Q&A: Colorectal Cancer Trials Involving Irinotecan and the Saltz Regimen
(Date reviewed: 12/15/2003)
Is irinotecan causing the deaths?
Will the trials be suspended permanently?
What are the doses of the drugs used in the Saltz regimen and the proposed changes?
Is the Saltz regimen the only approved method for administering the irinotecan drug combination?
In April 2001, two Phase III, NCI-funded colorectal cancer trials (N9741 1 and CLB 89803 2) were temporarily suspended because 28 of 2,060 patients receiving treatment had died, apparently as a result of known toxic side-effects. The treatment used in both trials was a standard multi-drug treatment known as the Saltz regimen, the most widely used combination of irinotecan, 5-flurouracil (5-FU) and leucovorin (LV) in the United States. The Saltz regimen has been considered the standard treatment for advanced colorectal cancer since its approval by the U.S. Food and Drug Administration (FDA) in April 2000. Intensive examination into the causes of the deaths is ongoing, but it is expected that the trials will eventually continue.
Which colorectal cancer studies have been suspended because of patient deaths? And how many deaths have been reported?
As of late April 2001, two Phase III studies sponsored by the National Cancer Institute (NCI) and involving a multi-drug treatment known as the Saltz regimen, which is a combination of irinotecan, 5-flurouracil (5-FU) and leucovorin (LV), have been suspended:
- NCCTG-N9741, carried out by North Central Cancer Treatment Group and others, and entitled "Phase III Randomized Study of Combinations of Oxaliplatin, Fluorouracil, Leucovorin Calcium, and Irinotecan as Initial Therapy in Patients With Advanced Adenocarcinoma of the Colon and Rectum."
This study, evaluating how oxaliplatin performs as compared to irinotecan as part of first-line therapy for metastatic colorectal cancer, had accrued more than 800 patients with colorectal cancer at the time of suspension--about 300 more patients are needed to complete the study. For patients receiving the Saltz regimen, fourteen deaths have been reported
- CLB-89803, carried out by the Cancer and Leukemia Group B and others, and entitled "Phase III Randomized Study of Fluorouracil and Leucovorin Calcium With or Without Irinotecan Following Curative Resection in Patients With Stage III Colon Cancer."
This trial, focusing on whether the irinotecan combination can keep tumors from recurring in patients whose initial colorectal cancer is successfully removed by surgery, had completed recruiting the 1260 patients needed at the time of suspension. Fourteen deaths have occurred among patients receiving the Saltz regimen.
Irinotecan, also known as CPT-11 and Camptosar®, is a drug that stops cancer cells from growing by inhibiting a key step in cell division. Specifically, irinotecan inhibits an enzyme known as topoisomerase that normally allows the cell's DNA, or genetic material, to unwind during the process of cell division. When cell division is stopped, the cancer ceases growing.
Is irinotecan causing the deaths?
It appears that a particular combination of irinotecan, 5-FU and LV -- known as the Saltz regimen -- has potentially lethal side effects. The metastatic colorectal trial (N9741) has a treatment arm that includes oxaliplatin and irinotecan and no increased deaths have been noted in that arm.
Will the trials be suspended permanently?
Further examination into the causes of the deaths will continue, but it is expected that the trials will continue. The national cooperative research groups responsible for these studies will submit a clear set of study changes, and amendments to implement these changes will be reviewed by NCI before the studies can be restarted.
It is anticipated that the N9741 study will continue with modifications -- a lowering of the initial doses of irinotecan and 5-FU and continued dose decreases and holds in treatment if side effects are seen. In addition, patients will be very closely monitored for any potential toxic effects.
The other trial, CLB-89803, for post-operative adjuvant treatment, had already enrolled the intended number of patients and will be closed to additional recruitment. Treatment modifications for patients on this study and receiving treatment have been put into place. Many of these patients appear not to be at high risk for severe toxicity and death because they have already received the treatment for some time. Most of the problems with toxicity seem to be associated with the initial exposure to the drugs.
What are the doses of the drugs used in the Saltz regimen and the proposed changes?
Initial doses for the current Saltz regimen:
- 125 mg/m2 irinotecan
- 500 mg/m2 5-FU
- 20 mg/m2 LV
Proposed initial doses for modified Saltz regimen:
- 100 mg/m2 irinotecan
- 400 mg/m2 5-FU
- 20 mg/m2 LV
In both regimens, patients receive all drugs intravenously. The irinotecan is administered over 90 minutes followed by LV over 15 minutes. 5-FU is administered by IV push and takes about a minute or so. The drugs are given once per week for four weeks, followed by two weeks of rest. This course is repeated for six cycles.
It is not known if the doses in the modified Saltz regimen will prove as effective as the higher doses approved by the FDA in April 2000.
Is the Saltz regimen the only approved method for administering the irinotecan drug combination?
Another schedule of infusing the drugs, in which 5-FU is administered over 24 hours, is also approved by the FDA. This method is currently more commonly used in Europe than in North America.
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