Section 4
Randomized Trial of Docetaxel-Capecitabine versus Docetaxel

CLINICAL IMPLICATIONS

The docetaxel-capecitabine study is intriguing, and there’s certainly a biologic rationale for why that combination might be useful. In terms of toxicity, that combination would be a lot more tolerable with capecitabine dosed at 2,000 mg/m2, and I think you could do that without decreasing the efficacy. But causing a few more side effects — if survival really is prolonged — is something a lot of my patients would be willing to do. But it’s difficult to know how to use the data from this study in my practice, because the trial didn’t have a traditional crossover.

The best study we have on the question of combination chemotherapy in metastatic disease was ECOG 1193 34, which randomized patients into one of three arms — doxorubicin alone, paclitaxel alone or the combination. The two single-agent arms crossed over to the other single agent at the time of progression. The combination resulted in a slightly higher response rate and a slightly longer time to progression but no difference in quality of life and overall survival.

—Kathy M i l l e r, MD

One could argue this either way. The issue is: We don’t have crossover data, so it’s all theoretical, although there is pre-clinical synergism. But we don’t see too many trials with survival advantages in late-line metastatic breast cancer. So, I’m not willing to say that it would be just as effective to give these agents sequentially. I’d rather err on the side of going with what we know, than just saying,“Oh, it’s very likely to be the same.” That’s too nihilistic for me.

There are certain situations in treating metastatic breast cancer patients when we really want to have the greatest possible impact on survival and tumor control — and those are women with greater tumor burden, maybe a little bit more rapidly progressive disease — where often times we think about using combination chemotherapy. Up to now, there really hasn’t been clear evidence there was any benefit to giving combination therapy as opposed to sequential single agents, and the sequential single agent theory had become very popular over the last several years. But nonetheless, there are times where you turn towards combination chemotherapy, and that’s when we can turn to the docetaxel-capecitabine combination, because it is one of the rare instances where you can actually say there is a survival advantage. That’s not to say that there aren’t going to be women for whom sequential use of single agents is not more appropriate, particularly women with relatively asymptomatic disease or indolent disease.

—Joyce O’Shaughnessy, MD

The trial was based on some very excellent pre-clinical science, and clinically there’s some excellent data in colorectal cancer related to intratumoral levels of thymidine phosphorylase.37 So, the scenario makes great sense that patients receiving docetaxel had upregulation of thymidine phosphorylase and supports the outcome of the trial. On the other hand, patients with metastatic disease aren’t cured.

So, here we have findings that perhaps can help us find a more effective regimen that could potentially improve curability in the adjuvant setting with a lower tumor volume. Patients who would be candidates for this combination might be those with extensive prior anthracycline therapy and perhaps more rapidly progressive breast cancer — lymphangitic spread, recurrent pleural effusion, perhaps liver metastases — that you haven’t been able to control. If the patient is having major symptoms or rapid progression, there is an indication to use combinations that have higher response rates, because a month or two could make a big difference. But these tend to be a minority of the patients in clinical practice.

—Hyman Muss, MD

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