Adjuvant trial of capecitabine as therapy for elderly women

Hy Muss is conducting an adjuvant trial comparing either AC or CMF to capecitabine in elderly women. We do not have convincing data that adjuvant chemotherapy provides a benefit to women over the age of 70. In the Overview Analysis, there was a decrease in the risk reduction with every decade of life. However, there were few women over the age of 70 included in that analysis. Today, many women over the age of 70 have a good performance status and no comorbid conditions.

Yet there is still reluctance, especially in women with ER-positive tumors who will receive adjuvant tamoxifen or perhaps anastrozole, to use adjuvant chemotherapy. We actually need to compare adjuvant hormonal therapy with or without chemotherapy in elderly women with ER-positive breast cancer. If chemotherapy improves survival, then we can look for regimens that are equally effective and less toxic. In women with ER-negative breast cancer, most physicians are comfortable using adjuvant chemotherapy. Therefore, Hy Muss’ trial may be more applicable to elderly women with ER-negative breast cancer.

Adjuvant trastuzumab in HER2-positive, node-positive disease

NSABP B-31 evaluates adjuvant trastuzumab in women with HER2-positive, node-positive breast cancer. It is a two-arm trial comparing doxorubicin/ cyclophosphamide followed by paclitaxel with or without trastuzumab. As demonstrated by the trials in metastatic disease, trastuzumab cannot be given concomitantly with anthracyclines because of the potential cardiac toxicity. We are evaluating whether they can be given sequentially. B-31 has very strict criteria for the evaluation of cardiac toxicity. An interim analysis conducted by the Data Safety Monitoring Committee did not find a significant incidence of cardiac toxicity associated with the addition of trastuzumab. In contrast, the NCCTG, because of cardiac toxicity, had to suspend the arm of trial 9831 that administered concomitant trastuzumab and paclitaxel.

In B-31, we conducted an analysis of the first 100 patients’ HER2 assays. There was significant inconsistency between the HER2 results obtained from nonreference laboratories and those obtained with FISH at a central laboratory. The protocol now mandates that a reference or central laboratory perform the IHC assay before the patient is enrolled on the trial.

In the metastatic setting, trastuzumab in combination with chemotherapy prolongs median survival by five months. We hope that adjuvant trastuzumab will also be of benefit. In light of the cardiac toxicity, we must, however, be careful not to adopt trastuzumab into the adjuvant setting before we have results from randomized clinical trials. Theoretically, one could justify using trastuzumab in a woman with inflammatory breast cancer; I would still be very hesitant without proven benefit, especially in lieu of the side effects.

Adjuvant clodronate

NSABP B-34 will evaluate adjuvant clodronate, an oral bisphosphonate, in women with node-negative and node-positive breast cancer. Data from Germany as well as the Canadian and UK trials demonstrate that clodronate reduces bone and non-bone metastases and also improves survival. B-34 will randomize 3,000 women to three years of clodronate or placebo. The choice of adjuvant therapy will be left to the investigator’s discretion. We chose clodronate for this trial because it is the only bisphosphonate with data in the adjuvant setting.

Clodronate is well tolerated compared to alendronate (Fosamax®). If the B-34 results are positive, hopefully clodronate will be FDA approved. In lieu of the ATAC trial results, it may be reasonable to combine an aromatase inhibitor with a bisphosphonate as adjuvant therapy. Eventually, NSABP plans to compare the bisphosphonates to find the best one. It may, however, be difficult to use an intravenous bisphosphonate in terms of patient acceptability.

Anastrozole in women with DCIS

We are close to initiating a trial in women with DCIS that will compare anastrozole to tamoxifen. This trial will replicate the ATAC trial in women with DCIS. Since these are very low-risk women, it is important to determine whether the risk-benefit ratio will justify the use of an aromatase inhibitor. The additional 50% reduction in contralateral breast cancer, associated with anastrozole in the ATAC trial, justifies the design of this trial in women with DCIS.

Implications of the ATAC trial results

This is the first time that an agent appears to be superior to tamoxifen. Even though the disease-free survival and contralateral breast cancer data are promising, it is still not known whether this will translate into a survival advantage. In elderly patients in whom one wants to avoid thromboembolic events and endometrial cancer, the ATAC trial results may lead to the adoption of anastrozole as adjuvant therapy. Eventually, anastrozole may be used in most postmenopausal women. In terms of the ongoing NSABP trials, we currently only allow the use of tamoxifen. However, that may have to change. For our new trials, the NCI is already stating that we must allow the use of an aromatase inhibitor. In Europe, the IBIS trial will compare tamoxifen to an aromatase inhibitor as preventative therapy.

Proposed trial of XT in ipsilateral breast tumor recurrence or local regional recurrence

We are planning a trial to determine the value of chemotherapy in patients with ipsilateral breast tumor recurrence (IBTR) or local regional recurrence. These patients have not been studied prospectively, and it is not known whether chemotherapy can improve survival. Patients with IBTR and local regional recurrence have a 50%-60% and 80%-90% risk respectively, of developing systemic disease in the next five years. In ER-positive patients, we will compare hormonal therapy with or without capecitabine/docetaxel. In ER-negative patients, we will compare capecitabine/ docetaxel to no treatment. Since most of the patients will have received either an anthracycline or alkylating agent as adjuvant therapy, we chose docetaxel as a noncross-resistant agent. Capecitabine was added to obtain the maximum benefit.

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