China: A report from the journey

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cancer, digital media, evidence based medicine, integrative oncology, medical education, oncology, participatory medicine, physician, social media, Traditional Chinese medicine, wellness

By Richard Just, MD

China is nothing like I imagined! The evolution of healthcare mirrors major events in Chinese history.  Traditional Chinese Medicine (TCM) dates back 5,000 years when the first documentation appears.  What is currently called TCM goes back 3,000 years, and was essentially passed from one generation to the next.  Another factor that resulted in fragmentation of medical practices was that China was a feudal society whose states were constantly at war with each other.  The emergence of the Qin state resulted in a single state system with a single script and standardized weights and measures.  But their reign was so oppressive it lasted only 15 years, overthrown by the Han Dynasty in 210 BC.  During this time fragments of the Great Wall were fused into one continuous structure, and the underground mausoleum of the terra-cotta warriors was constructed near modern day Xi’an which was China’s capitol at that time.

In my mind, China was still a monolithic society under a Communist regime and TCM was available to the masses while western medicine was for the ruling class.  Well that’s not exactly the case.  Prior to 1949, there had been a widening chasm between those who had access to healthcare and most everyone else who didn’t.  When the Party came to power, most workers were employed by the government and had access to healthcare.  All through the Cold War era, the only major leader who never left his country was Mao.  He was mainly concerned with unification of the country and building a strong infrastructure.  Many lesser officials did interface with the West, and when they returned with different ideas, the Cultural Revolution (1966-1976) ensued.

We all know that intellectuals, including doctors, suffered.  But Mao realized he needed some physicians to treat the population.  He also realized that TCM needed to be standardized so it could be disseminated to as many doctors as possible.  In this process, much of the practice of TCM was changed in China, but it continued as it had been practiced for 3,000 years in Japan.  In 1980, with the end of the Cultural Revolution, two policies were instituted that have resulted in major changes in society:

1. One child per family rule:  There are certain exceptions to this rule.  But, in general, if a family has more than one child they are fined, heavily.  And, if the practice continues, a sterilization procedure results.
2. Opening up China to western ideas and businesses:  One of the first businesses allowed into China was health insurance.  Hard  to believe but true.  What has resulted is a system resembling ours.  Government employees and  officials  have  government insurance, which is essentially free.  They have access to everything necessary for their care, and it is funded by taxing the entire population.  Non-governmental employees buy private health insurance which generally covers 70% of  costs, leaving 30% out-of-pocket.  These policies consume a  good  chunk of income, and are renewed for 25 years after which all costs are covered by Social Security and the government.  Again these funds derive from taxes.  Parents pay for healthcare of their children, and rural farmers who can’t afford insurance are eligible for something like Medicaid/MediCal with “bare-bones” coverage.  This latter situation is also not free.  Obviously, most young people prefer a government job.  These are hard to come by unless you know someone, and contribute to his “Red Pack.”  This is the local phrase for payola or bribe.

Does this sound familiar?  I found no one who felt the system was fair.  But I didn’t speak with a government official.

Meanwhile, my wife and I had a personal experience with TCM.  Prior to our trip, Dee Dee fractured two metatarsals in her left foot.  This was healing when we left.  But, I’ve dubbed China as the country of stairs.  Lots of walking and climbing.  This time both feet and ankles were extremely painful and swollen when we boarded the Yangtze River cruise.  Fortunately, there was a doctor on board who saw her the next day.  Her treatment consisted of acupuncture, acupressure, placement of antifungal patches on the tops of her feet and cupping.  Not what I learned in training.  It was recommended that she soak her feet and legs up to mid-calf level each night in very warm to hot water for 20-30 minutes.  The whole process lasted one hour and cost 550 yuan, equating to roughly 90 USD.  She was much improved by the following morning.  That afternoon, Dee Dee had a second treatment.  Both treatments were very painful, especially when the needles were inserted.  It turns out Chinese needles have a much larger bore than those used in the U.S.

We listened to a lecture on TCM given by the same doctor.  TCM involves not only acupuncture, acupressure and cupping, but also herbal medicine, Qigong, and Tai chi.  He discussed the use of TCM modalities in treatment of migraine and other headaches, motion sickness and back pain.  Every morning, the same Dr. John Lee gave Tai chi lessons on board, which we both attended.  The only excursion Dee Dee has missed was to the temples at Fengdu which involved over 500 stairs and inclined walkways.

Now for the big question:  “Is there any role for TCM in the treatment of cancer?”  He said that TCM is of little benefit in treating or preventing cancer, but may have some benefit as an adjunct to surgery or other conventional treatments.  More on this when we reach Shanghai.

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

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.

More On Screening: Barrett’s Esophagus

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Barrett’s Esophagus, cancer, CME, epatients, GERD, medical education, medicine, oncology, participatory medicine, patients, physicians, research

By Richard Just

Recently, a friend of mine asked me for medical advice concerning his condition, Barrett’s esophagus.  When the diagnosis was initially made, he was advised he would require annual screening endoscopies with random biopsies.  But, on his last visit, my friend was told he didn’t need another procedure for 5 years, with no explanation.  “What’s up?”  Since he had a copy of the biopsy report (not with him, but at home), I advised he read it and look for the word dysplasia.  Wikipedia defines dysplasia as

maturation abnormality.

So far, I haven’t heard back.  But this stimulated me to review current recommendations on the subject.

Between 2-3 decades ago, there was a sudden increase of adenocarcinomas (“glandular cancers”) of the lower esophagus usually in Caucasian males.  This event was noticeable in that the usual esophageal cancers were a different cell type, squamous cell carcinomas, that tended to occur in Black males.  Adenocarcinomas appeared to be correlated with gastroesophageal reflux disease (GERD), while squamous cell carcinomas (SCC) are associated with smoking and alcohol consumption.  These are tends, not absolutes.  GERD causes irritation of the cells of the lower esophagus resulting in conversion of the cell type (metaplasia) from squamous cells to columnar cells, the definition of Barrett’s esophagus.  Barrett’s, in turn, can progress to low grade dysplasia, high grade dysplasia, and adenocarcinoma.  Thus, it has been proposed that patients with at least weekly GERD symptoms (heartburn, regurgitation, and dysphagia, meaning difficulty swallowing) that have been present for at least 5 years, and who have multiple risk factors for esophageal adenocarcinoma including white ethnicity, male sex, older age, obesity and long duration of GERD undergo screening for Barrett’s esophagus.

Management of Barrett’s esophagus involves 3 major components:

1. Treatment of GERD:  Recommended to be initiated prior to surveillance endoscopies to minimize confusion caused by inflammation in diagnosing dysplasia.  Not thought to reduce incidence of esophageal adenocarcinomas.
2. Endoscopic surveillance:  If no dysplasia found, next scope in 3-5 years.  Follow up for low grade dysplasia is 6-12 months  For intensive endoscopic surveillance of high grade dysplasia, scope every 3 months.
3. Treatment of high-grade dysplasia:  Recommendations can include esophagectomy, endoscopic ablative therapies, and endoscopic mucosal resection in addition to intensive endoscopic surveillance.

Since the above recommendations were updated in 2011, my assumption is that no dysplasia was discovered on any of the 3 studies and risk of progression to cancer is low.  For the general population of patients with Barrett’s esophagus, the risk of esophageal adenocarcinoma is 0.5% per year.  Contrast this with 5-8% per year in patients with high grade dysplasia.  The risk for low grade dysplasia falls somewhere between these 2 extremes.

I’ve written previously about the limitations and risks of mass screening techniques, e.g., mammography for breast cancer, PSA testing for prostate cancer and PAP smears for cervical cancer.  The same applies to screening endoscopies for Barrett’s esophagus.  The procedure carries with it risks, including perforation and bleeding.  It’s also not very comfortable to have a hose snaked down your throat so that pre-anesthetics are sometimes necessary, creating more risk.  Random biopsies are performed because it’s sometimes difficult for the endoscopist to identify areas of dysplasia from just metaplastic cells, leading to falsely negative results.  In his new book “The Creative Destruction of Medicine”, Dr. Eric Topal opines “We’re not very good at detecting and fighting cancer.  The mass screening model, as with mammography or prostate specific antigen (PSA) testing……..is enormously expensive and leads to an untold number of false positive results and more unnecessary biopsy procedures.  Doing serial sensitive scans like PET or CT would likely make this problem worse, both by increasing the false positives and incidental findings and by exposing individuals to ionizing radiation that itself causes cancer.”  The use of innovative technologies such as circulating tumor cells (CTC), genomics (circulating DNA and RNA) and wireless sensors including implanted nanosensors are described.  Obviously, hope runs high that at least some of these techniques will be validated so that the ultimate goal, prevention, is achieved.

@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

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.

Cancer Survivorship

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12 steps, cancer, digital media, epatients, evidence based medicine, health, innovation, medical education, medicine, oncology, recovery, twitter, wellness

The fact that the term “Cancer Survivorship” is now part of our vocabulary is a testimony to advances made in management of these diseases.  Most cancer survivors, however, are not unscathed by the experience.  As I tell my patients, they won’t be entirely as they were before treatment.  How these issues are dealt with varies from person to person.  But, awareness that chronic problems may persist long after treatments end signals that even though we’ve won the battle, the war is not necessarily over.  We may need to address problems in the physical, mental/emotional and/or spiritual spheres.  After all, quality is as important as quantity.

Certainly, health care professionals are well trained to deal with physical issues.  Attempting to address the totality of needs in an organized manner is a recent phenomenon.  Certainly, in thinking about programs that have been successful in supporting people mentally, emotionally and spiritually, 12-Step Programs come to mind.  The Steps are compelling as they are for anyone affected by the disease alcoholism, including the alcoholic (A.A.) and the “caregiver” (Al-Anon).  Substitute “cancer” for “alcoholism.”  The value of The Steps is that they provide a guideline through the process of recovery.  In fact, I prefer the designation “recovery” over “survivorship” as it implies an ongoing process with relapses and remissions along the way.

At first glance, the verbiage doesn’t seem to be appropriate.  But, The Steps suggest four primary ideas:

• “We Are Powerless Over the Problem of Alcoholism.”  This notion of powerlessness is difficult for healthcare professionals, especially physicians, to accept.  The intention is that we as individuals have no ability to change attitudes and behaviors of others, but we do have control over ourselves.  Think the Serenity Prayer:

God, grant me the serenity to accept the things I cannot change, Courage to change the things I can, And the wisdom to know the difference.

In fact, this is a very empowering concept that releases each of us from worrying about issues that don’t concern us and address our energies to our own lives.

• “We Can Turn Our Lives Over to a Power Greater than Ourselves.”  Many find the idea of a Higher Power difficult to embrace, while others already believe in a Power greater than themselves, but feel that “God has deserted” them.  Both viewpoints hinder recovery as they tend to foster a victim mentality.  Personally, I dislike the designation “cancer victim” for this reason.

The slogan:  “Let Go and Let God” can also be very liberating, recognizing that The Higher Power is in charge of our lives and we are not victims.  The 11^th Step provides details:

Sought through prayer and meditation to improve our conscious contact with God as we understood Him, praying only for knowledge of His will for us and the power to carry that out.

• “We Need to Change Both Our Attitude and Our Actions.”  Both the cancer and its treatments can  result in distorted thinking.  Some are left with severe fatigue and pain; others with long-lasting memory deficits called chemobrain.  Anxiety and depression are not uncommon.  The possibility of recurrence is always present.  Some become angry and blame their situation on others.  Obviously, these behaviors can be self-destructive and ruin relationships.  In these difficult situations, a useful tool in 12-Step programs is sponsorship.  Having someone who has lived through similar circumstances and recovered always there for support and guidance is crucial for recovery.

• “We Keep the Gifts We’ve Received by Sharing Them with Others.”  Probably the most important concept.  Several studies have shown that participation in cancer support groups improves outcomes.  But many patients still are reticent to join.  Some prefer the privacy of one-on-one sessions with a therapist.  On the other hand, they lose the personal experiences of people who have experienced what they’re experiencing.  One compromise is to have a mentor or sponsor who has personal knowledge of the treatment guide the patient and family through the process.

For this reason, 12-Step programs rigidly subscribe to anonymity to encourage participation in meetings and sharing experiences with others.  The most important item in the success of these programs has not been identified, but several reports have suggested sharing at meetings as the major one.

I’m thrilled that we’re talking about Cancer Survivorship these days.  The fact that more people are living longer is very gratifying.  Therefore, formally addressing quality of life issues is the logical next step.  Incorporating 12-Step program concepts into Cancer Survivorship Programs, proven successful in other diseases, merits serious consideration.

Trials and Errors – Part II

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

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

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.

Happy New Year!

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cancer, epatients, medical education, medicine, mentoring, oncology, participatory medicine, social media, twitter, wellness

As opposed to last New Year, I’m beginning 2012 relatively peacefully.  I’ll take a little laryngitis and bronchitis rather than last year’s open heart surgery anytime.  Early in my recovery I had more time to read, which was a plus since reading is one of my favorite hobbies.  While reading my e-mail a few days ago, I noticed a Medscape review of books recommended for physicians.  Included were two books I read: The Emperor of All Maladies; A Biography of Cancer (1) by Siddhartha Mukherjee and The Immortal Life of Henrietta Lacks (2) by Rebecca Skloot.  I agree with Dr. Bruce Cheson who thought so much of these books he gave copies of each one to his fellows at Georgetown.  They read like historical novels, confirming that truth is sometimes stranger than fiction.

But after the “Must Read” list, one item caught my attention that resonated with me:  “Doctors’ Bucket List:  20 Things to Do Before You ‘Kick the Bucket’ “. The idea is derived from the movie starring Jack Nicholson and Morgan Freeman.   I’ve practiced hematology and medical oncology for 36 ½ years after 2 years of fellowship following 4 years of internship and residency in internal medicine.  That’s 42 ½ years in medicine, almost 2/3 of my life, dealing with everyone one else’s mortality, but devoting only a small amount of energy to mine.

After surgery, my surgeon said he got me 10-15 (or was it 15-20) more years.  The implication was to make the most of it.  Next Friday is my 1 year anniversary from surgery.  So far, the cow aortic valve and the 3 coronary artery grafts are doing well.  It’s hard for me to believe, but in 1 month I will be 70 years old.  So there’s no time like the present.  Citing Caroline Adams Miller, MAPP, a certified professional coach, “The list should consist of things you plan to attempt and want to reach for so that you leave behind the imprint you wanted to have.”  It is advised to set specific goals that move you beyond your comfort zone.

I was encouraged to realize that, without actually writing anything down, I had started the list.  My wife and I are planning a trip to China for both business and pleasure.  She will practice her Tai Chi and hopes to attend a psychology conference.  I am planning to visit hospitals and clinics to educate myself in Traditional Chinese Medicine.  Since we have the beginnings of an Integrated Oncology Program in our practice, future affiliation may be possible.

Speaking of reaching outside my comfort zone, blogging and podcasting were new to me 8 months ago.  I am enjoying this new technology more as I’ve gained experience with time.  Gaining knowledge in new technology certainly is exciting and keeps me young.  Same for research.

It’s now 2012.  I have places to go, things to do and people to see before I kick the bucket.  By the way:  the origin of the phrase “kick the bucket” is unclear.  One theory is that people hanged themselves by tying a noose around their necks, standing on a bucket and kicking the bucket away.

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