Breast Cancer Chemotherapy: An Interview with N.S. Tchekmedyian,

N. Simon Tchekmedyian, M.D., F.A.C.P., is associate clinical professor of medicine, University of California at Los Angeles School of Medicine, Los Angeles, Calif., and practices oncology and hematology in Long Beach, Calif.

What are the main chemotherapy drugs used for breast cancer?

The main chemotherapy drugs used for breast cancer are Adriamycin and Taxol or Taxotere. Those two compounds currently are the most important drugs and a close third is cyclophosphomide.

Are they effective?

They are effective. Chemotherapy for breast cancer works, and by that we mean it shrinks the cancer at least by 50 percent of its initial size. They work at least 70 to 80 percent of the time, meaning that if you have somebody who has either a large breast lump or has a growth somewhere else in their body, like the lungs or the bones or the liver, you give them these drugs and more than half of the time the cancer will shrink down by more than 50 percent.

It doesn't mean that the cancer is cured. In fact, I should say that if the cancer spreads outside the breast we do not currently have a cure for it. We can control it, often changing it into a more chronic pattern so that the person has a chronic illness like you have diabetes or hypertension or something like that, but you cannot really cure it and completely get rid of it.

How do chemotherapy drugs work?

Chemotherapy drugs work mostly by affecting the genetics of the cell. Cancer cells are immortal: they continue growing, they divide constantly as opposed to normal cells. Normal cells are born, they accomplish a function of some sort and then they die. The cancer cells are constantly dividing and that allows us to focus on them with these drugs. The drugs bind to the genetic material of the cell and when the cell tries to divide, instead of dividing it actually dies.

What are the most common side effects of chemotherapy?

When you talk about side effects of chemotherapy, one of the most important ones that I see as an oncologist is fatigue, just tiredness. It's like you get chemotherapy, you go home and you feel as if you were hit by a truck and you have to rest. Sometimes your family doesn't understand that. They want you to be active, they want you to fight your disease and you just are so tired and so weak that all you want to do is sleep and rest. It's important to recognize that it's probably the most frequent side effect of chemotherapy and it's pretty universal. It happens with most drugs.

There are certain drugs that have some specific side effects. For example, Taxol: that evening or the day after you are given Taxol you get joint pains, you get muscle aches, uh you feel very stiff. Nausea is not a problem with Taxol, but you get hair loss very often. Fatigue is a problem just as it is with all of the other drugs. Adriamycin, on the other hand, can give you mouth sores, can give you some nausea, and makes you very fatigued. It definitely make you have hair loss and if you give it at certain dose levels it can really cause a serious heart condition, with heart failure.

How do you choose which chemotherapy drug to use?

Oncologists have to work with drugs that have a lot of side effects and the ratio of efficacy to side effects is very narrow, so we tend to choose drugs that work well, that have a good level of efficacy and at the same time are well tolerated. When we have to choose which drug to use we look at the person, we look at, for example, what other conditions that person may have and then adjust the drugs that we choose to that condition.

For example, if somebody has breast cancer who is 72 years old and has had a couple of heart attacks you're not going with idiomycin because idiomycin can be toxic to the heart. If you have somebody who has a serious neurologic condition and severe weakness and problems with their nerves you may have a problem using Taxol because Taxol can cause neuropathy or nerve damage.

In terms of efficacy I think it's fair to say that idiomycin, Taxol and cyclophosphomide are the three most active drugs in breast cancer and clearly they are the front line choice in most cases.

How many do you have to choose from?

Oncologists have a fairly wide variety of drugs to choose from, and it goes into dozens but when you look at breast cancer in particular, there are just a handful of drugs that are truly effective, and these include Adriamycin, Taxol, Taxotere, cyclophosphamide. Gemcitabine (Gemzar) or vinorelbine (Navelbine) are other drugs that can be very useful.

How specific are these drugs?

The way we manage breast cancer and many cancers at present is certainly not optimal. ... My brother is a surgeon and I often say that surgery is quite barbaric and primitive; of course he'll tell you that chemotherapy is even worse and I don't disagree.

Chemotherapy has a lot of side effects. It's not a very specific treatment: it goes across the board penetrating to the blood stream because usually we give it intravenously. It will affect your whole body — all of your tissues, your skin, your liver, your kidneys, your urinary bladder, your lungs, your brain — they are all exposed to these toxins as we introduce them in your body although our purpose is to effect just a few cells or sometimes a large number of cells.

We have no way most of the time to specifically target those cells that need to be destroyed and spare the rest of the body. There are some situations where we can do this. For example, in ovarian cancer, if the cancer is completely into the abdominal cavity we can put in a catheter and instil the chemotherapy agent as a belly bath, so to speak ... but most of the time we are affecting your whole body just to kill a few cells.

Let's say for example that you have somebody who had a breast lump removed and whose chance of having the cancer come back is about 50 percent. Well, 50 percent of the time we're going to give chemotherapy to that person and yet it's not going to help because that person may be cured to begin with. It's just that we have no way of telling. And in the other 50 percent of the time we will deliver the chemotherapy and yet get a benefit only in a fraction of those patients, so that maybe 20 or 30 percent of the time on those 50 patients out of 100 we will have efficacy. So when you take the whole group of 100 people, you may end up helping 10 or 15, but you have to treat 100 of them. It's just as non-specific as it gets.

Chemotherapy Advancements & Combining Drugs

How has chemotherapy changed in the last 10 years?

I have been in oncology now for about 20 years and since I started my fellowship back in the early 80's things have not changed all that much. We do have a few good new drugs that we can choose, particularly the taxanes like Taxol and Taxotere, important new drugs, but overall the side effect profile of the drugs [and] their mechanism of action are pretty much the same. We have not had a lot of advances in conventional chemotherapy over the last decade. I should say, however, that we have had major advances in some other areas of biologic therapy, including antibodies, gene therapy and a variety of other things.

Has the chemotherapy experience changed per patient in the last 10 years?

Although chemotherapy drugs still have a lot of side effects and we have not had great advances in terms of the drugs themselves, we have had major breakthroughs in terms of diminishing the side effects. We have much, much better treatments to prevent nausea now than we had 10 or 15 or 20 years ago; we have much better control of the immune effects of chemotherapy; we have ways of preventing and treating anemia associated with chemotherapy; we have ways of preventing the white cell counts from going down to dangerous levels.

We seldom if ever have to admit a patient to the hospital because of side effects of chemotherapy. We're able to control those side effects very well. The quality of life is better. Most of my patients who come here to be treated — come over, they read, they watch TV, they have a visit, they chat and joke with their nurses and their doctors, and then they go home, and most of the time they have very few acute side effects.

What is the most exciting new chemotherapy drug that's been developed in the last few years?

I would say the most exciting chemotherapy drug that has been developed for breast cancer over the last decade is Taxol and the taxanes, including Taxotere. These are drugs that have a different mechanism of action. They actually work by interfering with cell division because they bind to microtubules, small filaments that are involved in the process of cell division. That is a different mechanism than most of the drugs that actually bind to the genetic material of the cell. They were very toxic when they were first discovered and tested. In fact, the first few patients who were treated got so sick that the drugs were almost thrown away because they thought that they wouldn't be able to use them. ... Their efficacy is very high and we have learned how to use them and therefore they are very well tolerated.

Why do some drugs work for some patients and not for others?

It can be quite frustrating to try to control a cancer both for the patient and the doctor ... Some cancers are inherently very resistant to chemotherapy and some others become resistant after a period of treatment. The reason why the cancer cells become resistant has to do with mutations or changes in their genetic material. As they divide, cells become progressively more derailed in the way their genetic material works and the more this process takes place, the more these cells become oblivious to the presence of these drugs around.

These genes are important in terms of telling the cell what to do, telling the cell how to behave. When this gene changes because of so many divisions and so many mutations, then the behavior of the cell becomes completely abnormal and that leads to resistance to drugs that normally kill cells.

So what's your strategy when you're giving chemotherapy drugs to a patient and it doesn't work on that patient? How do you decide what other drugs to try?

Generally we use the drugs with the higher level of efficacy and the lower level of toxicity up front and then as the cancer becomes more progressive and more resistant we have to go into drugs that perhaps are more toxic but that still have a chance of working, or we go into drugs of the lower levels of efficacy but used in a lower dose to approach what we call palliation.

So you're juggling dosage with a mixture of different drugs?

The choice of chemotherapy drugs for breast cancer is somewhat empirical and based on our knowledge and experience, but we usually can have a fairly rational and sound approach as to the selection of different drugs as we manage the patient. Many years and many decades of experience with drugs and different patients have shown us what works best and what should be used first and what should be used second and so on.

There are some tests available where you can take fresh cancer tissue and test it to see what drugs work better — what's called chemosensitivity assays. Unfortunately so far the results with these tests have been sub-optimal and they cannot be trusted. Most oncologists do not do those tests because they have not proven to result in improved patient outcome results.

How do you decide when to give chemotherapy in conjunction with surgery at the moment?

A one centimeter small growth contains a billion cells. It takes, we think, approximately eight years for a growth that size to show up in the breast. During those eight years and before you've reached that level of one billion cells. Many of those cells have penetrated into the blood stream and have been circulating around. Some of those cells will be knocked down by the immune system or some other factors and disappear, but some of them may survive and find a new place to live— the bone marrow inside the bones, in the liver, in the lungs, in the lymph glands or somewhere else, so when the surgeon cuts the breast open and takes a lump out, what we're taking out is what we see, the lump that contains the billion cells with some normal tissue around it, so that we get rid of the primary illness.

The problem with breast cancer is not that lump. The problem with breast cancer is the cells that left that lump and have been circulating around that can grow later on into new cancers, so-called metastasis. By using the combination of primary surgery with chemotherapy we approach the local problem and the systemic problem of those cells that have escaped, so chemotherapy used together with surgery makes a lot of sense. We've been doing that for many years and the results clearly show that we can cure patients who otherwise would have died of breast cancer by using chemotherapy as an adjuvant to surgery.

Treatment Side Effects

Not every patient who has a lumpectomy or a mastectomy also receives chemotherapy. How do oncologists decide that?

Well, you decide it on the basis of what the probabilities are that the cancer will come back, that the cancer has spread. What are the factors that we pay attention to? Well, the size of the cancer is very important. Tumors that are very small (less than one centimetre, less than half an inch in diameter) generally have a good prognosis. Tumors that are larger than one centimetre, particularly if they are larger than 2 centimeters, over an inch, are more serious. Tumors that have cells that look very wild — what we call poorly differentiated cells— a much higher chance to grow back. Tumors that penetrate into nearby small lymphatic or vascular channels tend to behave worse, and the presence of an abundance of certain genetic markers indicates that the cancer is more aggressive.

We know that cancers in young women tend to be more aggressive and they tend to come back more, and we know that we have to be more proactive and more aggressive in the treatment of younger patients. The so-called estrogen receptor and progesterone receptor, which have to do with the presence of compounds on the cell surface that indicate that the cells are sensitive to the female hormone estrogen also influence our course of therapy. The ones that have the receptors tend to have a slightly better prognosis.

So we put all of that information together and we try to come up with what is the probability of a cancer growing back in the future and recurring. Based on that probability we then decide whether chemotherapy is necessary.

So it might be necessary for someone who has a negative lymph node biopsy?

Oh, absolutely. Initially we used to apply chemotherapy when the risk of recurrence of the cancer was very high, so that we would use chemotherapy for patients who had a lump in the breast and had lymph glands under their arm that were involved. Under those circumstances the probability that the cancer will grow back with surgery alone is over 50 percent and chemotherapy reduces that risk fairly substantially.

As we were able to use drugs with a little better toxicity profile and as we were able to manage the side effects of chemotherapy better we started using chemotherapy in patients who have just a primary lump but no other invasion of lymph nodes or any other sign of spread. We now do so because by studying these patients we've learned that chemotherapy also improves the cure rate in those patients who have a lump in the breast without invasion of the lymph nodes.

Are there many patients at this stage receiving chemotherapy who shouldn't be receiving chemotherapy or for whom chemotherapy has no effect?

One of the factors that women use to try to decide whether to have chemotherapy or not for early breast cancer is determining what exactly will be the improvement. How can you quantify that improvement? My experience and some published reports indicate that if you ask women, you'll find that if the improvement in the chance of having the cancer come back exceeds 3 to 5 percent they will take it.

Now what do we mean by 3 to 5 percent? Well, if you take a hundred women with breast cancer and if the probability that the cancer will come back for each of those women is, let's say, 15 percent, and if you can lower that probability from 15 percent to 10 percent with chemotherapy, women will decide to take it. What does that mean? Well, it means that you're going to have to treat a hundred women to help five.

Do you find that's a great shame?

As a medical oncologist I see patients who have cancer and who need treatment, and my job is to provide everything that I have available to reduce the odds that that person is going to die of cancer. My job is to make sure that the person understands what the options are, and that we use those options wisely so that we improve the cure rate and maintain the quality of life and the function of that person.

When you're facing somebody with primary breast cancer, perhaps with a small lump in the breast and no lymph node involvement, you can say, well, the probability that this person will be cured with surgery alone without chemotherapy is 70 percent, and the probability is about 30 percent that this cancer will come back.

We have treatments such as chemotherapy that will improve that chance of recurrence from 30 percent down to 20 percent. We have no way of telling whether that particular person is the person who will benefit from it, so my question to that woman is "there are two buses leaving town. The women in one bus are going to have a 20 percent chance of recurrence and the women in the other bus are going to have a 30 percent chance of recurrence. Which bus do you want to take?"

So the issue is not as much about the fact that how non-specific and how toxic it is. The issue is what I face every day: this is what we have today, this is the best we can do today. I'm sure we'll be doing much better in ten years, but this is what we have to do now and that's my job: to help women make a decision as to what's the best choice today.