Oxaliplatin Regimen: New Option


Colorectal cancer remains the second most common cause of cancer mortality in the United States. Once the disease has spread to distant organs, mean survival in patients who choose not to undergo chemotherapy is approximately 6 months. Currently, the best chemotherapeutic regimen is the combination of irinotecan, 5-fluorouracil and leucovorin. This regimen has improved average survival to more than 14 months.

At ASCO, investigators reported a trial comparing this standard with oxaliplatin plus 5-fluorouracil/leucovorin. Investigators at 150 or medical centers around North America randomized nearly 800 patients with advanced colorectal cancer into the trial, known as N9741.

A significant survival advantage emerged for oxaliplatin plus 5-fluorouracil/leucovorin combination. Patients on that regimen survived an average of 18.6 months, versus 14.1 months for patients in the standard arm of irinotecan and 5-fluorouracil/leucovorin. In addition, time to tumor progression favored the oxaliplatin combination by 1.9 months.

According to Dr. Goldberg, 18.6 months is the longest average survival ever reported in a major trial in advanced colorectal cancer in the United States.

Patients on oxaliplatin plus 5-fluorouracil/leucovorin had less diarrhea, nausea, vomiting, severe infections and hair loss than patients on the reference arm. The oxaliplatin regimen does commonly cause numbness and tingling that is aggravated by cold exposure. This affected many patients, but generally only responders, since this adverse effect typically occurs late in therapy.

These results suggest oxaliplatin deserves a place in the armamentarium of agents for treatment of colorectal cancer, according to Dr. Goldberg.

Prominent colorectal cancer researcher Dr. Leonard Saltz said the regimen of oxaliplatin, 5-fluorouracil and leucovorin now represents an additional treatment option with a distinctly different side effect profile that may be more acceptable to some patients. However, he cautioned against overestimating the additional benefit this new treatment confers. Colorectal cancer remains an important cause of cancer related mortality.

No Excess Death with Irinotecan Regimens

The irinotecan, 5-fluorouracil and leucovorin combination, given as bolus or infusion, improves survival over 5-fluorouracil/leucovorin alone. However, investigators recently noted a 4.5% rate of death from any cause within 60 days of starting bolus treatment in the N9741 study. This contrasts with previously reported mortality rates of 1% for both the irinotecan plus 5-fluorouracil/leucovorin regimen and 5-fluorouracil/leucovorin alone.

However, earlier trials measured mortality differently: they typically looked at drug related deaths within 30 days of the end of therapy.

To put the 4.5% death rate into perspective, investigators calculated 60 day all cause mortality for randomized United States and European trials of irinotecan plus 5-fluorouracil/leucovorin or 5-fluorouracil/leucovorin. In both registration and post approval studies, 60 day all cause mortality rates for irinotecan plus 5-fluorouracil/leucovorin were as similar or lower than those for 5-fluorouracil/leucovorin.

For bolus treatment, 60 day mortality rates were 6.7% and 7.6% for the Mayo Clinic and Roswell Park 5-fluorouracil/leucovorin regimens, respectively. Combination irinotecan plus 5-fluorouracil/leucovorin, was actually somewhat lower at 4.4%, and lower still for oxaliplatin with 5-fluorouracil/leucovorin (1.9%).

Investigators said the analysis showed that irinotecan-containing regimens are not associated with excess risk of mortality, and treatment choice should be made according to efficacy and acute or chronic safety profiles, not concerns regarding early mortality.

Second Line Irinotecan: Safety Differences Emerge

After first line 5-fluorouracil treatment, an approved option for second line therapy of metastatic colorectal cancer in the United States is irinotecan in one of two schedules. These approved regimens, however, have never been directly compared in a safety and efficacy trial.

Dr. Fuchs and colleagues randomized 291 patients with proven metastatic colorectal cancer who progressed on first line 5-fluorouracil to an irinotecan regimen. The irinotecan regimens included either a 6 week course (125 mg/m² weekly for 4 weeks, 2 weeks rest) or a 3 week course (350 mg/m² every 3 weeks).

One year survival was 46% for the weekly group, and not significantly different for the every three weeks group (41%). Median survival was 9.9 months for both groups. Time to progression was not significantly different (4 months for weekly and 3 months for every 3 weeks).

Significant differences emerged in adverse effects. Grade 3-4 diarrhea occurred in 36% of the patients randomized to weekly irinotecan, but only 19% for patients in the every 3 weeks group (P = 0.002). Also, at week 4, more patients were able to receive full dose in the every 3 weeks group. Yet there were significantly more cholinergic symptoms at the first infusion for patients in the every 3 weeks group (61% versus 31%, P < 0.0001).

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