Neoadjuvant Therapy In Rectal Cancer

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The goals for surgical approaches to rectal cancer should be to develop improved local control and overall survival, while maintaining quality of life and preserving sphincter, genitourinary, and sexual function. Much has been made of neoadjuvant therapy and its application for mid- to lower-lying rectal tumors. The effects of downstaging possibly enhance the rate of curative surgery and may increase sphincter preservation. The Swedish rectal trial reported its five-year follow-up data on a randomized, prospective trial looking at the role of preoperative radiation in resectable rectal cancer (21,22). The study randomly assigned 1168 patients younger than 80 years of age who had resectable rectal cancer to undergo preoperative irradiation [25 Gray (Gy) delivered in five fractions in one week] followed by surgery within one week or to have surgery alone. No chemotherapy was given either pre- or postoperatively. Irradiation did not increase postoperative mortality. After five years of follow-up, the rate of local recurrence was 11% (63 of 553 patients) in the group that received radiotherapy before surgery and 27% (150 of 557) in the group treated with surgery alone (P < 0.001). Recently, Folkesson et al. (23) reported more recent data with a longer follow-up. A total of 908 patients, 454 patients in each arm, underwent an R0 resection with a 13-year median follow-up. The overall survival was 38% in the group receiving preoperative radiation and surgery versus 30% in that receiving surgery alone (P=0.008). The cancer-specific survival was 72% versus 62%, respectively (P=0.03). Local recurrence rates were 9% in the preoperative radiation and surgery group and 26% for the surgery alone group (P < 0.001). This decreased local recurrence was seen in all stages. Stage I (321 patients) had a 4.5% local recurrence in patients with preoperative radiation versus 23% with surgery alone. Stage II (307 patients) had a 6% versus 22% recurrence with surgery alone and stage III (280 patients) had 23% versus 46%, respectively.

The National Surgical Adjuvant Breast and Bowel Project Protocol R-03 (24) was designed to determine the value of preoperative chemotherapy and radiation therapy in the management of operable rectal cancer. All patients received seven cycles of 5-FU/LV chemotherapy. Cycles 1 and 4 through 7 used a high-dose weekly FU regimen. In cycles 2 and 3, FU and low dose LV chemotherapy was given during the first and fifth weeks of radiation therapy (5040 cGy). The preoperative arm (group 1) received the first three cycles of chemotherapy and all radiation therapy before surgery. The postoperative arm (group 2) received all radiation and chemotherapy after surgery. Primary-study end points included disease-free survival and overall survival. Secondary end points included local recurrence, primary tumor response to combination therapy, tumor downstaging, and sphincter preservation. Overall treatment-related toxicity was similar in both groups. However, due to poor accrual of only 267 patients of the expected 900, no long-term data is available.

A population-based prospective, randomized trial on preoperative radiotherapy (RT) in operable rectal cancer, conducted in Stockholm, Sweden (25), included 557 patients; 272 patients were randomized to receive preoperative irradiation with 25 Gy in five cycles during five to seven days to the rectum and pararectal tissues (RT+ group) and 285 patients were allocated to surgery alone (RT- group). The median follow-up time was 50 months. Surgery was considered curative in 479 patients (86%). Local recurrence occurred in 10% of the patients in the RT+ group versus 21% in the RT- group (P < 0.01). Among patients receiving curative surgery, distant metastases occurred in 19% in the RT+ group versus 26% in the RT- group (P=0.02). In addition to decreased local and distant recurrence, the overall survival was also improved in the irradiated patients (P=0.02). Postoperative complications were more common after irradiation but were usually mild (41% in RT+ vs. 28% in surgery only, P < 0.01). The postoperative mortality (2% in the RT+ group vs. 1% in the RT- group, P=0.289) was low in both groups. These studies support the view that treatment with radiation therapy prior to surgery could reduce local and distant recurrence rates, and thus potentially overall and cancer-related mortality rates with only a small increase in morbidity.

The more recent German Rectal Cancer Study group (26) addressed the issue of neoadjuvant versus adjuvant chemoradiation when they reported randomly assigned patients with clinical stage T3 or T4 or node-positive disease who received either preoperative or postoperative chemoradiotherapy. Four hundred and twenty-one patients were randomized to preoperative chemoradiotherapy which consisted of 5040 cGy and FU, given in a 120-hour continuous infusion at 1000 mg per square meter of body surface area per day during the first and fifth weeks of radiotherapy. Surgery was performed six weeks after the completion of chemoradiotherapy. One month after surgery, four five-day cycles of FU (500 mg per square meter per day) were given. Four hundred and two patients were allotted to receive postoperative chemoradiotherapy which was similar to the preoperative regimen but had in addition a boost of 540 Gy. The overall five-year survival rates were 76% in the preoperative chemoradiotherapy group and 74% in the postoperative group (P=0.80). The five-year cumulative incidence of local relapse was 6% for patients assigned to preoperative chemoradiotherapy versus 13% in the postoperative group (P=0.006). Grade 3 or 4 acute toxic effects occurred in 27% versus 40%, respectively (P=0.001); the corresponding rates of long-term toxic effects were 14% and 24%, respectively (P = 0.01).

The addition of intraoperative radiation therapy has also been reported. A retrospective study made a further comparison between patients who had received preoperative radiotherapy or chemoradiotherapy treatment plus intraoperative radiation therapy (IORT) and patients who received surgery only (27). The study comprised 99 patients with clinical T3-4NxM0 adenocarcinoma of the rectum who had received preoperative radio-/chemoradiotherapy, radical surgery, and IORT (group 1) and 68 patients who were treated with surgery alone (group 2). The investigators found that there was a lower local recurrence rate in patients with the combination of preoperative chemoradiotherapy and IORT (2% vs. 16% in the surgery only group, P = 0.002) and that patients in the combination group also had a higher disease-free and overall survival rate compared to the surgery only group (five-year disease free rate 71% vs. 54%, P=0.04 and overall survival 79% vs. 58%, P = 0.02). Additionally, they found a greater rate of sphincter preservation in the preoperative chemoradiotherapy subgroup than in the preop-erative radiotherapy subgroup (78% vs. 42%, P=0.002). The optimal time interval between neoadjuvant radiation and surgery was examined by the Lyon trial (28). This prospective trial compared a short interval (two weeks) between radiation therapy and surgery to a longer interval (six to eight weeks). Two hundred and one patients with T2-T3 tumors in the lower rectum were included. The long interval was associated with a significantly better clinical response and pathologic downstaging (53% vs. 72%, P = 0.007) and (10% vs. 26%, P = 0.005), respectively. In addition, there was a trend for increased sphincter preservation with the longer time interval (76% vs. 68%, P = 0.27). Although the surgery was not standardized in the trial they had a similar morbidity and two-month mortality between the two groups, similar overall five-year survival, similar local recurrence rates of 13% for the short interval group and 10% in the long interval group, and a similar percentage of patients who died from distant metastasis (18% in the short group and 20% in the long group), leading the authors to conclude that waiting longer between radiation therapy and surgical intervention, at least until eight weeks, is not harmful to the patient in terms of local and distant recurrence, mortality, morbidity, and overall survival. The findings in these studies would seem to imply that preoperative chemotherapy or radiation therapy or a combination of the two might help to decrease tumor size and rate of future recurrence, and increase sphincter preservation.

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