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!