The Improvisational Oncologist

It is a mere coincidence that I am reading his book entitled "The Emperor of all Maladies" this article appeared. Despite the enormous sufferings by cancer patients in the 19th and 20th century including the "radical surgery" even undergoing surgery without proper anaesthetics, less sophisticated equipment , the doctors and the patients contributed a lot to cancer understanding and treatment. A complete cure of certain cancers is still far away, control of cancer has remarkable progress and chemotherapy and along with spot X-radiation will make cancer more a villain to be vanquished than an Emperor of all maladies.

If only there were more docs like Mukherjee! But what happens to the patients who do not have a Mukerjee, like 95% of patients? Is there a way for these patients wondering “How do I find a cure for my cancer?” to quickly learn (before it’s too late) from what docs like Mukherjee are discovering, which will never get into the journals in time if at all, & then close the learning loop by the patients then sharing their experiences, so that the docs can learn from what patients are discovering? The exciting news is that there already is such a solution, a bold innovative information-based non profit initiative: CancerCommons (CC). Patients come to CC seeking help, & CC goes to the best docs like Mukerjee who then quickly share their thinking & advice with the patients much faster than what can now be done relying on journals. In this way, CC is building a rapid feedback-loop based learning community, which already involves many leading cancer researchers.

CC came out of the experience of their founder, Dr. Marty Tenenbaum, who only by talking to doctor after doctor, over weeks & weeks was he able to finally find a doc with a new drug protocol that cured his own cancer. That experience & the fact that he was a leading information scientist, was what gave him the insights & passion to develop CC, so that no patient with cancer will ever have to go through the vast amount of trial & error searching & doctor calls he had to go through to find a cure for their cancer.

Mukherjee is a good writer, but less so a scientist. He follows the orthodoxy of mainstream cancer research -which is painful. He commits the same error as 90% of cancer researchers: To think that there is only ONE type of cancer cell in a tumor with one single molecular “wiring diagram” that is miss-wired due to mutations, and that therefore, we can learn about what therapy to use from reading the list of mutations obtained from sequencing the tumor as a whole.
But in a tumor we do not have ONE miss-wired system –we have zillions of systems: Every cancer cell is different even if they carry the same set of mutations. This article is broadly wrong in that it relies on a mental cartoon of THE imaginary cancer cell and its wiring diagram to explain an entire tumor. This is like using the opinion poll of an entire country to predict how every individual voter would vote. Check this: A tumor consists of a trillion different cancer cells and even if we kill 99% of them there would be 10 billion cells surviving! Bad news: These cancer cells are not innocent bystanders. Having survived a near-death attack by the drug they ACTIVELY turn on more cancer genes as part of a stress response, without additional mutations. They become the dreaded “cancer stem cells”. Due to this much neglected dynamic heterogeneity of tumors, every drug is a double-edged sword. “What does not kill, strengthens”. Clinicians must learn to see BEYOND mutations -to the benefit of patients.

Hmmm... I am always a little surprised (and saddened) when such almost-thorough articles on the evolution of our understanding about disease don't include even one mention of nutrition, and the role that refined sugars have on cancer cells.

The problem is that most of this freewheeling is happening by individual docs in a vacuum outside of clinical trials, doesn't contribute to greater advancement of the field/treatment efficacy by gathering of collective data and evidence (any "knowledge" gained is not shared or part of a clinical trial), slows progress, creates vast cost waste, and likely increases collective suffering.

But it sounds cool, so who cares.

Jay Freireich is indeed a giant in oncology. Note that the NCI some years
ago took awy his grants because he dared to use "historical controls".
Now that historical controls have been renamed "meta data analysis",
the NRC embraces it wholeheartedly. Consider the fellow Houstonian
Dr. Stanislaw Burzynski who has had unprecedented success in
curing brain tumors in children. The medical establishment tried
unsuccessfully to send him to jail. Texas Attorney Morales had to face
respected oncologists whose grandchildren had been saved by Burzynski.

With the greatest respect to Dr. Mukherjee, let me point out that there has always been an element of the experimental, the artisanal, and the individual, and even playing-it-by-ear, in treating cancers using standardized protocols, because if cancers are individual, bodies also resist standardization. I was treated for relapsed Hodgkin's lymphoma in 1984-1985 at the Massachusetts General Hospital with an aggressive eight-drug protocol, MOPP/ABVD. It was not long before I realized that even standardized chemotherapy is an experimental practice. Body mass was not, in my case, a reliable indicator of appropriate dosage. My body's highly toxic reactions required constant adjustments in the dosages and postponement of treatments, but even so the damage was significant and cumulative. We never found the right balance, and eight and a half cycles into a projected 12 cycles, I ended my treatment, with my oncologist's agreement. What we both learned during that year of living dangerously was how to listen to each other. Every dose of every drug was the product of negotiation. Before I made the final decision to stop I carefully documented my body's chaotic responses during an agreed-upon month-long suspension of treatment, sending my oncologist weekly graphs and narrative interpretations. Because we ignored recommendations and bent or even broke rules, I am still alive to tell the story.

There are a lot more innovative treatments available in Europe. This cancer industry is so big that no cure will be ever be found. Very sad but very true.

"The treatment failed the patient" is how we refer to a poor response within our group. Thank you for this piece and thank you NY Times for all the articles in this series.

Very promising research indeed. Are all of the test results indexed in any sort of larger database? I would assume all of the individual tests around the country and world would be even more useful of part of a systemic review process.

The study of parasitic disease in animal models may shed light on cancer biology. With an uncanny resemblance to the Borellia Lyme parasite in humans, Theileria is a tick borne intracellular parasite, highly pathogenic for cattle causing East Coast Fever, a fatal lymphoproliferative disorder. The parasite resides in the cell cytoplasm where it inhibits apoptosis pathways and synchronizes replication with that of the host cell, so all daughter cells are also infected. This disease is reversible with the anti-parasitic drug buparvaquone. Cancer cells share many of these same features, such as inhibition of apoptosis and accelerated replication.

Another animal model of parasitic disease causing cancer is found in the laboratory of Dr Sadia Benamrouz. In a 2014 report, mice inoculated with Crytosporidium quite unexpectedly develop colon cancer with upregulated WNT signalling pathways.

The 2015 Nobel Prize in Medicine was awarded for anti-parasitic drugs Artemisinin and Ivermectin. These and other FDA approved anti-parasitic drugs have potent anti-cancer effects: Pyrvinium Pamoate (Vanquin), Niclosamide (Alinia), Mebenzadole (Vermox).

Will FDA approved anti-parasitic drugs serve as the new anticancer agents, and transform cancer treatment? For entire article with references:
http://jeffreydachmd.com/2016/05/cancer-as-a-parasitic-disease/
jeffrey dach md

I read this article with interest because of what we are learning about the immune system. There are many other immunological diseases that may be impacted by this cancer disease. I have been recently diagnosed with MS, which is an immunological disease that attacks the sheaths protecting the nerves. At least that's what it is believed to be. Cancer fighting drugs such as interferon works in the remissive type to stretch out the remissions. I have the other type, the primary progressive type for which there are no drug treatments. Primary progressive is much less common, about 10% of the MS patients, and, therefore, most of the MS research is focused on the remissive type. With all of the research being conducted on the immune system, there is a distinct possibility that treatment for MS, both types, might lay in research not now being aimed at MS. That's why these type of experimental treatments described in the article are so important. They can lead to more than a cancer treatment.

It would be great if the author could comment on the difference between an educated "hunch" and a quack practice.

As a clinical psychiatrist, I see the line between these two extremes blurred all the time. A patient with a complex set of symptoms that do not fit precisely into DSM criteria is placed on 4-5 different psychotropics by a psychiatrist attempting to personalize treatment based on symptoms -- when none of the psychotropics have been studied for these types of indications and have only been approved for disorder remission/response. The patient has trouble keeping up with so many medications and adverse effects occur -- maybe they got better but who knows if this is due to the "artistic" combination of medications prescribed.

Isn't the art of medicine in enhancing the therapeutic alliance, rather than creating a magical, non evidenced-based concoction? What does standard of care mean in this age of personalized medicine?

This is a comprehensive and informative article on the complex and terrifying subject of cancer.However,after reading many similar articles, specialized views on treatment results and new approaches through genetics ,chemotherapy ,surgery and radiation therapy,PREVENTION is always overlooked......the potential efficient causes of cancer TO BE AVOIDED ......pesticides,herbicides and fungicides,chemical- free food and water,air free of benzene from gasoline and diesel fumes and exhausts,man made radiation-from ANY source and the many cancer preventive measures which have been shown to work.... Vitamin D3(actully an essential cancer fighting hormone),antioxidants,botanicals(too many to list)shown to kill cancer cells(the comment, ALWAYS,by cancer societies,foundations,Sloan Kettering,Rockefeller Institute.....MORE RESEARCH NEEDS TO BE DO........the same response for 20 YEARS )...........isnt an ounce of prevention worth a pound of cure.........or is that not a PROFITABLE idea???..

A spectacular piece of writing, hugely difficult to accomplish given the subject matter and target audience: a tour de force. I go from here to Amazon in search of The Emperor of All Maladies.

Very pleased to read about this ongoing research. Currently being treated for early stage breast cancer with Cmf. Look forward to more research to crack the code and find alternate treatments for all stages of early and advanced cancers.

Earlier I read a book review about the author's new book about the history of our knowledge about genes. The review failed to compare and contrast the book to others that have written on the same topic, like Richard Dawkins. As one with a bioengineering and medical degree, I like to keep up with the latest publications geared towards laypeople, although I doubt I'll learn something that wasn't covered in the much more challenging scientific journals.
After reading this article, I know I won't be spending my money on his book. I sense too much arrogance in his approach, and am not impressed with his prose. As for Donna M, don't they have qualified oncologists in the Windy City? University of Chicago and Northwestern University aren't prestigious medical institutions? The money she's spending flying back and forth could be better spent donated to less fortunate families that can't afford these novel approaches, and she'd decrease her contribution to carbon emissions.
The trend in these articles thus far is worrisome, seemingly focused on those who can afford whatever medical care their hearts desire. But the NYT long ago stopped being a paper for the average American, just look at the wares they advertise or the merchandise (and prices) available on their online store.

Since we know that cancer is the result of genetic mutations and we can get a genetic profile in a rapid and relatively inexpensive manner today, can't we set computers to the task of analyzing the difference between, say, healthy lung cells and the mutation in a tumor? Once we find that variation, figure out the protein that the mutation is synthesizing and attack that protein with retrained T-cells made from our own bodies. That is being done, but does it need a boost in research funding? Is the problem that we are spending all our money on stupid wars and military hardware and not on medical research? I fear that is the case.

she is 78 years old and govt. is paying for her to go from one therapy from another and one experimental drug to another on the back of the taxpayer, she should be given some pain medication and told he the truth that there is no cure for her disease, so go home and enjoy and leave with the feeling that u did all u can , now it is time to meet the Lord.

This article and the discussion is wonderful,but only half the picture. It is based on the old "kill the invader" model of medicine,without looking at the big question,why has this organism turned from normal physiology to runaway proliferation characteristic of stressed organisms.The clearest demo of this is Mina Bissel's work where she shows that depending on the surrounding conditions,cells can become malignant or revert to normal. There is no mention of the quantum biological approach(see the work of Nick Lane and Jack Kruse) that makes it clear how we are stressing ourselves, and all organisms on the planet by:violating normal circadian rhythms(staying up too late or working night shifts, not getting enough sun);non native EMF pollution(all electricity,increased over 75,000 times since 1950);pollution of air,food,water by toxic chemicals;radioactive exposure(think depleted uranium and Fukushima)to name some of the major drivers. I am third generation physician and have been in practice for 60 years,please widen your perspectives.

This article is so self-serving! I'm supposed to feel sympathy for the faux-humble oncologists who's depriving himself of the impulse to blame the patient? The science is very interesting, but in practical terms it doesn't help most cancer patients, who are overwhelmed and just trying to survive.

www.cancerissofunny.com

If we spent half as much on cancer research as we do on the military, we would be much closer to curing many types of cancer...

About 10 years ago, I was diagnosed with what is called "triple negative breast cancer (TNBC)". As a molecular biologist, I knew two things. First, the name was ridiculous as the "triple negative" referred to the absence of known cell growth receptors (which - of known - can be used to identify and target cancer cell growth), rather than to the presence of anything informative. Why hadn't we figured this out yet? Second, I was going to be treated with a stable of drugs that not necessarily specific for my cancer, but had been developed - as Dr. Mukherjee wrote - for standardized patient. Was my cancer really the same as everyone else with TNBC?

The problem was that I knew too much. I knew that my colleagues were working on new tools to both identify and treat cancer types. Already, the standard orthodoxy of "cancer by organ type" was crumbling. Although the exact word was not used, I knew that "personalized treatment" was possible and on the near horizon.

In order to be a sane patient, I had to cut myself off from any scientific literature. It was too agonizing to read about the laboratory experiments with the potential to turn into viable and novel approaches to treat cancer without indiscriminately killing other cells, like collateral damage from a dirty bomb.

Fortunately for me, my TNBC was standard enough to be treatable by the alphabet soup of what passed for "standard therapy" at that time. Along the way, I did lose friends whose TNBC was recalcitrant.

As a scientist and the spouse of a AML patient who is 6 years in remission after being treated on a clinical trial, I applaud Dr. Mukherjee's well written article. Knowing the driver mutation that causes unregulated cell growth is key to finding the best treatment. There were 3 AML patients admitted to the hospital with in weeks of each other and 3 different protocols were followed based on their the PCR data from their cancer. Experimentation in medicine is key to advancement.

I am surprised the up and coming 'checkpoint inhibitors' are not discussed in the series. Immune white blood cell ("pac-man" cells?) can be rejoined to the battle against a crafty tumor cell that evaded detection and made it to "cancer". T-cells, it is thought, cleaned house to that point. With these strategies, the "pac-man" cells are allowed to win again. This is the cutting edge to many of the most sophisticated scientists (Einstein was a scientist not a PC? egalitarian? researcher, and Einsteins were required). It is an example of absolutely basic science (that took a while) and is (will) make a fundamental difference.... The trials are advanced and qualifications are increasingly less required. Do remember the 35+ years of incredible thinking, detailed experiments, funding (government always ealry on), Pharma trials, and.....blind alleys.

The childhood leukemia trial of the 60s/70s would 3 decades later save my nephew's life. We are grateful for the brave physicians who were willing to go beyond the common knowledge of the day and employ their wisdom of what might be possible.

Dr. Mukherjee's vision of the “artisanal” treatment model for cancer will remain out of reach for most patients until insurance payers are forcefully persuaded to embrace it, and develop cost-effective implementation tools.

As a healthcare attorney who deals with payers, including Medicare/Medicaid, in other contexts, I have had the opportunity to take on several compelling cases (pro bono). These clients have been denied benefits of "off label" drugs or "experimental" treatments. Their physicians have not persuaded the payers to cover the treatment(s), despite submission of voluminous medical records and letters of necessity from clinicians associated with some of the most highly-regarded research facilities in the US.

In every case the result has been coverage. Yes, the legal approach "beat" the insurance company, but it requires many hours of research, appeals and aggressive demands for expedited review. We work against a terrible time clock, as a patient's need for the treatment is generally critical by the time it goes this far.

After it’s accomplished, we briefly celebrate. And we agree that this work could be expanded to include other similarly-situated patients. We envision a model of advocacy, a clearinghouse of information for doctors and their patients, with a game plan of targeted appeals by disease, payer, geographical region, etc. Of course, it has not come to pass, as all this was done as an adjunct to our "regular" professional lives.

I do translational research in the development of new cancer therapeutics, and I always learn something from Dr. Mukherjee's writings. In this article, he gives a much more thorough response than I do when asked why cancer is so hard to treat: it's not a single disease, sometimes even in a single patient. (Different cells within a single tumor often have different pathologies.)

Many posts on the comment thread rightly point out the enormous costs involved with individualized medicine. While true and concerning, I would point out that the costs for the tests described in this article are dropping rapidly. When I first got into the field, hundreds of millions of dollars were spent on sequencing a single genome. That number has dropped orders of magnitude.

As this march towards faster, more precise and cheaper analyses continues, it is enormously important to build the knowledge base of cancer pathophysiology. Eventually we'll get to the point where every person with cancer will have his or her tumor fully parsed. With the understanding that develops from the work of physicians like Dr. Mukherjee, we'll have the knowledge available to effectively treat the majority of these patients.

Groundbreaking science and new technology is usually expensive at the outset, but in time the costs drop precipitously. Just look at digital technologies: your average laptop is orders of magnitude more powerful than computers a few decades ago, and almost everyone can afford one.

Dr. Mukherjee minimizes the importance of anatomical location. When we classify tumor by location, we are saying it arises from a particular cell in a particular organ. These cells are usually damaged in the same way each time. For example lung cells are damaged by smoking and skin cells are damaged by sunlight. So there is lot of information in that type of classification that is used to treat these tumors. Frequently specific mutations follow these old classifications and are very useful in new discoveries.

I have problems with all of this effort and experimentation being lavished on a 78 year old patient. Whether or not she is paying for this out of her own pocket or insurance, it seems that the potential for some new found life saving treatment be used for a younger person, perhaps one who has the responsibility for children or maybe someone just starting life's journey. I am 71, have grown children and probably have few accomplishments left in life, though I do continue to work. If I get cancer, I will probably opt for whatever the standard treatment is, and if it doesn't work accept my mortality and be thankful for the life I've been given and hope that the experimental treatment be given to someone who has more life in front of them.

Have you considered hypomethylation and gene expression as a possible underlying mechanism involved in sensitizing these cancer cells to immunological therapy?

Medicine is not an exact science, by any means. Its an art as well, and one does the best and hope the patient will gain relief if not a cure.

Carmine hits some targets well in her comments on this page.
Medicine must keep the mantra of "cost-benefit" in its sights, whether it's cancer treatment or whatever. Dr. Mukherjee does not give data on actual quality or quantity of life that these "success" stories generate. Often a headline, even in the NYT, as well as medical journals, will tout a "great" new drug or treatment modality. In fact, many of these are adding weeks or months to patients' lives, and little or nothing to the difficult deaths that they must endure anyway.
Cancer treatment often runs into $100,000 or more per patient /year in this country. Resources are limited, and we, particularly as physicians, need to recognize reality and be prudent in how we allocate human and technological options in the real continuum of prolonging life or preventing death.
Retired urologist/emergency physician

Thank you for this piece. Always a pleasure to read anything Dr. Siddhartha Mukherjee writes. I will have my students read this article as well.

Wonderful article!
Credit to you all for your hard work, and to the men and women in the clinical laboratories that have enabled such amazing advances in molecular pathology, cytogenetics, hematopathology, and flow cytometry.

There is a simple and sad consequence if individualized cancer therapies exceed either the patient or the insurer's ability to pay. The treatments will fail from lack of implementation unless society decides that a wealth-based process of selecting treatment candidates is morally acceptable which it is not.

I choose to believe that breakthrough treatment modalities that are not individualized and therefore affordable will emerge. In fact, they already have like using modified polio vaccine to awaken the immune system to fight a variety of cancers.

Interesting!

Anyone especially interested in this article's experimental-approach view, consider getting DeVita's book The Death of Cancer cited and quoted very near the article's end. DeVita seems to have written mainly to the medical-community hierarchy, with the central message a cry for more flexibility in enabling doctors to try more approaches, especially combination approaches. But his book is informative to laypersons too.

The New Yorker offered a review of DeVita's book which it titled Tough Medicine last December. It may still be available at this link:
http://www.newyorker.com/magazine/2015/12/14/tough-medicine

I am the patient profiled in the piece and this approach seems to have worked for me. It might not work for everyone as is pointed out in the piece. This approach is typically used for patients who don't respond to standard therapies. I have been very fortunate to be able to work with Dr. Mukherjee and Dr Raza. I have been able to have a full and very satisfying life because of them.

This is the best article I've read about cancer treatment since I read Mukherjee's magnificent book Emperor of All Maladies. Somehow he is able to capture intricate scientific and medical truth and turn it into poetry for the masses.

I wonder how many doctors have his ability to keep up to date on the vast and advancing science, while also practicing medicine as the art it still is.

As an Emergency Physician, our treatments are moving away from individualized plans toward protocols based on disease criteria. In Emergency Medicine, the trend seems to be exactly the opposite of what you describe in Oncology. With our protocols, outcomes are clearly improving, I suspect because we work in an environment inherently limited by a lack of data. We simply do not have the luxury of truly individualizing our medical care.

The need for individualized treatment is clear. The processes required to obtain FDA approval for a therapy are archaic with respect to developing cancer treatments. Patients who face virtually certain death should be able to agree to and undergo treatments recommended by qualified oncologists, even if those treatments are experimental, relatively untested, involve off-label uses of drugs, etc. as long as a second senior physician agrees with the treatment plan. The rules need to be relaxed in life or death situations. It is common sense.

But who is wealthy enough to have an individual doctor with the time, energy and willingness to run up against insurance or Medicare or hospital bureaucrats?