First-line therapy for patients with HER2-positive metastatic breast cancer

We now have two well-conducted, Phase III randomized clinical trials comparing the efficacy of a taxane in combination with trastuzumab to a taxane alone. The combination demonstrates an improvement in response rate, time to progression and survival.

In patients with HER2-positive metastatic breast cancer, my first-line recommendation would be a taxane and trastuzumab. Based on the Robert data, I may add carboplatin. I would not use doxorubicin-based chemotherapy as first-line therapy.

Continuing trastuzumab after disease progression

In my standard practice for HER2-positive metastatic disease, I use trastuzumab until disease progression or toxicity. The question of whether trastuzumab should be continued after disease progression is one we are wrestling with on a day-to-day basis. No one knows the answer.

NCCTG-N9831 adjuvant trastuzumab trial

N9831 is a randomized Phase III clinical trial building on several issues: (1) the relative importance of anthracyclines in the adjuvant management of patients with HER2-positive breast cancer, (2) the value of taxanes in patients eligible to receive adjuvant therapy, (3) the specific value of taxanes for patients with HER2-positive breast cancer, and (4) the value of weekly paclitaxel therapy for patients with breast cancer.

We were comforted by the data presented from CALGB-9741. That trial administered dose-dense chemotherapy with growth factor support once every two weeks, and in our trial we are using an even more dose-dense approach by administering paclitaxel on a weekly basis. The AC in our trial is still being given once every three weeks. Although we thought about potentially changing it to once every two weeks, we are not going to for several reasons.

First, we hypothesized that the advantage seen in CALGB-9741 may be due to the paclitaxel schedule. This theory is partially based on Marjorie Green’s data at MD Anderson, which evaluated the benefit of giving weekly paclitaxel compared to once every three weeks in the neoadjuvant setting. Additionally, we have data regarding the cardiac safety of AC administered once every three weeks followed by paclitaxel with or without trastuzumab. We didn’t want to introduce another factor that could impact on cardiac toxicity.

Right now we feel very comfortable with the schedule. We know patients in both the control or investigational arms are receiving dose-dense paclitaxel, which we think is perhaps the most important aspect of dose-dense treatment.

Cardiotoxicity in the NCCTG-N9831 adjuvant trastuzumab trial

In January 2002, we received notification of a few patients who developed congestive heart failure on NCCTG-N9831. Since we did not know if it was a real problem or if we just happened to have a few cases at the same time, we decided to temporarily halt accrual to the third arm of the trial — AC followed by paclitaxel and concurrent trastuzumab — until we had more time to do two things.

First, we had to evaluate the clinical course of those few patients who developed congestive heart failure. Second, we had to analyze the data based on all of the more than 700 patients enrolled up to that point. Eventually, we found that there were just a few patients who had developed congestive heart failure and that the patients who developed congestive heart failure had prompt improvements in their clinical symptoms with medication.

We submitted this information to our independent data monitoring committee. Since the cases of congestive heart failure were below the threshold we had established in the protocol in June 2002, it was recommended that we reopen accrual to this third arm of the trial. We meet with our cardiologists on a monthly basis to look at all of the data from this study. We have very good compliance with the cardiac testing we recommend as part of this clinical study.

Based on data in the metastatic setting, trastuzumab is associated with congestive heart failure. In the adjuvant setting, it is going to be a matter of assuring that the incidence of congestive heart failure is low and working on potential predictors of congestive heart failure. There are trials being devised to address this issue. We are looking at hypertension, the patient’s age and radiation therapy to the left chest as being predictors of cardiotoxicity. We are also doing quality control to avoid enhancing the potential cardiotoxicity of trastuzumab.

Theoretically, it makes sense that trastuzumab will have a role in the adjuvant setting. But first, we need to finish the clinical trials to prove that point. Then we will have to look at ways to ameliorate cardiotoxicity, even if it’s only a few percentage points.

Ejection fraction assessment in the NCCTG-N9831 adjuvant trastuzumab trial

We perform very thorough analyses of ejection fractions as part of NCCTGN9831, and we have submitted the data to the ASCO 2003 meeting. The specific data we will present are based on the evaluations of ejection fraction after AC chemotherapy. We have a lot of clinical experience with AC, but there’s a scarcity of data regarding its effect on ejection fraction. We found that AC, at a cumulative dose of 240 mg/m2, had a zero incidence of congestive heart failure, but there were decreases in ejection fraction. These decreases in ejection fraction tended to be transient.

Our opinion is that ejection fraction may be an interesting marker, but we don’t know if frequent measurements are good in terms of predicting who will develop congestive heart failure. At this time, I cannot comment on the effect of trastuzumab on ejection fraction.

Adjuvant trastuzumab use in and out of the clinical trial setting

If someone uses trastuzumab outside of the clinical trial setting, they’re essentially shooting in the dark. We do not yet understand the duration of therapy, the schedule to be used in combination with chemotherapy and the potential risks or benefits the patients may derive.

We have several clinical protocols available. I hope that every woman diagnosed with breast cancer tells her physician, “If I have this bad prognosis, I want to participate in the clinical trial that will help answer the question.”

The NSABP is also conducting a very good trial, also based on solid scientific principles. The NSABP trial has two arms — AC followed by paclitaxel, and AC followed by paclitaxel concurrent with trastuzumab for three months, followed by trastuzumab alone. The NCCTG trial has three arms. NSABP-B-31 is using paclitaxel once every three weeks, as in CALGB-9344, while N9831 is utilizing weekly paclitaxel.

Nonprotocol management of patients with node-positive breast cancer

The management of patients with node-positive breast cancer has become more complex in the last year, and we now have several very good regimens. However, we don’t have proof that any one of these regimens is absolutely better than another. The options today include the FEC regimen, which is not commonly used in the United States, TAC regimen and sequential AC followed by paclitaxel or docetaxel.

If I’m going to use AC followed by a taxane, I tend to use the dose-dense regimen published in the Journal of Clinical Oncology based on CALGB-9741, or I may still use AC once every three weeks followed by weekly paclitaxel. If I were to use docetaxel, then I would use AC once every three weeks followed by docetaxel once every three weeks, because of docetaxel’s tolerability when administered once every three weeks compared to weekly. When I use the AC every-two-week regimen, I use pegfilgrastim rather than filgrastim. While we do not have data on that, I believe it is much more convenient for patients, and we have incorporated it into our clinical practice.

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