Expanding Uses of Taxol Therapy in Breast Cancer

SAN ANTONIO—Although paclitaxel (Taxol) is still being evaluated asa single agent in advanced breast cancer, to determine optimal dosing andschedule, it is also being studied for use in combination with other cytotoxicagents, as adjuvant therapy in early-stage disease, and as part of high-dosechemotherapy 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 thatthe controversy over short versus long infusions cannot be settled by trialsthat do not use equitoxic dosing schedules.

3-Hour vs 24-Hour Infusions

He cited a Canadian/European study comparing a paclitaxel dose of 175mg/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 escalatedbecause of low toxicity, but few patients receiving 24-hour infusions weredose 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 betweenthe three- and 24-hour groups among the patients who had received adjuvanttherapy or among those who had received metastatic plus adjuvant therapy.However, response rates did differ among those who had received no priortherapy, 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-hourinfusions or 3-hour infusions at equitoxic dosing regimens, ie, higherdoses 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 thetwo infusion schedules converged at 225 mg/m².

Equitoxic dosing schedules are being tested by NSABP B-26, whichis using 250 mg/m² of paclitaxel with G-CSF given over three or 24hours. "I think this will more appropriately address the questionof 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 minimallytreated patients "argues strongly that perhaps we should not be sacrificingefficacy for convenience, especially as front-line therapy or in the adjuvantsetting."

A multicenter trial is comparing the maximum tolerated paclitaxel doseover 3 hours (250 mg/m²) with the MTD over 96 hours (140 mg/m²),and this trial may provide more definitive answers about the importanceof the concept of prolonged infusion.

Dr. Seidman devoted part of his talk to studies designed to integratepaclitaxel into the management of earlier stage disease, ie, as adjuvantsystemic 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 randomizationto either four courses of paclitaxel or no further therapy. The NSABP B-28trial is giving four cycles of standard AC (Adriamycin, cyclophosphamide),followed by either paclitaxel or no further therapy. Results are expectedsometime before the year 2000.

Another speaker, Gabriel Hortobagyi, MD, of M.D. Anderson, focused onstudies using paclitaxel in combination with other agents for metastaticbreast 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 radiationtherapy.

A Promising Combination

A promising combination, developed by Dr. Anthony Greco and his colleaguesat Vanderbilt, includes paclitaxel, mitoxantrone, fluorouracil, and leucovorin.In 32 patients at Vanderbilt, most of whom had received prior anthracyclinetherapy, this combination achieved a response rate of 45%, with responseduration equivalent to that of most first-line chemotherapy regimens, Dr.Hortobagyi said.

He also described ongoing studies using paclitaxel in high-dose chemotherapyregimens with stem cell support. If high-dose chemotherapy programs areto be successful, he said, "we have to get away from the single high-dosecycle, which just does not make a lot of kinetic sense for a chronic andsomewhat indolent disease like breast cancer. Repetitive high-dose therapiesmight be of greater interest."

In line with that thinking, Dr. George Raptis of the breast cancer groupat Memorial Sloan-Kettering is giving two consecutive cycles of high-dosecyclophosphamide plus paclitaxel to mobilize peripheral blood stem cellsfor harvesting, followed by more myeloablative therapy with two cyclesof high-dose thiotepa and paclitaxel plus stem cell support. Dr. Seidmansaid that this trial is ongoing "with a very high rate of conversionfrom partial to complete remission."

At M.D. Anderson Cancer Center, Dr. Hortobagyi said, researchers aregiving 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 supportplus G-CSF. "While we have not completed these trials, I can reportthat these regimens produce a high response rate and complete remissions,"he said.