Lung Cancer
Early phase II trials of paclitaxel(Drug information on paclitaxel) and docetaxel(Drug information on docetaxel) in patients with both non-small-cell and small-cell lung cancers, as well as in other tumor types, were performed using relatively aggressive dosing regimens (paclitaxel, 200 to 250 mg/m² over 24 hours, and docetaxel, 100 mg/m² over 1 hour). There have been only limited attempts to rigorously address questions regarding optimal dosing and scheduling using randomized trial designs in these tumor types. For both paclitaxel and docetaxel, comparisons of the results of phase II studies involving patients with similar relevant demographic characteristics suggest that there may be dose-response relationships that parallel dose-toxicity relationships, particularly on short taxane schedules.
For example, response rates in chemotherapy-naive patients with non-small-cell lung cancer treated with docetaxel, 60, 75, and 100 mg/m² on a 1-hour schedule, were 23%, 25%, and 31%, respectively.[85] For paclitaxel given on a 1-hour schedule to both previously treated and chemotherapy-naive patients with non-small-cell lung cancer, negligible toxicity and anti-tumor activity (2 responses in 17 patients [12%]) were reported at the 135-mg/m² dose level. A dose of 200 mg/m² resulted in much greater toxicity and antitumor activity (11 responses in 36 patients [31%]).[62]
A major concern during the development of the cisplatin(Drug information on cisplatin) (Platinol)/paclitaxel regimen was that the MTD of paclitaxel on a 24-hour schedule in combination with cisplatin (135 mg/m²) was significantly lower than the paclitaxel dose (250 mg/m²) that was determined to be active in early phase II studies in untreated patients with non-small-cell lung cancer. Since neutropenia was the principal toxicity of paclitaxel combined with cisplatin, phase I studies of the regimen subsequently focused on using G-CSF to enable further dose escalation of paclitaxel combined with cisplatin. In these trials, peripheral neurotoxicity precluded repetitive administration of paclitaxel doses above 250 mg/m² (day 1) on a 24-hour schedule followed by cisplatin 75 mg/m² (day 2) and G-CSF.
Randomized Trial
In view of the acceptable toxicity profile demonstrated for cisplatin (75 mg/m²) combined with higher doses of paclitaxel (250 mg/m²) plus G-CSF, the Eastern Cooperative Oncology Group (ECOG 5592) conducted a randomized trial of chemotherapy-naive patients with metastatic non-small-cell lung cancer. Patients received either standard therapy, consisting of etoposide(Drug information on etoposide) (VePesid), 100 mg/m² on days 1 to 3, and cisplatin, 75 mg/m² on day 1; or cisplatin, 75 mg/m², combined with either low doses of paclitaxel, 135 mg/m² on a 24-hour schedule, or high doses of paclitaxel, 250 mg/m² 24-hour schedule, plus G-CSF.[86]
Response rates in both the high- and low-dose paclitaxel arms (26.5% and 32.1%, respectively) were superior (P less than .001) to the rate in the etoposide arm (12%). Median survival times with high- and low-dose paclitaxel (9.56 and 9.99 months, respectively) also were significantly longer (P less than .001) than with etoposide (7.69 months). Despite similar rates of severe neutropenia, fever, and infection in both paclitaxel arms, the overall impact of high-dose paclitaxel with G-CSF support in this disease setting was negligible.
In accompanying pharmacodynamic studies, steady-state paclitaxel concentrations
(Css) in plasma were measured in courses 1 and 2 in both paclitaxel arms,
and Css was related to outcome.[87] Although there was a significant difference
in Css between the low- and high-dose paclitaxel
arms (mean ± SD, 0.35 ± 0.16 µM vs 0.94 ± 0.50
µM; P less than .001), no significant pharmacodynamic relationships
were evident between Css and both response and time to disease progression.
These results indicated that neither response nor time to disease progression
is influenced by either paclitaxel Css or dose in chemotherapy-naive patients
with non-small-cell lung cancer who are treated with paclitaxel doses ranging
from 135 to 250 mg/m² (24-hour schedule) followed by cisplatin.
Collectively, these results in non-small-cell lung cancer indicate that the relationship between taxane dose and response plateaus at lower taxane doses with progressively longer infusion schedules, which is similar to the situation demonstrated in ovarian cancer.
Head and Neck Cancer and Other Tumor Types
As in the use of taxanes in patients with advanced non-small-cell lung cancer, in which early phase II trials of paclitaxel and docetaxel were performed using relatively aggressive dosing regimens, there has been a paucity of clinical studies designed to rigorously explore dosing and scheduling issues in patients with advanced head and neck cancer and other tumor types.
Perhaps the only attempt to date is a phase III trial (ECOG 1393) that evaluated the optimal dosing of paclitaxel on a 24-hour schedule in combination with cisplatin in patients with advanced squamous cell carcinoma of the head and neck.[88] A previous phase II trial of paclitaxel, 250 mg/m² on a 24-hour schedule, produced a 40% response rate. Building on these data, Forastiere et al randomized patients with metastatic or locally advanced disease who had not previously received chemotherapy for recurrent disease to treatment with cisplatin (75 mg/m²) following either low-dose paclitaxel (135 mg/m² on a 24-hour schedule) or high-dose paclitaxel (200 mg/m² on a 24-hour schedule) plus G-CSF.
A preliminary analysis demonstrated that response rates were identical in both arms (35%) and there were no differences in survival parameters. In addition, there appeared to be no significant differences in rates of both severe hematologic and nonhematologic toxicities. The results of an accompanying pharmacodynamic study, which is similar to that performed in the ECOG 5592 trial in non-small-cell lung cancer, is undergoing analysis. As is the case with non-small-cell lung cancer, these clinical results indicate that there is no advantage to using paclitaxel doses above 135 mg/m² on a 24-hour schedule in combination with cisplatin in patients with advanced head and neck cancer.
Conclusions
Based on the current cumulative results of nonrandomized and randomized trials of the taxanes in cancers of breast, ovary, lung, and head and neck, there does not appear to be a single dosing schedule that produces a vastly superior clinical outcome. Although there are reports of both impressive and unimpressive antitumor activity with some paclitaxel schedules in several disease settings in nonrandomized studies, the overall aggressiveness of the treatment regimen itself must be taken into account.
In both tissue culture and clinical trials, there appears to be a threshold paclitaxel dose or concentration, below which only negligible antitumor activity is observed, and a plateau dose or concentration, above which minimal, if any, further antitumor effects occur. The doses at which both threshold and plateau effects occur appear to be inversely related to the duration of the administration schedule used in clinical practice.
For paclitaxel, it appears that comparable antitumor effects can be achieved with either short (1- and 3-hour) or prolonged (24- and 96-hour) schedules as long as equitoxic dosing regimens are used (ie, higher paclitaxel doses with short infusion schedules). For docetaxel, although there are insufficient data available for the gamut of possible dosing schedules relative to paclitaxel, the impressive results and toxicities noted with the most common dosing schedule, 100 mg/m² over 1 hour, indicate that both plateau and threshold effects are being achieved. It may not, therefore, be necessary to evaluate alternate administration schedules. However, lower docetaxel doses on the 1-hour schedule may result in vastly different toxicity profiles and therapeutic indices.
In disease settings in which the principal therapeutic goal is palliation (eg, women with recurrent or refractory breast and ovarian cancers), there appears to be little difference in outcome between various dosing schedules as long as a minimal plateau paclitaxel dose is exceeded (ie, 3 175 mg/m² on a 24-hour schedule or 3 175 mg/m² on a 3-hour schedule). However, the use of higher doses on shorter administration (ie, more than 200 mg/m² on 1- or 3-hour schedules) may be necessary to achieve a maximal therapeutic outcome in situations in which prolongation of survival is a reasonable expectation.
