Scope of the Problem
Although most patients undergo complete surgical resection as their primary therapy for stage I, II, and III colon cancer, patients with nodal involvement typically receive systemic chemotherapy (fluorouracil-based) conferring an approximately 10% absolute increase in five year survival (O’Connor et al. 2011). The benefit of chemotherapy in patients with non-nodal involvement is less convincing, and the use of systemic treatment has been implemented in patients who demonstrate poor prognostic features. The American Society of Clinical Oncology (ASCO) guidelines consider the following features as possible reasons to consider systemic therapy, including: elevated preoperative carcinoembryonic antigen (CEA) more than 5 ng/mL, presentation with bowel obstruction or perforation, need for emergent operative procedure, T4 stage at diagnosis, inadequate nodal resect ion (defined as < 12 nodes), or peritumoral lymphatic/venous invasion (Benson et al, 2004). However, consistent results demonstrating the survival advantage for those stage II patients who received adjuvant chemotherapy have not been published and systemic treatment is not without side effects for patients receiving therapy. O’Connor and colleagues (2011) attempted to determine the overall survival benefit of systemic chemotherapy for patients with stage II colon cancer and poor prognostic features in a large study of Medicare beneficiaries who received colectomy for stage II and III primary colon adenocarcinoma.
- Participating patients diagnosed from 1992 to 2005 were identified from the Surveillance, Epidemiology, and End Results (SEER) – Medicare database
- ?2and two-way analysis of variance were used to determine differences in patient and disease-related characteristics
- Five year overall survival was examined using Kaplan-Meier survival analysis and Cox proportional hazards regression with propensity score weighting
- 75% of the patients with stage II cancer (n =24,847) had one or more poor prognostic features
- Adjuvant chemotherapy was received by 20% of the patients with stage II disease and in 57% of patients with stage III disease
- Once adjusted, the five year survival benefit from systemic treatment was seen only in patients with stage III disease (hazard ratio [HR], 0.64; 95% CI, 0.60 to 0.67)
- No survival benefit was observed for patients with stage II cancer without poor prognostic features (HR, 1.02; 95% CI, 0.84 to 1.25) or stage II cancer with any poor prognostic features (HR, 1.03; 95% CI, 0.94 to 1.13)
The authors of the study noted that although some patients with stage II colon cancer have poor prognostic features, the characteristics do not predict survival benefits from chemotherapy in their study. The study population included older individuals which may also demonstrate the reason for a lower use of chemotherapy in node-positive stage III patients (O’Connor et al. 2011). It is possible that younger patients with poor prognostic features may have a different outcome. O’Connor and colleagues conclude that in practice, some stage II patients may be receiving chemotherapy without a clear risk-benefit ratio, and health care practitioners may wish to educate high-risk patients with colon cancer that the survival benefit is likely less than 2% at five years.
Determining the appropriate stage II colon cancer candidate for systemic therapy is challenging; the ASCO guidelines recommend that practitioners consider the use of adjuvant chemotherapy in Stage II patients who present with poor prognostic features. A recently published study by McKenzie and colleagues noted in their population-based analysis of 3,716 patients undergoing curative-intent surgical resection for stage II colon cancer that there was a survival advantage in select patients with stage II disease who received adjuvant chemotherapy (2011). The National Comprehensive Cancer Network guidelines (NCCN) guidelines call for consideration of chemotherapy in stage II patients without poor prognostic features and for the administration of chemotherapy in stage II patients with poor prognostic features, as well as the use of a clinical trial or observation (NCCN, 2011). The NCCN guidelines do note that risk assessment for stage II disease should include a thorough discussion of the potential risks of therapy compared to potential benefits, and report that survival benefits are not greater than 5 percent. This percentage is double the percentage benefit noted in the study reported by O’Connor and colleagues. Although the population in the study is primarily one of older patients, it is clear from this study that poor prognostic features do not predict survival benefit in this group of participants. Since many patients with stage II disease do eventually relapse and die of their disease, new prognostic tools need to be developed to determine who will benefit from adjuvant chemotherapy; gene expression profiles and new diagnostic assays under study may help to answer this question (Meropol, 2011).
Benson III, A.B.,Schrag, D., Somerfield, M.R., Cohen, A.M., Figueredo, A. T., Flynn, P.J.,…Haller, D.G. (2004). American Society ofClinical Oncology recommendations on adjuvant chemotherapy for stage II coloncancer. Journal of Clinical Oncology, 22:3408-3419. doi:10.1200/JCO.2004.05.063 Link to free, full text: http://jco.ascopubs.org/content/22/16/3408.full.pdf
Meropol, N.J. (2011). Ongoing challenge of stage II colon cancer. Journal of Clinical Oncology, 29 (25), 3346-3348. doi: 10.1200/JCO.2011.35.4571Link to free, full text at http://jco.ascopubs.org/content/29/25/3346.full.pdf+html
McKenzie, S., Nelson, R., Mailey, B., Lee, W., Chung, V., Shibata, S., …Kim, J. (2011). Adjuvant chemotherapy improves survival in patients with American Joint Committee on Cancer Stage II colon cancer. Cancer, June 20, epub ahead of print, doi:1002/cncr.26245 Link to abstract at: http://www.ncbi.nlm.nih.gov/pubmed?term=mckenzie%2C%20nelson%2C%20mailey
NCCN (2011). The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Colon Cancer, v. 3. 2011. Retrieved from: http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
O’Connor, E.S., Greenblatt, D.Y., Loconte, N.K., Gangnon, R.E., Liou, J.I., Heise, C.P.,…Smith, M.A. (2011). Adjuvant chemotherapy for stage II colon cancer with poor prognostic features. Journal of Clinical Oncology, 29 (25), 3381-3388. doi: 10.1200/JCO.2010.34.3426 Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/21788561