SAN ANTONIOAlthough 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
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
(Adriamycin) with a fixed dose of 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 (Novantrone), fluorouracil, vinorelbine (Navelbine), cisplatin
(Platinol), and cyclophosphamide, as well as in combination with radiation
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.
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 (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,"