An article was just released yesterday by the journal Cancer, which is published by the American Cancer Society. It deals with the question of whether or not adjuvant therapy with tamoxifen extends the lives of post-menopausal women treated with tamoxifen after primary treatment for breast cancer.
Ordinarily, I wouldn’t have paid much attention to the article for a variety of reasons, some of which are noted below. But several calls in response to a press release from the journal prompted me to take a closer look.
Tamoxifen is a drug that has been around for many years. I recall in the mid 1970’s when it first became available for the treatment of postmenopausal breast cancer. It was the first real alternative to estrogen therapy. Yes, you read that correctly: high dose estrogens were one of the primary hormonal treatments for women with breast cancer. And, they were effective although they did have side effects. We also used progesterone, and, not infrequently, prednisone. All of these were effective, and all had limiting side effects.
Then, along came tamoxifen. For oncologists at that time, it was close to a wonder drug: few side effects, a high degree of effectiveness, and a high degree of acceptance by patients. As an alternative to some of the other hormonal agents, and especially as an alternative to chemotherapy drugs with all of their attendant side effects, it was truly a blessing for many of our patients.
As years went on, side effects from tamoxifen became evident. Most notable were the increased incidences of venous thromboembolism (blood clots forming in the veins of the legs and traveling to the lungs) as well as cancer of the uterus. Although these side effects were and remain uncommon, they became of concern.
Eventually, a new class of hormonal-type agents called aromatase inhibitors was developed. These drugs are now demonstrated to be effective in both the adjuvant setting after the primary treatment of breast cancer, as well as for recurrent disease in post-menopausal women who have hormone sensitive breast cancer. They are moving into the mainstream, and for post-menopausal women they represent another viable option for the treatment of breast cancer.
As clinical trials for the adjuvant treatment of women with breast cancer progressed, it became evident that tamoxifen was effective for women with early stage breast cancer in preventing recurrence after primary treatment. One trial, reported in 1996 by the National Surgical Adjuvant Breast and Bowel Project, found that tamoxifen was effective in both pre- and post-menopausal women with truly early stage breast cancer (no lymph node involvement with cancer at the time of primary treatment). It significantly decreased the risk of recurrent breast cancer in all age groups. They also found that five years of treatment with the drug was sufficient to see the benefit and that, in fact, more treatment may be detrimental.
Tamoxifen is now considered a standard adjuvant treatment for many pre- and post-menopausal women who have primary breast cancer that is hormone sensitive.
The current study in Cancer, from a group of Italian investigators, looks at women who were treated with either two or five years of adjuvant tamoxifen in a study that took place in 1989 through 1996. In this report, the researchers “looked back” at these women and determined whether there was any difference in their death rates 12 years later after they had been treated on one of the two regimens. The women who participated were ages 50-70, and assumed to be post-menopausal.
Previous reports from this trial had demonstrated that there was in fact a benefit to 5 years of treatment with tamoxifen, compared to women treated for only 2 years, but there was no increase in overall survival.
The current study now reports that, on further analysis, women who were under 55 at the time they started the treatment had both an improved disease free survival and overall survival, but that women ages 55 and over had a similar improvement in disease free survival, but not overall survival. And, they report, it took 9 years for the difference in survival to appear in the younger women.
If this information confuses you, you are not alone. There are experts who understand the nuances of these various studies and somehow can keep all of them in mind and in some sort of order when they try to analyze the totality of the information and what it means. Make no mistake: there is a lot of digesting of a lot of information before it gets to the point where it is really needed, and that is in the care and decision making for a single patient.
The phone calls from the reporters were asking me what does this study really mean and how will it impact the care of women currently taking tamoxifen for the adjuvant treatment of breast cancer. My response was that it was hard to tell.
From a scientific point of view, there were several problems with how the study was constructed. We know more now about how to do these types of studies than we did 15 or 20 years ago. How we randomize patients into a trial, how we analyze the data using what we call “intent to treat” (that is, if you are randomized to a treatment you are considered part of that group no matter if you stop the treatment after the first dose), how we carefully pick out our primary goals of the study and how we determine in advance how many participants we need to best answer the question under investigation are some of the considerations in trial design that may not have been as rigorously followed in the past.
As a result, we now have more confidence in the results of our trials than may have been the case in some circumstances in the past.
Unfortunately, this trial didn’t have the benefits of currently accepted trial design, as was the case for many trials of that era. And the follow-up, although thorough for the question of whether the participants were alive or deceased, didn’t tell us whether the patient died from breast cancer or another cause. This could have told us if the women treated with tamoxifen may have died from causes other than breast cancer and may have avoided the pain and suffering that can come along with recurrent disease.
So what did I tell the reporters? First, in my opinion, this study really doesn’t add much to our current thinking about the treatment of breast cancer. Second, we are moving into a new and more complicated era in the adjuvant treatment of women with breast cancer who are post-menopausal and have hormone sensitive disease. This is especially true given the more recent reports of the effectiveness of the aromatase inhibitors.
My bottom line message was this: it is important for a woman to be informed about what her choices for treatment may be. And if she senses some confusion when confronted with all of the available information, she shouldn’t feel alone. Even people like me (who hopefully have some knowledge about this condition) can’t remember everything that has been written. But, most importantly, aside from a woman herself being informed, she needs to have a physician who is also informed and can explain rationally what treatment she or he is recommending, and why. It is the doctor’s responsibility to help guide you through the thicket of information so you can make the best decision for yourself. That’s what a good doctor is supposed to do.
What I also told the reporters was that I hope their stories on this report will underscore the need for women to speak with their physicians about their treatment, and not take this report as a signal that tamoxifen is not an effective drug. Far from it. Tamoxifen has withstood the test of time and served us well. There may be other therapies that appear to be more effective used either alone or following several years of tamoxifen, but in the right place, in the right time, for the right woman tamoxifen has proven itself again and again.
We’ll see what the news reports say. Hopefully, they will “get it right.” But, then again, they may not. In situations such as these, your oncologist should be your best guide. If they are not, maybe it’s time for a talk. And if you are still confused, give us a call at 1-800-ACS-2345 or check us out on the web at www.cancer.org and we will be glad to help.
Another source of information that I turn to repeatedly regarding the treatment of cancer is the National Comprehensive Cancer Center Network site at www.nccn.org. They have professional guideline algorithms which in my opinion represent the best example of what I call a “living guideline.” These are regularly updated and represent the best consensus recommendations of highly regarded oncologists and cancer centers. There is also some rather direct comment in the “manuscript section” when the experts don’t agree, which is unusual in any published guideline report.
Patient-friendly versions of their guidelines are also available for several different types of cancers through NCCN and the American Cancer Society contacts noted above.
One other brief postscript:
I took a look at my schedule yesterday and noted that I will be traveling for the next several weeks. I will do my best to put up regular postings during this time. For the next several days I will be out of the country, and will hopefully be able to find time and a safe internet connection. If I don’t, I hope you will understand.