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Center for Colon and Rectal Surgery
Preoperative Chemotherapy and Radiation for Locally Advanced Rectal Cancer
"Sandwich" preoperative and postoperative combined chemotherapy and radiation in tethered and fixed rectal cancer: impact of treatment intensity on local control and survival.
Int J Radiat Oncol Biol Phys 1997 Feb 1;37(3):629-637
Chan AK, Wong AO, Langevin JM, Jenken DA, Khoo R, Heine JA, Buie WD, Johnson DR
Department of Radiation Oncology, Tom Baker Cancer Centre, Southern Alberta Cancer Program; University of Calgary, Alberta, Canada; University of Colorado, Denver, CO.

PURPOSE: The present "sandwich" preoperative and postoperative chemotherapy and radiation study was undertaken to evaluate the impact of treatment intensity on the local control and survival in tethered or fixed rectal adenocarcinoma (T3, 4 NX M0).
METHODS AND MATERIALS: Between 1990 and 1992, 27 patients were treated with this sandwich protocol. Preoperative therapy consisted of 4 weeks of concurrent radiation (40 Gy) and chemotherapy (mitomycin C on day 1, 5-fluorouracil infusion and leucovorin on days 1-4 and days 15-18, respectively), and one cycle of bolus 5-fluorouracil and leucovorin chemotherapy. After surgery, they received 2 additional weeks of radiation (18 Gy) and 4 days of similar chemotherapy. The outcome was compared to another 54 patients who were treated with our previous preoperative chemoradiation protocol (mitomycin C, 5-fluorouracil infusion and 40 Gy of pelvic RT).
RESULTS: The complete resectability rate was improved from 91% in the preoperative protocol to 100% in the sandwich protocol, and the pathologic complete response rate (T0 N0 M0) was increased from 4 to 15%. There was no local recurrence in the sandwich protocol. The 4-year local failure rate was 23 vs. 0% (p = 0.005). The 4-year distant failure rate was 47 vs. 28% (p = 0.079). The 2-year and 4-year survival were 63 and 41% for the preoperative protocol, vs. 92 and 72% for the sandwich protocol, respectively (p = 0.014). There were more treatment-related Grade 2 diarrhea, but not Grade 3/4 diarrhea in the sandwich protocol. Two patients (7%) in the sandwich protocol developed late gastrointestinal complications.
CONCLUSIONS: More intensive radiation and chemotherapy appeared to improve the resectability, local control, and survival in tethered and fixed rectal cancers. There was a moderate but acceptable increase in the bowel morbidity.

In our original protocol which was initiated in 1986 (Int J Radiation Oncology Biol. Phys., Vol. 25, pp. 791-799), our group had noticed a significant increase in resectability of these locally advanced tumors as compared to historical controls. A British review published in 1984 (Br J Cancer 1984;50:435-442) found that tumor mobility was a significant pretreatment factor. Patients with tethered rectal cancer only had a 44% curative resection rate and their 5-year local disease-free rate was only 37%. In our first trial of using preop chemotherapy and radiation followed by surgery 8 weeks later, the curative resection rate increased to 89%. In fact 2% of the patients so treated had no residual tumor in the resected specimen. The intensive chemotherapy synergizes the radiation effect on the cancer. Subsequent sequential sigmodoscopic exams revealed that maximal tumor regression was seen by the 7th to 8th week after completion of radiation therapy. Morbidity from this pretreatment protocol was minimal. This pretreatment did not increase surgical morbidity significantly.

This treatment changed the behavior of these locally advanced rectal cancers. Local recurrence was not a significant problem. However, distant recurrences in odd sites such as the lung and brain were noted. This reinforced the fact that these tumors had been present for a long time and they had ample opportunity to metastasize.

In this new "sandwich" protocol, more radiation was given after the surgery to reduce local recurrence and more chemo was added to handle any systemic micrometastases.

To date, our group has used preoperative chemotherapy and radiation to treat over 190 patients with locally advanced rectal cancer.

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