Yesterday I posted a commentary on the STAR Trial presented at the ASCO meetings.
One of the issues that has received considerable attention in discussions about this trial is the importance of the increased risk of uterine cancer as a determining factor in which drug--raloxifene or tamoxifen—is a better prevention strategy for post-menopausal women who have a high risk of developing breast cancer.
But there is another factor that has received somewhat less attention, and that is the observation that the women taking tamoxifen had over twice as many hysterectomies during the trial compared to women who took raloxifene. There was no clear explanation for this difference, according to the researchers.
Maybe I can shed some light on the reasons for this, and why this may be an important consideration for women who are contemplating taking one of these medications to decrease their risk of breast cancer.
First, a bit of background.
Tamoxifen is a drug that has been used for over 3 decades. During that time, it has had a remarkable track record of helping women who had recurrent, hormone-sensitive breast cancer. Subsequently, it has also proven effective as an adjuvant therapy in both pre-menopausal and post-menopausal women in preventing recurrence of breast cancer after primary treatment. It has meaningfully increased survival rates from this disease.
Over time, it became apparent that tamoxifen had some undesirable side effects, including an increased incidence of deep vein thrombophlebitis (blood clots usually in the veins of the legs) and pulmonary embolism (blood clots that break off and travel to the lungs, and which can be a life-threatening situation).
However there was one side effect in particular that was most troublesome, and that was the increased risk of uterine cancer associated with long-term use of the drug. In one study, the risk of developing uterine cancer was 2 ½ times greater in the tamoxifen treated women compared to women taking a placebo, or “fake” pill.
Understanding this concern, the researchers closely followed the incidence of uterine cancer in women taking tamoxifen on the STAR trial compared to the women in the same trial who were taking raloxifene.
There were 19,747 postmenopausal women who participated in the STAR trial. As I have mentioned previously in yesterday’s blog entry, one half of the women took tamoxifen and one half took raloxifene.
To my surprise, a little over half of the women in each group had had a hysterectomy prior to entering this study. Although this seems high to me, I have no information to say whether this is typical for most post-menopausal women or not.
The implication of this fact, however, for the purposes of this discussion is that in the comments below we are essentially focusing on about 5000 women in each group who could have possibly developed uterine problems during their treatment with either tamoxifen or raloxifene while on the STAR trial.
Now, to the heart of the question: are there real differences between the two drugs and their effects on the uterus that women need to consider as they make their choice of preventive treatment with either raloxifene or tamoxifen?
36 women taking tamoxifen and 23 women taking raloxifene developed invasive uterine cancer during the course of their therapy on the STAR trial.
Looked at another way, for every 1000 women treated with tamoxifen, 2 women out of 1000 at risk (that is, with an intact uterus) on tamoxifen developed uterine cancer each year, compared to 1.25 women per 1000 at risk each year on raloxifene.
In plainer terms, for each year on treatment, for the approximately 5000 women on tamoxifen there were an average of 3.75 more cases of uterine cancer each year in the tamoxifen treated women compared to the raloxifene treated women (10/year with tamoxifen, and 6.25 with raloxifene).
(I should point out here that there is no evidence that raloxifene increases the risk of uterine cancer in this or prior studies.)
When looking at the data graphs provided in the articles published in the Journal of the American Medical Association, the difference in the incidence of uterine cancer between the two groups of women actually doesn’t begin to become evident until after 4 years of treatment on the drugs.
Here is the hooker: the difference between the two drugs with respect to the risk of uterine cancer is not statistically significant, which means that one cannot say with complete confidence that tamoxifen definitely increases the risk of uterine cancer compared to raloxifene. (For those scientists among you, the P value is 0.07.)
However, based on past experience with tamoxifen, one would have to err on the side of caution and say that these data are certainly suggestive of a difference in favor of raloxifene.
But the analysis shouldn’t stop there.
What was significant about the effects of the drugs on the uterus was that there was a clear and definite increase in uterine hyperplasia, both with and without atypia, in the women taking tamoxifen.
For a better understanding of this issue, I had to turn to my “in-house” gynecology expert, who happens to be my wife.
Hyperplasia refers to a proliferation, or thickening, of the cells lining the uterus.
In a post-menopausal woman, when this occurs, it can lead to the sign of post-menopausal bleeding. (By the way, whenever this happens and you are post-menopausal-- whether you are a woman taking tamoxifen or not-- it is critically important that you see your physician as soon as possible.)
When the doctor examines the uterus and takes a sample of the tissue, it can usually show one of three things: normal (without atypia), atypia, or cancer.
Normal means normal. There is no evidence of cancer or pre-cancer. Atypia is another word for pre-cancerous changes.
If the doctor finds cancer, then a hysterectomy is the next step. The same goes for atypia.
In the STAR trial, there were 84 women on tamoxifen who had hyperplasia of the uterus found during the course of their treatment, compared with 14 women on raloxifene. This difference was substantial and very significant.
Of the 84 women on tamoxifen with hyperplasia, 72 were normal on biopsy and 12 had atypia. Those 12 likely had a hysterectomy, which is the appropriate treatment according to my consultant.
For the women on raloxifene, there were only 14 women who developed hyperplasia. Of these women, 13 were normal on biopsy and 1 had atypia.
Going back to our “how many per thousand women treated” analysis, this essentially means that each year there were probably about 3.1 more hysterectomies for atypia in women taking tamoxifen compared to the women on raloxifene (3.35 hysterectomies per year for the 5000 women on tamoxifen and 1.25 for the 5000 women on raloxifene).
Now we get to a very interesting observation: There were over twice as many hysterectomies performed for reasons other than cancer on women taking tamoxifen compared to women taking raloxifene during the course of the study.
The actual numbers of hysterectomies done for reasons other than uterine cancer were 244 in the tamoxifen group, and 111 in the raloxifene group. Again, this difference was impressive, and clearly statistically significant. It is very likely a real difference between the two drugs.
But why such a big difference between the two groups? Why would doctors be doing so many more hysterectomies on women taking tamoxifen who had no evidence of cancer or pre-cancer in their uterus? (During the presentation at ASCO, the comment was made that the reason for this huge discrepancy was not clear.)
That is the question I posed to my wife.
Now, I must caution you that this is one doctor’s interpretation but it makes medical sense to me. And although I can’t back this up with data from the study, it may be an important consideration for you if you and your doctor are trying to make your minds up about which drug to take. (I would also point out that the data below are from the actual published research paper, so they are reliable.)
My wife pointed out that the gynecology community is very sensitive to the uterine cancer risk of tamoxifen.
Although post-menopausal bleeding is not a rare syndrome, in the gynecologist’s experience when it occurs in a post-menopausal women taking tamoxifen it has added significance and importance. The byword here is caution, especially in a woman who is usually taking tamoxifen because she has already had the diagnosis and treatment for a primary breast cancer.
So, when the doctor evaluates the patient for abnormal bleeding and she is on tamoxifen, even though the uterine biopsy may be negative for atypia or cancer, there remains a high level of concern that there may be cancer somewhere else in the uterus that was not “sampled” through the biopsy.
The net result is that combining the woman’s past history of breast cancer and her use of tamoxifen, even though the uterine biopsy is negative for any suggestion of cancer or pre-cancer, the doctor is going to be much more conservative and recommend a hysterectomy. They want to be certain they are not missing the small chance that there may be some small area of cancer elsewhere in the uterus in this woman at higher risk because she taking tamoxifen.
Mind you, as I said, this is a practical explanation for the observation of increased hysterectomies in the women in the STAR trial treated with tamoxifen. It is not based on a detailed analysis of the literature.
But if you are a woman at high risk of breast cancer who wants to take tamoxifen and you have not had a previous hysterectomy, the chances you will have a hysterectomy are about twice as high on tamoxifen compared to raloxifene. So, each year in the STAR trial, among 5000 women in each group, there were approximately 68 hysterectomies for reasons other than cancer in the women taking tamoxifen, compared to about 30 in the women taking raloxifene.
In my opinion, these are significant numbers and worthy of consideration in this discussion. The differences here are greater than any of the other side effects reported in this trial, and have real impact when we talk about the risks of hysterectomy with its own set of difficulties (such as hospitalization, cost, time off of work).
One final point is critical in this discussion: I probably would not have been going into this great a detail if I thought one drug was clearly better than the other.
What has stuck in my mind has been fact that although both drugs are equivalent in terms of decreasing the risk of invasive breast cancer for post-menopausal women at high risk, tamoxifen appears to also decrease the risk of non-invasive breast cancer (DCIS and LCIS), and raloxifene does not. At least that is what prior evidence has suggested.
In the STAR trial, the trend was in favor of tamoxifen being more effective in this regard, but again the data was very close to significance, but it didn’t cross the magic line where we would have considerable confidence that there was a real difference P value=0.052).
In fairness, one of the ASCO presenters made an argument based on his analysis that in fact there was no real difference regarding a reduction in the risk of non-invasive cancers.
But to me, this is a real concern since non-invasive cancers, although fortunately almost always curable, do require treatment and do reflect increased risk for the patient developing another invasive cancer at a later date. That is the main reason why I think there are tradeoffs between the two drugs, and neither was clearly superior to the other.
So what did the published data show in this regard, using the same type of analysis I have provided above?
In total, measuring both DCIS and LCIS, there would be about 7.5 non-invasive breast cancers per year in the 5000 women treated with tamoxifen who still had an intact uterus, and 10.5 non-invasive cancers for the 5000 women on raloxifene who had an intact uterus.
So, for women who still have their uterus intact and where the questions about uterine cancer would still be significant, there would have been about 3 fewer non-invasive cancers in the tamoxifen group compared to the raloxifene group (again, focusing only on those women who had not had a prior hysterectomy).
That compares to an extra 3.75 cases of uterine cancer and 3.1 cases of atypia (both requiring hysterectomies) each year, and an extra 38 hysterectomies in the women taking tamoxifen compared to the women taking raloxifene.
So that is the equation of the “trade-off” between the two treatments in somewhat absolute, stark terms: 3 fewer cases of breast cancer, compared to about 45 more hysterectomies, of which 7 will be done for cancer or pre-cancer of the uterus.
I don’t know how one makes a choice between these two options.
If your fear of uterine cancer is high, or your fear of gynecologic surgery is similarly elevated, then raloxifene would be your best bet. If you fear breast cancer, then tamoxifen might be your consideration. If you have already had a hysterectomy, then this part of the “toxicity” discussion is of no meaning to you since you are not at risk of uterine cancer.
As the investigators mentioned in their presentation, they are planning on continuing to follow these women. Perhaps some clarification will develop over time that will help sort out these questions further.
Until then, this information will hopefully give you something to use in discussions with your physician.