With all this in mind, I think it is easy to take the "watch and wait" strategy too far. Some folks will do anything possible to avoid treatment and get themselves into a deeper hole than they need to. Sometimes with a slow disease, it can feel like you can just wait it out a "little bit longer." For low grade lymphoma there are criteria for treatment. In CLL, I've written about "when to treat" which is my summary of the IWCLL guidelines. The caution here is that you can get yourself a lot sicker than you need too if you hold things off for too long. I would wager that it is even quite possible to feel a lot sicker from the disease than from some of the treatments available. I've seen quite a few patients literally feel A WHOLE LOT BETTER after starting treatment that they had delayed longer than they should have.
Sunday, April 21, 2013
Nothing can make a patients head spin faster than the two juxtaposed statements, “you have cancer” and “we’re not going to treat it right now.”
“Watch and wait” has been a mantra for patients with asymptomatic CLL and indolent lymphoma for quite a few years and sometimes no explanation is enough to comfort a patient who is understandably worried about their new diagnosis (see: when to treat CLL, choosing first treatment in CLL, and how I treat follicular lymphoma part 1). Quite a few people have dubbed this “watch and worry” instead of watch and wait. There is an avalanche of messaging out there about early detection and early treatment saving lives in so many cancers that watch and wait can sound more like medical quackery than good science. For some patients, taking a nutritional supplement and avoiding chemotherapy is an easy sell – but for others, the thought of living with untreated cancer is too much.The short answer is that CLL and low grade (indolent lymphoma) are different than a lot of solid tumors – but this blog is about the long answers – so here goes.
Historically, the argument in favor of watch and wait was that our treatments did not impact overall survival – so why take chemotherapy unless you needed to get rid of some bothersome symptom. We would argue that chemotherapy was a steep price to pay if it didn’t do you any good in the long run (see risk stratification in CLL). Admittedly, those conclusions were based on studies from the 80’s and 90’s that used fairly ineffective treatments or drug combinations with moderate to significant side effects of their own.
But science continuously evolves. Several recent studies have shown that IF you are going to treat CLL, certain treatments may improve survival compared to others (FCR better than FC, Fludarabine better than chlorambucil). While this later observation does not indicate that treatment is better than NO treatment, now that we know we can improve survival with some of our treatments those old assumptions need to be retested.
In follicular lymphoma (which is a model for many of theindolent diseases), an ongoing study already presented at ASH compared rituxan to observation. Not surprisingly that has shown that patients who get rituxan are generally able to wait longer until their next treatment compared to the folks who were randomized to observation – not necessarily an earth shattering observation. Whether this approach influences how long patients actually survive remains to be seen as that will take quite a few years for the study to collect data. While the data from that study continues to evolve, others have pointed to the SAAK study in which eight doses of rituxan were given over nine months (weekly x4 then every other month x4) and note that nearly 40% of patients have not required any more treatment over the next ten years. It is possible that early intervention may be better, but we really still do not know. I suspect the data will look different from those old studies now that we are using drugs like rituxan that are both effective and well tolerated – but whether that means you live longer has yet to be seen.
In CLL however, single agent rituxan doesn’t pack the same punch as it does in follicular lymphoma. There is less of the CD20 target on the surface of CLL cells than there is in follicular lymphoma. Furthermore, CLL has some tricky ways of lulling T cells to sleep (anergic). Interestingly revlimid may help wake those T cells up (not FDA approved for this indication and should be done very carefully as there have been reports of tumor lysis syndrome).
Along comes a new paper though that I think has profound implications on how we thing about managing ANY of our patients with ANY lymphoid cancer. I’ve written several times on clonal evolution (here and here) because I think CLL highlights this principle better than just about any other cancer and may actually have lessons for metastatic breast cancer or other solid tumors. I realize that I’ve probably been trying to write about watch and wait in these posts but never really put it into the right context – so here goes.
Consider the following hypothetical experiment. You are welcome to try this at home though I would not recommend it. Plant a lawn but make sure you have a few weed seeds included in the mixture. Let that lawn grow but resist the temptation to pick the dandelions. Once you have a nice back yard scattered with a few weeds here and there go down to Home Depot. Pick up a big bottle of round-up and spray your entire back yard. Make sure the entire lawn is covered well enough so that you will have a completely brown mess in two weeks. Now wait……
Ok, so you have waited twelve months without doing anything to the brown mess. Go out back again and tell me what is growing. Is it a lush green yard with a few scattered weeds or is it a mess of ugly weeds. Chances are, you will have a bunch of mutant dandelions that have totally taken the place over.
In SOME cases – that example MAY illustrate the effect of chemotherapy on CLL on the “clonal architecture” surviving cells. In evolutionary biology terms, we may refer to effective chemotherapy as a “mass extinction event” – think asteroids and dinosaurs. Any time you have a mass extinction event in a biologic system you may see “survival of the fittest” play out right in front of your eyes. In our example above, the reason the dandelions didn’t run amok before the round-up was that there was a lot of grass competing for the soil, water, etc. You could say that the grass was the dominant (incumbent) clone holding the dandelions back. Once you cleared out the grass though, the weeds had plenty of room to take over (boy with weed and grass both in this post – really curious to see what sort of google searches land on this page).
In this prior post, I highlighted a paper that followed a single individual at several time points and showed how there were three separate subclones at the time of diagnosis. Before FCR chemotherapy there was a small subclone (1% of total cells) with a bad mutation. After chemotherapy, that clone which was the “fittest” took off and became the dominant clone and ended up being the one that caused the patient to pass away. This example has been replicated in a few other papers too so I think it has some validity to it.
Now – it is really important to stress the things we DO NOT KNOW. If we go back to our analogy of the backyard, would we expect the dandelions to take over if we used napalm instead of round-up? What if we just turned on the hose and let it flood the backyard for a month – would that select for the dandelions? Or is it possible that may cause the crabgrass to run wild. Perhaps we could just put a bunch of biblically hungry locusts in the back yard. After they ate everything in sight – maybe it would be the grass that came back instead of the dandelions or the crabgrass. In other words – does the nature of mass extinction event select for different types of “fittest” to come back? Maybe the extinction has no bearing on what comes back in some cases. Put into chemotherapy terms – does bendamustine have different outcomes for clonal selection than fludarabine? Is rituxan different than chemotherapy? Do the new drugs like ibrutinib and idelalisib have any effect on clonal selection? We DON’T KNOW the answer to that question BUT we do know that treatment DOES exert a selection pressure on cancer cells and gives me an argument to consider “watch and wait” that I believe is more sophisticated than just saying, “our treatments don’t keep you alive longer.”
I often tell patients, “bad” may be a good enemy of “worse.” Yes, having indolent lymphoma or CLL may be a bummer, but it may be better than having a super mutant, chemotherapy resistant, transformed beast come back at you. I have often been puzzled by studies that show a dramatic improvement in “progression free survival” that have zero impact on “overall survival.” In other words, treatment “x” does a better job keeping your disease away than treatment “y” but ultimately you both pass away at the same time – huh? Maybe the better treatment is beating the disease back further – but also selecting for a more resistant set of cells to come back when it does come back.
In the paper I referenced above that shows how “clonal architecture” can change over time, one of the most interesting findings to me was that the presence of a “subclonal driver mutation” generally predicted for a shorter remission duration and the emergence of resistance. “Subclonal driver mutations” are a lot of the bad markers we’ve been describing in other posts such as BIRC3, NOTCH, SF3B1,P53 etc. but that these mutations are in a very small population of the cells. In other words, you may only have 3% of your cells that are really smart (ie P53 mutated) and 97% of your cells that are generally dumb (del 13q), but that 3% of cells are the dandelions. Your chemo may make your numbers look a whole lot better and even make you feel better, but now you’ve traded the devil you know for the devil you don’t know – and that second devil might be really nasty.
Newer sequencing technologies are about to enter the clinic and help us find these “subclonal driver mutations” with vastly better skill (though there will still be limitations on how well we can look). I HYPOTHESIZE (though this is absolutely conjecture and should not be taken as settled science) that in 5-10 years knowing the full clonal architecture will influence our recommendations surrounding watch and wait.
So a few key take home points
1) Watch and wait was historically based on ineffectiveness of therapy
2) Newer treatments have led scientists to revisit #1 but the answers are not in yet
3) One risk of treatment is the emergence of resistance but not all patients experience this
4) We may be able to begin measuring a patients risk for resistance based upon “subclonal driver mutations” soon
5) To date, we do not have much insight into what sorts of therapies influence emergence of resistance
6) Watch and wait is not crazy in appropriate patients – there may have been benefit to it for a long time that we are only just now starting to figure out.
7) Patients should not wait too long otherwise they just feel lousy when they could have been feeling better with treatment.
Thanks for reading
Tuesday, April 16, 2013
A while back, one of my readers asked if I would make a post about “grading” in follicular lymphoma. She has been a great help to me in attracting readers to this blog so I promised her I would write something up. Unfortunately I think I’ve had a mental cramp on this one for a while – but I am trapped on a seemingly endless flight (Dang Texas is big) so I thought I would give it a try. The flight doesn’t have internet so this one may be a little brief on the outside references.
Most of you know about “staging.” In lymphoma, staging is a clinical measurement of how much disease you actually have. Stage I disease is typically one affected lymph node or a few that are tightly clustered in one place. Stage II disease is when there are multiple affected lymph nodes in different areas, yet on the same side of the diaphragm (ie all in abdomen/pelvis or all in neck, chest, armpits). In stage III disease you can have lymph nodes on both sides of the diaphragm. Stage IV disease is when it either involves the marrow or more than one site outside of the lymph nodes (ie skin, liver, lungs, bone lesions).
I should make a comment here that frequently comes up in my clinic. Patients often ask me, “what stage am I?” There is nothing worse than the look you get when you tell someone they have stage IV disease. We are primed from our knowledge of a lot of cancers that stage IV means you are going to die. It can sometimes be a challenge to “pick up the pieces” after you tell someone their disease is that far advanced.
Stage IV lymphoma is very different than stage IV lung cancer. I tell my patients that lymphoma is a cancer of the immune system and that the immune system is pretty much everywhere to begin with (ok – we can make exceptions for both the brain and testicles which are considered immune “privileged” - draw your own conclusions).
In diseases like lung cancer, if that cancer has spread outside of the lung or adjacent lymph nodes – that becomes an incurable disease and the prognosis is often comparatively short. Same thing holds true with a bunch of other “solid” tumors for that matter (bladder, kidney, pancreas, colon, stomach, and so forth). It is certainly true that less lymphoma is better than more lymphoma – but not to the same degree as those other cancers. Stage IV lymphoma is very common but often still quite manageable (and even curable in DLBCL). In fact stage III/IV follicular is considerably more common than limited stages of disease – so most of the statistics you hear about survival are typically for patients with advanced stage disease (which are often way outdated since by their very definition are retrospective and do not necessarily account for improvements in therapy).
OK – moving on – this was supposed to be about grading right? Grade has absolutely NOTHING to do with stage. I tell patients, “grade is what it looks like under the microscope – stage is what it looks like on the CT scan.” Unfortunately, there is a fundamental problem with using appearance under a microscope as an objectivemeasurement – it is difficult to reproduce this well. Even though there are well established criteria about grading lymphoma – trying to make solid black / white distinctions can be hard when the biology does not conform to the rules. You can look at different regions of the same node and come to a different answer, or you can even look at the same region and have two different pathologists give you a different answer if they count things a little differently – and that is easy to do!
Grading typically applies to cases of follicular lymphoma. We assign one of four grades – you would probably guess I, II, IIIa and IIIb right? The way we distinguish between these are the number and arrangement of “large cells” within a node. Large cells are typically called “centroblasts” while small cells are called “centrocytes.” Large cells are thought to be more rapidly proliferating. Since faster proliferation is bad, the more large cells you have the worse we think it would be.Ultimately, there is VERY LITTLE difference between the grade I’s and the grade II’s either biologically or clinically. Even grade IIIa disease is pretty much something we can lump together. We treat them exactly the same way, they do just as well. It is pretty much just a pathology distinction without much clinical impact.
Distinguishing between grade IIIa and IIIb though can have clinical implications. In grade IIIa there are enough centroblasts seen in the lymph node (15 per “high powered field”) to be categorized differently than grade II yet clinically we still treat all these exactly the same. Grade IIIb on the other hand has “sheets” of centroblasts within the node and really starts to behave more like diffuse large B cell lymphoma (DLBCL). In the past that often meant the difference between getting R-CVP or R-CHOP (the latter being more intensive and causing hair loss – see my post about it). For a lot of docs though, R-CHOP was historically (and still is in some cases) the choice though even in grade I-IIIa follicular lymphoma so the distinction didn’t matter quite so much.
Now it is more significant because in grade I-IIIa utilization of bendamustine-rituxan is extremely common yet R-CHOP would probably still be considered standard for IIIb. Since BR is both superior and better tolerated than R-CHOP in I-IIIa, I sometimes anguish a little when I see a IIIb come into clinic. I will often call the pathologist to get a better feel as to how “clear” the distinction is to them in the sample. Alternatively, I may look for other clues about the aggressiveness of the disease. Does a PET scan show one area to be a lot worse than others to suggest a transformation? Does the clinical pace or labs suggest higher grade disease? etc.?
There are a few problems with this though. 1) This is an area where pathologist reproducibility is not so great. This is not to say they are not good pathologists but that there is a lot of judgment involved as well as sampling differences. 2) It is not clear that appearance is a good surrogate for biology. We are learning about the remarkable complexity of these cancers and I am not convinced that appearance gives us adequate insight into the molecular mechanisms that are going on. 3) As humans we like to compartmentalize things even if they are really continuous variables. In other words, if we use the number 50 as a cutoff – are patients with 49 or 51 really all that different from one another?
Clinical studies have tried to get at differences in outcomefor patients with grade IIIb follicular lymphoma but drawn somewhat different conclusions. (another link here and here)
If good researchers come to different conclusions when asking some of the same questions – it is often because the data input is faulty (ie. in a study of 100 patients- 15 are categorized incorrectly and results in a smaller difference than would have occurred if everyone was put in proper group). Other times we may be falling victim to the belief that appearance is a surrogate for biology AND that the biology is actually different.
One other key point I should make before wrapping up. Grade IIIb is not the same thing as histologic transformation which is evolution from low grade disease to high grade disease. We are getting to understand that biology better and histologic transformation is likely worse than grade IIIb on account of a different mutation profile.
For now, grades I-IIIa can be treated with rituxan, R-CVP, R-CHOP, BR, or any of the new research drugs. See my posts on “my approach to follicular lymphoma part 1 and part2.” Grade IIIb I will use R-CHOP even though I have all the questions I ask above.
I hope that helps – thanks Anjou!
Wednesday, April 10, 2013
There was a lot of press in the last year about the dangers of excess scans. Several key articles in the New York Times brought the topic to the forefront of people’s minds. Rarely does a day go by where at least one patient articulates concern about how many scans they have had. Other patients ask about the differences between PET and CAT scans. Well, here is my attempt to distinguish between them and characterize their risk.
CT scan (which is short for CAT scan) stands for “computerized axial tomography.” It uses an x-ray source to take pictures of the insides of the body. In the “olden days” (1980’s) tomography was utilized for a variety of purposes. You needed to move the x-ray source in one direction and the detector in the opposite direction at the same speed. This created blurriness to everything except for the “axis” or pivot point between the two. I am sure it was good for something but frankly, I cannot remember what.
The big advance came when you could begin to use computers to get a digital interpretation of the images and create an entire “plane” (two dimensions) within the body instead of a line (one dimension). This allowed you to take “cuts” of the body, nowadays it is typically 5mm in thickness. When your doc flips through the pictures in the office, each image is “one cut.” Using software that allows you to flip between images pretty quickly allows you to get a pretty good impression of what is going on in 3D space and compare from one scan to the next.
PET scans stand for “positron emission tomography.” Very different technology. There are a lot of different things you can measure with PET using different reagents but the one we are most accustomed to is metabolism. FDG (flurodeoxyglucose) is just a sugar with a small bit of radiation on it. For reasons we are only just now starting to understand, cancer cells have a different type of metabolism than normal tissues. They soak up the sugar and you can measure that with a positron detector (not an argument for low sugar diets – see my post on nutritional supplements).
In short – CT scans are just pictures of the inside and PET scans detect differences in metabolism. I think there is a bias to believe that PET scans are more “sensitive” than CAT scans because they are newer and cost more. Not necessarily true. Some diseases like CLL/SLL, and some cases of mantle cell are virtually invisible to PET scan because the metabolism isn’t all that different (though it can be helpful if Richter's Transformation is suspected). Other diseases like DLBCL can be very “hot” on the scan and sometimes you find disease in places you didn’t see on CAT scan.
There are sometimes that one scan is better than another. Most of the time when you get a PET scan, they are also doing a CT scan at the same time so that they can overlap or “fuse” the images. One of the problems though is that PET can find a lot of things that are not even there. Sometimes you get non-specific uptake in the colon. The kidneys, heart, and brain are always “hot” so reading PET scans there doesn’t always work well.
One other question I get all the time is about, “how many CAT scans can I get before I get another cancer from all the pictures?” In my mind this has gotten blown way out of proportion. I understand the concern, but studies have been done and show that even though there is a clear attributable risk – it is quite small.
Since CAT scans use X-rays they can cause DNA mutations. Keep in mind, that happens when you are bombarded by cosmic x-rays all the time – even worse if you fly in planes a lot. First of all, you need a lot of scans before you are in the risk zone (probably on the order of 15-25 scans of a particular body part). That is a number many cancer patients may actually accumulate – particularly in patients with a long natural history of disease. Once that number has been accumulated, there is approximately a 1-3% risk of developing a cancer at a time interval of about 20 years. Yes it is real – but it is not a major risk.
When I worked in ER’s I was always surprised to see an occasional young patient who had been in the ER monthly for two years complaining of abdominal pain. Perhaps they had some emotional issues or legitimately had an undiagnosed medical condition. Unfortunately, you cannot go into an ER with belly pain without getting a CT scan. It was not uncommon to see a young patient who had gotten 10 scans or more and never had anything going on. That is the patient I worry about most.
While I think you want to be judicious about scans – if you have a known cancer and there is an appropriate medical question being asked, I think it completely justifies the risk in most cases.
Hope that helps “shed some light” on the subject….
Sunday, April 7, 2013
Where do drugs come from? Sometimes they come from places far removed from where they were originally intended to go. The history of ibrutinib development is detailed in this article published in Forbes magazine. As David aptly points out – these drugs can come out of left field with wild histories. Lots of people played important roles – and I think it is a fantastic read. I would highly encourage any patient with CLL or NHL take the time to read it (yes I am proud to get a couple of personal mentions).
Unfortunately the initial approval will not serve as broad permission for any oncologist to prescribe it to any patient. It will probably have a narrow, “indication” at first for patients with relapsed Waldenstrom’s Macroglobulinemia and MantleCell Lymphoma having received some specific prior therapies. Second – I predict that patients with 17pdeleted CLL will get the next, “indication.” Over the next 1-3 years we will see the “indications” slowly expand in different patient populations
“Indications” matter because insurance companies pay close attention to what the FDA has approved. Different insurance companies take very different attitudes regarding “off label” prescribing of drugs. For a drug likely to cost nearly $90k per year (my guess only) – insurance will likely look quite closely at who is receiving it. While CLL patients will greet the approval – it may still take a while for them to access the medicine. That is why getting involved in research studies is so important!!!!
Wednesday, April 3, 2013
Update: A possible solution?
Huffington post article about patients traveling thousands of miles
Generating congressional activity
I don't want this blog to be about politics. I want this to be a place for educating patients about their disease. In this case though I need to highlight a topic that carries a lot of political emotions. Please know that I am not trying to argue left vs right - just to inform patients about some trouble that is brewing.
Our system of health care delivery is really broken. It was broken before Obamacare and I think a golden moment for positive change was blown up in terrible partisanship. Both sides carry plenty of blame - this is not about pointing fingers at either side. While the survival rates for patients with individuals with cancer in the US exceeds many other countries - the way it gets paid for is a true mess.
This headline sounds alarmist - but you need to know about it - and I encourage you to read the article (WP tends to be more conservative in opinions - but the facts of this article reflect pretty closely what I am seeing):
Cancer clinics are turning away thousands of Medicare patients. Blame the sequester.
Taking care of patients with cancer is extremely expensive. Drugs can cost unbelivable amounts of money. $5000-$10,000 per dose of some drugs is commonplace (Bendamustine, ofatumumab are over 100k / for a full course of treatment - neulasta 5-6k/dose, Rituxan - 40K/year).
When an oncologist in community practice (important to differentiate docs who are practicing under a hospital vs independent - right now the split in US is about 40/60% respectively) treats you with a drug, they have to purchase the drug, administer the drug, and hope against hope that they get reimbursed by insurance and that patients pay their co-payments. Often paymenst may lag by 30-90 days so that entire time docs are essentially "loaning" the drug to the patient until it is repaid by their insurance. If that ever breaks down - they eat the cost.
When I was searching for a job after training I interviewed with a practice close to where I grew up - so I could be near family. I had an offer to join a practice where all the docs ended up declaring personal bankruptcy when their practice got upside down on their drug costs. They were profiled in this CNN article - the problem is real.
Doctors going broke.
Here is another article - not about the group I personally know
Since many patients with cancer are older - they are frequently covered by Medicare. A number of years back payment reforms implemented a system called ASP+6% for drugs administered in the doctors office. It means that when a doctor treats you with rituxan, they get reimbursed the AVERAGE WHOLESALE PRICE of rituxan plus 6%. Your head can probably run a bunch of scenarios about this and come up with vastly different conclusions. I will tell you how I see it play out with many docs that I know.
First of all, let's talk about what that 6% is supposed to cover. In a family practice clinic, there may be 1-3 staff members per doctor. That includes front desk, medical records, nurse, etc. In an oncology practice it is often closer to 8-10 staff per doc. That includes a pharmacist, pharmacy technician, infusion nurse, insurance verification, front desk, medical assistants, etc. The idea is that the additional complexity of runing an infusion center is covered by that 6%.
The first major assumption is that you can actually buy your drugs for the average wholesale price. Docs in smaller practices have a difficult time buying their drugs for the same price as a 200 physician network. Hospitals have a special discount rate that independent docs simply cannot compete with. AVERAGE means some docs can buy their prices below and some docs buy their drugs for more than what other docs pay. The more you are above average price, the less revenue is there to run the infusion center.
Heaven forbid you should ever administer a drug and then have insurance deny payment. One single dose can really hurt when it is 20K. Sometimes these can be denied retroactively - even if several doses have been given.... I've had it happen (fortunately it wasn't one of the really expensive ones). Sometimes you can get a drug company to replace the drug - sometimes you can't.
The big issue with the headline above is that the sequester has resulted in a 2% cut in medicare part D payments - so now that reimbursement is ASP +4%. That represents a 33% reduction in the margin (6-2=4) any docs may have had if they were even able to buy the drug at the average price to begin with. For many docs the answer is clear - they are personally paying out of their pocket to treat some patients with chemotherapy. Even margins of -0.5% can be significant if the drug costs 10K and you are paying salaries of your infusion nurses - you simply cannot keep your infusion center open.
As a result, a number of practices are starting to close their practice to patients with medicare as their only insurance. Hospitals have the ability to charge more for their services than independent docs so they are less effected by these changes. There has been a tidal wave of docs selling their practice to hospitals because they just cannot afford to provide care independently even though it is generally 30% less expensive to receive care through an independent physician:
Oncologists struggle to stay independent
The first article above indicates that patients may be shifted into hospital based practices. The reality though is that many smaller communities don't have such groups - in exactly the same place where the problem is most acute.
The point here is that this is a time of great difficulty for a bunch of docs who really care a ton about their patients. I still love what I do. It gives me a ton of personal satisfaction to step into a patients life when they are terrified and provide some hope and comfort. I know not all patients end up with the outcome they want, but even when the outcome isn't going to be good, it makes me feel incredibly good if I can help the patient on their journey.
As hard as it is for docs - I am sure it is even more scary for patients who are not sure where they would get their care if their doc had to close up shop. I really empathisize with their fear. I don't want this to be a "boo-hoo" post - I know a lot of people are trying to sort their way through this economic train wreck - both patients and docs.
I wish I could tell you what you can do - unfortunately I don't see many easy answers. Let your elected officials know if you experience a lack of access to care or support efforts to reverse these cuts. Let your insurance know how much you value your provider (if you do). It all seems pretty weak to me quite frankly.
Sorry for the downer post -