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   Refining Multimodal Therapy for Rectal Cancer

For a short time, the treatment of rectal cancer seemed clear and definitive. The 1990 National Institutes of Health consensus statement concluded, "Combined postoperative chemotherapy and radiation therapy improves local control and survival in stage II and III patients and is recommended. At the time, the generally accepted treatment was conventional bowel resection followed by adjuvant radiation therapy (at a dose of 45 to 55 Gy) and chemotherapy if pathological findings confirmed the presence of transmural invasion or positive lymph nodes. Although the consensus statement introduced multimodal therapy as the standard treatment, results from subsequent randomized, controlled trials challenged that approach. Specifically, the following issues have been debated: the efficacy of radiation therapy when accompanied by optimal surgery, the dose of radiation (25 Gy vs. 50.4 Gy), the timing of radiation therapy (preoperative vs. postoperative), and the efficacy of radiation therapy plus chemotherapy as compared with chemotherapy alone.

Mesorectal Excision

In Germany, the introduction of a specialized technique, total mesorectal excision, has reduced local recurrence rates from 39 to 10 percent. Total mesorectal excision was developed after the recognition that discontinuous tumor deposits are often present in the lymphovascular tissue that surrounds the rectum (the mesorectum); left in place, such residual deposits are most likely the origin of local treatment failure (see picture above.) Total mesorectal excision has evolved to become more consistent with wide anatomical mesorectal excision, the essence of which is to use anatomical planes to dissect the mesorectum under direct visualization, so that the fascia propria is preserved with the rectal specimen for at least 4 cm distal to the tumor. In summary: Preoperative adjuvant therapy seems justified in patients who are known to have extensive local disease or lymph-node involvement. For patients with early-stage disease, the following strategy seems appropriate: perform surgery first and reserve adjuvant therapy for those with pathological findings that confirm the presence of transmural invasion or lymph-node involvement. Heidi Nelson, M.D.. Daniel J. Sargent, Ph.D. Mayo Clinic NEJM  2001;345:690

Preoperative Radiotherapy Combined with Total Mesorectal Excision for Resectable Rectal Cancer
Ellen Kapiteijn, M.D. for the Dutch Colorectal Cancer Group NEJM   2001;345:638

We randomly assigned 1861 patients with resectable rectal cancer either to preoperative radiotherapy (5 Gy on each of five days) followed by total mesorectal excision (924 patients) or to total mesorectal excision alone (937 patients). The trial was conducted with the use of standardization and quality-control measures to ensure the consistency of the radiotherapy, surgery, and pathological techniques.

Results Of the 1861 patients randomly assigned to one of the two treatment groups, 1805 were eligible to participate. The overall rate of survival at two years among the eligible patients was 82.0 percent in the group assigned to both radiotherapy and surgery and 81.8 percent in the group assigned to surgery alone (P=0.84). Among the 1748 patients who underwent a macroscopically complete local resection, the rate of local recurrence at two years was 5.3 percent. The rate of local recurrence at two years was 2.4 percent in the radiotherapy-plus-surgery group and 8.2 percent in the surgery-only group (P<0.001).

Conclusions Short-term preoperative radiotherapy reduces the risk of local recurrence in patients with rectal cancer who undergo a standardized total mesorectal excision.

Local Relapse Rate by 2 Years
Group Surgery Radiation + Surgery
all 8.2% 2.4%
procedure    
low anterior 7.3% 1.2%
APR 10.1% 4.9%
Stage    
I 0.7% 0.5%
II 5.7% 1.0%
III 15% 4.3%
IV 23.8% 10.1%

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