Cancer Prevention, Detection, and Chemotherapy 4

Now, some of you are aware of the Lynch Syndrome I and there’s a Lynch Syndrome II. It’s a very interesting type of illness. The mean age of onset is 45. It’s found in the proximal colon so when you’re trying to get it and find it and reverse the deaths due to the colon cancer, you have to think about the proximal colon. It has an unusually good prognosis which is usually found in all these types of syndromes and it’s an autosomally dominant type of inheritance.
Lynch Syndrome II is the same as I except multiple tumors, high frequency of colon, endometrium and ovary and less frequent breast, stomach and lymphoma. I have to bring this up because there’s a lot of fights and discussions over in Europe particularly about these two entities and the people felt that this really didn’t jive – that there wasn’t an increased incidence in these Lynch syndrome II. However, they found a number of families with this kind of a syndrome and it pretty well cleared this up. Indeed, this is a cause by the high incidence of the various types of cancers that are listed there.
Here’s a family that’s pretty prolific and as you can see there are seven cases with cancer and five without and you can see the various ages that they had this. Here’s one at 46 years of age. Here’s another one at 55, 42 and certainly a real problem and some of these patients get to the point they just don’t want to talk about it anymore and don’t get the proper studies that they should be getting.
The hereditary aspects of colorectal, again, in familial adenomatous polyposis, percent of colon cancers is less than 1% interestingly enough and that’s one that gets a lot of publicity. Chromosome 5Q21 and gene APC are found. In hereditary nonpolyposis you can see the incidence goes up from 1% to 9%. Chromosome is 2Q3P and then it’s chromosome COCA-1 which you probably know about as well as I do. Now when we’re screening for colorectal cancer, you want to do a digital rectal every year starting age 40. Fecal occult blood test every year age 50. Sigmoidoscopy every 3 to 5 years at age 50. Colonoscopy, first degree relatives of cancer patients at age 50 or less. Age 35 to 40, 2, 3 to 5 years for this test. You will find different groups will do this in a little bit different manner and you may not find the exact type of suggestions as is listed here.
Hemoccult testing. As you know, if the test is positive, 10% of these patients will have cancer and 23% will have polyps. So it’s not a very good test in terms of getting all the cancer patients involved with this. The Hemoccult II only screening test if we use it only like that for asymptomatic colorectal cancer, 50-60% will remain undetected. So not the best test.So if you look at what we’re doing with colorectal cancer, occult blood is a poor marker for colorectal cancer. Most cancers are missed and most bleeding is due to other causes. The HemoQuant is a specific test for blood and some groups are using these too in their studies but there’s really no improvement in picking up the cancers by using this newer test. Both are equally insensitive and we need better screening markers in order to do better in detecting this.

Cancer Prevention, Detection, and Chemotherapy 3

Primary liver cancer is associated with hepatitis, aflatoxin exposure and malnutrition. As you know, this is the most common cancer throughout the world.

Of course, AIDS is associated with a huge number of cases. That’s going up all the time and that is associated primarily with Kaposi’s sarcoma and lymphoma.

There will 186,000 new female breast cancers in the U.S. in 2006 and 46,000 deaths. There’s been no change over the last two or three years and as you know this is very hopeful and gratifying that maybe we’re finally going to start getting a handle on this and decrease this. At the present time, there are 20,000 less deaths than from lung in women. As we discussed, breast cancer, 186,000 and 45,000 deaths, no change.

High risk factors include family history, nulliparity, early menarche, infertility, first pregnancy after age 35. Negative risk factors include negative family history, first birth before age 20, surgical menopause before 40, pituitary insufficiency, early menopause and normal weight and low fat diet.

Now, caffeine, as you know, is associated with painful breasts and we seem to have an awful lot in this country of that and it’s associated with caffeine. If we use danazol, we can cut down the pain and discomfort by about 60% and the tenderness also. There’s no evidence that it does anything in terms of hyperplasia. However, if the patient has atypical hyperplasia, the incidence of cancer goes up about 4-fold.

The other thing we can mention is what about women who have osteoporosis. I’m sure you get this as a real problem all the time. What should we do about these? If we give them estrogens is that bad? Well, I think most of us who are in this business feel that that’s okay and if you use estrogen and progesterone at the same time, the incidence of developing the cancer is going to be so low that I don’t think it’s anything to worry about.

Now, the next thing as we come to a close in this area, if I came around and I said, “Hey, I can cut down the cancers that you’re seeing in your patients by 50%, would you like to do that?” Well, of course, everybody would just be enthralled if you could do that. If we look for lifestyle cancer control, you see in one group, the Mormons, all cancers are down one-third to one-half, lower save prostate. So in other words, we can cut it down by one-third to one-half and the diet is the same except no tea, coffee, tobacco or alcohol. That’s the only difference between the way these people eat and the difference with the cancers being reduced to one-half is really quite remarkable.

Some in terms of cancer control, asbestos and lung are associated, as you know, with being exposed to asbestos in the lung increases the likelihood. I know chloride, which is found in the chemical factories down in the south part of our country cause an increase in hemangiocarcinomas of the liver, dyes such as aniline dyes used by the Germans are associated with an increase in bladder cancer and you already discussed pesticides which are associated with an increase in lymphomas and leukemias.

Now viruses, again, you did discuss this a bit. Epstein-Barr is associated with lymphomas as you know. Papilloma viruses in the cervix cancer. Hepatitis B with hematoma, again, the most common cancer in the world, HIV, lymphomas and Kaposi’s sarcoma as we’ve already discussed.

The family physician is in a unique position to detect cancer based upon the evaluation of the family history, particularly as regards to breast, colon, endometrium and ovary. In the colon, we have approximately three types. As you know, familial polyposis in 100% of these patients eventually, ulcerative colitis in 25% over 25 years and this has to be a constant exposure. It can’t be just sporadic in order for it to be a real factor in this problem. The family cancer syndrome in 50%.

Cancer Prevention, Detection, and Chemotherapy 2

So in cancer control then, what we want to have is a 30% fat diet or less, daily fruits and vegetables, a high fiber grain, low cured, smoked or pickled food and moderate alcohol. Alcoholism as you know is a cocarcinogen with head and neck cancer, esophageal and rectal cancers. So we have to worry about that a little bit also.
This is an area that I was quite surprised at and that is that cholecystectomy raises the incidence of proximal colon cancer by a factor of two, as you can see. Two times greater in females. So we have to watch out for that and try to avoid it and treat conservatively with the things we have available.
Ultraviolet damage is another area we want to look at and as you know the ultraviolet rays will lead to skin problems, lower lip problems and melanomas. In melanomas, as you know, if we take it in 1950, there’s 1:500, in 1980 1:250, in 1985 1:150 and in 2000 1:90 so you can see why melanoma is a real concern because it’s winding up as a tumor that’s occurring at a much more rapid rate than we have seen in the past. Melanoma cases per year constitute 40,300 and 7300 deaths and it’s getting worse, as you know, all the time.
The ultraviolet damage we look for is we want to stop. The necessity of protective clothing. We want to use that to the maximum. Sunscreen. We need to start with the children. I don’t know about you folks but when I was a kid as soon as the period of the year about this time occurred, my family would send us out to get a nice tan so we’d be all protected. As you know, you don’t want to do that at all. But I’m sure that a lot of you have the same problems.
Causes of melanoma are genetic 11%, first degree relatives 1.7 time risk and, of course, sunlight. I don’t know if you’ve had many familial cases of melanoma in your group but I can remember when I was a resident at Minnesota, I was taking care of a lady, she was in her 30s, and there were 12 members of her family, all of them had died from melanoma except her and she was going to die very shortly thereafter. So this is a real problem for us and it’s going to get bigger. As you know, right now, they don’t recommend having studies of your patients. In other words, having breast cancer programs and having a melanoma program. So far most of the groups still don’t feel that that’s necessary. I’m not sure that’s true…

Cancer Prevention, Detection, and Chemotherapy

In the United States, there are some 1.25 million new cancer cases expected in 2006 and 550,000 deaths. Six million Americans have, or have had, a cancer. The types are lung, tongue, pharynx, larynx, esophagus, pancreas, bladder and cervix. Passive smoking in our area constitutes 53,000 deaths per year and 4000 lung cancer cases. So this is a real problem, this passive smoking and, as you know, there’s been a little bit of discussion of it in the papers recently. Not only do you have the passive smoking causing problems in terms of cancers but it also affects esophageal and patients who are having problems with shortness of breath as you are well aware.
When we talk about cancer control we want to tell them to stop and that’s very important. You know, most of us say, “Well, what’s the use of talking to them about it? They’re not going to do anything anyhow.” That’s not true. They really do pay attention to you folks and they will modify things. They can try Nicorette gum. Some of them like the patches. Either one of them we’ll find often they’ll tell you, “Well, it works the best if I just quit.” Then we have to educate children as to this. Get them out of cigarettes and all the problems related to that.
As far as most important areas to look at, diet is the most important and education of patients and families into prudent dietary habits is probably the second most cancer preventive activity. When we talk about this, we talk about a high fat diet. As you know that’s bad. That increases breast and colorectal. There are some recent studies that suggested adequate calcium and vitamin D reduce the incidence of cancer of the colon and of the rectum and this occurs throughout life.
Beta-carotene foods decrease the lung cancers and there’s a couple of studies that don’t really believe that, particularly from over in Sweden and those countries – Finland where the data they have suggests that it really doesn’t help much. In fact, it might make it worse.
The beta-carotene foods, of course, are being studied in lung cancer and head and neck cancers but as you know beta-carotene foods are toxic. They cause dryness, cheilosis, liver dysfunction and a rise in our lipids. All the kind of things we don’t want our people to have…

Diagnosis and Treatment of Breast Cancer 6

What are the short term side effects from chemotherapy? Clearly alopecia in most of the regimens used. Weight gain is very common. This always comes as a shock to patients. Fatigue is the overwhelming most common and problematic problem from adjuvant chemotherapy. Febrile neutropenia is quite rare. Neutropenia is quite common. It usually occurs with every course but febrile neutropenia is quite rare and hemorrhagic complications are even more rare.
Of more concern are the long term side effects from adjuvant chemotherapy particularly if you’re treating young women. It can cause premature menopause and then these women have usually not been thought to be eligible for hormone replacement therapy and are at risk for cardiovascular disease and osteoporosis.
If you look at women treated with adjuvant chemotherapy and compare them to women who have not had breast cancer and not been treated, their incidence of leukemia is actually fairly comparable. Now, there are some investigational arms who escalated doses of cytoxan where leukemia incidence appeared to be increased. But in the general adjuvant therapy we’ve given over the past few years, leukemia doesn’t appear to be increased, nor does cardiomyopathy.
Tamoxifen needs to be used at least more than two years and probably for five years and probably not for more than five years. At more than five years, there may actually be an ability for tumor cells to learn to use tamoxifen to grow and you have increased relapse of breast cancer with more than five years of tamoxifen. You also have an increased risk for other tumors, particularly uterine cancer. It clearly benefits people who are postmenopausal more than premenopausal and usually only those patients who are ER/PR positive will benefit the most. PR positive ER negative benefit also.
Tamoxifen, and you probably have heard so much about tamoxifen in the last few weeks you can’t stand it, probably benefits bone density and blood lipids. In the trial for prevention of breast cancer in normal women, they couldn’t really show that but with only four years followup I don’t think that’s so surprising and I think with longer followup they may be able to demonstrate that. But clearly in breast cancer patients we’ve known for a long time it reduces the risk of contralateral breast cancers by 50%. I think it reduces the risk of new breast cancers in the lumpectomy radiated breast and now we know that in women at risk for breast cancer who have not had breast cancer, tamoxifen reduces the risk of getting breast cancer.
What is the role of adjuvant radiation? I think the thinking about this has changed quite a bit in the past few months. I used to say that local radiation therapy only prevented relapse in the local area and didn’t do anything much for overall survival. There’s two very impressive articles in the New England Journal in October of last year and it showed that patients with any positive nodes receiving radiation therapy had a better survival when that was combined with chemotherapy versus chemotherapy alone. Most of the chemotherapy was with cytoxan methotrexate 5FU. Even in patients who had few nodes, one to three positive nodes, these are the patients who got radiation and chemotherapy versus chemotherapy alone, they seem to have a survival benefit.
In the past I had only applied radiation to patients with four or more positive nodes or large tumors or invasion of the chest wall or something like that. I am now radiating everyone with positive nodes. That may not be standard in all places.
What is the followup for patients who have had breast cancer and then adjuvant therapy or even just breast cancer? See a physician with a good history and physical every four months for the first two years and then every six months to complete five years and then yearly has been my practice and I think is fairly standard. I do a CBC and chemistry profile. You could argue that a CBC is not really necessary. The most important thing is clearly the physician breast exam, the yearly mammograms and other health care maintenance should be followed such as yearly pelvic exam, screening for blood in the stools and sigmoidoscopy after age 50.
Diagnosis and Treatment of Breast Cancer

Diagnosis and Treatment of Breast Cancer 5

In the node negative group, it’s a little more difficult to figure out but a conservative answer at this point in time, and this is changing kind of year by year, tumors more than a centimeter plus some other risk factor such as being ER/PR negative or having a high S phase, some people would say being HUR2 positive, even if they ER/PR positive, would make people treat them. Some people add in grading so if they’re poorly differentiated or moderately differentiated and have another one of these risk factors such as having a high S phase, they would give them systemic adjuvant therapy.

The choices for systemic adjuvant therapy, for estrogen receptor and progesterone receptor positive patients who are postmenopausal, hormone therapy can be as effective an adjuvant therapy as combination chemotherapy. For ER negative patients, combination chemotherapy is superior to hormone therapy and for all premenopausal women, regardless of their ER/PR status, combination chemotherapy is superior to hormone therapy. But hormone therapy may have a further additive benefit and those patients you may consider combined therapy. So chemotherapy is used for all premenopausal women and those postmenopausal women whose tumors are not much affected through hormonal manipulation.

Hormone therapy is useful for estrogen receptor positive postmenopausal women and my bent, and I think this is increasingly popular, is those women at low risk. So postmenopausal women, even if they’re ER positive with a number of positive nodes or other high risk factors, you may consider giving them chemotherapy then followed by hormone therapy. Premenopausal women who are ER positive would also be considered for chemotherapy then followed by tamoxifen. I don’t use tamoxifen and chemotherapy together and I don’t think most people do. It does increase your risk for clotting complications. If you sequence the therapy, it’s as effective and it avoids some of those clotting combinations. People clot on chemotherapy and they also have an increased risk for clotting on tamoxifen.

Adjuvant chemotherapy increases disease free survival more than overall survival. What that says is it just pushes back the time for relapse. In some patients it doesn’t actually cure them but in some patients it does absolutely cure them and you do add to quality life and you also do add to the bottom line a number of patients cured though not as many maybe as we’d like.

It’s clear you need more than one drug for adjuvant therapy and it’s increasingly clear that it’s much better to give good, high doses of chemotherapy over a short period of time than to string long doses over long periods of time and nobody should be getting adjuvant therapy for twelve months or more. Most adjuvant therapy is given over 12 weeks to 6 months, in that range.

This looks at patients given different doses of Cytoxan and Adriamycin 5-FU and this solid line, in terms of disease free survival and overall survival are those patients who are more aggressively dosed than patients who are given a lower dose. Dose does matter. Dose over time or dose intensity is a predictor for outcome.

These look at HUR2-nu expression and if you overexpress HUR2-nu, those patients who were HUR2 negative, they seem to fair pretty well whether they got high doses of chemotherapy or low doses of chemotherapy. But if you were going to get cured, you had to get high doses of chemotherapy if you overexpressed HUR2-nu. So I think HUR2-nu is a predictor for outcome. It also tells you how you have to treat patients. There’s also increasing information that hormone therapy is not useful for patients who overexpress HUR2-nu or their tumors overexpress HUR2-nu and that CMF probably isn’t very useful and that you need to use Adriamycin in good doses.

Diagnosis and Treatment of Breast Cancer 4

Tumor size does correlate with outcome. It’s not the strongest predictor of outcome but it certainly correlates and this just graphs tumor size against percent of disease free patients in five years. You can see as the tumor gets more than 5 cm, the chances to remain disease free gets less than 50%.
Nodes is the next way to stage and you either have negative nodes or positive nodes or N2 disease is nodes that have grown together or are matted. N3 disease is internal mammary nodes which, in fact, we don’t stage for very well but usually in patients who present with a real medial lesion, I will do a CAT scan to try and better assess those internal mammary nodes.
This correlates lymph nodes to disease free survival and lymph nodes are the biggest predictor of outcome in breast cancer. The predictive value increases with every positive node in a negative way. So if this is just the number of positive nodes against percent of disease free patients at five years, you can see that your chances to be disease free with ten or more positive nodes is less than 20%.
This is another way to look at that. If you have no positive nodes, your chance for relapse is about 20%, one to three about 60% and more than four positive nodes puts your chances to relapse in the 85% range. This, of course, has led us to target these patients with four or more positive nodes with more aggressive therapy such as high dose chemotherapy and autologous peripheral blood stem cell rescue or bone marrow rescue or get them into trials of more aggressive therapy.
If you have metastatic disease, then that makes you an M1. So it’s either you have metastatic disease or you don’t. Then you put these T and M classifications together. There’s only one way to be a Stage I breast cancer and that’s to have a tumor less than 2 cm, a T1 lesion, no nodes and no metastases. Anytime you have metastases, no matter what your T or your N, you’re a Stage IV.
Stage II can be all kinds of things and it’s easier to remember that Stage II is anything that’s not Stage I, III or IV. Stage III disease is anytime you have a T4 lesion, you’re going to be a Stage III. Let’s look at Stage III. Any T4 will put you in a Stage III. Any T3 with positive nodes is going to make you a Stage III. Any N2 disease will make you a Stage III and all the rest will be a Stage II. So the minute you have positive nodes, it makes you in Stage II or III. If it’s not N2 disease and it’s not a T4 lesion and it’s not a T3 lesion, you’ll be a Stage II.
If you go back and look at it, it makes a lot of sense. The only way you can be a T3 and still be a Stage II is not to have any positive nodes and that doesn’t happen very often. So all the T1 and N1 combinations make you a Stage II. Anytime you have nodes that aren’t N2 disease, you’ll end up being a Stage II usually.
This graph just shows you that this staging actually is pretty predictive and this is overall survival across years at 10 years. This black line at about 80% is Stage I disease. So no nodes tumor, 2 cm or less, this falls to about 50%. Anytime you have positive nodes, these are usually microscopically positive nodes, are a tumor that is greater than 2 cm. This line, Stage III disease, usually a big tumor or large matted nodes, puts you down to about 30-35% and you can see that there are no long term survivals in patients who have metastatic disease.
There are other prognostic features that we also consider. The one that’s most talked about, of course, is the estrogen and progesterone receptors. If you’re estrogen receptor positive and/or progesterone receptor positive you are less likely to relapse and have metastatic disease or if you do it takes a longer time. The S phase, the percent of cells that are in a dividing phase, usually determined by cell sorting, may have a predictive value and it’s becoming clear that the overexpression of the gene product from the epidermal growth factor gene or HUR2-nu is an independent predictor for outcome, independent of these other factors, and is probably in the future going to be increasingly used to predict risk of breast cancer.
Well, we use all these risk factors to decide who we think needs systemic therapy to try to eradicate microscopic disease and hopefully change that person from going on and relapsing from breast cancer to being cured of breast cancer. Clearly, when you saw a Stage II line that dropped right to 50%, all those patients are at high risk for relapse and they would be thought to need some sort of systemic adjuvant therapy to treat microscopic disease. So node positive patients, some sort of systemic adjuvant therapy.