WEDNESDAY, November 8, 2000

"Therapy After Surgery: Can we Change Fate?
Results of the NCI Consensus Conference"

Adjuvant therapy is therapy given after surgery for breast cancer. For a majority of women with early stage breast cancer there is now a recommendation for some post-surgical treatment. These recommendations are based on clinical trials which show a reduction in the risk of having the cancer return when adjuvant treatment is used. Hormone, chemo, or radiation therapy have each shown to be effective in different situations. In general cancer trials are underpowered, that is, they are smaller than trials for other diseases. They accrue thousands of patients versus the tens of thousands of patients who participate in trials for treatment of coronary heart disease. The smaller numbers make it harder for us to accurately estimate how good different treatment options are. Risk reduction with Tamoxifen has been estimated at about 40% over 5 years, but the confidence interval for all trials is between 25 and 75%. For the individual there is still uncertainty, but the greater the number of patients in the combined trials, the better the estimate will be. This risk reduction must be balanced against the side effects of therapy. A recent trial has shown a benefit from adding Taxol to chemotherapy, but the Consensus Conference is withholding recommendation of Taxol across the board, based on the fact that another trial is not showing the same benefitóthe results are too preliminary.

The NIH holds Consensus Conferences periodically on areas of high public impact. They bring researchers together to look at the data and make general recommendations. Previously they have been held on node negative breast cancer, mammography, and genetic testing. This conference did not address surgery. The presumption is that women will receive effective surgical intervention, either lumpectomy with radiation or mastectomy. The procedure of identifying sentinel lymph nodes has lessened some of the long term complications of lymph node dissection such as lymphedema. Surgery has been a mainstay of treatment for a very long time. It has never been subject to the clinical trials process, except for very specific situations like doing lumpectomy vs. mastectomy. In those studies people were more interested in recurrence rates than the quality of life issues which many clinical trials deal with currently. Here at UCSF, we will be taking a set of subjective, patient derived measurements from everyone that has surgery here, to get a better handle on how to deal with patient issues. Although it is an issue for many advocates that surgeons donít seem to talk with oncologists relative to patient concerns, this is really not feasible, it requires a formal study and research design.

Has there ever been a clinical study of surgery vs. no surgery? No, because all treatment is based on first removing the tumor. In studies where patients had positive margins (the cancer was not removed completely), the recurrence rates are much higher. Dr. Tripathy could not support a trial in which patients were randomized to receive surgery. There is an emotional component as well, the bias in this country is toward mastectomy because many women just want to have the tumor out. The standard of care is much different with inflammatory breast cancer, many women do not get surgery with this disease.

Studies have shown the sentinel node to be 95% effective in diagnosing metastasis, what happens in the other 5%? In about 5% of the cases, there is a ìskip metastasisî (positive nodes found when the sentinel node was negative). This happens most often with inexperienced surgeons. Sometimes the sentinel node is not identified because other nodes appear to drain first, or some lymphatic flow may not go to the sentinel node. Anytime you deal with biology there can be some imperfections in the system. Even with classical dissection, it takes 10 or more nodes to be 99% accurate. Three large multicenter collaborative sentinel node studies are ongoing. They are looking at lymphedema and recurrence rates.

Are FNA or biopsy risk factors for the spreading cancer? This data has not been systematically captured, except in prevention studies where it has been shown to be a risk factor for getting cancer in the first place. The notion that stirring up cells can be bad is found in Tibetan medicine. They think that surgery can spread cancer cells. Western medicine believes that the advantage of taking the cancer out outweighs any disturbance to the cells.

Findings from the Conference

All patients who are hormone receptor positive, either ER+ or ER-/PR+ (positive staining in 10% of cells or more), should get Tamoxifen. This may be partly for the prevention effect in the other breast, and partly for lowering the local recurrence risk for DCIS. Even very low risk patients have something to gain from Tamoxifen. Dr. Tripathy thinks that this should be an individualized decision. What you get out of Tamoxifen depends on your risk to begin with, that is, it has a relative effect. A ‡ cm. tumor which is low grade and node negative is the threshhold at which Tamoxifen would not be recommended in his practice. The benefits of Tamoxifen at this point (about 1-2%) begin to be outweighed by the potential side effects of uterine cancer, stroke, deep vein thrombosis. The benefit from Tamoxifen is more in the prevention of cancer in the contralateral breast than in the prevention of a distant metastasis. Duration seems to be optimum at five years.

The Conference feels that anyone with a 1cm. tumor should be offered chemotherapy. For someone over the age of 50, this can be a very small benefit (1-2%). These are only guidelines, the important point is that there be an individualized, balanced discussion between patient and physician to discuss the risks and benefits of treatment options in a probabilistic way.

Combination therapies are better than single drugs. Optimum duration of AC is still unknown, but on the average they are a little more effective than CMF chemotherapy. One small study seems to show that Taxol shows a benefit in patients with positive nodes who are ER-, but was essentially left as unknown at this point.

High dose therapy is still considered investigational.

In premenopausal women who are hormone receptor positive, oophrectomy when combined with Tamoxifen may be as good or better therapy than chemotherapy. It is unknown whether oophrectomy has added value over Tamoxifen. For women who donít want chemotherapy, or who have a positive family history of breast or ovarian cancer, it may present an option.

Comparing Tamoxifen to aromatase inhibitors (drugs that inhibit the enzyme that converts androgens to estrogen made by the adrenal glands), the response was better in both Arimidex and Letrozole for postmenopausal women. FDA has approved Arimidex as a first line therapy for ER+ patients, and Letrozole is on the fast track. Study comparing Faslodex to Arimidex will be presented in San Antonio, but will show that Faslodex is somewhat better, but is a second line therapy (after progression on Tamoxifen). Fat tends to store higher local concentrations of estrogen, so postmenopausal women should consider body weight as a risk factor for developing cancer and for recurrence. This should be considered a continuous variable, there is not an absolute ideal body weight.

Not much data was presented on radiation. It is always recommended after lumpectomy, but not always after mastectomy. Historically, it has not been considered to have an impact on metastasis. New research on women with positive nodes who got chemotherapy and post mastectomy radiation show a better outcome with both distant metastasis and survival. Women with tumors greater than 5 cm. and four or more positive nodes, or tumors that involve the chest wall, have such a high recurrence risk that one should consider radiation. In the more moderate group, 1-3 nodes, it is considered a study question.

Findings from the prevention study do not support the statement that Tamoxifen causes weight gain. Although many women on Tamoxifen do gain weight, this may be more related to the exercise and dietary changes that occur in a woman who has been diagnosed with breast cancer. The diagnosis also tends to occur in many women at a time when they are going through menopause and consequent body changes may result in weight gain unrelated to any medications taken.

It is premature to consider HER2/neu status in decision making for early stage breast cancer. It is considered in the metastatic setting to decide whether or not to use Herceptin.

The FDA and Consensus Conference disagree on Taxol as treatment for early stage breast cancer. FDA approved it on the basis of one large study (3000 patients) comparing AC alone to AC plus Taxol. The recurrence rate was about 6% lower and the mortality rate was 2% lower (statistically significant) with the addition of Taxol. The Conference sees benefit only in hormone negative patients and is withholding recommendation pending results of other studies. Dr. Tripathy thinks that women with hormone receptor negative tumors and more than a few positive nodes should get Taxol.

Complete findings on the Conference can be found at http://odp.od.nih.gov/consensus