‘You Don’t Know Jack’ by Morgan Spurlock

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cancer, clinical trials, digital media, evidence based medicine, health, innovation, Intel Science Fair, jack andraka, oncology, participatory medicine

By Gregg A. Masters, MPH

But you should! Get to know him here:

Earlier today we just finished chatting with Jack Andraka on This Week In Oncology. One of my favorite lines from the conversation is quoted below, Jack refers to the high school biology class as the:

absolute stifler of innovation

From which he none-the-less associates inspiration for his scientific inquiry. Suffice it to say, Jack was neither encouraged nor challenged by the curriculum, and found other ways to engage his mind and curiousity.

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The Shell Answer Man

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cancer, clinical trials, clinicaltrials, CME, digital media, evidence based medicine, health, Just Oncology, oncology, participatory medicine, social media, twitter

By Richard Just, MD

Over the past 37 years in practice, I’ve received thousands of requests from patients, family and friends to interpret results of clinical trials.  These requests have increased dramatically with the advent of the Internet.   Many of these reports involve poor trial design or are inappropriate for the patient under consideration.  Sometimes I’ve mumbled to myself “I feel like the Shell Answer Man”.  For those too young to remember, I’m referring to a Shell Oil Co. ad beginning in the 1960’s in which the ‘Shell Answer Man”, replete in his Shell gas station uniform, answered common questions about driving and the uses of gas and oil. He just memorized a script; sometimes I wish I had one.   

Over Labor Day weekend, while in Chicago for a family event, we turned on TV to catch up on the day’s news. As fate would have it, we stumbled upon a healthcare segment on the NBC affiliate.  The reporter was listing items individuals should consider in evaluating results of clinical trials.  It seemed to me that knowledge of these items would be very helpful to people who are not healthcare professionals; people who need some way to filter trials worth pursuing with their physicians.  The following are those questions:

1. Are the patients in the trial separated into groups, with one receiving the drug or regimen being tested (“Experimental Group”) while the other is treated with the agent(s) considered standard treatment (“Controls”)?  These groups are many times labeled “arms.”  The Control Arm may be a placebo if there is no known standard treatment.  This does not mean the patient receives no treatment at all.  These types of studies are considered the “gold standard” of clinical trials in that they involve large numbers of patients who are followed for long periods of time.  This increases the likelihood that resultant findings are valid.  The downside is they take a long time to complete and are very expensive (about $1 billion from start to finish).
2. What is the total number of patients entered into the trial?  As alluded to above, the more the better.  If one study includes 50 patients while another 350 (all other factors being equal), place more trust in the larger trial.
3. What is the length of the study? In other words, how long are the patients followed? Again, the longer the better.
4. Were the patients included in the trial representative of the proposed population to be studied?  For example, if the population to be studied involves pediatric patients, someone over 18 years of age should not be entered into the trial.
5. Who is funding the study? Pay attention here. If the study is paid for by the company who developed the experimental agent, how likely are they to give a completely unbiased report? Of course we want to assume that they will, but unfortunately, some won’t.  A government supported trial is more likely to report balanced findings than an industry funded one. The reporter added that patients should note what the authors say about their study, i.e., do they make overly optimistic claims for their treatments?  Most investigators add some type of cautionary note, like “the proposed treatment looks promising pending further studies.”  This disclaimer recognizes that no study is perfect.  In fact, there has been a marked increase in the number of studies initially reporting positive results that were retracted when similarly designed trials were subsequently negative.  The end result has been a delay in patients receiving appropriate treatments and a horrible waste of money.
6. I’m adding this one on my own. I’ve noticed that one of the most common mistakes people make is to search for clinical trials involving the wrong cancer, not realizing that we identify cancers by their organ-of-origin, not the organ where they spread (metastasize).  An example would be to collect articles about liver cancer instead of colon cancer that metastasized to liver.

As chairman of our hospital’s Investigational Review Committee, I and our members are in charge of reviewing proposed clinical trials conducted in our hospital district.  The above factors, as well as many others, are considered before studies are approved, denied or amendments recommended.  Consideration of the items discussed above could save everyone a lot of wasted time, and even lead to the retirement of the Shell Answer Man.

Western Meets Eastern Medicine: Or Ying Meets Yang?

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cancer, clinical trials, CME, digital media, epatients, evidence based medicine, innovation, integrative oncology, medicine, pharma, physician, research, Traditional Chinese medicine

By Richard Just, MD

In today’s China, both eastern and western medical philosophies and practices exist relatively harmoniously.  Patients with minor, usually self limited problems are treated initially with a seven day course of seven liquid herbal preparations taken each day.  If symptoms subside, usually treatment is discontinued.  If improved but not resolved, formula may be modified.  If worse, regimen can be changed and/or referral to specialists arranged.  There are hospitals that practice purely eastern or only western medicine.  But it is becoming more frequent to find hospitals that integrate both disciplines.  Chronic conditions, like cancer, tend to be treated with western techniques, with Traditional Chinese Medicine (TCM) used in a supportive or complementary role.

I was somewhat surprised to hear that the 2 largest cancer problems are breast cancer and liver cancer (mainly the former but not the latter).  Before I left, one of my patients had brought an article to my attention about a low incidence of breast cancer in China  compared to the West.  This may not be the case.  Primary liver cancer, hepatocellular carcinoma), has long been the number one cancer in frequency in the world due to a high incidence of hepatitis, especially in Asia.  This results in chronic active hepatitis, cirrhosis and, finally, cancer.  Even though we stayed at 5 star hotels, we didn’t brush our teeth or rinse our toothbrushes with tap water, and avoided ice.  Sanitation, or lack of it, is an issue.

Everywhere in China, especially big cities, there are forests of skyscrapers.  Private homes are essentially nonexistent as the government owns all the land.  New construction is ubiquitous, so cranes are numerous.  Many of these apartment spaces are empty due to high prices, and those that are bought or rented are shared by several families.  Same with kitchens and bathrooms.  Public bathrooms may lack toilets and simply be holes in the ground.  In some buildings, one bathroom per floor exists.  We saw the interiors of 3 residences.  First, the home of one of four of the farmers that first discovered the terra-cotta warriors outside Xi’an.  Clean.  Very little furniture as you buy empty spaces which you have to furnish yourselves.  But several generations of the family lives there.  Second, a more modest quarters of a woman in the old section of Beijing.  Bathrooms were down the road apiece.  The last was a tiny, single room in what used to be the French Concession section of Shanghai.  Five people slept on one cot.  No mystery why hepatitis and liver cancers are still issues.

Another surprise is lack of mention of lung cancer.  Cars everywhere.  Their gridlock is continuous and called “rush days”.  Mist or fog (mostly pollution) gives a surreal appearance to the landscape of high rises.  Seemingly everyone coughs.  Lots of spitting.  A perfect setup for respiratory problems including lung cancer.  There are several hospitals in major cities devoted to respiratory diseases, however.

An excellent article appeared in the Wall Street Journal, Tuesday, April 3, 2012, pg D4, entitled “Chinese Medicine Goes Under the Microscope” by Shirley S. Wang.  The main topic is a clinical trial studying a four herb combination, called huang qin tang in China and PHY906 in this trial, in combination with chemotherapy to see if effective in reducing side effects of chemo (nausea, vomiting, and diarrhea).  If so, patients might be able to tolerate higher doses of chemo with better results.  Trial design and quality control are issues when doing studies such as these:

One challenge with using herbal medicines is that the ratio of the chemicals they contain isn’t consistent when plants are grown under different conditions.  After testing various suppliers, Dr. (Yung-Chi) Cheng ended up creating a biotechnology company sponsored by Yale called PhytoCeutica to carefully monitor growing conditions to ensure plants from different batches were pharmacologically consistent and to continue clinical development of the compound.

Finally, an article that appeared in the China Daily entitled “There’s More to Life Than Money” by Cai Hong, a senior writer for the paper, cites the first World Happiness Report   released by the Earth Institute last month.  Not surprisingly, the top 4 rated are northern European welfare states:  Denmark, Finland, Norway and the Netherlands.  China doesn’t make the top 100.  One of the benchmarks evaluated is health:

……Increased insurance coverage has not yet been effective in reducing patients’ financial risks, as both health expenditure and out-of-pocket payments continue to rise rapidly.  And there are many reports of disgruntled patients and their relatives attacking the medical staff in hospitals.  Reform of public hospitals is essential to control health expenditure because such institutes deliver more than 90% of the country’s health services.  But Health Minister Chen Zhu said the cost of improving care remains an obstacle, and China is looking to other nations for cost-effective solutions.

While this notice appeared in the WSJ this last weekend:

U.S.-China Pharma: Some big pharmaceutical firms are partnering with Chinese companies in trying to discover the next blockbuster drug.  This Philadelphia conference will include venture capitalists and such Western firms as Novartis and Abbott Labs. Wednesday-Thursday, Hub Cira Centre.  Regular admission:  $1,799.00.

I find it interesting that both the U.S. and Chinese governments are investigating hospitals for price gouging in the sale of drugs. Further, given the emerging cost and access pressures they’re witnessing, might mainland China by eying the health system reform experiment underway in Taiwan?

China Bound: An Appeal to the China Clinical Trials Consortium (CCTC), et al

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cancer, china clinical trials consortium, clinical trials, clinicaltrials, evidence based medicine, integrative oncology, medical education, medicine, oncology, research, Traditional Chinese medicine

By Gregg A. Masters, MPH

Dr. Just will be heading to China this week and has an interest in connecting with clinicians associated with the China Clinical Trials Consortium, other academic or established medical group practices’ specializing ‘integrative oncology’, or solely traditional Chinese medicine for the care of cancer patients.

For a brief personal invitation please watch the video above. Dr. Just’s Twitter handle is @chemosabe1, if you are available during the timeline below and interested in meeting with an American colleague please follow @chemosabe1 on Twitter, he will follow you back and enable direct message sharing. Otherwise an @reply will work as well.

Travel dates and cities are: arriving Beijing, Thursday, May 3rd, and departing Shanghai on Friday, May 18th, 2012.

More To The Henrietta Lacks Story

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cancer, clinical trials, elder wisdom, epatients, evidence based medicine, health, Henrietta lack, medical education, medicine, physician, physicians, research, social media, twitter, wellness

By Richard Just, MD

A few weeks ago, my wife and I attended “A Conversation With David ‘Sonny’ Lacks” at the California Center for the Arts, Escondido.  The event was a sellout with 900 attendees.  As it turns out, most of the colleges and universities in San Diego County designated “The Immortal Life of Henrietta Lacks” as the book discussed by students and faculty this past academic year.  The conversation was sponsored by California State University, San Marcos.  As an added bonus, Mr. Lacks’ daughter appeared with him on the podium.  I had previously attended a similar lecture with the author, Rebecca Skloot, at UCSD.

The story of Henrietta Lacks can be viewed from several vantage points.  As a medical oncologist, and Chairman of the Investigational Review Committee as well as Medical Director of the Research Institute at Palomar- Pomerado Health, ethics in medical research certainly occupies a position of paramount importance to me.  In fact, the book is being discussed locally primarily from this perspective.  Ms. Skloot points out that obtaining ‘Informed Consent’ from patients to do research on their tissue was not required, nor was it considered, in 1951 when Mrs. Lacks’ biopsy was obtained for research purposes.  Mr. Lacks stated he did not feel the family should receive financial compensation for using her tissue for research purposes.  But, Henrietta and the family should have been told that her cells were going to be used for research purposes, what the research involved, and knowledge of the results.  In other words, essentially informed consent as we now require in all patients undergoing clinical trials.

On the other hand, he did feel that the family should receive financial remuneration from the companies that commercialized his mother’s cells by selling them to labs around the world.  This proposal seems fair.  To date, no financial restitution has occurred.

But despite all this, Mr. Lacks maintains an air of dignity that engenders respect.  Throughout the evening, there was no expression of anger or hostility; no complaining.  When asked if he thought that racial discrimination played a role in how they were treated, Mr. Lacks said no, people of all races were treated the same at that time.  Sonny said that although no one from Johns Hopkins has ever formally apologized, they have honored his mother in other ways.

Sonny Lacks was 3 years old when his mother died.  So, he has no direct recollection of her.  In fact, the picture on the front of the book is the only picture of Henrietta in existence.  All that he and his daughter know about her they learned from his older siblings and Ms. Skloot’s research for the book.  When Henrietta was treated, Johns Hopkins was the only hospital in the state of Maryland that treated the uninsured.  Fast forward to the present and this sore is still festering in our country.  Mr. Lacks stated that he recently required stents placed in his coronary arteries on an urgent basis and he, like all the members of his family, is uninsured.  This brought an audible gasp from the audience.  He said he had $100,000.00 in unpaid bills, and he opined that health care should be a right as it is in other countries, not a privilege for only those who can afford it.  This elicited a vigorous round of applause from the audience .  I would add that the number of people in the U.S. who can afford access to healthcare is dwindling also. [Editor’s Note: For specific discussion on the impact in the Black community, see: ‘Blacks See Largest Decline in Health Insurance Coverage.’]

The closest we have to universal healthcare provided by government is Medicare and Medicaid (MediCal in California), see: ‘Medicare: The Basics.’  I recently crunched the numbers in my own situation at age 70 to decide whether or not to convert from my medical group’s health plan (since I’m still working to full Medicare coverage.  Plan A is free and mandatory at age 65.  But I needed Plan B, a Medicare Supplement Plan and Medicare Part D for prescription drugs.  Part B involves an annual fee of $140.00 + monthly premiums of $99.00 + something called “Modified Adjusted Gross Income” (MAGI).  The IRS now sends Medicare a report of my income and a graduated monthly charge is added to my premium.  The monthly total amounted to $259.70.  Added to that is the cost of the Supplement and Medicare Part D.  Then the out of pocket expenses including cost of drugs in the donut hole and now you’re talking “real money.”  Of course, you can opt for a Medicare HMO but choices are limited. So for effect, I will quote myself (drum roll please!):

My conclusion was that being insured does not equate to being covered, and I needed to be a CPA to figure this out.  So, I stayed with my group health plan.

The most poignant moment of the evening occurred when Henrietta’s granddaughter was asked how she felt her grandmother should be remembered.  Her answer:

The gift that keeps on giving.

Not a dry eye in the room.

@JustOncology Acquires Top Level Domain ‘TumorBoard.com’

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cancer, cancer program, clinical trials, CME, digital media, evidence based medicine, innovation, medical education, medicine, oncology, physician, social media, tumor board

By Gregg A. Masters, MPH

Since the beginning of this blog, including @Chemosabe1 and @JustOncology Twitter participation, and the launch of ‘This Week in Oncology‘ on the BlogTalk Radio Network we’ve been developing the concept of @TumorBoard. The idea is to ‘up-level’ the traditional hospital based ‘bricks and sticks’ tumor board to the web for real time consultative access to peer sourced and evidenced based best practices.

Once the center piece of any community hospital with ‘cancer center’ aspirations, and a value added incentive for staff physicians to journey from the office to the hospital for either breakfast, lunch, or dinner as the case may be, for peer networking, education, including Category 1 accredited CME, and periodic guidance and support on difficult cases, the popularity of tumor board had waned somewhat. We believe this is due in part to the increasing complexity and demands on physician time particularly in community based practices.

Yet we reasoned, with the introduction of smart phones and devices such as iPads or their tablet derivatives, to the near universal prevalence of desktops and laptops in medical practices, plus a small but steadily growing interest and participation of physicians in social media applications, why not attempt to bridge the either/or ‘workflow divide’ via these ubiquitous devices and secured web based access?

We thought the experimentation to be well worthwhile, and that the technology, people and macro-economic trends were on our side. As a result, we met with several ‘infrastructure’ partners and vendors to evaluate the state of the art so to speak, and were pleasantly surprised. We have certain specifications and needs lined up but remain open as to our preferred relationship at this time.

To date, we’ve opened the Twitter account @TumorBoard, acquired the domain names TumorBoard.co and TumorBoard.tv, since TumorBoard.com was owned by someone else, though only in a ‘parked’ and passive status. But the ‘gold standard’ from a branding perspective remained the outside our reach dot com version. After some preliminary domain brokering exchanges, we finally settled on a price, and are now pleased to announce the acquisition of TumorBoard.com. We will be activating the site shortly.

There is lots more to come. So stay tuned!

A Glitch On the Road To Personalized Oncology

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biobanking, biomarkers, cancer, clinical trials, health, HeLa cells, medical education, medicine, oncology, participatory medicine, research

By Richard Just, MD

We receive a quarterly magazine in the office called CURE, which stands for Cancer Updates, Research & Education.  Browsing through the Winter, 2011 issue, I noticed a short article entitled “Lacks’ Legacy” with an accompanying picture of Henrietta Lacks.  I’ve previously published a blog on HeLa cells, the cell line cultured from her original cervical cancer.  These cells are immortal in that they contain an enzyme at the tips of their chromosomes which prevents them from undergoing programmed cell death (“apoptosis”).  “Lacks’ tissue has since spawned an estimated 50 metric tons of HeLa cells, and the total number of HeLa-related medical studies-roughly 60,000 to date-is growing by about 300 per month.”  These cells were so malignant they were able to rapidly proliferate despite primitive tissue culture procedures.

It then occurred to me that the article was actually a sidebar to another piece called “Why Banks Need Your Tissue for Research” by Paul Engstrom, about tissue repositories.  One major message is the wide gap that exists between knowledge generated in the laboratory (meaning biomarkers and targets for new therapies) and biobanking.  A partial list of problems includes “inconsistent collection, processing and storage of tissue, which can alter its molecular composition and skew experimental outcomes; shortages of high-quality tissue; outdated preservation techniques; the high cost of and inadequate funding for repositories; patients’ lack of awareness about tissue donation; and, for competitive and other reasons, institutions’ hoarding specimens they might otherwise share with researchers elsewhere.”  These are major issues.  Since it is becoming a standard practice in clinical trials to collect, store and study tissue, then maintain these specimens for future investigations, addressing these concerns is essential.  The recently completed TAILORx study of 10,000 newly diagnosed women with early stage, hormone receptor positive, node negative breast cancer is a good example.  The Oncotype DX Assay to identify patients who might benefit from the addition of adjuvant chemotherapy to hormonal therapy as opposed to those who won’t was obtained from archived tissue specimens.  It is therefore vital that all efforts are made to assure that all institutions supplying these tissues and the repositories processing and storing them follow standardized procedures to validate that results are accurate.

All of this sounded familiar to me.  Then, I remembered an article I’d read previously in one of my favorite medical journals, WIRED magazine, entitled “The FLESH FILES” by Steve Silberman, June, 2010, pg. 156.  This is when I first became aware of the extent of these problems.  In 2005, the NCI announced the plan to create the Cancer Genome Atlas using the same techniques employed to delineate the human genome-high-throughput DNA sequencing, lab automation and computational biology.  The pilot phase would catalog genetic mutations in three of the major cancer killers:  glioblastoma multiforme (the most malignant brain tumor), serous cancers of the ovaries, and squamous-cell lung cancers.  This Atlas could reveal new tests, like the Oncotype Dx test, that would help determine treatment, develop novel agents directed against these mutations, and new methods to detect these cancers at an earlier stage.  Unfortunately, the Atlas was put on hold not because of difficulty with scientific techniques, but due to lack of viable tissue specimens to test.  In short, the biobanking system was in shambles.

Reasons for the sorry state of tissue repositories are numerous.  Focusing in on one aspect, freezing and thawing of tissues, classical solutions used to cryopreserve cells and bodily fluids are glycerol and dimethyl sulfoxide (DMSO).  Tissue requires a different preservation method, using two relics from the Victorian era:  formaldehyde (in a diluted form called formalin) and paraffin.  Formalin acts as a fixative, arresting all cellular metabolic processes, while paraffin prevents oxidation.  Under the microscope, these substances preserve cellular structure.   But they play havoc with genetic material inside cells.  “Some cells get so stressed that hours after they thaw, they take themselves out of the gene pool permanently” by undergoing apoptosis, the same “programmed cell death” that is not seen in the immortalized HeLa cells.  Even cells that don’t die experience genetic changes in the freeze-thaw cycle that can lead to an overestimation of the quality of biospecimens.  The result is corruption of the genomic data.

Additionally, formalin causes significant alterations to cellular RNA, a major probe used to decode the genetic mechanisms of cancer.  And DMSO can actually accentuate the metastatic potential of a cancer.  If infused into patients, DMSO can result in chills, nausea, kidney failure and cardiac arrest, especially in children.  Use of DMSO can be reduced by “chilling tissue at a carefully controlled rate immediately after harvesting (using a technique appropriated from Eskimos in the early 1900s by Clarence Birdseye, father of the frozen-food industry).”  But, adoption of this procedure would disrupt the routine of already overworked hospital staff.

Enter Carolyn Compton, M.D., PhD, director of the Office of Biorepositories and Biospecimen Research at the National Cancer Institute (NCI) in Bethesda, Md.  She is spearheading the effort to establish a central, public-private cancer tissue repository called the Cancer Human Bank (caHUB).  Unfortunately, these plans are on hold due to lack of sufficient federal funds.  Instead, $23.5 million in federal stimulus funds will be used by the NCI to expand research on standards for collecting, processing, storing and disseminating tissue specimens.

Trials and Errors – Part II

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cancer, clinical trials, clinicaltrials, FDA, medical education, medicine, oncology, pharma, research, science, social media

By Richard Just, MD

So, the purpose of the Cancer Genome Atlas is to identify all mutations in the most common cancers.  A massive project.  Several maps have been completed including melanoma, pancreatic, ovarian, and lung cancers.  Activation of these mutated genes results in the 6 characteristics of cancer previously listed.  Therefore, it would stand to reason that aiming novel agents at these targets would inhibit growth and spread, possibly cure, cancer.  But which targets to aim at?  For example, pancreatic cancers contain between 50-60 mutations.  To make order out of chaos, the most frequently identified mutated genes are inferred to be causative or “driver” mutations while the rest are “bystanders.”  Also, by recognizing that driver mutations tend to be found in certain ”core” pathways but not others, this further reduces possible targets to a more manageable number.  Between 13-15 pathways, an average of 13, are affected in a typical cancer type.

Getting back to the issue of causation, this month’s issue of Wired Magazine contains an intriguing article by Jonah Lehrer headlined by the following statement:  “Dead –end experiments, useless drugs, unnecessary surgery.  Why science is failing us.”  The title, “TRIALS AND ERRORS”, persuaded me to read on.

The story starts with Big Pharma’s nightmare:  a failed clinical trial.  The drug, torcetrapib, appeared to be a slam dunk in that it lowered bad cholesterol (LDL) and increased the good (HDL) by inhibiting a protein that converts HDL to LDL. Inferred from these facts was that plaque formation would be reduced, which in turn would result in decreased morbidity and mortality from heart attacks and strokes.  In fact, the opposite occurred, and the Phase III trial was terminated.  Pfizer had invested more than $1 billion dollars to develop torcetrapib plus an additional $90 million to expand the manufacturing facility.  The value of the company dropped by $21 billion in 1 week.  Since 40% of drugs fail Phase II clinical trials, and 25,000 volunteers were participating in this trial alone, both the financial and human costs are staggering.  $100 billion is invested in biomedical research annually.

How could torcetrapib fail?  After all, the entire pathway of cholesterol metabolism had been mapped out and the drug’s exact site of action was known.  Sound familiar?  As the author states, “it is a tale of mistaken causation”.  By lowering LDL and increasing HDL, it was assumed that improved cardiovascular health would result.

“This assumption-that understanding a system’s constituent parts means we also understand the causes within the system-is not limited to the pharmaceutical industry or even to biology.  It defines modern science.  In general, we believe that the so-called problem of causation can be cured by more information, by our ceaseless accumulation of facts.  Scientists refer to this process as reductionism……Once we find the cause, of course, we can begin working on a cure.”

Over the years we have learned that our attitude toward cause and effect is perceptual and that causal explanations are oversimplifications.  We have learned to deal with the issue of causation through statistical correlation.  The central concept is statistical significance, which “defines a significant result as any data point that would be produced by chance less than 5% of the time.”  But significant correlation does not necessarily equal cause.  “While correlations help us track the relationship between independent measurements, such as the link between smoking and cancer, they are much less effective at making sense of systems in which the variables cannot be isolated.”  But the human body is extremely complex with inter-relationships between multiple pathways.  Mapping one pathway and identifying all mutations does not reveal interactions between multiple pathways that are connected.  This is why torcetrapib failed.

We are designing new clinical trials.  We are mapping all the pathways of various cancers.  By inference and statistical correlation, we think we have unearthed the driver mutations and core pathways that cause cancers, whose hallmarks have been identified.  Are we setting ourselves up for another torcetrapib?

Trials and Errors

Tags

cancer, clinical trials, clinicaltrials, CME, digital media, medical education, medicine, oncology, participatory medicine, pharma

By Richard Just, MD

The explosion of information in molecular oncology has identified a seemingly infinite number of targets for novel therapeutic agents.  This has spawned the concept of personalized oncology, which has “gone viral.”  However, a disconnect between the very large number of possible targets and the very small number of treatments is now apparent.  In addition, most (85%) of drugs thought to be beneficial in Phase II clinical trials cannot be validated when other labs and institutions attempt to reproduce these results.  And it is still taking up to 10 years and costing over $1 billion to bring a single new agent from the bench to the bedside.  A postulated major roadblock is that Clinical Trial design has not adapted to these new developments.

Maitland and Schilsky addressed this topic in a comprehensive article entitled:  Clinical Trials in the Era of Personalized Oncology; CA, A Cancer Journal for Clinicians; vol 61 no 6, Nov/Dec 2011:  pp 365-381.  Table 1, pg 366 summarizes “Oncology Care and Clinical Trials in the Eras of Population Oncology, Transition, and Personalized Oncology.”  In the areas of Screening, Diagnosis, Staging, Treatment determination, and Assessment intervals, we are headed for molecular-based and individual-based decision making, but we’re still in the transition phase.  As far as early phase clinical trials are concerned, the Population Oncology Era was oriented to maximum tolerated dose (MTD); the Transition Phase is oriented to “optimum biologic dose” and the Personalized Oncology Era to determine the range of tolerable and active doses.   Mid-phase clinical trials use histology and prior treatment-based eligibility in typically single-arm, non-comparator trials in the Population Oncology Era; the addition of some marker-based screening and some randomized controlled trials in the Transition Phase and some trials, histology, and prior treatment-based eligibility with rapid, serial assessments in the Personalized Oncology Era, many with eligibility restricted to tumor marker subsets.  Obviously, the trend is to stratify patients according to their biomarkers and to serially assess for response or lack of it at more frequent intervals to accelerate the conduct of trials.

Another issue is the complexity of the diseases we’re dealing with.  Weinberg and Hanahan proposed 6 “rules” that define the behavior of cancers, the so-called hallmarks of cancer:

1. Self-sufficiency in growth signals:  cancer cells acquire an autonomous drive to proliferate, so-called pathological mitosis, by virtue of the activation of oncogenes
2. Insensitivity to growth-inhibitory (antigrowth) signals:  cancer cells inactivate tumor suppressor genes that normally inhibit growth.
3. Evasion of programmed cell death (apoptosis):  cancer cells suppress and inactivate genes and pathways that normally enable cells to die.
4. Limitless replicative potential:  cancer cells activate specific gene pathways that render them immortal even after generations of growth.
5. Sustained angiogenesis:  cancer cells acquire the capacity to draw out their own supply of blood and blood vessels-tumor angiogenesis.
6. Tissue invasion and metastasis:  cancer cells acquire the capacity to migrate to other organs, invade other tissues, and colonize these organs, resulting in their spread throughout the body.

A Cancer Genome Atlas is currently in process of development for the major cancers to map all these mutations and pathways to hopefully identify targets important in the causation of these cancers.

When Less Is More

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cancer, carcinoembryonic antigen, cea, clinical trials, clinicaltrials, medical education, medicine, oncology, participatory medicine, podcasting, social media, twitter

The longer I continue in practice, the more complex it becomes.  I thought advances in our understanding of the molecular basis of cancer would clarify decision making ; instead answers have led to more questions.  In the spirit of the immortal Henny Youngman:  Take the issue of cancer screening, PLEASE!!

The story of screening for colorectal cancer (CRC) and prostate cancer has many similarities.  The primary screening and diagnostic tool during my training years was the digital rectal exam (DRE).  In CRC the manual examination was (and still is) supplemented with stool occult blood testing.  A positive result usually leads to an invasive procedure, e.g., barium enema or colonoscopy.  Not fun procedures!  And if the test is falsely positive, not only is unnecessary time wasted, cost expended, and anxiety generated, but severe morbidity (bowel perforation) and possible mortality can result.

Enter the great hope:  the carcinoembryonic antigen (CEA).  Finally a simple blood test that would solve all our problems.  It was originally marketed as a specific screening test that should save lives.  But within a short period of time, it was discovered that a positive test wasn’t specific for CRC and a negative test did not always rule it out.  CEA determinations are still useful in following patients treated for CRC to get an idea if they are responding or not.  But, they are not reliable enough in diagnosing CRC let alone reducing mortality from the disease.  Thus, CEA testing is not recommended as a screening test for the general population.

Contrary to the experience with CEA, PSA (prostate specific antigen) screening for prostate cancer has been made available to all middle age and elderly men for 20 years.  Its utility has not been seriously questioned until the U.S. Preventive Services Task Force (USPSTF) reviewed two negative clinical trials and recommended that PSA not be used to screen the population at large.  As with changes in recommendations involving screening mammograms made by USPSTF two years previously, response and pushback has been vocal and immediate.  But, these two trials demonstrated that PSA-based screening of the general population does not save lives.

I found the article ‘Prostate-Cancer Screening — What the U.S. Preventive Services Task Force Left Out‘ in the current issue of the New England Journal of Medicine frames the debate about screening into its proper perspective.  (Allan S. Brett, M.D. and Richard J. Ablin, Ph.D.:  NEJM, 10,1056, October 26, 2011).  They point out that PSA is not a cancer-specific protein and there is a wide variation in aggressiveness across the spectrum of prostate cancer.  Therefore, “controversy and debate about PSA screening were predictable from the outset.”  They cite three issues the panel didn’t address even though they “agree fully with the task force’s analysis”:

1. Every guideline recommends discussing the benefit/risk ratio and individualizing screening decisions taking into account patient values and preferences.  In this era of consumerism, a laudable approach.  However, before the publication of the two trials mentioned above, no data existed to support screening.  So a discussion based on evidence was impossible. “Thus, patients were not really making informed decisions, and office-based discussion of the pros and cons of PSA testing was essentially a charade.  Instead, most patients’ decisions reflected their general concerns about cancer or their general inclination to accept (or resist) medical interventions”.

I lost count of the number of times lengthy discussions ended with patient and family saying that I was the doctor and should make decisions for them.  Even in this age of patient advocacy.  As Brett and Ablin point out, the two screening trials only add to the confusion in that one did not demonstrate any mortality benefit while the other demonstrated a small reduction in prostate cancer related mortality, and there were differences in methodology between them.

1. Management of individual and serial PSA values is inconsistent and unpredictable even within practices.  Physicians are trying to adopt reproducible practices, but “the guidelines are vague precisely because the limitations of PSA screening preclude the kind of rational, standardized, evidence-based algorithm that should inform any routine preventive intervention”.  When one of my colleagues nonchalantly proclaims to practice Evidence-Based Medicine, I remain skeptical.
2. It has been estimated that $5.2 million is spent screening everyone to prevent one death from prostate cancer.  This does not include excessive PSA testing and extra encounters.  So some estimate the actual cost to be more than double this figure.  The authors argue that there are other more pressing uses for this money.  The argument that Black men, who have a higher incidence of prostate cancer than whites, should be screened.  Statistics don’t bear this out since the proportion of deaths from prostate cancer in 2007 was 3.3% in blacks and 2.3% in whites.  The difference is not great enough to justify race related screening, even if we knew how to do it.

A New York Times article entitled:  Considering When It Might Be Best Not to Know About Cancer, October 29, 2011, raises the possibility that more screening may not be productive and could possibly be harmful.  In 2009, the USPSTF, charged with reviewing evidence and publishing screening guidelines, recommended that screening mammograms not be performed on women in their 40’s, and they be reduced to every other year up to age 74.  A similar backlash occurred.  I will review this issue in my next blog.