Oxaliplatin-Based Regimens Prove Active in Advanced Colorectal Cancer

NASHVILLE, Tennessee—Regimens that contain oxaliplatin (Eloxatin) as well as irintoecan (CPT-11, Camptosar) and fluorouracil (5-FU)/ leucovorin have produced prolonged survival of 18 to 21 months in patients with advanced colorectal cancer and should be considered for first-line therapy, according to Mace L. Rothenberg, MD. Dr. Rothenberg, who is professor of medicine at Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, reviewed the current status of oxaliplatin-based regimens.

Oxaliplatin forms adducts that are bulkier and more hydrophobic than those formed by cisplatin and as a result may be more difficult to repair. Dr. Rothenberg said that oxaliplatin is also active against tumor cell lines that are resistant to cisplatin in vitro. "Colon cancer cell lines are not very sensitive to cisplatin or carboplatin (Paraplatin). Many are much more sensitive to oxaliplatin," Dr. Rothenberg said.

Improved Survival Not Initially Seen

Three European phase III trials of 5-FU/leucovorin with or without oxaliplatin showed a doubling or tripling of response rate and significant increases in progression-free survival, Dr. Rothenberg said, but this did not translate into an increase in overall survival. The US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee recommended in March 2000 against approval of oxaliplatin for first-line treatment of advanced colorectal cancer

"There is a requirement by the FDA that a therapy that adds toxicity must offset that toxicity with a tangible benefit to patients (ie, survival)," Dr. Rothenberg explained. "The committee also had knowledge of first-line irinotecan data, to be presented that same day, demonstrating a survival advantage in two phase III studies."

In analyzing why there was no improvement in survival despite improved time to progression, Dr. Rothenberg said that the trials might have been underpowered to detect a survival difference and might have been affected by subsequent therapy, including oxaliplatin that was administered to patients originally treated with 5-FU/leucovorin.

Shifted Strategy

At this point, the developer (Sanofi) shifted strategy to use of oxaliplatin as second-line treatment for patients whose disease had progressed despite treatment with irinotecan, fluorouracil, leucovorin (IFL). This indication received accelerated approved in August 2002.

A pivotal study in that application was a phase III trial comparing 5-FU/leucovorin to oxaliplatin and to FOLFOX4 (fluorouracil, leucovorin, oxaliplatin) in patients who had recurrent disease after IFL (see Table 1). A planned interim analysis conducted when 150 patients on each arm had at least 12 weeks of follow-up showed that confirmed response rate was 0% with 5-FU/leucovorin, 1% with oxaliplatin, and 9% with FOLFOX4 (P = .0002 for 5-FU/leucovorin vs FOLFOX4). "You need both 5-FU and oxaliplatin to get these results," Dr. Rothenberg said.

Median time to progression (TTP) was 2.7 months with 5-FU/leucovorin, 1.6 months with oxaliplatin alone, and 4.6 months with FOLFOX4 (P < .002 for 5-FU/leucovorin vs FOLFOX4). Data on survival and impact on tumor-related symptoms are expected in 2003.

Persistent, cumulative neuropathy occurs with this regimen (see Table 2). "This was an interim analysis and so may underestimate the incidence of this problem," Dr. Rothenberg said.

"The combination of oxaliplatin, bolus and infusional 5-FU, and leucovorin (FOLFOX4) is superior to 5-FU/leucovorin as second-line therapy in patients with progressive disease after IFL. When added to 5-FU/leucovorin, oxaliplatin is associated with increased rates of nausea, diarrhea, neutropenia, and neurotoxicity, but these toxicities are predictable and manageable, and efforts to reduce or delay neurotoxicity are currently being tested in clinical trials.

Other New Developments

An intergroup trial (N9741) of first-line treatment of metastatic colorectal cancer showed 1-year survival of 58% with IFL vs 71% with FOLFOX4 and 65% with oxaliplatin/irinotecan, Dr. Rothenberg reported.

Sequence remains a consideration, but a phase III study of FOLFIRI (fluorouracil, leucovorin, oxaliplatin, see Table 3) followed by FOLFOX or vice versa showed no significant differences in response or overall survival. This study was conducted by Tournigand and colleagues and reported at the 2001 meeting of the American Society of Clinical Oncology (ASCO abstract 494).

"Median survival for both arms of this trial was the highest of any phase III trial reported in advanced colorectal cancer. We are now breaking the 20-month survival barrier in this disease," Dr. Rothenberg said.