Epithelial ovarian cancer is a major source of mortality of women in the United States. It is the leading cause of gynecologic cancer death. The disease is unusual in women below the age of 40, and gradually increases to a peak rate of 57 per 100,000 in the 8th decade. The median age of diagnosis is 63 years of age. Although genetic factors have been noted, approximately 90% of the cases do not have an identifiable genetic predisposition. There are no early signs or symptoms of the disease, and most patients are diagnosed in an advanced state. Following surgical bulk reduction, chemotherapy is generally given. The prognostic factors for the disease remain the nature of the histology, the amount of residual disease following primary surgery, and the stage of the disease. The disease is staged according to the International Federation of Gynecology and Obstetrics (FIGO) nomenclature.
Chemotherapy for advanced ovarian cancer has evolved over the years into combination regimens that generally included cisplatin(Drug information on cisplatin) or carboplatin(Drug information on carboplatin) (Paraplatin). The introduction of paclitaxel(Drug information on paclitaxel)/platinum-based chemotherapy has resulted in a prolongation of the median progression-free survival and overall survival of patients. In the benchmark trial, Gynecologic Oncology Group (GOG)-111, the taxane/cisplatin arm had a median survival of 38 months vs 24 months (P < .001) for the cisplatin/cyclophosphamide arm. Superiority of the paclitaxel/cisplatin regimen over the cisplatin/cyclophosphamide regimen in terms of both progression-free survival and overall survival were later confirmed in a European trial.
The long-term impact on survival is not yet known. The cisplatin/paclitaxel combination has the major side effects of myelosuppression and neuropathy. The substitution of carboplatin for cisplatin has generally lessened, but does not eliminate, neuropathy. Furthermore, depending on the administration schedule of paclitaxel, hematologic toxicities may be less frequent. Taken together, the trial results indicate that the more convenient paclitaxel/carboplatin combination is generally better tolerated than paclitaxel/cisplatin and appears to be equally efficacious.
When used as a 3-hour infusion, paclitaxel is associated with significant neurotoxicity, however, and questions remain about the possibility that longer schedules of paclitaxel may be somewhat more efficacious as first-line therapy. As a result of this ambiguity, and based upon the results of docetaxel(Drug information on docetaxel) (Taxotere) in preclinical and clinical trials, numerous studies have investigated the substitution of docetaxel for paclitaxel in combined use with the platinum salts in the treatment of ovarian carcinoma. The remainder of this article will review preclinical and clinical trials of docetaxel in ovarian cancer, concluding with the preliminary results of a large, phase III randomized trial comparing docetaxel- and paclitaxel-based regimens in the first-line setting.
The relative activity of paclitaxel vs docetaxel in ovarian cancer cell lines has been the subject of several studies. Aapro et al compared the in vitro sensitivities of paclitaxel and docetaxel in bone marrow, head and neck, sarcoma, colon, and ovarian cancer cell lines. In a sulforhodamine or tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, 13 ovarian cancer lines were two- to fourfold more sensitive to docetaxel as compared with paclitaxel and up to 6,500-fold more potent than cisplatin.
Alberts et al conducted an in vitro study comparing the relative cytotoxicities of paclitaxel and docetaxel against 50 fresh ovarian cancers obtained at surgery prior to chemotherapy. A human tumor cloning assay was used to evaluate the degree of drug-induced inhibition of tumor colony formation (TCF) from the ovarian cancers. The achievable and median IC50 values (ie, 50% inhibition of TCF compared with control) were 47.8% achievable and 19.0 µM median IC50 for paclitaxel vs 48.5% achievable and 3.28 µM median IC50 for docetaxel. On the basis of this data, it was concluded that docetaxel had at least equivalent cytotoxicity to paclitaxel against fresh ovarian cancers.
Hanauske et al compared the antiproliferative action of docetaxel and paclitaxel against a variety of freshly explanted human tumor specimens using an in vitro soft agar cloning system. Cytotoxicity was observed against breast, lung, ovarian, colorectal cancer, and melanoma tumor colony-forming units. In a head-to-head comparison, 29 specimens were found more sensitive to docetaxel than paclitaxel, while only 13 were more sensitive to paclitaxel than docetaxel. At 10 µg/mL, significant cytotoxicity was observed in 41% of specimens tested with docetaxel and 33% of specimens tested with paclitaxel. The authors concluded that cross-resistance between the two agents was incomplete, and that, on a concentration basis, docetaxel was more cytotoxic than paclitaxel in the majority of human primary tumor specimens evaluated.
Silverstrini et al compared paclitaxel and docetaxel in three established cell lines and in 19 primary cultures of ovarian neoplasms. The assay used was clonogenic with a proliferative index based on tritiated thymidine incorporation. Both docetaxel and paclitaxel were more potent than cisplatin or doxorubicin(Drug information on doxorubicin) in all three established cell lines. In addition, docetaxel was two to four times more cytotoxic than paclitaxel in two of the established cell lines and showed similar activity in one cell line. In primary culture systems, however, the taxanes were less active than cisplatin and doxorubicin. Cell lines that were sensitive to the taxanes generally had a higher labeling index (ie, higher proliferative activity) than those observed in resistant cultures. The authors suggested that preclinical determination of the inherent sensitivity of individual tumors to taxanes and of the tumor cell population proliferation rate could be useful in identifying patients who could benefit from taxane treatment.
Untch et al used the adenosine(Drug information on adenosine) triphosphate cell viability assay in 14 cell lines, including 12 gynecologic and 2 breast cancer cell lines. On a concentration basis, docetaxel was more active than paclitaxel in 5 cell lines and paclitaxel was the more active drug in 6 cell lines. Of interest, total cross-resistance to cell lines between the taxanes was not demonstrated. The authors concluded that both compounds were quite active and showed partial non-cross-resistance. The authors indicated that paclitaxel and docetaxel appear to have a different spectrum of activity in gynecologic and breast cancers, both of which are diseases where tumor heterogenicity remains a challenging therapeutic problem.
Nicoletti et al reviewed the activity of both taxanes in human ovarian carcinoma xenografts. Intravenous drug was given once every 4 days for three consecutive doses in the nude mouse model. Xenografts were transplanted subcutaneously or intraperitoneally. Both taxanes cured all animals in early stage peritoneal implantation of HOC22 tumor lines. Of note, both docetaxel and paclitaxel were more effective than cisplatin, which was used as the reference compound. The authors concluded that both docetaxel and paclitaxel were highly effective in four human ovarian carcinoma xenograft models.
In summary, both taxanes have been found to be extremely active in a variety of human ovarian cancer models. Docetaxel and paclitaxel demonstrated varying degrees of activity in preclinical ovarian carcinoma models and did not demonstrate total cross-resistance. The research indicates that human tumor cell lines that are resistant to paclitaxel are not necessarily resistant to docetaxel. Taken together, the information provided an interesting avenue for the clinical investigation of docetaxel in ovarian carcinoma.
The role of docetaxel in the treatment of refractory or recurrent ovarian cancer has been well described.[12-16] Four major trials of single-agent docetaxel have been conducted in advanced, pretreated ovarian cancer patients. A total of 340 patients were treated in two European and two US trials (Table 1).[12-16] The dose of docetaxel used in these studies was 100 mg/m² every 3 weeks. All patients had received prior platinum salt-based therapy. The time interval from previous platinum therapy, as well as the definition of "platinum resistance," was variable in the trials. When analyzed together, the overall response rate in the four phase II studies combined was 30% among 315 evaluable patients (95% confidence interval[CI]: 25%-36%) as shown in Table 2.[12-16] This level of antitumor activity was maintained among the 155 patients who had the most refractory disease (defined as a treatment-free interval of less than 4 months), where the overall response rate was 28% (95% CI: 19%-36%).
The most common side effects were grade 4 neutropenia and fluid retention. The incidence of febrile neutropenia among patients varied from 8% to 44%. These studies confirmed the activity of docetaxel in platinum-pretreated patients. In addition, there was a trend demonstrating that longer treatment-free intervals and platinum-free intervals were associated with higher response rates. It was also noteworthy that even the most refractory cases demonstrated a significant response rate to docetaxel.