Topoisomerases are essential nuclear enzymes with a multiplicity of cellular functions involving DNA replication, RNA transcription, mitosis, and chromosome condensation. Two classes have been identified in mammalian cells: the class I topoisomerases, so named because such agents induce single-strand breaks and reunions of the DNA double helix; and the class II topoisomerases, so named because such agents induce double-strand breakage-reunion reactions with the DNA double helix. Both enzymes catalyze the interconversion of various topologic isomers of DNA.[2,3]
Camptothecin, an alkaloid from the tree Camptotheca acuminata (Nyssaceae), is the parent compound of topotecan(Drug information on topotecan) (Hycamtin), irinotecan(Drug information on irinotecan) (CPT-11, Camptosar), 9-aminocamptothecin, 9-nitrocamptothecin, and other analogs. Topotecan and irinotecan are commercially available water-soluble derivatives of camptothecin. The active form of the camptothecins is the closed lactone ring, which is pH-dependent. Preclinical activity screening of camptothecin and its analogs has been demonstrated in several models including gynecologic tumors. In addition, irinotecan is a prodrug and needs to be metabolized for optimal activity. A carboxylesterase catalyzes the conversion of irinotecan to its active metabolite SN-38 (7-ethyl-10-hydroxycamptothecin). Using a subrenal capsule assay, irinotecan showed growth-suppressive effects of greater than 50% in two cervical cell lines.
Camptothecin analogs also augmented the activity of cisplatin, fluorouracil(Drug information on fluorouracil) (5-FU), and etoposide(Drug information on etoposide) in HST-1, a human squamous cell carcinoma cell line.[8-11] This may result from inhibition of the removal of cisplatin(Drug information on cisplatin) DNA adducts. These compounds appear to have radiosensitization properties in small-cell and adenocarcinoma lung cancer cell lines, which has also been demonstrated in patients. The addition of recombinant tumor necrosis factor and irinotecan to several gynecologic cancer cell lines also demonstrated synergistic effects.
Therapy for cervical cancer is chosen according to the clinical stage. Most patients with early-stage disease (IA, IB1) are cured by surgery or radiotherapy; chemotherapy has no role in this setting. For patients with higher-stage disease (IB2 to IVA) or positive lymph nodes, chemoradiation is the treatment of choice. Irinotecan has not been studied in combination with radiotherapy for the treatment of cervical cancer. In animal studies, however, the combination is synergistic.
Experimental modalities for the primary treatment of cervical cancer stages IB to IVA include neoadjuvant chemotherapy followed by radical surgery. Sugiyama et al tested the combination of cisplatin (60 mg/m² on day 1) and irinotecan (60 mg/m² on days 1, 8, and 15) administered prior to surgery to 23 patients with stage IB2 to IIIB cervical cancer. The patients were chemotherapy-naive and had a median age of 59 years. Eighty-seven percent of patients had squamous cell histology. The overall response rate was 78%, with 3 complete remissions, 15 partial remissions, 4 stabilizations, and 1 progression of disease. Median survival has not yet been reached.
In contrast to the first-line setting, chemotherapy is used to treat recurrent or metastatic cervical cancer. Single-agent chemotherapy yields survival benefits similar to that of chemotherapy combination regimens; single-agent treatment is preferred because it is associated with fewer side effects. Response rates to single agents vary from 15% to 30% and complete responses are rare. Cisplatin and carboplatin(Drug information on carboplatin) (Paraplatin) are considered the most active single drugs. Patients with renal failure or poor performance status rarely benefit from chemotherapy. Combination chemotherapy has been tested in numerous trials. While high response rates have been documented even in heavily treated patients, response durations are short and survival is not improved over that achieved with single-agent treatment. Furthermore, results from randomized trials comparing single-agent and combination therapy demonstrated no significant benefits for the combination.
Irinotecan is the only active agent in platinum-refractory disease. This agent has been tested as a single agent in cervical cancer patients refractory to platinum-based therapy in five trials (Table 1). The first phase II trial in the United States used a schedule of 125 mg/m²/wk for 4 weeks followed by a 2-week rest. A total of 42 patients with a median age of 44 years (range: 24-59 years) were treated for a median of 2 cycles (range: 1-14 cycles). All patients had failed previous chemotherapy. The response rate was 21% with a median time to response of 6 weeks and a response duration of 12 weeks. The major dose-limiting side effects were nausea and vomiting (45%), diarrhea (24%), and myelosuppression (36%). Myelosuppression did not decrease when the irinotecan dose was reduced, whereas gastrointestinal side effects did. The investigators concluded that irinotecan had significant clinical activity and warranted further investigation, although hematologic and gastrointestinal side effects were problematic.