates a biomarker is associated with tumor response to the drug in the same tumor type. This could be a prospective trial where biomarker study is the secondary objective or an adequately powered retrospective cohort study or a case-control study.
2B | Clinical data that the biomarker predicts tumor response to drug in a different tumor type.
Level 3
3A | Single or few unusual responder(s), or case studies, show a biomarker is associated with response to drug, supported by scientific rationale.
3B | Preclinical data (in vitro or in vivo models or functional genomics) demonstrates that a biomarker predicts response of cells to drug treatment.
Bottomline, is that clinical studies provide highest level of evidence and pre-clinical studies lowest level of evidence (but at least provide some evidence for hope in the face of nothing).
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

The “Hutch” and Improving Baseball: World Series Edition

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

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.

  1. Make the DH available and optional for all games, all season long, in both leagues.
  2. Before each game, a designated specific team decides whether or not the DH will be used in that game.
  3. 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, then the visitor always picks. If MLB wants to strengthen home field advantage (and thus, shorten more games by 1/2 inning), then the home team always gets to pick.
  4. Major league rosters are allowed to grow from 25-26 to accommodate this change.

This change makes the use of the DH part of the everyday lineup strategy. If I’m the manager that gets to pick, if your DH is better than mine (think David Ortiz), then no DH for your team. If my team’s pitcher that day can hit (think Bumgarner) and yours can’t, no DH. If my team’s pitcher can’t hit or run (think Colon), then DH it is. This revised rule also can take into account lefty/righter pitcher/hitter match ups. And think about the Sabermetrics field-they will go into a frenzy developing the best algorithms for deciding the yea/nay DH decision.
Four simple steps, and our (at least this part of) country is healed.
Still curious?
Fred Hutchinson (Hutch) was a great (perhaps Seattle’s greatest ever) baseball player and major league manager. A chain smoker, he died of metastatic lung cancer at age 45. His brother, a surgeon, initiated the Fred Hutchinson Cancer Research Center (aka the Hutch) in his honor. The starting pitcher for the Chicago Cubs in the 2016 World Series is Jon Lester, a cancer survivor (since 2006), successfully treated at “the Hutch”.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

How to Decide to Offer a New Lab Test

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Jared N. Schwartz, MD PhD LLC Past President, College of American Pathologists; Opinions his own; Charlotte, NC.

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 numerous clinical studies published in peer-reviewed journals, suggesting that “at this time” having the test results for PD-L1 are important for the treating physician to have in a timely manner.
Now the question is do you send the test request out to another laboratory or introduce it into your own? There are many questions to be answered by lab director in order to make that determination. A short example list of important questions below in no specific order:
What would the number of requests for PD-L1 be in your lab?
Are these numbers high enough to ensure on-going experience in performing test?
Does your lab have skilled staff that can be trained to perform test?
Do you have the resources to ensure your staff have the time to introduce, validate and ensure ongoing quality control of the test?
What will be the costs to provide the test in-house or sent to outside lab?
What is turn-around-time expected from your ordering physicians?
Do you have ability to meet their expectations?
If volume is questionable can an outside lab meet the turn-around time expectations?
What process would you use to select an outside testing lab?
If you decide to perform test what method would you select?
What process would you use to validate, maintain quality control and select appropriate ongoing proficiency and competency testing as per CLIA?
The answers to these questions and others depending on your clinical setting would help you and your colleagues determine if the test for PD-L1 should be performed in-house or sent to another laboratory.
Important to remember: this decision needs to be revisited depending on changes to the answers to above questions occurring over time.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

Preventing Hair Loss from Cancer Chemotherapy

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Richard B. Schwab, MD. Associate Clinical Professor of Medicine, Moores Cancer Center, University of California, San Diego, School of Medicine

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 $2000.
Now centers must consider how to handle scalp cooling. If a center leases a Dignitana system there will be a financial incentive for utilization. Additionally centers will need to consider how to handle this for patients that cannot afford the added cost. Is reduction of hair loss a good use of limited charity resources? Additionally logistical issues could develop. Each system can only accommodate 2 users at a time so patients using this system will face additional scheduling limitations. Is waiting to start chemotherapy at a time when scalp cooling is available acceptable or will additional systems need to be leased to prevent delays in therapy?
Obviously numerous additional questions will arise if scalp cooling becomes more popular. For now, it seems to me that this is a good thing for our patients. Fortunately cure rates for breast cancer patients are relatively high and are rising. This gives us the luxury to focus more and more on reducing the toxicity of breast cancer treatment. Scalp cooling is undoubtedly an effective way to reduce one of the most troubling toxicities of chemotherapy for our patients.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

Mutational Oncology: The Basics

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Vivian B. Douglas, PhD. Associate Knowledge Engineer, CollabRx San Francisco, California

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.
These seemingly simple changes in DNA coding sequences can have profound effects on protein function. If the coding sequence of a protein is altered, this can lead to a number of different altered behaviors including inactivation or activation, mislocalization, or altered transcription (which can affect mRNA and protein expression). For example, the well-known missense mutations BRAF V600E and EGFR T790M mutations change these proteins from their normal functioning state to a hyperactive state. In the case of a truncating or frameshift mutations, this can result in the loss of key portions of the protein that are critical to its function. For example, a truncating mutation that results in the loss of a kinase domain in a tyrosine kinase protein will completely abrogate that function of the protein. It is these functional characterizations that lead to the classification of variants as deleterious/pathogenic or benign.
Knowing the tumor profile of a patient can aid in treatment decisions, aid in the identification of potential targeted therapies that may be beneficial, and identify clinical trials that can be beneficial to the patient. Additionally, genetic testing for certain germline mutations can identify patients that have an increased risk for developing certain cancers, a well-known example being BRCA testing for breast cancer risk. Another perhaps more critical role in personalized medicine that genetic profiling of patient tumors plays is the guidance on treatments that should not be used for a particular patient. In particular, some mutations can render a tumor resistant to certain drugs and others can lead to acquired resistance after an initial response. In the era of personalized medicine, determination of mutation type and the effect of that mutation on protein function can be a critical part of cancer treatment.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

The Most Relied Upon Journals in Precision Oncology

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George Lundberg, MS, MD, ScD, MASCP, FCAP, Chief Medical Officer and Editor in Chief, CollabRx, a Rennova Health Company; Editor at Large, Medscape; Executive Adviser, Cureus; Consulting Professor of Pathology and Health Research and Policy, Stanford University; President and Chair, The Lundberg Institute; @glundberg

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. This was a single pass survey.
The top 10 are:
New England Journal of Medicine-28;
Journal of Clinical Oncology- 27;
Lancet Oncology- 15;
Cancer Clinical Research-15;
Cancer Research-13;
Nature-12;
Nature Medicine-12;
Cancer Discovery-12;
Journal of the American Medical Association- 11;
JAMA Oncology-10.
Eight (8) journals drew 5-9 advocates.
Science-9; Blood-9; Science Translational Medicine -8; Cancer Cell-7; Oncotarget-7; Journal of the National Cancer Institute – 7; Molecular Cancer Therapeutics-7; Cell-6.
Sixteen (16) publications enjoyed 2-4 advocates.
Cancer-4; Cell Reports; Breast Cancer Research; British Journal of Cancer; Annals of Internal Medicine; Nature Review Clinical Oncology-3 each; these attracted 2 each: European Urology; Clinical Cancer Research; Annals of Hematology/Oncology; Proceedings of the National Academy of Sciences; PLoS ONE; PLoS; Journal of Precision Medicine; Journal of Thoracic Oncology; Nature Genetics; New York Times.
The remainder (36) were named by a single advocate.
AJCP; AACR; Annals of Oncology; Arch Path Lab Med; BMC Cancer; Brit J Urol; Cancer Genetics; Cancer Immunology and Immunotherapy; Cancer Science; Clin Adc in Hem and Onc; Euro J Cancer; HemOnc Today; Haematologica; Immunity; Int J of Cancer; JCI; J Comm and Supportive Oncology; JID; J of Onco Pract; JNCCN; J or Urol; Leukemia; Mayo Cl Proc; Molecular Cancer Research; Molecular Cell; Molecular Oncology; Nature Biotech; Nature Cancer Biology; Nature Review Drug Discovery; Nature Methods; Oncogene; Oncologist; Pig Cell Mel Res; PLoS Genetics; Urology; Prostate Diseases; WSJ.
The data source is: EXPERT OPINION. This may be as good a way as any to evaluate a medical publication, as long as you can engage “the best experts”. Was your favorite source included or missing?
Write to me at gdlundberg@gmail.com to add other favorites or to argue that some that are included here are unfairly ranked or should be delisted.
Medical and Scientific Journalology is a big deal. Once scientific work has been accomplished, unless it is written about, no one else will ever learn from it. The economics and sociology of medical publishing are also big deals, and are very much in flux. This blog may address other publishing issues as time goes by, especially topics like “paywalls” for readers and publication costs borne by the authors.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

Length and Quality of Life in Cancer Patient Treatment

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Professor Michael Baum, Professor Emeritus of Surgery & Visiting Professor of Medical Humanities. University College, London, UK.

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 impact the gold standard of overall survival. This disconnect will have profound influences on safety, efficacy, and cost of oncology drugs that is already reaching fever pitch after the passing of the U.S. Congressional “21st Century Cures” bill last year.
In an accompanying JAMA Internal Medicine editor’s note, Rita F. Redberg MD MSc commented, “We must reduce drug approvals based on unreliable surrogates and change practice when critical studies show no survival benefit… In our rush to find new effective treatments, we should not harm our patients with ineffective toxic ones.”
We recognize that surrogate end points continue to figure prominently in oncology studies, usually promoted as meaningful outcomes in desperate situations where it is better to have cancers respond than not respond, and it is better to live progression-free than with progression. But without QoL measures to account for the offsetting toxicity of such gains, and without financial data to account for the cost, we really don’t know what has been achieved for patients who ended up surviving for identical amounts of time.
As someone who has practised in the British NHS all his professional life why should that worry me? Sadly ill-considered lunacies from the USA often follow the prevailing winds to our shores. Last year Lord Saatchi tried to drive through the House of Lords a “Medical Innovations” bill that was considered a “Quacks Charter”, based on the same fundamental misconceptions. It was a close call but fortunately it came to nothing.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

Canadian/American Cancer

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Cynthia Martin, MA is a freelance/ghost writer (who tried to write a serious piece).

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 the zeitgeist of the past 45 years (!!!!) Whether another touching tribute in an father’s obituary who “fought valiantly” or sister who “battled bravely” – I’m sure that’s not what Nixon meant. You bet cancer is lucrative: with more than 56,400 clinical trials listed it’s not disappearing soon.
Another similarity is urban and rural cancer services; both the US and Canada are large landmasses which make comprehensive services impossible. This makes me want to run screaming off the end of my closest wharf since I do indeed live in a semi-rural area and if I got cancer, would be screwed in the bad kind of way (oh really, I’m the one not taking cancer seriously?).
Also similar: prevention is largely an afterthought, like no-name condiment packages stuck at the back of a drawer (“Right, we have some of that somewhere…”). In 2015, it was estimated that in the US 1,658,370 new cancer cases would be diagnosed with 589,430 cancer deaths; and 196,900 Canadians would develop cancer and 78,000 die of cancer. If extrapolated into deaths from plane crashes – say Boeing’s 737-800, likely the most common large aircraft–that’s some 43 planes full of individuals a day. I know those stats can’t be compared but think of each person as a mother, lover, child –losses impossible to calculate correctly. In a small sign of related prevention, consider Mexico, which applied an 8% tax on “non-essential” food in January 2014, seeing junk food sales drop 5.1%, while our governments dilly-dally. The only two jurisdictions: Berkeley California’s health tax on sugar-laden drinks (must be the dreamcatcher earrings) while Philadelphia’s recent vote for its sugary-drinks tax was approved precisely because it was pitched as a tax measure for city revenue. That the beverage industry spent $10.6 million to thwart Philadelphia’s tax is obscene, like opposition (in large part by US health insurance companies) to 1993’s US Health Security Act and recently Obamacare – your two-party feuds are emblematic, wasting so much energy and time, being infinitely more precious than jettisoning partisan vested interests for the good of your citizens.
Soon after she was appointed the 18th US Surgeon General, I interviewed Dr. Regina Benjamin. She seemed she’d bring spunk and honesty to the role, especially when she said disco dancing was exercise (be still my heart). But the PR gauntlet I had to negotiate told me not to put that in (it’s an article pull quote). One of Dr. Benjamin’s hopes was to see a “smoke-free world,” but…poof she resigned. I’m thinking since she was muzzled on disco dancing even whispering “Let’s address tobacco use” would have been like a scene from a mob movie, her being bundled out her office rolled up in a carpet. People have completely lost their minds and souls and misdirected their talents since Nixon’s proclamation. So very much has been and is still written and discussed and debated, so very many trial balloons sent up by politicians as to which policies incur less wrath and fewer lost votes, so many millions of people needlessly suffering and ever lost to us – because the will is not strong enough to shut down tobacco and change taxing policies, corral lobbyists and target chemicals, take less from whatever payment system because – oh, it’s great going to conferences (saying the same things said for decades). Although I deeply adore Obama and Biden, now there’s a Cancer MoonShot, as American as the war on cancer.
No cancer isn’t funny, not even the black humour wit needed to work in healthcare, nor are greeting cards now cheerily saying “Cancer Sucks!” instead of “Get Well.” I’m trying not to mention pink ribbon marketing so here’s a musical interlude. The lead singer of an iconic Canadian band has glioblastoma winding up their supposed last tour, every station playing their music ad nauseum as media, the public (many of whom never paid attention to the band prior) and medical community fawned over his “bravery” – as if he is the only patient in their waiting room, as if he is the only person to ever have cancer and be prescribed its itchy coat of hope – as if he is the ONLY one who will die. Meanwhile, funds roll in to cancer research and – of course – the band. Not so for the lead singer of another Canadian band, who has early Alzheimers and wound up his tour quietly–so Canadian-like – but then Alzheimers isn’t as sexy. The twin brother of a British guitarist, not parlaying cancer into sales, just announced his twin’s death at 28, while yet a member of another iconic Canadian band – who’s going to die somehow not raking in teary-eyed royalties – quit to work at a library. This is all so very very – to use a scientific term – nuts.
I hope I can hear keyboards stirring to action…not to flame me for opinions on this soggy gooey mess (don’t shoot the messenger), but in a universal demand for an end to cancer, mad enough to bite down hard, not just nibble away ad nauseum at its margins.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

Conflict of Interest in Cancer Clinical Trials

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Kevin B. Knopf, MD MPH, Medical Director, Cancer Commons
San Francisco, California

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.
I believe a partial solution is to reallocate assets in cancer care to ease some of the financial stress felt by academic medical centers and community based practices. When we stop paying so much for things that don’t help our patients we have more financial assets to investigate trials of drugs that can actually help them. For example, overly aggressive oncologic care at the end of a patients’ life with prolonged (and expensive) stays in the Intensive Care Unit rather than a timely referral to hospice are unlikely to help as many patients as discovering a novel therapy might. Reduplication of imaging studies at multiple institutions if they don’t add to patient outcome is a second. The ASCO “choosing wisely” campaign, if followed fully, would be cost-effective for the cancer care system. This will reduce some of the financial pressure that might drive patients into clinical trials for reasons other than purely altruistic ones.
Health economics – the fuel for the engine that drives cancer care in the United States – is a zero sum game. With the declining funding rate from the NIH funding for clinical trials is dependent on honest and moral relationships with PHARMA. The cooperative group trials from the NIH are financial “loss leaders”. At a time when funding for cancer research from the NCI is diminishing and we have a record number of new cancer drugs approved we are now dependent on industry sponsored trials to keep the research endeavor going. Value based cancer care seems to be the catchphrase as we struggle with rising costs of treatment. What may help us ultimately are a series of real world clinical trials with economic endpoints to find cost-effective opportunities for cancer treatment. We should redouble our efforts to curb endeavors that seem purely destined to bring “economic friction” in cancer care. A wiser approach to economic asset allocation in cancer care could free up the financial pressures at the heart of this conflict of interest and start to minimize – but never completely erase – this conflict.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.