Optimal Criteria for G3 (Poorly Differentiated) Stage II Colon Cancer: Prospective Validation in a Randomised Controlled Study (SACURA Trial)

Abstract

Background: Grade 3 (G3, poorly differentiated) is an important treatment-decision factor in stage II colon cancer, but no unified diagnostic criteria are established. According to previous studies, an intra-tumoural poorly differentiated area with no glandular formation (POR) that fills the microscopic field of a 40× objective lens was an essential factor that defined G3. We aimed to prospectively validate this in a randomised controlled study of adjuvant chemotherapy (SACURA trial). Methods: Between 2006 and 2010, we enrolled 991 patients with stage II colon cancer from 123 institutions. POR was quantitatively graded according to the 40× objective lens rule and the intensity of poorly differentiated clusters (GradePOR). The prognostic power of GradePOR was compared with that of the conventional tumour grade based on the predominant histology rule (Gradeconv). Findings: According to GradePOR, 313, 526 and 152 tumours were classified as G1POR, G2POR and G3POR, respectively, and the 5-year relapse-free survival (RFS) rates were 91·1%, 82·9%, and 74·7%, respectively (P < 0·0001). When G3POR and G3conv were alternatively added to the standard prognostic model consisting of eight conventional factors, only G3POR was a significant factor for RFS (P = 0·040, Wald test). The adverse impact of G3POR on RFS was greater in the microsatellite stable (MSS)/microsatellite instability (MSI)-low subset (hazard ratio [HR], 2·61; 95% confidence interval [CI], 1·81–3·77) compared with that in the full analysis set (HR, 1·93; 95% CI, 1·34–2·77). In the MSS/MSI-low subset, the 5-year RFS rate of patients with G3POR tumours in the adjuvant chemotherapy group achieved greater improvement (9·1%) than the surgery-alone group (HR, 0·65; 95% CI, 0·34–1·24). Interpretation: The validated prognostic value of the least differentiation policy with the 40× objective lens rule may be highlighted as the diagnostic criterion for G3 in the adjuvant treatment setting for stage II colon cancer, particularly for MSS/MSI-low tumours. Trial Registration: ClinicalTrials.gov NCT00392899 Funding: This study was supported by the Foundation for Biomedical Research and Innovation at Kobe, Translational Research Center for Medical Innovation (TRI), under the funding contract with Taiho Pharmaceutical Co. Ltd., Japan. Declaration of Interests: MI has received consulting fees from Taiho Pharmaceutical Co. Ltd., BristolMyers Squibb and Merck Serono Co. Ltd; honoraria from Taiho, Chugai Pharmaceutical Co. Ltd., and Yakult Honsha Co. Ltd. HM has received consulting fees from Otsuka Pharmaceutical Factory, Inc. and Sysmex Co.; honoraria from Taiho, Chugai, Yakult Honsha, Daiichi Sankyo Co. Ltd., Astellas Pharma Inc. NT has received research funding from Taiho, Chugai, and Yakult Honsha; honoraria from Taiho, Chugai, Takeda Pharmaceutical Co. Ltd., Merck Serono. YS has received honoraria from Taiho, Chugai and Yakult Honsha. KT has received honoraria from Taiho and Takeda. KK has received consulting fees from Taiho and Chugai; honoraria from Taiho, Chugai, Bristol-Myers, Merck Serono and Otsuka. MW has received research funding from Taiho, Chugai, Yakult Honsha, Johnson and Johnson K. K. and Covidien Japan Co. Ltd. YK has received honoraria from Taiho and Chugai. H. Ueno has received honoraria from Taiho, Chugai, Yakult Honsha, BristolMyers and Daiichi Sankyo. TI has received research funding from Taiho; honoraria from Chugai. H. Uetake has received consulting fees, research funding, and honoraria from Taiho, Chugai, Takeda, Bristol-Myers and Merck Serono. SM has no competing interest. ST has received consulting fees from Taiho, Daiichi Sankyo and Solasia Pharma K. K.; research funding from Daiichi Sankyo, Yakult Honsha and Kureha Co. Ltd.; honoraria from Daiichi Sankyo. KS has received consultant fees, research funding and honoraria from Taiho, Chugai, Takeda, Yakult Honsha, Daiichi Sankyo, Bristol-Myers, Merck Serono, and Pfizer Co. Ltd. Ethics Approval Statement: The study protocol was approved by the Institutional Review Boards of each participating institution and was conducted in accordance with the tenets of the Declaration of Helsinki and comparable Japanese ethical standards. Furthermore, written informed consent was obtained from all study participants.