Updated 6 May 2008

Surgery

Surgical resection of colon cancer is the accepted therapeutic approach. Wide clearance of the primary cancer with resection margins 5-10 cm from the cancer should be achieved. A wide removal of the mesentery with common vascular supply to achieve clearance of the appropriate nodal drainage basin should be carried out.

For selected patients, laparoscopic resection may be offered. In experienced hands, the laparoscopic procedure provides reduced hospitalization with equivalent oncologic outcome [Young-Fadok 2007].

Solitary or limited recurrences of colorectal cancer, especially in the liver or lung, are potentially curable by surgical excision. See Management of Isolated Liver or Lung Metastases.

Adjuvant Treatment

Adjuvant therapy is given to patients who have undergone potentially curative surgery, and who are considered at high risk for relapse.

Adjuvant chemotherapy is not required in Stage 1 disease.

The best evidence in support of adjuvant chemotherapy is in node positive (Stage 3) colon cancer. Studies have shown an improvement in cure or 5 year disease-free survival on the order of 10-15% in patients with node positive colon cancer. Some studies have shown the relative benefit of adjuvant chemotherapy in node negative (stage 2) disease is of similar magnitude but other studies have not shown any benefit. As the risk of relapse is generally less than for node positive disease, the potential absolute benefit of adjuvant treatment is smaller and would not routinely justify the toxicities of adjuvant chemotherapy. There are subgroups of patients with node negative disease, however, in whom the risk of relapse is greater than for node negative colon cancers in general. "High-risk" features include perforation and T4 status. In these populations, the higher recurrence risk merits consideration of adjuvant therapy. Some studies cite differentiation (ie poorly differentiated or anaplastic cancers) as an independent risk factor. There is some controversy here, as some poorly differentiated cancers may represent the "medullary" variant, associated with microsatellite instability (MSI). Patients with node negative MSI positive tumors are thought to do better than their "truly" poorly differentiated counterparts and may not benefit from (or indeed do worse with) adjuvant chemotherapy. Discussion with the pathologist and/or a GI team member may be helpful in distinguishing these.

Nodal status (ie negative (N0) or positive (N1-2)) should be based on the evaluation of a minimum of twelve lymph nodes. The retrieval and/or identification of fewer than twelve nodes is associated with poorer outcome, potentially related to inadequate staging (as, with fewer nodes evaluated, some node positive patients may be misclassified as node negative.) Some practitioners use low number of nodes retrieved/identified as a high-risk feature prompting them to offer adjuvant chemotherapy (in apparently node-negative disease), with the strength of that recommendation inversely related to the numbers of nodes evaluated. Discussion with a member of the GI Systemic Therapy Group may be helpful in assessing this risk factor in individual patients.

Adjuvant chemotherapy is given on an out patient basis for a 6 month period following surgery. Ideally, this treatment should commence within 8 weeks of operation. If patient health or other factors preclude treatment initiation within this time frame, adjuvant therapy may still be feasible, but the benefits may be more difficult to quantify. It is recommended that patients who have undergone potentially curative surgical excision for node positive or high risk node negative colon cancer be referred for consideration of adjuvant treatment.

5FU with Leucovorin was the mainstay of adjuvant colon cancer therapy for years, with North American centres favoring bolus 5FU/Leucovorin regimens. However, a recent study demonstrated equivalence between six months of bolus 5FU/Leucovorin and the oral 5FU pro-drug, Capecitabine. [Twelves 2005; Scheithauer 2003] With newer chemotherapy agents active in the metastatic setting, there has been interest in combination regimens in the adjuvant setting.

The results of the MOSAIC study [Andre 2004] have established a new standard for adjuvant therapy in colon cancer. This multi-institutional study compared a standard bolus and infusional 5FU/Leucovorin regimen (LV5FU2) to the same 5FU/LV regimen plus Oxaliplatin (FOLFOX-4). Both node negative and node positive cancers were included. Certain toxicities were increased with the Oxaliplatin regimen, including enteropathy and neuropathy. With a median follow up of six years, the most recent update [de Gramont 2007] confirms disease-free survival (DFS) and overall survival benefit in node-positive patients receiving the Oxaliplatin regimen.

Disappointingly, combinations of Irinotecan with 5FU and Leucovorin have not demonstrated significant benefit over standard 5FU/Leucovorin regimens in the adjuvant setting.

Chemotherapy Regimens

NODE POSITIVE (STAGE III)

For patients with resected node positive (Stage 3) colon cancer, the standard BCCA adjuvant recommendation is the Oxaliplatin/5FU/Leucovorin regimen, UGIAJFFOX. This is based on the simplified administration of the "FOLFOX-6" regimen used in metastatic colorectal cancer, which is slightly different than the day 1 and 2 FOLFOX-4 regimen used in the MOSAIC trial.

For patients for whom Oxaliplatin is not recommended (including those with pre-existing significant neuropathy), 5FU monotherapy is employed. The former BC Cancer Agency adjuvant regimen of bolus 5FU/Leucovorin (formerly GIFFAD) has been replaced by the more convenient orally-available form of 5FU, Capecitabine (GIAJCAP). Physicians are reminded that, as Capecitabine is renally excreted, there are mandatory dose adjustments for renal insufficiency.

HIGH RISK NODE NEGATIVE (STAGE II)

As a marked additional benefit of Oxaliplatin combination regimens over standard 5FU/Leucovorin regimens has not been demonstrated in the adjuvant management of resected high risk node negative colon cancer, the BCCA does not recommend use of the UGIAJFFOX regimen for Stage 2 disease. Selected patients with high risk features may be offered Capecitabine. (GIAJCAP)

Web-based decision making aids (www.mayoclinic.com/calcs and www.adjuvantonline.com) are available, providing an estimate of disease-free and overall survival with surgery alone or with adjuvant chemotherapy. These tools rely on several key patient and tumor characteristics. While they are not a substitute for assessment by a physician experienced in this field, they may be helpful in counseling patients with respect to the need for oncologic consultation or with decisions regarding therapy recommendations.

Given the expanding chemotherapeutic options for the management of metastatic colon cancer, it is anticipated that adjuvant therapy may be changing significantly over the next decade. An increasing number of clinical trials are ongoing and in development to determine the role of newer agents in the adjuvant setting. Eligible patients should be encouraged to participate in available trials.

References:

1. Andre T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer. N Engl J Med 2004; 350: 2343-51.
2. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005; 352:2696-704.
3. De Gramont A, Boni C, Navarro M et al. Oxaliplatin/5-FU/LV in adjuvant colon cancer: Efficacy results of the MOSAIC trial, including survival, with a median follow up of six years. J Clin Oncol 2007 Proc Am Soc Clin Oncol I; 25(18S): abst 4007.
4. Sargent DJ, Weiand S, Haller DG, et al. Disease-free survival versus overall survival as a primary endpoint for adjuvant colon cancer studies: Individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 2005; 23:1664-70.
5. Scheithauer W, McKendrick J, Begbie S et al. Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial. Ann Oncol 2003; 14:1735-43.
6. Sobrero A, Guglielmi A. Current controversies in the adjuvant therapy of colon cancer. (Review) Ann Oncol 2004; 15 (Suppl 4):iv39-41.
7. Young-Fadok TM, Fanelli RD, Price RR et al. Laparoscopic resection of curable colon and rectal cancer: an evidence-based review. Surg Endosc 2007; 21(7):1063-8.