As in the case of ovarian cancer, the determination of optimal taxane dosing and scheduling has been the principal goal of several clinical trials in breast cancer. To date, it appears that dose may be a critical determinant of response for both paclitaxel(Drug information on paclitaxel) and docetaxel(Drug information on docetaxel) administered on short schedules (eg, paclitaxel over 3 hours and docetaxel over 1 hour).
The results of a randomized trial (BMS 48) of paclitaxel doses of 135 vs 175 mg/m² on a 3-hour schedule in women with metastatic breast cancer who had previously been treated with adjuvant chemotherapy only, chemotherapy for metastatic disease only, or chemotherapy in both adjuvant and metastatic settings, revealed no differences in response rates (29% [high dose] vs 22% [low dose]) or in median survival (11.7 [high dose] vs 10.5 months [low dose]). Progression-free survival was longer, however, with the higher dose (4.2 vs 3 months; P = .02). Severe neutropenia was not common with either dose; the incidences of grade 4 neutropenia were 19% and 28% in patients treated with paclitaxel 135 and 175 mg/m², respectively. Although this trial used nondisparate paclitaxel doses, these results indicate that neutropenia and antitumor activity may be congruent indices of drug effect.
These results led to the regulatory approval of paclitaxel 175 mg/m² (3-hour schedule) in women with metastatic breast cancer after failure of combination chemotherapy or relapse within 6 months of adjuvant therapy. The Cancer and Leukemia Group B is currently evaluating whether higher paclitaxel doses achieve greater activity in women with metastatic breast cancer. In this trial (CALGB 9342), patients are being randomized to treatment with paclitaxel doses of 175, 210, or 250 mg/m² on a 3-hour schedule.
There has been a paucity of studies addressing optimal dosing with docetaxel.
This is because the agent has been evaluated almost exclusively at a dose
of 100 mg/m² over 1 hour, which induces severe neutropenia in most
patients. Although substantial activity with less toxicity has been noted
at lower docetaxel doses (60 to 75 mg/m²), the results of nonrandomized studies indicate that there may be a positive dose-response relationship with docetaxel given on a 1-hour schedule at doses ranging from 60 to 100 mg/m². In women with metastatic breast cancer who have progressed on anthracycline-based chemotherapy, response rates with docetaxel on a 1-hour schedule have averaged 35% and 47% at doses of 60 and 100 mg/m², respectively.[51,65,75-77] Respective response rates have averaged approximately 55% and 48% in patients who have not received chemotherapy in the metastatic setting.[78-81] A multicenter randomized trial, in which women with metastatic breast cancer are receiving docetaxel doses of either 75 or 100 mg/m² on a 1-hour schedule, is ongoing.
Optimal paclitaxel scheduling was studied in a randomized trial (BMS 71) in which women with metastatic breast cancer were treated with paclitaxel 175 mg/m² infused over either 3 or 24 hours.[82,83] Women who had received no prior chemotherapy, adjuvant chemotherapy only, or chemo- therapy for metastatic disease with or without prior adjuvant therapy were eligible. Paclitaxel dose escalations to 200 and 225 mg/m², as well as dose reductions to 135 mg/m², were permitted, depending on the degree of myelosuppression during the previous course.
There were no differences in cumulative response rates (29% vs 31%), median progression-free survival (3.5 vs 4.6 months), or survival (9.8 vs 13.4 months) between the 3- and 24-hour groups, respectively. However, it was apparent that the starting doses were not equitoxic, which is demonstrated by the fact that 30% and 79% of women in the 3- and 24-hour groups, respectively, developed grade 4 neutropenia. In the 3-hour group, paclitaxel doses were increased on one or two occasions in 65% of patients, whereas dose reductions were required in only 5% of patients. In contrast, 34% of patients in the 24-hour group required dose reductions, and paclitaxel doses were escalated in 36% of patients.
It is also important to note that responses rates in patients receiving paclitaxel over 3- and 24-hour schedules were more disparate in women who had no prior therapy (34% vs 57%) compared with those who had adjuvant therapy only (36% vs 40%) or chemotherapy in both adjuvant and metastatic settings (24% vs 22%). These results suggest that the more aggressive 24-hour schedule does not result in a significant improvement in outcome in the palliative setting. However, more aggressive dosing schedules should be considered for patients with earlier stages of disease. This does not necessarily imply that the 24-hour or more prolonged schedules are superior and should be used exclusively. Instead, alternate aggressive dosing schedules, as gauged by their potential to induce a degree of toxicity similar to paclitaxel 175 mg/m² over 24 hours, might suffice. For example, paclitaxel doses ranging from 200 to 250 mg/m² on a 3-hour schedule appear to be equivalent toxicologically to paclitaxel, 175 mg/m² on a 24-hour schedule.
Sigmoid curves that describe the relationships between paclitaxel effect (eg, the percentage decrement in absolute neutrophil counts) as a function of the duration of drug exposure above a critical threshold concentration on 1-, 3-, and 24-hour paclitaxel schedules are depicted in Figure 1. It should be noted that the magnitude of the effects induced by all three dosing schedules converge. For the percentage decrements in neutrophil counts, convergence occurs in the 225- to 250-mg/m² dosing range.
It seems reasonable that clinical evaluations of optimal taxane scheduling should be performed using equitoxic regimens (ie, 1- to 24-hour schedules using doses at or near the point of convergence). The design of an ongoing National Surgical Adjuvant Breast and Bowel Project study (NSABP B26) may be better suited than BMS 71 to discern whether an optimal paclitaxel schedule truly exists. In this study, women with metastatic or locally advanced breast cancer are being randomized to treatment with paclitaxel, 250 mg/m² given over either 3 or 24 hours with G-CSF. These dosing schedules are much more likely to be equitoxic compared with those employed in BMS 71, minimizing potential confounding variables.
Prolonged Paclitaxel Schedules
Much attention has been paid to more prolonged (96-hour) paclitaxel dosing schedules since Wilson et al reported an impressive response rate of 48% in women with advanced breast cancer who had either progressed during or following treatment with anthracycline-based chemotherapy. Most patients, however, were treated with paclitaxel at its MTD on this prolonged schedule (140 mg/m² over 96 hours), and patients often required G-CSF support.
Building on this experience, Seidman et al demonstrated that 7 (25%) of 28 women with metastatic breast cancer who developed recurrent or progressive disease following treatment with short schedules of either paclitaxel or docetaxel responded to paclitaxel, 140 mg/m² over 96 hours with G-CSF support, if necessary. Both hematologic and nonhematologic toxicities were substantial in this study, and the range of taxane doses that the responding patients had previously received was not reported. However, it is likely that most patients received prior treatment with paclitaxel, 175 mg/m² over 3 hours, a dosing schedule that produces substantially less toxicity than does 140 mg/m² over 96 hours.
Although these results are provocative, they do not necessarily indicate that the 96-hour schedule is superior to shorter taxane schedules, and it is likely that the aggressiveness of the dosing schedule itself may have accounted for this impressive activity. Indeed, such an effect might have been achieved with shorter taxane schedules, albeit at higher doses. Similar caution should be used in interpreting the preliminary reports of responses in women with heavily pretreated metastatic breast cancer who are treated with docetaxel on an aggressive dosing schedule (eg, 100 mg/m² over 1 hour) after developing progressive disease during or after treatment with less aggressive taxane dosing schedules (eg, paclitaxel, 135 to 175 mg/m² over 3 hours).
Clinical trials designed to compare the intrinsic antitumor efficacy of the various taxanes should use equitoxic regimens. An ongoing phase III multicenter trial (NCI T93-0165) being conducted at Memorial Sloan-Kettering Cancer Center, the M. D. Anderson Cancer Center, Swedish Tumor Institute, and British Columbia Cancer Agency is more appropriately designed to address the scheduling issue. In this trial, women with metastatic breast cancer are randomized to treatment with equitoxic paclitaxel dosing schedules at two extremes, 140 mg/m² over 96 hours and 250 mg/m² over 3 hours.
In contrast, an ongoing randomized phase III trial (RPR 56976-311) that is designed to determine whether paclitaxel or docetaxel possesses superior activity in women with metastatic breast cancer who have received prior chemotherapy in the metastatic setting does not use equitoxic regimens. In this study, patients are being randomized to treatment with either docetaxel, 100 mg/m² on an 1-hour schedule, or paclitaxel, 175 mg/m² on a 3-hour schedule. The paclitaxel dosing schedule is substantially less aggressive in terms of its potential to induce myelosuppression, and possibly, its antitumor activity; therefore, this may be an unfair comparison.