Kathleen I Pritchard, MD
Head, Clinical Trials & Epidemiology Toronto Sunnybrook Regional Cancer Centre Professor, Department of Medicine Faculty of Medicine, University of Toronto

Edited comments by Dr Pritchard

ATAC trial data update: 47-month follow-up

It shouldn’t have come as a surprise that anastrozole was better than tamoxifen in the adjuvant setting, given what we know from metastatic disease. This year’s updated results are important — it’s reassuring to see the efficacy of anastrozole holding up with little change in the toxicity profile. I expect we’ll have survival data in a year or so, and if that is significant, I think practice patterns will change quickly.

The unanswered questions that trouble me about anastrozole are: Why are we giving it for five years? Is it because giving tamoxifen for five years seemed to be best? Is three years better? Is seven years better? These questions don’t suggest anastrozole is an unacceptable alternative. We just seem to know less about it and its long-term side effects.

I use anastrozole in the adjuvant setting primarily for patients who can’t or won’t take tamoxifen, such as patients with a history of thrombophlebitis. Physicians in Canada use anastrozole as an alternative, rather than the standard, but patients are well-informed, and they ask about it. When I discuss the possible complications of tamoxifen, I tell my patients about anastrozole.

CALGB-9741: Dose-dense adjuvant chemotherapy

The data from CALGB-9741 is interesting. This trial had a two-by-two design, and one could argue whether you should look at the four individual blocks separately, or whether you can just interpret it as a two-by-two trial. The investigators’ interpretation is that the dose-dense approach is better than a standard approach.

We use doxorubicin/cyclophosphamide/paclitaxel as a standard regimen in clinical trials and in practice, so we’d be interested in knowing whether that combination is significantly better given in a dose-dense fashion. I don’t know if this study is powered to show that. The other question is whether the sequential therapy, given in a dose-dense fashion, is as good as any of the other three cells. If it is, that regimen may be the least toxic and that would be interesting to know.

Some people believe that these particular regimens should now be given in a dose-dense fashion. Some even believe that every regimen should be given in a dose-dense manner, and I think that’s wrong. It’s very intriguing that there may be a better approach, but it’s too early for me to change my practice. I’d like to see more data on the individual cells. Some data from other investigators support dose density, but other results do not, so it’s not clear to me whether we have enough data to support this approach.

Canadian study of neoadjuvant CEF versus dose-intensified EC

We are about to publish the results of a study comparing dose-intensive EC to CEF in locally advanced breast cancer in the Journal of Clinical Oncology. This was a large study of about 440 patients that we conducted with the EORTC and the Swiss group. We found that the dose-intensive EC was virtually the same as CEF. Patients in the dose-intensive EC arm were given G-CSF, and we saw less febrile neutropenia in that group but higher rates of thrombocytopenia and anemia, so it is a bit of a trade-off.

This isn’t a real dose-dense study because the drugs in the two arms aren’t the same. It’s more of a dose-intensive regimen because we gave the epirubicin and cyclophosphamide in half the time in the EC arm, and it was not superior. The curves separated somewhat, but there was never a significant difference between the two arms.

Canadian adjuvant trial comparing intensive CEF versus standard CMF in premenopausal patients with node-positive disease

At the 2002 San Antonio meeting, we presented data from our CMF versus dose-intensive CEF trial with a nine-year median follow-up. We designed the trial with a dose-intensive regimen to use as much anthracycline as we could. We used epirubicin in that arm because it is less cardiotoxic, and we matched the drug schedules in both arms.

We published the data in 1998 with five-year median follow-up. At that point, the data showed that the CEF was superior for disease-free and overall survival, and it remains superior at this much longer follow-up. We’ve looked at all the long-term side effects. We saw five cases of acute leukemia in the CEF arm versus one case in the CMF arm and four cases of congestive heart failure in the CEF arm versus one case in the CMF arm. So while there are some serious longterm toxicities, the rates are very low.

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