大腸

領域分類

大腸

糖鎖酵素遺伝子によるステージIII大腸癌の予後バイオマーカー

演　　者：: 岡山洋和¹，野田勝², 立花和之進², 坂本渉¹, 芦澤舞¹, 中島隆宏¹, 青砥慶太¹,
門馬智之¹, 大木進司¹, 河野浩二¹
所属機関：: ¹福島県立医科大学・消化管外科, ²福島県立医科大学・乳腺外科

Glycosylation is a common post-translational modification regulated through the multienzymatic reaction of glycosyltransferases. Aberrant glycosylation occurs during malignant transformation and tumor progression accompanied by unique biological functions, while cancer-associated glycan epitopes, such as CA19-9, are utilized as cancer biomarkers. The present study aimed to discover glycosyltransferase-derived subgroups of colorectal cancer (CRC) based on multi-step, high-throughput data analyses of comprehensive glycosyltransferase gene expression by integrating genetic and epigenetic alterations as well as non-tumor, pre-cancerous, preinvasive and cancerous lesions. Using a total of more than 4600 samples, we identified a distinct subclass exhibiting decreased levels of a glycosyltransferase gene, which encodes one of the polypeptide GalNAc transferase (ppGalNAc-T) family enzymes involved in the initiation of O-glycosylation. Downregulation of the ppGalNAc-T gene was appeared to occur during transition from premalignant/preinvasive lesions to invasive carcinoma, through epigenetic silencing, suggesting its role in the mechanism referred to as incomplete glycan synthesis. Indeed, in vitro loss-of-function of the ppGalNAc-T increased the invasive and migratory potentials along with cancer-associated glycan truncation, as confirmed by cell surface lectin microarray and FACS analysis. Notably, this subgroup lacking the ppGalNAc-T protein (~15% of CRC) was significantly associated with poor cancer-specific and overall survival, independent of clinical parameters, and those patients demonstrated worse disease-free survival when treated with 5-FU-based adjuvant chemotherapy. Since its prognostic and predictive values were particularly remarkable in stage III patients, the expression of the ppGalNAc-T may be used as a biomarker that can help guide clinical decisions, including adjuvant chemotherapy and post-operative surveillance plans for patients with stage III CRC.

RAS野生型進行再発大腸癌における抗EGFR抗体の治療効果における、NLR動態からの検討

演　　者：: 間中大¹，西躰隆太¹, 小西小百合¹, 濱洲晋哉¹, 池田有紀¹, 大田多加乃¹, 西川泰代¹, 工藤亮¹, 川口清隆¹, 安英男¹
所属機関：: ¹京都桂病院・消化器センター・外科

Background: mFOLFOX6+antiEGFR antibody is a standard-of-care in the 1st line chemotherapy of metastatic colorectal cancer. However, the proper use of two antibodies,i.e.cetuximab (Cet) and panitumumab (Pani), are not clarified yet. Cet, IgG subclass1 antibody, is demonstrated to have ADCC activity and other immune, inflammatory functions. Differences of the activities of these two antibodies could be analyzed from this standpoint using the kinetic evaluations of neutrophil-to-lymphocyte ratio (NLR), which is the indicator of cancer-related immune and inflammatory activities.
Methods: 50 pts with RAS wild metastatic colorectal cancer were enrolled and treated with mFOLFOX6+antiEGFR antibody (25 pts each). NLR was measured at the points of pre-treatment (preT), early-tumor-shrinkage (ETS) and progression of disease (PD). Associations of NLR and clinical outcomes were evaluating by Spearman's rank correlation coefficient, and two-sample Mann-Whitney U tests were performed with several variants between Cet and Pani pts.
Results: The median follow-up time for censored cases was 28 months (m) (IQR, 14-52). Progression free survival (PFS) and overall survival (OS) were 10.9m (95% C.I;7.9-12.6) and 30.0m (95% CI; 20.4-41.2), respectively. PFS and OS of Cet and Pani pts were not different significantly
[PFS: 12.0m (95% CI; 7.2-16.2) vs 9.5m (95% CI; 7.8-12.1), p=0.23; OS: 30.0m (95% CI; 21-49.9) vs 33.1m (95% CI; 13-41.9), p=0.202]. NLR at preT and PD were significantly correlated with OS, -0.291(p=0.0422) and -0.347 (p=0.0413), respectively. Correlation of PFS with NLR at ETS and with the difference of NLR between preT and ETS, were -0.415 (p=0.0391) and -0.355 (p=0.0816) in Cet pts, whereas there were no significant trends of correlation in Pani pts, 0.272 (p=0.209) and 0.598 (p=0.002), respectively.
Conclusions: Our results suggest that NLR kinetics could reflect the treatment outcomes and kinetic analysis would lead to the stratification of clinical use of Cet and Pani.

bevacizumab投与における血中VEGF値の推移と治療効果への影響

演　　者：: 原賢康¹，柳田剛¹, 安藤菜奈子¹, 仲井希¹, 前田祐三¹, 廣川高久¹, 志賀一慶¹, 高橋広城¹, 石黒秀行¹, 松尾洋一¹, 瀧口修司¹
所属機関：: ¹名古屋市立大学・消化器外科

Background: Anti-VEGF antibody, Bevacizumab (Bmab) is widely used clinically for metastatic colorectal cancer patient (mCRC), however, it is still difficult to predict its efficacy by laboratory examination. Recently, several biomarkers have been reported to increase through the Bmab therapy. Nevertheless, it is still unknown whether it is useful to predict the efficacy of Bmab and the presence of resistance for Bmab.
Aims: We evaluated the transition of serum VEGF value during Bmab chemotherapy to clarify as a predictor of Bmab effect and the presence of resistance for Bmab.
Materials and Methods: We measured serum VEGF value of 23 mCRC patients who started to undergo Bmab-containing chemotherapy as first or second line every month until tumor progression. From these results, we evaluated the correlation the effect of Bmab and serum VEGF value. Other biomarker (CEA,CA19-9,IL-6) were also evaluated and compared with serum VEGF as a biomarker of Bmab.
Results: Among these biomarkers, only serum VEGF increased at tumor progression compared with those of at the beginning of Bmab therapy. Mean measured VEGF value at the beginning of Bmab therapy and the tumor progression was 59pg/ml and 181pg/ml, respectively. On the other hand, those of other biomarkers were not different between at the beginning of Bmab therapy and the tumor progression. However, these results did not show the efficacy of measuring serum VEGF value to predict the presence of the resistance of Bmab. Once Bmab was administered, serum VEGF value increased independently of Bmab's anticancer effect. Of 23 cases, 14 cases obtained PR chemotherapy effect by Bmab. However, mean VEGF value when these patients obtained PR effect increased up to 142pg/ml. VEGF value at the beginning of therapy didn't influence Bmab effect.
Conclusion: Our study showed that serum VEGF increases since Bmab was administerd independently of its efficacy. This mechanism might influence Bmab resistance.

Stage III結腸癌におけるLNRの至適カットオフ値とその臨床的意義―左右差に着目して―

演　　者：: 神藤英二¹，池秀之², 肥田仁一³, 小林宏寿⁴, 橋口陽二郎⁵, 梶原由規¹, 望月早月¹, 岡本耕一¹, 山本順司¹, 長谷和生¹, 上野秀樹¹, 杉原健一⁶
所属機関：: ¹防衛医科大学校・外科, ²横浜市南部病院・外科, ³近畿大学・外科, ⁴東京都立広尾病院・外科, ⁵帝京大学・外科, ⁶東京医科歯科大学

Background: Prognostic significance of lymph node ratio (LNR) is not constant among studies. Because number of lymph nodes harvested is generally higher in right than in left colon cancer, exploration of appropriate location-specific cut-offs might be necessary. We aimed to determine appropriate cut-off values for LNR between right and left colon cancer and to clarify its clinical significance.
Methods: Clinicopathologic data of 5,463 patients with stage III colon cancer who underwent curative surgery with D2 or D3 dissection at the Japanese Society for Cancer of the Colon and Rectum participating institutions between 1995 and 2006 were derived from the multi-institutional database. The best cut-off for LNR was selected as a prognostic indicator among patients with right and left colon cancer. We compared the prognostic impact between LNR and number of lymph node metastasis based on the Akaike information criterion (AIC) and determined the prognostic significance of LNR in each stage III subcategory.
Results: The best performance was noted when LNR was categorized by cut-offs of 0.16 (AIC, 7309.05) and 0.22 (AIC, 6498.20) for right and left colon cancer, respectively. AIC scores were better with these categorizations than with subgrouping by number of positive nodes (AIC; right, 7309.75; left, 6501.32). Comparison of the 5-year cancer-specific survival revealed significant differences between LNR-low and LNR-high patients with stage IIIA (95.7% vs. 89.3%, P = 0.024), IIIB (86.7% vs. 77.2%, P < 0.0001), and IIIC (71.2% vs. 58.7%, P = 0.016) right colon cancer and between LNR-low and LNR-high patients with stage IIIB (88.3% vs. 80.7%, P < 0.0001) and IIIC (79.8% vs. 68.4%, P = 0.018) left colon cancer.
Conclusions: The appropriate cut-off for LNR was lower in right than in left colon cancer. Categorization by location-specific cut-off of LNR may be useful for risk stratification of patients with stage III cancer.

3D培養法を用いた大腸癌肝転移モデルの作成

演　　者：: 柳澤公紀^1,2，今野雅允^2,3, 浅井歩^2,3, 小関準², 水島恒和¹, 佐藤太郎³, 松崎典弥⁴, 土岐祐一郎¹, 森正樹¹, 石井秀始²
所属機関：: ¹大阪大学・消化器外科, ²大阪大学・疾患データサイエンス学, ³大阪大学・先進癌薬物療法開発学, ⁴大阪大学・応用化学

For translational research, new research tools with structural materials and tissue engineering are necessary to reflect the precise condition of patients. Liver metastasis of colorectal cancer (CRC) is the most numerous in the distant metastasis and recurrence, and new therapeutic development is desired. Human cell three-dimensional (3D) cultured organisms are new research tools for tissue engineering and pharmacology and may substitute animal vivo experiments. The purpose of this study is to demonstrate that 3D culture method shows effectiveness similarity to vivo experiment and verification of the mechanism of colon cancer liver metastasis using 3D cultured liver model. We practice 3D culture method using type I collagen as an extracellular matrix and fibroblast as stromal cells. First, 3D culture using colon cancer cell line was possible. Also, by co-culturing with HUVEC, network formation of HUVEC was observed in the organism. Next, the comparison between 2D culturing of hepatocyte cell line and PCR of 3D culture showed increased expression of hepatocyte function-related gene in RT-PCR. Furthermore, the functional expression of the hepatocyte cell line was compared between the 2D culture and the 3D culture by PCR, and it was found that the expression of the hepatocyte function-related gene was increased in the 3D culture. Utilizing this model, we studied the involvement of extracellular exosomes, which contain miRNAs and metabolites and are proposed to form the pre-metastatic niches in the liver at early stages of massive metastasis. The present study showed the feasibility of 3D model for the translational study of live metastasis in CRC.

dMMR/MSI-H大腸癌におけるTGF-β依存性間質型サブタイプの同定

演　　者：: 遠藤英成¹，岡山洋和¹, 菊池智宏¹, 氏家大輔¹, 多田武志¹, 坂本渉¹, 藤田正太郎¹, 遠藤久仁¹, 斎藤元伸¹, 佐瀬善一郎¹, 門馬智之¹, 三村耕作¹, 大木進司¹, 河野浩二¹
所属機関：: ¹福島県立医科大学・消化管外科

Recent transcriptomic studies for colorectal cancer (CRC) identified stem-like/mesenchymal subtypes associated with poor prognosis (Nat Med 2013, Plos Med 2013). Their predictive power relies on genes expressed by stromal components rather than epithelial tumor cells, where cancer-associated fibroblasts (CAFs) promote tumor progression enhanced by the TGF-β signaling (Nat Genet 2015). Here we conducted transcriptional profiling of CAFs, endothelial cells and immune cells in the tumor microenvironment based on a large-scale bioinfomatic approach utilizing microarray and RNA-sequence cohorts (n>950). Using a panel of relapse-related stromal genes that we recently identified (Carcinogenesis 2016), a TGF-β-responsive stromal signature was developed. We found that the signature can discriminate highly aggressive tumors, which correlated closely with Consensus Molecular Subtype 4 (CMS4, mesenchymal) proposed by the CRC Subtyping Consortium (Nat Med 2015). Notably, TGF-β-dependent stromal activation was found not only in CMS4 tumors but also in a subset of CMS1 (MSI immune) tumors, leading to the identification and validation of a novel stromal subclass within microsatellite instability-High (MSI-H) tumors displaying a high probability of recurrence and mortality. Those findings were further recapitulated by the immunohistochemistry cohort (n>450), in which mismatch-repair deficient (dMMR) tumors exhibiting high levels of a CAFs-specific stromal protein showed significant poor clinical outcome. This subtype was also associated with high levels of the angiogenesis and immune inhibitory signatures, but not with BRAF mutations. The present study suggests that patients in this novel subtype may benefit from intensive postoperative treatment, and that immune evasion, angiogenic activity as well as the TGF-β signaling dependence of those tumors may have strong potential for targeted stromal therapies.

腹腔鏡補助下直腸前方切除術における、骨盤計測を用いた遠位側腸管切離難易度の予測

演　　者：: 足立陽子¹，岡林剛史¹, 鶴田雅士¹, 石田隆¹, 安藤知史¹, 岩間望¹, 豊田尚潔¹, 池端昭慶¹, 森田覚¹, 山高謙¹, 牧野暁嗣¹, 松岡信成¹, 北川雄光¹
所属機関：: ¹慶應義塾大学・一般・消化器外科

Purpose:
It is difficult to perform rectal excision in patients with narrow pelvis. However, the impact of pelvic diameters on the division of rectum has been remained unclear. The purpose of this study is to clarify the influence of pelvic diameters on distal resection margin of rectum in a laparoscopic anterior resection.
Method:
A total of 59 patients who had undergone laparoscopic anterior resection for rectal cancer from January 2008 to March 2017 were included. The measured six pelvic dimensions using three-dimensional reconstruction of spiral computerized tomography (CT) images as follows; the anteroposterior diameters of the pelvic inlet (IAP) and outlet (OAP), the transverse diameters of the pelvic inlet (IT) and outlet (OT), the oblique diameters of the pelvic inlet (IO), and the pelvic depth (distance from the sacral promontory to the tip of coccyx). The distal margin and numbers of stapler firings were used as indicators of technical difficulty.
Results:
There were 39 males and 20 females, and the average age was 67.5 ± 11.4 years. The median length from the anal verge to lower edge of rectal tumor was 9.5 (6.5-10.5) cm. The distal resection margin was ≦2cm in 28 patients (DM1), and >2cm in 31 patients (DM2). Five patients (ST2) required three stapler firings in rectal division whereas other 54 patients (ST1) needed less than three. In DM1 patients, IAP were shorter (p=0.029) and IT/OT ratio were higher significantly than in DM2 patients (p=0.018). The pelvic depth in ST2 patients were significantly longer than in ST1 patients (odd's ratio=4.56; 95% CI 1.32-15.8; p=0.017). Our findings indicate that IAP, IT/OT ratio and pelvic depth may be useful for predicting difficulty of distal rectal division in a laparoscopic anterior resection.
Conclusions:
Pelvic measurement appeared to be valuable for avoiding multiple staple firings and smaller distal resection margins by choosing precise devices and also performing carefully due to the limited operative spaces.

下部進行直腸癌に対する腹腔鏡手術と開腹手術～長期予後の分析～

演　　者：: 肥田侯矢^1,2，岡村亮輔^1,2, 西崎大輔^1,2, 住井敦彦^1,2, 坂井義治^1,2, 小西毅², 赤木智徳², 山口智弘², 秋吉高志², 福田明輝², 山本聖一郎², 山本倫生¹, 森田智視¹, 有薗茂樹¹, 渡邊昌彦²
所属機関：: ¹京都大学・消化管外科, ²腹腔鏡下大腸切除研究会

[Background] We reported the results of a cohort study "Open versus Laparoscopic Surgery for Advanced Low Rectal Cancer -A Large, Multicenter, Propensity Score Matched Cohort Study in Japan-" (June 2017, PMID: 28628565). Although we demonstrated that the occurrence of postoperative morbidity was significantly lower in laparoscopic surgery than in open surgeries (30% vs 39%, p <0.01), long-term outcomes were still debatable (the median follow up period was 3.3 years).
[Aim] To assess the 5-year survival rates for the registered cohort of rectal cancer patients, and to further investigate the association between preoperative MRI or pathological findings and disease recurrence.
[Method] This study includes Japanese 69 institutes. A total of 1,500 patients who underwent radical surgery for clinical stage II/III rectal cancer were registered. The eligibility criteria, definition of the variables and method for the propensity score matching were previously reported.
[Study schedule] Preoperative MRI images are retrospectively evaluated by the central review, and survival data with more than 5 years of the median follow-up period will be obtained in April 2018.
[Discussion] This study is on-going and all analyzes from this study will be reported subsequently. More than 500 MRI images of low rectal cancer have been collected. This is one of the largest cohorts including patients who underwent surgical treatment for rectal cancer in the world.
(This study was funded by Japan Society of Clinical Oncology)

術中呼気終末二酸化炭素濃度(EtCO2)が大腸癌手術の術後合併症に与える影響について

演　　者：: 牧野曉嗣¹，鶴田雅士¹, 森田覚¹, 岡林剛史¹, 石田隆¹, 安藤知史¹, 岩間望¹, 豊田尚潔¹, 池端昭慶¹, 山高謙¹, 足立陽子¹, 松岡信成¹, 北川雄光¹
所属機関：: ¹慶應義塾大学・一般・消化器外科

[Background]
Although intraoperative hypercapnia due to extensive pneumoperitoneum with carbon dioxide could cause instability for circulation or ventilation, we previously reported that hypocapnia is rather risk for morbidity in laparoscopic surgery (LS) for colorectal cancer (CRC). In this study, we attempted to clarify the impact of intraoperative hypocapnia on postoperative complication even in open surgery(OS) for CRC based on our clinical experiences.
[Method]
The patients with cStageI to III colorectal cancer underwent curative resection in our hospital from January 2010 to December 2015 were enrolled into this analysis. The value of end tidal carbon dioxide concentration (EtCO2) was basically plotted every 15 minutes during systemic anesthesia, while in case of blank it was calculated by the before and after data. The EtCO2 value less than 35 mmHg was defined as hypocapnia, and the relationship between the duration of hypocapnia (DOH) and postoperative complication (Clavien-Dindo Grade2 or higher) was analyzed statistically.
[Result]
In total 524 patients were included (OS vs LS: 104 vs 420). The mean (± range) of DOH was 121 (90 ± 110) minutes. OS is significantly longer than LS [172 (188 ± 131) vs [104 (75 ± 97), p<0.001]. In total 100 patients (19.1 %) showed postoperative complications, which was significantly correlated with longer DOH (p=0.035). The morbidity rate in OS is 26.9 %, which did not show significant correlation with longer DOH, while significant correlation was observed in LS (p=0.035).
[Discussion]
Our study revealed that pneumoperitoneum with carbon dioxide reduced DOH in CRC surgery, however, rather longer DOH could cause postoperative complications, which were typical in OS. It might be due to forced ventilation to compensate hypercapnia, which reduce the peripheral oxygen or circulation.
[Conclusion]
Intraoperative hypocapnia might cause postoperative complication in CRC surgery.

TRICOLORE追跡結果：大腸癌一次治療のS-1/CPT-11+Bevの有用性を検証する第3相試験

演　　者：: 高橋信¹，沖田南津子², 傳田忠道³, 蒲生真紀夫⁴, 中村路夫⁵, 杉山克郎⁶, 岩指元⁷, 武藤理⁸, 佐藤敏彦⁹, 濱田和幸¹⁰, 小松嘉人¹¹, 山口達郎¹², 嶋田顕¹³, 森田智視¹⁴, 石岡千加史¹
所属機関：: ¹東北大学・腫瘍内科, ²国立がん研究センター中央院・消化管内科,³千葉県がんセンター・消化器内科, ⁴大崎市民病院・腫瘍内科, ⁵市立札幌病院・消化器内科, ⁶みやぎ県南中核病院・腫瘍内科, ⁷北医科薬科大学病院・肝胆膵外科, ⁸秋田赤十字病院・腫瘍内科, ⁹山形県立中央病院・外科, ¹⁰昭和大学病院・腫瘍内科, ¹¹北海道大学病院・腫瘍センター, ¹²がん・感染症センター都立駒込病院・外科・遺伝子診療科, ¹³昭和大学江東豊洲病院・腫瘍内科, ¹⁴京都大学・医学統計生物情報学

Background:
As previously reported (Yamada Y, et al. Ann Oncol. 2018), the TRICOLORE trial demonstrated that S-1/CPT-11+Bev was non-inferior to mFOLFOX6/CapeOX+Bev in terms of the primary endpoint of progression-free survival (PFS) as first-line treatment for metastatic colorectal cancer (mCRC). We now report the final overall survival (OS) after a median follow-up of more than 3 years.
Methods:
The TRICOLORE trial was a randomized, open-label phase 3 trial. Patients with previously untreated mCRC were randomized to receive either mFOLFOX6/CapeOX+Bev (arm A) or S-1/CPT-11+Bev (arm B; 3-week regimen: CPT-11 150 mg/m², Bmab 7.5mg/kg on day 1, and S-1 80mg/m²twice daily for 2 weeks, followed by a 1-week rest; or 4-week regimen: CPT-11 100 mg/m², Bmab 5mg/kg on day 1 and 15, and S-1 80mg/m²twice daily for 2 weeks, followed by a 2-week rest) . The primary endpoint was PFS. Patients' data were finally updated in September 2017.
Results:
At this final analysis, the median overall survival (mOS) was 32.6 months (95% CI: 27.9-35.9) with arm A and 34.3 months (95% CI: 31.5-38.7) with arm B (median follow-up, 48.7 months). The HR for OS was 0.89 (95% CI: 0.72-1.10). Median PFS (mPFS) in A/B were 10.8/14.0 months (HR 0.86,95% CI: 0.71-1.04), p < 0.0001 for non-inferiority). In RAS wild-type subgroup, mOS and mPFS in A/B were 35.1/38.0 months (HR 0.83, 95% CI 0.59 -1.15) and 11.5/15.9months (HR 0.79, 95% CI 0.59-1.06), respectively. In RAS mutant-type subgroup, mOS and mPFS in A/B were 25.5/29.0 months (HR 0.84, 95% CI 0.54-1.31) and 9.3/11.3 months (HR 0.79, 95% CI 0.54-1.15), respectively.
Conclusion:
Our updated analysis reconfirmed that S-1/CPT-11+Bev is non-inferior to mFOLFOX6/CapeOX+Bev in terms of PFS. S-1/CPT-11+Bev regimen has now become a recommended 1st-line treatment for mCRC.

RAS変異型大腸がんに対するmodified-FOLFOXIRI+bevacizumabの第Ⅱ相試験update

演　　者：: 片岡政人¹，砂川優², 渡邉貴紀³, 石榑清⁴, 田中千弘⁵, 若村邦彦⁶, 園田寛道⁷, 東風貢⁸, 山本大輔⁹, 石丸啓¹⁰, 道傳研司¹¹, 竹内正弘¹², 市川度¹³, 藤井雅志¹⁴, 関川高志¹³
所属機関：: ¹名古屋医療センター・外科, ²聖マリアンナ医科大学・臨床腫瘍学, ³日本赤十字社姫路赤十字病院・外科, ⁴江南厚生病院・外科, ⁵岐阜県総合医療センター・外科,:昭和大学横浜市北部病院・消化器センター, ⁷滋賀医科大学・消化器外科, ⁸日本大学・板橋病院・消化器外科, ⁹石川県立中央病院・消化器外科, ¹⁰愛媛大学附属病院・消化器腫瘍外科, ¹¹福井県立病院・外科, ¹²北里大学・臨床医学（臨床統計学）, ¹³昭和大学藤が丘病院・腫瘍内科・緩和医療科, ¹⁴日本大学・消化器外科

Background: We have reported that modified (m)-FOLFOXIRI (IRI 150mg/m², OHP 85mg/m², levofolinate 200mg/m², and 5-FU 2400mg/m² for 46-h continuous) plus bevacizumab (bev) has good objective response rate (ORR) of 76% and shrinkage of 49% as well as tolerability in Japanese patients (pts) with RAS mutant (mt) metastatic colorectal cancer (mCRC) [Satake H, et al. Oncotarget 2018]. However, the follow-up time was short; therefore, the information on post-treatment was missing.
Methods: 64 pts with unresectable/measurable tumors harboring RAS mt, were enrolled between October 2014 and August 2016. The primary endpoint was ORR, which was evaluated by the external review board. Progression-free survival (PFS), overall survival (OS), early tumor shrinkage, depth of response, and safety were secondary endpoints. Pre-planned updated analysis was performed in March 2018.
Results: 62 pts (median 62.5-y old, 92% PS0, 90%/10% KRAS/NRAS mt) were evaluable for efficacy and 63 pts for toxicity. The median cycle of treatment was 13 (range 1-45). Five pts still continued the protocol treatment. Thirty-seven (65%) pts received 2nd-line chemotherapy (triplet-regimen 27%, IRI-regimen+bev 24%, FOLFIRI+ramucirumab 16%, FOLFIRI+aflibercept 3%, OHP-regimen 8%, 5-FU+bev 11%, TAS-102 8%) and 15 (26%) pts underwent surgery after termination of the protocol therapy. Median PFS was 11.9 (95% CI 9.5-14.0) months, while median OS did not reach. In a sub-analysis by tumor sidedness, the median PFS was 11.9 and 10.1 months in the left (n=45) and right (n=17), respectively (long-rank p=0.39). Adverse events of Gr 3/4 were neutropenia (54%), leukopenia (29%), peripheral neuropathy (1.6%), diarrhea (13%), hypertension (32%), proteinuria (3.2%), and febrile neutropenia (4.8%).
Conclusions: Updated analysis of the JACCRO CC-11 trial shows that m-FOLFOXIRI plus bev is an active 1st-line treatment for RAS mt mCRC. This result suggests that modified-triplet regimen is clinically useful for Japanese mCRC pts.

ATOM試験：KRASwt大腸癌肝転移に対するFOLFOX+Bmab vs. FOLFOX+Cmab比較試験（病理解析）

演　　者：: 波多野悦朗¹，坂井義治², 山中竹春³, 江見泰徳⁴, 室圭⁵, 植竹宏之⁶, 坂元亨宇⁷, 井村穣二⁸, 相島慎一⁹, 石田和之¹⁰, 海野倫明¹¹, 兵頭一之介¹², 冨田尚裕¹³, 杉原健一¹⁴, 前原喜彦¹⁵
所属機関：: ¹兵庫医科大学・肝胆膵外科, ²京都大学・消化管外科, ³横浜市立大学・臨床統計学, ⁴福岡総合病院・外科, ⁵愛知県がんセンター中央病院・腫瘍内科, ⁶東京医科歯科大学・総合外科, ⁷慶應義塾大学・病理学, ⁸富山大学・病理診断学, ⁹佐賀大学・病因診断科, ¹⁰岩手医科大学・病理診断学, ¹¹東北大学・消化器外科, ¹²筑波大学・消化器内科, ¹³兵庫医科大学・下部消化管外科, ¹⁴東京医科歯科大学, ¹⁵九州大学・消化器・総合外科

Background: It is still under debate which anti-VEGF or anti-EGFR antibody is better to combine with chemotherapy for not-optimary resectable KRAS wild-type (wt) colorectal cancer (CRC) with liver-limited metastases. In addition, although several reports showed that both anti-VEGF and anti-EGFR antibody improved pathological response and prolong prognosis, there is neither prospective nor comparison data between anti-VEGF and anti-EGFR. Methods: ATOM trial (NCT01836653) is a multicenter, randomized phase II trial comparing mFOLFOX6+bevacizumab (Bmab arm) with mFOLFOX6+cetuximab (Cmab arm), and previously untreated CRC patients (pts) with KRAS wt tumor were eligible, if they had liver-limited metastatic lesions of 5 or more in number and/or more than 5cm in maximum diameter. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), liver resection rate, and overall survival (OS). This trial was also performed pathological assessment including Tumor regression grade (TRG), modified TRG, Dangerous halo and Sinusoidal Obstruction Syndrome for tumor samples of live resected pts. Results: Among 122 pts randomized, 116 pts (59 in Cmab arm and 57 in Bmab arm) were eligible. After a median follow-up of 24.3 months, median PFS was 14.8 months in Cmab arm and 11.5 months in Bmab arm with a hazard ratio of 0.80 (95%CI, 0.51-1.26). Totally 61 pts (Bmab arm vs. Cmab arm: 32pts (56.1%) vs. 29pts (49.2%)) underwent hepatic resection. In pathological assessment, liver tissue samples of 59/61pts were collected and were assessed by independent pathological review committee. Conclusions: Although PFS in Cmab arm showed better trends than Bmab arm, these were not statistically significant differences, and hepatic resection rates were similar between the two arms. Further pathological data and the correlation data with prognosis in each arm will be presented in this meeting.

REVERCE：大腸癌のRegorafenib-Cetuximab逐次投与ランダム化第Ⅱ相試験（biomarker解析）

演　　者：: 傳田忠道¹，設楽紘平², 山中竹春³, 辻靖⁴, 篠崎勝則⁵, 小松嘉人⁶, 小林良充⁷, 古瀬純司⁸, 加藤健志⁹, 大橋靖雄¹⁰, 吉野孝之²
所属機関：: ¹千葉県がんセンター・消化器内科, ²国立がん研究センター東病院・消化管内科, ³横浜市立大学・臨床統計学, ⁴KKR札幌医療センター斗南病院・腫瘍内科, ⁵県立広島病院・臨床腫瘍科, ⁶北海道大学病院・消化器内科, ⁷釧路労災病院・腫瘍内科, ⁸杏林大学・腫瘍内科, ⁹大阪医療センター・外科, ¹⁰中央大学・人間総合理工学科

Background: The study objective was to evaluate the efficacy and safety of the therapeutic sequence of regorafenib (R) followed by cetuximab (C), compared with C followed by R, as the current standard sequence for metastatic colorectal cancer (mCRC).
Methods: Patients with KRAS exon 2 wild-type mCRC after failure of chemotherapy were randomized to R-C or C-R arm. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) with initial treatment (PFS1) and PFS with second treatment (PFS2).Sequential biomarker analysis including oncogenic alterations from ctDNA or multiple serum proteins related to the EGF or VEGF pathway was an exploratory endpoint.
Results: One-hundred one patients were randomized to the study. Median OS for R-C and C-R was 17.4 and 11.6 months, respectively (p=0.0293), with a hazard ratio (HR) of 0.61 (95% CI, 0.39-0.96). R-C arm consistently showed longer The HR for PFS1 (regorafenib in R-C versus cetuximab in C-R) was 0.97 (95% CI, 0.61-1.54), and PFS2 (C in R-C versus R in C-R) was 0.29 (95% CI, 0.17-0.50). All subgroups in the R-C arm consistently showed longer OS according to the baseline levels of serum proteins biomarkers (median value as cut off). Significant interactions between baseline Tie-2, PlGF or VEGFR-3 level and PFS1 were observed; none correlated with PFS2 outcome.
Conclusions: The therapeutic sequence of R-C showed longer OS than the current standard sequence regardless of biomarker subgroups.

直腸癌前方切除術での下腸間膜動脈切離部位に対する無作為比較試験(HTLT study)

演　　者：: 藤井正一¹，前橋学¹, 今井俊一¹, 大山隆史¹, 板野理¹, 吉田雅博¹, 渡邉純², 石部敦士³, 大田貢由³, 國崎主税², 遠藤格³
所属機関：: ¹国際医療福祉大学市川病院・消化器外科, ²横浜市立大学附属市民総合医療センター・消化器病センター・外科, ³横浜市立大学・消化器・腫瘍外科

Background: The optimal level for inferior mesenteric artery (IMA) ligation during anterior resection for rectal cancer is controversial. The aim of this randomized trial was to clarify whether the IMA should be tied at the origin (high tie, HT) or distal to the left colic artery (low tie, LT).
Methods: Inclusion criterion was a patient who was scheduled to undergo anterior resection with double stapling technique. Patients were randomly allocated to undergo either HT or LT. A stratified factor was surgical approach (open or laparoscopy). Primary endpoint was the incidence of anastomotic leakage. Secondary endpoints were operating time, blood loss and overall survival rate.
Results: During 2006 to 2012, 331 patients were registered to the trial. Seven patients were excluded because of procedural changes. HT and LT were performed in 164 and160 patients respectively. For grade 2 or worse anastomotic leakages, the incidence was 9.8% in HT and 8.8% in LT (p=0.755). The incidence of severe leakages requiring intervention was 2.4% versus 5.0% (p=0.222). In multivariable analysis, the risk factors for leakage were male sex (RR4.608, 95%CI1.653-12.842) and distance of the tumor from the anal verge (RR1.013, 95%CI1.001-1.026). Operating times did not differ significantly although the time until ligation of the IMA was longer for LT (p< 0.001). Blood loss and the overall early complication rate were not significantly different between groups. Neither the total number nor each station of harvested lymph nodes differed. In the long-term results, overall survival rate did not differ significantly between HT and LT (5y: 87.2% vs. 89.4%, p=0.386). The relapse free survival rate was not significantly different between groups also (5y: 76.3% vs. 77.6%, p=0.765).
Conclusion: The short-term and long-term results were equal between groups. The level of ligation of the IMA did not significantly influence to anastomotic leakage. Registered number NCT01861678 (http://clinicaltrials.gov).

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