Research conducted at City of Hope National Medical Center in Duarte,
California, suggests that the most serious and costly side effects of
high-dose chemotherapy for breast cancer, including long-term
hospitalization and severe inflammation of the mouth, can be reduced
by a new approach to adjusting the dose of the chemotherapeutic agent
paclitaxel (Taxol). This approach, termed adaptive
control, adjusts dosage based on actual blood levels of
The results of this research were presented at the 1999 annual
meeting of the American Society of Clinical Oncology (ASCO) by James
H. Doroshow, MD, director of the Department of Medical Oncology and
Therapeutics Research at City of Hope.
Fivefold Difference in Paclitaxel Levels Seen
The study, which involved 102 patients, showed that blood
concentrations of paclitaxel vary widely from patient to patient.
Patients given the same dose by intravenous infusion can have as much
as a fivefold difference in blood concentrations of the drug.
Furthermore, the researchers found a correlation between blood
concentrations of the drug and serious side effects. Patients who had
the highest blood levels of paclitaxel were also those who suffered
from severe mucositis and required long hospital stays (more than a month).
To adjust the dose to reduce the variation in blood concentration,
the researchers developed a treatment model based on a technique
known as adaptive control. Each patient began high-dose chemotherapy
with the same dose of paclitaxel, but by the end of the second of 4
days of chemotherapy, the dose was increased or decreased to
compensate for low or high blood levels, respectively.
About one-third of the patients in the study needed an increase
in dose, one-third a decrease, and about one-third remained on the
same dose, said Dr. Doroshow. Dose in some patients was
increased by as much as 50%, while in others, it was decreased by 60%
to 70%. Using this treatment model, we were able to adjust the blood
concentration of paclitaxel to within plus or minus 10% of the
optimal concentration in each patient.
In the most significant result of the study to date, the researchers
found that reducing the dose of paclitaxel in patients with high
blood levels of the drug greatly reduced toxicity and other side
effects. None of the 57 patients treated using adaptive control of
paclitaxel required long hospitalizations.
Need for Longer Follow-up
Although the results of the study clearly show that adaptive control
benefits patients prone to high levels of paclitaxel, the question of
whether patients who manifest low levels of the drug will also
benefit from this approach remains open. In theory, low levels of
paclitaxel would be ineffective in killing breast cancer cells. By
raising blood levels of paclitaxel, adaptive control may help improve
tumor cell kill. Dr. Doroshow cautions, however, that longer
follow-up of patients is needed to determine whether adaptive control
improves long-term survival.