NCI Investigating Optimal Use of Paclitaxel in Breast Cancer

PARIS--Paclitaxel (Taxol), the flagship of the new taxanes, hasbeen hailed as a pharmacologic breakthrough, but its ideal usein the treatment of breast cancer is still a matter of debate.Speaking at the Sixth International Congress on Anti-Cancer Treatment(ICACT), National Cancer Institute oncologist Joyce O'Shaughnessyattempted to answer the most compelling unanswered questions aboutpaclitaxel use.

Dose and Infusion Duration

"Paclitaxel is a very active single agent in previously untreatedpatients with metastatic breast cancer, as well as in those previouslyexposed to doxorubicin, although complete responses occur primarilyin minimally pretreated patients," Dr. O'Shaughnessy said.

Doses of 200 to 250 mg/m² have generally been used as first-linetreatment, she said, but there does not appear to be any evidencethat doses over 175 mg/m² are superior as salvage therapy.

Scheduling of single-agent paclitaxel can be "tricky,"she said. In a recent randomized multicenter European trial ofpreviously untreated women, a 24-hour infusion yielded a responserate minimally superior to that of a 3-hour infusion, but at thecost of greater toxicity.

On the other hand, she said, side-by-side comparison of data fromMemorial Sloan-Kettering and the NCI indicates that, in patientsgiven previous chemotherapy, a 24-hour infusion of 175 mg/m²offers no advantages over a 3-hour infusion. However, a growingexperience suggests that 96-hour infusions might be beneficialin patients who fail to respond to 1- to 3-hour taxane infusions.

Dr. O'Shaughnessy and her colleagues at the NCI are now finishingup a phase I study of 14-day outpatient infusions of paclitaxel."What we have found to date is that patients who were startedat doses lower than the maximum tolerated dose of 175 mg/m²developed a tolerance phenomenon and could be escalated all theway to dose level 9 (273 mg/m²) without significant dose-limitingtoxicity," Dr. O'Shaughnessy said.

Randomized studies are ongoing in Europe and Australia to comparesingle-agent paclitaxel with standard chemotherapy options asfirst-line therapy for metastatic breast cancer, she said.

Recent studies have turned up an interaction between paclitaxeland doxorubicin that may have crucial ramifications for the orderin which the two agents are administered in combination.

Evidence that paclitaxel increases serum doxorubicin concentrationshas been invoked to explain the finding that administration ofpaclitaxel prior to doxorubicin is associated with more severemucositis than the administration of the anthracycline prior topaclitaxel.

Likewise, Dr. O'Shaughnessy said, a slowing of doxorubicin clearanceby paclitaxel may have accounted for both the "astoundinglyhigh" response rates and the 21% incidence of congestiveheart failure reported in a recent study from Dr. Gianni Bonadonna'sgroup at the National Tumor Institute, Milan.

Dr. O'Shaughnessy and her coworkers are now piloting a biweeklyregimen consisting of a 72-hour infusion of paclitaxel plus high-dosecyclophosphamide with G-CSF (Neupogen) support. She said thatthe combination was "safe and associated with significantantitumor activity."

Combination therapy with paclitaxel followed by cisplatin (Platinol)also looks promising, she commented.

"The logical thing to do with such an active regimen formetastatic breast cancer is to move it into the adjuvant settingof node-positive disease as soon as possible," Dr. O'Shaughnessysaid. Both the Intergroup and the NSABP are now looking at doxorubicinplus cyclophosphamide, 600 mg/m², followed by either a 3-hourpaclitaxel infusion or control.

The NCI team has demonstrated the safety of a regimen consistingof five cycles of dose-intensive 5-fluorouracil plus leucovorin,doxorubicin (Adriamycin), and cyclophosphamide (FLAC), followedby five cycles of 96-hour paclitaxel infusions as adjuvant therapyfor stage II and III breast cancer.

In addition, the NCI researchers have piloted a dose-intensiveadjuvant strategy for patients with four or more positive nodes,consisting of high-dose cyclophosphamide and doxorubicin withG-CSF every 2 weeks for three cycles, followed by 96-hour infusionalpaclitaxel every 2 weeks for three cycles.

"Once we know a little more from the ongoing studies of metastaticbreast cancer, we'll be able to bring that dose and schedule ofpaclitaxel into the adjuvant setting," Dr. O'Shaughnessysaid. "It's still an open question at this time."

P-glycoprotein Blockers

Dr. O'Shaughnessy also described the use of P-glycoprotein (Pgp)inhibitors as a promising technique for forestalling resistanceto paclitaxel. She and her colleagues at the NCI have conducteda phase I study using R-verapamil, to determine whether this P-glycoproteinblocker could reverse paclitaxel resistance in heavily pretreatedwomen with metastatic breast cancer.

Patients whose tumors were progressive or stable after escalatingdoses of paclitaxel were crossed over to receive oral verapamil,every 4 hours for 24 hours, followed by a 3-hour infusion of paclitaxeland additional verapamil for 18 hours.

"We were very happy to see that we could safely achieve levelsof 4 to 10 µmol of verapamil, which has been shown in vitroto be the concentration required to inhibit Pgp," Dr. O'Shaughnessynoted.

The NCI group defined the maximum tolerated dose as 200 mg/m²of paclitaxel given over 3 hours in combination with R-verapamil,225 mg/m². They then randomized patients to receive eitherpacli-taxel alone in cycle 1, followed by pac-litaxel plus verapamilin cycle 2, or paclitaxel plus verapamil in cycle 1, followedby paclitaxel alone in cycle 2.

Lower Hematologic Nadirs

They observed that adding R-verapamil to paclitaxel slowed theclearance and increased the Cmax of paclitaxel, effects that translatedclinically into lower hematologic nadirs and some increase inneurotoxicity over multiple cycles.

In addition, the NCI data suggest that upregulation of Pgp isat least one mechanism of resistance mounted in response to paclitaxel.Dr. O'Shaughnessy and her colleagues found that, prior to paclitaxeltherapy, breast cancer cells in pleural effusion showed only alow level of staining for Pgp, whereas after patients had becomerefractory to paclitaxel, there was a shift toward a higher proportionof Pgp-positive cells.

"I would eventually like to see a randomized study in patientswith metastatic breast cancer of paclitaxel vs the combinationof paclitaxel and R-verapamil or another Pgp blocker, such asthe cyclosporine analog PSC-833, which is currently in phase Itrials," Dr. O'Shaughnessy said. "When a drug is asexquisitely transported by Pgp as is paclitaxel, it makes senseto see whether you get an incremental benefit in efficacy by addingan effective blocker of Pgp," she concluded.