on sarcoma treatment.

Chemotherapy

Today I thought I’d spend some time talking about how little we know about sarcoma treatment and some of the challenges we face when trying to counsel patients about treatment options.

Basically, when developing a treatment plan for sarcomas, we usually have two problems.  Number 1: what can we do with the main tumor to ensure complete removal and prevent it from regrowing?  Number 2: What is the risk of the tumor metastasizing (spreading) to other locations, and is there anything we can do to decrease that risk?  If the sarcoma is already in multiple locations, these priorities reverse – first we try to shrink or control all of the tumors as much as possible, then we try to remove and neutralize what’s left behind.

The three pillars of sarcoma treatment – surgery, radiation, and chemotherapy. Other oncologists like to joke that for sarcoma, “when in doubt… cut it out.”  And for the most part that’s true.  However, it’s critical that the tumor can be removed with a wide edge of normal tissue or “margin.”  If you leave sarcoma cells behind, they will regrow.  That means that sometimes there is quite a major surgery that needs to happen to ensure complete removal, which can be deforming or lead to poor function – for example, a large sarcoma in the calf might require a significant amount of normal muscle to be removed, leading to weakening of lower leg strength.  As you can imagine, it takes an expert surgeon to understand the size and location of the tumor and anticipate the best way to remove the tumor in one piece as well as the margin around it.

Additionally, we use radiation to help control the surrounding area after a surgical removal.  Radiation treatment is like getting a daily xray to a carefully customized area – as the xray exposure adds up, the cells in that area are killed.  Tumor cells are more sensitive to radiation than normal cells.  For most sarcomas larger than 5 cm and high grade, the use of radiation improves the chance of “local control” – meaning that the tumor won’t grow back in the same place.  With modern radiation techniques, and again, a skilled sarcoma radiation oncologist, local control rates with surgery and radiation approach 90%.

So many sarcomas can be cured with surgery and radiation alone, but the problem comes when a sarcoma is not able to be removed with surgery, or when it has spread to other locations.  The risk of spread to the lungs or other organs over the following years is as high as 40% with large, high grade sarcomas, even when completely removed with surgery and radiation.  Unfortunately, it becomes much more difficult to cure sarcoma when it’s spread.

That’s where chemotherapy comes in.  Sigh.  I will preface the following by saying that chemotherapy use in sarcoma is not for the faint of heart – and that it’s still the source of debate if not frank tantrums even in rooms full of sarcoma experts.  Chemotherapy is anti-tumor medication that is designed to kill rapidly growing cells in the body at the expense of some of the normal, healthy quickly growing cells.  Most traditional chemotherapy is given in a vein, sometimes through a port.  The concept is that it goes everywhere in the body, not just the tumor, and thus should kill cancer cells that are floating around or lodged in other organs outside the main tumor.  Modern “targeted therapy” can come in the form of pills or IV drugs, and is different in that the medicine has a particular target it is designed to block – for example, in gastrointestinal stromal tumors (GIST), they have a hyperactive protein called KIT that drives the tumor cell growth.  Imatinib (brand name Gleevec) blocks the KIT action, thus is considered a targeted therapy.  Although all cells have some KIT, because the tumor is so dependent on that protein, treatment with imatinib kills tumor cells while sparing normal cells.  In sarcoma, we are trying more and more to identify the important targets to use “directed” therapies, instead of the chemotherapy that just kills everything that divides.  Think of it like using a guided missile instead of a nuclear bomb.

So if you had breast cancer, your oncologist would be able to plug the characteristics of your tumor including size, grade, the presence of certain proteins that predict what the tumor is dependent on (kind of like KIT), whether the cancer had spread into lymph nodes, and other information into an algorithm that can predict the percent benefit you are likely to achieve by doing chemotherapy.  Additionally, because of the numbers of women with breast cancer, clinical trials are performed with thousands and thousands of women, with years and years of follow up, so that even tiny differences in benefit between chemo drug A and chemo drug B can be picked up, and recommendations and guidelines change based on these findings.

Sarcomas are much more rare, and as we said, there are at least 100 different types.  Even sarcomas that fall into the same “type” under the microscope are different in terms of their genes, and certainly their response to treatment which we don’t yet understand.  Although this concept of “heterogeneity” is common throughout cancer types, it is particularly problematic in sarcomas.  Unfortunately, most of the largest trials of chemotherapy for sarcomas must include multiple different types of sarcoma into the trials in order to get high enough numbers of patients to be able to draw any meaningful conclusion.

Here’s an analogy to explain this.  Forget that you already know that a coin has heads and tails sides.  Let’s say you flip it 3 times and you get heads every time.  Based on those results, you could arrive at the conclusion that the coin only has heads on both sides.  But let’s say you flipped it 30 times – the chance that you would make the wrong conclusion, that the coin only has heads, is MUCH less likely, because the chance of flipping heads 30 times in a row is ridiculous.  It’s the same concept in clinical trials – if a clinical trial only has 10 patients in it, and no one treated with chemo A has a tumor shrinkage, the response to that chemo will be measured as 0%.  However, the likelihood that no one responded because of chance (meaning that the patient happened to “land on heads” repeatedly) is much higher than if the trial had 1000 patients enrolled.  Especially with the zillions of differences in sarcoma we already discussed, (not a 50% heads/tails flip) you can miss a potentially active treatment if it is only tried in a few patients that are randomly enrolled.  The more patients you have, the more likely you are to catch patients that could benefit from the treatment (meaning that the study has “higher power.”)  However, if the treatment really isn’t effective, then that is even more patients that have been treated for nothing – not good either.

This is what we see in sarcoma trials and early clinical trials exploring drug combinations.  To save money, a small phase I and phase II trial will be conducted to look for preliminary evidence of effect of the drug.  Pre-designed “stopping rules” will be put in the protocol so that if no benefit is seen in the first X number of patients, the trial will be stopped.  In today’s day and age, the apparent lack of effectiveness in that small sample is often enough for that treatment to be shelved, or at least not studied further in that disease type.  It certainly won’t lead to FDA approval or the ability to try that drug in patients.  This week I read a report of a trial of a combination of two drugs with a variety of cancer types.  The only patient in that study that had a response (tumor shrinkage) was a sarcoma.  But because it didn’t help the other patients, that regimen is not being further explored.  This is the same concept that can happen in sarcoma trials- even if a drug is active in one particular type of sarcoma, that activity can be missed if there aren’t enough patients with all of the different types in the study.

Anyways, now that we understand that sarcomas are a completely mixed fruit basket, this is the story with chemotherapy clinical trials in sarcoma.  There have been dozens of relatively small trials that tried to answer the question of whether chemotherapy given to sarcoma patients after surgery and radiation would help decrease the chance of the sarcoma coming back. To increase the power (the number of coin-flips) to determine the answer, analyses were done where all of the patients in all of those studies were combined – this is called a meta-analysis.  Now, in addition to having all different types of sarcoma included, they also included different variations of the chemotherapy drugs used, even with different doses.  This is because the exact recipe of chemotherapy for sarcoma varies in different countries and even in different institutions (and between different doctors at the same institution!)  In short, these monstrous averages demonstrated that if you randomly pick a patient out of the sarcoma hat in this scenario, and only if they have a sarcoma in an extremity (arm or leg), the average benefit of chemotherapy is that it improves survival (the chance of being alive) by about 10-15%.  If you start with a chance of metastasis at 40%, and going through toxic chemotherapy only gives you a shot at 15% improvement, you’re still left with a chance of it coming back at 25%.  No wonder no one wants to give (or receive) chemotherapy if you only go by this statistic.

Herein lies the problem.  In reality, that average is in the form of the bell curve.  You all remember the bell curve right?  That’s how that evil teacher in 9th grade decided who was getting As and who was getting Ds?  behold…

bell curve

borrowed from Bright Ideas Blog

So ignore the IQ score comment, but this is representative of how people benefit from chemotherapy.  There are some patients that will respond very well, and there are some patients that will not respond at all.  The rest might be in the middle with unclear benefit. So the “average” benefit is 15%, but some patients will benefit less, some will benefit more.  At least at this point in 2015, we still haven’t figured out the markers for which patients will benefit and which ones won’t to test ahead of time.

At my institution and others, we get around this by trying to give chemotherapy before surgery.  Four benefits – first, it can help shrink the tumor and make surgery easier for patients that have a shrinkage or even necrosis (cell death) without shrinkage.  Second, it allows us to get early exposure to chemotherapy to any cells floating around outside the tumor.  By waiting to give chemo after surgery and radiation, that delay can sometimes be months especially if there are complications with healing or infections, so any cells that have escaped the tumor have extra time to set up shop and grow elsewhere.  Third, it allows us to treat the patients at their healthiest, when they have the most reserve – again which could be impacted if they have complications with surgery or radiation.  Finally, and I think most importantly, it allows us to see in the individual patient if the chemo is working ahead of time.  If I have a patient who gets three cycles of chemo before surgery, and we can see the sarcoma shrinking during that time on scans or when the tumor comes out at surgery it is almost completely dead, that is going to make me much happier about continuing the same kind of chemotherapy after surgery to polish off any last cells floating around.  On the other hand, if the patient has a sarcoma that grows while on the chemotherapy, and the tumor is completely alive at the time of surgery, I don’t give that same treatment afterwards.

If I am meeting a patient for the first time after surgery is already done, when we talk about this statistical benefit of chemo, again I try to personalize the recommendation as much as possible.  There are some other features in the story that I think place patients further towards either end of the bell curve, such as complicated or unplanned surgeries, certain sarcoma types prone to recur, and evidence of tumor invasion into the blood vessels in the tumor itself.  Higher risk pushes me to recommend chemotherapy, as does a sarcoma type that is known to usually be sensitive to chemotherapy.  What it comes down to is this – essentially chemotherapy is an insurance policy.  The cost upfront of investing in the insurance policy is steep – some estimates predict as high as a 10% chance of death or severe illness resulting from chemotherapy treatment alone.  Additionally, it’s not 100% protection – think of it like an auto insurance policy that covers you if you get hit by a green, blue, or red car, but won’t if you get hit by a black or white car.  (obviously those numbers don’t add up as we’ve talked!)  Some patients will take their chances – they’d rather not go through the chemo if the benefit is not guaranteed, while others feel strongly that they want to do everything possible to minimize the risk of it coming back.

This is the same problem we encounter in patients with disease that comes back – the only way to know if a particular chemotherapy or targeted treatment is going to shrink tumors is to try it, at the expense of valuable time and side effects.  What everyone wishes for is the ability to understand sarcomas ahead of time – so called personalized medicine.  The NCI-Match trial is attempting to do that.  By profiling a cancer to try to understand what the mistake or mutation is that’s driving the tumor’s growth, one can then match the patient to a targeted therapy specific to that mistake in the context of a clinical trial.  Instead of lumping all breast cancers together, or all colon cancers together, they open a trial for all patients that have mutation X in their tumor, and then treat with Drug Y.  While this approach has had dramatic effects in tumors that have “driving” mutations (like KIT in GIST), this approach might not work if the mutation identified isn’t very powerful, and is just “along for the ride” (passenger mutation.)  The problem with most sarcomas is that their DNA looks like a bomb went off – very few have one central driver mutation, instead there are numerous abnormalities in genes that may or may not be significant or druggable.  Additionally, some of the most powerful “Driver” mutations common throughout cancer are not yet able to be drugged (like the gene p53.)

In summary, I think we’re in an exciting time for treatment of cancer, where the paradigm is shifting from treating all apples with drug A and all oranges with drug B.  I think more and more we’re beginning to delve into the specifics that make each apple unique, and designing smarter clinical trials that can prioritize patients that are more likely to respond, requiring fewer patients to show the signal.  With sarcoma, it really is its own fruit basket, and statistics are just not sufficient in predicting individual benefit or prognosis for that matter based on the limitations of a small population.  The more we can understand the biology of the particular sarcoma, the better we’ll be able to identify new treatments more likely to work, and avoid wasting time and leading to toxicity with ineffective therapies.

take-home – 1. statistics only get you so far and applying a one-size-fits-all approach isn’t the way to go.  2. treatment decisions need to be customized specifically for each case.  3. the ability to profile and understand individual tumor biology may be the way of the future when designing clinical trials and future cancer therapies.

a tall order.


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