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Stage III MSI High Colon Cancer May Benefit from Irinotecan

About 15 percent of people with stage III colon cancer may have fewer recurrences and better survival when they are treated with irinotecan. Although all stage III colon cancers don’t have an additional benefit when irinotecan is added to bolus 5-FU and leucovorin in a treatment called IFL, this smaller group does.

About 15 percent of colon cancers develop when damaged DNA is not repaired and mutated cells grow into malignant tumors.  So-called deficient mismatch repair (dMMR) tumors have features different from most colorectal cancer, including a better prognosis.  They also have a very poor response to 5-FU-based chemotherapy.

However, researchers studying tumor tissue from patients enrolled in a clinical trial comparing 5-FU and leucovorin alone to 5-FU, leucovorin, and irinotecan found that those with deficient mismatch repair tumors who received irinotecan had better disease-free survival and overall survival at five years than patients whose mismatch repair genes were working.  Those with dMMR on the 5-FU-only arm of the trial had no similar benefit.

Deficient mismatch repair can be identified by measuring  mutated microsatellites — short lengths of DNA that are abnormally shorter or longer because they were not caught and corrected during cell division.  This is known as microsatellite instability or MSI. dMMR can also be diagnosed by looking for missing mismatch repair gene expression in tumor tissue.

To find out if there was any benefit for irinotecan in deficient mismatch repair tumors, researchers tested tissue saved after surgery for both MSI and loss of MLH1 and MSH2 gene expression from patients enrolled in the CALGB-89803 clinical trial.

CALGB-89803 randomly assigned stage III colon cancer patients after surgery to chemotherapy to an IV shot of 5-FU plus intravenous leucovorin (FU/LV) or the same 5-FU and leucovorin treatment plus irinotecan (IFL).   Chemotherapy was given every week.

For all of the nearly 1,300 people enrolled in the trial, there was no significant difference in overall survival after 5 years (70 percent for IFL and 72 percent for FU/LV).  There was a significant increase in toxic side effects in the IFL arm and some unexpected deaths.

However, when tumors were analyzed by deficient mismatch repair status (dMMR), as evidenced by high microsatellite instability (MSI-H) compared to intact mismatch repair (iMMR) or low or stable microsatellite stability (MSI-L/S), adding irinotecan did make a difference in disease free survival and overall survival five years after surgery:

Five year disease free survival

  • All patients:  61 percent
  • FU/LV and MMR-D (MSI-high): 57 percent
  • FU/LV and MMR-I (MSI low or stable): 51 percent   (no significant difference)
  • IFL and MMR-I: 59 percent
  • IFL and MMR-D: 76 percent  (significant difference in this group)

Overall survival at five years

  • All patients:  67 percent
  • FU/LV MMR-D:  67 percent
  • FU/LV MMR-I:   72 percent
  • IFL  MMR-I:   70 percent
  • IFL MMR-D: 78 percent  (significant difference in this group of patients)

Some, but not all, dMMR tumors are caused by inherited genetic mutations in mismatch repair genes.  Lynch syndrome or hereditary non-polyposis colon cancer (HNPCC) leads to colorectal, uterine, and other cancers through such inherited mutations.

Since colon cancer caused by deficient mismatch repair does not benefit from 5-FU chemotherapy, it is common to test for MSI or missing MLH1 or MSH2 gene expression in tissue removed during surgery before prescribing chemotherapy.  Testing tissue also screens for Lynch syndrome.

Monica M. Bertagnolli, M.D. and her colleague in the Cancer and Leukemia Group B (CALGB) concluded,

Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV.

SOURCE:  Bertagnolli et al., Journal of Clinical Oncology, Volume 17, Number 11, April 10, 2009.

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2 Comments

  1. Christina Powers said:

    This is a very interesting article. My husband was diagnosed July 08 with Stage 3 CRC. Because of his young age (39 years at time of diagnosis) they suspected Lynch and began genetic testing after he had a right hemicolectomy. Due to inconclusive findings it took until June 4, 2009 to diagnose him with Lynch. Of course, during this time he was given the standard Folfox treatment…which we now realize was likely ineffective. We are looking to talk to someone who is an expert on Lynch and can provide us with advice on where to go from here. Is getting another type of chemo, such as Irinotecan, the next logical step?…Or do we just fight to get the proper scans (CT and PT) that we have been denied by our insurance company so that we can monitor him more closely. We would like to speak with someone who is an expert in Lynch as this syndrome appears to not be on the radar of many oncologists and it is, at best, a side note on most cancer sites (and most CRC online diagnostics do not even use Lynch to determine life expectancy, etc…) Any advice would be much appreciated.

  2. Kate Murphy said:

    At this point, it is very important to set up a schedule of regular surveillance to watch for new polyps or early cancers.

    Another colon, rectal, or Lynch-related cancer is a high risk, and it is probably more likely than spread of the current cancer.

    Most experts recommend colonoscopy every 1 to 2 years because Lynch cancers develop much more rapidly than sporadic colorectal cancers. (My own third colon cancer was diagnosed 15 months after a clear colonoscopy.)

    Since Lynch syndrome cancers can also occur in other places in the gastrointestinal tract and in the kidney, brain, and skin in men, you’ll want to talk with a good genetics expert about a plan for finding these cancers early as well.

    Finally, your children and your husband’s siblings and parents should be tested for the gene that was identified in him. They won’t need the full spectrum of gene testing he had, just testing for his mutation. This is not very expensive and should be covered by insurance.

    If they carry the gene — there is a 50/50 chance that they will — they need counseling about a surveillance program too. Children usually begin frequent (1-2 year) colonoscopy at age 20 or so.

    The women with a mutation are at very high risk of endometrial cancer and an increased risk of ovarian cancer, so they’ll need regular testing to find those cancers early when they are most curable.

    You can find a genetics counselor who specializes in cancer and will be very aware of your husband’s needs and probably can refer him to an oncologist who also understands Lynch syndrome by searching the membership of the National Society of Genetic Counselors.

    This is the advanced search page that will let you put in a city or zip code and also highlight “cancer” in area of specialization.

    If you don’t get a response to the city you enter, expand your search a little to a larger nearby city or your state.

    It may help you to know that this month I will have lived 26 years since my first Lynch colon cancer diagnosis at stage IIIB. I have had several other cancers since then, including colon cancer two years ago, but I am healthy and cancer-free today.

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