Adding Irinotecan to Infusional 5-FU Does Not Add Benefit for Stage III Colon Cancer

Five years after surgery, there was no improvement in either disease-free survival or overall survival when irinotecan was added to standard 5-FU treatments delivered via continous infusion for patients with stage III colon cancer.  Adding irinotecan increased the rate of serious side effects.

The PETACC-3  (Pan European Trial Adjuvant Colon Cancer trial was designed to see if adding irinotecan to 5-FU and leucovorin could increase the percentage of stage III patients who were alive and cancer-free (disease-free survival).  It also studied overall survival and relapse-free survival.

In a randomized Phase III trial over 2,000 patients with stage  III colon cancer received either:

  • Twelve standard treatments every two weeks of LV5FU2 (a two-hour infusion of leucovorin followed by a 400 mg/m2 bolus injection of 5-FU and a 22 hour continuous infusion of 5-FU each day for two days — the deGramont regimen)
  • Twelve treatments every two weeks  LV5FU2 (standard deGramont regimen)with an additional infusion of 180 mg/m2 of irinotecan on the first day.

Patient characteristics were well-balanced between the two groups, with more men than women (55 percent vs 45 percent), a median age of 60, and about a third of patients in both groups over 65.  About two thirds had cancer found in fewer than 4 nearby lymph nodes.  None had any sign of cancer elsewhere in their bodies.

Results found no significant differences in survival for stage III patients between the two treatments:

  • Five-year disease-free survival was 56.7 percent with the added irinotecan, 54.3 percent without.
  • Five-year overall survival was 73.6 percent with irinotecan, 71.3 percent without.

Serious (grade 3 and 4) side effects were more common in the irinotecan group:

  • Any  severe adverse event:  24.3 percent in LV5FU2 only group versus 37.7 percent with added irinotecan
  • Diarrhea: 5.6 percent with standard treatmnet, 11.9 percent with irinotecan
  • Neutropenia (lowered white cells counts): 6.0 percent versus 28.2 percent with irinotecan
  • Nausea:  1.2 percent versus 5.5 percent with added irinotecan

About half of patients in the irinotecan arm had some hair loss compared to about one in five patients receiving infusional 5FU.

The results of the trial are similar to those found by Dr. Leonard Saltz and colleagues in the CALGB 89803 clinical trial that compared bolus 5FU with leucovorin to the same bolus regimen with irinotecan (CPT-11).  In that study adding irinotecan did not increase either disease-free or overall survival and did result in more serious side effects and some unexpected deaths.

The addition of CPT-11 to weekly bolus FU plus leucovorin did not result in improvement in DFS or OS in stage III disease, but did increase both lethal and nonlethal toxicity. This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment, and it reinforces the need for randomized controlled adjuvant studies.

The ACCORD-2 trial compared infusional 5FU (LV5FU2) with and without irinotecan and found no difference in disease-free survival, even after adjusting for higher-risk colon cancers in the group of patients who received irinotecan.  ACCORD-2 also found substantially higher levels of grade 3 and 4 neutropenia in the irinotecan group — 4 percent versus 28 percent.  Marc Ychou wrote,

Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.

Irinotecan, also known by its original scientific designation CPT-11 and its brand name Camptosar®, was approved by the FDA in 1998 to treat colorectal cancer that had progressed on standard treatment with 5-FU and leucovorin.  It is now available in generic form.

Writing in the Journal of Clinical Oncology on May 18, 2009 Eric Van Cutsem and the PETACC team concluded,

In summary, PETACC-3 has failed to demonstrate a statistically significant DFS, RFS, or OS advantage for the addition of irinotecan to infusional FU/LV in the adjuvant treatment of stage III colon cancer.

SOURCES: Van Cutsem et al.,Journal of Clinical Oncology, JCO Early Release, May 18, 2009.

Saltz et al., Journal of Clinical Oncology, Volume 25, Number 23, August 10, 2007.

Ychou et al., Annals of Oncology, Volume 2, Number 4, April 2009.

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