Volume 1, Number 1
Release date: March, 2008 - Expiration date: March 2009
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Colorectal cancer (CRC) is classified by clinical presentation and pathologic interpretation. Adequate staging of CRC is imperative for appropriate treatment selection. Assessment of the depth of tumor (T) penetration, the number of lymph nodes (N) involved, and presence of distant metastasis (M) must be accurately established in order to determine prognosis. (Figure; NCCN, 2007).

Adjuvant Therapy for Stage II Colorectal Cancer
The controversy surrounding the role of adjuvant chemotherapy for stage II CRC persists (Benson et al., 2004; Zaniboni & Labianca, 2004). Recently reported results from the MOSAIC trial demonstrated that among patients with stage II disease, those with low-risk disease do not receive the same benefit from adjuvant chemotherapy as those with high-risk disease (de Gramont et al., 2007). Guidelines from the American Society of Clinical Oncology (ASCO) do not support the routine use of adjuvant chemotherapy for stage II disease based on the small, relative benefit derived from treatment and the lack of evidence from clinical trials but do suggest that adjuvant chemotherapy may be appropriate for high-risk patients. Guidelines from the National Comprehensive Cancer Network for the treatment of stage II disease support chemotherapy or observation, recognizing that this decision should follow in-depth dialogue between the patient and physician (Table).

Prognostic indicators that influence treatment decisions in CRC include the pathologic review, staging at time of diagnosis, and molecular markers (NCCN, 2007). Evaluation of these indicators is imperative for all stages of CRC, but particularly for stage II disease, as they may strongly influence decisions regarding provision of adjuvant therapy.

The pathologic review determines the grade of the cancer, based on TNM staging. A minimum of 12 lymph nodes must be examined before stage II disease can be established (NCCN, 2007).

Molecular markers have become increasingly important in establishing individualized cancer cell behavior (Benson et al., 2004). In CRC, poorer prognosis is conferred upon patients with p53 mutations, which are present in approximately half of cases, K-ras mutations, which are found frequently, and absence of DCC genes. Low thymidylate synthase levels and microsatellite instability (MSI) in tumor DNA are associated with a more favorable prognosis (Sinicrope et al., 2006).

The decision to treat patients with stage II CRC in the adjuvant setting requires examination of multiple factors. Arriving at the appropriate course of therapy is dependent upon the collaboration between the physician and patient. With this in mind, the NCCN has compiled the following directives for risk assessment of patients with stage II CRC:

Standard of Care for Stage III CRC
The standard of care for stage III CRC is 6 months of adjuvant therapy following surgical resection. The chemotherapeutic options in this setting have expanded during the past several years, and the use of FOLFOX and capecitabine are supported by findings from large controlled studies. The MOSAIC trial showed that patients with stage III disease had superior 6-year overall survival with FOLFOX4 compared to 5-FU/LV (73% vs. 68.6%; p = .029; Andre et al., 2004; de Gramont et al., 2007). The phase III X-ACT trial showed that capecitabine provided consistent benefits over bolus 5-FU/LV with at least equivalent disease-free survival (DFS) and an improved safety profile. Follow-up at 4.3 years revealed significantly higher DFS for capecitabine than for 5-FU/LV (HR = 0.87 [95% CI, 0.75–1.00] p = .0525; Twelves et al., 2005).

Targeted Therapies in the Adjuvant Setting
Considering their mechanisms of action, targeted agents may offer a means of enhancing the efficacy of adjuvant therapy. However, bevacizumab, cetuximab, and panitumumab are currently indicated only for metastatic disease. Ongoing studies are attempting to elucidate the role of targeted agents in the adjuvant setting. The INT-NO147 trial is randomly assigning patients with stage III CRC to receive mFOLFOX6 alone or mFOLFOX6 with cetuximab for 6 months following surgical resection. The primary end point is recurrence-free survival at 3 years. The PETACC8 trial in Europe is randomly assigning patients with stage III CRC to receive FOLFOX4 alone or FOLFOX4 with cetuximab. The primary end point is DFS. The NSABP C-08 trial is randomly assigning patients with stage II or III CRC to receive mFOLFOX6 alone for 6 months or mFOLFOX6 plus bevacizumab for 12 months. This study will be incorporating biologic prognostic variables, including MSI status (National Cancer Institute, 2007). The AVANT trial is evaluating patients with stage II or III CRC randomly assigned to FOLFOX4 alone, FOLFOX4 plus bevacizumab, or XELOX (capecitabine/oxaliplatin) plus bevacizumab. Although the trial was stopped at one point because of a higher rate of sudden death due to cardiovascular events in the XELOX plus bevacizumab arm, it has since been reopened.

Conclusion
The controversy surrounding the role of adjuvant chemotherapy for stage II CRC continues. Treatment decisions should follow in-depth discussion between the patient and physician regarding the benefits versus risks of treatment and prognosis. Based on findings from large, controlled studies, the NCCN supports the use of FOLFOX and capecitabine in the treatment of stage III CRC. Clinical trials are currently underway attempting to elucidate the role of targeted therapies in the adjuvant setting.

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