Adjuvant Therapy for completely resected Stage II Colon Cancer

Abstract

Background

: Colon cancer is potentially curable by surgery. Although adjuvant chemotherapy benefits patients with stage III disease, there is uncertainty of such benefit in stage II colon cancer. A systematic review of the literature was performed to better define the potential benefits of adjuvant therapy for patients with stage II colon cancer.

Objectives

: To determine the effects of adjuvant therapy on overall survival and disease‐free survival in patients with stage II colon cancer.

Search methods

: Ovid MEDLINE(R) (1986‐2007), EMBASE (1980‐2007), and EBM Reviews ‐ Cochrane Central Register of Controlled Trials (to 2007) were searched using the medical headings "colonic neoplasms", "colorectal neoplasms", "adjuvant chemotherapy", "adjuvant radiotherapy" and "immunotherapy", and the text words "colon cancer" and "colonic neoplasms". In addition, proceedings from the annual meetings of the American Society of Clinical Oncology and the European Society of Medical Oncology (1996 to 2004) as well as personal files were searched for additional information.

Selection criteria

: Randomized trials or meta‐analyses containing data on stage II colon cancer patients undergoing adjuvant therapy versus surgery alone.

Data collection and analysis

: Three reviewers summarized the results of selected studies. The main outcomes of interest were overall and disease‐free survival, however, data on toxicity and treatment delivery were also recorded.

Main results

: With regards to the effect of adjuvant therapy on stage II colon cancer, the pooled relative risk ratio for overall survival was 0.96 (95% confidence interval 0.88, 1.05). With regards to disease‐free survival, the pooled relative risk ratio was 0.83 (95% confidence interval 0.75, 0.92).

Authors' conclusions

: Although there was no improvement in overall survival in the pooled analysis, we did find that disease‐free survival in patients with stage II colon cancer was signficantly better with the use of adjuvant therapy. It seems reasonable to discuss the benefits of adjuvant systemic chemotherapy with those stage II patients who have high risk features, including obstruction, perforation, inadequate lymph node sampling or T4 disease. The co‐morbidities and likelihood of tolerating adjuvant systemic chemotherapy should be considered as well. There exists a need to further define which high‐risk features in stage II colon cancer patients should be used to select patients for adjuvant therapy. Also, researchers must continue to search for other therapies which might be more effective, shorter in duration and less toxic than those available today.

Author(s)

Alvaro Figueredo, Megan E Coombes, Som Mukherjee

Abstract

Plain language summary

Adjuvant therapy for completely resected stage II colon cancer

Colon cancer is the second most common cause of cancer deaths in the Western world. A large proportion of colon cancer patients can be cured by surgical resection alone. For those patients with lymph node positive (stage III) disease, the recurrence rate can exceed 50% and adjuvant chemotherapy has been shown to significantly reduce the risk of recurrence. In patients without lymph node involvement (stage I and II), the prognosis is quite good with surgery alone, with survival rates of 75% to 95% at 5 years. However, some patients with high risk stage II disease have a relapse rate approaching that of stage III colon cancer patients. Due to the effectiveness of systemic chemotherapy in stage III disease, a similar approach has been considered for patients with stage II disease. We performed a systematic review looking at all randomized clinical trials evaluating stage II colon cancer patients and adjuvant therapy versus surgery alone. Our review found that adjuvant therapy ‐either systemic or regional chemotherapy or immunotherapy‐ can improve the outcomes of stage II patients. In counselling individual patients, the advice given should be conditioned by the patient's age and comorbidities. In addition, the high risk features of the tumour should also be considered when contemplating the benefits of systemic therapy in patients with stage II colon cancer. Further investigation is needed to elucidate which patient and tumour factors can be used to select stage II colon cancer patients for adjuvant therapy. There also exists a need to continue to search for other adjuvant therapies which might be more effective, shorter in duration and less toxic than those available today.

Author(s)

Alvaro Figueredo, Megan E Coombes, Som Mukherjee

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

In a statistical perspective about whether patients with stage II colon cancer should receive adjuvant therapy (Buyse 2001) it is stated that to investigate benefits, four statistical approaches can be used short of a massive RCT: 1) consider overall treatment effects regardless of the stage; 2) estimate benefits for stage II patients only in a meta‐analysis; 3) compare the relative benefits among patients with stage II and stage III disease; and 4) perform tests of interaction between treatment and stage. All these tests have been done as well as a massive clinical trial. A benefit has been demonstrated by most procedures but the benefit is small even when statistically significant. The lack of major treatment effect in stage II colon cancer can be attributed to the good survival of patients treated with only surgery (75% to 80% at 5 years) and the competing mortality from causes other than colon cancer (Buyse 2001). This phenomenon had already been reported (Nauta 1989). These investigators compared the survival of patients with stage II colon cancer participating in 2 Gastro Intestinal Tumour Study Group (GITSG) trials to age, sex and race adjusted cohorts of healthy people. Further, they subdivided both cohorts into four age groups (<50, 50‐60, 60‐70 and > 70 years). The survival of patients with stage II colon cancer was similar for all 4 age groups. This has also been observed in the pooled analyses of Sargent and Gill (Sargent 2001; Gill 2004). The survival of the healthy cohorts, however, decreased steadily from the <50 to the >70 year groups. The difference between expected survival for the four age groups was 23% for those <50 years and declined to almost nil for those >70 years. As most patients with stage II colon cancer are over 60 years, it is clear that the potential benefit in survival must be small as has been found in all other trials and pooled analyses.

It is also important that the definition of stage II colon cancer be restricted to those with at least 10 to 13 lymph nodes examined (Baxter 2005; Berger 2005) and to those with T4 disease which have been resected in block and who did not have a perforated tumour. Otherwise, it is possible that lax criteria for stage II disease may include patients at higher risk of undetected lymph node metastases or spillage of cancer cells in the peritoneal cavity at surgery. These and other potential prognostic factors have bee described (Nathanson 1994; Hase 1998).

Patients with resected colon cancer should be staged appropriately, restricting the label stage II for those who had no tumour involvement in at least 10 to 13 regional lymph nodes, had real en block resection for T4 tumours and had no evidence of tumour perforation into the peritoneal cavity. These patients have an excellent prognosis from the cancer and, if over age 60 years, unlikely to benefit from adjuvant therapy. Patients less than 60 years old with co‐morbidities should be assessed in regard to the potential to survive the next 5 and possibly 10 years. If their probability of survival is lesser than a corresponding age cohort, then adjuvant therapy might not be beneficial.

All these factors and uncertainty of the benefit of adjuvant therapy must be clearly explained to patients stressing that to save one life treatment must be given to 17 to 100 patients. Or inversely that 16 to 99 patients will receive treatment for no gain. If systemic chemotherapy is planned it may include 5‐FU + leucovorin or oral capecitabine for 6 months. There is not enough evidence yet to support the use of additional drugs, such as oxaliplatin in patients with stage II colon cancer. Toxicity occurrence must also enter this discussion as potential non‐toxic therapies may become available and this small gain may then be more acceptable.

Implications for research 

Clinical adjuvant trials involving patients with stage II colon cancer must be restrictive in their definition of the stage. Further investigation of healthy cohorts are needed as the ones cited by Nauta are from the 1980's. Other prognostic factors may have to be included in the selection of patients considered at high risk such as genetic changes. Randomization of patients to an observation arm is still ethical if patients are well informed.

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