Elsevier

Seminars in Oncology

Volume 38, Issue 4, August 2011, Pages 511-520
Seminars in Oncology

Colorectal cancer
Challenges in the Management of Stage II Colon Cancer

https://doi.org/10.1053/j.seminoncol.2011.05.005Get rights and content

Approximately one third of patients diagnosed with early-stage colon cancer will present with lymph node involvement (stage III) and about one quarter with transmural bowel wall invasion but negative lymph nodes (stage II). Adjuvant chemotherapy targets micrometastatic disease to improve disease-free (DFS) and overall survival (OS). While beneficial for stage III patients, the role of adjuvant chemotherapy is unestablished in stage II disease. This likely relates to the improved outcome of these patients, and the difficulties in developing studies with sufficient power to document benefit in this patient population. However, recent investigation also suggests that molecular differences may exist between stage II and III cancers and within stage II patients. Validated pathologic prognostic markers are useful at identifying stage II patients at high risk for recurrence for whom the benefit from adjuvant chemotherapy may be greater. Such high-risk features include higher T stage (T4 v T3), suboptimal lymph node retrieval, presence of lymphovascular invasion, bowel obstruction, or bowel perforation, and poorly differentiated histology. However, for the majority of patients who do not carry any of these adverse features and are classified as “average-risk” stage II patients, the benefit of adjuvant chemotherapy remains unproven. Emerging understanding of the underlying biology of stage II colon cancer has identified molecular markers that may change this paradigm and improve our risk assessment and treatment choices for stage II disease. Assessment of microsatellite stability (MSI), which serves as a marker for DNA mismatch repair (MMR) system function, has emerged as a useful tool for risk stratification of patients with stage II colon cancer. Patients with high frequency of MSI have been shown to have increased OS and limited benefit from 5-fluorouracil (5-FU)–based chemotherapy. Additional research is necessary to clearly define the most appropriate way to use this marker and others in routine clinical practice.

Section snippets

Tumor Stage

The American Joint Committee of Cancer (AJCC) 7th edition staging manual classifies stage II tumors as T3 with invasion through the muscularis propria or into pericolic tissue, and T4 with invasion into adherent organs.10 T4 tumors are subclassified into T4a (penetrating visceral peritoneum) and T4b (penetrating other organs/structures). A Surveillance, Epidemiology, and End Results (SEER) database analysis supported the revised staging by demonstrating significant differences in 5-year

Molecular Markers

Increasing understanding of colon cancer biology has identified potential molecular markers to risk-stratify early-stage colon cancer patients. This may be most useful for patients with stage II colon cancer where adjuvant chemotherapy is debated. However, tests using immunohistochemistry or gene expression analysis are costly. In addition, proper validation of markers, techniques, and cutoff values is critical.

Addition of Oxaliplatin

While the role of adjuvant combination chemotherapy is well established in stage III colon cancer, the benefit in stage II patients remains controversial. The Multicenter International Study of Oxaliplatin/5-FU/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) study demonstrated improved DFS and OS for stage III patients treated with FOLFOX compared with those treated with 5-FU alone (DFS HR 0.80, P = .003; OS HR 0.84, P = .046 for OS), and established FOLFOX as the current standard

Summary

Adjuvant therapy for stage II colon cancer remains a topic of debate, primarily for “average-risk” patients without clear pathologic risk factors. As our knowledge of underlying biology expands, molecular markers will play a more prominent role in our decision-making. To date, MSI-H status has emerged as the marker most closely linked to improved outcome and limited benefit from adjuvant fluoropyrimidine therapy. Much work still remains to be done to improve our ability to risk-stratify

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