Irinotecan Plus Cisplatin Used as First-Line Treatment of Ovarian Cancers

NEW YORK CITY—Weekly irinotecan (Camptosar) and cisplatin (Platinol) can be successfully given as first-line treatment to women with advanced ovarian cancer. The toxicity is manageable, and some patients with suboptimally resected disease achieved an extended disease-free survival, David Spriggs, MD, reported. He is chief of the Developmental Chemotherapy Service at Memorial Sloan-Kettering Cancer Center in New York City.

Ovarian cancer is often responsive to early treatment, and platinum/paclitaxel (Taxol) combinations induce a complete clinical response in 50% to 70% of patients who have advanced disease. Dr. Spriggs said that only about a quarter of patients who have an initial complete response (CR) have a pathological complete remission at a second-look laparotomy. "And only about half of patients who do achieve such a pathologic complete response remain disease-free long-term, so we are always on the lookout for ways to enhance outcome," he said.

Risk Stratification

Risk stratification has been used in attempts to preserve the results in the good outcome patients while improving or intensifying treatment for poor-prognosis patients. Levels of the tumor marker CA-125 are expected to be a useful indicator in ovarian cancer patients because CA-125 is increased in about 80% of ovarian cancer cases, and normalization of CA-125 levels by the second or third cycle of therapy is a good prognostic factor.

"Since the use of paclitaxel and platinum began at Memorial Hospital, no patient with a CA-125 greater than 35 U/mL after three cycles of therapy achieved a pathologic CR in our institution," Dr. Spriggs said. Biostatisticians at the Gynecologic Oncology Group (GOG) confirmed that less than 10% of patients with an elevated CA-125 after three cycles went on to achieve pathologic CR in GOG trials.

"Patients with suboptimally debulked ovarian cancer and an elevated CA-125 after three cycles of treatment are a very high risk group for an inadequate response to primary treatment. High-dose chemotherapy unfortunately produced no improvement, so we looked at the possibility of adding different drugs," Dr. Spriggs said.

"Current treatment of ovarian cancer is graphically shown in the accompanying figure. A primary treatment such as with platinum and paclitaxel will give an early excellent response. When the disease recurs 6 to 12 months later, a second round of platinum/paclitaxel can induce a second response, but eventually all these patients die of the resistant clone, which is shown in red in the figure."

Attacking Resistant Clones

Improving treatment will require maintaining effectiveness against the sensitive clones while developing new ways to attack the resistant clones. One way is to add drugs, but due to the toxicities of carboplatin (Paraplatin) and paclitaxel, adding a third drug usually requires reducing carboplatin and paclitaxel doses. "Typically what happens is you have some effect against the resistant cancer cells but almost no effect against the sensitive line, and the result is no improvement in overall survival," Dr. Spriggs said.

The goal of dose-dense sequential chemotherapy is to use high doses to eliminate both sensitive and resistant clones, leaving at least the chance of a greater likelihood of cure. The objective is to deliver short intervals of full doses of therapy in the hope of increasing the efficacy of therapy.

In designing the Memorial Sloan-Kettering Cancer Center (MSKCC) trial regimen, Dr. Spriggs decided to continue platinum, which he said is by far the most active agent in ovarian cancer, but to switch from paclitaxel to another drug. Irinotecan was an attractive candidate because it has some single-agent activity in ovarian cancer and because the irinotecan/platinum combination has been active in other areas such as esophageal cancer.

"Because of the in vitro synergy between the two drugs, we felt that it was important to consistently give both platinum and irinotecan each time the dosing occurred. Rather than putting the platinum all on day 1, we left it as a lower dose of cisplatin (30 mg/m²/wk) throughout the 6-week cycle with irinotecan (65 mg/m²/wk), in order to maximize interactions," Dr. Spriggs said.

Encouraging Responses

The study has enrolled 8 patients with suboptimal ovarian cancer. It is also open to patients with suboptimal peritoneal or fallopian cancers. Patients must have received 3 cycles of platinum/taxane therapy and must have CA-125 > 35 U/mL prior to the fourth cycle of therapy. "These women are likely not to have successful treatment, although these are not classically primary resistant patients," Dr. Spriggs said.

Five of 8 patients were able to complete all three planned cycles of irinotecan/cisplatin. Grade 3 diarrhea occurred in 25% of cycles, and grade 1 diarrhea in 38%. Grade 3 myelosuppression occurred in 38% of cycles and grade 2 myelosuppression in 13%. Roughly half the patients had grade 2 or 3 anemia and required erythropoietin or transfusion.

"The responses to therapy have been quite encouraging," Dr. Spriggs said. "Three patients had pathologic complete responses confirmed by negative second-look laparotomy." This is substantially higher than we would expect with 6 cycles of paclitaxel and carboplatin. One patient had a partial response. Two patients had progressive disease. Two went off study early or were inevaluable for response because they didn’t go on to second-look. The other striking thing is that the median duration of response in this group is exceedingly long. All 3 patients who had a negative pathologic second-look surgery are still disease-free with a median follow-up of 28 months."

Toxicity is a concern, and Dr. Spriggs said the investigators are considering changing to a schedule in which the platinum/irinotecan is given 2 weeks on, 1 week off. "Patients would then have 3-week cycles," he said. "Our preliminary experience in another ad hoc group of patients is that there is a lot less diarrhea associated with that schedule."