Postoperative Adjuvant Chemotherapy For Stage Research Articles

Essential updates 2022–2023: Surgical and adjuvant therapies for locally advanced colorectal cancer

AbstractPivotal articles that had been published between 2022 and 2023 on surgical and perioperative adjuvant treatments for locally advanced colorectal cancer (CRC) were reviewed. This review focuses on new evidence in the following areas: optimization of surgical procedures for colon cancer, including the optimal length of bowel resection and use of the no‐touch isolation technique; minimally invasive surgery for rectal cancer, such as laparoscopic transanal total mesorectal excision and robotic surgery; neoadjuvant treatments for rectal cancer, including total neoadjuvant therapy; neoadjuvant chemotherapy for colon cancer; and postoperative adjuvant chemotherapy for Stage II and III colon cancer. Although the current understanding may not enable perfect decision‐making for patients and medical professionals, ongoing advancements are expected to result in more effective personalized treatment plans, ultimately improving the prognosis and quality of life of patients.

Effect of the number of cycles of docetaxel + S-1 therapy on long-term survival in adjuvant chemotherapy for stage III gastric cancer. A pooled analysis of the OGSG0604 and OGSG1002 trials.

S-1 plus docetaxel (DS) therapy followed by S-1 is the standard of care in Japan in postoperative adjuvant chemotherapy for stage III gastric cancer, but long-term survival and the number of DS cycles required are unclear. The purpose of this study was to investigate the impact of the number of cycles of DS therapy on the 5-year survival in stage III gastric cancer in a pooled analysis of two phase II trials (OGSG0604 and OGSG1002). Patients with histologically confirmed stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were enrolled in this pooled analysis. They received DS therapy for four or eight cycles, followed by S-1 until 1year postgastrectomy. The 5-year overall survival (OS) and the 5-year disease free survival (DFS) by the landmark analysis was evaluated. In total, 113 patients from the OGSG0604 and OGSG1002 trials were enrolled in this study. The landmark analysis showed a 5-year OS that was better with four to eight cycles of DS therapy than with one to three cycles of DS therapy, with the best 5-year OS of 77.4% (95% confidence interval, 66.5-90.1%) for eight cycles. The 5-year DFS was approximately 66% when four or eight cycles of DS therapy were given. Although eight cycles of DS therapy may prolong prognosis, the present study did not provide a clear conclusion as to how many DS therapy cycles are needed to improve prognosis after D2 gastrectomy for stage III gastric cancer. Registration number: UMIN00000714 and UMIN000004440.

Cost-effectiveness of 12 months of capecitabine as adjuvant chemotherapy for stage III colon cancer: preplanned cost-effectiveness analysis of the JFMC37-0801 study

ObjectivesWe evaluated the cost-effectiveness of a 12-month regimen of oral capecitabine versus a standard 6-month regimen as postoperative adjuvant chemotherapy for stage III colon cancer.MethodsWe utilized patient-level data from a multi-institutional randomized controlled trial (JFMC37-0801) that investigated prolonged oral fluoropyrimidine monotherapy. The analysis considered three health states: stable disease, post-metastasis, and death. A parametric statistical model with a cure model was used to estimate the survival curve. The analysis was conducted from the Japanese public healthcare payer’s perspective, considering only direct medical costs. A lifetime horizon was used, with a discount rate of 2% for both cost and health outcomes. Health outcomes were evaluated in terms of quality-adjusted life-years (QALYs).ResultsThe estimated cure rates for colon cancer were 0.726 [95% confidence interval (CI) 0.676–0.776] and 0.694 (95% CI 0.655–0.733) with the 12- and 6-month regimens, respectively; and the estimated 5-year relapse-free survival rates were 74.4% and 69.8%, respectively. The estimated lifetime cost for 12 months of capecitabine was JPY 3.365 million (USD 31,159), compared with JPY 3.376 million (USD 31,262) for 6 months. The estimated QALY were 12.48 and 11.77 for the 12- and 6-month regimens, respectively. Thus, the 12-month capecitabine regimen was dominant. Using a willingness-to-pay threshold of JPY 5 million per QALY, we determined a 97.4% probability that the 12-month capecitabine regimen is more cost-effective than the 6-month regimen.ConclusionsTwelve months of capecitabine is the favorable option for postoperative adjuvant chemotherapy for stage III colon cancer from the perspective of cost-effectiveness.

Intraperitoneal Chemotherapy Using Fluorouracil Implants Combined With Radical Resection and Postoperative Adjuvant Chemotherapy for Stage III Gastric Cancer: A Multi-Center, Randomized, Open-Label, Controlled Clinical Study.

BackgroundReducing peritoneal recurrence after radical surgery is an important choice to improve the prognosis of patients with advanced gastric cancer. Intraoperative intraperitoneal chemotherapy has the potential to be a promising treatment strategy. In the present study, we conducted a multi-center, randomized, controlled clinical study to evaluate the efficacy and safety of intraoperative intraperitoneal chemotherapy using sustained-release fluorouracil implants plus radical gastrectomy and adjuvant chemotherapy for cTNM stage III gastric cancer.MethodsThe patients were randomized into intraperitoneal chemotherapy group (sustained-release fluorouracil implants administration after standard D2 radical gastrectomy, and followed by XELOX adjuvant chemotherapy) and control group (standard D2 radical gastrectomy, and followed by XELOX adjuvant chemotherapy). A total of 122 patients from three centers were enrolled from September 2015 to February 2017.ResultsOne hundred and two eligible patients completed the treatment course. The median follow-up time was 41.7 months (36.1–52.9 months). The 3-year progression-free survival rate and overall survival of patients in the intraperitoneal chemotherapy group were 43.9% and 49.1%, respectively, which were significantly better than those of the control group, 31.0% and 38.4%. In the intraperitoneal chemotherapy group, the number of cases with peritoneal recurrence was significantly less than that of the control group, 9 cases (17.3%) vs. 19 cases (44.2%). There were neither significant differences between the groups in the incidence of hematogenous metastasis, lymph node metastasis, nor local metastasis.ConclusionFor cTNM stage III gastric cancer, intraoperative sustained-release fluorouracil implants after radical resection combined with postoperative adjuvant chemotherapy, could significantly reduce the risk of peritoneal recurrence and prolong PFS.Clinical Trial Registration https://clinicaltrials.gov/, identifier (NCT02269904).

The value of adjuvant chemotherapy in stage II/III colorectal signet ring cell carcinoma

This study aimed to assess the benefit of postoperative adjuvant chemotherapy in stage II–III colorectal signet ring cell carcinoma (SRCC). Qualified postoperative patients were extracted from Surveillance, Epidemiology, and End Results (SEER) database from 2004 until 2015. We collected 1675 patients in the research, and 936 patients were subjected to adjuvant chemotherapy group. The proportions of married status, male, rectal cancer, grade III/IV, AJCC stage III and radiotherapy were higher; While, the rates of white race, ≥ 65 years old and located in cecum–transverse colon were lower in patients of chemotherapy group compared to no chemotherapy group (all P < 0.05). K-M plots revealed significantly better OS of adjuvant chemotherapy group than no chemotherapy group (P < 0.001). Meanwhile, there was no significantly different in CSS between the two groups (P = 0.93). However, after adjusting for confounding factors by multivariable Cox regression analysis, receipt of postoperative chemotherapy was still associated with better CSS and OS (CSS: hazard ratio [HR] = 0.719, 95% CI 0.612–0.844, P < 0.001) ; (OS: HR = 0.618, 95% CI 0.537–0.713, P < 0.001). Patients with stage II/III colorectal SRCC could receive survival benefit from postoperative adjuvant chemotherapy.

TBX2 Expression predicts Tumor Recurrence and Adjuvant Chemotherapy Benefits in Gastric Cancer Patients following R0 Resection: a proposed approach for risk stratification

Aims: TBX2 is related to tumor progression and drug resistance. However, the roles of TBX2 in gastric cancer (GC) remain unclear. Our study aims at investigating the clinical roles of TBX2 in GC.Methods: The protein expression levels of TBX2 in fresh GC tissue (n=20) were investigated with Western blotting analyses. The correlation between TBX2 expression and its prognostic significance was evaluated by immunohistochemical analyses of 401 patients. The survival benefit of postoperative adjuvant chemotherapy (PAC) for patients was evaluated.Results: The expression of TBX2 was increased in GC tissue compared with adjacent paracancerous tissue (p=0.020). Immunohistochemistry demonstrated that TBX2 expression was significantly associated with lymphovascular invasion (p=0.024) and lymph node metastasis (p=0.044). A high level of TBX2 expression was an independent indicator of unfavorable recurrence-free and overall survival (p=0.002 and p=0.033, respectively). The prognostic model incorporating TBX2 expression exhibited greater predictive accuracy than the primary model. More importantly, the benefit of PAC noted in stage II/III GC patients with low TBX2 expression was superior to high TBX2 expression.Conclusion: TBX2 may be not only a useful prognostic marker for GC but also a predictive biomarker of response to PAC in stage II/III GC patients. The current findings warrant further verification.

A retrospective study of a dexamethasone-sparing strategy of preventing acute and delayed emesis caused by CapeOx regimen with aprepitant for colorectal cancer.

632 Background: CapeOx therapy which is combination with oxaliplatin (L-OHP) and capecitabine is one of the standard treatments for first line chemotherapy for unresectable colorectal cancer, or for postoperative adjuvant chemotherapy for stage III colon cancer. L-OHP-based regimen is classified as moderately emetogenic chemotherapy. In the SENRI trial which we previously conducted as phase III trial, aprepitant, an NK-1 antagonist, showed the efficacy for prevention of emesis against L-OHP. On the other hand, even when in highly emetogenic chemotherapy, it is reported that dexamethasone after day 2 could be spared. Methods: We retrospectively reviewed chemo-naive 94 patients with colorectal cancer who underwent CapeOx therapy at our institution from April 2012 to March 2017. We assessed the relationship between emesis during the first cycle of CapeOx (day1-5) and the use of dexamethasone on day 2-3. Results: 10 patients underwent CapeOx plus bevacizumab, and 84 underwent CapeOx. All patients received 5-HT3 receptor antagonist (palonosetron: 87, granisetron: 7). 50 patients received aprepitant on days 1-3 and dexamethasone on day 1 (APR+D1 group). 22 patients received aprepitant on days 1-3 and dexamethasone on days 1-3 (APR+D3 group). 15 were dexamethasone on days 1-3 without aprepitant (D3 group), and 7 were dexamethasone only on day 1 without aprepitant (D1 group). Acute complete response (CR; no vomiting and no rescue anti-emetics) rates were 100% in any groups. Delayed CR rate was 56% in APR+D1 group, 86% in APR+D3 group, 53% in D3 group, and 29% in D1 group, respectively. In multivariate linear regression with aprepitant, there was a significant difference in presence of dexamethasone (p = 0.028). Conclusions: Acute emesis could be prevented by even only 1-day administration of dexamethasone when combined with the triplet prophylactics. However, in order to sufficiently prevent delayed emesis induced by L-OHP, it was suggested that addition of DEX on days 2 and 3 might be better.

Feasibility of Neoadjuvant FOLFOX Therapy Without Radiotherapy for Baseline Resectable Rectal Cancer.

The combination of oxaliplatin, leucovorin and fluorouracil (FOLFOX) has been established as postoperative adjuvant chemotherapy for stage III colon cancer. However, the safety and efficacy of neoadjuvant FOLFOX in patients with rectal cancer are still controversial. This prospective pilot study aimed to evaluate the feasibility of neoadjuvant FOLFOX therapy without radiation for baseline resectable rectal cancer (RC). The study included 30 patients with clinical stage II/III RC between February 2012 and December 2015. The patients were treated with six cycles of FOLFOX followed by elective surgery. The primary endpoint was the R0 resection rate. The secondary endpoints were the scheduled treatment completion rate, adverse events, pathological response and the disease-free survival (DFS) rate. All the patients underwent elective R0 resection after neoadjuvant FOLFOX therapy. The completion rate of the 6-cycle regimen was 93.3% (28/30 patients). Grade 3-4 adverse events occurred in seven patients (23.3%). Pathological complete response was noted in two patients (6.7%). The 3-year DFS rate was 77.5% (95% confidence interval, 61.4%-93.7%). Neoadjuvant FOLFOX therapy without radiation is a feasible therapeutic strategy for baseline resectable RC.

Advances in colorectal cancer research from 2017 annual meeting of the American Society of Clinical Oncology

It is plentiful about the 289 abstracts for the colorectal cancer (CRC) in the 2017 annual meeting of the American Society of Clinical Oncology (ASCO), which include: (1) comparison between long and short courses of postoperative adjuvant chemotherapy for stage Ⅲ CRC in the early diseases, applications of the full course of neoadjuvant therapy for locally advanced rectal cancer and laparoscopic total mesorectal excision for rectal cancer. (2) The use of Vitamin D3 and selective interstitial radiotherapy for metastatic CRC in the advanced diseases showed an encouraging efficacy. Patients with BRAF mutation and poor prognosis underwent a combination therapy of BRAF inhibitor and epidermal growth factor receptor (EGFR), which has created a new situation for precision therapy. And China′s domestically designed Fruquintinib (small-molecule kinase inhi-bitor) and EGFR CMAB009 have showed better clinical efficacies in the second-line therapy. (3) On the precision medicine and translational researches, clinical value of consensus of molecular subtypes is being revealed and liquid biopsy is advantageous to predict postoperative tumor recurrence. These new therapies and researches would impact the clinical practices, promote clinical development and benefit the patients. Key words: Colorectal neoplasms; Therapy; Progress; American Society of Clinical Oncology

Application of Lepidic Component Predominance to Adjuvant Chemotherapy with Oral Fluoropyrimidines for Stage I Lung Adenocarcinoma

BackgroundIn the present study we aimed to investigate whether the predominance of the lepidic component in tumors was associated with the outcome of postoperative adjuvant chemotherapy for stage I lung adenocarcinoma. Patients and MethodsCharts for patients with pathological stage I lung adenocarcinoma were retrospectively reviewed and then outcomes of adjuvant chemotherapy were assessed according to the lepidic component predominance in tumors. Prognostic factors were evaluated using a Cox proportional hazard model. Propensity scores were determined using the optimal matching method on the basis of Cox modeling and matched (1:1) analysis was applied after classification into lepidic and nonlepidic predominant tumors. ResultsAmong 798 patients with stage I lung adenocarcinoma, 168 received adjuvant chemotherapy. Although adjuvant chemotherapy conferred no disease-free survival (DFS) advantage upon patients with lepidic predominant tumors, it improved DFS in T1b and T2a nonlepidic predominant tumors (P = .045 and P = .029, respectively). Propensity score matched analysis revealed no survival benefits of adjuvant oral fluoropyrimidines in lepidic predominant tumors (DFS, P = .461 and overall survival, P = .983) and the positive survival advantages in nonlepidic predominant tumors (DFS, P = .015 and overall survival, P = .027). ConclusionAdjuvant oral fluoropyrimidines conferred a better survival advantage upon patients with nonlepidic predominant tumors than patients with lepidic predominant tumors. The predominance of a lepidic component could serve as an indicator of adjuvant chemotherapy with oral fluoropyrimidines in stage I lung adenocarcinoma.

Abstract CT211: Biomarker search using gene expression databases in a phase III controlled clinical trial of postoperative adjuvant chemotherapy for stage III colon cancer (ACTS-CC): correlation between clinicopathological factors and gene expression level

Abstract Background: The ACTS-CC trial is a randomized, controlled phase III study designed to validate the noninferiority of S-1 to UFT/leucovorin as adjuvant chemotherapy for stage III colon cancer and rectosigmoid cancer. A prospective biomarker search was performed as an auxiliary study of the ACTS-CC trial, using formalin-fixed, paraffin-embedded (FFPE) specimens obtained from 892 patients. The gene expression levels of 5-FU metabolizing enzymes and folate metabolizing enzymes and alterations of genome-wide copy numbers in tumor have been reported (2012, 2013 and 2014 Annual Meetings of AACR). In the present study, we performed correlation analyses of clinicopathological feature and gene expression level. Methods: Blocks of resected tumor specimens for this biomarker study were obtained after receiving informed consent from 892 of 1535 patients enrolled between April 2009 and January 2010. Macro-dissections were manually performed to extract total RNA and genomic DNA from 10-μm-thick FFPE specimens of colon cancer. Gene expression levels of 11 enzymes (TS, DPD, TP, OPRT, FPGS, GGH, DHFR, MTHFR, MTHFD, FOLRA, GART) related to 5-FU and folic acid metabolism were studied according to the Danenberg Tumor ProfileTM method (Shirota, Y. JCO 2001). Results: Gene expression levels were successfully estimated in 521-808 samples (84.0-90.0%, median 89.4%). Among 11 genes, GGH most strongly correlated with tumor locations: expression level of GGH in the distal colon was 1.8 times higher than those in the proximal colon. Gene expressions of DPD and GGH were significantly influenced by differentiation of tumor. DPD and GGH mRNA levels in poorly differentiated tumors were 2.0 or 2.5 times higher than those in well differentiated tumors, respectively. Likewise, TS most strongly correlated with tumor depth: expression level in T1 or T2 tumor was 1.3 times higher than those in T4 tumor. Conclusions: Location, differentiation and depth of the tumor correlated with each gene expressions. Our findings will facilitate understanding the characteristics of colon cancer. Further investigation on gene expressions including genome-wide copy number analysis may contribute to the exploration of valid biomarkers. Citation Format: Hiroyuki Uetake, Toshiaki Ishikawa, Megimi Ishiguro, Shigeyuki Matsui. Biomarker search using gene expression databases in a phase III controlled clinical trial of postoperative adjuvant chemotherapy for stage III colon cancer (ACTS-CC): correlation between clinicopathological factors and gene expression level. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT211. doi:10.1158/1538-7445.AM2015-CT211

Abstract 5274: MSI, 18q LOH, and clinicopathological features in stage II sporadic colon cancers: Biomarker study in a phase III study of postoperative adjuvant chemotherapy for stage II colon cancer (SACURA trial)

Abstract Background and Purpose: SACURA trial is a multicenter, randomized phase III study which aims to evaluate the superiority of adjuvant treatment with UFT to observation only after surgery for stage II colon cancer. In an additional translational study, the mRNA expression of 5-FU-related enzymes, MSI and 18q LOH, and histopathological factors including budding are assessed to evaluate correlations with recurrences and survivals. Survival data will be open in 2016. In the present study, we investigated the correlations between clinicopathological features and the status of MSI and 18q LOH to reveal the characteristics of colon cancer in Japan. Material and Methods: From 1038 of 2024 patients enrolled from October 2006 to July 2010, formalin-fixed, paraffin-embedded samples of resected tumors were obtained under informed consent. MSI was evaluated using 5 markers, BAT25, BAT26, D2S123, D5S346, and D17S250 selected from the international guidelines suggested by the National Cancer Institute collaborative meeting. MSI high (MSI-H) was defined as the presence of instability in more than 20% of the markers. Microsatellite stability (MSS) was defined as no unstable marker. 18qLOH was evaluated by 3 markers, D18S69, D18S74E, and D18S851. 18qLOH positivity was defined as the presence of LOH in any of the 18q markers. 18q LOH negativity was strictly defined as the presence of at least two informative markers and the absence of LOH. Each marker were amplified by PCR using fluorescence-labeled primers and analyzed on ABI 3130 Genetic Analyzer using GeneMapper Software Ver. 3.0. Results: Among 1038 tumors, MSI-H was observed in 75 tumors (7.2%). MSI-L and MSS were observed in 24 (2.3%) and 936 tumors (90.5%), respectively. MSI-H was more frequent in female (p = 0.001), right-sided colon cancers (p 5cm tumors (p&amp;lt; 0.0001), poorly-differentiated or mucinous cancers (p&amp;lt; 0.0001), and abnormal CEA (p = 0.004). Age and Depth of tumor invasion had no correlation with MSI status. The 18q LOH phenotype was present in 531 tumors (51.2%) and LOH negativity was observed in 360 (34.7%). Informative LOH data was not available in 147 tumors (14.2%).Tumors with 18q LOH was more frequent in left -sided colon cancers(p&amp;lt; 0.0001) and well to moderately-differentiated cancers (p = 0.008). Age, gender, the tumor size, depth of tumor invasion, and CEA had no correlation with 18q LOH status. Conclusions: This is the first analysis for the status of MSI and 18q LOH in a large population of Japanese colon cancer patients from phase III study. Although the frequency of the MSI phenotype in this study was lower than those in the previous reports from western countries, clinicopathological characteristics of the tumors with MSI and 18q LOH were similar. Our future study in SACURA trial will contribute to establish the prognostic and/or predictive biomarkers in stage II colon cancer. Citation Format: Toshiaki Ishikawa, Hiroyuki Uetake, Megumi Ishiguro, Kenta Murotani, Hideki Ueno, Shigeyuki Matsui, Kenichi Sugihara, Naohiro Tomita, SACURA study group. MSI, 18q LOH, and clinicopathological features in stage II sporadic colon cancers: Biomarker study in a phase III study of postoperative adjuvant chemotherapy for stage II colon cancer (SACURA trial). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5274. doi:10.1158/1538-7445.AM2015-5274

Progress of Postoperative Adjuvant Chemotherapy in Stage I Non-small Cell Lung Cancer

肺癌发病率及死亡率居全球癌症首位，按组织病理学可分为非小细胞肺癌（non-small cell lung cancer, NSCLC）和小细胞肺癌。仅有不到20%的NSCLC患者在初次诊断时有手术机会，而术后5年生存率大约只有30%-60%，单纯手术治疗的效果难以令人满意。很多临床随机试验结果显示术后辅助化疗可使Ⅱ期-Ⅲa期NSCLC患者生存获益，而Ⅰ期NSCLC患者是否需要术后辅助化疗存在争议。本文就Ⅰ期NSCLC术后化疗人群选择的影响因素、化疗方案的选择以及生物学标志物等方面的研究进展做一综述。

Pre-planned feasibility and safety analyses of docetaxel/S-1 combination in a phase III study comparing docetaxel/S-1with S-1 alone as postoperative adjuvant chemotherapy for stage III gastric cancer (JACCRO GC-07).

e15000 Background: After the ACTS-GC trial, adjuvant postoperative chemotherapy with S-1 has become the standard for curatively resected stage II/III gastric cancer (GC) in Japan. However, the subs...

Abstract 283: Biomarker search using gene expression databases in a phase III, controlled clinical trial of postoperative adjuvant chemotherapy for stage III colon cancer (acts-cc): Correlation between gene expression and DNA copy number

Abstract Background: The ACTS-CC trial is a randomized, controlled phase III study designed to validate the noninferiority of S-1 to UFT/LV as adjuvant chemotherapy for stage III colon cancer and rectosigmoid cancer. A prospective biomarker search was performed as an auxiliary study of the ACTS-CC trial, using formalin-fixed, paraffin-embedded (FFPE) specimens obtained from 892 patients. The gene expression levels of 5-FU metabolizing enzymes and folate metabolizing enzymes and alterations of genome-wide copy numbers in tumor have been reported (2012 and 2013 Annual Meetings of AACR). In the present study, we performed correlation analyses of gene expression and DNA copy number data to characterize colorectal cancer and to prepare for a pre-planned analysis of predictive or prognostic biomarkers. Methods: FFPE specimens for this biomarker study were obtained after receiving informed consent from 892 (gene expression analysis) or 795 (DNA copy number analysis) of 1535 patients enrolled between April 2009 and January 2010. Macro-dissections were performed to extract total RNA and genomic DNA from 10-μm-thick FFPE specimens of colon cancer. Gene expression levels of 11 enzymes (TS, DPD, TP, OPRT, FPGS, GGH, DHFR, MTHFR, MTHFD, FOLRA, GART) related to 5-FU and folic acid metabolism were studied according to the Danenberg Tumor ProfileTM method (Shirota, Y. JCO 2001). Somatic copy-number alterations in cancer were analyzed by high-density SNP array analysis (Human 250K StyI array, Affymetrix, Santa Clara, CA). To detect copy-number alterations, the scanned image CEL files were imported into Partek Genomics Suite v6.6 (Partek Inc., St. Louis, MO, USA). We compared mRNA level, gene copy number and genome-wide segment copy number across a total of 161 colorectal cancers. Results: Gene expression levels were successfully estimated in 521-808 samples (84.0-90.0%, median 89.4%). Genome-wide DNA copy numbers profiles of 161 samples were obtained by GeneChip. Extracted genomic DNA from 616 of 777 samples that were not subjected to microarray analysis served as validation samples. Frequencies of copy number gain (&amp;gt;2.3) ranged from 0% to 57% for 11 genes, whereas frequencies of copy number loss (&amp;lt;1.7) ranged from 24.8% to 87%. Among 11 genes, the DNA copy numbers of GART, GGH, MTHFD1, and FPGS most strongly correlated with mRNA expression: correlation coefficients of these genes were 0.48, 0.45, 0.42, and 0.41, respectively. Gene expressions of OPRT or TP were influenced not only by their own DNA copy numbers but also by other genomic segments of 20q or 18q on genome-wide analysis. Conclusions: Gene expression of folate metabolizing enzymes positively correlated with DNA copy numbers in patients with stage III colorectal cancer. Such correlations may merit further evaluation to identify potential biomarkers. Citation Format: Hiroyuki Uetake, Toshiaki Ishikawa, Megimi Ishiguro, Shigeyuki Matsui, Kenichi Sugihara, ACTS-CC Study Group. Biomarker search using gene expression databases in a phase III, controlled clinical trial of postoperative adjuvant chemotherapy for stage III colon cancer (acts-cc): Correlation between gene expression and DNA copy number. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 283. doi:10.1158/1538-7445.AM2014-283

571P - Correlation Between Dna Copy Number and Clinicopathological Features: Biomarker Search Using Genome-Wide Analysis of Dna Copy Number Alterations in a Phase III Study of Postoperative Adjuvant Chemotherapy for Stage III Colon Cancer (Acts-Cc Trial)

ABSTRACT Aim: The ACTS-CC trial is a phase III designed to validate the noninferiority of S-1 to UFT/leucovorin as adjuvant chemotherapy for stage III colon cancer. As an additional study, a genome-wide analysis of DNA copy number alterations was performed prospectively to identify predictive and/or prognotic biomarkers. DNA copy number alteration profiles of stage III colon cancer was previously reported (AACR2013 adstr#4688). In the present study, we investigated the correlations between DNA copy number and clinicopathological features to extract the characteristics of colon cancer. Methods: From 795 of 1535 patients enrolled between April 2009 and January 2010, formalin-fixed paraffin-embedded samples of resected tumors were obtained under informed consent. Genomic DNA was extracted from 777 sepecimens using manual macro dissections. After quality assessments using arbitrary PCR and microfluidic analysis, somatic copy-number alterations in tumor were analyzed by high-density SNPs arrays (Human 250K StyI array, Affymetrix, Santa Clara, CA, USA). To detect copy number alterations, the scanned image CEL files were imported into Partek Genomics Suited v6.6 (Partek Inc., . Louis, MO, USA). The associations of genome-wide DNA copy number changes and clinicopathological features of colon cancer were investigated. Results: Genome-wide DNA copy number alteration profiles of 161 samples were obtained by GeneChip. In the profiles, we observed frequent DNA copy number gains at chromosome 7, 8q and 13, and losses at 4, 5q, 17p and 18q. Specific chromosomal aberrations were significantly related to the clinicopathological features; the tumor location significantly correlated with genomic segments in 7p and 20p, the depth of the tumor with genomic segments in 4q, 8p, chromosome 15 and chromosome 18, and the histological type of the tumor with genomic segments in chromosome 18. Age and gender had no correlation with DNA copy number alterations. Conclusions: The location, depth, and histological type of the tumor correlated with DNA copy number alteration. Our findings will facilitate understanding the characteristics of colon cancer. Further investigations may contribute to the exploration of valid biomarkers. Disclosure: T. Ishikawa: has received research funding from Taiho; honoraria from TaihoPharmaceutical Co., Ltd., Merck Serono Co., Ltd., Chugai Pharmaceutical Co., Ltd. and Takeda Pharmaceutical Co., Ltd.; H. Uetake: has received consulting fees, research funding, and honoraria from Taiho, Chugai, Takeda, Bristol-Myers Squibb, and Merck Serono; K. Murotani: has received research funding from Taiho; T. Kobunai: has been employed by Taiho; M. Ishiguro: has received consulting fees from Taiho, Bristol-Myers, and Merck Serono; honoraria from Taiho, Chugai, Yakult Honsha Co., Ltd.; S. Matsui: has received research funding from Taiho; K. Sugihara: has received consultant fees, research funding and honoraria from Taiho, Chugai, Takeda, Yakult Honsha, Daiichi Sankyo Co., Ltd., Bristol-myers, Merck Serono, and Pfizer Co., Ltd.

Randomized phase III clinical study comparing postoperative UFT/LV,UFT+LV/UFT and UFT+LV+PSK/UFT+PSK as adjuvant therapy for curatively resected stage III colorectal cancer HGCSG-CAD study.

3638 Background: Study showed that the oral anticancer agent UFT/LV is useful as postoperative adjuvant chemotherapy for stage III colorectal cancer. PSK, a protein-bound polysaccharide extracted from the mycelia of Coriolus versicolor, is an immunomodulator widely used in gastric, colorectal and lung cancers. Methods: Patients aged 20-80 years with stage III colorectal cancer registered in 35 facilities were randomized to: group A (UFT/LV 28 days/5 weeks for 6 months); group B (UFT+LV 28 days/5 weeks for 6 months, then UFT for 12 months); and group C (UFT+LV+PSK 28 days/5 weeks for 6 months, then UFT+PSK for 12 months). Treatment was started within 6 months after curative resection. Outcome measures were relapse-free survival (RFS), overall survival (OS), incidence and severity of adverse events, and QOL. Results: Of 342 patients registered, 340 eligible patients were analyzed (84 in group A, 85 in group B, and 171 in group C). At baseline, variation in QOL score was observed but histopathological parameters were not different among 3 groups. Median observation period was 36 months. 3-year RFS was 73.8%, 77.6% and 73.9% in groups A, B, and C [A vs C: hazard ratio (HR) 0.960, 95% confidence interval (CI) 0.575-1.601; B vs C: HR 0.837, CI 0.488-1.433; A vs B: HR 1.151, CI 0.623-2.126]. 3-year OS was 95.2%, 91.8% and 89.9% in groups A, B, and C (A vs C: HR 0.460, CI 0.155-1.367; B vs C: HR 0.814, CI 0.338-1.963 A vs B: HR 0.570, CI 0.167-1.947). Adverse events ≥grade 3 included gastrointestinal symptoms and general status. There was no treatment-related death. Excluding high fatigue score in QOL scale that showed pretreatment variation, stratification analysis showed interaction between family score and group, and efficacy was suggested especially in group C with high score (3-yesr RFS: 66.7%, 68.2% and 88.1% in groups A, B, and C. A vs C: HR 3.289, CI 0.951-11.375, B vs C: HR 3.070, CI 0.973-9.685, A vs B: HR 1.084, CI 0.344-3.417). Conclusions: A significant difference in primary endpoint was not detected. Variation in QOL at treatment initiation probably greatly affected outcome. Clinical trial information: NCT00209742.

Abstract 4684: Biomarker search using gene expression databases in a phase III, controlled clinical trial (ACTS-CC) of postoperative adjuvant chemotherapy for stage III colon cancer: Results of cluster analysis.

Abstract Background: The ACTS-CC trial is a randomized, controlled phase III study designed to validate the noninferiority of S-1 to UFT/leucovorin as adjuvant chemotherapy for stage III colon cancer and rectosigmoid cancer. Recurrence-free survival, the primary endpoint, is scheduled to be reported in 2013. A biomarker search was performed as an additional study of the ACTS-CC trial, using formalin-fixed, paraffin-embedded (FFPE) specimens obtained from 892 patients. The gene expression status of 5-FU metabolizing enzymes and folate metabolizing enzymes in tumor was reported (2012 Annual Meeting of AACR). In the present study, we performed cluster analysis of gene expression data from all patients to extract the characteristics of each cluster. Methods: Among the intratumoral expression of 11 genes related to 5-FU and folate metabolism (TS, DPD, TP, OPRT, FPGS, GGH, DHFR, MTHFR, MTHFD, FOLRA, and GART), the mean logarithmic values of DPD and TP (both nucleases, Rs = 0.68) and of TS, OPRT, DHFR, and MTHFD (DNA synthetases and folate-metabolizing enzymes: Rs = 0.39 to 0.55, median, 0.49), genes that showed strong correlations, were calculated and defined as Score 1 (S1) and Score 2 (S2). The K-means method was used to calculate clusters on the basis of S1 and S2 in each patient. Results: All colorectal cancers could be classified into 6 apparent clusters, designated A to F (A: both S1 and S2 high, 75 cases; B: only S2 high, 133 cases; C: both S1 and S2 low, 20 cases; D: only S2 low, 115 cases; E: only S1 low, 184 cases; and F: others, 261 cases). Conclusions: Six distinct clusters in patients with stage III colorectal cancer could be calculated on the basis of the gene expression status of 5-FU metabolizing enzymes and folate metabolizing enzymes. Correlations of the mRNA expression of each gene or herein elucidated clusters to clinicopathological findings are being studied. Average gene expression levels (normalized value, log2) Gene Cluster-A B C D E F TS 3.1 2.8 1.0 1.4 1.8 2.2 DPD −0.04 −2.1 −4.5 −1.5 −3.0 −1.4 TP 3.0 1.2 −0.74 1.6 0.31 1.4 OPRT −0.06 0.29 −1.3 −0.84 −0.62 −0.51 FPGS −0.12 −0.57 −0.42 −0.72 −0.67 −0.34 GGH 3.4 5.0 3.0 2.9 4.3 4.2 DHFR 3.0 3.0 0.73 1.4 2.1 2.3 MTHFR 0.81 0.40 −2.1 −0.25 −0.39 0.07 MTHFD 3.3 3.4 1.7 2.2 2.5 2.8 FOLRA −3.0 0.02 −4.0 −0.99 −1.6 −1.7 GART 0.49 0.87 −0.40 −0.29 0.24 0.39 Citation Format: Hiroyuki Uetake, Toshiaki Ishikawa, Megimi Ishiguro, Kenta Murotani, Shigeyuki Matsui, Kenichi Sugihara, ACTS-CC study group. Biomarker search using gene expression databases in a phase III, controlled clinical trial (ACTS-CC) of postoperative adjuvant chemotherapy for stage III colon cancer: Results of cluster analysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4684. doi:10.1158/1538-7445.AM2013-4684

Evaluation of an inflammation-based prognostic score for the identification of patients requiring postoperative adjuvant chemotherapy for stage II colorectal cancer

Recent studies have revealed the Glasgow prognostic score (GPS) to aid in the prediction of postoperative outcome in colorectal cancer patients. However, whether GPS predicts poor prognosis in curative colorectal cancer patients has yet to be ascertained. Furthermore, there is no information on the association between GPS and adjuvant chemotherapy in stage II or III colorectal cancer patients. A total of 219 patients with stage II and III colorectal cancer were included in this trial. The modified GPS (mGPS) defined in this study was calculated on the basis of admission data as follows: patients with an elevated level of both C-reactive protein (0.5 mg/dl) and hypoalbuminemia (Alb <3.5 mg/dl) were allocated a score of 2, and patients showing 1 or none of these blood chemistry abnormalities were allocated a score of 1 or 0, respectively. The association between the mGPS and clinicopathological findings and survival was retrospectively assessed. The mGPS was significantly higher in patients with an advanced age, serosal invasion, advanced stage cancer and pre-operative high CEA levels. Kaplan-Meier analysis revealed that a higher GPS predicted a higher risk of postoperative mortality in stage II and/or III colorectal cancer patients. Multivariate analyses revealed that the mGPS was the most sensitive predictor of postoperative mortality in stage II/III or stage II, respectively. The prognosis of stage II patients with a higher mGPS was as favorable as that of patients with a lower mGPS when adjuvant chemotherapy was undertaken. Pre-operative mGPS is considered to be a useful predictor of postoperative mortality in patients with stage II and/or III colorectal cancer, independently of the CEA test or TNM system. Postoperative adjuvant chemotherapy may be recommended for stage II colorectal cancer patients with a high mGPS.

The Rationale for Adjuvant Chemotherapy in Stage I Non-small Cell Lung Cancer

The past decade has witnessed renewed interest in studies exploring the benefits of adjuvant (postoperative) chemotherapy (± radiation therapy) in patients with resected non-small cell lung cancer (NSCLC). Recently completed adjuvant trials have included a heterogeneous group of patients with resected stages I to IIIA NSCLC. With rare exception, the published results of these studies indicate adjuvant chemotherapy imparts a significant overall survival advantage. Subset analyses suggest survival benefit occurs primarily in patients with resected stage II or IIIA and is less likely to occur in stage I patients. This apparent lack of survival benefit in stage I patients was seemingly validated in a prospective trial conducted by the Cancer and Leukemia Group B in which stage IB patients were randomized to observation or adjuvant carboplatin and paclitaxel. Survival at 5 -years was identical in the two arms of this trial. By contrast, two contemporary postoperative chemotherapy trials also conducted exclusively in stage I NSCLC patients yielded positive survival results. The divergent outcome of the prospective trials along with the negative subset analyses has created uncertainty as to the utility of postoperative adjuvant chemotherapy in stage I NSCLC. Herein we review the data underlying this controversy and offer a proposed algorithm to aid the clinician in selecting patients whom we believe may benefit from adjuvant chemotherapy. The treatment algorithm is based on currently available tumor- and host-related factors that affect prognosis.