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Irinotecan in Epithelial Ovarian Cancer

Irinotecan in Epithelial Ovarian Cancer

ABSTRACT: Ovarian cancer, the second most common gynecologic malignancy, accounts for approximately 14,000 deaths annually in the United States. Disease relapse after primary treatment, which consists mainly of surgery followed by platinum-based therapy, occurs in more than 60% of ovarian cancer patients overall, and in more than 80% of those diagnosed initially with advanced-stage disease. Responses to second-line chemotherapy agents range from 15% to 25%, and are usually partial responses of short duration. Irinotecan (CPT-11, Camptosar), a camptothecin derivative that inhibits topoisomerase I, is undergoing assessment for the treatment of ovarian cancer. Preclinical studies demonstrated antitumor activity in ovarian cancer. Early phase I or II trials showed response rates of 20% to 25% in patients with recurrent or refractory disease, with some responses noted in the relatively chemoresistant mucinous and clear cell tumors. Irinotecan has also been studied in combination regimens, most commonly irinotecan plus cisplatin. In a phase II trial of irinotecan plus cisplatin in platinum-sensitive or -resistant patients, response rates were 75% and 33%, respectively. Irinotecan seems to be relatively well tolerated; dose-limiting toxicities appear to be diarrhea, nausea and vomiting, and leukopenia/neutropenia. [ONCOLOGY 16(Suppl 5):29-31, 2002]

Ovarian cancer is the second most common gynecologic
malignancy, accounting for approximately 23,400 cases annually in the United
States.[1] Although it is only the fifth most common cancer among women in the
United States, its importance is far out of proportion to its incidence because
it is the most lethal of gynecologic cancers. Approximately 13,900 women die
from ovarian cancer annually in the United States.[1]

Because no effective screening method exists for ovarian cancer, more than
70% of women are diagnosed when the cancer has already spread beyond the ovary.
Standard treatment for the majority of patients with epithelial ovarian cancer
consists of primary surgery followed by platinum-based chemotherapy. The current
standard regimen is the combination of paclitaxel and carboplatin
(Paraplatin).[2]

Survival rates for patients with stage III and IV epithelial ovarian cancer
are approximately 15% to 20% and less than 5%, respectively. Therefore, more
than 60% of patients with ovarian cancer, regardless of stage, and more than 80%
of those with advanced-stage epithelial ovarian cancer, will have disease
relapse following primary treatment. In general, recurrent ovarian cancer is
incurable, partly because of the relative inefficacy of salvage therapy.

Patients with recurrent ovarian cancer are not a homogeneous group. To date,
the probabilities of responsiveness and outcome are related to a variety of
clinicopathologic factors. One of the strongest predictive factors is the length
of time from completion of primary chemotherapy to relapse.[3-6] This
observation has led to definitions of platinum sensitivity and platinum
resistance.[7]

Currently, conventional chemotherapeutic agents constitute the predominant
option for secondary therapy. However, in the setting of platinum-resistant
ovarian cancer, response rates associated with the most active agents, including
topotecan (Hycamtin),[8-10] liposomal doxorubicin (Doxil),[11,12] gemcitabine
(Gemzar),[13,14] vinorelbine (Navelbine),[15-17] and oral etoposide,[18] range
from 15% to 25%. Most responses are partial and not durable. Therefore, a
concerted effort to identify new active agents—both chemotherapeutic and
nonchemotherapeutic—against epithelial ovarian cancer is justified.

Irinotecan Chemotherapy in Ovarian Cancer

Irinotecan is a derivative of camptothecin and belongs to a class of
chemotherapeutic agents that inhibit topoisomerase I. Topoisomerase I is a
protein with enzymatic activity that relaxes supercoiled double-strand DNA,
thereby permitting DNA replication and RNA transcription.[19] Clinical
development of irinotecan began in Japan in the 1980s. Subsequent preclinical
studies demonstrated that it had antitumor activity in ovarian cancer.[20-23] O’Meara
and Sevin found that the median effective doses of irinotecan were significantly
lower than clinically achievable peak plasma concentrations in 7 of 12 fresh
ovarian carcinoma specimens, and 11 of 12 specimens showed sensitivity to the
active metabolite SN-38.[22]

Single-Agent Irinotecan Studies

Early clinical trials of irinotecan in ovarian cancer patients were conducted
almost exclusively in Japan. In 1991, Takeuchi et al reported results of a phase
II trial of irinotecan in 15 patients with recurrent ovarian cancer.[24] Three
drug schedules were used, including 100 mg/m² weekly, 150 mg/m² every 2 weeks,
and 200 mg/m² every 3 to 4 weeks. The authors reported one complete response and
two partial responses, for an overall response rate of 20%. Significant
toxicities were reported among the 30 patients in the study, which also included
cervical and uterine cancer patients. Leukopenia occurred in 30% of patients,
anemia in 20%, and nausea and vomiting in 13%. Subsequently, the same
researchers reported results of a late phase II study in which 55 patients with
ovarian cancer received irinotecan in one of two schedules: 100 mg/m² weekly
(regimen I) or 150 mg/m² every 2 weeks (regimen II).[25] Thirteen partial
responses were observed, for a response rate of 24%. A total of 24% of patients
receiving regimen I and 14% receiving regimen II responded. Major toxicities
again included leukopenia in 57%, anemia in 25%, and diarrhea in 19% of
patients.

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