Adjuvant Chemotherapy Benefit in Stage II Colon Cancers Is Small, May Even Cause Harm, Depending on Prognostic Markers

February 2014, Vol 5, No 1

San Francisco, CA—The majority of patients with stage II colorectal cancer (CRC) have a good prognosis with surgery and gain little with adjuvant chemotherapy, said Richard M. Goldberg, MD, Physician-in-Chief, Ohio State University Comprehensive Cancer Center, Columbus, OH, at the 2014 Gastrointestinal Cancers Symposium.

Microsatellite instability (MSI) manifested by deficient mismatch repair (dMMR) carries a particularly favorable prognosis (compared with microsatellite stable tumors) for patients with colon cancer that does not warrant adjuvant treatment. “Available data…do not provide compelling evidence for treating patients with MSI/dMMR stage II disease with chemotherapy, and have shown that treatment may be potentially harmful,” Dr Goldberg said.

In general, the recurrence rate in stage II colon cancer is 20% to 25%. The risk of recurrence after surgery can be estimated based on anatomic and genomic factors. Only patients with high-risk features appear to derive benefit from adjuvant therapy, and even then only modestly, Dr Goldberg said.

Patients with stage II disease who are at high risk for recurrence include those with a T4 tumor, poorly differentiated histology, lymphovascular invasion, bowel obstruction, less than 12 lymph nodes examined, perineural invasion, perforation, and positive margins. Patients exhibiting such features have an approximate 7% improvement in 3-year disease-free survival (DFS) when given adjuvant FOLFOX (5-fluorouracil [5-FU], leucovorin, and oxaliplatin [Eloxatin]) compared with 5-FU alone.

The Cancer and Leukemia Group B (CALGB) 9581 study investigators con­firmed that low-risk patients with colon cancer have extremely favorable long-term survival in the absence of adjuvant treatment, said Dr Goldberg. The CALGB 9581 trial enrolled low-risk patients, excluding those with T4b tumors, obstruction, perforation, or positive margins.

The 5-year overall survival (OS) rate was 93%, regardless of whether they received adjuvant treatment, and the OS was better than 90%, regardless of the subpopulation analyzed based on age, race, or ethnicity.

Low- or average-risk patients may even derive harm from adjuvant chemotherapy. “MSI high [MSI-H] phenotype is consistently a favorable prognostic marker,” said Dr Goldberg.

In a 2003 analysis, Ribic and colleagues showed worse outcomes in patients with stage II/III disease and MSI-H colon tumors who had received adjuvant chemotherapy: the 5-year DFS rate was 69.3% in patients with MSI-H tumors who received 5-FU plus leucovorin compared with 82.9% in patients with MSI-H tumors who did not receive adjuvant therapy. Similarly, the 5-year OS was reduced with chemotherapy administration (70.7% vs 88%, respectively; P = .07).

A 2010 pooled analysis of adjuvant trials showed a detrimental effect of chemotherapy in patients with stage II disease, but not in patients with stage III disease. In the Quick and Simple and Reliable (QUASAR) trial, comparing 5-FU plus leucovorin with no chemotherapy for stage II disease, 11% of tumors were dMMR; although the risk of recurrence was more than double in dMMR versus MMR-proficient tumors (pMMR), it was not predictive of a benefit to chemotherapy, said Dr Goldberg.

Tumors in patients with CRC and Lynch syndrome and in patients with sporadic MSI-H tumors are believed to develop by 2 distinct molecular pathways. Up to 70% of sporadic MSI-H tumors have mutations in the BRAF gene, whereas Lynch syndrome–associated tumors have virtually no mutations in BRAF. One study showed that 5-FU helped the patients who had Lynch syndrome and did not help the patients with acquired MSI, according to Dr Goldberg. “So it may not be as simple as we hoped…but it is certainly a provocative finding,” he said.

Dr Goldberg concluded by providing a suggested algorithm for stage II colon cancer. “Be sure patients are adequately staged, and do mismatch repair,” he suggested.

Patients with T3 and dMMR tumors are low risk, “and don’t even think about treatment.” In patients with T4 and pMMR tumors, “I would give FOLFOX without thinking about it very much, unless there is a contraindication,” Dr Goldberg said. The vast majority of stage II cancers are T3 and pMMR tumors, in which case gene-expression profiling may be useful, but treatment with 5-FU plus capecitabine is reasonable.

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