Risk Assessment in Stage II Colon Cancer: To Treat or Not to Treat

Two decades since the first demonstration that fluorouracil (5-FU)-based adjuvant chemotherapy improves outcomes in resected colon cancer,[1] clinicians are still struggling with the question of which patients with stage II colon cancer should receive postoperative therapy. It is well-accepted that the absolute survival benefit associated with 5-FU–based therapy for unselected patients with stage II colon cancer is in the range of 3% at 5 years. But it is also obvious that some patients with stage II cancers have excellent outcomes and do not require additional therapy, whereas other patients have cancers that biologically behave more like stage III tumors.

Over the past years, our understanding of stage II colon cancer has made significant advances leading to a refinement in the identification of the patient population and the treatment options considered appropriate as adjuvant therapy in this setting.

First of all, it has been shown that the addition of oxaliplatin (Eloxatin) to 5-FU does not improve overall survival outcomes in unselected stage II colon cancer, and that even in patients with so-called “high-risk” stage II colon cancers the use of oxaliplatin might improve disease-free but not overall survival.[2]

With regard to staging, T4N0 tumors (stage IIB according to the American Joint Committee on Cancer [AJCC] Cancer Staging Manual, 6th edition, or stage IIB/IIC per the 7th edition) have clearly been associated with poor prognosis that is worse than T3N1 colon cancers.[3,4]

In addition, the number of lymph nodes identified in the surgical specimen has routinely been correlated with clinical outcome.[5] This finding appears to go beyond the fact that the number of analyzed lymph nodes will enhance accurate staging; unknown biological factors potentially reflecting the immunocompetence of the patient have been discussed to explain this phenomenon. Other clinical parameters such as obstruction/perforation at presentation, undifferentiated histology, perineural infiltration, and lymphovascular invasion might be helpful to further characterize the prognosis of patients with stage II colon cancer although not all of these parameters have been validated in multivariate analyses.[6]

More recently, novel approaches to identify single molecular factors or molecular signatures as prognostic markers in colon cancer have shown promising results.[7] In fact, various studies have confirmed that those 10% to 20% of stage II tumors exhibiting a defective mismatch repair (MMR-D) or microsatellite-unstable (MSI-H) phenotype have an excellent prognosis, are potentially 5-FU resistant, and should thus not receive adjuvant 5-FU.[7-9] Unfortunately, with the exception of MSI-H/MMR-D tumors no further predictive markers for chemosensitivity in adjuvant colon cancer have been identified to date.

Molecular techniques might also be helpful to enhance the correct classification of stage II cancers as truly lymph node negative. In this context, the detection of guanylyl cyclase 2C (GCC), an enzyme exclusively expressed in luminal cells of the intestinal tract, in lymph nodes of cancers characterized as stage II by conventional means has been associated with poor prognosis.[10]

With this background, the three papers presented in this supplement to ONCOLOGY will discuss adjuvant therapy considerations in stage II colon cancer from different angles.

Nadine Jackson McCleary and Jeffrey Meyerhardt provide an overview of phase III trials in adjuvant colon cancer, analyzing clinical data to identify patients with stage II colon cancer who should or should not receive adjuvant therapy. They discuss in detail the use of adjuvant therapy in the elderly patient, a complex issue with great importance for clinical practice.

The paper by John Marshall highlights questions on patient selection for adjuvant therapy in stage II colon cancer beyond the standard criteria of TNM staging and conventional, clinical risk factors for recurrence. Dr. Marshall evaluates the promise of refined treatment decisions with the use of molecular tests that will soon enter clinical practice.

Ian Lavery and Luiz Felipe de Campos-Lobato give a surgeon’s perspective on risk assessment in stage II colon cancer by outlining the new AJCC version 7 classification that has just come into effect in 2010. They further discuss the role of surgical techniques to ensure adequate lymph node sampling and tumor-free resection margins as a precondition for curative surgery.

FIGURE 1

Decision algorithm in adjuvant therapy.

The prerogative as editor allows me to integrate the issues discussed in the three papers with regard to their implications for clinical practice and propose a strategic approach toward the management of stage II colon cancers (Figure 1).

In stage II colon cancer, patients with T4 tumors should receive treatment according to guidelines established for stage III disease in view of their poor prognosis. This would lead to the recommendation of an oxaliplatin-based adjuvant therapy for most of these patients. A similar approach can be considered for patients in whom fewer than 12 lymph nodes have been identified in the surgical specimen-after the case has been discussed with the pathologist. If none of these two high-risk features is present, a MMR-D phenotype should be excluded since these cancers exhibit excellent prognosis (3-year disease-free survival of 90% to 95%) and should not receive adjuvant therapy.

For the remaining group of intermediate-risk patients, molecular signatures could provide further data on prognosis. The first molecular signature in colon cancer is expected to be available to clinicians this year. Hopefully at some time in the future also predictive information will be available leading to further refinement of our adjuvant approach toward patients with stage II colon cancer.

This supplement and associated publication costs were funded by Genomic Health.

References:

REFERENCES

1. Moertel CG, Fleming TR, Macdonald JS, et al: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352-358, 1990.

2. Andre T, Boni C, Navarro M, et al: Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27:3109-3116, 2009.

3. Gunderson LL, Jessup JM, Sargent DJ, et al: Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol 2009 Nov 30 [Epub ahead of print].

4. O’Connell JB, Maggard MA, Ko CY: Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 96:1420-1425, 2004.

5. Chang GJ, Rodriguez-Bigas MA, Skibber JM, et al: Lymph node evaluation and survival after curative resection of colon cancer: Systematic review. J Natl Cancer Inst 99:433-441, 2007.

6. Tsai HL, Chu KS, Huang YH, et al: Predictive factors of early relapse in UICC stage I-III colorectal cancer patients after curative resection. J Surg Oncol 100:736-743, 2009.

7. Kerr D, Gray R, Quirke P, et al: A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study (4000). J Clin Oncol 27(suppl 15s):2009.

8. Ribic CM, Sargent DJ, Moore MJ, et al: Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247-257, 2003.

9. Sargent DJ, Marsoni S, Thibodeau SN, et al: Confirmation of deficient mismatch repair (dMMR) as a predictive marker for lack of benefit from 5-FU based chemotherapy in stage II and III colon cancer (CC): A pooled molecular reanalysis of randomized chemotherapy trials (abstract 4008). J Clin Oncol 26(May 20 suppl):2008.

10. Waldman SA, Hyslop T, Schulz S, et al: Association of GUCY2C expression in lymph nodes with time to recurrence and disease-free survival in pN0 colorectal cancer. JAMA 301:745-752, 2009.