Adjuvant Irinotecan Shows Promise for Subset of Stage III Colon Cancer Patients

A trend toward improved survival observed in patients with CpG island methylator phenotype, mismatch repair intact colon cancer

A subset of patients with stage III colon cancer had improved survival rates when treated with adjuvant irinotecan-based therapy, according to a new study published in the journal Gastroenterology. The researchers found in particular that CpG island methylator phenotype (CIMP) might be associated with response to adjuvant irinotecan.

When added to fluorouracil and leucovorin, adjuvant irinotecan therapy showed a trend toward improved overall survival rates for patients with the CIMP. CIMP is seen in about 10 to 20% of colorectal cancers. CIMP, defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumours with distinct clinical and molecular features.

Cohort studies have produced conflicting results on responses of CIMP-positive tumours to chemotherapy. However, in this study in patients with CIMP-negative tumours, addition of irinotecan to fluorouracil/leucovorin resulted in overall survival rate of 68% compared with 78% (p = 0.049) for those receiving fluorouracil/leucovorin alone.

"Our results serve as an example that the molecular characterization of individual tumors may help to determine the most appropriate treatment for patients with colon cancer," said lead study author Dr Stacey Shiovitz from the Department of medicine, University of Washington, Seattle, USA, and the Clinical research division of Fred Hutchinson Cancer Research Center, also in Seattle. "Based on our findings, identification of a tumor's CIMP status should play a greater role in the clinical setting."

Interactions with Treatment and BRAF, KRAS, and Mismatch Repair Status

The researchers analysed data from patients with stage III colon cancer randomly assigned to groups given adjuvant fluorouracil and leucovorin with or without irinotecan after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival.

DNA isolated from available 615 tumour samples was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci.

Of the tumour samples characterised for CIMP status, 145 were CIMP positive (23%). Patients were followed for eight years. Patients with CIMP-positive tumours demonstrated a trend toward improved overall survival (p = 0.07) when treated with adjuvant irinotecan versus the standard treatment at that time, 69% versus 56%, respectively.

Results were most pronounced among patients with stage III CIMP-positive, mismatch repair intact (MMR-I) colon cancer. CIMP was more strongly associated with response to irinotecan/fluorouracil/leucovorin than MMR status.

No significant associations or interactions between CIMP and KRAS or BRAF mutations were observed, suggesting that the effectiveness of this treatment is not influenced by KRAS/BRAF mutation status.

Results for disease-free survival times were comparable among all analyses.

"This analysis serves to increase our understanding of which subset of patients might benefit from irinotecan adjuvant therapy. This research is an important step in the medical community's work to classify tumors into groups that would result in optimized treatment strategies, thus delivering a higher level of personalized care to patients," added Dr Shiovitz.

Future studies are needed to better understand the origin of the CIMP phenotype and to test these findings in a larger subset.

Reference

Shiovitz S, Bertagnoli MM,  Renfro LA, et al. CpG Island Methylator Phenotype Is Associated With Response to Adjuvant Irinotecan-Based Therapy for Stage III Colon Cancer. Gastroenterology 2014; 147(3): 637-645.

This study was supported by funding from the Lattner Family Foundation, RACE Charities, Burroughs Wellcome Fund and National Institutes of Health.