New Approach Reduces Side Effects of High-Dose Chemotherapy
Atlanta, May 18, 1999 Research conducted at City of Hope Cancer Center in Los Angeles suggests that the most serious and costly side effects of high-dose chemotherapy including long-term hospitalization and severe inflammation of the mouth can be reduced by a new approach to adjusting dosage of the chemotherapy agent Taxol (Paclitaxel). This approach, termed "adaptive control," adjusts dosage based on actual blood levels of Taxol. The results of the research were presented at the 1999 American Society of Clinical Oncology's (ASCO) Annual Meeting by james H. Doroshow, MD, director of the department of Medical Oncology and Therapeutics Research at City of Hope.
In both high-dose and conventional chemotherapy, the dosage of chemotherapy agents is based on the surface area of the patient. The therapeutic effect, however, is determined by the actual concentration of chemotherapy agent in the blood, which can vary from patient to patient due to differences in metabolism.
Taxol is considered the most effective drug in breast cancer treatment. City of Hope studies conducted over the past four years have helped establish the optimal therapeutic doses for high-dose chemotherapy regimens, which are deliverd intravenously. But in a departure from standard chemotherapy research, the researchers also measured the blood concentration of Taxol during treatment and established the optimal therapeutic level of this drug.
The research, which involved 102 patients, showed that blood levels of Taxol vary widely -- patients given the same dose by intravenous infusion can have blood concentrations differing by as much as five-fold. Importantly, the researchers found a correlation between blood concentrations of Taxol and serious side effects -- patients who had the highest levels of Taxol in their blood were also those who suffered from severe mucositis (inflammation of the mouth) and required long hospitalizations (more than a month).
To adjust dosage 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 dosage of Taxol, but by the end of the second of four days of chemotherapy, the dosage 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 dosage, one-third a decrease, and about one-third remained on the same dosage," says Dr. Doroshow. "Dosage in some patients was increased by as much as 50 percent, while in others it was decreased by 60 or 70 percent. Using this treatment model, we were able to adjust the blood concentration of Taxol to within plus or minus 10 percent of the optimal concentration in each patient."
In the most significant finding of the study to date, the researchers found that reducing Taxol dosage 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 Taxol required long hospitalizations. While clearly showing that adaptive control benefits patients prone to high levels of Taxol, the research leaves open the question of whether patients prone to low levels of Taxol will also benefit from this approach. In theory, low levels of Taxol would be ineffective at killing breast cancer cells. By raising blood levels of Taxol, adaptive control may help improve tumor cell kill. Dr. Doroshow cautions, however, that longer-term follow-up of patients is needed to determine if adaptive control improves long-term survival.