SAN ANTONIOAlthough paclitaxel(Drug information on paclitaxel) (Taxol) is still being evaluated as a single agent in advanced breast cancer, to determine optimal dosing and schedule, it is also being studied for use in combination with other cytotoxic agents, as adjuvant therapy in early-stage disease, and as part of high-dose chemotherapy regimens used with stem cell transplant.
Speaking at a minisymposium at the San Antonio Breast Cancer Symposium, Eric D. Rowinksy, MD, director of Clinical Research, Cancer Therapy & Research Center, Institute for Drug Development, San Antonio, noted that the controversy over short versus long infusions cannot be settled by trials that do not use equitoxic dosing schedules.
3-Hour vs 24-Hour Infusions
He cited a Canadian/European study comparing a paclitaxel dose of 175 mg/m² given over three hours or 24 hours (with dose adjustments allowed) in three groups of advanced breast cancer patients:
- Those who had no prior chemotherapy.
- Those who had prior adjuvant therapy only.
- Those who had prior treatment for metastatic disease and adjuvant chemotherapy.
The majority of those receiving three-hour infusions were dose escalated because of low toxicity, but few patients receiving 24-hour infusions were dose escalated and many were de-escalated.
There were no significant differences overall in response, time to progression, and survival. A subgroup analysis showed no difference in response between the three- and 24-hour groups among the patients who had received adjuvant therapy or among those who had received metastatic plus adjuvant therapy. However, response rates did differ among those who had received no prior therapy, with a trend in favor of the 24-hour infusion.
"In patients who have not received prior therapy," he said, "I think there is a concern that they should probably get 24-hour infusions or 3-hour infusions at equitoxic dosing regimens, ie, higher doses of the drug should be used when given over three hours."
This study, he believes, did not compare equitoxic dosing regimens. In this trial, which involved frequent dosing changes, toxicities for the two infusion schedules converged at 225 mg/m².
Equitoxic dosing schedules are being tested by NSABP B-26, which is using 250 mg/m² of paclitaxel with G-CSF given over three or 24 hours. "I think this will more appropriately address the question of schedule," he said.
In his presentation, Andrew Seidman, MD, of Memorial Sloan-Kettering, agreed that the higher response rate with a 24-hour infusion in minimally treated patients "argues strongly that perhaps we should not be sacrificing efficacy for convenience, especially as front-line therapy or in the adjuvant setting."
A multicenter trial is comparing the maximum tolerated paclitaxel dose over 3 hours (250 mg/m²) with the MTD over 96 hours (140 mg/m²), and this trial may provide more definitive answers about the importance of the concept of prolonged infusion.
Dr. Seidman devoted part of his talk to studies designed to integrate paclitaxel into the management of earlier stage disease, ie, as adjuvant systemic therapy. Two important multi-center trials are ongoing, he said.
An Intergroup study is evaluating three different doses of doxorubicin(Drug information on doxorubicin) (Adriamycin) with a fixed dose of cyclophosphamide(Drug information on cyclophosphamide) followed by randomization to either four courses of paclitaxel or no further therapy. The NSABP B-28 trial is giving four cycles of standard AC (Adriamycin, cyclophosphamide), followed by either paclitaxel or no further therapy. Results are expected sometime before the year 2000.
Another speaker, Gabriel Hortobagyi, MD, of M.D. Anderson, focused on studies using paclitaxel in combination with other agents for metastatic breast cancer. Paclitaxel has been used in two-drug combinations with Adriamycin, mitoxantrone(Drug information on mitoxantrone) (Novantrone), fluorouracil(Drug information on fluorouracil), vinorelbine (Navelbine), cisplatin(Drug information on cisplatin) (Platinol), and cyclophosphamide, as well as in combination with radiation therapy.
A Promising Combination
A promising combination, developed by Dr. Anthony Greco and his colleagues at Vanderbilt, includes paclitaxel, mitoxantrone, fluorouracil, and leucovorin. In 32 patients at Vanderbilt, most of whom had received prior anthracycline therapy, this combination achieved a response rate of 45%, with response duration equivalent to that of most first-line chemotherapy regimens, Dr. Hortobagyi said.
He also described ongoing studies using paclitaxel in high-dose chemotherapy regimens with stem cell support. If high-dose chemotherapy programs are to be successful, he said, "we have to get away from the single high-dose cycle, which just does not make a lot of kinetic sense for a chronic and somewhat indolent disease like breast cancer. Repetitive high-dose therapies might be of greater interest."
In line with that thinking, Dr. George Raptis of the breast cancer group at Memorial Sloan-Kettering is giving two consecutive cycles of high-dose cyclophosphamide plus paclitaxel to mobilize peripheral blood stem cells for harvesting, followed by more myeloablative therapy with two cycles of high-dose thiotepa and paclitaxel plus stem cell support. Dr. Seidman said that this trial is ongoing "with a very high rate of conversion from partial to complete remission."
At M.D. Anderson Cancer Center, Dr. Hortobagyi said, researchers are giving four cycles of two different high-dose regimens: cyclophosphamide, paclitaxel, and carboplatin(Drug information on carboplatin) (Paraplatin) or cyclophosphamide, doxorubicin, and paclitaxel. The cycles are given every 28 days with stem cell support plus G-CSF. "While we have not completed these trials, I can report that these regimens produce a high response rate and complete remissions," he said.