Adjuvant S-1 reduces recurrence rate in surgically resected rectal cancer

A year-long course of adjuvant S-1 chemotherapy improved RFS compared with tegafur–uracil in patients undergoing curative resection for stage II or stage III rectal cancer, according to the results of a randomized phase 3 trial.

Thus, adjuvant S-1 should be considered the standard of care in this patient population, according to the researchers.

“Colorectal cancer is one of the most prevalent cancers worldwide, and rectal cancer accounts for 40% of all colorectal cancers,” Eiji Oki, MD, PhD, FACS, of the department of surgery and science at Kyushu University’s Graduate School of Medical Sciences in Fukuoka, Japan, and colleagues wrote. “Different Western countries have taken various approaches to its treatment, which includes conducting clinical studies of neoadjuvant chemotherapy without radiotherapy and following the ‘watch-and-wait’ philosophy, but the standard treatment for rectal cancer is to perform total mesorectal excision following preoperative radiation, or chemoradiation, therapy.”

Although the use of adjuvant chemotherapy to prevent distant and local recurrence after surgery has been studied, no phase 3 trial has demonstrated the superiority of a specific regimen.

Oki and colleagues sought to determine whether S-1 chemotherapy — a combination of tegafur, gimeracil and oteracil potassium — is superior to tegafur–uracil (UFT) for patients with curatively resected stage II or stage III rectal cancer.

The analysis included 959 patients (median age, 62 years; range, 27-80; 67% men) from Japan who were enrolled April 2006 to March 2009 within 42 days of surgery. Researchers randomly assigned them to UFT (500-600 mg per day on days 1-5, followed by 2 days’ rest; n = 480) or S-1 (80-120 mg per day for 28 days, followed by 14 days’ rest; n = 479) for 1 year.

RFS served as the primary endpoint; secondary outcomes included OS and incidence of adverse events.

The median follow-up for RFS was 5 years (range, 0-8.01).

S-1 appeared superior for RFS, with a 5-year rate of 66.4% (95% CI, 61.9-70.5), compared with 61.7% (95% CI, 57.1-65.9) for UFT (HR = 0.77; 95% CI, 0.63-0.96).

The 5-year cumulative local recurrence rate was 9.8% (95% CI, 7.2-13.1) in the S-1 arm and 13% (95% CI, 10-16.7) in the UFT arm (HR = 0.72; 95% CI, 0.48-1.09). The rates of distant recurrence at 5 years were 24.7% (95% CI, 21-30) for S-1 and 26.9% (95% CI, 23-31.3) for UFT.

The researchers did not observe a significant difference in OS rates between patients treated with S-1 (82%; 95% CI, 78.3-85.2) and UFT (80.2%; 95% CI, 76.3-83.5) after a median follow-up of 5.5 years (range, 0.3-8.1).

Adverse events of any grade occurred in 82.3% of the S-1 arm and 73.9% of the UFT arm, with comparable rates of grade 3 or higher adverse events (13.4% vs. 11.7%).

Among patients assigned S-1, common severe adverse events included anorexia (2.6%), diarrhea (2.6%), fatigue (2.1%), decreased hemoglobin (1.3%), increased total bilirubin (1.3%) and nausea (1.3%).

Common grade 3 or higher adverse events among patients assigned UFT included increased alanine transaminase (2.3%), diarrhea (2.3%), increased aspartate transaminase (1.5%) and decreased hemoglobin (1.3%).

Both arms had similar 1-year completion rates (61.8% vs. 61.3%) and 6-month treatment discontinuation (25.9% vs. 23.8%).

The researchers acknowledged the homogeneity of their cohort as a potential study limitation. “S-1 could potentially cause a high incidence of gastrointestinal toxicities in Caucasian patients if administered at the dose used in this study,” Oki and colleagues wrote.

“In conclusion, 1-year S-1 treatment has become a standard adjuvant chemotherapy regimen for stage II and stage III rectal cancer following curative resection,” the researchers added. “S-1 can be considered an important option, especially for patients who have not received preoperative chemoradiotherapy.” – by Cameron Kelsall

Disclosure: Oki reports honoraria from Chugai Pharmaceuticals, Merck Serono, Taiho Pharmaceuticals, Takeda Pharmaceuticals and Yakult Honsha. Please see the full study for a list of all other researchers’ relevant financial disclosures.