New Agents Tested with 5-FU in Rectal Cancer

NEW YORK CITY—Irinotecan (Camptosar), oxaliplatin, and other new agents have shown promising activity in rectal cancer and are now being tested in combination regimens with 5-fluorouracil (5-FU) and in new chemoradiotherapy regimens, according to Bruce Minsky, MD.

"The addition of irinotecan to 5-FU/leucovorin has improved overall survival for patients with metastatic rectal cancer. In the adjuvant setting, in the preoperative setting, and in the neoadjuvant setting, irinotecan is an active agent, and we are actively pursuing it," Dr. Minsky said.

"Whether irinotecan will be better than some of the other agents such as oxaliplatin is unknown, but certainly this drug’s activity in advanced disease provides a very good rationale for incorporating it into preoperative regimens and perhaps into postoperative regimens as well," he continued. Dr. Minsky is professor and vice chairman of the Department of Radiation Oncology at Memorial Sloan-Kettering Cancer Center in New York City.

With irinotecan-based programs Dr. Minsky recommended conventional radiation rather than the twice-daily schedule used in some European studies. "The available phase I/phase II data also suggest that irinotecan should be combined with 5-FU based therapy and not used as a single agent in treating rectal cancer," he said.

European Studies

Investigators in the Scandinavian countries as well as in England and some other European countries favor short, intensive, preoperative courses of radiation without chemotherapy. "In general, patients receive 5 Gy times five. That’s 500 cGy for 5 days in a row, followed 1 week later by surgery," Dr. Minsky said. He pointed out that the European studies include patients with T1 through T3 disease, which complicates comparison to US studies, which include only patients with T3 or node-positive disease.

Dr. Minsky said that the Dutch CVKO 95-04 study will report that total mesorectal resection followed by radiation reduced local failure rates but had no effect on survival. "These data suggest that even with the best of operations we still need adjuvant treatment for local control improvement," he said.

"With preoperative therapy in the US, we have already made the assumption that chemoradiation is better than chemotherapy alone, extrapolating from the postoperative data. However, we do not have direct evidence that that is true," Dr. Minsky added. "The European Organization for Research and Treatment of Cancer (EORTC) is addressing the question of giving preoperative radiation alone or preoperative chemoradiation followed by either observation or postoperative chemotherapy. Until this study is completed, the standard of care is not clear."

Unanswered Questions

A number of new agents are being tested in preoperative chemoradiation programs. Selected agents include irinotecan, oxaliplatin, capecitabine (Xeloda), and SU-5416.

Dr. Minsky said that an important unanswered question for clinical researchers is whether a complete response after preoperative therapy improves outcomes. "Retrospective analysis suggests that a high response rate may improve results, but we do not have randomized data proving this point," he said.

Five phase I/phase II studies using preoperative radiation combined with irinotecan alone or with other agents have been presented in the past 2 years at the American Society of Clinical Oncology (ASCO). Two used irinotecan alone as preoperative chemotherapy. Three used irinotecan plus continuous infusion of 5-FU.

Dr. Minsky’s phase I study of preoperative irinotecan and radiation included 28 patients with clinical T3 or T4 rectal cancers. Irinotecan was escalated from 8 to 13 mg/m² given Monday through Friday on weeks 1, 2, 4, and 5 with 50.4 Gy of preoperative radiation. "In this particular study the toxicity rate was high, and almost 30% of patients had grade 3+ toxicity. The pathologic complete response rate was only 5%, which was about 10% or 15% lower than our prior regimens, so we elected to bring this into phase II study only in combination with 5-FU," he said.

More Preoperative Irinotecan Studies

French investigators tested preoperative irinotecan alone plus twice daily radiation. They found that the recommended irinotecan dose level of 90 mg/m² was associated with a 39% incidence of anastomotic leak or abscess. "I would predict that this is associated with twice a day as opposed to once a day pelvic radiation. With twice a day radiation, the acute side effects are higher," Dr. Minsky said.

German researchers conducted a phase II study in 26 rectal cancer patients treated in a preoperative irinotecan/5-FU/radiotherapy trial with continuous infusion 5-FU (250 mg/m² as a 7-day continuous infusion) and weekly irinotecan (40 mg/m² weekly) plus 50.4 Gy of radiation. Dr. Minsky said that toxicity was acceptable, with 15% of patients having grade 3 or worse hematologic toxicity and 35% having grade 3 or worse diarrhea. Twenty-six percent of the 15 patients who went on to surgery had pathologic complete remissions (CR), and 26% had clinical CR.

Weekly Irinotecan

Stanford researchers tested continuous infusion 5-FU (200 mg/m², 7 days per week) plus weekly irinotecan at 50 mg/m² and radiotherapy of 50.4 Gy in a phase II trial including 22 patients with clinical T3 rectal cancer. Grade 3 toxicity included diarrhea in 20% of patients and mucositis in 15%. Dr. Minsky said this trial reported 61% pathologic CR and 17% clinical CR in the 18 patients who had surgery.

Researchers at Thomas Jefferson University in Philadelphia reported 24% pathologic CR and 15% clinical CR in 46 patients with clinical T3 or T4 rectal cancer treated on a phase I protocol. Treatment included weekly irinotecan escalated from 30 to 60 mg/m², 5 or 7 days of continuous infusion 5-FU at 225 to 300 mg/m², and radiotherapy at 45 to 54 Gy. Recommended dose levels were irinotecan 50 mg/m², 5-FU 225 mg/m² for 5 days, and radiotherapy 54 Gy. Dr. Minsky said that these doses are being used in ongoing phase II studies.

New Agents Tested In Preoperative Setting

5-FU-based regimens remain the standard for preoperative chemotherapy, but new agents are being tested in the preoperative setting, combined with pelvic radiation. "Our new preoperative program will incorporate SU-5416, irinotecan, and radiation in a dual phase I trial with two different escalations," Dr. Minsky reported.

"First we will combine continuous infusion 5-FU with standard pelvic radiation and SU-5416. Once we find the recommended dose of SU-5416, we will escalate irinotecan," he continued. "Postoperatively patients will receive all four drugs (including leucovorin), and there will be both pretreatment and posttreatment biopsies."