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Kim YJ, Chung WC, Choi S, Jung YD, Lee J, Chae SY, Jun KH, Chin HM. The Detection of Messenger RNA for Carcinoembryonic Antigen and Cytokeratin 20 in Peritoneal Washing Fluid in Patients with Advanced Gastric Cancer. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2018; 69:220-225. [PMID: 28449423 DOI: 10.4166/kjg.2017.69.4.220] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Background/Aims Peritoneal micrometastasis is known to play an important role in the recurrence of gastric cancer. However, its effects remain equivocal. Herein, we examine the messenger RNA (mRNA) as tumor markers, carcinoembryonic antigen (CEA), and cytokeratin 20 (CK20), in peritoneal washing fluid. Moreover, we evaluate whether these results could predict the recurrence of gastric cancer following curative resection. Methods We prospectively enrolled 132 patients with gastric cancers, who had received an operation, between January 2010 and January 2013. The peritoneal lavage fluid was collected at the operation field and semi-quantitative PCR was performed using the primers for CEA and CK20. We excluded patients with stage IA (n=28) early gastric cancer, positive cytologic examination of peritoneal washings (n=7), and those who were lost during follow up (n=18). Results A total of 79 patients with gastric cancers were enrolled, and the mean follow-up period was 39.95±19.25 months (range, 5-72 months). According to the multivariate analysis, T4 stage at the initial diagnosis was significantly associated with recurrence. All cases of recurrence were CEA positive and 6 cases were CK20 positive. The positive and negative predictive values of CEA were 32.0% and 100%, respectively, whereas those of CK20 were 37.5% and 71.4%, respectively. Disease free survival of CK20-negative cases was 36.17±20.28 months and that of CK20-positive cases was 32.06±22.95 months (p=0.39). Conclusions It is unlikely that the real time polymerase chain reaction results of mRNA for CEA and CK20 in peritoneal washing fluid can predict recurrence. However, negative results can convince surgeons to perform curative R0 resection.
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Affiliation(s)
- Yeon Ji Kim
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Woo Chul Chung
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Sooa Choi
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Yun Duk Jung
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Jaejun Lee
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Seung Yun Chae
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Kyong Hwa Jun
- Department of Surgery, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Hyung Min Chin
- Department of Surgery, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
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Khomyakov V, Ryabov A, Ivanov A, Bolotina L, Utkina A, Volchenko N, Kaprin A. Bidirectional chemotherapy in gastric cancer with peritoneal metastasis combining intravenous XELOX with intraperitoneal chemotherapy with low-dose cisplatin and Doxorubicin administered as a pressurized aerosol: an open-label, Phase-2 study (PIPAC-GA2). Pleura Peritoneum 2016; 1:159-166. [PMID: 30911619 PMCID: PMC6386494 DOI: 10.1515/pp-2016-0017] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Accepted: 09/02/2016] [Indexed: 01/11/2023] Open
Abstract
Background: Peritoneal metastasis (PM) develop in more than 50 % of gastric cancer (GC) patients. Median survival without treatment is not more than 3-7 months, and 8-12 months after modern combination chemotherapy. Innovative therapeutic approaches are urgently needed. Methods: Phase-2, open label prospective clinical trial assessing safety and efficacy of bidirectional chemotherapy for treating peritoneal metastasis of gastric cancer (PMGC). Treatment protocol included initial staging laparoscopy or laparotomy, 3-4 courses of systemic chemotherapy (XELOX) followed by Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) procedures every 6 weeks until progression of disease or death. Primary endpoints were overall survival and histological peritoneal regression grading score after rebiopsy. Results: 31 patients were included (9 men, 22 women, mean age 52 years), 24 with synchronous PM at diagnosis, 7 with metachronous PM after previous chemotherapy. Mean PCI was 13.8 (min-max 6-34). XELOX was administered in all patients and combined with 56 PIPAC procedures. Complete and partial pathological response was found in 60 % of the 15 patients eligible for tumor response assessment (4 and 5 patients, respectively). Median survival was 13 months. Conclusions: Bidirectional chemotherapy combining XELOX with PIPAC with cisplatin and doxororubicin is well tolerated, can induce objective tumor regression and is associated with a promising survival in PMGC.
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Affiliation(s)
- Vladimir Khomyakov
- Moscow Research Oncological Institute n.a. P.A. Herzen, Thoracoabdominal, 2-nd Botkinsky proesd, 3, Moscow 125284, Russian Federation
| | - Andrey Ryabov
- Moscow Research Oncological Institute n.a. P.A. Herzen, Thoracoabdominal, Moscow, Russian Federation
| | - Andrey Ivanov
- Moscow Research Oncological Institute n.a. P.A. Herzen, Thoracoabdominal, Moscow, Russian Federation
| | - Larisa Bolotina
- Moscow Research Oncological Institute n.a. P.A. Herzen, Chemotherapy
| | - Anna Utkina
- Moscow Research Oncological Institute n.a. P.A. Herzen, Thoracoabdominal, Moscow, Russian Federation
| | | | - Andrey Kaprin
- Moscow Research Oncological Institute n.a. P.A. Herzen, Director General
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Jagric T, Potrc S, Mis K, Mars T, Gradisnik L, Gorenjak M, Goropevsek A. Flow cytometry as the new ‘gold standard’ for detection of free tumour cells in abdominal lavage fluid in gastric cancer patients: A comparative study of molecular and conventional methods. SURGICAL PRACTICE 2016. [DOI: 10.1111/1744-1633.12173] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Tomaz Jagric
- Department of Abdominal and General Surgery; University Clinical Centre Maribor; Maribor Slovenia
| | - Stojan Potrc
- Department of Abdominal and General Surgery; University Clinical Centre Maribor; Maribor Slovenia
| | - Katarina Mis
- Institute of Pathophysiology; University of Ljubljana; Ljubljana Slovenia
| | - Tomaz Mars
- Institute of Pathophysiology; University of Ljubljana; Ljubljana Slovenia
| | - Lidija Gradisnik
- Department of Laboratory Diagnostics; University Medical Centre Maribor; Maribor Slovenia
| | - Maksimiljan Gorenjak
- Department of Laboratory Diagnostics; University Medical Centre Maribor; Maribor Slovenia
| | - Ales Goropevsek
- Department of Laboratory Diagnostics; University Medical Centre Maribor; Maribor Slovenia
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Cabalag CS, Chan STF, Kaneko Y, Duong CP. A systematic review and meta-analysis of gastric cancer treatment in patients with positive peritoneal cytology. Gastric Cancer 2015; 18:11-22. [PMID: 24890254 DOI: 10.1007/s10120-014-0388-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 05/02/2014] [Indexed: 02/07/2023]
Abstract
Gastric cancer patients with positive peritoneal cytology as the only marker of metastatic disease have poor prognoses. There is no universal consensus on the most appropriate treatment regimen for this particular patient group. We reviewed and analyzed published data to determine the optimal treatment regimen for patients with peritoneal cytology-positive gastric adenocarcinomas. Six electronic databases were explored [PubMed, Cochrane (Systematic Reviews and Controlled Trials), PROSPERO, DARE, and EMBASE]. The primary outcome was overall survival with secondary outcomes including patterns of recurrence and treatment-related morbidity. Six studies were included for data extraction. There was no significant heterogeneity between studies. The use of S1 monotherapy was associated with a significant survival benefit (HR 0.48; 95% CI 0.32-0.70; p = 0.0002). Intraoperative intraperitoneal chemotherapy (IIPC) with adjuvant chemotherapy showed a trend toward improvement in overall survival (HR 0.70; 9 % CI 0.47-1.04; p = 0.08). A recent randomized controlled trial examining extensive intraperitoneal lavage (EIPL) with IIPC showed a significant improvement in overall survival (5-year overall survival, 43.8% for EIPL-IPC group compared with 4.6% for IPC group). However, these promising results need to be validated in larger prospective randomized trials.
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Affiliation(s)
- Carlos Suhady Cabalag
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, 7 St. Andrews Place, East Melbourne, VIC, 3002, Australia,
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Zhang XL, Shi HJ, Wang JP, Tang HS, Wu YB, Fang ZY, Cui SZ, Wang LT. MicroRNA-218 is upregulated in gastric cancer after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy and increases chemosensitivity to cisplatin. World J Gastroenterol 2014; 20:11347-11355. [PMID: 25170221 PMCID: PMC4145775 DOI: 10.3748/wjg.v20.i32.11347] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2014] [Revised: 04/09/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the molecular mechanisms of miRNA in advanced gastric cancers (AGCs) before and after cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC).
METHODS: A miRNA microarray containing human mature and precursor miRNA sequences was used to compare expression profiles in serum samples of 5 patients with AGC before and after CRS + HIPEC. The upregulation of miR-218 was confirmed by real-time reverse transcription polymerase chain reaction and its expression was analyzed in SGC7901 gastric cancer cells.
RESULTS: miRNA microarray chip analysis found that the level of miR-218 expression was upregulated more than 8 fold after CRS + HIPEC. Furthermore, miR-218 increased gastric cancer cell chemosensitivity to cisplatin in vitro and inhibited gastric cell tumor growth in nude mice in vivo (0.5 vs 0.78, P < 0.05).
CONCLUSION: Our results indicated that targeting miR-218 may provide a strategy for blocking the development of gastric cancer and reverse the multi-drug resistance of gastric cell lines.
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Ruf C, Thomusch O, Goos M, Makowiec F, Illerhaus G, Ruf G. Impact of neoadjuvant chemotherapy with PELF-protocoll versus surgery alone in the treatment of advanced gastric carcinoma. BMC Surg 2014; 14:5. [PMID: 24461063 PMCID: PMC3909936 DOI: 10.1186/1471-2482-14-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 01/17/2014] [Indexed: 12/14/2022] Open
Abstract
Background In a retrospective study we analyzed the impact of neoadjuvant chemotherapy (CTx) with the PELF - protocol (Cisplatin, Epirubicin, Leukovorin, 5-Fluoruracil) on mortality, recurrence and prognosis of patients with advanced gastric carcinoma, UICC stages Ib-III. Methods 64 patients were included. 26 patients received neoadjuvant CTx followed by surgical resection, 38 received surgical resection only. Tumor staging was performed by endoscopy, endosonography, computed tomography and laparoscopy. Patients staged Ib – III received two cycles of CTx according to the PELF-protocol. Adjuvant chemotherapy was not performed at all. Results Complete (CR) or partial response (PR) was seen in 20 patients (77%), 19% showing CR and 58% PR. No benefit was observed in 6 patients (23%). Two of these 6 patients displayed tumor progression during CTx. Major toxicity was defined as grade 3 to 4 neutropenia or gastrointestinal side effects. One patient died under CTx because of neutropenia and was excluded from the overall patient collective. The curative resection rate was 77% after CTx and 74% after surgery only. The perioperative morbidity rate after CTx was 39% versus 66% after resection only. Recurrence rate after CTx was 38% and 61% after surgery alone; we detected an effective reduction of locoregional recurrence (12% vs. 26%). The overall survival was 38% after CTx and 42% after resection only. The 5-year survival rates were 45% in responders, 20% in non - responders and 42% in only resected patients. A subgroup analysis indicates that responders with stage III tumors may benefit with respect to their 5-year survival in comparable patients without neoadjuvant CTx. As to be expected, non-responders with stage III tumors did not benefit with respect to their survival. The 5-year-survival was approximated using a Kaplan-Meier curve and compared using a log-rank test. Conclusion In patients with advanced gastric carcinoma, neoadjuvant CTx with the PELF- protocol significantly reduces the recurrence rate, especially locoregionally, compared to surgery alone. In our study, there was no overall survival benefit after a 5-year follow-up period. Alone a subgroup of patients with stage III tumors appear to benefit significantly in the long term from neoadjuvant CTx.
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Affiliation(s)
| | | | | | | | | | - Guenther Ruf
- Department of Surgery, University of Freiburg, Universitätsklinikum, Hugstetterstr, 55, D-79106 Freiburg, Germany.
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A proposal of a practical and optimal prophylactic strategy for peritoneal recurrence. JOURNAL OF ONCOLOGY 2012; 2012:340380. [PMID: 22481921 PMCID: PMC3306955 DOI: 10.1155/2012/340380] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Accepted: 11/04/2011] [Indexed: 12/27/2022]
Abstract
Peritoneal metastasis, which often arises in patients with advanced gastric cancer, is well known as a miserable and ill-fated disease. Once peritoneal metastasis is formed, it is extremely difficult to defeat. We advocated EIPL (extensive intraoperative peritoneal lavage) as a useful and practical adjuvant surgical technique for those gastric cancer patients who are likely to suffer from peritoneal recurrence. In this paper, we review the effect of EIPL therapy on prevention of peritoneal recurrence on patients with peritoneal free cancer cells without overt peritoneal metastasis (CY+/P−) through the prospective randomized study, and we verified its potential as an optimal and standard prophylactic therapeutic strategy for peritoneal recurrence.
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Rossi Del Monte S, Ranieri D, Mazzetta F, Kazemi Nava A, Raffa S, Torrisi MR, Ziparo V. Free peritoneal tumor cells detection in gastric and colorectal cancer patients. J Surg Oncol 2012; 106:17-23. [PMID: 22258756 DOI: 10.1002/jso.23052] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Accepted: 01/05/2012] [Indexed: 12/16/2022]
Abstract
BACKGROUND Free peritoneal tumor cells (FPTC) derive from the detachment of primary cancer and may result in peritoneal carcinomatosis. Since peritoneal lavage cytology has low sensitivity in detecting FPTC, our aim was to estimate the clinical relevance of FPTC detected using an approach based on multiple molecular techniques. MATERIALS AND METHODS Samples of peritoneal lavage were collected from 27 gastric and 48 colorectal cancer patients. FPTC recovery and detection from peritoneal washes was performed by cytological examination and immunomagnetic enrichment for epithelial cells followed by immunofluorescence analysis for epithelial marker EpCAM/CD326 and carcinoembryonic antigen (CEA). CEA and CK20 mRNA levels were quantified using a real-time qRT-PCR system. RESULTS For gastric carcinoma the FPTC positivity rate acquired by cytology, immunofluorescence and qRT-PCR was 14.8%, 14.8%, and 78% and for colorectal carcinoma was 0%, 17%, and 42%, respectively. qRT-PCR positivity was correlated with a poor cancer-specific survival and time-to-recurrence rates in both gastric and colorectal carcinoma. CONCLUSIONS Epithelial immunoenrichment and immunofluorescence analysis allows unequivocal identification of the FPTC. The real time qRT-PCR showed higher sensitivity for the detection of CEA and CK20 mRNA levels and confirmed its prognostic value in gastrointestinal cancers.
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Affiliation(s)
- Simone Rossi Del Monte
- Department of General Surgery, Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy.
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Tang L, Mei LJ, Yang XJ, Huang CQ, Zhou YF, Yonemura Y, Li Y. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival of gastric cancer with peritoneal carcinomatosis: evidence from an experimental study. J Transl Med 2011; 9:53. [PMID: 21548973 PMCID: PMC3098163 DOI: 10.1186/1479-5876-9-53] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Accepted: 05/07/2011] [Indexed: 01/01/2023] Open
Abstract
Background Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has been considered as a promising treatment modality for gastric cancer with peritoneal carcinomatosis (PC). However, there have also been many debates regarding the efficacy and safety of this new approach. Results from experimental animal model study could help provide reliable information. This study was to investigate the safety and efficacy of CRS + HIPEC to treat gastric cancer with PC in a rabbit model. Methods VX2 tumor cells were injected into the gastric submucosa of 42 male New Zealand rabbits using a laparotomic implantation technique, to construct rabbit model of gastric cancer with PC. The rabbits were randomized into control group (n = 14), CRS alone group (n = 14) and CRS + HIPEC group (n = 14). The control group was observed for natural course of disease progression. Treatments were started on day 9 after tumor cells inoculation, including maximal removal of tumor nodules in CRS alone group, and maximal CRS plus heperthermic intraperitoneal chemoperfusion with docetaxel (10 mg/rabbit) and carboplatin (40 mg/rabbit) at 42.0 ± 0.5°C for 30 min in CRS + HIPEC group. The primary endpoint was overall survival (OS). The secondary endpoints were body weight, biochemistry, major organ functions and serious adverse events (SAE). Results Rabbit model of gastric cancer with PC was successfully established in all animals. The clinicopathological features of the model were similar to human gastric PC. The median OS was 24.0 d (95% confidence interval 21.8 - 26.2 d ) in the control group, 25.0 d (95% CI 21.3 - 28.7 d ) in CRS group, and 40.0 d (95% CI 34.6 - 45.4 d ) in CRS + HIPEC group (P = 0.00, log rank test). Compared with CRS only or control group, CRS + HIPEC could extend the OS by at least 15 d (60%). At the baseline, on the day of surgery and on day 8 after surgery, the peripheral blood cells counts, liver and kidney functions, and biochemistry parameters were all comparable. SAE occurred in 0 animal in control group, 2 animals in CRS alone group including 1 animal death due to anesthesia overdose and another death due to postoperative hemorrhage, and 3 animals in CRS + HIPEC group including 1 animal death due to anesthesia overdose, and 2 animal deaths due to diarrhea 23 and 27 d after operation. Conclusions In this rabbit model of gastric cancer with PC, CRS alone could not bring benefit while CRS + HIPEC with docetaxel and carboplatin could significantly prolong the survival with acceptable safety.
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Affiliation(s)
- Li Tang
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
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Mei LJ, Yang XJ, Tang L, Hassan AHAS, Yonemura Y, Li Y. Establishment and identification of a rabbit model of peritoneal carcinomatosis from gastric cancer. BMC Cancer 2010; 10:124. [PMID: 20359350 PMCID: PMC2858745 DOI: 10.1186/1471-2407-10-124] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2009] [Accepted: 04/01/2010] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Gastric cancer peritoneal carcinomatosis is a common clinical problem, but there are no suitable large animal models to study this problem. This study was to establish a stable rabbit peritoneal carcinomatosis model of gastric cancer using VX2 tumor, and analyze the clinico-pathological features. METHODS VX2 tumor was implanted into 36 New Zealand rabbits by 3 methods: laparotomic orthotopic injection of cancer cells into the submucosal layer of the stomach (Group A), laparotomic implantation of tumor tissue into the greater omentum immediately beneath the gastric antrum (Group B), and percutaneous injection of tumor cells directly into the peritoneal cavity (Group C), 12 rabbits in each group. The animals were closely observed and detailed clinico-pathological studies were conducted. RESULTS The success rates of peritoneal carcinomatosis formation were 100% (12/12), 91.7% (11/12) and 58.3% (7/12), respectively, for Groups A, B and C (P = 0.019, A versus C; P = 0.077, B versus C; P = 0.500, A versus B, Fisher's exact test). Two weeks after submucosal cancer cells injection in Group A, ulcerative gastric cancer with peritoneal carcinomatosis showed typical VX2 tumor pathology, with widespread intraperitoneal metastatic nodules, bloody ascites and perspicuous pulmonary metastases. The clinico-pathological progression pattern was very similar to patients of advanced gastric cancer with peritoneal carcinomatosis. Groups B and C showed similar pattern of cancer progression, but less aggressive. CONCLUSIONS First large animal model of peritoneal carcinomatosis from gastric cancer has been established by laparotomic orthotopic injection of VX2 cancer cells into the submucosal layer of the stomach, providing a more suitable model for surgical interventional studies. The clinico-pathological features of this model resemble human peritoneal carcinomatosis.
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Affiliation(s)
- Lie-Jun Mei
- Department of Oncology, Zhongnan Hospital of Wuhan University & Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, 430071, China
| | - Xiao-Jun Yang
- Department of Oncology, Zhongnan Hospital of Wuhan University & Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, 430071, China
| | - Li Tang
- Department of Oncology, Zhongnan Hospital of Wuhan University & Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, 430071, China
| | - Alaa Hammed al-shammaa Hassan
- Department of Oncology, Zhongnan Hospital of Wuhan University & Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, 430071, China
| | - Yutaka Yonemura
- NPO Organization to Support Peritoneal Dissemination Treatment, Osaka, Japan
| | - Yan Li
- Department of Oncology, Zhongnan Hospital of Wuhan University & Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, 430071, China
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Kuramoto M, Shimada S, Ikeshima S, Matsuo A, Yagi Y, Matsuda M, Yonemura Y, Baba H. Extensive intraoperative peritoneal lavage as a standard prophylactic strategy for peritoneal recurrence in patients with gastric carcinoma. Ann Surg 2009; 250:242-6. [PMID: 19638909 DOI: 10.1097/sla.0b013e3181b0c80e] [Citation(s) in RCA: 184] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE This prospective randomized multicenter study aims to evaluate the efficacy of extensive intraoperative peritoneal lavage followed by intraperitoneal chemotherapy (EIPL-IPC) on the overall 5-year survival of advanced gastric cancer patients with intraperitoneal free cancer cells without overt peritoneal metastasis (CY+/P-). The study also aims to determine the merit and reliability of EIPL-IPC therapy as a prophylactic strategy for peritoneal metastasis. SUMMARY BACKGROUND DATA Although the prognosis of advanced gastric cancer patients with CY+/P- is extremely poor, a suitable standard regimen for treating such patients has not yet been established. METHODS A total of 88 patients with CY+/P- from 1522 patients with advanced gastric cancer at multicenters were enrolled in this study and were randomly allocated to 3 groups: surgery alone group, surgery plus intraperitoneal chemotherapy (IPC) group, and surgery plus EIPL and IPC (EIPL-IPC) group. Prognostic significance of EIPL-IPC therapy was evaluated by Kaplan-Meier curves, and its value as an independent prognostic factor was assessed by univariate and multivariate analyses. RESULTS The overall 5-year survival rate of the patients with EIPL-IPC was 43.8%, and this data were significantly better than that of the IPC group (4.6%, P < 0.0001) and the surgery alone group (0%, P < 0.0001). Among various recurrent patterns, the EIPL-IPC group had a significantly lower incidence of peritoneal recurrence than both of the other groups (P < 0.0001). Univariate and multivariate analyses revealed that EIPL was the most significant impact factor. CONCLUSIONS The present study clearly revealed that EIPL-IPC therapy significantly improved the 5-year survival span of advanced gastric cancer patients with CY+/P-. Thus, EIPL-IPC therapy is strongly recommended as a standard prophylactic strategy for peritoneal dissemination.
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Affiliation(s)
- Masafumi Kuramoto
- Department of Surgery, Yatsushiro Social Insurance General Hospital, Kumamoto, Japan
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12
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Kodera Y, Ito S, Mochizuki Y, Kondo K, Koshikawa K, Suzuki N, Kojima H, Kojima T, Matsui T, Takase T, Tsuboi K, Fujiwara M, Nakao A. A phase II study of radical surgery followed by postoperative chemotherapy with S-1 for gastric carcinoma with free cancer cells in the peritoneal cavity (CCOG0301 study). Eur J Surg Oncol 2009; 35:1158-63. [PMID: 19328643 DOI: 10.1016/j.ejso.2009.03.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2008] [Revised: 01/07/2009] [Accepted: 03/05/2009] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Patients with gastric cancer who have positive cytologic results for cancer cells in peritoneal washings (CY1) have poor outcomes, even in the absence of other distant metastases. A standard treatment for such patients remains to be established. METHODS We conducted a phase II trial with the 2-year survival rate as the primary endpoint. Patients who had gastric cancer with CY1 status but no other residual disease received postoperative chemotherapy with S-1 (1M tegafur-0.4M gimestat-1M otastat potassium) at a daily dose of 80mg/m(2) for 4 weeks, followed by 2 weeks of rest. This cycle was continued until disease progression or intolerable adverse events. D2 dissection was the recommended surgical procedure; splenectomy could be omitted at the discretion of the surgeon. Accrual of 50 patients was planned, and a 2-year survival rate of more than 36% was needed to exceed the historical control. RESULTS Forty-eight patients were enrolled, among whom 47 were assessable for survival and 46 for adverse reactions. Median overall survival was 705 days, and progression-free survival was 376 days. The 2-year survival rate was 47%. Median time to treatment failure was 288 days. Neutropenia was the commonest > or = grade 3 toxicity (6 patients), and anorexia was the most frequent > or = grade 2 non-hematologic toxicity (10 patients). CONCLUSIONS Gastrectomy followed by S-1 monotherapy resulted in survival that surpassed historical data and can serve as an active control treatment for future trials in patients who have gastric cancer with CY1 status in the Far East.
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Affiliation(s)
- Y Kodera
- Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
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Yang W, Luo D, Wang S, Wang R, Chen R, Liu Y, Zhu T, Ma X, Liu R, Xu G, Meng L, Lu Y, Zhou J, Ma D. TMTP1, a Novel Tumor-Homing Peptide Specifically Targeting Metastasis. Clin Cancer Res 2008; 14:5494-502. [PMID: 18765541 DOI: 10.1158/1078-0432.ccr-08-0233] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Wanhua Yang
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
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al-Shammaa HAH, Li Y, Yonemura Y. Current status and future strategies of cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis. World J Gastroenterol 2008; 14:1159-66. [PMID: 18300340 PMCID: PMC2690662 DOI: 10.3748/wjg.14.1159] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
This article is to offer a concise review on the use of cytoreductive surgery (CRS) plus intraperitoneal hyperthermic chemotherapy (IPHC) for the treatment of peritoneal carcinomatosis (PC). Traditionally, PC was treated with systemic chemotherapy alone with very poor response and a median survival of less than 6 mo. With the establishment of several phase II studies, a new trend has been developed toward the use of CRS plus IPHC as a standard method for treating selected patients with PC, in whom sufficient cytoreduction could be achieved. In spite of the need for more high quality phase III studies, there is now a consensus among many surgical oncology experts throughout the world about the use of this new treatment strategy as standard care for colorectal cancer patients with PC. This review summarizes the current status and possible progress in future.
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Fujiwara Y, Doki Y, Taniguchi H, Sohma I, Takiguchi S, Miyata H, Yamasaki M, Monden M. Genetic detection of free cancer cells in the peritoneal cavity of the patient with gastric cancer: present status and future perspectives. Gastric Cancer 2008; 10:197-204. [PMID: 18095074 DOI: 10.1007/s10120-007-0436-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2007] [Accepted: 08/28/2007] [Indexed: 02/07/2023]
Abstract
The purpose of this review is to examine the current status and future perspectives of the molecular analysis of peritoneal lavage fluid in patients with gastric cancer. During the past 10 years, the polymerase chain reaction (PCR) has been applied for the molecular detection of free cancer cells in the abdominal cavity of patients with gastric cancer, and its clinical significance in establishing the presence of peritoneal dissemination has been assessed by several groups especially in Japan. The majority of these studies have confirmed the predictive value of the molecular detection of peritoneal metastasis and recurrence using peritoneal lavage fluid. Based on these findings, since April 2006, the genetic diagnosis of body fluids has been included in the Japanese Government public health insurance program for patients with solid tumors. However, there are still many obstacles to overcome before the genetic diagnosis of micrometastasis can be considered a routine laboratory assay. Here we review the importance of the molecular detection of cancer cells in the abdominal cavity, and the molecular techniques used for such diagnosis; we also provide some clinical examples to illustrate the value of molecular diagnosis.
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Affiliation(s)
- Yoshiyuki Fujiwara
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka (E-2), Suita, 565-0871, Japan
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Yamamura Y, Ito S, Mochizuki Y, Nakanishi H, Tatematsu M, Kodera Y. Distribution of free cancer cells in the abdominal cavity suggests limitations of bursectomy as an essential component of radical surgery for gastric carcinoma. Gastric Cancer 2007; 10:24-8. [PMID: 17334714 DOI: 10.1007/s10120-006-0404-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2006] [Accepted: 10/13/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND Bursectomy, which has been performed so as to resect peritoneal deposits disseminated within the omental bursa, is considered as an essential component of radical surgery for gastric carcinoma in Japan. Bursectomy has also been described in the Japanese Treatment Guidelines for Gastric Carcinoma as a mandatory procedure for the treatment of serosa-positive cancer. However, no evidence to support the prognostic significance of this procedure has been reported to date. METHODS Cytologic examination and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of the peritoneal washes obtained from the Douglas pouch, left subphrenic cavity, and inside the omental bursa were performed for 136 patients who underwent potentially curative surgery for gastric carcinoma. RESULTS Carcinoembryonic antigen (CEA) or cytokeratin (CK) 20 mRNA was detected in one or more samples from the three different sites of peritoneal washes in 43 of the 136 patients. In 14 patients, the mRNAs were detected in samples obtained from the bursa omentalis (10.3% of all patients and 32.6% of patients with positive RT-PCR results). In 12 of these 14 patients, the mRNAs were also detected in samples taken from either or both of the remaining two sites. Only in the 2 other patients was the sample only from inside the omental bursa positive for CEA. CONCLUSION It is unlikely that viable cancer cells disseminated into the bursa remain restricted to this cavity without migrating into the free abdominal cavity. Routine bursectomy may not be an essential procedure for resecting gastric cancer, from the viewpoint of eliminating microscopic peritoneal deposits within the omental bursa.
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Affiliation(s)
- Yoshitaka Yamamura
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
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Suo J, Wang Q, Jin HJ, Li H, Zhao H. K-19 mRNA RT-PCR in detecting micrometastasis in regional lymph nodes of gastric cancer. World J Gastroenterol 2006; 12:5219-22. [PMID: 16937537 PMCID: PMC4088024 DOI: 10.3748/wjg.v12.i32.5219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the value and prospect of RT-PCR in detecting micrometastasis in regional lymph nodes of gastric cancer.
METHODS: Histopathology was used and K19 mRNA expression was detected by RT-PCR in tumor tissues and lymph nodes from gastric cancer patients undergoing radical resection of gastric carcinoma.
RESULTS: K19 mRNA was expressed in all tumor specimens of 30 cases; of the 126 lymph nodes, 26 were histopathologically positive (20.6%), and 42 positive (33.3%) by RT-PCR. Amplification fragments of 460 and 540 bp were shown in all the tumor tissues and metastatic lymph nodes after K19 and β-actin RT-PCR, while only a 540 bp fragment appeared in the lymph nodes of non-tumor patients.
CONCLUSION: K19 mRNA RT-PCR is sensitive and specific in testing micrometastasis in regional lymph nodes of gastric cancer, and it is superior to routine histopathology.
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Affiliation(s)
- Jian Suo
- Department of General Surgery, First Hospital, Changchun 130021, Jilin Province, China
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Kodera Y, Nakanishi H, Ito S, Yamamura Y, Fujiwara M, Koike M, Hibi K, Ito K, Tatematsu M, Nakao A. Prognostic significance of intraperitoneal cancer cells in gastric carcinoma: detection of cytokeratin 20 mRNA in peritoneal washes, in addition to detection of carcinoembryonic antigen. Gastric Cancer 2005; 8:142-8. [PMID: 16086116 DOI: 10.1007/s10120-005-0318-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2004] [Accepted: 01/24/2005] [Indexed: 02/07/2023]
Abstract
BACKGROUND In patients with gastric cancer, the presence of gastric cancer cells in the peritoneal cavity detected by cytologic examination, is a significant prognostic factor. A more sensitive, reverse transcriptase-polymerase chain reaction (RT-PCR) technique, amplifying carcinoembryonic antigen (CEA), was introduced as a new detection system, but produced some false-positive results. A search for other molecular markers is ongoing. METHODS Peritoneal washes were obtained from 195 patients with gastric carcinoma during surgery. Cytokeratin 20 (CK20) mRNA levels were quantified, in addition to those of CEA, using the LightCycler, and the feasibility of CK20 as a target was evaluated. RESULTS CK20 was limited, in terms of sensitivity, for detecting disseminated cancer cells (sensitivity, 63%; specificity, 91%; positive predictive value, 70%; and negative predictive value, 88%). Multimarker analysis was performed, in which samples positive for either CK20 or CEA mRNA were considered to be positive for cancer cells. Multivariate analysis identified the multimarker analysis as a significant independent prognostic determinant. CONCLUSION CK20 RT-PCR produced information that could add a significant impact to the knowledge obtained by CEA RT-PCR, although detection by CK20 alone was not sufficiently sensitive to replace CEA in the detection system.
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Affiliation(s)
- Yasuhiro Kodera
- Second Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
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Kodera Y, Nakanishi H, Ito S, Mochizuki Y, Ohashi N, Yamamura Y, Fujiwara M, Koike M, Tatematsu M, Nakao A. Prognostic significance of intraperitoneal cancer cells in gastric carcinoma: analysis of real time reverse transcriptase-polymerase chain reaction after 5 years of followup. J Am Coll Surg 2005; 202:231-6. [PMID: 16427547 DOI: 10.1016/j.jamcollsurg.2005.09.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2005] [Revised: 08/20/2005] [Accepted: 09/08/2005] [Indexed: 12/23/2022]
Abstract
BACKGROUND The presence of gastric cancer cells in the peritoneal cavity detected by cytologic examination is an important prognostic factor. A reverse transcriptase-polymerase chain reaction (RT-PCR) technique amplifying carcinoembryonic antigen mRNA was recently introduced to detect these cells more sensitively. STUDY DESIGN Five-year followup was completed for 284 gastric carcinoma patients who underwent CEA RT-PCR testing. Analyses to assess the accuracy and prognostic value of this procedure were performed, along with univariate and multivariable analyses to evaluate RT-PCR as a technique with peritoneal carcinomatosis and cancer death as the outcomes variables. RESULTS CEA mRNA levels exceeded the cutoff value defining a positive result in 9.5%, 29%, 66%, and 81% of patients with pT1, pT2, pT3, and pT4 stage disease, respectively. Sensitivity, specificity, positive predictive value, and negative predictive value for peritoneal carcinomatosis within 5 years of surgery were 88.5%, 81.6%, 64.5%, and 94.9%, respectively. Multivariable analysis revealed that a positive CEA mRNA result was an independent risk factor for cancer death (hazard ratio 2.82, 95% CI 1.17 -3.07) among 274 patients (10 patients with no record of nodal status were excluded from the analysis) and for peritoneal carcinomatosis (hazard ratio 1.57, 95% CI 1.07-2.29) among 242 patients who had no peritoneal deposits at operation. CONCLUSIONS CEA RT-PCR is useful as a prognostic marker for increased risk of cancer death and peritoneal carcinomatosis, and might be useful in the clinical setting for selecting patients for various adjuvant treatments.
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Affiliation(s)
- Yasuhiro Kodera
- Department of Surgery II, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Ishii T, Fujiwara Y, Ohnaka S, Hayashi T, Taniguchi H, Takiguchi S, Yasuda T, Yano M, Monden M. Rapid genetic diagnosis with the transcription-reverse transcription concerted reaction system for cancer micrometastasis. Ann Surg Oncol 2004; 11:778-85. [PMID: 15289240 DOI: 10.1245/aso.2004.12.043] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND Detection of cancer micrometastases is required for improvement of cancer therapy. The aim of this study was to establish a rapid and practical genetic assay to detect micrometastasis in gastric cancer and to assess its clinical significance with respect to prognosis. METHODS A novel RNA amplification system with transcription-reverse transcription concerted reaction (TRC) was introduced for quantitative detection of cancer-specific carcinoembryonic antigen messenger RNA. The sensitivity and quantitative aspects of the assay were assessed with the full-length carcinoembryonic antigen messenger RNA, a gastric cancer cell line (MKN-45), and metastatic lymph nodes obtained from patients with gastric cancer. Peritoneal lavage fluid specimens that were collected from gastric cancer surgery were subjected to the assay, and the clinical significance of the results was examined for prediction of recurrence and survival. RESULTS The quantification, sensitivity, and reproducibility of the assay with the TRC reaction were equal to those of quantitative reverse transcriptase-polymerase chain reaction with LightCycler. The most important advantages of the assay were its simplicity and rapidity. Molecular diagnosis of peritoneal lavage fluid by the TRC reaction significantly correlated with depth of invasion, peritoneal metastasis, clinical stage, overall survival, and peritoneal recurrence-free survival. CONCLUSIONS Molecular diagnosis of peritoneal lavage fluid with the TRC reaction could be a useful prognostic indicator for peritoneal recurrence and survival. Because the TRC reaction is more rapid and simpler than reverse transcriptase-polymerase chain reaction as a format for detecting RNA sequences, it may enhance the genetic diagnosis of cancer micrometastasis and may improve cancer therapy.
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Affiliation(s)
- Takaaki Ishii
- Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2 E2 Yamadaoka, Suita-City, Osaka 565-0871, Japan
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