Two to three times a week, I tell my patients, usually my new ones, exactly the same thing. It feels like a sales pitch, sometimes, like I am a used car salesman, and I often think I should video the whole thing and just let them watch the show–but that would be too impersonal, and everyone is different. Still…
It is like a fuzzy marble, sort of. You can hide a 100,000 cancer cells on a period on a page, that’s how small they are, give or take an order of magnitude. The little bits of fuzz, four, eight, sixteen cells in a clump, can fly off and go elsewhere, and nobody would ever be able to find them. Likes seeds on the wind they take up growth where they land if the site is compatible. Not quite like seeds of course, because different examples of the same type of cancer may like different tissues. So it is we see patterns of spread, sometimes rather curious.
Lung cancer, especially non-small cell, (silly designation: we have small cell, and non-small cell. You’d think we could be more imaginative) for example, likes to go to the adrenal glands. Breast cancer often has a pattern of going to bone mostly, or liver and lung, or skin, crossing over to the other sites later in its history.
Cancer grows by cell duplication, although mutations of the DNA are common during the process (after all, that’s what a cancer is caused by, mutations) and so the cells can differ quite a bit (heterogeneous). One becomes two, and then four, eight, sixteen, thirty two and so on.
It takes about 40 doublings to get a lump of cells big enough for anybody to find. Go ahead, sit down and multiply 2 times 2 forty times, you get a 1 with ten zeros after it. That’s the power of exponential growth. Each doubling occurs about once every twenty days (a lot of variation here, but it can be in that ball park). Forty times twenty is 800 days, or two and a half years.
And so it is that the surgeon comes into the patient’s room and says “We got it all,” and a couple of years later it comes back. There is nothing magical; it’s not a different cancer necessarily. The cells were always there, just way too small to detect by any method we have available today. Maybe some day we’ll have the ability to detect single cells, and that will be a huge step toward a cancer cure, but today, those small clumps of cells, and there can be lots of them, remain hidden for a long time.
Such a simple paradigm, it is sort of amazing it took us so long to figure it out. Oh, there are refinements to this, with cells in resting phase, in suspended animation or something, but basically this is why cancer returns. Rarely, it can be a brand new cancer, but mostly it is this kinetic pattern of behavior.
Now, if we give drugs that kill cancer cells, we can kill cancer cells. The problem is, because they continue to mutate, and are therefore heterogeneous, that don’t all respond to the chemo we give. There are several ways to get around this problem.
We usually give more than just one drug, in the hopes that if the cancer cell is resistant to one, it might not be resistant to the other, or, at the very least, it might not be resistant to the combination. This also has the advantage that if one drug causes a nasty effect on one organ, maybe we can pick the second drug to have a different, instead of additive, toxicity.
Secondly, we try to give the chemotherapy when the clumps of cells are smaller so that the drug can diffuse into the small lump (it might not get to the center of a large lump), and there are fewer cells leading to less change of resistance, les chance of heterogeneity.
Although cancer cells are characterized by uncontrolled growth (they don’t stop growing like normal cells do) they typically have less ability to self-repair. We rely upon that differential self-correction. Normal cells recover, while cancer cells don’t. We hope.
We don’t get all the cancer cells with one cycle of chemotherapy. A rule of thumb is that we lop off two zeros from the end of the number with each cycle. A one with ten zeros after it, by that rule, would take five or six cycles to destroy. That’s why so many chemotherapy protocols call for six cycles, but our knowledge about that is getting better, and less is acceptable.
Forty years ago, when I started in this profession, young women received twenty-four cycles, one each month, of chemotherapy, for breast cancer. In the 70’s it dropped to twelve, and I remember well telling my group of Breast Cancer ladies in the chemo suite one day in 1987 that standards had dropped it to six. Several protocols now are down to four cycles, and for some we are thinking of going to two. But any change like that needs a great deal of study before we can be sure it is safe. But even then, sometimes, not all the cells are sensitive, and some get left over, to come back to haunt the patient later.
Realize that if a cubic centimeter of tumor contains a gazillion cells, a five centimeter lump contains–5 x 5 x 5–one hundred and twenty-five times that.
This is why surgery is often involved up front. Surgery gets rid of a HUGE burden of those cells, reducing the potential resistance, and clearing away a bulk of tumor into which the drugs may not be able to penetrate. Surgeons try to get a clear margin about the tumor, because every little bit helps, any little bit might just contain a bundle of cells that just happen to be resistant.
RELATIVE RISK REDUCTION
After fifty years of close study, we are getting very good at predicting, for the most part, what the chances are for a cancer to come back, based on its stage, grade, the age of the patient, and other lesser factors. One curious feature of many cancers is that the relative risk reduction, the percentage of the cells left behind after surgery that may be destroyed by a usual protocol of chemotherapy, seems to be roughly the same, regardless of the stage. This is tricky though.
If the relative risk reduction for a treatment protocol is, say, twenty per cent, that is the drop in the risk of recurrence that we can expect. Of course, it is pretty obvious that a more advanced stage of cancer may have a more advanced risk of coming back. For example, a stageIII Non Small Cell Lung Cancer may have a risk of recurrence of 70% after surgery, whereas a stage I risk might be only 30%. In this situation, the absolute risk reduction for the stage I cancer would only be twenty per cent of that: 20% times 30% is 6%. For the stage III cancer it would be 20% times 70% or fourteen percent.
Absolute Risk Reduction = Relative Risk Reduction x Risk
The RELATIVE risk reduction remains approximately the same, but the ABSOLUTE risk reduction is clearly different, dependent as it is on the initial untreated risk.
For early disease, then, at some point, the benefit may get so small as to be no better nor no worse than no treatment. Chemotherapy toxicity is still worrisome, and rarely, thankfully, does it lead to mortality. For some aggressive protocols though, depending on the state of health of the patient, the benefit may be equal to the risks. In this situation we often advise that no adjuvant therapy (treatment when there is no sign of any disease) is the better decision. This is good news bad news. Bad that we can’t make the chances zero, but good in that the patient’s prognosis is so good, chemo won’t help.
FATE WORSE THAN DEATH
This title sounds ominous, but values of patients vary. Not everybody has the same goal in life. Indeed, as patients age and approach that time they know logically cannot leave them much time left (after all, we all know very few people make to 100; that’s a fact of life we all realize by some age) they may very well choose not to go through the tribulations of chemotherapy. This is on part because the older we get, the less likely we are of destroying the chemotherapy drugs and recovering from its indignities. Here is truly the art and judgement of the physician, and the experience, to be able to communicate what they know in an easily understandable way, so that the patient and family may make a reasoned and very personal decision.
Death is not always the fearsome result we think of when we are younger. It is sad, for sure, and often more so for the loved ones left behind. But many of my elderly patient fear loss of control, loss of independence far more than loss of a few months of life. It is always a balance of the up-side and down-side effects of the treatment. Modern medicine takes the ethical position that such a decision is and always should be in the best interest of the patient. The interest will be different for everyone, and can truly only be defined by the patient themselves. In fact, when the patient is not capable of thinking of or understanding these things, then the job of all those responsible for them is to try to decide what the patient would have wanted, were they competent to make their own decision.
Cancer is common, now. Really, it always has been. As other illnesses are controlled, cancer becomes the last big threat outside of old age. But now it is out of the closet, and the stigma is lessened. People talk about it, and every family seems to have one or two. Understanding it makes it less frightening.