Adjuvant Oral Uracil-Tegafur with Leucovorin for Colorectal Cancer Liver Metastases: A Randomized Controlled Trial

<div><p>Background</p><p>The high recurrence rate after surgery for colorectal cancer liver metastasis (CLM) remains a crucial problem. The aim of this trial was to evaluate the efficacy of adjuvant therapy with uracil-tegafur and leucovorin (UFT/LV).</p><p>Methods</p><p>In the multicenter, open-label, phase III trial, patients undergoing curative resection of CLM were randomly assigned in a 1:1 ratio to either the UFT/LV group or surgery alone group. The UFT/LV group orally received 5 cycles of adjuvant UFT/LV (UFT 300mg/m² and LV 75mg/day for 28 days followed by a 7-day rest per cycle). The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included overall survival (OS).</p><p>Results</p><p>Between February 2004 and December 2010, 180 patients (90 in each group) were enrolled into the study. Of these, 3 patients (2 in the UFT/LV group and 1 in the surgery alone group) were excluded from the efficacy analysis. Median follow-up was 4.76 (range, 0.15–9.84) years. The RFS rate at 3 years was higher in the UFT/LV group (38.6%, n = 88) than in the surgery alone group (32.3%, n = 89). The median RFS in the UFT/LV and surgery alone groups were 1.45 years and 0.70 years, respectively. UFT/LV significantly prolonged the RFS compared with surgery alone with the hazard ratio of 0.56 (95% confidence interval, 0.38–0.83; P = 0.003). The hazard ratio for death of the UFT/LV group against the surgery alone group was not significant (0.80; 95% confidence interval, 0.48–1.35; P = 0.409).</p><p>Conclusion</p><p>Adjuvant therapy with UFT/LV effectively prolongs RFS after hepatic resection for CLM and can be recommended as an alternative choice.</p><p>Trial Registration</p><p>UMIN Clinical Trials Registry <a href="http://www.umin.ac.jp/ctr/index.htm" target="_blank">C000000013</a></p></div

Results of analyses of the primary and secondary endpoints.

<p>A: The recurrence-free survival curves of the UFT/LV group (red line) and surgery alone group (black line) group are shown. The 3-year recurrence-free rate was significantly higher in the UFT/LV group than in the surgery alone group (38.6% vs. 32.3%, P = 0.003). B: The overall survival curves of the two groups are shown. The 5-year overall survival rates of the two groups were similar (66.1% vs. 66.8%, P = 0.409).</p

Baseline characteristics.

<p>Baseline characteristics.</p

Locations and treatments of first recurrence.

<p>Locations and treatments of first recurrence.</p

Results of subgroup analyses.

<p>A: The recurrence-free survival curves of the UFT/LV group (red line) and surgery alone group (black line) are shown for patients with a single liver metastasis. B: The recurrence-free survival curves of the two groups are shown for patients with multiple liver metastases. C: The recurrence-free survival curves of the two groups are shown for patients with synchronous liver metastases. D: The recurrence-free survival curves of the two groups are shown for patients with metachronous liver metastases.</p

The trial profile.

<p>The Participant flow is shown.</p

Identification of a Suppressive Mechanism for Hedgehog Signaling through a Novel Interaction of Gli with 14-3-3*

Gli transcription factors are central effectors of Hedgehog signaling in development and tumorigenesis. Using a tandem affinity purification (TAP) strategy and mass spectrometry, we have found that Gli1 interacts with 14-3-3ϵ, and that Gli2 and Gli3 also bind to 14-3-3ϵ through homologous sites. This interaction depends on their phosphorylation, and cAMP-dependent protein kinase (PKA), a known negative regulator of Hedgehog signaling serves as a responsible kinase. A Gli2 mutant engineered to eliminate this interaction exhibited increased transcriptional activity (2 ∼ 3×). Transcriptional repression by 14-3-3 binding was also observed with Gli3, when its N-terminal repressor domain was deleted. The phosphorylation sites responsible for the binding to 14-3-3 are distinct from those required for proteolysis, the known mechanism for PKA-induced repression of Hh signaling. Our data propose a novel mechanism in which PKA down-regulates Hedgehog signaling by promoting the interaction between Gli and 14-3-3 as well as proteolysis. Given the certain neuronal or malignant disorders in human caused by the abnormality of 17p13 encompassing 14-3-3ϵ overlap with increased Hh signaling, the Gli-14-3-3 interaction may have pathological significance for those human diseases