A broad range of dosing schedules has been evaluated for paclitaxel(Drug information on paclitaxel), whereas most clinical trials with docetaxel(Drug information on docetaxel) have used a single-dosing schedule (100 mg/m² over 1 hour). Evaluations of paclitaxel were initially limited to the 24-hour schedule because of the high incidence of major hypersensitivity reactions in patients receiving short schedules without premedication, and the 24-hour schedule was the first to be approved for women with recurrent or refractory ovarian cancer. Most available information about paclitaxel in various disease settings thus pertains to the 24-hour schedule.
However, prominent antitumor activity has also been observed with 1- and 3-hour schedules of paclitaxel in women with recurrent or refractory breast and ovarian cancers. This activity has also been apparent in both chemotherapy-naive and previously treated patients with non-small-cell lung cancer and other tumor types. The results of the NCIC-CTG's pivotal Ov.9 (or BMS 016) trial that addressed the relative merits of administration schedule and premedication led to the regulatory approval of the 3-hour schedule in women with recurrent or refractory ovarian cancer, and it stimulated broader interest in exploring alternate doses and schedules.
The equivalence of both the 3- and 24-hour schedules of paclitaxel in this setting, in which the overall basal response rate is low and large numbers of patients are required to detect small differences, does not necessarily imply that both schedules are equivalent in other tumor types and settings, particularly when equivalent doses are used. Intriguing results, consisting of some of the highest response rates achieved with paclitaxel, have been noted on more prolonged schedules (particularly the 96-hour infusion) in women with recurrent or refractory breast cancer.[60,61] Impressive antitumor activity has been observed in patients with both chemotherapy-naive and previously treated non-small-cell lung cancer treated with paclitaxel on an even shorter 1-hour schedule. However, it should also be noted that the impressive results with both schedules occurred with doses that resulted in a level of neutropenia comparable to that observed in initial pivotal trials using the 24-hour schedule.
Paclitaxel at its MTD
A concern during the early development of paclitaxel was that its limited supply would preclude the scope and number of phase II evaluations.[63,64] Because heavily pretreated women with advanced ovarian cancer were able to tolerate substantially lower paclitaxel doses than untreated or minimally pretreated patients, investigators initially opted to perform most phase II evaluations of paclitaxel at its MTD with granulocyte colony-stimulating factor (G-CSF [Neupogen]) support, as well as limited phase II trials at lower paclitaxel doses without G-CSF. In several clinical situations, such as in untreated or minimally pretreated women with advanced breast cancer, phase II studies using high doses of paclitaxel and occasional G-CSF were performed from the outset.
In essence, the decision to evaluate paclitaxel at its MTD with G-CSF support was based on the possibility that the demonstration of unimpressive activity at higher paclitaxel doses would obviate the need to perform additional phase II trials of paclitaxel at lower doses. It was similarly felt that the demonstration of negligible activity at submaximal doses would not conclusively prove that paclitaxel was inactive across its entire dosing spectrum, and additional studies evaluating higher drug doses might be required.
In studies of paclitaxel at its MTD, negligible activity was demonstrated in patients with advanced melanoma and colorectal, renal, and gastric cancers,[63,64] which argued strongly against performing additional phase II trials of lower doses in these tumor types. A similar reasoning was subsequently used during the development of docetaxel in that broad phase II evaluations were performed using an MTD schedule (100 mg/m² over 1 hour).[51,65] This approach results in unequivocally negative conclusions regarding activity when high-dose phase II studies are negative. The potential benefits of this approach are offset by the dilemma that often arises when significant antitumor activity is observed in nonrandomized phase II studies employing maximal drug doses with or without hematopoietic colony-stimulating factor support. In this situation-as was the case for paclitaxel in phase II trials in lymphoma and carcinomas of the breast, lung, cervix, and head and neck-further clinical investigations may focus solely on the most intensive dosing schedule, in which lower, less toxic doses and/or dose intensity may also produce substantial antitumor activity.
In clinical practice, paclitaxel is usually administered at a dose of 175 mg/m² over 3 hours or 135 to 175 mg/m² over 24 hours every 3 weeks. These dosing schedules may result in optimal therapeutic indices in many disease settings, such as in palliating patients with refractory or recurrent advanced ovarian and breast cancers. It may, however, be more appropriate to use alternate dosing schedules in other tumor types and settings, particularly in less heavily pretreated patients and when prolongation of survival is a tangible objective.
A broad range of paclitaxel doses has been evaluated on almost all schedules, and the most appropriate dose for any schedule is currently being studied in randomized trials in ovarian, breast, and non-small-cell lung cancers. Although several administration schedules for docetaxel have been studied in phase I evaluations, the agent is most commonly administered at a dose of 100 mg/m² as a 1-hour infusion every 3 weeks. Lower doses (60 to 75 mg/m²) on a 1-hour schedule may be associated with a lower incidence of both hematologic and nonhematologic toxicities; however, the relative therapeutic advantages of high vs low doses are not clear.
In the initial five phase II studies of paclitaxel on a 24-hour schedule
in women with recurrent or refractory ovarian cancer, which were used for
registration of the agent in the United States, doses ranged from 110 to
300 mg/m².[66-70] Individual study reports used somewhat different
criteria to define patient eligibility and evaluability for response. In
these reports, response rates were seemingly higher (36% to 48%) in trials
evaluating higher paclitaxel doses (170 to 300 mg/m²) and dose intensity
than in trials in which most patients were treated with lower paclitaxel
doses (response rates, 30% to 37%; 110 to 175 mg/m²) or higher doses,
albeit administered in a
less dose-intensive regimen (response rate, 20%; 250 mg/m² with treatment delays).[66-70]
G-CSF support was also used from the outset to ameliorate severe neutropenia
and maintain dose intensity in trials that employed high paclitaxel doses
or dose intensity.[68-70] Nonhematologic toxicities, particularly neurotoxicity,
occurred more frequently than in those trials that evaluated
lower paclitaxel doses or dose intensity.[66,67]
At first glance, such observations may suggest that higher paclitaxel doses and dose intensity are optimal in this and other settings. For example, using the correlative methods of Hrynick and Levin, Reed et al retrospectively analyzed the relationships between paclitaxel dose intensity and antitumor activity in women with advanced ovarian and breast cancers. They demonstrated strong positive relationships in both settings (P = .022 and .004, respectively). It should be stressed that these trials were nonrandomized and incorporated diverse patient populations with respect to pertinent demographic and prognostic variables.
Results of a Meta-analysis
To more appropriately evaluate the effects of paclitaxel dose and dose intensity on the antitumor activity and survival of patients with refractory or recurrent advanced ovarian cancer, a pooled analysis of individual patient data (meta-analysis) was performed. The database was derived from the initial five studies that were used for registration of paclitaxel in the United States for recurrent or refractory disease. It audited demographic, categorical response, and successive tumor measurement data from 191 ovarian cancer patients who were treated with paclitaxel on a 24-hour schedule every 3 weeks.
In this analysis, the probability of achieving a partial or complete
response was not related to the average paclitaxel dose (odds ratio, 1.0
per 10 mg/m²; P = .60). In fact, the probability of responding appeared
to decrease with increasing dose intensity (odds ratio, -0.77 per 10 mg/m²/wk;
P = .06). A strong negative relationship between the maximum percent reduction
tumor size and dose intensity was also apparent (odds ratio, -6.1% per 10 mg/m²/wk; P = .007). Not only was a negative effect demonstrated in the logistic regression analysis of the data from all studies but also a negative effect was found in each individual study.
With respect to overall survival, the analysis suggested a negative relationship between average paclitaxel dose and survival (hazard ratio, 1.06 per 10 mg/m²; P = .0001). There was also a strong negative relationship between dose intensity and survival (hazard ratio, 1.3 per 10 mg/m²/wk; P = .0001). Similar relationships were demonstrated between paclitaxel dose, dose intensity, and progression-free survival. These relationships were minimally affected when the analyses were controlled for individual study, performance status, number of prior regimens, platinum sensitivity, and response to prior therapy. These results indicate no clear benefit of increasing paclitaxel doses above 135 mg/m² when the drug is administered as a 24-hour infusion every 3 weeks to women with recurrent or refractory advanced ovarian cancer. This is supported by the known saturable pharmacologic behavior of paclitaxel.
There are several possible explanations that may account for the lack of an effect of higher paclitaxel doses on both the categorical response and percentage reduction in measurable disease (such as tissue saturation, as discussed previously). It is difficult, however, to propose reasonably strong biologic or pharmacologic explanations for why antineoplastic activity might decrease with higher paclitaxel dose intensity.
Liebmann et al reported a negative relationship between paclitaxel concentration and cytotoxicity in a panel of eight human tumor cell lines that were treated for 24 hours. Increasing paclitaxel concentrations from 2 to 20 nM/L sharply increased cytotoxicity. No additional cytotoxicity occurred with paclitaxel concentrations above 50 nM/L, and treatment with very high drug concentrations (more than 10 µM) resulted in even less cytotoxicity. Furthermore, the principal constituent of paclitaxel's clinical formulation vehicle, polyoxyethylated castor oil, at a concentration of 0.135%, antagonized the cytotoxic effects of paclitaxel. Even in light of these experimental data, the potentially negative effects of paclitaxel dose intensity on antitumor activity and survival in the meta-analysis must be interpreted with considerable caution and awaits confirmation in larger prospective studies.
These results argue strongly against the possibility that increasing paclitaxel dose above 135 mg/m² on a 24-hour schedule or dose intensity might enhance clinical antitumor activity. The analysis suggests that the optimal paclitaxel dose intensity for similar patients is at the lower end of the range of dose intensity used in these investigations, ie, 45 mg/m²/wk (or 135 mg/m² every 3 weeks) as a 24-hour infusion. At this juncture, however, it is not known whether these results can be generalized to describe paclitaxel dose and dose-intensity relationships using other dosing schedules (eg, 3- or 96-hour schedules) and in other disease settings.
Two Randomized Trials
To date, the effect of paclitaxel dose on clinical response in women with refractory or recurrent ovarian cancer has been evaluated prospectively in two randomized trials.[59,73] The salient features of randomized clinical trials of the taxanes that focused on dosing and scheduling issues in ovarian and other neoplasms are listed in Table 2.
In Ov.9 (BMS 016), the NCIC-CTG evaluated the effects of two different paclitaxel doses (135 vs 175 mg/m²) and two different schedules (24 vs 3 hours) on both response and toxicity. With respect to the dosing issue, progression-free survival was significantly, albeit not profoundly, longer in the high-dose arm (19 vs 14 weeks, P = .02), but response rates and survival were similar. Nevertheless, the two paclitaxel doses were not very disparate, and the study design and patient numbers precluded comparisons between each of the four individual treatment arms, so that patients treated with both schedules were analyzed together. It is possible the patients receiving paclitaxel on the 3-hour schedule, and not the 24-hour schedule, contributed to the significant difference between the two doses.
The dose-response issue has also been assessed in an intergroup study in which a similar group of patients were treated with 24-hour infusions of paclitaxel at one of three doses: 135, 175, and 250 mg/m² plus G-CSF. However, the lowest dose arm was terminated after the regulatory approval of paclitaxel, which resulted in reduced patient accrual. A preliminary analysis of the results of the study indicates only modest differences in response rates. Response rates were 36% vs 28% in the 250-mg/m²-plus-G-CSF and 175 mg/m²-arms, respectively, but there were no differences in either progression-free or overall survival.
Based on the results of nonrandomized trials, meta-analyses, and the
limited randomized trials to date, there is no compelling reason to administer
paclitaxel as a 24-hour infusion in
women with recurrent or refractory ovarian cancer at doses above 135 to 175 mg/m². The cumulative results indicate that paclitaxel doses above 135 mg/m² result in either little or no further benefit with respect to obtaining categorical responses and certainly do not prolong disease-free and overall survival times.
In the Ov.9 study, myelosuppression was substantially more severe in patients receiving identical doses of paclitaxel over 24 hours compared with 3 hours, probably due to longer drug exposure above a critical threshold concentration. Toxicologically, the results suggest that the precise paclitaxel dose capable of inducing any given effect depends on the specific administration schedule.
These findings preclude extrapolation of the relationships between dose and effect (ie, toxicity, disease activity) from one dosing schedule to another. The limited availability of comparable data with shorter (eg, 3-hour) schedules in this disease setting, particularly at paclitaxel doses above 175 mg/m², preclude making similar recommendations. Study results in this and other disease settings nonetheless indicate that paclitaxel doses below 175 mg/m² on short schedules may be suboptimal. For docetaxel in this disease setting, there are sufficient impressive results available only for 100 mg/m² over a 1-hour dosing schedule [51,65].