Timing of Surgical Resection for Curative Colorectal Cancer with Liver Metastasis. Ali Shahzad M,Pawlik Timothy M,Rodriguez-Bigas Miguel A,Monson John R T,Chang George J,Larson David W Annals of surgical oncology PURPOSE AND DESIGN:Optimal surgical strategy for resectable synchronous colorectal cancer with liver metastasis (SCRLM) remains a therapeutic dilemma. Multiple retrospective studies including several meta-analyses have been published since 2001 to help facilitate the decision making process and identify the optimal surgical approach. Controversy limits the generalization of available data to draw conclusions. A review of available literature on appropriate surgical timing may alleviate confusion among physicians and promote a more evidence based approach. RESULTS AND CONCLUSION:Current evidence supports the feasibility, safety, and equivalent oncological outcomes of simultaneous curative resection of stage IV colorectal cancer with liver metastasis in appropriately selected patients. 10.1245/s10434-016-5745-7
    Oncologic results of laparoscopic liver resection for malignant liver tumors. Akyuz Muhammet,Yazici Pinar,Yigitbas Hakan,Dural Cem,Okoh Alexis,Aliyev Shamil,Aucejo Federico,Quintini Cristiano,Fung John,Berber Eren Journal of surgical oncology BACKGROUND:There are scant data regarding oncologic outcomes of laparoscopic liver resection (LLR). The aim of this study is to analyze the oncologic outcomes of LLR for malignant liver tumors (MLT). METHODS:This was a prospective IRB-approved study of 123 patients with MLT undergoing LLR. Kaplan-Meier disease-free (DFS) and overall survival (OS) was calculated. RESULTS:Tumor type was colorectal in 61%, hepatocellular cancer in 21%, neuroendocrine in 5% and others in 13%. Mean tumor size was 3.2 ± 1.9 cm and number of tumors 1.6 ± 1.2. A wedge resection or segmentectomy was performed in 63.4%, bisegmentectomy in 24.4%, and hemihepatectomy in 12.2%. Procedures were totally laparoscopic in 67% and hand-assisted in 33%. Operative time was 235.2 ± 94.3 min, and conversion rate 7.3%. An R0 resection was achieved in 90% of patients and 94% of tumors. Median hospital stay was 3 days. Morbidity was 22% and mortality 0.8%. For patients with colorectal liver metastasis, DFS and OS at 2 years was 47% and 88%, respectively. CONCLUSIONS:This study shows that LLR is a safe and efficacious treatment for selected patients with MLT. Complete resection and margin recurrence rate are comparable to open series in the literature. 10.1002/jso.24119
    Evaluation of resectability after neoadjuvant chemotherapy for primary non-resectable colorectal liver metastases: A multicenter study. Takatsuki M,Tokunaga S,Uchida S,Sakoda M,Shirabe K,Beppu T,Emi Y,Oki E,Ueno S,Eguchi S,Akagi Y,Ogata Y,Baba H,Natsugoe S,Maehara Y, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology BACKGROUND/AIM:The Kyushu Study Group of Clinical Cancer (KSCC) previously reported the safety and efficacy of neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab for H2/H3 liver metastases of colorectal cancer. The aim of the current study was to evaluate the resectability of these metastases before and after chemotherapy as determined by independent liver surgeons. METHODS:Between May 2008 and April 2010, 40 patients were registered in a multicenter phase 2 trial of neoadjuvant chemotherapy (KSCC 0802). In Study 1, 5 independent liver surgeons from five different KSCC centers evaluated the resectability of liver metastases of colorectal cancer based on imaging studies performed before and after chemotherapy. Each surgeon was blinded to the other surgeons' evaluations. In addition, no information about the patients' characteristics was provided. In Study 2, 3 surgeons evaluated the resectability of these lesions based on imaging studies with discussion with each other, with the surgeons being provided with information on the patients' characteristics. RESULTS:In Study 1, 13 patients (36.1%) were evaluated to be resectable at baseline, whereas 17 patients (47.2%) were evaluated to be resectable after chemotherapy. In Study 2, 4 patients (11.1%) were evaluated to be resectable at baseline, compared to 23 patients (63.9%) after chemotherapy. CONCLUSION:Neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab was confirmed to increase the resectability of non-resectable liver metastases of colorectal cancer according to the independent assessments of surgeons. 10.1016/j.ejso.2015.11.007
    Management of resectable colorectal lung metastases. Moorcraft Sing Yu,Ladas George,Bowcock Anne,Chau Ian Clinical & experimental metastasis Lung metastases occur in 10-20 % of patients with colorectal cancer. The biology of colorectal lung metastases is poorly understood, however lung metastases are more common in patients with rectal cancer and in patients with RAS mutations. Although the majority of patients have extrapulmonary disease, a small proportion of patients with lung metastases are suitable for lung metastasectomy and surgical resection has become a standard of care, based on data from retrospective series demonstrating a 5-year overall survival of 40-68 %. However, there remains uncertainty regarding the optimal management approach for these patients due to the lack of evidence from randomized controlled trials and current practice varies between institutions. For example, the role for neoadjuvant and adjuvant chemotherapy is not yet defined and there are no randomized trials comparing surgery with alternative treatment options such as radiofrequency ablation and stereotactic ablative radiotherapy. Further research is needed to improve the selection of patients for surgery, but favourable prognostic factors include a normal pre-operative CEA, solitary metastasis, complete resection and a long disease-free interval. There is also evidence that patients with resectable liver and lung metastases may benefit from resection of both sites of disease, and that re-resection may be of benefit in selected patients who relapse with resectable lung metastases. This article summarizes the biology of colorectal lung metastases and discusses the management of patients with lung metastases. 10.1007/s10585-015-9774-6
    Radiofrequency Ablation versus Liver Resection for Colorectal Cancer Liver Metastasis: An Updated Systematic Review and Meta-analysis. Han Yue,Yan Dong,Xu Fei,Li Xiao,Cai Jian-Qiang Chinese medical journal BACKGROUND:Controversial results about the therapeutic value of radiofrequency ablation (RFA) and liver resection (LR) in the treatment of colorectal cancer liver metastasis (CRCLM) have been reported. Thus, we performed the present meta-analysis to summarize the related clinical evidences. METHODS:A systematic literature search was conducted using PubMed (Medline), EMBASE, Cochrane Library, and Web of Science, for all years up to April 2016. Pooled analyses of the overall survival (OS), progression-free survival (PFS), and morbidity rates were performed. RESULTS:A total of 14 studies were finally enrolled in the meta-analysis. Patients treated by LR gained a longer OS and PFS than those of patients treated by RFA. Patients in the RFA group had lower morbidity rates than those of patients in the LR group. Publication bias analysis revealed that there was no significant publication bias in the meta-analysis. CONCLUSIONS:Patients with CRCLM gained much more survival benefits from LR than that from RFA. RFA rendered lower rates of morbidities. More well-designed randomized controlled trails comparing the therapeutic value of LR and RFA are warranted. 10.4103/0366-6999.195470
    A 20-year single center experience in the surgical treatment of colorectal liver metastasis. Tsalis Konstantinos,Ioannidis Orestis,Cheva Angeliki,Antigoni Savvala Natalia,Antoniou Nikolaos,Parpoudi Styliani,Kyziridis Dimitrios,Tatsis Dimitrios,Konstantaras Dimitrios,Kitsikosta Loukiani,George Pramateftakis Manousos,Kotidis Efstathios,Avgerinos Antonios,Mantzoros Ioannis Journal of B.U.ON. : official journal of the Balkan Union of Oncology PURPOSE:To present our experience in the treatment of patients with liver metastases from colorectal cancer. METHODS:The surgical and histopathological records of our department dating from 1st January 1997 to 31 December 2016 were examined, searching for patients who have undergone surgical treatment of colorectal liver metastasis. RESULTS:A total of 90 patients with colorectal liver metastases were treated in the last 20 years in our department. Their mean age was 65.28 years and 54 (60%) were male. The primary tumor was in the colon in 71 patients (78.9%) and in 19 (21.1%) patients in the rectum. Thirty-six (40%) patients presented with synchronous metastatic liver disease, from which 27 were subjected to simultaneous resection, 2 underwent a liver-first approach and 7 were subjected to resection of primary tumor first. Regarding the number of metastases 67 (74.4%) patients had single metastasis, 12 (13.3%) had 2 lesions, 4 (4.4%) had 3 lesions and 7 (7.8%) had 4-8 lesions. In-hospital and 30-day mortality was 3.85%. Median survival was 41 months. CONCLUSION:Surgical resection is the treatment of choice for the management of liver metastasis from colorectal cancer and can be safely performed. Follow up of patients with colorectal cancer is imperative as metachronous metastasis presents in a significant percentage of patients with negative locoregional lymph nodes of the primary tumor. The order of resection doesn't seem to alter outcome in synchronous metastasis. Recurrence is common and re-resection if feasible is the only chance of cure.
    Surgical stress response and promotion of metastasis in colorectal cancer: a complex and heterogeneous process. Behrenbruch Corina,Shembrey Carolyn,Paquet-Fifield Sophie,Mølck Christina,Cho Hyun-Jung,Michael Michael,Thomson Benjamin N J,Heriot Alexander G,Hollande Frédéric Clinical & experimental metastasis Surgery remains the curative treatment modality for colorectal cancer in all stages, including stage IV with resectable liver metastasis. There is emerging evidence that the stress response caused by surgery as well as other perioperative therapies such as anesthesia and analgesia may promote growth of pre-existing micro-metastasis or potentially initiate tumor dissemination. Therapeutically targeting the perioperative period may therefore reduce the effect that surgical treatments have in promoting metastases, for example by combining β-adrenergic receptor antagonists and cyclooxygenase-2 (COX-2) inhibitors in the perioperative setting. In this paper, we highlight some of the mechanisms that may underlie surgery-related metastatic development in colorectal cancer. These include direct tumor spillage at the time of surgery, suppression of the anti-tumor immune response, direct stimulatory effects on tumor cells, and activation of the coagulation system. We summarize in more detail results that support a role for catecholamines as major drivers of the pro-metastatic effect induced by the surgical stress response, predominantly through activation of β-adrenergic signaling. Additionally, we argue that an improved understanding of surgical stress-induced dissemination, and more specifically whether it impacts on the level and nature of heterogeneity within residual tumor cells, would contribute to the successful clinical targeting of this process. Finally, we provide a proof-of-concept demonstration that ex-vivo analyses of colorectal cancer patient-derived samples using RGB-labeling technology can provide important insights into the heterogeneous sensitivity of tumor cells to stress signals. This suggests that intra-tumor heterogeneity is likely to influence the efficacy of perioperative β-adrenergic receptor and COX-2 inhibition, and that ex-vivo characterization of heterogeneous stress response in tumor samples can synergize with other models to optimize perioperative treatments and further improve outcome in colorectal and other solid cancers. 10.1007/s10585-018-9873-2
    Oncologic and surgical outcomes in colorectal cancer patients with liver cirrhosis: A propensity-matched study. Han Eon Chul,Ryoo Seung-Bum,Park Ji Won,Yi Jin Wook,Oh Heung-Kwon,Choe Eun Kyung,Ha Heon-Kyun,Park Byung Kwan,Moon Sang Hui,Jeong Seung-Yong,Park Kyu Joo PloS one The management of colorectal cancer in patients with liver cirrhosis requires a thorough understanding of both diseases. This study evaluated the effect of liver cirrhosis on oncologic and surgical outcomes and prognostic factors in colorectal cancer patients. Fifty-five consecutive colorectal cancer patients with liver cirrhosis underwent colorectal resection (LC group). Using a prospectively maintained database, these patients were matched 1:4 using propensity scoring with R programming language, package "MatchIt" and "optmatch" by sex, age, cancer location, and tumor stage with 220 patients without liver cirrhosis (non-LC group), resulting in 275 patients. The 5-year overall survival (OS) was significantly worse in the LC group than in the non-LC group (46.7% vs. 76.2% respectively, P < 0.001); however, the 5-year proportion of recurrence free (PRF) rates were similar (73.1% vs. 84.5% respectively, P = 0.094). On multivariate analysis of the LC group, tumor-node-metastasis (TNM) stage ≥III disease, venous invasion, and a model for end-stage liver disease plus serum sodium (MELD-Na) score >10 were prognostic factors for OS. However, the OS was not different between the LC group with MELD-Na score ≤10 and the non-LC group (5-year OS rate, TNM stage ≤II, 85.7 vs 89.5%, p = 0.356; TNM stage ≥III, 41.1 vs 66.2%, p = 0.061). Colorectal cancer patients with liver cirrhosis have poorer OS compared to those without liver cirrhosis; however, the PRF rates are similar. It might be due to the mortality from the liver, and surgical treatment should be actively considered for patients with MELD-Na score <10. 10.1371/journal.pone.0178920
    Prognostic value of distant metastasis sites and surgery in stage IV colorectal cancer: a population-based study. Luo Dakui,Liu Qi,Yu Wencheng,Ma Yanlei,Zhu Ji,Lian Peng,Cai Sanjun,Li Qingguo,Li Xinxiang International journal of colorectal disease PURPOSE:We investigated the prognostic value of distant metastasis sites among patients with metastatic colorectal cancer (CRC) and the significance of metastasectomy and resection of the primary CRC. METHODS:Between 2010 and 2014, patients diagnosed with metastatic colorectal adenocarcinoma were selected using the surveillance, epidemiology, and end results (SEER) database. The prognosis of these patients was compared according to the site of metastasis (liver, lung, bone, and brain). A total of 15,133 patients suffered from isolated organ involvement, while 5135 patients experienced multiple organ metastases. RESULTS:In the isolated organ metastasis cohort, median overall survival (OS) for patients with liver, lung, bone, and brain metastases was 16, 20, 7, and 5 months, respectively. Patients with isolated lung metastases had better cancer-specific survival (CSS) and OS as compared to patients with metastases at any other sites (p < 0.0001 for both CSS and OS). Patients with isolated liver metastases had better prognosis as compared to patients with isolated bone or brain metastases (p < 0.0001 for both CSS and OS). Moreover, patients with a single metastatic site had better prognosis than patients with multiple organs involved (p < 0.0001 for both CSS and OS). Multivariate analysis in patients with isolated organ metastases demonstrated that age ≤ 60 years, rectal cancer, being married, non-black race, N0 stage, and surgery of the primary and distant lesions showed more favorable prognosis. CONCLUSIONS:The metastatic site was an independent prognostic factor in stage IV colorectal cancer. Also, carefully chosen patients may benefit from surgery. 10.1007/s00384-018-3091-x
    A clinical model to predict the risk of synchronous bone metastasis in newly diagnosed colorectal cancer: a population-based study. Guan Xu,Ma Chen-Xi,Quan Ji-Chuan,Li Shuai,Zhao Zhi-Xun,Chen Hai-Peng,Yang Ming,Liu Zheng,Jiang Zheng,Wang Xi-Shan BMC cancer BACKGROUND:The early detection of synchronous bone metastasis (BM) in newly diagnosed colorectal cancer (CRC) affects its initial management and prognosis. A clinical model to individually predict the risk of developing BM would be attractive in current clinical practice. METHODS:A total of 55,869 CRC patients were identified from Surveillance, Epidemiology, and End Results (SEER) database, of whom 317 patients were diagnosed with synchronous BM. Risk factors for BM in CRC patients was identified using multivariable logistic regression. A weighted scoring system was built with beta-coefficients (P < 0.05). A random sample of 75% of the CRC patients was used to establish the risk model, and the remaining 25% was used to validate its accuracy of this model. The performance of risk model was estimated by receiver operating curve (ROC) analysis. RESULTS:The risk model consisted of 8 risk factors including rectal cancer, poorly-undifferentiation, signet-ring cell carcinoma, CEA positive, lymph node metastasis, brain metastasis, liver metastasis and lung metastasis. The areas under the receiver operating curve (AUROC) were 0.903 and 0.889 in the development and validation cohort. Patients with scores from 0 to 4 points had about 0.1% risk of developing BM, and the risk increased to about 30% in patients with scores ≥15 points. CONCLUSIONS:This clinical risk model is accurate enough to identify the CRC patients with high risk of synchronous BM and to further provide more individualized clinical decision. 10.1186/s12885-019-5912-x
    Outcomes of Radioembolization in Patients with Chemorefractory Colorectal Cancer Liver Metastasis: a Single-Center Experience. Türk Gamze,Eldem Gonca,Kılıçkap Saadettin,Bozkurt Fani Murat,Salancı Bilge Volkan,Çil Barbaros Erhan,Peynircioğlu Bora,Yalçın Şuayip,Balkancı Ferhun Journal of gastrointestinal cancer PURPOSE:We aimed to evaluate the efficacy and outcomes of radioembolization with Yttrium-90 (Y-90) microspheres in patients with unresectable and chemorefractory colorectal cancer liver metastasis (CRCLM). METHODS:This single-center study included 43 patients (34 male, 9 female) who underwent radioembolization with Y-90 for unresectable, chemorefractory CRCLM between September 2008 and July 2014. Overall survival (OS), liver progression-free survival (LPFS), overall response rate (ORR), local disease control rate (LDCR), and relations of these parameters with patient disease characteristics were evaluated. OS and LPFS rates were compared according to microspheres. Survival rates were calculated with Kaplan-Meier method, and potential prognostic variables were evaluated on univariate analyses. RESULTS:Post-procedural median OS was 12.8 months. LPFS was 5.6 months. ORR was 33%, LDCR was 67% on 3rd month follow-up. Low tumor burden (< 25%) was associated with higher median OS after radioembolization (< 25 vs > 25-50% p < 0.0001 and < 25 vs > 50% p = 0.005). Patients with left colon tumors exhibited significantly longer median OS after metastasis than right colon tumors (p = 0.046). Extrahepatic disease and synchronicity showed poorer survival parameters; however, the difference was not significant (p = 0.1 and p = 0.3, respectively). In subgroup analyses, the distribution of patient number and characteristics showed heterogeneity as number of patients with low tumor burden was higher in resin Y-90 group. Resin Y-90 group exhibited significantly higher median OS and LPFS compared to glass Y-90 group (16.5 vs. 7 months, p = 0.001; 6.73 vs. 3.38 months, p = 0.023, respectively). CONCLUSION:Radioembolization is a safe local-regional treatment option in chemorefractory, inoperable CRCLM. Radioembolization at earlier stages may lead to more favorable results especially with lower tumor burden patients. 10.1007/s12029-018-0053-z
    Current status of nanoscale drug delivery systems for colorectal cancer liver metastasis. Hong Yun,Rao Yuefeng Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Tumor metastasis is a major cause of colorectal cancer-related deaths. The liver is a common site of colorectal cancer metastasis. There is no effective treatment for patients with colorectal cancer with liver metastasis. Due to the complicated and variable metastasis process, the current treatment methods for colorectal cancer liver metastasis cannot meet the clinical needs. Currently, no effective delivery system is available for clinical use which could specifically target metastatic cancers. The emergence of nanoscale drug delivery systems indicates a new direction for the treatment of colorectal cancer liver metastasis. This article summarizes the current common drug and metastasis-related signaling pathways for the treatment of hepatic metastatic colorectal cancer. This review introduces the progress of use nano-formulations for liver metastatic colorectal cancer and provides new ideas. 10.1016/j.biopha.2019.108764
    Characteristics and Prognostic Factors of Bone Metastasis in Patients With Colorectal Cancer. Kawamura Hidetaka,Yamaguchi Tatsuro,Yano Yuuta,Hozumi Takahiro,Takaki Yasunobu,Matsumoto Hiroshi,Nakano Daisuke,Takahashi Keiichi Diseases of the colon and rectum BACKGROUND:Because bone metastasis from colorectal cancer is rare, there are little available data regarding such cases. OBJECTIVE:The study aim was to identify the prognostic factors and characteristics associated with survival in colorectal cancer patients with bone metastasis. DESIGN:This was a retrospective study from a prospectively collected database. SETTINGS:The study took place in a multidisciplinary, high-volume tertiary cancer center in Japan. PATIENTS:Examined were records from 104 consecutive patients treated between 2004 and 2015 for bone metastasis from colorectal cancer. MAIN OUTCOME MEASURES:The primary outcome measure was overall survival. RESULTS:The spine was the most common site of bone metastasis from colorectal cancer. Right colon cancer correlated significantly with long bone metastasis (p = 0.046), whereas left colon cancer correlated significantly with spinal bone metastasis (p = 0.034). Liver metastasis was also significantly correlated with spinal bone metastasis (p = 0.036). The median interval between the primary therapy for colorectal cancer and the metachronous diagnosis of bone metastasis was 20.0 months (quartile 1 to quartile 3, 9.0-46.5 mo). The median survival time from diagnosis of bone metastasis from colorectal cancer was 5.0 months (95% CI, 4.0-9.0 mo), and the 1-year survival rate was 30.0% (95% CI, 21.1%-39.4%). Multivariate analysis revealed that ≥2 extra-bone metastatic organs, hypercalcemia, and pathologic fractures were independent poor prognostic factors (p < 0.001, 0.001, and 0.033). The number of extra-bone metastatic organs correlated with prognosis. LIMITATIONS:This study was limited by its retrospective, nonrandomized design, as well as selection bias and performance at a single institute. CONCLUSIONS:The location of colorectal cancer correlates significantly with the site of bone metastasis; the prognosis of patients with bone metastasis from colorectal cancer is very poor, and the significant prognostic factors are number of extra-bone metastatic organs, hypercalcemia, and pathologic fractures. See Video Abstract at http://links.lww.com/DCR/A589. 10.1097/DCR.0000000000001071
    Smoking is a risk factor for pulmonary metastasis in colorectal cancer. Yahagi M,Tsuruta M,Hasegawa H,Okabayashi K,Toyoda N,Iwama N,Morita S,Kitagawa Y Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland AIM:The hepatic microenvironment, which may include chronic inflammation and fibrosis, is considered to contribute to the pathogenesis of liver metastases of colorectal cancer. A similar mechanism is anticipated for pulmonary metastases, although no reports are available. Smoking causes pulmonary inflammation and fibrosis. Thus, we hypothesized that smokers would be especially affected by pulmonary metastases of colorectal cancer. In this study, we attempted to clarify the impact of smoking on pulmonary metastasis of colorectal cancer. METHOD:Between September 2005 and December 2010 we reviewed 567 patients with pathological Stage I, II or III colorectal cancer, whose clinicopathological background included a preoperative smoking history, pack-year history from medical records. Univariate and multivariate analyses using the Cox proportional hazard model were performed to determine the independent prognostic factors for pulmonary metastasis-free survival. RESULTS:Pulmonary metastases occurred in 39 (6.9%) patients. The smoking histories revealed 355 never smokers, 119 former smokers and 93 current smokers among the subjects. Multivariate analysis revealed that being a current smoker (hazard ratio = 2.72, 95% CI 1.18-6.25; P = 0.02) was an independent risk factor for pulmonary metastases. CONCLUSION:Smoking may be a risk factor for pulmonary metastasis of colorectal cancer. Cessation of smoking should be recommended to prevent pulmonary metastasis, although further basic and clinical studies are required. 10.1111/codi.13833
    Sinusoidal Obstruction Syndrome and Postoperative Complications Resulting from Preoperative Chemotherapy for Colorectal Cancer Liver Metastasis. Hisaka Toru,Ishikawa Hiroto,Sakai Hisamune,Kawahara Ryuichi,Goto Yuichi,Nomura Yoriko,Yasunaga Masafumi,Kinugasa Tetsushi,Fujita Fumihiko,Mizobe Tomoaki,Fukahori Masaru,Miwa Keisuke,Nakashima Osamu,Tanigawa Masahiko,Naito Yoshiki,Akiba Jun,Yano Hirohisa,Tanaka Hiroyuki,Akagi Yoshito,Okuda Koji Anticancer research BACKGROUND/AIM:The aim of this study was to investigate the effects of preoperative chemotherapy on the healthy, metastasis-free part of the liver in colorectal cancer patients with liver metastasis, and the relationship between chemotherapy and postoperative complications. PATIENTS AND METHODS:Our study included 90 cases of colorectal cancer liver metastasis resected after preoperative chemotherapy. The patients were divided into three groups according to the received chemotherapy regimen: 20 cases received mFOLFOX6, 54 cases a combination of mFOLFOX6 with bevacizumab, and 16 cases a combination of mFOLFOX6 and cetuximab or panitumumab. RESULTS:The mean numbers of sinusoidal injuries for each chemotherapy type were compared. The group treated with the combination of mFOLFOX6 and bevacizumab showed a lower extent of sinusoidal injury relative to other groups; this intergroup difference became increasingly remarkable as the number of chemotherapy cycles increased. Complications of various extents were found in all three groups, but no significant differences were observed between the three groups. CONCLUSION:In cases where preoperative chemotherapy was extended over a long period, combined use of bevacizumab was thought to be effective because of stabilization of disturbed liver hemodynamics resulting from sinusoidal injury suppression effects, allowing effective distribution of anti-cancer agents to tumors. 10.21873/anticanres.13632