HOUSTONVarious combinations of a taxane and doxorubicin (Adriamycin) have been studied in patients with advanced breast cancer, with good response rates.
In this issue, we report on two presentations in this area from the San Antonio Breast Cancer Symposium: an ECOG study of paclitaxel (Taxol)-doxorubicin (Adriamycin) and a Canadian trial of docetaxel (Taxotere), doxorubicin, and cyclophosphamide . The question remains as to whether such combinations offer advantages over standard regimens such as FAC (fluorouracil, Adriamycin, cyclophosphamide).
Oncology News International interviewed Gabriel Hortobagyi, MD, the Nylene Eckles Professor in Breast Cancer Research at the University of Texas M.D. Anderson Cancer Center, for a perspective on this issue.
ONI: Do the taxane/doxorubicin combinations offer an advantage over FAC?
DR. HORTOBAGYI: The answer to that is somewhat complex. There is an enormous literature with FAC in advanced breast cancer showing a response rate of from 50% to 85%, depending on patient selection. The Milan study of paclitaxel/doxorubicin (Gianni et al) showed a response rate of 90%, with about a 40% complete remission rate. The problem is that these rates have not been confirmed by other trials.
The ECOG study of paclitaxel/doxorubicin, described in your report on page 2, and other confirmatory trials give a response rate of between 50% and 80%, which would put this combination in the same ballpark as FAC. The ECOG study also did not confirm the high complete remission rate seen in the Milan trial but, rather, suggests a complete remission rate similar to that of FAC.
Perhaps even more important, the remission durations and overall survival rates with paclitaxel/doxorubicin in the Milan trial and the confirmatory studies are not very different from FAC results.
Thus, the bottom line is that until I see a randomized trial of paclitaxel/doxorubicin versus FAC, I would say that these two combinations are about equivalent in efficacy in this setting.
ONI: What about the combination of docetaxel/doxorubicin?
DR. HORTOBAGYI: Preliminary results suggest that this combination is quite similar in efficacy to paclitaxel/doxorubicin and FAC, even though docetaxel appears to be superior to both paclitaxel and doxorubicin when used as a single agent. There are, however, differences in cost and toxicity. The taxane/doxorubicin combinations are more expensive than FAC.
Again, in the absence of randomized trials that look at therapeutic ratio and cost effectiveness, I would say that the two taxane/doxorubicin combinations are equivalent to, but not better than, the standard FAC regimen.
ONI: Even when the taxane regimens produce higher response rates than FAC, survival does not seem to increase. Can you comment on this?
DR. HORTOBAGYI: First of all, its not clear that the higher response rate with taxane combinations seen in some studies is a reproducible finding. But if you accept that for the sake of discussion, then I think you are seeing the same phenomenon as occurs with high-dose therapy with bone marrow transplant, where we clearly see a higher response rate and a much higher complete remission rate without any apparent effect on survival.
It may be that these combinations are more effective and can produce a slight improvement in response rate, but you need a much greater improvement in efficacy to affect survival.
ONI: Is cardiotoxicity a concern with the taxane/doxorubicin regimens?
DR. HORTOBAGYI: The Milan trial reported a 20% rate of congestive heart failure with paclitaxel/doxorubicin, which is four or five times higher than what you would observe with FAC. The original docetaxel/doxorubicin combinations have about the same cardiotoxicity as FAC. However, if you limit the total doxorubicin dose, as was done in the ECOG trial reported by Dr. Sparano, you can bring the cardiotoxicity of paclitaxel/doxorubicin down to the same range as the other two regimens.
My group at M.D. Anderson is currently completing a trial with paclitaxel/doxorubicin, in which we are doing a very close analysis of heart function, to determine why this combination may be more cardiotoxic.
ONI: So what do you recommend for patients not enrolled in a clinical trial?
DR. HORTOBAGYI: Outside of a protocol, I still recommend FAC to my patients, both in the adjuvant and metastatic breast cancer setting. I use paclitaxel or docetaxel as my drugs of choice as single agents in second-line treatment of breast cancer. In this setting, I think they are clearly better than other agents, including doxorubicin, although more expensive.