The Landmark Series: Chemotherapy for Non-Metastatic Colon Cancer
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CONTINUING EDUCATION– COLORECTAL CANCER
The Landmark Series: Chemotherapy for Non-Metastatic Colon Cancer Salvador Alonso, MD1, and Leonard Saltz, MD1,2 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; 2Department of Medicine, Weill Cornell Medicine, New York, NY
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ABSTRACT Micrometastatic disease that is present at the time of surgery is responsible for the overwhelming majority of deaths in patients with what is otherwise perceived to be local and regional colon cancer. The goal of perioperative therapy is to eliminate microscopic residual disease that would otherwise be left behind following surgery. A secondary goal specific to neoadjuvant (preoperative) therapy is to downstage tumors deemed potentially not amenable to an R0 resection on the basis of a suspected T4b primary (locally invading into a surrounding structure). In this landmark series paper, we review the current standard for perioperative therapy in patients with colon cancer.
Ongoing research efforts are trying to predict which patients are more likely to harbor residual disease. Despite the development of newer tests such as tumor genomic profiling and circulating tumor DNA (ctDNA) 1–5 disease stage still remains the best presurgical prognostic indicator of the risk of recurrence.6 Stage I disease has a favorable prognosis with surgery alone, and data do not support the use of adjuvant chemotherapy for any stage I colon cancer patient. Stage II disease is more complicated and remains the most controversial area with regard to adjuvant therapy. Risk stratification is used, with low-risk, stage II patients offered observation, and those with high-risk factors for recurrence offered adjuvant chemotherapy.7 Stage III
Ó Society of Surgical Oncology 2020 First Received: 21 October 2020 Accepted: 2 November 2020 S. Alonso, MD e-mail: [email protected]
disease carries a more substantial risk of recurrence following surgery, and, in the absence of medical contraindications, stage III patients are routinely offered adjuvant chemotherapy. Below we review the landmark studies that have defined the current standard for perioperative therapy in patients with stage II and III colon cancer. ADJUVANT THERAPY Fluoropyrimidine-Based Adjuvant Therapy The North Central Cancer Treatment Group trial was the first to demonstrate a benefit of adjuvant 5-fluorouracil compared with observation in patients with resected colon cancer.8 The study showed an improvement in disease-free survival (DFS) in the pooled analysis of patients with stage II and III colon cancer, and improved overall survival (OS) in the subset of patients with stage III disease. These findings were confirmed in the US Intergroup Trial INT0035, which showed a 33% reduction in mortality in patients receiving 1 year of adjuvant 5-fluorouracil plus levamisole, compared with surgery alone.9 Levamisole, considered a putative immunomodulator at the time, was later found to be inactive. Subsequently, the INT-0089 trial showed that 6 months of 5-fluorouracil plus leucovorin (5F
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