Adjuvant Therapy After Resection of Metastatic Colorectal Cancer: Clear Proof of Principle in This Setting

January 15, 2016
Anelisa Coutinho, MD

,
Axel Grothey, MD

Oncology, Oncology Vol 30 No 1, Volume 30, Issue 1

There is clear proof of principle for adjuvant therapy in patients at high risk for tumor recurrence, such as those with resected metastatic colorectal cancer. For that reason, this strategy has been largely adopted, especially using 5-FU– and oxaliplatin-based regimens, thereby mirroring the approach in resected stage III colon cancer.

Nearly 60% to 70% of patients will relapse within the first 2 years after resection of metastatic colorectal cancer.[1] The principle of adjuvant treatment is to eradicate residual micrometastatic disease in patients at high risk for recurrence. This concept was established 25 years ago in stage III colon cancer.[2] The current standard of care in the adjuvant management of stage III colon cancer is based on the MOSAIC study, which showed the superiority of FOLFOX (leucovorin [LV; folinic acid], fluorouracil [5-FU], oxaliplatin) over 5-FU and LV more than a decade ago.[3] Patients with resected stage IV colorectal cancer have at least the same-or, more commonly, a significantly higher-risk of tumor recurrence and death as those with stage III disease. These prognostic implications constitute the biological rationale for adjuvant therapy in patients with resected metastatic colorectal cancer.[4]

Here we will focus on the role of adjuvant therapy after resection of metastatic disease. We will not discuss the results of the European Organisation for Research and Treatment of Cancer (EORTC) 40983 trial, which confirmed the benefit of perioperative FOLFOX in terms of disease-free survival (DFS), since the study included neoadjuvant chemotherapy before metastasectomy.[5,6] Its results can, however, serve as confirmatory data for the efficacy of systemic chemotherapy in the context of resection of metastases with curative intent.

The first multicenter trial that compared systemic intravenous adjuvant chemotherapy (5-FU/LV) with surgery alone after resection of liver metastases showed a result that favored the treatment arm.[7] A total of 173 out of 200 previously planned patients were randomized over a period of 10 years. Patients in the chemotherapy group achieved a 5-year DFS of 33.5%, compared with 26.7% in the control group, with statistical significance after multivariate analysis (odds ratio [OR] for recurrence or death in the chemotherapy group, 0.66 [95% confidence interval (CI), 0.46–0.96]; P = .028). There was a trend toward increased 5-year overall survival (OS) for those who received adjuvant chemotherapy compared with those who had surgery alone: 51.1% vs 41.1% (OR for death in the chemotherapy group, 0.73 [95% CI, 0.48–1.10]; P = .13).

Subsequently, the EORTC/National Cancer Institute of Canada Clinical Trials Group/Gruppo Italiano di Valutazione Interventi in Oncologia (ENG) trial, which had a similar design, randomized 107 patients, and again an advantage was observed for adjuvant chemotherapy with a 5-FU bolus–based regimen. The lack of a significant survival benefit in these two trials when their results were analyzed separately was thought to be due to the smaller than planned sample size, slow accrual, and premature closure in both trials. Thus, a pooled analysis of the results of these trials was conducted. This analysis-with a total of 278 patients-showed a strong trend toward a survival benefit for adjuvant chemotherapy, with borderline statistical significance. Median progression-free survival (PFS) was 27.9 months in the chemotherapy group vs 18.8 months in the surgery-alone group (hazard ratio [HR], 1.32 [95% CI, 1.00–1.76]; P = .058). Median OS was 62.2 months in the chemotherapy group vs 47.3 months in the surgery-alone group (HR, 1.32 [95% CI, 0.95–1.82]; P = .095). However, in a multivariable analysis there was a significant association in favor of adjuvant treatment for both PFS (P = .036) and OS (P = .046).[8]

Several retrospective series have also shown benefit for adjuvant systemic treatment after liver resection. A large study that included two prospective databases with a total of 792 patients demonstrated that 5-FU–based chemotherapy improved survival (P = .007), even after stratification by clinical risk score (CRS) (P = .001). Patients treated with adjuvant chemotherapy had a 1.3 to 2.0 times higher chance of survival.[9]

Another prospective database, with 297 patients, evaluated the predictive value of a CRS along with the benefit of adjuvant therapy after resection of metastases. This analysis included patients treated with FOLFOX (53%), FOLFIRI (LV, 5-FU, irinotecan) (14%), or 5-FU/LV (33%).[10] An OS benefit for patients who received adjuvant systemic chemotherapy (HR, 0.69 [95% CI, 0.49–0.98]; P = .04) was found to be even more robust in the higher-risk group with CRS > 2 (HR, 0.40 [95% CI, 0.23–0.70]; P = .001).

Hepatic arterial chemotherapy infusion (HAI) has also been studied as adjuvant treatment after resection of liver metastases, either alone or combined with systemic chemotherapy. Despite the high heterogeneity concerning the protocols for HAI, its safety and efficacy have been demonstrated, particularly when HAI is combined with systemic chemotherapy.[11,12] A recent systematic review and meta-analysis that included six randomized trials, three cohort studies, and a total of 1,057 patients assessed the long-term outcomes of adjuvant HAI.[13] The review showed that patients who received adjuvant HAI, whether or not combined with systemic chemotherapy, exhibited a significantly higher 5-year OS (HR, 0.75 [95% CI, 0.56–0.99]; P = .048) and 5-year DFS (HR, 0.61 [95% CI, 0.48–0.79]; P = .001) than those who did not receive HAI. Nevertheless, the adverse events following HAI-particularly sclerosing cholangitis and complications related to HAI pumps-should be considered; thus, this modality has not achieved widespread acceptance.[14]

In conclusion, there is clear proof of principle for adjuvant therapy in patients at high risk for tumor recurrence, such as those with resected metastatic colorectal cancer. For that reason, this strategy has been largely adopted, especially using 5-FU– and oxaliplatin-based regimens, thereby mirroring the approach in resected stage III colon cancer. Therefore, we do favor systemic adjuvant therapy after resection of metastases for most patients.

Financial Disclosure: Dr. Coutinho serves as a speaker for and receives honoraria from Sanofi. Dr. Grothey has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. de Jong MC, Pulitano C, Ribero D, et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients. Ann Surg. 2009;250:440-8.

2. Moertel CG, Fleming TR, MacDonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990;322:352-8.

3. 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.

4. Power DG, Kemeny NE. Role of adjuvant therapy after resection of colorectal cancer liver metastases. J Clin Oncol. 2010;28:2300-9.

5. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371:1007-16.

6. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14:1208-15.

7. Portier G, Elias D, Bouche O, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol. 2006;24:4976-82.

8. Mitry E, Fields AL, Bleiberg H, et al. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol. 2008;26:4906-11.

9. Parks R, Gonen M, Kemeny N, et al. Adjuvant chemotherapy improves survival after resection of hepatic colorectal metastases: analysis of data from two continents. J Am Coll Surg. 2007;204:753-61.

10. Rahbari NN, Reissfelder C, Schulze-Bergkamen H, et al. Adjuvant therapy after resection of colorectal liver metastases: the predictive value of the MSKCC clinical risk score in the era of modern chemotherapy. BMC Cancer. 2014;14:174.

11. Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999;341:2039-48.

12. Kemeny NE, Gonen M. Hepatic arterial infusion after liver resection. N Engl J Med. 2005;352:734-5.

13. Liu W, Song QK, Xing BC. A systematic review and meta-analysis to reappraise the role of adjuvant hepatic arterial infusion for colorectal cancer liver metastases. Int J Colorectal Dis. 2015;30:1091-102.

14. Zhang W, Song T. The progress in adjuvant therapy after curative resection of liver metastasis from colorectal cancer. Drug Discov Ther. 2014;8:194-200.