Camptothecins Look Particularly Promising in Treating Recurrent or Refractory Ovarian Cancer

HOUSTON—New studies of irinotecan-based regimens for gynecologic cancers were reviewed by Andrzej P. Kudelka, MD, and Claire Verschaegen, MD. He is associate professor and she is an assistant professor in the Division of Cancer Medicine at the University of Texas M.D. Anderson Cancer Center in Houston.

A number of second-line agents have been tried, Dr. Kudelka noted, with responses ranging from about 10% to 30%. "In platinum-refractory patients, the disease stabilization rate with topotecan (Hycamtin) can be as high as 50%," Dr. Kudelka said.

Chemotherapy regimens for ovarian cancer evolved from cisplatin-based regimens in the early 1980s to cisplatin/paclitaxel as a result of the Gynecologic Oncology Group (GOG)-111 trial and then to carboplatin/paclitaxel regimens as a result of GOG158. Regardless of chemotherapy, survival is highly dependent on the amount of residual disease remaining after surgery. "If chemotherapy is working, interval tumor reductive surgery does translate into increased survival," Dr. Kudelka said.

The role of single-agent paclitaxel (Taxol) in primary treatment of ovarian cancers is unclear. Dr. Kudelka said that data from the GOG-132 trial found no advantage to paclitaxel/cisplatin compared to cisplatin alone in either progression-free or overall survival. "Paclitaxel alone had an inferior response rate," he said.

Current research initiatives are directed at finding better ways to treat patients who have either recurrent or refractory disease. "Recurrent disease is that with a prior good response and a treatment-free interval of more than six months. About 20% to 50% of patients with recurrent disease respond to platinum-based reinduction," Dr. Kudelka noted. "Refractory disease is that which progressed on platinum-based therapy. Resistant disease is residual tumor and typically recurs within 6 months" he continued.

Dr. Kudelka described a study of single-agent irinotecan in 14 patients with recurrent or refractory ovarian cancer. Irinotecan was given at a dose of either 100 mg/m² every week or 150 mg/m² every other week. "The response rate was 21.4%," he reported. A similar study in 55 patients given either irinotecan 100 mg/m² every week or 150 mg/m² every 2 weeks produced a 23.6% response rate overall (23.1% in cisplatin-pretreated patients).

Kigawa et al tested cisplatin/irinotecan as second-line therapy after CAP. Thirty patients were treated with cisplatin 60 mg/m² on day 1 and irinotecan 50-60 mg/m² on days 1, 8, and 15. The response rate was 60%.

"The increase of topoisomerase I activity after CAP treatment leads to a better response rate to irinotecan," Dr. Kudelka said.

This approach was further studied in 25 platinum-pretreated patients with recurrent ovarian cancer. The treatment regimen was cisplatin 60 mg/m² on day 1 and irinotecan 50-60 mg/m² on days 1, 8, and 15. The response rate was 40%, and overall survival was 12 months. "Response to second-line therapy in these patients is typically less than 15%, but this study had a 40% response rate. This is a regimen that should be studied further," Dr. Kudelka said.

"Irinotecan as a single agent has activity in recurrent paclitaxel-naive ovarian cancer. The combination of cisplatin and irinotecan is well tolerated in second-line therapy and yields a response rate around 40%-60%, and both mucinous and clear-cell tumors are sensitive to irinotecan-based combinations."

Ovarian cancer is the sixth most common type of cancer and the fourth most important cause of death, accounting for 14,000 deaths each year in the United States. Incidence peaks in the seventh decade of life, and ovarian cancer is uncommon before 50 years of age. "Ovarian cancer has a great psychological impact, partly because it is difficult to diagnose in the early stages while it is sneaking up on people," said Dr. Kudelka.

Cervical Cancer

Calling it a "huge public health problem worldwide," Dr. Kudelka observed that cervical cancer is the main cause of cancer death in young women, second only to breast cancer. Five-year survival is dependent on stage at diagnosis. Standard treatment is surgery or radiotherapy for stage 0 to IB1 and concurrent chemoradiation for stage IB2 and above. Neoadjuvant chemotherapy prior to surgery is being studied in clinical trials.

"Irinotecan as a single agent produces 10%-25% response rates in chemotherapy-pretreated recurrent squamous cell cancer of the cervix, especially in patients who had not had radiation. The combination of cisplatin and irinotecan is very active in chemotherapy-naive cervical cancer, and an ongoing GOG study should help define the role of this combination in the treatment of recurrent cervical cancer. The same combination has activity in untreated cervical cancer and may have a role in countries where radiation is not available. Clearly, studies of radiation sensitization with irinotecan are needed in cervical cancer," Dr. Kudelka said.