Friday, December 27, 2013

Health Care Reform

The affordable care act is rapidly reconfiguring a massive segment of the entire US economy.  Most estimates I've seen indicate that 1/6 of spending in the United States is on health care.  With the most comprehensive, rapidly evolving, often times unpredictable change rippling through a system most of us encounter in a very personal way, there are going to be winners and losers, and they are likely to be very vocal about it.

Imagine if the captain of the Titanic had seen the iceberg prior to the impact that sank the massive ship and tried to turn the boat with emergency maneuvers.  I imagine passengers would be knocked against the wall, dishes would fall, the boat would lean heavily, people would grab for anything stable.  Confusion and panic would abound. 

I feel like I am living in that moment in healthcare right now.

I wanted to blog about how this reform is affecting my care for patients and the patients I care for.  It is a post that is necessarily limited in scope but it is also very personal and specific.  Like many prior posts on controversial topics, I want to do my best to leave politics out of it.  You may try to guess my political persuasion but I will tell you up front that I am not a believer in either political party. 

So far, the changes seem mostly focused on reforming how care gets paid for rather than how care is actually delivered.   I want to explain how the money works because so much of the debate appears disconnected from reality. 

Private practice oncology is under attackDespite the fact that cancer care delivered in the outpatient setting is 30% less expensive than the exact same care provided within hospitals that may be only several yards away, current policies are making it nearly impossible to maintain viable outpatient oncology clinics.  If these trends persist, you will see access to care diminish regionally.  While providers in major cities may find ways to keep patients coming through the doors, practices in more rural areas are closing at an alarming rate.

The infrastructure it requires to continue delivering care cannot be reasonably supported by physicians in small groups.  When there are only 1-3 doctors in a group, the revenue cannot continue to cover the costs of maintaining infusion nurses, insurance verification, reception, pharmacy, back office, clinic nursing and so forth.  While that will disproportionately affect smaller areas, I've written previously about "Doctors going broke" in urban Southern California.  Small groups are getting snatched up by hospitals and struggling to remain independent.  This will have a bad ripple effect for access to care for many patients

I am concerned because the way I see the change progressing, I think these trends may be accelerated.  Many of the healthcare changes have been referred to as "bumps along the way."  For any of you who have hit a speed bump while driving 90 miles an hour, you know those bumps can be very destructive.  Now before you Canadians and Europeans get all smug, I hope you can respect that our health care system has evolved very organically over quite a few years.  Change is hard - bear with us.

Cancer care is extremely expensive.  Single doses of drugs that may need to be given every three weeks can cost thousands of dollars.  Effective pills can cost more than several hundred dollars each - which really starts to add up if you take it daily forever (see post about drug costs).

With the new exchange plans, it appears to me that much of the middle class will be considerably more financially vulnerable if they get sick.  If you do not qualify for the generous subsidies given to individuals who earn less than a specific threshold, you may be on the hook for $5000-10,000 deductible repeated annually (on top of premiums).  I can tell you that will be impossible for many of the patients that I see.

So what am I supposed to do if a patient comes to see me and simply cannot afford the visit or the treatment?  While I am wired to believe I should see any patient no matter what the circumstances, there are limits.  I can put myself out of business very quickly if we perform more charity care than we can afford.  If a patient does not or cannot pay, what am I supposed to do?  Our office tries to do just about anything to work with a patient or their family, but sometimes things are never going to be collected and we call that, "bad debt." 

I think most patients are unaware of how drugs are delivered in outpatient oncology clinics.   My office literally purchases all the drugs we plan to administer.  This is a lot like going shopping for groceries -  when we purchase them, payment is due immediately.  Normally we do make this purchase 24-48 hours before the patient is to be seen in clinic.  Often drug is arriving in my office at the same time as my first patients for the day. 

When the patient comes to clinic, we check blood counts, ask about symptoms, etc.  Provided everything seems right, we then administer an "intravenous loan" to the patient which is the cost we paid for the drug.  Over the next 30-90 days, we try to get the insurance and the patient to repay the loan.  If that system breaks down, the money we paid for the drug never comes back.  Even single doses of some expensive drugs can be a genuine nightmare if we don't get reimbursed.  Imagine loaning your car to someone and then finding out they were not going to bring it back.  Sometimes those same individuals come back asking for another car (treatment) as if keeping the first one wasn't a major problem.  If "bad debt" percentage goes up even a little, it is a huge problem.  This is a number we monitor extremely closely because of the enormous impact it makes.  I worry that "bad debt" will skyrocket when patients become financially responsible for more of their care.

While some may conclude that giving chemotherapy must be very profitable because of how expensive drug are, keep in mind that they are just as expensive for us to purchase and the government limits how much we can charge for administering drugs.  The "average price (ASP) plus 6%" rule for medicare sets caps on prices.  Some may argue that 6% could be a lot of money, but keep in mind that has to cover the cost of infusion nurse staff, pharmacy staff, infusion equipment, etc.  Furthermore, the sequester knocked that back by 2% to ASP+4% and was the final blow for many oncology practices that had to radically restructure their practices to keep things afloat. If a "2% reduction" to reimbursement rates killed some practices, imagine what happens when bad debt goes from 1% to 7% or more....

In cancer care, it probably isn't a surprise that a lot of our patients are in Medicare - but not all are.  Indeed there can be enormous variations depending on whether your community has a lot of older patients or not.  For those patients with private insurance, we have to re-negotiate our contracts with insurance companies like Blue Cross, Aetna, etc. every few years.  The contracting always starts with Medicare rates then either goes up or down depending on the relative strength of the insurance company or the provider group.  Some oncologists have contracts with major insurers that are better then Medicare, some oncologists have contracts that are worse.  These contracts then determine how much a service in the office gets reimbursed.  The physician offices with one or two docs, simply have zero leverage in these negotiations.  They either accept the rates offered to them or they get excluded and made "out of network."

Settling these contracts requires is the full time job (practice expense) of one of our office employees.  In recent news reports from California, some of the exchange plans have come in offering rates that are simply too low to enable the doctors to keep their doors open if they were to accept those contracts.  That is why you are seeing "skinny networks" or networks with very small groups of providers who are able to accept the contract.

Many patients may simply not understand how much it costs to keep the doors open.  If you completely exclude the cost of drugs, and only factor in things like rent, staff compensation, malpractice insurance, etc, and simply add up those costs and divide by the number of patients I see in a day it results in a "cost to see patient" that averages several hundred dollars.  Literally, when I walk through the door to see a patient (one who is just coming in and not getting treatment), I have spent several hundred dollars to do so.

Obviously the more patients I see with the same resources, the lower the cost per patient, but you can only take that so far.  On an average day, I may see over twenty patients, and on a extremely busy day, I can see thirty.  In the last several years, as reimbursement pressures have gotten harder everyone has tried to compensate with seeing larger volume of patients.  Unfortunately, as that margin gets closer and closer to zero, you simply cannot humanly make it up by volume.  In some cases (contracts) you actually loose money every time you see a patient but you do it because it is the right thing to do.  Obviously, the more such patients you see, the faster you reach financial oblivion.

So this is where I have to return to the impending changes.  Very soon, patients are going to be more financially responsible for their care than ever before.  Enormous deductibles and larger copayments are going to become financially devastating to more and more individuals.  As that destruction unfolds, it is going to take down a lot of community practice oncology sites who see their bad debt skyrocket.  "Bad debt" is set to explode and I cannot predict how broadly the damage will extend.

Patients are going to avoid care a lot longer hoping that the pain in their side goes away rather than incurring a $4000 personal bill for an ER visit that makes a diagnosis.  We will begin to see patients with far more advanced disease because they delayed things too long, or their docs were too busy to get them in quickly enough.  Annual deductibles will become an extraordinarily painful reminder of a chronic illness.  I have to imagine that CLL patients may fully exhaust their deductible every year.  Many people are just not in a position to cough up 10K per year if that is what their plan requires.

While much of the above discussion only applies to the 5 million patients who lost their insurance in the "individual market" and were kicked into the exchanges, next year we see the employer mandate begin.  This may impact an enormous number of individuals who get their insurance through their work.  Everything that is happening to patients in the individual marketplace is going to happen on a much larger scale when employer plans lose their grandfather status. 

Some readers will see this and conclude that it is finally time for a "single payer health system" ie. Medicare for all.  Frankly, I predict that come Jan 1 when a lot of individuals discover they don't have insurance because the application process was so broken (Oregon's webpage still has yet to enroll a single patient), you will hear demands to allow these people to "temporarily" be given Medicare coverage.  What happens after all to the patient who has paid their premium faithfully and covered their bills with my office for years but now needs treatment and they have lost their coverage because of a broken system?

If we go to single payer though, Medicare will have to be radically restructured.  My practice did an analysis of what would happen if every patient we saw suddenly had their contracts revert to "medicare rates."  After reviewing the consequences, we all agreed this would be our "Armageddon."  We would go from a practice that is surviving to one in which none of the doctors would receive ANY income from working and EVERY DOCTOR would all have to pitch in thousands of dollars PER MONTH keep the doors open.

Naturally, that means we would not be able to keep our doors open in our current structure.  The city of Eugene would lose significant access to cancer care and patients might have to drive two hours to find it in Portland - provided it was available there.  While that sounds terrible, it is already happening throughout the country in many places and the biggest changes have yet to hit.

I am sorry if this is such a sour post.  I know I typically aim for optimism, but I am having a hard time getting there when I think about the changes I am seeing. 

Thanks for reading.

Tuesday, December 10, 2013

Ibrutinib in front line elderly

This is the final publication from our original phase II study.  This was a group of patients we started treating at the same time as the group that was presented in NEJM with relapsed and refractory disease.

Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial

Prof Susan O'Brien MD a Corresponding AuthorEmail AddressRichard R Furman MD b, Prof Steven E Coutre MD c, Jeff P Sharman MD d, Jan A Burger MD a, Kristie A Blum MD e, Barbara Grant MD g, Donald A Richards MD h, Prof Morton Coleman MD b, William G Wierda MD a, Jeffrey A Jones MDe, Weiqiang Zhao MD f, Prof Nyla A Heerema PhD f, Amy J Johnson PhD e, Raquel Izumi PhD i, Ahmed Hamdy MD i, Betty Y ChangPhD i, Thorsten Graef MD i, Fong Clow ScD i, Joseph J Buggy PhD i, Danelle F James MD i, Prof John C Byrd MD e


Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia.


In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with, number NCT01105247.


Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65—84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1—2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22·1 months (IQR 18·4—23·2), 22 (71%) of 31 patients achieved an objective response (95% CI 52·0—85·8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response.


The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials.

Monday, December 9, 2013

IWCLL videos - thanks Brian

Brian Koffman does a great job compiling video interviews of CLL physicians.  We sat down for a marathon session in Cologne Germany not too long ago and he produced seven different videos from our time together. 

He does a great job giving a text of the contents of the video so it is probably better for me to link directly to his page rather than just reposting the videos. 

Part 1: New Prognostic Markers

Part 2: Another on New Prognostic Markers

Part 3: High risk CLL

Part 4: Feeling run down from CLL

Part 5: Options for patients who need treatment "NOW"

Part 6: Minimal Residual Disease and 17P

Part 7: Richters Transformation

Thursday, December 5, 2013

Diffuse Large B Cell Lymphoma (knowing your ABC's and GCB's)

Growing up, I religiously read the comic strip, “The Far Side.”  In one strip I remember clearly, there was a woman reading her veterinary medicine textbook.  In chapter 9 she came to equine medicine where the remedy for just about anything that bothered a horse was exactly the same.  The captions said, “Like most students, Doreen breezed through equine medicine.”  I’ve posted a link here for a quick laughSometimes treating patients with diffuse large b cell lymphoma (DLBCL) can feel the same  - R-CHOP for all (here is a description of R-CHOP and my personal approach to DLBCL).  
If you look at the most recent update of the world health organization classification of blood cancers, they identify thirteen different types of “aggressive lymphoma.”  Most patients are familiar with the most common subtype lovingly called DLBCL-NOS (not otherwise specified).  The “plain vanilla” DLBCL proves to be far and away the most common version of the disease.

Despite being lumped together as a single entity, if you pop the hood and look deeper inside DLBCL-NOS, there is a lot of biologic heterogeneity – those differences are starting to look more and more important.  A number of years ago, one of my colleagues (who I still insist is the smartest guy I’ve ever met – Ash Alizadeh at Stanford) took advantage of a brand new technology called “Gene Expression Profiling” to look at a bunch of DLBCL samples and got his findings published in the journal Nature.  Other labs (Lou Staudt at NIH and Margaret Shipp at Dana Farber) had similar findings – it is pretty robust.  This allowed scientists to take cancer samples and test them to see which genes were turned on and turned off (a term we call “expression”) and evaluate tens of thousands of genes at a time.

What they all found was that there were two “main” subtypes of DLBCL-NOS.  Those two subtypes were the “Germinal Center DLBCL” and the “Activated B Cell DLBCL” (GCB and ABC subtypes respectively).  Purists who know the science well could fault me for not being completely precise here, but that will do for now.  When normal B cells undergo proliferation in response to discovering the “germ” they were destined for all their life, they do so in a specialized region of the lymph node called the “germinal center.”  GCB-DLBCL-NOS appears to have similar genes turned on and turned off (ie expressed) whereas ABC-DLBCL-NOS looks like a cell that has left the germinal center in an “activated” state.”

Why does this matter?  It turns out that these biologic differences have significant clinical impact.  If you segregate ABC from GCB DLBCL, the ABC do quite a bit worse than the GCB in terms of overall survival and response to R-CHOP chemotherapy. 

Since there is such a big clinical impact, you would think we would all know if our DLBCL patients were ABC or GCB subtype – but we don’t!  It turns out that gene expression profiling (GEP) is pretty expensive and it has to be done on biopsies handled a certain way that most surgeons / pathologists don’t do.  Instead of GEP testing, pathologists figured out how to make the determination of ABC vs. GCB using tests that are a lot cheaper and easier to use – called “immuno-histo-chemistry” (or IHC).  Any pathologist who looks at cancer specimens knows how to do IHC.  You essentially take a small slice of the tumor / lymph node / marrow / etc., stain it with an antibody of interest, and use a marker on the antibody to help you know if it stuck after you washed the heck out of it.  ABC has different IHC staining than GCB DLBCL when you look at markers like CD10, BCL-6, MUM-1, and so forth – so just about any lab can do this testing – but they don’t always do it!  There are two main reasons why many don’t.  First, the test isn’t nearly as reliable as GEP testing.  In fact, there are several different antibody combinations that can help make the IHC distinction, but get a bunch of pathologists together and they will only agree about 70% of the time when they do the stains themselves.  The second reason is when I come back to the far side comic strip.  At least for now, you pretty much have the same R-CHOP no matter what the test shows – but that is starting to change.

For patients interested in a purely “prognostic” test, I suggest getting this one done.  It distills all of the gene expression profiling down to two genes and can be ordered easily today.

Since fewer than half of ABC DLBCL patients are likely to be cured with their R-CHOP chemotherapy, lots of pharmaceutical companies are interested in building a better version of R-CHOP.  Quite a few drugs have been explored in DLBCL in the last few years that seem to have preferential benefit in the ABC subtype of DLBCL.  Ibrutinib yields a 40% response rate as a single agent in relapsed ABC-DLBCL but only a 5% response rate in GCB subtype.  For Celgene’s lenalidomide, it is more like 50% versus 5%.  Millennium’s bortezomib can be added to R-CHOP and when you look at the patients with ABC vs GCB, they do almost identically suggesting that the drug overcomes the negative impact of the ABC subtype of the disease.  Indeed, adding ibrutinib to R-CHOP gives a 100% response rate in preliminary studies, and adding lenalidomide to R-CHOP makes the ABC look ever so slightly better than the GCB subtype.  Not surprisingly there is intense interest in ongoing phase III studies that restrict enrollment to patients with ABC subtype DLBCL to see if any of these three drugs can be added to standard R-CHOP.

My prediction?  I bet several of these end up crossing the finish line and getting approved by the FDA (disclaimer: I am not currently involved in ANY of these studies and have not seen any preliminary data).  So what happens if two or three such drugs actually get approved – how would a doc and patient choose which combo to take?  Now we go back deeper into the biology.

If we look at gene expression profiling or use immunohistochemistry staining to categorize DLBCL-NOS into ABC or GCB we are really only using surrogates for a more fundamental process – what mutations have occurred at the DNA level.  Several publications have recently come out where the entire genome of DLBCL has been “sequenced” and when you look at the data, you realize there are a handful of mutations that seem to recur.  Those mutations often determine which genes are expressed, and how the cell looks under the microscope when you use IHC.  In essence GEP and IHC are merely proxies for the underlying mutations.

Here is where it gets really interesting and makes a lot of sense.  The ABC subtype of DLBCL appears to have “chronic active signaling” through the B-Cell receptor (BCR).  This has some similarities to what we have seen in CLL through different mechanisms.  If you look at the BCR signaling pathway (think of an electrical circuit), you can create a “short circuit” at any number of steps along the way, yet the result seems to be a light that either won’t turn on or off appropriately.  In this case, that is a protein called NF-kB which regulates the expression of a bunch of important B cell genes.

If that short circuit is really high up in the pathway (CD79 stuck in the “on” position) or low in the pathway (CARD-11 mutation) you get the same activation of NF-kB, but turning it off at different places may make a difference.  BTK is a protein that lies just “downstream” of CD79 in the BCR signaling pathway and lies “upstream” of CARD-11.  It is also the target for ibrutinib.  You can have ABC-DLBCL where there is a mutation in EITHER CD79 or CARD11.  Interestingly, very preliminary work makes it look like ibrutinib works well when there is a CD79 mutation but it isn't clear yet how well it works when  there is a CARD-11 mutation.  This makes a lot of sense.  To get to NF-kB, BCR signaling from abnormal CD79 has to go through BTK but BCR signaling that starts from abnormal CARD-11 does not.  That would perfectly explain why ibrutinib might work in one case but not the other (if larger numbers of patients make that theory hold up).

So my challenge to my pharma colleagues is the following: figure out which mutations confer activity for your drug (as some are trying to do right now) so that the docs know what to do once your drug is approved.  Molecular diagnostic tests are now available that enable you to test for each of these mutations all at once.  This should be in their interest anyway because the FDA loves "companion diagnostics" for selecting individuals for therapy.  I predict that in the future, DLBCL management will go like this:
Patient walks in with new diagnosis of DLBCL

Since therapy is often needed very quickly, the patient will get their first cycle of R-CHOP

While the three weeks between cycles has passes, the patient will have their cancer sent for analysis and they will find out what unique mutations they have

The patient will come back for the second dose of therapy and an appropriate targeted drug will be added based upon the mutation analysis

In some cases no “pathway specific” mutation will be found.  In these cases, there are other drugs working through the system that may be added like the antibody drug conjugates (see here and here).  Pharma companies developing such drugs would be wise to know where their drug works even if it is felt not to be mutation specific so that they can pick up the pieces for the patients who don’t get ibrutinib, lenalidomide, bortezomib or others.

R-CHOP has served us well for quite a few years.  We are spoiled in NHL management that we get to cure a lot of our patients.  It is really fun as a doc to have a patient walk in doing great with their cancer a fading memory.  Unfortunately “a lot”doesn’t feel that great if you are not one of the ones who is cured.  I think we are getting really close to making some important steps forward in the management of DLBCL-NOS and it will be driven by molecular information that leads to targeted therapies that are specific to the patient.

Thanks for reading!


Tuesday, November 26, 2013

Off label drug use

How do you get access to a hot new drug if it isn't approved in your condition?  With recent or pending approvals of ibrutinib, idelalisib, lenalidomide, obinutuzumab, etc. lots of people are asking these questions.

In the past, a drug that got approved by the FDA could largely be used by oncologists without much regard to the the specific "labeled indications"  (see ibrutinib / imbruvica here) When a clinical trial is done that leads to the approval of a drug, the FDA evaluates the data and creates a "label."  That label defines what the drug is approved for and that is generally based upon the specifics of the study that led to the approval (ie. the specific population, what other drugs were used, etc).  There is a lot of attention to how broadly or narrowly a label is written because it will have enormous downstream impacts on utilization.

When brentuximab was approved in Hodgkin's lymphoma, it was originally approved for patients with relapse following stem cell transplant, or for patients ineligible for transplant who had received two prior regimens.  Some were hoping the label would be more inclusive (ie to get patients to transplant, or in first relapse etc).  That is why the stock initially went down substantially immediately after approval. Since it was a more narrow label doc's couldn't go prescribe it as frequently as some had hoped.

Many of the same questions surround ibrutinib.  It was given "breakthrough designation" for patients with relapsed CLL that has the 17P deletion.  Recall that 17P is one marker for high risk CLL among several others that determine prognosis.  If I read the press releases correctly though, pharmacyclics submitted for approval in patients with relapsed CLL (irrespective of the 17P deletion).  That sets up a potential scenario where the specifics of the label can make a huge difference in the initial approval in CLL.  In relapsed CLL patients with 17P represent only about 20-30% of all patients.  So if you don't have that marker will you be able to get the drug?  What if you have a P53 mutation without the deletion?  That is essentially the same population?  How will insurance make that decision?  If the drug is approved for relapsed disease only, what would stop a patient from taking a single dose of rituximab and then saying their disease is "previously treated?"

So who governs what can or can't be prescribed?  That is complicated.  For patients with medicare, it is hard to prescribe any of the "new" medications "off label."  This is because medicare won't pay for it.  For some of the older drugs though, they really got established into disease management before they became super expensive.  If a drug gets "NCCN compendia listing" (which is an association of leading academic medical centers who agree on standards of care) it often gets covered by medicare.  Nowadays it is pretty hard to get "compendia" listed unless a specific trial proves that a drug has a role in a very specific situation.

It is possible to prescribe a drug and administer it, but if it goes for ten thousand dollars per dose and medicare won't reimburse you for it, you can put yourself into enormous financial pain very quickly as an oncologist by getting too adventurous.

For patients with private insurance, it can be a lot more difficult to predict.  If ibrutinuib or lenalidomied are currently approved for mantle cell lymphoma, what would stop you from prescribing them in CLL? Since the drugs can cost 10K/month, getting insurance to pay for it is the biggest issue.  These drugs have been clearly well studied in these diseases, it is not like a doc would just be "flying by the seat of their pants" to recommend such a drug.  The reality is that some insurance will cover it and some won't.  In the case of ibrutinib, it will likely be approved in CLL in a few months so it may not be as much of an issue, but for a patient who needs therapy for CLL NOW and wants ibrutinib it all comes down to whether insurance will pay for it or not.

Since the doses are a little different between the two diseases, it shouldn't be a surprise that insurance could figure it is being given "off label."  When you submit a "prior authorization" to insurance for a drug, they also ask for a diagnosis code (ICD-9) that is specific to the disease - i.e. CLL vs MCL vs other.  If the code and the drug don't match, that is another red flag.

Does that mean it can't be done?  I've had success giving patients unusual drugs off label where it was clear to the patient, insurance, and everyone else that we were off label.  In some cases there was something uniquely compelling such as a specific mutation that matched a specific drug in a patient who had received all the available therapies already.  In short - there really are not rules - just financial realities.  In the UK, Europe, and Canada, it is a lot more strict and "off label" use is a lot less frequent. I guess our reputation as cowboys in the US has some truth.

For patients who are determined, a careful, thoughtful letter to the insurance company by the patient or the doctor citing relevant medical literature can sometimes help.  I would suggest strongly that a respectful dialogue goes a lot farther than yelling and screaming in such a situation.

With a bunch of new drugs coming, the landscape of CLL and NHL are going to change dramatically. It will move fits and spurts.  With all the dramatic changes coming in health care (that I have written and tweeted about quite a bit)  it is really hard to predict how it is going to play out.

Thanks for reading

Thursday, November 14, 2013

ASH 2013 - my abstracts

ASH abstracts are out.  This has been a productive year.  I had a few more that we just not quite ready when the ASH deadline hit - but I guess that means ASCO will also be pretty busy.  The following are the presentations I will be a part of this year.  Many of these are familiar from prior blog posts.

Should be pretty easy to pick out two themes.  The B cell receptor signaling pathway involves a sequence of enzymes that start with Syk (fostamatanib, GS-9973), goes to BTK (ibrutinib and CC-292), then on to PI3K (idelalisib).  Antibody drug conjugates are another favorite topic of mine.  Brentuximab leads the way in several diseases but others are coming on strong.

Clinical Activity Of Idelalisib (GS-1101), a Selective Inhibitor Of PI3Kδ, In Phase 1 and 2 Trials In Chronic Lymphocytic Leukemia (CLL): Effect Of Del(17p)/TP53 Mutation, Del(11q), IGHV Mutation, and NOTCH1 Mutation

Phase 1 Study Of Single Agent CC-292, a Highly Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor, In Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Monotherapy Demonstrates Long-Term Safety and Durability Of Response In Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Patients In An Open-Label Extension Study

A Phase 1 Study Of The Selective PI3Kδ Inhibitor Idelalisib (GS-1101) In Combination With Therapeutic Anti-CD20 Antibodies (Rituximab or Ofatumumab) In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia

Chemo-Immunotherapy Combination Of Idelalisib With Bendamustine/Rituximab Or Chlorambucil/Rituximab In Patients With Relapsed/Refractory CLL Demonstrates Efficacy and Tolerability

Idelalisib, a Selective Inhibitor Of PI3Kδ, In Combination With Bendamustine, Fludarabine Or Chlorambucil In Patients With Relapsed Or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

Phase 2 Trial Of GS-9973, a Selective Syk Inhibitor, In Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL)

A Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory CD30-Positive Non-Hodgkin Lymphomas:  Interim Results In Patients With DLBCL and Other B-Cell Lymphomas

A Phase 2 Study Of Single-Agent Brentuximab Vedotin For Front-Line Therapy Of Hodgkin Lymphoma In Patients Age 60 Years and Above:  Interim Results

Wednesday, November 13, 2013

Ibrutinib gets first approval in Mantle Cell Lymphoma

Not sure if you caught the news (see NY Times) but the FDA has now approved ibrutinib (now called Imbruvica) for treatment of patients with mantle cell lymphoma (see my post on the different types of NHL). 

ASCO has put out a broadcast so that you can see the data here.

The label is fairly broad (approved for patients who have had one prior therapy).  That is significant because historically drugs that have been approved on the basis of single arm phase II studies (read NEJM article here) have required patients to have had exposure to all approved drugs in a particular disease.  In mantle cell lymphoma, that would include bortezomib which does not have a huge role in the management of the disease.  Keep in mind that lenalidomide was also recently approved in this disease. You can tell by stock price that the analysts think this is a good result for the company.

This is great news for MCL patients as it will give another treatment option.  Furthermore, once approved it will allow for a lot more research to begin taking place.  Not sure how much off label use will be allowed (will vary from insurance to insurance), but certainly hoping that the CLL indication comes soon. 

Thursday, November 7, 2013

FCR versus BR in frontline CLL

The abstract I have been most eager to review in this years ASH meeting details the results of the German CLL10 study in which FCR (fludarabine, cyclophosphamide, rituximab) is compared to BR (bendamustine, rituximab) in the front line management of patients with symptomatic CLL.

Here is a link to the data

The data is based upon a planned interim analysis and concludes with the statement, "In light of these results, no firm recommendation of one regimen over the other can be given at the present time"

Why the balance?

It looks like FCR is better than BR in terms of depth of response.  While the overall response rate was identical between the two arms, the CR rate favored FCR (47% versus 38%) and MRD negativity (71% versus 66%).  This translated to a more durable progression free survival (85% versus 78%) at two years of follow up but not surprisingly the overall survival at this early time of follow up are equal.

While that may lead you to conclude that FCR is better than BR, it comes with a price.  4% of FCR treated patients died during treatment as opposed to 2% of patients who received BR.  That was in part because 90% of FCR treated patients versus 78% of BR treated patients had side effects rated grade 3-5 in severity (the higher the worse).  This was particularly evident in the rates of severely low blood counts which translated into a considerably higher rate of severe infections (40% vs 25% in favor of BR).

Not surprisingly, the outcome seems to have an age effect.  In the population less than age 65 with good performance status the progression free survival more strongly favored the FCR over BR but above age 65 it was a wash - totally equal.

One tragedy of this study was that there was an imbalance in the randomization that resulted in considerably more patients with an unmutated BCR ending up in the BR group.  This less favorable group may have handicapped the BR arm of the study making it appear worse when perhaps it was just that that arm had patients destined to do worse genomically.

Keep in mind that the average age at diagnosis is 72 and average age at first therapy is 74 years old.  I think a lot of the bias against FCR comes from experiences docs have treating patients with FCR that probably should have never had the combination of drugs because they were never likely to handle it well in the first place.

FCR is also pretty close to the limits of what a person can tolerate while BR seems to be a good platform for adding new drugs.  Drugs like idelalisib and ibrutinib combine very well with BR.  I suspect GA-101 would also be a good partner with bendamustine.  I wouldn't be surprised if some of the new combo treatments make BR much better while maintaining the better tolerability.

This study sheds very important new light on selecting first line therapy for patients with CLL.  How will I handle the data?  For patients above age 65 I will probably favor the BR therapy - particularly if I can do it in a clinical trial that adds a novel agent.  Below age 65 I will look very closely at parameters like renal function and medical comorbidities.  In the very healthy sub-65 year olds FCR will probably get my nod (unless I have a trial with BR with a new drug).  If I have concern about marrow or renal function, I would probably go with BR in this group.  Of course a close discussion with the patient will be very important.

Thanks for reading

More on Gazyva (Obinutuzumab)

Genentech / Roche put out a press release this morning about the German CLL11 study that we have talked about several times previously.  American Society of Hematology meets in December and the abstracts were just released - hence the multiple press releases you will see in the news.

The drug was approved last week for the front line treatment of "typical patients" with CLL (they tended to be older and sicker than the FCR crowd).  Our center has had the opportunity to study the drug extensively and in the surrounding news coverage, one of my patients was featured in local news.  I think it is a nice story about a person taking the drug.  I encourage you to watch it (note this was different study design than CLL11, there was no chlorambucil in this study).

The reason for the press release today is the big news that we had been expecting / waiting for to show that GA-101 (obinutuzumab, gazyva) looks like it did quite a bit better than rituximab.  If you recall, at ASCO, they did a presentation where they compared chlorambucil (C) alone to C-Rituximab and a second comparison of C alone to C-Obinutuzumab.  They did not release the comparison that everyone wanted to see which was the C-Rituximab versus C-Obinutuzumab.  That is what is in the press release and will be presented in the plenary session at ASH in December.

The "progression free survival"  is actually two separate criteria: 1) alive AND 2) no relapse of CLL.  In the C-R arm the rate was 15 months and in the C-G arm it was 26 months - a full year better.  The rest of the data will need to wait for the presentation - can't wait to see it.

Thanks for reading

Tuesday, November 5, 2013

11q deletion CLL

Most patients who make the effort to learn about FISH in CLL know that 17P is bad and 13Q is generally favorable.  Trisomy 12 segregates based upon Notch mutations (if you can find a way to test for it) .  Somewhere between the badness of 17P and the middle of the rode trisomy 12 lies 11Q.

CLL with 11Q deletion has a unique personality.  It is notorious for having disproportionately bulky lymph nodes compared to the elevation of white blood cells (though WBC elevations are common).  Men with 11Q are considerably more common than women, and patients are often younger than the typical 72 year old average.  Furthermore the substantial majority also have unmutated B-cell receptors (unfavorable).  Patients often have need for initial therapy more quickly than others following diagnosis and patients with 11Q have shorter survival than many others.  This is in part because 11Q is often thought of as a “chemotherapy resistance” marker and I wanted to go into a deeper biology of this marker as I have for 13Q, trisomy 12, and 17P.

Once again, recent biologic insight has dramatically reshaped our thinking about 11Q.  We have previously addressed “clonal evolution” where CLL is a mixture of different “subclones” that jockey for dominance.  In the past it was observed that patients with greater than 25% of cells on FISH had worse prognosis than patients with less.  In light of clonal evolution, I tend to just think it is a continuous spectrum and if you have an 11Q clone it is likely to become dominant over time in most cases.  At any given time point, the less you have the better.  Like all other high risk genomic alterations, 11q deletion increases over time (10-15% at initial diagnosis but as high as 30% in relapsed / refractory).

Classically, 11Q deletion was thought to be all about a single protein called ATM (for ataxia telangiectasia mutated – the gene that causes a rare genetic syndrome Ataxia Telangectasia).  The gene for ATM is truly massive.  The DNA that encodes the gene (like most all genes) is broken up into a bunch of smaller pieces (exons) that all get glued together into one sequence (mRNA) before the cell can use the template to synthesize the protein.  The protein is very large and has quite a few different functions.  Consequently older techniques of measuring mutations in DNA (sequencing) couldn’t really address whether an individual patient had a mutation in the gene or not.  Furthermore, we didn’t really know the functional significance of many of the mutations because they were scattered throughout the entire gene.

Newer sequencing technologies allow us to measure with considerable precision BOTH the mutations AND the fraction of cells that have them.  It should therefore not come as a surprise that we have found an important number of cases where ATM can be mutated whether there is an 11Q deletion or not.  It is very similar to the P53 story on 17P.  You can therefore have deletion with or without mutation and vice versa.  It appears that having BOTH deletion of ATM on one copy of the chromosome and mutation on the other copy of the chromosome is worse than only having the deletion.

Whether it is deleted or mutated or both (you do have two copies of the gene), ATM plays an important role in detecting DNA damage, passing that information along to P53, and triggering an arrest in cell division and cell death.  Without ATM in place, you don't have the same response to DNA damage.  Drugs like fludarabine, cyclophosphamide, bendamustine, chlorambucil all require an intact DNA damage response for their efficacy. 

While that may seem complicated – it gets a lot worse.  I wrote quite a bit about the deletion size in cases of 13Q deletion where there are type I, type IIA, and type IIB chromosome changes that may have different prognostic significance.  Not all losses of DNA are equal to one another.  Bigger deletion sizes may include other important genes.  Indeed, the far end of the 11Q deletion variably affects a protein I’ve written about previously that is extremely important – BIRC3.  It has been shown recently that some 11Q’s have loss of BIRC3 and some don’t.  While we don’t directly know how important that is just yet, BIRC3 is a big deal as having a mutation in that protein is about as bad as 17P.  I think we will be hearing more and more about BIRC3 in the coming years as we look at it more frequently.  Finally, there seems to be an association between mutations in the protein called SF3B1 and cases with 11Q.  SF3B1 is not in the region of the deletion - BUT - there seems to be a relationship between this mutation and 11Q (sort of like NOTCH and trisomy 12).  SF3B1 is a mutation that confers resistance to fludarabine and possibly other chemotherapies.  Why this associates with 11Q really isn't known just yet but it is an important observation.  Patients with SF3B1 mutations often need therapy earlier on and don't do as well in the long term.

Wikipedia has a short description of BIRC3 here.  This pathway is also quite important as it governs the "execution pathway."  Once a cell has made the decision to die, it uses a series of enzymes called caspases.  BIRC3 is involved in governing that pathway.  BIRC3 abnormalities appear to be particularly bad thing to get.  Some data sets make it look just about as bad as having 17P deletion.  I think we are only at the start of understanding the interaction between ATM and BIRC3 in terms of deletion size, inclusiveness, exclusiveness etc.

Terry Hamblin did a very good job explaining the role of alkylating agents in CLL with del 11q, you should definitely see his discussion of the topic - link here.  In short, if you are going to give fludarabine based regimen to a CLL patient with 11q minus, many experts think you should include cyclophosphamide (ie. FCR more than FR) if the patient can tolerate it.  Some have even gone farther and asked if you need the "C" in FCR if you don't have an 11q deletion.  Most of this was based upon data generated when fludarabine was compared to fludarabine / cyclophosphamide (and rituximab wasn't in the mix).  Newer publications have suggested that the combination of FCR overcomes the negative prognostic implications of del(11q).  They definitely respond well to the regimen, but earlier relapse remains an issue.

Some are anticipating the results of the big German study comparing FCR to BR in the frontline setting.  These results may come as early as this December at ASH.  I am most interested in the subgroup of patients with 11q deletion in this study because of the question marks about alkylating drugs (chlorambucil, cyclophosphamide, bendamustine) in this patient group.

New drugs like ibrutinib and idelalisib do not have a long track record in subgroups like 11Q.  In our New England Journal of Medicine article, we saw that patients with 11Q OR 17P didn't do as well as patients without either abnormality.  The still did very well on this drug - but I expect that 11Q will remain problematic under most circumstances since it is a marker of genomic instability which is NEVER a good thing in cancer.  My guess is that earlier utilization of these targeted agents in smart combinations with other drugs may be best strategy (I've written about that here).

Anyhow, that is probably enough for now.
Thanks for reading.

Sunday, November 3, 2013

Nutritional Supplements

This post was originally posted in February 2013 but I've read several recent articles that shed additional light on the topic so clearly that I felt an encore was necessary with specific links to the articles.  The original post was one of the most widely read on my blog so perhaps a re-post is in order anyhow.  I've added the links at the bottom of this article and embedded them in the text as well.


Here is my original post:

I recognize how frightening cancer can be for a lot of patients.    One day you are cruising along in life taking care of business, the next day you are confronted with a life threatening diagnosis.  For many patients, it is a journey with unfamiliar terms, clouded along the way by scary thoughts of chemotherapy, illness, and death.

For some patients, fully embracing the health care system and trusting that it will provide the best care possible is too much to swallow.   Suspicion may even be healthy.  Does my doctor know what is best for my case?  Has my doctor adequately explained why we are taking the steps we are taking?  Add in the cost of getting ill and the craziness of navigating a broken healthcare system and just about anyone could go nuts.

In a situation that feels so out of control, I can completely understand why patients may want to take control of some aspect of their care.  In many cases that can be educating themselves to engage in the decision making, in some cases it may be traveling to see a “specialist.”  One of the more common manifestations I encounter is the use supplements.  I think self-treatment through use of supplements can often provide an aura of control that really appeals to quite a few patients or their loved ones.

Maybe it is because I practice in the Northwest where complementary alternative care competes with “western medicine” in the minds of many, but it comes up as a discussion point with the majority of patients I take care of.  I suspect quite a few patients never even tell me what they are taking.  Patients often bring the topic up somewhat sheepishly – as though they know they are doing something a “western” doctor would never endorse.

So let’s talk about what we know and what we don’t know and I will share my opinion.  I recognize this is a “near-religious” topic for many so I have no doubt I will offend a number of readers.  My apologies in advance – my intent is not to offend but to try to make sense of a topic that a lot of patients want to know more about.

Let’s start with the admission that EVERYTHING that we encounter is a “drug.”  Every so often, some uber-athlete dies in a marathon from drinking too much water.  Yes – water can be fatal!  If you sweat too much, lose a lot of sodium, and replace your fluids without the salt, you can have seizures and die.  Oxygen is clearly important, but give too much to a person with emphysema and their brain forgets to breath.  We are complex biologic organisms and things need balance.  Introduce ANY variable and the body has to adapt.  For MOST things we encounter day to day the body is up to the task – but start mixing lots of variables and sometimes you get unexpected results.

Another misconception is that if you are taking a “natural” product, it is somehow less likely to be harmful.  Interestingly several important chemotherapies came straight out of nature. Taxol was isolated from the bark of the Pacific Yew tree, adriamycin was discovered from soil samples near an Italian castle, and vincristine comes from the Madagascar periwinkle plant.  I’m not sure how that fits the idea that “natural” products are somehow safer than chemotherapy – in some cases they ARE chemotherapy.  While you may be tempted to conclude that naturopathic clinicians are therefore onto something, I would also point out that these compounds were then subjected to many years of intensive, focused research and clinical development that refined and re-refined the precursor compounds into validated effective therapies.  When you take one of these drugs, you know what you are getting.

There is also a near mystical belief that if it comes out of a culture that has practiced medicine for thousands of years it is likely to either be extra effective or maybe very safe.  Try telling that to thousands of Taiwanese who developed bladder canceror renal failure from Aristrlochia.  Before I sound too negative though, I should point out a favorable example too.  There is a rare form of very dangerous leukemia called “Acute Promyelocytic Leukemia.”  Perhaps the single most effective drug ever identified for this condition is actually arsenic.  Yes, arsenic has literally saved the lives of thousands of people.  It is approved for this use by the FDA – and guess where it was discovered…. traditional Chinese medicine.

So if we can agree that everything can be a drug, the lines between “natural” and “synthetic” are more blurry than we would like, and “traditional medicine” has its highs and lows I think most readers would agree that we are best off if we can really sort out fact from fantasy.

The sad reality however is that we know VERY LITTLE about the interactions between supplements and chemotherapy.  This link references a good description of the problem.  I wish there was a more rigorous scientific effort to understand these things but it has always been too close to “fringe science” for grant driven academic researchers to risk taking their careers.  Once you start publishing about astragalus effects in lymphoma, research funding may start to dry up.  There have been several laudable exceptions such as curcumin, resveratrol, and green tea, but unfortunatley very few of these have made it far enough for human clinical testing. Things can look very compelling in laboratory experiments but until you do the human subject testing you really do not know much at all. 

So let’s consider some examples that might surprise you.

Grapefruit juice should seem harmless enough right?  Actually grapefruit is one of the worst things out there for just about anyone who takes drugs.  Grapefruit shuts off a set of liver enzymes that are responsible for clearing drugs out of the bloodstream.  I remember hearing about a colleague’s patient on a cholesterol lowering drug who decided to go on a grapefruit juice diet.  Unfortunately this resulted in toxic levels of the cholesterol drug.  The subsequent muscle tissue injury caused kidney failure.  It is so well recognized that when companies are developing drugs sometimes the FDA mandates that they study the interaction with grapefruit juice (another reason drug development sometimes takes so long).

Most of us would agree that smoking is bad – but did you know that the metabolic byproducts of tobacco can mess with the same liver enzymes as grapefruit juice but in the opposite direction?  Ironically (and sadly) this can rev up the metabolism of drugs such as erlotinib which we use to treat lung cancer.  There have been some publications suggesting that smokers taking erlotinib need much higher doses to get the same effect as lung cancer patients who have given up on smoking. 

Green tea is quite the rage these days.  There have actually been a number of good quality studies that have looked into its anti-cancer properties.  The “polyphenols” contained in green tea may indeed possess important anti-cancer properties – but just like water and oxygen, context is everything.  Green tea also contains ECGC.  Unfortunately a very important drug for treating myeloma called bortezomib (aka. Velcade) gets metabolically inactivated by green tea.  Not too long ago one of my myeloma patients on velcade having a suboptimal response to treatment informed me that she had been started on Green Tea by a local naturopathic practitioner.  While I don’t know if it was the green tea or just a bad case of myeloma you can imagine how we all felt.  Other green tea supplements have recently been linked to liver failure.  

Take st. john’s wart for depression?  You might be particularly depressed if it causes cataracts or gets you a horrific sunburn.  More freightening still is that it alters metabolism of quite a few different drugs.

The point of these examples is to highlight the dangerous interactions between things that we might not expect to interact.   If we agree that we know very little about the majority of supplements, the interactions that we DO know about give me reason to be VERY careful putting unknown drugs into the system.  I believe these examples should give us pause before launching into a twenty supplement regimen to “strengthen our immune system.”

I know one very reputable academic doc with a fantastic career who simply refuses to take care of patients if they engage in using supplements during chemotherapy.  While I don’t go that far, I do tell patients it introduces a level of uncertainty and risk that I cannot predict.  I often tell patients to try to avoid supplements during chemotherapy though I don’t so much mind them doing whatever they want when chemo is not in the mix.  On the other hand, if it seems like a patient is going to be doing a lot of supplements no matter what I say, I may not offer them participation in a clinical trial.  It isn’t fair to blame unpredictable side effects caused by a supplement / drug interaction on a research medication.  It could potentially slow down the development of a lifesaving drug.
By now, I've blurred the distinction on natural vs non-natural, traditional vs western, side effects, interactions, and so forth - but that is just the start of it!  In the nutritional supplement business there is comparatively little oversight.  Supplement manufacturers do not have to submit their processes to the same regulatory scrutiny as traditional drugs.  There can be big variations in dose between different manufacturers - as if we even knew what dose mattered in the first place.  Add in a pretty sophisticated science in pill manufacturing which influences how much drug even gets into your system and it is really impossible to know if you are even taking what you think you are taking.
With all that in mind, I ask my patients to avoid suplements during chemotherapy.  I don't get all upset if they ignore the recommendation - some people are going to look at the same information and make a different judgement.  I tell patients they are paying me for my opinion.  After eight years in the UC system, three at Harvard, and three at Stanford, hopefully it is worth the money.  They can disagree with me and choose a different path but it isn't one I would take for myself. 
There are a few things about the "supplement industry" that irritate me and one that makes me extremely mad.

I occasionally hear the assertion that there is some enormous conspiracy to keep a cure for cancer under wraps.   Sometimes the drive for supplements has a distinctly "conspiratorial" overlay.  If there is a huge conspiracy I must really be a dope because I am smack dab in the middle of it and I had no idea.

Two things that bother me about the "supplement industry" are the ridiculously false claims you occasionally see or the claims that have some truth at their basis but takes it far beyond what the data supports.  Yes glucose is an important nutrient for cancer cell survival but you cannot really get your sugar levels low enough to kill the cancer without having a serious brain injury at the same time.  Yes pH is important but the body very tightly regulates pH so try making yourself more acidic or alkaline and you are either wasting your time or risking serious injury.
What really makes me furious though is the occasional exploitation of really sick patients.  I have seen a number of patients exploited by the “alternative care industry” when they are at their most vulnerable time.   Not a week goes by where I am not asked about some form of alternative care and some cost huge amounts of money.  Many times thesetreatments are dressed up to look like real science.  Sometimes I have a hard time at first glance sorting out the real from the fake but if I take the time, I can usually tell them apart.  
But what about the desperate mother of a dying child whose treatment has failed at the hands of “Western Medicine?  I can’t blame her for grasping for hope – but what makes me furious are the charlatans out there ready to take her money knowing full well they are selling crap (see this amazing 60 minutes documentary for point of reference).   

There are MANY well-meaning alternative care providers out there who try their hardest to help their patients and sincerely believe their interventions will help.  I am not writing about them.   My advice: if they are both recommending and selling the product - and it costs a lot - ask them where else you can buy it - and how the other products compare to theirs.  If the answer is “nowhere” or “the others are not as good” I would be concerned.

One last thought.  The American diet is truly awful.  I was shocked when taking a human anatomy class in medical school how fat we all are.  Even people who look "average" often have inches of goey yellow fat padding huge areas of the body.  Our fast / quick food culture undoubtedly leaves our bodies wanting something different.  I like to eat organic when possible.  I've watched Food Inc and realized that corporate agriculture introduces things into my diet that I want to avoid.  For me, eating at McDonalds is truly an act of desperation.

The first time "chemotherapy" was tried in children with acute leukemia should serve as a grave warning though about trying to replace "missing nutrients."  Sydney Farber - the American "father" of chemotherapy was studying pernicious anemia and had found that some patients responded to folic acid - a common additive in multivitamins.  His first experiment involved giving children with acute leukemia large doses of folic acid.  Unfortunately, this was a "missing ingredient" for the cancer cells and they immediately started growing faster and the children died.  Sydney almost got ran out of Harvard for it, but after deciding what he really needed was an "anti-folate" he started work on methotrexate -  a drug that we still use today.  60 years later the Dana Farber cancer institute in Boston still gives tribute to his early discoveries.

I need to wrap this up. 

I think a lot of patients or their loved ones seek out supplements to try to make a bad situation better.  Sadly, I think it is possible to accept some myths about alternative care and get yourself into a worse situation.  For most alternative care providers, I don't question their intent - most are good people who want to help.  Cancer is an incredibly savvy enemy though and I  believe there are extremely few magic bullets out there to be discovered amongst the supplement aisle.  If you are going to do supplements, it is probably safest to do it when chemotherapy is not in the mix.  If you are in watch and wait or some remission, it is probably fine in most cases - just beware that you can hurt yourself with supplements and the claims are not regulatred by the FDA. 

That is my opinion.

Herbal Supplements Are Often Not What They Seem

Herb-Drug Interactions in Oncology

The Quackish Cult of Alternative Medicine

Common US Supplements linked to liver failure