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Docetaxel in the Treatment of Ovarian Cancer

Docetaxel in the Treatment of Ovarian Cancer

ABSTRACT: Docetaxel (Taxotere) has extended the armamentarium of agents with significant activity in the treatment of ovarian cancer. As a single agent in advanced ovarian cancer patients previously treated with a platinum agent, docetaxel at 100 mg/m² every 3 weeks yields a 30% overall response rate and a 6-month duration of response. In vitro data demonstrate a lack of complete cross-resistance between docetaxel and paclitaxel. As a result, antitumor activity has also been demonstrated in patients refractory to a paclitaxel-containing regimen. In both platinum- and paclitaxel-pretreated patients, the highest response rates were obtained in patients with the longest interval of time since receipt of prior chemotherapy. Docetaxel has been successfully combined with the platinum salts for the first-line treatment of ovarian cancer patients. In combination with cisplatin, response rates of 69% were reported. In an effort to minimize hematologic toxicities and asthenia associated with the cisplatin/docetaxel combination, investigators have substituted carboplatin (Paraplatin) for cisplatin. Several phase II studies and the Scottish Randomized Trial in Ovarian Cancer (SCOTROC), a large phase III randomized trial, of the docetaxel/carboplatin combination have been completed. The most frequent toxicity noted is neutropenia, which is generally of brief duration, predictable, and manageable. The docetaxel/carboplatin combination has a notably low rate of neurotoxicity. Therefore, the SCOTROC comparative trial, demonstrating equivalent overall response rates and progression-free survival rates, suggests that the docetaxel/carboplatin combination may represent a new alternative to paclitaxel/carboplatin as first-line chemotherapy for advanced ovarian cancer. [ONCOLOGY 16(Suppl 6):73-81, 2002]

Epithelial ovarian cancer is a major source of
mortality of women in the United States. It is the leading cause of gynecologic
cancer death.[1] 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.[2] 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.[3] 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 or carboplatin
(Paraplatin). The introduction of 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.[4]

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.[5] 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 (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.

Preclinical Data

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.[6] 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.[7] 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.[8] 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.[9] 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 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 triphosphate cell viability assay in 14 cell
lines, including 12 gynecologic and 2 breast cancer cell lines.[10] 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.[11] 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.

Docetaxel in Refractory, Platinum-Pretreated Ovarian Cancer

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.

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