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Xing Q, Cui Y, Liu M, Gu XL, Li XT, Xing BC, Sun YS. Preoperative CT-based morphological heterogeneity for predicting survival in patients with colorectal cancer liver metastases after surgical resection: a retrospective study. BMC Med Imaging 2024; 24:343. [PMID: 39696033 DOI: 10.1186/s12880-024-01524-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 12/09/2024] [Indexed: 12/20/2024] Open
Abstract
OBJECTIVE To explore the value of preoperative CT-based morphological heterogeneity (MH) for predicting local tumor disease-free survival (LTDFS) and progression-free survival (PFS) in patients with colorectal cancer liver metastases (CRLM). METHODS The latest CT data of 102 CRLM patients were retrospectively analyzed. The morphological score of each liver metastasis was obtained, and the morphological heterogeneity difference (MHD) was calculated. The receiver operating characteristic (ROC) curve was drawn, and the cutoff value was found. The Kaplan-Meier method was used to draw survival curves of patients with or without MH. The Cox regression analysis was used to build the model with MH and clinical characteristics for predicting PFS. RESULTS In 78 patients without MH, median PFS was 9.0 months (95% CI:6.5-11.5), while in 24 patients with MH, median PFS was 6.0 months (95% CI:4.0-8.1), indicating that MH significantly affected PFS (p = 0.001). MH affected PFS in both the chemotherapy group and the chemotherapy combined with targeted therapy group (p = 0.005, p = 0.043). MH, preoperative carcinoembryonic antigen (CEA) and chemotherapy after surgery were independent predictors for postoperative PFS in patients with CRLM. CONCLUSION Preoperative CT-based MH had good efficacy for predicting LTDFS and PFS of CRLM patients after surgical resection, regardless of preoperative treatment. MH is one of the independent predictors of PFS.
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Affiliation(s)
- Qian Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China
| | - Yong Cui
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China
| | - Ming Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China
| | - Xiao-Lei Gu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China
| | - Xiao-Ting Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China
| | - Bao-Cai Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China.
| | - Ying-Shi Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China.
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Khessairi N, Mallek I, Mbarek M, Zaafouri EB, Gharbi L, Boufaroua AL, Bacha D, Ben-Slama S. NEOADJUVANT TREATMENT OF LIVER METASTASES OF COLORECTAL CANCER: PREDICTIVE FACTORS OF PATHOLOGICAL RESPONSE. ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA : ABCD = BRAZILIAN ARCHIVES OF DIGESTIVE SURGERY 2024; 37:e1829. [PMID: 39475884 PMCID: PMC11520675 DOI: 10.1590/0102-6720202400036e1829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 08/28/2024] [Indexed: 11/02/2024]
Abstract
BACKGROUND Surgery after neoadjuvant chemotherapy (CT) improves the prognosis of colorectal liver metastases (CRLM). AIMS The aim of this study was to evaluate the predictive factors of the histological response of CRLM after neoadjuvant treatment. METHODS A retrospective monocentric study including patients with CRLM operated after neoadjuvant treatment. Assessment of histological response was based on the Rubbia-Brandt tumor regression grading score. The scores were grouped into two types of response: Response Group (R) and No Response Group (NR). RESULTS The study included 77 patients (mean age=56 years, sex ratio=1.57). Node metastases were noticed in 62% of cases. Synchronous liver metastasis was present in 42 cases (55%) and metachronous liver metastasis in 45%. Neoadjuvant treatment consisted of CT only in 52 patients (68%) and CT with targeted therapy in 25 patients (32%). Chemo-induced lesions were present in 44 patients (57%). Histological response was presented (Group R) in 36 cases (47%) and absent (Group NR) in 41 cases (53%). The overall survival of our patients was 32 months. For Group R, survival was significantly greater (p=0.001). The predictive factors of histological response identified were delay in the onset of liver metastasis greater than 14 months (p=0.027) and neoadjuvant treatment combining CT and targeted therapy (p=0.031). In multivariate analysis, the type of neoadjuvant treatment (p=0.035) was an independent predictive factor of histological response. CONCLUSIONS Predictive factors of histological response would allow us to identify patients who would benefit most from neoadjuvant treatment. These patients with CRLM onset of more than 14 months and treated with CT combined with targeted therapy would be the best candidates for a neoadjuvant CT strategy followed by surgical resection.
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Affiliation(s)
- Nayssem Khessairi
- Salah Azaiz Institute, Surgical Oncology Department - Tunis, Tunísia
- University of Tunis El-Manar, Faculty of Medicine - Tunis, Tunísia
| | - Ines Mallek
- University of Tunis El-Manar, Faculty of Medicine - Tunis, Tunísia
- Mongi Slim University Hospital, Pathology Department - La Marsa, Tunis, Tunísia
| | - Mehdi Mbarek
- Salah Azaiz Institute, Surgical Oncology Department - Tunis, Tunísia
- University of Tunis El-Manar, Faculty of Medicine - Tunis, Tunísia
| | - Elmontassar Belleh Zaafouri
- University of Tunis El-Manar, Faculty of Medicine - Tunis, Tunísia
- Mongi Slim University Hospital, Digestive Surgery Department - La Marsa, Tunis, Tunísia
| | - Lassaad Gharbi
- University of Tunis El-Manar, Faculty of Medicine - Tunis, Tunísia
- Mongi Slim University Hospital, Digestive Surgery Department - La Marsa, Tunis, Tunísia
| | - Ahlem Lahmar Boufaroua
- University of Tunis El-Manar, Faculty of Medicine - Tunis, Tunísia
- Mongi Slim University Hospital, Pathology Department - La Marsa, Tunis, Tunísia
| | - Dhouha Bacha
- University of Tunis El-Manar, Faculty of Medicine - Tunis, Tunísia
- Mongi Slim University Hospital, Pathology Department - La Marsa, Tunis, Tunísia
| | - Sana Ben-Slama
- University of Tunis El-Manar, Faculty of Medicine - Tunis, Tunísia
- Mongi Slim University Hospital, Pathology Department - La Marsa, Tunis, Tunísia
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Takahashi T, Ishida K, Emi Y, Sakamoto M, Imura J, Aishima S, Muro K, Uetake H, Oki E, Katayose Y, Yoshida K, Unno M, Hyodo I, Tomita N, Sugihara K, Maehara Y. Pathological Evaluation of Resected Colorectal Liver Metastases: mFOLFOX6 Plus Bevacizumab versus mFOLFOX6 Plus Cetuximab in the Phase II ATOM Trial. Cancers (Basel) 2022; 14:cancers14184392. [PMID: 36139557 PMCID: PMC9496839 DOI: 10.3390/cancers14184392] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/30/2022] [Accepted: 09/06/2022] [Indexed: 11/16/2022] Open
Abstract
We compared the preplanned histopathological responses of resected liver metastases from patients who received modified FOLFOX6 plus bevacizumab or modified FOLFOX6 plus cetuximab for liver-limited colorectal metastases in the ATOM trial. Fibrosis and viable tumor cells in tumor regression grade (TRG), infarct-like necrosis in modified TRG (mTRG), and dangerous halo (DH) were assessed. Fifty-five patients (28 and 27 patients in the bevacizumab and cetuximab arms, respectively) were divided into the low (viable tumor cells ≤ 50%) and high (>50%) TRG or mTRG groups. DH was characterized as absent/rare or focal/diffuse. Compared to the bevacizumab arm, the cetuximab arm was more effective, with respect to low TRG (13 vs. 23 patients) and absent/rare DH (14 vs. 19 patients), respectively. Low mTRG was similarly observed in both arms. Low TRG/mTRG and absent/rare DH showed better relapse-free survival (RFS) than high TRG/mTRG and focal/diffuse DH. In the bevacizumab arm, a significant difference in RFS existed between the low and high TRG groups, while in the cetuximab arm, for TRG, mTRG, and DH, the low and absent/rare groups demonstrated significantly longer RFS than the high and focal/diffuse groups, respectively. TRG could estimate RFS in patients who underwent liver metastasectomy after bevacizumab or cetuximab chemotherapy.
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Affiliation(s)
- Takao Takahashi
- Department of Digestive Surgery, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194, Japan
- Correspondence: ; Tel.: +81-058-230-6235; Fax: +81-058-230-6236
| | - Kazuyuki Ishida
- Department of Diagnostic Pathology, Dokkyo Medical University, 880 Kitakobayashi, Mibu 321-0293, Japan
| | - Yasunori Emi
- Department of Surgery, Saiseikai Fukuoka General Hospital, 1-3-46 Tenjin, Chuou-ku, Fukuoka 810-0001, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Johji Imura
- Department of Pathology, Kumagaya General Hospital, 4-5-1 Nakanishi, Kumagaya 360-8567, Japan
| | - Shinichi Aishima
- Department of Pathology and Microbiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanoko-den Chikusa-ku, Nagoya 464-8681, Japan
| | - Hiroyuki Uetake
- Department of Clinical Research, National Disaster Medical Center, 3256 Midoricho, Tachikawa 190-0014, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Yu Katayose
- Hepato-Biliary and Pancreatic Surgery, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aobaku, Sendai 981-8558, Japan
| | - Kazuhiro Yoshida
- Department of Digestive Surgery, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Ichinosuke Hyodo
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama 791-0280, Japan
| | - Naohiro Tomita
- Cancer Treatment Center, Toyonaka Municipal Hospital, 4 Chome-14-1 Shibaharacho, Toyonaka 560-8565, Japan
| | - Kenichi Sugihara
- Department of Surgical Oncology and Gastroenterology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yoshihiko Maehara
- Department of Surgery, Kyushu Central Hospital of the Mutual Aid Association of Public-School Teachers, 3-23-1 Shiobara, Minami-ku, Fukuoka 815-8588, Japan
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Matsuhashi N, Tomita H, Tanaka H, Iwata Y, Matsui S, Imai H, Fukada M, Mizutani C, Takahashi T, Yasufuku I, Suetsugu T, Mori R, Tanaka Y, Okumura N, Futamura M, Yoshida K. Evaluation of histopathological heterogeneity of colorectal cancer liver metastasis sites after preoperative chemotherapy. Mol Clin Oncol 2022; 16:61. [PMID: 35127086 PMCID: PMC8771193 DOI: 10.3892/mco.2022.2494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 07/14/2021] [Indexed: 11/30/2022] Open
Abstract
Patients with liver metastases from colorectal cancer (CRLMs) frequently receive chemotherapy prior to liver resection. Histopathological assessment of the resected specimen can evaluate the response to chemotherapy. The present study analyzed the association between histopathological changes in the primary site and liver metastases. The present study comprised 45 patients with resectable CRLMs at the Surgical Oncology Department of Gifu University School of Medicine (Gifu, Japan) between January 2006 and August 2015. The study included 24 men and 21 women. The primary colonic tumor was located in the right side in 13 (28.9%) patients and the left side in 32 (71.9%) patients. The present study evaluated patients with metastatic colorectal cancer (31/45) after excluding those in whom histopathological heterogeneity between the primary and liver metastasis changed to grade 3 after chemotherapy. The group that underwent hepatectomy after chemotherapy (n=25) was compared with the group that underwent hepatectomy alone (n=6). In 16 (53.3%) out of 25 patients, histopathological heterogeneity of the liver metastasis was lost (P=0.04). In conclusion, chemotherapy appeared to change histopathological heterogeneity. The present study suggested that the histopathological change of intratumoral heterogeneity is reflected by the response to chemotherapy.
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Affiliation(s)
- Nobuhisa Matsuhashi
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Hidenori Tanaka
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Yoshinori Iwata
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Satoshi Matsui
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Hisashi Imai
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Masahiro Fukada
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Chika Mizutani
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Takao Takahashi
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Itaru Yasufuku
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Tomonari Suetsugu
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Ryutaro Mori
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Yoshihiro Tanaka
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Naoki Okumura
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Manabu Futamura
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
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Stift J, Graf A, Neudert B, Herac M, Woeran K, Tamandl D, Laengle J, Schwarz C, Wrba F, Kaczirek K, Stremitzer S. Immune checkpoints and liver resection after neoadjuvant chemotherapy including bevacizumab in patients with microsatellite-stable colorectal liver metastases. HPB (Oxford) 2022; 24:40-46. [PMID: 34158230 DOI: 10.1016/j.hpb.2021.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 05/21/2021] [Accepted: 05/27/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND The clinical value of immune checkpoint expression as prognostic biomarker in bevacizumab-pretreated patients with resected microsatellite-stable (MMS) colorectal liver metastases is unclear and was retrospectively investigated in this study. METHODS Expression analyses of IDO-1, PD-L1, and CTLA-4 were performed by immunohistochemistry in resected bevacizumab-pretreated colorectal liver metastases. Association of immune checkpoint expression in tumor cells and immune cells with response and clinical outcome was investigated. Expression profiles were compared with those of patients with anti-EGFR-targeted therapy and lung metastases, respectively. RESULTS One hundred thirty-six patients with MMS disease were investigated (79 (58.1%) male/57 (41.9%) female, median age 62.9 years (range 31.0-80.4)). High expression of IDO-1 in immune cells was associated with longer OS (not reached versus 44.8 months, HR 0.23 (95% CI 0.09, 0.55), P = 0.001). Low expression of CTLA-4 in tumor cells was associated with better histological response (26 major, 19 partial, 18 none versus 14 major, 23 partial, 30 none, P = 0.032). Expression profiles differed compared to patients with anti-EGFR-targeted therapy and patients with lung metastases. CONCLUSION Immune checkpoint expression was associated with response and survival. IDO-1 may serve as a novel prognostic and/or predictive biomarker in patients with MMS colorectal liver metastases.
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Affiliation(s)
- Judith Stift
- Clinical Institute of Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Alexandra Graf
- Institute for Medical Statistics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Barbara Neudert
- Clinical Institute of Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Merima Herac
- Clinical Institute of Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Katharina Woeran
- Clinical Institute of Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Dietmar Tamandl
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Johannes Laengle
- Department of Surgery, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Christoph Schwarz
- Department of Surgery, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Friedrich Wrba
- Clinical Institute of Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Klaus Kaczirek
- Department of Surgery, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Stefan Stremitzer
- Department of Surgery, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
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Jácome AA, Oliveira FA, Lino F, Lima JPSN. Effect of Adding Bevacizumab to Chemotherapy on Pathologic Response to Preoperative Systemic Therapy for Resectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis. Clin Colorectal Cancer 2021; 20:265-272. [PMID: 34158251 DOI: 10.1016/j.clcc.2021.05.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 05/04/2021] [Accepted: 05/17/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Liver-limited metastatic colorectal cancer is a potentially curable disease. Pathologic response (pR) to preoperative chemotherapy (CT) for colorectal liver metastases (CLM) is a surrogate endpoint for overall survival (OS). We conducted the first meta-analysis of observational studies to estimate the overall effect of bevacizumab on pR in preoperative systemic therapy for CLM. METHODS We systematically searched PubMed, Cochrane Library, CINAHL, Web of Science, Embase, and LILACS for studies published between January 2004 and August 2019 that compared the pR of CT plus bevacizumab to CT alone as preoperative therapy for CLM. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were pathologic major (pMaR) and minor (pMiR) response. Overall effects were expressed by odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. RESULTS Of the 1,452 studies yielded by the search, 9 were eligible, totaling 1,202 patients (516 CT plus bevacizumab and 686 CT alone). The addition of bevacizumab to CT increased the pCR rate without reaching statistical significance (OR: 1.24, 95% CI 0.81 to 1.92, P = .32). However, pMaR was significantly higher (OR: 2.45, 95% CI 1.85 to 3.25, P < .001), and pMiR was significantly lower (OR: 0.41, 95% CI 0.31 to 0.54, P < .001), in the bevacizumab group. The analyses showed a low level of heterogeneity (I2 = 0% to 6%). Publication bias was not found. CONCLUSIONS This meta-analysis demonstrates that bevacizumab plus preoperative CT is associated with higher rates of pR in CLM. Antiangiogenics might improve the OS of CLM patients and should be evaluated in randomized clinical trials. MICROABSTRACT The benefit of perioperative chemotherapy for colorectal liver metastases (CLM) is uncertain, but pathologic response (pR) to preoperative chemotherapy is a strong prognostic factor. Our meta-analysis of observational studies compared the pR of bevacizumab plus chemotherapy to chemotherapy alone as preoperative systemic therapy in the management of CLM. The addition of bevacizumab was associated with significantly higher rates of pR.
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Affiliation(s)
- Alexandre A Jácome
- Department of Gastrointestinal Medical Oncology, Oncoclinicas, Belo Horizonte, Brazil.
| | | | - Flora Lino
- Department of Gastrointestinal Medical Oncology, Oncoclinicas, Rio de Janeiro, Brazil
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Rovers KP, Bakkers C, Nienhuijs SW, Burger JWA, Creemers GJM, Thijs AMJ, Brandt-Kerkhof ARM, Madsen EVE, van Meerten E, Tuynman JB, Kusters M, Versteeg KS, Aalbers AGJ, Kok NFM, Buffart TE, Wiezer MJ, Boerma D, Los M, de Reuver PR, Bremers AJA, Verheul HMW, Kruijff S, de Groot DJA, Witkamp AJ, van Grevenstein WMU, Koopman M, Nederend J, Lahaye MJ, Kranenburg O, Fijneman RJA, van 't Erve I, Snaebjornsson P, Hemmer PHJ, Dijkgraaf MGW, Punt CJA, Tanis PJ, de Hingh IHJT. Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal Metastases: A Phase 2 Randomized Clinical Trial. JAMA Surg 2021; 156:710-720. [PMID: 34009291 DOI: 10.1001/jamasurg.2021.1642] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Importance To date, no randomized clinical trials have investigated perioperative systemic therapy relative to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM). Objective To assess the feasibility and safety of perioperative systemic therapy in patients with resectable CPM and the response of CPM to neoadjuvant treatment. Design, Setting, and Participants An open-label, parallel-group phase 2 randomized clinical trial in all 9 Dutch tertiary centers for the surgical treatment of CPM enrolled participants between June 15, 2017, and January 9, 2019. Participants were patients with pathologically proven isolated resectable CPM who did not receive systemic therapy within 6 months before enrollment. Interventions Randomization to perioperative systemic therapy or CRS-HIPEC alone. Perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin. Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles. Main Outcomes and Measures Proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity. Key secondary outcomes were centrally assessed rates of objective radiologic and major pathologic response of CPM to neoadjuvant treatment. Analyses were done modified intention-to-treat in patients starting neoadjuvant treatment (experimental arm) or undergoing upfront surgery (control arm). Results In 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62 [10] years), experimental (n = 37) and control (n = 42) arms did not differ significantly regarding the proportions of macroscopic complete CRS-HIPEC (33 of 37 [89%] vs 36 of 42 [86%] patients; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74) and Clavien-Dindo grade 3 or higher postoperative morbidity (8 of 37 [22%] vs 14 of 42 [33%] patients; risk ratio, 0.65; 95% CI, 0.31-1.37; P = .25). No treatment-related deaths occurred. Objective radiologic and major pathologic response rates of CPM to neoadjuvant treatment were 28% (9 of 32 evaluable patients) and 38% (13 of 34 evaluable patients), respectively. Conclusions and Relevance In this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM, justifying a phase 3 trial. Trial Registration ClinicalTrials.gov Identifier: NCT02758951.
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Affiliation(s)
- Koen P Rovers
- Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands
| | - Checca Bakkers
- Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands
| | - Simon W Nienhuijs
- Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands
| | - Jacobus W A Burger
- Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands
| | - Geert-Jan M Creemers
- Department of Medical Oncology, Catharina Cancer Institute, Eindhoven, the Netherlands
| | - Anna M J Thijs
- Department of Medical Oncology, Catharina Cancer Institute, Eindhoven, the Netherlands
| | | | - Eva V E Madsen
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Esther van Meerten
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Jurriaan B Tuynman
- Department of Surgery, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands
| | - Miranda Kusters
- Department of Surgery, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands
| | - Kathelijn S Versteeg
- Department of Medical Oncology, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands
| | - Arend G J Aalbers
- Department of Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Niels F M Kok
- Department of Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Tineke E Buffart
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Marinus J Wiezer
- Department of Surgery, Sint Antonius Hospital, Nieuwegein, the Netherlands
| | - Djamila Boerma
- Department of Surgery, Sint Antonius Hospital, Nieuwegein, the Netherlands
| | - Maartje Los
- Department of Medical Oncology, Sint Antonius Hospital, Nieuwegein, the Netherlands
| | - Philip R de Reuver
- Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Andreas J A Bremers
- Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Henk M W Verheul
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Schelto Kruijff
- Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Derk Jan A de Groot
- Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands
| | - Arjen J Witkamp
- Department of Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | | | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Joost Nederend
- Department of Radiology, Catharina Cancer Institute, Eindhoven, the Netherlands
| | - Max J Lahaye
- Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Onno Kranenburg
- Cancer Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Remond J A Fijneman
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Iris van 't Erve
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Petur Snaebjornsson
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Patrick H J Hemmer
- Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Marcel G W Dijkgraaf
- Department of Epidemiology and Data Science, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Cornelis J A Punt
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Pieter J Tanis
- Department of Surgery, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Ignace H J T de Hingh
- Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands.,GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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8
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Azam F, Vazquez A. Trends in Phase II Trials for Cancer Therapies. Cancers (Basel) 2021; 13:E178. [PMID: 33430223 PMCID: PMC7825663 DOI: 10.3390/cancers13020178] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 12/27/2020] [Accepted: 01/05/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Drug combinations are the standard of care in cancer treatment. Identifying effective cancer drug combinations has become more challenging because of the increasing number of drugs. However, a substantial number of cancer drugs stumble at Phase III clinical trials despite exhibiting favourable efficacy in the earlier Phase. Methods: We analysed recent Phase II cancer trials comprising 2165 response rates to uncover trends in cancer therapies and used a null model of non-interacting agents to infer synergistic and antagonistic drug combinations. We compared our latest efficacy dataset with a previous dataset to assess the progress of cancer therapy. Results: Targeted therapies reach higher response rates when used in combination with cytotoxic drugs. We identify four synergistic and 10 antagonistic combinations based on the observed and expected response rates. We demonstrate that recent targeted agents have not significantly increased the response rates. Conclusions: We conclude that either we are not making progress or response rate measured by tumour shrinkage is not a reliable surrogate endpoint for the targeted agents.
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Affiliation(s)
- Faruque Azam
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK;
| | - Alexei Vazquez
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK;
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK
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9
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Delgado-Osuna JA, García-Martínez C, Gómez-Barbadillo J, Ventura S. Heuristics for interesting class association rule mining a colorectal cancer database. Inf Process Manag 2020. [DOI: 10.1016/j.ipm.2020.102207] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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10
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Stremitzer S, Vermeulen P, Graver S, Kockx M, Dirix L, Yang D, Zhang W, Stift J, Wrba F, Gruenberger T, Lenz HJ, Scherer SJ. Immune phenotype and histopathological growth pattern in patients with colorectal liver metastases. Br J Cancer 2020; 122:1518-1524. [PMID: 32205863 PMCID: PMC7217855 DOI: 10.1038/s41416-020-0812-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 02/18/2020] [Accepted: 03/03/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Patients with desmoplastic (angiogenic) histopathological growth pattern (HGP) colorectal liver metastases (CLM) might derive more benefit from bevacizumab-based chemotherapy than those with replacement (non-angiogenic) HGP. This study investigated the association of HGP with the immune phenotype (IP) and clinical outcome after liver resection. METHODS CLM of patients treated with perioperative bevacizumab-based chemotherapy and liver resection were investigated. Association of HGP and IP with response, recurrence-free survival (RFS) and overall survival (OS) was investigated. RESULTS One hundred and eighteen patients (M/F 66/52, median age 62.3 (31.0-80.4) years, median follow-up 32.2 (5.0-92.7) months) were enrolled. The inflamed IP was associated with the desmoplastic HGP. The desmoplastic HGP was associated with better radiological and histological response compared to the replacement HGP, respectively. The replacement HGP was associated with shorter RFS (8.7 versus 16.3 months, HR 2.60, P = 0.001) and OS (36.6 months versus not reached, HR 2.32, P = 0.027), respectively. The non-inflamed IP was associated with shorter RFS (10.8 versus 16.5 months, HR 1.85, P = 0.029). The HGP but not the IP remained significant in multivariable analysis for RFS. CONCLUSIONS The desmoplastic HGP is associated with the inflamed IP and HGP may be a potential biomarker for adjuvant treatment that includes targeting the immune contexture.
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Affiliation(s)
- Stefan Stremitzer
- USC/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA, 90033, USA.
- Department of Surgery, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
| | | | - Shannon Graver
- University of Wuerzburg, Biocenter, Am Hubland, 97074, Wuerzburg, Germany
| | - Mark Kockx
- Histogenex, Sint-Bavostraat 78, 2610, Antwerp, Belgium
| | - Luc Dirix
- Sint-Augustinus Hospital Oncology Center, Medical Oncology, Oosterveldlaan 24, 2610, Antwerp, Belgium
| | - Dongyun Yang
- USC/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA, 90033, USA
| | - Wu Zhang
- USC/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA, 90033, USA
| | - Judith Stift
- Clinical Institute of Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Friedrich Wrba
- Clinical Institute of Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Thomas Gruenberger
- Department of Surgery, Social Medical Center South, Kundratstrasse 3, 1100, Vienna, Austria
| | - Heinz-Josef Lenz
- USC/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA, 90033, USA
| | - Stefan J Scherer
- University of Wuerzburg, Biocenter, Am Hubland, 97074, Wuerzburg, Germany
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11
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Du Pasquier C, Roulin D, Bize P, Sempoux C, Rebecchini C, Montemurro M, Schäfer M, Halkic N, Demartines N. Tumor response and outcome after reverse treatment for patients with synchronous colorectal liver metastasis: a cohort study. BMC Surg 2020; 20:78. [PMID: 32306936 PMCID: PMC7169034 DOI: 10.1186/s12893-020-00738-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 04/06/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The reverse treatment of patients with synchronous colorectal liver metastases (CRLM) is a sequential approach with systemic chemotherapy first, followed by liver resection, and finally, primary tumor resection. The aim of this study was to assess the feasibility, the radiological and pathological tumor response to neoadjuvant therapy, recurrence rates and long-term survival after reverse treatment in a cohort study. METHODS Data from patients with CRLM who underwent a reverse treatment from August 2008 to October 2016 were extracted from our prospective hepato-biliary database and retrospectively analyzed for response rates and survival outcomes. Radiological tumor response was assessed by RECIST (Response Evaluation Criteria In Solid Tumor) criteria and pathological response according to TRG (Tumor Regression Grade). Disease-free and overall survival were estimated with Kaplan-Meier survival curves. RESULTS There were 44 patients with 19 rectal and 25 colonic tumors. The reverse treatment was fully completed until primary tumor resection in 41 patients (93%). Radiological assessment after chemotherapy showed 61% of complete/partial response. Pathological tumor response was major or partial in 52% of patients (TRG 1-3). Median disease-free survival after primary tumor resection was 10 months (95% CI 5-15 months). Disease-free survival at 3 and 5 years was 25% and 25%, respectively. Median overall survival was 50 months (95% CI 42-58 months). Overall survival at 3 and 5 years was 59% and 39%, respectively. CONCLUSION The reverse treatment approach was feasible with a high rate of patients with complete treatment sequence and offers promising long-term survival for selected patients with advanced simultaneous colorectal liver metastases.
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Affiliation(s)
- Céline Du Pasquier
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland.,Department of Pathology, Lausanne University Hospital (CHUV), University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Didier Roulin
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland.,Department of Pathology, Lausanne University Hospital (CHUV), University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Pierre Bize
- Department of Radiology, Lausanne University Hospital (CHUV), University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Christine Sempoux
- Department of Pathology, Lausanne University Hospital (CHUV), University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Caterina Rebecchini
- Department of Pathology, Lausanne University Hospital (CHUV), University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Michael Montemurro
- Department of Medical Oncology, Lausanne University Hospital (CHUV), University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Markus Schäfer
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Nermin Halkic
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Nicolas Demartines
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland.
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12
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Serrablo A, Paliogiannis P, Paradisi C, Hörndler C, Sarría L, Tejedor L, Serrablo L, Azoulay D. Radio-Pathological Correlations in Patients with Liver Metastases for Colorectal Cancer. Dig Surg 2020; 37:383-389. [PMID: 32224622 DOI: 10.1159/000506105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 01/22/2020] [Indexed: 12/10/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is the most frequent gastrointestinal cancer. The liver is the organ most commonly affected by CRC metastases. Synchronous CRC liver metastases (CRCLM) are present in 15-25% at diagnosis, and metastases are confined to the liver in 70-80% of these cases. The aim of the present study was to investigate the existence of significant correlations between the pathological features and computed tomography scan morpho-densitometric findings. SUMMARY A retrospective study of prospectively collected data has been performed; all patients underwent curative-intent hepatic resection from January 2004 to December 2012 and had histologically confirmed CRCLM. Key Messages: Thirty-four (57%) patients were males; the mean age was 64.4 (±10.2) years. Statistically significant differences have been found with the percentages of intra-tumoral fibrosis (p = 0.038) and necrosis (p = 0.007); the values of fibrosis are higher in the absence of a peri-lesional ring, while those of necrosis are higher in the presence of a peri-lesional ring.There was a correlation between the histopathological response to treatments and the global attenuation levels observed in the computed tomography scan of CRCLM. Furthermore, the presence of a radiologically evidenced peripheral ring was associated with the amount of viable tumor cells in the periphery of the tumor, and with responses predominated by necrosis. More studies are needed to clarify the radiological and histological correlation and to be able to better select patients who are going to undergo surgery.
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Affiliation(s)
- Alejandro Serrablo
- HPB Surgical Division, Miguel Servet University Hospital, Zaragoza, Spain,
| | - Panagiotis Paliogiannis
- Experimental Pathology and Oncology, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Carlos Paradisi
- Radiology Department, Clinic University Hospital, Zaragoza, Spain
| | - Carlos Hörndler
- Pathological Department, Miguel Servet University Hospital, Zaragoza, Spain
| | - Luis Sarría
- Radiology Department, Miguel Servet University Hospital, Zaragoza, Spain
| | - Luis Tejedor
- General Surgery Department Puerta Europa Hospital, Algeciras, Spain
| | | | - Daniel Azoulay
- The Center of Liver Diseases, Sheba Medical Center, Tel Aviv, Israel
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13
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Sarathy V, Kothandath Shankar RK, Mufti SS, Naik R. FOLFOX and capecitabine-induced hepatic granuloma mimicking metastasis in a rectal cancer patient. BMJ Case Rep 2020; 13:13/3/e232628. [PMID: 32139448 DOI: 10.1136/bcr-2019-232628] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
A 49-year-old male carcinoma rectum patient was treated with neoadjuvant FOLFOX (folinic acid, fluorouracil (5-FU) and oxaliplatin) chemotherapy, chemoradiotherapy with capecitabine, surgery and adjuvant FOLFOX. On follow-up, the patient developed a metabolically active liver lesion mimicking metastasis. Liver biopsy and histopathology showed sinusoidal dilatation with non-caseating granulomas. Follow-up fluorodeoxyglucose positron-emission tomography CT scan demonstrated increase in size of the lesion with metabolic activity suspicious of metastasis. The patient underwent segmental liver resection and histopathology showed non-necrotising granuloma with no evidence of malignancy. It is crucial to consider potential side effects of chemotherapeutic agents and have an unbiased approach when evaluating new liver lesions during post treatment follow-up of colorectal cancer. A multidisciplinary tumour board approach comprising of gastroenterologists, medical oncologists, pathologists, radiologists and surgeons is suggested in the management of such patients. The patient is currently doing well and on regular follow-up.
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Affiliation(s)
- Vinu Sarathy
- Medical Oncology, HealthCare Global Enterprises Ltd, Bangalore, India
| | | | - Suhail Sayeed Mufti
- Translational Medicine and Therapeutics, HealthCare Global Enterprises Ltd, Bangalore, India
| | - Radheshyam Naik
- Medical Oncology, HealthCare Global Enterprises Ltd, Bangalore, India
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14
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Aykan NF, Özatlı T. Objective response rate assessment in oncology: Current situation and future expectations. World J Clin Oncol 2020; 11:53-73. [PMID: 32133275 PMCID: PMC7046919 DOI: 10.5306/wjco.v11.i2.53] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 11/05/2019] [Accepted: 11/28/2019] [Indexed: 02/06/2023] Open
Abstract
The tumor objective response rate (ORR) is an important parameter to demonstrate the efficacy of a treatment in oncology. The ORR is valuable for clinical decision making in routine practice and a significant end-point for reporting the results of clinical trials. World Health Organization and Response Evaluation Criteria in Solid Tumors (RECIST) are anatomic response criteria developed mainly for cytotoxic chemotherapy. These criteria are based on the visual assessment of tumor size in morphological images provided by computed tomography (CT) or magnetic resonance imaging. Anatomic response criteria may not be optimal for biologic agents, some disease sites, and some regional therapies. Consequently, modifications of RECIST, Choi criteria and Morphologic response criteria were developed based on the concept of the evaluation of viable tumors. Despite its limitations, RECIST v1.1 is validated in prospective studies, is widely accepted by regulatory agencies and has recently shown good performance for targeted cancer agents. Finally, some alternatives of RECIST were developed as immune-specific response criteria for checkpoint inhibitors. Immune RECIST criteria are based essentially on defining true progressive disease after a confirmatory imaging. Some graphical methods may be useful to show longitudinal change in the tumor burden over time. Tumor tissue is a tridimensional heterogenous mass, and tumor shrinkage is not always symmetrical; thus, metabolic response assessments using positron emission tomography (PET) or PET/CT may reflect the viability of cancer cells or functional changes evolving after anticancer treatments. The metabolic response can show the benefit of a treatment earlier than anatomic shrinkage, possibly preventing delays in drug approval. Computer-assisted automated volumetric assessments, quantitative multimodality imaging in radiology, new tracers in nuclear medicine and finally artificial intelligence have great potential in future evaluations.
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Affiliation(s)
- Nuri Faruk Aykan
- Department of Medical Oncology, Istinye University Medical School, Bahcesehir Liv Hospital, Istanbul 34510, Turkey
| | - Tahsin Özatlı
- Department of Medical Oncology, Istinye University Medical School, Bahcesehir Liv Hospital, Istanbul 34510, Turkey
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15
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Impact of Genetics on Neoadjuvant Therapy with Complete Pathological Response in Metastatic Colorectal Cancer: Case Report and Review of the Literature. Balkan J Med Genet 2019; 22:75-80. [PMID: 31523624 PMCID: PMC6714337 DOI: 10.2478/bjmg-2019-0004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Treatment of colorectal metastatic cancer is still challenging, despite recent improvements in chemotherapy. A genetic cancer profile, such as the KRAS (Kirsten rat sarcoma) gene status, plays a key role in individualized tailored therapy. Molecular targeted therapy added to neo-adjuvant chemotherapy can achieve a better pathological response and prolong survival. Pathological complete response of colorectal cancer stage IV is rare. A 47-year-old female patient presented with rectal adenocarcinoma and three liver metastases (cT3d/4, N2, Ml). After seven cycles of Bevacizumab and CAPOX in neoadjuvant setting, we noted more than 70.0% regression of metastases and complete regression of the primary tumor. We performed low anterior resection of rectum and synchronous subsegmental resection of S3, because the other two lesions were not detectable. Pathology revealed complete response of the primary and also secondary tumors. After 8 months, diagnostic tests did not show any sign of recurrence and the remaining liver lesions disappeared. Colorectal cancer is a heterogeneous disease and it is necessary to identify patients who are at-risk of recurrence and suitable for neoadjuvant therapy. Genetic biomarkers play an important role in metastatic colorectal cancer treatment. Because of the mutated KRAS gene, Bevacizumab was added to cytotoxic therapy achieving a complete pathological response of primary tumor and metastasis. This case is unique because all reported cases with similar results, described staged surgery and one of reverse staged surgery, but with similar results. This neoadjuvant therapy has extraordinary results for colorectal cancer stage IV and can help disease-free and long-term survival.
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16
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Kawagoe S, Nakano M, Uchino K, Arimizu K, Kajitani T, Shimokawa H, Kusumoto T, Ikejiri K, Baba E. Analysis of Response Evaluation Criteria in Solid Tumors reduction ratio of primary chemotherapy in unresectable advanced or recurrent colorectal cancer. Mol Clin Oncol 2019; 11:243-251. [PMID: 31396385 PMCID: PMC6667888 DOI: 10.3892/mco.2019.1894] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 06/14/2019] [Indexed: 02/07/2023] Open
Abstract
Response Evaluation Criteria in Solid Tumors (RECIST) is used to assess the objective response of solid tumors to treatment. However, it remains unclear to what extent the response rate assessed by RECIST reflects a reduction of tumor size in multiple organs in patients with unresectable advanced or recurrent colorectal cancer (CRC) with multiple organ metastases. It is also unclear whether the management of liver metastases with systemic chemotherapy in CRC patients with multiple organ metastases improves their prognosis, although surgical resection has been shown to be the most effective treatment approach to CRC cases with liver metastases. A total of 38 CRC patients who underwent systemic chemotherapy in Kyushu Medical Center Hospital between January 2013 and April 2016 were examined. The patients had measurable lesions in multiple organs, including the liver, and did not undergo curative surgery for metastatic lesions after initiation of chemotherapy. The association between the total reduction ratio (TRR) of all lesions and liver lesion reduction ratio (LRR) was retrospectively analyzed. A total of 18 patients (47%) had H3 liver metastases, and the median liver lesion occupancy rate in the sum of the measured lesions with RECIST was 76%. TRR and LRR were strongly correlated, regardless of the volume of the liver metastases. Although a TRR of >30% was significantly associated with improved overall survival (OS), this improvement was not observed in patients with H3 liver metastases. TRR was correlated with LRR and was associated with a better OS. CRC patients with both multiple organ and H3 liver metastases exhibited poor survival, even with a high reduction ratio by chemotherapy.
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Affiliation(s)
- Shiho Kawagoe
- Department of Medical Oncology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Fukuoka 810-8563, Japan
| | - Masahiro Nakano
- Department of Nursing, Faculty of Health Sciences, Junshin Gakuen University, Fukuoka, Fukuoka 815-0036, Japan
| | - Keita Uchino
- Department of Medical Oncology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Fukuoka 810-8563, Japan
| | - Kohei Arimizu
- Department of Medical Oncology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Fukuoka 810-8563, Japan
| | - Tatsuhiro Kajitani
- Department of Medical Oncology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Fukuoka 810-8563, Japan
| | - Hozumi Shimokawa
- Department of Medical Oncology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Fukuoka 810-8563, Japan
| | - Tetsuya Kusumoto
- Department of Gastrointestinal Surgery, National Hospital Organization Kyushu Medical Center, Fukuoka, Fukuoka 810-8563, Japan
| | - Koji Ikejiri
- Department of Gastrointestinal Surgery, National Hospital Organization Kyushu Medical Center, Fukuoka, Fukuoka 810-8563, Japan
| | - Eishi Baba
- Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
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17
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Total neoadjuvant approach with FOLFOXIRI plus bevacizumab followed by chemoradiotherapy plus bevacizumab in locally advanced rectal cancer: the TRUST trial. Eur J Cancer 2019; 110:32-41. [DOI: 10.1016/j.ejca.2019.01.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 12/31/2018] [Accepted: 01/06/2019] [Indexed: 01/22/2023]
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18
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Perioperative Bevacizumab-based Triplet Chemotherapy in Patients With Potentially Resectable Colorectal Cancer Liver Metastases. Clin Colorectal Cancer 2019; 18:34-43.e6. [DOI: 10.1016/j.clcc.2018.11.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 08/10/2018] [Accepted: 11/19/2018] [Indexed: 01/14/2023]
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19
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Ishida K, Tamura A, Kato K, Uesugi N, Osakabe M, Eizuka M, Hasegawa Y, Nitta H, Otsuka K, Sasaki A, Ehara S, Sugai T. Correlation between CT morphologic appearance and histologic findings in colorectal liver metastasis after preoperative chemotherapy. Abdom Radiol (NY) 2018; 43:2991-3000. [PMID: 29616287 DOI: 10.1007/s00261-018-1588-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PURPOSE Radiological evaluation of the efficacy of preoperative chemotherapy for colorectal liver metastasis (CRLM) is the most important tool for determining treatment strategies. The aim of this study was to identify a correlation between morphologic appearance on computed tomography (CT) and histologic findings of CRLM after preoperative chemotherapy. METHODS We examined 47 patients who had undergone a first hepatic resection for CRLM after preoperative chemotherapy and had received contrast-enhanced CT scans. We assessed the morphologic appearance of the overall attenuation based on metastases changing from heterogeneous to mixed and homogenous lesions, the tumor-liver interface, and the peripheral rim enhancement on CT. Histologic parameters included usual necrosis (UN), infarct-like necrosis (ILN), three-zonal change, dangerous halo, mucous lake, shape of ILN, dominant type of necrosis, and presence of viable tumor cells. The relationship between morphologic appearance and histologic findings was evaluated. RESULTS CT overall attenuation revealed that UN predominance was more common in the heterogeneous group than in the mixed and homogeneous groups (P = 0.011). The frequency of ILN increased sequentially from ill-defined to variable and sharp at the tumor-liver interface (P = 0.038), and the frequency of UN decreased sequentially from present to partially resolved and completely resolved in the peripheral rim enhancement (P = 0.023). The histologic presence of viable tumor cells was closely associated with the tumor-liver interface (P = 0.0003) and the peripheral rim enhancement (P = 0.004). CONCLUSIONS CT morphologic appearance of CRLM after preoperative chemotherapy is correlated with histologic findings regarding necrosis.
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20
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Hirata F, Ishiyama K, Tanaka Y, Kobayashi T, Hashimoto M, Saeki Y, Ishida N, Taguchi K, Tanaka J, Arihiro K, Ohdan H. Effect of bevacizumab plus XELOX (CapeOX) chemotherapy on liver natural killer cell activity in colorectal cancer with resectable liver metastasis. Ann Gastroenterol Surg 2018; 2:383-393. [PMID: 30238080 PMCID: PMC6139723 DOI: 10.1002/ags3.12195] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 05/28/2018] [Accepted: 06/26/2018] [Indexed: 12/22/2022] Open
Abstract
AIM We investigated the chemotherapy effect of resectable colorectal cancer with liver metastasis (CRLM) on the function of intrahepatic immune cells. METHODS We classified patients into adjuvant chemotherapy (bevacizumab+CapeOX) after hepatectomy group (group A) and neoadjuvant chemotherapy followed by hepatectomy group (group B), and collected peripheral blood mononuclear cells (PBMC) and liver mononuclear cells (LMNC) to ascertain phenotypic and functional differences. RESULTS There were no significant differences in lymphocyte fractions of either PBMC or LMNC between groups, except for the significantly lower percentage of natural killer (NK) cells in LMNC in group B than in group A. Significantly higher percentage of natural-killer group 2, member D (NKG2D)- positive NK cells in PBMC and percentage of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-, NKp30-, and signal regulatory protein β (SIRPβ)-positive NK cells in LMNC were found in group B. Furthermore, significantly higher expressions of NKG2D and SIRPβ in peripheral blood NK cells and of NKp46 and CD122 in liver NK cells were found in group B. When LMNC were incubated with interleukin (IL)-2 in vitro, no difference was observed in the expression of these molecules in NK cells between groups. Consistently, there was no difference in the cytotoxic activity of those LMNC against a colon adenocarcinoma cell line between groups. CONCLUSION Colorectal cancer with liver metastasis patients treated with neoadjuvant chemotherapy showed enhanced expression of activation markers on peripheral blood and liver NK cells in comparison with patients who did not receive therapy; however, the difference in those function remains unclear. These results suggest that neoadjuvant chemotherapy does not have a negative impact on intrahepatic immune cells in resectable CRLM patients.
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Affiliation(s)
- Fumihiro Hirata
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Kohei Ishiyama
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
- Department of SurgeryNational Hospital Organization Kure Medical Center and Chugoku Cancer CenterHiroshimaJapan
| | - Yuka Tanaka
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Masakazu Hashimoto
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Yoshihiro Saeki
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Nobuki Ishida
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Kazuhiro Taguchi
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Junko Tanaka
- Department of EpidemiologyInfectious Disease Control and PreventionGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Koji Arihiro
- Department of Anatomical PathologyHiroshima University HospitalHiroshimaJapan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
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21
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Cremolini C, Milione M, Marmorino F, Morano F, Zucchelli G, Mennitto A, Prisciandaro M, Lonardi S, Pellegrinelli A, Rossini D, Bergamo F, Aprile G, Urbani L, Morelli L, Schirripa M, Cardellino GG, Fassan M, Fontanini G, de Braud F, Mazzaferro V, Falcone A, Pietrantonio F. Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials. Br J Cancer 2018; 118:955-965. [PMID: 29531324 PMCID: PMC5931102 DOI: 10.1038/s41416-018-0015-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 01/10/2018] [Accepted: 01/10/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs. METHODS We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials. RESULTS Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615). CONCLUSIONS The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents.
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Affiliation(s)
- Chiara Cremolini
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, 56126, Italy
| | - Massimo Milione
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori - Via Venezian, 20100, Milano, Italy.
| | - Federica Marmorino
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, 56126, Italy
| | - Federica Morano
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori - Via Venezian, 1, 20100, Milano, Italy
| | - Gemma Zucchelli
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, 56126, Italy
| | - Alessia Mennitto
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori - Via Venezian, 1, 20100, Milano, Italy
| | - Michele Prisciandaro
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori - Via Venezian, 1, 20100, Milano, Italy
| | - Sara Lonardi
- Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, 35128, Padova, Italy
| | - Alessio Pellegrinelli
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori - Via Venezian, 20100, Milano, Italy
| | - Daniele Rossini
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, 56126, Italy
| | - Francesca Bergamo
- Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, 35128, Padova, Italy
| | - Giuseppe Aprile
- Department of Oncology, University & General Hospital, Udine - Pz.le S. Maria della Misericordia 15, 33100, Udine, Italy
- General Hospital, ULSS8 Berica - East District, 36100, Vicenza, Italy
| | - Lucio Urbani
- General Surgery Unit, Azienda Ospedaliero-Universitaria Pisana, Ospedale Nuovo Santa Chiara, Cisanello, 56124, Pisa, Italy
| | - Luca Morelli
- 1st General Surgery Unit, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56124, Pisa, Italy
| | - Marta Schirripa
- Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, 35128, Padova, Italy
| | - Giovanni Gerardo Cardellino
- Department of Oncology, University & General Hospital, Udine - Pz.le S. Maria della Misericordia 15, 33100, Udine, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine University of Padua, Padua, via Giustiniani 2, 56126, Padova, Italy
| | - Gabriella Fontanini
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa - Via Roma, 67 56126, Pisa, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori - Via Venezian, 1, 20100, Milano, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Vincenzo Mazzaferro
- General Surgery and Liver Surgery, Transplantation and Gastroenterology, University of Milan, IRCCS Istituto Nazionale Tumori Fondazione, 20100, Milan, Italy
| | - Alfredo Falcone
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, 56126, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori - Via Venezian, 1, 20100, Milano, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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22
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Li-Chang HH, Driman DK. Comment on: Pathologic Response to Preoperative Chemotherapy in Colorectal Liver Metastases: Fibrosis, Not Necrosis, Predicts Outcome. Ann Surg Oncol 2017; 24:607. [PMID: 29181678 DOI: 10.1245/s10434-017-6198-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Hector H Li-Chang
- Deparment of Laboratory Medicine and Pathobiology, Mount Sinai Hospital, University of Toronto, 600 University Avenue, Suite 600 Toronto, Toronto, ON, M5G 1X5, Canada.
| | - David K Driman
- Department of Pathology, Western University, London, Canada
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23
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Stift J, Graf A, Schwarz C, Tamandl D, Starlinger P, Herac M, Beer A, Wrba F, Bodingbauer M, Kaczirek K, Stremitzer S. Microscopic biliary and perineural invasion and clinical outcome after neoadjuvant bevacizumab-based chemotherapy and liver resection in patients with colorectal liver metastases. Eur J Surg Oncol 2017; 44:139-147. [PMID: 29203074 DOI: 10.1016/j.ejso.2017.11.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 10/21/2017] [Accepted: 11/19/2017] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND The value of microscopic biliary and perineural invasion as prognostic biomarkers in patients with resectable colorectal liver metastases (CLM) who undergo neoadjuvant chemotherapy and liver resection is still unclear. This retrospective study was performed to elucidate this issue. METHODS Histologic slides of resected CLM of patients who underwent neoadjuvant bevacizumab-based chemotherapy and liver resection were investigated with respect to biliary and perineural invasion. Presence of invasion was correlated with radiologic and histologic response, recurrence-free survival (RFS) and overall survival (OS). RESULTS One hundred forty-one patients were enrolled. There was a significant association between biliary and perineural invasion, respectively (P = 0.001). Moreover, both biliary and perineural invasion were associated with bilobar metastatic spread and higher number of metastases, while perineural invasion was also associated with a higher Fong score. No significant association was found with response. In univariable analysis, biliary and perineural invasion were associated with shorter RFS (median 10.1 vs. 13.5 months, HR 2.09, P = 0.010 and 7.6 vs. 14.0, HR 2.23, P = 0.001, respectively). Biliary invasion was also associated with shorter OS (median 32.8 months vs. not reached, HR 2.78, P = 0.010), however these results did not remain significant in multivariable analysis. CONCLUSIONS In patients with resectable colorectal liver metastases undergoing neoadjuvant bevacizumab-based chemotherapy and liver resection, biliary and perineural invasion are associated with higher tumor load but may not be prognostic biomarkers.
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Affiliation(s)
- Judith Stift
- Clinical Institute of Pathology, Medical University Vienna, Austria
| | - Alexandra Graf
- Institute for Medical Statistics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University Vienna, Austria
| | | | - Dietmar Tamandl
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University Vienna, Austria
| | | | - Merima Herac
- Clinical Institute of Pathology, Medical University Vienna, Austria
| | - Andrea Beer
- Clinical Institute of Pathology, Medical University Vienna, Austria
| | - Friedrich Wrba
- Clinical Institute of Pathology, Medical University Vienna, Austria
| | | | - Klaus Kaczirek
- Department of General Surgery, Medical University Vienna, Austria.
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24
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Pathologic response after preoperative therapy predicts prognosis of Chinese colorectal cancer patients with liver metastases. CHINESE JOURNAL OF CANCER 2017; 36:78. [PMID: 28969708 PMCID: PMC5625647 DOI: 10.1186/s40880-017-0244-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 09/17/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Pathologic response is evaluated according to the extent of tumor regression and is used to estimate the efficacy of preoperative treatment. Several studies have reported the association between the pathologic response and clinical outcomes of colorectal cancer patients with liver metastases who underwent hepatectomy. However, to date, no data from Chinese patients have been reported. In this study, we aimed to evaluate the association between the pathologic response to pre-hepatectomy chemotherapy and prognosis in a cohort of Chinese patients. PATIENTS AND METHODS In this retrospective study, we analyzed the data of 380 liver metastases in 159 patients. The pathologic response was evaluated according to the tumor regression grade (TRG). The prognostic role of pathologic response in recurrence-free survival (RFS) and overall survival (OS) was assessed using Kaplan-Meier curves with the log-rank test and multivariate Cox models. Factors that had potential influence on pathologic response were also analyzed using multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests. RESULTS Patients whose tumors achieved pathologic response after preoperative chemotherapy had significant longer RFS and OS than patients whose tumor had no pathologic response to chemotherapy (median RFS: 9.9 vs. 6.5 months, P = 0.009; median OS: 40.7 vs. 28.1 months, P = 0.040). Multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests showed that metastases with small diameter, metastases from the left-side primary tumors, and metastases from patients receiving long-duration chemotherapy had higher pathologic response rates than their control metastases (all P < 0.05). A decrease in the serum carcinoembryonic antigen (CEA) level after preoperative chemotherapy predicted an increased pathologic response rate (P < 0.05). Although the application of targeted therapy did not significantly influence TRG scores of all cases of metastases, the addition of cetuximab to chemotherapy resulted in a higher pathologic response rate when combined with irinotecan-based regimens rather than with oxaliplatin-based regimens. CONCLUSIONS We found that the evaluation of pathologic response may predict the prognosis of Chinese colorectal cancer patients with liver metastases after preoperative chemotherapy. Small tumor diameter, long-duration chemotherapy, left primary tumor, and decreased serum CEA level after chemotherapy are associated with increased pathologic response rates.
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25
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Pietrantonio F, Di Bartolomeo M, Cotsoglou C, Mennitto A, Berenato R, Morano F, Coppa J, Perrone F, Iacovelli R, Milione M, Alessi A, Vaiani M, Bossi I, Ricchini F, Scotti M, Caporale M, Bajetta E, de Braud F, Mazzaferro V. Perioperative Triplet Chemotherapy and Cetuximab in Patients With RAS Wild Type High Recurrence Risk or Borderline Resectable Colorectal Cancer Liver Metastases. Clin Colorectal Cancer 2017; 16:e191-e198. [DOI: 10.1016/j.clcc.2016.09.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 09/09/2016] [Accepted: 09/22/2016] [Indexed: 12/19/2022]
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26
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Suzuki K, Muto Y, Ichida K, Fukui T, Takayama Y, Kakizawa N, Kato T, Hasegawa F, Watanabe F, Kaneda Y, Kikukawa R, Saito M, Tsujinaka S, Futsuhara K, Takata O, Noda H, Miyakura Y, Kiyozaki H, Konishi F, Rikiyama T. Morphological response contributes to patient selection for rescue liver resection in chemotherapy patients with initially un-resectable colorectal liver metastasis. Oncol Lett 2017; 14:1491-1499. [PMID: 28789370 PMCID: PMC5529781 DOI: 10.3892/ol.2017.6338] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 02/13/2017] [Indexed: 12/12/2022] Open
Abstract
Morphological response is considered an improved surrogate to the Response Evaluation Criteria in Solid Tumors (RECIST) model with regard to predicting the prognosis for patients with colorectal liver metastases. However, its use as a decision-making tool for surgical intervention has not been examined. The present study assessed the morphological response in 50 patients who underwent chemotherapy with or without bevacizumab for initially un-resectable colorectal liver metastases. Changes in tumor morphology between heterogeneous with uncertain borders and homogeneous with clear borders were defined as an optimal response (OR). Patients were also assessed as having an incomplete response (IR), and an absence of marked changes was assessed as no response (NR). No significant difference was observed in progression-free survival (PFS) between complete response/partial response (CR/PR) and stable disease/progressive disease (SD/PD), according to RECIST. By contrast, PFS for OR/IR patients was significantly improved compared with that for NR patients (13.2 vs. 8.7 months; P=0.0426). Exclusion of PD enhanced the difference in PFS between OR/IR and NR patients (15.1 vs. 9.3 months; P<0.0001), whereas no difference was observed between CR/PR and SD. The rate of OR and IR in patients treated with bevacizumab was 47.4% (9/19), but only 19.4% (6/31) for patients that were not administered bevacizumab. Comparison of the survival curves between OR/IR and NR patients revealed similar survival rates at 6 months after chemotherapy, but the groups exhibited different survival rates subsequent to this period of time. Patients showing OR/IR within 6 months appeared to be oncologically stable and could be considered as candidates for surgical intervention, including rescue liver resection. Comparing the pathological and morphological features of the tumor with representative optimal response, living tumor cells were revealed to be distributed within the area of vascular reconstruction induced by bevacizumab, resulting in a predictive value for prognosis in the patients treated with bevacizumab. The present findings provided the evidence for physicians to consider patients with previously un-resectable metastatic colorectal cancer as candidates for surgical treatment. Morphological response is a useful decision-making tool for evaluating these patients for rescue liver resection following chemotherapy.
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Affiliation(s)
- Koichi Suzuki
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Yuta Muto
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Kosuke Ichida
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Taro Fukui
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Yuji Takayama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Nao Kakizawa
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Takaharu Kato
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Fumi Hasegawa
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Fumiaki Watanabe
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Yuji Kaneda
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Rina Kikukawa
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Masaaki Saito
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Shingo Tsujinaka
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Kazushige Futsuhara
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Osamu Takata
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Hiroshi Noda
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Yasuyuki Miyakura
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Hirokazu Kiyozaki
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Fumio Konishi
- Department of Surgery, Nerima-Hikarigaoka Hospital, Tokyo 179-0072, Japan
| | - Toshiki Rikiyama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
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27
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Duwe G, Knitter S, Pesthy S, Beierle AS, Bahra M, Schmelzle M, Schmuck RB, Lohneis P, Raschzok N, Öllinger R, Sinn M, Struecker B, Sauer IM, Pratschke J, Andreou A. Hepatotoxicity following systemic therapy for colorectal liver metastases and the impact of chemotherapy-associated liver injury on outcomes after curative liver resection. Eur J Surg Oncol 2017; 43:1668-1681. [PMID: 28599872 DOI: 10.1016/j.ejso.2017.05.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 05/05/2017] [Accepted: 05/08/2017] [Indexed: 02/08/2023] Open
Abstract
Patients with colorectal liver metastases (CLM) have remarkably benefited from the advances in medical multimodal treatment and surgical techniques over the last two decades leading to significant improvements in long-term survival. More patients are currently undergoing liver resection following neoadjuvant chemotherapy, which has been increasingly established within the framework of curative-indented treatment strategies. However, the use of several cytotoxic agents has been linked to specific liver injuries that not only impair the ability of liver tissue to regenerate but also decrease long-term survival. One of the most common agents included in modern chemotherapy regimens is oxaliplatin, which is considered to induce a parenchymal damage of the liver primarily involving the sinusoids defined as sinusoidal obstruction syndrome (SOS). Administration of bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), has been reported to improve response of CLM to chemotherapy in clinical studies, concomitantly protecting the liver from the development of SOS. In this review, we aim to summarize current data on multimodal treatment concepts for CLM, give an in-depth overview of liver damage caused by cytostatic agents focusing on oxaliplatin-induced SOS, and evaluate the role of bevacizumab to improve clinical outcomes of patients with CLM and to protect the liver from the development of SOS.
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Affiliation(s)
- G Duwe
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Germany
| | - S Knitter
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Germany
| | - S Pesthy
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Germany
| | - A S Beierle
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Germany
| | - M Bahra
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Germany
| | - M Schmelzle
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Germany
| | - R B Schmuck
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Germany
| | - P Lohneis
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Germany
| | - N Raschzok
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Germany
| | - R Öllinger
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Germany
| | - M Sinn
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Germany
| | - B Struecker
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Germany
| | - I M Sauer
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Germany
| | - J Pratschke
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Germany
| | - A Andreou
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Germany; Berlin School of Integrative Oncology, Charité - Universitätsmedizin Berlin, Germany.
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28
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Kakizawa N, Suzuki K, Fukui T, Takayama Y, Ichida K, Muto Y, Hasegawa F, Watanabe F, Kikugawa R, Tsujinaka S, Futsuhara K, Miyakura Y, Noda H, Rikiyama T. Clinical and molecular assessment of regorafenib monotherapy. Oncol Rep 2017; 37:2506-2512. [PMID: 28259999 DOI: 10.3892/or.2017.5456] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 01/30/2017] [Indexed: 11/05/2022] Open
Abstract
Regorafenib has shown survival benefits in metastatic colorectal cancer patients who were exacerbated after all standard therapies. Some patients, however, exhibit severe adverse events (AEs) resulting in treatment discontinuation. Therefore, the selection of patients likely to benefit from regorafenib is crucial. Twenty patients were treated with regorafenib for metastatic colorectal cancer; 122 plasma samples were taken from 16 of these patients for monitoring of circulating tumor DNA (ctDNA) in the blood. The treatment response, AEs, overall survival (OS), progression-free survival (PFS) and tumor morphologic changes on CT images were evaluated. KRAS mutant ctDNA was determined using digital PCR. Median PFS and OS were 2.5 and 5.9 months, respectively. Treatment was discontinued because of disease progression (PD) in 10 patients, and AEs in another 10 patients. AEs included hyperbilirubinemia, severe fatigue and skin rash. Hyperbilirubinemia was seen in two patients with multiple bilateral liver metastases, and severe fatigue in another 2 patients with poor performance status (PS). These severe AEs resulted in treatment discontinuation. Ten patients had a median PFS of 2.1 months with AE related discontinuation; PD occurred at 3.5 months (p=0.00334). Four patients exhibited a morphologic response, achieving better PFS times of 3.5, 5.3, 5.6 and 14.2 months. Emergence of the KRAS mutation in ctDNA was observed during anti-EGFR antibody treatment in 3 patients among 11 with KRAS wild-type tumors; it was detectable in the blood prior to radiographic detection of PD. Moreover, the KRAS mutation declined in two patients during regorafenib monotherapy. These patients were re-challenged with anti-EGFR antibody. Patients with extensive multiple liver metastases or poor PS are unlikely to benefit from regorafenib. Patients with a morphologic response will probably benefit from regorafenib with adequate management of other AEs. KRAS monitoring in ctDNA could be useful regarding treatment response and in determining treatment strategy.
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Affiliation(s)
- Nao Kakizawa
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
| | - Koichi Suzuki
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
| | - Taro Fukui
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
| | - Yuji Takayama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
| | - Kosuke Ichida
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
| | - Yuta Muto
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
| | - Fumi Hasegawa
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
| | - Fumiaki Watanabe
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
| | - Rina Kikugawa
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
| | - Shingo Tsujinaka
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
| | - Kazushige Futsuhara
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
| | - Yasuyuki Miyakura
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
| | - Hiroshi Noda
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
| | - Toshiki Rikiyama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan
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Sasaki K, Margonis GA, Andreatos N, Wilson A, Weiss M, Wolfgang C, Sergentanis TN, Polychronidis G, He J, Pawlik TM. Prognostic impact of margin status in liver resections for colorectal metastases after bevacizumab. Br J Surg 2017; 104:926-935. [PMID: 28266705 DOI: 10.1002/bjs.10510] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Revised: 01/13/2017] [Accepted: 01/16/2017] [Indexed: 01/09/2023]
Abstract
BACKGROUND Margin status with resection of colorectal liver metastasis (CRLM) was an important prognostic factor in the years before the introduction of biological chemotherapy. This study examined outcomes following CRLM resection in patients who received neoadjuvant chemotherapy with or without the monoclonal antiangiogenic antibody bevacizumab. METHODS Patients who underwent surgery for CRLM at the Johns Hopkins Hospital between 2000 and 2015 were identified from an institutional database. Data regarding surgical margin status, preoperative bevacizumab administration and overall survival (OS) were assessed using multivariable analyses. RESULTS Of 630 patients who underwent CRLM resection, 417 (66·2 per cent) received neoadjuvant chemotherapy with (214, 34·0 per cent) or without (203, 32·2 per cent) bevacizumab. The remaining 213 (33·8 per cent) did not receive neoadjuvant chemotherapy. Univariable analysis found that positive margins were associated with worse 5-year OS than R0 resection (36·2 versus 54·9 per cent; P = 0·005). After dichotomizing by the receipt of preoperative bevacizumab versus chemotherapy alone, the prognostic value of pathological margin persisted among patients who did not receive preoperative bevacizumab (5-year OS 53·0 versus 37 per cent after R0 versus R1 resection; P = 0·010). OS was not significantly associated with margin status in bevacizumab-treated patients (5-year OS 46·8 versus 33 per cent after R0 versus R1 resection; P = 0·081), in whom 5-year survival was slightly worse (presumably reflecting more advanced disease) than among patients treated with cytotoxic agents alone. Pathological margin status was not significantly associated with 5-year OS in patients with a complete or near-complete response to chemotherapy and bevacizumab (43 versus 30 per cent after R0 versus R1 resection; P = 0·917), but this may be due to a type II error. CONCLUSION The impact of margin status varied according to the receipt of bevacizumab. Bevacizumab may have a role to play in improving outcomes among patients with more advanced disease.
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Affiliation(s)
- K Sasaki
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - G A Margonis
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - N Andreatos
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - A Wilson
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - M Weiss
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - C Wolfgang
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - T N Sergentanis
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - G Polychronidis
- Department of General, Abdominal and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - J He
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - T M Pawlik
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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30
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Stremitzer S, Zhang W, Yang D, Ning Y, Sunakawa Y, Matsusaka S, Parekh A, Okazaki S, Hanna D, Astrow SH, Moran M, Hernandez J, Stephens C, Scherer SJ, Stift J, Wrba F, Gruenberger T, Lenz HJ. Expression of Genes Involved in Vascular Morphogenesis and Maturation Predicts Efficacy of Bevacizumab-Based Chemotherapy in Patients Undergoing Liver Resection. Mol Cancer Ther 2016; 15:2814-2821. [PMID: 27535973 PMCID: PMC8547597 DOI: 10.1158/1535-7163.mct-16-0275] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 08/02/2016] [Indexed: 11/16/2022]
Abstract
Angiogenesis-related gene expression is associated with the efficacy of anti-VEGF therapy. We tested whether intratumoral mRNA expression levels of genes involved in vascular morphogenesis and early vessel maturation predict response, recurrence-free survival (RFS), and overall survival (OS) in a unique cohort of patients with colorectal liver metastases (CLM) treated with bevacizumab-based chemotherapy followed by curative liver resection. Intratumoral mRNA was isolated from resected bevacizumab-pretreated CLM from 125 patients. In 42 patients, a matching primary tumor sample collected before bevacizumab treatment was available. Relative mRNA levels of 9 genes (ACVRL1, EGFL7, EPHB4, HIF1A, VEGFA, VEGFB, VEGFC, FLT1, and KDR) were analyzed by RT-PCR and evaluated for associations with response, RFS, and OS. P values for the associations between the individual dichotomized expression level and RFS were adjusted for choosing the optimal cut-off value. In CLM, high expression of VEGFB, VEGFC, HIF1A, and KDR and low expression of EGFL7 were associated with favorable RFS in multivariable analysis (P < 0.05). High ACVRL1 levels predicted favorable 3-year OS (P = 0.041) and radiologic response (PR = 1.093, SD = 0.539, P = 0.002). In primary tumors, low VEGFA and high EGFL7 were associated with radiologic and histologic response (P < 0.05). High VEGFA expression predicted shorter RFS (10.1 vs. 22.6 months; HR = 2.83, P = 0.038). High VEGFB (46% vs. 85%; HR = 5.75, P = 0.009) and low FLT1 (55% vs. 100%; P = 0.031) predicted lower 3-year OS rates. Our data suggest that intratumoral mRNA expression of genes involved in vascular morphogenesis and early vessel maturation may be promising predictive and/or prognostic biomarkers. Mol Cancer Ther; 15(11); 2814-21. ©2016 AACR.
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Affiliation(s)
- Stefan Stremitzer
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
- Department of Surgery, Medical University Vienna, Vienna, Austria
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Dongyun Yang
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Yan Ning
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Yu Sunakawa
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Satoshi Matsusaka
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Anish Parekh
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Satoshi Okazaki
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Diana Hanna
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | | | | | | | | | | | - Judith Stift
- Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria
| | - Friedrich Wrba
- Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria
| | | | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
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31
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Neoadjuvant chemotherapy (NCT) plus targeted agents versus NCT alone in colorectal liver metastases patients: A systematic review and meta-analysis. Oncotarget 2016; 6:44005-18. [PMID: 26515604 PMCID: PMC4791282 DOI: 10.18632/oncotarget.5875] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 09/27/2015] [Indexed: 12/16/2022] Open
Abstract
Purpose To assess the efficacy of neoadjuvant chemotherapy (NCT) plus targeted agents versus NCT alone for the treatment of colorectal liver metastases (CRLM) patients. Methods Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). All clinical studies were independently identified by two authors for inclusion. Demographic data, treatment regimens, objective response rate (ORR), hepatic resection and R0 hepatic resection rate were extracted and analyzed using Comprehensive MetaAnalysis software (Version 2.0). Results A total of 40 cohorts with 2099 CRLM patients were included: 962 patients were treated with NCT alone, 602 with NCT plus anti-epidermal growth-factor receptor (EGFR)-monoclonal antibodies (MoAbs) and 535 with NCT plus bevacizumab. Pooled ORR was significantly higher for NCT plus bevacizumab or anti-EGFR-MoAbs than NCT alone [relative risk (RR) 1.53, 95% CI 1.30–1.80; p < 0.001; RR 1.53, 95% CI: 1.27–1.83, p < 0.001; respectively]. NCT plus bevacizumab significantly improved R0 hepatic resection rate (RR 1.61, 95% CI: 1.27–2.04, p < 0.001), but not for overall hepatic resection rate (RR 1.26, 95% CI: 0.81–1.94, p = 0.30). While hepatic resection and R0 hepatic resection rate was comparable between NCT plus anti-EGFR-MoAbs and NCT alone (p = 0.42 and p = 0.37, respectively). Conclusions In comparison with NCT alone, NCT plus bevacizumab significantly improve ORR and R0 hepatic resection rate but not for hepatic resection rate. Our findings support the need to compare NCT plus bevacizumab with NCT alone in the neoadjuvant setting in large prospective trials due to its higher hepatic resection rate and R0 hepatic resection rate in CRLM patients.
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32
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Arata R, Itamoto T, Ikeda S, Nakahara H, Oshita A, Shinozaki K, Nishisaka T. Pathological complete response after neoadjuvant chemotherapy for rectal cancer with synchronous multiple liver metastases: a report of an unusual case. Surg Case Rep 2016; 2:106. [PMID: 27686666 PMCID: PMC5042956 DOI: 10.1186/s40792-016-0231-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 09/20/2016] [Indexed: 01/05/2023] Open
Abstract
Background Systemic chemotherapy for stage IV colorectal cancer has advanced markedly in the recent years. We report an unusual case of 13 synchronous liver metastases for which a pathological complete response was achieved with neoadjuvant chemotherapy (NAC) consisting of a combination of 5-fluorouracil (5-FU), oxaliplatin, leucovorin (mFOLFOX6), and bevacizumab. Case presentation A 44-year-old man was diagnosed with colorectal cancer with synchronous liver metastases. We resected the primary rectal tumor first. Further, after providing NAC for hepatic metastases, lateral segmentectomy and partial resection of the liver were performed. The subsequent result was compatible with a complete pathological response. The postoperative course was uneventful, and the patient is currently alive 5 years after the first surgery without evidence of recurrence and without adjuvant chemotherapy. Conclusions For patients with initially resectable colorectal liver metastases, the survival benefits of NAC are still unclear. We report a rare case of 13 synchronous liver metastatic lesions from rectal cancer with a complete pathological response after neoadjuvant bevacizumab-containing chemotherapy.
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Affiliation(s)
- Ryosuke Arata
- Department of Gastroenterological Surgery, Hiroshima Prefectural Hospital, 1-5-54 Ujina-kanda, Minami-ku, Hiroshima, 734-8530, Japan
| | - Toshiyuki Itamoto
- Department of Gastroenterological Surgery, Hiroshima Prefectural Hospital, 1-5-54 Ujina-kanda, Minami-ku, Hiroshima, 734-8530, Japan. .,Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
| | - Satoshi Ikeda
- Department of Gastroenterological Surgery, Hiroshima Prefectural Hospital, 1-5-54 Ujina-kanda, Minami-ku, Hiroshima, 734-8530, Japan
| | - Hideki Nakahara
- Department of Gastroenterological Surgery, Hiroshima Prefectural Hospital, 1-5-54 Ujina-kanda, Minami-ku, Hiroshima, 734-8530, Japan
| | - Akihiko Oshita
- Department of Gastroenterological Surgery, Hiroshima Prefectural Hospital, 1-5-54 Ujina-kanda, Minami-ku, Hiroshima, 734-8530, Japan.,Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Katsunori Shinozaki
- Department of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima, Japan
| | - Takashi Nishisaka
- Department of Pathology Clinical Laboratory, Hiroshima Prefectural Hospital, Hiroshima, Japan
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33
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Impact of novel histopathological factors on the outcomes of liver surgery for colorectal cancer metastases. Eur J Surg Oncol 2016; 42:1268-77. [DOI: 10.1016/j.ejso.2016.02.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Revised: 12/23/2015] [Accepted: 02/03/2016] [Indexed: 12/17/2022] Open
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34
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Use of Bevacizumab in the Management of Potentially Resectable Colorectal Liver Metastases: Safety, Pathologic Assessment and Benefit. CURRENT COLORECTAL CANCER REPORTS 2016. [DOI: 10.1007/s11888-016-0326-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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35
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Lu ZH, Peng JH, Wang FL, Yuan YF, Jiang W, Li YH, Wu XJ, Chen G, Ding PR, Li LR, Kong LH, Lin JZ, Zhang RX, Wan DS, Pan ZZ. Bevacizumab with preoperative chemotherapy versus preoperative chemotherapy alone for colorectal cancer liver metastases: a retrospective cohort study. Medicine (Baltimore) 2016; 95:e4767. [PMID: 27583930 PMCID: PMC5008614 DOI: 10.1097/md.0000000000004767] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
This study aimed to assess the efficacy and safety of bevacizumab plus preoperative chemotherapy as first-line treatment for liver-only metastatic colorectal cancer in Chinese patients compared with those of preoperative chemotherapy alone.Patients with histologically confirmed liver-only metastatic colorectal cancer were sequentially reviewed, and received either preoperative chemotherapy plus bevacizumab (bevacizumab group, n = 32) or preoperative chemotherapy alone (chemotherapy group, n = 57). Progression-free survival, response rate, liver resection rate, conversion rate, and safety were analyzed.With median follow-up of 28.7 months, progression-free survival was 10.9 months (95% confidence interval: 8.7-13.1 months) in bevacizumab group and 9.9 months (95% confidence interval: 6.8-13.1 months) in chemotherapy group (P = 0.472). Response rates were 59.4% in bevacizumab group and 38.6% in chemotherapy group (P = 0.059). Overall liver resection (R0, R1, and R2) rate was 68.8% in bevacizumab group and 54.4% in chemotherapy group (P = 0.185). Conversion rate was 51.9% in bevacizumab group and 40.4% in chemotherapy group (P = 0.341). No postoperative complication was observed in all patients.Bevacizumab plus preoperative chemotherapy as first-line treatment for liver-only metastatic colorectal cancer tends to achieve better clinical benefit with controllable safety in Chinese patients.
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Affiliation(s)
| | | | | | | | - Wu Jiang
- Department of Colorectal Surgery
| | - Yu-Hong Li
- Department of Medical Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China
| | | | | | | | | | | | | | | | | | - Zhi-Zhong Pan
- Department of Colorectal Surgery
- Correspondence: Zhi-Zhong Pan, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, PR China (e-mail: )
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36
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Groom K, Penna M, Arul D, Steward M, Leonard P, Wilson J. Capecitabine-related liver lesions: sinusoidal dilatation mimicking liver metastasis. Clin Case Rep 2016; 4:545-8. [PMID: 27398193 PMCID: PMC4891475 DOI: 10.1002/ccr3.539] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 02/01/2015] [Accepted: 02/15/2015] [Indexed: 01/01/2023] Open
Abstract
A 30‐year‐old lady treated with capecitabine for primary colon adenocarcinoma developed liver lesions suspicious for metastasis. Liver biopsies showed sinusoidal dilatation thought to be secondary to capecitabine. This case highlights the importance of differentiating between benign and malignant liver lesions during cancer surveillance preventing unnecessary liver resections for benign disease.
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Affiliation(s)
- Katherine Groom
- Department of General Surgery Whittington Health Magdala Avenue London N19 5NF UK
| | - Marta Penna
- Department of General Surgery Whittington Health Magdala Avenue London N19 5NF UK
| | - Dhili Arul
- Department of General Surgery Whittington Health Magdala Avenue London N19 5NF UK
| | - Michael Steward
- Department of General Surgery Whittington Health Magdala Avenue London N19 5NF UK
| | - Pauline Leonard
- Department of General Surgery Whittington Health Magdala Avenue London N19 5NF UK
| | - Jonathan Wilson
- Department of General Surgery Whittington Health Magdala Avenue London N19 5NF UK
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37
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Willaert W, Van Der Speeten K, Liberale G, Ceelen W. BEV-IP: Perioperative chemotherapy with bevacizumab in patients undergoing cytoreduction and intraperitoneal chemoperfusion for colorectal carcinomatosis. BMC Cancer 2015; 15:980. [PMID: 26673788 PMCID: PMC4682259 DOI: 10.1186/s12885-015-1954-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 11/24/2015] [Indexed: 12/29/2022] Open
Abstract
Background Selected patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) benefit from cytoreductive surgery (CRS) combined with intraperitoneal chemoperfusion (IPC). However, even after optimal cytoreduction, systemic and locoregional recurrence are common. Perioperative chemotherapy with bevacizumab (BEV) may improve the outcome of these patients. Methods/Design The BEV-IP study is a phase II, single-arm, open-label study aimed at patients with colorectal or appendiceal adenocarcinoma with synchronous or metachronous PC. This study evaluates whether perioperative chemotherapy including BEV in combination with CRS and oxaliplatin-based IPC results in acceptable morbidity and mortality (primary composite endpoint). Secondary endpoints are treatment completion rate, chemotherapy-related toxicity, pathological response, progression free survival, and overall survival. Discussion The BEV-IP trial is the first prospective assessment of the safety and efficacy of perioperative chemotherapy combined with anti-angiogenic treatment in patients undergoing CRS and IPC for colorectal peritoneal metastases. Trial registration ClinicalTrials.gov Identifier: NCT02399410 EudraCT number: 2015-001187-19 (registered March 9, 2015).
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Affiliation(s)
- Wouter Willaert
- Department of Gastrointestinal Surgery, Ghent University Hospital, 2K12 IC UZ De Pintelaan 185, B-9000, Ghent, Belgium.
| | | | - Gabriel Liberale
- Clinic of Digestive Surgical Oncology, Jules Bordet Institute, Brussels, Belgium.
| | - Wim Ceelen
- Department of Gastrointestinal Surgery, Ghent University Hospital, 2K12 IC UZ De Pintelaan 185, B-9000, Ghent, Belgium.
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38
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García-Alfonso P, Ferrer A, Gil S, Dueñas R, Pérez MT, Molina R, Capdevila J, Safont MJ, Castañón C, Cano JM, Lara R. Neoadjuvant and conversion treatment of patients with colorectal liver metastasis: the potential role of bevacizumab and other antiangiogenic agents. Target Oncol 2015; 10:453-65. [PMID: 25752908 PMCID: PMC4668275 DOI: 10.1007/s11523-015-0362-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Accepted: 01/28/2015] [Indexed: 12/25/2022]
Abstract
More than 50 % of patients with colorectal cancer develop liver metastases. Surgical resection is the only available treatment that improves survival in patients with colorectal liver metastases (CRLM). New antiangiogenic targeted therapies, such as bevacizumab, aflibercept, and regorafenib, in combination with neoadjuvant and conversion chemotherapy may lead to improved response rates in this population of patients and increase the proportion of patients eligible for surgical resection. The present review discusses the available data for antiangiogenic targeted agents in this setting. One of these therapies, bevacizumab, which targets the vascular endothelial growth factor (VEGF) has demonstrated good results in this setting. In patients with initially unresectable CRLM, the combination of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab has led to high response and resection rates. This combination is also effective for patients with unresectable CRLM. Moreover, the addition of bevacizumab to chemotherapy in the neoadjuvant setting of liver metastasis has a higher impact on pathological response rate. This drug also has a manageable safety profile, and according to recent data, bevacizumab may protect against the sinusoidal dilation provoked in the liver by certain cytotoxic agents. In phase II trials, antiangiogenic therapy has demonstrated benefits in the presurgical treatment of CRLM and may represent a new treatment pathway for these patients.
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Affiliation(s)
- Pilar García-Alfonso
- Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
| | - Ana Ferrer
- Medical Oncology Service, Hospital General Universitario de Albacete, Albacete, Spain
| | - Silvia Gil
- Medical Oncology Service, Hospital Universitario Carlos Haya, Málaga, Spain
| | - Rosario Dueñas
- Medical Oncology Service, Complejo Hospitalario de Jaén, Jaén, Spain
| | | | - Raquel Molina
- Medical Oncology Service, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
| | - Jaume Capdevila
- Medical Oncology Service, Hospital Universitario Vall d'Hebron, Barcelona, Spain
| | - María José Safont
- Medical Oncology Service, Hospital General Universitario de Valencia, Valencia, Spain
| | - Carmen Castañón
- Medical Oncology Service, Complejo Asistencial de León, León, Spain
| | - Juana María Cano
- Medical Oncology Service, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain
| | - Ricardo Lara
- Medical Oncology Service, Hospital Obispo Polanco, Teruel, Spain
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39
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Eefsen RL, Engelholm L, Willemoe GL, Van den Eynden GG, Laerum OD, Christensen IJ, Rolff HC, Høyer-Hansen G, Osterlind K, Vainer B, Illemann M. Microvessel density and endothelial cell proliferation levels in colorectal liver metastases from patients given neo-adjuvant cytotoxic chemotherapy and bevacizumab. Int J Cancer 2015; 138:1777-84. [PMID: 26510166 DOI: 10.1002/ijc.29904] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 08/28/2015] [Accepted: 10/09/2015] [Indexed: 01/28/2023]
Abstract
The treatment of patients with colorectal liver metastasis has improved significantly and first line therapy is often combined chemotherapy and bevacizumab, although it is unknown who responds to this regimen. Colorectal liver metastases grow in different histological growth patterns showing differences in angiogenesis. To identify possible response markers, histological markers of angiogenesis were assessed. Patients who underwent resection of colorectal liver metastasis at Rigshospitalet, Copenhagen, Denmark from 2007 to 2011 were included (n = 254) including untreated and patients treated with chemotherapy or chemotherapy plus bevacizumab. The resected liver metastases were characterised with respect to growth pattern, endothelial and tumour cell proliferation as well as microvessel density and tumour regression. Tumour regression grade of liver metastases differed significantly between untreated/chemotherapy treated patients in comparison to chemotherapy plus bevacizumab treated patients (both p < 0.0001). Microvessel density was decreased in liver metastases from patients treated with bevacizumab in comparison to those from untreated/chemotherapy-treated patients (p = 0.006/p = 0.002). Tumour cell proliferation assessed by Ki67 expression correlated to a shorter recurrence free survival in the total patient cohort. In conclusion, liver metastases from patients treated with neo-adjuvant chemotherapy and bevacizumab had significantly lower microvessel densities and tumour regression grades when compared to liver metastases from untreated or chemotherapy treated patients. This may indicate that bevacizumab treatment results in altered vascular biology and tumour viability, with possible tumour reducing effect.
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Affiliation(s)
- Rikke Løvendahl Eefsen
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.,Department of Oncology, Rigshospitalet, Copenhagen, Denmark
| | - Lars Engelholm
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Gro L Willemoe
- Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | | | - Ole Didrik Laerum
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Medicine, the Gade Laboratory of Pathology, University of Bergen, Norway
| | - Ib Jarle Christensen
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Hans Christian Rolff
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.,Department of Surgery, Rigshospitalet, Copenhagen, Denmark
| | - Gunilla Høyer-Hansen
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Kell Osterlind
- Department of Oncology, Rigshospitalet, Copenhagen, Denmark
| | - Ben Vainer
- Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Martin Illemann
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
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40
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Jary M, Borg C, Bouché O, Kim S, André T, Bennouna J. [Anti-angiogenic treatments in metastatic colorectal cancer: Does a continuous angiogenic blockade make sense?]. Bull Cancer 2015; 102:758-71. [PMID: 26232849 DOI: 10.1016/j.bulcan.2015.05.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2014] [Accepted: 09/10/2014] [Indexed: 01/07/2023]
Abstract
Ten years after the approval of bevacizumab in colorectal cancer patients, results from ML18147 and CORRECT studies have recently demonstrated the possibility to target angiogenesis in patients previously exposed to anti-VEGF. An increasing number of anti-angiogenic treatments are now available, however, no biomarker has yet succeeded in rationalizing our therapeutic strategies. Nevertheless, several lessons have been learned from preclinical and pivotal clinical studies. The first clinical trials demonstrated a survival benefit, adding VEGFA targeting monoclonal antibodies to chemotherapy in metastatic colorectal cancer patients (AVF2107, ECOG 3200). Many phase III clinical trials confirmed the interest of this strategy, in combination with chemotherapies containing irinotecan, oxaliplatin, or with 5-fluorouracil in monotherapy. To date, such results have not been reproduced with tyrosine kinase inhibitors targeting the angiogenesis pathways, with an increasing rate of chemotherapy related toxicities. Clinical trials performed in the adjuvant setting (AVANT, NSABPC08) failed to demonstrate any efficacy of the anti-VEGFA treatments on the micrometastatic disease, encouraging its prescription in the unresectable cases. On the other hand, a continuous inhibition of angiogenesis during the course of the metastatic disease was shown to be feasible and to extend colon cancer patient's survival in two recent randomized trials. For these patients, the continuation of bevacizumab beyond progression in first line improves overall survival. Lastly, results achieved by the CORRECT and CONCUR studies demonstrated that anti-angiogenics might be effective in colorectal cancers resistant to chemotherapy. This review presents the main results of preclinical and clinical studies sustaining the prescription of anti-angiogenics in metastatic colorectal cancers. The future challenge is to promote the development of biomarkers to enable the stratification of the different therapeutic strategies.
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Affiliation(s)
- Marine Jary
- CHRU de Besançon, IRFC, service d'oncologie médicale, 25000 Besançon, France.
| | - Christophe Borg
- CHRU de Besançon, IRFC, service d'oncologie médicale, 25000 Besançon, France; Unité Inserm 1098, université de Franche-Comté, 25000 Besançon, France
| | - Olivier Bouché
- CHU de Reims, services de gastroentérologie et d'oncologie médicale, 51100 Reims, France
| | - Stéfano Kim
- CHRU de Besançon, IRFC, service d'oncologie médicale, 25000 Besançon, France
| | - Thierry André
- Hôpital Saint-Antoine, service d'oncologie médicale, 75012 Paris, France
| | - Jaafar Bennouna
- Institut de cancérologie de l'Ouest, Nantes-Angers, 44805 Nantes, France
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41
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Konda B, Shum H, Rajdev L. Anti-angiogenic agents in metastatic colorectal cancer. World J Gastrointest Oncol 2015; 7:71-86. [PMID: 26191351 PMCID: PMC4501927 DOI: 10.4251/wjgo.v7.i7.71] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 05/13/2015] [Accepted: 06/01/2015] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is a major public health concern being the third leading cause of cancer mortality in the United States. The availability of better therapeutic options has led to a decline in cancer mortality in these patients. Surgical resection should be considered in all stages of the disease. The use of conversion therapy has made surgery a potentially curative option even in patients with initially unresectable metastatic disease. In this review we discuss the role of various anti-angiogenic agents in patients with metastatic CRC (mCRC). We describe the mechanism of action of these agents, and the rationale for their use in combination with chemotherapy. We also review important clinical studies that have evaluated the safety and efficacy of these agents in mCRC patients. Despite the discovery of several promising anti-angiogenic agents, mCRC remains an incurable disease with a median overall survival of just over 2 years in patients exposed to all available treatment regimens. Further insights into tumor biology and tumor microenvironment may help improve outcomes in these patients.
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42
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Pietrantonio F, Mazzaferro V, Miceli R, Cotsoglou C, Melotti F, Fanetti G, Perrone F, Biondani P, Muscarà C, Di Bartolomeo M, Coppa J, Maggi C, Milione M, Tamborini E, de Braud F. Pathological response after neoadjuvant bevacizumab- or cetuximab-based chemotherapy in resected colorectal cancer liver metastases. Med Oncol 2015; 32:182. [PMID: 26003673 DOI: 10.1007/s12032-015-0638-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 05/13/2015] [Indexed: 02/07/2023]
Abstract
Neoadjuvant chemotherapy (NACT) prior to liver resection is advantageous for patients with colorectal cancer liver metastases (CLM). Bevacizumab- or cetuximab-based NACT may affect patient outcome and curative resection rate, but comparative studies on differential tumour regression grade (TRG) associated with distinct antibodies-associated regimens are lacking. Ninety-three consecutive patients received NACT plus bevacizumab (n = 46) or cetuximab (n = 47) followed by CLM resection. Pathological response was determined in each resected metastasis as TRG rated from 1 (complete) to 5 (no response). Except for KRAS mutations prevailing in bevacizumab versus cetuximab (57 vs. 21 %, p = 0.001), patients characteristics were well balanced. Median follow-up was 31 months (IQR 17-48). Bevacizumab induced significantly better pathological response rates (TRG1-3: 78 vs. 34 %, p < 0.001) as well as complete responses (TRG1: 13 vs. 0 %, p = 0.012) with respect to cetuximab. Three-year progression-free survival (PFS) and overall survival (OS) were not significantly different in the two cohorts. At multivariable analysis, significant association with pathological response was found for number of resected metastases (p = 0.015) and bevacizumab allocation (p < 0.001), while KRAS mutation showed only a trend. Significant association with poorer PFS and OS was found for low grades of pathological response (p = 0.009 and p < 0.001, respectively), R2 resection or presence of extrahepatic disease (both p < 0.001) and presence of KRAS mutation (p = 0.007 and p < 0.001, respectively). Bevacizumab-based regimens, although influenced by the number of metastases and KRAS status, improve significantly pathological response if compared to cetuximab-based NACT. Possible differential impact among regimens on patient outcome has still to be elucidated.
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Affiliation(s)
- Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori (National Cancer Institute), Via Venezian, 1, 20133, Milan, Italy,
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43
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Ishida K, Uesugi N, Hasegawa Y, Sugimoto R, Takahara T, Otsuka K, Nitta H, Kawasaki T, Wakabayashi G, Sugai T. Proposal for novel histological findings of colorectal liver metastases with preoperative chemotherapy. Pathol Int 2015; 65:367-73. [PMID: 25940915 PMCID: PMC4690511 DOI: 10.1111/pin.12300] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Accepted: 03/28/2015] [Indexed: 12/24/2022]
Abstract
This study aimed to clarify the histological characteristics related to preoperative chemotherapy for colorectal liver metastases (CRLM). Sixty-three patients with CRLM were divided into two groups: CRLM with chemotherapy (41 cases, group A) and CRLM without chemotherapy (22 cases; surgical treatment alone, group S) to identify the histological differences associated with chemotherapy. In addition, we investigated the effects of combination chemotherapy on the histology of metastatic lesions. Infarct-like necrosis (ILN), three-zonal changes, and cholesterol clefts were more frequent in group A than in group S (P < 0.05). ILN and three-zonal changes were more common in the 5-FU with leucovorin and oxaliplatin (FOLFOX), or 5-FU with leucovorin and irinotecan (FOLFIRI) with or without additional bevacizumab groups than in group S (P < 0.05). Cholesterol clefts in the FOLFOX or FOLFIRI with bevacizumab group and foamy macrophages in the FOLFOX or FOLFIRI group were more common than in group S (P < 0.05). Cases with more than three of the four histological findings--i.e. ILN, three-zonal changes, cholesterol clefts, and foamy macrophages--were more frequent in the FOLFOX or FOLFIRI with or without additional bevacizumab groups than in group S (P < 0.05). We showed histological findings for every representative chemotherapy regimen for CRLM to clarify the effects of preoperative chemotherapy.
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Affiliation(s)
- Kazuyuki Ishida
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Noriyuki Uesugi
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | | | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | | | - Koki Otsuka
- Department of Surgery, Iwate Medical University, Morioka, Japan
| | - Hiroyuki Nitta
- Department of Surgery, Iwate Medical University, Morioka, Japan
| | - Tomonori Kawasaki
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Go Wakabayashi
- Department of Surgery, Iwate Medical University, Morioka, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
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44
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Pietrantonio F, Orlandi A, Inno A, Da Prat V, Spada D, Iaculli A, Di Bartolomeo M, Morosi C, de Braud F. Bevacizumab-based neoadjuvant chemotherapy for colorectal cancer liver metastases: Pitfalls and helpful tricks in a review for clinicians. Crit Rev Oncol Hematol 2015; 95:272-81. [PMID: 25958297 DOI: 10.1016/j.critrevonc.2015.04.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 02/01/2015] [Accepted: 04/14/2015] [Indexed: 12/16/2022] Open
Abstract
Bevacizumab added to chemotherapy has shown encouraging efficacy in the neoadjuvant therapy of colorectal cancer liver metastases. In absence of biological predictor factors of efficacy to bevacizumab-based treatment, the assessment of response may be a crucial point to select patients who may benefit the most from surgery. At the same time the pathological response after liver resection could represent a guide for the next therapeutic plan. In the pre-surgical phase, conventional computed tomography and response evaluation with RECIST criteria may underestimate the response to anti-angiogenic drugs. Modified computed tomography criteria of response, morphologic changes as well as novel imaging techniques and metabolic assessment by fluorodeoxyglucose positron emission tomography seem to be promising methods for the assessment of response and for leading the clinical choices. Pathological response at the time of surgery is an important prognostic factor and a surrogate of survival for resected patients. Different classification criteria to assess pathological response have been developed, residual viable tumor, tumor regression grade (TRG), modified TRG and tumor thickness at the tumor-normal interface, but to date a superiority of one approach over the others has not been clearly established. In this review, we evaluate the available data with the aim to help the clinicians in the pre- and post-surgical care of patient with colorectal cancer liver metastases treated with bevacizumab-based neoadjuvant strategy.
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Affiliation(s)
- Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
| | - Armando Orlandi
- Medical Oncology Department, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alessandro Inno
- Medical Oncology, Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy
| | - Valentina Da Prat
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Daniele Spada
- Medical Oncology Department, Hospital of Urbino, Urbino, Italy
| | | | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Carlo Morosi
- Radiology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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45
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Stremitzer S, Stift J, Singh J, Starlinger P, Gruenberger B, Tamandl D, Gruenberger T. Histological response, pattern of tumor destruction and clinical outcome after neoadjuvant chemotherapy including bevacizumab or cetuximab in patients undergoing liver resection for colorectal liver metastases. Eur J Surg Oncol 2015; 41:868-74. [PMID: 25865557 DOI: 10.1016/j.ejso.2015.03.223] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 02/27/2015] [Accepted: 03/05/2015] [Indexed: 02/07/2023] Open
Abstract
AIM We investigated whether the type of antibody [bevacizumab (bev) or cetuximab (cet)] added to neoadjuvant combination chemotherapy before curative liver resection was associated with histological response, the pattern of tumor destruction and clinical outcome in patients with colorectal liver metastases (CLM). METHODS We investigated 138 patients with KRAS wild-type status (codon 12, 13 and 61) who received neoadjuvant chemotherapy including bev (n = 101) or cet (n = 37). The primary endpoint was histological response. Secondary endpoints were necrosis and fibrosis of metastases, radiological response, recurrence-free survival (RFS) and overall survival (OS). RESULTS Histological response was not significantly different between the two groups (P = 0.19). A significantly higher fraction of patients in the bev group showed necrosis of the metastases of ≥ 50% (P < 0.001), while a higher fraction of patients in the cet group showed fibrosis of ≥ 40% (P = 0.030). Radiological response was not significantly different (P = 0.17). Median RFS was significantly shorter in the cet group in univariable analysis (HR 1.59 (95% CI 1.00, 2.51), P = 0.049), but this difference did not remain significant in multivariable analysis (P = 0.45). The 3-year OS rate was not significantly different (P = 0.73). CONCLUSIONS The addition of bevacizumab to combination chemotherapy showed more necrosis but less fibrosis of metastases compared to cetuximab and a trend towards higher histological and radiological response and longer RFS. Further investigations of biological tumor characteristics are required to individualize treatment combinations.
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Affiliation(s)
- S Stremitzer
- Department of General Surgery, Medical University Vienna, Vienna, Austria
| | - J Stift
- Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria
| | - J Singh
- Department of General Surgery, Medical University Vienna, Vienna, Austria
| | - P Starlinger
- Department of General Surgery, Medical University Vienna, Vienna, Austria
| | - B Gruenberger
- Department of Internal Medicine, St. John of God's Hospital, Vienna, Austria
| | - D Tamandl
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University Vienna, Vienna, Austria
| | - T Gruenberger
- Department of Surgery I, Rudolfstiftung Hospital, Vienna, Austria.
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46
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Geva R, Shamai S, Brazowsky E, Paoulas M, Ben-Haim M, Johnstone E, Alex B, Shacham-Shmueli E. The Predictive Role of ERCC1 Status in Oxaliplatin Based Neoadjuvant Therapy for Metastatic Colorectal Cancer (mCRC) to the Liver. Cancer Invest 2015; 33:89-97. [PMID: 25723812 DOI: 10.3109/07357907.2014.998834] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Increased expression of excision repair cross-complementing 1 (ERCC1) in mCRC patients could be related to their response to Oxaliplatin based chemotherapy. We evaluated ERCC1 mRNA expression levels in primary bowel and liver metastases of 51 patients, and correlated with pathologic parameters and clinical outcomes. A significant negative correlation was detected between primary tumor ERCC1 and both the extent of clear surgical margins (P = 0.0011) and the percent of liver metastasis necrosis (P = 0.0167). No relationship was observed between ERCC1 expression and survival. Further study is needed to assess the promising role of ERCC1 expression as a predictive marker benefiting subgroups for Oxaliplatin.
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Affiliation(s)
- Ravit Geva
- Gastrointestinal Malignancies Service, Oncology Division 1
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47
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Stremitzer S, Stift J, Graf A, Singh J, Starlinger P, Gruenberger B, Tamandl D, Gruenberger T. CEA change after neoadjuvant chemotherapy including bevacizumab and clinical outcome in patients undergoing liver resection for colorectal liver metastases. Ann Surg Oncol 2014; 22:1315-23. [PMID: 25323471 DOI: 10.1245/s10434-014-4158-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Indexed: 01/04/2023]
Abstract
BACKGROUND Liver resection after neoadjuvant chemotherapy offers the chance of cure and long-term survival in patients with resectable colorectal liver metastases (CLM). Currently, there are no established biomarkers that could help identify patients with low risk of recurrence who may benefit most from liver resection in curative intent. To address this issue, the value of carcinoembryonic antigen (CEA) change after neoadjuvant chemotherapy was investigated to predict clinical outcome in this study. METHODS CEA levels before (baseline) and after neoadjuvant chemotherapy including bevacizumab before liver resection were obtained in 154 patients with CLM from a prospectively maintained database. Changes of CEA in percent through neoadjuvant treatment were correlated with recurrence-free survival and overall survival (OS). Patients with normal CEA levels at all times (baseline and follow-up) were excluded from the analyses. RESULTS After exclusion of 15 patients with normal CEA levels at all times, 139 patients were available for analysis. Receiver operating characteristic analyses revealed a CEA change (decrease) cutoff value of 50 %, which significantly separated 88 patients with respect to OS (P = 0.017). Cox regression analyses showed that the change of CEA at a cutoff value of 50 % was predictive for OS (hazard ratio 0.37, P = 0.025) independent from the baseline CEA level, but not for recurrence-free survival. Furthermore, a CEA change of >50 % was associated with a higher radiologic response rate (P = 0.016). CONCLUSIONS CEA change induced through neoadjuvant treatment was associated with radiologic response and OS, and this measure is a promising tool to predict clinical outcome in the future.
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Affiliation(s)
- Stefan Stremitzer
- Department of General Surgery, Medical University Vienna, Vienna, Austria
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48
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Recondo GJ, Díaz-Cantón E, de la Vega M, Greco M, Recondo GS, Valsecchi ME. Advances and new perspectives in the treatment of metastatic colon cancer. World J Gastrointest Oncol 2014; 6:211-24. [PMID: 25024813 PMCID: PMC4092338 DOI: 10.4251/wjgo.v6.i7.211] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 03/04/2014] [Accepted: 05/29/2014] [Indexed: 02/05/2023] Open
Abstract
During the last decade we have witnessed an unprecedented outburst of new treatment approaches for the management of metastatic colon cancer. Anti-angiogenic drugs, epidermal growth factor receptor blockers and multi-kinase inhibitors have all resulted in small but consistent improvement in clinical outcomes. However, this progress has paradoxically leaded us into new challenges. In many cases the clinical development was done in parallel and the lack of head-to-head comparison evolved into circumstances where several valid new "standards of care" are available. Even though desirable in essence, the availability of many options as well as different possible combinations frequently leaves the busy clinician in the difficult situation of having to choose between one or the other, sometimes without solid evidence to support each decision. In addition, progress never stops and new agents are continuously tested. For these reason this review will try to summarize all the clinical trials that constitute the theoretical framework that support our daily practice but will also procure the reader with rational answers to common clinical dilemmas by critically appraising the current literature. Lastly, we will provide with a compilation of promising new agents that may soon become our next line of defense against this deadly disease.
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49
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Dede K, Salamon F, Landherr L, Jakab F, Bursics A. Pathologic assessment of response to chemotherapy in colorectal cancer liver metastases after hepatic resection: which method to use? Pathol Oncol Res 2014; 21:173-9. [PMID: 24898285 DOI: 10.1007/s12253-014-9803-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Accepted: 05/22/2014] [Indexed: 01/05/2023]
Abstract
BACKGROUND Patients with metastatic colorectal cancer receive chemotherapy prior liver resection more and more frequently. Histopathologic assessment methods of the resected specimen could evaluate the response to chemotherapy. In this study it is analyzed if these histopathologic changes are specific to preoperative chemotherapy and if these methods have correlation with survival. METHODS Sixty three patients with available pathology slides, resected for colorectal cancer liver metastases were enrolled in this study. 46 patients (73%) received neoadjuvant chemotherapy. Five pathological evaluation methods were compared according to the literature: [1] residual tumor cell ratio, [2] tumor regression grade (TRG) scoring system, [3] modified tumor regression grade (mTRG) scoring system with the type of necrosis, [4] pattern of tumor regression and [5] the tumor thickness at the tumor-normal interface (TNI). RESULTS Analyzing the pathological methods between the chemotherapy (CTX) and the non-chemotherapy group (NC), we found that that four evaluation methods showed significant and one showed strong correlation with the use of chemotherapy. (Residual tumor cell ratio: p = 0.08; TRG: p <0.01; mTRG: p = 0.03; pattern of tumor regression: p <0.01; TNI: p = 0.02). In the chemotherapy group none of the analyzed pathological methods showed significant correlation with progression free survival (PFS) or with overall survival (OS). Residual tumor cell ratio, TRG and the pattern of tumor cells showed positive but not significant correlation with OS and PFS and a slight difference in the group of patients with TNI <2 mm could be documented. CONCLUSIONS Tumor regression grade (TRG) and tumor thickness at the tumor-normal interface (TNI) were the most useful methods for pathological response evaluation and these methods had some correlation with survival. According to these data, authors concluded, that a reproducible and well defined scoring system, based on different histopathological evaluation methods should be developed to predict more accurately the effect of neoadjuvant chemotherapy in CRCLM patients.
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Affiliation(s)
- K Dede
- Department of Surgery-Oncological Surgery, Uzsoki Teaching Hospital, 1145, Budapest, Uzsoki utca 29, Hungary,
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Spolverato G, Ejaz A, Azad N, Pawlik TM. Surgery for colorectal liver metastases: The evolution of determining prognosis. World J Gastrointest Oncol 2013; 5:207-221. [PMID: 24363829 PMCID: PMC3868716 DOI: 10.4251/wjgo.v5.i12.207] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 11/05/2013] [Accepted: 11/16/2013] [Indexed: 02/05/2023] Open
Abstract
Despite improvements in the multi-modality treatment of colorectal liver metastasis (CRLM), survival after resection remains varied. Determining prognosis after surgical resection has historically been predicated on preoperative clinicopathological factors such as primary tumor stage, carcinoembryonic antigen levels, number of liver metastases, presence of extrahepatic disease, as well as other factors. While scoring systems have been developed by combining certain preoperative factors, these have been inconsistent in accurately determining prognosis. There has been increasing interest in the use of biologic and molecular markers to predict prognosis following CRLM. The role of markers such as KRAS, BRAF, p53, human telomerase reverse transcriptase, thymidylate synthase, Ki-67, and hypoxia inducible factor-1α and their correlation with accurately predicting survival after surgical resection have been supported by several studies. Furthermore, other elements such as pathological response to chemotherapy and the presence of circulating tumor cells have shown promise in accurately determining prognosis after resection for colorectal liver metastasis. We herein review past, present, and possible future markers of prognosis among colorectal cancer patients with liver metastasis undergoing resection with curative intent.
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