Continuous Infusions of Doxorubicin and Paclitaxel in Refractory Ovarian Cancer

Abstract & Commentary

Synopsis: Some tumors that are resistant to drugs administered by intravenous bolus may be sensitive to prolonged exposure achieved through continuous infusion.

Source: Duska LR, et al. Clin Cancer Res 1999;5: 1299-1305.

Ovarian cancer is responsive to paclitaxel-containing chemotherapy programs, but only about 20% of patients are cured. Eighty percent relapse after a partial or complete remission or progress during primary treatment. Patients with primary progressive ovarian cancer are usually refractory to salvage therapy. Patients who relapse from a remission may be responsive transiently to a variety of agents including carboplatin, etoposide, topotecan, ifosfamide, or liposomal doxorubicin. However, curative salvage therapy does not exist.

Clinical studies in breast cancer have suggested that women who progress after primary therapy that includes paclitaxel may, nevertheless, respond to re-exposure to paclitaxel when it is given by continuous infusion.1 Doxorubicin is not frequently used in primary therapy of ovarian cancer, but the activity of the liposomal preparation and the interaction between doxorubicin and paclitaxel in other tumor types led Duska and colleagues to do a phase I study of four-day infusions of doxorubicin and paclitaxel in women with relapsed ovarian cancer.

The dose of paclitaxel was held constant at 25 mg/m2/d and the dose of doxorubicin was escalated in 2.5 mg/m2/d increments from 7.5 mg/m2/d to 15 mg/m2/d. Blood counts were supported with granulocyte colony-stimulating factor 5 mcg/kg/d. Fifteen patients with documented progressive disease following primary treatment were entered into the study. Dose-limiting toxicity was hematologic. The maximum tolerated dose of doxorubicin was 12.5 mg/m2/d. Nonhematologic toxicity was minimal. In particular, no cardiovascular complications were noted. Five of the 15 evaluable patients responded, four with partial responses and one with a complete response. At the maximum tolerated dose, no patients required dose modification or treatment delays.

Four-day infusions of paclitaxel and doxorubicin are active and well-tolerated in patients with relapsed ovarian cancer. Additional studies will define the response rate and duration in larger numbers of patients.

Commentary

These results certainly seem promising. There has been remarkably little to cheer about in the salvage therapy of women with relapsed ovarian cancer. Continuous infusions are relatively easy to manage in patients with indwelling central-venous catheters and the side effects of this particular combination are sufficiently minor that outpatient therapy should be routine rather than the exception. It has been recognized that the administration of paclitaxel along with doxorubicin can slow doxorubicin clearance, an effect that appears to be attributable to the cremaphor vehicle in which the paclitaxel is formulated.2 However, when paclitaxel is administered by slow continuous infusion, it is possible that the serum concentration of cremaphor does not reach the levels necessary to interfere with doxorubicin clearance. Certainly the pharmacokinetic data collected in this study did not suggest that the doxorubicin half-life was dramatically altered. It may be interesting to examine whether liposomal doxorubicin may have an even more impressive therapeutic index when combined with paclitaxel infusion.

References

1. Seidman AD, et al. J Clin Oncol 1996;14:1877-1884.

2. Webster LK, et al. Br J Cancer 1996;73:522-524.

Which of the following statements is true about the combination of 4-day infusions of paclitaxel and doxorubicin in relapsed ovarian cancer?

a. The combination is too toxic for further development.

b. The combination results in prolonged neutropenia.

c. The combination results in enhanced cardiac toxicity.

d. The combination is modestly toxic and produces responses in one-third of patients.

e. Continuous infusions are too difficult to manage on an outpatient basis.