Effective Surgical Adjuvant Therapy for High-Risk Rectal Carcinoma

TLDR

Radiation therapy reduces local recurrence in rectal cancer but does not improve survival, and adding chemotherapy to radiation improves survival over surgery alone but not over adjuvant radiation alone. The study aimed to assess whether a postoperative regimen combining radiation with fluorouracil and systemic fluorouracil‑semustine would lower recurrence and improve survival versus adjuvant radiation alone. Patients received 4500–5040 cGy of postoperative radiation together with fluorouracil and a pre‑ and post‑systemic cycle of fluorouracil plus semustine, with acute toxicities of nausea, vomiting, diarrhea, leukopenia, and thrombocytopenia and rare severe delayed complications such as small‑bowel obstruction. The combined therapy lowered overall recurrence by 34 %, local recurrence by 46 %, distant metastasis by 37 %, cancer‑related deaths by 36 %, and overall deaths by 29 % compared with radiation alone, while acute toxicity was mild and severe delayed complications were infrequent and comparable between groups.

Abstract

Radiation therapy as an adjunct to surgery for rectal cancer has been shown to reduce local recurrence but has not improved survival. In a previous study, combined radiation and chemotherapy improved survival significantly as compared with surgery alone, but not as compared with adjuvant radiation, which many regard as standard therapy. We designed a combination regimen to optimize the contribution of chemotherapy, decrease recurrence, and improve survival as compared with adjuvant radiation alone.Two hundred four patients with rectal carcinoma that was either deeply invasive or metastatic to regional lymph nodes were randomly assigned to postoperative radiation alone (4500 to 5040 cGy) or to radiation plus fluorouracil, which was both preceded and followed by a cycle of systemic therapy with fluorouracil plus semustine (methyl-CCNU).After a median follow-up of more than seven years, the combined therapy had reduced the recurrence of rectal cancer by 34 percent (P = 0.0016; 95 percent confidence interval, 12 to 50 percent). Initial local recurrence was reduced by 46 percent (P = 0.036; 95 percent confidence interval, 2 to 70 percent), and distant metastasis by 37 percent (P = 0.011; 95 percent confidence interval, 9 to 57 percent). In addition, combined therapy reduced the rate of cancer-related deaths by 36 percent (P = 0.0071; 95 percent confidence interval, 14 to 53 percent) and the overall death rate by 29 percent (P = 0.025; 95 percent confidence interval, 7 to 45 percent). Its acute toxic effects included nausea, vomiting, diarrhea, leukopenia, and thrombocytopenia. These effects were seldom severe. Severe, delayed treatment-related reactions, usually small-bowel obstruction requiring surgery, occurred in 6.7 percent of all patients receiving radiation, and the frequencies of these complications were comparable in both treatment groups.The combination of postoperative local therapy with radiation plus fluorouracil and systemic therapy with a fluorouracil-based regimen significantly and substantively improves the results of therapy for rectal carcinoma with a poor prognosis, as compared with postoperative radiation alone.